3-dialkylaminomethyl-1,4-dihydro-4-oxo-1,8-naphthyridines
United States Patent 91 Lesher et al.  
 [451 Apr. 8, 1975 S-DIALKYLAMINOMETHYL-l,4-Dll-lYDRO- 4-OXO-1,8-NAPHTHYRIDINES [75] Inventors: George Y. Lesher, Schodac&#39;k; Monte D. Gruett, East Greenbush, both of NY.  
 [73] Assignee: Sterling Drug Inc., New York, NY.  
 [22] Filed: Mar. 22, 1974 [21] Appl. No.: 453,927  
  Related US. Application Data [62] Division of Ser. No. 339,090, March 8, I973.  
 [52] US. Cl 260/295 N [5 1] Int. Cl C07d 39/10 [58] Field of Search 260/295 N [56] References Cited UNITED STATES PATENTS 3.l49 l()4 9/1964 Lesher et ai. 260/295 N OTHER PUBLlCATlONS Lesher et 211., Chemical Abstracts 58: 7953 a (1963). Lappin. J. Am. Chem. Soc., 70, pp. 33484350 (1948).  
 Primary Examiner-Albert T. Meyers Assistant Examiner-Norman A. Drezin A ttorney, Agent, or Firm Robert K. Bair; B. Woodrow Wyatt [57] ABSTRACT Process of reacting 1,4-dihydro-4-oxo-7-O-l,8- naphthyridine (l) with a lower-tertiaryaminomethylating agent to produce 1,4-dihydro-3- (R R NCH )-4-oxo-7-Q-1,8-naphthyridine Il, reacting II with a lower-alkylating agent to produce l-(loweralkyl l ,4-dihydro-3-(R R NCH )-4-oxo-7-Q-l ,8- naphthyridine (Ill), and oxidizing III to produce 1- (lower-alkyl l ,4-dihydro-4-oxo-7-Q-l ,8- naphthyridine-3-carboxylic acid (IV), where Q is lower-alkyl, lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3 )-pyridyl having one or two lower-alkyl substituents. The final products (IV) are known antibacterial agents, as are the corresponding 7-hydroxymethyl compounds which are prepared by hydrolysis of the final products where Q is 7-(loweralkanoyloxymethyl). A further process comprises reacting l ,4-dihydro-7-methyl-4-oxo-l ,8-naphthyridine- 8-oxide (V) with a lower-tertiary-aminomethylating agent to produce l,4-dihydro-3-(R R NCH )-7- methyl-4-oxo-l.8-naphthyridine-8-oxide (Vl) and oxidizing VI to produce 3-carboxy-l ,4-dihydro-7-methyl- 4-oxo-l,8-naphthyridine-8-oxide (VII). The 8-oxide (Vll) is converted in three steps via the 7-(loweralkanoyloxymethyl) compound to l-ethyl-l,4-dihydro- 7-hydroxymethyl-4-oxol ,8-naphthyridine-3- carboxylic acid.  
 4 Claims, No Drawings 3-DIALKYLAMINOMETHYL-1 ,4-DIHYDRO-4- OXO-1,8-NAPHTHYRIDINES PROCESS AND INTERMEDIATES This application is a division of copending application Ser. No. 339,090, filed Mar. 8, 1973.  
  This invention relates to steps in the process of preparing l,8-naphthyridine-3-carboxylic acids and to compositions used therein,  
  The invention in a process aspect comprises the combination of the three steps of reacting l,4-dihydro-4- oxo-7-Q-l,S-naphthyridine (I), which is tautomeric with 4-hydroxy-7-Q-l,S-naphthyridine (IA), with a lower-tertiary-aminomethylating agent to produce 1.4- dihydro-3-( R R- ,NCH )-4-oxo-7-Q- l ,8-naphthyridine (II), which is tautomeric with 4-hydroxy-3- (R R NCH )-7-Q-l,8-naphthyridine (IIA), reacting II (or IIA) with a lmvenalkylating agent to produce 1- (lower-alkyl )-1 ,4-dihydro-3-( R R NCH )-4-oxo-7-Q- 1,8-naphthyridine (III), and reacting III with an oxidizing agent capable of converting CH NR R to COOH to produce l-(lower-alkyl)-l,4-dihydro-4- oxo-7-Q-I,8-naphthyridine-3-carboxylic acid (IV), where Q is lower-alkyl, lower-alkanoyloxymethyl, 4(or 3 )-pyridyl or 4(or 3 )-pyridyl having one or two loweralkyl substituents, R and R are each lower-alkyl or, optionally NR,R. is piperidino, pyrrolidino, morpholino or such saturated N-heteromonocyclic radicals having one or two lower-alkyl substituents. The final products (IV) are known antibacterial agents, as are the corresponding 7-hydroxymethyl compounds which are prepared by hydrolysis of the final products where Q is lower-alkanoyloxymethyl. In addition to said combination of the three steps, other process aspects of the invention are each individual step and the two consecutive combinations of two steps.  
