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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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ZY 19489, MMV 253


str1

2-N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-5-[(3R)-3,4-dimethylpiperazin-1-yl]-4-N-(1,5-dimethylpyrazol-3-yl)pyrimidine-2,4-diamine.png

ZY 19489, MMV 253

C24 H32 FN9, 465.5

CAS 1821293-40-6

MMV253, GTPL10024, MMV674253

N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-5-((3R)-2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-3,4-dimethylpiperazin-1-yl)pyrimidin-2-amine

2-N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-5-[(3R)-3,4-dimethylpiperazin-1-yl]-4-N-(1,5-dimethylpyrazol-3-yl)pyrimidine-2,4-diamine

  • N2-(4-Cyclopropyl-5-fluoro-6-methyl-2-pyridinyl)-5-[(3R)-3,4-dimethyl-1-piperazinyl]-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-2,4-pyrimidinediamine
  • (R)-N2-(4-Cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-1-yl)pyrimidine-2,4-diamine

Key biological and physical properties of MMV253. logD and in vivo ED90 kindly provided by V. Sambandamurthy, S. Hameed P. and S. Kavanagh, personal communication, 2018

SYN

IN 201721031453

The invention relates to triaminopyrimidine compd. of formula I, pharmaceutically acceptable salts thereof, hydrates, solvates, polymorphs, optically active forms thereof, in solid state forms useful for preventing or treating malaria.  The invention also relates to a process for prepn. of triaminopyrimidine compd. and intermediates thereof.  Compd. I was prepd. by condensation of 5-bromouracil with tert-Bu (R)-2-methylpiperazine-1-carboxylate to give tert-Bu (R)-4-(2,4-dichloropyrimidin-5-yl)-2-methylpiperazine-1-carboxylate, which underwent chlorination followed by condensation with 1,5-dimethyl-1H-pyrazol-3-amine followed by condensation with 4-cyclopropyl-5-fluoro-6-methylpyridin-2-amine hydrochloride to give (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diamine, which underwent Boc-deprotection followed by methylation to give I.

SYN

WO 2019049021

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019049021

Malaria is caused by protozoan parasites of the genus Plasmodium that infect and destroy red blood cells, leading to fever, severe anemia, cerebral malaria and, if untreated, death.

International (PCT) Publication No. WO 2015/165660 (the WO ‘660) discloses triaminopyrimidine compounds, intermediates, pharmaceutical compositions and methods for use for preventing or treating malaria. The WO ‘660 discloses a process for preparation of 4-cyclopropyl-5-fluoro-6-methylpyridin-2-amine (compound 5) as depicted in scheme-1.

Scheme 1

WO ‘660 discloses a process for preparation of triaminopyrimidine compounds depicted in scheme-2.

WO ‘660 discloses the preparation of compounds 8 and 4 by using microwave technique using Biotage microwave vial. WO ‘660 in example- 13, discloses the isolation of compound 1 by concentration of reaction mixture to obtain crude product, which was purified through reverse phase HPLC GILSON instrument to obtain pure solid compound 1 in 40.8% yield, without providing the purity of the solid compound 1. The process disclosed in WO ‘660 is not industrially advantageous as it requires microwave conditions as well as chromatographic purification and provides compound 1 with lower yields. The compound 1 prepared may not be suitable for pharmaceutical preparations based on various regulatory requirements.

Polymorphism, the occurrence of different crystalline forms, is a property of some molecules. A single molecule can exist in different crystalline forms having distinct physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis – TGA, or different scanning calorimetry – DSC, Powder x-ray diffraction pattern – PXRD, infrared absorption – IR). One or more these techniques may be used to distinguish different polymorphic forms of a compound.

Different salts and solid states (e.g. solvates, hydrates) of an active pharmaceutical ingredient may possess different physio-chemical properties. Such variation in the properties of different salts and solid states forms may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (both chemical and polymorph) and shelf-life. These variations in the properties of different salts and solid states forms may offer improvements to the final dosage form for example, to improve bioavailability. Different salts and solid state forms of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms or amorphous form, which may in turn provide additional opportunities to assess variations in the properties and characteristics of an active pharmaceutical ingredient.

In view of the above, the present invention provides a process for the preparation of triaminopyrimidine compound 1 or pharmaceutically acceptable salts thereof or hydrates or solvates or polymorphs or optically active forms thereof, which is industrially scalable, environment friendly and efficient so as to obtain compounds of the invention in higher yields and purity.

The process for the preparation of triaminopyrimidine compound 1 or intermediates thereof of the present invention, takes the advantage by using appropriate solvent systems and isolation techniques as well as purification techniques, thereby to overcome problems of lower yields, chromatography purifications and microwave reactions of the prior art.

SUMMARY OF THE INVENTION

The present invention provides solid state forms of triaminopyrimidine compound

1,

1

Examples: Preparation of Intermediates

Example-1: Preparation of 6-chloro-4-cyclopropyl-3-fluoro-2-methylpyridine

In a 250 mL 4N round bottom flask, process water (30 ml) and cyclopropanecarboxylic acid (14.19 g, 164.88 mmol) were added at 25 to 35°C and started stirring. Sulphuric acid (4.4 ml, 82.44 mmol) was charged to the reaction mixture. Silver nitrate (4.18 g, 24.73 mmol), 6-Chloro-3-fluoro-2-methylpyridine (6 g, 41.22 mmol) were charged to the reaction mixture. Aqueous solution of ammonium persulphate (65.85 g, 288.54 mmol in 90 mL water) was added to the reaction mixture in 30 to 60 min at temperature NMT 60 °C. After the completion of the reaction as monitored by HPLC, toluene (30 ml) was added to the reaction mixture and stirred for 15 min. The reaction mixture filtered, separated layers from filtrate and extracted aqueous layer using toluene (30 mL). The organic layer was washed with aqueous sodium carbonate solution (30 mL) and water. The organic layer was distilled completely under vacuum at 60 °C to obtain 3.37 g syrupy mass as titled compound.

Example-2: Preparation of 6-chloro-4-cyclopropyl-3-fluoro-2-methylpyridine

In a suitable glass assembly, process water (7.5 L) and cyclopropanecarboxylic acid (3.55 Kg, 41.24 mol) were added at 25 to 35 °C and stirred. Sulphuric acid (2.02 Kg, 20.59 mol), silver nitrate (1.05 Kg, 6.21 mol), 6-chloro-3-fluoro-2-methylpyridine (1.5 Kg, 10.3 mol) were added to the reaction mixture. Aqueous solution of ammonium persulphate (16.46 g, 72.13 mmol in 22.5 L water) was added to the reaction mixture at 55 to 60 °C and maintained. After the completion of the reaction as monitored by HPLC, toluene (7.5 L) was added to the reaction mixture and stirred for 15 min. The reaction mixture was filtered, organic layer was separated and aqueous layer was extracted using toluene (6 L), filtered the reaction mixture and washed the solid with toluene (1.5 L). The combined organic layer was washed with 20% sodium carbonate solution (9 L) and water. The organic layer was concentrated completely under vacuum at 60 °C to obtain 880 g (86.50%) syrupy mass of titled compound.

Example-3: Preparation of N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-l,l-diphenyl-methanimine

In a 100 mL 3N round bottom flask, 6-chloro-4-cyclopropyl-3-fluoro-2-methylpyridine (2.69 g, 14.48 mmol) and toluene (30 mL) were added at 25 to 35 °C. Diphenylmethanimine (3.15 g, 17.38 mmol) was charged to the reaction mixture and stirred for 5-10 min under nitrogen purging. Racemic BINAP (270 mg, 0.43 mmol) and palladium acetate (98 mg, 0.43 mmol) were added to the reaction mixture. Sodium-ie/ -butoxide (2.78 g, 28.96 mmol) was added to the reaction mixture and heated to 100 to 110° C under nitrogen. After the completion of the reaction as monitored by HPLC, the reaction mixture was cooled to 25 to 35 °C and filtered over hyflo bed and washed with toluene. The filtrate containing titled compound was preserved for next stage of reaction.

Example-4: Preparation of N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-l,l-diphenyl-methanimine

In a suitable assembly, 6-chloro-4-cyclopropyl-3-fluoro-2-methylpyridine (880) and toluene (7.5 L) were added at 25 to 35 °C. Diphenylmethanimine (787 g, 4.34 mmol) and BOC anhydride (237 g, 1.086 mol) was added to the reaction mixture and stirred for 5-10 min under nitrogen purging. Racemic BINAP (67.6 g, 0.108 mmol) and palladium acetate (24.4 g, 0.108 mol) were added to the reaction mixture. S odium- ieri-butoxide (870 g, 9.05 mol) was added to the reaction mixture and heated to 100 to 110 °C under nitrogen. After the completion of the reaction as monitored by HPLC, the reaction mixture was cooled to 25 to 35 °C, water (6 L) was added. The reaction mixture was filtered over hyflo bed and washed with toluene. The filtrate containing titled compound was preserved for next stage of reaction.

Example-5: Preparation of 4-cyclopropyl-5-fluoro-6-methylpyridin-2-amine hydrochloride monohydrate

In a 100 mL 3N round bottom flask, N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-l,l-diphenylmethanimine in toluene as obtained in example-3 was added water (25 mL) at 25 to 35° C. The cone. HCl (3 mL) was charged to the reaction mixture and heated to 40 to 50 °C. After the completion of the reaction as monitored by HPLC, the reaction mixture was cooled to 25 to 35 °C. Layers were separated. The aqueous layer was treated with methylene dichloride and pH was adjusted to 7.5 to 8.5 using sodium carbonate solution, stirred for 15 min and layers were separated. Aqueous layer was extracted with methylene dichloride, charcoaled and acidified to pH 3 to 4 with aqueous HCl. The solvent was distilled completely and acetonitrile (9 mL) and ethyl acetate (9 mL) was added. The reaction mixture was stirred for 1 hour at 25 to 35° C. The product was filtered and washed with ethyl acetate. The product was dried at 50° C for 4 hours under vacuum to obtain 1.62 g title compound as monohydrate yellow crystalline solid having 99.51% HPLC purity.

Example-6: Preparation of 4-cyclopropyl-5-fluoro-6-methylpyridin-2-amine hydrochloride monohydrate

In a suitable glass assembly, N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-l,l-diphenylmethanimine in toluene as obtained in example-4 was added water (6 L) at 25 to 35° C. The cone. HCl (750 mL) was charged to the reaction mixture and heated to 40 to 50 °C. After the completion of the reaction as monitored by HPLC, the reaction mixture was cooled to 25 to 35 °C. Layers were separated. The aqueous layer was treated with methylene dichloride (3 L) and pH was adjusted to 7.5 to 8.5 using sodium carbonate solution, stirred for 15 min and layers were separated. Aqueous layer was extracted with methylene dichloride (3 L), charcoaled and acidified to pH 3 to 4 with aqueous HCl. The solvent was distilled completely and acetonitrile (1.5 L) and ethyl acetate (1.5 L) were added. The reaction mixture was stirred for 1 hour at 25 to 35° C. The product was filtered and washed with ethyl acetate. The product was dried at 50° C for 4 hours under vacuum to obtain 489 g (96.80%) title compound as monohydrate yellow crystalline solid having 99.51% HPLC purity. The crystalline compound is characterized by Powder x-ray diffraction pattern (FIG.5), Differential scanning calorimetry (FIG.6) and Thermogravimetric analysis (FIG.7).

Example 7: Preparation of 2,3-dibromobutanenitrile

In a 2 L round bottom flask, dichloromethane (550 mL) and 2-butenenitrile 110 g

(1.64 mol) were cooled to 20 to 25 °C. A solution of bromine 275 g (1.72 mol) in dichloromethane (220 mL) was dropwise added at 20 to 25 °C. Hydrobromic acid 1.43 ml (0.0082 mol) in acetic acid (33%) solution was added into the reaction mixture and stirred for 4 hours. After the completion of reaction, Na2S203 (550 mL) 4% aqueous solution was added and the reaction mixture was stirred for 15 min. The separated organic layer was distilled under vacuum completely to obtain 364.2 g (97.9%) of title compound as an oil.

Example 8: Preparation of l,5-dimethyl-lH-pyrazol-3-amine

In a 5 L round bottom flask, water (1. 36 L), sodium hydroxide 340 g (8.99 mol) were added and the reaction mixture was cooled to 0 to 5°C. A solution of methyl hydrazine sulphate 237.8 g (1.65 mol) in 680 mL water was added dropwise to the reaction mixture and stirred below 10 °C. 2,3-dibromobutanenitrile 340 g (1.5 mol) prepared in example-7 was added and the reaction mixture was stirred below 10 °C for 2 hours. After the completion of reaction, toluene (630 mL) was added and the reaction mixture was stirred for 15 min. The aqueous layer was separated and the organic layer was removed. The aqueous layer was extracted with dichloromethane (5.1 L). The combined organic layer was distilled completely under vacuum to obtain residue. Diisopropyl ether (680 mL) was added and the reaction mixture was stirred at 0 to 5 °C for 1 hour. The reaction mixture was filtered, washed with diisopropyl ether and dried to obtained 121.5 g (72.93%) of title compound having 95.63% purity.

Examples: Preparation of triaminopyrimidine compounds

Example-9: Preparation of tert-butyl (R)-4-(2,4-dioxo-l,2,3,4-tetrahydro- pyrimidin-5-yl)-2-methylpiperazine-l-carboxylate

In 2 L four neck round bottom flask, 1.25 Kg (6.545 mol) 5-bromouracil, 1.87 Kg (9.360 mol) tert-butyl (R)-2-methylpiperazine-l-carboxylate and 5L pyridine were added at 25 to 35° C. The reaction mass was stirred for 15 hours at 115 to 120°C. After completion, the reaction mass was cooled to 25 to 35°C. 12.5 L water was added and stirred for 1 hour. The reaction mass was filtered, washed with 2.5 L water and dried to obtain 1.37 Kg (67.4%) of title compound.

Example-10: Preparation of tert-butyl (R)-4-(2,4-dichloropyrimidin-5-yl)-2-methylpiperazine- 1 -carboxylate

In 20 L four neck round bottom flask, 1.36 Kg (4.382 mmol) tert-butyl (R)-4-(2,4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl)-2-methylpiperazine-l -carboxylate and 6.8 L phosphorus oxychloride were added at 25 to 35° C. 26.5 mL pyridine (0.329 mol) was added and the reaction mass was heated to 105 to 110 °C and stirred for 4 hours. After the completion of the reaction, phosphorus oxychloride was distilled completely at atmospheric pressure. 2.72 L acetone was added and the reaction mixture was quenched into 4.08 L water. Acetone was removed by distillation under vacuum. 20% sodium carbonate solution was added to adjust pH 7.5-8.5 of the reaction mixture. 1.14 Kg (5.258 mol) di-tert-butyl dicarbonate and 9.52 L ethyl acetate were added and stirred for 2 hours at 25 to 35 °C. After the completion of the reaction, the organic layer was separated and aqueous layer was extracted with 6.8 L ethyl acetate. The combined ethyl layers were distilled to remove ethyl acetate completely under vacuum to obtain residue. 1.36 L isopropyl alcohol was added to the residue and isopropyl alcohol was removed completely. 4.08 L isopropyl alcohol and 6.8 L water were added to the residue and stirred for 1 hour. The reaction mass was filtered, washed with water and dried to obtain 1.25 Kg of title compound.

Example-11: Preparation of tert-butyl (R)-4-(2-chloro-4-[(l,5-dimethyl-lH-pyrazol-3-yl)amino)pyrimidin-5-yl]-2-methylpiperazine-l-carboxylate

In 20 L round bottom flask, 640 g (1.843 mol) tert-butyl (R)-4-(2, 4-dichloropyrimidin-5-yl)-2-methylpiperazine-l -carboxylate, 225.3 g (2.027 g) 1,5-dimethyl-lH-pyrazol-3-amine and 9.6L toluene were added at 25 to 35°C. 1.2 Kg (3.686 mol) cesium carbonate was added. The reaction mixture was purged for 15 min under nitrogen. 12.41 g (0.0553 mol) palladium acetate and 34.43 g (0.0553 mol) racemic 2,2′-bis(diphenylphosphino)-l,l’-binaphthyl were added and the reaction mass was maintained for 16 hours at 110 to 115 °C under nitrogen. After the completion of the reaction, the reaction mixture was filtered through a celite bed and washed the bed with 1.28 L toluene. Toluene was distilled completely and 2.56 L dichlromethane was added. The compound was adsorbed by 1.92 Kg silica gel (60-120 mesh). The dichloromethane was distilled completely under vacuum and 12.8 L mixture of ethyl acetate and hexane was added to the residue and stirred for 2 hours. The silica gel was filtered and the filtrate was distilled completely under vacuum to obtain 595 g title compound.

Example-12: Preparation of tert-butyl (R)-4-(2-((4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)amino)-4-((l,5-dimethyl-lH-pyrazol-3-yl)amino) pyrimidin-5-yl)-2-methylpiperazine-l-carboxylate

In 20 L round bottom flask, 595 g (1.40 mol) tert-butyl (R)- 4-(2-chloro-4-[(l,5-dimethyl-lH-pyrazol-3-yl)amino)pyrimidin-5-yl]-2-methylpiperazine-l-carboxylate, 305 g (1.38 mol) 4-cyclopropyl-5-fluoro-6-methylpyridin-2-amine hydrochloride and 11.5 L toluene were added at 25 to 35°C. 1.08 Kg (3.32 mol) cesium carbonate was added. The reaction mixture was purged for 15 min under nitrogen. 17.21 g (27.6 mmol) palladium acetate and 6.21 g (27.6 mmol) racemic 2,2′-bis(diphenylphosphino)-l, -binaphthyl were added. The reaction mass was stirred for 6 hours at 110 tol l5 °C under nitrogen. After the completion of the reaction, the reaction mixture was filtered through a celite bed and washed with toluene. The filtrate was used as such in the next step without further treatment.

Example-13: Preparation of tert-butyl (R)-4-(2-((4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)amino)-4-((l,5-dimethyl-lH-pyrazol-3-yl)amino) pyrimidin-5-yl)-2-methylpiperazine-l-carboxylate

In 500 mL four neck round bottom flask, 7.5 g (17.77 mmol) (R)-tert-butyl 4-(2-chloro-4-[(l,5-dimethyl-lH-pyrazol-3-yl)amino)pyrimidin-5-yl]-2-methylpiperazine-l-carboxylate, 3.92 g (17.77 mmol) 4-cyclopropyl-5-fluoro-6-methylpyridin-2-amine hydrochloride compound and 150 mL toluene were added at 25 to 35 °C. 20 g (61.3 mmol) cesium carbonate was added. The reaction mixture was purged for 15 min under nitrogen. Then, 130 mg (0.58 mmol) palladium acetate and 360 mg (0.58 mmol) racemic 2,2′-bis(diphenylphosphino)-l,l’-binaphthyl were added. The reaction mass was stirred for 18 hours at 110 to 115° C under nitrogen. After completion, the reaction mixture was filtered through a celite bed and washed with toluene. The filtrate was used as such in the next step without further treatment.

2 4

Example-14: (R)-N -(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N -(1, 5-dimethyl-lH-pyrazol-3-yl)-5-(3-methylpiperazin-l-yl)pyrimidine-2,4-diamine

In 50 L glass assembly, the filtrate containing tert-butyl (R)-4-(2-((4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)amino)-4-((l,5-dimethyl-lH-pyrazol-3-yl)amino) pyrimidin-5-yl)-2-methylpiperazine-l-carboxylate from example 13 was taken. 11.5 L water and 1.28 L Cone. HC1 were added at 25 to 35 °C. The reaction mass was stirred for 2 hours at 50 to 55 °C. After the completion of the reaction, reaction mixture was cooled to room temperature and filtered over celite bed and washed with water. The separated the aqueous layer from filtrate was basified by using 20% sodium carbonate solution and extracted with 12.8 L methylene dichloride. The organic layer was distilled completely under vacuum to obtain residue. 9.6 L acetonitrile was added to the residue and heated to reflux for 30 min. The reaction mixture was cooled and stirred at 25 to 35 °C for 1 hour. The reaction mixture was filtered, washed with 640 mL acetonitrile and dried to obtain 360 g titled compound.

2 4

Example-15: (R)-N -(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N -(1,5-dimethyl-lH-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-l-yl)pyrimidine-2,4-diamine

In 250 mL four neck round bottom flask, 4.7 g (10.4 mmol) (R)-N -(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(l,5-dimethyl-lH-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-l-yl)pyrimidine-2,4-diamine was dissolved in 56 mL ethanol. 1.89 g (23.32 mmol) formaldehyde and 1.44 g (22.90 mmol) sodium cyanoborohydride were added. Adjusted pH 5-6 using acetic acid and stirred the reaction mass at 25 to 35 °C for 2 hours. After completion, ethanol was distilled completely under vacuum. 47 mL water was added to the residue. The reaction mass was basified by 20% sodium carbonate solution and extracted with methylene dichloride. Both the organic layers were combined and distilled completely under vacuum. 94 mL acetonitrile was added to the residue and heated to reflux for 15 min. The reaction mass was cooled to 25 to 35° C and stirred for 1 hour. The reaction mass was filtered, washed with 5 mL acetonitrile and dried to obtain 3.7 g title compound as crystalline solid, having HPLC purity of about 99.61%.

2 4

Example-16: (R)-N -(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N -(1,5-dimethyl-lH-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-l-yl)pyrimidine-2,4-diamine

In 20 L round bottom flask, 725 g (1.60 mol) (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(l,5-dimethyl-lH-pyrazol-3-yl)-5-(3,4-dimethylpiperazine-l-yl)pyrimidine-2,4-diamine was dissolved in 6.52 L dichloromethane. 261.5 g (3.2 mol) formaldehyde and 510.4 g (2.4 mol) sodium triacetoxyborohydride were added and stirred the reaction mixture at 25 to 35 °C for 2 hours. After the completion of the reaction, 3.63 L water was added into the reaction mixture. The reaction mixture was basified by 20% sodium carbonate solution and the organic layer was separated. The aqueous layer was extracted with 1.45 L methylene dichloride. The combined organic layers were distilled completely under vacuum. 14.5 L acetonitrile was added to the residue and heated to reflux for 15 min. The reaction mixture was cooled to 25 to 35° C and stirred for 1 hour. The reaction mass was filtered, washed with 1.45 L acetonitrile and dried to obtain 632 g of title compound as crystalline solid having 99.01% HPLC purity. The crystalline compound is characterized by Powder x-ray diffraction pattern (FIG.l) and Differential Scanning Calorimetry (FIG.2).

2 4

Example-17: Preparation of (R)-N -(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N -(l,5-dimethyl-lH-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-l-yl)pyrimidine-2,4-diamine In a 10 mL round bottom flask, 300 mg (0.644 mmol) (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(l,5-dimethyl-lH-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-l-yl)pyrimidine-2,4-diamine, 2.7 mL acetonitrile and 0.3 mL water were added and the reaction mixture was heated to reflux for 15 min. The reaction mixture was cooled to 25 to 35 °C and stirred for 1 hour. The reaction mass was filtered, washed with acetonitrile and dried to obtain 201 mg (67%) title compound as crystalline solid. The crystalline compound is characterized by Powder x-ray diffraction pattern (FIG.3) and Differential Scanning Calorimetry (FIG.4).

SYN

WO 2015165660

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015165660

Example 13

Synthetic scheme 1

Synthetic scheme 2

(R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-1-yl)pyrimidine-2,4-diamine

In a 50 mL round-bottomed flask (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diamine hydrochloride (190 mg, 0.42 mmol, Example 2) was taken in DCM (2 mL) to give a yellow suspension. To this Hunig’s Base (0.184 mL, 1.05 mmol) was added and the suspension turned clear. After 10 minutes, it turned into a white suspension. After another 10 minutes, the mixture was concentrated to dryness. Resultant residue was dissolved in ethanol (absolute, 99.5%) (3 mL) and formaldehyde (0.042 mL, 0.63 mmol) was added and stirred for 10 minutes. White suspension slowly cleared to yellow solution. To this clear solution sodium cyanoborohydride (26.4 mg, 0.42 mmol) was added in one portion to get white suspension. After 30 minutes LCMS showed completion of reaction. The reaction mixture was concentrated and the crude was purified through reverse phase HPLC GILSON instrument to get the pure solid of (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-1-yl)pyrimidine-2,4-diamine (80 mg, 40.8 %).1H NMR (300

MHz, DMSO-d6) δ ppm 0.67 – 0.78 (m, 2 H) 1.00 (d, J=6.22 Hz, 3 H) 1.02 – 1.08 (m, 2 H) 1.96 – 2.10 (m, 1 H) 2.23 (s, 7 H) 2.30 – 2.38 (m, 4 H) 2.73 – 2.96 (m, 4 H) 3.33 (s, 3 H) 6.83 (s, 1 H) 7.67 (d, J=5.09 Hz, 1 H) 8.00 (s, 1 H) 8.03 (s, 1 H) 9.26 (s,1 H) MS (ES+), (M+H)+ = 466.45 for C21H32FN9.

SYN

Nature Communications (2015), 6, 6715.

https://www.nature.com/articles/ncomms7715

Hameed P., S., Solapure, S., Patil, V. et al. Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate. Nat Commun 6, 6715 (2015). https://doi.org/10.1038/ncomms7715

The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED99 <30 mg kg−1 and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4–5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development.

figure1

(A) Pyridine, microwave, 150 °C, 45 min. (B) (i) POCl3, reflux, 6 h (ii) sodium carbonate, di-tert-butyl dicarbonate, room temperature, 16 h. (C) N,N-Diisopropylethylamine (DIPEA), ethanol, microwave, 110 °C, 1 h. (D) (i) Potassium tert-butoxide, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), pd2(dba)3, toluene, reflux, 12 h. (E) HCl (4 N) in dioxane, 15–30 min. (F) Compound 9, DIPEA, dichloromethane, formaldehyde (HCHO), sodium cyanoborohydride, 15 min.

Synthesis of (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1, 5-dimethyl-1H-pyrazol-3-yl)-5-(3, 4-dimethylpiperazin-1-yl)pyrimidine-2,4-diamine (12). (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diamine hydrochloride (compound 9, 190 mg, 0.42 mmol) was taken in dichloromethane (2 ml) to give a yellow suspension. To this Hunig’s Base (0.184 ml, 1.05 mmol) was added and the suspension turned clear. After 10 min of stirring, reaction mixture turned into a white suspension and then it was concentrated to dryness. Resultant residue was dissolved in ethanol (absolute, 99.5%) (3 ml), and formaldehyde (0.042 ml, 0.63 mmol) was added and stirred for 10 min. To this clear solution, sodium cyanoborohydride (26.4 mg, 0.42 mmol) was added in one portion to get a white suspension. The reaction mixture was concentrated and the crude product was purified through reverse-phase chromatography to get the pure off-white solid of (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1, 5-dimethyl-1H-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-1-yl)pyrimidine-2,4-diamine (80 mg, 40.8%). Yield: 40.8%, purity: >95% by HPLC (ultraviolet at 220 and 254 nm). 1H NMR (300 MHz, DMSO-d6δ 9.26 (s,1H), 8.03 (s, 1H) 8.00 (s, 1H) 7.67 (d, J=5.1 Hz, 1H) 6.83 (s, 1H) 3.33 (s, 3H) 2.96–2.73 (m, 4H) 2.75–2.50 (m, 1H) 2.38–2.30 (m, 4H) 2.23 (s, 7H) 2.10–1.96 (m, 1H),1.08–1.02 (m, 2H) 1.00 (d, J=6.2 Hz, 3H) 0.78–0.67 (m, 2H). 13C-NMR (126 MHz, DMO-d6δ 155.30, 154.67, 152.10, 150.93, 148.98, 146.81. 145.29, 141.95, 140.31, 138.81, 124.91, 106.20, 97.07, 58.78, 51.87, 42.16, 35.28, 17.23. 10.99 and 8.77, HRMS (ESI): m/z calculated for C24H32FN9+H [M+H]: 466.2765. Found: 466. 2838. Traces of LC-MS, HRMS, 1H NMR and 13C-NMR of compound 12 are shown in Supplementary Figs 1–3.

Product vision
  • Uncomplicated malaria treatment and resistance management
MoA
  • Unknown

Key features
  • Predicted human dose 900mg for a 9-log parasite killing
  • Low resistance potential from in vitro studies
Challenges
  • Synthesis and cost of goods
Status
  • First-in-human study started in February 2019
Next milestone
  • Initiate phase IIb study of ZY19489 with FQ
Previously
  • Discovery partnership between MMV and AstraZeneca, Bangalore
  • Name AZ13721412; full reference name is MMV674253

Zydus receives Orphan Drug Designation from USFDA for ZY-19489, a novel compound to treat malaria;

https://www.indiainfoline.com/article/news-top-story/zydus-receives-orphan-drug-designation-from-usfda-for-zy-19489-a-novel-compound-to-treat-malaria-stock-down-1-121121600282_1.html

ZY19489 is a novel antimalarial compound active against all current clinical strains of P. falciparum and P. vivax, including drug-resistant strains.

December 16, 2021 11:38 IST | India Infoline News Service

Zydus Cadila listed as Cadila Healthcare Limited announced that its antimalarial compound ZY19489 (MMV253), currently in development together with Medicines for Malaria Venture (MMV), a leading product development partnership (PDP) in antimalarial drug research, has received Orphan Drug Designation from the USFDA.

