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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
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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
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MOLECULAR FORMULA C231H386N64O67S5 + (C2H4O)4n MOLECULAR WEIGHT approx. 45 kDa
The structure of navepegritide (YUVIWEL®) is built using a “prodrug” design. It is not a simple small molecule, but rather a complex conjugate consisting of three distinct components designed to release the active drug slowly over time.
1. The Active Part: C-Type Natriuretic Peptide (CNP)
The core of the molecule is a synthetic 38-amino acid peptide (CNP-38).
Sequence: This peptide mimics the natural human C-type natriuretic peptide, which is essential for bone growth.
Function: Once released, this peptide binds to the natriuretic peptide receptor B (NPR-B) on the surface of chondrocytes (cartilage cells) in the growth plates, stimulating bone formation.
2. The Carrier: Polyethylene Glycol (PEG)
To prevent the body from clearing the small peptide too quickly, it is attached to a large, inert carrier.
Type: It uses a multi-arm, branched 40 kDa Polyethylene Glycol (PEG) molecule.
Purpose: The PEG carrier acts as a shield and a “weight,” making the molecule too large to be filtered out rapidly by the kidneys. This is what allows for once-weekly dosing instead of daily injections.
3. The Linker: TransCon™ Technology
This is the most critical part of the structure. The peptide is attached to the PEG carrier via a cleavable linker.
Mechanism: This linker is designed to break down spontaneously at a predictable rate under physiological conditions (neutral pH and body temperature).
The Result: As the linker slowly breaks, it releases the unmodified, active CNP-38 into the bloodstream. Because the peptide is released in its natural state, it retains its full biological activity.
Summary Table: Structural Components
Component
Description
Role
Peptide
CNP-38 (38 amino acids)
The “payload” that stimulates bone growth.
Linker
pH-sensitive cleavable bond
Controls the slow release of the peptide.
Carrier
40 kDa PEG
Increases the half-life and prevents rapid clearance.
Note: This structure is technically a prodrug because the large PEG-bound version is inactive; only the released CNP-38 peptide performs the therapeutic work.
C-Type natriuretic peptide (CNP), human, (89-126)-fragment (1-38) (CNP-38), conjugated at N6 of Lys26 with four O-methylpoly(ethylene glycol) chains (approx. 10 kDa each) via a cleavable tetra-antennary linker; L-leucyl-L-glutaminyl-L-?-glutamyl-L-histid
Poly(oxy-1,2-ethanediyl), ?-hydro-?-methoxy-, 26,26,26,26-tetraether with L-leucyl-L-glutaminyl-L-?-glutamyl-L-histidyl-L-prolyl-L-asparaginyl-L-alanyl-L-arginyl-L-lysyl-L-tyrosyl-L-lysylglycyl-L-alanyl-L-asparaginyl-L-lysyl-L-lysylglycyl-L-leucyl-L-sery
FDA 2026, APPROVALS 2026, 2/27/2026, Yuviwel, Y3BH8M899D, MN-266, TRANSCON CNP, PA (224-233), Influenza, DA-66438, ACP-015, WHO 11981,
To increase linear growth in pediatric patients 2 years and older with achondroplasia with open epiphyses
Navepegritide is a prodrug consisting of a 38-amino acid C-type natriuretic peptide (CNP) moiety conjugated to a multi-arm polyethylene glycol (PEG) carrier via a cleavable linker. This structure allows for the once-weekly dosing approved by the FDA for children with achondroplasia.
Key Details
Purpose: It is designed to increase linear growth by providing continuous exposure to C-type natriuretic peptide (CNP), a protein that helps regulate bone growth.
Mechanism: As a prodrug, it uses Ascendis Pharma’s TransCon technology to release active CNP slowly into the body over a week, maintaining steady levels and avoiding high peaks.
Clinical Benefits: In the pivotal ApproaCH trial, patients treated with navepegritide showed a significant improvement in annualized growth velocity (AGV) compared to those on a placebo. It also showed potential improvements in body proportionality and lower-limb alignment.
Administration: It is administered via a once-weekly subcutaneous injection, offering a less frequent alternative to daily treatments like vosoritide.
Safety: Most common side effects include injection site reactions (redness, itching, or swelling) and a risk of low blood pressure (hypotension).
Pebezertinib is a small molecule drug. The usage of the INN stem ‘-ertinib’ in the name indicates that Pebezertinib is a epidermal growth factor receptor (EGFR) inhibitor. Pebezertinib is under investigation in clinical trial NCT05241873 ((Concerto) Study of BLU-451 in Advanced Cancers With EGFR Exon 20 Insertion Mutations). Pebezertinib has a monoisotopic molecular weight of 497.16 Da.
Pebezertinib is an orally bioavailable, central nervous system (CNS) penetrating, mutant-selective covalent inhibitor of epidermal growth factor receptor (EGFR) exon 20 insertion (Ex20ins) activating mutations, with potential antineoplastic activity. Upon oral administration, pebezertinib selectively targets, irreversibly binds to and inhibits the activity of EGFR Ex20ins and some other oncogenic point mutations. This prevents EGFR Ex20ins-mediated signaling. This may induce cell death and inhibit tumor growth in EGFR Ex20ins-overexpressing tumor cells. EGFR, a receptor tyrosine kinase mutated in many tumors, plays a key role in tumor cell proliferation and tumor vascularization. Pebezertinib is able to penetrate the blood-brain-barrier (BBB) and may therefore exert its activity against EGFR Ex20ins-driven CNS primary tumors and CNS metastases. Pebezertinib does not inhibit the activity of wild-type (WT) EGFR. EGFR Ex20ins are oncogenic driver mutations that constitutively upregulate kinase activity.
(Concerto) Study of BLU-451 in Advanced Cancers With EGFR Exon 20 Insertion Mutations
Scheme 21: Synthesis of N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 37):
Step 1: Synthesis of 5-bromo-2-chloro-N-(2-fluoro-5-nitrophenyl)pyrimidin-4-amine (89):
[0286] Title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure A. The crude was purified by combiflash eluted with 40% ethyl acetate in hexane to get (89) as pale yellow solid (1.3 g, Yield: 44.24 %). MS: [M+H]+ 346.97.
