March 1962
I,2,4-TRIAZOLES
383
waa obtained with Raney nickel catalyst. Reduction of Vb to 1Vb.-A solution of 6 g. (0.02 mole) of Vb in 200 ml. of ethanol was reduced in the Parr hydrogenerator in the presence of 5 g. of 5% palladium-on-carbon at room temperature and an initial hydrogen pressure of 4.22 kg./cm.a for 18 hr. The catalyst was removed and the filtrate was concentrated to a residue, which was dissolved in 400 ml. of absolute ether and acidified with an alcoholic solution of hydrogen chloride. The white crystalline product was filtered and recrystallized from a mixture of absolute ethanol and absolute ether; m.p. 183-185'. Anal. Calcd. for C2oH2sClN: C, 76.04; H, 8.30. Found: C, 76.47; H, 8.37.
The Anticonvulsant Activity of 1,2,4-Triazoles C. AINSWORTH, KELSON R. EASTON, M. LIVEZEY, D. E. MORRISON, AND W. R. GIBSON Eli LilEy and Company, Indianapolis 6, Indiana Received September 29, 1961
A series of 1- and 4-substituted 1,2,4-triazoles has been studied for convulsant and anticonvulsant activity by both the maximal electroshock seizure and subcutaneous pentylenetetrazole seizure tests in rats. 1,2,4-Triazole and 1- and 4lower alkyl-1,2,4-triazoles are inactive a t 200 mg./kg. 1-Aryl, 4 - m and p substituted phenyl-1,2,4-triazoles are anticonvulsants. 4-o-Chlorophenyl-1,2,4triaeole and 4-o-tolyl-1,2,4-triazoleare convulsants, whereas 4-o-methoxyphenyl1,2,4-triazole is an anticonvulsant orally but a convulsant when administered by I.P. injection. Qualitatively opposite effects were noted for several isomeric compounds. 1-(1,2,4-Triazolyl-l)-4-(4,1,4-triaeolyl-4)benzene(Compound A) showed weak anti-electroshock activity.
Recently, Gibson, Swanson, and Meyersl reported the pharmacology of the structurally isomeric compounds l-phenyl-1,2,4triazole and 4-phenyl-l,2,4-triazole.They substantiated the earlier report of Pellizzariz which stated that 4-phenyl-l,2,4-triazole was a (1) W. R. Gibson, E. E. Swanson, and D. B. Myers, J . Am. Pharm. Assoc., 47, 778 (1958). (2) G . Pellisaari and C. Mrtssa, Atti Real. Acad. Lincei, 10, 363 (1901); J . Chem. Soc., 80,
I, 488 (1901).
c~~ivulsaiit . 111 coiitrndt , tiicy iountl 1-phciiyl- 1,2,.f-triaxolc to 1 ~ 1 an aiiticorivulsaiit . This paper reports thc prcparatioii wid p2iarrnacological evaluation of a series of 1 and 4-substituted 1,2,4-tria?oIeb. In addition, Compound -1 was prepared. This inolcculc ciicoiiipasses structural features of both 1 and I-phonyl-l,"~-tr.iazoles.
A
Experimental Preparation of l-Substituted-1,2,4-triazoles. (a) 1-Alkyl and Aralkyl-1,2,4trkzu1es.-+ RCI
$3
N-NR
General Procedure.-A mixture of 0.1 mole of 1,2,4-triazole,30.1 mole of sodiuni niethoxide, 0.1 mole of alkyl bromide, and 50 ml. of ethanol was heated overnight iindcr reflux. About 100 ml. of ether was added and the sodium chloride was removed by filtration. The filtrate was concentrated and the residue was distilled under reduced pressure. In this way 1-alkyl and l-aralkyl-1,2,4trittzoles shou-n in Table I were prepared in about 50y0 yield. (b) l-Aryl-l,2,4-triazoles.-Data given in Table I. l-p-Nitrophenyl-1,2,4-triazole.-A mixture of 60 g. (0.33 mole) of l-forniyl2-p-nitrophenylhydrazline* and 45 g. (1.0 mole) of formamide was heated under rcflux for 4 hr. The solid that formed on cooling was recrystallized from ethanol and gave 21 g. (37%) of product,. l-p-Aminophenyl-1,2,4-triazole.-A mixture of 19 g. (0.1 niole) of l-p-nitrophenyl-l,2,4triasole, 500 ml. of 9501, ethanol, 20 nil. of 85% hydrazine hydrate, and 0.5 g. of Raney nickel was heated on a steam bath under mild reflux for 1 hr.5 About, 2 g. of Raney nickel was added and the mixture was heated for an additional 0.5 hr. The nickel was removed by filtration and the filtrate w m concentrated to approximately 100 ml. About 500 nil. of ice m t e r was added and t.he solid that separated was recrystallized from water. (Some high melting material did not dissolve in the wat.er.) The yield was 8 g. (50%). l-p-Acetamidophenyl-1,2,4-triazole.-A solution of 3.2 g. (0.02 mcle) of l-paminophenyl-1,2,4-triazole and 10 ml. of acetic anhydride was heated on a steambath for 0.5 hr. About 100 ml. of 1 N sodium hydroxide was added, and the mix(3) C. Ainsworth, &panic Syntheses, 40, 99 (1960). (4) E. Hyde, Ber., 34, 1810 (1899). ( 5 ) D. Balooiri and A. Furst. J. A m . C h e m . Soc., 76, 1334 flY53).
