SYNTHESIS OF ANTITUBERCULAR COMPOUNDS,Ⅱ.2-ALKOXY-AMINOQUINOLINES AND THEIR DERIVATIVES AND 2-ALKOXY-6-AMINOCINCHONINIC ACID HYDRAZIDES

The fact that 2-alkoxy-5-aminopyridines(Ⅰ)and 2-alkoxy-6-aminobenzothiazole(Ⅱ)possess high tuberculostatic activities in vitro as well as in experimental animals led us to prepare a num- ber of analogous compounds belonging to quinoline series,namely,2-alkoxy(n-propoxy,or n- butoxy)-6-aminoquinoline(Ⅲe or Ⅲa)and its structural isomers,2-butoxy-5-(or 7-,or 8-)- aminoquinoline(Ⅲb,Ⅲc,or Ⅲd);and 2-butoxy-6-acetamino-(or dichloroacetamino-,or dimethy- lamino)-quinoline(Ⅳa,or Ⅳb,or Ⅳc)for the purpose of testing their antimycobacterial ac- tivities,and also of studying the relationships between antibacterial activity and chemical structure. Besides,several 2-alkoxy-6-aminocinchoninic acid hydrazides(Ⅳa,Ⅳb,Ⅳc,Ⅳd,Ⅳe),were also prepared.As can be seen from the formula,there is an additional—CONHNH₂ group present in the molecule as compared with Ⅲa and its alkoxy analogues. The results of antimycobacterial activities against mycobacterium 607 and smegmatis activities are listed in tables 1—3. Ⅲa possesses 1/2—1/4 activity against mycobact.607 as compared with that of INH,but is comparable to the latter in the case of antismegmatis activity.Ⅲb,Ⅲc and Ⅲd possess the similar order of activity as Ⅲa.2-Hydroxy-6-aminoquinoline and also all the corresponding nitro- compounds of Ⅲa,Ⅲb,Ⅲc,Ⅲd and Ⅲe are of no significant activity.The acylated and methylated compounds of Ⅲa are also with much less activities,p-Amino-N-carbobutoxyaniline (Ⅴ)which was thought to be an open-ring compound of Ⅲa is also inactive.These facts show that the free amino and alkoxyl groups attached to aromatic structure are necessary for the exhibition of antimycobacterial activity.As to the position of the amino group attached to the benzene moiety of quinoline nucleus seems without practical influence.The introduction of a carbohydrazino group to the 4-position of Ⅲa or of its alkoxyl analogues is unfavorable to the in vitro antimycobacterial activity. The methods of preparation of compounds of type Ⅲ were by treating at first the 2-chloro- nitroquinolines(Ⅶ)with an appropriate sodium alcoholate to form 2-alkoxy-nitroquinolines (Ⅷ),and then the latter reduced by stannous chloride to give the required products(Ⅲ). The synthesis of the compounds of type Ⅵ was to begin with 2-chloro-6-nitrocinchoninic acid chloride(Ⅸ),which by treating with methyl or ethyl alcohol to give the corresponding methyl or ethyl esters(Ⅹ).The latter were then reacted with the appropriate sodium alcoholates to afford 2-alkoxy-6-nitrocinchoninic acid methyl or ethyl esters(Ⅺ),which were then catalytically reduced in the presence of Pd-C to give the corresponding amino-compounds (ⅩⅢ).The desired pro- ducts(Ⅵ)were obtained by treating the latter with hydrazine hydrate.Ⅺ directly reacted with hydrazine hydrate to give Ⅻ. Solvents of crystallization,melting points,yields of the compounds synthesized in this inves- tigation are summarized in table Ⅳ.