September 1969
HYPOGLY C
E ~ CTHTAZOLPLPY RIDTSIUJ~ SALTS
give colorless needles of 9, mp 73-74', nmr consistent. Anal. (C4HsClaNS) C, H, N, S. 2,2-Dimethylthiazolidine Hydrochloride (lo).-Thiol 1 (16.84 g, 148 mmoles) was dissolved i n XeOII (25 ml) and excess MezCO (300 ml), miti Ihe ~iiixt~iire was heated under reflux for 8.5 hr. 1Svaporatioir of solvelit, gave it vcsidiie (20.3 g), mp 162-166", which was cryst itllixeti Ohrec t inies f I Y J 1 1 ~hleOII by addition of &O to give 10 as colorless iieedlw (8.6 g, :Byc), having constant mp 170-171.5" (lik3d 164-166'). rlnal. (C&&lNS) '2, H, S. 2-Benzoylthiazolidine Hydrochloride (ll).-Thiol 1 (5.50 g, 48.5 mmoles) and phenylglyoxal hydrate (7.60 g, 50 mmoles) were heated together at ca. 85' for ca. 5 min; the mixture then was dissolved in RIeOH (30 ml) and Et20 (120 ml) was added to incipient turbidity. Cooling gave colorless 11 (4.4 g, 397c), mp 151-153' dec. Recrystallization three times from MeOH by addition of Et20 gave 11 with a melting point of 151.5-152.5' dec, nmr consistent. .4nal. (C1oH&lNOS) C, H, N, S. Spiro [ 2,3-dihydroindole-3,2'-thiazolidine] -2-one Hydrochloride (If).-Finely powdered isat,in (10.95 g, 75 mmoles) was slowly added to thiol 1 (8.5 g, 75 mmoles) in i-PrOH (80 ml) to give a red mixt,ure which, after being stirred for 24 hr a t ca. 25O, became pale brown. Filtration separated pale brown 12 (15.4 g, S5yo), mp 200-203" dec. A sample was recrystallized three times from
891
MeOH by addition of Et20 and had a constant melting point of 203-204" dec; ir (KBr), 2370, 1735 (amide -0) cm-'. Anal. (CloHiiClN2OS) C, H, N, S. ~-5,5-Dimethylthiazolidine-4-carboxylic Acid ( 13).-~-Penicillamine (35 g, 235 mmoles)I0was dissolved in 45% aqueous HCHO (200 ml, 3.0 moles). Within ca. 5 min, solid started to separate. The mixture was stirred for ca. 20 hr. Filtration then removed the colorless intermediate 14 (29 g, 6970)~mp 111-112', after a wash with dioxane then Et20 and drying over silica gel; ir (KBr), 3420, 2990, 2750, 1635, 1475, 1400, 1380, 1360, 1340, 1135 (s), 1105,1010,830, and 705 em-'. Conversion to the thiaxolidine 13, generally in ca. 757, yields, was achieved by dissolving ihe intermediate 14 in H 2 0 (10 ml/g of 14) and adding EtOH (4 vol) to incipient turbidity, then cooling. The thiaxolitlirir 13 had mp 195-195.5' dec," ir and nmr consistent. (10) Kindly supplied b y Dr. Elmer Alpert, Merck Sharp and Dolime Research Laboratories, West Point, Pa. (11) Reference 4, p 958, reports mp 196-197' dec. The melting point reported there for the L form was 193-194'; a later patent abstract indicates this preparation was from L-penicillamine rather than the hydrochloride, but the identity of the procedures suggests a n error in the abstract [J. H. Hunter and B. E. Leach, U. S. Patent 2,480,079 (1949); Chem. Ahstr., 44, 2569 (1950)l.
Quaternary Thiazolylpyridinium Salts.
Oral Hypoglycemic Agents
GRETCHEN E. WIEGAND, VICTOR J. BAUER,S. R. SAFIR, Organic Chemical Research Section
D. A. BLICKENS, AND S . J. RIGGI Department of Metabolic Chemotherapy, Lederle Laboratories,
.4 Division of American Cyanamid Company, Pearl River, New York 10965 Received M a y 1 , 1969
A series of quaternary 4-(thiazolyl)pyridinium salts has been synthesized. Blood glucose concentration of normal mice was decreased following oral administration of these compounds.
A number of azolylpyridinium salts, including members of the pyrazolyl-,' iso~azolyl-,~-~ 1,2,4-oxadiazolyl-,j and oxazolylpyridinium6 salt families, have been found to induce hypoglycemia in laboratory animals. As a further development of this series, we have investigated the replacement of the five-membered ring with still other het,erocycles. We describe herein the synthesis of some novel 4-(thiazolyl)pyridinium salts. The choice of substituents was influenced by structure-activity correlat'ions developed in the pyrazolylpyridinium salt series.' The 4-(t~hiazolyl)pyridiniumsalts 10-29 were prepared from t'he thiazolylpyridine bases 4-9 by quaternization with the appropriate alkyl halide. The base 4 was prepared as described by Wallenfels and Gellrich.' The bases 5, 7, and 8 were prepared by modification of this procedure. Thus, reaction of thioisonicotinamide wit'h 3-bromo-2-butanone gave 5 , reaction of thioacetamide with l8gave 7, and reaction of cyclopropane(1) V. J. Bauer, H. P. Dalalian, \V. .J. Fanshawe, s. R. Safir. E. C. Tocus. and C. R. Boshart, J . Med. Chem., 11, 981 (1968). (2) V. J. Bauer, IV. J. Fanshawe, H. P.Dalalian, and S. R. Safir, ibid., 11, 984 (1968). (3) D . A. Bliokens and S. J . Riggi, Tozicol. A p p l . Pharmacol., 14, 303 (1969); Diabetes, in press. (4) S.J. Riggi, D . A. Blickens, and C. R. Boshart, ibid., 17, 646 (1968). ( 5 ) W. J. Fanshawe, V. J. Bauer, S. R. Safir, D . A. Blickens, and S. J. Riggi. J. Med. Chem.. 12, 381 (1969). (6) G. E. Wiegand, V. J. Bauer, S. R. Safir, D . A. Blickens, and S. J . Riggi, ibid., 12, 943 (1969). ( i ) IC Wallenfels and M. Gellrich, A n n . Chem., 621, 210 (1959). (8) 13. Polo-Fria, Fnrmnco, E d . S c 7 . . 18, 9 7 2 ( l W { ) .
