i VIII) \vas obtained froiii :~-t~enzyl-::-iiieth~ldiazil.idirie i n isf( yield and had b.p. 110' (0.125 n u n . ) , nZ7n 1.5033, . l n n l . Calcd. for ClbH?&: C, 68.66: H , !i.!I!i: $, 21,:35. Fiiund: C, 68.65; H, 9.82; K,21,;3!i. 1-Methyl-3-phenyldiaziridine iX 1. -13euz:d- S-Iiiet tiyl Schiff t)ase17 (47.6 g., 0.4 niole) \WS :tdded t o 200 nil. o f 1 : 1 rtiethano! Lvater. The mixture was (aooleti t i , 0" ant1 ti2 g. ( 2 riioles) of ~tior~oriiethyl:iriiirle\vas sl~iwlyhuhtiletl into t h e s i i l i i t i o n . Thr re:wticiii temperntiire \vas lowered t i , - 10" i i r i i l 52 g. 10.14 riiolc) of 9,5(-; liydrox~l:~rnine-C~-sulioni~~ arid was :idtied river a .-i-iiiiii. j~eriiitl with stirring. The reaction tenipernture rrise t o 10" i i i Cniiipbeli, .\. I f . Soiiior.;, a n d 13. 1;. Cauipbell, . I . .lm. 6 6 , 82 11944).
C
Antidepressants.' 11. Derivatives of Polynuclear lndoles
h series of S-sutistituted derivatives of polycyclic indule systems iv:w prepared :tiid esuniiiietl f i c.eiitral ~ iiervous system activity. Examples of 1 , : 2 , 4 , j - t e t r . a h ~ ~ d r i ~ t ~ i i[4,:Z-6] i i ~ ~ ~indiiles, a i i i ~ 5,(kliIiydr~i-llH-benzo [(I]c~arbazole-2,3-pentanieth~~lene-1"benz[g]indole,3.ti-dih!-dro-13H-dihenzc,lrr,iic~arbnzrile, and 1OH-benzofur11ni(dific.ntioiis 1 i f the Fisc1her iiidc i I r [3,2-b]indoles were included. The indole systems required were ohi:iiiied synthesis and converted t o S-substituted derivatives by varied methods. of the compounds are discussed.
'l'he hrst paper? iii this series described the sgiitliesis and phariuacological behavior of a series of substituted 2,:3-polyiiiethylerieindoles (I). Because of the intercstiiig pharmacological properties of certain iiieinhcr.. of this series, the irivestigatioii was exteiided to iiicludc a iiuiiiher of related types. The 1,5,1,5-tctrahydi.othiopyrano [1,3-b]iiidoles (11. I i = H) \\ere selected
I
I
R I
R I1
hecause of aii isosteric relationship I\ ith tlic 2,:3-pciitaiiiethyleiieiiidoles (I, I I = 5 ) previously repoited.? I i i a n effort to iiivestigate the effect 011 pliariliacological activity of varying the size aiid shape of the aroiiiatic iiioiety, aiialogous S-substituted derivatives of 5,tj-dihydro-11H-benzo [a]carbazole3 (111, I< = H), 2,3peiitainethylene-lH-beiiz [glindole (ITT, I< = H), ;,ti-
m\ I11
IV
R
/
v
VI
O
\
ASTIDEPREYSAKT POLYNUCLEAR IEDOLES
September, 1964
629
