Verubecestat (MK-8931)

Merck Alzheimer’s drugs Verubecestat (MK-8931) is an oral β- amyloid precursor protein cleaving enzyme (BACE1 or β-secretase enzyme) inhibitor, is currently in Phase III clinical trials

Verubecestat
MK 8931, MK-8931, SCH 900931
2-Pyridinecarboxamide, N- (3 – ((5R) -3-amino-5,6-dihydro-2,5-dimethyl-1 , 1-dioxido-2H-1,2,4-thiadiazin-5-yl) -4-fluorophenyl) -5-fluoro-

N-[3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide

CAS : 1286770-55-5

C₁₇ H₁₇ F₂ N₅ O₃ S, 409.41
Mechanism: Oral β- amyloid precursor protein cleavage enzyme (BACE) inhibitors
Indications: Alzheimer’s disease
Development progress: phase III clinical
Companies: Merck

Verubecestat (MK-8931) is a small-molecule inhibitor of beta-secretase cleaving enzyme (BACE) 1 and BACE2 in development by Merck for the treatment of Alzheimer’s Disease.

MK-8931 is a beta-secretase 1 (BACE1) inhibitor in phase III development for the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer’s disease at Merck & Co. The company is also conducting phase II/III trials for the treatment of Alzheimer’s type dementia.

Smiles: C [C @] 1 (CS (= O) (= O) N (C (= N1) N) C) c2cc (ccc2F) NC (= O) c3ccc (cn3) F

COSY PREDICT

PATENT

https://www.google.co.in/patents/CN102639135A?cl=en

Scheme 3a:

https://www.google.co.in/patents/CN102639135A?cl=en

Scheme 3b:

The amine A (Scheme 3a, step 4) (13.7 g) in n-butanol (150 mL) was added a slurry solution of cyanogen bromide (5M, in MeCN). The resulting mixture was heated to reflux for 4 hours. The mixture was concentrated to 1/3 of original volume. To this mixture was added Et20 (200 mL). The resulting solid was removed by filtration, and the solid was washed with Et20 (2x). The solid was partitioned between EtOAc and saturated Na2CO3 (aq). The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 10.6 g

Scheme 10:

The nitro compound (Scheme 3b) (2. 50 g, 6. 0 mmol) of Et0H (150 mL) was degassed (To this solution was bubbled with nitrogen time 3 min). To this solution was added Pd / C (10% w / w, 50% water, 698 mg). The mixture was placed in a nitrogen atmosphere. Exhaust, and backfilled with H2 (3x). The obtained mixture at room temperature, followed by stirring under H2 balloon for 2 hours. Bubbling nitrogen gas, and the mixture was purged, filtered through Celite, and concentrated.Small plug filtered through a silica gel column, eluting with EtOAc, and the product was purified to give the aniline (2. 2g, 97%).

SEE

PATENT

http://www.google.co.in/patents/WO2011044181A1?cl=en

SNAPSHOT

SYNTHESIS CONSTUCTION

AND

ON RXN WITH WITH BuLi GIVES

THIS GIVES

THIS ON TREATMENT WITH BrCN

ON BOC2O TREATMENT GIVES

GIVES ON HYDGN

REACTION WITH

GIVES

FINAL COMPD Verubecestat

1H NMR PREDICT

13C NMR PREDICT

Updated…….WATCH OUT FOR MORE

https://www.google.co.in/patents/US8729071?cl=en

Steps 1-4:

These steps were performed using similar procedures to those described in steps 1-4 of Scheme 1a.

Step 5:

To a solution of the amine from step 4 (10.5 g, 36 mmol) in CH₂Cl₂ (200 mL) was added benzoylisothiocyanate (4.3 mL, 1.1 eq.). The resulting solution was stirred at RT for 2.5 days. Additional benzoylisothiocyanate (0.86 mL, 0.2 eq.) was added and the solution was stirred at RT for an additional 2 hours. The solution was then concentrated in vacuo.

A portion of this material (6.5 g, ˜14 mmol) was dissolved in MeOH (200 mL). To this solution was added Na₂CO_{3 (s)} (1.52 g, 14 mmol). The resultant mixture was stirred at RT for 45 min. After that time, a slight excess of HOAc was added to the solution. The mixture was then concentrated. The residue was partitioned between CH₂Cl₂ and ½ sat. NaHCO_{3 (aq.)}. The aqueous layer was extracted with CH₂Cl₂ (3×). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The thiourea (˜4.9 g) was carried onto the next reaction without further purification.