March 1962
Y
;1
~,~,~-TRIAZOLES
385
t,ure wit^ concentrated to near dryness by heating under reduced pressure. T h e insoluble product that separated \VRS recrystallized from water. The yicltl was almost quantitative. l-p-Chlorophenyl-1,2,4-triazole.-A mixture of 5.7 g. (0.033 rnolej of 2-pchlorophenyl-1-formylhydrazine(m.p. 190") arid 50 nil. of forniamide was heated under reflux for 3 hr. The solid that formed on cooling was recrystallized from water and gave 3 g. (50y0)of product. Preparation of 4-Substituted 1,2,4-Triazoles. General Pr0cedure.O---A mixture of 0.1 mole of N,N'-diformylhydrazint17 and 0.1 niolc of t8he substituted aniline was heated at 180-200" (depending on t'lic tctniprrature at which \vat,er was evolved) for 1 hr. The material vas distilled under reduccd pressurc, and the product was either recrystdiized froiii ethanol-rater mixture or \vas converted to the hydrochloride salt by treating an ethanol solution with ethereal hydrogen chloride. I n t,hie way the huhstituted 1,2,4-t8riaaoleashoivii iii Tshle I1 wero prepared in about 20-50(% yield. The formyl tlerivai ivo I J f Itic> starting aniinc: m a s also usually formed. 4-Benzyl-1,2,4-triazole Hydrochloride.-Benzylamine mid diformylhydrazinc treated according t o the general procedure above failed to farm 4-benzy1-1,2,4triazole but gave :V-bcnzylformamide. The 4-b~nzyl-1,2,4-triazc~l~ \vas prepared in a manner analogous to that reported by F'reund* for the prcpimition of 4-ct,hyl1,2,1-triazolr. Tt \v:ii ronvcrtcd t o the hydroc;hloridc salt, m.p. 301-202" dec. (capillary). .tn,ul. Cnlcd. for C~HYS~.H(,'I: C . 35.24; II. 5.15; S, 2l:iT. I;ountl: C. 55.02; H, 5.16; S , 21.21. 1-(1,2,4-Triazolyl-l) -4-(4,1,2-triazolyl-4)-benzene(Compound A).--A niixt,urc, of 6.4 g. (0.04 mole) of l-p-aminophenyl-1,2,4-triazoleand 3.5 g. (0.04 mole) of N,K'-diformylhydrazinei was heated at 190" for 2 hr. The rcsiduca \vas extracted with 100 ml. of boiling c%lianol. Thc insoluble fraction was recr:;stallized from water and gave 2 g. (23% yidd) of Compound A, m.p. 300". -1nal. Calcd. for C!oH,Ss: C, 56.59: H. 3.80; 9, til. E'ounct: c, 5ti.83: H, 3.43; S,39.iG.
Pharmacological Testing Methods The rompouiids wcre givrii orally as 5% gum acxia suspeiisioiis to Wistar-Strain rats of both hexes wighiiig 160 to 220 g. The ttaticoiirulsaat activity n u e\-aluatcd Lit u prcdetermined tirnc of peak actiyity hy the maximal electroshock seizure test (31.E.S.) of Toman, P t aZ.,9 and b y the subcutaneous peiitylenetetrnzole seizure test described b y Goodmaii, et aZ.Io A4tleast three dosage groups of (6) Based on t h e method of Prlliasari, ref. 2. (7) C. Ainsworth and R. G. Jones, ,I. Am. Chem. SOC.,77, 621 (lY5.5). (8) M. Freund and H. P. Sohwara, B e y . , 89, 2483 (1896). (9) J. E. P. Toman, E. A. Swinyard, and L. S. Goodman, J . N e u r o p h y s i o l . , 9, 231 (1946). (10) L. S. Goodman, J. E. P. Toman, m d E. A . Sainyard, Am. J . .Wed., 1, 213 (1946).
387
March 19132
3 3
&?&
=:
'3 'N
a
m 0
'N
d
B
8 aiiimals earh \v('rc used to comput (' tlic mctliati c1licv.t 1i.o tlo-ci.
j I ~ : 1 ) ~with ~ ) standard c'r1w-b I Jthe~rnc.thod of Bliss."
