WO2016101794A1 - 替唑尼特磷酸酯和烷基磺酸酯及其在药学中的应用 - Google Patents

替唑尼特磷酸酯和烷基磺酸酯及其在药学中的应用 Download PDF

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WO2016101794A1
WO2016101794A1 PCT/CN2015/097074 CN2015097074W WO2016101794A1 WO 2016101794 A1 WO2016101794 A1 WO 2016101794A1 CN 2015097074 W CN2015097074 W CN 2015097074W WO 2016101794 A1 WO2016101794 A1 WO 2016101794A1
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compound
group
nitrothiazol
ylcarbamoyl
phenyl
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PCT/CN2015/097074
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English (en)
French (fr)
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李松
李行舟
钟武
郑志兵
肖军海
周辛波
谢云德
王晓奎
王莉莉
陈伟
谢菲
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中国人民解放军军事医学科学院毒物药物研究所
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Priority to JP2017533858A priority Critical patent/JP2018501268A/ja
Priority to US15/539,266 priority patent/US10196411B2/en
Priority to EP15871863.5A priority patent/EP3239160B1/en
Publication of WO2016101794A1 publication Critical patent/WO2016101794A1/zh

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    • 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
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/58—Nitro radicals
    • 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

Definitions

  • the present invention relates to tizoxanide phosphate or alkyl sulfonate compounds, and pharmaceutically acceptable salts thereof, isomers thereof, hydrates thereof or solvates thereof, and the use of such compounds in pharmacy.
  • Nitazoxanide is a thiazole benzamide compound developed by Romark Laboratories with diverse biological activities. Its chemical name is "2-acetoxy-N-(5-nitro-2-thiazole) benzamide", the chemical formula is C 12 H 9 N 3 O 5 S, melting point is 202 ° C, is a light yellow Powder, insoluble in water, slightly soluble in ethanol, soluble in organic solvents such as tetrahydrofuran, dimethyl sulfoxide (DMSO) and N,N-dimethylformamide (DMF).
  • DMSO dimethyl sulfoxide
  • DMF N,N-dimethylformamide
  • nitazoxanide can effectively fight against a variety of protozoal and helminth parasites, including: Larval-type flagellate, amoeba, Cryptosporidium, Cyclospora, Trichomonas, Entero encephalitis Microsporidia, Plasmodium ethamae, Blastocystis hominis, colonic pouch worm, human aphid, Pichia microsporidia, aphids (including beef aphids, short-shelled aphids), microcapsule aphids, Giardia , Leishmania, Fasciola hepatica, etc.
  • Nitrozolidine is well treated for viral infections such as hepatitis B (HBV), hepatitis C (HCV), influenza (including canine influenza), and viral gastroenteritis caused by rotavirus or norovirus. effect. Nitrozolidine can also prevent infections caused by bacteria such as Clostridium difficile (CD), Mycobacterium tuberculosis (including drug-resistant tuberculosis) and Helicobacter pylori, and also inhibit the formation of bacterial biofilm. effect.
  • HBV hepatitis B
  • HCV hepatitis C
  • influenza including canine influenza
  • viral gastroenteritis caused by rotavirus or norovirus.
  • Nitrozolidine can also prevent infections caused by bacteria such as Clostridium difficile (CD), Mycobacterium tuberculosis (including drug-resistant tuberculosis) and Helicobacter pylori, and also inhibit the formation of bacterial biofilm. effect.
  • Nitrozolidine is a prodrug that is rapidly hydrolyzed into its active metabolite Tizoxanide (TIZ) in vivo.
  • TIZ active metabolite Tizoxanide
  • Pharmacokinetic studies in humans have shown that nitazoxanide can be absorbed from the gastrointestinal tract after oral administration, about one-third of the oral dose is excreted from the urine, and two-thirds of the oral dose is excreted from the feces.
  • nitazoxanide is rapidly metabolized by plasma esterase (half-life at 37 ° C for about 6 minutes), hydrolytically deacetylated to become its active metabolite tazoxanide, thus in plasma, urine, bile and The presence of nitazoxanide was not detected in the feces.
  • Tizoxanide can continue to be glucuronylated in vivo to glucuronidized tizoxanide without pharmaceutically active activity.
  • Tizoxanide is present in plasma, urine, bile, and feces, and Tizoxanide Glcuronide is also present in plasma, urine, and bile.
  • Nitrozolidine has good biological properties such as diverse biological activities and good safety, but there are also some obvious deficiencies.
  • the shortcomings mainly exist in the following two aspects:
  • nitazoxanide The problem of nitazoxanide is low bioavailability, short half-life, and low blood concentration.
  • healthy adults Oral nitazoxanide after a single dose of 500mg, the peak time of the active metabolite tizoxanide was 3-4h, the AUC value was about 3.9-11.3 ⁇ g*h/mL, and the peak concentration Cmax was 1.9 ⁇ g/mL. (range 1.1-2.5), the half-life is very short, only 1.03 to 1.6 hours.
  • the minimum inhibitory concentration MIC of nitazoxan to Mycobacterium tuberculosis is 12 to 28 ⁇ g/mL (median 16 ⁇ g/mL); nitazoxanide and tizoxanide
  • the minimum inhibitory concentration (MICs) of 103 strains of Helicobacter pylori was between 0.25 to 8 ⁇ g/mL, the 50% minimum inhibitory concentration (MIC 50 ) was 1 ⁇ g/mL, and the 90% minimum inhibitory concentration (MIC 90 ) was 4 ⁇ g/ mL;
  • the minimum inhibitory concentration (MIC) of nitazoxanide and tizoxanide against Staphylococcus epidermidis or other staphylococci (including methicillin-resistant Staphylococcus aureus) under aerobic or microaerobic conditions is 8 ⁇ 16 ⁇ g/mL; nitazoxanide in MDCK cells, the EC 50 of the PR8 influenza virus strain was 1 ⁇ g
  • nitazoxanide has a low bioavailability, a short half-life, and a low blood concentration.
  • nitazoxanide When nitazoxanide is used to treat parasitic infections such as intestinal protozoa and helminths, it does not require nitazoxanide to enter the bloodstream. Therefore, nitazoxanide has poor oral absorption, low bioavailability, and blood concentration. The low nature does not affect the efficacy of parasitic infections such as protozoa and helminths.
  • nitazoxanide is used in the treatment of drug-resistant Mycobacterium tuberculosis, Helicobacter pylori or methicillin-resistant Staphylococcus aureus, or in the treatment of viral infections such as influenza and rotavirus, the blood concentration should be at least Above its minimum inhibitory concentration (MIC) or minimum effective concentration.
  • MIC minimum inhibitory concentration
  • the oral absorption of nitazoxanide is poor, the bioavailability is not high, and the shortcomings of low blood concentration are inevitable, which directly affects the exertion of the drug effect.
  • nitazoxanide drugs are to be applied to the treatment of drug-resistant Mycobacterium tuberculosis, Helicobacter pylori or methicillin-resistant Staphylococcus aureus, or for the treatment of viral infections such as influenza and rotavirus, It is necessary to increase the bioavailability of tizoxide, increase the blood concentration, and prolong the half-life to adapt to the therapeutic effects in antibacterial and antiviral aspects.
  • tazoxantide is the parent compound which is engineered into a tizoxanide phosphate or an alkyl sulfonate derivative, and oral administration can effectively increase tizozinide.
  • the special bioavailability increases the blood concentration and prolongs the half-life, thus improving the therapeutic effect of the drug in antibacterial and antiviral aspects.
  • Some of the compounds can also significantly improve the water solubility, and can be made into a solution liquid preparation for intramuscular injection or intravenous administration, which greatly improves the bioavailability and blood concentration in terms of tizoxanide.
  • the present invention provides a class of tizoxanide phosphate or alkyl sulfonate compounds which can be converted into the form of tizoxanide in vivo to exert an antiprotozoal, anti-helminth, antiviral or antibacterial effect.
  • the bioavailability and blood concentration of tizoxanide can be significantly improved, and the effective blood concentration can be improved.
  • the maintenance time is longer and the blood concentration curve is more stable.
  • a first aspect of the invention relates to a tizoxanide phosphate or alkyl sulfonate compound of the formula I, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof,
  • R 1 , R 2 are each independently hydroxy or C 1-6 alkoxy, and the C 1-6 alkoxy is optionally substituted by 1-2 substituents independently selected from: Aryl, amino, hydroxy, cyano, nitro, C 1-4 alkyl and halogen (e.g., fluoro, chloro, bromo or iodo), said aryl being optionally substituted by 1-2 independently selected from Base substitution: amino, hydroxy, cyano, nitro, C 1-4 alkyl and halogen (eg fluorine, chlorine, bromine or iodine);
  • R 1 is O
  • R 2 is C 1-6 alkyl or aryl
  • the C 1-6 alkyl or aryl group is optionally substituted by 1-2 substituents independently selected from Amino, hydroxy, cyano, nitro, C 1-4 alkyl, halogen (eg fluorine, chlorine, bromine or iodine) and tert-butyloxycarbonylamino.
  • the compound of formula I a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof, according to any one of the first aspects of the invention, wherein
  • R 1 , R 2 are each independently hydroxy or C 1-4 alkoxy, and the C 1-4 alkoxy is optionally substituted by 1-2 substituents independently selected from: Phenyl, amino, hydroxy, cyano, nitro, C 1-4 alkyl, halogen (eg, fluoro, chloro, bromo or iodo), said phenyl optionally being substituted by 1-2 independently selected from Substituent: amino, hydroxy, cyano, nitro, C 1-4 alkyl, halogen (eg fluorine, chlorine, bromine or iodine);
  • R 1 is O
  • R 2 is C 1-4 alkyl or phenyl
  • said C 1-4 alkyl or phenyl is optionally substituted by 1-2 substituents independently selected from Amino, hydroxy, cyano, nitro, C 1-4 alkyl, halogen (eg fluorine, chlorine, bromine or iodine), tert-butyloxycarbonylamino.
  • the compound of formula I a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof, according to any one of the first aspects of the invention, wherein
  • R 1 and R 2 are each independently selected from the group consisting of a hydroxyl group, a methoxy group, an ethoxy group, a n-propyloxy group, an isopropyloxy group, a n-butyloxy group, a sec-butyloxy group, and a different one.
  • R 1 is O
  • R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, phenyl, fluoromethyl , difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, p-methylphenyl, m-methylphenyl, o-methylphenyl, aminomethyl, aminoethyl , hydroxymethyl, hydroxymethyl, nitromethyl, nitroethyl, tert-butyloxycarbonylaminomethyl and tert-butyloxycarbonylaminoethyl.
  • the compound of formula I a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof, according to any one of the first aspects of the invention, wherein
  • R 1 and R 2 are each independently selected from the group consisting of a hydroxyl group, a methoxy group, an ethoxy group, and a benzyloxy group;
  • R 1 is O
  • R 2 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, p-methylphenyl and aminoethyl.
