Napazimone

 

Napazimone

CAS 1800405-30-4

MF C14H12N2O2 MW240.26 g/mol

2-(propan-2-yl)-1H-naphtho[1,2-d]imidazole-4,5-dione
NAD(P)H dehydrogenase [quinone] 1 (NQO1) activator, KL 1333, KL-1333, NA2ZOL5UGM

Napazimone (also known as KL1333) is an investigational small molecule drug currently being developed for the treatment of primary mitochondrial disease. It is an orally available modulator that aims to improve energy production in patients with rare genetic conditions affecting mitochondrial DNA (mtDNA). 

Mechanism of Action

According to ProbeChem.com and Synapse, Napazimone works through the following mechanisms:

• NAD+ Modulation: It increases intracellular levels of NAD+ by reacting with the enzyme NQO1, which helps shift the NAD+/NADH ratio.
• Signaling Pathway Activation: The drug activates the SIRT1/AMPK/PGC-1α signaling network, which is critical for regulating mitochondrial biogenesis and function.
• Mitochondrial Improvement: In laboratory studies using MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) fibroblasts, the compound increased ATP levels and decreased harmful reactive oxygen species (ROS) and lactate. 

Clinical Development and Indications

Napazimone is being developed by Pharming Group for adult patients with primary mitochondrial disease, a condition often characterized by extreme fatigue and muscle weakness. 

• Trial Status: As of early 2026, the drug is in Phase II/III clinical trials.
• FALCON Trial: A pivotal study known as the FALCON trial is currently ongoing, with a data readout expected in 2027.
• Potential Indications: It is primarily being investigated for mtDNA-driven mitochondrial diseases and has shown potential in research for protecting against hearing loss (ototoxicity) caused by chemotherapy drugs like cisplatin. 

Chemical Properties

The following specifications are provided by Inxight Drugs and PubChem:

• Chemical Name: 2-isopropyl-3H-naphtho[1, 2-d]imidazole-4,5-dione.
• Molecular Formula: C14H12N2O2.
• Molecular Weight: 240.26 g/mol. 

Would you like more information on the FALCON clinical trial or details about the mitochondrial diseases Napazimone is intended to treat?

• Efficacy of KL1333 in Adult Patients With Primary Mitochondrial DiseaseCTID: NCT05650229Phase: Phase 2Status: RecruitingDate: 2025-10-09
• A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial DiseaseCTID: NCT03888716Phase: Phase 1Status: CompletedDate: 2021-10-20
• Drug-drug Interaction Study of KL1333 in Healthy SubjectsCTID: NCT04643249Phase: Phase 1Status: CompletedDate: 2021-10-20
• Safety, Tolerability and Pharmacokinetic Study of KL1333 in Healthy Male VolunteersCTID: NCT03056209Phase: Phase 1Status: CompletedDate: 2018-04-27

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015102371&_cid=P21-MLPZ73-91594-1

Example 1 [Synthesis of Compound 1]: 2-isopropyl-lH-naphtho [2, l-d] imidazole-4,5-dione

1) IStep Pyridine (5 ml) is added to compound A (4-amino-1 -naphthol hydrochloride, 500 mg, 2.55 mmol), and the ice bath is dehydrated and cooled. This is followed by dropwise isobutyric anhydride (1.7 ml, 10.2 mmol). The reaction product is stirred for 2.5 hours at the same temperature. The reactants are quenched with methanol and concentrated under reduced pressure to remove any pyridine. After adding EA and distilled water, adjust pH to about 6.5 with 1 N HC1 solution, and then wash the organic layer several times to remove the remaining pyridine. The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The concentrated reaction product was purified by silica gel column chromatography to obtain compound B-1 (686 mg, 90%).

2) 2Step

 Add Acetic anhydride (3 ml) to Compound B-1 (300 mg, 1.00 mmol) and dropwise fuming nitric acid (0.20 ml, 2.00 mmol) at 0 ° C. The reaction product is stirred for 1 hour and then filtered. The filtered solid is then washed several times with Hexane with compound B-2. compound B-2 (217 mg, 63%).

1 H NMR (300 MHz, Acetone-d ₆ ) δ 9.55 (s, IH), 8.33 (d, J = 6.6 Hz, IH), 8.06 (d, J = 6.2 Hz, IH), 7.86 (s, IH), 7.81-7.73 (m, 2H), 3.16-3.07 (m, IH), 2.96-2.87 (m, IH), 1.41 (d, J-7.0 Hz, 6H), 1.25 (d, J-7.0 Hz, 6H)

3) 3 Step

 Compound B-2 (500 mg, 1.45 mmol) is dissolved in ethanol (5 ml), and then Pd / C (50 mg) and Hydrazine (0.29 ml, 5.81 mmol) are added in this order. The reaction is allowed to react for 1 hour at 70 degrees. The reaction product is cooled to room temperature and the Pelite / C is removed by celite filter. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B-3 (232 mg, 51%).

MR NMR (300 MHz, CD ₃ OD) δ 8.02 (d, J = 8.4 Hz, IH), 7.50 (d, J = 8.0 Hz, IH), 7.35 (t, J-8.0 Hz, IH), 7.13 (t, J = 8.1 Hz, IH), 6.47 (s, IH), 2.85-2.83 (m, IH), 1.31 (d, J = 7.0 Hz, 6H)

 LC-MS m / z 245.1 (M + l)

4) 4Step

 Acetic acid (15 ml) is added to Compound B-3 (700 mg, 2.86 mmol), and the mixture is stirred and refluxed for 3 hours. Acetic acid is removed by concentration under reduced pressure, and purified by silica gel column chromatography to obtain compound B-4 (575 mg, 89%) ¾-

MR NMR (300 MHz, CD ₃ OD) δ 8.30 (d, J = 8.4 Hz, 2H), 7.60 (t, J = 8.0 Hz, IH), 7.47

(t, J = 8.1 Hz, IH), 6.99 (s, IH), 3.35-3.28 (m, IH), 1.46 (d, J = 7.0 Hz, 6H)

 LC-MS m / z 227.0 (M + l)

5) 5 Step

Dissolve DMF (2.5 ml) in Compound B-4 (50 mg, 0.22 mmol), and add IBX (159 mg, 0.26 mmol). The reaction is reacted at room temperature for 1 hour. After adding EA, the organic layer is washed with NaHC0 ₃ saturated aqueous solution. The separated organic layer was dried over MgS0 ₄ and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain compound B-5 (47 mg, 89%).

