CN115536525B - S- (+) -flurbiprofen salt and preparation method, pharmaceutical composition and application thereof - Google Patents

S- (+) -flurbiprofen salt and preparation method, pharmaceutical composition and application thereof Download PDF

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CN115536525B
CN115536525B CN202211170689.3A CN202211170689A CN115536525B CN 115536525 B CN115536525 B CN 115536525B CN 202211170689 A CN202211170689 A CN 202211170689A CN 115536525 B CN115536525 B CN 115536525B
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flurbiprofen
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CN115536525A (en
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石江涛
付海舰
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Nanjing Zhihe Medical Technology Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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]
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • 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
    • C07C229/04—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
    • C07C229/26—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 more than one amino group bound to the carbon skeleton, e.g. lysine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention relates to a S- (+) -flurbiprofen salt derivative, a compound shown as a formula (I) as well as a preparation method, a pharmaceutical composition and application thereof.

Description

S- (+) -flurbiprofen salt and preparation method, pharmaceutical composition and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method and application of salts, stereoisomers, hydrates and solvates formed by S (+) -flurbiprofen and basic amino acid.
Background
Flurbiprofen is a clinically commonly used nonsteroidal anti-inflammatory drug, and since 1977, has been put on the market, it is widely used for treating rheumatic arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, etc., and also for treating soft tissue diseases (such as sprains and strains) and light and moderate pain (such as dysmenorrhea and postoperative pain, toothache, etc.). The anti-inflammatory effect and the analgesic effect of flurbiprofen are respectively 250 times and 50 times of that of aspirin, and the effect and the tolerance are stronger than those of similar ibuprofen, and the toxicity is low.
Flurbiprofen is a chiral drug, and chiral centers exist in molecules, and has a pair of enantiomers of S type and R type. The racemate thereof is clinically used at present, however, the antiphlogistic activity of flurbiprofen is mainly derived from the (S) -enantiomer thereof, while the (R) -enantiomer lacks significant cyclooxygenase inhibitory activity (Japanese patent laid-open No. Hei 8-119859); furthermore, the gastrointestinal side effects of the racemate are greatly enhanced by the presence of the (R) -enantiomer. Regarding analgesic activity, literature (Experientia 1991,47 (3), 257-261) shows that the R (-) -flurbiprofen isomer exerts analgesic effects by acting on cellular kinases, with effects comparable to the S configuration. The resolution and synthesis of S (+) -flurbiprofen are reported in the patent (WO 2010001103, WO2015145163, US3959364A, CN 201680057083.5).
Flurbiprofen is a white or off-white crystalline powder at room temperature. The flurbiprofen is a salt with a high pH-dependent solubility, and the solubility is greatly influenced by pH. In addition, because of limited physicochemical properties, various APIs are often adopted in the formulations related to flurbiprofen on the market at present, such as flurbiprofen ester for injection, flurbiprofen sodium for eye drops, and the like, so that it is necessary to develop new flurbiprofen derivatives to improve the drug effect and meet the requirements of all related formulation forms.
Disclosure of Invention
The invention provides a salt of S (+) -flurbiprofen and basic amino acid, a preparation method and a pharmaceutical composition thereof.
The water solubility of the derivative prepared by salifying S (+) -flurbiprofen and basic amino acid is obviously higher than that of salts formed by salifying agents such as tromethamine and the like, and the salt compound has stronger anti-inflammatory and analgesic effects; in addition, it has been unexpectedly found that the gastrointestinal side effects of the derivatives prepared by salifying S (+) -flurbiprofen with basic amino acids in the present invention are significantly reduced; when used in eye drops, the compound has better anti-inflammatory effect and lower eye irritation.
The invention provides a preparation method, a pharmaceutical composition and application of a derivative, a stereoisomer, a hydrate or a solvate thereof after salt formation of S (+) -flurbiprofen and basic amino acid.