t,hiocarboxamidewith 1 gave 8. The bases 6 and 9 were prepared by fusion of the amido ket'ones 2j and 3,9 respectively, with PzSj using a modification of the procedure of Gabriello as described by Ot't, et al.,I1 for the preparation of arylthiazoles. I n the nmr spectra of the 4-(thiazoly1)pyridine bases 4-9, the pyridyl protons appear as two doublets at 6 7.73-7.76 and 8.60-9.01. Upon quaternizat'ion, these signals shift to new values of 6 8.33-8.53 and 8.83-9.18. These changes, a downfield displacement of both doublets, as well as a smaller separation between chemical shifts, were found to be diagnost'ic of pyridine quaternization in our earlier study of pyrazolylpyridinium salts. Spin-decoupling experiments demonstrate that the quaternary methyl of 11 is coupled with the a-pyridyl protons, further confirming that alkylation has occurred on the pyridyl nitrogen. Hypoglycemic Activity.13-Saline solutions or 0.5% aqueous carboxymet'hylcellulose suspensions of t,est, compounds were administered by gavage to male CF-1 mice (Carworth Farms, 25-30 g) at dose$ of 0.5-1.5 mmoljkg; controls received an equal volume of vehicle. (9) S. van der M e w , H. Kofmann, and H. Veldstra, Rrc. Trim. Chim. P U ~ ~ - B72, ~ 236 S , (1953). (10) 9. Gabriel, Chem. Ber., 48, 134 (1910). (11) D . G. Ott, F. K. Hayes, and V. N . Kerr, J . Amer. Chem. Soc.. 78, 1941 (1956). ( 1 2 ) T'. J . Bauer, H. P.Dalalian, and S. R . Rafir, .I. M r d . Chrm., 11, 1263 (1868). (13) Technical arsistanr? of Mr. E. Lock?. Mr. H . Siegripst, and Miss I.. \Vi11 is p,rmll), auprrriated.
Experimental Section16 2
1
w 3
CH,
9
7, R, = CH
8. R, =
@..-
Rl
10-19 (Table 1)
20-28 (Table 11)
CHI
29
Blood samples (0.05 ml) obtained from retrobulbar plexuws 3 and 5 hr after dosing were assayed4 for blood glucose using the method of Hoffman14 as adapted for the Technicon AutoAnalyzer. Results are included in Tables I and 11. Blood glucose concentration was \ignificantly reduced following administration of the +(t hiazoly1)pyridinium salts. The average decreases from control of 37 + 4 (20-28) and 63 f 7% (10-19) :it a dose of I..> mmol/kg suggest that the 4-(4-thiazoly1)pyridiniiim salts are l e v nctivc t h a n t h e 4-11't Iiiazolyl) pyritli t i 1 1 1 1 1 1 c~onipoiind-.
4- (4,5-Dimethyl-2-thiazoIyl)pyridine(5).--A mixture (IC 3 g (0.036 mol) of t,hioi.sotiicotiriamide, 8.8 g (0.058 mol) of 3 - b ~ ~ m o %butanone, and 50 ml of EtOH \vas heated under reflux for 6 tir a i d concentrated under reduced prehsure to dryness. A suspeiinitin of the solid residue in 50 ml of Ha0 was made alkaline (1 S SaOH) and extracted ICHCL). The CHCL solution \vas dried (1IgSO4) a i d coiiceiitrated tinder reduced presslire tu a solid residiie which w (307;1 of off-u-hite
.41 ( 5 , 3 each, CH3), 7.76 and 9.01 id, J = 0 cps, 2 each, pyridyl-Hi. .lnnl. (CloHlaNaS) C, H, S , 8. 4-(5-Methyl-2-thiazolyl)pyridine is).---.$ mixture of 2 g 10.011 mol) of isonicotinamidoacetone (2)6and 3 g (0.013 m v l ) of P2Sjwas heated at, 110-140" uiitil gas evolution ceased. 'The oily residue vas warmed with excess 1 S KOH and extracted ( CI-ICl,). The CI-ICI, solution was dried (hIgSO4) arid coticeiitrated under reduced pressure to 1.5 g (go%,) of tan crystals. Sublimation at 63" (0.03 mm) gnve yellow needles: mp 88-90". . I n d (CgHsNtS) Cy, €1, S . 4-(2-Methy1-4-thiazolyl)pyridine( 7 ).-- A mixture of 18.2 g (0.27 mol) of thioacetamide, 37.8 g (0.135 mol) of $-bromoacetylpyridine hydrobromide i l )," aiid 1 1. of MeOH was heated iiiider reflux for 0.5 hr arid coriceritrated under reduced pressure. .I solution of the solid residue in 100 ml of ILO was made alkaline ( 1 A' S a O H ) a i d extrarted (CHC13). The CHCL solution \vas ncentrated under reduced pressure to a allization (
