JPS5938238B2 - Heterocyclic fused naphthyridine derivatives - Google Patents
Heterocyclic fused naphthyridine derivativesInfo
- Publication number
- JPS5938238B2 JPS5938238B2 JP19876A JP19876A JPS5938238B2 JP S5938238 B2 JPS5938238 B2 JP S5938238B2 JP 19876 A JP19876 A JP 19876A JP 19876 A JP19876 A JP 19876A JP S5938238 B2 JPS5938238 B2 JP S5938238B2
- Authority
- JP
- Japan
- Prior art keywords
- ethyl
- naphthyridine
- carboxylic acid
- oxo
- dihydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
【発明の詳細な説明】
本発明は、優れた抗菌作用を有する新規な複素環縮合ナ
フチリジン誘導体に関するものであり、その製法を反応
式で示せぱ次の通りである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel heterocyclic fused naphthyridine derivative having excellent antibacterial activity, and the method for producing the same is shown in the following reaction formula.
ｆ１２Ｈ二□ＣＯＯＲ（１１）。f12H2□COOR (11).
−、（二□゜−（１１［）１
Ｃ２Ｈ、
ＨＲ９〈二□ＣＯＯＨ
（ｌ）
Ｃ２Ｈ、
（式中、Ｘは０、５あるいはＮＲ′を表わし、Ｒ、Ｒ′
およびＲ″は水素あるいは低級アルキル基を表わ・す。-, (2□゜-(11[)1 C2H, HR9〈2□COOH (l) C2H, (wherein, X represents 0, 5 or NR', R, R'
and R'' represents hydrogen or a lower alkyl group.
Ａは有機酸、有機酸無水物または有機酸エステルを表わ
す。）尚、Ｒが水素の場合、（ｍは（■こ一致する。す
なわち、本発明は（■）と（■）を反応させることによ
つて側を生成せしめ、更に生成物（ＩＶ）がエステルフ
の場合はこれを加水分解することによつて製造される複
素環縮合ナフチリジンー３−カルボン酸（Ｉ）に関する
。A represents an organic acid, an organic acid anhydride or an organic acid ester. ) When R is hydrogen, (m corresponds to (■). That is, in the present invention, the side is produced by reacting (■) and (■), and furthermore, the product (IV) is an ester phthalate. The case relates to heterocyclic fused naphthyridine-3-carboxylic acid (I) produced by hydrolyzing this.
（１）を製造するには、通常（）が有機酸、有機酸無水
物あるいは有機酸エステルの場合は、無溶媒あるいは非
極性溶媒（こ溶解あるいは懸濁させ加熱して反応させる
。To produce (1), when () is an organic acid, an organic acid anhydride, or an organic acid ester, it is usually reacted without a solvent or in a nonpolar solvent (dissolved or suspended in this solvent and heated).
ここで、有機酸とはギ酸、酢酸、プロピオン酸等を有機
酸無水物とは無水酢酸、無水プロピオン酸等を、また有
機酸エステルとはオルトギ酸エチル、プロピオン酸エチ
ル等をいう。Here, the organic acid refers to formic acid, acetic acid, propionic acid, etc., the organic acid anhydride refers to acetic anhydride, propionic anhydride, etc., and the organic acid ester refers to ethyl orthoformate, ethyl propionate, etc.
非極性溶媒としてトルエン、キシレン等が用いられるが
、この他にも（）および（）と反応せず、しかも（）お
よび（ｌ）を若干でも溶解するものであればよい。反応
条件としては６０〜２００℃の温度で１時間ないし２０
時間反応させればよく、試剤等の種類によつて若干異る
が、一般に反応は極めて好収率で行われる。Toluene, xylene, etc. are used as non-polar solvents, but any other solvents may be used as long as they do not react with () and () and can even slightly dissolve () and (l). The reaction conditions are 60-200℃ for 1 hour to 20 minutes.
The reaction may be carried out for a certain amount of time, and although it differs slightly depending on the type of reagent etc., the reaction is generally carried out in an extremely good yield.