  The invention in its composition aspect resides in the compounds: l,4-dihydro-3-(R,R NCH )-4-oxo-7-Q- l&#39;,8-naphthyridine and its tautomeric 4-hydroxy-3- (R,R NCH )-7-Q-l,8-naphthyridine of the respective formulas II and IIA and I-(lower-alkyl)-1,4-dihydro3-(R,R NCH )-4-oxo- 7-Q-l ,8-naphthyridine of formula III I I E I Z III CH NR dihydro-3-(R R NCH )-7-methyl-4-oxo-l ,8-naphthyridine-8-oxide (VI), which is tautomeric with 4-hydroxy- 3-( R,R NCH )-7-methyl- I ,8-naphthyridine-8-oxide (VIA), and reacting VI (or VIA) with an oxidizing agentcapable of converting CH NR,R to COOI-I to produce 3-carboxy-l ,4-dihydro-7-methyl-4-oxo-1,8- naphthyridine-8-oxide (VII), which is tautomeric with 3-carboxy-4-hydroxy-7-methyll .8-naphthyridine-8- oxide (VIIA). The 8-oxide (VII or VIIA) is then converted by known means to produce l-ethyl-l,4- dihydro-7-hydroxymethyl-4-oxo-l ,8-naphthyridine-3- carboxylic acid by first reacting it (or its lower-alkyl ester) with a lower-alkanoic acid anhydride to produce 7-(lower-alkanoyloxymethyl)-1,4-dihydro-4-oxo-l ,8- naphthyridine-3-carboxylic acid (or its lower-alkyl ester), ethylating the latter to produce 7-(loweralkanoyloxymethyl l -ethyl-l ,4-dihydro-4-oxo-l ,8- naphthyridine-3-carboxylic acid (or its lower-alkyl ester) and heating the latter with aqueous alkali metal hydroxide solution to produce said corresponding 7- hydroxymethyl-l ,8-naphthyridine-3-carboxylic acid.  
  Because of their ready availability and the relatively low cost of intermediates and because of the high antibacterial activity of the corresponding final products. preferred embodiments in the process and composition aspects of the invention are those compounds where Q is methyl, acetoxymethyl, 4(or 3)-pyridyl, 2-methyl-4- pyridyl or 2,6-dimethyl-4-pyridyl, R is ethyl, and NR,R is di-(lower-alkyl)amino, particularly preferred embodiments being those compounds where NR Rg is dimethylamino or diethylamino.  
  The term lower-alkyl,&#34; as used herein, e.g., as represented by R in formula III or as a substituent of4(or 3 )-pyridyl when represented by Q in formulas lI&#39;, IIA or III, means alkyl radicals having from one to six carbon atoms which can be arranged as straight or branched chains, illustrated by methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-amyl. n-hexyl, and the like.  
  The term lower-alkanoyl, as used herein, e.g., in the definition of the Q substituent as loweralkanoyloxymethyl in formulas II, IIA or III, means alkanoyl radicals having from one to six carbon atoms, including the straightand branched-chain radicals, illustrated by formyl, acetyl, propionyl (propanoyl), butyryl (butanoyl), isobutyryl (2-methylpropan0yl) and caproyl (hexanoyl).  
  Illustrative of the Q substituent in formulas II, IIA or III where Q is 4(or 3 )-pyridyl having one or two loweralkyl substituents are the following: 2-methyl-4-pyridyl, 2,6-dimethyI-4-pyridyl, 3-methyl-4-pyridyl, Z-methyl- 3-pyridyl, 6-methyl-3-pyridyl (preferably named Z-methyl-S-pyridyl), 2,3-dimethyl-4-pyridyl, 2,5-dimethyl-4-pyridyl, 2-ethyl-4-pyridyl, 2-isopropyl- 4-pyridyl, 2-n-butyl-4-pyridyl, 2-n-hexyl-4-pyridyl, 2,6-diethyl-4-pyridyl, 2,6-diethyl-3-pyridyl, 2,6diisopropyl-4-pyridyl, 2,6-di-n-hexyl-4-pyridyl, and the like.  
