5-DEAZA-5,7-DISUBSTITUTED-AMINOPTERIN ANALOGUES

Abstract: This invention relates to the compound having structure (I), wherein R5 is a hydrogen atom, a lower alkyl group of 1-4 carbons or a phenyl group, R7 is a lower alkyl group of 1-4 carbons or a phenyl group, and R10 is a hydrogen atom, a methyl group or an ethyl group. The invention also relates to methods and intermediates involed in synthesizing the compound, pharmaceutical composition of the compound and use of the compound to kill tumor cells and treat subjects.

Description: -J- 5-DEA2A-5,7-DISUBSTITUTED-AMINOPTERIN ANALOGUES The invention described herein was made in the course of work under Grant No. CA-18856 from the National Cancer Institute. The U.S. Government has certain rights in this invention. Background of the Invention: The antitumor agents, methotrexate and aminopterin, inhibit dihydrofolate reductase to exert their antitumor activity (J.S. Erickson, et al., J. Biol. Aminopterin is prepared from 2, 4, 5, 6 - tetramino pyrimidine sulfate, 2, 3-dibromopropionablehyde and p- a inobenzoylglutamic acid (Seeger, et al., J. Am. Chem. Soc, vol. 69, p. 2567, 1947) or from 6-(bromomethyl)- 2,4-diaminopteridine HBr (Piper, Montgomery, J. Heterocycl. Chem., vol. 11, p. 279, 1974). Methotrexate preparation is described in Seeger, et al., J. Am. Chem. Soc, vol. 71, p. 1753, 1949. These antitumor agents are metabolized to their corresponding 7-oxo derivatives. The present invention provides a method for syntheis of 5-deaza-7-substituted and 5- deaza-5, 7-disubstituted analogues of methotrexate and aminopterin. The analogues of the present invention can not be metabolized to their corresponding 7-oxo derivatives since the 7 position of these molecules is already substituted. These analogues are also found not to inhibit dihydrofolate reductase, yet some of them exhibit potent antitumor activity. The present application describes derivatives of methotrexate and aminopterin which are useful as antitumor agents, methods of synthesizing such derivatives and the biological application derivatives. The derivatives of the present invention are particularly useful for treating tumors resistant to methotrexate or aminopterin because of large production of dihydrofolate reductase. Summarv of the Invention; Compounds of the present invention can be represented by the formula: wherein R g is a hydrogen atom, lower alkyl group of 1 - 4 carbon atoms or a phenyl group, R ? is a lower alkyl group of 1 - 4 carbon atoms or a phenyl group, and R.. is a hydrogen atom, a methyl group or a ethyl group. The invention also concerns methods of synthesizing the compounds, and precursors and intermediates useful in the manufacture of the compounds. The invention further provides pharmaceutical compositions, methods of killing tumor cells, and methods of treating a subject having a tumor which comprises the use of the compounds described hereinabove. Description of the Invention: The present invention concerns 7-monosubstituted and 5, 7-disubstituted-5-deazaaminopterin and 5-deazametho- trexate derivatives of the formula I. Compound of general formula I may be obtained by the synthetic route which begins with condensation of cyanothioacetamide with 4-substituted alkyl 2- alkoxymethylene-3-oxopropanoates of formula II or 3- carbalkoxypropane-1, 3-diones of formula III to give the substitued 2-^thiopyxidine derivatives of general IV or V, respectivelyT II III IV V wherein R_ and R_ are the same or different and are lower alkyl groups of 1 -4 carbon atoms or phenyl groups (Ph) and R is a methyl (Me) or ethyl (Et) group. The reaction is carried out in alcohol such as methanol, ethanol or propanol, in the presence of corresponding alkoxide of alkali metal, such as lithium, sodium or potassium, or organic base such as N, N-dimethylaminoethanol, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5,4,0] undec-7-ene (DBU) , 1,5 diazabicyclo[4,3,0]non-5-ene (DBN) or piperidine, at temperature range of from 25 *C to 97 *C (boiling poin of propanol) for aperiod of from 10 minutes to 2 days. Alkylation of IV and V with Mel, Etl, Me 2 S0 4 or Et-SO. gives in a polar solvent such as N,N-dimethylformamide or water in the presence of potassium carbonate at room temperature for a period of from 2 to 8 hours, the corresponding 2-alkyl-mercaptopyridines of formulae VI and VII wherein R« is Me or Et: R, R 5 and R ? are as defined above. VI VII VIII IX Compounds of formulae VI and VII are then reduced to the corresponding 5-hydroxymethylpyridines of formulae VIII and IX with a reducing agent, preferably lithium aluminum hydride, in an inert solvent, preferably diethyl ether, at a temperature range of from -78 ' C to 25 *C for a period of from 1 to 8 hours. The hydroxy group of pyridines of formulae VIII and IX are protected to intermediates of formulae X and XI, wherein R' is MeOCH, or PhCH.OCH, respectively, by treatment with chloromethyl methyl ether or chloromethyl benzyl ether, preferably chloromethyl methyl ether, in an inert solvent such as chlorinated hydrocarbon, preferably chlorofrom in the presence of base described above, preferably 4- dimethylaminopyridine, at a temperature range from -5 *C to 50 *C for a period of from 1 to 10 hours. XI XII XIII Oxidation of compounds of formulae X and XI with an oxidizing agent, such as sodium hypochlorate, hydrogen peroxide or m-chloroperbenzoic acid, preferably m- chloroperbenzoic acid, in an inert solvent, such as a chlorinated hydrocarbon or alcohol, perferably ethanol, at room temperature for a period from 30 minutes to 2 hours affords their corresponding sulfones of formulae of XII and XIII. Condensation of the sulfones of the formulae XII and XIII with guanidine gives the 2, 4-diamino-7- substituted-pyrido[2,3-d]-pyrimidine XIV and and 2,4- diamino-5,7-disubstituted-pyrido[2,3-d]-pyrimidine XV, respectively. The condensation reaction can be done either by treatment of the sulfones of formulae XII and XIII with free guanidine in refluxing alcohols, such as methanol, ethanol or propanol and the like, or by heating a mixture of the sulfone and guanidine carbonate in a high boiling inert solvent, such as diglyme or diphenyl ether, at a tempterature from 160 * C to 210 'C for a period of 2 to 8 hours. XIV R'=OCH 2 OMe or OCH 2 OPh XV R / =OCH 2 OMe or OCH 2 OCH 2 PH XVI R'=OH XVII R' =OH XVIII R' = Br XIX R' - Br Deprotection of compounds of formulae XIV and XV to the corresponding 6-hydroxymethylpyrido[2,3-d]pyrimidines XVI and XVII can be achieved by treatment of XIV and XV with concentrated hydrochloric acid in alcohol at reflux temperature for a period of from 2 to 6 hours, or with a Lewis acid, such as boron trichloride, in an inert solvent such as chlorinated hydrocarbon, preferably methlene chloride, at a temperature range of from -78 *C to 25 "C for a period of from 2 to 24 hours. The 6-hydroxymethyl derivatives of formulae XVI and XVII are converted into the corresponding 6-bromomethyl derivatives of general formulae XVIII and XIX by treatment with a brominating agent, preferably hydrogen bromide in dioxan. Condensation of XVIII and XIX with diethyl (p_- aminobenzoyl)-L-glutamate followed by saponification gives the products of general formula I. The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting. EXAMPLE 1 A mixture of cyanothioacetamide (10.0 g, 0.1 mol) , ethyl 2-ethoxymethyleneacetoacetate (22.3 g, 0.12 mol) and DBU (4mL) in anhydrous ethanol (200mL) is heated at 60 'C