Heterocyclic Building Blocks-Pyridazine

Lim, Jongwon et al. published their research in Bioorganic & Medicinal Chemistry Letters in 2015 | CAS: 19064-65-4

3-Methoxypyridazine (cas: 19064-65-4) belongs to pyridazine derivatives. Pyridazines are rare in nature, possibly reflecting the scarcity of naturally occurring hydrazines, common building blocks for the synthesis of these heterocycles. Pyridazine compounds have attracted interest in various fields like medicinal, industrial, and agricultural research as they are used for numerous biological activities and other applications.Recommanded Product: 19064-65-4

Identification of N-(1H-pyrazol-4-yl)carboxamide inhibitors of interleukin-1 receptor associated kinase 4: Bicyclic core modifications was written by Lim, Jongwon;Altman, Michael D.;Baker, James;Brubaker, Jason D.;Chen, Hongmin;Chen, Yiping;Kleinschek, Melanie A.;Li, Chaomin;Liu, Duan;MacLean, John K. F.;Mulrooney, Erin F.;Presland, Jeremy;Rakhilina, Larissa;Smith, Graham F.;Yang, Ruojing. And the article was included in Bioorganic & Medicinal Chemistry Letters in 2015.Recommanded Product: 19064-65-4 This article mentions the following:

IRAK4 plays a critical role in the IL-1R and TLR signaling, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of permeable N-(1H-pyrazol-4-yl)carboxamides was developed by introducing lipophilic bicyclic cores in place of the polar pyrazolopyrimidine core of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides. Replacement of the pyrazolo[1,5-a]pyrimidine core with the pyrrolo[2,1-f][1,2,4]triazine, the pyrrolo[1,2-b]pyridazine, and thieno[2,3-b]pyrazine cores guided by c Log D led to the identification of highly permeable IRAK4 inhibitors with excellent potency and kinase selectivity. In the experiment, the researchers used many compounds, for example, 3-Methoxypyridazine (cas: 19064-65-4Recommanded Product: 19064-65-4).

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Yamagami, Chisako et al. published their research in Quantitative Structure-Activity Relationships in 1990 | CAS: 19064-65-4

3-Methoxypyridazine (cas: 19064-65-4) belongs to pyridazine derivatives. The pyridazine structure is also found within the structure of several drugs such as cefozopran, cadralazine, minaprine, pipofezine, and hydralazine. In the past decade, X-ray data were reported with regard to the characterization and structural elucidation of a number of pyridazine-metal complexes, including pyridazine ligands with zinc, nickel, copper, cadmium and ruthenium.Formula: C5H6N2O

Hydrophobicity parameter of diazines. 1. Analysis and prediction of partition coefficients of monosubstituted diazines was written by Yamagami, Chisako;Takao, Narao;Fujita, Toshio. And the article was included in Quantitative Structure-Activity Relationships in 1990.Formula: C5H6N2O This article mentions the following:

The octanol/water partition coefficient (P) of a number of monosubstituted diazines was measured. The composition of the π value of substituents, the increment in the log P value accompanying the introduction of substituents, was examined in terms of physicochem. substituent parameters and correlation anal. The diazine-π value of substituents was generally higher than the pyridine-π value of corresponding substituents, indicating that the intramol. electronic interactions between the ring-N atoms and substituent are more pronounced than those in substituted pyridines in governing the log P value of the mol. Except for 2-substituted pyrimidines, the π value of substituents in each series of monosubstituted diazines was in general nicely correlated with the π value of the corresponding substituents in substituted pyridines along with electronic parameter terms representing bidirectional electronic effects on the relative solvation of the ring-N atom(s) and the hydrogen-bondable substituents with partitioning solvents according to the procedure proposed previously for the anal. of the π value in disubstituted benzenes and monosubstituted pyridines. Keeping in mind that 2-pyrimidines substituted by hydrogen-bondable groups sometimes behave as outliers, the correlations were believed to be usable for prediction of log P values of monosubstituted diazines. In the experiment, the researchers used many compounds, for example, 3-Methoxypyridazine (cas: 19064-65-4Formula: C5H6N2O).

