JPH04208288A - 7h-pyrido(3,2,1-ij) (2,1)benzoxazine derivative - Google Patents
7h-pyrido(3,2,1-ij) (2,1)benzoxazine derivativeInfo
- Publication number
- JPH04208288A JPH04208288A JP33895890A JP33895890A JPH04208288A JP H04208288 A JPH04208288 A JP H04208288A JP 33895890 A JP33895890 A JP 33895890A JP 33895890 A JP33895890 A JP 33895890A JP H04208288 A JPH04208288 A JP H04208288A
- Authority
- JP
- Japan
- Prior art keywords
- pyrido
- compound
- benzoxazine
- 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.)
- Granted
Links
- IBXMZTZRHDDGBI-UHFFFAOYSA-N O1N2C3=C(C=C1)C=CC=C3CC=C2 Chemical class O1N2C3=C(C=C1)C=CC=C3CC=C2 IBXMZTZRHDDGBI-UHFFFAOYSA-N 0.000 title claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 38
- 150000001875 compounds Chemical class 0.000 abstract description 27
- 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 abstract description 11
- -1 saturated cyclic amine Chemical class 0.000 abstract description 10
- 239000003242 anti bacterial agent Substances 0.000 abstract description 7
- 241000894006 Bacteria Species 0.000 abstract description 5
- 125000000217 alkyl group Chemical group 0.000 abstract description 3
- 241000192125 Firmicutes Species 0.000 abstract 1
- 125000005842 heteroatom Chemical group 0.000 abstract 1
- 239000012442 inert solvent Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 22
- 238000002844 melting Methods 0.000 description 18
- 230000008018 melting Effects 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- 238000004949 mass spectrometry Methods 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 239000013078 crystal Substances 0.000 description 14
- 238000000354 decomposition reaction Methods 0.000 description 13
- 238000000921 elemental analysis Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 230000000844 anti-bacterial effect Effects 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 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 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000005130 benzoxazines Chemical class 0.000 description 2
- 210000000941 bile Anatomy 0.000 description 2
- 239000003638 chemical reducing agent Substances 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
- 238000001816 cooling Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229960001699 ofloxacin Drugs 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- HPIVVOQIZYNVJE-UHFFFAOYSA-N 1,2-oxazolidin-2-ium;chloride Chemical compound Cl.C1CNOC1 HPIVVOQIZYNVJE-UHFFFAOYSA-N 0.000 description 1
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical group N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- CBRRMOVUBRANJW-UHFFFAOYSA-N 1-hydroxypiperazine;dihydrochloride Chemical compound Cl.Cl.ON1CCNCC1 CBRRMOVUBRANJW-UHFFFAOYSA-N 0.000 description 1
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical class OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 description 1
- PVTXJGJDOHYFOX-UHFFFAOYSA-N 2h-1,4-benzoxazine Chemical compound C1=CC=C2N=CCOC2=C1 PVTXJGJDOHYFOX-UHFFFAOYSA-N 0.000 description 1
- JCLFHZLOKITRCE-UHFFFAOYSA-N 4-pentoxyphenol Chemical compound CCCCCOC1=CC=C(O)C=C1 JCLFHZLOKITRCE-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 101000613598 Carica papaya Caricain Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 101000650578 Salmonella phage P22 Regulatory protein C3 Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- 101001040920 Triticum aestivum Alpha-amylase inhibitor 0.28 Proteins 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 229960002549 enoxacin Drugs 0.000 description 1
- ZNXSRAUZVHCWSF-UHFFFAOYSA-N ethyl 8-(2-acetyloxyethyl)-4-chloro-6,7-difluoroquinoline-3-carboxylate Chemical compound CC(=O)OCCC1=C(F)C(F)=CC2=C(Cl)C(C(=O)OCC)=CN=C21 ZNXSRAUZVHCWSF-UHFFFAOYSA-N 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- HDCCJUCOIKLZNM-UHFFFAOYSA-N n-pyrrolidin-3-ylacetamide Chemical compound CC(=O)NC1CCNC1 HDCCJUCOIKLZNM-UHFFFAOYSA-N 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000007686 potassium Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- DJXNJVFEFSWHLY-UHFFFAOYSA-M quinoline-3-carboxylate Chemical compound C1=CC=CC2=CC(C(=O)[O-])=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-M 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は一般式（１）
（式中、Ｘは窒素原子で置換した５〜７員環の飽和環状
アミン類を意味し、これらのアミン類はへテロ原子を含
むこともあり、低級アルキル基、アミノ基、低級アルキ
ルアミノ基、アセチルアミノ基もしくはヒドロキシル基
が置換することもある。）−／−
で表される新規な７１１−ピリド［３，２，１−ｉｊｌ
［２，１１ベンズオキサジン誘導体およびその薬理学的
に許容しうる塩に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (1) (wherein, A novel 711-pyrido[3,2,1-ijl represented by
[This article relates to 2,11 benzoxazine derivatives and pharmacologically acceptable salts thereof.
ここでＸとしては、ピペラジニル基、チメモルホリニル
基、ピロリジニル基、ホモピペラジニル基、ピラゾリジ
ニル基またはイソオキサゾリジニル基等が包含される。Here, X includes a piperazinyl group, a thimemorpholinyl group, a pyrrolidinyl group, a homopiperazinyl group, a pyrazolidinyl group, an isoxazolidinyl group, and the like.
低級アルキル基は、メチル、エチル、Ｘｌ−プロピル及
びイソプロピル基等が挙げられる。また、塩としては、
＠酸、硫酸、メタンスルホン酸等の如き熊機もしくはグ
ルコン酸、酒石酸等の有機酸との塩、あるいはカルボン
酸のナトリウム、カリ −ラム、アンモニウム塩等が
几体例として挙げら九る。Examples of lower alkyl groups include methyl, ethyl, Xl-propyl, and isopropyl groups. In addition, as salt,
Examples of the substances include salts with organic acids such as sulfuric acid, sulfuric acid, methanesulfonic acid, etc., or organic acids such as gluconic acid and tartaric acid, and sodium, potassium, and ammonium salts of carboxylic acids.
サシン（特公昭５５−３４１４４） 、エノキサシン（
特公昭５７−１０１０９）及びシプロフロキサシン（特
公昭０３−！ｌ［１２２４）等の合成抗菌剤が開発され
用いられている。しかし、これらはキノリンやナフチリ
ジン環を基本骨格とするピリドンカルボン酸系誘導体で
あり、この母核は抗菌活性と生体利用率のバランスの点
で種々の欠点が指摘されている。Sacin (Special Publication No. 55-34144), Enoxacin (
Synthetic antibacterial agents such as Japanese Patent Publication No. 57-10109) and ciprofloxacin (Japanese Patent Publication No. 1983-10109) have been developed and used. However, these are pyridonecarboxylic acid derivatives having a quinoline or naphthyridine ring as their basic skeleton, and it has been pointed out that this core has various drawbacks in terms of the balance between antibacterial activity and bioavailability.
一方、これらの欠点を解決するため、近年、７１１−ピ
リド［１，２，３−ｄｅ］［１，４］ベンズオキサジン
を基本骨格として持つオフロキサシンなる抗菌剤が開発
された（特公昭８ｌ−１１（１５５）。この化合物は、
抗菌活性に優れかつ生体利用率も良く、ｉｎ ｖｉｌ；
ｒｏ及びｊｎｖｉｖｏにおいてバランスのとれた挙動を
示す抗菌剤である。On the other hand, in order to solve these drawbacks, an antibacterial agent called ofloxacin, which has 711-pyrido[1,2,3-de][1,4]benzoxazine as its basic skeleton, was recently developed (Japanese Patent Publication No. 81-11). (155) This compound is
Excellent antibacterial activity and good bioavailability, in vil;
It is an antibacterial agent that shows balanced behavior in ro and jnvivo.
発明が解決しようとする問題点
この様に、合成抗菌剤が生体に対して有効に作用するた
めには、抗菌活性と生体利用率の両方が優れている必要
がある６本発明はこのような問題点を解決したものであ
る。Problems to be Solved by the Invention As described above, in order for a synthetic antibacterial agent to effectively act on living organisms, both antibacterial activity and bioavailability must be excellent6. This solves the problem.
問題点を解決するための手段
我々は、以前から抗菌活性が優れかつ生体利用率の良い
抗、ｌｉＭの開発に着手し研究を重ねてきた。そして、
７１１−ピリド［３１２１１−ＩＪ］［２，１］ベンズ
オキサジンの如き新規な縮合ヘテロ環骨格を有する化合
物が、低毒性でかつ適度な親水性、親油性のバランスを
持つことを見い出した。そこで、既存の合成抗菌剤の［
換基である飽和環状アミン類をこれに導入した多くの化
合物を合成し、種々の菌に対する抗菌活性を測定したと
ころ、これらの化合物が緑膿菌の如きグラム陰性菌のみ
ならずダラム陽性菌に対しても強い抗菌活性を有し、か
つ生体利用亭の点で優れていることを見い出し本発明を
完成した。Means to Solve the Problems We have long undertaken and conducted repeated research on the development of anti-liM, which has excellent antibacterial activity and high bioavailability. and,
It has been found that a compound having a novel fused heterocyclic skeleton, such as 711-pyrido[31211-IJ][2,1]benzoxazine, has low toxicity and an appropriate balance between hydrophilicity and lipophilicity. Therefore, existing synthetic antibacterial agents [
When we synthesized many compounds with saturated cyclic amines as substituents and measured their antibacterial activity against various bacteria, we found that these compounds were effective not only against Gram-negative bacteria such as Pseudomonas aeruginosa but also against Durham-positive bacteria. They discovered that it has strong antibacterial activity against humans and is excellent in terms of bioavailability, and completed the present invention.
作用
上記一般式（１）で表される化合物は新規骨格を有する
文献末載の化合物であり、我々によって初めて製造され
た。製造方法の例を下記の反応式に示して説明する。Effect The compound represented by the above general formula (1) is a compound described in a literature document having a new skeleton, and was produced by us for the first time. An example of the production method will be explained using the reaction formula below.
（ｎ） （１）
（式中、Ｘは上記に同じ。）
すなわち、上記（１ｌ）で表される化合物を，エタノー
ル、アセトニトリル、ジオキサン、ジメチルホルムアミ
ド、ジメチルスルホキシド、ビリジン、トルエン、キシ
レンの如き不活性溶媒中で、上記の飽和環状アミン類ま
たはその塩と室温〜２００℃、好ましくは７０℃〜１５
０℃で、１０分〜ＩＯ時間、通常２０分〜５時ＩｌＯ混
合撹拌することによって化合物（１）は製造することが
出来る。本反応で、アミン類の量は化合物（１１）より
過剰！ｋ（２〜２０当量）が好ましい。それは遊離のア
ミン類を過剰に用いることで、反応によって副生ずるＦ
ＢＩＩＩＦの受容体の役割を兼させることが出来るから
である。アミン類の塩酸塩を用いる場合は，別に酸受容
体として塩基、例えば炭酸アル゛カリ、アルカリ金属ア
ルコラート、トリエチルアミン等を使用するのが一般的
である。(n) (1)
(wherein, of saturated cyclic amines or salts thereof at room temperature to 200°C, preferably 70°C to 15°C.
