LORPUCITINIB

JNJ 64251330

2230282-02-5

UNII-OE1QTY7C25

2-[3-[4-(cyanomethyl)cyclohexyl]-3,5,8,10-tetrazatricyclo[7.3.0.0^2,6]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 40^oC for 4 hours, and further stirred for 14 hours at 25^oC, then heptane was slowly added (1:2, for example 20 ml of heptane into the compound/DCM slurry/solution) at 25^oC, stirred at 40^oC for 4 hours, cooled to 25^oC and stirred for further 14 hours at 25^oC. 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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Clip

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 site. APC 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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Terlipressin acetate

テルリプレシン酢酸塩

C52H74N16O15S2. (C2H4O2)x

Terlipressin acetate (JAN);
Heamopressin (TN);
Terlivaz (TN)

Cardiovascular agent

Antidiuretic, Vasoconstrictor, Arginine vasopressin receptor agonist

USFDA APPROVED 2022/9/14

An inactive peptide prodrug that is slowly converted in the body to lypressin. It is used to control bleeding of ESOPHAGEAL VARICES and for the treatment of HEPATORENAL SYNDROME.

• EINECS 238-680-8
• Terlipressin
• Terlipressina
• Terlipressina [INN-Spanish]
• Terlipressine
• Terlipressine [INN-French]
• Terlipressinum
• Terlipressinum [INN-Latin]
• UNII-7Z5X49W53P

acetic acid;(2S)-1-[(4R,7S,10S,13S,16S,19R)-19-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-13-benzyl-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]-N-[(2S)-6-amino-1-[(2-amino-2-oxoethyl)amino]-1-oxohexan-2-yl]pyrrolidine-2-carboxamide

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14636-12-5

(2S)-1-[(4R,7S,10S,13S,16S,19R)-19-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]-13-benzyl-10-(2-carbamoylethyl)-7-(carbamoylmethyl)-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]-N-[(1S)-5-amino-1-(carbamoylmethylcarbamoyl)pentyl]pyrrolidine-2-carboxamide;N-(N-(N-Glycylglycyl)glycyl)-8-L-lysinevasopressin;Glypressin;Terlipressin Acetate;Remestyp;Thymosin α1 Acetate;Gly-Gly-Gly-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2 (disulfide bridge 4:9);Glycylpressin;

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Terlipressin, sold under the brand name Terlivaz among others, is an analogue of vasopressin used as a vasoactive drug in the management of low blood pressure. It has been found to be effective when norepinephrine does not help. Terlipressin is a vasopressin receptor agonist.^[1]

Medical uses

Terlipressin is indicated to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function.^[1]

Indications for use include norepinephrine-resistant septic shock^[2] and hepatorenal syndrome.^[3] In addition, it is used to treat bleeding esophageal varices.^[4]

Contraindications

Terlipressin is contraindicated in people experiencing hypoxia or worsening respiratory symptoms and in people with ongoing coronary, peripheral or mesenteric ischemia.^[1] Terlipressin may cause fetal harm when used during pregnancy.^[1]

Society and culture

Terlipressin is available in New Zealand,^[5] Australia, the European Union,^[6] India, Pakistan & UAE. It is sold under various brand names including Glypressin.

References

1. ^ Jump up to:^{a b c d e} “Archived copy” (PDF). Archived (PDF) from the original on 2022-09-19. Retrieved 2022-09-19.
2. ^ O’Brien A, Clapp L, Singer M (2002). “Terlipressin for norepinephrine-resistant septic shock”. Lancet. 359 (9313): 1209–10. doi:10.1016/S0140-6736(02)08225-9. PMID 11955542. S2CID 38463837.
3. ^ Uriz J, Ginès P, Cárdenas A, Sort P, Jiménez W, Salmerón J, Bataller R, Mas A, Navasa M, Arroyo V, Rodés J (2000). “Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome”. J Hepatol. 33 (1): 43–8. doi:10.1016/S0168-8278(00)80158-0. PMID 10905585.
4. ^ Ioannou G, Doust J, Rockey D (2003). Ioannou GN (ed.). “Terlipressin for acute esophageal variceal hemorrhage”. Cochrane Database Syst Rev (1): CD002147. doi:10.1002/14651858.CD002147. PMC 7017851. PMID 12535432.
5. ^ http://www.medsafe.govt.nz/profs/datasheet/g/Glypressin01mgmlFerringinj.pdf Archived 2021-12-20 at the Wayback Machine^{[bare URL PDF]}
6. ^ “Terlipressin”. Archived from the original on 2019-06-26. Retrieved 2018-01-23.

External links

• “Terlipressin”. Drug Information Portal. U.S. National Library of Medicine.

////Terlipressin acetate, テルリプレシン酢酸塩 , FDA 2022, APPROVALS

2022, CC(=O)O.C1CC(N(C1)C(=O)C2CSSCC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N2)CC(=O)N)CCC(=O)N)CC3=CC=CC=C3)CC4=CC=C(C=C4)O)NC(=O)CNC(=O)CNC(=O)CN)C(=O)NC(CCCCN)C(=O)NCC(=O)N

Eflapegrastim

エフラペグラスチム;

Molecular Formula

• C15-H28-N2-O6(C2-H4-O)n

Molecular Weight

• 376.4468

UNII: UT99UG9QJX

HM10460A
SPI-2012

• HNK460

Reducing neutropenia and the incidence of infecton in patients with cancer

(2S)-1-{3-[2-(3-{[(1S,2R)-1-carboxy-2-hydroxypropyl]amino}propoxy)ethoxy]propyl}pyrrolidine-2-carboxylic acid

APPROVED FDA 2022/9/9, Rolvedon

CAS: 1384099-30-2

LAPS-GCSF, ROLONTIS

Antineutropenic, Leukocyte growth factor

Poly(oxy-1,2-ethanediyl), α-hydro-ω-hydroxy-, 1-ether with immunoglobulin G4 [1-[1-(3-hydroxypropyl)proline]] (human Fc fragment), (3→3′)-disulfide with immunoglobulin G4 (human Fc fragment), 1′′-ether with granulocyte colony-stimulating factor [N-(3-hydroxypropyl),17-serine,65-serine] (human) (ACI)

A long-acting, recombinant analog of the endogenous human granulocyte colony-stimulating factor (G-CSF) with hematopoietic activity. Similar to G-CSF, eflapegrastim binds to and activates specific cell surface receptors and stimulates neutrophil progenitor proliferation and differentiation, as well as selected neutrophil functions. Therefore, this agent may decrease the duration and incidence of chemotherapy-induced neutropenia. Eflapegrastim extends the half-life of G-CSF, allowing for administration once every 3 weeks.

• A long-acting GCSF that consists of 17th serine-G-CSF conjugated to the G4 fragment HMC001 via a PEG linker.

PATENT

 WO2021113597

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021113597

Neutropenia is a relatively common disorder most often due to chemotherapy treatments, adverse drug reactions, or autoimmune disorders. Chemotherapy-induced neutropenia is a common toxicity caused by the administration of anticancer drugs. It is associated with life-threatening infections and may alter the chemotherapy schedule, thus impacting on early and long term outcome. Febrile Neutropenia (FN) is a major dose-limiting toxicity of myelosuppressive chemotherapy regimens such as docetaxel, doxorubicin, cyclophosphamide (TAC); dose-dense doxorubicin plus cyclophosphamide (AC), with or without subsequent weekly or semiweekly paclitaxel; and docetaxel plus cyclophosphamide (TC). It usually leads to prolonged hospitalization, intravenous administration of broad-spectrum antibiotics, and is often associated with significant morbidity and mortality.

Current therapeutic modalities employ granulocyte colony-stimulating factor (G-CSF) and/or antibiotic agents to combat this condition. G-CSF or its other polypeptide derivatives are easy to denature or easily de-composed by proteolytic enzymes in blood to be readily removed through the kidney or liver. Therefore, to maintain the blood concentration and titer of the G-CSF containing drugs, it is necessary to frequently administer the protein drug to patients, which causes excessive suffering in patients. To solve such problems, G-CSF was chemically attached to polymers having a high solubility such as polyethylene glycol (“PEG”), thereby increasing its blood stability and maintaining suitable blood concentration for a longer time.

Filgrastim, tbo-filgrastim, and pegfilgrastim are G-CSFs currently approved by the US Food and Drug Administration (FDA) for the prevention of chemotherapy-induced neutropenia, While the European guidelines also include lenograstim as a recommended G-CSF in solid tumors and non-myeloid malignancies, it is not approved for use in the US. Binding of PEG to G-CSF, even though may increase blood stability, does dramatically reduce the titer needed for optimal physiologic effect. Thus there is a need to address this shortcoming in the art.

PATENT

WO2021112654

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021112654

Eflapegrastim

[54]

Eflapegrastim, as known as Rolontis ^®, SPI-2012, HM10460A, and ^17,65S-G-CSF, is a long-acting granulocyte-colony stimulating factor (G-CSF) that has been developed to reduce the severity and duration of severe neutropenia, as well as complications of neutropenia, associated with the use of myelosuppressive anti-cancer drugs or radiotherapy. Eflapegrastim consists of a recombinant human G-CSF analog (ef-G-CSF) and a recombinant fragment of the Fc region of human immunoglobulin G4 (IgG4), linked by a Bifunctional polyethylene glycol linker. In certain embodiments, the recombinant human G-CSF analog (ef-G-CSF) varies from human G-CSF (SED ID NO: 1) at positions 17 and 65 which are substituted with serine (SED ID NO: 2). Without wishing to be bound by theory, it is believed that the Fc region of human IgG4 increases the serum half-life of ef-G-CSF.

[55]

ef-G-CSF is produced by transformed E. coli in soluble form in the periplasmic space. Separately, the Fc fragment is produced in transformed E. coli as an inclusion body. The ef-G-CSF and the Fc fragment are independently isolated and purified through successive purification steps. The purified ef-G-CSF (SEQ ID NO: 2) and Fc fragment (SEQ ID NOs: 3 and 4) are then linked via a 3.4 kDa PEG molecule that was designed with reactive groups at both ends. Eflapegrastim itself is the molecule resulting from the PEG linker binding at each of the N-termini of ef-G-CSF and the Fc fragment. The G-CSF analog is conjugated to the 3.4 kDa polyethylene glycol analogue with propyl aldehyde end groups at both ends, (OHCCH ₂CH ₂(OCH ₂CH ₂) _nOCH ₂CH ₂CHO) at the nitrogen atom of its N-terminal Thr residue via reductive amination to form a covalent bond. The resulting G-CSF-PEG complex is then linked to the N-terminal Pro at the nitrogen of the recombinant Fc fragment variant produced in E. coli via reductive amination to yield the final conjugate of Eflapegrastim.

[56]

Example 1: Preparation of Eflapegrastim ( ^17,65S-G-CSF-PEG-Fc)

[120]

Step 1: Preparation of Immunoglobulin Fc Fragment Using Immunoglobulin

[121]

Preparation of an immunoglobulin Fc fragment was prepared as follows.

[122]

200 mg of 150-kDa immunoglobulin G (IgG) (Green Cross, Korea) dissolved in 10 mM phosphate buffer was treated with 2 mg of a proteolytic enzyme, papain (Sigma) at 37℃ for 2 hrs with gentle agitation.

[123]

After the enzyme reaction, the immunoglobulin Fc fragment regenerated thus was subjected to chromatography for purification using sequentially a Superdex column, a protein A column and a cation exchange column. In detail, the reaction solution was loaded onto a Superdex 200 column (Pharmacia) equilibrated with 10 mM sodium phosphate buffer (PBS, pH 7.3), and the column was eluted with the same buffer at a flow rate of 1 ml/min. Unreacted immunoglobulin molecules (IgG) and F(ab’)2, which had a relatively high molecular weight compared to the immunoglobulin Fc fragment, were removed using their property of being eluted earlier than the Ig Fc fragment. Fab fragments having a molecular weight similar to the Ig Fc fragment were eliminated by protein A column chromatography (FIGURE 1). The resulting fractions containing the Ig Fc fragment eluted from the Superdex 200 column were loaded at a flow rate of 5 ml/min onto a protein A column (Pharmacia) equilibrated with 20 mM phosphate buffer (pH 7.0), and the column was washed with the same buffer to remove proteins unbound to the column. Then, the protein A column was eluted with 100 mM sodium citrate buffer (pH 3.0) to obtain highly pure immunoglobulin Fc fragment. The Fc fractions collected from the protein A column were finally purified using a cation exchange column (polyCAT, PolyLC Company), wherein this column loaded with the Fc fractions was eluted with a linear gradient of 0.15-0.4 M NaCl in 10 mM acetate buffer (pH 4.5), thus providing highly pure Fc fractions. The highly pure Fc fractions were analyzed by 12% SDS-PAGE (lane 2 in FIGURE 2).

[124]

Step 2: Preparation of ^17,65S-G-CSF-PEG Complex

[125]

3.4-kDa polyethylene glycol having an aldehyde reactive group at both ends, ALD-PEG-ALD (Shearwater), was mixed with human granulocyte colony stimulating factor ( ^17,65S-G-CSF, MW: 18.6 kDa) dissolved in 100 mM phosphate buffer in an amount of 5 mg/ml at a ^17,65S-G-CSF: PEG molar ratio of 1:5. To this mixture, a reducing agent, sodium cyanoborohydride (NaCNBH ₃, Sigma), was added at a final concentration of 20 mM and was allowed to react at 4℃ for 3 hrs with gentle agitation to allow PEG to link to the amino terminal end of ^17,65S-G-CSF. To obtain a 1:1 complex of PEG and ^17,65S-G-CSF, the reaction mixture was subjected to size exclusion chromatography using a Superdex ^R　column (Pharmacia). The ^17,65S-G-CSF-PEG complex was eluted from the column using 10 mM potassium phosphate buffer (pH 6.0) as an elution buffer, and ^17,65S-G-CSF not linked to PEG, unreacted PEG and dimer byproducts where PEG was linked to ^17,65S-G-CSF molecules were removed. The purified ^17,65S-G-CSF-PEG complex was concentrated to 5 mg/ml. Through this experiment, the optimal reaction molar ratio for ^17,65S-G-CSF to PEG, providing the highest reactivity and generating the smallest amount of byproducts such as dimers, was found to be 1:5.

[126]

Step 3: Preparation of the ^17,65S-G-CSF-PEG-Fc Conjugate

[127]

To link the ^17,65S-G-CSF-PEG complex purified in the above step 2 to the N-terminus of an immunoglobulin Fc fragment, the immunoglobulin Fc fragment (about 53 kDa) prepared in Step 1 was dissolved in 10 mM phosphate buffer and mixed with the ^17,65S-G-CSF-PEG complex at an ^17,65S-G-CSF-PEG complex:Fc molar ratio of 1:1, 1:2, 1:4 and 1:8. After the phosphate buffer concentration of the reaction solution was adjusted to 100 mM, a reducing agent, NaCNBH ₃, was added to the reaction solution at a final concentration of 20 mM and was allowed to react at 4℃ for 20 hrs with gentle agitation. Through this experiment, the optimal reaction molar ratio for ^17,65S-G-CSF-PEG complex to Fc, providing the highest reactivity and generating the fewest byproducts such as dimers, was found to be 1:2.

[128]

Step 4: Isolation and Purification of the G-CSF-PEG-Fc Conjugate

[129]

After the reaction of the above step 3, the reaction mixture was subjected to Superdex size exclusion chromatography so as to eliminate unreacted substances and byproducts and purify the ^17,65S-G-CSF-PEG-Fc protein conjugate produced. After the reaction mixture was concentrated and loaded onto a Superdex column, 10 mM phosphate buffer (pH 7.3) was passed through the column at a flow rate of 2.5 ml/min to remove unbound Fc and unreacted substances, followed by column elution to collect ^17,65S-G-CSF-PEG-Fc protein conjugate fractions. Since the collected ^17,65S-G-CSF-PEG-Fc protein conjugate fractions contained a small amount of impurities, unreacted Fc and interferon alpha dimers, cation exchange chromatography was carried out to remove the impurities. The ^17,65S-G-CSF-PEG-Fc protein conjugate fractions were loaded onto a PolyCAT LP column (PolyLC) equilibrated with 10 mM sodium acetate (pH 4.5), and the column was eluted with a linear gradient of 0-0.5 M NaCl in 10 mM sodium acetate buffer (pH 4.5) using 1 M NaCl. Finally, the ^17,65S-G-CSF-PEG-Fc protein conjugate was purified using an anion exchange column. The ^17,65S-G-CSF-PEG-Fc protein conjugate fractions were loaded onto a PolyWAX LP column (PolyLC) equilibrated with 10 mM Tris-HCl (pH 7.5), and the column was then eluted with a linear gradient of 0-0.3 M NaCl in 10 mM Tris-HCl (pH 7.5) using 1 M NaCl, thus isolating the ^17,65S-G-CSF-PEG-Fc protein conjugate in a highly pure form.

[130]

[131]

Example 2: Efficacy Study of Eflapegrastim by Different Dosing Regimens in Rats with Docetaxel/Cyclophosphamide induced Neutropenia

[132]

The efficacy of Eflapegrastim (HM10460A), a long acting G-CSF analogue, was compared with Pegfilgrastim by different dosing regimens in a chemotherapy-induced neutropenic rat model.

[133]

In the following study, the Eflapegrastim was created essentially as described in Example 1.

[134]

(i) Materials for Study

[135]

[Table 1] Test Articles

[136]

[Table 2] Vehicles

[137]

[Table 3] Neutropenia-Inducing Agents

[138]

Preparing HM10460A Solutions for Subcutaneous Administration

[139]

Preparation of a 61.8 ㎍/kg HM10460A solution for subcutaneous administration: a stock solution of HM10460A (6.0 mg/mL) 92.7 μL was diluted with DPBS 17907.3 μL.

[140]

Preparation of a 372.0 ㎍/kg HM10460A solution for subcutaneous administration: a stock solution of HM10460A (6.0 mg/mL) 558.0 μL was diluted with DPBS 17442.0 μL.

[141]

Preparation of a 496.0 ㎍/kg HM10460A solution for subcutaneous administration: a stock solution of HM10460A (6.0 mg/mL) 744.0μL was diluted with DPBS 17256.0 μL.

[142]

The test article was prepared based on G-CSF protein dosage on drug label(HM10460A.)

[143]

The HM10460A solution for subcutaneous administration was then diluted with DPBS to a final dose concentration of 2 mL/kg.

[144]

Preparing Pegfilgrastim Solutions for Subcutaneous Administration

[145]

Preparation of a 103.3 ㎍/kg Pegfilgrastim solution for subcutaneous administration: a stock solution of Pegfilgrastim (10 mg/mL) 93.0 μL was diluted with DPBS 17907.0 μL.

[146]

Preparation of a 620.0 ㎍/k Pegfilgrastim solution for subcutaneous administration: a stock solution of Pegfilgrastim (10 mg/mL) 558.0 μL was diluted with DPBS 17442.0 μL.

[147]

The Pegfilgrastim solution for subcutaneous administration was then diluted with DPBS to a final dose concentration of 2 mL/kg.

[148]

Preparing Solutions of Neutropenia-Inducing Agents

[149]

To induce neutropenia in rats, Docetaxel/cyclophosphamide was administered using a 1/3 human equivalent dose (Docetaxel 4 mg/kg and CPA 32 mg/kg) (“TC”).

[150]

Preparation of a 32 mg/kg cyclophosphamide solution for subcutaneous administration: cyclophosphamide powder (CPA, Sigma, USA) 2560.0 g was diluted with distilled water (DW, Daihan, Korea) 80000.0 μL.

[151]

Preparation of a 4 mg/kg docetaxel solution for subcutaneous administration: Docel inj. (Hanmi Pharmaceutical, Korea) (42.68 mg/mL) 29070.0 μL was diluted with a commercial formulation buffer (FB, Etahnol 127.4mg/mL in DW) 30930.0 μL.

[152]

The docetaxel and cyclophosphamide solutions for subcutaneous administration were then diluted with FB to a final dose concentration of 1 mL/kg. HM10460A and Pegfilgrastim were diluted with DPBS to a final dose concentration of 2 mL/kg.

[153]

(ii) Methods

[154]

Test System

[155]

[Table 4]

[156]

Animal Care and Identification

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Eflapegrastim

25/10/2019by Christian Hilscher

Neutropenia in Breast Cancer: Spectrum Pharmaceuticals has submitted an updated regulatory submission to the US FDA for its biologic Rolontis

10/25/2019 Spectrum Pharmaceutical announced that it has filed an updated Biologics License Application (BLA) with the US Food and Drug Administration (FDA) for Rolontis (eflapegrastim).

The BLA for Rolontis is supported by data from two identically designed Phase 3 clinical trials – ADVANCE and RECOVER – that evaluated the safety and efficacy of eflapegrastim in 643 patients with early breast cancer for the treatment of neutropenia with myelosuppressive chemotherapy.

In both studies, eflapegrastim demonstrated the pre-specified hypothesis of non-inferiority (NI) in Duration of Severe Neutropenia (DSN) and a similar safety profile to pegfilgrastim .

