777-12-8|6-(Trifluoromethyl)benzo[d]thiazol-2-amine| Ambeed

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Structure of 777-12-8

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Quality Control of [ 777-12-8 ] Purity: 98% SDS Specification

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Product Citations

Novel amides of mycophenolic acid and some heterocyclic derivatives as immunosuppressive agents

Walczak, Juliusz Maksymilian ; Iwaszkiewicz-Grzes, Dorota ; Ziomkowska, Michalina ; Sliwka-Kaszynska, Magdalena ; Dasko, Mateusz ; Trzonkowski, Piotr , et al.

DOI: 10.1080/14756366.2022.2127701 PubMed ID: 36189734 J. Enzym. Inhib. Med. Ch.,2022,37(1):2725-2741.

Abstract: The group of 18 new amide derivatives of mycophenolic acid (MPA) and selected heterocyclic amines was synthesised as potential immunosuppressive agents functioning as inosine-5′-monophosphate dehydrogenase (IMPDH) uncompetitive inhibitors. The synthesis of 14 of them employed uronium-type activating system (TBTU/HOBt/DIPEA) while 4 of them concerned phosphonic acid anhydride method (T3P/Py) facilitating amides to be obtained in moderate to excellent yields without the need of phenolic group protection. Most of optimised protocols did not require complicated reaction work-ups, including chromatographic, solvent-consuming methods. The biological activity assay was performed on the T-Jurkat cell line and peripheral mononuclear blood cells (PBMCs) which are both dedicated for antiproliferative activity determination. Each of designed derivatives was characterised by reduced cytotoxicity and benzoxazole analogue (A2) revealed the most promising activity. Subsequently, an observed structure-activity relationship was discussed.

Keywords: Mycophenolic acid ; amide derivatives ; heterocycles ; benzoxazole ; IMPDH inhibition

Purchased from AmBeed: 934-32-7 ; 1477-42-5 ; 5464-79-9 ; 5464-79-9 ; 136-95-8 ; 95-24-9 ; 533-30-2 ; 1123-93-9 ; 6285-57-0 ; 15864-32-1 ; 29927-08-0 ; 348-40-3 ; 58-63-9 ; 4570-41-6 ; 75985-45-4 ; 24280-93-1 ; 2536-91-6 ; 19952-47-7 ; 1747-60-0 ; 777-12-8 ; 63837-12-7 ; 58-63-9

Product Details of [ 777-12-8 ]

CAS No. :	777-12-8
Formula :	C₈H₅F₃N₂S
M.W :	218.20
SMILES Code :	NC1=NC2=CC=C(C(F)(F)F)C=C2S1
MDL No. :	MFCD00269597
InChI Key :	WEDYEBJLWMPPOK-UHFFFAOYSA-N
Pubchem ID :	2735955

Safety of [ 777-12-8 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H300-H315-H319-H335
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P310+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P403+P233-P405-P501
Class:	6.1
UN#:	2811
Packing Group:	Ⅱ

Computational Chemistry of [ 777-12-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	9
Fraction Csp3	0.12
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	49.03
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	67.15 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.79
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	2.92
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.06
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.	2.32
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	3.38
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.89

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.44
Solubility	0.0788 mg/ml ; 0.000361 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.99
Solubility	0.0223 mg/ml ; 0.000102 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	-3.5
Solubility	0.0682 mg/ml ; 0.000313 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	Yes
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.	-5.56 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	0.0
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)	2.02

Application In Synthesis of [ 777-12-8 ]

* 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.

Downstream synthetic route of [ 777-12-8 ]

[ 777-12-8 ] Synthesis Path-Downstream 1~35

1
[ 455-14-1 ]
[ 540-72-7 ]
[ 777-12-8 ]

References: [1]Patent: US2832761,1954, .
[2]European Journal of Organic Chemistry,2011,p. 3421 - 3429.

2
[ 455-14-1 ]
[ 1147550-11-5 ]
[ 777-12-8 ]

References: [1]Journal of Organic Chemistry,2018,vol. 83,p. 12129 - 12142.
[2]Journal of general chemistry of the USSR,1963,vol. 33,p. 2240 - 2245.
Zhurnal Obshchei Khimii,1963,vol. 33,p. 2301 - 2307.
[3]European Journal of Medicinal Chemistry,2018,vol. 148,p. 477 - 486.

3
[ 777-12-8 ]
[ 91-99-6 ]
[ 2193-90-0 ]

References: [1]Journal of general chemistry of the USSR,1963,vol. 33,p. 2240 - 2245.
Zhurnal Obshchei Khimii,1963,vol. 33,p. 2301 - 2307.

4
[ 777-12-8 ]
[ 121-69-7 ]
[ 3879-63-8 ]

References: [1]Journal of general chemistry of the USSR,1963,vol. 33,p. 2240 - 2245.
Zhurnal Obshchei Khimii,1963,vol. 33,p. 2301 - 2307.

