Structure of 54221-96-4
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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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Nicholas O. Schneider ; Kendra Gilreath ; Daniel J. Burkett ; Martin St. Maurice ; William A. Donaldson ;
Abstract: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase which plays a center role in the phosphorylation of a wide variety of proteins, generally leading to their inactivation. As such, GSK-3 is viewed as a therapeutic target. An ever-increasing number of small organic molecule inhibitors of GSK-3 have been reported. Phenylmethylene hydantoins are known to exhibit a wide range of inhibitory activities including for GSK-3β. A family of fourteen 2-heterocycle substituted methylene hydantoins (14, 17–29) were prepared and evaluated for the inhibition of GSK-3β at 25 μM. The IC50 values of five of these compounds was determined; the two best inhibitors are 5-[(4′-chloro-2-pyridinyl)methylene]hydantoin (IC50 = 2.14 ± 0.18 μM) and 5-[(6′-bromo-2-pyridinyl)methylene]hydantoin (IC50 = 3.39 ± 0.16 μM). The computational docking of the compounds with GSK-3β (pdb 1q41) revealed poses with hydrogen bonding to the backbone at Val135. The 5-[(heteroaryl)methylene]hydantoins did not strongly inhibit other metalloenzymes, demonstrating poor inhibitory activity against matrix metalloproteinase-12 at 25 μM and against human carbonic anhydrase at 200 μM, and were not inhibitors for Staphylococcus aureus pyruvate carboxylase at concentrations >1000 μM.
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Keywords: nitrogen heterocycles ; glycogen synthase kinase 3β ; computational docking
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Purchased from AmBeed: 63071-13-6 ; 53547-60-7 ; 31181-90-5 ; 34160-40-2 ; 4985-92-6 ; 1121-60-4 ; 54221-96-4 ; 55589-47-4 ; 500-22-1 ; 1805434-14-3
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CAS No. : | 54221-96-4 |
Formula : | C7H7NO2 |
M.W : | 137.14 |
SMILES Code : | O=CC1=NC(OC)=CC=C1 |
MDL No. : | MFCD05664030 |
InChI Key : | YDNWTNODZDSPNZ-UHFFFAOYSA-N |
Pubchem ID : | 12325392 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 36.12 |
TPSA ? Topological Polar Surface Area: Calculated from |
39.19 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.33 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.95 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.9 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.08 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.48 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.92 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.6 |
Solubility | 3.44 mg/ml ; 0.0251 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.36 |
Solubility | 5.99 mg/ml ; 0.0437 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.07 |
Solubility | 1.16 mg/ml ; 0.00849 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 |
-6.46 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) |
1.41 |
* 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 |
---|---|---|
To a solution of the compound of Preparation 113 (5.6 g, 29.8 mmol) in anhydrous tetrahydrofuran (100 ml), at -78° C. and under nitrogen, was added n-butyllithium (1.6M in hexane, 19.5 ml), via syringe. The mixture was stirred at -78° C. for 30 min, before addition of N,N-dimethylformamide (2.5 ml, 32.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 h, before being acidified with sulphuric acid (2M) and then neutralised by addition of sodium hydrogen carbonate. The mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (4*150 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (3.0 g). 1H-NMR (CDCl3): 4.01-4.05 (3H), 6.95-7.00 (1H), 7.54-7.58 (1H), 7.70-7.76 (1H), 9.95-9.98 (1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; mesitylenesulfonylhydroxylamine; | EXAMPLE 90 7-Bromo-2-(6-methoxy-pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine The title compound, MS m/e (percent): 320 (M+, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonyl-hydroxylamine, and 6-methoxy-pyridine-2-carbaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 8 N-[1-(6-methoxy-2-pyridylmethyl)piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide STR12 Using as the starting material 13 mg of 6-methoxy-2-pyridinecarbaldehyde which had been synthesised following the method of D. L. Comins, et al. [J. Org. Chem. Vol. 55, pp. 69-73 (1990)] in a method similar to Step (3) of Example 2, 37 mg of the title compound was obtained as a colorless oily substance. FAB-MS (m/e, (C25 H33 N3 O3 +H)+): 424 1 H-NMR(CDCl3) delta: 1.10-1.75 (10H, m), 1.75-1.90 (2H, m), 2.15-2.30 (2H, m), 2.75-2.86 (2H, m), 2.95-3.08 (1H, m), 3.12 (1H, s), 3.55 (2H, s), 3.65-3.80 (1H, m), 3.90 (3H, s), 6.31 (1H, d, J=7.9 Hz), 6.59 (1H, d, J=8.2 Hz), 6.93 (1H, d, J=7.2 Hz), 7.22-7.38 (3H, m), 7.51 (1H, dd, J=7.2, 8.2 Hz), 7.56-7.62 (2H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; at 0 - 25℃; for 19h; | To a solution of the compound of Preparation 68 (1.0 g, 7.3 mmol) in acetone (3.2 ml, 43.8 mmol), at 0° C., was added aqueous sodium hydroxide solution (5M, 2.2 ml). The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 18 h. The mixture was acidified with hydrochloric acid (4M, 4 ml) and then neutralised with sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and the combined organic extracts were concentrated in vacuo to give the title compound (1.4 g). 1H-NMR (CDCl3): 2.40-2.42 (3H), 3.89-3.94 (3H), 6.73-6.78 (1H), 6.98-7.02 (1H), 7.37-7.44 (1H), 7.48-7.61 (3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; for 4h;Inert atmosphere; Reflux; | Preparation of Example 72 - (3.pound.4fl)-iV-((y)-l-(6-methoxypyridin-2- yl)ethyl)-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxamide; (S)-I -(6-methoxypyridin-2-yl)ethanamine (51) was prepared by the following procedures.[0216] In a 250 mL of round bottom flask, equipped with Dean-Stark trap and a reflux condenser, 6-methoxypicolinaldehyde 45 (500 mg, 3.65 mmol), (S)-2 (+)- phenylglycinol 46 (500 mg, 3.65 mmol) and anhydrous THF (30 mL) were mixed and heated at reflux under argon for 4 h. (S,E)-2-((6-methoxypyridin-2-yl)methyleneamino)- 2-phenylethanol 47 was used directly in the next step without further purification.[0217] HDMS (470 mg, 2.92 mmol), (NH4)2SO4 (53 mg, 0.4 mmol) and anhydrous THF (15 mL) were added to compound 47 (934 mg, 3.65 mmol). The reaction mixture was heated at 800C for 2 h under argon. Then the solvent was removed in vacuo to afford crude (S,E)-N-((6-methoxypyridin-2-yl)methylene)-l-phenyl-2-(trimethylsilyloxy)ethanamine 48 (1.2 g).[0218] In a 100 mL of round bottom flask (flame-dried), at -78 "C, were added anhydrous THF (10 mL) and CH3MgBr (3.0 M in Et2O, 3.5 mL). At -50 0C, compound 48 (1.2 g, 3.65 mmL) in anhydrous THF (10 mL) was added dropwise. The reaction mixture was stirred at -40 0C for 1 h, and at rt. for 1 h. The reaction was then quenched with a cold, sat. NH4Cl with stirring at 00C. EtOAc was added and layers were separated. The organic layer was concentrated to afford (S)-N-((S)-l-(6-methoxypyridin- 2-yl)ethyl)-l-phenyl-2-(trimethylsilyloxy)ethanamine 49 (1 g).