May 1969
451
PHOPYNYL-SUBSTITUTED INDOLEAMIKES &'HEME
H
SCHEME I1
1
H
4
I
CH'yH
I
H
H
CHJ
Sa, R', R = H b, R' = H; R = CHj
7a, R', R = H
5
b, R'-H; R=CH3 BiCH.C=CH
- 3
c,
/
R'=OMe; R - H
H
TABLE I I\IOXO.IMINE OXIDASEINHIBITION^ Sa
llci
150
>3 b
H 9a, R', R H b, R'=H; R=CH3 c, R = OMe; R = H
Comments
.it
i=
.\I, compound precipitated from solution
9b 9c 11 2 5 Pargyline Tranylcypromine Reference 8.
R'=OMe; R = H
HNCH,CECH)?
6
Compd
c,
>lob
R~Q,--~~H;N(CH~C-CH),
IVeak, 9% inhib at If 2 0 5 inhib a t 31, but 16y0 stim at -12
H 11, R, R'= H
8.4 175, inhib at 10-4 .If
I
0.017 0.027 Inactive a t this concentration.
was added. The mixture was hydrogenated in a Parr low-pressure hydrogenator until the theoretical amount of HZ was absorbed (about 5 min) and then was filtered through Celite, to yield a solution of 3-(methylaminomethy1)indole. The oxalate salt was prepared by adding an equimolar amount of solid oxalic acid (as dihydrate or anhydrous) to a hot solution of the amine in EtOH. Et20 equal t o about half the volume of EtOH was added, and cooling caused the oxalate salt to crystallize. The yield was 60% from indole-3-carboxaldehyde. The salt was slightly hydroscopic and discolored on standing in the air or upon heating. In the melting point apparatus, it changed color t o red, mp 126-128", then resolidified, melting again at 150-165" dec. The ir and nmr spectra agree with the assigned structure. The analytical sample of the oxalate was obtained after recrystallization from i-PrOH-EttO, under Sa;nmr (CDCL-CFaCOOH), 8 2.93 ( 3 H triplet), 462 (2 H multiplet), 7.1-7.7 (multiplet). Anal. (C12H14K~02)C, H, K. 3- [N-Methyl-N-( 2-propynyl)aminomethyl]indole Hydrogen Oxalate (3*Salt).--A solution of 3-(methylaminomethyl)indole (6)in 250 ml of NeOH was stirred with an excess of anhydrous KZC03 while an equimolar amount of propargyl bromide was added dropwise. After the mixture had been stirred overnight, the solvent was removed under reduced pressure and the residue was redissolved in 500 ml of C6H6 and 100 ml of HzO. The C6H6 layer was washed (50 ml of saturated SaCl solution) and the aqueous layers were washed (100 ml of CHCb). An equimolar quantity of oxalic acid in EtOH was added to the CHC13-CeHe solution, causing the propynylamine to precipitate as the oxalate, mp 130-131". S o suitable solvent could be found for this salt for an nmr specmum. An ir spectrum was consistent with the proposed structure. Anal. ( C I ~ H I ~ N ZC,O H, ~ ) ?;. 3-Indoleglyoxyiyl Chlorides (Sa).-A solution of 54 g (0.428 mole) of oxalyl chloride in 150 ml of dry Et20 was added t o a solution of 25 g (0.214 mole) of indole in 500 ml of dry EtzO. After the mixture had stood a t room temperature for 12 hr, the solid was collected and dried to yield 39.8 g (90%) of Sa, mp 128". Similarly prepared were Bb and Sc. 2-1Llethyl-3-indoleglyoxylyl chloride (Sb) (17.7 g, 807,), mp 147-147.5", was obtained from 13.1 g (0.1 mole) of 2-methylindole (Aldrich Chemical Co.) and 25.4 g (0.2 mole) of oxalyl chloride. 5-iVlethoxy-3-indoleglyoxylyl chloride (8c) (15 g, 81%), mp 118-119" dec, was obtained from 10 g (0.068 mole) of 5methoxyindole (Aldrich Chemical Co.) and 17.2 g (0.136 mole) of oxalyl chloride. N,N-Di( 2-propynyl)indole-3-glyoxylamide (9a).-A solution of 22.5 g (0.108 mole) of 3-indolylglyoxylyl chloride (Sa) in 300 ml uf anhydrous T H F was cooled to 0' and a solution of 10 g (0.108