1 H NM (300 MHz, CDC1 ₃ ) δ 9.96 (NH, s, IH), 8.06 (d, J = 7.7 Hz, IH), 7.99 (d, J = 7.7 Hz, IH), 7.65 (t, J = 7.7 Hz, IH), 7.44 (t, J = 7.7 Hz, IH), 3.26-3.17 (m, IH), 1.45 (d, j = 7.0 Hz, 6H)

PAT

1,2-naphthoquinone based derivative and method of preparing the same

Publication Number: US-10766882-B2

Priority Date: 2013-12-30

Grant Date: 2020-09-08

• 1,2-naphthoquinone based derivative and method of preparing the samePublication Number: US-2016376258-A1Priority Date: 2013-12-30
• 1,2-naphthoquinone based derivative and method of preparing the samePublication Number: CA-2935317-CPriority Date: 2013-12-30Grant Date: 2022-11-22
• 1,2-naphthoquinone derivative and method for preparing samePublication Number: EP-3091003-B1Priority Date: 2013-12-30Grant Date: 2025-06-04
• 1,2-naphthoquinone derivative and method for preparing samePublication Number: EP-4582424-A2Priority Date: 2013-12-30
• 1, 2-naphthoquinone derivative and preparation method thereofPublication Number: CN-105992759-BPriority Date: 2013-12-30Grant Date: 2020-10-30

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////////////napazimone, NAD(P)H dehydrogenase [quinone] 1 (NQO1) activator, KL 1333, KL-1333, NA2ZOL5UGM

#napazimone, #NAD(P)H dehydrogenase [quinone] 1 (NQO1) activator, #KL 1333, #KL-1333, #NA2ZOL5UGM

Navepdekinra

 

Navepdekinra

CAS 2467732-66-5

MF C33H48FN7O4 MW625.78

1H-Pyrazole-5-carboxamide, 1-ethyl-N-[(1S)-2-[[2-fluoro-4-[(1S,2R)-1-methyl-3-(4-methyl-1-piperazinyl)-3-oxo-2-[(1-oxopropyl)amino]propyl]phenyl]amino]-1-(trans-4-methylcyclohexyl)-2-oxoethyl]-

1-ethyl-N-{(1S)-2-{2-fluoro-4-[(2S,3R)-4-(4-methylpiperazin-1-yl)-4-oxo-3-propanamidobutan-2-yl]anilino}-1-[(1r,4S)-4-methylcyclohexyl]-2-oxoethyl}-1H-pyrazole-5-carboxamide

1-ethyl-N-{(1S)-2-{2-fluoro-4-[(2S,3R)-4-(4-methylpiperazin-1-yl)-4-oxo-3-propanamidobutan-2-
yl]anilino}-1-[(1r,4S)-4-methylcyclohexyl]-2-oxoethyl}-1H-pyrazole-5-carboxamide
interleukin-17A (IL-17A) inhibitor, anti-inflammatory, DC-806, LY4100504, DC 806, LY 4100504, Y64F9MC2QM

Navepdekinra (also known as DC-806 or LY4100504) is an experimental, orally active small-molecule inhibitor of interleukin-17A (IL-17A). It was primarily developed to treat autoimmune and inflammatory conditions, such as psoriasis, by disrupting the interaction between IL-17A and its receptor.

Key Properties and Development

• Mechanism: It is a potent inhibitor with an IC50 of 10.81 nM, designed to provide an oral alternative to existing injectable IL-17 biologic therapies.
• Acquisition: The drug was originally developed by DICE Therapeutics, which was acquired by Eli Lilly and Company in 2023 for approximately $2.4 billion to bolster their immunology pipeline.

Navepdekinra (DC-806) is an orally active, potent interleukin-17A (IL-17A) inhibitor (IC₅₀ = 10.81 nM). Navepdekinra disrupts the IL-17A protein-receptor interaction, suppressing the downstream pro-inflammatory signaling pathway. Navepdekinra inhibits arthritis in a collage-induced arthritis (CIA) rat model. Navepdekinra can be used for psoriasis, psoriatic arthritis, and ankylosing spondylitis

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US300737225&_cid=P12-MLRFH1-76079-1

Example 210: N-[(2R,3S)-3-{4-[(2S)-2-[(1-ethyl-1H-pyrazol-5-yl)formamido]-2-[(1r,4S)-4-methylcyclo hexyl]acetamido]-3-fluorophenyl}-1-(4-methylpiperazin-1-yl)-1-oxobutan-2-yl]propanamide) (234)

