Category: 5018-38-2

Fang, Yuanying; Zhang, Shaokun; Li, Min; Xiong, Lijuan; Tu, Liangxing; Xie, Saisai; Jin, Yi; Liu, Yanhua; Yang, Zunhua; Liu, Ronghua published the artcile< Optimisation of novel 4, 8-disubstituted dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119 agonists>, Application of C5H4Cl2N2O, the main research area is dihydropyrimido oxazine derivative preparation GPR 119 agonist diabetes; GPR 119 agonists; Optimisation; pyrimidodihydrooxazine; type 2 diabetes mellitus.

GPR119 is a promising target for discovery of anti-type 2 diabetes mellitus agents. We described the optimization of a novel series of pyrimido[5,4-b][1,4]oxazine derivatives as GPR119 agonists. Most designed compounds exhibited good agonistic activities. Among them, compound and demonstrated the potent EC50 values (13 and 12 nM, resp.) and strong inherent activities. Moreover, significant hypoglycemic effect of compound was observed by reducing the blood glucose AUC0-2h at the dose of 30 mg/kg, which is stronger than Vildagliptin (23.4% reduction vs. 17.9% reduction).

Journal of Enzyme Inhibition and Medicinal Chemistry published new progress about Antidiabetic agents. 5018-38-2 belongs to class pyrimidines, and the molecular formula is C5H4Cl2N2O, Application of C5H4Cl2N2O.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Sagong, Hye Yeon; Bauman, Joseph D.; Patel, Disha; Das, Kalyan; Arnold, Eddy; LaVoie, Edmond J. published the artcile< Phenyl Substituted 4-Hydroxypyridazin-3(2H)-ones and 5-Hydroxypyrimidin-4(3H)-ones: Inhibitors of Influenza A Endonuclease>, Application of C5H4Cl2N2O, the main research area is aryl hydroxypyridazinone preparation influenza A endonuclease inhibitor antiviral; hydroxypyrimidinone aryl preparation influenza A endonuclease inhibitor antiviral.

Seasonal and pandemic influenza outbreaks remain a major human health problem. Inhibition of the endonuclease activity of influenza RNA-dependent RNA polymerase is attractive for the development of new agents for the treatment of influenza infection. Authors’ earlier studies identified a series of 5- and 6-Ph substituted 3-hydroxypyridin-2(1H)-ones that were effective inhibitors of influenza endonuclease. These agents identified as bimetal chelating ligands binding to the active site of the enzyme. In the present study, several aza analogs of these Ph substituted 3-hydroxypyridin-2(1H)-one compounds were synthesized and evaluated for their ability to inhibit the endonuclease activity. In contrast to the 4-aza analog of 6-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one, the 5-aza analog (5-hydroxy-2-(4-fluorophenyl)pyrimidin-4(3H)-one) did exhibit significant activity as an endonuclease inhibitor. The 6-aza analog of 5-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one (6-(4-fluorophenyl)-4-hydroxypyridazin-3(2H)-one) also retained modest activity as an inhibitor. Several varied 6-phenyl-4-hydroxypyridazin-3(2H)-ones and 2-phenyl-5-hydroxypyrimidin-4(3H)-ones, e.g., I (X-rays crystal structure in complex with endonuclease shown), were synthesized and evaluated as endonuclease inhibitors. The SAR observed for these aza analogs are consistent with those previously observed with various Ph substituted 3-hydroxypyridin-2(1H)-ones.

Journal of Medicinal Chemistry published new progress about Antiviral agents. 5018-38-2 belongs to class pyrimidines, and the molecular formula is C5H4Cl2N2O, Application of C5H4Cl2N2O.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Yang, Jiao; Chen, Kai; Zhang, Guo; Yang, Qiu-Yuan; Li, Yue-Shan; Huang, Shen-Zhen; Wang, Yan-Lin; Yang, Wei; Jiang, Xiao-Juan; Yan, Heng-Xiu; Zhu, Jing-Qiang; Xiang, Rong; Luo, You-Fu; Li, Wei-Min; Wei, Yu-Quan; Li, Lin-Li; Yang, Sheng-Yong published the artcile< Structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of inhibitors of RET and its drug resistance mutants>, Recommanded Product: 4,6-Dichloro-5-methoxypyrimidine, the main research area is phenyldihydro pyrimido oxazinamine derivative preparation RET inhibitor cancer; Drug resistance mutant; Medullary thyroid cancer; RET kinase; Structure-activity relationship.