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Zhang, Min et al. published their research in Youji Huaxue in 2007 | CAS: 33097-39-1

3,6-Difluoropyridazine (cas: 33097-39-1) belongs to pyridazine derivatives. Pyridazines are rare in nature, possibly reflecting the scarcity of naturally occurring hydrazines, common building blocks for the synthesis of these heterocycles. The unsubstituted pyridazines are more resistant to eletrophilic substitution due to the nature of withdrawal of electron density from the ring by two heteroatoms, while the related electron deficiency of the ring makes pyridazine more easily attacked by nucleophiles.Product Details of 33097-39-1

Synthesis and herbicidal activity of 3-(benzyloxy)-6-fluoropyridazine derivatives was written by Zhang, Min;Hu, Fang-Zhong;Zhu, You-Quan;Zou, Xiao-Mao;Liu, Bin;Yang, Hua-Zheng. And the article was included in Youji Huaxue in 2007.Product Details of 33097-39-1 This article mentions the following:

A series of novel 3-(un)substituted benzyloxy-6-fluoropyridazine derivatives was synthesized by a reaction of various benzyl alcs. with 3,6-difluoropyridazine in CH₃CN catalyzed by NaOH. Their structures were identified by ¹H NMR, IR spectra and elemental anal. Preliminary bioassay showed that all of them possessed herbicidal activity to some extent against Brassica napus (rape) and Echinochloa crus-galli (barnyard grass). Their structure-activity relationship was discussed. In the experiment, the researchers used many compounds, for example, 3,6-Difluoropyridazine (cas: 33097-39-1Product Details of 33097-39-1).

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Hu, Fang-Zhong et al. published their research in Youji Huaxue in 2007 | CAS: 33097-39-1

3,6-Difluoropyridazine (cas: 33097-39-1) belongs to pyridazine derivatives. Pyridazines is a six-membered nitrogen-containing significant heterocycle. It has received considerable interest because of its useful applications as natural products, pharmaceuticals, and various bioactive molecules. The unsubstituted pyridazines are more resistant to eletrophilic substitution due to the nature of withdrawal of electron density from the ring by two heteroatoms, while the related electron deficiency of the ring makes pyridazine more easily attacked by nucleophiles.Quality Control of 3,6-Difluoropyridazine

Synthesis and herbicidal activity of 3-(substituted benzyloxy)-6-(substituted amino)pyridazines was written by Hu, Fang-Zhong;Zhang, Min;Zhu, You-Quan;Zou, Xiao-Mao;Liu, Bin;Yang, Hua-Zheng. And the article was included in Youji Huaxue in 2007.Quality Control of 3,6-Difluoropyridazine This article mentions the following:

A series of new 3-(substituted benzyloxy)-6-(substituted amino)pyridazines were synthesized through the reaction of 3-(substituted benzyloxy)-6-fluoropyridazines with the solution of dimethylamine, morpholine or piperidine. The title compounds were identified by IR, ¹H NMR spectra and elemental analyses. Preliminary bioassay showed that some of them had certain extent herbicidal activities, and the structure-activity relationship was also discussed. In the experiment, the researchers used many compounds, for example, 3,6-Difluoropyridazine (cas: 33097-39-1Quality Control of 3,6-Difluoropyridazine).

