WO2010130139A1 - 芳基(乙)丙酸抗坏血酸酯，其制备方法及含有它们的药物 - Google Patents

芳基(乙)丙酸抗坏血酸酯，其制备方法及含有它们的药物 Download PDF

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WO2010130139A1
WO2010130139A1 PCT/CN2009/075994 CN2009075994W WO2010130139A1 WO 2010130139 A1 WO2010130139 A1 WO 2010130139A1 CN 2009075994 W CN2009075994 W CN 2009075994W WO 2010130139 A1 WO2010130139 A1 WO 2010130139A1
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ascorbic acid
formula
reaction
ibuprofen
compound
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PCT/CN2009/075994
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English (en)
French (fr)
Inventor
汤鲁宏
戴阿娟
王择
孙阳
刘信宁
徐玲燕
方鑫
邱爽
曹雅晴
徐晓敏
姜瑞霞
吴超
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江南大学
汤宁
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Application filed by 江南大学, 汤宁 filed Critical 江南大学
Priority to US13/320,101 priority Critical patent/US8703975B2/en
Priority to EP09844550A priority patent/EP2431361A4/en
Priority to JP2012510092A priority patent/JP2012526151A/ja
Publication of WO2010130139A1 publication Critical patent/WO2010130139A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom 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
    • C07D307/62—Three oxygen atoms, e.g. ascorbic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/04—Oxygen as only ring hetero atoms containing a five-membered hetero ring, e.g. griseofulvin, vitamin C
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/188—Heterocyclic compound containing in the condensed system at least one hetero ring having nitrogen atoms and oxygen atoms as the only ring heteroatoms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/01—Carboxylic ester hydrolases (3.1.1)
    • C12Y301/01003—Triacylglycerol lipase (3.1.1.3)

Definitions

  • Aryl (ethyl) propionate ascorbate preparation method thereof and medicament containing the same
  • the present invention relates to novel ester derivatives of non-retained anti-inflammatory drugs, processes for their preparation and pharmaceutical compositions containing them. Specifically, it is an ascorbate derivative belonging to aryl (ethyl) propionic acid and an addition salt thereof with a pharmaceutically acceptable acid or base, a process for producing the same, and a pharmaceutical composition containing the same. Skill *
  • Non-steroidal anti-inflammatory drugs represented by ibuprofen are among the most successful antipyretic and analgesic drugs in recent years. In addition to anti-inflammatory effects, they also have significant analgesic, antipyretic effects and good safety; not only suitable for adults but also for the elderly and infants. It is widely used as a major antipyretic analgesic in foreign countries. It is widely used in over-the-counter (OTC), which is highly safe. It is considered to be one of the more promising varieties than paracetamol and aspirin.
  • OTC over-the-counter
  • CN99800474.X discloses a pharmaceutical preparation containing a water-soluble ketoprofen salt and use thereof; CN00807563.8 discloses a drinkable ibuprofen pharmaceutical suspension; CN02109536.1 discloses an ibuprofen Triazole nucleoside ester, preparation method and use thereof; CN02110476.X discloses a preparation method of ketoprofen and anthracycline or its derivative inclusion compound; CN02115459.7 discloses polycaprolactone cloth Lofen composition, preparation method and application thereof; CN02821502.8 discloses ibuprofen salt emulsifier and cream preparation containing same; CN03139 L 16.8 discloses an ibuprofen conjugate and preparation method and application thereof CN03144095.9 discloses
  • CN200510024043.4 discloses an ibuprofen sugar derivative, preparation method and application thereof
  • CN200510026269.8 discloses a preparation of 2-aryl lactate and naphthalene Method for purifying and ibuprofen
  • CN200510040242.4 discloses a clean production method of phenoxybuprofen calcium
  • CN200510060924.1 discloses a water-dispersible nano-scale ibuprofen injection preparation and preparation method thereof
  • CN200510096990.4 A method and a preparation for preparing an amino acid salt of dextroprofen is disclosed
  • CN200610038794.6 discloses a soft capsule composition containing zinc gluconate, ibuprofen and chlorpheniramine maleate
  • CN200610044134.9 discloses that ibuprofen is contained Injection and preparation method thereof;
  • CN200 10044528.4 discloses an injection containing ketoprofen and a preparation method thereof;
  • CN200610090025.0 discloses a arginine ibuprofen agent suitable for children;
  • CN200610129620.0 discloses an arginine ibuprofen salt Preparation;
  • CN200610130587.3 discloses an ibuprofen oral dissolution tablet and a preparation method thereof
  • CN200610170923.7 discloses an ibuprofen infusion preparation and a preparation method thereof
  • CN2006S0001752.3 discloses a glycoside composition containing right ibuprofen as an active ingredient And a preparation method thereof
  • CN200680016935.2 discloses solubilized ibuprofen
  • CN200710004659.4 discloses a dextroprofen pharmaceutical composition having improved dissolution properties and a preparation method thereof
  • CN200S 10000637.5 discloses an ibuprofen amino acid Salt injection and preparation method thereof
  • CN200810102110.3 discloses a preparation method of ibuprofen arginine salt
  • CN200810105086.9 discloses an amino acid salt of dextroprofen and a pharmaceutical composition thereof.