The RET tyrosine kinase is an important therapeutic target for medullary thyroid cancer (MTC), and drug resistance mutations of RET, particularly V804M and V804L, are a main challenge for the current targeted therapy of MTC based on RET inhibitors. In this investigation, we report the structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of RET inhibitors. Among all the obtained kinase inhibitors, 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-yl)amino)phenyl)urea (17d) is a multi-kinase inhibitor and potently inhibits RET and its drug resistance mutants. It showed IC50 (half maximal inhibitory concentration) values of 0.010 μM, 0.015 μM, and 0.009 μM against RET-wild-type, RET-V804M, and RET-V804L, resp. 17d displayed significant anti-viability potencies against various RET-driving tumor cell lines. In a xenograft mouse model of NIH3T3-RET-C634Y, 17d exhibited potent in vivo anti-tumor activity, and no obvious toxicity was observed Mechanisms of action were also investigated by Western blot and immunohistochem. assays. Collectively, 17d could be a promising agent for the treatment of MTC, hence deserving a further investigation.

European Journal of Medicinal Chemistry published new progress about Antitumor agents. 5018-38-2 belongs to class pyrimidines, and the molecular formula is C5H4Cl2N2O, Recommanded Product: 4,6-Dichloro-5-methoxypyrimidine.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Ma, Bin; Metrick, Claire M.; Gu, Chungang; Hoemberger, Marc; Bajrami, Bekim; Bame, Eris; Huang, Jiansheng; Mingueneau, Michael; Murugan, Paramasivam; Santoro, Joseph C.; Tang, Hao; Wang, Ti; Hopkins, Brian T. published the artcile< Optimization of a novel piperazinone series as potent selective peripheral covalent BTK inhibitors>, HPLC of Formula: 5018-38-2, the main research area is piperazinone antiinflammatory BTK inhibitor autoimmune disease; B cell; BTK; Covalent inhibitor; Piperazinone; Selectivity; X-ray.

BTK is a tyrosine kinase playing an important role in B cell and myeloid cell functions through B cell receptor (BCR) signaling and Fc receptor (FcR) signaling. Selective inhibition of BTK has the potential to provide therapeutical benefits to patients suffering from autoimmune diseases. Here we report the design, optimization, and characterization of novel potent and highly selective covalent BTK inhibitors. Starting from a piperazinone hit derived from a selective reversible inhibitor, we solved the whole blood cellular potency issue by introducing an electrophilic warhead to reach Cys481. This design led to a covalent irreversible BTK inhibitor series with excellent kinase selectivity as well as good whole blood CD69 cellular potency. Optimization of metabolic stability led to representative compounds like 42, which demonstrated strong cellular target occupancy and inhibition of B-cell proliferation measured by proximal and distal functional activity.

Bioorganic & Medicinal Chemistry Letters published new progress about Autoimmune disease. 5018-38-2 belongs to class pyrimidines, and the molecular formula is C5H4Cl2N2O, HPLC of Formula: 5018-38-2.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Wu, Xiao-qiong published the artcile< New method for synthesis of 4,6-dichloro-5-methoxypyrimidine>, Category: pyrimidines, the main research area is dichloro methoxypyrimidine aminolysis cyclization chlorination.

The research aimed to improve the synthesis method of 4,6-dichloro-5-methoxypyrimidine. 2-Methoxy di-Me malonate was used to prepare 4,6-dichloro-5- methoxypyrimidine by aminolysis, cyclization and chlorination. Results showed that the synthetic product was analyzed by IR spectrum, hydrogen NMR and mass spectrometry. The overall yield was 42%. It was concluded that the synthesis method was suitable for industrial production, because of its warm condition and higher yield.

