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Structure of 2516-34-9
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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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Yuan, Gengyang ; Dhaynaut, Maeva ; Lan, Yu ; Guehl, Nicolas J. ; Huynh, Dalena ; Iyengar, Suhasini M. , et al.
Abstract: Metabotropic glutamate receptor 2 (mGluR2) is a therapeutic target for several neuropsychiatric disorders. An mGluR2 function in etiology could be unveiled by positron emission tomography (PET). In this regard, 5-(2-fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide ([11C]13, [11C]mG2N001), a potent negative allosteric modulator (NAM), was developed to support this endeavor. [11C]13 was synthesized via the O-[11C]methylation of phenol 24 with a high molar activity of 212 ± 76 GBq/μmol (n = 5) and excellent radiochemical purity (>99%). PET imaging of [11C]13 in rats demonstrated its superior brain heterogeneity and reduced accumulation with pretreatment of mGluR2 NAMs, VU6001966 (9) and MNI-137 (26), the extent of which revealed a time-dependent drug effect of the blocking agents. In a nonhuman primate, [11C]13 selectively accumulated in mGluR2-rich regions and resulted in high-contrast brain images. Therefore, [11C]13 is a potential candidate for translational PET imaging of the mGluR2 function.
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Purchased from AmBeed: 16289-54-6 ; 5521-55-1 ; 22047-25-2 ; 98-80-6 ; 40155-47-3 ; 5720-05-8 ; 879-65-2 ; 98-96-4 ; 31519-62-7 ; 23688-89-3 ; 23611-75-8 ; 33332-25-1 ; 20737-42-2 ; 61442-38-4 ; 17933-03-8 ; 50681-25-9 ; 13924-99-7 ; 40155-43-9 ; 166744-78-1 ; 36070-80-1 ; 4595-61-3 ; 118853-60-4 ; 41110-28-5 ; 40155-42-8 ; 937669-80-2 ; 31462-59-6 ; 16419-60-6 ; 5424-01-1 ; 59-67-6 ; 34604-60-9 ; 27398-39-6 ; 1196151-53-7 ; 19847-12-2 ; 13965-03-2 ; 876161-05-6 ; 27825-21-4 ; 2164-61-6 ; 4604-72-2 ; 98-97-5 ; 24005-61-6 ; 5521-61-9 ; 2516-34-9 ; 2719-27-9 ; 123-90-0 ; 6761-50-8 ; 625-43-4 ; 872-64-0 ; 1309866-36-1 ; 36932-49-7 ; 1528085-68-8 ; 1195533-51-7 ; 13534-79-7
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Structure activity relationship of pyrazinoic acid analogs as potential antimycobacterial agents
Hegde, Pooja V. ; Aragaw, Wassihun W. ; Cole, Malcolm S. ; Jachak, Gorakhnath ; Ragunathan, Priya ; Sharma, Sachin , et al.
Abstract: Tuberculosis (TB) remains a leading cause of infectious disease-related mortality and morbidity. Pyrazinamide (PZA) is a critical component of the first-line TB treatment regimen because of its sterilizing activity against non-replicating Mycobacterium tuberculosis (Mtb), but its mechanism of action has remained enigmatic. PZA is a prodrug converted by pyrazinamidase encoded by pncA within Mtb to the active moiety, pyrazinoic acid (POA) and PZA resistance is caused by loss-of-function mutations to pyrazinamidase. We have recently shown that POA induces targeted protein degradation of the enzyme PanD, a crucial component of the CoA biosynthetic pathway essential in Mtb. Based on the newly identified mechanism of action of POA, along with the crystal structure of PanD bound to POA, we designed several POA analogs using structure for interpretation to improve potency and overcome PZA resistance. We prepared and tested ring and carboxylic acid bioisosteres as well as 3, 5, 6 substitutions on the ring to study the structure activity relationships of the POA scaffold. All the analogs were evaluated for their whole cell antimycobacterial activity, and a few representative mols. were evaluated for their binding affinity, towards PanD, through isothermal titration calorimetry. We report that analogs with ring and carboxylic acid bioisosteres did not significantly enhance the antimicrobial activity, whereas the alkylamino-group substitutions at the 3 and 5 position of POA were found to be up to 5 to 10-fold more potent than POA. Further development and mechanistic anal. of these analogs may lead to a next generation POA analog for treating TB.
