S(+)-pranoprofen derivative, process for its preparation and use thereof

Abstract

The present invention relates to S(+)‑pranoprofen derivatives, such as compounds of the following formula (I), or hydrates, solvates, polymorphs, isotopic derivatives, pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions and uses.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to a S(+)-pranoprofen derivative, a preparation method and a pharmaceutical use thereof. BACKGROUND

[0002] Pranoprofen is a non-steroidal anti-inflammatory and analgesic drug developed by Welfide (formerly Yoshitomi Pharmaceutical Co., Ltd.), and its preclinical research began in 1972. Pranoprofen capsule was approved for marketing in 1981. Pranoprofen belongs to propionic acid drugs, which inhibits the synthesis of prostaglandins by inhibiting the activity of cyclooxygenase (COX) in the arachidonic acid cascade. By regulating the hypothalamic thermoregulatory center to inhibit the synthesis of prostaglandin E2, it has a stronger antipyretic effect than indomethacin and ibuprofen. At present, the use of non-steroidal anti-inflammatory drugs to eliminate inflammation and pain caused by inflammation is a widely recognized treatment method for diseases related to inflammation, such as synovitis, gout, lumbago, arthritis and the like. Pranoprofen has shown good efficacy in the fields of analgesia and anti-inflammatory. Clinical laboratory studies have also shown that pranoprofen has no obvious safety defects. So far, the marketed dosage forms include tablets, eye drops, capsules, oral solutions and syrup. All of its two isomers have different physiological activities, and the right-handed (S-type) pranoprofen has higher activity than the left-handed (R-type) pranoprofen.

[0003] Pranoprofen has good effects, but its inherent physicochemical property defects limit its application, and further improvement is needed. SUMMARY

[0004] The present application provides a S(+)-pranoprofen derivative and a preparation method thereof, thereby improving the physicochemical properties, cytotoxicity and pharmacokinetic characteristics of pranoprofen.

[0005] The present application first provides a S(+)-pranoprofen derivative as shown in the following general formula (I), or a hydrate, a solvate, a polymorph, an isotopic derivative, a pharmaceutically acceptable salt thereof:

[0006]

[0007] In formula (I), X is selected from C1-C4 alkylene substituted with one or more groups A or unsubstituted;

[0008] L is selected from -O-, -OC(O)O-, -NHC(O)O-, -OC(O)NH-, -NHC(O)NH-, -OC(O)-;

[0009] R1is selected from hydrogen, or the following groups substituted or unsubstituted by one or more groups B: C1-C8alkyl, C1-C8alkoxy, C1-C6alkylamino, C2-C8alkenyl, C2-C8alkynyl, C3-C8carbocyclyl, C2-C8heterocyclyl, C5-C18aryl, C3-C12heteroaryl;

[0010] said group A is selected from: hydrogen, methyl, hydroxyl or amino substituted methyl;

[0011] said group B is selected from: amino, hydroxyl, cyano, carboxyl, nitro, halogen, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, acetyl.

[0012] Unless otherwise specifically defined herein, the professional terms used in the present application have the same meaning as commonly understood by one of ordinary skill in the art.

[0013] In the embodiments of the present application, the heteroatom refers to nitrogen (N), oxygen (O), sulfur (S) atom.

[0014] In the embodiments of the present application, the C1-C4alkylene refers to a fatty alkylene group containing only 1-4 carbon atoms and hydrogen atoms, and the C1-C4alkyl includes but is not limited to methylene, ethylene, propylene, isopropylene, butylene, isobutylene, etc.; the C1-C8alkyl refers to a fatty alkyl group containing only 1-8 carbon atoms and hydrogen atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.

[0015] In the embodiments of the present application, the C1-C8alkoxy refers to a substituent containing 1-8 carbon atoms of alkyl and oxygen atoms, wherein the alkyl is as described above, and the C1-C8alkoxy includes but is not limited to methoxy, ethoxy, methylethoxy, ethoxymethyl, ethoxyethyl, etc.

[0016] In the embodiments of the present application, the C1-C6alkylamino refers to a substituent containing 1-6 carbon atoms of alkyl and nitrogen atoms, wherein the alkyl is as described above, and the C1-C6alkylamino includes but is not limited to methylamine, ethylamine, methylethylamine, N-ethylpropyl, etc.

