WO2016029330A1 - 新的膦酸酯衍生物及其医药用途 - Google Patents
新的膦酸酯衍生物及其医药用途 Download PDFInfo
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- WO2016029330A1 WO2016029330A1 PCT/CN2014/000797 CN2014000797W WO2016029330A1 WO 2016029330 A1 WO2016029330 A1 WO 2016029330A1 CN 2014000797 W CN2014000797 W CN 2014000797W WO 2016029330 A1 WO2016029330 A1 WO 2016029330A1
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- Prior art keywords
- pharmaceutically acceptable
- formula
- fosfomycin
- solvate
- acceptable salt
- Prior art date
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- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 239000004480 active ingredient Substances 0.000 claims abstract description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 5
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical class C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 claims description 28
- 229960000308 fosfomycin Drugs 0.000 claims description 27
- 239000012453 solvate Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 231100000252 nontoxic Toxicity 0.000 claims description 6
- 230000003000 nontoxic effect Effects 0.000 claims description 6
- 239000003242 anti bacterial agent Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims 3
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 230000003115 biocidal effect Effects 0.000 abstract 1
- 230000000844 anti-bacterial effect Effects 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- XPADMSPIANPGCR-UHFFFAOYSA-N 1-(3-bromopropoxy)hexadecane Chemical compound CCCCCCCCCCCCCCCCOCCCBr XPADMSPIANPGCR-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 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
- 230000001580 bacterial effect Effects 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 3
- MJRNQLFBXOUWCZ-UHFFFAOYSA-N 1-(3-bromopropoxy)tetradecane Chemical group CCCCCCCCCCCCCCOCCCBr MJRNQLFBXOUWCZ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- DRQMOYPIABRLIF-UHFFFAOYSA-N 1-(3-bromopropoxy)octadecane Chemical compound CCCCCCCCCCCCCCCCCCOCCCBr DRQMOYPIABRLIF-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108090000204 Dipeptidase 1 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
- 241001465754 Metazoa Species 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 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 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229960000510 ammonia Drugs 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
Definitions
- the present invention relates to a novel phosphonate derivative of fosfomycin represented by Formula I, and a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound as an active ingredient, and the phosphonate derivative or The use of a pharmaceutically acceptable salt thereof for the preparation of an antibacterial agent.
- n is an integer of 0 to 5
- R is a linear alkyl group having 4 to 20 carbon atoms, a branched alkyl group, an unsaturated alkyl group or an alkyl group substituted with a ??
- Fosfomycin is a broad-spectrum antibacterial agent that produces a bactericidal action by inhibiting the synthesis of bacterial cell walls.
- Phosphamycin has no cross-resistance with ⁇ -lactamase inhibitors, aminoglycosides and quinolones, and includes G for methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum ⁇ -lactamase - Antibiotics such as bacteria (ESBL) and vancomycin-resistant enterococci (VE) have good antibacterial effects.
- MRSA methicillin-resistant Staphylococcus aureus
- ESBL bacteria
- VE vancomycin-resistant enterococci
- fosfomycin has poor fat solubility, low tissue permeability, short biological half-life, frequent administration, and large dosage. Summary of the invention The present invention provides a monoester derivative of fosfomycin of formula I:
- n is an integer of 0 to 5
- R is a linear alkyl group having 4 to 20 carbon atoms, a branched alkyl group, an unsaturated alkyl group or a substituted alkyl group.
- the phosphonic acid group in the molecule of the fosfomycin monoester derivative represented by the formula I may form a salt with an inorganic base such as sodium hydroxide or calcium hydroxide, or may be combined with ammonia, meglumine, choline and trimethylol.
- An organic base such as an amine forms a salt; the fosfomycin monoester derivative represented by the formula I and a salt thereof can form a solvate with a solvent such as water, ethanol or the like.
- the present invention also provides a salt of a monoester derivative of fosfomycin represented by I and a solvate thereof.
- the present invention also provides a pharmaceutical composition comprising the fosfomycin monoester derivative of the formula I and a non-toxic pharmaceutically acceptable salt thereof and a solvate thereof as an active ingredient.
- These pharmaceutical compositions may be administered by an oral route or by parenteral routes such as intramuscular injection, intravenous injection, inhalation, and the like.
- the present invention finally provides a fosfomycin monoester derivative of the formula I and non-toxic pharmaceutically acceptable salts thereof and solvates thereof, and a fosfomycin monoester derivative represented by I and a non-toxic pharmaceutically acceptable Use of a pharmaceutical composition comprising an acceptable salt and a solvate thereof as an active ingredient in the preparation of an antibacterial agent.
