CSS ACTIVITY OF AMINOALKYLINDOLES
h'ovcmbcr l M 7
1013
Aminoalkylindoles with Central Nervous System Activity JVILLIMI J. WELSTEAD, JR.,JOHN P. DAYASZO,GROVER C. HELSLET,CARLD. LUSSFOHD, AND C. ROYTAYLOR, JR. Eesearch Laboratories, A . H . Robins Company, Inc., Richiiiond, ViryirLiu Receiied June 7 , 1967
h number of novel ainiiioalkylindoles have been prepared and tested for central nervous system depressant activity. >Zany of the compounds have significant activity against the aggressive behavior of fighting mice. The tiemiiloiis syndronie produced i l l mice by injections of p-methoxyphenethylxmine was effectively blocked hy l l l : l l l ~(Jf the ~ ~ O l l l ~ ~ ~tC'\(Cd. J l l l l ~ ~ ~
Interest in indole-containing molecules has continued to grox in recent years because of the increasing spectrum of biological activity found among this group of compounds. Within the narrower field of tryptamines, wide variations in biological activity exist even between relatively closely related compounds,' many of which strongly affect the central nervous system.' Becaupe of our interest in compounds possessing central depressant activity, a series of novel substituted tryptamine derivatives has been prepared for pharinacological evaluation. One of the specific objectives of this study was to prepare tryptamine analogs containing a 3-anilinopyrrolidinyl group (A) or a 1-phenyl-3-pyrrolidinylamino group (B), both of which have structural features in common with the known phenylpiperazinyl analog (C). Derivatives of C are reported to have tranquilizing properties.
C H - ~ RIT
H
,R, R-
I
CHARTIIa
B = =
+
QoTs
I
C
Y
-
R=C,H,orC,H.,CH-
R
substituted 3-indolylethyl H or alkyl
Isosters A and B have a degree of conformat>ional freedom that C does not have and t'hus may fit more comfort'ably into the same recept'or as C or possibly prefer a different one. One then might expect isosters h and B to produce a physiological response which differs either in degree or kind from each &her or from
H
by catalytic debenzylation in the case of the 1-benzyl compound, (B) displacement of the chlorine from 1benzyl-3-chloropyrrolidine' followed by catalytic debenzylation, or (C) addition of an amine to K-phenylmaleimide followed by lithium aluminum hydride reduction to the desired pyrrolidine (Chart 11).
'4 A
I
R-
H
R'
R
R R'
pJF2CH2NRJR4
p
y
1
R
B
C. Chemistry.-Most of t'he tryptamines in this series were prepared by the general method of Speeter and Anthony4 which involves the acylat'ion of an appropriately substituted indole with oxalyl chloride, conversion of the resulting glyoxyl chloride to the desired glyoxamide, and lithium aluminum hydride (LAH) reduction to t'he corresponding tryptamine (Chart I). The novel pyrrolidines (Table I) used in the synt hetic sequence were prepared by (A) t'he nucleophilic displacement of the tosylate of 1-benzyl- or l-phenyl-3pyrrolidino15s6by an amine or phenoxide ion followed (1) (a) R . V. Heineleman and J. Szmuszkovicz, Progr. D u g . Res., 6 , 75 (1963); (b) V. Erspamer, ihid.. 8 , 161 ( 1 9 6 1 ) ; ( c ) RI. Gordon in "Medicinal
('hemistry," -4.Burger, Ed., Interscience Publishers, Inc., New York, N. T., 1960, p 398; (d) J . 1:. K e r a i n , ('. 1'. H a l a n t , and G . E. Ullyot, ihid., pp 568Ail).
