TW202128645A - 喹諾酮羧酸衍生物 - Google Patents
喹諾酮羧酸衍生物 Download PDFInfo
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- TW202128645A TW202128645A TW109136780A TW109136780A TW202128645A TW 202128645 A TW202128645 A TW 202128645A TW 109136780 A TW109136780 A TW 109136780A TW 109136780 A TW109136780 A TW 109136780A TW 202128645 A TW202128645 A TW 202128645A
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- Prior art keywords
- compound
- pharmaceutically acceptable
- hydrogen
- alkyl
- prodrug
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- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 98
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 239000000651 prodrug Substances 0.000 claims abstract description 29
- 229940002612 prodrug Drugs 0.000 claims abstract description 29
- 239000012453 solvate Substances 0.000 claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- 208000015181 infectious disease Diseases 0.000 claims abstract description 14
- 230000000813 microbial effect Effects 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 45
- 150000002367 halogens Chemical class 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 33
- 150000002431 hydrogen Chemical class 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 238000000034 method Methods 0.000 abstract description 17
- -1 their stereoisomers Chemical class 0.000 description 27
- 239000000203 mixture Substances 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 10
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
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- 241000894006 Bacteria Species 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
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- 238000001727 in vivo Methods 0.000 description 3
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- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 2
- KWLIGHXPUYUTBH-UHFFFAOYSA-N 2,4-difluoro-3-methoxybenzoic acid Chemical compound COC1=C(F)C=CC(C(O)=O)=C1F KWLIGHXPUYUTBH-UHFFFAOYSA-N 0.000 description 2
- XNXHTLMYBNXMJK-UHFFFAOYSA-N 4-fluoro-2-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=C2NC(=O)C(C(=O)O)=C(F)C2=C1 XNXHTLMYBNXMJK-UHFFFAOYSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
