WO2017012556A1 - 一种芳基丙酸类化合物及其制药用途 - Google Patents

一种芳基丙酸类化合物及其制药用途 Download PDF

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WO2017012556A1
WO2017012556A1 PCT/CN2016/090764 CN2016090764W WO2017012556A1 WO 2017012556 A1 WO2017012556 A1 WO 2017012556A1 CN 2016090764 W CN2016090764 W CN 2016090764W WO 2017012556 A1 WO2017012556 A1 WO 2017012556A1
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group
membered ring
compound
acid
salt
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PCT/CN2016/090764
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French (fr)
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叶海
晁阳
郭彦飞
丁伯祥
曹卫
魏丹
闵涛
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南京海融医药科技股份有限公司
南京海融制药有限公司
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Priority to CN201680000788.3A priority Critical patent/CN106661061B/zh
Publication of WO2017012556A1 publication Critical patent/WO2017012556A1/zh

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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
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    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • 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
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    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
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    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
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    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/67—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
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    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/69—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a carbon skeleton substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
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    • C07C69/12—Acetic acid esters
    • C07C69/14—Acetic acid esters of monohydroxylic compounds
    • C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
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    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/24—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with monohydroxylic compounds
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    • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
    • C07C69/614—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety of phenylacetic acid
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus

Definitions

  • the invention relates to the field of medicinal chemistry, in particular to an aryl propionic acid derivative and a pharmaceutically acceptable salt thereof, and to the use in the field of treatment of non-steroidal anti-inflammatory drugs.
  • Loxoprofen Sodium is an anti-inflammatory analgesic that inhibits the cyclooxygenases COX-1 and COX-2.
  • the effect of loxoprofen sodium is mainly manifested as an analgesic effect, and the anti-inflammatory and antipyretic effects are equivalent to those of other similar drugs.
  • Clinical trials show that after oral administration, they are metabolized into trans-OH type drugs in the human body. At the same time, the concentration distribution in liver and plasma is higher than other parts, and then they are quickly converted into glucose conjugates, and finally excreted in the form of urine.
  • the analgesic effect of loxoprofen sodium is 10-20 times stronger than that of ketoprofen, indomethacin and naproxen. It also has the advantages of rapid and significant effect, small side effects and wide clinical application.
  • COX-2 specific inhibitors that were previously considered “perfect” also gradually exposed the following problems: (1) no improvement in efficacy, (2) no adverse reactions; (3) ulceration rate Reduced in the short term, no difference in long-term use; (4) severe myocardial infarction. Therefore, how to find non-steroidal anti-inflammatory drugs with less side effects and safer and more effective has become one of the hot spots in the industry.
  • Prodrug design is one of the common strategies in drug development.
  • Prodrugs contain more than an ester bond, which can be hydrolyzed in vivo to an active drug molecule by an esterase or a hydrolyzable esterase.
  • the design of the prodrug is usually to improve the physicochemical properties of the prototype drug such as water solubility, improve the absorption efficiency of the original drug, improve the metabolic stability, or reduce the toxic side effects of the original drug.
  • a trans-alcohol metabolite formed by the activity of loxoprofen in vivo is used as a precursor, and a series of ester derivatives such as a phosphate ester are designed and prepared starting from a chiral hydroxyl group on trans-cyclopentanol. , sulfonate, carbonate, amino acid ester, and the like.
  • the present invention provides an aryl propionic acid derivative having the structure of Formula I, and a pharmaceutically acceptable salt, hydrate or solvate thereof,
  • substituent A is selected from the group consisting of
  • G 1 or G 2 each independently represents a hydroxyl group, a linear or branched C 1 -C 6 alkane or a linear or branched C 1 -C 6 alkoxy group; or a G 1 , G 2 ring synthesizes a 5-membered ring containing a hetero atom , six-membered ring or seven-membered ring;
  • G 3 or G 4 each independently represents hydrogen, a hydroxyl group, a linear or branched C1 to C6 alkane, a linear or branched C1 to C6 alkoxy group or a phenyl group; or a G 3 or G 4 ring synthesis containing a hetero group a five-membered ring, a six-membered ring, or a seven-membered ring of an atom;
  • n 0 ⁇ 6;
  • E is CH, C(CH 3 ) or N;
  • the substituent A is selected from the group after the amino acid has removed the hydroxyl group in the carboxyl group.
  • the salt of the structural compound of formula I is selected from the group consisting of sodium, calcium, zinc, magnesium, meglumine, lysine, arginine, histidine or tromethamine.
  • the salt form is selected from the group consisting of a sodium salt, an arginine salt, a lysine salt or a tromethamine salt.
  • G 1 or G 2 each independently represents a hydroxyl group, a C1-C5 alkane or a C1-C5 alkoxy group.
  • G 3 or G 4 each independently represents hydrogen, a hydroxyl group, a C 1 -C 5 alkane or a phenyl group; or a G 3 or G 4 ring synthesizes a five-membered ring, a six-membered ring or a seven-membered ring containing a nitrogen atom. ring.
  • substituent A is selected from:
  • n 2 or 3
  • n is selected from 0, 1, 2, 3 or 4;
  • E is selected from CH, C(CH 3 ) or N;
  • G 1 or G 2 are each independently selected from the group consisting of hydroxyl, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, methoxy, ethoxy, C.
  • G 3 or G 4 are each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or phenyl; or G 3 , G 4
  • the ring synthesizes a five-membered ring, a six-membered ring or a seven-membered ring containing a nitrogen atom.
  • the amino acid is selected from the group consisting of glycine, lysine, arginine, histidine, cysteine, phenylalanine, Proline, aspartic acid, leucine, alanine or methionine.
  • the compound of formula I of the present invention may be selected from the group consisting of the following compounds in group a, group b, group c, group d, group e, group f:
  • the compound of the formula I according to the invention is selected from the group consisting of the following compounds:
  • the compound of the formula I according to the invention is selected from the group consisting of the following compounds:
  • the invention also provides a process for the synthesis of a compound of formula I, i.e., a process for the preparation of a compound from group a to group f.
  • the condensation reaction is obtained.
  • the basic conditions may use an inorganic base such as sodium hydroxide or potassium carbonate; or an organic base such as triethylamine or diisopropylethylamine.
  • the phosphoryl chloride starting material may be commercially available or may be prepared by using the corresponding alkyl alcohol and phosphorus oxychloride.
  • 2-chloro-2-oxo-1,3,2-dioxaphosphane can be prepared by cyclization of 1,3-propanediol at low temperature by phosphorus oxychloride. Particular embodiments.
  • the condensation reaction is obtained.
  • the basic condition is selected from the group consisting of sodium hydroxide, potassium carbonate, triethylamine or diisopropylethylamine.
  • the carbonyl chloride starting material can be prepared from the corresponding alcoholate by the action of triphosgene (BTC).
  • a compound of formula II under basic conditions with a carboxylic acid chloride starting material ie The condensation reaction is obtained.
  • the basic condition is selected from the group consisting of sodium hydroxide, potassium carbonate, triethylamine or diisopropylethylamine.
  • the carboxyacyl chloride starting material can be prepared from the corresponding carboxylate under the action of thionyl chloride.
  • the amino group can be protected by a Boc protecting group or a Cbz protecting group, and then a condensation reaction is carried out by using a condensing agent commonly used in multi-child synthesis, such as DCC, DIC, HOBT. Finally, the amino protecting group is removed. This is a method well known to those skilled in the art, as detailed in the "Detailed Description" section.
  • Alkyl means a saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms, including both straight chain and branched chain groups (the numerical ranges mentioned in this application, such as “1-20” or “C1 to C20", are Refers to the group, which is an alkyl group, which may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 20 carbon atoms.
  • An alkyl group having 1 to 5 carbon atoms is called a lower alkane. base. When the lower alkyl group has no substituent, it is referred to as an unsubstituted lower alkyl group.
  • the alkyl group is a medium size alkyl group having from 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl Base.
  • the alkyl group is a lower alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, a propyl group, a 2-propyl group, a n-butyl group, an isobutyl group or a t-butyl group.
  • the alkyl group can be substituted or unsubstituted.
  • the substituent is preferably one or more, more preferably 1 to 3, most preferably 1 or 2 substituents, which are independently preferably selected from the group consisting of halogen, hydroxy, lower alkane Oxy, aryl, aryloxy, heteroaryl, heteroalicyclic.
  • Aryl means an all-carbon monocyclic or fused polycyclic group of 1 to 12 carbon atoms having a fully conjugated pi-electron system.
  • Non-limiting examples of aryl groups are phenyl, naphthyl and anthracenyl. The aryl group can be substituted or unsubstituted.
  • the substituent is preferably one or more, more preferably one, two or three, still more preferably one or two, independently selected from lower alkyl, trihaloalkyl, halogen, hydroxy , lower alkoxy, fluorenyl, (lower alkyl)thio, cyano, acyl, thioacyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thioamino Formyl, C-amido, N-amido, nitro, N-sulfonylamino, S-sulfonylamino.
  • the aryl group is optionally substituted by one or two substituents independently selected from halogen, lower alkyl, trihaloalkyl, hydroxy, decyl, cyano, N-amido, mono or dioxane Amino group, carboxyl group or N-sulfonylamino group.
  • substituents independently selected from halogen, lower alkyl, trihaloalkyl, hydroxy, decyl, cyano, N-amido, mono or dioxane Amino group, carboxyl group or N-sulfonylamino group.
  • Heterocyclyl means a monocyclic or fused ring group which is a saturated or unsaturated group, typically having from 5 to 9 ring atoms in the ring, wherein one or two ring atoms are selected from N, O or A hetero atom of S(O) m (wherein m is an integer of 0 to 2), and the remaining ring atoms are C; for example, a five-membered ring, a six-membered ring or a seven-membered ring containing a hetero atom. These rings may have one or more double bonds, but these rings do not have a fully conjugated pi-electron system.