(2) S. . i d l e r , 11. T \ ~ .IVyIie, I,. S.Ilarrib, T. It. Lewis, .J. 5V. Sclrulenllery, AI. R. Bell, R. I(.Kullnig, and rnold, J . A m . Chem. Soc., 84, 1306 (1962). ( 3 ) D. !I7. Wylie and S..\rc .I. .lied. Pharm. Chem., 5 , 932 (1962). ( I ) 11. I?. Si)eet?r a n d \\.. (?. .\ntlin)-,.I. A m . Chem. Yoc., 1 6 , 6208 !.?I 1 1 1 . .\. . \ ~ ~ I I I Z Iani1 ~ ~ - >'u, .\, O r ( ~ l ~ i n n i k o v I ),o k l . Ah.,,,/. n'nuk 117, SI:+ (l!l.?7); ~ ' h c m A. l b , 4 r , , 62, 81.1) (1058).
I
CJ&
O GI F H d C,&
LAH
I
C, H,
See Table I for assignment of Y.
Several tryptamines produced by the lithiuiii duminum hydride reduction of the glyoxamides wer'c further transformed by standard procedures into ester and carbamate derivatives as described in the Experimental Section. I n all cases but one, the styrene double bond of the tetrahydropyridine glyoxamides (19 and 21-24, Table 11) WIS &le to withstmd lithium : h m i n u m hydride
1016
I
I
CH
C"
20
56 I
C"
H 16
I
H
31
17
1017
Sovember 1967 TABLE I1 GLYOXIMIDES~
R3 I
R, Comyd
Recrystn solventC
Indole substituent&
-- Found, (h---
%---
11p QCd
Yield,
%
---Calcd, C
H
N
C
H
N
11
H
AE
216-218
io
65.10
6.46
10.85
65.19
5.48 10.97
12
H
AI
170-1 72
30
72.05
6.75
12.60
71.63
5.91
13.02
13
H
1C
200-202
48
69.40
6.83
11.56
69.59
5.84
11.64
14
€1
E.1-I
199-201
55
72.39
5.79
8.04
72.12
L 9 i
8,li
15
H
B-I
175-177
83
69.21
5.53
7.69
69,55 5 . 5 i
i.99
16
H
AE
218-220
i6
74.98 6 , 3 0
9.21
74.89
5,19
9 31
17
Ri = CHB’
B-I
113-114
70
i 5 88
6 07
8 43
i 5 82
6.29
8 41
18
H
B-I
160-162
i9
65.99
4.78
7.00
66.05
4.94
7.08
.i C
193-195
86
i8.34
5.49
8.48
76.25
5.37
8 23
A-w
173-175
92
76.72
5.85
8.13
76.71
5.80
8.16
\
CF, 19
H
20
Rz
21
Ra = CHa
E
165-167
72
76.72
5.85
8.X3
i6.75
5.89
8,14
22
Ra = 5,6-OCHs
.ic
236-239
65
70.75
5.68
7.18
iO,55 5.85
7.18
23
Ra
E-W
200-202
49
69.13
4.70
7.68
68.83
4.5i
7.71
24
H
AE
195-19i
68
72.40
4.92
8.04
i 2 . 3 3 4.90
8.li
= CHd
=
5-CI
* R1,R,,and Ra = hydrogen except m-here noted. a Many of the intermediate glyoxamides were not isolated in a purified form. Solvent abbreviations: iiE, absolute ethanol; E, 95yc ethanol; A, acetone; Ac, acetonitrile; B, benzene; E A , ethyl acetate: Et, ether: llelting poiiits are uiicorrected. e Prepared tiy I, isooctane; IE, isopropyl ether: Ip, isopropyl alcohol; 31, methanol; W, water. methylation of 16; see Experimental Section. J Prepared by methylation of 19; see Experimental Section. In general, the most active compounds (Table IV) which blocked the aggressive behavior of fighting mice were the 4-phenyltetrahydropyridine derivatives 34, 35, 51, 52, and 55. It is interesting, however, that tetrahydropyridine derivatives containing &methyl and 5-chloro substituents on the indole ring (53 and 54) mere completely devoid of tranquilizing activity in this test. The aminopyrrolidine analogs (25, 42, and 43) ~i hich are structurally related to the known phenylpiperazine derivatives all had similar potencies but were not as active as the tetrahydropyridine analogs. The most active compound in this test (31) n a s also shown t o be a potent analgesic.“ Introduction of a In-trifluoromethyl group, however, resulted in a compound (33) which denionstrated no tranquilizing action at the dose tested as well as sharply reduced malgesic potency compared to 31, (11) Compounds 31 a n d 33 demonstrated analgetic actirities ( t L ) , o i n mice) of 0 40 a n d 26 8 ip mg/kg, respectively, usine the elertric stimulation method of P. Nilsen [ A c t a P h a r m . Tozzcol, 18, 10 (1961)l. Csing the same method rnorpliine demonstrated a n analgetic EDra of 1.72 mg/kg.
