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MAVORIXAFOR

April 19, 2023 3:14 am / Leave a comment

MAVORIXAFOR

AMD 070

N1-(1H-BENZIMIDAZOL-2-YLMETHYL)-N1-((S)-5,6,7,8-TETRAHYDROQUINOLIN-8-YL)-BUTANE-1,4-DIAMINE

fda approved 4/26/2024, To treat WHIM syndrome (warts, hypogammaglobulinemia, infections and myelokathexis), Xolremdi

Mavorixafor (AMD-070) is a potent, selective and orally available CXCR4 antagonist, with an IC₅₀ value of 13 nM against CXCR4 ¹²⁵I-SDF binding, and also inhibits the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC₅₀ of 1 and 9 nM, respectively.

Molecular Weight	349.47
Appearance	Solid
Formula	C₂₁H₂₇N₅
CAS No.	558447-26-0
SMILES	NCCCCN(CC1=NC2=C(N1)C=CC=C2)[C@@H]3C4=C(CCC3)C=CC=N4

PHASE 2

Mavorixafor trihydrochloride

Molecular Weight	458.86
Appearance	Solid
Formula	C₂₁H₃₀Cl₃N₅
CAS No.	2309699-17-8
SMILES	[H]Cl.[H]Cl.[H]Cl.NCCCCN(CC1=NC2=CC=CC=C2N1)[C@@H]3C4=NC=CC=C4CCC3

AMD-070 is a small molecule drug candidate that belongs to a new investigational class of anti-HIV drugs known as entry (fusion) inhibitors. Approximately 76% of HIV-patients with measurable viral load are infected with a strain of virus that is resistant to one or more classes of antiretroviral agents, thus reducing treatment options. Unlike many existing HIV drugs that target the virus after it has infected a healthy cell, AMD-070 blocks the virus from entering a healthy cell, thus preventing the replication process. AMD-070 targets the CXCR4 receptor on HIV and prevents the virus from entering and infecting healthy cells. AMD-070 is specific for the CXCR4 receptor and does not interact with any other chemokine receptors in vitro. AMD-070 strongly inhibits viral infection by all CXCR4 using virus (including virus using CXCR4 alone and/or virus using CXCR4 and CCR5) in vitro. AMD-070 is orally bioavailable in animals, it has suitable PK and toxicity profile for oral dosing. AMD-070 shows additive or synergistic effects in vitro in combination with other known anti-HIV agents. AMD-070 is active against CXCR4 using HIV strains that are resistant to existing antiretroviral therapies in vitro, reveals potent anti-HIV activity against CXCR4-using laboratory strains and clinical isolates. MD-070 had been in phase II clinical trials by Genzyme for the treatment of HIV infection. However, this research has been discontinued. AMD-070 has been studied in Phase I/II clinical trials for the treatment of Renal cell carcinoma and Phase I clinical trials for the treatment of malignant melanoma and solid tumours.

PAPER

https://pubs.acs.org/doi/10.1021/acs.oprd.2c00076

Org. Process Res. Dev. 2022, 26, 6, 1831–1836

A novel and practical synthesis of mavorixafor (1) is reported. The novelty of this synthetic route is the use of 8-chloro-5,6,7,8-tetrahydroquinoline (9) and 1,4-diaminobutane as the materials, instead of 8-amino-5,6,7,8-tetrahydroquinoline (4) and N,N-diprotected aminobutyraldehyde (6a or 6b). The preparation of (S)-8-(4-aminobutylamino)-5,6,7,8-tetrahydroquinoline (13) by resolution with N-acetyl-l-leucine was first achieved. Then the one-pot synthesis of 1 from 13 involving protection, condensation, and subsequent hydrolysis was successfully developed. In addition, the final product with a satisfactory purity (>99.5%, detected by both achiral and chiral HPLC) was obtained by a simple operation (salification) without column chromatographic purification.

NEW PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023059903&_gid=202315

Scheme I

Mavorixafor

EXEMPLIFICATION

Example 1: Synthesis of Sulfonate adduct F-2d:

Scheme V:

1) AcOH, NaCI, water 1) Na ₂ S ₂ O ₅ , THF, water

2) n-Heptane, THF 2) THF/n-heptane, acetonitrile

Step 1C Step 1 D

Step 1A: Preparation of Dl

Charge diethyl-4-aminobutyl acetal (E) (1.00 wt, 1.00 eq) to vessel A. Charge acetonitrile (10.0 vol, 7.8 wt) and adjust temperature to 20°C. Heat the mixture to 40°C. Concentrate the reaction mixture to 6.0 vol under reduced pressure at 35 to 45°C.

[0098] Acetonitrile filler (5.0 vol, 3.9wt) at 35 to 45°C. Concentrate the reaction mixture to 6.0 vol under reduced pressure 35 to 45°C. This step is repeated once as described below.

[0099] Acetonitrile filler (5.0 vol, 3.9wt) at 35 to 45°C. Concentrate the reaction mixture to 6.0 vol under reduced pressure at 35 to 45°C. Cool to 20°C.

[00100] Charge di-tert-butyl dicarbonate (1.1 eq, 1.5 wt) to a drum, followed by acetonitrile (0.4 vol, 0.3 wt) and agitate until fully dissolved. Concentrate the reaction mixture to 6.0 vol under reduced pressure at 35 to 45°C.

[00101] Charge this di-tert-butyl dicarbonate solution in acetonitrile to vessel A maintaining 20°C. Charge acetonitrile (1.5 vol, 1.1 wt) to the solution as a line rinse and stir at 20°C for 30 to 60 min..

[00102] Charge 4-dimethylaminopyridine (0.076 wt, 0.10 eq) to the vessel A at 20°C. Heat the solution to 40°C. Concentrate the reaction mixture to 5.0 vol under reduced pressure. Charge acetonitrile (5.0 vol, 3.9 wt) to the solution. Concentrate the reaction mixture to 5.0 vol under reduced pressure.

[00103] Take the resulting solution of Dl into next reaction without isolation.

Step IB: Preparation of Cl

[00104] Charge acetonitrile (2.0 vol, 1.6 wt) at 35 to 45°C to vessel A containing solution of D-1 from Step 1A.

[00105] Charge di-tert-butyl dicarbonate (1.4 eq, 1.9 wt) to a drum, followed by acetonitrile (10.0 vol, 7.8 wt) and agitate until fully dissolved. Charge this di-tert-butyl dicarbonate solution to vessel A, 2 to 6 h while distilling under vacuum at 35 to 45°C maintaining the volume of the reaction at 7.0 vol. Load acetonitrile (3.0 vol, 2.4 wt) over 20 to 40 min. as a line rinse while distilling under vacuum at 35 to 45°C, maintaining the volume of the reaction at 7.0 vol.

[00106] Charge di-tert-butyl dicarbonate, (0.14 eq, 0.19 wt) to a drum, followed by acetonitrile (1.0 vol, 0.74 wt) and agitate until fully dissolved. Charge this di-tert-butyl dicarbonate solution to vessel A over 20 to 40 min.. Charge acetonitrile (0.3 vol, 0.24 wt) over 10 to 20 min as a line rinse while distilling under vacuum at 35 to 45°C, maintaining the volume of the reaction at 7.0 vol.

[00107] Concentrate the reaction mixture to 5.0 vol distilling under vacuum at 35 to 45°C.

[00108] Charge n-heptane, (7.5 vol, 5.1 wt) to the reaction mixture, and concentrate the reaction mixture to 5.0 vol under reduced pressure at 40°C. This step is repeated once as described below.

[00109] Charge n-heptane, (7.5 vol, 5.1 wt) to the reaction mixture, and concentrate the reaction mixture to 5.0 vol under reduced pressure at 40°C.

[00110] Charge decolorizing, activated charcoal (0.2 wt) to the solution and stir for 1 to 2 h at 40°C. Filter the reaction mixture at 40°C. Charge n-heptane, (2.0 vol, 1.4 wt) to the reactor vessel and stir for 5 to 15 min. at 20°C before charging to the filter as a line rinse. Combine the filtrate and wash, and as required adjust to 20°C.

[00111] Take the resulting solution of Cl into next reaction without isolation.

Step 1C: Preparation of Bl

[00112] Charge 15% v/v acetic acid (2.0 vol) caution gas evolution, to vessel A containing solution of Cl from Step IB, maintaining the temperature at 20°C and stir for 10 min. at 20°C. Allow the phases to separate for 15 min. at 20°C. Discharge the aqueous phase to waste, retaining the organic phase in vessel A. This step is repeated once as described below.

[00113] Charge 15% v/v acetic acid (2.0 vol) maintaining 20°C and stir for 10 min. at 20°C. Allow the phases to separate for 15 min. at 20°C. Discharge the aqueous phase to waste, retaining the organic phase in vessel A.

[00114] Adjust the reaction to 30°C. Charge 4% w/w sodium chloride solution (2.1 vol) to the vessel maintaining the temperature at 30°C. Charge glacial acetic acid (4.1 vol, 4.3 wt) to the vessel maintaining 30°C. Stir the reaction mixture for 2 h maintaining the temperature at 30°C.

[00115] Charge purified water, (6.0 vol) at 30°C. Stir the contents for 5 to 10 min. at 30°C, and separate the phases, retaining the upper organic phase in vessel A. Charge the lower aqueous phase to vessel B.

[00116] Charge purified water (4.0 vol) at 30°C and stir for 5 to 10 min. maintaining the temperature at 30°C. Separate the phases at 30°C, retaining the upper organic phase in vessel A. Charge the lower aqueous phase to vessel B.

[00117] Adjust the temperature to 30°C of vessel B containing combined aqueous phases. Charge n-heptane, (2.0 vol, 1.4 wt) to vessel B and stir for 5 to 10 min. maintaining the temperature at 30°C. Separate the phases at 30°C, over 15 min.. Charge the upper organic phase to vessel A and recharge the lower aqueous phase to vessel B. This step is repeated two additional times as described below.

[00118] Charge n-heptane, (2.0 vol, 1.4 wt) to vessel B and stir for 5 to 10 min. maintaining the temperature at 30°C. Separate the phases at 30°C, over 15 min.. Charge the upper organic phase to vessel A and recharge the lower aqueous phase to vessel B.

[00119] Charge n-heptane, (2.0 vol, 1.4 wt) to vessel B and stir for 5 to 10 min. maintaining the temperature at 30°C. Separate the phases at 30°C, over 15 min., discharge the lower aqueous phase to waste and charge the upper organic layer to vessel A.

[00120] Concentrate the combined organic phases in vessel A to 3.0 vol at 10 to 20°C under reduced pressure. Offload the solution to new HDPE drum(s) and line rinse with n-heptane (0.5

vol, 0.4 wt) at 20°C. Homogenize the drum and store as “Bl solution in n-heptane,” and take into next reaction without isolation.

Step ID: Preparation of F-2d

[00121] Calculate a new 1.00 wt based on the above assay.

[00122] Charge “Bl solution in n-heptane” from Step 1C (1.00 wt, 1.00 eq, corrected for w/w assay, ca. 3.0 vol), into an appropriate vessel. THF load (3.0 vol, 2.7 wt). Heat the reaction mixture to 40°C.

[00123] Charge purified water, (0.02 vol, 0.02 wt) followed by sodium metabisulphite, (0.125 eq, 0.08 wt) as a solid via the charge hole at 40°C. Stir the resulting mixture for 30 to 35 min. at 40°C. This step was repeated four additional times to add the reagent in five portions total, as detailed below.

[00124] Charge purified water, (0.02 vol, 0.02 wt) followed by sodium metabisulphite, (0.125 eq, 0.08 wt) as a solid via the charge hole at 40°C. Stir the resulting mixture for 30 to 35 min. at 40°C.

[00125] Charge purified water, (0.02 vol, 0.02 wt) followed by sodium metabisulphite, (0.125 eq, 0.08 wt) as a solid via the charge hole at 40°C. Stir the resulting mixture for 30 to 35 min. at 40°C.

[00126] Charge purified water, (0.02 vol, 0.02 wt) followed by sodium metabisulphite, (0.125 eq, 0.08 wt) as a solid via the charge hole at 40°C. Stir the resulting mixture for 30 to 35 min. at 40°C.

[00127] Charge purified water, (0.02 vol, 0.02 wt) followed by sodium metabisulphite, (0.125 eq, 0.08 wt) as a solid via the charge hole at 40°C. Stir the resulting mixture for 36 hours at 40°C.

[00128] Cool the reaction mixture to 20°C over 3 to 4 h at a target constant rate. Filter the reaction mixture at 20°C on a 1-2 pm cloth.

[00129] Wash the solid with a pre-mixed mixture of THF (0.5 vol, 0.5 wt) and n-heptane (0.5 vol, 0.3 wt) maintaining the temperature at 20°C. This step was repeated an additional three times, as detailed below.

