JP2552101B2 - Novel pyridonecarboxylic acid derivative and method for preparing the same - Google Patents
Novel pyridonecarboxylic acid derivative and method for preparing the sameInfo
- Publication number
- JP2552101B2 JP2552101B2 JP6504362A JP50436293A JP2552101B2 JP 2552101 B2 JP2552101 B2 JP 2552101B2 JP 6504362 A JP6504362 A JP 6504362A JP 50436293 A JP50436293 A JP 50436293A JP 2552101 B2 JP2552101 B2 JP 2552101B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- diazabicyclo
- pyrido
- dihydro
- oxo
- 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 - Fee Related
Links
- 238000000034 method Methods 0.000 title claims description 10
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical class OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 35
- CFLBIADORGSMCX-UHFFFAOYSA-N 2h-1,4-benzoxazine-6-carboxylic acid Chemical compound O1CC=NC2=CC(C(=O)O)=CC=C21 CFLBIADORGSMCX-UHFFFAOYSA-N 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 10
- MVPRTQUJUCFIRT-UHFFFAOYSA-N 2,3,5,6,7,7a-hexahydro-1h-pyrrolo[3,4-b]pyridine Chemical compound C1CNC2CNCC2=C1 MVPRTQUJUCFIRT-UHFFFAOYSA-N 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- DBBCPJBZSLOISJ-UHFFFAOYSA-N 1,2,4,5,6,6a-hexahydropyrrolo[3,4-b]pyrrole Chemical compound C1NCC2=CCNC21 DBBCPJBZSLOISJ-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052717 sulfur Chemical group 0.000 claims description 3
- 239000011593 sulfur Chemical group 0.000 claims description 3
- YKIFUKBIPASDAU-UHFFFAOYSA-N 1-methyl-2,3,5,6,7,7a-hexahydropyrrolo[3,4-b]pyridine Chemical compound CN1CCC=C2CNCC12 YKIFUKBIPASDAU-UHFFFAOYSA-N 0.000 claims description 2
- HPBAWSWKDBBAPJ-UHFFFAOYSA-N 2-methyl-1,2,4,5,6,6a-hexahydropyrrolo[3,4-b]pyrrole Chemical compound C1NCC2=CC(C)NC21 HPBAWSWKDBBAPJ-UHFFFAOYSA-N 0.000 claims description 2
- CZWIKMFONZVOOB-UHFFFAOYSA-N 3-methyl-1,2,4,5,6,6a-hexahydropyrrolo[3,4-b]pyrrole Chemical compound C1NCC2NCC(C)=C21 CZWIKMFONZVOOB-UHFFFAOYSA-N 0.000 claims description 2
- GPCHPDURGNNMJV-UHFFFAOYSA-N 4-methyl-2,3,5,6,7,7a-hexahydro-1h-pyrrolo[3,4-b]pyridine Chemical compound N1CCC(C)=C2CNCC21 GPCHPDURGNNMJV-UHFFFAOYSA-N 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000011541 reaction mixture Substances 0.000 description 21
- 238000002360 preparation method Methods 0.000 description 17
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- -1 hydrochloride 2,8-diazabicyclo [4.3.0] non-5-ene dihydrochloride Chemical compound 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000000725 suspension Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- JPJSPWJOQBDACX-UHFFFAOYSA-N 2h-1,4-benzothiazine-6-carboxylic acid Chemical compound S1CC=NC2=CC(C(=O)O)=CC=C21 JPJSPWJOQBDACX-UHFFFAOYSA-N 0.000 description 3
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229960001699 ofloxacin Drugs 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CKWVLYMQJIWVOB-UHFFFAOYSA-N 4-oxa-1-azatricyclo[7.3.1.05,13]trideca-5,7,9(13),11-tetraene-11-carboxylic acid Chemical compound C1COC2=CC=CC3=C2N1C=C(C(=O)O)C3 CKWVLYMQJIWVOB-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VDAXTGIPFPUSLK-UHFFFAOYSA-N 2,3,5,6,7,7a-hexahydro-1h-pyrrolo[3,4-b]pyridine;dihydrochloride Chemical compound Cl.Cl.C1CNC2CNCC2=C1 VDAXTGIPFPUSLK-UHFFFAOYSA-N 0.000 description 1
- NSWYKPBOPCHODO-UHFFFAOYSA-N 2-methyl-2,3,5,6,7,7a-hexahydro-1h-pyrrolo[3,4-b]pyridine Chemical compound N1C(C)CC=C2CNCC21 NSWYKPBOPCHODO-UHFFFAOYSA-N 0.000 description 1
- AQNOPFHAWMMARU-UHFFFAOYSA-N 2H-1,4-benzoxazine-6-carboxylic acid hydrochloride Chemical compound Cl.O1CC=NC2=C1C=CC(=C2)C(=O)O AQNOPFHAWMMARU-UHFFFAOYSA-N 0.000 description 1
- KOLKOMCXZHUCEY-UHFFFAOYSA-N 3-methyl-2,3,5,6,7,7a-hexahydro-1h-pyrrolo[3,4-b]pyridine Chemical compound CC1CNC2CNCC2=C1 KOLKOMCXZHUCEY-UHFFFAOYSA-N 0.000 description 1
- VGLICMWLSVFAQM-UHFFFAOYSA-N 6,7-difluoro-10-oxo-4-thia-1-azatricyclo[7.3.1.05,13]trideca-5(13),6,8,11-tetraene-11-carboxylic acid Chemical compound C1CSC2=C(F)C(F)=CC3=C2N1C=C(C(=O)O)C3=O VGLICMWLSVFAQM-UHFFFAOYSA-N 0.000 description 1
- NVKWWNNJFKZNJO-UHFFFAOYSA-N 82419-35-0 Chemical compound O1CC(C)N2C=C(C(O)=O)C(=O)C3=C2C1=C(F)C(F)=C3 NVKWWNNJFKZNJO-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 150000007529 inorganic bases Chemical class 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
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KPADFPAILITQBG-UHFFFAOYSA-N non-4-ene Chemical compound CCCCC=CCCC KPADFPAILITQBG-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229940072132 quinolone antibacterials Drugs 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 技術分野 本発明は、広範な抗菌性を有する新規ピリドンカルボ
ン酸誘導体に関する。本発明はまた、前記化合物の調製
方法にも関する。TECHNICAL FIELD The present invention relates to a novel pyridonecarboxylic acid derivative having a wide range of antibacterial properties. The invention also relates to the process for the preparation of said compounds.
背景技術 多くのピリドンカルボン酸タイプの抗菌剤が知られて
いる。それらのうち、オフロキサシンは、他のキノロン
抗菌剤に比較して生物適合性及び効能において卓越した
特徴を有し、そして卓越した抗菌活性を示すことが知ら
れている。しかしながら、オフロキサシンは、それはグ
ラム陰性細菌に対して活性ではあるが、それはグラム陽
性細菌に対して比較的弱い抗菌活性を示す欠点を有す
る。BACKGROUND ART Many pyridonecarboxylic acid type antibacterial agents are known. Among them, ofloxacin is known to have excellent characteristics in biocompatibility and efficacy as compared to other quinolone antibacterial agents, and to exhibit excellent antibacterial activity. However, ofloxacin, although it is active against Gram-negative bacteria, has the disadvantage that it exhibits relatively weak antibacterial activity against Gram-positive bacteria.
発明の開示 本発明の化合物は広範な抗菌活性を有する。DISCLOSURE OF THE INVENTION The compounds of the present invention have a wide range of antibacterial activity.