Anhui Nongye Kexue published new progress about Aminolysis. 5018-38-2 belongs to class pyrimidines, and the molecular formula is C5H4Cl2N2O, Category: pyrimidines.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Darout, Etzer; Robinson, Ralph P.; McClure, Kim F.; Corbett, Matthew; Li, Bryan; Shavnya, Andrei; Andrews, Melissa P.; Jones, Christopher S.; Li, Qifang; Minich, Martha L.; Mascitti, Vincent; Guimaraes, Cristiano R. W.; Munchhof, Michael J.; Bahnck, Kevin B.; Cai, Cuiman; Price, David A.; Liras, Spiros; Bonin, Paul D.; Cornelius, Peter; Wang, Ruduan; Bagdasarian, Victoria; Sobota, Colleen P.; Hornby, Sam; Masterson, Victoria M.; Joseph, Reena M.; Kalgutkar, Amit S.; Chen, Yue published the artcile< Design and Synthesis of Diazatricyclodecane Agonists of the G-Protein-Coupled Receptor 119>, Safety of 4,6-Dichloro-5-methoxypyrimidine, the main research area is diazatricyclodecane derivative preparation agonist G protein coupled receptor 119; Hofmann Loeffler Freytag reaction formation bicyclic framework; ligand lipophilic efficiency diazatricyclodecane.

A series of GPR119 agonists based on a 2,6-diazatricyclo[3.3.1.1∼3,7∼]decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann-Loeffler-Freytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the mol. in the “”agonist conformation”” as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of carbamate analogs of the diazatricyclic compounds led to the identification of I as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these mols.

Journal of Medicinal Chemistry published new progress about Crystal structure. 5018-38-2 belongs to class pyrimidines, and the molecular formula is C5H4Cl2N2O, Safety of 4,6-Dichloro-5-methoxypyrimidine.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Guan, Aiying; Zhao, Yu; Wang, Weiwei; Liu, Xinlei; Wang, Ming-an published the artcile< Synthesis and fungicidal activity of 3-Acetyl-4-phenyl-1-oxaspiro[4,5]dec-3-en-2-one derivatives>, COA of Formula: C5H4Cl2N2O, the main research area is fungicide acetyl phenyl oxaspiro decenone derivative synthesis.

The diversity-oriented synthesis strategy was utilized to diversely derive from the carbonyl of 3-acetyl-4-phenyl-1-oxaspiro[4,5]dec-3-en-2-one, a series of novel 3-acetyl-4-phenyl-1-oxaspiro[4,5]dec-3-en-2-one derivatives were synthesized. The preliminary in vivo and in vitro bioassay results showed that some compounds exhibited excellent fungicidal activity against phytopathagens, such as 3-allyloxyethyl-4-phenyl-1-oxaspiro[4,5]dec-3-en-2-one had 100% control rates against Pseudoperonospora cubensis and Puccinia polysora at the concentration of 400μg/mL.

Youji Huaxue published new progress about Agrochemical fungicides. 5018-38-2 belongs to class pyrimidines, and the molecular formula is C5H4Cl2N2O, COA of Formula: C5H4Cl2N2O.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Anderson, Neal G.; Ary, Thomas D.; Berg, James L.; Bernot, Peter J.; Chan, Yeung Y.; Chen, Chien-Kuang; Davies, Merrill L.; DiMarco, John D.; Dennis, Ronald D.; Deshpande, Rajan P.; Do, Hoang D.; Droghini, Roberto; Early, William A.; Gougoutas, Jack Z.; Grosso, John A.; Harris, John C.; Haas, Oscar W.; Jass, Paul A.; Kim, Daniel H.; Kodersha, Gus A.; Kotnis, Atul S.; LaJeunesse, Jean; Lust, David A.; Madding, Gary D.; Modi, Sandeep P.; Moniot, Jerome L.; Nguyen, Andrew; Palaniswamy, Venkatapuram; Phillipson, Douglas W.; Simpson, James H.; Thoraval, Dominique; Thurston, David A.; Tse, Kai; Polomski, Robert E. published the artcile< Process Development of 5-Fluoro-3-[3-[4-(5-methoxy-4-pyrimidinyl)-1- piperazinyl]propyl]-1H-indole Dihydrochloride>, SDS of cas: 5018-38-2, the main research area is fluoromethoxy pyrimidinyl piperazinylpropyl indole dihydrochloride synthesis; antidepressant fluoromethoxypyrimidinyl piperazinylpropyl indole dihydrochloride preparation.

