Ervogastat
CAS 2186700-33-2
Non-alcoholic Steatohepatitis (NASH) with Liver Fibrosis (FAST TRACK – U.S.)
- 2-[5-[(3-Ethoxy-2-pyridinyl)oxy]-3-pyridinyl]-N-[(3S)-tetrahydro-3-furanyl]-5-pyrimidinecarboxamide
- (S)-2-(5-((3-Ethoxypyridin-2-yl]oxy]pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide
- PF 06865571
- BSOIY5AKQW
407.4 g/mol, C21H21N5O4
2-[5-(3-ethoxypyridin-2-yl)oxypyridin-3-yl]-N-[(3S)-oxolan-3-yl]pyrimidine-5-carboxamide
- OriginatorPfizer
- ClassAmides; Ethers; Furans; Hepatoprotectants; Pyridines; Pyrimidines; Small molecules
- Mechanism of ActionDiacylglycerol O-acyltransferase inhibitors
Phase IINon-alcoholic fatty liver disease; Non-alcoholic steatohepatitis
- 08 Jan 2025Chemical structure information added.
- 21 Feb 2024Pfizer completes a phase II trial in Non-alcoholic steatohepatitis (Combination therapy) in Slovakia, Japan, Bulgaria, Canada, China, Hong Kong, India, Poland, Puerto Rico, South Korea, Taiwan (PO) (NCT04321031) (EudraCT2019-004775-39)
- 21 Feb 2024Pfizer completes a phase II trial in Non-alcoholic steatohepatitis (Monotherapy) in Slovakia, Japan, Bulgaria, Canada, China, Hong Kong, India, Poland, Puerto Rico, South Korea, Taiwan (PO) (NCT04321031) (EudraCT2019-004775-39)
Ervogastat is an experimental small-molecule drug and selective diacylglycerol O-acyltransferase 2 inhibitor developed by Pfizer for non-alcoholic steatohepatitis.[1] Its development was previously halted by the company but resumed in 2022.[2]
Scheme
SIDE CHAIN
MAIN
https://doi.org/10.1021/acs.jmedchem.2c01200
SYN
WO2023026180
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023026180&_cid=P11-MB5XF4-40032-1
Preparation of Intermediates and Examples
Preparation of Intermediate 1 and Example 1 (Forms 1 and 2) were described in WO2018/033832 and are reproduced below.
Intermediate 1 : 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid
Step 1 : 3-Ethoxypyridine
Cesium carbonate (12 mol, 1.5 equiv) and ethyl iodide (9.7 mol, 1.2 equiv) were added to a solution of 3-hydroxypyrdine (8.10 mol, 1.0 equiv) in acetone (12 L) at 15 °C. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered and the organic layer was concentrated to give crude product. Ethyl acetate (20 L) was added and washed with water (3×5 L). The organic layer was dried over sodium sulfate, filtered and concentrated to give 3-ethoxypyridine (620 g, 62%) as an oil. 1H NMR (400 MHz, CDCh) 5 1.44 (t, 3H), 4.07 (q, 2H), 7.15-7.23 (m, 2H), 8.20 (dd, 1 H), 8.30 (d, 1 H).
Step 2: 3-Ethoxypyridine-1 -oxide
m-Chloroperoxybenzoic acid (6.5 mol, 1.3 equiv) was added to a solution of 3-ethoxypyridine (5.0 mol, 1.0 equiv) in dichloromethane (12 L) at 10 °C. The reaction mixture was stirred at room temperature for 24 hours. Sodium thiosulfate (4 kg, in 5 L of water) was added. The reaction mixture was stirred at 15 °C for 2 hours. Another portion of sodium thiosulfate (1.5 kg, in 5 L of water) was added. The reaction mixture was stirred at 15 °C for 1 hour. The mixture was extracted with dichloromethane (16×10 L). The combined organic layers were concentrated to give crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol; 100:1-10:1) to give the title compound (680 g, 97%) as brown oil. This was further purified by trituration with petroleum ether (4 L) at room temperature for 24 hours to give 3-ethoxypyridine-1 -oxide (580 g, 83%) as yellow solid. 1H NMR (400 MHz, CDCh) 5 1.41 (t, 3H), 4.02 (q, 2H), 6.84 (dd, 1 H), 7.12 (dd, 1 H), 7.85 (d, 1 H), 7.91-7.95 (m, 1 H).
Step 3: 2-((5-Bromopyridin-3-yl)oxy)-3-ethoxypyridine
This reaction was carried out in five parallel batches.