  • Non-limiting examples of unsubstituted heterocyclic groups are pyrrolidinyl, piperidino, piperazino, morpholino, thiomorpholino, homopiperazino, tetrahydropyranyl, 2,2-Dimethyl-1,3-dioxolane, piperidino, N-methylpiperidine-3-yl, piperazino, N-methylpyrrolidine-3-yl, pyrrole Alkyl, morpholino, thiomorpholino, thiomorpholino-1 oxide, thiomorpholino-1,1-dioxide, 4-ethoxycarbonylpiperazino, 3-oxopiperazino, 2-imidazolidinone, 2-pyrrolidone, 2-oxopiperazino, tetrahydropyrimidin-2-one, and the like.
  • the heterocyclic group may be substituted or unsubstituted.
  • the substituents are preferably one or more, more preferably one, two or three, and still more preferably one or two, independently selected from the group consisting of lower alkyl, trihalo Alkyl, halogen, hydroxy, lower alkoxy, fluorenyl, (lower alkyl)thio, cyano, acyl, thioacyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl , N-thiocarbamoyl, C-amido, N-amido, nitro, N-sulfonylamino, S-sulfonylamino.
  • Haldroxy means an OH group.
  • Alkoxy means ⁇ O ⁇ (unsubstituted alkyl) and —O—(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy, cyclopropoxy, cyclobutoxy, Cyclopentyloxy, cyclohexyloxy, tert-butyloxy, n-pentyloxy and the like.
  • the remaining group after the amino acid has removed the hydroxyl group in the carboxyl group means various amino acids.
  • the remaining group after removing the hydroxyl group in the carboxyl group Wherein R is a variable group corresponding to a different amino acid.
  • “Pharmaceutically acceptable salt” means those salts which retain the biological effectiveness and properties of the parent compound. Such salts include: (1) salt formation with an acid obtained by reacting a free base of a parent compound with an inorganic or organic acid, including hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid.
  • organic acids including acetic acid, trifluoroacetic acid, propionic acid, acrylic acid, caproic acid, cyclopentanopropionic acid, glycolic acid, pyruvic acid, oxalic acid, (D) or (L) malic acid, fumaric acid , maleic acid, benzoic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid , p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, cinnamic acid, lauryl sulfate, gluconic acid, glutamic acid, aspartic acid, stearic acid, mandelic acid, succinic acid or sodium Diacid and
  • an organic base such as ethanolamine, diethanolamine, or the like.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I according to the invention and a pharmaceutically acceptable adjuvant.
  • the pharmaceutical compositions of the present invention can be prepared by conventional methods using pharmaceutical excipients well known in the art.
  • the pharmaceutical composition of the present invention may be in the form of a solid preparation, a semi-solid preparation, and a liquid preparation
  • the specific dosage form may be, for example, a tablet, a suppository, a granule, a capsule, a microcapsule, a pill, a paste, an injection.
  • a particularly preferred formulation form is selected from the group consisting of a tablet, a capsule, an injection, a powder, a gel, a cream, an ointment, or a cataplasm.
  • conventional pharmaceutical excipients include fillers, binders, disintegrants, lubricants.
  • Fillers include starch, lactose, mannitol, microcrystalline cellulose; binders include starch, lactose, mannitol, microcrystalline cellulose; disintegrants include crosslinked cellulose sodium, crospovidone, low substituted Hydroxypropylmethylcellulose; lubricants include magnesium stearate, talc, polyethylene glycol, magnesium lauryl sulfate, micronized silica gel, talc; pharmaceutical excipients may also include colorants, sweeteners.
  • the excipient is selected from the group consisting of lactose, glucose, mannitol, glycine, dextran;
  • the antioxidant is selected from the group consisting of amino acids or salts thereof, sulfites, thiosulfates; acid-base regulators It is selected from the group consisting of phosphoric acid, lactic acid, hydrochloric acid, citric acid, and sodium hydroxide or potassium hydroxide;
  • the osmotic pressure adjusting agent is selected from sodium chloride or glucose;
  • the metal ion complexing agent is selected from sodium edetate or disodium edetate.
  • the co-solvent and stabilizer are selected from the group consisting of tromethamine, arginine, and methotrexate. Acid, cysteine, ascorbic acid, sodium citrate.
  • the pharmaceutical composition of the present invention can be formulated into a tablet, granule or capsule form.
  • the tablet may be a common tablet, a dispersible tablet, an effervescent tablet, a sustained release tablet, a controlled release tablet or an enteric coated tablet
  • the capsule may be a general capsule, a sustained release capsule, a controlled release capsule or an enteric capsule.
  • the pharmaceutical composition of the present invention can be formulated into a semisolid preparation such as a gel, a cream, a cataplasm, a transdermal patch, a film, and a film.
  • the ointment base is a water-soluble base such as polyethylene glycol (PEG4000, PEG6000, PEG600, etc.);
  • the cream base is a water-in-oil type, or an oil-in-water type
  • the oil phase is stearic acid, paraffin, vegetable oil or higher alcohol;
  • the emulsifier is selected from the group consisting of calcium soap, lanolin, fatty acid ester of polyhydric alcohol, sorbitan fatty acid, preferred emulsifier is Span 80, or monostearyl Acid glyceride.
  • a penetration enhancer, a moisturizer, a preservative, a stabilizer and the like may be added as needed.
  • composition of the present invention can be formulated into a gel preparation for external use comprising a main drug component and a gel matrix.
  • the gel matrix is selected from the group consisting of carbomer, polyvinylpyrrolidone, polyethylene glycol, methylcellulose, ethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, Further, a transdermal enhancer, a moisturizer, a pH adjuster, a preservative, a stabilizer, etc. may be added as needed.
  • the above pharmaceutical compound or composition thereof of the present invention can be used for medical use in the preparation of a medicament for treating diseases including, but not limited to, various inflammations or various conditions or pains caused by diseases, particularly selected from the group consisting of: Rheumatoid arthritis, osteoarthritis, low back pain, inflammation around the shoulder joints, anti-inflammatory and/or analgesic of neck and shoulder syndrome, analgesia and/or anti-inflammatory after surgery, trauma or extraction, acute upper respiratory tract inflammation (including acute upper respiratory tract inflammation with or without acute bronchitis) antipyretic and / or analgesia.
  • diseases including, but not limited to, various inflammations or various conditions or pains caused by diseases, particularly selected from the group consisting of: Rheumatoid arthritis, osteoarthritis, low back pain, inflammation around the shoulder joints, anti-inflammatory and/or analgesic of neck and shoulder syndrome, analgesia and/or anti-inflammatory after surgery, trauma or extraction, acute upper respiratory tract inflammation (including acute upper respiratory tract inflammation with or without
  • a series of phosphate esters, sulfonates, carbonates, amino acid esters and the like are prepared by using the most active alcohol metabolite of loxoprofen in the metabolic process as a mother nucleus.
  • the obtained derivative can enhance the anti-inflammatory and analgesic effects, reduce toxicity, and has good metabolic dynamic properties. At the same time, it also greatly reduces the stimulating effect of the drug on the gastrointestinal tract and improves the patient's medication compliance. It is a potential non-steroidal anti-inflammatory analgesic drug.
  • Figure 1 is a mass spectrum (positive ion mode) of compound a-1.
  • Figure 2 is a mass spectrum (negative ion mode) of compound a-1.
  • Figure 3 is a schematic illustration of the results of Example 24.
  • chlorophosphoric acid is The preparation is carried out in accordance with the synthesis method of "Methyl(S)-4-(chloromethoxyphosphinyl)-3(tert-butyldiphenylsiloxy)butyrate" on page 6 of the specification of the patent document US Pat. No. 4,992,429 A1.
  • the preparation method of using phosphorus oxychloride 7.2 g of the compound of the formula II is dissolved in 100 mL of anhydrous tetrahydrofuran, 14 mL of pyridine is added, cooling is cooled, the internal temperature is maintained between -10 and -15 ° C, and 10 mL of phosphorus oxychloride is added dropwise.
  • the solution of tetrahydrofuran in 30 mL was added dropwise, and stirred at 0-5 ° C for 1 h. The mixture was removed to room temperature, and 2 mL of phosphorus oxychloride was added thereto. The mixture was stirred at room temperature until the reaction was completed.
  • the preparation was carried out by the method of Example 17, except that the methionine of the compound of the formula II was prepared by using Boc-protected amino group methionine as a starting material.
  • the preparation was carried out in accordance with the method of Example 17, except that the phenylalanine of the compound of the formula II was prepared by using the phenylalanine of the Boc-protected amino group as a starting material.
  • a-2, a-4 to 5, c-1, c-3 to 5, c-7, c-9, d-1, d-3 to 8, e-2 to 7, e- Compounds such as 9, f-2 can be obtained by using different raw materials according to the above various synthesis methods. Mass spectral data of the obtained compound was collected as follows.
  • the preparation of the pharmaceutical composition of the present invention is prepared by taking the compounds b-1 and b-2 as an example, specifically as follows.
  • Preparation process the raw material drug compound b-1 over 100 mesh sieve, lactose, starch, sodium carboxymethyl starch over 80 mesh sieve, the raw material drug and sodium carboxymethyl starch, starch, lactose, evenly mixed, 1.5% carboxy Methyl cellulose sodium solution to obtain a soft material, 30 mesh granulation, drying at 60 ° C for 1.5 h, to obtain a dry material, adding magnesium stearate, mixing for 10 min, 24 mesh granules, tableting, that is.
