DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Potrasertib
Potrasertib
CAS 2226938-19-6
MFC28H30Cl2N8O MW 565.5 g/mol
6-(2,6-dichlorophenyl)-2-{3-methyl-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]anilino}-8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one
7-(2,6-dichlorophenyl)-12-[3-methyl-4-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]anilino]-2,5,7,11,13-pentazatricyclo[7.4.0.02,6]trideca-1(13),5,9,11-tetraen-8-one
serine/ threonine kinase inhibitor, antineoplastic, IMP 7068, WEE1-IN-10, orb2664172, 621K13UG4B, Phase 1, Solid tumours
- OriginatorIMPACT Therapeutics
- ClassAntineoplastics; Small molecules
- Mechanism of ActionWEE1 protein inhibitors
- Phase ISolid tumours
- 28 Mar 2024No recent reports of development identified for phase-I development in Solid-tumours(Late-stage disease, Monotherapy) in Taiwan (PO)
- 28 Mar 2024No recent reports of development identified for phase-I development in Solid-tumours(Late-stage disease, Monotherapy) in USA (PO)
- 20 Oct 2023Efficacy, adverse events, pharmacodynamics and pharmacokinetics data from the phase I WEE1 trial in Solid tumours presented at the 48th European Society for Medical Oncology Congress (ESMO-2023)
Potrasertib is an investigational drug that is a selective inhibitor of WEE1 kinase, a protein crucial for the cell cycle. It is being studied for the treatment of various advanced solid tumors, including small cell lung cancer, ovarian, and colorectal cancers. By blocking the WEE1 kinase, potrasertib causes cancer cells with DNA damage to undergo premature, error-prone mitosis, which leads to cell death.
How it works
- Potrasertib is a serine/threonine kinase inhibitor.
- It works by targeting WEE1 kinase, which regulates the cell’s response to DNA damage.
- By inhibiting WEE1, it prevents cancer cells from repairing DNA damage before dividing, forcing them into a state that leads to cell death.
- This mechanism is particularly effective in tumors with a defective p53 gene, as these tumors rely more heavily on the WEE1 checkpoint for survival.
Potential uses
- Combination therapy: It is being explored in combination with chemotherapy (like gemcitabine and cisplatin) or radiotherapy to enhance their effectiveness against cancer.
- Monotherapy: It is also being studied as a standalone treatment for certain cancers, including ovarian, colorectal, and non-small cell lung cancer, especially those with high replication stress or WEE1 dependency.
Current status
- Potrasertib is still an investigational drug and is not yet approved for widespread clinical use.
- It is undergoing clinical trials to evaluate its safety and effectiveness in treating advanced cancers.
Potrasertib is an investigational new drug that is being evaluated by IMPACT Therapeutics for the treatment of advanced solid tumors. It is oral inhibitor of WEE1 kinase, a key regulator of cell cycle checkpoints.[1][2]
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018090939&_cid=P21-MI6TEY-70275-1
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021073491&_cid=P21-MI6TF3-70349-1
Example 1
SIMILAR NOT SAME
[0117]6-(2,6-dichlorophenyl)-2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one
SIMILAR NOT SAME
[0128]6-(2,6-dichlorophenyl)-2-((4-((3S,5R)-3,5-dimethyl-4-(methyl-d3)piperazin-1-yl)-3-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one
[0130]a) Preparation of (2S,6R)-2,6-dimethyl-1-(methyl-d3)-4-(2-methyl-4-nitro)piperazine: Sodium hydride (385.03 mg, 9.63 mmol, 60% purity) was added to a solution of (3S,5R)-3,5-dimethyl-1-(2-methyl-4-nitro)piperazine (2 g, 8.02 mmol) in N,N-dimethylformamide (15 mL). The mixture was stirred at 0 °C for 25 hours, then trideuterated iodomethane (1.16 g, 8.02 mmol, 499.09 μL) was added, and the mixture was stirred at 0 °C for 2 hours. The reaction was quenched by adding an aqueous sodium bicarbonate solution (30 mL) at 0 °C, extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target crude product (1.5 g, yellow-green solid). LC-MS(ESI): m/z(M+1) + 267.1. 1 H NMR (400MHz, CDCl
3 ): δ8.04-8.01 (m, 2H), 6.96 (d, J = 12.0Hz, 1H), 3.10 (d, J = 12Hz, 2H), 2.65 (t , J=12Hz, 2H), 2.45-2.43 (m, 2H), 2.36 (s, 3H), 1.16-1.15 (d, J=4.0Hz, 6H).
[0131]b) Preparation of 4-((3S,5R)-3,5-dimethyl-4-(methyl-d3)piperazin-1-yl)-3-methylaniline: Under nitrogen protection, palladium on carbon (281.58 μmol, 10% purity) was added to a methanol (5 mL) solution of (2S,6R)-2,6-dimethyl-1-(methyl-d3)-4-(2-methyl-4-nitro)piperazine (1.5 g, 5.63 mmol). The resulting suspension was purified multiple times under vacuum with hydrogen. The mixture was stirred at 25 °C for 12 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the target crude product (1.3 g, black solid). LC-MS (ESI): m/z (M+1) + 237.1.
[0132]c) Preparation of 6-(2,6-dichlorophenyl)-2-((4-(((3S,5R)-3,5-dimethyl-4-(methyl-d3)piperazin-1-yl)-3-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one: 4-((3S,5R)-3,5-dimethyl-4-(methyl-d3)piperazin-1-yl)-3-methylaniline (459.32 mg, 1.94 mmol) and the prepared 6-(2,6-dichlorophenyl)-2- A mixture (700 mg, crude) of crude (methanesulfonyl)-8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one and 6-(2,6-dichlorophenyl)-2-(methanesulfonyl)-8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one was dissolved in acetonitrile (5 mL) and trifluoroacetic acid (20.14 mg, 0.177 mmol, 13.08 μL) was added. The mixture was stirred at 20–25 °C for 2 hours, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by reversed-phase HPLC to give the target compound (56.89 mg, 100.00 μmol, yellow solid, 5.66% yield). LC-MS (ESI): m/z (M+1) + 568.0.
1 H NMR (400MHz, CDCl 3 ): δ8.81 (s, 1H), 7.49 (d, J=3.8Hz, 3H), 7.41-7.34 (m, 3H), 7.02 (d, J=4.2Hz, 1H), 4.25-4.21 (m, 2H), 4.02 (t, J=8.0Hz, 2H), 2.95 (d, J=6.0Hz 2H), 2.62 (t, J=6.0Hz, 2H), 2.46-2.41 (m, 2H), 2.34 (s, 6H), 1.15 (d, J=6.4Hz, 6H).
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022188802&_cid=P21-MI6TVM-79837-1
PAT
- 8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-onesPublication Number: US-11345711-B2Priority Date: 2016-11-16Grant Date: 2022-05-31
- 8,9-dihydroimidazole[1,2-a]pyrimido[5,4-e]pyrimidine-5(6h)-ketone compoundPublication Number: EP-3543242-B1Priority Date: 2016-11-16Grant Date: 2024-01-03
- Compound 8,9-dihydroimidazole[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-ketonePublication Number: ES-2968252-T3Priority Date: 2016-11-16Grant Date: 2024-05-08
- 8,9-dihydroimidazole[1,2-a]pyrimido[5,4-e]pyrimidine-5(6h)-ketone compoundPublication Number: EP-3543242-A1Priority Date: 2016-11-16
- 8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-onesPublication Number: US-10703759-B2Priority Date: 2016-11-16Grant Date: 2020-07-07
- 8,9-DIHYDROIMIDAZO[1,2-a]PYRIMIDO[5,4-e]PYRIMIDIN-5(6H)-ONESPublication Number: US-2019308984-A1Priority Date: 2016-11-16
- 8,9-DIHYDROIMIDAZO[1,2-a]PYRIMIDO[5,4-e]PYRIMIDIN-5(6H)-ONESPublication Number: US-2020385394-A1Priority Date: 2016-11-16
- 8,9-Dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-onesPublication Number: CN-109906227-BPriority Date: 2016-11-16Grant Date: 2022-03-11
- Dihydroimidazo pyrimido pyrimidinone compoundPublication Number: WO-2021073491-A1Priority Date: 2019-10-16
- DihydroimidazopyrimidopyrimidinonesPublication Number: CN-114502559-APriority Date: 2019-10-16
- Dihydroimidazopyrimidopyrimidinone compoundsPublication Number: CN-114502559-BPriority Date: 2019-10-16Grant Date: 2024-02-02
- Dihydroimidazo pyrimido pyrimidinone compoundPublication Number: US-2024010655-A1Priority Date: 2019-10-16
- 8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6h)-onesPublication Number: CA-3043945-A1Priority Date: 2016-11-16
- Use of Wee1 kinase inhibitors in the treatment of cancerPublication Number: CN-118338905-APriority Date: 2021-11-26
- Use of wee1 kinase inhibitors in the treatment of cancerPublication Number: WO-2023093840-A1Priority Date: 2021-11-26
- Use of wee1 kinase inhibitors in the treatment of cancerPublication Number: WO-2022188802-A1Priority Date: 2021-03-10
- The use of Wee1 kinase inhibitors in the treatment of cancer diseasesPublication Number: CN-117202908-APriority Date: 2021-03-10
- Use of wee1 kinase inhibitors in the treatment of cancerPublication Number: US-2024091233-A1Priority Date: 2021-03-10
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……
| Clinical data | |
|---|---|
| Other names | IMP7068 |
| Identifiers | |
| IUPAC name | |
| CAS Number | 2226938-19-6 |
| PubChem CID | 139503236 |
| UNII | 621K13UG4B |
| Chemical and physical data | |
| Formula | C28H30Cl2N8O |
| Molar mass | 565.50 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
References
- “IMP 7068”. AdisInsight. Springer Nature Switzerland AG.
- Wang Z, Li W, Li F, Xiao R (January 2024). “An update of predictive biomarkers related to WEE1 inhibition in cancer therapy”. Journal of Cancer Research and Clinical Oncology. 150 (1): 13. doi:10.1007/s00432-023-05527-y. PMC 10794259. PMID 38231277.
///////potrasertib, antineoplastic, IMP 7068, WEE1-IN-10, orb2664172, 621K13UG4B, Phase 1, Solid tumours
Plosaracetam
Plosaracetam
CAS 1651179-19-9
MF C13H10ClF3N4O MW330.69 g/mol
(4R)-1-[(5-chloro-1H-1,2,4-triazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one
(4R)-1-[(5-chloro-1,2,4-triazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one
(4R)-1-[(5-Chloro-1H-1,2,4-triazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)-2-pyrrolidinone
(4R)-1-[(5-chloro-1H-1,2,4-triazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one
2-Pyrrolidinone, 1-[(5-chloro-1H-1,2,4-triazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)-, (4R)-
synaptic vesicle glycoprotein 2A (SV2A) positive modulator, ABBV-552, ABBV552, SDI-118, SDI118, ABBV 552, ABBV552, SDI 118, SDI118, W3LYF2KQ6F
Plosaracetam (INNTooltip International Nonproprietary Name; developmental code names ABBV-552, SDI-118) is a synaptic vesicle glycoprotein 2A (SV2A) ligand which is under development for the treatment of Alzheimer’s disease and other cognition disorders.[1][3][4][2] In contrast to earlier SV2A ligands like levetiracetam and brivaracetam, polsaracetam does not have anticonvulsant activity and instead shows pro-cognitive effects.[2] The drug is being developed by UCB Biopharma and AbbVie.[1][3] As of October 2024, it is in phase 2 clinical trials for Alzheimer’s disease and phase 1 trials for cognition disorders.[1][3]
Plosaracetam is a small molecule drug. The usage of the INN stem ‘-racetam’ in the name indicates that Plosaracetam is a piracetam type amide type nootrope agent. Plosaracetam is under investigation in clinical trial NCT05199142 (A Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of SDI-118 in Elderly Male and Female Study Participants With Cognitive Decline). Plosaracetam has a monoisotopic molecular weight of 330.05 Da.
PAT
- Compounds for Enhancing the Cognitive FunctionPublication Number: US-2016185761-A1Priority Date: 2013-08-02
- Compounds for enhancing the cognitive functionPublication Number: US-9630948-B2Priority Date: 2013-08-02Grant Date: 2017-04-25
- Compounds for enhancing the cognitive functionPublication Number: WO-2015014785-A1Priority Date: 2013-08-02
- Connections to improve cognitive functionPublication Number: DK-3027606-T3Priority Date: 2013-08-02Grant Date: 2018-04-30
- Compounds for enhancing the cognitive functionPublication Number: EP-3027606-A1Priority Date: 2013-08-02
- Compounds for enhancing the cognitive functionPublication Number: EP-3027606-B1Priority Date: 2013-08-02Grant Date: 2018-02-28
- Compounds to enhance cognitive functionPublication Number: ES-2666134-T3Priority Date: 2013-08-02Grant Date: 2018-05-03
- Compounds for enhancing the cognitive functionPublication Number: SI-3027606-T1Priority Date: 2013-08-02
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015014785&_cid=P11-MI5R7J-79014-1
Example 1 : Synthesis of (4R)-1 -[(5-chloro-1H-1,2,4-triazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one 7.
1.1 Synthesis of tert-butyl 2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidine-1 -carboxylate 3 and enantiomers.
To a solution of tert-butyl 2-oxo-2,5-dihydro-1 H-pyrrole-1-carboxylate 1 (10 g, 1 eq., 54.6 mmol) in dioxane/water (100 ml/30 ml) are added at room temperature (3,4,5-trifluorophenyl)boronic acid 2 (19.2 g, 2 eq., 109.2 mmol), cesium fluoride (24.9 g, 3 eq., 163.8 mmol), (±)-2,2′-bis(diphenyl-phosphino)-1 , 1′-binaphthyl (1.5 g, 4.5%, 2.5 mmol), potassium carbonate (22.6 g, 3 eq., 163.8 mmol) and chloro(1 ,5-cyclooctadiene)rhodium(l)dimer (0.82 g, 1.5%, 8.2 mmol). The mixture is heated at 1 10°C for 2 h. Solvent are removed under reduced pressure and the residue is purified by chromatography over silicagel (eluent: CI-^C^/MeOH/NI-^OH 96/3.5/0.5 v/v/v) to afford tert-butyl 2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidine-1-carboxylate 3. The enantiomers are
resolved by chiral chromatography (chiralpak IC, 150*4.6 mm, eluent: heptane/AcOEt/diethylamine 80/20/0.1 v/v/v) to afford tert-butyl (4R)-2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidine-1-carboxylate 3A (second eluted, 5.1 g), and its enantiomer tert-butyl (4S)-2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidine-1-carboxylate 3B (first eluted, 5.2 g) as white solids.