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- XKXIQBVKMABYQJ-UHFFFAOYSA-M tert-butyl carbonate Chemical compound CC(C)(C)OC([O-])=O XKXIQBVKMABYQJ-UHFFFAOYSA-M 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DVFXLNFDWATPMW-IWOKLKJTSA-N tert-butyldiphenylsilyl Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO[Si](C=2C=CC=CC=2)(C=2C=CC=CC=2)C(C)(C)C)[C@@H](OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 DVFXLNFDWATPMW-IWOKLKJTSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
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- 239000003981 vehicle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
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Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- 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
-
- 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
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
一種如下所示之式(I)化合物、其藥學上可接受之鹽、立體異構物、溶劑合物或前藥：
Description
本公開涉及非氟喹諾酮羧酸衍生物、其藥物組合物及其在製備用於治療微生物感染的藥物中的用途。
感染性疾病一直是人類存在以來的主要死亡原因之一，微生物感染嚴重威脅著人類的生命。雖然已經有抗生素被開發出來對抗微生物感染，然而，在過去的幾十年中，與抗生素抗藥性有關的感染已成為醫學領域的主要挑戰。
喹諾酮類是眾所周知的抗微生物劑，其已經在市面上存在超過30年。喹諾酮類藥物包括傳統的氟喹諾酮類藥物(例如吉米沙星、加替沙星、莫西沙星和左氧氟沙星)和非氟喹諾酮類藥物。非氟喹諾酮類藥物(例如奈諾沙星)與氟喹諾酮類藥物的不同之處在於，非氟喹諾酮類藥物在C6部位缺少氟。參見，例如，Ledoussal Benoit等人所公開的WO9914214。喹諾酮類藥物的作用方式是通過抑制細菌DNA旋轉酶(DNA gyrase)。喹諾酮類藥物已被證明在臨床上非常有效，但是這些現有藥物的大規模使用危及了它們未來的長期實用性。隨著對上市抗生素的耐藥性不斷提高，新的抗生素開發有望幫助解決這一重要且尚未滿足的醫療需求。
本公開涉及一種非氟喹諾酮羧酸衍生物，這些衍生物顯示出優異的活性及出乎意料的有利特性。
本文提供以下式(I)的化合物、其醫藥學上可接受的鹽、立體異構體、溶劑合物或前藥：
式中，R1是氫；R2是被1至3個鹵素所取代的環丙基；R3是氫、鹵素、C1-3烷基或C1-3烷氧基，其中，C1-3烷基或C1-3烷氧基可各自任選地被1至3個鹵素所取代；R5、R6和R7中的每一個獨立地是氫、鹵素、C1-3烷基或NH2，其中，C1-3烷基可任選地被1至3個鹵素所取代，條件是R5、R6和R7中只有一個是NH2。
本公開還提供了藥物組合物，其包含本文公開的化合物，例如式(I)的化合物，包括其立體異構體、其對映異構體、其醫藥學上可接受的鹽、溶劑合物或其前藥，和一個或多個醫藥學上可接受的載劑或賦形劑。該藥物組合物可用於治療微生物感染或與病原性微生物有關的疾病。
本公開還提供了一種治療、預防或改善個體微生物感染或病原性微生物介導的病症、疾病或一個或多個症狀的方法，包括向個體施用治療有效量的本文公開的化合物，例如式(I)的化合物，包括其立體異構體、其對映異構體、其醫藥學上可接受的鹽、溶劑合物或其前藥。在相關的實施例中，該方法可以進一步包括給予本文公開的化合物(例如式(I)
的化合物，包括其立體異構體、其對映異構體、其醫藥學上可接受的鹽、溶劑合物或其前藥)以及與一個或多個其他治療劑的組合，其中，本文公開的化合物和一個或多個其他治療劑的組合可以以單一製劑的形式一起施用，或以不同的製劑形式分別施用，此外，本文公開的化合物和其他治療劑可以是同時或依續進行給藥的。
本公開另外提供了製備本文公開的化合物(例如式(I)的化合物，包括其立體異構體、其對映異構體、其醫藥學上可接受的鹽、溶劑合物或其前藥)的方法。
為便於理解本文所闡述之本發明，下文定義多個術語。
一般而言，本文所用之命名法及本文所描述之有機化學、醫藥化學及藥理學中之實驗室程序為熟知且常用於此項技術中之彼等命名法及實驗室程序。除非另外定義，否則本文所用之所有技術及科學術語一般具有與本揭露所屬領域之一般熟習此項技術者通常所理解相同的含義。