In one aspect, the invention provides a S (+) -flurbiprofen salt derivative, hydrate or solvate according to formula (I);
in the formula (I), wherein,
r is selected from basic amino acids including, but not limited to, the following structures: d-arginine, D-lysine, D-histidine, D-ornithine, L-arginine, L-lysine, L-histidine, L-ornithine.
Further, the S (+) -flurbiprofen axetil derivative has the following structure:
in another aspect, the present invention provides a method for preparing the above-mentioned S (+) -flurbiprofen salt, which comprises the following steps:
(1) The racemized flurbiprofen and S-1-phenylethylamine form salt, split and disalt to obtain S (+) -flurbiprofen pure product;
(2) And (3) reacting the S (+) -flurbiprofen pure product obtained in the step (1) with basic amino acid to obtain the S (+) -flurbiprofen salt derivative.
In the above embodiment, the preparation method includes the steps of:
(1) Dissolving racemic flurbiprofen in an organic solvent 1, dropwise adding an organic solvent 2 solution of S-1-phenylethylamine in a reflux state to form salt, and obtaining a pure product of S (+) -flurbiprofen through cooling, crystallization, recrystallization, purification and salt decomposition;
(2) And reacting the obtained S (+) -flurbiprofen pure product with basic amino acid under a reflux state to obtain the S (+) -flurbiprofen salt derivative.
Further, in the step (1), the solvent used in the salt forming process with the S-1-phenylethylamine is one or a combination of several of methanol, ethanol, ethyl acetate, butyl acetate, isopropyl ether, dichloromethane, chloroform, tetrahydrofuran, acetone, acetonitrile, 1, 4-dioxane, toluene and xylene.
Further, in the step (1), the solvent used for recrystallization purification is one or a combination of several of methanol, ethanol, ethyl acetate, butyl acetate, isopropyl ether, methylene dichloride, chloroform, tetrahydrofuran, acetone, acetonitrile, 1, 4-dioxane, toluene, xylene and water.
Further, in the step (1), the organic solvent used in the salt decomposition process is one or a combination of several of methanol, ethanol, ethyl acetate, butyl acetate, isopropyl ether, methylene dichloride, chloroform, toluene and xylene.
Further, in the step (2), the S (+) -flurbiprofen reacts with basic amino acid to obtain S (+) -flurbiprofen salt derivative, and the solvent used in the process is one or a combination of several of methanol, ethanol, isopropanol, tertiary butanol, acetone, acetonitrile, ethyl acetate, butyl acetate, isopropyl ether, dichloromethane, 1-chlorobutane trichloromethane, tetrahydrofuran, toluene, xylene and water.
Further, in the step (2), the molar ratio of the S (+) -flurbiprofen to the basic amino acid used in the salification process is 1:0.4-1:1.5.
The infrared spectrum of the compound shows that the carbonyl stretching vibration peak moves to a low wave number after salification, which indicates that the compound has salified.
Further, the preparation of the S (+) -flurbiprofen salt derivative is prepared by adding pharmaceutically required auxiliary materials into the S (+) -flurbiprofen salt derivative.
Further, the preparation formulation of the S (+) -flurbiprofen axetil comprises, but is not limited to: tablets, capsules, powders, granules, pills, suspensions, syrups, drop pills, ointments, plaster, cataplasm, patches, films, injections, eye drops or sprays.
Further, in the preparation of the S (+) -flurbiprofen axetil derivative, the content range of the S (+) -flurbiprofen axetil derivative is as follows: 0.001% -80% (W/W%).
Further, the S (+) -flurbiprofen salt derivative has obvious activity of inhibiting Cyclooxygenase (COX).
Further, the S (+) -flurbiprofen salt derivative and the pharmaceutical composition are used for treating rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and the like, and can also be used for treating soft tissue diseases such as sprains and strains, and mild to moderate pains such as dysmenorrhea, postoperative pain, toothache and the like.
Further, the S (+) -flurbiprofen axetil derivative and the pharmaceutical composition are used for anti-inflammatory after operation and treating inflammatory reaction after laser trabeculoplasty and other anterior segment inflammation. Preventing and treating macular cystoid edema after cataract intraocular lens implantation. Also used for treating giant papillary conjunctivitis. The application in inhibiting pupil constriction in the intraocular operation and the like.
