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ORGANIC SPECTROSCOPY

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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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LORPUCITINIB


Structure of LORPUCITINIB
Lorpucitinib Chemical Structure
Lorpucitinib.png

LORPUCITINIB

JNJ 64251330

2230282-02-5

UNII-OE1QTY7C25

Molecular Weight408.50
FormulaC22H28N6O2
1-(TRANS-4-(CYANOMETHYL)CYCLOHEXYL)-1,6-DIHYDRO-N-(2-HYDROXY-2-METHYLPROPYL)IMIDAZO(4,5-D)PYRROLO(2,3-B)PYRIDINE-2-ACETAMIDE

2-[3-[4-(cyanomethyl)cyclohexyl]-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaen-4-yl]-N-(2-hydroxy-2-methylpropyl)acetamide

is a Gut-Restricted JAK Inhibitor for the research of Inflammatory Bowel Disease.

Lorpucitinib is an orally bioavailable pan-inhibitor of the Janus associated-kinases (JAKs), with potential immunomodulatory and anti-inflammatory activities. Upon oral administration, lorpucitinib works in the gastrointestinal (GI) tract where it targets, binds to and inhibits the activity of the JAKs, thereby disrupting JAK-signal transducer and activator of transcription (STAT) signaling pathways and the phosphorylation of STAT proteins. This may inhibit the release of pro-inflammatory cytokines and chemokines, reducing inflammatory responses and preventing inflammation-induced damage. The Janus kinase family of non-receptor tyrosine kinases, which includes tyrosine-protein kinase JAK1 (Janus kinase 1; JAK1), tyrosine-protein kinase JAK2 (Janus kinase 2; JAK2), tyrosine-protein kinase JAK3 (Janus kinase 3; JAK3) and non-receptor tyrosine-protein kinase TYK2 (tyrosine kinase 2), plays a key role in cytokine signaling and inflammaton.

PATENT

WO2019239387

WO2018112379 

WO2018112382

PATENT

WO/2022/189496LORPUCITINIB FOR USE IN THE TREATMENT OF JAK MEDIATED DISORDERS

Example 1

[0117] 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide

Step A: 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide. To ensure dry starting material, ethyl 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate (Intermediate 3) was heated under vacuum at 50 °C for 18 h prior to the reaction. In a 1 L flask, ethyl 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate (Intermediate 3, 52.585 g, 104.01 mmol) was suspended in DMA (50 mL). 1-Amino-2-methylpropan-2-ol (50 mL) was added and the reaction was heated to 110 °C for 45 minutes, then to 125 °C for 5 hours. The reaction was cooled to room temperature and diluted with EtOAc (800 mL). The organic layer was extracted three times with a solution of water/ brine wherein the solution was made up of 1 L water plus 50 mL brine. The aqueous layers were back extracted with EtOAc (2 × 600 mL). The combined organic layers were dried over anhydrous MgSO4,

concentrated to dryness, and then dried for 3 days under vacuum to provide the title compound (65.9 g, 98% yield) as a yellow foam. The product was taken to the next step with no further purification. MS (ESI): mass calcd. for C28H32N6O4S, 548.22; m/z found, 549.2 [M+H]+.1H NMR (400 MHz, CDCl3): δ 8.76 (s, 1H), 8.26 – 8.19 (m, 2H), 7.84 (d, J = 4.1 Hz, 1H), 7.60 – 7.53 (m, 1H), 7.50 – 7.44 (m, 2H), 6.84 (d, J = 4.2 Hz, 1H), 4.76 – 4.61 (m, 1H), 3.97 (s, 2H), 3.45 (s, 1H), 3.27 (d, J = 5.9 Hz, 2H), 2.41 (d, J = 6.5 Hz, 2H), 2.38 – 2.25 (m, 2H), 2.23 – 2.12 (m, 2H), 2.09 -1.94 (m, 4H), 1.48 (qd, J = 13.6, 4.0 Hz, 2H), 1.21 (s, 6H).

[0118] Step B: 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide. 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide (65.90 g, 102.1 mmol) was added to a 1 L flask containing a stir bar. 1,4-dioxane (300 mL) was added, followed by aq KOH (3 M, 150 mL). The reaction was heated at 80 °C for 2 h. The reaction was cooled to room temperature and the solvent volume was reduced to about 200 mL on a rotovap. The residue was treated with a solution of water/brine (100 mL/100mL), then extracted with 10% MeOH in CH2Cl2 (2 x 1L). The organic layers were combined, dried over anhydrous MgSO4, and concentrated to dryness to provide a yellow solid. The solid was suspended in CH2Cl2 (200 mL), stirred vigorously for 30 minutes, and then collected by filtration. The solid was rinsed with CH2Cl2 (100 mL), dried by pulling air through the filter, and then further dried under vacuum at room temperature for 16 h to provide the title compound (41.59 g, 89% yield) as a white solid. MS (ESI): mass calcd. for C22H28N6O2, 408.23; m/z found, 409.2 [M+H]+1H NMR (600 MHz, DMSO-d6): δ 11.85 (s, 1H), 8.50 (s, 1H), 8.21 – 8.10 (m, 1H), 7.49 – 7.43 (m, 1H), 6.74 – 6.65 (m, 1H), 4.53 – 4.42 (m, 2H), 4.07 (s, 2H), 3.08 (d, J = 6.0 Hz, 2H), 2.58 (d, J = 6.1 Hz, 2H), 2.41 – 2.28 (m, 2H), 2.09 – 1.92 (m, 5H), 1.42 – 1.31 (m, 2H), 1.09 (s, 6H). The synthesis and active compound characterization of each of the aspects of this invention are provided herein in the form of examples. Due to the crystal structure of some of the aspects of this invention, polymorph screening may be pursued to further characterize specific forms of any such compound. This is illustrated in a non-limiting manner for compound of Formula I by the example under the heading polymorph screening.

[0119] The following compounds were prepared in reference to the foregoing synthesis:

Intermediate 1

[0120] 2-((1r,4r)-4-((5-Nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile

[0121] Step A: tert-butyl N-[(1r,4r)-4-(Hydroxymethyl)cyclohexyl]carbamate. To a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed (1r,4r)-4-[[(tert-butoxy)carbonyl]amino]cyclohexane-1-carboxylic acid (1066 g, 4.38 mol, 1.00 equiv) and THF (10 L). This was followed by the dropwise addition of BH3-Me2S (10 M, 660 mL) at -10 °C over 1 h. The resulting solution was stirred for 3 h at 15 °C. This reaction was performed three times in parallel and the reaction mixtures were combined. The reaction was then quenched by the addition of methanol (2 L). The resulting mixture was concentrated under vacuum. This resulted in of tert-butyl N-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]carbamate (3000 g, 99.6%) as a white solid. MS (ESI): mass calcd. for C12H23NO3, 229.32; m/z found, 215.2 [M-tBu+MeCN+H]+1H NMR: (300 MHz, CDCl3): δ 4.40 (s, 1H), 3.45 (d, J = 6.3 Hz, 2H), 3.38 (s, 1H), 2.05-2.02 (m, 2H), 1.84-1.81 (m, 2H), 1.44 (s, 11H), 1.17-1.01 (m, 4H).

[0122] Step B: tert-butyl N-[(1r,4r)-4-[(Methanesulfonyloxy)methyl]cyclohexyl]carbamate. To a 20 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]carbamate (1000 g, 4.36 mol, 1.00 equiv.), dichloromethane (10 L), pyridine (1380 g, 17.5 mol, 4.00 equiv.). This was followed by the dropwise addition of MsCl (1000 g, 8.73 mol, 2.00 equiv.) at -15 °C. The resulting solution was stirred overnight at 25 °C. This reaction was performed in parallel for 3 times and the reaction mixtures were combined. The reaction was then quenched by the addition of 2 L of water. The

water phase was extracted with ethyl acetate (1 x 9 L). The organic layer was separated and washed with 1 M HCl (3 x 10 L), NaHCO3 (saturated aq.) (2 x 10 L), water (1 x 10 L) and brine (1 x 10 L). The mixture was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. This resulted in of tert-butyl N-[(1r,4r)-4-[(methanesulfonyloxy)methyl]cyclohexyl]carbamate (3300 g, 82%) as a white solid. LC-MS: MS (ESI): mass calcd. for C13H25NO5S, 307.15; m/z found 292.1, [M-tBu+MeCN+H]+1H NMR: (300 MHz, CDCl3): δ 4.03 (d, J = 6.6 Hz, 2H), 3.38 (s, 1H), 3.00 (s, 3H), 2.07-2.05 (m, 2H), 1.87-1.84 (m, 2H), 1.72-1.69 (m, 1H), 1.44 (s, 9H), 1.19-1.04 (m, 4H).

[0123] Step C: tert-butyl N-[(1r,4r)-4-(Cyanomethyl)cyclohexyl]carbamate. To a 10 L 4-necked round-bottom flask, was placed tert-butyl N-[(1r,4r)-4-[(methanesulfonyloxy)methyl]cyclohexyl]carbamate (1100 g, 3.58 mol, 1.00 equiv.), DMSO (5500 mL) and NaCN (406 g, 8.29 mol, 2.30 equiv.). The resulting mixture was stirred for 5 h at 90 °C. This reaction was performed in parallel 3 times and the reaction mixtures were combined. The reaction was then quenched by the addition of 15 L of water/ice. The solids were collected by filtration. The solids were washed with water (3 x 10 L). This resulted in tert-butyl N-[(1r,4r)-4-(cyanomethyl)cyclohexyl]carbamate (2480 g, 97%) as a white solid. MS (ESI): mass calcd. for C13H22N2O2, 238.17; m/z found 224 [M-tBu+MeCN+H]+1H NMR: (300 MHz, CDCl3): δ 4.39 (s, 1H), 3.38 (s, 1H), 2.26 (d, J = 6.9 Hz, 2H), 2.08-2.04 (m, 2H), 1.92-1.88 (m, 2H), 1.67-1.61 (m, 1H), 1.44 (s, 9H), 1.26-1.06 (m, 4H).

[0124] Step D: 2-[(1r,4r)-4-Aminocyclohexyl]acetonitrile hydrochloride. To a 10-L round-bottom flask was placed tert-butyl N-[(1r,4r)-4-(cyanomethyl)cyclohexyl]carbamate (620 g, 2.60 mol, 1.00 equiv.), and 1,4-dioxane (2 L). This was followed by the addition of a solution of HCl in 1,4-dioxane (5 L, 4 M) dropwise with stirring at 10 °C. The resulting solution was stirred overnight at 25 °C. This reaction was performed for 4 times and the reaction mixtures were combined. The solids were collected by filtration. The solids were washed with 1,4-dioxane (3 x 3 L), ethyl acetate (3 x 3 L) and hexane (3 x 3 L). This resulted in 2-[(1r,4r)-4-aminocyclohexyl]acetonitrile hydrochloride (1753 g, 96%) as a white solid. MS (ESI): mass calcd. for C8H14N2, 138.12; m/z found 139.25, [M+H]+1H NMR: (300 MHz, DMSO-d6): δ 8.14 (s, 3H), 2.96-2.84 (m, 1H), 2.46 (d, J = 6.3 Hz, 2H), 1.98 (d, J = 11.1 Hz, 2H), 1.79 (d, J = 12.0 Hz, 2H), 1.64-1.49 (m, 1H), 1.42-1.29 (m, 2H), 1.18-1.04 (m, 2H).

[0125] Step E: 2-((1r,4r)-4-((5-Nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile. To a 1000 mL round bottom flask containing 2-[(1r,4r)-4-aminocyclohexyl]acetonitrile hydrochloride (29.10 g, 166.6 mmol) was added DMA (400 mL). The resulting suspension was treated with 4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (51.53 g, 152.6 mmol), followed by DIPEA (63.0 mL, 366 mmol). The reaction mixture was placed under N2 and heated at 80 °C for 4 h. The crude reaction mixture was cooled to room temperature and slowly poured into a vigorously stirred 2 L flask containing 1.6 L water. The resulting suspension was stirred for 15 minutes at room temperature, then filtered and dried for 16 h in a vacuum oven with heating at 70 °C to provide the title compound (63.37 g, 95%) as a yellow solid. MS (ESI): mass calcd. for C21H21N5O4S, 439.1; m/z found, 440.1 [M+H]+1H NMR (500 MHz, CDCl3): δ 9.10 (s, 1H), 8.99 (d, J = 7.8 Hz, 1H), 8.23 – 8.15 (m, 2H), 7.66 – 7.59 (m, 2H), 7.56 – 7.49 (m, 2H), 6.67 (d, J = 4.2 Hz, 1H), 3.95 – 3.79 (m, 1H), 2.38 (d, J = 6.2 Hz, 2H), 2.32 -2.21 (m, 2H), 2.08 – 1.98 (m, 2H), 1.88 – 1.76 (m, 1H), 1.60 – 1.32 (m, 4H).

Intermediate 2

[0126] 2-((1r,4r)-4-((5-Amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile

[0127] 2-((1r,4r)-4-((5-Nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1, 58.60 g, 133.3 mmol) was dissolved in THF/MeOH (1:1, 4800 mL). The mixture was passed through a continuous-flow hydrogenation reactor (10% Pd/C), such as a Thales Nano H-Cube®, at 10 mL/min with 100 % hydrogen (atmospheric pressure, 80 °C), then the solution was concentrated to provide the product as a purple solid. The solid was triturated with EtOAc (400 mL) and then triturated again with MeOH (200 mL) then filtered and dried under vacuum to provide the title compound (50.2 g, 91.9% yield).

MS (ESI): mass calcd. for C21H23N5O2S, 409.2; m/z found, 410.2 [M+H]+1H NMR (400 MHz, CDCl3) δ 8.10 – 8.03 (m, 2H), 7.76 (s, 1H), 7.51 – 7.43 (m, 1H), 7.43 – 7.34 (m, 3H), 6.44 (d, J = 4.2 Hz, 1H), 4.61 (d, J = 8.5 Hz, 1H), 3.65 – 3.51 (m, 1H), 2.74 (s, 2H), 2.26 (d, J = 6.4 Hz, 2H), 2.19 – 2.05 (m, 2H), 1.97 – 1.86 (m, 2H), 1.76 – 1.59 (m, 1H), 1.33 – 1.12 (m, 4H).

Intermediate 3

[0128] Ethyl 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate

[0129] To a 1L round bottom flask containing a stir bar and 2-((1r,4r)-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 2, 58.31 g, 142.4 mmol) was added ethyl 3-ethoxy-3-iminopropanoate (60.51 g, 309.3 mmol), followed by EtOH (600 mL, dried over 3Å molecular sieves for 48 h). A reflux condenser was attached to the reaction flask, the reaction was purged with N2, and was heated at 90 °C for 9 h. The reaction mixture was cooled to room temperature and left to stand for 30 h where the product crystallized out as brown needles. The solids were broken up with a spatula and the reaction mixture was transferred to a 2 L flask. Water (1.4 L) was added slowly via separatory funnel with vigorous stirring. After addition of the water was complete, the suspension was stirred for 30 minutes. The brown needles were isolated by filtration and then dried by pulling air through the filter for 1 h. The product was transferred to a 500 mL flask and treated with EtOAc (200 mL). A small quantity of seed crystals were added, which induced the formation of a white solid precipitate. The suspension was stirred for 30 minutes at room temperature, filtered, rinsed with EtOAc (25 mL), and dried under vacuum to provide the product as a white solid (48.65 g, 68% yield). MS (ESI): mass calcd. for C26H27N5O4S, 505.2; m/z found, 506.2 [M+H]+1H NMR (400

MHz, CDCl3) δ 8.85 (s, 1H), 8.28 – 8.19 (m, 2H), 7.84 (d, J = 4.0 Hz, 1H), 7.61 – 7.53 (m, 1H), 7.52 – 7.43 (m, 2H), 6.84 (d, J = 4.1 Hz, 1H), 4.32 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.09 (s, 2H), 2.44 (d, J = 6.2 Hz, 2H), 2.40 – 2.27 (m, 2H), 2.16 (d, J = 13.3 Hz, 2H), 2.12 – 1.96 (m, 3H), 1.54 – 1.38 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H).

Polymorph screening example

[0130] Some embodiments of compound of Formula I as free bases present multiple crystalline configurations that have a complex solid-state behavior, some of which in turn can present distinguishing features among themselves due to different amounts of incorporated solvent. Some embodiments of compound of Formula I are in the form of pseudopolymorphs, which are embodiments of the same compound that present crystal lattice compositional differences due to different amounts of solvent in the crystal lattice itself. In addition, channel solvation can also be present in some crystalline embodiments of compound of Formula I, in which solvent is incorporated within channels or voids that are present in the crystal lattice. For example, the various crystalline configurations given in Table 2 were found for compound of Formula I. Because of these features, non-stoichiometric solvates were often observed, as illustrated in Table 2. Furthermore, the presence of such channels or voids in the crystal structure of some embodiments according to this invention enables the presence of water and/or solvent molecules that are held within the crystal structure with varying degrees of bonding strength. Consequently, changes in the specific ambient conditions can readily lead to some loss or gain of water molecules and/or solvent molecules in some embodiments according to this invention. It is understood that “solvation” (third column in Table 2) for each of the embodiments listed in Table 2 is the formula solvation, and that the actual determination of the same as a stoichiometry number (fourth column in Table 2) can slightly vary from the formula solvation depending on the actual ambient conditions when it is experimentally determined. For example, if about half of the water molecules in an embodiment may be present as hydrogen-bonded to the active compound in the crystal lattice, while about the other half of water molecules may be in channels or voids in the crystal lattice, then changes in ambient conditions may alter the amount of such loosely contained water molecules in voids or channels, and hence lead to a slight difference between the formula solvation that is assigned according to, for example, single crystal diffraction, and the

stoichiometry that is determined by, for example, thermogravimetric analysis coupled with mass spectroscopy.

Table 2. Embodiments of crystalline forms of compound of Formula I

[0131] The compound that was obtained as described in Example 1 was further crystallized by preparing a slurry in DCM (1:3, for example 10 g of compound in 30 ml DCM) that was stirred at 40oC for 4 hours, and further stirred for 14 hours at 25oC, then heptane was slowly added (1:2, for example 20 ml of heptane into the compound/DCM slurry/solution) at 25oC, stirred at 40oC for 4 hours, cooled to 25oC and stirred for further 14 hours at 25oC. Subsequent filtration led to compound of Formula I in the form of an off-white solid, that was identified as a monohydrate, a 1s embodiment.

