Local anesthetic activity
ECbO,
It z
KU.
1i 2 3i 4 5k
6 7 8 9 10 11
12 i3i t t j
16 17 18k 191 20 21
22 23 24: 251 26 27 28 2Y 30" 31 32 33 34 35
36 37 38 39 400
41 42
43 44
45 46 47 48P
40 50" 51 52 53 54 55 56 57
58 XI
(io 61 62P 63 64
.
.
(C2Hs)2N (CzHs)zN [(CHa)zCH]& [(CHdzCHltN [(CHa)?CHl?N [(CHa)iCHlnN [(CHa)zCHlzN [(CH3)zCH]zN [(CHdzCHIzN [(CHa)?CH]?N [(CIIa)zCHIzN [(CIIs)?CHl?N [(CHdzCIIlzN [(CHa)?CHlzN hlorpholino hlorpholino hlorpholino Morpholino llorpholino Norpholino Morpholino hlorpholino hlorpholino llorpholino AI orpliolino Norptiolino llorpholino llorpholino Piperidino Piperidino Piperidino I'iperidino Piperidino Piperidino Piperidino Piperidino Piperidino Piperidino Piperidino
P-COCHa 2-COCHa 2-COCzHs 2-COCzHs 2-COCzHs 2-COCzHs Z-CO(CHz)zCHa Z-CO(CHdzCHa 2-COCH(CHs)? Z-CO(CHz)dCHa 2-CHOHCHzCHa 4-COCHa 4-COCHzCHa 4-CO(CHdzCHa 2-COC?Hs Z-COCZHK 2- COC?HK 2-COC?H6 2-CO(CH?)?CHa Z-CO(CHz)zCHa 2-CO(CHz)?CHa 2-COCHzCH (CHa)z Z-CHOH(CHz)zCHa 4-COCHa 4-COCzHs 4-CO (CH?)zCH3 4-COCH?CH(CHa)z 2-COCHa 2-COCzHs Z-CO(CHz)?CHa Z-COCH(CHa)z ~-CO(CHZ)?CHJ 2-CO(CH?)?CHa 2-CO(CHz)zCHa 2-CO(CHz)rCHa 2-CHOH(CH?)zC€Ia 3-COCHa 4-CO(CHz)zCHa 4-CO(CHz)aCHa 2-COCHa 2-COCzHs 2-COC2Hs 2-COCzHs 2-COCzHa 2-CO (CHz)2CH3 ~-CO(CH~)ZCHJ Z-CO(CHz)aCHa 4-COCHa 4-COCH3 4-COCiHs 4-COC?Fls l-Co(Ckj2)2('1!J 4-CO(CHi).fiiCaHio'7 2-COCzHs 2-COCzHs 2-COCzHs 2-COC2Ha P-CO(CHdzCH3 2-CO(CHz)zCHa 2-CO(CH*)aCHa 4-COCH8 4-COCzHs 4-COC2Hs 4-CO(CHz)zCHa
Ra
mdml
...
16 10 6 G 10 8 1 14 7 0.7
5-OCHa
...
4-Br 4-CHa 5-OCHa
... 5-OCHa
... ... ...
3-OH
... 3-OH
...
5-OCHa 4-Br 4-CHa
...
ti-NO? 6-NHs
... ...
3-OH
...
3-OH
... ...
... ... ... 4-CI ti-NO? ti-"?
... ... ,..
...
... 5-OCHa
...
4-Br 5-OCHa 4-CH3
...
5-OCHa
... ...
3-OH
... 3-0I I 3-Ut1
... ...
4-Br 5-0 CH 3 4-CHa , . .
5-OCHa
... 3-OH
... 3-OH 3-OH
2 25
20 5 6 2 4
Antispasinodic activity, E&, ~ n g / I . AeetylHistEpinephcholine amine rine 5HT 2 8
0.3
4
0.5 2 0.4
2
9 1 22 2
4 0.03
5 14
0.7 0.4 0.1 0.3 9 8 2 0.4
1 8 42 37 6 2 8 3
8 1
4
ti
4
5
0.2 0.4 2 32 50 21 4 4 1
30 1 0 8 34 18
0.4 9 3 20 0.1 3 0.5 55 20 18 56 14 22 15 8 16 11 15 100 58 250 22 I8 50 4
7 8 1
7 2 3 2 3 2 19 20 30 21
4
2 0 1 0 0 0
6
2 0 4
0 3 1 i6 2 1
71 40 12 i6 30 29 13 19 74 6i 56 33 18 I58
4
7 0 4 13 0 9 3 0 4 1 3
...
