Journal of Medicinal and Pharmaceutical Chemistry VOL. 1, No. 4 (1959)
Compounds Related to Pethidine-11. Mannich Bases Derived from Various Esters of 4-Carboxy-4-phenylpiperidineand Acetophenones PAUL A. J. JANSSEN, ANTON H. M. JAGENEAIJ, PAUL J. A. DEMOEN, CORN. VAN DE WESTERINGH, JULIENNE H. M. DE CANNIGRE, ALFONS H. M. RAEYMAEKERS, MARIA S. J. WOUTERS, STEFAN SANCZUK and BERT K . F. HERMANS Research Laboratories Dr. C. Jnnssen, Beerse ( T u r n h o u t ) , Belgium
Introduction I n a previous paper1 some physical and pharmacological properties of a series of 3-{ 1-[4'-carbethoxy-4'-phenyl]piperidino) propiophenones ( I : R' = C,H,) were described. The purpose of this second part is to present a series of 29 related esters (I) and t o compare their pharmacological properties. 0 0
p>-h-cHz-cHz-N R =
I1
' ' 7 ,o C-0-R'
I
These compounds are of general formula (I)in which R is a substituent such as alkyl, hydroxyl and halogen, and R' an unsubstituted alkyl- or aralkyl-group other than ethyl.
Preparation of the compounds The compounds were obtained by one of the methods of condensation mentioned in Part I,l using the appropriate ester. The intermediate esters of 4-carboxy-4-phenylpiperidine(11) 309
PAUL A. J. JAXSSEN ET AL.
310
0
II
C-0-R'
I1
were prepared by the procedure described by Eisleb ; the analyticad data are reported in Table I. Table I. Analytical data for the intermediate norpethidine-like esters (11)
R'
Formula
Y.P., oC, (b.p.) ~
1 2 3 4
5
CHa CH, CH, C,H, n-C,H, n-C,H, n.C,H, iso.C,H, iso-C,H, VZ-C~H~ n-C,H, sec-C,Hg n-C,H,, n-CEH,,
6 7 8 9 10 11 12 13 14 15 C E H l l 16 'EH,, 17 n-C,H,, 18 CH,CH,C,H,
C1,Hl,NO, C,,H,,NO, C,,H,;NO, Cl,HIJO, C,,H,,NO, C,,H,,XO, C,,H,lNO, C,,H,,KO,
C1,H,,NO, C,,H,,NO, C1,H,,NO, CI,H,,NO2 C,,H,SNO, C,,H,,NO, CI,H, ,NO C,,H,,NO, C,,H,,NO, C,,H,,NO,
base'"' HBr HCl HCl base HBr HC1 base@) HCl base'") HCI HC1 base(d) base@) HBr HC1 base(!) HCl
,
~~~
(b, 145) 230.5-1 209.5-12 108.8-9.4 (b, 180) 103.6-4.2 93.6-4 (b, 174) 68-9.6 (h, 165) 112-3 99-105 (h, 174-6) (b, 175-80) 185-6 244-5.5 (b, 183) 161-3
Equivalent weight
Halogen
+ -Calcd. Found Calcd.
yo
+ T
Found
~~~~~
219 300 256 282 247 328 284 247 284 261 298 298 275 289 368 324 303 346
222 306 255 277 247 326 275 243 263 260 293 309 263 271 371 323 283 345
_
_
26.62 26.37 13.86 13.53 12.58 12.40
_
_
24.35 22.50 12.49 11.91
_
-
12.49 15.22
_
_
11.91 11.80 11.91 11.95
_
-
-
-
21.70 21.76 1 0 . 9 5 10.58
-
10.25
_
9.79
The following preparation is illustrative of the general procedure.
COMPOLXDS R E L A T E D TO PETHIDINE-11
u
$ 3 -
icuv
p:
311
PAUL A. J. JANSSEN ET AL.
