Journal of Medicinal and Pharmaceutical Chemistry TOL. I, S O . 1 (1959)
Compounds Related to Pethidine-I. Mannich Bases Derived from Norpethidine and Acetophenones PAUL A. J . JANSSEN, ANTON H. M. JAGENEAU, PAUL J 9 DEMOEN, CORN. VAN DE WESTERINGH, ALFONS H. M. RAEYMAEKERS, MARIA S. J. WOUTERS, STEFAN SANCZUK, BERT K. F. HERMANS and JOZEF L. M. LOOMAN S Pharmacological, Analytical and Chemical Departments of Research Laboratories Dr. C. Janssen, Beerse ( Turnhout), Belgium
Introduction Since the discovery of pethidine (I) a large number of compounds of related structure have been prepared and screened for analgesic activity. A nEmber of excellent reviews on this subject are available.l-10
I
The purpose of this series of papers is to summarize our experinientswith ‘compoundsrelated to pethidine ’,which are symbolized by general structure 11. Structure I1 represents a secondary or tertiary heterocyclic amine (pyrrolidine, piperidine, hexa- or
TI 105
106
PAUL A. J. JARSSEN ET AL.
hepta-methyleneimine), R” is a substituent such as ester, ketone, aldehyde, amide, and R”’ is an aromatic nucleus which may be substituted. R” and R”’ are attached to the same carbon atom of the heterocyclic ring, which may also be substituted by alkyl or aralkyl groups, e.g. 3-niethylpiperidine, 2-benzylpyrrolidine, etc. I n this paper? the physical and pharmacological properties proof a series of 3-{ 1-[4’-carbethoxy-4’-(R-)phenyl]-piperidino-} piophenones (111),i.e. N-substituted norpethidine derivatives, are described. 0
0
/I
Methods
Xyizthesis Mannich bases of type I11 are available by using one of the three following classical methods :
Method A : Mannich reaction between a suitable acetophenone and norpethidine. Method B : condensation of a suitable phenyl vinyl ketone and iiorpet hidine. Nethod C: condensation of a suitable 2-haloethyl phenyl ketone and norpethidine. The use of the methods as exemplified in the preparation of 2-(4’-csrbethoxy-4’-phenylpiperidyl) -propiophenone hydrochloride (R 951) is described. Method A . A mixture of 10.8 g ( 0 . 0 4 mol) of 4-carbethoxy4-phenyl piperidine hydrochloride, 1 . 8 g (0.06 mol) of paraformaldehyde, 4 . 8 g ( 0 . 0 4 mol) of acetophenone, and 0.25 rnl of
concentrated hydrochloric acid in 30 ml of isopropanol pfas heated under reflux. After boiling for 1 h, another 1.2 g (0.04 mol) of paraformaldehyde was added, and refluxing continued for 2 h. The resulting solution was slowly cooled to -loo, and the
COMPOUNDS R E L A T E D TO P E T H I D I N E
107
white crystalline product which precipitated was filtered. Concentration of the mother liquor yielded a second crop of crystals. Recrystallization from a mixture of ethanol and acetone gave pure 2-(4'-carbethoxy-4'-phenylpiperidyl)-propiophenone hydrochloride (R 951) m.p. 176 to 176" in 90 per cent yield. Method B. A mixture of 13.5 g (0.06 mol) of norpethidine hydrochloride, 6.4 g (0 * 05 mol) of phenyl vinyl ketone and 0 25 ml of concentrated hydrochloric acid in 60 ml of isopropanol was heated under reflux for 40 h. The hot reaction mixture was filtered and the filtrate slowly cooled to -10". The precipitate was recrystallized from acetone to give 2-( 4'-carbethoxy-4'-phenylpiperidyl) propiophenone hydrochloride in 80 per cent yield. Method C. A mixture of 13.5 g ( 0 . 0 5 mol) of norpethidine, 0.025 mol of w-chloropropiophenone and 0 . 1 g of potassium iodide in 30 ml of xylene were heated in a sealed tube for 48 h at a temperature of 140 to 146". After cooling, 50 ml of petroleum ether w+ere added to the clear solution and norpethidine hydrochloride precipitated. After filtration, the solvents were evaporated and the residue dissolved in dilute aqueous hydrochloric acid. The filtrate of this solution was made alkaline with sodium hydroxide and extracted with ether, the base converted to the hydrochloride and recrystallized as described above. The physical date of the compounds used in this investigation are recorded in Table I. The majority of these compounds were prepared only once and no effort was made to study optimal conditions of synthesis. Crude yields were satisfactory (40-90 per cent) in most cases. All compounds were purified by repeated crystallization of the hydrochlorides in a variety of solvents. The intermediates were prepared using classical methods of synthesis.