本発明は、下記式（Ｉ）： 〔式中、R1,R2,R3及びR4は同じであっても又は異なって
も良く、そして独立して、水素又は低級アルキルを表わ
し、 Ｘは酸素又は硫黄を表わし、 Ｙは水素又はメチルを表わし、 ｎは０又は１の整数である〕で表わされる化合物、 その立体異性体及び医薬的に許容できるその塩を提供す
る。The present invention has the following formula (I): [Wherein R 1 , R 2 , R 3 and R 4 may be the same or different and independently represent hydrogen or lower alkyl, X represents oxygen or sulfur, and Y represents hydrogen. Or methyl, and n is an integer of 0 or 1], its stereoisomers and pharmaceutically acceptable salts thereof.
本発明のもう１つの目的は、下記式（I a）及び（I
b）： 〔式中、R1,R2,R3,R4,X及びｎは上記の通りである〕で
表わされる立体特異的化合物又はそのラセミ混合物を供
給することである。Another object of the present invention is to provide the following formulas (I a) and (I
b): [Wherein R 1 , R 2 , R 3 , R 4 , X and n are as described above] or a racemic mixture thereof.
本発明のもう１つの目的は、上記式（Ｉ）の化合物を
調製するための方法を提供することである。Another object of the present invention is to provide a process for preparing the compounds of formula (I) above.
本発明は下記にさらに説明される。 The present invention is further described below.
本発明によれば、式（Ｉ）の化合物は、次の反応図に
例示されているように式（II）の化合物と化合物（II
I）とを反応せしめることによって調製され得る： 上記式において、R1,R2,R3,R4,X,Y及びｎは上記の通
りであり、そしてＺは離脱基、たとえばフルオロ基であ
る。According to the present invention, a compound of formula (I) can be obtained by reacting a compound of formula (II) with a compound of formula (II) as illustrated in the following reaction scheme.
It can be prepared by reacting with I): In the above formula, R 1 , R 2 , R 3 , R 4 , X, Y and n are as described above, and Z is a leaving group such as a fluoro group.
本明細書に使用される用語“低級アルキル”とは、直
鎖又は枝分れ鎖のC1-3アルキル、たとえばメチル、エチ
ル、ｎ−プロピル又はイソプロピルを意味する。The term "lower alkyl" as used herein means a straight or branched chain C 1-3 alkyl, such as methyl, ethyl, n-propyl or isopropyl.
上記で言及したように、式（Ｉ）の化合物は、式（I
I）の化合物と式（III）の化合物との反応により調製さ
れ得る。As mentioned above, the compound of formula (I) has the formula (I)
It can be prepared by reacting a compound of I) with a compound of formula (III).
前記方法は溶媒の存在下で実施され得る。適切な溶媒
は、アセトニトリル、ジメチルホルムアミド、ジメチル
スルホキシド、ピリジン、水、アルコール及びそれらの
混合物を包含する。The method can be carried out in the presence of a solvent. Suitable solvents include acetonitrile, dimethylformamide, dimethylsulfoxide, pyridine, water, alcohols and mixtures thereof.
その方法は、反応の副生成物を結合できる塩基、たと
えば弗化水素ガスの存在下で好ましくは実施される。The process is preferably carried out in the presence of a base capable of binding the by-products of the reaction, such as hydrogen fluoride gas.
この目的のための適切な塩基は、無機塩基、たとえば
炭酸カリウム及び炭酸カルシウム、及び有機塩基、たと
えばトリエチルアミン、ピリジン、1,8−ジアザビシク
ロ〔5.4.0〕ウンデカ−７−エン（DBU）及び1,5−ジア
ザビシクロ〔4.3.0〕ノン−５−エン（DBN）を包含す
る。Suitable bases for this purpose are inorganic bases such as potassium and calcium carbonate, and organic bases such as triethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and 1,2. Includes 5-diazabicyclo [4.3.0] non-5-ene (DBN).
反応は約20℃〜約200℃、好ましくは約60℃〜約130℃
の温度で実施され得る。反応時間は、好ましくは約１時
間〜約24時間である。The reaction is about 20 ° C to about 200 ° C, preferably about 60 ° C to about 130 ° C.
Can be carried out at temperatures of The reaction time is preferably about 1 hour to about 24 hours.
出発材料として本発明で使用される式（II）の化合物
の合成は、Chem.Pharm.Bull.34,4098（1986）に開示さ
れる。The synthesis of compounds of formula (II) used in the present invention as a starting material is disclosed in Chem. Pharm. Bull. 34 , 4098 (1986).
出発材料として本発明で使用される式（III）の化合
物の合成は、本発明者の名称で出願された“新規ジアザ
ビシクロアルケン誘導体及びその調製方法”の標題の朝
鮮特許出願第92−13212号に詳細に開示される。The synthesis of the compound of formula (III) used in the present invention as a starting material is carried out according to Korean Patent Application No. 92-13212 entitled “Novel diazabicycloalkene derivative and its preparation method” filed in the name of the present inventor. Issue is disclosed in detail.
次の例は本発明をさらに説明するものであって、本発
明の範囲を限定するものではない。The following examples further illustrate the invention and are not intended to limit the scope of the invention.
例1:9−フルオロ−３−（Ｓ）−メチル−10−〔（2,8−
ジアザビシクロ〔4.3.0〕ノン−５−エン）−８−イ
ル〕−７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3
−デ〕〔1,4〕−ベンゾキサジン−６−カルボン酸及び
その塩酸塩の調製 2,8−ジアザビシクロ〔4.3.0〕ノン−５−エン二塩酸
塩0.2g及び9,10−ジフルオロ−３−（Ｓ）−メチル−７
−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3−デ〕
〔1,4〕−ベンゾキサジン−６−カルボン酸0.28gを、無
水アセトニトリル5mlに添加し、そして次にDBU0.36mlを
それに攪拌しながら添加した。その反応混合物を、還流
下で５時間加熱した。反応混合物を冷却した後、そのよ
うにして沈殿された固体を濾過し、そして冷アセトニト
リル及び水により連続的に洗浄し、そして減圧下で乾燥
し、標記化合物0.25gを得た。Example 1: 9-Fluoro-3- (S) -methyl-10-[(2,8-
Diazabicyclo [4.3.0] non-5-ene) -8-yl] -7-oxo-2,3-dihydro-7H-pyrido [1,2,3
Preparation of -de] [1,4] -benzoxazine-6-carboxylic acid and its hydrochloride 2,8-diazabicyclo [4.3.0] non-5-ene dihydrochloride 0.2 g and 9,10-difluoro-3- (S) -methyl-7
-Oxo-2,3-dihydro-7H-pyrido [1,2,3-de]
0.28 g of [1,4] -benzoxazine-6-carboxylic acid was added to 5 ml of anhydrous acetonitrile and then 0.36 ml of DBU was added thereto with stirring. The reaction mixture was heated under reflux for 5 hours. After cooling the reaction mixture, the solid thus precipitated was filtered and washed successively with cold acetonitrile and water and dried under reduced pressure to give 0.25 g of the title compound.
分析： 計算値（％） C;62.33 H;5.17 N;10.90 実測値（％） C;62.28 H;5.18 N;11.21 この標記化合物を20％メタノール性塩酸塩10mlに溶解
し、そして約３時間攪拌した後、その反応混合物を減圧
下で乾燥し、標記化合物の塩酸塩0.2gを得た。Analysis: Calculated value (%) C; 62.33 H; 5.17 N; 10.90 Found value (%) C; 62.28 H; 5.18 N; 11.21 This title compound was dissolved in 10 ml of 20% methanolic hydrochloride and stirred for about 3 hours. After that, the reaction mixture was dried under reduced pressure to obtain 0.2 g of the hydrochloride of the title compound.