Step 2: Synthesis of 2-chloro-N-(2-fluoro-5-nitrophenyl)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-amine (91):
[0287] Title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure M3. The crude was purified by combiflash eluted with 35% ethyl acetate in hexane to get desired product (91) as light yellow solid (700 mg; Yield: 50.12%). MS:
[M+H]+ 413.10
Step 3: Synthesis of N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (92):
[0288] Title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure H. The crude was purified by combiflash eluted with 1% methanol in dichloromethane to get desired product (92) as pale yellow solid (500 mg; Yield: 70.24%). MS:
[M+H]+ 474.09
Step 4: Synthesis of N4-(5-amino-2-fluorophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (93):
[0289] Title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure L to get (93) as semi solid (350 mg; Yield: 74.78%). MS: [M+H]+ 444.11
Step 5: Synthesis of N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 37):
[0290] Title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure K. The crude was purified by Prep HPLC to get Compound 37 as off white solid (30 mg, Yield: 13.33%).1H NMR (400 MHz, DMSO-d6): δ 10.21 (bs, 1H), 9.24 (bs, 1H), 8.53 (bs, 1H), 7.99 (s, 1H), 7.71-7.81 (m, 5H), 7.57 (s, 1H), 7.08-7.16 (m, 3H), 6.37-6.44 (m, 1H), 6.21-6.26 (m, 1H), 5.74 (d, J = 8.4 Hz, 1H), 3.54 (s, 3H). LCMS: [M+H]+ 498.35.
International Patent Application No. PCT/US2021/057472, the entire teachings of which are incorporated herein by reference, discloses selective inhibitors of EGFR, including exon 20 mutant proteins, which can be used to treat various cancers. The structure of one of the inhibitors disclosed in PCT Patent Application No. PCT/US2021/057472, referred to
herein as “Compound (I)” is shown below:
Example 1 : Preparation of Compound (I)
Synthesis of N-(4-fluoro-3-((2-((l-methyl-lH-pyrazol-4-yl)amino)-5-(4-(trifluoro methyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound I):
Step 1 : Synthesis of 5-bromo-2-chloro-N-(2-fluoro-5-nitrophenyl)pyrimidin-4-amine (89):
To an ice cold solution of 2-fluoro-5-nitroaniline (12) (1.0 eq) in tetrahydrofuran was added sodium hydride (60% dispersion in mineral oil, 3.0 eq) portion-wise. The resulting reaction mixture was stirred at room temperature for 30 minutes and followed by the addition of 2, 4-di chi oro-5 -bromopyrimidine (88) (1.0 eq). The resulting reaction mixture was heated at 60 °C for 16 hours. After completion (TLC monitoring), quenched with ice, extracted with ethyl acetate (3 times). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by combiflash eluted with 40% ethyl acetate in hexane to get (89) as pale yellow solid (1.3 g, Yield: 44.24 %). MS: [M+H]+ 346.97.
Step 2: Synthesis of 2-chloro-N-(2-fluoro-5-nitrophenyl)-5-(4-(trifluoromethyl)phenyl) pyrimidin-4-amine (91):
To a solution of halo derivative (89) (1.0 eq) and respective boronate acid/ester derivative (90) (1.1 eq) in A A i methyl form am ide: water (4: 1) was added sodium carbonate or sodium bicarbonate (2.0 eq). The resulting reaction mixture was degassed under argon atmosphere for 15 minutes, followed by addition of tetrakis(triphenylphosphine)palladium(0) (0.1 eq). The resulting reaction mixture was heated at 90 °C for 16 hours. After completion of reaction (TLC monitoring), the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by combiflash eluted with 35% ethyl acetate in hexane to get desired product (91) as light yellow solid (700 mg; Yield: 50.12%). MS: [M+H]+413.10.
Step 3 : Synthesis of N4-(2-fluoro-5-nitrophenyl)-N2-(l-methyl-lH-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (92):
To an ice-cold solution of chloro compound (91) (1.0 eq) in isopropanol was added amine (22) (1.2 eq) and trifluoroacetic acid (2.0 eq). The reaction mixture was heated at 110 °C for 16 hours. After completion of the reaction (TLC monitoring), the reaction mixture was concentrated under reduced pressure, added saturated solution of sodium bicarbonate and extracted with dichloromethane (3 times). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude was purified by combiflash eluted with 1% methanol in di chloromethane to get desired product (92) as pale yellow solid (500 mg; Yield: 70.24%). MS: [M+H]+ 474.09.
Step 4: Synthesis of N4-(5-amino-2-fluorophenyl)-N2-(l-methyl-lH-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (93):
To an ice cold solution of nitro derivative (92) (1.0 eq) in methanol: tetrahydrofuran: water (2:2: 1) were added zinc-dust or iron powder (5 eq) and ammonium chloride (5 eq). The resultant reaction mixture was stirred at room temperature for 2 hours. After completion of reaction (TLC monitoring), reaction mixture passed through celite bed washed with 5% methanol in dichloromethane. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to get the desired product (93) as semi solid (350 mg; Yield: 74.78%). MS: [M+H]+ 444.11.
Step 5 : Synthesis of N-(4-fluoro-3-((2-((l-methyl-lH-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound I):
To a solution of amino compound (93) (1.0 eq) in dichloromethane: tetrahydrofuran (1 :1) was cooled to -40 °C followed by triethylamine (3-5 eq) and acryloyl chloride (1.0 eq) were added. The mixture was stirred at the same temperature for 2 hours. After completion of reaction (monitored by TLC), added water and extracted with dichloromethane (3 times). The combined organic layers washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crudes were purified by Prep-HPLC purification to to obtain Compound I as off white solid (30 mg, Yield: 13.33%). ‘H NMR (400 MHz, DMSO-de): 8 10.21 (bs, 1H), 9.24 (bs, 1H), 8.53 (bs, 1H), 7.99 (s, 1H), 7.71-7.81 (m, 5H), 7.57 (s, 1H), 7.08-7.16 (m, 3H), 6.37-6.44 (m, 1H), 6.21-6.26 (m, 1H), 5.74 (d, J= 8.4 Hz, 1H), 3.54 (s, 3H). LCMS: [M+H]+ 498.35.
