Structure of 75985-45-4
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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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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.
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.
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Keywords: Mycophenolic acid ; amide derivatives ; heterocycles ; benzoxazole ; IMPDH inhibition
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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
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CAS No. : | 75985-45-4 |
Formula : | C5H7N3 |
M.W : | 109.13 |
SMILES Code : | N1=C(N=CC=C1)CN |
MDL No. : | MFCD06212857 |
InChI Key : | ROSKZJGILXBSFM-UHFFFAOYSA-N |
Pubchem ID : | 4658047 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.2 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 29.71 |
TPSA ? Topological Polar Surface Area: Calculated from |
51.8 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.96 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.9 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.22 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.99 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.55 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.12 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.44 |
Solubility | 39.8 mg/ml ; 0.364 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
0.29 |
Solubility | 215.0 mg/ml ; 1.97 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.63 |
Solubility | 2.53 mg/ml ; 0.0232 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 |
No |
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 |
-7.6 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 |
0.0 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) |
1.24 |
* 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 |
---|---|---|
99% | With dicyclohexyl-carbodiimide; 1-hydroxy-1,2,3-benzotriazine-4(3H)-one; In N,N-dimethyl-formamide; at 0℃; | In the reaction flask, anhydrous DMF 3930 mL, compound 5 (393 g, 1.0 mol), 2-aminopyrimidine (163.5 g,1.5 mol), DCC (210 g, 1.02 mol) and 1-hydroxy-1,2,3-benzotriazine-4(3H)-one (166 g, 1.02 mol) at 0 CThe reaction was stirred, monitored until Compound 5 was completely reacted, filtered, and the filtrate was added to water, extracted with chloroform, washed with organic phase and dried.After the filtrate is too short, the silica gel layer is spin-dried to obtain crude avervavir, and the crude avervavir is purified by methanol to obtain pure avenue.The yield was 99.0% and the purity was 99.85%. |
91.2% | With 5,10,15,20-tetrakis[4-(dihydroxyboryl)phenyl]-21H,23H-porphine; In toluene; for 16h;Reflux; Green chemistry; | 4-[(3-Chloro-4-methoxyphenyl)methylamino]-2-[(S)-2-hydroxymethylpyrrol-1-yl]pyrimidine-5-carboxylic acid(39.3g, 100mmol, 1.0eq),2-Aminomethylpyrimidine (12.0 g, 110 mmol, 1.1 eq) and porphyrin borate (7.9 g, 10 mmol, 0.1 eq) were added to 500 mL of toluene.The mixture was heated to reflux to carry out a reaction for 16 hours.After the reaction,Slowly cool the reaction solution to 10-20 C.1000 mL of a 2 wt% aqueous hydrochloric acid solution was added dropwise.The temperature of the control system does not exceed 20 C,Stir for 30min,The boric acid porphyrin catalyst was recovered by filtration.Dispensing the lower aqueous phase,Add 500 mL of dichloromethane to wash the aqueous phase.Slowly add solid NaOH to adjust the pH of the aqueous phase to 7.0, and stir and crystallize for 2 h at room temperature.FiltrationThat is not crude, the filter cake is washed twice with purified water.Add the crude afarafatin to 1000 mL of anhydrous methanol and heat to reflux.After adding 3.0g of activated carbon, stirring and decolorizing for 30min,Hot filtered,The filtrate was stirred and cooled to 30 C, and crystallization was carried out for about 3 hours.filter,After ice-washing with methanol twice, it was dried at 50 C to obtain 44.1 g of a white needle solid (yield 91.2%, purity: 99.63%). |
90% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 20℃; for 4h; | To is equipped with a thermometer and constant pressure dropping funnel a 250 ml three-mouth bottle by adding 20g a compound represented by the formula VI, 6.9gHOBT, 6 g2-amine methyl pyrimidine and 100 ml dimethyl sulfoxide; at room temperature to the reaction system under the conditions of adding dropwisely 11g DCC, after dropping, stirring the mixture at room temperature for 4 hours; after the reaction, the reaction system into the dumping 200g ice water, a large amount of solid precipitated, filtered, the filter cake is washed with ethyl acetate to recrystallize, that shall be atorvastatin non -22g, white solid, molar yield is 90%, HPLC purity 99.8%. |
57% | With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; In dichloromethane; at 20℃; | add M6, EDCI, HOBT, DCM and SM5 into a three-necked flask, and react at room temperature for 10-15h. The reaction was quenched, the organic phase was separated and evaporated to dryness, a solvent was added for crystallization, and a large amount of white solid was obtained by filtration and drying, and the yield was 57%. |
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; for 8h; | (5) A mixture of the compound (600 mg) obtained in the above (4), 2-aminomethylpyrimidine (217 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (323 mg), 1-hydroxybenzotriazole monohydrate (227 mg) and N,N-dimethylformamide (12 ml) is stirred at room temperature for 8 hours, and the reaction mixture is poured into aqueous sodium hydrogen carbonate solution. The mixture is extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo, and the residue is purified by a column chromatography on silica gel (solvent: chloroform:methanol = 50:1) to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidylmethyl)carbamoyl]pyrimidine (610 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 6h; | tert-Butyl (pyrimidin-2-ylmethyl) carbamate (25):To a stirred solution of compound 24 (370 mg, 3.39 mmol) in THF (1 mL) at 0 C, Et3N (0.562 mL, 4.07 mmol) was added followed by (Boc)20 (0.86 mL, 3.73 mmol). The reaction mixture was stirred at RT for 6 h and the solvent from the reaction was removed under reduced pressure to give the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 3:7) to furnish compound 25 (240 mg, 34%).TLC: 50% EtOAc Hexane (Rf: 0.3)1H NMR (400MHz, CDC13): δ 8.71 (d, J = 4.8 Hz, 2H), 7.19 (d, J = 4.8 Hz, 1H), 5.69 (br s, 1H), 4.61 (d, J = 4.4 Hz, 2H), 1.48 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.5g | With triethylamine; In dichloromethane; at -10 - 20℃; | At room temperature, take 21.1g 2,4-dichloro-5-pyrimidine carboxylic acid chloride was added to the reaction mixture of the reaction flask was dissolved in 180mL of dichloromethane is first reaction mixture was formed, and 11. 4g 2-methylamino-pyrimidin 10. 6g triethylamine were dissolved in 100mL of dichloromethane second reaction mixture is formed, the first reaction mixture to cool -10 C, at this temperature, slowly adding the second reaction liquid to the first reaction mixture, the addition was complete after slowly warming to room temperature, 300mL water was added, layers were separated and the organic phase was washed three times 100mL were washed with water, dried over anhydrous sodium sulfate, suction filtered, the organic phase evaporated to dryness under reduced pressure to give an oil that non 25. 5g of intermediate iva A2, 4- dichloro -N- (2- methyl-pyrimidinyl) -5-pyrimidinecarboxamide. |
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