Physicochemical Analysis Equivalent weights were determined by titration with perchloric acid in glacial acetic acid. The Hershberg apparatus was used for melting-point determinations. Ultraviolet spectra were recorded with a calibrated Beckman DK-2 recording spectrophotometer (solvent : 90 nil isopropanol + 10 1111 HCl O - l X ) .
108
PAUL A. J. JANSSEK ET AL.
COMPOUNDS R E L A T E D TO P E T H I D I N E ? ?
k l N N I l l
110
PAUL A. J. JANSSEN ET AL.
Pharmacological Methods ,411 methods used have been described previously.11 Analgesic activity in mice and rats after subcutaneous injection was determined using the ‘hot plate’ method. Mydriatic activity in mice (subcutaneous injection) was evaluated using a modified Pulewka method. The inhibition of the gastro-intestinal rate of propulsion of a charcoal meal in mice was determined after intraperitoneal injection. The results were statistically evaluated using the graphical method of LITCHFIELDand WILCOXON~~, and expressed using the following symbols :-ED50 : median effective dose (mg/kg); L.L. and U.L. : lower and upper fiducial (confidence) limits (P= 0.05) ; S : slope ; f, : factor for computing confidence limits (P= 0 * 05) ; S.C. = subcutaneous injection; I.P.=intraperitoneal injection.
Results and Discussion The main purpose of this series of papers is to describe experimental results. KO effort is made in this series to consider the correlations between structure and activity from the theoretical point of view. I n our opinion such a study should be based on quantitative data obtained and confirmed by various independent investigators. There are good reasons to believe that comparable analgesic potency ratios in mice by subcutaneous injection may be obtained by various independent investigators with the modification of Eddy’s hot plate method used in these investigations.l3 The reproducibility of the three other tests used in this experiment has not yet been investigated. The analytical and pharmacological results obtained with 44 Mannich bases derived from norpethidine and various acetophenones are listed in Tables I and 11. For the hydrochloride of the simplest representative of this series, derived from acetophenone itself (I11:R = H ; R 951), the following potency ratios are computed: analgesia in mice analgesia in rats mydriasis in mice charcoal meal test
pethidine =I 58 195 34 12
morphine =1 26 68 17 2
heroin =1 4.5 4.8 2,7 2.4
111
CONPOUNDS R E L A T E D TO P E T H I D I N E Table 11. Pharmacological results Serial number
1
R951
2
RlllO
3
R1597
4
Rl564
5
R 1180
6
R1208
7
R958
8
R966
9
R967
10
R1296
11
R987
12
R1250
13
R956
ED50
L.L.7
0.44 0.76 0.21 4.52 0.37 0.78 0.14 3.38 0.51 M.M. 1.47 A.R. 0.18 A.X. 1.10 M.M. 4.60 0.44 A.R. A.M. 27.0 M.M. > 3 7 . 5 CH 11.5 1.29 A X 3I.X 2.56 A.R. 1.44 A.M. 7.80 M.M. 17.0 CH 10.5 5.90 A.N. J1.N. 9.65 9.85 CH A.M. 9.00 M.M. 16.2 CH 11.3 A.M. 14.6 M.i\I. 16.7 A.M. 2.00 M.M. 4.10 A.R. 1.94 CH 6 . do A.M. 0.88 1CI.M. 2.10 A.R. 0.73 3.46 CH A.M. 3.34 31.31. 4.00 A.R. 1.62 c13 9.10
0.40 0.69 0.19 3.48 0.32 0.66 0.12 2.56 0.39 0.98 0.15 0.81 3.11 0.35 22.0 8.46 1.09 2.15 1.29 6.39 12.7 9.15 5.04 8.62 6.94 7.83 14.1 7.11 11.7 13.1 1.56 3.11 1.57 5.46 0.78 1.53 0.60 2.23 2.90 3.39 1.36 7.34
Test"
A.31. M.M. A.R. CH A.M. 31.31. A.R. CH A.M.