for 1 hurs, then cooled in an ice-bath. The solid precipitates are collected by filtration. The solid is extracted with boiling chloroform (6 x 200 mL) . The chloroform extracts are concentrated in vacuo, and the residue is crystallized from chloroform- ethanol to give 3-cyano-5-(ethoxycarbonyl)-6- methylpyridine-2(lH)-thione (9.10 g, 41%), mp 232-233 • C, IR (KBr) 2230 -1 (CN) , X H NMR (CDC1 3 ) 61.41 (3H, t, CH 2 Me) , 2.68 (3H, s, 6-Me) , 4.38 (2H, q, CH^Me) , 8.30 (1H, s, H-4) . Analyses claculated for C 10 H. 0 N 2 O 2 S: C, 54.04, H, 4.54, N, 12.60, S, 14.43 %. Found: C, 53.81, H, 4.75, N, 12,73, S, 14.25 %. By following the same procedure but using the corresponding 4-substituted ethyl 2-ethyoxymethylene-3- oxo-propanoates or 3-ethoxycarbonylpropane-l,3-diones insteated of 2-ethyoxymethylene-acetoacetate, the following 2-thiopyridines are obtained: 3-cyano-5-(ethoxycarbonyl)-6-ethoxymethylpyridine- 2(lH)-thione, 3-cyano-5-(ethoxycarbonyl)-6-ethylpyridine-2(1H)- thione, 3-cyano-5-(ethoxycarbonyl)-6-propylpyridine-2(1H)- thione 3-cyano-5-(ethoxycarbonyl)-6-phenylpyridine-2(1H)- thione 3-cyano-5-(ethoxycarbonyl)-6-(2-fluorophenyl) yridine- 2(1H)-thione. 3-cyano-5-(ethoxycarbonyl)-6-(4-nitrophenyl)pyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-6-(4-methylphenyl)pyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-6-(3-methylphenyl)pyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-6-(4-methylphenyl) yridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-6-(3-methoxyphenyl)pyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-4,6-dimethylpyridine-2(1H)- thione, EXAMPLE 2 A mixture of cyanothioacetamide (54 g, 0.54 mol), 3- ethoxycarbonyl-l-phenylpropane-l,3-dione (189 g, 0.81 mol) and piperidine (37 mL) in anhydrous ethanol (600 L) is stirred at room temperature for 1 day, and then heated under reflux for another day. The mixture is concentrated in vacuo, and the residue is dissolved in chloroform, washed with water, dried over sodium sulfate, concentrated in vacuo, and chromatographed on a silica gel column (10 x 50 cm) using chloroform- hexane (4:1 v/v) as the eluent. 3-Cyano-5- (ethoxycarbonyl)-4-methyl-6-phenylpyridine-2(1H)-thione is eluted from the column first followed by 3-cyano-5- (ethoxy-carbonyl)-6-methyl-4-phenylpyridine-2(1H)- thione is eluted from the column first followed by 3- cyano-5-(ethoxy-carbonyl)-6-methyl-4-phenylpyridine- 2(1H)-thione. After crystallization from ethanol, 26.5 g (16.4 %) of the pure 4-methyl-6-phenyl derivative is obtained, mp 147-148 # C, IR (KBr) 2230 cm- 1 (CN) , X H NMR (CDC1 3 ) δ 0.91 (3H, t, CH 2 Me), 2.54 (3H, s, 4-Me) , 4 .03 (2H, q, Ch 2 Me) , 2.54 (3H, s, 4-Me), 4.03 (2H, q, CH 2 Me) , 7.40- 7.62 (5H, m, Ph) . Analyses calculated for C 16 H 14 N 2 0 2 S: C, 64.41, H, 4.73, N, 9.39, S, 10.75%. Found: C, 64.34, H, 4.65, N. 9.37, S, 10.89%. The pure 6-methyl-4-phenyl isomer (6.8 g, 4.2%) is 0 obtained after crystallization from ethanol, mp 252-253 • C, IR (KBr) 2230 cm- 1 (CN) , 2 H NMR (CDC1 3 ) S 0.81 (3H, t, Ch 2 Me) , 2.61 (3H, s, 6-Me) , 3.92 (2H, q, CH : Me) . 7.36-7.53 (5H, m, Ph) . Analyses calculated for C lg H 24 N 2 0 2 S: C, 64.41, H, 5 4.73, N, 9.39, S, 10.75%. Found: C, 64.62, H, 4.85, N, 9.40, S, 10.71 %. By the same procedure but using ethyl 2- 0 ethoxymethylene-2-propanoylacetate or ethyl 2- ethoxymethylene-2-(substituted-benzoyl)acetate, the following 4,6-disubstituted-2-thiopyridine derivatives are prepared: _ 5 3-cyano-5-(ethoxycarbonyl)-6-ethyl-4-methylpyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-4-ethyl-6-methylpyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-4-methyl-6-propylpyridine- 30 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-6-methyl-4-propylpyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-4-(2-fluorophenyl)-6- methylpyridine-2(1H)-thione, 35 3-cyano-5-(ethoxycarbonyl)-6-(2-fluorophenyl)-4- methylpyridine-2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-4-methyl-6-(4-nitrophenyl)- pyridine-2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-6-methyl-4-(4-nitrophenyl)- pyridine-2(1H)-thione, EXAMPLE 3 A mixture of 3-cyano-5-(ethoxycarbonyl)-4,6- dimethylpyridine-2(lH)-thione (11.8 g. 0.05 mol), Mel (14.2 g, 0.1 mol) and 2 C0 3 (14.0 g, 0.1 mol) in DMF (200 mL is stireed at room temperature for 4 hours. The mixture is then diluted with cold water (300 mL) . The precipitated solid is collected by filtration, washed with water (200 mL) , air-dried, and crystallized from chloroform-ethanol to afford 3-cyano-5- (ethoxycarbonyl)-4,6-dimethyl-2-methylmercaptopyridine (22.2 g, 89%), mp 61-61 # C, IR (KBr) 2225 cm- 1 (CN) , X H NMR (CDC1 2 ) 8 1.40 (3H, t, CH 2 Me) , 2.47 (3H, s, SMe) , 2.56 (3H, S, 4-Me), 2.62 (3H, s, 6-Me) , 4.42 (2H, q, CH 2 Me) . Analyses calcutated for c 12 H i N 2 0 2 S: C ' 57,58 ' H ' 5 - 64 N, 11.19, S, 12.81%. Found: C, 57.00, H, 5.68, N, 12.47, S. 12.53%. By following the same procedure but using the corresponding pyridine-2(lH)-thiones, the following 2- methylmercaptopyridines are prepared: 3-cyano-5-(ethoxycarbonyl)-6-methyl-2- methylmercaptopyridine, 3-cyano-5-(ethoxycarbonyl)-6-ethyl-2- methylmercaptopyridine , 3-cyano-5-(ethoxycarbonyl)-2-methylmercapto-6- propylpyridine, 3-cyano-5-(ethoxycarbonyl)-2-methylmercapto-6- phenylpyridine, 3-cyano-5-(ethoxycarbonyl)-6-(2-fluorophenyl)-2- methyl ercaptopyridine, 3-cyano-5-(ethoxycarbonyl)-2-methylmercapto-6-(4- nitropheny1)pyridine, 3-cyano-5-(ethoxycarbonyl)-2-methylmercapto-6-(4- methylphenyl)pyridine, 3-cyano-5-(ethoxycarbonyl)-2-methylmercapto-6-(3- methylpheny1)pyridine, 3-cyano-5-(ethoxycarbonyl)-2-methylmercapto-6-(4- methoxypheny)pyridine, 3-cyano-5-(ethoxycarbonyl)-2-methylmercapto-6-(3- methoxyphenyl)pyridine, 3-cyano-5-(ethoxycarbonyl)-4-ethyl-6-methyl-2- methylmercaptopyridine, 3-cyano-5-(ethoxycarbonyl)-6-ethyl-4-methyl-2- methyImercaptopyridne, 3-cyano-5-(ethoxycarbonyl)-4-methyl-2-methylmercapto-6- propylpyridine, 3-cyano-5-(ethoxycarbonyl)-6-methyl-2-methylmercapto-4- propyIpyridine, 3-cyano-5-(ethoxycarbonyl)-4-methyl-2-methylmercapto-6- phenyIpyridine, 3-cyano-5-(ethoxycarbonyl)-6-methyl-2-methylmercapto-4- phenyIpyridine, 3-cyano-5-(ethoxycarbonyl)-4-(2-fluorphenyl)-6-methyl- 2-methylmercaptopyridine, 3-cyano-5-(ethoxycarbonyl)-6-(2-fluorophenyl)-4-methyl- 2-methylmercaptopyridine, 3-cyano-5-(ethoxycarbonyl)-4-methyl-2-methylmercapto-6- (4-nitrophenyl) pyridine, 3-cyano-5-(ethoxycarbonyl)-6-methyl-2-methylmercapto-4- (4-nitrophenyl) pyridine. Example 4 To a stirred suspension of 3-cyano-5-(ethoxycarbonyl)- 6-ethoxymethyl-2-methylercaptopyridine (56.0 g, 0.2 mol) in dry ether (IL) is added portionwise lithium aluminum hydride (9.1 g, 0.24 mol at -15 to -10 *C for 3 hours, and then excess lithium aluminum hydride is destroyed with IN hydrochloric acid to about pH 3. Cold water (500mL) is added tothe mixture and the ethereal layer is separated. The aqueous layer is extracted with ethyl acetate (3 x 300 mL) . The combined organic solutions ' are washed with water, dried over sodium sulfate, concentrated, and the residue is chromatographed on a silica gel column ( 8 x 50 cm) with chloroform as the eluent which eluted unreacted starting material. The column is then washed with chlorofor -methanol (50:1 v/v) to elute 3-cyano-6- ethoxymethyl-5-hydroxymethyl-2-methylmercaptopyridine which is obtained as colorless crystals after crystallization from ethanol (21.4 g, 45%), mp 67-69 • C, IR (KBr) 2225 cm "1 (CN) , ^"H NMR (CDC1 2 ) δ 1.23 (3H, t, CH 2 Me) , 2.63 (3H, s, SMe) , 3.03 (1H, brs, OH), 3.64 (2H, q, CH j Me) , 4.65 (2H, S, CH 3 ) , 4.74 (2H, s, CH 2 ), 7.83 (1H, s, H-4) . Analyses calculated for c n H i 4 N 2°2 S: ' 55.44, H, 5.92, N. 11.76, S, 13.46%. Found C, 55.24, H, 5.79, N. 11.60, S, 13.21 %. By following the same procedure but using the corresponding 5-(ethoxycarbonyl)pyridines, the following compounds are prepared: 3-cyano-5-hydroxymethyl-6-methyl-2- methylmercaptopyridine, 3-cyano-5-hydroxymethyl-6-ethyl-2- methylmercaptopyridine, 3-cyano-5-hydroxymethyl-2-methylmercapto-6- propylpyridine, 3-cyano-5-hydroxymethyl-2-methylmercapto-6- phenylpyridine, 3-cyano-5-hydroxymethy1-6-(2-fluorophenyl)-2- methylmercaptopyridine, 3-cyano-5-hydroxymethyl-2-methylmercapto-6- (4-nitropheny1)pyridine, 3-cyano-5-hydroxymethyl-2-methylmercapto-6- (3-methylphenyl)pyridine, 3-cyano-5-hydroxymethyl-2-methylmercapto-6- (4-methylphenyl)pyridine, 3-cyano-5-hydroxymethyl-6-(3-methoxyphenyl)-2- methylmercaptopyridine, 3-cyano-5-hydroxymethyl-6-(4-methoxyphenyl)-2- methylmercaptopyridine, 3-cyano-5-hydroxymethyl-4,6-dimethyl-2- methylmercaptopyridine, 3-cyano-6-ethyl-5-hydroxymethyl-4-methyl-2- methylmercaptopyridine, 3-cyano-4-ethyl-5-hydroxymethyl-6-methyl-2- methylmercaptopyridine, 3-cyano-5-hydroxymethy1-4-methy1-2-methylmercapto-6- phenyIpyridine, 3-cyano-5-hydroxymethyl-6-methyl-2-methylmercapto-4- phenylpyridine, 3-cyano-4-(2-fluorophenyl)-5-hydroxymethyl-6-methyl- 2-methylmercaptopyridine, 3-cyano-6-(2-fluorophenyl)-5-hydroxymethyl-4-methyl- 2-methylmercaptopyridine , 3-cyano-5-hydroxymethyl-4-methy1-2-methylmercapto-6- (4-nitropheny1)pyridine. -15- 3-cyano-5-hydroxymethyl-6-methyl-2-methylmercapto-4- (4-nitrophenyl)pyridine, Example 5 A solution of 3-cyano-5-hydroxymethyl-6-methyl-2- ethylmercaptopyridine (44.0 g, 0.27 mol) and N,N- dimethylaniline (80.5 g, 0.54 mol) in dry chloroform (500 mL) is treated with methoxymethyl chloride (43.2 g, 0.54 mol) for 5 hours at room temperature. The mixture is washed successively with 2% hydrochloric acid (4 x 200 L) , water, and saturated sodium bicarbonate solution, then is dried over sodium sulfate and concentrated. The residue is crystallized from hexane-ether to give 3-cyano-5-(methoxymethoxy)meth 1- 6-methyl-2-methylmercaptopyridine (55.1 g, 84%), mp 50- 51 * C, X H NMR (CDCL 3 ) δ 2.55 (3H, s, SMe) , 2.62 (3H, s, 6-Me) , 3.40 (3H, s, OMe) , 4.53 (2H, s, CH 2 ) , 4.71 (2H, s, CH 2 ), 7.76 (1H, s, H-4) . Analyses calculated for C.-H-.N-O.S.1/4H 2 0: C, 55.44, H, 5.92, N, 11.76, S, 13.46%. Found: C, 55.41, 6.19, 11.54, 13.21%. By the same procedure but using the corresponding 5- hydroxymethylpyridines, the following compounds are synthesized: 3-cyano-6-ethyl-5-(methoxymethoxy)methyl-2- methylmercaptopyridine, 3-cyano-5-(methoxymethoxy)methyl-2-methylmercapto-6- phenylpyridine, 3-cyano-5-(methoxymethoxy)methyl-2-methylmercapto-6- propylpyridine, 3-cyano-5-(2-fluorophenyl)-5-(methoxymethoxy)methyl-2- mercaptopyridine, 3-cyano-5-(methoxymethoxy)methyl-2-methylmercapto-6-(4- nitropheny1)pyridine, 3-cyano-5-(methoxymethoxy) ethyl-2-methylmercapto-6-(3- methylphenyl)pyridine, 3-cyano-5-(methoxymethoxy)methyl-2-methylmercapto-6-(4- methylphenyl)pyridine, 3-cyano-5-(methoxymethoxy)methyl-2-methylmercapto-6-(3- methoxyphenyl)pyridine, 3-cyano-5-(methoxymethoxy)methy1-2-methylmercapto-6-(4- methoxyphenyl)pyridine, 3-cyano-5-(methoxymethoxy)methyl-4,6-dimethγl-2- methylmercaptopyridine, 3-cyano-6-ethyl-5-(methoxymethoxy)methyl-4-methyl-2- methylmercaptopyridine, 3-cyano-4-ethyl-5-(methoxymethoxy)methyl-4-methyl-2- methylmercaptopyridine, 3-cyano-5-(methoxymethoxy)methyl-4-methyl-2- methylmercapto-6-phenyIpyridine, 3-cyano-5-(methoxymethoxy)methyl-6-methyl-2- methylmercapto-4-phenyIpyridine, 3-cyano-4-(2-fluorophenyl)-5-(methoxymethoxy)methyl-6- methyl-2-methylmercaptopyridine, 3-cyano-6-(2-fluorophenyl)-5-(methoxymethoxy) ethyl-4- methyl-2-methylmercaptopyridine, 3-cyano-5-(methoxymethoxy)methyl-4-methyl-2- methylmercapto-6-(4-nitropheny1)pyridine, 3-cyano-5-(methoxymethoxy)methyl-6-methyl-2- methylmercapto-4-(4-nitrophenyl)pyridine, Example 6 A mixture of 3-cyano-5-(methoxymethoxy)methyl-2-methy1 mercapto-6-phenyIpyridine (69 g, 0.23 mol) and m chloroperbenzoic acid (120 g, 0.69 mol) in ethanol (60 mL) is stirred for 1 hour at room temperature, and then the solvent is removed in vacuo. The residue is redissolved in ethyl acetate (800 L) , and the solution is washed with 2% sodium hydroxide solution and water, dried over sodium sulfate, and concentrated. The residue is crystallized from ether to give 70.3 g of 3- cyano-5-(methoxymethoxy)methyl-2-methylsulfonyl-6- phenylpyridine (92%), mp 101-102'C. X H NMR (CDC1 3 ) 6 3.39 (3H, S, Me), 4.72 (2H, S, CH 2 ) , 4.73 (2H, S, CH 2 ) , 7.55 (5H, s, Ph), 8.51 (1H, s, H-4) . Analyses calculated for C 16 H 16 N 2 O.S: C, 57.82, H, 4.85, N, 8.43, S, 9.65%. Found: C, 58.06, H, 5.07, N, 8.51, S, 9.81%. By following the same procedure but using the corresponding 2-methylmercaptopyridines, the following sulfones are obtained: 3-cyano-5-(methoxymethoxy)methyl-6-methyl-2-methyl- sulfonylpyridine, 3-cyano-6-ethyl-5-(methoxymethoxy)methyl-2-methyl- sulfonylpyridine, 3-cyano-5-(methoxymethoxy) ethy1-2-methylsulfonyl-6- propylpyridine, 3-cyano-6-(2-fluorophenyl)-5-(methoxymethoxy)methyl-2- methylsulfonylpyridine, 3-cyano-5-(methoxymethoxy)methyl-2-methylsulfonyl-6- (4-nitrophenyl)pyridine, 3-cyano-5-(methoxymethoxy)methyl-6-(3-methylphenyl)-2- methylsulfonylpyridine, 3-cyano-5-(methoxymethoxy)methyl-6-(4-methylphenyl)-2- methylsulfonylpyridine, 3-cyano-5-(methoxymethoxy)methyl-6-(3-methoxphenyl)-2- ethyl-sulfonylpyridine, -cyano-5-(methoxymethoxy)methyl-6-(4-methoxyphenyl)-2- methylsulfonylpyridine, -cyano-5-(methoxymethoxy)methyl-4,6-dimethyl-2-methyl- sulfonylpyridine, -cyano-5-(methoxymethoxy)methyl-4-methyl-2-methyl- sulfonyl-6-phenylpyridine, -cyano-5-(methoxymethoxy)methyl-6-methyl-2-methyl- sulfonyl-4-phenyIpyridine, 3-cyano-6-ethyl-5-(methoxymethoxy)methyl-4-methyl-2- methylsulfonylpyridine, 3-cyano-4-ethyl-5-(methoxymethoxy)methyl-6-methyl-2- methylsulfonylpyridine, 3-cyano-6-(2-fluorophenyl)-5-(methoxymethoxy)methyls- methyl-2-methylsulfonylpyridine, 3-cyano-4-(2-fluorophenyl)-5-(methoxymethoxy)methyl-6- methy1-2-methylsulfonylpyridine, 3-cyano-5-(methoxymethoxy)methyl-4-methyl-2-methyl- mercapto-6-(4-nitrophenyl)pyridine, 3-cyano-5-(methoxymethoxy)methyl-6-methyl-2-methyl- sulfonyl-4-(4-nitropheny1)pyridine. Example 7 A mixture of 3-cyano-5-(methoxymethoxy)methyl-4-methyl- 2-methylsulfonyl-6-phenylpyridine (6.72 g, 20 mmol) and guanidine carbonate (3.60 g, 20 mmol) in diphenyl ether (20 mL) is heated at 180-185*C with vigorous stirring for 2 hours. After cooling, the mixture is diluted with ethanol-diethyl ether (1:1, 200 mL) . The precipitates are collected, redissolved in ethanol- water (5:1, 300 L) , decolorlized with Norit A. and the solution is concentrated to about 150 mL. Colorless crystals that deposit are collected by filtration, washed with ethanol and diethyl ether, and dried to give 2,4-diamino-6-(methoxymethoxy)methyl-5-methyl-7- phenylpyrido[2.3-d]pyrimidine (48.7 g, 75%), mp 290- 291*C. ^ NMR (Me 2 SO-d g ) δ 2.76 (3H, S, Me), 3.26 (3H, s, OMe), 4.40 (2H, s, CH 2 ) , 4.62 (2H, s, CH 2 ) , 6.26 (2H, brs, NH 2 ), 7.09 (2H, brs, NH 2 ) , 7.41-7.70 (5H, m, Ph) . Analyses calculated for C._H ιg N 5 0 2 : C, 62.75, H, 5.89, N, 21.53%. Found: C, 62.63, H, 6.12, N, 21.56%. By using the same procedure but using the corresponding 2-methylsulfonylpyridines, the following pyrido[2.3- djpyri idines are synthesized: 2,4-diamino-6-(methoxymethoxy)methyl-7-methylpyrido- [2.3-d]pyrimidine, 2,4-diamino-6-(methoxymethoxy)methyl-7-ethylpyrido- [2.3-d]pyrimidine , 2,4-diamino-6-(methoxymethoxy)methyl-7-phenylpyrido- [2.3-d]pyrimidine , 2 ,4-diamino-6-(methoxymethoxy)methy1-7-(2- fluorophenyl)pyrido[2.3-d]pyrimidine, 2,4-diamino-6-(methoxymethoxy)methyl-7-(4-nitropheny1)- pyrido[2.3-d]pyrimidine, 2,4-diamino-6-(methoxymethoxy)methyl-7-(3- methylphenyl)pyrido[2.3-d]pyrimidine, 2,4-diamino-6-(methoxymethoxy)methyl-7-(4- ethylpheny1)pyrido[2.3-d]pyrimidine, 2,4-diamino-6-(methoxymethoxy)methyl-7-(3- methoxyphenyl)pyrido[2.3-d]pyrimidine, 2,4-diamino-6-(methoxymethoxy)methyl-7-(4- methoxypheny1)pyrido[2.3-d]pyrimidine, 2,4-diamino-6-(methoxymethoxy)methyl-5,7-dimethyl- pyrido[2.3-d]pyrimidine, 2,4-diamino-6-(methoxymethoxy)methyl-7-methyl-5-phenyl- pyrido[2.3-d]pyrimidine. 