例2:9−フルオロ−３−（Ｓ）−メチル−10−〔（２−
メチル−2,8−ジアザビシクロ〔4.3.0〕ノン−５−エ
ン）−８−イル〕−７−オキソ−2,3−ジヒドロ−7H−
ピリド〔1,2,3−デ〕〔1,4〕−ベンゾキサジン−６−カ
ルボン酸の調製 無水アセトニトリル5ml中、２−メチル−2,8−ジアザ
ビシクロ〔4.3.0〕ノン−５−エン二塩酸塩0.2g及び9,1
0−ジフルオロ−３−（Ｓ）−メチル−７−オキソ−2,3
−ジヒドロ−7H−ピリド〔1,2,3−デ〕〔1,4〕−ベンゾ
キサジン−６−カルボン酸0.30gの懸濁液に、攪拌しな
がらDBN0.32mlを添加した。その反応混合物を還流下で
５時間加熱した。反応混合物を冷却した後、そのように
して沈殿された固体を濾過し、そして冷アセトニトリ
ル、水及びメタノールにより連続的に洗浄し、そして真
空下で乾燥し、標記化合物0.27gを得た。Example 2: 9-Fluoro-3- (S) -methyl-10-[(2-
Methyl-2,8-diazabicyclo [4.3.0] non-5-ene) -8-yl] -7-oxo-2,3-dihydro-7H-
Preparation of pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid 2-methyl-2,8-diazabicyclo [4.3.0] non-5-ene dihydrochloride in 5 ml anhydrous acetonitrile 0.2g salt and 9,1
0-difluoro-3- (S) -methyl-7-oxo-2,3
To a suspension of 0.30 g of -dihydro-7H-pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid was added 0.32 ml of DBN with stirring. The reaction mixture was heated under reflux for 5 hours. After cooling the reaction mixture, the solid thus precipitated is filtered and washed successively with cold acetonitrile, water and methanol and dried under vacuum, yielding 0.27 g of the title compound.
分析： 計算値（％） C;63.15 H;5.55 N;10.52 実測値（％） C;63.21 H;5.58 N;10.49 例3:9−フルオロ−３−（Ｓ）−メチル−10−〔（５−
メチル−2,8−ジアザビシクロ〔4.3.0〕ノン−５−エ
ン）−８−イル〕−７−オキソ−2,3−ジヒドロ−7H−
ピリド〔1,2,3−デ〕〔1,4〕−ベンゾキサジン−６−カ
ルボン酸の調製 無水アセトニトリル5ml中、５−メチル−2,8−ジアザ
ビシクロ〔4.3.0〕ノン−５−エン二塩酸塩0.2g及び9,1
0−ジフルオロ−３−（Ｓ）−メチル−７−オキソ−2,3
−ジヒドロ−7H−ピリド〔1,2,3−デ〕〔1,4〕−ベンゾ
キサジン−６−カルボン酸0.29gの懸濁液に、攪拌しな
がらDBU0.32mlを添加した。その反応混合物を還流下で
５時間加熱した。反応混合物を室温に冷却した後、その
ようにして沈殿された固体を濾過し、そして冷アセトニ
トリル、水及びメタノールにより連続的に洗浄し、そし
て真空下で乾燥し、標記化合物0.3gを得た。Analysis: Calculated value (%) C; 63.15 H; 5.55 N; 10.52 Measured value (%) C; 63.21 H; 5.58 N; 10.49 Example 3: 9-Fluoro-3- (S) -methyl-10-[(5 −
Methyl-2,8-diazabicyclo [4.3.0] non-5-ene) -8-yl] -7-oxo-2,3-dihydro-7H-
Preparation of pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid 5-methyl-2,8-diazabicyclo [4.3.0] non-5-ene dihydrochloride in 5 ml anhydrous acetonitrile 0.2g salt and 9,1
0-difluoro-3- (S) -methyl-7-oxo-2,3
0.32 ml of DBU was added to a suspension of 0.29 g of dihydro-7H-pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid with stirring. The reaction mixture was heated under reflux for 5 hours. After cooling the reaction mixture to room temperature, the solid thus precipitated was filtered and washed successively with cold acetonitrile, water and methanol and dried under vacuum to give 0.3 g of the title compound.
分析： 計算値（％） C;63.15 H;5.55 N;10.52 実測値（％） C;63.19 H;5.51 N;10.46 例4:9−フルオロ−３−（Ｓ）−メチル−10−〔（３−
メチル−2,8−ジアザビシクロ〔4.3.0〕ノン−５−エ
ン）−８−イル〕−７−オキソ−2,3−ジヒドロ−7H−
ピリド〔1,2,3−デ〕〔1,4〕−ベンゾキサジン−６−カ
ルボン酸の調製 無水アセトニトリル5ml中、３−メチル−2,8−ジアザ
ビシクロ〔4.3.0〕ノン−５−エン二塩酸塩0.2g及び9,1
0−ジフルオロ−３−（Ｓ）−メチル−７−オキソ−2,3
−ジヒドロ−7H−ピリド〔1,2,3−デ〕〔1,4〕−ベンゾ
キサジン−６−カルボン酸0.30gの懸濁液に、攪拌しな
がらDBN0.32mlを添加した。その反応混合物を還流下で
５時間加熱した。反応混合物を冷却した後、そのように
して沈殿された固体を濾過し、そして冷アセトニトリ
ル、水及びメタノールにより連続的に洗浄し、そして真
空下で乾燥し、標記化合物0.27gを得た。Analysis: Calculated value (%) C; 63.15 H; 5.55 N; 10.52 Actual value (%) C; 63.19 H; 5.51 N; 10.46 Example 4: 9-Fluoro-3- (S) -methyl-10-[(3 −
Methyl-2,8-diazabicyclo [4.3.0] non-5-ene) -8-yl] -7-oxo-2,3-dihydro-7H-
Preparation of pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid 3-methyl-2,8-diazabicyclo [4.3.0] non-5-ene dihydrochloride in 5 ml anhydrous acetonitrile 0.2g salt and 9,1
0-difluoro-3- (S) -methyl-7-oxo-2,3
To a suspension of 0.30 g of -dihydro-7H-pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid was added 0.32 ml of DBN with stirring. The reaction mixture was heated under reflux for 5 hours. After cooling the reaction mixture, the solid thus precipitated is filtered and washed successively with cold acetonitrile, water and methanol and dried under vacuum, yielding 0.27 g of the title compound.
