,IiU!Z. CaICd. flJr CwI%aC1:S40:C, 41.7; H, 3.1; N, 21.6. I.'ound: c:41.8; 13,3 . 3 ; 21.1. 2-Amino-6-benzylthio-9-methylpu:ine.-To B stirred solution of 150 rnl. of c~onrentrated aqueoiis nnirnonirt, containing 7.0 g. OF 2-nmino-$1-nretli!.l-A-piirinethi01,'6 w t s :idded 'LO ml. of p-ilirixtne ant1 5.0 g. OF Iimzyl c~lrloridt~.This mixturr WI,S s t i r r i d arid he:tt,ed i10" j for 1 hr. during which t,irne tlie prciduc~i I)revipit:tt,ed froni the soliition :tncl w:ts I'iltered, wished with a.:iter, :tilt1 dried. '1'21~rritde product WI.S recrystallized from :Ic,ct:ite-I.'etrolei!iii ether 160- I I O 0 ) t o give 3.6 g. R.ec:r>,st tion froin benzene provided a sample with :inieltirig po l ~ ~ l - l X 3 ° . Ultrnviolet spectrrt: p H 1, A, 821 mp, enlax 11,ii)O; ] I l l 1 I, A,,:31:1 ill@, emnx 12, MeOH, A,,,,, :313 nip, 12,500. _ I ne!!. C:tli,tl. for Cl,possibilit,y tliat
~
I I j .5npliorted by Carrcr D e v t ~ l o ~ ~ m .%ward ent C:M-K3-7415 and rpsexrch xi-:int B-2508 froin the Xational Institutes of Health, V S P H J . I t i i a i , I m s i t r * to acknowleiise, t l i e a s ~ i s t n n c eof L I r . R. Friernan, 311.31. Laupsnii. a n i i X r . AI. Abdrl-Hahnran in sonic? (11 t,lir r x p i . r i i n ~ n t ~ s m. Ciiem. S o r . . , 79, 3215 ( l ( J i 7 ) . SiiiiapPlinrin. :nilti It. I.. Hin:nsn, A r c h . Bioelicm.
their purification has lxwi described.'"-" The componnds ind u d e : 1-azaindole i 1H-pyrrolo [3,2-b]pyridine) ; 5( 1 H-pyrrolo[3,2-c]p)ridine); 6-:tz:~indole ( lH-pyrrolo[2 tline j : :3,-t-diazaindolt: ( IT€-irnidaeo [1,.5-b]pyridine): iwtindole (lH-iinidozo[,~!.i-c] pyridine); and purine (7Tf [ 4,541pyrimidinc~).
(1) 1%'. It. N . l V i I l i : ~ ~ r r s ~.J. i n ,C ' h e m . d o c . . 2833 (1902). (5) .J. . A . ~Vailiii~Il. .I. 1"hnrmacnl. h'zptl. Thernp.. 31, 205 (1927). i l i ) I . AI. Feinbt~re.i h i d . , 66, 12 (1939j, 17) 11. X-. Ets and I. RI. l'einherp, A m . .J. F'hysiol., 136,647 (1942). I s q r i i t ~ r d oa n d A . 0. 31. Stogpani, Brii. J. Phwmocol., 8 , .'38!I 1
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( 9 ) I . 31. l ~ e i i i l : e t ~unil p (1$)44). I O ) I.. (~IJI~III~III, iI$ll,'i9,
\V. S. ~ I ~ * C ' u I ll'roi,. ~ ~ ~ hSOC. . E t p l l . Biol. .?fed., 56,
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I
AZAINDOLES
September, 1963
481
TABLEI PHYSICAL AND BIOLOGICAL PROPERTIES OF AZAIXDOLES
Compound (-4)
Indole 2-hzaindole (indazole) 3-Azaindole (benzimidazole) 4-Azaindole 6-Azaindole 6-Azaindole 7-Azaindole 2,3-Diazaindole (benatriazolel 3,4-Diazaindole 3,5-Diaaaindole 3.5,7-Triazaindole (purine) a
LipidIn vitro effects on smooth muscle water 3 ’,” 3 distribu- In vivo effects after i.n. R a t stomach fundus Guinea pig ileum ~.injection in mice p& ionized tion Gross EDwa LDd Concn. Concn Effect (lO-‘W) Effect ratio effects (basic) a t pH 7.4 mg./kg. (10-4.U) mg./kg. (1) (B) (C) (D) (E) (F) (G) (H) Very slight 185 316 0.4 Very marked 0 4 -2,4 0.0000001 8 5 . 7 Convulsions (170-202) (266-376) relax. relax. Mod. relax. .5 1.22 ,00009 41,5 Mixed effects .i) 70 440 Very slight (54-91) (326-595) relax. Mod. relax. .5 195 640 .5 Slight relax. 5.53 1.33 16.4 Paralysis (174-218) (587-697) Mod. relax. Slight relax. .8 260 .8 36 6 . 9 4 27.75 13.1 Convulsions (32-41) (221-306) Marked 3Iarked cont. 6.3 16.5 3.9 .9 8 . 2 6 87.87 17.3 Convulsions (5.2-7.6) (14.8-19.0) contraction Marked cont. 2.2 1.1 36.8 Convulsions 5.9 12.0 Marked 7 9.5 78 02 (4.6-7.5) (10.0-14.4) cuntraction 1 1 \foil. trlax. 1 1 Fl.yI1t t o Illotl. 166 490 4.5Y 0.15 53.2 Paralysis icla‘i (148-187) (44.5-539) 230 500 1.6 ,0002 3.0 Mixed effects 4.0 6.1 2.4
.4 4.76 ,001
0.93 1.03 0.36
Convulsions Paralysis “Shock”
> 200 >41
a i d t h ( h 23-. 4-.aiicl 7-iizaisomers all procluc~relaxation of t h ( t I < I + storriaoh hiii(Iii:, strip :ind of the isolatcd ~ U I I I C Y I pi' i l t u i i i i i i a c~otic,r,iitratioii01 appi'oxiniately .i t o 10 p g . 1111. Wltile a11 tliese coinpounds antagoiiihr, t l i t , effect of .i-hydrostryptamiiie (,i-HT) o i l tlit guinc . pi ileuin. hi cwtaiii in.;tances ( c z x . T\ ith 8-aztt- and I-amiildole) the fundus strip Tva.; rriidered moie wenaiti\ e ' ( 1 .i-HT. Stimulation of sinooth iiiuscle evoked hy 2,; 3) pg. .i-aza- and 6-azaiiit-lolt. prr 1111. i~eiciiihlc~ tliLLtpi o(31
1
'27) 1 ' H 0'L)oll I It \Iilaon, ,\I I J hapull Ii 1 ) \ \ l i i t ( d n I I I 1 \Iirsk>, J P h n r m a ~ o l C x p t l T h e r a p , 128, 67 (19FO) 128) Yen -uhqtnnrv P r p p a r e d h\ R E Killrtte I ) e p a i t i ~ l e i i t uf \ l m l ~ < .rl
