Journal of Medicinal Chemistry, 1974, Vol. 17, No. 7 745
Notes
Notes tial therapeutic utility as neuroleptics or anti-Parkinson agents. John L. Archibald* and Meier E. Freed In general, the pharmacological outcome of replacing a piperidine by a piperazine ring in these 1,4-bis(indolylethResearch Division, Wyeth Laboratories Znc., yl) compounds was to enhance central nervous system efRadnor, Pennsylvania 19087. Received December 26, 1973 fects. Considerable control of the ratio of CNS and CVS activities was accomplished through variation of the numIn a previous publication1 we described a series of 1,4ber and positions of alkyl substituents in the indole and bis(2-indol-3-ylethyI)piperidinespossessing antihypertenpiperazine rings. sive and central nervous system depressant activities. The Chemistry. Two main synthetic approaches were pharmacological interest in that series prompted us to extend the work to include 1,4-bis(Z-indo1-3-ylethyl)pipera- adopted. Firstly, the convenient route to tryptamine derivatives established by Speeter and Anthony5 was emzines and a considerable number of these compounds are deployed, following the conditions used by Ames, et u L . , ~ for patent^.^,^ A recent publiscribed in our U. K. and U. preparation of the indoleglyoxyloyl chlorides. These were , ~ the synthesis of cation by Brewster, et ~ l . presented then allowed to react with the appropriately substituted some 1,4-bis(2-indol-3-ylethyl)piperazines,two of which piperazines in 1,Z-dimethoxyethane (DME) a t room temwere disclosed in the foregoing patents; the remaining perature to give the amides (Table I) in virtually quantithree differed in the position of a methoxyl substituent. tative yields; only bis products were produced even in the The main pharmacological activity found by these authors presence of excess piperazine. LiAlH4 reduction of the was a long-lasting lowering of the blood pressure of metaamides was preferably carried out in DME to give the corticoid hypertensive rats. We were prompted to present final products in high yield (Table 11, method A). Alternaour results here since pharmacological evaluation of our tively, these final products could be obtained in one step more extensive series emphasized different aspects of the by dialkylation of the piperazines with indol-3-ylethyl haactivity profiles of these compounds and indicated poten-
1,4-Bis(2-indo1-3-ylethyl)piperazines
s.
Table I. 1,4-Bis (indoleglyoxyloyl)piperazines
RI
NN -
Crystn solvent
% yield
R1
RP
1
H
H
H
DMEa
97
>360
2
H
H
H
DMFb-HZO
65
330 dec
3
H
H
H
DMF
63
361-362 dec
4
H
H
H
DMACc-H2O
52
337-339
5
H
H
H
DMF-H20
55
290-291
6
H
Me
H
DMF-HZO
95
345-346 dec
7
H
Me
H
DMF-H20
44
342-343 dec
8
H
H
H
DMF-H20
18
342-343 dec
9
H
H
H
DMF-Hz0
55
322-324
10
H
H
H
DMF-H20
43
348-350 dec
11
H
H
H
DMF-Hz0
71
307-308 dec
12
H
H
Br
DMF-HzO
70
>360
13
H
H
Me0
DMF-H20
46
365 dec
Compd
W
MP, "C
Formulae
a1,2-Dimethoxyethane. bN,N-Dimethylformamide. cN,N-Dimethylacetamide. dDMF solvate. C, H, and N analyses were obtained on all compounds and were within ~50.4% of theory except where noted. f C : calcd, 67.28; found, 66.69. C: calcd, 68.41; found, 68.92.