Orphan drug designation provides eligibility for certain development incentives, including tax credits for qualified clinical testing, prescription drug user fee exemptions, and seven-year marketing exclusivity upon FDA approval.

The company said that the Phase I study of ZY19489 has demonstrated a long half-life and potential for a single-dose cure for malaria. In a separate malaria challenge trial, potent antimalarial activity has been demonstrated following single-dose oral administration of ZY19489.

“As a global community facing threats from rapidly mutating malaria strains and the rise in artemisinin resistance cases, we have to be prepared with novel therapeutic drugs. ZY-19489 is a potential single dose radical cure for P. falciparum and P. vivax malaria which is a major global health risk today,” Pankaj R. Patel, Chairman, Zydus Group, said.

“ZY19489 is a potent, first in class molecule, originally discovered and elaborated in India” said Dr. Timothy Wells, Chief Scientific Officer, MMV. “It has tremendous potential as part of a new generation of treatments and is fully active against drug resistant strains of malaria which are increasingly a concern.”

Artemisinin resistance is seen as a mounting challenge to the global fight against malaria. ZY19489 is being developed to provide an effective alternative to the current front-line antimalarial drugs for the treatment of P. falciparum and P. vivax malaria, as artemisinin-based combination therapies (ACTs) are under threat of resistance.

As per the World Malaria Report 2021, there were an estimated 241 million cases of malaria worldwide and the estimated number of malaria deaths stood at 627,000 in 2020. A major health concern, it is estimated that a child dies from malaria every minute. About 96% of malaria deaths globally were in 29 countries. India accounted for about 82% of all malaria deaths in the WHO South-East Asia Region.

 
CLIP
 
Identified by AstraZeneca in 2015, MMV253  is a novel triaminopyrimidine (TAP) that has shown good
invitro potency and in vivo efficacy, and acts through another novel MoA [81].
High-throughput screening of 500,000 compounds from AstraZeneca’s library against blood stage P. falci
parum resulted in the identification of a promising series of TAPs. e initial hit (M’1, Fig.9) suffered from hERG
inhibition and poor solubility which, through lead optimization, was improved upon to give a compound that
possessed high potency and desirable pharmacokinetic properties (MMV253).
When screened against numerous mutant resistant strains with various mechanisms of resistance,
MMV253 showed no spontaneous reduction in potency which can be attributed to its novel MoA (PfATP4 inhi
bition, vide infra). Good in vitro-in vivo correlation (IVIVC) was shown with a predicted human half-life
of ∼36 h (which is long compared to another fast-killing drug, artemisinin, which has a human half-life of 1
hour).
As of late 2016, the pharmaceutical company CadilaHealthcare owns the license for the compound series and
is now doing further lead development in order to progress the drug through preclinical trials [82
81. Hameed PS, Solapure S, Patil V, Henrich PP, Magistrado PA, Bharath S, et al. Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate. Nat Commun. 2015;6:6715.
82. MMV and Zydus join forces to develop new antimalarial 2017. https ://http://www.mmv.org/newsr oom/press -relea ses/mmv-and-zydus -join-forces-devel op-new-antim alari al. Accessed 17 June 2018

////////////ZY 19489, MMV 253, Orphan Drug Designation, PHASE 1, ZYDUS CADILA, ANTIMALARIAL

Cn1nc(Nc2nc(Nc3cc(C4CC4)c(F)c(C)n3)ncc2N2C[C@@H](C)N(C)CC2)cc1C

CC1CN(CCN1C)C2=CN=C(N=C2NC3=NN(C(=C3)C)C)NC4=NC(=C(C(=C4)C5CC5)F)C

RP 12146


RP 12146

RP-12146 is an oral poly (ADP-ribose) polymerase (PARP) inhibitor in phase I clinical development at Rhizen Pharmaceuticals for the treatment of adult patients with locally advanced or metastatic solid tumors.

Solid TumorExtensive-stage Small-cell Lung CancerLocally Advanced Breast CancerMetastatic Breast CancerPlatinum-sensitive Ovarian CancerPlatinum-Sensitive Fallopian Tube CarcinomaPlatinum-Sensitive Peritoneal Cancer

Poly(ADP-ribose) polymerase (PARP) defines a family of 17 enzymes that cleaves NAD+ to nicotinamide and ADP-ribose to form long and branched (ADP-ribose) polymers on glutamic acid residues of a number of target proteins, including PARP itself. The addition of negatively charged polymers profoundly alters the properties and functions of the acceptor proteins. Poly(ADP-ribosyl)ation is involved in the regulation of many cellular processes, such as DNA repair, gene transcription, cell cycle progression, cell death, chromatin functions and genomic stability. These functions have been mainly attributed to PARP-1 that is regarded as the best characterized member of the PARP family. However, the identification of novel genes encoding PARPs, together with the characterization of their structure and subcellular localization, have disclosed different roles for poly(ADP-ribosyl)ation in cells, including telomere replication and cellular transport.

Recently, poly(ADP-ribose) binding sites have been identified in many DNA damage checkpoint proteins, such as tumor suppressor p53, cyclin-dependent kinase inhibitor p21Cip1/waf1, DNA damage recognition factors (i.e., the nucleotide excision repair xeroderma pigmentosum group A complementing protein and the mismatch repair protein MSH6), base excision repair (BER) proteins (i.e. DNA ligase III, X-ray repair cross-complementing 1, and XRCC1), DNA-dependent protein kinase (DNA-PK), cell death and survival regulators (i.e.,

NF-kB, inducible nitric oxide synthase, and telomerase). These findings suggest that the different components of the PARP family might be involved in the DNA damage signal network, thus regulating protein-protein and protein-DNA interactions and, consequently, different types of cellular responses to genotoxic stress. In addition to its involvement in BER and single strand breaks (SSB) repair, PARP-1 appears to aid in the non-homologous end-joining (NHEJ) and homologous recombination (HR) pathways of double strand breaks (DSB) repair. See Lucio Tentori et al., Pharmacological Research, Vol. 45, No. 2, 2002, page 73-85.

PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutations but also for the treatment of a wider range of tumors bearing a variety of deficiencies in the HR pathway. Further, the existing clinical data (e.g., Csaba Szabo et al., British Journal of Pharmacology (2018) 175: 192-222) also indicate that stroke, traumatic brain injury, circulatory shock and acute myocardial infarction are some of the indications where PARP activation has been demonstrated to contribute to tissue necrosis and inflammatory responses.

As of now, four PARP inhibitors, namely olaparib, talazoparib, niraparib, and rucaparib have been approved for human use by regulatory authorities around the world.

Patent literature related to PARP inhibitors includes International Publication Nos. WO 2000/42040, WO 2001/016136, WO 2002/036576, WO 2002/090334, WO2003/093261, WO 2003/106430, WO 2004/080976, WO 2004/087713, WO 2005/012305, WO 2005/012524, WO 2005/012305, WO 2005/012524, WO 2005/053662, W02006/033003, W02006/033007, WO 2006/033006, WO 2006/021801, WO 2006/067472, WO 2007/144637, WO 2007/144639, WO 2007/144652, WO 2008/047082, WO 2008/114114, WO 2009/050469, WO 2011/098971, WO 2015/108986, WO 2016/028689, WO 2016/165650, WO 2017/153958, WO 2017/191562, WO 2017/123156, WO 2017/140283, WO 2018/197463, WO 2018/038680 and WO 2018/108152, each of which is incorporated herein by reference in its entirety for all purposes.

There still remains an unmet need for new PARP inhibitors for the treatment of various diseases and disorders associated with cell proliferation, such as cancer.

PATENT

Illustration 1

CLIP

https://cancerres.aacrjournals.org/content/81/13_Supplement/1233

Abstract 1233: Preclinical profile of RP12146, a novel, selective, and potent small molecule inhibitor of PARP1/2

Srikant Viswanadha, Satyanarayana Eleswarapu, Kondababu Rasamsetti, Debnath Bhuniya, Gayatriswaroop Merikapudi, Sridhar Veeraraghavan and Swaroop VakkalankaProceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA 

Abstract

Background: Poly (ADP-ribose) polymerase (PARP) activity involves synthesis of Poly-ADP ribose (PAR) polymers that recruit host DNA repair proteins leading to correction of DNA damage and maintenance of cell viability. Upon combining with DNA damaging cytotoxic agents, PARP inhibitors have been reported to demonstrate chemo- and radio-potentiation albeit with incidences of myelosuppression. A need therefore exists for the development selective PARP1/2 inhibitors with a high therapeutic window to fully exploit their potential as a single agent or in combination with established therapy across various tumor types. Additionally, with the emerging concept of ‘synthetic lethality’, the applicability PARP inhibitors can be expanded to cancers beyond the well-defined BRCA defects. Herein, we describe the preclinical profile of RP12146, a novel and selective small molecule inhibitor of PARP1 and PARP2.

Methods: Enzymatic potency was evaluated using a PARP Chemiluminescent Activity Assay Kit (BPS biosciences). Cell growth was determined following incubation with RP12146 in BRCA1 mutant and wild-type cell lines across indications. Apoptosis was evaluated following incubation of cell lines with compound for 120 h, subsequent staining with Annexin-V-PE and 7-AAD, and analysis by flow cytometry. For cell cycle, cells were incubated with compound for 72 h, and stained with Propidium Iodide prior to analysis by flow cytometry. Expression of downstream PAR, PARP-trapping, phospho-γH2AX and cleaved PARP expression were determined in UWB1.289 (BRCA1 null) cells by Western blotting. Anti-tumor potential of RP12146 was tested in OVCAR-3 Xenograft model. Pharmacokinetic properties of the molecule were also evaluated. Results: RP12146 demonstrated equipotent inhibition of PARP1 (0.6 nM) and PARP2 (0.5 nM) with several fold selectivity over the other members of the PARP family. Compound caused a dose-dependent growth inhibition of both BRCA mutant and non-mutant cancer cell lines with GI50 in the range of 0.04 µM to 9.6 µM. Incubation of UWB1.289 cells with RP12146 caused a G2/M arrest with a corresponding dose-dependent increase in the percent of apoptotic cells. Expression of PAR was inhibited by 86% at 10 nM with a 2.3-fold increase in PARP-trapping observed at 100 nM in presence of RP12146. A four-fold increase in phospho-γH2AX and > 2-fold increase in cleaved PARP expression was observed at 3 µM of the compound. RP12146 exhibited anti-tumor potential with TGI of 28% as a single agent in OVCAR-3 xenograft model. Efficay was superior compared to Olaparib tested at an equivalent dose. Pharmacokinetic studies in rodents indicated high bioavailability with favorable plasma concentrations relevant for efficacy

Conclusions: Data demonstrate the therapeutic potential of RP12146 in BRCA mutant tumors. Testing in patients is planned in H1 2021.

Citation Format: Srikant Viswanadha, Satyanarayana Eleswarapu, Kondababu Rasamsetti, Debnath Bhuniya, Gayatriswaroop Merikapudi, Sridhar Veeraraghavan, Swaroop Vakkalanka. Preclinical profile of RP12146, a novel, selective, and potent small molecule inhibitor of PARP1/2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1233.

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https://www.businesswire.com/news/home/20211101005515/en/Rhizen-Pharmaceuticals-AG-Announces-First-Patient-Dosing-in-a-Phase-IIb-Study-of-Its-Novel-PARP-Inhibitor-RP12146-in-Patients-With-Advanced-Solid-Tumors

Rhizen Pharmaceuticals AG Announces First Patient Dosing in a Phase I/Ib Study of Its Novel PARP Inhibitor (RP12146) in Patients With Advanced Solid Tumors

RHIZEN’S PARP INHIBITOR EFFORTS ARE PART OF A LARGER DDR PLATFORM THAT ALSO INCLUDES AN EARLY STAGE POLθ-DIRECTED PROGRAM; PLATFORM ENABLES PROPRIETARY IN-HOUSE COMBINATIONS

  • Rhizen Pharma commences dosing in a phase I/Ib trial to evaluate its novel PARP inhibitor (RP12146) in patients with advanced cancers.
  • Rhizen indicated that RP12146 has comparable preclinical activity vis-à-vis approved PARP inhibitors and shows improved preclinical safety that it expects will translate in the clinic.
  • The two-part multi-center phase I/Ib study is being conducted in Europe and is designed to initially determine safety, tolerability and MTD/RP2D of RP12146 and to subsequently assess its anti-tumor activity in expansion cohorts with HRR mutation-enriched ES-SCLC, ovarian and breast cancer patients.
  • RP12146 is part of a larger DDR platform at Rhizen that includes a preclinical-stage Polθ inhibitor program; the DDR platform enables novel, proprietary, in-house combinations

November 01, 2021 07:24 AM Eastern Daylight Time

BASEL, Switzerland–(BUSINESS WIRE)–Rhizen Pharmaceuticals AG (Rhizen), a Switzerland-based privately held, clinical-stage oncology & inflammation-focused biopharmaceutical company, announced today that it has commenced dosing in a multi-center, phase I/Ib trial to evaluate its novel poly (ADP-ribose) polymerase (PARP) inhibitor (RP12146) in patients with advanced solid tumors. This two-part multi-center phase I/Ib study is being conducted in Europe and has been designed to initially determine safety, tolerability, maximum tolerated dose (MTD), and/or recommended phase II dose (RP2D) of RP12146 and to subsequently assess its anti-tumor activity in expansion cohorts with HRR mutation-enriched ES-SCLC, ovarian and breast cancer patients.

“Our PARP program is foundational for our DDR platform efforts and will be the backbone for several novel proprietary combinations that we hope to bring into development going forward.”

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Rhizen indicated that RP12146 has shown preclinical activity and efficacy comparable to the approved PARP inhibitor Olaparib, and shows improved safety as seen in the preclinical IND-enabling toxicology studies; an advantage that Rhizen hopes will translate in the clinical studies. Rhizen also announced that its PARP program is part of a larger DNA Damage Response (DDR) platform effort, which includes a preclinical-stage polymerase theta (Polθ) inhibitor program. Rhizen expects the platform to enable novel proprietary combinations of its PARP and Polθ assets given the mechanistic synergy and opportunity across PARP resistant/refractory settings.

PARP inhibitors are a great success story in the DNA damage response area, but they are not without safety concerns that have limited realization of their full potential. Although our novel PARP inhibitor is competing in a crowded space, we expect its superior preclinical safety to translate into the clinic which will differentiate our program and allow us to extend its application beyond the current landscape of approved indications and combinations”, said Swaroop Vakkalanka, Founder & CEO of Rhizen Pharma. Swaroop also added that “Our PARP program is foundational for our DDR platform efforts and will be the backbone for several novel proprietary combinations that we hope to bring into development going forward.

About Rhizen Pharmaceuticals AG.:

Rhizen Pharmaceuticals is an innovative, clinical-stage biopharmaceutical company focused on the discovery and development of novel oncology & inflammation therapeutics. Since its establishment in 2008, Rhizen has created a diverse pipeline of proprietary drug candidates targeting several cancers and immune associated cellular pathways.

Rhizen has proven expertise in the PI3K modulator space with the discovery of our first PI3Kδ & CK1ε asset Umbralisib, that has been successfully developed & commercialized in MZL & FL by our licensing partner TG Therapeutics (TGTX) in USA. Beyond this, Rhizen has a deep oncology & inflammation pipeline spanning discovery to phase II clinical development stages.

Rhizen is headquartered in Basel, Switzerland.

REF

Safety, Pharmacokinetics and Anti-tumor Activity of RP12146, a PARP Inhibitor, in Patients With Locally Advanced or Metastatic Solid Tumors….https://clinicaltrials.gov/ct2/show/NCT05002868

//////////RP 12146,  oral poly (ADP-ribose) polymerase (PARP) inhibitor, phase I,  clinical development, INCOZEN,  Rhizen Pharmaceuticals, adult patients,  locally advanced, metastatic solid tumors, PARP, CANCER

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XL 114, AUR 104 and XL 102, AUR 102 (NO CONCLUSIONS, ONLY PREDICTIONS)


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XL 102

XL 114

FOR BOTH, JUST PREDICTION

PREDICTIONS

or

front page image
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Figure imgf000024_0001

N[C@@H](CO)c1nc(on1)[C@@H](NC(=O)N[C@H](C(=O)O)C(C)O)CC(N)=O

(2S)-2-[[(1S)-3-Amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid.png
SVG Image

(2S)-2-[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid

CAS 2305027-62-5

C12 H20 N6 O7, 360.32Threonine, N-[[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]amino]carbonyl]-, (2S,3ξ)-N[C@@H](CO)c1nc(on1)[C@@H](NC(=O)N[C@H](C(=O)O)C(C)O)CC(N)=O

ALSO SEE

Figure imgf000003_0002
str1
(2S,3R)-2-[[(1S)-3-Amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid.png

1673534-76-3C12 H20 N6 O7, 360.32
L-Threonine, N-[[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]amino]
(2S,3R)-2-[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acidN-[[[(1S)-3-Amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]amino]carbonyl]-L-threonine

CAS 1673534-76-3

PD-1-IN-1 free base, EX-A1918, CS-6240NSC-799645CA-170 (AUPM-170)|PDL1 inhibitorHY-101093, PD-1-IN-1

N[C@@H](CO)c1nc(on1)[C@@H](NC(=O)N[C@H](C(=O)O)[C@@H](C)O)CC(N)=O

XL 114, AUR 104

A novel covalent inhibitor of FABP5 for cancer therapy

XL 102,  AUR 102

A potent, selective and orally bioavailable inhibitor of cyclin-dependent kinase 7 (CDK7)

NO CONCLUSIONS, ONLY PREDICTIONS

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(2R,3R)-2-[[(1S)-3-Amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid.png
SVG Image

(2R,3R)-2-[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid

C12H20N6O7, 360.32

(2S,3S)-2-[[(1S)-3-Amino-1-[3-[(1S)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid.png
SVG Image

(2S,3S)-2-[[(1S)-3-amino-1-[3-[(1S)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid

XL102, AUR 102

XL102 is a potent, selective and orally bioavailable covalent inhibitor of CDK7, which is an important regulator of the cellular transcriptional and cell cycle machinery. CDK7 helps regulate cell cycle progression, with overexpression observed in multiple cancers, such as breast, prostate and ovarian cancers. In preclinical studies, XL102 revealed potent anti-proliferative activity, induced cell death in a large panel of cancer cell lines and caused tumor growth inhibition and regression in xenograft models, demonstrating its potential as a targeted antitumor agent.

In late 2020, Exelixis exercised its option to in-license XL102 (formerly AUR102) from Aurigene per the companies’ July 2019 collaboration, option and license agreement. Exelixis has assumed responsibility for the future clinical development, manufacturing and commercialization of XL102. Aurigene retains limited development and commercial rights for India and Russia.

SYN

ABOUT Fatty acid-binding proteins (FABPs)

Fatty acid-binding proteins (FABPs) are involved in binding and storing hydrophobic ligands such as long-chain fatty acids, as well as transporting them to the appropriate compartments in the cell. Epidermal fatty acid-binding protein (FABP5) is an intracellular lipid-binding protein that is abundantly expressed in adipocytes and macrophages. Previous studies have revealed that the FABP5 expression level is closely related to malignancy in various types of cancer. However, its precise functions in the metabolisms of cancer cells remain unclear. Here, we revealed that FABP5 knockdown significantly induced downregulation of the genes expression, such as hormone-sensitive lipase (HSL), monoacylglycerol lipase (MAGL), elongation of long-chain fatty acid member 6 (Elovl6), and acyl-CoA synthetase long-chain family member 1 (ACSL1), which are involved in altered lipid metabolism, lipolysis, and de novo FA synthesis in highly aggressive prostate and breast cancer cells. Moreover, we demonstrated that FABP5 induced inflammation and cytokine production through the nuclear factor-kappa B signaling pathway activated by reactive oxygen species and protein kinase C in PC-3 and MDA-MB-231 cells. Thus, FABP5 might regulate lipid quality and/or quantity to promote aggressiveness such as cell growth, invasiveness, survival, and inflammation in prostate and breast cancer cells. In the present study, we have revealed for the first time that high expression of FABP5 plays a critical role in alterations of lipid metabolism, leading to cancer development and metastasis in highly aggressive prostate and breast cancer cells.

Fatty acid-binding protein, epidermal is a protein that in humans is encoded by the FABP5 gene

Function

This gene encodes the fatty acid binding protein found in epidermal cells, and was first identified as being upregulated in psoriasis tissue. Fatty acid binding proteins are a family of small, highly conserved, cytoplasmic proteins that bind long-chain fatty acids and other hydrophobic ligands. It is thought that FABPs roles include fatty acid uptake, transport, and metabolism.[6]

The phytocannabinoids (THC and CBD) inhibit endocannabinoid anandamide (AEA) uptake by targeting FABP5, and competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids.[7] Results show that cannabinoids inhibit keratinocyte proliferation, and therefore support a potential role for cannabinoids in the treatment of psoriasis.[8]

Interactions

FABP5 has been shown to interact with S100A7.[

ABOUT CD47/SIRPa axis

CD47/SIRPa axis is established as a critical regulator of myeloid cell activation and serves as an immune checkpoint for macrophage mediated phagocytosis. Because of its frequent upregulation in several cancers, CD47 contributes to immune evasion and cancer progression. CD47 regulates phagocytosis primarily through interactions with SIRPla expressed on macrophages. Blockade of SIRPla/CD47 has been shown to dramatically enhance tumor cell phagocytosis and dendritic cells maturation for better antigen presentation leading to substantially improved antitumor responses in preclinical models of cancer (M. P. Chao et al. Curr Opin Immunol. 2012 (2): 225-232). Disruption of CD47-SIRPa interaction is now being evaluated as a therapeutic strategy for cancer with the use of monoclonal antibodies targeting CD47 or SIRPa and engineered receptor decoys.

CD47 is expressed on virtually all non-malignant cells, and blocking the CD47 or the loss of CD47 expression or changes in membrane distribution can serve as markers of aged or damaged cells, particularly on red blood cells (RBC). Alternatively, blocking SIRPa also allows engulfment of targets that are not normally phagocytosed, for those cells where pre-phagocytic signals are also present. CD47 is a broadly expressed transmembrane glycoprotein with a single Ig-like domain and five membrane- spanning regions, which functions as a cellular ligand for SIRPa with binding mediated through the NH2-terminal V-like domain of SIRPa. SIRPa is expressed primarily on myeloid cells, including macrophages, granulocytes, myeloid dendritic cells (DCs), mast cells, and their precursors, including hematopoietic stem cells.

CD47 is also constitutively upregulated on a number of cancers such as Non-Hodgkin Lymphoma (NHL), Acute myeloid leukemia (AML), breast, colon, glioblastoma, glioma, ovarian, bladder and prostate cancers, etc. Overexpression of CD47 by tumor cells, which efficiently helps them to escape immune surveillance and killing by innate immune cells. However, in most of the tumor types, blockade of the CD47-SIRPa interaction as a single agent may not be capable of inducing significant phagocytosis and antitumor immunity, necessitating the need to combine with other therapeutic agents. The concomitant engagement of activating receptors such as Fc-receptors (FcRs) or other prophagocytic receptors (collectively known as “eat-me” signals) may be necessary for exploiting the maximum potential of the CD-47-SIPRa pathway blockade.

The role of engagement of prophagocytic receptors is proved by inefficiency to trigger phagocytosis either by anti-CD47 F(ab) fragments, single chain variable fragments of CD-47 or non-Fc portion- containing SIRPa proteins in blocking of the CD47-SIRPa interaction. When activating prophagocytic receptors are engaged, as evident in the case of using Fc portion-containing blocking anti-CD47 antibodies, CD47- SIRPa blockade is able to trigger more efficient phagocytosis. Combining CD47-SIRPa blocking agents with therapeutic antibodies (Fc-containing) targeting tumor antigens stimulate activating Fc receptors (FcRs) leading to efficient phagocytosis. The Fc portion of therapeutic antibody targeting tumor antigen also induces antibody-dependent cellular cytotoxicity (ADCC), which also adds to the therapeutic efficacy. Hence antibodies selected from the group consisting of rituximab, herceptin, trastuzumab, alemtuzumab, bevacizumab, cetuximab and panitumumab, daratumumab due to its tumor targeting nature and ADCC, can trigger more efficient phagocytosis.

Earlier approaches to disrupt CD47- SIRPa interaction utilized monoclonal antibodies targeting CD47 or SIRPa and engineered receptor decoys fused to Fc fragment. However, a concern with this approach is that CD47 is highly expressed on both hematopoietic and non-hematopoietic normal cells. Hence along with tumor cells CD47-SIRPa blocking agents containing Fc-portion may also target many normal cells potentially leading to their elimination by macrophages. The interaction of blocking antibodies with normal cells is considered as a major safety issue resulting in anemia, thrombocytopenia, and leukopenia. These agents may also affect solid tissues rich in macrophages such as liver, lung, and brain. Hence it may be ideal to block the CD47- SIRPa interaction by agents devoid of Fc portion, such as small

molecules, peptides, Fab fragments etc. while activating prophagocytic receptors in tumor cells by appropriate combinations to induce efficient phagocytosis of tumor cells.

Apart from Fc Receptors, a number of other prophagocytic receptors are also reported to promote engulfment of tumor cells in response to CD47-SIRPa blockade by triggering the phagocytosis. These include receptors for SLAMF7, Mac-l, calreticulin and possibly yet to identified receptors. B cell tumor lines such as Raji and other diffuse large B cell lymphoma express SLAMF7 and are implicated in triggering prophagocytic signals during CD47-SIRPa blockade.

Therapeutic agents known to activate prophagocytic receptors are also therefore ideal partners for use in combination with CD47-SIRPa blocking agents to achieve efficient phagocytosis. These agents include proteasome inhibitors (bortezomib, ixazomib and carfilzomib), Anthracyclines (Doxorubicin, Epirubicin, Daunorubicin, Idarubicin, Mitoxantrone) Oxaliplatin, Cyclophosphamide, Bleomycin, Vorinostat, Paclitaxel, 5-Fluorouracil, Cytarabine, BRAF inhibitory drugs (Dabrafenib, Vemurafenib), PI3K inhibitor, Docetaxel, Mitomycin C, Sorafenib, Tamoxifen and oncolytic viruses.

Apart from the specific agents known to have effect on‘eat me’ signals other agents including Abiraterone acetate, Afatinib, Aldesleukin, Aldesleukin, Alemtuzumab, Anastrozole, Axitinib, Belinostat, Bendamustine, Bicalutamide, Blinatumomab, Bosutinib, Brentuximab, Busulfan, Cabazitaxel, Capecitabine, Carboplatin, Carfilzomib, Carmustine, Ceritinib, Clofarabine, Crizotinib, Dacarbazine, Dactinomycin, Dasatinib, Degarelix, Denileukin, Denosumab, Enzalutamide, Eribulin, Erlotinib, Everolimus, Exemestane, Exemestane, Fludarabine, Fulvestrant, Gefitinib, Goserelin, Ibritumomab, Imatinib, Ipilimumab, Irinotecan, Ixabepilone, Lapatinib, Lenalidomide, Letrozole, Leucovorin, Leuprolide, Lomustine, Mechlorethamine, Megestrol, Nelarabine, Nilotinib, Nivolumab, Olaparib, Omacetaxine, Palbociclib, Pamidronate, Panitumumab, Panobinostat, Pazopanib, Pegaspargase, Pembrolizumab, Pemetrexed Disodium, Pertuzumab, Plerixafor, Pomalidomide, Ponatinib, Pralatrexate, Procarbazine, Radium 223, Ramucirumab, Regorafenib, rIFNa-2b, Romidepsin, Sunitinib, Temozolomide, Temsirolimus, Thiotepa, Tositumomab, Trametinib, Vinorelbine, Methotrexate, Ibrutinib, Aflibercept, Toremifene, Vinblastine, Vincristine, Idelalisib, Mercaptopurine and Thalidomide could potentially have effect on‘eat me’ signal pathway on combining with CD-47-SIRPa blocking agents.

In addition to the therapeutic agents mentioned above, other treatment modalities that are in use in cancer therapy also activate prophagocytic receptors, and thus can be combined with CD47-SIRPa blocking agents to achieve efficient phagocytosis. These include Hypericin-based photodynamic therapy (Hyp-PDT), radiotherapy, High-hydrostatic pressure, Photofrin-based PDT and Rose Bengal acetate -based PDT.

However, there is an unmet need for combining small molecule CD-47-SIRPa pathway inhibitors with agents capable of stimulating activating receptors such as Fc-receptors (FcRs) or other prophagocytic receptors, or combining with other treatment modalities that are in use in cancer therapy to activate prophagocytic receptors for exploiting the maximum potential of the CD-47- SIRPa pathway blockade.