312
Preparation of 4-Curbobutoxy-4-phenylpiperidine (11: R' = n = C,H,) A solution of 170 g (0.5 M)of AT-tosyl-4-phenyl-4-cyanopiperidine2 in 230 g of 75 per cent sulphuric acid was made, with stirring and heating a t 140-150'. The heating was continued for 3 h. After cooling t o l l O o , the reflux condenser was replaced to allow distillation and 2 1. n-butanol added to the mixture drop-wise over a period of 3 h. The reflux condenser was then re-inserted and the mixture refluxed for another 4 h. Stirring was continued throughout the whole operation. After cooling to room temperature the solution was diluted with 1 1. of distilled water carefully made alkaline with 2 N NaOIl and the mixture extracted 4 times with 500 ml of benzene and twice with 200 ml of ether. The organic layers were collected, dried (potassium carbonate), the solvent evaporated and the residual oil fractionated in vacuo bl. 5 : 163'. Yield 76 g (58 per cent). The hydrochlorides are obtained by dissolving the free bases, before or after distillation, in ether and passing dry HC1 gas through the solution. The crude salts are filtered and re-crystallized from an appropriate solvent (e.g. isopropanol). Analytical data are recorded in Table I. The propiophenones (I) and their analytical results are listed in Table 11. Pharmacological Methods and Results The pharmacological methods were described in Part 1.1 The results for the compounds of Table I1 are recorded in Table 111. The following symbols are used : L.L. and U.L. : lower and upper fiducial (confidence) limits ( P = 0 * 05) ; S : slope ;fg : factor for computing confidence limits (P = 0.05). Table 111. Pharmacological Results
Testa
Serial number
L.L.b
U.L."
0.78 1.1 0.94
1.1 4.0
3.7
7.6
s*
fs"
mg/kg
Number of animals
~
1
R993
A.M. A.M. A.R.
CH
0.93 2.1 1.1 5.3
1.2
1.4 2.1 1.3 2.5
1.1 1.9 1.1 1.9
SO SO 60 60
COMPOUKDS R E L A T E D TO PETHIDINE-I1
313
Table 111. Pharmacological Results-cont.
Serial number
2
R 1404
3
R 1007
Testa
ED50 mg/kg
A.M. M.M. A.M.
M.X. 4
R 1041
5
R 1262
6
R 1298
7
R 1367
8
R 1494
CH A.M. M.M. A.R. CH A.M. M.M. A.M. M.M. A.hL M.M A.M.
M.M. 9
R1361
CH A.M.
L.L.*
U.L.b
3.4 11 25 41 37 2.3 3.7 3.8 16 > 80 > 80 12 13 9.2 28
3.1 8.4 22 33 30 2.0 3.3 2.8 13
3.8 15 29 51 45 2.6 4.2 5.2 18
> 80 > 80
-
21
> 80 > 80 > 80 > 80
M.M. A.M. M.M. CH
21
__ -
7.2 9.0 7.7 19
14 __
-
10
R 1488
11
R 1373
A.M. M.M.
> 80 > 80
12
R2036
A.M. M.M.
5.4 11
13
R2100
A.M.
37
M.M. A.M. X.M. A.M.
> 80
M.M.
> 80
-
A.M. M.M. A.M. M.M. CH
5.6 > 10 > 80 > 80 11 22 > 60
14 15
R 1447 R 1450
16
R 1227
17
R1233
18
R1217
A.M.
M.M.
19
> 80 103
16
_.
19 19 11 40
-
32 -
28
-
-
4.2 7.9 21
7.0 15
67
13
27
73
145
4.8
6.7
7.0 16
__ 18 30
-
-
-
-
-
-
-
-
Sb
f.6
Number of animals 170 170 85 85 30 140 140 50 37 20 25 65 65 245 245 20 20 50 15 15 20 20 39 25 25 70 70 40 40 260 260 75 75 76 75 26 25 40 76 76
PAUL A. J. JAKSSEK ET AL.
314
Table 111. Pharmacological Results-cont.
-
, .
berial
number 19
l7 1307
20
Ft 1444
21
R 1453
22 23
24
B 1446 R 1478
R 1001
R 1257
26
R 1292
A.M. h!t,M. A.hL M.BI. A.M. MAT.
> 80 > 80
2.0
72
1.7
> 80 > 80 > 80
-
86
1.4
R1278
28
R 1443
29
R 1451
L.L.8
S*
-
-
A.M. N.M. A.M.
> 80
-
56
1.2
hI.hI.
> 80
-
A.M.
4.4 5.8 3.9 16 > 80 > 80 12 > 40 > 80 > 80 15 > 26 66
1.2 1.2 1.5 3.0
A.R. CH A.M. hI.hI. A.hf.
M.X. 27
j:
ED50 mg,'kg
x3r.
25
U.L.*
Testa
A.M. 31.31. A.M. X.3S. A.h1. hf.M. a
*
> :
80
1.3
1.2
1.7
-
Number of animals 35 35 40 40 15 15 90 90 35 35 80 80 90 50 25 25 365 365 10 10 110 110 60 60
1.31.analgesic activity in mice (S.C.) M.M. mydriatic activity in mice (S C.) A.R. analgesic activity in rats (S.C.) CH charcoal meal test in mice (LP.) For deflnition see page 312.