The derivative prepared by salifying S (+) -flurbiprofen and basic amino acid has the characteristic of high water solubility;
the derivative prepared by salifying S (+) -flurbiprofen and basic amino acid has better anti-inflammatory and analgesic effects;
in addition, it has been unexpectedly found that the gastrointestinal side effects of the derivatives prepared by salifying S (+) -flurbiprofen with basic amino acids in the present invention are significantly reduced; when used in eye drops, the compound has better anti-inflammatory effect and lower eye irritation.
Drawings
FIG. 1 shows the effect of S (+) -flurbiprofen axetil on a model of pain in mice due to glacial acetic acid, showing that the analgesic activity is high as the number of twists of mice is small.
The specific embodiment is as follows:
unless otherwise indicated, the following specific examples are given by way of general procedures in the art:
embodiment one: resolution of S (+) -flurbiprofen isomer
Step 1: preparation of S-flurbiprofen/S-1-phenylethanamine salt
(RS) -flurbiprofen (3.0 kg) was charged to a 20L jacketed glass reactor. Methanol (2.0L) and toluene (8.0L) were added. The mixture was heated to dissolve the solids. S-1-phenylethylamine (1.49 kg) was dissolved in toluene (3L) and the solution was added to a 20L reactor with stirring at 60℃for about 30 minutes. The mixture was gradually cooled to 0 ℃ to 5 ℃ to cause crystallization. The crystals were filtered off, washed with toluene (3L) and dried in a vacuum oven at 55deg.C to give crude S-flurbiprofen/S-1-phenylethanamine salt (2.8 kg) in 62.4% yield.
The crude S-flurbiprofen/S-1-phenylethanamine salt (2.8 kg) was charged to a 20L jacketed glass reactor. Toluene (12.0L) and methanol (2.5L) were added, and the mixture was stirred and heated to 60℃to dissolve the solids. The solution was gradually cooled to 0 ℃ to 5 ℃ to cause crystallization. The crystals were filtered off, washed with toluene (4L) and dried in a vacuum oven at 55℃to give a refined S-flurbiprofen/S-1-phenethylamine salt (2.05 kg) in 73.2% yield.
Step 2: preparation of S-flurbiprofen
S-flurbiprofen/S-1-phenylethanamine salt concentrate (1.2 kg) was added to a 10L jacketed glass reaction flask. Toluene (4L) was added with stirring. Water (1.0L) and concentrated hydrochloric acid (0.5L) were added to the solution, and the mixture was stirred at 60 ℃. The lower aqueous layer was separated and the upper organic layer was retained. The hydrochloric acid wash was repeated, followed by washing the toluene solution with water. Additional toluene (0.7L) was added and then toluene (2.0L) was distilled off to ensure that the solution was free of water. The toluene solution was gradually cooled to-10 ℃ to cause crystallization. The crystals were filtered off, washed with n-heptane (1.0L) and dried in a vacuum oven at 40℃to give S-flurbiprofen (0.6 kg) in 74.8% yield. The total yield was 34.2% (calculated as flurbiprofen). Purity: 99.2%. Methanol is used as a solvent to prepare the aqueous solution, 1 H-NMR(300MHz,CDCl 3 )δ7.45-7.56(m,2H),7.29-7.47(m,4H),7.12-7.26(m,2H),3.75-3.84(m,1H),1.38-1.59(d,3H)。
embodiment two: preparation of S (+) -flurbiprofen L-arginine salt (DSC 5001)