CLIP

Exelixis In-Licenses Second Anti-Cancer Compound from Aurigene Following FDA Acceptance of Investigational New Drug Application for Phase 1 Clinical Trial in Non-Hodgkin’s Lymphoma

– Robust preclinical data support Exelixis’ clinical development of XL114, with phase 1 trial in Non-Hodgkin’s lymphoma expected to begin in the coming months –

– Exelixis will make an option exercise payment of $10 million to Aurigene –

https://www.businesswire.com/news/home/20211014005549/en/Exelixis-In-Licenses-Second-Anti-Cancer-Compound-from-Aurigene-Following-FDA-Acceptance-of-Investigational-New-Drug-Application-for-Phase-1-Clinical-Trial-in-Non-Hodgkin%E2%80%99s-LymphomaOctober 14, 2021 08:00 AM Eastern Daylight Time

ALAMEDA, Calif.–(BUSINESS WIRE)–Exelixis, Inc. (Nasdaq: EXEL) and Aurigene Discovery Technologies Limited (Aurigene) today announced that Exelixis has exercised its exclusive option under the companies’ July 2019 agreement to in-license XL114 (formerly AUR104), a novel anti-cancer compound that inhibits the CARD11-BCL10-MALT1 (CBM) signaling pathway, which promotes lymphocyte survival and proliferation. Exelixis has now assumed responsibility for the future clinical development, commercialization and global manufacturing of XL114. Following the U.S. Food and Drug Administration’s (FDA) recent acceptance of its Investigational New Drug (IND) application, Exelixis will soon initiate a phase 1 clinical trial evaluating XL114 monotherapy in patients with Non-Hodgkin’s lymphoma (NHL). At the American Association of Cancer Research Annual Meeting in April of this year, Aurigene presented preclinical data (Abstract 1266) demonstrating that XL114 exhibited potent anti-proliferative activity in a large panel of cancer cell lines ranging from hematological cancers to solid tumors with excellent selectivity over normal cells. In addition, oral dosing of XL114 resulted in significant dose-dependent tumor growth inhibition in diffuse large B-cell lymphoma (DLBCL) and colon carcinoma models.

“We are pleased that our agreement with Aurigene has generated a second promising compound that warrants advancement into clinical development and believe the collaboration will continue to play an important role in expanding our pipeline”

XL114 is the second molecule that Exelixis in-licensed from Aurigene under the companies’ July 2019 collaboration, option and license agreement. Exelixis previously exercised its option to in-license XL102, a potent, selective and orally bioavailable inhibitor of cyclin-dependent kinase 7 (CDK7), from Aurigene in December 2020 and initiated a phase 1 trial of XL102 as a single agent and in combination with other anti-cancer agents in patients with advanced or metastatic solid tumors in January 2021.

“We are pleased that our agreement with Aurigene has generated a second promising compound that warrants advancement into clinical development and believe the collaboration will continue to play an important role in expanding our pipeline,” said Peter Lamb, Ph.D., Executive Vice President, Scientific Strategy and Chief Scientific Officer, Exelixis. “XL114 has shown potent anti-proliferative activity in lymphoma cell lines that have aberrant activation of the CBM signaling pathway and may have a differentiated profile and potential as a best-in-class molecule that could improve outcomes for patients with Non-Hodgkin’s lymphoma and other hematologic cancers.”

XL114 was identified to have anti-proliferative activity in cell lines with constitutive activation of CBM signaling, including activated B-cell-like DLBCL (ABC-DLBCL), mantle cell lymphoma and follicular lymphoma cell lines. Further characterization of XL114 in cell-based assays demonstrated a functional role in B-cell (BCR) signaling pathways. Additionally, XL114 showed dose-dependent tumor growth inhibition in an ABC-DLBCL mouse xenograft tumor model. In preclinical development, XL114 also demonstrated a high degree of selectivity against a broad safety pharmacology panel of enzymes and receptors. While the precise molecular mechanism underlying XL114’s function in repressing BCR signaling and MALT1 activation has yet to be characterized, the fatty acid-binding protein 5 (FABP5) has been identified as a prominent XL114-binding target.

“XL114 is the second molecule that Exelixis has opted to in-license under our July 2019 agreement, underscoring the significant potential of our approach to the discovery and preclinical development of innovative cancer therapies that target novel mechanisms of action,” said Murali Ramachandra, Ph.D., Chief Executive Officer, Aurigene. “Exelixis has a track record of success in the clinical development and commercialization of anti-cancer therapies that provide patients with important new treatment options, and we are pleased that the continued advancement of XL114 will be supported by the company’s extensive clinical, regulatory and commercialization infrastructure.”

Under the terms of the July 2019 agreement, Exelixis made an upfront payment of $10 million for exclusive options to obtain an exclusive license from Aurigene to three preexisting programs, including the compounds now known as XL102 and XL114. In addition, Exelixis and Aurigene initiated three Aurigene-led drug discovery programs on mutually agreed upon targets, in exchange for an additional upfront payment of $2.5 million per program. The collaboration was expanded in 2021 to include three additional early discovery programs. Exelixis is also contributing research funding to Aurigene to facilitate discovery and preclinical development work on all nine programs. Exelixis may exercise its option for a program at any time up until the first IND for the program becomes effective. Having exercised options on two programs thus far (XL102 and XL114), if and when Exelixis exercises a future option, it will make an option exercise payment to Aurigene and assume responsibility for that program’s future clinical development and commercialization including global manufacturing. To exercise its option for XL114, Exelixis will make an option exercise payment to Aurigene of $10 million. Once Exelixis exercises its option for a program, Aurigene will be eligible for clinical development, regulatory and sales milestones, as well as royalties on future potential sales of the compound. Under the terms of the agreement, Aurigene retains limited development and commercial rights for India and Russia.

About Aurigene

Aurigene Discovery Technologies Limited is a development stage biotech company engaged in discovery and clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases and a wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY, NYSE: RDY, NSEIFSC: DRREDDY). Aurigene is focused on precision-oncology, oral immune checkpoint inhibitors, and the Th-17 pathway. Aurigene’s programs currently in clinical development include an oral ROR-gamma inhibitor AUR101 for moderate to severe psoriasis in phase 2 under a U.S. FDA IND and a PD-L1/VISTA antagonist CA-170 for non-squamous non-small cell lung cancer in phase 2b/3 in India. Additionally, Aurigene has multiple compounds at different stages of pre-clinical development. Aurigene has also partnered with several large and mid-pharma companies in the U.S. and Europe and has multiple programs in clinical development. For more information, please visit Aurigene’s website at www.aurigene.com.

About Exelixis

Founded in 1994, Exelixis, Inc. (Nasdaq: EXEL) is a commercially successful, oncology-focused biotechnology company that strives to accelerate the discovery, development and commercialization of new medicines for difficult-to-treat cancers. Following early work in model system genetics, we established a broad drug discovery and development platform that has served as the foundation for our continued efforts to bring new cancer therapies to patients in need. Our discovery efforts have resulted in four commercially available products, CABOMETYX® (cabozantinib), COMETRIQ® (cabozantinib), COTELLIC® (cobimetinib) and MINNEBRO® (esaxerenone), and we have entered into partnerships with leading pharmaceutical companies to bring these important medicines to patients worldwide. Supported by revenues from our marketed products and collaborations, we are committed to prudently reinvesting in our business to maximize the potential of our pipeline. We are supplementing our existing therapeutic assets with targeted business development activities and internal drug discovery – all to deliver the next generation of Exelixis medicines and help patients recover stronger and live longer. Exelixis is a member of the Standard & Poor’s (S&P) MidCap 400 index, which measures the performance of profitable mid-sized companies. In November 2020, the company was named to Fortune’s 100 Fastest-Growing Companies list for the first time, ranking 17th overall and the third-highest biopharmaceutical company. For more information about Exelixis, please visit www.exelixis.com, follow @ExelixisInc on Twitter or like Exelixis, Inc. on Facebook.

Dinesh Chikkanna

Dinesh Chikkanna

Director, Medicinal Chemistry Aurigene Discovery Technologies

Murali Ramachandra

Murali Ramachandra

CEO at Aurigene Discovery Technologies

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CLIP

https://cancerres.aacrjournals.org/content/81/13_Supplement/1266

Abstract 1266: Discovery and preclinical evaluation of a novel covalent inhibitor of FABP5 for cancer therapyDinesh Chikkanna, Leena Khare Satyam, Sunil Kumar Pnaigrahi, Vinayak Khairnar, Manoj Pothuganti, Lakshmi Narayan Kaza, Narasimha Raju Kalidindi, Vijaya Shankar Nataraj, Aditya Kiran Gatta, Narasimha Rao Krishnamurthy, Sandeep Patil, DS Samiulla, Kiran Aithal, Vijay Kamal Ahuja, Nirbhay Kumar Tiwari, KB Charamannna, Pravin Pise, Thomas Anthony, Kavitha Nellore, Sanjeev Giri, Shekar Chelur, Susanta Samajdar and Murali Ramachandra 
DOI: 10.1158/1538-7445.AM2021-1266 Published July 2021 
Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA

Abstract

Dysregulated fatty acid metabolism is thought to be a hallmark of cancer, wherein fatty acids function both as an energy source and as signals for enzymatic and transcriptional networks contributing to malignancy. Fatty acid-binding protein 5 (FABP5) is an intracellular protein that facilitates transport of fatty acids and plays a role in regulating the expression of genes associated with cancer progression such as cell growth, survival, and metastasis. Overexpression of FABP5 has been reported to contribute to an aggressive phenotype and a poor survival correlation in several cancers. Therefore, inhibition of FABP5 is considered as a therapeutic approach for cancers. Phenotypic screening of a library of covalent compounds for selective sensitivity of cancer cells followed by medicinal chemistry optimization resulted in the identification of AUR104 with desirable properties. Chemoproteomic-based target deconvolution revealed FABP5 as the cellular target of AUR104. Covalent adduct formation with Cys43 of FABP5 by AUR104 was confirmed by mass spectrometry. Target occupancy studies using a biotin-tagged AUR104 demonstrated potent covalent binding to FABP5 in both cell-free and cellular conditions. Ligand displacement assay with a fluorescent fatty acid probe confirmed the competitive binding mode of AUR104 with fatty acids. Binding at the fatty acid site and covalent bond formation with Cys43 were also demonstrated by crystallography. Furthermore, AUR104 showed a high degree of selectivity against a broad safety pharmacology panel of enzymes and receptors. AUR104 exhibited potent anti-proliferative activity in a large panel of cell lines derived from both hematological and solid cancers with a high degree of selectivity over normal cells. Anti-proliferative activity in lymphoma cell lines correlated with inhibition of MALT1 pathway activity, cleavage of RelB/Bcl10 and secretion of cytokines, IL-10 and IL-6. AUR104 displayed desirable drug-like properties and dose-dependent oral exposure in pharmacokinetic studies. Oral dosing with AUR104 resulted in dose-dependent anti-tumor activity in DLBCL (OCI-LY10) and NSCLC (NCI-H1975) xenograft models. In a repeated dose MTD studies in rodents and non-rodents, AUR104 showed good tolerability with an exposure multiple of >500 over cellular EC50 for up to 8 hours. In summary, we have identified a novel covalent FABP5 inhibitor with optimized properties that showed anti-tumor activity in in vitro and in vivo models with acceptable safety profile. The data presented here strongly support clinical development of AUR104.

Citation Format: Dinesh Chikkanna, Leena Khare Satyam, Sunil Kumar Pnaigrahi, Vinayak Khairnar, Manoj Pothuganti, Lakshmi Narayan Kaza, Narasimha Raju Kalidindi, Vijaya Shankar Nataraj, Aditya Kiran Gatta, Narasimha Rao Krishnamurthy, Sandeep Patil, DS Samiulla, Kiran Aithal, Vijay Kamal Ahuja, Nirbhay Kumar Tiwari, KB Charamannna, Pravin Pise, Thomas Anthony, Kavitha Nellore, Sanjeev Giri, Shekar Chelur, Susanta Samajdar, Murali Ramachandra. Discovery and preclinical evaluation of a novel covalent inhibitor of FABP5 for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1266.

Patent

US20200147054 – COMBINATION OF SMALL MOLECULE CD-47 INHIBITORS WITH OTHER ANTI-CANCER AGENTS

Muralidhara Ramachandra
Pottayil Govindan Nair Sasikumar
Girish Chandrappa Daginakatte
Kiran Aithal Balkudru

PATENT

WO 2020095256

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020095256

Example- 1: The synthetic procedures for the preparation of compounds described in the present invention were described in co-pending Indian provisional patent application 201841001438 dated 12* Jan 2018, which is converted as PCT application

PCT/IB2019/050219, the contents of which are hereby incorporated by reference in their entirety.

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PATENT

WO 2018178947https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018178947&tab=PCTDESCRIPTION

PATENT

WO 2019138367

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019138367

PATENT

WO 2019073399

https://patents.google.com/patent/WO2019073399A1/en

Priority to IN201741036169

Example 4 of WO 2015/033299

Figure imgf000002_0001
Figure imgf000003_0002

PATENT

https://patents.google.com/patent/BR112020014202A2/en

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PATENT

The present invention relates to substituted alkynylene compounds represented by compound of formula (I) pharmaceutically acceptable salts and stereoisomers thereof. The present invention further provides the methods of preparation of compound of formula (I) and therapeutic uses thereof as anti-cancer agents.

Patent

Example 1

(((S)-4-amino-1-(3-((S)-1,5-diaminopentyl)-1,2,4-oxadiazol-5-yl)-4-oxobutyl)carbamoyl)-L-proline (Compound 1)


 (MOL) (CDX)

Synthesis of Compound 1 b


 (MOL) (CDX)
      Ethylchloroformate (2.47 mL, 25.9 mmol) and NMM (2.9 mL, 25.9 mmol) were added to a solution of compound 1a (6.0 g, 17.3 mmol) in THF (60 mL) and stirred at −20° C. for 20 min. After 20 minutes 25% of aq.ammonia (24 mL) was added to the active mixed anhydride resulting from the reaction and the reaction mass was stirred at 0-5° C. for 30 min. The completeness of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with NaHCO solution followed by citric acid solution and brine solution. The separated organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure to yield 5.6 g of compound 1 b. LCMS: 346.4 [M+H] +.

Synthesis of Compound 1C


 (MOL) (CDX)
      Trifluroacetic anhydride (6.85 mL, 48.6 mmol) was added to a solution of compound 1b (5.6 g, 16.2 mmol), pyridine (7.84 mL, 97.2 mmol) in DCM (60 mL) at 0° C. and stirred at room temperature for an hour. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and CH 2Cl 2. The organic layer was washed with NaHCO solution followed by citric acid and brine solution. The separated organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure to yield 5.42 g of compound 1c, which was used for next step directly.

Synthesis of Compound 1d


 (MOL) (CDX)
      Hydroxylamine hydrochloride (3.43 g, 49.5 mmol), water (10 mL) and K 2CO (4.54 g, 32.9 mmol) were added to a solution of compound 1c (5.4 g, 16.5 mmol) in EtOH (60 mL) and stirred at room temperature for overnight. The completion of the reaction was confirmed by TLC analysis. After the completion of reaction, the compound from the water was extracted by using the CH 2Cl followed washing the organic layer with water, brine and concentrated under reduced pressure to yield 5.8 g of compound 1d. LCMS: 361.3 [M+H] +.

Synthesis of Compound 1f


 (MOL) (CDX)
      HOBt (3.24 g, 24.0 mmol) and DIC (3.36 mL, 24.0 mmol) were added to a solution of Fmoc-Gln(Trt)-OH (compound 1e) (9.83 g, 16.1 mmol) in DMF (100 mL) at 0° C. and stirred for 15 min. Compound 1d (5.8 g, 16.1 mmol) was added to the reaction mass at the same temperature and the resulting mixture was stirred for an hour at the same temperature, followed by stirring at room temperature for an additional 2 h. The completion of the reaction was confirmed by TLC analysis. The reaction mixture was quenched with ice water; precipitated white solid was filtered; washed with water (150 mL) and dried under high under reduced pressure to yield 8.62 g of compound 1f. LCMS: 953.7 [M+H] +.

Synthesis of Compound 1g


 (MOL) (CDX)
      Acetic acid (5 mL) was added to a solution of compound 1f (5.0 g, 5.0 mmol) in acetonitrile (50 ml) at room temperature and the reaction mass was refluxed at 85° C. for 12 h. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure to obtain crude semi solid which was diluted with water and ethyl acetate. The organic layer was washed with NaHCO solution followed by citric acid and brine solution. The organic layer was dried over Na 2SO 4; filtered and evaporated under reduced pressure to obtain crude solid. Compound was purified using column chromatography to yield 4.3 g of title compound. LCMS: 935.6 [M+H] +.

Synthesis of Compound 1h


 (MOL) (CDX)
      Compound 1g (4.3 g, 4.5 mmol) was added to a solution of 20% piperidine in DMF (20 mL) at 0° C. and the reaction mass was stirred at same temperature for an hour. The completion of the reaction was confirmed by TLC analysis. After completion, the reaction mixture was quenched with ice-cold water and the resulting white precipitate was filtered and dried under vacuum. The crude product obtained was diluted with hexane, stirred and filtered to yield 3.0 g of compound 1h. LCMS: 713.4 [M+H] +.

Synthesis of Compound 1i


 (MOL) (CDX)
      Pyridine (0.33 mL, 4.2 mmol) was added to a solution of compound 1h (1.5 g, 2.1 mmol) in CH 2Cl (15 mL) and the resulting solution was stirred at room temperature for 10 min. 4-nitrophenyl chloroformate (0.84 g, 4.2 mmol) in CH 2Cl (15 mL) was added to the above mixture and the resultant mixture was stirred at room temperature for an hour. After completion of reaction (confirmed by TLC), it was diluted with CH 2Cl (50 mL) and washed with water (100 mL×2), 1N HCl (100 mL×2), water followed by brine solution (100 mL×2). The organic layer was dried over Na 2SO 4; filtered and evaporated under reduced pressure to yield 0.72 g compound 1i, which was taken to the next step without any further purification. LCMS: 878.9 [M-100].

Synthesis of compound 1j


 (MOL) (CDX)
      TEA (0.34 mL, 2.46 mm) was added to a solution of H-Pro-O tBu.HCl (0.21 g, 1.23 mmol) and compound 1i (0.72 g, 0.82 mmol) in THF (10 mL) at room temperature and stirred for 12 h. The volatiles were evaporated and portioned between ethyl acetate and water. The reaction mixture was diluted with ice cold water and extracted with EtOAc. The Organic layer was separated and dried over Na 2SO and concentrated under reduced pressure. The crude compound obtained was purified by column chromatography and compound elutes in 50% of ethyl acetate in hexane. Yield: 0.5 g of compound 1j. LCMS: 910.6 [M+H] +.

Synthesis of Compound 1


 (MOL) (CDX)
      Compound 1j (0.5 g, 0.55 mmol) was added to a cocktail mixture (10 m L) of TFA:TIPS:H 2O (95:2.5:2.5) and was stirred at room temperature for 3 h. The resulting reaction mixture was evaporated under reduced pressure, diluted with diethyl ether and filtered to yield 0.2 g of crude compound 1. The crude solid material was purified by preparative HPLC method described under experimental conditions. LCMS: 412.2 [M+H] +. HPLC t (min): 9.6.

Example 2

(S)-4-(3-((S)-1-amino-4-guanidinobutyl)-1,2,4-oxadiazol-5-yl)-4-(3-((S)-1-carboxy-2-phenylethyl) ureido)butanoic acid (Compound 7)


 (MOL) (CDX)

Synthesis of Compound 2b


 (MOL) (CDX)
      Ethylchloroformate (1.75 mL, 18.23 mmol) and NMM (2.0 mL, 18.23 mmol) were added into a solution of compound 2a (8.0 g, 15.18 mmol) in THF (45 mL) and the resulting mixture was stirred at −20° C. for 20 min. After 20 minutes 25% of aqueous ammonia (25 mL) was added to the active mixed anhydride generated and stirred at 0-5° C. for 30 min. The completeness of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with NaHCO solution followed by citric acid solution and brine solution. The separated organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure to yield 7.1 g of compound 2b. LCMS: 526.3 [M+H] +.

Synthesis of Compound 2c


 (MOL) (CDX)
      Trifluroacetic anhydride (TFAA) (2.83 mL, 20.26 mmol) was added to a solution of compound 2b (7.1 g, 13.51 mmol) in pyridine (7.08 g, 87.80 mmol) and the resulting mixture was stirred at room temperature for 2 h. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with citric acid and brine solution. The separated organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure. The crude solid was purified via column chromatography (60-120 silicagel) to yield 5.8 g of compound 2c. LCMS: 508.3 [M+H] +.

Synthesis of Compound 2d


 (MOL) (CDX)
      Hydroxylamine hydrochloride (1.56 g, 22.50 mmol), water (30 mL) and potassium carbonate (3.11 g, 11.25 mmol) were added to a solution of compound 2c (5.8 g, 11.25 mmol) in EtOH (60 mL) and stirred at 90° C. for 3 h. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with brine solution, dried over Na 2SO then filtered and evaporated under reduced pressure, the solid obtained was washed with 20% ethyl acetate to yield 6.1 g of compound 2d. LCMS: 541.3 [M+H] +.

Synthesis of Compound 2f


 (MOL) (CDX)
      HOBt (2.28 g, 16.9 mmol) and DIC (2.62 mL, 16.9 mmol) were added to a solution of Fmoc-Glu(O tBu)-OH (compound 2e) (4.0 g, 9.02 mmol) in DMF (60 mL) at 0° C. and the resulting mixture was stirred for 15 min. Then compound 2d (6.1 g, 11.28 mmol) was added to the above mixture at the same temperature and the reaction mixture was continued stirring for an hour and then at room temperature for 2 h. The completion of the reaction was confirmed by TLC analysis. The reaction mixture was quenched with ice cold water, the precipitated white solid was filtered, washed with water (150 mL) and dried under high under reduced pressure. The solid was taken into 10% MeOH in DCM and washed the organic layer with 10% NaHCO 3, water and brine solution. The organic layer was dried over Na 2SO and concentrated under reduced pressure to yield 8.0 g of compound 2f. LCMS: 948.7 [M+H] +.

Synthesis of Compound 2g


 (MOL) (CDX)
      Acetic acid (7 mL) was added to a solution of compound 2f (7.0 g, 7.38 mmol) in THF (70 ml) at room temperature and the resulting mixture was refluxed at 70° C. for 12 h. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure to obtain crude semi solid which was diluted with water and ethyl acetate. The organic layer was washed with NaHCO solution followed by brine solution. The organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure to get crude solid. The compound was purified by column chromatography (60-120 silicagel) to yield 5.4 g of compound 2g. LCMS: 930.5 [M+H] +.

Synthesis of Compound 2h


 (MOL) (CDX)
      Compound 2g (5.4 g, 5.80 mmol) was added to a solution of 50% piperidine in DMF (20 mL) at 0° C. and stirred at same temperature for 2 h. The completion of the reaction was confirmed by TLC analysis. The reaction mass was quenched with water (100 mL), the resulted precipitate was filtered. The solid obtained was dissolved in ethyl acetate and washed the organic layer with 10% NaHCO 3, water and brine. The organic layer was dried over Na 2SO and concentrated under reduced pressure. The crude product obtained was diluted with hexane and the resulted precipitate was filtered followed by washing with hexane to obtain 3.0 g of compound 2h. LCMS 708.6 [M+H] +.

Synthesis of Compound 2i


 (MOL) (CDX)
      Pyridine (0.75 mL, 9.3 mmol) was added to a solution of H-Phe-O tBu.HCl (2.0 g, 7.75 mmol) in CH 2Cl (20 mL) was added pyridine and the resulting solution was stirred at room temperature for 10 min. To this reaction mixture a solution of 4-nitrophenyl chloroformate (1.87 g, 9.30 mmol) in CH 2Cl (20 mL) was added and the resultant mixture was stirred at room temperature for 3 h. After completion of reaction (confirmed by TLC) it was diluted with CH 2Cl (50 mL) and washed with water (100 mL×2), 10% citric acid (100 mL×2), water (100 mL), followed by brine solution (100 mL). The organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure to yield 1.7 g compound 2i, which was taken to the next step without any further purification.

Synthesis of Compound 2j


 (MOL) (CDX)
      TEA (0.29 mL, 2.1 mmol) was added to a solution of compound 2h (1.0 g, 1.41 mmol) and compound 2i (0.54 g, 1.41 mmol) in THF (10 mL) at room temperature and stirred for 3 h. The volatiles were evaporated and portioned between EtOAc and water. The reaction mixture was diluted with ice cold water and extracted with EtOAc followed by washing with 10% K 2CO (100 mL×4), water and brine solution. Organic layer separated and dried over Na 2SO and concentrated under reduced pressure. The crude product obtained was diluted with hexane and the resulted precipitate was filtered followed by washing with hexane yielded 0.98 g of compound 2j. LCMS: 955.6 [M+H] +.

Synthesis of Compound 7


 (MOL) (CDX)
      Compound 2j (0.5 g, 5.2 mmol) was added to cocktail mixture (5 m L) of trifluoroacetic: TIPS: water (95:2.5:2.5). The cleavage solution was stirred at room temperature for 3 h. The resulting reaction mixture was evaporated under reduced pressure, diluted with diethyl ether and filtered to yield 0.34 g of crude compound 2. The crude solid material was purified by preparative HPLC method as described under experimental conditions. LCMS: 491.1 [M+H] +. HPLC t R: (min): 11.1

PATENT

WO 2015/033299

https://patents.google.com/patent/WO2015033299A1/en?oq=WO+2015%2f033299

Pottayil Govindan Nair SasikumarMuralidhara RamachandraSeetharamaiah Setty Sudarshan Naremaddepalli

Figure imgf000024_0001

Example 1: Synthesis of Compound 1

Figure imgf000019_0001

Step la:

Figure imgf000019_0002

Ethylchloroformate (1.5 g, 13.78 mniol) and N-Methylmorpholine ( 1.4 g, 13.78 mmol) were added to a solution of compound la (3 g, 11.48 mmol) in THE (30 mL) arid stirred at -20 °C. After 20 min. Liquid ammonia (0.77 g, 45.92 mmol) was added to the active mixed anhydride formed in- situ and stirred at 0-5 °C for 20 min. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. Organic layer was washed with NaHCOs, citric acid, brine solution, dried over Na2S04 and evaporated under reduced pressure to get 2.9 g of compound lb (Yield: 96.3%). LCMS: 261.0 ( Vi+H ; .

Step lb:

Figure imgf000020_0001

1 b 1cTrifluroacetic anhydride (9.7 g, 46.0 mmol) was added to a solution of compound lb (8 g, 30.7 mmol) in pyridine (24.3 g, 307.0 mmol) and stirred at room temperature for 3 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. Organic layer was washed with NaHCO?,, citric acid, brine solution, dried over Na2-S04 and evaporated under reduced pressure to afford 7 g of compound lc (Yield: 94.0%). LCMS: 187.2 (M-¾u )+.

Step lc:

Figure imgf000020_0002

1 c 1dHydroxylamine hydrochloride (3 g, 43.37 mmol) and potassium carbonate (6 g, 43.37 mmol) were added to a solution of compound lc (7 g, 28.91 mmol) in EtOH (70 m L) and stirred at 90 °C for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. Organic layer was washed with brine solution, dried over Na2S04 and evaporated under reduced pressure. The crude compound was purified by silica gel column chromatography (Eluent: 0-5% ethyl acetate in hexane) to get 4.2 g of compound Id (Yield: 52.8%). LCMS: 276.4 (M+H)+.Step Id:

Figure imgf000021_0001

Deoxo-Fluor® (1.83 g, 8.3 mmol) was added to a solution of Fmoc-Asn(Trt)-OH (4.5 g, 7.5 mmol) in CH2Q2 (50 mL) and stirred at 0 °C for 3 h. Then CH2CI2 was evaporated and triturated with hexane, decanted and evaporated under vacuum to get the corresponding acid fluoride. NMM (1.17 g, 1 1.6 mmol) and compound Id (1.6 g, 5.8 mmol) in THF were added to the acid fluoride and stirred at room temperature for 12 h. Then THF was evaporated and sodium acetate (0.72 g, 8.7 mmol) was added followed by EtOH (50 mL). The reaction mixture was stirred at 90 °C for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. Organic layer was washed with NaHCOa, citric acid, brine solution, dried over Na2S04 and evaporated under reduced pressure, which was further purified by silica gel column chromatography (Eluent: 0-5% ethyl acetate in hexane) to afford 2.8 g of compound le (Yield: 44.4%). LCMS: 836.4 (M+Hf .Step le:

Ph3

Figure imgf000021_0002

To compound le (2.3 g, 2.7 mmol) in CH2CI2 (10 mL) diethyiarnine (10 mL) was added and the reaction mixture was stirred at room temperature for 30 min. The resulting solution was concentrated in vacuum to get gummy residue. The crude compound was purified by neutral alumina column chromatography (Eluent: 0-50% ethyl acetate in hexane then 0-5% methanol in chloroform) to get 1.4 g of If (Yield: 90 %). LCMS: 636.5 (M+Na)+.

Figure imgf000022_0001

1f 1To a solution of compound If (0.45 g) in CH2CI2 (5 mL), trifluoroacetic acid (5 mL) and catalytic amount of triisopropylsilane were added and stirred for 3 h at room temperature to remove the acid sensitive protecting groups. The resulting solution was concentrated in vacuum to afford 0.29 g of crude compound 1 which was purified using prep-HPLC method described under experimental conditions. \H NMR (DMSQ-d6, 400 MHz): δ 2.58 (m, 2H), 3.53 (m, 3H), 3.91 (t, 1H), 4.36 (t, 1H), 6.91 (s, 1H), 7.45 (s, 1H); 1 C NMR (DMSO-de, 400 MHz): δ 20.85, 45.71 , 50.23, 65.55, 171.03, 171 .41, 181.66. LCMS: 216.2 (Μ+ΗΓ; HPLC: tR = 13.1 min.Example 2: Synthesis of Co

Figure imgf000022_0002

Step 2a:

Figure imgf000022_0003

1f2a

The urea linkage was carried out by the coupling compound If (2.7 g, 4.39 mmoi) in THF (30 mL) at room temperature with compound 2b (1.67 g, 4.39 mmoi). The coupling was initiated by the addition of TEA (0.9 g, 8.78 mmoi) in THF (10 m L) and the resultant mixture was stirred at room temperature. After completion of 20 h, THF was evaporated from the reaction mass, and partitioned between water and ethyl acetate. Organic layer was washed with water, brine, dried over Na2S04 and evaporated under reduced pressure to get compound 2a, which was further purified by silica gel column chromatography (Fluent: 0-50% ethyl acetate in hexane) to afford 3.46 g of compound 2a (Yield: 92.10%). LCMS 857.4 (M+H)+.