このようにして製造される複素環縮合ナフチリジン類は
すべて新規化合物であり、一般細菌特にグラム陰性菌に
対して優れた抗菌力を示し医薬品として有用である。All of the heterocyclic fused naphthyridines produced in this manner are new compounds, and exhibit excellent antibacterial activity against general bacteria, particularly gram-negative bacteria, and are useful as pharmaceuticals.
一例として、本発明の化合物８−エチル−５，８−ジヒ
トロー５−オキソーチアゾロ〔４，５−ｇ〕１，８−ナ
フチリジン一６−カルボン酸（４）の抗菌力をグラム陰
性菌に対する化学療法薬として知られているナリジクス
酸（Ｂ）を対照としてハード・インヒユージヨン寒天培
地を用いて試験した結果を示すと次表の通りである。以
下、実施例により本発明に係る化合物の製法を述べる。
尚、実施例において使用される新規な原料化合物は参考
例に挙げた方法によつて製することができる。As an example, the antibacterial activity of the compound 8-ethyl-5,8-dihydro-5-oxothiazolo[4,5-g]1,8-naphthyridine-16-carboxylic acid (4) was evaluated as a chemotherapeutic agent against Gram-negative bacteria. The following table shows the results of a test using hard infusion agar medium using nalidixic acid (B), known as nalidixic acid (B), as a control. Hereinafter, the method for producing the compound according to the present invention will be described with reference to Examples.
Incidentally, the novel raw material compounds used in the examples can be produced by the methods listed in the reference examples.
参考例 １
１−エチルーJメ[アミノ一１，４−ジヒトロー４−オキ
ソ一１，８−ナフチリジン一３−カルボン酸２５９を濃
硫酸２６０ｍ１に溶解し、これに濃硝酸２６ｍ１を加え
て８０℃で２時間加熱する。Reference example 1 259 1-ethyl-J-amino-1,4-dihythro-4-oxo-1,8-naphthyridine-3-carboxylic acid was dissolved in 260 ml of concentrated sulfuric acid, 26 ml of concentrated nitric acid was added thereto, and the mixture was heated at 80°C. Heat for 2 hours.
反応混合物を氷水にあけ、析出晶を濾取してジメチルホ
ルムアミド−メタノールの混液から再結晶すれば淡黄色
針状晶として融点２７５〜２７７℃の１−エチル−６−
ニトローJメ[ヒドロキシ一１，４−ジヒトロー４−オキ
ソ一１，８−ナフチリジン一３−カルボン酸２８．７９
（９６．０％）を得る。元素分析値 Ｃ，ｌＨ，Ｎ３Ｏ
６計算値 Ｃ４７．３２，Ｈ３．２５，Ｎｌ５．６５実
験値 Ｃ４７．Ｏ２，Ｈ３．２ｌ，Ｎｌ５．３５このよ
うにして得た１−エチル−６−ニトロJメ[ヒドロキシ一
１，４−ジヒトロー４−オキソー１，８−ナフチリジン
一３−カルボン酸１０．５９および塩化チオニル３０ｍ
１の混合物を室温で１６時間撹拌する。The reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration and recrystallized from a dimethylformamide-methanol mixture to give 1-ethyl-6- as pale yellow needle crystals with a melting point of 275-277°C.
Nitro J me[Hydroxy-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 28.79
(96.0%). Elemental analysis values C, lH, N3O
6 Calculated value C47.32, H3.25, Nl5.65 Experimental value C47. O2, H3.2 l, Nl 5.35 1-ethyl-6-nitroJ-[hydroxy-1,4-dihythro-4-oxo-1,8-naphthyridine-3-carboxylic acid 10.59 and chloride thionyl 30m
The mixture of 1 is stirred at room temperature for 16 hours.