Compound 3A:
Yield: 30%.
LC-MS (MH+): 316.
alphaD (MeOH, 25°C): -19.9.
1.2 Synthesis of (4R)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one 4.
At 0°C, TFA (20 ml, 261 mmol) is added to a solution of tert-butyl (4R)-2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidine-1-carboxylate 3A (8 g, 1 eq., 25.4 mmol) in dichloromethane (100 ml). The mixture is stirred at room temperature for 2 h. Then, TFA and solvent are removed under reduced pressure. The crude mixture is poured in an aqueous saturated solution of NaHCC>3 (100 ml) and extracted with AcOEt (3*200 ml). The combined organic extracts are dried over MgS04 and concentrated under reduced pressure. The conversion is total and the evaporation affords 5.5 g of (4R)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one 4, which is used in the next step without any further purification.
LC-MS (MH+): 216; LC-MS (MKT): 214.
alphaD (MeOH, 22°C): -20.1.
1.3 Synthesis of (4R)-1 -(hydroxymethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one 5.
To a solution of (4R)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one 4 (5.5 g, 1 eq., 25.6 mmol) in THF (20 ml) are added potassium tert-butoxide (0.049 g, 0.02 eq., 0.44 mmol) and paraformaldehyde (0.95 g, 1.2 eq., 31.1 mmol) at room temperature. After overnight stirring at 60°C, the mixture is quenched with brine (100 ml) and the aqueous phase is extracted with AcOEt (2*100 ml). The combined organic extracts are dried over MgS04 and concentrated under reduced pressure yielding 4.7 g of (4R)-1-(hydroxymethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one 5, which is used in the next step without any further purification.
LC-MS (MH+): 246.
H NMR (DMSO) δ 7.34 (dd, J-| =9.2 Hz, J2=6.8 Hz, 2 H), 5.87 (t, J=6.8 Hz, 1 H), 4.70 (m, 2 H), 3.78 (m, 1 H), 3.62 (m, 1 H), 3.40 (m, 1 H), 2.68 (m, 1 H), 2.43 (dd, J<l =16.6 Hz, J2=8.6 Hz, 1 H).
1.4 Synthesis of (4R)-1 -[(5-chloro-1 H-1 ,2,4-triazol-1-yl)methyl]-4-(3,4,5-trifluoro- phenyl)pyrrolidin-2-one 7.
1 ) To a cold solution (0°C) of (4R)-1-(hydroxymethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one 5 (4.7 g, 1 eq., 19.4 mmol) in CH2CI2 (200 mL) is added oxalyl chloride (3.7 ml, 2 eq., 38 mmol). After stirring for 30 minutes at 0°C, the reaction mixture is evaporated in vacuum yielding (4R)-1-(chloromethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one 6 which is dissolved in THF (100 ml) to afford Solution A.
2) To a cold solution (0°C) of 5-chloro-1 H-1 ,2,4-triazole (3.0 g, 1.5 eq., 29.1 mmol) in THF (100 ml) is added NaH 95% in mineral oil (0.9 g, 2 eq., 38.7 mmol). The reaction mixture is stirred during 30 minutes at 0°C to afford Solution B.
3) Solution A is added to solution B at 0°C and the reaction mixture is maintained under stirring overnight at room temperature. The mixture is quenched with water (100 ml) and extracted with AcOEt (2*100 mL). The combined organic extracts are washed with brine (100 ml), dried over MgS04 then concentrated under reduced pressure yielding 7 g of compound 7 as crude material. The crude residue is purified by chromatography on silicagel (eluent: CH2Cl2/MeOH/NH4OH 95/5/0.5 v/v/v) and recrystallized from iPr20/EtOH affording 1.6 g of (4R)-1-[(5-chloro-1 H-1 ,2,4-triazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one 7 as a white solid.
Yield: 25%.
LC-MS (MH+): 331/333.
H NMR (DMSO) δ 8.12 (s, 1 H), 7.32 (dd, J-| =9.2 Hz, J2=6.9 Hz, 2 H), 5.63 (d, J=1.5 Hz, 2 H), 3.81 (t, J=8.6 Hz, 1 H), 3.62 (t, J=8.4 Hz, 1 H), 3.39 (m, 1 H), 2.71 (dd, J<l =16.7 Hz, J2=8.8 Hz, 1 H), 2.54 (d, J=9.1 Hz, 1 H).
alphaD (MeOH, 25°C): + 9.2.
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……
| Clinical data | |
|---|---|
| Other names | ABBV-552; ABBV552; SDI-118; SDI118 |
| Routes of administration | Oral[1] |
| Drug class | Synaptic vesicle glycoprotein 2A (SV2A) ligand[2] |
| Identifiers | |
| IUPAC name | |
| CAS Number | 1651179-19-9 |
| PubChem CID | 90467376 |
| ChemSpider | 129532952 |
| UNII | W3LYF2KQ6F |
| KEGG | D13077 |
| ChEMBL | ChEMBL5314929 |
| Chemical and physical data | |
| Formula | C13H10ClF3N4O |
| Molar mass | 330.70 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
References
- “ABBV 552”. AdisInsight. 28 October 2024. Retrieved 26 February 2025.
- Botermans W, Koole M, Van Laere K, Savidge JR, Kemp JA, Sunaert S, et al. (2022). “SDI-118, a novel procognitive SV2A modulator: First-in-human randomized controlled trial including PET/fMRI assessment of target engagement”. Frontiers in Pharmacology. 13 1066447. doi:10.3389/fphar.2022.1066447. PMC 9887116. PMID 36733374.
- “Delving into the Latest Updates on Plosaracetam with Synapse”. Synapse. 22 February 2025. Retrieved 26 February 2025.
- “ABBV-552”. ALZFORUM. 28 February 2023. Retrieved 26 February 2025.
/////////Plosaracetam, ABBV-552, ABBV552, SDI-118, SDI118, ABBV 552, ABBV552, SDI 118, SDI118, W3LYF2KQ6F
Pilavapadin
Pilavapadin
CAS1815613-42-3
MFC19H23F4N3O MW 385.4 g/mol
(2S)-1-{[2′,6-bis(difluoromethyl)[2,4′-bipyridin]-5-yl]oxy}-2,4-dimethylpentan-2-amine
(2S)-1-[[2-(difluoromethyl)-6-[2-(difluoromethyl)-4-pyridinyl]-3-pyridinyl]oxy]-2,4-dimethylpentan-2-amine
adaptor protein 2-associated kinase 1 (AAK1) inhibitor, LX9211, BMS-986176, LX 9211, BMS 986176, Phase 2, Neuropathic pain, Postherpetic neuralgia, AAK1-IN-1, 9G4RLM5X6Z
Pilavapadin (also known as LX9211 or BMS-986176) is an investigational, orally available small molecule developed by Lexicon Pharmaceuticals for the treatment of neuropathic pain, primarily diabetic peripheral neuropathic pain (DPNP).
Key Information
- Mechanism of Action: Pilavapadin is a selective inhibitor of AAK1 (AP2 associated kinase 1), a novel target identified through Lexicon’s gene science research. It is designed to inhibit the reuptake and recycling of neurotransmitters involved in pain signaling in the central nervous system without affecting opiate pathways.
- Indication: It is being investigated for the management of chronic and debilitating conditions such as diabetic peripheral neuropathic pain (DPNP), chemotherapy-induced peripheral neuropathy (CIPN), and multiple sclerosis (MS) pain.
- Development Stage: Pilavapadin has completed Phase 2 clinical trials for DPNP and is expected to advance to a Phase 3 trial.
- Status/Designation: The U.S. Food and Drug Administration (FDA) has granted Fast Track designation for the development of pilavapadin in DPNP.
Clinical Trial Results
Phase 2 studies (RELIEF-DPN-1 and PROGRESS) demonstrated that pilavapadin can provide meaningful pain reduction in adults with DPNP.
- In a post-hoc analysis of the PROGRESS study, the 10 mg dose was found to be effective, achieving a clinically meaningful, two-point reduction in average daily pain scores from baseline, with an acceptable safety and tolerability profile.
- The data has been presented at several medical meetings, including the European Association for the Study of Diabetes (EASD).
- OriginatorBristol-Myers Squibb; Lexicon Pharmaceuticals
- DeveloperLexicon Pharmaceuticals
- ClassAnalgesics; Small molecules
- Mechanism of ActionAdaptor-associated kinase 1 inhibitors
- Phase IINeuropathic pain; Postherpetic neuralgia
- 20 Jun 2025Updated efficacy data from the phase II PROGRESS trial in Neuropathic pain presented at 85th Annual Scientific Sessions of the American Diabetes Association (ADA-2025)
- 13 May 2025Lexicon Pharmaceuticals plans an End of Phase 2 meeting with FDA for Pilavapadin
- 13 May 2025Updated efficacy data from the phase II PROGRESS trial in Neuropathic pain released by Lexicon Pharmaceuticals
- A Dose-ranging Study in Patients With Diabetic Peripheral Neuropathic Pain (DPNP)CTID: NCT06203002Phase: Phase 2Status: CompletedDate: 2025-08-29
- Efficacy, Safety, and PK of LX9211 in Participants With Diabetic Peripheral Neuropathic PainCTID: NCT04455633Phase: Phase 2Status: CompletedDate: 2025-06-25
- Efficacy and Safety of LX9211 in Participants With Postherpetic NeuralgiaCTID: NCT04662281Phase: Phase 2Status: CompletedDate: 2023-11-18
Molecular FormulaC19H23F4N3O.H3O4P
Molecular Weight483.4
CAS 2977251-24-2
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=US215884039&_cid=P11-MI4ESM-19570-1
Example 123
(S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine
Part A: (2-(difluoromethyl)pyridin-4-yl)boronic acid
Part B: (S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine
SYN
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021216441&_cid=P11-MI4EP8-16561-2
REF
- Discovery and Optimization of Biaryl Alkyl Ethers as a Novel Class of Highly Selective, CNS-Penetrable, and Orally Active Adaptor Protein-2-Associated Kinase 1 (AAK1) Inhibitors for the Potential Treatment of Neuropathic PainPublication Name: Journal of Medicinal ChemistryPublication Date: 2022-03-09PMID: 35261239DOI: 10.1021/acs.jmedchem.1c02132
- Discovery of (S)-1-((2′,6-Bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211): A Highly Selective, CNS Penetrable, and Orally Active Adaptor Protein-2 Associated Kinase 1 Inhibitor in Clinical Trials for the Treatment of Neuropathic PainPublication Name: Journal of Medicinal ChemistryPublication Date: 2022-03-08PMID: 35257579DOI: 10.1021/acs.jmedchem.1c02131
- Discovery, Structure–Activity Relationships, and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic PainPublication Name: Journal of Medicinal ChemistryPublication Date: 2021-07-16PMID: 34270254DOI: 10.1021/acs.jmedchem.1c00472
PAT
- Biaryl kinase inhibitorsPublication Number: US-2021277001-A1Priority Date: 2014-04-02
- Biaryl kinase inhibitorsPublication Number: KR-102379518-B1Priority Date: 2014-04-02Grant Date: 2022-03-25
- Biaryl kinase inhibitorsPublication Number: US-12065437-B2Priority Date: 2014-04-02Grant Date: 2024-08-20
- Biaryl kinase inhibitorsPublication Number: US-2024360131-A1Priority Date: 2014-04-02
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////////////Pilavapadin, LX9211, BMS-986176, LX 9211, BMS 986176, Phase 2, Neuropathic pain, Postherpetic neuralgia, AAK1-IN-1, 9G4RLM5X6Z
Paluratide
Paluratide
CAS 2676177-63-0
MFC73H105F5N12O12 MW 1437.7 g/mol
1,11-anhydro[N-methyl-L-alanyl-(2S)-azetidine-2-carbonyl-N-ethyl-4-methyl-L-phenylalanyl-N-methylglycyl-3-{[3,5-difluoro-4-(trifluoromethyl)phenyl]methyl}-L-alanyl-L-prolyl-2-
aminocyclopentane-1-carbonyl-(2S)-N-methyl-3-cyclopentylglycyl-1-
(dimethylamino)-N-methyl-L-aspart-4-yl-N-methyl-L-leucyl-Lisoleucine]
(3S,9S,12S,17S,20S,23S,27S,30S,36S)-20-[(2S)-butan-2-yl]-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-N,N,7,17,18,24,28,31-octamethyl-9-[(4-methylphenyl)methyl]-23-(2-methylpropyl)-2,5,8,11,16,19,22,25,29,32,35-undecaoxospiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.012,15]nonatriacontane-33,1′-cyclopentane]-27-carboxamide
G-protein Ras (rat sarcoma virus) inhibitor, antineoplastic, LUNA 18, CHUGAI, AW3YP3CD9X
Paluratide (development code LUNA18) was an investigational cyclic peptide KRAS inhibitor developed by Chugai Pharmaceutical, a member of the Roche Group, for the treatment of cancers with KRAS mutations.[1] The compound was notable as an orally bioavailable macrocyclic peptide that could target intracellular protein-protein interactions, a class of targets traditionally considered “undruggable.”[2]
Development was discontinued in July 2025 due to a narrow therapeutic window compared to competing KRAS inhibitors.[3]
Ras Inhibitor LUNA18 is an orally bioavailable cyclic peptide and Ras inhibitor, with potential antineoplastic activity. Upon oral administration, Ras inhibitor LUNA18 selectively targets, binds to and inhibits Ras, thereby inhibiting Ras-dependent signaling and inhibits proliferation of tumor cells in which Ras is overexpressed and/or mutated. Ras serves an important role in cell signaling, division and differentiation. Mutations of Ras may induce constitutive signal transduction leading to tumor cell growth, proliferation, invasion, and metastasis.
Paluratide (LUNA18 is synthesized using a novel liquid-phase peptide synthesis (LPPS) method, not traditional solid-phase methods, to overcome challenges with N-alkylated cyclic peptides. This process involves a convergent route of 24 telescoped chemical transformations, a final crystallization step, and a focus on specific strategies to manage side reactions like diketopiperazine formation and low reactivity of sterically hindered amino acids.