術語「約」意謂由一般熟習此項技術者所理解，並且將在使用它的上下文中有所變化。如本文所使用，當涉及諸如量、期間等可測量之數值時，術語「約」意在包括±20%或±10%的變化，包括±5%、±1%或相對於既定值的±0.1%範圍，這樣的變化適合於所公開的方法。
術語「治療」意謂包括緩解或消除病症、疾病或與該病症、疾病或病狀相關聯的一個或多個症狀；或緩解或根除該病症、疾病或症狀
本身的起因。
術語「預防」意謂包括一種實現以下目的之方法：延緩及/或排除病症、疾病或病狀及/或其伴隨症狀之發作；防止個體罹患病症、疾病或病狀；或降低個體罹患病症、疾病或病狀之風險。
術語「個體」係指人類或非屬人類之哺乳動物。術語「個體」及「患者」在本文中可互換使用。在一個實施例中，個體係指人類。
術語「治療有效量」意謂包括在投與時足以防止所治療之病症、疾病或病狀之一或多種症狀之發展或在一定程度上減輕該一或多種症狀的化合物之量。
術語「醫藥學上可接受之載劑」或「醫藥學上可接受之賦形劑」係指醫藥學上可接受之材料、組合物或媒劑，諸如液體或固體填充劑、稀釋劑、溶劑或包封材料，其不會消除活性化合物的生物活性或特性，並且是相對無毒的，亦即，可以將該材料施用於個體而不會引起不良的生物學效應或以有害的方式與組合物中的任何組分相互作用。參見Remington：The Science and Practice of Pharmacy，第21版；Lippincott Williams & Wilkins：Philadelphia,PA,2005；Handbook of Pharmaceutical Excipients，第6版；Rowe等人編；The Pharmaceutical Press and the American Pharmaceutical Association：2009；Handbook of Pharmaceutical Additives，第3版，Ash及Ash編；Gower Publishing Company：2007；Pharmaceutical Preformulation and Formulation，第2版，Gibson編；CRC Press LLC：Boca Raton,FL,2009。
術語「一個或多個」或「一種或多種」意謂一個或大於一的個數(例如2、3、4、5、6或7)。術語「一個或多個」及「一種或多種」在
本文中可互換使用。
術語「鹵素」或「鹵代」(可單獨或與另一個術語組合)係指氟、氯、溴或碘原子。
術語「C1-3烷基」(可單獨或與另一個術語組合)係指含有1至3個碳原子之具支鏈或直鏈單價飽和脂肪族烴基團。C1-3烷基的實例包含甲基、乙基、正丙基、異丙基及諸如此類基團。
術語「C1-3烷氧基」(可單獨或與另一個術語組合)係指基團-OR’，其中R’是C1-3烷基，C1-3烷氧基的實例包含甲氧基、乙氧基、丙氧基及異丙氧基。
術語“羥基保護基”是指防止OH官能團用於進一步反應並且可以在受控條件下被除去的化學基團。羥基保護基是本領域眾所周知的，代表性的保護基包括但不限於烯丙基、甲氧基甲基(MOM)、2-甲氧基乙氧基甲基(MEM)、甲硫基甲基(MTM)、芐氧基甲基(BOM)、2-(三甲基甲矽烷基)乙氧基甲基(SEM)、四氫吡喃基(THP)、2,4-二硝基芐基、二苯甲基(DPM)、三苯甲基(Tr)、對甲氧基苯基二苯甲基(MMTr)、芐基(Bn)、萘基(NAP)、對甲氧基芐基(PMB)、對硝基芐基、甲醯基、醯基(Ac)、氯醯基、甲氧醯基、新戊醯基(Piv)、苯甲醯基(Bz)、對硝基苯甲醯基、對甲氧基苯甲醯基、對溴苯甲醯基、對苯苯甲醯基、三甲基甲矽烷基(TMS)、三甲基甲矽烷基(TES)、異丙基二甲基甲矽烷基(IPDMS)、三異丙基甲矽烷基(TIPS)、叔丁基二甲基甲矽烷基(TBS)、叔丁基二苯基甲矽烷基(TBDPS)、甲基二苯基甲矽烷基、己基二甲基甲矽烷基(TDS)、碳酸甲酯、碳酸乙酯、2,2,2-三氯乙基碳酸酯(Troc)、烯丙基碳酸酯(Alloc)、
9-芴甲基碳酸酯(Fmoc)、芐基碳酸酯(Cbz)、碳酸叔丁酯(Boc)、硫酸鹽、烯丙基磺酸鹽、甲磺酸鹽、芐基磺酸鹽、甲苯磺酸鹽及諸如此類的保護基。
術語「溶劑合物」意謂活性化合物和醫藥學上可接受之溶劑所形成的絡合物。醫藥學上可接受之溶劑的實例包括但不限於水、乙醇、異丙醇、乙酸乙酯、乙酸和乙醇胺。
本文的公開內容涉及式(I)的化合物、醫藥學上可接受的鹽、立體異構體、溶劑合物或其前藥：
其中，R1是氫；
R2是被1至3個鹵素所取代的環丙基；
R3是氫、鹵素、C1-3烷基或C1-3烷氧基，其中，C1-3烷基或C1-3烷氧基可各自任選地被1至3個鹵素所取代；
R5、R6和R7中的每一個獨立地是氫、鹵素、C1-3烷基或NH2，其中，C1-3烷基可任選地被1至3個鹵素所取代，條件是R5、R6和R7中只有一個是NH2。
在另一個實施例中，本文涉及式(II)的化合物、醫藥學上可接受的鹽、立體異構體、溶劑合物或其前藥：
其中，R1是氫；
R2是被1至3個鹵素所取代的環丙基；
R3是氫、鹵素、C1-3烷基或C1-3烷氧基，其中，C1-3烷基或C1-3烷氧基可各自任選地被1至3個鹵素所取代；
R5、R6和R7中的每一個獨立地是氫、鹵素、C1-3烷基或NH2，其中，C1-3烷基可任選地被1至3個鹵素所取代，條件是R5、R6和R7中只有一個是NH2。
在另一個實施例中，本文還涉及式(III)的化合物、醫藥學上可接受的鹽、立體異構體、溶劑合物或其前藥：
其中，R3是氫、鹵素、C1-3烷基或C1-3烷氧基，其中，C1-3烷基或C1-3烷氧基可各自任選地被1至3個鹵素所取代；