[00130] Wash the solid with n-heptane, (2.0 vol, 1.4 wt) as a line rinse and apply to the filtercake at 20°C.

[00131] Wash the solid with n-heptane, (2.0 vol, 1.4 wt) as a line rinse and apply to the filtercake at 20°C.

[00132] Wash the solid with acetonitrile, (2.0 vol, 1.6 wt) as a line rinse and apply to the filtercake at 20°C.

[00133] Dry the solid at 38°C under a flow of nitrogen for 12 h.

[00134] Determine residual solvent content. Pass criteria acetonitrile <2.0% w/w, n-heptane <2.0% w/w and tetrahydrofuran <2.0% w/w.

[00135] Yield of compound F-2d: 52-69%.

[00136] ‘H NMR (400 MHz, d ₆ -DMSO): 8 5.22 (s, 1H), 3.77 (s, 1H), 3.45 (t, 2H), 1.70 (m, 2H), 1.44 (m, 20H) ). ¹³ C NMR (400 MHz, d ₆ -DMSO): 8 152.6, 83.2, 82.0, 46.5, 29.6, 28.1, 26.0. FTIR (wavenumber, cm’ ¹ ) 3294, 1721, 1738, 1367, 1233, 1180, 1135, 1109, 1045.

Example 2: Synthesis of F-3a:

Scheme VI:

Step 2A: Preparation of Gl

[00137] Charge J, (1.00 wt, 1.00 eq) to vessel A. Charge purified water, (1.0 vol, 1.0 wt) to vessel A and as necessary adjust the temperature to 20°C. Charge concentrated hydrochloric acid, (4.0 eq, 3.0 vol, 3.6 wt) to vessel A maintaining the temperature at 20°C. Line rinse with purified water, (0.5 vol, 0.5 wt) maintaining the contents of vessel A at 15 to 25°C.

[00138] Charge chloroacetic acid, (1.3 wt, 1.5 eq) and purified water, (1.0 vol, 1.0 wt) to vessel B and as necessary, adjust the temperature to 20°C. Stir until fully dissolved, expected 10 to 20 min.

[00139] Charge the chloroacetic acid solution to vessel A maintaining the temperature of vessel A at 20°C. Line rinse vessel A with purified water, (0.5 vol, 0.5 wt) at 15 to 25°C and charge to vessel B at 20°C. Heat the reaction mixture to 80°C. Stir the reaction mixture at 80°C for 20 h.

[00140] Cool the reaction mixture to 10°C over 1.5 h. Load 47% w/w potassium phosphate solution (6.0 vol) over 60 min. targeting a constant rate maintaining 10°C. Adjust the pH of the reaction mixture by charging 47% w/w potassium phosphate solution to pH 7.0 maintaining the reaction temperature at 10°C. Expected charge is 2.0 to 3.5 vol 47% w/w potassium phosphate solution.

[00141] Stir the slurry for >30 min. maintaining 10°C and rechecking the pH, pass criterion pH 7.0. Filter the reaction mixture through 20 pm cloth at 10°C. Wash the filter-cake with purified water, (1.0 vol, 1.0 wt) at 10°C. This step is repeated additional three times as described below.

[00142] Slurry wash the filter-cake in the reactor vessel with purified water, (10.0 vol, 10.0 wt) for 45 min. to 90 min. at 10°C. Filter the mixture through 20 pm cloth at 10°C.

[00143] Slurry wash the filter-cake in the reactor vessel with purified water, (10.0 vol, 10.0 wt) for 45 min. to 90 min. at 10°C. Filter the mixture through 20 pm cloth at 10°C.

[00144] Slurry wash the filter-cake in the reactor vessel with purified water, (10.0 vol, 10.0 wt) for 45 min. to 90 min. at 10°C. Filter the mixture through 20 pm cloth at 10°C.

[00145] Wash the filter-cake with purified water, (1.0 vol, 1.0 wt) at 10°C. The filter-cake was washed with purified water additional five times as described below.

[00146] Wash the filter-cake with purified water, (1.0 vol, 1.0 wt) at 10°C.

[00147] Wash the filter-cake with acetonitrile, (2×1.3 vol, 2×1.0 wt) at 10°C.

[00148] Dry the filter-cake on the filter under vacuum and strong nitrogen flow through the filter cake at 20°C until the water content is <15.0% w/w by Karl-Fisher analysis.

[00149] Dry the filter-cake on the filter under vacuum and strong nitrogen flow through the filter cake at 30°C until the water content is <5.0% w/w by Karl-Fisher analysis.

[00150] Dry the filter-cake on the filter under vacuum and strong nitrogen flow through the filter cake at 50°C until the water content is <1.0% w/w by Karl-Fisher analysis.

[00151] Yield of compound Gl: about 75%.

Step 2B: Preparation of F-3a

Charge di-/c/7-butyl dicarbonate, (1.85 wt, 1.4 eq) to vessel A followed by N,N-dimethylformamide, (2.6 wt, 2.7 vol) and stir at 20°C for 20 min. until dissolution achieved. Add A,A-diisopropylethylamine, (0.08 wt, 0.11 vol, 0.1 eq) to contents of vessel A at 20°C. Heat the contents of vessel A to 40°C.

[00153] Charge Gl, (1.00 wt) to vessel B followed by YW-di methyl form am ide, (5.2 wt, 5.5 vol) and adjust to 14°C.

[00154] Charge the Gl/DMF solution from vessel B to vessel A over 5 h at 40°C, at an approximately constant rate. Line rinse with Y,Y-di methyl form am ide, (0.4 wt, 0.4 vol), maintaining vessel A at 40°C. Stir the resulting reaction mixture at 40°C for 16 h.

[00155] Charge decolorizing charcoal activated, (0.20 wt). Adjust the mixture to 40°C and stir at 40°C for 60 to 90 min..

[00156] Clarify (filter) the reaction mixture into vessel B at 40°C. Charge N,N-dimethylformamide, (0.9 wt, 1.0 vol) via vessel A and filter at 40°C. Charge purified water, (3.5 vol) to the combined filtrates, over 60 min., maintaining the temperature at 40°C. As required, cool the mixture to 35°C over 30 to 60 min..

[00157] Filler F-3a, (0.02 wt) as seed material at 35°C. Stir at 34°C for 1.5 h then check for crystallization. Cool slurry to 30°C over 40 min.

[00158] Filler F-3a, (0.02 wt) as seed material at 30°C. Stir at 30°C for 1.5 h then check for crystallization.

[00159] Cool slurry at 20°C over 3.5 h at a targeted constant rate. Stir at 20°C for 3 hours. Charge purified water, (1.0 vol), maintaining the temperature at 20°C over 60 min..

Stir at 20°C for 3 hours.

[00160] Cool slurry to 2°C over 2.5 h. Stir at 2°C for 2.5 hours. Filter through 20 pm cloth and pull dry until no further filtrate passes. Wash the solid with pre-mixed Y,Y-di methyl form am ide / purified water, (2.0 vol, 1:2 v:v) at 2°C. Wash the solid with purified water, (2 x 3.0 vol) at 2°C. Dry under vacuum at 28°C until KF <0.2% w/w, and Y,Y-di methyl form am ide <0.4% w/w.

[00161] Yield of compound F-3a: 62-70%.

Example 3: Synthesis of Mavorixafor:

Scheme VI:

nce

Step 3A: Preparation of imine Q-1

[00162] To vessel A charge purified water, (8.7 vol, 8.7 wt) followed by potassium phosphate, (5.52 eq, 5.3 wt) portion-wise and cool to 15°C. Charge tetrahydrofuran, (4.3 vol, 3.8 wt) and n-heptane, (2.2 vol, 1.5 wt) to vessel A and cool the biphasic mixture to 0°C. Charge Fl, (1.00 eq, 1.00 wt) to the vessel in 2 portions maintaining 0°C.

[00163] Charge F-2d, (1.10 eq, 1.95 wt) to the vessel in 4 portions maintaining 0°C, ensuring portions are spaced by 10 min.. Stir the resulting biphasic mixture for 1.5 h at 0°C. Allow the layers to separate for 45 min. at 0°C before separating the layers. Retain the upper organic phase within vessel A.

[00164] Take the resulting solution of Ql into next reaction without isolation.

Step 3B: Preparation of amine P-1

[00165] To vessel B, charge tetrahydrofuran, (6.0 vol, 5.3 wt) and adjust to 15°C. Charge zinc chloride, (1.5 eq, 0.92 wt) to vessel B in 4 portions, maintaining 10 to 30°C. Adjust the reaction mixture in vessel B to 15°C. Stir the mixture at 15°C for 1 hour. Charge sodium borohydride,(1.0 eq, 0.17 wt) to vessel B in 2 portions maintaining 15°C. Cool the reaction mixture in vessel B to 15°C. Stir the mixture for 1 hour maintaining 15°C. Cool the reaction mixture in vessel B to -5°C.

[00166] Cool the retained organic solution of Ql in vessel A, from Step 3A, to -5°C.

[00167] Charge the organic solution in vessel A into vessel B over 1 to 2 h maintaining -5°C. Charge tetrahydrofuran, (1.0 vol, 0.9 wt) to vessel A as a line rinse and adjust to -5°C. Transfer the contents of vessel A to vessel B maintaining -5°C.

[00168] Stir the resulting reaction mixture in vessel B for 1.5 h maintaining -5°C.

[00169] Charge purified water, (4.5 vol, 4.5 wt) and glacial acetic acid, (1.0 eq, 0.27 wt, 0.26 vol) to the cleaned vessel A and cool to 0°C. Charge the contents of vessel B to vessel A over 1 to 2 h maintaining 0°C. Charge tetrahydrofuran, (1.0 vol, 0.9 wt) to vessel B as a vessel rinse, cool to 0°C and transfer to vessel A maintaining 0°C.

[00170] Warm the resulting mixture in vessel A to 30°C. Stir the resulting mixture in vessel A at 30°C for 1 h. Allow the layers to settle for 15 min. at 30°C before separating the layers. Retain the upper organic phase.

[00171] Cool the retained organic phase to 15°C. Charge to the vessel 25% w/w ammonia solution (3.0 vol) at 10 to 30°C. Cool the reaction mixture to 20°C. Charge to the vessel 25% w/w ammonium chloride solution (3.0 vol) at 20°C and stir for 1 h. Separate the layers for 15 min. at 20°C, retain the upper organic phase. Wash the retained organic phase with 10% w/w sodium chloride solution (3.0 vol) at 20°C for 10 min.. Allow the layers to settle for 10 min. at 20°C before separating and retaining the upper organic phase within the vessel.

[00172] Charge tert-butyl methyl ether, (0.5 vol, 0.4 wt) to the organic phase. Cool the mixture to 5°C. Adjust the pH of the reaction mixture to pH 5 with hydrochloric acid aqueous solution (expected ca. 9.0 vol) over 1 h at a targeted constant rate at 5°C. Stir the mixture at 5°C for 45 min.. Measure the pH of the aqueous phase to confirm the value is pH 5.

[00173] Charge sodium chloride, (2.1 wt) to the reaction mixture at 5°C and stir the mixture until everything is dissolved. Adjust the temperature of the reaction mixture to 20°C. Separate the layers at 20°C and retain the organic phase within the vessel. Tetrahydrofuran charge, (1.5 vol, 1.3 wt) maintaining 20°C.

[00174] Charge to the vessel 24% w/w sodium chloride solution (7.5 vol) at 20°C and stir for 10 min.. Separate the layers at 20°C and retain the organic phase in the vessel. This step is repeated additional one more time as described below.

[00175] Charge to the vessel 24% w/w sodium chloride solution (7.5 vol) at 20°C and stir for 10 min.. Separate the layers at 20°C and retain the organic phase in the vessel.

[00176] Heat the retained organic phase to 35°C and concentrate the mixture to 6.0 vol under reduced pressure maintaining 35°C.

[00177] Tetrahydrofuran charge, (15.0 vol, 13.2 wt) maintaining 35°C. Concentrate the mixture to 6.0 vol under reduced pressure maintaining 35°C.

[00178] Tetrahydrofuran charge, (15.0 vol, 13.2 wt) maintaining 35°C. Concentrate the mixture to 11.0 vol under reduced pressure maintaining 35°C.

[00179] Cool the mixture to -5°C. Load tert-butyl methyl ether, (10.0 vol, 7.4 wt) over 1 h maintaining -5°C. Stir the mixture at -5°C for 1.5 hours. Filter the solid on 1 to 2 pm filter cloth at -5°C. Wash the solid with pre-mixed tetrahydrofuran, (1.9 vol, 1.7 wt) and tert-butyl methyl ether, (3.1 vol, 1.9 wt) at -5°C as a displacement wash.