Key aspects of the synthesis
- Liquid-phase synthesis: A novel, high-yielding LPPS process was developed to enable the large-scale production of paluratide. This is a departure from traditional solid-phase methods, which have limitations with solubility and waste.
- Convergent synthetic route: The synthesis uses a convergent approach, meaning smaller fragments of the peptide are synthesized separately and then joined together. The overall process includes 24 telescoped chemical transformations followed by a final crystallization step.
- Addressing synthesis challenges: Specific strategies were employed to overcome key difficulties:
- Low reactivity: Amino acids with N-alkylation are sterically hindered, so more reactive and stable protecting groups were used to ensure efficient coupling.
- Side reactions: The method was designed to prevent side reactions like diketopiperazine formation in intermediates and incomplete hydrolysis of active esters.
- Instability: The peptide backbone is sensitive to acidic conditions, so a mildly acidic aqueous medium was chosen for workup and purification to maintain stability.
- Protecting group selection: Cbz-protected amino acid active esters were preferred over Boc-protected ones because they are less prone to forming N-carboxyanhydrides (NCA) under activating conditions, which can reduce yield and purity.
- Purification: A final crystallization step is used for purification.
PAT
- Method for producing eutectic of cyclic peptidePublication Number: WO-2024195801-A1Priority Date: 2023-03-20
- Method for producing cyclic peptide crystalsPublication Number: WO-2024085235-A1Priority Date: 2022-10-20
- Composition containing peptide, surfactant, and polymerPublication Number: WO-2024080308-A1Priority Date: 2022-10-12
- Methods for producing cyclic compounds comprising n-substituted amino acid residuesPublication Number: EP-4086272-A1Priority Date: 2021-05-07
- Methods for producing cyclic compounds comprising n-substituted amino acid residuesPublication Number: US-2022411462-A1Priority Date: 2021-05-07
SYN
https://pubs.acs.org/doi/10.1021/acs.oprd.5c00260?ref=PDF
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US383248369&_cid=P20-MI3YXS-80609-1
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Mechanism of action
Paluratide functions as a pan-RAS inhibitor, targeting multiple RAS isoforms including KRAS, NRAS, and HRAS.[1] The compound binds with high affinity to KRASG12D, with a dissociation constant (Kd) of 0.043 nM, and blocks the interaction between KRASG12D and the guanine nucleotide exchange factor SOS1 with an IC50 of less than 2.2 nM.[4]
Unlike covalent KRAS inhibitors that target specific mutations (such as sotorasib for KRASG12C), paluratide was designed to inhibit RAS proteins through disruption of protein-protein interactions with guanine nucleotide exchange factors (GEFs).[1] This mechanism allows the drug to affect RAS signalling regardless of the specific mutation, theoretically providing broader applicability across different KRAS-mutant cancers. The compound also demonstrates activity against downstream signalling pathways, affecting ERK and AKT phosphorylation.[4]
Medical uses
Paluratide was being developed for the treatment of locally advanced or metastatic solid tumors harbouring RAS gene alterations.[5] The drug demonstrated significant cellular activity against multiple cancer types with KRAS mutations in preclinical studies, including colorectal cancer, gastric cancer, non-small cell lung cancer, and pancreatic cancer.[1]
Chemistry
Paluratide is an 11-member (11-mer) cyclic peptide with a molecular weight in the range of 1000–2000 g/mol, classified as a “middle-size” cyclic peptide.[1] The compound features extensive N-alkylation, a modification that reduces hydrogen bond donors and improves oral absorption while maintaining cellular permeability.[2] Its structure allows it to navigate the challenging boundary between small molecules and biologics, achieving properties of both classes. The compound demonstrated oral bioavailability ranging from 21% to 47% in preclinical animal studies without requiring special formulations.[1]
Discovery
Paluratide was discovered through Chugai Pharmaceutical’s cyclic peptide platform using an mRNA display library screening approach.[1] The initial hit compound, designated AP8747, was identified from the mRNA display library and subsequently underwent extensive chemical optimization without scaffold hopping (maintaining the basic cyclic peptide structure).[1] The optimization focused on increasing plasma stability, improving absorption, reducing clearance, and reducing hydrogen bond donors to achieve oral bioavailability.
The final clinical compound, LUNA18, emerged after modifications to four amino acid positions (positions 5, 7, 10, and 11) from an intermediate compound (compound 40). Key structure-activity relationship findings included: the side chain at position 5 preferring aromatic over aliphatic groups; physicochemical properties being adjustable at position 11; and biological activity enhancement through modifications at positions 7 and 10.[1]
Chugai also developed a novel synthetic methodology that enabled the broadly applicable synthesis of highly N-alkylated cyclic peptide-like drugs.[6] This method overcame three major technical challenges: formation of diketopiperazine, insufficient reactivity of amidation due to steric hindrance, and instability of cyclic peptides under acidic conditions. Using this approach, more than 4,000 cyclic peptides were synthesized with a process yield of 31% and final product purity of 97%.[6]
Clinical trials
A Phase 1 dose-escalation and cohort expansion study (NCT05012618) was initiated in August 2021 to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of paluratide administered as a single agent or in combination with other anti-cancer drugs.[5] The study, in the United States and Japan, was designed to enrol approximately 195 patients with locally advanced or metastatic solid tumors positive for documented RAS alterations.[5]
Paluratide was administered orally as capsules.[5] The study also evaluated combination therapy with cetuximab, an EGFR inhibitor.[5]
References
- Tanada M, Tamiya M, Matsuo A, Chiyoda A, Takano K, Ito T, et al. (August 2023). “Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor”. Journal of the American Chemical Society. 145 (30): 16610–16620. Bibcode:2023JAChS.14516610T. doi:10.1021/jacs.3c03886. PMID 37463267.
- Ohta A, Tanada M, Shinohara S, Morita Y, Nakano K, Yamagishi Y, et al. (November 2023). “Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets”. Journal of the American Chemical Society. 145 (44): 24035–24051. Bibcode:2023JAChS.14524035O. doi:10.1021/jacs.3c07145. PMID 37874670.
- Taylor NP (24 October 2025). “Roche axes 4 Chugai solid tumor assets in early-phase clear-out”. Fierce Biotech.
- “LUNA18 (Paluratide) – KRAS Inhibitor, ERK Inhibitor, RAS Inhibitor”. MedChemExpress.
- “A Dose-escalation Study of LUNA18 in Patients With Locally Advanced or Metastatic Solid Tumors (With Expansion)”. ClinicalTrials.gov. 29 July 2025. NCT05012618.
- Nomura K, Hashimoto S, Takeyama R, Tamiya M, Kato T, Muraoka T, et al. (October 2022). “Broadly Applicable and Comprehensive Synthetic Method for N-Alkyl-Rich Drug-like Cyclic Peptides”. Journal of Medicinal Chemistry. 65 (19): 13401–13412. doi:10.1021/acs.jmedchem.2c01296. PMID 36109865.
- “Chugai Announces 2025 2nd Quarter Results” (Press release). Chugai Pharmaceutical. 24 July 2025.
External links
- Phase 1 Clinical Trial Information at ClinicalTrials.gov
- Development of LUNA18 at Journal of the American Chemical Society
| Clinical data | |
|---|---|
| Other names | LUNA18 |
| Routes of administration | Oral administration |
| Legal status | |
| Legal status | Development discontinued |
| Identifiers | |
| IUPAC name | |
| CAS Number | 2676177-63-0 |
| PubChem CID | 166509683 |
| ChemSpider | 129321315 |
| UNII | AW3YP3CD9X |
| Chemical and physical data | |
| Formula | C73H105F5N12O12 |
| Molar mass | 1437.707 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
//////Paluratide, antineoplastic, LUNA 18, CHUGAI, AW3YP3CD9X
Padoprazan
Padoprazan
CAS 2756367-23-2
MF C19H20FN3O4S MW 405.4 g/mol
1-[5-(2-fluorophenyl)-4-methoxy-1-(6-methoxypyridine-3-sulfonyl)-1Hpyrrol-3-yl]-N-methyl methanamine
1-[5-(2-fluorophenyl)-4-methoxy-1-[(6-methoxy-3-pyridinyl)sulfonyl]pyrrol-3-yl]-N-methylmethanamine
1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1 H -pyrrol-3-yl)- N -methylmethanamine
proton pump inhibitor, 95BJ28E2RP, ID-120040002, ID 120040002
Padoprazan is a new-generation potassium-competitive acid blocker (P-CAB) used to treat acid-related disorders like gastroesophageal reflux, according to MedchemExpress.com and Patsnap Synapse. It works by inhibiting the proton pump in the stomach and is different from traditional proton pump inhibitors (PPIs) because it is not dependent on acid activation. Padoprazan is currently undergoing Phase 3 clinical trials in Korea, notes THE BIO (더바이오).
Key facts about padoprazan
- Drug class: Potassium-competitive acid blocker (P-CAB), a type of proton pump inhibitor, according to DrugBank and GlpBio.
- Mechanism: It inhibits the proton pump in the stomach to reduce acid production and is not acid-activated like older PPIs, per DrugBank.
- Indications: Used for acid-related conditions like gastroesophageal reflux, reports Patsnap Synapse.
- Status: Currently undergoing Phase 3 clinical trials in Korea, says THE BIO (더바이오).
- Development: It is a new-generation drug being developed by companies like Daewon Pharmaceutical.
Padoprazan is a small molecule drug. The usage of the INN stem ‘-prazan’ in the name indicates that Padoprazan is a proton pump inhibitor, not dependent on acid activation. Padoprazan has a monoisotopic molecular weight of 405.12 Da.
PAT
- NEW INHIBITOR OF ACID SECRETION AND USE OF THE SAMEPublication Number: PE-20231652-A1Priority Date: 2020-06-17
- Novel acid secretion inhibitors and use thereofPublication Number: TW-I839161-BPriority Date: 2020-06-17Grant Date: 2024-04-11
- Novel acid secretion inhibitor and use thereofPublication Number: US-2023373954-A1Priority Date: 2020-06-17
- Novel acid secretion inhibitor and use thereofPublication Number: EP-4148050-B1Priority Date: 2020-06-17Grant Date: 2024-12-18
- Novel acid secretion inhibitors and use thereofPublication Number: TW-I797645-BPriority Date: 2020-06-17Grant Date: 2023-04-01
- Acid secretion inhibitor and use thereofPublication Number: US-11767311-B2Priority Date: 2020-06-17Grant Date: 2023-09-26
- Novel Acid Secretion Inhibitor and use thereofPublication Number: AU-2021293694-B2Priority Date: 2020-06-17Grant Date: 2023-12-21
- Novel acid secretion inhibitor and use thereofPublication Number: CN-115884968-BPriority Date: 2020-06-17Grant Date: 2024-06-21
- Novel acid secretion inhibitors and their usesPublication Number: JP-7404561-B2Priority Date: 2020-06-17Grant Date: 2023-12-25
- Novel acid secretion inhibitors and use thereofPublication Number: KR-102432523-B1Priority Date: 2020-06-17Grant Date: 2022-08-16
- Novel acid secretion inhibitor and use thereofPublication Number: CN-115884968-APriority Date: 2020-06-17
- Novel acid secretion inhibitor and use thereofPublication Number: JP-2023524172-APriority Date: 2020-06-17
- Novel acid secretion inhibitor and use thereofPublication Number: US-2023192650-A1Priority Date: 2020-06-17
- Novel acid secretion inhibitors and use thereofPublication Number: TW-202325702-APriority Date: 2020-06-17
- Novel acid secretion inhibitor and use thereofPublication Number: WO-2021256861-A1Priority Date: 2020-06-17
- Novel acid secretion inhibitors and use thereofPublication Number: TW-202214588-APriority Date: 2020-06-17
- Novel Acid Secretion Inhibitor and use thereofPublication Number: AU-2021293694-A1Priority Date: 2020-06-17
- Novel acid secretion inhibitor and use thereofPublication Number: CA-3182882-A1Priority Date: 2020-06-17
- Novel acid secretion inhibitor and use thereofPublication Number: EP-4148050-A1Priority Date: 2020-06-17
- Novel salt of 1-sulfonyl pyrrole derivative, preparation method thereof and pharmaceutical composition comprising thereofPublication Number: TW-I828476-BPriority Date: 2021-12-15Grant Date: 2024-01-01
- Novel salt of 1-sulfonyl pyrrole derivative, preparation method thereof and pharmaceutical composition comprising thereofPublication Number: WO-2023113458-A1Priority Date: 2021-12-15
- Novel salt of 1-sulfonyl pyrrole derivative, method for preparing same, and pharmaceutical composition including samePublication Number: WO-2023113474-A1Priority Date: 2021-12-15
- Novel salt of 1-sulfonyl pyrrole derivative, method for preparing same, and pharmaceutical composition including samePublication Number: US-2025042872-A1Priority Date: 2021-12-15
- Novel acid secretion inhibitors and use thereofPublication Number: KR-20210156234-APriority Date: 2020-06-17
- Novel salt of 1-sulfonylpyrrole derivative, preparation method thereof and pharmaceutical composition comprising the samePublication Number: CN-118541361-APriority Date: 2021-12-15