>250 100 3
4
11
... 3 2 2
0.8 0 9 1.4 3 7 30 28 6
...
4
4
17
0.8 0.2 0.4
2
4
2
2 1 1 30
4 3 0.04
1.5 21 > 50 4
32
io
4 20 74 44 7 13 12 8 1 3 0 7 2 3 11 37 4Y 14 4 59 35 32 47 20 23 11 0.08 186 40 >250 35
I
47
J
!J
>250 1
0.1 6 10 1 2 0.6 0.8 0.1 0.2 0.2 2 2
0.07 0.7 19 12 3 20 11 10 4
8 8 35 7 78 61 30
1 7 0 8
0.8 0.4 2 0.8 0.3 4 0.4
4
4
3 2 0 4
0.8 0.5 0.3
3 2 4 2
6 11
0.8 83 190 4
129 100 84 21 18 17 19 22 17 62 >P50 121 32 110 7 42 61 37 7 40
6
> 250
195 >250
11 2 3 0 9 3 0.9
22 41 4 13
>230
35 3 3 4 0 2 4
0 1 11 18 8 4
LDSO, mg/kg
ip 2oOa 20w 150b 140" 1105 140a 5Ob
13P 1oOa 1005 10oc 27w 240' 250" 100a 13Oa 70" 1305 1ow 60" 70a 15IY 2506 200"
200" 300" l5W 9Oa lOOQ 1025 15OU 200" 200" 385 100*
Other pliarrnacol activities
e e e
f? Y e, 0 e e NO118
e, h Ql
h
e
e None e, f e
f Sone e , 0, h e, h
f f e, A e , ti e, f h e, 8 ,
h
f, h
f3h f h
e, h
f,
11,
i
I,h f 16
300'b
e
250d 250" 150a 60OC 250d 300d 35OC 300' 280d 180C 35oc
e, k f , 11
600'
NOIIC e NOIE None None
850C 76°C 850'8 i00'
f, h None
e None None Y
o, h Kone B
120" 150" 150d 150d 120" l5P 130"
f
120c 200L" 150a 220" 200u
f, 11
e, h I1
Y, h
e, Y e, A Q e
h e e,
h
a Coiivulsions. 5 Tremors. Depression. Tremors followed by depression. e Transient decrease of arterial blood pressure. Increase of resistance of isolated heart to anoxia. 0 Inhibition of formaldehyde paw edema. h Protection against CaClz ventricular G. Di Paco and C. S. Tauro, British Patent 905,903 (Sept 12, 1962); Chem. Abstr., 58, 55768 (1963). 1 R. I. Meltzer fibrillation. and A. B. Lewis, J. Org. Chem., 22, 612 (1957). Aktiebolaget Pharmacia, British Patent 872,997 (Jan 23, 1958); Chem. Abstr., 56, 2 3 8 4 ~(1962). K. E. Kitz, W. P e w h , and A. Schmidt, ArzlzeimitteGForsch., 5,357 (195.5). m H. Grasshof (Firma hI. Woelni), German P. D a Re and I. Setnikar, Experientia, 20, 607 (1964). 0 S.-C. Patent 1,174,311 (July 23, 1864); Chem. Abstr., 61, 11933g (1964). K ~ u i gaiid C.-C. Chang, H u a Hsueh Hsueh Pao, 22, 467 (1956); Chem. Abstr., 52, 1097lh (1958). p H. Najer, P. Chabrier, and It. Guidicelli, Uu//. SOC.Chzrn. France, 16i2 (1956). f
Solx-ent of NU.