S (+) -flurbiprofen (2.44 g,10.0 mmol) is added into 25.0mL of ethanol and water mixed solvent (20:1, V/V), L-arginine (compound 1,1.91g,11.0 mmol) is added into the mixed solvent, the mixture is heated to reflux and fully dissolved, the reflux is continued for 2.0h, cooling crystallization is carried out, white solid is separated out, filtration is carried out after the mixture is cooled to room temperature, the obtained filter cake is leached by ethanol (5.0 mL multiplied by 2), and the obtained solid is dried in vacuum for 12h at 50 ℃ to obtain 1.46g of product DSC5001, the yield: 35%, purity: 98.7%. 1 H-NMR(400MHz,H 2 O)δ7.36-7.45(m,2H),7.29-7.33(m,4H),7.04-7.09(m,2H),3.53-3.63(m,2H),3.02-3.07(m,2H),1.72-1.79(m,2H),1.44-1.60(m,2H),1.30-1.32(d,3H)。
Embodiment III: preparation of S (+) -flurbiprofen L-lysine salt (DSC 5003)
S (+) -flurbiprofen (2.44 g,10.0 mmol) is added into a mixed solvent of ethanol and water (4:1, V/V), L-lysine (compound 3,1.62g,11.0 mmol) is added into the mixed solvent, the mixture is heated to reflux and fully dissolved, the reflux is continued for 2.0h, cooling crystallization is carried out, white solid is separated out, the mixture is filtered after being cooled to room temperature, the obtained filter cake is leached by water (5.0 mL multiplied by 2), and the obtained solid is dried in vacuum for 12h at 50 ℃ to obtain 2.47g of product DSC5003, the yield: 63%, purity: 98.4%. 1 H-NMR(400MHz,H 2 O)δ7.49(m,2H),7.35-7.42(m,4H),7.12(m,2H),3.59-3.64(m,2H),2.91(m,2H),1.79(m,2H),1.60-1.62(m,2H),1.30-1.40(m,5H)。
Embodiment four: preparation of S (+) -flurbiprofen D-histidine salt (DSC 5006)
S (+) -flurbiprofen (2.44 g,10.0 mmol) was taken and added to 100mL absolute ethanolTo this, D-histidine (Compound 6,1.70g,11.0 mmol) was added, and the mixture was heated to reflux for total dissolution, and then refluxed for 5.0 hours, cooled to crystallize, and a white solid was precipitated, cooled to room temperature and then filtered, and the obtained cake was rinsed with absolute ethanol (5.0 mL. Times.2), and the obtained solid was dried under vacuum at 50℃for 12 hours to give 1.56g of the product DSC5006. Yield: 39%. Purity: 98.1%. 1 H-NMR(400MHz,H 2 O)δ7.59(s,1H),7.35-7.41(m,2H),7.24-7.30(m,4H),7.07-7.09(m,2H),6.87(s,1H),3.79-3.82(m,2H),2.97-3.01(m,2H),1.33-1.34(d,3H)。
Fifth embodiment: preparation of S (+) -flurbiprofen D-ornithine salt (DSC 5008)
S (+) -flurbiprofen (2.44 g,10.0 mmol) was added to 20.0mL of ethanol and water mixed solvent (4:1, V/V), ornithine (compound 8,1.45g,11.0 mmol) was added thereto, heating was performed until reflux was complete, reflux was continued for 2.0h, cooling crystallization was performed, white solid was precipitated, filtration was performed after cooling to room temperature, the obtained filter cake was rinsed with absolute ethanol (5.0 mL. Times.2), and the obtained solid was dried under vacuum at 50℃for 12h to obtain 2.67g of product DSC5008. Yield: 71%. Purity: 98.5%. 1 H-NMR(400MHz,H 2 O)δ7.44-7.54(m,2H),7.32-7.42(m,4H),7.09-7.17(m,2H),3.52-3.58(m,2H),2.70-2.73(m,2H),1.64-1.90(m,2H),1.28-1.32(m,5H)。
The following examples were synthesized in the same manner as in the above examples, using commercially available compounds or intermediate compounds appropriately synthesized from the commercially available compounds.