2,4-diamino-6-(methoxymethoxy)methyl-5-ethyl-7-methyl- pyrido[2.3-d]pyrimidine, 2,4-diamino-6-(methoxymethoxy)methyl-7-ethyl-5-methyl- pyrido[2.3-d]pyrimidine, 2,4-diamino-6-(methoxymethoxy)methyl-5-methyl-7-(2- fluorophenyl)pyrido[2.3-d]pyrimidine, 2,4-diamino-6-(methoxymethoxy)methyl-7-methyl-5-(2- fluorophenyl)pyrido[2.3-d]pyrimidine, 2,4-diamino-6-(methoxymethoxy)methyl-5-methyl-7-(4- nitrophenyl)pyrido[2.3-d]pyrimidine, 2,4-diamino-6-(methoxymethoxy)methyl-7-methyl-5-(4- ni_trophenyT)pyrido[2.3-d]pyrimidine. Example 8 A mixture of 2,4-diamino-6-(methoxymethoxy)methyl-7- methyl-5-phenylpyrido[2.3-d]pyrimidine monohydrate (24.0 g, 70 mmol) and concentrated hydrochloric acid (20 L) in methanol (800 mL) is heated under reflux for 4 hours, and then concentrated in vacuo. The residue is suspended in water (300 mL) and neutralized to pH 7 with IN sodium hydroxide solution. The solid is filtered, washed successively with water, ethanol, and diethyl ether, and dried in vacuo over phosphorus pentaoxide to give 2,4-diamino-6-hydroxymethyl-7- methyl-5-phenylpyrido[2.3-d]pyrimidine in quantitative yield. This product is sufficiently pure to be used i the next step. An analytical sample can be obtained b recrystallization of the crude product from ethano (12.7 g, 40%), mp >300 * C. X H NMR (Me 2 SO-d g ) 8 2.6 (3H, s, 7-Me) , 4.09 (2H, m, CH 2 ) , 5.60 (1H, brs, OH), 7.31-7.66 (5H, , Ph) , 7.40 (4H, brs, 2 x NH 2 ) . Analyses calculated for C.-H. ς NgO.HCl: C, 56.65, H 5.08, N, 22.04%. Found: C, 56.55, H, 5.07, N, 21.83%. By following the same procedure but using the corresponding 6-(methoxymethoxy) ethylpyrido[2.3- d]pyrimidines, the following 6-hydroxymethy1 derivatives are obtained: 2,4-diamino-6-hydroxymethyl-7-methylpyrido[2.3-d]- pyrimidine, 2,4-diamino-6-hydroxymethyl-7-ethylpyrido[2.3-d]- pyrimidine, 2,4-diamino-6-hydroxymethyl-7-phenylpyrido[2.3-d]- pyrimidine, 2,4-diamino-6-hydroxymethyl-7-(2-fluorophenyl)-pyrido [2.3-d]-pyrimidine, 2,4-diamino-6-hydroxymethyl-7-(4-nitrophenyl)pyrido- [2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-7-(3-methylphenyl)pyrido- [2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-7-(4-methylphenyl)pyrido- 2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-7-(3-methoxyphenyl)pyrido- [2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-7-(4-methoxyphenyl)pyrido- [2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-5,7-dimethylpyrido[2.3-d]- pyrimidine, 2,4-diamino-6-hydroxymethyl-5-methyl-7-phenylpyrido- [2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-7-methyl-5-phenylpyrido- [2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-5-methyl-7-ethylpyrido- [2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-7-methyl-5-ethylpyrido- [2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-5-methyl-7-(2- fluorophenyl)pyrido[2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-7-methyl-5-(2- fluorophenyl)pyrido[2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-5-methyl-7-(4-nitropheny1)- pyrido[2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-7-methyl-5-(4-nitropheny1)- pyrido[2.3-d]pyrimidine. Example 9 A suspension of 2,4-diamino-6-hydroxymethyl-7- methylpyrido[2.3-d]pyrimidine (1.05 g, 5 mmol) in dry dioxan (150 mL) is saturated with dry hydrogen bromide. The mixture is stirred overnight at room temperature, and the solvent is removed in vacuo (<35*C) . Traces of hydrogen bromide are removed azeotropically by several coevaporations with toluene, and the residue is dissolved in dry N, N-dimethylacetamide (30 mL, distilled over calcium hydride) . To the solution is added diethyl (p_-aminobenzoyl)-L-glutamate (3.22 g, 10 mmol) , and the mixture is stirred for 3 days at room temperature. After concentration of the mixture in vacuo, the residue is triturated thoroughly with warm chloroform to remove unreacted diethyl (p- aminobenzoyl)-L-glutamate. The gummy residue is then solidified by trituration with diethyl ether, and the microcrystals are collected by filtration and dried in vacuo to give diethyl N-[p_-[[ (2,4-diamino-7- methylpyrido[2.3-d]pyrimidin-6-yl)methyl]amino]- benzoyl)-L-glutamate (2.13 g, 84%), mp 239-240 *C, X H NMR (Me 2 S0-d g ) δ 1.15 (3H, t, CH 2 Me) , 1.18 (3H, t, CH 2 Me) , 1.95-2.21 (2H, m, CH 2 ) , 2.25-2.45 (2H, , CH 2 ) , 2.57 (3H, s, 7-Me), 4.03 (2H, q, CH 2 Me) , 4.08 (2H, q, CH 2 Me) , 4.33-4.54 (3H, brm, CH. 2 NH, CONHCH) , 6.58-6.6 (3H, brm, NH 2 , CH 2 NH) , 6.66 and 7.64 (4H, ABq, Ph) , 7.53-7.71 (2H, brs, NH 2 ) , 8.31 (1H, s, H-5) . Analyses calculated for C 25 H 31 N 7 0 5 .4H 2 0: C, 51.62, H, 6.75, N, 16.85%. Found: C, 51.92, H, 6.91, N, 16.54%. By following the same procedure but using the corresponding 6-hydroxymethylpyridopyrimidines, the following protected analogues of aminopterin are synthesized: diethyl N-[p_-[ (2,4-diamino-7-ethylpyrido[2.3-d] pyrimidin-6-yl)methyl]amino]benzoy1]-L-glutamate, diethyl N-[p_-[[ (2,4-diamino-7-phenylpyrido[2.3-d] pyrimidin-6-yl)methyl]amino]benzoy1]-L-glutamate, diethyl N-[p_-[[(2,4-diamino-7-(2-fluorophenyl) pyrido[2.3-d]-pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamate, diethyl N-[p_-[ (2,4-diamino-7-(4-nitrophenyl) pyrido[2.3-d -pyrimidin-6-yl)methyl]amino]benzoyl]• L-glutamate, diethyl N-[p_-[ (2,4-diamino-7-(3-methylphenyl) pyrido[2.3-d -pyrimidin-6-yl)methyl]amino]benzoyl]• L-glutamate, diethyl N-[£-[ (2,4-diamino-7-(4-methylphenyl) pyrido[2.3-d -pyrimidin-6-yl)methyl]amino]benzoyl]• L-glutamate, diethyl N-[p.-[ (2,4-diamino-7-(3-methoxyphenyl) pyrido[2.3-d -pyrimidin-6-yl)methyl]amino]benzoyl] L-glutamate, diethyl N-[p_-[ (2,4-diamino-7-(4-methoxyphenyl) pyrido[2.3-d -pyrimidin-6-yl)methyl]amino]benzoyl] L-glutamate, diethyl N-[p.-[[ (2,4-diamino-5,7-dimethylpyrido [2.3-d]-pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamate, o diethyl N-[p_-[[(2,4-diamino-5-methyl-7-phenylpyrido [2.3-d]-pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamate, diethyl N-[p_-[[(2,4-diamino-7-methyl-5-phenylpyrido [2.3-d]-pyrimidin-6-y1)methyl]amino]benzoyl]- L-glutamate, diethyl N-[p_-[[(2,4-diamino-5-methyl-7-ethylpyrido [2.3-d]-pyrimidin-6-y1) ethyl]amino]benzoyl]- L-glutamate, diethyl N-[p_-[[(2,4-diamino-7-methyl-5-ethylpyrido [2.3-d]-pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamate, diethyl N-[p_-[[ (2,4-diamino-5-methyl-7-(2-fluorophenyl) pyrido[2.3-d]-pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamate, diethyl N-[p_-[[ (2,4-diamino-7-methyl-5-(2-fluorophenyl) pyrido[2.3-d]-pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamate, diethyl N-[p_-[[(2,4-diamino-5-methyl-7-(4-nitrophenyl) pyrido[2.3-d]-pyrimidin-6-y1)methyl]amino]benzoy1]- L-glutamate, diethyl N-[p_-[[(2, -diamino-7-methyl-5-(4-nitrophenyl) pyrido[2.3-d]-pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamate, Example 10 A solution of diethyl N-[p.