[0017] In embodiments of the application, the C2-C8 alkenyl group refers to a fatty hydrocarbon group consisting of 2 to 8 carbon atoms containing at least one unsaturated carbon-carbon double bond, including straight chain, branched chain, or cyclic alkenes, and also including hydrocarbyl groups substituted with alkenyl groups and alkenyl groups substituted with hydrocarbyl groups, wherein the alkenyl group can be internal or terminal to the carbon chain or ring, and including but not limited to allyl, 2-butenyl, cis-2-pentenyl, cyclopentenyl, 2-methyl-2-pentenyl, 1,3-cyclohexadienyl, and the like.

[0018] In embodiments of the application, the C2-C8 alkynyl group refers to a fatty hydrocarbon group consisting of 2 to 8 carbon atoms containing at least one unsaturated carbon-carbon triple bond, including straight chain, branched chain, or cyclic alkynes, and also including hydrocarbyl groups substituted with alkynyl groups and alkynyl groups substituted with hydrocarbyl groups, wherein the alkynyl group can be internal or terminal to the carbon chain or ring, and including but not limited to ethynyl, hexynyl, 5-methyl-1-alkynyl, ethynyl, 2-butynyl, 1-butyne-4-yl, and the like.

[0019] In embodiments of the application, the C3-C8 carbocyclyl group refers to a saturated or unsaturated cyclic hydrocarbyl group consisting of 3 to 8 carbon atoms, and including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and the like.

[0020] In embodiments of the application, the C2-C8 heterocyclyl group refers to a monovalent saturated or unsaturated ring group consisting of 1 to 3 rings and 1 to 4 heteroatoms (selected from N, O, or S) and 2 to 8 carbon atoms, and including but not limited to oxiranyl, oxetanyl, aziridinyl, piperidinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, morpholinyl, and the like.

[0021] In embodiments of the application, the C5-C18 aryl group refers to a ring group having 1 to 3 aromatic carbon ring systems containing 5 to 18 carbon atoms, such rings include fused or non-fused, and the fused rings can be fully saturated, partially unsaturated, or fully unsaturated. Wherein the term "fused" means that the second ring is attached to the first ring by sharing 2 carbon atoms. The C5-C18 aryl group includes but is not limited to phenyl, naphthyl, biphenyl, benzo[b][1,4]oxazin-3(4H)-onyl, tetrahydronaphthyl, and the like.

[0022] In the embodiments of the present application, the C3-C12 heteroaryl group refers to a group containing one or more fused aromatic ring structures with 1-4 heteroatoms (i.e. N, O or S) and 3-12 carbon atoms, and the fused ring can be fully saturated, partially unsaturated or fully unsaturated. The C3-C12 heteroaryl group includes, but is not limited to, pyridyl, pyrazinyl, pyridazinyl, triazolyl, imidazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl, triazinyl, purinyl, benzoxazolyl, benzofuranyl, benzothiazolyl, indolyl, etc. Further, the C3-C12 heteroaryl group also includes N-oxides of nitrogen-containing heterocycles.

[0023] In the embodiments of the present application, the S(+)-pranoprofen refers to a substance substantially free of R(-)-pranoprofen isomer, and preferably contains S(+)-pranoprofen in a mass fraction of at least 90%, more preferably ≥ 99.5%.

[0024] In the embodiments of the present application, the tablet refers to a solid drug prepared by compression, granulation, enteric coating, sugar coating, film coating or multiple compression with suitable excipients such as binders, diluents, disintegrants, colorants, flavoring agents, preservatives, etc.

[0025] In the embodiments of the present application, the liquid oral agent refers to a liquid and / or suspension prepared from aqueous and non-aqueous solutions, emulsions, suspensions, etc., which can contain suitable solvents, preservatives, diluents, sweeteners, taste masking agents, colorants, etc.

[0026] Further, the pharmaceutically acceptable salt of the S(+)-pranoprofen derivative includes inorganic acid salts and organic acid salts thereof.

[0027] In the preparation route of the present application, the pranoprofen raw material can be synthesized according to the prior art.

[0028] Further, the compound has the following structure:

[0029]

[0030]

[0031] Further, the S(+)-pranoprofen derivative or its hydrate, solvate, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof is used as a cyclooxygenase inhibitor for the preparation of a drug for preventing and / or treating inflammation-related diseases.

[0032] Further, the inflammation and inflammation-related diseases include one or more of rheumatoid arthritis, arthroncus, lumbago, neck-shoulder-wrist syndrome, periodontitis, common cold, acute respiratory inflammation, post-traumatic and post-surgical inflammation, blepharitis, conjunctivitis, keratitis, scleritis, episcleritis, trachoma, uveitis, lacrimal gland inflammation, lacrimal sac inflammation, and corneal ulcer.