Figure imgf000023_0001

2aTo a solution of compound 2a (0.22 g, 0.25 mmol) in 0¾ί¾ (5 m L), trifluoroaeetic acid (5 mL) and catalytic amount of triisopropyisilane were added and stirred for 3h at room, temperature. The resulting solution was concentrated under reduced pressure to obtain 0.35 g of crude compound. The crude solid material was purified using preparative- HPLC method described under experimental conditions. LCMS: 347.1 (M+H)+; HPLC: tR = 12.9 min.

Synthesis of

Figure imgf000023_0002

2bTo the compound H-Ser(tBu)-OiBu (2 g, 9.2 mmol) in C I I■(.{■ (20 mL), triethylamine (1.39 g, 13.8 mmol) was added and the solution was stirred at room temperature for 5-10 min. To this mixture, solution of 4-Nitrophenyl chioro formate (2.22 g, 11.04 mmol) in CH2CI2 was added and the resultant mixture was stirred at room temperature for 30 min. The completion of the reaction was confirmed by TLC analysis. After completion of reaction, reaction mixture was diluted with CH2CI2 and washed with water and 5.0 M citric acid solution, dried over Na2SC>4 and evaporated under reduced pressure to get crude compound 2b, which was further purified by silica gel column chromatography (Eiuent: 0-20% ethyl acetate in hexane) to yield 2.1 g (58.9%) of 2b.Example 3: Synthesis of Compound 3

Figure imgf000023_0003

The compound was synthesised using similar procedure as depicted in Example 1 (compound 1) and D-amino acids are linked up in reverse order. Boc-D-Thr(‘Bu)-OH was used in place of Boc-Ser(‘Bu)-OH (compound la, Example 1) and Fmoc-D- Asn(trt)-OH in place of Fmoc-Asn(trt)-OH to yield 0.15 g crude material of the title compound 3. LCMS: 230.1 (M+H)+.Example 4: Synthesis of Co

Figure imgf000024_0001

The compound was synthesised using similar procedure as depicted in Example 2 for synthesising compound 2 using

Figure imgf000024_0002

instead of H-Ser(‘Bu)-0’Bu (in synthesis of compound 2b) to yield 0.35 g crude material of the title compound. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 361.2 (M+H)+, HPLC: tR = 12.19 min.Example 5: Synthesis of

Figure imgf000024_0003

The compound was synthesised using similar procedure as depicted in Example 4 (compound 4) using D-amino acids are linked up in reverse order. Boc-D-Thr(‘Bu)-OH was used in place of Boc-Ser(‘Bu)-OH, Fmoc-D-Asn(trt)-OH in place of Fmoc-Asn(trt)- OH and H-D-Ser(‘Bu)-0’Bu was used in place of H-Thr^Bu^O’Bu to yield 0.3 g crude material of the title compound. The cmde solid material was purified using preparative HPLC described under experimental conditions. LCMS: 361.3 (M+H)+. HPLC: tR = 13.58 min.Example 6: Synthesis of Compound 6

Figure imgf000024_0004

The compound was synthesised using similar procedure as depicted in Example 2 by using H-Thr(‘Bu)-OMe instead of H-Ser(‘Bu)-0’Bu (in synthesis of compound 2b) to yield 0.2 g crude material of the title compound. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 375.1 (M+H)+, HPLC: tR = 1.84 min.Example 7: Synthesis of Compound 7

Figure imgf000025_0001

Step 7a:

Figure imgf000025_0002

1f7aThe compound 7a was synthesised using similar procedure as for compound 2a (Example 2, step 2a) using H-Thr(‘Bu)-OMe instead of H-Ser(‘Bu)-OtBu to get crude material which was further purified by silica gel column chromatography (Eluent: 0-50% ethyl acetate in he ane) to get 2.0 g of compound 7a (Yield: 74 %). LCMS: 829.2 (M+H)+.Step 7b:

Figure imgf000025_0003

7a 7bTo a solution of compound 7a (0.35 g, 4.0 mmol) in THF (5 mL) was added lithium hydroxide (0.026 g, 0.63 mmol) at 0 °C and the mixture was stirred for 2 h at room temperature. The completion of the reaction was confirmed by TLC analysis. THF was evaporated from the reaction mass, and partitioned between water and ethyl acetate. Organic layer was washed with citric acid, brine solution, dried over Na2S04 and evaporated under reduced pressure to afford 7b, which was further purified by silica gel column chromatography (Eluent: 0-5% methanol in DCM) to get 0.3 g of product 7b (Yield: 86.7%). LCMS 815.2 (M+H)+.

Step 7c:

Figure imgf000026_0001

7b 7Compound 7b (0.295 g, 0.39 mmol) was anchored to Rink amide resin (0.7 g, 0.55 mmol/g) using HOBT (0.072 g, 0.54 mmol) and DIC (0.068 g, 0.54 mmol) method in DMF (10 mL). The resin was stirred for 12 h at room temperature. The resin was washed with DCM, DMF and DCM and dried. The target compound was cleaved from the rink amide resin using TFA (5 mL) and catalytic amount of TIPS. The resin was allowed to remain at room temperature for 2 h with occasional stirring. After 2 h, TFA and TIPS were evaporated under nitrogen atmosphere and the resulting residue was washed with diethyl ether to yield 0.1 g crude material of the title compound 7. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 360.0 (M+H)+, HPLC: tR = 13.88 min.Example 8: Synthesis of

Figure imgf000026_0002

The compound was synthesised using similar procedure as depicted in Example 2 (compound 2) using Fmoc-Glu(0’Bu)-OH instead of Fmoc-Asn(Trt)-OH to get 0.4 g crude material of the title compound. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 362.1 (M+H)+. HPLC: tR = 13.27 min.

PATENThttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019061324&tab=FULLTEXT

Patenthttps://patents.google.com/patent/WO2019067678A1/enPATENThttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019061324

PATENThttps://patents.google.com/patent/WO2018073754A1/en
PATENThttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019087087
PAPERSScientific Reports (2019), 9(1), 1-19. https://www.nature.com/articles/s41598-019-48826-6

figure1

Chemical structures of PD-L1 inhibitors developed by Aurigene (Aurigene-1) and Bristol-Meyers Squibb (BMSpep-57, BMS-103, and BMS-142). Chemical structures were generated using ChemDraw Professional 15. PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019087087

L-threonine’ mentioned in compound of formula (I) thereof can be represented by any one of the following formulae:

Publication NumberTitlePriority DateGrant Date
US-2020289477-A1Conjoint therapies for immunomodulation2017-11-06 
WO-2019073399-A1CRYSTALLINE FORMS OF 1,2,4-OXADIAZOLE SUBSTITUTED IN POSITION 32017-10-11 
AU-2018341583-A1Crystal forms of immunomodulators2017-09-29 
WO-2019061324-A1CRYSTALLINE FORMS OF IMMUNOMODULATORS2017-09-29 
WO-2019067678-A1CRYSTALLINE FORMS OF IMMUNOMODULATORS2017-09-29
Publication NumberTitlePriority DateGrant Date
US-2020247766-A1Crystal forms of immunomodulators2017-09-29 
US-2020061030-A1Dual inhibitors of vista and pd-1 pathways2016-10-20 
WO-2018073754-A1Dual inhibitors of vista and pd-1 pathways2016-10-20 
US-2020361880-A11,2,4-Oxadiazole and Thiadiazole Compounds as Immunomodulators2015-03-10 
EP-3041827-B11,2,4-oxadiazole derivatives as immunomodulators2013-09-062018-04-18
Publication NumberTitlePriority DateGrant Date
EP-3363790-B11,2,4-oxadiazole derivatives as immunomodulators2013-09-062020-02-19
US-10173989-B21,2,4-oxadiazole derivatives as immunomodulators2013-09-062019-01-08
US-10590093-B21,2,4-oxadiazole derivatives as immunomodulators2013-09-062020-03-17
US-2015073024-A11,2,4-Oxadiazole Derivatives as Immunomodulators2013-09-06 
US-2017101386-A11,2,4-Oxadiazole Derivatives as Immunomodulators2013-09-06
Publication NumberTitlePriority DateGrant Date
US-2018072689-A11,2,4-Oxadiazole Derivatives as Immunomodulators2013-09-06 
US-2019144402-A11,2,4-Oxadiazole Derivatives as Immunomodulators2013-09-06 
US-2020199086-A11,2,4-Oxadiazole Derivatives as Immunomodulators2013-09-06 
US-9771338-B21,2,4-oxadiazole derivatives as immunomodulators2013-09-062017-09-26
WO-2015033299-A11,2,4-oxadiazole derivatives as immunomodulators2013-09-06

////////////Investigational New Drug Application,  Phase 1,  Clinical Trial, Non-Hodgkin’s Lymphoma, XL 114, AUR 104, aurigene, Exelixis 

N[C@@H](CO)c1nc(on1)[C@@H](NC(=O)N[C@H](C(=O)O)C(C)O)CC(N)=O

https://patentscope.wipo.int/search/en/result.jsf?inchikey=HFOBENSCBRZVSP-WHFCDURNSA-N

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PATENT

The present invention relates to substituted alkynylene compounds represented by compound of formula (I) pharmaceutically acceptable salts and stereoisomers thereof. The present invention further provides the methods of preparation of compound of formula (I) and therapeutic uses thereof as anti-cancer agents.

XL 102

EXELIXIS AND AURIGENE ANNOUNCE THAT PROMISING PRECLINICAL DATA TO BE PRESENTED AT THE ENA SYMPOSIUM SUPPORT THE CLINICAL DEVELOPMENT OF A NOVEL CDK7 INHIBITOR

https://www.aurigene.com/exelixis-and-aurigene-announce-that-promising-preclinical-data-to-be-presented-at-the-ena-symposium-support-the-clinical-development-of-a-novel-cdk7-inhibitor/

Exelixis and Aurigene Announce That Promising Preclinical Data to Be Presented at the ENA Symposium Support the Clinical Development of a Novel CDK7 Inhibitor

– Detailed characterization of an oral inhibitor of CDK7 demonstrates potent activity against multiple hematologic and solid tumor cell lines, as monotherapy and in combination with chemotherapies –

October 09, 2020 03:02 AM Eastern Daylight Time

ALAMEDA, Calif.–(BUSINESS WIRE)–Exelixis, Inc. (Nasdaq: EXEL) and Aurigene Discovery Technologies Limited (Aurigene) today disclosed new preclinical data showing that AUR102 has potent anti-tumor activity in a large panel of cancer cell lines. AUR102 is a potent, selective, and orally bioavailable covalent inhibitor of cyclin-dependent kinase 7 (CDK7), which is an important regulator of the cellular transcriptional and cell cycle machinery. Exelixis has an exclusive option for AUR102 under its July 2019 exclusive collaboration, option and license agreement with Aurigene. The new data will be presented in a poster (Abstract 170) at the 32nd EORTC-NCI-AACR (ENA) Symposium, which is being held virtually on October 24-25, 2020.

“CDK7 plays a critical role in regulating cellular transcription and cell cycle machinery, making it an exciting target for cancer therapy”

“CDK7 plays a critical role in regulating cellular transcription and cell cycle machinery, making it an exciting target for cancer therapy,” said Murali Ramachandra, Ph.D., Chief Executive Officer of Aurigene. “The data to be presented at ENA 2020 demonstrate that AUR102 effectively engages CDK7 and inhibits a key mediator of the cell cycle and transcription. The ability to inhibit CDK7 activity with an orally available therapeutic such as AUR102 holds great potential to improve care and outcomes for patients with diverse cancer indications, including breast cancer, prostate cancer, leukemia and lymphoma.”

The abstract provides a summary of results from a detailed characterization of AUR102 in cancer cell lines and animal tumor models. Additional data will be presented in the poster. Key findings included in the abstract are:
• AUR102 exhibited potent anti-proliferative activity in a large panel of cell lines with induction of cell death in cell lines derived from multiple cancer types.
• The observed anti-proliferative activity correlated with cellular CDK7 target engagement and decreased levels of P-Ser5 RNAPII, a key mediator of transcription.
• AUR102 studies showed synergy when used in combination with multiple chemotherapies.
• Oral dosing with AUR102 resulted in dose-dependent anti-tumor activity, including complete tumor regression in diffuse large B-cell lymphoma, acute myeloid leukemia, and triple-negative breast cancer xenograft models.
• Inhibition of tumor growth was accompanied by complete target engagement as demonstrated in a parallel PK-PD study.
• AUR102 significantly impacts several pathways and key cancer driver and immune-response genes.

The study authors conclude that the data support clinical evaluation of AUR102 as a single agent and in combination with chemotherapies for the treatment of cancer.

“The exciting AUR102 data to be presented at ENA 2020 provide further validation of our partnering strategy, which gives us multiple opportunities to build a pipeline of best-in-class cancer therapies,” said Peter Lamb, Ph.D., Executive Vice President of Scientific Strategy and Chief Scientific Officer of Exelixis. “AUR102 could be the subject of an Investigational New Drug filing later this year, which would be an important value driver for the program itself and for our collaboration with Aurigene. We commend the Aurigene team on their ongoing success in building a robust body of data supporting the broad clinical potential of AUR102.”

Under the terms of the July 2019 agreement, Exelixis made an upfront payment of $10 million for exclusive options to license three preexisting programs from Aurigene. In addition, Exelixis and Aurigene initiated three Aurigene-led drug discovery programs on mutually agreed upon targets, in exchange for additional upfront option payments of $2.5 million per program. Exelixis is also contributing research funding to Aurigene to facilitate discovery and preclinical development work on all six programs. As the programs mature, Exelixis will have the opportunity to exercise an exclusive option for each program up until the time of Investigational New Drug (IND) filing acceptance. If Exelixis decides to exercise an option, it will make an option exercise payment to Aurigene and assume responsibility for that program’s future clinical development and commercialization including global manufacturing. Aurigene will be eligible for clinical development, regulatory, and sales milestones, as well as royalties on sales. Under the terms of the agreement, Aurigene retains limited development and commercial rights for India and Russia.

About Aurigene

Aurigene is a development stage biotech company engaged in discovery and clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases and a wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY, NYSE: RDY). Aurigene is focused on precision-oncology, oral immune checkpoint inhibitors, and the Th-17 pathway. Aurigene’s programs currently in clinical development include an oral ROR-gamma inhibitor AUR101 for moderate to severe psoriasis in phase 2 under a U.S. FDA IND and a PD-L1/ VISTA antagonist CA-170 for non-squamous non-small cell lung cancer in phase 2b/3 in India. Additionally, Aurigene has multiple compounds at different stages of pre-clinical development. Aurigene has also partnered with several large and mid-pharma companies in the United States and Europe and has multiple programs in clinical development. For more information, please visit Aurigene’s website at http://www.aurigene.com.

About Exelixis

Founded in 1994, Exelixis, Inc. (Nasdaq: EXEL) is a commercially successful, oncology-focused biotechnology company that strives to accelerate the discovery, development and commercialization of new medicines for difficult-to-treat cancers. Following early work in model system genetics, we established a broad drug discovery and development platform that has served as the foundation for our continued efforts to bring new cancer therapies to patients in need. Our discovery efforts have resulted in four commercially available products, CABOMETYX® (cabozantinib), COMETRIQ® (cabozantinib), COTELLIC® (cobimetinib) and MINNEBRO® (esaxerenone), and we have entered into partnerships with leading pharmaceutical companies to bring these important medicines to patients worldwide. Supported by revenues from our marketed products and collaborations, we are committed to prudently reinvesting in our business to maximize the potential of our pipeline. We are supplementing our existing therapeutic assets with targeted business development activities and internal drug discovery – all to deliver the next generation of Exelixis medicines and help patients recover stronger and live longer. Exelixis is a member of Standard & Poor’s (S&P) MidCap 400 index, which measures the performance of profitable mid-sized companies. For more information about Exelixis, please visit http://www.exelixis.com, follow @ExelixisInc on Twitter or like Exelixis, Inc. on Facebook.

EXELIXIS AND AURIGENE ANNOUNCE THAT PROMISING PRECLINICAL DATA TO BE PRESENTED AT THE ENA SYMPOSIUM SUPPORT THE CLINICAL DEVELOPMENT OF A NOVEL CDK7 INHIBITOR

https://www.aurigene.com/exelixis-and-aurigene-announce-that-promising-preclinical-data-to-be-presented-at-the-ena-symposium-support-the-clinical-development-of-a-novel-cdk7-inhibitor/

Exelixis and Aurigene Announce That Promising Preclinical Data to Be Presented at the ENA Symposium Support the Clinical Development of a Novel CDK7 Inhibitor

– Detailed characterization of an oral inhibitor of CDK7 demonstrates potent activity against multiple hematologic and solid tumor cell lines, as monotherapy and in combination with chemotherapies –

October 09, 2020 03:02 AM Eastern Daylight Time

ALAMEDA, Calif.–(BUSINESS WIRE)–Exelixis, Inc. (Nasdaq: EXEL) and Aurigene Discovery Technologies Limited (Aurigene) today disclosed new preclinical data showing that AUR102 has potent anti-tumor activity in a large panel of cancer cell lines. AUR102 is a potent, selective, and orally bioavailable covalent inhibitor of cyclin-dependent kinase 7 (CDK7), which is an important regulator of the cellular transcriptional and cell cycle machinery. Exelixis has an exclusive option for AUR102 under its July 2019 exclusive collaboration, option and license agreement with Aurigene. The new data will be presented in a poster (Abstract 170) at the 32nd EORTC-NCI-AACR (ENA) Symposium, which is being held virtually on October 24-25, 2020.

“CDK7 plays a critical role in regulating cellular transcription and cell cycle machinery, making it an exciting target for cancer therapy”

“CDK7 plays a critical role in regulating cellular transcription and cell cycle machinery, making it an exciting target for cancer therapy,” said Murali Ramachandra, Ph.D., Chief Executive Officer of Aurigene. “The data to be presented at ENA 2020 demonstrate that AUR102 effectively engages CDK7 and inhibits a key mediator of the cell cycle and transcription. The ability to inhibit CDK7 activity with an orally available therapeutic such as AUR102 holds great potential to improve care and outcomes for patients with diverse cancer indications, including breast cancer, prostate cancer, leukemia and lymphoma.”

The abstract provides a summary of results from a detailed characterization of AUR102 in cancer cell lines and animal tumor models. Additional data will be presented in the poster. Key findings included in the abstract are:
• AUR102 exhibited potent anti-proliferative activity in a large panel of cell lines with induction of cell death in cell lines derived from multiple cancer types.
• The observed anti-proliferative activity correlated with cellular CDK7 target engagement and decreased levels of P-Ser5 RNAPII, a key mediator of transcription.
• AUR102 studies showed synergy when used in combination with multiple chemotherapies.
• Oral dosing with AUR102 resulted in dose-dependent anti-tumor activity, including complete tumor regression in diffuse large B-cell lymphoma, acute myeloid leukemia, and triple-negative breast cancer xenograft models.
• Inhibition of tumor growth was accompanied by complete target engagement as demonstrated in a parallel PK-PD study.
• AUR102 significantly impacts several pathways and key cancer driver and immune-response genes.

The study authors conclude that the data support clinical evaluation of AUR102 as a single agent and in combination with chemotherapies for the treatment of cancer.

“The exciting AUR102 data to be presented at ENA 2020 provide further validation of our partnering strategy, which gives us multiple opportunities to build a pipeline of best-in-class cancer therapies,” said Peter Lamb, Ph.D., Executive Vice President of Scientific Strategy and Chief Scientific Officer of Exelixis. “AUR102 could be the subject of an Investigational New Drug filing later this year, which would be an important value driver for the program itself and for our collaboration with Aurigene. We commend the Aurigene team on their ongoing success in building a robust body of data supporting the broad clinical potential of AUR102.”

Under the terms of the July 2019 agreement, Exelixis made an upfront payment of $10 million for exclusive options to license three preexisting programs from Aurigene. In addition, Exelixis and Aurigene initiated three Aurigene-led drug discovery programs on mutually agreed upon targets, in exchange for additional upfront option payments of $2.5 million per program. Exelixis is also contributing research funding to Aurigene to facilitate discovery and preclinical development work on all six programs. As the programs mature, Exelixis will have the opportunity to exercise an exclusive option for each program up until the time of Investigational New Drug (IND) filing acceptance. If Exelixis decides to exercise an option, it will make an option exercise payment to Aurigene and assume responsibility for that program’s future clinical development and commercialization including global manufacturing. Aurigene will be eligible for clinical development, regulatory, and sales milestones, as well as royalties on sales. Under the terms of the agreement, Aurigene retains limited development and commercial rights for India and Russia.

About Aurigene

Aurigene is a development stage biotech company engaged in discovery and clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases and a wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY, NYSE: RDY). Aurigene is focused on precision-oncology, oral immune checkpoint inhibitors, and the Th-17 pathway. Aurigene’s programs currently in clinical development include an oral ROR-gamma inhibitor AUR101 for moderate to severe psoriasis in phase 2 under a U.S. FDA IND and a PD-L1/ VISTA antagonist CA-170 for non-squamous non-small cell lung cancer in phase 2b/3 in India. Additionally, Aurigene has multiple compounds at different stages of pre-clinical development. Aurigene has also partnered with several large and mid-pharma companies in the United States and Europe and has multiple programs in clinical development. For more information, please visit Aurigene’s website at http://www.aurigene.com.

About Exelixis

Founded in 1994, Exelixis, Inc. (Nasdaq: EXEL) is a commercially successful, oncology-focused biotechnology company that strives to accelerate the discovery, development and commercialization of new medicines for difficult-to-treat cancers. Following early work in model system genetics, we established a broad drug discovery and development platform that has served as the foundation for our continued efforts to bring new cancer therapies to patients in need. Our discovery efforts have resulted in four commercially available products, CABOMETYX® (cabozantinib), COMETRIQ® (cabozantinib), COTELLIC® (cobimetinib) and MINNEBRO® (esaxerenone), and we have entered into partnerships with leading pharmaceutical companies to bring these important medicines to patients worldwide. Supported by revenues from our marketed products and collaborations, we are committed to prudently reinvesting in our business to maximize the potential of our pipeline. We are supplementing our existing therapeutic assets with targeted business development activities and internal drug discovery – all to deliver the next generation of Exelixis medicines and help patients recover stronger and live longer. Exelixis is a member of Standard & Poor’s (S&P) MidCap 400 index, which measures the performance of profitable mid-sized companies. For more information about Exelixis, please visit http://www.exelixis.com, follow @ExelixisInc on Twitter or like Exelixis, Inc. on Facebook.

Exelixis Forward-Looking Statements

This press release contains forward-looking statements, including, without limitation, statements related to: Exelixis’ and Aurigene’s plans to present preclinical data in support of the continued development of AUR102 in a poster as part of the 32nd ENA Symposium; the potential for AUR102 to improve care and outcomes for patients with diverse cancer indications, including breast cancer, prostate cancer, leukemia and lymphoma; the potential for AUR102 to be the subject of an Investigational New Drug filing later in 2020; Exelixis’ potential future financial and other obligations under the exclusive collaboration, option and license agreement with Aurigene; and Exelixis’ plans to reinvest in its business to maximize the potential of the company’s pipeline, including through targeted business development activities and internal drug discovery. Any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements and are based upon Exelixis’ current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: the availability of data at the referenced times; the level of costs associated with Exelixis’ commercialization, research and development, in-licensing or acquisition of product candidates, and other activities; uncertainties inherent in the drug discovery and product development process; Exelixis’ dependence on its relationship with Aurigene, including Aurigene’s adherence to its obligations under the exclusive collaboration, option and license agreement and the level of Aurigene’s assistance to Exelixis in completing clinical trials, pursuing regulatory approvals or successfully commercializing partnered compounds in the territories where they may be approved; the continuing COVID-19 pandemic and its impact on Exelixis’ research and development operations; complexities and the unpredictability of the regulatory review and approval processes in the U.S. and elsewhere; Exelixis’ and Aurigene’s continuing compliance with applicable legal and regulatory requirements; Exelixis’ and Aurigene’s ability to protect their respective intellectual property rights; market competition; changes in economic and business conditions; and other factors affecting Exelixis and its product pipeline discussed under the caption “Risk Factors” in Exelixis’ Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on August 6, 2020, and in Exelixis’ future filings with the SEC. All forward-looking statements in this press release are based on information available to Exelixis as of the date of this press release, and Exelixis undertakes no obligation to update or revise any forward-looking statements contained herein, except as required by law.

Exelixis, the Exelixis logo, CABOMETYX, COMETRIQ and COTELLIC are registered U.S. trademarks. MINNEBRO is a registered Japanese trademark.

MEVOCICLIB, SY 1365


Mevociclib.png

 

Mevociclib Chemical Structure

MEVOCICLIB,

CAS 1816989-16-8

SY 1365

N-[(1S,3R)-3-[[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]-1-methylcyclohexyl]-5-[[(E)-4-(dimethylamino)but-2-enoyl]amino]pyridine-2-carboxamide

N-((lS,3R)-3-(5-chloro-4-(lH-indol-3-yl)pyrimidin-2-ylamino)-l-methylcvclohexyl)-5-((E)-4-(dimethylamino)but-2-enamido)picolinamide

HS Tariff Code: 2934.99.9001

Syros

Molecular Weight 587.12
Formula C₃₁H₃₅ClN₈O₂
  • OriginatorSyros Pharmaceuticals
  • ClassAmides; Amines; Antineoplastics; Chlorinated hydrocarbons; Cyclohexanes; Indoles; Pyridines; Pyrimidines; Small molecules
  • Mechanism of ActionCyclin-dependent kinase-activating kinase inhibitors
  • DiscontinuedAcute myeloid leukaemia; Breast cancer; Haematological malignancies; Ovarian cancer; Solid tumours
  • 23 Oct 2019Discontinued – Preclinical for Haematological malignancies and Acute myeloid leukaemia in the USA (Parenteral); Phase-I for Solid tumours, Ovarian cancer and Breast cancer in the USA (IV) because data obtained did not support an optimal profile for patients and indicated higher or frequent dosing
  • 07 Dec 2018Pharmacodynamics data from preclinical trials in Breast cancer presented at the 41st Annual San Antonio Breast Cancer Symposium (SABCS-2018)
  • 15 Nov 2018Adverse events, efficacy and pharmacokinetics data from a phase I trial in Solid tumours presented at the 30th EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium (EORTC-NCI-AACR-2018)
Clinical Trial NCT NumberSponsorConditionStart DatePhaseNCT03134638Syros PharmaceuticalsAdvanced Solid Tumors|Ovarian Cancer|Breast CancerMay 12, 2017Phase 1

Mevociclib (SY-1365) is a potent and first-in-class selective CDK7 inhibitor, with a Ki of 17.4 nM. Mevociclib exhibits anti-proliferative and apoptotic effects in solid tumor cell lines. Mevociclib possesses anti-tumor activity in hematological and multiple aggressive solid tumors.

Mevociclib, also known as SY-1365, is a CDK7 inhibitor. In vitro, SY-1365 inhibited cell growth of many different cancer types at nanomolar concentrations. SY-1365 treatment decreased MCL1 protein levels, and cancer cells with low BCL-XL expression were found to be more sensitive to SY-1365. Transcriptional changes in acute myeloid leukemia (AML) cell lines were distinct from those following treatment with other transcriptional inhibitors. SY-1365 demonstrated substantial anti-tumor effects in multiple AML xenograft models as a single agent; SY-1365-induced growth inhibition was enhanced in combination with the BCL2 inhibitor venetoclax.

Syn

WO2015154038

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015154038

Example 16. Synthesis of N-((lS,3R)-3-(5-chloro-4-(lH-indol-3-yl)pyrimidin-2-ylamino)-l-methylcvclohexyl)-5-((E)-4-(dimethylamino)but-2-enamido)picolinamide (Compound 267).

[251] (+/-) Benzyl tert-butyl ((lS,3R)-l-methylcvclohexane-l,3-diyl)dicarbamate

(+/-)

[252] A solution of (+/-)-(lS,3R) -3-((ieit-¾itoxycarbonyl)amino)–l -raethylcyclohexanecarboxylic acid prepared as in WO2010/148197 (4.00 g, 15.5 mmol) in toluene (Ϊ 55 mL) was treated with Et3N (2.4 mL, 17.1 mmol) and DPPA (3.68 mL, Ϊ7.1 mmol) and heated at reflux for lh. Benzyl alcohol (8.0 mL, 77.7 mmol) and Et3N (4.4 mL , 31 .4 mmol) were added to the reaction mixture and the solution was heated at 100 °C for 72h. The mixture was cooled to room temperature and then diluted with EtOAc (300 mL) and H20 (300 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organics layers were washed with brine (100 mL), filtered and evaporated to dryness. The residue was purified by Si02 chromatography (EtOAc in hexanes, 0 to 50% gradient) and afforded the title compound (3.40 g, 9.38 mmol, 60%) as a white solid.