Compound (1) can be produced by mixing and stirring at 0° C. for 10 minutes to 10 hours, usually 20 minutes to 5 hours. In this reaction, the amount of amines is in excess of compound (11)! k (2 to 20 equivalents) is preferred. By using excessive amounts of free amines, the F produced as a by-product of the reaction
This is because it can also serve as a receptor for BIIIF. When a hydrochloride of an amine is used, a base such as alkali carbonate, alkali metal alcoholate, triethylamine, etc. is generally used as an acid acceptor.
また、化合物（１）で、アミン類の窒素原子が低級アル
キル基で置換した化合物は、対応する非置換化合物を種
々のアルデヒドと還元剤存在下反応させることでも得ら
れる。ここで、アルデヒド類としてはホルムアルデヒド
、アセトアルデヒド、，プロピオンアルデヒドなどが用
いられ、還元剤としてはギ酸，水素化ホウ素ナトリウム
、亜釦／ｍ酸など、特にギ酸が好適である。Compounds (1) in which the nitrogen atom of the amine is substituted with a lower alkyl group can also be obtained by reacting the corresponding unsubstituted compound with various aldehydes in the presence of a reducing agent. Here, as the aldehyde, formaldehyde, acetaldehyde, propionaldehyde, etc. are used, and as the reducing agent, formic acid, sodium borohydride, submersible acid, etc., and particularly formic acid is preferable.
， かくして得られる目的化合物及びその塩は、広くダ
ラム陰性菌および陽性菌に対し優れた抗菌活性を発揮す
ると共に、吸収性に優れ各種感染症の治療薬として有川
である。The target compound and its salt thus obtained exhibit excellent antibacterial activity against a wide range of Durham-negative and Durum-positive bacteria, and have excellent absorbability, making them useful as therapeutic agents for various infectious diseases.
実施例
次に、参考例及び実施例を挙げて本発明化合物を更に只
体的に説明する。EXAMPLES Next, the compounds of the present invention will be further explained in detail with reference to reference examples and examples.
参考例
９，ｌＯ−ジフルオロ−７−オキソー１，２−ジヒドロ
−７１１−ビリド［３，２，Ｈｊ］［：４１］ペンズオ
キサジン−６−カルボン酸（化合物ＩＩ）（ａ） （０
−アミノー２，３−ジプルオロ）フエネチルアルコール
４．６８ｇ（２７ｍｍｏｌ）及びエトキシメチレンマロ
ン酸ジエチル５．９ｇ（２７ｍｍｏｌ）をエタノール３
０ｎｌに溶解し２．５時間還流する。反応後、溶媒を留
去し得られた残液を四塩化炭素・ヘキサン（４：１）か
ら再Ｎｉ品すると白色結晶として３，４−ジフルオ口−
２−（２−ヒドロキシエチル）アニリノメチレンマロン
酸ジエチル７．８１ｇを得る。Reference Example 9, lO-difluoro-7-oxo 1,2-dihydro-711-pyrido[3,2,Hj][:41]penzoxazine-6-carboxylic acid (compound II) (a) (0
-Amino-2,3-difluoro)phenethyl alcohol 4.68 g (27 mmol) and ethoxymethylene diethyl malonate 5.9 g (27 mmol) were added to ethanol 3
Dissolve in 0 nl and reflux for 2.5 hours. After the reaction, the solvent was distilled off and the resulting residue was re-purified from carbon tetrachloride/hexane (4:1) to give 3,4-difluoro-Ni as white crystals.
7.81 g of diethyl 2-(2-hydroxyethyl)anilinomethylene malonate are obtained.
融点 ： １０２−１０４℃
質量分折 ：３４３（Ｍつ，２９８，２７８，１７９，
１６６，１５４ＩＲ ： ３４８０，３１５０
，２！１７０，１８８０，１６４０，１０２５，１０１
０，１４０５，１２７０，１１００，８００ （ａｎ−
’）
ＮＭＲ ： ＣＤＣ１３（ＰＰＩＩＩ）１．３１
，１．３６ （各々３１１， ｔ， Ｊ＝７ｔｌｚ，
−ＣＩＩ２Ｃｈ）２．６８ （ＩＩＩ， ｂｒｓ
， −Ｃｌ１２ＣＩＩ２０１１）２．９８
（２１１， ｄｔ， Ｊ＝２１１ｚ，６１１ｚ，
−Ｃｊｊ７，ＣＩｌ２０１ｌ）３．９４ （
２１１， Ｌ；， Ｊ：ＯＩｌｚ， −ＣＩ１２Ｃ胆０
１１）４．２３，ＩＩ．加（各々２１１， ｑ， Ｊ＝
７１ｌｚ， −Ｃｊｌ７ＣＩｂ）０．８−７．４ （
２１１， ｓ， ＣＩ，−Ｉｆ，Ｃｏ−Ｉｔ）８．２９
（Ｉｌｌ， ｄ， Ｊ＝１３１ｌｚ， Ｎｌｌ
−Ｃｌｉ＝）１１．１５ （ＩＨ， ｂｒｄ，
Ｊ−１３！ｌｚ， −Ｎｌｌ−Ｃｌｌ＝）（ｂ）上記化
合物７．８９ｇ（２２ｍｍｏ１）を酢酸３軸ｌに溶解し
、無水酢酸２．１ｍｌ（２２關ｏｆ）、濃硫酸２滴を加
え、室温で１時間攪拌する。反応後、溶媒を留去し得ら
れた残液を四塩化炭素から再結晶すると白色結晶として
２−（２−アセチルオキシエチル）−３．４−ジフルオ
ロアニリノメチレンマロン酸ジエチル８．６１ｇを得る
。Melting point: 102-104℃ Mass spectrometry: 343 (M, 298, 278, 179,
166,154IR: 3480,3150
,2!170,1880,1640,1025,101
0,1405,1270,1100,800 (an-
') NMR: CDC13 (PPIII) 1.31
, 1.36 (311, t, J=7tlz,
-CII2Ch) 2.68 (III, brs
, -Cl12CII2011) 2.98
(211, dt, J=211z, 611z,
-Cjj7, CIl201l) 3.94 (
211, L;, J: OIlz, -CI12C bile 0
11) 4.23, II. addition (respectively 211, q, J=
71lz, -Cjl7CIb)0.8-7.4 (
211, s, CI, -If, Co-It) 8.29
(Ill, d, J=131lz, Nll
-Cli=)11.15 (IH, brd,
J-13! lz, -Nll-Cll=) (b) Dissolve 7.89 g (22 mmol) of the above compound in 3 volumes of acetic acid, add 2.1 ml (22 mmol) of acetic anhydride and 2 drops of concentrated sulfuric acid, and stir at room temperature for 1 hour. Stir. After the reaction, the solvent was distilled off and the resulting residue was recrystallized from carbon tetrachloride to obtain 8.61 g of diethyl 2-(2-acetyloxyethyl)-3.4-difluoroanilinomethylenemalonate as white crystals. .
融点 ： １１７−１１８℃
質量分析 ：３８５（Ｍつ，３４０，２７８，２０５，
１７９，１６６−４一
ＩＲ ： ３２３０，２９８０，１７４０，１
８８５，１６４０，１５９０，１２８０，１２３５，１
０４０，８００（ｃｍ−’）ＮＭＲ ： ＣＤＣ
ｈ （ｐｐ誼）’１．３２，Ｉ．３Ｄ （各々３１１，
ｌ；， ．Ｉ＝７１Ｉｚ， −ＣｌｌｐＣＩｌ３）２
．０３ ． （３１１， ｓ， −ＣＯＣｌｌａ）
３．０９ （２１１， ｄＬ；， Ｊ＝２１ｌｚ
，６１１ｚ， −Ｃｌｌｌ！，ＣＩ＋２０−）４．０−
４．６ （６１１， ａ， −Ｃｌｌ２ＣＫＯ−，−
Ｃｊｊｇ−Ｃｌ１３）０．７−７．５ （２１１，
ｍ，’ ｅｓ．−Ｉ１，Ｃ６−Ｉｆ）８．３２
（ｉｌｌ， ｄ， Ｊ；１３１ｌｚ， Ｎｌｌ−ＣＩ！
−）１１．１０ （ＩＩＩ， ｂｒｄ， Ｊ＝ｌ
３１１ｚ， −Ｎ…−ＣＩ＋＝）（ｃ）上記化合物６．
４４ｇ（１７ｍｍｏｌ）、ポリリン酸エチル３０ｇを仕
込み、メカニカルスターラーで激しく攪拌しながら１１
０〜１３０℃で３０分攪拌する。反応後、混合物を氷水
１５０＋ｎｌに注ぎ室温でしばらく攪拌した後、クロロ
ホルムで３回抽出する。有ｉａＭを５％炭酸カリウム、
水の順に洗浄したのち無水硫酸ナトリウムで乾燥して濃
縮し、得られた残液をシリカゲルカラムクロマトグラフ
ィーに付す。塩化メチレンで溶出し、目的両分を集めて
濃縮すると８−（２−アセチルオキシエチル）−８．７
−ジフルオ口−４一ヒドロキシキノリン−３−カルボン
酸エチル３．４０ｇを得る。Melting point: 117-118℃ Mass spectrometry: 385 (M, 340, 278, 205,
179,166-4-IR: 3230,2980,1740,1
885, 1640, 1590, 1280, 1235, 1
040,800 (cm-') NMR: CDC
h (pp 誼)'1.32, I. 3D (311 each,
l;, . I=71Iz, -CllpCIl3)2
．． 03. (311, s, -COClla)
3.09 (211, dL;, J=21lz
,611z, -Cllll! , CI+20-)4.0-
4.6 (611, a, -Cll2CKO-,-
Cjjg-Cl13)0.7-7.5 (211,
m,' es. -I1,C6-If)8.32
(ill, d, J; 131lz, Nll-CI!
-)11.10 (III, brd, J=l
311z, -N...-CI+=) (c) The above compound 6.
44g (17mmol) and 30g of ethyl polyphosphate were prepared, and stirred vigorously using a mechanical stirrer.