-
St
fs 7
0.49 0.84 0.24 5.88 0.43 0.92 0.17 4.46 0.65 2.21 0.21 1.49 6.81 0.55 33.2
1.57 1.75 2.06 2.04 1.87 2.05 1.65 1.70 1.51 1.93 1.50 2.13 2.07 1.85 2.08
1.04 1.04 1.11 130 1.14 1.20 1.12 1.40 1.22 1.65 1.11 1.37 1 .50 1.17 1.29
15.6 1.52 3.05 1.61 9.52 22.8 12.5 6.90 10.8 14.0 10.4 18.6 18.0 18.3 18.8 2.56 5.91 2.41 7.74 0.99 2.88 0.87 5.36 3.84 4.72 1.94 11.3
3.52 1.82 1.65 1.57 1.86 1. 76 1.36 1.79 1.51 1.77 1-82 1.65 1.71 1.71 1.72 2.15 2.13 1.74 1.62 1.44 1.98 2.10 2.77 1.56 1.53 1.60 1.39
1.81 1.15 1.13 1.12 1* 19 1.34 1.11 1.20 1.16 1.46 1.11 1.11 1.61 1.31 1.25 1.29 1.34 1.24 1.11 1.07 1.34 1.70 1.90 1.14 1.36 1.26 1.16
U.L:r
-
-
-
Number of animals 310 310 505 99 260 260 148 48 e0 60 97 99 99 120 115 115 141 140 140 120 85 85 60 130 130 29 130 130 28 9.5 95 85 85 90 128 150 150 119 4i 80 80 80 38
PAUL A. J. JAXSSEN ET AL.
112
Table 11. Serial number
14
R96l
15
R 962
16
17
18
R963
R 965
R986
Test"
A.N. 1I.X CH A.M. M.M. CH A.M.
M.M. CH A.M. 31.M. CH A.M.
M.M. 19
Rlll5
20
R1140
21
RlOll
22
R 1017
23
R 1008
24
R 1256
A.R. CII A.M. X.M. CH A.M. 31.x CH A.M. M.M. CH A.M. M.M. CH A.M. M.M. CH A.M.
M.M. 33
R 1213
26
R955
CI-I &4.M. R1.M. A.R. CH A.M. M.M. -4.R. CH
Pharmacological results-cont.
ED50
L.L.?
U.L.?
St
85.0
(51.6
117.3
1.88
1.48
34.0 33.5 > 80 14.1 46.0 > 75 23.8 > 50 > 50 10.0 0.87 1.22 1.57 7.10 4.82 7.30 37.4 12.1 14.2
29.6 23.9
39.1 46.9
1.26 2.19
1.14 1.46
8.81 35.9
22.6 58.9
2.17 1.85
2.00 1.27
15.3
37.1
2.07
1.83
-
-
-
-
-
-
5.81 0.76 1.03 1.08 4.44 4.27 6.19 29.9 10.7 11.8 5.12 59.3 __ 19.1 40.3
17.2 0.99 1.45 2.28 11.4 5.45 8.61 46.8 13.7 17.0 14.1 126.3
2.42 1.55 1.93 1.53 2.15 1.36 1.61 1.67 1.36 1.72 2.68 1.86
1.97 1.09 1.17 1.48 1.98 1.09 1.20 1.54 1.16 1.44 1.99 1.38
48.8 77.8
2.15 2-13
1.68 1.55
7.26
15.5
1.87
1.59
-
> 100
8.50
86.5
> 100 30.5 56.0 > 50 10.6 > 50 > 50 30.0 9.80 21.2 5.05 2.60 4.22 2.22 10.4 12.2 29.9 13.1 28.0
-
-
-
-
-
-
-
-
-
-
-
-
-
f,?