[253] Benzyl tert-butyl ((lS,3R)-l-methylcvclohexane-l,3-diyl)dicarbamate and benzyl tert- -l-methylcvclohexane-l,3-diyl)dicarbamate

(+/-)

[254] Both enantiomers of (+/-)-Benzyl tert-butyl ((lS,3R)-l-methylcyclohexane-l,3-diyl)dicarbamate (3.40 g, 9.38 mmol) were separated using preparative chiral HPLC (Chiralpak IA, 5 urn, 20×250 mm; hex/MeOH/DCM = 90/5/5) to yield both compounds benzyl tert-butyl ((lS,3R)-l-methylcyclohexane-l,3-diyl)dicarbamate (1.20 g, 3.31 mmol) and benzyl iert-butyl ((lR,3S)-l-methylcyclohexane-l,3-diyl)dicarbamate (1.15 g, 3.17 mmol) as white solids.

255 Benzyl ((lS,3R)-3-amino-l-methylcvclohexyl)carbamate hydrochloride

[256] A solution of benzyl tert-butyl ((lS,3R)-l-methylcyclohexane-l,3-diyl)dicarbamate (700 mg, 1.93 mmol) in DCM (19 mL) was treated with a 4M solution of HCI in dioxane (9.66 mL, 38.6 mmol) and stirred 16h at rt. The mixture was evaporated to dryness and afforded the title compound (577 mg, 1.93 mmol, 100%) as a white solid which was used in the next step without further purification.

[257] (lS,3R)-Benzyl-3-(5-chloro-4-(l-(phenylsulfonyl)-lH ndol-3-yl)pyrimidin-2-ylamino)-1-methylcyclohexylcarbamate

[258] A solution of 3-(2,5-dichloropyrimidin-4-yl)-l-(phenylsulfonyl)-lH-indole (1.02 g, 2.53 mmol), benzyl (( iS,3 )-3- amino- 1 -methylcyclohexyljcarbaniaie hydrochloride (577 mg, 1.93 mmol) and DIPEA (1.15 mL, 6.60 mmol) in NMP (11 mL) was heated at 135 °C (microwave) for 60 min. The cooled mixture was diluted with EtOAc (250 mL), washed with H20 (100 mL), brine (100 mL), dried over MgS04, filtered and evaporated to dryness. The residue was purified by Si02 chromatography (EtOAc in DCM, 0 to 50% gradient) and afforded the title compound (747 mg, 1.19 mmol, 54%) as a yellow foam.

[259] (lS,3R)-N-(5-chloro-4-(l-(phenylsulfonyl)-lH ndol-3-yl)pyrimidin-2-yl)-3-methylcvclohexane-l,3-diamine

[260] A cooled (-78°C) solution of (lS,3R)-benzyl-3-(5-chloro-4-(l-(phenylsulfonyl)-lH-indol-3-yl)pyrimidin-2-ylamino)-l-methylcyclohexylcarbamate (747 mg, 1.19 mmol) in DCM (39 mL) was treated with a 1M solution of BBr3 in DCM (2.83 mL, 2.83 mmol) and was slowly warmed up to rt. MeOH (10 mL) was added to the mixture was the resulting solution was stirred lh at rt. The resulting mixture was evaporated to dryness. The residue was purified by reverse phase chromatography (C18, H20/ACN +0.1% HC02H, 0 to 60% gradient) and afforded the title compound (485 mg, 0.978 mmol, 83%) as a yellow solid.

[261] 5-amino-N-( ( lS,3R)-3-( 5-chloro-4-(l-(phenylsulfonyl)-lH-indol-3-yl)pyrimidin-2-ylamino)-l-methylcvclohexyl)picolinamide

[262] A solution of (lR,3S)-N-(5-chloro-4-(l-(phenylsulfonyl)-lH-indol-3-yl)pyrimidin-2-yl)-3-methylcyclohexane-l,3-diamine (75.0 mg, 0.150 mmol) and 5-aminopicolinic acid (25.0 mg, 0.180 mmol) in DMF (5.0 mL) was treated with HBTU (86.0 mg, 0.230 mmol) and DIPEA (79 μί, 0.45 mmol). The resulting mixture was stirred 5h at rt and diluted with MeTHF (50 mL) and saturated NaHC03 (50 mL). The layers were separated and the aqueous layer was extracted with MeTHF (2 x 50 mL). The combined organic layers were dried over MgS04, filtered and evaporated to dryness. The residue was purified by Si02 chromatography (EtOAc in DCM, 0 to 50% gradient) and afforded the title compound (74.0 mg, 0.120 mmol, 79%) as a light yellow oil.

[263] 5-amino-N-((lS,3R)-3-(5-chloro-4-(lH ndol-3-yl)pyrimidin-2-ylamino)-l-methylcyclohexyDpicolinamide

[264] A solution of 5-amino-N-((lS,3R)-3-(5-chloro-4-(l-(phenylsulfonyl)-lH-indol-3-yl)pyrimidin-2-ylamino)-l-methylcyclohexyl)picolinamide (74.0 mg, 0.120 mmol) in 1,4-dioxane (4.0 mL) was treated with a 2M solution of NaOH in H20 (960 μί, 4.78 mmol) and heated at 60°C for lh. The cooled mixture was diluted with MeTHF (30 mL) and H20 (30 mL). The layers were separated and the aqueous layer was extracted with MeTHF (3 x 30 mL). The combined organic layers were dried over MgS04, filtered and evaporated to dryness affording the title compound (57.0 mg, 0.120 mmol, 100%) as a light yellow oil which was used in the next step without further purification.

[265] N-((lS,3R)-3-(5-chloro-4-(lH ndol-3-yl)pyrimidin-2-ylamino)-l-methylcvd^

( ( E)-4-(dimethylamino)but-2-enamido )picolinamide ( Compound 267)

[266] A cooled (-78°C) solution of 5-amino-N-((lS,3R)-3-(5-chloro-4-(lH-indol-3-yl)pyrimidin-2-ylamino)-l-methylcyclohexyl)picolinamide (57.0 mg, 0.120 mmol) and DIPEA (104 0.598 mmol) in THF/NMP (4.0 mL/1.0 mL) was treated with a 54.2 mg/mL solution of (E)-4-bromobut-2-enoyl chloride in DCM (104 μί, 0.598 mmol). The resulting mixture was stirred 4h at -78°C before addition of a 2M solution of dimethylamine in THF (359 μί, 0.717 mmol). The resulting mixture was warmed up to rt and stirred 45min at this temperature before being evaporated to dryness. The residue was purified by reverse phase chromatography (C18, H20/ACN +0.1% HC02H, 0 to 50% gradient) and afforded the title compound (15.0 mg, 0.026 mmol, 22%) as a white solid after lyophilization. LCMS: Calculated: 587.12; Found (M+H+): 587.39. 1H NMR (500 MHz, DMSO) δ 11.84 (s, 1H), 10.54 (s, 1H), 8.82 (d, J = 2.3 Hz, 1H), 8.64 (s, 1H), 8.47 (s, 1H), 8.25 (dd, J = 8.6, 2.4 Hz, 2H), 7.98 (d, J = 8.9 Hz, 2H), 7.50 (d, J = 7.7 Hz, 1H), 7.25 – 7.07 (m, 3H), 6.81 (dt, J = 15.5, 5.8 Hz, 1H), 6.29 (d, J = 15.4 Hz, 1H), 4.23 – 4.08 (m, 1H), 3.08 (dd, J = 5.7, 1.1 Hz, 2H), 2.46 – 2.37 (m, 1H), 2.18 (s, 6H), 2.04 – 1.95 (m, 2H), 1.87 – 1.70 (m, 3H), 1.63 – 1.46 (m, 4H), 1.39 – 1.26 (m, 1H).

Ref

///////////////

CN(C)C\C=C\C(=O)Nc1ccc(nc1)C(=O)N[C@]1(C)C[C@@H](CCC1)Nc1ncc(Cl)c(n1)c1c[NH]c2ccccc21

 

wdt-5
wdt-15

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SY 5609



[ Fig. 0001] 
[ Fig. 0002] [ Fig. 0003] [ Fig. 0004] 

SY 5609

CAS 2519828-12-5

Cancer, solid tumor

PHASE 1

A highly selective and potent oral inhibitor of cyclin-dependent kinase 7 (CDK7) for potential treatment of advanced solid tumors that harbor the Rb pa thway alterations (Syros Pharmaceuticals, Inc., Cambridge, Massachusetts, USA)

SY-5609 is an oral non-covalent CDK7 inhibitor in early clinical development at Syros Pharmaceuticals for the treatment of patients with advanced breast, colorectal, lung or ovarian cancer, or with solid tumors of any histology that harbor Rb pathway alterations.

  • OriginatorSyros Pharmaceuticals
  • ClassAntineoplastics; Small molecules
  • Mechanism of ActionCyclin-dependent kinase-activating kinase inhibitors
  • Phase IBreast cancer; Solid tumours
  • 05 Aug 2021Roche plans the phase I/Ib INTRINSIC trial in Colorectal cancer (Combination therapy, Metastatic disease) in USA, Canada, Italy, South Korea, Spain and United Kingdom (NCT04929223)
  • 05 Aug 2021Roche and Syros Pharmaceuticals enters into a clinical trial collaboration to evaluate atezolizumab in combination with SY 5609 in a clinical trial
  • 05 Aug 2021Syros Pharmaceuticals plans a phase I trial in Cancer in second half of 2021
  • NCT04247126
  • https://clinicaltrials.gov/ct2/show/NCT04247126
Syros Pharmaceuticals, Inc.

At #ESMO21, we will be presenting new preclinical and clinical data on SY-5609, our highly selective and potent oral CDK7 inhibitor. #oncology #biotech Learn more: https://lnkd.in/gqYmWYhb

A Promising Approach for Difficult-to-Treat Cancers

SY-5609 is a highly selective and potent oral inhibitor of the cyclin-dependent kinase 7 (CDK7) in a Phase 1 dose-escalation trial in patients with advanced breast, colorectal, lung, ovarian or pancreatic cancer, or with solid tumors of any histology that harbor Rb pathway alterations.

SY-5609 represents a new approach to treating cancer that we believe has potential in a range of difficult-to-treat cancers. It has shown robust anti-tumor activity, including complete regressions, in preclinical models of breast, colorectal, lung and ovarian cancers at doses below the maximum tolerated dose. In preclinical studies of breast, lung and ovarian cancers, deeper and more sustained responses were associated with the presence of Rb pathway alterations. SY-5609 has also shown substantial anti-tumor activity in combination with fulvestrant in treatment-resistant models of estrogen receptor-positive breast cancer, including those resistant to both fulvestrant and a CDK4/6 inhibitor. Early dose-escalation data demonstrated proof-of-mechanism at tolerable doses.

Syros to Present New Data from Phase 1 Clinical Trial of SY-5609 in Oral Presentation at ESMO Congress 2021SEPTEMBER 13, 2021

Management to Host Conference Call on Monday, September 20, 2021 at 4:00 p.m. ET

CAMBRIDGE, Mass.–(BUSINESS WIRE)– Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, today announced that it will present new data from the dose-escalation portion of the Phase 1 clinical trial of SY-5609, its highly selective and potent oral cyclin-dependent kinase 7 (CDK7) inhibitor, at the ESMO Congress 2021, taking place virtually September 16-21, 2021. The oral presentation will include safety, tolerability, and initial clinical activity data for SY-5609 in patients with breast, colorectal, lung, ovarian and pancreatic cancers, as well as in patients with solid tumors of any histology harboring Rb pathway alterations.

In separate poster presentations, Syros will present new preclinical data evaluating the antitumor and pharmacodynamic activity of intermittent dosing regimens for SY-5609 in ovarian cancer models, as well as new preclinical data evaluating antitumor activity of SY-5609 as a single agent and in combination with chemotherapy in KRAS-mutant models.

The abstracts for the two poster presentations are now available online on the ESMO conference website at: https://www.esmo.org/meetings/esmo-congress-2021/abstracts, and the presentations will become available for on-demand viewing starting September 16 at 08:30 CEST (September 16 at 2:30 a.m. ET). The abstract for the oral presentation on the Phase 1 dose-escalation data will remain embargoed until September 17 at 00:05 CEST (September 16 at 6:05 p.m. ET).

Details of the oral presentation are as follows:

Presentation Title: Tolerability and Preliminary Clinical Activity of SY-5609, a Highly Potent and Selective Oral CDK7 Inhibitor, in Patients with Advanced Solid Tumors
Session Date & Time: Monday, September 20, 17:30-18:30 CEST (11:30-12:30 p.m. ET)
Presentation Time: 17:55-18:00 CEST (11:55-12:00 p.m. ET)
Session Title: Mini Oral Session: Developmental Therapeutics
Presenter: Manish Sharma, M.D., START Midwest
Abstract Number: 518MO

Details of the poster presentations are as follows:

Presentation Title: Preclinical Evaluation of Intermittent Dosing Regimens on Antitumor and PD Activity of SY-5609, a Potent and Selective Oral CDK7 Inhibitor, in Ovarian Cancer Xenografts
Abstract Number: 14P
Presentation Title: SY-5609, a Highly Potent and Selective Oral CDK7 inhibitor, Exhibits Robust Antitumor Activity in Preclinical Models of KRAS Mutant Cancers as a Single Agent and in Combination with Chemotherapy
Abstract Number: 13P

Conference Call Information

Syros will host a conference call on Monday, September 20, 2021 at 4:00 p.m. ET to discuss the new clinical and preclinical data for SY-5609, which will be presented at the ESMO Congress 2021.

To access the live conference call, please dial 866-595-4538 (domestic) or 636-812-6496 (international) and refer to conference ID 4648345. A webcast of the call will also be available on the Investors & Media section of the Syros website at www.syros.com. An archived replay of the webcast will be available for approximately 30 days following the conference call.

About Syros Pharmaceuticals

Syros is redefining the power of small molecules to control the expression of genes. Based on its unique ability to elucidate regulatory regions of the genome, Syros aims to develop medicines that provide a profound benefit for patients with diseases that have eluded other genomics-based approaches. Syros is advancing a robust clinical-stage pipeline, including: tamibarotene, a first-in-class oral selective RARα agonist in RARA-positive patients with higher-risk myelodysplastic syndrome and acute myeloid leukemia; SY-2101, a novel oral form of arsenic trioxide in patients with acute promyelocytic leukemia; and SY-5609, a highly selective and potent oral CDK7 inhibitor in patients with select solid tumors. Syros also has multiple preclinical and discovery programs in oncology and monogenic diseases.

PATENT

CN(C)C\C=C\C(=O)Nc1ccc(cc1)C(=O)Nc1cccc(c1)Nc1ncc(Cl)c(n1)c1c[NH]c2ccccc21

THZ1; 1604810-83-4; THZ-1; HY-80013

CLIP

SY 1365 MEVOCICLIB, CAS 1816989-16-8

CN(C)C\C=C\C(=O)Nc1ccc(nc1)C(=O)N[C@]1(C)C[C@@H](CCC1)Nc1ncc(Cl)c(n1)c1c[NH]c2ccccc21

str1

PATENT

PATENT

3-fluoro-4-(methylamino)-N-[(1S,3R)-1-methyl-3-[[4-(7-methyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclohexyl]benzamide (Compound 130)

      

3-chloro-4-[[4-(dimethylamino)-3-hydroxy-butanoyl]amino]-N-[(1S,3R)-3-[[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1-methyl-cyclohexyl]benzamide (Compound 129)

      

4-amino-N-((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-1-methylcyclohexyl)benzamide (Compound 128)

      

4-amino-3-fluoro-N-[(1S,3R)-3-[[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1-methyl-cyclohexyl]benzamide (Compound 127)

      

4-amino-N-((1S,3R)-3-((5-chloro-4-(2-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)benzamide (Compound 126)

      

4-amino-N-((1S,3R)-3-((5-chloro-4-(1H-indazol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)benzamide (Compound 124)

      

Example 25 Synthesis of N1-(4-(((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamoyl)phenyl)oxalamide (Compound 113)

      

Example 24 Synthesis of N-((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)-4-(4-(dimethylamino)butanamido)benzamide (Compound 105)

      

PATENT

4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)tricyclo[3.3.1.13,7]decanyl)benzamide (Compound 100).

+/−)-4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-5 hydroxycyclohexyl)benzamide (Compound 101)

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide (Compound 102)

(1S,3R)-N-(4-aminophenyl)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexanecarboxamide (Compound 106)

4-amino-N-((1S,3R)-3-(5-cyclopropyl-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide.HCl (Compound 103)

4-amino-N-((1S,3R)-3-(5-chloro-4-(pyridin-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide (Compound 108)

4-amino-N-((1S,3R)-3-(5-cyano-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide (Compound 107)

(+/−)-4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-5-fluorocyclohexyl)benzamide (Compound 110)

4-amino-N-(5-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)bicyclo[3.1.1]heptan-1-yl)benzamide (Compound 104)

4-amino-N4(1R,5S)-5-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-3,3-difluorocyclohexyl)benzamide (Compound 115)

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzenesulfonamide (Compound 109).

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-2-fluorobenzamide (Compound 112)

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-3-fluorobenzamide (Compound 111).

(+/−)-4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-1-methylcyclohexyl)benzamide (Compound 116).

N-((1S,3R)-3-(4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-4-aminobenzamide (Compound 114).

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-2-morpholinobenzamide(Compound 117).

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyridin-2-ylamino)cyclohexyl)benzamide (Compound 118).

3-amino-N-(trans-4-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide.HCl (Compound 119).

(1S,3R)-N1-(R)-1-(4-aminophenyl)-2,2,2-trifluoroethyl)-N3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine (Compound 120).

(1S,3R)-N1-(4-aminobenzyl)-N3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-N1-methylcyclohexane-1,3-diamine.HCl (Compound 122).

4-amino-N-((1S,3R)-3-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide.HCl (Compound 123).

Synthesis of 5-amino-N-((1S,3R)-3-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)picolinamide (Compound 125)

Synthesis of N-((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)-4-(4-(dimethylamino)butanamido)benzamide (Compound 105)

Synthesis of N1-(4-(((1S,3R)-3-)(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamoyl)phenyl)oxalamide (Compound 113)

Synthesis of 4-amino-N-((1S,3R)-3-((5-chloro-4-(1H-indazol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)benzamide (Compound 124)

Synthesis of 4-amino-N-((1S,3R)-3-((5-chloro-4-(2-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)benzamide (Compound 126)

Synthesis of 4-amino-3-fluoro-N-[(1S,3R)-3-[[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1-methyl-cyclohexyl]benzamide (Compound 127).

Synthesis of 4-amino-N-((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl) pyrimidin-2-yl)amino)-1-methylcyclohexyl)benzamide (Compound 128)

Synthesis of 3-chloro-4-[[4-(dimethylamino)-3 hydroxy-butanoyl]amino]-N-[(1S,3R)-3-[[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1-methyl-cyclohexyl]benzamide (Compound 129).

Synthesis of 3-fluoro-4-(methylamino)-N-[(1S,3R)-1-methyl-3-[[4-(7-methyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclohexyl]benzamide (Compound 130)

//////////////SY 5609, 2519828-12-5, Cancer, solid tumor, PHASE 1, SYROS

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MAX 40279


Thieno(3,2-d)pyrimidin-2-amine, 7-(4-fluoro-2-methoxyphenyl)-6-methyl-N-(1-(4-piperidinyl)-1H-pyrazol-4-yl)-.png
2D chemical structure of 2070931-57-4

MAX 40279, EX-A4057

Max 4; MAX-40279; MAX-40279-001; MAX-40279-01

UNII-DL772G3NN7

2070931-57-4

C22H23FN6OS, 438.5

7-(4-fluoro-2-methoxyphenyl)-6-methyl-N-(1-piperidin-4-ylpyrazol-4-yl)thieno[3,2-d]pyrimidin-2-amine

Thieno[3,2-d]pyrimidin-2-amine, 7-(4-fluoro-2-methoxyphenyl)-6-methyl-N-[1-(4-piperidinyl)-1H-pyrazol-4-yl]-

Structure of MAX-40279 HEMIFUMARATE
Unii-JU19P2M2KM.png

7-(4-FLUORO-2-METHOXYPHENYL)-6-METHYL-N-(1-(PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL) THIENO (3,2-D)PYRIMIDIN-2-AMINE SEMI-FUMARATE CAS 2388506-43-0 

  • 7-(4-Fluoro-2-methoxyphenyl)-6-methyl-N-[1-(4-piperidinyl)-1H-pyrazol-4-yl]thieno[3,2-d]pyrimidin-2-amine
  • Originator Maxinovel Pharmaceuticals
  • ClassAntineoplastics
  • Mechanism of ActionFibroblast growth factor receptor antagonists; Fms-like tyrosine kinase 3 inhibitors
  • Orphan Drug StatusYes – Acute myeloid leukaemia
  • Phase IAcute myeloid leukaemia; Solid tumours

Most Recent Events

  • 28 Nov 2019Phase-I clinical trials in Solid tumours (Late-stage disease, Metastatic disease) in China (PO) (NCT04183764)
  • 16 Apr 2019Phase-I clinical trials in Acute myeloid leukaemia (Second-line therapy or greater) in China (PO) (NCT04187495)
  • 23 Jan 2019Guangzhou Maxinovel Pharmaceuticals plans a phase I trial in China (ChiCTR1900020971)
  • MaxiNovel Pharmaceuticals, Inc. Announces FDA Orphan Drug Designation for MAX-40279 for the Treatment of Acute Myeloid Leukemia (AML)
Jobs with Maxinovel Pharmaceuticals

March 29, 2018 11:24 AM Eastern Daylight Timehttps://www.businesswire.com/news/home/20180329005826/en/MaxiNovel-Pharmaceuticals-Inc.-Announces-FDA-Orphan-Drug-Designation-for-MAX-40279-for-the-Treatment-of-Acute-Myeloid-Leukemia-AML

GUANGZHOU, China–(BUSINESS WIRE)–MaxiNovel Pharmaceuticals, Inc. announced today that the U.S. Food and Drug Administration (“FDA”) has granted MaxiNovel Orphan Drug Designation for MAX-40279 in the treatment of Acute Myeloid Leukemia (AML).

AML is the most common acute leukemia which accounts for approximately 25% of all adult leukemias worldwide. Approximately one-third of AML patients have a FLT3 gene mutation. Such mutation can result in faster disease progression, higher relapse rates and lower rates of survival than other forms of AML. Inhibition of FLT3 mutation is of high importance in combating AML.

In the preclinical testing, MAX-40279 demonstrated potent inhibition of both FLT3 and FGFR with excellent drug concentration in the bone marrow. It is designed to overcome the observed drug resistance of the current FLT3 inhibitors due to the bone marrow FGF/FGFR pathway activation.

“We are very pleased to receive the ODD,” commented MaxiNovel’s Vice President Dr. Elizabeth Ashraf. “Our objective is to bring the best in class medicine to the patients worldwide.”

The FDA Office of Orphan Products Development grants orphan drug designation to novel drugs and biologics that are intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the United States. The designation allows manufacturers to qualify for various incentives including federal grants, tax credits for qualified clinical trials, a waiver of PDUFA filing fees and 7 years of market exclusivity upon regulatory approval.

About MaxiNovel Pharmaceuticals, Inc:

Maxinovel Pharmaceuticals, Inc. is a biotech company focusing on the discovery and development of Immuno-oncology therapy and targeted therapy. It will use its orally active Immuno-oncology product platform to bring effective combo product of multi-components in a single oral pill to the patients worldwide. For more info: www.maxinovel.com

The JAK-STAT (Janus kinase-signal transducer and activator of transcription) signal pathway is a signal transduction pathway stimulated by cytokines discovered in recent years, and it participates in many important biology such as cell proliferation, differentiation, apoptosis and immune regulation. Process (Aaronson, D Set al. Science 2002, 296, 1653-1655; O’Shea, J Jet al. Nat. Rev. Drug Discovery 2004, 3, 555-564). Compared with other signal pathways, the transmission process of this signal pathway is relatively simple. It mainly consists of three components, namely tyrosine kinase-related receptor, tyrosine kinase JAK and transcription factor STAT. JAK (Janus Kinase), a type of molecule in the cell, is rapidly recruited and activated on the receptor after receiving the signal from the upstream receptor molecule. The activated JAK catalyzes the receptor tyrosine phosphorylation, and the phosphorylation of tyrosine on the receptor molecule Amino acid is the recognition and binding site of a kind of signal molecule STAT SH2. Tyrosine phosphorylation occurs after STAT binds to the receptor. Tyrosine phosphorylated STAT forms a dimer and enters the nucleus. As an active transcription factor, dimeric STAT molecules directly affect the expression of related genes, thereby changing the proliferation or differentiation status of target cells.

The JAK-STAT pathway is widely present in various tissues and cells in the body, and has an important role in the differentiation, proliferation, and anti-infection of lymphocytes, and participates in the interaction of various inflammatory factors and signal transduction (Kiesseleva T. et al. . J. Gene, 2002, 285, 1-24). The abnormal activation of this pathway is closely related to a variety of diseases. Finding and screening JAK inhibitors can help in-depth study of the regulatory mechanism of JAK-STAT, thereby providing new drugs and methods for the prevention and treatment of related diseases

The occurrence, growth, invasion and metastasis of tumors are related to the JAK-STAT signal transduction pathway. In normal signal transduction, the activation of STATs is rapid and transient. The continuous activation of STATs is closely related to the process of malignant transformation of cells (Buettner R. et al. Clin. Cancer Res. 2002, 8(4), 945-954). STAT3 is the focus of multiple oncogenic tyrosine kinase signal channels such as EGFR, IL-6/JAK, Src, etc. It is activated in a variety of tumor cells and tissues, such as breast cancer, ovarian cancer, and head and neck squamous cells. Like cell carcinoma, prostate cancer, malignant melanoma, multiple myeloma, lymphoma, brain tumor, non-small cell lung cancer and various leukemias, etc. (Niu G. et al. Oncogene 2002, 21(13), 2000-2008 ). JAK-STAT pathway inhibitors belong to PTK inhibitors, and this enzyme is a member of the oncogene protein and proto-oncoprotein family, and plays an important role in the normal and abnormal cell proliferation. The occurrence and growth of tumors are inseparable from PTK. Therefore, JAK-STAT pathway inhibitors inhibit tumor growth by antagonizing PTK, and have obvious anti-tumor effects (Mora LBet al.J.Cancer Res.2002,62(22) , 6659-6666).

In addition, the latest research shows that: organ transplant rejection, psoriasis, tissue and organ fibrosis, bronchial asthma, ischemic cardiomyopathy, heart failure, myocardial infarction, blood system diseases, and immune system diseases are all related to JAK-STAT signaling. The pathway is closely related. This signaling pathway is not only important for maintaining the normal physiological functions of cells, but also has an important regulatory role for the occurrence and development of diseases.

The Fibroblast Growth Factor Receptor family belongs to a new type of receptor kinase family, which includes four receptor subtypes (FGFR-1,2,3) encoded by four closely related genes. And 4) and some heterogeneous molecules, which form a ternary complex with fibroblast growth factor (FGF) and heparan sulfate, and then trigger a series of signal transduction pathways to participate in the regulation of physiological processes in the organism. FGFR has a wide range of physiological and pathological effects in the body: (1) Embryo development. Studies have shown that during embryonic development, FGFR signal transduction is essential for most organ development and the formation of embryonic patterns. (2) Cell division, migration and differentiation. FGFR stimulates cell proliferation and participates in the regulation of cell transformation in the pathological process. There are many parallel pathways to achieve FGFR-mediated cell division signal transduction, which has been confirmed by many studies (JKWang et al., Oncogene 1997, 14, 1767 -1778.). (3) Bone diseases. The growth and differentiation of bones are also regulated by the FGF family, and mutations in FGFR can cause bone deformities (R. Shang et al., Cell 1994, 78, 335-342.). (4) The occurrence of tumors. FGFR can promote the migration, proliferation and differentiation of endothelial cells, and plays an important role in the regulation of angiogenesis and angiogenesis. Uncontrolled angiogenesis can lead to the occurrence of tumors and the growth of metastases (J.Folkman.Nat.Med.1995) ,1,27-31.).

FMS-like tyrosine kinase 3 (FMS-like tyrosine kinase 3, FLT3) belongs to the type III receptor tyrosine kinase (receptor tyrosine kinase III, RTK III) family member, it is composed of extracellular domain, intracellular domain and The transmembrane region is composed of 3 parts, which are first expressed in human hematopoietic stem cells. FLT3 interacts with its ligand FL to stimulate or act on stem cells, which is of great significance to the growth and differentiation of stem cells. FLT3 kinase has wild-type FLT3-WT and its main activation mutant FLT3-ITD and FLT3-D835Y. FLT3 is mainly expressed in the precursors of normal myeloid cells, but its abnormal expression is also found in a large part of acute myeloid leukemia (AML) cells. 