- Novel salt of 1-sulfonyl pyrrole derivative, preparation method thereof and pharmaceutical composition comprising thereofPublication Number: KR-20230091056-APriority Date: 2021-12-15
- Novel salts of 1-sulfonyl pyrrole derivatives, methods for producing the same, and pharmaceutical compositions containing the samePublication Number: KR-20240119083-APriority Date: 2021-12-15
- Novel salt of 1-sulfonyl pyrrole derivative, preparation method thereof and pharmaceutical composition comprising thereofPublication Number: TW-202334114-APriority Date: 2021-12-15
- Novel formulation comprising acid secretion inhibitorsPublication Number: KR-20240161598-APriority Date: 2023-05-04
- Method for preparation of 6-methoxypyridine-3-yl derivativesPublication Number: TW-202411216-APriority Date: 2022-05-23
- Method for preparing 6-methoxypyridin-3-yl derivativesPublication Number: WO-2023229322-A1Priority Date: 2022-05-23
- Method for preparation of 6-methoxypyridine-3-yl derivativesPublication Number: KR-20230163283-APriority Date: 2022-05-23
- NOVEL SALT OF A DERIVATIVE OF 1-SULFONYLPYRROL, METHOD OF PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION THAT INCLUDES THE SAMEPublication Number: AR-127964-A1Priority Date: 2021-12-15
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021256861&_cid=P22-MI13VU-05837-1
Synthesis Example 1. Synthesis of Example 1
[267]
[Example 1] 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1 H -pyrrol-3-yl)- N -methylmethanamine
[268]
(1) Synthesis of step methyl 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1 H -pyrrole-3-carboxylate
[269]Methyl 5-(2-fluorophenyl)-4-methoxy-1
H -pyrrole-3-carboxylate (intermediate 1, 1.0 eq., 1.2 g, 4.8 mmol) was dissolved in THF (20.0 mL), and NaH (2.0 eq., 384.8 mg, 9.6 mmol) was added dropwise at 0 °C and stirred at room temperature for 10 min. 6-Methoxypyridine-3-sulfonyl chloride (1.5 eq., 1.6 g, 7.2 mmol) was added and stirred at room temperature for 1 h. Water was added to the reaction solution, and the mixture was extracted with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain methyl 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1
H -pyrrole-3-carboxylate as a light brown solid. (1.85 g, 91.6%)
[270]
(2) Synthesis of step 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1 H -pyrrol-3-yl)methanol
[271]Methyl 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1
H -pyrrole-3-carboxylate (1.0 eq., 1.0 g, 2.38 mmol) was dissolved in THF (5.0 mL), and 1.0 M DIBAL in
n -hexane solution (5.0 eq., 11.9 mL, 11.9 mmol) was added dropwise at 0 °C, followed by stirring at room temperature for 1 h. The reaction solution was cooled to 0 °C, quenched with an aqueous Rochelle salt solution, and extracted with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1
H -pyrrol-3-yl)methanol as a yellow oil. (654.8 mg, 70.2%)
[272]
(3) Synthesis of step 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1 H -pyrrole-3-carbaldehyde
[273]5-(2-Fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1
H -pyrrol-3-yl)methanol (1.0 eq., 500.0 mg, 1.3 mmol) and Dess-Martin periodinane (1.0 eq., 540.4 mg, 1.3 mmol) were dissolved in DCM (10.0 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated and purified by column chromatography to give 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1
H -pyrrole-3-carbaldehyde as a pale brown solid. (388.2 mg, 78.1%)
[274]
(4) Step 1 Synthesis of (5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1 H -pyrrol-3-yl)- N -methylmethanamine
[275]5-(2-Fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1
H -pyrrole-3-carbaldehyde (1.0 eq., 385.0 mg, 0.99 mmol) was dissolved in THF (5.0 mL), and 2.0 M methylamine in THF (10 eq., 4.9 mL, 9.9 mmol) was added. After stirring at room temperature for 1 h, the reaction mixture was cooled to 0 °C, and NaBH
4 (10 eq., 373.4 mg, 9.9 mmol) was added, followed by stirring at room temperature for 1 h. 6.0
N aqueous hydrogen chloride solution was slowly added dropwise to the reaction solution, and the resulting solid was filtered. The filtered solid was dissolved in water, 1
N aqueous sodium hydroxide solution was added, and extraction was performed with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1 H -pyrrol-3-yl)-
N -methylmethanamine as a white solid. (125.8 mg, 28.3%) [M+H] + : 405
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023113474&_cid=P22-MI1405-08231-1
7) Preparation of 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine free base[211]
(1) Step: Synthesis of methyl 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1 H -pyrrole-3-carboxylate[212]Methyl 5-(2-fluorophenyl)-4-methoxy-1
H -pyrrole-3-carboxylate (intermediate 1, 1.0 eq., 920 g, 3.69 mol) was dissolved in DMF (9.2 L), and t-BuOK (2.0 eq., 828 g, 7.38 mmol) was added dropwise at 0 °C and stirred for 30 min. 6-Methoxypyridine-3-sulfonyl chloride (1.5 eq., 1.15 kg, 5.54 mol) was added and stirred at 0 °C for 1 h. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain methyl 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1
H -pyrrole-3-carboxylate as a white solid. (1.20 kg, 77.4%) [213]
(2) Step: Synthesis of 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1 H -pyrrol-3-yl)methanol[214]Methyl 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1
H -pyrrole-3-carboxylate (1.0 eq., 1.1 kg, 2.62 mol) was dissolved in THF (11.0 L), and DIBAL 2.0 M in THF solution (3.0 eq., 3.93 L, 7.86 mol) was added dropwise at 0 °C, followed by stirring for 30 min. The reaction solution was quenched with 5% aqueous Rochelle’s salt solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1
H -pyrrol-3-yl)methanol as a light yellow oil. (870 g, 84.8%) [215]
(3) Step: Synthesis of 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1 H -pyrrole-3-carbaldehyde[216]5-(2-Fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1
H -pyrrol-3-yl)methanol (1.0 eq., 830 g, 2.12 mol) and TEA (4.0 eq., 1.59 kg, 15.7 mol) were dissolved in DMSO (4.15 L), and SO
3 -pyridine (4.0 eq., 1.35 kg, 8.48 mol) was added dropwise, and the mixture was stirred at room temperature for 1.5 h. Water was added to the reaction mixture at 0 °C, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1
H -pyrrole-3-carbaldehyde as a yellow solid. (722 g, 87.6%) [217]
(4) Step: Synthesis of 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1 H -pyrrol-3-yl)- N -methylmethanamine[218]5-(2-Fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1
H -pyrrole-3-carbaldehyde (1.0 eq., 715 g, 1.83 mol) was dissolved in methanol (7.2 L), and methylamine in methanol (5.0 eq., 916 g, 9.16 mol) was added. After stirring at room temperature for 1 h, the reaction mixture was concentrated, dissolved in ethanol (7.2 L), cooled to 0 °C, and NaBH
4 (2.0 eq., 139 g, 3.66 mol) was added, and stirred at 0 °C for 1 h. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1 H -pyrrol-3-yl)-
N -methylmethanamine as a brown oil. (347 g, 46.7%)
<Example 1> Preparation of hydrochloric acid salt of 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine About 500 mg of the free base of 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine was weighed and placed in a glass vial, and then dissolved in 2 mL of ethanol while heating at 25°C. Then, 647.44 μL (2 M) hydrochloric acid was added to the vial. The sample was continuously stirred on a magnetic stirrer at room temperature for 24 hours, and after stirring for 24 hours, the solid precipitate was separated by centrifugation. Subsequently, the wet solid was dried at 40°C for 20 hours to obtain a grayish white dried powder.
SYN
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/////////Padoprazan, proton pump inhibitor, 95BJ28E2RP, ID-120040002, ID 120040002
Ofirnoflast
Ofirnoflast
CAS 2731294-23-6
MFC23H19F4N7O2 MW501.4 g/mol
N-[4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N’-{5-[1-
(trifluoromethyl)cyclopropyl]-1,2-oxazol-3-yl}urea
N-(4-(4-AMINO-7-CYCLOPROPYL-7H-PYRROLO(2,3-D)PYRIMIDIN-5-YL)-2-FLUOROPHENYL)-N’-(5-(1-(TRIFLUOROMETHYL)CYCLOPROPYL)-3-ISOXAZOLYL)UREA
N-(4-(4-AMINO-7-CYCLOPROPYL-7H-PYRROLO(2,3-D)PYRIMIDIN-5-YL)-2-FLUOROPHENYL)-N’-(5-(1-(TRIFLUOROMETHYL)CYCLOPROPYL)-1,2-OXAZOL-3-YL)UREA
OFIRNOLAST [USAN]
OFIRNOFLAST
UREA, N-(4-(4-AMINO-7-CYCLOPROPYL-7H-PYRROLO(2,3-D)PYRIMIDIN-5-YL)-2-FLUOROPHENYL)-N’-(5-(1-(TRIFLUOROMETHYL)CYCLOPROPYL)-3-ISOXAZOLYL)-
OFIRNOFLAST [INN]
serine/ threonine-protein kinase Nek7 inhibitor, antiinflammatory, HT-6184, HT 6184, 54PY2PBN7S
Ofirnoflast is an investigational drug, a NEK7 inhibitor, that targets and disrupts the formation of the NLRP3 inflammasome, a key driver of chronic inflammation. Developed by Halia Therapeutics, it is being explored for conditions like myelodysplastic syndromes (MDS), obesity, and Alzheimer’s disease. The drug’s unique mechanism aims to address inflammation at a root cause level, potentially offering a new approach to treating these diseases.
How it works
- Ofirnoflast is a “first-in-class” molecule that selectively inhibits the NEK7 protein.
- NEK7 is essential for the assembly of the NLRP3 inflammasome, a molecular complex that causes chronic inflammation.
- By inhibiting NEK7, ofirnoflast prevents the inflammasome from forming and promotes its disassembly.
- This approach aims to reduce inflammation without causing broad immunosuppression.
Therapeutic applications
- Myelodysplastic Syndromes (MDS): Ofirnoflast has completed a Phase 2 study for this condition and received Orphan Drug Designation from the FDA. It is being investigated for its potential to improve blood cell production by targeting the underlying inflammation.
- Obesity: An ongoing Phase 2 study is exploring ofirnoflast in combination with semaglutide to target inflammation and metabolic issues.
- Alzheimer’s Disease: Ofirnoflast is part of an early-stage program looking into its potential for this disease.
Ofirnoflast is a first-in-class, orally bioavailable NEK7 inhibitor currently undergoing Phase 2 clinical evaluation. It disrupts NLRP3 inflammasome assembly by targeting NEK7’s scaffolding function—blocking complex formation independently of NLRP3 activation status, upstream of caspase activation, pyroptosis, and inflammatory cytokine release. This mechanism offers a novel therapeutic approach for chronic inflammation. Unlike NSAIDs, corticosteroids, cytokine-neutralising biologics, and NLRP3-directed small molecules—which are frequently limited by off-target effects, immunosuppression, or incomplete efficacy—ofirnoflast provides a targeted approach with fewer anticipated liabilities
- A Ph2 Study to Evaluate the Safety, Efficacy and Tolerability of HT-6184 and Semaglutide in Obese Participants With T2DMCTID: NCT07172867Phase: Phase 2Status: Not yet recruitingDate: 2025-09-15
- HT-6184 in Subjects With MDSCTID: NCT07052006Phase: Phase 2Status: Active, not recruitingDate: 2025-07-14
- Evaluating Ability of HT-6184 to Reduce Inflammation and Pain After Third Molar ExtractionCTID: NCT06241742Phase: Phase 2Status: CompletedDate: 2025-03-30
- Study to Evaluate HT-6184 in Healthy SubjectsCTID: NCT05447546Phase: Phase 1Status: CompletedDate: 2023-08-28
SYN
https://www.tandfonline.com/doi/full/10.1080/1061186X.2025.2542856
SYN
COMPD 10
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021242505&_cid=P11-MHZPDU-32878-1
INTERMEDIATE D1
5-(4-AMINO-3-FLUOROPHENYL)-7-CYCLOPROPYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4- AMINE
A mixture of 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.160 g, 0.533 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.190 g, 0.800 mmol), and K2CO3 (0.221 g, 1.599 mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was purged with N2 for 10 min. Pd(PPh3)4 (0.062 g, 0.053 mmol) was then added and the reaction mixture was stirred at 100 °C for 12 h. Following completion of the reaction (as indicated by TLC), the mixture was filtered through a pad celite which was then rinsed with EtOAc (2 x 10 mL). The combined filtrates were concentrated under reduced pressure to yield crude material which was purified by flash chromatography (silica gel 230-400 mesh, eluting with 3% MeOH in DCM), affording
the title compound as a yellow solid (0.110 g, 73% yield).1H NMR (400 MHz, DMSO-d6) δ = 8.14 (s, 1H), 7.13 (s, 1H), 7.05-7.09 (m, 1H), 6.95-6.98 (m, 1H), 6.82-6.86 (m, 1H), 6.10 (bs, 2H), 5.22 (bs, 2H), 3.52-3.58 (m, 1H), 1.00-1.04 (m, 4H). LCMS: 284.1 [M+H].
3-(1-(Trifluoromethyl)cyclopropyl)isoxazol-5-amine (precursor to E6) and 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine (precursor to E7) were synthesized as reported in Synthesis 2013, 45, 171–173
EXAMPLE 5
1-(4-(4-AMINO-7-CYCLOPROPYL-7H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-2- FLUOROPHENYL)-3-(3-(1-(TRIFLUOROMETHYL)CYCLOPROPYL)ISOXAZOL-5-YL)UREA
The title compound was prepared following the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.080 g, 0.282 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.088 g, 0.282 mmol), and was obtained as a white solid (0.031 g, 22% yield).1H NMR (400 MHz, DMSO-d6) δ = 10.59 (bs, 1H), 8.84 (bs, 1H), 8.11-8.17 (m, 2H), 7.26-7.37 (m, 3H), 6.20 (s, 1H), 6.16 (bs, 2H), 3.55-3.61 (m, 1H), 1.45-1.49 (m, 2H), 1.38-1.43 (m, 2H), 1.03-1.08 (m, 4H). LCMS: 502.1 [M+H].
