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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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PIMICOTINIB

July 8, 2025 2:56 am / Leave a comment


PIMICOTINIB

CAS 2253123-16-7

ABSK021

WeightAverage: 420.473
Monoisotopic: 420.190988657

Chemical FormulaC22H24N6O3

3,3-dimethyl-N-[6-methyl-5-[2-(1-methylpyrazol-4-yl)pyridin-4-yl]oxypyridin-2-yl]-2-oxopyrrolidine-1-carboxamide

CSF-1R inhibitor Pimicotinib (ABSK021) of Abbisko Therapeutics, HV1XI8HST2

Pimicotinib (ABSK021), an oral, highly potent and selective small molecule blocker of the colony-stimulating factor 1 receptor (CSF-1R) independently discovered by Abbisko Therapeutics. A number of studies have shown that blocking the CSF-1R signaling pathway could effectively modulate and change macrophage functions, and potentially treat many macrophage-dependent human diseases.[1]

Pimicotinib is under investigation in clinical trial NCT05804045 (Study of Pimicotinib (ABSK021) for Tenosynovial Giant Cell Tumor (MANEUVER)).

History

In December 2023, Abbisko Therapeutics entered into a licensing agreement for pimicotinib in all indications for China rights with Merck KGaA.[2] [3][4]

In April 2023, a global phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial designed to evaluate the safety and efficacy of pimicotinib in patients with tenosynovial giant cell tumor was started (NCT05804045).[5]

Following with pimicotinib for tenosynovial giant cell tumor treatment in phase III, pimicotinib has also entered into a phase II trial in June 2023 for cGVHD treatment in China.[6]

The U.S. Food and Drug Administration (FDA) and the Center for Drug Evaluation (CDE) of NMPA granted pimicotinib breakthrough therapy designation (BTD) for the treatment of tenosynovial giant cell tumor patients that are not amenable to surgery in January 2023 and July 2022, respectively.[7]

Research

Pimicotinib is being investigated as a treatment for tenosynovial giant cell tumor,[8][9] chronic graft-versus-host-disease (cGVHD), and pancreatic cancer.

PATENTS

example 41 [WO2018214867A9]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018214867&_cid=P10-MCTXKZ-70170-1

Example 41: Preparation of 3-hydroxy-3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-carbonylpyrrolidine-1-carboxamide 

[0463]

[0464]Palladium carbon (50 mg) was added to a solution of 3-(benzyloxy)-3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-carbonylpyrrolidine-1-carboxamide (80 mg, 0.15 mmol) in methanol (10 mL). The reaction was stirred at 50° C. for 2 hours in the presence of hydrogen. Filtered and concentrated. Plate chromatography (dichloromethane/methanol=18:1) gave 3-hydroxy-3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-carbonylpyrrolidine-1-carboxamide (10 mg, yield 15%). MS m/z(ESI):423[M+1] 

+ . 

[0465]

1H NMR(400MHz,DMSO-d 6)δ10.93(s,1H),8.37(d,J＝5.7Hz,1H),8.27(s,1H),8.01–7.85(m,2H),7.67(d,J＝8.8Hz,1H),7.19(d,J＝2.4Hz,1H),6.62(dd,J＝5.7,2.4Hz,1H),5.89(s,1H),3.86(s,3H),3.83–3.76(m,1H),3.67–3.61(m,1H),2.29(s,3H),2.09–1.98(m,2H),1.34(s,3H)。