[0219] A solution of compound 49 (1 g, 0.29 mmol) in THF was cooled to 0 °C, H2SO4 (2.5 M, 5 rnL) was added dropwise with stirring. The resulting mixture was stirred at rt. for 2 h. The mixture was basified with 2N NaOH at 0 °C and extracted with EtOAc (3 x 30 mL). Combined organic layers were dried over Na2SO4 and concentrated. The residue was purified with flash column (eluted with 30percent EtOAc/hexane) to give (S)- 2-((S)-l-(6-methoxypyridin-2-yl)ethylamino)-2-phenylethanol 50 (860 mg).[0220] Methylamine in water (40 percent in water, 10 mL) was added to a solution of compound 50 (860 m g, 3.16 mmol) in MeOH (15 mL). At 0 0C, H5IO6 (4.33 g,) in water (15 mL) was added dropwise. White precipitates were formed. The resulting mixture was stirred at rt overnight. EtOAc and water were added. Organic layer was separated, and aq. layer was extracted with EtOAc. Combined organic layers were concentrated. The crude product was purified by prep. HPLC to give (S)-I -(6- methoxypyridin-2-yl)ethanamine 51 (80 mg).[0221] Data for compound 51: 1H NMR (400 MHz, CD3OD) delta 7.62 (t, IH), 6.89 (d, IH), 6.64 (d, IH), 3.97 (m, IH), 3.90 (s, 3H), 1.42 (d, 3H). The above method can be used to prepare other chiral amines. For examples, the chiral amines used in Example 117, 118 and 120. Example 72[0223] Example 72 was prepared from (-)-5 (prepared from Procedure K) and (S)-l-(6-methoxypyridin-2-yl)ethanamine 51 using the similar procedures in Example 96. 1H NMR Data for Example 72 (see Table 5). Preparation of Example 91 - (3S,4R)-4-(3,4-dichlorophenyl)-N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | LiHMDS (2.45 mL, 1.2 M in THF, 2.94 mmole) was added to a flame-dried round bottom flask. The mixture was cooled to 00C then <strong>[54221-96-4]6-methoxypyridine-2-carbaldehyde</strong> (Comins, Daniel L.; Killpack, Michael O. J.Org.Chem. 1990, 55, 69-73, 161 mg, 1.18 mmole) was added. After 30 minutes di-3-pyridylmethane (200 mg, 1.18 mmole) in dry THF (2.0 mL) was added. After 2 hr the mixture was warmed to RT, quenched with saturated NH4Cl, and extracted with CH2Cl2(3x) and iBuOH (2x). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was taken up in MeOH (5 mL) and H2NOH (0.4 mL, 50percent in H2O) was added. After 18 hr the mixture was concentrated. Flash column (gradient, 0-10percent MeOH/CH2Cl2) gave l-(6-methoxypyridin-2-yl)-2,2-dipyridin-3- ylethanamine as a pale yellow oil (168 mg, 47percent): 1H-NMR (500 MHz, CDCl3) delta 8.64 (d, J = 1.95 Hz, 1 H), 8.51 (dd, J = 1.46 and 3.17 Hz, 1 H), 8.36 (d, J = 1.95 Hz, 1 H), 8.32 (dd, J = 1.46 and 3.18 Hz, 1 H), 7.76 (d, J = 7.82 Hz, 1 H), 7.49 (d, J = 8.06 Hz, 1 H), 7.37-7.27 (m, 2 H), 7.09 (m, 1 H), 6.56 (d, J = 7.08 Hz, 1 H), 6.52 (d, J = 7.81 Hz, 1 H), 4.59 (d, J = 9.28 Hz, 1 H), 4.42 (d, J = 9.28 Hz, 1 H), 3.91 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In toluene; at 60℃; | EXAMPLE 26; S-C-Methoxypyridin^-yO-N'-CCS-methylquinolin-- yl)methylene)propanehydrazide; [0547] (a) (E)-Methyl 3-(6-methoxypyridin-2-yl)acrylate: To a stirred solution of <strong>[54221-96-4]6-methoxypyridine-2-carboxaldehyde</strong> (0.35 mL, 2.9 mmol) in toluene was added methyl (triphenylphosphoranylidene) acetate (1.95 g, 5.8 mmol) and the reaction was heated at 60 0C overnight. The reaction was diluted with EtOAc and washed with water, brine and dried (Na2SO4). Purification on silica gel using EtOAc-hexane (0 to 30percent) provided 530 mg (94percent) of the desired product. |
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