Journal of Medicinal Chemistry, 19Y0, Vol. 13, N o . 3 545
NOTES
TABLE I
/"'
Yield,
X--Rr
Compd
N p , OC
Recrystn solvent
%
Analysis
Formula
C2lH32N203.2HCl C, H, C1, K C21H3oN201.2HCl C, H, C1, K,0 C, H, C1, N, 0 CzJLzN203 ) 0.5H20.2HCl C, H I N 6 4-CsHa-CaHsX;?'z 180-1 82 60 MeOH-DMF C~H36N303 C?iH3&203 2HC1 C, H, C1, K,0 190-192b 50 MeOH 7 CdHsS C, H, N S 4-(2-OCH3CsH,)C,H,X',>n 152-1.54 65 MeOH-EtOH C2&?N304 240b 40 EtOH C23H34X203.2HCl C, H, K 9 3-CHa-C,HgN CnaHaaNZO3.2HCl 22t3-227b 45 EtOH C, H, N 10 ?;(C3H;)2 C, H, N 119 50 EtOH C22HaN3Ot 11 4-HO-H2C-H2C-C4HsN2' b Dihydrochloride salt. The synthesis of these compounds was disclosed by Cassella Farbwerke a 4-Substituted piperazinyl. LIninkur .4ktiengesellschaft to the author i n a private communication after the above studies were complete. 200b 260b,c 27ObmC
N(CnH:)n CaHsXO CaHioN
3 4
Compd
Iritenraiii :3
4 1
6 7 8 9 10 11
-----
Dosage, mp k
2 10 10 10 >
10 2 7.2 2
10
45 j0 40
MezCO-EtOH hIeOH-EtOH Me2CO-hleOH
TABLE I1 -p02----7
Change percentage
Duration (min)
30 0 0 - 15 52 24 6 -7 - 57 19
60 0 0 8 4 15 10 60 5 36
The common characteristic feature of these compounds is the 7-oxycoumarin skeleton as in 1. Recently a
1
synthetic 7-hydroxy coumarin derivative, 3-0-diethylaminoethyl-4- methylcoumarin- 7- ethyloxyacetate- HC1 (11,R = CH2COOC2H5)has been introduced as an antianginal d r ~ g . ~ , ~
2
The present report includes the synthesis and evaluation of substituted 7-OH coumarin JIannich bases of the general structure 3-11 (Table I ) . Compounds 3-11
(3) .k. C. S3nntaq Annu. R e p . M e d . Chem. 1 0 6 7 , 71 (1968). (4) (IntensainB) (:assella Farhiverke Mainkur A.G., C. S. Patent3,259,635 (1966): Chem. A h t r . . 59, 11438 (1963).
,---Blood Change mm Hg
--o
0 0 - 10 7 2 - 20 0 0 0
pressure--Duration (min)
60 0 0 5 31 20 10 0 0 0
,----Heart Change percentage
2 0 0 16 -21 6 4 0 0 0
rate---Duration (min)
60 0 0 5 30 20 10 0 0 0
are synthesized by refluxing an alcoholic solution of equimolar amounts of 3-/3-diethylaminoethyl-4-methyl7-hydroxycoumarin (2, R = H), paraformaldehyde and a secondary amine. By analogy with previous work in this area,5,6the Nannich reaction is assumed to result in substitution on the 8 position of 2. Pharmacology.-The compounds recorded in Table I were injected in the jugular vein of anesthetized dogs a t doses of 2-10 mg/k. The change in the oxygen tension of the coronary sinus blood (PO*), heart rate and blood pressure were recorded by a procedure described by Schoepke, et aL7 (Table 11). A compound possessing good coronary vasodilating activity should cause an increase in pOz for extended periods with minimal effects on heart rate and blood pressure.8 4-Substituted piperazine Mannich bases, 6, 8, and 11, and pyrrolidine Mannich base 7 of 2 (R = H) showed an increase in pOz. 4-Aryl and substituted arylpiperazine Nannich bases, 6 and 8, affected the heart rate and blood pressure significantly as compared to 4-0hydroxyethylpiperazine Mannich base 11. Compounds 7 and 11 showed an appreciable increase in pOz with minor or no effect on heart rate and blood pressure, but the duration of the increased pop was too short (relative t o the effect of 11, R = C02Et) to warrant further investigation.
(5) P. Dare. L. Verlicchi, and I. Setniker, J. O w . C h ~ m .26, , 1097 (1060). (6) V. N . Gupta, l3. R. S iarma, And R. B . Aroru. J. Sei. I n a d a n Res. Sccf. B , 20, 300 (1961). (7) H. G. Schoepke, T. D . Darby, and H . D. Brondyk, Pharmocologisl, 8 , 204 (1966). ( 8 ) Von P. H e i s t r ~ c h e r0. , Kraupp, and G. Spring, Arrncim. Forsch.. 14, 1098 (1961).