Diisopropylethylamine (2.69 mol, 3.7 equiv) and bromotripyrrolidinophosphonium hexafluorophosphate (0.93 mol, 1.3 equiv) were added to a stirred solution of 3-ethoxypyridine-1-oxide (0.72 mol, 1.0 equiv) and 3-bromo-5-hydroxypyridine (0.72 mol, 1.0 equiv) in tetrahydrofuran (2500 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 days then the separate batches were combined to a single batch. The resulting suspension was concentrated to dryness and dissolved in dichloromethane (25 L). The organic layer was washed with 1 N sodium hydroxide (15 L), water (3×20 L), and brine (20 L). The organic layer was dried over sodium sulfate, filtered and concentrated to give an oil. The crude oil was purified by silica gel column chromatography (petroleum ether : ethyl acetate; 10:1-1 :1) to give crude product as brown solid. This solid was triturated with methyl tert-butyl ether: petroleum ether (1 :10; 11 L) to afford 2-((5-bromopyridin-3-yl)oxy)-3-ethoxypyridine (730 g, 69%) as off yellow solid. 1H NMR (400 MHz, CDCh) 5 1.49 (t, 3H), 4.16 (q, 2H), 7.04 (dd, 1 H), 7.25 (dd, 1 H), 7.68-7.73 (m, 2H), 8.44 (d, 1 H), 8.49 (d, 1 H). MS (ES+) 297.1 (M+H).
Step 4: Ethyl 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylate
A solution of 2-((5-bromopyridin-3-yl)oxy)-3-ethoxypyridine (300 mmol, 1.0 equiv) in tetrahydrofuran (1.3 L) was degassed with nitrogen for 30 minutes. Turbo Grignard
(390 mmol, 1.3 equiv, 1.3 M in tetrahydrofuran) was added at room temperature at a rate to maintain the internal temperature below 30 °C. The reaction mixture was allowed to cool to room temperature and stirred for 3 hours. The reaction was cooled to 10 °C and zinc chloride (390 mmol, 1.3 equiv, 1.9 M in 2-methyltetrahydrofuran) was added at a rate to maintain the temperature below 15 °C. The resulting suspension was warmed to room temperature until all the precipitate was dissolved and then cooled back to 10 °C. Ethyl 2-chloropyrimidine-5-carboxylate (360 mmol, 1.2 equiv) and dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(ll) (6.00 mmol, 0.02 equiv) were added as solids. The resulting suspension was degassed with nitrogen for 30 minutes then heated to 50 °C for 16 hours. The reaction was worked up under aqueous conditions then treated sequentially with ethylenediaminetetraacetic acid disodium salt, thiosilica, and charcoal to remove metal impurities. The crude compound was recrystallized from methanol (450 mL) to yield ethyl 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylate (77 g, 70%) as a pale, yellow solid. 1H NMR (400 MHz, CDCI3) 5 1.44 (t, 3H), 1.50 (t, 3H), 4.19 (q, 2H), 4.46 (q, 2H), 7.00-7.04 (m, 1 H), 7.25 (s, 1 H), 7.71 (d, 1 H), 8.59 (s, 1 H), 8.66 (d, 1 H), 9.32 (s, 2H), 9.55 (s, 1 H).
Step 5: 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid
Sodium hydroxide (307 mmol, 1.5 equiv, 4M aqueous) and methanol (50 mL) were added to a suspension of 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylate (205 mmol, 1.0 equiv) in tetrahydrofuran (300 mL). The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (400 mL) and extracted with 2:1 diethyl ether: heptanes (2x 300 mL). The aqueous layer was acidified to pH of 4 with 4M hydrochloric acid. The resulting suspension was stirred at room temperature for 1 hour. The solid was filtered, washed with water, and dried to yield 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid (69 g, 100%) as a pale, yellow solid. 1H NMR (400 MHz, DMSO-de) 51.37 (t, 3H), 4.18 (q, 2H), 7.19 (dd, 1 H), 7.58 (dd, 1 H), 7.70 (dd, 1 H), 8.35-8.40 (m, 1 H), 8.66 (d, 1 H), 9.33 (s, 2H), 9.41 (d, 1 H), 13.9 (br. s, 1 H).
