1097
KOTES
November. 1069 TABLE
1
YIELDS, PHYSICAL, AND ANALYTIC.4L
LIP, "C
/o
' 3
5 ield
XO.
9 70 10 41 11 48 12 79 13 78 14 72 15 87 16 87 17 76 18 29 19 62 20 46 21 65 22 90 23 48 24 77 25 83 26 96 27 67 28 68 29 .55 P = petroleum ether (30-60°), E calcd, 50.9; found, 50.4. C1: calcd,
Recrystn solventa
-
F'
RSH,
7,X=H 9, x = c1 X NaOH
10 11 12 13 14
X H H H C1 C1
15 16 17 18 19
C1 C1 C1
20
e1
Snalyses
Formula
C, H, C1, iK 77 P Ci2HgClzN02 105 E CisHiZ3N202 C, H, F, N C, H, C1, F, K 144 E CiJIiiClF3Nz0~ C, H, Cl, F, X 157 E CiSH1dClF3S202 C, H, C1, ?; 134 E CiJIi5ClN20z C, H, C1, F, X 147 E Ci sHi4ClFsK 20? C, H, C1, F, N 14-5 E CigH13C12F3N203 C, H, C1, F, N 195 E Ci9Hi3ClAF3N20z C, H, C1, N 132 E CigHi7ClS?03 C, H, C1, N 120 E CigHnClX;203 C, H, C1, N 190 E C2iH2iC1x206 C, H, S ; Clb 91 E Ci7H15ClN203 270 11 Ci7HiiF3S202 C, H, F, N C, H, C1, F, S 266 11 Ci~HioClF3K202 Ci7HioClF3N20,.HzO H, C1, F, N , 0 283 AI C, H, C1, N 262 11 CisHiiC1N202 C, H, C1, F, X 272 31 CnHioClF3N20, 0.5H10 H, F, S ; C, Cld 267 p\I C~~H~C~ZF~N~O? C, H, C1, F, N 279 11 Ci7HgCl?F3X20> C, H, C1, N 265 11 Ci7Hi3ClK203 H , S , C, CP 248 11 Ci6HiiClrY1203.0.5HzO = EtOH, 11 = hIeOH. * C1: calcd, 10.7, found, 11.2. c C. calcd. 53.1 foimd. 53.8. 17.7; found 17.2. e C: calcd, 57.8; found, 58.5. C1: calcd, 1 1 4; found, 11.9.
SCHEME I1
X~J~JCOOCJL
DAT~
d
C
O
O
H
N' 21 22 23 24 25 26 27 28
C:
quinolinecarboxylates (10-20).--.1 mixture containing 0 004 mole of an ethyl 4-chloro-3-quinolinecarboxylate and 0.006 mole of the desired aniline was heated on the steam bath for 10 min. Upon cooling, the mixture settled to a gum which solidified on standing for 30 min. Dissolution of this i n H 2 0 and basification xith SH3 yielded the product which was flirther purified by crystallization (EtOH). General Procedure for the Substituted 4-Anilino-3-quinolinecarboxylic Acids (21-29).-To 20 ml of 5% S a O H i n EtOH was added 0.003 mole of the substituted ethyl 4-anilino-3-quinolinecarboxylate. After stirring for 1 hr, HC1 was bubbled through the solution to pH 1. SaOAc was then added slowly to pH 3. Upon filtering, the yellow precipitate was washed (EtOH, Hz0). The precipitate was t,hen heated in H 2 0 and the solution was adjusted to pH 5 . After washing (H20),the product was dried in uacuo. An analytical sample was prepared by rrystallization (AleOH).
Heterocyclic Substituted Ureas. 111. Immunosuppressive and Antiviral 2-Pyrimidylureas J. PAGET, CHARLES w.ASHBROOK, ROBERTL. STONE, AKD DONALD C. DELONG
c1
CHARLES
c1 29
exhibited any significant diuretic activity in the dog at the S-nig/kg dose level. Experimental Sections Ethyl 4,6-dichloroquinoline-3-carboxylate(9) was prepared from ethyl 6-chloro-4-hydroxy-3-quii1olinecarboxylateby the method of Kaslow and Clark.3 General Procedure for the Substituted Ethyl 4-Anilino-3-
The Lilly Reseaich Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46206 Receited July 11, 1969
Benzimidazole-,' benzothiazole-, and benzoxazoleureas2 are potent immunosuppressives and are effective against certain virus diseases in mice. We have searched for other heterocyclic urea3 that have these biological properties. We report the synthesis and testing of a series of 2-pyrimidylureas, certain members of which have the desired biological properties (Table I).