Eflapegrastim also demonstrated non-inferiority to pegfilgrastim in DSN across all 4 cycles in both studies (all NI p<0.0001), the company writes.
© arznei-news.de – Source: Spectrum Pharmaceuticals

Eflapegrastim, sold under the brand names Rolvedon among others, is a long-acting G-CSF analog developed by Hanmi Pharmaceutical and licensed to Spectrum Pharmaceuticals.^[2] Eflapegrastim is a leukocyte growth factor.^[1] It is used to reduce the risk of febrile neutropenia in people with non-myeloid malignancies receiving myelosuppressive anti-cancer agents.^[1]

Eflapegrastim was approved for medical use in the United States in September 2022.^[1][3][4]

Medical uses

Eflapegrastim is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in adults with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia.^[1]

Its efficacy has been shown to be non-inferior to pegfilgrastim.^[1]

References

1. ^ Jump up to:^{a b c d e f} “Archived copy” (PDF). Archived (PDF) from the original on 19 September 2022. Retrieved 19 September 2022.
2. ^ pharmaceutical, hanmi. “Pipeline – R&D”. Hanmi Pharmaceutical. Archived from the original on 2 February 2017. Retrieved 23 January 2017.
3. ^ “Rolvedon: FDA-Approved Drugs”. U.S. Food and Drug Administration (FDA). Archived from the original on 19 September 2022. Retrieved 18 September 2022.
4. ^ “Spectrum Pharmaceuticals Receives FDA Approval for Rolvedon (eflapegrastim-xnst) Injection”. Business Wire (Press release). 9 September 2022. Archived from the original on 9 September 2022. Retrieved 18 September 2022.

External links

• “Eflapegrastim”. Drug Information Portal. U.S. National Library of Medicine.
• Clinical trial number NCT02643420 for “SPI-2012 vs Pegfilgrastim in the Management of Neutropenia in Participants With Breast Cancer With Docetaxel and Cyclophosphamide (ADVANCE) (ADVANCE)” at ClinicalTrials.gov
• Clinical trial number NCT02953340 for “SPI-2012 vs Pegfilgrastim in Management of Neutropenia in Breast Cancer Participants With Docetaxel and Cyclophosphamide” at ClinicalTrials.gov

////////////Eflapegrastim, Rolvedon, APPROVALS 2022, FDA 2022, エフラペグラスチム , HM10460A, SPI-2012, HNK460, ROLONTIS

NEW DRUG APPROVALS

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Gadopiclenol

ガドピクレノール;

FDA APPROVED 2022/9/21, Elucirem

Diagnostic agent (MR imaging), WHO 10744, P 03277, UNII: S276568KOY

EluciremTM; G03277; P03277; VUEWAY

(alpha3,alpha6,alpha9-Tris(3-((2,3-dihydroxypropyl)amino)-3-oxopropyl)-3,6,9,15-tetraazabicyclo(9.3.1)pentadeca-1(15),11,13-triene-3,6,9-triacetato(3-)-kappaN3,kappaN6,kappaN9,kappaN15,kappaO3,kappaO6,kappaO9)gadolinium

• OriginatorGuerbet
• ClassDiagnostic agents; Gadolinium-containing contrast agents; Macrocyclic compounds; Propylamines; Pyridines
• Mechanism of ActionMagnetic resonance imaging enhancers

• RegisteredCNS disorders
• Phase IIIUnspecified
• Phase IILiver cancer

• 21 Sep 2022Registered for CNS disorders (Diagnosis) in USA (IV)
• 13 Jun 2022Guerbet plans to launch Gadopiclenol in Europe
• 13 Jun 2022The European Medicines Agency (EMA) accepts brand name Elucirem^TM for Gadopiclenol

PATENT

https://patents.google.com/patent/WO2020030618A1/en

MRI contrast agents used in daily diagnostic practice typically include gadolinium complex compounds characterized by high stability constants that guarantee against the in vivo release of the free metal ion (that is known to be extremely toxic for living organisms).

Another key parameter in the definition of the tolerability of a gadolinium-based contrast agent is the kinetic inertness (or kinetic stability) of Gd(III)-complex, that is estimated through the half-life (ti_/2) of the dissociation (i.e. decomplexation) of the complex.

A high inertness becomes crucial in particular for those complex compounds having lower thermodynamic stability and/or longer retention time before excretion, in order to avoid or minimize possible decomplexation or transmetallation reactions.

EP1931673 (Guerbet) discloses PCTA derivatives of formula

and a synthetic route for their preparation.

EP 2988756 (same Applicant) discloses a pharmaceutical composition comprising the above derivatives together with a calcium complex of 1,4,7, 10-tetraazacyclododecane- 1,4,7, 10-tetraacetic acid. According to the EP 2988756, the calcium complex compensates the weak thermodynamic stability observed for PCTA-based gadolinium complexes, by forming, through transmetallation, a strong complex with free lanthanide ion, thereby increasing the tolerability of the contrast agent.

Both EP1931673 and EP 2988756 further refer to enantiomers or diastereoisomers of the claimed compounds, or mixture thereof, preferentially chosen from the RRS, RSR, and RSS diastereoisomers. Both the above patents disclose, among the specific derivatives, (a3, a6, a9)-tris(3- ((2,3-dihydroxypropyl)amino)-3-oxopropyl)-3,6,9,15-tetraazabicyclo(9.3.1)pentadeca- l(15),l l,13-triene-3,6,9-triacetato(3-)-(KN3,KN6,KN9,KN15,K03,K06,K09)gadolinium, more recently identified as gadolinium chelate of 2,2′,2″-(3,6,9-triaza-l(2,6)- pyridinacyclodecaphane-3,6,9-triyl)tris(5-((2,3-dihydroxypropyl)amino)-5-oxopentanoic acid), (CAS registry number: 933983-75-6), having the following formula

otherwise identified as P03277 or Gadopiclenol.

For Gadopiclenol, EP1931673 reports a relaxivity of 11 mM ^_1s ^_1Gd ¹ (in water, at 0.5 T, 37°C) while EP 2988756 reports a thermodynamic equilibrium constant of 10 ^{14 9} (log K^term

= 14.9).

Furthermore, for this same compound a relaxivity value of 12.8 mM ^_1s ¹ in human serum (37°C, 1.41 T), stability (log K^term) of 18.7, and dissociation half-life of about 20 days (at pH 1.2; 37°C) have been reported by the proprietor (Investigative Radiology 2019, Vol 54, (8), 475-484).

The precursor for the preparation of the PCTA derivatives disclosed by EP1931673 (including Gadopiclenol) is the Gd complex of the 3,6,9,15-tetraazabicyclo- [9.3.1]pentadeca-l(15),l l,13-triene-tri(a-glutaric acid) having the following formula

Gd(PCTA-tris-glutaric acid)

herein identified as “Gd(PCTA-tris-glutaric acid)”. In particular, Gadopiclenol is obtained by amidation of the above compound with isoserinol.

As observed by the Applicant, Gd(PCTA-tris-qlutaric acid) has three stereocenters on the glutaric moieties (identified with an asterisk (*) in the above structure) that lead to a 2³ = 8 possible stereoisomers. More particularly, the above structure can generate four pairs of enantiomers, schematized in the following Table 1

Table 1

Isomer RRR is the mirror image of isomer SSS and that is the reason why they are called enantiomers (or enantiomer pairs). As known, enantiomers display the same physicochemical properties and are distinguishable only using chiral methodologies, such as chiral chromatography or polarized light.

On the other hand, isomer RRR is neither equal to nor is it the mirror image of any of the other above six isomers; these other isomers are thus identified as diastereoisomers of the RRR (or SSS) isomer. Diastereoisomers may display different physicochemical properties, (e.g., melting point, water solubility, relaxivity, etc.).

Concerning Gadopiclenol, its chemical structure contains a total of six stereocenters, three on the glutaric moieties of the precursor as above discussed and one in each of the three isoserinol moieties attached thereto, identified in the following structure with an asterisk (*) and with an empty circle (°), respectively:

This leads to a total theoretical number of 2⁶ = 64 stereoisomers for this compound. However, neither EP1931673 nor EP 2988756 describe the exact composition of the isomeric mixture obtained by following the reported synthetic route, nor does any of them provide any teaching for the separation and characterization of any of these isomers, or disclose any stereospecific synthesis of Gadopiclenol. Summary of the invention

The applicant has now found that specific isomers of the above precursor Gd(PCTA- tris-glutaric acid) and of its derivatives (in particular Gadopiclenol) possess improved physico-chemical properties, among other in terms of relaxivity and kinetic inertness.

An embodiment of the invention relates to a compound selected from the group consisting of:

the enantiomer [(aR,a’R,a”R)-a,a’,a”-tris(2-carboxyethyl)-3,6,9,15- tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,6,9-triacetato(3-)- Kl\l3,Kl\l6,Kl\l9,Kl\ll5,K03,K06,K09]-gadolinium (RRR enantiomer) having the formula (la):

the enantiomer [(aS,a’S,a”S)-a,a’,a”-tris(2-carboxyethyl)-3,6,9,15-tetraazabicyclo- [9.3.1]pentadeca-l(15),ll,13-triene-3,6,9-triacetato(3-)KN3,KN6,KN9,KN15,K03,K06,K09]- gadolinium (SSS enantiomer) having the formula (lb):

the mixtures of such RRR and SSS enantiomers, and a pharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to an isomeric mixture of Gd(PCTA-tris- glutaric acid) comprising at least 50% of the RRR isomer [(aR,a’R,a”R)-a,a’,a”-tris(2- carboxyethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,6,9- triacetato(3-)-KN3,KN6,KN9,KN15,K03,K06,K09]-gadolinium, of formula (la), or of the SSS isomer [(aS,a’S,a”S)-a,a’,a”-tris(2-carboxyethyl)-3,6,9,15- tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,6,9-triacetato(3-)- Kl\l3,Kl\l6,Kl\l9,Kl\ll5,K03,K06,K09]-gadolinium of formula (lb), or of a mixture thereof, or a pharmaceutically acceptable salt thereof. Another aspect of the invention relates to the amides obtained by conjugation of one of the above compounds or isomeric mixture with an amino group, e.g. preferably, serinol or isoserinol.

An embodiment of the invention relates to an amide derivative of formula (II A)

F( N RI R₂)₃ (II A)

in which :

F is:

a RRR enantiomer residue of formula Ilia

a SSS enantiomer residue of formula Illb

or a mixture of such RRR and SSS enantiomer residues;

and each of the three -NRIR₂ group is bound to an open bond of a respective carboxyl moiety of F, identified with a full circle (·) in the above structures;

Ri is H or a Ci-Ce alkyl, optionally substituted by 1-4 hydroxyl groups;

R₂ is a Ci-Ce alkyl optionally substituted by 1-4 hydroxyl groups, and preferably a C1-C3 alkyl substituted by one or two hydroxyl groups.

Another embodiment of the invention relates to an isomeric mixture of an amide derivative of Gd(PCTA-tris-glutaric acid) having the formula (II B)

F'( N RI R₂)3 (II B)

in which :

F’ is an isomeric mixture of Gd(PCTA-tris-glutaric acid) residue of formula (III)

said isomeric mixture of the Gd(PCTA-tris-glutaric acid) residue comprising at least 50 % of an enantiomer residue of the above formula (Ilia), of the enantiomer residue of the above formula (Illb), or of a mixture thereof; and each of the -NR1R2 groups is bound to an open bond of a respective carboxyl moiety of F’, identified with a full circle (·) in the above structure, and is as above defined for the compounds of formula (II A).

EXPERIMENTAL PART

HPLC characterization of the obtained compounds.

General procedures

Procedure 1: HPLC Characterization of Gd(PCTA-tris-glutaric acid) (isomeric mixture and individual/enriched isomers).

The HPLC characterization of the Gd(PCTA-tris-glutaric acid) obtained as isomeric mixture from Example 1 was performed with Agilent 1260 Infinity II system. The experimental setup of the HPLC measurements are summarized below.

Analytical conditions

HPLC system HPLC equipped with quaternary pump, degasser, autosampler,

PDA detector ( Agilent 1260 Infinity II system)

Stationary phase: Phenomenex Gemini® 5pm C18 lloA

Mobile phase: H2O/HCOOH 0.1% : Methanol

Elution : Gradient Time (min) H2O/HCOOH 0.1% Methanol

0 95 5

5 95 5

30 50 50

35 50 50

40 95 5

Flow 0.6 mL/min

Temperature 25 °C

Detection PDA scan wavelenght 190-800nm

Injection volume 50 pL

Sample Cone. 0.2 mM Gd(PCTA-tris-glutaric acid) complex

Stop time 40 min

Retention time GdL = 18-21 min.

Obtained HPLC chromatogram is shown in Figure 1

The HPLC chromatogram of the enriched enantiomers pair C is shown in Figure 2.

Procedure 2: HPLC Characterization of Gadopiclenol (isomeric mixture) and compounds obtained by coupling of enantiomers pair C with R, S, or racemic isoserinol.

The HPLC characterization of Gadopiclenol either as isomeric mixture obtained from Example 2, or as the compound obtained by conjugation of enantiomers pair C of the Gd(PCTA-tris-glutaric acid) with R, S, or racemic isoserinol was performed with Thermo Finnigan LCQ DECA XPPIus system. The experimental setup of the HPLC measurements are summarized below.

Analytical conditions

HPLC system HPLC equipped with quaternary pump, degasser, autosampler,

PDA and MS detector (LCQ Deca XP-Plus – Thermo Finnigan )

Stationary phase: Phenomenex Gemini 5u C18 110A

Mobile phase: H2O/TFA 0.1% : Acetonitrile/0.1%TFA

Elution : Gradient Time (min) H2O/TFA 0.1% Acetonitrile/0.1%TFA

0 100 0

5 100 0

22 90 10

26 90 10

Flow 0.5 mL/min

Temperature 25 °C

Detection PDA scan wavelenght 190-800nm

MS positive mode – Mass range 100-2000

Injection volume 50 pL

Sample cone. 0.2 mM Gd complex

Stop time 26 min

Retention time GdL = 20-22min.

Obtained HPLC chromatograms are shown in Figure 6.

Procedure 3: Chiral HPLC method for the separation of enantiomers of the compound C

A specific chiral HPLC method was set up in order to separate the RRR and SSS enantiomers of the enantiomers pair C (compound VI), prepared as described in Example 3. The separation and characterization of the enantiomers were performed with Agilent 1200 system or Waters Alliance 2695 system. The experimental setup of the HPLC measurements are summarized below.

Analytical conditions

HPLC System HPLC equipped with quaternary pump, degasser, autosampler,

PDA detector

Stationary phase SUPELCO Astec CHIROBIOTIC 5 pm 4.6x250mm

Mobile phase H2O/HCOOH 0.025% : Acetonitrile

Elution : isocratic 2% Acetonitrile for 30 minutes

Flow 1 mL/min

Column Temperature 40°C

Detection 210-270 nm. Obtained HPLC chromatogram is shown in Figure 5a) compared to the chromatograms of the pure RRR enantiomer (compound XII of Example 5, Tr. 7.5 min.) and the pure SSS enantiomer (Compound XVII of Example 6, Tr. 8.0 min), shown in figure 5b) and 5c), respectively.

Example 1: Synthesis of Gd(PCTA-tris-glutaric acid) (isomeric mixture)

Gd(PCTA-tris-glutaric acid) as an indiscriminate mixture of stereoisomers has been prepared by using the procedure reported in above mentioned prior-art, according to the following synthetic Scheme 1 :

Scheme 1

a) Preparation of Compound II

Racemic glutamic acid (33.0 g, 0.224 mol) and sodium bromide (79.7 g, 0.782 mol) were suspended in 2M HBr (225 ml_). The suspension was cooled to -5°C and NaN0₂ (28.0 g, 0.403 mol) was slowly added in small portions over 2.5 hours, maintaining the inner temperature lower than 0 °C. The yellow mixture was stirred for additional 20 minutes at a temperature of -5°C; then concentrated sulfuric acid (29 ml.) was dropped in the mixture. The obtained dark brown mixture was warmed to RT and then extracted with diethyl ether (4×150 ml_). The combined organic phases were washed with brine, dried over Na₂S04 and concentrated to a brown oil (21.2 g), used in the following step without further purification. The oil was dissolved in ethanol (240 ml_), the resulting solution was cooled in ice and thionyl chloride (14.5 ml_, 0.199 mol) was slowly added. The slightly yellow solution was stirred at RT for 2 days. Then the solvent was removed in vacuum and the crude oil was dissolved in dichloromethane (200 ml.) and washed with 5% aq. NaHCC>₃ (4×50 ml_), water (1×50 ml.) and brine (1×50 ml_). The organic phase was concentrated and purified on silica eluting with petroleum ether-ethyl acetate 3: 1, obtaining 19.5 g of pure product. (Yield 33%).

b) Preparation of Compound IV

A solution of Compound II (17.2 g, 0.0645 mol) in acetonitrile (40 ml.) was added to a suspension of 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene (pyclen) Compound (III) (3.80 g, 0.018 mol) and K2CO3 (11.2 g, 0.0808 mol) in acetonitrile (150 ml_). The yellow suspension was heated at 65 °C for 24 h, then the salts were filtered out and the organic solution was concentrated. The orange oil was dissolved in dichloromethane and the product was extracted with 1M HCI (4 x 50 ml_). The aqueous phases were combined, cooled in ice and brought to pH 7-8 with 30% aq. NaOH. The product was then extracted with dichloromethane (4 x 50 ml.) and concentrated to give a brown oil (10.1 g, yield 73%). The compound was used in the following step without further purification.

c) Preparation of compound V

Compound IV (9.99 g, 0.013 mol) was dissolved in Ethanol (40 ml.) and 5M NaOH (40 ml_). The brown solution was heated at 80 °C for 23 h. Ethanol was concentrated; the solution was cooled in ice and brought to pH 2 with cone HCI. The ligand was purified on resin Amberlite XAD 1600, eluting with water-acetonitrile mixture, obtaining after freeze- drying 5.7 g as white solid (yield 73%). The product was characterized in HPLC by several peaks.

d) Preparation of compound VI

Compound V (5.25 g, 0.0088 mol) was dissolved in deionized water (100 ml.) and the solution was brought to pH 7 with 2M NaOH (20 ml_). A GdCh solution (0.0087 mol) was slowly added at RT, adjusting the pH at 7 with 2M NaOH and checking the complexation with xylenol orange. Once the complexation was completed, the solution was concentrated and purified on resin Amberlite XAD 1600 eluting with water-acetonitrile gradient, in order to remove salts and impurities. After freeze-drying the pure compound was obtained as white solid (6.79 g, yield 94%). The product was characterized in HPLC; the obtained HPLC chromatogram, characterized by several peaks, is shown in Figure 1 A compound totally equivalent to compound VI, consisting of an isomeric mixture with a HPLC chromatogram substantially superimposable to that of Figure 1 is obtained even by using (S)-methyl a-bromoglutarate obtained starting from L-glutamic acid.

Example 2: Synthesis of Gadopiclenol (isomeric mixture)

Gadopiclenol as an indiscriminate mixture of stereoisomers has been prepared as disclosed in EP11931673 B1 by coupling the isomeric mixture of Gd(PCTA-tris-glutaric acid) obtained from Example 1 with racemic isoserinol according to the following synthetic Scheme 2:

Scheme 2

Preparation of compound VII

Compound VI (0.90 g, 0.0011 mol) obtained from Example 1 was added to a solution of racemic isoserinol (0.40 g, 0.0044 mol) in water adjusted to pH 6 with cone. HCI. Then N- ethyl-N’-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCI) (1.0 g, 0.0055 mol) and hydroxybenzotriazole (HOBT) (0.12 g, 0.00088 mol) were added and the resulting solution was stirred at pH 6 and RT for 24 h. The product was then purified on preparative HPLC on silica C18, eluting with water/acetonitrile gradient. Fractions containing the pure compound were concentrated and freeze-dried, obtaining a white solid (0.83 g, yield 78%). The product was characterized in HPLC; the obtained HPLC chromatogram is shown in Figure 4a.

Example 3: Isolation of the enantiomers pair related to the peak C.

Compound VI obtained as described in Example 1 (step d) (1.0 g, 0.0013 mol) was dissolved in water (4 ml.) and the solution was acidified to pH 2-3 with cone. HCI. The obtained solution was loaded into a pre-packed column of silica C18 (Biotage® SNAP ULTRA C18 120 g, HP-sphere C18 25 pm) and purified with an automated flash chromatography system eluting with deionized water (4 CV) and then a very slow gradient of acetonitrile. Fractions enriched of the enantiomers pair related to the peak C were combined, concentrated and freeze-dried obtaining a white solid (200 mg).

The HPLC chromatogram of the obtained enriched enantiomers pair C is shown in Figure 2.

Corresponding MS spectrum (Gd(H₄L)⁺:752.14 m/z) is provided in Figure 3

Example 4: Coupling of the enantiomers pair C with isoserinol.

a) Coupling of the enantiomers pair C with R-isoserinol.

Enriched enantiomers pair C collected e.g. as in Example 3 (34 mg, titer 90%, 0.040 mmol) was dissolved in deionized water (5 ml_), and R-isoserinol (16 mg, 0.17 mmol) was added adjusting the pH at 6 with HCI 1M. Then, EDCI-HCI (39 mg, 0.20 mmol) and HOBT (3 mg, 0.02 mmol) were added and the solution was stirred at RT at pH 6 for 48 h. The solution was concentrated and loaded to pre-packed silica C18 column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with water/acetonitrile gradient using an automated flash chromatography system. Fractions containing the pure product, or showing a major peak at the HPLC with area greater than 90%, were combined, concentrated and freeze-dried giving a white solid (21 mg, yield 54%).

The HPLC chromatogram of the obtained product is shown in Figure 6b.

b) Coupling of the enantiomers pair C with S-isoserinol

Enriched enantiomers pair C collected e.g. as in Example 3 (55 mg, titer 90%, 0.066 mmol) was dissolved in deionized water (5 mL), and S-isoserinol (34 mg, 0.29 mmol) was added adjusting the pH at 6 with 1M HCI. Then, EDCI-HCI (64 mg, 0.33 mmol) and HOBT (4.5 mg, 0.033 mmol) were added and the solution was stirred at RT at pH 6 for 48 h. The solution was concentrated and loaded to pre-packed silica C18 column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with water/acetonitrile gradient using an automated flash chromatography system. Fractions containing the pure product, or showing a major peak at the HPLC with area greater than 90%, were combined, concentrated and freeze-dried giving a white solid (52 mg, yield 81%).

