1054
Journal of Medicznal Chemistry, 1971, Vol. 14, iYo. 11
ARCHIBALD,et al.
T.IRLI:I1 I n J'c'tro IKHIHITION OF I\Iousi- BRAISAIoxo.\msr: OXID.GSE
with caution followed by 20% NaOH (90 ml) and H 2 0 (420 ml). The slurry was filtered, and the filtrate concd arid distd to yield See Table I for physical constants. The yields _____---- Molar concn----7 in Table I are based o n starting nitroso compd. 10-5 5 x 10-5 10-4 5 X 10-4 150" 11.-The benzyl halides were prepd by the reaction of the Test compd benzyl alcohol with excess concd HC1, HBr, or with excess SOC12 Iproniazide 37 88 97 I .5 (pyridine catalysis in CHC13 or 1,2-C2H4Cl,s o h should be used 1 32 i -1 07 2..i particularly for ortho-substituted examples-hee 7, Table I). If ;3 49 92 the t'oluene was the commercial starting material, it. was treated 97 1.0 Kith S B S (used crude after removal of the sliccinimide and CC14) 4 61 90 99 0.4 or with Brg and light.. The presence of the a,a-dibroniotolueiie I .6i 95 100 0.6 i n the S B S product reduces the yield. 6 39 s7 100 1.7 Typical Alkylation of Methylhydrazine with an Ortho-SubS 14 .1 i h6 7.0 stituted Benzyl Halide. 1-(0-Chlorobenzy1)-1-methylhydrazine !I 22 7% 93 3 .5 (3).-To n mixt of methyl hydrazine (161 g, 3.5 moles) arid 10 46 h7 98 1.2 anhyd Et013 was added with stirring o,a-dichlorotoluene 11 17 70 94 4.0 (161 g, 1.0 mole). The mixt was refluxed 1 hr after the temp 1s 6 .i 87 93 100 0 .3 began to fall. 11. was concd in tacuo, made alk (50$; SaOlT), and extd (Etn()). The exts were wahhed with H 2 0 , dried (3Ig' 8 Concn X lo-" I \. for .iOycinhibition of M A 0 activity. SO4), concd, and dihtd to yield 3, 138 g (92%). See Table I for physical characteristies. The yield$ i n Table I are based o n the starting alcohol or toluene with the exception of 3, 20, arid 22 of scintillation fluid and the radioactivity was measured. A where the beiizyl chlorides were commercial. blank coiitg boiled enzyme was carried through the entire pro111.--The aroyl chlorides were prepd by t,he use of S0Cl2 on the cedure. The reported result's are the averages of replicates and commercial aroni carboxylic :icid.: mid Jvere used crude or were the average variation in the same experiment was i.iyc. The commercially available. T:,o was derived from a graph of the log concn 'per cent inhibition. Chemistry. 1.-The ,\'-nitrosoamines were prepd by t,he Typical Aroylation of Methylhydrazine and LAH Redn of the HC1 was replaced by AcOH, method of Hartman aiid Resulting Mixt. 1-(na-Methoxybenzy1)-1-methylhydrazine(9). -A mist of methylhydrazine (170 g, r3.7 moles) arid HyO (6SO g ) the reaction was carried out under p i p (HONO is lost by reaction ivas cooled l o 0" aiid with stirriiig a solii of crude m-methosywith 0 2 ) , and the niixt was heated to 60-70" after the addn of benzoyl chloride (:300 g, I .76 moles) in T H F (400 mi) was added. the h'nN0, s o h . The compds were distd and anald, but can The mixt was stirred overnight and extd fEt20). The exts were be \wed crude in the redns. The nmr apectra show split X e and dried ( l I g S 0 4 ) ,wncd, arid used crude. A mist of LAH (114 g, CHg peaks. 3.0 moles) and T H F (l,.? 1.) >vas heated t o 30-40" under S,, and Typical LAH Redn of the .\'-Nitrosoamine. 1-( m-Chloroa soln of the (.rude ni-niethoxybenzoic acid I-methylhydrazide iri benzyl)-1-methylhydrazine (4).-A su3pension of LAH (114 g, T H F 1300 nil) vas added dropwise. The H Z evoln was moni3.0 moles) in aiihyd EtpO ( 2 . 2 1.) was heated t o a gentle reflux iiiider Ng, xiid a s o h of ?n-chloro-AV-methyl-L\'-iiitrosobenzylamine tored," and the mist was refliixed overiiight, cooled under N,, and worked up as in I t o +eld 9, 158 g (47r;). (26s g, 1.4,5 moles) in T H F (500 ml) was added dropwise over See Table I for physical data. The yields in Table I are based on the starting aryl :;-4 hr. IT2 evoln began immediately. The mixt was refluxed carboxylic acid o r acid cvliloride if conimercinl. overiiight, cooled wider N2, and H2O (120 nil) was added dropwise 3-
Synthesis and Hypotensive Activity of Benzamidopiperidylethylindoles' J. L. ARCHIBALD,* B. J. ALPS, J. F.C A V A L L A ,
AND
J. L. JACKSOX
John JVzjeth and Brother Lznzited, Taplow, JIazdenhead, Berkshire, England
Receaved March 12, 2971 The bynthesis arid hypot,eiisive activity of a series of indole piperidine amides are described. One member of the series--3-[2(4-benzamidopiperid-l-yl)ethyl]indole (indoramin) (35)-has undergone intensive pharmacological investigation. The sudtained hypoknsive action of 35 is believed to be due t o a combinat'ion of local anesthetic and a-receptor blocking properties.