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3′,5′-trifluoro-[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethane-1-sulfonamide orexin type 2 receptor agonist, TAK-861, TAK 861, 59MF6P2ATF
Oveporexton is a small molecule drug. The usage of the INN stem ‘-orexton’ in the name indicates that Oveporexton is a orexin receptor agonist. Oveporexton has a monoisotopic molecular weight of 520.15 Da.
Oveporexton is being developed by Takeda.[1] As of July 2025, it has completed phase 3 clinical trials for treatment of narcolepsy, whereas no recent development has been reported for treatment of idiopathic hypersomnia.[1][5][10] Takeda plans to submit a New Drug Application (NDA) of oveporexton for the treatment of narcolepsy to the United StatesFood and Drug Administration (FDA) in 2025.[5] Oveporexton is a follow-on and replacement compound for Takeda’s earlier lead drug danavorexton (TAK-925), which is administered intravenously and stopped being developed due to unexpected liver toxicity findings.[10]
A Trial of TAK-861 for the Treatment of Narcolepsy With CataplexyCTID: NCT07363720Phase: Phase 3Status: Not yet recruitingDate: 2026-01-23Conditions: Narcolepsy Type 1 (NT1); Narcolepsy With CataplexyInterventions: PlaceboLinked Compound CID: 154617563
A Study of TAK-861 for the Treatment of Selected Central Hypersomnia ConditionsCTID: NCT05816382Phase: Phase 2/Phase 3Status: RecruitingDate: 2025-12-01Conditions: Narcolepsy Type 1Interventions: TAK-861Linked Compound CID: 154617563
A Study of TAK-861 in People With Narcolepsy Type 1CTID: NCT06505031Phase: Phase 3Status: CompletedDate: 2025-09-15Conditions: Narcolepsy Type 1Interventions: PlaceboLinked Compound CID: 154617563
A Study of TAK-861 for the Treatment of Narcolepsy Type 1CTID: NCT06470828Phase: Phase 3Status: CompletedDate: 2025-07-01Conditions: Narcolepsy Type 1Interventions: PlaceboLinked Compound CID: 154617563
A Study of TAK-861 in Participants With Narcolepsy Type 1CTID: NCT05687903Phase: Phase 2Status: CompletedDate: 2025-01-09Conditions: Narcolepsy Type 1Interventions: PlaceboLinked Compound CID: 154617563
A Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-861 for the Treatment of Narcolepsy With Cataplexy (Narcolepsy Type 1)EudraCT: 2022-001654-38Phase: Phase 2Status: CompletedDate: 2023-05-26Linked Compound CID: 154617563
A Long-term Extension Study to Evaluate the Safety and Tolerability of TAK-861 in Participants With Selected Central Hypersomnia ConditionsEudraCT: 2022-002965-13Phase: Phase 2, Phase 3Status: Trial now transitionedDate: 2023-04-11Linked Compound CID: 154617563
A Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-861 for the Treatment of Narcolepsy Without Cataplexy (Narcolepsy Type 2)EudraCT: 2022-002966-34Phase: Phase 2Status: CompletedDate: 2023-03-20Linked Compound CID: 154617563
A) tert-butyl (2S,3R)-3-(ethylsulfonamido)-4,4-difluoro-2-((2,3′,5′-trifluoro-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-1-carboxylate
To a mixture of tert-butyl (2S,3R)-2-(3-chloro-2-fluorobenzyl)-3-(ethylsulfonamido)-4,4-difluoropyrrolidine-1-carboxylate (3.70 g), (3,5-difluorophenyl)boronic acid (2.56 g) and 1 M aqueous potassium phosphate solution (24.3 mL) in DME (50 mL) was added XPhos Pd G3 (0.343 g) at room temperature. The mixture was stirred at 90° C. under nitrogen atmosphere for 15 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EOAc/hexane) to give the title compound (3.30 g).
MS: [M−H] − 533.2.
B) N-((2S,3R)-4,4-difluoro-2-((2,3′,5′-trifluoro-[1,1′-biphenyl]-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride
A mixture of tert-butyl (2S,3R)-3-(ethylsulfonamido)-4,4-difluoro-2-((2,3′,5′-trifluoro-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-1-carboxylate (3.30 g) and 4 M HCl/CPME solution (30 mL) was stirred overnight at room temperature. By filtration, the title compound (2.86 g) was obtained.
MS: [M+H] + 435.1.
C) N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3′,5′-trifluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
To a mixture of N-((2S,3R)-4,4-difluoro-2-((2,3′,5′-trifluoro-[1,1′-biphenyl]-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride (200 mg) and DIPEA (0.367 ml) in THF (3 mL) was added alpha-acetoxy-isobutyryl chloride (0.074 ml) at 0° C., and the mixture was stirred at same temperature for 10 min. To the mixture were added water (1 ml) and 4 M lithium hydroxide solution (1.06 ml), and the mixture was stirred overnight at room temperature. The mixture was diluted with saturated brine and extracted with EtOAc. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/hexane) and recrystallized from EtOAc/hexane to give the title compound (154 mg).
1H NMR (400 MHz, CDCl 3) δ 1.32-1.40 (9H, m), 2.27-2.54 (1H, m), 2.88-3.16 (4H, m), 4.02-4.49 (3H, m), 4.86-5.20 (2H, m), 6.78-6.86 (1H, m), 7.02-7.10 (2H, m), 7.16-7.22 (1H, m), 7.27-7.31 (1H, m), 7.35-7.43 (1H, m).
N-{(2S,3R)-4,4-difluoro-l-(2-hydroxy-2-methylpropanoyl)-2-[(2,3′,5′-trifluoro[l,l’-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide, (hereafter referred as to “Compound A”) is described in U.S. Patent No. 11,028,048.
Dauvilliers Y, Plazzi G, Mignot E, Lammers GJ, Del Río Villegas R, Khatami R, et al. (May 2025). “Oveporexton, an Oral Orexin Receptor 2-Selective Agonist, in Narcolepsy Type 1”. The New England Journal of Medicine. 392 (19): 1905–1916. doi:10.1056/NEJMoa2405847. PMID40367374.
Orenasitecan is a small molecule drug. The usage of the INN stem ‘-tecan’ in the name indicates that Orenasitecan is a antineoplastic, topoisomerase I inhibitor. Orenasitecan has a monoisotopic molecular weight of 1470.58 Da.