[0033] Further, the S(+)-pranoprofen derivative or hydrate, solvate, polymorph, isotopic derivative, or pharmaceutically acceptable salt thereof is used for preparing a drug for preventing and / or treating gout.

[0034] Further, the pharmaceutical composition comprises the S(+)-pranoprofen derivative or hydrate, solvate, polymorph, isotopic derivative, or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0035] Further, the pharmaceutically acceptable excipient comprises one or more of a filler, a binder, a diluent, a lubricant, a colorant, a buffer, a preservative, a taste masking agent, or a solubilizer.

[0036] Further, the pharmaceutical composition comprises the S(+)-pranoprofen derivative or hydrate, solvate, polymorph, isotopic derivative, or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0037] The series of compounds of the present application improves the cytotoxicity of the drug, has better distribution in ocular tissues, and has better stability at pH 7.4.

[0038] To make the person skilled in the art more clearly and comprehensively understand the present application, the following specific examples are further described in detail, but do not limit the present application in any way. It should be noted that, in the case of no conflict, the examples in the present application and the features in the examples can be combined with each other at will. DETAILED DESCRIPTION

[0039] In the following specific examples, the preparation and purification methods used are conventional methods in the art unless otherwise specified:

[0040] The synthesis of racemic pranoprofen and the chiral resolution of S(+)-pranoprofen are obtained by using the prior art.

[0041] In the following specific examples, the preparation and purification methods used are conventional methods in the art unless otherwise specified:

[0042] Example 1: Preparation of S(+)-pranoprofen

[0043] Reaction Scheme:

[0044]

[0045] Preparation Process:

[0046] Step 1: Preparation of Compound 1

[0047] Compound 1 was prepared by adding pranoprofen (255.27 g, 1.0 mol) into ethanol (4.0 L) and heating to reflux. The compound was dissolved completely during heating. Then, R(-)-naphthyl ethylamine (188.36 g, 1.1 mol) in ethanol (1.0 L) was slowly added into the solution. White solid was precipitated during the dropwise addition. After the dropwise addition was completed, the solution was refluxed for another 3.0 h. After cooling to room temperature, the solution was filtered. The obtained filter cake was washed with ethanol (200 mL x 2). The obtained solid was air-dried at 45 °C for 12.0 h to obtain crude Compound 1 (335.70 g) with a yield of 78.7%.

[0048] The obtained crude Compound 1 (335.00 g) was added into a mixed solvent of acetone and ethanol (12:1, V / V, 3.5 L) and heated to reflux. After the compound was dissolved completely, the solution was refluxed for another 2.0 h. After cooling to room temperature, the solution was filtered. The obtained filter cake was washed with the mixed solvent of acetone and ethanol (200 mL x 2). The obtained filter cake was air-dried at 45 °C for 12.0 h to obtain Compound 1. The above operation was repeated for 5 times. The obtained solid was collected to obtain refined Compound 1 (79.90 g) with a refined yield of 23.9%. The total yield was 18.8%.

[0049] Step 2: Preparation of S(+)-pranoprofen

[0050] Refined Compound 1 (79.00 g, 0.185 mol) was added into water (0.6 L) and adjusted to pH 3.0 by using concentrated hydrochloric acid under ice bath. The solution was heated to 60 °C and salted for 2.0 h. After cooling to room temperature, the solution was extracted with dichloromethane (1.0 L x 3). The combined organic phase was washed with saturated brine (1.0 L x 2). After drying with anhydrous sodium sulfate, the solution was concentrated. The residue was recrystallized with ethanol to obtain a solid. The solid was air-dried at 45 °C for 12.0 h to obtain pure S(+)-pranoprofen (35.74 g) with a yield of 75.6%. The total yield was 14.2% (calculated from pranoprofen). The purity was 99.7%. [M+H] + = 256.10. 1 H NMR (300 MHz, CDC13) δ: 7.52 (d, J = 6.5 Hz, 1H), 7.20-7.18 (m, 3H), 6.99 (s, 1H), 6.85-6.82 (m, 1H), 3.86 (s, 2H), 3.76-3.74 (m, 1H), 1.50 (d, J = 4.3 Hz, 3H).