Comparative example one: preparation of S (+) -flurbiprofen tromethamine salt (SDB-1)
A solution of S (+) -flurbiprofen (2.44 g,10 mmol) and 1-chlorobutane (25 mL) was heated to 70℃and after dissolution, a mixed solution of tromethamine (compound 9,1.21g,10 mmol), methanol (10 mL) and 1-chlorobutane (25 mL) was added dropwise. After stirring for 2h, cooling and crystallizing. Suction filtration and drying overnight at 50℃under reduced pressure gave 1.5g of the product SDB-1 as a white solid in yield: 41%. 1 H-NMR(400MHz,H 2 O)δ7.39-7.42(m,2H),7.28-7.33(m,2H),7.20-7.26(m,2H),7.07-7.14(m,2H),3.54-3.68(m,7H),1.34-1.36(d,3H)。
Comparative example two: preparation of S (+) -flurbiprofen piperazine salt (SDB-2)
S (+) -flurbiprofen (2.44 g,10.0 mmol) is taken and added into 50mL of absolute ethanol, piperazine (compound 14,0.86g,10.0 mmol) is added into the absolute ethanol, the mixture is heated to reflux and fully dissolved, the reflux is continued for 5.0h, cooling crystallization is carried out, white solid is separated out, the mixture is filtered after being cooled to room temperature, the obtained filter cake is leached by absolute ethanol, the obtained solid is dried in vacuum for 12h at 50 ℃ to obtain 1.75g of product SDB-2, the yield is: 53%. Purity: 98.5%. 1 H-NMR(400MHz,H 2 O)δ7.35-7.40(m,2H),7.27-7.30(m,2H),7.20-7.24(m,2H),7.09-7.17(m,2H),5.57(q,1H),3.38-3.46(m,4H),3.24-3.33(m,4H),1.43(d,3H)。
Comparative example three: synthesis of RS-flurbiprofen-L-lysine salt (SDB-3)
Completely according to the DSC5003 synthesis method, racemic flurbiprofen (RS-flurbiprofen) is used as a raw material to synthesize RS-flurbiprofen-L-lysine salt (SDB-3).
Example six: solubility test of S (+) -flurbiprofen salt derivatives in water
The solubility of the S- (+) -pranoprofen salt derivative in water is tested according to the method for measuring the solubility of the valve in the 2020 edition of Chinese pharmacopoeia:
the test method comprises the following steps: weighing a proper amount of the test sample ground into fine powder, adding the fine powder into water with a certain volume at 25+/-2 ℃, shaking forcefully for 30 seconds every 5 minutes, and observing the dissolution condition within 30 minutes, wherein the dissolution condition is regarded as complete dissolution when no solute particles are visible. The test results are shown in table 1 below:
table 1: solubility of S (+) -flurbiprofen salt derivatives in water
* Fold 1 relative to S (+) -flurbiprofen tromethamine salt;
* Fold 2 relative to S (+) -flurbiprofen
The results show that the solubility of S (+) -flurbiprofen amino acid salt in the present invention is much greater than the solubility of S (+) -flurbiprofen and S (+) -flurbiprofen tromethamine salt.
Wherein the solubility of the S-flurbiprofen-L-lysine salt, the S-flurbiprofen-L-histidine salt, the S-flurbiprofen-D-ornithine salt and the S-flurbiprofen-D-lysine salt is increased by more than 6.7 times compared with the solubility of S-flurbiprofen-tromethamine salt; the solubility of S-flurbiprofen-L-arginine salt and S-flurbiprofen-D-arginine salt is increased by more than 2 times.
The solubility of the S-flurbiprofen-L-lysine salt, the S-flurbiprofen-L-histidine salt, the S-flurbiprofen-D-ornithine salt and the S-flurbiprofen-D-lysine salt is increased by more than 500 times compared with the solubility of the S-flurbiprofen; the solubility of S-flurbiprofen-L-arginine salt and S-flurbiprofen-D-arginine salt is increased by more than 150 times.