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2024249257&_cid=P11-MHZP9H-30149-1
PAT
- Targeted nek7 inhibition for modulation of the nlrp3 inflammasomePublication Number: US-2023210853-A1Priority Date: 2020-05-08
- Inhibitors of NEK7 kinasePublication Number: US-11713321-B2Priority Date: 2020-05-08Grant Date: 2023-08-01
- Inhibitors of nek7 kinasePublication Number: EP-4146348-B1Priority Date: 2020-05-08Grant Date: 2024-07-03
- Inhibitors of nek7 kinasePublication Number: US-2023416259-A1Priority Date: 2020-05-08
- Inhibitors of NEK7 kinasePublication Number: US-12091413-B2Priority Date: 2020-05-08Grant Date: 2024-09-17
- Inhibitors of nek7 kinasePublication Number: TW-202208356-APriority Date: 2020-05-08
- Inhibitors of NEK7 kinasePublication Number: AU-2021280893-A1Priority Date: 2020-05-08
- Inhibitors of NEK7 kinasePublication Number: CN-115843272-APriority Date: 2020-05-08
- Inhibitors of nek7 kinasePublication Number: EP-4146348-A1Priority Date: 2020-05-08
- Inhibitors of NEK7 kinasePublication Number: KR-20230008763-APriority Date: 2020-05-08
- Polymorphs of nek 7 inhibitorsPublication Number: WO-2024249257-A1Priority Date: 2023-05-26
- Inhibitors of NEK7 kinasePublication Number: US-11161852-B1Priority Date: 2020-05-08Grant Date: 2021-11-02
- Inhibitors of nek7 kinasePublication Number: US-2021355130-A1Priority Date: 2020-05-08
- Inhibitors of nek7 kinasePublication Number: US-2022064173-A1Priority Date: 2020-05-08
- Inhibitors of nek7 kinasePublication Number: WO-2021242505-A1Priority Date: 2020-05-08
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///////////ofirnoflast, serine/ threonine-protein kinase Nek7 inhibitor, antiinflammatory, HT-6184, HT 6184, 54PY2PBN7S
Odentegravir
Odentegravir
CAS 2495436-99-0
MF C20H18F3N3O4 MW421.4 g/mol
(7S)-12-hydroxy-1,11-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,4,5,6,7,11-hexahydro-3H-2,7-
methanopyrido [1,2-a][1,4]diazonine-10-carboxamide
(7S)-1,4,5,6,7,11-HEXAHYDRO-12-HYDROXY-1,11-DIOXO-N-((2,4,6-TRIFLUOROPHENYL)METHYL)-3H-2,7-METHANOPYRIDO(1,2-A)(1,4)DIAZONINE-10-CARBOXAMIDE
(7S)-12-HYDROXY-1,11-DIOXO-N-((2,4,6-TRIFLUOROPHENYL)METHYL)-1,4,5,6,7,11-HEXAHYDRO-3H-2,7-METHANOPYRIDO(1,2-A)(1,4)DIAZONINE-10-CARBOXAMIDE
3H-2,7-METHANOPYRIDO(1,2-A)(1,4)DIAZONINE-10-CARBOXAMIDE, 1,4,5,6,7,11-HEXAHYDRO-12-HYDROXY-1,11-DIOXO-N-((2,4,6-TRIFLUOROPHENYL)METHYL)-, (7S)-
antiviral, H8B26JZ4A4, orb2664247
Odentegravir is a small molecule drug classified as a
HIV integrase inhibitor, indicated by the “-tegravir” stem in its name. It is a chemical compound with the molecular formula
has been used in research for its antiviral properties.
- Drug Class: HIV integrase inhibitor
- Chemical Formula:
C20H18F3N3O4cap C sub 20 cap H sub 18 cap F sub 3 cap N sub 3 cap O sub 4𝐶20𝐻18𝐹3𝑁3𝑂4
- Molecular Weight:
421.12421.12421.12 Da (monoisotopic)
- Classification: Small molecule drug
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020197991&_cid=P12-MHY8KB-06018-1
Example 23: Preparation of racemic-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26), (7R)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-
methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26-1) and (7S)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26-2):
Synthesis of 12-Hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26):
[0335] 12-(Benzyloxy)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxylic acid (57 mg, 0.155 mmol) was dissolved in DCM (2 mL) with (2,4,6-trifluorophenyl)methanamine (27 mg, 0.17 mmol) and triethylamine (60 mg, 0.464 mmol). HATU (60 mg, 0.186 mmol) was added and the mixture was stirred at room
temperature. After overnight reaction, the reaction was concentrated to dryness, purified by silicon gel chromatography to obtain compound 12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a) MS (m/z) 512.06 [M+H]+.
[0336] Compound 12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a) (7 mg, 0.014 mmol) was dissloved in Tolune (1 mL), then followed by the addition of TFA (1 mL). The resulting mixture was stirred at rt for overnight. The solvent was removed under vacuo an the residue was purifed by HPLC to obtain the title compound (26). MS (m/z) 422.091 [M+H]+.1H NMR (400 MHz, DMSO-d6) d 10.39 (t, J = 5.8 Hz, 1H), 8.45 (s, 1H), 7.24 – 7.11 (m, 2H), 4.72 (dd, J = 5.9, 2.9 Hz, 1H), 4.54 (dd, J = 6.0, 2.4 Hz, 2H), 4.11 (d, J = 13.3 Hz, 1H), 3.88 – 3.79 (m, 1H), 3.64 (dd, J = 14.7, 1.9 Hz, 1H), 3.05 (dq, J = 9.5, 3.4 Hz, 1H), 2.06 – 1.91 (m, 1H), 1.89 – 1.74 (m, 3H), 1.61 (d, J = 7.7 Hz, 1H), 1.11 (d, J = 12.7 Hz, 1H).
Synthesis of (7S)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26-2) and (7R)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26-1):
[0337] Racemic 12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a) was separated by chiral HPLC separation (SFC chromatography on an IB 4.6X100mm 5mic column using MeOH(20) as co-solvent) to obtain compounds (7R)-12-(Benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a-1) and (7S)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a-2)
[0338] Compound (7S)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a-2) (20 mg, 0.039 mmol) was dissloved in Tolune (1 mL), then followed by the addition of TFA (1 mL). The resulting mixture was stireed at rt for overnight. The solvent was removed under vacuo an the residue was purifed by HPLC to obtain the title compound (26-2). (MS (m/z) 422.123 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d 10.59 (s, 1H), 10.39 (d, J = 5.9 Hz, 1H), 8.45 (s, 1H), 7.18 (t, J = 8.6 Hz, 2H), 4.72 (s, 1H), 4.59 – 4.48 (m, 2H), 4.11 (d, J = 13.2 Hz, 1H), 3.85 (d, J = 14.6 Hz, 1H), 3.69 – 3.59 (m, 1H), 3.05 (ddd, J = 11.3, 6.7, 3.6 Hz, 1H), 1.97 (m, 1H), 1.87 – 1.71 (m, 3H), 1.67 – 1.55 (m, 1H), 1.10 (m, 1H).
[0339] Compound (7R)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a-1) ((20 mg, 0.039 mmol) was dissloved in Tolune (1 mL), then followed by the addition of TFA (1 mL). The resulting mixture was stireed at rt for overnight. The solvent was removed under vacuo an the residue was purifed by HPLC to obtain the title compound (26-1). MS (m/z) 422.116 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d 10.58 (s, 1H), 10.39 (t, J = 5.8 Hz, 1H), 8.45 (s, 1H), 7.18 (dd, J = 9.2, 8.0 Hz, 2H), 4.73 (s, 1H), 4.58 – 4.49 (m, 2H), 4.11 (d, J = 13.3 Hz, 1H), 3.85 (d, J = 14.6 Hz, 1H), 3.65 (d, J = 14.2 Hz, 1H), 3.10 – 3.00 (m, 1H), 1.96 (m, 1H), 1.82 (d, J = 12.2 Hz, 3H), 1.61 (d, J = 7.4 Hz, 1H), 1.18 – 1.05 (m, 1H).
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023196875&_cid=P12-MHY8FJ-02517-1
PAT
- Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical usesPublication Number: JP-2025013503-APriority Date: 2019-03-22
- Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical usesPublication Number: KR-102714084-B1Priority Date: 2019-03-22Grant Date: 2024-10-08
- Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical usePublication Number: KR-20240151256-APriority Date: 2019-03-22
- Bridged Tricyclic Carbamoylpyridone Compounds and Their Pharmaceutical UsePublication Number: ES-2927041-T3Priority Date: 2019-03-22Grant Date: 2022-11-03
- Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical usePublication Number: US-11548902-B1Priority Date: 2019-03-22Grant Date: 2023-01-10
- Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical usePublication Number: US-2023027019-A1Priority Date: 2019-03-22
- Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical usePublication Number: AU-2020245350-B2Priority Date: 2019-03-22Grant Date: 2023-04-20
- Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical usePublication Number: US-2023203061-A1Priority Date: 2019-03-22
- Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical usePublication Number: US-11084832-B2Priority Date: 2019-03-22Grant Date: 2021-08-10
- Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical usePublication Number: AU-2020245350-A1Priority Date: 2019-03-22
- Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical usePublication Number: EP-3938047-A1Priority Date: 2019-03-22
- Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical usePublication Number: EP-3938047-B1Priority Date: 2019-03-22Grant Date: 2022-06-22
- Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical usePublication Number: EP-4122537-A1Priority Date: 2019-03-22
- Bridged tricyclic carbamoylpyridone compounds and uses thereofPublication Number: US-2023339971-A1Priority Date: 2022-04-06
- Bridged tricyclic carbamoylpyridone compounds and uses thereofPublication Number: US-2023339972-A1Priority Date: 2022-04-06
- Bridged tricyclic carbamoylpyridone compounds and uses thereofPublication Number: WO-2023196875-A1Priority Date: 2022-04-06
- Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical usePublication Number: US-2020317689-A1Priority Date: 2019-03-22
- Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical usePublication Number: WO-2020197991-A1Priority Date: 2019-03-22
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……
//////Odentegravir, antiviral, H8B26JZ4A4, orb2664247
Nuvisertib
Nuvisertib
CAS 1361951-15-6
MF C22H26ClF3N4O MW418.5 g/mol
2-[(1r,4r)-4-({3-[3-(trifluoromethyl)phenyl]imidazo[1,2-b]pyridazin-6-yl}amino)cyclohexyl]propan-2-ol
serine/ threonine kinase inhibitor, antineoplastic, Orphan Drug, myelofibrosis, SGI-9481, SGI 9481, TP-3654, TP 3654, EOB0N7BOY4
The chemical structure for nuvisertib was obtained from proposed INN list 130 (Feb. 2024), in which the compound is described as a serine/ threonine kinase inhibitor with antineoplastic action. A structure match to clinical lead TP-3654 was made via PubChem. TP-3654 is declared as an orally available, second-generation pan-PIM kinase inhibitor [1-2].
| References |
| 1. Foulks JM, Carpenter KJ, Luo B, Xu Y, Senina A, Nix R, Chan A, Clifford A, Wilkes M, Vollmer D et al.. (2014) A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas. Neoplasia, 16 (5): 403-12. [PMID:24953177] |
| 2. Wu CP, Li YQ, Chi YC, Huang YH, Hung TH, Wu YS. (2021) The Second-Generation PIM Kinase Inhibitor TP-3654 Resensitizes ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs. Int J Mol Sci, 22 (17). [PMID:34502348] |
Nuvisertib is an orally available, second-generation and selective ATP-competitive inhibitor of proviral integration site for Moloney murine leukemia virus (PIM) kinases, with potential antineoplastic activity. Upon oral administration, nuvisertib selectively binds to and prevents the activation of the PIM kinases. This prevents the activation of PIM-mediated signaling pathways and inhibits proliferation in cells that overexpress PIM. PIMs, constitutively active proto-oncogenic serine/threonine kinases, are upregulated in various types of cancers and play key roles in tumor cell proliferation and survival.
Nuvisertib, also known as TP-3654, is an oral, investigational, and highly selective PIM1 kinase inhibitor being studied in a Phase 1/2 clinical trial for intermediate- or high-risk myelofibrosis (MF). It is not currently an approved medication.
Key Information
- Mechanism of Action: Nuvisertib targets the PIM1 kinase pathway, which is often overactive in myelofibrosis and can promote cancer cell growth. By inhibiting this pathway, nuvisertib is being investigated for its potential to manage symptoms, reduce spleen size, improve blood counts, and slow the progression of bone marrow fibrosis.
- Current Status: Nuvisertib is in ongoing Phase 1/2 clinical trials (NCT04176198) as a monotherapy and in combination with JAK inhibitors like ruxolitinib and momelotinib.
- Designations: Nuvisertib has received Orphan Drug Designation for myelofibrosis
Study of TP-3654 in Patients With Advanced Solid Tumors
CTID: NCT03715504
Phase: Phase 1
Status: Completed
Date: 2023-11-14
SYN
WO2013013188
Example 31
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=US427659372&_cid=P10-MHWTVL-76212-1
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=US130491286&_cid=P10-MHWU33-81462-1
31. 4-((3-(3-(Trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)-trans-cyclohexyl)propan-2-ol (EX. 8-31)
| EX. 8-31 was prepared by similar procedures as in EX. 8-1 using 2-(trans-4-aminocyclohexyl)propan-2-ol. |
| 1H-NMR (CD 3OD/400 MHz): δ 8.82 (s, 1H), 8.19 (m, 1H), 7.88 (s, 1H), 7.62 (m, 3H), 6.70 (d, J=9.6 Hz, 1H), 3.71 (m, 1H), 2.26 (m, 2H), 1.95 (m, 2H), 1.36 (m, 1H), 1.27 (m, 4H), 1.21 (s, 6H). MS (ES +, m/z): (M+H) +: 419.6. |
| To a solution of trans-4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (823 g, 3.38 mol) in EtOAc (4000 mL) was added EA/HCl (2500 mL). The mixture was stirred at 0° C. overnight. The reaction mixture was filtered and dried in vacuo to give a product of hydrochloride salt of trans-4-aminocyclohexanecarboxylic acid as white solid (604 g, 99.42% yield). |
| 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine was prepared according to procedure in EX. 8-29. |
PAT
- Heterocyclic protein kinase inhibitorsPublication Number: ES-2834093-T3Priority Date: 2011-07-21Grant Date: 2021-06-16
- Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitorsPublication Number: US-2021238183-A1Priority Date: 2011-07-21
- Imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine derivatives and their use as protein kinase inhibitorsPublication Number: US-2012058997-A1Priority Date: 2006-11-06
- Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitorsPublication Number: US-9416132-B2Priority Date: 2011-07-21Grant Date: 2016-08-16
- Heterocyclic protein kinase inhibitorsPublication Number: WO-2013013188-A1Priority Date: 2011-07-21
- Heterocyclic protein kinase inhibitorsPublication Number: EP-3409278-B1Priority Date: 2011-07-21Grant Date: 2020-09-16
- Substituted imidazo[1,2-B]pyridazines as protein kinase inhibitorsPublication Number: US-10875864-B2Priority Date: 2011-07-21Grant Date: 2020-12-29
- Heterocyclic protein kinase inhibitorsPublication Number: EP-3812387-A1Priority Date: 2011-07-21
- Substituted imidazo[1,2-B]pyridazines as protein kinase inhibitorsPublication Number: US-10392392-B2Priority Date: 2011-07-21Grant Date: 2019-08-27
- Heterocyclic protein kinase inhibitorsPublication Number: US-2014329807-A1Priority Date: 2011-07-21
- Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitorsPublication Number: US-2017002014-A1Priority Date: 2011-07-21
- Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitorsPublication Number: US-2019071446-A1Priority Date: 2011-07-21
- Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitorsPublication Number: US-2020102313-A1Priority Date: 2011-07-21
- Heterocyclic protein kinase inhibitorsPublication Number: EP-2734205-B1Priority Date: 2011-07-21Grant Date: 2018-03-21
- Heterocyclic protein kinase inhibitorsPublication Number: EP-3409278-A1Priority Date: 2011-07-21
- Heterocyclic protein kinase inhibitorsPublication Number: JP-2014520898-APriority Date: 2011-07-21
- Heterocyclic protein kinase inhibitorsPublication Number: JP-6105578-B2Priority Date: 2011-07-21Grant Date: 2017-03-29
- Substituted imidazo[1,2-B]pyridazines as protein kinase inhibitorsPublication Number: US-10047093-B2Priority Date: 2011-07-21Grant Date: 2018-08-14
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REF
– Nuvisertib (TP-3654), an investigational highly selective oral PIM1 kinase inhibitor, is being evaluated in patients with relapsed or refractory myelofibrosis (MF) –
– Nuvisertib demonstrated symptom and spleen responses correlating with cytokine modulation in the preliminary Phase 1/2 data recently presented at the European Hematology Association (EHA) 2025 Congress –
MARLBOROUGH, Mass., June 12, 2025 /PRNewswire/ — Sumitomo Pharma America, Inc. (SMPA) today announced that the U.S. Food and Drug Administration (FDA) granted Fast Track Designation to nuvisertib (TP-3654) for the treatment of patients with intermediate or high-risk myelofibrosis (MF). The FDA Fast Track Designation is granted to investigational therapies being developed to treat serious or life-threatening conditions that demonstrate the potential to address unmet medical needs. Nuvisertib is an oral, investigational, highly selective inhibitor of PIM1 kinase, which demonstrated clinical activity including symptom and spleen responses correlating with cytokine modulation in the updated preliminary Phase 1/2 data presented at the European Hematology Association (EHA) 2025 Congress in Milan, Italy.