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Keywords: Tuberculosis ; Pyrazinoic acid ; pyrazinamide
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Purchased from AmBeed: 16289-54-6 ; 5521-55-1 ; 22047-25-2 ; 98-80-6 ; 40155-47-3 ; 5720-05-8 ; 879-65-2 ; 98-96-4 ; 31519-62-7 ; 23688-89-3 ; 23611-75-8 ; 33332-25-1 ; 20737-42-2 ; 61442-38-4 ; 17933-03-8 ; 50681-25-9 ; 13924-99-7 ; 40155-43-9 ; 36070-80-1 ; 4595-61-3 ; 118853-60-4 ; 41110-28-5 ; 40155-42-8 ; 937669-80-2 ; 98-98-6 ; 31462-59-6 ; 16419-60-6 ; 5424-01-1 ; 59-67-6 ; 34604-60-9 ; 27398-39-6 ; 1196151-53-7 ; 19847-12-2 ; 13965-03-2 ; 876161-05-6 ; 27825-21-4 ; 2164-61-6 ; 4604-72-2 ; 98-97-5 ; 24005-61-6 ; 103-67-3 ; 5521-61-9 ; 2516-34-9 ; 2719-27-9 ; 123-90-0 ; 6761-50-8 ; 625-43-4 ; 872-64-0 ; 36932-49-7 ; 1528085-68-8 ; 1195533-51-7 ; 13534-79-7
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CAS No. : | 2516-34-9 |
Formula : | C4H9N |
M.W : | 71.12 |
SMILES Code : | NC1CCC1 |
MDL No. : | MFCD00001328 |
InChI Key : | KZZKOVLJUKWSKX-UHFFFAOYSA-N |
Pubchem ID : | 75645 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H225-H314 |
Precautionary Statements: | P210-P280-P305+P351+P338-P310 |
Class: | 3(8) |
UN#: | 2733 |
Packing Group: | Ⅱ |
* 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 |
---|---|---|
71% | With pyridine; In dichloromethane; at 0 - 20℃; for 2.5h; | A solution of cyclobutylamine (0.552 mL, 6.44mmol) and pyridine (0.709 mL, 8.79 mmol) in dichloromethane (15 mL) was cooled at 0 0C. After the addition of 4-chloro-3-nitrobenzenesulfonyl chloride (1.5 g, 5.86 mmol), the mixture was warmed to room temperature and stirring was continued for 2.5 h. The solvent was evaporated at reduced pressure and the residue was partitioned between 1 N HCI and ethyl acetate. The organic was washed with water, brine, dried over Na2SO4 and evaporated to give the desired product as a yellow solid (1.21 g, 71%). 1H NMR (400 MHz, CDCI3) delta ppm 8.35 (d, J=2.3 Hz, 1 H), 7.99 (dd, J=8.5, 2.2, 1 H), 7.72 (d, J=8.3 Hz, 1 H), 4.96 (d, J=8.5 Hz, 1 H), 3.87 (sext, J=8.2 Hz, 1 H), 2.26-2.19 (m, 2H), 1.90-1.80 (m, 2H), 1.73-1.62 (m, 2H). |
71% | With pyridine; In dichloromethane; at 0 - 20℃; for 2.5h; | A solution of cyclobutylamine (0.552 ml_, 6.44mmol) and pyridine (0.709 ml_, 8.79 mmol) in dichloromethane (15 ml.) was cooled at 0 0C. After the addition of 4-chloro-3- nitrobenzenesulfonyl chloride (1.5 g, 5.86 mmol), the mixture was warmed to room temperature and stirring was continued for 2.5 h. The solvent was evaporated at reduced pressure and the residue was partitioned between 1 N HCI and ethyl acetate. The organic was washed with water, brine, dried over Na2SO4 and evaporated to give the desired product as a yellow solid (1.21 g, 71 %). 1H NMR (400 MHz, CDCI3) delta ppm 8.35 (d, J=2.3 Hz, 1 H), 7.99 (dd, J=8.5, 2.2, 1 H), 7.72 (d, J=8.3 Hz, 1 H), 4.96 (d, J=8.5 Hz, 1 H), 3.87 (sext, J=8.2 Hz, 1 H), 2.26-2.19 (m, 2H), 1.90-1.80 (m, 2H), 1.73-1.62 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