CLIP

Journal of Medicinal Chemistry (2020), 63(6), 2915-2929

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https://clinicaltrials.gov/ct2/show/NCT04552197

The purpose of this study is to evaluate: systemic and local gut (rectum and sigmoid colon) exposure to JNJ-64251330, local tissue Pharmacodynamics (PD) using gut (rectum and sigmoid colon) biopsies (Part 1) and the effect of food on the rate and extent of absorption of JNJ-64251330 from oral tablet dosed with or without food (Part 2).

Familial adenomatous polyposis (FAP) is the most common polyposis syndrome. It is an autosomal dominant inherited disorder characterized by the early onset of hundreds to thousands of adenomatous polyps throughout the colon. JNJ-64251330 (lorpucitinib) is an oral, small molecule, potent pan-janus kinase (JAK) inhibitor that blocks phosphorylation of Signal Transducer and Activator of Transcription (STAT) proteins. pSTAT induces transcription of multiple genes involved in the progression of inflammatory disease. JNJ-64251330 has chemical properties that limits the amount of drug in the blood while delivering the drug to the tissues of the gut. Local inhibition of JAK in the gut may present a promising method to treat inflammatory diseases of the intestinal tract, such as FAP. The study consists of 3 phases: screening phase (30 days) a treatment phase (24 weeks), and follow-up visit (up to 30 days after last dose of study drug). The total duration of the study will be up to 32 weeks. Study evaluations will include efficacy via endoscopies, safety (monitoring of adverse events (AE), serious adverse events (SAEs), events of infections including tuberculosis (TB), clinical laboratory blood tests (complete blood count and serum chemistries), vital signs, and concomitant medication review), pharmacokinetics, pharmacodynamic and biomarkers evaluations.

Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the APC gene.[4] The APC protein is a negative regulator that controls beta-catenin concentrations and interacts with E-cadherin, which are involved in cell adhesion. Mutations in the APC gene may result in colorectal cancer.[5]

APC is classified as a tumor suppressor gene. Tumor suppressor genes prevent the uncontrolled growth of cells that may result in cancerous tumors. The protein made by the APC gene plays a critical role in several cellular processes that determine whether a cell may develop into a tumor. The APC protein helps control how often a cell divides, how it attaches to other cells within a tissue, how the cell polarizes and the morphogenesis of the 3D structures,[6] or whether a cell moves within or away from tissue. This protein also helps ensure that the chromosome number in cells produced through cell division is correct. The APC protein accomplishes these tasks mainly through association with other proteins, especially those that are involved in cell attachment and signaling. The activity of one protein in particular, beta-catenin, is controlled by the APC protein (see: Wnt signaling pathway). Regulation of beta-catenin prevents genes that stimulate cell division from being turned on too often and prevents cell overgrowth.

The human APC gene is located on the long (q) arm of chromosome 5 in band q22.2 (5q22.2). The APC gene has been shown to contain an internal ribosome entry siteAPC orthologs[7] have also been identified in all mammals for which complete genome data are available.

////////////////JNJ-64251330, JNJ 64251330, LORPUCITINIB, PHASE 1, CANCER, Adenomatous Polyposis Coli

O=C(NCC(C)(O)C)CC1=NC2=CN=C(NC=C3)C3=C2N1[C@H]4CC[C@H](CC#N)CC4

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NEW DRUG APPROVALS

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Camizestrant, AZD 9833


img
Unii-jup57A8epz.png

Camizestrant, AZD 9833

AZ 14066724

PHASE 2

CAS: 2222844-89-3
Chemical Formula: C24H28F4N6
Exact Mass: 476.2312
Molecular Weight: 476.5236
Elemental Analysis: C, 60.49; H, 5.92; F, 15.95; N, 17.64

 N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine

  • AZ14066724
  • AZD-9833
  • AZD9833
  • Camizestrant
  • UNII-JUP57A8EPZ
  • WHO 11592
  • OriginatorAstraZeneca
  • ClassAmines; Antineoplastics; Azetidines; Fluorinated hydrocarbons; Isoquinolines; Pyrazolones; Pyridines; Small molecules
  • Mechanism of ActionSelective estrogen receptor degraders
  • Phase IIIBreast cancer
  • 13 Jun 2022AstraZeneca initiates a phase I drug-drug interaction trial of AZD 9833 Healthy postmenopausal female volunteers, in USA (NCT05438303)
  • 10 Jun 2022AstraZeneca and Quotient Sciences complete the phase I QSC205863 trial in Breast cancer (In volunteers) in United Kingdom (PO, Liquid) (NCT05364255)
  • 03 Jun 2022Safety, efficacy and pharmacokinetics data from the phase I SERENA 1 trial for Breast cancer presented at the 58th Annual Meeting of the American Society of Clinical Oncology (ASCO-2022)
  • Mechanism:selective estrogen receptor degrader
  • Area under investigation:estrogen receptor +ve breast cancer
  • Date commenced phase:Q1 2019
  • Estimated Filing Acceptance:
  • CountryDateUS: EU: Japan: China:

AZD9833 is an orally available selective estrogen receptor degrader (SERD), with potential antineoplastic activity. Upon administration, SERD AZD9833 binds to the estrogen receptor (ER) and induces a conformational change that results in the degradation of the receptor. This prevents ER-mediated signaling and inhibits the growth and survival of ER-expressing cancer cells

Camizestrant is an orally available selective estrogen receptor degrader (SERD), with potential antineoplastic activity. Upon administration, camizestrant binds to the estrogen receptor (ER) and induces a conformational change that results in the degradation of the receptor. This prevents ER-mediated signaling and inhibits the growth and survival of ER-expressing cancer cells

SYN

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0040-1719368

Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist J. Med. Chem. 2020, 63, 14530–14559, DOI: 10.1021/acs.jmedchem.0c01163.

SYN

doi: 10.1021/acs.jmedchem.0c01163.

aReagents and Conditions: (a) n-BuLi, THF, −78 oC to 0 oC, 1 h, then 4 N HCl/dioxane, RT, 1 h, 60%; (b) alkyl triflate, DIPEA, 1,4-dioxane, 90 oC, 63-74% or isobutyrylaldehyde, Na(OAc)3BH, THF, 0 oC, 56%; (c) benzophenone imine, Pd2dba3, Rac-BINAP, NaOtBu, toluene, 90 oC, then 1 N aq. HCl, 71-85%; (d) nBuLi, THF, −78 oC to 0 oC, 1 h, then 4 N HCl/dioxane, RT, 4 h; e) NH2OH, NH2OH.HCl, EtOH, reflux. 84% over 2 steps; (f) alkyl triflate, DIPEA, 1,4-dioxane, 90 oC, 44-100% or 1-fluorocyclopropane-1- carboxylic acid, HATU, Et3N, DMF, RT, 61%, then BH3.THF, THF, 65 oC, 82%.

[α]26 D -147 (c 2.3, MeOH); 1H NMR (500 MHz, DMSO-d6, 27 °C) 1.08 (d, J = 6.6 Hz, 3H), 1.64 (dp, J = 25.0, 6.3 Hz, 2H), 2.45 (t, J = 6.9 Hz, 2H), 2.73(t, J = 6.8 Hz, 2H), 2.84 (dd, J = 17.1, 8.2 Hz, 1H), 2.96 (dt, J = 19.6, 9.8 Hz, 1H), 3.07 (dd, J = 17.2, 4.6 Hz, 1H), 3.49 (m, 1H), 3.50 – 3.58 (m, 1H), 3.58 – 3.66 (m, 2H), 3.92 (h, J = 6.5 Hz, 1H), 4.44 (dtd, J = 47.4, 6.1, 1.3 Hz, 2H), 4.93 (s, 1H), 6.23 (d, J = 6.9 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 6.83 (dt, J = 8.8, 2.0 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 1.3 Hz, 1H), 12.97 (s, 1H); 13C NMR (125 MHz, DMSO-d6, 27 °C) 16.2, 28.2 (d, J = 19.4 Hz), 30.1, 43.0, 47.3, 48.7 (q, J = 30.1 Hz), 54.8 (d, J = 5.6 Hz), 61.3 (2C), 67.1, 82.0 (d, J = 161.3 Hz), 107.5, 119.0, 122.4, 123.7, 126.1, 126.2 (q, J = 278.5 Hz), 126.4, 127.5, 131.7, 132.9, 138.5, 142.3, 150.0; 19F NMR (376 MHz, DMSO-d6, 27 °C) -218.1 (1F), -69.7 (3F); m/z (ES+), [M+H]+ = 477, HRMS (ESI) (MH+ ); calcd, 477.2408; found, 477.2390

/////////

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AZD9833 is selective oestrogen receptor degrader (SERD). It works by breaking down the site where oestrogen attaches to the cancer cell. This can help stop or slow the growth of hormone receptor breast cancer. Researchers think that AZD9833 with palbociclib might work better than anastrozole and palbociclib.

AZD9833 + palbociclib

The patients will receive AZD9833 (75 mg, PO, once daily) + palbociclib (PO, once daily, 125 mg for 21 consecutive days followed by 7 days off treatment) + anastrozole placebo (1 mg, PO, once daily)

SERENA-1: Study of AZD9833 Alone or in Combination in Women With Advanced Breast Cancer. (clinicaltrials.gov)…..https://veri.larvol.com/news/azd9833/drug

P1, N=305, Recruiting, AstraZeneca | Trial primary completion date: Dec 2022 –> Oct 2023

2 months ago

Trial primary completion date

|

HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)

|

HER-2 negative

Ibrance (palbociclib) • everolimus • Verzenio (abemaciclib) • capivasertib (AZD5363) • camizestrant (AZD9833)

DescriptionCamizestrant (AZD-9833) is a potent and orally active estrogen receptor (ER) antagonist. Camizestrant is used for the study of ER+ HER2-advanced breast cancer[1].
IC50 & TargetIC50: estrogen receptor (ER)[1]
In VitroCamizestrant is extracted from patent US20180111931A1, example 17[1].MCE has not independently confirmed the accuracy of these methods. They are for reference only.
In VivoCamizestrant (oral administration; 0.2-50 mg/kg; 20 days) exhibits anti-tumour efficacy as a dose-dependent manner in human parental MCF7 mice xenograft[1].
Camizestrant (oral administration; 0.8-40 mg/kg; 30 days) decreases tumor growth as a dose-dependent manner. It gives almost complete tumour growth inhibition at the doses >10 mg/kg in mice[1].
MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Model:Human ESR1 mutant breast cancer patient derived xenograft with CTC174 cells in female NSG mice[1]Dosage:0.8 mg/kg, 3 mg/kg, 10 mg/kg, 20 mg/kg, 40 mg/kgAdministration:Oral administration; 30 days; once dailyResult:Inhibited tumor growth in a dose-dependent manner.
Clinical TrialNCT NumberSponsorConditionStart DatePhaseNCT04711252AstraZenecaER-Positive HER2-Negative Breast CancerJanuary 28, 2021Phase 3NCT04964934AstraZenecaER-Positive HER2-Negative Breast CancerJune 30, 2021Phase 3NCT04214288AstraZenecaAdvanced ER-Positive HER2-Negative Breast CancerApril 22, 2020Phase 2NCT04588298AstraZenecaHER2-negative Breast CancerNovember 2, 2020Phase 2NCT04541433AstraZenecaER&addition; HER2- Advanced Breast CancerSeptember 29, 2020Phase 1NCT03616587AstraZenecaER&addition; HER2- Advanced Breast CancerOctober 11, 2018Phase 1NCT04546347AstraZeneca|Quotient SciencesHealthy VolunteersSeptember 17, 2020Phase 1NCT04818632AstraZenecaER&addition;, HER2-, Metastatic Breast CancerOctober 11, 2021Phase 1

////////////Camizestrant, AZD 9833, AZ 14066724, UNII-JUP57A8EPZ, WHO 11592, PHASE 2, ASTRA ZENECA, CANCER

C[C@@H]1CC2=C3C(NN=C3)=CC=C2[C@@H](C4=NC=C(NC5CN(CCCF)C5)C=C4)N1CC(F)(F)F

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GEMCITABINE


Gemcitabine.svg

GEMCITABINE

95058-81-4

WeightAverage: 263.1981
Monoisotopic: 263.071762265

Chemical FormulaC9H11F2N3O4

4-amino-1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one

Product Ingredients

INGREDIENTUNIICASINCHI KEY
Gemcitabine hydrochlorideU347PV74IL122111-03-9OKKDEIYWILRZIA-OSZBKLCCSA-N
  • LY-188011
  • LY188011

Gemcitabine

CAS Registry Number: 95058-81-4

CAS Name: 2¢-Deoxy-2¢,2¢-difluorocytidine

Additional Names: 1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose; dFdC; dFdCyd

Manufacturers’ Codes: LY-188011

Trademarks: Gemzar (Lilly)

Molecular Formula: C9H11F2N3O4

Molecular Weight: 263.20

Percent Composition: C 41.07%, H 4.21%, F 14.44%, N 15.97%, O 24.32%

Literature References: Prepn: L. W. Hertel, GB2136425idem,US4808614 (1984, 1989 both to Lilly); L. W. Hertel et al.,J. Org. Chem.53, 2406 (1988); T. S. Chou et al.,Synthesis1992, 565. Antitumor activity: L. W. Hertel et al.,Cancer Res.50, 4417 (1990). Mode of action study: V. W. T. Ruiz et al.,Biochem. Pharmacol.46, 762 (1993). Clinical pharmacokinetics and toxicity: J. L. Abbruzzese et al.,J. Clin. Oncol.9, 491 (1991). Review of clinical studies: B. Lund et al.,Cancer Treat. Rev.19, 45-55 (1993).

Properties: Crystals from water, pH 8.5. [a]365 +425.36°; [a]D +71.51° (c = 0.96 in methanol). uv max (ethanol): 234, 268 (e 7810, 8560). LD10 i.v. in rats: 200 mg/m2 (Abbruzzese).

Optical Rotation: [a]365 +425.36°; [a]D +71.51°

Absorption maximum: uv max (ethanol): 234, 268 (e 7810, 8560)

Toxicity data: LD10 i.v. in rats: 200 mg/m2 (Abbruzzese)

Derivative Type: Hydrochloride

CAS Registry Number: 122111-03-9

Molecular Formula: C9H11F2N3O4.HCl

Molecular Weight: 299.66

Percent Composition: C 36.07%, H 4.04%, F 12.68%, N 14.02%, O 21.36%, Cl 11.83%

Properties: Crystals from water-acetone, mp 287-292° (dec). [a]D +48°; [a]365 +257.9° (c = 1.0 in deuterated water). uv max (water): 232, 268 nm (e 7960, 9360).

Melting point: mp 287-292° (dec)

Optical Rotation: [a]D +48°; [a]365 +257.9° (c = 1.0 in deuterated water)

Absorption maximum: uv max (water): 232, 268 nm (e 7960, 9360)

Therap-Cat: Antineoplastic.

Keywords: Antineoplastic; Antimetabolites; Pyrimidine Analogs.

Gemcitabine is a nucleoside metabolic inhibitor used as adjunct therapy in the treatment of certain types of ovarian cancer, non-small cell lung carcinoma, metastatic breast cancer, and as a single agent for pancreatic cancer.

Gemcitabine hydrochloride was first approved in ZA on Jan 10, 1995, then approved by the U.S. Food and Drug Administration (FDA) on May 15, 1996, and approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on Aug 31, 2001. It was developed and marketed as Gemzar® by Eli Lilly.

Gemcitabine hydrochloride is a nucleoside metabolic inhibitor. It kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary. It is indicated for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy, in combination with paclitaxel, for first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated, and it is also indicated in combination with cisplatin for the treatment of non-small cell lung cancer, and treated as a single agent for the treatment of pancreatic cancer.

Gemzar® is available as injection of lyophilized powder for intravenous use, containing 200 mg or 1000 mg of free Gemcitabine per vial. The recommended initial dosage is 1000 mg/m2 over 30 minutes on days 1 and 8 of each 21 day cycle for ovarian cancer, 1250 mg/m2 over 30 minutes on days 1 and 8 of each 21 day cycle for breast cancer, 1000 mg/m2 over 30 minutes on days 1, 8, and 15 of each 28 day cycle or 1250 mg/m2 over 30 minutes on days 1 and 8 of each 21 day cycle for non-small cell lung cancer, and 1000 mg/m2 over 30 minutes once weekly for the first 7 weeks, then one week rest, then once weekly for 3 weeks of each 28 day cycle for pancreatic cancer.

