Synthesis of Potential Antimalarial Agents. 11. 6,8-J)isubstituted Pyrido[2,3-b]pyrazines
i.
VHR
NHIi
tance to chloroquine of +traiii- of P/asmodiuni Dei !//lei iind presumahly of I'las~~~orlzun~ Julcipai u m ha< been +kiowri t o involve the decreased accumulntion of chloroquine in pura-itized erythrocyte< apparently c3:iused by a r i inipairnieiit of the tranqport mechanism dine:, with Iiitiiey iiickel g:ivc the .5,ti-diiimiriopyrior ;L1oub in the efficacy of iritracellular binding t o DSA.? dines 6-9 ;md ethyl 5,Ci-diamino-4-{[~-(dietIiylwniirio)A+ part of ii program to develop compouridq effective l-methylbutyl]aniiiio 1 -'-pyridiriecarbamlit c>. Thc 1:it againit chlorociuine-resistarit strain.: of P . b e q h e z , the rinitive to air and was condensed Z / I situ with effect on antimalarial activity of the addition of (1) eouy glyoxal, 3074 aqueou:, pyruvaldehyde, ring nitrogen:,, ( 2 ) cw)cgclic group< coritaitiirig electronbenzil, p-chorophenylglyoxal, arid ~,~'-dichlorobenzil, rich center+, and (3) g r o u p capable of hydrophobic respectively, t o give the ethyl pyrido [2,3-b]pyrilziiie-tihotidingj to the cluinoline ring wa< investigated by the carb:unate+ 10, 12, 14, 16, :tnd 18. The carbamates 10 prepimtioii of sornc' (i-nmirio-8-~ub~titutecliimino:md 12 werc purified by column chroniiitogr:iphy to givcb pyrido [:',:2-0]pyrazine-. tlic products a- :imorphou- glasqc>. The Iicactiori of ethyl (i-aniino-~-chloro-~-~iitro-:'-~)yr-of the oricntntion of the methyl group iri 12, and t h c idiriccarbnmat c4 with SI, S t-cliethyl-l.&pentanedi1)-chloropheiiyl group in 16 i+ baqed 011 a1i:tlogy with umiricx, 1)-chloroaiiiline, a-amino-ji-tciluerie~ulfonamide, the dirclction of cyclization in the conden~ation ( i t I,-("-:tniiiioethyl)beiizeii~~iilforiamide,j:ind p-(:'-aminopgruvaldehyde with other .i,G-diarninopyridiiie~.'] cthyl)-S,S-diethylberlzenesuli'onamide, reupectively, Simi1:irly t h e coIideilskttiol1 of the .i,(i-diaminopyi.-gave t hc corre+powhg .i-iiitropyridine+ 1-5 (see idiiiey 6-9 with thc, a-dicarbonyl reagents described l':tble I nnd Schemc I ) . Hydrogerioly:,i- of the5e pyn-
li
h::
EtOZCHN
Et0,CHN
NOTES
Sovember 1968
1217
TABLE I1 P Y R r D O [2,3-b]PYRAZISES
YHR
Compd
Method
Time, hr
Reaction--Temp, Time, Temp, Recrystn' "C hr "C solvent
Yield,
hI p,b, d
%
OC
92 87 81 85 78 77 84
. . .d
Formula
;\nalyses
1
R = CHICH(CH~)~NE~~ 10,
RI
11, Ri 12. R I 13, Ri 14, R I 15, Ri 16, R I 17, R1 18, R I 19, Ri
= =
= = = =
= = = =
R? Rz H; R3 R? R? H; R3 Rr
= H ; R3 = COaEt
R3 = H Ra = CH3; R3 = CO?Et = H ; R? = CH3 = C6Hs; R3 = C02Et = C6Hj; R3 = H R2 = CsHaCI-p; R3 = COzEt = H ; R? = CeHaC1-p = CeHaC1-p; R3 = COZEt R? = CsHaCl-p; R3 = H =
48
C
48 7 24 7 2 6 1 7
D
E D E D E D
F
20, R I = 21, RI = 22. R I = 23, R I = 24, R I = 25, RI = 26, R I = 2 i , Ri = 28, Ri = 29, R I =
Rr R? H; R3 R?
R2 = C H I ; R3 = COaEt = H; R ? = CHI = CsHs; R3 = COaEt R ? = CaHs; R3 = H H ; R, = CGHICI-p; R3 = C02Et R3 = H ; Ra = CoHaCI-p R ? = CeHrCI-p; R3 = COiEt R ? = CoHaC1-p; R3 = H
F G F G F G F G
Ri RI RI RI Ri 35, R I
Rr R2 H; R3 Rr Rr
F
30, 31, 32, 33, 34,
=
= = = =
= H ; R3 = COzEt = R3 = H
C D
H ; R3 = CO?Et R3 = H R ? = CH3; Ra = CO?Et = H ; R ? = CHI = CeHs; R3 = CO?Et = CsHs; R3 = H = =
G
G F G F H
,
2 6 4
7 6
7 0 5 18 1 I
1 4 18 7 48
8
... ...
RI RI RI RI
= = = = RI= 41, Ri =
42, 43, 44, 45, 46, 47,
R1 Ri RI RI RI
= = = = =
R? R? H; R3 R2 Ri
H ; R , = CO?Et R3 = H Ra = C H I ; R3 = COIEt = H ; Rz = CH3 = CsHs; R3 = CO?Et = C6Hs; R3 = H = =
R? = H ; R3 = COaEt R ? = R3 = H H ; Rr = CH3; R3 = COrEt R ? = C6Hs; R3 = CO?Et R ? = CaHs; R3 = H H ; Rs = C6H4Cl-p; R3 = COaEt
F
1
G
7
F
2
G
7 3 7
F G F G
I F G
1 7 48 6
,
. . .0
78 6
, . .
+ B, + I3
D C
78
. . . i,*
78 65 78 78 78
24
..,c
+B
; i
+ Be
D 48
0
...l
..
. n.
18 50 78 60 2 . . .' 78 78 Eo 78 R = CHLhHaSOrNH?-p 60 24 . . .c 150' EO'Q
...
C0.T
F
78
. . .c
+ B'
60 C".' 8 153 C7'** CH?CHnCsHnSOrPu"rp 18 ...c .io P I3 48 ...' C EO 14
80 =
+ +t
... 16
. . .c
AO,'
-+
, . .
... 254-256 2 78-2 79 ' 242-243' 280-281' 251-253< 281-283
