SOTES
September 1968
1093
Recrystn solventa
Tielii,
167-168 144-146 135-137 91-93 133-134 77-79 117-118
A
A
67 71 78 81 80 57 55
8
121-122
A
9
140-141 122- 124 106-108 132-134 174- 175 99-100
R
NO.
1 2 3 4
Formuhe
NHCH, NHCzHB NHCH(CH8)Z NH(CH2)zCHj NH-cyclohexyl N(CH1)z N(C2HS)z
7
6 7
10 11 12 13 14
NHCHZCHZOH SHCHZCHZCHIOH XHCHZCHOHCH, NCH2CHzOH
hlp,
oc
Toxicity M L D (mice),
.-in tiinflam act (rat)‘
;\nalyetic act. (mice)d
>3000 >3000 >4000 4000 3000 750 >e5000
0.65 0 0 0 0.67 0.80
0 0 0.50 0 0 1.20 0.39
76
>4000
1
0.57
A
86
2500
0.50
0
A C
A D
75 64 66 61
A
77
2000 1000 >2000 800 900
1.10 0.70 0.60 0.50 0.68
0.30 0.71 0.80 0.60 0
A C
A
-4 C
70
mg
‘kr p o h
0
I
15
CH3 NCHZCHzOH
55-57
A
53
1600
0.i4
1.04
16
CZHB XCHzCH?OII
76-77
C
78
>2000
0.70
0.80
CH2CHZCHzCITI NCHzCHzOII
70-i2
C
57
>2000
0.80
1.10
18 19 20 21 22 23
96-98 139-140 84-85 83-84 92-93 100-1 0 1
A A
B B B B
70 64 62 48 81 70
2300 2000 400 >3000 1000 400
1.15 0.90 0.70 0 0.90 0.80
1.00 1.20
24
115-116
C
66
350
0.64
2.i
85-86
B
67
850
1.10
0
26
97-98
A
75
4000
0
0.20
I
I
17
I
...
0 0
...
...
A fl NCH,CH,OH
D 700 0.80 27 273-274 64 0.40 U M n i m u m lethal dose. A = EtOH 95%, B = hexane, C = ether-petroleum ether (bp 30-60°), D = absolute EtOH-ether. The figures represent the activity potency obseried after administration of 100 mglkg po of substance, the antiinflammatory activity a
c
of 100 mg/kg p o of phenylbutazone being arbitrarily assumed as equal to 1. The figures represent the activity potency observed after administration of 300 mg/kg po of substance, the analgetic activity of an equal dose of aminopyrine being arbitiarily aisumed ab equal
to 1.
e
All compounds were analyzed for C, H, X.
with H,O, the CsHs layer was dried, and after elimination of the solvent a solid residue was usually obtained, which was directly crystallized from a suitable solvent (see Table I). K h e n EtOH was used as the reaction solvent, crystalline materials could often be obtained simply by dilution with HzO. When the products failed to crystallize, crystalline hydrochlorides were easily obtained. A few of the 2-substituted aminoosazoles gave crystals containing 1 mole of H,O, which could be removed by heating in vucuo. Dry crystals of 18 rapidly acquired 1 mole of H2O on standing. Z-Diethylamino-4,5-diphenyloxazole.-A solution of 11.3 g (0.15 mole) of desyl bromide and 70 g (0.6 mole) of N,N-diethylurea in 150 ml of DMF was heated on a water hath under stirring for 2 days. After removal of the solvent a t reduced pressure, the residue was treated with 150 ml of 1 XaOH solution and repeatedly extracted with ether. The ed ethereal layers left an oily residue, which was taken into i o ml of warm EtOH; hy cooling, the alcoholic solution gave 22.4 g of the titlecompound, rrystals with mp 74-75”. Pharmacological Procedures.-The acute toxicity was determined in groups of five mice treated orally with increasing doses of each compound, suspended in 5% gum arahic. All the animals were ohserved for 5 days. Llinimum lethal dose was recorded. Antiinflammatory activity was tested primarily with the rarrageenin tert.10 Grolips of ten Wistar rats (150-170 g) were
treated orally with the compounds to be tested, suspended in 3 ml of 5% gum arabic. One hour later the edema was produced by injection of 0.1 ml of 1‘2 carrageenin i n saline into the plantar siirface of the hind paw of each rat. The foot volume was measured pletysmographically immediately after the injection and 3 hr later. The per cent volume was obtained from the formula: %b edema = (J’, - T’h)100 17t,, where vh i,? the mean volume of the hind paw before, and T’, after, the carrageenin injection. A4ntiinflammatoryeffect was esprepsed as cc inhibition of edema =-: ( E , - Et)lOO/E,,where E , is the per cent edema in the control animals and Et in the treated animals. The compounds were tested a t a dose of 100 mg, kg po in comparison with the same dose of phenylbutazone. Analgetic activity was determined by the hot plate test,” using mice weighing 18-22 g. The analgetic activity was evaliiated on the basis of the percentage of animal? which showed a n increase in the reaction time recorded before and after treatment. The compounds were administrated orally i n 55; gum arabic to groups of ten mice and the activity was compared Tvith that obtained with an equal dose of aminopyrine.
(10) C. A . Winter, E. A . Risley, a n d G . 71.. Xu’s, Proc. Soc. E r p . B i d . M e d . , 111, 544 (1962). (11) G. Woolfe and A . D. MacDonald, J . Phnrmacol. E r p . T k e r . , 80, 300 (1944).
