CN1395569A - 含有哌嗪酰胺取代基的噁唑二酮硫代酰胺 - Google Patents
含有哌嗪酰胺取代基的噁唑二酮硫代酰胺 Download PDFInfo
- Publication number
- CN1395569A CN1395569A CN01803631A CN01803631A CN1395569A CN 1395569 A CN1395569 A CN 1395569A CN 01803631 A CN01803631 A CN 01803631A CN 01803631 A CN01803631 A CN 01803631A CN 1395569 A CN1395569 A CN 1395569A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- methyl
- oxazolidine
- oxo
- thiopropionamide
- 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.)
- Pending
Links
- -1 Oxazolidinone thioamides Chemical class 0.000 title claims description 26
- IVXQBCUBSIPQGU-UHFFFAOYSA-N piperazine-1-carboxamide Chemical group NC(=O)N1CCNCC1 IVXQBCUBSIPQGU-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- WPZSAUFQHYFIPG-UHFFFAOYSA-N propanethioamide Chemical compound CCC(N)=S WPZSAUFQHYFIPG-UHFFFAOYSA-N 0.000 claims description 77
- 239000000203 mixture Substances 0.000 claims description 61
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 54
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 17
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 230000003287 optical effect Effects 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 3
- 230000037396 body weight Effects 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims 1
- 208000001860 Eye Infections Diseases 0.000 claims 1
- 125000005842 heteroatom Chemical group 0.000 claims 1
- 206010040872 skin infection Diseases 0.000 claims 1
- 230000000699 topical effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 10
- 241000894006 Bacteria Species 0.000 abstract description 6
- 230000003389 potentiating effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 66
- 239000000460 chlorine Substances 0.000 description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- 239000000741 silica gel Substances 0.000 description 31
- 229910002027 silica gel Inorganic materials 0.000 description 31
- 229960001866 silicon dioxide Drugs 0.000 description 31
- 238000004587 chromatography analysis Methods 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 29
- 238000003756 stirring Methods 0.000 description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- 238000002360 preparation method Methods 0.000 description 28
- 239000000047 product Substances 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- AWXNZFCUBFCTKK-UHFFFAOYSA-N C(CC)(=O)OCC.[S] Chemical class C(CC)(=O)OCC.[S] AWXNZFCUBFCTKK-UHFFFAOYSA-N 0.000 description 19
- 238000002425 crystallisation Methods 0.000 description 18
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- 239000011734 sodium Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 238000000605 extraction Methods 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 150000001408 amides Chemical class 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 13
- 230000008878 coupling Effects 0.000 description 12
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- 238000010511 deprotection reaction Methods 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 7
- 244000005700 microbiome Species 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000005984 hydrogenation reaction Methods 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 241000606768 Haemophilus influenzae Species 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- COWNFYYYZFRNOY-UHFFFAOYSA-N oxazolidinedione Chemical compound O=C1COC(=O)N1 COWNFYYYZFRNOY-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
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- 238000005516 engineering process Methods 0.000 description 3
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- 150000003462 sulfoxides Chemical class 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
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- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
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- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
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- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
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- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 2
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- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
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- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
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- A—HUMAN NECESSITIES
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
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- Engineering & Computer Science (AREA)
- Ophthalmology & Optometry (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明提供了一种对抗革兰氏-阳性和革兰氏-阴性细菌具有高效活性的通式(I)的化合物。