  • the compound of formula I a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof, according to any one of the first aspects of the invention, wherein
  • R 1 and R 2 are each independently selected from the group consisting of a hydroxyl group, a methoxy group, and an ethoxy group;
  • R 1 is O
  • R 2 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, and aminoethyl.
  • the compound of formula I a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof, according to any one of the first aspects of the invention, wherein
  • R 1 and R 2 are the same substituent selected from the group consisting of a hydroxyl group, a methoxy group, and an ethoxy group;
  • R 1 is O
  • R 2 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, and aminoethyl.
  • the compound of formula I a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof, according to any one of the first aspects of the invention, wherein
  • R 1 and R 2 are the same substituent selected from the group consisting of a hydroxyl group, a methoxy group, and an ethoxy group.
  • the compound of formula I a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof, according to any one of the first aspects of the invention, wherein
  • R 1 is O
  • R 2 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, and aminoethyl.
  • the compound of formula I according to any one of the first aspects of the invention, a pharmaceutically acceptable salt, an isomer thereof, a hydrate thereof or a solvate thereof, wherein
  • the pharmaceutically acceptable salt is an addition salt of a compound of formula I with a suitable base, such as a monosodium salt, a disodium salt, a calcium salt, a monopotassium salt, a dipotassium salt, a meglumine. salt;
  • the pharmaceutically acceptable salt is an addition salt of a compound of formula I with a suitable acid, such as a hydrochloride, a sulfate, an acetate, a nitrate.
  • the suitable base may be an organic base or an inorganic base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium acetate, meglumine or the like.
  • a pharmaceutically acceptable salt of a compound of formula I is a monosodium salt, a disodium salt, a calcium salt, a monopotassium salt, a dipotassium salt or a meglumine salt of a compound of formula I.
  • the pharmaceutically acceptable salt is a monosodium salt, a disodium salt, a calcium salt, a monopotassium salt, a dipotassium salt or a meglumine salt of a compound of formula I.
  • the suitable acid may be an organic acid or an organic acid such as hydrochloric acid, sulfuric acid, acetic acid, nitric acid or the like.
  • a pharmaceutically acceptable salt of a compound of formula I is a hydrochloride, sulfate, acetate or nitrate of a compound of formula I, preferably a hydrochloride salt of a compound of formula I.
  • X S
  • the pharmaceutically acceptable salt is the hydrochloride, sulfate, acetate, nitrate of the compound of formula I.
  • the compound of formula I a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof, according to any one of the first aspects of the invention, which is selected from the group consisting of:
  • Compound 5 calcium salt of 2-(5-nitrothiazol-2-ylcarbamoyl)phenyl phosphate
  • Compound 12 2-(5-nitrothiazol-2-ylcarbamoyl)phenyl taurate hydrochloride
  • a second aspect of the invention provides a process for the preparation of a compound of formula I according to any of the first aspects of the invention
  • an aprotic solvent such as N,N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.
  • organic base such as triethylamine, diisopropylethylamine.
  • DBU 1,8-diazabicycloundec-7-ene
  • R 1 , R 2 and The definition of the key is as set forth in claim 1.
  • a third aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I according to any one of the first aspects of the invention, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof,
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or adjuvant, and in particular, the pharmaceutical composition is a solid preparation, an injection, an external preparation, a spray, a liquid preparation, or a combination preparation.
  • a fourth aspect of the invention provides the pharmaceutical composition of the third aspect of the invention, or a compound of formula I according to any one of the first aspects of the invention, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvent thereof
  • the compound is prepared for the treatment and/or prevention of parasitic (including protozoa, helminth, etc.) infection, hepatitis B (HBV), hepatitis C (HCV), influenza, rotavirus or Norovirus
  • a toxic infectious disease such as viral gastroenteritis caused by rotavirus or Norovirus
  • a drug caused by bacteria such as Clostridium difficile or Mycobacterium tuberculosis (including drug-resistant tuberculosis) or Helicobacter pylori Use, or in the preparation of a medicament for inhibiting bacterial-induced biofilm formation.
  • a fifth aspect of the invention provides a method of treating and/or preventing a disease in a mammal in need thereof, the method comprising administering to a mammal in need thereof a therapeutically and/or prophylactically effective amount of the third aspect of the invention
  • a pharmaceutical composition or a compound of formula I according to any one of the first aspects of the invention, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof, wherein the disease comprises a parasite (including protozoa) , worms, etc.) infection, hepatitis B (HBV), hepatitis C (HCV), influenza, rotavirus or norovirus-induced viral infections (such as rotavirus or norovirus-induced viral gastroenteritis) ), infection caused by bacteria such as Clostridium difficile or Mycobacterium tuberculosis (including drug-resistant tuberculosis) or Helicobacter pylori.
  • a sixth aspect of the invention provides a method of inhibiting bacterial-induced biofilm formation in a mammal in need thereof, the method comprising administering to a mammal in need thereof a therapeutically and/or prophylactically effective amount of the third aspect of the invention
  • a seventh aspect of the invention relates to at least one of the above compounds of formula I, pharmaceutically acceptable salts, isomers thereof, hydrates or solvates thereof, said compound of formula I, pharmaceutically acceptable salts thereof, isomers thereof Body, hydrate or solvate thereof for the treatment and/or prevention of parasitic (including protozoa, helminth, etc.) infection, hepatitis B (HBV), hepatitis C (HCV), influenza, rotavirus or Norovirus Infection caused by a virus-infectious disease (such as viral gastroenteritis caused by rotavirus or Norovirus), Clostridium difficile or Mycobacterium tuberculosis (including drug-resistant tuberculosis) or Helicobacter pylori, or Used to inhibit bacterial biofilm formation.
  • parasitic including protozoa, helminth, etc.
  • HBV hepatitis B
  • HCV hepatitis C
  • influenza rotavirus or Norovirus Infection caused by
  • the parasites include: intestinal Larval flagellate, amoeba, Cryptosporidium, cyclosporia, Trichomonas, enteroencephalitis microsporidia, Bayesian spore coccidia, human bud Cystices, colonic pouches, human aphids, Pichia microspores, aphids (including beef aphids, short-shelled aphids), microcapsule aphids, Giardia, Leishmania, Fasciola hepatica.
  • the suitable base may be an organic base or an inorganic base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, meglumine or the like.
  • the suitable acid may be an organic acid or a mineral acid such as hydrochloric acid, sulfuric acid, acetic acid, nitric acid or the like.
  • alkyl refers to a saturated straight or branched chain monovalent hydrocarbon radical having from 1 to 12 carbon atoms, preferably having from 1 to 6, 1 to 4 or 1 to 3 carbon atoms.
  • C 1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, tert-amyl, new Amyl, hexyl and the like.
  • aryl as used herein means an unsaturated aromatic carbocyclic group of 5 to 14 carbon atoms having one single ring or two or more fused rings.
  • the aryl group preferably has 5-10, 5-8 or 5-6 carbon atoms.
  • Typical examples of “aryl” include, but are not limited to, phenyl, naphthyl, anthryl and the like.
  • amino as used herein means -NH 2.
  • hydroxy as used herein means -OH.
  • nitro as used herein means -NO 2 .
  • cyano as used herein means -CN.
  • alkoxy refers to the group -OR', wherein R' is alkyl as defined herein. Typical examples of “alkoxy” include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, tert-butyloxy, sec-butyloxy and the like.
  • halogen as used herein means fluoro, chloro, bromo or iodo. Preferred halogen groups are fluorine, chlorine or bromine.
  • the tizoxanide phosphate or alkyl sulfonate compound of the formula I provided by the present invention can be converted into the form of tizoxanide in vivo to exert an anti-worm, anti-helminth, anti-viral or anti-bacterial effect.
  • the compound I can significantly improve the bioavailability and blood concentration in terms of tizoxanide, the effective blood concentration is maintained for a longer period of time, and the blood concentration curve is more stable.
  • Figure 1 Blood concentration-time plot of tizoxanide (TIZ) in blood of mice after oral administration of nitazoxanide (NTZ), compounds 1, 2, 6, 7, 8, and 9;
  • FIG. 1 Blood concentration-time plot of tizoxanide (TIZ) in the blood of mice after oral administration of the compound nitazoxanide (NTZ), compounds 3, 4, 5, 12, 14, 17, 18.
  • TIZ tizoxanide
  • NTZ nitazoxanide
  • Example 2 The compound 2 (354.23 mg, 1 mmol) prepared in Example 2 was suspended in 20 mL of methanol, and a 2 mol/L aqueous NaOH solution (0.5 mL, 1 mmol) was added thereto, and the mixture was stirred at room temperature for 20 minutes, and the sample was completely dissolved, and concentrated to dryness under reduced pressure at 50 ° C. Drying under vacuum gave 367 mg of the title compound, yield: 100%, mp: 260-263 ° C, IR (KBr) cm-1: 3448, 1664, 1576, 1478, 1354, 1318, 1279, 1229, 923.
  • Example 2 The compound 2 (354.23 mg, 1 mmol) prepared in Example 2 was suspended in 20 mL of methanol, and a 2 mol/L aqueous solution of NaOH (1 mL, 2 mmol) was added thereto, and the mixture was stirred at room temperature for 20 minutes, the sample was completely dissolved, and concentrated to dryness under reduced pressure at 50 ° C. Drying in vacuo gave 398 mg of the title compound, ield: 100%, mp: 192-194 ° C, IR (KBr) cm-1:3424,1656,1477,1356,1309,1215,1096,982,907.
  • Example 2 The compound 2 (354.23 mg, 1 mmol) prepared in Example 2 was suspended in 20 mL of methanol, and a 2 mol/L aqueous calcium acetate solution (0.5 mL, 1 mmol) was added thereto, and the mixture was stirred at room temperature for 20 minutes. After concentration, the obtained sample was at 50 ° C. Drying under vacuum afforded the title compound 313 mg, ield: 80%, mp: 238-241 ° C, IR (KBr) cm-1: 3558, 3268, 1662, 1601, 1524, 1468, 1365, 1316, 1220, 1170, 1106 , 996, 912, 738.
  • N-Boc-taurosulfonyl chloride solution In a dry three-necked flask with a thermometer and a drying tube, freshly prepared N-Boc-taurine tetrabutylamine salt (3.74 g, 8 mmol) was added. Methyl chloride (28 mL) was dissolved, and DMF 0.016 mL was added. The solution was cooled to 0 ° C, and triphosgene (0.95 g, 3.2 mmol) was added and the mixture was gradually warmed to room temperature for half an hour.
  • the mixture was washed with a saturated sodium chloride solution, dried over Na 2 SO 4 , and concentrated by flash column chromatography (eluent: ethyl acetate and petroleum ether mixture, the volume ratio of the two was 1..1) to obtain the target product of 1.6 g. 56%.
  • Example 2 The compound 2 (354.23 mg, 1 mmol) prepared in Example 2 was suspended in 20 mL of methanol, and a 2 mol/L aqueous solution of KOH (0.5 mL, 1 mmol) was added thereto, and the mixture was stirred at room temperature for 20 minutes, and the sample was completely dissolved, and concentrated to dryness under reduced pressure at 50 ° C. Drying under vacuum gave the title compound 383 mg, yield 100%, mp: 252-264 ° C, IR (KBr) cm-1:3423,3333,1671,1528,1465,1358,1313,921.