 Following General Procedure R, 0.227 g, 0.310 mmol, 1.0 eq) of 82d in DMF (1 mL) were added 1-ethyl-1H-pyrazole-5-carboxylic acid (0.052 g, 0.372 mmol, 1.2 eq), DIPEA (0.43 mL, 2.482 mmol, 8.0 eq) and then HATU (0.177 g, 0.465 mmol, 1.5 eq.) and the resulting mixture was stirred at RT for 1 h. The mixture was concentrated to dryness and the residue was purified via reverse phase column chromatography on a 120 g C18 cartridge eluting with a 5-95% H ₂O:MeCN eluent (0.1% ammonia) to afford 234 (0.025 g) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 9.86 (s, 1H), 8.46 (d, J=8.3 Hz, 1H), 8.26 (d, J=8.7 Hz, 1H), 7.75 (t, J=8.3 Hz, 1H), 7.47 (d, J=2.1 Hz, 1H), 7.15-7.07 (m, 1H), 7.05-6.97 (m, 2H), 4.86 (t, J=9.4 Hz, 1H), 4.53 (t, J=8.4 Hz, 1H), 4.47 (q, J=7.2 Hz, 2H), 3.46-3.38 (m, 2H), 3.29-3.14 (m, 2H), 3.12-2.99 (m, 2H), 2.25-2.03 (m, 5H), 1.98 (s, 3H), 1.81 (ddt, J=15.0, 9.9, 5.6 Hz, 2H), 1.74-1.60 (m, 4H), 1.58-1.47 (m, 1H), 1.28 (t, J=7.1 Hz, 4H), 1.20 (d, J=7.0 Hz, 3H), 1.14-1.02 (m, 1H), 0.99 (t, J=7.6 Hz, 3H), 0.93-0.87 (m, 1H), 0.86 (d, J=6.5 Hz, 3H). UPLC-MS (basic 4 min): rt=1.76 min; m/z=626.4 for [M+H] ⁺.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021055376&_cid=P12-MLRFH1-76079-1

Example 1: Exemplary Scheme—Synthesis of Intermediate Compounds 62a-62d

PAT

IL-17 Ligands And Uses Thereof

Publication Number: US-2020247785-A1

Priority Date: 2019-02-06

• Substituted benzenecarboxamides as IL-17A modulatorsPublication Number: US-11274094-B2Priority Date: 2019-09-16Grant Date: 2022-03-15
• Il-17a modulators and uses thereofPublication Number: US-2021101886-A1Priority Date: 2019-09-16
• IL-17 ligands and uses thereofPublication Number: US-11447468-B2Priority Date: 2019-02-06Grant Date: 2022-09-20
• Il-17 ligands and uses thereofPublication Number: US-2023053746-A1Priority Date: 2019-02-06
• IL-17 ligands and uses thereofPublication Number: US-12234225-B2Priority Date: 2019-02-06Grant Date: 2025-02-25
• Mannose 6-phosphate or asgpr receptor binding compounds for the degradation of extracellular proteinsPublication Number: WO-2023028338-A2Priority Date: 2021-08-27
• Potent asgpr-binding compounds for the degradation of immunoglobulins and other proteinsPublication Number: WO-2022235699-A2Priority Date: 2021-05-03
• Il-17a modulators and uses thereofPublication Number: WO-2021055376-A1Priority Date: 2019-09-16
• Substituted benzenecarboxamides as il-17a modulatorsPublication Number: US-2023141212-A1Priority Date: 2019-09-16
• Substituted benzenecarboxamides as il-17a modulatorsPublication Number: US-2023145481-A1Priority Date: 2019-09-16

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• [1]. Paul R. Fatheree, et al. IL-17 Ligands And Uses Thereof. US20200247785A1.[2]. Kim D, et al. Next-Generation Anti-IL-17 Agents for Psoriatic Disease: A Pipeline Review. Am J Clin Dermatol. 2025 May;26(3):307-320.  [Content Brief][3]. Xiaobing Deng, et al. The Critical and Unexpected Role of a Methyl Group in Interleukin-17A Inhibitors. bioRxiv 2025.10.02.680113

//////////navepdekinra, interleukin-17A (IL-17A) inhibitor, anti-inflammatory, DC-806, LY4100504, DC 806, LY 4100504, Y64F9MC2QM

#navepdekinra, #interleukin-17A (IL-17A) inhibitor, #anti-inflammatory, #DC-806, #LY4100504, #DC 806, #LY 4100504, #Y64F9MC2QM

Naxtarubicin, Annamycin

 

Naxtarubicin, Annamycin

CAS 92689-49-1

MF C26H25IO11 MW 640.4 g/mol

2'-Iodo-3'-hydroxy-4'-epi-4-demethoxydoxorubicin

(7S,9S)-7-[(2R,3R,4R,5R,6S)-4,5-dihydroxy-3-iodo-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-8,10-dihydro-7H-tetracene-5,12-dione

(7S,9S)-7-[(2,6-dideoxy-2-iodo-α-L-mannopyranosyl)oxy]-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-7,8,9,10-
tetrahydrotetracene-5,12-dione
DNA topoisomerase II inhibitor, antineoplastic, Annamycin, Annamycin-LF, Annamycin-liposomal, L-ANNA, L-annamycin, Liposomal annamycin, S-ANNA, SNU299M83Q

• OriginatorUniversity of Texas M. D. Anderson Cancer Center
• DeveloperAronex Pharmaceuticals; Callisto Pharmaceuticals; Moleculin Biotech; University of Texas M. D. Anderson Cancer Center
• ClassAnthracyclines; Antineoplastics; Cytostatic antibiotics; Small molecules
• Mechanism of ActionType II DNA topoisomerase inhibitors
• Orphan Drug StatusYes - Soft tissue sarcoma; Precursor cell lymphoblastic leukaemia-lymphoma; Acute myeloid leukaemia
• Phase II/IIIAcute myeloid leukaemia
• Phase IIOvarian cancer
• Phase I/IISoft tissue sarcoma
• PreclinicalColorectal cancer; Liver cancer; Pancreatic cancer; Solid tumours
• DiscontinuedChronic myeloid leukaemia; Precursor cell lymphoblastic leukaemia-lymphoma; Triple negative breast cancer
• 30 Oct 2025Moleculin biotech plans future regulatory filings based on data from phase III MIRACLE trial
• 29 Oct 2025Moleculin Biotech has patent protection for Naxtarubicin in Australia
• 23 Oct 2025Moleculin Biotech plans to submit an IND application to the US FDA for Pancreatic cancer

Naxtarubicin is a lipophilic, anthracycline antineoplastic antibiotic.Naxtarubicin intercalates into DNA and inhibits topoisomerase II, thereby inhibiting DNA replication and repair as well as inhibiting RNA and protein synthesis. This agent appears to not be a substrate for the p-glycoprotein associated multidrug-resistance (MDR) transporter; therefore, overcoming the resistance pattern seen with other anthracycline compounds.

