Structure of 1747-60-0
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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. : | 1747-60-0 |
Formula : | C8H8N2OS |
M.W : | 180.23 |
SMILES Code : | C1=CC(=CC2=C1N=C(N)S2)OC |
MDL No. : | MFCD00005787 |
InChI Key : | KZHGPDSVHSDCMX-UHFFFAOYSA-N |
Pubchem ID : | 15630 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 9 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 50.52 |
TPSA ? Topological Polar Surface Area: Calculated from |
76.38 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.87 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.4 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.9 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.97 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.38 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.9 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.96 |
Solubility | 0.198 mg/ml ; 0.0011 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.65 |
Solubility | 0.0408 mg/ml ; 0.000226 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.74 |
Solubility | 0.33 mg/ml ; 0.00183 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) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
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 |
-5.7 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) |
2.13 |
* 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 ammonia; bromine; chlorine; In water; 1,2-dichloro-ethane; | EXAMPLE 1 182 parts of p-methoxyphenyl-thiourea are suspended in 2,200 parts of ethylene chloride. To dehydrate the mixture, 200 parts of the solvent are distilled off under atmospheric pressure. The suspension is cooled to 30 C. and 6 parts of bromine are added. 71 parts of chlorine gas are then passed in over 4 hours at the same temperature, whilst cooling the mixture slightly, and the batch is then refluxed for 1 hour. Thereafter it is allowed to cool to about 70 C. and 1,000 parts of water are hereupon added, causing the solid to dissolve. After removing the organic phase, the ethylene chloride emulsified in the aqueous phase is stripped off in steam. The clear solution is then rendered alkaline, at 50 C., with 130 parts of concentrated ammonia. After the mixture has cooled to room temperature, the precipitate is filtered off, washed neutral with water and dried. The yield is 171 parts of 6-methoxy-2-aminobenzothiazole of melting point 163-165 C., corresponding to 95% of theory. | |
With bromine; acetic acid; at 0 - 15℃; for 2h; | General procedure: One of compounds 6a-6d (10 mmol) and ammonium thiocyanate (0.91 g, 12 mmol) were dissolved in glacial acetic acid and the reaction mixture was stirred for 4 h. Bromine (0.6 mL, 11 mmol) in glacial acetic acid (8 mL) was added dropwise to the reaction mixture and it was stirred at 15C for 2 h. Then, the solid was filtered off and dissolved in hot water. The filtrate was quenched with saturated aqueous sodium bicarbonate. The solid residue of the corresponding product 8a-8d was filtered off. | |
With bromine; In dichloromethane; at 5℃; | General procedure: Substituted phenylthiourea (0.1 mol) was taken in CHCl3 and stirred with a mechanical stirrer and bromine (0.1 mol) was added drop by drop for a period of an hour with continuous stirring. The temperature was maintained <5C. After bromine addition, the stirring was maintained for 4-5 hours. The product obtained was dried, followed by SO2 water treatment and filtered. The filtrate obtained was treated with aq. NH3 in neutral conditions. The obtained precipitate was filtered, dried, and recrystallized from absolute alcohol. |