[00180] Wash the solid with tert-butyl methyl ether, (5.0 vol, 3.7 wt) at -5°C.

[00181] Dry the solid on the filter under a flow of nitrogen at 23°C.

[00182] Yield of compound P-1: 76-87%.

Step 3C: Preparation of compound 0-1

[00183] Charge purified water, (2.0 vol, 2.0 wt) followed by potassium phosphate, (3.3 eq, 1.54 wt), carefully portion-wise, maintaining <15°C, to vessel A. Charge toluene, (4.5 vol, 3.9 wt) to the vessel maintaining <15°C. As necessary, adjust the temperature to 10°C.

[00184] Charge P-1, (1.00 eq, 1.00 wt) to the vessel in two portions maintaining 10°C. Stir the reaction mixture at 10°C for 15 min..

[00185] Load F-3a, (1.1 eq, 0.64 wt) in 4 equal portions ensuring portions are spaced by 10 min. at 10°C.

[00186] Tetrabutylammonium iodide (TBAI) filler (0.20 eq, 0.16 wt). Heat the reaction mixture to 40°C. Stir the reaction mixture at 40°C for 30 h.

[00187] Charge pre-mixed 2-mercaptoacetic acid, (0.40 eq, 0.08 wt, 0.06 vol), and toluene, (0.5 vol, 0.4 wt) over 20 min. to Vessel A at 40°C. Line rinse with toluene, (0.5 vol, 0.4 wt) at 40°C. Adjust the temperature of the reaction mixture to 50°C. Stir the mixture at 50°C for 2.5 hours.

[00188] Adjust the temperature of Vessel A to 20°C. Charge purified water, (3.0 vol, 3.0 wt) maintaining 20°C. Stir the reaction mixture at 20°C for 15 min. and transfer to a new, clean HDPE container. Line/vessel rinse with toluene, (0.5 vol, 0.4 wt) at 20°C. Clarify (filter) the reaction mixture via a 1 pm filter at 20°C into clean Vessel A. Wash the vessel and the filter with toluene, (0.5 vol, 0.4 wt) at 20°C. Allow the layers to separate for 15 min. at 20°C, retaining the upper organic layer (organic layer 1).

[00189] Wash the aqueous layer with toluene, (2.5 vol, 2.2 wt) at 20°C for 15 min.. Allow the layers to separate for 15 min. at 20°C. Retain the upper organic layer (organic layer 2).

[00190] Combine the organic layer 1 and organic layer 2 and adjust the temperature to 20°C. Wash the combined organic layers with 10% w/w sodium chloride solution (5.0 vol) at 20°C for 15 min.. Allow the layers to settle for 15 min. at 20°C. Retain the upper organic layer.

[00191] Take the resulting solution of Ol into next reaction without isolation.

Step 3D: Preparation of compound Kl

[00192] Charge n-butanol, (2.4 wt, 3.0 vol) to vessel B and adjust to 5°C. Charge concentrated sulfuric acid, (1.1 wt, 5.0 eq, 0.6 vol) slowly to Vessel B maintaining <15°C. Line rinse with toluene, (0.4 wt, 0.5 vol) maintaining <15°C. Adjust the temperature of Vessel B to 25°C.

[00193] Heat the n-butanol/ sulfuric acid solution in Vessel B to 55°C. Charge the organic layer from Vessel A (from Step 3C) to the butanol/ sulfuric acid solution in Vessel B over 60 to 90 min. maintaining 55°C. Charge toluene, (1.3 wt, 1.5 vol) to Vessel A as a line rinse and transfer to Vessel B maintaining 55°C. Stir the contents of Vessel B at 55°C for 1.5 h.

[00194] Stir the mixture in Vessel B for 4.5 h at 55°C. Cool the contents of Vessel B to 20°C over 10 h. Filter the slurry over 1-2 pm filter cloth under nitrogen at 20°C. Wash the filter cake with pre-mixed toluene, (3.5 wt, 4.0 vol) and n-butanol, (1.0 vol, 0.8 wt) at 20°C. Wash the filter cake with toluene, (4.3 wt, 5.0 vol) at 20°C. Dry the solid at 30°C under vacuum.

[00195] Correct the output weight for assay. Expected 50-55% w/w.

[00196] Yield of compound K1: 89-92%.

Step 3E: Preparation of Mavorixafor Drug Substance

[00197] Charge Kl, (1.00 eq, 1.00 wt, corrected for HPLC assay) in vessel A followed by nitrogen-purged purified water, (2.0 wt, 2.0 vol) and if necessary, adjust the temperature to 20°C. Charge nitrogen-purged toluene, (12.0 wt, 14.0 vol) to the solution maintaining 20°C. Charge nitrogen-purged n-butanol, (0.8 wt, 1.0 vol) to the solution maintaining 20°C. Heat the biphasic mixture to 30°C. Charge nitrogen-purged 3.0 M aqueous sodium hydroxide solution (6.2 eq, 5.9 vol) maintaining 30°C. Check the pH (expected 12 to 13). Adjust the pH of the aqueous layer to pH 10.0 with nitrogen-purged 0.3 M sulfuric acid solution (expected up to 2.5 vol) maintaining 30°C. Stir the mixture at 30°C for 45 min..

[00198] Measure the pH to confirm the value is pH 10.0.

[00199] Allow the layers to settle at 30°C for 30 min. and separate the layers retaining the organic phase in the vessel, and discharge the aqueous layer into a separate container (container C).

[00200] Charge pre-mixed toluene, (4.1 wt, 4.7 vol) and n-butanol, (0.24 wt, 0.3 vol) to a separate vessel; heat the contents to 30°C and charge the aqueous layer from container C. As required adjust the temperature to 30°C and stir for 5 to 10 min. at 30°C. Allow the phases to separate for 10 to 15 min. at 30°C. Discharge the aqueous phase to waste and combine the organic phase to the organic phase in vessel A.

[00201] Charge nitrogen-purged purified water, (2.0 wt, 2.0 vol) to the organic layer maintaining the temperature at 30°C and stir for 5 to 10 min. at 30°C. Allow the phases to separate for 10 to 15 min. at 30°C. Discharge the aqueous phase to waste retaining the organic phase in the vessel. Heat the retained organic solution to 40°C. Concentrate the resulting organic phase to 7.0 vol by vacuum distillation at 40°C.

[00202] Charge nitrogen -purged toluene, (13.0 wt, 15.0 vol) to the mixture and concentrate the solution 7.0 vol by vacuum distillation at 40°C. This step is repeated additional one time as described below.

[00203] Charge nitrogen -purged toluene, (13.0 wt, 15.0 vol) to the mixture and concentrate the solution 7.0 vol by vacuum distillation at 40°C.

[00204] Charge nitrogen-purged toluene, (7.0 wt, 8.0 vol) to the mixture at 40°C, heat to 55°C and clarify the hot reaction mixture under nitrogen via a 1 pm filter.

[00205] Charge clarified nitrogen-purged toluene, (1.7 wt, 2.0 vol) to the mixture as a line and vessel rinse at 40°C. Concentrate the solution to 7.0 vol by vacuum distillation at 40°C. At the end of the distillation the product is expected to have precipitated. Heat the mixture to 63°C.

[00206] Adjust the temperature to 60.5°C. This batch will be referred to as the main batch.

[00207] Load seed material, (0.02 wt) to a new clean container. Charge clarified nitrogen-purged toluene, (0.09 wt, 0.10 vol) to this seed material and gently shake.

[00208] Seed the main batch with the slurry maintaining the temperature at 60.5 ± 2°C. Stir the reaction at the 60.5± 2°C for 1 hour.

[00209] Cool to 40°C for 2.5 h. Stir the reaction at 40°C for 1 hour.

[00210] Cool to 30°C over 2 h.. Stir the reaction at 30°C for 1 h.

[00211] Cool to 25°C 50 min. Stir the reaction at 25°C over 2 hours.

[00212] Cool to 2°C over 4 h. Stir the mixture for 12 hours at 2°C.

[00213] Filter the mixture at 2°C over 1 to 2 pm cloth. Wash the filter cake with clarified nitrogen-purged toluene, (2.0 vol, 1.7 wt) at 2°C. Dry the filter cake under vacuum and a flow of nitrogen for 1.5 h.

[00214] Dry the solid at 40°C under vacuum and a flow of nitrogen until drying specification is achieved.

[00215] Yield of the final compound mavorixafor: 72%.

[00216] When toluene is used as the recrystallization solvent, optionally with a dissolution aid such butanol or methanol, for maxorixa for recrystallization, advantages were found compared to using dichloromethane and isopropyl acetate. We have found that these solvents do not react with the API, and accordingly we believe that this change has caused the significant reduction of impurities A (imine), B (N-formyl) and C (acetamide) that we have observed.

[00217] In some embodiments, the mavorixafor composition included 7000, 6000, 5000, 4500, 4450, 4000, 3500, 3000, 2500, 2000, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1400, 1400, 1400 gold 50 ppm of toluene or less. In some embodiments, the mavorixafor composition comprises a detectable amount of toluene. In some embodiments, the mavorixafor composition comprises from a detectable amount of toluene to 1350 ppm of toluene.

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Description	Mavorixafor (AMD-070) is a potent, selective and orally available CXCR4 antagonist, with an IC₅₀ value of 13 nM against CXCR4 ¹²⁵I-SDF binding, and also inhibits the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC₅₀ of 1 and 9 nM, respectively.
IC₅₀ & Target^[1]	¹²⁵I-SDF-CXCR413 nM (IC₅₀)HIV-1 (NL4.3 strain)1 nM (IC₅₀, in MT-4 cells)HIV-1 (NL4.3 strain)9 nM (IC₅₀, in PBMCs)HIV-1 (NL4.3 strain)3 nM (IC90, in MT-4 cells)HIV-1 (NL4.3 strain)26 nM (IC90, in PBMCs)
In Vitro	Mavorixafor (AMD-070) is a potent and orally available CXCR4 antagonist, with an IC₅₀ value of 13 nM against CXCR4 ¹²⁵I-SDF binding, and also inhibits the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC₅₀ of 1 and 9 nM, respectively. Mavorixafor (AMD-070) shows no effect on other chemokine receptors (CCR1, CCR2b, CCR4, CCR5, CXCR1, and CXCR2)^[1]. Mavorixafor (AMD-070) (6.6 µM) significantly suppresses the anchorage-dependent growth, the migration and matrigel invasion of the B88-SDF-1 cells^[2].MCE has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo	Mavorixafor (AMD-070) (2 mg/kg, p.o.) significantly reduces the number of metastatic lung nodules in mice, and lowers the expression of human Alu DNA in mice, without body weight loss^[2].MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial	NCT NumberSponsorConditionStart DatePhaseNCT00089466National Institute of Allergy and Infectious Diseases (NIAID)\|AIDS Clinical Trials GroupHIV InfectionsNovember 2004Phase 1\|Phase 2NCT02667886X4 PharmaceuticalsClear Cell Renal Cell CarcinomaJanuary 2016Phase 1\|Phase 2NCT02823405X4 PharmaceuticalsMelanomaSeptember 15, 2016Phase 1NCT00361101Genzyme, a Sanofi Company\|SanofiHIV Infections\|X4 Tropic VirusOctober 2005Phase 1NCT03005327X4 PharmaceuticalsWHIM SyndromeDecember 2016Phase 2NCT04274738X4 PharmaceuticalsWaldenstrom´s MacroglobulinemiaApril 30, 2020Phase 1NCT04154488X4 PharmaceuticalsNeutropeniaOctober 16, 2020Phase 1NCT03995108X4 PharmaceuticalsWHIM SyndromeOctober 17, 2019Phase 3NCT05103917Abbisko Therapeutics Co, LtdTriple Negative Breast CancerJuly 21, 2021Phase 1\|Phase 2NCT00063804National Institute of Allergy and Infectious Diseases (NIAID)\|AIDS Clinical Trials GroupHIV Infections Phase 1NCT02923531X4 PharmaceuticalsClear Cell Renal Cell CarcinomaDecember 7, 2016Phase 1\|Phase 2NCT02680782X4 Pharmaceuticals\|CovanceHealthyJanuary 12, 2016Phase 1

REF

[1]. Skerlj RT, et al. Discovery of novel small molecule orally bioavailable C-X-C chemokine receptor 4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication. J Med Chem. 2010 Apr 22;53(8):3376-88. [Content Brief][2]. Chow LN, et al. Impact of a CXCL12/CXCR4 Antagonist in Bleomycin (BLM) Induced Pulmonary Fibrosis and Carbon Tetrachloride (CCl4) Induced Hepatic Fibrosis in Mice. PLoS One. 2016 Mar 21;11(3):e0151765. [Content Brief][3]. Uchida D, et al. Effect of a novel orally bioavailable CXCR4 inhibitor, AMD070, on the metastasis of oral cancer cells. Oncol Rep. 2018 Jul;40(1):303-308. [Content Brief]

/////////////////////////////////////////////////////////////////////////////MAVORIXAFOR, AMD 070, PHASE 2

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March 9, 2023 1:34 pm / 1 Comment on SMARTCHEM FROM ROW2 TECHNOLOGIES

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Amcenestrant (SAR 439859)

January 26, 2023 3:15 am / Leave a comment

Amcenestrant (SAR 439859)

アムセネストラント

Molecular Weight	554.48
Formula	C₃₁H₃₀Cl₂FNO₃
CAS No.	2114339-57-8

6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid

Amcenestrant

8-(2,4-dichlorophenyl)-9-(4-{[(3 S )-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro – 5H- Benzo[7]annulene-3-carboxylic acid

8-(2,4-Dichlorophenyl)-9-(4-{[(3 S )-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5 H -benzo [7]annulene-3-carboxylic acid

C31H30Cl2FNO3 : _554.48 [ 2114339-57-8 ] _{_} _ _{_} _ _{_}_

Efficacy	Antineoplastic, Selective estrogen receptor downregulator
Comment	Selective estrogen receptor downregulator (SERD) Treatment of breast cancer

SAR439859 (compound 43d) is an orally active, nonsteroidal and selective estrogen receptor degrader (SERD). SAR439859 is a potent ER antagonist and has ER degrading activity with an EC₅₀ of 0.2 nM for ERα degradation. SAR439859 demonstrates robust antitumor efficacy and limited cross-resistance in ER⁺ breast cancer.

