Heterocyclic Building Blocks-Pyridazine

Heinisch, G. published the artcileSynthesis and reactions of pyridazine derivatives. II. 4-Hydroxymethylpyridazine, Category: pyridazine, the publication is Monatsh. Chem. (1973), 104(5), 1354-9, database is CAplus.

4-(Hydroxymethyl)pyridazine (I) was obtained together with Et 2,5-dihydropyridazine-4-carboxylate by LiAlH4 or NaBH4 reduction of Et 4-pyridazinecarboxylate, the ratios depending on the reaction conditions. Reduction of 4-pyridazinecarboxaldehyde or 4-acetylpyridazine with NaBH4 gave I or 4-(1-hydroxyethyl)pyridazine, resp., in quant. yield. Treatment of I with SOCl2 gave 4-(chloromethyl)pyridazine.

Monatsh. Chem. published new progress about 50901-42-3. 50901-42-3 belongs to pyridazine, auxiliary class Pyridazine,Aldehyde, name is Pyridazine-4-carbaldehyde, and the molecular formula is C5H4N2O, Category: pyridazine.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Rak, Gregory D. published the artcileIntermittent dosing of the transforming growth factor beta receptor 1 inhibitor, BMS-986260, mitigates class-based cardiovascular toxicity in dogs but not rats, COA of Formula: C18H12ClFN6O, the publication is Journal of Applied Toxicology (2020), 40(7), 931-946, database is CAplus and MEDLINE.

Small-mol. inhibitors of transforming growth factor beta receptor 1 (TGFβRI) have a history of significant class-based toxicities (eg, cardiac valvulopathy) in preclin. species that have limited their development as new medicines. Nevertheless, some TGFβRI inhibitors have entered into clin. trials using intermittent-dosing schedules and exposure limits in an attempt to avoid these toxicities. This report describes the toxicity profile of the small-mol. TGFβRI inhibitor, BMS-986260, in rats and dogs. Daily oral dosing for 10 days resulted in valvulopathy and/or aortic pathol. at systemic exposures that would have been targeted clin., preventing further development with this dosing schedule. These toxicities were not observed in either species in 1-mo studies using the same doses on an intermittent-dosing schedule of 3 days on and 4 days off (QDx3 once weekly). Subsequently, 3-mo studies were conducted (QDx3 once weekly), and while there were no cardiovascular findings in dogs, valvulopathy and mortality occurred early in rats. The only difference compared to the 1-mo study was that the rats in the 3-mo study were 2 wk younger at the start of dosing. Therefore, a follow-up 1-mo study was conducted to evaluate whether the age of rats influences sensitivity to target-mediated toxicity. Using the same dosing schedule and similar doses as in the 3-mo study, there was no difference in the toxicity of BMS-986260 in young (8 wk) or adult (8 mo) rats. In summary, an intermittent-dosing schedule mitigated target-based cardiovascular toxicity in dogs but did not prevent valvulopathy in rats, and thus the development of BMS-986260 was terminated.

Journal of Applied Toxicology published new progress about 2001559-19-7. 2001559-19-7 belongs to pyridazine, auxiliary class TGF-beta/Smad,TGF-beta Receptor, name is 6-(4-(3-Chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1H-imidazol-5-yl)imidazo[1,2-b]pyridazine-3-carbonitrile, and the molecular formula is C18H12ClFN6O, COA of Formula: C18H12ClFN6O.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Sadler, Scott A. published the artcileIridium-catalyzed C-H borylation of pyridines, Application In Synthesis of 1350543-95-1, the publication is Organic & Biomolecular Chemistry (2014), 12(37), 7318-7327, database is CAplus and MEDLINE.

The iridium-catalyzed C-H borylation is a valuable and attractive method for the preparation of aryl and heteroaryl boronates. However, application of this methodol. for the preparation of pyridyl and related azinyl boronates can be challenged by low reactivity and propensity for rapid protodeborylation, particularly for a boronate ester ortho to the azinyl nitrogen. Competition experiments have revealed that the low reactivity is due to inhibition of the active catalyst through coordination of the azinyl nitrogen lone pair at the vacant site on the iridium. This effect can be overcome through the incorporation of a substituent at C-2. Moreover, when this is sufficiently electron-withdrawing protodeborylation is sufficiently slowed to permit isolation and purification of the C-6 boronate ester. Following functionalization, reduction of the directing C-2 substituent provides the product arising from formal ortho borylation of an unhindered pyridine ring.

