JPH0124153B2 - - Google Patents
Info
- Publication number
- JPH0124153B2 JPH0124153B2 JP7277281A JP7277281A JPH0124153B2 JP H0124153 B2 JPH0124153 B2 JP H0124153B2 JP 7277281 A JP7277281 A JP 7277281A JP 7277281 A JP7277281 A JP 7277281A JP H0124153 B2 JPH0124153 B2 JP H0124153B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- acid
- compound
- salt
- piperazino
- 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- -1 piperazino-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid Chemical compound 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- XNIVKSPSCYJKBL-UHFFFAOYSA-N 2h-1,2-benzoxazine-6-carboxylic acid Chemical compound O1NC=CC2=CC(C(=O)O)=CC=C21 XNIVKSPSCYJKBL-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYMMKXPMUYFWGI-UHFFFAOYSA-N 7h-pyrido[2,3-f][2,1]benzoxazine Chemical class C1=CC2=CC=CN=C2C2=C1NOC=C2 RYMMKXPMUYFWGI-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 description 1
- 229960001732 pipemidic acid Drugs 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
本発明は一般式〔〕
（式中、Ｒは水素原子または低級アルキル基を意
味する。）で表わされるオキサジノキノリン誘導
体およびその塩に関するものである。
ここで、低級アルキル基はメチル、エチル、ｎ
−プロピル、ｉ−プロピル等が挙げられる。ま
た、塩としては塩酸、硫酸、メタンスルホン酸の
如き無機もしくは有機酸との塩、あるいはカルボ
ン酸のナトリウム塩やカリウム塩が具体例として
挙げられる。
本発明の一般式〔〕で表わされる化合物およ
びその塩は、緑膿菌を含むグラム陰性菌に対して
強い抗菌作用を示し、医薬品としての使用が期待
できる。例えば、医薬品として使用されているピ
ペミド酸を対照として試験管内抗菌試験において
最小発育阻止濃度（MIC）を測定した結果は次
表に示すように優れた抗菌活性を示す。
最小発育阻止濃度（MIC、μｇ／ml）
平板希釈法（ハートインフユージヨン寒天培地）
接種菌量106／ml
培養条件37゜、18時間
The present invention is based on the general formula [] (In the formula, R means a hydrogen atom or a lower alkyl group.) The present invention relates to an oxazinoquinoline derivative and a salt thereof. Here, the lower alkyl group is methyl, ethyl, n
-propyl, i-propyl and the like. Specific examples of the salt include salts with inorganic or organic acids such as hydrochloric acid, sulfuric acid, and methanesulfonic acid, and sodium and potassium salts of carboxylic acids. The compounds represented by the general formula [ ] and salts thereof of the present invention exhibit strong antibacterial activity against Gram-negative bacteria including Pseudomonas aeruginosa, and can be expected to be used as pharmaceuticals. For example, the results of measuring the minimum inhibitory concentration (MIC) in an in vitro antibacterial test using pipemidic acid, which is used as a pharmaceutical, as a control, show excellent antibacterial activity as shown in the table below. Minimum inhibitory concentration (MIC, μg/ml) Plate dilution method (heart infusion agar medium) Inoculum amount: 10 6 /ml Culture conditions: 37°, 18 hours
【表】【table】
【表】【table】
【表】
次に、本発明の化合物の製造方法の例を反応式
で示して説明する。
（式中、Ｒは前記に同じ。）
すなわち、化合物〔〕をジメチルスルホキシ
ド、スルホラン、ジメチルホルムアミド、ジメチ
ルアセトミド、水の如き極性溶媒中でピペラジノ
と50〜200℃、好ましくは100〜180℃で１時間な
いし48時間加熱することによつて化合物〔〕が
得られる。化合物〔〕は希塩酸、希硫酸の如き
酸または水酸化ナトリウム水溶液、炭酸カリウム
の如き塩基に溶け易く、対応する塩を容易に形成
する。
次に、実施例を示す。
実施例 １
９，10−ジクロロ−３−メチル−７−オキソ−
２，３−ジヒドロ−7H−ピリド［１，２，３−
de］［１，４］ベンゾオキサジン−６−カルボン
酸320mgおよび無水ピペラジン1.2ｇをジメチルス
ルホキシド５mlに加え、110〜130℃で24時間撹拌
する。減圧下で溶媒を留去し、残渣を冷水で処理
して不溶物を濾取する。これを５％塩酸10mlに加
えて室温で20分撹拌する。不溶物を濾去し、濾液
を減圧乾固する。残渣は水−エタノール−アセト
ンから再結晶すると、融点＞300℃の９−クロロ
−３−メチル−７−オキソ−10−ピペラジノ−
２，３−ジヒドロ−7H−ピリド［１，２，３−
de］［１，４］ベンゾオキサジン−６−カルボ酸
の塩酸塩170mgを得る。
元素分析値 C17H18ClN3O4・HCl・1/2H2Oとし
て
計算値 C49.89、H4.93、N10.27