  • Preparation method the formula amount of the drug substance compound b-2 is dissolved in 70% water for injection, the formula amount of arginine is added, the pH of the solution is adjusted to 7.0-8.5, and then the volume is adjusted with water for injection to the solution after constant volume. After adding 0.1% (g/ml) of activated carbon for adsorption for 20 min, the carbon was filtered off, and the solution was passed through a 0.22 ⁇ m filter for fine filtration. After the content of the intermediate was tested, it was filled into 10 ml each, and the semi-finished product obtained was filled. After sterilizing at 121 °C for 15 minutes in the cabinet, the finished product is obtained after the lamp is qualified.
  • Preparation method the formula amount of propylparaben is dissolved in the formula amount of propylene glycol, ethylenediaminetetraacetic acid disodium salt is dissolved in an appropriate amount of distilled water, mixing the two, and then adding the formula amount of glycerin, and stirring; carbomer 940 Slowly put into the above solution, stir constantly, let stand for 24h, get blank glue, spare. Slowly add the sodium hydroxide solution to the blank gel with stirring, adjust the pH 6.0-6.5, dissolve the formula amount of compound b-1 with an appropriate amount of distilled water, and add it to the white glue adjusted to pH value with constant stirring. Add the formula oleic acid and mix well. Weigh, add distilled water to the total weight, and dispense.
  • test male rats (body weight about 200 g) were fasted for 24 hours, the test compound was orally administered, and the dose was equal to the molar amount of loxoprofen.
  • the stomach was removed, and the ulcer area generated inside the stomach was measured. The area of all the ulcers was totaled as the ulcer coefficient.
  • the comparator drug was loxoprofen at a dose of 40 mg/Kg.
  • the dose of the new compound b-1, the compound b-2, is equivalent to 40 mg/kg of loxoprofen.
  • the ulcer coefficient of loxoprofen was 9.4 (mm 2 )
  • the ulcer coefficient of the compound b-1 was 2.2 (mm 2 )
  • the ulcer coefficient of the compound b-2 was 2.4 (mm 2 ). This indicates that the new compounds b-1, b-2 have almost no side-effect ulcers, the ulcer area of the stomach is small, and the ulcer coefficient is very low.
  • Wister male rats (body weight 180-200 g) were used for 18 hours, and the test compound was weighed orally. After 8 hours, the stomach was removed and the area of ulcer produced inside the stomach was measured. The area of all the ulcers was totaled as the ulcer coefficient. Rats were orally administered with the comparative drug loxoprofen, the new compounds a-1, c-10, e-1, f-1, all at a dose of 20 mg/Kg. The test results are shown in Figure 3.
  • Example 25 Analgesic Test (Inhibition Rate of Loxoprofen and New Compounds b-1, b-2 on Mouse Wounds)
  • mice The number of writhings which occurred after intraperitoneal administration of acetic acid solution in mice was counted, and the inhibition rate of the writhing body was calculated based on the control group. Twenty-four mice were divided into 4 groups of 6 each. Group A was the control group, and the blank preparation was given; group B was orally administered with loxoprofen 40 mg/Kg, and group C and group D were orally administered with compound b-1 corresponding to the dose of loxoprofen 40 mg/Kg, compound b-2. . The test compound was administered to the mice 60 minutes before the administration of the acetic acid solution, and the results are shown in Table 1.
  • Group Group Group A Group B Group C Group D Dose (mg/Kg) 0 40 40 40 40 40 Number of writhing 42.1 22.1 15.6 17.2 Percent inhibition (%) no 47 61 59
  • mice were weighed at 18-22 g, and each mouse was placed on a metal hot plate at 55 °C. The latency required for painful reactions such as kicking, hindfoot, and jumping was measured. The mean pain threshold was taken twice. The average pain threshold of rats, which should be excluded if the value is less than 6 seconds or greater than 30 seconds. Qualified mice were randomly divided into groups of 10, the vehicle control group was 0.5% CMC-Na, the positive control group was loxoprofen, and the test group selected compounds were compound a-1, c-10, e-1. , f-1. The doses used in the positive control group and the test group were both 30 mg/Kg. After taking the mice in each group, the pain threshold of the mice was measured at 60, 90, and 120 minutes, respectively. The test results are shown in Table 2.
  • test male rats (body weight about 200g) were fasted for 24 hours, and the test compound was orally administered at a dose equal to that of loxoprofen.
  • 1% carrageenan was injected subcutaneously into the left ankle, resulting in Puffiness, the carrageenan was dissolved in 100 ⁇ l of physiological saline, and the volume of the hind paw of the rat was measured every 1 h after carrageenan administration, and the volume growth rate of the hind paw was calculated as the swelling rate (%).
  • Group A was the control group, and the blank preparation was given; group B was orally administered with loxoprofen 40 mg/Kg, group C and group D were orally administered with compound b-1 corresponding to the dose of loxoprofen 40 mg/Kg, compound b-2. .
  • the swelling rate (%) results of the different groups at different time points are shown in Table 3. The results showed that the same doses of the new compounds b-1 and b-2 had better anti-inflammatory effects than the positive drug loxoprofen.
  • Example 28 Anti-inflammatory test (mouse ear xylene inflammation test)
  • mice weighing 24-28 g were randomly divided into groups of 10, the vehicle control group was 0.5% CMC-Na, the positive control group was loxoprofen, and the compound selected in the test group was compound a-1, c-10. , e-1, f-1.
  • the doses used in the positive control group and the test group were both 30 mg/Kg. 60 minutes after the administration of each group of mice, 0.05 mL of xylene was evenly dropped on the right auricle, and the left ear was compared.
  • the mice were sacrificed 1 hour later, and the round ears were placed on the left and right ears with the 8 mm diameter puncher. Piece, weighing, the difference in weight between the left and right ears is the degree of swelling.
  • Table 4 The test results are shown in Table 4.
  • the prescribed amount of compound a-1 is added to 80% deoxy-injected water for injection, stirred under a 40 ° C water bath to dissolve completely, adjusted to pH 6.5-7.5 with sodium hydroxide or citric acid, 0.05% activated carbon is added, and filtered under reduced pressure to remove Activated carbon, the solution was passed through a 0.22 ⁇ m filter, and filled in an ampoule of 20 mg/10 mL, 30 mg/10 mL, 40 mg/10 mL, or 50 mg/10 mL each, and sterilized by steam pressing at 121 ° C for 10 min.
  • the drug concentration of this test is 4mg/mL, using self-control, left ear administration, and right ear for the same amount of 0.9% sodium chloride injection.
  • the solution was administered once a day for 3 consecutive days. Before each administration, after administration, and 24 hours and 48 hours after the last administration, it was observed that there was no irritating reaction such as erythema or edema. After the last administration for 48 hours, the animals were sacrificed and the site of administration was taken for vascular histopathological section. When the blood vessels were examined, there was a stimulating reaction such as tissue degeneration or necrosis.
  • Test results The blood vessels of the above injection group and 0.9% sodium chloride injection group were visually observed. No erythema, edema, ulcer and other irritative symptoms were observed during the administration period and recovery period; pathological examination showed that each rabbit ear None of the three points of reference See vascular endothelial cells swelling, necrosis, clear vascular lumen, no thrombus in the lumen, no inflammatory cell infiltration or bleeding in the perivascular tissue. Therefore, the injection has no irritating effect on rabbit ear vessels.
  • the drug concentration in this test was 4 mg/mL.
  • the 6th and 7th tubes are negative respectively.
  • Test method The control drug loxoprofen and the test drug (ie, compound a-1, c-10, e-1, f-1) were dissolved in physiological saline to prepare a solution of 10 mg/mL. If it is not easy to completely dissolve, add a small amount of ethanol to help dissolve. Rats weighing 180-220 g were randomly divided into groups of 6 each. According to the dose of 20 mg/Kg, the rats in the loxoprofen group, the a-1 group, the c-10 group, the e-1 group, and the f-1 group were administered with the drug solution through the tail vein. According to the preset time point, blood was taken from the rat eye, blood samples were collected, and blood concentration was measured. The data collected are shown in Table 6.