MF, a serious and rare type of blood cancer, is characterized by the buildup of fibrous tissues in the bone marrow which is caused by dysregulation in the Janus-associated kinase (JAK) signaling pathway. The clinical manifestations of MF include an enlarged spleen, debilitating symptoms and reduction in hemoglobin and/or platelets. MF affects 1 in 500,000 people worldwide.1
“This positive momentum for nuvisertib signals strong promise in our pipeline and reflects our dedication to addressing unmet medical needs on behalf of patients with myelofibrosis and their families,” said Tsutomu Nakagawa, Ph.D, President and Chief Executive Officer of SMPA. “Receiving FDA Fast Track Designation for nuvisertib in the treatment of myelofibrosis reinforces our confidence in its potential as a treatment option for patients facing a poor prognosis with limited treatment options. We are committed to working closely with the FDA to progress the clinical development of nuvisertib and bring an alternative treatment option to patients with myelofibrosis.”
Updated data from the ongoing Phase 1/2 study of nuvisertib in patients with relapsed/refractory MF were presented at the EHA Congress on June 12, 2025. Preliminary data showed that nuvisertib monotherapy appears to be well tolerated with no dose-limiting toxicities (DLTs). Evaluable patients showed clinical activity including a ≥25% spleen volume reduction (SVR25) in 22.2% of patients and a ≥50% reduction in total symptom score (TSS50) of 44.4% of patients, as well as improvement of bone marrow fibrosis (42.9% patients), hemoglobin (24% patients) and platelet count (26.7% patients). Data also showed that nuvisertib treatment led to significant cytokine modulation [reduction of pro-inflammatory cytokines (e.g. EN-RAGE, MIP-1β) and increase of anti-inflammatory cytokines (e.g. adiponectin)], which demonstrated significant (p<0.001) correlation with symptom and spleen responses. Preclinical2 and emerging clinical data support the development of nuvisertib in combination with JAK inhibitors for the treatment of patients with MF.
“The data observed to date demonstrate promising clinical activity for nuvisertib and the strong potential for selective PIM1 inhibition to slow the progression of myelofibrosis,” said Jatin Shah, MD, Chief Medical Officer, Oncology. “Patients with myelofibrosis are in need of new therapeutic approaches, including combination treatment options, that can provide increased and durable response rates with limited hematologic adverse events. The FDA Fast Track Designation reinforces the potential of nuvisertib to provide clinical benefits for patients with myelofibrosis, an unmet medical need.”
About Nuvisertib (TP-3654)
Nuvisertib (TP-3654) is an oral investigational selective inhibitor of PIM1 kinase, which has shown potential antitumor and antifibrotic activity through multiple pathways, including induction of apoptosis in preclinical models.2,3 Nuvisertib was observed to inhibit proliferation and increase apoptosis in murine and human hematopoietic cells expressing the clinically relevant JAK2 V617F mutation.3 Nuvisertib alone and in combination with ruxolitinib showed white blood cell and neutrophil count normalization, and also reduced spleen size and bone marrow fibrosis in JAK2 V617F and MPLW515L murine models of myelofibrosis.2 The safety and efficacy of nuvisertib is currently being clinically evaluated in a Phase 1/2 study in patients with intermediate and high-risk myelofibrosis (NCT04176198). The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to nuvisertib for the indication of myelofibrosis in May 2022. The Japan Ministry of Health, Labour and Welfare (MHLW) granted Orphan Drug Designation to nuvisertib for the treatment of myelofibrosis in November 2024.
About Sumitomo Pharma
Sumitomo Pharma Co., Ltd., is a global pharmaceutical company based in Japan with key operations in the U.S. (Sumitomo Pharma America, Inc.), Canada (Sumitomo Pharma Canada, Inc.), and Europe (Sumitomo Pharma Switzerland GmbH) focused on addressing patient needs in oncology, urology, women’s health, rare diseases, psychiatry & neurology, and cell & gene therapies. With several marketed products in the U.S., Canada, and Europe, a diverse pipeline of early- to late-stage assets, we aim to accelerate discovery, research, and development to bring novel therapies to patients sooner. For more information on SMPA, visit our website https://www.us.sumitomo-pharma.com or follow us on LinkedIn.
The Sumitomo corporate symbol mark is a trademark of Sumitomo Pharma Co., Ltd., used under license. SUMITOMO PHARMA is a trademark of Sumitomo Pharma Co., Ltd., used under license. SUMITOMO is a registered trademark of Sumitomo Chemical Co., Ltd., used under license. Sumitomo Pharma America, Inc. is a U.S. subsidiary of Sumitomo Pharma Co., Ltd.
©2025 Sumitomo Pharma America, Inc. All rights reserved.
References
- U.S. National Library of Medicine. (n.d.). Primary myelofibrosis: Medlineplus Genetics. MedlinePlus. https://medlineplus.gov/genetics/condition/primary-myelofibrosis/
- Dutta A., Nath D, Yang Y, et al. Genetic ablation of Pim1 or pharmacologic inhibition with TP-3654 ameliorates myelofibrosis in murine models. Leukemia. 2022; 36 (3): 746-759. doi: 10.1038/s41375-021-01464-2.
- Foulks JM, Carpenter KJ, Luo B, et al. A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas. Neoplasia. 2014;16(5):403-412.
SOURCE Sumitomo Pharma America
- BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor–resistant BRCA -mutant ovarian cancerPublication Name: Science Translational MedicinePublication Date: 2023-06-21PMCID: PMC10758289PMID: 37343085DOI: 10.1126/scitranslmed.add7872
- The Second-Generation PIM Kinase Inhibitor TP-3654 Resensitizes ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer DrugsPublication Name: International Journal of Molecular SciencesPublication Date: 2021-08-30PMCID: PMC8431370PMID: 34502348DOI: 10.3390/ijms22179440
- High-Throughput Screening to Identify Inhibitors of the Type I Interferon–Major Histocompatibility Complex Class I Pathway in Skeletal MusclePublication Name: ACS Chemical BiologyPublication Date: 2020-05-27PMCID: PMC7859889PMID: 32459468DOI: 10.1021/acschembio.0c00343
- PIM kinase inhibitors: Structural and pharmacological perspectivesPublication Name: European Journal of Medicinal ChemistryPublication Date: 2019-06-15PMID: 30954777DOI: 10.1016/j.ejmech.2019.03.050
- A Small-Molecule Inhibitor of PIM Kinases as a Potential Treatment for Urothelial CarcinomasPublication Name: Neoplasia (New York, N.Y.)Publication Date: 2014-05PMCID: PMC4198696PMID: 24953177DOI: 10.1016/j.neo.2014.05.004
- BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor–resistant BRCA -mutant ovarian cancerPublication Name: Science Translational MedicinePublication Date: 2023-06-21PMCID: PMC10758289PMID: 37343085DOI: 10.1126/scitranslmed.add7872
- The Second-Generation PIM Kinase Inhibitor TP-3654 Resensitizes ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer DrugsPublication Name: International Journal of Molecular SciencesPublication Date: 2021-08-30PMCID: PMC8431370PMID: 34502348DOI: 10.3390/ijms22179440
- High-Throughput Screening to Identify Inhibitors of the Type I Interferon–Major Histocompatibility Complex Class I Pathway in Skeletal MusclePublication Name: ACS Chemical BiologyPublication Date: 2020-05-27PMCID: PMC7859889PMID: 32459468DOI: 10.1021/acschembio.0c00343
- PIM kinase inhibitors: Structural and pharmacological perspectivesPublication Name: European Journal of Medicinal ChemistryPublication Date: 2019-06-15PMID: 30954777DOI: 10.1016/j.ejmech.2019.03.050
- A Small-Molecule Inhibitor of PIM Kinases as a Potential Treatment for Urothelial CarcinomasPublication Name: Neoplasia (New York, N.Y.)Publication Date: 2014-05PMCID: PMC4198696PMID: 24953177DOI: 10.1016/j.neo.2014.05.004
///////Nuvisertib, serine/ threonine kinase inhibitor, antineoplastic, Orphan Drug, myelofibrosis, SGI-9481, SGI 9481, TP-3654, TP 3654, EOB0N7BOY4
Nurandociguat
Nurandociguat
CAS 2781965-75-9
MF C30H36ClF2N5O2 MW 572.1 g/mol
1-[(3R)-1-{4-chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl} piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid
1-[(3R)-1-[5-chloro-2-[4-[4-(2-methylpropyl)piperazin-1-yl]phenyl]phenyl]piperidin-3-yl]-5-(difluoromethyl)pyrazole-4-carboxylic acid
guanylate cyclase activator, BAY 3283142, LPU8429UK5
Nurandociguat is a small molecule drug candidate, previously known as BAY 3283142, that is a guanylate cyclase activator being developed by Bayer for cardiovascular conditions. The “ciguat” stem in its name indicates its function as a guanylate cyclase activator, a mechanism that is also being investigated for related drugs like runcaciguat. It is currently in clinical trials, including a Phase 2 program for chronic kidney disease (CKD).
- Drug class: Guanylate cyclase activator
- Developer: Bayer
- Previous name: BAY 3283142
- Indication: Investigated for cardiovascular conditions
- Current status: In clinical development, including a Phase 2 study for chronic kidney disease (CKD)
- OriginatorBayer
- ClassAntihypertensives; Cardiovascular therapies; Hepatoprotectants; Urologics
- Mechanism of ActionGuanylate cyclase stimulants
- Phase IIRenal failure
- Phase ICardiovascular disorders; Diabetic retinopathy; Hypertension; Liver disorders
- 28 Sep 2025No recent reports of development identified for phase-I development in Renal-failure in Germany (PO, Immediate release)
- 16 Sep 2025(CTIS2024-510856-11-00) (EudraCT2024-510856-11-00): Trial initiation and completion info added; updated DevT; Corrected intro to match DevT as most of the info about indication and countries missing
- 28 May 2025No recent reports of development identified for phase-I development in Renal-failure(In volunteers, In adults) in Japan (PO, Immediate release)
Nurandociguat is a small molecule drug. The usage of the INN stem ‘-ciguat’ in the name indicates that Nurandociguat is a guanylate cyclase activator and stimulator. Nurandociguat has a monoisotopic molecular weight of 571.25 Da.
PAT
- Soluble guanylate cyclase activators for use in the treatment of heart failure with preserved ejection fraction in womenPublication Number: WO-2023237577-A1Priority Date: 2022-06-09
- Substituted pyrazolo piperidine carboxylic acidsPublication Number: WO-2022122910-A1Priority Date: 2020-12-10
- The use of sgc activators for the treatment of ophthalmologic diseasesPublication Number: WO-2022122917-A1Priority Date: 2020-12-10
- Use of sGC activators for the treatment of ophthalmic diseasesPublication Number: CN-115175681-APriority Date: 2020-12-10
- Use of sgc activators for the treatment of ophthalmologic diseasesPublication Number: US-2022241273-A1Priority Date: 2020-12-10
- Use of sGC activators for the treatment of ophthalmic diseasesPublication Number: JP-2023514928-APriority Date: 2020-12-10
- The use of sgc activators for the treatment of ophthalmologic diseasesPublication Number: EP-4259140-A1Priority Date: 2020-12-10
- Use of sGC activators for the treatment of ophthalmic diseasesPublication Number: KR-20230118143-APriority Date: 2020-12-10
- Substituted pyrazolo piperidine carboxylic acidsPublication Number: US-2023265072-A1Priority Date: 2020-12-10
- Use of sGC activators for the treatment of ophthalmic diseasesPublication Number: JP-2024073585-APriority Date: 2020-12-10
- Use of sGC activators for the treatment of ophthalmological diseasesPublication Number: JP-7458683-B2Priority Date: 2020-12-10Grant Date: 2024-04-01
- Use of sgc activators for the treatment of ophthalmologic diseasesPublication Number: US-2023346777-A1Priority Date: 2020-12-10
- Use of sGC activators for treating ophthalmic diseasesPublication Number: CN-115175681-BPriority Date: 2020-12-10Grant Date: 2024-10-25
SYN
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022122917&_cid=P20-MHVQYD-96133-1
soluble guanylate cyclase (sGC) activators for use in the treatment and/or prophylaxis of ophthalmologic diseases, including non-proliferative diabetic retinopathy (NPDR), diabetic macular edema (DME), retinal ganglion cell/photoreceptor neurodegeneration and cataract, especially wherein the soluble guanylate cyclase (sGC) activators are compounds selected from the group consisting of
Example 1
1 – [ 1 – { 4-Chloro-4′- [4-(2-methylpropyl)piperazin- 1 -yl] [1,1 ’-biphenyl] -2-yl }piperidin-3-yl] -5- (difluoromethyl)-lH-pyrazole-4-carboxylic acid hydrochloride (Enantiomer 1)
Ethyl 1 – [ 1 – { 5-chloro-2- [(trifluoromethanesulfonyl)oxy]phenyl }piperidin-3-yl] -5-(difluoromethyl)- 1 H-pyrazole-4-carboxylate (prepared in analogy to Example 11A, Enantiomer 1, 80.0 mg, 147 pmol) and l-(2-methylpropyl)-4- [4-(4,4,5 ,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl]piperazine (Example 18 A 62.8 mg, 97 % purity, 177 pmol) were placed under argon in toluene/ethanol (820/820 pl). 2 M sodium carbonate solution (220 pl, 2.0 M, 440 pmol) and tetrakis(triphenylphosphine)palladium(0) (8.52 mg, 7.37 pmol) were added and the mixture was stirred at 100°C. overnight. The reaction mixture was diluted with ethyl acetate and 1 M hydrochloric acid was added. The aqueous phase was extracted three times with ethyl acetate. The organic phase was dried with sodium sulfate, filtered off and evaporated. The crude mixture was dissolved with THF/ethanol (2.0/0.2 ml), 1 M lithium hydroxide solution (1.5 ml, 1.5 mmol) was added and the mixture was stirred at room temperature overnight. A I M lithium hydroxide solution (740 pl, 740 pmol) was added again. After about 6 h the reaction mixture was evaporated at 50°C. The residue was dissolved in
SUBSTITUTE SHEET (RULE 26)
acetonitrile/water/0.25 ml trifluoroacetic acid and purified by preparative HPLC (RP18 column, acetonitrile/water gradient with the addition of 0.1% trifluoroacetic acid). The crude product was purified by means of thick layer chromatography (dichloromethane/methanol/formic acid: 10/1/0.1). The silica gel mixture was stirred with dichloromethane/1 M hydrochloric acid in dioxane (10/1) in ethanol, filtered off and carefully evaporated at 30°C and lyophilized. 34 mg of the target compound (36% of theory, purity 95%) were obtained.