ORENASITECAN is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.
25 Feb 2026Vanda Pharmaceuticals has patent protection for an improved method of treatment with milsaperidone in USA
25 Feb 2026Vanda Pharmaceuticals has patents pending for an improved method of treatment with milsaperidone in China, Australia, Israel, Mexico and worldwide
56.36 g of boran complex of (3aR, 7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1 ,3,2]oxazaborole (1 equivalent) is dissolved under nitrogen in methylenchloride, and the solution is cooled to 0°C. A 1M solution of 1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propoxy}-3-methoxy-phenyl)-ethanone (iloperidone; 1 equivalent) in methylenchloride is added via a dropping funnel over 90 minutes while the internal temperature is maintained at 0°C ± 2°C. After the addition is complete, the mixture is stirred at 0°C for 20 hours. The reaction mixture is then poured into precooled methanol (0-5°C) during 1 hour. The solution is warmed to room temperature and stirred until the H2 evolution ceases. The solution is concentrated by distillation and the residue dried in vacuum, treated with methanol and stirred for about 1 hour at 50°C and an additional hour at 0CC. The product is isolated by filtration and dried under reduced pressure for 3 hours at 50°C. The title compound is obtained (white crystals).
[α]D20– 19.3° (c=1 in chloroform) Mp: 138.2 – 138.8°C
The boran complex used as starting material can be obtained as follows:
200 ml of a solution of (3aR, 7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole (1M in toluene) is stirred at room temperature under nitrogen. 1.2 equivalent borane-dimethylsulfide complex is added with a syringe. The solution is stirred for 2 further hours at room temperature. The borane complex is then crystallised by addition of 4 vol dry hexane and cooling to -12°C for 1.5 hour. The product is isolated by filtration in a sintered glass funnel and dried in vacuum at 40°C. The boran complex is obtained /white crystals).
Olomorasib (LY3537982) is an investigational, oral, second-generation KRAS G12C inhibitor designed to treat advanced solid tumors, particularly non-small cell lung cancer (NSCLC). Developed by Eli Lilly and Company, it shows promising antitumor activity and a manageable safety profile, often combined with pembrolizumab (Keytruda). Eli Lilly and Company +3
Key details about olomorasib include:
Mechanism & Target: It targets the KRAS G12C mutation, a common driver in lung and colorectal cancers.
Clinical Status: It is undergoing Phase 1/2 (LOXO-RAS-20001) and Phase 3 (SUNRAY-01) clinical trials.
Breakthrough Therapy: The FDA granted Breakthrough Therapy designation for first-line treatment of advanced NSCLC (PD-L1 50%) in September 2025.
Combination Efficacy: When combined with pembrolizumab, it showed an objective response rate of 73.9% in first-line patients, with higher efficacy in those with high PD-L1 expression.
Safety Profile: Common adverse events include diarrhea, elevated liver enzymes (ALT/AST), and rash, which were generally manageable. Eli Lilly and Company +4
Olomorasib is designed to be more potent with potentially better tolerability than earlier KRAS G12C inhibitors, aiming to improve outcomes in first-line settings.
OriginatorEli Lilly and Company
ClassAntineoplastics; Small molecules
Mechanism of ActionKRAS protein inhibitors
Phase IIINon-small cell lung cancer
Phase ISolid tumours
05 Jan 2026Eli Lilly and Company completes a phase-I trial (In volunteers) in Japan (PO, Capsule) (NCT07124013)
22 Dec 2025Phase-I/II clinical trials in Non-small cell lung cancer (Metastatic disease, Second-line therapy or greater, Combination therapy) in USA, Canada, China, South Korea (PO) (NCT07227025)
12 Nov 2025Janssen Research & Development plans a phase I/II (KaRAnaSa) trial for Non-small cell lung cancer (Combination Therapy, Metastatic disease, Second-line therapy or greater) in December 2025 (NCT07227025)
Olomorasib is an orally available inhibitor of the oncogenic KRAS substitution mutation, G12C, with potential antineoplastic activity. Upon oral administration, olomorasib selectively targets the KRAS G12C mutant and inhibits KRAS G12C mutant-dependent signaling. KRAS, a member of the RAS family of oncogenes, serves an important role in cell signaling, division and differentiation. Mutations of KRAS may induce constitutive signal transduction leading to tumor cell growth, proliferation, invasion, and metastasis.
Olomorasib (LY3537982) is an experimental anticancer drug which acts as an inhibitor of the G12C mutant form of Kirsten rat sarcoma virus (KRAS), an oncogene commonly present in several forms of cancer. It is in early stage clinical trials against lung and colorectal cancers and advanced solid tumors.[1][2][3][4][5]
A suspension of 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-lH-pyrazino[2,ld][l,5]benzoxazocin-9-yl]-2-amino-benzothiophene-3-carbonitrile (1.58 g, 3.46 mmol) in EtOAc (35 mL), THF (15 mL) and water (40 mL) is charged with potassium carbonate (1.90 g, 13.7 mmol). The mixture is stirred rapidly and cooled to 0 °C. Acryloyl chloride in DCM (13.0 mL, 3.25 mmol, 0.25M) is added dropwise through a dropping funnel. After 10 minutes of stirring in an ice bath, the mixture is diluted with EtOAc and poured into a separatory funnel. The layers are separated and the aqueous layer is again extracted with EtOAc. The combined organic extracts are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is purified by silica gel flash column chromatography, eluting first with 0-100% (10% MeOH in DCM) / DCM, and second with 0-100% [10% (7N NH 3 in MeOH) in DCM] / DCM to give the desired product as fluffy solid. The solid is sonicated in ether for 30 minutes, filtered, and dried in high vacuum to give the title compound (1.60 g, 91%). ES/MS m/z ( 35 C1/ 37 C1) 511.0/513.0 [M+H] + .
Table 22: Compounds synthesized in a manner essentially analogous to that of Example
Peng SB, Si C, Zhang Y, Van Horn RD, Lin X, Gong X, et al. (July 2021). “Preclinical characterization of LY3537982, a novel, highly selective and potent KRAS-G12C inhibitor”. Cancer Research. 81 (13_Supplement): 1259. doi:10.1158/1538-7445.AM2021-1259.
