Synthesis of potential antimalarial agents. II. 6, 8-Disubstituted pyrido

II. 6,8-Disubstituted pyrido[2,3-b]pyrazines. Carroll Temple Jr., Jerry D. Rose, Robert D. Elliott, and John A. Montgomery. J. Med. Chem. , 1968, 11 (...
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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