Annamycin is an anthracycline antibiotic being investigated for the treatment of cancer.

SYN

US 4537882

The reaction of racemic 4-demethoxydaunomycinone (I) with Br2 followed by hydrolysis in basic medium gives 4-demethoxyadriamycinone (II), which is treated with tert-butyldimethylsilyl chloride and imidazole in DMF to yield the monoprotected compound (III). The condensation of (III) with 3,4-di-O-acetyl-2,6-dideoxy-2-iodo-alpha-L-mannopyranose (IV) by means of N-iodosuccinimide (NIS), followed by chromatographic separation of the diastereomers affords (7S,9S)-14-O-(tert-butyldimethylsilyl)-4-demethoxy-7-O-(3,4-di-O-acetyl-2,6-dideoxy-2-iodo-alpha-L-mannopyranosyl)adriamycinone (V). The hydrolysis of (V) with sodium methoxide in methanol gives the silylated compound (VI), which is finally desilylated with tetrabutylammonium fluoride (TBAF) in dichloromethane/THF/pyridine.

SYN

https://patents.google.com/patent/US5977327A/en

EXAMPLE VIIIPURIFICATION OF ANNAMYCIN

Crude product was purified further by triple precipitation from THF. To accomplish this, approximately 87 mL of THF was used to redissolve each gram of Annamycin product and an equal volume of one of the following solvents was added to precipitate the Annamycin in each successive precipitation step. In the preferred method, the first precipitation was accomplished by adding an equal volume of a 7:3 mixture of hexane\diethylether, the second precipitation was accomplished by the addition of an equal volume of hexane, and the third precipitation was by addition of an equal volume of water and evaporation of half of the THF. Product obtained in this way (9.0146 g; 59%) was a complex containing 3 molecules of Annamycin per 2 molecules of THF and its purity by HPLC analysis was better than 98%. HPLC analysis was on an analytical C-18 reverse phase column with increasing concentrations of methanol/acetonitrile in water. The purity was determined by measuring the area of the absorbance peaks. ¹ H NMR (DMSO-d6) d 1.20 (d, 3H, J_6', 5' =6.2 Hz, H-6'), 1.75 (m, 2.7H, Ha from THF), 2.10 (dd, 1H, J_8a,7 =5.6 Hz, J_8a,8e =14.5 Hz, H-8a), 2.18 (dd, 1H, J_8e,8a =14.8 Hz, J_8e,7 =2.9 Hz, H-8e), 250 (DMSO peak), 2.75 (dd, 1H, J_3',2' =3.9 Hz, J_3',4' =8.8 Hz, H-3'), 2.95 (d, 1H, J_10a,10e =18.4 Hz, H-10a), 3.00 (d, 1H, J_10e,10a =18.4 Hz, H-10e), 3.20 (t, 1H, SJ=18.1 Hz, H-4'), 3.59 (m, 2.7H, Hb from THF), 3.95 (m, 1H, H-5'), 4.30 (d, 1H, J_2',3' =4.0 Hz, H-2'), 4.55 (s, 2H, H-14), 4.89 (t, 1H, exchangeable, OH), 4.92 (m, 1H, H-7), 5.18 (d, 1H, exchangeable, OH), 5.38 (d, 1H, exchangeable, OH), 5.49 (s, 1H, H-1'), 5.50 (d, 1H, exchangeable, OH), 7.9, 8.4 (2m, 4H,H-1,2,3,4); ¹³ C NMR (DMSO-d6) d 17.0(s, 1C, C-6'), 24.5 (s, 1C, THFb), 31.7 (s, 1C, C-2'), 31.9 (s, 1C, C-10), 36.4 (s, 1C, C-8), 63.0 (s, 1C, C-3'), 66.4 (s, 1C, C-5'), 67.4 (s, 1C, THFa), 69.4, ¹³ C-NMR (DMSO-d6) δ 17.9 (s, 1C, C-6'), 25.1 (s, 1C, THFb), 40.6, 36.6, 32.1 (3s, 3C, C-2',8,10), 63.6 (s, 1C, C-14), 67.0, 67.5, 70.4, 69.7 (4s, 4C, C-7, 5', 3', THFa), 74.2, 74.7 (2s, 2C, C-9, 4'), 104.5 (s, 1C, C-1'), 110.1, 110.8 (2s, 1C, C-11a, 5a), 126.6, 132.6, 132.8, 134.4, 135.1, 135.0, 136.0 (7s, 8C, C-2, 3, 1, 4, 4a, 12a, 10a), 136.0 (s, 1C, C-6a), 155.1, 156.4 (2s, 2C, C-6, 11), 186.2, 186.3 (2s, 2C, C-5, 12), 214 (s, 1C, C-13).

SYN

WO-9739007-A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO1997039007&_cid=P11-MLSUQX-01231-1

SYN

WO-9639121-A1

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO1998003522&_cid=P11-MLSUWB-04506-1