  • Example 2 The compound 2 (354.23 mg, 1 mmol) prepared in Example 2 was suspended in 20 mL of methanol, and a 2 mol/L aqueous solution of KOH (1 mL, 2 mmol) was added thereto, and the mixture was stirred at room temperature for 20 minutes, and the sample was completely dissolved, and concentrated to dryness under reduced pressure at 50 ° C. Drying in vacuo gave 422 mg of the title compound. Mp: 192-194 ° C, IR (KBr) cm-1: 3424, 1656, 1477, 1356, 1309, 1215, 1096, 982, 907.
  • Example 2 The compound 2 (354.23 mg, 1 mmol) prepared in Example 2 was suspended in 20 mL of methanol, and a solution of megamine (195.22 mg, 1 mmol) in 10 ml of methanol was added, and the mixture was stirred at room temperature for 20 minutes, concentrated, and dried at 50 ° C under vacuum. The title compound was obtained 550 mg,yield solid, yield 100%.
  • Sample configuration 32.57 ⁇ mol of the test compound was dissolved in 100 ⁇ L of dimethyl sulfoxide (DMSO), and a solution of 3.257 ⁇ mol/mL was prepared by adding 10 mL of a 0.5% sodium carboxymethylcellulose (CMC-Na) solution.
  • DMSO dimethyl sulfoxide
  • CMC-Na sodium carboxymethylcellulose
  • test compounds were the compounds prepared in the examples of the present invention and the positive control compound nitazoxanide.
  • the first batch of test compounds were compound 1, 2, 6, 7, 8, 9 and the positive control compound nitazoxanide; the second batch of test compounds were compounds 3, 4, 5, 12, 14, 17, 18 and the positive control compound nitazoxanide.
  • mice purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • SPS grade Male, 25 ⁇ 2 mg
  • mice were randomly divided into groups according to body weight, with 3 rats in each group.
  • the nitazoxanide and the test compound were administered by intragastric administration at a dose of 10 mL/kg per mouse, which was equivalent to 32.57 ⁇ mol/kg of the corresponding drug in each mouse, wherein nitazoxan was positive.
  • 0.1 mL of blood was taken from the fundus vein at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8 and 12 hours after administration, placed in a centrifuge tube containing sodium heparin, centrifuged for 20 min (relative centrifugal force RCF was 3000 g) ), the plasma was stored in a refrigerator at -20 ° C for testing.
  • mice The results of pharmacokinetic screening of oral administration of mice showed (see Table 1, Table 2, Table 3, Table 4 and Figures 1, 2):
  • NTZ nitazoxanide
  • nitazoxanide-substituted phosphate compound-dibenzyl 2-(5-nitrothiazol-2-ylcarbamoyl)phenyl phosphate (Compound 1), after oral administration in mice, in the blood
  • the zonid peak time (Tmax) is shorter than the positive drug nitazoxanide
  • Cmax is close to nitazoxanide
  • the overall exposure (AUC) is slightly higher than nitazoxanide
  • the bioavailability (F) in terms of tizoxanide is 1.04 times that of nitazoxanide.
  • the peak time (Tmax) of tazoxide in the blood is shorter than that of the positive drug nitazoxanide.
  • Cmax is higher than nitazoxanide, and the bioavailability (F) in terms of tizoxanide is close to that of nitazoxanide.
  • Tizoxanide alkyl sulfonate compounds including methyl sulfonate (compound 6), ethyl sulfonate (compound 7), tizoxime propyl sulfonate (compound 8),
  • Tmax peak time
  • tizoxide in the blood was higher than that of the positive drug nitazoni
  • the Cmax value was significantly higher than the positive compound nitazoxanide (except compound 6)
  • the mean residence time (MRT0- ⁇ ) and overall exposure (AUC) of tizoxanide were also significantly higher than that of nitazoxanide.
  • the bioavailability (F) in terms of tizoxanide was 1.32 times, 1.74 times, 11.6 times 13.0 times and 39.6 times that of nitazoxanide, respectively, which had certain advantages compared with nitazoxanide.
  • SD rats (provided by the Experimental Animal Center of the Academy of Military Medical Sciences), SPF grade, male, weighing 200 ⁇ 10g, 9 were randomly divided into 3 groups, 3 in each group.
  • Compound 3 intravenous administration group the dose is 5 mg/kg (equivalent to 13.67 ⁇ mol/kg of tizoxanide); the administration volume: 0.2 mL/200 g rat (formation of the administration solution: precise scale 315.00 mg of the compound prepared in Example 3, dissolved in 100 ⁇ L of DMSO, and then added with sterile water to prepare a clear solution of 5 mg/mL), and the compound 3 was injected into the tail vein of the rats, respectively, 0.03, 0.08, 0.25, 0.5 after administration. Blood was taken at 1, 2, 4, 6, 8, 12, and 24 hours. The plasma was separated and stored in a refrigerator at -20 °C for testing.
  • Ornidazole oral administration group administration dose: 12.5 mg/kg (equivalent to 41 ⁇ mol/kg tizoxanide); administration volume: 2 mL/200 g rat (dosing solution preparation: precision weighing 10.96 mg of nitazoxanide, dissolved in 600 ⁇ L of DMSO, and added with 8.768 mL of sterile water to form a 1.25 mg/mL clear solution); rats were orally administered with nitazoxan 12.5 mg/kg before and after administration. Blood was taken at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours. The plasma was separated and stored in a refrigerator at -20 ° C for testing.
  • Plasma sample treatment Take 100 ⁇ L of plasma sample, add 300 ⁇ L of acetonitrile solution containing internal standard (500 nmol/L tolbutamide acetonitrile solution), mix, vortex for 1 min, centrifuge at 10 ° C for 10 min (relative centrifugal force RCF is 14000 g), and take The supernatant was injected, 20 ⁇ L, and determined by LC-MS-MS. The plasma concentrations of tizoxanide and the original drug were measured separately. The results are shown in Tables 5 and 6.
