Larubrilstat

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Larubrilstat

CAS 2765226-31-9

MF C21H25N5O2 MW379.5 g/mol

[2-[[(5R)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl]amino]pyrimidin-5-yl]-(8-oxa-2-azaspiro[4.5]decan-2-yl)methanone

(2-{[(5R)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl]amino}pyrimidin-5-yl)(8-oxa-2-azaspiro[4.5]decan-2-
yl)methanone
vascular non-inflammatory molecule-1 (VNN1) inhibitor, AG6K4Y29B4

Larubrilstat is the International Nonproprietary Name (INN) for an experimental, small-molecule vascular non-inflammatory molecule-1 (VNN1) inhibitor. VNN1, also commonly known as Vanin-1 or pantetheinase, is an enzyme involved in tissue response to oxidative stress and inflammation.

Current Status

Development Context: Larubrilstat is a designated compound linked to therapeutic exploration in inflammatory pathways. Research and patent filings, such as those cataloged by the IUPHAR/BPS Guide to PHARMACOLOGY, track its evaluation alongside similar Vanin-1 inhibitors

SYN

US20240083873,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US425298584&_cid=P20-MQHGA8-93141-1

COMP 2-1 IS PRODUCT

Example 2: Synthesis of Compound 2, Compound 2-1 and Compound 2-2

Step 1

To a solution of compound 2a (500 mg) in ethanol/water (v/v=4:1, 10 mL) mixed solvent was added successively sodium acetate (740 mg) and hydroxylamine hydrochloride (630 mg). The resulting reaction mixture was heated to 94° C. and stirred continuously for 2 hours. The reaction was completed. The reaction mixture was cooled, added with water (50 mL), and then extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product of compound 2b (500 mg).

Step 2

To a solution of compound 2b (320 mg) in acetic acid (6 mL) was added zinc powder (421 mg) in batches. The resulting reaction mixture was heated to 70° C. and stirred continuously for 2 hours. The reaction was completed. The mixture was cooled, filtered and concentrated. The reaction mixture was added with NaOH aqueous solution (10%) to adjust the pH to 9, and then extracted with ethyl acetate (20 mL×4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product of compound 2c (100 mg).

Step 3

Compound 2 (66 mg) was obtained from compound if (168 mg) and compound 2c (100 mg) according to the method of Example 1.

¹H NMR (400 MHz, MeOH-d ₄) δ 8.58 (s, 2H), 8.35 (d, J=4.69 Hz, 1H), 7.78-7.70 (m, 1H), 7.27-7.18 (m, 1H), 5.71 (t, J=7.15 Hz, 1H), 3.80-3.59 (m, 6H), 3.54 (d, J=20.77 Hz, 2H), 3.13 (ddd, J=16.55, 9.14, 3.68 Hz, 1H), 3.00 (td, J=16.84, 8.51 Hz, 1H), 2.67 (ddd, J=16.06, 8.24, 3.91 Hz, 1H), 2.14-1.99 (m, 1H), 1.93 (dd, J=16.94, 7.33 Hz, 2H), 1.72-1.51 (m, 4H).

LCMS (ESI), [M+H] ⁺=380.3

Two enantiomers 2-1 (retention time: 8.483 min) and 2-2 (retention time: 13.580 min) were obtained by chiral separation of compound 2.

The chromatographic conditions are as follows:chromatographic column: CHIRALPAK AD-H (5 μm, 4.6×250 mm)flow rate: 0.4 mL/minwavelength: 254 nmcolumn temperature: 35° C.mobile phase: A: n-hexane, B: isopropanol, A:B=1:4run time: 50 min
Preparation Method of Compound 2-1

Step 4: Preparation of Compound 2-1

Compound 2-1e (284 g, 1.375 mol), compound 2-1f (350 g, 1.25 mol) and K ₂CO ₃(862.5 g, 6.25 mol) were dissolved in isopropanol, and the reaction mixture was heated at reflux overnight. After the reaction was completed, the reaction mixture was cooled to room temperature. The reaction system was distilled under reduced pressure to remove the solvent, added with dichloromethane, stirred, and filtered. The filtrate was dissolved in 2 N HCl, and the pH of the aqueous phase was adjusted to 8 to 9 by adding 1 N NaOH. The mixture was extracted with dichloromethane, dried and concentrated to obtain compound 2-1.

¹H NMR (400 MHz, CD ₃OD) δ 8.58 (s, 2H), 8.37 (d, J=5.1 Hz, 1H), 7.77 (s, 1H), 7.26 (d, J=2.5 Hz, 1H), 5.72 (t, J=7.7 Hz, 1H), 4.53 (s, 2H), 3.80-3.58 (m, 7H), 3.54 (d, J=18.8 Hz, 2H), 3.15 (ddd, J=16.9, 9.2, 3.7 Hz, 1H), 3.02 (dt, J=16.8, 8.5 Hz, 1H), 2.68 (dq, J=12.8, 4.4 Hz, 1H), 2.14-2.02 (m, 1H), 1.93 (q, J=8.1 Hz, 2H), 1.67 (d, J=5.8 Hz, 2H), 1.59 (d, J=5.7 Hz, 2H).

The absolute stereochemical configuration of compound 2-1 was determined by comparative determination of the above preparation method of the chiral compounds.

PAT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=28F257EBC3EA6EE7D447E4442C7CC489.wapp2nA?docId=US458059800&_cid=P20-MQHG5H-85832-1