Description
发明的技术领域
本发明涉及新的含有新哌嗪酰胺取代基的噁唑二酮硫代酰胺;及其制备方法。这些化合物对革兰氏阳性和革兰氏阴性细菌具有强烈活性。
发明的背景技术
噁唑二酮抗菌剂是新合成的一类抗菌药,它对人和禽兽的病原体,包括革兰氏阳性需氧菌如多种抗性的葡萄球菌属(staphylococci)和链球菌属(streplococci)和厌氧微生物如类杆菌属和梭状芽胞杆菌属和抗酸微生物如结核分枝杆菌(Mycobacterium laberculosis)和鸟分枝杆菌(Mycobacterium avium)都具有强烈活性。
但是,噁唑二酮类在抗需氧的革兰氏阴性微生物使用的浓度一般显示不出活性。所以,这些噁唑二酮抗菌剂的使用被局限于由革兰氏阳性细菌所引起的感染。所以,本发明的目的是提供具有广谱抗菌活性包括抗需氧的革兰氏阴性微生物的药用组合物。我们现在已经发现本发明的噁唑二酮硫代酰胺增加了对包括革兰氏阴性微生物如流感嗜血杆菌(Haemophilus influenza)和粘膜炎莫拉氏菌属(Moraxellacatarrhalis)的活性谱。
信息的公开
PCT国际申请WO 98/54161公开了含有硫代羰基功能团的噁唑二酮抗菌剂。
PCT国际申请WO 93/23384公开了含有取代的二嗪基团的噁唑二酮及其作为抗菌剂的用途。
PCT国际申请WO 95/07271公开了取代的噁嗪和硫嗪噁唑二酮及其作为抗菌剂的用途。
PCT国际申请WO 99/12914公开了抗菌药硫脲衍生物。
发明概述本发明提供了通式I的化合物:或其可药用盐,其中:A是结构i、ii或iii:R1是H、NH2、NHC1-4烷基、C1-4的亚烷基、OC1-4烷基、SC1-4烷基、(CH2)n-C3-6-环烷基或C1-4烷基,任选用1-3F、1-2Cl或CN取代;R2和R3各自独立地是H、F、Cl或C1-2烷基;R4是
(a)-C(=O)-CR5R6-O-R7,
(b)-C(=O)-CH2S(O)n-CH3,
(c)-C(=O)-CH2-S(=O)(=NR8)CH3,
(d)-C(=S)-R9,
(e)-C(=O)-CH2-O-R10,
(f)-C(=O)-(CH2)m-C(=O)-CH3,
(g)-C(=O)-(CH2OH)2-CH3,
(h)-C(=O)-CH2-CH2-OR14,或
(i)-CN;R5是H;R6是苯基、苄基、CH2OH或CH2OCH3;或者R5和R6一起形成C3-5环烷基;R7是H、CH3或C1-4烷酰基;R8是H、C1-4烷基、C1-4烷酰基、-C(=O)NH-C1-4烷基或-CO2C1-4烷基;R9是C1-4烷基、CH2OR11、S-C1-4烷基、OC1-4烷基或NR12R13;R10是苯基、-CO2-(CH2)2-OCH3、-P(=O)(OH)2、-C(=O)-NR12R13或者-C(=O)-(CH2)2-CO2H;R11是H、苯基、苄基、CH3或C(=O)CH3;R12和R13各自独立地是H或C1-3烷基;或者R12和R13一起形成5或6元饱和杂环,其中所述的饱和杂环还可含有一个或两个另外的选自由O、S(O)n或NR7组成的组中的杂原子;R14是H、CH3或苄基;n是0、1或2;而m是0或1。
另一方面,本发明也提供了:
一种含有通式I化合物或其可药用盐和可药用载体的药用组合物,
一种通过给需要这种治疗的人或其他温血动物给予有效量的通式I的化合物或其可药用盐治疗革兰氏阳性微生物感染的方法,
一种通过给需要这种治疗的人或其他温血动物给予有效量的通式I的化合物或其可药用盐治疗革兰氏阴性微生物感染的方法。
本发明也包含用于制备通式I化合物的新的中间体和工艺。
本发明的详细描述
除非另有说明,使用下列定义。
烷基、亚烷基等术语是指直链和支链基团两种,但对单一残基如“丙基“只包括直链残基,支链的异构体如”异丙基“会特别指出。
各含烃基团的碳原子数是用表示基团中最小和最大碳原子数的代号表示的,即代号CI-j表示整数“i”到整数“j”碳原子数的基团。这样,例如C1-7烷基就是指1到7个碳原子的烷基。
哺乳动物是指人或动物。
本发明的化合物一般按照IUPAC或CAS命名原则命名。本领域中普通技术人员熟知的缩写也可以使用(例如“Ph”表示苯基,“Me”表示甲基,“Et”表示乙基,“h”表示小时或小时数和“rt”表示室温)。
以下所列的自由基、取代基和范围的具体含义和优选含义只是用于详细说明;它们不排除自由基和取代基定义范围内的其他限定含义或其他含义。
A的具体含义是如上所定义的结构ii。
R1的具体含义是C1-4烷基。
R1的具体含义是乙基。
R2和R3的具体含义各自独立地是H或F。
R2的具体含义是H。
R3的具体含义是F。
R4的具体含义是C(=O)-CH(CH2-苯基)(OH)。
R4的具体含义是C(=O)-CH2-SO2-CH3。
R4的具体含义是C(=O)-CH(OH)(CH2OH)。
R4的具体含义是C(=O)-C(=O)-CH3。
R4的具体含义是C(=O)-CH(OH)(CH2-O-CH3)。
R4的具体含义是C(=O)-CH2CH2-OH。
R4的具体含义是C(=O)-CH2-O-CO2-(CH2)2-OCH3。
R4的具体含义是C(=S)-CH3。
R4的具体含义是CN。
本发明优选的化合物是其中含有下列具有光学构型的结构i、ii或iii的那些化合物:这些绝对构型按照Cahn-Ingold-Prelog命名原则称之为(S)-构型。本领域的技术人员会想到本发明的化合物可以有其他手性中心并且可以旋光或外消旋形式分离出来。本发明包括了本发明化合物的任何外消旋、旋光、互变异构体或立体异构体形式或其混合物。
本发明更优选的化合物是其中A为在噁唑二酮环的C5上有(S)-构型的纯光学对映体的结构ii。
本发明的例子有:
(1)N{[(5S)-3-(3-氟-4-{4-[2-(甲基亚硫酰基)乙酰基]-1-哌嗪基}
苯基)-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺,
(2)N-{[(5S)-3-(3-氟-4-{4-[2-(甲基硫基)乙酰基]-1-哌嗪基}苯
基)-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺,
(3)N-{[(5S)-3-(3-氟-4-{4-[2-(甲基硫酰基)乙酰基]-1-哌嗪基}
苯基)-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺,
(4)N-({(5S)-3-[4-(4-硫代乙酰基-1-哌嗪基)-3-氟苯基]-2-氧代
-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,
(5)N-({(5S)-3-[4-(4-氰基-1-哌嗪基)-3-氟苯基]-2-氧代-1,3-
噁唑烷-5-基}甲基)硫代丙酰胺,
(6)N-({(5S)-3-(3-氟-4-{4-[2-(甲基氨基羰基氧)乙酰基]-1-哌
嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,
(7)N-({(5S)-3-(3-氟-4-{4-[2-[(2-甲氧基乙氧基)羰基氧]乙酰
基]-1-1-哌嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰
胺,
(8)N-[((5S)-3-{3-氟-4-[4-((2S)-2-羟基-3-甲氧基丙酰基)-1-
哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,
(9)N-[((5S)-3-{3-氟-4-[4-((2S)-2,3-二甲氧基丙酰基)-1-哌嗪
基]苯基}-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,
(10)N-[((5S)-3-{3-氟-4-[4-((2S)-3-羟基-2-甲氧基丙酰基)-1-
哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,
(11)N-({(5S)-3-[3-氟-4-(4-乙酰乙酰基-1-哌嗪基)苯基]-2-氧代
-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,
(12)N-({(5S)-3-[3-氟-4-(4-丙酮酰基-1-哌嗪基)苯基]-2-氧代
-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,
(13)N-({(5S)-3-[3-氟-4-[4-(3-羟基丙酰基)-1-哌嗪基]苯基]-2-
氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,
(14)N-{[(5S)-3-(3-氟-4-{4-[(1-羟基环丙基)羰基]-1-哌嗪基}苯
基)-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺,
(15)N-[((5S)-3-{3-氟-4-[4-(2-苯氧基乙酰基)-1-哌嗪基]苯
基}-2-氧代-1,3-噁唑烷-5-基)甲基]硫代丙酰胺,
(16)N-({(5S)-3-[3-氟-4-[4-((2S)-2,3-二羟基丙酰基)-1-哌嗪基]
苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,
(17)N-({(5S)-3-[3-氟-4-[4-((2R)-2,3-二羟基丙酰基)-1-哌嗪基]
苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,
(18)N-{[(5S)-3-(3-氟-4-{4-[3-羟基-2-(羟基甲基)-2-甲基丙酰
基]-1-哌嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰
胺,
(19)N-[((5S)-3-{3-氟-4-[4-((2S)-2-羟基-3-苯基丙酰基)-1-哌
嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基)甲基]硫代丙酰胺,
(20)N-[((5S)-3-{3-氟-4-[4-((2R)-2-羟基-3-苯基丙酰基)-1-哌
嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基)甲基]硫代丙酰胺,
(21)N-[((5S)-3-{3-氟-4-[4-((2R)-2-羟基-2-苯基乙酰基)-1-哌
嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基)甲基]硫代丙酰胺,或