  • the ibuprofen non-anti-inflammatory drugs are combined with ascorbic acid and converted into ascorbate, which is formed with a pharmaceutically acceptable acid or base.
  • ascorbate which is formed with a pharmaceutically acceptable acid or base.
  • the study of salt to improve its solubility characteristics, onset speed, bioavailability, and blood cerebral barrier penetration has not been reported.
  • the invention discloses a new ester derivative of an ibuprofen non-resistance anti-inflammatory drug, an ascorbate ester of an ibuprofen non-steroidal anti-inflammatory drug, and an additive with a pharmaceutically acceptable acid or base salt.
  • the compound of the present invention has a novel structure and is therefore novel, especially having valuable pharmacokinetic properties such as good solubility, high bioavailability, fast onset, high blood-brain barrier penetration, and ability to be treated.
  • the invention relates to compounds of formula (I), enantiomers, racemic mixtures and diastereomers thereof, as well as addition salts thereof with pharmaceutically acceptable acids or bases -
  • phosphoric acid trimellitic acid, tripolyphosphoric acid and the like.
  • those which can be mentioned in a non-limiting manner are: sodium hydroxide, potassium hydroxide, aqueous ammonia, zinc hydroxide, magnesium hydroxide, calcium hydroxide and the like.
  • Preferred compounds of the invention are such compounds:
  • the invention further relates to a process for the preparation of a compound of formula (I), characterized in that L-ascorbic acid is used as a substrate, catalyzed by a lipase, in a specific reaction system, with another substrate, a compound of formula (II)
  • the method consists of the following steps:
  • a catalyst for the lipase may be a lipase common varieties N OVO zym435, pancreatic lipase commercially available;
  • the reaction medium may be acetone, t-butanol (2-methyl-2-propanol ), tert-amyl alcohol (2-methyl-2-butanol), hexanol, octane, cyclohexane, benzene, toluene, xylene, ionic liquid, supercritical fluid, etc., in which a lipase catalyzes the reaction
  • the esterification reaction should be carried out at a reaction temperature of -30 - 200 ° C and a reaction pressure of 0.0001 - 0.5 MPa; separation and extraction, including extraction, crystallization, column chromatography, solvent recovery and any other
  • the usual procedure for obtaining the pure material from the reaction mixture should be carried out at a temperature of -30 - 200 ° (
  • the compounds of formula (I) have important pharmacokinetic and pharmacological properties.
  • Their pharmaceutically acceptable acid or base addition salts have good water solubility, excellent bioavailability and blood-brain barrier penetration, fast onset, low effective dose, and ability to neutralize the cerebral vessels in the central nervous system. Play a role in these properties that make them medically useful for anti-inflammatory, antipyretic, analgesic, arthritis, dysmenorrhea, multiple sclerosis, cystic fibrosis, premature patent ductus arteriosus, prevention and treatment of the brain Stroke, ischemic brain damage, Alzheimer's disease and certain cancers.