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Haider, N. et al. published their research in Science of Synthesis in 2004 | CAS: 105537-97-1

5-Phenylpyridazin-3-amine (cas: 105537-97-1) belongs to pyridazine derivatives. Pyridazines are rare in nature, possibly reflecting the scarcity of naturally occurring hydrazines, common building blocks for the synthesis of these heterocycles. Pyridazine is bioavailable (especially in the CNS) and can reduce toxicity. Pyridazine is a component of several drug molecules, and the pyridazine pharmacophore has contributed to a variety of pharmacologically active compounds.Quality Control of 5-Phenylpyridazin-3-amine

Product class 8: pyridazines was written by Haider, N.;Holzer, W.. And the article was included in Science of Synthesis in 2004.Quality Control of 5-Phenylpyridazin-3-amine The following contents are mentioned in the article:

A review. Methods of preparing pyridazines are reviewed including cyclization, ring transformation, aromatization, and substituent modification. This study involved multiple reactions and reactants, such as 5-Phenylpyridazin-3-amine (cas: 105537-97-1Quality Control of 5-Phenylpyridazin-3-amine).

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Sitamze, Jean Marie et al. published their research in Journal of Organic Chemistry in 1992 | CAS: 105537-97-1

5-Phenylpyridazin-3-amine (cas: 105537-97-1) belongs to pyridazine derivatives. Pyridazine-based compounds continued to be a great source of biologically active compounds as evidenced by the number of publications which emerged in 2021. Pyridazine can act as a hydrogen bond acceptor to improve the physicochemical properties of drug molecules by increasing their water solubility, and has a high affinity for complexing with targets due to its dipole moment.Category: pyridazine

A general and convenient synthesis of 3-aminopyridazines was written by Sitamze, Jean Marie;Schmitt, Martine;Wermuth, Camille Georges. And the article was included in Journal of Organic Chemistry in 1992.Category: pyridazine The following contents are mentioned in the article:

Hydrogenolysis of 3-hydrazinopyridazines I (R = H, Ph, 4-MeOC₆H₄; R¹ = H, Me, Pr, Ph; R² = H, Me, Et, CHMe₂, CH₂Ph, CH₂CH₂Ph; R³ = NHNH₂) by means of nickel-aluminum alloy in alk. medium yield the corresponding 3-aminopyridazines I (R³ = NH₂) in approx. 80 % yield. This study involved multiple reactions and reactants, such as 5-Phenylpyridazin-3-amine (cas: 105537-97-1Category: pyridazine).

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Chen, Zhao et al. published their research in Journal of Medicinal Chemistry in 2019 | CAS: 1439400-46-0

N-(6-Chloropyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (cas: 1439400-46-0) belongs to pyridazine derivatives. The pyridazine derivatives are mostly present in biologically active compounds and are also present with different pharmacophores. The activity depends upon the changes of substituted groups in the pyridazine ring system resulting in different biological activities. In addition, the natural pyrimidine bases uracil, thymine, and cytosine, which are constituents of the nucleic acids, are found to be the most important naturally occurring diazines.Application In Synthesis of N-(6-Chloropyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

Novel 1,3,4-Selenadiazole-Containing Kidney-Type Glutaminase Inhibitors Showed Improved Cellular Uptake and Antitumor Activity was written by Chen, Zhao;Li, Di;Xu, Ning;Fang, Jinzhang;Yu, Yan;Hou, Wei;Ruan, Haoqiang;Zhu, Panpan;Ma, Renchao;Lu, Shiying;Cao, Danhui;Wu, Rui;Ni, Mowei;Zhang, Wei;Su, Weike;Ruan, Benfang Helen. And the article was included in Journal of Medicinal Chemistry in 2019.Application In Synthesis of N-(6-Chloropyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide The following contents are mentioned in the article:

Kidney-type glutaminase [KGA/isoenzyme glutaminase C (GAC)] is becoming an important tumor metabolism target in cancer chemotherapy. Its allosteric inhibitor, CB839, showed early promise in cancer therapeutics but limited efficacy in in vivo cancer models. To improve the in vivo activity, the authors explored a bioisostere replacement of the sulfur atom in bis-2-(5-phenylacetamido-1,2,4-thiadiazol)ethyl sulfide and CB839 analogs with selenium using a novel synthesis of the selenadiazole moiety from carboxylic acids or nitriles. The resulting selenadiazole compounds showed enhanced KGA inhibition, more potent induction of reactive oxygen species, improved inhibition of cancer cells, and higher cellular and tumor accumulation than the corresponding sulfur-containing mols. However, both CB839 and its selenium analogs show incomplete inhibition of the tested cancer cells, and a partial reduction in tumor size was observed in both the glutamine-dependent HCT116 and aggressive H22 liver cancer xenograft models. Despite this, tumor tissue damage and prolonged survival were observed in animals treated with the selenium analog of CB839. This study involved multiple reactions and reactants, such as N-(6-Chloropyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (cas: 1439400-46-0Application In Synthesis of N-(6-Chloropyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide).