-
-
-
-
-
__
-
-
-
26.6 8.67 16.1 3.28 2.24 3.70 1.63 6.71 10.2 21.8 10.7 18.9
33.9 11.1 28.0 7.78 3.02 4.81 3.02 16.1 14.6 41.0 16.0 41.4
1.15 1.51 1.82 4.13 1.69 1.43 2.36 4.14 2.06 3.43 1.88 1.57
1.10 1.10 1.40 1.77 1.19 1.12 1.67 2.48 1.28 2.00 1.30 1.42
Number of animals 30 30 50 65 65 30 58
55 30 60 60 37
155 155 40 30 105 105 38 70 70 38 30 30 39 65 65 30 25 25 48 125 125 99 140 140 58 78 145 145 99 30
COMPOUNDS R E L A T E D TO P E T H I D I K E
113
Table 11. Pharmacological results-cont.
Serial number
Test"
ED50
L.L.7
U.L.?
St
fst
1.64
1.67
Xumber of animals
27
R 1382
A.M. M.M. CH
55.0 > 50 4.95
42.0
72.1
3.13
7.82
3.87
28
R 1385
7.22 27.7 43.7
2.19 1.74 1.93
1.35 1.26 1.65
R1189
-
-
-
-
-
-
30
R1108
5.55 20.8 29.1 > 100 > 100 5.85 8.75 34.8
4.27 l5.G 19.4
29
AX. M.M. CH A.M. M.M. A.M. 1f.M. CH
4.88 7.06 27.8
7.02 10.9 43.5
1.86 1.90 1.56
1.31 1.38 1.45
120 120 30 15 15 100 100 29
31
R 1003
A.M. CH
3.80 4.63 3.79 13.7
3.28 4.03 2.85 9.13
4.41 5.32 5.04 20.6
1.50 1.37 2.49 1.90
1.18 1.12 1.90 1.63
90 90 80 29
A.M. M.31. A.R. CH
2.60 3.65 4.60 17.2
2.18 3.23 3.33 14.1
3.09 4.12 6.35 21.0
1.74 1.45 1.88 1.46
1.16 1.09 1.61 1.34
125 123 30 26
A.M.
14.0 26.8 26.3
11.1 23.1 14.0
17.6 31.1 50.4
2.74 1.58 3.53
1.40 1.10 3.10
180 180 40
4.84 12.3 4.50 16.4
2.28 2.85 3.34 1.73
1.35 1.71 1.40 1.49
95
1.19
M.M. A.R. 32
R977
33
R988
X.N. CH
34
35
R1157
R1141
37
R1105
R 1085
1.97
3.75 8.60
A.R. CH
3.75 11.7
2.91 6.01 3.13 8.36
A.M. M.31.
17.3
14.3
20.9
1.54
> 20
-
-
-
-
28.0
19.3
40.6
2.59
2.08
41.8 > 50 52.5 > 100 > 100 29.0
32.4
53.9
1.86
1.79
A.M. M.M. CH A.M. CH
39
-
A.M.
R1.X 35
-
M.M.
CH 3G
-
R 122G
A.M.
54.0
> 75
R 994
M.M. AM. ivr.&f. CH
29.1 > 40 34.0
-
-
-
-
34.1
80.9
1.65
1.51
-
-
-
-
19.5
43.2
1.91
1.62
38.0
76.7
2.25
1.85
-
25.5
-
26.4
-
33.2
-
43.9
-
-
1.52
1.26
-
-
1.34
1.32
35 35 85
95 309 39 65 65 49 45 45 30 15 15 30 39 39 80 80 40
PAUL A. J. JAKSSEN ET AL.
114
Table 11. Serial number
Pharmacological results-conl.
Test"
ED50
L.L.?
U.L.t
St
fst
Number of animals
5.80 15.5
9.96 32.6
4.22 2.67
1.44 1.41
265 265 50 50
40
R1388
-4.X 3I.RI.
7.60 22.5
41
R1284
A.M. M.M.