p-Methoxyphenethylamine (PM0PA)-Induced Tremors.-It has been reported that certain methoxylated derivatives of phenethylamine produce catatonia or a hypokinetic rigid syndrome when injected into a cat, and it has been suggested that the biosynthesis of these compounds in the Parkinsonian may explain the symptoms of this disease.12 We have found that administratioil of p-methoxyphenethylamine (50 mg/kg ip) to mice results in L: syndrome consisting of tremors, lateral head shake, straub tail, horripilation, and lacrimation. Female Dublin albino mice are given the test drugs, solubilized or suspended in saline. 60 miri prior to being challenged with l’A\\IOPA. &idequate numbers of controls are given only PA\IOPA,when the test animals receive it. The animals are observed for 20 niin or until such time as the symptoms abate in the controls. The end point used in this test is complete abolition of the syndrome. When warranted, EDjii’s were established by the method referred to in the previous bection.I0 (12) (a) .I 11. Ernst, V u t u r e , 193, 178 (1962). (I)) Acta P h y d . Phurmucol. JVeerL., 11, 48 (1962); (c) Pbychopharmacologzu, 7, 383 (1965).
2.7
II
21;
II
P i
II
L'h
I1
'!I
11
.:I!
II
7 2 1:;
;!I
l l 2 l l l
I: /ill
1I
S 10
h
I Ii
111 .?li 7 2 0 1
h
I7
I O 77
I 2 lill
X 22
I .: I 1 I
;!J
;I!)
Soveinbcr 19G7 TABLE I11 (Contznued) Recristn sol\enth
--Caled, C
H
N
C
H
S
71
72.79
7.70
11.07
73.00
7.59
11.17
..
58.80
7.09
8.57
5Y.09
6.96,
8.2!J
125-127
31
76.21
7.23
7.73
7 5 . 7 8 7.14
i.97
116-118
51
76.56
7.50
7.44
iG.17
7.40
7.50
150-152
61
8X.69
7.93
8.42
89.38
7.92
8.72
OCC
e
9.j-1OOj
51
R3
=
5,6-OCH3
5---
%
AIp
Yield
,
%------Found.
54
R3 = 5-CI
168-170
53
74.87
6.28
8.32
75.10
6.20
8.26
53
R,=Clls
219-222'b
.. ,
74.87
7.14
7.94
ii.67
7.26,
8.011
137-139
34
T9.00
7.84
8 . 3 8 79.20
7.95
8.&1
k
42
78.71
7.55
8.74
7.51
8.71
57
78.56
c Melting points are uncora It,, 112r a i d It3 = hydrogen except where ~ioted. h See footnote c of Table I1 for solvent abbreviations. Hexamate. e Viscous oil purified by column chromatograrected and refer to the free base except where solid derivatives are noted. phy on Florisil, eluted with benzene-acetone. J Precipitated from ether with ethereal HCl. * Ether solvate. * Hydrochloride salt. Viscous oil, purified by coliimn chromatography * Benzene solvate. j Hydrochloride monohydrate: water removed before analysis. on grade I11 neutral aliimina, eluted with benzene-petroleum ether.