Amcenestrant is an orally available, nonsteroidal selective estrogen receptor degrader/downregulator (SERD), with potential antineoplastic activity. Upon oral administration, amcenestrant specifically targets and binds to the estrogen receptor (ER) and induces a conformational change that promotes ER degradation. This prevents ER-mediated signaling and inhibits both the growth and survival of ER-expressing cancer cells.

Amcenestrant is reported to be a selective estrogen receptor degrader (SERD) which has estrogen receptor antagonist properties and accelerates the proteasomal degradation of the estrogen receptor. Amcenestrant is under clinical investigation as an anticancer agent, in particular for treatment of breast cancer.

The compound and processes for preparation thereof are described in International Publication No. WO 2017/140669.

Crystalline forms are described in International Publication No. WO 2021/116074.

PAPER

Journal of Medicinal Chemistry (2020), 63(2), 512-52

https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01293

6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3- yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic Acid (43d).

To a solution of 6-(2,4-dichloro-phenyl)-5-[4-[1-(3-fluoropropyl)-pyrrolidin-3-yloxy]-phenyl]-8,9-dihydro-7H-benzocycloheptene-2-carboxylic acid methyl ester (42d) (80 mg, 140.72 μmol) in methanol (5 mL) was added 5 N NaOH (562.88 μL), the reaction mixture was heated to 60 °C for 5 h, and the solvent was removed under reduced pressure. The residue was taken up in water (10 mL), and aqueous HCl (5 M) was added to pH 7. The slurry was extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of dichloromethane, acetonitrile, and methanol (90/5/5 v/v/v) to give 60 mg (77%) of 6- (2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]- oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (43d). 1 H NMR (400 MHz, DMSO-d6): 1.68 (m, 1H), 1.79 (dm, J = 25.3 Hz, 2 H), 2.07 to 2.23 (m, 5H), 2.38 (m, 1H), 2.46 (t, J = 7.2 Hz, 2H), 2.52 (m, 1H), 2.62 (m, 1H), 2.55 to 2.89 (m, 3H), 4.47 (td, J = 6.2 and 47.6 Hz, 2H), 4.72 (m, 1H), 6.63 (d, J = 8.9 Hz, 2H), 6.71 (m, 3H), 7.18 (d, J = 8.4 Hz, 1H), 8.26 (dd, J = 2.0 and 8.4 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 12.3 (m, 1H). LCMS: 554 (M + H)+ .

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023287938&_cid=P22-LDCH1V-08798-1

Amcenestrant can be prepared according to methods known from the literature, for example U.S. Patent No. 9,714,221.

Example 1: Preparation of amorphous Amcenestrant

[00164] Amcenestrant (20 mg, prepared according to U.S. Patent No. 9,714,221) was dissolved in ethyl acetate (0.2 mL) at room temperature (25°C). Solution was left in opened flask at RT for 16 days, until all the solvent evaporated. Obtained solid was analyzed by XRPD.

PATENT

U.S. Patent No. 9,714,221

https://patents.google.com/patent/US9714221B1/en

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017140669

Example 51. 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid

Methode B:

Step 1 : 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.

To a solution of methyl 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide (D5) (150 mg, 298.56 μιηοΙ), in dioxane (12 ml) and water (2 ml), was added 2,4-dichlorophenyl-boronic acid (62.67 mg, 328.41 μηηοΙ), Cs₂C0₃ (204.48 mg, 626.97 μηιοΙ), and Pd(dppf)CI₂ (14.63 mg, 17.91 μιηοΙ). The reaction mixture was heated at 90°C for 3 hours, and partitioned between AcOEt and water. The phases were separated and the organic phase washed with brine, dried over MgS0₄ and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (96/2/2; V/V/V) to give 80 mg (47%) of 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.

LC/MS (m/z, MH⁺): 568

Step 2 : 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid

7. The slurry was extracted with DCM, dried over MgS0₄ and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (90/5/5; V/V/V) to give 60 mg (77%) of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019020559

Intermediate (c). Tert-butyl (3S)-3-[4-(4,4_!5_!5-tetramethyl-1 _!3,2-dioxaborolan-2yl)phenoxy]pyrrolidine-1 -carboxylate

To a solution of commercially available 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (a) (82.7 g, 364.51 mmol) in THF (2 L) was added under argon (R)-1 -N-Boc-3-hydroxypyrrolidine (b) (84.43 g, 437.41 mmol) followed by Ν,Ν,Ν’,Ν’-tetramethylazodicarboxamide (99.1 g, 546.77 mmol). The clear reaction mixture turned orange and triphenylphosphine (143.41 g, 546.77 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours, meanwhile a precipitate of triphenylphosphine oxide formed (Ph₃P=0). The reaction mixture was poured in water (1 .5 L) and extracted with ethyl acetate (AcOEt) (3×1 .5 L). Gathered organic phases were dried over magnesium sulfate (MgS0₄), filtered and concentrated under reduced pressure. The residue was taken up into diisopropylether (1 .5 L) and the solid formed (Ph₃P=0) was filtered. The solvent was concentrated under reduced pressure and the residue purified by column chromatography eluting with a mixture of heptane with AcOEt (90/10; v/v) to give 145 g (100%) of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1 -carboxylate (c) as a colorless oil.

¹H NMR (400 MHz, DMSO-d6, δ ppm): 1 .27 (s : 12H); 1 .39 (s : 9H); 2.05 (m : 1 H); 2.14 (m : 1 H); 3.37 (3H); 3.55 (m : 1 H); 5.05 (s : 1 H); 6.94 (d, J = 8.4 Hz : 2H); 7.61 (d, J = 8.4 Hz : 2H)

Intermediate (d). (3S)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine, hydrochloride

To a solution of (S)-tert-butyl 3-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1 -carboxylate (c) (80 g, 195.23 mmol) in MeOH (450 ml) was added slowly HCI 4N in dioxane (250 ml).

After 1 .5 hours, the reaction mixture was concentrated under reduced pressure and the residue was taken up into Et₂0 with stirring to give a solid which then was filtered and dried under vacuum to give 61.8 g (95%) of (3S)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine, hydrochloride (d) as a white powder.

¹H NMR (400 MHz, DMSO-d6, δ ppm): 1.28 (s : 12H); 2.10 (m : 1 H); 2.21 (m : 1 H); 3.31 (3H); 3.48 (m : 1 H); 5.19 (m : 1 H); 6.97 (d, J = 8.4 Hz : 2H); 7.63 (d, J = 8.4 Hz : 2H); 9.48 (s : 1 H); 9.71 (s : 1 H).

LC/MS (m/z, MH⁺): 290

Intermediate (e). (3S)-1 -(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine

To a suspension of (S)-3-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine hydrochloride (d) (20 g, 61.42 mmol) in acetonitrile (100 ml), was added K₂C0₃ (21 .22 g, 153.54 mmol) and 1 -iodo-3-fluoropropane (12.15 g, 61.42 mmol), under argon. The reaction

mixture was stirred at 40°C for 24 hours. After cooling to room temperature, the reaction mixture was filtered and washed with acetonitrile. The filtrate was concentrated under reduced pressure and the residue was taken up in DCM and the solid formed was filtered and washed with DCM. The filtrate was concentrated to give 21.5 g (100%) of (3S)-1 -(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) as a yellow foam.

¹H NMR (400 MHz, DMSO-d6, δ ppm): 1.27 (s : 12H); 1 .77 (m : 2H); 1 .84 (m : 1 H); 2.27 (m : 1 H); 2.41 (m : 1 H); 2.49 (2H); 2.62 (dd, J = 2.6 and 10.4Hz : 1 H); 2.69 (m : 1 H); 2.83 (dd, J = 6.2 and 10.4Hz : 1 H); 4.47 (td, J = 6.2 and 47Hz : 2H) ; 4.99 (m : 1 H); 6.77 (d , J = 8.4 Hz : 2H); 7.58 (d, J = 8.4 Hz : 2H).

LC/MS (m/z, MH⁺): 350

Intermediate (B). 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate

To a solution of 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A) (1 .52 g, 8.63 mmol), in acetone (60 ml), was added K₂C0₃ (1 .19 g, 8.63 mmol) and pivaloyl chloride (1.06 ml, 8.63 mmol). The reaction mixture was stirred at room temperature for 16 hours, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane in AcOEt (100/0 to 85/15, v/v) to give 1.55 g (69%) of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate (B) as a colorless oil.

¹H NMR (400 MHz, DMSO-d6, δ ppm): 7.65 (d, 1 H); 7.10-7.04 (m, 2H); 2.95 (t, 2H); 2.68 (t, 2H); 1 .85-1 .65 (m, 4H).

LC/MS (m/z, MH⁺): 261

Intermediate (C). 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate

To a solution of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate (B) (15 g, 57.62 mmol) in DCM (500 ml) was added dropwise under argon pyridine (7.28 ml, 86.43 mmol) and trifluoromethanesulfonic anhydride (19.58 ml, 1 15.24 mmol). The reaction mixture was stirred at room temperature for 2 hours and ice (200 g) was added. The phases were separated, the aqueous phase was washed with DCM and the gathered organic phases were dried over MgS0₄, filtered and evaporated under reduced pressure to give 22 g (97%) of 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate (C) as a white solid.

LC/MS (m/z, MH-): 391

Intermediate (D). 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimeth lpropanoate

To a solution of 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (C) (22 g, 56.07 mmol) and (3S)-1 -(3-fluoropropyl)-3-[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) (20.56 g, 58.87 mmol) in dioxane (420 ml) and water (120 ml) was added under argon Pd(dppf)CI₂ (2.75 g, 3.36 mmol) and Cs₂C0₃ (36.57 g, 1 12.13 mmol). The reaction mixture was stirred for 1 hour at room temperature and was partitioned between water and DCM. The aqueous phase was washed with DCM and the gathered organic phases dried over MgS0₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0 to 5%; V/V) to give 31 g (100 %) of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (D).

LC/MS (m/z, MH⁺): 466

Intermediate (E). 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol

To a solution under argon of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (D) (24.8 g, 53.26 mmol) in MeOH (300 ml), was added NaOH 5M (23 ml, 1 15.00 mmol). The reaction mixture was stirred for 2 hours at room temperature. pH was then adjusted to 7 by addition of 6N aqueous HCI solution. The MeOH was concentrated under reduced pressure, then DCM was added. The organic phase was dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/ MeOH from 100/0 to 95/05 to give 18.8 g (93%) of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (E) as a beige solid.

LC/MS (m/z, MH⁺): 382

Intermediate (F). 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate

To a solution of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (E) (20.6 g, 54.00 mmol) in DCM (200 ml) and pyridine (6.55 ml, 81 .00 mmol), cooled to 5°C (ice bath), was added dropwise trifluoromethanesulfonic anhydride (18.93 ml, 108.00 mmol) under argon, and the reaction temperature was maintained <15°C. The ice bath was removed, and the brown suspension was stirred at room temperature for 2 hours. Ice (200 g) and DCM (200 ml) were added and the phases separated. The organic phase was dried over MgS0₄, and concentrated under reduced pressure. The residue was

purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 24.7 g (89.1 %) of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (F) as a brown oil.