  As shown above, l,4-dihydro-3-(R,R NCH )-7-Q-4- oxo-l,8-naphthyridine of formula II is tautomeric with 4-hydroxy-3-(R R NCI-I )-7-Q-1,8-naphthyridine of formula IIA. As with all tautomeric systems, the rate of the transformation II IIA and the ratio II/IIA are dependent on the thermodynamic environment, including I the state of aggregation; so that measurements by any particular techniques do not necessarily have validity except under the conditions of the measurement, thereby, among other consequences, giving rise to problems for any simple designation of the physical embodiments. Thus, measurements of the infrared spectra, in potassium bromide admixture. or in chloroform or mineral oil, indicate existence predominantly as ll and the names of the compounds herein therefore are preferably based on structure ll, although it is understood that either or both structures are comprehended.  
  The intermediate l ,4-dihyclro-4-oxo-7-Q- l .8- naphthyridines (l) or tautomers (IA) are either known or, where novel, are prepared from known compounds by methods illustrated hereinbelow.  
  One such method, which is disclosed and claimed in copendingapplication Ser. No. 335,733, filed Feb. 26, 1973, comprises the steps of reacting cyclic alkylidenyl N-(6=Q-2-pyridyl)aminomethylenemalonate. where Q is lower-alkyl, 4(or 3)-pyrid vl, or 4(or 3 )-pyridyl having one or two lower-alkyl substituents, with an oxidizing agent capable of converting pyridines to pyridine- N-oxides to produce cyclic alkylidenyl N-(6-Q&#39;-l-oxo- Z-pyridyl)aminomethylenemalonate, where Q is lower-alkyl, l-oxo-4(or 3 )-pyridyl or l-oxo-4(or 3 )-pyridyl having one or two lower-alkyl substituents, heating said 6-Q-l-oxo-2-pyridyl compound to produce 1,4- dihydro-4-oxo-7-Q- l ,8-naphthyridine-8-oxide and then converting said 8-oxide to the corresponding 1,4- dihydro-4-oxo-7-Q-l,S-naphthyridine. Illustrations of this method are given below in Examples 76-122.  
  The molecular structures of the composition aspects (ll, HA and III) of our invention were assigned on the basis ofievidence provided by infrared, ultraviolet and nuclear magnetic resonance spectra, by chromatographic mobilities, and, by the correspondence of cal culated and found values for the elementary analyses for representative examples.  
  The manner of making and using the instant invention will now be generally described so as to enable a person skilled in the art of chemistry to make and use the same, as follows:  
  The reaction of l,4-dihydro-4-ox0-7-Q-1,8- naphthyridine (l) or its tautomeric 4-hydroxy-7-Q-l ,8- naphthyridine (lA) with a lower-tertiaryaminomethylating agent to produce 1,4-dihydro-3- (R,R N.CH )-4-oxo-7-Q-l,S-naphthyridine (II) or its tautomeric 4-hydroxy-3-( R R- ,NCH )-7-Q- l ,8- naphthyridine (HA) is carried out preferably by reacting 1 (or 1A) with aqueous formaldehyde and a lowersecondary-amine of the formula R R NH where R and R are defined as hereinabove, the combination of formaldehyde and lower-secondary-amine here being the lower-tertiary-aminomethylating agent, which generally comprehends any equivalent reagent or combination of reagents providing a lower-tertiaryaminomethyl group. The reaction is conveniently run in a lower-alkanol, preferably in refluxing ethanol, or in any other suitable solvent which is inert under the reaction conditions. The product (II or llA) can be isolated in its free base form or as its acid addition salt, e.g., hydrochloride, sulfate, methanesulfonate, p-toulenesulfonate, and the like.  
  The reaction of l,4-dihydro-3-(R,R NCl-l )-4-oxo-7- Q- l ,8-naphthyridine (II) or its tautomeric 4-hydroxy-3- (R,R NCH )-7-Q-l,8-naphthyridine (llA)gwith a lower-alkylating agent to produce l-(lower-alkyl)-l,4-  
 dihydro-3-( R R NCH )-4-oxo-7-Q- l .S-naphthyridine (III) is generally carried out by reacting said compound of formula II or llA with a lower-alkyl ester ofa strong inorganic acid or an organic sulfonic acid, said ester having the formula R-An, where An is an anion of a strong inorganic acid or an organic sulfonic acid, e.g., chloride, bromide, iodide, sulfate, methanesulfonate, benzenesulfonate, and para-toluenesulfonate, and R is lower-alkyl. This alkylation is preferably run using one molar equivalent quantity of the alkylating agent and preferably adding it slowly to ll (or IIA). Alternatively, two or more molar equivalent quantities of alkylating agent (RA&#39;fi) can be used to produce the 3-(lowerquaternary-ammonium-methyl salt) of III, that is, N-R,-NR NR-N- [l-(lower-alkyl)-l ,4- dihydro-4-oxo-7-Q- l ,8-naphthyridine-3- yl]methylammonium salt (An), which, like III, also can be oxidized to the corresponding 3-carboxylic acid (IV) by the procedure described hereinbelow.  