In recent years, many large-scale studies have confirmed that activating mutations of FLT3 play a very important pathological role in the occurrence and progression of acute myeloid leukemia. FLT3 has become an important target for the treatment of acute myeloid leukemia.

rc family kinase (SFK) is a family of non-receptor tyrosine kinases, including c-Src, LYN, FYN, LCK, HCK, FGR, BLK, YES and YRK, among which LYN kinase has LYNα and LYNβ Both subtypes, LYN kinase and its two subtypes can cause similar intracellular tyrosine phosphorylation. According to the amino acid sequence, SFK can be divided into two sub-families: one family is c-Src, FYN, YES and FGR, which are widely expressed in different tissues; the other family is LCK, BLK, LYN and HCK, which are closely related to hematopoietic cells. SFK is connected to multiple signal transduction pathways in the body, and can be activated by growth factors, cytokines and immune cell receptors, G protein-coupled receptors, integrins and other cell adhesion molecules, and then activate the corresponding signal transduction pathways , Causing a variety of physiological effects of cells. The activity of SFK mainly includes the regulation of cell morphology, cell movement, cell proliferation and survival. The abnormal activation and expression of these kinases leads to the occurrence and development of a wide range of diseases, such as a large number of solid tumors, various hematological malignancies and some neuronal pathologies. Therefore, looking for SFK inhibitors is a promising research topic in the field of medicinal chemistry.

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Patent

CN106366093A

PATENT

WO 2017012559

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017012559Example 31
N-[7-(4-Fluoro-2-methoxyphenyl)-6-methylthieno[3,2-d]pyrimidin-2-yl]-1-(piperidin-4-yl)- 1H-pyrazole-4-amine (Compound 31)

Synthesis of compound 31-e
2,4-Dichloro-6-methylthiophene [3,2-d] pyrimidine (10g, 45.6mmol) was dissolved in tetrahydrofuran (100mL) and ethanol (100mL), and the reaction solution was cooled to 0°C and divided Sodium borohydride (12.5 g, 198 mmol) was added in batches. The reaction solution was raised to room temperature and continued to stir for 16 hours, diluted with water (500 mL), and then adjusted to pH=7 with 1N aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate (150 mL×3). The organic phase was washed sequentially with water (100mL×3) and saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid 31-e (7.5g, yield: 88%). The product does not require further purification. LC-MS(ESI): m/z=187[M+H] + .[0492]Synthesis of compound 31-d[0493]Compound 31-e (7.5 g, 40 mmol) was dissolved in chloroform (300 mL) at 0°C, active manganese dioxide (35 g, 400 mmol) was added, the reaction solution was raised to room temperature and stirring was continued for 16 hours. The reaction solution was filtered through Celite, and the filter cake was washed with chloroform (100 mL×3). The combined filtrates were concentrated under reduced pressure to obtain white solid 31-d (6.6 g, yield: 89%), which did not require further purification. LC-MS(ESI): m/z=185[M+H]+.[0494]Synthesis of compound 31-c[0495]Compound 31-d (3.1g, 16.8mmol) was dissolved in trifluoroacetic acid (30mL) at 0℃, N-iodosuccinimide (5.7g, 25.3mmol) was added in batches, and the reaction solution was raised to Keep stirring at room temperature for 1 hour. Water (50 mL) was added to the reaction solution to quench the reaction, and it was extracted with dichloromethane (50 mL×3). The organic phase was washed successively with water (50mL×3) and saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid 31-c (4.9g, yield: 94%). The product does not require further purification. LC-MS(ESI): m/z=311[M+H] + .[0496]Synthesis of compound 31-b[0497]Compound 31-c (615mg, 1.98mmol), 2-methoxy-4-fluorophenylboronic acid (405mg, 2.38mmol) and sodium carbonate (630mg, 5.94mmol) were suspended in dioxane (5mL) water (5mL) ), add [1,1′-bis(diphenylphosphorus)ferrocene]dichloropalladium dichloromethane complex (163mg, 0.2mmol). Replace with nitrogen 3 times, and heat to 80°C to react for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was partitioned with dichloromethane (50mL) and water (50mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum Ether: dichloromethane=1:1) to obtain a white solid 31-b (240 mg, yield: 39%). LC-MS(ESI): m/z=309[M+H] + .[0498]Synthesis of compound 31-a[0499]Compound 31-b (240mg, 0.78mmol) and compound 32-c (208mg, 0.78mmol) were dissolved in N,N-dimethylformamide (3mL), potassium carbonate (323mg, 2.34mmol) was added, 2- Dicyclohexylphosphine-2′,6′-diisopropoxy-1,1′-biphenyl (112 mg, 0.24 mmol) and tris(dibenzylideneacetone) dipalladium (134 mg, 0.24 mmol). Under the protection of nitrogen, heat to 110°C to react for 16 hours. After cooling to room temperature, the reaction solution was partitioned with dichloromethane (50 mL) and water (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography preparation plate (petroleum Ether: ethyl acetate = 1:1) to obtain a yellow viscous oil 31-a (190 mg, yield: 45%). LC-MS(ESI): m/z=539[M+H] + .[0500]Synthesis of compound 31[0501]31-a (190 mg, 0.35 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was layered with ethyl acetate (50mL) and 1N aqueous hydrochloric acid (50mL). The aqueous phase was adjusted to pH=10 with saturated aqueous potassium carbonate solution. 3) Washing and vacuum drying the solid to obtain a light yellow solid 31 (22 mg, yield: 14%). LC-MS(ESI): m/z=439[M+H] + .[0502]1 H-NMR (400MHz, MeOD) δ: 8.78 (d, J = 5Hz, 1H), 7.87 (s, 1H), 7.48 (s, 1H), 7.35 (m, 1H), 7.05 (dd, J = 11Hz) ,J = 2Hz, 1H), 6.91 (m, 1H), 4.10 (m, 1H), 3.79 (s, 3H), 3.22 (m, 2H), 2.77 (m, 2H), 2.47 (s, 3H), 2.03(m,2H),1.73(m,2H)ppm

PATENT

WO 2019228171

Example 1 Preparation of fumarate of fused ring pyrimidine compound as shown in formula 2
Weigh the compound N-[7-(4-fluoro-2-methoxyphenyl)-6-methylthieno[3,2-d]pyrimidin-2-yl]-1-(piperidine-4- Base)-1H-pyrazol-4-amine (synthesized according to Example 31 of patent CN106366093A) 100mg (0.228mmol, 1eq) into the vial, add 10mL 88% acetone-water solution, add the vial at about 50°C and stir until dissolved clear. 1.1 mL of fumaric acid with a concentration of 0.25 mol/L in ethanol (0.275 mmol, 1.2 eq) was slowly added dropwise to the free base solution of fused ring pyrimidine compounds, and stirred at 50 ℃ for 1 hour, and then the solution was The rate of 5°C/h was slowly reduced to room temperature, and the solid was collected and dried under vacuum at 40°C overnight.
1 H-NMR (400MHz, DMSO-d 6 ) δ: 9.45 (s, 1H), 8.94 (s, 1H), 7.75 (s, 1H), 7.78-7.33 (m, 2H), 7.15 (d, J = 6.4Hz, 1H), 6.99 (dd, J = 7.6 Hz, J = 7.2 Hz, 1H), 6.42 (s, 1H), 4.10 (m, 1H), 3.73 (s, 3H), 3.17 (d, J = 12.4 Hz, 2H), 2.77 (dd, J = 12.4 Hz, J = 11.6 Hz, 2H), 2.40 (s, 3H), 1.94 (d, J = 11.6 Hz, 2H), 1.73 (m, 2H) ppm.

PATENT

WO2021175155

7-(4-Fluoro-2-methoxyphenyl)-6-methyl-N-(1-piperidin-4-yl)-1hydro-pyrazol-4-yl)thieno[3,2 -D]pyrimidine-2-amino is a strong JAK, FGFR, FLT3 kinase inhibitor, and has a good application prospect in the treatment of tumors, immune system diseases, allergic diseases and cardiovascular diseases. This compound is described in patent CN106366093A and has the following chemical structure:

CN106366093A discloses the preparation method of the compound:

In the above synthetic route, NaBH 4 is sodium borohydride, MnO 2 is manganese dioxide, NIS is N-iodosuccinimide, TFA is trifluoroacetic acid, and Pd(dppf)Cl 2 is [1,1′- Bis(diphenylphosphino)ferrocene]palladium dichloride, DIAD is diisopropyl azodicarboxylate, PPh 3 is triphenylphosphine, Pd/C is palladium on carbon, Pd 2 (dba) 3 is Tris(dibenzylideneacetone)dipalladium, RuPhos is 2-bicyclohexylphosphine-2′,6′-diisopropoxybiphenyl.

However, the above method has the problems of a large number of reaction steps, low yield, and requires column chromatography for separation and purification, and is not suitable for industrial scale-up production. Therefore, it is necessary to improve its preparation method.

The present invention provides a method for preparing a compound represented by formula B, which comprises the following steps: under a protective gas atmosphere, in a solvent, in the presence of a catalyst and a base, a compound represented by formula C is combined with a compound represented by formula K The compound can be subjected to the coupling reaction shown below; the catalyst includes a palladium compound and a phosphine ligand;

The preparation method of the compound represented by formula B may further include the following steps: in an organic solvent, in the presence of a base, the compound represented by formula E and the compound represented by formula D are subjected to the substitution reaction shown below, To obtain the compound represented by formula C;

The present invention provides a method for preparing a compound represented by formula C, which comprises the following steps: in an organic solvent, in the presence of a base, a compound represented by formula E and a compound represented by formula D are subjected to the following steps: Substitution reaction is enough;

Example 1: 2-Chloro-6-methylthieno[3,2-D]pyrimidine (Compound I) 
Into a 500L reactor, add 10% palladium on carbon (4.6Kg), 2,4-dichloro-6-methylthieno[3,2-D]pyrimidine (24.2Kg, 109.5mol), and tetrahydrofuran (150Kg) in sequence And N,N-diisopropylethylamine (17.0Kg, 131.5mol). Fill the kettle with hydrogen, and control the hydrogen pressure at 0.5 MPa. Turn on the stirring and keep the temperature at 25±5°C to react for 120 hours. Filter, collect the filtrate, concentrate the filtrate under reduced pressure, add ethanol (58Kg) to the concentrate, and concentrate again to bring out residual tetrahydrofuran. Add ethanol (60Kg) and stir at 70±5°C until all solids are dissolved. Cool down, control the temperature at 25±5°C, add 360Kg of purified water dropwise to the kettle, control the dropping rate, and keep the temperature at 25±5°C. The solid product was separated out, centrifuged, and the filter cake was vacuum dried to obtain the product 2-chloro-6-methylthieno[3,2-D]pyrimidine 18.94Kg, yield: 93.2%. LC-MS(ESI): m/z=185.1[M+H] + . 
1 H NMR (400MHz, d 6 -DMSO): δ9.30 (s, 1H), 7.34 (s, 1H), 2.73 (s, 3H). 
Example 2: 2-Chloro-6-methylthieno[3,2-D]pyrimidine (Compound I) 
To a 100mL reaction flask, add 10% palladium on carbon (0.17g), 2,4-dichloro-6-methylthieno[3,2-D]pyrimidine (2g, 9.2mmol), tetrahydrofuran (40mL) and N,N-Diisopropylethylamine (1.412 g, 10.9 mmol). Fill the bottle with hydrogen and control the hydrogen pressure at 0.5MPa. Turn on the stirring and keep the temperature at 25±5°C to react for 20 hours. Filter, collect the filtrate, concentrate the filtrate under reduced pressure, add ethanol (2.1 g) to the concentrate, and concentrate again to bring out residual tetrahydrofuran. Add ethanol (2.2g) and stir at 70±5°C until all solids are dissolved. Cool down, control the temperature at 25±5°C, add 13.3g of purified water dropwise to the kettle, control the dropping rate, and keep the temperature at 25±5°C. The solid product was precipitated, centrifuged, and the filter cake was vacuum dried to obtain 2.4 g of 2-chloro-6-methylthieno[3,2-D]pyrimidine as a product, with a yield of 82%. The LC-MS and 1 H NMR are the same as in Example 1. 
Example 3: 7-Bromo 2-chloro-6-methylthieno[3,2-D]pyrimidine (Compound E) 
Add trifluoroacetic acid (150Kg) and 2-chloro-6-methylthieno[3,2-D]pyrimidine (18.90Kg, 102.4mol) into a 500L enamel reactor. Add N-bromosuccinimide (18.33Kg, 103.0mol) under temperature control at 15±5℃. After the addition, the temperature is controlled at 25±5℃ to react for 2 hours. Sampling to monitor the reaction, there is still a small amount of raw materials remaining. Additional N-bromosuccinimide (1.0 Kg, 5.6 mol) was added, stirring was continued for 1 hour, sampling and monitoring showed that the reaction was complete. Control the temperature at 10±5°C, and add 274Kg of water dropwise. After the addition, stir at 10±5°C for 2 hours. After centrifugation, the solid was vacuum-dried to obtain the product, 7-bromo-2-chloro-6-methylthieno[3,2-D]pyrimidine, 24.68Kg, yield: 91.4%. LC-MS(ESI): m/z=265.0[M+H] + . 
1 H NMR (400MHz, d 6 -DMSO): δ9.33 (s, 1H), 2.64 (s, 3H). 
Example 4: 4-(p-toluenesulfonyl)-piperidine-1-tert-butyl carbonate (Compound G) 
Add pyridine (176Kg) and N-BOC-4-hydroxypiperidine (36.00Kg, 178.9mol) to a 500L enamel reactor. Add p-toluenesulfonyl chloride (50.5Kg, 264.9mol) in batches under temperature control at 10±10°C. After the addition, the temperature is controlled at 25±5°C to react for 18 hours. The reaction solution was transferred to a 1000L reactor, the temperature was controlled at 15±5°C, and 710Kg of water was added dropwise. After the addition, stir at 15±5°C for 2 hours. After filtration, the solid was washed with water and dried in vacuum to obtain the product 4-(p-methylbenzenesulfonyl)-piperidine-1-carbonate tert-butyl ester, 59.3Kg, yield: 93.3%. LC-MS(ESI): m/z=378.0[M+Na] + . 
Example 5: 4-(4-Nitro-1hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (Compound F) 
Add N,N-dimethylformamide (252Kg), 4-(p-methylbenzenesulfonyl)-piperidine-1-carbonate tert-butyl ester (59.3Kg, 166.8mol), 4-nitro to the reaction kettle Pyrazole (21.5Kg, 190.1mol), and anhydrous potassium carbonate (34.3Kg, 248.2mol). The temperature was controlled at 80±5°C and the reaction was stirred for 18 hours. Cool down to 15±5°C, add 900Kg of water dropwise, control the dropping rate, and keep the temperature at 15±5°C. After the addition, stir at 5±5°C for 2 hours. After filtering, the solid was washed twice with water and dried in vacuum to obtain the product 4-(4-nitro-1hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate 39.92Kg, yield: 80.8%. LC-MS (ESI): m/z=319.1 [M+Na] + . 
1 H NMR (400MHz, d 6 -DMSO): δ8.96(s,1H), 8.27(s,1H), 4.44-4.51(m,1H), 4.06-4.08(m,2H), 2.75-2.91( m, 2H), 2.04-2.07 (m, 2H), 1.80-1.89 (m, 2H), 1.41 (s, 9H). 
Example 6: 4-(4-Amino-1hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (Compound D) 
Add 10% palladium-carbon (2.00Kg), 4-(4-nitro-1hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (39.94Kg, 134.09mol) to the reaction kettle, nothing Water ethanol (314Kg) and ammonia (20.0Kg, 134.09mol). Fill the kettle with hydrogen, and control the hydrogen pressure at 0.2MPa. Turn on the stirring and keep the temperature at 45±5°C to react for 4 hours. Filter, collect the filtrate, and concentrate the filtrate under reduced pressure. Add ethyl acetate (40Kg) and n-heptane (142Kg) to the concentrate, stir at 25±5°C for 1 hour, and then lower the temperature to 5±5°C and stir for 2 hours. After filtration, the solid was vacuum dried to obtain the product 4-(4-amino-1hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate 31.85Kg, yield: 88.6%. LC-MS(ESI): m/z=267.2[M+H] + . 
1 H NMR (400MHz, d 6 -DMSO): δ7.06 (s, 1H), 6.91 (s, 1H), 4.08-4.15 (m, 1H), 3.98-4.01 (m, 2H), 3.81 (brs, 2H), 2.83-2.87 (m, 2H), 1.88-1.91 (m, 2H), 1.63-1.72 (m, 2H), 1.41 (s, 9H). 
Example 7: 4-(4-(7-Bromo-6-methylthieno[3,2-D]pyrimidin-2-yl)amino)-1hydro-pyrazol-1-yl)piperidine-1 -Tert-butyl carbonate (compound C) 
Add n-butanol (117Kg), N,N-diisopropylethylamine (15.00Kg, 116.06mol), 4-(4-amino-1hydro-pyrazol-1-yl)piperidine to the reaction kettle 1-tert-butyl carbonate (32.02Kg, 120.22mol) and 7-bromo-2-chloro-6-methylthieno[3,2-D]pyrimidine (24.68Kg, 93.65mol). Turn on the stirring and keep the temperature at 100±5°C to react for 42 hours. Concentrate under reduced pressure. Methanol was added to the concentrate to be beaten. The solid was filtered and dried under vacuum to obtain the product 4-(4-(7-bromo-6-methylthieno[3,2-D]pyrimidin-2-yl)amino)-1hydro-pyrazol-1-yl ) Piperidine-1-tert-butyl carbonate 37.26Kg, yield: 80.6%. LC-MS(ESI): m/z=493.1[M+H] + . 
1 H NMR (400MHz, d 6 -DMSO): δ9.73 (s, 1H), 8.97 (s, 1H), 8.18 (s, 1H), 7.68 (s, 1H), 4.30-4.36 (m, 1H) ,4.01-4.04(m,2H),2.87-2.93(m,2H),2.53(s,3H),2.00-2.03(m,2H),1.70-1.80(m,2H),1.41(s,9H) . 
Example 8: 4-(4-((7-(4-fluoro-2-methoxyphenyl)-6-methylthieno[3,2-D]pyrimidin-2-yl)amino)-1 Hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (Compound B) 
Add purified water (113Kg), dioxane (390Kg), 4-(4-(7-bromo-6-methylthieno[3,2-D]pyrimidin-2-yl)amino) into the reactor -1H-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (37.26Kg, 93.65mol), 2-methoxy-4-fluorophenylboronic acid pinacol ester (23.05Kg, 120.22mol) , Anhydrous potassium carbonate (20.95Kg, 151.8mol), palladium acetate (0.18Kg, 0.80mol) and 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (0.90Kg, 1.89mol). Under the protection of nitrogen, the temperature is controlled at 70±5℃ to react for 4 hours. Cool down to 40±5°C, add ammonia water (68Kg), and stir for 8 hours. Cool down to 20±5°C and dilute with water (1110Kg). Dichloromethane extraction twice (244Kg, 170Kg). Combine the organic phases, wash sequentially with water and then with saturated brine. Add 3-mercaptopropyl ethyl sulfide-based silica (4.0Kg, used to remove heavy metal palladium) into the organic phase, and stir at 40±5°C for 20 hours. After filtration, the filtrate was concentrated under reduced pressure. The remainder was slurried sequentially with methyl tert-butyl ether and ethanol. Filter and dry in vacuo to obtain 4-(4-((7-(4-fluoro-2-methoxyphenyl)-6-methylthieno[3,2-D]pyrimidin-2-yl)amino) -1H-pyrazol-1-yl)piperidine-1-tert-butyl carbonate 34.6Kg, yield: 68.6%. LC-MS(ESI): m/z=539.3[M+H] + . 
1 H NMR (400MHz, d 6 -DMSO): δ9.46 (s, 1H), 8.94 (s, 1H), 7.76 (s, 1H), 7.38 (s, 1H), 7.33 to 7.35 (m, 1H) ,7.08-7.11(m,1H),6.91-6.95(m,1H),4.03-4.12(m,3H),3.73(s,3H),2.85-2.89(m,2H),2.39(s,3H) ,1.90-1.93(m,2H),1.55-1.60(m,2H),1.41(s,9H). 
Comparative Example 1: 2-Chloro-6-methylthieno[3,2-D]pyrimidine (Compound I) 
Into a 100mL reaction flask, add 10% palladium on carbon (0.1g), 2,4-dichloro-6-methylthieno[3,2-D]pyrimidine (2g, 9.2mmol), methanol (40mL) and N,N-Diisopropylethylamine (1.412 g, 10.9 mmol). Fill the bottle with hydrogen and control the hydrogen pressure at 0.5MPa. Turn on the stirring and keep the temperature at 25±5°C to react for 21 hours. Filter, collect the filtrate, concentrate the filtrate under reduced pressure, add ethanol (2.1 g) to the concentrate, and concentrate again to bring out residual tetrahydrofuran. Add ethanol (2.2g) and stir at 70±5°C until all solids are dissolved. Cool down, control the temperature at 25±5°C, add 13.3g of purified water dropwise to the kettle, control the dropping rate, and keep the temperature at 25±5°C. The solid product was precipitated, centrifuged, and the filter cake was vacuum dried to obtain 1.6 g of 2-chloro-6-methylthieno[3,2-D]pyrimidine as a product, with a yield of 54%. Methoxy substituted impurities in 20% yield.
Comparative Example 2: 2-Chloro-6-methylthieno[3,2-D]pyrimidine (Compound I) 
After replacing the solvent tetrahydrofuran in Example 2 with ethyl acetate, the solubility of 2-chloro-6-methylthieno[3,2-D]pyrimidine in ethyl acetate was poor, and only a small amount of product was formed, which was not calculated Specific yield. 
Comparative example 3: 4-(p-toluenesulfonyl)-piperidine-1-tert-butyl carbonate (Compound G) 
Triethylamine (25mL), N-BOC-4-hydroxypiperidine (5g) were added to a 100mL reaction flask. P-toluenesulfonyl chloride (7.1g) was added in batches while controlling the temperature at 10±10°C. After the addition, the temperature is controlled at 25±5℃ to react for 25 hours. Monitoring by LC-MS showed a large amount of unreacted raw materials and the reaction liquid was black and red. 

Publication Number TitlePriority Date Grant Date
WO-2019228171-A1Salt of fused ring pyrimidine compound, crystal form thereof and preparation method therefor and use thereof2018-05-31 
AU-2016295594-A1Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-21 
AU-2016295594-B2Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-212020-04-16
EP-3354653-A1Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-21 
EP-3354653-B1Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-212019-09-04
Publication Number TitlePriority Date Grant Date
JP-2018520202-AFused ring pyrimidine compounds, intermediates, production methods, compositions and applications thereof2015-07-21 
KR-20180028521-ACondensed ring pyrimidine-based compounds, intermediates, methods for their preparation, compositions and applications2015-07-21 
US-10494378-B2Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-212019-12-03
US-2018208604-A1Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-21 
WO-2017012559-A1Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-21
CTID TitlePhaseStatusDate
NCT03412292MAX-40279 in Subjects With Acute Myelogenous Leukemia (AML)Phase 1Recruiting2021-05-21

///////////////Orphan Drug, Acute myeloid leukaemia, MAX 40279, EX-A4057, Max 4,  MAX-40279, MAX-40279-001, MAX-40279-01, PHASE 1, Maxinovel Pharmaceuticals

CC1=C(C2=NC(=NC=C2S1)NC3=CN(N=C3)C4CCNCC4)C5=C(C=C(C=C5)F)OC

TRK 700


1-[4-(Dimethylamino)piperidin-1-yl]-3-(1-methylimidazol-2-yl)propan-1-one.png

TRK-700

CAS 1463432-16-7C14 H24 N4 O264.371-Propanone, 1-[4-(dimethylamino)-1-piperidinyl]-3-(1-methyl-1H-imidazol-2-yl)-

1-[4-(dimethylamino)piperidin-1-yl]-3-(1-methylimidazol-2-yl)propan-1-one

  • 1-[4-(Dimethylamino)-1-piperidinyl]-3-(1-methyl-1H-imidazol-2-yl)-1-propanone
  • OriginatorToray Industries
  • ClassAnalgesics
  • Mechanism of ActionUndefined mechanism
  • Phase IIPostherpetic neuralgia
  • PreclinicalPeripheral nervous system diseases
  • 12 Sep 2018Pharmacodynamics data from a preclinical trial in Peripheral neuropathy presented at the 17th World Congress on Pain (WCP-2018)
  • 01 Jul 2017Toray Industries completes a phase II trial for Postherpetic neuralgia (In adults, In the elderly) in Japan (PO) (NCT02701374)
  • 21 May 2017Toray Industries completes a phase I drug-drug interaction trial in Healthy volunteers in Japan (PO) (NCT03043248)

developed by Toray for treating neuropathic pain and investigating for fibromyalgia. In August 2021, this drug was reported to be in phase 1 clinical development.

PATENT

WO 2016136944

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016136944

(Reference Example 22) Synthesis of (E) -methyl 3- (1-methyl-1H-imidazol-2-yl) acrylate:
[Chemical 56]


 1-methyl-1H-imidazol-2-carbaldehyde (10.0 g, Methyl (triphenylphosphoranylidene) acetate (33.4 g, 99.9 mmol) was added to a solution of 90.8 mmol) in dichloromethane (240 mL) at room temperature, and the mixture was stirred for 16 hours and then concentrated under reduced pressure. The residue was washed with a mixed solvent of hexane / dichloromethane = 19/1, and the washing liquid was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (E) -methyl 3- (1-methyl-1H-imidazol-2-yl) acrylate as a white solid (11.9 g, 71. 6 mmol, 79%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.76 (3H, s), 3.81 (3H, s), 6.82 (1H, d, J = 15.6 Hz), 6.98 (1H, brs), 7.16 (1H, brs), 7.53 (1H, d, J = 15.6Hz).
ESI-MS: m / z = 167 (M + H) + .

(Reference Example 27) Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one:
[Chemical 61]


 (E) )-Methyl 3- (1-methyl-1H-imidazol-2-yl) acrylate (0.180 g, 1.08 mmol) in ethanol (4.0 mL) solution of palladium-carbon (10% wet, 15 mg) at room temperature In a hydrogen atmosphere, the mixture was stirred for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Methanol (1.0 mL) was added to the obtained residue at room temperature to dissolve it, and the mixture was cooled to 0 ° C. An aqueous sodium hydroxide solution (1.0 N, 1.19 mL, 1.19 mmol) was added to the reaction solution at 0 ° C., the mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. Chloroform (10.0 mL) was added to the obtained residue at room temperature to dissolve it. Add diisopropylethylamine (0.568 mL, 3.25 mmol), HBTU (0.616 g, 1.63 mmol) and 4- (dimethylamino) piperidine (0.125 g, 0.975 mmol) to the reaction solution at room temperature, and add the reaction solution. The mixture was stirred at the same temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, chloroform / methanol) and 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propane. -1-one (0.179 g, 0.68 mmol, 63%) was obtained as a colorless oil.
1 1 H-NMR (400 MHz, CDCl 3) δ: 1.29-1.43 (2H, m), 1.80-1.88 (2H, m), 2.27 (6H, s), 2.29-2.38 (1H, m), 2.54-2.63 (1H, m), 2.88-3.04 ( 5H, m), 3.62 (3H, s), 3.98-4.05 (1H, m), 4.57-4.65 (1H, m), 6.79 (1H, d, J = 1.2 Hz), 6.91 (1H, d, J = 1.2 Hz).
ESI-MS: m / z = 265 (M + H) + .

(Comparative Example 1) Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one hydrochloride:
[Chemical 66]


 1- (4- (Dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one (1.50 g, 5.67 mmol) diethyl ether (60) A dioxane solution of hydrogen chloride (4.0 M, 3.69 mL, 14.8 mmol) was added to the (0.0 mL) solution at 0 ° C. The reaction mixture was stirred at the same temperature for 1 hour and then at room temperature for 30 minutes. The precipitated white solid was collected by filtration, washed with diethyl ether (100 mL), dried at room temperature for 36 hours, and then 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-). Imidazole-2-yl) propan-1-one hydrochloride (1.41 g, 4.18 mmol, 74%) (hereinafter, the compound of Comparative Example 1) was obtained as a white solid.
1 1 H-NMR (400 MHz, D 2 O) δ: 1.53-1.80 (2H, m), 2.12-2.23 (2H, m), 2.68-2.80 (1H, m), 2.88 (6H, s), 3.01- 3.08 (2H, m), 3.15-3.26 (3H, m), 3.47-3.58 (1H, m), 3.84 (3H, s), 4.08-4.16 (1H, m), 4.50-4.59 (1H, m), 7.29-7.33 (2H, m).
ESI-MS; 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) as propan-1-one : m / z = 265 (M + H) + .

(Comparative Example 2) Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one sulfate monohydrate:
[Chemical 67]


 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one (6.72 g, 25.4 mmol) Concentrated sulfuric acid (2.49 g, 25.4 mmol), water (1.83 g, 102 mmol) and 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl) in a DMSO (100 mL) solution. Seed crystals (50 mg, 0.13 mmol) of -1H-imidazol-2-yl) propan-1-one sulfate monohydrate were added at 80 ° C. The reaction was stirred at the same temperature for 2.5 hours, at 50 ° C. for 2.5 hours and at room temperature for 15 hours. The precipitated white solid was collected by filtration, washed successively with DMSO (20 mL) and methyl ethyl ketone (40 mL), dried at room temperature, and then 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl). -1H-imidazol-2-yl) propan-1-one sulfate monohydrate (8.42 g, 22.1 mmol, 87%) (hereinafter, the compound of Comparative Example 2) was obtained as white crystals.
1 1 H-NMR (400 MHz, DMSO-d 6)) δ: 1.36 (1H, m), 1.58 (1H, m), 1.95 (2H, br), 2.44-2.57 (1H, m), 2.65 (6H, s), 2.74-2.88 (4H, m), 3.00 (1H, t, J = 12.0 Hz), 3.22 (1H, m), 3.61 (3H, s), 4.02 (1H, d, J = 14.0 Hz), 4.47 (1H, d, J = 12.8 Hz), 6.87 (1H, d, J = 1.2 Hz), 7.11 (1H, d, J = 1.2 Hz).
ESI-MS; 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-) As 1H-imidazol-2-yl) propan-1-one: m / z = 265 (M + H) + .