  • Compound 3 has significantly better solubility than nitazoxanide, solubility > 10 mg / mL, can be formulated into a solution, administered orally or by intravenous or intramuscular injection, and nitazoxan can only be mixed Oral administration in the form of a suspension or the like.
  • Compound 3 can be rapidly converted to its active form of tizoxanide, whether administered orally or intravenously, and the concentration of the prototype drug is less than the concentration of tizoxanide.
  • the plasma peak of nitazoxanide active product tizoxanide was 0.989 ⁇ 0.23 ⁇ g/mL, the overall exposure (AUC) was 1996.9 ⁇ 974.1 ⁇ g/L*h, and the Cmax and AUC values of compound 3 were respectively nitazoxanide. 3.1 and 1.7 times. It was calculated that the bioavailability of oral compound 3 in rats was 12.2% compared with intravenous administration, and nitazoxanide was about 7.2%.
  • the tizoxanide alkyl sulfonate compounds (such as compounds 6, 7, 8, 9 and 12) synthesized in the present invention and the nitazoxan-substituted phosphate compounds (for example, compounds 17, 18) are administered orally.
  • the Cmax of tizoxanide in the blood was significantly increased, and the bioavailability (F) in terms of tizoxanide was significantly higher than that of nitazoxanide.
  • the tizoxanide dihydrogen phosphate compound (for example, compound 2) synthesized by the present invention and a salt thereof (for example, compounds 3, 4, 5, and 14) are close to nitazoxan in bioavailability (F).

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Abstract

本发明涉及一类式I所示的替唑尼特磷酸酯或烷基磺酸酯类化合物、其可药用盐、其异构体、其水合物或其溶剂合物，以及该类化合物在药学中的应用。

Description

替唑尼特磷酸酯和烷基磺酸酯及其在药学中的应用 技术领域
本发明涉及替唑尼特磷酸酯或烷基磺酸酯类化合物及其可药用盐、其异构体、其水合物或其溶剂合物，以及该类化合物在药学中的应用。
背景技术
硝唑尼特(Nitazoxanide，NTZ)是由Romark实验室开发的一种噻唑苯甲酰胺类化合物，有多样性的生物学活性。其化学名为“2-乙酰氧基-N-(5-硝基-2-噻唑)苯甲酰胺”，化学式为C12H9N3O5S，熔点为202℃，是一种淡黄色粉末，不溶于水，微溶于乙醇，能溶于四氢呋喃、二甲基亚砜(DMSO)和N,N-二甲基甲酰胺(DMF)等有机溶剂。
研究表明硝唑尼特在人体可以有效对抗多种原虫、蠕虫类寄生虫，具体包括：肠兰伯式鞭毛虫、阿米巴虫、隐孢子虫、环孢子虫、毛滴虫、肠脑炎微孢子虫、贝氏等孢子球虫、人芽囊原虫、结肠小袋虫、人体蛔虫、毕氏肠微孢子虫、绦虫(包括牛肉绦虫、短膜壳绦虫)、微小膜壳绦虫、贾第虫、利什曼原虫、肝片吸虫等。硝唑尼特对乙型肝炎(HBV)、丙型肝炎(HCV)、流感(包括犬流感)、以及轮状病毒或诺若病毒引起的病毒性肠胃炎等病毒感染性疾病有很好的治疗效果。硝唑尼特还可以对抗难辨梭状芽胞杆菌(Clostridium difficile，CD)、结核杆菌(包括耐药结核菌)和幽门螺旋杆菌等细菌引起的感染，对细菌生物膜的形成也有很好的抑制作用。
硝唑尼特是一种前药，给药后在体内很快水解为其活性代谢产物替唑尼特(Tizoxanide，TIZ)。对人体进行药物代谢动力学研究显示，经口服给药后硝唑尼特可以从胃肠道吸收，大约1/3的口服剂量从尿液排泄，2/3的口服剂量从粪便中排泄。在血液中，硝唑尼特快速地被血浆酯酶代谢(在37℃下半衰期约6分钟)，水解脱去乙酰基成为其活性代谢产物替唑尼特，因而在血浆、尿液、胆汁和粪便中检测不到硝唑尼特的存在。替唑尼特在体内可继续被葡萄糖醛酸化为没有药物活性的葡萄糖醛酸化替唑尼特。替唑尼特存在于血浆、尿液、胆汁和粪便中,葡萄糖醛酸化替唑尼特(Tizoxanide Glcuronide)也存在于血浆、尿液和胆汁中。
硝唑尼特具有生物活性多样，安全性好等良好的药物性质，但也存在一些明显的不足。不足之处主要存在于以下两个方面：
(1)硝唑尼特存在生物利用度不高，半衰期较短，血药浓度较低的问题。军事医学科学院毒物药物研究所药代动力学研究室的检测发现，大鼠口服硝唑尼特混悬液的绝对生物利用度仅为7.2％。另据文献报道，健康成年人 口服硝唑尼特，单次给药500mg后，活性代谢产物替唑尼特的达峰时间为3-4h，AUC值约为3.9-11.3μg*h/mL，峰浓度Cmax为1.9μg/mL(range 1.1-2.5)，半衰期很短，只有为1.03到1.6小时。
(2)活性相对较低，例如，硝唑尼特对结核分枝杆菌的最低抑菌浓度MIC是12到28μg/mL(中位数为16μg/mL)；硝唑尼特和替唑尼特对103株幽门螺旋杆菌最低抑菌浓度(MICs)在0.25to 8μg/mL之间，50％最低抑菌浓度(MIC50)是1μg/mL，90％最低抑菌浓度(MIC90)是4μg/mL；硝唑尼特和替唑尼特在好氧或者微氧条件下，对表皮葡萄球菌或其它葡萄球菌(包括抗甲氧西林金黄色葡萄球菌株)的最小抑菌浓度(MIC)为8～16μg/mL；硝唑尼特在MDCK细胞中，对PR8流感病毒株的EC50为1μg/mL,EC90为7μg/mL。
可以看出，硝唑尼特存在生物利用度不高，半衰期短，血药浓度较低的不足。当硝唑尼特用于治疗肠道原虫、蠕虫等寄生虫感染时，不需要硝唑尼特进入血液即可发挥作用，因此硝唑尼特口服吸收差，生物利用度不高，血药浓度低的性质并不会对其治疗原虫、蠕虫等寄生虫感染的疗效产生影响。但如果将硝唑尼特应用于耐药结核杆菌、幽门螺旋杆菌或抗甲氧西林金黄色葡萄球菌的治疗，或抗流感、轮状病毒等病毒感染性疾病的治疗时，血药浓度应该至少高于其最低抑菌浓度(MIC)或最低有效浓度。这时硝唑尼特口服吸收差，生物利用度不高，血药浓度低的缺点必然会体现出来，而直接影响药效的发挥。
因此，如果要将硝唑尼特类药物应用于耐药结核杆菌、幽门螺旋杆菌或抗甲氧西林金黄色葡萄球菌的治疗，或抗流感、轮状病毒等病毒感染性疾病的治疗，就有必要提高其以替唑尼特计的生物利用度，增加血药浓度，延长半衰期，以适应在抗菌和抗病毒等方面的治疗效果。
发明内容
本发明的发明人令人惊讶地发现，以替唑尼特为母体化合物，将其改造为替唑尼特磷酸酯或烷基磺酸酯衍生物，口服给药可有效的提高以替唑尼特计的生物利用度，增加血药浓度，延长半衰期，从而可以改善药物在抗菌和抗病毒等方面的治疗效果。部分化合物还可以明显提高水溶性，可做成溶液性液体制剂，用于肌肉注射或静脉注射给药，大幅度提高以替唑尼特计的生物利用度和血药浓度。
本发明提供了一类替唑尼特磷酸酯或烷基磺酸酯类化合物，此类化合物在体内可转化为替唑尼特的形式而发挥抗原虫、抗蠕虫、抗病毒或抗菌的作用，同时可明显提高以替唑尼特计的生物利用度和血药浓度，有效血药浓度 维持时间更长，血药浓度曲线也更平稳。
本发明的第一方面涉及式I所示的替唑尼特磷酸酯或烷基磺酸酯化合物、其可药用盐、其异构体、其水合物或其溶剂合物，
Figure PCTCN2015097074-appb-000001
其中：X＝P或S，
当X＝P时,“
Figure PCTCN2015097074-appb-000002
”表示单键，R1、R2各自独立地为羟基或C1-6烷氧基，所述的C1-6烷氧基任选被1-2个独立选自以下的取代基取代：芳基、氨基、羟基、氰基、硝基、C1-4烷基和卤素(例如氟、氯、溴或碘)，所述的芳基任选被1-2个独立选自以下的取代基取代：氨基、羟基、氰基、硝基、C1-4烷基和卤素(例如氟、氯、溴或碘)；
当X＝S时，“
Figure PCTCN2015097074-appb-000003
”表示双键，R1为O，R2为C1-6烷基或芳基，所述的C1-6烷基或芳基任选被1-2个独立选自以下的取代基取代：氨基、羟基、氰基、硝基、C1-4烷基、卤素(例如氟、氯、溴或碘)和叔丁基氧羰基氨基。
在一个实施方案中，本发明第一方面任一项所述的式I化合物、其可药用盐、其异构体、其水合物或其溶剂合物，其中，
当X＝P时，“
Figure PCTCN2015097074-appb-000004
”表示单键，R1、R2各自独立地为羟基或C1-4烷氧基，所述的C1-4烷氧基任选被1-2个独立选自以下的取代基取代：苯基、氨基、羟基、氰基、硝基、C1-4烷基、卤素(例如氟、氯、溴或碘)，所述的苯基任选被1-2个独立选自以下的取代基取代：氨基、羟基、氰基、硝基、C1-4烷基、卤素(例如氟、氯、溴或碘)；
当X＝S时，“
Figure PCTCN2015097074-appb-000005
”表示双键，R1为O，R2为C1-4烷基或苯基，所述的C1-4烷基或苯基任选被1-2个独立选自以下的取代基取代：氨基、羟基、氰基、硝基、C1-4烷基、卤素(例如氟、氯、溴或碘)、叔丁基氧羰基氨基。
在另一个实施方案中，本发明第一方面任一项所述的式I化合物、其可药用盐、其异构体、其水合物或其溶剂合物，其中，
当X＝P时，“
Figure PCTCN2015097074-appb-000006
”表示单键，R1、R2各自独立地选自羟基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、正丁基氧基、仲丁基氧基、异丁基氧基、叔丁基氧基、苄基氧基、苯基乙氧基、1-苯基丙氧基、1-苯基丁氧基、 氟代甲氧基、二氟甲氧基、三氟甲氧基、氯代甲氧基、二氯甲氧基、三氯甲基、氨基甲氧基、氨基乙氧基、羟基甲氧基、羟基乙氧基、硝基甲氧基和硝基乙氧基；
当X＝S时，“
Figure PCTCN2015097074-appb-000007
”表示双键，R1为O，R2选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、苯基、氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、对甲基苯基、间甲基苯基、邻甲基苯基、氨基甲基、氨基乙基、羟基甲基、羟基甲基、硝基甲基、硝基乙基、叔丁基氧羰基氨基甲基和叔丁基氧羰基氨基乙基。
在另一个实施方案中，本发明第一方面任一项所述的式I化合物、其可药用盐、其异构体、其水合物或其溶剂合物，其中，
当X＝P时，“
Figure PCTCN2015097074-appb-000008
”表示单键，R1、R2各自独立地选自羟基、甲氧基、乙氧基和苄基氧基；
当X＝S时，“
Figure PCTCN2015097074-appb-000009
”表示双键，R1为O，R2选自甲基、乙基、正丙基、正丁基、对甲基苯基和氨基乙基。
在另一个实施方案中，本发明第一方面任一项所述的式I化合物、其可药用盐、其异构体、其水合物或其溶剂合物，其中，
当X＝P时，“
Figure PCTCN2015097074-appb-000010
”表示单键，R1、R2各自独立地选自羟基、甲氧基和乙氧基；
当X＝S时，“
Figure PCTCN2015097074-appb-000011
”表示双键，R1为O，R2选自甲基、乙基、正丙基、正丁基和氨基乙基。
在另一个实施方案中，本发明第一方面任一项所述的式I化合物、其可药用盐、其异构体、其水合物或其溶剂合物，其中，
当X＝P时，“
Figure PCTCN2015097074-appb-000012
”表示单键，R1和R2为相同的取代基，其选自羟基、甲氧基和乙氧基；
当X＝S时，“
Figure PCTCN2015097074-appb-000013
”表示双键，R1为O，R2选自甲基、乙基、正丙基、正丁基和氨基乙基。
在另一个实施方案中，本发明第一方面任一项所述的式I化合物、其可药用盐、其异构体、其水合物或其溶剂合物，其中，
X＝P，“
Figure PCTCN2015097074-appb-000014