Approved Countries or AreaUpdate US, JP, CN, ZA

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
1996-05-15First approvalGemzarOvarian cancer,Breast cancer,Non small cell lung cancer (NSCLC),Pancreatic cancerInjection, Lyophilized powder, For solutionEq. 200 mg/1000 mg Gemcitabine/vialLillyPriority

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2013-02-01New indicationGemzarRelapsed or refractory malignant lymphomaInjection, Lyophilized powder, For solution200 mg; 1 gLilly 
2011-02-23New indicationGemzarAdvanced ovarian cancerInjection, Lyophilized powder, For solution200 mg; 1 gLilly 
2010-02-05New indicationGemzarAdvanced breast cancerInjection, Lyophilized powder, For solution200 mg; 1 gLilly 
2008-11-25New indicationGemzarUrothelial cancerInjection, Lyophilized powder, For solution200 mg; 1 gLilly 
2006-06-15New indicationGemzarBiliary cancerInjection, Lyophilized powder, For solution200 mg; 1 gLilly 
2001-08-31First approvalGemzarPancreatic cancer,Non small cell lung cancer (NSCLC)Injection, Lyophilized powder, For suspension200 mg; 1 gLilly 

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2014-04-15Marketing approval Ovarian cancer,Breast cancer,Non small cell lung cancer (NSCLC),Pancreatic cancerInjectionEq. 1000 mg Gemcitabine per vial湖北一半天制药 
2014-04-15Marketing approval Ovarian cancer,Breast cancer,Non small cell lung cancer (NSCLC),Pancreatic cancerInjectionEq. 200 mg Gemcitabine per vial湖北一半天制药6类
2014-04-08Marketing approval Ovarian cancer,Breast cancer,Non small cell lung cancer (NSCLC),Pancreatic cancerInjectionEq.1000 mg Gemcitabine per vial南京正大天晴制药6类
2011-12-02Marketing approval健择/GemzarOvarian cancer,Breast cancer,Non small cell lung cancer (NSCLC),Pancreatic cancerInjectionEq. 200 mg/1000 mg Gemcitabine per vialLilly 
2010-08-31Marketing approval Ovarian cancer,Breast cancer,Non small cell lung cancer (NSCLC),Pancreatic cancerInjection1000 mg/200 mg北京协和药厂6类

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
1995-01-10First approvalGemzarOvarian cancer,Breast cancer,Non small cell lung cancer (NSCLC),Pancreatic cancerInjection, Lyophilized powder, For solutionEq. 200 mg/1000 mg Gemcitabine per vialLilly

Gemcitabine, with brand names including Gemzar,[1] is a chemotherapy medication.[2] It treats cancers including testicular cancer,[3]breast cancerovarian cancernon-small cell lung cancerpancreatic cancer, and bladder cancer.[2][4] It is administered by intravenous infusion.[2] It acts against neoplastic growth, and it inhibits the replication of Orthohepevirus A, the causative agent of Hepatitis E, through upregulation of interferon signaling.[5]

Common side effects include bone marrow suppression, liver and kidney problems, nauseafeverrashshortness of breath, mouth sores, diarrhea, neuropathy, and hair loss.[2] Use during pregnancy will likely result in fetal harm.[2] Gemcitabine is in the nucleoside analog family of medication.[2] It works by blocking the creation of new DNA, which results in cell death.[2]

Gemcitabine was patented in 1983 and was approved for medical use in 1995.[6] Generic versions were introduced in Europe in 2009 and in the US in 2010.[7][8] It is on the WHO Model List of Essential Medicines.[9]

Medical uses

Gemcitabine treats various carcinomas. It is used as a first-line treatment alone for pancreatic cancer, and in combination with cisplatin for advanced or metastatic bladder cancer and advanced or metastatic non-small cell lung cancer. It is used as a second-line treatment in combination with carboplatin for ovarian cancer and in combination with paclitaxel for breast cancer that is metastatic or cannot be surgically removed.[10][11][12]

It is commonly used off-label to treat cholangiocarcinoma[13] and other biliary tract cancers.[14]

It is given by intravenous infusion at a chemotherapy clinic.[2]

Contraindications and interactions

Taking gemcitabine can also affect fertility in men and women, sex life, and menstruation. Women taking gemcitabine should not become pregnant, and pregnant and breastfeeding women should not take it.[15]

As of 2014, drug interactions had not been studied.[11][10]

SYN

. Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M. J. Org. Chem. 1988, 53, 2406– 2409.

NEXT

a) Noe, C. R.; Jasic, M.; Kollmann, H.; Saadat, K. WO009147, 2007.; b) Noe, C. R.; Jasic, M.; Kollmann, H.; Saadat, K. US0249119, 2008. Note: no stereochemistry was indica

NExT

15. Hanzawa, Y.; Inazawa, K.; Kon, A.; Aoki, H.; Kobayashi, Y. Tetrahedron Lett. 1987, 28, 659–662. 16. Wirth, D. D. EP0727432, 1996

Synthesis Reference

John A. Weigel, “Process for making gemcitabine hydrochloride.” U.S. Patent US6001994, issued May, 1995.US6001994Route 1

Reference:1. J. Org. Chem. 198853, 2406-2409.

2. US4808614A.Route 2

Reference:1. CN102417533A.Route 3

Reference:1. Nucleosides, Nucleotides and Nucleic Acids 201029, 113-122.Route 4

Reference:1. CN102617677A.Route 5

Reference:1. CN103012527A.

SYN

U.S. Patent No. 4,808,614 (the ‘614 patent) describes a process for synthetically producing gemcitabine, which process is generally illustrated in Scheme Scheme 1

Figure imgf000003_0001

5

Figure imgf000003_0002

SYN

U.S. Patent No. 4,965,374 (the ‘374 patent) describes a process for producing gemcitabine from an intermediate 3,5-dibenzoyl ribo protected lactone of the formula:

Figure imgf000004_0001

11 where the desired erythro isomer can be isolated in a crystalline form from a mixture of erythro and threo isomers. The process described in the ‘374 patent is generally outlined in Scheme 2.

Scheme 2

Figure imgf000005_0001

mixture of α and β anomers

SYN

U.S. Patent No. 5,521,294 (the ‘294 patent) describes l-alkylsulfonyl-2,2- difluoro-3 -carbamoyl ribose intermediates and intermediate nucleosides derived therefrom. The compounds are reportedly useful in the preparation of 2′-deoxy-2′,2’- difluoro-β-cytidine and other β-anomer nucleosides. The ‘294 patent teaches, inter alia, that the 3-hydroxy carbamoyl group on the difluororibose intermediate may enhance formation of the desired β-anomer nucleoside derivative. The ‘294 patent describes converting the lactone 4 to the dibenzoyl mesylate 13, followed by deprotection at the 3 position to obtain the 5-monobenzoyl mesylate intermediate 15, which is reacted with various isocyanates to obtain the compounds of formula 16. The next steps involve coupling and deprotection using methods similar to those described in previous patents. The process and the intermediates 15 and 16 are illustrated by scheme 3 below: Scheme 3

Figure imgf000007_0001

13 15

PhCOCK

PhNCO/TEA -o. -~- j*«0Ms

PhNHCOO -r F

16

1 coupling 2 deprotection

Figure imgf000007_0003
Figure imgf000007_0002

16 gemcitabine

CLIP

https://www.sciencedirect.com/science/article/abs/pii/S0008621514000500

WO2008129530A1 - Gemcitabine production process - Google Patents

PATENT

https://patents.google.com/patent/WO2008129530A1/en

Scheme 4

Figure imgf000013_0001

e3

13A deprotection isomer separation

Figure imgf000013_0002

deprotection

Figure imgf000013_0004
Figure imgf000013_0003

EXAMPLE 1

[0045] This example demonstrates the preparation of 2-deoxy-2,2-difluoro-D- ribofuranose-3,5-dicinnamate-l-p-toluenesulfonate.

[0046] Crude 2-deoxy-2,2-difluoro-D-riboufuranose-3,5-dicinnamate (2.5g, 6 mmol) was dissolved in dichloromethane (20 ml) in a round flask, and diethylamine (0.7g, 9.6 mmol) was added followed by p-toluenesulfonyl chloride (1.32 g, 6.92 mmol), which was added drop wise while cooling to 0-50C. The mixture was stirred for 1 hour, and washed with IN HCl (15 ml), concentrated solution OfNaHCO3 (15 ml), and dried over MgSO4. The solvent was distilled off under reduced pressure to obtain crude 2-deoxy-2,2-difluoro-D-ribofuranose-3,5-dicinnamate-l-p- toluenesulfonate as light oil. Yield: 3.22 g, (5.6 mmol), 93%.

EXAMPLE 2

[0047] This example demonstrates the preparation of 3′,5′-dicinnamoyl-2′-deoxy- 2′,2′-difluorocytidine.

[0048] Dry 1 ,2-dichloroethane (800 ml) was added to N,O-bis(trimethylsilyl)- cytosine (136 g, 487 mmol) under nitrogen blanket to produce a clear solution, followed by adding trimethylsilyl triflate (Me3SiOTf), (100 ml, 122.8 g, 520 mmol) and stirred for 30 minutes. A solution of 2-deoxy-2,2-difluoro-D-ribofuranose-3,5- dicinnamate-1-p-toluenesulfonate (128 g, 224 mmol) in 1 ,2-dichloroethane (400 ml) was added drop wise, and the mixture was refluxed overnight. After cooling, the solvent was distilled off to obtain crude 3,5-dicinnamoyl-N4-trimethylsilyl-2′-deoxy- 2′,2′-difluorocytidine as a light yellow solid. The residue was dissolved in ethyl acetate (1600 ml) and washed 3 times with water (3X400 ml). The ethyl acetate phase was mixed with concentrated solution OfNaHCO3 (800 ml) for about 5 minutes, and then the mixture was set aside for about 20 minutes without stirring. The thus formed solid, which was precipitated in the inter-phase of the two layers, was filtered off and washed with 60 ml of ethyl acetate. The solid was dried under reduced pressure to obtain 116.7 g (223 mmol, 99.5%) of the crude 3′,5′-dicinnamoyl- 2′-deoxy-2′,2′- difluorocytidine containing 73.3 % of the β-anomer and 11.8 % of the α-anomer.

EXAMPLE 3

[0049] This example demonstrates the preparation of 3′,5′-dicinnamoyl-2′-deoxy- 2′,2′-difluorocytidine.

[0050] Dry 1,2-dichloroethane (1.5 L) was added to bis(trimethylsilyl)cytosine (417 g, 1.49 mol) under nitrogen blanket to produce a clear solution followed by adding trimethylsilyl triflate (Me3SiOTf), (300 ml, 368.4 g, 1.56 mol) and stirred for 30 minutes. A solution of 2-deoxy-2,2-difluoro-D-ribofuranose-3,5-dicinnamate-l-p- toluenesulfonate (384 g, 673 mmol) in 1,2-dichloroethane (1.2 L) was added drop wise, and the mixture was refluxed overnight. After cooling, the solvent was distilled off to obtain crude 3,5-dicinnamoyl-N4-trimethylsilyl-2l-deoxy-2′,2′-difluorocytidine as a light yellow solid. The residue was dissolved in ethyl acetate (2.4 L) and washed 3 times with water (3X1.2 L). The ethyl acetate phase was mixed with concentrated solution OfNaHCO3 (1.34 L) for about 20 minutes. The thus formed solid, which was precipitated in the inter-phase of the two layers, was filtered off and washed with 180 ml of ethyl acetate. The solid was dried under reduced pressure to obtain 346.5 g (0.66 mol, 99.9% yield) of the crude 3l,5l-dicinnamoyl-2′-deoxy-2′,2′-difluorocytidine containing 43 % of the β-anomer and 52 % of the α-anomer.

EXAMPLE 4

[0051] This example demonstrates the preparation of gemcitabine hydrochloride. [0052] To a solution of ammonia-methanol (15.8 %, 4.57 L), the crude 3,5- dicirmamoyl-2′-deoxy-2′,2′-difluorocytidine of example 3 was added (346.5 g, 0.66 mol), and stirred at ambient temperature for 6 hours. The mixture was concentrated to afford a light yellow solid (306 g). Purified water (3 L) was added to the solid, followed by addition of ethyl acetate (1.8 L), and stirring was maintained for about 10 minutes. The aqueous layer was separated and the organic layer was extracted with water (1.05 L). The aqueous layers were combined and water was removed by evaporation under reduced pressure to obtain an oil (154.7 g). Water was added (660 ml) and the mixture was heated to 50-550C to dissolve the solid. The mixture was cooled to 5-1O0C during about one hour and mixed for about 16 hours at that temperature. The thus formed solid was filtered and dried to afford 46.75 g (0.177 mol), containing 98 % of the β-anomer and 1.3 % of the α-anomer. 0.5N HCl (936 ml) was added followed by addition of dichloromethane (300 ml) with stirring. The water phase was separated and the aqueous phase was washed with dichloromethane (300 ml). After filtration, the aqueous phase was concentrated to dryness under reduced pressure to obtain gemcitabine hydrochloride as a solid (46.9 g). The solid was dissolved in water (187 ml) at ambient temperature and the mixture was heated to 500C to afford a clear solution and cooled to ambient temperature. Acetone (1.4 L) was added and stirring was maintained for about one hour. Then, the precipitate was collected by filtration and washed twice with acetone (2X30 ml) and dried at 450C under vacuum to obtain 39.2 g of gemcitabine hydrochloride, containing 99.9% of the β-anomer

EXAMPLE 5

[0053] This example demonstrates the preparation of gemcitabine hydrochloride. [0054] To a solution of ammonia-methanol (about 15.8 %, 1.35 L), the crude 3′,5′- dicinnamoyl-2′-deoxy-2′,2′-difluorocytidine prepared as described in example 2 was added (96 g, 183.4 mmol), and stirred at ambient temperature for 4 hours. The mixture was concentrated to afford a light yellow solid (80.5 g). Purified water (1 L) was added to the solid, followed by addition of ethyl acetate (600 ml), and stirring was maintained for about 10 minutes. The aqueous layer was separated and the organic layer was extracted with water (350 ml). The aqueous layers were combined and water was removed by evaporation under reduced pressure to obtain an oil (46.4 g). Water was added (220 ml) and the mixture was heated to 50-550C to dissolve the solid. The mixture was cooled to 0-50C during about one hour and mixed for about 16 hours at that temperature. The thus formed solid was filtered and dried to afford 11.1 g of gemcitabine free base. 0.5N HCl (240 ml) was added followed by addition of dichloromethane (100 ml) with stirring. The water phase was separated and the aqueous phase was washed with dichloromethane (300 ml). After filtration, the aqueous phase was concentrated to dryness under reduced pressure to obtain gemcitabine hydrochloride as a solid (12.0 g). The solid was dissolved in water (48 ml) at ambient temperature and the mixture was heated to 5O0C to afford a clear solution and cooled to ambient temperature. Acetone (360 ml) was added and stirring was maintained for about one hour. Then, the precipitate was collected by filtration and washed twice with acetone (2X30 ml) and dried at 450C under vacuum to obtain 9.9 g of gemcitabine hydrochloride, containing 99.6% of the β-anomer.

EXAMPLE 6

[0055] This example demonstrates the slurrying procedure of the 3 ‘,5′- dicinnamoyl-2′-deoxy-2’,2l-difluorocytidine in different solvents. [0056] 1 g of the crude 3′,5′-dicinnamoyl-2′-deoxy-2l,2′-difluorocytidine, containing 73.7 % of the β-anomer and 17.5 % of the α-anomer, was placed in flask and 10 ml of a solvent was added and the mixture was mixed at ambient temperature for one hour. Then, the solid was obtained by filtration, washed with 5 ml of the solvent and dried. The liquid obtained after filtering the solid and the liquid obtained after washing the solid were combined (hereinafter the mother liquor). The ratio between the β-anomer and the α-anomer in the solid and in the mother liquor was determined by HPLC and the results are summarized in Table 1.

Table 1

Figure imgf000020_0001

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Adverse effects

Gemcitabine is a chemotherapy drug that works by killing any cells that are dividing.[10] Cancer cells divide rapidly and so are targeted at higher rates by gemcitabine, but many essential cells also divide rapidly, including cells in skin, the scalp, the stomach lining, and bone marrow, resulting in adverse effects.[16]: 265 

The gemcitabine label carries warnings that it can suppress bone marrow function and cause loss of white blood cellsloss of platelets, and loss of red blood cells, and that it should be used carefully in people with liver, kidney, or cardiovascular disorders. People taking it should not take live vaccines. The warning label also states it may cause posterior reversible encephalopathy syndrome, that it may cause capillary leak syndrome, that it may cause severe lung conditions like pulmonary edemapneumonia, and adult respiratory distress syndrome, and that it may harm sperm.[10][17]

More than 10% of users develop adverse effects, including difficulty breathing, low white and red blood cells counts, low platelet counts, vomiting and nausea, elevated transaminases, rashes and itchy skin, hair loss, blood and protein in urine, flu-like symptoms, and edema.[10][15]

Common adverse effects (occurring in 1–10% of users) include fever, loss of appetite, headache, difficulty sleeping, tiredness, cough, runny nose, diarrhea, mouth and lip sores, sweating, back pain, and muscle pain.[10]

Thrombotic thrombocytopenic purpura (TTP) is a rare but serious side effect that been associated with particular chemotherapy medications including gemcitabine. TTP is a blood disorder and can lead to microangipathic hemolytic anemia (MAHA), neurologic abnormalities, fever, and renal disease.[18]

Pharmacology

Gemcitabine is hydrophilic and must be transported into cells via molecular transporters for nucleosides (the most common transporters for gemcitabine are SLC29A1 SLC28A1, and SLC28A3).[19][20] After entering the cell, gemcitabine is first modified by attaching a phosphate to it, and so it becomes gemcitabine monophosphate (dFdCMP).[19][20] This is the rate-determining step that is catalyzed by the enzyme deoxycytidine kinase (DCK).[19][20] Two more phosphates are added by other enzymes. After the attachment of the three phosphates gemcitabine is finally pharmacologically active as gemcitabine triphosphate (dFdCTP).[19] [21]

After being thrice phosphorylated, gemcitabine can masquerade as deoxycytidine triphosphate and is incorporated into new DNA strands being synthesized as the cell replicates.[2][19][20]

When gemcitabine is incorporated into DNA it allows a native, or normal, nucleoside base to be added next to it. This leads to “masked chain termination” because gemcitabine is a “faulty” base, but due to its neighboring native nucleoside it eludes the cell’s normal repair system (base-excision repair). Thus, incorporation of gemcitabine into the cell’s DNA creates an irreparable error that leads to inhibition of further DNA synthesis, and thereby leading to cell death.[2][19][20]

The form of gemcitabine with two phosphates attached (dFdCDP) also has activity; it inhibits the enzyme ribonucleotide reductase (RNR), which is needed to create new DNA nucleotides. The lack of nucleotides drives the cell to uptake more of the components it needs to make nucleotides from outside the cell, which also increases uptake of gemcitabine.[2][19][20][22]

Chemistry

Gemcitabine is a synthetic pyrimidine nucleoside prodrug—a nucleoside analog in which the hydrogen atoms on the 2′ carbon of deoxycytidine are replaced by fluorine atoms.[2][23][24]

The synthesis described and pictured below is the original synthesis done in the Eli Lilly Company labs. Synthesis begins with enantiopure D-glyceraldehyde (R)-2 as the starting material which can made from D-mannitol in 2–7 steps. Then fluorine is introduced by a “building block” approach using ethyl bromodifluroacetate. Then, Reformatsky reaction under standard conditions will yield a 3:1 anti/syn diastereomeric mixture, with one major product. Separation of the diastereomers is carried out via HPLC, thus yielding the anti-3 gemcitabine in a 65% yield.[23][24] At least two other full synthesis methods have also been developed by different groups.[24]

Illustration of the original synthesis process used and published by Hertel et al. in 1988 of Lilly laboratories.