PATENTS

EP3643715

WO2018233527

US20200140431

US11180495 WO2018233527  US20200140431

References

  1. ^ Vaynrub A, Healey JH, Tap W, Vaynrub M (2022). “Pexidartinib in the Management of Advanced Tenosynovial Giant Cell Tumor: Focus on Patient Selection and Special Considerations”. OncoTargets and Therapy. 15: 53–66. doi:10.2147/OTT.S345878. PMC 8763255. PMID 35046667.
  2. ^ Merck Strengthens Oncology Portfolio Through Commercialization Agreement With Abbisko for Phase III Asset, Pimicotinib. (2023) https://www.merckgroup.com/en/news/abbisko-pimicotinib-agreement-04-12-2023.html
  3. ^ Merck KGaA buys into Abbisko’s late-stage joint tumor med for $70M upfront. Fierce Biotech. (2023) https://www.fiercebiotech.com/biotech/merck-kgaa-buys-abbiskos-late-stage-joint-tumor-med-70m-upfront
  4. ^ “Abbisko Therapeutics Announced the Entry into a Licensing Agreement for Pimicotinib (ABSK021) with Merck”. http://www.prnewswire.com (Press release). Retrieved 18 April 2024.
  5. ^ Study of Pimicotinib (ABSK021) for Tenosynovial Giant Cell Tumor (MANEUVER). U. S. National Institutes of Health, National Cancer Institute. https://classic.clinicaltrials.gov/ct2/show/NCT05804045
  6. ^ A Phase II Study Evaluating the Efficacy and Safety of ABSK021 (Pimicotinib)) in the Treatment of cGvHD Chronic Graft Versus Host Disease (cGvHD)U. S. National Institutes of Health, National Cancer Institute.https://classic.clinicaltrials.gov/ct2/show/NCT06186804
  7. ^ “FDA Grants Breakthrough Therapy Designation to Abbisko’s Pimicotinib”. Global genes. Retrieved 18 April 2024.
  8. ^ “Pimicotinib”. TGCT Support. Retrieved 18 April 2024.
  9. ^ “A Phase 3, Randomized, Double-blind, Placebo-Controlled, Multicenter Study of ABSK021 to Assess the Efficacy and Safety in Patients With Tenosynovial Giant Cell Tumor”. clinicaltrials. clinicaltrials.gov. 10 April 2024. Retrieved 18 April 2024.
  • “Pimicotinib”. NCI Drug Dictionary. National Cancer Institute.
  • Clinical trial number NCT06186804 for “A Phase II Study Evaluating the Efficacy and Safety of ABSK021 (Pimicotinib)) in the Treatment of cGvHD Chronic Graft Versus Host Disease (cGvHD)” at ClinicalTrials.gov
Clinical data
Other namesABSK021
Routes of
administration		Oral
Identifiers
showIUPAC name
CAS Number2253123-16-7
PubChem CID139549388
ChemSpider128942304
UNIIHV1XI8HST2
KEGGD12938
Chemical and physical data
FormulaC22H24N6O3
Molar mass420.473 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

//////////PIMICOTINIB, ABSK 021, Abbisko Therapeutics, HV1XI8HST2

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PALAZESTRANT

July 5, 2025 8:26 am / Leave a comment


PALAZESTRANT

CAS 2092925-89-6

OP-1250, VU35KM56Q4

449.6 g/mol, C28H36FN3O

(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-[4-(1-propylazetidin-3-yl)oxyphenyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole

Palazestrant (OP-1250) is an investigational drug being developed for estrogen receptor-positive (ER+) breast cancer. It is a small molecule with a dual mechanism of action, acting as both a complete estrogen receptor antagonist and a selective estrogen receptor degrader (SERD). This means it can block estrogen receptor activity and also degrade the receptor itself, potentially offering a more effective treatment approach. 

Here’s a more detailed breakdown:

  • Dual Mechanism:Palazestrant is a complete ER antagonist, meaning it blocks all estrogen receptor activity. It is also a SERD, which means it degrades the estrogen receptor, preventing it from functioning. 
  • Oral Administration:Palazestrant is an orally available drug. 
  • Clinical Trials:Palazestrant is currently in clinical trials, including Phase 1/2 and Phase 3 studies, for the treatment of ER+, HER2- metastatic breast cancer. 
  • Combination Therapy:Palazestrant is being evaluated in combination with other drugs like CDK4/6 inhibitors (e.g., ribociclib). 
  • Promising Results:Preliminary results from clinical trials have shown promising antitumor efficacy and favorable pharmacokinetic properties for palazestrant. 
  • FDA Fast Track Designation:The FDA has granted Fast Track designation for the treatment of ER+/HER2- metastatic breast cancer that has progressed following endocrine therapy with a CDK4/6 inhibitor. 
  • Brain Metastasis:Palazestrant has shown activity in brain metastasis animal models. 
  • ESR1 Mutation Status:Palazestrant has demonstrated activity against both wild-type and mutant ER (ESR1) breast cancer models. 