- the fosfomycin monoester derivative of formula I can be prepared according to the following synthetic route:
- n is an integer of 0 to 5
- R is a linear alkyl group having 4 to 20 carbon atoms, a branched alkyl group, an unsaturated alkyl group or a substituted alkyl group.
- Nuclear magnetic resonance spectrum ⁇ (ppm, DMSO-d6): 0.85 (t, 3H); 1.13-1.23 (m, 26H); 1.40 (d, 3H); 1.42-1.48 (m, 2H); 1.61-1.64 (m , 2H); 2.55 (q, IH); 3.01 (m, IH); 3.12-3.4 (m, 6H).
- the concentration of fosfomycin in blood, liver, lung and kidney at different time points after intragastric administration of the target compound mice was determined by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).
- HPLC-MS/MS high performance liquid chromatography-tandem mass spectrometry
- LC/MS/MS American Finnigan TSQ Quantum Liquid Chromatography-Mass Spectrometer consisting of Finnigan Surveyor LC pump, Surveyor AS autosampler, electrospray ionization ionization source (ESI) and tertiary tandem mass spectrometry .
- the control software is Xcalibur 1.4 and the mass spectrometry data is analyzed using the Lcquan 2.0 data processing system; the column is UltimateTM XB-CN column (150 mm X 4.6 mm, 5 ⁇ m), CI 8 guard column (4 mm X 3.0 mm), mobile phase It was methanol-5 mM ammonium acetate aqueous solution (1:9, V/V), flow rate 0.7 ml/min; injection volume 20 ⁇ L; column temperature was room temperature.
- Balb/C mice male, fasted for 16 h, were randomly divided into 3 groups, 3 rats in each group, respectively, given intragastric administration of fosfomycin (200 mg/kg) or an equimolar dose of the target compound.
- the suspension of sodium cellulose was collected at 1 hour, 4 hours and 16 hours after administration, and the serum was taken by centrifugation.
- the liver, kidney and lung were prepared and homogenized, and the supernatant was centrifuged. The same group of tissues were combined at the same time. For the sample, the concentration of fosfomycin in the blood and organs of fosfomycin was determined. The results are shown in Table 2.
- the target compound after oral administration of the target compound, it can be converted into fosfomycin in vivo, and the half-life in blood, liver, kidney and lung is significantly greater than that of fosfomycin; the target compound is sputum in the liver and lung after oral administration.
- the concentration ofmycin was significantly higher than the concentration after oral administration of fosfomycin.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