R5、R6和R7中的每一個獨立地是氫、鹵素、C1-3烷基或NH2，其中，C1-3烷基可任選地被1至3個鹵素所取代，條件是R5、R6和R7中只有一個是NH2。
以下的實施例包括在式(I)、(II)及/或(III)化合物的定義內。
在一實施例中，R2是被1個鹵素所取代的環丙基；在另一實施例中，R2是被1個氟原子所取代的環丙基。
在一實施例中，R3是鹵素、C1-3烷基或C1-3烷氧基；在另一實施例中，R3是氯原子、甲基或甲氧基。
在一實施例中，R5是氫、鹵素、可被1至3個鹵素所取代的C1-3烷基或是NH2；在另一實施例中，R5是氫、氟原子、C1-3烷基或NH2；在另一實施例中，R5是氫或NH2；在其他實施例中，R5是氫；在其他實施例中，R5是NH2。
在一實施例中，R6是氫、鹵素、可被1至3個鹵素所取代的C1-3烷基或是NH2；在另一實施例中，R6是氫、氟原子、可被1至3個鹵素所取代的C1-3烷基或NH2；在另一實施例中，R6是NH2；在其他實施例中，R6是氫、氟原子、可被1至3個鹵素所取代的C1-3烷基。
在一實施例中，R7是氫、鹵素或可被1至3個鹵素所取代的C1-3烷基；在另一實施例中，R7是氫、鹵素或C1-3烷基；在另一實施例中，R7是氫、氟原子或甲基。
在一實施例中，本文所公開的化合物可選自：
本公開的化合物是針對廣泛的病原微生物的有效抗微生物劑，其具有出乎意料的抗微生物活性和對微生物耐藥性的敏感性小的特性。
除非指定特定立體化學，否則本文所提供之化合物意欲涵蓋所有可能的立體異構體。當本文所提供之化合物含有烯基或伸烯基時，化合物可以一種幾何順式/反式(或Z/E)異構體形式存在或以其混合物形式存
在。當結構異構體可經由低能量障壁相互轉化時，化合物可以單一互變異構體形式或互變異構體之混合物形式存在。此在含有例如亞胺基、酮基或肟基之化合物中可呈質子互變異構形式；或在含有芳族部分之化合物中呈所謂的價互變異構形式。由此得出結論：單一化合物可呈現一種以上類型之異構現象。
本文所提供之化合物可為對映異構純的，諸如單一對映異構體或單一非對映異構體或立體異構混合物，諸如對映異構體混合物、外消旋混合物或非對映異構體混合物。因而，熟習此項技術者應認識到對於經歷活體內差向異構化反應之化合物而言，投與呈(R)形式之化合物與投與呈(S)形式之化合物等效。製備/分離個別對映異構體之習知技術包括自適合光學純前驅體合成、自非對掌性起始物質不對稱合成或拆分對映異構體混合物，例如對掌性層析、再結晶、拆分、非對映異構鹽形成或在衍生成非對映異構加合物後分離。
當本文提供的化合物包含酸性或鹼性部分時，它也可以作為醫藥學上可接受的鹽提供。醫藥學上可接受的鹽通常由醫藥學上可接受的無毒鹼或酸(包括無機或有機鹼以及無機或有機酸)製備。適用於製備醫藥學上可接受之鹽的酸包括但不限於乙酸鹽、抗壞血酸鹽、己二酸鹽、海藻酸鹽、天冬胺酸鹽、苯磺酸鹽、苯甲酸鹽、碳酸氫鹽、硫酸氫鹽、酒石酸氫鹽、硼酸鹽、溴化物、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、右旋樟腦磺酸鹽、碳酸鹽、氯化物、克拉維酸鹽(clavulanate)、檸檬酸鹽、環戊烷丙酸鹽、二乙基乙酸、二葡萄糖酸鹽、二鹽酸鹽、十二烷基磺酸鹽、依地酸鹽、乙二磺酸鹽、依託酸鹽(estolate)、乙磺酸鹽、乙烷磺酸鹽、甲酸鹽、
富馬酸鹽、葡庚糖酸鹽、葡庚酸鹽、葡萄糖酸鹽、麩胺酸鹽、甘油磷酸鹽、對羥乙醯胺基苯胂酸鹽(glycollylarsanilate)、半硫酸鹽、庚酸鹽、己酸鹽、己基間苯二酚鹽、哈胺(hydrabamine)、氫溴酸鹽、鹽酸鹽、2-羥基乙烷磺酸鹽、羥基萘甲酸鹽、碘化物、異菸鹼酸鹽、羥乙磺酸鹽、乳酸鹽、乳糖酸鹽、月桂酸鹽、蘋果酸鹽、馬來酸鹽、扁桃酸鹽、甲磺酸鹽、甲基溴化物、甲基硝酸鹽、甲基硫酸鹽、甲烷磺酸鹽、黏酸鹽、2-萘磺酸鹽、萘磺酸鹽、菸鹼酸鹽、硝酸鹽、N-甲基葡萄糖胺銨鹽、油酸鹽、草酸鹽、雙羥萘酸鹽(恩波酸鹽(embonate))、棕櫚酸鹽、泛酸鹽、果凍酸鹽、過硫酸鹽、磷酸鹽/磷酸氫鹽、庚二酸鹽、苯基丙酸鹽、聚半乳糖醛酸鹽、丙酸鹽、柳酸鹽、硬脂酸鹽、硫酸鹽、次乙酸鹽、琥珀酸鹽、鞣酸鹽、酒石酸鹽、茶氯酸鹽、硫氰酸鹽、甲苯磺酸鹽(tosylate)、三乙碘化物、三氟乙酸鹽、十一酸鹽、戊酸鹽及諸如此類。適用於製備醫藥學上可接受之鹽的鹼包括但不限於氫氧化鎂、氫氧化鈣、氫氧化鉀、氫氧化鋅或氫氧化鈉；及有機鹼，諸如第一、第二、第三及四級、脂族及芳族胺，包括L-精胺酸、苄苯乙胺(benethamine)、苄乙二胺(benzathine)、膽鹼、二甲胺乙醇、二乙醇胺、二乙胺、二甲胺、二丙胺、二異丙基胺、2-(二乙胺基)-乙醇、乙醇胺、乙胺、乙二胺、異丙胺、N-甲基-葡糖胺、海卓胺(hydrabamine)、1H-咪唑、L-離胺酸、嗎啉、4-(2-羥乙基)-嗎啉、甲胺、哌啶、哌嗪、丙胺、吡咯啶、1-(2-羥乙基)-吡咯啶、吡啶、啶、喹啉、異喹啉、二級胺、三乙醇胺、三甲胺、三乙胺、N-甲基-D-葡糖胺、2-胺基-2-(羥甲基)-1,3-丙二醇、胺丁三醇及諸如此類。
本文所提供之化合物亦可以前藥形式提供，其為例如式(I)
之化合物的官能性衍生物，且可易於活體內轉化成母體化合物。前藥通常適用，因為在一些情況下，其可能比母體化合物更容易投與。其可例如藉由經口投藥而生物利用，而母體化合物不能。前藥亦可在醫藥組合物中相較於母體化合物具有增強的溶解度。前藥可藉由各種機制轉化成母藥，包括酶促方法及代謝水解。