History[

Gemcitabine was first synthesized in Larry Hertel’s lab at Eli Lilly and Company during the early 1980s. It was intended as an antiviral drug, but preclinical testing showed that it killed leukemia cells in vitro.[25]

During the early 1990s gemcitabine was studied in clinical trials. The pancreatic cancer trials found that gemcitabine increased one-year survival time significantly, and it was approved in the UK in 1995[10] and approved by the FDA in 1996 for pancreatic cancers.[4] In 1998, gemcitabine received FDA approval for treating non-small cell lung cancer and in 2004, it was approved for metastatic breast cancer.[4]

European labels were harmonized by the EMA in 2008.[26]

By 2008, Lilly’s worldwide sales of gemcitabine were about $1.7 billion; at that time its US patents were set to expire in 2013 and its European patents in 2009.[27] The first generic launched in Europe in 2009,[7] and patent challenges were mounted in the US which led to invalidation of a key Lilly patent on its method to make the drug.[28][29] Generic companies started selling the drug in the US in 2010 when the patent on the chemical itself expired.[29][8] Patent litigation in China made headlines there and was resolved in 2010.[30]

Society and culture

As of 2017, gemcitabine was marketed under many brand names worldwide: Abine, Accogem, Acytabin, Antoril, axigem, Bendacitabin, Biogem, Boligem, Celzar, Citegin, Cytigem, Cytogem, Daplax, DBL, Demozar, Dercin, Emcitab, Enekamub, Eriogem, Fotinex, Gebina, Gemalata, Gembin, Gembine, Gembio, Gemcel, Gemcetin, Gemcibine, Gemcikal, Gemcipen, Gemcired, Gemcirena, Gemcit, Gemcitabin, Gemcitabina, Gemcitabine, Gemcitabinum, Gemcitan, Gemedac, Gemflor, Gemful, Gemita, Gemko, Gemliquid, Gemmis, Gemnil, Gempower, Gemsol, Gemstad, Gemstada, Gemtabine, Gemtavis, Gemtaz, Gemtero, Gemtra, Gemtro, Gemvic, Gemxit, Gemzar, Gentabim, Genuten, Genvir, Geroam, Gestredos, Getanosan, Getmisi, Gezt, Gitrabin, Gramagen, Haxanit, Jemta, Kalbezar, Medigem, Meditabine, Nabigem, Nallian, Oncogem, Oncoril, Pamigeno, Ribozar, Santabin, Sitagem, Symtabin, Yu Jie, Ze Fei, and Zefei.[1]

Research

Because it is clinically valuable and is only useful when delivered intravenously, methods to reformulate it so that it can be given by mouth have been a subject of research.[31][32][33]

Research into pharmacogenomics and pharmacogenetics has been ongoing. As of 2014, it was not clear whether or not genetic tests could be useful in guiding dosing and which people respond best to gemcitabine.[19] However, it appears that variation in the expression of proteins (SLC29A1SLC29A2SLC28A1, and SLC28A3) used for transport of gemcitabine into the cell lead to variations in its potency. Similarly, the genes that express proteins that lead to its inactivation (deoxycytidine deaminasecytidine deaminase, and NT5C) and that express its other intracellular targets (RRM1RRM2, and RRM2B) lead to variations in response to the drug.[19] Research has also been ongoing to understand how mutations in pancreatic cancers themselves determine response to gemcitabine.[34]

It has been studied as a treatment for Kaposi sarcoma, a common cancer in people with AIDS which is uncommon in the developed world but not uncommon in the developing world.[35]

References

  1. Jump up to:a b c “Gemcitabine International Brands”. Drugs.com. Archived from the original on 25 May 2014. Retrieved 6 May 2017.
  2. Jump up to:a b c d e f g h i j k l “Gemcitabine Hydrochloride”. The American Society of Health-System Pharmacists. Archived from the original on 2 February 2017. Retrieved 8 December 2016.
  3. ^ “Drug Formulary/Drugs/ gemcitabine – Provider Monograph”Cancer Care Ontario. Retrieved 6 December 2020.
  4. Jump up to:a b c National Cancer Institute (2006-10-05). “FDA Approval for Gemcitabine Hydrochloride”National Cancer InstituteArchived from the original on 5 April 2017. Retrieved 22 April 2017.
  5. ^ Li Y, Li P, Li Y, Zhang R, Yu P, Ma Z, Kainov DE, de Man RA, Peppelenbosch MP, Pan Q (December 2020). “Drug screening identified gemcitabine inhibiting hepatitis E virus by inducing interferon-like response via activation of STAT1 phosphorylation”Antiviral Research184: 104967. doi:10.1016/j.antiviral.2020.104967PMID 33137361.
  6. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 511. ISBN 9783527607495.
  7. Jump up to:a b Myers, Calisha (13 March 2009). “Gemcitabine from Actavis launched on patent expiry in EU markets”FierceBiotechArchived from the original on 11 September 2017.
  8. Jump up to:a b “Press release: Hospira launches two-gram vial of gemcitabine hydrochloride for injection”. Hospira via News-Medical.Net. 16 November 2010. Archived from the original on 2 October 2015.
  9. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  10. Jump up to:a b c d e f g “UK label”. UK Electronic Medicines Compendium. 5 June 2014. Archived from the original on 10 July 2017. Retrieved 6 May 2017.
  11. Jump up to:a b “US formLabel” (PDF). FDA. June 2014. Archived (PDF) from the original on 16 February 2017. Retrieved 6 May 2017. For label updates see FDA index page for NDA 020509 Archived 2017-04-29 at the Wayback Machine
  12. ^ Zhang XW, Ma YX, Sun Y, Cao YB, Li Q, Xu CA (June 2017). “Gemcitabine in Combination with a Second Cytotoxic Agent in the First-Line Treatment of Locally Advanced or Metastatic Pancreatic Cancer: a Systematic Review and Meta-Analysis”. Targeted Oncology12 (3): 309–321. doi:10.1007/s11523-017-0486-5PMID 28353074S2CID 3833614.
  13. ^ Plentz RR, Malek NP (December 2016). “Systemic Therapy of Cholangiocarcinoma”Visceral Medicine32 (6): 427–430. doi:10.1159/000453084PMC 5290432PMID 28229078.
  14. ^ Jain A, Kwong LN, Javle M (November 2016). “Genomic Profiling of Biliary Tract Cancers and Implications for Clinical Practice”. Current Treatment Options in Oncology17 (11): 58. doi:10.1007/s11864-016-0432-2PMID 27658789S2CID 25477593.
  15. Jump up to:a b Macmillan Cancer Support. “Gemcitabine”Macmillan Cancer SupportArchived from the original on 25 March 2017. Retrieved 6 May 2017.
  16. ^ Rachel Airley (2009). Cancer Chemotherapy. Wiley-Blackwell. ISBN 978-0-470-09254-5.
  17. ^ Siddall E, Khatri M, Radhakrishnan J (July 2017). “Capillary leak syndrome: etiologies, pathophysiology, and management”Kidney International92 (1): 37–46. doi:10.1016/j.kint.2016.11.029PMID 28318633.
  18. ^ Kasi PM (January 2011). “Thrombotic thrombocytopenic purpura and gemcitabine”Case Reports in Oncology4 (1): 143–8. doi:10.1159/000326801PMC 3114619PMID 21691573.
  19. Jump up to:a b c d e f g h i Alvarellos ML, Lamba J, Sangkuhl K, Thorn CF, Wang L, Klein DJ, Altman RB, Klein TE (November 2014). “PharmGKB summary: gemcitabine pathway”Pharmacogenetics and Genomics24 (11): 564–74. doi:10.1097/fpc.0000000000000086PMC 4189987PMID 25162786.
  20. Jump up to:a b c d e f Mini E, Nobili S, Caciagli B, Landini I, Mazzei T (May 2006). “Cellular pharmacology of gemcitabine”Annals of Oncology. 17 Suppl 5: v7-12. doi:10.1093/annonc/mdj941PMID 16807468.
  21. ^ Fatima, M., Iqbal Ahmed, M. M., Batool, F., Riaz, A., Ali, M., Munch-Petersen, B., & Mutahir, Z. (2019). Recombinant deoxyribonucleoside kinase from Drosophila melanogaster can improve gemcitabine based combined gene/chemotherapy for targeting cancer cells. Bosnian Journal of Basic Medical Sciences, 19(4), 342-349. https://doi.org/10.17305/bjbms.2019.4136
  22. ^ Cerqueira NM, Fernandes PA, Ramos MJ (2007). “Understanding ribonucleotide reductase inactivation by gemcitabine”. Chemistry13 (30): 8507–15. doi:10.1002/chem.200700260PMID 17636467.
  23. Jump up to:a b Brown K, Weymouth-Wilson A, Linclau B (April 2015). “A linear synthesis of gemcitabine”Carbohydrate Research406: 71–5. doi:10.1016/j.carres.2015.01.001PMID 25681996.
  24. Jump up to:a b c Brown K, Dixey M, Weymouth-Wilson A, Linclau B (March 2014). “The synthesis of gemcitabine”Carbohydrate Research387: 59–73. doi:10.1016/j.carres.2014.01.024PMID 24636495.
  25. ^ Sneader, Walter (2005). Drug discovery: a history. New York: Wiley. p. 259. ISBN 978-0-471-89979-2.
  26. ^ “Gemzar”. European Medicines Agency. 24 September 2008. Archived from the original on 11 September 2017.
  27. ^ Myers, Calisha (18 August 2009). “Patent for Lilly’s cancer drug Gemzar invalidated”FiercePharmaArchived from the original on 11 September 2017.
  28. ^ Holman, Christopher M. (Summer 2011). “Unpredictability in Patent Law and Its Effect on Pharmaceutical Innovation” (PDF). Missouri Law Review76 (3): 645–693. Archived from the original (PDF) on 2017-09-11. Retrieved 2017-05-06.
  29. Jump up to:a b Ravicher, Daniel B. (28 July 2010). “On the Generic Gemzar Patent Fight”Seeking AlphaArchived from the original on 9 December 2012.
  30. ^ Wang M, Alexandre D (2015). “Analysis of Cases on Pharmaceutical Patent Infringement in Great China”. In Rader RR, et al. (eds.). Law, Politics and Revenue Extraction on Intellectual Property. Cambridge Scholars Publishing. p. 119. ISBN 9781443879262Archived from the original on 2017-09-11.
  31. ^ Dyawanapelly S, Kumar A, Chourasia MK (2017). “Lessons Learned from Gemcitabine: Impact of Therapeutic Carrier Systems and Gemcitabine’s Drug Conjugates on Cancer Therapy”. Critical Reviews in Therapeutic Drug Carrier Systems34 (1): 63–96. doi:10.1615/CritRevTherDrugCarrierSyst.2017017912PMID 28322141.
  32. ^ Birhanu G, Javar HA, Seyedjafari E, Zandi-Karimi A (April 2017). “Nanotechnology for delivery of gemcitabine to treat pancreatic cancer”. Biomedicine & Pharmacotherapy88: 635–643. doi:10.1016/j.biopha.2017.01.071PMID 28142120.
  33. ^ Dubey RD, Saneja A, Gupta PK, Gupta PN (October 2016). “Recent advances in drug delivery strategies for improved therapeutic efficacy of gemcitabine”. European Journal of Pharmaceutical Sciences93: 147–62. doi:10.1016/j.ejps.2016.08.021PMID 27531553.
  34. ^ Pishvaian MJ, Brody JR (March 2017). “Therapeutic Implications of Molecular Subtyping for Pancreatic Cancer”Oncology31 (3): 159–66, 168. PMID 28299752Archived from the original on 3 July 2017.
  35. ^ Krown SE (September 2011). “Treatment strategies for Kaposi sarcoma in sub-Saharan Africa: challenges and opportunities”Current Opinion in Oncology23 (5): 463–8. doi:10.1097/cco.0b013e328349428dPMC 3465839PMID 21681092.

External links

Clinical data
Pronunciation/dʒɛmˈsaɪtəbiːn/
Trade namesGemzar, others[1]
Other names2′, 2′-difluoro 2’deoxycytidine, dFdC
AHFS/Drugs.comMonograph
Pregnancy
category
AU: D
Routes of
administration
Intravenous
ATC codeL01BC05 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)UK: POM (Prescription only)US: ℞-onlyIn general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding<10%
Elimination half-lifeShort infusions: 32–94 minutes
Long infusions: 245–638 minutes
Identifiers
showIUPAC name
CAS Number95058-81-4 
PubChem CID60750
IUPHAR/BPS4793
DrugBankDB00441 
ChemSpider54753 
UNIIB76N6SBZ8R
KEGGD02368 
ChEBICHEBI:175901 
ChEMBLChEMBL888 
CompTox Dashboard (EPA)DTXSID3040487 
ECHA InfoCard100.124.343 
Chemical and physical data
FormulaC9H11F2N3O4
Molar mass263.201 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (verify)

/////////////GEMCITABINE, LY 188011, LY188011, CANCER

NC1=NC(=O)N(C=C1)[C@@H]1O[C@H](CO)[C@@H](O)C1(F)F

Patent

Publication numberPriority datePublication dateAssigneeTitle

EP0577303A1 *1992-06-221994-01-05Eli Lilly And CompanyStereoselective glycosylation process

WO2006070985A1 *2004-12-302006-07-06Hanmi Pharm. Co., Ltd.METHOD FOR THE PREPARATION OF 2&num;-DEOXY-2&num;,2&num;-DIFLUOROCYTIDINE

WO2007027564A2 *2005-08-292007-03-08Chemagis Ltd.Process for preparing gemcitabine and associated intermediates

WO2007069838A1 *2005-12-142007-06-21Dong-A Pharm.Co., Ltd.A manufacturing process of 2′,2′-difluoronucleoside and intermediate

Family To Family Citations

JPS541315B2 *1974-11-221979-01-23

US4526988A *1983-03-101985-07-02Eli Lilly And CompanyDifluoro antivirals and intermediate therefor

US4751221A *1985-10-181988-06-14Sloan-Kettering Institute For Cancer Research2-fluoro-arabinofuranosyl purine nucleosides

US5223608A *1987-08-281993-06-29Eli Lilly And CompanyProcess for and intermediates of 2′,2′-difluoronucleosides

US4965374A *1987-08-281990-10-23Eli Lilly And CompanyProcess for and intermediates of 2′,2′-difluoronucleosides

US5256798A *1992-06-221993-10-26Eli Lilly And CompanyProcess for preparing alpha-anomer enriched 2-deoxy-2,2-difluoro-D-ribofuranosyl sulfonates

US5371210A *1992-06-221994-12-06Eli Lilly And CompanyStereoselective fusion glycosylation process for preparing 2′-deoxy-2′,2′-difluoronucleosides and 2′-deoxy-2′-fluoronucleosides

US5256797A *1992-06-221993-10-26Eli Lilly And CompanyProcess for separating 2-deoxy-2,2-difluoro-D-ribofuranosyl alkylsulfonate anomers

US5480992A *1993-09-161996-01-02Eli Lilly And CompanyAnomeric fluororibosyl amines

US5521294A *1995-01-181996-05-28Eli Lilly And Company2,2-difluoro-3-carbamoyl ribose sulfonate compounds and process for the preparation of beta nucleosides

US5559222A *1995-02-031996-09-24Eli Lilly And CompanyPreparation of 1-(2′-deoxy-2′,2′-difluoro-D-ribo-pentofuranosyl)-cytosine from 2-deoxy-2,2-difluoro-β-D-ribo-pentopyranose

US5602262A *1995-02-031997-02-11Eli Lilly And CompanyProcess for the preparation of 2-deoxy-2,2-difluoro-β-D-ribo-pentopyranose

US5633367A *1995-03-241997-05-27Eli Lilly And CompanyProcess for the preparation of a 2-substituted 3,3-difluorofuran

GB9514268D0 *1995-07-131995-09-13Hoffmann La RochePyrimidine nucleoside

US5756775A *1995-12-131998-05-26Eli Lilly And CompanyProcess to make α,α-difluoro-β-hydroxyl thiol esters

CA2641719A1 *2006-02-072007-08-16Chemagis Ltd.Process for preparing gemcitabine and associated intermediates

US20070249823A1 *2006-04-202007-10-25Chemagis Ltd.Process for preparing gemcitabine and associated intermediates

Publication numberPriority datePublication dateAssigneeTitle

CN102617483A *2011-06-302012-08-01江苏豪森药业股份有限公司Process for recycling cytosine during preparing process of gemcitabine hydrochloride

WO2013164798A12012-05-042013-11-07Tpresso AgPackaging of dry leaves in sealed capsules

CN105566418A *2014-10-092016-05-11江苏笃诚医药科技股份有限公司2′,3′-di-O-acetyl-5′-deoxy-5-fluorocytidine synthesis method

EP3817732A4 *2018-08-032022-06-08Cellix Bio Private LimitedCompositions and methods for the treatment of cancer

Family To Family Citations

CA2641719A1 *2006-02-072007-08-16Chemagis Ltd.Process for preparing gemcitabine and associated intermediates

US20070249823A1 *2006-04-202007-10-25Chemagis Ltd.Process for preparing gemcitabine and associated intermediates

IT1393062B1 *2008-10-232012-04-11Prime Europ TherapeuticalsPROCEDURE FOR THE PREPARATION OF GEMCITABINE CHLORIDRATE

PublicationPublication DateTitle

CA2509687C2012-08-14Process for the production of 2'-branched nucleosides

WO2008129530A12008-10-30Gemcitabine production process

AU2005328519B22012-03-01Intermediate and process for preparing of beta- anomer enriched 21deoxy, 21 ,21-difluoro-D-ribofuranosyl nucleosides

EP1931693A22008-06-18Process for preparing gemcitabine and associated intermediates

EP2164856A12010-03-24Processes related to making capecitabine

US8193354B22012-06-05Process for preparation of Gemcitabine hydrochloride

EP3638685A12020-04-22Synthesis of 3'-deoxyadenosine-5'-0-[phenyl(benzyloxy-l-alaninyl)]phosphate (nuc-7738)

EP2456778A12012-05-30Process for producing flurocytidine derivatives

US20090221811A12009-09-03Process for preparing gemcitabine and associated intermediates

JP5114556B22013-01-09A novel highly stereoselective synthetic process and intermediate for gemcitabine

EP0350292B11994-05-04Process for preparing 2'-deoxy-beta-adenosine

KR100908363B12009-07-20Stereoselective preparation method of tri-O-acetyl-5-deoxy-β-D-ribofuranose and separation method thereof

US20070249823A12007-10-25Process for preparing gemcitabine and associated intermediates

WO2007070804A22007-06-21Process for preparing gemcitabine and associated intermediates

KR101259648B12013-05-09A manufacturing process of 2′,2′-difluoronucloside and intermediate

US8338586B22012-12-25Process of making cladribine

WO2010029574A22010-03-18An improved process for the preparation of gemcitabine and its intermediates using novel protecting groups and ion exchange resins

KR20080090950A2008-10-09Process for preparing gemcitabine and associated intermediates

WO2012115578A12012-08-30Synthesis of flg

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OTERACIL

UNII4R7FFA00RX, CAS Number2207-75-2,  WeightAverage: 195.175, Monoisotopic: 194.96823705, Chemical FormulaC4H2KN3O4

[K+].OC1=NC(=NC(=O)N1)C([O-])=O

1,3,5-Triazine-2-carboxylic acid, 1,4,5,6-tetrahydro-4,6-dioxo-, potassium salt (1:1)

218-627-5[EINECS]

2207-75-2[RN]

4,6-Dihydroxy-1,3,5-triazine-2-carboxylic acid potassium salt

  • KOX
  • NSC 28841
  • Oxonate
  • Oxonate, potassium

CDSCO APPROVED,01.02.2022

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Gimeracil bulk & Oteracil potassium bulk and Tegafur 15mg/20mg, Gimeracil 4.35mg/5.8mg and Oteracil 11.8mg/15.8mg capsules

indicated in adults for the treatment of advanced gastric cancer when given in combination with cisplatin.