I n general, the compounds which blocked the PNOPA syndrome most effectively (Table IT') were the same ones that most effectively blocked the aggressive behavior of fighting mice (31, 34, 35, 52, and 55). I n addition, several glyoxamides were also effective (16 arid 17). The most active compound in this test was the analgesic (31). Again, no activity was found in the ?it-trifluoromethyl analog 33. A number of classical anti-Parkinson agents such as trihexyphenidyl hydrochloride and scopolamine were found to be without effect in preventing or reversing the P1\IOPA4-inducedsyndrome. Large doses of chlorpromazine prevented the syndrome but not without concomitant neurotoxicity. Monamine Oxidase.-The method described by Youngdale, et al.,IJ was used for these determinations. Guinea pig liver W:LR used as 5~ source of enzyme. Only four compounds in this series showed significant 1\IL40-inhibitory activity in the test used. By far the most active compounds were the related pyrrolidinol analogs 38 and 45. Experimental Section All nielliiig poiiit,s (uncorrect,ed) were taken by the capillary met,hod in a Thomas-Hoover Uni-Melt apparatus. Nmr spectra were determined with a Varian A-60 spectrometer (TMS as reference). Infrared spectra were determined on a Reckman IR-S recording spectrophotometer. hlicroanalyses were conducted by the Micro-Tech Laboratories, Skokie, Ill., and Spang Microanalytical Laboratory, Anii Arbor, 3fich. The following experiment a1 procwliirr.: illustrate the grneixl methods :uid (13) G . Youngdale, D. .Inger, IT. Anthony, J. DaVanzo, &I. Greie, 11. Ileirizelnian, IT. Keanlins, a n d .I. Ssrnrisakovicz, .I. J f e d . Cl~em.,7, 415 (I!I6, 1 ) .
modifications thereof used to synthesize the compounds listed i n Tables 1-111. l-Benzyl-3-(o-methoxyanilino)pyrrolidineFumarate (3).-The crude tosylate prepared from 3 moles of 1-benzyl-3-pyrrolidinol was dissolved in 500 g of o-anisidine (practical), and the mixture was stirred and heated slowly under nitrogen until the temperature reached 130". At this temperature] a rapid exothermic reaction took place which raised the temperature rapidly to 160". After cooling with ice-HZO to 130", the mixture was stirred for 2 hr. The temperature was raised to 16OoI and the mixture was stirred an additional 2 hr. After cooling to room temperature, the mixture was dissolved in 3 S HCl and extracted several times with ether. The acidic layer was neutralized with 50% NaOH, and the resulting free base was extracted into CHCl3. The CHC13extracts were dried over hIgSO4 and evaporated iunder reduced preisnre to an oil. The oil was fractionally diqtilled (Vigreux column) yielding 333.7 g (407,) of purr product. 3 4 o-Methoxyani1ino)pyrrolidine Hexamate ('I).-Three 95-g batches of l-benzyl-3-(o-methoxyanilino)pyrrolidiiie in 300 ml of ethanol were catalytically reduced in a Parr apparatus using 10% Pd-C. The bomb was heated t o ca. 50" before reduction would take place. After the theoretical amount of hydrogen was taken up, the catalyst was filtered, and the solvent mas evaporated. The product was distilled a t reduced pressure; yield 149 g (77%). 1-Benzyl-3-( o-methoxyphenoxy)pyrrolidine (4).-A mixture of 102 g (0.70 mole) of sodium guaiacolate, 137 g (0.70 mole) of 3-chloro-3-benzylpyrrolidine, and 1 1. of dimethyl sulfoxide was heated with stirring for 16 hr a t 112-115". The mixture wa> cooled, diluted with 1 1. of HzO, and treated with SO g (1.0 mole) of 507, NaOH solution. The solution was extracted with ether, and the combined extracts were washed with HzO and dried (MgSod). After the solvent was evaporated] the residual oil was distilled a t reduced pressure; yield 92 g (477,). 34 o-Methoxyphenoxy )pyrrolidine Hydrochloride (8).-A solution of 85.0 g (0.3 mole) of l-benayl-3-(o-methoxyphenoxy)pvrrolidine in 300 ml of 957, ethanol was treated with S g of Raney nickel. The niixtuie H B S shaken seveial hours a i d filtered. The filtrate was placed in a Paar reduction apparatus and ca. 10 g of 10% Pd-C was shaken with hydrogen at 60". absorption ceased when one-third the reqiiired amoiirit wit5 :ihsorbrtl. 3lore csatalyst (ca. 15 g) wa5 added arid hytirogeri:ilioii