本公開提供醫藥組合物，其包含本公開所提供的化合物，例如式(I)化合物(包括其立體異構體或非對映異構體、或其醫藥學上可接受的鹽、溶劑合物或前藥)作為活性成分，以及至少一個醫藥學上可接受的載劑或賦形劑。
適合之載劑或賦形劑為熟習此項技術者所熟知，且適合之賦形劑的非限制性實例提供於本文中。特定賦形劑是否適合於併入醫藥組合物或劑型中視此項技術中熟知之多種因素而定，包括(但不限於)投藥方法。載體或賦形劑可包括黏合劑、填充劑、稀釋劑、崩解劑、pH調節劑、濕潤劑、潤滑劑、滑動劑、著色劑、染料遷移抑製劑(dye-migration inhibitors)、甜味劑、調味劑、乳化劑、懸浮和分散劑、防腐劑、溶劑、非水性液體、有機酸和二氧化碳來源及諸如此類。載體或賦形劑的實例包括但不限於水、乳糖、右旋糖、果糖、蔗糖、山梨糖醇、甘露醇、聚乙二醇、丙二醇、澱粉、樹脂、明膠、海藻酸鹽、矽酸鈣、磷酸鈣、纖維素、水性糖漿、甲基纖維素、聚乙烯吡咯烷酮、對羥基苯甲酸山梨酯烷基酯、滑石粉、硬脂酸鎂、硬脂酸、甘油、各種油，例如芝麻油、橄欖油和大豆油，及諸如此類。
本公開的藥物組合物包含本公開的化合物(例如，包括其立
體異構體或非對映異構體的式(I)化合物、或其醫藥學上可接受的鹽、溶劑合物或前藥)，以及一個或多個醫藥學上可接受的載劑或賦形劑，和任選的其他治療成分或佐劑。該藥物組合物包括適合於經口、直腸、局部和腸胃外(包括皮下、肌肉內和靜脈內)給藥的組合物。這些劑型可以根據本領域技術人員已知的常規方法和技術來製備。
本公開所提供之醫藥組合物可以單位劑型或多重劑型提供。如本公開所用之單位劑型係指以物理方式分散適合於向人類及動物個體投與之單元，且如此項技術中已知地個別封裝。各單位劑量含有預定量之活性成分，其與所需藥物載劑或賦形劑結合足以產生所要之治療效應。單位劑型之實例包括安瓿、注射器及個別封裝之錠劑及膠囊。舉例而言，100mg單位劑量在封裝之錠劑或膠囊中中含有約100mg活性成分。單位劑型可以其部分或倍數投與。多重劑型為複數個封裝於單一容器中的待以分離之單位劑型形式投與的相同單位劑型。多重劑型之實例包括小瓶、錠劑或膠囊之瓶，或品脫、加侖之瓶。
本公開所提供之醫藥組合物可一次性或以時間間隔多次投與。應理解，精確劑量及治療持續時間可隨所治療之患者的年齡、體重及條件而變化，且可使用已知測試協定憑經驗確定或藉由自活體內或活體外測試或診斷資料外推來確定。此外，應理解，對於任何特定個體，應根據個體需要及投與調配物或監督調配物投藥之個人的專業判斷隨時間推移而調整具體劑量方案。
本公開所提供的用於經口投藥之醫藥組合物可以用於經口投藥之固體、半固體或液體劑型提供。如本公開所用，經口投藥亦包括頰
內、經舌及舌下投藥。適合的口服劑型包括但不限於錠劑、速溶劑、咀嚼錠、膠囊、丸劑、帶狀物、糖衣錠、口含錠、片劑、扁囊劑、丸粒、藥用口嚼錠、塊狀粉末、發泡或非發泡粉末或顆粒、口服噴霧、溶液、乳液、懸浮液、粉片、撒劑、酏劑、糖漿劑、脂質體、膠束、微球體、奈米系統、緩釋劑及諸如此類。
本公開所提供之醫藥組合物可藉由注射、灌注或植入而非經腸(腸胃外)投與，以用於局部或全身投藥。如本公開所用，非經腸投藥包括靜脈內、動脈內、腹膜內、鞘內、心室內、尿道內、胸骨內、顱內、肌內、滑膜內、膀胱內及皮下投藥。本公開提供的用於腸胃外給藥的藥物組合物可以配製成適合於腸胃外給藥的任何劑型，包括溶液、懸浮液、乳液、膠束、脂質體、微球體、奈米系統和適合於注射前在液體中的溶液或懸浮液的固體形式。這樣的劑型可以根據本領域技術人員已知的常規方法和技術來製備。
本公開所提供之醫藥組合物可向皮膚、孔口或黏膜局部投與。如本公開所用，局部投藥包括經皮(皮內)、經結膜、角膜內、眼內、經眼、經耳、透皮、經鼻、經陰道、經尿道、經呼吸道及經直腸投藥。本公開所提供之醫藥組合物可以適合於局部投藥之任何劑型調配以獲得局部或全身作用，包括乳液、溶液、懸浮液、乳膏、凝膠、水凝膠、軟膏、敷粉、敷料、酏劑、洗劑、懸浮液、酊劑、糊劑、發泡體、膜、氣霧劑、沖洗劑、噴霧劑、栓劑、繃帶及經皮貼片。本公開所提供之醫藥組合物之局部調配物亦可包含脂質體、膠束、微球體、奈米系統及其混合物。
本公開還提供所公開的化合物，例如式(I)的化合物(包
括立體異構體或其對映異構體、或其醫藥學上可接受的鹽、溶劑合物或前藥)與一種或多種其他治療劑(包括但不限於第二種不同的抗微生物劑)的組合。在一個實施例中，本公開之化合物與一種或多種另外的治療劑組合還可以同時、分開或依序施用。
本公開還提供了套組(Kit)，其包含本公開所提供的化合物，例如式(I)的化合物(包括立體異構體或其對映異構體、或其藥學上可接受的鹽、溶劑合物或前藥)，及/或不同劑型的其他活性成分。套組可進一步包含使用說明書，例如用於治療微生物感染的說明書。使用說明通常是書面說明，但是包含說明的電子存儲介質(例如磁盤或光盤)也是可以接受的。
本文還提供了一種治療、預防或改善個體微生物感染或病原性微生物介導的病症、疾病或一個或多個症狀的方法，包括向個體施用治療有效量的本文公開的化合物，例如式(I)的化合物，包括其立體異構體、其對映異構體、其醫藥學上可接受的鹽、溶劑合物或其前藥。這種微生物感染或病源性微生物介導的疾病的一個或多各症狀包括(例如)中樞神經系統感染、外耳感染、中耳感染(例如急性中耳炎)、顱竇感染、眼部感染、口腔感染(例如牙齒、牙齦和粘膜感染)、上呼吸道感染、下呼吸道感染(包括肺炎)、泌尿生殖系統感染、胃腸道感染、婦科感染、敗血病、敗血症、腹膜炎、骨和關節感染、皮膚和皮膚結構的感染、細菌性心內膜炎、燒傷、手術的抗菌預防、術後患者或免疫抑制患者的抗菌預防(例如接受癌症化療的患者或器官移植患者)。