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PATENT

WO-2021153744

PATENT

WO-2021153743

Novel crystalline polymorphic form of 1-(4-(dimethylamino) piperidin-1-yl)-3-(1-methyl-1H-imidazol-2-yl)propan-1-one, useful as an analgesic in treating neuropathic pain and/or fibromyalgia.Pain is an experience with unpleasant sensations and emotions that occurs when or may cause tissue damage. Pain is mainly classified into nociceptive pain, neuropathic pain or psychogenic pain according to its cause. In addition, fibromyalgia is known as pain of unknown cause. 
 Neuropathic pain is pathological pain caused by dysfunction of the peripheral or central nervous system itself, and is caused by direct damage or compression of nervous tissue even though nociceptors are not stimulated. It refers to the pain that occurs. As a therapeutic agent for neuropathic pain, an anticonvulsant, an antidepressant, anxiolytic, or an antiepileptic drug such as gabapentin or pregabalin is used. 
 Fibromyalgia is a disease in which systemic pain is the main symptom and neuropsychiatric symptoms and autonomic nervous system symptoms are secondary symptoms. Pregabalin approved in the United States and Japan, duloxetine and milnacipran approved in the United States are mainly used as therapeutic agents for fibromyalgia, and non-approved agents for fibromyalgia are not approved. It has also been used for steroidal anti-inflammatory agents, opioid compounds, antidepressants, anticonvulsants and antiepileptic drugs. However, the therapeutic effects of non-steroidal anti-inflammatory drugs and opioid compounds are generally considered to be low (Non-Patent Document 1). 
 On the other hand, Patent Document 1 discloses that certain substituted piperidins have cardiotonic activity, and Patent Document 2 discloses that an imidazole derivative exhibits an FXa inhibitory effect. Patent Document 3 suggests that the substituted piperidins may have a medicinal effect on overweight or obesity, and Patent Documents 4 to 6 and Non-Patent Document 2 indicate that the imidazole derivative has an analgesic effect. It is disclosed. 
 In addition, the quality of pharmaceutical products needs to be maintained over a long period of time such as distribution and storage, and the compound as an active ingredient is required to have high chemical and physical stability. Therefore, as the active ingredient of a pharmaceutical product, a crystal that can be expected to have higher stability than an amorphous substance is generally adopted. Further, if crystals are obtained, a purification effect due to recrystallization during production can be expected. Further, it is preferable to have low hygroscopicity from the viewpoint of maintaining stability and handling during manufacturing, storage, formulation and analysis of the drug substance. In addition, since a drug needs to be dissolved in the digestive tract in order to exhibit its medicinal effect, it is preferable that the drug has excellent solubility, which is a physical property contrary to stability. 
 In order to obtain crystals of a compound that is an active ingredient of a pharmaceutical product, it is necessary to study various conditions for precipitating crystals from the solution. It is common to carry out crystallization under the condition of being dissolved in.

Patent documents

Patent Document 1: French Patent Invention No. 2567885
Patent Document 2: Japanese Patent Application Laid-Open No. 2006-0083664
Patent Document 3: International Publication No. 2003/031432
Patent Document 4: International Publication No. 2013/147160
Patent Document 5: International Publication No. 2015/046403
Patent Document 6: International Publication No. 2016/136944

Non-patent literature

Non-Patent Document 1: Okifuji et al., Pain and Therapy, 2013, Volume 2, p. 87-104
Non-Patent Document 2: Takahashi et al., Toxicological Pathology, 2019, Vol. 47. p. 494-503

Compound (I) was synthesized by the method described in the following reference example. For the compounds used in the synthesis of the reference example compounds for which the synthesis method is not described, commercially available compounds were used. 
(Reference Example 4) Synthesis of amorphous compound (I):
[Chemical formula 2] 2 of

crude ethyl 3- (1-methyl-1H-imidazol-2-yl) propanol (5.00 g, 27.4 mmol) Aqueous sodium hydroxide solution (1.0N, 30.2 mL, 30.2 mmol) was added to a solution of -propanol (55 mL) at 0 ° C., and the mixture was stirred at room temperature for 12 hours. 2-Propanol (220 mL) was added to the reaction solution at room temperature, and crude 4- (dimethylamino) piperidine (3.17 g, 24.7 mmol) and DMT-MM (8.35 g, 30.2 mmol) were added at room temperature to react. The liquid was stirred at the same temperature for 3 hours. A 10% aqueous sodium chloride solution and a 1.0N aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound (I) (6.98 g) as an amorphous substance.
1 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.29-1.43 (2H, m), 1.80-1.88 (2H, m), 2.27 (6H, s), 2.29-2.38 (1H, m), 2.54-2.63 (1H, m), 2.88-3.04 (5H, m), 3.62 (3H, s), 3.98-4.05 (1H, m), 4.57-4.65 (1H, m), 6.79 (1H, d, J = 1.2 Hz) ), 6.91 (1H, d, J = 1.2 Hz).
ESI-MS: m / z = 265 (M + H) + .
(Reference Example 5) Synthesis of crude 4- (dimethylamino) piperidine:
[Chemical

formula 3] 1-benzyloxycarbonyl-4- (dimethylamino) piperidine (20.1 g, 77.0 mmol) in methanol (154.0 mL) Palladium-carbon (10% wet, 2.01 g) was added thereto, and the mixture was stirred at room temperature for 19 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give a crude product of 4- (dimethylamino) piperidine (9.86 g).
(Reference Example 6) Synthesis of crude ethyl 3- (1-methyl-1H-imidazol-2-yl) propanoate:
[Chemical

formula 4] Sodium hydride (55%, 4.36 g, 100 mmol) aqueous solution and tetrahydrofuran (150 mL) To the mixture was added triethylphosphonoacetate (19.1 mL, 95.0 mmol) at 0 ° C. After stirring the reaction solution for 20 minutes, a solution of 1-methyl-1H-imidazol-2-carbaldehyde (10.0 g, 91.0 mmol) in tetrahydrofuran (150 mL) was added at 0 ° C., and then ethanol (30 mL) was added in the same manner. The mixture was added at temperature and stirred at room temperature for 2 hours. A 10% aqueous sodium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, chloroform / methanol). After adding methanol (310 mL) to the residue, palladium-carbon (10% wet, 1.40 g) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (14.2 g) of ethyl 3- (1-methyl-1H-imidazol-2-yl) propanoate.
(Reference Example 7) Synthesis of 1-benzyloxycarbonyl-4- (dimethylamino) piperidine:
[Chemical

formula 5] dichloromethane (55.7 mL) of 1-benzyloxycarbonyl-4-oxopiperidine (13.0 g, 55.7 mmol) ) Solution of dimethylamine in tetrahydrofuran (2.0 M, 34.8 mL, 69.7 mmol), acetic acid (0.32 mL, 5.6 mmol) and sodium triacetoxyborohydride (4.8 g, 22.6 mmol). Added at ° C. After stirring the reaction solution at the same temperature for 30 minutes, sodium triacetoxyborohydride (4.8 g, 22.6 mmol) was added at 0 ° C. The reaction mixture was stirred at the same temperature for 30 minutes, sodium triacetoxyborohydride (8.1 g, 38.2 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 12 hours. The reaction solution was cooled to 0 ° C. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane / ethyl acetate) and then again by flash chromatography (silica gel, chloroform / methanol) to obtain 1-benzyloxycarbonyl-4- (dimethylamino) piperidine (dimethylamino) piperidine. 13.6 g, 51.8 mmol, 93%) was obtained as a colorless oil.
1 1 H-NMR (400 MHz, CDCl 3) δ: 1.34-1.46 (2H, m), 1.78-1.86 (2H, m), 2.28 (6H, s), 2.29-2.34 (1H, m), 2.75-2.85 (2H, m), 4.14-4.28 ( 2H, m), 5.12 (2H, s), 7.29-7.36 (5H, m).
ESI-MS: m / z = 263 (M + H) + .
(Reference Example 8) Synthesis of 1-benzyloxycarbonyl-4-oxopiperidine:
[Chemical

formula 6] Hydrochloride (130 mL) and water (130 mL) of 4-piperidinone hydrochloride monohydrate (10.0 g, 65.1 mmol) Sodium carbonate (13.8 g, 130.2 mmol) and benzyl chloroformate (8.79 mL, 61.8 mmol) were added to the mixed solution with and at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane / ethyl acetate) to give 1-benzyloxycarbonyl-4-oxopiperidine (13.1 g, 56.2 mmol, 86%) as a colorless oil.
1 1 H-NMR (400 MHz, CDCl 3 ) δ: 2.42-2.50 (4H, m), 3.78-3.82 (4H, m), 5.18 (2H, s), 7.32-7.38 (5H, m).
(Example 1) Production of A-type crystal of
compound (I): Amorphous compound (6.98 g) of compound (I) prepared in Reference Example 4 is purified and concentrated with chloroform / methanol by silica gel column chromatography. After that, the wall surface of the flask was rubbed with a spartel and mechanical stimulation was applied to obtain A-type crystals of compound (I) as a powder. For the obtained crystals, measurement of powder X-ray diffraction using a powder X-ray diffractometer (Rigaku Co., Ltd .; 2200 / RINT ultima + PC) and TG-DTA using a TG-DTA device (Rigaku Co., Ltd .; TG8120) Was done. The results of these measurements are shown in FIGS. 1 and 2.
Diffraction angle 2θ: 5.9, 16.5, 17.7, 20.8, 26.7 °
Endothermic peak: 55 ° C

PATENT

WO2013147160

Example 1 Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one:
[Chemical 27]

(E) )-Methyl 3- (1-methyl-1H-imidazol-2-yl) acrylate (0.180 g, 1.08 mmol) in ethanol (4.0 mL) solution of palladium-carbon (10% wet, 15 mg) at room temperature In a hydrogen atmosphere, the mixture was stirred for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Methanol (1.0 mL) was added to the obtained residue at room temperature to dissolve it, and the mixture was cooled to 0 ° C. An aqueous sodium hydroxide solution (1.0 N, 1.19 mL, 1.19 mmol) was added to the reaction solution at 0 ° C., the mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. Chloroform (10.0 mL) was added to the obtained residue at room temperature to dissolve it. Add diisopropylethylamine (0.568 mL, 3.25 mmol), HBTU (0.616 g, 1.63 mmol) and 4- (dimethylamino) piperidine (0.125 g, 0.975 mmol) to the reaction solution at room temperature, and add the reaction solution. The mixture was stirred at the same temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (NH silica gel, chloroform / methanol) and 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan- 1-one (0.179 g, 0.68 mmol, 63%) (hereinafter, the compound of Example 1) was obtained as a colorless oil.
1 1 H-NMR (400 MHz, CDCl 3) δ: 1.29-1.43 (2H, m), 1.80-1.88 (2H, m), 2.27 (6H, s), 2.29-2.38 (1H, m), 2.54-2.63 (1H, m), 2.88-3.04 ( 5H, m), 3.62 (3H, s), 3.98-4.05 (1H, m), 4.57-4.65 (1H, m), 6.79 (1H, d, J = 1.2 Hz), 6.91 (1H, d, J = 1.2 Hz).
ESI-MS: m / z = 265 (M + H) + .

Publication Number TitlePriority Date Grant Date
WO-2016136944-A1Cyclic amine derivative and pharmaceutical use thereof2015-02-27 
JP-WO2013147160-A1Cyclic amine derivatives and their pharmaceutical use2012-03-29 
TW-201350119-ACyclic amine derivatives and their medical uses2012-03-29 
WO-2013147160-A1Cyclic amine derivative and use thereof for medical purposes2012-03-29 
Publication Number TitlePriority Date Grant Date
RU-2667062-C1Dynamic cyclic amine and pharmaceutical application thereof2015-02-272018-09-14
TW-201639826-ACyclic amine derivatives and their medical uses2015-02-27 
TW-I682927-BCyclic amine derivatives and their medical uses2015-02-272020-01-21
US-10173999-B2Cyclic amine derivative and pharmaceutical use thereof2015-02-272019-01-08
US-2018065950-A1Cyclic amine derivative and pharmaceutical use thereof2015-02-27 
Publication Number TitlePriority Date Grant Date
EP-3263565-A1Cyclic amine derivative and pharmaceutical use thereof2015-02-27 
EP-3263565-B1Cyclic amine derivative and pharmaceutical use thereof2015-02-272019-06-26
ES-2744785-T3Cyclic amine derivative and pharmaceutical use thereof2015-02-272020-02-26
JP-6569671-B2Cyclic amine derivatives and their pharmaceutical use2015-02-272019-09-04
JP-WO2016136944-A1Cyclic amine derivatives and their pharmaceutical use2015-02-27 
Publication Number TitlePriority Date Grant Date
WO-2019189781-A1Agent for inhibiting rise in intraneuronal calcium concentration2018-03-30 
AU-2016224420-A1Cyclic amine derivative and pharmaceutical use thereof2015-02-27 
AU-2016224420-B2Cyclic amine derivative and pharmaceutical use thereof2015-02-272019-08-22
CA-2977614-A1Cyclic amine derivative and pharmaceutical use thereof2015-02-27 
CN-107250128-BCyclic amine derivatives and its medical usage2015-02-272019-07-26

//////////TRK-700, phase 1, neuropathic pain, fibromyalgia, toray

O=C(CCc1nccn1C)N1CCC(CC1)N(C)C

PRN 473, SAR 444727


str1

2-[(3R)-3-[4-Amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4,4-dimethylpent-2-enenitrile.png

SAR-444727

1414354-91-8C30 H30 F N7 O2 Molecular Weight539.601-Piperidinepropanenitrile, 3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-α-(2,2-dimethylpropylidene)-β-oxo-, (3R)-

(3R)-3-[4-Amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-α-(2,2-dimethylpropylidene)-β-oxo-1-piperidinepropanenitrile

2-(3-(4-amino~3-(2-fiuoro~4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile

  • OriginatorPrincipia Biopharma
  • ClassSmall molecules
  • Mechanism of ActionAgammaglobulinaemia tyrosine kinase inhibitors
  • Phase IAutoimmune disorders
  • DiscontinuedArthritis
  • 28 Sep 2020Principia Biopharma has been acquired by Sanofi
  • 22 Jun 2020Principia Biopharma plans a pharmacokinetic phase I trial (In volunteers) for Hypersensitivity (for Immunoglobulin E-mediated allergies) in Australia (Topical) (ACTRN12620000693921)
  • 10 Mar 2020Phase-I clinical trials in Autoimmune disorders (In volunteers) in Australia (Topical)
  • US 8957080
  • US 8673925
  • WO 2014022569
  • WO 2013191965
  • WO 2012158764

Useful for treating pemphigus vulgaris, immune thrombocytopenia, inflammatory bowel disease, Sjogren’s syndrome, multiple sclerosis, chronic lymphocytic leukemia and ankylosing spondylitis. Principia Biopharma is developing a topical formulation PRN-473 (presumed to be SAR-444727), a reversible covalent bruton’s (BTK) tyrosine kinase inhibitor, developed based on Principia’s reversible, tailored covalency platform, for treating immune-mediated diseases [phase I, July 2021]. Principia Biopharma was also investigating BTK inhibitors , developed based on Principia’s reversible, tailored covalency platform, for treating hematologic malignancies [no development reported since July 2019]. At the time of publication, Zhu was also affiliated with Nurix Therapeutics , while By and Phiasivongsa were based at Rain Therapeutics and Kronos Bio , respectively.

PATENT

WO-2021142131

Novel crystalline polymorphic forms (I to V) of PRN-473 and their preparation method.

CRYSTALLINE FORMS OF 2- [3- [4- AMINO-3-(2- FLUORO-4-PHENOXY- PHENYL)-1H-PYRAZOLO[3,4-D]PYRIMIDIN-1-YL]PIPERIDINE-1-CARBONYL]- 4,4-DIMETHYLPENT-2-ENENITRILE

This application claims the benefit of priority to U.S. Provisional Application No. 62/958,389, filed January 8, 2020, the contents of which are incorporated by reference herein in their entirety.

Disclosed herein are crystalline forms of 2-(3-(4-amino~3-(2-fiuoro~4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (Compound (I)), methods of using the same, and processes for making Compound (I), including its various crystalline forms. The crystalline forms of Compound (I) are inhibitors of Bruton’s tyrosine kinase (BTK). The enzyme BTK is a member of the Tec family non-receptor tyrosine kinases.

BTK is expressed in most hematopoietic cells, including B cells, mast cells, and macrophages. BTK plays a role in the development and activation of B cells and has been implicated in multiple signaling pathways across a wide range of immune-mediated diseases. BTK activity has been implicated in the pathogenesis of several disorders and conditions, such as B cel1-related hematological cancers (e.g,, non-Hodgkin lymphoma and B cell chronic lymphocytic leukemia) and autoimmune diseases (e.g, rheumatoid arthritis,

Sjogren’s syndrome, pemphigus, IBD, lupus, and asthma).

Compound (I) and various solid forms thereof may inhibit BTK and be useful in the treatment of disorders and conditions mediated by BTK activity. Compound (I) is disclosed as, e.g., Compound 125A in Table 1 of WO 2012/158764 and has the following structure:

str1

Example 1: Preparation of Crystalline Form (I) of Compound (I)

Methyl isobutyl ketone (MIBK; 6 mL) was added to amorphous (R)-2-(3-(4-amino-3- (2-fluoro-4-phenoxyphenyJ)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4- dimethylpent-2-enenitrile (1,0 g) and stirred to fonn a solution. After approximately five minutes of agitation, a precipitate began to form. Additional MIBK (10 mL) was charged, and the slurry was stirred. After approximately ten days, the solid was filtered and rinsed with MIBK (10 mL). The solid was dried under vacuum with heating to afford approximately 0.5 g of crystalline Form (I) of Compound (I) as a white solid.

PATENT

WO2012158764 , claiming BTK tyrosine kinase inhibitors, useful for treating cancer.

https://patents.google.com/patent/WO2012158764A1/en

WO 2012/158764 125A

Figure imgf000057_0001

PATENT

US20210205313

PATENT

US20210205312 ,

for concurrently published filings, claiming a gel composition comprising PRN-473 and use of another BTK tyrosine kinase inhibitor ie PRN1008 , respectively.

PATENT

WO2016100914 , claiming use of a BTK inhibitor ie PRN-473, alone or in combination with corticosteroid therapy, for treating pemphigus vulgaris.

PATENT

WO 2014022569

https://patents.google.com/patent/WO2014022569A1/en

//////// PRN-473,  PRN 473, SAR 444727, PHASE 1

CC(C)(C)C=C(C#N)C(=O)N1CCC[C@H](C1)n1nc(c2c(N)ncnc21)c1ccc(Oc2ccccc2)cc1F

NEW DRUG APPROVALS

ONE TIME

$10.00

PF-07321332, Nirmatrelvir


PF-07321332.svg
Unii-7R9A5P7H32.png

PF-07321332

Nirmatrelvir

UNII-7R9A5P7H32

7R9A5P7H32

PF07321332

CAS 2628280-40-8

C23H32F3N5O4, 499.5

(1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

Paxlovid

(1R,2S,5S)-N-((1S)-1-Cyano-2-((3S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-(3-methyl-N-(trifluoroacetyl)-L-valyl)-3-azabicyclo(3.1.0)hexane-2-carboxamide

https://clinicaltrials.gov/ct2/show/NCT04756531

wdt-16

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SYN

https://pubmed.ncbi.nlm.nih.gov/34726479/

https://www.science.org/doi/10.1126/science.abl4784

Science. 2021 Dec 24;374(6575):1586-1593. doi: 10.1126/science.abl4784. Epub 2021 Nov 2.

An oral SARS-CoV-2 M pro inhibitor clinical candidate for the treatment of COVID-19

Dafydd R Owen 1,

file:///C:/Users/Inspiron/Downloads/science.abl4784_sm.pdf

The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.

Synthesis of PF-07321332 (Compound 6): Anhydrous, MTBE solvate form

(1R,2S,5S)-N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N- (trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide (1 eq tert-butyl methyl ether solvate) (6, MTBE solvate). This experiment was carried out in 2 parallel batches. Methyl N- (triethylammoniosulfonyl)carbamate, inner salt (Burgess reagent; 69.3 g, 276 mmol) was added to a solution of T18 (61 g, 111 mmol) in dichloromethane (550 ml). After the reaction mixture had been stirred at 25 °C for 1 h. The reaction mixture was quenched by a mixture of saturated aqueous sodium bicarbonate solution (200 ml) and saturated aqueous sodium chloride solution (100 ml). The separated organic phase was concentrated. The resulting residue was dissolved in 50% ethyl acetate/ tert-butyl methyl ether (600 ml), washed by a mixture of saturated aqueous sodium bicarbonate solution (200 ml) and saturated aqueous sodium chloride solution (100 ml) twice, saturated aqueous sodium chloride solution (200 ml), a mixture of HCl (1 M; 200 ml) and saturated aqueous sodium chloride solution (100 ml) twice. The organic layer was then dried over magnesium sulfate, filtered, and concentrated. The residue was treated with a mixture of ethyl acetate and tert-butyl methyl ether (1:10, 400 ml) and heated to 50 °C; after stirring for 1 hour at 50 °C, it was cooled to 25 °C and stirred overnight. The solid was collected via filtration, dissolved in dichloromethane (100 ml) and filtered through silica gel (200 g); the silica gel was then washed with ethyl acetate (1 Liter), 10% methanol in ethyl acetate (2 Liters). The combined eluates were concentrated. The 2 batches were combined, taken up in a mixture of ethyl acetate and tert-butyl methyl ether (5:95, 550 ml). This mixture was heated to 50 °C for 1 h, cooled to 25 °C, and stirred overnight. Filtration afforded 6, MTBE solvate, as a white solid. Yield: 104 g, 75 %. 1H NMR (600 MHz, DMSO-d6) δ 9.43 (d, J = 8.4 Hz, 1H), 9.03 (d, J = 8.6 Hz, 1H), 7.68 (s, 1H), 4.97 (ddd, J = 10.9, 8.6, 5.1 Hz, 1H), 4.41 (d, J = 8.4 Hz, 1H), 4.15 (s, 1H), 3.91 (dd, J = 10.4, 5.5 Hz, 1H), 3.69 (d, J = 10.4 Hz, 1H), 3.17 – 3.11 (m, 1H), 3.07 (s, 3H, MTBE), 3.04 (td, J = 9.4, 7.1 Hz, 1H), 2.40 (tdd, J = 10.4, 8.4, 4.4 Hz, 1H), 2.14 (ddd, J = 13.4, 10.9, 4.4 Hz,

1H), 2.11 – 2.03 (m, 1H), 1.76 – 1.65 (m, 2H), 1.57 (dd, J = 7.6, 5.5 Hz, 1H), 1.32 (d, J = 7.6 Hz, 1H), 1.10 (s, 9H, MTBE), 1.03 (s, 3H), 0.98 (s, 9H), 0.85 (s, 3H). Anal. Calcd for C23H32F3N5O4 .C5H12O: C, 57.23; H, 7.55; N, 11.92. Found: C, 57.08; H, 7.55; N, 11.85. mp = 118.8 oC

cry

Compound 6 (anhydrous MTBE solvate, 200 g, 332.8 mmol, 83.11 mass%) was charged into a reactor with overhead half-moon stirring at 350 rpm. Heptane (1000 ml) was charged, followed by isopropyl acetate (1000 ml) and the stirring was continued at 20 oC overnight. Additional heptane (1000 ml) was charged over 120 minutes. The reaction vessel was then cooled to 10 oC over 30 min and stirred at that temp for 3 days. The solid was filtered, washing with a mixture of isopropyl acetate (80 ml) and heptane (320 ml). It was then dried under vacuum at 50 °C to provide 6, anhydrous ‘Form 1’, as a white crystalline solid. Yield: 160.93 g, 322 mmol, 97%. 1H NMR (600 MHz, DMSO-d6) δ 9.43 (d, J = 8.4 Hz, 1H), 9.03 (d, J = 8.6 Hz, 1H), 7.68 (s, 1H), 4.97 (ddd, J = 10.9, 8.6, 5.1 Hz, 1H), 4.41 (d, J = 8.4 Hz, 1H), 4.15 (s, 1H), 3.91 (dd, J = 10.4, 5.5 Hz, 1H), 3.69 (d, J = 10.4 Hz, 1H), 3.17 – 3.11 (m, 1H), 3.04 (td, J = 9.4, 7.1 Hz, 1H), 2.40 (tdd, J = 10.4, 8.4, 4.4 Hz, 1H), 2.14 (ddd, J = 13.4, 10.9, 4.4 Hz, 1H), 2.11 – 2.03 (m, 1H), 1.76 – 1.65 (m, 2H), 1.57 (dd, J = 7.6, 5.5 Hz, 1H), 1.32 (d, J = 7.6 Hz, 1H), 1.03 (s, 3H), 0.98 (s, 9H), 0.85 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 177.50, 170.72, 167.45, 156.95 (q, J = 37.0 Hz), 119.65, 115.84 (q, J = 286.9 Hz), 60.08, 58.19, 47.63, 37.77, 36.72, 34.60, 34.15, 30.28, 27.34, 26.86, 26.26, 25.72, 18.86, 12.34. 19F NMR (376 MHz, DMSO-d6) δ -72.94. HRMS (ESI-TOF) m/z calcd. for C23H33F3N5O4 [M + H]+ 500.2474, found 500.2472. Anal. Calcd for C23H32F3N5O4: C, 55.30; H, 6.46; N, 14.02. Found: C, 55.30; H, 6.49; N, 13.96. mp = 192.9 oC

SYN

Bioorganic & medicinal chemistry letters (2021), 50, 128333. 

https://www.sciencedirect.com/science/article/pii/S0960894X21005606

https://pubmed.ncbi.nlm.nih.gov/34418570/

pecific anti-coronaviral drugs complementing available vaccines are urgently needed to fight the COVID-19 pandemic. Given its high conservation across the betacoronavirus genus and dissimilarity to human proteases, the SARS-CoV-2 main protease (Mpro) is an attractive drug target. SARS-CoV-2 Mpro inhibitors have been developed at unprecedented speed, most of them being substrate-derived peptidomimetics with cysteine-modifying warheads. In this study, Mpro has proven resistant towards the identification of high-affinity short substrate-derived peptides and peptidomimetics without warheads. 20 cyclic and linear substrate analogues bearing natural and unnatural residues, which were predicted by computational modelling to bind with high affinity and designed to establish structure-activity relationships, displayed no inhibitory activity at concentrations as high as 100 μM. Only a long linear peptide covering residues P6 to P5‘ displayed moderate inhibition (Ki = 57 µM). Our detailed findings will inform current and future drug discovery campaigns targeting Mpro.

SYN

https://pubmed.ncbi.nlm.nih.gov/34498651/

Chemical communications (Cambridge, England) (2021), 57(72), 9096-9099We present a detailed computational analysis of the binding mode and reactivity of the novel oral inhibitor PF-07321332 developed against the SARS-CoV-2 3CL protease. Alchemical free energy calculations suggest that positions P3 and P4 could be susceptible to improvement in order to get a larger binding strength. QM/MM simulations unveil the reaction mechanism for covalent inhibition, showing that the nitrile warhead facilitates the recruitment of a water molecule for the proton transfer step.

PATENT

 WO 2021234668 

SYNOral inhibitors of the SARS-CoV-2 main protease for the treatment of COVID-19Owen, D., 261st Am Chem Soc (ACS) Natl Meet · 2021-04-05 Abst 243Synthesis of intermediate : Aminolysis of methyl N-Boc-3-[2-oxopyrrolidin-3(S)-yl]-L-alaninate  in the presence of NH3 and subsequent N-deprotection using HCl leads to 2(S)-amino-3-[2-oxopyrrolidin-3(S)-yl]propenamide hydrochloride 

Condensation of Boc-L-tert-leucine with methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate  using HATU gives the corresponding amide, which upon hydrolysis of methyl ester moiety in the presence of LiOH and subsequent N-deprotection by means of HCl affords intermediate,. N-Acylation of amine  with ethyl trifluoroacetate yields diamide derivative, which upon condensation with 2(S)-amino-3-[2-oxopyrrolidin-3(S)-yl]propenamide hydrochloride using EDC and HOPO generates compound N-1 STEP. Burgess dehydration of amide derivative  furnishes PF-7321332 . 

In about November to December 2019 a novel coronavirus was identified as the cause of pneumonia cases in Wuhan (China). It spread, resulting in an epidemic throughout China, and thereafter in other countries throughout the world. In February 2020, the World Health Organization designated the disease COVTD-19, which stands for coronavirus disease 2019. The virus is also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1)

COVID-19 is a betacoronavirus in the same subgenus as the severe acute respiratory syndrome (SARS) virus (as well as several bat coronaviruses), but in a different clade. The structure of the receptor- binding gene region is very similar to that of the SARS coronavirus, and the virus has been shown to use the same receptor, the angiotensin converting enzyme 2 (ACE2), for cell entry (2).

