Soms
of pyridine quaternization',? and demonstrate that :&ylation has occurred on the pyridine rather than the oxazole nitrogen. Hypoglycemic Activity."---Sxllne solutions of compounds \yere admnistered by gavage t o male CF-1 niicc (Carirorth Farms, 25-30 g) at dose> of 1.5 and 3.0 mniol/lrg; controls received an equal volume of vehicle.. Blood samples (0.05 inl) obtained from retrobulbar plexuses 3 arid 5 hr after dosing were i using the method of Hoffman"l :ii adapted for the Twhnicon AutoAnalyzer. Blood glucosc 15 as decreabed 21-9Oc/, following the administration of oxazolylpyridinium salts (Table I ) . Further studies are in progrew to conipare the potency, toxicity, arid mode of :Lction of thcse agents with those of other hypoglyrrniic
reflux for 1 hr :tiid cooled. The superiiatant liquid was tlecanteti, excess 1 -I'NaOH was added tu the tarry residrie, arid the oily mixture was extracted with CIIC1,. The CHC13 d u t i o i i is dried (RIgSOr) aiid cr)nceiitrated wider reduced pressiirt' t i i ILII off-white solid. Siiblimation at 90" (12 nim) gave 0.95 g (595; j of colorless needle., nip Z - X I " , I I V 310 nip ( e 20,XZI). .lital. (CrHaNIO) C, H , ?;. l-iMethyl-4-(2-oxazolyl)pyridiniumChloride (6). ~ - Arriixt i i t v of 2.1 g (0.014 niol) of ~-(L'-oxazoI~I)pyridiiie (l)F atid 3 1111 lleC1 was heated at, 1003 for 4 hr i i i a glass-lineti steel h i i r i t ) . The excess l1eC:l war; allo~vetl evaporate and the solid residut. \vas recrystallized (i-PrOII) t,o give 0.3 g (20';;) of off-white crystals, nip 244" tfec, IIV :$I2 mp ( e 16,900). A n d . ( C ~ H Q C ~ N L ) .
drugh. Experimental Section11 Isonicotinamidoacetone (4).--TCJ a cold solution of freshly prepared isonicot~inoylchloride12 !from 20 g (0.16 mol) of isonicotinic acid] in 1.50 in1 of dry pyridine was added, in portions, a t such a rate 17.6 g (0.16 mol) of aminoacetorie hydrochl~ridel~ that the temperature never rose above 10". The mixture was &wed t o come slow1y to room temperature, stirred for 1 hr, poiired into 1.5 1. of ice, and extracted with CHC1,. The CHCl, aolution wa.7 dried (lIgSOa), decolorized (Darco), and cunceii[rated under rediiced pressure to a brown solid. liecryatallization (EtOH) gave 6.5 g (2551) of tan Three recry~tallizations (EtOH-perita crystals, mp 143-144". Anal. (CsH,&,On) C, H, N. 4-(5-Methyl-2-oxazolyl)pyridine(Z).---To a solution of 3.6 g (0.03 mol) of 4 in 54 ml of AcnO was added 4.4 ml of 85% H3P01. rition was heated under reflux for 3 hr, then cooled, aiid olvent was decanted. The tarry residue was treated with excess 1 'I' XaOH, which caused precipit,atiori of au off-white solid. Three recrystallizations (€120) gave 1.3 g (40%) of colorless crystals, mp 99-loo", I N 289 nip ( € 15,600). The analytical sample was obtained by sublimation at 60" (0.1 mm). Anal. (CgH,?r'zO) C, H, N. 4-(2-Methyl-5-oxazolyl)pyridine(3).--To a suspension of 1.8 g 10.01 m i l l ) of 4-acetylaminoacetylpyridine (5)' in 27 ml of AczO \ Y Z I Sadded 2.2 ml of 8.57, H~POI. The mixture was heated under ( $ 4 ) Tei.liniraI assistance of 31r. E. I u k e , 3Ir. H. Siegriest, a n d Miss I,. \Vi11 is greatly appreciated. ( I O ) \V. S. Hoffman, J . B i d . Cheffk.,120, 51 (1937). 1 1 1 ) illnltinp points were determined in a Heruhberg apparatus and are iincorrected. hlicroanalyses were performed h y M r . L. M. Brancone and * l u f f . \Vilere analrses are indicated only by symbols of t h e elements, arlal.stica1 results obtained for rhose elements were within +0.4:% of t h e ilitmrrtical values. C v spectra were determined b y M r . W. Fulmor ancl .-tuff i n MeOII with a C a r s 11 si~ectropbotometer. ( 1 2 ) I€. Meyer and B. G r a f , Chem. Ber., 61, 2206 (1928). ( I : $ \ I-. P. EllingPr and .'i.A . Goldberg, J . Chen. Soe., 263 (1947).