LC-MS (Method 6): Rt = 1.23 min; MS (ESIpos): m/z = 572 [M-HC1+H]+
‘H-NMR (600 MHz, DMSO-d6) 5 [ppm]: 1.004 (15.87), 1.015 (16.00), 1.500 (0.51), 1.521 (0.57), 1.728 (0.73), 1.750 (0.61), 1.897 (0.57), 1.917 (0.62), 1.975 (0.79), 2.122 (0.42), 2.133 (0.84), 2.144 (1.02), 2.156
(0.79), 2.571 (0.47), 2.587 (0.91), 2.610 (0.52), 3.004 (0.84), 3.022 (2.01), 3.026 (2.20), 3.038 (3.72), 3.048
(2.50), 3.065 (0.75), 3.154 (2.66), 3.161 (2.75), 3.169 (2.36), 3.177 (1.88), 3.224 (0.84), 3.237 (0.70), 3.589
(1.41), 3.602 (1.80), 3.825 (1.02), 3.841 (0.78), 3.866 (1.05), 3.882 (0.75), 4.223 (2.57), 4.445 (0.68), 4.463
(0.97), 4.481 (0.57), 7.045 (0.55), 7.055 (3.63), 7.070 (3.72), 7.084 (2.72), 7.087 (3.09), 7.110 (1.47), 7.113
(1.11), 7.123 (2.19), 7.127 (2.02), 7.163 (3.67), 7.177 (2.19), 7.215 (0.46), 7.428 (0.83), 7.495 (4.24), 7.510
(4.02), 7.515 (2.07), 7.602 (0.82), 7.959 (4.79), 9.484 (0.54).
Example 2
1 – [ 1 – { 4-Chloro-4′- [4-(2-methylpropyl)piperazin- 1 -yl] [1,1 ’-biphenyl] -2-yl }piperidin-3-yl] -5-(difluoromethyl)-lH-pyrazole-4-carboxylic acid (Enantiomer 2)
Method A
A solution of ethyl l-[l-{4-chloro-4′-[4-(2-methylpropyl)piperazin-l-yl][l,T-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-lH-pyrazole-4-carboxylate (prepared in analogy to Example 17A, Enantiomer 2, 50.8 g, 84.6 mmol) in a THF/methanol mixture 9:1 (1.0 1) was treated with an aqueous solution of lithium hydroxide (850 ml, 1.0 M, 850 mmol) and stirred overnight at room temperature. The reaction mixture was
SUBSTITUTE SHEET (RULE 26)
concentrated, diluted with dichloromethane (1.5 1) and adjusted to pH = 2 with an aqueous solution of hydrogen chloride (2N). The resulting suspension was stirred 45 minutes at room temperature. The solid was filtered, washed with water and dried under vacuum affording 43 g (90 % yield) of the title compound.
LC-MS (Method 7): Rt = 1.27 min; MS (ESIpos): m/z = 572 [M+H]+
‘H-NMR (600 MHz, DMSO-d6) 5 [ppm]: 1.002 (15.68), 1.013 (16.00), 1.080 (0.57), 1.092 (1.18), 1.103 (0.63), 1.498 (0.74), 1.519 (0.83), 1.719 (1.03), 1.741 (0.88), 1.902 (0.78), 1.908 (0.74), 1.922 (0.88), 1.928
(0.83), 1.943 (0.45), 1.978 (1.13), 1.994 (0.74), 2.102 (0.71), 2.112 (0.85), 2.123 (0.70), 2.571 (1.40), 2.591
(0.77), 2.882 (1.10), 3.018 (1.27), 3.035 (3.01), 3.053 (2.14), 3.239 (2.40), 3.254 (2.32), 3.368 (1.13), 3.379
(1.40), 3.391 (1.33), 3.403 (0.92), 3.493 (0.76), 4.463 (0.65), 4.482 (1.12), 4.500 (0.62), 7.033 (4.22), 7.048
(4.45), 7.074 (3.47), 7.077 (4.04), 7.100 (1.85), 7.103 (1.52), 7.113 (2.53), 7.117 (2.34), 7.162 (4.18), 7.175
(2.71), 7.439 (1.03), 7.481 (4.88), 7.495 (4.57), 7.526 (2.04), 7.613 (0.91), 7.952 (5.28).
Method B
1 – { 1 – [4-Chloro-4′-(4-isobutylpiperazin- 1 -yl) [biphenyl] -2-yl]piperidin-3-yl } -5-(difluoromethyl)- 1 H-pyrazole-4-carboxylic acid hydrochloride (prepared in analogy to Example 3, Enantiomer 2, 31.2 mg, 51.3 pmol) were dissolved in 17 ml of dichloromethane and 1 ml of methanol. The solution was shaken once with 1.5 ml of saturated, aqueous sodium bicarbonate solution. The phases were separated. 5 ml of dichloromethane and 3 ml of methanol were added to the organic phase. The organic phase was then dried over sodium sulfate, filtered, evaporated and purified by preparative HPLC (RP18 column, acetonitrile/water gradient, neutral without acid addition). Product fractions were combined and lyophilized. 22 mg of the target compound (74% of theory) were obtained.
LC-MS (Method 3): Rt = 1.73 min; MS (ESIpos): m/z = 572 [M+H]+
‘H-NMR (600 MHz, DMSO-d6) 5 [ppm]: 0.887 (15.60), 0.898 (16.00), 1.493 (0.64), 1.514 (0.70), 1.695 (0.89), 1.718 (0.74), 1.799 (0.48), 1.811 (0.88), 1.822 (1.12), 1.833 (0.92), 1.844 (0.48), 1.890 (0.68), 1.910
(0.74), 1.977 (0.93), 1.995 (0.62), 2.118 (3.91), 2.130 (3.66), 2.516 (5.14), 3.017 (1.09), 3.035 (2.76), 3.053
(1.94), 3.181 (5.03), 3.185 (5.02), 3.267 (1.53), 4.473 (0.55), 4.491 (0.96), 4.509 (0.54), 6.963 (3.96), 6.977
(4.06), 7.048 (3.13), 7.051 (3.31), 7.081 (1.60), 7.084 (1.26), 7.095 (2.21), 7.098 (1.89), 7.152 (3.52), 7.165
(2.42), 7.434 (4.45), 7.448 (4.50), 7.533 (1.51), 7.621 (0.67), 7.930 (4.14).
Example 3
1 – { 1 – [4-Chloro-4′-(4-isobutylpiperazin- 1 -yl) [biphenyl] -2-yl]piperidin-3-yl } -5-(difluoromethyl)- 1 H-pyrazole-4-carboxylic acid hydrochloride (Enantiomer 2)
SUBSTITUTE SHEET (RULE 26)
Method A
A suspension of 1 – [ 1 – { 4-chloro-4′- [4-(2-methylpropyl)piperazin- 1 -yl] [1,1 ’-biphenyl] -2-yl }piperidin-3-yl] -5-(difluoromethyl)-lH-pyrazole-4-carboxylic acid (prepared in analogy to Example 2, Enantiomer 2, 43.5 g, 76.0 mmol) in diethyl ether (870 ml) was treated with a solution of hydrogen chloride in diethyl ether (84 ml, 1.0 M, 84 mmol). The resulting mixture was stirred overnight at room temperature and evaporated affording 46.1 g (quant.) of the title compound.
LC-MS (Method 3): Rt = 1.72 min; MS (ESIpos): m/z = 572 [M+H]+
‘H-NMR (600 MHz, DMSO-d6) 5 [ppm]: 1.026 (15.64), 1.037 (16.00), 1.497 (0.56), 1.519 (0.61), 1.722 (0.78), 1.743 (0.65), 1.903 (0.59), 1.910 (0.53), 1.924 (0.66), 1.930 (0.61), 1.978 (0.82), 1.994 (0.50), 2.142
(0.45), 2.154 (0.91), 2.165 (1.11), 2.176 (0.89), 2.187 (0.45), 2.557 (0.64), 2.577 (1.02), 2.594 (0.55), 2.992
(1.81), 3.002 (2.77), 3.012 (1.87), 3.018 (1.15), 3.036 (2.40), 3.054 (1.60), 3.133 (1.12), 3.148 (1.19), 3.168
(0.53), 3.237 (0.88), 3.250 (0.76), 3.338 (0.81), 3.360 (1.42), 3.379 (0.88), 3.580 (1.61), 3.791 (0.89), 3.819
(1.25), 3.844 (0.81), 4.463 (0.89), 4.474 (0.97), 4.481 (1.26), 4.488 (0.99), 4.499 (0.88), 7.051 (3.56), 7.065
(3.77), 7.077 (2.72), 7.080 (3.14), 7.103 (1.42), 7.106 (1.13), 7.116 (2.00), 7.120 (1.84), 7.165 (3.40), 7.178
(2.22), 7.443 (0.84), 7.489 (4.04), 7.504 (3.79), 7.531 (1.66), 7.618 (0.72), 7.954 (4.33), 10.519 (0.49).
Method B
Ethyl 1 – [ 1 – { 5-chloro-2- [(trifluoromethanesulfonyl)oxy]phenyl }piperidin-3-yl] -5-(difluoromethyl)- 1 H-pyrazole-4-carboxylate (prepared in analogy to Example 14A, Enantiomer 2, 80.0 mg, 150 pmol) and l-(2-methylpropyl)-4- [4-(4,4,5 ,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl]piperazine (Example 18 A 64.1 mg, 97 % purity, 180 pmol) were dissolved under argon in toluene/ethanol (0.83/0.83 ml). Tetrakis(triphenylphosphine)palladium(0) (8.69 mg, 7.52 pmol) and 2 M sodium carbonate solution (226 pl, 452 pmol) were added and the mixture was stirred at 100°C overnight. The reaction mixture was diluted with ethyl acetate and water. The aqueous phase was acidified with 1 M hydrochloric acid. The phases were
SUBSTITUTE SHEET (RULE 26)
separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The crude product was dissolved in THF/ethanol (3.9/0.39 ml), 1 M aqueous lithium hydroxide solution (1.5 ml, 1.5 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was evaporated, the residue was dissolved in acetonitrile/TFA/water and purified using preparative HPLC (RP18 column, acetonitrile/water gradient with the addition of 0.1% TFA). The product fractions were combined and evaporated. The residue was mixed with 0.1 M hydrochloric acid in dioxane, carefully evaporated at 30°C (twice) and then lyophilized. 53 mg of the target compound (55% of theory, purity 95%) were obtained.
LC-MS (Method 4): Rt = 0.91 min; MS (ESIpos): m/z = 572 [M-HC1+H]+
‘H-NMR (400 MHz, DMSO-d6) 5 [ppm]: 1.004 (15.46), 1.020 (16.00), 1.491 (0.44), 1.522 (0.50), 1.722 (0.68), 1.753 (0.55), 1.890 (0.47), 1.920 (0.55), 1.967 (0.84), 2.129 (0.76), 2.146 (0.96), 2.163 (0.76), 2.582
(0.91), 2.613 (0.48), 2.999 (0.86), 3.010 (1.71), 3.025 (3.88), 3.041 (2.30), 3.131 (0.88), 3.161 (1.25), 3.177
(2.08), 3.213 (1.75), 3.242 (1.16), 3.467 (1.06), 3.496 (0.84), 3.503 (0.60), 3.519 (0.54), 3.525 (0.50), 3.549
(0.75), 3.555 (0.84), 3.572 (1.57), 3.582 (1.48), 3.589 (1.38), 3.601 (2.78), 3.608 (1.89), 3.633 (0.44), 3.640
(0.41), 3.811 (0.94), 3.847 (1.32), 3.878 (0.71), 4.329 (0.49), 4.439 (0.46), 4.466 (0.73), 4.477 (0.52), 4.839
(0.49), 7.047 (3.30), 7.070 (3.64), 7.082 (2.61), 7.087 (3.29), 7.104 (1.46), 7.109 (0.86), 7.124 (2.34), 7.129
(2.03), 7.160 (3.99), 7.181 (1.96), 7.388 (0.88), 7.490 (4.02), 7.512 (3.81), 7.519 (2.20), 7.650 (0.72), 7.959
(3.78), 9.708 (0.41).
[OC]D20 = -73.05°, c = 0.465g/100cm3, trichloromethane.
Enantiomer 2 has an absolute configuration of R as shown in example 3 A below.