HPLC chromatogram of the obtained product is shown in Figure 6c.

c) Coupling of the enantiomers pair C with racemic isoserinol.

The enriched enantiomers pair C collected e.g. as in Example 3 (54 mg, titer 90%, 0.065 mmol) was dissolved in deionized water (5 mL), and racemic isoserinol (27 mg, 0.29 mmol) was added adjusting the pH at 6 with 1M HCI. Then, EDCI-HCI (62 mg, 0.32 mmol) and HOBT (4.3 mg, 0.032 mmol) were added and the solution was stirred at RT at pH 6 for 24 h. The solution was concentrated and loaded to pre-packed silica C18 column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with water/acetonitrile gradient using an automated flash chromatography system. Fractions containing the pure product, or showing a major peak at the HPLC with area greater than 90%, were combined, concentrated and freeze-dried giving a white solid (60 mg, yield 95%).

HPLC chromatogram of the obtained product is shown in Figure 6d. Example 5: Stereoselective synthesis of the RRR Gd(PCTA-tris-glutaric acid) (compound XII).

RRR enriched Gd(PCTA-tris-glutaric acid) acid has been prepared by following the synthetic Scheme 3 below

Scheme 3

comprising :

a) Preparation of Compound VIII

The preparation was carried out as reported in Tetrahedron 2009, 65, 4671-4680.

In particular: 37% aq. HCI (50 pL) was added to a solution of (S)-(+)-5- oxotetrahydrofuran-2-carboxylic acid (2.48 g, 0.019 mol) (commercially available) in anhydrous methanol (20 ml_). The solution was refluxed under N₂ atmosphere for 24 h. After cooling in ice, NaHCC>₃ was added, the suspension was filtered, concentrated and purified on silica gel with hexanes/ethyl acetate 1 : 1. Fractions containing the pure product were combined and concentrated, giving a colorless oil (2.97 g, yield 89%).

b) Preparation of Compounds IX and X

Compound VIII (445 mg, 2.52 mmol) obtained at step a) was dissolved in anhydrous dichloromethane (6 ml.) and triethylamine (0.87 ml_, 6.31 mmol) was added. The solution was cooled at -40°C and then (triflic) trifluoromethansulfonic anhydride (0.49 ml_,2.91 mmol) was slowly added. The dark solution was stirred at -40°C for 1 h, then a solution of Compound III (104 mg, 0.506 mmol) in anhydrous dichloromethane (3 ml.) and triethylamine (1 ml_, 7.56 mmol) were added and the solution was slowly brought to RT and stirred at RT overnight. The organic solution was then washed with 2M HCI (4x 10 ml_), the aqueous phase was extracted again with dichloromethane (3 x 10 ml_). The organic phases were combined and concentrated in vacuum, obtaining 400 mg of a brown oil that was used in the following step with no further purification.

c) Preparation of Compound XI

Compound X (400 mg, 0.59 mmol) was dissolved in methanol (2.5 ml.) and 5M NaOH (2.5 ml_). The brown solution was heated at 80°C for 22 h to ensure complete hydrolysis. Methanol was concentrated, the solution was brought to pH 1 with concentrated HCI and purified through an automated flash chromatography system with a silica C18 pre-packed column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with deionized water/acetonitrile gradient. Fractions containing the pure product were combined, concentrated and freeze-dried (64 mg, yield 18 %). The HPLC showed a major peak.

d) Compound XII

Compound XI (32 mg, 0.054 mmol) was dissolved in deionized water (4 mL) and the pH was adjusted to 7 with 1M NaOH. GdCl₃-6H₂0 (20 mg, 0.054 mmol) was added and the pH was adjusted to 7 with 0.1 M NaOH. The clear solution was stirred at RT overnight and the end of the complexation was checked by xylenol orange and HPLC. The HPLC of the crude showed the desired RRR isomer as major peak: about 80% in area %. The mixture was brought to pH 2 with concentrated HCI and purified through an automated flash chromatography system with a silica C18 pre-packed column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with deionized water/acetonitrile gradient. Fractions containing the pure product were combined, concentrated and freeze-dried (36 mg, yield 90%).

By reaction of the collected compound with isoserinol e.g. by using the procedure of the Example 2, the corresponding RRR amide derivative can then be obtained.

Example 6: stereoselective synthesis of the SSS Gd(PCTA-tris-glutaric acid) (compound XVII).

SSS enriched Gd(PCTA-tris-glutaric acid) acid has been similarly prepared by following the synthetic Scheme 4 below Scheme 4

comprising :

a) Preparation of Compound XIII

37% aq. HCI (100 pl_) was added to a solution of (R)-(-)-5-oxotetrahydrofuran-2- carboxylic acid (5.0 g, 0.038 mol) (commercially available) in anhydrous methanol (45 ml_). The solution was refluxed under N₂ atmosphere for 24 h. After cooling in ice, NaHC03 was added, the suspension was filtered, concentrated and purified on silica gel with hexanes/ethyl acetate 1 : 1. Fractions containing the pure product were combined and concentrated, giving a colorless oil (6.7 g, yield 99%).

b) Preparation of Compounds XIV and XV

Compound XIII (470 mg, 2.67 mmol) was dissolved in anhydrous dichloromethane (6 ml.) and trimethylamine (0.93 ml_, 6.67 mmol) was added. The solution was cooled down at -40°C and then trifluoromethanesulfonic anhydride (0.50 ml_, 3.07 mmol) was slowly dropped. The dark solution was stirred at -40°C for 1 h, then Compound III (140 mg, 0.679 mmol) and trimethylamine (0.93 ml_, 6.67 mmol) were added and the solution was slowly brought to RT overnight. The organic solution was then washed with water (3 x 5 ml.) and 2M HCI (4 x 5 ml_). The aqueous phase was extracted again with dichloromethane (3 x 10 ml_). the organic phases were combined and concentrated in vacuum, obtaining 350 mg of a brown oil that was used in the following step with no further purification. c) Preparation of Compound XVI

Compound XV (350 mg, 0.514 mmol) was dissolved in methanol (4.5 ml.) and 5M NaOH (4.5 ml_). The obtained brown solution was heated at 80°C for 16 h to ensure complete hydrolysis. Methanol was concentrated, the solution was brought to pH 2 with concentrated HCI and purified through an automated flash chromatography system with a silica C18 pre-packed column (Biotage® SNAP ULTRA C18 12 g, HP-SPHERE C18 25 pm), eluting with a water/acetonitrile gradient. Fractions containing the pure product were combined, concentrated and freeze-dried (52 mg, yield 17%). The HPLC showed a major peak.

d) Preparation of Compound XVII

Compound XVI (34 mg, 0.057 mmol) was dissolved in deionized water (5 mL) and the pH was adjusted to 7 with 1 M HCI. GdCl₃-6H₂0 (20 mg, 0.0538 mmol) was added and the pH was adjusted to 7 with 0.1 M NaOH. The solution was stirred at RT overnight and the end of complexation was checked by xylenol orange and HPLC. The HPLC of the crude showed the desired SSS isomer as major peak: about 85% in area %. The solution was brought to pH 2.5 with concentrated HCI and purified through an automated flash chromatography system with a silica C18 pre-packed column (Biotage® SNAP ULTRA C18 12 g, HP-SPHERE C18 25 pm), eluting with a water/acetonitrile gradient. Fractions containing the pure product SSS were combined, concentrated and freeze-dried (39 mg, yield 87%).

Example 7: Kinetic studies of the dissociation reactions of Gd(PCTA-tris- glutaric acid) (isomeric mixture) in 1.0 M HCI solution (25°C)

The kinetic inertness of a Gd(III)-complex is characterized either by the rate of dissociation measured in 0.1-1.0 M HCI or by the rate of the transmetallation reaction, occurring in solutions with Zn(II) and Cu(II) or Eu(III) ions. However, the dissociation of lanthanide(III)-complexes formed with macrocyclic ligands is very slow and generally proceeds through a proton-assisted pathway without the involvement of endogenous metal ions like Zn²⁺ and Cu²⁺.

We characterized the kinetic inertness of the complex Gd(PCTA-tris-glutaric acid) by the rates of the dissociation reactions taking place in 1.0 M HCI solution. The complex (isomeric mixture from Example 1) (0.3 mg) was dissolved in 2.0 mL of 1.0 M HCI solution and the evolution of the solution kept at 25 °C was followed over time by HPLC. The HPLC measurements were performed with an Agilent 1260 Infinity II system by use of the analytical Procedure 1.

The presence of a large excess of H⁺ ([HCI] = 1.0 M), guarantees the pseudo-first order kinetic conditions.

GdL + yH÷ ^ Gd³⁺ + H_yL y=7 and 8 (Eg. 1) where L is the protonated PCTA-tri-glutaric acid, free ligand, and y is the number of protons attached to the ligand.

The HPLC chromatogram of Gd(PCTA-tris-glutaric acid) is characterized by the presence of four signals (A, B, C and D) having the same m/z ratio (Gd(H4L)+ :752.14 m/z) in the MS spectrum. Each of these peaks is reasonably ascribable to one of the 4 pairs of enantiomers generated by the three stereocenters on the three glutaric arms of the molecule, formerly identified in Table 1. The HPLC chromatogram of this complex in the presence of 1.0 M HCI changes over time: in particular, the areas of peaks A, B, C, and D decrease, although not in the same way for the different peaks, while new signals corresponding to non-complexed diastereoisomers are formed and grow over time. Differences in the decrease of the integral areas of the peaks can be interpreted by a different dissociation rate of the enantiomer pairs associated to the different peaks.

In the presence of [H + ] excess the dissociation reaction of enantiomer pairs of Gd(PCTA-tris-glutaric acid) can be treated as a pseudo-first-order process, and the rate of the reactions can be expressed with the following Eq. 2, where k_A, k_B, k_c and k_D are the pseudo-first-order rate constants that are calculated by fitting the area-time data pair, and [A]_t, [B]_t, [C]_t and [D]_t are the total concentration of A, B, C and D compounds at time t.

The decrease of the area values of signals of A, B, C, and D has been assessed and plotted over time. Area values of A, B, C and D signals as a function of time are shown in Figure 7.

Area value at time t can be expressed by the following equation:

A. = A + (A₀ – A )e k_xt

(Eg. 3)

where A_t, A₀ and A_e are the area values at time t, at the beginning and at the end of the reactions, respectively, kx pseudo-first-order rate constants (/f_X=/f_A, k_B, k_c and k_D) characterizing the dissociation rate of the different enantiomer pairs of Gd(PCTA-tris-glutaric acid) complex were calculated by fitting the area – time data pairs of Figure 7 to the above equation 3. kx rate constants and half-lives (ti_/2= In2/ _x) are thus obtained, as well as the average the half-life value for the isomeric mixture of Gd(PCTA-tris-glutaric acid), calculated by considering the percentage composition of the mixture. Obtained values are summarized in the following Table 2, and compared with corresponding values referred in the literature for some reference contrast agents. (Gd-DOTA or DOTAREM). Table 2. Rate constants ( kx ) and half-lives (ti_/2= In2/ _x) characterizing the acid catalyzed dissociation of the different stereoisomers of Gd(PCTA-tris-glutaric acid), Dotarem® and Eu(PCTA) in 1.0 M HCI (pH 0) ( 25°C)

A B C D

Ms ¹) (4.5±0.1) x10⁵ (1.1±0.1)x10⁴ (1.6±0.1)x10-⁶ (1.2±0.1)x10-⁵ fi/₂ (hour) 4.28 ± 0.03 1.76 ± 0.02 120 ± 3 15.8 ± 0.5

fi_/2 (hour)

average

Dotarem ^a

k, (S^‘1) 8.0×10-⁶

fi_/2 (hour) 23 hour

Eu(PCTA) ^b

*1 (s·¹) 5.08X10·⁴

fi_/2 (hour) 0.38 hour

a) Inorg. Chem. 1992, 31 ,1095-1099.

b) Tircso, G. et al. Inorg Chem 2006, 45 (23), 9269-80.

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A gadolinium-based paramagnetic contrast agent, with potential imaging enhancing activity upon magnetic resonance imaging (MRI). Upon administration of gadopiclenol and placement in a magnetic field, this agent produces a large magnetic moment and creates a large local magnetic field, which can enhance the relaxation rate of nearby protons. This change in proton relaxation dynamics, increases the MRI signal intensity of tissues in which this agent has accumulated; therefore, contrast and visualization of those tissues is enhanced compared to unenhanced MRI.

FDA Approves New MRI Contrast Agent Gadopiclenol

September 22, 2022

https://www.diagnosticimaging.com/view/fda-approves-new-mri-contrast-agent-gadopiclenol

Requiring only half of the gadolinium dose of current non-specific gadolinium-based contrast agents (GBCAs), gadopiclenol can be utilized with magnetic resonance imaging (MRI) to help detect lesions with abnormal vascularity in the central nervous system and other areas of the body.

Gadopiclenol, a new magnetic resonance imaging (MRI) contrast agent that offers high relaxivity and reduced dosing of gadolinium, has been approved by the Food and Drug Administration (FDA).¹

Approved for use with MRI in adults and pediatric patients two years of age or older, gadopiclenol is a macrocyclic gadolinium-based contrast agent that aids in the diagnosis of lesions with abnormal vascularity in the brain, spine, abdomen, and other areas of the body.

Recently published research demonstrated that gadopiclenol provides contrast enhancement and diagnostic efficacy at half of the gadolinium dosing of other gadolinium-based contrast agents (GBCAs) such as gadobutrol and gadobenate dimeglumine.²

Co-developed by Bracco Diagnostics and Guerbet, gadopiclenol will be manufactured and marketed as Vueway (Bracco Diagnostics) and Elucirem (Guerbet).^1,3

Alberto Spinazzi, M.D., the chief medical and regulatory officer at Bracco Diagnostics, said gadopiclenol is “a first of its kind MRI agent that delivers the highest relaxivity and highest kinetic stability of all GBCAs on the market today.”

Reference

1. Bracco Diagnostics. Bracco announces FDA approval of gadopiclenol injection, a new macrocyclic high-relaxivity gadolinium-based contrast agent which will be commercialized as VUEWAY (gadopiclenol) injection and VUEWAY (gadopiclenol) phamarcy bulk package by Bracco. Cision PR Newswire. Available at: https://www.prnewswire.com/news-releases/bracco-announces-fda-approval-of-gadopiclenol-injection-a-new-macrocyclic-high-relaxivity-gadolinium-based-contrast-agent-which-will-be-commercialized-as-vueway-gadopiclenol-injection-and-vueway-gadopiclenol-pharmacy-bulk-p-301630124.html . Published September 21, 2022. Accessed September 21, 2022.

2. Bendszus M, Roberts D, Kolumban B, et al. Dose finding study of gadopiclenol, a new macrocyclic contrast agent, in MRI of central nervous system. Invest Radiol. 2020;55(3):129-137.

3. Guerbet. Guerbet announces U.S. Food and Drug Administration (FDA) approval of Elucirem (gadopiclenol) injection for use in contrast-enhanced MRI. Cision PR Newswire. Available at: https://www.prnewswire.com/news-releases/guerbet-announces-us-food-and-drug-administration-fda-approval-of-elucirem-gadopiclenol-injection-for-use-in-contrast-enhanced-mri-301630085.html . Published September 21, 2022. Accessed September 21, 2022.

////Gadopiclenol, FDA 2022, APPROVALS 2022, ガドピクレノール, WHO 10744, P 03277,  EluciremTM, G03277; P03277, VUEWAY, Guerbet

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Valemetostat tosilate

バレメトスタットトシル酸塩

PMDA JAPAN approved 2022/9/26, Ezharmia

• 1,3-Benzodioxole-5-carboxamide, 7-chloro-N-((1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-, (2R)-, compd. with 4-methylbenzenesulfonate (1:1)

Antineoplastic, histone methyltransferase inhibitor

1809336-39-7 (free base). 1809336-93-3 (tosylate)   1809336-92-2 (mesylate)   1809336-94-4 (fumarate)   1809336-95-5 (tarate)

Synonym: Valemetostat; DS-3201; DS 3201; DS3201; DS-3201b

(2R)-7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide mono(4-methylbenzenesulfonate)

C₂₆H₃₄ClN₃O₄C₇H₈O₃S : 660.22
[1809336-93-3]

1809336-39-7 (free base)
Chemical Formula: C26H34ClN3O4
Exact Mass: 487.2238
Molecular Weight: 488.02

(2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide

 Valemetostat, also known as DS-3201 is a potent, selective and orally active EZH1/2 inhibitor. DS-3201 selectively inhibits the activity of both wild-type and mutated forms of EZH1 and EZH2. Inhibition of EZH1/2 specifically prevents the methylation of lysine 27 on histone H3 (H3K27). This decrease in histone methylation alters gene expression patterns associated with cancer pathways, enhances transcription of certain target genes, and results in decreased proliferation of EZH1/2-expressing cancer cells.

• OriginatorDaiichi Sankyo Inc
• DeveloperCALYM Carnot Institute; Daiichi Sankyo Inc; Lymphoma Academic Research Organisation; Lymphoma Study Association; University of Texas M. D. Anderson Cancer Center
• ClassAmides; Amines; Antineoplastics; Benzodioxoles; Chlorinated hydrocarbons; Cyclohexanes; Pyridones; Small molecules
• Mechanism of ActionEnhancer of zeste homolog 1 protein inhibitors; Enhancer of zeste homolog 2 protein inhibitors

• Orphan Drug StatusYes – Adult T-cell leukaemia-lymphoma; Peripheral T-cell lymphoma
• New Molecular EntityYes

• RegisteredAdult T-cell leukaemia-lymphoma
• Phase IIB-cell lymphoma; Peripheral T-cell lymphoma
• Phase I/IISmall cell lung cancer
• Phase INon-Hodgkin’s lymphoma; Prostate cancer; Renal cell carcinoma; Urogenital cancer
• PreclinicalDiffuse large B cell lymphoma
• No development reportedAcute myeloid leukaemia; Precursor cell lymphoblastic leukaemia-lymphoma

• 26 Sep 2022First global approval – Registered for Adult T-cell leukaemia-lymphoma (Monotherapy, Second-line therapy or greater) in Japan (PO)
• 26 Sep 2022Updated efficacy and adverse events data from a phase II trial in Adult T-cell leukaemia-lymphoma released by Daiichi Sankyo
• 28 Dec 2021Preregistration for Adult T-cell leukaemia-lymphoma (Monotherapy, Second-line therapy or greater) in Japan (PO

PATENT

WO 2015141616

 Watson, W. D. J. Org. Chem. 1985, 50, 2145.
 Lengyel, I. ; Cesare, V. ; Stephani, R. Synth. Common. 1998, 28, 1891.

PATENT

WO2022009911

The equipment and measurement conditions for the powder X-ray diffraction measurement in the examples are as follows.
Model: Rigaku Rint TTR-III
Specimen: Appropriate
X-ray generation conditions: 50 kV, 300 mA
Wavelength: 1.54 Å (Copper Kα ray)
Measurement temperature: Room temperature
Scanning speed: 20°/min
Scanning range: 2 to 40°
Sampling width: 0.02°

[0043]

(Reference Example 1) Production of ethyl trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

[0044]

[hua 6]

[0045]

　Under a nitrogen atmosphere, ethanol (624 L) and ethyl trans-4-aminocyclohexanecarboxylate monohydrochloride (138.7 kg, 667.8 mol) were added to a reaction vessel and cooled. Triethylamine (151.2 kg, 1495 .5 mol) and di-tert-butyl dicarbonate (160.9 kg, 737.2 mol) were added dropwise while maintaining the temperature below 20°C. After stirring at 20-25°C for 4 hours, water (1526 kg) was added dropwise at 25°C or lower, and the mixture was further stirred for 2 hours. The precipitated solid was collected by filtration, washed with a mixture of ethanol:water 1:4 (500 L), and dried under reduced pressure at 40°C to obtain 169.2 kg of the title compound (yield 93.4%). .
¹ H NMR (500 MHz, CDCl ₃ ): δ 4.37 (br, 1H), 4.11 (q, J = 2.8 Hz, 2H), 3.41 (br, 1H), 2.20 (tt, J = 4.8, 1.4 Hz, 1H),2.07(m,2H),2.00(m,2H),1.52(dq,J=4.6,1.4Hz,2H),1.44(s,9H),1.24(t,J=2.8Hz,3H), 1.11(dq,J=4.6,1.4Hz,2H)

[0046]

(Reference Example 2) Production of tert-butyl = [trans-4-(hydroxymethyl)cyclohexyl]carbamate

[0047]

[hua 7]

[0048]

　Under a nitrogen atmosphere, tetrahydrofuran (968 kg), ethyl = trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate (110 kg, 405.4 mol), lithium chloride (27.5 kg, 648 kg) were placed in a reaction vessel. .6 mol), potassium borohydride (32.8 kg, 608.1 mol), and water (2.9 L, 162.2 mol) were added, the temperature was slowly raised to 50°C, and the mixture was further stirred for 6 hours. Cooled to 0-5°C. Acetone (66 L) and 9 wt % ammonium chloride aqueous solution (1210 kg) were added dropwise while maintaining the temperature at 20° C. or lower, and the mixture was stirred at 20-25° C. for 1 hour. Additional ethyl acetate (550 L) was added, the aqueous layer was discarded and the organic layer was concentrated to 550 L. Ethyl acetate (1650 L) and 9 wt% aqueous ammonium chloride solution (605 kg) were added to the residue, and the aqueous layer was discarded after stirring. Washed sequentially with water (550 L). The organic layer was concentrated to 880 L, ethyl acetate (660 L) was added to the residue, and the mixture was concentrated to 880 L while maintaining the internal temperature at 40-50°C. The residue was cooled to 0-5° C. and stirred for 1 hour, petroleum ether (1760 L) was added dropwise over 30 minutes, and the mixture was stirred at the same temperature for 2 hours. The precipitated solid was collected by filtration, washed with a petroleum ether:ethyl acetate 3:1 mixture (220 L) cooled to 0-5°C, and dried at 40°C under reduced pressure to give 86.0 kg of the title compound (yield: obtained at a rate of 92.3%).
¹ H NMR (500 MHz, CDCl ₃ ): δ 4.37 (br, 1H), 3.45 (d, J = 2.2 Hz, 2H), 3.38 (br, 1H), 2.04 (m, 2H),
1.84(m,2H),1.44(m,10H),1.28-1.31(m,1H),1.00-1.13(m,4H)

[0049]

(Reference Example 3) Production of tert-butyl = [trans-4-(2,2-dibromoethenyl)cyclohexyl]carbamate

[0050]

[hua 8]

[0051]

(Step 1)
　Under a nitrogen atmosphere, ethyl acetate (50 L), tert-butyl = [trans-4-(hydroxymethyl)cyclohexyl]carbamate (2.5 kg, 10.90 mol), potassium bromide ( 39.3 g, 0.33 mol), 2,2,6,6-tetramethylpiperidine 1-oxyl (51.1 g, 0.33 mol), 4.8% aqueous sodium hydrogen carbonate solution (26.25 kg ) was added and cooled to 0-5°C, 9.9% sodium hypochlorite (8.62 kg, 11.45 mol) was added at 5°C or lower, and the mixture was further stirred at 0°C for 4 hours. Sodium sulfite (250 g) was added to the mixture and stirred at 0-5°C for 30 minutes before warming to 20-25°C. Thereafter, the aqueous layer was discarded and washed with a 20% aqueous sodium chloride solution (12.5 kg), then the organic layer was dried over sodium sulfate and concentrated to 7.5 L. Ethyl acetate (12.5 L) was added to the residue, the mixture was concentrated again to 7.5 L, and used in the next reaction as a tert-butyl=(trans-4-formylcyclohexyl)carbamate solution.