(22)N-[((5S)-3-{3-氟-4-[4-((2S)-2-乙酰氧基-2-苯基乙酰基)-1-哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基)甲基]硫代丙酰胺。
方案I描述了本发明化合物的制备。所有的起始物都是由这些方案中所述的步骤或有机化学中普通技术人员熟知的步骤制备的。方案I中所用的各种变化都在下列给予限定或在权利要求书中加以限定。纯光学物质可能通过许多不对称合成的一种或从外消旋混合物中拆分得到。
在方案I的步骤1中,将适当保护的哌嗪(II)与激活的羧酸衍生物反应得到化合物III。在该反应中,被激活的羧酸衍生物可包括在叔胺碱如三乙胺或吡啶于溶剂如二氯甲烷、四氢呋喃(THF)或过量的吡啶存在下与II反应的酰卤和酸酐或混合无水化物。在大约0℃到大约24℃范围的温度一般适合于该反应。另外在步骤1中也可使用能够与适当的羧酸形成酰胺反应的所熟知的偶合剂。在该反应中试剂如二环己基碳二亚胺(DCC)和1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸化物(EDC)能够与激活的试剂如1-羟基苯并三唑(HOBT)或4-(二甲基氨基)吡啶(DMAP)一起使用。溶剂如THF或二甲基甲酰胺(DMF)和2℃到24℃范围的温度是适合的。R4为氰基的化合物可以通过将化合物II与溴化氰在溶剂如甲醇中反应制得。醋酸钠是适合在0℃到24℃范围的温度下进行的该反应的碱(参见实施例5)。保护基团(P)可以按照分子上与其他功能基团的相容性来选择。苄基氧羰基(Cbz)和叔丁氧基羰基(Boc)一般是这些化合物的合适的保护基团;但是,有时也需要使用其他保护基团。实施例1详细说明了使用邻苯二甲酰亚胺保护基团。在该实施例中,亚砜对除去Boc基团所需的酸性条件敏感。邻苯二甲酰亚胺能够在非酸性条件下用水合肼或甲胺除去。
在方案I的步骤2中,将保护基团(P)除去可得到相应的胺(IV)。在0℃到24℃的二噁烷中用盐酸可以方便地除去Boc基团;但是,也能够使用其他的脱保护方法。Cbz基团的脱保护一般用钯催化剂的氢化完成。
在方案I的步骤3中,胺(IV)可以被转化成通式I的化合物。硫代酰胺可以通过化合物(IV)与二硫酯和叔胺碱如三乙胺反应制得。在该反应中,经常在没有第一次分离游离碱的情况下方便地使用含有步骤2中Boc脱保护所制备的铵盐的过量的叔胺碱。溶剂如THF、二氯甲烷或优选的甲醇和大约24℃到大约50℃的温度可以用于该反应中。按照PCT国际公开号WO 98/54161中所述的步骤能够制备通式I的其他硫代羰基化合物。
如果需要的话,将化合物I或III的R4改良得到另外的通式I的化合物。这一点在实施例4中有详细说明,其中将乙酰胺14与Lawesson试剂反应得到硫代酰胺15,一种通式I的化合物。在实施例1中步骤3显示了在甲醇-水中将硫化物3用过碘化钠氧化成亚砜4。接着该中间体4可被转化成式I的化合物。在多磷酸中在40℃到70℃亚砜例如4(实施例1)与叠氮化钠的反应得到也能转化成通式I(R4为-C(=O)-CH2-S(=O)(=NR8)CH3)的相应化合物的sulfoximine中间体。其他sulfoximine类似物能够按照例6295中所述得到。在实施例3中显示了在丙酮-水中硫化物中间体8能够用四氧化锇和4-甲基吗啉N-氧化物氧化成砜11。中间物11能够随后被转化成化合物13,一种通式I的化合物。在实施例6中显示了在24℃DMF中醇19与异氰酸甲酯和氯化亚铜催化剂反应得到可转化成一种通式I的化合物22的20。并且在实施例7中在吡啶中用2-甲氧乙基氯甲酸酯酰化醇23得到一种通式I的化合物24。以相似方式用本领域中已知的化学物,将方案I中的化合物I或III的其他R4取代基修饰得到其他通式I的化合物。
方案I
本发明的药用组合物可以通过使用标准和常规技术将本发明的通式I的化合物与可药用固态或液态载体并且任选与可药用辅助剂和赋型剂组合来制备。固体形式的组合物包括粉剂、片剂、分散颗粒、胶囊、扁胶囊和栓剂。固体载体可以至少是也起稀释剂、矫味剂、增溶剂、润滑剂、悬浮剂、粘合剂、片剂崩解剂和胶囊包裹剂作用的一种物质。惰性固体载体包括碳酸镁、硬脂酸镁、滑石、糖、乳糖、果糖、右旋糖、淀粉、明胶、纤维素类物质、低熔点蜡、可可脂等。液体形式的组合物包括溶液、悬浮液和乳浊液。例如,提供了溶于水和水-丙二醇和水-聚乙二醇系统中的本发明化合物的溶液,任选含有合适的常用着色剂、矫味剂、稳定剂和增稠剂。
该药用组合物优选使用常用技术以含有有效或适当用量的活性成分即,本发明通式I的化合物的单位剂型提供。
在药用组合物及其单位剂型中本发明通式I的化合物的活性成分的含量可以根据特殊用途、特殊化合物的功效和所需浓度改变或广泛调整。一般来说,活性成分的含量在0.5%到90%重量化合物的范围。
在治疗或抵抗温血动物的细菌感染的治疗用途中,该化合物或其药用组合物将被口服、局部、经皮和/或胃肠外给药,以得到和维持在治疗动物中活性化合物的血药水平达到有效抗菌浓度的剂量。一般来说,活性成分剂量的抗菌有效量在大约0.1到大约100,更优选大约1.0到大约50mg/kg体重/天的范围。应当理解到该剂量可以根据患者的需要、被治疗的细菌感染的严重程度和使用的特殊化合物而改变。还要想到给予的初始剂量可以增加到超过上限,从而迅速达到所需血药浓度或者初始剂量可以小于最佳剂量并且在疗程中根据特殊情况每日剂量还可以逐渐增加。如果需要的话,也可以将每日剂量分为多次给药剂量,如每天两次到四次。
本发明的通式I化合物可以胃肠外即注射例如静脉注射或其他胃肠外给药途径进行给药。胃肠外给药的药用组合物一般包括作为可溶性盐(酸加成盐或碱盐)溶于可药用液体载体如注射用水和提供适当缓冲等渗溶液的缓冲液,例如pH大约3.5-6的药学上可接受量的通式I化合物。适当的缓冲剂包括例如正磷酸三钠、碳酸氢钠、柠檬酸钠、N-甲基葡糖胺、L(+)-赖氨酸和L(+)-精氨酸到有名称但是具代表性的缓冲剂。通式I的化合物一般可以足以提供可药用注射浓度的量即在大约1mg/ml到大约400mg/ml的溶液的范围溶于载体中。可以施用所得到的液体药用组合物以达到上述抗菌有效剂量。本发明通式I的化合物最好以固体和液体剂型口服给药。
本发明的噁唑二酮抗菌剂具有抗多种微生物的有用活性。本发明化合物的体外活性能够用常规测试步骤如用琼脂稀释液测定最小抑制浓度(MIC)来评估,其中用琼脂稀释液测定最小抑制浓度(MIC)正如在“批准的稀释抗生素对需氧生长的细菌的敏感性试验的标准方法”,第3版,1993年由国家临床试验标准委员会Villanova,Pennsylvania,美国所公开的方法。本发明化合物抗金黄色葡萄球菌(staphylococcus aureus)、表皮葡萄球菌(staphylococcus epidermidis)、肺炎链球菌(streptococcus pneunoniae)、粪链球菌(Enterococcus faecalis)、粘膜炎莫拉氏菌属(Moraxalla catarrhalis)和流感嗜血杆菌(H.Influenzae)的活性显示在表1中。
表1
抗菌活性的最小抑制浓度(μg/mL)
SAUR9213MIC | SEPI30593MIC | EFAE12712MIC | SPNE9912MIC | HINF30063MIC | HINF30063MIC | EFAE9217MIC | MCAT30607MIC | |
实施例1 | 4 | 1 | 2 | 0.5 | 2 | 8 | 1 | 8 |
实施例2 | 2 | 1 | 1 | <0.5 | 1 | >64 | 1 | 4 |
实施例3 | 2 | 0.5 | 1 | 0.25 | 0.5 | 8 | 0.5 | 2 |
实施例4 | 0.5 | 0.25 | 0.5 | 0.125 | 0.125 | 1 | 0.5 | 1 |
实施例5 | 0.25 | 0.25 | 0.25 | 0.125 | 0.125 | 2 | 0.25 | 1 |
实施例7 | 2 | 1 | 2 | 0.25 | 0.25 | 4 | 2 | 4 |
实施例8 | 2 | 1 | 2 | 0.5 | 0.5 | 16 | 1 | 2 |
实施例9 | 4 | 2 | 4 | 1 | 1 | 32 | 2 | 4 |
实施例10 | 4 | 2 | 2 | 1 | 1 | 16 | 1 | 4 |
实施例12 | 2 | 1 | 1 | 0.5 | 0.5 | 8 | 1 | 2 |
实施例13 | 2 | 1 | 1 | 0.5 | 0.5 | 8 | 1 | 2 |
实施例14 | 4 | 1 | 2 | 0.5 | 1 | 32 | 1 | 2 |
实施例15 | 2 | 0.5 | 1 | 0.25 | 0.5 | 32 | 0.5 | 2 |
实施例16 | 4 | 0.5 | 1 | 0.5 | 0.5 | 8 | 0.5 | 2 |
实施例17 | 4 | 0.5 | 1 | 0.25 | 0.5 | 8 | 0.5 | 2 |
实施例18 | 4 | 1 | 2 | 0.5 | 1 | 32 | 2 | 4 |
实施例19 | 2 | 2 | 2 | <0.5 | 1 | >64 | 2 | 8 |
实施例20 | 1 | 1 | 1 | <0.5 | 1 | 64 | 1 | 4 |
实施例21 | 4 | 1 | 2 | 1 | 2 | 64 | 2 | 4 |
实施例22 | 8 | 4 | 4 | 2 | 4 | >64 | 4 | 8 |
在初始压力32p.s.i.下将1(可按照美国专利5,547,950所制备的)(5.00g,8.95mmol)、EtOH(150ml)、THF(150ml)、浓盐酸(1.5ml)和10%钯碳催化剂(2g)混合物氢化18小时。过滤该混合物并用MeOH/CH2Cl2冲洗该固体。浓缩合并的滤液得到固体,将其用NaHCO3(100ml)和EtOAc(100ml)的饱和水溶液的混合物搅拌18小时,过滤收集并用水冲洗并干燥。将其溶于20%的MeOH/CH2Cl2中,干燥(MgSO4)并浓缩得到1.94g化合物2。步骤2
将搅拌好的2(1.70g,4.01mmol)、1-羟基苯并三唑水合物(HOBT,650mg,4.81mmol)、(甲基硫)乙酸(419μL,4.81mmol)和DMF(38ml)的混合物冷却到0℃并用1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸化物(EDC,1.54g,8.02mmol)处理。将其在0℃下保持两天并在50℃真空浓缩。将残余物与水混合并用EtOAc萃取。将萃取物干燥(MgSO4)并浓缩。在硅胶柱上用含有1-2%MeOH的MeOH/CH2Cl2混合物对残余物进行色谱层析得到1.75g化合物3。步骤3:
将搅拌好的冰冷的3(1.70g,3.32mmol)的甲醇(17ml)和水(8.5ml)的混合物用过碘化钠(1.06g,4.98mmol)处理并在冰浴下保持4小时和室温(24℃)下保持4天。将其真空浓缩、与水混合并用CH2Cl2萃取。干燥(MgSO4)萃取液并浓缩。残余物在硅胶柱上用5%MeOH-CH2Cl2进行色谱层析得到1.22g的化合物4。步骤4
在80℃将搅拌好的4(964mg,1.82mmol)、水合肼(177μL,3.64mmol)和甲醇(16ml)的混合物温热到6小时并在室温下保持4天。将其真空浓缩。残余物在硅胶柱上用10%MeOH-1%NH4OH-CH2Cl2色谱层析得到630mg的化合物5。步骤5
将搅拌好的5(326mg,0.815mmol)、三乙胺(0.91mL,6.55mmol)和二硫丙酸甲酯(393mg,3.27mmol)的CH2Cl2(8.0ml)和THF(8ml)的混合物在室温(24℃)下保持18小时,与水混合并用CH2Cl2萃取。将萃取液干燥(MgSO4)并浓缩。残余物在硅胶柱上用含有2.5-5%MeOH的MeOH/CH2Cl2混合物色谱层析得到产物,从MeOH中重结晶得到257mg的化合物6。对C10H27FN4O4S2的分析计算值:C,51.05;H,5.78;N,11.91。测定值:C,50.82;H,5.85;N,11.80。实施例2 N-{[(5S)-3-(3-氟-4-{4-[2-(甲基硫基)乙酰基]-1-哌嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺(10)(PNU-247827)的制备步骤1
将搅拌好的冰冷的7(按照PCT国际公开WO 98/54161制备的)(3.00g,7.61mmol)、HOBT(1.13g,2.79mmol)和甲基硫乙酸(0.66mL,2.54mmol)的DMF(69ml)的溶液用EDC(3.21g,5.58mmol)处理并在18小时内使其缓慢加温到室温(24℃)。在50℃将其真空浓缩并将残余物与水混合并用EtOAc萃取。将萃取液用水和盐水洗涤,干燥(MgSO4)并浓缩。残余物从MeOH/EtOAc/己烷中结晶得到2.36g的化合物8。步骤2
将样品8(1.00g,2.07mmol)在冰浴中冷却,用4N的HCl的二噁烷(10ml)溶液处理并在冰浴中搅拌1.5小时和在室温(24℃)搅拌1小时。浓缩混合物并将残余物与三份CH2Cl2混合,每次加入后浓缩得到9。步骤3
将搅拌好的化合物9(578mg,1.38mmol)、三乙胺(1.5mL,11.0mmol)、二硫丙酸乙酯(0.76mL,5.52mmol)、CH2Cl2(15.5ml)和THF(15.5ml)的混合物在室温(24℃)下放置18小时并真空浓缩。将残余物与水(30ml)和10%EtOAc-己烷(30ml)的混合物搅拌2小时并过滤收集固体,用水洗涤、干燥并从EtOAc-MeOH-己烷中结晶。所得到的固体在硅胶柱上用2%MeOH-CH2Cl2进行色谱层析并将产物从MeOH/EtOAc中结晶得到465mg的化合物10:MS(EI)m/z 454(M+)。对C20H27FN4O3S2分析计算值:C,52.84;H,5.99;N,12.32。测定值:C,52.83;H,6.02;N,12.23。实施例3 N-{[(5S)-3-(3-氟-4-{4-[2-(甲基硫酰基)乙酰基]-1-哌嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺(13)(PNU-248337)的制备步骤1
将搅拌好的化合物8(100mg,0.207mmol)、4-甲基吗啉、N-氧化物(73mg,0.621mmol)、丙酮(1.5ml)和水(0.5ml)的混合物用2.5%的四氧化锇的2-甲基-2-丙醇(17μL)溶液处理并在室温(24℃)下放置18小时。然后将其用10%的含水NaHSO4(60ml)处理并用CH2Cl2萃取。萃取液用10%的NaHSO4洗涤、干燥(MgSO4)并浓缩。残余物从EtOAc-己烷中结晶得到96mg的11:MS(EI)m/z 514(M+)。步骤2
正如实施例2中所述,步骤3的化合物12与二硫丙酸乙酯和三乙胺反应得到13,将其在硅胶柱上用1%MeOH-CH2Cl2进行色谱层析纯化并从MeOH-EtOAc中结晶:MS(EI)m/z 486(M+);对C20H28FN4O5S2计算的HRMS(FAB)(M+H+)487.1485,测定值:487.1494。对C20H27FN4O5S2分析计算值:C,49.37;H,5.59;N,11.51。测定值:C,49.25;H,5.63;N,11.47。实施例4 N-({(5S)-3-[4-(4-硫代乙酰基-1-哌嗪基)-3-氟苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺(15)(PNU-276575)的制备
将搅拌好的14((S)-N-[[3-[3-氟-4-(4-乙酰基-1-哌嗪基)苯基]-2-氧代-5-噁唑烷]甲基]硫代丙酰胺(可以按照PCT国际公开WO 98/54161制备)(0.53g,1.3mmol)、Lawesson试剂(0.53g)和二噁烷(27ml)混合物在氮气下回流90分钟,冷却并真空浓缩。残余物在硅胶柱上用2%MeOH-CH2Cl2色谱层析得到产物,将其用活性炭脱色并从乙腈中结晶得到0.303g的15:mp 209-210℃。对C19H25FN4O2S2分析计算值:C,53.75;H,5.93;N,13.20。测定值:C,53.69;H,6.00;N,13.25。实施例5 N-({(5S)-3-[4-(4-氰基-1-哌嗪基)-3-氟苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺(18)(PNU-278605)的制备步骤1
将搅拌好的冰冷的7(0.488g,1.24mmol)和醋酸钠(0.55g,6.7mmol)的MeOH(40ml)的混合物用5M溴化氰的CH2Cl2(0.35ml,1.48mmol)的MeOH(10ml)溶液处理1分钟,并在冰浴中放置2小时。然后将其真空浓缩并将残余物与稀释的NaHCO3混合并用CH2Cl2萃取。萃取液用水洗涤,干燥(Na2SO4)和浓缩。残余物在硅胶柱上用2%的MeOH-CH2Cl2进行色谱层析得到0.42g的16:MS(ES)m/z 420(M+H+)。步骤2
在氮气下,向搅拌好的冰冷的16(0.42g,10mmol)的二噁烷(10ml)悬浮液滴加冰冷的4N的HCl二噁烷(10ml)溶液进行处理,将其放置在冰浴中2小时并真空浓缩。残余物在真空下干燥18小时得到17:MS(ES)m/z320(M+H+)。步骤3
在氮气下将搅拌好的17(0.25g,0.64mmol)和三乙胺(0.178ml)的MeOH(5ml)的混合物在30分钟内加温到50℃,在50℃放置30分钟并在冰浴中放冷。过滤收集固体并从EtOH中结晶得到18:mp 182-184℃;对C18H23FN5O2S计算的HRMS(FAB)(M+H+)392.1556,测定值392.1550。实施例6 N-({(5S)-3-(3-氟-4-{4-[2-(甲基氨基羰基氧)乙酰基]-1-哌嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺(22)(PNU-281328)的制备步骤1
在20分钟内将搅拌好的冰冷的a(PCT国际公开WO 98/54161)(20.0g,50.7mmol)、丙酮(1500mL)和饱和的碳酸氢钠水溶液(500ml)的混合物用苄氧基乙酰氯(9.5ml,60.8mmol)的丙酮(150ml)溶液处理。将该混合物缓慢加温到室温(24℃)并放置18小时。将其用Et2O萃取,萃取液用水和盐水洗涤、干燥(MgSO4)并浓缩得到25.4g的产物b。步骤2
在初始压力35p.s.i.下将2(25.0g,46.1mmol)、MeOH(1700ml)和10%钯炭催化剂(6.25g)氢化4天。加入另外的催化剂(6.25g)并持续氢化1天。过滤该化混合物并浓缩滤液。残余物在硅胶柱上用2.5%MeOH-CH2Cl2进行色谱层析得到产物,将其从丙酮-CH2Cl2结晶得到13.7g的3。步骤3
将搅拌好的19和氯化亚铜(0.075g)的DMF(4ml)的混合物用异氰酸甲酯(0.081ml)处理,在室温(24℃)下保持60分钟并真空浓缩。残余物与水和Et2O混合得到固体,将其过滤收集并在硅胶柱上用2.5%MeOH-CH2Cl2进行色谱层析得到0.28g的20。步骤4
在氮气下将冰冷的搅拌好的20(0.37g,0.726mmol)的二噁烷(10ml)的混合物中滴加冰冷的4N盐酸的二噁烷(8ml)溶液进行处理。将混合物在冰浴下放置1小时15分钟并且在室温(24℃)下放置1小时。将其用另外的二噁烷(10ml)稀释,在室温下保持30分钟,在0℃18小时并且在室温下6小时。将其真空浓缩得到21:MS(ES)m/z 410(M+H+)。步骤5
在氮气下,室温(24℃)将搅拌好的21(0.20g,0.416mmol)、二硫丙酸乙酯(0.17ml)和三乙胺(0.5ml)的CH2Cl2(20ml)和MeOH(5ml)的混合物放置21小时并在氮气流下浓缩。残余物在硅胶柱上用2%的MeOH-CH2Cl2色谱层析得到22:对C21H29FN5O5S的HRMS(FAB)的计算值(M+H+)482.1873,测定值:482.1873。实施例7 N-({(5S)-3-(3-氟-4-{4-[2-[(2-甲氧基乙氧基)羰基氧]乙酰基]-1-哌嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺(24)(PNU-276528)的制备
将搅拌好的冰冷的23(按照PCT国际公开WO 98/54161所述的步骤制备)(0.212g,0.496mmol)和吡啶(0.2ml,2.5mmol)的CH2Cl2(5ml)和THF(5ml)的混合物通过滴加2-甲氧基乙基氯甲酸酯(0.069g,0.5mmol)进行处理并将其放置在冰浴中1小时和在室温(24℃)2小时。再加入2-甲氧基乙基氯甲酸酯(0.07ml);将混合物在室温放置3小时并再用另外的2-甲氧基乙基氯甲酸酯(0.1ml)处理。该混合物在室温(24℃)下放置18小时。将其与饱和的NaHCO3水溶液混合并用CH2Cl2萃取。萃取液用水和盐水洗涤,干燥(Na2SO4)并浓缩。残余物在硅胶柱上用2.5%MeOH-CH2Cl2色谱层析得到产物,将其从EtOAc中结晶得到0.185g的24:mp 150-151℃。对C23H31FN4O7S的分析计算值:C,52.46;H,5.93;N,10.64。测定值:C,52.45;H,6.05;N,10.61。实施例8 N-[((5S)-3-{3-氟-4-[4-((2S)-2-羟基-3-甲氧基丙酰基)-1-哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺(33)(PNU-272200)的制备步骤1