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Wermuth, Camille Georges et al. published their research in Journal of Medicinal Chemistry in 1987 | CAS: 105537-97-1

5-Phenylpyridazin-3-amine (cas: 105537-97-1) belongs to pyridazine derivatives. Pyridazines is a six-membered nitrogen-containing significant heterocycle. It has received considerable interest because of its useful applications as natural products, pharmaceuticals, and various bioactive molecules. Specifically, the pyridazine moiety is an important structural feature of various pharmacologically important compounds with activities like antimicrobial, analgesic, anti-inflammatory, antiplatelet, anticancer, antisecretory, antiulcer, antidepressant, cardiotonic, vasodilator, antiarrhythmic, and hypocholesterolaemic.Quality Control of 5-Phenylpyridazin-3-amine

Synthesis and structure-activity relationships of a series of aminopyridazine derivatives of γ-aminobutyric acid acting as selective GABA-A antagonists was written by Wermuth, Camille Georges;Bourguignon, Jean Jacques;Schlewer, Gilbert;Gies, Jean Pierre;Schoenfelder, Angele;Melikian, Anita;Bouchet, Marie Jeanne;Chantreux, Dominique;Molimard, Jean Charles. And the article was included in Journal of Medicinal Chemistry in 1987.Quality Control of 5-Phenylpyridazin-3-amine The following contents are mentioned in the article:

Thirty-eight title compounds, e.g., I, were prepared by attaching various pyridazinic structures to GABA or GABA-like side chains. Thus, aminopyridazine II was treated with BrCH₂CH₂CO₂Et, followed by K₂CO₃ and then HCl-AcOH to give I. Most of the compounds displaced [³H]GABA from rat brain membranes. All the active compounds antagonized the GABA-elicited enhancement of [³H]diazepam binding, strongly suggesting that all these compounds are GABA-A receptor antagonists. None of the compounds that displaced [³H]GABA from rat brain membranes interacted with other GABA recognition sites (GABA-B receptor, GABA uptake binding site, glutamate decarboxylase, GABA-transaminase). They did not interact with the Cl^– ionophore associated with the GABA-A receptor and did not interact with the benzodiazepine, strychnine, and glutamate binding sites. Thus, these compounds appear to be specific GABA-A receptor antagonists. In terms of structure-activity, it is concluded that a GABA moiety bearing a pos. charge is necessary for optimal GABA-A receptor recognition. Addnl. binding sites are tolerated only if they are part of a charge-delocalized amidinic or guanidinic system. If this delocalization is achieved by linking a butyric acid moiety to the N(2) nitrogen of a 3-aminopyridazine, GABA-antagonistic character is produced. The highest potency (≃250 times bicuculline) was observed when an aromatic π system, bearing electron-donating substituents, was present on the 6-position of the pyridazine ring. This study involved multiple reactions and reactants, such as 5-Phenylpyridazin-3-amine (cas: 105537-97-1Quality Control of 5-Phenylpyridazin-3-amine).

Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem

Nakagome, Takenari’s team published research in Yakugaku Zasshi in 82 | CAS: 89532-79-6

Yakugaku Zasshi published new progress about 89532-79-6. 89532-79-6 belongs to pyridazine, auxiliary class Pyridazine,Alcohol,Ether, name is (6-Methoxypyridazin-3-yl)methanol, and the molecular formula is C6H8N2O2, Computed Properties of 89532-79-6.