EXAMPLE I. SYNTHESIS OF (+)-4-DEMETHOXY-14-O-TERT-BUTYL
DIMETHYLSILYL-7-O-(2,6-DIDEOXY-2-IODO-α-L-MANNOPYRANOSYL)ADRIAMYCINONE (8)
To a solution consisting of a mixture of compounds (6) and (7), shown in Figure 1 , (1.8530g, 2.21mmol) in CH2CI2 (48 mL) and EtOH (16 mL), a IN MeONa solution in MeOH (1.6 mL) was added at room temperature with stirring. Next 1.6 mL of a IN MeONa solution in MeOH (1.6 mL) was added after 50 min. After 1.5 hr. the reaction was checked by TLC developed with CCl4/MeOH (96:4), and the reaction mixture was diluted with dichloromethane (300 mL) and 0.05N HCL (100 mL) was added. The resulting mixture was shaken in a separatory funnel and, after separation, the organic layer was washed with water (2 x 50 mL), dried over Na2SO4, filtered and evaporated. The residue left after evaporation was precipitated from 4 mL of CH2CI2 by addition of 35 mL of hexane. The precipitate was filtered, washed with hexane (40 mL) and then dried in vacuo (1 lmbar) at ambient temperature for 30 min. to give crude product (8) (1.3618g, 82%). The crude product was then filtered through silica with a solution of 95:5 toluene/acetone and precipitated from CH2CI2 by addition of hexane. Product was then dried in vacuo (1 lmbar) at ambient temperature for 30 minutes to give pure compound (8) (1.358g; 55%): ^H NMR d 0.15 (s, 6H, Me2Si), 0.95 (s, 9H, CMe3), 1.40 (d, 3H, J6',5'=6.2Hz, H-6'), 2.18 (dd, 1H, J8a,7=4.4Hz, J8a,8e=l 5.0Hz, H-8a), 2.35 (d, 1H, J8e,8a=14.9Hz, H-8e), 2.85 (dd, 1H, J3',2'*=4-0Hz, J3'₅4'=8.9Hz, H-3'), 3.02 (d, 1H, Jl0a,10e=19.0Hz, H-lOa), 3.24 (d, 1H, Jl0e,10a=l 9.0Hz, H-lOe), 3.58 (t, 1H, SJ=18.2Hz, H-4'), 3.94 (m, 1H, H-5'), 4.18 (s, 1H, 9OH), 4.54 (d, 1H, J2',3'=3.9Hz, H-2') 4.84, 4.90 (2d, 2H, H-14), 5.22 (bs, 1H, H-7), 5.75 (s, 1H, H-l'), 7.9, 8.4 (2m, 4H, H-1,2,3,4).

EXAMPLE II. DESILYLATION IN THF/HCl
To a solution of compound (8), (16.5928g, 21.99mmol) in THF (415 mL), IN HC1 (415 mL) was added. After 25 minutes the progress of the reaction was checked by TLC developed in toluene/acetone (6:4 or 5:1) and half of the THF was evaporated in vacuo at 20°C (35mbar). The precipitate was filtered off and washed with water until the pH reached neutral (14 x 40 mL), then washed with ether (Et2θ, 5 x 32 mL) and subsequently with water (3 x 40 mL). The crude product was pre-dried on a Buchner funnel and then dried in vacuo (0.08mbar) at room temperature for 38 hrs.
EXAMPLE III. DESILYLATION IN METHANOL/HC1
To a solution/suspension of compound (8) (1.0064 g, 1.33 mmol) in methanol (45 mL), IN HC1 (10 mL) was added. The progress of the reaction was monitored by TLC developed in toluene/acetone, 6:4 and chloroform methanol, 94:6. After 45 min. 5 mL of IN HC1 solution was added to the reaction mixture. After 1 hr. 15 min. the product of the reaction was precipitated by addition of 30 mL water and filtered off. Product was washed with water until neutral pH (4 x 10 mL), diethylether (3 x 10 mL) and again with water (2 x 10 mL). Crude product was pre-dried on Buchner funnel and then dried in vacuo (0.1 mbar) at room temperature for 24 hrs. to give 0.6722 g (79% yield) of deep red powder.
EXAMPLE IV. DESILYLATION IN METHANOL/H₂SO₄
To a solution suspension of compound (8) (1.0065 g, 1.33 mmol) in methanol (45 mL), 10 mL of IN H2SO4 was added. The progress of the reaction was monitored by TLC developed in toluene/acetone, 6:4 and chloroform/methanol, 94:6. After 15 min. the product of the reaction was precipitated by adding 35 mL of water and filtered off. Product was washed with water until neutral pH (4 x 10 mL), diethylethe (3 x 10 mL) and again with water (2 x 10 mL). Crude product was pre-dried on Buchner funnel and then dried in vacuo (0.1 mbar) at room temperature for 24 hrs. to give 0.6318 g (74% yield) of deep red powder. EXAMPLE V. DESILYLATION IN ACETONE/H₂SO₄
To a solution of compound (8) (0.7592 g, 1.01 mmol) in acetone (30 mL) 3.5 mL IN H2SO4 was added. The progress of the reaction was monitored by TLC developed in toluene/acetone, 6:4 and chloroform/methanol, 94:6. After 1 hr. the product of the reaction was precipitated by addition of 35 mL water and filtered off. The product was washed with water until neutral pH (4 x 10 mL), dicthyleher (3 x 10 mL) and again with water (2 x 10 mL). Crude product was pre-dried on Buchner funnel and then dried in vacuo (0.1 mbar) at room temperature for 48 hrs. to give 0.4994 g (77% yield) of deep red powder.

EXAMPLE VI. DESILYLATION IN DMSO/HC1
To a solution of compound (8) (0.7815 g, 1.04 mmol) in DMSO (30 mL) 7.5 mL of IN HC1 was added. Progress of the reaction was monitored by TLC developed in toluene/acetone, 6:4 and chloroform/methanol, 94:6. After 1 hr. 20 min. the product of the reaction was precipitated by addition of water (37 mL) and filtered off. The product was washed with water until neutral pH (4 x 10 mL), dietheylether (3 x 10 mL) and again with water (2 x 10 mL). Crude product was pre-dried on Buchner funnel and then dried in vacuo (0.1 mbar) at room temperature for 48 hrs. to give 0.5165 g (78% yield) of deep red powder. EXAMPLE VII. DESILYLATION IN DMSO/H₂SO
To a solution of compound (8) (0.7613 g, 1.01 mmol) in DMSO (5 mL) and ethanol