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Abstract

本发明公开了一种芳基丙酸类化合物及其制药用途。本发明是以洛索洛芬在代谢过程中最具活性的醇代谢物为母核，制备了一系列磷酸酯、磺酸酯、碳酸酯、氨基酸酯等衍生物。所得衍生物能够增强抗炎镇痛的药效，减轻毒性反应，具有良好的代谢动力学性质。同时，也大大降低了药物对胃肠道的刺激作用，提高了病人用药顺应性，是一种颇具潜力的非甾体抗炎镇痛药物。

Description

一种芳基丙酸类化合物及其制药用途 技术领域
本发明涉及药物化学领域，具体涉及一种芳基丙酸类衍生物及其可药用盐，以及在非甾体类抗炎药的治疗领域中的应用。
背景技术
洛索洛芬钠(Loxoprofen Sodium)是一种对环氧化酶COX-1和COX-2均有抑制作用的消炎镇痛药。作为首个被合成的芳基丙酸类的前体型的非甾体抗炎药，洛索洛芬钠的疗效主要表现为镇痛作用显著，消炎、解热作用与其他同类药疗效相当。临床试验表现为口服后在人体内代谢为trans-OH型药物，同时在肝和血浆中浓度分布比其他部位高，之后便迅速转变为葡萄糖类结合物，最后以尿液的形式排出体外。洛索洛芬钠的镇痛效果比酮洛芬、吲哚美辛、萘普生要强10-20倍，还具有作用效果迅速且显著、毒副作用小、临床应用范围广等优点。
经过长期临床实践，早先被视为“完美”的COX-2特异性抑制剂也逐步暴露出如下问题：(1)疗效并未增加，(2)不良反应并未减少；(3)导致溃疡率短期内降低，长期使用无差异；(4)严重的心肌梗塞出现。因此，如何寻找毒副作用小的、更为安全有效的非甾体抗炎药成为业界研发的热点之一。
前药设计是药物开发中的常用策略之一。前体药物多含有酯键，其在体内可被酯酶或具有水解活性的类酯酶水解为活性药物分子。前药设计通常是为了提高原型药物的水溶性等理化性质，改善原药吸收效率，提高代谢稳定性，或是降低原药的毒副作用。
发明内容
本发明中根据洛索洛芬在体内活性生成的反式醇代谢物为母体，以反式环戊醇上的手性羟基为出发点，设计并制备了一系列的酯类衍生物，如磷酸酯、磺酸酯、碳酸酯、氨基酸酯等。
本发明提供一种如式I结构的芳基丙酸类衍生物，以及其药学上可接受的盐、水合物或溶剂合物，
Figure PCTCN2016090764-appb-000001
其中，取代基A选自：
Figure PCTCN2016090764-appb-000002
其中，G1或G2各自独立地表示羟基、直链或支链的C1～C6烷烃或直链或支链的C1～C6烷氧基；或G1、G2环合成含有杂原子的五元环、六元环或七元环；
G3或G4各自独立地表示氢、羟基、直链或支链的C1～C6烷烃、直链或支链的C1～C6烷氧基或苯基；或G3、G4环合成含有杂原子的五元环、六元环或七元环；
m＝2或3；
n＝0～6；
E为CH、C(CH3)或N；
或者，取代基A选自氨基酸去掉羧基中的羟基后余下的基团。
优选的，式I结构化合物的盐选自钠盐、钙盐、锌盐、镁盐、葡甲胺盐、赖氨酸盐、精氨酸盐、组氨酸盐或氨丁三醇盐。特别优选的，盐型选自钠盐、精氨酸盐、赖氨酸盐或氨丁三醇盐。
在一种优选方案中，G1或G2各自独立地表示羟基、C1～C5烷烃或C1～C5烷氧基。
在一种优选方案中，G3或G4各自独立地表示氢、羟基、C1～C5烷烃或苯基；或G3、G4环合成含有氮原子的五元环、六元环或七元环。
优选的，当取代基A选自：
Figure PCTCN2016090764-appb-000003
时，
m选自2或3，
n选自0、1、2、3或4；
E选自CH、C(CH3)或N；
G1或G2各自独立地选自羟基、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁 基、正戊基、甲氧基、乙氧基、丙氧基、异丙基氧基、异丁基氧基、叔丁基氧基或正戊基氧基；
G3或G4各自独立地选自氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或苯基；或者G3、G4环合成含有氮原子的五元环、六元环或七元环。
本发明中，基团
Figure PCTCN2016090764-appb-000004
中，m为2时，该基团为
Figure PCTCN2016090764-appb-000005
当m为3时，该基团为
Figure PCTCN2016090764-appb-000006
其所形成的式I化合物是环状的磷酸酯。
优选的，当取代基A是氨基酸去掉羧基中的羟基后余下的基团时，所述氨基酸选自甘氨酸、赖氨酸、精氨酸、组氨酸、半胱氨酸、苯丙氨酸、脯氨酸、天冬氨酸、亮氨酸、丙氨酸或甲硫氨酸。
优选地，本发明式I化合物，可选自a组、b组、c组、d组、e组、f组中的下列化合物：
Figure PCTCN2016090764-appb-000007
Figure PCTCN2016090764-appb-000008
进一步优选地，本发明式I化合物，选自下列化合物：
Figure PCTCN2016090764-appb-000009
更进一步优选地，本发明式I化合物，选自下列化合物：
Figure PCTCN2016090764-appb-000010
本发明还提供了式I化合物的合成方法，即化合物从组a到组f的制备方法。
当式I化合物中取代基A为
Figure PCTCN2016090764-appb-000011
反应式如下所示，
Figure PCTCN2016090764-appb-000012
将式II化合物在碱性条件下与磷酰氯起始物，即
Figure PCTCN2016090764-appb-000013
进行缩合反应即得。所述碱性条件可使用无机碱，例如氢氧化钠、碳酸钾；或有机碱，例如三乙胺，二异丙基乙胺。所述磷酰氯起始物，可以购买市售品，也可以采用相应的烷基醇与三氯氧磷制备得到。
当式I化合物中取代基A为
Figure PCTCN2016090764-appb-000014
具体地，反应式如下所示，
Figure PCTCN2016090764-appb-000015
其中，2-氯-2-氧-1,3,2-二氧磷杂环己烷的制备可以通过三氯氧磷在低温下与1，3-丙二醇的环合反应制得，详见“具体实施方式”部分。
当式I化合物中取代基A为
Figure PCTCN2016090764-appb-000016
反应式如下所示，
Figure PCTCN2016090764-appb-000017
将式II化合物在碱性条件下与磺酰氯起始物，即
Figure PCTCN2016090764-appb-000018
进行缩合反应即得；所述碱性条件选自氢氧化钠，碳酸钾，三乙胺或二异丙基乙胺。
当起始原料是牛磺酸时，还需要增加氨基的上保护基和脱除保护基的步骤。
不常见的磺酰氯的合成如下所示，
Figure PCTCN2016090764-appb-000019
当式I化合物中取代基A为
Figure PCTCN2016090764-appb-000020
反应式如下所示，
Figure PCTCN2016090764-appb-000021
将式II化合物在碱性条件下与碳酰氯起始物，即
Figure PCTCN2016090764-appb-000022
进行缩合反应即得。所述碱性条件选自氢氧化钠，碳酸钾，三乙胺或二异丙基乙胺。碳酰氯起始物可由相应的醇化物在三光气(BTC)的作用下制得，
Figure PCTCN2016090764-appb-000023
当式I化合物中取代基A为
Figure PCTCN2016090764-appb-000024
反应式如下所示，
Figure PCTCN2016090764-appb-000025
将式II化合物在碱性条件下与羧基酰氯起始物，即
Figure PCTCN2016090764-appb-000026
进行缩合反应即得。所述碱性条件选自氢氧化钠，碳酸钾，三乙胺或二异丙基乙胺。羧基酰氯起始物可由相应的羧基化物在氯化亚砜的作用下下制得，
Figure PCTCN2016090764-appb-000027
当取代基A为氨基酸的羧基对应的酰基部分的结构，可通过Boc保护基或Cbz保护基对氨基进行保护后，再采用多胎合成中常用的缩合剂，如DCC，DIC，HOBT，进行缩合反应，最后脱除氨基保护基即得。这是本领域技术人员熟知的方法，详见“具体实施方式”部分。
除非另外说明，在说明书和权利要求中使用的以下术语具有下面讨论的含义：
“烷基”表示1‐20个碳原子的饱和的脂烃基，包括直链和支链基团(本申请书中提到的数字范围，例如“1‐20”或“C1～C20”，是指该基团，此时为烷基，可以含1个碳原子、2个碳原子、3个碳原子等，直至包括20个碳原子)。含1－5个碳原子的烷基称为低级烷 基。当低级烷基没有取代基时，称其为未取代的低级烷基。更优选的是，烷基是有1‐10个碳原子的中等大小的烷基，例如甲基、乙基、丙基、2‐丙基、正丁基、异丁基、叔丁基、戊基等。最好是，烷基为有1‐4个碳原子的低级烷基，例如甲基、乙基、丙基、2‐丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的。当是取代的烷基时，该取代基优选是一或多个，更优选1‐3个，最优选1或2个取代基，它们独立地优选自以下的基团：卤素、羟基、低级烷氧基、芳基、芳氧基、杂芳基、杂脂环基。
“芳基”表示1至12个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。芳基的非限制性实例有苯基、萘基和蒽基。芳基可以是取代的或未取代的。当被取代时，取代基优选为一个或多个，更优选为一个、两个或三个，进而更优选为一个或两个，独立地选自由低级烷基、三卤烷基、卤素、羟基、低级烷氧基、巯基、(低级烷基)硫基、氰基、酰基、硫代酰基、O‐氨基甲酰基、N‐氨基甲酰基、O‐硫代氨基甲酰基、N‐硫代氨基甲酰基、C‐酰氨基、N‐酰氨基、硝基、N‐磺酰氨基、S‐磺酰氨基。优选地，芳基可选地被一个或两个取代基取代，取代基独立地选自卤素、低级烷基、三卤烷基、羟基、巯基、氰基、N‐酰氨基、单或二烷基胺基、羧基或N‐磺酰氨基。