  • the invention further relates to a pharmaceutical combination comprising a compound of formula (I), an enantiomer thereof or an addition salt thereof with a pharmaceutically acceptable acid or base, or in combination with one or more inert, non-toxic excipients or carriers Things.
  • compositions of the present invention are particularly worth mentioning that those suitable for oral, parenteral, nasal, rectal, translingual, transocular or respiratory administration, especially tablets or dragees, sublingual Tablets, cachets, paquets, gelatin capsules, lingual tablets (gl 0SSe tte), lozenges, suppositories, creams, ointments, dermatological gels, injectable or drinkable preparations, gas Aerosol, eye drops or nose drops.
  • the useful dose depends on the age and weight of the patient, the route of administration, the nature of the indication for treatment, and any related treatment, ranging from
  • the filtrate was washed 4-5 times with an equal amount of saturated brine, and the tert-amyl alcohol was distilled off under reduced pressure at 49 ° C.
  • the obtained solid was weighed and added to the cyclohexane at a concentration of 10% at 45 ° C.
  • the mixture was slightly warmed on a water bath, stirred well, and then placed in a refrigerator at 4 ° C overnight to obtain crystals. Filtration, rinsing the filter cake several times with cyclohexane, recovering the filter cake, and drying the filter cake at room temperature to give the title compound.
  • Solubility Solubility in methanol, Ethanol, Propylene glycol, Insoluble in chloroform, Cyclohexanide, Water Example 3, L-ascorbic acid-6-0-ibuprofen
  • Example 2 The method was the same as that used in Example 1, except that it was replaced by racemic loxoprofen (S> ibuprofen. Melting point: 168 to 169 ° C
  • Example 10 L-ascorbic acid -6-0-(S)-ibuprofen sodium salt: arteriovenous loop thrombosis