Oteracil Potassium is the potassium salt of oxonate, an enzyme inhibitor that modulates 5- fluorouracil (5-FU) toxicity. Potassium oxonate inhibits orotate phosphoribosyltransferase, which catalyzes the conversion of 5-FU to its active or phosphorylated form, FUMP. Upon oral administration, Oxonate is selectively distributed to the intracellular sites of tissues lining the small intestines, producing localized inhibitory effects within the gastrointestinal tract. As a result, 5-FU associated gastrointestinal toxic effects are reduced and the incidence of diarrhea or mucositis is decreased in 5-FU related therapy.

Oteracil is an adjunct to antineoplastic therapy, used to reduce the toxic side effects associated with chemotherapy. Approved by the European Medicines Agency (EMA) in March 2011, Oteracil is available in combination with Gimeracil and Tegafur within the commercially available product “Teysuno”. The main active ingredient in Teysuno is Tegafur, a pro-drug of Fluorouracil (5-FU), which is a cytotoxic anti-metabolite drug that acts on rapidly dividing cancer cells. By mimicking a class of compounds called “pyrimidines” that are essential components of RNA and DNA, 5-FU is able to insert itself into strands of DNA and RNA, thereby halting the replication process necessary for continued cancer growth.

Oteracil’s main role within Teysuno is to reduce the activity of 5-FU within normal gastrointestinal mucosa, and therefore reduce’s gastrointestinal toxicity 1. It functions by blocking the enzyme orotate phosphoribosyltransferase (OPRT), which is involved in the production of 5-FU.

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SYNTHESIS

https://patents.google.com/patent/CN103435566A/zh

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SYN

https://europepmc.org/article/pmc/pmc7717319

Poje et al. reported a two-step, gram-scale preparation of the TS-1 additive oteracil 21 (Scheme 16).226 Iodine-mediated-oxidation of uric acid 116 produced dehydroallantoin 117 as the major product, and subsequent treatment with potassium hydroxide resulted in the rearranged product oteracil 21.227

An external file that holds a picture, illustration, etc.
Object name is nihms-1649941-f0037.jpg

Synthesis of Oteracil 21a

aReagents and conditions: (a) LiOH, I2, H2O, 5 °C, 5 min, then AcOH, 75%; (b) aq KOH, 20 min, rt, 82%.

(226) Poje M; Sokolić-Maravić L The mechanism for the conversion of uric acid into allantoin and dehydro-allantoin: A new look at an old problem. Tetrahedron 1986, 42 (2), 747–751. [Google Scholar]

(227) Sugi M; Igi M EP Patent 0957096, 1999.

EP0957096A1 *1998-05-111999-11-17SUMIKA FINE CHEMICALS Co., Ltd.Method for producing potassium oxonate

CN101475539A *2009-02-112009-07-08鲁南制药集团股份有限公司Refining method for preparing high-purity oteracil potassium

CN102250025A *2011-05-182011-11-23深圳万乐药业有限公司Preparation method suitable for industrially producing oteracil potassium

CN102746244A *2012-07-272012-10-24南京正大天晴制药有限公司Refining method of oteracil potassium

//////////OTERACIL POTTASIUM, KOX, NSC 28841, Oxonate, Oxonate potassium, INDIA 2022, APPROVALS 2022, CANCER

[K+].OC1=NC(=NC(=O)N1)C([O-])=O

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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

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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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AUPM 170, CA 170, PD-1-IN-1


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 https://www.nature.com/articles/s42003-021-02191-1
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(2S,3R)-2-(3-((S)-3-amino-1-(3-((R)-1-amino-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)-3-oxopropyl)ureido)-3-hydroxybutanoic acid

CA-170
GLXC-15291
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PD-1-IN-1 Chemical Structure
Molecular Weight (MW) 360.33
Formula C12H20N6O7
CAS No. 1673534-76-3

N-[[[(1S)-3-Amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]amino]carbonyl]-L-threonine

L-Threonine, N-[[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]amino]carbonyl]-

 AUPM 170, CA 170, AUPM-170, CA-170, PD-1-IN-1

Novel inhibitor of programmed cell dealth-1 (PD-1)

CA-170 (also known as AUPM170 or PD-1-IN-1) is a first-in-class, potent and orally available small molecule inhibitor of the immune checkpoint regulatory proteins PD-L1 (programmed cell death ligand-1), PD-L2 and VISTA (V-domain immunoglobulin (Ig) suppressor of T-cell activation (programmed death 1 homolog; PD-1H). CA-170 was discovered by Curis Inc. and has potential antineoplastic activities. CA-170 selectively targets PD-L1 and VISTA, both of which function as negative checkpoint regulators of immune activation. Curis is currently investigating CA-170 for the treatment of advanced solid tumours and lymphomas in patients in a Phase 1 trial (ClinicalTrials.gov Identifier: NCT02812875).

References: www.clinicaltrials.gov (NCT02812875); WO 2015033299 A1 20150312.

Aurigene Discovery Technologies Limited INNOVATOR

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CURIS AND AURIGENE ANNOUNCE AMENDMENT OF COLLABORATION FOR THE DEVELOPMENT AND COMMERCIALIZATION OF CA-170

PRESS RELEASE

https://www.aurigene.com/curis-and-aurigene-announce-amendment-of-collaboration-for-the-development-and-commercialization-of-ca-170/

Curis and Aurigene Announce Amendment of Collaboration for the Development and Commercialization of CA-170

– Aurigene to fund and conduct a Phase 2b/3 randomized study of CA-170 in patients with non-squamous non-small cell lung cancer (nsNSCLC) –

– Aurigene to receive Asia rights for CA-170; Curis entitled to royalty payments in Asia –

LEXINGTON, Mass., February 5, 2020 /PRNewswire/ — Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, today announced that it has entered into an amendment of its collaboration, license and option agreement with Aurigene Discovery Technologies, Ltd. (Aurigene). Under the terms of the amended agreement, Aurigene will fund and conduct a Phase 2b/3 randomized study evaluating CA-170, an orally available, dual
inhibitor of VISTA and PDL1, in combination with chemoradiation, in approximately 240 patients with nonsquamous
non-small cell lung cancer (nsNSCLC). In turn, Aurigene receives rights to develop and commercialize CA-170 in Asia, in addition to its existing rights in India and Russia, based on the terms of the original agreement. Curis retains U.S., E.U., and rest of world rights to CA-170, and is entitled to receive royalty payments on potential future sales of CA-170 in Asia.

In 2019, Aurigene presented clinical data from a Phase 2a basket study of CA-170 in patients with multiple tumor types, including those with nsNSCLC. In the study, CA-170 demonstrated promising signs of safety and efficacy in nsNSCLC patients compared to various anti-PD-1/PD-L1 antibodies.

“We are pleased to announce this amendment which leverages our partner Aurigene’s expertise and resources to support the clinical advancement of CA-170, as well as maintain our rights to CA-170 outside of Asia,” said James Dentzer, President and Chief Executive Officer of Curis. “Phase 2a data presented at the European Society for Medical Oncology (ESMO) conference last fall supported the potential for CA-170 to serve as a therapeutic option for patients with nsNSCLC. We look forward to working with our partner Aurigene to further explore this opportunity.”

“Despite recent advancements, patients with localized unresectable NSCLC struggle with high rates of recurrence and need for expensive intravenous biologics. The CA-170 data presented at ESMO 2019 from Aurigene’s Phase 2 ASIAD trial showed encouraging results in Clinical Benefit Rate and Prolonged PFS and support its potential to provide clinically meaningful benefit to Stage III and IVa nsNSCLC patients, in combination with chemoradiation and as oral maintenance” said Kumar Prabhash, MD, Professor of Medical Oncology at Tata Memorial Hospital, Mumbai, India.

Murali Ramachandra, PhD, Chief Executive Officer of Aurigene, commented, “Development of CA-170, with its unique dual inhibition of PD-L1 and VISTA, is the result of years of hard-work and commitment by many people, including the patients who participated in the trials, caregivers and physicians, along with the talented teams at Aurigene and Curis. We look forward to further developing CA-170 in nsNSCLC.”

About Curis, Inc.

Curis is a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, including fimepinostat, which is being investigated in combination with venetoclax in a Phase 1 clinical study in patients with DLBCL. In 2015, Curis entered into a collaboration with Aurigene in the areas of immuno-oncology and precision oncology. As part of this collaboration, Curis has exclusive licenses to oral small molecule antagonists of immune checkpoints including, the VISTA/PDL1 antagonist CA-170, and the TIM3/PDL1 antagonist CA-327, as well as the IRAK4 kinase inhibitor, CA- 4948. CA-4948 is currently undergoing testing in a Phase 1 trial in patients with non-Hodgkin lymphoma.
In addition, Curis is engaged in a collaboration with ImmuNext for development of CI-8993, a monoclonal anti-VISTA antibody. Curis is also party to a collaboration with Genentech, a member of the Roche Group, under which Genentech and Roche are commercializing Erivedge® for the treatment of advanced basal cell carcinoma. For more information, visit Curis’ website at http://www.curis.com.

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 currently has several programs from its pipeline in clinical development. Aurigene’s ROR-gamma inverse agonist AUR-101 is currently in phase 2 clinical development under a US FDA IND. Additionally, Aurigene has multiple compounds at different stages of pre-clinical development. Aurigene has partnered with many large and mid-pharma companies in the United States and Europe and has 15 programs  currently in clinical development. For more information, please visit Aurigene’s website at https://www.aurigene.com/

Curis with the option to exclusively license Aurigene’s orally-available small molecule antagonist of programmed death ligand-1 (PD-L1) in the immuno-oncology field

Addressing immune checkpoint pathways is a well validated strategy to treat human cancers and the ability to target PD-1/PD-L1 and other immune checkpoints with orally available small molecule drugs has the potential to be a distinct and major advancement for patients.

Through its collaboration with Aurigene, Curis is now engaged in the discovery and development of the first ever orally bioavailable, small molecule antagonists that target immune checkpoint receptor-ligand interactions, including PD-1/PD-L1 interactions.  In the first half of 2016, Curis expects to file an IND application with the U.S. FDA to initiate clinical testing of CA-170, the first small molecule immune checkpoint antagonist targeting PD-L1 and VISTA.  The multi-year collaboration with Aurigene is focused on generation of small molecule antagonists targeting additional checkpoint receptor-ligand interactions and Curis expects to advance additional drug candidates for clinical testing in the coming years. The next immuno-oncology program in the collaboration is currently targeting the immune checkpoints PD-L1 and TIM3.

In November 2015, preclinical data were reported. Data demonstrated tha the drug rescued and sustained activation of T cells functions in culture. CA-170 resulted in anti-tumor activity in multiple syngeneic tumor models including melanoma and colon cancer. Similar data were presented at the 2015 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference in Boston, MA

By August 2015, preclinical data had been reported. Preliminary data demonstrated that in in vitro studies, small molecule PD-L1 antagonists induced effective T cell proliferation and IFN-gamma production by T cells that were specifically suppressed by PD-L1 in culture. The compounds were found to have effects similar to anti-PD1 antibodies in in vivo tumor models

 (Oral Small Molecule PD-L1/VISTAAntagonist)

Certain human cancers express a ligand on their cell surface referred to as Programmed-death Ligand 1, or PD-L1, which binds to its cognate receptor, Programmed-death 1, or PD-1, present on the surface of the immune system’s T cells.  Cell surface interactions between tumor cells and T cells through PD-L1/PD-1 molecules result in T cell inactivation and hence the inability of the body to mount an effective immune response against the tumor.  It has been previously shown that modulation of the PD-1 mediated inhibition of T cells by either anti-PD1 antibodies or anti-PD-L1 antibodies can lead to activation of T cells that result in the observed anti-tumor effects in the tumor tissues.  Therapeutic monoclonal antibodies targeting the PD-1/PD-L1 interactions have now been approved by the U.S. FDA for the treatment of certain cancers, and multiple therapeutic monoclonal antibodies targeting PD-1 or PD-L1 are currently in development.

In addition to PD-1/PD-L1 immune regulators, there are several other checkpoint molecules that are involved in the modulation of immune responses to tumor cells1.  One such regulator is V-domain Ig suppressor of T-cell activation or VISTA that shares structural homology with PD-L1 and is also a potent suppressor of T cell functions.  However, the expression of VISTA is different from that of PD-L1, and appears to be limited to the hematopoietic compartment in tissues such as spleen, lymph nodes and blood as well as in myeloid hematopoietic cells within the tumor microenvironment.  Recent animal studies have demonstrated that combined targeting/ blockade of PD-1/PD-L1 interactions and VISTA result in improved anti-tumor responses in certain tumor models, highlighting their distinct and non-redundant functions in regulating the immune response to tumors2.

As part of the collaboration with Aurigene, in October 2015 Curis licensed a first-in-class oral, small molecule antagonist designated as CA-170 that selectively targets PD-L1 and VISTA, both of which function as negative checkpoint regulators of immune activation.  CA-170 was selected from the broad PD-1 pathway antagonist program that the companies have been engaged in since the collaboration was established in January 2015.  Preclinical data demonstrate that CA-170 can induce effective proliferation and IFN-γ (Interferon-gamma) production (a cytokine that is produced by activated T cells and is a marker of T cell activation) by T cells that are specifically suppressed by PD-L1 or VISTA in culture.  In addition, CA-170 also appears to have anti-tumor effects similar to anti-PD-1 or anti-VISTA antibodies in multiple in vivo tumor models and appears to have a good in vivo safety profile.  Curis expects to file an IND and initiate clinical testing of CA-170 in patients with advanced tumors during the first half of 2016.

Jan 21, 2015

Curis and Aurigene Announce Collaboration, License and Option Agreement to Discover, Develop and Commercialize Small Molecule Antagonists for Immuno-Oncology and Precision Oncology Targets

— Agreement Provides Curis with Option to Exclusively License Aurigene’s Antagonists for Immuno-Oncology, Including an Antagonist of PD-L1 and Selected Precision Oncology Targets, Including an IRAK4 Kinase Inhibitor —

— Investigational New Drug (IND) Application Filings for Both Initial Collaboration Programs Expected this Year —

— Curis to issue 17.1M shares of its Common Stock as Up-front Consideration —

— Management to Host Conference Call Today at 8:00 a.m. EST —

LEXINGTON, Mass. and BANGALORE, India, Jan. 21, 2015 (GLOBE NEWSWIRE) — Curis, Inc. (Nasdaq:CRIS), a biotechnology company focused on the development and commercialization of innovative drug candidates for the treatment of human cancers, and Aurigene Discovery Technologies Limited, a specialized, discovery stage biotechnology company developing novel therapies to treat cancer and inflammatory diseases, today announced that they have entered into an exclusive collaboration agreement focused on immuno-oncology and selected precision oncology targets. The collaboration provides for inclusion of multiple programs, with Curis having the option to exclusively license compounds once a development candidate is nominated within each respective program. The partnership draws from each company’s respective areas of expertise, with Aurigene having the responsibility for conducting all discovery and preclinical activities, including IND-enabling studies and providing Phase 1 clinical trial supply, and Curis having responsibility for all clinical development, regulatory and commercialization efforts worldwide, excluding India and Russia, for each program for which it exercises an option to obtain a license.

The first two programs under the collaboration are an orally-available small molecule antagonist of programmed death ligand-1 (PD-L1) in the immuno-oncology field and an orally-available small molecule inhibitor of Interleukin-1 receptor-associated kinase 4 (IRAK4) in the precision oncology field. Curis expects to exercise its option to obtain exclusive licenses to both programs and file IND applications for a development candidate from each in 2015.

“We are thrilled to partner with Aurigene in seeking to discover, develop and commercialize small molecule drug candidates generated from Aurigene’s novel technology and we believe that this collaboration represents a true transformation for Curis that positions the company for continued growth in the development and eventual commercialization of cancer drugs,” said Ali Fattaey, Ph.D., President and Chief Executive Officer of Curis. “The multi-year nature of our collaboration means that the parties have the potential to generate a steady pipeline of novel drug candidates in the coming years. Addressing immune checkpoint pathways is now a well validated strategy to treat human cancers and the ability to target PD-1/PD-L1 and other immune checkpoints with orally available small molecule drugs has the potential to be a distinct and major advancement for patients. Recent studies have also shown that alterations of the MYD88 gene lead to dysregulation of its downstream target IRAK4 in a number of hematologic malignancies, including Waldenström’s Macroglobulinemia and a subset of diffuse large B-cell lymphomas, making IRAK4 an attractive target for the treatment of these cancers. We look forward to advancing these programs into clinical development later this year.”

Dr. Fattaey continued, “Aurigene has a long and well-established track record of generating targeted small molecule drug candidates with bio-pharmaceutical collaborators and we have significantly expanded our drug development capabilities as we advance our proprietary drug candidates in currently ongoing clinical studies. We believe that we are well-positioned to advance compounds from this collaboration into clinical development.”