[0052]

(Step 2)
Under a nitrogen atmosphere, tetrahydrofuran (30 L) and triphenylphosphine (5.72 kg, 21.8 mol) were added to a reaction vessel, heated to 40°C, and stirred for 5 minutes. Carbon tetrabromide (3.61 kg, 10.9 mol) was added over 30 minutes and stirred at 40-45° C. for another 30 minutes. A mixture of tert-butyl (trans-4-formylcyclohexyl)carbamate solution and triethylamine (2.54 kg, 25.1 mol) was added below 45°C over 20 minutes and stirred at 40°C for an additional 15 hours. After cooling the reaction solution to 0° C., water (0.2 L) was added at 10° C. or lower, and water (25 L) was added. After heating to 20-25° C., the aqueous layer was discarded, ethyl acetate (4.5 kg) and 10% aqueous sodium chloride solution (25 kg) were added, and after stirring, the aqueous layer was discarded again. After the obtained organic layer was concentrated to 15 L, 2-propanol (19.65 kg) was added and concentrated to 17.5 L. 2-Propanol (11.78 kg) and 5 mol/L hydrochloric acid (151.6 g) were added to the residue, and the mixture was stirred at 25-35°C for 2.5 hours. Water (16.8 L) was added dropwise to the resulting solution, and the mixture was stirred at 20-25°C for 30 minutes and then stirred at 0°C for 2 hours. The precipitated solid was collected by filtration, washed with a mixture (11 kg) of acetonitrile:water 60:40 cooled to 0-5°C, and dried at 40°C under reduced pressure to give 3.05 kg of the title compound (yield 73%). .0%).
¹ H NMR (500 MHz, _CDCl3):δ6.20(d,J=3.6Hz,1H),4.37(br,1H),3.38(br,1H),2.21(dtt,J=3.6,4.6,1.4Hz,1H),2.05-2.00(m,2H),1.80-1.83(m,2H),1.44(s,9H),1.23(ddd,J=9.9,5.3,1.2 Hz,2H),　1.13(ddt,J=4.6,1.4,5.2 Hz,2H)

[0053]

(Reference Example 4) Production of tert-butyl = (trans-4-ethynylcyclohexyl) carbamate

[0054]

[Chemical 9]

[0055]

Under a nitrogen atmosphere, toluene (1436 kg), tert-butyl = [trans-4-(2,2-dibromoethenyl)cyclohexyl]carbamate (110 kg, 287.1 mol), and N,N,N ‘,N’-Tetramethylethane-1,2-diamine (106.7 kg, 918.8 mol) was added and cooled to -10°C. An isopropylmagnesium chloride-tetrahydrofuran solution (2.0 mol/L, 418 kg, 863 mol) was added dropwise at -5°C or lower, and stirred at -10°C for 30 minutes. After the reaction, 5 mol/L hydrochloric acid (465 kg) was added at 5°C or lower, heated to 20-25°C, and further 5 mol/L hydrochloric acid (41.8 kg) was used to adjust the pH to 5.0-. adjusted to 6.0. After discarding the aqueous layer, the organic layer was washed twice with water (550 L) and concentrated to 550 L. 2-Propanol (1296 kg) was added to the concentrate and concentrated to 550 L again. Further, 2-propanol (1296 kg) was added to the residue, and after concentrating to 550 L, water (770 L) was added dropwise in 4 portions. At that time, it was stirred for 30 minutes after each addition. After the addition, the mixture was stirred for 1 hour and further stirred at 0° C. for 1 hour. The precipitated solid was collected by filtration, washed with a 5:7 mixture of 2-propanol:water (550 L) cooled to 0-5°C, and dried at 40°C under reduced pressure to yield 57.8 kg of the title compound. obtained at a rate of 90.2%).
¹ H NMR (500 MHz, CDCl ₃ ): δ 4.36 (br, 1H), 3.43 (br, 1H), 2.18-2.23 (m, 1H), 1.97-2.04 (m, 5H), 1.44-1.56 (m, 11H ),1.06-1.14(m,2H)

[0056]

(Reference Example 5) Production of 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile

[0057]

[Chemical 10]

[0058]

Under a nitrogen atmosphere, water (300 L), 2-cyanoacetamide (20 kg, 238 mol), 1-pentane-2-4-dione (26.2 kg, 262 mol), potassium carbonate (3.29 mol) were added to a reaction vessel. kg, 23.8 mol) was added and stirred at room temperature for 6 hours or longer. After the reaction, the precipitated solid was collected by filtration, washed with water (60 L), further washed with a mixture of methanol (40 L) and water (40 L), and dried under reduced pressure at 40°C to give the title compound as 34 Obtained in .3 kg (97.3% yield).
¹ H NMR (500 MHz, DMSO-d ₆ ): δ 2.22 (s, 3H), 2.30 (s, 3H), 6.16 (s, 1H), 12.3 (brs, 1H)

[0059]

(Reference Example 6) Production of 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one monohydrochloride

[0060]

[Chemical 11]

[0061]

　Under a nitrogen atmosphere, water (171 L), methanol (171 L), 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (17.1 kg, 116 mol), concentrated After adding hydrochloric acid (15.8 kg, 152 mol) and 5% palladium carbon (55% wet) (3.82 kg), the inside of the reaction vessel was replaced with hydrogen. Then, the mixture was pressurized with hydrogen and stirred overnight at 30°C. After the reaction, the reaction vessel was purged with nitrogen, the palladium on carbon was removed by filtration, and the palladium on carbon was washed with a 70% aqueous solution of 2-propanol (51 L). Activated carbon (0.86 kg) was added to the filtrate and stirred for 30 minutes. Activated carbon was removed by filtration and washed with 70% aqueous 2-propanol solution (51 L). The filtrate was concentrated under reduced pressure until the liquid volume became 103 L, and 2-propanol (171 L) was added. The mixture was again concentrated under reduced pressure until the liquid volume reached 103 L, then 2-propanol (171 L) was added, and the mixture was stirred for 1 hour or longer. Precipitation of a solid was confirmed, and the solution was concentrated to a volume of 103 L. Further, 2-propanol (51 L) was added, and after concentration under reduced pressure until the liquid volume reached 103 L, the mixture was stirred at 50° C. for 30 minutes. After adding acetone (171 L) over 1 hour while keeping the internal temperature at 40° C. or higher, the mixture was stirred at 40 to 45° C. for 30 minutes. The solution was cooled to 25°C and stirred for 2 hours or longer, and the precipitated solid was collected by filtration, washed with acetone (86 L) and dried under reduced pressure at 40°C to give 19.7 kg of the title compound (yield 90.4%). ).
¹ H NMR (500 MHz, methanol-d ₄ ): δ 2.27 (s, 3H), 2.30 (s, 3H), 4.02 (s, 2H), 6.16 (s, 1H)

[0062]

(Example 1-1) Production of methyl 5-chloro-3,4-dihydroxy-2-methylbenzoate

[0063]

[Chemical 12]

[0064]

　Under a nitrogen atmosphere, water (420 L), toluene (420 L), acetonitrile (420 L), and methyl 3,4-dihydroxy-2-methylbenzoate (1) (60 kg, 329 mol) were added to the reactor and cooled. After that, sulfuryl chloride (133.4 kg, 988 mol) was added dropwise while maintaining the temperature at 20°C or lower. After the reaction, the mixture was separated into an organic layer 1 and an aqueous layer, acetonitrile (60 L) and toluene (120 L) were added to the aqueous layer, and the mixture was stirred. Water (420 L) and acetonitrile (210 L) were added to the organic layer 1, and after cooling, sulfuryl chloride (88.9 kg, 659 mol) was added dropwise at 20°C or lower, and sulfuryl chloride (53.2 kg, 394 mol) was added. ) was added in portions. After the reaction, the mixture was separated into an organic layer 3 and an aqueous layer, and the organic layer 2 was added to the aqueous layer and stirred. Water (420 L), acetonitrile (210 L) were added to the combined organic layer, sulfuryl chloride (44.5 kg, 329 mol) was added dropwise below 20°C, and sulfuryl chloride (106.4 kg, 788 mol) was added. ) was added in portions. After the reaction, the organic layer 4 and the aqueous layer were separated, acetonitrile (60 L) and toluene (120 L) were added to the aqueous layer, and the mixture was stirred. The combined organic layers were washed three times with 20 wt % aqueous sodium chloride solution (300 L) and then concentrated under reduced pressure to 600 L. After repeating the operation of adding toluene (300 L) and concentrating under reduced pressure to 600 L again twice, the mixture was heated and stirred at 60° C. for 1 hour. After cooling to room temperature, the precipitated solid was collected by filtration, washed with toluene (120 L), and dried under reduced pressure at 40°C to give 52.1 kg of the crude title compound (2) (yield: 73.0%). ).

[0065]

　Under a nitrogen atmosphere, toluene (782 L) and crude title compound (52.1 kg, 241 mol) were added to a reactor and heated to 80°C. After confirming that the crystals were completely dissolved, they were filtered and washed with heated toluene (261 L). The mixture was cooled to 60° C. and stirred for 0.5 hours after crystallization. After cooling to 10°C, the precipitated solid was collected by filtration, washed with toluene (156 L), and dried under reduced pressure at 40°C to give 47.9 kg of the title compound (2) (yield 91.9%). Acquired.
¹ H NMR (500 MHz, methanol-d ₄ ): δ 2.41 (s, 3H), 3.82 (s, 3H), 7.41 (s, 1H)

[0066]

(Example 1-2) Examination of chlorination conditions 1 Since
it is difficult to remove compound (1), which is the starting material, and compound (4), which is a by-product of the reaction, even in subsequent steps, need to control. Therefore, chlorination was investigated in the same manner as in Example 1-1 using compound (1) as a starting material. Table 1 shows the results.

[0067]

[Chemical 13]

[0068]

[Table 1]

[0069]

HPLC condition
detection: 220 nm
column: ACQUITY UPLC BEH C18 (2.1 mm ID x 50 mm, 1.7 μm, Waters)
column temperature: 40 ° C
　mobile phase: A: 0.1 vol% trifluoroacetic acid aqueous solution, B: acetonitrile
Gradient conditions:

[0070]

[Table 2]

[0071]

Flow rate: 1.0 mL/min
Injection volume: 1 μL
Sample solution: acetonitrile/water (1:1)
wash solution: acetonitrile/water (1:1)
purge solution: acetonitrile/water (1:1)
seal wash solution : Acetonitrile/water (1:1)
Sample cooler temperature: None
Measurement time: 5 minutes
Area measurement time: about 0.5 minutes – 4.0 minutes
Comp. 1: 1.11 min, Comp. 2: 1.55 min,
Comp. 3: 1.44 min, Comp. 4: 1.70 min

[0072]

(Example 1-3) Examination of chlorination conditions 2
Compound (1) was used as a starting material, sulfuryl chloride was used as a chlorination reagent, and chlorination in various solvents was examined. Table 3 shows the results.

[0073]

[table 3]

[0074]

(Example 2) Methyl (2RS)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5- Manufacture of carboxylates

[0075]

[Chemical 14]

[0076]

　Toluene (9.0 L), tert-butyl = (trans-4-ethynylcyclohexyl) carbamate (2.23 kg, 9.99 mol), methyl = 5-chloro-3,4- were added to a reaction vessel under a nitrogen atmosphere. Dihydroxy-2-methylbenzoate (1.80 kg, 8.31 mol), tri(o-tolyl)phosphine (76.0 g, 250 mmol), triruthenium dodecacarbonyl (53.0 g, 82.9 mmol) ) was added, and the mixture was heated and stirred at 80 to 90° C. for 7 hours under an oxygen-containing nitrogen stream. The reaction solution was cooled to room temperature to obtain a toluene solution of the title compound.

[0077]

(Example 3) (2RS)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carvone acid production

[0078]

[Chemical 15]

[0079]

Methyl = (2RS)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole obtained in Example 2 -5-carboxylate toluene solution (13 L, equivalent to 7.83 mol), methanol (9.0 L), 1,2-dimethoxyethane (3.6 L), 5 mol / L sodium hydroxide aqueous solution ( 2.50 L, 12.5 mol) was added and stirred at 55-65° C. for 3 hours. After adding water (5.4 L), the mixture was allowed to stand and separated into an organic layer and an aqueous layer. After cooling to room temperature, 1,2-dimethoxyethane (16.2 L) was added to the aqueous layer, and after adjusting the pH to 4.0 to 4.5 with 3 mol/L hydrochloric acid, toluene (5.4 L) was added. added. After heating to 50-60° C., the organic layer and aqueous layer were separated, and the organic layer was washed with a 20 wt % sodium chloride aqueous solution (7.2 L). Then, 1,2-dimethoxyethane (21.6 L) was added to the organic layer, and after concentration under reduced pressure to 9 L, 1,2-dimethoxyethane (21.6 L) was added and heated to 50-60°C. After that, filtration was performed to remove inorganic substances. Then, after washing with 1,2-dimethoxyethane (1.8 L), the 1,2-dimethoxyethane solution of the title compound (quantitative value 89.6% (Example 2 total yield from ), corresponding to 7.45 mol).

[0080]

(Example 4) (1S)-1-phenylethanaminium (2R)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1, Preparation of 3-benzodioxole-5-carboxylate

[0081]

[Chemical 16]

[0082]

(2RS)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5 obtained in Example 3 – A solution of carboxylic acid in dimethoxyethane (21.6 L, corresponding to 7.45 mol) was heated to 75-80°C, and then (1S)-1-phenylethanamine (1.02 kg, 8.42 mmol). was added and stirred for 4 hours. A mixture of 1,2-dimethoxyethane (9.2 L) and water (3.4 L) heated to 50-60° C. was added, stirred, and then cooled to room temperature. The precipitated solid was collected by filtration and washed with 1,2-dimethoxyethane (9 L) to give a crude title compound (1.75 kg (converted to dry matter), yield 38.5% (Example 2 total yield from ) and an optical purity of 93.8% ee).

[0083]

　Under a nitrogen atmosphere, a 1,2-dimethoxyethane aqueous solution (13.6 L) was placed in a reaction vessel, and (1S)-1-phenylethanaminium obtained in step 1 (2R)-2-{trans-4-[(tert -Butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate crude (1.70 kg equivalent, 3.11 mol) was added. After that, 5 mol/L hydrochloric acid (0.56 L, 2.8 mol) was added dropwise. After stirring at room temperature for 10 minutes or longer, the mixture was heated to 75° C. or higher, and (1S)-1-phenylethanamine (360 g, 2.97 mmol) was dissolved in 1,2-dimethoxyethane (2.6 L). The solution was added dropwise over 1 hour. It was then washed with 1,2-dimethoxyethane (0.9 L), stirred for 2 hours and cooled to 0-5°C. The slurry was collected by filtration and washed with 1,2-dimethoxyethane (5.1 L) cooled to 0-5° C. to give the title compound (1.56 kg, yield 91.9%, obtained with an optical purity of 99.5% ee).
¹ H NMR (500 MHz, methanol-d ₄ ): δ 1.15-1.23(m,2H), 1.28-1.35(m,2H), 1.42(s,9H),
1.59(s,3H), 1.60-1.61(d ,3H,J=7.0Hz,3H),1.80-1.86(dt,J=12.0,3.0Hz,1H),1.95-1.96(m,4H),2.27(s,3H),3.24-3.28(m,1H ),4.39-4.43(q,J=7.0Hz,1H),7.07(s,1H),7.37-7.45(m,5H)

[0084]

(Example 5) (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid monohydrochloride Manufacturing A

[0085]

[Chemical 17]

[0086]

(Step 1)
Under a nitrogen atmosphere, 1,2-dimethoxyethane (200 L) and (1S)-1-phenylethanaminium (2R)-2-{trans-4-[(tert-butoxycarbonyl) were placed in a reaction vessel. Amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate (equivalent to 87.64 kg, 160 mol), 35% hydrochloric acid (16.7 kg, 160 mol) was added and heated to 45-55° C., 35% hydrochloric acid (36.7 kg, 352 mol) was added dropwise in 7 portions and stirred for 3 hours after dropping. After cooling to room temperature, the reaction solution was added to a mixture of water (982 L) and 5 mol/L sodium hydroxide (166.34 kg, 702 mol). 3 mol/L hydrochloric acid (22.4 kg) was added dropwise to the resulting solution at 30°C, crystal precipitation was confirmed, and the mixture was stirred for 30 minutes or more, cooled to 10°C, and further stirred for 2 hours. After stirring, 3 mol/L hydrochloric acid (95.1 kg) was added dropwise at 10°C to adjust the pH to 7.0. The slurry liquid was collected by filtration, washed with water (293 L) cooled to 10° C., and (2R)-2-(trans-4-aminocyclohexyl)-7-chloro-2,4-dimethyl-1,3- Benzodioxol-5-carboxylic acid trihydrate was obtained (57.63 kg (converted to dry matter), yield 94.7%).
¹ H NMR (500 MHz, methanol- d4 + D2O): _1.32-1.44 ( m, 4H), 1.61 (s, 3H), 1.89-1.94 (m, 1H), 2.01-2.13 (m, 4H) ,2.27(s,3H),2.99-3.07(m,1H),7.06(s,3H)

[0087]

(Step 2)
Under nitrogen atmosphere, 1,2-dimethoxyethane (115 L), (2R)-2-(trans-4-aminocyclohexyl)-7-chloro-2,4-dimethyl-1,3 -benzodioxole-5-carboxylic acid trihydrate (57.63 kg equivalent, 152 mmol), formic acid (34.92 kg, 759 mol), 37% formaldehyde aqueous solution (93.59 kg, 1153 mol) was added and stirred at 55-65°C for 2 hours. Cool to room temperature, add 2-propanol (864 L) and concentrate to 576 L under reduced pressure. 2-Propanol (231 L) was added thereto and concentrated under reduced pressure to 576 L. Further, 2-propanol (231 L) was added and concentrated under reduced pressure to 576 L. After concentration, 35% hydrochloric acid (20.40 kg, 196 mol) was added dropwise over 2 hours and stirred at room temperature for 30 minutes. Ethyl acetate (576 L) was added to the resulting slurry over 30 minutes and concentrated to 692 L. Ethyl acetate (461 L) was added followed by further concentration to 519 L. Ethyl acetate (634 L) was added to the residue and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with ethyl acetate (491 L) and dried under reduced pressure at 40°C to give the title compound (51. 56 kg, 87.1% yield).
¹ H NMR (500 MHz, methanol-d ₄ ): δ 1.38-1.47 (m, 2H), 1.53-1.61 (m, 2H), 1.67 (s, 3H), 1.99-2.05 (m, 1H), 2.13 -2.18(m,4H),2.38(s,3H),2.84(s,6H),3.19-3.25(dt,J=12.5,3.5Hz,1H),
7.53(s,1H)

[0088]

(Example 6) (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid monohydrochloride Manufacturing B

[0089]

[Chemical 18]

[0090]

　Under a nitrogen atmosphere, formic acid (20 mL), 37% formaldehyde aqueous solution (15 mL), dimethoxyethane (10 mL), (1S)-1-phenylethanaminium (2R)-2-{trans-4- [(tert-Butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate (10 g, 18.3 mmol) was added and Stirred for 10 hours. After cooling to room temperature and filtering the insolubles, 2-propanol (100 mL) was added and the mixture was concentrated under reduced pressure until the liquid volume became 30 mL. While stirring at room temperature, ethyl acetate (120 mL) and concentrated hydrochloric acid (6.1 mL) were added to form a slurry. This was concentrated under reduced pressure to 30 mL, ethyl acetate (120 mL) was added, and then concentrated under reduced pressure to 30 mL again. After adding ethyl acetate (120 mL), the precipitated solid was collected by filtration, washed with ethyl acetate (50 mL) and dried under reduced pressure at 40°C to give 6.56 g of the title compound (yield 92.0%). Acquired.