“杂环基”表示单环或稠合环基团，它为饱和或不饱基团，一般在环中具有5到9个环原子，其中一个或两个环原子是选自N、O或S(O)m(其中m是0至2的整数)的杂原子，其余环原子是C；例如含有杂原子的五元环、六元环或七元环。这些环可以具有一条或多条双键，但这些环不具有完全共轭的π电子系统。未取代的杂环基的非限制性实例有吡咯烷基、哌啶子基、哌嗪子基、吗啉代基、硫代吗啉代基、高哌嗪子基、四氢吡喃基、2,2‐二甲基‐1,3‐二氧戊环、哌啶子基、N‐甲基哌啶‐3‐基、哌嗪子基、N‐甲基吡咯烷‐3‐基、吡咯烷基、吗啉代基、硫代吗啉代基、硫代吗啉代‐1‐氧化物、硫代吗啉代‐1,1‐二氧化物、4‐乙氧羰基哌嗪子基、3‐氧代哌嗪子基、2‐咪唑啉酮、2‐吡咯烷酮、2‐氧代高哌嗪子基、四氢嘧啶‐2‐酮等。杂环基可以是取代的或未取代的。当被取代时，取代基优选为一个或多个、更优选为一个、两个或三个，进而更优选为一个或两个，独立地选自以下基团，包括：低级烷基、三卤烷基、卤素、羟基、低级烷氧基、巯基、(低级烷基)硫基、氰基、酰基、硫代酰基、O‐氨基甲酰基、N‐氨基甲酰基、O‐硫代氨基甲酰基、N‐硫代氨基甲酰基、C‐酰氨基、N‐酰氨基、硝基、N‐磺酰氨基、S‐磺酰氨基。
“羟基”表示‐OH基团。
“烷氧基”表示‐O‐(未取代的烷基)和‐O‐(未取代的环烷基)。代表性实例包括但不限于甲氧基、乙氧基、丙氧基、异丙基氧基、丁氧基、异丁基氧基、环丙氧基、环丁氧基、 环戊氧基、环己氧基、叔丁基氧基、正戊基氧基等。
“氨基酸去掉羧基中的羟基后余下的基团”，是指各种氨基酸
Figure PCTCN2016090764-appb-000028
中去掉羧基中的羟基后剩余的基团
Figure PCTCN2016090764-appb-000029
其中R为对应不同氨基酸的可变基团。
“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括：(1)与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸包括盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸包括乙酸、三氟乙酸、丙酸、丙烯酸、己酸、环戊烷丙酸、羟乙酸、丙酮酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、苯甲酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、肉桂酸、十二烷基硫酸、葡糖酸、谷氨酸、天冬氨酸、硬脂酸、扁桃酸、琥珀酸或丙二酸等。(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属例子例如碱金属离子、碱土金属离子或铝离子，有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺、奎宁等。
本发明还提供一种药物组合物，包含本发明所述的式I化合物和药用辅料。本发明的药物组合物可采用本领域公知的药用辅料通过常规方法制得。
本发明所述的药物组合物的制剂形式可以是固体制剂、半固体制剂，以及液体制剂，具体剂型可以是，例如片剂、栓剂、颗粒剂、胶囊剂、微囊剂、丸剂、膏剂、注射液(水针或输液)、冻干粉针剂、乳剂、混悬剂，溶胶剂，凝胶剂，乳膏剂，巴布剂。特别优选的制剂剂型选自片剂，胶囊剂，注射液，粉针剂，凝胶剂，乳膏剂，软膏剂，或巴布剂。
对于固体制剂而言，常规药用辅料包括填充剂、粘合剂、崩解剂、润滑剂。填充剂包括淀粉、乳糖、甘露醇、微晶纤维素；粘合剂包括淀粉、乳糖、甘露醇、微晶纤维素；崩解剂包括交联纤维素钠、交联聚维酮、低取代的羟丙甲基纤维素；润滑剂包括硬脂酸镁、滑石粉、聚乙二醇、十二烷基硫酸镁、微粉硅胶、滑石粉；药用辅料还可以包括着色剂、甜味剂。
对于液体制剂尤其是注射制剂而言，赋形剂选自乳糖、葡萄糖、甘露醇、甘氨酸、右旋糖苷；抗氧化剂选自氨基酸或其盐、亚硫酸盐、硫代硫酸盐；酸碱调节剂选自磷酸、乳酸、盐酸、枸橼酸以及氢氧化钠或氢氧化钾；渗透压调节剂选自氯化钠或葡萄糖；金属离子络合剂选自依地酸钙钠或依地酸二钠；助溶剂和稳定剂选自氨丁三醇，精氨酸，甲硫氨 酸，半胱氨酸，抗坏血酸，柠檬酸钠。
本发明所述的药物组合物可以制成片剂、颗粒剂或胶囊剂的剂型。其中，片剂可以是普通片剂、分散片、泡腾片、缓释片、控释片或肠溶片，胶囊剂可以是普通胶囊、缓释胶囊、控释胶囊或肠溶胶囊。
本发明所述的药物组合物可以制成半固体制剂的形式，例如：凝胶剂，乳膏剂，巴布剂，透皮贴剂，膜剂，涂膜剂。当该药物组合物的剂型是软膏或乳膏时，软膏基质为水溶性基质，例如聚乙二醇类(PEG4000，PEG6000，PEG600等)；乳膏基质为油包水型，或水包油型；油相为硬脂酸，石蜡，植物油或高级醇；乳化剂选自钙皂，羊毛脂，多元醇的脂肪酸酯，脂肪酸山梨坦类，优选的乳化剂是司盘80，或单硬脂酸甘油酯。在上述的软膏和乳膏的制备过程中，还可根据需要添加促渗剂，保湿剂，防腐剂，稳定剂等。
本发明所述的组合物可以制成外用的凝胶制剂，其包含有主药成分和凝胶基质。其中，凝胶基质选自卡波姆，聚乙烯吡咯烷酮，聚乙二醇，甲基纤维素，乙基纤维素，羟丙基纤维素，羧甲基纤维素钠，羟丙基甲纤维素，另外还可根据需要添加透皮促进剂，保湿剂，pH调节剂，防腐剂，稳定剂等。
本发明上述的药物化合物或其组合物可以用于在制备治疗下列疾病的药物中的医药用途，所述疾病包括但不限于各种炎症或各种情况或疾病引起的疼痛，特别选自：类风湿关节炎，骨性关节炎，腰痛症，肩关节周围炎，颈肩腕综合征的消炎和/或镇痛，手术后、外伤后或拔牙后的镇痛和/或消炎，急性上呼吸道炎(包括伴有或不伴有急性支气管炎的急性上呼吸道炎)解热和/或镇痛。
本发明以洛索洛芬在代谢过程中最具活性的醇代谢物为母核，制备了一系列磷酸酯、磺酸酯、碳酸酯、氨基酸酯等衍生物。所得衍生物能够增强抗炎镇痛的药效，减轻毒性反应，具有良好的代谢动力学性质。同时，也大大降低了药物对胃肠道的刺激作用，提高了病人用药顺应性，是一种颇具潜力的非甾体抗炎镇痛药物。
附图说明
附图1是化合物a-1的质谱图(正离子模式)。
附图2是化合物a-1的质谱图(负离子模式)。
附图3是实施例24的结果示意图。
具体实施方式
下面结合具体实施例对本发明技术方案作进一步说明。
本发明涉及的母核结构，即式II化合物，是根据文献“TetrahedronAsymmetry，2011，
22：1125-1132”中的实验方法制得。
Figure PCTCN2016090764-appb-000030
实施例1化合物a-1的合成
Figure PCTCN2016090764-appb-000031
使用氯磷酸的制备方法：式II化合物25g溶于无水乙腈70mL中，加入二异丙基乙胺13g，降温至-5～0℃，缓慢滴加氯磷酸12g的无水二氯甲烷溶液20mL，滴毕，保温搅拌1h，缓慢升至室温搅拌2h，TLC监控反应完全，减压除去反应溶剂，加水150mL和二氯甲烷150mL搅拌，静置分层，浓缩二氯甲烷层，残余物用甲醇/乙酸乙酯重结晶，得到白色固体14g。
其中，氯磷酸的结构是
Figure PCTCN2016090764-appb-000032
其制备参考专利文献US4992429 A1的说明书第6页中有关“Methyl(S)-4-(chloromethoxyphosphinyl)-3(tert-butyldiphenylsiloxy)butyrate”的合成方法制得。
质谱ESI-MS：m/z＝329.5，[M+H]+，详见附图1。
核磁氢谱1H-NMR：δppm 7.23(d，2H)，7.15(d，2H)，4.9(br，2H)，3.86(m，1H)，3.65(m，1H)，2.74(m，1H)，2.46(m，1H)，2.0(m，2H)，1.9-1.6(m，5H)，1.47(d，3H)。
实施例2化合物a-1的合成
使用三氯氧磷的制备方法：式II化合物7.2g溶于无水四氢呋喃100mL中，加入吡啶14mL，降温冷却，内温维持在-10至-15℃间，滴加三氯氧磷10mL溶于四氢呋喃30mL中的溶液，滴毕，0-5℃搅拌1h，移出至室温下，补加2mL三氯氧磷，室温搅拌至反应完全，TLC监控的展开剂为乙酸乙酯：冰醋酸＝10:1，反应完毕，抽滤，滤液滴入到保温在0-5℃的纯水约600mL中，滴毕，室温25-30℃搅拌1h，加入乙酸乙酯300mL搅拌0.5h， 静置分层，有机相用纯水、饱和食盐水洗涤，无水硫酸钠干燥，浓缩至干，残余物用甲醇/乙酸乙酯重结晶，得到白色固体5.9g。
质谱ESI-MS：m/z＝327.1，[M-H]-，详见附图2。
核磁碳谱13C NMR(CDCl3)：δppm 18.2,21.5,29,6,34.0,39.5,44.7,49.5,78.3,127.3,137.8,140.1,180.1。
实施例3化合物a-3的合成
Figure PCTCN2016090764-appb-000033
参照实施例1的方法来进行制备，不同之处是滴加氯磷酸二乙酯的无水二氯甲烷溶液。
质谱ESI-MS m/z＝385.6，[M+H]+。
核磁氢谱1H-NMR：δppm 7.25(d，2H)，7.16(d，2H)，4.04(m，4H)，3.85(m，1H)，3.64(m，1H)，2.74(m，1H)，2.46(m，1H)，2.03(m，2H)，1.93-1.66(m，5H)，1.55(m，6H)，1.44(d，3H)。
实施例4化合物a-6的合成
Figure PCTCN2016090764-appb-000034