> 100 > 100
-
-
-
-
-
-
-
-
A.M. JIM.
66.1 > 75
50.5
86.6
-
1.65
1.45
-
> 100 > 100 > 100 > 100
-
-
-
-
-
-
10 10
-
-
-
-
15
53.0 70.0 142.0 32.5
48.2 61.4 118.3 20.3
58.3 79.8 170.4 52.0
1.52 1.58 1.45 2.16
1.22 1.32 1.20 1.49
135 135 40 30
42
R1293
-
-
-
45 43
43
R1304
A.M. M.N.
44
R1184
A.M. JI.1II.
45
Codeine A.M. phosM.I.1\1. phate A.R. CH
46
Pethidine HCI
A.M. M.M. A.R. CH
25.3 25.7 41.0 56.0
23.2 24.0 36.6 38.1
27.6 27.5 45.9 82.3
1.71 1.43 1.51 1.56
1.11 1.05 1.13 1.40
364 364 201 30
47
Xorphine hydrochloride
A.M. M.M. A.R. CH
11.4 12.9 14.3 9.00
10.8 11.9 13.0 6.25
12.1 13.9 15.7 13.0
1.69 2.01 1.54 7.47
1.07 1.19 1.04 1.58
705 570 368 279
48
(+) Methadone HCl
A.M. A.R. CH
5.19 4.69 5.14 3.50
4.81 4.42 4.59 2.67
5.61 4.97 5.76 4.59
1.61 1.33 1.56 2.57
1.20 1.10 1 *20 1.33
285 285 110 124
M.M.
15
49
Heroin
A.M. M.M. A.R. CH
2.00 2.03 1.00 10.8
1.84 1.85 0.85 6.39
2.18 2.29 1.17 18.3
1.52 1.59 1.20 2.79
1* 15 1.17 1.12 2.03
185 185 40 40
50
R875 (Dextromoramide, Palfium)
A.M. 3f.M. A.R. CH
0.65 0.73 0.38 3.72
0.58 0.64 0.35 3.05
0.72 0.82 0.42 4.54
1.64 1.78 1.39 1.68
1.07 1.10 1.05 1.17
185 185 358 70
*A t
X analgesic activity in mice (S.C.) M.M. mydriatic activity in mice (S.C.) A.R. analgesic activity in rats (S.C.) charcoal meal test in mice (I.P.) CH For definition, see page 110.
COMPOUNDS RELATED TO P E T H I D I X E
115
Replacement of the N-methyl group of pethidine by propiophenone increases the analgesic potency in mice and rats respectively about 60 and 200 times. R951, therefore, is about as active as Dextromoramide (R 875) in both species. A detailed pharmacological investigation of R 95 1 will be published elsewhere ;12 the free base, R 1110, exhibits pharmacological results identical with those of the salt. Substitution in the Phenyl Ring of 111 The influence of a substituent R in the phenyl ring N-alkyl group (111)of R 951 on the analgesic activity in mice is summarized below. The ED50 values are expressed as ,umol/kg to allow comparison. (1) Kine substituents were introduced in meta- and parapositions (see Table 111).I n all cases the meta-isomer was an average of 4 times more active than the para-isomer. The meta-fluor0 Table 111 ED50 (pmol/lrg) 111, R =
c
F CH 3
c1 KO * OCH, CN OH Br Piperidine
ineta
para
1.2 2.1 3.0
2.6 8.0 17.9 31.3 28.2 40.5 28.9 18.7 > 200
5.8
6.0 8.8
11.5 12.3 127
-7 p / m ratio
Order of activity r------
meto
7
paru
2.2 3.8 6.0 5.4 4.7 4.6
2.5 1.5 > 1.6
derivative, R1597, is about as active as R95l itself (ED50= 1 1 pmol/kg), while all other derivatives are significantly less active. I n order of decreasing activity these meta- and paraderivatives may be ranked as follows: F > CH, > C1> NO, OCH, CN OH Br > piperidine.
- - -
-
PAUL A. J. JANSSEN ET AL.