Nakagome, Takenari published the artcileSyntheses of pyridazine derivatives. III. Structure of 3-substituted 6-methylpyridazine N-oxides., Computed Properties of 89532-79-6, the publication is Yakugaku Zasshi (1962), 249-53, database is CAplus and MEDLINE.

3-Methylpyridazine (I) (9.7 g.) in 140 ml. AcOH, 14 ml. H₂O, and 14 ml. 30% H₂O₂ heated 8 hrs. at 80°, the AcOH removed, the residue in H₂O made alk. with Na₂CO₃, and the product extracted with CHCl₃ gave 9.3 g. liquid, b_0.5 110-13°; this in 1:1 C₆H₆CHCl₃ chromatographed through Al₂O₃ and the first eluate concentrated gave 3.9 g. I 2-oxide (II) m. 85-6° and the last effluent gave 4 g. I 1-oxide (III), m. 68-9°. Catalytic reduction of 0.1 g. II in 30 ml. MeOH with 0.5 g. 5% Pd-C absorbed 22 ml. H and gave 0.2 g. I (picrate m. 148-9°). Similarly, III yielded I. 3-Methyl-6-chloropyridazine (IV) (30 g.) and 420 ml. CHCl₃ containing 30 g. BzO₂H kept 3 days at room temperature, the solution concentrated and the residue washed with Et₂O gave 29 g. 3-chloro-6-methylpyridazine 1-oxide (V), m. 160-1°. Catalytic reduction of 2 g. V in 2 ml. 28% NH₄OH and 20 ml. H₂O at room temperature absorbed 1 mole H in 50 min. and gave 1.2 g. II, m. 85-6°; picrate m. 103-4°. 3-Methoxy-O-methylpyridazine (VI) (44 g.), 350 ml. AcOH, and 50 ml. 30% H₂O₂ kept 1 week at 40-5°, the AcOH removed, the residue in H₂O made alk. with Na₂CO₃ and the product extracted with CHCl₃ gave 41 g. VI 1-oxide (Via) m. 98-9° (AcOEt). VIa (0.7 g.) in 20 ml. 5% NaOH heated 1 hr., the solution acidified with HCl, evaporated to dryness, and the product extracted with EtOH gave 0.3 g. 6-methyl-3-pyridazinol 1-oxide, m. 201-2°. VIa (9 g.) and 60 ml. Ac₂O heated 2 hrs. at 100°, the Ac₂O removed, the residue made alk. with Na₂CO₃ and the product extracted with CHCl₃ gave 9 g. 6-methoxy-3-pyridazinemethyl acetate (VII), m. 59-61°. VI (8 g.) and 60 ml. 10% HCl refluxed 30 min. and the product treated as usual gave 4 g. 6-methoxy-3-pyridazinemethanol (VIII), m. 55-6.5°. VIII (1.6 g.), 0.8 g. SeO₂ and 25 ml. dioxane stirred 4 hrs. at 70-5°, the solution concentrated, and the residue treated with NH₂CONHNH₂ gave 6-methoxy-3-pyridazinealdehyde semicarbazone, m. 248° (decomposition).

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

Nakagome, Takenari’s team published research in Yakugaku Zasshi in 82 | CAS: 89532-79-6

Nakagome, Takenari published the artcileSyntheses of pyridazine derivatives. II. 3-Methoxy-6-pyridazinol 1-oxide, Recommanded Product: (6-Methoxypyridazin-3-yl)methanol, the publication is Yakugaku Zasshi (1962), 244-8, database is CAplus and MEDLINE.