-[[(2,4-diamino-5,7-dimethyl pyrido[2,3-d]pyrimidin-6-y1)methyl] ethyl]amino]- benzoyl]-L-glutamate (1.74 g, 3 mmol) in methanol (40 mL) containing 7 mL of 1 N sodium hydroxide is stirre for 3 days at room temperature. After concentration i vacuo to about 7 L, the solution is neutralized wit IN hydrochloric acid (7 mL) . N-p(p_-[[ (2,4-diamino-5,7 dimethylpyrido[2.3-d]pyrimidin-6-yl)methyl]amino]- benzoyl]-L-glutamic acid precipitates as microcrystals is collected by filtration, washed with cold water, acetone and diethyl ether, and dried in vacuo over phosphorus pentoxide, (588 mg, 42%), mp 226-227*C. 1 H NMR (Me 2 SO-d g ) δ 1.78-2.10 (2H, brm, CH 2 CH 2 C0 2 H) , 2.3- 2.4 (2H, brm, CH 2 CH 2 C0 2 H) , 2.54 (3H, s, 7-Me) , 2.66 (3H, s, 5-Me) , 3.72-4.77 (3H, brm, CH j NH, CONHCH) , 6.70 (2H, d, Ph) , 7.71 (4H, d, Ph, NH 2 ) , exchangeable NH at 6.20, 7.16, 8.10 and 8.20. Analyses calculated for C 22 H 25 N 7 0 5 : C, H, N, %. Found: By the same procedure but using the corresponding diethyl L-glutamates, the following antifolates are obtained: N-[E~CC (2,4-diamino-7-methylpyrido[2.3-d]pyrimidin-6- yl)methyl]amino]benzoyl]-L-glutamic acid, N-[E~C[ (2,4-diamino-7-eth ' ylpyrido[2.3-d]pyrimidin-6- yl)methyl]amino]benzoyl]-L-glutamic acid, N-[p_-[ [ (2,4-diamino-7-phenylpyrido[2.3-d]pyrimidin-6- yl)methyl]amino]benzoyl]-L-glutamic acid, N ~[£"[ C (2,4-diamino-7-(2-fluorophenyl)pyrido[2.3-d] pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamic acid, N-[p_-[[(2,4-diamino-7-(4-nitrophenyl)pyrido[2.3-d] pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamic acid, N-[£-[[ (2,4-diamino-7-(3-methylphenyl)pyrido[2.3-d] pyrimidin-6-y1)methyl]amino]benzoyl]-L-glutamic acid , N-[p_-[[ (2,4-diamino-7-(4-methylphenyl)pyrido[2.3-d] pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamic acid, N-[p_-[[ (2,4-diamino-7-(3-methoxyphenyl)pyrido[2.3-d] pyrimidin-6-y1)methyl]amino]benzoyl]-L-glutamic acid, N-[p_-[ [ (2,4-diamino-7-(4-methoxyphenyl)pyrido[2.3-d] pyrimidin-6-y1) eth l]amino]benzoyl]-L-glutamic acid, N-[p_-[[ (2,4-diamino-5,7-dimethylpyrido[2.3-d] pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamic acid, N-[p_-[[ (2,4-diamino-5-methyl-7-phenylpyrido[2.3-d] pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamic acid, N-[p_-[[(2,4-diamino-7-methy1-5-phenylpyrido[2.3-d] pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamic acid, N-[p_-[[(2,4-diamino-5-methyl-7-ethylpyrido[2.3-d] pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamic acid, N-[£-[[(2,4-diamino-7-methyl-5-ethylpyrido[2.3-d] pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamic acid, N-[E"CC(2,4-diamino-5-methyl-7-(L-fluorophenyl) pyrido[2.3-d]pyrimidin-6-y1)methyl]amino]benzoyl]- L-glutamic acid, N ~[E~CC(2,4-diamino-7-methyl-5-(2-fluorophenyl) pyrido[2.3-d]pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamic acid, N ~CE~CC (2,4-diamino-5-methyl-7-(4-nitrophenyl) pyrido[2.3-d]pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamic acid, N-[p_-[[ (2,4-diamino-7-methyl-5-(4-nitrophenyl) pyrido[2.3-d]pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamic acid. Biological Studies HL-60 cells (1.5 x 10 /mL) are grown in RPMI 1640 medi containing 10% fetal calf serum, 100 μg/mL streptomycin lOOU/mL penicillin, in humidified 5% CO_ at 37*C. Fiv concentrations of each compound are added for up to 7 hours exposure. Viable cells are counted with trypa blue exclusion method. The incorporation of [6- H]dUrd (0.05 μM, 1 μCl/mL) int DNA in HL-60 cells at 37*C for 30 minutes is measure by the method of Chou et al. , (Mol. Pharm.. 1984, 2j5 587) . Cells are preincubated with the compound for 4 minutes prior to the addition of [6- H]dUrd. ED 5Q values are calculated by the median-effect equation and plot using microcomputer software. Five concentrations of each compound are used for each ED__ 50 determinatio . The ID 5Q values of representative 5-deaza-5,7- disubstituted aminopterin analogues for cell growth inhibition in vitro are listed in Table 1. It is interesting to note that the 7-methyl and 5,7-dimethyl analogues exhibited cell growth inhibition which approached that of methotrexate during 72 hours of exposure, though they cannot be metabolized to their corresponding 7-oxo derivatives, are extremely weak inhibitors of dihydrofolate reductase, and are 1,200- fold less potent than methotrexate in inhibiting [6- 3 H]dUrd incorporation into DNA (Table 2) . These compounds show little dose-effct relationship in which a large increase in inhibitor concentration produces only a small increase in cell growth inhibition (Table 2) , but they show time-dependent cytotoxicity in inhibiting leukemic cell growth. Preliminary study shows that N-[p_-[ [ (2,4-diamino-5,7- dimethylpyrido[2.3-d]pyrimidin-6-y1)methyl]amino]- benzoyl]-L-glutamic acid (5-deaza-5,7-dimethyl- a inopterin) produces an increase in lifespan (ILS) at maximum tolerated dose of 100 mg/kg/day x 5 (i.p.) of 71% in BDF mice inoculated i.p. with 10 L-1210 cells. Table 1. Inhibition of growth and OHFR of L-1210 by the 5- and/or 7- substituted 5-deazaamlnopterln analogues. co pd. R, ID 50 ( μ M) K1 (uN) MTX Compound R 5 -Me, R ? =H R 5 =H, R ? « Me R 5 =R 7 =Me MTX

Claims: What is claimed is: 1. A compound having the structure: wherein R 5 is hydrogen atom, a lower alkyl group of 1 - 4 carbons or a phenyl group, R 7 is a lower alkyl group of 1 - 4 carbons or a phenyl group, and R.- is a hydrogen atom, a methyl group or an ethyl group. 2. A compound of claim 1 selected from the group consisting of: diethyl N-[p_-[[(2,4-diamino-7-methylpyfido[2.3-d]- pyrimidin-6-yl) ethyl]amino]-benzoyl]-L-glutamate, diethyl N-[p_-[[ (2,4-diamino-7-ethylpyrido[2.3-d]- pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamate, -diethyl N-[p_-[[ (2,4-diamino-7-propylpyrido[2.3-d]- pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamate, diethyl N-[p_-[[(2,4-diamino-7-phenylpyrido(2.3-d]- pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamate, diethyl N-[p_-[[ (2,4-diamino-7-(2-fluorophenyl)pyrido- [2.3-d]pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamate, diethyl N-[p_-[[(2,4-diamino-7-(4-nitrophenyl)pyrido- [2.3-d]-pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamate, diethyl N-[p_-[[ (2, -diamino-7-(3-methylphenyl)pyrido- [2.3-d]-pyrimidin-6-y1)methyl]amino]benzoyl]- L-glutamate, diethyl N-[E~[[ (2,4-diamino-7-(4-methylphenyl)pyrido- [2.3-d)-pyrimidin-6-yl)methyl] mino]benzoyl]- L-glutamate, diethyl N-[p_-[[ (2,4-iamino-7-(3-methoxyphenyl)pyrido- [2.3-d)pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamate, diethyl N-[p_-[[(2,4-diamino-7-(4-methoxyphenyl)pyrido [2.3-d]pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamate, diethyl N-[p.-[[ (2,4-diamino-5,7-dimethypyrido[2.3-d]- pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamate, diethyl N-[p_-[[ (2,4-diamino-5-methyl-7-phenylpyrido- [2.3-d]pyrimidin-6-y1)methyl]amino]benzoyl]- L-glutamate, diethyl N-[p_-[[ (2,4-diamino-7-methyl-5-phenylpyrido- [2.3-d]-pyrimidin-6-yl) ethyl]amino]benzoyl]- L-glutamate, diethyl N-[p_-[[ (2,4-diamino-5-methyl-7-ethylpyrido- [2.3-d]-pyrimidin-6-yl) ethyl]amino]benzoyl]- L-glutamate, diethyl N-[p_-[ [ (2,4-diamino-7-methyl-5-ethylpyrido[2.3- d]-pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamate, -diethyl N-[£-[[ (2,4-diamino-5-methyl-7-(2- fluorophenyl)pyrido[2.3-d]pyrimidin-6-y1)- methyl]amino]benzoyl]-L-glutamate, diethyl N-[p.