Organic & Biomolecular Chemistry published new progress about 1350543-95-1. 1350543-95-1 belongs to pyridazine, auxiliary class Pyridazine,Boronic acid and ester,Boronate Esters,Boronic Acids,Boronic acid and ester, name is 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine, and the molecular formula is C11H17BN2O2, Application In Synthesis of 1350543-95-1.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Parrish, Karen E. published the artcilePharmacodynamics-based approach for efficacious human dose projection of BMS-986260, a small molecule transforming growth factor beta receptor 1 inhibitor, HPLC of Formula: 2001559-19-7, the publication is Biopharmaceutics & Drug Disposition (2021), 42(4), 137-149, database is CAplus and MEDLINE.

For decades, tumor biol. implicated TGF-β as an attractive therapeutic target due to its immunosuppressive effects. Toward this end, multiple pharmaceutical companies developed a number of drug modalities that specifically target the TGF-β pathway. BMS-986260 is a small mol., selective TGF-βR1 kinase inhibitor that was under preclin. development for oncol. In vivo studies across mouse, rat, dog, and monkey and cryopreserved hepatocytes predicted human pharmacokinetics (PK) and distribution of BMS-986260. Efficacy studies of BMS-986260 were undertaken in the MC38 murine colon cancer model, and target engagement, as measured by phosphorylation of SMAD2/3, was assessed in whole blood to predict the clin. efficacious dose. The human clearance is predicted to be low, 4.25 mL/min/kg. BMS-986260 provided a durable and robust antitumor response at 3.75 mg/kg daily and 1.88 mg/kg twice-daily dosing regimens. Phosphorylation of SMAD2/3 was 3.5-fold less potent in human monocytes than other preclin. species. Taken together, the projected clin. efficacious dose was 600 mg QD or 210 mg BID for 3 days followed by a 4-day drug holiday. Mechanism-based cardiovascular findings in the rat ultimately led to the termination of BMS-986260. This study describes the preclin. PK characterization and pharmacodynamics-based efficacious dose projection of a novel small mol. TGF-βR1 inhibitor.

Biopharmaceutics & Drug Disposition published new progress about 2001559-19-7. 2001559-19-7 belongs to pyridazine, auxiliary class TGF-beta/Smad,TGF-beta Receptor, name is 6-(4-(3-Chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1H-imidazol-5-yl)imidazo[1,2-b]pyridazine-3-carbonitrile, and the molecular formula is C18H12ClFN6O, HPLC of Formula: 2001559-19-7.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Floyd, David M. published the artcileHit-to-Lead Studies for the Antimalarial Tetrahydroisoquinolone Carboxanilides, Application In Synthesis of 50901-42-3, the publication is Journal of Medicinal Chemistry (2016), 59(17), 7950-7962, database is CAplus and MEDLINE.

Phenotypic whole-cell screening in erythrocytic co-cultures of Plasmodium falciparum identified a series of dihydroisoquinolones that possessed potent anti-malarial activity against multiple resistant strains of P. falciparum in vitro and show no cytotoxicity to mammalian cells. Systematic structure-activity studies revealed relationships between potency and modifications at N-2, C-3 and C-4. Careful structure-property relationship studies, coupled with studies of metabolism, addressed the poor aqueous solubility and metabolic vulnerability, as well as potential toxicol. effects, inherent in the more potent primary screening hits such as (I). Analogs (II) and (+)-SJ733 (13i), with structural modifications at each site, were shown to possess excellent anti-malarial activity in vivo. The (+)-(3S,4S) enantiomer of 13i and similar analogs were identified as the more potent. Based on these studies, the authors have selected (+)-13i for further study as a preclin. candidate.

Journal of Medicinal Chemistry published new progress about 50901-42-3. 50901-42-3 belongs to pyridazine, auxiliary class Pyridazine,Aldehyde, name is Pyridazine-4-carbaldehyde, and the molecular formula is C5H4N2O, Application In Synthesis of 50901-42-3.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Cacciari, Barbara published the artcileFacile and versatile route to the synthesis of fused 2-pyridones: useful intermediates for polycyclic systems, Safety of 3-Aminopyridazine-4-carbonitrile, the publication is Synthetic Communications (2006), 36(9), 1177-1183, database is CAplus.