分析： 計算値（％） C;63.15 H;5.55 N;10.52 実測値（％） C;63.19 H;5.50 N;10.49 例5:9−フルオロ−３−（Ｓ）−メチル−10−〔（４−
メチル−2,8−ジアザビシクロ〔4.3.0〕ノン−５−エ
ン）−８−イル〕−７−オキソ−2,3−ジヒドロ−7H−
ピリド〔1,2,3−デ〕〔1,4〕−ベンゾキサジン−６−カ
ルボン酸の調製 無水アセトニトリル5ml中、４−メチル−2,8−ジアザ
ビシクロ〔4.3.0〕ノン−５−エン二塩酸塩0.2g及び9,1
0−ジフルオロ−３−（Ｓ）−メチル−７−オキソ−2,3
−ジヒドロ−7H−ピリド〔1,2,3−デ〕〔1,4〕−ベンゾ
キサジン−６−カルボン酸0.29gの懸濁液に、攪拌しな
がらDBN0.32mlを添加した。その反応混合物を還流下で
５時間加熱した。反応混合物を室温に冷却した後、その
ようにして沈殿された固体を濾過し、そして冷アセトニ
トリル、水及びメタノールにより連続的に洗浄し、そし
て真空下で乾燥し、標記化合物0.35gを得た。Analysis: Calculated value (%) C; 63.15 H; 5.55 N; 10.52 Measured value (%) C; 63.19 H; 5.50 N; 10.49 Example 5: 9-Fluoro-3- (S) -methyl-10-[(4 −
Methyl-2,8-diazabicyclo [4.3.0] non-5-ene) -8-yl] -7-oxo-2,3-dihydro-7H-
Preparation of pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid 4-methyl-2,8-diazabicyclo [4.3.0] non-5-ene dihydrochloride in 5 ml anhydrous acetonitrile 0.2g salt and 9,1
0-difluoro-3- (S) -methyl-7-oxo-2,3
To a suspension of 0.29 g of dihydro-7H-pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid was added 0.32 ml of DBN with stirring. The reaction mixture was heated under reflux for 5 hours. After cooling the reaction mixture to room temperature, the solid thus precipitated is filtered and washed successively with cold acetonitrile, water and methanol and dried under vacuum, yielding 0.35 g of the title compound.
分析： 計算値（％） C;63.15 H;5.55 N;10.52 実測値（％） C;63.10 H;5.55 N;10.48 例6:9−フルオロ−３−（Ｓ）−メチル−10−〔（2,7−
ジアザビシクロ〔3.3.0〕オクト−４−エン）−７−イ
ル〕−７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3
−デ〕〔1,4〕−ベンゾキサジン−６−カルボン酸の調
製 無水アセトニトリル5ml中、2,7−ジアザビシクロ〔3.
3.0〕オクト−４−エン二塩酸塩0.2g及び9,10−ジフル
オロ−３−（Ｓ）−メチル−７−オキソ−2,3−ジヒド
ロ−7H−ピリド〔1,2,3−デ〕〔1,4〕−ベンゾキサジン
−６−カルボン酸0.26gの懸濁液に、攪拌しながらDBN0.
32mlを添加した。その反応混合物を還流下で10時間加熱
した。反応混合物を冷却した後、そのようにして沈殿さ
れた固体を濾過し、そして冷アセトニトリル、水及びメ
タノールにより連続的に洗浄し、そして再び水及びメタ
ノールの混合物により洗浄し、そして減圧下で乾燥し、
標記化合物0.32gを得た。Analysis: Calculated value (%) C; 63.15 H; 5.55 N; 10.52 Measured value (%) C; 63.10 H; 5.55 N; 10.48 Example 6: 9-Fluoro-3- (S) -methyl-10-[(2 , 7−
Diazabicyclo [3.3.0] oct-4-en) -7-yl] -7-oxo-2,3-dihydro-7H-pyrido [1,2,3
Preparation of -de] [1,4] -benzoxazine-6-carboxylic acid 2,7-diazabicyclo [3.
3.0] Oct-4-ene dihydrochloride 0.2 g and 9,10-difluoro-3- (S) -methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [ To a suspension of 0.26 g of 1,4] -benzoxazine-6-carboxylic acid was added DBN0.
32 ml was added. The reaction mixture was heated under reflux for 10 hours. After cooling the reaction mixture, the solid thus precipitated is filtered and washed successively with cold acetonitrile, water and methanol and again with a mixture of water and methanol and dried under reduced pressure. ,
0.32 g of the title compound was obtained.
分析： 計算値（％） C;61.45 H;4.89 N;11.31 実測値（％） C;61.51 H;4.83 N;11.27 例7:9−フルオロ−３−（Ｓ）−メチル−10−〔（４−
メチル−2,7−ジアザビシクロ〔3.3.0〕オクタ−４−エ
ン）−７−イル〕−７−オキソ−2,3−ジヒドロ−7H−
ピリド〔1,2,3−デ〕〔1,4〕−ベンゾキサジン−６−カ
ルボン酸の調製 無水アセトニトリル5ml中、４−メチル−2,7−ジアザ
ビシクロ〔3.3.0〕オクタ−４−エン二塩酸塩0.2g及び
9,10−ジフルオロ−３−（Ｓ）−メチル−７−オキソ−
2,3−ジヒドロ−7H−ピリド〔1,2,3−デ〕〔1,4〕−ベ
ンゾキサジン−６−カルボン酸0.25gの懸濁液に、攪拌
しながらDBU0.32mlを添加した。その反応混合物を還流
下で７時間加熱した。反応混合物を室温に冷却した後、
そのようにして沈殿された固体を濾過し、そして冷アセ
トニトリル、水及びメタノールにより連続的に洗浄し、
そして減圧下で乾燥し、標記化合物0.33gを得た。Analysis: Calculated value (%) C; 61.45 H; 4.89 N; 11.31 Found value (%) C; 61.51 H; 4.83 N; 11.27 Example 7: 9-Fluoro-3- (S) -methyl-10-[(4 −
Methyl-2,7-diazabicyclo [3.3.0] oct-4-ene) -7-yl] -7-oxo-2,3-dihydro-7H-
Preparation of pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid 4-methyl-2,7-diazabicyclo [3.3.0] oct-4-ene dihydrochloride in 5 ml anhydrous acetonitrile 0.2g salt and
9,10-Difluoro-3- (S) -methyl-7-oxo-
To a suspension of 0.25 g of 2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid, 0.32 ml of DBU was added with stirring. The reaction mixture was heated under reflux for 7 hours. After cooling the reaction mixture to room temperature,
The solid thus precipitated is filtered and washed successively with cold acetonitrile, water and methanol,
Then, it was dried under reduced pressure to obtain 0.33 g of the title compound.
分析： 計算値（％） C;62.33 H;5.17 N;10.90 実測値（％） C;62.30 H;5.13 N;10.81 例8:9−フルオロ−３−（Ｓ）−メチル−10−〔（３−
メチル−2,7−ジアザビシクロ〔3.3.0〕オクタ−４−エ
ン）−７−イル〕−７−オキソ−2,3−ジヒドロ−7H−
ピリド〔1,2,3−デ〕〔1,4〕−ベンゾキサジン−６−カ
ルボン酸の調製 無水アセトニトリル5ml中、３−メチル−2,7−ジアザ
ビシクロ〔3.3.0〕オクタ−４−エン二塩酸塩0.2g及び
9,10−ジフルオロ−３−（Ｓ）−メチル−７−オキソ−
2,3−ジヒドロ−7H−ピリド〔1,2,3−デ〕〔1,4〕−ベ
ンゾキサジン−６−カルボン酸0.26gの懸濁液に、攪拌
しながらDBU0.32mlを添加した。その反応混合物を還流
下で10時間加熱した。反応混合物を室温に冷却した後、
そのようにして沈殿された固体を濾過し、そして冷アセ
トニトリル、水及びメタノールにより連続的に洗浄し、
そして減圧下で乾燥し、標記化合物0.35gを得た。Analysis: Calculated value (%) C; 62.33 H; 5.17 N; 10.90 Measured value (%) C; 62.30 H; 5.13 N; 10.81 Example 8: 9-Fluoro-3- (S) -methyl-10-[(3 −
Methyl-2,7-diazabicyclo [3.3.0] oct-4-ene) -7-yl] -7-oxo-2,3-dihydro-7H-
Preparation of pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid 3-methyl-2,7-diazabicyclo [3.3.0] oct-4-ene dihydrochloride in 5 ml anhydrous acetonitrile 0.2g salt and
9,10-Difluoro-3- (S) -methyl-7-oxo-
To a suspension of 0.26 g of 2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid was added 0.32 ml of DBU with stirring. The reaction mixture was heated under reflux for 10 hours. After cooling the reaction mixture to room temperature,
The solid thus precipitated is filtered and washed successively with cold acetonitrile, water and methanol,
Then, it was dried under reduced pressure to obtain 0.35 g of the title compound.