hydrogenchloride; In butan-1-ol; at 130℃; for 0.5h;Microwave; | Synthesis of Intermediate (1) 1.21[00654] In a25-mL microwave seal tube <strong>[1196155-38-0]2-chloro-6-trifluoromethylisonicotinonitrile</strong> (lg) Isopropyl amine(0.517g) was dissolved in n-butanol(lOmL) and one drop of con. HC1 was added. Reaction mixture was irradiated at 130°C for 30 min in Microwave. The Completion of the reaction was confirmed by TLC using 10percent EtOAc-n-hexane as mobile phase. Reaction mixture was quenched into ice water slurry. Extract compound in ethyl acetate, organic layer washed with water two times dried over Nu3/4804, filtered, and concentrated by rotary evaporation(40°C,20 mmHg) to afford 8g of a yellow oil. The resulting crude compound was purified by column chromatography. The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate :n-hexane as mobile phase. The columnwas packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection(25 -mL fractions) from 1-3 percent ethyl acetate in hexane. Compound started eluting with 2 percent ethylacetate in hexane. Fraction containing such TLC profile was collected together to obtain pure compound(0.8 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(Step 1) [0308] Toluene (30 mL) and cyclobutylamine (2.25 mL) were added to <strong>[148625-35-8]methyl 3-formyl-4-nitrobenzoate</strong> (5.00 g), and the reaction solution was stirred at room temperature for 5 minutes. The solvent was evaporated under vacuum, then triethyl phosphite (11.3 mL) was added to the residue, and the reaction solution was stirred at 100°C for 7 hours. The solvent was evaporated under vacuum, the resultant residue was purified by column chromatography on silica gel [0309] (developing solvent: hexane/ethyl acetate). Ethanol (2 mL) and a 5 N aqueous sodium hydroxide solution (5.0 mL) were added to the resultant crude product, and the reaction solution was stirred at room temperature for 1 hour. A 10percent aqueous phosphoric acid solution was added to acidify the reaction solution. Furthermore, water was added, and the deposited precipitate was filtrated to obtain 2-cyclobutyl-2H-indazole-5-carboxylate as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; In methanol; at 20℃;Inert atmosphere; | General procedure: Typical procedure for reductive amination with cyclobutyl or cyclopentyl amine: Aldehyde (1 equiv) was dissolved in anhydrous MeOH under N2. Cyclobutyl amine (1.05 equiv) was added and the reaction stirred overnight at room temperature. NaBH4 (1.6 equiv) was added and the reaction stirred for 1 hour. The reaction was quenched with saturated NH4Cl, taken up in ethyl acetate, washed with brine, dried over MgSO4, concentrated, and taken directly to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; | To a stirred mixture of <strong>[723280-98-6]7-bromo-4-chloro-3-nitroquinoline</strong> (2 g, 6.96 mmol, 1 equiv) and TEA (1.06 g, 10.43 mmol, 1.5 equiv) in DCM (80 mL) was added cyclobutanamine (0.59 g, 8.35 mmol, 1.2 equiv) dropwise at room temperature. The resulting mixture was stirred for overnight at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 7-bromo-N-cyclobutyl-3- nitroquinolin-4-amine (1.8 g, 80.32%) as a yellow crude solid. LC-MS: (ES, m/z): [M+H]+ =322.0. | |
With triethylamine; In dichloromethane; at 20℃; | To a stirred mixture of <strong>[723280-98-6]7-bromo-4-chloro-3-nitroquinoline</strong> (2 g, 6.96 mmol, 1 equiv) and TEA (1.06 g, 10.44 mmol, 1.5 equiv) in DCM (80 mL) was added cyclobutanamine (0.59 g, 8.35 mmol, 1.2 equiv) dropwise at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 7-bromo-N-cyclobutyl-3-nitroquinolin-4-amine (1.8 g, 80.32%) as a yellow crude solid. LC-MS: (ES, m/z): [M+H]+ =322.0. |
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