of acrylonitrile to a benzene solution of I1 or I11 containing a catalytic amount of triniethylbenzylammoniuni methoxide. The cyanoethyl derivatives VIIa and VIIb were reduced with lithium aluminum hydride, SCHEMEI yielding VIIIa and VIIIb. To obtain the required CH>=CH-CN LlhlHa monomethyl derivative, VIIb was esterified with anhyRSH RSCHlCH2CS RXCH~CH~CHIXH. drous hydrogen chloride in methanol. When the methyl TMR VIIa and b VIIIa and b ester IXb was allowed to stand with methylamine in methanol for several days, a good yield of S-niethylamide (Xb) resulted. Treatment of this substance CtOH with lithium aluininuni hydride produced the K-(3R X C H ~ C H ~ C O I C RSCH,CH,COlH H~ niethylaniinopropyl) conipound XIb. When this seXIIa H + IXb quence was attempted in the tetrahydrothiopyranoR?;CH&HPC02C?H5 XIIIa [4,3-b]indole series, treatment of VIIa with hydrogen chloride in methanol apparently caused cleavage of the sulfur-containing ring, as indicated by a strong odor cH a H * CHJNIII of hydrogen sulfide. The material then underwent RNCH&H,COKHCHa extensive resinification, and no definite product could X a and b be isolated. As an alternative method, VIIa was hy+I,iAlHa drolyzed with alcoholic sodium hydroxide and the RXCH2CHsCH2SHCH3 carboxyethyl conipound XIIa v a s then esterified X I a and b with ethanol, using sulfuric acid catalyst. The reTLlB = trimethylbenzylammonium methoxide niainiiig steps were as anticipated : XIIIa with alcoholic met hylaniine gave S-met hyl- 1,3,4,5-tetrahydrothiopyrano [4,3-b]indole-5-propionaniide(Xa), from which K - 3-i~ietl~ylan~inopropyl-1,3,4,~-tetrahydrothiopyrano[4,3-b]indole (XIa) was obtained by reduction with a b lithium aluniinuni hydride. These reactions are suni-
derivatives of I1 and 111 were prepared by the route previously described. The unsubstituted conipound (I1 or 111, R = H) was cyanoethylated by the addition
-
-
J
\
TABLEI 5-L)IALK'iLA~IrOALKk-L-~,3,4,5-TETRAHYD~ [4,3-b]lNDOLES U
h.0.
R
&I.p.,aoc.
---%
Yield.
%
(CH,),NCH?CH, 200-201 65.5 (C2Hj)&CH2CH2 176177 64.8 (CH,),KCH( CH,)CH, 169-172 44.4 CIH,NCH?CH? 222-224 64.1 5 CjHioNCHQCHz 217-220 91.0 189-191 69.2 6 CJH8OKCH2CHa 41.8 7 (CH,)zN(CH& 199-200b 150-153 78.8 8 (CBH~)~N(CH~)~ 103-107 32.6 9 (CHa)~x(cHz), Fumaric acid salt. Hydrochloride: C1, calcd., 11.42; 1 2 3 4
a
Calcd.
Found
-%
H--% E---yo SCalcd. F o u n d Calcd. Found Calcd. Found
60.61 62.35 61.51 62.66 63.43 60.26 61.80 64.54 63.86
60.55 62.48 61.27 62.38 63.36 60.00 61.61 64.64 63.63
6.43 6.98 6.71 6.51 6.78 6.26 7.45 7.67 7.46
C--
6.40 7.10 6.55 6.36 6.87 6.54 7.30 7.59 7.66
7.44 6.93 7.18 6.90 6.73 6.70 9.03 6.27 6.48
7.61 6.91 6.99 7.12 6.43 6.54 9.24 6.46 6.57
8.52 7.93 8.21 7.97 7.69 7.66 10.30 7.18 7.41
8.00 7.67 7.6 7.83 7.49 7.45 Y,9l 6.92 7.15
TABLE I1 11-L)IALKYLAWIXOALKYL-5,6-DIHYDRU-11H-BENZO [a] CAItBdZOLES
____yc C--Calcd.
Found
---% Calcd.
HFound
---% Calcd.
73.49 73.42 7.09 7.18 8.57 71.86 71.79 6.96 7.05 6.45 71.40 71.61 6.71 6.74 6.66 72.62 72.63 6.77 6.88 6.28 72.20 72.35 6.52 6.70 6.4s 73.65 73.41 7.39 7.28 8.22 73.08 72.88 7.61 7.74 5.88 72.70 72.70 7.41 7.70 6.06 Hydrochloride: C1, calcd., 1028; found, 10.25.