[0091]

(Example 7) (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl ) Preparation of methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide p-toluenesulfonate

[0092]

[Chemical 19]

[0093]

　Under nitrogen atmosphere, acetone (6.5 L), purified water (1.3 L), (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-2,4- Dimethyl-1,3-benzodioxole-5-carboxylic acid monohydrochloride (650.4 g, 1.67 mol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one Monohydrochloride (330.1 g, 1.75 mol) and triethylamine (337 g, 3.33 mol) were added and stirred at room temperature for 30 minutes. After that, 1-hydroxybenzotriazole monohydrate (255 g, 1.67 mol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (383 g, 2.00 mmol) were added, and the mixture was stirred overnight at room temperature. Stirred. After adjusting the pH to 11 with 5 mol/L sodium hydroxide, toluene (9.8 L) was added, and after stirring, the mixture was separated into an organic layer 1 and an aqueous layer. Toluene (3.3 L) was added to the aqueous layer, and after stirring, the aqueous layer was discarded, and the obtained organic layer was combined with the previous organic layer 1. The combined organic layers were concentrated under reduced pressure to 9.75 L, toluene (6.5 L) was added and washed twice with purified water (3.25 L). The resulting organic layer was concentrated under reduced pressure to 4.875 L and 2-propanol (1.625 L) was added. A solution of p-toluenesulfonic acid monohydrate (0.12 kg, 0.631 mol) dissolved in 4-methyl-2-pentanone (1.14 L) was added to the organic layer heated to 68°C. The mixture was added dropwise over 5 hours and stirred at 68°C for 30 minutes. Furthermore, a solution of p-toluenesulfonic acid monohydrate (0.215 kg, 1.13 mol) dissolved in 4-methyl-2-pentanone (2.11 L) was added dropwise over 3.5 hours, Stirred at 68° C. for 30 minutes. After that, 4-methyl-2-pentanone (6.5 L) was added dropwise over 1 hour. After cooling to room temperature, the precipitated solid was collected by filtration, washed with 4-methyl-2-pentanone (3.25 L) and dried under reduced pressure at 40°C to give 1.035 kg of the crude title compound (yield 94%). .2%).

[0094]

Under a nitrogen atmosphere, 2-propanol (6.65 L) and the obtained crude title compound (950 g) were added to the reactor and stirred. Purified water (0.23 L) was added to completely dissolve the solid at 68° C., filtered, and washed with warm 2-propanol (0.95 L). After confirming that the solid was completely dissolved at an internal temperature of 68°C, the solution was cooled to 50°C. After cooling, seed crystals* (9.5 g, 0.01 wt) were added and stirred at 50° C. overnight. tert-Butyl methyl ether (11.4 L) was added dropwise thereto in 4 portions over 30 minutes each. At that time, it was stirred for 30 minutes after each addition. After cooling to room temperature, the precipitated solid was collected by filtration, washed with a mixture of 2-propanol (0.38 L) and tert-butyl methyl ether (3.42 L), and further treated with tert-butyl methyl ether (4.75 L). ) and dried under reduced pressure at 40° C. to obtain the title compound (915.6 g, yield 96.4%).
¹ H NMR (500 MHz, methanol-d ₄ ): δ 1.35-1.43 (m, 2H), 1.49-1.57 (m, 2H), 1.62 (s, 3H),
1.94-2.00 (dt, J = 12.5, 3.0Hz ,1H),2.09-2.13(m,4H),2.17(s,3H),2.24(s,3H),2.35(s,3H),2.36(s,3H),2.82(s,6H),3.16- 3.22(dt,J=12.0,3.5Hz,1H),4.42(s,2H),
6.10(s,1H),6.89(s,1H),7.22-7.24(d,J=8.0Hz,2H),7.69 -7.71(dt,J=8.0,1.5 Hz,2H)
*Seed crystal preparation method
Under a nitrogen atmosphere, 2-propanol (79.0 L) and the obtained crude title compound (7.90 kg) were added to a reactor and stirred. Purified water (7.9 L) was added to completely dissolve the solid, and activated carbon (0.40 kg) was added and stirred. After filtering the activated carbon, it was washed with 2-propanol (79.0 L) and concentrated to 58 L. 2-Propanol (5 L) was added to the residue, and after heating to 64° C., tert-butyl methyl ether (19.8 L) was added, and after crystal precipitation was confirmed, tert-butyl methyl ether (75. 1 L) was added in three portions. At that time, it was stirred for 30 minutes after each addition. After cooling to room temperature, the precipitated solid was collected by filtration, washed with a mixture of 2-propanol (7.9 L) and tert-butyl methyl ether (15.8 L), and dried under reduced pressure at 40°C to obtain seed crystals. The title compound was obtained (7.08 kg, 89.6% yield).

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///////Valemetostat tosilate, japan 2022, approvals 2022, Ezharmia, バレメトスタットトシル酸塩 , DS-3201, DS 3201, DS3201, DS-3201b, Orphan Drug

CN(C)[C@@H]1CC[C@H](CC1)[C@]2(C)Oc3c(C)c(cc(Cl)c3O2)C(=O)NCC4=C(C)C=C(C)NC4=O

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ELRAGLUSIB

RN: 1034895-42-5
UNII: ND1SOF0DLU, WHO 11553,  9-ING-41

• 1H-Pyrrole-2,5-dione, 3-(5-fluoro-3-benzofuranyl)-4-(5-methyl-5H-1,3-dioxolo(4,5-F)indol-7-yl)-
• 3-(5-Fluoro-benzofuran-3-yl)-4-(5-methyl-5H-(1,3)dioxolo(4,5-F)indol-7-yl)-pyrrole-2,5-dioneAntineoplastic

Molecular Formula

• C22-H13-F-N2-O5

Molecular Weight

• 404.3517

• OriginatorNorthwestern University; University of Illinois at Chicago
• DeveloperActuate Therapeutics; Incyte Corporation; Levine Cancer Institute; University of Kansas Medical Center
• ClassAntineoplastics; Benzofurans; Dioxolanes; Indoles; Pyrroles; Small molecules
• Mechanism of ActionGlycogen synthase kinase 3 beta inhibitors
• Orphan Drug StatusYes – Glioblastoma; Neuroblastoma

• Phase IIAdenoid cystic carcinoma; Myelofibrosis; Neuroblastoma; Pancreatic cancer; Salivary gland cancer
• Phase I/IICancer
• PreclinicalBrain cancer; Chronic lymphocytic leukaemia; Colorectal cancer

• 20 Sep 2022Elraglusib – Actuate Therapeutics receives Fast Track designation for Pancreatic cancer [IV] (Combination therapy, First-line therapy, Late-stage disease, Metastatic disease, Recurrent) in USA
• 03 Jun 2022Efficacy and safety data from a phase I trial in cancer presented at the 58th Annual Meeting of the American Society of Clinical Oncology (ASCO-2022)
• 08 Apr 2022Preclinical trials in Brain cancer in USA (unspecified route)

9-ING-41 is under investigation in clinical trial NCT04218071 (Actuate 1901: 9-ING-41 in Myelofibrosis).

SYN

WO2019079299

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019079299

3-(5-Fluorobenzofuran-3-yl)-4-(5-methyl-5H-[l,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5-dione (“9-ING-41”) has the following chemical structure:

[0004] 9-ING-41 has been reported as being useful for the treatment of cancers, including brain, lung, breast, ovarian, bladder, neuroblastoma, renal, and pancreatic cancers, as well as for treatment of traumatic brain injury.

[0005] The structure, properties, and/or biological activity of 9-ING-41 are set forth in U.S. Patent Number 8,207,216; Gaisina et al., From a Natural Product Lead to the Identification of Potent and Selective Benzofuran-3-yl-(indol-3-yl)maleimides as Glycogen Synthase Kinase 3β Inhibitors That Suppress Proliferation and Survival of Pancreatic Cancer Cells, J. Med. Chem. 2009, 52, 1853-1863; and Hilliard, et al., Glycogen synthase kinase 3β inhibitors induce apoptosis in ovarian cancer cells and inhibit in-vivo tumor growth, Anti-Cancer Drugs 2011, 22:978-985.

Example 1: Preparation of 9-ING-41

[0056] Crude 9-ING-41 can be obtained by the general methods described in U.S. Patent Number 8,207,216, and in Gaisina et al., From a Natural Product Lead to the

Identification of Potent and Selective Benzofuran-3-yl-(indol-3-yl)maleimides as Glycogen Synthase Kinase 3β Inhibitors That Suppress Proliferation and Survival of Pancreatic Cancer Cells, J. Med. Chem. 2009, 52, 1853-1863.

Example 2: Preparation of 9-ING-41 Crystalline Form I

[0057] Crystalline Form I of 9-ING-41 may also be prepared as follows.

Synthesis of Intermediate 1

[0058] Into a 3-L 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 6-nitro-2H-l,3-benzodioxole-5-carbaldehyde (200 g, 1.02 mol, 1.00 equiv), ammonium acetate (200 g, 2.59 mol, 2.53 equiv), acetic acid (2 L), and nitromethane (313 g, 5.13 mol, 5.00 equiv). The solution was stirred for 12 h at lOOoC. The reaction repeated three times. The solutions were combined and diluted with 20 L of water. The resulting solution was extracted with 3×10 L of ethyl acetate and the organic layers were combined. The mixture was washed with 3×10 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 450 g (crude) of 5-nitro-6-[(E)-2-nitroethenyl]-2H-l,3-benzodioxole (1) as a dark green solid.

Synthesis of Intermediate 2

[0059] Fe (120 g, 2.14 mol, 17.01 equiv) was slowly added in portions into a suspension of 5-nitro-6-[(Z)-2-nitroethenyl]-2H-l,3-benzodioxole (30 g, 125.97 mmol, 1.00 equiv), silica gel (120 g) in acetic acid (300 mL), toluene (200 mL), and cyclohexane (400 mL) at 80oC under nitrogen. The resulting black mixture was stirred for 8h at 80oC.The reaction repeated ten times. The reaction mixtures were combined. The solids were filtrated out. The filtrate was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/5). The collected fractions were combined and concentrated under vacuum to give 67.3 g (33%) of 2H, 5H-[1, 3] dioxolo [4, 5-f] indole (2) as an off-white solid.

Synthesis of Intermediate 3

[0060] Sodium hydride (19.9 g, 497.50 mmol, 1.18 equiv, 60%) was added in portions into a solution of 2H,3H,5H-furo[2,3-f]indole (67.3 g, 422.78 mmol, 1.00 equiv) in N,N-

dimethylformamide (1.3 L) at 0°C under nitrogen. The mixture was stirred for lh at 0°C and CH3I (70.9 g, 499.51 mmol, 1.18 equiv) was added dropwise. The resulting solution was stirred for 3 h at room temperature. The solution was quenched by added 1 L of ice water. The resulting solution was extracted with 3×1 L of ethyl acetate and the organic layers were combined. The mixture was washed with 3×1 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). The collected fractions were combined and concentrated under vacuum to give 71 g (97%) of 5-methyl-2H,3H,5H-furo[2,3-f]indole (3) as a light yellow solid.

Synthesis of Int rmediate 4

[0061] Ethyl 2-chloro-2-oxoacetate (220 g, 1.61 mol, 3.96 equiv) was added dropwise into a solution of 5-methyl-2H,3H,5H-furo[2,3-f]indole (70.4 g, 406.44 mmol, 1.00 equiv) in ethyl ether (1.6 L) at OoC under nitrogen. The resulting solution was warmed to room temperature and stirred for 4 h. The reaction was quenched slowly by the addition of 2 L of ice water and the pH value of the resulting solution was adjusted to 9 by Na2C03. The resulted mixture was extracted with 3×1.5 L of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 92.8 g (84%) of ethyl 2-[5-methyl-2H,3H,5H-furo[2,3-f]indol-7-yl]-2-oxoacetate (4) as a light yellow solid.

[0062] 1H MR (300 MHz, DMSO-d6): δ 8.28 (s, 4H), 7.56 (s, 4H), 7.27 (s, 4H), 6.17 (s, 1H), 6.08 (s, 8H), 4.35 (q, J = 7.1 Hz, 7H), 3.85 (s, 11H), 3.35 (s, 2H), 1.35 (t, J = 7.1 Hz, 11H), 1.25 (s, 2H).

Synthesis of Intermediate 5

5

[0063] Into a 10-L 4-necked round-bottom flask was placed 2-bromo-4-fluorophenol (500 g, 2.62 mol, 1.00 equiv), N,N-dimethylformamide (5 L), potassium carbonate (1253 g, 9.07 mol, 3.46 equiv), and ethyl (2E)-4-bromobut-2-enoate (1010 g, 5.23 mol, 2.00 equiv). The resulting solution was stirred for 12 h at room temperature. The solids were collected by filtration. The reaction was then quenched by the addition of 15 L of water and extracted with 3×10 L of ethyl acetate. The organic layers were combined and washed with 4×20 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/20). The collected fractions were combined and concentrated under vacuum to give 500 g (63%) of ethyl (2E)-4-(2-bromo-4-fluorophenoxy)but-2-enoate (5) as a white solid.

Synthesis of Intermediate 6

[0064] Into a 2-L 3 -necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed ethyl (2E)-4-(2-bromo-4-fluorophenoxy)but-2-enoate (125 g, 412.37 mmol, 1.00 equiv), benzyltri ethyl azanium chloride (99 g, 434.64 mmol, 1.05 equiv), sodium formate dihydrate (45.1 g), Pd(OAc)₂ (2.9 g, 12.92 mmol, 0.03 equiv), sodium carbonate (92 g, 868.01 mmol, 2.10 equiv), and N,N-dimethylformamide (1.25 L). The resulting solution was stirred for 12 h at 80°C. The reaction repeated four times. The reaction mixtures were combined and the solids were filtrated out. The filtrate was diluted with 10 L of brine and extracted with 3×5 L of ethyl acetate. The organic layers were combined and washed with 4×6 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/20). The collected fractions were combined and concentrated under vacuum. This resulted in 258 g (crude) of ethyl 2-(5-fluoro-l-benzofuran-3-yl)acetate (6) as light yellow oil.

Synthesis of Intermediate 7

7

[0065] Into a 5-L round-bottom flask was placed ethyl 2-(5-fluoro-l-benzofuran-3-yl)acetate (147 g, 661.53 mmol, 1.00 equiv), methanol (1 L), tetrahydrofuran (1 L), water (1 L), and Li OH (47.7 g, 1.99 mol, 3.01 equiv). The resulting solution was stirred for 3 h at room temperature. The reaction repeated twice. The mixture was concentrated under vacuum and then extracted with 1 L of dichloromethane. The aqueous layer was collected and the pH of the layer was adjust to 1-3 by hydrogen chloride (1 mol/L). The resulting solution was extracted with 3×1 L of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 160 g (62%) of 2-(5-fluoro-l-benzofuran-3-yl)acetic acid (7) as a white solid.

Synthesis of Intermediate 8

[0066] Into a 10-L round-bottom flask was placed 2-(5-fluoro-l-benzofuran-3-yl) acetic acid (160 g, 824.1 mmol, 1.00 equiv), H4C1 (436 g, 8.16 mol, 9.89 equiv), N,N-dimethylformamide (6L), DIEA (1064 g, 8.24 mol, 9.99 equiv), and HATU (376 g, 988.88 mmol, 1.20 equiv). The resulting solution was stirred for 12 h at room temperature. The resulting solution was diluted with 10 L of water. The solids were collected by filtration to give in 126 g (78%) of 2-(5-fluoro-l-benzofuran-3-yl) acetamide (8) as a white solid.

Synthesis of 9-ING-41 in cr stalline Form I

8 9-ING-41

[0067] t-BuOK (1200 mL, 1 mol/L in THF) was added dropwise into a solution of ethyl 2-[5-methyl-2H,3H,5H-furo[2,3-f]indol-7-yl]-2-oxoacetate (100 g, 365.9 mmol, 1.00 equiv), 2-(5-fluoro-l-benzofuran-3-yl)acetamide (72 g, 372.7 mmol, 1.02 equiv) in tetrahydrofuran (3 L) at 0°C under nitrogen. The reaction was stirred for 2h at room temperature. The reaction was cooled to 0°C and poured into of 2 L of H4C1 (saturated solution in water) and extracted with 4×2 L of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/dichloromethane/petroleum ether (1/1/5). The collected fractions were combined and concentrated under vacuum to give 107.9 g (74%) of 3-(5-fluoro-l-benzofuran-3-yl)-4-[5-methyl-2H,5H-[l,3]dioxolo[4,5-f]indol-7-yl]-2,5-dihydro-lH-pyrrole-2,5-dione as a red solid. This red solid is 9-ING-41 crystalline Form I. MS-ESI: [M+H]+ = 405.

PATENT

WO2019032958

PATENT

US20100004308

REF

Journal of Medicinal Chemistry (2009), 52(7), 1853-1863

PATENT

WO2008077138

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Elraglusib is a maleimide-based, small molecule inhibitor of glycogen synthase kinase-3 (GSK-3; serine/threonine-protein kinase GSK3) with potential antineoplastic activity. Upon intravenous administration, elraglusib binds to and competitively inhibits GSK-3, which may lead to downregulation of nuclear factor kappa B (NF-kappaB) and decreased expression of NF-kappaB target genes including cyclin D1, B-cell lymphoma 2 (Bcl-2), anti-apoptotic protein XIAP, and B-cell lymphoma extra-large (Bcl-XL). This may inhibit NF-kappaB-mediated survival and chemoresistance in certain tumor types. GSK-3, a constitutively active serine/threonine kinase that plays a role in numerous pathways involved in protein synthesis, cellular proliferation, differentiation, and metabolism, is aberrantly overexpressed in certain tumor types and may promote tumor cell survival and resistance to chemotherapy and radiotherapy.

Actuate Therapeutics Announces Initiation of a Multicenter Randomized Trial of Elraglusib Plus FOLFIRINOX As First Line Therapy for Advanced Pancreatic Cancer

https://www.biospace.com/article/releases/actuate-therapeutics-announces-initiation-of-a-multicenter-randomized-trial-of-elraglusib-plus-folfirinox-as-first-line-therapy-for-advanced-pancreatic-cancer/

Published: Feb 07, 2022

CHICAGO and FORT WORTH, Texas, Feb. 07, 2022 (GLOBE NEWSWIRE) — Actuate Therapeutics (Actuate), a clinical stage biopharmaceutical company, today announced the opening of a randomized study of elraglusib (9-ING-41) plus FOLFIRINOX alone or with Losartan for patients with advanced pancreatic cancer in the first-line setting (NCT05077800). Elraglusib is Actuate’s proprietary small molecule glycogen synthase kinase-3 beta (GSK-3β) inhibitor which is being developed for adults and children with advanced refractory cancers. This multicenter investigator-initiated study, which is receiving substantial support from the Lustgarten Foundation for Pancreatic Cancer Research, is being led by Colin D. Weekes MD at the Massachusetts General Hospital and will also enroll patients at the University of Washington, University of Colorado Denver, and Johns Hopkins University.

“Novel approaches for patients with advanced pancreatic cancer are urgently required,” said Dr Weekes. “The pre-clinical and clinical data being generated with elraglusib in a spectrum of cancers, including pancreatic cancer, is extremely encouraging and we are delighted to have initiated this study with elraglusib. Elraglusib is the first clinically relevant specific GSK-3β inhibitor that we can thoroughly investigate. In preclinical models, elraglusib has multiple biologic effects relevant to targeting pancreatic cancer including direct cytotoxicity, reversal of chemoresistance, reversal of pathologic fibrosis, and there is increasing evidence of its immune-modulatory activity. In our study, we are particularly focused on elraglusib’s potential to synergize with TGF-β suppression mediated by Losartan. This study builds on the work of our investigative teams demonstrating the roles of TGF-β and GSK-3β in acquired chemotherapy resistance. This study uniquely attempts to harness the mechanisms that pancreatic cancer utilizes to combat the effects of chemotherapy as an Achilles heel for therapeutic intent. We believe that a multi-pronged attack as represented by elraglusib plus Losartan is a potentially sophisticated approach to a complex, often lethal, situation. It is an honour to lead this multicenter collaboration with my clinical and pre-clinical colleagues across the US and Europe. We are very grateful for the critical support of this program by the Lustgarten Foundation.”

“At the Lustgarten Foundation, we understand time is everything for patients and their families,” said Andrew Rakeman, PhD, VP of Research. “Dr. Weekes’ study will help us understand and address a critical issue in pancreatic cancer treatment—acquired chemotherapy resistance. This trial builds on exciting observations from previous preclinical and clinical research. The Foundation established the Clinical Accelerator Initiative for projects like this; bringing more trials based on the best science to the clinic and expanding our understanding of pancreatic cancer biology and treatment. We believe Dr. Weekes’ trial and others like it have the potential to change the way we think about treating pancreatic cancer, ultimately transforming it into a curable disease.”