以下說明合成本公開示例化合物的方法。除非另有說明，否
則所有試劑和溶劑均購自商業來源並且無需進一步純化即可使用。所有反應均在乾燥氮氣或氬氣下進行，並使用Merck Silica Gel 60 F254玻璃背板藉由薄層色譜(TLC)監測。藉由Merck Silica Gel 60(0.040-0.063mm,230-400mesh)進行管柱層析。通過Varian Mercury-300和Varian Bruker AVIII-500光譜儀測量1H NMR和13C NMR光譜，化學位移(δ)以每百萬分之一(ppm)計且相對於溶劑共振峰。使用以下縮寫來表示多重性：s(單重態)、d(雙重態)、t(三重態)、q(四重態)、quin(五重態)、m(多重態)或br(寬)。藉由HP Hewlett Packard 1100系列來測量低分辨率質譜。
式(I)化合物可依方案1的通用步驟來合成：
在一實施例中，可以如方案1所示的方法製備式(I)化合物。首先通過常規的喹諾酮合成方法將化合物A轉化為化合物B。隨後，通過側鏈偶聯延伸方法將側鏈基團G鍵結到化合物B以獲得化合物C。將化合物C去
保護以獲得化合物D。對於方案1中所示的化合物，其中R1、R2和R3如本文所述的任何實施例所定義，R是羥基保護基。
藉由以下非限制性實施例將進一步理解本公開。
實施例1：化合物1至15的製備及表徵
對於所有以下實例，可使用熟習此項技術者已知之標準處理及純化方法。除非另外指示，否則所有溫度均以℃(攝氏度)表示。除非另外指出，否則所有反應均在室溫下進行。本文中之合成方法意欲經由使用具體實例來例示可適用之化學方法且不指示本發明之範疇。在本公開所描述之實例中使用的起始材料為市售可得的或可藉由熟習此項技術者已知之方法來製備。
化合物1(7-(3-氨基-4-甲基-哌啶-1-基)-1-(2-氟-環丙基)-8-甲氧基-4-氧代-1,4-二氫-喹啉-3-羧酸的合成。
化合物I-5首先按照以下所示方案由市售的2,4-二氟-3-甲氧基-苯甲酸進行製備：
(b)(1R,2S)-2-fluorocyclopropanamine 4-methylbenzenesulfonate,TEA,DCM；
(c)NaH,THF；(d)12N HCl,EtOH,reflux；(e),H3BO3,Ac2O,AcOH,
在環境溫度下，向2,4-二氟-3-甲氧基-苯甲酸(12g，63.8
mmol)在100毫升甲苯的溶液中滴加DMF(1mL)和亞硫醯氯(23mL，316mmol)。將混合物攪拌3小時，接著真空濃縮得到棕色油狀物。向(E)-3-(二甲基氨基)丙烯酸乙酯(11.8mL，107mmol)和TEA(13.8mL，95.6mmol)在50毫升甲苯的攪拌溶液中逐滴加入20毫升在甲苯溶液中的棕色油狀物。將反應混合物回流16小時，接著用100毫升的水洗滌，用MgSO4乾燥並真空濃縮，得到化合物I-1(20g)。
在冰浴中向化合物I-1(20g)的DCM(300mL)溶液中添加TEA(20mL，138mmol)和(1R,2S)-2-氟環丙胺-4-甲基苯磺酸鹽(20g，80.8mmol)，將混合物持續攪拌2小時，接著用200毫升的水洗滌，用MgSO4乾燥並真空濃縮，得到化合物I-2(21g)。
在0℃下向氫化鈉(2.7g，67.5mmol)在100毫升的甲苯溶液中滴加100毫升在甲苯溶液中的化合物I-2(21g)，攪拌1小時。在0℃下將反應混合物逐滴加入100毫升的10%H2SO4，然後攪拌30分鐘。通過過濾收集沉澱物，並用水洗滌以得到化合物I-3(15g，產率73%)。
將化合物I-3(15g，46.4mmol)在200毫升EtOH和12N HCl(19.5mL，230mmol)的混合物加熱並攪拌16小時。冷卻後，通過過濾收集沉澱物，並用水洗滌，得到化合物I-4(12.5g，產率92%)。
將H3BO3(1g，16.2mmol)在Ac2O(21mL，222mmol)的溶液加熱至115℃，並攪拌30分鐘。在115℃下於1小時內將兩部分的H3BO3(3.2g，51.6mmol)逐步加入反應中。在115℃下向反應混合物添加AcOH(30mL)，並攪拌30分鐘。在115℃下向反應混合物進一步添加化合物I-4(12.5g，42.3mmol)，並攪拌16小時。在0℃下將200毫升的水滴加到反應
混合物中並攪拌10分鐘。通過過濾收集沉澱物，並用水洗滌以得到化合物I-5(15g，產率86%)。
進一步，通過以下所示的合成方式製備化合物1
在10毫升的燒瓶中，添加化合物I-5(0.17g，0.4mmol)、化合物I-6(0.10g，0.46mmol)的乙腈(3mL)溶液及三乙胺(0.08mL，0.6mmol)。將反應混合物加熱至50℃維持15小時，接著將反應混合物冷卻至20℃，然後在30±10℃下添加10%的NaOH(0.5mL，2.4mmol)，並攪拌1小時。相分離後收集有機層。用2毫升乙腈萃取水相並與有機層合併。含有化合物I-7的合併有機層無需進一步處理即可用於下一步。