Results.-'The compound:, 1io1ed n ~ w devoid of :wtivity, eitt-lei, cmvulsant or anticonvulsaiit at 200 mg.;kg. : 1.2,4-triazole, 1methpl-1,2.4-tria~ole.~~ 1-ethyl-] ,2,1-triazo1e,l3 (,ompounds 1-3 of Table I, l-acetyl-1,2,-l-triasolr,'? 1,"A-t riazolc-l-ac.ct:imide,' and 1-P-aminoethyl-1,2,4-tria~ole.~ Only two of thP l-alkyl-l,2,4-trizoles were active and these were the butyl isomers 4 and 3 (Table I). Table I shows the anticonvulsant activity of I-phenyl-1 2,1triazole (Compound 6) aiid related compounds. Of the p-substituted phenyl compounds (7-10), l-p-chloropheiiyl-l,'.~-triazolc is the most active compound against elertroshock >eizure but has weak activity against peiitylenetetrazole. Addition of a methyl groiip to rither carbon atom of the iiucleus (Compounds 11 and 12) dec~easedanticonvulsant action compared with Compound 6. The l-:iralkyl-l,~,,-l-triazole~i n which one methylene group separates the aryl group from the triazolc nucleus (Compounds 13-15) are similar or slightly improved in antielectroshock activity compared ivith the rcfcrriicc compound. However. the activity is dccwasctl ir1it.n thtl aryl i ing i i two c~arhon:itomremoved (Compound 16) Table I1 s h o w the cffcct of siihstitutioii at the &position of the 1,2,4-triazolc ring.lJ It is r e d l e d from the work of Gihsonl that 4-phenyl-1 ,2,4-triazole is a c~m\-ulsant. Substitution on the phenyl ring in the meta or para position reversed the activity (compounds 18. 19, 21, 22, 24-28). The ortho-substituted phenyl cwmpounds had particularly interesting activity. o-Tolyl (Compound 17) and ochlorophenyl (Compound 23) were convulsants and o-methoxyphenyl (Compound 20) was an anticoin-ulsant even at high dosc levels (900 mg. 'kg.). Compound 20 wae a coiivuleant, however, when administered by intraperitoneal injection at 800 mg. 'lig. 4-Benzyl-1,2,4-trinzole (Compound 29) showed weak antielectroshocak activity orally and also was a convulsant wheii given by iiitraprritoneal injertion. Compounds 21 and 22 did not r r w r v activity whcii (11) C. I. Bliss, Quart. J . Pharm. and I'iiurmacoE.. 11, 192 (1938). (12) hl. R. Atkinson and J. B. Polya. J . Chem. Sac., 141 (1954). (13) G. Pellirzari and A. Soldi, G a m Chim. Ital., 86, 373 (1905). (14) A short note by G. R. Breese, ,J. W. Martin, and D. H. 3leyPrs ronceminn 4-halorihenyl-l,2,4-triaeoles appeared in Abstracts, Scimtific S?rtion, \mrrii:nn l'li~iri,i:irpilti~~Ll Association, Chicago Meeting, hliril 23-28, 19131
March 1962
8-HYDROXY-2-YUINOLIN~.4CRYLIC ACID.
11.
389
given by injection. 4-Ethyl-1,2,4-triazoleJ as a representative of the 4-alkyl- 1,2,4-triazole series, was inactive. 1-(1,2,4-Triazo1y1-1)-4-(4,1,2-triazo1y1-4)-benzene(Compound A) showed weak anti-electroshock activity at 100 mg./kg. Acknowledgment.-The authors wish to thank J. I(. Henderson and W. C. Wood for technical assistance.
Derivatives of 8-Hydroxy-2-quinolineacrylic Acid. II1t2 MADHUKAR G. V.41DYA3
AND J O S E P H
G. C.4KNON4
Division of Pharmaceutical Chemistry, School of Pharmacy, University of Wisconsin, Madison 6 , Wisconsin Received August 25, 1961 A series of halogenated derivatives of 8-hydroxy-2-quinolineacrylic acid and related compounds has been prepared as a part of a study of the structure-activity relationship of quinoline compounds having potential anti-infective properties.
As a part of a study of the structure activity relationships of antiinfective agents containing a quinoline nucleus a series of 2-quinolineacrylic acids with a hydroxyl or an alkoxy1 group in the 8-position has been described.2 This paper will report a series of halogenated derivatives of these compounds. It was demonstrated by earlier workers that substitution of halogen atoms at the 5- and 7-positions of 8 - q ~ i n o l i n o and l~~~ of 2-methyl-8(1) Presented before the Medical Chemistry Division of the American Chemical Society a t the 140th Meeting at Chicago, Ilhnois, September 3-8, 1961. (2) M. G.Vaidya and J. G. Cannon, J. A m . Pharm. Assoc., Scz. Ed., 48,10 (1959), should he considered a8 paper I of the series. (3) Wisconsin Alumni Research Foundation Fellow 1957-1961. Abstracted from a thesis submitted by M. G. Vaidya in partial fulfilment of the requirements for the degree of Doctor of Philosophy, University of Wisconsin, 1961. (4) To whom all correspondence should be addressed. 37,42Y (1948). (6) K . A. Oster and M. J. Golden, J . Am. Pharm. ASEOC., ( 6 ) E. Schraufstatter, 2. Natwforsch., Ilb, 190 (1950).