Palazestrant is an investigational new drug which is being evaluated for the treatment of estrogen receptor-positive (ER+) breast cancer, with a dual mechanism of action as both a complete estrogen receptor antagonist (CERAN) and a selective estrogen receptor degrader (SERD). This orally bioavailable small molecule has demonstrated potent activity against both wild-type and mutant forms of the estrogen receptor.[1]

SCHEME

MAIN

PAPER

https://pubs.acs.org/doi/10.1021/acsomega.4c11023

PATENTS

US11672785, Compound B

https://patentscope.wipo.int/search/en/detail.jsf?docId=US379744130&_cid=P22-MCPZ5L-11621-1

PATENTS’

WO2017059139 

WO2023225354

WO2023091550

WO2023283329

WO2021178846

References

  1. ^ Parisian AD, Barratt SA, Hodges-Gallagher L, Ortega FE, Peña G, Sapugay J, et al. (March 2024). “Palazestrant (OP-1250), A Complete Estrogen Receptor Antagonist, Inhibits Wild-type and Mutant ER-positive Breast Cancer Models as Monotherapy and in Combination”. Molecular Cancer Therapeutics. 23 (3): 285–300. doi:10.1158/1535-7163.MCT-23-0351. PMC 10911704. PMID 38102750.
Clinical data
Other namesOP-1250
Identifiers
showIUPAC name
CAS Number2092925-89-6
PubChem CID135351887
DrugBankDB18971
ChemSpider128922074
UNIIVU35KM56Q4
KEGGD12827
ChEMBLChEMBL5314475
Chemical and physical data
FormulaC28H36FN3O
Molar mass449.614 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

///////////PALAZESTRANT, OP 1250, A1AEA, VU35KM56Q4

Orforglipron’

July 2, 2025 8:23 am / Leave a comment


Orforglipron’

CAS 2212020-52-3

C48H48F2N10O5

883.0 g/mol MW

LY-3502970

  • OWL833
  • 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
  • 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one

SCHEME

PATENT

JP2019099571

PATENT

WO2018056453 

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018056453&_cid=P22-MCLODW-73083-1

 <Example Compound 67>
　Main cycle isomer

　 1 H-NMR (600 MHz, CDCl 

3 ) δ: 11.32 (1H, s), 8.13 (1H, d, J 

ＨＦ＝0.7 Hz), 7.59 (1H, d, J ＝8.6 Hz), 7.52 (1H, s), 7.48 (1H, dd, J ＝8.9 Hz, J 

ＨＦ ＝6.9 Hz ), 7.28 (1H, d, J ＝8.9 Hz), 7.26 (1H, dd, J ＝8.6, 1.7 Hz), 7.16 (2H, d, J 

ＨＦ =6.1Hz), 6.70 (1H, s), 6.61 (1H, dd, J = 3.0Hz, 

JHF =1.1Hz), 6.31 (1H, d, J = 3.0Hz), 5.79 (1H, q, J = 6.7Hz), 4.4 7 (1H, dd, J=13.5, 5.2Hz), 4.12 (3H, s), 3.88 (1H, m), 3.83 (1 H, m), 3.60 (1H, ddd, J = 13.5, 12.9, 3.6Hz), 3.15 (1H, ddd, J = 15.8, 12.9, 5.2Hz), 3.04 (1H, m), 3.00 (1H, m), 2.29 (6H, d, J 

HF =1.1Hz), 1.91 (1H, dd, J = 6.1, 5.8Hz), 1.79-1.76 ( 2H, m), 1.74 (1H, m), 1.65 (1H, m), 1.57 (3H, d, J=6.7 Hz), 1.60-1.55 (1H, m), 1.52 (1H, dd, J=9.5, 5.8Hz ), 1.34 (3H, s), 1.28 (3H, s), 1.20 (3H, d, J=6.0Hz). 

[0437]　Parainversion isomer

　 1 H-NMR (600 MHz, CDCl 

3 ) δ: 11.27 (1H, s), 8.04 (1H, s), 7.55 (1H, d, J = 8.7 Hz), 7.52 (1H, s), 7.25-7.22 (2H, m), 7.12 (1H, d, J = 8.8 Hz), 7.06 (2H, d, J 

HF =6.0Hz), 6.71 (1H, s), 6.47 (1H, m), 6.08 ( 1H, d, J=3.0Hz), 5.26 (1H, q, J=6.6Hz), 4. 87 (1H, dd, J = 13.1, 4.8Hz), 4.07 (3H, s), 3 .90-3.80 (2H, m), 3.39 (1H, ddd, J = 13.1, 1 2.2, 4.6Hz), 3.08-2.97 (3H, m), 2.25 (6H, s), 1.79-1.73 (3H, m), 1.67 (3H, d, J=6.6H z), 1.64 (1H, m), 1.45-1.37 (2H, m), 1.34 ( 3H, s), 1.28 (3H, s), 1.06 (3H, d, J=6.0Hz).