向最後步驟取得的化合物I-7的2毫升CH2Cl2混合物中，添加0.33毫升的2N HCl。在室溫攪拌2小時後，將混合物用蒸餾水(2.5mL)稀釋。接著該水溶液用二氯甲烷(5mL×3)洗滌，以30%氨水滴定至pH=7.8-8.0，形成黃色粉末漿液。在兩小時內將所得漿液冷卻至15±2℃並抽濾。將黃色粉末依次用蒸餾水(1mL×2)和95%EtOH(0.5mL×2)洗滌，然後真空乾燥，得到化合物1(0.1g，產率67%)。MS：m/z 390.2(M+1)；1H NMR(300MHz,CD3OD)δ ppm 8.83(s,1H),8.14(d,1H),7.35(d,1H),5.06(s,1H),4.18-4.08(m,2H),3.83(s,1H),3.14-3.09(m,1H),2.92-2.85(m,2H),1.99-1.94(m,1H),1.74-1.70(m,4H),1.19(d,3H)。
依照前述方案1以及製備化合物1中所描述的相似方法來製備化合物2至化合物15。化合物2至15的光譜分析數據如下所列：
化合物2：MS：m/z 404.2(M+1)；1H NMR(300MHz,CD3OD)δ ppm 8.84(s,1H),8.15(d,1H),7.36(d,1H),5.08(s,1H),4.19-4.03(m,2H),3.85(s,1H),3.31(s,1H),2.97-2.90(m,2H),2.14-1.34(m,7H),1.06-1.01(m,3H)。
化合物3：MS：m/z 418.2(M+1)；1H NMR(300MHz,CD3OD)δ ppm 8.84(s,1H),8.13(s,1H),7.36(s,1H),4.26-4.17(m,2H),3.77-3.61(m,1H),3.10-2.94(m,2H),2.15-2.12(m,1H),1.71-1.17(m,10H),1.03-0.93(m,3H)。
化合物4：MS：m/z 444.2(M+1)；1H NMR(300MHz,CD3OD)δ ppm 8.87(s,1H),8.18(d,1H),7.39(d,1H),5.07(s,1H),4.16-3.72(m,4H),3.29-2.71(m,3H),2.29(d,1H),1.98-1.67(m,3H)。
化合物5：MS：m/z 394.2(M+1)；1H NMR(300MHz,CD3OD)δ ppm 8.84(s,1H),8.15(d,1H),7.36(d,1H),5.05-4.84(m,2H),4.18-3.64(m,4H),3.03(t,2H),2.39-2.05(m,2H),1.49(m,2H)。
化合物6：MS：m/z 380.2(M+1)；1H NMR(300MHz,CD3OD)δ ppm 8.85(s,1H),8.16(d,1H),7.34(d,1H),4.17-4.15(m,1H),3.92-3.85(m,2H),3.70-3.51(m,2H),3.29-2.94(m,2H),2.22-1.47(m,6H)。
化合物7：MS：m/z 394.2(M+1)；1H NMR(300MHz,CD3OD)δ ppm 8.88(s,1H),8.31(d,1H),7.43(d,1H),5.14(s,1H),4.39(s,1H),3.87-3.47(m,2H),3.29-2.93(m,3H),2.03-1.33(m,5H),1.21(d,3H)。
化合物8：MS：m/z 408.2(M+1)；1H NMR(300MHz,CD3OD)δ ppm 8.89(s,1H),8.35(d,1H),7.45(d,1H),5.15(s,1H),4.38(s,1H),3.85
(d,1H),3.53-2.99(m,4H),2.17-2.14(m,1H),1.98-1.32(m,6H),1.07-1.02(m,3H)。
化合物9：MS：m/z 360.2(M+1)；1H NMR(300MHz,CD3OD)δ ppm 8.90(s,1H),8.26(d,1H),7.38(d,1H),4.30-4.28(m,1H),3.62-3.58(m,3H),3.31-3.13(m,2H),2.77(s,3H),2.30-1.68(m,5H),1.32-1.28(m,2H)。
化合物10：MS：m/z 388.2(M+1)；1H NMR(300MHz,CD3OD)δ ppm 8.87(d,1H),8.25(d,1H),7.36(d,1H),4.27(s,1H),3.68(s,1H),3.38-2.91(m,5H),2.17(d,1H),1.84-1.23(m,9H),1.07-1.02(m,3H)。
化合物11：MS：m/z 394.2(M+1)；1H NMR(300MHz,CD3OD)δ ppm 8.90(d,1H),8.37(d,1H),7.48(d,1H),4.39-4.37(m,1H),3.75(s,1H),3.59-3.48(m,2H),3.34-3.29(m,2H),2.77(t,1H),2.32(br,1H),2.05-1.98(m,1H),1.76-1.68(m,2H),1.63-1.36(m,1H),1.09-1.06(m,3H)。
化合物12：MS：m/z 374.2(M+1)；1H NMR(300MHz,CD3OD)δ ppm 8.86(d,1H),8.26(d,1H),7.34(d,1H),4.27-4.23(m,1H),3.77(s,1H),3.38(s,1H),2.79(s,3H),2.62-2.59(m,1H),2.32-1.70(m,6H),1.33-1.07(m,5H)。