“We are honored and excited to collaborate with Dr. Weekes, his colleagues at world-leading cancer research centers, and the Lustgarten Foundation on this important trial, which will advance the development of elraglusib for treating patients with one of the most challenging types of cancer,” said Daniel Schmitt, Actuate’s President & CEO. “The results we have seen to date with elraglusib combined with chemotherapy in pancreatic cancer are very promising, and this Phase 2 trial in combination with FOLFIRINOX leverages significant positive preclinical and clinical experience for potentially better outcomes for patients.”

Based on positive data from a prior Phase 2 open-label single arm study of elraglusib plus gemcitabine/nab-paclitaxel, Actuate has also recently initiated an international randomized controlled study of elraglusib in combination with gemcitabine/nab-paclitaxel, in patients with advanced pancreatic cancer in the first-line setting (NCT03678883, EudraCT#:2018-003739-32). Actuate is also conducting studies in pediatric patients with refractory tumors in preparation for a neuroblastoma-specific clinical program (NCT04239092). Actuate is also collaborating with investigators at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital on a Phase 2 study focused on elraglusib combined with cytotoxic therapy for patients with advanced salivary gland carcinomas (NCT05010629).

About Actuate Therapeutics, Inc.
Actuate is a clinical stage pharmaceutical company focused on the development and commercialization of novel therapeutics for cancers and inflammatory diseases. For additional information, please visit the Company’s website at http://www.actuatetherapeutics.com.

///////////ELRAGLUSIB, WHO 11553, 9-ING-41, Orphan Drug

Cn1cc(C2=C(C(=O)NC2=O)c3coc4ccc(F)cc34)c5cc6OCOc6cc15

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Lutetium (177Lu) chloride

塩化ルテチウム (177Lu)

2022/9/15 EMA 2022, Illuzyce

EndolucinBeta

(177Lu)lutetium(3+) trichloride

Lutetium 177 is an isotope of a rare-earth lanthanide metal lutetium. Radioactive decay of Lu 177 produces electrons with low energies making the isotope suitable for treatment of metastatic disease. A complex of Lu177 and somatostatin analog DOTA-TATE was approved by the FDA for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, including foregut, midgut, and hindgut neuroendocrine tumors in adults. It is marketed under a tradename Lutathera. Lutetium in the complex with other carriers – phosphonates and monoclonal antibodies – was investigated in clinical trials as radiotherapy to prostate, ovarian, renal and other types of cancer.Lutetium (¹⁷⁷Lu) chloride is a radioactive compound used for the radiolabeling of pharmaceutical molecules, aimed either as an anti-cancer therapy or for scintigraphy (medical imaging).^[5][6] It is an isotopomer of lutetium(III) chloride containing the radioactive isotope ¹⁷⁷Lu, which undergoes beta decay with a half-life of 6.65 days.

Medical uses

Lutetium (¹⁷⁷Lu) chloride is a radiopharmaceutical precursor and is not intended for direct use in patients.^[5] It is used for the radiolabeling of carrier molecules specifically developed for reaching certain target tissues or organs in the body. The molecules labeled in this way are used as cancer therapeutics or for scintigraphy, a form of medical imaging.^[5] 177Lu has been used with both small molecule therapeutic agents (such as ¹⁷⁷Lu-DOTATATE) and antibodies for targeted cancer therapy^[8][9]

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Contraindications

Medicines radiolabeled with lutetium (¹⁷⁷Lu) chloride must not be used in women unless pregnancy has been ruled out.^[5]

Adverse effects

The most common side effects are anaemia (low red blood cell counts), thrombocytopenia (low blood platelet counts), leucopenia (low white blood cell counts), lymphopenia (low levels of lymphocytes, a particular type of white blood cell), nausea (feeling sick), vomiting and mild and temporary hair loss.^[5]

Society and culture

Legal status

Lutetium (¹⁷⁷Lu) chloride (Lumark) was approved for use in the European Union in June 2015.^[5] Lutetium (¹⁷⁷Lu) chloride (EndolucinBeta) was approved for use in the European Union in July 2016.^[6]

On 21 July 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Illuzyce, a radiopharmaceutical precursor.^[10] Illuzyce is not intended for direct use in patients and must be used only for the radiolabelling of carrier medicines that have been specifically developed and authorized for radiolabelling with lutetium (177Lu) chloride.^[10] The applicant for this medicinal product is Billev Pharma ApS.^[10] Illuzyce was approved for medical use in the European Union in September 2022.^[7]

References

1. ^ “Lutetium (177Lu) Chloride”. Therapeutic Goods Administration (TGA). 21 January 2022. Archived from the original on 5 February 2022. Retrieved 5 February 2022.
2. ^ “Updates to the Prescribing Medicines in Pregnancy database”. Therapeutic Goods Administration (TGA). 12 May 2022. Archived from the original on 3 April 2022. Retrieved 13 May 2022.
3. ^ “TGA eBS – Product and Consumer Medicine Information Licence”. Archived from the original on 5 February 2022. Retrieved 5 February 2022.
4. ^ http://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=1C7A40803A3A3F94CA2587D4003CE48A&agid=(PrintDetailsPublic)&actionid=1 Archived 30 July 2022 at the Wayback Machine^{[bare URL PDF]}
5. ^ Jump up to:^{a b c d e f g} “Lumark EPAR”. European Medicines Agency (EMA). Archived from the original on 25 October 2020. Retrieved 7 May 2020. Text was copied from this source under the copyright of the European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
6. ^ Jump up to:^a b c “EndolucinBeta EPAR”. European Medicines Agency (EMA). Archived from the original on 28 October 2020. Retrieved 7 May 2020. Text was copied from this source under the copyright of the European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
7. ^ Jump up to:^a b “Illuzyce EPAR”. European Medicines Agency (EMA). 18 July 2022. Archived from the original on 22 September 2022. Retrieved 21 September 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
8. ^ Lundsten S, Spiegelberg D, Stenerlöw B, Nestor M (December 2019). “The HSP90 inhibitor onalespib potentiates 177Lu‑DOTATATE therapy in neuroendocrine tumor cells”. International Journal of Oncology. 55 (6): 1287–1295. doi:10.3892/ijo.2019.4888. PMC 6831206. PMID 31638190.
9. ^ Michel RB, Andrews PM, Rosario AV, Goldenberg DM, Mattes MJ (April 2005). “177Lu-antibody conjugates for single-cell kill of B-lymphoma cells in vitro and for therapy of micrometastases in vivo”. Nuclear Medicine and Biology. 32 (3): 269–78. doi:10.1016/j.nucmedbio.2005.01.003. PMID 15820762.
10. ^ Jump up to:^a b c “Illuzyce: Pending EC decision”. European Medicines Agency. 21 July 2022. Archived from the original on 30 July 2022. Retrieved 30 July 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

External links

• “Lutetium chloride Lu-177”. Drug Information Portal. U.S. National Library of Medicine.

.///////////Lutetium (177Lu) chloride, EMA 2022, EU 2022, APPROVALS 2022,  Illuzyce, EndolucinBeta, 塩化ルテチウム (177Lu), 

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Futibatinib

フチバチニブ

2022/9/30 FDA APPROVED, Lytgobi

1-[(3S)-3-[4-amino-3-[2-(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one

TAS-120, TAS 120, TAS120; Futibatinib

Futibatinib, also known as TAS-120 is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) with potential antineoplastic activity. FGFR inhibitor TAS-120 selectively and irreversibly binds to and inhibits FGFR, which may result in the inhibition of both the FGFR-mediated signal transduction pathway and tumor cell proliferation, and increased cell death in FGFR-overexpressing tumor cells. FGFR is a receptor tyrosine kinase essential to tumor cell proliferation, differentiation and survival and its expression is upregulated in many tumor cell types.

SYN

Patent Document 1: International Publication WO 2007/087395 pamphlet
Patent Document 2: International Publication WO 2008/121742 pamphlet
Patent Document 3: International Publication WO 2010/043865 pamphlet
Patent Document 4: International Publication WO 2011/115937 pamphlet

Unlicensed Document 1 : J. Clin. Oncol. 24, 3664-3671 (2006)
Non-licensed Document 2: Mol. Cancer Res. 3, 655-667 (2005)
Non-licensed Document 3: Cancer Res. 70, 2085-2094 (2010)
Non-licensed Document 4: Clin. Cancer Res. 17, 6130-6139 (2011)
Non-licensed Document 5: Nat. Med. 1, 27-31 (1995)

WO2020095452

WO2020096042

WO2020096050

WO2019034075

WO2015008844

WO2015008839

WO2013108809

SYN

US9108973

SYN

Reference Example 1: WXR1

Compound WXR1 was synthesized according to the route reported in patent WO2015008844. ¹ H NMR(400MHz, DMSO-d ₆ )δ8.40(d,J=3.0Hz,1H),6.93(d,J=2.5Hz,2H),6.74-6.52(m,2H),6.20-6.16( m,1H), 5.74-5.69(m,1H), 5.45-5.61(m,1H), 4.12-3.90(m,2H), 3.90-3.79(m,8H), 2.47-2.30(m,2H). MS m/z: 419.1[M+H] ⁺

PAPER

Bioorg Med Chem, March 2013, Vol.21, No.5, pp.1180-1189

SYN

WO2015008844

PATENT

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Futibatinib, sold under the brand name Lytgobi, is a medication used for the treatment of cholangiocarcinoma (bile duct cancer).^[1][2] It is a kinase inhibitor.^[1][3] It is taken by mouth.^[1]

Futibatinib was approved for medical use in the United States in September 2022.^[1][2][4]

Medical uses

Futibatinib is indicated for the treatment of adults with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements.^[1][2]

Names

Futibatinib is the international nonproprietary name (INN).^[5]

References

1. ^ Jump up to:^{a b c d e f} “Lytgobi (futibatinib) tablets, for oral use” (PDF). Archived (PDF) from the original on 4 October 2022. Retrieved 4 October 2022.
2. ^ Jump up to:^a b c https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2022/214801Orig1s000ltr.pdf Archived 4 October 2022 at the Wayback Machine  This article incorporates text from this source, which is in the public domain.
3. ^ “Lytgobi (Futibatinib) FDA Approval History”. Archived from the original on 4 October 2022. Retrieved 4 October 2022.
4. ^ “FDA Approves Taiho’s Lytgobi (futibatinib) Tablets for Previously Treated, Unresectable, Locally Advanced or Metastatic Intrahepatic Cholangiocarcinoma” (Press release). Taiho Oncology. 30 September 2022. Archived from the original on 4 October 2022. Retrieved 4 October 2022 – via PR Newswire.
5. ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81”. WHO Drug Information. 33 (1). hdl:10665/330896.

External links

• “Futibatinib”. Drug Information Portal. U.S. National Library of Medicine.

//////////Futibatinib, Lytgobi, FDA 2022, APPROVALS 2022, フチバチニブ , ANTINEOPLASTIC, TAS 120

C=CC(N1C[C@@H](N2N=C(C#CC3=CC(OC)=CC(OC)=C3)C4=C(N)N=CN=C42)CC1)=O

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Ozoralizumab

PMDA JAPAN  APPROVED 2022 2022/9/26 Nanozora

anti-TNFα Nanobody^®; ATN-103; Nanozora; PF-5230896; TS-152

Ozoralizumab is a humanized monoclonal antibody designed for the treatment of inflammatory diseases.^[1]

Ozoralizumab was developed by Pfizer Inc, and now belongs to Ablynx NV. Ablynx has licensed the rights to the antibody in China to Eddingpharm.

Ozoralizumab has been used in trials studying the treatment of Rheumatoid Arthritis and Active Rheumatoid Arthritis.

Ozoralizumab is a 38 kDa humanized trivalent bispecific construct consisting of two anti-TNFα NANOBODIES^® and anti-HSA NANOBODY^® that was generated at Ablynx by a previously described method (23). Llamas were immunized with human TNFα and human muscle extract, which is rich in HSA, to induce the formation of anti-TNFα VHH and anti-HSA VHH. Both the anti-TNFα VHH and anti-HSA VHH were humanized by a complementary determining regions (CDR) grafting approach in which the CDR of the gene encoding llama VHH was grafted onto the most homologous human VHH framework sequence. Since binding to serum albumin prolongs the half-life of VHH (23, 26, 27), an anti-HSA VHH which efficiently binds murine serum albumin as well was incorporated into the two anti-TNFα VHHs. The three components were fused using a flexible Gly-Ser linker.

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• OriginatorAblynx
• DeveloperAblynx; Eddingpharm; Pfizer; Taisho Pharmaceutical
• ClassAnti-inflammatories; Antirheumatics; Monoclonal antibodies; Proteins
• Mechanism of ActionTumour necrosis factor alpha inhibitors

• Orphan Drug StatusNo
• New Molecular EntityYes

• RegisteredRheumatoid arthritis
• DiscontinuedAnkylosing spondylitis; Crohn’s disease; Psoriatic arthritis

• 05 Oct 2022Sanofi’s affiliate Ablynx has worldwide patent pending for Nanobodies^® (Sanofi website, October 2022)
• 05 Oct 2022Sanofi’s affiliate Ablynx has worldwide patent protection for Nanobodies^® (Sanofi website, October 2022)
• 26 Sep 2022First global approval – Registered for Rheumatoid arthritis in Japan (SC)

References

1. ^ Kratz F, Elsadek B (July 2012). “Clinical impact of serum proteins on drug delivery”. J Control Release. 161 (2): 429–45. doi:10.1016/j.jconrel.2011.11.028. PMID 22155554.

////////Ozoralizumab, Nanozora, Monoclonal antibody, nanobody, Treatment inflammation, ATN 103, APPROVALS 2022, JAPAN 2022

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Daxibotulinumtoxin A

FDA APPROVED 2022 2022/9/7, Daxxify

Daxibotulinumtoxin A-lanm

Treatment of galbellar lines, cervical dystonia, lateral canthal lines, migraine headaches and hyperhidrosis

• DeveloperRevance Therapeutics; Shanghai Fosun Pharmaceutical
• ClassAnalgesics; Anti-inflammatories; Antiarrhythmics; Antidepressants; Antimigraines; Antipruritics; Antispasmodics; Bacterial proteins; Bacterial toxins; Botulinum toxins; Eye disorder therapies; Foot disorder therapies; Muscle relaxants; Skin disorder therapies; Urologics; Vascular disorder therapies
• Mechanism of ActionAcetylcholine inhibitors; Glutamate antagonists; Membrane transport protein modulators; Neuromuscular blocking agents
• Orphan Drug StatusYes – Torticollis

• RegisteredGlabellar lines
• Phase IIITorticollis
• Phase IIMuscle spasticity
• No development reportedSkin disorders
• DiscontinuedPlantar fasciitis

• 19 Sep 2022Efficacy data from a phase IIa FHL trials in Glabellar-lines (crow’s feet) released by Revance
• 19 Sep 2022Updated efficacy and safety data from the phase III SAKURA 1, SAKURA 2 and SAKURA 3 trials in Glabellar lines released by Revance Therapeutics
• 18 Sep 2022Updated efficacy and safety data from the phase III SAKURA 1, SAKURA 2 and SAKURA 3 trials in Glabellar lines released by Revance Therapeutics

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DAXI Impresses; Approaches FDA Approval

March 2, 2021

Lisette Hilton

Dermatology Times, Dermatology Times, February 2021 (Vol. 42, No. 2), Volume 42, Issue 2

The investigational neuromodulator, evaluated in clinical trials as a treatment for glabellar lines and as a combined therapy for glabellar, dynamic forehead, and lateral canthal lines, is quickly nearing an approval by the FDA.

The long-awaited, longer-lasting neuromodulator drug candidate DaxibotulinumtoxinA for Injection (DAXI), a botulinum toxin type A formulated with a novel peptide excipient, may be nearing FDA approval.

In mid-December 2020, Revance Therapeutics shared results from its phase 2 upper facial lines study (NCT04259086),¹ in which investigators looked at DAXI for combined treatment of glabellar, dynamic forehead, and lateral canthal lines.

The authors reported on a multicenter study of 48 patients enrolled to receive 40, 32, and 48 U of DAXI for injection in the glabellar complex, forehead, and lateral canthal areas, respectively. At week 4, nearly 92% of patients achieved an Investigator Global Assessment (IGA) score indicating no or mild wrinkle severity with maximum contraction on their lateral canthal lines. Nearly 96% achieved similar results on their forehead and glabellar lines at week 4.

Wrinkle severity returned to baseline at a median of 7.6 months post treatment, according to the phase 2 study findings.

The treatment was well tolerated in all upper facial regions. The most common adverse event (AE) was injection site erythema, which occurred in 6.3% of patients. The authors reported no eyelid or brow ptosis.

This was Revance’s first DAXI study on not just glabellar lines but also on forehead and periocular lines, or crow’s-feet, according to Jeffrey S. Dover, MD, FRCPC, a phase 2 study investigator and a dermatologist at SkinCare Physicians in Chestnut Hill, Massachusetts. “I think this is yet more evidence that the Revance neuromodulator produces an impressive effect on lines of negative facial expression and lasts longer than any of the other neuromodulators approved by the FDA thus far,” said Dover.

Dermatologic Surgery published 2 papers on the investigational neuromodulator in January 2021. In one study,² investigators evaluated the use of up to 3 DAXI treatments for moderate or severe glabellar lines. They focused on data from SAKURA 1 and 2 (NCT03014622 and NCT03014635), two identical phase 3, open label, multicenter studies in which investigators evaluated single and repeat treatment of the glabellar lines with 40 U of DAXI.

The authors reported on safety results for nearly 2700 patients, including 882 who received a second treatment and 568 who got DAXI a third time. Treatment-related AEs, which were generally mild and resolved, occurred in 17.8% of patients. Eyelid ptosis occurred in 0.9% of treatments.

Investigators of 2 other studies^3,4 focused on DAXI efficacy among nearly 2700 subjects enrolled in Revance’s preceding pivotal trials. Participants received repeat treatments when they returned to baseline on the IGA–Frown Wrinkle Severity (FWS) and IGA–Patient Frown Winkle Severity (PFWS) scales at 12 weeks and up to 36 weeks after treatment.

More than 96% of patients achieved no or mild severity in glabellar wrinkles on the IGA- FWS scale after each of the 3 treatments, with peak responses between weeks 2 to 4, and about one-third or more saw no or mild severity at week 24. Response rates reached highs of 92% or more at weeks 2 to 4 on the IGA-PFWS scale.

“The median duration for return to moderate or severe severity was 24 weeks,” the authors said. “If approved, I believe daxibotulinumtoxinA will change the landscape of neuromodulators significantly. The approved ones all last 3 months. They all give nice results and have few adverse effects,” Dover said.

He and other investigators have seen no rise in AEs, and those that did occur lasted no longer than those of Botox, he said.

Revance appears to be preparing for approval. The company announced on December 22, 2020, that it has a strategic commercial manufacturing agreement with Ajinomoto Bio- Pharma Services for the supply of DAXI.⁵

As of November 24, 2020, the FDA had deferred a decision on the neuromodulator because the required factory inspection could not be conducted due to travel restrictions related to coronavirus disease 2019.⁶ The FDA did not indicate any other issues.

References:

1. Green JB, Mariwalla K, Coleman K, et al. A large, open-label, phase 3 safety study of DaxibotulinumtoxinA for Injection in glabellar lines: a focus on safety from the SAKURA 3 study. Derm Surg. 2021;47(1):42-46. doi:10.1097/DSS.0000000000002463
2. Carruthers JD, Jean D, Fagien S, et al; SAKURA 1 and SAKURA 2 Investigator Group. DaxibotulinumtoxinA for Injection for the treatment of glabellar lines: results from each of two multicenter, randomized, double-blind, placebo-controlled, phase 3 studies (SAKURA 1 and SAKURA 2).Plast Reconstr Surg. 2020;1(145):45-58.doi: 10.1097/PRS.0000000000006327
3. Fabi SG, Cohen JL, Green LJ, et al. DaxibotulinumtoxinA for Injection for the treatment of glabellar lines: efficacy results from SAKURA 3, a large, open-label, phase 3 safety study. Derm Surg. 2021;47(1):48-54. doi:10.1097/DSS.0000000000002531
4. https://investors.revance.com/news-releases/news-release-details/ajinomoto-bio-pharma-services-and-revance-therapeutics-announce. December 22, 2020. Accessed January 15, 2021.
5. FDA defers approval of DaxibotulinumtoxinA for Injection in glabellar lines due to COVID-19 related travel restrictions impacting manufacturing site inspection. News release. Revance Therapeutics, Inc. November 25, 2020. Accessed January 13, 2021. https://www.businesswire.com/news/home/20201125005462/en/FDA-Defers-Approval-DaxibotulinumtoxinA-Injection-Glabellar-Lines

///////////Daxibotulinumtoxin A, FDA 2022, APPROVALS 2022, DAXI, Daxibotulinumtoxin-A, DaxibotulinumtoxinA for Injection, daxibotulinumtoxinA-lanm, DAXXIFY, RT-002, Orphan Drug

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(Light chain)
DIQMTQSPSS LSASVGDRVT ITCRASQSIN SYLDWYQQKP GKAPKLLIYA ASSLQSGVPS
RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YYSTPFTFGP GTKVEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Heavy chain)
QVQLVESGGG VVQPGRSLRL SCAASGFTFS SYGMHWVRQA PGKGLEWVAV IWYDGSNKYY
ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARDP RGATLYYYYY GMDVWGQGTT
VTVSSASTKG PSVFPLAPCS RSTSESTAAL GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA
VLQSSGLYSL SSVVTVPSSN FGTQTYTCNV DHKPSNTKVD KTVERKCCVE CPPCPAPPVA
GPSVFLFPPK PKDTLMISRT PEVTCVVVDV SHEDPEVQFN WYVDGVEVHN AKTKPREEQF
NSTFRVVSVL TVVHQDWLNG KEYKCKVSNK GLPAPIEKTI SKTKGQPREP QVYTLPPSRE
EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP MLDSDGSFFL YSKLTVDKSR
WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K
(Disulfide bridge: L23-L88, L134-L194, L214-H139, H22-H96, H152-H208, H265-H325, H371-H429, H227-H’227, H228-H’228, H231-H’231, H234-H’234)

Fab fragment of tremelimumab (blue) binding CTLA-4 (green). From PDB entry 5GGV.