分析： 計算値（％） C;62.33 H;5.17 N;10.90 実測値（％） C;62.30 H;5.11 N;11.20 例9:9−フルオロ−10−〔（2,8−ジアザビシクロ〔4.3.
0〕ノン−５−エン）−８−イル〕−７−オキソ−2,3−
ジヒドロ−7H−ピリド〔1,2,3−デ〕〔1,4〕−ベンゾチ
アジン−６−カルボン酸の調製 無水アセトニトリル5ml中、2,8−ジアザビシクロ〔4.
3.0〕ノン−５−エン二塩酸塩0.2g及び9,10−ジフルオ
ロ−７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3−
デ〕〔1,4〕−ベンゾチアジン−６−カルボン酸0.35gの
懸濁液に、攪拌しながらDBU0.32mlを添加した。その反
応混合物を還流下で５時間加熱した。反応混合物を室温
に冷却した後、そのようにして沈殿された固体を濾過
し、そして冷アセトニトリル、水及びメタノールにより
連続的に洗浄し、そして減圧下で乾燥し、標記化合物0.
36gを得た。Analysis: Calculated value (%) C; 62.33 H; 5.17 N; 10.90 Measured value (%) C; 62.30 H; 5.11 N; 11.20 Example 9: 9-Fluoro-10-[(2,8-diazabicyclo [4.3.
0] Non-5-ene) -8-yl] -7-oxo-2,3-
Preparation of dihydro-7H-pyrido [1,2,3-de] [1,4] -benzothiazine-6-carboxylic acid 2,8-diazabicyclo [4.
3.0] Non-5-ene dihydrochloride 0.2 g and 9,10-difluoro-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-
To a suspension of 0.35 g of de] [1,4] -benzothiazine-6-carboxylic acid was added 0.32 ml of DBU with stirring. The reaction mixture was heated under reflux for 5 hours. After cooling the reaction mixture to room temperature, the solid thus precipitated is filtered and washed successively with cold acetonitrile, water and methanol and dried under reduced pressure, the title compound.
36 g were obtained.
分析： 計算値（％） C;58.90 H;4.68 N;10.85 実測値（％） C;58.81 H;4.59 N;10.27 例10:9−フルオロ−10−〔（2,7−ジアザビシクロ〔3.
3.0〕−タ−４−エン）−７−イル〕−７−オキソ−2,3
−ジヒドロ−７−Ｈ−ピリド〔1,2,3−デ〕〔1,4〕−ベ
ンゾチアジン−６−カルボン酸の調製 無水アセトニトリル5ml中、2,7−ジアザビシクロ〔3.
3.0〕オクタ−４−エン二塩酸塩0.2g及び9,10−ジフル
オロ−７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3
−デ〕〔1,4〕−ベンゾチアジン−６−カルボン酸0.35g
の懸濁液に、攪拌しながらDBU0.30mlを添加した。その
反応混合物を還流下で５時間加熱した。反応混合物を室
温に冷却した後、そのようにして沈殿された固体を濾過
し、そして冷アセトニトリル、水及びメタノールにより
連続的に洗浄し、そして減圧下で乾燥し、標記化合物0.
35gを得た。Analysis: Calculated value (%) C; 58.90 H; 4.68 N; 10.85 Actual value (%) C; 58.81 H; 4.59 N; 10.27 Example 10: 9-Fluoro-10-[(2,7-diazabicyclo [3.
3.0] -Ta-4-ene) -7-yl] -7-oxo-2,3
-Preparation of dihydro-7-H-pyrido [1,2,3-de] [1,4] -benzothiazine-6-carboxylic acid In 2,5 ml of anhydrous acetonitrile 2,7-diazabicyclo [3.
3.0] Oct-4-ene dihydrochloride 0.2 g and 9,10-difluoro-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-De] [1,4] -benzothiazine-6-carboxylic acid 0.35 g
0.30 ml of DBU was added to the above suspension with stirring. The reaction mixture was heated under reflux for 5 hours. After cooling the reaction mixture to room temperature, the solid thus precipitated is filtered and washed successively with cold acetonitrile, water and methanol and dried under reduced pressure, the title compound.
Obtained 35 g.
分析： 計算値（％） C;66.44 H;4.96 N;12.91 実測値（％） C;66,51 H;5.02 N;12.88 例11:9−フルオロ−３−（R,S）−メチル−10−〔（2,8
−ジアザビシクロ〔4.3.0〕ノン−５−エン）−８−イ
ル〕−７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3
−デ〕〔1,4〕−ベンゾキサジン−６−カルボン酸の調
製 2,8−ジアザビシクロ〔4.3.0〕ノン−５−エン二塩酸
塩0.2g及び9,10−ジフルオロ−３−（R,S）−メチル−
７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3−デ〕
〔1,4〕−ベンゾキサジン−６−カルボン酸0.28gを、例
１に記載される方法に類似する方法により処理し、標記
化合物0.27gを得た。Analysis: Calculated value (%) C; 66.44 H; 4.96 N; 12.91 Found value (%) C; 66,51 H; 5.02 N; 12.88 Example 11: 9-Fluoro-3- (R, S) -methyl-10 − [(2,8
-Diazabicyclo [4.3.0] non-5-ene) -8-yl] -7-oxo-2,3-dihydro-7H-pyrido [1,2,3
Preparation of -de] [1,4] -benzoxazine-6-carboxylic acid 2,8-diazabicyclo [4.3.0] non-5-ene dihydrochloride 0.2 g and 9,10-difluoro-3- (R, S ) -Methyl-
7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]
0.28 g of [1,4] -benzoxazine-6-carboxylic acid was treated by a method similar to that described in Example 1 to give 0.27 g of the title compound.
分析： 計算値（％） C;62.33 H;5.17 N;10.90 実測値（％） C;62.28 H;5.19 N;10.11 例12:9−フルオロ−３−（R,S）−メチル−10−〔（2,7
−ジアザビシクロ〔3.3.0〕オクタ−４−エン）−７−
イル〕−７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,
2,3−デ〕〔1,4〕−ベンゾキサジン−６−カルボン酸の
調製 2,7−ジアザビシクロ〔3,3,0〕オクタ−４−エン二塩
酸塩0.2g及び9,10−ジフルオロ−３−（R,S）−メチル
−７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3−
デ〕〔1,4〕−ベンゾキサジン−６−カルボン酸0.26g
を、例６に記載される方法に類似する方法により処理
し、標記化合物0.24gを得た。Analysis: Calculated value (%) C; 62.33 H; 5.17 N; 10.90 Measured value (%) C; 62.28 H; 5.19 N; 10.11 Example 12: 9-Fluoro-3- (R, S) -methyl-10- [ (2,7
-Diazabicyclo [3.3.0] oct-4-ene) -7-
Yl] -7-oxo-2,3-dihydro-7H-pyrido [1,
Preparation of 2,3-de] [1,4] -benzoxazine-6-carboxylic acid 2,7-diazabicyclo [3,3,0] oct-4-ene dihydrochloride 0.2 g and 9,10-difluoro-3 -(R, S) -Methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-
De] [1,4] -benzoxazine-6-carboxylic acid 0.26 g
Was treated by a method similar to that described in Example 6 to give 0.24 g of the title compound.
