Journal of Medicinal Chemistry, 1970, 5'01. IS, iVo. 6
NOTES ther 1.5 hr, poured into H20, and extracted twice with EbO. The aq layer was acidified with aq HC1 and the precipitated solid collected and dried. Recrystallizat'ion from H20-EtOH gave 21 g of the product (757,), mp 117-118'. Anal. (c14Hie05)
c, H.
The LAH reduction of 20 resulted in the formation of the known compound 23 confirming the assigned structure. The direction of ring opening of styrene oxide when combined with l a was established by a LAH reduction of 9, while the amide 7 using the same reducing agent was converted into the tertiary amine 19.
5,6-Dimethoxyindan-2-one(VII, R = H).-VI1 (R = COzEt) (10 g) was heated a t 100" with 20% H$Oa (70 ml) for 2 hr. The solution was extracted with EtOAc and the organic phase washed with HzO, dried, and concentrated in vacuo. The dark red residue was filtered through a Florisil column in C6Hsj when removal of solvent and recrystallization from EtOH gave 6 g (83%) H of product, mp 137-139". Anal. (C11Hl203) C, H. Spiro(5,6-dimethoxyindan)-2,5'-hydantoin (VIII).-5,6-Dimethoxgindan-?-one (7 g ) , NaCN (3.6 g), and (NH4)2C03 (16.T g) were heated in 40yo EtOH (300 ml) for 3 hr at 60". The temperature was maintained a t 100" until unreacted (SH4)?COa was removed, and alloir.ed to cool when 4 g (42y0 yield) of the hydantoin, mp 298" dec was obtained. d n a l . ( C I ~ H I ~ N Y O I ) C, H, S . 2-Amino-5,6-dimethoxyindan-2-carboxylicAcid (11, R = Me).--A mixture of the hydantoin (VIII) (3.4 g) and Ba(OH), (6 g) in H20 (50 ml) was refluxed for 24 hr, the hot solution filtered, and the filtrate boiled with (NH4)ZCOa (2 g). The filtrate was concentrated in c1acuo until crystallization occurred, and MeOH (100 ml) was added, when 2.5 g (82y0yield) of the prodH, S . uct, mp 299-300" dec was obtained. Anal. (CI?H~~NOI)C, 2-Amino-5,6-dihydroxyindan-2-carboxylic Acid Hydrobromide (11, R = H).-The amino acid (11, R = Me) (1 g) in CHIC12 (30 ml) was treated a t -70" with a solution of BBr3 (0.5 g) ill CH2Cln (10 ml) and cooled to -io". The reaction mixture wa': allowed to reach room temp overnight, HzO (1 ml) added, and *. the dark brown solid filtered off. Treatment of the solid with H charcoal in hot EtOH gave on concentration in e~acuo,0.7 g ( 5 7 5 yield) of the product, mp 250-254'. 4 n analvtical sample was Eecrystallized-from EtOH-EtQO, mp 260" de;. d n a l . ( C I U H I ~ BrNO,)C, H, N, Br.
LAH
CH,NC,H,
I
COCH3 :!0
I
J
a,l(
H
CH,NCH,
I
Received -4pril 20, 1970
I n a search for compounds which have an effect on the CNS, it was found that certain substituted 2-aminomethylpyrroles demonstrated a significant degree of depressant activity coupled with a relatively high LD50. This note reports the compounds prepared in this area, in addition to their biological activity. Chemistry.-The preparation of the necessary starting materials utilizing a Mannich reaction on pyrrole has been reported.2 These substituted aminomethylpyrroles (la-d) were treated with compounds having electrophilic groups (acid chlorides, acid anhydrides, isocyanates, isothiocyanates, etc.) giving in all cases the expected products (Table I). R'
tm ,2H,A,8
R' CH3 Ib H C2H5 IC H (CH,),CH, Id CH3 CH, la H
I
R'
(1) -411 reprint requests should be sent t o Air. Frank P. Palopoli; Wm. S . Merrell Company; Cincinnati, Ohio 45215. (2) S. Rainesand C. A . Kovacs, J . Helerocycl. Chern., 7, 223 (1970).
18
9
4
Synthesis and Pharmacology of a Series of Substituted 2-Aminomethylpyrroles'
The .Vat ional Drug Company, Research Laboratories, Diz,ision of Richardson-Xerrell Inc., Philadelphia, Pennsylvania 19144
CH2N(CH3)CH,CHOHCGHS
~OCH(C~H,)O,CCH,
CH,O
OCH,
4
pH C H , N CI H 3
BNB\CH,NCH, H I
STEPHEN RAIKESASD CSARAA. Kov.ics
1227
-*LAH
CH30
OCH,
OCHB OCH3 19
7
Pharmacology.-A number of compounds prepared demonstrated a significant degree of CNS depressant activity (see Table I) in dose range studies in mice. The 3ILD (2000 mg/kg, PO) and the minimal symptomatic dose (31 mg/kg, PO) were determined for 20. Phenobarbital when employed in dose range studies was fourtd to have a minimal symptomatic dose of 15 mg/kg PO. I n addition, the compounds reported in this paper were adininistered orally and screened for antihypertensive activity in renal hypertensive antiinflammatory activity in the carrageenin abscess test in rats5 and analgetic activity in the phenylquinone-induced writhing test in mice.6 There was no significant activity noted in these areas. Experimental Section All compounds had ir spectra in agreement with their assigned structures and analyzed for C, H, and N within &0.4 per cent of their theoretical values. (3) W. Herz, K . Dittmer, a n d S. J. Cristol, J . Amer. Chem. Soc., 69, 1698 (1947). (4) A . Grollman, Proc. Soc. E z p . B i d . M e d . , 61, 102 (1944). ( 5 ) 5. Goldstein and M . Schnall, S r c h . Inl. Pharmacodyn., 144, 269 (1'363). (6) L. C. Hendershot a n d J. Forsaith. J . Pharmacol. E z p . Ther., 186, 237 (1959).
