Pyridinyl Compounds

5-Dibromopyridine (21.1 mmol) and sodium ethoxide (42.2 mmol) were dissolved in 10 ml N,N-dimethylformamide and heated to 65 °C. 15 hours. The mixture was poured into 70 ml water, 155 ml diethyl ether added, and then filtered. The layers was separated, extracted with additional diethyl ether, and combined. The extracts were dried, concentrated, purified by vacuum distillation, and 17.9% product isolated, bp = 105 °C at 5mmHg. H- and C-NMR data supplied. 

3-Buten-l-ol (2.0 mmol), the product from Step 1 (2.1 mmol), palladium(II) acetate (0.02 mmol), tri-o-tolylphosphine (0.08 mmol) and 0.5 ml triethylamine were mixed in 1 ml acetonitrile and refluxed for 21 hours. Thereafter, the mixture was diluted with 10 ml water and extracted with CH2CI2. The combined extracts were dried, concentrated, purified by chromatography on silica gel using a gradient of 100% methyl alcohol to methyl alcohol/ 8% EtOAc, and the product isolated in 66.3% yield. H- and C-NMR data supplied. 

The product from Step 2 (1.24 mmol) was dissolved in 1ml CH2CI2 containing 1 drop pyridine, tosyl chloride (1.36 mmol) added, and the mixture stirred 12 hours. Thereafter, 

The 4-substituted analogue of the current invention, (E)-4- 4-[2-(4-pyridinyl)-ethenyl]-phenoxy -butyric acid ethyl ester, (I), was also prepared by the author and is discussed. 

The preparation of amine analogues of the product of Step 3, (E)-N-methyl-4-[3-(5-ethoxypyridin)yl]-3-buten-l-amine, (II), and derivatives is described (2). 

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Reaction between 2-chIoronicotinic acid (130) and 2-amino-4-phenyl-thiazole furnishes 3-phenyl-5-H-pyrido[2,3,-d]thiazolo[3.2-fl]pyximidin-5-one (131) (Scheme 86) (293). This reaction was extended to other pyridinyl compounds (294). 

Extraction data of alkali metals with the picrate method have shown that pyridinyl compounds are better ionophores than their A-oxide counterparts (deleterious role of hydrogen bonding between A-oxide functionalities and water molecules). The highest phase-transfer values are observed for cone conformers, where selectivity follows the order Na" " > K" " > Rb" " > Cs" " > Li. In aprotic solvents A-oxide ligands are much stronger complexers, and alkali and lanthanide metal complexes have been prepared and characterized. The Eu(III) and Tb(III) complexes of tetra-A-oxide cone conformer are fluorescent upon UV light excitation at 312 nm. Unfortunately, these complexes totally lose their luminescence upon addition of water, indicating their modest stability in aqueous medium [56,57]. 

There is insufficient evidence to unequivocally link nitrosamine exposure to elevated risk for human cancer (159). There are, however, a number of specific cases, especially with respect to the tobacco-related nitrosamines, in which exposure to V/-nitroso compounds is of concern. The strongest evidence in this context is probably that relating to oral cancer rates among habitual users of smokeless tobacco (snuff). Oral cancer rates among this group are significantly elevated over those of nonusers, and /V-nitrosonornicotine, and 4-(methylnitrosamino)-l-(3-pyridinyl)-l-butanone [64091 -91 both of... 

Many other reactions of ethylene oxide are only of laboratory significance. These iaclude nucleophilic additions of amides, alkaU metal organic compounds, and pyridinyl alcohols (93), and electrophilic reactions with orthoformates, acetals, titanium tetrachloride, sulfenyl chlorides, halo-silanes, and dinitrogen tetroxide (94). 

The most extensive development of pharmacological inhibitors of MAPK cascades members has been for p38 (Table 1) [3]. Small-molecule inhibitors have been developed for two p38 isoforms (a and (3). Pyridinyl imidazole compounds have been known to block inflammation since the early 1970s. Structural analyses have revealed that p38 kinase inhibitors binds to the ATP-binding pocket of p38 thereby acting as competitive inhibitors. The p38 kinase inhibitor SB202190 is able to bind both the low-activity nonphosphorylated... 