Orforglipron (LY-3502970) is an oral, non-peptide, small-molecule GLP-1 receptor agonist developed as a weight loss drug by Eli Lilly and Company.[1] It was discovered by Chugai Pharmaceutical Co., then was licensed to Lilly in 2018.[1]

Orforglipron is easier to produce than existing peptide GLP-1 agonists and is expected to be cheaper.[2]

Mechanism

Orforglipron is a small-molecule, partial GLP-1 receptor agonist affecting the activity of cyclic adenosine monophosphate (cAMP); its effects are similar to the actions of glucagon-like peptide-1 (GLP-1) for reducing food intake and lowering blood glucose levels.[1][3]

Clinical trials

The results of Phase I safety and Phase II ascending-dose clinical trials enrolling people with obesity or type 2 diabetes were published in 2023.[4][5]

Orforglipron has a half-life of 29 to 49 hours across the doses tested and is taken once per day by mouth without food or water restrictions.[3]

Safety and dosing trials showed that the incidence of adverse events in orforglipron-treated participants was 62–89%, mostly from gastrointestinal discomfort (44–70% with orforglipron, 18% with placebo) having mild to moderate severity.[6] The most common side effects of orforglipon are diarrhea, nausea, upset stomach, and constipation.[1][6]

The ability of orforglipron to reduce blood sugar levels and body weight was judged favorable compared to dulaglutide.[6]

Phase III ACHIEVE-1 trial

In April 2025, results from a Phase III clinical trial involving 559 people with type 2 diabetes who took an oral orforglipron pill, injectable dulaglutide or a placebo daily for 40 weeks showed that orforglipron produced a reduction in blood glucose levels by 1.3 to 1.6 percentage points from a starting level of 8%.[1][7]

More than 65% of participants taking the highest dose of orforglipron achieved a reduction of hemoglobin A1C level by more than or equal to 1.5 percentage points, bringing them into the non-diabetic range as defined by the American Diabetes Association.[1] People taking the highest dose of the pill lost 8% of their weight, or around 16 lb (7.3 kg), on average after 40 weeks.[1][8]

Side effects were similar to those seen with other GLP-1 agonists, and no significant liver problems were observed.[1]

References

  1. ^ Jump up to:a b c d e f g h “Lilly’s oral GLP-1, orforglipron, demonstrated statistically significant efficacy results and a safety profile consistent with injectable GLP-1 medicines in successful Phase 3 trial” (Press release). Eli Lilly. April 17, 2025. Retrieved April 18, 2025.
  2. ^ Sidik S (2023). “Beyond Ozempic: brand-new obesity drugs will be cheaper and more effective”. Nature. 619 (7968): 19. Bibcode:2023Natur.619…19S. doi:10.1038/d41586-023-02092-9. PMID 37369789.
  3. ^ Jump up to:a b Kokkorakis M, Chakhtoura M, Rhayem C, et al. (January 2025). “Emerging pharmacotherapies for obesity: A systematic review”. Pharmacological Reviews. 77 (1): 100002. doi:10.1124/pharmrev.123.001045. PMID 39952695.
  4. ^ Pratt E, Ma X, Liu R, et al. (June 2023). “Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1b, multicentre, blinded, placebo-controlled, randomized, multiple-ascending-dose study in people with type 2 diabetes”. Diabetes, Obesity & Metabolism. 25 (9): 2642–2649. doi:10.1111/dom.15150. PMID 37264711. S2CID 259022851.
  5. ^ Wharton S, Blevins T, Connery L, et al. (June 2023). “Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity”. The New England Journal of Medicine. 389 (10): 877–888. doi:10.1056/NEJMoa2302392. PMID 37351564.
  6. ^ Jump up to:a b c Frias J, et al. (2023). “Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study”. The Lancet. 402 (10400): 472–83.
  7. ^ Constantino AK (April 17, 2025). “Eli Lilly’s weight loss pill succeeds in first late-stage trial on diabetes patients”. CNBC. Retrieved April 17, 2025.
  8. ^ Kolata G (April 17, 2025). “Daily Pill May Work as Well as Ozempic for Weight Loss and Blood Sugar”. The New York Times. ISSN 0362-4331. Retrieved April 17, 2025.