The reaction of various heteroaromatic amino nitriles with di-Et malonate under basic conditions is reported. This reaction affords a series of different highly functionalized 2-pyridone condensed systems, which can be suitable intermediates in the construction of polyheterocyclic structures.

Synthetic Communications published new progress about 119581-52-1. 119581-52-1 belongs to pyridazine, auxiliary class Pyridazine,Nitrile,Amine, name is 3-Aminopyridazine-4-carbonitrile, and the molecular formula is C5H4N4, Safety of 3-Aminopyridazine-4-carbonitrile.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Vetrichelvan, Muthalagu published the artcileDevelopment of a Scalable Synthesis of the Small Molecule TGFβR1 Inhibitor BMS-986260, Product Details of C18H12ClFN6O, the publication is Organic Process Research & Development (2020), 24(7), 1310-1320, database is CAplus.

A scalable route to the small mol. TGFβR1 inhibitor BMS-986260 I was developed. This alternative approach circumvented the purification of intermediates by column chromatog. and provided access to multikilogram quantities of the key intermediate, 6-formylimidazo[1,2-b]pyridazine-3-carbonitrile. The safety aspects of the synthetic approach to the other fragment of the API (TosMIC) were critically evaluated, and a robust process for its large-scale synthesis was successfully demonstrated.

Organic Process Research & Development published new progress about 2001559-19-7. 2001559-19-7 belongs to pyridazine, auxiliary class TGF-beta/Smad,TGF-beta Receptor, name is 6-(4-(3-Chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1H-imidazol-5-yl)imidazo[1,2-b]pyridazine-3-carbonitrile, and the molecular formula is C10H10O6, Product Details of C18H12ClFN6O.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Liu, Yuji published the artcileConstruction of Bicyclic 1,2,3-Triazine N-Oxides from Aminocyanides, HPLC of Formula: 119581-52-1, the publication is Organic Letters (2021), 23(3), 734-738, database is CAplus and MEDLINE.

Using a facile and cost-effective method, nine bicyclic 1,2,3-triazine 2-oxides were synthesized from o-aminocyanide substrates through an unusual nitration cyclization. The reaction mechanism was studied exptl. and theor. Moreover, nine 1,2,3-triazine 3-oxides were also obtained in good yields.

Organic Letters published new progress about 119581-52-1. 119581-52-1 belongs to pyridazine, auxiliary class Pyridazine,Nitrile,Amine, name is 3-Aminopyridazine-4-carbonitrile, and the molecular formula is C5H4N4, HPLC of Formula: 119581-52-1.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Helm, Matthew D. published the artcileA novel approach to functionalized pyridazinone arrays, Quality Control of 919197-88-9, the publication is Organic & Biomolecular Chemistry (2006), 4(23), 4278-4280, database is CAplus and MEDLINE.

A series of 3,6-dichloro-1H-pyridazin-4-ones have been prepared via the cycloaddition of 3,6-dichlorotetrazine with alkynylboronates, and their employment as useful synthetic intermediates was highlighted through a selection of highly regioselective C-O, C-S and C-C bond forming reactions.

Organic & Biomolecular Chemistry published new progress about 919197-88-9. 919197-88-9 belongs to pyridazine, auxiliary class Pyridazine,Chloride,Boronic acid and ester,Boronate Esters,Boronic Acids,Boronic acid and ester,Boronate Esters,, name is 3,6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine, and the molecular formula is C10H13BCl2N2O2, Quality Control of 919197-88-9.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Heinisch, G. published the artcilePyridazines. Part 55. Electron-ionization mass spectrometry of selected monosubstituted pyridazines, Category: pyridazine, the publication is Scientia Pharmaceutica (1991), 59(2), 111-13, database is CAplus.

The electron-ionization mass spectrometric fragmentations of 20 3- or 4-substituted pyridazines (I, R or R¹ = H, CH₂OH, CH:NOH, CN, COOH, CONH₂, COOMe, COOEt, CHO, COMe, COEt) are given.

Scientia Pharmaceutica published new progress about 50901-42-3. 50901-42-3 belongs to pyridazine, auxiliary class Pyridazine,Aldehyde, name is Pyridazine-4-carbaldehyde, and the molecular formula is C5H4N2O, Category: pyridazine.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem