Isonicotinic acid hydrazine

The three standard drugs used in the treatment of tuberculosis were streptomycin (considered above), -aminosalicylic acid (PAS) and isoniazid (isonicotinylhydrazide, INH synonym, isonicotinic acid hydrazine, INAH). The tubercle bacillus rapidly becomes resistant to streptomycin, and the role of PAS was mainly that of preventing this development of resistance. The current approach is to treat tuberculosis in two phases an initial phase where a combination of three dmgs is used to reduce the bacterial level as rapidly as possible, and a continuation phase in which a combination of... 

A) The pharmacological properties of the drug (hydralazine, diphenylhydantoin, procainamide, isonicotinic acid hydrazine and possibly sulphonamides)... 

Haber E, Osborne LRK (1959) Icterus and febrile reactions in response to isonicotinic acid hydrazine. Report of two cases and review of the hterature. N Engl J Med 260 417 Haegi V (1975) Neuere Gesichtspunkte zur Tuberkulosetherapie. Schweiz Med Wochenschr 105 245... 

Pharmaceuticals. The tuberculostatic dmg isoniazid [54-85-3] (60), the hydrazide of 4-pyridinecarboxyhc acid, was one of the eadiest hydrazine-based dmgs introduced in the United States. It is made by the reaction of hydrazine and an isonicotinic acid ester (219). 

A variety of miscellaneous derivatives of gulonolactone has been reported. Linn treated D-glucofuranurono-6,3-lactone (7) with chlorobenzene and aluminum trichloride in order to obtain115 6-deoxy-6,6-diphenyl-L-gulonic acid (70). Various related compounds were also prepared. When 7 was treated with sulfur dioxide and 2-(isonicotin-oyl)hydrazine in water, 6-deoxy-6-(2-isonicotinoylhydrazino)-6-sulfo-D-gulono-1,4-lactone (71) was formed in 81% yield.116,117 Kawabata... 

Kelly MG et al Comparative carcinogenic-ity of -isopropyl- -(2 -methylhydrazino)-p-tolu-amide HCl (procarbazine hydrochloride), its degradation products, other hydrazines, and isonicotinic acid hydrazide. J Natl Cancer Inst 42 337-344, 1969... 

Isoniazid Isoniazid, isonicotinic acid hydrazide (34.1.1), is synthesized by reacting ethyl ester of isonicotinic acid with hydrazine [1-5]. 

GABA synthesis inhibitors act on the enzymes involved in the decarboxylation and transamination of GABA. Glutamic acid decarboxylase (GAD), the first enzyme in GABA biosynthesis, is inhibited easily by carbonyl reagents such as hydrazines [e.g., hydrazinopropionic acid (4.164) or isonicotinic acid hydrazide (4.165)], which trap pyridoxal, the essential cofactor of the enzyme. A more specific inhibitor is allylglycine (4.166). All of these compounds cause seizures and convulsions because they decrease the concentration of GABA. 

The drug isoniazid (isonicotinic acid hydrazide) is hydrolyzed in vivo to the corresponding acid and hydrazine, as shown in Figure 4.45. Hydrazine is toxic and could be responsible for... 

Methyl acrylate, 28.0 g (0.4 mol) was added dropwise during one hour to a solution containing 54.8 g (0.4 mol) of isonicotinic acid hydrazide (isoniazid) and 10 ml of glacial acetic acid in 400 ml of tertiary butyl alcohol. The resulting solution then was heated for 18 hours on a steam bath. Concentration of the reaction mixture to 100 ml yielded 13.0 g of unreacted isonicotinic acid hydrazide. The filtrate was concentrated to a thick syrup which was triturated with anhydrous ether and recrystallized from isopropyl alcohol MP 87°C to 88.5°C. Elemental analysis of the product gave 1-isonicotinyl-2-(p-carbomethoxyethyl)hydrazine. 

Isonicotinic acid hydrazide (isoniazid 275), a drug used in treating tuberculosis269, has been 1 -labelled264 by introduction of a [nC]cyano group at the 2-position of the pyridine ring of l-methoxy-4-methoxcarbonyl pyridinium methyl sulphate and subsequent treatment of the 1 -labelled methyl ester 276 with hydrazine hydrate. The reaction has been carried out on a solid support (silica gel) to yield methyl 2[11C]cyano-isonicotinate in 32.4+12% (EOB) yield. 275 was obtained in 10% (EOB), radiochemical... 

Ammonium hexanitratocerate(IV) as a standard oxidant for reactions at room temperature has been developed for several substances. " Oxalate can be titrated with Ce(IV) in 0.5 M HNO3 with an iodide catalyst mandelic acid at a lower acid concentration, 0.1 MHNO3 Mn(II) with excess Ce(TV) in 0.5 to 2M HNO3 with silver nitrate catalyst hydrazine or isonicotinic acid in HCl-KBr solution and As(III) in HCl, HNO3, or H2SO4 solution with a trace of iodine as catalyst. 

Fenske, M. Determination of cortisol in plasma and urine by thin layer chromatography and fluorescence derivatiza-tion with isonicotinic acid and hydrazine. Chromatographia... 

Isoniazid, U5P. Isonicotinic acid hydru/.ide. isonicoti-nyl hydrazide. or INH (Nydrazid) (K curs as a nearly culoi-less crystalline solid that is very soluble in water. It is prepared by reacting the methyl ester of isonicotinic acid iih hydrazine. 

Isonicotinic acid hydrazide (isoniazid) and its N-isopropyl analog, iproniazid, were used as antitubercular drugs in the early 1950s. Independent reports showed that iproniazid (but not isoniazid) exhibited CNS stimulant properties in TB patients and had the ability to inhibit the enzyme MAO. Reports showed that the expected depressant effect of reserpine in animals could be prevented (reversed ) by pretreatment with iproniazid and resulted in CNS stimulation. In fact, NE s and 5-HT s neuronal depletion produced by reserpine was actually blocked by this pretreatment. This work, then, led to the proposal that the clinical antidepressant efficacy of iproniazid (and related MAO inhibitors synthesized in the interim) resulted from the increased levels of NE and 5-HT, which were allowed to rise because of MAO inhibition. Many other hydrazine and hydrazide variants were soon introduced into clinical use. 

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. 

This technique has also been used to add a cyano group to an aromatic ring. l-Methoxy-4-methoxycarbonyl pyridinium methyl sulphate was absorbed on silica gel particles. After these particles had been dried under vacuum, they were placed in a column and H CN was passed through the column. Then the column was sealed and heated at 40 °C for 5 minutes. After the methyl-2[ C]cyano-isonicotinate had been purified by HPLC chromatography, it was converted into 2-[ C]-isonicotinic acid hydrazide in a 30% radiochemical yield by treatment with hydrazine in anhydrous ethanol (equation 78). The synthesis took 30 minutes to complete. 

Some examples of free-radicals generated by the bioactivation of drug molecules are shown in Fig. 10.31. Isoniazid is acetylated to its major metabolite acetylisoniazid, which is hydrolyzed to acetylhydrazine and isonicotinic acid (Fig. 10.31-1). Acetylhydrazine is further metabolized by the CYP2E1 to an N-hydroxy intermediate that hydrates into an acetyl radical, which can then initiate the process that leads to hepatic necrosis. Other carbon-centered radicals are formed from hydrazines such as the antihypertensive hydralazine, and thio-radicals from the ACE inhibitor captopril (Fig. 10.31-2 and -3). 

An extensive series of derivatives of nicotinaidehyde, isonicotinaidehyde, and substituted isonicotinic acid hydrazide have been prepared and investigated for their tubercuiostatic activity, isoniazid hydrazones were found to possess activity, but these compounds were shown to be unstabie in the gastrointestinai (Gi) tract, reieasing the active isonicotinic acid hydrazide (i.e., iNH). Thus, it wouid appear that their activity resuited from the iNH and not from the derivatives (17,18). Substitution of the hydrazine portion of iNH with aikyi and araikyi substituents resuited in a series of active and inactive derivatives (19,20,21,22). 

Aq. NaOH added dropwise with stirring and heating to isonicotinic acid nitrile and water, boiled 1 hr., 48%-hydrazine hydrate added dropwise during 1 hr., and boiled 3 hrs. isonicotinic acid hydrazide. Y 60-65%. K.-K. Moll et al., Phar-mazie 23, 36 (1968). 

Reduction of 2,6-dichloroisonicotinic acid with hydrazine hydrate in presence of palladium on charcoal is claimed to yield isonicotinic acid. ... 

An example is the establishment of the shelf life of an Isoniazid injection solution. Isoniazid when dissolved in water, may hydrolyse and oxidise. Upon hydrolysis, isonicotinic acid, isonicotinamide, di-isonicotinoylhydrazine and hydrazine are formed [10, 29b]. The increase in hydrazine does not match a decrease of isoniazid content Since hydrazine is genotoxic, the shelf life of the product is limited to the formation of hydrazine, which is measurable even before the degradation of isoniazid is measureable. 

Isonicotinic acid hydrazide with a molecular weight of 137.14 forms white crystals, melting at 171°. It is soluble in water (14% at 25°) and alcohol (2% at 25°). It is slightly soluble in chloroform and insoluble in ether or benzene. It may be heated in aqueous solution at 120° for 30 min with no apparent destruction and is prepared by condensation of ethyl isonicotinate with hydrazine. 

Carboxylic acid hydrazines from carboxylic acids. Hydrazine hydrate added to a soln. prepared from isonicotinic acid and N,N -carbonyldiimidazole in tetrahydrofuran, and allowed to stand 12 hrs. at room temp. isonicotinoyl hydrazide. Y 80%. Also from 1-isonicotinoylimidazole and f. e.,... 

CeHyONa, Isonicotinic acid hydrazide, 17, 742 CsHsNj, Phenylhydrazine, 33B, 54 CsHjClNj, Phenylhydrazine hydrochloride, 30B, 47 CsHijNjOn, Diethyl hydrazine-1,2-dicarboxylate, 43B, 8 CsHi2N2S4, 3,6-Bis(methylthio)-4,5-diaza-2,7-dithiaocta-3,5-diene, 41B, 76... 

In a first step, isoniazid is quantitatively hydrolyzed to give isonicotinic acid and hydrazine, which is titrated by the iodatometry at four electrons. 

Isonicotinic acid hydrazide (INH) Hydrazine derivatives Fatty acid hydrazides, fatty acid aryl hydrazine sulfonic acids Polyhydrazino and amino hydrazine derivatives Phenyl hydrazine, rotenone derivatives, semicarbozones, thiosemicarbozones, sulfonic acid hydrazides 3-Amino-phthalyl hydrazide Phenyl hydrazine and unsymmetrical diphenyl hydrazine (UDPH)... 

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