benzamido derivative 35 (indoramin) was a potent A continuing interest in indole derivat'ives incorpohypotensive agent. Detailed pharmacological invesrating a tryptamine residue as potential antihgpertentigation of 35 has since revealed a combination of propsive agents stemmed from our work with 1,4-bis(inerties that seems likely to be advantageous in the treatdolylethy1)piperidines. In that series, the indolylmerit of cardiovascular disease in ethyl moiety attached to the piperidine 4 position was This compound then became the prototype for a11 riot an essential feature for retention of antihypertensive extensive synthetic program designed to investigate activity. It could, for instance, be replaced without detriment by a 3-carbet~hoxy-2,4-dimethylpyrrol-5-y1-structure-activity relationships and to optimize activity. ethyl group.3 We decided t30 retain the indolylethylpiperidine moiety of the earlier series while varying t'he 4 substituent, of the piperidine ring, concent'rating in particuH lar 011 amino derivatives, which had received little atten35 tion in the past. I t was soon discovered that the 4(1) Presented in part a t the IT International Congress of Medicinal Chemistry, Clermont-Ferrand, France, Sept 1968. J. L. Archibald, Chim. T k r r . , 3, 397 (1968). (2) J. 1., Archibald, T. Baum, and 9 . J. Childresa, J . AJIed. C k e m . , 13, 138 (1970). ( 3 ) .J. L. Archibald, J . Heteroevcl. Chem., 3, 409 (1966).
(4) B. J. Alps, J. L. .Irchihald, E. S.Johnson, and A . B. Wilson, Curdioeasc. Rea., 62 (1970). ( r ) ) B. J. Alps, E. S , Johnson, and .i, 13. Wilson, Brit. J . Phnrmrrcol., 40, 1 5 l P (1970). (6) B. J. -41113, RI. Hill, E. S. Johnson, and A . n. Wilson, (bid.,40, 153P
(1970).
Journal of Medicinal Chemistry, 1971, Vol. 14, Ro. 11 1055
HYPOTEKSIVE BENZAMIDOPIPERIDYLETHYLINDOLES
TABLE I X
Compd
a
yield
MP, 'C
Hz0 EtOH EtOH EtOH EtOH
76 34 32 79 82
268-270 190-192 228-230 312-315 202-203
4 4 4
EtOH EtOH
EtOH
60 41 66
205-207 258-259 267-269
0
3 4
EtOH Hz0
77 73
266-267 248-250
H H
Hz Hz
4 4
EtOH-Hz0 EtOH
69 21
274-276 220-225
H H
Hz Hz Hz
4 4 4
MeOH EtOH-Et20 EtOH
73 20 59
129-131 224-226 176-178
5
H H H H
6 7 8
CHI CH3 H
H OCH3 H
9 10
H
H
H H
11 12
H H
H 13 14 H 15 H Anal. were obtd for
Crystn solvent
4 3 2 4 4
H
H H H H H
1 2 3 4
%
Posn of NHRP
X
R3
Rz
Hz HP Hz
0 Hz HP
Hz HP HP
H the elements C, H, Br.