Embodiment seven: s (+) -flurbiprofen salt analgesic efficacy experiment
30 SPF-class female KM mice (manufacturer: S Bei Fu (Beijing) biotechnology Co., ltd.; license number: SCXK (Beijing) 2019-0010) were randomly divided into 5 groups of 6 animals each. Each group was aspirated with 1mL syringe (group 1 was sterile water for injection, the remaining 4 groups of samples were dissolved with sterile water for injection, wherein group 2 was DSC5003 in water, group 3 was DSC5004 in water, group 4 was SDB-1 in water, group 5 was SDB-3 in water), 0.2mL, groups 2 to 5 were all equimolar administered (calculated as flurbiprofen, dose was 5 mg/kg), the needle was introduced at the 2-3mm position between the two legs on the left of the abdominal line of the animal, the needle was withdrawn after the needle had entered the abdominal cavity, and solution injection was performed under vacuum conditions. After the last administration for 30min, 0.2mL of 0.6% glacial acetic acid was injected into the abdominal cavity of each mouse, and the time of each torsion reaction (abdomen contraction into S shape, body distortion, hindlimb extension, vermicular movement, etc.) and the number of torsion times of the mouse within 20min were recorded in detail. The results are shown in FIG. 1.
As can be seen from FIG. 1, the number of twists of each test sample group is smaller than that of the vehicle group, wherein the number of twists of the DSC5003 group and the DSC5004 group is smaller than that of the SDB-3 group, and the number of twists of the DSC5003 group and the DSC5004 group is unexpectedly found to be smaller than that of the SDB-1 group. This shows that the compounds DSC5003 and DSC5004 of the present invention have higher analgesic activity than the comparative compound SDB-3 (racemic flurbiprofen-L-lysine salt) and than the comparative compound SDB-1 (S-flurbiprofen tromethamine salt).
Example eight: preparation of S (+) -flurbiprofen salt eye drops
Taking about 900ml of physiological saline, controlling the temperature at 25+/-2 ℃, adding S (+) -flurbiprofen salt (0.3 g calculated by flurbiprofen), stirring until the S (+) -flurbiprofen salt is dissolved, adding the physiological saline to 1000ml, finely filtering, checking that the clarity is qualified, and carrying out sterile split charging to obtain the eye drop sample solution with the specification of 0.03 percent. The DSC5001 eye drops, DSC5004 eye drops, flurbiprofen sodium eye drops and SDB-1 eye drops are prepared according to the method. Filtration was performed using a microporous membrane of 0.22 μm before each use.
Example nine: s (+) -flurbiprofen salt derivative eye drop pharmacodynamic test
SPF-grade Japanese white rabbits, male, weight 2.0-2.2kg. Animal pass number: SCXK (Liao) 2020-0001. Animals and feeds were purchased from Liaoning long biotechnology limited, standard rabbit rearing cages, 1 animal/cage. The temperature is 25+/-2 ℃, and the food and the water can be taken freely. After 3 days of adaptive feeding, the culture was used for experiments. And adopting a self-comparison method of the left side and the right side of the homozygote. The eyes of each animal were examined with a magnifying glass and a fluorescein dye within 24 hours before the test, and the conjunctival blood vessel, the cornea transparency, the ocular secretion and the like of the eyes were recorded. Animals with symptoms of eye irritation, corneal defects, and conjunctival lesions cannot be used for the test. There were 15 rabbits at random, and each group was divided into 3 groups of 5 rabbits. All animals were given test samples to the left eye (group A was racemic flurbiprofen sodium eye drops; group B was DSC5001 eye drops; group C was DSC5004 eye drops) and physiological saline (negative control) to the right eye. Each group was dosed at 50 μl, with the microinjector accurately dosed, and the rabbit eyes were passively closed for 10s after each dose.
