6274-82-4

Usage

Uses

Used in Pharmaceutical Industry:
2,6-Dimethoxyisonicotinic acid is used as a key intermediate in the synthesis of various pharmaceuticals for its potential biological activities, including anti-tumor and anti-inflammatory effects. Its unique structure allows for the development of novel drugs with improved therapeutic properties.
Used in Agrochemical Industry:
2,6-Dimethoxyisonicotinic acid is used as a building block in the synthesis of agrochemicals, contributing to the development of effective and environmentally friendly pesticides and other agricultural products.
Used in Medicinal Chemistry Research:
2,6-Dimethoxyisonicotinic acid serves as a valuable compound in medicinal chemistry research, where its structural features and potential biological activities are explored for the design and development of innovative bioactive molecules with therapeutic applications.
Used in Drug Development:
2,6-Dimethoxyisonicotinic acid is utilized in drug development as a versatile platform for the functionalization and modification of its structure, enabling the creation of new compounds with enhanced pharmacological properties and targeted therapeutic effects.

InChI:InChI=1/C8H9NO4/c1-12-6-3-5(8(10)11)4-7(9-6)13-2/h3-4H,1-2H3,(H,10,11)

Upstream product

• 5398-44-7 2,6-dichloropyridine-4-carboxylic acid 
• 67-56-1 methanol 
• 124-41-4 sodium methylate 

Downstream Products

• 91013-20-6 2,6-dimethoxy-isonicotinic acid ethyl ester 
• 1312559-48-0 (S)-2,6-dimethoxy-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)isonicotinamide 
• 52606-01-6 2,6-dimethoxy-4-pyridinecarboxaldehyde 
• 717871-77-7 2,6-dimethoxyisonicotinoyl chloride 

Relevant academic research and scientific papers

Potent colchicine-site ligands with improved intrinsic solubility by replacement of the 3,4,5-trimethoxyphenyl ring with a 2-methylsulfanyl-6-methoxypyridine ring

Colchicine site antimitotic agents typically suffer from low aqueous solubilities and are formulated as phosphate prodrugs of phenolic groups. These hydroxyl groups are the aim of metabolic transformations leading to resistance. There is an urgent need for more intrinsically soluble analogues lacking these hydroxyl groups. The 3,4,5-trimethoxyphenyl ring of combretastatin A-4 is a liability in terms of solubility but it is considered essential for high cytotoxic and tubulin polymerization inhibitory (TPI) activity. We have synthesized 36 new analogues of combretastatin A-4 replacing the trimethoxyphenyl moiety with more polar pyridine based moieties, measured their aqueous solubility, and studied their anti-proliferative effects against 3 human cancer cell lines. We show here that pyridine rings can be successful replacements for the trimethoxyphenyl ring, resulting in potent and more soluble analogues. The more straightforward replacement, a 2,6-dimethoxypyridine ring led to inactive analogues, but a 2-methoxy-6-methylsulfanylpyridine moiety led to active analogues when combined with different B rings. This replacement led to potent cytotoxic activity against sensitive human cancer cell lines due to tubulin inhibition, as shown by cell cycle analysis, confocal microscopy, and tubulin polymerization inhibitory activity studies. Cell cycle analysis also showed apoptotic responses following treatment. Docking studies suggested binding at the colchicine site of tubulin and provided a good agreement with the observed SAR. A 2-methoxy-6-methylsulfanylpyridine moiety is a good trimethoxyphenyl ring replacement for the development of new colchicine site ligands.

ANTIBACTERIAL COMPOUNDS AND METHODS OF USE

The present invention generally relates to pyridine derivatives of formula (I) with antibacterial activity, especially anti-tuberculosis activity, and pharmaceutical compositions containing them. Methods of using the compounds to treat bacterial infections, especially tuberculosis infections, are also described.

TBAJ-876, a 3,5-dialkoxypyridine analogue of bedaquiline, is active against Mycobacterium abscessus

Lung disease caused by Mycobacterium abscessus is very difficult to cure, and treatment failure rates are high. The antituberculosis drug bedaquiline (BDQ) is used as salvage therapy against this dreadful disease. However, BDQ is highly lipophilic, displays a long terminal half-life, and presents a cardiotoxicity liability associated with QT interval prolongation. Recent medicinal chemistry campaigns resulted in the discovery of 3,5-dialkoxypyridine analogues of BDQ which are less lipophilic, have higher clearance, and display lower cardiotoxic potential. TBAJ-876, a clinical development candidate of this series, shows attractive in vitro antitubercular activity and efficacy in a murine tuberculosis model. Here, we asked whether TBAJ-876 is active against M. abscessus. TBAJ-876 displayed submicromolar in vitro activity against reference strains representing the three subspecies of M. abscessus and against a collection of clinical isolates. Drug-drug potency interaction studies with commonly used anti-M. abscessus antibiotics showed no antagonistic effects, suggesting that TBAJ-876 could be coadministered with currently used drugs. Efficacy studies, employing a mouse model of M. abscessus infection, demonstrated potent activity in vivo. In summary, we demonstrate that TBAJ-876 shows attractive in vitro and in vivo activities against M. abscessus, similar to its BDQ parent. This suggests that next-generation BDQ, with improved tolerability and pharmacological profiles, may be useful for the treatment of M. abscessus lung disease in addition to the treatment of tuberculosis.

Synthetic studies to help elucidate the metabolism of the preclinical candidate TBAJ-876—a less toxic and more potent analogue of bedaquiline

Bedaquiline is a novel drug approved in 2012 by the FDA for treatment of drug-resistant tuberculosis (TB). Although it shows high efficacy towards drug-resistant forms of TB, its use has been limited by the potential for significant side effects. In particular, bedaquiline is a very lipophilic compound with an associated long terminal half-life and shows potent inhibition of the cardiac potassium hERG channel, resulting in QTc interval prolongation in humans that may result in cardiac arrhythmia. To address these issues, we carried out a drug discovery programme to develop an improved second generation analogue of bedaquiline. From this medicinal chemistry program, a candidate (TBAJ-876) has been selected to undergo further preclinical evaluation. During this evaluation, three major metabolites arising from TBAJ-876 were observed in several preclinical animal models. We report here our synthetic efforts to unequivocally structurally characterize these three metabolites through their independent directed synthesis.

Macrocyclic Compounds Useful as Bace Inhibitors

The invention relates to novel macrocyclic compounds of the formula (I), in which all of the variables are as defined in the specification, the number of ring atoms included in the macrocyclic ring being 14, 15, 16 or 17, in free base form or in acid addition salt form, to their preparation, to their use as medicaments and to medicaments comprising them.