Frespaciguat

Frespaciguat

CAS 2101645-33-2

MF C27H22ClF5N6O3 MW 608.9 g/mol

3-[4-[(5S)-4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)indazol-3-yl]-5-methyl-6-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]propanoic acid

3-{4-[(5S)-4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic acid
guanylate cyclase activator, MK5475, MK 5475, sGC activator 1, 6DXN080KGB

Frespaciguat (development code MK-5475) is an experimental inhaled soluble guanylate cyclase stimulator developed by Merck for pulmonary arterial hypertension.^[1][2][3][4]

Frespaciguat is a small molecule drug. The usage of the INN stem ‘-ciguat’ in the name indicates that Frespaciguat is a guanylate cyclase activator and stimulator. Frespaciguat is under investigation in clinical trial NCT05612035 (Frespaciguat (MK-5475) INSIGNIA-PH-COPD: A Study of the Efficacy and Safety of Frespaciguat (an Inhaled sGC Stimulator) in Adults With PH-COPD). Frespaciguat has a monoisotopic molecular weight of 608.14 Da.

• Frespaciguat (MK-5475) in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD) (MK-5475-006)CTID: NCT04370873Phase: Phase 1Status: CompletedDate: 2025-05-28
• A Study of the Efficacy and Safety of Frespaciguat (MK-5475) in Participants With Pulmonary Arterial Hypertension (INSIGNIA-PAH: Phase 2/3 Study of an Inhaled sGC Stimulator in PAH) (MK-5475-007)CTID: NCT04732221Phase: Phase 2/Phase 3Status: CompletedDate: 2025-05-25
• Frespaciguat (MK-5475) in Participants With Hypoxemia Due to COVID-19 Pneumonia (MK-5475-009)CTID: NCT04425733Phase: Phase 1Status: WithdrawnDate: 2025-05-15
• Frespaciguat (MK-5475) INSIGNIA-PH-COPD: A Study of the Efficacy and Safety of Frespaciguat (an Inhaled sGC Stimulator) in Adults With PH-COPDCTID: NCT05612035Phase: Phase 2Status: Active, not recruitingDate: 2025-10-07
• A Study of Single Doses of Frespaciguat (MK-5475) on Pulmonary Vascular Resistance (MK-5475-002)CTID: NCT03744637Phase: Phase 1Status: CompletedDate: 2025-06-04

SYN

US10030027,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US199416000&_cid=P12-MKUJSJ-89968-1

Example 10B

(S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid

Step A—(S)-Methyl 3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoate

In a flask containing I-A1 (91 mg, 0.27 mmol), I-11B (80 mg, 0.24 mmol) and potassium bicarbonate (73.2 mg, 0.73 mmol) in t-BuOH (2.4 mL) was stirred at 80° C. for 16 h. The reaction was cooled to RT, diluted with EtOAc and water, and extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried over anhydr. Na 2SO 4, and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography with (EtOAc:EtOH 3:1):hexane (0-40%) to afford the title compound. m/z=623 (M+1).

Step B—(S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid

In a flask containing (S)-methyl 3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoate (120 mg, 0.19 mmol) in dioxane (8.7 mL) was added LiOH (46 mg, 1.93 mmol) in water (1 mL). The reaction was stirred 2 h at 50° C. The reaction was cooled to RT, concentrated in vacuo and diluted with EtOAc. Acetic acid (132 μl, 2.31 mmol) was added and the mixture was extracted with EtOAc (3×). The organic layers were combined, washed with brine (2×), dried over anhydr. MgSO 4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography with (EtOAc:EtOH 3:1):hexane (0-100%) to afford the title compound Ex-10B. 1H NMR (400 MHz, DMSO-d 6) δ 12.12 (s, 1H), 11.09 (s, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.03 (d, J=1.7 Hz, 1H), 7.26 (dd, J=8.7, 1.7 Hz, 1H), 7.22-7.11 (m, 4H), 6.54 (s, 2H), 4.82 (t, J=6.8 Hz, 2H), 2.90 (tt, J=19.4, 6.9 Hz, 2H), 2.77 (t, J=7.6 Hz, 2H), 2.52-2.49 (m, 2H), 1.76 (s, 3H); m/z=609 (M+1).

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2025006295&_cid=P12-MKUJNS-84717-1

EXAMPLE 2

[0038] To an autoclave was charged anisole (12.78 L), indazole ester (IV) (2.13 kg, 5.64 mol), and hexamethyldisilazane (4.55 kg, 28.2 mol). The mixture was cooled to 0-5 ^oC and the vessel was placed under slight positive pressure with no N₂ sweeping. A solution of H₂O (203.21 g, 11.27 mol) in sulfolane (6.39 L) was added while keeping at < 10 ^oC in order to minimize NH3 gas escaping. The resulting mixture was cooled to -10 ^oC, then TfOH (1.692 kg, 11.27 mol) was slowly added at < 22 ^oC. The vessel was sealed and the mixture was heated at 120-130 °C for 24 h. The upper vessel was kept warm so that solid ammonium triflate did not deposit there.

[0039] After cooling the mixture to rt, the batch (biphasic) was further cooled to 0-10 ^oC.2.4 equiv 1N KOH (13.53 L, 14.207 kg, 13.53 mol) was slowly added at < 25 ^oC. After agitating for 30 min, and letting settle at rt, the bottom aqueous layer was removed (pH~14). The organic layer was washed with 18% brine (10.5 L). The aqueous layer was removed (pH ~12). To the organic phase was added ¼ (101 mL, 149 g) of 1.1 equiv methanesulfonic acid (402 mL, 595 g, 6.20 mol), then seeded with 0.2 wt% amidine MSA type A (8.5 g). The rest of MSA (447 g, 302 mL) was then slowly added over 1 h. During MSA addition, the temperature was controlled at < 25 ^oC. The resulting slurry, after aging at 22 ^oC for 15 h, was filtered, then displacement washed with 2 x 3 vol 2-MeTHF (2 x 6.4 L), and vacuum dried under N₂ at < 30 °C for 24 h. The product (III) was obtained (4.62 kg, 10.58 mol, 93 % yield) as an off-white to light beige solid.