Hollebecque A, Kuboki Y, Murciano-Goroff YR, Yaeger R, Cassier PA, Heist RS, et al. (2024). “Efficacy and safety of LY3537982, a potent and highly selective KRAS G12C inhibitor in KRAS G12C-mutant GI cancers: Results from a phase 1 study”. Journal of Clinical Oncology. 42 (3_suppl): 94. doi:10.1200/JCO.2024.42.3_suppl.94.
Burns TF, Dragnev KH, Fujiwara Y, Murciano-Goroff YR, Lee DH, Hollebecque A, et al. (2024). “Efficacy and safety of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in combination with pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC”. Journal of Clinical Oncology. 42 (16_suppl): 8510. doi:10.1200/JCO.2024.42.16_suppl.8510.
Heist RS, Koyama T, Murciano-Goroff YR, Hollebecque A, Cassier PA, Han J, et al. (2024). “Pan-tumor activity of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in patients with KRAS G12C-mutant advanced solid tumors”. Journal of Clinical Oncology. 42 (16_suppl): 3007. doi:10.1200/JCO.2024.42.16_suppl.3007.
DeveloperEli Lilly and Company; Rigel Pharmaceuticals
ClassAnti-inflammatories; Antirheumatics; Small molecules
Mechanism of ActionRIPK1 protein inhibitors
Phase IIRheumatoid arthritis
No development reportedUnspecified
28 Mar 2025No recent reports of development identified for phase-I development in Unspecified(In volunteers) in Singapore (PO, Suspension)
14 Nov 2024Pharmacodynamics data from preclinical trials in Rheumatoid arthritis presented at the ACR Convergence 2024 (ACR-2024)
14 Nov 2024Safety and pharmacokinetics data from a phase I trial in Rheumatoid arthritis presented at the ACR Convergence 2024 (ACR-2024)
Ocadusertib (LY3871801/R552) is an oral, potent, and selective small-molecule RIPK1 inhibitor developed by Rigel Pharmaceuticals and Eli Lilly for autoimmune and inflammatory diseases. It is currently in Phase 2 clinical trials for treating moderate-to-severe rheumatoid arthritis. ACR Meeting Abstracts +4
Key Aspects of Ocadusertib:
Mechanism of Action: It inhibits receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which blocks necroptotic (cell death) responses and, consequently, reduces inflammation.
Target Indications: Primarily focused on rheumatoid arthritis, it has also been investigated for psoriasis and general inflammatory joint conditions.
Development Status: As of late 2025, it is in Phase 2 clinical trials (NCT05848258), with previous trials evaluating its safety, tolerability, and pharmacokinetics in healthy volunteers.
Characteristics: It is designed to be a selective inhibitor, showing no significant inhibition in a broad panel of other kinases. ACR Meeting Abstracts +3
Ocadusertib is a small molecule drug. The usage of the INN stem ‘-sertib’ in the name indicates that Ocadusertib is a serine/threonine kinase inhibitor. Ocadusertib is under investigation in clinical trial NCT05848258 (An Adaptive Phase 2a/2b Study of LY3871801 in Adult Participants With Rheumatoid Arthritis). Ocadusertib has a monoisotopic molecular weight of 459.19 Da.
An Adaptive Phase 2a/2b Study of LY3871801 in Adult Participants With Rheumatoid ArthritisCTID: NCT05848258Phase: Phase 2Status: RecruitingDate: 2025-12-09
A Study of LY3871801 in Healthy Asian and Non-Asian ParticipantsCTID: NCT05960851Phase: Phase 1Status: CompletedDate: 2024-01-10
A Drug Interaction Study of LY3871801 in Healthy ParticipantsCTID: NCT05602675Phase: Phase 1Status: CompletedDate: 2023-04-18
A Study of LY3871801 in Healthy ParticipantsCTID: NCT05222399Phase: Phase 1Status: CompletedDate: 2022-03-18
(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (WO 2014/125444), having a structure as illustrated below, was used as a comparative compound and was examined using a similar protocol as described by WO 2014/125444. This comparison
compound exhibited 93% inhibition at a dose of 30 mg/kg according to WO 2014/125444; however, in the inventors hands, the compound inhibited only 70% at 30 mg/kg. In comparison, compound I-30 of the present disclosure achieved greater than 85% inhibition at a dose of just 5 mg/kg using the similar assay protocol described above.
Nivegacetor is an investigational gamma-secretase modulator being developed by Roche for the treatment of Alzheimer’s disease.[1] The compound is also known by its development code name RG6289 and represents a second-generation gamma-secretase modulator designed to selectively alter amyloid beta peptide production while avoiding the toxicity issues associated with first-generation compounds.[2]
Mechanism of action
Nivegacetor is a gamma-secretase modulator (GSM) that targets the gamma-secretase enzyme complex, which plays a central role in the production of amyloid beta peptides implicated in the pathogenesis of Alzheimer’s disease.[1] It specifically modulates the catalytic subunit presenilin-1 (PSEN1), stabilizing the interaction between the complex and the amyloid precursor protein (APP) at the enzyme’s active site. This stabilization increases the processivity of APP cleavage—that is, the enzyme’s ability to carry out sequential cleavage steps before releasing the APP substrate.[3]
Unlike gamma-secretase inhibitors that completely block enzyme function and cause significant side effects, nivegacetor selectively reduces the production of amyloidogenic long amyloid beta peptides, particularly Aβ42 and Aβ40 that form insoluble amyloid fibrils, while simultaneously increasing the formation of shorter, non-amyloidogenic species such as Aβ38 and Aβ37. The compound demonstrates high potency with an IC50 below 10 nM for gamma-secretase modulation of APP cleavage, and importantly shows no effect on the processing of other gamma-secretase substrates, potentially avoiding the toxicity issues that plagued earlier compounds.[2]
A Study of Donanemab, RG6289, or the Combination of Donanemab and RG6289 in Presenilin 1 (PSEN1) E280A Mutation Carriers for the Treatment of Autosomal-Dominant Alzheimer’s Disease
Mechanism of ActionAmyloid precursor protein secretase modulator
Phase IIAlzheimer’s disease
03 Dec 2025Efficacy data from a phase II trial in Alzheimer’s disease presented at the Alzheimer’s Association International Conference 2025 (AAIC-2025)
13 Aug 2025Chemical structure information added.
14 Nov 2024Banner Alzheimers Institute and Neurosciences Group at the University of Antioquia (GNA) in Medellin plans a clinical trial for Alzheimer’s-disease (Monotherapy, Prevention, In adults), in fall 2025 (IV) (NCT06996730)
(R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine and (S)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine
A Buchwald type coupling using the general procedure 1, between 2-bromo-7-(3,5-difluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole 7-1 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2, followed by a separation of the enantiomeres by preparative chiral HPLC afforded the title products as white solid (example 1): 27 mg, MS (ES+) m/z: 470.2 [(M+H) +] and (example 2): 28 mg, MS (ES+) m/z: 470.2 [(M+H) +].