Above: molecular structure of orforglipron Below: 3D representation of an orforglipron molecule
Clinical data
Other namesLY-3502970
Routes of
administration		Oral
ATC codeNone
Pharmacokinetic data
Elimination half-life29–49 hours
Identifiers
showIUPAC name
CAS Number2212020-52-3
PubChem CID137319706
ChemSpider71117507
UNII7ZW40D021M
ChEMBLChEMBL4446782
Chemical and physical data
FormulaC48H48F2N10O5
Molar mass882.974 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

///////////Orforglipron, LY-3502970, LY 3502970, OWL833, OWL 833

Nerandomilast

June 25, 2025 2:45 am / Leave a comment


Nerandomilast

CAS 1423719-30-5

C20H25ClN6O2S

Molecular Weight448.97
FormulaC20H25ClN6O2S
I5DGT51IB8

fda 2025, approvals 2025, Jascayd,10/7/2025, To treat idiopathic pulmonary fibrosis

[1-[[(5R)-2-[4-(5-chloropyrimidin-2-yl)piperidin-1-yl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol

Cyclobutanemethanol, 1-[[(5R)-2-[4-(5-chloro-2-pyrimidinyl)-1-piperidinyl]-6,7-dihydro-5-oxidothieno[3,2-d]pyrimidin-4-yl]amino]-

1-[[(5R)-2-[4-(5-Chloro-2-pyrimidinyl)-1-piperidinyl]-6,7-dihydro-5-oxidothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutanemethanol

Nerandomilast (BI 1015550) is an investigational oral medication being studied for the treatment of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). It is a preferential inhibitor of phosphodiesterase 4B (PDE4B) and has shown potential in slowing lung function decline in patients with IPF. 

Key points about nerandomilast:

  • Mechanism of Action:Nerandomilast inhibits PDE4B, an enzyme that plays a role in inflammation and fibrosis. 
  • Clinical Trials:Phase 3 clinical trials have shown that nerandomilast can slow lung function decline in patients with IPF and PPF. 
  • Efficacy:The trials demonstrated that nerandomilast led to a smaller decline in forced vital capacity (FVC), a measure of lung function, compared to placebo. 
  • Safety:Diarrhea was the most frequent adverse event, but serious adverse events were balanced across treatment groups. 
  • Progressive Fibrosing ILDs:Nerandomilast is also being investigated in other progressive fibrosing interstitial lung diseases (ILDs) beyond IPF. 
  • FDA Designation:Nerandomilast received Breakthrough Therapy Designation from the FDA for the treatment of IPF. 
  • Not a Cure:While nerandomilast can slow disease progression, it does not cure pulmonary fibrosis. 
  • Not Yet Approved:Nerandomilast is still an investigational drug and is not yet approved for use. 

Nerandomilast (BI 1015550) is an orally active inhibitor of PDE4B with an IC50 value of 7.2 nM. Nerandomilast has good safety and potential applications in inflammation, allergic diseases, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD).

SCHEME

1H NMR (400 MHz, DMSO-D6)  1.57–1.84 (m, 2H), 1.96 (br d, J = 12.5 Hz, 2H), 2.10–2.21 (m, 2H), 2.24–
2.41 (m, 2H), 2.82–2.98 (m, 2H), 3.06 (br t, J = 11.7 Hz, 2H), 3.13–3.27 (m, 2H), 3.36–3.47 (m, 1H), 3.71 (d, J =
5.64 Hz, 2H), 4.70 (br d, J = 12.5 Hz, 2H), 4.84 (t, J = 5.7 Hz, 1H), 7.35 (s, 1H), 8.85 (s, 2H).

1H NMR (DMSO-d6, 400 MHz)  1.87–1.92 (m, 2H), 2.12–2.17 (m, 2H), 3.08 (ddd, J = 12.8, 12.8, 2.8 Hz,
2H), 3.21 (m, 1H), 3.34–3.42 (m, 2H), 8.47 (br, 2H), 8.19 (s, 2H).

