Structure of 7357-70-2
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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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Gaofenngwe Nkomba ; Gisella Terre’Blanche ; Helena D. Janse van Rensburg ; Lesetja J. Legoabe ;
Abstract: Due to the implication of adenosine in seizure suppression, adenosine-based therapies such as adenosine receptor (AR) agonists have been investigated. This study aimed at investigating thieno[2,3-b]pyridine derivatives as non-nucleoside A1 agonists that could be used in pharmaco-resistant epilepsy (PRE). Compound 7c (thieno[2,3-b]pyridine derivative), displayed good binding affinity to the rA1 AR (Ki = 61.9 nM). This could be a breakthrough for further investigation of this heterocyclic scaffold as potential ligand. In silico evaluation of this compound raised bioavailability concerns but performed well on drug-likeness tests. The effect of intramolecular cyclisation that occurs during synthesis of thieno[2,3-b]pyridines from the lead compounds, amino-3,5-dicyanopyridine derivatives (6a-s) in relation to AR binding was also evaluated. A significant loss of activity against rA1/rA2A ARs with cyclisation was revealed. Amino-3,5-dicyanopyridines exhibited greater affinity towards rA1 ARs (Ki < 10 nM) than rA2A. Compound 6c had the best rA1 affinity (Ki = 0.076 nM). Novel compounds (6d, 6k, 6l, 6m, 6n, 6o, 6p) were highly selective towards rA1 AR (Ki between 0.179 and 21.0 nM). Based on their high selectivity for A1 ARs, amino-3,5-dicyanopyridines may be investigated further as AR ligands in PRE with the right structural optimisations and formulations.
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Keywords: Amino-3,5-dicyanopyridines ; Thieno[2,3-b]pyridines ; Intramolecular cyclisation ; Adenosine A1/A2A receptors ; Epilepsy
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CAS No. : | 7357-70-2 |
Formula : | C3H4N2S |
M.W : | 100.14 |
SMILES Code : | NC(CC#N)=S |
MDL No. : | MFCD00010025 |
InChI Key : | BHPYMZQTCPRLNR-UHFFFAOYSA-N |
Pubchem ID : | 1416277 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302+H312+H332-H315-H319-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 6 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 26.78 |
TPSA ? Topological Polar Surface Area: Calculated from |
81.9 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.57 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.37 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.19 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.89 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.71 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.04 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.16 |
Solubility | 69.0 mg/ml ; 0.689 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.89 |
Solubility | 13.0 mg/ml ; 0.13 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.09 |
Solubility | 82.3 mg/ml ; 0.822 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 |
No |
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 |
-7.17 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 |
2.0 |
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) |
1.8 |
* 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 |
---|---|---|
99% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; | 10 g (58.74 mmol) of [bis(methylthio)methylene]malononitrile and 6.5 g (64.61 mmol) of cyanothioacetamide are initially charged in 20 ml of DMF, and 16.4 ml (117.5 mmol) of triethylamine are added dropwise at room temperature. The mixture is stirred at room temperature for 8 h and allowed to stand for a further two days. The mixture is then added to 250 ml of 3 N hydrochloric acid. The resulting precipitate is filtered off with suction, washed with water and acetone and dried. This gives a yellow powder.Yield: 12.9 g (99% of theory)1H-NMR (400 MHz, CDCl3): δ=3.98 (s, 1H), 2.72 (s, 3H).LC-MS (Method 3): Rt=1.43 min; MS (ESIpos): m/z=222 [M+H]+. |
93% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | 2-(Bis(methylthio)methylene)malononitrile (10 g, 58.7 mmol) and cyanothioacetamide (7.06 g, 70.5 mmol) were added to a round-bottom flask and dissolved in N,N-dimethylformamide (21 mL). Triethylamine (16.37 mL, 117 mmol) was added dropwise at room temperature and the mixture was stirred for 18 hours. The reaction mixture was added to 300 mL of 3 N hydrochloric acid. The resulting precipitate was filtered off, washed with water and dried with suction to afford 2-amino-6-mercapto-4-(methylthio)pyridine-3,5-dicarbonitrile (13.5 g, 54.7 mmol, 93% yield). LCMS m/z = 222.9 [M+H]+. |
89% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; | 10 g (58.74 mmol) of 2-(di(methylthio))methylidenemalononitrile and 7.1 g (70.48 mmol) of cyanothioacetamide were initially charged in 21 ml of DMF, and 16.4 ml (117.47 mmol) of triethylamine were added dropwise at room temperature. The mixture was stirred at room temperature for 8 h. The reaction mixture was added to 300 ml of 3N hydrochloric acid. The resulting precipitate was filtered off with suction, washed with water and dried. This gave the product as a powder.Yield: 12.2 g (89% of theory, 96% pure)1H-NMR (400 MHz, CDCl3): δ=3.98 (s, 1H), 2.72 (s, 3H).LC-MS (Method 7): Rt=1.56 min; MS (ESIpos): m/z=223 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With acetic anhydride;Reflux; | General procedure: The title compounds 1a-d were prepared from the reaction ofthe appropriate quinoline N-oxide (10 mmol) with the desired activemethylene nitrile in refluxing Ac2O. The adopted procedurefollowed the earlier protocol employed by Hamana, Klemm andOchiai for related derivatives [15,17,19]. Each product was recrystallizedfrom acetonitrile. The IR and NMR spectroscopic data aresummarized in Table 1. Yield of 1a: 89% (2.0 g). Anal. Calcd. (found)for C12H9N3S: C, 63.41 (63.33); H, 3.99 (4.11). Yield of 1b: 81%(1.8 g). Anal. Calcd (found) for C13H9N3O: C, 69.50 (69.73); H,4.06 (4.13). Yield of 1c: 76% (2.0 g). Anal. Calcd. (found) forC15H14N2O3: C, 66.66 (66.55); H, 5.22 (5.22). Yield of 1d: 81%(2.1 g). Anal. Calcd (found) for C13H11N3OS: C, 60.68 (60.90); H,4.31 (4.35). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In butan-1-ol; at 170℃; for 0.166667h;Microwave irradiation; | General procedure: A 10-ml reaction vessel was charged with the corresponding 2-dialkylaminobenzaldehyde (2.0 mmol), n-butanol (4 ml), and cyano-thioacetamide (0.2 g, 2.0 mmol). The reaction vessel was closed with a silicone cap and perforated septum, and heated in microwave reactor at 150-200 temperature. After the reaction was complete (TLC control, 2:1 hexane-ethyl acetate), the reaction mixture was cooled with compressed air flow and transferred to a round-bottom flask. The solvent was removed in vacuo. The solid residue was crystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | General procedure: A mixture of 0.6 mL(10 mmol) of freshly distilled acetaldehyde 1, 1.0 g(10 mmol) of cyanothioacetamide 2, and 1 drop of triethylaminein 20 mL of anhydrous ethanol at 20Cwere stirred for 30 min, 1.4 g (10 mmol) of enamine 3was added, the mixture was stirred for 2 h and leftstanding for 24 h. Then while stirring was addedsuccessively 5.6 mL (10 mmol) of 10% aqueoussolution of KH and 10 mmol of α-haloketone 4a-4r, the mixture was stirred for 3 h, diluted with 15 mL of DMF, and again 5.6 mL (10 mmol) of 10% KHsolution was added. The reaction mixture was stirredfor 30 min and diluted with equal amount of water.The precipitate was filtered off, washed with water,ethanol, and hexane. (3-Amino-4,5,6-trimethylthieno[2,3-b]pyridin-2-yl)(2,4-dimethylphenyl)methanone (5m). Yield 2.4 g(73%), yellow powder, mp 205-207C (OH). IRspectrum, cm-1: 3318, 3295, 3204 [ν(NH2)], 1702[ν(C=O)], 1642 [δ(NH2)]. 1H NMR spectrum, δ, ppm:2.18 s (3H, Me), 2.22 s (3H, Me), 2.34 s (3H, Me), 2.41 s (3H, Me), 2.68 s (3H, Me), 6.84 br.s (2H, NH2),6.99 s (1Harom), 7.14 d (1Harom, J 7.7 Hz), 7.82 d (1Harom,J 7.7 Hz). Mass spectrum, m/z (Irel, %): 325 (100) [M + 1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
210.6 mg | With potassium tert-butylate; In N,N-dimethyl-formamide; at 20 - 90℃; for 4h;Inert atmosphere; | To a solution of ethyl 3-oxo-3-(pyridin-3-yl)propanoate (500 g, 2.59 mmol) and 2-cyanoethanethioamide (388 mg, 3.9 mmol) in DMF (50 mL) was added t-BuOK (1.45 g,12.95 mmol) at room temperature. The reaction mixture was heated at 90 oc for 4 h underN2. TLC (50% PE/50% EtOAc, silica gel plate) showed complete consumption of thestarting material after this time. The mixture was concentrated in vacuo. The residue waspurified via reverse phase column chromatography (MeOH/H20 = 5%-80%) to give thedesired compound (210.6 mg) as a yellow solid. LC-MS (ESI+): m/z 230.0 (M+Ht. |