Step 6:

Example 15 was prepared using a method similar to that described in Scheme 1a step 6.

To a shiny of amine A (Scheme 3a step 4) (13.7 grams) in n-butanol (150 mL) was added a solution of cyanogen bromide (5M in MeCN). The resultant mixture was heated to reflux for 4 hours. The mixture was concentrated to ⅓ of the original volume. To the mixture was added Et₂O (200 mL). The resultant solid was removed via filtration and the solid was washed with Et₂O (2×). The solid was partitioned between EtOAc and sat. Na₂CO₃ (aq.). The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to afford 10.6 grams of Ex. 15. This material was converted to the t-butyl carbamate using a procedure similar to that described in Scheme 3.

Step 7:

A mixture of the bromide (3.00 g, 6.92 mmol), benzophenone imine (1.39 mL, 8.30 mmol), Pd₂(dba)₃ (0.634 g, 0.692 mmol), John-Phos (0.413 g, 1.38 mmol), sodium tert-butoxide (2.13 g, 22.1 mmol), and toluene (51 mL) was degassed (vacuum/N₂). The mixture was then stirred at 65° C. under nitrogen for 3 h. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of Celite and rinsed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The residue was then dissolved in methanol (76 mL) and the resulting solution was charged with hydroxyl amine hydrochloride (2.16 g, 31.1 mmol) and sodium acetate (2.55 g, 31.1 mmol). The reaction mixture was stirred at room temperature for 40 min. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (100 mL), water (100 mL), and brine (100 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0-100% ethyl acetate/heptane) to afford the amino pyridine (0.880 g, 34%).

To a flame-dried flask was added a pyridyl bromide (Table IIb, Entry 15, 1.5 g, 3.3 mmol), Pd₂(dba)₃ (305 mg, 0.3 mmol), (2-biphenyl)di-tert-butylphosphine (200 mg, 0.7 mmol), sodium tert-butoxide (1.02 g, 0.011 mmol), benzophenone imine (670 ul, 4 mmol), and toluene (21 mL). The mixture was evacuated under vacuum and back-filled with N₂ (3×). The mixture was stirred at 60° C. for 1 h. After filtration through celite, the filtrate was concentrated. The crude residue was dissolved in 36 mL of methanol, and hydroxyl amine hydrochloride (458 mg, 6.6 mmol) and sodium acetate (541 mg, 6.6 mmol) were added. The reaction was stirred for 35 min and then quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the combined organic portions were dried over magnesium sulfate and concentrated. The crude residue was purified by a flash silica column (50% ethyl acetate/hexane) to get an aminopyridine product (730 mg, 68%).

A solution of the nitro compound (Scheme 3b) (2.50 g, 6.0 mmol) in EtOH (150 mL) was degassed by bubbling N₂ through the solution for 3 min. To this solution was added Pd/C (10% w/w, 50% H₂O, 698 mg.). The mixture was placed under an atmosphere of N₂. The atmosphere was evacuated and back-filled with H₂ (3×). The resulting mixture was stirred at RT under a H₂ balloon for 2 h. The mixture was purged by bubbling N₂ through it, filtered through Celite and concentrated. The product was purified by filtering through a small plug of silica gel column eluting with EtOAc to afford the aniline (2.2 g, 97%).

ENTRY 25

MH+: 410.0, HPLC1.79 min, LCMSMETHOD D

Method D:

• Column: Agilent Zorbax SB-C18 (3.0×50 mm) 1.8 uM

Mobile phase: A: 0.05% Trifluoroacetic acid in water

• • B: 0.05% Trifluoroacetic acid in acetonitrile

Gradient: 90:10 (A:B) for 0.3 min, 90:10 to 5:95 (A:B) over 1.2 min, 5:95 (A:B) for 1.2 min.

Flow rate: 1.0 mL/min

UV detection: 254 and 220 nm

Mass spectrometer: Agilent 6140 quadrupole

update…………..

Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)–A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer’s Disease

Abstract

Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer’s disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.

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17. 17.

    The CAS name represents the 3-aminothiadiazine tautomer, and the structures depicted in the manuscript represent the 3-iminothiadiazinane tautomer.

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