  • the two ends were connected with a heparin-filled cannula (about 3cm long), one end inserted into the jugular vein and the other end inserted into the common carotid artery.
  • the blood flow of the extracorporeal circuit was formed. After 15 minutes, the blood flow was interrupted, and the thrombus was quickly taken out, and the weight of the silk wire was subtracted from the weight of the wire to obtain the wet weight of the thrombus.
  • Thrombosis inhibition rate (blank group thrombus wet weight - administration group thrombus wet weight) / blank group thrombus wet weight
  • L-ascorbic acid-6-0-(S)-ibuprofen ester 300g wheat starch 300g potato starch 300g lactose 1000g magnesium stearate 50g silica 20g hydroxypropyl cellulose 30g Example 12, each containing 200mg L-ascorbic acid

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  • Organic Chemistry (AREA)
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  • Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Wood Science & Technology (AREA)
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  • Veterinary Medicine (AREA)
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  • Genetics & Genomics (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Biomedical Technology (AREA)
  • Rheumatology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Pain & Pain Management (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Immunology (AREA)
  • Endocrinology (AREA)
  • Vascular Medicine (AREA)
  • Psychiatry (AREA)
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  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

说明书
芳基 (乙)丙酸抗坏血酸酯， 其制备方法及含有它们的药物 技术领域
本发明涉及新的非留类抗炎药物的酯类衍生物， 其制备方法以及含有它们的药物组合物。 具体地 讲是属于芳基 (乙)丙酸的抗坏血酸酯类衍生物以及其与可药用酸或碱的加成盐，其制备方法以及含有它 们的药物组合物。 技 *
以布洛芬为代表的非甾类抗炎药物是近年来发展最为成功的解热镇痛药物之一。 它们除抗炎作用 外， 又具显著的镇痛、 退热作用及很好的安全性； 不仅适于成年人同样适用于老年人和婴幼儿服用。 在国外布洛芬巳成为解热镇痛药的主要品种， 广泛用于安全性要求很高的非处方药（OTC), 被视为比 扑热息痛、 阿司匹林更具有发展前景的品种之一。
但这类药物普遍存在水溶性较差、 剌激肠胃道、 吸收慢、 生物利用度低、 起效相对较慢等不足， 对儿童、 老年人和不能吞服固体制剂的患者也带来诸多不便。