在室温下将搅拌好的(S)-(-)-2,2-二甲基-1,3-二噁烷-4-羧酸甲酯(25)(5.0g,0.031mol)的醋酸(10ml)和水(2.5ml)溶液放置72小时并真空浓缩得到(S)-26。步骤2
在氮气下将搅拌好的步骤1中的(s)-26(1.0g)和甲基碘(20ml)混合物用氧化银(1.3g)和3A分子筛(2g)处理并在43℃加温90分钟。将其冷却并过滤。浓缩滤液并将残余物在硅胶柱上用含有2-4%MeOH的MeOH-CH2Cl2混合物色谱层析。从柱中洗脱的产物是(S)-27(0.15g)、(S)-28(0.08g)和(S)-29(0.28g)。步骤3
在氮气下将搅拌好的(S)-28(0.08g,0.6mmol)和MeOH(3.0ml)混合物用1M氢氧化锂(0.57ml)处理并在室温(24℃)放置3小时和在氮气流下18小时。然后将其真空浓缩得到(S)-30。步骤4
在氮气下将搅拌好的7(0.237g,0.601mmol)、步骤3中的产物((S)-30)、HOBT 0.095g(0.703mmol)和DMF(4ml)的混合物用EDC(0.26g,1.36mmol)处理,在室温(24℃)放置2.5小时并真空浓缩。残余物在硅胶柱上用2.5%MeOH-CH2Cl2色谱层析得到0.18g的31:MS(ES)m/z497(M+H+)。步骤5
在氮气下将冰冷的搅拌好的31(0.17g,0.342mmol)的二噁烷(10ml)的混合物中在3分钟内滴加冷的4N HCl的二噁烷(10ml)溶液进行处理,并将其在冰浴中放置50分钟,在室温(24℃)放置90分钟并在0℃放置18小时。然后将其真空浓缩得到32:MS(ES)m/z 397(M+H+)。步骤6
将搅拌好的步骤5中的32、三乙胺(0.5ml,3.5mmol)、CH2Cl2(10ml)和THF(7ml)的混合物通过滴加二硫丙酸乙酯(0.22ml,1.71mmol)进行处理并将其在室温(24℃)放置72小时。再加入另外的二硫丙酸乙酯(0.22ml)并将混合物在室温放置24小时并浓缩。将还含有32的残余物与CH2Cl2(10ml)、THF(7ml)和三乙胺(0.75ml)和二硫丙酸乙酯(0.35ml)混合,在室温放置24小时并浓缩。残余物在硅胶柱上用2.5%MeOH-CH2Cl2色谱层析得到0.0457g的33:mp 190-191℃(测定)。对C21H29FN4O5S的分析计算值:C,53.82;H,6.24;N,11.96。测定值:C,53.59;H,6.35;N,11.83。实施例9 N-[((5S)-3-{3-氟-4-[4-((2S)-2,3-二甲氧基丙酰基)-1-哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺(34)(PNU-272199)的制备
正如实施例8中所述,将酯((S)-27,步骤2中制备的)用氢氧化锂水解并与7偶合。将所得到的酰胺脱去保护并使其与二硫丙酸乙酯和三乙胺反应。产物在硅胶柱上用2.5%MeOH-CH2Cl2色谱层析纯化并从EtOAc-己烷中结晶得到34:mp 140-142℃(测定)。对C22H31FN4O5S的分析计算值:C,54.76;H,6.47;N,11.61。测定值:C,54.53;H,6.54;N,11.50。实施例10 N-[((5S)-3-{3-氟-4-[4-((2S)-3-羟基-2-甲氧基丙酰基)-1-哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺(35)(PNU-272198)的制备
正如实施例8所述的,将酯((S)-29,步骤2中制备的)用氢氧化锂水解并与7偶合。将所得到的酰胺脱去保护并与二硫丙酸乙酯缩合。产物在硅胶柱上用2.5%MeOH-CH2Cl2色谱层析纯化得到35。对C21H29FN4O5S的分析计算值:C,53.83;H,6.24;N,11.96。测定值:C,53.71;H,6.32;N,11.85。实施例11 N-({(5S)-3-[3-氟-4-(4-乙酰乙酰基-1-哌嗪基)苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺(36)的制备
正如实施例8(步骤4-6)中所述,将乙酰乙酸锂盐与7偶合并且将所得到的酰胺脱去保护并使其与二硫丙酸乙酯和三乙胺反应。产物在硅胶柱上色谱层析纯化得到36:MS(ES)m/z 451(M+H+),473(M+Na+)。实施例12 N-({(5S)-3-[3-氟-4-(4-丙酮酰基-1-哌嗪基)苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺(37)PNU-264886的制备
正如实施例8(步骤4-6)所述的,将丙酮酸与7偶合并将所得到的酰胺脱去保护并与二硫丙酸乙酯三乙胺缩合。产物在硅胶柱上用2.5%MeOH-CH2Cl2色谱层析纯化并从EtOAc-己烷中结晶得到37:mp 173-175℃(测定);MS(ES)m/z 437(M+H+),459(M+Na+)。对C20H25FN4O4S·0.1EtOAc的分析计算值:C,54.97;H,5.84;N,12.57。测定值:C,55.05;H,6.15;N,12.12。实施例13 N-({(5S)-3-[3-氟-4-[4-(3-羟基丙酰基)-1-哌嗪基]苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺(43)(PNU-272690)的制备步骤1
在40分钟内将冰冷的搅拌过的苯甲醇(4.0mL,0.0386mol)的THF(20mL)的溶液分批用60%的氢化钠(1.6g,0.04mol)的油分散液处理,放置在冰浴中20分钟并在5分钟内用3-氯丙基氯(1.50mL,0.0157mol)的THF(3mL)的溶液处理。将混合物缓慢加温到室温(24℃),保持23小时,与饱和的氯化铵(15mL)和冰水混合并用EtOAc萃取。将萃取液用水和盐水洗涤,干燥(Na2SO4)并浓缩得到38:MS(ES)m/z 293(M+Na+)。步骤2
在氮气中将冰冷的搅拌过的步骤1中的38的MeOH(50mL)溶液用氢氧化钾(0.94,0.0168mol)处理并放置在冰浴中10分钟、室温1小时和在-20℃18小时。将其用另外的氢氧化钾(0.98g)处理,在室温放置8.5小时并在-20℃放置18小时并真空浓缩。残余物与冰水混合,在冰浴中冷却并用2N HCl处理到pH 3。将其用EtOAc萃取。萃取液用2N的NaOH和水洗涤并将洗涤液用2N的HCl再酸化并用EtOAc萃取。浓缩萃取液得到1.48g的39:MS(ES)m/z 181(M+H+),203(M+Na+)。步骤3
在氮气下,用4-(二甲基氨基)吡啶(DMAP,8mg)、EDC(0.243g,1.26mmol)和39(0.228g,1.26mmol)的CH2Cl2(2mL)的溶液处理搅拌好的7(0.5g,1.26mmol)和吡啶(6mL)的混合物并在室温(24℃)保持2小时20分钟。将其真空浓缩并将残余物与CH2Cl2混合,用饱和的NaHCO3、水和盐水洗涤,干燥(Na2SO4)并浓缩。残余物在硅胶柱上用2.5%MeOH-CH2Cl2色谱层析得到0.43g的40:MS(ES)m/z 557(M+H+),579(M+Na+)。步骤4
在氮气中,将搅拌好的冰冷的40(0.43g,0.772mmol)的二噁烷(12mL)溶液用4N的氯化氢的二噁烷(10mL)溶液在3分钟内滴加处理。将其在90分钟内加温到室温(24℃),保持3小时30分钟并浓缩得到0.43g的41。步骤5
在初始压力为44p.s.i.下将41(0.21g),10%钯碳催化剂(0.17)和EtOH(50mL)混合物氢化90分钟,用另外的催化剂(0.1g)处理并在初始压力为40p.s.i.下氢化22小时。将其过滤并将固体用MeOH洗涤。浓缩滤液,将残余物在硅胶柱上用含有5-7.5%的MeOH和0.25-0.5%的NH4OH的MeOH-NH4OH-CH2Cl2的混合物色谱层析得到0.07g的42:MS(ES)m/z367(M+H+)。步骤6
将搅拌过的42(0.07g,0.19mmol)、CH2Cl2(8mL)和THF(8mL)的混合物用三乙胺(0.20mL)和二硫丙酸乙酯(0.08mL)处理并将其在室温(24℃)保持24小时、在45℃保持7.5小时并在室温保持16小时。然后将其浓缩,残余物在硅胶柱上用含有2-3.5%的MeOH的MeOH-CH2Cl2的混合物色谱层析。产物(43)的量为0.057g:对C20H28FN4O4S计算的HRMS(FAB)(M+H+)439.1815,测定值439.1812。实施例14 N-{[(5S)-3-(3-氟-4-{4-[(1-羟基环丙基)羰基]-1-哌嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺(44)(PNU-251110)的制备
正如实施例8(步骤4-6)所述的,将1-羟基-1-环丙烷羧酸与7偶合并将所得到的酰胺脱去保护并与二硫丙酸乙酯和三乙胺反应。产物在硅胶柱上用含有2-12%的MeOH的MeOH-CH2Cl2混合物色谱层析纯化并从MeOH-EtOAc中结晶得到44:mp185-186℃(测定);MS(ES)m/z451(M+H+),473(M+Na+)。对C21H27FN4O4S的分析计算值:C,55.99;H,6.04;N,12.44。测定值:C,55.78;H,6.09;N,12.18。实施例15 N-[((5S)-3-{3-氟-4-[4-(2-苯氧基乙酰基)-1-哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基)甲基]硫代丙酰胺(47)(PNU-251037)的制备步骤1
在氮气下,向冰冷的搅拌好的7(0.5g,1.26mmol)和三乙胺(0.385ml,2.76mmol)的CH2Cl2(25ml)溶液滴加苯氧基乙酰氯(0.35ml,2.52mmol)的CH2Cl2(3ml)并将其在冰浴中保持2小时和在室温保持30分钟。将其用CH2Cl2稀释,并用饱和的NaHCO3、水和盐水洗涤,干燥(Na2SO4)并浓缩。残余物从MeOH-EtOAc中结晶得到0.53g的45:MS(ES)m/z 529(M+H+),551(M+Na+)。步骤2
正如实施例8(步骤5)所述,在二噁烷中将化合物45用氯化氢脱保护得到46:MS(ES)m/z 429(M+H+)。步骤3
