159783-22-9|3,5-Difluoropyridin-4-amine| Ambeed

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Quality Control of [ 159783-22-9 ] Purity: 98% SDS Specification

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Product Citations

Aminopyridines Restore Ventilation and Reverse Respiratory Acidosis at Late Stages of Botulism in Mice

William T. McClintic ; Zachary D. Chandler ; Lalitha M. Karchalla ; Celinia A. Ondeck ; Sean W. O’Brien ; Charity J. Campbell , et al.

DOI: 10.1124/jpet.123.001773 J. Pharmacol. Exp. Ther.,2024,388(2):637-646.

Abstract: Botulinum neurotoxin (BoNT) is a potent protein toxin that causes muscle paralysis and death by asphyxiation. Treatments for symptomatic botulism are intubation and supportive care until respiratory function recovers. Aminopyridines have recently emerged as potential treatments for botulism. The clinically approved drug 3,4-diaminopyridine (3,4-DAP) rapidly reverses toxic signs of botulism and has antidotal effects when continuously administered in rodent models of lethal botulism. Although the therapeutic effects of 3,4-DAP likely result from the reversal of diaphragm paralysis, the corresponding effects on respiratory physiology are not understood. Here, we combined unrestrained whole-body plethysmography (UWBP) with arterial blood gas measurements to study the effects of 3,4-DAP, and other aminopyridines, on ventilation and respiration at terminal stages of botulism in mice. Treatment with clinically relevant doses of 3,4-DAP restored ventilation in a dose-dependent manner, producing significant improvements in ventilatory parameters within 10 minutes. Concomitant with improved ventilation, 3,4-DAP treatment reversed botulism-induced respiratory acidosis, restoring blood levels of CO2, pH, and lactate to normal physiologic levels. Having established that 3,4-DAP–mediated improvements in ventilation were directly correlated with improved respiration, we used UWBP to quantitatively evaluate nine additional aminopyridines in BoNT/A-intoxicated mice. Multiple aminopyridines were identified with comparable or enhanced therapeutic efficacies compared with 3,4-DAP, including aminopyridines that selectively improved tidal volume versus respiratory rate and vice versa. In addition to contributing to a growing body of evidence supporting the use of aminopyridines to treat clinical botulism, these data lay the groundwork for the development of aminopyridine derivatives with improved pharmacological properties.

Purchased from AmBeed: 18614-51-2 ; 159783-22-9 ; 1990-90-5 ; 618439-82-0

Product Details of [ 159783-22-9 ]

CAS No. :	159783-22-9
Formula :	C₅H₄F₂N₂
M.W :	130.10
SMILES Code :	FC1=C(C(=CN=C1)F)N
MDL No. :	MFCD01862101
InChI Key :	XWAOYJHUAQFFMT-UHFFFAOYSA-N
Pubchem ID :	2737654

Safety of [ 159783-22-9 ]

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

Computational Chemistry of [ 159783-22-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	28.56
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.91 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.15
Log P_o/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 P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.79
Log P_o/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.	0.67
Log P_o/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	1.55
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.11

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.37
Solubility	5.51 mg/ml ; 0.0424 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.	-0.75
Solubility	23.0 mg/ml ; 0.177 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	-2.19
Solubility	0.846 mg/ml ; 0.0065 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	Yes
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.	-6.83 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	1.0
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	0.0 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)	1.46

Application In Synthesis of [ 159783-22-9 ]

* 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 [ 159783-22-9 ]

[ 159783-22-9 ] Synthesis Path-Downstream 1~35

1
[ 159783-22-9 ]
[ 159782-94-2 ]
4-(methylthio)-3-(tetrahydro-furan-3-yloxy)-benzoyl chloride [ No CAS ]
N-(3,5-difluoropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)benzamide [ No CAS ]
[ 171803-98-8 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 25 Compounds FQ-FR By proceeding as in Example 24 but using <strong>[159783-22-9]4-amino-3,5-difluoropyridine</strong> instead of 4-amino-3,5-dichloropyridine, and using 3-cyclopentyloxy-4-(methylthio)benzoyl chloride and 4-(methylthio)-3-(tetrahydro-3-furyloxy)benzoyl chloride, there are prepared: N-(3,5-difluoropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)benzamide is synthesised; m.p. 174-5C. [Elemental analysis: C,59.4; H,5.1;; N,7.6; S,8.3%; calculated: C,59.3; H,5.0; N,7.7; S,8.3%]; and N-(3,5-difluoropyrid-4-yl)-4-(methylthio)-3-(tetrahydro-3-furyloxy)benzamide.

References: [1]Patent: EP741707,1998,B1 .

2
cupric sulfate [ No CAS ]
[ 105252-95-7 ]
[ 159783-22-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine hydrate; In ethanol; water;	REFERENCE EXAMPLE 74 A solution of 4-amino-2,3,5-trifluoropyridine [23.1 g; that is prepared as described in J.Med.Chem.30, 340-347,(1987)] and hydrazine hydrate (113 ML) in ethanol (925 ML) is stirred and heated at 100C for 2 days. The solution is then evaporated to low volume and the resulting 4-amino-3,5-difluoro-2-hydrazinopyridine (22.5 g) is filtered off in the form of a cream solid. This damp solid is added portionwise to a stirred solution of cupric sulfate (132 g) in water (462 ML) below 25C, and the reaction mixture is stirred at room temperature for 48 hours. The reaction mixture is basified by treatment with aqueous potassium hydroxide solution (2 N) and extracted with dichloromethane (1500 ML). The organic layer is filtered through diatomaceous earth, dried over magnesium sulpate, and concentrated to give an off-white solid (13.72 g). This solid is subjected to mplc, using diethyl ether as eluent, to give 4-amino-3,5-difluoropyridine (3.4 g), m.p. 99-101C. [NMR (CDCl3): 4.32(bs,2H),8.1(s,2H)].

