EIDD-2173; also known as ATI-2173
Fosclevudine alafenamide
| Molecular Weight |
529.45 |
|---|---|
| Formula |
C22H29FN3O9P |
| CAS No. |
phase 2
Hepatitis B virus (HBV) is an infectious disease that targets the liver resulting in either an acute infection, with symptoms arising in 45 to 160 days, or a chronic infection, which 350 million people worldwide are affected by. Estimates indicate that 600,000 deaths occur each year as a result of consequences related to HBV infection. HBV possesses a 3.2- kb relaxed circular DNA (rcDNA) genome that is used to form covalently closed circular DNA (cccDNA) in a host cell. The cccDNA is then transcribed by RNA polymerase II, a host DNA-dependent RNA polymerase, to produce pregenomic RNA (pgRNA). The pgRNA is then used by the virally encoded reverse transcriptase to form rcDNA. The goals of current treatments for chronic HBV infections are to reduce HBV replication and reduce liver damage.
Current treatments for chronic HBV infections include pegylated alpha interferon and nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). NRTIs are converted to their corresponding 5 ‘-triphosphate, or diphosphate in the case of phosphonate containing NRTIs, and reduce viral replication by inhibiting the HBV encoded polymerase. Clevudine is an NRTI that is no longer being developed for the treatment of chronic HBV because of drug-related skeletal myopathy that was a result of mitochondrial dysfunction in patients.
Interestingly, clevudine triphosphate has been shown to be a competitive nonsubstrate inhibitor of the HBV encoded polymerase, and due to its long intracellular half-life, is able to suppress HBV replication for an extended period of time after drug withdrawal.
The discovery and synthesis of the (S,S) and (S,R) diastereomers of clevudine phosphoramidate has been previously reported. These studies were undertaken to address the myopathy concerns associated with clevudine. The phosphoramidate moiety was utilized to deliver clevudine, as its 5 ‘-monophosphate, to the liver reducing 1) systemic exposure to clevudine and 2) the possibility of skeletal myopathy. Both phosphoramidates showed anti-HBV activity similar to clevudine with the (S,S) diastereomer being slightly more potent.
SYN
See U.S. Patent No. 10,683,319.
PATENT
WO20 17223421
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022256490&_gid=202333
EXAMPLE 11 :
[0374] Preparation of intermediate ATI-2173 from Compound-10.
[0375] Experimental Procedure
[0376] (H-l) Crude Compound-10 in THF (see Example 10) was divided into three aliquots and stirred with 2% HC1 aq. solution at pH 5-6, 4-5, and 3-4; for 16 h at 20-25 °C; the aliquots were combined and stirred at 15-20 °C for 72 h, with no degradation of ATI-2173 observed over the second time period;
[0377] (H-2) the pH of the mixture was adjusted to 7 with 7% NaHCCh;
[0378] (H-3) phase separation was carried out using 2-MeTHF, the organic phase was washed with NA2SO4 aqueous soltion, then concentrated to 1-3 V, and MTBE (5 V) was added; this operation was repeated twice;
[0379] (H-5) ATI-2173 was precipitated gradually upon addition of seed crystal and addition of n-heptane (5 V);
[0380] (H-6) the product was filtered; and
[0381] (H-7) the wetcake was dried, resulting in ATI-2173 in 99.73a% purity and
84.4% yield.
[0382] EXAMPLE 12:
[0383] Crystallization of ATI-2173
[0384] Initial studies examined the use of single or mixed solvent systems to crystalize the amorphous product, ATI-2173. Several solvent conditions were screened, including single solvent and mixed solvent systems, in order to determine the potential for obtaining a crystalline material from the amorphous material. None of the solvents tested worked and all conditions produced an oil product. The results are shown below in Tables 8 and 9.
[0385] Table 8: Single Solvent Systems
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////////// EIDD-2173, ATI-2173, EIDD 2173, ATI 2173, Hepatitis B virus, ANTI HBV, Fosclevudine alafenamide, PHASE 2