1 – { 3(2?)- 1 – [4-Chloro-4′-(4-isobutylpiperazin- 1 -yl) [biphenyl] -2-yl]piperidin-3-yl } -5-(difluoromethyl)- 1H-pyrazole-4-carboxylic acid hydrochloride
Example 3A
1 – { 3(7?)- 1 – [4-Chloro-4′-(4-isobutylpiperazin- 1 -yl) [biphenyl] -2-yl]piperidin-3-yl } -5-(difluoromethyl)- 1H-pyrazole-4-carboxylic acid hydrochloride hemihydrate
SUBSTITUTE SHEET (RULE 26)
100 mg 1 – { 1 – [4-Chloro-4′-(4-isobutylpiperazin- 1 -yl) [biphenyl] -2-yl]piperidin-3-yl } -5-(difluoromethyl)-lH-pyrazole-4-carboxylic acid hydrochloride (Enantiomer 2) (example 3) were solved at 60°C in 3,5 ml 2 -propanol, wherein the 2-propanol was dosed portion wise in lOOpl -portions at 60°C until a clear solution was obtained. Afterwards the vessel was closed with a septum and placed into a slowly cooling sand bath from 60°C to roomtemperature over the weekend -> small amounts of solids were detected. Thereafter the septum was provided with a canula, in order to slowly let the solvent evaporate. After 4 weeks crystals were collected and inspected under a microscope.
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/////////Nurandociguat, guanylate cyclase activator, BAY 3283142, LPU8429UK5
Nibrozetone
Nibrozetone
CAS 925206-65-1
MF C5H6BrN3O5 MW268.02 g/mol
2-bromo-1-(3,3-dinitroazetidin-1-yl)ethan-1-one
2-Bromo-1-(3,3-dinitroazetidin-1-yl)ethanone
2-BROMO-1-(3,3-DINITROAZETIDIN-1-YL)ETHAN-1-ONE
anti-inflammatory, RRx-001, RRx 001, ABDNAZ
Nibrozetone is an investigational new drug that is being evaluated by EpicentRx for the treatment of oral mucositis in head and neck cancer patients. It is a small molecule that combines direct inhibition of the NLRP3 inflammasome, induction of NRF2, and release of nitric oxide under hypoxic conditions.[1][2] It has received Fast Track designation from the FDA for severe oral mucositis in head and neck cancer patients.[3]
Nibrozetone (RRx-001) is an investigational, multi-action small molecule drug that is being developed by EpicentRx for a range of conditions, including head and neck cancers, small cell lung cancer, and neurodegenerative diseases like Parkinson’s and ALS. Its mechanism involves inhibiting the NLRP3 inflammasome, activating the Nrf2 pathway, and releasing nitric oxide in hypoxic tumor environments, while also protecting healthy tissues. It is being evaluated for its potential to reduce the side effects of cancer treatments and as a disease-modifying therapy itself.
How it works
- Anti-inflammatory: Nibrozetone inhibits the NLRP3 inflammasome, which is a key driver of inflammation in several diseases.
- Antioxidant: It activates the Nrf2 pathway, a cellular defense mechanism that protects against oxidative stress.
- Tumor-specific delivery: It acts as a “hypoxia-activated” drug, releasing a nitric oxide-releasing radical only in the low-oxygen environment of tumors, which can be toxic to cancer cells.
- Protective to normal tissue: The drug’s protective mechanisms are thought to keep it from causing harm to healthy tissues outside of the tumor environment.
Current and potential uses
- Oral mucositis: It is being studied to prevent and treat severe mouth sores that can be a side effect of head and neck cancer radiation therapy.
- Small cell lung cancer (SCLC): It is being investigated in a Phase 3 trial for the treatment of SCLC.
- Neurodegenerative diseases: Animal studies have shown promising neuroprotective effects in models of Parkinson’s and ALS.
- Other potential applications: Research is ongoing for its use as a treatment for other conditions, including endometriosis, toxic exposures, and various types of cancers.
- RRx-001 in Lung Cancer, Ovarian Cancer and Neuroendocrine Tumors Prior to Re-administration of Platinum Based Doublet Regimens (QUADRUPLE THREAT)CTID: NCT02489903Phase: Phase 2Status: CompletedDate: 2025-03-17
- RRx-001 for Reducing Oral Mucositis in Patients Receiving Chemotherapy and Radiation for Head and Neck CancerCTID: NCT05966194Phase: Phase 2Status: RecruitingDate: 2024-11-15
- Safety and Efficacy of RRx-001 in the Attenuation of Oral Mucositis in Patients Receiving Chemoradiation for the Treatment of Oral CancersCTID: NCT03515538Phase: Phase 2Status: CompletedDate: 2024-11-04
- Safety and Pharmacokinetic Study of RRx-001 in Cancer SubjectsCTID: NCT01359982Phase: Phase 1Status: CompletedDate: 2024-11-01
- RRx-001 Given With Irinotecan and Temozolomide for Pediatric Patients With Recurrent or Progressive Malignant Solid and Central Nervous System TumorsCTID: NCT04525014Phase: Phase 1Status: TerminatedDate: 2024-10-31
REF
- Dinitroazetidines Are a Novel Class of Anticancer Agents and Hypoxia-Activated Radiation Sensitizers Developed from Highly Energetic MaterialsPublication Name: Cancer ResearchPublication Date: 2012-05-14PMID: 22589277DOI: 10.1158/0008-5472.can-11-2303
- Properties of delta5-3beta-hydroxysteroid oxidoreductase isolated from Streptomyces griseocarneusPublication Name: Acta microbiologica Academiae Scientiarum HungaricaePublication Date: 1975PMID: 5856
PAT
- Dinitroazetidines Are a Novel Class of Anticancer Agents and Hypoxia-Activated Radiation Sensitizers Developed from Highly Energetic MaterialsPublication Name: Cancer ResearchPublication Date: 2012-05-14PMID: 22589277DOI: 10.1158/0008-5472.can-11-2303
- Properties of delta5-3beta-hydroxysteroid oxidoreductase isolated from Streptomyces griseocarneusPublication Name: Acta microbiologica Academiae Scientiarum HungaricaePublication Date: 1975PMID: 5856
- Cyclic nitro compounds, pharmaceutical compositions thereof and uses thereofPublication Number: US-8927527-B2Priority Date: 2005-08-12Grant Date: 2015-01-06
- Cyclic nitro compounds, pharmaceutical compositions thereof and uses thereofPublication Number: US-9226915-B2Priority Date: 2005-08-12Grant Date: 2016-01-05
- Cyclic nitro compounds, pharmaceutical compositions thereof and uses thereofPublication Number: WO-2007022225-A2Priority Date: 2005-08-12
- Cyclic nitro compounds, pharmaceutical compositions thereof and uses thereofPublication Number: US-2022016077-A1Priority Date: 2005-08-12
- Cyclic nitro compounds, pharmaceutical compositions thereof and uses thereofPublication Number: US-11925617-B2Priority Date: 2005-08-12Grant Date: 2024-03-12
- Methods of synthesizing and isolating N-(bromoacetyl)-3,3-dinitroazetidine and a composition including the samePublication Number: US-8471041-B2Priority Date: 2010-02-09Grant Date: 2013-06-25
- Methods of synthesizing and isolating n-(bromoacetyl)-3,3-dinitroazetidine and a composition including the samePublication Number: WO-2011100090-A1Priority Date: 2010-02-09
- Methods of synthesizing and isolating n-(bromoacetyl)-3,3-dinitroazetidine and a composition including the samePublication Number: IL-221141-A0Priority Date: 2010-02-09
- Cyclic nitro compounds, pharmaceutical compositions thereof and uses thereofPublication Number: EP-1924253-A2Priority Date: 2005-08-12
- Cyclic nitro compounds, pharmaceutical compositions thereof and uses thereofPublication Number: EP-1924253-B1Priority Date: 2005-08-12Grant Date: 2014-12-10
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011100090&_cid=P11-MHTYGA-61308-1
Cyclic nitro compounds, such as ABDNAZ, are being investigated for their potential use in treating cancer. Methods of synthesizing ABDNAZ have been described, such as in United States Patent No. 7,507,842 to Bednarski et al.
(“Bednarski”). In Bednarski, ABDNAZ is synthesized by reacting
l-½rt-butyl-3,3-dinitroazetidine (DNAZ) with bromoacetyl bromide and boron trifluoride etherate. For every mole of ABDNAZ produced, a mole of a hydrogen bromide salt of DNAZ (DNAZ HBr) is also produced as a coproduct. The ABDNAZ is isolated from the DNAZ HBr by cooling the reaction mixture, adding
dichloromethane, and filtering the DNAZ HBr. Solid DNAZ HBr is sensitive to impact, friction, and other external stimuli and, therefore, must be handled carefully. The dichloromethane filtrate is washed with water, dried, and then the dichloromethane is evaporated, producing a crude ABDNAZ mixture. The product is washed sequentially with diethyl ether and dried under vacuum, yielding ABDNAZ that is approximately 98% pure and at a yield of approximately 75% (based on bromoacetyl bromide). The 2% of impurities remaining in the ABDNAZ are believed to include
bromoacetic acid, unreacted DNAZ, and DNAZ HBr. This method of producing ABDNAZ is referred to herein as the Bednarski process. While the Bednarski process provides ABDNAZ at a reasonable purity and yield, the purity is not sufficient for pharmaceutical uses. In addition, solid DNAZ HBr produced during the Bednarski process is an explosive compound, which adds to the complexity of producing
Example 2
Synthesis of ABDNAZ from DNAZ
A three neck round bottom flask (3 L) equipped with a magnetic stir bar and a water jacketed reflux condenser was charged with the dichloromethane solution of DNAZ (produced as described in Example 1). A nitrogen gas purge of the apparatus was initiated and, after ten minutes, boron trifluoride diethyletherate (6.37 mL, 52 mmol) was added, followed by bromoacetyl bromide (33.77 mL, 388 mmol). The flask was sealed, except for a small vent at the top of the condenser, and the solution was heated to a mild reflux. After six hours (± 0.5 hour), heating was stopped and dichloromethane (1000 mL) and distilled water (800 mL) were added, in that order, to the heterogeneous mixture. The two-phase system was stirred vigorously for sixteen hours, until all solids (DNAZ HBr) were dissolved. The two-phase system was then transferred to a separatory funnel. The aqueous phase was removed and the organic phase was washed with additional distilled water (4 x 500 mL). The organic phase was dried with sodium sulfate (100 g – 150 g) and then transferred to a single neck, round bottom flask. The solution was concentrated on a rotary evaporator to approximately half of its initial volume and then ethanol (250 mL) was added. The remaining dichloromethane was removed by a rotary evaporator, causing precipitation of clear, colorless crystals. The flask was chilled in an ice bath for thirty minutes. The precipitate was isolated by vacuum filtration, rinsed with additional cold ethanol (5 x 150 mL), and dried to afford pure ABDNAZ (56.04 g, 81% yield): Ή NMR
(d6-acetone) δ 4.02 (s, 2H, -CH2Br ), 4.96 (br s, 2H, ring -CH2), 5.36 (br s, 2H, ring -CH2); 13C NMR (d6-acetone) δ 25.58, 58.58, 60.53, 107.69, 167.48.
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007022225&_cid=P11-MHTYDP-59218-1
Example 5: Synthesis of ABDNAZ
[00139] A 25 ml, three-neck, round bottom flask was charged with 7 ml of methylene chloride and 2.50 g (12.3 mmol) of t-BuDNAZ prepared as described in Archibald et at, Journal of Organic Chemistry, 1990, 2920. Under nitrogen, 0.16 ml (1.23 mmol) of boron trifluoride etherate was added. After stirring 5 min. at ambient temperature, 0.54 ml (6.15 mol) of bromoacetyl bromide was added. The solution was heated between 50-600C for 2 h. The darkened reaction mixture was cooled to ambient temperature, diluted with 50 ml methylene chloride, and filtered. The solid was identified as the HBr salt of t-BuDNAZ. The methylene chloride filtrate was washed with two 20 ml portions of water, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The resultant solid was washed with three 20 ml portions of ethyl ether and dried under vacuum to yield 1.24 g (75.2% based on bromoacetyl bromide) of BrADNAZ as a white solid (mp = 124-1250C). 1H NMR (CDCl3): δ 3.76 (s, 2H), 4.88 (br s, 2H), 5.14 (br s, 2H); 13C NMR (CDCl3): δ 165.2, 105.0, 59.72, 57.79, 23.90. CaIc. for C5H6BrN3O5: %C 22.41, %H 2.26, %N 15.68; Found: %C 22.61, %H 2.36, %N 15.58.
HPLC/MS C-8 reverse phase column with acetonitrile/water mobile phase – m/e 266.95 (100%), 268.95 (98.3%). FT-IR 3014.24 (weak), 1677.66, 1586.30, 1567.65, 1445.55 (NO2), 1367.80, 1338.00, 1251.27 cm‘1.
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References
- Oronsky B, Takahashi L, Gordon R, Cabrales P, Caroen S, Reid T (2023). “RRx-001: a chimeric triple action NLRP3 inhibitor, Nrf2 inducer, and nitric oxide superagonist”. Frontiers in Oncology. 13 1204143. doi:10.3389/fonc.2023.1204143. PMC 10258348. PMID 37313460.
- Jayabalan N, Oronsky B, Cabrales P, Reid T, Caroen S, Johnson AM, et al. (April 2023). “A Review of RRx-001: A Late-Stage Multi-Indication Inhibitor of NLRP3 Activation and Chronic Inflammation”. Drugs. 83 (5): 389–402. doi:10.1007/s40265-023-01838-z. PMC 10015535. PMID 36920652.
- Ryan C (30 March 2023). “FDA Grants Fast Track Designation to RRx-001 for Severe Oral Mucositis in Head and Neck Cancer”. OncLive.
| Clinical data | |
|---|---|
| Other names | Rrx-001 |
| Identifiers | |
| IUPAC name | |
| CAS Number | 925206-65-1 |
| PubChem CID | 15950826 |
| DrugBank | DB12060 |
| ChemSpider | 13092644 |
| UNII | 7RPW6SU9SC |
| KEGG | D12720 |
| ChEMBL | ChEMBL3526802 |
| Chemical and physical data | |
| Formula | C5H6BrN3O5 |
| Molar mass | 268.023 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
/////////Nibrozetone, anti-inflammatory, RRx-001, RRx 001, ABDNAZ
New Drug Approvals 