filtrat,es gave an oil which was coiivert,ed to a hydrochloride sali,. 1-(l-Methylindol-3-yl)-2-(4-phenyl-l-piperidiny~)-l-ethanol (56).-To a stirred suspension of 8.6 g (0.23 mole) of LiAlEIa in 85 rnl of T H F was added slowly 15.5 g (0.05 mole) of 1-[(lmethylindol-3-yl~g1yoxyloyl]-4-~henyl-1,2,3,6-tetrahydropyridine in 50 ml of THF. The stirred mixture was allowed to reflux under nitogen for 2 hr, then worked up in the usual manner. The crude oil was dissolved in benzene arid chromatographed on 400 g of 60-100 mesh Florisil. The product was eluted with benzene containing increasing amounts of acetone. The purified product crystallized. 1 -( 1 -Methylindol-3-y1)-2-( N-trans-2-phenylcyclopropyl-Nmethylamino)-1-ethanol(57).-A solution of 10 g (0.03 mole) of S-methvl-?rT-[( 1-methylindol-3-yl)glvoxyloyl] -trans-:! -phenyleyclopropylamine in 50 ml of T H F was added dropwise to a htirred suspension of 6 g of LiAlHa in 200 mi of T H F under iiitrogen. The mixture was refluxed for 3 hi- after addition, vooled, treated with 200 ml of TRF, then neutralized with a JlgS04-H,0 slimy. The salt was removed by filtratioti, then washed well with THF. Evaporation of the filtrate gave 0 g of an oil which was chromatographed on grade I11 tieiitral alumiiia using benzene-petroleum ether (bp 30-60') (50: 50) to elute 4.0 g (427,) of oil. The oil (probably an isomeric mixture) was molecularly distilled for analysis.
3-(2-[4-(m-Trifluoromethylphenyl)-l,2,3,6-tetrahydro-l -pyridinyl1ethyl)indole (36).--4 solution of 10 g (0.023 mole) of 3( 2- [4-hydroxy-4-( m-trifluoromethylpheny1)-I-piperidinyl] ethyl ] indole (benzene solvate) in 75 ml of glacial acetic acid-concen-
-
2-Methyl-3-{ 2-[ 3-(3,4,5-trimethoxybenzoyloxy)pyrrolidinyl] ethy1)indole (46).-To a suspensiori of 5 g (0.02 mole) of 2methyl-3-[2-( 3-hydroxypyrrolidinyl)ethyl]indole and 8 g (0.08 mole) of Na2C03in 40 ml of CHCla was added 4.2 g (0.02 mole) of 3,4,5-trimethoxybenzoyl chloride in 30 ml of CHC13. The mixt,ure was stirred under anhydrous conditions for 24 hr, then treated with 25 ml of H,O, and stirred 1 additional hr. The CHC4 layer was dried (MgSOa) and evaporated to a viscous oil which was chrnniatographed on a Florisil colimii (60-100 mesh) and eluted m-it#hbenzene cotitaining increasing amomit,s of acetone. The pure oil slowly crystallized from methanol. 3-{2-[3-(3,4,5-Trimethoxybenzoyloxy)-l-pyrrolidinyl]ethyl}indole (39).-A mixture of 3 g (0.01 mole) of 3-[2-(3-hydroxy-lpyrrolidinyl)ethyl]indole, 3 g (0.01 mole) of 3,4,S-trimethoxybenzoyl chloride, and 5 g (0.05 mole) of Na2C03in 40 ml of CHC13 was stirred under anhydrous conditions for 24 hr. Then, 0.3 g of acid chloride v a s added, aud the mixture was stirred another 24 hr. The mixture was treated with 50 ml of HzO and stirred for 1 hr, and the CHC13 was dried over MgS04. Evaporation of the CHCl;j gave ail oil which was chromatographed on a Florisil column (60-100 mesh) and eluted with beiizerie containing increajirig amounts of acetone. The glassy solid was crystallized from beiizene or benzene-ligroin giving a solid, mp 79-86" (gas evolut,ion). Analysis as well as the nmr spectrum indicated benzene solvation. 3-{ 2-[3-(p-Methoxyphenylcarbamoyloxy)-1-pyrrolidinyl] ethyl }indole(40).-A stirred suspension of 3.5 g (0.015 mole) of 3-[~-(3-hydroxy-l-pyrrolidinyl)et'hyl]indole in -15 ml of dry benzeiie was t,reated dropaTise with 2.3 g (0.015 mole) of p methoxyphenyl isocyanate in 15 ml of dry benzene. After the addition (0..5 hr) the mixture %-as refluxed for 12 hr when only a small amourit of solid remained suspended. It was filtered, and the filtrate was evaporated under vacuum to ail orange gum. The product, io benzene, was chromatographed 011 200 g of 60-100 mesh Florid, eluting with benzene containing increasing amounts of acetone. The glassy solid would not crystallize.