为改进制剂的产品溶解性及给药途径问题， 提高产品的稳定性和生物利用度， 加快起效速度， 现 有技术中巳公开了大量的各种改良技术。 CN99800474.X公开了一种含有水溶性酮基布洛芬盐的药用 制剂及其应用； CN00807563.8公开了一种可饮用布洛芬药物悬浮液； CN02109536.1公开了一种布洛 芬三氮唑核苷酯及制备方法和用途； CN02110476.X公开了酮基布洛芬与卩一环糊精或其衍生物包合物 的制备方法； CN02115459.7公开了聚己内酯一布洛芬组合物及其制法和用途； CN02821502.8公开了 布洛芬盐乳化剂和包含其的霜剂制剂； CN03139 L 16.8公开了一种布洛芬糖缀合物及其制备方法和应 用； CN03144095.9公开了含有布洛芬和盐酸伪麻黄碱的液态软胶囊； CN03145504.2公开了精氨酸-布 洛芬混合物的制法和用途； CN03805774.3公开了用于硬壳胶囊的布洛芬溶液； CN200410014369.4公 开了一种新的制备布洛芬精氨酸盐的方法； CN200410021005.9公开了布洛芬酯、可药用盐及其制备工 艺以及它的药物组合物； CN200410021590.2公开了丁香酚布洛芬酯药用化合物及其制剂和制备方法； CN200510024043.4公开了一种布洛芬糖衍生物及其制备方法和应用； CN200510026269.8公开了一种 制备 2-芳基乳酸酯及萘普生、布洛芬的方法; CN200510040242.4公开了苯氧布洛芬钙的清洁生产方法; CN200510060924.1公开了一种水分散性纳米级布洛芬注射制剂及其制备方法； CN200510096990.4公 开了右布洛芬氨基酸盐制备方法和应用； CN200610038794.6公开了含葡萄糖酸锌、布洛芬和马来酸氯 苯那敏的软胶囊组合物； CN200610044134.9公幵了含有布洛芬的注射剂及其制备方法；
CN200 10044528.4公开了含有酮基布洛芬的注射剂及其制备方法； CN200610090025.0公开了一种儿 童适用的精氨酸布洛芬药剂； CN200610129620.0公开了一种精氨酸布洛芬盐的制备方法；
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但将布洛芬类非 类抗炎药物与抗坏血酸结合， 转化为抗坏血酸酯， 利用其与可药用酸或碱形成 的盐来改善其溶解特性、 起效速度、 生物利用度以及血脑屛障穿透性能的研究尚未见任何报道。
本发明发明了一种布洛芬类非留类抗炎药物的酯类衍生物新品种， 布洛芬类非留类抗炎药物的抗 坏血酸酯， 及其与可药用酸或碱的加成盐。 本发明化合物具有新的结构， 因此是新颖的， 尤其是具有 溶解性好、 生物利用度高、 起效快、 血脑屛障穿透性能强等有价值的药代动力学特性和能够作为治疗 早产儿动脉导管未闭、脑卒中、缺血性脑损伤、老年痴呆症和某些癌症的药物的有价值的药理学特性。
更具体的说， 本发明涉及式 (I)化合物， 其对映体、 外消旋混合物和非对映异构体， 以及其与可药 用酸或碱的加成盐-
Figure imgf000004_0001
在可药用酸中， 能以非限制性方式提及的是： 磷酸， 三偏磷酸， 三聚磷酸等。
在可药用碱中， 能以非限制性方式提及的是： 氢氧化钠， 氢氧化钾， 氨水， 氢氧化锌， 氢氧化镁， 氢氧化钙等。
本发明的优选化合物是这样一些化合物：
L-抗坏血酸 -6-0-(S)-布洛芬酯
L-抗坏血酸 -6-0-(S)-酮洛芬酯
L-抗坏血酸 -6-0-(S)-萘普生酯
L-抗坏血酸 -6-0-(S)-吲哚美辛酯
本发明优选化合物的对映体、 外消旋混合物、 非对映异构体及其与可药用酸或碱的加成盐也构成 本发明的一个重要部分。 本发明还涉及式 (I)化合物的制备方法， 其特征在于以 L-抗坏血酸为底物， 在脂肪酶的催化下， 在 特定的反应体系中， 跟另一底物， 式 (II)化合物
RCOOH (II)
式中 R如上文定义。 按照下面的反应方程式发生酯化反应制得：
Figure imgf000005_0001
该方法由下列步骤组成：
(1) 以脂肪酶为催化剂， 在特定的反应体系中， 使 L-抗坏血酸的 6-羟基和式 (Π)化合物发生酯化反应， 生成 L-抗坏血酸的 6-0-酯， 得到一个由反应物 L-抗坏血酸、 式 (II)化合物和反应产物 -L-抗坏血酸的 6-0- 酸酯以及水构成的平衡混合物。
(2)对该平衡混合物进行分离提取， 得到目的产物， 式 化合物。