5
[ 70-23-5 ]
[ 777-12-8 ]
ethyl-7-trifluoromethylimidazo<2,1-b>benzothiazole-2-carboxylate [ No CAS ]

References: [1]Il Farmaco,1993,vol. 48,p. 31 - 43.
[2]European Journal of Pharmaceutical Sciences,2001,vol. 14,p. 209 - 216.

6
[ 638-07-3 ]
[ 777-12-8 ]
ethyl-7-trifluoromethylimidazo<2,1-b>benzothiazole-2-acetate [ No CAS ]

References: [1]Il Farmaco,1993,vol. 48,p. 31 - 43.

7
[ 777-12-8 ]
[ 131105-90-3 ]

References: [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 108 - 122.

8
[ 777-12-8 ]
[ 131106-70-2 ]

Yield	Reaction Conditions	Operation in experiment
46%	With isopentyl nitrite; In tetrahydrofuran; for 0.5h;Reflux;	[00180] To a solution of 6-(trifluoromethyl)benzothiazol-2-amine ( 1) (2.00 g, 9.17 mmol) in 20 mL of THF was added isoamyl nitrite (3.22 g, 27.5 mmol). The mixture was heated to reflux for 30 min, quenched with water, and extracted with ethyl acetate. The organic extract was dried over Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to afford 860 mg (46%) of the title compound as a yellow solid. NMR (400 MHz, CDC13) delta 9.16 (s, 1H), 8.26 (m, 2H), 7.78 (d, J= 1.2 Hz, 1H).
43.2%	With isopentyl nitrite; In tetrahydrofuran; for 1.5h;Inert atmosphere; Reflux;	6-(Trifluoromethyl)benzo[d]thiazol-2-amine (6.8 g, 31.16 mmol)was dissolved in THF (60 mL) under N2. Isoamyl nitrite (8.03 g,68.55 mmol) was added dropwise and the mixture was refluxed for1.5 h. Then the mixture was poured into ice-H2O (60 mL) andextracted with EtOAc. The organic layer was washed by saturatedaqueous NaCl and dried over Na2SO4. It was then concentrated andpurified via flash chromatography on silica gel to get 6 g (Yield43.2%) of 6-(trifluoromethyl)benzo[d]thiazole (21n) as a yellow oil.ES-LCMS m/z: 204.0 (MH).

References: [1]European Journal of Organic Chemistry,2011,p. 3421 - 3429.
[2]Patent: WO2015/197861,2015,A1 .Location in patent: Paragraph 00179-00180.
[3]European Journal of Medicinal Chemistry,2019,vol. 183.
[4]Journal of Medicinal Chemistry,1991,vol. 34,p. 108 - 122.

9
[ 455-14-1 ]
[ 333-20-0 ]
[ 777-12-8 ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; In acetic acid;Cooling with ice;	General procedure: A mixture of 0.1 mol of 4?substituted aniline and 0.1 mol ofPotassium thiocyanate (KCNS) in 100 ml glacial acetic acid (AcOH) was cooled inan ice bath and stirred for 10 to 20 min, and then 0.1 mol bromine in glacialacetic acid was added dropwise at such a rate to keep the temperature below 10C throughout the addition. Theprogress of the reaction was monitored by Thin Layer Chromatography usingtoluene: acetone (8:2) solvent system. The reaction mixture was stirredat room temperature for 2 to 4 hrs, the hydrobromide (HBr) salt thus separatedout was filtered, washed with acetic acid, dried, dissolved in hot water and basified to pH 11.0 with ammonia solution (NH4OH)and the resulting precipitate was filtered, washed with water and dried to getthe desired product 2a-q.

References: [1]Synlett,2012,vol. 23,p. 2219 - 2222.
[2]Journal of Organic Chemistry,2017,vol. 82,p. 9312 - 9320.
[3]Journal of Pharmaceutical Sciences,1994,vol. 83,p. 1425 - 1432.
[4]Journal of Medicinal Chemistry,1999,vol. 42,p. 2828 - 2843.
[5]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 5561 - 5565.

10
[ 777-12-8 ]
[ 70-11-1 ]
[ 182554-22-9 ]

References: [1]Il Farmaco,1996,vol. 51,p. 483 - 491.
[2]RSC Advances,2016,vol. 6,p. 67086 - 67095.

11
[ 777-12-8 ]
[ 693-07-2 ]
[ 130569-71-0 ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 2828 - 2843.

12
[ 777-12-8 ]
[ 86691-07-8 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 5678 - 5682.
[2]European Journal of Organic Chemistry,2011,p. 3421 - 3429.
[3]Patent: WO2015/197861,2015,A1 .
[4]European Journal of Medicinal Chemistry,2019,vol. 183.

13
[ 1736-72-7 ]
[ 777-12-8 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 5678 - 5682.
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 9814 - 9824.

14
[ 777-12-8 ]
(3-methyl-7-trifluoromethyl-4H-benzo[1,4]thiazin-2-yl)-phenyl-methanone [ No CAS ]