提供一种式I所示的磷霉素的新磷酸酯衍生物及其药学上可接受的盐,含有这些化合物作为活性成分的药物组合物,以及所述磷酸酯衍生物或其药学上可接受的盐用于制备抗菌药物的用途。式I中,n为0-5的整数,R为碳原子数4-20的直链烷基、支链烷基、不饱和烷基或卤素取代的烷基。
Description
新的膦酸酯^ "生物及其医药用途
技术领域 本发明涉及式 I 所示的磷霉素的新的膦酸酯衍生物及其药学上可接受的 盐, 含有这些化合物作为活性成分的药物組合物, 以及所述膦酸酯衍生物或 其药学上可接受的盐用于制备抗菌药物的用途。
式 I中, n为 0-5的整数, R为碳原子数 4-20的直链烷基、 支链烷基、 不饱和烷基或 !¾素取代的烷基。
背景技术
磷霉素为广谱抗菌药, 通过抑制细菌细胞壁的合成, 产生杀菌作用。 磷 霉素与 β -内酰胺酶抑制剂、 氨基糖苷类及喹诺酮类药物没有交叉耐药性, 对 包括耐甲氧西林金黄色葡萄球菌 (MRSA) 、 产超广谱 β -内酰胺酶的 G-菌 (ESBL) 、 万古霉素耐药肠球菌 (V E) 等耐药菌均具有较好的抗菌作用。 但是磷霉素脂溶性差, 組织渗透性低, 生物半衰期短, 需频繁给药, 而且用药 剂量大。 发明内容
本发明提供式 I所示的磷霉素的单酯衍生物:
H3C P— OCH2-(CH2) n-CH20-R
O
I
式 I中, n为 0-5的整数, R为碳原子数 4-20的直链烷基、 支链烷基、 不饱和烷基或 1¾素取代的烷基。 式 I所示的磷霉素单酯衍生物分子中的膦酸基可以与氢氧化钠、 氢氧化钙 等无机碱成盐, 也可与氨、 葡甲胺、 胆碱及三羟甲基甲胺等有机碱成盐; 式 I 所示的磷霉素单酯衍生物及其盐可以与溶剂如水、 乙醇等形成溶剂合物。 因 此, 本发明还提供 I所示的磷霉素的单酯衍生物的盐及其溶剂合物。 本发明还提供式 I所示的磷霉素单酯衍生物及其非毒性药学上可接受的盐 及其溶剂合物作为活性成分的药物组合物。 这些药物组合物可以通过口服的 途径给药, 也可以通过非胃肠道途径如肌注、 静注、 吸入等途径给药。 本发明最后还提供式 I 所示磷霉素单酯衍生物及其非毒性药学上可接受 的盐及其溶剂合物, 以及 I 所示磷霉素单酯衍生物及其非毒性药学上可接受 的盐及其溶剂合物作为活性成分的药物組合物在制备抗菌药物中的用途。
式 I所示磷霉素单酯衍生物可以按照如下合成路线制备:
在 25ml DMF中, 依次加入 1.38克磷霉素, 3.8克 1-溴 -3-十六烷氧基丙 烷, 1.2ml三乙胺, 于 75°C搅拌加热, 10小时, 减压蒸干, 将残留物用二氯 甲烷溶解后过滤, 将滤液减压蒸干, 将残留物用硅胶柱层折分离, 用二氯甲 烷: 石油醚:甲醇 (5:5:1) 洗脱, 收集所需組分, 减压蒸千, 得到 1.30克。 核磁共振氢谱 δ (ppm, DMSO-d6): 0.85(t, 3H); 1.13-1.23(m, 26H); 1.40(d, 3H); 1.42-1.48(m, 2H) ; 1.61-1.64(m, 2H); 2.55 (q, IH) ; 3.01 (m, IH); 3.12-3.4(m, 6H)。
实施例 2 0- ( 3-十四烷氧基-丙基) -磷霉素 ( 12 ) 的制备
H P— OCH2-CH2-CH2OCH2-(CH2)12 -CH3
O
I2
参照实施例 1的方法, 用 1-溴 -3-十四烷氧基丙烷代替 1-溴 -3-十六烷氧基 丙烷, 与磷霉素反应, 得到目标化合物 12 , 产率 41% 核磁共振氢谱 δ (ppm, DMSO-d6): 0.87(t, 3H); 1.12-1.23(m, 22H); 1.41(d, 3H) ; 1.43-1.49(m, 2H) ; 1.61-1.64(m, 2H); 2.55 (q, 1H) ; 3.01 (m, 1H); 3.12- 3.4(m, 6H)。
实施例 3 0- ( 3-十八烷氧基-丙基) -磷霉素 ( 13 ) 的制备 H P— OCH2-CH2-CH2OCH2-(CH2)16 -CH3
O
I3
参照实施例 1的方法, 用 1-溴 -3-十八烷氧基丙烷代替 1-溴 -3-十六烷氧基 丙烷, 与磷霉素反应, 得到 3标化合物 13 , 产率 46% 核磁共振氢谱 δ (ppm, DMS〇- d6): 0.88(t, 3H); 1.12-1.23(m, 3 OH); 1.41(d, 3H) ; 1.43-1.49(m, 2H) ; 1.61-1.64(m, 2H); 2.55 (q, 1H) 3.01 (m, 1H) ; 3.12-3.4(m, 6H)。
实施例 4 0- ( 3-十六烷氧基-乙基) -磷霉素 ( 14 ) 的制备 H3C P— OCH2-CH2OCH2-(CH2)14 -CH3
eH0- 9 (ZH0)- HOOSHO-2HOO— d 0Ή
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氧基丙烷,与磷霉素反应,得到目标化合物 I1G,产率 44% 核磁共振氢谱 δ (ppm, DMSO-d6): 1.14-1.23(m, 22H); 1.38 (m, 2H) 1.40(d, 3H); 1.44-1.49(m, 2H); 2.55 (q, 1H) ; 3.01 (m, 1H); 3.12- 3.4(m, 6H) ; 4.90(d, 1H); 4.94 (d, 1H); 5.75 (m, 1H)。
实施例 11 0- ( 3- ( 15, 15, 16, 16, 16-五氟十六烷氧基 ) -丙基)-磷霉素 ( In )