A Buchwald type coupling using the general procedure 1, between 2-bromo-7-(3,5-difluorophenoxy)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole 7-1 and (lR,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2, followed by a separation of the enantiomeres by preparative chiral HPLC afforded the title products as white solid (example 1): 27 mg, MS (ES+) m/z 470.2 [(M+H)+] and (example 2): 28 mg, MS (ES+) m/z 470.2 [(M+H)+]
Nivegacetor has completed Phase I clinical trials in healthy volunteers, where it demonstrated a favorable safety profile and dose-dependent pharmacodynamic effects.[3] The study showed that treatment with nivegacetor resulted in a dose-dependent shift in amyloid beta monomers in cerebrospinal fluid (CSF), with significant reductions in Aβ42 levels and corresponding increases in shorter amyloid beta species.[4]
The Phase I results were presented at the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, where researchers reported that nivegacetor appeared safe and effectively shifted amyloid beta production toward smaller, less aggregation-prone peptides.[3]
Phase II studies
Based on the positive Phase I results, nivegacetor has been selected for advancement to Phase II clinical trials for Alzheimer’s disease treatment.[3] The dose selection for the Phase II study was informed by population pharmacokinetic/pharmacodynamic modeling derived from the Phase I data.[5][6][7]
Historical context
Nivegacetor represents a significant advancement in gamma-secretase modulator development, addressing the limitations of first-generation compounds that failed due to toxicology problems.[2] Previous attempts at gamma-secretase modulation were hampered by safety concerns and off-target effects, leading to the discontinuation of several promising candidates in the 2000s and early 2010s.[2] The development of nivegacetor as a second-generation GSM reflects improved understanding of gamma-secretase biology and more selective targeting approaches.[8]
References
“nivegacetor | Ligand page”. IUPHAR/BPS Guide to IMMUNOPHARMACOLOGY. International Union of Basic and Clinical Pharmacology (IUPHAR). Retrieved 22 July 2025.
“RG6289”. ALZFORUM. Archived from the original on 9 October 2024. Retrieved 22 July 2025.
The present invention is based in part on the surprising discovery that the substantially pure enantiomers (S)2-N(3-0-((S)propan 2-ol)-l-propyl-4-hydroxybenzene)-3-phenylpropylamide (also known as the (S,S) enantiomer or El) and (S)2-N(3-0-((R)propan 2-ol)-l -propyl -4-hydroxybenzene)-3-phenylpropyl amide (also known as the (S,R) enantiomer or E2) modulate the activity of specific tyrosine kinases in an opposite manner. It was unexpectedly found that while the (S,S) enantiomer activated protein tyrosine kinases LynA and BLK, the (S,R) enantiomer inhibited their activity. It was further unexpectedly shown that the (S,S) enantiomer was effective as a pain analgesic in animal models of pain, while the (S,R) enantiomer was shown to be ineffective or less effective in these models. Furthermore, the analgesic effect of the (S,S) enantiomer was long acting as it was efficacious for more than 24 hours post administration, in comparison to the commonly used analgesic agent gabapentin which was effective for no longer than 5 hours post administration.
The isolated enantiomers according to some embodiments of the invention may be synthesized as a racemate by known in the art methods described for example in US 7,754,771, US 7,642,290, US 7,674,829 or US 2011/0086910. The racemate may be further separated by known in the art methods for the separation of chiral compounds. According to an exemplary embodiment, the enantiomers may be synthesized as a racemate (comprising (S)2-N(3-0-((S)propan 2-ol)-l-propyl-4-hydroxybenzene)-3-phenylpropylamide and (S)2-N(3-0-((R)propan 2-ol)-l-propyl-4-hydroxybenzene)-3-phenylpropylamide and be further separated by a supercritical fluid chromatography (SFC) in combination with chiral stationary phases. Specifically, the (S,S) and (S,R) compounds may be separated on RegisPack™ column a polysaccharide coated chiral column (with a tris-(3,5-dimethylphenyl) carbamoyl cellulose selector) generally used for enantiomeric separations of a wide range of racemate classes (Figure 7A-C).
According to some embodiments, the enantiomers may be synthesized directly using for example, the process described in scheme 1 for the preparation of the (S,S) enantiomer.
The bis-protected ether (15.7 g) was exposed to one-pot hydrogenation-debenzylation conditions (10% loading of 10% Pd/C and 0.25 eq of p-toluenesulfonic acid) in methanol. After 2 hours at 60° C. under a hydrogen atmosphere, HPLC analysis indicated that the hydrogenation of the benzyl and the debenzylation of PMB ring was complete. The reaction mixture was filtered over Celite and concentrated under reduced pressure. The residue was dissolve in ethyl acetate and a saturated aqueous sodium bicarbonate treatment was conducted to effectively remove p-toluenesulfonic acid, then DURP to provide 12.13 g of an oil (PR030-120-4). Desired product was isolated from an EA/Heptane recrystallization to provide 8.83 g of a white solid (PR030-120-6, 89.4% yield). The purity of PR030-120-6 was 99.3% via HPLC analysis. 1H NMR and Mass spec analysis supported the assigned structure for desired product.