反応混合物をエタノール３００ｍ１にあけ、室温（こ３
０分間放置後、減圧下４こエタノールを濃縮する。析出
晶を濾取し、クロロホルム−メタノールの混液から再結
晶すれば、淡黄色針状晶として融点２３９〜２４１℃の
１−エチル−６−ニトローJメ[ヒドロキシ一１，４−ジ
ヒトロー４−オキソ一１，８−ナフチリジン一３−カル
ボン酸エチルエステル８．８０９（７５．８％）を得る
。このようにして得た１−エチル−６−ニトローJメ[ヒ
ドロキシ一１，４−ジヒトロー４−オキソ一１，８−ナ
フチリジン一３−カルボン酸エチルエステル１５．０９
およびオキシ塩化燐８０ＴｆＬ１の混合物を８０〜９０
℃で２時間撹拌する。Pour the reaction mixture into 300 ml of ethanol and cool to room temperature (300 ml).
After standing for 0 minutes, concentrate 4 drops of ethanol under reduced pressure. If the precipitated crystals are collected by filtration and recrystallized from a mixture of chloroform and methanol, 1-ethyl-6-nitro-1-hydroxy-1,4-dihydro-4-oxo-1,4-dihydroxy-1,4-dihydroxy, and 8.809 (75.8%) of 1,8-naphthyridine-3-carboxylic acid ethyl ester is obtained. Thus obtained 1-ethyl-6-nitro-J-[hydroxy-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 15.09
and a mixture of 80 TfL1 and phosphorus oxychloride at 80 to 90
Stir at ℃ for 2 hours.
冷後反応混合物を氷水にあけ、炭酸水素ナトリウムで中
和したのち、生成物をクロロホルムで抽出する。抽出液
を水洗し、乾燥したのち、減圧下に濃縮すると無色針状
晶として融点１９５〜１９７℃の１一エチル一６−ニト
ローJメ[クロロ一１，４−ジヒトロー４−オキソ一１，
８−ナフチリジン一３一カルボン酸エチルエステル１２
．８９（８０．４％）を得る。このようにして得た１−
エチル−６−ニトローJメ[タロロ一１，４−ジヒトロー
４−オキソ一１，８−ナフチリジン一３−カルボン酸エ
チルエステル１２．６９を酢酸４００ｍ１に懸濁し、攪
拌しながら鉄粉２０９を加えて８『Ｃに２時間加熱する
。After cooling, the reaction mixture was poured into ice water, neutralized with sodium bicarbonate, and the product was extracted with chloroform. The extract was washed with water, dried, and concentrated under reduced pressure to give colorless needle crystals with a melting point of 195-197°C.
8-Naphthyridine-13-carboxylic acid ethyl ester 12
．． 89 (80.4%). 1- obtained in this way
Suspend 12.69 ethyl-6-nitro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester in 400 ml of acetic acid, and add 209 ml of iron powder while stirring. 8. Heat to 2 hours.
反応混合物にエタノール５００ｍ１を加えて温時不溶物
を濾去し、濾液を２００ｍ１まで濃縮して冷水にあけ、
析出晶を濾取する。クロロホルム−酢酸エチルから再結
晶すれば淡黄色針状晶として融点２８９〜２９１℃の１
−エチル−６−アミノーJ■■８−ナフチリジン一３−
カルボン酸エチルエステル９．７１９（８９．５％）を
得る。このようにして得られた１−エチル−６−アミノ
ーJメ[クロロ一１，４−ジヒトロー４−オキソ１，８−
ナフチリジン一３−カルボン酸エチルエステル８．００
９と１ＮＨＣＩ一酢酸８０ｍ１の混合物を１００℃で５
時間攪拌し、冷後、析出晶を濾取してジメチルホルムア
ミドから再結晶すれば淡黄色針状晶として融点３００℃
以上の１−エチル６−アミノーJメ[クロロ一１，４−ジ
ヒドロ４−オキソ一１，８−ナフチリジン一３−カルボ
ン酸３．４４９（４７．６％）を得る。Add 500 ml of ethanol to the reaction mixture, filter off insoluble matter when hot, concentrate the filtrate to 200 ml, pour into cold water,
The precipitated crystals are collected by filtration. Recrystallization from chloroform-ethyl acetate gives pale yellow needle crystals with a melting point of 289-291°C.