正如实施例8(步骤6)所述,将胺的氢氯化物(46)与二硫丙酸乙酯和三乙胺的CH2Cl2-THF反应。产物在硅胶柱上用2.5%MeOH-CH2Cl2色谱层析并从EtOAc结晶得到47:mp 171-172℃;MS(ES)m/z 501(M+H+),523(M+Na+)。对C25H29FN4O4S的分析计算值:C,59.98;H,5.84;N,11.19。测定值:C,59.59;H,5.89;N,11.03。实施例16 N-({(5S)-3-[3-氟-4-[4-((2S)-2,3-二羟基丙酰基)-1-哌嗪基]苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺(48)(PNU-248440)的制备
正如实施例8(步骤4-6)中所述,L-甘油酸、钙盐的二水合物与7偶合并且将所得到的酰胺脱保护,使其与二硫丙酸乙酯和三乙胺反应。产物在硅胶柱上用7.5%MeOH-EtOAc色谱层析得到48:mp 142℃(测定的);MS(ES)m/z 455(M+H+),477(M+Na+)。对C20H27FN4O5S·0.3EtOAc的分析计算值:C,52.94;H,6.15;N,11.65。测定值:C,52.75;H,6.02;N,11.53。实施例17 N-({(5S)-3-[3-氟-4-[4-((2R)-2,3-二羟基丙酰基)-1-哌嗪基]苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺(49)(PNU-248438)的制备
正如实施例8(步骤4-6)中所述,D-甘油酸、钙盐的二水合物与7偶合并且将所得到的酰胺脱保护,使其与二硫丙酸乙酯和三乙胺反应。产物在硅胶柱上用7.5%MeOH-CH2Cl2色谱层析纯化并从EtOAc-己烷中结晶得到49:mp 132℃(测定的);MS(ES)m/z 455(M+H+),477(M+Na+)。对C20H27FN4O5S·0.5H2O的分析计算值:C,51.88;H,6.09;N,12.09;H2O,3.88。测定值:C,51.77;H,6.09;N,11.96;H2O,3.85。实施例18 N-{[(5S)-3-(3-氟-4-{4-[3-羟基-2-(羟基甲基)-2-甲基丙酰基]-1-哌嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺(50)(PNU-248437)的制备
正如实施例8(步骤4-6)所述,将2,2-双(羟基甲基)丙酸与7偶合并将所得到的酰胺脱保护,使其与二硫丙酸乙酯和三乙胺反应。产物在硅胶柱上用5%MeOH-CH2Cl2色谱层析并从MeOH-EtOAc-己烷中结晶纯化得到50:mp 202-203℃(测定的);MS(ES)m/z 483(M+H+),502(M+Na+)。对C22H31FN4O5S的分析计算值:C,54.76;H,6.47;N,11.61。测定值:C,54.38;H,6.54;N,11.43。实施例19 N-[(5S)-3-{3-氟-4-[4-((2S)-2-羟基-3-苯基丙酰基)-1-哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺(51)(PNU-246967)的制备
正如实施例8(步骤4-6)所述,将L-3-苯基乳酸与7偶合并将所得到的酰胺脱保护,使其与二硫丙酸乙酯和三乙胺反应。产物在硅胶柱上用2.5%MeOH-CH2Cl2色谱层析纯化并从EtOAc-己烷中结晶得到51:mp174-175℃。对C26H31FN4O4S的分析计算值:C,60.68;H,6.07;N,10.89。测定值:C,60.56;H,6.17;N,10.68。实施例20 N-[(5S)-3-{3-氟-4-[4-((2R)-2-羟基-3-苯基丙酰基)-1-哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺(52)(PNU-246966)的制备
正如实施例8(步骤4-6)所述,将D-3-苯基乳酸与7偶合并将所得到的酰胺脱保护,使其与二硫丙酸乙酯和三乙胺反应。产物在硅胶柱上用2.5%MeOH-CH2Cl2色谱层析纯化并从EtOAc-己烷中结晶得到52:mp128-130℃(测定的)。对C26H31FN4O4S的分析计算值:C,60.68;H,6.07;N,10.98。测定值:C,60.50;H,6.17;N,10.80。实施例21 N-[(5S)-3-{3-氟-4-[4-((2R)-2-羟基-2-苯基乙酰基)-1-哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺(53)(PNU-245689)的制备
正如实施例8(步骤4-6)所述,将(R)-(-)-扁桃酸与7偶合并将所得到的酰胺脱保护,使其与二硫丙酸乙酯和三乙胺反应。产物在硅胶柱上用含有2-3.5%的MeOH的MeOH-CH2Cl2混合物色谱层析纯化得到53:对C25H30FN4O4S的HRMS(FAB)分析计算值(M+H+)501.1971,测定值:501.1980。实施例22 N-[(5S)-3-{3-氟-4-[4-((2S)-2-乙酰氧基-2-苯基乙酰基)-1-哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺(54)(PNU-245878)的制备
正如实施例8(步骤4-6)所述,将(S)-(+)-O-乙酰基扁桃酸与7偶合并将所得到的酰胺脱保护,使其与二硫丙酸乙酯和三乙胺反应。产物在硅胶柱上用2%的MeOH-CH2Cl2色谱层析纯化得到54:对C27H32FN4O5S的HRMS(FAB)分析计算值(M+H+)543.2077,测定值:543.2063。
Claims (20)
(a)H,
(b)NH2,
(c)NHC1-4烷基,
(d)C1-4的亚烷基,
(e)OC1-4烷基,
(f)SC1-4烷基,
(g)(CH2)n-C3-6-环烷基,或
(h)C1-4烷基,任选用1-3F、1-2Cl或CN取代;R2和R3各自独立地是H、F、Cl或C1-2烷基;R4是
(a)-C(=O)-CR5R6-O-R7,
(b)-C(=O)-CH2S(O)n-CH3,
(c)-C(=O)-CH2-S(=O)(=NR8)CH3,
(d)-C(=S)-R9,
(e)-C(=O)-CH2-O-R10,
(f)-C(=O)-(CH2)m-C(=O)-CH3,
(g)-C(=O)-(CH2OH)2-CH3,
(h)-C(=O)-CH2-CH2-OR14,或
(i)-CN;R5是H;R6是苯基、苄基、CH2OH或CH2OCH3;或者R5和R6一起形成C3-5环烷基;R7是H、CH3或C1-4烷酰基;R8是H、C1-4烷基、C1-4烷酰基、-C(=O)NH-C1-4烷基或-CO2C1-4烷基;R9是C1-4烷基、CH2OR11、S-C1-4烷基、OC1-4烷基或NR12R13;R10是苯基、-CO2-(CH2)2-OCH3、-P(=O)(OH)2、-C(=O)-NR12R13或者-C(=O)-(CH2)2-CO2H;R11是H、苯基、苄基、CH3或C(=O)CH3;R12和R13各自独立地是H或C1-3烷基;或者R12和R13一起形成5或6元饱和杂环,其中所述的饱和杂环还含有一个或两个选自于由O、S(O)n或NR7组成的组中的其他杂原子;R14是H、CH3或苄基;N是0、1或2;而m是0或1。
2.按照权利要求1的通式I化合物,其中R1是C1-4烷基。
3.按照权利要求1的通式I化合物,其中R1是乙基。
4.按照权利要求1的通式I化合物,其中R1和R2各自独立地是H或F。
5.按照权利要求1的通式I化合物,其中R2或R3中至少一个H,而另一个是F。
6.按照权利要求1的通式I化合物,其中R4是:
(a)C(=O)-CH(CH2-苯基)(OH),
(b)C(=O)-CH2-SO2-CH3,
(c)C(=O)-CH(OH)(CH2OH),
(d)C(=O)-C(=O)-CH3,
(e)C(=O)-CH(OH)(CH2-O-CH3),
(f)C(=O)-CH2CH2-OH,
(g)C(=O)-CH2-O-CO2-(CH2)2-OCH3,
(h)C(=S)-CH3或
(i)CN。
9.权利要求1的化合物,它是(1)N{[(5S)-3-(3-氟-4-{4-[2-(甲基亚硫酰基)乙酰基]-1-哌嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺,(2)N-{[(5S)-3-(3-氟-4-{4-[2-(甲基硫基)乙酰基]-1-哌嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺,(3)N-{[(5S)-3-(3-氟-4-{4-[2-(甲基硫酰基)乙酰基]-1-哌嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺,(4)N-({(5S)-3-[4-(4-硫代乙酰基-1-哌嗪基)-3-氟苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,(5)N-({(5S)-3-[4-(4-氰基-1-哌嗪基)-3-氟苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,(6)N-({(5S)-3-(3-氟-4-{4-[2-(甲基氨基羰基氧)乙酰基]-1-哌嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,(7)N-({(5S)-3-(3-氟-4-{4-[2-[(2-甲氧基乙氧基)羰基氧]乙酰 