[0051] Example 2: Synthesis of DSC4301

[0052] Reaction Scheme:

[0053]

[0054] Preparation Procedure:

[0055] To S(+)-pranoprofen (2.55 g, 0.01 mol) was added to tetrahydrofuran (50 mL), NaH (0.80 g, 0.02 mol) was added slowly under ice-bath, after stirring at room temperature for 30 min, bromomethyl methyl ether (2.50 g, 0.02 mol) was added slowly, after the addition was completed, the reaction was stirred at room temperature for 12.0 h, the solid was concentrated, ice water (25 mL) was added and stirred for 1.0 h, suction filtration, water washing (10 mL x 2), the obtained solid was purified by recrystallization with acetonitrile / water, and dried at 45 °C under air blast for 12.0 h to obtain DSC4301 refined product (1.35 g), yield: 45.2%. Purity: 98.1%. [M+H] + = 300.13. 1 H NMR (300 MHz, CDC13) δ: 7.54 (d, J = 6.2 Hz, 1H), 7.21-7.19 (m, 3H), 7.00 (s, 1H), 6.86-6.83 (m, 1H), 6.15 (s, 2H), 3.89 (s, 2H), 3.77-3.75 (m, 1H), 3.35 (s, 3H), 1.51 (d, J = 4.4 Hz, 3H).

[0056] Example 3: Synthesis of DSC4303

[0057] Reaction Scheme:

[0058]

[0059] Preparation Procedure:

[0060] To S(+)-pranoprofen (2.55 g, 0.01 mol) was added to tetrahydrofuran (50 mL), NaH (0.80 g, 0.02 mol) was added slowly under ice-bath, after stirring at room temperature for 30 min, chloromethyl isopropyl carbonate (3.05 g, 0.02 mol) was added slowly, after the addition was completed, the reaction was stirred at room temperature for 12.0 h, the solid was concentrated, ice water (25 mL) was added and stirred for 1.0 h, suction filtration, water washing (10 mL x 2), the obtained solid was separated by column chromatography to obtain DSC4303 refined product (1.08 g), yield: 29.1%. Purity: 98.7%. [M+H] + = 372.15. 1H NMR (300 MHz, CDC13) δ: 7.54 (d, J = 6.3 Hz, 1H), 7.21-7.19 (m, 3H), 7.01 (s, 1H), 6.87-6.84 (m, 1H), 6.24 (s, 2H), 5.07-5.05 (m, 1H), 3.90 (s, 2H), 3.77-3.75 (m, 1H), 1.50 (d, J = 4.3 Hz, 3H), 1.25-1.22 (m, 6H).

[0061] Example Four: Synthesis of DSC4305, DSC4306

[0062] Reaction Scheme:

[0063]

[0064] Preparation Process:

[0065] Synthesis of DSC4305:

[0066] S(+)-pranoprofen (2.55 g, 10.0 mmol) was added to dichloromethane (60 mL) under nitrogen protection, and sulfurous chloride (1.78 g, 15.0 mmol) was slowly added under ice bath. After stirring at room temperature for 30 min, the system was cooled to 0°C, and triethylamine (2.02 g, 20.0 mmol) was added. The above system was slowly added dropwise to a dichloromethane solution (60 mL) of ethylene glycol (6.21 g, 0.1 mol) under ice bath. After completion of the addition, the reaction was carried out at room temperature for 3.0 h. The product was washed with water (100 mL x 1) and saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, and concentrated. Column chromatography was used to separate the product to obtain refined DSC4305 (2.06 g) with a yield of 68.9%. The purity was 98.3%. [M+H] + = 300.14. 1 H NMR (300 MHz, CDC13) δ: 7.54 (d, J = 6.3 Hz, 1H), 7.21-7.19 (m, 3H), 7.01 (s, 1H), 6.87-6.84 (m, 1H), 6.24 (s, 2H), 5.07-5.05 (m, 1H), 3.90 (s, 2H), 3.77-3.75 (m, 1H), 1.50 (d, J = 4.3 Hz, 3H), 1.25-1.22 (m, 6H).

[0067] Synthesis of DSC4306:

[0068] DSC4305 (0.60 g, 2.0 mmol) was taken in dichloromethane (50 mL) and acetyl chloride (0.24 g, 3.0 mmol) was added slowly under ice bath and triethylamine (0.41 g, 4.0 mmol) was added drop wise slowly. After completion of addition, the reaction was allowed to proceed for 3.0 h at room temperature. The reaction mixture was washed with water (30 mL x 1) and saturated brine (30 mL x 1). The organic layer was dried over anhydrous sodium sulphate and concentrated. The crude product was purified by column chromatography to get DSC4306 (0.48 g) as a pure product. Yield: 70.1 %. Purity: 98.3 %. [M+H] + = 342.13. 1 H NMR (300 MHz, CDC13) δ: 7.53 (d, J = 6.4 Hz, 1H), 7.20-7.17 (m, 3H), 6.99 (s, 1H), 6.87-6.85 (m, 1H), 4.30-4.28 (m, 2H), 4.25-4.23 (m, 2H), 3.89 (s, 2H), 3.76-3.74 (m, 1H), 2.02 (s, 3H), 1.49 (d, J = 4.4 Hz, 3H).