我们发现， 可供用作催化剂的脂肪酶可以是 NOVOzym435， 胰脂肪酶等市场上可以买到的常见脂 肪酶品种； 反应介质可以是丙酮、 叔丁醇 (2-甲基 -2-丙醇)、 叔戊醇 (2-甲基 -2-丁醇)、 己院、 辛烷、 环己 垸、 苯、 甲苯、 二甲苯、 离子液体、 超临界流体等可供脂肪酶在其中催化该反应进行的液体或流体； 酯化反应应当在反应温度为 -30 - 200°C, 反应压力为 0.0001 - 0.5 MPa的条件下进行； 分离提取， 包 括萃取、 结晶、 柱层析、 溶剂回收以及其他任何必要的从反应混合物中得到纯物质的常规操作过程， 应当在温度为 -30 - 200° (， 压力为 0.0001 - 3.5 MPa的条件下进行。
式 (I)化合物具有重要的药代动力学性能和药理学性能。 它们的可药用酸或碱的加成盐具有良好的 水溶解性、 极佳的生物利用度和血脑屏障穿透性能， 起效快， 有效剂量低， 能够在中枢神经系统中和 脑血管中发挥作用， 这些性能使得它们可以在医疗上用于消炎、 解热、 镇痛、 治疗关节炎、 痛经、 多 发性硬化症、 囊性纤维化肺炎、 早产儿动脉导管未闭、 预防和治疗脑卒中、 缺血性脑损伤、 老年痴呆 症和某些癌症。
本发明还涉及含有式 (I)化合物、 其对映体或其与可药用酸或碱的加成盐本身或者与一种或多种惰 性、 无毒的赋形剂或载体结合的药物组合物。
在本发明的药物组合物中， 尤其值得一提的是适于口服、 肠胃外、 经鼻、 直肠、 经舌、 经眼或经 呼吸给药的那些，尤其是片剂或糖衣丸、舌下片剂、扁囊剂、扇形剂 (paquet)、明胶胶囊、舌含片 (gl0SSette)、 锭剂、 栓剂、 膏霜剂、 油膏剂、 皮肤用凝胶、 可注射或可饮用制剂、 气雾剂、 滴眼或滴鼻剂。
有用剂量根据患者的年龄和体重、 给药途径、 治疗适应症的性质及任何相关治疗而定， 范围是从
0.1 mg/天至 800 mg/天， 分一次或多次给药。 具体实施方式
为了更好地理解本发明， 下面以实施例说明之， 但并不限止本发明的内容。 实施例 1， L-抗坏血酸 -6-0-(
Figure imgf000005_0002
在一个 500ml具塞三角瓶中加入 0.85g L-抗坏血酸和 60ml 25%(W/v)的 (S)-布洛芬叔戊醇溶液， 然 后放入恒温空气浴振荡器中加热， 使物料达到 55°C, 然后加入 Novozym 435 lg, 在 200rpm的震摇速 度下让体系反应 12hrs， 然后加入 lg分子筛 A4, 在同样条件下继续震摇 12hrs， 得到反应混合物。 趁热过滤， 除去未反应的反应物和酶， 得到澄清的滤液。 滤液用等量的饱和食盐水洗 4-5次， 并 在减压条件下 49°C， 旋蒸出叔戊醇， 称量得到的固体， 按 10%的量加入环己浣， 在 45°C水浴上微热， 充分搅拌溶解， 然后放入 4°C冰箱中过夜， 得到结晶。 过滤， 用环己烷冲洗滤饼多次， 回收滤饼， 室 温干燥滤饼， 得到标题化合物。
熔点： ^45—146°。
元素微量分析：
计算值％: C: 62.64; H: 6.63
实测值％： C: 62.68; H: 6.69 实例 2， 实施例 1的标题化合物的结构确认
经结构确认， 所得产物为 L-抗坏血酸 -6-0-(S 布洛芬酯。 其特征的理化及结构分析参数为： m.p. 145~146°C
[a]D = +21.8° (c =0.00232g/ml, CH3OH)„ 0.1003g、 50ml(c =0.006 l lg/ml, CH3OH)
IR (KBr, cm"1): 3395.52, 3222.26, 3022.03, 2954.93, 2876.59, 2954.93, 2876.59, 1761.60, 1709.72, 1665.92, 1665.92, 1510.01, 1463.13, 1382.85
'H NM (400MHZ, CD3OD): 7.20 (d, 2H)， 7.11 (d， 2H), 4.39 (d, 1H), 4.12 (t, 2H), 3.99 (t， 1H), 3.75 (t, 1H), 2.44 (d, 2H)， 1.82 (t, 1H)， 1.47(d, 3H)， 0.88 (t， 6H)
1 C NMR (400MHz, CD3OD): 5(ppm) 18.8533 (C8), 22.8453, 22.7906 (Ci+Cr), 31.6083 (C3), 46.3302, 46.1564 (C9+C2), 65.7436 (C12)， 67.7221 (Cu)， 76.8915 (C13)， 120.1202 (C15)， 128.4167 (C5+C5'), 130.5936 (Cg+Q , 141.9723, 139.4376 (C7+C4), 154.1888 (C14), 173.2871, 176.1047 (C10+C16)