Hypoglycemic Quaternary Azolylpj ridiniutti Salts. Inactive Analogs
A% number of quaternary :izolylpyridinium halt.;, including member> of the pyrazolyl-, iwxazolyl-,2 1,2.-l.-osadiazolyl-,' ~ x a z o l y l - , m ~ t l thiazolylpyridiriiuni) salt families, have been found t o display interesting hypoglycemic activity in laboratory animals, arid l-methy1-4-(3-rnethyl-.i-isoxazolyl)pyridiniumchloride (1) has been chosen6,' for study as it potential nntidiubetic drug. Other rlas of uzolylpyridiniuni s:tlt have been examined arid found to lack hypoglycemic activity in mice. In this report, we describe the syrithe and properties of these compounds (1) \ . J Bauer 11 I' 1)alalian \\ I I anbliane, and S It Safir, .7 lfed. Chem , 11,981 (1968) ( 2 ) V. J. Bauer W I 1 a n q l i a n i . I I €' 1)alalian and Y I< Safir, zbrrl 11, 98%(1968). (3) W. J. Frtnstiant-. 1'. .1. I3aiin.. S, I t . Bafir, I). A . Illickens. and S. .I.
Noms
Septcmber 19GO
946
(2b).-A solution of 1.61 g (0.01 mol) of 4-(5-methyl-1,3,4oxadiazol-2-yl)pyridine,* 1.50 g (0.011 mol) of MeI, and 10 ml of MeOH was heated under reflux for 1 hr. An orange solid, 1.60 g, mp 150-250", separated and was collected. Three recrystallizat,ions (MeOH-H20) gave 0.31 g (10%) of orange needles, mp 275-277" dec, uv 217 ( E 17,900) and 278 mp ( E 19,1 200). Anal. (CgHloINaO) C, H , I, N. l-Methyl-4-(5-methyl-l,3,4-thiadiazol-2-yI)pyridinium Iodide (2c).-A solution of 1.77 g (0.01 mol) of 4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridine,g 1 mi of BleI, and 10 ml of MeOH was heated under reflux for 2 hr. Upon cooling 2.58 g (81%) of a yellow solid, mp 225-230°, separated and was collected. Two recrystallizations (MeOH) gave yellow prisms, mp 226-227" dec, 2a,Z= NH; X =C1 3 uv 218 ( e 18,100) and 287 mp ( 6 16,400). Anal. ( C ~ H ~ O I K ~ S ) b,Z =O;X = I C, H, I, N, S. l-MethyI-4-(5-tetrazoIyl)pyridinium Chloride (3).--9 mixt'ure c,Z=S;X=I of 7.8 g (0.053 mol) of 4-(5-tetrazolyl)pyridinelO and 10 ml of Reaction of 4-(5-methyl-l,2,4-triaz01-3-yl)pyridine,~MeCl mas heated a t 130" in a glass-lined steel bomb for 18 hr. The excess MeC1 was allowed to evaporate, and the colorless 4- (5-methyl-l,3,4-oxadiazol-2-yl)pyridine,4- (5-methresidue was recrystallized (MeOH-H20) to provide 3.2 g (31%) of yl- 1,3,4-thiadiazol-2-yl) pyridine, and 4-(5-te trazcolorless crystals, mp 238-239". Four recrystallizations gave o1yl)pyridine'O with nIeCl or Ale1 provided the desired the analytical sample, mp 235' dec, uv 277 mp ( e 13,600). Anal. quaternary salts 2 a 3 3. For the synthesis of animidaz(CiHsClXs) C, H, C1, N. N-(Formylmethy1)isonicotinamidine Diethyl Acetal (4).-A olyl analog, 4-cyanopyridine was converted by the solution of 20.8 g (0.20 mol) of 4-cyanopyridine and 1.1 g (0.02 method of Schaefer and Peters" to methyl isonicotinmol) of NaOMe in 200 ml of RleOH was stirred a t room temperaimidate, which was allowed to react with aminoacetture for 20 hr. To this solution of methyl isonicotinimidate was aldehyde diethyl acetal to yield the amidino acetal 4. added 52 ml (0.20 mol) of 3.8 A- HCl in EtOH and 26.6 g (0.20 Acidic cyclization of 4 gave the imidazolylpyridine 5, mol) of aminoacetaldehyde diethyl acetal. The solution was heat,ed under reflux for 4 hr and was Concentrated under reduced which was quaternized to the desired salt 6. pressure. The residual oil was treated with 160 ml of 0.5 N NH SaOH, and the resultant mixture was extracted with CHC13. The CHC13 extract was dried (MgSO,) and concentrated to give a (EtO)2CHCH2N= C white solid. Recrystallization (EtOAc-petroleum ether (bp 30-60")) gave 34.1 g (72%) of colorless crystals, mp 92-94'. 4 Several recrystallizations provided the analytical sample, mp 93-94', uv 265 mp ( e 3900). Anal. (C&&302) C, H, N. 4-(2-ImidazolyI)pyridine (5).