Example 1 : (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-/V-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide
Preparation of Form 1 of (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-/\/- (tetrahydrofuran-3-yl)pyrimidine-5-carboxamide
Oxalyl chloride (13.8 mL, 160 mmol, 1.2 equiv) and dimethylformamide (0.510 mL, 6.65 mmol, 0.05 equiv) were added to a suspension of 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid (45.0 g, 133 mmol, 1.0 equiv) in dichloromethane (500 mL). The suspension was stirred for 2 hours when a solution was achieved. The reaction mixture was concentrated to yield crude acid chloride as a red solid. A solution of (S)-tetrahydrofuran-3-amine (12.2 g, 140 mmol, 1.05 equiv) and diisopropylethylamine (51.0 mL, 293 mmol, 2.2 equiv) in tetrahydrofuran (100 mL) was added dropwise to a solution of the crude acid chloride in dichloromethane (200 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 16 hours. Water (1.0 L) and ethyl acetate (600 mL) were added and the organic layer was separated, washed with saturated sodium bicarbonate, dried over magnesium sulfate, and filtered. The filtrate was treated with activated charcoal (20 g) was stirred at 65 °C for 20 minutes. The suspension was filtered warm and filtrate was concentrated to a pale, yellow solid which was recrystallized from methanol in ethyl acetate (1 :4, 1 L) to yield (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-/\/-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide (43.5 g, 81%) as a colorless solid. The title compound was combined with previous batches (108.7 g, 266.8 mmol) prepared in the same manner and slurried with ethyl acetate (1 .0 L) at 80 °C for 4 hours. The suspension was allowed to cool to room temperature and stirred for 4 days. The solid was filtered, washed with ethyl acetate (3×200 mL) and dried under high vacuum at 50 °C for 24 hours to yield (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-/\/-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide (100.5 g, 92%) as a colorless solid. 1H NMR (300 MHz, DMSO-de) 5 1.38 (t, 3H), 1.89-1.98 (m, 1 H), 2.15-2.26 (m, 1 H), 3.65 (dd, 1 H), 3.70-3.78 (m, 1 H), 3.85-3.92 (m, 2H), 4.18 (q, 2H), 4.46-4.55 (m, 1 H), 7.18 (dd, 1 H), 7.58 (dd, 1 H), 7.69 (dd, 1 H), 8.37 (dd, 1 H), 8.64 (d, 1 H), 8.95 (d, 1 H), 9.28 (s, 2H), 9.39 (d, 1 H). MS (ES+) 408.4 (M+H). Melting point 177.5 °C. Elemental analysis for C21H21N5O4: calculated C, 61.91 ; H, 5.20; N, 17.19; found C, 61.86; H, 5.18; N, 17.30.
PATENT
WO2020234726
WO2020044266
WO2018033832
WO2021171164
WO2016036636 EG 1
References
- ^ Futatsugi, Kentaro; Cabral, Shawn; Kung, Daniel W.; Huard, Kim; Lee, Esther; Boehm, Markus; Bauman, Jonathan; Clark, Ronald W.; Coffey, Steven B.; Crowley, Collin; Dechert-Schmitt, Anne-Marie; Dowling, Matthew S.; Dullea, Robert; Gosset, James R.; Kalgutkar, Amit S.; Kou, Kou; Li, Qifang; Lian, Yajing; Loria, Paula M.; Londregan, Allyn T.; Niosi, Mark; Orozco, Christine; Pettersen, John C.; Pfefferkorn, Jeffrey A.; Polivkova, Jana; Ross, Trenton T.; Sharma, Raman; Stock, Ingrid A.; Tesz, Gregory; Wisniewska, Hanna; Goodwin, Bryan; Price, David A. (24 November 2022). “Discovery of Ervogastat (PF-06865571): A Potent and Selective Inhibitor of Diacylglycerol Acyltransferase 2 for the Treatment of Non-alcoholic Steatohepatitis”. Journal of Medicinal Chemistry. 65 (22): 15000–15013. doi:10.1021/acs.jmedchem.2c01200. PMID 36322383. S2CID 253257260.
- ^ “With the right partner, Pfizer gains fast-track tag for previously shelved NASH drug”. Retrieved 20 November 2023.
| Clinical data | |
|---|---|
| Other names | PF-06865571 |
| Legal status | |
| Legal status | Investigational |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 2186700-33-2 |
| PubChem CID | 134262752 |
| ChemSpider | 114929473 |
| UNII | BSOIY5AKQW |
| ChEMBL | ChEMBL4760665 |
| Chemical and physical data | |
| Formula | C21H21N5O4 |
| Molar mass | 407.430 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
////////////Ervogastat, PF 06865571, fast track, BSOIY5AKQW, PFIZER, PHASE 2,