PATENT

US20150045376

WO2013026797

PAPER

https://pubs.acs.org/doi/10.1021/acs.oprd.4c00309

A robust and scalable synthesis process for Nerandomilast (1, BI 1015550), a selective PDE4B inhibitor with potential therapeutic properties for the treatment of respiratory diseases, was developed and implemented at a pilot plant on a multikilogram scale. Key aspects of the process include the efficient synthesis of intermediate (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (4) by means of a regioselective SNAr reaction between (1-aminocyclobutyl)methanol (6) and 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (5), a new convergent synthesis of 5-chloro-2-(piperidin-4-yl)pyrimidine (3) by means of a Suzuki coupling, and a highly enantioselective sulfide oxidation to give chiral nonracemic (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (2).

//////////Nerandomilast, BI 1015550, I5DGT51IB8, fda 2025, approvals 2025, Jascayd,

Nemorexant

June 24, 2025 2:40 am / Leave a comment


Nemorexant

Nedometinib

June 23, 2025 2:41 am / Leave a comment


Nedometinib

CAS 2252314-46-6

NFX-179, K5T4I78IYZ

Molecular Weight470.24
FormulaC17H16FIN4O3

2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1-methylpyrrolo[2,3-b]pyridine-3-carboxamide

Nedometinib (NFX-179) is a specific MEK1 inhibitor with an IC50 of 135 nM. Nedometinib inhibits p-ERK, MAPK. Nedometinib exerts anticancer activity against squamous cell carcinoma. Nedometinib can be used for research in dermatosis, neurofibromatosis.

Nedometinib is a topical gel formulation composed of an inhibitor of mitogen-activated protein kinase kinase (MAP2K; MAPKK; MEK), with potential antineoplastic activity. Upon topical administration, nedometinib penetrates into the dermis of the skin where it specifically targets, binds to and inhibits the catalytic activity of MEK, thereby inhibiting the activation of MEK-dependent effector proteins including extracellular signal-regulated kinase (ERK) and inhibits the proliferation of tumor cells in which the RAS/RAF/MEK/ERK signaling pathway is overactivated. The threonine/tyrosine protein kinase MEK plays a key role in the RAS/RAF/MEK/ERK signaling pathway, which is frequently upregulated in a variety of tumor cell types and regulates key cellular activities including cell growth, proliferation, survival, differentiation and apoptosis. Rapid degradation of NFX-179 upon reaching the systemic circulation minimizes side effects caused by systemic exposure.

SCHEME

PATENTS

US11161845, https://patentscope.wipo.int/search/en/detail.jsf?docId=US295432044&_cid=P20-MC8HLL-16550-1

Example 2: 2-((2-Fluoro-4-iodophenyl)amino)—N-(2-hydroxyethoxy)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl chloride

      
 (MOL) (CDX)
      To tert-butyl 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (0.6 g, 1.3 mmol), thionyl chloride (0.9 mL, 12.8 mmol) was added followed by H 2O (23 μL). The flask was sealed with a rubber septum and the mixture was stirred at room temperature for 18 h. The mixture was concentrated to dryness in vacuo to give the product (0.5 g, 94%) as a beige solid. UPLC-MS (Acidic Method, 2 min): rt 1.28 min, m/z 426.0 [M+H] + (detected as the corresponding methyl ester after quenching an aliquot of the mixture with MeOH).
      Alternative preparation: A stirred solution of tert-butyl 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (5.00 g, 10.7 mmol) in anhydrous 1,4-dioxane (28 mL) was treated with thionyl chloride (7.7 mL, 107 mmol) at ambient temperature, followed by a 4 N solution of hydrogen chloride in 1,4-dioxane (14 mL, 5.35 mmol), and the resulting mixture was heated to 50° C. for 48 h. The reaction mixture was cooled to 40° C. and subjected to a continuous distillation process under vacuum from anhydrous toluene (maintaining the total volume of the batch around 30 mL) to remove the thionyl chloride and 1,4-dioxane. The resulting dark grey suspension of 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl chloride was used in subsequent steps without further purification. UPLC-MS (Acidic Method, 2 min): rt 1.29 min, m/z 426.0 [M+H] + (following the quenching of an aliquot of the batch into methanol to give the corresponding methyl ester).