E---Found
8.59 6.51 6.59 ti.31 6.32 8.26 5.83 6.07
S-l'ipcridiiioetliyl-~,ti-dihydl'o-llH-benzo[ n ] c a r t ) a ~I (( 'i niarized in Schciiie 1. The iiiteriiiediates aiid products (Table TI, 11) c~u1iihitc.daii aiitiiiiorphiiir effect tu iw are shown in Tables 1V and I-. that of iinipraiiiiile but s h o w d only slight activity i t ] Pharmacol~gy.~--The S-arninoalkF1 derivatives of the antirescrpiiic tr,st. Hotli o f tliesc. c w i i i p o i i i i d h 11, IIT, IT', T', and I7 prepared 111 the m i m e of thi:. Iiiarkedly poteiitiatcd t h c stiiiiulatioli caused by niriplir~tinvestigation were submitted to a preliminary pharmaairline in the sclf-stniiulatioii test nscd t o S W ~ C JfIo r vologic. assessment for general stimulation, depression. antidepressant activity and autonomic activity. Compounds which eshihited activity i n this test were teated for a~itirnorphiiie~~ and antireserpine" artil-ity Sonic of the r e d t s ai (' shown in Table 1-I. The coinpounds porsessiiig the most sigiiihcaiit activity w ( ~ rthose (~ of types I1 and 111, i.e., the derivative3 of 1,3,3-,3-tetrahydrothiopyraiio[-1.,3-b]iiidole and 3,Gdihydro-l1H-henzo [a]carbaxole. I n type 11, aiitireserpine effects predominated over antimorphine, while in typc 111 this order was reversed. S-Diniethylaininoethyl-l,3,4,5-tetrahydrothiopyrano [4,3-b ]indole (Table VI, 10) was found t o have ailtireserpine activity cqual t o imipramine aiid little antimorphine effect.
Septeiiiher, 1'3N
I
k
R W
R I1
I11
v
IV
VI EDsu,
EDW, so.
1 2 9
4 5
I1 I11 IV i-
1-1 I1 I1
mg. 'kg. morphine
1's.
240 160 >"0 >400
mg. 'kp. reserpine
PZ.
180 188 >400 >400 >800 220 210 15 120 42 390 430 >400
D.m.a.,b mg.)'ky.
100 50 200 400 100 >400 400 400 127 200 50 127 40 127 127 40
240 115 382 Synergistic I1 8 > 127 I1 0 >400 I1 10 91 I11 11 376 I11 12 >400 111 13 >400 40 I11 14 >127 >127 I11 15 40 258 Imipramine' 16 Mice, p . 0 . The values reported are minimum doses producing activity; > means the compound was inactive up to indicated dose. Used as standard. Ilecreased motor activity. 6 7
0
Compd type
was added dropwise, with stirring. The mixture was stirred a t 30-:35" for 1 hr. A solution of freshly distilled dialkylaminoalkyl chloride (0.1 mole) in diniethylformamide wxs added and the mixture was stirred 18 hr. a t 26-30". The react,ion mixtaure was poured into ice-water (600 ml.) and acidified with concentrated HC1. The solution was extracted with ether to remove nonbasic, components and then made alkaline with aqueous NaOH. The product was extracted with ether, and the extract' was washed with saline and dried over Na2S04. After removal of the drying agent, the base was converted to the salt with dry HCl. 1,3,4,5-Tetrahydrothiopyrano [4,3-b] indole-5-propionitrile (VIIa).-A 200-ml. three-necked flask fitted with thermometer, stirrer, addition funnel, and condenser protected by a drying tube was charged with 1,3,4,5-tetrahydrothiopyrano[4,3-b]indole i 12.