(10 mL) 1 mL of IN H2SO4 was added. Progress of the reaction was monitored by TLC developed in toluene/acetone, 6:4 and chloroform/methanol, 94:6. After 1 hr. 10 min. product of the reaction was precipitated by addition of water (15 mL) and filtered off. Product was washed with water until neutral pH (4 x 10 mL), diethylether (3 x 10 mL) and again with water (2 x 10 mL). Crude product was pre-dried on Buchner funnel and then dried in vacuo (0.1 mbar) at room temperature for 48 hrs. to give 0.5338 g (83% yield) of deep red powder. EXAMPLE VIII. PURIFICATION OF ANNAMYCIN
Crude product was purified further by triple precipitation from THF. To accomplish this, approximately 87 mL of THF was used to redissolve each gram of Annamycin product and an equal volume of one of the following solvents was added to precipitate the .Annamycin in each successive precipitation step. In the preferred method, the first precipitation was accomplished by adding an equal volume of a 7:3 mixture of hexane\diethylether, the second precipitation was accomplished by the addition of an equal volume of hexane, and the third precipitation was by addition of an equal volume of water and evaporation of half of the THF. Product obtained in this way (9.0146g; 59%) was a complex containing 3 molecules of .Annamycin per 2 molecules of THF and its purity by HPLC analysis was better than 98%. HPLC analysis was on an analytical C-18 reverse phase column with increasing concentrations of methanol/acetonitrile in water. The purity was determined by measuring the area of the absorbance peaks. H NMR (DMSO-d6) d 1.20 (d, 3H, J6',5'-=6.2Hz, H-6'), 1.75 (m, 2.7H, Ha from THF), 2.10 (dd, IH, J8_a,7=5.6Hz, J8a,8e=14.5Hz, H-8a), 2.18 (dd, IH, J8e,8a=14.8Hz, J8e,7=2.9Hz, H-8e), 2.50 (DMSO peak), 2.75 (dd, IH, J3',2'=3.9Hz, J3',4'=8.8Hz, H-3'), 2.95 (d, IH, Jl0a,10e=18.4Hz, H-10a), 3.00 (d, IH, Jl0e,10a=18.4Hz, H-lOe), 3.20 (t, IH, SJ=18.1Hz, H-4'), 3.59 (m, 2.7H, Hb from THF), 3.95 (m, IH, H-5'), 4.30 (d, IH, J2',3'=4.0Hz, H-2'), 4.55 (s, 2H, H-14), 4.89 (t, IH, exchangeable, OH), 4.92 (m, IH, H-7), 5.18 (d, IH, exchangeable, OH), 5.38 (d, IH, exchangeable, OH), 5.49 (s, IH, H-l'), 5.50 (d, IH, exchangeable, OH), 7.9, 8.4 (2m, 4H,H- 1,2,3,4); ¹³C NMR (DMSO-d6) d 17.0(s, IC, C-6'), 24.5 (s, IC, THFb), 31.7 (s, IC, C-2'), 31.9 (s, IC, C-10), 36.4 (s, IC, C-8), 63.0 (s, IC, C-3'), 66.4 (s, IC, C-5'), 67.4 (s, IC, THFa), 69.4, ^,3C-NMR (DMSO-d6) δ 17.9 (s, IC, C-6'), 25.1 (s, IC, THFb), 40.6, 36.6, 32.1 (3s, 3C, C-2', 8, 10), 63.6 (s, IC, C-14), 67.0, 67.5, 70.4, 69.7 (4s, 4C, C-7, 5', 3', THFa), 74.2, 74.7 (2s, 2C, C-9, 4'), 104.5 (s, IC, C-l'), 110.1, 110.8 (2s, IC, C-lla, 5a), 126.6, 132.6, 132.8, 134.4, 135.1, 135.0, 136.0 (7s, 8C, C-2, 3, 1, 4, 4a, 12a, 10a), 136.0 (s, IC, C-6a), 155.1, 156.4 (2s, 2C, C-6, 11), 186.2, 186.3 (2s, 2C, C-5, 12), 214 (s, IC, C-13).

PAT

• Co-solvent compositions and methods for improved delivery of dantrolene therapeutic agentsPublication Number: US-2011160261-A2
• HER2 mutation inhibitorsPublication Number: US-12447153-B2Grant Date: 2025-10-21
• Submicron liposome suspensions obtained from preliposome lyophilizatesPublication Number: US-7238366-B1Priority Date: 1995-06-06Grant Date: 2007-07-03
• Submicron liposome suspension obtained from freeze-dried preliposomePublication Number: JP-H11507369-APriority Date: 1995-06-06
• Submicron liposome suspensions obtained from preliposome lyophilizatesPublication Number: EP-1800665-A3Priority Date: 1995-06-06
• Submicron liposome suspensions obtained from preliposome lyophilizatesPublication Number: EP-0831781-A1Priority Date: 1995-06-06
• Process for preparing aminoglycsidic antibioticsPublication Number: CS-202570-B2Priority Date: 1976-04-14
• Methods and systems for assessing biological materials using optical and spectroscopic detection techniquesPublication Number: US-2004052730-A1Priority Date: 1995-10-04
• Submicron liposome suspensions obtained from preliposome lyophilizatesPublication Number: EP-1800665-A2Priority Date: 1995-06-06
• Submicron liposome suspensions obtained from preliposome lyophilizatesPublication Number: US-5902604-APriority Date: 1995-06-06Grant Date: 1999-05-11
• Submicron liposome suspensions obtained from preliposome lyophilizatesPublication Number: WO-9639121-A1Priority Date: 1995-06-06
• Submicron liposome suspensions obtained from preliposome lyophilizatesPublication Number: CA-2221341-A1Priority Date: 1995-06-06
• Compounds and methods for the selective treatment of cancer and bacterial infectionsPublication Number: WO-9739007-A1Priority Date: 1996-04-12
• Compounds and methods for the selective treatment of cancer and bacterial infectionsPublication Number: US-6218519-B1Priority Date: 1996-04-12Grant Date: 2001-04-17
• Methods and systems for assessing biological materials using optical and spectroscopic detection techniquesPublication Number: US-6573063-B2Priority Date: 1995-10-04Grant Date: 2003-06-03
• Methods and systems for assessing biological materials using optical and spectroscopic detection techniquesPublication Number: US-6319682-B1Priority Date: 1995-10-04Grant Date: 2001-11-20
• Methods and systems for assessing biological materials using optical and spectroscopic detection techniquesPublication Number: US-2002055092-A1Priority Date: 1995-10-04