CSN Murthy, Chief Executive Officer of Aurigene, said, “We are excited to enter into this exclusive collaboration with Curis under which we intend to discover and develop a number of drug candidates from our chemistry innovations in the most exciting fields of cancer therapy. This unique collaboration is an opportunity for Aurigene to participate in advancing our discoveries into clinical development and beyond, and mutually align interests as provided for in our agreement.  Our scientists at Aurigene have established a novel strategy to address immune checkpoint targets using small molecule chemical approaches, and have discovered a number of candidates that modulate these checkpoint pathways, including PD-1/PD-L1. We have established a large panel of preclinical tumor models in immunocompetent mice and can show significant in vivo anti-tumor activity using our small molecule PD-L1 antagonists.  We are also in the late stages of selecting a candidate that is a potent and selective inhibitor of the IRAK4 kinase, demonstrating excellent in vivo activity in preclinical tumor models.”

In connection with the transaction, Curis has issued to Aurigene approximately 17.1 million shares of its common stock, or 19.9% of its outstanding common stock immediately prior to the transaction, in partial consideration for the rights granted to Curis under the collaboration agreement. The shares issued to Aurigene are subject to a lock-up agreement until January 18, 2017, with a portion of the shares being released from the lock-up in four equal bi-annual installments between now and that date.

The agreement provides that the parties will collaborate exclusively in immuno-oncology for an initial period of approximately two years, with the option for Curis to extend the broad immuno-oncology exclusivity.

In addition Curis has agreed to make payments to Aurigene as follows:

  • for the first two programs: up to $52.5 million per program, including $42.5 million per program for approval and commercial milestones, plus specified approval milestone payments for additional indications, if any;
  • for the third and fourth programs: up to $50 million per program, including $42.5 million per program for  approval and commercial milestones, plus specified approval milestone payments for additional indications, if any; and
  • for any program thereafter: up to $140.5 million per program, including $87.5 million per program in approval and commercial milestones, plus specified approval milestone payments for additional indications, if any.

Curis has agreed to pay Aurigene royalties on any net sales ranging from high single digits to 10% in territories where it successfully commercializes products and will also share in amounts that it receives from sublicensees depending upon the stage of development of the respective molecule.
About Immune Checkpoint  Modulation and Programmed Death 1 Pathway

Modulation of immune checkpoint pathways has emerged as a highly promising therapeutic approach in a wide range of human cancers. Immune checkpoints are critical for the maintenance of self-tolerance as well as for the protection of tissues from excessive immune response generated during infections. However, cancer cells have the ability to modulate certain immune checkpoint pathways as a mechanism to evade the immune system. Certain immune checkpoint receptors or ligands are expressed by various cancer cells, targeting of which may be an effective strategy for generating anti-tumor activity. Some immune-checkpoint modulators, such as programmed death 1 (PD-1) protein, specifically regulate immune cell effector functions within tissues. One of the mechanisms by which tumor cells block anti-tumor immune responses in the tumor microenvironment is by upregulating ligands for PD-1, such as PD-L1. Hence, targeting of PD-1 and/or PD-L1 has been shown to lead to the generation of effective anti-tumor responses.
About Curis, Inc.

Curis is a biotechnology company focused on the development and commercialization of novel drug candidates for the treatment of human cancers. Curis’ pipeline of drug candidates includes CUDC-907, a dual HDAC and PI3K inhibitor, CUDC-427, a small molecule antagonist of IAP proteins, and Debio 0932, an oral HSP90 inhibitor. Curis is also engaged in a collaboration with Genentech, a member of the Roche Group, under which Genentech and Roche are developing and commercializing Erivedge®, the first and only FDA-approved medicine for the treatment of advanced basal cell carcinoma. For more information, visit Curis’ website at www.curis.com.

About Aurigene

Aurigene is a specialized, discovery stage biotechnology company, developing novel and best-in-class therapies to treat cancer and inflammatory diseases. Aurigene’s Programmed Death pathway program is the first of several immune checkpoint programs that are at different stages of discovery and preclinical development. Aurigene has partnered with several large- and mid-pharma companies in the United States and Europe and has delivered multiple clinical compounds through these partnerships. With over 500 scientists, Aurigene has collaborated with 6 of the top 10 pharma companies. Aurigene is an independent, wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (NYSE:RDY). For more information, please visit Aurigene’s website at http://aurigene.com/.

POSTER

STR3
STR3
STR3

WO2011161699, WO2012/168944, WO2013144704 and WO2013132317 report peptides or peptidomimetic compounds which are capable of suppressing and/or inhibiting the programmed cell death 1 (PD1) signaling pathway.

PATENT

WO 2015033299

Inventors

  • SASIKUMAR, Pottayil Govindan Nair
  • RAMACHANDRA, Muralidhara
  • NAREMADDEPALLI, Seetharamaiah Setty Sudarshan

Priority Data

4011/CHE/2013 06.09.2013 IN

Example 4: Synthesis of Co

str1

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

Pottayil Sasikumar

Pottayil Sasikumar

Murali Ramachandra

Murali Ramachandra

REFERENCES

US20150073024

WO2011161699A227 Jun 201129 Dec 2011Aurigene Discovery Technologies LimitedImmunosuppression modulating compounds
WO2012168944A121 Dec 201113 Dec 2012Aurigene Discovery Technologies LimitedTherapeutic compounds for immunomodulation
WO2013132317A14 Mar 201312 Sep 2013Aurigene Discovery Technologies LimitedPeptidomimetic compounds as immunomodulators
WO2013144704A128 Mar 20133 Oct 2013Aurigene Discovery Technologies LimitedImmunomodulating cyclic compounds from the bc loop of human pd1

http://www.curis.com/pipeline/immuno-oncology/pd-l1-antagonist

http://www.curis.com/images/stories/pdfs/posters/Aurigene_PD-L1_VISTA_AACR-NCI-EORTC_2015.pdf

References:

1) https://bmcimmunol.biomedcentral.com/articles/10.1186/s12865-021-00446-4

2) https://www.nature.com/articles/s42003-021-02191-1

3) https://www.esmoopen.com/article/S2059-7029(20)30108-3/fulltext

4) https://www.mdpi.com/1420-3049/24/15/2804

////////Curis, Aurigene,  AUPM 170, CA 170, AUPM-170, CA-170, PD-L1, VISTA antagonist, PD-1-IN-1, phase 2, CANCER

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

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Tisotumab vedotin


Pipeline – Tisotumab Vedotin – Seagen
A first-in-human antibody–drug conjugate: Hope for patients with advanced solid tumours? | Immunopaedia

Tisotumab vedotin

チソツマブベドチン (遺伝子組換え)Immunoglobulin G1, anti-(human blood-coagulation factor III) (human monoclonal HuMax-TF heavy chain), disulfide with human monoclonal HuMax-TF κ-chain, dimer, tetrakis(thioether) with N-[[[4-[[N-[6-(3-mercapto-2,5-dioxo-1-pyrrolidinyl)-1-oxohexyl]-L-valyl-N5-(aminocarbonyl)-L-ornithyl]amino]phenyl]methoxy]carbonyl]-N-methyl-L-valyl-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide 

  • HuMax-TF-ADC
  • Immunoglobulin G1, anti-(human tissue factor) (human monoclonal HuMax-TF heavy chain), disulfide with human monoclonal HuMax-TF κ-chain, dimer, tetrakis(thioether) with N-[[[4-[[N-[6-(3-mercapto-2,5-dioxo-1-pyrrolidinyl)-1-oxohexyl]-L-valyl-N5-(aminocarbonyl)-L-ornithyl]amino]phenyl]methoxy]carbonyl]-N-methyl-L-valyl-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide

Protein Sequence

Sequence Length: 1324, 448, 448, 214, 214multichain; modified (modifications unspecified)

FormulaC6418H9906N1710O2022S44.(C68H106N11O15)n
EfficacyAntineoplastic
  DiseaseCervical cancer
CommentAntibody-drug conjugateCAS:1418731-10-8
  • HuMax-TF-ADC
  • Tisotumab vedotin
  • Tisotumab vedotin [WHO-DD]
  • UNII-T41737F88A
  • WHO 10148

US FDA APPROVED 2021/9/20 , TIVDAK

25 Great American USA Animated Flags Gifs

FDA grants accelerated approval to tisotumab vedotin-tftv for recurrent or metastatic cervical cancer………..  https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tisotumab-vedotin-tftv-recurrent-or-metastatic-cervical-cancer

On September 20, 2021, the Food and Drug Administration granted accelerated approval to tisotumab vedotin-tftv (Tivdak, Seagen Inc.), a tissue factor-directed antibody and microtubule inhibitor conjugate, for adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

Approval was based on innovaTV 204, an open-label, multicenter, single-arm clinical trial (NCT03438396). Efficacy was evaluated in 101 patients with recurrent or metastatic cervical cancer who had received no more than two prior systemic regimens in the recurrent or metastatic setting, including at least one prior platinum-based chemotherapy regimen. Sixty-nine percent of patients had received bevacizumab as part of prior systemic therapy. Patients received tisotumab vedotin-tftv 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity.

The main efficacy outcome measures were confirmed objective response rate (ORR) as assessed by an independent review committee (IRC) using RECIST v1.1 and duration of response (DOR). The ORR was 24% (95% CI: 15.9%, 33.3%) with a median response duration of 8.3 months (95% CI: 4.2, not reached).

The most common adverse reactions (≥25%), including laboratory abnormalities, were hemoglobin decreased, fatigue, lymphocytes decreased, nausea, peripheral neuropathy, alopecia, epistaxis, conjunctival adverse reactions, hemorrhage, leukocytes decreased, creatinine increased, dry eye, prothrombin international normalized ratio increased, activated partial thromboplastin time prolonged, diarrhea, and rash. Product labeling includes a boxed warning for ocular toxicity.

The recommended dose is 2 mg/kg (up to a maximum of 200 mg for patients ≥100 kg) given as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

View full prescribing information for Tivdak.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

A fully human monoclonal antibody specific for tissue factor conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable valine-citrulline linker.

Tisotumab vedotin, sold under the brand name Tivdak is a human monoclonal antibody used to treat cervical cancer.[1]

Tisotumab vedotin was approved for medical use in the United States in September 2021.[1][2]

Tisotumab vedotin is the international nonproprietary name (INN).[3]

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References

  1. Jump up to:a b c d https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761208s000lbl.pdf
  2. ^ “Seagen and Genmab Announce FDA Accelerated Approval for Tivdak (tisotumab vedotin-tftv) in Previously Treated Recurrent or Metastatic Cervical Cancer”. Seagen. 20 September 2021. Retrieved 20 September 2021 – via Business Wire.
  3. ^ World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75”. WHO Drug Information30 (1): 159–60. hdl:10665/331046.

External links

Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetTissue factor (TF)
Clinical data
Trade namesTivdak
Other namesTisotumab vedotin-tftv
License dataUS DailyMedTisotumab_vedotin
Pregnancy
category
Contraindicated[1]
Routes of
administration
Intravenous
Drug classAntineoplastic
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
CAS Number1418731-10-8
UNIIT41737F88A
KEGGD11814

//////////Tisotumab vedotin, チソツマブベドチン (遺伝子組換え) , FDA 2021, APPROVALS 2021, Antineoplastic, CERVICAL CANCER, CANCER, MONOCLONAL ANTIBODY, UNII-T41737F88A, WHO 10148

JBI-802 BY JUBILANT


 

EXAMPLE

O=C(OC)/C=C/c1ccc(CNC2CC2c2ccc(F)cc2)cc1

EXAMPLE ONLY NOT CONFIRMED

JBI-802

  • Myeloid Leukemia Therapy
  • Solid Tumors Therapy

Epigenetic Modifier Modulators

  • Histone Deacetylase 6 (HDAC6) Inhibitors
  • Lysine-Specific Histone Demethylase 1A (KDM1A; LSD1) Inhibitors

Jubilant Therapeutics Announces Successful Completion of Pre-IND Meeting with FDA for its Novel Dual LSD1 and HDAC6 Inhibitor JB1-802

https://markets.businessinsider.com/news/stocks/jubilant-therapeutics-announces-successful-completion-of-pre-ind-meeting-with-fda-for-its-novel-dual-lsd1-and-hdac6-inhibitor-jb1-802-1030834551
PRESS RELEASE PR Newswire

Sep. 30, 2021, 10:23 AM

BEDMINSTER, NJ, Sept. 30, 2021 /PRNewswire/ — Jubilant Therapeutics Inc., a biopharmaceutical company advancing small molecule precision therapeutics to address unmet medical needs in oncology and autoimmune diseases, today announced the successful completion of a pre-IND (Investigational New Drug) meeting with the U.S. Food and Drug Administration (FDA) regarding the development plan, clinical study design and dosing strategy for the Phase I/II trial of JB1-802, a dual inhibitor of LSD1 and HDAC6, for the treatment of small cell lung cancer, treatment-induced neuro-endocrine prostate cancer and other mutation-defined neuroendocrine tumors.

Jubilant Therapeutics LogoA pre-IND meeting provides the drug development sponsor an opportunity for an open communication with the FDA to discuss the IND development plan and to obtain the agency’s guidance regarding planned clinical evaluation of the sponsor’s new drug candidate. After reviewing the preclinical data provided, plans for additional data generation and the Phase I/II clinical trial protocol, the FDA addressed Jubilant Therapeutics’ questions, provided guidance and aligned with the sponsor on the proposed development plan for JBI-802.

“We appreciate the FDA’s guidance as we endeavor to find an innovative new treatment for high unmet-need tumors with devastatingly low survival rates,” said Hari S Bhartia, Chairman, Jubilant Therapeutics Inc.

“We are pleased with the outcome of the pre-IND meeting with the FDA and plan to submit the IND application by the end of 2021,” said Syed Kazmi, Chief Executive Officer, Jubilant Therapeutics Inc.

About Jubilant TherapeuticsJubilant Therapeutics Inc. is a patient-centric biopharmaceutical company advancing potent and selective small molecule modulators to address unmet medical needs in oncology and autoimmune diseases. Its advanced discovery engine integrates structure-based design and computational algorithms to discover and develop novel, precision therapeutics against both first-in-class and validated but intractable targets in genetically defined patient populations. The Company plans to file an IND later this year for the first in class dual inhibitor of LSD1/HDAC6, followed by two additional INDs in 2022 with novel modulators of PRMT5 and PAD4 in oncology and inflammatory indications. Jubilant Therapeutics is headquartered in Bedminster NJ and guided by globally renowned key opinion leaders and scientific advisory board members. For more information, please visit www.jubilanttx.com or follow us on Twitter @JubilantTx and LinkedIn.

View original content:https://www.prnewswire.com/news-releases/jubilant-therapeutics-announces-successful-completion-of-pre-ind-meeting-with-fda-for-its-novel-dual-lsd1-and-hdac6-inhibitor-jb1-802-301388983.html

SOURCE Jubilant Therapeutics Inc.

Mohd Zainuddin

Mohd Zainuddin

Director at Jubilant Therapeutics Inc

PATENT

IN 201641016129

PATENT

US20200308110 – CYCLOPROPYL-AMIDE COMPOUNDS AS DUAL LSD1/HDAC INHIBITORS

https://patentscope.wipo.int/search/en/detail.jsf?docId=US306969204&tab=NATIONALBIBLIO&_cid=P21-KUANET-85789-2ApplicantsJubilant Epicore LLC
Inventors

Sridharan RAJAGOPAL
Mahanandeesha S. HALLUR
Purushottam DEWANG
Kannan MURUGAN
Durga Prasanna KUMAR C.H.
Pravin IYER
Chandrika MULAKALA
Dhanalakshmi SIVANANDHAN
Sreekala NAIR
Mohd ZAINUDDIN
Subramanyam Janardhan TANTRY
Chandru GAJENDRAN
Sriram RAJAGOPAL
Priority Data201641016129 09.05.2016 IN

Sridharan Rajagopal

Sridharan Rajagopal

Vice President-Head of Medicinal Chemistry at Jubilant Therapeutics Inc

Dhanalakshmi Sivanandhan

Dhanalakshmi Sivanandhan

Vice President at Jubilant Therapeutics Inc

Mahanandeesha Hallur

Mahanandeesha Hallur

Associate Director at Jubilant Biosys

Sreekala Nair

Sreekala Nair

Chandrika Mulakala

Chandrika Mulakala

  

Pravin Iyer

Pravin Iyer

Purushottam (M.) Dewang

Purushottam (M.) Dewang

ERRORS CALL ME , +919321316780

AND TO ADD TOO

SCHEMBL19590792.png

 EXAMPLE

CAS 2152635-16-8

C20 H20 F N O22-​Propenoic acid, 3-​[4-​[[[2-​(4-​fluorophenyl)​cyclopropyl]​amino]​methyl]​phenyl]​-​, methyl ester, (2E)​-Molecular Weight, 325.38

Patent

WO2017195216

I-3methyl (E)-3-(4-(((tert-butoxycarbonyl)(2-(4-((4-fluorobenzyl)oxy)phenyl) cyclopropyl)amino)methyl)phenyl)acrylate

Figure imgf000167_0001

The compound was synthesized using amine B6 and (E)-3-(4-Formyl-phenyl)-acrylic acid methyl esterfoUowing the procedure for the synthesis of 1-2. LC-MS m/z calcd for C32H34FN05, 531.2; found 532.2 [M+H]+.