参照实施例1的方法来进行制备，不同之处是滴加氯磷酸二正丁酯的无水二氯甲烷溶液。
质谱ESI-MS m/z＝441.4，[M+H]+。
核磁氢谱1H-NMR：δppm7.24(d，2H)，7.12(d，2H)，4.07(m，4H)，3.80(m，1H)，3.65(m，1H)，2.77(m，1H)，2.49(m，1H)，2.04(m，2H)，1.90-1.67(m，5H)，1.66(m，4H)，1.49(d，3H)，1.39(m，4H)，1.11(m，6H)。
实施例5化合物b-1的合成
Figure PCTCN2016090764-appb-000035
2-氯-2-氧-1,3,2-二氧磷杂环戊烷的制备：将三氯化磷16g溶于二氯甲烷20mL，室温下加入1,2-乙二醇5g，滴加完毕，室温搅拌2h，减压蒸去溶剂，残余物减压蒸馏，收集50-53℃/3.0Kpa的馏分，所得无色液体溶于无水甲苯25mL，室温搅拌下通入氧气12h，减压蒸馏，收集81-85℃/6.0Kpa馏分，得到2-氯-2-氧-1,3,2-二氧磷杂环戊烷约9.2g。
式II化合物12.3g溶于无水四氢呋喃50mL中，加入三乙胺6.5g，降温至-5～0℃，缓慢滴加上述所得磷酰氯约7.2g的无水二氯甲烷溶液25mL，滴毕，保温搅拌1h后，再缓慢升至室温搅拌2h，TLC监控反应完全，减压除去反应溶剂，加水200mL和乙酸乙酯20mL搅拌，静置分层，乙酸乙酯层浓缩所得残余物用异丙醇重结晶，得到白色固体约10.4g。
质谱ESI-MS m/z＝355.3，[M+H]+。
核磁氢谱1H-NMR：δppm7.26(d，2H)，7.13(d，2H)，4.45(m,4H)，3.82(m，1H)，3.65(m，1H)，2.78(m，1H)，2.46(m，1H)，2.09(m，2H)，1.93-1.64(m，5H)，1.47(d，3H)。
实施例6化合物b-2的合成
Figure PCTCN2016090764-appb-000036
2-氯-2-氧-1,3,2-二氧磷杂环己烷的制备：将三氯氧磷8.0g溶于甲苯12mL，室温下滴加1,3-丙二醇4.1g，滴加完毕，室温搅拌2h，减压蒸去溶剂，残余物中加入无水乙醚40mL，0℃冷藏12h，过滤析出固体，无水乙醚重结晶得到白色固体约3.5g。
式II化合物12.5g溶于无水二氧六环40mL，加入无水碳酸钾7g，降温至-5～0℃，缓慢滴加上述所得磷酰氯7.5g的无水二氯甲烷溶液25mL，滴毕，保温搅拌1h后，再缓慢升至室温搅拌2h，TLC监控反应完全，减压除去反应溶剂，加水和乙酸乙酯搅拌，静置分层，乙酸乙酯层浓缩所得残余物用甲醇/叔丁基醚重结晶，得到白色固体8.9g。
质谱ESI-MS m/z＝369.4，[M+H]+。
核磁氢谱1H-NMR：δppm7.23(d，2H)，7.17(d，2H)，4.03(m,4H)，3.90(m，1H)，3.63(m，1H)，2.71(m，1H)，2.48(m，1H)，2.16(m，2H)，2.06(m，2H)，1.93-1.65(m，5H)，1.48(d，3H)。
实施例7化合物c-2的合成
Figure PCTCN2016090764-appb-000037
式II化合物12.8g溶于无水四氢呋喃45mL，加入三乙胺6.8g，降温至-5～0℃，缓慢滴加丙基磺酰氯7.9g的无水二氯甲烷溶液25mL，滴毕，保温搅拌1h后，再缓慢升至室温搅拌2h，TLC监控反应完全，减压除去反应溶剂，加水200mL和乙酸乙酯200mL搅拌，静置分层，乙酸乙酯层浓缩所得残余物用乙醇/乙酸乙酯重结晶，得到白色固体9.2g。
质谱ESI-MS m/z＝355.7，[M+H]+。
核磁氢谱1H-NMR：δppm7.26(d，2H)，7.13(d，2H)，3.86(m，1H)，3.67(m，1H)，3.11(m，2H)，2.76(m，1H)，2.49(m，1H)，2.02(m，2H)，1.91-1.64(m，5H)，1.62(m，2H)，1.46(d，3H)，1.09(m，3H)。
实施例8化合物c-6的合成
Figure PCTCN2016090764-appb-000038
参照实施例7的方法来进行制备，不同之处是滴加苄基磺酰氯的无水二氯甲烷溶液
质谱ESI-MS m/z＝403.9，[M+H]+。
核磁氢谱1H-NMR：δppm 7.39(m，2H)，7.22(d，2H)，7.18(m，3H)，7.14(d，2H)，4.31(m，2H)，3.87(m，1H)，3.65(m，1H)，2.73(m，1H)，2.49(m，1H)，2.05(m，2H)，1.91-1.65(m，5H)，1.47(d，3H)。
实施例9化合物c-8的合成
Figure PCTCN2016090764-appb-000039
2-(二甲基胺基)乙基-1-磺酰氯的制备方法：在反应瓶中加入氯化亚砜30mL，搅拌下分批加入2-(二甲基胺基)乙基-1-醇9g，回流4-5h，蒸去氯化亚砜，得到残余物淡黄色液体9.2g，将硫脲8g和上述淡黄色液体9.2g溶于95％乙醇150mL，加入四甲基氯化铵0.5g，回流反应24h，冷却，收集粗品，乙醇重结晶，得到白色晶体为该异硫脲盐酸盐，不经纯化，将该白色固体缓慢加入到5％稀硫酸溶液中，加入乙醚100mL，在冰水浴条件下缓慢加入5％次氯酸钠溶液，控制反应体系内温度在10-20℃之间，加毕继续反应0.5h，反应结束，分液所得有机相用无水硫酸钠干燥，浓缩至干得到2-(二甲基胺基)乙基-1-磺酰氯，溶于无水甲苯中备用。后续试验是参照实施例7的方法来进行制备，不同之处是滴加2-(二甲基胺基)乙基-1-磺酰氯的无水二氯甲烷溶液。
质谱ESI-MS m/z＝384.8，[M+H]+。
核磁氢谱1H-NMR：δppm7.24(d，2H)，7.13(d，2H)，3.14(m，2H)，3.83(m，1H)，3.69(m，1H)，2.75(m，2H)，2.74(m，1H)，2.49(m，1H)，2.20(m，6H)，2.06(m，2H)，1.89-1.61(m，5H)，1.47(d，3H)。
实施例10化合物c-10的合成
Figure PCTCN2016090764-appb-000040
将牛磺酸12.5g溶于二甲基乙酰胺50mL和水50mL的混合溶剂中，加入无水碳酸钾14g，降温至-5～0℃，滴加约17.6g的Cbz-Cl的无水四氢呋喃30mL，滴毕，缓慢升至室温搅拌12h，TLC监控反应完全，过滤除去不溶物，浓缩至干，加入无水乙腈10mL和式II化合物20g，降温至0℃左右，滴加DCC 19.5g与DMAP 1.0g的四氢呋喃20mL，35-40℃搅拌10h，反应完全后，过滤除去不溶物，反应物浓缩至干，加入适量甲醇溶剂和5％重 量的钯碳，常压氢化反应6h，反应结束，过滤，浓缩物加入水200mL和乙酸乙酯200mL，静置分层，乙酸乙酯层浓缩所得残余物用甲醇/乙酸乙酯重结晶两遍，得到白色固体10.5g。
质谱ESI-MS m/z＝356.7，[M+H]+。
核磁氢谱1H-NMR：δppm7.24(d，2H)，7.16(d，2H)，3.89(m，1H)，3.64(m，1H)，3.27(m，2H)，3.05(m，2H)，2.74(m，1H)，2.47(m，1H)，2.05(m，2H)，1.97-1.60(m，5H)，1.61(s，2H)，1.47(d，3H)。
实施例11化合物d-2的合成
Figure PCTCN2016090764-appb-000041
将式II化合物12.4g溶于无水四氢呋喃50mL，加入三乙胺6g，降温至-5～0℃，缓慢滴加氯甲酸乙酯6g的无水二氯甲烷溶液20mL，滴毕，保温搅拌1h，缓慢升至室温搅拌2h，TLC监控反应完全，减压除去反应溶剂，加水100mL和乙酸乙酯100mL搅拌，静置分层，乙酸乙酯层用5％碳酸氢钠溶液50mL洗涤，干燥，浓缩所得残余物用乙醇/乙酸乙酯重结晶，得到白色固体7.3g。
质谱ESI-MS m/z＝321.8，[M+H]+。
核磁氢谱1H-NMR：δppm7.25(d，2H)，7.17(d，2H)，4.26(m，2H)，3.89(m，1H)，3.64(m，1H)，2.78(m，1H)，2.48(m，1H)，2.07(m，2H)，1.90-1.67(m，5H)，1.458(d，3H)，1.35(m，3H)。
实施例12化合物d-9的合成
Figure PCTCN2016090764-appb-000042
参照实施例11的方法来进行制备，不同之处是滴加氯甲酸异戊酯的无水四氢呋喃溶液。
质谱ESI-MS m/z＝363.5，[M+H]+。
核磁氢谱1H-NMR：δppm7.25(d，2H)，7.14(d，2H)，4.22(m，2H)，3.91(m，1H)，3.69(m，1H)，2.74(m，1H)，2.48(m，1H)，2.05(m，2H)，1.93(m，1H)，1.9-1.6(m，5H)，1.59(m，2H)，1.47(d，3H)，1.08(m，1H)。
实施例13化合物d-10的合成
Figure PCTCN2016090764-appb-000043
参照实施例11的方法来进行制备，不同之处是滴加氯甲酸苄酯的无水四氢呋喃溶液。
质谱ESI-MS m/z＝383.5，[M+H]+。
核磁氢谱1H-NMR：δppm 7.34-7.36(m，5H)，7.24(d，2H)，7.14(d，2H)，4.85(m，2H)，3.89(m，1H)，3.63(m，1H)，2.74(m，1H)，2.47(m，1H)，2.06(m，2H)，1.91-1.65(m，5H)，1.47(d，3H)。
实施例14化合物e-1的合成
Figure PCTCN2016090764-appb-000044