TABLE I1
-
R 3 n - - . C H 2 g &
NHR,
H Compd
RZ
Posn of NHRi
Ra
% Crystn solvent
Rlp, o c
yield
Formula
Hypotensive activity'
++ ++ + ++' +" ++ +"
193-195 56 h4eCN 4 CnHnNaO 16 H +b,c H 225-226 71 4 Hz0-EtOH C18H23x30 +a,d H 17 CH3 t57 176-175 MeCN Ci&LiN30z 4 OCHI +d 18 CH3 209-21 1 95 H 20-E t 0H 4 CzzHz3x30 H to 19 H MeCN 56 180-1 82 CzzHZ3N30 H 20 H 3 37 225-230 H DMSO 21 H CzzHzzClNaO +a,c 4 65 22 H H 4 MeCN 187-1 89 Cz3Hzjx30 +c 83 197-198 23 EtOH H H 4 Cz?Hd30 69 162-164 24 EtOH 4 H H Cz3Hz1N30z +c +; at a dose of 5 mg/kg, iv. Effect obtained at a Falls in blood pressure were < 20 mm, ; 20-33 mm, ; 3-5-30 mm, high doses only (10-20 mg/kg, iv). c Acute ip LDjDin mice >400 mg/kg. d Approx ip LDjo in mice 127-400 mg/kg.
+
++
A number of synthetic approaches were developed to meet various objectives, depending, for instance, on which part of the molecule required systematic alteration. Scheme I depicts most of the major synthetic routes employed and is restricted, for clarity, to the synthesis of 35 itself. The original route to 35 involved quaternization of 4-benzamidopyridine with 3-(2bromoethyl)indole, followed by Raney Xi catalyzed reduction. This proved satisfactory only on a small scale oning t o the insolubility of the quaternary salt 8. I n an alternative tn-o-stage process, S a B H 4 reduction of 8 gave the tetrahydropyridine 19 in excellent yield, but catalytic reduction of 19 n-as complicated by elimination of benzamide with resultant erratic yields of 35. Quaternary salts and tetrahydropyridines prepared in this way are listed in Tables I and 11. 3-Benzamido compounds were prepared in the same way as the 4 isomers. Approaches which progressed through aminopiperidine intermediates 25-29 \$-ere investigated next, since
++
these enable easy variation of the amide portion of 35. The amine 25 was readily obtained on a small scale by reduction of the quaternary salt 1, but again insolubility prevented satisfactory large scale operation. The acetamido quaternary salt 5 , however, was more soluble and less resistant to reduction. The acetamidopiperidine 307 was hydrolyzed t o the amine 25 which \vas reacylated with BzCl as well as with a large number of other acid chlorides (method F). The amine 25 was alkylated on the indole S \$-ith Me or benzyl halide to give either 27 or the corresponding 1-benzylindolamine. Amines substituted in the indole 2 and/or 5 positions or in the chain linking the indole and piperidine rings were also prepared. The amine 28 n-as obtained by hydrogenolysis of the N,O-dibenzyl compound 85. The most satisfactory approach to the large scale preparation of 35 involved alkylation of 4-benzamidopiperidine (86, Scheme I). This v a s prepared by hy(7) B . L. Zenitz,
U. S. Patent 3,238,215 (1966)
ARCHIBALD, et ai.