-Ethyl-6-aminoJ■■8-naphthyridine-3-
9.719 (89.5%) of carboxylic acid ethyl ester is obtained. The thus obtained 1-ethyl-6-amino-J-chloro-1,4-dihythro-4-oxo-1,8-
Naphthyridine-3-carboxylic acid ethyl ester 8.00
A mixture of 80 ml of 9 and 1N HCI monoacetic acid was heated at 100°C
After stirring for an hour and cooling, the precipitated crystals are collected by filtration and recrystallized from dimethylformamide to give light yellow needle-shaped crystals with a melting point of 300°C.
3.449 (47.6%) of the above 1-ethyl 6-amino-J-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was obtained.
参考例 ２
参考例１で得られた１−エチル−６−アミノJメ[クロロ
一１，４−ジヒトロー４−オキソ一１８−ナフチリジン
一３−カルボン酸エチルエステル８．００ｇを８％水酸
化ナトリウム水溶液１２０Ｔｎ１に加え、１００℃で１
１時間加熱する。Reference Example 2 8.00 g of 1-ethyl-6-amino J-chloro-1,4-dihydro-4-oxo-18-naphthyridine-3-carboxylic acid ethyl ester obtained in Reference Example 1 was added to 8% sodium hydroxide. In addition to 120Tn1 aqueous solution, 1
Heat for 1 hour.
冷後、塩酸々性として析出晶を濾取し、ジメチルホルム
アミドから再結晶すると淡黄色粉末として融点３００℃
以上の１−エチル−６−アミノーJメ[ヒドロキシ一１，
４−ジヒトロー４−オキソ一１，８−ナフチリジン一３
−カルボン酸３，９０仄６０．０％）を得る。参考例
３
参考例１で得られた１−エチル−６−アミノJメ[クロロ
一１，４−ジヒトロー４−オキソ一１，８−ナフチリジ
ン一３−カルボン酸エチルエステル２．０ｇおよび１０
％水硫化カリウム２．０ｍ１の混合物を３時間還流する
。After cooling, the precipitated crystals are collected by filtration as hydrochloric acid, and recrystallized from dimethylformamide to give a pale yellow powder with a melting point of 300°C.
The above 1-ethyl-6-amino-J[hydroxy-1,
4-dihythro-4-oxo-1,8-naphthyridine-3
-carboxylic acid 3.90% to 60.0%). Reference example
3 2.0 g of 1-ethyl-6-amino J-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester obtained in Reference Example 1 and 10
A mixture of 2.0 ml of % potassium hydrosulfide is refluxed for 3 hours.
冷後、塩酸々性として析出晶を濾取すると黄色粉末とし
て１−エチル−６アミノーJメ[メルカプト一１，４−ジ
ヒドロ４−オキソ一１，８−ナフチリジン一３−カルボ
ン酸１．４８９（８２．７％）を得る。参考例 ４
参考例１で得られた１−エチル−６−アミノJメ[クロロ
一１，４−ジヒトロー４−オキソ一１，８−ナフチリジ
ン一３−カルボン酸１．０９，３０％メチルアミン水溶
液２０ｍ１およびエタノール２０ＷＬＩの混合物を封管
中１００℃で５時間加熱する。After cooling, the precipitated crystals were collected by filtration as a yellow powder. 82.7%). Reference Example 4 1-Ethyl-6-amino J-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid obtained in Reference Example 1 1.09, 30% methylamine aqueous solution A mixture of 20 ml and ethanol 20 WLI is heated in a sealed tube at 100° C. for 5 hours.
反応液を濃縮し、析出晶をジメチルホルムアミド−エタ
ノールの混液から再結晶すれば融点３０００Ｃ以上の１
−エチル−６−アミノーJメ[メチルアミノ一１，４−ジ
ヒトロー４−オキソ一１，８−ナフチリジン一３−カル
ボン酸０．８１５９（８３，３％）を得る。実施例 １
６−アミノ−１−エチルーJメ[ハイドロオキシ１，４−
ジヒトロー４−オキソ一１，８−ナフチリジン一３−カ
ルボン酸３９０７７？および無水酢酸６ＴｆＬ１の混合
物を１６０℃で６時間攪拌する。If the reaction solution is concentrated and the precipitated crystals are recrystallized from a mixture of dimethylformamide and ethanol, 1.