MS(m/z); 365.4 (M+H+), 363.3 (M-l)。
Figure imgf000006_0001
溶解性： 易溶于甲醇， 乙醇， 丙二醇， 难溶于氯仿， 环己垸， 水 实施例 3， L-抗坏血酸 -6-0-布洛芬酯
Figure imgf000006_0002
方法与实施例 1中所用的相同， 只是用外消旋的布洛芬替代 (S)-布洛芬。
熔点： ^45—146°。
元素微量分析：
计算值％： C: 62.64; H: 6.63
实测值％： C: 62.65; H: 6.70
[ ]D = 0。（c =0.0061 lg/ml, C¾OH) 实施例 4， L-抗坏血酸 -6-0-(S)-酮洛芬酯
Figure imgf000007_0001
方法与实施例 1中所用的相同， 只是用 (S)-酮洛芬替代 (S)-布洛芬。
熔点： 165~166°C
元素微量分析- 计算值％: C: 64.07; H: 4.88
实测值％: C: 64.15; H: 4.90
[a]D = +20.3° (c =0.003 llg/ml, CH3OH) 实施例 5， L-抗坏血酸 -6-0-落索洛芬酯
Figure imgf000007_0002
方法与实施例 1中所用的相同， 只是用外消旋的落索洛芬替代 (S>布洛芬。 熔点： 168~169°C
元素微量分析：
计算值％： C: 62.36; H: 5.98
实测值％: C: 62.45; H: 6.13
[a]D = 0° (c =0.0023 lg/ml, CH3OH) 实施例 6， L-抗坏血酸 -6-0-普拉洛芬酯
Figure imgf000007_0003
方法与实施例 1中所用的相同， 只是用外消旋的普拉洛芬替代 (S>布洛芬。 熔点： 198~199°C
元素微量分析- 计算值％： C: 61.01; H: 4.63; N: 3.39
实测值0 /0 : C: 61.05; H: 4.73; N: 3.41
[a]D = 0° (c =0.0023 lg/ml, CH3OH) 实施例 7， L-抗坏血酸 -6-0-(S)-萘普生酯
Figure imgf000007_0004
方法与实施例 1中所用的相同， 只是用 (S)-萘普生替代 (S)-布洛芬。
熔点： 215 216°C
元素微量分析：
计算值％: C: 61.85; H: 5.15
实测值％: C: 61.87; H: 5.18
[a]D = +18.5° (c =0.005 llg/ml, CH3OH) 实施例 8， L-抗坏血酸 -6-0-依托度酸酯
Figure imgf000008_0001
方法与实施例 1中所用的相同， 只是用依托度酸替代 (S)-布洛芬。
熔点： 218〜219°C
元素微量分析：
计算值％: C: 62.01; H: 6.06; N; 3.14
实测值％: C: 62.07; H: 6.10; N: 3.21
[a]D = 0。（c =0.0020 lg/ml, CH3OH) 实施例 9， L-抗坏血酸 -6-0-(S)-布洛芬酯钠盐的制备
在连续搅拌的条件下， 取 0.05mol/L的 L-抗坏血酸 -6-0-(S)-布洛芬酯甲醇溶液 100ml与等体积等 摩尔浓度的氢氧化钠甲醇溶液混合， 然后置旋转蒸发仪上真空浓缩至原体积的三分之一， 4°C下放置 过夜， 过滤， 得到标题化合物 1.8g。
经测定， 其在水中的溶解度为 12.8g。 实例 10， L-抗坏血酸 -6-0-(S)-布洛芬酯钠盐： 动静脉环路血栓
正常大鼠，雌雄各半，按表 1随机分组,灌胃给药 L-抗坏血酸 -6-0-(S 布洛芬酯钠盐水溶液 (pH 7.4) 及空白对照组 (等 pH生理盐水)， 连续给药 3d。末次给药后 lh腹腔注射 8%水合氯醛 350 π¾1ί^麻醉， 仰卧位固定， 分离右侧颈总动脉和左侧颈外静脉。 在 10cm长的聚乙烯管中段放入一根提前称重的 7 号手术线 (长约 8cm)并充满生理盐水， 其两端连接充满肝素的插管 (长约 3cm)， 一端插入颈静脉， 另一 端插入颈总动脉。 打开动脉夹后， 形成体外环路血流。 15min后中断血流， 迅速取出血栓称重， 该重 量减去丝线重量即得血栓湿重。
血栓抑制率： （空白组血栓湿重-给药组血栓湿重 )/空白组血栓湿重
统计学处理： 实验数据以 ±s表示， 用单因素方差分析判断差异的显著性。 康示空白对照组和 L- 抗坏血酸 -6-0-(S)-布洛芬酯钠盐之间的 t检验结果。 表 1 血栓抑制率