1056 Journal of Medicinal Chemistry, 1971, Vol. 14, N o . 11
1
$2;:
$
Ba Zz + + . . + s a + + + +
2 i ?. + + i l - - i i, + . . i++ + + ..+,+++,++ 3 + i 0
. e 4
w
++++?+++++++++++++ + +
Y
x
j
zmzz
3 e4 m d Lc: w r . x 3r 0 3 m m ti ! L co m m n m n m m m m m m e t i e e e + e
3r 0
i F % ;i;.i- t . i + . + +* i+ii++?l+++
HYPOTENSIVE BENZAMIDOPIPERIDYLETHYLINDOLES
Journal of Medicinal Chemistry, 1571, Vol. 14, A-a, 11 1057
drogenolysis of l-benzyl-4-benzamidopiperidine8 or from 4-benzamidopyridine, either by quaternization i c i .*. , c ; , , E with PhCH2C1, followed by sequential NaBH4 and i++ 20 catalytic reduction or, alternatively, by reduction of 4+%+++++ii,++ +7 2k benzamidopyridine in Ac20 to give I-acetyl-4-benzamidopiperidine which was selectively hydrolyzed to 86. Alkylation of 86 with a variety of indolylalkyl halides or ON tosylates provided products in which the length and nature of the linking chain and substitution in the indole ring were altered. Acylation of 86 with the appropriate indole-3-glyoxylyl chloride provided the glyoxylamides 79 and 80, the three carbonyl groups of the latter being reduced by LAH to give 85 as an intermediate to 28 and 72. Mannich reactions with 86 and indole and with 86 and 3-acetylindole gave products 83 and 81, while a Alannich reaction with 86 and propiolaldehyde diethyl acetal provided 87 which was readily reduced to 88 (Scheme I). Fischer cyclization occurred when 88 was allowed to react with p-methoxyphenylhydrazine to give a good yield of 73. When phenylhydrazine was *t- u3:3 tu-: mw w Nu: *o, E5x r-* LMQ r-u: ccps t-Q1 used, only a low yield of 35 was obtained. Biological Activity.-An evaluation of the hypotensive actions of members of the series was made in dialurethane-anesthetized (0.7 ml/kg, ip) normotensive rats. Results are shonn in Tables I1 and 111. Some
..+ #
+,
++ +- +.. ++
+ b i
y3
I
.,c
N
R
R
R
ui
+E?
c-
compounds were also examined for antihypertensive activity in conscious renal hypertensive rats using oral doses of 20-40 mg/kg. Systolic blood pressure was measured by an indirect tail-cuff technique. Results were in general agreement n ith those obtained in anesthetized normotensive rats when blood pressure was measured directly. Compound 35 was selected for further evaluation of effect on general hemodynamics in sodium pentobarbital anesthetized cats (30 mg/kg iv). Low dosages (0.1-3.2 mg/kg iv) induced significant sustained decreases in aortic systolic and diastolic pressures (>40 mm) compared with measurements in control animals. The compound nas devoid of an adrenergic P-receptor blocking action on the heart, but was found to possess local anesthetic membrane stabilizing properties, and to exert an adrenergic Qreceptor blocking action. In common with many compounds in the series it was found to cause potent competitive antagonism of histamine. The sustained hypotensive action of 35 could be accounted for by combined cardioinhibitory actions (z.e., decreased myocardial contractile force, bradycardia, and decreased cardiac output), by virtue of its membrane stabilizing properties on the heart, and decreased peripheral resistance due to partial adrenergic areceptor blockade of vasoconstrictor tone. Structure-Activity Relationship.-Structural features necessary for a high level of hypotensive activity may be summarized as folloas. The 4-benzamido group is necessary, except in very few examples where there is a 2 substituent on the indole ring and/or a double bond in the piperidine ring, e . g . , 16, 17, and 31. KO ( 8 ) N. J. Harper and C. F. Chignell, J . .Wed. Chem., 7, 729 (1964)
1058 Journal of Medicinal Chemzstry, 1971, Vol. 14, LYo. 11
SCHEME I NHCOCH,]
NH,
I
NHCOCGHj
NHCOC6Hj
H
I
b -9
I
CH,CECCH(OEt),
86
1
1
RBr
NHCOCHj
RBr
1
87
RBr
lRBr
1
6 0 NHCOCsHs
I+
R
R 5
1
1
1 -CH2CH2
I
H
30
25
19
simple relationship exists between substitution in the benzene ring and degree of activity; furthermore the effect of such substitution may be markedly altered by substitution elsenhere in the molecule. Thus para iubstitutioii of CHa does riot greatly reduce activity (39), but p-OCH3 only retains high activity J\ hen there is also an indole-2-CHa (63). nz-OCH? does not reduce activity (41) nor does o-CH3 (37) or 0-C1 (43). 1Iultiiubstitution reduces activity except for 50. Substituents on the indole S generally decrease activity, but as previously exemplified may counteract ari undesirable substituent in the benzene ring, c . g . , 44 and 66. Indole 2 substituents have n variable effect. \\-hereas 5 subbtituentb are gencrall? less desirable. .llteration of the ethylene linkage between the indok :md piperidine rings reduces activity. except for 74. The quaternary compounds listed in Table I did not produce :I potentially useful lowering of blood pressure (lxcept a t high doses. Biological results are therefore not included in Table I.