0.8159 (83.3%) of -ethyl-6-amino-J-methylamino-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained. Example 1 6-amino-1-ethyl-[hydroxy-1,4-
Dihythro-4-oxo-1,8-naphthyridine-3-carboxylic acid 39077? A mixture of 6TfL1 and acetic anhydride is stirred at 160° C. for 6 hours.
冷後、析出物を濾取し、ＤＭＦから再結晶すると融点３
００℃以上の無色針状晶として８−エチル２−メチル−
５，８−ジヒトロー５−オキソオキサゾロ〔４，５−ｇ
〕１，８−ナフチリジン一６−カルボン酸３４０〜（６
８％）を得る。実施例 ２
６−アミノ−１−エチルーJメ[メチルアミノ１，４−ジ
ヒトロー４−オキソ一１，８−ナフチリジン一３−カル
ボン酸１２０ｍｙ１オルトギ酸エチル１ｍ１およびＤＭ
Ｆ２ｍｌの混合物を１５時間還流する。After cooling, the precipitate is collected by filtration and recrystallized from DMF, resulting in a melting point of 3.
8-ethyl 2-methyl- as colorless needle crystals above 00℃
5,8-dihythro 5-oxooxazolo [4,5-g
]1,8-naphthyridine-6-carboxylic acid 340~(6
8%). Example 2 120 ml of 6-amino-1-ethyl-methylamino-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 1 ml of ethyl orthoformate and DM
The mixture of 2 ml of F is refluxed for 15 hours.
冷後、反応液にＥｔＯＨを加えて不溶物を濾取し、ＤＭ
Ｆから再結晶すると融点３００℃以上の淡黄色針状晶と
して５−エチル−３−メチル５，８−ジヒトロー８−オ
キソ一１Ｈ−イミダゾ〔４，５−ｇ〕１，８ナフチリジ
ンーJメ[カルボン酸５７η（４６％）を得る。実施例
３
６−アミノ−１−エチルーJメ[メルカプト一１，４−ジ
ヒトロー４−オキソ一１，８−ナフチリジン一３−カル
ボン酸２００ηおよびギ酸２ｄの混合物を６時間還流す
る。After cooling, EtOH was added to the reaction solution, insoluble matter was filtered, and DM
When recrystallized from F, 5-ethyl-3-methyl 5,8-dihydro-8-oxo-1H-imidazo[4,5-g]1,8naphthyridine-J-carbon Acid 57η (46%) is obtained. Example
3 A mixture of 200 η of 6-amino-1-ethyl-mercapto-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and 2d of formic acid is refluxed for 6 hours.
Claims (1)
Ｒ″は水素または低級アルキル基を表わす。 ）で示される複素環縮合ナフチリジン誘導体２ ８−エ
チル−５，８−ジヒドロ−５−オキソ−チアゾロ〔４、
５−ｇ〕１，８−ナフチリジン−６−カルボン酸である
特許請求の範囲第１項記載の化合物。[Claims] 1 General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, X represents O, S or NR', and R' and R'' represent hydrogen or a lower alkyl group.) Heterocyclic fused naphthyridine derivatives 2 8-ethyl-5,8-dihydro-5-oxo-thiazolo[4,
5-g] The compound according to claim 1, which is 1,8-naphthyridine-6-carboxylic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19876A JPS5938238B2 (en) | 1976-01-01 | 1976-01-01 | Heterocyclic fused naphthyridine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19876A JPS5938238B2 (en) | 1976-01-01 | 1976-01-01 | Heterocyclic fused naphthyridine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5283595A JPS5283595A (en) | 1977-07-12 |
| JPS5938238B2 true JPS5938238B2 (en) | 1984-09-14 |
Family
ID=11467279
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP19876A Expired JPS5938238B2 (en) | 1976-01-01 | 1976-01-01 | Heterocyclic fused naphthyridine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5938238B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5484924A (en) * | 1991-11-25 | 1996-01-16 | Kyowa Hakko Kogyo Co., Ltd. | Imidazonaphthyridine derivatives |
-
1976
- 1976-01-01 JP JP19876A patent/JPS5938238B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5283595A (en) | 1977-07-12 |
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