116
( 2 ) When a methyl group or a halogen atom as substituent R is replaced by a heavier alkyl group or halogen atom, the analgesic activity decreases. The following examples are available to illustrate this point ; the figures in parentheses representing ED50 values in pmol/kg.
3-F ( 1 * 2) > 3-Cl ( 3 0) 4-F (2.6)>4-C1 ( 1 7 . 9 ) > 4 - B r ( 1 8 . 7 ) > 4 - 1 (27.7) 4-CH3 (S * 0) > 4-C,H5 (107 * 0) > 4-t-C4H9 ( > 110) 4-OCH, (2S.2) > 4-OC3H, ( > 200) 3-N(CH,) ( 15* 8) > 3-piperidine ( 126.6). (3) The introduction of more than one substituent R in the phenyl group of R 9 5 1 results in considerable loss of activity in seven out of eight examples studied : 2,5-(CH,),: 7 7 . 9 pmol/kg 2,4-(CH,),: 197.7 pmol/kg 2,5-(OH),: 1 9 9 . 3 pmol/kg 2-OH, 4-CH3: 129.6 pmol/kg 2-CH3, 4-OH : > 110 pmol/kg 3, 4 : 5-(OCH,),: 111.8pmol/kg 4-OH. 3,5-(0CH3)2:1 1 . 6 pmol/kg 3,5-(COCH,),: 111.1 pmol/kg
No correlation between the effects on activity of separate and combined substituents is apparent. (4) The results for five sets of ortho-, naeta- and para-isomers are recorded in Table IV. Table I V
ED50 in +mol/kg
111, R =
ortho
ineta
para 28.9 8.0 31.3 28.2
OH
2.1
11.5
CH,
4.8 8.5 22.7
2.1
N O2
OCH, C1
Order of activity r
r----h___-7
61.9
5.8 6.0 3.0
17.9
ortho
rnetn
paTa
1
5 1
4
a 3
3
4
4
5
2
1 6 3 2
COMPOUNDS R E L A T E D TO P E T H I D I N E
117
I n three cases (CH,, NO, and OCH,) the order of activity of the isomers was meta > ortho >para. For chlorine the ortho-isomer was less active and for OH the ortho-isomer was more active than both other isomers. ( 5 ) Acylation of the 3-OH-derivative of R951 resulted in a twofold increase in activity (ED50= 5 85 and 11 5 pmol/kg respectively). (6) Introduction of the para-substituents CH,CN, COOCH,, 9
Table
V Order of activity
ED50 in pmol/lrg 111, R =
analgesia
H 3-F 2-OH 3-CH3 4-F 3-C1 2-CH, 3-NO, 3-OCH3 4-CH3 &NO, 3-CR’ 3-OH 4-OH, 3,5-(OCH,), 3-Br 3-OCOCHa 3-N(CH,), 4-C1 4-Br 2-OCH, 4-1 4-OCH3 4-OH 4-N02 3,4,5-(OCH,)a
Ratio
7 \
1.1
1.2 2.1 2.1 2.6 3.0 4.8 5.8 6.0 8.0 8.6 8.8 11.5
11.6 12.3 12.7 15.8 17.9 18.7 22.7 27.7 28.2 28.9 31.3 111.8
mydriasis 1.9 3.5 2.9
------
analgesia
mydriasis
1 2 34 36
1 3 2 4 11 5 9 6 8 7
11.0 5.9 9.9 8.1 9.7 9.6 10.4 20.1 17.5 43.5 20.0 19.0
1.7 2.9 1.4 2.4 4.2 2.0 2.1 1.4 1.6 1.2 1.2 2.3 1.5 3.8 1.G 1.5
9 10 11 12 13 14 16 16
46.7 39.0 33.7 49.1 29.7 69.2 34.0 60.0 85.4
3.0 2.1 1.8 2.2 1.1 2.5 1.2 1.9 0.8
17 18 19 20 21 22 23 24 23
5.0
5
6 7 8
10 15
12 20 14 13 21 19 17 22 16 24 18 23 25
PAUL A. J. JANSSEN ET AL.