LC/MS (m/z, MH⁺): 514

Intermediate (G). Methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (F) (10.1 g, 19.67 mmol) in DMF (66 ml) and MeOH (33 ml), were added Pd(dppf)CI₂ (909 mg, 1.18 mmol) and diisopropylethylamine (7.21 ml). The black suspension was carbonylated in an autoclave at 70°C under 5 bars of CO for 5 hours. The reaction mixture was filtered, then the filtrate was partially concentrated under reduced pressure. The residue was partitioned between AcOEt and water. The organic phase was washed with water (2x 100 ml), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCIW MeOH from 100/0 to 95/05 to give 7.13 g (86%) of methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (G) as a brown gum.

LC/MS (m/z, MH⁺): 424

Intermediate (A1 ). 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yltrifluoromethanesulfonate

To a solution of commercially available 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A) (18.5 g, 105 mmol) in DCM (185 ml) and lutidine (13.35 ml, 1 13.505 mmol), cooled at 5°C under argon, was added dropwise trifluoromethanesulfonic anhydride (20.22 ml,

123.29 mmol) while keeping temperature between 10 and 20°C. The reaction mixture was stirred for 1 hour at 5°C then at room temperature for 1 hour.

Then, ice (200 g) was added and the slurry partitioned between water and DCM. The organic phase was washed with aqueous NaHC0₃ solution, dried over MgS0₄, filtered off and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane/AcOEt from 100 to 90/10 to give 28.2 g (87%) of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate (A1 ) as an orange oil. LC/MS (m/z, MH⁺): 309

Intermediate (B1 ). Methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate

To a solution of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate (A1 ) (5.03 g, 16.32 mmol) in DMF (24 ml) and MeOH (12 ml), were added Pd(dppf)CI₂ (754 mg, 0.98 mmol) and diisopropylethylamine (6 ml). The black suspension was carbonylated in an autoclave at 70°C under 5 bars of CO for 2.5 hours. The reaction mixture was filtered, then the filtrate was partially concentrated under reduced pressure, and the residue, was partitioned between AcOEt and water. The organic phase was washed with water (2x 75 ml) and aqueous HCI 0.5 N, dried over MgS0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane/AcOEt from 100/0 to 90/10 to give 3.4 g (95%) of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (B1 ) as a colorless oil.

LC/MS (m/z, MH⁺): 219

Intermediate (C1 ). Methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (B1 ) (18,19 g, 83,34 mmol) in DCM (500 ml) and anhydrous pyridine (1 1 ml, 130,56 mmol), cooled at 5°C under argon, was added dropwise trifluoromethanesulfonic anhydride (30 ml, 176,54 mmol). The reaction mixture, a thick suspension, was stirred at room temperature for 24 hours, then ice was added and partitioned between water and DCM. The organic phase was dried over MgS0₄, filtered off and concentrated under reduced pressure to give 29 g (100%) of methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (C1 ) as a yellow gum.

LC/MS (m/z, MH⁺): 351

Intermediate (G). Methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution of methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (C1 ) (29 g, 82.9 mmol), (3S)-1 -(3-fluoropropyl)-3-[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) (28.9 g, 82.9 mmol), in dioxane (225 ml) were added Pd(dppf)CI₂ under argon, complex with DCM (3.73 g, 4.57 mmol) and Cs₂C0₃ 1 .5 M aqueous solution (1 1 1.12 ml, 166.68 mmol). The reaction mixture was stirred at 60°C for 1 hour.

After cooling to room temperature, the reaction mixture was poured into a mixture of water (500 ml) and AcOEt (400ml). The organic phase was washed with brine, dried over MgS0₄, filtered on celite and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 23 g (65%) of methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (G) as a brown gum.

LC/MS (m/z, MH⁺): 424

Intermediate (H). Methyl 8-bromo-9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide

To a solution of methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro- 5H-benzo[7]annulene-3-carboxylate (G) (13.93 g, 32.89 mmol), in DCM (150 ml) was added under argon pyridinium tribromide (15.78 g, 44.41 mmol). The reaction mixture was stirred for 1 hour at room temperature. Water (200 ml) was added, organic phase was then dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 16.4 g (85%) of methyl 8-bromo-9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro- 5H-benzo[7]annulene-3-carboxylate hydrobromide (H) as a yellow meringue.

LC/MS (m/z, MH⁺): 502

Intermediate (I). 6-(2,4-dichloro-phenyl)-5-{4-[1 -(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}- -dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.

To a solution of methyl 8-bromo-9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide (H) (150 mg, 298.56 μηηοΙ), in dioxane (12 ml) and water (2 ml), was added 2,4-dichlorophenyl-boronic acid (62.67 mg, 328.41 μηιοΙ), Cs₂C0₃ (204.48 mg, 626.97 μπιοΙ), and Pd(dppf)CI₂ (14.63 mg, 17.91 mol). The reaction mixture was heated at 90°C for 3 hours, and partitioned between AcOEt and water. The phases were separated and the organic phase washed with brine, dried over MgS0₄ and concentrated under reduced pressure. The residue was purified by column

chromatography eluting with a mixture of DCM, acetonitrile and MeOH (96/2/2; V/V/V) to give 80 mg (47%) of 6-(2,4-dichloro-phenyl)-5-{4-[1 -(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (I).

LC/MS (m/z, MH⁺): 568

Compound (1 ). 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen -2-carboxylic acid

To a solution of 6-(2,4-dichloro-phenyl)-5-{4-[1 -(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (I) (80 mg, 140.72 μηηοΙ) in MeOH (5 ml) was added a solution of NaOH (562.88 μΙ, 5 M) and the reaction mixture was heated at 60°C for 5 hours and the solvent removed under reduced pressure. The residue was taken up in water (10 ml) and aqueous HCI (5 M) added to pH 7. The slurry was extracted with DCM, dried over MgS0₄ and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (90/5/5; V/V/V) to give 60 mg (77%) of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid. ¹H NMR (400 MHz, DMSO-d6, δ ppm): 1 .68 (m, 1 H); 1 ,79 (dm, J=25.3 Hz, 2 H); 2.07 to 2.23 (m, 5 H); 2.38 (m, 1 H); 2.46 (t, J=7.2 Hz, 2 H); 2.52 (m, 1 H); 2.62 (m, 1 H); 2.55 to 2.89 (m, 3 H); 4.47 (td, J=6.2 and 47.6 Hz, 2 H); 4.72 (m, 1 H); 6.63 (d, J=8.9 Hz, 2 H); 6.71 (m, 3 H); 7.18 (d, J=8.4 Hz, 1 H); 8.26 (dd, J=2.0 and 8.4 Hz, 1 H); 7.58 (d, J=2,0 Hz, 1 H); 7.63 (d, J=8.4 Hz, 1 H); 7.79 (s, 1 H); 12.3 (m, 1 H)

LC/MS (m/z, MH+): 554

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‘Top 10 Prominent & Great Personalities of the year 2022’ campaign by Fame Finders.
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SC-52458, FORASARTAN

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ChemSpider 2D Image | Forasartan | C23H28N8

SC-52458, FORASARTAN

Molecular FormulaC₂₃H₂₈N₈
Average mass416.522 Da

PHASE 2, PFIZER, HYPERTENSION

145216-43-9[RN]

5-[(3,5-Dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-[2-(1H-tetrazol-5-yl)phenyl]pyridine

5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]pyridine

форасартан[Russian][INN], فوراسارتان[Arabic][INN], 福拉沙坦[Chinese][INN]

065F7WPT0B[DBID]

7415[DBID]

UNII-065F7WPT0B[DBID]

SC 52458[DBID]

Type-1 angiotensin II receptor

Forasartan, otherwise known as the compound SC-52458, is a nonpeptide angiotensin II receptor antagonist (ARB, AT₁ receptor blocker).^[2]^[3]^[4]^[5]

Forasartan, a specific angiotensin II antagonist, is used alone or with other antihypertensive agents to treat hypertension. Forasartan competes with angiotensin II for binding at the AT1 receptor subtype. As angiotensin II is a vasoconstrictor which also stimulates the synthesis and release of aldosterone, blockage of its effects results in a decreases in systemic vascular resistance.

Indications

Forasartan is indicated for the treatment of hypertension^[6] and, similar to other ARBs, it protects the kidneys from kidney blood vessel damage caused by increased kidney blood pressure by blocking renin–angiotensin system activation.^[7]

Administration

Forasartan is administered in the active oral form ^[6] which means that it must go through first pass metabolism in the liver. The dose administered ranges between 150 mg-200 mg daily.^[6] Increasing to more than 200 mg daily does not offer significantly greater AT₁ receptor inhibition.^[6] Forasartan is absorbed quickly in the GI, and within an hour it becomes significantly biologically active.^[6] Peak plasma concentrations of the drug are reached within one hour.^[6]

Contraindications

Negative side effects of Forasartan are similar to other ARBs, and include hypotension and hyperkalemia.^[8] There are no drug interactions identified with forasartan.^[6]

Bioorganic & Medicinal Chemistry Letters (1994), 4(1), 99-104

PATENT

EP508445

https://worldwide.espacenet.com/patent/search/family/024755845/publication/EP0508445A1?q=EP508445A1

PATENT

WO1992018092

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO1992018092&_cid=P12-LCVD1B-78257-1

Example 2

2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yI)methyl]- 2-pyridinyl]benzoic acid

Step 1 : Preparation of 2-bromo-5-picoline .

A solution of 1500 mL (14 mol) of 48%
hydrobromic acid was cooled to 10 °C and 300 g (2.8 mol) of 2-amino-5-picoline (Aldrich) was added slowly. The
solution was maintained at or below 0 °C while 450 mL (8.8 mol) of bromime was added dropwise. After the bromine addition was complete, a solution of 500 g (7.3 mol) of sodium nitrite in 1000 mL of water was added slowly over 6 h. The reaction pH was adjusted by the careful addition of 1500 mL (56 mol) of 50% sodium hydroxide at such a rate that the temperature was maintained below 30 °C. The product precipitated from the nearly colorless reaction mixture; filtration gave 450 g (94%) of 2-bromo-5-picoline as a yellow powder: mp 38-40 °C; NMR 7.27 (s, 1H), 7.28 (s, 1H), 7.12 (br s, 1H).

Step 2 : Preparation of N-methyl-N-tertbutylbenzamide.

Under nitrogen, 96.7 g (1.1 mol) of N-methyl-N-tertbutylamine and 111 g (1.1 mol) of triethylamine was dissolved in 1050 mL of anhydrous tetrahydrofuran (THF).

The solution was cooled to 0 °C and treated with 140.6 σ (1.0 mol) of benzoyl chloride. The reaction was allowed to slowly warm to ambient temperature and stir overnight.
Filtration and subsequent concentration in vacuo of the filtrate gave the crude product which was purified by sublimation (65 °, 0.2 torr) to give 184 g (96%) of
colorless N-methyl-N-tertbutybenzamide: mp 80.5-82.0 °C; NMR (CDCI₃) δ1.52 (s, 9H), 2.87 (s, 3H), 7.34-7.40 (m, 3H), 7.40-7.46 (m, 2H).

Step 3 : Preparation of 2-(N-methyl-N-tertbutylcarboxamido)phenyIboronic acid.

Under nitrogen, a solution of 50.0 g (262 mmol) of N-methyl-N-tertbutylbenzamide from step 2 and 44 ml (2S2 mmol) of tetramethylethylenediamine (TMEDA) in 3350 mL of anhydrous THF was cooled to -78 °C and slowly treated with 262 mmol of sec-butyllithium in cyclohexane. After 1 h at -78 °C, the reaction was treated with 45 mL (393 mmol) of trimethyl borate and allowed to slowly warm to ambient temperature overnight with stirring. The reaction was concentrated in vacuo; the residue was dissolved in IK sodium hydroxide and extracted with methylene chloride. The pH of the aqueous phase was adjusted to six with dilute hydrochloric acid and extracted with methylene chloride; the organic layer was dried (MgSO₄) and concentrated in vacuo to give 55.7 g (90%) of a 80:20 mixture of syn/anti isomers of 2-(N-methyl-N-tertbutylcarboxamido)phenyIboronic acid as a pale yellow glass: NMR (CDCI₃) δ 1.30 (s, syn C(CH₃)₃, 7.3H), 1.54 (s, anti 0(0.3)3, 1.7H), 2.81 (s, anti CH₃, 0.6H), 2.94 (s, syn CH₃, 2.4H), 7.29-7.46 (m, 3H), 7.95-8.01 (m, 1H).

step 4 : Preparation of N-methyl-N-tertbwtyl-2-(5-methyl-2-pyridinyl)benzamide.