Stir at 0-130°C for 30 minutes. After the reaction, the mixture was poured into 150+ nl of ice water, stirred for a while at room temperature, and extracted three times with chloroform. 5% potassium carbonate,
After sequentially washing with water, it is dried over anhydrous sodium sulfate and concentrated, and the resulting residue is subjected to silica gel column chromatography. Elute with methylene chloride, collect both target fractions and concentrate to obtain 8-(2-acetyloxyethyl)-8.7
3.40 g of ethyl difluoro-4-hydroxyquinoline-3-carboxylate are obtained.
融点 ： ２０９−２１１℃（分解）質量分析
： ３３９ （Ｍ”），２９６，２８０，２５０，２
３４，２０７ＩＲ ： ３０８０，１７４０，
１７２０．１Ｂ９０，１４７５，１２３０，１０３０，
８０５（ｃｒ’）ＮＭＲ ： ＣＩ’３ＧＯＯＤ
（ｐｐｍ）１．５０ （３１１， ｔ，Ｊ＝７１ｌｚ
， −ＣＩ１２Ｃｌｌ１）２．２０ （３１１， ’ｓ
， −ＣＯＣＩｌｉ）３．７０ （２１１， ｄｌｒ，
Ｊ＝２１Ｉｚ，７１Ｉｚ， −Ｃｌｌ−ＣＩｌ２０−
）４．００ （２１１， ．ｔ， Ｊ＝７１Ｉｚ， −
ＣＩ１２ＣｋＯ−）４．７７ （２１１， ｑ， Ｊ＝
７Ｑｚ， −Ｃｊｊ．−Ｃｌｌａ）８．４１ （ＩＩＩ
， ｔ， Ｃｓ−ＩＩ）！１．４Ｂ．（ｉｌｌ， ｓ，
Ｃ２−Ｉ！）（．１！）上紀化合物３．８１ｇ（１１
ｍｍｏ１）、オキシ塩化リン９．１ｍｌ（９ｊＩＩｍｏ
ｌ）およびトルエン５０膳ｌを仕込み、 １．５時間還
流する。反応後、溶媒を留去し残液をクロロホルムに溶
解した後，５％炭酸カリウム、水の順に洗浄し無水硫酸
ナトリウムで乾燥して濃縮し、得られた残液をシリカゲ
ルカラムクロマトグラフイーに付す。クロロホルムで溶
出し目的画分を集めて濃縮すると、８−（２−アセチル
オキシエチル）−４−クロロー６，７ージフルオロキノ
リン−３−カルボン酸エチル３．５７ｇを得る。Melting point: 209-211℃ (decomposition) Mass spectrometry
: 339 (M”), 296, 280, 250, 2
34,207IR: 3080,1740,
1720.1B90, 1475, 1230, 1030,
805(cr')NMR: CI'3GOOD
(ppm) 1.50 (311, t, J=71lz
, -CI12Cll1)2.20 (311,'s
, -COCIli)3.70 (211, dlr,
J=21Iz, 71Iz, -Cll-CIl20-
)4.00 (211, .t, J=71Iz, -
CI12CkO-)4.77 (211, q, J=
7Qz, -Cjj. -Clla) 8.41 (III
, t, Cs-II)! 1.4B. (ill, s,
C2-I! ) (.1!) Upper period compound 3.81g (11
mmo1), phosphorus oxychloride 9.1ml (9jIImo
1) and 50 liters of toluene were charged and refluxed for 1.5 hours. After the reaction, the solvent was distilled off and the residual liquid was dissolved in chloroform, then washed with 5% potassium carbonate and water in that order, dried over anhydrous sodium sulfate and concentrated, and the resulting residual liquid was subjected to silica gel column chromatography. . Elution with chloroform and collection of target fractions were concentrated to obtain 3.57 g of ethyl 8-(2-acetyloxyethyl)-4-chloro-6,7-difluoroquinoline-3-carboxylate.
融点 ： ５ ９ − ６１℃
質量分析 ： ３５７ （Ｍ’），３１４，２９７，
２８６，２６８ＩＲ ： ３０７０，２９００
，１７３０，１４９０，１２６０，１２４０，１０３５
．８０５（ａｍ−’）ＮＭＲ ： ＣＤＣ１３（
ｐｐｍ）１．’１８ （３１Ｌ ｌ；，Ｊ＝７１Ｉ
ｚ， −Ｃｌ１２ＣＩｌ乳）１．９８ （３１１，
ｓ， ［）Ｃｌｌ３）３．８３ （２１１， ｄｔ，
Ｊ＝２＋１ｚ，７１１ｚ， −Ｃｌｌ１Ｃｌｌ２０−）
４．４４ （２１１， ｔ， Ｊ＝７１ｌｚ， −ＣＩ
１２ＣＫＯ−）１１．５１ （２１１， ｑ， Ｊ＝７
１Ｉｚ， −Ｃ肝ＣＩ＋３）８．０［ｉ （Ｉｌｌ，
ｄｄ， Ｊ−ｇＩＩｙ．，ｌｌｌｌｚ， Ｃｓ−ＩＩ）
９．１０ （ｉｌｌ， ｓ， Ｃ２−Ｉ＋）（ｅ）上記
化合物３．９７ｇ（ｌｌｍｍｏｌ）をエタノール２００
ｍｌに溶解し氷冷する。そこへ２Ｎ−水酸化ナトリウム
５．５５＋ｎＨ１１ｎ＋ｎｃ＋．ｌ）を内温３〜４℃で
滴下し、同温度で１時間攪拌する。反応後、ｌＮ４ＰＷ
１ １１＋ｎｌ（１１＋ＩＩｍｏｌ）を滴下し溶媒を留
去し、クロロホルムに溶解して水で洗浄する。有機層を
無水硫酸ナトリウムで乾燥して濃縮し、得られた残渣を
シリカゲルカラムクロマトグラフィーに付し、四塩化炭
素・クロロホルム（１ ： ｌ）で溶出しＩ；１的両分
を集めて濃縮する。四塩化炭素から再結晶して４−クロ
ロー６，７−ジフルメ口−８−（２−ヒドロキシエチル
）キノリン−３−カルボン酸エヂル２．０７，を得る。Melting point: 59-61℃ Mass spectrometry: 357 (M'), 314,297,
286,268IR: 3070,2900
,1730,1490,1260,1240,1035
．． 805 (am-') NMR: CDC13 (
ppm)1. '18 (31L l;, J=71I
z, -Cl12CIl milk) 1.98 (311,
s, [)Cll3)3.83 (211, dt,
J=2+1z, 711z, -Cll1Cll20-)
4.44 (211, t, J=71lz, -CI
12CKO-)11.51 (211, q, J=7
1Iz, -C Liver CI+3) 8.0[i (Ill,
dd, J-gIIy. ,llllz, Cs-II)
9.10 (ill, s, C2-I+) (e) 3.97 g (llmmol) of the above compound was added to 200 g of ethanol.
ml and cool on ice. 2N-sodium hydroxide 5.55+nH11n+nc+. 1) was added dropwise at an internal temperature of 3 to 4°C, and stirred at the same temperature for 1 hour. After reaction, lN4PW
1 11+nl (11+II mol) is added dropwise, the solvent is distilled off, the solution is dissolved in chloroform, and the solution is washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting residue was subjected to silica gel column chromatography, eluted with carbon tetrachloride/chloroform (1:1); both fractions were collected and concentrated. . Recrystallization from carbon tetrachloride gives 2.07 g of 4-chloro6,7-diflume-8-(2-hydroxyethyl)quinoline-3-carboxylate.
融点 ： １０３−４℃
ｇｔ量分析 ：３１５（Ｍつ，２９８，２８５，２７０
，２５７ＩＲ ？ ３２００，２９４０，１７
３５，１７１０，１４９０，１２６０，１２１５，１０
４０．８０５（ｃ＋＊−’）ＮＭＲ ： ＣＤＣ
．１３ （ｐｐ＋＊）１−４４ （３１１， ｔ， Ｊ
＝７１１ｚ， −ＣＩＬＣ［１）３．１４ （ＩＩＬ
ｂｒｓ， −ＣＩ１２ＣＩ＋２０１１）３．４９ （２
１１， ｄｌｒ， Ｊ＝２１１ｚ，６１１ｚ， −Ｃ服
ＣＩ＋２０−）３．０５ （２１１， ｔ， ．Ｉ＝Ｏ
Ｉｌｚ， −ＣＩ１２Ｃｊｉｇ．０−）４．４６ （２
１１， ｑ， Ｊ＝７１１ｚ， −Ｃｌｌｐｌｌ：ｆｂ
）一Ｇ−
７．９７ （ＩＨ，ｄｄ、 Ｊ＝８１１ｚ、１０１１ｚ
、 Ｃｌ１−Ｈ）９．０８ （Ｉｌｌ、 ｓ、 Ｃ２−
１１）（「）」―配化合物２．０７ｇ（０，Ｏｍｗ＋ｏ
ｌ）及び１−クロ口過安息香Ｗ１２．２（Ｉｇ（１３，
’１ｍｍｏ、ｌ）をクロロホルム５０１１１に溶解し、
６４時間還流する。反応後、５％炭酸カリウム、水の順
に洗浄したのち無水ａｌｌｌ！ナトリウムで乾燥して濃
縮し、得られた残液をシリカゲルカラムクロマトグラフ
ィー（溶出波：クロロホルム）に付す。目的物は混合画
分として溶出されるので、これを更にカラムクロマトグ
ラフィー（溶出液二四塩化炭素：酢酸エヂル＝４ ：
ｌ）に付す。目的の両分を集めて濃縮すると９，１０−
ジフルオロ−７−オキソ−１，２−ジヒドロ−７１１−
ピリド［３，２，１−ｉＪ］［Ｌ１］ベンズオキサジン
−６−カルボン酸エチル０．１２Ｋを得る。Melting point: 103-4℃ gt amount analysis: 315 (M, 298, 285, 270
,257IR? 3200, 2940, 17
35,1710,1490,1260,1215,10
40.805 (c++-') NMR: CDC
．． 13 (pp+*)1-44 (311, t, J
=711z, -CILC[1)3.14 (IIL
brs, -CI12CI+2011) 3.49 (2
11, dlr, J=211z, 611z, -C clothes CI+20-)3.05 (211, t, .I=O
Ilz, -CI12Cjig. 0-)4.46 (2
11, q, J=711z, -Cllpll:fb
) - G- 7.97 (IH, dd, J=811z, 1011z
, Cl1-H)9.08 (Ill, s, C2-
11) (")" - 2.07 g of combination compound (0, Omw+o
Ig(13,
'1 mmo, l) was dissolved in chloroform 50111,
Reflux for 64 hours. After the reaction, wash with 5% potassium carbonate and water in that order, then anhydride ALL! Dry with sodium and concentrate, and the resulting residue is subjected to silica gel column chromatography (elution wave: chloroform). Since the target product is eluted as a mixed fraction, this is further subjected to column chromatography (eluent: carbon ditetrachloride: ethyl acetate = 4:
l). Collecting and concentrating both the desired components yields 9,10-
Difluoro-7-oxo-1,2-dihydro-711-
0.12K of ethyl pyrido[3,2,1-iJ][L1]benzoxazine-6-carboxylate is obtained.