”表示单键，R1和R2为相同的取代基，其选自羟基、甲氧基和乙氧基。
在另一个实施方案中，本发明第一方面任一项所述的式I化合物、其可药用盐、其异构体、其水合物或其溶剂合物，其中，
X＝S，“
Figure PCTCN2015097074-appb-000015
”表示双键，R1为O，R2选自甲基、乙基、正丙基、正丁基和氨基乙基。
在另一个实施方案中，本发明第一方面任一项所述的式I化合物、其 可药用盐、其异构体、其水合物或其溶剂合物，其中，
当X＝P时，所述的可药用盐为式I化合物与合适的碱形成的加成盐，例如单钠盐、双钠盐、钙盐、单钾盐、双钾盐、葡甲胺盐；
当X＝S时，所述的可药用盐为式I化合物与合适的酸形成的加成盐，例如盐酸盐、硫酸盐、醋酸盐、硝酸盐。
在一个优选的实施方案中，所述的合适的碱可以是有机碱，也可以是无机碱，例如氢氧化钠、氢氧化钾、氢氧化钙、醋酸钙、葡甲胺等。例如式I化合物的可药用盐为式I化合物的单钠盐、双钠盐、钙盐、单钾盐、双钾盐或葡甲胺盐。例如当X＝P时，所述的可药用盐为式I化合物的单钠盐、双钠盐、钙盐、单钾盐、双钾盐或葡甲胺盐。
在另一个优选的实施方案中，所述的合适的酸可以是有机酸，也可以是有机酸，例如盐酸、硫酸、醋酸、硝酸等。例如式I化合物的可药用盐为式I化合物的盐酸盐、硫酸盐、醋酸盐或硝酸盐，优选为式I化合物的盐酸盐。例如当X＝S时，所述的可药用盐为式I化合物的盐酸盐、硫酸盐、醋酸盐、硝酸盐。
在另一个实施方案中，本发明第一方面任一项所述的式I化合物、其可药用盐、其异构体、其水合物或其溶剂合物，其选自：
化合物1：二苄基2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯；
化合物2：2-(5-硝基噻唑-2-基氨基甲酰基)苯基二氢磷酸酯；
化合物3：2-(5-硝基噻唑-2-基氨基甲酰基)苯基一氢磷酸酯单钠盐；
化合物4：2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯二钠盐；
化合物5：2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯钙盐；
化合物6：2-(5-硝基噻唑-2-基氨基甲酰基)苯基甲基磺酸酯；
化合物7：2-(5-硝基噻唑-2-基氨基甲酰基)苯基乙基磺酸酯；
化合物8：2-(5-硝基噻唑-2-基氨基甲酰基)苯基1-丙基磺酸酯；
化合物9：2-(5-硝基噻唑-2-基氨基甲酰基)苯基1-丁基磺酸酯；
化合物10：2-(5-硝基噻唑-2-基氨基甲酰基)苯基对甲苯基磺酸酯；
化合物11：2-(5-硝基噻唑-2-基氨基甲酰基)苯基N-BOC-牛磺酸酯；
化合物12：2-(5-硝基噻唑-2-基氨基甲酰基)苯基牛磺酸酯盐酸盐；
化合物13：2-(5-硝基噻唑-2-基氨基甲酰基)苯基牛磺酸酯
化合物14：2-(5-硝基噻唑-2-基氨基甲酰基)苯基一氢磷酸酯单钾盐；
化合物15：2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯二钾盐；
化合物16：2-(5-硝基噻唑-2-基氨基甲酰基)苯基一氢磷酸酯葡甲胺盐；
化合物17：二甲基2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯；和
化合物18：二乙基2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯。
本发明的第二方面提供本发明第一方面任一项所述的式I化合物的制备方法，
当X＝P时，在非质子溶剂(例如二甲基甲酰胺、四氢呋喃、乙腈等)中，在四氯化碳和有机碱(例如三乙胺、二异丙基乙胺等)存在下，以二甲基氨基吡啶(DMAP)为催化剂，替唑尼特与式II所示的亚磷酸酯反应得到式I化合物，可选择地，将得到的式I化合物与合适的碱(例如氢氧化钠、氢氧化钙、氢氧化钾、葡甲胺等)形成的加成盐；
Figure PCTCN2015097074-appb-000016
当X＝S时，替唑尼特用非质子溶剂(如N,N-二甲基甲酰胺、乙腈、四氢呋喃等)溶解或悬浮，以有机碱(如三乙胺、二异丙基乙胺、1,8-二氮杂二环十一碳-7-烯(DBU)等)或无机碱(如碳酸钠、碳酸钾、氢钠、碳酸氢钠等)做缚酸剂，与式III所示的R2取代的磺酰氯反应，得到式I化合物，可选择地，将得到的式I化合物与合适的酸(例如盐酸、硫酸、醋酸、硝酸等)形成的加成盐，
Figure PCTCN2015097074-appb-000017
其中所述的R1、R2和“
Figure PCTCN2015097074-appb-000018
”键的定义如权利要求1所述。
本发明第三方面提供一种药物组合物，其包含本发明第一方面任一项所述的式Ⅰ化合物、其可药用盐、其异构体、其水合物或溶剂合物，
优选地，述的药物组合物还包含药学上可接受的载体或辅料，具体地，所述药物组合物为固体制剂、注射剂、外用制剂、喷剂、液体制剂、或复方制剂。
本发明的第四方面提供本发明第三方面所述的药物组合物或本发明第一方面任一项所述的式Ⅰ化合物、其可药用盐、其异构体、其水合物或溶剂合物在制备用于治疗和/或预防寄生虫(包括原虫、蠕虫等)感染、乙型肝炎(HBV)、丙型肝炎(HCV)、流感、轮状病毒或诺若病毒引起的病 毒感染性疾病(例如轮状病毒或诺若病毒引起的病毒性肠胃炎)、难辨梭状芽孢杆菌或结核杆菌(包括耐药结核菌)或幽门螺旋杆菌等细菌引起的感染的药物中的用途，或在制备用于抑制细菌引起的生物膜形成的药物中的用途。
本发明的第五方面提供一种在有需要的哺乳动物中治疗和/或预防疾病的方法，该方法包括给有需要的哺乳动物施用治疗和/或预防有效量的本发明第三方面所述的药物组合物或本发明第一方面任一项所述的式Ⅰ化合物、其可药用盐、其异构体、其水合物或溶剂合物，其中所述的疾病包括寄生虫(包括原虫、蠕虫等)感染、乙型肝炎(HBV)、丙型肝炎(HCV)、流感、轮状病毒或诺若病毒引起的病毒感染性疾病(例如轮状病毒或诺若病毒引起的病毒性肠胃炎)、难辨梭状芽孢杆菌或结核杆菌(包括耐药结核菌)或幽门螺旋杆菌等细菌引起的感染。
本发明的第六方面提供一种在有需要的哺乳动物中抑制细菌引起的生物膜形成的方法，该方法包括给有需要的哺乳动物施用治疗和/或预防有效量的本发明第三方面所述的药物组合物或本发明第一方面任一项所述的式I化合物、其可药用盐、其异构体、其水合物或溶剂合物。
本发明的第七方面涉及至少一种上述的式Ⅰ化合物、其可药用盐、其异构体、其水合物或溶剂合物，所述式Ⅰ化合物、其可药用盐、其异构体、其水合物或溶剂合物用于治疗和/或预防寄生虫(包括原虫、蠕虫等)感染、乙型肝炎(HBV)、丙型肝炎(HCV)、流感、轮状病毒或诺若病毒引起的病毒感染性疾病(例如轮状病毒或诺若病毒引起的病毒性肠胃炎)、难辨梭状芽孢杆菌或结核杆菌(包括耐药结核菌)或幽门螺旋杆菌等细菌引起的感染，或用于抑制细菌引起的生物膜形成。
本文中，所述的寄生虫包括：肠兰伯式鞭毛虫、阿米巴虫、隐孢子虫、环孢子虫、毛滴虫、肠脑炎微孢子虫、贝氏等孢子球虫、人芽囊原虫、结肠小袋虫、人体蛔虫、毕氏肠微孢子虫、绦虫(包括牛肉绦虫、短膜壳绦虫)、微小膜壳绦虫、贾第虫、利什曼原虫、肝片吸虫等。
本文中，所述的合适的碱可以是有机碱，也可以是无机碱，例如氢氧化钠、氢氧化钾、氢氧化钙、葡甲胺等。
本文中，所述的合适的酸可以是有机酸，也可以是无机酸，例如盐酸、硫酸、醋酸、硝酸等。
本文中使用的术语“烷基”是指饱和的直链或支链一价烃基，具有1－12个碳原子，优选具有1－6、1－4或1－3个碳原子。“C1-6烷基”的典型实例包括但不限于甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，正戊基，叔戊基，新戊基，己基等。
本文所用的术语“芳基”意指具有一个单环或两个或多个稠合环的5－14个碳原子的不饱和芳族碳环基。所述芳基优选具有5－10、5－8或5－6个碳原子。“芳基”的典型实例包括但不限于苯基，萘基和蒽基等。
本文中使用的术语“氨基”意指-NH2。
本文中使用的术语“羟基”意指-OH。
本文中使用的术语“硝基”意指-NO2。
本文中使用的术语“氰基”意指-CN。
本文所用的术语“烷氧基”意指基团-OR’，其中R’为如本文所定义的烷基。“烷氧基”的典型实例包括但不限于甲氧基，乙氧基，正丙氧基，异丙氧基，正丁基氧基，叔丁基氧基，仲丁基氧基等。
本文所用的术语“卤素”意指氟，氯，溴或碘。优选的卤素基团为氟、氯或溴。
本文中使用的化合物名称与化学结构式不一致时，以化学结构式为准。
发明的有益效果
本发明提供的式I所示的替唑尼特磷酸酯或烷基磺酸酯化合物在体内可转化为替唑尼特的形式而发挥抗原虫、抗蠕虫、抗病毒或抗菌的作用，同时式I化合物可明显提高以替唑尼特计的生物利用度和血药浓度，有效血药浓度维持时间更长，血药浓度曲线也更平稳。
附图说明
图1：小鼠口服化合物硝唑尼特(NTZ)、化合物1、2、6、7、8、9后的血液中替唑尼特(TIZ)的血药浓度-时间曲线图；
图2：小鼠口服化合物硝唑尼特(NTZ)、化合物3、4、5、12、14、17、18后的血液中替唑尼特(TIZ)的血药浓度-时间曲线图。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1：二苄基2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯(化合物1)的制备
Figure PCTCN2015097074-appb-000019
替唑尼特(3.12g，12mmol)的乙睛(150mL)溶液中，于N2保护环境中，0℃下，依序加入四氯化碳(9.61g，62.4mmol)、二异丙基乙基胺(3.4g，26.4mmol)、4-(N,N-二甲基氨基)吡啶(180mg,1.32mmol)、亚磷酸二苄基酯(90％)(6.0g,20.6mmol)，然后在相同温度下搅拌3小时，将反应液冲入450mL冰水中，用150mL的二氯甲烷分3次洗涤，合并有机层，然后并依序使用2mol/L盐酸、饱和NaHCO3水溶液、饱和食盐水洗涤，并以无水硫酸纳干燥后，将溶剂减压蒸去，乙醚中固化，得标题化合物的白色粉末，产率：79.3％,熔点(mp)：122-123℃，1H-NMR(DMSO-d6，400MHz)，δppm，13.64(1H,brs)，8.66(1H,s)，7.75(1H,d,J＝7.6Hz)，7.64(1H,td,J＝8.0Hz,2.0Hz)，7.38-7.43(2H,m)，7.28-7.34(10H,m)，5.12(4H,m).ESI-MS(+Q)，526(MH+)，548(MNa+).
实施例2：2-(5-硝基噻唑-2-基氨基甲酰基)苯基二氢磷酸酯(化合物2)的制备
Figure PCTCN2015097074-appb-000020
在0℃，N2保护下，向化合物1(5.0g，9.52mmoL)的无水乙腈(90mL)悬浮液，加入三甲基溴硅烷(3.70mL，28.33mmoL)，在0℃反应3小时后，加入无水乙醇(2.7mL，47mmoL)，搅拌4小时后抽滤，乙酸乙酯洗涤，风干后得到黄色固体粉末产物2.63g，收率:80％；mp：224-226℃，1H-NMR(DMSO-d6,400MHZ)δ：8.69(1H,s),7.67(1H,m),7.62(1H,m),7.42(1H,m),7.32(1H,m).ESI-MS(-Q)：344[M-H]+；264[TIZ-H]+.
实施例3：2-(5-硝基噻唑-2-基氨基甲酰基)苯基一氢磷酸酯单钠盐(化合物3)的制备
Figure PCTCN2015097074-appb-000021
将实施例2制备的化合物2(354.23mg,1mmol)悬浮于甲醇20mL中，加入2mol/LNaOH水溶液(0.5mL，1mmol),室温下搅拌20分钟，样品全部溶解，减压浓缩至干，50℃下真空干燥，得到标题化合物367mg，收率100％,mp:260-263℃,IR(KBr)cm-1:3448，1664，1576，1478，1354，1318，1279，1229，923.
实施例4：2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯双钠盐(化合物4)的制备
Figure PCTCN2015097074-appb-000022
将实施例2制备的化合物2(354.23mg,1mmol)悬浮于甲醇20mL中，加入2mol/LNaOH水溶液(1mL，2mmol),室温下搅拌20分钟，样品全部溶解，减压浓缩至干，50℃下真空干燥，得到标题化合物398mg，收率:100％，mp：192-194℃，IR(KBr)cm-1:3424，1656，1477，1356，1309，1215，1096，982，907.
实施例5：2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯钙盐(化合物5)的制备
Figure PCTCN2015097074-appb-000023
将实施例2制备的化合物2(354.23mg,1mmol)悬浮于甲醇20mL中，加入2mol/L醋酸钙水溶液(0.5mL，1mmol),室温下搅拌20分钟，浓缩后，将得到的样品在50℃下真空干燥，得到标题化合物313mg，收率80％,mp:238-241℃,IR(KBr)cm-1:3558，3268,1662,1601,1524,1468,1365,1316,1220,1170,1106,996,912,738.