Under nitrogen, 4.44 g (25.8 mmcl) cf 2-bromo-5-picoline from step 1 in 60 mL of toluene was treated with 6.75 g (29 mmol) of 2- (N-methyl-N- tertbutylcarboxamido)phenyIboronic acid from step 3, 1.0 g of tetrakis (triphenylphosphine)palladium zero, 26 mL of ethanol, and 29 mL of 2M sodium carbonate; this mixture was heated to reflux and vigorously stirred for 24 h. The reaction was partitioned between water and ether; the organic layer was separated, dried (MgSθ₄), and
concentrated in vacuo. Purification by silica gel
chromatography (Waters Prep-500A) using ethyl
acetate/hexane (1:2) gave 6.51 g (90%) of N-methyl-N- tertbutyl-2-(5-methyl-2-pyridinyl)benzamide as an oil : NMR (CDCI₃) δ 1.40 (s, 9H), 2.33 (s, 3H), 2.61 (s, 3H), 7.27- 7.33 (m, 1H), 7.35-7.41 (m, 2H), 7.47-7.51 (m, 2H), 7.60- 7.66 (m, 1H), 8.43 (br s, 1H).

Step 5 : Preparation of sodium 2-(5-methyl-2- pyridinyl)benzoate.

Under nitrogen, 6.5 g (23 mmol) of N-methyl-N- tertbutyl-2-(6-methyl-3-pyridinyl)benzamide from step 4 was treated with 65 mL of anhydrous trifluoroacetic acid (TFA) at reflux for 6 h. The reaction was concentrated in vacuo and the residue dissolved in water. The pH was adjusted to 10 with aqueous sodium hydroxide and lyophilized to give the sodium salt of 2- (5-methyl-2-pyridinyl)benzoic acid as a colorless solid: NMR [CDCI₃/CF₃CO₂H (97:3)] δ 2.62 (s, 3H), 7.42-7.48 (m, 1H), 7.67-7.80 (m, 3H), 8.18-8.24 (m, 1H), 8.28 (dd, J=8 and 2 HZ, 1H), 7.67-7.80 (m, 3H), 8.18-8.24 (m, 1H), 8.28 (dd, J=8 and 2 Hz, 1H), 8.61 (s, 1H) ; MS (FAB) m/e (rel intensity) 214 (20), 196 (100); HRMS.
Calc’d for M+H: 214.0868. Found: 214.0846.

step 6 : Preparation of ethyl 2-(5-methyl-2-pyridinyl)benzoate.

Under nitrogen, the crude sodium salt from step 5 was suspended in 50 mL of chloroform and treated with 9 mL (103 mmol) of oxalyl chloride. The reaction was stirred for 72 h, filtered under nitrogen, and concentrated in vacuo; the residue was dissolved in absolute ethanol.
Concentration in vacuo gave 2.0 g (8 mmol) of ethyl 2-(5-methyl-2-pyridinyl)benzoate as a brown oil: NMR (CDCI₃) δ 1.09 (t, J=7 Hz, 3H), 2.36 (s, 3H), 4.15 (q, J=7 Hz, 2H), 7.34 (d, J=8 Hz, 1H), 7.38-7.48 (m, 1H), 7.48-7.58 (m, 3H), 7.80 (d, J=8 Hz, 1H), 8.46 (s, 1H).

Step 7 : Preparation of ethyl 2-(5-bromomethyl-2-pyridinyl)benzoate.

Under nitrogen, the crude ethyl 2-(5-methyl-2-pyridinyl)benzoate from step 6 was treated with 1.7 g (9.5 mmol) of NBS and 160 mg (0.66 mmol) of benzoyl peroxide in 145 mL of anhydrous carbon tetrachloride at reflux for 2.5 h. The reaction was filtered under nitrogen and
concentrated in vacuo to give crude ethyl 2-(5-bromomethyl-2-pyridinyl)benzoate; no purification was attempted.

step 8 : Preparation of ethyl 2-[5-[(3,5-dibutyl-1H- 1 , 2 , 4-triazol-1 -yl )methy] 1 -2-pyridinyl ] benzoate .

Under nitrogen, 630 mg (3.5 mmol) of 3,5-dibutyl-1H-1,2,4-triazole from step 3 of Example 1 was added in small portions to 5.4 mmol of sodium hydride in 8 mL of DMF; stirring was continued until hydrogen evolution had ceased. The anion solution was cooled to 0 °C and treated with a solution of the crude ethyl 2-(5-bromomethyl-2-pyridinyl)benzoate from step 7 in 10 mL of DMF. The reaction was stirred at ambient temperature overnight, quench with 1 mL of absolute ethanol, and concentrated in vacuo; the resulting residue was redisolved in methylene chloride, filtered, and reconcentrated in vacuo to give crude ethyl 2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]benzoate.

step 9 : Preparation of 2- [5- [ (3, 5-dibutyl-1H-1 , 2, 4 -triazol-1-yl)methyl]-2-pyridinyllbenzoic acid.

A 1.0 g sample of the crude ethyl 2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]benzoate from step 8 in 10 mL of water was treated with 3 mL of 101 aqueous sodium hydroxide and stirred at ambient temperature overnight. The reaction mixture was washed with 30 mL of ether and the pH adjusted to six with dilute hydrochloric acid. Purification by reverse phase chromatography (Waters Deltaprep-3000) using isocratic acetonitrile/water (28:72) (0.05% TFA) gave 5 mg of 2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]benzoic acid: NMR (D₂O + NaO₃S(CH₂)₃ Si(CH₃)₃] δ 0.80 (t, J=7 Hz, 3H), 0.86 (t, J=7 Hz, 3H), 1.19-1.33 (m, 4H), 1.54-1.68 (m, 4H), 2.65 (t, J=7 Hz, 2H), 2.82 (t, _ϊ=7 Hz, 2H), 5.43 (s, 2H), 7.45-7.59 (m, 5H), 7.64 (dd, J=8 and 2 Hz, 1H), 8.37-8.45 (m, 1H); MS (FAB) m/e (rel intensity) 393 (80), 375 (30), 212 (40), 182 (100); HRMS. Calc’d for M+Li: 399.2373. Found:
399.2374.

Example 3

5-[2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]- 2-pyridinyl]phenyl]-1H-tetrazole

Step 1 : Preparation of 2-bromo-5-bromomethylpyridine.

A solution of 296.3 g (1.72 mol) of 2-bromo-5-picoline from step 1 of Example 2 in 6000 mL of carbon tetrachloride was treated with 306.5 g (1.72 mol) of N-bromosuccinimide (NBS) and 28.3 g (173 mmol) of
azobisisobutyronitrile (AIBN). The reaction was stirred at reflux under nitrogen for 3 h, filtered, and concentrated in vacuo providing 476 g of crude 2-bromo-5-bromomethylpyridine as a brownish yellow solid (NMR indicates that this material is only 60% monobromomethyl product): NMR (CDCI₃ δ 4.42 (s, 2H), 7.48 (d, .J=9 Hz, 1H), 7.60 (dd, J=9 and 3 Hz, 1H), 8.37 (d, J=3 Hz, 1H).

Step 2: Preparation of 2-bromo-5-[(3.5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]pyridine.

Under nitrogen, 3.15 g (17 mmol) of solid 3,5-dibutyl-1H-1,2,4-triazole from step 3 of Example 1 was added in small portions to 33 mmol of sodium hydride in 31 ml of dimethylformamide (DMF); stirring was continued until hydrogen evolution had ceased. The anion solution was cooled to 0 °C and treated with a solution of 7.9 g (19 mmol) of crude 2-bromo-5-bromomethylpyridine from step 1 in 10 ml of dry DMF. The reaction was allowed to warm to ambient temperature and stir overnight. Methanol (10 ml) was added to destroy any unreacted sodium hydride and the

DMF was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and dried (MgSO₄).
Silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (60:40) gave 4.8 g (47%) of 2-bromo-5-[(3,5- dibutyl-1H-1,2,4-triazol-1-yl)methyl]pyridine as an oil: NMR (CDCI₃) δ 0.88 (t, J=7 Hz, 1H), 0.92 (t, J=7 Hz, 1H), 1.27-1.44 (m, 4H), 1.59-1.76 (m, 4H), 2.60-2.71 (m, 4H), 5.18 (s, 2H), 7.35 (dd, J=8 and 3 Hz), 7.46 (d, J=8 Hz, 1H), 8.23 (d, .1=3 Hz, 1H).

Step 3: Preparation of 5-[2-[5-[(3,5-dibutyl-1H-1,2,4- triazol-1-yl)methyl]-2-pyridinyl]phenyl]-1H-tetrazole.

Under nitrogen, 1.03 g (2.9 mmol) of 2-bromo-5- [(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]pyridine from step 2 and 2.46 g (5.7 mmol) of 2-(N-triphenyImethyltetrazol-5-yl)phenyIboronic acid from step 5 of Example 1 were treated with 1.0 g (0.86 mmol) of tetrakis (triphenyl-phosphine)palladium zero, 15 mL of toluene, 10 mL of ethanol, and 6.3 mL of 2M aqueous sodium carbonate. The reaction mixture was heated to reflux and vigorously stirred overnight. The product was purified by reverse phase chromatography (Waters Deltaprep-3000) using acetonitrile/water (20-40:80-60) (0.05% TFA). The pure fractions (by analytical HPLC) were combined, the
acetonitrile removed in vacuo, the pH adjusted to four with dilute sodium hydroxide, and the resulting suspension extracted 4 times with ether. The extracts were combined, dried (MgSθ4), and concentrated in vacuo to give 340 mg (28%) of 5-[2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]phenyl-1H-tetrazole as a colorless solid: mp 139-141 °C; NMR (CD₃OD) δ 0.90 (t, J=7 Hz, 3H), 0.93 (t, J=7 Hz, 3H), 1.29-1.44 (m, 4H), 1.58-1.75 (m, 4H), 2.65 (t, J=7 Hz, 2H), 2.81 (t, J=7 Hz, 2H), 5.40 (s, 2H), 7.47 (d, J=8 Hz, 1H), 7.61-7.77 (m, 5H), 8.33 (d, J=2 Hz, 1H); MS (FAB) m/e (rel intensity) 417 (100), 208 (30); HRMS. Calc’d for M+H: 417.2515. Found: 417.2527.

PATENT

WO2001076573

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2001076573&_cid=P12-LCVCXR-77816-1

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Pharmacology

The angiotensin II receptor, type 1

Angiotensin II binds to AT₁ receptors, increases contraction of vascular smooth muscle, and stimulates aldosterone resulting in sodium reabsorption and increase in blood volume.^[9] Smooth muscle contraction occurs due to increased calcium influx through the L-type calcium channels in smooth muscle cells during the plateau component, increasing the intracellular calcium and membrane potential which sustain depolarization and contraction.^[10]

Effects

Forasartan is a competitive and reversible ARB that competes with the angiotensin II binding site on AT₁^[11] and relaxes vascular smooth muscle,^[10] resulting in decreased blood pressure. Forasartan has a high affinity for the AT₁ receptor (IC50=2.9 +/- 0.1nM).^[12] In dogs, it was found to block the pressor response of Angiotensin II with maximal inhibition, 91%.^[10] Forasartan administration selectively inhibits L-type calcium channels in the plateau component of the smooth muscle cells, favoring relaxation of the smooth muscle.^[10] Forasartan also decreases heart rate by inhibiting the positive chronotropic effect of high frequency preganglionic stimuli.^[13]

Scarce use

Even though experiments have been conducted on rabbits,^[6] guinea pigs,^[10] dogs ^[14] and humans,^[6]^[13] forasartan is not a popular drug of choice for hypertension due to its short duration of action; forasartan is less effective than losartan.^[6] Research demonstrates that forasartan is also significantly less potent than losartan.^[6]