Alternative 1 for the preparation of 2-((2-Fluoro-4-iodophenyl)amino)—N-(2-hydroxyethoxy)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

      
 (MOL) (CDX)
      A solution of 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl chloride (460 mg, 1.07 mmol) in dry DCM (27 mL) was cooled to 0° C. in an ice bath and then treated with dry pyridine (970 μL, 11.98 mmol) and the mixture was stirred for 15 min followed by an addition of (2-aminooxy)ethanol (124 mg, 1.61 mmol) in dry DCM (2 mL). The mixture was stirred for 15 min, then diluted with DCM and acidified with 1 M citric acid aqueous solution to pH 3. The organic phase was washed with H 2O, brine, dried over Na 2SO 4 and concentrated in vacuo. The crude was purified by preparative HPLC to give the product (181 mg, 36%) as a white solid. UPLC-MS (Acidic Method, 4 min): rt 2.67 min, m/z 471.2 [M+H] +. 1H NMR (400 MHz, DMSO-d 6) δ ppm 10.84 (br s, 1H), 8.69 (br s, 1H), 8.25 (dd, J=4.8, 1.4 Hz, 1H), 8.13 (dd, J=7.9, 1.5 Hz, 1H), 7.63 (dd, J=10.8, 1.9 Hz, 1H), 7.33 (dd, J=8.5, 1.1 Hz, 1H), 7.21 (dd, J=7.8, 4.8 Hz, 1H), 6.52 (t, J=8.8 Hz, 1H), 4.74 (br s, 1H), 3.79 (t, J=4.9 Hz, 2H), 3.48-3.54 (m, 5H)

Alternative 2 for the Preparation of 2-((2-Fluoro-4-iodophenyl)amino)—N-(2-hydroxyethoxy)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

      To a solution of 2-(aminooxy)ethanol (8.41 g, 109 mmol) in anhydrous THF (20 mL) at 0° C. was added a suspension of 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl chloride (9.37 g, 21.8 mmol) in anhydrous THF (80 mL) and residual toluene via syringe. After 40 minutes UPLC analysis showed complete conversion. The reaction mixture was partitioned between EtOAc (300 mL) and H 2O (300 mL), the biphasic mixture was filtered and the organic layer separated. The aqueous layer was extracted with EtOAc (200 mL) and the organics combined, washed with brine, dried over Na 2SO 4 and the solvent removed in vacuo. The crude solid was suspended in EtOAc (40 mL, 4 volumes), stirred over the weekend and filtered to give the desired product (7.45 g, 73%) as a dark beige solid which can be recrystallized from anisole. UPLC-MS (Acidic Method, 2 min): rt 1.01 min, m/z 471.2 [M+H] +. 1H NMR (400 MHz, DMSO-d 6) δ ppm 10.84 (br s, 1H), 8.69 (br s, 1H), 8.25 (dd, J=4.8, 1.4 Hz, 1H), 8.13 (dd, J=7.9, 1.5 Hz, 1H), 7.63 (dd, J=10.8, 1.9 Hz, 1H), 7.33 (dd, J=8.5, 1.1 Hz, 1H), 7.21 (dd, J=7.8, 4.8 Hz, 1H), 6.52 (t, J=8.8 Hz, 1H), 4.74 (br s, 1H), 3.79 (t, J=4.9 Hz, 2H), 3.48-3.54 (m, 5H).

PATENTS

WO2018213810

Science Translational Medicine (2023), 15(717), eade1844 

WO2018213810, Nflection Therapeutics, Inc.

WO2023096935

WO2022262797 

WO2020106303

WO2020106304

WO2020106303 

WO2020106307 

WO2020106304 

WO2018213810 

WO2020106304 

WO2020106303  

REF


[1]. Kincaid, et al. Preparation of pyrrolopyridine-aniline compounds for treatment of dermal disorders. World Intellectual Property Organization, WO2018213810 A1. 2018-11-22.
[2]. Sarin KY, et al. Development of a MEK inhibitor, NFX-179, as a chemoprevention agent for squamous cell carcinoma. Sci Transl Med. 2023 Oct 11;15(717):eade1844.  [Content Brief]

/////////Nedometinib, NFX-179, NFX 179, K5T4I78IYZ, EN300-27122249

Modoflaner 

June 22, 2025 2:34 am / Leave a comment


Modoflaner ‘

Molecular Weight715.23
FormulaC23H10F12IN3O2
CAS No.1331922-53-2

6-fluoro-N-[2-fluoro-3-[[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2-iodo-6-(trifluoromethyl)phenyl]carbamoyl]phenyl]pyridine-3-carboxamide

E583FHZ8C9

Modoflaner is an isophenylamide insecticide. Modoflaner may act through allosteric regulation of gamma-aminobutyric acid-gated chloride channels.