分折値 C49.62、H5.00、N9.82
NMR（D2O）δ（ppm）
1.62（3H、ｄ、３位ＣＨ 3基）
3.46、3.60（各4H、ｂ、ｄ、ピペラジン環−Ｃ
Ｈ2CＨ 2−）
4.4〜4.7（2H、ｑ、２位Ｈ 2）
4.8〜5.1（1H、ｍ、３位Ｈ）
7.66（1H、ｓ、８位Ｈ）
8.80（1H、ｓ、５位Ｈ） [Table] Next, an example of a method for producing the compound of the present invention will be explained using a reaction formula. (In the formula, R is the same as above.) That is, the compound [] is mixed with piperazino in a polar solvent such as dimethyl sulfoxide, sulfolane, dimethyl formamide, dimethyl acetomide, or water at 50 to 200°C, preferably 100 to 180°C. Compound [ ] can be obtained by heating for 1 to 48 hours. Compound [] is easily soluble in acids such as dilute hydrochloric acid and dilute sulfuric acid, or bases such as aqueous sodium hydroxide and potassium carbonate, and easily forms the corresponding salt. Next, examples will be shown. Example 1 9,10-dichloro-3-methyl-7-oxo-
2,3-dihydro-7H-pyrido[1,2,3-
320 mg of de][1,4]benzoxazine-6-carboxylic acid and 1.2 g of anhydrous piperazine are added to 5 ml of dimethyl sulfoxide and stirred at 110-130°C for 24 hours. The solvent is distilled off under reduced pressure, the residue is treated with cold water, and the insoluble matter is filtered off. Add this to 10 ml of 5% hydrochloric acid and stir at room temperature for 20 minutes. Insoluble matters were removed by filtration, and the filtrate was dried under reduced pressure. The residue was recrystallized from water-ethanol-acetone to give 9-chloro-3-methyl-7-oxo-10-piperazino- with a melting point >300°C.
2,3-dihydro-7H-pyrido[1,2,3-
170 mg of hydrochloride of [de][1,4]benzoxazine-6-carboxylic acid are obtained. Elemental analysis value C 17 H 18 ClN 3 O 4・HCl・1/2H 2 O Calculated value C49.89, H4.93, N10.27 Fractional value C49.62, H5.00, N9.82 NMR (D 2 O) δ (ppm) 1.62 (3H, d, 3-position C H 3 group) 3.46, 3.60 (4H, b, d, piperazine ring -C
H 2 C H 2 -) 4.4-4.7 (2H, q, 2nd position H 2 ) 4.8-5.1 (1H, m, 3rd position H) 7.66 (1H, s, 8th position H) 8.80 (1H, s, 5th position H) H)
Claims (1)
示される化合物またはその塩。 ２ ９−クロロ−３−メチル−７−オキソ−10−
ピペラジノ−２，３−ジヒドロ−7H−ピリド
［１，２，３−de］［１，４］ベンゾオキサジン
−６−カルボン酸またはその塩酸塩である特許請
求の範囲第１項記載の化合物。[Claims] 1. General formula (R represents hydrogen or a lower alkyl group) or a salt thereof. 2 9-chloro-3-methyl-7-oxo-10-
The compound according to claim 1, which is piperazino-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid or its hydrochloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7277281A JPS57188592A (en) | 1981-05-14 | 1981-05-14 | Substituted oxazinoquinolinecarboxylic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7277281A JPS57188592A (en) | 1981-05-14 | 1981-05-14 | Substituted oxazinoquinolinecarboxylic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS57188592A JPS57188592A (en) | 1982-11-19 |
| JPH0124153B2 true JPH0124153B2 (en) | 1989-05-10 |
Family
ID=13498995
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7277281A Granted JPS57188592A (en) | 1981-05-14 | 1981-05-14 | Substituted oxazinoquinolinecarboxylic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS57188592A (en) |
-
1981
- 1981-05-14 JP JP7277281A patent/JPS57188592A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57188592A (en) | 1982-11-19 |
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