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Further reading

• Priebe W (1995). "Mechanism of action-governed design of anthracycline antibiotics: a "turn-off/turn-on" approach". Current Pharmaceutical Design. 1 (1): 51–68. doi:10.2174/1381612801666220524190711. S2CID 90406009.
• Trevino AV, Woynarowska BA, Herman TS, Priebe W, Woynarowski JM (November 2004). "Enhanced topoisomerase II targeting by annamycin and related 4-demethoxy anthracycline analogues". Mol Cancer Ther. 3 (11): 1403–10. doi:10.1158/1535-7163.1403.3.11. PMID 15542779.

External links

• National Cancer Institute Definition of Annamycin

Clinical data
ATC code	none
Identifiers
IUPAC name
CAS Number	92689-49-1
PubChem CID	115212
ChemSpider	103088
UNII	SNU299M83Q
KEGG	D12844
CompTox Dashboard (EPA)	DTXSID901027238
ECHA InfoCard	100.235.298
Chemical and physical data
Formula	C26H25IO11
Molar mass	640.379 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

//////////naxtarubicin, DNA topoisomerase II inhibitor, antineoplastic, Annamycin, Annamycin-LF, Annamycin-liposomal, L-ANNA, L-annamycin, Liposomal annamycin, S-ANNA, SNU299M83Q

#naxtarubicin, #DNA topoisomerase II inhibitor, #antineoplastic, #Annamycin, #Annamycin-LF, #Annamycin-liposomal, #L-ANNA, #L-annamycin, #Liposomal annamycin, #S-ANNA, #SNU299M83Q

Nedemelteon

 

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}acetamide
melatonin receptor agonist, CW62HV1TTF, MT1/2 Agonist (S)-3b

Nedemelteon is a melatonin receptor agonist.

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.

SYN

Discovery of a Potent and Orally Bioavailable Melatonin Receptor Agonist

Publication Name: Journal of Medicinal Chemistry

Publication Date: 2021-03-08

PMID: 33682410

DOI: 10.1021/acs.jmedchem.0c01836

SYN

US8552037,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US76841372&_cid=P22-MLU9PK-87296-1

EXAMPLE 11

N-[2-(2-Methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide

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),

MS (ESI+): 259 (M+H),

Elemental analysis: for C 15H 18N 2O 2

Calcd. (%): C, 69.74; H, 7.02; N, 10.84

Found (%): C, 69.77; H, 6.97; N, 10.95.

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: 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),

MS (ESI+): 259 (M+H),

[α] D 20: −53.4° (c 0.5035, methanol),

Elemental analysis: for C 15H 18N 2O 2

Calcd. (%): C, 69.74; H, 7.02; N, 10.84

Found (%): C, 69.53; H, 7.01; N, 10.96.

SYN

WO-2007148808

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007148808&_cid=P22-MLU9Y2-93563-1

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:

0.65 mg/mL (hexane/ethanol) , injection volume: 10 μL) .
¹H-NMR (CDCl₃) 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 (IH, brs), 7.15 (IH, d, J = 8.0 Hz), 7.44 (IH, d, J = 8.0Hz),
melting point: 111 - 113°C (recrystallized from hexane/ethyl acetate) ,
MS (ESI+) : 259 (M+H) ,
[α] _D²⁰: -53.4° (c 0.5035, methanol),
Elemental analysis: for Ci₅Hi₈N₂O₂
Calcd. (%) : C, 69.74; H, 7.02; N, 10.84
Found (%) : C, 69.53; H, 7.01; N, 10.96.

PAT

• Tricyclic compounds, pharmaceutical compositions comprising such and pharmaceutical uses thereof.Publication Number: NO-341739-B1Priority Date: 2006-06-19
• Tricyclic compounds and their pharmaceutical usePublication Number: CN-101506181-APriority Date: 2006-06-19
• Tricyclic compound and pharmaceutical use thereofPublication Number: US-8895591-B2Priority Date: 2006-06-19Grant Date: 2014-11-25
• Tricyclic compound and use thereof as a melatonin receptor agonistPublication Number: CA-2655753-A1Priority Date: 2006-06-19
• TRICYCLE COMPOUND AND PHARMACEUTICAL USE OF THE SAME.Publication Number: MX-2008015842-APriority Date: 2006-06-19
• Tricyclic compound and pharmaceutical use thereofPublication Number: US-8236837-B2Priority Date: 2006-06-19Grant Date: 2012-08-07
• Tricyclic compounds and their pharmaceutical usesPublication Number: JP-2009541202-APriority Date: 2006-06-19
• Tricyclic compound and pharmaceutical use thereofPublication Number: US-8030337-B2Priority Date: 2006-06-19Grant Date: 2011-10-04
• Tricyclic compound and pharmaceutical use thereofPublication Number: US-2014011849-A1Priority Date: 2006-06-19
• Tricyclic compound and pharmaceutical use thereofPublication Number: US-2011196003-A1Priority Date: 2006-06-19
• Tricyclic compound and pharmaceutical use thereofPublication Number: EP-2029561-B1Priority Date: 2006-06-19Grant Date: 2014-08-13
• TRICYCLIC COMPOUND AND ITS PHARMACEUTICAL APPLICATIONPublication Number: RU-2009101299-APriority Date: 2006-06-19
• Tricyclic compounds and their pharmaceutical usesPublication Number: JP-5222737-B2Priority Date: 2006-06-19Grant Date: 2013-06-26
• Indeno[1,3]oxazoles and indeno[1,3-thiazoles] and pharmaceutical use thereofPublication Number: NZ-574037-APriority Date: 2006-06-19
• Tricyclic compound and pharmaceutical use thereofPublication Number: US-2013079374-A1Priority Date: 2006-06-19
• Tricyclic compound and use thereof as a melatonin receptor agonistPublication Number: CA-2655753-CPriority Date: 2006-06-19Grant Date: 2015-08-04
• Tricyclic compound and pharmaceutical use thereofPublication Number: US-2009182023-A1Priority Date: 2006-06-19
• Tricyclic compound and pharmaceutical use thereofPublication Number: EP-2029561-A1Priority Date: 2006-06-19
• Tricyclic compounds and their pharmaceutical usePublication Number: CN-101506181-BPriority Date: 2006-06-19Grant Date: 2011-12-07
• Tricyclic compound and pharmaceutical use thereofPublication Number: US-8349879-B2Priority Date: 2006-06-19Grant Date: 2013-01-08
• Tricyclic compound and pharmaceutical use thereofPublication Number: US-2011190361-A1Priority Date: 2006-06-19
• Tricyclic compound and pharmaceutical use thereofPublication Number: WO-2007148808-A1Priority Date: 2006-06-19

