Synthesis of 6-(N-alkyl-N-arylamino)pyrimidines as potential antimetabolites

Abstract

Thirty-eight new 6-(AT-alkyl-Ar-arylamino)pyrimidines were prepared as open-chain analogs of riboflavin that lack the Ni" atom of the central ring. Most of these compounds were prepared by simple coupling reaction between the appropriate 2,4-disubstituted 6-chloropyrimidine and an Ar-alkylamline, usually under fusion conditions, except in the case of the 5-N02 derivatives where Cl was sufficiently activated to react in refluxing EtOH, Et3N, or DMF. Several of the compounds showed in vitro activity against Sarcoma 180 cells, 2,4-diamino-6-(AT-ethy 1-3,4-dime thylanilino)pyrimidine•HCl (34) being the most active.2,4-Diamino-6,7-dimethyl-2,4-dideoxyalloxazine (I) has been found to antagonize both riboflavin (II) and folinic acid in several microbiological test systems5•6 and to inhibit the growth of transplanted tumors in mice.7,8 However, the poor tissue absorption properties of I limited further in vivo studies with this compound. It was felt that introduction of various alkyl and hydroxyalkyl chains in the X9 position of I might lead to compounds with increased solubility and better absorption properties.9 Such compounds would also bear a greater structural resemblance to II. However, direct alkylation of I resulted in substitution in the Ni position,9 and our attempts to react dimeric 4,5dimethyl-o-benzoquinone6 with a variety of 4-substit-uted 6-alkylammo-2,5-diaminopyrimidines10 led to condensation products which were difficult to purify.Cheng, O'Brien, and coworkers reported the antitumor activities of various 5-nitro-(and 5-nitroso)-2,4-diamino-6-arylaminopyrimidines, and noted the structural resemblance of 6-arylaminopyrimidines to ribo-(1) This research was supported by Grant No. CA 06695-7 from the Na-

Pyrimido[5,4‐b]quinolines. I. Synthesis of substituted tricyclic systems related to riboflavin

“…293-294' dec.; uv and ir spectra identical with those of VII (see below). 7,8( 8,9)-Dimethyl-1O-chloropyrimido [ 5,[4][5][6]…”

“…Fractions #I 1 through #I8 were combined, evaporated to dryness, then crystallized from cyclohexane t o yield 150 mg. On the basis of the nmr spectra, VIIIa was identified as 7,8dimethyl-2,4,1O-trichloropyrimido[ 5,441 quinoline, and VIIIb as 8,9-dimethyl-2,4,10-trichloropyrimido [ 5,441 quinoline. The structure of VIIIa was further confirmed by unambigous synthesis from XVI (see below).…”

“…The structure of VIIIa was further confirmed by unambigous synthesis from XVI (see below). 8(8,9)-Dimethy1-2,4,1O-triphenoxypyrimido [5,[4][5][6]…”

“…on the 6-position would be sterically favored. Initial attempts to synthesize V liy condensing 5-bromoorotir acid with 3,4-xylidine in homogenous solutions (cg., i n tlimvtliyl sulfoxide), or untlrr fusion conditions, w m t unsuc:cc:ssful and usually led to the isolation of 5bromouracil, or thc: corresponding decarboxylated product Va. Howw(:r, V was obtained in good yield by a modified Ullmau-typc: condensation (14) Ring closure was effected by treatment of V with polyphosphoric acid, to give a product identified by elemental analysis and infrared spectrum as 7,8 (8,9)dimethylpyrimido [ 5,[4][5][6] quinolin-2,4,10( lH, 3H, 5H) trione (VI). Due t o the insolubility of this material, its nmr spectrum could not be taken.…”

“…Cyclization of XVI with polyphosphoric acid proceeded smoothly, t o give 2,4-dimethoxy-7,0-dimethylpyrimido[ S,4-6 ] quinolin-lO(5H)one (XVII) in u p to 76% yield. When the reaction was allowed to proceed longer, partial cleavagc of the methoxyl groups occurred, and in addition to XVII, some 2-me t hoxy-7,8-dimethylpyrimido [ 5,[4][5][6]q II i n o l in-4,10(3H,W)dione (XVIII) was also isolated (see Chart HI).…”