Figure imgf000166_0003
Publication NumberTitlePriority DateGrant Date
EP-3455204-A1Cyclopropyl-amide compounds as dual lsd1/hdac inhibitors2016-05-09
WO-2017195216-A1Cyclopropyl-amide compounds as dual lsd1/hdac inhibitors2016-05-09
US-2020308110-A1Cyclopropyl-amide compounds as dual lsd1/hdac inhibitors2016-05-09
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Step 2: (E)-3-[4-({tert-Butoxycarbonyl-[2-(4-fluoro-phenyl)-cyclopropyl]-amino}-methyl)-phenyl]-acrylic acid methyl ester (I-2)


(MOL)(CDX)
      To a stirred solution of (E)-3-(4-{[2-(4-fluoro-phenyl)-cyclopropylamino]-methyl}-phenyl)-acrylic acid methyl ester (XLVI, 0.25 g, 0.76 mmol) in tetrahydrofuran and water mixture (6 mL, 1:1) was added sodium bicarbonate (0.087 g, 2.3 mmol) and Boc anhydride (0.22 mL, 0.92 mmol) at room temperature and the resulting mixture was stirred at that temperature for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethylacetate and the organic portion was washed with water and brine solution, dried over sodium sulphate and concentrated under reduced pressure to get the crude product which was purified by column chromatography using ethylacetate-hexane gradient to afford the titled product as sticky oil (I-2, 0.19 g, 58%). LC-MS m/z calcd for C 2528FNO 4, 425.2; found 326.3 [M-Boc+1] +.
      The following compounds were synthesized using procedure for the synthesize of I-2

REFJBI-802, novel dual inhibitor of LSD1-HDAC6 for treatment of cancerSivanandhan, D.; Rajagopal, S.; Nair, S.; et al.Annu Meet Am Assoc Cancer Res (AACR) · 2020-06-22 / 2020-06-24 · Virtual, N/A · Abst 1756Synthesis and optimization of a novel series of LSD1-HDAC dual inhibitors led to the discovery of JBI-802 as the lead compound, with IC50 of 0.05 mcM against LSD1 and isoform selective HDAC6/8 activity, with IC50 of 0.011 and 0.098 mcM for HDAC6 and HDAC8, respectively. The candidate also showed excellent selectivity against other HDACs, with approximately 77-fold selectivity for HDAC6. In vitro, JBI-802 showed strong antiproliferative activity on selected cell lines, including acute myeloid leukemia, chronic lymphocytic leukemia, lymphoma and certain solid tumors, such as small cell lung cancer and sarcoma. In vivo, JBI-802 demonstrated strong efficacy in erythroleukemia xenograft model, leading to prolonged survival of mice bearing HEL92.1.7 tumors. The candidate showed excellent dose-response and superior efficacy compared to single agents in this model, with ED50 of approximately 6.25 mg/kg twice-daily by oral administration. When evaluated in CT-26 syngeneic model, JBI-802 showed promising activity as single agent and in the combination of JBI-802 plus anti-programmed cell death protein 1 (PD-1) monoclonal antibody (MAb), with approximately 80% tumor growth inhibition observed for the combination. Exploratory toxicology studies showed that JBI-802 was well tolerated at efficacious doses. Further preclinical IND-enabling studies are currently underway for this molecule, which is to be developed as a clinical candidate for the treatment of acute myeloid leukemia and other tumor types. 

REFNovel dual inhibitor of LSD1-HDAC6/8 for treatment of cancerDhanalakshmi, S.; Rajagopal, S.; Sadhu, N.; et al.62nd Annu Meet Am Soc Hematol · 2020-12-05 / 2020-12-08 · Virtual, N/A · Abst 3378 Blood 2020, 136(Suppl. 1) 


REFJubilant Therapeutics Presents Preclinical Data at the American Association for Cancer Research, Reveals Unique Dual-Action Anti-Cancer Mechanism Underscoring First-in-Class Pipeline Asset in Hematological Tumors 
Jubilant Therapeutics Press Release 2020, June 22

////////////////JB1-802, JUBILANT, CANCER,  PRECLINICAL

EXTRAS…………

PATENTWO2021062327 – FUSED PYRIMIDINE COMPOUNDS, COMPOSITIONS AND MEDICINAL APPLICATIONS THEREOFhttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021062327&_cid=P21-KUAMRR-83330-1PCT/US2020/052953

Priority Data

201941039277 27.09.2019 IN

Inventors

  • VENKATESHAPPA, Chandregowda
  • SIVANANDHAN, Dhanalakshmi
  • RAJAGOPAL, Sridharan
  • ROTH, Bruce
  • PANDEY, Anjali
  • SAXTON, Tracy
  • HALLUR, Gurulingappa
  • MADHYASTHA, Naveena
  • SADHU M, Naveen

Lung cancer accounts for the greatest number of cancer deaths, and approximately 85% of lung cancer cases are non-small cell lung cancer (NSCLC). The development of targeted therapies for lung cancer has primarily focused on tumors displaying specific oncogenic drivers, namely mutations in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Three generations of tyrosine kinase inhibitors (TKIs) have been developed for cancers with the most frequently observed EGFR mutations, however, other oncogenic drivers in the EGFR family of receptor tyrosine kinases have received less research and development focus and several oncogenic drivers, including insertions in the exon 20 gene of EGFR, have no currently approved therapeutics to treat their cancers.

[0003] The mutation, amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2), another member of the human epidermal growth factor receptor family of receptor tyrosine kinases, has been implicated in the oncogenesis of several cancers, including lung, breast, ovarian, and gastric cancers. Although targeted therapies such as trastuzumab and lapatinib have shown clinical efficacy especially in breast tumors, their utility in lung cancer has been limited. It is likely that this variation is due to tissue-specific factors, including the low potency of kinase inhibitors like lapatinib for the mutagenic alterations in HER2 that are observed in the lung cancer patient population, including insertions in the exon 20 gene of HER2.

[0004] Given that many patients with mutations in EGFR and HER2 do not derive clinical benefit from currently available therapies against these targets, there remains a significant unmet need for the development of novel therapies for the treatment of cancers associated with EGFR and HER2 mutations.

Compound 49: (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide

Step 1: Synthesis of (E)-4-(dimethylamino)but-2-enoyl chloride

[0280] To a stirred mixture of acetonitrile (2 mL) and DMF (2 drop) under N2 atmosphere was added N,N-dimethylamino crotonic acid hydrochloride (0.1 g, 0.77 mmol). After 10 min, this solution was cooled to 0-5 °C. Oxalyl chloride (0.122 g, 0.968 mmol) was added and the reaction mixture was maintained at 0-5 °C for 30 min. It was allowed to warm to RT and stirring was continued for 2 h. It was then heated to 40 °C for 5 min and again brought to RT and stirred for 10 min. Formation of product was confirmed by TLC and the reaction mass was used as such to the next step without any workup.

Step-2: Synthesis of (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 49)

[0281] 1-(3-Aminophenyl)-3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.11g, 0.7 mmol) in DMP (2 mL) was cooled to -15 °C and then (E)-4-(dimethylamino)but-2-enoylchloride was added. The reaction mixture was stirred for 1 h at -15 °C to RT. After the completion of reaction, the reaction mass was quenched with ice water, sodium bicarbonate solution and extracted with DCM (100 mL x 2). The combined organic layer was washed with cold water (3 x 50 mL), brine solution (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified by prep HPLC to get pure product (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 49, 0.022 g, 16 % yield) as white solid.1H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.32 (s, 1H), 8.06 (s, 1H), 7.76 (bs, 1H) 7.65 (s, 1H), 7.48 (bs, 1H), 7.39-7.29 (m, 5H), 7.03 (d, J = 7.2 Hz, 2H), 6.74-6.68 (m, 1H), 6.62 (s, 1H), 6.25 (d, J = 15.2 Hz, 1H), 4.62 (s, 2H), 4.37 (s, 2H), 3.47 (s, 3H), 3.03 (d, J = 5.6 Hz, 2H), 2.15 (s, 6H); LCMS Calcd for [M+H] + 538.2, found 538.5

Compound 50: (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-3-chloroacrylamide

Step-1: Synthesis of (Z)-3-chloroacrylic acid

[0282] To a stirred solution propiolic acid (2 g, 28.5 mmol) in DMF (15 mL) under N2 atmosphere was added thionyl chloride (4.07 g, 34.2 moles) slowly and the reaction mixture was maintained at 25 °C for 1 h. The reaction was monitored by TLC, after the completion of reaction, the residue was poured into ice and the resulting aqueous solution was extracted with ether (3 x100 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified to get pure product (Z)-3-chloroacrylic acid (1.9 g, 62.9 % yield). LCMS Calcd for [M-H] +, 104.98, found 105.1

Step-2: Synthesis of (Z)-3-chloroacryloyl chloride

[0283] To a stirred solution of acetonitrile (3 mL) and DMF (3 drop) under N2 atmosphere was added of (Z)-3-chloroacrylic acid (0.2 g, 1.87 mmol). After 10 min this solution was cooled 0-5 °C. Oxalyl chloride (0.122 g, 0.968 mmol) was added and the reaction mixture was maintained at 0-5 °C for 30 min. It was allowed to warm to RT and stirring was continued for 2 h to get (Z)-3-chloroacryloyl chloride. Formation of product was confirmed by TLC and the reaction mass was used as such to the next step without any workup.

Step-3: Synthesis of (E)-3-((3-(3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)amino)acryloyl chloride (Compound 50)

[0284] A solution of 1-(3-Aminophenyl)-3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.11 g, 0.7 mmol) in DMP (2 mL) was cooled to -15 °C and then (Z)-3-chloroacryloyl chloride was added. The reaction mixture was stirred for 1 h at -15 °C to RT. The reaction was monitored by TLC. After the completion of reaction, reaction mass was quenched with ice water and sodium bicarbonate solution. The aqueous layer was e 0.028 g, 22% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 9.32 (s, 1H), 8.06 (s, 1H), 7.74 (s, 1H), 7.59 (s, 1H), 7.51 (s, 1H), 7.41-7.35 (m, 5H), 7.30-7.29 (m, 1H), 7.08-7.02 (m, 2H), 6.62-6.58 (m, 2H), 4.62 (s, 2H), 4.37 (s, 2H), 3.47 (s, 3H); LCMS Calcd for [M+H] + 515.1, LCMS found 515.2

Compound 51: (E)-N-(3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide

Step-1: Synthesis of 2,4-dichloro-5-(chloromethyl)pyrimidine

[0285] Title compound was prepared in a similar manner to general procedure I.5-(hydroxymethyl)pyrimidine-2,4-diol (15 g, 106 mmol) gave 2,4-dichloro-5-(chloromethyl)pyrimidine (11.50 g, 55% yield) as a white solid.1H NMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 4.65 (s, 2H).

Step-2: Synthesis of 2,4-dichloro-5-(iodomethyl)pyrimidine

[0286] Title compound was prepared in a similar manner to general procedure J.2,4-dichloro-5-(chloromethyl)pyrimidine (11.50 g, 58.20 mmol) on treatment with NaI (10.50 g, 69.0 mmol) in acetone (100 mL) resulted in 2,4-dichloro-5-(iodomethyl)pyrimidine (15.20 g, 91% yield). The solid was immediately taken up in toluene and stored under refrigeration.1H NMR (400 MHz, CDCl3): δ 8.60 (s, 1H), 4.39 (s, 2H).

Step-3: Synthesis of N-((2,4-dichloropyrimidin-5-yl)methyl)aniline

[0287] A solution of iodo compound (18, 7.0 g, 24.20 mmol) in toluene (50 mL) was cooled to 0 °C and aniline (2.20 g, 24.20 mmol) was added. The reaction mixture was stirred for 30 min at 0 °C. Then a solution of sodium hydroxide (1.30 g, 32.50 mmol) in water (5 ml) was added and reaction mixture was stirred for 16 h at RT. The reaction was monitored by TLC. After completion of the reaction, water (25 mL) was added and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude residue. The crude compound was purified by silica gel column chromatography to afford the title compound as a white solid (10 g, 81% yield). LCMS Calcd for [M+H] + 254.11, found 254.09

Step-4: Synthesis of tert-butyl (3-((2-chloro-5-((phenylamino)methyl)pyrimidin-4-yl)amino)phenyl)carbamate

[0288] To a stirred solution of N-((2,4-dichloropyrimidin-5-yl)methyl)aniline (4.0 g, 15.08 mmol) in IPA (30 mL), tert-butyl (3-aminophenyl)carbamate (4.90 g, 23.0 mmol) and DIPEA (8.20 mL, 47 mmol) were added. The reaction mixture was heated at 100 °C for 16 h in a sealed tube. Solvent was then evaporated and the crude thus obtained was purified by flash column chromatography to afford the title compound as off white solid (2.50 g, 37% yield). LCMS Calcd for [M+H] + 425.92, found 426.35

Step-5: Synthesis of tert-butyl (3-(7-chloro-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate

[0289] To a solution of tert-butyl (3-((2-chloro-5-((phenylamino)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (1.50 g, 3.50 mmol) in THF (35 mL) was added DIPEA (2.40 mL, 14.10 mmol) and thiophosgene (0.27 g, 3.50 mmol) at 0 °C. The reaction mixture was stirred at RT for 24 h with TLC monitoring. After completion of the reaction, sodium bicarbonate solution was added. The reaction mixture was partitioned between DCM (2 x 100 mL) and water (50 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography to afford the title compound as a yellow solid (1.36 g, 82% yield). LCMS Calcd for [M+H] + 467.97, found 468.27

Step-6: Synthesis of tert-butyl (3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate

[0290] To a solution of tert-butyl (3-(7-chloro-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (1.30 g, 2.78 mmol) in IPA (15 mL) was added 3-

chloro-1-methyl-1H-pyrazol-4-amine (0.44 g, 3.34 mmol) and TFA (1 mL). The reaction mixture was heated for 16 h at 110 °C. Reaction was monitored by TLC. After the completion of reaction, the reaction mixture was concentrated, water (10 mL) and saturated sodium bicarbonate (20 mL) solution were added to the residue and extracted with DCM (3 x 200 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound (1.30 g) that was used as such for the next step without further purification. LCMS Calcd for [M+H] + 563.08, found 562.90

Step-7: Synthesis of 1-(3-aminophenyl)-7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-thione

[0291] To an ice-cold solution of tert-butyl (3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (1.30 g, 2.30 mmol) in DCM (20 mL) and MeOH (10 mL) was added 4N HCl in dioxane (5 mL). The reaction mixture was stirred for 16 h at RT. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated followed by addition of water (10 mL) and saturated sodium bicarbonate (20 mL) solution and extraction with DCM (3 x 200 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography to afford the title compound as a brown solid (0.20 g). LCMS Calcd for [M+H] + 462.96, found 463.0. Purity: 68%

Step-8: Synthesis of (E)-N-(3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 51)

[0292] To an ice-cold solution of 1-(3-aminophenyl)-7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-thione (0.18 g, 0.39 mmol) and trans-N,N-dimethylaminocrotonic acid hydrochloride (0.077 g, 0.47 mmol) in dichloromethane (10 mL) was added triethyl amine (1.2 mmol) followed by drop wise addition of propylphosphonic anhydride (T3P) (0.26 g, 0.97 mmol). The mixture was stirred at RT for 6 h. Completion of the reaction was monitored by TLC. The reaction mixture was portioned between 5% methanol in dichloromethane and saturated bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude obtained was purified by silica gel chromatography to afford the title compound as off white solid (Compound 51, 0.010 g, 5% yield).1H NMR (400 MHz, DMSO-d6): δ 10.36 (bs, 1H), 8.97 (bs, 1H), 8.25 (s, 1H), 7.72 (bs, 2H), 7.48-7.42 (m, 5H), 7.36-7.32 (m, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.76-6.60 (m, 2H), 6.30 (d, J = 14.8 Hz, 1H), 4.95 (s, 2H), 3.50 (s, 3H), 3.12 (bs, 2H), 2.21 (s, 6H); LCMS Calcd for [M+H] + 574.10, found 574.41

Scheme 28: Preparation of (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 52):

 Step 1: Preparation of ethyl 4-((3-((tert-butoxycarbonyl) amino) phenyl) amino)-2-(methylthio) pyrimidine-5-carboxylate (106):

[0293] Title compound (106) was prepared as off-white solid (142 g; Yield: 74%) in a manner substantially similar to procedure mentioned in General procedure O.1H-NMR (400 MHz, CDCl3): ^ 10.36 (s, 1H), 8.77 (d, 1H), 7.89 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.51 (s, 1H), 4.35 (q, J = 7.2 Hz, 2H), 2.54 (s, 3H), 1.51 (s, 9H), 1.42-1.38 (m, 3H). LCMS: [M+H]+ 405.21, 89.28%.

Step 2: Preparation of tert-butyl (3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (107):

[0294] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure P. The crude was triturated with dichloromethane afforded 107 as off white solid (40.0 g; Yield: 31%).1H-NMR (400 MHz, CDCl3): ^ 8.09 (s, 1H), 7.86 (m, 2H),

7.36 (d, J = 8.0 Hz, 1H), 7.25-7.15 (m, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 4.59 (s, 2H), 2.50 (s, 3H), 1.51 (s, 9H). LCMS: [M+H]+ 363.05, 91.24%.

Step 3: Preparation of tert-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (108):

[0295] Title compound (108) was prepared as a pale yellow solid (31.0 g; Yield: 78%) in a manner substantially similar to procedure mentioned in General procedure Q.1H-NMR (400 MHz, CDCl3): ^ 10.59 (s, 1H), 9.75 (s, 1H), 8.42 (s, 1H), 7.97 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.59 (s, 1H), 3.48 (s, 1H), 2.58 (s, 3H), 1.52 (s, 9H). LCMS: [M+H]+ 361.30, 97.51%.

Step 4: Preparation of tert-butyl (E)-(3-((5-((benzylimino)methyl)-2(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (110):

[0296] Title compound (110) was prepared as a yellow solid (28 g; Yield: 72%) in a manner substantially similar to procedure mentioned in General procedure R.1H-NMR (400 MHz, CDCl3): ^ 12.15 (s, 1H), 8.31 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.41 (m, 4H), 7.35-7.33 (m, 1H), 7.32-7.29 (m, 1H), 7.26-7.22 (m, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.46 (s, 1H), 4.84 (s, 2H), 2.59 (s, 3H), 1.52 (s, 9H). LCMS: [M+H]+ 450.38; 99.66%.

Step 5: Preparation of tert-butyl (3-((5-((benzylamino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (111):

[0297] Title compound (111) was prepared as a pale yellow solid (40 g; Yield: 80%) in a manner substantially similar to procedure mentioned in General procedure S. LCMS: [M+H]+ 452.44; 83.57%

Step 6: Preparation of tert-butyl (3-(3-benzyl-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (112):

[0298] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure T. The crude was triturated with diethyl ether afforded 112 as off white solid (12 g; Yield: 28%).1H-NMR (400 MHz, CDCl3): ^ 8.03 (s, 1H), 7.50 (s, 1H), 7.37 (m, 6H), 7.26 (m, 1H), 6.96 (m, 1H), 6.59 (s, 1H), 4.69 (s, 2H), 4.34 (s, 2H), 2.16 (s, 3H), 1.50 (s, 9H). LCMS: [M+H]+ 478.16; 95.62%.

Step 7: Preparation of tert-butyl (3-(3-benzyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido [4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (113):

[0299] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure U. The crude was triturated with diethyl ether afforded 113 as an off white solid (8.0 g; Yield: 76%).1H-NMR (400 MHz, CDCl3): ^ 8.39 (s, 1H), 7.63 (s, 1H), 7.40 (m, 6H), 7.17 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.61 (s, 1H), 4.71 (s, 2H), 4.48 (s, 2H), 2.97 (s, 3H), 1.49 (s, 9H). LCMS: [M+H]+ 510.31, 93.69%.