分析： 計算値（％） C;61.45 H;4.89 N;11.31 実測値（％） C;61.36 H;4.79 N;11.24 例13:9−フルオロ−３−（Ｒ）−メチル−10−〔（2,8
−ジアザビシクロ〔4.3.0〕ノン−５−エン）−８−イ
ル〕−７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3
−デ〕〔1,4〕−ベンゾキサジン−６−カルボン酸の調
製 2,8−ジアザビシクロ〔4.3.0〕ノン−５−エン二塩酸
塩0.2g及び9,10−ジフルオロ−３−（Ｒ）−メチル−７
−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3−デ〕
〔1,4〕−ベンゾキサジン−６−カルボン酸0.28gを、例
１に記載される方法に類似する方法により処理し、標記
化合物0.26gを得た。Analysis: Calculated value (%) C; 61.45 H; 4.89 N; 11.31 Found value (%) C; 61.36 H; 4.79 N; 11.24 Example 13: 9-Fluoro-3- (R) -methyl-10-[(2 , 8
-Diazabicyclo [4.3.0] non-5-ene) -8-yl] -7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-De] [1,4] -Benzoxazine-6-carboxylic acid preparation 2,8-diazabicyclo [4.3.0] non-5-ene dihydrochloride 0.2 g and 9,10-difluoro-3- (R)- Methyl-7
-Oxo-2,3-dihydro-7H-pyrido [1,2,3-de]
0.28 g of [1,4] -benzoxazine-6-carboxylic acid was treated by a method similar to that described in Example 1 to give 0.26 g of the title compound.
分析： 計算値（％） C;62.33 H;5.17 N;10.90 実測値（％） C;62.45 H;5.19 N;10.97 例14:9−フルオロ−３−（Ｓ）−メチル−10−〔（2,8
−ジアザビシクロ〔4.3.0〕ノン−５−エン）−８−イ
ル〕−７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3
−デ〕〔1,4〕−ベンゾキサジン−６−カルボン酸の塩
酸塩の調製 例１で得られた９−フルオロ−３−（Ｓ）−メチル−
10−〔（2,8−ジアザビシクロ〔4.3.0〕ノン−５−エ
ン）−８−イル〕−７−オキソ−2,3−ジヒドロ−7H−
ピリド〔1,2,3−デ〕〔1,4〕−ベンゾキサジン−６−カ
ルボン酸0.30gを、3NのHCl−メタノール溶液に０℃で添
加し、そしてその混合物を２時間攪拌した。溶媒を減圧
下で除去し、そして残留物をメタノール−エチルエーテ
ル（1:4）により洗浄し、そして濾過し、淡黄色の標記
化合物1.29gを生成した。1 H−NMR（DMSO−d6,δ）:1.55（3H,d）,1.85（1H,m）,
2.20（2H,m）,3.05（1H,m）,3.56（1H,m）,4.00（3H,
m）,4.38（2H,m）,4.65（1H,m）,5.90（1H,s（broa
d））,7.60（1H,d）,8.30（1H,s）,8.25（NH3+,s） 例15:9−フルオロ−３−（Ｓ）−メチル−10−〔（2,7
−ジアザビシクロ〔3.3.0〕オクタ−４−エン）−７−
イル〕−７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,
2,3−デ〕〔1,4〕−ベンゾキサジン−６−カルボン酸の
塩酸塩の調製 例６で得られた９−フルオロ−３−（Ｓ）−メチル−
10−〔（2,7−ジアザビシクロ〔3.3.0〕オクタ−４−エ
ン）−７−イル〕−７−オキソ−2,3−ジヒドロ−7H−
ピリド〔1,2,3−デ〕〔1,4〕−ベンゾキサジン−６−カ
ルボン酸0.25gを、酒石酸0.15gを含む、クロロホルム−
メタノール（10:1）10mlに添加し、そしてその混合物を
10時間室温で攪拌した。溶媒を減圧下で除去し、そして
残留物をアセトニトリル5mlにより処理し、そして攪拌
し、そして濾過し、白色の標記化合物0.16gを生成し
た。1 H−NMR（DMSO−d6,δ）:1.55（3H,d）,2.25（2H,m）,
3.05（1H,m）,3.65（1H,m）,4.00（3H,m）,4.10（2H,
m）,4.38（2H,m）,4.62（1H,m）,5.90（1H,s）,7.60（1
H,d）,8.16（NH3,s）,8.30（1H,s）． 本発明のキノロン誘導体の抗菌活性を、Muller−Hint
on寒天培地を用いることによって、寒天培地二倍希釈方
法（Hoechst345）に従って評価した。Hoechst標準菌株
を試験菌株として使用した。107CFU/mlを有する菌株を
培養培地上に接種し、そして菌株の増殖を、37℃で18時
間それらをインキュベートした後に観察し、ここでシプ
ロフロキサシン及びオフロキサシンを対照材料として使
用した。それらの試験結果は下記第１及び２表に示され
る。Analysis: Calculated value (%) C; 62.33 H; 5.17 N; 10.90 Measured value (%) C; 62.45 H; 5.19 N; 10.97 Example 14: 9-Fluoro-3- (S) -methyl-10-[(2 , 8
-Diazabicyclo [4.3.0] non-5-ene) -8-yl] -7-oxo-2,3-dihydro-7H-pyrido [1,2,3
Preparation of Hydrochloride of De- [1,4] -benzoxazine-6-carboxylic acid 9-Fluoro-3- (S) -methyl-obtained in Example 1
10-[(2,8-diazabicyclo [4.3.0] non-5-ene) -8-yl] -7-oxo-2,3-dihydro-7H-
0.30 g of pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid was added to a 3N HCl-methanol solution at 0 ° C. and the mixture was stirred for 2 hours. The solvent was removed under reduced pressure and the residue was washed with methanol-ethyl ether (1: 4) and filtered to yield 1.29 g of the pale yellow title compound. 1 H-NMR (DMSO-d 6 , δ): 1.55 (3H, d), 1.85 (1H, m),
2.20 (2H, m), 3.05 (1H, m), 3.56 (1H, m), 4.00 (3H,
m), 4.38 (2H, m), 4.65 (1H, m), 5.90 (1H, s (broa
d)), 7.60 (1H, d), 8.30 (1H, s), 8.25 (NH3 + , s) Example 15: 9-Fluoro-3- (S) -methyl-10-[(2,7
-Diazabicyclo [3.3.0] oct-4-ene) -7-
Yl] -7-oxo-2,3-dihydro-7H-pyrido [1,
Preparation of 2,3-de] [1,4] -benzoxazine-6-carboxylic acid hydrochloride 9-Fluoro-3- (S) -methyl-obtained in Example 6
10-[(2,7-diazabicyclo [3.3.0] oct-4-ene) -7-yl] -7-oxo-2,3-dihydro-7H-
Chloroform containing pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid 0.25g and tartaric acid 0.15g.
Add 10 ml of methanol (10: 1), and mix the mixture.