PAT

• 4-amino-2-(1h-pyrazolo[3,4-b]pyridin-3-yl)-6-oxo-6,7-dihydro-5h-pyrrolo[2,3-d]pyrimidine derivatives and the respective (1h-indazol-3-yl) derivatives as cgmp modulators for treating cardiovascular diseasesPublication Number: EP-3394067-B1Priority Date: 2015-12-22Grant Date: 2020-04-01
• Soluble guanylate cyclase stimulatorPublication Number: TW-201734017-APriority Date: 2015-12-22
• 4-Amino-2- (1h-pyrazolo [3,4-b] pyridin-3-yl) -6-oxo-6,7-dihydro-5h-pyrrolo [2,3-d] pyrimidine derivatives and respectively (1h- indazol-3-yl) are derived as cgmp activators for the treatment of cardiovascular diseasePublication Number: IL-260020-APriority Date: 2015-12-22
• Soluble guanylate cyclase stimulatorsPublication Number: TW-I724079-BPriority Date: 2015-12-22Grant Date: 2021-04-11
• cGMP modulators for the treatment of cardiovascular diseasePublication Number: CN-108738320-BPriority Date: 2015-12-22Grant Date: 2021-11-19
• 4-Amino-2-(1H-pyrazolo[3,4-b]pyridin-3-yl)-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidine derivatives and their respective (1H-indazol-3-yl) derivativesPublication Number: CN-108738320-APriority Date: 2015-12-22
• 4-amino-2-(1H-pyrazolo[3,4-B]pyridin-3-yl)-6-oxo-6,7-dihydro-5H-pyrrolo[ as a cGMP modulator for the treatment of cardiovascular disease 2,3-D]pyridine derivatives and respective (1H-indazol-3-yl) derivativesPublication Number: KR-102191312-B1Priority Date: 2015-12-22Grant Date: 2020-12-15
• Soluble guanylate cyclase stimulatorsPublication Number: US-10030027-B2Priority Date: 2015-12-22Grant Date: 2018-07-24
• 4-Amino-2- (1H-pyrazolo [3,4-b] pyridin-3-yl) -6-oxo-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine derivatives and cardiovascular disease (1H-indazol-3-yl) derivatives as cGMP modulators for treatingPublication Number: JP-2018538333-APriority Date: 2015-12-22
• Soluble guanylate cyclase stimulatorsPublication Number: US-2018305366-A1Priority Date: 2015-12-22
• Processes for preparing crystalline soluble guanylate cyclase stimulatorsPublication Number: WO-2025006294-A2Priority Date: 2023-06-26
• Processes for preparing soluble guanylate cyclase stimulatorsPublication Number: WO-2025006295-A1Priority Date: 2023-06-26
• 4-Amino-2- (1H-pyrazolo [3,4-b] pyridin-3-yl) -6-oxo-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine derivatives and cardiovascular disease (1H-indazol-3-yl) derivatives as cGMP modulators for treatingPublication Number: JP-6454448-B2Priority Date: 2015-12-22Grant Date: 2019-01-16
• Soluble guanylate cyclase stimulatorsPublication Number: US-10428076-B2Priority Date: 2015-12-22Grant Date: 2019-10-01
• Soluble guanylate cyclase stimulatorsPublication Number: US-2017174693-A1Priority Date: 2015-12-22

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Legal status
Legal status	Investigational
Identifiers
IUPAC name
CAS Number	2101645-33-2
PubChem CID	129242560
ChemSpider	129394387
UNII	6DXN080KGB
ChEMBL	ChEMBL5944803
Chemical and physical data
Formula	C27H22ClF5N6O3
Molar mass	608.95 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

References

1.  Bajwa, Ednan K.; Cislak, Dawn; Palcza, John; Feng, Hwa-ping; Messina, Eric J.; Reynders, Tom; Denef, Jean-François; Corcea, Vasile; Lai, Eseng; Stoch, S. Aubrey (January 2023). “Effects of an inhaled soluble guanylate cyclase (sGC) stimulator MK-5475 in pulmonary arterial hypertension (PAH)”. Respiratory Medicine. 206 107065. doi:10.1016/j.rmed.2022.107065. PMID 36521262.
2.  Patel, Mahesh J.; Bajwa, Ednan K.; Cislak, Dawn; Palcza, John; Reynders, Tom; Barthson, Jenny; Lai, Eseng; Stoch, S. Aubrey (9 September 2023). “A randomized study to evaluate the effects of single-dose MK-5475 co-administered with sildenafil on systemic hemodynamics”. European Respiratory Journal PA1208. doi:10.1183/13993003.congress-2023.PA1208.
3.  El-Kersh, Karim; Jalil, Bilal A. (July 2023). “Pulmonary hypertension inhaled therapies: An updated review”. The American Journal of the Medical Sciences. 366 (1): 3–15. doi:10.1016/j.amjms.2023.03.002. PMID 36921672.
4.  Tawa, Masashi; Okamura, Tomio (August 2022). “Factors influencing the soluble guanylate cyclase heme redox state in blood vessels”. Vascular Pharmacology. 145 107023. doi:10.1016/j.vph.2022.107023. PMID 35718342.

/////////frespaciguat, ANAX, ADVECT, guanylate cyclase activator, MK5475, MK 5475, sGC activator 1, 6DXN080KGB