  In the alkylation step of the invention, the chloride, bromide or iodide is preferred because of the ready availability of the requisite lower-alkyl halides; and the reaction is carried out preferably in the presence of an acid-acceptor. The acid-acceptor is a basic substance which preferably forms freely water-soluble byproducts easily separable from the product of the reaction, including for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium alkoxides, potassium alkoxides, sodium amide, and the like. The acid-acceptor takes up the hydrogen halide (or HAn) which is split out during the course of the reaction. The reaction is preferably carried out in the presence of a suitable solvent which is inert under the reaction conditions, e.g., a solvent such as lower-alkanol, acetone, dioxane, dimethylformamide, dimethyl sulfoxide, hexamethyl phosphoramide, or a mixture of solvents, e.g., a mixture of water and a lower-alkanol. The reaction is generally carried out at a temperature between about room temperature (about 20-25 C.) and 150 C., preferably heating on a steam bath in a stirred mixture of dimethylformamide and anhydrous potassium carbonate.  
  The reaction of l-(lower-alkyl)-l,4-dihydro-3- (R R NCH )-4-oxo-7-Q-l,8-naphthyridine (lIl) withi an oxidizing agent to produce l-(lower-alkyl)-l ,4- dihydro-4-oxo-7-Q- l ,8-naphthyridine-3-carboxylic acid (IV) is generally carried out by reacting III with an&#39; oxidizing agent capable of converting lower-tertiaryaminomethyl to carboxy. The oxidation is conveniently&#39; and preferably run using an alkali permangante, e.g., KMnO in a basic medium, preferably in pyridine which also acts as solvent. Two to three moles of potassium permanganate per mole of the 3-(R R NCH compound are preferably used. The reaction is run at} a low temperature, preferably below 20 C. As noted? above, this oxidative step to form the 3-carboxylic acid (IV) can be carried out by said procedure using the corresponding &#39;7 &#39;7 NR NR NRN- l-(lower-alkyl)-1,4-dihydro-4-oxoa7-Q-l,8- naphthyridine-B-yl]methylammonium salttAfi).  
  The best mode contemplated for carrying out the invention is now set forth as follows: a  
 EXAMPLE. 1 V  
 3-Diethylaminomethyl-1.4-dih&#39;ydrO-7-&#39;methyl-4-oxo- 1.8 -naphthyridine A mixture containing 16 g. of l.4-dihydro-7-methyl- 4-oxo-1,S-naphthyridine, ml. of 40% aqueous formaldehyde solution. 8.4 g&#39;. of diethylamine and 90 ml. of ethanol was refluxed for 2 hours and then heated in vacuo on a steam bath to dryness. The solid residue was crystallized from ethyl acetate and dried in vacuo at 80 C. to yield 10.3 g. of 3-diethylaminomethyl-1.4- dihydro-7-methyl-4-oxo-l .S-naphthyridine. m.p. l80l8 1 C. with decomposition. Treatment of an ether solution of a sample of said product with ethanolic hydrogen chloride precipitated its hydrochloride salt which was triturated with acetone and air-dried to yield 3-diethylaminomethyll .4-dihydro-7-methyl-4- oxo-l.8-naphthyridine hydrochloride. m.p. 225227 C.  
