2-Carbomethoxy-4-(p-carbomethoxyphenyl)cyclohexanone was prepared in a four-step process and thermally condensed with 2,4,6-triaminopyrimidine to afford methyl 2,4-diamino-4-deoxy-7-hydroxy-5,10-ethano-5,10-dideazapteroate+ ++. Reduction of the 7-oxo function with borane gave the 7,8-dihydro pterin which was subsequently oxidized to the fully aromatic pteroate ester with dicyanodichlorobenzoquinone. Saponification of the benzoate ester, coupling with diethyl glutamate and final ester hydrolysis afforded the title compound. This novel deazaaminopterin analogue was approximately as potent as methotrexate in vitro in terms of DHFR and L1210 cell growth inhibition. There are indications of diastereomeric differences in the enzyme inhibition measurements. A significant transport advantage over MTX for influx into L1210 cells was observed. The compound was active against the E 0771 murine mammary solid tumor, but further investigation with individual diastereomers is required to define the ED50.

The synthesis of 5,lO-dideazaaminopterin by two independent routes is described. Condensation of the piperidine enamine of 4-p-carbomethoxyphenylbutyraldehyde (4) with ethoxymethylenemalononitrile followed by treatment of the resultant arylethylenaminomalononitrile (5) with methanolic ammonia produced Z-amino-3-cyano-5-p-carbomethoxyphenethylpyridine (6). Cyclization of the aminocyanopyridine with guanidine afforded 4-amino-4-deoxy-5,10-dideazapteroic acid (8). Coupling of the pteroate intermediate with glutamate yielded the target 5,lO-dideazaaminopterin (10).Alternatively, reduction of 2,4-diamino-6-formyl-5-deazapteridine (11) with sodium borohydride gave the 6-hydroxymethyl compound 12. Conversion to the bromide was followed by alkylation of dimethyl homoterephthalate to afford methyl 4-amino-4-deoxy-lO-carbomethoxy-5,1O-dideazapteroate (14). Decarboxylation with ester cleavage (sodium cyanide in dimethyl sulfoxide at 180O) also gave the diaminopteroic acid (8).5,lO-dideazaaminopterin (10) was an effective growth inhibitorof folate dependent bacteria, S.fuechrn and L. casei.

Synthesis of the 10-methyl and 10-ethyl analogues of 5,10-dideazatetrahydrofolic acid (DDTHF), a potent inhibitor of glycinamide ribotide (GAR) formyltransferase, is reported. Key intermediates in the process were 10-methyl- and 10-ethyl-4-amino-4-deoxy-5,10-dideazapteroic acid. Condensation of the piperidine enamines of branched 4-(p-carbomethoxyphenyl)butyraldehydes with (acetoxymethylene)malononitrile afforded 1,1-dicyano-4-piperidinobutadiene 5a,b. Subsequent reaction with alcoholic ammonium hydroxide yielded the appropriately substituted 2-amino-3-cyanopyridines 6a,b. Ring closure with guanidine gave 10-methyl- and 10-ethyl-4-amino-4-deoxy-5,10-dideazapteroic acids (7a,b). Coupling with diethyl glutamate followed by ester hydrolysis afforded 10-alkyl-5,10-dideazaminopterin analogues 9a,b. Hydrolysis of the 4-amino group of 7a,b yielded the 10-alkylpteroic acids, which were coupled with diethyl glutamate, hydrogenated over PtO2, and saponified to afford 10-alkyl-5,10-dideazatetrahydrofolic acids 13a,b. Aminopterin analogues 9a,b were effective inhibitors of DHFR derived from L1210, but were less potent than methotrexate for inhibition of growth of L1210 in culture. The 10-ethyl (13b) analogue of 5,10-DDTHF was about twice as potent an inhibitor of L1210 cell growth as 5,10-DDTHF, but was only 1/7 as potent for inhibition of GAR formyltransferase. 10-Methyl analogue 13a was similar in potency to 5,10-DDTHF. All of the compounds showed moderately improved transport into L1210 cells relative to methotrexate.

2-(3-Indolyl)propan-l-ol (V). A.-Racemic V was prepared by lithium aluminum hydride reduction of methyl <*-(3-indolyl)propionate (prepared from (±)-VI and diazomethane) in tetrahydrofuran. Work-up gave (±)-V as a pink, viscous oil, bp 155°( 0.1 mm). The p-nitrobenzoate melted at 117°.

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