5-Fluoro-3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-1H-indole dihydrochloride (1) facilitates 5-HT neurotransmission and was an antidepressant drug candidate. The development of a safe, rugged process for the large-scale, chromatog.-free preparation of this compound is described. The main areas of optimization included a Fischer indole synthesis, preparation and chlorination of a monohydroxypyrimidine, and coupling of the resultant fragments to prepare the drug substance.

Organic Process Research & Development published new progress about Antidepressants. 5018-38-2 belongs to class pyrimidines, and the molecular formula is C5H4Cl2N2O, SDS of cas: 5018-38-2.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Picazo, Edwige M. H.; Heptinstall, Amy B.; Wilson, David M.; Cano, Celine; Golding, Bernard T.; Waring, Michael J. published the artcile< Cyclizations and fragmentations in the alkylation of 6-chloro-5-hydroxy-4-aminopyrimidines with aminoalkyl chlorides>, Electric Literature of 5018-38-2, the main research area is polysubstituted aminopyrimidine preparation; chlorohydroxyaminopyrimidine aminoalkyl chloride alkylation.

Substituted aminopyrimidines are an important class of compounds, in part because they frequently show biol. activity. Facile synthesis of polysubstituted aminopyrimidines is highly desirable for the synthesis of screening libraries. Authors describe a route to 4,6-diamino-5-alkoxypyrimidines via a SNAr-alkylation-SNAr sequence from readily available 4,6-dichloro-5-methoxypyrimidine, which allows the synthesis of such compounds with regiochem. control. The extension of this approach to alkylating agents bearing amino substituents led to unexpected and, in some cases, unprecedented products resulting from intramol. SNAr cyclization and subsequent fragmentation.

Journal of Heterocyclic Chemistry published new progress about Alkylation. 5018-38-2 belongs to class pyrimidines, and the molecular formula is C5H4Cl2N2O, Electric Literature of 5018-38-2.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Gruessner, A.; Montavon, M.; Schnider, O. published the artcile< Disubstituted 4-sulfanilamidopyrimidines>, Formula: C5H4Cl2N2O, the main research area is .