实施例6：2-(5-硝基噻唑-2-基氨基甲酰基)苯基甲基磺酸酯(化合物6)的制备
Figure PCTCN2015097074-appb-000024
向替唑尼特(0.50g,1.89mmol)的无水N,N-二甲基甲酰胺溶液(20mL)溶液，加入三乙胺(0.38g,3.78mmol)，降温至0℃，加入甲烷磺酰氯(0.24g,2.07mmol)，逐渐升至于室温下搅拌反应，TLC检测至原料点消失，再将反应液加入水中，用乙酸乙酯萃取，乙酸乙酯层依序使用水，饱和食盐水洗涤，无水硫酸钠干燥后浓缩，再用硅胶柱层析法精制，得到产物0.51g，产率：86.58％,mp:188-190℃,1H-NMR(DMSO-d6,400Hz)δppm:13.68(1H,s),8.71(1H,s),7.83(1H,dd,J＝1.82,8.02Hz),7.77-7.72(1H,m),7.58-7.54(2H,m),3.37(1H,s).ESI-MS(+Q),m/z:344.1[M+H]+,366.0[M+Na]+.
实施例7:2-(5-硝基噻唑-2-基氨基甲酰基)苯基乙基磺酸酯(化合物7)的制备
Figure PCTCN2015097074-appb-000025
使用乙基磺酰氯代替甲基磺酰氯，与替唑尼特反应，其它皆依实施例6的操作，得标题化合物,产率：85.93％,mp：178-180℃,1H-NMR(DMSO-d6,400Hz)δppm:13.69(s,1H),8.71(s,1H),7.82(dd,J＝1.68,7.56Hz,1H),7.76-7.71(m,1H),7.57-7.51(m,2H),3.55(q,J＝8.0Hz,2H),1.32(t,J＝8.0Hz,3H).ESI-MS m/z:358.2[M+H]+,380.3[M+Na]+.
实施例8:2-(5-硝基噻唑-2-基氨基甲酰基)苯基1-丙基磺酸酯(化合物8)的制备
Figure PCTCN2015097074-appb-000026
使用1-丙基磺酰氯代替甲基磺酰氯，与替唑尼特反应，其它皆依实施例6的操作，得标题化合物，产率：88.57％,mp：144-146℃,1H-NMR (DMSO-d6,400Hz)δppm:13.68(s,1H),8.72(s,1H),7.83-7.71(m,2H),7.57-7.51(m,2H),3.52(t,J＝8.0Hz,2H),1.82-1.76(m,2H),0.96(t,J＝6.0Hz,3H).ESI-MS(+Q)m/z:372.0[M+H]+,394.2[M+Na]+.
实施例9:2-(5-硝基噻唑-2-基氨基甲酰基)苯基1-丁基磺酸酯(化合物9)的制备
Figure PCTCN2015097074-appb-000027
使用1-丁基磺酰氯代替甲基磺酰氯，与替唑尼特反应，其它皆依实施例6的操作，得标题化合物，产率：92.03％，mp：142-144℃，1H-NMR(CDCl3,400Hz)δppm：10.81(s,1H)，8.25(s,1H)，8.01(dd,J＝1.82,7.70Hz,1H)，7.72-7.55(m,1H)，7.53-7.50(m,2H)，3.47(t,J＝8.0,2H)，2.04-2.00(m,2H)，1.57-1.51(m,2H)，0.97(t,J＝8.0,3H).ESI-MS m/z:386[M+H]+,408[M+Na]+.
实施例10:2-(5-硝基噻唑-2-基氨基甲酰基)苯基对甲苯基磺酸酯(化合物9)的制备
Figure PCTCN2015097074-appb-000028
使用对甲基苯磺酰氯代替甲基磺酰氯，与替唑尼特反应，其它皆依实施例6的操作，得标题化合物,产率：84.81％,mp：236-238℃,1H-NMR(DMSO-d6,400Hz)δppm:13.37(s,1H),8.71(s,1H),7.71-7.67(m,2H),7.53-7.50(m,3H),7.33-7.28(m,3H),2.29(s,3H).ESI-MS m/z:420[M+H]+,442[M+Na]+.
实施例11:2-(5-硝基噻唑-2-基氨基甲酰基)苯基N-Boc-牛磺酸酯(化合物11)的制备
Figure PCTCN2015097074-appb-000029
(1)制备N-Boc-牛磺酰氯溶液：在加有温度计和干燥管干燥三口瓶中，加入新制备的N-Boc-牛磺酸四丁基胺盐(3.74g，8mmol)，用二氯甲烷(28mL)溶解，加入DMF0.016mL。将此溶液降温至0℃，加入三光气(0.95g,3.2mmol)，逐渐升至室温反应半小时。
(2)向替唑尼特(1.59g，6mmol)的20mL DMF悬浮液中，加入三乙胺(1.41g，14mmol)，降温至0℃，滴入上述步骤(1)制备的N-Boc-牛磺酰氯溶液，逐渐升至室温反应7小时，将反应液冲入冰水中，分出有机层，水层用二氯甲烷洗涤两次，洗涤液与有机层合并，用稀盐酸洗涤，水洗，饱和氯化钠溶液洗涤，Na2SO4干燥，浓缩后Flash柱层析(洗脱液为：乙酸乙酯和石油醚的混合液，二者的体积比为1︰1)得到目标产物1.6g，收率56％。mp：164-166℃，1H-NMR(DMSO-d6,400Hz)δppm:13.70(s,1H),8.71(s,1H),7.84(m,1H),7.73(m,1H),7.56(m,2H),7.08(t,J＝5.6Hz),3.64(m,2H),3.41(m,2H),1.36(s,9H),ESI-MS m/z:473[M+H]+.
实施例12：2-(5-硝基噻唑-2-基氨基甲酰基)苯基牛磺酸酯盐酸盐的制备(化合物12)
Figure PCTCN2015097074-appb-000030
将1mol/L的HCl的乙酸乙酯溶液(10mL，所述的HCl的乙酸乙酯溶液是氯化氢气体溶解于乙酸乙酯形成的溶液)降温至0℃，加入上述实施例11制备的2-(5-硝基噻唑-2-基氨基甲酰基)苯基N-Boc-牛磺酸酯(化合物11，472mg，1mmol)，逐渐升至室温反应4小时，将反应液抽滤，得到固体，先用甲醇溶解得到的固体，再加入异丙醇，重结晶，得到380mg产物，收率93％，mp：168-170℃,1H-NMR(DMSO-d6,400Hz)δppm:13.73(s,1H),8.72(s,1H),8.35(brs,3H),7.87(d,J＝7.6Hz,1H),7.75-7.79(m,1H),7.58-7.65(m,2H),3.96-4.00(m,2H),3.32(m,2H).ESI-MS m/z:373[M+H]+.
实施例13：2-(5-硝基噻唑-2-基氨基甲酰基)苯基牛磺酸酯的制备(化合物13)
Figure PCTCN2015097074-appb-000031
将上述实施例12制备的2-(5-硝基噻唑-2-基氨基甲酰基)苯基牛磺酸酯盐酸盐(化合物12)用乙酸乙酯溶解，加入等摩尔的NaOH水溶液，充分搅拌后水洗，有机层用Na2SO4干燥，浓缩后，得到标题化合物。
实施例14：2-(5-硝基噻唑-2-基氨基甲酰基)苯基一氢磷酸酯单钾盐(化合物14)的制备
Figure PCTCN2015097074-appb-000032
将实施例2制备的化合物2(354.23mg,1mmol)悬浮于甲醇20mL中，加入2mol/LKOH水溶液(0.5mL，1mmol),室温下搅拌20分钟，样品全部溶解，减压浓缩至干，50℃下真空干燥，得到标题化合物383mg，收率100％,mp:252-264℃,IR(KBr)cm-1:3423,3333，1671,1528,1465,1358,1313,921.
实施例15：2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯双钾盐(化合物15)的制备
Figure PCTCN2015097074-appb-000033
将实施例2制备的化合物2(354.23mg,1mmol)悬浮于甲醇20mL中，加入2mol/LKOH水溶液(1mL，2mmol),室温下搅拌20分钟，样品全部溶解，减压浓缩至干，50℃下真空干燥，得到标题化合物422mg，收率100％。mp：192-194℃，IR(KBr)cm-1：3424，1656，1477，1356，1309，1215，1096，982，907.
实施例16：2-(5-硝基噻唑-2-基氨基甲酰基)苯基一氢磷酸酯葡甲胺盐(化合物16)的制备
Figure PCTCN2015097074-appb-000034
将实施例2制备的化合物2(354.23mg,1mmol)悬浮于甲醇20mL中，加入葡甲胺(195.22mg，1mmol)的10ml甲醇溶液，室温下搅拌20分钟，浓缩，在50℃下真空干燥，得到标题化合物550mg，无定形固体，收率100％。
实施例17二甲基2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯(化合物17)的制备
Figure PCTCN2015097074-appb-000035
替唑尼特(3.12g，12mmol)的乙睛(150mL)溶液中，于N2保护环境中，0℃下，依序加入四氯化碳(9.61g，62.4mmol)、二异丙基乙基胺(3.4g，26.4mmol)、4-(N,N-二甲基氨基)吡啶(180mg,1.32mmol)、亚磷酸二甲基酯(90％)(2.52g,20.6mmol)，然后在相同温度下搅拌3小时,将反应液冲入450mL冰水中，用150mL的二氯甲烷分3次洗涤，合并有机层，然后并依序使用2mol/L盐酸、饱和NaHCO3水溶液、饱和食盐水洗涤，并以无水硫酸纳干燥后，将溶剂减压蒸去，乙醚中固化，得标题化合物的白色粉末3.2g，产率：72％,mp：165-167℃,1H NMR(400MHz,CDCl3)δ11.78–11.52(m,1H),8.33(s,1H),8.00(d,J＝8.1Hz,1H),7.61(td,J＝8.1,1.8Hz,1H),7.45-7.35(m,2H),3.96(s,3H),3.93(s,3H).ESI-MS m/z:374[M+H]+,396[M+Na]+.
实施例18二乙基2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯(化合物18)的制备
Figure PCTCN2015097074-appb-000036
替唑尼特(3.12g，12mmol)的乙睛(150mL)溶液中，于N2保护环境中，0℃下，依序加入四氯化碳(9.61g，62.4mmol)、二异丙基乙基胺(3.4g，26.4mmol)、4-(N,N-二甲基氨基)吡啶(180mg,1.32mmol)、亚磷酸二乙基酯(98％)(2.90g,20.6mmol)，然后在相同温度下搅拌3小时,将反应液冲入 450mL冰水中，用150mL的二氯甲烷分3次洗涤，合并有机层，然后并依序使用2mol/L盐酸、饱和NaHCO3水溶液、饱和食盐水洗涤，并以无水硫酸纳干燥后，将溶剂减压蒸去，乙醚中固化，得标题化合物的白色粉末3.6g，产率：75％,mp：138-138℃,1H NMR(400MHz,CDCl3)δ11.83–11.68(m,1H),8.37(s,1H),8.03(d,J＝7.6Hz,1H),7.60(t,J＝7.6Hz,1H),7.46-7.34(m,2H),4.31(dd,J＝15.0,7.2Hz,4H),1.38(t,J＝7.2Hz,6H).ESI-MS m/z:402[M+H]+,424[M+Na]+.