 EXAMPLE 2 1-Ethyl-3-diethylaminomethyl-1.4-dihydro-7-methyl- 4-oxo-1.8-naphthyridine To a stirred suspension heated on a steam bath and containing 2.45 g. of 1.4-dihydro-3- diethylaminomethyl-7-methyl-4-oxol .8-naphthyridine in 25 ml. of dimethylformamide is added 3.4 g. of anhydrous potassium carbonate and the mixture is stirred for about fifteen minutes. To the stirred hot mixture is added dropwise a solution of 1.56 g. of ethyl iodide in 7 ml. of dimethylformamide and the resulting mixture is stirred with heating on the steam bath for 90 minutes. The hot reaction mixture is filtered and the filtrate chilled. The resulting crystalline precipitate is collected. triturated with warm water. washed sparingly with warm water and dried in vacuo at 60 C. to yield 1-ethyl-3-diethylaminomethyl-1,4-dihydro-7-methyl-4- oxo-l.S-naphthyridine. If desired. this compound can be recrystallized from dimethylformamide. Following the above procedure but using twice as much or more of the ethyl iodide there is obtained the corresponding quaternary ammonium salt. that is. N.N,N-triethyl-N- l-ethyl-l.4-dihydro-7-methyl4-oxo-1.8-naph&#39;thyridin- 3-yl)methylammonium iodide;  
 EXAMPLE3 l-Ethyl-l.4-dihydro-7-methyl-4-oxo-1.8- naphthyridine-3-carboxylic acid A suspension of 2.8 g. of 1-ethyl-3- diethylaminomethyl-l.4-dihydro-7-methyl-4-oxo-1,8- naphthyridine in 25 m1. of pyridine and 5 ml. of water is stirred and cooled to 10C. in an ice bath. Solid potassium permanganate (5g.)&#39;i&#39;s added in small-portions over the course of about 55 minutes. The temperature is not allowed to rise above C. and small amounts of water totalling ml. is added during the course of the addition. The resulting mixture is stirred about minutes longer at 1020 C. and then filtered through infusorial earth. The cake of collected manganese dioxide is washed with a little water and the combined filtrates are treated with saturated aqueous sodium bisul-&#39; fite solution until the excess permanganate is deexcess 6N hydrochloric&#39;acid. After cooling in ice, the  
 - stroyed. The pale yellow solution is then acidified with fresh water and sucked &#39;as dry as possible. T her&#39;naterial is recrystallized from 12 ml. of&#39;dimethylform&#39;amide and l dried for 18 hours in a vacuum oven C.). There is obtained. as pale yellow crystals, 1-ethyl-l,4-dihydro- 7-methyl-4-oxo-&#39;1-.8-naphthyridine-3-carboxylic acid,  
  l-Ethyl- 1 .4-dihydro-7-inethyl-4-0xo- 1 ,8- naphthyridine-3-carboxylic acid also is obtained by fol lowing the above procedure but using a molar equivalent quantity ,of N.N.N.-triethyl-N-(1-ethyl-l.4- dihydro-7-methy1-4-oxo 1,8-naphthyridin-3-yl)- methylanimonium iodide in place of the said corresponding 3-(diethylaminomethyl) compound.  
  Following the procedure described in Example 1 but using in place of 1,4-dihydro-7-methyl-4-oxo-l,8- naphthyridine and diethylamine molar equivalent quantities of the appropriate 1.4-dihydro-4-oxo-7-Q- 1.8-naphthyridine and lower-seeondary-amine (R,R Nl-l), respectively, the compounds of Examples 423 are obtained:  
 EXAMPLE 4 7-Ethy1-l .4-dihydro-3-dimethylaminomethyl-4-oxo- 1.8-naphthyridine using 7-ethyl-l ,4-dihydro-4-oxo-l .8- naphthyridine and dimethylamine.  
 EXAMPLE 5 3-( Ethylmethylaminomethyl l .4-dihydro-4-oxo-7- n-propyl-1,8-naphthyridine using 1.4-dihydro-4-oxo-7- n-propyl-1.8-naphthyridine and ethylmethylamine (i.e.. C H -,NHCH;,).  
 EXAMPLE 6 3-( Di-n-hexylaminomethyl l ,4-dihydro-7-isobutyl- 4-oxo-1.S-naphthyridine using 1.4-dihydro-7-isobutyl- 4-oxo-1.8-naphthyridine and di-n-hexylamine.  
 EXAMPLE 7 7-n-Hexyl-1,4-dihydro-3-(diisopropylmethyl)-4-oxo- 1.8-naphthyridine using 7-nhexyl-l.4-dihydro-4-oxo- 1,8-naphthyridine and diisopropylamine.  
 EXAMPLE 8 l,4-Dihydro-7-methyl-3-dimethylaminomethyl-4- oxo-1.8-naphthyridine using 1,4-dihydro-7-methyl-4- oxo-1.8-naphthyridine and dimethylamine.  
 EXAMPLE 9 1,4-Dihydro-7-methyl-4-oxo-3-(piperidinomethyl LS-naphthyridine using 1,4-dihydro-7-methyl-4-oxo- 1,8-naphthyridine and piperidine.  
 EXAMPLE l0 1.4-Dihydro-7-methyl-4-oxo-3-( pyrrolidinomethyl 1,8-naphthyridine using 1.4-dihydro-7-methyl-4-oxo- LS-naphthyridine and pyrrolidine.  