将式II化合物12.3g溶于无水乙腈60mL中，加入二异丙基乙胺7g，降温至-5～0℃，缓慢滴加乙酰氯4g的无水甲苯溶液20mL，滴毕，保温搅拌1h，缓慢升至室温搅拌2h，TLC监控反应完全，减压除去反应溶剂，加水100mL和乙酸乙酯100mL搅拌，静置分层，乙酸乙酯层用5％碳酸氢钠溶液洗涤，干燥，浓缩所得残余物用甲醇/乙酸乙酯重结晶，得到白色固体8.8g。
质谱ESI-MS m/z＝291.6，[M+H]+。
核磁氢谱1H-NMR：δppm7.23(d，2H)，7.16(d，2H)，3.89(m，1H)，3.68(m，1H)，2.77(m，1H)，2.49(m，1H)，2.10(m，3H)，2.02(m，2H)，1.91-1.64(m，5H)，1.45(d，3H)。
实施例15化合物e-8的合成
Figure PCTCN2016090764-appb-000045
参照实施例14的方法来进行制备，不同之处是滴加特戊酰氯的无水甲苯溶液。
质谱ESI-MS m/z＝333.7，[M+H]+。
核磁氢谱1H-NMR：δppm7.24(d，2H)，7.16(d，2H)，3.80(m，1H)，3.66(m，1H)，2.75(m，1H)，2.49(m，1H)，2.06(m，2H)，1.90-1.62(m，5H)，1.48(d，3H)，1.29(s，9H)。
实施例16化合物e-10的合成
Figure PCTCN2016090764-appb-000046
将氯化亚砜20mL加入反应瓶中，缓慢加入苯乙酸7.2g，搅拌均匀，加热回流3h，减压浓缩反应液至干，溶于无水甲苯，得到苯乙酰氯的无水甲苯溶液，备用
参照实施例14的方法来进行制备，不同之处是滴加苯乙酰氯的无水甲苯溶液。
质谱ESI-MS m/z＝367.4，[M+H]+。
核磁氢谱1H-NMR：δppm 7.26-7.28(m，5H)，7.24(d，2H)，7.14(d，2H)，3.85(m，1H)，3.67(m，1H)，3.38(m，2H)，2.76(m，1H)，2.47(m，1H)，2.03(m，2H)，1.90-1.61(m，5H)，1.47(d，3H)。
实施例17化合物f-1的合成
Figure PCTCN2016090764-appb-000047
将Boc保护氨基的甘氨酸10g投入到反应瓶中，加入无水乙腈50mL，搅拌溶解，加 入式II化合物12.5g与DMAP 0.5g，降温至0-5℃，滴加DCC约10g的无水乙腈溶液30mL，滴毕，升至室温反应12h，过滤，浓缩后残余物中加入二氯甲烷15mL和三氟乙酸15mL的等体积混合溶液30mL，0-5℃反应2h，TLC监控反应完全，浓缩反应液至干，异丙醇/乙酸乙酯重结晶两遍，得到白色固体11.8g。
质谱ESI-MS m/z＝306.4，[M+H]+。
核磁氢谱1H-NMR：δppm 7.25(d，2H)，7.11(d，2H)，3.86(m，1H)，3.65(m，1H)，3.48(m，2H)，2.75(m，1H)，2.49(m，1H)，2.08(m，2H)，1.91-1.63(m，5H)，1.49(d，3H)。
实施例18化合物f-3的合成
Figure PCTCN2016090764-appb-000048
参照实施例17的方法来进行制备，不同之处是以Boc保护氨基的甲硫氨酸为原料，制备式II化合物的甲硫氨酸酯。
质谱ESI-MS m/z＝380.6，[M+H]+。
核磁氢谱1H-NMR：δppm7.24(d，2H)，7.15(d，2H)，3.81(m，1H)，3.68(m，1H)，3.41(m,1H)，2.75(m，1H)，2.61(m,2H)，2.48(m，1H)，2.17(m，2H)，2.07(s，3H)，2.01(m，2H)，1.92-1.64(m，5H)，1.47(d，3H)。
实施例19化合物f-4的合成
Figure PCTCN2016090764-appb-000049
参照实施例17的方法来进行制备，不同之处是以Boc保护氨基的苯丙氨酸为原料，制备式II化合物的苯丙氨酸酯。
质谱ESI-MS m/z＝396.5，[M+H]+。
核磁氢谱1H-NMR：δppm7.25(d，2H)，7.17(d，2H)，7.14-7.16(m，5H)， 4.17(m，1H)，3.89(m，1H)，3.64(m，1H)，3.54(m，1H)，3.30(m,1H)，2.74(m，1H)，2.46(m，1H)，2.03(m，2H)，1.92-1.64(m，5H)，1.47(d，3H)。
本发明中的a-2，a-4～5，c-1，c-3～5，c-7，c-9，d-1，d-3～8，e-2～7，e-9，f-2等化合物均可按上述各合成方法通过采用不同的原料制得。所得化合物的质谱数据收集如下。
化合物编号 [M+H]+ 化合物编号 [M+H]+ 化合物编号 [M+H]+
a-2 357.6 a-4 413.5 a-5 441.4
c-1 341.3 c-3 369.2 c-4 369.5
c-5 382.7 c-7 370.3 c-9 411.4
d-1 307.2 d-3 335.2 d-4 349.3
d-5 363.4 d-6 349.5 d-7 335.2
d-8 348.3 e-2 305.3 e-3 319.3
e-4 333.4 e-5 347.3 e-6 333.7
e-7 319.5 e-9 347.3 f-2 362.4
关于药物组合物方面，以化合物b-1、b-2为例，制备本发明所述药物组合物的制剂，具体如下。
实施例20式I衍生物的片剂制备
配方：
Figure PCTCN2016090764-appb-000050
制备工艺：将原料药化合物b-1过100目筛，乳糖，淀粉，羧甲基淀粉钠过80目筛，将原料药与羧甲基淀粉钠，淀粉，乳糖，混合均匀，加入1.5％羧甲基纤维素钠溶液制得软材，30目制粒，60℃干燥1.5h，得干物料，加入硬脂酸镁，混合10min，24目整粒，压片，即得。
实施例21式I衍生物的注射剂制备
配方：
Figure PCTCN2016090764-appb-000051
制备方法：将配方量的原料药化合物b-2溶于70％注射用水，加入配方量的精氨酸，调节溶液的pH＝7.0-8.5，再用注射用水定容，向定容后的溶液中加入0.1％(g/ml)的活性炭吸附20min后过滤除炭，将溶液通过0.22μm的滤膜精滤，中间体检测含量合格后灌装成10ml每支，将灌装得到的半成品至于灭菌柜中121℃灭菌15min后，灯检合格后分装即得成品。
实施例22式I衍生物的凝胶剂制备
配方：
Figure PCTCN2016090764-appb-000052
制备方法：将配方量的尼泊金丙酯溶于配方量丙二醇，乙二胺四乙酸二钠盐溶于适量蒸馏水中，混合两者，再加入配方量甘油，搅匀；将卡波姆940缓慢投入上述溶液中，不断搅拌，静置24h，得空白胶，备用。将氢氧化钠溶液在搅拌下缓慢加入空白胶中，调节pH6.0-6.5，将配方量的化合物b-1用适量蒸馏水溶解，不断搅拌下，加到调好pH值的空白胶中，最后加入配方量油酸搅匀。称重，补加蒸馏水至总重，分装。
实施例23药物引发的胃溃疡的形成
参考Biochemical Pharmacology,2004(67):575-585中记载的方法进行试验。
将试验用雄性大鼠(体重约200g)断食24h，口服给予试验化合物，使给药剂量与洛索洛芬相等的摩尔量，12h后摘除胃部，测定胃内部产生的溃疡面积。对全部溃疡的面积进行合计，作为溃疡系数。对比药物是洛索洛芬，剂量是40mg/Kg。新化合物b-1，化合物b-2的给药剂量是相当于洛索洛芬40mg/Kg的用量。
结果如下：洛索洛芬的溃疡系数为9.4(mm2)，而化合物b-1的溃疡系数是2.2(mm2)，化合物b-2的溃疡系数是2.4(mm2)。这表明，新化合物b-1，b-2几乎不形成副作用的溃疡，胃部的溃疡面积很小，溃疡系数很低。
实施例24药物引发胃溃疡的对比试验
使用Wister系雄性大鼠(体重180-200g)，断食18h，口服等重量的试验化合物，8h后摘除胃，测定胃内部产生的溃疡面积。对全部溃疡的面积进行合计，作为溃疡系数。分别给予大鼠口服对比药物洛索洛芬，新化合物a-1，c-10，e-1，f-1，剂量都是20mg/Kg。试验结果如附图3所示。
实施例25镇痛试验(洛索洛芬和新化合物b-1，b-2的对小鼠扭体的抑制率)
对小鼠腹腔给药醋酸溶液后出现的扭体次数进行计数，并基于对照组计算扭体的抑制率。24只小鼠被分成了4个小组，每组6只。组A为对照组，给空白制剂；组B口服给予洛索洛芬40mg/Kg，组C、组D分别口服给予相当于洛索洛芬40mg/Kg剂量的化合物b-1，化合物b-2。在给药醋酸溶液60min前将被测化合物给药于小鼠，结果如表1所示。
表1扭体试验结果
组别 组A 组B 组C 组D
剂量(mg/Kg) 0 40 40 40
扭体次数 42.1 22.1 15.6 17.2
抑制百分率(％) 无 47 61 59
结果表明：化合物b-1与b-2的镇痛作用好于阳性药洛索洛芬。
实施例26镇痛试验(热板法)
取体重在18-22g的小鼠，每支小鼠放在55℃金属热板上，测定出现踢脚、舔后足、跳跃等疼痛反应所需潜伏期，取两次痛阈均值，为该小鼠痛阈均值，此值小于6秒或大于30秒者应剔除。取合格小鼠，随机分组，每组10只，溶媒对照组为0.5％CMC-Na，阳性对照组为洛索洛芬，试验组选用的化合物是化合物a-1，c-10，e-1，f-1。阳性对照组和试验组的使用剂量均为30mg/Kg。各组小鼠服药后，分别于60、90、120分钟时测定小鼠痛阈值。试验结果如表2所示。
表2热板试验结果
Figure PCTCN2016090764-appb-000053
本发明中所指出的a组、b组、c组、d组、e组、f组的其他化合物也具有类似效果。
实施例27抗炎试验(给药角叉菜胶的肿胀率试验)