(8) Yields, physical data, and analysee are listed in Table I .
Melting JIieroanalyaes were performed by Mr. L. M . Brancone and staff: where analyses are indicated only by symbols of the elements, analytical results obtained for those elements were within k0.47, of the theoretical values. I J u I I i I b WCI'P
t a k r n url a hIPi-'[rnll~ r l ! ~ l b r a ~ xrld ~ l a a r e ulrcurrrctr&
( 1 ) L'. .I. l'aget, K . Kiylier. Chem., 19, 1010 (1969). (2) C. J . Paget, IC. Kisner,
1016 (1969).
R . I,.
Ytuiie, and
I).
C . DcLouy. J . .\led.
R. L . Stone, and D. C. DeLong. tbi,?..
19,
Immunosuppressive activity has not, to our k n o d cdge, been reported for any pyrimidineureas. Buu-Hoi. ct al.," have reported the synthesis of 1,3-disubstituted 2-pyrimidylureas iis potential antiinfluenza agents : howver, they report only in vitro antibacterial activity. Some 1- [.l-nitropheny1-3-(2-pyrimidyl) ]ureas have been patented for the treatment of co~cidiosis;.~ Biological Testing.-The compounds \\-ere tested for immunosuppression in the sheep erythrocyte assay iri mice and for antiviral activity against Coxsackie A21 virus infections in mice, as previously described.
Discussion This investigation, dthough limited riiairily to modification of the aryl substituents, emphasized that the 2-pyrimidyl group is less effective than the 2:trninobenximidazole or 2-aminobenzothiazole*~2as a basic nucleus for the desired activities. .As immuriosuppressants only compounds 1 and 2 (3-trifluoroinethylphenyl and 4-nitrophenyl) are worthy of mention. They both contain strong electron-withdrawing groups on the aryl ring. The moht potent antiviral activity \ w s found in compounds 4, 11, 15, 17, :md 18, 1hc majority of which are chloroplietigl derivative.. 'l'hci potrnt aiitivirals 1% c w :dl vwy poor iniiiiiuio~ i i p p r ( ~ s s ~iridicat i i t ~ , irig two heparate htructure-activity relationship-. Experimental Section6
The reactions were run in aprotic solvents in which both starting materials were reasonably solrible. An example follows, ( 3 ) 13iiu-IIoi. I). Xuong, and V. 'T.Siiu. ./. C h r m . Suc., 2185 (19.58). (4) R . C. O'Neill and A. J. Basso. U. S.P a t e n t 2,762,742 (1956); Chem. Ahslr.. 51, 5129 (1957). (J) Melting points vere taken on a AIel-Temp apparatus and are t i n corrected. I r a n d nmr spectra were consistent for the proposed structurca. All compounds were anal>-sedfor C, T I , N and gave results within + O A c G of tlle tireoretical value.
3-(l-Naphthyl)-l-(2-pyrimidinyl)urea.-\ ini\tuie
o! 3.b; g
(0.03 mole) of 2-amiirop~rimidiiie and 5.6 g (0.03 mole) of 1 naphthyl iwcpiiate wa- iefliired :tiid itirred 8 hr 111 150 in1 of luliiene. The cooled wlution \\a\ filtered, and the solid dt led. mp 2-16-28', lield h.0 g This miterial nas uiie spot on siliw gel tlc in EtC),ic arid. therefore. x i t s r u i t further purified.
Acknowledgments. - I\*P\\ uuld like to tharik 3lessrc. IJiiiville B a l m and Rubert Wolf'e for the biological test result*.
\luscle Relaxant and Anticonvulsant P r o p e r t i e s of Some 1-Carbanlo>I-3-aroylpyrrolidines and 1-Carbamoyl -4-aroylpiperidines
1 11. 11
=
1
As u part of ii coiitiiiuing study concerning the effects of structural modificatioris 011 the activity of this n o r r l class of compounds, several 1-carbamoyl arialogs w w prepared. I n the initial pharniacological evaluatioii