[0069] Example Five: Synthesis of DSC4307

[0070] Reaction Scheme:

[0071]

[0072] Preparation Process:

[0073] Step 1: Synthesis of compound 3:

[0074] Compound 2 (glycerol, 9.21 g, 0.1 mol) was taken in dichloromethane (150 mL) and 1,3-bis[3,5-bis(trifluoromethyl)phenyl]thiourea (5.00 g, 10.0 mmol) and 1,4-dihydropyran (16.82 g, 0.2 mol) was added slowly under ice bath. After completion of addition, the reaction was allowed to proceed for 24.0 h at 50 °C. After completion of reaction, the reaction mixture was filtered through celite and the filter cake was washed with dichloromethane (30 mL x 3). The combined organic layer was concentrated and purified by column chromatography using basic alumina as packing material to get compound 3 (10.15 g) as a pure product. Yield: 38.7 %. It was used as such for the next reaction.

[0075] Step 2: Synthesis of compound 4:

[0076] S(+)-pranoprofen (2.55 g, 10.0 mmol) was taken in dichloromethane (60 mL) and under nitrogen protection, thionyl chloride (1.78 g, 15.0 mmol) was added slowly under ice bath. After stirring at room temperature for 30 min, the above system was added slowly dropwise to a dichloromethane solution (40 mL) of compound 3 (3.12 g, 12.0 mmol) at 0 °C under ice bath. After the addition was completed, the reaction was carried out at room temperature for 3.0 h. The reaction mixture was washed with water (50 mL x 1) and saturated brine (50 mL x 1), dried over anhydrous sodium sulfate and concentrated. Compound 4 was obtained as a refined product (2.58 g) by column chromatography, with a yield of 51.8%. It was directly used in the next step.

[0077] Step 3: Synthesis of compound DSC4307:

[0078] Compound 4 (1.00 g, 2.0 mmol) was taken in methanol (25 mL) and under nitrogen protection, ammonium chloride (0.10 g, 2.0 mmol) was added slowly under ice bath. The reaction was carried out at reflux for 2.0 h. After cooling to room temperature, the reaction mixture was filtered through celite. The filter cake was washed with methanol (10 mL x 3). The combined organic phase was concentrated. Compound DSC4307 was obtained as a refined product (0.33 g) by column chromatography, with a yield of 50.1%. Purity: 98.2%. [M+H] + = 330.13. 1 H NMR (300 MHz, CDCl3) δ: 7.53 (d, J = 6.2 Hz, 1H), 7.21-7.18 (m, 3H), 6.99 (s, 1H), 6.88-6.86 (m, 1H), 4.60-4.58 (m, 1H), 3.90 (s, 2H), 3.76-3.74 (m, 1H), 3.58-3.56 (m, 4H), 1.50 (d, J = 4.3 Hz, 3H).

[0079] Example Six: Synthesis of DSC4312

[0080] Reaction scheme:

[0081]

[0082] Preparation process:

[0083] Step 1: Synthesis of compound 5:

[0084] To compound 5 (0.60 g, 2.0 mmol) was taken in dichloromethane (30 mL) under nitrogen atmosphere, ethyl chloroformate (0.26 g, 2.4 mmol) and triethylamine (0.30 g, 3.0 mmol) were added slowly under ice bath, stirred for 2.0 h at room temperature, washed with water (10 mL x 1), saturated brine (10 mL x 1), dried over anhydrous sodium sulphate and concentrated, the obtained solid was purified by column chromatography to get DSC4312 pure (0.30 g), yield: 41%. Purity: 98.0%. [M+H] + = 299.12.

[0085] Synthesis of compound DSC4312:

[0086] To compound 5 (0.60 g, 2.0 mmol) was taken in dichloromethane (30 mL) under nitrogen atmosphere, ethyl chloroformate (0.26 g, 2.4 mmol) and triethylamine (0.30 g, 3.0 mmol) were added slowly under ice bath, stirred for 2.0 h at room temperature, washed with water (10 mL x 1), saturated brine (10 mL x 1), dried over anhydrous sodium sulphate and concentrated, the obtained solid was purified by column chromatography to get DSC4312 pure (0.30 g), yield: 41%. Purity: 98.0%. [M+H] + = 371.10. 1 H NMR (300 MHz, CDCl3) δ: 7.52 (d, J = 6.1 Hz, 1H), 7.19-7.17 (m, 3H), 6.97 (s, 1H), 6.86-6.84 (m, 1H), 4.30-4.28 (m, 2H), 3.89 (s, 2H), 3.90-3.88 (m, 2H), 3.74-3.71 (m, 1H), 3.13-3.10 (m, 2H), 1.48 (d, J = 4.2 Hz, 3H), 1.06 (t, J = 6.9 Hz, 3H).