-[[ (2,4-diamino-7-methyl-5-(2- fluorophenyl)pyrido[2.3-d]pyrimidin-6- y1)methyl]amino]benxoyl]-L-glutamate, diethyl N-[p.-[ [ (2,4-diamino-5-methyl-7-(4-nitrophenyl)- pyrido[2.3-d]pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamate, and diethyl N-[E~[[ (2,4-diamino-7-methyl-5-(4-nitrophenyl)- pyrido[2.3-d]pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamate. 3. A compound of claim 1 selected from the grou consisting of: N-[E~CC(2,4-diamino-7-methylpyrido[2.3-d]pyrimidin-6- yl)methyl]amino]benzoyl]-L-glutamic acid, N-[p_-[[(2,4-diamino-7-ethylpyrido[2.3-d]pyrimidin-6- yl)methyl]amino]benzoyl]-L-glutamic acid, N-[E~CC(2,4-diamino-7-propylpyrido[2.3-d]pyrimidin-6- yl)methyl]amino]benzoyl]-L-glutamic acid, N-[E~C[(2,4-diamino-7-phenylpyrido[2.3-d]pyrimidin-6- yl)methyl]amino]benzoyl]-L-glutamic acid, N- E-CC(2,4-diamino-7-(2-fluorophenyl)pyrido[2.3-d]- pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamic acid, N " -[E~CC( ,4-diamino-7-(4-nitrophenyl)pyrido[2.3-d]- pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamic acid, N-[E~CC(2 ,4-diamino-7-(3-methylphenyl)pyrido[2.3-d]- pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamic acid, N ~CE~CC(2 4-diamino-7-( -methylphenyl)pyrido[2.3-d]- pyrimidin-6-yl)methyl]amino]benzoyl)-L-glutamic acid N ~[E~CC(2,4-diamino-7-(3-methoxyphenyl)pyrido[2.3-d]- pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamic acid, N-[£-[[(2,4-diamino-7-(4-methoxyphenyl)pyrido(2.3-d]- pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamic acid N ""CE~CC(2,4-diamino-5,7-dimethylpyrido[2.3-d]pyrimidin 6-yl)methyl]amino]benzoyl]-L-glutamic acid , N ~CE~CC(2 4-diamino-5-methyl-7-phenylpyrido[2.3-d]- . pyrimidin-6-yl) ethyl]amino]benzoyl]-L-glutamic acid N- E~[[(2,4-diamino-7-methyl-5-phenylpyrido[2.3-d]- pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamic acid N—[ -[[ (2,4-diamino-5-methyl-7-ethylpyrido[2.3-d]- pyrimidin-6-y1)methyl]amino]benzoyl]-L-glutamic acid N "CE~[C (2,4-diamino-7-methyl-5-ethylpyrido[2.3-d]- pyrimidin-6-yl)methyl] mino]benzoyl]-L-glutamic acid N-[£-[[ (2,4-diamino-5-methy1-7-(2-fluorophenyl)pyrido- [2.3-d]pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamic acid, N-[£-[[ (2,4-diamino-7-methy1-5-(2-fluorophenyl)pyrido- [2.3-d]pyrimidin-6-yl)methyl]amino]benzoyl]- L-glutamic acid, N-[£-[[ (2,4-diamino-5-methyl-7-(4-nitrophenyl)pyrido- [2.3-d]pyrimidin-6-yl)methyl)amino]benzoyl]- L-glutamic acid, and N-[E~CC (2,4-diamino-7-methyl-5-(4-nitrophenyl)pyrido- [2.3-d]pyrimidin-6-y1)methyl]amino]benzoy1]- L-glutamic acid. 4. A method of preparing compounds of claim 1 which comprises: a) contacting a cyanothioaceta ide with a 4- substituted alkyl 2-alkoxymethylene-3-oxo- propanoate having the structure: wherein R_ is a lower alkyl group of 1-4 carbons or a phenyl group (Ph) and R is a methyl (Me) or ethyl (Et) group. or with a 3-carbalkoxy propane-l,3-dione having the structure: -34- wherein 5 is a lower alkyl group of 1-4 carbons or a Ph and R and R7 are previousl 10 defined under suitable conditions so as to obtain substituted 2-thiopyridine derivative havin the structure: 15 20 wherein R, R5 and R7 are as previousl defined; 25 b) reacting the substituted 2-thiopyridin derivative with a compound seleted from th group consisting of methyl iodide (Hel) ethyl iodide (Etl) , methyl sulfate Me 2 S0 4 ) 30 and ethyl sulfate (Et-SO.) so as to obtain 2-alkyl-mercaptopyridine having th structure: 35 wherein R 2 is Me or Et and R, _ and R_ ar previously defined; 10 c) reducing the 2-alkyl-mercaptopyridine to a 5 hydroxymethylpyridine having the structure: 20 wherein R., R_ and R_ are previously defined; d) treating the 5-hydroxymethylpyridine so as to obtain an intermediate compound having the structure: 25 30 wherein R' is MeOCH 2 or PhCH 2 OCH_ and 2 , and R- are previously defined; 35 e) oxidizing the intermediate compound with an oxidizing agent under suitabl conditions as to obtain a sulfone of th structure: 10 wherein R', 2 , R_ and R_ are previousl defined; 15 f) condensing the sulfone with guanidine t yield. 20 wherein R' is OCH 2 OMe or OCH 2 OPh and R_ ar wherein R' is OCH 2 OMe or OCH 2 OCH 2 Ph and R 30 and R_ are previously defined g) deprotection of the compounds of claim 4(f to yield the corresponding 6 hydroxymethylpyrido[2,3-d]pyrimidines. 35 wherein R' is OH and R g and R_ are previously defined 10 h) bromination of the compounds derived in claim 4(g) to yield 6-hydroxymethy1 derivatives. wherein R' is Br and R g and R_ are previously 20 defined i) condensation of the compound, derived in claim 4(h) followed by saponification to yield: 30 wherein R 5 is hydrogen atom, a lower alkyl group of 1 - 4 carbons or a phenyl group (Ph) , R_ is a lower alkyl group of 1 - 4 carbons or a Ph, and 35 R 10 is a hydrogen atom, a methyl group or an ethyl group. 5. A method of claim 4, wherein the contacting in step (a) is effected in the presence of a lower alkyl alcohol solvent. 6. A method of claim 5, wherein the lower alkyl alcohol solvent is methanol, ethanol or propanol. 7. A method of claim 4, wherein the reacting in ste (b) is effected in the presence of a polar solveπtr- 8. A method of claim 7, wherein the polar solven comprises potassium carbonate. 9. A method of claim 4, wherein the reducing in ste (c) is effected by reacting with lithium aluminu hydride in an inert solvent. 10. A method of claim 9, wherein the inert solvent i diethyl ether. 11. A method of claim 4, wherein the reducing in ste ~{c) is performed at a temperature in the range of -78* to 25*C. 12. A method of claim 4, wherein the reducing in ste (c) is performed for a period of 2 to 8 hours. 13. A method of claim 4 wherein the treating in ste (d) is effected by contacting with chloromethyl methy ether or chloromethyl benzyl ether. 14. A method of claim 13, wherein the contacting is effected in an inert chlorinated hydrocarbon solvent. 15. A method of claim 14, wherein the solvent is chloroform. 16. A method of claim 14, wherein the contacting is effected in a base. 17. A method of claim 16, wherein the base is 4- dimethyl-amino pyridine. 18. A method of claim 17, wherein the contacting is effected at a temperature in the range from -5*C to 50 * C. 19. A method of claim 18, wherein the contacting is effected for a period of from 1 to 10 hours. 20. A method of claim 4, wherein the oxidizing agent of step (e) is sodium hypochlorate, hydrogen peroxide or m-chloroperbenzoic acid. 21. A method of claim 4, wherein the suitable "conditions of step (e) comprise oxidizing in an inert, chlorinated hydrocarbon solvent or alcohol. 22. A method of claim 21, wherein the alcohol is ethanol. 23. A method of claim 4, wherein the suitable conditions of step (e) comprise oxidizing at room temperature for a period from 30 minutes to 2 hours. " 24. A method of claim 4, wherein the condensing of step (e) comprises treatment with free guanidine in refluxing alcohols. 25. A method of claim 21, wherein the refluxing alcohols are chosen from methanol, ethanol or propanol. 26. A method of claim 4, wherein the condensing of step (f) is effected in a temperature range of from lOO'C-210-C. 27. A method of claim 26, wherein the condensing of step (f) is performed for a period of 2-8 hours. 