Stir for 10 hours at room temperature. The solvent was removed under reduced pressure and the residue was treated with 5 ml of acetonitrile and stirred and filtered to yield 0.16 g of the white title compound. 1 H-NMR (DMSO-d 6 , δ): 1.55 (3H, d), 2.25 (2H, m),
3.05 (1H, m), 3.65 (1H, m), 4.00 (3H, m), 4.10 (2H,
m), 4.38 (2H, m), 4.62 (1H, m), 5.90 (1H, s), 7.60 (1
H, d), 8.16 (NH 3, s), 8.30 (1H, s). The antibacterial activity of the quinolone derivative of the present invention was confirmed by Muller-Hint
Evaluation was performed according to the double agar dilution method (Hoechst345) by using on agar medium. Hoechst standard strain was used as test strain. Strains with 10 7 CFU / ml were inoculated onto the culture medium and growth of the strains was observed after they had been incubated for 18 hours at 37 ° C, where ciprofloxacin and ofloxacin were used as control materials. The test results are shown in Tables 1 and 2 below.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 キム，モーン フワン 大韓民国，ダエジョン 305―333，ユー ソン―ク，アイェウン―ドン，99，ハン ビット アパート 138―1203 ─────────────────────────────────────────────────── ───Continued from the front page (72) Inventor Kim, Morn Hwang, Republic of Korea, Daejeong 305-333, Yousung-ku, Ayeung-Don, 99, Hanbit Apartment 138-1203
Claims (5)
も良く、そして独立して、水素又は低級アルキルを表わ
し、 Ｘは酸素又は硫黄を表わし、 Ｙは水素又はメチルを表わし、そして ｎは０又は１の整数である〕で表わされる化合物、 その立体異性体及び医薬的に許容できるその塩。1. The following formula (I): [Wherein R 1 , R 2 , R 3 and R 4 may be the same or different and independently represent hydrogen or lower alkyl, X represents oxygen or sulfur, and Y represents hydrogen. Or methyl and n is an integer of 0 or 1], its stereoisomers and pharmaceutically acceptable salts thereof.
表わされる３−（Ｒ）−メチルピリドンカルボン酸誘導
体及びそれらの医薬的に許容できる塩である請求の範囲
第１項記載の化合物。2. The following formula (I a): [Wherein R 1 , R 2 , R 3 , R 4 , X and n are as described above] represented by the formula 3- (R) -methylpyridonecarboxylic acid derivatives and pharmaceutically acceptable salts thereof. A compound according to claim 1.
表わされる３−（Ｓ）−メチルピリドンカルボン酸誘導
体である請求の範囲第１項記載の化合物。3. The following formula (II b): The 3- (S) -methylpyridonecarboxylic acid derivative represented by the formula: wherein R 1 , R 2 , R 3 , R 4 , X and n are as described above. Compound.
アザビシクロ〔4.3.0〕ノン−５−エン）−８−イル〕
−７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3−
デ〕〔1,4〕−ベンゾキサジン−６−カルボン酸、 ９−フルオロ−３−（Ｓ）−メチル−10−〔（２−メチ
ル−2,8−ジアザビシクロ〔4.3.0〕ノン−５−エン）−
８−イル〕−７−オキソ−2,3−ジヒドロ−7H−ピリド
〔1,2,3−デ〕〔1,4〕−ベンゾキサジン−６−カルボン
酸、 ９−フルオロ−３−（Ｓ）−10−〔（５−メチル−2,8
−ジアザビシクロ〔4.3.0〕ノン−５−エン）−８−イ
ル〕−７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3
−デ〕〔1,4〕−ベンゾキサジン−６−カルボン酸、 ９−フルオロ−３−（Ｓ）−メチル−10−〔（３−メチ
ル−2,8−ジアザビシクロ〔4.3.0〕ノン−５−エン）−
８−イル〕−７−オキソ−2,3−ジヒドロ−7H−ピリド
〔1,2,3−デ〕〔1,4〕−ベンゾキサジン−６−カルボン
酸、 ９−フルオロ−３−（Ｓ）−メチル−10−〔（４−メチ
ル−2,8−ジアザビシクロ〔4.3.0〕ノン−５−エン）−
８−イル〕−７−オキソ−2,3−ジヒドロ−7H−ピリド
〔1,2,3−デ〕〔1,4〕−ベンゾキサジン−６−カルボン
酸、 ９−フルオロ−３−（Ｓ）−メチル−10−〔（2,7−ジ
アザビシクロ〔3.3.0〕オクタ−４−エン）−７−イ
ル〕−７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3
−デ〕〔1,4〕−ベンゾキサジン−６−カルボン酸、 ９−フルオロ−３−（Ｓ）−メチル−10−〔（４−メチ
ル−2,7−ジアザビシクロ〔3.3.0〕オクタ−４−エン）
−７−イル〕−７−オキソ−2,3−ジヒドロ−7H−ピリ
ド〔1,2,3−デ〕〔1,4〕−ベンゾキサジン−６−カルボ
ン酸、 ９−フルオロ−３−（Ｓ）−メチル−10−〔（３−メチ
ル−2,7−ジアザビシクロ〔3.3.0〕オクタ−４−エン）
−７−イル〕−７−オキソ−2,3−ジヒドロ−7H−ピリ
ド〔1,2,3−デ〕〔1,4〕−ベンゾキサジン−６−カルボ
ン酸、 ９−フルオロ−10−〔（2,8−ジアザビシクロ〔4.3.0〕
ノン−５−エン）−８−イル〕−７−オキソ−2,3−ジ
ヒドロ−7H−ピリド〔1,2,3−デ〕〔1,4〕−ベンゾチア
ジン−６−カルボン酸、 ９−フルオロ−10−〔（2,7−ジアザビシクロ〔3.3.0〕
オクタ−４−エン）−７−イル〕−７−オキソ−2,3−
ジヒドロ−7H−ピリド〔1,2,3−デ〕〔1,4〕−ベンゾチ
アジン−６−カルボン酸、 ９−フルオロ−３−（R,S）−メチル−10−〔（2,8−ジ
アザビシクロ〔4.3.0〕ノン−５−エン）−８−イル〕
−７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3−
デ〕〔1,4〕−ビンゾキサジン−６−カルボン酸、 ９−フルオロ−３−（R,S）−メチル−10−〔（2,7−ジ
アザビシクロ〔3.3.0〕オクタ−４−エン）−７−イ
ル〕−７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3
−デ〕〔1,4〕−ベンゾキサジン−６−カルボン酸、 ９−フルオロ−３−（Ｒ）−メチル−10−〔（2,8−ジ
アザビシクロ〔4.3.0〕ノン−５−エン）−８−イル〕
−７−オキソ−2,3−ジヒドロ−7H−ピリド〔1,2,3−
デ〕〔1,4〕−ベンゾキサジン−６−カルボン酸 の１種である請求の範囲第１項記載の化合物。4. The compound of formula (I) is the following compound: 9-fluoro-3- (S) -methyl-10-[(2,8-diazabicyclo [4.3.0] non-5-ene)- 8-yl]
-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-
De] [1,4] -benzoxazine-6-carboxylic acid, 9-fluoro-3- (S) -methyl-10-[(2-methyl-2,8-diazabicyclo [4.3.0] non-5-ene ) −
8-yl] -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid, 9-fluoro-3- (S)- 10-[(5-methyl-2,8
-Diazabicyclo [4.3.0] non-5-ene) -8-yl] -7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-De] [1,4] -benzoxazine-6-carboxylic acid, 9-fluoro-3- (S) -methyl-10-[(3-methyl-2,8-diazabicyclo [4.3.0] non-5- EN)-
8-yl] -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid, 9-fluoro-3- (S)- Methyl-10-[(4-methyl-2,8-diazabicyclo [4.3.0] non-5-ene)-
8-yl] -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid, 9-fluoro-3- (S)- Methyl-10-[(2,7-diazabicyclo [3.3.0] oct-4-ene) -7-yl] -7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-De] [1,4] -benzoxazine-6-carboxylic acid, 9-fluoro-3- (S) -methyl-10-[(4-methyl-2,7-diazabicyclo [3.3.0] oct-4- En)
-7-yl] -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid, 9-fluoro-3- (S) -Methyl-10-[(3-methyl-2,7-diazabicyclo [3.3.0] oct-4-ene)
-7-yl] -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid, 9-fluoro-10-[(2 , 8-diazabicyclo (4.3.0)
Non-5-ene) -8-yl] -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] -benzothiazine-6-carboxylic acid, 9-fluoro -10-[(2,7-diazabicyclo [3.3.0]
Oct-4-ene) -7-yl] -7-oxo-2,3-
Dihydro-7H-pyrido [1,2,3-de] [1,4] -benzothiazine-6-carboxylic acid, 9-fluoro-3- (R, S) -methyl-10-[(2,8-diazabicyclo [4.3.0] Non-5-ene) -8-yl]
-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-
De] [1,4] -vinzoxazine-6-carboxylic acid, 9-fluoro-3- (R, S) -methyl-10-[(2,7-diazabicyclo [3.3.0] oct-4-ene)- 7-yl] -7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-De] [1,4] -benzoxazine-6-carboxylic acid, 9-fluoro-3- (R) -methyl-10-[(2,8-diazabicyclo [4.3.0] non-5-ene) -8 -Ill]
-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-
The compound according to claim 1, which is one of de] [1,4] -benzoxazine-6-carboxylic acid.