Tremelimumab

FDA APPROVED2022/10/21, Imjudo

PEPTIDE, CP 675206

Tremelimumab (formerly ticilimumab, CP-675,206) is a fully human monoclonal antibody against CTLA-4. It is an immune checkpoint blocker. Previously in development by Pfizer,^[1] it is now in investigation by MedImmune, a wholly owned subsidiary of AstraZeneca.^[2] It has been undergoing human trials for the treatment of various cancers but has not attained approval for any.

Imjudo (tremelimumab) in combination with Imfinzi approved in the US for patients with unresectable liver cancer

PUBLISHED24 October 2022

https://www.astrazeneca.com/media-centre/press-releases/2022/imfinzi-and-imjudo-approved-in-advanced-liver-cancer.html

24 October 2022 07:00 BST
 

Approval based on HIMALAYA Phase III trial results which showed single priming dose of Imjudo added to Imfinzi reduced risk of death by 22% vs. sorafenib
 

AstraZeneca’s Imjudo (tremelimumab) in combination with Imfinzi (durvalumab) has been approved in the US for the treatment of adult patients with unresectable hepatocellular carcinoma (HCC), the most common type of liver cancer. The novel dose and schedule of the combination, which includes a single dose of the anti-CTLA-4 antibody Imjudo 300mg added to the anti-PD-L1 antibody Imfinzi 1500mg followed by Imfinzi every four weeks, is called the STRIDE regimen (Single Tremelimumab Regular Interval Durvalumab).

The approval by the US Food and Drug Administration (FDA) was based on positive results from the HIMALAYA Phase III trial. In this trial, patients treated with the combination of Imjudo and Imfinzi experienced a 22% reduction in the risk of death versus sorafenib (based on a hazard ratio [HR] of 0.78, 95% confidence interval [CI] 0.66-0.92 p=0.0035).¹ Results were also published in the New England Journal of Medicine Evidence showing that an estimated 31% of patients treated with the combination were still alive after three years, with 20% of patients treated with sorafenib still alive at the same duration of follow-up.²

Liver cancer is the third-leading cause of cancer death and the sixth most commonly diagnosed cancer worldwide.^3,4 It is the fastest rising cause of cancer-related deaths in the US, with approximately 36,000 new diagnoses each year.^5,6

Ghassan Abou-Alfa, MD, MBA, Attending Physician at Memorial Sloan Kettering Cancer Center (MSK), and principal investigator in the HIMALAYA Phase III trial, said: “Patients with unresectable liver cancer are in need of well-tolerated treatments that can meaningfully extend overall survival. In addition to this regimen demonstrating a favourable three-year survival rate in the HIMALAYA trial, safety data showed no increase in severe liver toxicity or bleeding risk for the combination, important factors for patients with liver cancer who also have advanced liver disease.”

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: “With this first regulatory approval for Imjudo, patients with unresectable liver cancer in the US now have an approved dual immunotherapy treatment regimen that harnesses the potential of CTLA-4 inhibition in a unique combination with a PD-L1 inhibitor to enhance the immune response against their cancer.”

Andrea Wilson Woods, President & Founder, Blue Faery: The Adrienne Wilson Liver Cancer Foundation, said: “In the past, patients living with liver cancer had few treatment options and faced poor prognoses. With today’s approval, we are grateful and optimistic for new, innovative, therapeutic options. These new treatments can improve long-term survival for those living with unresectable hepatocellular carcinoma, the most common form of liver cancer. We appreciate the patients, their families, and the broader liver cancer community who continue to fight for new treatments and advocate for others.”

The safety profiles of the combination of Imjudo added to Imfinzi and for Imfinzi alone were consistent with the known profiles of each medicine, and no new safety signals were identified.

Regulatory applications for Imjudo in combination with Imfinzi are currently under review in Europe, Japan and several other countries for the treatment of patients with advanced liver cancer based on the HIMALAYA results.

Notes

Liver cancer
About 75% of all primary liver cancers in adults are HCC.³ Between 80-90% of all patients with HCC also have cirrhosis.⁷ Chronic liver diseases are associated with inflammation that over time can lead to the development of HCC.⁷

More than half of patients are diagnosed at advanced stages of the disease, often when symptoms first appear.⁸ A critical unmet need exists for patients with HCC who face limited treatment options.⁸ The unique immune environment of liver cancer provides clear rationale for investigating medications that harness the power of the immune system to treat HCC.⁸

HIMALAYA
HIMALAYA was a randomised, open-label, multicentre, global Phase III trial of Imfinzi monotherapy and a regimen comprising a single priming dose of Imjudo 300mg added to Imfinzi 1500mg followed by Imfinzi every four weeks versus sorafenib, a standard-of-care multi-kinase inhibitor.

The trial included a total of 1,324 patients with unresectable, advanced HCC who had not been treated with prior systemic therapy and were not eligible for locoregional therapy (treatment localised to the liver and surrounding tissue).

The trial was conducted in 181 centres across 16 countries, including in the US, Canada, Europe, South America and Asia. The primary endpoint was overall survival (OS) for the combination versus sorafenib and key secondary endpoints included OS for Imfinzi versus sorafenib, objective response rate and progression-free survival (PFS) for the combination and for Imfinzi alone.

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi was recently approved to treat patients with advanced biliary tract cancer in the US based on results from the TOPAZ-1 Phase III trial. It is the only approved immunotherapy in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiotherapy and is the global standard of care in this setting based on the PACIFIC Phase III trial.

Imfinzi is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage small cell lung cancer (ES-SCLC) based on the CASPIAN Phase III trial. In 2021, updated results from the CASPIAN trial showed Imfinzi plus chemotherapy tripled patient survival at three years versus chemotherapy alone.

Imfinzi is also approved for previously treated patients with advanced bladder cancer in several countries.

Since the first approval in May 2017, more than 100,000 patients have been treated with Imfinzi.

As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several gastrointestinal (GI) cancers, ovarian cancer, endometrial cancer, and other solid tumours.

Imfinzi combinations have also demonstrated clinical benefit in metastatic NSCLC in the POSEIDON Phase III trial.

Imjudo
Imjudo (tremelimumab) is a human monoclonal antibody that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Imjudo blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death.

Beyond HIMALAYA, Imjudo is being tested in combination with Imfinzi across multiple tumour types including locoregional HCC (EMERALD-3), SCLC (ADRIATIC) and bladder cancer (VOLGA and NILE).

Imjudo is also under review by global regulatory authorities in combination with Imfinzi and chemotherapy in 1st-line metastatic NSCLC based on the results of the POSEIDON Phase III trial, which showed the addition of a short course of Imjudo to Imfinzi plus chemotherapy improved both overall and progression-free survival compared to chemotherapy alone.

AstraZeneca in GI cancers
AstraZeneca has a broad development programme for the treatment of GI cancers across several medicines spanning a variety of tumour types and stages of disease. In 2020, GI cancers collectively represented approximately 5.1 million new diagnoses leading to approximately 3.6 million deaths.⁹

Within this programme, the Company is committed to improving outcomes in gastric, liver, biliary tract, oesophageal, pancreatic, and colorectal cancers.

Imfinzi (durvalumab) is being assessed in combinations in oesophageal and gastric cancers in an extensive development programme spanning early to late-stage disease across settings.

The Company aims to understand the potential of Enhertu (trastuzumab deruxtecan), a HER2-directed antibody drug conjugate, in the two most common GI cancers, colorectal and gastric cancers. Enhertu is jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

Lynparza (olaparib) is a first-in-class PARP inhibitor with a broad and advanced clinical trial programme across multiple GI tumour types including pancreatic and colorectal cancers. Lynparza is developed and commercialised in collaboration with MSD (Merck & Co., Inc. inside the US and Canada).

AstraZeneca in immuno-oncology (IO)
Immunotherapy is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. The Company’s immuno-oncology (IO) portfolio is anchored in immunotherapies that have been designed to overcome evasion of the anti-tumour immune response. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumour types.

The Company is pursuing a comprehensive clinical trial programme that includes Imfinzi as a single treatment and in combination with Imjudo (tremelimumab) and other novel antibodies in multiple tumour types, stages of disease, and lines of treatment, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient.

In addition, the ability to combine the IO portfolio with radiation, chemotherapy, and targeted small molecules from across AstraZeneca’s oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

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Mechanism of action

Tremelimumab aims to stimulate an immune system attack on tumors. Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, there is also an inhibitory mechanism (immune checkpoint) that interrupts this destruction. Tremelimumab turns off this inhibitory mechanism and allows CTLs to continue to destroy the cancer cells.^[3] This is immune checkpoint blockade.

Tremelimumab binds to the protein CTLA-4, which is expressed on the surface of activated T lymphocytes and inhibits the killing of cancer cells. Tremelimumab blocks the binding of the antigen-presenting cell ligands B7.1 and B7.2 to CTLA-4, resulting in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation; subsequently, B7.1 or B7.2 may interact with another T-cell surface receptor protein, CD28, resulting in a B7-CD28-mediated T-cell activation unopposed by B7-CTLA-4-mediated inhibition.

Unlike Ipilimumab (another fully human anti-CTLA-4 monoclonal antibody), which is an IgG1 isotype, tremelimumab is an IgG2 isotype.^[4][5]

Clinical trials

Melanoma

Phase 1 and 2 clinical studies in metastatic melanoma showed some responses.^[6] However, based on early interim analysis of phase III data, Pfizer designated tremelimumab as a failure and terminated the trial in April 2008.^[1][7]

However, within a year, the survival curves showed separation of the treatment and control groups.^[8] The conventional Response Evaluation Criteria in Solid Tumors (RECIST) may underrepresent the merits of immunotherapies. Subsequent immunotherapy trials (e.g. ipilimumab) have used the Immune-Related Response Criteria (irRC) instead.

Mesothelioma

Although it was designated in April 2015 as orphan drug status in mesothelioma,^[9] tremelimumab failed to improve lifespan in the phase IIb DETERMINE trial, which assessed the drug as a second or third-line treatment for unresectable malignant mesothelioma.^[10][11]

Non-small cell lung cancer

In a phase III trial, AstraZeneca paired tremelimumab with a PD-L1 inhibitor, durvalumab, for the first-line treatment of non-small cell lung cancer.^[12] The trial was conducted across 17 countries, and in July 2017, AstraZeneca announced that it had failed to meet its primary endpoint of progression-free survival.^[13]

References

1. ^ Jump up to:^a b “Pfizer Announces Discontinuation of Phase III Clinical Trial for Patients with Advanced Melanoma”. Pfizer.com. 1 April 2008. Retrieved 5 December 2015.
2. ^ Mechanism of Pathway: CTLA-4 Inhibition^{[permanent dead link]}
3. ^ Antoni Ribas (28 June 2012). “Tumor immunotherapy directed at PD-1”. New England Journal of Medicine. 366 (26): 2517–9. doi:10.1056/nejme1205943. PMID 22658126.
4. ^ Tomillero A, Moral MA (October 2008). “Gateways to clinical trials”. Methods Find Exp Clin Pharmacol. 30 (8): 643–72. doi:10.1358/mf.2008.30.5.1236622. PMID 19088949.
5. ^ Poust J (December 2008). “Targeting metastatic melanoma”. Am J Health Syst Pharm. 65 (24 Suppl 9): S9–S15. doi:10.2146/ajhp080461. PMID 19052265.
6. ^ Reuben, JM; et al. (1 Jun 2006). “Biologic and immunomodulatory events after CTLA-4 blockade with tremelimumab in patients with advanced malignant melanoma”. Cancer. 106 (11): 2437–44. doi:10.1002/cncr.21854. PMID 16615096. S2CID 751366.
7. ^ A. Ribas, A. Hauschild, R. Kefford, C. J. Punt, J. B. Haanen, M. Marmol, C. Garbe, J. Gomez-Navarro, D. Pavlov and M. Marsha (May 20, 2008). “Phase III, open-label, randomized, comparative study of tremelimumab (CP-675,206) and chemotherapy (temozolomide [TMZ] or dacarbazine [DTIC]) in patients with advanced melanoma”. Journal of Clinical Oncology. 26 (15S): LBA9011. doi:10.1200/jco.2008.26.15_suppl.lba9011.^{[permanent dead link]}
8. ^ M.A. Marshall, A. Ribas, B. Huang (May 2010). “Evaluation of baseline serum C-reactive protein (CRP) and benefit from tremelimumab compared to chemotherapy in first-line melanoma”. Journal of Clinical Oncology. 28 (15S): 2609. doi:10.1200/jco.2010.28.15_suppl.2609.^{[permanent dead link]}
9. ^ FDA Grants AstraZeneca’s Tremelimumab Orphan Drug Status for Mesothelioma [1]
10. ^ “Tremelimumab Fails Mesothelioma Drug Trial”. Archived from the original on 2016-03-06. Retrieved 2016-03-06.
11. ^ AZ’ tremelimumab fails in mesothelioma trial
12. ^ “AstraZeneca’s immuno-oncology combo fails crucial Mystic trial in lung cancer | FierceBiotech”.
13. ^ “AstraZeneca reports initial results from the ongoing MYSTIC trial in Stage IV lung cancer”.

///////////Tremelimumab, Imjudo, APPROVALS 2022, FDA 2022, PEPTIDE, CP 675206, Antineoplastic, Immune checkpoint inhibitor, Anti-CTLA4 antibody

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TEREVALEFIM

Molecular Formula

• C9-H8-N2-S

Molecular Weight

• 176.2382

RN: 1070881-42-3
UNII: GG91UXK2M5

• 5-((E)-2-Thiophen-2-yl-vinyl)-lh-pyrazole
• 1H-Pyrazole, 3-((1E)-2-(2-thienyl)ethenyl)-

• ANG-3777
• SNV-003

• OriginatorAngion Biomedica
• ClassAnti-ischaemics; Antifibrotics; Heart failure therapies; Pyrazoles; Small molecules; Thiophenes; Urologics; Vascular disorder therapies
• Mechanism of ActionProto oncogene protein c met stimulants
• Orphan Drug StatusYes – Renal failure

• Phase IIIDelayed graft function
• Phase IIAcute kidney injury; Acute lung injury; Renal failure
• PreclinicalBrain injuries
• No development reportedHeart failure
• DiscontinuedHepatic fibrosis; Myocardial infarction; Stroke

• 02 Aug 2022Vifor Pharma has been acquired by CSL and renamed to CSL Vifor
• 14 Dec 2021Efficacy and adverse events data of a phase II GUARD trial in Acute kidney injury released by the company
• 26 Oct 2021Top-line efficacy and adverse events data from the phase III trial GIFT (Graft Improvement Following Transplant) trial in Delayed graft function released by Angion Biomedica and Vifor Pharma

Terevalefim, an hepatocyte growth factor (HGF) mimetic, selectively activates the c-Met receptor.

PATENT

WO 2004/058721

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2004058721

PATENT

PCT Application No. PCT/US2003/040917, filed December 19, 2003 and published as WO2004/058721 on July 15, 2004, the entirety of which is hereby incorporated by reference, describes certain compounds that act as HGF/SF mimetics . Such compounds include terevalefim:

Terevalefim has been demonstrated to be remarkably useful for treatment of a variety of conditions including, for example, fibrotic liver disease, ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, renal disease, lung fibrosis, damaged and/or ischemic organs, transplants or grafts, stroke, cerebrovascular disease, and renal fibrosis, among others (see, for example, WO 2004/058721, WO 2010/005580, US 2011/0230407, US 7879898, and WO 2009/064422, each of which is hereby incorporated by reference.) Exemplary methods of using terevalefim for, eg, treating delayed graft function after kidney transplantation and acute lung injury, are described in WO 2021/087392 and WO 2021/183774, each of which is hereby incorporated by reference. In particular, Terevalefim is or has been the subject of clinical trials for delayed graft function in recipients of a deceased donor kidney (Clinicaltrials.gov identifier: NCT02474667), acute kidney injury after cardiac surgery involving cardiopulmonary bypass (Clinicaltrials.gov identifier: NCT02771509), and COVID -19 pneumonia (Clinicaltrials.gov identifier: NCT04459676). Without wishing to be bound by any particular theory, it is believed that terevalefim’s HGF mimetic capability imparts a variety of beneficial attributes and activities.

[0035] Terevalefim has a CAS Registry No. of 1070881-42-3 and is also known by at least the following names:

● 3-[(1E)-2-(thiophen-2-yl)ethen-1-yl]-1H-pyrazole; and

● (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole.

Synthesis of Terevalefim

[0057] In some embodiments, the present disclosure provides methods for preparing compounds useful as HGF/SF mimetics, such as terevalefim. A synthesis of terevalefim is described in detail in Example 7 of WO 2004/058721 (“the ‘721 Synthesis”). The ‘721 Synthesis is depicted in Scheme 1:

The ‘721 Synthesis includes certain features which are not desirable for preparation of terevalefim at scale and/or with consistency and/or with suitable purity for use in humans. For example, the ‘721 Synthesis includes preparation of aldehyde compound 1.2, a viscous oil that is difficult to purify with standard techniques. Additionally, the ‘721 Synthesis uses a diethoxyphosphorylacetaldehyde tosylhydrazone reagent in step 1-2. As such, step 1-2 has poor atom economy and results in multiple byproducts that must be purified away from the final product of terevalefim. Step 1-2 also uses sodium hydride, a highly reactive base that can be difficult to control and often results in byproducts that must be purified away from the final product of terevalefim. Such purification steps can be costly and time-consuming. In some embodiments, the present disclosure encompasses the recognition that one or more features of the ‘721 Synthesis can be improved to increase yield and/or increase reliability and/or increase scale and/or reduce byproducts. In some embodiments, the present disclosure provides such a synthesis, as detailed herein.

[0059] In some embodiments, the present disclosure provides a synthesis of terevalefim as depicted in Scheme 2:

Scheme 2

wherein X and R ¹ are defined below and in classes and subclasses as described herein.

[0060] It will be appreciated that compounds described herein, eg, compounds in Scheme 2, may be provided and/or utilized in a salt form. For example, compounds which contain a basic nitrogen atom may form a salt with a suitable acid. Alternatively and/or additionally, compounds which contain an acidic moiety, such as a carboxylic acid group, may form a salt with a suitable base. Suitable counterions are well known in the art, eg, see generally, March ‘s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, MB Smith and J.

March, 5 ^th Edition, John Wiley & Sons, 2001. All forms of the compounds in Scheme 2 are contemplated by and within the scope of the present disclosure.

Step 2-1 of Scheme 2

[0061] Step 2-1 includes a condensation-elimination reaction between commercially available thiophene-2-carboxaldehyde (1.1) and acetone to provide an α,β-unsaturated ketone compound (2.1).

[0062] In some embodiments, the present disclosure provides a method comprising steps of:

(i) providing compound 1.1:

(ii) contacting compound 1.1 with acetone in the presence of a suitable base,

to compound provide 2.1:

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///////TEREVALEFIM, ANG-3777, SNV-003, Phase 3, Delayed graft function

C(=C\c1cccs1)/c2cc[nH]n2

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Mirvetuximab soravtansine-gynx

FDA 11/14/2022,To treat patients with recurrent ovarian cancer that is resistant to platinum therapy

FDA Approves Mirvetuximab Soravtansine-gynx for FRα+ Platinum-resistant Ovarian Cancer

https://www.biochempeg.com/article/315.html

4846-85a8-48171ab38275

FDA Approves Mirvetuximab Soravtansine-gynx for FRα+ Platinum-resistant Ovarian Cancer

November 15, 2022

Kristi Rosa

The FDA has granted accelerated approval to mirvetuximab soravtansine-gynx (Elahere) for the treatment of select patients with folate receptor α–positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.

The FDA has granted accelerated approval to mirvetuximab soravtansine-gynx (Elahere) for the treatment of adult patients with folate receptor α (Frα)–positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received 1 to 3 prior systemic treatment regimens.^1-3

The regulatory agency also gave the green light to the VENTANA FOLR1 (FOLR-2.1) RxDx Assay for use as a companion diagnostic device to identify patients who are eligible to receive the agent. Testing can be done on fresh or archived tissue. Newly diagnosed patients can be tested at diagnosis to determine whether this agent will be an option for them at the time of progression to platinum resistance.

The decision was supported by findings from the phase 3 SORAYA trial (NCT04296890), in which mirvetuximab soravtansine elicited a confirmed investigator-assessed objective response rate (ORR) of 31.7% (95% CI, 22.9%-41.6%); this included a complete response rate of 4.8% and a partial response rate of 26.9%. Moreover, the median duration of response (DOR) was 6.9 months (95% CI, 5.6-9.7) per investigator assessment.

“The approval of Elahere is significant for patients with FRα-positive platinum-resistant ovarian cancer, which is characterized by limited treatment options and poor outcomes,” Ursula Matulonis, MD, chief of the Division of Gynecologic Oncology at the Dana-Farber Cancer Institute, professor of medicine at the Harvard Medical School, and SORAYA co-principal investigator, stated in a press release. “Elahere impressive anti-tumor activity, durability of response, and overall tolerability observed in SORAYA demonstrate the benefit of this new therapeutic option, and I look forward to treating patients with Elahere.”