-
trated HC1 ( 2 : l ) was refluxed under nitrogen for 24 hr. The mixt,ure was cooled in ice and made alkaline with 3 S NaOH. The organic product was ext,ract,edwith CHC13 which was then dried over 3lgSOa. Evaporation of the solvent gave impure product (after several recrystallizations). I t was dissolved iri benzene and chromatographed on 300 g of 60-100 mesh Florisil usiiig benzene cont'aining increasing amounts of acetone to elute. The ptire oil obtained solidified. 3-{2-[ 3-(3,4,5-Trimethoxyphenylcarbamoyloxy)-l-pyrrolidinyl] 3-[2-( 4-Phenyl-4-propionoxy-l-piperidinyl)ethyl] indole ( 31). -A mixture of 4 g (0.01 mole) of 3-[2-(4-hydroxy-4-phenyl-l- ethy1)indole (41).-A suspension of 3 g (0.01 mole) of 3-[2-(3piperidinyl)ethyl]indole, 1.2 g (0.01 mole) of propionyl chloride, hydroxy-1-pyrrolidinvl)ethyl]indole and 3.05 g (0.013 mole) of 7 g of K2C03,and 50 ml of CHCh was st'irred for 2 hr. Then 0.4 3,4,5-trimethoxybenzovl azide in 40 ml of dry benzene was g of additional propionyl chloride was added (stirring for another refluxed under nitrogen for 8 hr; the suspension slowly dissolved. 30 min). The mixture was treated with 50 ml of HzO and Removal of the solvent under vacuum gave a dark, glassy solid stirred 30 min. The CHCl3 layer was dried (XgSO,) and evapowhich, in benzene, was chromatographed on 200 g of 60-100 rated under reduced pressure to an oil which cryst'allized from mesh Florisil, eluting with benzene containing increasing amounts benzene-isomoctaiie. of acetone. The glassy solid did not, crystallize. 3-[ 2 4 3-N-Propionyl-o-methoxyanilino-1 -pyrrolidinyl)ethyl] indole (28).-To a stirred mixture of 4.9 g (0.15 mole) of 3-12(3-o-methoxyanilino-l-p;rrolidinyl)ethyl] indole and 7 g of KUCOJ Acknowledgments.-We wjsh t o thank Dr. S. D. in 7 5 nil of CHC13 was added, all a t otice, 1.5 g (0.02 mole) of 11awso11,,1I.L. Fielden, and 12. P. Mays for the preparapropionyl chloride. The mixt,ure wai: stirred 2.5 hr, then treat,ed tion of certain key intermediates and AI. Daugherty, with .io nil of 1120and 10 ml of 3 A' hTaOH,a i d stirred an addiIt. Ruckart, aiid L. Karig for pharmacological technical tional 2 hr. The CHC1;jlayer was dried (XgSO,) and evaporated assistance. to an oil w-hich was molecularly distilled for analysis.
-
-