In the situation of rapidly increasing cases, inappropriate management of mild cases could increase the burden of healthcare system and medical costs. Viral clearance is a major standard in the assessment of recovery and discharge from medical care, but early results illustrated that the persistence of viral RNA is heterogeneous despite the rapid remission of symptoms and can last over three weeks even in very mild cases. In addition, long hospitalization stays may increase the risk for hospital-associated mental health problems and unexpected hospital-acquired infections. (9)

At the beginning, the outbreak identified an initial association with a seafood market that sold live animals in Wuhan, China. However, as the outbreak progressed, person-to-person spread became the main mode of transmission.

Person to person transmission is thought to occur mainly via respiratory droplets, resembling the spread of influenza. With droplet transmission, the virus is released in respiratory secretions when an infected person breathes, coughs, sneezes, or talks, and can infect another person if such secretions make direct contact with the mucous membranes. Infection can also occur if a person touches an infected surface and then touches his or her eyes, nose, or mouth. Droplets typically do not travel more than six feet (about two meters) and do not linger in the air. There is still controversy about this topic.

Whether SARS-CoV-2 can be transmitted through the airborne route (through particles smaller than droplets that remain in the air over time and distance) under natural conditions has been controversial.

Reflecting the current uncertainty regarding transmission mechanisms, recommendations on airborne precautions in the health care setting vary by location; airborne precautions are universally recommended when aerosol-generating procedures are performed.

It appears that SARS-CoV-2 can be transmitted prior to the development of symptoms and throughout the course of illness. However, most data informing this issue is from studies evaluating viral RNA detection from respiratory and other specimens, and detection of viral RNA does not necessarily indicate the presence of infectious virus.

A study suggested infectiousness started 2.3 days prior to symptom onset, peaked 0.7 days before symptom onset, and declined within seven days; however, most patients were isolated following symptom onset, which would reduce the risk of transmission later in illness regardless of infectiousness. These findings raise the possibility that patients might be more infectious in the earlier stage of infection, but additional data is needed to confirm this hypothesis (3).

How long a person remains infectious is also uncertain. The duration of viral shedding is variable; there appears to be a wide range, which may depend on severity of the illness. In one study of 21 patients with mild illness (no hypoxia), 90 percent had repeated negative viral RNA tests on nasopharyngeal swabs by 10 days after the onset of symptoms; tests were positive for longer in patients with more severe illness (4). In contrast, in another study of 56 patients with mild to moderate illness (none required intensive care), the median duration of viral RNA shedding from nasal or oropharyngeal specimens was 24 days, and the longest was 42 days (5). However, as mentioned above, detectable viral RNA does not always correlate with isolation of infectious virus, and there may be a threshold of viral RNA level below which infectivity is unlikely. In the study of nine patients with mild COVID-19 described above, infectious virus was not detected from respiratory specimens when the viral RNA level was <106 copies/mL (6).

Risk of transmission from an individual with SARS-CoV-2 infection varies by the type and duration of exposure, use of preventive measures, and likely individual factors (e.g., the amount of virus in respiratory secretions).

Antibodies against the virus are induced in those who have become infected. Preliminary evidence suggests that some of these antibodies are protective, but this remains to be definitively established. It is unknown whether all infected patients develop a protective immune response and how long any protective effect will last.

Diagnosis of COVID-19 is made by detection of SARS-CoV-2 RNA by reverse transcription polymerase chain reaction (RT-PCR). Various RT-PCR assays are used around the world; different assays amplify and detect different regions of the SARSCoV-2 genome. Common gene targets include nucleocapsid (N), envelope (E), spike (S), and RNA-dependent RNA polymerase (RdRp), as well as regions in the first open reading frame (7).

Serologic tests detect antibodies to SARS-CoV-2 in the blood, and those that have been adequately validated can help identify patients who have had COVID-19. However, sensitivity and specificity are still not well defined. Detectable antibodies generally take several days to weeks to develop, for example, up to 12 days for IgM and 14 days for IgG(Si-

………………………………..

PF-07321332 (or nirmatrelvir) is an antiviral drug developed by Pfizer which acts as an orally active 3CLprotease inhibitor. The combination of PF-07321332 with ritonavir has been in phase III trials for the treatment of COVID-19 since September 2021[2][3][4] and is expected to be sold under the brand name Paxlovid.[5] After promising results preventing hospitalization and death if given within the first 3 days of symptoms, Pfizer submitted an application to the U.S. Food and Drug Administration (FDA) for emergency authorization for PF-07321332 in combination with ritonavir in November 2021.[6]

PF-07321332 is an azabicyclohexane that is (1R,5S)-3-azabicyclo[3.1.0]hexane substituted by {(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}aminoacyl, 3-methyl-N-(trifluoroacetyl)-L-valinamide, methyl and methyl groups at positions 2S, 3, 6 and 6, respectively. It is an inhibitor of SARS-CoV-2 main protease which is currently under clinical development for the treatment of COVID-19. It has a role as an EC 3.4.22.69 (SARS coronavirus main proteinase) inhibitor and an anticoronaviral agent. It is a nitrile, a member of pyrrolidin-2-ones, a secondary carboxamide, a pyrrolidinecarboxamide, a tertiary carboxamide, an organofluorine compound and an azabicyclohexane.

Development

Pharmaceutical

Coronaviral proteases cleave multiple sites in the viral polyprotein, usually after glutamine residues. Early work on related human rhinoviruses showed that the flexible glutamine side chain could be replaced by a rigid pyrrolidone.[7][8] These drugs had been further developed prior to the SARS CoV2 pandemic for other diseases including SARS.[9] The utility of targeting the 3CL protease in a real world setting was first demonstrated in 2018 when GC376 (a prodrug of GC373) was used to treat the previously 100% lethal cat coronavirus disease, feline infectious peritonitis, caused by Feline coronavirus.[10]

The Pfizer drug is an analog of GC373, where the aldehyde covalent cysteine acceptor has been replaced by a nitrile.[11][12]

PF-07321332 was developed by modification of an earlier clinical candidate lufotrelvir,[13][14] which is also a covalent inhibitor but its warhead is a phosphate prodrug of a hydroxyketone. However, lufotrelvir needs to be administered intravenously limiting its use to a hospital setting. Stepwise modification of the tripeptide protein mimetic led to PF-0732133, which is suitable for oral administration.[1] Key changes include a reduction in the number of hydrogen bond donors, and the number of rotatable bonds by introducing the rigid bicyclic non-canonical amino acid, which mimics the leucine residue found in earlier inhibitors. This residue had previously been used in the synthesis of boceprevir.[15]

Clinical

In April 2021, Pfizer began phase I trials.[16] In September 2021, Pfizer began a phase II/III trial.[17] In November 2021, Pfizer announced 89% reduction in hospitalizations of high risk patients studied when given within three days after symptom onset.[5]

On December 14, Pfizer announced that Paxlovid, when given within three days of symptom onset, reduced risk of hospitalization or death by 89% compared to placebo in 2,246 high risk patients studied.[18]

Chemistry and pharmacology

Full details of the synthesis of PF-07321332 were first published by scientists from Pfizer.[1]

In the penultimate step, a synthetic homochiral amino acid is coupled with a homochiral amino amide using the water-soluble carbodiimide EDCI as coupling agent. The resulting intermediate is then treated with Burgess reagent, which dehydrates the amide group to the nitrile of the product.

PF-07321332 is a covalent inhibitor, binding directly to the catalytic cysteine (Cys145) residue of the cysteine protease enzyme.[19]

In the drug combination, ritonavir serves to slow down metabolism of PF-07321332 by cytochrome enzymes to maintain higher circulating concentrations of the main drug.[20]

Public health system reactions to development

Despite not being approved yet in any country, the UK placed an order for 250,000 courses after Pfizer´s press release in October 2021,[21][22] and Australia pre-ordered 500,000 courses of the drug.[23]

As of November 2021, the US government was expected to sign a contract to buy around 10 million courses of the combination treatment.[24][25]

In November 2021, Pfizer signed a license agreement with the United Nations–backed Medicines Patent Pool to allow PF-07321332 to be manufactured and sold in 95 countries.[26] Pfizer stated that the agreement will allow local medicine manufacturers to produce the pill “with the goal of facilitating greater access to the global population”. However, the deal excludes several countries with major COVID-19 outbreaks including Brazil, China, Russia, Argentina, and Thailand.[27][28]

On 16 November 2021, Pfizer submitted an application to the U.S. Food and Drug Administration (FDA) for emergency authorization for PF-07321332 in combination with ritonavir.[29][30][31]

Misleading comparison with ivermectin

Conspiracy theorists on the internet have claimed that Paxlovid is merely a “repackaged” version of the antiparasitic drug ivermectin, which has been erroneously promoted as a COVID-19 “miracle cure”. Their claims, sometimes using the nickname “Pfizermectin”,[32] are based on a narrative that Pfizer is suppressing the true benefits of ivermectin and rely on superficial correspondences between the drugs and a misunderstanding of their respective pharmacokinetics.[33] Paxlovid is not structurally related or similar to ivermectin, and while both are 3C-like protease inhibitors, Paxlovid is much more potent with an IC50 around 10,000 times lower, allowing for effective oral dosing within the therapeutic margin.[34]

References

  1. Jump up to:a b c Owen DR, Allerton CM, Anderson AS, Aschenbrenner L, Avery M, Berritt S, et al. (November 2021). “An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19″Science: eabl4784. doi:10.1126/science.abl4784PMID 34726479S2CID 240422219.
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  5. Jump up to:a b “Pfizer’s Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk Of Hospitalization Or Death By 89% In Interim Analysis Of Phase 2/3 EPIC-HR Study”. Pfizer Inc. 5 November 2021.
  6. ^ Mahase E (November 2021). “Covid-19: Pfizer’s paxlovid is 89% effective in patients at risk of serious illness, company reports”. BMJ375: n2713. doi:10.1136/bmj.n2713PMID 34750163S2CID 243834203.
  7. ^ Anand K, Ziebuhr J, Wadhwani P, Mesters JR, Hilgenfeld R (June 2003). “Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs”. Science300 (5626): 1763–1767. Bibcode:2003Sci…300.1763Adoi:10.1126/science.1085658PMID 12746549S2CID 13031405.
  8. ^ Dragovich PS, Prins TJ, Zhou R, Webber SE, Marakovits JT, Fuhrman SA, et al. (April 1999). “Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements”. Journal of Medicinal Chemistry42 (7): 1213–1224. doi:10.1021/jm9805384PMID 10197965.
  9. ^ Pillaiyar T, Manickam M, Namasivayam V, Hayashi Y, Jung SH (July 2016). “An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy”Journal of Medicinal Chemistry59 (14): 6595–6628. doi:10.1021/acs.jmedchem.5b01461PMC 7075650PMID 26878082.
  10. ^ Pedersen NC, Kim Y, Liu H, Galasiti Kankanamalage AC, Eckstrand C, Groutas WC, et al. (April 2018). “Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis”Journal of Feline Medicine and Surgery20 (4): 378–392. doi:10.1177/1098612X17729626PMC 5871025PMID 28901812.
  11. ^ Halford B (7 April 2021). “Pfizer unveils its oral SARS-CoV-2 inhibitor”Chemical & Engineering News99 (13): 7. doi:10.47287/cen-09913-scicon3S2CID 234887434.
  12. ^ Vuong W, Khan MB, Fischer C, Arutyunova E, Lamer T, Shields J, et al. (August 2020). “Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication”Nature Communications11 (1): 4282. doi:10.1038/s41467-020-18096-2PMC 7453019PMID 32855413.
  13. ^ Clinical trial number NCT04535167 for “First-In-Human Study To Evaluate Safety, Tolerability, And Pharmacokinetics Following Single Ascending And Multiple Ascending Doses of PF-07304814 In Hospitalized Participants With COVID-19 ” at ClinicalTrials.gov
  14. ^ Boras B, Jones RM, Anson BJ, Arenson D, Aschenbrenner L, Bakowski MA, et al. (February 2021). “Discovery of a Novel Inhibitor of Coronavirus 3CL Protease for the Potential Treatment of COVID-19”bioRxiv: 2020.09.12.293498. doi:10.1101/2020.09.12.293498PMC 7491518PMID 32935104.
  15. ^ Njoroge FG, Chen KX, Shih NY, Piwinski JJ (January 2008). “Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection”. Accounts of Chemical Research41 (1): 50–59. doi:10.1021/ar700109kPMID 18193821S2CID 2629035.
  16. ^ Nuki P (26 April 2021). “Pfizer is testing a pill that, if successful, could become first-ever home cure for COVID-19”National Post. Archived from the original on 27 April 2021.
  17. ^ “Pfizer begins dosing in Phase II/III trial of antiviral drug for Covid-19”Clinical Trials Arena. 2 September 2021.
  18. ^ Press release (14 December 2021). “Pfizer Announces Additional Phase 2/3 Study Results Confirming Robust Efficacy of Novel COVID-19 Oral Antiviral Treatment Candidate in Reducing Risk of Hospitalization or Death”.
  19. ^ Pavan M, Bolcato G, Bassani D, Sturlese M, Moro S (December 2021). “Supervised Molecular Dynamics (SuMD) Insights into the mechanism of action of SARS-CoV-2 main protease inhibitor PF-07321332”J Enzyme Inhib Med Chem36 (1): 1646–1650. doi:10.1080/14756366.2021.1954919PMC 8300928PMID 34289752.
  20. ^ Woodley M (19 October 2021). “What is Australia’s potential new COVID treatment?”The Royal Australian College of General Practitioners (RACGP). Retrieved 6 November 2021.
  21. ^ “Pfizer Covid pill ‘can cut hospitalisations and deaths by nearly 90%'”The Guardian. 5 November 2021. Retrieved 17 November 2021.
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  23. ^ “What are the two new COVID-19 treatments Australia has gained access to?”ABC News (Australia). 17 October 2021. Retrieved 5 November 2021.
  24. ^ “U.S. to Buy Enough of Pfizer’s Covid Antiviral Pills for 10 Million People”The New York Times. 17 November 2021. Retrieved 17 November 2021.
  25. ^ Pager T, McGinley L, Johnson CY, Taylor A, Parker C. “Biden administration to buy Pfizer antiviral pills for 10 million people, hoping to transform pandemic”The Washington Post. Retrieved 16 November 2021.
  26. ^ “Pfizer and The Medicines Patent Pool (MPP) Sign Licensing Agreement for COVID-19 Oral Antiviral Treatment Candidate to Expand Access in Low- and Middle-Income Countries” (Press release). Pfizer. 16 November 2021. Retrieved 17 November 2021 – via Business Wire.
  27. ^ “Covid-19: Pfizer to allow developing nations to make its treatment pill”BBC News. 16 November 2021. Archived from the original on 16 November 2021. Retrieved 17 November 2021.
  28. ^ “Pfizer Will Allow Its Covid Pill to Be Made and Sold Cheaply in Poor Countries”The New York Times. 16 November 2021. Retrieved 17 November 2021.
  29. ^ “Pfizer Seeks Emergency Use Authorization for Novel COVID-19 Oral Antiviral Candidate”Business Wire (Press release). 16 November 2021. Retrieved 17 November 2021.
  30. ^ Kimball S (16 November 2021). “Pfizer submits FDA application for emergency approval of Covid treatment pill”CNBC. Retrieved 17 November 2021.
  31. ^ Robbins R (5 November 2021). “Pfizer Says Its Antiviral Pill Is Highly Effective in Treating Covid”The New York TimesISSN 0362-4331. Archived from the original on 8 November 2021. Retrieved 9 November 2021.
  32. ^ Bloom J (2 December 2021). “How Does Pfizer’s Pavloxid Compare With Ivermectin?”. American Council on Science and Health. Retrieved 12 December 2021.
  33. ^ Gorski D (15 November 2021). “Pfizer’s new COVID-19 protease inhibitor drug is not just ‘repackaged ivermectin'”Science-Based Medicine.
  34. ^ von Csefalvay C (27 November 2021). “Why Paxlovid is not Pfizermectin”Bits and Bugs. Chris von Csefalvay. Retrieved 28 November 2021.

Pfizer to make COVID-19 pill available in low- and middle-income nations

If authorized by global health authorities, the drug promises to reduce deaths and hospitalizations linked to

the novel coronavirus.

By Brian Buntz | November 16, 2021FacebookTwitterLinkedInShare

In late October, Merck (NYSE:MRK) and its partner Ridgeback Biotherapeutics agreed to make the COVID-19 antiviral molnupiravir available in the developing world.

Now, Pfizer (NYSE:PFE) is taking a similar approach for its investigational antiviral cocktail Paxlovid, which contains PF-07321332 and ritonavir.

Pfizer, like Merck, struck an agreement with the Medicines Patent Pool (MPP) related to Paxlovid.

MPP’s mission is to expand low- and middle-income countries’ access to vital medicines. The United Nations supports the organization.

Pfizer announced earlier this month that Paxlovid was 89% effective in reducing the risk of hospitalization or death in an interim analysis of the Phase 2/3 EPIC-HR trial.

The collaboration with MPP will enable generic drug makers internationally with sub-licenses to produce Paxlovid for use in 95 countries, which comprise more than half of the world’s population.

“This license is so important because, if authorized or approved, this oral drug is particularly well-suited for low- and middle-income countries and could play a critical role in saving lives, contributing to global efforts to fight the current pandemic,” said Charles Gore, executive director of MPP, in a press release. “PF-07321332 is to be taken together with ritonavir, an HIV medicine we know well, as we have had a license on it for many years, and we will be working with generic companies to ensure there is enough supply for both COVID-19 and HIV.”

At present, MPP has signed agreements with ten patient holders for 13 HIV antiretrovirals and several other drugs.


Filed Under: clinical trialsDrug DiscoveryInfectious Disease
Tagged With: Medicines Patent PoolMerckPF-07321332PfizerRidgeback Biotherapeuticsritonavir

PFIZER INITIATES PHASE 1 STUDY OF NOVEL ORAL ANTIVIRAL THERAPEUTIC AGENT AGAINST SARS-COV-2

Tuesday, March 23, 2021 – 11:00am

  • In-vitro studies conducted to date show that the clinical candidate PF-07321332 is a potent protease inhibitor with potent anti-viral activity against SARS-CoV-2
  • This is the first orally administered coronavirus-specific investigational protease inhibitor to be evaluated in clinical studies, and follows Pfizer’s intravenously administered investigational protease inhibitor, which is currently being evaluated in a Phase 1b multi-dose study in hospitalized clinical trial participants with COVID-19

NEW YORK–(BUSINESS WIRE)– Pfizer Inc. (NYSE: PFE) announced today that it is progressing to multiple ascending doses after completing the dosing of single ascending doses in a Phase 1 study in healthy adults to evaluate the safety and tolerability of an investigational, novel oral antiviral therapeutic for SARS-CoV-2, the virus that causes COVID-19. This Phase 1 trial is being conducted in the United States. The oral antiviral clinical candidate PF-07321332, a SARS-CoV2-3CL protease inhibitor, has demonstrated potent in vitro anti-viral activity against SARS-CoV-2, as well as activity against other coronaviruses, suggesting potential for use in the treatment of COVID-19 as well as potential use to address future coronavirus threats.

“Tackling the COVID-19 pandemic requires both prevention via vaccine and targeted treatment for those who contract the virus. Given the way that SARS-CoV-2 is mutating and the continued global impact of COVID-19, it appears likely that it will be critical to have access to therapeutic options both now and beyond the pandemic,” said Mikael Dolsten, MD, PhD., Chief Scientific Officer and President, Worldwide Research, Development and Medical of Pfizer. “We have designed PF-07321332 as a potential oral therapy that could be prescribed at the first sign of infection, without requiring that patients are hospitalized or in critical care. At the same time, Pfizer’s intravenous antiviral candidate is a potential novel treatment option for hospitalized patients. Together, the two have the potential to create an end to end treatment paradigm that complements vaccination in cases where disease still occurs.”

Protease inhibitors bind to a viral enzyme (called a protease), preventing the virus from replicating in the cell. Protease inhibitors have been effective at treating other viral pathogens such as HIV and hepatitis C virus, both alone and in combination with other antivirals. Currently marketed therapeutics that target viral proteases are not generally associated with toxicity and as such, this class of molecules may potentially provide well-tolerated treatments against COVID-19.

The Phase 1 trial is a randomized, double-blind, sponsor-open, placebo-controlled, single- and multiple-dose escalation study in healthy adults evaluating the safety, tolerability and pharmacokinetics of PF-07321332.

Initiation of this study is supported by preclinical studies that demonstrated the antiviral activity of this potential first-in-class SARS-CoV-2 therapeutic designed specifically to inhibit replication of the SARS-CoV2 virus. The structure of PF-07321332, together with the pre-clinical data, will be shared in a COVID-19 session of the Spring American Chemical Society meeting on April 6.

Pfizer is also investigating an intravenously administered investigational protease inhibitor, PF-07304814, which is currently in a Phase 1b multi-dose trial in hospitalized clinical trial participants with COVID-19.

About Pfizer: Breakthroughs That Change Patients’ Lives

At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 170 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.Pfizer.com. In addition, to learn more, please visit us on www.Pfizer.com and follow us on Twitter at @Pfizer and @Pfizer NewsLinkedInYouTube and like us on Facebook at Facebook.com/Pfizer.

.CLIP

https://cen.acs.org/content/cen/articles/99/i13/Pfizer-unveils-oral-SARS-CoV.html

09913-scicon3-struct.jpg

Drugmaker Pfizer revealed its oral COVID-19 antiviral clinical candidate PF-07321332 on Tuesday at the American Chemical Society Spring 2021 meeting. The compound, which is currently in Phase 1 clinical trials, is the first orally administered compound in the clinic that targets the main protease (also called the 3CL protease) of SARS-CoV-2, the virus that causes COVID-19. By inhibiting the main protease, PF-07321332 prevents the virus from cleaving long protein chains into the parts it needs to reproduce itself. Dafydd Owen, director of medicinal chemistry at Pfizer, presented the compound in a symposium of the Division of Medicinal Chemistry.

Last year, Pfizer reported PF-07304814, a different small molecule inhibitor of SARS-CoV-2’s main protease. The work to develop that compound began during the 2002-2003 outbreak of SARS-CoV, severe acute respiratory syndrome. But that molecule can only be given intravenously, which limits its use to hospital settings.

Because PF-07321332 can be taken orally, as a pill or capsule, it could be given outside of hospitals if it proves to be safe and effective. People who have been exposed to SARS-CoV-2 could take it as a preventative measure, for example.

“For the foreseeable future, we will expect to see continued outbreaks from COVID-19. And therefore, as with all viral pandemics, it’s important we have a full toolbox on how to address it,” Charlotte Allerton, Pfizer’s head of medicine design, told C&EN.

PF-07321332 was developed from scratch during the current pandemic. It’s a reversible covalent inhibitor that reacts with one of the main protease’s cysteine residues. Owen also discussed the chemistry involved in scaling up the compound. The first 7 mg of the compound were synthesized in late July 2020. Encouraged by the early biological data, the Pfizer team aimed to scale up the synthesis. By late October, they’d made 100 g of the compound. Just two weeks later, the chemists had scaled up the synthesis to more than 1 kg. Owen said 210 researchers had worked on the project. Ana Martinez, who studies COVID-19 treatments at the Spanish National Research Council CSIC and also presented during the symposium, told C&EN that having a COVID-19 antiviral is of critical importance. She eagerly anticipates the safety and efficacy data from the trials of PF-07321332. “Hopefully we will have a new drug to fight against COVID-19,” Martinez said. And because the molecule targets the main protease, she said that it might be useful for fighting other coronaviruses and preventing future pandemics.Chemical & Engineering News

Clinical data
ATC codeNone
Identifiers
showIUPAC name
CAS Number2628280-40-8
PubChem CID155903259
UNII7R9A5P7H32
KEGGD12244
ChEBICHEBI:170007
Chemical and physical data
FormulaC23H32F3N5O4
Molar mass499.535 g·mol−1
3D model (JSmol)Interactive image
Melting point192.9[1] °C (379.2 °F)
showSMILES
showInChI

Xray crystal structure (PDB:7SI9 and 7VH8) of the SARS-CoV-2 protease inhibitor PF-07321332 bound to the viral 3CLpro (Mpro) protease enzyme. Ribbon diagram of the protein with the drug shown as sticks. The catalytic residues (His41, Cys145) are shown as yellow sticks.

 

./////////////////PF-07321332, PF 07321332, COVID 19, CORONA VIRUS, SARS-CoV-2 inhibitor, PHASE 1, nirmatrelvir, PAXLOVID, CORONA VIRUS, COVID 19

C1N(C([C@@H]2C1[C@]2(C)C)C(=O)N[C@@H](CC3C(NCC3)=O)C#N)C(C([C@@](C)(C)C)NC(=O)C(F)(F)F)=O

C1N(C(C2C1C2(C)C)C(=O)N[C@@H](CC3C(NCC3)=O)C#N)C(C([C@@](C)(C)C)NC(=O)C(F)(F)F)=O

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ABBV 744


ABBV-744 Chemical Structure

ABBV 744

N-Ethyl-4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(1-hydroxy-1-methylethyl)phenyl]-6,7-dihydro-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

1H-Pyrrolo[2,3-c]pyridine-2-carboxamide, N-ethyl-4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(1-hydroxy-1-methylethyl)phenyl]-6,7-dihydro-6-methyl-7-oxo-

Molecular Weight

491.55

Formula

C₂₈H₃₀FN₃O₄

CAS No.

2138861-99-9

ABBV-744 is a highly BDII-selective BET bromodomain inhibitor, used in the research of inflammatory diseases, cancer, and AIDS.

Acute Myeloid Leukemia (AML)

Phase I, AbbVie is evaluating oral agent ABBV-744 in early clinical trials for the treatment of metastatic castration resistant prostate cancer (CRPC) and for the treatment of relapsed or refractory acute myeloid leukemia (AML).

PATENT

WO 2017177955

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017177955&tab=FULLTEXT

Bromodomains refer to conserved protein structural folds which bind to N-acetylated lysine residues that are found in some proteins. The BET family of bromodomain containing proteins comprises four members (BRD2, BRD3, BRD4 and BRDt) . Each member of the BET family employs two bromodomains to recognize N-acetylated lysine residues typically, but not exclusively those found on transcription factors (Shi, J., et al. Cancer Cell 25 (2) : 210-225 (2014) ) or on the amino-terminal tails of histone proteins. Numbering from the N-terminal end of each BET protein the tandem bromodomains are typically labelled Binding Domain I (BDI) and Binding Domain II (BDII) . These interactions modulate gene expression by recruiting transcription factors to specific genome locations within chromatin. For example, histone-bound BRD4 recruits the transcription factor P-TEFb to promoters, resulting in the expression of a subset of genes involved in cell cycle progression (Yang et al., Mol. Cell. Biol. 28: 967-976 (2008) ) . BRD2 and BRD3 also function as transcriptional regulators of growth promoting genes (LeRoy et al., Mol. Cell 30: 51-60 (2008) ) . BET family members were recently established as being important for the maintenance of several cancer types (Zuber et al., Nature 478: 524-528 (2011) ; Mertz et al; Proc. Nat’l. Acad. Sci. 108: 16669-16674 (2011) ; Delmore et al., Cell 146: 1-14, (2011) ; Dawson et al., Nature 478: 529-533 (2011) ) . BET family members have also been implicated in mediating acute inflammatory responses through the canonical NF-KB pathway (Huang et al., Mol. Cell. Biol. 29: 1375-1387 (2009) ) resulting in the upregulation of genes associated with the production of cytokines (Nicodeme et al., Nature 468: 1119-1123, (2010) ) . Suppression of cytokine induction by BET bromodomain inhibitors has been shown to be an effective approach to treat inflammation-mediated kidney disease in an animal model (Zhang, et al., J. Biol. Chem. 287: 28840-28851 (2012) ) . BRD2 function has been linked to pre-disposition for dyslipidemia or improper regulation of adipogenesis, elevated inflammatory profiles and increased susceptibility to autoimmune diseases (Denis, Discovery Medicine 10: 489-499 (2010) ) . The human immunodeficiency virus utilizes BRD4 to initiate transcription of viral RNA from stably integrated viral DNA (Jang et al., Mol. Cell, 19: 523-534 (2005) ) . BET bromodomain inhibitors have also been shown to reactivate HIV transcription in models of latent T cell infection and latent monocyte infection (Banerjee, et al, J. Leukocyte Biol. doi: 10.1189/jlb. 0312165) . BRDt has an important role in spermatogenesis that is blocked by BET bromodomain inhibitors (Matzuk, et al., Cell 150: 673-684 (2012) ) . Thus, compounds that inhibit the binding of BET family bromodomains to their cognate acetylated lysine proteins are being pursued for the treatment of cancer, inflammatory diseases, kidney diseases, diseases involving metabolism or fat accumulation, and some viral infections, as well as for providing a method for male contraception. Accordingly, there is an ongoing medical need to develop new drugs to treat these indications.

FIDANZE, Steven D., et al. BROMODOMAIN INHIBITORS. WO 2017177955 A1.

////////////ABBV 744, Acute Myeloid Leukemia, AML,  Phase 1 , AbbVie

CC(O)(C)C1=CC(C(C2=C3NC(C(NCC)=O)=C2)=CN(C)C3=O)=C(OC4=C(C)C=C(F)C=C4C)C=C1

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