NOTES
September 1969
927
T.\RLEI : DIAMIDES O F CYCLOBCT.IXE-~,~-DIC \RROXTLIC ACID CONHR
Gross effect'
s s
s
8 8 1 9 2 3 2 :3
?;
1 2
1;
8
8
-@I
R'd
I 1
63
232
A
C~OH~~N~OL
N
N
0 9
75
258
A
ClsHleC12Xz02
N
N
1 2
Drug dose was 1000 mg/kg orally. N = no effect, S = slight reduction in spontaneous a Corrected. b A, acetone; P, pentane. motor activity, subjectively graded and compared with control animals receiving medium only. Drrig dose was .500 mg/kg orally. R' = (dirig pentobarbital sleep time)/(pentobarbital sleep time). Pentobarbital dose, 50 mg'kg ip administered 30 min after test drug.
+
true potentiation and becomes significant when greater than 1.5. The fact that 1 is act,ive as a depressant but inactive as a barbiturate potentiator lends some support to the suggestion that there is functional independence of sites for the two types of a ~ t i v i t y . ~ Two of the compounds, 1 and 2, were also tested for anticonvulsant6 (pentylenetet'razole antagonism), antist,rychnine lethality,' and antitremorhe* e f f e ~ t s . ~ Seither showed antagonism to pent'ylenetetrazole- or strychnine-induced convulsions. However, they completely protected 40-607, of the test animals from tremorine-induced tremors at an oral dose of 1000 mg/k Experimental Section Microanalyses were performed by Midwest, Microlab Inc., Indianapolis, Ind. Where analyses are indicated only by elemental symbols, analytical results for those elements were within &0.4% of theoret,ical values. Preparation of Diamides.-The methods used in synthesizing diamides of cyclobiitaiie-1,l-dicarboxylic acid were essentially t,he same as those reported for producing diimides of that acid.' stallizat,ion solvents and yields are reported in Table 1.
Acknowledgments.-This work was made possible by research Gra,nt SB-7548 of the National Institutes of Health, U. S. Public Health Service.
OCH, I
This paper describes the synthesis and vasodilators. pharmacological properties of a number of new subkituted chromonbs (111-XII) which were prepared as potential coronary vasodilators (Table I). I n addition to the fact that 111-XI1 share the characteristic features of active c h r o m ~ n e s ,these ~ ? ~ compounds could also be considered khellin analogs in which the furane ring of the khellin molecule (I) is not a part of the rigid furanochromone structure, but instead is attached to the chromone molecule through an ether linkage as in VI, VII, and XI. Chemistry.-2-Furyl-7-hydroxychromone (11, R = 2-furyl) a as synthesized from 2,4-dihydroxyacetophenone and 2-furoyl chloride by a standard three-step p r ~ c e d u r e . ~The synthesis of 2-aryl-7-hydroxychromones (11, R = C6Hj and C6H40CH3-4) is already described in the literature.5
(6) E. Soaje-Echayiie and R . K. S. Lim, J . Pharmacol. Ezptl. Therap.. 138, 224 (1962). (7) G. L.Hassert, Jr., J. 15.. Pontsiaka, D. Papandrianos, J. C. Burke, and 13. S . Craver. Tozicol. A p p l . P ~ L w ~ R c3,o 726 ~ . , (1961). (8) T. L. Kerley. A . B. Richards, R. W. Begley, B. E. Abreu, and L. C. \Veaver, J . Pharmacol. Ezptl. Therap., 132, 360 (1961).
I1
Substituted Chromones as Coronary Vasodilators D. S . BARIANA Research Department, Abbott Laboratories Ltd., Montreal, Canada Received Januaru 13, 1969
Khellin or 2-methyl-5,8-dimethoxyfuranochromone (I) and some of its analogs are known to be coronary
The chromones I1 (R = C&, C6H40CH3-4,and 2-furyl) were treated with various chloromethyl intermediates and acid chlorides to give the desired compounds 111-XII. (1) R. Charlier, "Coronary Vasodilators," Pergamon Press Inc., New York, N. Y., 1961, P 84. (2) G . Jongehreur, Areh. I n t . Pharmacodyn. The?., 90, 384 (1952). (3) Koninklijke Industrieele Maatschappij voorheen Noury a n d van der Lande N. V., Dutch Patents 70,267 and 70,268 (June 16, 1952); Chem. Abstr., 47, 64458,h (1953). (4) D . Donnelly, R. Geoghegan, C. O'Brien, E. Phillin, and T. 9. Wheeler, J. ,Wed. Chem., 8, 872 (1965). ( 5 ) W.Baker, J. Chem. S o c . , 1381 (1933).
