Antimalarials. 4-Substituted 1H-pyrazolo[3,4-b]quinolines - Journal of

4-Substituted 1H-pyrazolo[3,4-b]quinolines. Robert G. Stein, John H. Biel, Tara Singh. J. Med. Chem. , 1970, 13 (1), pp 153–155. DOI: 10.1021/jm0029...
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KOTES

January 19iO

K

JIe Et n-Pr n-Bri

R' K

Bp, O C (mmj

1Ie Et n-Pr n-Bu

Formula

90-9.' (0. .i) 104-10.5 ( 0 . 6 ) 12.5-127 (1) 1:3.5-1:37 (0.8)

ClrHli?j ClaHl& CI,H,,S ClaH&

Xt,,,x,

mw

266,278 266,273 266,273 266, 273

e

X lo-*

11.43, 12.43 11.89, 13.03 11.42,9.88 11.63, 10.18

153

and is also a strong CKS stimulant.' 5-Amiiiopyra2010 [3,4-b]pyridines are vasodilators or cardiotonics.2 1- Substituted 3 - dimethylamirloalkoxy - 1H - indazoles show sedative, muscle relaxant, and antiinflammatory proper tie^.^ Several pyrazole derivatives, where the pyrazole ring is not fused with another ring, such as substituted aminopyrazoles, possess antiinflammatory, analgetic, antipyretic, adrenolytic, Iiarcosis-potelltiating, and antirheumatic a ~ t i v i t y . ~ Several derivatives of l-pheny1-3-methyl-i-(substituted amino)-lH-pyrazolo [3,4-b]quinolines (anilino arid substituted ani1ino)j and 1,3-dimethyl-lH-pyrazole [3,i-bJ q u i t i ~ I i n e have ~~~ been prepared but not tested. We were interested in combiliing the features of the pyrazole ring, a substituted quinoline, and an "antimalarial" hide chain in one molecule for antimalarial testing. The key intermediate required was a i-chloro1H-pyrazolo [3,4-b]quinoline (I),in which the active C1 could be replaced with suitable amines expected to impart antinlalarial activity to the final products. The method for preparing it is outlined in Scheme I.

TABLEI11

I

I R R

11e

Et n-Pr

n-Bri

BP, 'C (mm)

83-83 (0 .5) 114-11.5 ( 0 . 6 ) 120-122 ( 0 . 8 ) 107-109 (1)

Formula

CI?Hi,?U' C13HliTi CI,HlqN Ci,H,,S

Amax, mp

e X 10-2

265 268 267 262

67.59 64.13 38.04 31.72

the mixture wa5 heated at, 70-80" with stirring for 0.5 hr in the presence of light. I t was then cooled and poured onto ice, ba-ified with XaOH under cooling, extracted (PhH), and tosylated with TsCl (6 g, 81.6 ntrnole~)i n P h H solut,ion under stirring at 5-8" iii the begiilning and later at 40" with simultaneous addition of 3 -YKaOH ( 2 5 nil) to keep the mass alkaline. The PhH layer was separated oiit and the t,ertiary amine was repeatedly extracted (6 S HCl). The combined acid extracts were basified with NaOIl under cooling, extracted (Et,O), and dried (Na?SO,), aiid the baie was distilled. The yield varied from 30-40q. The physical characteristics of V I are reported in Table 111.

Acknowledgments.-The authors' thanks are due to the Council of Scientific and Industrial Research, Se\v Delhi, India, for part financial support arid to the Director, Central Drug Research Institute, Lucktion-, India, for the aniebicidal test report.

Antimalarials. 4-Substituted lH-Pyrazol0[3,4-b]quinolines I?oni:irr G . STI;IS)JOHS11. BIEL, . \ I D T.ma S r s c ; ~ Research Loboratorz'es, Aldrich Chemical Co., Inc., Jlilwaiikre, M.isconsin 63210

R e c e i u d A iigitst 11, 1969

l'yrazole derivatives are known to possess various kinds of biological activity. For example, the pyrazole[3,4-b]pyrimidine derivative, an isostere of caffeine, is indistinguishable from caffeine in itcl diuretic properties

R I1

f

I

I\'

R I11

Hoo' H-N Q

t

-[

CH COCH-COSH

VI. X = H.C1

+

CH.=C-CH

1 1 -

0-CO VI1

(1) 1'. Schmidt, Ii. Eichenberger. and AI. Kilheim, Arrgeu. Chem., 73, 1.5 ( l U 6 l ) : G. deStevens, "Diuretics," Academic Press, Pie\v I-ork. N. Y., 1963, pp 21-23. (2) CIl3.L Ltd., Netherlands Patents S\Y 359/66, 15786,'66, 16738/66 (.July 18. 1967); Netherlands Patents Report, Vol. 4 , N o , 29, 1967. (:O G. Palazzo. G . Corsi, L. Raiocchi, and U . Silveetrini, J . .lied, C h e m . , 9, 38 (1966). J. Lindenmann, and E. Kissi, U. S . Patent 3,041,342 (1962). For other references see K . Eicbenherger, el ul., Hel-o. C h i m . Acta, 48, 524 (1965); Sulzlrwisrenschrqlten, 62, 106 (1965); J. Druery and P. Schmidt, U. S.Patent 3,064,005 (1962); H. Snyder, U. S. Patent 3,293.261; ( l Y 6 6 ) ; Chem. Abstr.. 6 6 , 46424g (1967); J. R. Bockiny. U. S.Patent 3,097,21U (1963); Belgian Patent 612,971 (1962); L). E. \Vrigllt, U. S. Patent 3,102,890 (1963). (5) A . Brack, Ann.,681, 105 (196fi). (6) G. Wolfrum, R. Puetter, H. G . Hanke. and I