cf. CA 55, 21134c. 3-Chloro-6-methoxypyridazine (I) (7.3 g.) in 50 mL. AcOH treated with 24 mL. 30% H₂O₂, kept 5 h. at 70°, the solution concentrated in vacuo, the residue made alk. with Na₂CO₃ and the product extracted with CHCl₃ gave 1.4 g. 3-methoxy-6-chloropyridazine 1-oxide (II), m. 157-8° (C₆H₆). The mother liquor from washing II with 2N NaOH gave 0.4 g. 3-methoxy-6(1H)-pyridazinone (III), plates, m. 162-3° (AcOEt). A solution of 18 g. BzO₂H in 337 mL. CHCI₃ treated with 14.5 g. I, kept 3 days at room temperature and the product treated as above gave 14.3 g. II, m. 157-8°. I (3 g.), 20 mL. AcOH, and 3.4 g. AcOK in a sealed tube heated 1.5 h. at 140-50° and the AcOH removed gave 3.6 g. III, m. 162-3°. III (4 g.) and 30 mL. POCl₃ heated 30 min. at 100° the product poured into ice-H₂O and extracted with Et₂O gave 1.5 g. 3,6-dichloropyridazine (IV), m. 68-9°. Catalytic reduction of 0.5 g. II in 3 mL. 28% NH₄OH and 30 mL. MeOH with 0.05 g. 10% Pd-C absorbed 77 mL. H and gave 0.35 g. 3-methoxypyridazine 1-oxide (V), m. 79-80°. Catalytic reduction of 0.5 g. II in 3 mL. 28% NH₄OH and 30 mL. MeOH with Pd-C (from 10 mL. 1% PdCl₂ and 0.5 g. C) absorbed 160 mL. H in 15 min. and gave 0.5 g. 3-methoxypyridazine; picrate m. 111°. II (3.2 g.), 12 mL. AcOH, and 1.64 g. AcONa in a sealed tube heated 1 h. at 150-60° and the product concentrated gave 1.64 g. 1-hydroxy-3-methoxy-5(1H)-pyridazinone (VI), m. 178-9°. A solution of 29.5 g. 3,6-dimethoxypyridazine I-oxide in 400 mL. 2N HCl heated 20 min. at 80-90° and the solution concentrated gave 25.3 g. VI, m. 178-9°. VI (2.8 g.), 2.54 g. BzCl, 0.46 g. Na and 30 mL. MeOH in a sealed tube heated 2 h. at 100° the solution concentrated and the residue extracted with CHCl₃ gave 3.1 g. 1-benzoyloxy-3-methoxy-6(1H)pyridazinone (VII), m. 86.5-87°. VI (2 g.), 2.5 g. MeI, Ag₂O (from 3 g. AgNO₃), and 20 mL. MeOH in a sealed tube heated 2 h. at 100° and the solution concentrated gave 100% 1,3-dimethoxy-6(1H)-pyridazinone, m. 66-7°. A solution of 250 mL. dry C₆H₆, 20.6 g. PhCH₂OH, and 4.4 g. Na, refluxed 1 h., after disappearance of Na, with 20 g. 3-chloropyridazine, and the product distilled gave 18 g. 3-benzyloxypyridazine (VIII), b_0.15 120-5°, m. 49-50°. VIII (6 g) and 84.5 mL. CHCl₃ containing 4.46 g. BzO₂H kept 2 days at room temperature gave 100% VIII I-oxide (VIIIa), m. 118-18.5°. Catalytic reduction of 0.5 g. VIIIa in 30 mL. MeOH with 0.05 g. 10% Pd-C absorbed 64 mL. H in 5 min.and gave 3-pyridazinol 1-oxide, m. 201-2° (decomposition). Catalytic reduction of 0.5 g. VIIIa in 30 mL. MeOH with 0.2 g. 10% Pd-C absorbed 128 mL. H in 15 min. and gave 0.25 g. 3(2H)-pyridazinone-H₂O, m. 74°. IV (21 g.) and 240 mL. CHCl₃ containing 18.7 g. BzO₂H kept 2 days at room temperature and the product concentrated gave 10.4 g. IV 1-oxide, m. 110-12°. IV 1-oxide (1 g.) and 0.33 g. 22.6% MeONa-MeOH heated several min. on a water bath, the solution acidified with AcOH and the product extracted with CHCl₃ gave 0.6 g. II, m. 155-7°.

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