基]-1-哌嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,(8)N-[((5S)-3-{3-氟-4-[4-((2S)-2-羟基-3-甲氧基丙酰基)-1-哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,(9)N-[((5S)-3-{3-氟-4-[4-((2S)-2,3-二甲氧基丙酰基)-1-哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,(10)N-[((5S)-3-{3-氟-4-[4-((2S)-3-羟基-2-甲氧基丙酰基)-1-哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,(11)N-({(5S)-3-[3-氟-4-(4-乙酰乙酰基-1-哌嗪基)苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,(12)N-({(5S)-3-[3-氟-4-(4-丙酮酰基-1-哌嗪基)苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,(13)N-({(5S)-3-[3-氟-4-[4-(3-羟基丙酰基)-1-哌嗪基]苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,(14)N-{[(5S)-3-(3-氟-4-{4-[(1-羟基环丙基)羰基]-1-哌嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺,(15)N-[((5S)-3-{3-氟-4-[4-(2-苯氧基乙酰基)-1-哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基)甲基]硫代丙酰胺,(16)N-({(5S)-3-[3-氟-4-[4-((2S)-2,3-二羟基丙酰基)-1-哌嗪基]苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,(17)N-({(5S)-3-[3-氟-4-[4-((2R)-2,3-二羟基丙酰基)-1-哌嗪基]苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,(18)N-{[(5S)-3-(3-氟-4-{4-[3-羟基-2-(羟基甲基)-2-甲基丙酰基]-1-哌嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺,(19)N-[((5S)-3-{3-氟-4-[4-((2S)-2-羟基-3-苯基丙酰基)-1-哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基)甲基]硫代丙酰胺,(20)N-[((5S)-3-{3-氟-4-[4-((2R)-2-羟基-3-苯基丙酰基)-1-哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基)甲基]硫代丙酰胺,
(21)N-[((5S)-3-{3-氟-4-[4-((2R)-2-羟基-2-苯基乙酰基)-1-哌
嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基)甲基]硫代丙酰胺,或
(22)N-[((5S)-3-{3-氟-4-[4-((2S)-2-乙酰氧基-2-苯基乙酰
基)-1-哌嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基)甲基]硫代丙酰
胺。
10.权利要求1的化合物,它是:
(1)N-{[(5S)-3-(3-氟-4-{4-[2-(甲基硫酰基)乙酰基]-1-哌嗪基}
苯基)-2-氧代-1,3-噁唑烷-5-基]甲基}硫代丙酰胺,或
(2)N-({(5S)-3-[4-(4-硫代乙酰基-1-哌嗪基)-3-氟苯基]-2-氧代
-1,3-噁唑烷-5-基}甲基)硫代丙酰胺。
11.权利要求1的化合物,它是N-({(5S)-3-[4-(4-氰基-1-哌嗪
基)-3-氟苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺。
12.权利要求1的化合物,它是:
(1)N-({(5S)-3-(3-氟-4-{4-[2-[(2-甲氧基乙氧基)羰基氧]乙酰
基]-1-哌嗪基}苯基)-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,
(2)N-[((5S)-3-{3-氟-4-[4-((2S)-2-羟基-3-甲氧基丙酰基)-1-哌
嗪基]苯基}-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,
(3)N-({(5S)-3-[3-氟-4-[4-(3-羟基丙酰基)-1-哌嗪基]苯基]-2-
氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,
(4)N-({(5S)-3-[3-氟-4-[4-((2S)-2,3-二羟基丙酰基)-1-哌嗪基]
苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,
(5)N-({(5S)-3-[3-氟-4-[4-((2R)-2,3-二羟基丙酰基)-1-哌嗪基]
苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺,
(6)N-[((5S)-3-{3-氟-4-[4-((2R)-2-羟基-3-苯基丙酰基)-1-哌嗪
基]苯基}-2-氧代-1,3-噁唑烷-5-基)甲基]硫代丙酰胺。
13.权利要求1的化合物,它是N-({(5S)-3-[3-氟-4-(4-丙酮酰基-1-哌嗪基)苯基]-2-氧代-1,3-噁唑烷-5-基}甲基)硫代丙酰胺。
14.一种治疗微生物感染的方法,包括对需要这种治疗的哺乳动物给予有效量的权利要求1中所示的通式I化合物。
15.权利要求14的方法,其中将通式I的化合物以药用组合物的形式口服、胃肠外、经皮或局部给药。
16.权利要求14的方法,其中该化合物以大约0.1到大约100mg/kg的体重/天的用量给药。
17.权利要求14的方法,其中该化合物以大约1到大约50mg/kg的体重/天的用量给药。
18.一种权利要求14的治疗微生物感染的方法,其中的感染是皮肤感染。
19.权利要求14的治疗微生物感染的方法,其中感染是眼部感染。
20.一种药用组合物,含有权利要求1的化合物和可药用载体。
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CN01803631A Pending CN1395569A (zh) | 2000-02-10 | 2001-02-07 | 含有哌嗪酰胺取代基的噁唑二酮硫代酰胺 |
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US (1) | US20010047004A1 (zh) |
EP (1) | EP1263742B1 (zh) |
JP (1) | JP2003522763A (zh) |
KR (1) | KR20020072311A (zh) |
CN (1) | CN1395569A (zh) |
AR (1) | AR029226A1 (zh) |
AT (1) | ATE302762T1 (zh) |
AU (1) | AU2001234428A1 (zh) |
BR (1) | BR0107645A (zh) |
CA (1) | CA2395648A1 (zh) |
CO (1) | CO5271737A1 (zh) |
DE (1) | DE60112903T2 (zh) |
ES (1) | ES2248284T3 (zh) |
MX (1) | MXPA02007719A (zh) |
NZ (1) | NZ520696A (zh) |
PE (1) | PE20011089A1 (zh) |
WO (1) | WO2001058885A1 (zh) |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6465456B2 (en) * | 2000-06-29 | 2002-10-15 | Bristol-Myers Squibb Company | Isoxazolinone antibacterial agents |
ATE321024T1 (de) | 2000-10-17 | 2006-04-15 | Pharmacia & Upjohn Co Llc | Verfahren zur herstellung von oxazolidinonverbindungen |
WO2003072575A1 (en) | 2002-02-28 | 2003-09-04 | Astrazeneca Ab | 3-cyclyl-5-(nitrogen-containing 5-membered ring) methyl-oxazolidinone derivatives and their use as antibacterial agents |
NZ535591A (en) * | 2002-02-28 | 2006-07-28 | Astrazeneca Ab | Oxazolidinone derivatives, processes for their preparation, and pharmaceutical compositions containing them |
CA2478502A1 (en) * | 2002-04-01 | 2003-10-09 | Cadila Healthcare Limited | Novel antiinfective compounds, process for their preparation and pharmaceutical compositions containing them |
TW200403240A (en) | 2002-06-28 | 2004-03-01 | Upjohn Co | Difluorothioacetamides of oxazolidinones as antibacterial agents |
TW200404069A (en) * | 2002-06-28 | 2004-03-16 | Upjohn Co | Difluorothioacetamides of oxazolidinones with a glycoloylpiperazine substituent |
CA2492194A1 (en) * | 2002-07-11 | 2004-01-22 | Wockhardt Limited | Antibacterial cyano-(substituted)-methylenepiperidinophenyl oxazolidinones targeting multiple ribonucleoproteins sites |
CA2492743A1 (en) * | 2002-07-11 | 2004-01-22 | Wockhardt Limited | Antimicrobial oxazolidinones, process of their preparation, and pharmaceutical compositions containing them |
AU2003253141A1 (en) * | 2002-08-22 | 2004-03-11 | Orchid Chemicals And Pharmaceuticals Ltd | Novel antibacterial agents |
US7091196B2 (en) | 2002-09-26 | 2006-08-15 | Rib-X Pharmaceuticals, Inc. | Bifunctional heterocyclic compounds and methods of making and using same |