组别 n 剂量 血栓湿重 /体重 x l 00 血栓抑制率 /% t
mg-kg"1
空白对照 4 - 11.914± 0.241 - -
L-抗坏血酸 -6-0-(S)-布洛芬酯钠 8 5.4 10.372± 0.801** 12.9 0.003 盐
方差分析， p<0.05; 与空白组比较 **P<0.01， *P<0.05 由表 1 可知， L-抗坏血酸 -6-0-(S)-布洛芬酯钠盐的血栓抑制率与对照组的差异具有显著性 (P<0.01), L-抗坏血酸 -6-0-(S)-布洛芬酯钠盐能抑制血栓形成，增强其抗凝血功能。 L-抗坏血酸 -6-0-(S)- 布洛芬酯钠盐血栓抑制率达 L2.9%。 实例 11， 每片包含 300mg L-抗坏血酸 -6-0-(S)-布洛芬酯的片剂 用于制备 1000片的配方：
L-抗坏血酸 -6-0-(S)-布洛芬酯 300g 小麦淀粉 300g 土豆淀粉 300g 乳糖 1000g 硬脂酸镁 50g 二氧化硅 20g 羟丙基纤维素 30g 实例 12， 每支含 200mg L-抗坏血酸 -6-0-(S)-布洛芬酯钠的针剂 用于制备 1000支的配方：
L-抗坏血酸 -6-0-(S)-布洛芬酯钠 200g 乳糖 200g

Claims

权利要求书
1. 一类芳基 (乙)丙酸抗坏血酸酯， 其特征为符合式 的化合物， 其对映体、外消旋混合物和非对映异 构体， 以及其与可药用酸或碱的加成盐-
Figure imgf000010_0001
2. 如权利要求 1所述的式 化合物， 它是 L-抗坏血酸 -6- HS)-布洛芬酯， 其外消旋混合物 L-抗坏血 酸 -6-0-布洛芬酯， 以及其与可药用酸或碱的加成盐。
3. 如权利要求 1所述的芳基 (乙)丙酸抗坏血酸酯的制备方法， 其特征是以 L-抗坏血酸为底物， 在脂 肪酶的催化下， 在特定的反应介质中， 跟另一底物， 式 (II)化合物
COOH (II)
式中 R如上文定义；
按照下面的反应方程式发生酯化反应制得：
Figure imgf000010_0002
该方法由下列步骤组成-
(1) 以脂肪酶为催化剂， 在特定的反应介质中， 使 L-抗坏血酸的 6-羟基和式 (Π)化合物发生酯化反应， 生成 L-抗坏血酸的 6-0-酸酯， 得到一个由反应物 L-抗坏血酸、 式 (II)化合物和反应产物 -L-抗坏血酸的 6-0-酸酯以及水构成的平衡混合物； (2)对该平衡混合物进行分离提取， 得到目的产物， 式 化合物。
4. 如权利要求 3所述的的制备方法， 其特征是脂肪酶， 系指 NOVOzym435， 胰脂肪酶等市场上可以买 到的常见脂肪酶品种。
5. 如权利要求 3所述的芳基 (乙)丙酸抗坏血酸酯的制备方法，其特征是反应介质系指丙酮、叔丁醇 (2- 甲基 -2-丙醇)、 叔戊醇 (2-甲基 -2-丁醇)、 己烷、 辛烷、 环己烷、 苯、 甲苯、 二甲苯、 离子液体、 超 临界流体以及其他任何可供脂肪酶在其中催化该反应进行的液体或流体。
6. 如权利要求 3所述的芳基 (乙)丙酸抗坏血酸酯的制备方法，其特征是酯化反应系指反应体系在反应 温度为 -30 - 200°C， 反应压力为 0.0001 - 0.5 MPa的条件下进行的， 利用脂肪酶， 催化底物发生化 学变化生成反应产物的过程。
7. 如权利要求 3所述的芳基 (乙)丙酸抗坏血酸酯的制备方法， 其特征是分离提取为萃取、结晶、柱层 析、 溶剂回收以及其他任何必要的从反应混合物中得到纯物质的操作过程。
8. 如权利要求 7 所述的芳基 (乙)丙酸抗坏血酸酯的制备方法， 其特征是分离提取在温度为 -30 - 200°C, 压力为 0.0001 - 3.5 MPa的条件下进行。
9. 药物组合物， 它包含作为活性成分的至少一种按照权利要求 1-2任一项所述的化合物本身或其与 一种或多种惰性、 无毒的可药用赋形剂或载体的组合。
10. 如权利要求 9所述的药物组合物， 它包含至少一种活性成分： 按照权利要求 1-2任一项所述的非 甾类抗炎药物， 用于消炎、 解热、 镇痛、 治疗关节炎、 痛经、 多发性硬化症、 囊性纤维化肺炎、 早产儿动脉导管未闭、 预防和治疗脑卒中、 缺血性脑损伤、 老年痴呆症和某些癌症。
PCT/CN2009/075994 2009-05-11 2009-12-24 芳基(乙)丙酸抗坏血酸酯，其制备方法及含有它们的药物 WO2010130139A1 (zh)

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