Structure of 102-56-7
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Matrix-Designed Bright Near-Infrared Fluorophores for Precision Peripheral Nerve Imaging
Montaño, Antonio R ; Masillati, Anas ; Szafran, Dani A ; Shams, Nourhan A ; Hubbell, Grace E ; Barth, Connor W , et al.
Abstract: The FDA's recent approval of pafolacianine, the first molecular targeted contrast agent for fluorescence-guided surgery (FGS), signifies a remarkable milestone in precision medicine. This advance offers new hope for cancer patients by enabling guided removal of cancerous tissues, where completed surgical removal remains a consistent challenge without real-time intraoperative guidance. For optimal surgical outcomes, delicate nerve tissues must be preserved to maintain patient quality of life. Despite advances in the clinical translation pipeline, the development of clinically viable nerve-specific contrast agents for FGS remains a significant challenge. Herein, a medicinal chemistry-based matrix design strategy was applied to effectively generate a synthetic roadmap permitting management of nerve-specificity within the near-infrared (NIR) oxazine fluorophore family. Many of these newly developed fluorophores demonstrated robust nerve-specificity and superior safety profiles, while also offering spectral profiles that are compatible with the clinical surgical FGS infrastructure. Notably, improving observed brightness in vivo enabled exceptional visibility of buried nerve tissue, a priority during surgical procedures. Critically, the lead probe showed a large dosage safety window capable of generating substantial contrast at doses 100x lower than the maximum tolerated dose. Following clinical translation, such NIR nerve-specific fluorophores stand poised to significantly improve outcomes for surgical patients by improving identification and visualization of surface and buried nerve tissues in real time within the surgical arena.
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Keywords: Near-infrared (NIR) ; Fluorescence imaging ; Oxazine ; Nerve-specific imaging ; Fluorescence-guided surgery (FGS)
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CAS No. : | 102-56-7 |
Formula : | C8H11NO2 |
M.W : | 153.18 |
SMILES Code : | NC1=CC(OC)=CC=C1OC |
MDL No. : | MFCD00008368 |
InChI Key : | NAZDVUBIEPVUKE-UHFFFAOYSA-N |
Pubchem ID : | 7613 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P301+P312+P330 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 43.83 |
TPSA ? Topological Polar Surface Area: Calculated from |
44.48 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.86 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.2 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.29 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.87 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.09 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.26 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.82 |
Solubility | 2.33 mg/ml ; 0.0152 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.73 |
Solubility | 2.85 mg/ml ; 0.0186 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.28 |
Solubility | 0.809 mg/ml ; 0.00528 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.38 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.36 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | Example 219 N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-2,5-dimethoxyaniline 2,5-Dimethoxyaniline (0.172 g, 1.125 mmol), triethylamine (0.114 g, 1.125 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.190 g, 1.125 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.281 g, 0.750 mmol) and the resulting solution was stirred at room temperature for 4 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform: methanol = 95:5) to obtain the titled compound (0.149 g, 0.292 mmol, 39percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | EXAMPLE 20 6-Bromo-N-(2,5-dimethoxyphenyl)thieno[3,2-d]pyrimidin-4-amine To a mixture of <strong>[56844-12-3]6-bromo-4-chlorothieno[2,3-d]pyrimidine</strong> (96 mg, 0.38 mmol) and 2,5-dimethoxybenzenamine (65 mg, 0.42 mmol) in 2.5 mL of isopropanol was added 2 drops of concentrated HCl and the mixture was heated at 75 C. for 3 h. The reaction mixture was cooled to room temperature and diluted with 25 mL of ethyl acetate, and washed with saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (40% ethyl acetate/hexane) to give the title compound (116 mg, 0.32 mmol, 84%). 1H NMR (CDCl3) 8.70 (s, 1H), 8.07 (d, 1H, J=3.0), 7.45 (s, 1H), 7.18 (s, 1H, broad), 6.87 (d, 1H, J=8.7), 6.67 (dd, 1H, J=9.0, 3.0), 3.88 (s, 3H), 3.83 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | General procedure: To a solution of the acid derivative (1mmol) in CH2Cl2 were added triethylamine (2mmol) and ethyl chloroformate (1mmol), followed by stirring at 0C for 30min. After addition of the appropriate amine derivative (1.2mmol), the mixture was stirred for an additional 1h at 0C. Then, the reaction mixture was warmed to room temperature and stirred overnight. After the solvent was evaporated under reduced pressure, acetone was added, filtered, and evaporated. The residue was dissolved in CH2Cl2, and the organic phase was washed with a 1% NaHCO3 solution and brine, dried over Na2SO4, and evaporated under vacuum. The final residue was purified by flash column chromatography (Combiflash Rf) using CH2Cl2-MeOH (0-5%) as eluents. |