[0087] Example Seven: Synthesis of DSC4314

[0088] Reaction scheme:

[0089]

[0090] Preparation process:

[0091] Compound 5 (0.60 g, 2.0 mmol) was taken in dichloromethane (30 mL) and isopropyl carbamoyl chloride (0.29 g, 2.4 mmol) and triethylamine (0.30 g, 3.0 mmol) was added slowly under ice bath. It was stirred for 2.0 h at room temperature. It was washed with water (10 mL x 1) and saturated brine (10 mL x 1). The organic phase was dried over anhydrous sodium sulphate and concentrated. The obtained solid was separated by column chromatography to get DSC4316 (0.28 g) as a pure product. Yield: 36.3 %. Purity: 98.5 %. [M+H] + = 385.12. 1 H NMR (300 MHz, CDCl3) δ: 7.52 (d, J = 6.1 Hz, 1H), 7.19-7.17 (m, 3H), 6.96 (s, 1H), 6.85-6.83 (m, 1H), 4.35-4.33 (m, 2H), 4.31-4.29 (m, 2H), 4.15-4.13 (m, 1H), 3.87 (s, 2H), 3.74-3.72 (m, 1H), 1.48 (d, J = 4.3 Hz, 3H), 1.15-1.13 (m, 6H).

[0092] Example Eight: Synthesis of DSC4316

[0093] Reaction Scheme:

[0094]

[0095] Preparation Process:

[0096] Compound 5 (0.60 g, 2.0 mmol) was taken in dichloromethane (30 mL) and isopropyl carbamoyl chloride (0.29 g, 2.4 mmol) and triethylamine (0.30 g, 3.0 mmol) was added slowly under ice bath. It was stirred for 2.0 h at room temperature. It was washed with water (10 mL x 1) and saturated brine (10 mL x 1). The organic phase was dried over anhydrous sodium sulphate and concentrated. The obtained solid was separated by column chromatography to get DSC4316 (0.28 g) as a pure product. Yield: 36.3 %. Purity: 98.5 %. [M+H] + = 384.13. 1H NMR (300 MHz, CDC13) δ: 7.51 (d, J = 6.2 Hz, 1H), 7.19-7.17 (m, 3H), 6.95 (s, 1H), 6.85-6.82 (m, 1H), 4.32-4.30 (m, 2H), 3.33-3.31 (m, 2H), 3.85 (s, 2H), 3.71-3.69 (m, 1H), 4.10-4.07 (m, 1H), 1.47 (d, J = 4.4 Hz, 3H), 1.14-1.12 (m, 6H).

[0097] Example Nine: Synthesis of DSC4319, DSC4321

[0098] Reaction Scheme:

[0099]

[0100] Preparation Process:

[0101] Synthesis of compound DSC4319:

[0102] S(+)-pranoprofen (2.55 g, 10.0 mmol) was taken in tetrahydrofuran (50 mL) and NaH (0.60 g, 15.0 mmol) was added slowly under ice bath and stirred for 1.0 h. Bromo methyl acetate (1.83 g, 12.0 mmol) was added to it and stirred for 3.0 h at room temperature. After completion of the reaction, it was filtered and concentrated to get brown solid. Dichloromethane (50 mL) was added to it and washed with water (30 mL x 1) and saturated brine (30 mL x 1). The organic phase was dried over anhydrous sodium sulfate and concentrated. The obtained solid was separated by column chromatography to get DSC4319 (1.35 g) as a pure product. Yield: 41.3 %. Purity: 98.8 %. [M+H] + = 328.11. 1 H NMR (300 MHz, CDC13) δ: 7.51 (d, J = 6.2 Hz, 1H), 7.19-7.17 (m, 3H), 6.95 (s, 1H), 6.85-6.82 (m, 1H), 4.32-4.30 (m, 2H), 3.33-3.31 (m, 2H), 3.85 (s, 2H), 3.71-3.69 (m, 1H), 4.10-4.07 (m, 1H), 1.47 (d, J = 4.4 Hz, 3H), 1.14-1.12 (m, 6H).

