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
Kovcrnbcr 1969
1099
KOTES
TABLE I AROYLPYRROLIDINES ASD AROYLPIPERIDINES
X No.
x
1 2 3 4
p-F m-CF3 m-CF3
3
H
6 7 S 9 10 11 12 13 14 13
16
It
H
SI-I2 KHp NH2 SHCH3 OCZHS
H I1 p-F P-F P-F p-OCH3 m-CF3 P-F p-F p-OCH3 F
a
0 Purificnb solvent
yield
4 4 3 1 5
58 41 35 68 50
128-129 137-138 130-132 102-104 d
EA EA-E EA-I
3 2 3 1 2 3
118-121 71-73 137-1 40 122-124 105-107 147-148 90-92 169-172 d d
EA-I B-0 C 11-1
5 5
28 67 62 46 33 67 86 59 95 95
1
75
149-150
1 1
-
%
Prepna method
Mp,
oc
I
L IP IP IP
13
See Experimental Section. * B = C6&, C = CHCla, E = EtOH, EA = EtOAc, I = i-PmO, Ip = GPrOH, 12 iwoctane. c All compounds were analyzed for C, H, N. Analytical sample was molecularly distilled. t~
it was shown that these compounds did not generally possess potent CNS depressant activity, but did have anticonvulsant and/or muscle relaxant properties. The object of this paper is consequently to report on the preparation and anticonvulsant as well as muscle relaxant evaluation of a series of l-carbamoyl-3aroylpyrrolidines (111) and 1-carbamoyl-Caroylpiperidines (IV). I n several instances the 1-carbethoxy analogs were also synthesized.
/R XD
coDcoN
'R'
I11 DCO