-To 30 ml of 12 X H2SOa TYas added in portions 2.3 g (0.01 mol) of 4. The solution was then heated for 30 min on a steam bath, cooled, and made basic by H H the dropwise addition of 10 N NaOH. The solution was ex5 6 tracted with CHC18. The CHC1, solution was dried (MgSO4) and concentrated to a white solid. Two recrystallizations Compounds 2a-q 3, and 6 (0.5-3.0 mmol/lig) were (EtOAc-petroleum ether) gave 0.5 g (33Yc)of colorless crystals, administered orally as saline solutions to male mice mp 211-212", uv 290 mp ( e 15,390). Anal. (CsHiN3) C, H, K. (Carworth Farms, 18-25 g) ; controls received an equal l-Methyl-4-(2-imidazolyl)pyridiniumChloride (6).--A mixture volume of vehicle. Blood glucose levels were deterof 2.9 g (0.02 mol) of 5 and 5 ml of NeC1 was heated at 120" in a mined12 3 and 5 hr after dosing by the method of Hoffglass-lined steel bomb for 18 hr. The excess hIeCl was allowed to evaporate, and the solid residiie \vas recrystallized (EtOH) man13 as adapted for the Technicon AutoAnalyzer. three times t o provide 2.5 g iG4Cc)of pale yellow crystals, mp Glucose concentrations were not different from controls, 277-278" dec, uv 345 mp ( e 21,510). Anal. (C~HIOKZCI) C, H, except for an uninteresting slight nondose related hypoC1, N.
glycemia following administration of 2b. Experimental Sectionla
l-MethyI-4-(5-methyI-l,2,4-triazoI-3-yI)pyridiniumChloride (2a).-A mixture of 3.0 g (0.019 mol) of 4-(5-methyl-1,2,4triazol-3-y1)pyridines arid 10 ml of MeCl was heated for 20 hr a t 85" in a glass-lined steel bomb. The excess MeCl was allowed to evaporate, and the residual solid was recrystallized (EtOH) to provide 1.2 g (30%) of colorless crystals, mp 290-291" dec. Three recrystallizations gave colorless needles, mp 281-284" dec, uv 283 mp ( e 13,400). Anal. (CgHllC1N,.0.25H20) C, H, C1; K: calcd: 26.1; found, 26.7. l-Methyl-4-(5-methyl-l,3,4-oxadiazol-2-yl)pyridinium Iodide (8) I-.Postovskii and N . N. Vereshchagina, J. Gen. Chem. L'SSR, 29, 2105 (1959). (9) F. H. hIcMillan, F. Leonard, R. I. Meltzer, a n d J. A. King. J. A m . l'harm. Assoc., 42, 457 (1953). (IO) D. D. Libman and R . Slack, J. Chem. Soc., 2253 (1956). (11) F. C . Schaefer and G . A. Peters, .I. Ory. Chrm.. 26, 412 (1961). (12) 'leatin:: d a t a was supplied b y Urs. U. A . Bliokena and S. J. Riggi of the Metabolic Chemotherapy Department of these laboratories. (13) W.S. Hoffman, J. B i d . Chem.. 120, 51 (1937). (14) Melting points were determined in a Hershberg apparatus and are iincorrectcd. Microanalyses were performed by hlr. I,. &I. Brancone and s t a f f ; where analyses are indicated only by symbols of the elements, analytical results obtained for those elements were within 0.47, of the theoretical values. U v spectra were recorded in MeOH solution with a Cary 11 speotrophotometer b y Mr. W. Fulmor and staff.
4-Azolylpyridine 1-Oxides. Analogs of the Hypoglycemic 4-Azolylpyridinium Salts VICTORJ. BAUER, WILLIAM J. FANSHAWVE, G n E w H m E. WTIEGAND, .LSD 8. R . PAFIR
Organic Chemical Research Soction, I,ctlerlc. Laboratories, ii Division o,f A v w i c a n C?/unanLirlCompany, Pearl R i w r , .\-ew 170rk 10.965 Received X a y 23, 1969
A number of 4-azolylpyridinium salts, iiicludiiig the pyrazolyl- (la),l i~oxazolyl- (lb),2 thinzolyl- ( l ~ ) , ~ (1) V. J. Bauer, H. P. Dalalian, W.J. Fanshawe, S. R. Safir. E. C. Tocus, and C . R. Roshart. J . > I d Chem., 11, 981 (1968). ( 2 ) V. J . Aarirr. IT.J. Fanshawe. H. P . Dalalian, and S. R . Safir, ib!d., 11, 984 (lues); 1). A. Ulickens and S,J. Riggi, T'osicol. A p p l . I'hurmucol., 14, 393 (1969). (3) G. E. Wiegand, V. J. Bauer. S. R. Safir, D. A. Blickens, and S. J. Riggi, J. M e d . Chem., 12, 891 (1969).