将试验用雄性大鼠(体重约200g)断食24h，口服给予试验化合物，给药剂量与洛索洛芬是相等的摩尔量，1h后，向左足跖皮下注射1％角叉菜胶，从而引起浮肿，该角叉菜胶溶于100微升的生理盐水中，给药角叉菜胶后每隔1h测量一次大鼠后爪的体积，计算后爪的体积增长率来作为肿胀率(％)。组A为对照组，给空白制剂；组B口服给予洛索洛芬40mg/Kg，组C，组D分别口服给予相当于洛索洛芬40mg/Kg剂量的化合物b-1，化合物b-2。各个组别在不同时间点的肿胀率(％)结果如表3所示，结果表明：相同剂量的新化合物b-1与b-2的抗炎效果好于阳性药洛索洛芬。
表3角叉菜胶试验结果
Figure PCTCN2016090764-appb-000054
实施例28抗炎试验(小鼠耳二甲苯致炎实验)
取体重24-28g的小鼠，随机分组，每组10只，溶媒对照组为0.5％CMC-Na，阳性对照组为洛索洛芬，试验组选用的化合物是化合物a-1，c-10，e-1，f-1。阳性对照组和试验组的使用剂量均为30mg/Kg。各组小鼠分别给药后60分钟，将二甲苯0.05mL均匀滴于右耳廓，左耳对照，1小时后处死小鼠，用直径8mm打孔器在左、右耳同一部位打下圆耳片，称重，左右耳片重量差值即为肿胀程度。试验结果如表4所示。
表4二甲苯致炎试验结果
组别 肿胀程度(mg) 抑制率(％)
溶媒对照组 15.5 0
阳性对照组 11.4 26.45
a-1组 2.6 83.22
c-10组 4.2 72.90
e-1组 3.5 77.41
f-1组 3.8 75.48
本发明中所指出的a组、b组、c组、d组、e组、f组的其他化合物也具有类似效果。
实施例29化合物a-1注射液的局部毒性试验研究
(一)化合物a-1注射液的制备
将处方量的化合物a-1加入80％脱氧注射用水，40℃水浴条件下搅拌至全部溶解，用氢氧化钠或柠檬酸调节pH6.5-7.5，加入0.05％活性炭，减压抽滤，除去活性炭，溶液过0.22μm滤膜，灌装于每支20mg/10mL，30mg/10mL，40mg/10mL,或50mg/10mL的安瓿瓶中，121℃热压蒸汽灭菌10min。
(二)血管刺激性试验
依据《化学药物刺激性、过敏性和溶血性研究技术指导原则》，本次试验的药物浓度为4mg/mL，采用自身对照，左耳给药，右耳给予等量的0.9％氯化钠注射液，每天给药1次，连续给药3天，每次给药前、给药后，以及最后一次给药后24h、48h仔细观察给呀不为有无红斑、水肿等刺激性反应。最后一次给药48h后处死动物，去给药部位，作血管组织病理切片，检查血管时候有组织变性或坏死等刺激性反应。
试验结果：肉眼观察上述注射液组及0.9％氯化钠注射液组血管，在给药期及恢复期，均未见红斑、水肿、溃疡等刺激性症状；病理检查显示，每只兔耳的三个取材点均未 见血管内皮细胞肿胀、坏死，血管腔清晰，管腔内无血栓，血管周围组织无炎症细胞浸润或出血等病变。因此，该注射液对兔耳血管无刺激性作用。
(三)溶血试验
依据《化学药物刺激性、过敏性和溶血性研究技术指导原则》，本次试验的药物浓度为4mg/mL。取试管7支，按下表一次加入2％的红细胞混悬液和0.9％氯化钠注射液，混匀后按表5加入不同体积的供试品初始溶液，第6，7管分别为阴性和阳性。摇匀后，置37℃恒温箱中，开始每隔15min观察一次，1h后，每隔1h观察1次，观察4h，判断溶液是否出现溶血或红细胞聚集现象。
表5溶血试验试管编号
试管编号 1 2 3 4 5 6 7
2％红细胞悬液(mL) 2.5 2.5 2.5 2.5 2.5 2.5 2.5
氯化钠注射液(mL) 2.4 2.3 2.2 2.1 2.0 2.5 0
蒸馏水(mL) 0 0 0 0 0 0 2.5
供试品(mL) 0.1 0.2 0.3 0.4 0.5 0 0
试验结果：本次试验未见溶血作用，亦无红细胞凝聚现象。
实施例30试验药物在大鼠体内代谢速率的测定
试验方法：将对照药洛索洛芬以及试验药物(即化合物a-1，c-10，e-1，f-1)溶于生理盐水，配置得到10mg/mL的溶液。如遇不易完全溶清，则加入少量乙醇助溶。取体重180-220g的大鼠，随机分组，每组6只。按照20mg/Kg剂量，分别给予洛索洛芬组，a-1组，c-10组，e-1组，f-1组的大鼠，通过尾静脉注射药液。根据预设时间点，大鼠眼眶取血，收集血样，测定血药浓度，收集数据如表6所示。
表6大鼠体内代谢速度的试验结果
Figure PCTCN2016090764-appb-000055
应当说明的是，以上所述仅为本发明的较佳实施例而已，并不用于限制本发明的范围。凡在本发明的精神和原则之内所作出的任何修改、等同的替换和改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种如式I结构的芳基丙酸类化合物，以及其药学上可接受的盐，
    Figure PCTCN2016090764-appb-100001
    其中，取代基A选自：
    Figure PCTCN2016090764-appb-100002
    其中，G1或G2各自独立地表示羟基、直链或支链的C1～C6烷烃或直链或支链的C1～C6烷氧基；或G1、G2环合成含有杂原子的五元环、六元环或七元环；
    G3或G4各自独立地表示氢、羟基、直链或支链的C1～C6烷烃、直链或支链的C1～C6烷氧基或苯基；或G3、G4环合成含有杂原子的五元环、六元环或七元环；
    m＝2或3；
    n＝0～6；
    E为CH、C(CH3)或N；
    或者，取代基A选自氨基酸去掉羧基中的羟基后余下的基团。
  2. 根据权利要求1所述的化合物，其特征在于，式I结构化合物的盐选自钠盐、钙盐、锌盐、镁盐、葡甲胺盐、赖氨酸盐、精氨酸盐、组氨酸盐或氨丁三醇盐。
  3. 根据权利要求1所述的化合物，其特征在于，G1或G2各自独立地表示羟基、C1～C5烷烃或C1～C5烷氧基；G3或G4各自独立地表示氢、羟基、C1～C5烷烃或苯基；或G3、G4环合成含有氮原子的五元环、六元环或七元环。
  4. 根据权利要求1所述的化合物，其特征在于，
    当取代基A选自
    Figure PCTCN2016090764-appb-100003
    时，
    m选自2或3，
    n选自0、1、2、3或4；
    E选自CH、C(CH3)或N；
    G1或G2各自独立地选自羟基、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、甲氧基、乙氧基、丙氧基、异丙基氧基、异丁基氧基、叔丁基氧基或正戊基氧基；
    G3或G4各自独立地选自氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基或苯基；或者G3、G4环合成含有氮原子的五元环、六元环或七元环。
  5. 根据权利要求1所述的化合物，其特征在于，当取代基A是氨基酸去掉羧基中的羟基后余下的基团时，所述氨基酸选自甘氨酸、赖氨酸、精氨酸、组氨酸、半胱氨酸、苯丙氨酸、脯氨酸、天冬氨酸、亮氨酸、丙氨酸或甲硫氨酸。
  6. 根据权利要求1所述的化合物，其特征在于，选自下列化合物：
    Figure PCTCN2016090764-appb-100004
    Figure PCTCN2016090764-appb-100005
  7. 根据权利要求1所述的化合物，其特征在于，选自下列化合物：
    Figure PCTCN2016090764-appb-100006
  8. 根据权利要求1所述的化合物，其特征在于，选自下列化合物：
    Figure PCTCN2016090764-appb-100007
  9. 一种药物组合物，其特征在于，包含如权利要求1-8中任一项所述的化合物，以及药学上可接受的辅料；该药物组合物的制剂形式选自片剂、胶囊剂、注射液、粉针剂、凝胶剂、乳膏剂、软膏剂或巴布剂。
  10. 权利要求1-8中任一项所述化合物在制备治疗下列疾病的药物中的医药用途，所述疾病选自：类风湿关节炎，骨性关节炎，腰痛症，肩关节周围炎，颈肩腕综合征的消炎和/或镇痛，手术后、外伤后或拔牙后的镇痛和/或消炎，急性上呼吸道炎解热和/或镇痛中的一种或几种。
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013014660A1 (en) * 2011-07-22 2013-01-31 Venantius Limited Indane dimers for use in the treatment of autoimmune inflammatory disease

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013014660A1 (en) * 2011-07-22 2013-01-31 Venantius Limited Indane dimers for use in the treatment of autoimmune inflammatory disease

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TANAKA, Y. ET AL.: "Species Differences in Metabolism of sodium 2-[4-(2-oxocyclopentylmethyl) phenyl]propionate dihydrate (loxoprofen sodium), a New Antiinflammatory Agent", CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 31, no. 10, 31 December 1983 (1983-12-31), pages 3656 - 3664, XP055348095 *

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