References: [1]Patent: EP741707,1998,B1 .

3
[ 159783-22-9 ]
[ 166742-18-3 ]
[ 166741-54-4 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; In tetrahydrofuran; N-methyl-acetamide; water; toluene;	EXAMPLE 18 Compound CR Thionyl chloride (0.46 mL) is added to a solution of 5-cyclopentyloxy-6-methoxynicotinic acid (500 mg) and dimethylformamide (1 drop) in toluene (10 mL). The mixture is heated and stirred at reflux for 1 hour. The mixture is cooled and concentrated to give crude acid chloride. Meanwhile, sodium hydride (128 mg of a 60% dispersion in oil) is added to a stirred solution of <strong>[159783-22-9]4-amino-3,5-difluoropyridine</strong> (208 mg) in dry tetrahydrofuran (10 mL) under a nitrogen atmosphere. The mixture is stirred at room temperature for 60 minutes. The crude acid chloride is dissolved in dry tetrahydrofuran (5 mL) and the resulting solution added dropwise to the mixture. After 3 hours the mixture is treated with water and concentrated. The residue is diluted with water and the mixture extracted with ethyl acetate. The extracts are dried (MgSO4) and concentrated to give a white solid. The solid is triturated with n-pentane and methyl t-butyl ether to give 5-cyclopentyloxy-N-(3,5-difluoropyrid-4-yl)-6-methoxynicotinamide (230 mg), as a white solid, m.p.210-11 C. [Elemental analysis: C, 58.4; H, 4.93; N, 11.8% calculated: C, 58.45; H, 4.91; N, 12.03%.]

References: [1]Patent: US6472412,2002,B1 .

Yield	Reaction Conditions	Operation in experiment
		This damp solid is added portionwise to a stirred solution of cupric sulfate (132 g) in water (462 mL) below 25 C., and the reaction mixture is stirred at room temperature for 48 hours. The reaction mixture is basified by treatment with aqueous potassium hydroxide solution (2N) and extracted with dichloromethane (1500 mL). The organic layer is filtered through diatomaceous earth, dried over magnesium sulpate, and concentrated to give an off-white solid (13.72 g). This solid is subjected to mplc, using diethyl ether as eluent, to give 4-amino-3,5-difluoropyridine (3.4 g), m.p. 99-101 C. ?NMR (CDCl3): 4.32(bs,2H),8.1[(s,2H)].
		This damp solid is added portionwise to a stirred solution of cupric sulfate (132 g) in water (462 mL) below 25 C., and the reaction mixture is stirred at room temperature for 48 hours. The reaction mixture is basified by treatment with aqueous potassium hydroxide solution (2N) and extracted with dichloromethane (1500 mL). The organic layer is filtered through diatomaceous earth, dried over magnesium sulpate, and concentrated to give an off-white solid (13.72 g). This solid is subjected to mplc, using diethyl ether as eluent, to give 4-amino-3,5-difluoropyridine (3.4 g), m.p. 99-101 C. ?NMR (CDCl3): 4.32(bs,2H),8.1[(s,2H)].

5
[ 159783-22-9 ]
[ 1253113-59-5 ]
[ 1253113-01-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In chloroform; N,N-dimethyl-formamide; at 20℃;	To a solution of <strong>[159783-22-9]3,5-difluoro-4-pyridinamine</strong> (6.5 mg, 0.05 mmol, Apollo) in N, N- dimethylformamide (0.1 ml) was added Lambda/,Lambda/-diisopropylethylamine (0.035 ml_), followed by 1-[2-(phenyloxy)phenyl]methyl}-1 H-pyrazole-3-carbonyl chloride (15.6 mg, 0.05 mmol) in chloroform (0.1 ml). The resulting solution was shaken for 10 min and then left to stand at room temperature for a further 20 min. Dimethylsulphoxide (0.6 ml.) was added and the solution purified by MDAP on SUNFIRE C18 column (Method D). The appropriate fraction was concentrated in vacuo then under nitrogen flow to give the title compound (1.2 mg); LCMS: (System 3) MH+= 407, tRET = 1.15 min.

References: [1]Patent: WO2010/122088,2010,A1 .Location in patent: Page/Page column 74-75.

6
[ 159783-22-9 ]
[ 1253113-60-8 ]
[ 1253113-05-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In chloroform; N,N-dimethyl-formamide; at 20℃;	To a solution of <strong>[159783-22-9]3,5-difluoro-4-pyridinamine</strong> (6.5 mg, 0.05 mmol, Apollo) in N, N- dimethylformamide (0.1 ml.) was added Lambda/,Lambda/-diisopropylethylamine (0.035 ml), followed by 1-[2-(butyloxy)phenyl]methyl}-1 H-pyrazole-3-carbonyl chloride (14.6 mg, 0.05 mmol) in chloroform (0.1 ml). The resulting solution was shaken for 10 min and then left to stand at room temperature for a further 20 min. Dimethylsulphoxide (0.6 ml) was added and the solution purified by MDAP on SUNFIRE C18 column (Method D). The appropriate fraction was concentrated in vacuo then under nitrogen flow to give the title compound as a colourless solid (2.8 mg); LCMS: (System 3) MH+= 387, tREtau = 1.2 min.

References: [1]Patent: WO2010/122088,2010,A1 .Location in patent: Page/Page column 77.

7
[ 159783-22-9 ]
[ 79455-63-3 ]
[ 1365992-45-5 ]
[ 1365992-46-6 ]