 &#34; EXAMPLE 11 1,4-Dihydro-7-methyl-3-( morpholinomethyl )-4-oxo- 1,8-naphthyridine using l,4-dihydro-7-methy1-4-oxo- =1,8-naphthyridine and morpholine.  
 EXAMPLE 12 7-Acetoxymethyl-3-diethylaminomethyl-1.4-  
 dihydro&#39;-4&#39;-oxol QS-naphthyridine using 7- lidenyl EXAMPLE 72 l-Et&#39;hyl-7-( 2-ethyl-4- pyridyl l ,4-dihydro-4-oxo- 1 8 naphthyridine-3-carboxylic acid using l-ethyl-3- diethylaminomethyl-7-( 2-ethyl-4-pyridyl l ,4-dihydro- 4-oxo-l ,S-naphthyridine.  
 EXAMPLE 73 l-Ethyl-7-( 3-ethyl-4-pyridyl )-l .4-dihydro-4-oxo-l ,8- naphthyridine-3-carboxylic acid using l-ethyl-3- diethylaminomethyl-7-(3-ethyl-4-pyridyl )-1,4-dihydro- 4-oxo-l,8-naphthyridine. r  
 EXAMPLE 74.  
  l-Ethyll ,4-dihydro-7-( 2,6-dimethyl-4-pyridyl )-4- oxo-l ,8-naphthyridine-3-carboxylic acid using l-ethyl- Ldiethylaminomethyl-l ,4-dihydro-7-( 2,6-dimethyl-4- pyridyl )-4-oxo-l ,S-naphthyridine.  
 EXAMPLE 75 EXAMPLE 76 Cyclic isopropylidenyl N-(6-methyl-l-oxo-2-pyridyl- )aminomethylenemalonate To a solution containing 26.2 g. of cyclic isopropylidenyl N-(6-methyl-2-pyridyl)aminomethylenemalonate in 150 ml. of chloroform is slowly added with stirring l&#39;9-&#34;g. of 3-chloroperbenzoic acid, keeping the reaction temperature below about 40 C. After the addition is completed, the reaction mixture is heated on a steam bath for about 30 minutes. The reaction mixture is extracted successively with ml. of ice cold 10% aqueous potassium bicarbonatesolution, 70 ml. of water, 30 ml. of ice cold 1071 aqueous potassium bicarbonate solution and 25 ml. of water. The resulting chloroform solution is washed with water. dried over anhydrous p0- tassium carbonate, filtered and the filtrate concentratedin acuo to remove the chloroform. The remaining solid is triturated with isopropyl alcohol and then recrystallized from ethanol using decolorizing charcoal to yield cyclic isopropylidenyl N-(6 methyl-l-oxo-2- pyridyl)aminomethylenemalonate,- m.p. 222-223 C. with-decomposition.  
  Theabove preparation also is carried out using a molar equivalent quantity of other oxidizing agents in a suitable solvent inert under the reaction conditions, e.g. use of peracetic acid in aceticacid.  
 EXAMPLE 77 l,4-Dihydro-7-methyl 4-oxo-l ,8-naphthyridine-8- oxide To a 150 ml. portion of diethyl phthalate heated to 275 C. is added with stirring 2.78 gi&#39;of cyclic isopropy- N-(o-methyl-l-oxo-2-pyridyl)aminomethylenemalonate. The stirred reaction mixture is heated at the same temperature for 2 minutes and then allowed to cool to room temperature. The precipitated solid is collected, washedwel l wi-th ether and air-dried to yield the product, 1,4-dihydro-7-methyl-4-oxo-l.8- naphthyridine-8-oxide, which is tautomeric with 4- hydroxy-7-methyll ,8-naphthyridine-8-oxide. Recrystallization, if desired, is carried out using dimethylformamide.  
  The above cyclization also is carried out in 255 ml. of refluxing Dowtherm A in place of the diethyl phthalate..  
 EXAMPLE 78 l,4-Dihydro-7-methyl-4-oxo-l ,8-naphthyridine A mixture containing 8.75 g. of 1,4-dihydro-7- methyl-4-oxo-l ,8-naphthyridine-8-0xide, 250 ml. of absolute ethanol and 5 g. of Raney nickel is hydrogenated at about 25 C. in a Parr apparatus using an initial pressure of 55 p.s.i. of hydrogen. The catalyst is filtered off, the filtrate&#39;treated with decolorizing charcoal and filtered, and the filtrate concentrated in vacuo and chilled. The precipitate is collected, recrystallized from ethanol and dried over P 0 at 25 C. overnight to yield l,4-dihydro-7-methyl-4-oxol ,S-naphthyridine.  