BR0316483A (pt) | 2002-11-21 | 2005-10-11 | Upjohn Co | Derivados de n-(4-(piperazin-1-il)-fenil-2-oxazolidinona-5-carboxami da e compostos relacionados como agentes antibacterianos |
JP4607107B2 (ja) | 2003-07-02 | 2011-01-05 | メルク・シャープ・エンド・ドーム・コーポレイション | シクロプロピル基置換されたオキサゾリジノン抗生物質およびこれらの誘導体 |
WO2005005420A1 (en) * | 2003-07-02 | 2005-01-20 | Merck & Co., Inc. | Cyclopropyl group substituted oyazolidinone antibiotics and derivatives thereof |
CN102816194A (zh) | 2004-02-27 | 2012-12-12 | 瑞伯-X医药品有限公司 | 大环化合物以及其制作和使用方法 |
EP1934237A2 (en) | 2005-08-24 | 2008-06-25 | Rib-X Pharmaceuticals, Inc. | Triazole compounds and methods of making and using the same |
DK1934238T3 (en) | 2005-08-24 | 2017-09-18 | Melinta Therapeutics Inc | TRIAZOL COMPOUNDS AND METHODS FOR THE PREPARATION AND USE OF THESE |
US20100210602A1 (en) * | 2006-12-12 | 2010-08-19 | The Johns Hopkins University | PhoU (PerF), A PERSISTENCE SWITCH INVOLVED IN PERSISTER FORMATION AND TOLERANCE TO MULTIPLE ANTIBIOTICS AND STRESSES AS A DRUG TARGET FOR PERSISTER BACTERIA |
JO2972B1 (en) | 2007-06-08 | 2016-03-15 | جانسين فارماسوتيكا ان. في | Piperidine / piperazine derivatives |
AR066911A1 (es) | 2007-06-08 | 2009-09-23 | Janssen Pharmaceutica Nv | Derivados de piperidina / piperazina |
WO2008148851A1 (en) | 2007-06-08 | 2008-12-11 | Janssen Pharmaceutica N.V. | Piperidine/piperazine derivatives |
JP5443342B2 (ja) | 2007-06-08 | 2014-03-19 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | ピペリジン/ピペラジン誘導体 |
EP2170874A4 (en) * | 2007-06-22 | 2011-08-31 | Orchid Res Lab Ltd | NEW COMPOUNDS AND THEIR USE |
JP5579170B2 (ja) | 2008-06-05 | 2014-08-27 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Dgat阻害剤とppar作動薬を含有する薬剤組み合わせ物 |
CN115466253A (zh) * | 2021-06-16 | 2022-12-13 | 沈阳药科大学 | 含二硫代氨基甲酸酯结构的噁唑烷酮类化合物及其制备方法 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
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RO84456B (ro) * | 1981-09-08 | 1984-08-30 | Eli Lilly And Co | Procedeu pentru prepararea unor derivati de cefalosporina tieno si furopiridiniu substituita |
US6218413B1 (en) * | 1997-05-30 | 2001-04-17 | Pharmacia & Upjohn Company | Oxazolidinone antibacterial agents having a thiocarbonyl functionality |
AU9001598A (en) * | 1997-09-11 | 1999-03-29 | Hokuriku Seiyaku Co. Ltd | Thiourea derivatives |
JPH11322729A (ja) * | 1998-03-09 | 1999-11-24 | Hokuriku Seiyaku Co Ltd | ジチオカルバミド酸誘導体 |
JP2000204084A (ja) * | 1998-11-11 | 2000-07-25 | Hokuriku Seiyaku Co Ltd | チオカルバミド酸誘導体 |
NZ515754A (en) * | 1999-05-27 | 2003-10-31 | Upjohn Co | Bicyclic oxazolidinone compounds, pharmaceuticals thereof and their use as antibacterial agents |
-
2001
- 2001-02-07 CA CA002395648A patent/CA2395648A1/en not_active Abandoned
- 2001-02-07 ES ES01906529T patent/ES2248284T3/es not_active Expired - Lifetime
- 2001-02-07 NZ NZ520696A patent/NZ520696A/en unknown
- 2001-02-07 KR KR1020027010298A patent/KR20020072311A/ko not_active Application Discontinuation
- 2001-02-07 AU AU2001234428A patent/AU2001234428A1/en not_active Abandoned
- 2001-02-07 PE PE2001000132A patent/PE20011089A1/es not_active Application Discontinuation
- 2001-02-07 CN CN01803631A patent/CN1395569A/zh active Pending
- 2001-02-07 EP EP01906529A patent/EP1263742B1/en not_active Expired - Lifetime
- 2001-02-07 US US09/778,603 patent/US20010047004A1/en not_active Abandoned
- 2001-02-07 BR BR0107645-0A patent/BR0107645A/pt not_active IP Right Cessation
- 2001-02-07 AT AT01906529T patent/ATE302762T1/de not_active IP Right Cessation
- 2001-02-07 MX MXPA02007719A patent/MXPA02007719A/es unknown
- 2001-02-07 DE DE60112903T patent/DE60112903T2/de not_active Expired - Fee Related
- 2001-02-07 WO PCT/US2001/000682 patent/WO2001058885A1/en active IP Right Grant
- 2001-02-07 JP JP2001558436A patent/JP2003522763A/ja active Pending
- 2001-02-08 CO CO01009443A patent/CO5271737A1/es not_active Application Discontinuation
- 2001-02-09 AR ARP010100602A patent/AR029226A1/es unknown
Also Published As
Publication number | Publication date |
---|---|
NZ520696A (en) | 2004-03-26 |
DE60112903D1 (de) | 2005-09-29 |
BR0107645A (pt) | 2002-10-08 |
CA2395648A1 (en) | 2001-08-16 |
US20010047004A1 (en) | 2001-11-29 |
ES2248284T3 (es) | 2006-03-16 |
ATE302762T1 (de) | 2005-09-15 |
EP1263742B1 (en) | 2005-08-24 |
WO2001058885A1 (en) | 2001-08-16 |
KR20020072311A (ko) | 2002-09-14 |
AR029226A1 (es) | 2003-06-18 |
CO5271737A1 (es) | 2003-04-30 |
DE60112903T2 (de) | 2006-06-14 |
EP1263742A1 (en) | 2002-12-11 |
JP2003522763A (ja) | 2003-07-29 |
AU2001234428A1 (en) | 2001-08-20 |
PE20011089A1 (es) | 2001-10-04 |
MXPA02007719A (es) | 2002-10-11 |
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