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CAS No. : | 953769-46-5 | MDL No. : | MFCD28142668 |
Formula : | C20H22N4O3S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ADZBMFGQQWPHMJ-RHSMWYFYSA-N |
M.W : | 398.48 | Pubchem ID : | 46184986 |
Synonyms : |
BLZ945
|
Num. heavy atoms : | 28 |
Num. arom. heavy atoms : | 15 |
Fraction Csp3 : | 0.35 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 109.32 |
TPSA : | 124.61 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.3 cm/s |
Log Po/w (iLOGP) : | 2.86 |
Log Po/w (XLOGP3) : | 3.42 |
Log Po/w (WLOGP) : | 3.37 |
Log Po/w (MLOGP) : | 1.48 |
Log Po/w (SILICOS-IT) : | 3.18 |
Consensus Log Po/w : | 2.86 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.47 |
Solubility : | 0.0136 mg/ml ; 0.0000342 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.72 |
Solubility : | 0.000765 mg/ml ; 0.00000192 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -5.85 |
Solubility : | 0.000564 mg/ml ; 0.00000142 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.95 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
With oxone In methanol; water at 20℃; for 23h; | 211 Preparation of 4-(2-((1R,2R)-2-hydroxycyclohexylamino)-1-oxo-benzo[d]thiazol-6-yloxy)-N-methylpicolinamide Example 211 Preparation of 4-(2-((1R,2R)-2-hydroxycyclohexylamino)-1-oxo-benzo[d]thiazol-6-yloxy)-N-methylpicolinamide A solution of OXONE (KHSO5, 380 mg, mmol) in water (4 ml) was added dropwise to a solution of 4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (25 mg, mmol) in methanol (4 ml) at rt. After stirring for 23 hours the suspension is diluted with water (50 ml) and extracted with ethyl acetate (2*10 ml). The combined organic layers were washed with brine, concentrated, and purified by prep HPLC to yield the title compound as white solid. Yield: 2.4 mg. ES/MS m/z 415.1 (MH+), Rt=1.81 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In isopropyl alcohol at 55 - 60℃; | (Form B) Mono-hydrochloride salt of (0109) 4-(2-((lR,2R)-2-hydroxycyclohexylamino)benzothiazol-6-yloxy)-N-methylpicolinamide To a suspension of (0111) 4-(2-((lR,2R)-2-hydroxycyclohexylamino)benzothiazol-6-yloxy)-N-methylpicolinamide free base in isopropyl alcohol (IPA) at 55-60°C was added HCl in IPA (1.1-1.2 equivalents). The resulting solution was allowed to stir, after which the solution was diluted with isopropyl acetate, concentrated and the solids isolated and analyzed by XRPD. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In tetrahydrofuran; water at 60 - 65℃; for 6h; | (Form A) Di-hydrochloride monohydrate salt of (0099) 4-(2-((lR,2R)-2-hydroxycyclohexylamino)benzothiazol-6-yloxy)-N-methylpicolinamide To a clear solution of (0101) 4-(2-((lR,2R)-2-hydroxycyclohexylamino)benzothiazol-6-yloxy)-N-methylpicolinamide free base in THF at 60-65°C was added 6N HC1 in H20 (3.0 equivalents). The reaction mixture was stirred at 60-65°C for about 6 hours. The resulting solids were filtered, washed with fresh THF and dried to yield crystalline Form A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; for 24h; | Synthesis of CSF-1R inhibiting amphiphile: BLZ-945 (BLZ) was dissolved in 2 ml anhydrous Dichloromethane (Fisher Scientific) to which 1.1 molar equivalents of cholesterol hemisuccinate, DMAP and EDC was added. The reaction was stirred for 24 hours at room temperature. The reaction was monitored through thin layer chromatography and once the reaction was completed, the crude product was purified using column chromatography, eluting it with a 3% Methanol: DCM gradient to give the CSF-1R inhibiting amphiphile