Mu,
O('
143--146
130-140 134-13.i 142-144 129-130 159-160 144-146 1.58-160 1.52-1.i3 167-168
T LRLI: I1 h ' l l r H ~ I ~ o I DACTION ~L IS I N P I C l ' 1: Comgd"
('11~1
Blank Thiouracil (0 500) I (0 913) IT (1 2 2 ) I11 (1 15) IV (1 13) 1- (1 30)
12rI
uptahe
ivroid radioactix it?. dpm PR'2II
272,189 f 13,670
39,428 i 9233* 13,714 i 6683b 41,152 i- 17,73;ib 21,761 i 5672b 64,26.5 i 12,0,5Rh 22,967 i Xllh \ I (1 54) 29,OO.i zt 4056b VI1 (1 46) 63,647 i 10,866h VI11 (1 01) 87,403 i 2 3 , 3 3 2 IX (1 06) 71,005 i 12,561b x (1 19) 128,604 i 33,855c Concentration of test compounds equimolar to thiouracil.
\l'h
std error----
=t
Inorg
1261
237,730 f 12,340
2.5,017 i 1238
30,679 i 764.ib 38,247 i 3837b 31,984 =t16,240'' 18,318 i- 4762b :2,448 i 10,TOKb 1,5,674 i 1131h 22,.i38 i 3638b .i2,93.i i 8888b 74,372 i- 21,921" 62,403 i. 22,.i13b 113,338 i 31,297 * P < 0.001. c P < 0.01.
8,102 i 1694h 3,933 i 89gh 1,837 2 1341" .5,15.5 i 601" 9,8.72 i 12,51b 6,253 i 691b .5,408 i 33gb 8,482 f 1203" 8,468 =k 2041'' 8,324 i 979" 10,189 i 176gb
1100-125 g ) \\-ere maintained on a low-iodide diet for 3 days theti divided into groups consisting of four rats in each group. The animals in each groiip received an intraperitoneal injection of 1 ml of either a blank (0,10 mg/kg for 28. Since phenylbutazone (see footnotes k and 1, Table 11) has considerably greater activity than 1 or 28 in the above tests, further development of these compounds as useful antiinflammatory agents was terminated. Experimental Section6 Preparation of Arylpyridylcarbinols. Method A. Arylaldehyde and 2-Pyridyl1ithium.-A stirred solution of 50 ml of 15% nBuLi-hexane (0.053 mol) and 100 ml of anhydrous EtzO, maintained under Nz and cooled to -40" internally, was treated with 12.1 g (0.077 mol) of 2-bromopyridine in 30 ml of Et20 (0.3 hr) and then dropwise (1.5 hr) with 0.075 mol of halobenzaldehyde in 100 ml of EtnO. After an additional 1 hr a t -4O", the mixture was allowed to warm to 5' and then treated dropwise (0.3 hr) with 125 ml of 1 N HCl. The acid layer was separated, made basic with 2 N NaOH, extracted with CHCL, dried (MgSO1), filtered, and concentrated i n vucuo to give 31, 32, or 33 (Table 111). Method B. Aryllithium and Pyridinecarboxa1dehyde.-An ( 5 ) H. Konzett and R . Rosisler, Arch. Exptl. Pathol. Pharmakol., 196, 71 (1940). ( 6 ) Melting points were determined on E Thomas-Hoover aapillary melting point apparatus and have not been corrected. The uv spectra were obtained on a Beokman Model DB spectrophotometer attached t o a Sargent SRL recorder or on a Cary Model 15 spectrophotometer. Where analyses are indicated only by symbols of the elements, analytical results obtained for those elements were within &0.4% of the theoretical values.
Formula
AnalysesC
CizHioClNO C, H, iV C12HgClzXO c, H, N , 0 C, H, C1, N,0 CisH,Cl,SO CirHiSXO C, H, N, 0 CnHioF3iVO c, H, N C,,IIgF,NO C, H, N See footnote d in Table I.
organolithium reagent was prepared by refluxing a mixture of 0.27 mol of 1-bromo-r-benzene and 3.8 g (0.30 g-atom) of Li wire in 300 ml of anhydrous Et20 for 3 hr under Nz. The reagent was cooled to an internal temperature of -40", treated dropwise (0.5 hr) with 31.9 g of 2-pyridinecarboxaldehyde in 50 ml of EtzO, and processed as in method A to give 34, 35, or 36 (Table 111). Method C. 3-Thienyllithium and Pyridinecarboxa1dehyde.To 68 ml of 1.6 N n-BuLi-hexane (0.11 mol) maintained under Xi and cooled to an internal temperature of -io", there was added dropwise (1.5 hr) 16.3 g (0.10 mol) of 3-brom~thiophene~ in 50 ml of anhydrous Et20. After an additional 1 hr a t -70" the solution was treated with 8.5 g (0.08 mol) of 2-, 3-, or 4 pyridinecarboxaldehyde in 50 ml of E t 2 0 and then after 2 hr of stirring was poured onto ice. The organic layer was separated and the HdO layer was washed with CHCla (four times, 75 ml). The combined organic layers were dried (Xa2SOd) and concentrated in vacuo, and the resultant crude alcohols were used directly to prepare 28, 29, and 30 by method E. Method D. 2-Thienyllithiurn and Pyridinecarboxa1dehyde.A solution containing 5 g (0.059 mol) of thiophene, 34 ml of 1.6 N n-Buli-hexane (0.054 mol), and 100 ml of anhydrous Et20 was stirred and refluxed for 5 hr under Xz then cooled to an internal temperature of -30", and treated dropwise with 6.6 g (0.061 mol) of 2-, 3-, or 4-carboxaldehyde in 50 ml of EtzO. After an additional 1 hr a t -30°, the mixture was allowed to warm to 0" and then was treated with ca. 15 ml of H20. The organic phase was separated, dried (NazSOA), and concentrated in vacuo and the resultant products from 3- and 4-pyridinecarboxaldehyde were used directly to prepare 26 and 27 by method E, and that from 2-pyridinecarboxaldehyde gave 2'-
(7) P. Moses and S. Gronowita, ATkiu Kemi,18, 119 (1961).