28. A method of claim 4, wherein the condensing of step (f) is effected in a high boiling inert solvent. 29. A method of claim 28, wherein the solvent is diglyme or diphenyl ether. 30. A method of claim 4, wherein the condensing of step (f) is performed in a temperature range of from 160*C-210*C. 3 * 1. A method of claim 4, wherein the condensing of step (f) is performed for a period of 2-8 hours. 32. A method of claim 4, wherein deprotection of step (g) is effected by treatment with concentrated hydrochloric acid in alcohol. 33. A method of claim 4, wherein deprotection of step (g) is effected at reflux temperature for 2 to 6 hours. 34. A method of claim 4, wherein deprotection of step (g) is effected by treatment with a Lewis acid. 35. A method of claim 34, wherein the Lewis acid is borontrichloride. 36. A method of claim 4, wherein the deprotection of step (g) is effected in an inert chlorinated hydrocarbon solvent. 37. A method of claim 36, wherein the solvent is methlene chloride 38. A method of claim 4, wherein the deprotection of step (g) is performed at a temperature range of from - 78'C to 25*C. 39. A method of claim 4, wherein the deprotection of step 4(g) is performed for a period of from 2-24 hours. 40. A method of claim 4, wherein the brominating agent of step (h) is hydrogen bromide in dioxan. 41. A method of claim 4, wherein condensation of step (i) is with diethyl(p_-aminobenzoyl)-L-glutamate. 42. An intermediate compound having the structure: wherein R 5 and 7 are the same or different and are lower alkyl groups of 1-4 carbon atoms or phenyl groups and R is a methyl or ethyl group. 43. An intermediate compound of claim 42 selected from the group consisting of. 3-cyano-5-(ethoxycarbonyl)-6-methylpyridine-2(1H)- thione, 3-cyano-5-(ethoxycarbonyl)-6-ethoxymethylpyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-6-ethylpyridine-2(1H)- thione, _> 3-cyano-5-(ethoxycarbonyl)-6-propylpyridine-2(1H)- thione, 3-cyano-5-(ethoxycarbonyl)-6-phenylpyridine-2(1H)- thione, 3-cyano-5-(ethoxycarbonyl)-6-(2-fluorophenyl)pyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-6-(4-nitrophenyl)pyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-6-(4-methylphenyl)pyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-6-(3-methylphenyl)pyridine- ~ 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-6-(4-methoxyphenyl)pyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-6-(3-methoxyphenyl)pyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-4,6-dimethylpyridine-2(1H)- thione. 3-cyano-5-(ethoxycarbonyl)-4-methyl-6-phenylpyridine- 2(1H)-thione, 3-cyano-5-(ethoxy-carbonyl)-6-methyl-4-phenylpyridine- 2(1H)-thione. 3-cyano-5-(ethoxycarbonyl)-6-ethyl-4-methylpyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-4-ethyl-6-methylpyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-4-methyl-6-propylpyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-6-methyl-4-propylpyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-4-methyl-6-phenylpyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-6-methyl-4-phenylpyridine- 2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-4-(2-fluorophenyl)-6-methyl- pyridine-2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-6-(2-fluorophenyl)-4-methyl- pyridine-2(1H)-thione, 3-cyano-5-(ethoxycarbonyl)-4-methyl-6-(4-nitro¬ phenyl)pyridine-2(1H)-thione, and 3-cyano-5-(ethoxycarbonyl)-6-methyl-4-(4-nitro¬ phenyl)pyridine-2(1H)-thione. 44. A 2-Methylmercaptopyridine intermediate compound having the structure: wherein R ς and R_ are the same or different and are lower alkyl groups of 1-4 carbon atoms or phenyl groups, R 2 and R are the same or different and are methyl or ethyl groups. -44- 45. An intermediate compound of claim 44 selected from the group consisting of: 3-cyano-5-(ethoxycarbonyl)-6-methy1-2-methylmercapto¬ pyridine, 3-cyano-5-(ethoxycarbonyl)-6-ethyl-2-methylmercapto- pyridine, 3-cyano-5-(ethoxycarbonyl)-2-methylmercapto-6-propyl- pyridine, 3-cyano-5-(ethoxycarbonyl)-2-methylmercapto-6-phenyl- pyridine, 3-cyano-5-(ethoxycarbonyl)-6-(2-fluorophenyl)-2-methyl- mercaptopyridine, 3-cyano-5-(ethoxycarbonyl)-2-methylmercapto-6-(4-nitro¬ phenyl)-pyridine, 3-cyano-5-(ethoxycarbonyl)-2-methylmercapto-6-(4- methylphenyl)-pyridine, 3-cyano-5-(ethoxycarbonyl)-2-methylmercapto-6-(3- Q methylphenyl)-pyridine, 3-cyano-5-(ethoxycarbonyl)-2-methylmercapto-6-(4-meth¬ oxyphenyl)-pyridine, 3-cyano-5-(ethoxycarbonyl)-2-methylmercapto-6-(3-metho¬ xyphenyl)-pyridine, 5 -3-cyano-5-(ethoxycarbonyl)-4,6-dimethyl-2-methyl- mercaptopyridine, 3-cyano-5-(ethoxycarbonyl)-4-ethyl-6-methyl-2-methyl- mercaptopyridine, 3-cyano-5-(ethoxycarbonyl)-6-ethyl-4-methyl-2-methyl- 0 ercaptopyridine, 3-cyano-5-(ethoxycarbonyl)-4-methyl-2-methylmercapto-6 propylpyridine, 3-cyano-5-(ethoxycarbonyl)-6-methyl-2-methylmercapto-4 propylpyridine, 35 3-cyano-5-(ethoxycarbonyl)-4-methyl-2-methylmercapto-6- phenylpyridine, 3-cyano-5-(ethoxycarbonyl)-6-methyl-2-methylmercapto-4- phenyIpyridine, 3-cyano-5-(ethoxycarbonyl)-4-(2-fluorophenyl)-6-methyl- 2-methylmercaptopyridine, 3-cyano-5-(ethoxycarbonyl)-6-(2-fluorophenyl)-4-methyl- 2-methylmercaptopyridine, 3-cyano-5-(ethoxycarbonyl)-4-methyl-2-methylmercapto- pyridine-6-(4-nitrophenyl)pyridine, and 3-cyano-5-(ethoxycarbonyl)-6-methyl-2-methylmercapto-4- (4-nitrophenyl)pyridine. 46. A 5-Hydroxypyridine intermediate compound having the structure: wherein R = and R_ are the same or different and are lower alkyl groups of 1-4 carbon atoms or phenyl groups and R 2 is a methyl or ethyl group. 47. An intermediate compound of claim 46 selected from the group consisting of. 3-cyano-5-hydoxymethyl-6-methyl-2-methylmercapto¬ pyridine, 3-cyano-5-hydoxymethyl-6-ethyl-2-methylmercapto- pyridine, 3-cyano-5-hydoxymethyl-6-ethoxymethy1-2-methylmercapto- npvyrrilddiinnee. 3-cyano-5-hydoxymethy1-2-methyl ercapto-6-propyl- pyridine, 3-cyano-5-hydoxymethyl-2-methylmercapto-6-phenyl- pyridine, 3-cyano-5-hydoxymethyl-6-(2-fluorophenyl)-2-methyl- mercaptopyridine, 3-cyano-5-hydoxymethyl-6-(4-nitrophenyl)-2-methyl- mercaptopyridine, 3-cyano-5-hydoxymethyl-6-(3-methylphenyl)-2-methyl- mercaptopyridine, 3-cyano-5-hydoxymethyl-6-( -methylphenyl)-2-methyl- ercaptopyridine, 3-cyano-5-hydoxymethyl-6-(3-methoxyphenyl)-2-methyl- mercaptopyridine, 3-cyano-5-hydoxymethyl-6-(4-methoxyphenyl)-2-methyl- mercaptopyridine, 3-cyano-5-hydoxymethyl-4,6-dimethyl-2-methylmercapto¬ pyridine, 3-cyano-5-hydoxymethyl- -methyl-2-methylmercapto¬ pyridine, 3-cyano-5-hydoxymethy1-6-methyl-2-methylmercapto¬ pyridine, 3-cyano-5-hydoxymethyl-4-methyl-2-methylmercapto-6- phenylpyridine, —3-cyano-5-hydoxymethyl-6-methyl-2-methylmercapto-4- phenylpyridine , 3-cyano-4-(2-fluorophenyl)-5-hydroxymethyl-6-methyl-2- methylmercaptopyridine, 3-cyano-4-(2-fluorophenyl)-5-hydroxymethyl-4-methyl-2- methylmercaptopyridine, 3-cyano-5-hydoxymethyl-4-methyl-2-methylmercapto-6-(4- nitropheny1)pyridine, and 3-cyano-5-hydoxymethyl-6-methyl-2-methylmercapto-4-(4- nitrophenyl) yridine, 47. A 5-(Methoxymethoxy)methylpyridine intermediat compound having the structure: wherein R_ and R 7 are the same or different an are lower alkyl groups of 1-4 carbon atoms o phenyl groups, 2 and R are the same or differen and are methyl or ethyl groups and R' is CH-OCH 2 or PhCH 2 OCH 2 . 