References

^ Bräse, Stefan; Banert, Klaus (2010). Organic Azides: Syntheses and Applications. New York: Wiley. p. 38. ISBN 978-0-470-51998-1.
^ Knox C, Law V, Jewison T, Liu P, Ly S, Frolkis A, et al. (January 2011). “DrugBank 3.0: a comprehensive resource for ‘omics’ research on drugs”. Nucleic Acids Research. DrugBank. 39 (Database issue): D1035-41. doi:10.1093/nar/gkq1126. PMC 3013709. PMID 21059682.
^ Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, et al. (January 2008). “DrugBank: a knowledgebase for drugs, drug actions and drug targets”. Nucleic Acids Research. 36 (Database issue): D901-6. doi:10.1093/nar/gkm958. PMC 2238889. PMID 18048412.
^ Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, et al. (January 2006). “DrugBank: a comprehensive resource for in silico drug discovery and exploration”. Nucleic Acids Research. 34 (Database issue): D668-72. doi:10.1093/nar/gkj067. PMC 1347430. PMID 16381955.
^ Olins GM, Corpus VM, Chen ST, McMahon EG, Palomo MA, McGraw DE, et al. (October 1993). “Pharmacology of SC-52458, an orally active, nonpeptide angiotensin AT1 receptor antagonist”. Journal of Cardiovascular Pharmacology. 22 (4): 617–25. doi:10.1097/00005344-199310000-00016. PMID 7505365. S2CID 93468.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k Hagmann M, Nussberger J, Naudin RB, Burns TS, Karim A, Waeber B, Brunner HR (April 1997). “SC-52458, an orally active angiotensin II-receptor antagonist: inhibition of blood pressure response to angiotensin II challenges and pharmacokinetics in normal volunteers”. Journal of Cardiovascular Pharmacology. 29 (4): 444–50. doi:10.1097/00005344-199704000-00003. PMID 9156352.
^ Naik P, Murumkar P, Giridhar R, Yadav MR (December 2010). “Angiotensin II receptor type 1 (AT1) selective nonpeptidic antagonists–a perspective”. Bioorganic & Medicinal Chemistry. 18 (24): 8418–56. doi:10.1016/j.bmc.2010.10.043. PMID 21071232.
^ Ram CV (August 2008). “Angiotensin receptor blockers: current status and future prospects”. The American Journal of Medicine. 121 (8): 656–63. doi:10.1016/j.amjmed.2008.02.038. PMID 18691475.
^ Higuchi S, Ohtsu H, Suzuki H, Shirai H, Frank GD, Eguchi S (April 2007). “Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology”. Clinical Science. 112 (8): 417–28. doi:10.1042/cs20060342. PMID 17346243.
^ Jump up to:^a ^b ^c ^d ^e Usune S, Furukawa T (October 1996). “Effects of SC-52458, a new nonpeptide angiotensin II receptor antagonist, on increase in cytoplasmic Ca2+ concentrations and contraction induced by angiotensin II and K(+)-depolarization in guinea-pig taenia coli”. General Pharmacology. 27 (7): 1179–85. doi:10.1016/s0306-3623(96)00058-4. PMID 8981065.
^ Olins GM, Chen ST, McMahon EG, Palomo MA, Reitz DB (January 1995). “Elucidation of the insurmountable nature of an angiotensin receptor antagonist, SC-54629”. Molecular Pharmacology. 47 (1): 115–20. PMID 7838120.
^ Csajka C, Buclin T, Fattinger K, Brunner HR, Biollaz J (2002). “Population pharmacokinetic-pharmacodynamic modelling of angiotensin receptor blockade in healthy volunteers”. Clinical Pharmacokinetics. 41 (2): 137–52. doi:10.2165/00003088-200241020-00005. PMID 11888333. S2CID 13185772.
^ Jump up to:^a ^b Kushiku K, Yamada H, Shibata K, Tokunaga R, Katsuragi T, Furukawa T (January 2001). “Upregulation of immunoreactive angiotensin II release and angiotensinogen mRNA expression by high-frequency preganglionic stimulation at the canine cardiac sympathetic ganglia”. Circulation Research. 88 (1): 110–6. doi:10.1161/01.res.88.1.110. PMID 11139482.
^ McMahon EG, Yang PC, Babler MA, Suleymanov OD, Palomo MA, Olins GM, Cook CS (June 1997). “Effects of SC-52458, an angiotensin AT1 receptor antagonist, in the dog”. American Journal of Hypertension. 10 (6): 671–7. doi:10.1016/s0895-7061(96)00500-6. PMID 9194514.

Clinical data

Other names	SC-52458
Pregnancy category	Not assigned
Routes of administration	Oral
ATC code	C09CA (WHO)
Legal status
Legal status	Development halted, never marketed^[1]
Pharmacokinetic data
Elimination half-life	1–2 hours
Identifiers
show IUPAC name
CAS Number	145216-43-9
PubChem CID	132706
DrugBank	DB01342
ChemSpider	117146
UNII	065F7WPT0B
KEGG	D04243
ChEBI	CHEBI:141552
ChEMBL	ChEMBL315021
CompTox Dashboard (EPA)	DTXSID70162942
Chemical and physical data
Formula	C₂₃H₂₈N₈
Molar mass	416.533 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI

////////SC-52458, FORASARTAN, форасартан , فوراسارتان , 福拉沙坦 , PHASE 2, PFIZER, HYPERTENSION

CCCCC1=NN(CC2=CN=C(C=C2)C2=CC=CC=C2C2=NNN=N2)C(CCCC)=N1

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Adagrasib

January 4, 2023 2:52 am / Leave a comment

Adagrasib

Formula	C32H35ClFN7O2
cas	2326521-71-3
Mol weight	604.1174

Antineoplastic
Disease	Non-small cell lung cancer

2022/12/12

FDA APPROVED, KRAZATI (Mirati Therapeutics)

MRTX-849
MRTX849
KRAS G12C inhibitor MRTX849

Adagrasib, sold under the brand name Krazati, is an anticancer medication used to treat non-small cell lung cancer.^[1]^[2] Adagrasib is an inhibitor of the RAS GTPase family.^[1] It is taken by mouth.^[1] It is being developed by Mirati Therapeutics.^[1]^[3]

The most common adverse reactions include diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation.^[2] The most common laboratory abnormalities include decreased lymphocytes, increased aspartate aminotransferase, decreased sodium, decreased hemoglobin, increased creatinine, decreased albumin, increased alanine aminotransferase, increased lipase, decreased platelets, decreased magnesium, and decreased potassium.^[2]

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

Synthesis Reference

Fell, Jay B et al. “Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer.” Journal of medicinal chemistry vol. 63,13 (2020): 6679-6693. doi:10.1021/acs.jmedchem.9b02052

Journal of Medicinal Chemistry (2020), 63(13), 6679-6693

PATENT

WO2020101736 https://patents.google.com/patent/WO2020101736A1/en

EXAMPLE 7

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

[0432] 2-fluoroprop-2-enoyl chloride. To a solution of 2-fluoroprop-2-enoic acid (400 mg, 4.44 mmol, 1 eq) in DCM (4 mL) was added (COCl)₂ (846 mg, 6.66 mmol, 583 µL, 1.5 eq) and DMF (32.5 mg, 444 umol, 34.2 µL, 0.1 eq). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove a part of solvent and give a residue in DCM. Compound 2-fluoroprop-2-enoyl chloride (400 mg, crude) was obtained as a yellow liquid and used into the next step without further purification. [0433] Step A: 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2- yl]acetonitrile. To a solution of 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)- 1-methylpyrrolidin- 2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile (300 mg, 528 umol, 1 eq, HCl) in DCM (5 mL) was added DIEA (1.73 g, 13.4 mmol, 2.33 mL, 25.4 eq) and 2-fluoroprop-2-enoyl chloride (286 mg, 2.64 mmol, 5 eq) in DCM (5 mL). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Al2O3, Dichloromethane/Methanol = 10/1 to 10/1). The residue was purified by prep-HPLC (column: Gemini 150 * 25 5u; mobile phase: [water (0.05% ammonia hydroxide v / v) – ACN]; B%: 55% – 85%, 12min). The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150 * 30mm * 4um; mobile phase: [water (0.225% FA) – ACN]; B%: 20% – 50%, 10.5min). The residue was concentrated under reduced pressure to remove ACN, and then lyophlization. Title compound 2-[(2S)-4-[7-(8-chloro- 1-naphthyl)-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin- 4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (EXAMPLE 7, 24.1 mg, 36.7 umol, 7% yield, 99.1% purity, FA) was obtained as a brown solid. [0434] SFC condition: “AD – 3S_3_5_40_3ML Column: Chiralpak AD – 3 100 × 4.6mm I.D., 3um Mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40% Flow rate: 3mL/min Wavelength: 220nm”. [0435] ¹H NMR (400 MHz, Acetic) d = 7.82 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.41 – 7.30 (m, 2H), 5.58 – 5.25 (m, 2H), 5.17 – 4.59 (m, 4H), 4.57 – 4.28 (m, 3H), 4.24 – 3.78 (m, 4H), 3.67 – 3.13 (m, 7H), 3.08 (br d, J = 2.4 Hz, 3H), 2.98 (br d, J = 6.4 Hz, 1H), 2.83 – 2.61 (m, 1H), 2.45 – 2.29 (m, 1H), 2.24 – 2.08 (m, 3H).

PATENT

US20190144444 https://patents.google.com/patent/US20190144444A1/en

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Adagrasib (MRTX849) is an oral, small-molecule KRAS inhibitor developed by Mirati Therapeutics. KRAS mutations are highly common in cancer and account for approximately 85% of all RAS family mutations.⁵ However, the development of KRAS inhibitors has been challenging due to their high affinity for guanosine triphosphate (GTP) and guanosine diphosphate (GDP), as well as the lack of a clear binding pocket.¹ Adagrasib targets KRAS^G12C, one of the most common KRAS mutations, at the cysteine 12 residue and inhibits KRAS-dependent signalling.² In a phase I/IB clinical study that included patients with KRAS^G12C-mutated advanced solid tumors (NCT03785249), adagrasib exhibited anti-tumor activity. The phase II of the same study showed that in patients with KRAS^G12C-mutated non-small-cell lung cancer (NSCLC), adagrasib was efficient without new safety signals.^2,3,6

In February 2022, the FDA accepted a new drug application (NDA) for adagrasib for the treatment of patients with previously treated KRAS^G12C–positive NSCLC.⁷ In December 2022, the FDA granted accelerated approval to adagrasib for the treatment of KRAS^G12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy.^8,9 Adagrasib joins sotorasib as another KRAS^G12C inhibitor approved by the FDA.⁴

Medical uses

Adagrasib is indicated for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA approved test, who have received at least one prior systemic therapy.^[1]^[2]^[4]

History

Approval by the US Food and Drug Administration (FDA) was based on KRYSTAL-1, a multicenter, single-arm, open-label clinical trial (NCT03785249) which included participants with locally advanced or metastatic non-small cell lung cancer with KRAS G12C mutations.^[2] Efficacy was evaluated in 112 participants whose disease has progressed on or after platinum-based chemotherapy and an immune checkpoint inhibitor, given either concurrently or sequentially.^[2]

The FDA granted the application for adagrasib fast-track, breakthrough therapy, and orphan drug designations.^[2]

Research

It is undergoing clinical trials.^[5]^[6]^[7]^[8]^[9]^[10]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216340s000lbl.pdf
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSC”. U.S. Food and Drug Administration (FDA). 12 December 2022. Retrieved 14 December 2022. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b “Mirati Therapeutics Announces U.S. FDA Accelerated Approval of Krazati (adagrasib) as a Targeted Treatment Option for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) with a KRASG12C Mutation” (Press release). Mirati Therapeutics Inc. 12 December 2022. Retrieved 13 December 2022 – via MultiVu.
^ https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2022/216340Orig1s000ltr.pdf This article incorporates text from this source, which is in the public domain.
^ Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, et al. (January 2020). “The KRAS^G12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients”. Cancer Discovery. 10 (1): 54–71. doi:10.1158/2159-8290.CD-19-1167. PMC 6954325. PMID 31658955.
^ Fell JB, Fischer JP, Baer BR, Blake JF, Bouhana K, Briere DM, et al. (July 2020). “Identification of the Clinical Development Candidate MRTX849, a Covalent KRAS^G12C Inhibitor for the Treatment of Cancer”. Journal of Medicinal Chemistry. 63 (13): 6679–6693. doi:10.1021/acs.jmedchem.9b02052. PMID 32250617.
^ Thein KZ, Biter AB, Hong DS (January 2021). “Therapeutics Targeting Mutant KRAS”. Annual Review of Medicine. 72: 349–364. doi:10.1146/annurev-med-080819-033145. PMID 33138715. S2CID 226242453.
^ Christensen JG, Olson P, Briere T, Wiel C, Bergo MO (August 2020). “Targeting Kras^g12c -mutant cancer with a mutation-specific inhibitor”. Journal of Internal Medicine. 288 (2): 183–191. doi:10.1111/joim.13057. PMID 32176377.
^ Dunnett-Kane V, Nicola P, Blackhall F, Lindsay C (January 2021). “Mechanisms of Resistance to KRAS^G12C Inhibitors”. Cancers. 13 (1): 151. doi:10.3390/cancers13010151. PMC 7795113. PMID 33466360.
^ Jänne PA, Riely GJ, Gadgeel SM, Heist RS, Ou SI, Pacheco JM, et al. (July 2022). “Adagrasib in Non–Small-Cell Lung Cancer Harboring a KRASG12C Mutation”. New England Journal of Medicine. 387 (2): 120–131. doi:10.1056/NEJMoa2204619. PMID 35658005. S2CID 249352736.