746 Journal of Medicinal Chemistry,1974, Vol. 17, No. 7
Notes
Table 11. 1,4-Bis (indolylethyl) piperazines
R3 R3
R1 n
R1
Compd
R2
R3
R1 Crystn solvent
% yield
Mp, OC
14
H
H
H
EtOH-HzO
72
195-197
16
H
H
H
CsHs
66
107-108
16
H
H
H
DMAC
76
202-204
17
H
H
H
EtOH-H20
42
157-158
18
H
H
H
EtOAc
48
175-176
19
H
Me
H
DMF-H20
81
240-243
20
H
Me
H
DMF-HI0
76
182-208
21
H
H
H
EtOH
97
174-176
22
H
H
H
EtOH
34
80-105
23
H
H
H
E tOH-H20
36
100-107
24
H
H
H
EtOH
51
189-190
25
H
H
Me0
DMF-Hg0
23
210-211
26
Me
H
H
EtOH
71
129-131
27
Me
H
H
n-Hexane
54
81-84
28
Me
Me
H
DMF-H20
85
176-178
29
Et
H
H
EtOH
97
125-127
30
C6HsCHi
H
H
EtOAc
68
158-161
Formula.
Method
"C, H, and N analyses were obtained on all compounds and were within &0.4% of theory except where noted. 'C: calcd, 77.96; found, 77.47. cC: calcd, 68.30; found, 68.85. dFumarate. eMaleate. lides in DMF a t room temperature (method B). Particular emphasis was placed on introducing an increasing number of alkyl substituents including stereoisomers where appropriate. Modifications to the piperazine ring included increasing the size (homopiperazine), introducing a fused phenyl ring (tetrahydroquinoxaline), and an open-chain variant (ethylenediamine). Substitution in the indole ring was achieved either by starting with the appropriately substituted monoindole intermediate or, in the case of N substituents, by alkylation of the corresponding N-unsubstituted bis compound (method C). Biological Results. Renal hypertension was produced in female rats and their systolic blood pressure was rewere administered intraperitocorded i n d i r e ~ t l y .Drugs ~ neally to groups of four animals and pressures were recorded before and a t 2 and 4 hr after dosing. Maximal effects usually occurred at 2 hr and are shown in Table 111. The compounds were subjected to a battery of tests for evaluation of CNS properties,s commencing with a pre-
liminary pharmacological assessment in which each compound was administered orally a t four dose levels to groups of three mice. The animals were observed for a t least 2 hr and Table I11 records the minimal doses causing decreased motor activity, ptosis, and hyperemia. Of particular interest among the more specific evaluation procedures were the results of tests for antimorphineg and antitremorinelO activity which are also recorded in Table III. Compounds a t four dose levels were administered orally to groups of six mice; the animals were then challenged with tremorine or morphine sulfate. Protection against tremors, salivation, lachrymation, and diarrhea in the former case, or the incidence of circling and "Straub-tail" in the latter, was determined by comparison with controls. For comparison the results obtained with chlorpromazine ( a neuroleptic) and cogentin (an anti-Parkinson agent) in these tests are included in Table In. The parent unsubstituted compound 14 showed moderate antimorphine and antitremorine activity, as well as slight antihypertensive activity
Journal ofMedicina1 Chemistry, 1974,Vol. 17,No.7 747
Notes Table 111. Biological Activities0 Compd 14 15 16
17 18 19 20 21 22 23 24 25 26 27 28 29 30 Chlorpromazine Cogentin
Antihypertensive Dose6 Activity“
D MAd
+
50 75 75 30 60 20 25 60
>400 12.7 12.7 4 >400 40 40 12.7 127 12.7 >400 400 40 40 127 40 127 12.7 >400
+++ ++++ Z t
f
++
60 40
+t
30 30
=I= =k
75 5
=k
i
++
Prelim assessment Antimorphine Antitremorinel Ptosis Hyperemia EDNb EDwb
>400 40 12.7 4 400 12.7 40 0.4 40 1.27 >400 >400 12.7 12.7 127 40 >400 4.0 >400
400 400 12.7 12.7 400 40 40 12.7 127 12.7 >400 >400 12.7 12.7 >400 400 >400 >400 >400
74 200 13 17 Synn 9.5 35 2.6 120 4.5 330 155 22 66 320 350 >400 5.6 20.5
16 >400 21 21 Syng 34 Syno 31 118 15 60 120 6.4 7 240 47 370 10.5 1.39
Osee test for experimental details. *Dose expressed as mg/kg. CFalls in systolic pressure 2 hr after an intraperitoneal dose: >50 mm, 50-30 mm, 30-15 mm,
