Novel Pirfenidone Analogues: Synthesis of Pyridin‐2‐ones for the Treatment of Pulmonary Fibrosis

Abstract

A new series of polysubstituted 1-aryl-2-oxo-1,2-dihydropyridine-3-carbonitriles and pyrazolo[3,4-b]pyridine-5-carbonitriles and pyrido[2,3-d]pyrimidine-6-carbonitriles have been synthesized and tested for their antifibrotic activity. Among the tested compounds, compounds IIc and IVb exhibited higher antifibrotic activity than the standard pirfenidone PD with a reduction of the hydroxyproline level to 50 and 140 micromol/lung, respectively. However, bicyclic pyridone VIIIb displayed a high mortality rate. Detailed syntheses, spectroscopic and biological data are reported.

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

“…P. Li, Li, He, Yi, & Kaplan, 2004), Methylprednisolone (Phan, Thrall, & Williams, 1981), Prednisolone (Chaudhary, Schnapp, & Park, 2006;Entzian et al, 1998) 1986) etc. ), and Pirfenidone (Ammar et al, 2006;Gurujeyalakshmi, Hollinger, & Giri, 1999;Iyer, Gurujeyalakshmi, & Giri, 1999;Iyer, Hyde, & Giri, 2000;Iyer, Margolin, Hyde, & Giri, 1998;Iyer et al, 1995;Kakugawa et al, 2004;Mansoor, Chen, Schelegle, & Giri, 1999;Schelegle, Mansoor, & Giri, 1997). Considering the extensive number of compounds we will discuss only a few representative examples in greater detail.…”

“…Compound Name Application Reference 1 Pirfenidone analogues early (Ammar et al, 2006) (Azuma et al, 1998) 8 14-MRMLs early (Azuma et al, 2001) 9 IFN-beta early (Azuma, Li et al, 2005) 10 Taurine and Niacin early (Blaisdell & Giri, 1995) 11 EC-SOD early (Bowler, Nicks, Warnick, & Crapo, 2002) 12 Erdosteine early (Boyaci et al, 2006) 13 CME early (Breuer et al, 1995) 14 Tetrathiomolybdate early (Brewer, Ullenbruch, Dick, Olivarez, & Phan, 2003) …”

Synthesis of Novel 1‐Pyrazolylpyridin‐2‐ones as Potential Anti‐Inflammatory and Analgesic Agents

“…The 4-alkyl-2-oxo-1,2-dihydropyridine-3-carbonitrile 2 was obtained through a one-pot reaction of cyanoacetanilide 1 with acetaldehyde and malononitrile in ethanol / piperidine [7 -9]. On the other hand, reaction of 1 with different arylidenes in presence of piperidine as catalyst [10] afforded substituted 4-aryl-2-oxo-1,2-dihydropyridine-3-carbonitriles 3a-e. Cyclocondensation of 1 with acetyl acetone or benzoyl acetone in ethanol using catalytic amount of piperidine [8,9] furnished 1-pyrazolyl-4-methyl-2-oxo-6-substituted-1,2-dihydropyridine-3-carbonitriles 4a, b. It is important to emphasize that the presence of the nitrile group at the 3-position of the pyridone ring activates the methyl group at position 4.…”

“…It is important to emphasize that the presence of the nitrile group at the 3-position of the pyridone ring activates the methyl group at position 4. Condensation of the 4-methyl group of compound 4a with dimethylformamide-dimethylacetal (DMF-DMA) in xylene [8,9,11] produced the 4-enamine derivative 5. Treatment of 1 with 4-anisaldehyde afforded the aryli-dine 6 which was allowed to react in a Michael -addition fashion with cyanoacetamide or cyano-acetic acid hydrazide [12,13] [9].…”

The Utility of 1-Cyanoacetyl-4-(4-Ethoxyphenyl) Thio-Semicarbazide for Synthesis of Pyrazole, Triazole, Thiazole, Pyridine and Chromene Derivatives

“…THE UTILITY OF 1-CYANOACETYL-4-(4-ETHOXYPHENYL):,… Six-membered nitrogen heterocycles are key units in medicinal chemistry and versatile intermediates in organic synthesis [25][26][27]. Pyridones have shown various pharmacological effects such as antibacterial [28], antifungal [29], antimalarial [30], antineoplastic [31] and anti-inflammatory agents [32].…”