External links

“Adagrasib”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03785249 for “Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1” at ClinicalTrials.gov

///////Adagrasib, KRAZATI, FDA 2022, APPROVALS 2022, MRTX-849, MRTX849, Mirati Therapeutics

[H][C@@]1(COC2=NC3=C(CCN(C3)C3=CC=CC4=C3C(Cl)=CC=C4)C(=N2)N2CCN(C(=O)C(F)=C)[C@@]([H])(CC#N)C2)CCCN1C

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Nirsevimab

December 27, 2022 2:49 am / Leave a comment

(Heavy chain)
QVQLVQSGAE VKKPGSSVMV SCQASGGLLE DYIINWVRQA PGQGPEWMGG IIPVLGTVHY
GPKFQGRVTI TADESTDTAY MELSSLRSED TAMYYCATET ALVVSETYLP HYFDNWGQGT
LVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP
AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKRVEPKSCD KTHTCPPCPA
PELLGGPSVF LFPPKPKDTL YITREPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP
REEQYNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKALPAP IEKTISKAKG QPREPQVYTL
PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSKLT
VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPGK
(Light chain)
DIQMTQSPSS LSAAVGDRVT ITCQASQDIV NYLNWYQQKP GKAPKLLIYV ASNLETGVPS
RFSGSGSGTD FSLTISSLQP EDVATYYCQQ YDNLPLTFGG GTKVEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H153-H209, H229-L214, H235-H’235, H238-H’238, H270-H330, H376-H434, H’22-H’96, H’153-H’209, H’229-L’214, H’270-H’330, H’376-H’434, L23-L88, L’23-L’88, L134-L194, L’134-L’194)

>Heavy_chain
QVQLVQSGAEVKKPGSSVMVSCQASGGLLEDYIINWVRQAPGQGPEWMGGIIPVLGTVHY
GPKFQGRVTITADESTDTAYMELSSLRSEDTAMYYCATETALVVSETYLPHYFDNWGQGT
LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP
AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPA
PELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP
REEQYNSTYRVVSVLTVLHQDWLEGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL
PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT
VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

>Light_chain
DIQMTQSPSSLSAAVGDRVTITCQASQDIVNYLNWYQQKPGKAPKLLIYVASNLETGVPS
RFSGSGSGTDFSLTISSLQPEDVATYYCQQYDNLPLTFGGGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Nirsevimab

EMS APPROVED 2022/10/31, Beyfortus, AstraZeneca AB

Formula	C6494H10060N1708O2050S46
CAS	1989556-22-0
Mol weight	146334.5658

Monoclonal antibody
Prevention of respiratory syncytial virus infection

Immunoglobulin g1-kappa, anti-(human respiratory syncytial virus fusion glycoprotein f0 (protein f))human monoclonal antibody.gamma.1 heavy chain (1-456) (human vh (homo sapiens ighv1-69*01(ighd)-ighj4*01 (90.1%)) (8.8.19) (1-126) -homo sapiens ighg1*03
Immunoglobulin g1, anti-(human respiratory syncytial virus fusion protein)(human monoclonal med18897 .gamma.1-chain), disulfide with monoclonal med18897 .kappa.-chain, dimer

Synthesis Reference

Khan, AA et al. (2020) Dosage regimens for and compositions including anti-rsv antibodies. (U.S. Patent No. 2020/0347120 A1). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/6b/d2/10/a841b66e0c90cf/US20200347120A1.pdf

Nirsevimab, sold under the brand name Beyfortus, is a human recombinant monoclonal antibody with activity against respiratory syncytial virus, or RSV for infants.^[2]^[3] It is under development by AstraZeneca and Sanofi.^[2]^[3] Nirsevimab is designed to bind to the fusion protein on the surface of the RSV virus.^[4]^[5]

The most common side effects reported for nirsevimab are rash, pyrexia (fever) and injection site reactions (such as redness, swelling and pain where the injection is given).^[6]

Nirsevimab was approved for medical use in the European Union in November 2022.^[1]^[7]

Nirsevimab (MEDI8897) is a recombinant human immunoglobulin G1 kappa (IgG1ĸ) monoclonal antibody used to prevent respiratory syncytial virus (RSV) lower respiratory tract disease in neonates and infants.⁶ It binds to the prefusion conformation of the RSV F protein, a glycoprotein involved in the membrane fusion step of the viral entry process, and neutralizes several RSV A and B strains.^6,1 Compared to palivizumab, another anti-RSV antibody, nirsevimab shows greater potency at reducing pulmonary viral loads in animal models. In addition, nirsevimab was developed as a single-dose treatment for all infants experiencing their first RSV season, whereas palivizumab requires five monthly doses to cover an RSV season.⁵ This is due to a modification in the Fc region of nirsevimab that grants it a longer half-time compared to typical monoclonal antibodies.^1,6

On November 2022, nirsevimab was approved by the EMA for the prevention of RSV lower respiratory tract disease in newborns and infants during their first RSV season.⁶

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Monoclonal antibody
Type	Whole antibody
Source	Human
Target	F protein of RSV
Clinical data
Trade names	Beyfortus
Other names	MED-18897, MEDI8897
Routes of administration	Intramuscular
ATC code	None
Legal status
Legal status	EU: Rx-only ^[1]
Identifiers
CAS Number	1989556-22-0
PubChem SID	384585358
DrugBank	DB16258
UNII	VRN8S9CW5V
KEGG	D11380
ChEMBL	ChEMBL4297575
Chemical and physical data
Formula	C₆₄₉₄H₁₀₀₆₀N₁₇₀₈O₂₀₅₀S₄₆
Molar mass	146336.58 g·mol⁻¹

Adverse effects

No major hypersensitivity reactions have been reported, and adverse events of grade 3 or higher were only reported in 8% (77 of 968) of participants in clinical trial NCT02878330.^[8]^[4]

Pharmacology

Mechanism of action

Nirsevimab binds to the prefusion conformation of the RSV fusion protein, i.e. it binds to the site at which the virus would attach to a cell; effectively rendering it useless. It has a modified F_c region, extending the half-life of the drug in order for it to last the whole RSV season.^[4]

History

The opinion by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) is based on data from two randomized, double-blind, placebo-controlled multicenter clinical trials that investigated the efficacy and safety of nirsevimab in healthy preterm (premature) and full-term infants entering their first respiratory syncytial virus (RSV) season.^[6] These studies demonstrated that nirsevimab prevents lower respiratory tract infection caused by RSV requiring medical attention (such as bronchiolitis and pneumonia) in term and preterm infants during their first RSV season.^[6]

The safety of nirsevimab was also evaluated in a phase II/III, randomized, double‑blind, multicenter trial in infants who were born five or more weeks prematurely (less than 35 weeks gestation) at higher risk for severe RSV disease and infants with chronic lung disease of prematurity (i.e. long-term respiratory problems faced by babies born prematurely) or congenital heart disease.^[6] The results of this study showed that nirsevimab had a similar safety profile compared to palivizumab (Synagis).^[6]

Society and culture

Legal status

On 15 September 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 Beyfortus, intended for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in newborns and infants.^[9]^[6] Beyfortus was reviewed under EMA’s accelerated assessment program.^[9] The applicant for this medicinal product is AstraZeneca AB.^[9] Nirsevimab was approved for medical use in the European Union in November 2022.^[1]^[7]

Research

Nirsevimab is being investigated as an experimental vaccine against respiratory syncytial virus, RSV, in the general infant population.^[2]^[3] The MELODY study is an ongoing, randomized, double-blind, placebo-controlled to evaluate the safety and efficacy of nirsevimab in late preterm and term infants. Initial results have been promising, with nirsevimab reducing LRTI (lower respiratory tract infections) by 74.5% compared to placebo in infants born at term or late preterm.^[5]^[10]^[11]

Ongoing trials for nirsevimab are:

References

^ Jump up to:^a ^b ^c “Beyfortus”. Union Register of medicinal products. 3 November 2022. Retrieved 6 November 2022.
^ Jump up to:^a ^b ^c “Nirsevimab demonstrated protection against respiratory syncytial virus disease in healthy infants in Phase 3 trial” (Press release). Sanofi. 26 April 2021. Archived from the original on 27 December 2021. Retrieved 27 December 2021.
^ Jump up to:^a ^b ^c “Nirsevimab MELODY Phase III trial met primary endpoint of reducing RSV lower respiratory tract infections in healthy infants” (Press release). AstraZeneca. 26 April 2021. Archived from the original on 26 December 2021. Retrieved 27 December 2021.
^ Jump up to:^a ^b ^c Griffin MP, Yuan Y, Takas T, Domachowske JB, Madhi SA, Manzoni P, et al. (Nirsevimab Study Group) (July 2020). “Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants”. The New England Journal of Medicine. 383 (5): 415–425. doi:10.1056/NEJMoa1913556. PMID 32726528. S2CID 220876651.
^ Jump up to:^a ^b Hammitt LL, Dagan R, Yuan Y, Baca Cots M, Bosheva M, Madhi SA, et al. (March 2022). “Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants”. The New England Journal of Medicine. 386 (9): 837–846. doi:10.1056/NEJMoa2110275. PMID 35235726. S2CID 247220023.
^ Jump up to:^a ^b ^c ^d ^e ^f “New medicine to protect babies and infants from respiratory syncytial virus (RSV) infection”. European Medicines Agency (EMA) (Press release). 16 September 2022. Archived from the original on 19 September 2022. Retrieved 18 September 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ Jump up to:^a ^b “Beyfortus approved in the EU for the prevention of RSV lower respiratory tract disease in infants”. AstraZeneca (Press release). 4 November 2022. Retrieved 6 November 2022.
^ Clinical trial number NCT02878330 at ClinicalTrials.gov
^ Jump up to:^a ^b ^c “Beyfortus: Pending EC decision”. European Medicines Agency (EMA). 15 September 2022. Archived from the original on 19 September 2022. Retrieved 18 September 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ Zacks Equity Research (25 March 2022). “Pfizer’s (PFE) RSV Jab Gets Another Breakthrough Therapy Tag”. Nasdaq. Archived from the original on 8 April 2022. Retrieved 8 April 2022.
^ “Nirsevimab significantly protected infants against RSV disease in Phase III MELODY trial”. AstraZeneca (Press release). 3 March 2022. Retrieved 6 November 2022.

////////////Nirsevimab, EU 2022, APPROVALS 2022, PEPTIDE, Monoclonal antibody, respiratory syncytial virus infection, ANTIVIRAL, 1989556-22-0, MED-18897, MEDI8897, AstraZeneca AB

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Olutasidenib

December 20, 2022 2:50 am / Leave a comment

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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Clinical data

Trade names	Rezlidhia
Other names	FT-2102
License data	US DailyMed: Olutasidenib
Routes of administration	By mouth
ATC code	None
Legal status
Legal status	US: ℞-only ^[1]^[2]
Identifiers
CAS Number	1887014-12-1
PubChem CID	118955396
IUPHAR/BPS	10319
DrugBank	DB16267
ChemSpider	72380144
UNII	0T4IMT8S5Z
KEGG	D12483
ChEMBL	ChEMBL4297610
PDB ligand	PWV (PDBe, RCSB PDB)
Chemical and physical data
Formula	C₁₈H₁₅ClN₄O₂
Molar mass	354.79 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES

References

^ Jump up to:^a ^b ^c ^d ^e ^f https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215814s000lbl.pdf
^ 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.
^ “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.
^ “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.
^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 82”. WHO Drug Information. 33 (3). hdl:10665/330879.

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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ABY 737

December 4, 2022 3:04 am / Leave a comment

ABT-737

Molecular Weight	813.43
Formula	C₄₂H₄₅ClN₆O₅S₂
CAS No.	852808-04-9

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

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022246929&_cid=P10-LB5WBS-20634-1

PATENT

CN113248415

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN334799516&_cid=P22-LB8RFE-22163-1

PATENT

US20070015787

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

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

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Names

Preferred IUPAC name4-{4-[(4′-Chloro[1,1′-biphenyl]-2-yl)methyl]piperazin-1-yl}-N-(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrobenzene-1-sulfonyl)benzamide
Identifiers
CAS Number	852808-04-9
3D model (JSmol)	Interactive image
ChEBI	CHEBI:47575
ChemSpider	9403232
PubChemCID	11228183
UNII	Z5NFR173NV
CompTox Dashboard (EPA)	DTXSID7042641
show InChI
show SMILES
Properties
Chemical formula	C₄₂H₄₅ClN₆O₅S₂
Molar mass	813.43 g·mol⁻¹
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

References

^ 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.
^ 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.
^ Vogler, Meike, et al. “Bcl-2 inhibitors: small molecules with a big impact on cancer therapy.” Cell Death & Differentiation 16.3 (2008): 360–367.
^ 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.
^ 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.
^ 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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