Experimental Sectiong Benzamidopyridines were either kiio~\-iior were prepd by htaiidard procedures. 4-Benzamidopiperidine (86).-1-Beiizyl-4-benzamidopiperitiiiie8 i i i EtOH was hydrogenated iii the pieserice of 10c7c P d / C at v50"and 3.25 kgjcm,. The product (mp 136-137") was recrystd from EtOAc. The same product was obtd by catalytic reduction of 4-benzamidopyridine in AcnO, followed by hydrolysis of the resulting l-acetyl-4-benzamidopiperidine, and by quaternization of 4-benzamidopyridine with PhCHnCl, followed by NaBH4reduction of the quaternary salt, and catalytic reduction of the resulting l-benzyl-1,2,5,6-tetrahydropyridine. Quaternary Salts (Table I). 4-Benzamido-1- [2-(3-indolyl)ethylpyridinium Bromide (8).-A so111 of 4-benzamidopyridiiie (1.08 g) and :3-(2-bromoethgl)indole (2.24 g) in EtOH (15 ml) ~~
..
(0) Melting points are uncor. I r spectra supporting t h e assigned structures were obtd for all compounds. C, H, and K analysis were obtd f o r all compounds except where noted in t h e tables and were within f0.47, of tlie theor values except where noted in Table 111. K m r spectra of 1 5 representative compounds fully supported tlie assigned structures.
was refluxed for 2 hr, and the cryst product (3.13 g, mp 264-266") was collected by filtration from the hot reaction mixt. Recrystn gave the hydrate. 4-Aeetamido-1- [2-(5-methoxy-2-methylindol-3-yl)ethyl] pyriacid dinium Bromide (7).-5-Methoxy-2-methylindole-3-acetic (50 g) in T H F (400 ml) was added dropwise to a stirred siisperision of LAH (50 g) in T H F (800 ml). The mixt was refluxed 1 hr, then HzO (150 nil) xyas added dropwise, and the inorg material was filtered off arid washed well by suspending in Et&. Evapri of the combined Et20 phases provided 3-(2-hydroxyethy1)-5methoxy-2-methylindole as a cryst solid (45.3 g, mp 98-101". This alcohol (45.3 g) x a s added as quickly as possible to boiling 48'3 HBr (4.50 ml). One minute later the soln was poured onto ice (1kg) arid extd with EtnO. The exts were washed twice with satd NaHCO3 s o h , dried (KtCOI), arid evapd to provide 3-(2-bromoethyl)-5-methoxy-2-methylindole as an oil (56.3 g). This oil was dissolved in N e C N (223 ml) and a s o h of 4-acetamidopyridine (28.4 g) in MeCK (120 ml) was added. After 3 hr at room temp the cryst product (58.7 g, 81.7y0)was c.ollected. Tetrahydropyridines (Table 11). 3- [2-(4-Benzamido-l,2,5,6tetrahydropyrid-1-yl)ethyl]indole (19).-To a stirred s~ispe~isioii bromide (8) of S-beiizamido-l-[2-(3-iiidol~l)ethyl]pyridinitim (2.0 g) iii MeOH (100 ml) was added NaBH4 (6.0 g) portionwise over 30 min. Stirring was coiitd 1 hr after the addn, and the ppt was collected, washed (AleOH), and dried to give the crude product (1.56 g), mp 205-207". Recrystri from LIeOH raised the mp to 209-211". Piperidines (Table 111). 3- [2-(4-Aminopiperid-l-yl)ethyl] indole (25). Method A.-4-Amino-l-[2-(3-indolyl)ethyl] pyridinium bromide (1) (3.18 g) iri 'JOYc EtOH (300 ml) contg Et,?; (1.0 g ) and IT-7 Rariey Xi (en. 3 g ) was hydrogenated a i 80' and 56.25 kg/cm2 18 hr. The catalyst was filtered off and the filtrate was evapd. The residue was shaken with 2 N NaOH until it crystd to give the hydrate (1.94 6). Method B.--3- [2-(4-Acetamidopiperid-l-yl)ethyl] indole (30) (13.0 g) was dissolved in 2 11' HC1 (430 ml) and refluxed for 2.5 hr. The reaction mixt was cooled, filtered, and basified with 10 S a O H to give the hydrate (36.4 g). 3- [2-(4-Aminopiperid-l-yl)ethyl] -1-methylindole (27). Method C.-3-[2-(4-Aminopiperid-l-yl)ethyl]indole (25) (13.05 g ) was added poriioni&e to ?rTaSH2in liq NHa (from 2.5 g of Na and ea. 500 ml of XH3). After stirring 1 hr, CHJ (7.8 g) in dry Et& (100 ml) was added dropwise. Stirring was contd a t room t'emp imtil i%Ha had evapd; then H20 (100 ml) was added dropwise to the residue. The resulting solid was collected and recrystd from X e C S coiitg lyGof H20 to give the hydrate (10.16 g).
