[CONTRIBUTION FROM TEE CHEMICAL LABORATORY OF THE UNIVERSITY OF SOUTHERN
CALIFORNIA]
POTENTIAL ANTIMALARIALS IN THE 4-DIALKYLAMINOMETHYL2-MET.HYL-3-PYRIDOL SERIES RONALD F. BROWN
AND
STANLEY J. MILLER
Received March 25, 1846
The activity of the minimal effective dose of quinine and of Atabrine against P. Zophurae infection in Pekin ducklings has been shown by Seeler (1) t o be inhibited by the administration of pyridoxine in quantities three thousand times the basic nutritive requirements of the host. It appeared, therefore, that pyridoxine might be an essential metabolite for the malaria organisms, and it seemed a reasonable expectation that similar compounds might interfere with this metabolism. In order to investigate this possibility, several compounds of type 11, which contain structural features of pyridoxine as well as the dialkylaminoalkyl side chain found in active antimalarials, were synthesized from picolinol I by means of Mannich reactions. CHzNRz
A/
/\
L,
CHS
4"\I
SOaH
OH
----$
CH8
/\\/OH
C( - L( CH3
I
CH3
I1
Sulfonation of 2-picoline and the subsequent alkaline fusion t o yield I were carried out according to the methods of Wulff (2), except that sulfonation with fuming sulfuric acid was found to be expedient. The crude 2-picolin-3-01 (I) was recrystallized from ethyl acetate in order t o remove inorganic salts. The usual procedure for the Mannich reaction with phenols (3) was found t o be applicable t o picolinol I. Participation of the methyl group of I in a Mannich reaction requires relatively rigorous conditions (4)and no interference from that source was observed. The aminopyridols which were prepared in the aforedescribed manner are shown in Table 1. EXPERIMENTAL
/t-Diethylaminomethyl-d-methyl-S-pyridol (ZZ,R = ethyl). To a solution of 16.35 g. (0.15 mole) of 2-picoline-3-01 and 11 g. (0.15 mole) of diethylamine in 50 cc. of water was added 1 The work described in this paper was done under a contract, recommended by the Committee on Medical Research, between the Office of Scientific Research and Development and the University of Southern California. The Survey h'umber, designated SN,identifies a drug in the records of the Survey of Antimalarial Drugs. The antimalarial activity of those compounds t o which such a number has been assigned will be tabulated in a forthcoming monograph. 388
389
DIALKYLAMINOMETHnPYRIDOLS
ANALYSES~
ss
R
M.P.,
"C. (CORR.)
--CHxN (c2H.5)~(HCI) CH2CHz 13,636 --CH&( 'CHZ
CH~CH/
B.p. 100-100.5/3 68.05 9.3467.34 9.29 mm. 49.03 7.5549.03 7.56 210-211.5 (2 HCl)
14,069 - - C H ~ N ( C H ~ C H & H ~ C H ~ ) Z
____
Found
%C % H %C % H ----
13,484 --CHzN (CzHs)z
Calc'd
I
250-252 dec.
51.56 7.2251.68 7.12
B.p. 134-136/3
71.95 10.47 71.68 10.52
-.