as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate In tetrahydrofuran at 50℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: triethylamine / 1-methyl-pyrrolidin-2-one / 48 h / 120 °C 2: triethylamine; boron tribromide / dichloromethane / 3 h / 0 - 20 °C 3: potassium carbonate / N,N-dimethyl-formamide / 16 h / 100 °C 4: potassium carbonate / tetrahydrofuran / 16 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: triethylamine / 1-methyl-pyrrolidin-2-one / 48 h / 120 °C 2: triethylamine; boron tribromide / dichloromethane / 3 h / 0 - 20 °C 3: potassium carbonate / N,N-dimethyl-formamide / 16 h / 100 °C 4: potassium carbonate / tetrahydrofuran / 16 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethylamine; boron tribromide / dichloromethane / 3 h / 0 - 20 °C 2: potassium carbonate / N,N-dimethyl-formamide / 16 h / 100 °C 3: potassium carbonate / tetrahydrofuran / 16 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 100 °C 2: potassium carbonate / tetrahydrofuran / 16 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium hydroxide In water monomer at 20℃; for 24h; | 1-1. 4-{2-[((1R,2R)-2-hydroxycyclohexyl)(methyl)amino]benzothiazol-6-yloxy}-Nmethylpicolinamide(NCGG401) 4-[2-((1R,2R)-2-hydroxycyclohexylamino)benzothiazol-6-yloxy]-Nmethylpicolinamide(BLZ945, MedChemExpress, NJ, USA) (108.6 mg, 0.27 mmol)was dissolved in DMSO/H2O (9/1, 2.50 mL), added methyl iodide (15.6 μL, 0.252mmol) and stirred at room temperature for 24 h under basic conditions by potassiumhydroxide (8M solution, 31.4 μL, 0.25 mmol). The mixture was concentrated and theresidue was purified by column chromatography (SiO2, methanol:ethyl acetate:hexane =3:47:50) to give NCGG401 (91.0 mg, 77%). 1H NMR (400 MHz, DMSO-d6) 8.78 (q,1H, J = 4.0 Hz), 8.49 (d, 1H, J = 4.4 Hz), 7.68 (d, 1H, J = 2.0 Hz), 7.49 (d, 1H, J = 6.8Hz), 7.36 (d, 1H, J = 2.4 Hz), 7.13 (dd, 1H, J = 4.8, 2.4 Hz), 7.09 (dd, 1H, J = 6.8, 2.4Hz), 4.87 (d, 1H. J = 2.8 Hz), 3.62-3.56 (1H, m), 3.37-3.31 (1H, m), 3.05 (s, 3H), 2.77(d, 3H, J = 4.4 Hz), 1.99-1.95 (1H, m), 1.71-1.57 (4H, m), 1.30-1.24 (3H, m); 13C NMR(100.5 MHz, DMSO-d6) 169.3, 166.4, 163.8, 152.4, 150.9, 150.4, 146.6, 131.3, 119.2,118.8, 113.9, 113.9, 108.7, 68.3, 55.0, 35.0, 27.9, 26.0, 24.8, 24.0, HRMS (ESI) m/z;calcd. for C21H24N4Na1O3S1 [M + Na]+ 435.1467, found 435.1492. |
77% | With potassium hydroxide In water monomer at 20℃; for 24h; | 1-1. 4-{2-[((1R,2R)-2-hydroxycyclohexyl)(methyl)amino]benzothiazol-6-yloxy}-Nmethylpicolinamide(NCGG401) 4-[2-((1R,2R)-2-hydroxycyclohexylamino)benzothiazol-6-yloxy]-Nmethylpicolinamide(BLZ945, MedChemExpress, NJ, USA) (108.6 mg, 0.27 mmol)was dissolved in DMSO/H2O (9/1, 2.50 mL), added methyl iodide (15.6 μL, 0.252mmol) and stirred at room temperature for 24 h under basic conditions by potassiumhydroxide (8M solution, 31.4 μL, 0.25 mmol). The mixture was concentrated and theresidue was purified by column chromatography (SiO2, methanol:ethyl acetate:hexane =3:47:50) to give NCGG401 (91.0 mg, 77%). 1H NMR (400 MHz, DMSO-d6) 8.78 (q,1H, J = 4.0 Hz), 8.49 (d, 1H, J = 4.4 Hz), 7.68 (d, 1H, J = 2.0 Hz), 7.49 (d, 1H, J = 6.8Hz), 7.36 (d, 1H, J = 2.4 Hz), 7.13 (dd, 1H, J = 4.8, 2.4 Hz), 7.09 (dd, 1H, J = 6.8, 2.4Hz), 4.87 (d, 1H. J = 2.8 Hz), 3.62-3.56 (1H, m), 3.37-3.31 (1H, m), 3.05 (s, 3H), 2.77(d, 3H, J = 4.4 Hz), 1.99-1.95 (1H, m), 1.71-1.57 (4H, m), 1.30-1.24 (3H, m); 13C NMR(100.5 MHz, DMSO-d6) 169.3, 166.4, 163.8, 152.4, 150.9, 150.4, 146.6, 131.3, 119.2,118.8, 113.9, 113.9, 108.7, 68.3, 55.0, 35.0, 27.9, 26.0, 24.8, 24.0, HRMS (ESI) m/z;calcd. for C21H24N4Na1O3S1 [M + Na]+ 435.1467, found 435.1492. |