Hoveyda and coworkers [142] developed the Cu-catalyzed allylic substitutions of phosphonate derivatives with pyridinyl peptide structures as efficient ligands. The structure of the ligands was chosen through synthesis, and analysis of libraries. Optimized compounds were used as ligands for the... 

Bowl-shaped coordination compounds have been assembled spontaneously from 10 small components, such as six (en)Pd2+ units and four 2,4,6-tri(3-pyridinyl)triazene moieties the overall structure approaches 3oA <00JA2665>. A different construct was derived from the 4-pyridinyl isomer and Pt(bpy)2+ and shown to facilitate self-assembly within the coordination... 

Yu and coworkers reported the design and synthesis of a series of conductive OPEs possessing a ferrocene and thiol at each terminus [101]. The solubility is achieved by substitution at the phenyl groups with methyl and propoxy substituents (67). Several new reactions for preparing novel arenethiol-protected compounds (e.g., 2-(4-pyridinyl)ethyl-4 -(ethyl)phenyl sulfide) are reported. 

Anabaseine (201) Tetrahydro-pyridinyl pyridine derivative (a nicotinic compound) 3-(2,4-Dimethoxy benzylidene)-anabaseine (DMXBA GTS-21) (202) Neurology (Alzheimer s disease) Enhances cognition it acts as a partial agonist at neural nicotinic acetylcholine receptors. It binds to both the o4p2 and a subtypes, but activates only the a to a significant extent Phase I/II CoMentis 927-933... 

A series of novel 4-substituted-l,4-dihydroquinolines 140 were prepared and found to exhibit moderate to excellent mammalian topo II inhibitory activity. Among the compounds prepared, in general, the nitrogen analogues are the most active compounds and the sulfur analogue is the least active one. The most potent analogue 140 (X=NH-2-pyridinyl), had a topo II potency nearly equivalent to VP-16, a clinically useful topo II interactive antitumor agent, q. (55) [197]. 

Substantially fewer studies have been published for the reactions of alkyl-substituted heteroaromatics, although these compounds also have implications for coal combustion. Several references discussed in the previous section contain information on methylated heteroaromatic rings. Mackie and coworkers completed experimental and theoretical studies of the pyrolytic decomposition of 2-picoline (2-methylpyridine). They concluded that decomposition proceeded mainly through o-pyridinyl and 2-picolinyl radicals. The former tended to decompose predominantly to yield cyanoacetylene, while the latter favored decomposition to a cyano-functionalized cyclopentadiene (Fig. 16). 

Pyrrolo[2,3-/ ]pyridinones react with diethyl cyanomethanylphosphonate to give two different products, depending on the substitution pattern of the starting material. For compounds without substituents in the 2-position, pyrrolo[2,3-3]-pyridinyl acetonitriles, 55, are produced. When the nitrogen atom is protected with a pivaloyl group, alkenyl nitriles, 56, are formed (Scheme 2) <2001T1995>. 

In a rearrangement reaction, 2-hydroxy-2-phenyl-2-(3-pyridinyl)acetic hydrazide, 102, reacts with methanesulfonyl chloride to generate a mixture of pyrrolo[2,3-. ]pyridine derivatives (Equation 42) <1998JHG145>. The proposed mechanism for the rearrangement involves intramolecular attack of compound 102 on a reactive pyridinium intermediate formed during the reaction. 

Thiazoles are less electron-rich isosteres of pyridines and therefore it was speculated that compounds with such substitution may have improved metabolic stability [30]. The modeling of A-82200 in which the N-terminal pyridinyl group was substituted by a 4-thiazolyl moiety indicated that the 5-membered ring binds in the S3 subsite and can be further derivatized at the 2 position by an isopropyl group. The isopropyl functionality makes van der Waals contacts with Val82 and fills the hydrophobic part of the S3 subsite in nearly optimal fashion. 

Heteroaryl radicals, generated by aprotic diazotization of heteroarylamines, have been reacted with thiophene to form the heterylthiophenes in 20-50% yields (75JOC3183, 78HCA2941). The 2/3 isomer ratio was generally about 85 15. Other heterylthiophenes have been prepared by photolysis of the iodoheteroaromatic compound in a solution of thiophene in acetonitrile thus the 2-(5-pyrimidinyl)thiophene (224) was obtained in 58% yield (with 2% of the 3-isomer) (77JCS(Pl)62l) and 2-(3-pyridinyl)thiophene (225) in 42% yield (2/3 isomer ratio 7 1) (72CC594). 