%.is,),
HYPOTENSIVE BENZAMIDOPIPERIDYLETHYLINDOLES 4-Benzamido-1- (5-benzyloxyindole-3-glyoxy1oyl)piperidine (SO). Method D(i).-5-Benzyloxyindole-3-glyoxylyl chloride10 (23.2 g) was added portionwise to a stirred sohi of 4-benzamidopiperidine (30.2 g) in dry 1,2-dimethoxyethane. After 1 hr the solid was collected and siispended in H2O (1 1.) for 1 hr. The product (34.49 g) was filtered off, washed (HzO), and dried. An anal. sample was recrystd from D M F - ~ H Z O . 5-Benzyloxy-3- [2-(4-benzylaminopiperid-1-yl)ethyl] indole (85). Method D(ii).-Compd 80 (33.88 g) was added portionwise to a stirred, refluxing suspension of LAH (20 g) in dry T H F . Stirring and refluxing were contd for 4 hr, then H 2 0 (20 ml) and 2 iV NaOH (40 ml) were added dropwise. Filtration and evapn of the filtrate plus washings gave an oil which was dissolved in hot EtOH and acidified with dry HC1. The product, crystd on cooling as the dihydrochloride, hemihydrate (31.03 g). 3- [2-(4-Aminopiperid-l-yl)ethyl] -5-hydroxyindole (28). Method D(iii).-Compd 85 (10.0 g) in Hz0 (100 nil) and MeOH (100 ml) was hydrogenated in the presence of 57, Pd/C (1.0 g) a t 50" and 3.92 kg/cmZ for 5 hr. Evapn of the filtered soln gave the product as a pink foam (6.29 g) which analyzed correct,ly for the dihydrochloride, hemihydrate. 3- [2-(4-Acetamidopiperid-l-yl)ethyl] -5-methoxy-2-methylindole (32). Method E.-3-[2-(4-Acetamido-1,2,5,6-tetrahydropyrid-l-yl)ethyl]-5-methoxy-2-methylindole(18) (4.66 g) in 50% aq AcOH (50 ml) was hydrogenated for 18 hr at 3.52 kg/cm2 and 50" in the presence of PtO2 (500 mg). After filtering off the catalyst and evapg the filtrate, the residue was dissolved in Ha0 and basified with K2C03. Extn with CHCl, and evapn of the dried exts gave a foam which was chromatogd on basic alumina. The purified product was crystd from EtOAc as colorless prisms (3.27 g). 3- [2-(4-Benzamidopiperid-l-yI)ethyl]indole (35). Method F. -3-[2-(4-.4minopiperid-l-yl)ethyl]indole (25) (2.61 g) in dry CHZC12 (100 ml) was stirred with ILCO3 (2.76 g ) in H 2 0 (50 ml) a t 5' while BeCl (1.69 g) in CHzCl2 (20 ml) was added during 10 min. The mixt was kept at 5" for 18 hr, then the product was filtered off, washed, and dried, giving 2.95 g, 85%. A n anal. sample was recrystd from EtOH-H2O. Method G.-4-Benzamido-l- [2- (3-indolyl)ethyl]pyridinium bromide (8) (3.0 g) in 91y0 EtOH (300 ml) coiitg E t s S (0.8 g) T a s hydrogenated i n the presence of freshly prepared W-7 Raney Ni catalyst (ca. 3 g) at, 28.12 kg/cmz and 50" for 4 hr. After filtering off the catalyst, the filtrate was evapd and the residue was shaken with CHCla and 2 -1' NaOH. The resulting insol material (1.61 g, mp 203-206") was collected and dried. Recrystn from EtOH gave the product (1.34 g), as colorless needles. Method H.-A mixt of 3-(2-bromoethyl)indole (200 mg), 4benzamidopiperidine (200 mg), and Et3N (108 mg) in dry D M F (5 ml) was stirred a t room temp overnight,. H20 (10 ml) was slowly added whereupon the product (225 mg, 72.57,) crystd. The yield was increased (287 mg, 92.57,) when an extra equiv of 4-benzamidopiperidine was used in place of the EtsN. The base (215 mg) in MeOH (12 ml) was made jiist acid with dry HC1 and the boiling MeOH was gradually replaced with EtOAc until the (10) M. E. Speeter and W. C . Anthony, J . Amer. Chem. Soc., 76, 6208 (1954).