A series of 5,6-dialkoxy-4-sulfanilamidopyrimidines was prepared and tested for chemotherapeutic activity. Thus, to a mixture of 1 mole ROCH2CO2Me, 1200 ml. benzene, and 1.5 moles oxalic acid dialkyl ester was added in small portions at 22° during 3 hrs. with cooling and stirring 60 g. NaOMe. The mixture was stirred overnight, worked up, the crude product heated with 3 g. glass powder and 5 mg. Fe powder at 210°/400 mm. for 3 hrs. followed by distillation at 11 mm. After distillation was complete the residue was heated with an addnl. 5 g. glass powder and 5 mg. iron powder for 3 hrs. at 210° and then distilled at 11 mm. The successive distillations gave ROCH(CO2Me)2 (I). I was converted to the diamide ROCH(CONH2)2 (II) by treatment with liquid NH3 for 14 hrs. at room temperature The table lists the methyl esters and amides prepared I, II; R, b11, % yield, M.p. (H2O), % yield; Me, 103-4°, 78, 217-18°, 97; Et, 114-16°, 80, 202°, 97; iso-Pr, 118-21°, 72, 218-19°, 94; Pr, 124-8°, 65, –, –; Bu, 128-30°, 63, 174-6°, 85; To a solution of 20.4 g. Na in 410 ml. absolute alc. was added 42 g. II (R = Me) followed by 20.4 ml. formamide. The solution was heated for 3 hrs. After cooling the Na salt of 4,6-dihydroxypyrimidine was filtered off, washed with absolute alc., and dried in vacuo at 50°. The crude Na salt (72.4 g.) was added slowly to 314 ml. POCl3 below 30°, followed by 31 ml. PhNMe2. The mixture was heated at 130° for 3 hrs. to give 4,6-dichloro-5-methoxypyrimidine (III), m. 57-8°. Similarly prepared were the following IV (R and b12 given): Et, 102-7°; iso-Pr, 108-13°; Bu, 128-33°. A mixture of 48 g. III and 170 ml. liquid NH3 under N at 20 atm. was shaken in an autoclave overnight to give 82% 4-amino-5-methoxy-6-chloropyrimidine (V), m. 176-8°. The 5-ethoxy, m. 119-20° (MeCN), 5-isopropoxy, m. 139-41° (MeCN), and 5-butoxy, m. 103-4°, analogs were prepared To a solution of 29.4 g. Na in 1 l. MeOH was added 170 g. V and the solution heated 18 hrs. to yield 94% 4-amino-5,6-dimethoxypyrimidine (VI), m. 88-9° (isopropyl ether). Similarly prepared were the following VIa (R, R1, and m.p. given): Me, Et, 64-58°; Me, iso-Pr, 111-12°; Me, Pr, 70-1°; Me, CH2CH:CH2, 41-2°; Me, C10H21, 53-4°; Et, Et, 83-4°; Bu, C10H21, 32-3°; Bu, CH2CH2OCH2Me, 98-9°. To a solution of 62 g. VI in 160 ml. absolute pyridine was added over 3 hrs. 130 g. 4-acetamidobenzenesulfonyl chloride at 3-4° and the solution kept overnight to yield 89.5% VII (R = Me, R1 = OMe, X = Ac), m. 230-1° (HOAc), hydrolysis of which with 2N NaOH gave VII (R = Me, R1 = OMe, X = H), m. 201-2°. The following VII (R = Me) were similarly prepared (R1, X, and m.p. given): EtO, Ac, 201-2°; EtO, H, 170-1°; PrO, Ac, 186-7°; PrO, H, 142-3°; iso-PrO, Ac, 195-7°; iso-PrO, H, 136-7°; MeO, HCO, 194-5°. Also prepared were the following VII (X = H) (R, R1, and m.p. given): Me, OC10H21, 94-6°; Me, OPr-iso, 136-7°; Et, Cl, 215-16°; Et, OMe, 228-9°; Et, OEt, 173-4°; Et, OCH2CH:CH2, 152°; Et, OPr, 162°; Et, OPr-iso, 181-3°; Me, OCH2CH:CH2, 145-6°; iso-Pr, OMe, 193-5°; iso-Pr, OEt, 183-4°; iso-Pr, OPr-iso, 170-1°; Bu, Cl, 172-4°; iso-Pr, OCH2CH:CH2, 146-8°; Bu, OMe, 192-3°; H, OC10H21, 142-4°; Cl, OPr-iso, 172-4°. To a solution of 155 g. Na sulfanilamide in 500 ml. Me2NCHO was added slowly 71.6 g. III at 100°. Work-up gave 82% 4-sulfanilamido-5-methoxy-6-chloropyrimidine (VIII), m. 200-2° (alc.-H2O). To a solution of 5.75 g. Na in 200 ml. allyl alc. was added 31.4 g. VIII to give 4-sulfanilamido-5-methoxy-6-allyloxypyrimidine, m. 145 (BuOAc). To 31 g. VI in 140 ml. absolute pyridine was added 88 g. p-nitrobenzenesulfonyl chloride to give 105 g. 4-[bis(4-nitrophenylsulfonyl)amino]-5,6-dimethoxypyrimidine (IX), m. 216-17° (glacial HOAC). Partial hydrolysis of IX with NaOH in absolute MeOH gave 4-(4-nitrobenzenesulfonamido)-5,6-dimethoxypyrimidine (X), m. 136-8° (MeCN). Treatment of X with Ac2O in absolute pyridine for 3 hrs. on a steam bath gave 4-(N-acetyl-4-nitrobenzenesulfonamido)-5,6-dimethoxypyrimidine (XI), m. 160-2° (MeCN). Reduction of 13 g. XI in 540 ml. HOAc in the presence of 13 g. 5% Pd-C at room temperature gave 8.5 g. 4-(N’-acetylsulfanilamido)-5,6-dimethoxypyrimidine, m. 196-8 (MeCN). The following XII were similarly prepared (R, R1, X, and m.p. given): OMe, C10H21, 4-O2NC6H4SO2, 112-13°; OMe, C10H21, H, 114-15°; OBu, OCH2CH2OEt, 4-O2NC6H4SO2, 124-5°; OBu, OCH2CH2OEt, H, 96-8°.

Monatshefte fuer Chemie published new progress about 5018-38-2. 5018-38-2 belongs to class pyrimidines, and the molecular formula is C5H4Cl2N2O, Formula: C5H4Cl2N2O.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia