KR910005857B1 - 피리돈 카르복실산과 항균제 - Google Patents
피리돈 카르복실산과 항균제 Download PDFInfo
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- KR910005857B1 KR910005857B1 KR1019890006907A KR890006907A KR910005857B1 KR 910005857 B1 KR910005857 B1 KR 910005857B1 KR 1019890006907 A KR1019890006907 A KR 1019890006907A KR 890006907 A KR890006907 A KR 890006907A KR 910005857 B1 KR910005857 B1 KR 910005857B1
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- South Korea
- Prior art keywords
- alkyl
- group
- alkoxy
- hydrogen
- halogen
- Prior art date
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- 239000002253 acid Substances 0.000 title description 4
- 150000007513 acids Chemical class 0.000 title description 2
- 239000003242 anti bacterial agent Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- -1 azido, hydroxy Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 6
- 230000000845 anti-microbial effect Effects 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
- 239000004599 antimicrobial Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 2
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 125000001207 fluorophenyl group Chemical group 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- NMASXYCNDJMMFR-UHFFFAOYSA-N 1-cyclopropyl-6,7,8-trifluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(F)C(F)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 NMASXYCNDJMMFR-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- ZHVULPDNOFUIML-UHFFFAOYSA-N octane;hydrochloride Chemical compound Cl.CCCCCCCC ZHVULPDNOFUIML-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical compound OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- DCTOHCCUXLBQMS-UHFFFAOYSA-N 1-undecene Chemical compound CCCCCCCCCC=C DCTOHCCUXLBQMS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 241000588724 Escherichia coli Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000007101 Muscle Cramp Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- WDCDAAMJNUHOIY-UHFFFAOYSA-N ethyl acetate;2-propan-2-yloxypropane Chemical compound CCOC(C)=O.CC(C)OC(C)C WDCDAAMJNUHOIY-UHFFFAOYSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229940073584 methylene chloride Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
내용없음.
Description
본 발명은 그램양성균과 그램음성균에 대한 우수한 항균 활성도를 나타내는 신규의 피리돈 카르복실산에 관한 것이다.
미국 특허 제 4,382,892호, 프랑스 특허 제 2,563,521호 그리고 미국 특허 4,528,287호 명세서에 서술되어 있는 화합물은 피리돈 카르복실산 항균제라고 공지되어 있다. 이런 통상적인 생성물 중 많은 것은, 인간에게 투여되었을 때, 경련 같은 유해효과를 유발하는 등의 문제점을 가지고 있다. 결론적으로, 본 발명의 목적은 경련과 같은 CNS유해작용을 감소시키면서 강한 항균 활성을 가지고 있는 항균제를 제공하는 것이다.
본 발명은 7-위치에 아자비시클로환을 가지고 있는 피리돈 카르복실산에 관한 것이다. 그리고 본 발명의 화합물은 경구 투여에 의한 항균제로서 특히 가치가 있다.
본 발명은 하기의 화합물 또는 그것의 약학적으로 허용 가능한 염에 관한 것이다.
상기 식에서 R1은 수소, 히드록시 C1-C4알킬, C1-C4알콕시, 옥소, 할로겐이거나, 또는 C1-C4알킬 및 C1-C4알카노일로 구성된 군에서 선택되는 기로 임의 치환된 아미노기이고 : R2는 아지도, 히드록시, C1-C4알콕시, C1-C4알콕시카르보닐, C1-C4알카노일이거나, 또는 C1-C4알킬 및 C1-C4알카노일로 구성된 군에서 선택되는 기로 임의적으로 치환된 아미노기이고 : A는 하기식과 같다.
R3는 수소 또는 카르복시-보호기이고 : R4는 C1-C4알킬, C2-C5알케닐, C3-C5시클로알킬, 모노- 또는 디-플루오로페닐이거나, 또는 C1-C4알킬과 할로겐으로 구성된 군에서 선택되는 기로 임의로 치환된 5- 또는 6-원 헤테로 시클릭기이고 : R5는 수소, 아미노, 히드록시, 또는 C1-C4알콕시이고 :R6는 할로겐이고, X는 CH-(C1-C4알킬), C=CH2, N-H 또는 N-(C1-C4알킬)이고 : Z는 CQ 또는 N이고 : Q는 수소, C1-C4알콕시, 할로겐, C1-C4알킬, 또는 시아노이고 : m은 0 또는 1의 정수이고 : n과 p 각각은 1 내지 3 사이의 정수이다.
명세서에서 C1-C4알킬은 직쇄 또는 측쇄 C1-C4알킬을 의미하며, 메틸, 에틸 n-프로필, 이소프로필, n-부틸, sec-부틸, 이소부틸, tert-부틸등이 있다.
할로겐은 염소, 브롬, 또는 불소를 의미한다.
카르복시-보호기는 C1-C4알킬을 의미한다.
5-또는 6-원 헤테로 시클릭기는 티에닐, 푸릴, 피라닐, 피롤릴, 이미다졸릴, 티아졸릴, 및 피라지닐 등을 의미한다.
본 발명의 화합물(Ⅰ)은 하기식(Ⅱ)의 화합물을 하기식(Ⅲ)의 화합물과 반응시킴으로써 제조될 수 있다.
Hal-A (II) 및
상기식에서 Hal은 할로겐이고, A, R1, R2, m, n 및 p는 상기 정의된 바와 동일한 의미를 갖는다.
치환된 아미노가 R1및/또는 R2에 함유되어 있을 때는 그것을 탈보호 반응시키고, 소망한다면, R1및 / 또는 R2중의 치환된 아미노에서 치환체를 제거시킨 화합물(Ⅰa)를 제조한다.
즉, 화합물(Ⅰ)제조방법은 하기 도식으로 보여진다.
상기식에서 A, R1, R2, m, n과 p는 상기 정의된 바와 동일한 의미를 가지고 있다. 다음은 각각의 단계에 대한 설명이다.
단계 1
본 발명의 화합물(Ⅰ)은 출발물질(Ⅱ)와 아민(Ⅲ)을 반응시킴으로써 제조될 수 있다. 본 반응은 물, 알코올, 아세토니트릴, 디메틸 설폭사이드(DMSO) 또는 디메틸 포름아마이드(KMF) 같은 용매에서 수행할 수 있다. 반응은 15~200℃에서, 바람직하게는 80~120℃에서 또는 용매의 비등점 근처에서 1시간 내지 여러시간 동안 수행된다. 통상의 방법에 따라, 트리에틸아민, 피리딘, 또는 DBU 같은 염기를 반응을 촉진시키기 위해 첨가할 수 있다.
단계 2
치환된 아미노가 식(Ⅰ)의 R1또는 R2에 포함되어 있을 때, Ⅰ은, 원한다면, 탈보호 반응시키고, (Ⅰa)로 되게 된다. 바꾸어 말하면 탈보호 반응은, 수산화나트륨 또는 수산화칼륨 같은 염기와 염산, 아세트산 같은 산을 사용하여 물, 수성 알코올 또는 수성 아세트산 같은 용매에서 실온 내지 용매의 비등점 부근의 온도에서 , 통상의 방법으로 쉽게 시행될 수 있다. 식(Ⅱ)의 출발 물질은 미국 특허 제 4,382,892호 명세서에서 서술되는 방법에 의해 합성될 수 있다.
식(Ⅰ)에 의해 표시되는 화합물은, 원한다면, 통상의 방법으로 그들의 산부가염으로 전환시킬 수 있다.
염-형성 산으로는 예를들면, 염산, 황산 또는 인산 같은 무기산과 메탄설폰산, 락트산, 옥살산 또는 아세트산과 같은 유기산이 있다.
화합물은 또한 나트륨 또는 칼륨 같은 알칼리 금속염으로 도입될 수도 있다.
본 발명의 화합물(Ⅰ)은 경구 또는 비경구로 인간 또는 포유동물에 투여될 수도 있다. 그들은 통상의 약제학적 실시에 의해 정제, 켑슐제, 환제, 과립제, 주사제, 좌제 및 시럽제로 제형화될 수 있다. 약학적으로 허용되는 담체, 희석체, 충전제로는 유당, 자당 밀전분, 감자전분, 마그네슘스테아레이트, 젤라틴, 메틸셀폴로오스, 한천 물 등이 있다. 안정제, 유화제, 습윤 증량제, 완충제, 및 다른 보조제들을 필요하다면 적절히 첨가할 수 있다. 적절한 하루 복용량은 경구 투여에 대해 1~500mg이고, 주사제에 대해 0.1~300mg이다.
하기 실시예, 참고예 및 제형예를 기재하여 본 발명의 실제적인 구현예를 명확하게 한다.
실시예, 참고예, 표에서 사용되는 약어들은 다음 의미를 갖는다.
Et=에틸
Me=메틸
Ac=아세틸
DBU=1.8-디아자비시클로[5,4,0]운데센-1
[실시예 1]
1-시클로프로필-7-[(IR*,5S*,6S*)-6-아미노메틸-3-아자비시클로[3,3,0]옥탄-3-일]-6,8-디플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산〈I-1〉
아세토니트릴 12ml에 현탁된 1-시클로프로필-6,7,8-트리플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산(Ⅱ-1) 200mg과 (IR*,5S*,6S*)-6-아미노메틸-3-아자비시클로[3,3,0] 옥탄(Ⅲ-1) 149mg의 현탁액에 아세토니트릴중의 DBU 161mg의 용액을 교반하에 가하고, 혼합물을 가열 및 2시간 동안 질소대기하에서 환류시킨다. 냉각후, 결과된 결정을 여과로 수집하고 메탄올-클로로포름에서 재결정하여 목적화합물(Ⅰ-1) 108mg(수율 38%)을 산출한다.
융점 : 235~242℃
분석 : C21H23F2N3O3
계산값(%) : C ; 62.21, H ; 5.72, F ; 9.37, N ; 10.36
측정값(%) : C ; 62.43, H ; 5.83, F ; 9.20, N ; 10.28
[실시예 2~20]
반응은 실시예 1에서 서술된 대로 수행하고, 이에 의해 목적화합물(Ⅰ)을 수득한다.
목적화합물의 물리학적 성질을 표 1 및 2에 기재한다.
[표 1]
[표 2]
[실시예 21]
카르복실산(Ⅰ-21)
(1)아세토니트릴 10ml에 현탁시킨 (1R*,5S*)-1-아세틸아미노메틸-3-아자비시클로[3,3,0]옥탄히드로클로라이드(Ⅲ-1) 230mg과 250mg의 현탁액에 DBU 160mg을 교반하에 가하고, 용액을 교반하에 2시간 동안 환류시킨다. 반응 혼합물을 농축하고 잔류물을 메틸렌클로라이드에 용해시킨다. 유기층을 물로 세척하고 Na2SO4로 건조시키고 농축한다. 잔류물을 7% 메탄올-메틸렌클로라이드로 용리하는 실리카 겔 컬럼으로 크로마토그래피한다. 용출액을 농축하고, 잔류물을 에틸아세테이트-이소프로필에테르로 세척하고, 여과로 수집하여, 밝은 황색결정(Ⅰ-21) 208mg을 산출한다.
융점 : 123~125℃
분석 :C26H23F4N3O4·O5CH3COOC2H5:
계산값(%) : C : 59.89, H : 4.85, F : 13.53, N : 7.48
측정값(%) : C : 60.04, H : 4.76, F : 13.58 N : 7.80
(2) 진한 염산 8ml에 화합물(Ⅰ-21') 150mg을 가하고 혼합물을 130℃에서 2시간 동안 환류시킨다. 용매를 농축하고, 잔류물을 메탄올-에테르의 혼합물로 세척하고, 여과하고 메탄올-에틸아세테이트로 재결정하여 목적화합물(Ⅰ-21) 86mg을 결정체로 산출한다.
융점 : 214~216℃
분석 :C24H21F4N3O3·HCl
계산값(%) : C : 56.31, H : 4.33, Cl : 6.93, F : 14.85, N : 8.21
측정값(%) : C : 56.16, H : 4.57, Cl :7.15, F : 14.59, N : 8.23
[실시예 22~42]
반응을 실시예 21에서 서술된 대로 시행하고 이에 목적화합물(Ⅰ)을 수득한다.
목적화합물의 물리적 성질은 표 3 및 4에 기재한다.
[표 3]
[표 4]
[실시예 43]
1-시클로프로필-7-[(1R*,5S*)-6-옥소-3-아자비시클로[3,3,0]옥탄-3-일]-6,8-디플루오르-1,4-디히드로-4-옥소-3-퀴놀린카르복실산(I-43)
아세토니트릴 10ml에 현탁시킨 1-시클로프로필-6,7,8-트리플루오로-1,4-디히드로-4-옥소-3-퀴놀린카르복실산(Ⅱ-1) 200mg과 60-옥소-3-아자비 시클로[3,3,0]옥탄 히드로클로라이드(Ⅲ-3) 350mg의 현탁액에 DBU 330mg 교반하면서 가하고 1시간 동안 환류시킨다.
혼합물을 농축하고 잔류물을 메탄올에서 재결정하여 목적화합물(Ⅰ-43) 78mg을 (수율 :28%)산출한다.
융점 : 158~162℃ (분해)
분석 : C20H18F2N2O4
계산값(%) : C : 61.85, H : 4.67, F : 9.78, N : 7.21
측정값(%) : C : 61.65, H : 4.56, F : 9.54, N : 7.25
[실시예 44]
1-시클로프로필-7-[(1R*,5S*)-6-히드록시-3-아자비시클로[3,3,0]옥탄-3-일]-6,8-디플루오르-1,4-디히드로-4-옥소-3-퀴놀린카르복실산(I-44)
반응은 실시예 43에서 서술된 대로 수행되며, 이에 의해 목적화합물(Ⅰ-44) 150mg(수율=64%)을 수득한다.
분석 : C20H20F2N2O4:
계산값(%) : C ; 61.53, H ; 5.61, F ; 9.03, N ; 7.18
측정값(%) : C ; 61.52, H ; 5.16, F ; 9.51, N ; 7.22
실험(항균범위)
항균 활성도는 일본 화학요법학회 (Japan Society of Chemotherapy)에 의해 지시되는 방법에 따라 최소성장 저해농도를 측정하여 결정하였다. 결과는 표 3에 기재한다.
표에서 A,B,C 및 D는 다음 의미를 나타낸다.
A : 스타필로코커스 아우레우스(Stapyhlococcus aureus)SMITH
B : 스타필로코커스 아우레우스(Stapyhlococcus aureus)SR 77
C : 에쉐리키아 콜라이(Escherichia coli)EC-14
D : 에쉐리키아 콜라이(Escherichia coli)SR 377(R)
시험 미생물은 108세포/ml으로 사용하였다.
[표 5]
본 결과들은 본 발명의 화합물들이 그램 양성균에 특별히 저항하는 강한 항균 활성을 보여준다는 것을 명확하게 해준다.
Claims (2)
- 하기식의 화합물 또는 약학적으로 허용 가능한 그의 염 :
[상기식에서 R1은 수소, 히드록시, C1-C4알킬, C1-C4알콕시, 옥소 할로겐이거나 또는 C1-C4알킬 및 C1-C4알카노일로 구성된 군에서 선택되는 기로 임의 치환된 아미노이고 : R2는 아지도, 히드록시, C1-C4알콕시, C1-C4알콕시카르보닐, C1-C4알카노일이거나, 또는 C1-C4알킬 및 C1-C4알카노일로 구성된 군에서 선택되는 기에 의해 임의 치환된 아미노이고 : A는 하기식과 같다.또는
(식중, R3는 수소 또는 카르복시-보호기이고 : R4는 C1-C4알킬, C2-C5알케닐, C3-C5시클로알킬, 모노- 또는 디-플루오로페닐이거나, 또는 할로겐 및 C1-C|4알킬로 구성된 군에서 선택된 기에 의해 임의 치환된 5- 또는 6-원 헤케로시클릭기이고 : R5는 수소 아미노, 히드록시, 또는 C1-C4알콕시이고 : R6는 하로겐이고 : X는 CH-(C1-C4알킬), C=CH2, N-H 또는 N-(C1-C4알킬)이고 : Z는 CQ또는 N이고 : Q는 수소, C1-C4알콕시, 할로겐, C1-C4알킬, 또는 시아노이고 : m은 0또는 1의 정수이고 : n과 p는 각각은 1 내지 3의 정수이다.)] - 활성성분으로서 제1항에 따른 화합물의 약리학적 유효량 및 담체를 함유하는 항균 조성물.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63-126695 | 1988-05-23 | ||
| JP12669588 | 1988-05-23 | ||
| JP126695 | 1988-05-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR900018098A KR900018098A (ko) | 1990-12-20 |
| KR910005857B1 true KR910005857B1 (ko) | 1991-08-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019890006907A KR910005857B1 (ko) | 1988-05-23 | 1989-05-23 | 피리돈 카르복실산과 항균제 |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US4988709A (ko) |
| EP (1) | EP0343524A1 (ko) |
| JP (1) | JP2844079B2 (ko) |
| KR (1) | KR910005857B1 (ko) |
| AU (1) | AU620401B2 (ko) |
| CA (1) | CA1337523C (ko) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA1336090C (en) * | 1988-08-31 | 1995-06-27 | Isao Hayakawa | Spiro-substituted cyclic amines of quinolone derivatives |
| US5140033A (en) * | 1989-04-03 | 1992-08-18 | Bayer Aktiengesellschaft | Antibacterial 5-alkylquinolonecarboxylic acids |
| HU219403B (hu) * | 1989-08-16 | 2001-04-28 | Pfizer Inc. | Azabiciklo-csoporttal helyettesített kinolon- és naftiridon-karbonsavak és eljárás ezek előállítására |
| KR910009331B1 (ko) * | 1989-10-23 | 1991-11-11 | 재단법인 한국화학연구소 | 디아자비시클로아민 화합물과 그의 제조방법 |
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| EP2149571A4 (en) * | 2007-05-24 | 2010-09-01 | Kyorin Seiyaku Kk | MUTILINE DERIVATIVE WITH A RINGED, HETEROCYCLIC AND AROMATIC CARBOXYLIC ACID STRUCTURE IN A SUBSTITUTE AT POSITION 14 |
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| JPS5746986A (en) * | 1980-09-02 | 1982-03-17 | Dai Ichi Seiyaku Co Ltd | Pyrido(1,2,3-de)(1,4)benzoxazine derivative |
| IE55898B1 (en) * | 1982-09-09 | 1991-02-14 | Warner Lambert Co | Antibacterial agents |
| AU553415B2 (en) * | 1983-09-19 | 1986-07-17 | Abbott Japan Co., Ltd. | 6-fluoro-1-4-dihydro-4-oxo-7-substituted piperazinyl- quinoline-3-carboxylic acids |
| US4571396A (en) * | 1984-04-16 | 1986-02-18 | Warner-Lambert Company | Antibacterial agents |
| JPS60228479A (ja) * | 1984-04-26 | 1985-11-13 | Toyama Chem Co Ltd | １，４−ジヒドロ−４−オキソナフチリジン誘導体およびその塩 |
| IE58742B1 (en) * | 1984-07-20 | 1993-11-05 | Warner Lambert Co | Substituted-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7h-pyrido[1,2,3-de] [1,4]benzoxauine-6-carboxylic acids; sibstituted-5-amino-6-6fluoro-4-oxo.1,4-dihydroquinoline-3 carboxylic acids; substituted-5-amino-6-fluoro-1,4-dihydro-4-oxo-1.8-naphthyridine-3-carboxylic acids; derivatives thereof; pharmaceutical compositions comprising the compounds; and processes for producing the compounds |
| EP0181521A1 (en) * | 1984-10-19 | 1986-05-21 | Otsuka Pharmaceutical Co., Ltd. | Antimicrobial 1-substituted Phenyl-4-oxoquinoline-3-carboxylic acid compounds |
| US4977154A (en) * | 1985-12-12 | 1990-12-11 | Warner-Lambert Company | 5-amino and 5-hydroxy-6-fluoroquinolones as antibacterial agents |
| US4851418A (en) * | 1987-08-21 | 1989-07-25 | Warner-Lambert Company | Naphthyridine antibacterial agents containing an α-amino acid in the side chain of the 7-substituent |
-
1989
- 1989-04-25 JP JP1106948A patent/JP2844079B2/ja not_active Expired - Fee Related
- 1989-05-02 CA CA000598512A patent/CA1337523C/en not_active Expired - Fee Related
- 1989-05-15 US US07/353,321 patent/US4988709A/en not_active Expired - Lifetime
- 1989-05-19 EP EP89109018A patent/EP0343524A1/en not_active Withdrawn
- 1989-05-23 KR KR1019890006907A patent/KR910005857B1/ko not_active IP Right Cessation
- 1989-05-23 AU AU35118/89A patent/AU620401B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0256479A (ja) | 1990-02-26 |
| CA1337523C (en) | 1995-11-07 |
| KR900018098A (ko) | 1990-12-20 |
| AU620401B2 (en) | 1992-02-20 |
| JP2844079B2 (ja) | 1999-01-06 |
| AU3511889A (en) | 1989-11-23 |
| US4988709A (en) | 1991-01-29 |
| EP0343524A1 (en) | 1989-11-29 |
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