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Chemical Structure| 7357-70-2 Chemical Structure| 7357-70-2

Structure of 7357-70-2

Chemical Structure| 7357-70-2

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Product Citations

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.

Keywords: Amino-3,5-dicyanopyridines ; Thieno[2,3-b]pyridines ; Intramolecular cyclisation ; Adenosine A1/A2A receptors ; Epilepsy

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Product Details of [ 7357-70-2 ]

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

Safety of [ 7357-70-2 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302+H312+H332-H315-H319-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 7357-70-2 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

81.9 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

0.57
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

-0.37
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

0.19
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

-0.89
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

0.71
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.04

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-0.16
Solubility 69.0 mg/ml ; 0.689 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-0.89
Solubility 13.0 mg/ml ; 0.13 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-0.09
Solubility 82.3 mg/ml ; 0.822 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-7.17 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

2.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

1.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.8

Application In Synthesis of [ 7357-70-2 ]

* 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.

  • Downstream synthetic route of [ 7357-70-2 ]

[ 7357-70-2 ] Synthesis Path-Downstream   1~6

  • 2
  • [ 7357-70-2 ]
  • [ 5147-80-8 ]
  • 2-amino-6-mercapto-4-(methylthio)pyridine-3,5-dicarbonitrile [ No CAS ]
YieldReaction ConditionsOperation 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]+.
  • 3
  • [ 6563-13-9 ]
  • [ 7357-70-2 ]
  • (2Z)-2-cyano-2-(6-methoxyquinolin)-2(1H)-ylidene-ethanethioamide [ No CAS ]
YieldReaction ConditionsOperation 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).
  • 4
  • [ 7357-70-2 ]
  • [ 34595-26-1 ]
  • 5-cyano-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinoline-5-carbothioamide [ No CAS ]
  • 5-cyano-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinoline-5-carbothioamide [ No CAS ]
YieldReaction ConditionsOperation 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.
  • 5
  • [ 13809-02-4 ]
  • [ 7357-70-2 ]
  • [ 26346-85-0 ]
  • [ 75-07-0 ]
  • (3-amino-4,5,6-trimethylthieno[2,3-b]pyridin-2-yl)(2,4-dimethylphenyl)methanone [ No CAS ]
YieldReaction ConditionsOperation 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]+.
  • 6
  • [ 6283-81-4 ]
  • [ 7357-70-2 ]
  • 2'-mercapto-6'-oxo-1',6'-dihydro-[3,4'-bipyridine]-3'-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation 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.
 

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