((S,S)-2-N(3-0-(propan-2-ol)-1 -propyl-4-hydroxybenzene)-3-phenylpropylamide), including its enantiomers and diastereomers may be prepared as described in WO 2013/084238,
Example 1 – Preparation of -2-N(3-Q-(propan-2-ol)-1-propyl-4-hvdroxybenzene)-3-
phenylpropylamide
(S,S)-2-N(3-0-(propan-2-ol)-1 -propyl-4-hydroxybenzene)-3-phenylpropylamide was prepared as described in WO 2013/084238 and US 201 1/0086910.
In a first step, 2 g of methyl lactate was reacted with excess of benzyl bromide to get 880 mg of (S)-benzyloxymethyl lactate. The reaction was performed by slurring sodium hydride in THF and cooling down to approximately -15°C. The reaction mixture was then allowed to warm slowly to room temperature and stirred for approximately 1 to 2 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with MTBE twice followed by the removal of solvent on a rotary evaporator to obtain a crude oil. The crude product was purified by column chromatography to yield pure (S)-2-benzyloxymethyl lactate. The (R)-2-benzyloxymethyl lactate isomer was present at 0.93% only. The yield of this step may be increased by avoiding the presence of moisture in the reaction solution.
In a second step, 880 mg (S)-2-benzyloxymethyl lactate obtained in step 1 were reduced using lithium aluminum hydride to obtain (S)-2-benzyloxypropylene glycol in 83.8% yield with 98.7% purity. A solution of pure (S)-2-benzyloxymethyl lactate in methylene chloride was stirred and a solution of lithium aluminum hydride was slowly added thereto at approximately 5°C. The reaction was monitored by TLC and quenched by USP-PW water very carefully. No racemization occurred in this step.
In a third step, the (S)-2-benzyloxypropylene glycol was then reacted with methane sulfonyl chloride in methylene chloride in the presence of triethyl amine to yield the mesylate in 88% yield. A solution of step 2 was stirred in methylene chloride and methane sulfonyl chloride was added to it dropwise at <5°C. After the addition was complete, the progress of the reaction was monitored by TLC. The reaction was quenched with USP-PW water. After the layers were separated, the aqueous layer was back extracted with methylene chloride. The methylene chloride layers were then combined and washed with USP-PW water 3 times to remove most of the methane sulfonic acid. No racemization occurred in this step.
In a fourth step, the mesylate (of step 3) was coupled with S-O-benzyl tyrosinol to form the bis-protected product in 22.7% yield, with a purity of 97.4%. The reaction was carried out at room temperature using a combination of DMF as the solvent and sodium hydride as the base. The reaction went to completion after stirring for at least 12 hours at room temperature.
In a fifth step, 340 mg of the product of step 4 were reduced by hydrogenation in the presence of 10% palladium on carbon catalyst and hydrochloric acid using methylene chloride as a solvent at 50°C. The reaction went to completion in approximately 4 hours with no racemization to yield the desired product in 84.3% yield and 98.9% purity. More specifically, the catalyst was removed by filtration and the filtrate was then concentrated at 33°C. The resulting mixture of solid and oil was mixed with ethyl acetate. The resulting slurry was filtered and the solids washed with ethyl acetate and dried under vacuum at 40 to 45°C to obtain the desired product.
Example 1—Preparation of (S,S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide
(S,S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide was prepared as described in WO 2013/084238 and US 2011/0086910.
In a first step, 2 g of methyl lactate was reacted with excess of benzyl bromide to get 880 mg of (S)-benzyloxymethyl lactate. The reaction was performed by slurring sodium hydride in THF and cooling down to approximately −15° C. The reaction mixture was then allowed to warm slowly to room temperature and stirred for approximately 1 to 2 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with MTBE twice followed by the removal of solvent on a rotary evaporator to obtain a crude oil. The crude product was purified by column chromatography to yield pure (S)-2-benzyloxymethyl lactate. The (R)-2-benzyloxymethyl lactate isomer was present at 0.93% only. The yield of this step may be increased by avoiding the presence of moisture in the reaction solution.
In a second step, 880 mg (S)-2-benzyloxymethyl lactate obtained in step 1 were reduced using lithium aluminum hydride to obtain (S)-2-benzyloxypropylene glycol in 83.8% yield with 98.7% purity. A solution of pure (S)-2-benzyloxymethyl lactate in methylene chloride was stirred and a solution of lithium aluminum hydride was slowly added thereto at approximately 5° C. The reaction was monitored by TLC and quenched by USP-PW water very carefully. No racemization occurred in this step.
In a third step, the (S)-2-benzyloxypropylene glycol was then reacted with methane sulfonyl chloride in methylene chloride in the presence of triethyl amine to yield the mesylate in 88% yield. A solution of step 2 was stirred in methylene chloride and methane sulfonyl chloride was added to it dropwise at <5° C. After the addition was complete, the progress of the reaction was monitored by TLC. The reaction was quenched with USP-PW water. After the layers were separated, the aqueous layer was back extracted with methylene chloride. The methylene chloride layers were then combined and washed with USP-PW water 3 times to remove most of the methane sulfonic acid. No racemization occurred in this step.
In a fourth step, the mesylate (of step 3) was coupled with S—O-benzyl tyrosinol to form the bis-protected product in 22.7% yield, with a purity of 97.4%. The reaction was carried out at room temperature using a combination of DMF as the solvent and sodium hydride as the base. The reaction went to completion after stirring for at least 12 hours at room temperature.
In a fifth step, 340 mg of the product of step 4 were reduced by hydrogenation in the presence of 10% palladium on carbon catalyst and hydrochloric acid using methylene chloride as a solvent at 50° C. The reaction went to completion in approximately 4 hours with no racemization to yield the desired product in 84.3% yield and 98.9% purity. More specifically, the catalyst was removed by filtration and the filtrate was then concentrated at 33° C. The resulting mixture of solid and oil was mixed with ethyl acetate. The resulting slurry was filtered and the solids washed with ethyl acetate and dried under vacuum at 40 to 45° C. to obtain the desired product.
Nedemelteon is a small molecule drug. The usage of the INN stem ‘-melteon’ in the name indicates that Nedemelteon is a melatonin receptor agonist. Nedemelteon has a monoisotopic molecular weight of 258.14 Da.
N-[2-(2-Methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]acetamide (165 mg, 0.644 mmol) was dissolved in methanol (6.4 mL), a 10% palladium-carbon powder (82 mg) was added, and the mixture was stirred at room temperature for 12 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→95/5) to give the title compound (148 mg, yield 89%).