实施例19口服给药在小鼠体内药代动力学评价及结果
样品配置：将32.57μmol的受试化合物，用100μL二甲基亚砜(DMSO)溶解，加入10mL 0.5％羧甲基纤维素钠(CMC-Na)溶液配制配成3.257μmol/mL的样品。
上述受试化合物为本发明实施例制备的化合物以及阳性对照化合物硝唑尼特。实验分两批进行，第一批的受试化合物为化合物1、2、6、7、8、9以及阳性对照化合物硝唑尼特；第二批的受试化合物为化合物3、4、5、12、14、17、18以及阳性对照化合物硝唑尼特。
实验方法：ICR小鼠(购自北京维通利华实验动物技术有限公司)，SPS级，雄性，25±2mg，按体重随机分为组，每组3只。分别灌胃给予硝唑尼特和受试化合物，给药剂量为每只小鼠灌胃10mL/kg,相当于每只小鼠给与32.57μmol/kg的相应药物，其中硝唑尼特作为阳性对照，于给药后0.08、0.25、0.5、1、2、4、6、8和12小时从眼底静脉取血0.1mL，置于含肝素钠的离心管中，离心20min(相对离心力RCF为3000g)，取血浆置于-20℃冰箱中冻存待测。
检测时取血浆50μL，加内标溶液(5000ng/mL格列吡嗪水溶液)10μL，加乙腈200μL混匀，涡流3min，离心10min(相对离心力RCF为8500g)，分取上清液50μL与50μL水混匀后，吸取10μL进行LC/MS/MS分析，检测替唑尼特的血药浓度。结果见表1、表2、表3、表4以及图1、图2。
表1小鼠口服化合物硝唑尼特(NTZ)、化合物1、2、6、7、8、9后的血液中替唑尼特(TIZ)的血药浓度(Mean±SD，n＝3)
Figure PCTCN2015097074-appb-000037
Figure PCTCN2015097074-appb-000038
注：ND：低于定量限；*：一组实测值，无SD值
表2是小鼠口服化合物硝唑尼特(NTZ)、化合物3，5，12，14，17，18后的血液中替唑尼特(TIZ)的血药浓度(Mean±SD，n＝3)
Figure PCTCN2015097074-appb-000039
表3小鼠口服硝唑尼特(NTZ)以及化合物1、2、6、7、8、9后，以替唑尼特(TIZ)计算的主要药动学参数(Mean±SD，n＝3)
Figure PCTCN2015097074-appb-000040
Figure PCTCN2015097074-appb-000041
表4小鼠口服硝唑尼特(NTZ)以及化合物3、5、12、14、17、18后，以替唑尼特(TIZ)计算的主要药动学参数(Mean±SD，n＝3)
Figure PCTCN2015097074-appb-000042
小鼠口服给药的药代动力学筛选结果显示(参见表1、表2，表3，表4以及图1、图2)：
(1)化合物1、2、6、7、8、9、和3、4、5、12、14、17，18小鼠口服给药后，与硝唑尼特(NTZ)一样，在体内可以转化为活性形式替唑尼特，而且转化较为充分。
(2)硝唑尼特取代磷酸酯类化合物—二苄基2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯(化合物1)小鼠口服给药后，血液中替唑尼特达峰时间(Tmax)较阳性药硝唑尼特短，Cmax与硝唑尼特接近，整体暴露量 (AUC)略高于硝唑尼特，以替唑尼特计的生物利用度(F)是硝唑尼特的1.04倍。而另外两个硝唑尼特取代磷酸酯类化合物—二甲基2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯(化合物17)和二乙基2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯(化合物18)小鼠口服给药后，血液中替唑尼特达峰时间(Tmax)较阳性药硝唑尼特后延，Cmax与和整体暴露量(AUC)明显高于硝唑尼特，以替唑尼特计的生物利用度(F)分别是硝唑尼特的12.8倍和20.1倍。
(3)硝唑尼特二氢磷酸酯(2-(5-硝基噻唑-2-基氨基甲酰基)苯基二氢磷酸酯，化合物2)，及其盐—包括单钠盐(化合物3)、二钠盐(化合物4)、钙盐(化合物5)、单钾盐(化合物14)口服给药后，血液中替唑尼特达峰时间(Tmax)较阳性药硝唑尼特短，Cmax比硝唑尼特高，以替唑尼特计的生物利用度(F)与硝唑尼特接近。
(4)替唑尼特烷基磺酸酯类化合物，包括甲基磺酸酯(化合物6)，乙基磺酸酯(化合物7)，替唑尼特丙基磺酸酯(化合物8)，替唑尼特丁基磺酸酯(化合物9)以及牛磺酸酯盐酸盐(化合物12)小鼠口服给药后，血液中替唑尼特达峰时间(Tmax)较阳性药硝唑尼特后延，Cmax值比阳性化合物硝唑尼特明显增加(化合物6除外)，替唑尼特体内平均驻留时间(MRT0-∞)和整体暴露量(AUC)也明显高于硝唑尼特，以替唑尼特计的生物利用度(F)分别是硝唑尼特的1.32倍，1.74倍，11.6倍13.0倍和39.6倍与硝唑尼特相比有一定的优势。
实施例20口服及静脉注射硝唑尼特和化合物3的大鼠体内药代动力学评价
SD大鼠(军事医学科学院实验动物中心提供)，SPF级，雄性，体重为200±10g，9只，随机分为3组，每组3只。
(1)化合物3静注给药组，剂量5mg/kg(相当于替唑尼特的给药量13.67μmol/kg)；给药体积：0.2mL/200g大鼠(给药溶液配制：精密称取实施例3制备的化合物315.00mg，加入100μL DMSO溶解后加入无菌水配成5mg/mL的澄清溶液)，大鼠尾静脉注射化合物3后，分别于给药后0.03、0.08、0.25、0.5、1、2、4、6、8、12、24小时取血，分离血浆，置于-20℃冰箱中保存待测。
(2)化合物3口服给药组，剂量15mg/kg(相当于41μmol/kg替唑尼特)；给药体积：2mL/200g大鼠(取上述配制的5mg/mL化合物3的溶液加入无菌水，稀释成1.5mg/mL澄清溶液)；大鼠口服化合物3后(剂量15mg/kg)，于给药后0.08、0.25、0.5、1、2、4、6、8、12和24小时取血，分离血浆， 置于-20℃冰箱中保存待测。
(3)硝唑尼特口服给药组：给药剂量：12.5mg/kg(相当于41μmol/kg替唑尼特)；给药体积：2mL/200g大鼠(给药溶液配制：精密称取硝唑尼特10.96mg，加入600μL DMSO溶解后加入8.768mL无菌水配成1.25mg/mL的澄清溶液)；大鼠口服硝唑尼特12.5mg/kg后，于给药前及给药后0.08、0.25、0.5、1、2、4、6、8、12、24小时取血，分离血浆，置于-20℃冰箱中保存待测。
血浆样品处理：取血浆样品100μL，定量加入含内标(500nmol/L甲苯磺丁脲乙腈溶液)的乙腈溶液300μL混匀，涡旋1min，4℃离心10min(相对离心力RCF为14000g)，取上清液，进样20μL，LC-MS-MS测定。分别检测替唑尼特和原药的血药浓度。结果见表5和表6。
表5化合物3口服或静注给药与硝唑尼特口服给药后的血药浓度
Figure PCTCN2015097074-appb-000043
表6.化合物3口服或静注给药与硝唑尼特口服给药的大鼠药代动力学参数(Mean±SD，n＝3)
Figure PCTCN2015097074-appb-000044
大鼠口服或静脉注射化合物3和硝唑尼特的药代动力学评价结果显示(参见表5、表6)：
(1)化合物3的溶解性明显好于硝唑尼特，溶解度>10mg/mL，可配成溶液，以口服或以静脉注射或肌肉注射的方式给药，而硝唑尼特只能以混悬液等形式口服给药。
(2)化合物3无论口服还是静注给药，均可以很快转化为其活性形式替唑尼特，原型药物浓度均小于替唑尼特浓度。
(3)化合物3溶液口服给药(15mg/kg，相当于41μmol/kg替唑尼特)和硝唑尼特混悬液(12.5mg/kg，相当于41μmol/kg替唑尼特)口服给药后，化合物3的活性产物替唑尼特的血浆峰值为3.05±1.86μg/mL，整体暴露(AUC)为3433.1±718.9μg/L*h。硝唑尼特活性产物替唑尼特的血浆峰值为0.989±0.23μg/mL，整体暴露(AUC)为1996.9±974.1μg/L*h，化合物3的Cmax和AUC值分别为硝唑尼特的3.1和1.7倍。经计算，与静脉给药比较，大鼠口服化合物3的生物利用度为12.2％，硝唑尼特约为7.2％。
(4)化合物3溶液静脉注射给药(5mg/kg)，血液中替唑尼特Cmax值为23.32μg/mL，以替唑尼特计的整体暴露量[AUC(0-∞)]为9204.1μg/L*h，而三倍摩尔剂量硝唑尼特(12.5mg/kg)口服给药，血液中替唑尼特Cmax值为0.989μg/mL，整体暴露量[AUC(0-∞)]为1996.9μg/L*h。化合物3注射给药与硝唑尼特口服给药相比，在以替唑尼特计的的Cmax和整体暴露量AUC(0-∞)这两个指标上有非常明显的 优势。
总结：本发明所合成的替唑尼特烷基磺酸酯类化合物(例如化合物6、7、8、9和12)和硝唑尼特取代磷酸酯类化合物(例如化合物17、18)口服给药后，血液中替唑尼特的Cmax明显升高，以替唑尼特计的生物利用度(F)明显高于硝唑尼特。本发明所合成的替唑尼特二氢磷酸酯类化合物(例如化合物2)及其盐(例如化合物3、4、5、14)，虽然在生物利用度(F)上与硝唑尼特接近，但是溶解度明显好于硝唑尼特，不光可以口服给药，还可以静注给药。检测发现替唑尼特二氢磷酸酯单纳盐(化合物3)静注给药时，在血药浓度和生物利用度等指标上都明显好于硝唑尼特口服给药。

Claims (12)

  1. 式I所示化合物、其可药用盐、其异构体、其水合物或其溶剂合物，
    Figure PCTCN2015097074-appb-100001
    其中：X＝P或S，
    当X＝P时,
    Figure PCTCN2015097074-appb-100002
    表示单键，R1、R2各自独立地为羟基或C1-6烷氧基，所述的C1-6烷氧基任选被1-2个独立选自以下的取代基取代：芳基、氨基、羟基、氰基、硝基、C1-4烷基和卤素(例如氟、氯、溴或碘)，所述的芳基任选被1-2个独立选自以下的取代基取代：芳基、氨基、羟基、氰基、硝基、C1-4烷基和卤素(例如氟、氯、溴或碘)；
    当X＝S时，
    Figure PCTCN2015097074-appb-100003
    表示双键，R1为O，R2为C1-6烷基或芳基，所述的C1-6烷基或芳基任选被1-2个独立选自以下的取代基取代：氨基、羟基、氰基、硝基、C1-4烷基、卤素(例如氟、氯、溴或碘)和叔丁基氧羰基氨基。
  2. 权利要求1所述的化合物、其可药用盐、其异构体、其水合物或其溶剂合物，其中，
    当X＝P时，
    Figure PCTCN2015097074-appb-100004
    表示单键，R1、R2各自独立地为羟基或C1-4烷氧基，所述的C1-4烷氧基任选被1-2个独立选自以下的取代基取代：苯基、氨基、羟基、氰基、硝基、C1-4烷基和卤素(例如氟、氯、溴或碘)，所述的苯基任选被1-2个独立选自以下的取代基取代：氨基、羟基、氰基、硝基、C1-4烷基和卤素(例如氟、氯、溴或碘)；
    当X＝S时，
    Figure PCTCN2015097074-appb-100005
    表示双键，R1为O，R2为C1-4烷基或苯基，所述的C1-4烷基或苯基任选被1-2个独立选自以下的取代基取代：氨基、羟基、氰基、硝基、C1-4烷基、卤素(例如氟、氯、溴或碘)和叔丁基氧羰基氨基。
  3. 权利要求1所述的化合物、其可药用盐、其异构体、其水合物或其溶剂合物，其中，
    当X＝P时，
    Figure PCTCN2015097074-appb-100006
    表示单键，R1、R2各自独立地选自羟基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、正丁基氧基、异丁基氧基、叔丁基氧基、苄基氧基、苯基乙氧基、1-苯基丙氧基、1-苯基丁氧基、氟代甲氧基、二氟甲氧基、三氟甲氧基、氯代甲氧基、二氯甲氧基、三氯甲基、氨基甲氧基、氨基乙氧基、羟基甲氧基、羟基乙氧基、硝基甲氧基和硝基乙氧基；
    当X＝S时，
    Figure PCTCN2015097074-appb-100007
    表示双键，R1为O，R2选自甲基、乙基、正丙基、异 丙基、正丁基、异丁基、叔丁基、苯基、氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、对甲基苯基、间甲基苯基、邻甲基苯基、氨基甲基、氨基乙基、羟基甲基、羟基甲基、硝基甲基、硝基乙基、叔丁基氧羰基氨基甲基和叔丁基氧羰基氨基乙基。
  4. 权利要求1所述的化合物、其可药用盐、其异构体、其水合物或其溶剂合物，其中，当X＝P时，
    Figure PCTCN2015097074-appb-100008
    表示单键，R1、R2各自独立地选自羟基、甲氧基、乙氧基和苄基氧基；当X＝S时，
    Figure PCTCN2015097074-appb-100009
    表示双键，R1为O，R2选自甲基、乙基、正丙基、正丁基、对甲基苯基和氨基乙基；
    优选地，其中，当X＝P时，
    Figure PCTCN2015097074-appb-100010
    表示单键，R1、R2各自独立地选自羟基、甲氧基和乙氧基；当X＝S时，
    Figure PCTCN2015097074-appb-100011
    表示双键，R1为O，R2选自甲基、乙基、正丙基、正丁基和氨基乙基；
    优选地，其中，当X＝P时，
    Figure PCTCN2015097074-appb-100012
    表示单键，R1和R2为相同的取代基，其选自羟基、甲氧基和乙氧基；当X＝S时，
    Figure PCTCN2015097074-appb-100013
    表示双键，R1为O，R2选自甲基、乙基、正丙基、正丁基和氨基乙基；
    优选地，其中，X＝P，
    Figure PCTCN2015097074-appb-100014
    表示单键，R1和R2为相同的取代基，其选自羟基、甲氧基和乙氧基；
    优选地，其中，X＝S，
    Figure PCTCN2015097074-appb-100015
    表示双键，R1为O，R2选自甲基、乙基、正丙基、正丁基和氨基乙基。
  5. 权利要求1－4任一项所述的化合物、其可药用盐、其异构体、其水合物或其溶剂合物，其中，
    当X＝P时，所述的盐为式I化合物与碱形成的加成盐，例如单钠盐、双钠盐、钙盐、单钾盐、双钾盐、葡甲胺盐；
    当X＝S时，所述的盐为式I化合物与酸形成的加成盐，例如盐酸盐、硫酸盐、醋酸盐、硝酸盐。
  6. 权利要求1－5任一项所述的化合物、其可药用盐、其异构体、其水合物或其溶剂合物，其选自：
    化合物1：二苄基2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯；
    化合物2：2-(5-硝基噻唑-2-基氨基甲酰基)苯基二氢磷酸酯；
    化合物3：2-(5-硝基噻唑-2-基氨基甲酰基)苯基一氢磷酸酯单钠盐；
    化合物4：2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯二钠盐；
    化合物5：2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯钙盐；
    化合物6：2-(5-硝基噻唑-2-基氨基甲酰基)苯基甲基磺酸酯；
    化合物7：2-(5-硝基噻唑-2-基氨基甲酰基)苯基乙基磺酸酯；
    化合物8：2-(5-硝基噻唑-2-基氨基甲酰基)苯基1-丙基磺酸酯；
    化合物9：2-(5-硝基噻唑-2-基氨基甲酰基)苯基1-丁基磺酸酯；
    化合物10：2-(5-硝基噻唑-2-基氨基甲酰基)苯基对甲苯基磺酸酯；
    化合物11：2-(5-硝基噻唑-2-基氨基甲酰基)苯基N-BOC-牛磺酸酯；
    化合物12：2-(5-硝基噻唑-2-基氨基甲酰基)苯基牛磺酸酯盐酸盐；
    化合物13：2-(5-硝基噻唑-2-基氨基甲酰基)苯基牛磺酸酯
    化合物14：2-(5-硝基噻唑-2-基氨基甲酰基)苯基一氢磷酸酯单钾盐；
    化合物15：2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯二钾盐；
    化合物16：2-(5-硝基噻唑-2-基氨基甲酰基)苯基一氢磷酸酯葡甲胺盐；
    化合物17：二甲基2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯；和
    化合物18：二乙基2-(5-硝基噻唑-2-基氨基甲酰基)苯基磷酸酯。
  7. 一种药物组合物，其包含权利要求1至6中任一项所述的式Ⅰ化合物、其可药用盐、其异构体、其水合物或溶剂合物，
    优选地，述的药物组合物还包含药学上可接受的载体或辅料，具体地，所述药物组合物为固体制剂、注射剂、外用制剂、喷剂、液体制剂、或复方制剂。
  8. 权利要求1-6任一项所述的式I化合物的制备方法，
    当X＝P时，在非质子溶剂(例如二甲基甲酰胺、四氢呋喃、乙腈等)中，在四氯化碳和有机碱(例如三乙胺、二异丙基乙胺等)存在下，以二甲基氨基吡啶(DMAP)为催化剂，替唑尼特与式II所示的亚磷酸酯反应得到式I化合物，可选择地，将得到的式I化合物与碱(例如氢氧化钠、氢氧化钙、氢氧化钾、葡甲胺等)形成的加成盐；
    Figure PCTCN2015097074-appb-100016
    当X＝S时，替唑尼特用非质子溶剂(如N,N-二甲基甲酰胺、乙腈、四氢呋喃等)溶解或悬浮，以有机碱(如三乙胺、二异丙基乙胺、1,8-二氮杂二环十一碳-7-烯(DBU)等)或无机碱(如碳酸钠、碳酸钾、氢钠、碳酸氢钠等)做缚酸剂，与式III所示的R2取代的磺酰氯反应，得到式I化合物，可选择地，将得到的式I化合物与酸(例如盐酸、硫酸、醋酸、硝酸等)形成的加成盐，
    Figure PCTCN2015097074-appb-100017
    其中所述的R1和R2、以及
    Figure PCTCN2015097074-appb-100018
    的定义如权利要求1所述。
  9. 权利要求7的药物组合物或权利要求1至6中任一项所述的式Ⅰ化合物、其可药用盐、其异构体、其水合物或溶剂合物在制备用于治疗和/或预防寄生虫(包括原虫、蠕虫等)感染、乙型肝炎(HBV)、丙型肝炎(HCV)、流感、轮状病毒或诺若病毒引起的病毒感染性疾病(例如轮状病毒或诺若病毒引起的病毒性肠胃炎)、难辨梭状芽孢杆菌或结核杆菌(包括耐药结核菌)或幽门螺旋杆菌等细菌引起的感染的药物中的用途，或在制备用于抑制细菌引起的生物膜形成的药物中的用途。
  10. 一种在有需要的哺乳动物中治疗和/或预防疾病的方法或者在有需要的哺乳动物中抑制细菌引起的生物膜形成的方法，该方法包括给有需要的哺乳动物施用治疗和/或预防有效量的权利要求7的药物组合物或权利要求1至6中任一项所述的式Ⅰ化合物、其可药用盐、其异构体、其水合物或溶剂合物，其中所述的疾病包括寄生虫(包括原虫、蠕虫等)感染、乙型肝炎(HBV)、丙型肝炎(HCV)、流感、轮状病毒或诺若病毒引起的病毒感染性疾病(例如轮状病毒或诺若病毒引起的病毒性肠胃炎)、难辨梭状芽孢杆菌或结核杆菌(包括耐药结核菌)或幽门螺旋杆菌等细菌引起的感染。
  11. 权利要求1至6中任一项所述的式Ⅰ化合物、其可药用盐、其异构体、其水合物或溶剂合物，用于治疗和/或预防寄生虫(包括原虫、蠕虫等)感染、乙型肝炎(HBV)、丙型肝炎(HCV)、流感、轮状病毒或诺若病毒引起的病毒感染性疾病(例如轮状病毒或诺若病毒引起的病毒性肠胃炎)、难辨梭状芽孢杆菌或结核杆菌(包括耐药结核菌)或幽门螺旋杆菌等细菌引起的感染，或用于抑制细菌引起的生物膜形成。
  12. 权利要求9的用途或权利要求10的方法或权利要求11的化合物、其可药用盐、其异构体、其水合物或溶剂合物，其中所述的寄生虫包括：肠兰伯式鞭毛虫、阿米巴虫、隐孢子虫、环孢子虫、毛滴虫、肠脑炎微孢子虫、贝氏等孢子球虫、人芽囊原虫、结肠小袋虫、人体蛔虫、毕氏肠微孢子虫、绦虫(包括牛肉绦虫、短膜壳绦虫)、微小膜壳绦虫、贾第虫、利什曼原虫、肝片吸虫等。
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