Omeprazole is obtained [15] by the reaction of acetyl ethyl propionate 1 with ammonia to give ethyl -3-amino-2,3-dimethyl acrylate 2. Compound 2 was converted to to 2,4-dihydroxy-3,5,6-trimethyl pyridine 3 by treatment with methyl diethylmalonate. Treatment of compound 3 with phosphorous oxychloride produced 2,4-dichloro-3,5/6-trimethyl pyridine 4. 4-Chloro-3/5,6-trimethyl pyridine 5 was obtained by treatment of compound 4 with hydrogen. On treatment of compound 5 with hydrogen peroxide and acetic acid, 4-chloro-3,5,6-trimethyl-pyridine-N-oxide 6 was produced. Treatment of compound 6 with acetic anhydride gave 4-chloro-2-hydroxymethyl-3,5-dimethyl pyridine 7 which was converted to 2-hydroxymethyl-3,5-dimethyl-4-methoxypyridine 8 by treatment with sodium methoxide. Compound 8 was treated with thionyl chloride to produce 2-chloromethyl-3,5-dimethyl-4-methoxypyridinc 9. Compound 9 interacts with 5-methoxy-2-mercaptobenzimidazole to give 5-methoxy 2-[((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio]-lH-bcnzimidazole 10 which is oxidized to omeprazole 11. 

Methyl-l-penten-3-one-l-ol 1 and glacial acetic acid in benzene was added to pyrrolidine to give 2-methyl-l-pen ten-1-[N-pyrrolidinyl]-3-one 2. Compound 2 when treated with oxalyl chloride and methanol was added, 3,5-dimethyl-2-methoxycarbonyl-4-pyrone 3 was produced. Treatment of compound 3 with sodium borohydride in methanol gives 3,5-dimethyl-2-hydroxymethyl-4-pyrone 4. Compound 4 was converted to 3,5-dimethyl-2-hydroxymethyl-4-pyridone 5 by heating compound 4 with aqueous ammonia in a sealed flask. Compound 5 was converted to 4-chloro-2-chloromethyl-3,5-dimethyl pyridine 6 by treatment with phosphorous oxychloride. Treatment of compound 6 with 5-methoxy-2-mer-captobenzimidazole in tetrahydrofuran gave 2-[2-(4-chloro-3,5-dimethyl pyridinyl)methylthio]-5-methoxy benzimidazole 7. When compound 7 was treated with potassium hydroxide in dimethyl sulfoxide containing methanol, 2-[2-(3,5-dimethyl-4-methoxypyridinyl)methylthio]-5-methoxy... 

A suspension of the diazonium salt in toluene was gradually heated and kept at 120°C (bath temp.) for 30 minutes with stirring. After evaporation of the solvent under reduced pressure, the residue was made alkaline with 10% sodium carbonate and then extracted with chloroform. The chloroform extract was dried over anhydrous potassium carbonate. After evaporation of the solvent, the crystalline residue was recrystallized from ethyl acetate to give 6-acetylamino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-fluoropyridine (mp 132°-133°C). The 3-fluoro derivative was hydrolyzed with a mixture of 15% hydrochloric acid and methanol (1 2 v/v) to give 6-amino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-fluoropyridine. This compound was treated with diethyl ethoxymethylenemalonate at 130°-140°C to give N-[2-(4-ethoxycarbonyl-l-piperazinyl)-3-fluoro-6-pyridinyl]aminomethylenemalonate (mp 144°-145°C) and then the product was cyclized by heating at 255°C to give ethyl 7-(4-ethoxycarbonyl-l-piperazinyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate (mp 279°-281°C). 

There has been considerable interest in the thienothiazine ring system from the pharmaceutical and pharmacological view point since 1976 when tenoxicam (4-hydroxy-2-methyl-7V-2-pyridinyl-2//-thieno[2,3-c]-l,2-thiazine-3-carboxamide-1,1-dioxide) (376) was patented by Hoffmann-La Roche as an antiinflammatory agent. Since then there have been hundreds of references to analogues, and to related compounds, and their pharmacological action, metabolism, and analytical methods for these compounds. It would be beyond the scope of this chapter to attempt to review these data. 

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