SCHEME

PATENT

WO2019059412

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019059412&_cid=P20-MC71WG-08056-1

SYN

 Modoflaner is another isophthalamide insecticide developed by Mitsui Chemicals Agriculture Co., Ltd. in Japan. Its structure is similar to broflanilide and cyproflanilide created in China, except that it introduces iodine and fluoropyridine structures. It is speculated that the mechanism of action of modoflaner is mainly through allosteric regulation of 
γ -aminobutyric acid-gated chloride ion channels, which is similar to isoxazoline insecticides and acaricides such as mivolana and eumivolana. Indoor bioassay studies have shown that modoflaner has a killing rate of more than 70% (6 days) against Spodoptera litura, Plutella xylostella and Laodelphax 
striatum at a concentration of 100 mg/L. It has a killing rate of 95% (48 hours) against adult 
Ctenocephalides felis at a dose of 0.04 μg/ 
cm2 or 0.0064 mg/ L . It has a killing rate of 90% (48 hours) 
against nymphs of American flower ticks, adults of 
Ixodes ricinus and adults of 
R. sanguineus at a dose of 0.2 μg/cm2. It can prevent female adults of R. sanguineus from laying eggs or hatching eggs after 7 days of in vitro injection at a dose of 0.032 μg/tick. The creation idea and synthetic route of Modoflaner are shown in Figure 2. The synthetic order of iodination and amidation deserves further study.

[1]. International Nonproprietary Names for Pharmaceutical Substances (INN). WHO Drug Information, Vol. 34, No. 2, 2020.

//////////Modoflaner, E583FHZ8C9

MIVORILANER

June 21, 2025 2:36 am / Leave a comment


MIVORILANER

1414642-93-5

Molecular FormulaC22H17Cl2F6N3O3S
Molecular Weight588.35
  • 3-[(5S)-5-(3,5-Dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-[(2,2-difluoroethyl)amino]-2-oxoethyl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide (ACI)
  • 3-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-N-[2-[(2,2-difluoroethyl)amino]-2-oxoethyl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide
  • ITABH 19-01
  • LY 3116151
  • WHO 11674
  • XN7QGY28HM
  • HI-154

1-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-1,2-oxazol-3-yl]-N-[2-(2,2-difluoroethylamino)-2-oxoethyl]-5,6-dihydro-4H-cyclopenta[c]thiophene-3-carboxamide

MIVORILANER is a small molecule drug with a maximum clinical trial phase of I and has 1 investigational indication.

Mivorilaner, an antineoplastic, can be used for the research of veterinary medicine

SCHEME

PATENT

WO2012155676

(S)-3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid [(2,2-difluoro-ethylcarbamoyl)-methyl]-amide

3 g of 3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid [(2,2-difluoro-ethylcarbamoyl)-methyl]-amide is separated by SFC separation to give desired product (1.4 g, 93%). SFC conditions are as follows: Instrument: Thar 350 Column: AD 250 mm*50 mm, 10 um Mobile phase: A: Supercritical CO2, B: EtOH, A:B=60:40 at 240 ml/min Column Temp: 38° C. Nozzle Pressure: 100 Bar Nozzle Temp: 60° C. Evaporator Temp: 20° C. Trimmer Temp: 25° C. Wavelength: 220 nm. 1H NMR (CDCl3, 400 MHz): δ 7.56 (d, J=6.0, 2H), 6.64 (brs, 1H), 6.40 (brs, 1H), 6.03-5.73 (m, 1H), 4.15 (d, J=5.2, 2H), 4.01 (d, J=17.2, 1H), 3.74-3.65 (m, 1H), 3.62 (d, J=17.2, 1H), 2.97 (t, J=7.6, 2H), 2.89 (t, J=7.6, 2H), 2.56 (m, 2H).

WO2012158396

(WO2012155676, Example 245).

/////////MIVORILANER, ITABH 19-01, LY 3116151, XN7QGY28HM, WHO 11674, HI-154

MIRDAMETINIB

June 20, 2025 2:36 am / Leave a comment


MIRDAMETINIB

Milademetan

June 20, 2025 2:25 am / Leave a comment


MILADEMETAN

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