HN(CH,C=CH),
10
mole) of di-2-propynylamine (illdrich Chemical Co.) and 11 g (0.108 mole) of E t J in 150 ml of T H F was added dropwise with cooling. A white precipitate formed. The mixture was stirred a t room temperature for 12 hr. The precipitate was filtered and washed (THF), and the combined filtrates were evaporated. The residual solid was recrystallized from t-BuOH-petroleum ether, yielding 21.8 g (767,) of yellow needles of 9a, mp 158-159'. The analytical sample (from EtOH) had the same melting point. And. (ci~Hns20z)C, H, S. Similarly prepared were 9b and 9c. N,N-Di(2-propynyl)-2-methylindole-3-glyoxylamide (9b).-A 78% yield of 9b, mp 147-180' (from EtOH), was obtained from 2-methyl-3-indoleglyoxylyl chloride and di-2-propynylamine. The analytical sample, mp 149-150 ', was recrystallized from EtOHpetroleum ether. Anal. (CnH14S202) C, H, N. N,N-Di(2-propynyl)-5-methoxyindole-3-glyoxy~amide (9c).The 5-methoxy derivative (11 g, 72y0), mp 199-201" (from EtOH), was obtained from 12.7 g (0.054 mole) of 5methoxy-3indoleglyoxylyl chloride and 5 g (0.054 mole) of di-2-propynylamine (Aldrich Chemical Co.). Anal. (Cl?H14S?O3)C, H, S . 3-(2-Rromoethyl)ihdole (lO).-PBrS (3.6 g, 0.0133 mole) was added to a solution of 3 g (0.0186 mole) of tryptophol (prepared by LAH reduction of ethyl 3-indoleglyo~ylate)~~ in 225 ml of dry C6H6 containing a few drops of pyridine. The solution was then refluxed under dry K2 overnight. An orange-brown precipitate formed. The supernatant solution was decanted into 100 ml of cold HZO. The mixture was stirred vigorously and neutralized with 100 ml of 5% SaHC08. The CeH, layer was separated, washed (5% SaHC03, saturated SaCl), and dried (xIgsO4). After evaporation of the solvent, 3.5 g (80%) of 10 was obtained as a pale yellow solid, mp 97-98" (lit.I2mp 100-102"). N,N-Dipropynyltryptamine (ll).-.% solution of 4.16 g (0.04 mole) of dipropynylamine (Aldrich Chemical Co.) in 50 ml of i-PrOH was added to 5 g (0.02 mole) of 3-(2-bromoethyl)indole in 75 ml of 2-PrOH and the mixture was stirred a t reflux for 4 hr. cooled, and filtered. The filtrate was evaporated and the solid remaining was extracted (EtzO). A solid was recovered from the Et20 upon evaporation. It was recrystallized from EtOAcpetroleum ether to yield 2.4 g (46co) of 11 as yellow needles, mp 92-93'. Anal. (ClSHI6NZ) C, H, S. The HC1 salt was pre( 1 1 ) Upjohn Co., British Patent 778,823 (July 10, 1957); Chem. Abslr., 52, 1265 (1958).
(12) 31. S. Fish, N. 11.Johnson, and E. C . Homing, J . .4m. Chrm. Sac., 78, 3668 (1956).
