3- isonicotinic acid derivatives

Mecfianism of Action An isonicotinic acid derivative that interferes with RNA synthesis. Therapeutic Effect Suppresses the multiplication of mycobacteria. Pharmacokinetics Rapidly and well absorbed from the G1 tract. Protein binding 20%-30%. Widely distributed. Metabolized in the liver. Primarily excreted in urine. Removed by hemodialysis. Half-life 3-4 hr (increased in impaired renal function). 

Cyclocondensation of 3-(alkylthio)isonicotinic acid derivatives catalyzed by strong bases also provides a convenient method for thiophene ring closure. For example, treatment of isonicotinate 215 with sodium hydride produced thienopyridine 216 (1991USP4904672). Cyclization of isonicotinamide 217 in the presence of an excess of MeONa is accompanied by the nucleophilic substitution of the chlorine atom to give finally 3-hydroxy-7-methoxy-2-phenylthieno[2,3-c]pyridine (218) (1993TL2875). 

Chemical/Pharmaceutical/Other Class Isonicotinic acid derivative Antitubercular agent... 

Pyridyl)-4ff-l,2,4-triazole-3-thiol [l,2-Dihydro-5-(4-pyridinyl)-3H-l,2y4-triazole-3-thlone] [14910-06-6] M 178.2, m 301-303 (dec), 305-308 (dec), 308-313 , 320-322 (dec), 321-322 (dec), pKes,(d 3.5 (py N), pKj stp) 9 (SH). This thio-l,2,4-triazole was prepared and purified as for the 3-pyridyl-isomer above but by using isonicotinic acid derivatives. It has mild diuretic and natriuretic activity. [Blackman et al. J Chem Soc C 661 1967, Beyerman et al. Rec Trav Chim Pays Bas 73 109 1954, Yale Piala JMeJ Chem 9 42 1966, Yoshida Asai J Pharm Soc Jpn 74 948 1954, Chem Abstr 49 10937 1955, Beilstein 26 IV 2129], 5-(4-Pyridyl)-4H-l,2,4-triazole-3-sulfonic add hydrate was obtained by oxidising the 3-thiol with saturated aqueous KMn04 25° (1 hour), decomposed with EtOH, filtered, precipitated as the Ag salt, filtered off, and decomposed with 5% HCl, then evaporated, and the residue was recrystallised from H2O. It decomposed on heating. [Blackman et al. J Chem Soc C 661 19677 ... 

A comprehensive study of the solubility of riboflavin in a range of hydrotropes [295] revealed some interesting differences due to structural changes in the hydrotrope (Table 6.31). The effect of a range of nicotinic acid and isonicotinic acid derivatives was not affected by the structure of the side chain to any great extent, but alterations to the hydrophobic radical proved more startling 3-hydroxy-2-naphthoic acid and its mono-ethanolamide has approximately ten times the effect of salicylic acid and its mono-ethanolamide. 

The des-ethyl derivative 251 of Flavopereirine was prepared similarly starting from 2-chloro isonicotinic acid methyl ester 250 (Scheme 81). The resulting hydrochloride was converted into the pseudo-cross-conjugated... 

With N,0 mixed donor ligands several complexes have been reported with ligands such as 4,5-dichloro-2-cyano-3,6-dione-l,4-cyclohexen-l-ol,1445 isonicotinic acid,1446 p-aminobenzoic acid,1447 alanine, histidine or histamine derivatives,1448-1450 [N(0)C(CN)2]-,1451 pyridine-carboxylate derivatives, 1452 1454 [N(pph20)2] (263),1455 bis(sulfonyl)amide derivatives,1456,1457 tris(pyridyl)-... 

The TMS derivative of 4-picolinic acid (isonicotinic acid) was identified in the TMS-treated reaction mixture from the UV-ozonation of paraquat. This suggests a sequence of reactions, in which Slade (10), Funderburk et al, (11), and others have made... 

Ethionamide (Trecator) is a derivative of isonicotinic acid and is chemically related to isoniazid. It is a secondary agent used in combination when primary agents are ineffective or contraindicated it is a bacteriostatic antituberculosis agent. Its exact mechanism of action is unknown but is believed to involve inhibition of oxygen-dependent mycolic acid synthesis. It is thought that mutations in the region of the (tnhA) gene that are involved in mycolic acid synthesis can cause both isoniazid and ethionamide resistance. 