参照实施例 1 的方法, 用 1-溴 -3- ( 15,15,16,16,16-五氟十六烷氧基) -丙 烷代替 1-溴 -3-十六烷氧基丙烷,与磷霉素反应,得到目标化合物 Iu ,产率 37% 核磁共振氢谱 δ (ppm, DMSO-d6):1.13-1.26(m, 24H); 1.41-1.48(m, 5H); 1.61-1.68(m, 4H); 2.55 (q,H) ; 3.01 (m, 1H) ; 3.12-3.4(m, 6H)。
实施例 12 目标化合物口服给药后的抗菌作用
测定了目标化合物口服给药后的不同时间点采得的血清对三株 MRSA菌 株 (A为 ATCC29213 , B为 SA99 , C为 SARN450) 的抗菌作用。
雄性 SD大鼠禁食 16 h,随机分组,每组 3只,分别灌胃给予磷霉素 (100mg/kg) 或等摩尔剂量目标化合物的羧甲基纤维素钠悬浮液, 于给药后不同时间点从 眼底静脉丛采血 0.5 mL, 分离出血清;合并同組动物同时间点的血清, 取 ΙΟΟμΙ, 与 0.9ml细菌培养液 (菌液终浓度为 lOOCFU/ml) 混合; 取混合液 ΙΟΟμΙ, 均匀
涂布于 MH琼脂的平板上, 在 35°C孵育 24小时,对菌落进行计数。 结果见表一。
目标化合物口服给药后的抗菌作用
由表一可知, 目标化合物口服给药后, 能够在体内转化为具有抗菌作用 的活性药物,且能够维持有效抗菌浓度达 16小时,而磷霉素口服给药后 16小时, 血液中活性药物浓度已低于有效抗菌浓度。 实施例 13 目标化合物口服给药后的组织分布
采用高效液相色谙 -串联质谱法 (HPLC- MS/MS) 测定目标化合物小鼠灌 胃给药后不同时间点, 血、 肝、 肺及肾中磷霉素的浓度。
美国 Finnigan公司 TSQ Quantum型液相色谱-质谱联用仪 (LC/MS/MS) , 由 Finnigan Surveyor LC泵、 Surveyor AS自动进样器、电喷雾离子化电离源 (ESI) 及三级串联质谱組成。 控制软件为 Xcalibur 1.4 , 质谱数据分析采用 Lcquan 2.0 数据处理系统; 色谱柱为 UltimateTM XB-CN 柱(150 mm X 4.6 mm , 5 μ m), CI 8保护柱(4 mm X 3.0 mm), 流动相为甲醇 -5mM醋酸铵水溶液(1:9, V/V), 流速 0.7 ml/min; 进样量 20 μ L; 柱温为室温。
Balb/C小鼠, 雄性, 禁食 16 h, 随机分为 3組, 每組 3只, 分别灌胃给 予分别灌胃给予磷霉素 (200mg/kg)或等摩尔剂量的目标化合物的羧甲基纤维 素钠的悬浮液, 分别于给药后 1 小时、 4小时及 16小时采血离心取血清, 取 肝、 腎、 肺制备匀浆, 离心取上清; 合并同組同组织同时间点的样本, 测定磷 霉素的血液及脏器中磷霉素的浓度。 结果见表 2。
目标化合物口服给药后的抗菌作用的组织分布
Claims
2、 含有权利要求 1 中所述的式 I所示的化合物或其药学上可接受的盐或其溶 剂合物作为活性成分, 以及一种或多种药用载体或赋形剂的药物组合物。
3、 通过口服途径给药的含有权利要求 1 中所述的式 I化合物或其药学上可接 受的盐或其溶剂合物作为活性成分, 以及一种或多种药用载体或赋形剂的 药物組合物。
4、 非胃肠道途径给药的含有权利要求 1 中所述的式 I所示的化合物或其药学 上可接受的盐或其溶剂合物作为活性成分, 以及一种或多种药用载体或赋 形剂的药物组合物。
5、 权利要求 1 中所述的式 I 所示的磷霉素单酯衍生物及其非毒性药学上可接 受的盐及其溶剂合物, 以及权利要求 2-4 所述的含有式 I 所示的磷霉素单 酯衍生物及其非毒性药学上可接受的盐及其溶剂合物作为活性成分的药物 组合物在制备抗菌药物中的用途。
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Citations (3)
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GB1239987A (en) * | 1967-10-30 | 1971-07-21 | Merck & Co Inc | Phosphonic acid derivatives |
US3595869A (en) * | 1968-05-15 | 1971-07-27 | Merck & Co Inc | Process for preparing a diastereomer of an optically active ester or amide of (cis-1,2-epoxypropyl)-phosphonic acid |
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GB1239987A (en) * | 1967-10-30 | 1971-07-21 | Merck & Co Inc | Phosphonic acid derivatives |
US3595869A (en) * | 1968-05-15 | 1971-07-27 | Merck & Co Inc | Process for preparing a diastereomer of an optically active ester or amide of (cis-1,2-epoxypropyl)-phosphonic acid |
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