[0103] Synthesis of compound DSC4321:

[0104] S(+)-pranoprofen (2.55 g, 10.0 mmol) was taken in tetrahydrofuran (50 mL) under nitrogen protection, NaH (0.60 g, 15.0 mmol) was added slowly under ice bath, stirring was continued for 1.0 h, 1-bromoethyl acetate (2.00 g, 12.0 mmol) was added to it, after completion of addition, stirring was continued at room temperature for 3.0 h, after completion of reaction, it was filtered, concentrated to get brown solid, 50 mL dichloromethane was added, washed with water (30 mL x 1), saturated brine (30 mL x 1), dried over anhydrous sodium sulphate, concentrated, the obtained solid was separated by column chromatography to get DSC4321 (1.47 g), yield: 43.1%, purity: 98.3%. [M+H] + = 342.33. 1 H NMR (300 MHz, CDCl3) δ: 7.50 (d, J = 6.3 Hz, 1H), 7.17-7.15 (m, 3H), 6.94 (s, 1H), 6.85-6.83 (m, 1H), 6.55-6.53 (m, 1H), 3.84 (s, 2H), 3.70-3.67 (m, 1H), 2.19 (s, 3H), 1.78 (d, J = 4.4 Hz, 3H), 1.47 (d, J = 4.2 Hz, 3H).

[0105] The following example compounds were synthesized according to the same procedure as described in the above examples, using commercially available compounds or compounds synthesized appropriately from commercially available compounds:

[0106]

[0107]

[0108] Example Ten: MTT assay for determination of cytotoxicity of S(+)-pranoprofen derivatives

[0109] Human normal hepatocytes (HHL-5 cells) were seeded at 1 x 10 4 Human normal hepatocytes (HHL-5 cells) were seeded at 1 x 10 5The above, add pre-configured S (+) -pranoprofen derivative or pranoprofen solution 50 μL (containing 0.2% DMSO in culture medium), the final drug concentration is controlled to be 10 μM, each group is repeated three times, and after the addition of drug, it is placed in a 37°C incubator for incubation for 24h. MTT is prepared into 5.0mg / mL with PBS, 20 μL is added to each well, and after the addition is completed, it is placed into the incubator for incubation for 4.0h. The culture medium is removed, 200 μL of DMSO is added to each well, and after uniform shaking, the absorbance of each well is measured at 490nm wavelength. The absorbance value of the well without drug is taken as 100% cell survival, and the cell survival rate is calculated by using Graphpad Prism7.0 software, and the data is expressed as percentage. The data is as follows in Table 1:

[0110] Table 1: Cell survival rate determined by MTT method

[0111]

[0112] The experimental results show that the cytotoxicity of the S (+) -pranoprofen derivative of the application is significantly reduced compared with pranoprofen.

[0113] Example XI: Determination of chemical stability of S (+) -pranoprofen derivative

[0114] Take S (+) -pranoprofen derivative 100 mg and place it in a 100 mL volumetric flask. Methanol is used to dilute to 100 mL as a stock solution. Take 1.0 mL of the stock solution and place it in a 25 mL volumetric flask. Use 50.0 mM phosphate buffer solution (pH 7.4) preheated to (37.0±0.5) °C to dilute to the calibration mark. After the preparation is completed, it is placed in a (37.0±0.5) °C water bath for incubation and stirring. At 0, 24h, the purity change is determined by using HPLC (High Performance Liquid Chromatography) normalization method. The chromatographic column conditions are as follows: Waters XBridge C18 chromatographic column (250mm×4.6mm, 5μm), and the mobile phase is methanol / water (90:10). Each group of experiments is repeated three times, and the peak area of each S (+) -pranoprofen derivative at 0h is taken as 100%. The ratio of the HPLC peak area value of each S (+) -pranoprofen derivative solution tested at 24h to the peak area at 0h is taken as the evaluation index, and the hydrolysis of S (+) -pranoprofen derivative at 24h is calculated. The calculation results are as follows in Table 2:

[0115] Table 2: Degree of hydrolysis of S (+) -pranoprofen derivative in pH 7.4 buffer solution

[0116]

[0117]

[0118] The stability data show that the S(+)-pranoprofen derivative of the present application has good stability in a pH 7.4 buffer solution.

[0119] Example Twelve: Intraocular tissue distribution and pharmacokinetics study after intravenous injection

[0120] An appropriate amount of the compound DSC4303 with lower cytotoxicity and pranoprofen were weighed, a cosolvent DMSO was added, and after shaking to dissolve completely, a 0.22 μm microporous filter was used for filtration, and the solution was diluted with PBS (pH 7.4) and a physiological saline solution, and was ready for use.