Mechanism of Action An isonicotinic acid hydrazide (INH) derivative that inhibits my-colic acid synthesis and causes disruption of the bacterial cell wall and loss of acid-fast properties in susceptible mycobacteria. Active only during bacterial cell division. Therapeutic Effect Bactericidal against activelygrowingintracelleluar and extracellular susceptible mycobacteria. 

There has been some exploration of the mechanism of reduction of d transition metal complexes by M2+(aq) (M = Eu, Yb, Sm). Both inner- and outer-sphere mechanisms are believed to operate. Thus the ready reduction of [Co(en)3]3+ by Eu2+(aq) is necessarily outer-sphere. 2 However, the strong rate dependence on the nature of X when [Co(NH3)5X]2+ or [Cr(H20)5X]2+ (X = F, Cl, Br or I) are reduced by Eu2+(aq) possibly suggests an inner-sphere mechanism.653 The more vigorous reducing agent Yb2+ reacts with [Co(NH3)6]3+ and [Co(en)3]3+ by an outer-sphere route but with [Cr(H20)5X]2+ (X = halide) by the inner-sphere mechanism.654 Outer-sphere redox reactions are catalyzed by electron-transfer catalysts such as derivatives of isonicotinic acid, one of the most efficient of which is iV-phenyl-methylisonicotinate, as the free radical intermediate does not suffer attenuation through disproportionation. Using this catalyst, the outer-sphere reaction between Eu2+(aq) and [Co(py)(NH3)5]3+ proceeds as in reactions (18) and (19). Values found were ki = 5.8 x KFM-1 s 1 and k kx = 16.655... 

Isoniazid (isonicotinic acid hydrazide), a drug frequently used to treat tuberculosis, can induce a B6 deficiency by forming an iiactive derivative with pyridoxal phosphate. Dietary supplementation with B is, thus, an adjunct to isoniazide treatment. Otherwise, cletary deficiencies in pyridoxine are rare but have been observed in newborn infants fed formulas low in vitamin B6, in women taking oral contraceptives, and in alcoholics. 

Analogously, thiosemicarbazides 91-96, derived from d- and L-arabinose, have been synthesized.72 Treatment of isonicotinic acid hydrazide (97) with... 

Groups of reportedly photochromic systems which deserve further study include (a) disulfoxides (123,124), (b) hydrazones (125-129), (c) osazones (130-133), (d ) semicarbazones (134-143), (e) stilbene derivatives (144), (/) succinic anhydrides (145-148), and (g) various dyes (149,150). A number of individual compounds also remain unclassified as to their mechanism of photochromic activity. These include o-nitro-benzylidine isonicotinic acid hydrazide (151), 2,3-epoxy-2-ethyl-3-phenyl-1-indanone (152), p-diethyl- and p-dimethyl-aminophenyli-minocamphor (153), brucine salts of bromo- and chloro-nitromethionic acid (154), diphenacyldiphenylmethane (155,156), 2,4,4,6-tetraphenyl-1,4,-dihydropyridine (155,156), 2,4,4,6-3,5-dibenzoyltetrahydropyran (155,156), o-nitrobenzylidenedesoxybenzoin (157), p-nitrobenzylidene-desoxybenzoin (157), N-(3-pyridyl)sydnone (158,159), tetrabenzoyl-ethylene (160), and the oxidation product of 2,4,5-triphenylimidazole (161,162). 

A number of exogenously applied chemicals, including polyacrylic acid, acetylsalicylic acid, salicylic acid and isonicotinic acid (NA) derivatives, have also been shown to induce resistance. Usually the resistance is localised to the treated parts of the plants (Gianinazzi Kassanis, 1974 White, 1979), but in the IN A compounds the resistance can be systemic (Metraux et al., 1991). These observations led to the suggestion that SAR might provide a new strategy for crop protection, either by discovering... 

Attempts to use nicotinic acid, isonicotinic acid and some derivatives in a manner similar to that described above for the corresponding amides and oximes... 

A group of l,3,4-oxadiazolin-5-ones and l,3,4-oxadiazoline-5-thiones show antitubercular activity.18,43a 76,84 86,181, 132,157 160 They have been investigated with regard to their mode of action. 2-(4 -Pyridyl)-l,3,4-oxadiazolin-5-one (S 57) has shown itself active against Mycobacterium tuberculosis and Mycobacterium leprae.86-158 It possesses some advantages compared with isonicotinic acid hydrazide. Derivatives of S 57 also have some tuberculostatic activity.159, lfl1,162 Further tuberculostatic compounds are derived from p-aminosalicylic acid, for example WS 127 [2-(4 -amino-2 -hydroxyphenyl)-l,3,4-oxadiazoline-5-thione] and WS 174 [2-(4 -acetamido-2 -hydroxyphenyl)-l,3,4-oxadiazolin-5-one].85 2-Cyano-methyl-l,3,4-oxadiazolin-5-one shows a tuberculostatic activity comparable with that of Reazid. 18 Oxadiazolin-5-ones and oxa-... 

Certain drug therapies (e.g. isoniazid) can lead to niacin deficiency. Isoniazid (the hydrazide derivative of isonicotinic acid) is the primary drug for chemotherapy of tuberculosis. 

Isoniazid, one of the most active of the tuberculostatic drugs, was discovered because it had been shown that nicotinamide exerted some tuberculostatic action (J). A deliberate search for more effective but related chemicals revealed that many pyridine derivatives, including congeners of isonicotinic acid, also were active. Further, it was known that the thiosemicarbazones could inhibit the growth of M. tuberculosis. An attempt to synthesize the thiosemicarbazone of isonicotinaldehyde provided, as the first intermediate compound, isonicotinylhydrazine, or isoniazid. 

USE Manuf isonicotinic acid and derivatives. In waterproofing agents for fabrics. As solvent for resins. 

Palladium on carbon has been used successfully to obtain piperi-dine-2-carboxylic in almost quantitative yield after reduction of picolinic acid in aqueous solution at 60° and 3 atm pressure (53). The time of reduction, however, is much longer than with rhodium or platinum catalyst. Since there is always a difference in reduction time between the 2- and 4-derivatives, hydrogenation of isonicotinic acid should be prohibitively long at low pressure with palladium. However, if pressure equipment is available, reaction time should be decreased considerably. 

Pyridine is a tertiary amine its aqueous solution shows an alkaline reaction and precipitates the hydroxides of metals, some of which are soluble in an excess of the amine. Salts of pyridine like those of other amines form characteristic double salts with metallic halides. The ferrocyanide of pyridine and the addition-product of pyridine and mercuric chloride are difficultly soluble in water these compounds are used in the purification of the base. Pyridine is a very stable compound it can be heated with nitric acid or chromic acid without undergoing change but at 330° it is converted by a mixture of nitric acid and fuming sulphuric acid into nitropyridine, a colorless compound that melts at 41° and boils at 216°. At a high temperature pyridine is converted into a sulphonic acid by sulphuric acid. Chlorine and bromine form addition-products, e.g., C5H5N.CI2, at the ordinary temperature when these are heated to above 200°, substitution-products are formed. The hydroxyl derivative of pyridine is made by fusing the sulphonic acid with sodium hydroxide it resembles phenol in chemical properties. The three possible carboxyl derivatives of pyridine are known. The a-acid is called picolinic acid, the jS-acid nicotinic acid (664), and the 7-acid isonicotinic acid. 

Homologues of Pyridine.—Many homologues of pyridine have been obtained from bone-oil and coal-tar or by syntheses from other compounds. The methyl derivatives of pyridine are called picoUneSy the dimethyl derivatives are called lutidines, and the trimethyl derivatives are called collidines. As in the case of toluene and the xylenes, the side-chains are converted into carboxyl groups by oxidation. The a, /S, and 7 mono-carboxylic acids of pyridine are called picolinic acid, nicotinic acid, and isonicotinic acid, respectively. 

Pyridine derivatives are important as pharmaceuticals. Nicotinic acid derivatives are used as vasodilators, anticoagulants and hypolipidaemic agents. Derivatives of isonicotinic acid (pyridine-4-carboxylic acid) such as isoniazide 215 and ethionamide 216 are used as tuberculostatics, and of 2-benzylpyridine in the form of pheniramine 217 as antihistamine. 

Robitzek, E.H., Selikoff, J. and Omstein, G.G. (1952) Chemotherapy of human tuberculosis with hydrazine derivatives of isonicotinic acid, (preliminary report of representative cases). Quart. Bull. Sea View Hasp. 13 27-51. 

---