化合物13：MS：m/z 394.2(M+1)；1H NMR(300MHz,CD3OD)δ ppm 8.86(s,1H),8.18(d,1H),7.39(d,1H),5.18-4.89(m,2H),4.19-4.08(m,3H),3.82-3.79(m,4H),3.22-3.00(m,2H),2.59-2.51(m,1H),1.98-1.49(m,3H)。
化合物14：MS：m/z 394.2(M+1)；1H NMR(300MHz,CD3OD)δ ppm 8.89(s,1H),8.16(d,1H),7.38(d,1H),5.08-4.73(m,1H),4.26-4.13(m,3H),3.85-3.81(m,4H),3.53-3.49(m,1H),3.30-2.99(m,2H),2.26(br,1H),1.98-1.58(m,3H)。
化合物15：MS：m/z 380.1(M+1)；1H NMR(300MHz,CD3OD)δ ppm 8.89(s,1H),8.34(d,1H),7.43(d,1H),5.15(s,1H),4.40-4.37(m,1H),3.76-3.66(m,2H),3.36-3.34(m,1H),3.16-3.00(m,2H),2.19-1.40(m,6H)。
實施例2：MIC(最低抑菌濃度)測定
根據臨床和實驗室標準協會的指南，使用微量稀釋法確定了針對所有細菌菌株的化合物的MIC。從新鮮條紋培養板中選出來自兩個或三個克隆的細菌，並在培養液中溫育8小時。然後將細菌培養物用雙倍濃縮培養液稀釋至終濃度為5×105CFU/ml。通過用DMSO稀釋儲備溶液來製備測試化合物。將稀釋的細菌懸浮液添加到單個微孔中的等體積藥物溶液中，並在37℃下培育24小時。沒有可見細菌生長的微孔中的最小濃度定義為MIC。所有MIC測定在不同的日期重複兩次。化合物1-15對革蘭氏陽性(gram(+))和革蘭氏陰性(gram(-))細菌的MIC如下所示：
此外，觀察到在C7位含有哌啶和在C1位含有氟取代的環丙基的本揭露式(I)化合物出乎意料地表現出比結構相似的類似化合物更高的抑制細菌生長的效力。比較例化合物(結構上相似的類似化合物)和實施例化合物(在C7位含有哌啶和在C1位含有氟取代的環丙基)之間的MIC差異的結果顯示在下表中：
這些結果表示，與其結構上相似的類似比較例化合物相比，本揭露的化合物出乎意料地表現出更高的抑制細菌生長的效力。
其他實施例
說明書中所揭示的所有特徵可以以任意的組合方式結合。說明書中所揭示的各種特徵可以被起到相同、等同或類似目的的特徵所替換。因此，除非另有說明，所揭示的各種特徵僅僅是一系列等同或類似特徵的示例。
通過以上說明，本領域技術人員可以很容易地確定本公開的主要特徵，同時可以在不背離本公開的精神和範圍的前提下，對本公開進行各種改變和改良，以使其適用於各種應用和條件。因此，其他的實施方式也在所附申請專利範圍之內。
Claims (10)
- 一種式(I)化合物、其醫藥學上可接受之鹽、立體異構體、溶劑合物或前藥，
其中，R1是氫；R2是被1至3個鹵素所取代的環丙基；R3是氫、鹵素、C1-3烷基或C1-3烷氧基，其中，C1-3烷基或C1-3烷氧基可各自任選地被1至3個鹵素所取代；R5、R6和R7中的每一個獨立地是氫、鹵素、C1-3烷基或NH2，其中，C1-3烷基可任選地被1至3個鹵素所取代，條件是R5、R6和R7中只有一個是NH2。 - 如請求項1的化合物、其醫藥學上可接受之鹽、立體異構體、溶劑合物或前藥，其中，式(I)化合物是以式(II)表示：
- 如請求項1的化合物、其醫藥學上可接受之鹽、立體異構體、溶劑合物或前藥，其中，式(I)化合物是以式(III)表示：
- 如請求項1到3中任1項的化合物、其醫藥學上可接受之鹽、立體異構體、溶劑合物或前藥，其中，R3是氯原子、甲基或甲氧基。
- 如請求項1至3中任1項的化合物、其醫藥學上可接受之鹽、立體異構體、溶劑合物或前藥，其中，R5是氫或NH2；R6是氫、鹵素、可任選地被1至3個鹵素所取代的C1-3烷基、或NH2；R7是氫、鹵素或C1-3烷基；條件是R5和R6中只有一個是NH2。
- 如請求項1或2的化合物、其醫藥學上可接受之鹽、立體異構體、溶劑合物或前藥，其中，R3是氯原子、甲基或甲氧基；R5是氫或NH2；R6是氫、鹵素、可任選地被1至3個鹵素所取代的C1-3烷基、或NH2；R7是氫、鹵素或C1-3烷基；條件是R5和R6中只有一個是NH2。
- 如請求項3的化合物、其醫藥學上可接受之鹽、立體異構體、溶劑合物或前藥，其中，R3是氯原子、甲基或甲氧基；R5是氫或NH2；R6是氫、鹵素、可任選地被1至3個鹵素所取代的C1-3烷基、或NH2；R7是氫、鹵素或C1-3烷基；條件是R5和R6中只有一個是NH2。
- 如請求項1的化合物、其醫藥學上可接受之鹽、立體異構體、溶劑合物或前藥，其選自以下的群組：
- 一種醫藥組合物，其包含請求項1至8中任一項之化合物、其醫藥學上可接受之鹽、立體異構體、溶劑合物或前藥，以及一種或多種醫藥學上可接受之載劑。
- 一種如請求項1至8中任一項之化合物、其醫藥學上可接受 之鹽、立體異構體、溶劑合物或前藥或請求項9之醫藥組合物在製備治療微生物感染之藥物的用途。
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