融点 ： ２４２−３℃
質量分析 ： ２９５ （Ｍ”）、２５０，２２３，
２２０，１９３，１６５ＩＲ： ２０８０，１７２０
．１Ｂ２０，１８００，１４７０，１２４０，１０４０
．８０５（ａｎ−’）ＮＭＩ２ ： ＣＦ３ＣＯ
０ｐ （Ｐ口）１．５５ （３ＩＩ、ｔ、Ｊ＝７１１ｚ
、−ＣＩｌｐＣｈｌ）３．５８ （２１１，ｔ、 Ｊ＝
８１１ｚ、 −ＣｉｊｌＣｌｈＯ−）４．７１ （２１
１，ｑ、 Ｊ＝７１１ｚ、 −Ｃ１ｊ、；Ｃｌ１３）４
．９９ （２１１，ｔ、 Ｊ＝６１１ｚ、 −ＣＩ１２
ＣｋＯ−）８．４０ （ＩＩＩ、 ｄｄ、 Ｊ＝８１１
ｚ、５１１ｚ、 Ｃｏ−ＩＩ）０．３０ （Ｉｌｌ、
ｓ、 Ｃｓ−Ｉｆ）（ｇ） Ｊ：配化合物１．１７ｇ（
４，０ｍ＋ｎｏｌ） ニ１塩酸・ｓ’酸混液（１： ４
） ２０ｍ１を加工、１００〜１１０℃で３．５時間攪
拌する。反応後、水５軸１を加え氷浴で攪拌しながら冷
却する。Melting point: 242-3°C Mass spectrometry: 295 (M”), 250,223,
220,193,165IR: 2080,1720
．． 1B20, 1800, 1470, 1240, 1040
．． 805(an-')NMI2: CF3CO
0p (P mouth) 1.55 (3II, t, J=711z
, -CIlpChl)3.58 (211,t, J=
811z, -CijlClhO-)4.71 (21
1, q, J=711z, -C1j,;Cl13)4
．． 99 (211,t, J=611z, -CI12
CkO-)8.40 (III, dd, J=811
z, 511z, Co-II) 0.30 (Ill,
s, Cs-If) (g) J: 1.17 g of combination compound (
4,0m+nol) di-hydrochloric acid/s' acid mixture (1:4
) Process 20 ml and stir at 100-110° C. for 3.5 hours. After the reaction, add 5x1 of water and cool with stirring in an ice bath.
析出結晶を濾取しアセトンで洗浄後乾燥し、ＤＭＦ・エ
タノール（１： ３）から再結晶すると白色結晶として
０，１０−ジフルメロー７−オキソー１，２−ジヒドロ
−７１１−ピリド［３，２＋１−ｊｊ］［２Ｊ’ベンズ
オキサジン−６−カルボン酸（ＩＩ） ０．７４６ｇを
得る。The precipitated crystals were collected by filtration, washed with acetone, dried, and recrystallized from DMF/ethanol (1:3) to yield 0,10-diflumelow 7-oxo 1,2-dihydro-711-pyrido [3,2+1- 0.746 g of benzoxazine-6-carboxylic acid (II) is obtained.
融点 ： ２７９−８３℃（分解）−元素分析
： Ｃ１２１１７Ｆ２Ｎα （ＭＷ＝２６７．１８
７）理論（ｆｉ Ｈ２，６４％、Ｃ５３，９４ＬＮ
５．２４ ％実測値 Ｈ２，５１％、Ｃ５３，９
４％、Ｎ ５．２０％質量分析 ： ２６７ （Ｍ
’）、２２３，１９３，１６５ＩＲ： ３０５０，
１７０５，１６２５．．１５５０，１４７０，１３２０
．８１５（ａｍ−首）ＮＭＲ： ＣＦ３ＧＯＯＤ （
ｐｐｍ）：（，０１（２１１，１，、、ｌ：［１ｌｌｚ
、 −Ｃ１ｌｐＣＩｌｐＯ−）５．０１ （２１１，ｔ
、 Ｊ＝ＯＩＩｚ、 −ＣｌｌｌＩＣｋＯ−）８．４２
ＣＩＩＩ、 ｄｄ、 Ｊ＝８１１ｚ、９１１ｚ、 Ｃ
ｏ−Ｉｆ）０．４０ （ＩＩＩ、 ８． Ｃ５−Ｉｆ）
実施例１゜
９−フルオロ−７−オキソ−１０−（１−ピペラジニル
）−１，２−ジヒドロ−７１１−ピリド［３，２，１−
ｉｊ］［２，１３ベンズオキサジン−６−カルボン酸参
考例で得た化合物ｕ Ｏ，２１ｇ（０，７７ｇｍｏ１）
及び無水ピペラジン０．３３ｇ（３，８５關０１）をジ
メチルスルホキシド２ｍｌに加え、ｔｏｏ−ｔｉｏ℃で
２０分攪拌する。反応後、水を加え１０％ＦＩＮ酸で中
和し水浴で攪拌しながら冷却する。析出結晶を濾取し水
及びアセトンで洗浄後乾燥し、ＤＭＦ・水から再結晶し
て得る（収ｆｉ Ｏ，２０［） 。Melting point: 279-83℃ (decomposition) - elemental analysis
: C12117F2Nα (MW=267.18
7) Theory (fi H2, 64%, C53, 94LN
5.24% actual value H2,51%, C53,9
4%, N 5.20% Mass spectrometry: 267 (M
'), 223,193,165IR: 3050,
1705, 1625. ．． 1550, 1470, 1320
．． 815 (am-neck) NMR: CF3GOOD (
ppm):(,01(211,1,,,l:[1llz
, -C1lpCIlpO-)5.01 (211,t
, J=OIIz, -ClllICkO-)8.42
CIII, dd, J=811z, 911z, C
o-If) 0.40 (III, 8. C5-If)
Example 1 9-Fluoro-7-oxo-10-(1-piperazinyl)-1,2-dihydro-711-pyrido[3,2,1-
ij][2,13benzoxazine-6-carboxylic acid Compound u obtained in reference example O, 21 g (0,77 gmol)
and 0.33 g (3,85 mm) of anhydrous piperazine were added to 2 ml of dimethyl sulfoxide and stirred at too-tio<0>C for 20 minutes. After the reaction, water was added, neutralized with 10% FIN acid, and cooled with stirring in a water bath. The precipitated crystals are collected by filtration, washed with water and acetone, dried, and recrystallized from DMF/water (yield: fi O, 20[)].
融点 ： ２４６℃（分解）
元素分析 ： ＣｌｅＨ＋５ＦＮａＯ４・３／４Ｈ２
０理論値 Ｈ５，０９％、Ｃ５５゜４１ ＬＮ １２
．１２ズ実ｉＩ！！Ｉ値 １−Ｉ ５．０９％、Ｃ
５５，６５％、Ｎ １２．００％質量分析 ：３３３（
Ｍつ、２９１，２８９，２５９，２３３．１８９ＩＲ：
２Ｂ５０，１８１０，１５８０，１４５０．１３８
０．１路５，８３０ （ａｍ−’）ＮＭＲ： ＣＦ３
ＧＯＯＤ （ＰＰＭ）３．２−４．４ （１０１１，ｗ
ｘ、 −Ｃ１１１ＣｌｌｔＯ−＋ｐｉｐｅｒａｚｉｎｅ
−Ｃ１ｋ）４．９１ （２１１，ｔ、 −Ｃ１
１ＣＩＩ２０−）８−３４ （１１１，ｄ、Ｊ＝１
２＋１ｚ、 Ｃ１１−１１）（１，３７（ｉｌｌ、 ｓ
、 Ｃ５−ＩＩ）実施例２゜
９−フルオロ−１０−（４−メチル−１−ピペラジニル
）−７−オキソ−１，２−ジヒドロ−７１１−ピリド［
３＋２Ｊ−１ｊコ［２，１］ベンズオキサジン−６−カ
ルボン酸（ａ）参考例で得た化合物ＩＩ Ｏ，１８ｇ（
０，８７ａｎｏ１）にＮ−メチルピペラジン０．３７＋
＊１（３，３４關ｏ１）及びジメチルスルホキシド１．
８ｍｌを加え、１００〜１１０℃で２５分攪拌する。反
応後、溶媒を留去し残渣に水とメタノールを加えて溶解
し、これをシリカゲルに吸着後カラムクロマトグラフィ
ーに付す。クロロホルム・メタノール（１１：ｌ）で溶
／ＢＬｎ的両分を集めて濃縮し、ヘキサン・エタノール
から再結晶して得る（収、ｔ Ｏ，１７８ｇ）。Melting point: 246℃ (decomposition) Elemental analysis: CleH+5FNaO4・3/4H2
0 theoretical value H5,09%, C55゜41 LN 12
．． 12's Real II! ! I value 1-I 5.09%, C
55.65%, N 12.00% Mass spectrometry: 333 (
M, 291,289,259,233.189IR:
2B50, 1810, 1580, 1450.138
0.1 road 5,830 (am-') NMR: CF3
GOOD (PPM) 3.2-4.4 (1011, w
x, -C111ClltO-+piperazine
-C1k)4.91 (211,t, -C1
1CII20-)8-34 (111, d, J=1
2+1z, C11-11)(1,37(ill, s
, C5-II) Example 2 9-fluoro-10-(4-methyl-1-piperazinyl)-7-oxo-1,2-dihydro-711-pyrido [
3+2J-1j co[2,1]benzoxazine-6-carboxylic acid (a) Compound II obtained in Reference Example O, 18 g (
0.87ano1) to N-methylpiperazine 0.37+
*1 (3,34 o1) and dimethyl sulfoxide 1.
Add 8 ml and stir at 100-110°C for 25 minutes. After the reaction, the solvent is distilled off and the residue is dissolved in water and methanol, which is adsorbed onto silica gel and subjected to column chromatography. Both the soluble and BLn fractions were collected with chloroform/methanol (11:l), concentrated, and recrystallized from hexane/ethanol (yield, tO, 178 g).
融点 ： ２２４−５℃（分解）元素分析 ：
Ｃ＋７Ｈ＋＊ＦＮ３０４ （ＭＷ＝３４７．３４６
）理論？ｆｉ Ｈ５，２２％、Ｃ５８，７８ＬＮ１
２．１０％実測値 ）Ｉ ５．２３％、Ｃ５８，７
８％、Ｎ １２．１２％質量分析 ： ３４７ （Ｍ
’）、３３２，３０３，２７５，２０３，１４８ＩＲ：
２９３０，１７１５，１６２０，１５４０，１４５
５，１３７０，１３５５，１２０５，８２０（ｃｒ’）
ＮＭＲ： ＣＦ３ＣＯ０Ｄ （ＰＰ１１）３．２１
（３１１，ｓ、 ｐｉｐｅｒａｚｉｎｅ−Ｎｃｌ１
３）３．３−４．４ （ｌｏｌｌ、 ｍ、 −１４ｃ１
１ｐＯ−＋Ｐｉｐｅｒａｚｉｎｅ−Ｃ１１２）４．０１
（２１１，ｔ、 −ＣＩＩ２Ｃ胆０−）８．３２
（Ｉｌｌ、 ｄ、 Ｊ＝１１１１ｚ、 Ｃ５−Ｉ
ｔ）９．３３ （Ｉｌｌ、 ｓ、 Ｃ５４１）（ｂ
）実施例１．で得た化合物０．０７ｇ（０，２１ａｎｏ
１）に９０％ギ酸０．５＋ｎｌ及び３５％ホルマリン０
．５ｍｌを加え２時間還流する。反応後、水を加え炭酸
カリウムで１中和後濃縮し、残渣をシリカゲルカラふク
ロマトグラフィーに付し、 （ａ）と同様に処理して得
る（収量０．０３８ｇ）。分析結果は（ａ）で得た化合
物と−・致した。Melting point: 224-5℃ (decomposition) Elemental analysis:
C+7H+*FN304 (MW=347.346
)theory? fi H5,22%, C58,78LN1
2.10% actual value) I 5.23%, C58,7
8%, N 12.12% Mass spectrometry: 347 (M
'), 332,303,275,203,148IR:
2930, 1715, 1620, 1540, 145
5,1370,1355,1205,820(cr')
NMR: CF3CO0D (PP11) 3.21
(311, s, piperazine-Ncl1
3) 3.3-4.4 (roll, m, -14c1
1pO-+Piperazine-C112) 4.01
(211,t, -CII2C bile 0-)8.32
(Ill, d, J=1111z, C5-I
t) 9.33 (Ill, s, C541) (b
) Example 1. 0.07g of the compound obtained (0.21ano
1) 90% formic acid 0.5+nl and 35% formalin 0
．． Add 5 ml and reflux for 2 hours. After the reaction, water is added, the mixture is neutralized with potassium carbonate, and concentrated. The residue is subjected to silica gel column chromatography and treated in the same manner as in (a) (yield: 0.038 g). The analysis results were consistent with the compound obtained in (a).
実施例３゜
９−フルオロ−１０−（４−ヒドロキシ−１−ピペラジ
ニル）−７−オキソ−１，２−ジヒドロ−７１１−ピリ
ド［３１２１１−ＩＪ］［２１１］ベンズオキサジン−
６−カルボン酸参考例で得た化合物ＩＩ Ｏ，３０ｇ（
１，１２ＩＩ＋ｎｏｌ）、 １−ヒドロキシピペラジン
・２塩酸塩１．９７ｇ（１１，２ｗ＋ｗ＋ｏｌ）及び炭
酸水素ナトリウム１．８９ｇ（２２，５ｗｏｌ）を仕込
み、ジメチルスルホキシド２０ｍ１を加えて室温でしば
らく攪拌した後１２０℃で３．５時間攪拌する。反応後
、溶媒を留去し残渣に水及びＩＮ−酢酸を加え、水浴で
攪拌しながら冷却して粗結晶を得る。これをクロロホル
ム・メタノール（１５： １）を溶離液とするカラムク
ロマトグラフィーに付す。目的両分を集めて濃縮し、Ｄ
ＭＦ・エタノール・ヘキサンから再結晶して得る（収量
０．０５１ｇ） −融点 ： ２７０℃（分解）
元素分析 ： Ｃ＋ａｌＩ＋ｅＦＮａＯｓ （Ｍ
Ｗ＝３４４）、３１８）理論値 Ｈ４，０２％、Ｃ５
５，０１ＬＮ １２．０３ ％実ｉｌ！！ｌ値 ＩＩ
４．６０％、Ｃ５４，９４％、Ｎ １１．８５％質
量分析 ： ３４９ （Ｍ’）、３３２，３０５，２
２９，２１６Ｊ、Ｒ′： ２８３０，１７１０，１
６２０，１４４５，１２０５，１０５０．８１０ （
ｃ＋＊−’ ）ＮＭＲ： ＣＦ３ＣＯ０Ｄ （ＰＰＩ
Ｉ）３．３−４．７ （１０１１，ｍ、 −ＣｋＣ１１
２０−＋Ｐｉｐｅｒａｚｉｎｅ−Ｃｌ１２）４．９３
（２１１，ｂｒｔ、 −Ｃ１１２ＣＫＯ−）８．３
１ （ｉｌｌ、 ｄ、 Ｊ＝１２１１ｚ、 Ｃ５−
Ｉｆ）９．３１ （ｉｌｌ、 ｓ、 Ｃ５−Ｉｔ）
実施例４゜
９−フルオロ−１０−（４−チオモルホリニル）−７−
オキソ−１，２−ジヒドロ−７１１−ピリド［３，２，
１−１ｊｌ［２＋１］ベンズオキサジン−６−カルボン
酸参考例で得た化合物ＩＩ ０．３０ｇ（１，１２ａｎ
ｏ１）、チオモルホリン１．５ｍ１（１４，９關０１）
及びジメチルスルホキシド１５ｉ１を仕込み、７５℃で
４時間攪拌する。反応後、溶媒を留去し残液に水を加え
て析出結晶を濾取する。これをクロロホルムを溶離液と
するカラムクロマトグラフィーに付し目的両分を集めて
濃縮し、ＤＭＦ・エタノール・ヘキサンから再結晶して
得る（ＪｂｌＪＦｋ ０．０５８ｇ）。Example 3 9-Fluoro-10-(4-hydroxy-1-piperazinyl)-7-oxo-1,2-dihydro-711-pyrido[31211-IJ][211]benzoxazine-
Compound II O obtained in 6-carboxylic acid reference example, 30 g (
1,12 II + nol), 1.97 g (11,2 w + w + ol) of 1-hydroxypiperazine dihydrochloride, and 1.89 g (22,5 wol) of sodium hydrogen carbonate, 20 ml of dimethyl sulfoxide was added, and after stirring at room temperature for a while, the mixture was heated to 120°C. Stir for 3.5 hours. After the reaction, the solvent is distilled off, water and IN-acetic acid are added to the residue, and the mixture is cooled with stirring in a water bath to obtain crude crystals. This was subjected to column chromatography using chloroform/methanol (15:1) as an eluent. Collect and concentrate the desired amounts, D
Obtained by recrystallization from MF, ethanol, hexane (yield: 0.051 g) - Melting point: 270°C (decomposition) Elemental analysis: C+alI+eFNaOs (M
W=344), 318) Theoretical value H4,02%, C5
5,01LN 12.03% Actual! ! l value II
4.60%, C54, 94%, N 11.85% Mass spectrometry: 349 (M'), 332,305,2
29,216J, R': 2830,1710,1
620,1445,1205,1050.810 (
c++-' ) NMR: CF3CO0D (PPI
I) 3.3-4.7 (1011,m, -CkC11
20-+Piperazine-Cl12) 4.93
(211,brt, -C112CKO-)8.3
1 (ill, d, J=1211z, C5-
If) 9.31 (ill, s, C5-It)
Example 4゜9-Fluoro-10-(4-thiomorpholinyl)-7-
Oxo-1,2-dihydro-711-pyrido[3,2,
1-1jl[2+1]benzoxazine-6-carboxylic acid Compound II obtained in Reference Example 0.30g (1,12an
o1), thiomorpholine 1.5ml (14,9關01)
and dimethyl sulfoxide 15i1, and stirred at 75°C for 4 hours. After the reaction, the solvent is distilled off, water is added to the residual liquid, and the precipitated crystals are collected by filtration. This was subjected to column chromatography using chloroform as an eluent, and both desired fractions were collected, concentrated, and recrystallized from DMF, ethanol, and hexane (JblJFk 0.058 g).
融点 ： ２９３℃（分解）
元素分析 ： ＣｌｅＨ＋５ＦＮ２０ｎＳ （ＭＷ
＝３５０．３６８）理論値 Ｈ４，３２％、Ｃ５４，
８５％、Ｎ ８．００％実測値 Ｈ４，３３％、Ｃ
５４，８９％、Ｎ 、７．９３％質微分析 ＝ ３５０
（Ｍつ、３０６，２７６．２３２，１７４ＩＲ： ２
９１０，１７２５，１６２５，１５２０，１４５０，１
２９５，１１１５．８１０（ｃｒ’）ＮＭＲ： ＣＦ
ａＣＯＯＤ （ｐｐｍ）２．８−３．２ （４１１，４
、ｔｈｉｏｍｏｒｐｈｏｌｉｎｅ−ＣＩＩ２Ｓ）３．４
８ （２１１，ｔ、 Ｊ＝ｆｌｌｌｚ、 −Ｃ１１
ＣＩＩ２０−）３．７−４．１ （４１Ｌ Ｊ ｔｔｈ
ｉｏｍｏｒｐｈｏｌｉｎｅ−ＣＩＩＪ）４．８９
（２１１，Ｌ、 Ｊ＝（ｌｌｌｚ、 −ＣＩＩ２ＣＩｌ
ｌＯ−）Ｒ−２！Ｉ（ＩＩＩ、 ｄ、 、Ｉ＝１２１１
ｚ、 Ｃｅ−Ｉｆ）９．２７ （ＩＩＩ、 ｓ、
Ｃｓ−１ｆ）実施例５゜
１Ｏ−（３−アセトアミド−１−ピロリジニル）−９−
フルオロ−７−オキソ−１，２−ジヒドロ−７１１−ピ
リド［３，２＋１−１Ｊ］［２，’］ベンズオキサジン
ー８−カルボン酸参考例で得た化合物ＩＩ ０．３２ｇ
（１，２ｍｍｏｌ）、３−アセトアミドピロリジン１．
０３ｇ（８，０ｍｍｏｌ）及びジメチルスルホキシド１
３ｍ１を仕込み、８０〜９０℃で３０分攪拌する。反応
後、溶媒を留去し残液に水を加えＩＮ−酢酸で中和し、
水浴で攪拌しながら冷却する。析出結晶を濾取し水で洗
浄後乾燥して得る（収量０．４１ｇ）。Melting point: 293℃ (decomposition) Elemental analysis: CleH+5FN20nS (MW
=350.368) Theoretical value H4, 32%, C54,
85%, N 8.00% actual value H4, 33%, C
54.89%, N, 7.93% quality microanalysis = 350
(M, 306,276.232,174IR: 2
910, 1725, 1625, 1520, 1450, 1
295,1115.810 (cr') NMR: CF
aCOOD (ppm)2.8-3.2 (411,4
, thiomorpholine-CII2S) 3.4
8 (211,t, J=fllllz, -C11
CII20-) 3.7-4.1 (41L J tth
iomorpholine-CIIJ) 4.89
(211,L, J=(llllz, -CII2CIl
lO-)R-2! I(III, d, , I=1211
z, Ce-If)9.27 (III, s,
Cs-1f) Example 5゜1O-(3-acetamido-1-pyrrolidinyl)-9-
Fluoro-7-oxo-1,2-dihydro-711-pyrido[3,2+1-1J][2,']benzoxazine-8-carboxylic acid Compound II obtained in Reference Example 0.32 g
(1.2 mmol), 3-acetamidopyrrolidine 1.
03g (8,0mmol) and dimethyl sulfoxide 1
Charge 3ml and stir at 80-90°C for 30 minutes. After the reaction, the solvent was distilled off, water was added to the residual solution, and the mixture was neutralized with IN-acetic acid.
Cool with stirring in a water bath. The precipitated crystals were collected by filtration, washed with water, and dried (yield: 0.41 g).
元素分析 ： Ｃｕ＋ＩＩ＋ｅＦＮ３０ｓ （Ｍ
Ｗ＝３７５．３５６）理論値 Ｈ４，８３％、Ｃ５７
，６０％、Ｎ １１．１９％実測（＋１１ １．１
４．９２ｇ％、Ｃ５７，５４％、Ｎ １１．０８％質量
分析 ： ３１６，２７２，２４１，２０３ （Ｍ
”：３７５無し）ＩＲ： ３２８０．３０Ｂ０，１７
２０，１８３０，１５４５，１５２０，１４４５，１３
７０．８００（ｃｍ−’）ＮＭＲ： ＣＦ３ＣＯ０Ｄ
（ｐｐｍ）２．４（１（５１１，ｂｒｓ、 −ＣＯＣ
Ｉ１３＋ｐｙｒｒｏｌｉｄｉｎｅ−Ｃａ−１１２）３．
２−３．７ （２１１，ｂｒ４−Ｃ１１１Ｃｌ１２０−
）３．７−４．５ （４１Ｌ ｍ、 ｐｙｒｒｏｌｉｄ
ｉｎｅ−Ｃ２−１１２，Ｃｓ−１１２）４、ｔｒ５．１
（３１Ｌ ｌ、 −Ｃ１１２Ｇ１１Ｂ−０−、ｐｙｒ
ｒｏｌｉｄｉｎｅ−Ｃｓ−１１）８．２１ （Ｈｌ
、 ｄ、 Ｊ＝１２１１ｚ、 Ｃ５−Ｉｆ）８．６０
（Ｉｌｌ、 ｂｒｄ、 −ＮＩＩＣＯ−）９．２１
（ＩＩＩ、 ｓ、 Ｃ５−ＩＩ）実施例６゜
１０− （３−アミノ−１−ピロリジニル）−９−フル
オロ−７−オキソ−１，２−ジヒドロ−７１１−ピリド
［３，２，１−ｉｊ］［２，１］ベンズオキサジン−６
−カルボン酸実施例５．で得た化合物０．５０３ｇ（１
，３４順ｏ１）に塩酸・ｔｔｐ酸混液（２： １）
２４ｍ１を加え、１００〜１１０℃で４時間攪拌する。Elemental analysis: Cu+II+eFN30s (M
W=375.356) Theoretical value H4, 83%, C57
, 60%, N 11.19% actual measurement (+11 1.1
4.92g%, C57,54%, N 11.08% Mass spectrometry: 316,272,241,203 (M
”:375 none) IR: 3280.30B0,17
20, 1830, 1545, 1520, 1445, 13
70.800 (cm-') NMR: CF3CO0D
(ppm)2.4(1(511,brs, -COC
I13+pyrrolidine-Ca-112)3.
2-3.7 (211,br4-C111Cl120-
)3.7-4.5 (41L m, pyrrolid
ine-C2-112, Cs-112) 4, tr5.1
(31L l, -C112G11B-0-, pyr
rolidine-Cs-11) 8.21 (Hl
, d, J=1211z, C5-If) 8.60
(Ill,brd, -NIICO-)9.21
(III, s, C5-II) Example 6゜10-(3-amino-1-pyrrolidinyl)-9-fluoro-7-oxo-1,2-dihydro-711-pyrido[3,2,1-ij ][2,1]benzoxazine-6
-Carboxylic acid Example 5. 0.503g (1
, 34 order o1), hydrochloric acid/ttp acid mixture (2:1)
Add 24ml and stir at 100-110°C for 4 hours.
反応後、溶媒を留去し残液にエタノールを加え水浴で攪
拌しながら冷却し０．４０８ｇの粗結晶を得る。これを
クロロホルム・メタノール・２８％アンモニア水（８５
： １５ ： ２） を用いてシリカゲルに吸着させ
た後、カラムクロマトグラフィーに付す。クロロホルム
・メタノール・１１１′酸（８：２：ｉ） で溶出し
、［１的画分を集めて濃縮乾固し、へ渣を２Ｎ−塩酸・
エタノールから再結晶し塩１ｇｌ＃Ａとして得る（収量
０．１０１ｇ）。After the reaction, the solvent was distilled off, ethanol was added to the residual liquid, and the mixture was cooled with stirring in a water bath to obtain 0.408 g of crude crystals. This was mixed with chloroform, methanol, 28% ammonia water (85%
: 15 : 2) and then subjected to column chromatography. Elute with chloroform/methanol/111' acid (8:2:i) and collect the fractions and concentrate to dryness.
Recrystallized from ethanol to obtain 1 gl of salt #A (yield: 0.101 g).
融点 ：２８０．５℃（分解）
元素分析 ７：Ｃ盲ａＨ＋ｅＦＮ３０ａ・ＨＣＱ −Ｉ
ｈＯ理論値 Ｈ４，９４％、Ｃ４９，５６％、Ｎ １
０．８４％実測値 Ｔ−１５，０４％、Ｃ４９，１９
％、Ｎ １０．８１％■Ｒ： ３３００，３０５０，
１６９０，１，０３０，１５５０，１４５０，１０５０
，８１．０（ｃｍ−’）ＮＭＲ： ＣＦａＣＯＯＤ
（ｐｐｍ）２．１−２．７ （２１１，ｂｒ、 ｐｙｒ
ｒｏｌｉｄｉｎｅ−Ｃ４−１１２）２．９４．６ （２
１１，ｂｒ、 −ＣｋＣＩＩｐＯ−）３．７−４．５
（５１１，ｂｒｎ、 ｐｙｒｒｏｌｉｄｉｎｅ−Ｃ２−
１１２，Ｃｒ＋−ｔｉ２．Ｃａ４１）４．５−５．２
（２１１，ｂｒ、 −Ｃ１１２Ｃ＆０−）６．９４．８
（３１１，ｂｒ、 −Ｎ１１３’）８．１５ （
ＩＩＩ、 ｄ、 Ｊ＝１３１１ｚ、 Ｃ１＋−１１）９
．１２ （ＩＩＩ、 ｓ、へ−１１）実施例７゜
９−フルオロ−１０−、（１−ホモピペラジニル）−７
−オキソ−１，２−ジヒドロ−７１１−ピリド［３，２
，１−ｉｊ］［２，１］ベンズオキサジン−６−カルボ
ン酸参考例で得た化合物ＩＩ ０．３ｇ（１，１２關ｏ
１）及びホモピペラジン０．５（！２ｇ（５，８２ｎｎ
ｏｌ）をジメチルスルホキシド３．５ｍ＋１に加え、１
００〜１１０℃で５分間攪拌する。反応後、溶媒を留去
し残液に水を加え攪拌する。析出結晶を濾取し水、メタ
ノール及びアセトンの順に洗浄後乾燥し、ＤＭＦ・エタ
ノールから再結晶して得る（収ｌＩＣ０，２５２ｇ）。Melting point: 280.5℃ (decomposition) Elemental analysis 7: C blind aH + eFN30a・HCQ -I
hO theoretical value H4, 94%, C49, 56%, N 1
0.84% actual value T-15.04%, C49.19
%, N 10.81%■R: 3300,3050,
1690, 1,030, 1550, 1450, 1050
,81.0(cm-')NMR: CFaCOOD
(ppm) 2.1-2.7 (211,br, pyr
rolidine-C4-112) 2.94.6 (2
11,br, -CkCIIpO-)3.7-4.5
(511,brn, pyrrolidine-C2-
112, Cr+-ti2. Ca41) 4.5-5.2
(211,br, -C112C&0-)6.94.8
(311,br, -N113')8.15 (
III, d, J=1311z, C1+-11)9
．． 12 (III, s, to-11) Example 7゜9-Fluoro-10-, (1-homopiperazinyl)-7
-oxo-1,2-dihydro-711-pyrido[3,2
,1-ij][2,1]benzoxazine-6-carboxylic acid Compound II obtained in Reference Example 0.3 g (1,12
1) and homopiperazine 0.5 (!2 g (5,82nn
ol) to 3.5m+1 dimethyl sulfoxide,
Stir for 5 minutes at 00-110°C. After the reaction, the solvent is distilled off, water is added to the remaining liquid, and the mixture is stirred. The precipitated crystals were collected by filtration, washed with water, methanol and acetone in that order, dried, and recrystallized from DMF/ethanol (yield: IC0, 252 g).
元素分析 ： Ｃ＋ｔＨ＋ｅＦＮ３０ａ （ＭＷ
＝３４７．３４６）理論値 Ｈ５，２２ズ、Ｃ５８，
７８ズ、Ｎ １２．１０ズ実測値 ）ｉ ５．４１
％、Ｃ５８，０５％、Ｎ １２．０４％質量分析 ：
３４７ （Ｍ’）、３０５，２８７，２２３，１２９
ＩＲ： ３４５０，３０５０，２９００．１Ｂ２０，
１５７０，１４５５，１３５０，１２８５，８２０，７
５５（ａｍ−’）更に、この結晶を５５％塩酸に加温溶
解しエタノールで結晶化して塩酸塩を得る。Elemental analysis: C+tH+eFN30a (MW
=347.346) Theoretical value H5,22z, C58,
78z, N 12.10z actual measurement) i 5.41
%, C58.05%, N 12.04% Mass spectrometry:
347 (M'), 305, 287, 223, 129
IR: 3450, 3050, 2900.1B20,
1570, 1455, 1350, 1285, 820, 7
55(am-') Furthermore, this crystal is dissolved in 55% hydrochloric acid with heating and crystallized with ethanol to obtain the hydrochloride.
融点 ： ２６５℃（分解）
元素分析 ： Ｃ：＋ｖ４１ｕ＋ＦＮ３０４−１１ｃ
Ｑ・１／２１１ｐＯ理論値 Ｈ５，１３ＬＣ５１，９
８％、Ｎ １０．７０ ％実測値 Ｉ−Ｉ ５．２
８ぶ、Ｃ５２，２０％、Ｎ １０．５４％質量分析 ：
３４７ （Ｍ’）、３０５，２８７，２２９，１７
４，１４０［Ｒ： ３５００，３０３０，２９７０，
１，７２０，１０２０，１５４０，１４４５，１３００
．８０５（ｃｍ−１）ＮＭＲ： ＣＦａＣＯＯＤ （
ｐｐｍ）２．１−２．７ （２１１，ｒｈ、 ｈｏｍｏ
ｐｉｐｅｒａｚｉｎｅ−Ｃｅ−１１２）３．３−４．２
（１０１１，ｍ、 −ＣｋＣ１１＋０−、ｈｏｍｏｐ
ｉｐｅｒａｚｉｎｅ−１１ｅ）４、（１２（２１１，Ｉ
Ｎ、 −Ｃ１１２ＣＩ＋２Ｏ−）８．３１ （Ｉｌ
ｌ、 ｄ、 Ｊ＝１１１１ｚ、 Ｃｅ−ＩＩ）９．３１
（ＩＩＩ、 ｓ、 Ｃ５−Ｉｆ）実施例８゜
９−フルオロ−１０−（４−メチルートホモピペラジニ
ル）−７−オキソ−１，２−ジヒドロ−７１１−ピリド
［３，２，１−ｉｊ］［２，１］ベンズオキサジン−６
−カルボン酸実施例７．で得た遊離塩基化合物０．１４
２ｇ（０，４１１ＮＩｌｌｏｌ）に９０％ギ酸１ｍｌ及
び；１５％ホルマリン１ｍｌを加え１．５時間還流する
。反応後、溶媒を留去し残液にアセトン・エーテル混酸
を加え攪拌し粗結晶を得る。これをクロロホルム・メタ
ノール（，１！ｌ：Ｉ）を溶離液とするカラムクロマト
グラフィーに付す。目的画分を集めて濃縮し、ヘキサン
・エタノールから再結晶して得る（収Ｊ＆ ０．０９５
ｇ）。Melting point: 265℃ (decomposition) Elemental analysis: C: +v41u+FN304-11c
Q・1/211pO theoretical value H5,13LC51,9
8%, N 10.70% Actual value I-I 5.2
8bu, C52, 20%, N 10.54% Mass spectrometry:
347 (M'), 305, 287, 229, 17
4,140[R: 3500,3030,2970,
1,720,1020,1540,1445,1300
．． 805 (cm-1) NMR: CFaCOOD (
ppm) 2.1-2.7 (211, rh, homo
piperazine-Ce-112) 3.3-4.2
(1011, m, -CkC11+0-, homop
iperazine-11e) 4, (12(211,I
N, -C112CI+2O-)8.31 (Il
l, d, J=1111z, Ce-II) 9.31
(III, s, C5-If) Example 8 9-Fluoro-10-(4-methyltohomopiperazinyl)-7-oxo-1,2-dihydro-711-pyrido[3,2,1- ij][2,1]benzoxazine-6
-Carboxylic acid Example 7. Free base compound obtained with 0.14
Add 1 ml of 90% formic acid and 1 ml of 15% formalin to 2 g (0,411 NIllol) and reflux for 1.5 hours. After the reaction, the solvent is distilled off, and acetone/ether mixed acid is added to the remaining liquid and stirred to obtain crude crystals. This was subjected to column chromatography using chloroform/methanol (1!l:I) as an eluent. The target fractions are collected, concentrated, and recrystallized from hexane/ethanol (yield J & 0.095
g).
融点 ： ２０４−６℃（分解）元素分析 ：
Ｃ＋ｅＨ２＠ＦＮａ’Ｏｎ ・１／４Ｈ２０理論値
Ｈ５，６５％、Ｃ５９，０９％、Ｎ １１．４９ズ実
ｌ！ｌ値 Ｈ５，６９％、Ｃ５９，２０％、Ｎ １１
．３４％質量分析 ： ３６１（Ｍつ、３４５，３３１
．’３’１７，２５８１ Ｒ： ２０４０，１７２０
，１（１２５，１４５０，１３８０，’１２７０，８０
５ （ｃｍ−’）１３一
実施例９゜
９−フルオロ−１０−（１−ピラゾリジニル）−７−オ
キソ−１，２−ジヒドロ−７１１−ピリド［３，２，１
，−ｉ、ｉ］［２，Ｉ］ペンズメキサジンー０−カルボ
ン酸参考例で得た化合物Ｉ Ｏ，４０ｇ（１，５關０１
）と粗製のピラゾリジン５．４ｇを仕込み、ジメチルス
ルホキシド４ｍｌを加えて７５〜１１５℃で２５分間攪
拌する。反応後、系に水及び１０％酢酸を加えて水冷下
撹拌する。析出結晶を濾取し水で洗浄後乾燥して得る（
収１ｋ ０．２３ｇ）。Melting point: 204-6℃ (decomposition) Elemental analysis:
C+eH2@FNa'On ・1/4H20 theoretical value
H5.65%, C59.09%, N 11.49%! l value H5, 69%, C59, 20%, N 11
．． 34% mass spectrometry: 361 (M, 345,331
．． '3'17,2581 R: 2040,1720
,1(125,1450,1380,'1270,80
5 (cm-') 13-Example 9゜9-Fluoro-10-(1-pyrazolidinyl)-7-oxo-1,2-dihydro-711-pyrido[3,2,1
, -i,i] [2,I]penzmexazine-0-carboxylic acid Compound IO obtained in Reference Example 40g (1,5
) and 5.4 g of crude pyrazolidine were added, 4 ml of dimethyl sulfoxide was added, and the mixture was stirred at 75 to 115°C for 25 minutes. After the reaction, water and 10% acetic acid were added to the system, and the mixture was stirred under water cooling. The precipitated crystals are collected by filtration, washed with water, and dried (
Yield 1k 0.23g).
元素分析 ′：Ｃ鵞ｓＨ＋ａＦＮａｏ４ （ＭＷ＝３
１９．２９２）理論値 Ｈ４’、４２％、Ｃ５６，４
３％、Ｎ １３．１６％実測値 Ｈ４，５５％、Ｃ５
Ｂ、２３１Ｎ １３．０２ ％質量分析 ： ３１９
（Ｍ’）、２７３，２４５，２１７，１８７実施例１
０゜
９−フルオロ−１０−（２−メチル−１−ピラゾリジニ
ル）−７−オキソ−１，２−ジヒドロ−７１１−ピリド
［３，２１１−ＩＪ］［：２１’］ベンズオキサジン−
６−カルボン酸実施例９．で得た化合物０．２．’１ｇ
（０，７２ｎｎｏｌ）に、９０％ギ酸０．７４ｍ１及び
３５％ホルマリン０．７４Ｉｎｌを加え９０℃で３０分
攪拌する。反応後、溶媒を留去し残液に水を加え攪拌し
粗結晶を得る。これをクロロホルム・メタノール（５０
：１）を溶離液とするカラムクロマトグラフィーに付す
。目的画分を集めて濃縮し、エタノールから再結晶して
得る（収量０．０８に）。Elemental analysis ′: C-sH+aFNao4 (MW=3
19.292) Theoretical value H4', 42%, C56,4
3%, N 13.16% actual value H4, 55%, C5
B, 231N 13.02% Mass spectrometry: 319
(M'), 273, 245, 217, 187 Example 1
0゜9-Fluoro-10-(2-methyl-1-pyrazolidinyl)-7-oxo-1,2-dihydro-711-pyrido[3,211-IJ][:21']benzoxazine-
6-Carboxylic acid Example 9. The compound obtained in 0.2. '1g
(0.72 nnol) were added with 0.74 ml of 90% formic acid and 0.74 Inl of 35% formalin, and stirred at 90°C for 30 minutes. After the reaction, the solvent is distilled off, water is added to the residual liquid, and the mixture is stirred to obtain crude crystals. Add this to chloroform/methanol (50
: Subjected to column chromatography using 1) as an eluent. The desired fractions are collected, concentrated, and recrystallized from ethanol (yield: 0.08).
融点 ： ２１７−８℃
元素分析 ： Ｃ＋ｅＨ＋ｅＦＮａＯ４（ＭＷ＝３３
３．３１９）理論値 Ｈ４，８４％、ｃ ｓ７．ｏ６
ＬＮ １２．６１％実測値 Ｈ４，８４％、ｃ ５
７．４８ズ、Ｎ １２．４７％質量分析 ： ３３３
（Ｍ’）、３１７，２９１，２５９，２２９，２０３
Ｈ（： ２０６０．１７２０．１６２５，１５２０，
１４４０，１２９５，１１８５，８００（ｃｍ−’）Ｎ
ＭＲ’： ＣＰｓＣＯＯＤ （ｐｐｍ）２．８２’
（２１１，ｍ、 ｐｙｒａｚｏｌｉｄｉｎｅ−Ｃａ−
１１２）３、、Ｔｌ （３１１１８，ｐｙｒａｚｏ
ｌｉｄｉｎｅ−ＮＣ１１３）３．５−４．７ （Ｏｆｆ
、 ｍ、 −Ｃ１１１Ｃ１１２０−＋Ｐｙｒａｚｏ１ｉ
ｄｉｎｅ−Ｃａ−１１２＋ｃｓ−１１２）５．０２
（２１１，ｔ、 −ＣＩ１２Ｃ１１１０−）８．４９
（１１１，ｄ、 Ｊ＝１２１１ｚ、 Ｃ５−Ｉｆ
）９．４１ （１，１１，ｓ、 Ｃ３−Ｉｆ）実施
例１１゜
９−フルオロ−１０−（２−イソオキサゾリジニル）−
７−オキソ−１，２−ジヒドロ−７■−ピリド［３ｒ
２１１−ＩＩＩ［２１１コベンズオキサジン−６−カル
ボン酸参考例で得た化合物ＩＩ Ｏ，ｋ（１、１２ｍｍ
ｏｌ）、イソオキサゾリジン塩酸ＪＪＫ ２．４（ｌ１
ｇ（２２゜５ｍｍｏｌ ）及び炭酸水素ナトリウム１．
８８８ｇ（２２，５關ｏ１）を仕込み、ジメチルスルホ
ギシド３（１ｍｌを加えて室温でしばらく攪拌した後１
２０℃で４．５時間攪拌する。反応後、水を加えて水冷
上攪拌し粗結晶を得る。これをクロロホルムを溶離液と
するカラムクロマトグラフィーに付し目的両分を集めて
濃縮し、ヘキサン・クロロホルムから再結晶して得る（
収量０．１０４ｇ）。Melting point: 217-8℃ Elemental analysis: C+eH+eFNaO4 (MW=33
3.319) Theoretical value H4, 84%, c s7. o6
LN 12.61% actual value H4, 84%, c 5
7.48z, N 12.47% Mass spectrometry: 333
(M'), 317, 291, 259, 229, 203
H(: 2060.1720.1625,1520,
1440,1295,1185,800(cm-')N
MR': CPsCOOD (ppm)2.82'
(211, m, pyrazolidine-Ca-
112)3,,Tl (31118,pyrazo
lidine-NC113) 3.5-4.7 (Off
, m, -C111C1120-+Pyrazo1i
dine-Ca-112+cs-112) 5.02
(211,t, -CI12C1110-)8.49
(111, d, J=1211z, C5-If
)9.41 (1,11,s, C3-If) Example 11゜9-Fluoro-10-(2-isoxazolidinyl)-
7-oxo-1,2-dihydro-7■-pyrido [3r
211-III [211 Cobenzoxazine-6-carboxylic acid Compound II obtained in Reference Example O,k (1, 12 mm
ol), isoxazolidine hydrochloride JJK 2.4 (l1
g (22°5 mmol) and sodium hydrogen carbonate 1.
888 g (22.5 o 1) was charged, and dimethyl sulfogide 3 (1 ml) was added and stirred for a while at room temperature.
Stir at 20°C for 4.5 hours. After the reaction, water is added and stirred while cooling with water to obtain crude crystals. This is subjected to column chromatography using chloroform as an eluent, and both desired fractions are collected and concentrated, and recrystallized from hexane/chloroform to obtain (
Yield 0.104g).
融点 ：２２５−６℃（分解）
元素分析 ： Ｃ＋ｓＨ＋３ＦＮ２０ｓ （ＭＷ
＝３２０．２７６）理ｄ−薯イｍ Ｉ−１４，０９
％、ＣＦｌｏ、２５％、Ｎ ８．７５ ％実測値
Ｈ４，０５％、Ｃ５５，９３グ、Ｎ ８．４０％質量
分析 ： ３２０ （Ｍ”）、２７６．２４６，２２
０］、Ｒ： ３０００，１７２０．１［＋２０．１５
２０，１４４５，１３１０，１０３５，８０５（ａｍ−
’）ＮＭＩＺ ： ＣＩ’３ＣＯＯＩｌ （ｐｐ
ｍ）２．０１ （２１１，ｑｕｉｎＬ、 Ｊ＝７
１１ｚ、 １ｓｏｘａＺｏｌｉｄ、１ｎａ−Ｃｎ−１１
ｐ）３．０９ （２１１，ｔ、Ｊ＝ＯＩＩｚ
、 −ＣｋＣＩＩ２０−）４．１０，４．１０ （各
々ＩＩＩ、 ｔ、 Ｊ＝７１１ｚ、 １ｓｏｘａｚｏｌ
ｉｄｉｎｅ−Ｃ３−１１）４．３０ （２１
１，ｔ、、１＝７１１ｚ、１ｓｏｘａｚｏ１．ｔｄｉｎ
ｅ−Ｃｓ−１１２）４．８１ （２１１，ｔ、
Ｊ＝６１１ｚ、 −ＣＩ１２Ｃｊｌ−０−）８．１５
（ｉｌｌ、 ｄ、 Ｊ＝１３＋１ｚ、 Ｃｅ−Ｉ
Ｉ）９．１７ （ＩＩＩ、 ｓ、 Ｃ５−ＩＩ）
７）発明の効果
本発明化合物の抗菌剤としての有用性は、以下の生物学
的試験によりその効果が証明された。試験管内抗菌試験
は日本化学療法学会指定の方法［ＣＩ＋ａｍｏＬ；ｂｅ
ｒａｐｙ、幻、７０ ｏｎｇ＋）］にｖ（へじて実施し
、対照薬物としてはノルフロキサシン、オフロキサシン
を用いた。本発明化合物中、実施例１及び２の化合物に
おける試験結果を表１゜に示す。Melting point: 225-6℃ (decomposition) Elemental analysis: C+sH+3FN20s (MW
=320.276) Ri-d-Im I-14,09
%, CFlo, 25%, N 8.75% Actual value
H4.05%, C55.93g, N 8.40% Mass spectrometry: 320 (M”), 276.246,22
0], R: 3000,1720.1[+20.15
20,1445,1310,1035,805(am-
') NMIZ: CI'3COOIl (pp
m) 2.01 (211, quinL, J=7
11z, 1soxaZolid, 1na-Cn-11
p) 3.09 (211,t, J=OIIz
, -CkCII20-) 4.10, 4.10 (respectively III, t, J=711z, 1soxazol
idine-C3-11) 4.30 (21
1,t,,1=711z,1soxazo1. tdin
e-Cs-112) 4.81 (211,t,
J=611z, -CI12Cjl-0-)8.15
(ill, d, J=13+1z, Ce-I
I) 9.17 (III, s, C5-II)
7) Effects of the Invention The usefulness of the compound of the present invention as an antibacterial agent was proven by the following biological tests. In vitro antibacterial testing is performed using the method specified by the Japanese Society of Chemotherapy [CI+amoL;be
rapy, phantom, 70 ong+)], and norfloxacin and ofloxacin were used as control drugs. Among the compounds of the present invention, the test results for the compounds of Examples 1 and 2 are shown in Table 1.
手続補正書く自発）
平成３年３月７３日
平成２年特許願第３３８９５８号
２、発明の名称
７Ｈ−ピリド［３，２，１−ｉｊ］ ［２，１］ベンズ
オキサジン誘導体
３、補正をする者
事件との関係 特許出願人
住 所 大阪府松原市西大塚１丁目３番４０号名 称
藤本製薬株式会社
代表者 謄本 邦介
４、代理人
住所〒５４０
大阪市中央区北浜東１番１５号
６、補正の対象
明細書の発明の詳細な説明の欄
７、補正の内容
別紙の通り
［別紙］
１、明細書第１１頁１１行と１２行の間に下記を挿入す
る。Procedural amendment voluntarily) March 73, 1991 1990 Patent Application No. 338958 2, Title of invention 7H-pyrido [3,2,1-ij] [2,1] benzoxazine derivative 3, make amendment Relationship with the Patent Case Patent Applicant Address 1-3-40 Nishi-Otsuka, Matsubara City, Osaka Prefecture Name
Fujimoto Pharmaceutical Co., Ltd. Representative: Kunisuke 4, Agent Address: 1-15-6, Kitahama Higashi, Chuo-ku, Osaka 540, Column 7 of the detailed description of the invention in the specification subject to amendment, Contents of amendment as attached [ Attachment] 1. Insert the following between lines 11 and 12 on page 11 of the specification.
ｒ融点： ２６５．５℃〜６℃（分解）」２、同第１
４頁７行と８行の間に下記を挿入する。r Melting point: 265.5°C to 6°C (decomposition)” 2, same No. 1
Insert the following between lines 7 and 8 on page 4.
「融点： ２３９．５℃〜２４０℃（分解）」３、同
第１４頁１１行と１２行の間に下記を挿入する。"Melting point: 239.5°C to 240°C (decomposition)" 3, page 14, insert the following between lines 11 and 12.
’ＩＲ：３０５０，１７２０．１６２０，１５３０，１
４３０，９９０，８１０．（ｃｍ−リＮＭＲ：ＣＦ、Ｃ
Ｃ００Ｄ（ｐｐ＞
２．８０ （２Ｆ（、ｍ、ｐｙｒａｚｏｌｉｄｉｎｅ−
Ｃ４−Ｈ２）４．９６ （２Ｈ，ｔ、−ＣＨ２ＣＨ２叶
）８．４０ （ＩＨ，ｄ、Ｊ＝１２Ｈｚ、Ｃ４−Ｈ）９
．３８ （ＩＨ，Ｓ、Ｃ３−Ｈ）
Ｊ４、同第１４頁２０行に
ｒ２１７−８℃」とあるを
Ｆ２１７℃−８℃（分解）Ｊと訂正する。'IR:3050,1720.1620,1530,1
430,990,810. (cm-Re NMR: CF, C
C00D(pp>2.80 (2F(,m,pyrazolidine-
C4-H2) 4.96 (2H, t, -CH2CH2 leaf) 8.40 (IH, d, J=12Hz, C4-H) 9
．． 38 (IH, S, C3-H)
J4, page 14, line 20, "r217-8°C" is corrected to F217-8°C (decomposition) J.
Claims (1)
アミン類を意味し、これらのアミン類はヘテロ原子を含
むこともあり、低級アルキル基、アミノ基、低級アルキ
ルアミノ基、アセチルアミノ基もしくはヒドロキシル基
が置換することもある。）で表される７Ｈ−ピリド［３
，２，１−ｉｊ］［２，１］ベンズオキサジン誘導体お
よびその薬理学的に許容しうる塩。[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, X means a 5- to 7-membered saturated cyclic amine substituted with a nitrogen atom; 7H-pyrido [3
,2,1-ij][2,1]benzoxazine derivatives and pharmacologically acceptable salts thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP33895890A JP3013262B2 (en) | 1990-11-30 | 1990-11-30 | 7H-pyrido [3,2,1-ij] [2,1] benzoxazine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP33895890A JP3013262B2 (en) | 1990-11-30 | 1990-11-30 | 7H-pyrido [3,2,1-ij] [2,1] benzoxazine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04208288A true JPH04208288A (en) | 1992-07-29 |
| JP3013262B2 JP3013262B2 (en) | 2000-02-28 |
Family
ID=18322938
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP33895890A Expired - Lifetime JP3013262B2 (en) | 1990-11-30 | 1990-11-30 | 7H-pyrido [3,2,1-ij] [2,1] benzoxazine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3013262B2 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8588880B2 (en) | 2009-02-16 | 2013-11-19 | Masimo Corporation | Ear sensor |
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1990
- 1990-11-30 JP JP33895890A patent/JP3013262B2/en not_active Expired - Lifetime
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| Publication number | Publication date |
|---|---|
| JP3013262B2 (en) | 2000-02-28 |
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