After the start of the experiment, each group was dosed once every 1h for a total of 6 times. After 30min after the 6 th eye drop, accurately dropping 50 mu L of 10% capsicum tincture by mass fraction into each eye microinjector, and continuing to drop the medicine for 4 times every 2 hours after 30 min; then, the time is changed to 6 hours, and 68 hours are continued. And (3) observing the local eye reaction condition at 6, 12, 24, 36, 48, 60 and 72 hours after eye drops of the capsicum tincture, slightly modifying the content of the eye irritation reaction score standard in the research technical guidelines of drug irritation, allergy and hemolysis issued by the eye inflammation judgment standard CDE on 5 th and 13 th 2014, respectively scoring the classified matters, cornea, iris and anterior chamber fluid, calculating average scores, and carrying out statistical treatment. The results are shown in Table 5:
table 5: results of pharmacodynamic test of S (+) -flurbiprofen salt eye drops
The average value of the scores of the ophthalmia in each experimental group is obviously lower than that of the physiological saline treatment group, which shows that the anti-inflammatory effect of the medicines in each experimental group is obviously better than that of the physiological saline. The eye inflammation scores of group a, group B and group C were not significantly different within 6-24 hours after eye inflammation of the capsicum tincture, but were significantly lower than group a within 36-72 hours after eye inflammation of the capsicum tincture, indicating that: compared with flurbiprofen sodium eye drops, the compound DSC5001 eye drops and DSC5004 eye drops have better effect of resisting ocular inflammation, and particularly after 24 hours of ocular inflammation, the compound DSC5001 eye drops and DSC5004 eye drops have better effect of resisting ocular inflammation.
Example ten: s (+) -flurbiprofen salt eye irritation test
SPF-grade Japanese white rabbits, male, weight 2.0-2.2kg. Animal pass number: SCXK (Liao) 2020-0001. Animals and feeds were purchased from Liaoning long biotechnology limited, standard rabbit rearing cages, 1 animal/cage. The temperature is 25+/-2 ℃, and the food and the water can be taken freely. After 3 days of adaptive feeding, the culture was used for experiments. And adopting a self-comparison method of the left side and the right side of the homozygote. The eyes of each animal were examined with a magnifying glass and a fluorescein dye within 24 hours before the test, and the conjunctival blood vessel, the cornea transparency, the ocular secretion and the like of the eyes were recorded. Animals with symptoms of eye irritation, corneal defects, and conjunctival lesions cannot be used for the test.
Adult male rabbits were randomly divided into 3 groups of 5 animals. The method comprises the steps of adopting a self-contrast method on the left side and the right side of the same body, taking blank solvent (physiological saline) by the right eye of all animals in each group, taking DSC5001 eye drops by the left eye of the group A, taking DSC5004 eye drops by the left eye of the group B and taking SDB-1 eye drops by the left eye of the group C; the eyes of each animal were examined with a magnifying glass and a fluorescein dye within 24 hours before the test, and the conjunctival blood vessel, the cornea transparency, the ocular secretion and the like of the eyes were recorded. Animals with symptoms of eye irritation, corneal defects, and conjunctival lesions cannot be used for the test.
Single eye irritation experiments: in the experiment, 0.05ml of the test substance is dripped into the left eye of each animal, and the solvent is added into the right eye to serve as a blank control. The eyelid is then gently closed for about 10 seconds. During the observation, a fluorescein staining examination was performed, and a sodium fluorescein solution was dropped onto the cornea, which was then rinsed with sterilized normal saline after 1-5 minutes. If there is a lesion, a yellow-green fluorescent ring appears immediately around. Eyes were examined prior to dosing and 1, 2, 4, 24, 48 and 72 hours after dosing, no irritation was observed in all groups in the single dosing rabbit eye irritation experiments.
Multiple eye irritation experiments: the number of subjects administered per day should be the same as the frequency of clinical administration, 3 times per day, for 2 weeks continuously, with a fixed time of daily administration. Eyes were examined, including corneal fluorescein staining, prior to daily dosing and 1, 2, 4, 24, 48, and 72 hours after the last dose. If no irritation symptoms were seen at 72 hours.
The evaluation was performed according to the eye irritation response score criteria in the guidelines of the drug irritation, allergy and hemolysis study technology issued by CDE at 5.13 of 2014. The results are shown in Table 6.