AIotl1ocl
A A
h l p , "C
crystn"
2 15-2 16 147-149 182-183 115-116 101-102 146-148 104- 106 123-124 185-187 154-156 118-120 97-99 114-1 16 175-177 118-120 99-101 155- 157 105-107 142-144 142-143 123-124 167-16gd 146-147 235-236 124-126 142-144 119-120 126-128 125-127 130-1 3 1 145-146 128-130 130- I 3 1 124- 125 152-153 109-1 11 175-177 193-195 180-182 107-109 132-133 165- 166 149-151 141-143 178 131-132 166-168 181-183 145-147
4 A-E A 8-E A-E A-E A-E Ac A A A-E A-E A I .\-E B A &E
--Citlcd, N
56--
7--
c1
Pound, %-~--.
N
5.12 12.95 5.17 4.19 10.61 4.23 -4 4.87 12.32 4.99 5.06 7 13.05 ,4 5.21 4.64 A 8 11.74 4.55 5.06 9 A 13.05 5.36 4.6i 10 A 11.82 4.95 5.39 11 D 13.65 5.69 5.39 12 13.65 -4 5.41 4.87 14 12.32 A 4.86 4.43 11.23 '4 16 4.49 3.84 17 9.72 3.86 .4 8.12 10.28 B 20 8.22 7.98 20.19 21 C 7.94 4.46 22 11.29 A 4.23 4.64 11.75 23 D 4.60 4.43 11.23 26 A 4.45 4.46 11.20 A 27 4.57 4.67 -4 11.82 28 A 4.56 4.46 A 11.29 20 4.36 A 4.27 A 10.81 ,4 31 4.31 4.30 10.88 32 B 4.44 7.51 33 A 9.51 7.70 7.38 18.70 I 34 7.32 C 4.10 A 10.37 3.85 35 A 4.24 10.74 I 4.25 D 36 4.67 A 11.82 4.63 37 -4 4.27 10.81 A 4.38 A 38 4.10 A 10.37 4.08 A 39 4.67 11.83 A-E: A 4.70 41 3.70 A-E 9.36 3.i 8 A 42 4.25 10.75 4.24 A A 43 11.29 4.46 A-E 4.40 A 44 11.29 4.46 A 4.47 45 A 4.07 10.31 A A 4.05 46 4.27 10.81 -4-I2 4.25 A 47 4.64 11.75 A A 4.64 49 4.44 11.23 4.41 A A 51 4.25 10.75 A-E A 4.22 52 4.76 11.91 A-E 4.76 A 54 3.72 9.42 A-E 3.77 A 55 4.27 10.81 A A 4.30 56 4.49 11.36 A-E 4.55 57 A 11.36 4.49 A 4.52 A 58 4.10 10.37 A A 4.36 59 10.88 4.30 I 4.63 A GO 11.83 4.67 4.66 A B 61 4.46 11.29 A A 4.50 63 10.81 4.27 A A 4.27 64 A n d . Calrd: C, 60.11; H,8.54. 0 A = ethanol, E = ethyl ether, I = %propanol, Ac = acetolie, B = 2-bulniioiie. Bp, "C (1 nun). e A n d . Calcd: C, 60.19; H, 8.79. Anal. Calcd: C, 63.66; H, 9.35. Found: C, 63.33; €1, 9.44. 13, 8.66. Found: C, 66.31; H, 8.70. AnaE. Calcd: C, 65.53; H, 9.78. Found: C, 65.58; H, 9.56. 2 4 6
u
Anal. Calcd for C11H,403:
C, 68.02;
H, i.27. Found:
C, 67.80; H, 7.02.
Pharmacological Methods. Acute Toxicity.-LDro values were determined on Swiss "S3IZ" mice, intraperitoneally, and the mortality within 24 hr was recorded. The animals were also observed for qualitative signs of intoxication following the Irwing scheme. Local Anesthetic Activity.-All compounds were tested for subcutaneous local anesthetic activity on the mouse tail according to Bianchi's method.' ( 8 ) C. Dianchi, Brit. J . Phurrnacol., 11, 104 (19Sti).
c1 13.05 10.70 12.15 13.18 11.45 13.26 11.99 13.63 13.61 12,28 11.36 9.72 10.22 20.19 10,99 11.64 11.06 11.21 12.11 11.08 11.07 10.90 9.67 18.91 10.59 10.90 11.50 10.51 11.85 9.43 10.55 11.29 11.37 10.38 10.F4 11.75 11.23 10.64 11.91 9,48 10.85 11.57 11.