1H-NMR (CDCl 3) δ: 1.69-1.96 (2H, m), 1.99 (3H, s), 2.23-2.50 (2H, m), 2.63 (3H, s), 2.89-3.15 (2H, m), 3.28-3.56 (3H, m), 5.54 (1H, brs), 7.15 (1H, d, J=8.0 Hz), 7.44 (1H, d, J=8.0 Hz),
melting point: 93-95° C. (recrystallized from hexane/ethyl acetate),
Racemic N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide (768 mg, 3.00 mmol) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRALPAK AD (50 mmID×500 mL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/diethylamine=90/10/0.1, flow rate: 60 mL/min, column temperature: 30° C., sample concentration: 1.02 mg/mL, injection weight: 31 mg). A fraction containing an optically active compound having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated. The concentrate was re-dissolved in ethanol, and concentrated to dryness. Hexane was added again, and the mixture was concentrated to dryness to give the title compound (381 mg, 99.9% ee). Enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mmID×250 mL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/diethylamine=90/10/0.1, flow rate: 0.5 mL/min, column temperature: 30° C., sample concentration: 0.65 mg/mL (hexane/ethanol), injection volume: 10 μL).
1H-NMR (CDCl 3) δ: 1.69-1.96 (2H, m), 1.99 (3H, s), 2.23-2.50 (2H, m), 2.63 (3H, s), 2.89-3.15 (2H, m), 3.28-3.56 (3H, m), 5.54 (1H, brs), 7.15 (1H, d, J=8.0 Hz), 7.44 (1H, d, J=8.0 Hz),
melting point: 111-113° C. (recrystallized from hexane/ethyl acetate),
Example 12 (S) -N- [2- (2-Methyl-7, 8-dihydro-6H-indeno [5, 4-d] [1, 3] oxazol-8-yl) ethyl] acetamide
Racemic N- [2- (2-methyl-7, 8-dihydro-6H-indeno [5, 4-d] [1,3] oxazol-8-yl) ethyl] acetamide (768 mg, 3.00 mmol) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRΔLPAK AD (50 mmID x 500 mmL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/diethylamine=90/10/0.1, flow rate: 60 mL/min, column temperature: 30°C, sample concentration: 1.02 mg/mL, injection weight: 31 mg) . A fraction containing an optically active compound having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated. The concentrate was re-dissolved in ethanol, and concentrated to dryness. Hexane was added again, and the mixture was concentrated to dryness to give the title compound (381 mg, 99.9%ee). Enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/diethylamine=90/10/0.1, flow rate: 0.5 mL/min, column temperature: 300C, sample concentration:
Navepegritide Cas 2413551-27-4 Molecular Formula: C₂₃₁H₃₈₆N₆₄O₆₇S₅ + (C₂H₄O)₄ₙ (approx. 45 kDa), 1804.0 g/mol MOLECULAR FORMULA C231H386N64O67S5 + (C2H4O)4nMOLECULAR WEIGHT approx. 45 kDa The structure of navepegritide (YUVIWEL®) is built using…
Oveporexton CAS 2460722-04-5 MF C23H25F5N2O4S MW 520.5 N-[(2S,3R)-2-[[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl]-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide N-[(2S,3R)-1-(2-ヒドロキシ-2-メチルプロピオニル)-2-(2,3′,5′-トリフルオロビフェニル-3-イルメチル)-4,4-ジフルオロピロリジン-3-イル]エタンスルホンアミド ETHANESULFONAMIDE, N-((2S,3R)-4,4-DIFLUORO-1-(2-HYDROXY-2-METHYL-1-OXOPROPYL)-2-((2,3′,5′-TRIFLUORO(1,1′-BIPHENYL)-3-YL)METHYL)-3-PYRROLIDINYL)- N-[(2S,3R)-2-[[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl]-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3′,5′-trifluoro-[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethane-1-sulfonamideorexin type 2 receptor agonist, TAK-861, TAK 861, 59MF6P2ATF Oveporexton is a small…
Orenasitecan CAS 2418533-89-6 MF C72H86N12O20S MW1471.59 (3S)-3-[3-[2-[2-[2-[[4-[[(1R)-2-carboxy-1-[3-[[3-(propylcarbamoylamino)phenyl]sulfonylamino]phenyl]ethyl]carbamoylamino]phenyl]carbamoylamino]ethoxy]ethoxy]ethoxy]propanoylamino]-4-[(2S)-2-[[(2S)-1-[[(19S)-10,19-diethyl-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaen-19-yl]oxy]-3-methyl-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-4-oxobutanoic acid (4S)-4,11-diethyl-3,14-dioxo-3,4,12,14-tetrahydro-1Hpyrano[ 3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl N-{1-[4-({[(1R)-2-carboxy-1-(3-{3-[(propylcarbamoyl)amino]benzene-1-sulfonamido}phenyl)ethyl]carbamoyl}amino)anilino]-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oyl}-L-alpha-aspartyl-L-prolyl-L-valinate (4S)-4,11-diethyl-3,14-dioxo-3,4,12,14-tetrahydro-1Hpyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl N-{1-[4-({[(1R)-2-carboxy-1-(3-{3-[(propylcarbamoyl)amino]benzene-1-sulfonamido}phenyl)ethyl]carbamoyl}amino)anilino]-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oyl}-L-α-aspartyl-L-prolyl-L-valinateantineoplastic, L3KV5NR5PG Orenasitecan is a small molecule drug. The usage of the INN…
Milsaperidone CAS 501373-88-2 C24H29FN2O4 MW 428.50 FDA APPROVED 2/20/2026, Bysanti, To treat schizophrenia and to treat manic or mixed episodes associated with bipolar I disorder…
Nedemelteon CAS 1000334-38-2 MF C15H18N2O2 MW258.32 N-[2-[(8S)-2-methyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzoxazol-8-yl]ethyl]acetamide N-{2-[(8S)-2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl]ethyl}acetamidemelatonin receptor agonist, CW62HV1TTF, MT1/2 Agonist (S)-3b Nedemelteon is a melatonin receptor agonist. Nedemelteon is a small molecule drug. The…
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