pared in Et20. It was recrystallized (EtZO-EtOH) as whitr needles, mp 143-144". .1.nal. ( C I S H I ~ C I S C,~ )H, S . N-(2-Propynyl)isoindole (2) Hydrochloride.---A aolut ion of 11.9 g (0.1 mole) of 3-hromopropyne in 25 ml of Et20 was added dropwise at 0" to a solution of 23.8 g (0.2 mole) of isoindoline6 i n 200 ml of anhydrous EtzO. The mixture was allowed 11) stir in an ire bath for 3 hr and at room temperature overnighf. Isoindoline hydrohromide was filtered off. and the EtzO solution was dried (SaaCOs)and evaporated. The resulting orange oil waR distilled at 65" (0.3 mm), resulting in 8.8 g (55('(I of 2 :is a slight,ly yellowish oil, na% 1.5620. .Iiiui. (CI1HIlS) C, H, S . The hydrochloride of 2 WRS fornied in b:t,O. TI iiielted a i
+Adrenergic Blocking Agents. IV. Variation of the &Naphthyl Group of Pronethalol [2-Isopropylamino-l-(2-naphthyl)ethanol] R. HOWE,B. J . MCLOUGHLIS, R.S.RAO,1,. H. SMITH.A \ D 11. 8 . C"ODVEP;AR Iniperzal Chenizcal Zndustraes Lld, Phai nkuteictzcals lierewed
L ) Z L I S I O I.1 I , ldei ley
P a r h , Iluctleafielrl, Cheshnrf. Bngland
entbei 26, iFXcs
In attempts to improve the potency of the adrenergic preceptor anlagom+l PI onet halo1 ["-isoprop?-larniii~-1(2-naphthyl)ethanol] the 2-naphthyl group has been replaced bv, for example, I-naphthyl, tetrahydro-"naphthyl, h n d a n y l , and various tricarbocyclic groups. .halogs have also been made with subqtituents other than 2-Pr oil S . Structure-activity relationships are discussed. Several of the compoundi desvrihed Iiaw the iame level ot potency as pronethalol.
In the course of our synthetic program' ainied a t irnproving the potency of the adrenergic @-receptorantagonist 2-isopropylamino- I- (2-naphthyl)ethanol (pronet hdol)* we have prepared the analogs described in m
C
H tOH)CH.NHP~-~
pronethalol
tion of 4-meth2-i-l-acetonaphthoiir.6 obtaiiied I)y :tq-Iation of 1-niethylnnphthaleiie uiid used to preparc' brornomethyl 4-nic.th;vl-1 -naphthyl ketone. w:ih checketl by oxidation I ia -I-inetliSI-l-n:iphthoic acid to nuphthalene-l..l-c~icarbor;ylicacid.' ('hloromethyl 1.2,3,4tetrahgdro-2-naplitliyl k c t o w 165) was prep:ired by thc. following rout e. IICOCL
--+
I t C O C H l ? --+ ItCOCHiCl 65
Table I. The 2-naphthyl group of pronethalol has been replaced by for example l - r ~ a p h t h y l ,tetrahydro-2~ riaphthylJ45-indanyl,* and various tricarbocyclic groupsb to provide a series of 16 compounds having an isopropylaminoethanol side chain. Analogs have also been made with substituents other than isopropyl on S. The compounds were prepared mainly by three of the methods dem-ibed in part 1.l" In method A. an intermediate aminomethyl ketone iTsthle TI) was rcduccd hy XaBH4 in good yield.
I
dro-2-naphthj 1
In method ( ' iiii intermediatc lialoliydriii was treated with ;in nmiiic, to givc ( [ , i n xn cpoxitle) R mixture of 0
ICH(OH)CH?\+IICH-
3
CH.
I1CH(OH )CH:SII'R'
L
IICH( l It'ltZ)CH?OH
position isoniers, n-hich large]? cwisistetl of thc clesiretl secondary alcohol isomer. Purificatioii hy fractional crystallizatio~igave tlic required isomer. daniples of 13 4, 13, anti 15 obtained by mcthod (' were itlciitical with IICOCH2X -+ 11'112SH e 1 those produced uii:rml,igously by method A. The strucItCOCH2SR%' -+R C H ( O H ) C H Z S R ' R ~ tures of those compounds prepared oiilj- by nirthotl ( ' SaBHI S = Br or C1 n-ere confirimd by nnir and, in pwrticulnr, hy tlic chemical shift of thcl protoll ('H[O)- which in pronc~tliYevcrnl specific methods are described for the isolatioii alol (CCI,) is T