Step 8: Preparation of tert-butyl (3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (114):

[0300] Title compound was prepared in a manner substantially similar to General procedure V, tert-butyl (3-(3-benzyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (113) and 1-methyl-1H-pyrazol-3-amine (41) gave (tert-butyl (3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (114) as a brown solid (Yield: 77%), which was used directly for the next step without any further purification. MS: [M+H]+ 527.46.

Step 9: Preparation of 1-(3-aminophenyl)-3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (115):

[0301] Title compound was prepared in a manner substantially similar to General procedure W, tert-butyl (3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (114) gave 1-(3-aminophenyl)-3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (115) as a brown solid (Yield: 93%), which was used directly for the next step. MS: [M+H]+ 427.44.

Step 10: Preparation of (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 52):

[0302] Title compound was prepared in a manner substantially similar General procedure X, 1-(3-aminophenyl)-3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (115) and trans-N,N-dimethylaminocrotonic acid hydrochloride gave (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide Compound 52, as a white solid (48 mg; Yield: 13%), after prep-HPLC purification.1H-NMR (400 MHz, CDCl3): δ 10.17 (s, 1H), 9.51 (s, 1H), 8.08 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.43-7.35 (m, 5H), 7.33-7.29 (m, 1H), 7.10 (s, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.75-6.69 (m, 1H), 6.27 (d, J = 15.3 Hz, 1H), 5.51 (s, 1H), 4.62 (s, 2H), 4.39 (s, 2H), 3.59 (s, 3H), 3.06 (d, J = 4.8 Hz, 2H), 2.17 (s, 6H). MS: [M+H]+ 538.32.

Scheme 30: Alternative Preparation of (E)-N-(3-(7-((3-chloro-1-methyl-1H-pyrazol-4- yl)amino)-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4- (dimethylamino)but-2-enamide (Compound 35):

Step 1: Preparation of 5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (119):

[0308] An ice-cold solution of pyrimidine-2,4(1H,3H)-dione (118) (10 g, 89.21 mmol) and paraformaldehyde (9.63 g, 107.05 mmol) in aqueous potassium hydroxide (132 mL, 0.5 M,

66.74 mmol) was heated at 55 °C for 14 hours. After completion of starting material (TLC), the reaction mixture was cooled to 0 °C and the pH was adjusted to 6 with 12N hydrochloric acid, the resulting white precipitate was filtered through sintered funnel and washed with diethyl ether afforded 119 as a white solid (6.3 g, Yield: 50%) which was used directly for the next step.1H-NMR (400 MHz, DMSO-d6): ^ 10.98 (bs, 1H), 10.64 (bs, 1H), 7.24 (s, 1H), 4.78 (m, 1H), 4.12 (d, J = 12.8 Hz, 2H). LCMS: [M+H]+ 143.04 (99.92% purity).

Step 2: Preparation of 2,4-dichloro-5-(chloromethyl)pyrimidine (120):

[0309] To an ice-cold solution of 5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (119) (10 g, 70.36 mmol) in toluene (25 mL) was added phosphoryl chloride (14 mL, 140.72 mmol) then N,N-diisopropylethylamine (37 mL, 211 mmol). The reaction mixture was heated at 120 °C for 16 hours. After the complete disappearance of starting material on TLC, the reaction mixture was quenched slowly with sodium bicarbonate solution and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure afforded 120 as a brown solid (12 g, Yield: 86%) which was used directly for the next step.1H NMR (400 MHz, CDCl3): ^ 8.66 (s, 1H), 4.64 (s, 2H). MS: [M+H]+ 197.0

Step 3: Preparation of 2,4-dichloro-5-(iodomethyl)pyrimidine (121):

[0310] To a solution of 2,4-dichloro-5-(chloromethyl)pyrimidine (120) (8.0 g, 40.51 mmol in acetone (40 mL) was added sodium iodide (9.71 g, 64.82 mmol). The reaction mixture was stirred at room temperature for 30 min and heated to reflux for 2 hours. After completion of reaction (TLC monitoring), the reaction mixture cooled to room temperature. The resulting white precipitate was filtered through sintered funnel and washed with acetone. The filtrate was concentrated under reduced pressure afforded 121 as a brown solid (10 g, Yield: 85%) which was used directly for the next step.1H-NMR (400 MHz, CDCl3): ^ 8.60 (s, 1H), 4.39 (s, 2H). Step 4: Preparation of N-((2,4-dichloropyrimidin-5-yl)methyl)aniline (122):

[0311] To an ice-cold solution of 2, 4-dichloro-5-(iodomethyl)pyrimidine (121) (5.0 g, 17.30 mmol) in acetone (50 mL) was added potassium carbonate (5.26 g, 38.06 mmol) and aniline (1.93 g, 20.76 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. After completion the reaction (as per TLC monitoring), the resulting white precipitate was filtered through sintered funnel and washed with acetone. The filtrate was concentrated under reduced pressure and crude was purified by column chromatography on silica gel (100-200 mesh) using 15% ethyl acetate-hexane as an eluent afforded 122 as a brown solid (2.5 g, Yield: 57%).1H-NMR (400 MHz, CDCl3): ^ 8.61 (s, 1H), 7.07 (t, J = 7.6 Hz, 2H), 6.58 (m, 3H), 6.30 (bs, 1H), 4.33 (m, 2H). LCMS: [M+H]+ 254.03 (99.01% purity).

Step 5: Preparation of tert-butyl (3-(7-chloro-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (123):

[0312] To an ice-cold solution of N-((2,4-dichloropyrimidin-5-yl)methyl)aniline (122) (500 mg, 1.96 mmol), in isopropanol (5 mL) was added N,N-diisopropylethylamine (1.47 mL, 8.42 mmol) and tert-butyl (3-aminophenyl)carbamate (105) (409 mg, 1.96 mmol). The resulting reaction mixture was heated at 100 °C for 16 hours in a sealed tube. After completion of reaction (TLC monitoring), the solvent was then evaporated under reduced pressure and resulting crude was purified by column chromatography on silica gel (100-200 mesh) using 30% ethyl acetate-hexane as an eluent afforded 123 as a brown solid (500 mg, Yield: 60%).1H-NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H), 8.96 (s, 1H), 8.10 (s, 1H), 7.73 (s, 1H), 7.25 (m, 2H), 7.12 (m, 3H), 6.61 (m, 3H), 6.14 (t, J = 7.2 Hz, 1H), 4.26 (m, 2H) and 1.53 (s, 9H). LCMS: [M+H]+ 426.14 (93% purity).

Step 6: Preparation of tert-butyl (3-(7-chloro-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (124):

[0313] To an ice-cold solution of tert-butyl (3-(7-chloro-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (123) (500 mg, 1.17 mmol) in tetrahydrofuran (6 mL) was added N,N-diisopropylethylamine (0.81 ml, 4.68 mmol) and triphosgene (139 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction (TLC monitoring), aqueous triethylamine solution was added and extracted with dichloromethane (3 times). The combined organic layer was washed with brine and dried over sodium sulfate and evaporated under reduced pressure to obtain the crude residue. The crude was purified by column chromatography on silica gel (100-200 mesh) using 30% ethyl acetate-hexane as an eluent afforded 124 as a brown solid (450 mg, Yield: 85%).1H-NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 8.43 (s, 1H), 7.58 (s, 1H), 7.44 (m, 4H), 7.29 (t, J = 7.2 Hz, 3H), 6.94 (s, 1H), 5.0 (s, 2H) and 1.47 (s, 9H). LCMS: [M+H]+ 452.27 (99% purity).

Step 7: Preparation of tert-butyl (3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (125):

[0314] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure V, (tert-butyl(3-(7-chloro-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (124) and 3-chloro-1-methyl-1H-pyrazol-4-amine (44) gave tert-butyl (3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (125) as a brown solid in 70% yield, which was used directly for the next step. MS: [M+H]+ 547.17.

Step 8: Preparation of 1-(3-aminophenyl)-7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (126):

[0315] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure W, tert-butyl (3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (125) gave 1-(3-aminophenyl)-7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (126) as a brown solid (800 mg, Yield: 82%) which was used directly for the next step. MS: [M+H]+ 447.08.

Step 9: Preparation of (E)-N-(3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 35):

[0316] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure X, 1-(3-aminophenyl)-7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (126) and trans-N,N-dimethylaminocrotonic acid hydrochloride gave the titled compound, which was purified by prep-HPLC purification to afforded the title compound Compound 35 as a white solid (285 mg, Yield: 23%).1H-NMR (400 MHz, DMSO-d6): δ 10.27 (bs, 1H), 8.86 (s, 1H), 8.21 (s, 1H), 7.73 (s, 2H), 7.51-7.40 (m, 5H), 7.30-7.25 (m, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.76-6.70 (m, 2H), 6.29 (d, J = 15.4 Hz, 1H), 4.88 (s, 2H), 3.50 (s, 3H), 3.05 (d, J = 4.8 Hz, 2H) and 2.16 (s, 6H). MS:

[M+H]+ 558.16.

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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

wdt-13

wdt-13

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Dostarlimab


(Heavy chain)
EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYDMSWVRQA PGKGLEWVST ISGGGSYTYY
QDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCASPY YAMDYWGQGT TVTVSSASTK
GPSVFPLAPC SRSTSESTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS
LSSVVTVPSS SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP
PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE QFNSTYRVVS
VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS QEEMTKNQVS
LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSRLTVDK SRWQEGNVFS
CSVMHEALHN HYTQKSLSLS LGK
(Light chain)
DIQLTQSPSF LSAYVGDRVT ITCKASQDVG TAVAWYQQKP GKAPKLLIYW ASTLHTGVPS
RFSGSGSGTE FTLTISSLQP EDFATYYCQH YSSYPWTFGQ GTKLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H130-L214, H143-H199, H222-H’222, H225-H’225, H257-H317, H363-H421, H’22-H’96, H’130-L’214, H’143-H’199, H’257-H’317, H’363-H’421, L23-L88, L134-L194, L’23-L’88, L’194-L’134)

>Heavy Chain
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISGGGSYTYY
QDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSASTK
GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP
PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS
VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS
LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS
CSVMHEALHNHYTQKSLSLSLGK
>Light Chain
DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTLHTGVPS
RFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTKLEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]

Dostarlimab

Immunoglobulin G4, anti-​(programmed cell death protein 1 (PDCD1)​) (humanized clone ABT1 γ4-​chain)​, disulfide with humanized clone ABT1 κ-​chain, dimer

Protein Sequence

Sequence Length: 1314, 443, 443, 214, 214multichain; modified (modifications unspecified)

  • GSK-4057190
  • GSK4057190
  • TSR 042
  • TSR-042
  • WBP-285
  • ANB 011
FormulaC6420H9832N1680O2014S44
CAS2022215-59-2
Mol weight144183.6677

Jemperli FDA 2021/4/22 AND EMA 2021/4/21

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Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody medication used for the treatment of endometrial cancer.[1][2][3][4]

The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation.[1][2] The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased.[1][2]

Dostarlimab is a programmed death receptor-1 (PD-1)–blocking antibody.[1][2]

Dostarlimab was approved for medical use in the United States in April 2021.[1][2][5]

NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
JemperliInjection50 mg/1mLIntravenousGlaxoSmithKline LLC2021-04-22Not applicableUS flag 

Medical uses

Dostarlimab is indicated for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen.[1][2]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC) for adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior  platinum-containing regimen.

Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors. The efficacy population consisted of 71 patients with dMMR recurrent or advanced endometrial cancer who progressed on or after  a platinum-containing regimen. Patients received dostarlimab-gxly, 500 mg intravenously, every 3 weeks for 4 doses followed by 1,000 mg intravenously every 6 weeks.

The main efficacy endpoints were overall response rate (ORR) and duration of response (DOR), as assessed by blinded independent central review (BICR) according to RECIST 1.1. Confirmed ORR was 42.3% (95% CI: 30.6%, 54.6%). The complete response rate was 12.7% and partial response rate was 29.6%. Median DOR was not reached, with 93.3% of patients having  durations  ≥6 months (range: 2.6 to 22.4 months, ongoing at last assessment).

Serious adverse reactions occurred in 34% of patients receiving dostarlimab-gxly. Serious adverse reactions in >2% of patients included sepsis , acute kidney injury , urinary tract infection , abdominal pain , and pyrexia . The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation. The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased. Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The recommended dostarlimab-gxly dose and schedule (doses 1 through 4) is 500 mg every 3 weeks. Subsequent dosing, beginning 3 weeks after dose 4, is 1,000 mg every 6 weeks until disease progression or unacceptable toxicity. Dostarlimab-gxly should be administered as an intravenous infusion over 30 minutes.

View full prescribing information for Jemperli.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

FDA also approved the VENTANA MMR RxDx Panel as a companion diagnostic device for selecting endometrial cancer patients for treatment with dostarlimab-gxly.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review, and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Side effects

Serious adverse reactions in >2% of patients included sepsis, acute kidney injury, urinary tract infection, abdominal pain, and pyrexia.[1][2]

Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.[1][2]

History

Like several other available and experimental monoclonal antibodies, it is a PD-1 inhibitor. As of 2020, it is undergoing Phase I/II and Phase III clinical trials.[6][7][8] The manufacturer, Tesaro, announced prelimary successful results from the Phase I/II GARNET study.[6][9][10]

In 2020, the GARNET study announced that Dostarlimab was demonstrating potential to treat a subset of women with recurrent or advanced endometrial cancer.[11]

April 2021, Dostarlimab is approved for the treatment of recurrent or advanced endometrial cancer with deficient mismatch repair (dMMR), which are genetic anomalies abnormalities that disrupt DNA repair.[12]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC).[1] Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors.[1]

Society and culture

Legal status

On 25 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Jemperli, intended for the treatment of certain types of recurrent or advanced endometrial cancer.[13] The applicant for this medicinal product is GlaxoSmithKline (Ireland) Limited.[13]

References[

  1. Jump up to:a b c d e f g h i j k “FDA grants accelerated approval to dostarlimab-gxly for dMMR endometri”U.S. Food and Drug Administration(FDA) (Press release). 22 April 2021. Retrieved 22 April 2021. This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b c d e f g h i “Jemperli- dostarlimab injection”DailyMed. Retrieved 28 April 2021.
  3. ^ Statement On A Nonproprietary Name Adopted By The USAN Council – DostarlimabAmerican Medical Association.
  4. ^ World Health Organization (2018). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 119” (PDF). WHO Drug Information32 (2).
  5. ^ “FDA grants accelerated approval for GSK’s Jemperli (dostarlimab-gxly) for women with recurrent or advanced dMMR endometrial cancer” (Press release). GlaxoSmithKline. 22 April 2021. Retrieved 22 April 2021 – via PR Newswire.
  6. Jump up to:a b Clinical trial number NCT02715284 for “A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors (GARNET)” at ClinicalTrials.gov
  7. ^ Clinical trial number NCT03981796 for “A Study of Dostarlimab (TSR-042) Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Patients With Recurrent or Primary Advanced Endometrial Cancer (RUBY)” at ClinicalTrials.gov
  8. ^ Clinical trial number NCT03602859 for “A Phase 3 Comparison of Platinum-Based Therapy With TSR-042 and Niraparib Versus Standard of Care Platinum-Based Therapy as First-Line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer (FIRST)” at ClinicalTrials.gov
  9. ^ “Data from GARNET study indicates robust activity of dostarlimab in patients with advanced or recurrent endometrial cancer”Tesaro (Press release). Retrieved 1 January 2020.
  10. ^ Scalea B (28 May 2019). “Dostarlimab Effective in Endometrial Cancer Regardless of MSI Status”Targeted Oncology. Retrieved 1 January 2020.
  11. ^ “GSK Presents New Data from the GARNET Study Demonstrating Potential of Dostarlimab to Treat a Subset of Women with Recurrent or Advanced Endometrial Cancer – Drugs.com MedNews”Drugs.com. Retrieved 29 April 2020.
  12. ^ “FDA Approves New Immunotherapy for Endometrial Cancer”Medscape. Retrieved 23 April 2021.
  13. Jump up to:a b “Jemperli: Pending EC decision”European Medicines Agency (EMA) (Press release). 25 February 2021. Retrieved 22 April 2021.

External links

  • “Dostarlimab”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02715284 for “Study of TSR-042, an Anti-programmed Cell Death-1 Receptor (PD-1) Monoclonal Antibody, in Participants With Advanced Solid Tumors (GARNET)” at ClinicalTrials.gov
  1. Kaplon H, Muralidharan M, Schneider Z, Reichert JM: Antibodies to watch in 2020. MAbs. 2020 Jan-Dec;12(1):1703531. doi: 10.1080/19420862.2019.1703531. [Article]
  2. Temrikar ZH, Suryawanshi S, Meibohm B: Pharmacokinetics and Clinical Pharmacology of Monoclonal Antibodies in Pediatric Patients. Paediatr Drugs. 2020 Apr;22(2):199-216. doi: 10.1007/s40272-020-00382-7. [Article]
  3. Green AK, Feinberg J, Makker V: A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer. Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-7. doi: 10.1200/EDBK_280503. [Article]
  4. Deshpande M, Romanski PA, Rosenwaks Z, Gerhardt J: Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability. Cancers (Basel). 2020 Nov 10;12(11). pii: cancers12113319. doi: 10.3390/cancers12113319. [Article]
  5. FDA Approved Drug Products: Jemperli (dostarlimab-gxly) for intravenous injection [Link]
  6. FDA News Release: FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer [Link]
  7. Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]
Monoclonal antibody
TypeWhole antibody
SourceHumanized
TargetPCDP1
Clinical data
Trade namesJemperli
Other namesTSR-042, WBP-285, dostarlimab-gxly
License dataUS DailyMedDostarlimab
Routes of
administration
Intravenous
Drug classAntineoplastic
ATC codeL01XC40 (WHO)
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
CAS Number2022215-59-2
PubChem SID384585344
DrugBankDB15627
UNIIP0GVQ9A4S5
KEGGD11366
Chemical and physical data
FormulaC6420H9832N1690O2014S44
Molar mass144325.73 g·mol−1

/////////Dostarlimab,  PEPTIDE, ANTINEOPLASTIC, CANCER, ドスタルリマブ , GSK 4057190, GSK4057190, TSR 042, TSR-042, WBP-285, FDA 2021, EU 2021

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