The global, single-arm SORAYA trial enrolled a total of 106 patients with platinum-resistant ovarian cancer whose tumors expressed high levels of FRα. Patients were allowed to have received up to 3 prior lines of systemic treatment, and all were required to have received bevacizumab (Avastin).

If patients had corneal disorders, ocular conditions in need of ongoing treatment, peripheral neuropathy that was greater than grade 1 in severity, or noninfectious interstitial lung disease, they were excluded.

Study participants received intravenous mirvetuximab soravtansine at 6 mg/kg once every 3 weeks until progressive disease or unacceptable toxicity. Investigators conducted tumor response assessments every 6 weeks for the first 36 weeks, and every 12 weeks thereafter.

Confirmed investigator-assessed ORR served as the primary end point for the research, and the key secondary end point was DOR by RECIST v1.1 criteria.

In the efficacy-evaluable population (n = 104), the median age was 62 years (range, 35-85). Ninety-six percent of patients were White, 2% were Asian, and 2% did not have their race information reported; 2% of patients were Hispanic or Latino. Regarding ECOG performance status, 57% of patients had a status of 0 and the remaining 43% had a status of 1.

Ten percent of patients received 1 prior line of systemic treatment, 39% received 2 prior lines, and 50% received 3 or more prior lines. All patients previously received bevacizumab, as required, and 47% previously received a PARP inhibitor.

The safety of mirvetuximab soravtansine was evaluated in all 106 patients. The median duration of treatment with the agent was 4.2 months (range, 0.7-13.3).

The all-grade toxicities most commonly experienced with mirvetuximab soravtansine included vision impairment (50%), fatigue (49%), increased aspartate aminotransferase (50%), nausea (40%), increased alanine aminotransferase (39%), keratopathy (37%), abdominal pain (36%), decreased lymphocytes (35%), peripheral neuropathy (33%), diarrhea (31%), decreased albumin (31%), constipation (30%), increased alkaline phosphatase (30%), dry eye (27%), decreased magnesium (27%), decreased leukocytes (26%), decreased neutrophils (26%), and decreased hemoglobin (25%).

Thirty-one percent of patients experienced serious adverse reactions with the agent, which included intestinal obstruction (8%), ascites (4%), infection (3%), and pleural effusion (3%). Toxicities proved to be fatalfor 2% of patients, and these included small intestinal obstruction (1%) and pneumonitis (1%).

Twenty percent of patients required dose reductions due to toxicities. Eleven percent of patients discontinued treatment with mirvetuximab soravtansine because of adverse reactions. Toxicities that resulted in more than 2% of patients discontinuing treatment included intestinal obstruction (2%) and thrombocytopenia (2%). One patient discontinued because of visual impairment.

References

1. ImmunoGen announces FDA accelered approval of Elahere (mirvetuximab soravtansine-gynx) for the treatment of platinum-resistant ovarian cancer. News release. ImmunoGen Inc. November 14, 2022. Accessed November 14, 2022. http://bit.ly/3GgrCwL
2. FDA grants accelerated approval to mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or peritoneal cancer. News release. FDA. November 14, 2022. Accessed November 14, 2022. http://bit.ly/3UP742w
3. Elahere (mirvetuximab soravtansine-gynx). Prescribing information; ImmunoGen Inc; 2022. Accessed November 14, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761310s000lbl.pdf

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//////////Mirvetuximab soravtansine-gynx, FDA 2022, APPROVALS 2022,  recurrent ovarian cancer, 

Tolebrutinib

SAR442168

• Treatment of Multiple Sclerosis (MS)

CAS 1971920-73-6

PRN 2246, example 3 [WO2016196840A1]

C26H25N5O3, 

GTPL10625

BTK’168

EX-A4699

BDBM50557487

WHO 11268

4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]imidazo[4,5-c]pyridin-2-one

4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]imidazo[4,5-c]pyridin-2-one

(R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one

4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-(prop-2-

enoyl)piperidin-3-yl]-1,3-dihydro-2H-imidazo[4,5-

2H-Imidazo(4,5-C)pyridin-2-one, 4-amino-1,3-dihydro-1-((3R)-1-(1-oxo-2-propen-1-yl)-3-piperidinyl)-3-(4-phenoxyphenyl)-

4-Amino-1,3-dihydro-1-((3R)-1-(1-oxo-2-propen-1-yl)-3-piperidinyl)-3-(4-phenoxyphenyl)-2H-imidazo(4,5-C)pyridin-2-one

Tolebrutinib (R&D code SAR442168), developed by Principia and later acquired by Sanofi and included in its product line, Tolebrutinib is a BTK inhibitor used to treat cancer, autoimmune diseases such as multiple sclerosis and myasthenia gravis, inflammatory diseases and thromboembolic diseases, etc.,

Tolebrutinib is an orally bioavailable, brain-penetrant, selective, small molecule inhibitor of Bruton’s tyrosine kinase (BTK), with potential immunomodulatory and anti-inflammatory activities. Upon oral administration, tolebrutinib is able to cross the blood-brain barrier and inhibits the activity of BTK both peripherally and in the central nervous system (CNS). This prevents the activation of the B-cell antigen receptor (BCR) signaling pathway, and the resulting immune activation and inflammation. The inhibition of BTK activity also prevents microglial inflammatory signaling in the CNS, and the resulting immune activation, neuroinflammation and neurodegeneration. BTK, a cytoplasmic tyrosine kinase and member of the Tec family of kinases, plays an important role in B lymphocyte development, activation, signaling, proliferation and survival. In addition to B cells, BTK is also expressed in innate immune cells, including macrophages and microglia, and plays an important role in the regulation of microglial inflammatory signaling.

BTK, a member of the Tec family non-receptor tyrosine kinases, is essential for B cell signaling downstream from the B-cell receptor. It is expressed in B cells and other hematopoietic cells such as monocytes, macrophages and mast cells. It functions in various aspects of B cell function that maintain the B cell repertoire (see Gauld S. B. et al., B cell antigen receptor signaling: roles in cell development and disease. Science,

296: 1641 -2. 2002.) B cells pay a role in rheumatoid arthritis (see Perosa F., et ai, CD20-depleting therapy in autoimmune diseases: from basic research to the clinic. / Intern Med. 267:260-77. 2010 and Dorner T, et at. Targeting B cells in immune-mediated

inflammatory disease: a comprehensive review of mechanisms of action and identification of biomarkers. Pharmacol The 125:464-75. 2010 and Honigberg, L., et. ai, The selective BTK inhibitor PCI-32765 blocks B cell and mast cell activation and prevents mouse collagen indiced arthritis. Clin. Immunol. 127 SI :S 111. 2008) and in other autoimmune diseases such as systemic lupus erythematosus and cancers (see Shlomchik M. J., et. ai, The role of B cells in lpr/lpr-induced autoimmunity. /. Exp Med. 180:1295-1306. 1994; Honigberg L. A., The Braton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc. Natl. Acad. Sci. 107: 13075-80. 2010; and Mina-Osorio P, et al., Suppression of

glomerulonephritis in lupus-prone NZB x NZW mice by RN486, a selective inhibitor of Bruton’s tyrosine kinase. Arthritis Rheum. 65: 2380-91. 2013).

There is also potential for BTK inhibitors for treating allergic diseases (see Honigberg, L., et. al., The selective BTK inhibitor PCI-32765 blocks B cell and mast cell activation and prevents mouse collagen indiced arthritis. Clin. Immunol. 127 SI :S111. 2008). It was noted that the irreversible inhibitor suppresses passive cutaneous anaphylaxis (PCA) induced by IgE antigen complex in mice. These findings are in agreement with those noted with BTK-mutant mast cells and knockout mice and suggest that BTK inhibitors may be useful for the treatment of asthma, an IgE-dependent allergic disease of the airway.

Accordingly, compounds that inhibit BTK would be useful in treatment for diseases such as autoimmune diseases, inflammatory diseases, and cancer.

PATENT

WO2022242740 TOLEBRUTINIB SALT AND CRYSTAL FORM THEREOF, PREPARATION METHOD THEREFOR, PHARMACEUTICAL COMPOSITION THEREOF, AND USE THEREOF (wipo.int)

PATENT

example 3 [WO2016196840A1]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016196840

Example 3

Synthesis of (R)-l-(l-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-lH- imidazo[4,5-c]pyridin-2(3H)-one

Into a 100-mL round-bottom flask, was placed (R)-4-amino-3-(4-phenoxyphenyl)-l-(piperidin-3-yl)-lH-imidazo[4,5-c]pyridin-2(3H)-one (150 mg, 0.37 mmol, 1.00 equiv), DCM-CH30H (6 mL), TEA (113 mg, 1.12 mmol, 3.00 equiv). This was followed by the addition of prop-2-enoyl chloride (40.1 mg, 0.44 mmol, 1.20 equiv) dropwise with stirring at OoC in 5 min. The resulting solution was stirred for 2 h at 0 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (30: 1). The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column, XBridge Prep CI 8 OBD

Column,5um, 19*150mm; mobile phase, water with 0.05%TFA and ACN (25.0% ACN up to 45.0% in 8 min). 54.5 mg product of (R)-l-(l -acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-lH-imidazo[4,5-c]pyridin-2(3H)-one was obtained as a white solid. LC-MS m/z: 465.2 (M+l)

Step 2

Into a 25-mL round-bottom flask was placed tert-butyl (3R)-3-[4-[(E)-[(dimethy]amino)-methylidene]-amino]-2-oxo-3-(4-phenoxyphenyl)-lH,2H,3H-imidazo[4,5-c]pyridin-l -yl]piperidine- l-carboxylate (150 mg, 0.27 mmol, 1.00 equiv), 1,4-dioxane (6 mL), and hydrogen chloride (3 mL). The resulting solution was stirred overnight at 50° C. The reaction mixture was quenched with water. The pH of the solution was adjusted to 9 with sodium bicarbonate. The resulting solution was extracted with dichloromethane:CH₃OH=10: 1 and the organic layers were combined. The resulting mixture was washed with sodium chloride and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (30: 1) to give 80 mg (74%) of 4-amino-3-(4-phenoxyphenyl)-l -[(3R)-piperidin-3-yl]-lH,2H,3H-imidazo[4,5-c]pyridin-2-one as a light yellow solid.

////////

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/////////Tolebrutinib, SAR 442168, PRN 2246, GTPL10625, BTK’168, EX-A4699, BDBM50557487, WHO 11268,  Multiple Sclerosis,  (MS), 

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ABT-737

ABT-737 is a small molecule drug that inhibits Bcl-2 and Bcl-xL, two members of the Bcl-2 family of evolutionarily-conserved proteins that share Bcl-2 Homology (BH) domains. First developed as a potential cancer chemotherapy,^[1] it was subsequently identified as a senolytic (a drug that selectively induces cell death in senescent cells).^[2]

The Bcl-2 family is most notable for their regulation of apoptosis, a form of programmed cell death, at the mitochondrion; Bcl-2 and Bcl-xL are anti-apoptotic proteins. Because many cancers have mutations in these genes that allow them to survive, scientists began working to develop drugs that would inhibit this pathway in the 1990s.^[1] ABT-737 was one of the earliest of a series of drugs developed by Abbott Laboratories (now Abbvie) to target this pathway, based on their resolution of the 3D structure of Bcl-xL and studies using high-field solution nuclear magnetic resonance (NMR) that revealed how the BH domains of these proteins interacted with their targets.^[1]

ABT-737 was superior to previous BCL-2 inhibitors given its higher affinity for Bcl-2, Bcl-xL and Bcl-w. In vitro studies showed that primary cells from patients with B-cell malignancies are sensitive to ABT-737.^[3] In animal models, it improved survival, caused tumor regression, and cured a high percentage of mice.^[4] In preclinical studies utilizing patient xenografts, ABT-737 showed efficacy for treating lymphoma and other blood cancers.^[5]

Unfortunately, ABT-737 is not bioavailable after oral administration, leading to the development of navitoclax (ABT-263) as an orally-available derivative with similar activity on small cell lung cancer (SCLC) cell lines.^[1][6] Navitoclax entered clinical trials,^[1][6] and showed promise in haematologic cancers, but was stalled when it was found to cause thrombocytopenia (severe loss of platelets), which was discovered to be caused by the platelets’ requirement for Bcl-xL for survival.^[1]

Subsequently, it was reported that ABT-737 specifically induces apoptosis in senescent cells in vitro and in mouse models.^[2]

ABT-737, a BH3 mimetic, is a potent Bcl-2, Bcl-x_L and Bcl-w inhibitor with EC₅₀s of 30.3 nM, 78.7 nM, and 197.8 nM, respectively. ABT-737 induces the disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway. ABT-737 induces autophagy and has the potential for acute myeloid leukemia (AML) research.

PATENT

PATENT

CN113248415

PATENT

US20070015787

Journal of Medicinal Chemistry (2007), 50(4), 641-662

https://pubs.acs.org/doi/10.1021/jm061152t

////////

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References

1. ^ Jump up to:^{a b c d e f} Croce, Carlo M; Reed, John C (October 2016). “Finally, An Apoptosis-Targeting Therapeutic for Cancer”. Cancer Research. 76 (20): 5914–5920. doi:10.1158/0008-5472.CAN-16-1248. PMC 5117672. PMID 27694602.
2. ^ Jump up to:^a b Yosef, Reut; Pilpel, Noam; Tokarsky-Amiel, Ronit; Biran, Anat; Ovadya, Yossi; Cohen, Snir; Vadai, Ezra; Dassa, Liat; Shahar, Elisheva; Condiotti, Reba; Ben-Porath, Ittai; Krizhanovsky, Valery (2016). “Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL”. Nature Communications. 7: 11190. Bibcode:2016NatCo…711190Y. doi:10.1038/ncomms11190. PMC 4823827. PMID 27048913.
3. ^ Vogler, Meike, et al. “Bcl-2 inhibitors: small molecules with a big impact on cancer therapy.” Cell Death & Differentiation 16.3 (2008): 360–367.
4. ^ Oltersdorf, Tilman; Elmore, Steven W.; Shoemaker, Alexander R.; Armstrong, Robert C.; Augeri, David J.; Belli, Barbara A.; Bruncko, Milan; Deckwerth, Thomas L.; Dinges, Jurgen; Hajduk, Philip J.; Joseph, Mary K.; Kitada, Shinichi; Korsmeyer, Stanley J.; Kunzer, Aaron R.; Letai, Anthony; Li, Chi; Mitten, Michael J.; Nettesheim, David G.; Ng, ShiChung; Nimmer, Paul M.; O’Connor, Jacqueline M.; Oleksijew, Anatol; Petros, Andrew M.; Reed, John C.; Shen, Wang; Tahir, Stephen K.; Thompson, Craig B.; Tomaselli, Kevin J.; Wang, Baole; Wendt, Michael D.; Zhang, Haichao; Fesik, Stephen W.; Rosenberg, Saul H. (2005). “An inhibitor of Bcl-2 family proteins induces regression of solid tumours”. Nature. 435 (7042): 677–81. Bibcode:2005Natur.435..677O. doi:10.1038/nature03579. PMID 15902208. S2CID 4335635.
5. ^ Hann CL, Daniel VC, Sugar EA, Dobromilskaya I, Murphy SC, Cope L, Lin X, Hierman JS, Wilburn DL, Watkins DN, Rudin CM (April 2008). “Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer”. Cancer Research. 68 (7): 2321–8. doi:10.1158/0008-5472.can-07-5031. PMC 3159963. PMID 18381439.
6. ^ Jump up to:^a b Hauck P, Chao BH, Litz J, Krystal GW (April 2009). “Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737”. Mol Cancer Ther. 8 (4): 883–92. doi:10.1158/1535-7163.MCT-08-1118. PMID 19372561. Retrieved 9 September 2019.

///////////ABT-737, ABT 737

CN(CC[C@@H](NC1=CC=C(C=C1[N+]([O-])=O)S(NC(C2=CC=C(C=C2)N3CCN(CC3)CC4=CC=CC=C4C5=CC=C(C=C5)Cl)=O)(=O)=O)CSC6=CC=CC=C6)C

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Olutasidenib

• FT-2102
• FT2102

C₁₈H₁₅ClN₄O₂

354.79

CAS1887014-12-1

Rezlidhia (Forma Therapeutics)

SYN Caravella JA, et al. Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor. J Med Chem. 2020 Feb 27;63(4):1612-1623. doi: 10.1021/acs.jmedchem.9b01423. Epub 2020 Feb 12.

FDA 12/1/2022, To treat adults with relapsed or refractory acute myeloid leukemia with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation, Rezlidhia

Olutasidenib, sold under the brand name Rezlidhia, is an anticancer medication used to treat relapsed or refractory acute myeloid leukemia.^[1][2] Olutasidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor.^[1] It is taken by mouth.^[1]

Olutasidenib was approved for medical use in the United States in December 2022.^[1][2][3][4]

Medical uses

Olutasidenib is indicated for the treatment of adults with relapsed or refractory acute myeloid leukemia with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.^[1][2]

Society and culture

Names

Olutasidenib is the international nonproprietary name.^[5]

Olutasidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of patients with relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation as detected by an FDA-approved test.

Olutasidenib (FT-2102) is a selective and potent isocitrate dehydrogenase-1 (IDH1) inhibitor approved by the FDA in December 2022.5,6 It is indicated for the treatment of relapsed or refractory acute myeloid leukemia (AML) in patients with a susceptible IDH1 mutation as determined by an FDA-approved test.5 IDH1 mutations are common in different types of cancer, such as gliomas, AML, intrahepatic cholangiocarcinoma, chondrosarcoma, and myelodysplastic syndromes (MDS), and they lead to an increase in 2-hydroxyglutarate (2-HG), a metabolite that participates in tumerogenesis.1,2 Olutasidenib inhibits the mutated IDH1 specifically, and provides a therapeutic benefit in IDH1-mutated cancers.1,5

Other IDH1 inhibitors, such as ivosidenib, have also been approved for the treatment of relapsed or refractory AML.3,4 Olutasidenib is orally bioavailable and capable of penetrating the blood-brain barrier, and is also being evaluated for the treatment of myelodysplastic syndrome (MDS), as well as solid tumors and gliomas (NCT03684811).4

SYN

https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01423

a Reagents and conditions: (a) DIEA, DMSO, 80−110 °C, 16 h, 67%; (b) (R)-2-methylpropane-2-sulfinamide, CuSO4, 55 °C, DCE, 16 h, 81%; (c) MeMgBr, DCM, −50 to −60 °C, 3 h, 63%; (d) 1 N HCl, dioxane, reflux, 16 h, >98%, 98.4% ee; (e) m-CPBA, CHCl3, reflux, 4 days, 52%; (f) Ac2O, reflux, 3 days, 60%; (g) K2CO3, MeOH, 4 h, 92%; (h) MeI, K2CO3, DMF, 45 min, 67%.

1H NMR (300 MHz,
DMSO-d6) δ 12.07 (s, 1 H), 7.71−7.76 (m, 2 H), 7.51 (dd, J = 8.79,
2.35 Hz, 1 H), 7.31 (d, J = 8.79 Hz, 1 H), 6.97 (d, J = 7.92 Hz, 1 H),
6.93 (d, J = 7.92 Hz, 1 H), 5.95 (d, J = 7.92 Hz, 1 H), 4.62−4.75 (m,
1 H), 3.58 (s, 3 H), 1.50 (d, J = 6.74 Hz, 3 H); 13C NMR (75 MHz,
DMSO-d6) δ 161.0, 155.9, 141.4, 136.6, 135.0, 133.4, 129.8, 126.7,
125.8, 120.1, 119.4, 116.7, 115.1, 104.5, 103.7, 47.4, 34.0, 20.3; LCMS
(method 2) >95% purity; tR 10.18 min; m/z 355, 357 [M + H]+
;
HRMS (ESI) calcd for C18H16ClN4O2 [M + H]+ 355.0962 found
356.0956.

////////

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References

1. ^ Jump up to:^{a b c d e f} https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215814s000lbl.pdf
2. ^ Jump up to:^a b c d https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2022/215814Orig1s000ltr.pdf  This article incorporates text from this source, which is in the public domain.
3. ^ “Rigel Announces U.S. FDA Approval of Rezlidhia (olutasidenib) for the Treatment of Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with a Susceptible IDH1 Mutation”. Rigel Pharmaceuticals, Inc. (Press release). 1 December 2022. Retrieved 2 December 2022.
4. ^ “Rigel Announces U.S. FDA Approval of Rezlidhia (olutasidenib) for the Treatment of Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with a Susceptible IDH1 Mutation” (Press release). Rigel Pharmaceuticals. 1 December 2022. Retrieved 2 December 2022 – via PR Newswire.
5. ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 82”. WHO Drug Information. 33 (3). hdl:10665/330879.

Further reading

• Liu X, Gong Y (2019). “Isocitrate dehydrogenase inhibitors in acute myeloid leukemia”. Biomarker Research. 7: 22. doi:10.1186/s40364-019-0173-z. PMC 6806510. PMID 31660152.
• Watts JM, Baer MR, Yang J, Prebet T, Lee S, Schiller GJ, et al. (November 2022). “Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial”. The Lancet Haematology. doi:10.1016/S2352-3026(22)00292-7. PMID 36370742. S2CID 253471380.

External links

• “Olutasidenib”. Drug Information Portal. U.S. National Library of Medicine.
• Clinical trial number NCT02719574 for “Open-label Study of FT-2102 With or Without Azacitidine or Cytarabine in Patients With AML or MDS With an IDH1 Mutation” at ClinicalTrials.gov

/////////////Olutasidenib, FDA 2022, APPROVALS 2022, Rezlidhia, FT-2102, FT 2102

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