118
NHCOCH,, NEt, and OC,H,NMe, results in a considerable decrease of activity (ED50= 94.8 ; > 200; 63 4 ; > 200 ; > 200 pmol/kg respectively). Ten of the most active compounds were screened for analgesic activity in mice and in rats. I n spite of the small differences in activity between the successive members of this series, the correlation between analgesic activity in mice and in rats is satisfactory. However, four compounds (H, 3-F, 4-F and 4-CHJ are about twice as 'active' in rats than in mice, and one compound (2-OH) is less active in rats.
Comparison of Analgesic and Mydriatic Activities The analgesic and mydriatic activities for 25 compounds of this series are recorded in Table V and illustrated in Fig. 1. The correlation between both sets of values is highly significant. The average 'mydriatic ED50: analgesic ED50' ratio of 2 is significantly higher than observed with codeine, morphine, pethidine, heroin, and Dextromoramide (R 875).
~;1~~~-~~~-~%~2~5
0
HCL
o
9
R
-
0
A 1
m
>
1
1
~
1
~
1
1
l
1
Analgesia in mice 17 rats Mydriasis in mice 31
1
Y
A -
*'
100-
P
R 0 ,
m
I
R= H
p
o
m
,
I
p
m
I
I
I
l
p
p
---v-v--v--+-
1
I
F
CL
Br
I
I
l
,
o
I
,
~
m
~
I CH3 C2H5 OH
l
~ O ,".
l
o
l
m
I
OAc
l
l
l
I
p o m ~ I / / NO2 CN NMe,
~ 1
m T
1
l I
~
o m I NHAc
0
Fig. 1. Influence of the nature and the position of substituent R on analgesic and mydriatic activity
P
~
~
~
~
P
~
CONPOUNDS RELL4TED TO PETHIDINE
119
Comparison of Charcoal Meal Results and Analgesic Activities The correlation between analgesic activity in mice and the activity in the charcoal meal test is very poor. This point is graphically illustrated in Fig. 2 . The most active analgesics are
E D 5 0 (analgesia) -+
Fig. 2 .
mg/kg S.C.
Correlation between analgesic activity in mice and activity in the charcoal test of R 951 and 32 related compounds
relatively weakly active in the charcoal meal test, but relatively high antiperistaltic activity is observed among some of the weaker analgesics related to R 951. Summary. The analgesic, mydriatic and antiperistaltic properties in mice and rats of a series of 44 &Iannich bases derived from norpethidine and various acetophenones are described.
(ReceiGed 8 N a y , 1958.) References
*
BRAENDEN, 0. F. and WOLFF,P. 0. Bull. World Hlth Org., 10, 1003 (1954) BRAENDEN, 0. F., EDDY,N. 13. and HALBACH, H. Bull. World Hlth Org., 13, 937 (1955) BERGEL,F. and MORRISON,A. L. Quart. Rev.chem. SOC.,Lond., 2, 349 (1948) BECKETT, A. H. and Casu, A. F. Bull. Narcot., 9, 37 (1967) EDDY,pu’. B., HALBACH, H. and BRsENDEN, 0 . J. Bull. World Hlth Org., 14, 353 (1956)
120
PAUL A . J. JANSSEN ET AI,.
EDDY,N. B. J . Amer. Geriat. SOC.,4, 177 (1956) EDDY,N. B. J . chron. Dis., 4, 59 (1956) 8 HARPER, N. J. Mfg Chem., 28, 213, 271, 322 (1957) LEE,J. Medicinal Chem., John Wilsy, New York, 1, 438 (1951) I DSUTER,C. &I. Medicinal Chem., John W h y , New York, 2, 218 (1956) l 1 JANSSEN, P., JAGENEAU, A. J. Pharm., Lond., 9, 381 (1957) l a JANSSEN, P., JAGENEAU, A., DE JONGH, D. K. and VAN PROOSDIJHARTZEMA, E. G . Acta physiol. pharm. neerl., 7 , 373 (1958) I* EDDY,N. B., DE JONGH, D. K. and JANSSEN, P. In preparation 14 LITCRFIELD, J. and WILCOXON, F. J. Pharmacol., 96, 99 (1949)