 &#39;235236 C. When recrystallized from water and dried, this compound melted at 235-237 C.  
  Following the procedure described in Example 64 but using in place of cyclic isopropylidenyl N-(6- methyl-2-pyridyl)aminomethylenemalonate a molar equivalent quantity of the appropriate cyclic alkylidenyl N-(6-Q-Z-pyridylaminomethylenemalonate, the compounds of Examples 79-93 are obtained:  
 Example 79 Cyclic isoproplid&#39;enyl N-(6-ethyl-l-oxo-2-pyridyl- )aminomethylenemalonate using cyclic isopropylidenyl N-( 6-ethyl-2-pyridyl )aminomethylenemalonate. the latter prepared by reacting 2-amino-6-ethylpyridine with a mixture of triethyl orthoformate and cyclic isopropylidenyl malonate.  
 EXAMPLE 80 Cyclic isopropylidenyl N-( l-oxo-6-n-propyl-2- pyridyl)aminomethylenemalonate using cyclic isopropylidenyl N-( 6-n-propyl-2-pyridyl )aminomethylenemalonate, the latter prepared -by reacting 2-amino-6-n-propylpyridine with a mixture of triethyl orthoformate and cyclic isopropylidenyl malonate.  
 EXAMPLE s1 EXAMPLE 82 Cyclic isopropylidenyl N-(6-n-butyl-1-ox0-2-pyridyl- )aminomethylenemalonate using cyclic isopropylidenyl ,N-( 6-n-butyl-2-pyridyl )aminomethylenemalonate, the  
 latter prepared by reacting 2-amino-6-n-butylpyridine with a mixture of triethyl orthoformate and cyclic isopropylidenyl malonate.  
 EXAMPLE 83 Cyclic isopropylidenyl N-(6-n-hexyl-l-oxo-2-pyridyl- )aminomethylenemalonate using cyclic isopropylidenyl N-(6n-hexyl-2-pyridyl)aminomethylenemalonate, the latter prepared by reacting Z-amino-6-n-hexylpyridine with a mixture of triethyl orthoformate and cyclic isopropylidenyl malonate.  
 EXAMPLE 84 Cyclic 3-pentylidenyl N-(-methyl-l-oxo-Z-pyridyl- )aminomethylenemalonate using cyclic 3-pentylidenyl N-(6-methyl-2-pyridyl)aminomethylenemalonate. the latter prepared by reacting 2-amino-6-methylpyridine with a mixture of triethyl orthoformate and cyclic 3- pentylidenyl malonate.  
 EXAMPLE 85 Cyclic Z-butylidenyl N-(6-methyl-l-oxo-2-pyridyl- )aminomethylenemalonate using cyclic l-butylidenyl N-(6-methyl-2-pyridyl)aminomethylenemalonate. the latter prepared by reacting 2-amino-6-methylpyridine with a mixture of triethyl orthoformate and cyclic 2- butylidenyl malonate.  
 EXAMPLE 86 Cyclic 4-heptylidenyl N-(6-methyl-l-oxo-2-pyridyl- )aminomethylenemalonate using cyclic 4-heptylidenyl N-(6-methyl-2-pyridyl)aminomethylenemalonate. the latter prepared by reacting 2-amino-o-methylpyridine with a mixture of triethyl orthoformate and cyclic 4- heptylidenyl malonate.  
 EXAMPLE 87 Cyclic isopropylidenyl N-[ l-oxo-6-( l-oxo-4- pyridyl)-2-pyridy|1aminomethylenemalonate using cyclic isopropylidenyl N-[ 6-( 4-pyridyl )-2-pyridyl- ]aminomethylenemalonate, the latter prepared by reacting 2-amino-6-(4-pyridyl)pyridine with a mixture of triethyl orthoformate and cyclic isopropylidenyl malonate.  
 EXAMPLE 88 Cyclic isopropylidenyl N-l l-oxo-6-( l-oxo-3- pyridyl)-2-pyridyl]aminomethylenemalonate using cy&#39; clic isopropylidenyl N-[ 6-( 3-pyridyl )-2-pyridyl- 1aminomethylenemalonate, the latter prepared by reacting 2-amino-6-(3-pyridyl)-pyridine with a mixture of triethyl orthoformate and cyclic isopropylidenyl malonate.  