48. An intermediate compound of claim 47 selected fro the group consisting of. 3-cyano-5-(methoxymethoxy)methy1-6-methy1-2- ethyl- mercaptopyridine, 3-cyano-5-(methoxymethoxy)methyl-2-methylmercapto-6- propylpyridine, 3-cyano-5-(methoxymethoxy)methyl-2-methylmercapto-6- phenylpyridine, " 3-cyano-5-(2-fluorophenyl)-5-(methoxymethoxy)methyl-2- methylmercaptopyridine, 3-cyano-5-(methoxymethoxy)methyl-2-methylmercapto-6-(4- nitrophenyl)pyridine, 3-cyano-5-(methoxymethoxy)methyl-2-methylmercapto-6-(3- methylphenyl)pyridine, 3-cyano-5-(methoxymethoxy)methyl-2-methylmercapto-6-(4- methylphenyl)pyridine, 3-cyano-5-(methoxymethoxy) ethyl-2-methylmercapto-6-(3- methoxypheny1)pyridine, 3-cyano-5-(methoxymethoxy)methyl-2-methylmercapto-6-(4- methoxypheny1)pyridine, 3-cyano-5-(methoxymethoxy)methyl- ,6-dimethyl-2-methyl- mercaptopyridine, 3-cyano-6-ethyl-5-(methoxymethoxy) ethyl-4-methyl-2- methylmercaptopyridine, 3-cyano-4-ethyl-5-(methoxymethoxy)methyl-6-methy1-2- methyl mercaptopyridine, 3-cyano-5-(methoxymethoxy)methyl-4-methyl-2-methyl- mercapto-6-phenyIpyridine, 3-cyano-5-(methoxymethoxy)methyl-6-methyl-2-methyl- mercapto-4-phenyIpyridine, 3-cyano-5-(2-fluorophenyl)-5-(methoxymethoxy)methyl-6- ethy1-2-methylmercaptopyridine, 3-cyano-5-(2-fluorophenyl)-5-(methoxymethoxy)methyl-4- methy1-2-methylmercaptopyridine, 3-cyano-5-(methoxymethoxy)methyl-4-methyl-2-methyl- mercapto-6-(4-nitrophenyl)pyridine, and 3-cyano-5-(methoxymethoxy)methyl-6-methyl-2-methyl- mercapto-4-(4-nitrophenyl)pyridine, 49. A 2-Methylsulfonylpyridine intermediate compoun of having the structure: wherein R„ and R_ are the same or different and ar lower alkyl groups of 1-4 carbon atoms or pheny groups, R 2 is an ethyl or methyl group and R' i CH 3 OHCH 2 or PhCH 2 OCH 2 -49- 50. An intermediate compound of claim 44 selected from the group consisting of. 3-cyano-5-(methoxymethoxy)methyl-6-methyl-2-methyl- sulfonylpyridine, 3-cyano-6-ethyl-5-(methoxymethoxy)methyl-2-methyl- sulfonylpyridine, 3-cyano-5-(methoxymethoxy)methyl-2-methylsulfonyl-6- propylpyridine, 3-cyano-5-(methoxymethoxy)methyl-2-methylsulfonyl-6- phenylpyridine, 3-cyano-6-(2-fluorophenyl)-5-(methoxymethoxy)methyl-2- methylsulfonylpyridine, 3-cyano-5-(methoxymethoxy)methyl-2-methylsulfonyl-6-(4- nitrophenyl)pyridine, 3-cyano-5-(methoxymethoxy)methyl-6-(3-methylphenyl)-2- methylsulfonylpyridine, 3-cyano-5-(methoxymethoxy)methyl-6-(4-methylphenyl)-2- methylsulfonylpyridine, 3-cyano-5-(methoxymethoxy)methyl-6-(3-methoxyphenyl),-2- methylsulfonylpyridine, 3-cyano-5-(methoxymethoxy)methyl-6-(4-methoxyphenyl)-2- methylsulfonylpyridine, 3-cyano-5-(methoxymethoxy)methyl-4,6-dimethyl-2-methyl- "" sulfonylpyridine, 3-cyano-5-(methoxymethoxy)methyl-4-methyl-2-methyl- sulfonyl-6-phenylpyridine, . 3-cyano-5-(methoxymethoxy)methyl-6-methyl-2-methyl- sulfonyl-4-phenyIpyridine, 3-cyano-6-ethyl-5-(methoxymethoxy)methyl-4-methyl-2- ethylsulfonylpyridine, 3-cyano-4-ethyl-5-(methoxymethoxy)methy1-6-methy1-2- methylsulfonylpyridine, 3-cyano-6-(2-fluorophenyl)-5-(methoxymethoxy)methyl-4- methyl-2-methylsulfonylpyridine, 3-cyano-4-(2-fluorophenyl)-5-(methoxymethoxy)methy1-6- methyl-2-methylsulfonylpyridine, 3-cyano-5-(methoxymethoxy)methyl-4-methyl-2-methyl- sulfonyl-6-(4-nitrophenyl)pyridine, and 3-cyano-5-(methoxymethoxy)methyl-6-methy1-2-methyl- sulfonyl-4-(4-nitrophenyl)pyridine. 51. A Pyrido[2.3-d]pyrimidine intermediate compound having the structure: wherein R- and R- are the same or different and are lower alkyl groups of 1-4 carbon atoms or phenyl groups and R' is 0CH 2 0CH- or OCH 2 OPh or wherein R. and R_ are the same or different and are lower alkyl groups of 1-4 carbon atoms or phenyl groups and R' is OCH 2 OCH 3 or OCH 2 OCH 2 Ph. 52. An intermediate compound of claim 51 selected from the group consisting of. 2 r 4-diamino-6-(methoxymethoxy)methyl-7-methyl- pyrido[2.3-d]pyrimidine. , -diamino-6-(methoxymethoxy)methyl-7-ethylpyrido[2.3- d]pyrimidine, ,4-diamino-6-(methoxymethoxy)methyl-7-propyl- pyrido[2.3-d] yrimidine, , -diamino-6-(methoxymethoxy)methyl-7-phenyl- pyrido[2.3- ] yrimidine, ,4-diamino-6-(methoxymethoxy)methyl-7-(2- fluorophenyl)pyrido[2.3-d]pyrimidine, ,4-diamino-6-(methoxymethoxy)methyl-7-(4- nitrophenyl)pyrido[2.3-d]pyrimidine, , -diamino-6-(methoxymethoxy)methyl-7-(3- ethylphenyl)pyrido[2.3-d]pyrimidine, , -diamino-6-(methoxymethoxy)methyT-7-(4- ethylpheny1)pyrido[2.3-d]pyrimidine, , -diamino-6-(methoxymethoxy)methyl-7-(3- methoxypheny1)pyrido[2.3-d]pyrimidine, ,4-diamino-6-(methoxymethoxy) ethyl-7-(4- methoxyphenyl)pyrido[2.3-d]pyrimidine, ,4-diamino-6-(methoxymethoxy) ethyl-5,7- dimethylpyrido[2.3-d] yrimidine, ,4-diamino-6-(methoxymethoxy)methyl-5-phenylpyrido- [2.3-d]pyrimidine, ,4-diamino-6-(methoxymethoxy)methyl-7-methyl-5- phenylpyrido[2.3-d]pyrimidine, , -diamino-6-(methoxymethoxy)methyl-5-ethyl-7- ■ethylpyrido[2.3-d]pyrimidine, , -diamino-6-(methoxymethoxy)methyl-7-ethyl-5- methylpyrido[2.3-d]pyrimidine, , -diamino-6-(methoxymethoxy)methyl-5-methyl-7-(2- fluorophenyl)pyrido[2.3-d]pyrimidine, , -diamino-6-(methoxymethoxy)methyl-7-methyl-5-(2- fluorophenyl)pyrido[2.3-d]pyrimidine, ,4-diamino-6-(methoxymethoxy) ethyl-5-methyl-7-(4- nitrophenyl)pyrido[2.3-d]pyrimidine, and 2, -diamino-6-(methoxymethoxy)methyl-7-methyl-5-(4- nitrophenyl)pyrido[2.3-d]pyrimidine. 53. A pyrido[2.3-d]pyrimidine intermediate compound having the structure: wherein R 5 and R ? are the same or different and are lower alkyl groups of 1-4 carbon atoms or phenyl groups and R' is OH. 54. An intermediate compound of claim 53 selected from the group consisting of. 2,4-diamino-6-hydroxymethyl-7-methylpyrido[2.3- d]pyrimidine, 2,4-diamino-6-hydroxymethyl-7-ethylpyrido[2.3- d]pyrimidine, 2,4-diamino-6-hydroxymethyl-7-propylpyrido[2.3- d] yrimidine, ,4-diamino-6-hydroxymethyl-7-phenylpyrido[2.3- d]pyrimidine, , -diamino-6-hydroxymethyl-7-(2- fluorophenyl)pyrido[2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-7-(4- nitrophenyl)pyrido[2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-7-(3- ethylpheny1)pyrido[2.3-d]pyrimidine, 2, -diamino-6-hydroxymethyl-7-(4- meth lphenyl)pyrido[2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-7-(3- methoxypheny1)pyrido[2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-7-(4- methoxyphenyl)pyrido[2.3-d)pyrimidine, 2,4-diamino-6-hydroxymethyl-5,7-dimethylpyrido[2.3- d]pyrimidine, 2,4-diamino-6-hydroxymethyl-5-methyl-7- phenylpyrido[2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-7-methyl-5- phenylpyrido[2.3-d]pyrimidine, 2,4-diamino-6-hydroxymethyl-5-methyl-7-ethylpyrido[2,_3 d]pyrimidine, ~~ —^ 2,4-diamino-6-hydroxymethyl-7-methyl-5-ethylpyrido[2.3- d]pyrimindine, 2,4-diamino-6-hydroxymethyl-5-methyl-7-(2- fluorophenyl)pyrido[2.3-d]pyrimidine, 2,4-diamino-6-hydroxymechyl-7-methyl-5-(2- fluorophenyl)pyrido[2.3-d]pyrimidine, 2, -diamino-6-hydroxymethyl-5-methyl-7-(4- nitrophenyl)pyrido[2.3-d]pyrimidine, and 2,4-diamino-6-hydroxymethyl-7-methyl-5-(4- nitropheny1)pyrido[2.3-d]pyrimidine. 55. A pharmaceutical composition comprising the " compound of claim 1 or a pharmaceutically acceptable acid salt thereof together with a pharmaceutically acceptable carrier. 56. A method of killing tumor cell comprising contacting the tumor cells with the compound of claim 55. 57. A method of treating a subject having a tumor which comprises administering to the subject an effective tumor-killing amount of the composition of claim 55,

Inventors: HUANG JAI-TUNG, SU TSANN-LONG, WATANABE KYOICHI A, HUANG, JAI-TUNG, SU, TSANN-LONG, WATANABE, KYOICHI, A.
Applicants: SLOAN KETTERING INST CANCER, SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH
Application year: 1989
Main classification: C07D487
IPC codes: A61K31, A61P35, C07D213, C07D471