Table 6: results of multiple ocular irritation experiments with S (+) -flurbiprofen salt
As is evident from table 6, the score of group C was significantly higher than that of the blank group (group D) and the two test article groups (group a and group B), indicating significantly lower eye irritation of the DSC5001 and DSC5004 eye drops than that of the SDB-1 eye drops.
Example eleven: experiment of influence of S (+) -flurbiprofen salt on rat body weight and gastrointestinal function
After 40 SD rats (180-220 g) were adaptively bred for 3 days, they were randomly divided into 4 groups of 10 animals each. Groups 1 to 3 were each given by gavage with 0.4ml of test suspension (S-flurbiprofen, DSC5004, SBD-2, each suspended in 1% aqueous methylcellulose), and three samples were given equimolar, 7.2mg/kg of flurbiprofen was calculated, and group 4 was the vehicle group, and the same volume of aqueous methylcellulose was given by gavage. Each group was dosed daily or vehicle 1 time, for 30 consecutive days, weighed on day 15 and day 30, respectively, and then analyzed against the body weight of each group on day 1 to evaluate the body weight change. The results are shown in Table 7.
Table 7:S (+) -flurbiprofen salt changes in weight of rats (unit: g) after prolonged administration
Grouping Number of animals 15 days 15 days body weight change Number of animals for 30 days Weight change of 30 days
S-flurbiprofen 10 7.5±5.8 10 12.9±6.1
DSC5004 group 10 11.3±6.3 10 18.7±5.5
SBD-2 group 10 6.8±5.2 10 13.3±5.7
Solvent group 10 14.7±6.2 10 20.1±6.6
As can be seen from the above table, the animals survived 30 days after administration. The weight gain was reduced in the other animals compared to the vehicle group, wherein the weight gain was lower in the S-flurbiprofen and SDB-2 groups than in the DSC5004 group, which means that S-flurbiprofen and SDB-2 significantly reduced the weight gain in the rats, and thus the effect on gastrointestinal function in the rats was judged to be greater, and the effect on the weight gain in the rats by DSC5004 was judged to be less, and thus the effect on gastrointestinal function in the rats was judged to be relatively less.
The present application describes a number of embodiments, but the description is illustrative and not limiting and it will be apparent to those of ordinary skill in the art that many more embodiments and implementations are possible within the scope of the embodiments described herein.

Claims (8)

1. An S (+) -flurbiprofen salt derivative:
2. a pharmaceutical composition comprising the S (+) -flurbiprofen axetil derivative according to claim 1 and pharmaceutically acceptable excipients.
3. The pharmaceutical composition according to claim 2, wherein the content of S (+) -flurbiprofen salt derivatives is in the range of: 0.001% -80% (W/W).
4. The pharmaceutical composition according to claim 2 or 3, wherein the formulation dosage form of the pharmaceutical composition comprises a dosage form of a tablet, capsule, powder, granule, pill, suspension, syrup, dripping pill, patch, film, injection, eye drop, or spray.
5. Use of the S (+) -flurbiprofen axetil derivative according to claim 1, or the pharmaceutical composition according to any one of claims 2-4, for the preparation of analgesic, and/or anti-inflammatory drugs.
6. Use of the S (+) -flurbiprofen salt derivative according to claim 1, or the pharmaceutical composition according to any one of claims 2 to 4, for the preparation of a medicament for the treatment of rheumatoid arthritis, osteoarthritis, or ankylosing spondylitis, or soft tissue disease, or mild to moderate pain.
7. The use according to claim 6, wherein the soft tissue disease is sprain or strain; the mild to moderate pain is dysmenorrhea, postoperative pain or toothache.
8. Use of the S (+) -flurbiprofen salt derivative according to claim 1, or the pharmaceutical composition according to any one of claims 2-4, for the manufacture of a medicament for the treatment of a disease, wherein the disease is post-operative anti-inflammatory, treatment of inflammatory response after laser trabeculoplasty or other anterior ocular segment inflammation; macular edema after cataract intraocular lens implantation; giant papillary conjunctivitis; or pupil constriction in intraocular surgery.
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