 EXAMPLE 89 Cyclic isopropylidenyl N-l l-oxo-6-(2-methyl-l-0xo- 4-pyridyl)-2-pyridyl1aminomethylenemalonate using cyclic isopropylidenyl N-l6-(2-methyl-4-pyridyl)-2- pyridyl]aminomethylenemalonate, the latter prepared by reacting 2-amino-6-(2-methyl-4-pyridyl)pyridine with a mixture of triethyl orthoformate and cyclic isopropylidenyl mal onate.  
 EXAMPLE 9O Cyclic isopropylidenyl N-l l-0xo-6-(2-ethyl-l-0xo-4- pyridyl)-2-pyridyllaminomethylenemalonate using cyclic isopropylidenyl N-[ 6-( 2-ethyl-4-pyridyl)-2-pyridyl- ]aminomethylenemalonate, the latter prepared by reacting 2-amino-6-(2-ethyl-4-pyridyl)pyridine with a mixture of triethyl orthoformate and cyclic isopropylidenyl malonate. a  
 EXAMPLE 9] Cyclic isopropylidenyl N-[ l-oxo-6-( 3-ethyl-l-oxo-4- pyridyl)-2-pyridyl]aminomethylenemalonate using cyclic isopropylidenyl N-[6-( 3-ethyl-4-pyridyl)-2-pyridyl- ]aminomethylenemalonate, the latter prepared by reacting 2-amin0-6-(3-ethyl-4-pyridyl)pyridine with a mixture of triethyl orthoformate and cyclic isopropylidenyl malonate.  
 EXAMPLE 92 Cyclic isopropylidenyl N-[l-oxo-6-(2,6-dimethyl-loxo-4-pyridyl)-2-pyridyl]aminomethylenemalonate using cyclic isopropylidenyl N-[6-(2,6-dimethyl-4- pyridyl )-2-pyridyl]aminomethylenemalonate. the latter prepared by reacting 2-amino-6-(2,6-dimethyl-4- pyridyl)pyridine with a mixture of triethyl orthoformate and cyclic isopropylidenyl malonate.  
 EXAMPLE 93 EXAMPLE 94 7-Ethyl-l ,4-dihydro-4-oxol .8-naphthyridine-8 oxide using cyclic isopropylidenyl N-(6-ethyl--- -oxo-2-pyridyl)aminomethylenemalonate.  
 EXAMPLE 95 l,4-Dihydro-4-oxo-7-n-propyl-1,8-naphthyridine-8- oxide using cyclic isopropylidenyl N-(l-oxo-6-npropyl-Z-pyridyl )aminomethylenemalonate.  
 EXAMPLE 96 l.4-Dihydro-7-isopropyl-4-oxol ,8-naphthyridine-8 oxide using cyclic isopropylidenyl N-(6-isopropyl-loxo-Z-pyridyl )aminomethylenemalonate.  
 EXAMPLE 97 l 7-n-Butyl-l ,4-dihydro-4-oxo- 1 ,8-naphthyridine-8- oxide using cyclic isopropylidenyl N-(-n-butyl-l-oxo-v Z-pyridyl )aminomethylenemalonate.  
 EXAMPLE 98 7-n-Hexyll ,4-dihydro-4-oxo-l ,8-naphthyridine-8- oxide using cyclic isopropylidenyl N-(6-n-hexyl-l-ox0- 2-pyridyl )aminomethylenemalonate.  
 EXAMPLE 99 1 ,4-Dihydro-7-methyl-4-oxo- 1 ,8-naphthyridine-8- oxide using cyclic 3-pentylidenyl N-(6-methyl-l-oxo-2- pyridyl)aminomethylenemalonate.  
 EXAMPLE I00 l,4-Dihydro-7-methyl-4-oxo-1,8-naphthyridine-8- oxide using cyclic 2-butylidenyl N-(6-methyl-l-oxo-2- pyridyl )aminomethylenemalonate.  
 EXAMPLE lOl l,4-Dihydro-7-methyl-4-oxo-l ,S-naphthyridine-S- R are each lower alkyl.  
  2. The compound according to claim 1 where Q is methyl, and R and R are each ethylf 3. A compound of the formula l-(lower alkyl)-l,4- dihydro-3-(R,R NCH- 1)-4-oxo-7-Q-l ,8 naphthyridine, wherein Q is lower alkyl, lower alkanoyloxymethyl, 3 or 4-pyridyl unsubstituted or having one or two lower alkyl substituents. and R and R are each lower alkyl.  
 4. The compound according to claim 3 where Q is methyl. and R and R are each ethyl.