も良く、そして独立して、水素又は低級アルキルを表わ
し、 Ｘは酸素又は硫黄を表わし、 Ｙは水素又はメチルを表わし、 ｎは０又は１の整数である〕で表わされる化合物、 その立体異性体及び医薬的に許容できるその塩を調製す
るための方法であって： 下記式（II）： 〔式中、Ｘ及びＹは上記の通りであり、そしてＺは脱離
基、たとえばフルオロである〕で表わされる化合物と、 下記式（III）： 〔式中、R1,R2,R3,R4及びｎは上記の通りである〕で表
わされる化合物とを反応せしめることを含んで成る方
法。5. The following formula (I): [Wherein R 1 , R 2 , R 3 and R 4 may be the same or different and independently represent hydrogen or lower alkyl, X represents oxygen or sulfur, and Y represents hydrogen. Or methyl, and n is an integer of 0 or 1], a method for preparing a stereoisomer thereof, and a pharmaceutically acceptable salt thereof: [Wherein X and Y are as described above, and Z is a leaving group, for example, fluoro], and a compound of the following formula (III): A method comprising reacting with a compound represented by the formula: wherein R 1 , R 2 , R 3 , R 4 and n are as described above.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019920013213A KR960003616B1 (en) | 1992-07-23 | 1992-07-23 | New pyridone carboxylic acid derivatives having potent antibacterial activities and the preparation process thereof |
| KR1992-13213 | 1992-07-23 | ||
| CN93119572A CN1102184A (en) | 1992-07-23 | 1993-10-25 | Novel pyridonecarboxylic acid derivatives and processes for preparing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH07509240A JPH07509240A (en) | 1995-10-12 |
| JP2552101B2 true JP2552101B2 (en) | 1996-11-06 |
Family
ID=36930224
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6504362A Expired - Fee Related JP2552101B2 (en) | 1992-07-23 | 1993-07-23 | Novel pyridonecarboxylic acid derivative and method for preparing the same |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0651753A1 (en) |
| JP (1) | JP2552101B2 (en) |
| KR (1) | KR960003616B1 (en) |
| CN (1) | CN1102184A (en) |
| AU (1) | AU4587493A (en) |
| MX (1) | MX9304444A (en) |
| WO (1) | WO1994002487A1 (en) |
| ZA (1) | ZA935345B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5440112A (en) * | 1977-09-02 | 1979-03-28 | Kubota Ltd | Open culture method for continuous nursery plant for rice transplanter |
| JPS5686748A (en) * | 1979-12-18 | 1981-07-14 | Toppan Printing Co Ltd | Multilayer hollow vessel |
| JPS6046243A (en) * | 1983-08-24 | 1985-03-13 | 三菱油化株式会社 | Thermoplastic fluoroplastic laminate |
| JPS62275134A (en) * | 1986-02-18 | 1987-11-30 | Tosoh Corp | Bonding |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3906365A1 (en) * | 1988-07-15 | 1990-01-18 | Bayer Ag | 7- (1-PYRROLIDINYL) -3-CHINOLONE AND NAPHTHYRIDONE CARBOXYLIC ACID DERIVATIVES, METHOD AND SUBSTITUTED (OXA) DIAZABICYCLOOCTANES AND NONANESE AS INTERMEDIATE PRODUCTS, AND ANTIBACTERIAL AGENTS AND FOOD ADDITIVES CONTAINING THEM |
| DE69132314T2 (en) * | 1990-12-05 | 2000-12-14 | Naeja Pharmaceutical Inc., Edmonton | 7-SUBSTITUTED-6-FLUOR-1,4-DIHYDRO-4-OXO-CHINOLIN-3-CARBONIC ACID DERIVATIVES AS AN ANTIBACTERIAL ACTIVE SUBSTANCES |
-
1992
- 1992-07-23 KR KR1019920013213A patent/KR960003616B1/en not_active IP Right Cessation
-
1993
- 1993-07-22 MX MX9304444A patent/MX9304444A/en unknown
- 1993-07-23 JP JP6504362A patent/JP2552101B2/en not_active Expired - Fee Related
- 1993-07-23 WO PCT/KR1993/000064 patent/WO1994002487A1/en not_active Application Discontinuation
- 1993-07-23 EP EP93916265A patent/EP0651753A1/en not_active Ceased
- 1993-07-23 ZA ZA935345A patent/ZA935345B/en unknown
- 1993-07-23 AU AU45874/93A patent/AU4587493A/en not_active Abandoned
- 1993-10-25 CN CN93119572A patent/CN1102184A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5440112A (en) * | 1977-09-02 | 1979-03-28 | Kubota Ltd | Open culture method for continuous nursery plant for rice transplanter |
| JPS5686748A (en) * | 1979-12-18 | 1981-07-14 | Toppan Printing Co Ltd | Multilayer hollow vessel |
| JPS6046243A (en) * | 1983-08-24 | 1985-03-13 | 三菱油化株式会社 | Thermoplastic fluoroplastic laminate |
| JPS62275134A (en) * | 1986-02-18 | 1987-11-30 | Tosoh Corp | Bonding |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0651753A1 (en) | 1995-05-10 |
| AU4587493A (en) | 1994-02-14 |
| JPH07509240A (en) | 1995-10-12 |
| CN1102184A (en) | 1995-05-03 |
| MX9304444A (en) | 1994-04-29 |
| KR940002252A (en) | 1994-02-17 |
| ZA935345B (en) | 1994-02-14 |
| KR960003616B1 (en) | 1996-03-20 |
| WO1994002487A1 (en) | 1994-02-03 |
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