Journal of Medicinal Chemistry, 1971, Vol. 14, No. 11 1059 dist temp reached 68", a t which point crystn occurred to give the hydrochloride (227 mg), mp 230-232'. Recrystn from MeOHi-PrOH gave a different cryst modification, mp 258-260". 5-Methoxy-3-[2-(4-benzamidopiperid-1-yl)ethyl]indole(73). Method I(i).-4-Benzamidopiperidine (62 g) was %dded to a stirred suspension of cupric acetate (1.1 g) and paraformaldehyde (9.5 g) in dry dioxane (300 ml). Propiolaldehyde diethyl acetal (38.6 g) was then added and stirring was contd a t 80" under NZ for 24 hr. The hot' reaction mixt was filtered and the filtrate was evapd. Recrystn of the solid residue from a mixt of EtOAc and petr ether (bp 60-80") gave 4-benzamido-l-(4,4diethoxybut-2-yny1)piperidine(87) (84.6 g, 827,), mp 130". Method I(ii).-The product of part i (70 g) in EtOH (1 1.) was hydrogenated in the presence of 10% Pd/C (7 g) a t 3.52 kg/cm2 for 0.5 hr. Evapn of the filtrate after removal of the catalyst and recrystn of the residue from petr ether gave 4benzamido-l-(4,4diethoxybuty1)piperidine (88) (61.29 g, 86.57,), mp 95". Method I(iii).-The product of part ii (3.48 g) was added portionwise to a soln of p-methoxyphenylhydraeine.HC1 (1.75 g) in aq AcOH (15 ml) with stirring at 80" which was contd for 2.5 hr. The cooled mixt was dild with ice water, basified wit,h I12C03,and extd with CIICl,. Evapn of the combined and dried exts gave a brown oil. Ciystn from MeCX gave 5-methoxy-3[2-(4-benxamidopiperid-l-yl)ethyl] indole (73) (1.95 9). 3- [3-(4-Benzamidopiperid-1-yl )propyl]indole (82). Method J.-A mixt of 4-benzamidopiperidine (1.02 g), 3-(3-hydroxypropy1)iodole tosylate (1.73 g), and KzCOs (1.38 g) iu i-PrOII (25 ml) was stirred and refluxed for 24 hr. The filtrate from t,he hot reaction mixt crystd on cooling to give the crude product (1.83 g, loo'%), mp 174-178'. Recrystn from EtOH-H20 gave the anal. pure product. 3- [3-(4-Benzamidopiperid-1 -yl)-l -oxopropyl]indole (81). Method K.--9 mixt of 3-acetylindole (1.57 g), 4-benzamidopiperidine (2.0 g), 40y0 aq CHI0 (1.0 g), and AcOH (0.8 g) in EtOH (25 ml) was stirred for 4 hr. The product was filtered off and recrystd from RTeCX to give colorless needles (1.53 9). 3- [2-(4-Benzamidopiperid-1-yl)-l -hydroxyethyl] indole (78). Method L.-3- [2-(CBenzamidopip erid- 1-y1)-1-oxoethyl] indole (74) (0.9 g) in MeOH (50 ml) was treated dropwise with ISaBH4 (1.0 g) in H20 (9 ml) and 2 N SaOH (1 ml). The mixt was stirred under reflux for 2 hr, cooled, and evapd. The residue was slurried with H2O and the resulting crystals were collected and recrystd from EtOH to give the product (511 mg) as colorless needles. 3-[2-(4-[2-Carboxybenzamido]piperid-l-yl)ethyl]indole(52). Method M.-3-[2-(CAminopiperid-l-yl)ethyl]indole (25) (1.0 g ) in CHCla (50 ml) was stirred at 40" and phthalic anhydride (570 mg) was added portionwise. The resulting solid was collected after 2 hr, and recrystd from EtOH-HZO t o give the hydrate (855 mg).
Acknowledgment.-The authors express their appreciation t o Drs. E. S. Johnson and A. B. Wilson for their invaluable advice and encouragement during the biological evaluation of these compounds.