Discussion ANALGESIC AND MYDRIATICACTIVITY IN MICE Unsubstitzcted compounds ( I : R = H ) . Table IV shows the unsubstituted compounds (I : R = H) arranged in decreasing order or analgesic effectiveness (ED50 values in pmol/kg) in mice. The results are compared with the corresponding values for serial The corresponding number R951 (I : R = H ; R' =C,R,). mydriatic activities are also shown.
COMPOUNDS RELATED TO PETHIDINE-11 Table IV.
Pharmacological results on unsubstituted compounds I (R=H)
Serial number
R951 R 993 R 1041 R 1404 R 1367 R 1298 R 1007 R 1494 R 1488 R 1262 R 1361 R 1373
315
R'
'ZH5
CH, iso-C,H, CH,-CH CH, n-C gH 11 sec-C,H, n-C,H, n-C,H,, "-C,H,, n-C,H, C,Hll CH2CH,C,H5
1.1 2.6 6.1 9.0 23 30 66 > 180 > 180 > 180 > 180 > 180
1.9 6.0 9.7 29 69 33 109 > 180 > 180 > 180 > 180 > 180
(1) For the compounds tested, shortening, lengthening, unsaturation, cyclization, or aryl substitution of the ethyl group in the ester function results in a decrease of the analgesic and mydriatic potency in mice. (2) The decrease of the analgesic and mydriatic activities proceeds in the same order (with one minor exception for R' = n-C,H,,). ( 3 ) The activity of a compound having a branched alkyl group in the ester function is a t least 6 times greater than that of the corresponding non-hranched homologue. (4)No simple relation exists between the number of methylene groups in the unbranched alkyl radical R' and analgesic or mydriatic activity. Substituted compounds I (R#H ) . I n view of the fact that predictable pharmacological effects might result from simultaneous modification of R and R' in I, the analgesic potencies of the most active esters of this series were compared with the corresponding ethyl esters discussed in Part I (Table V). As indicated by the similarity of the three activity orders of Table V, the influence of the listed R substituents on the analgesic 18
PAUL A. J. JANSSEN ET AL.
316
Table V.
Analgesic potency (ED50 in pmol/kg) and activity order of certain esters of type I R’ = Methyl
R‘
H 2-OH 4-F 4-CH3 4-OCHS 3-Br 4-CgH6 2,5-(CH,) a
R’ = Ethyl r-----J--
+ 7
R’ = isoPropy1 7
7 -
ED50
activity order
ED50
activity order
ED50
activity order
2.3 11 13 14 35 41 >I80 >180
1 2 3 4 5 6 7) 7:
1.1 2.1 2.6
1 2 3
1 2
8.0
4
28 12 100 75
6 5 8 7
5.4 28 85 51 145 >180 127 >180
4 3 6 7) 5 71
activity of methyl-, ethyl- and isopropyl-esters of structure I is almost independent of the nature of the ester function. The order of the mydriatic activities in mice of these methyl-, ethyl-, and isopropyl esters are recorded in Table VI. Table VI.
Mydriatic activity in mice (ED50: pmol/kg) and activity order R’ =Methyl
R’ =Ethyl
R’ = iso-Propyl
/---+ , r-----J+
R ;”’T/I’
H 2-OH 4-CH, 4-F 3-Br 4-OCH3 2-C,H6 2,5-(CH,)a
2.1 14 25 27 >180 60
>180 >180
activity order 1 2 3 4 7 5 7 7
>1,>f, activity order 1.9 2.9 9.6 11 20 69 >180 >180
1 2 3 4 5 6 7: 7)
activity order 3.7 93 117 >180 >180 >180 >180
>180
1 2 3 6 6 6 6 6
The correlation between analgesic and mydriatic activity is satisfactory for the more active analgesics and rather poor for the less active ones.
COMPOUNDS RELATED T O PETHIDINE-I1
317
Generally speaking, the following order of decreasing analgesic and mydriatic activity, as found in the various esters discussed in this paper, seems to be quite independent of the nature of substituent R : C,H, > CH, > iso-C,H, > others. ANALGESIC ACTIVITYIN RATS(A.R.) Only 5 compounds out of 29 have been tested for analgesic activity in rats. The results may be correlated quite well with those obtained in mice. ANTIPERISTALTIC ACTIVITYIN MICE (CH) As shown in Part I, correlation between the analgesic activity and the activity in the charcoal meal test is rather poor (see Table 111). Summary. Some pharmacological properties of a series of 29 Mannich bases derived from various norpethidine-like esters and acetophenones are described.
(Received 11 March, 1959) References Janssen, Paul A. J. et al. J . med. pharm. Chem., 1, 105 (1959) a Eisleb, 0. Ber. Dtsch. chem. Ges., B74, 1433 (1941)
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