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///////////nedemelteon, melatonin receptor agonist, CW62HV1TTF, MT1/2 Agonist (S)-3b

#nedemelteon, #melatonin receptor agonist, #CW62HV1TTF, #MT1/2 Agonist (S)-3b

Nispomeben

 

Nispomeben

CAS 1443133-41-2

MF C21H27NO4 MW357.4 g/mol

N-[(2S)-1-(4-hydroxyphenyl)-3-[(2S)-2-hydroxypropoxy]propan-2-yl]-3-phenylpropanamide

N-{(2S)-1-(4-hydroxyphenyl)-3-[(2S)-2-hydroxypropoxy]propan-2-yl}-3-phenylpropanamide
non-opioid analgesic, 470338M5XD,  E1, NRD 135S E1, NRD E1, NRD.E1, NRD135S, NRD135S.E1, NRD135SE.1

Nispomeben is a small molecule drug. Nispomeben has a monoisotopic molecular weight of 357.19 Da.

• OriginatorNovaremed
• ClassAlcohols; Amides; Anti-inflammatories; Benzene derivatives; Non-opioid analgesics; Phenols; Small molecules
• Mechanism of ActionLyn protein-tyrosine kinase modulators
• Phase IINeuropathic pain
• 02 Sep 2025Updated adverse events data from a phase II trial in Neuropathic pain released by Novaremed
• 07 May 2025Novaremed completes enrolment in a phase-II clinical trial in Neuropathic pain in USA (PO) (NCT05480228)
• 16 Sep 2022Phase-II clinical trials in Neuropathic pain in USA (PO) (NCT05480228)

PAT

WO 2013/084238

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013084238&_cid=P12-MLVQKQ-84446-1

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.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US73212948&_cid=P12-MLVQ44-77600-1

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.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020152226&_cid=P12-MLVQFW-82529-1

((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.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US346680873&_cid=P12-MLVQFW-82529-1

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.

PAT

• Method of treating or preventing painPublication Number: US-2016317479-A1Priority Date: 2009-09-09
• Method of treating or preventing painPublication Number: US-8802734-B2Priority Date: 2009-09-09Grant Date: 2014-08-12
• Method of Treating or Preventing PainPublication Number: US-2014350099-A1Priority Date: 2009-09-09
• N-substituted benzenepropanamide or benzenepropenamide for use in the treatment of pain and inflammationPublication Number: WO-2011030205-A1Priority Date: 2009-09-09
• Method of treating or preventing painPublication Number: US-2011086910-A1Priority Date: 2009-09-09
• Isolated stereoisomeric forms of (S)2-N(3-O-(propan 2-Ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamidePublication Number: US-9381173-B2Priority Date: 2011-12-08Grant Date: 2016-07-05
• Isolated Stereoisomeric Forms Of (S)2-N(3-O-(Propan 2-Ol)-1-Propyl-4-Hydroxybenzene)-3-PhenylpropylamidePublication Number: US-2014275270-A1Priority Date: 2011-12-08
• N-substituted benzenepropanamide and benzenepropenamide for use in the prevention or the treatment of affective disordersPublication Number: US-9133103-B2Priority Date: 2011-09-21Grant Date: 2015-09-15
• N-Substituted Benzenepropanamide and Benzenepropenamide For Use in the Prevention or the Treatment of Affective DisordersPublication Number: US-2014275273-A1Priority Date: 2011-09-21
• N-substituted benzenepropanamide and benzenepropenamide for use in the prevention or the treatment of affective disordersPublication Number: EP-2758046-B1Priority Date: 2011-09-21Grant Date: 2015-10-21
• Compounds for treatment or prevention of an infection resulting from a coronavirus and/or a coronavirus-induced diseasePublication Number: EP-3939578-A1Priority Date: 2020-07-13
• Compounds for use in the treatment or prophylaxis of pain, inflammation and/or autoimmunityPublication Number: EP-3860582-B1Priority Date: 2019-01-23Grant Date: 2022-05-04
• Compounds for use in the treatment or prophylaxis of pain, inflammation and/or autoimmunityPublication Number: WO-2020152226-A1Priority Date: 2019-01-23
• Compounds for use in the treatment or prophylaxis of pain, inflammation and/or autoimmunityPublication Number: US-2022002228-A1Priority Date: 2019-01-23
• Pharmaceutical composition comprising stereoisomers of n-(1-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide for the prevention and treatment of type ii diabetesPublication Number: WO-2015173813-A1Priority Date: 2014-05-14

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