[0121] Forty-two New Zealand rabbits (2.5-3.0 kg) without eye diseases were selected and randomly divided into a pranoprofen group and a DSC4303 group, 21 rabbits in each group. The pranoprofen group and the DSC4303 group were each randomly divided into 7 subgroups, 3 rabbits in each subgroup, 6 eyes in total. The New Zealand rabbits in each group were respectively injected intravenously with pranoprofen and the compound DSC4303 at 30 mg / kg, and were respectively air embolized at 0.5 h, 1.0 h, 2.0 h, 3.0 h, 4.0 h, 6.0 h, and 8.0 h after injection. The eyeballs were quickly removed and washed repeatedly with a physiological saline solution. The aqueous humor and vitreous body were extracted, and then the eyeball was opened to take out the cornea, iris ciliary body, and lens, which were dried by filter paper, weighed, cut into pieces, and homogenized in a test tube. 1 ml of the homogenate was taken and placed in a 10 ml test tube, 20 ul of an internal standard and 4 ml of dichloromethane were sequentially added, and oscillation was performed for 1 min, and centrifugation was performed for 1 min (4500 r / min). 3.0 ml of the dichloromethane layer was taken and placed in a 5 ml centrifuge tube, and was dried under a nitrogen gas at a 50℃ water bath, and was redissolved with 100 ul of a mobile phase, so that a sample for injection was prepared. In the pranoprofen group, racemic pranoprofen was detected, and in the DSC4303 group, S(+)-pranoprofen was detected. The obtained data were automatically fitted by 3p97 to obtain pharmacokinetic parameter values, and the experimental results are shown in Table 3.

[0122] Table 3: Intraocular tissue distribution and pharmacokinetic parameters after intravenous injection

[0123]

[0124]

[0125] Note: " / " represents undetected.

[0126] The data show that after pranoprofen and DSC4303 were injected in a single dose in New Zealand rabbits, except that the corresponding detection objects were not detected in the vitreous body tissue, compared with the pranoprofen group, DSC4303 has better ocular tissue distribution in the aqueous humor, cornea, iris ciliary body, and lens tissues of the eye in the DSC4303 group.

[0127] The present application describes a number of embodiments, but the description is exemplary rather than limiting, and those ordinarily skilled in the art can readily determine features of the present application, and there can be more embodiments and implementations within the scope of the embodiments described in the present application.

Claims

1. A S(+)-propranolol derivative of the following formula (I) or a pharmaceutically acceptable salt thereof: ###0001### (I) wherein, X is selected from C1-C4 alkylene substituted with one or more groups A or unsubstituted; L is selected from -O-, -OC(O)O-, -NHC(O)O-, -OC(O)NH-, -NHC(O)NH-, -OC(O)-; R1 is selected from hydrogen, or the following groups substituted with one or more groups B or unsubstituted: C1-C8 alkyl, C1-C8 alkoxy, C1-C6 alkylamino; said groups A are selected from: hydrogen, methyl; said groups B are: hydroxyl, halogen, methyl, ethyl.

2. The pharmaceutically acceptable salt of claim 1 includes inorganic acid salts, organic acid salts.

3. A S(+)-propranolol derivative is one of the following compounds: ###0002### ###0003### ###0004### ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### ###0066### ###0067### ###0068### ###0069### ###0070### ###0071### ###0072### ###0073### ###0074### ###0075### ###0076### ###0077### ###0078### ###0079### ###0080### ###0081### ###0082### ###0083### ###0084### ###0085### ###0086### ###0087### ###0088### ###0089### ###0090### ###0091### ###0092### ###0093### ###0094### ###0095### ###0096### ###0097### ###0098### ###0099### ###0100### ###0101### ###0102### ###0103### ###0104### ###0105### ###0106### ###0107### ###0108### ###0109### ###0110### ###0111### ###0112### ###0113### ###0114### ###0115### ###0116### ###0117### ###0118### ###0119### ###0120### ###0121### ###0122### ###0123### ###0124### ###0125### ###0126### ###0127### ###0128### ###0129### ###0130### ###0131### ###0132### ###0133### ###0134### ###0135### ###0136### ###0137### ###0138### ###0139### ###0140### ###0141### ###0142### ###0143### ###0144### ###0145### ###0146### ###0147### ###0148### ###0149### ###0150### ###0151### ###0152### ###0153### ###0154### ###0155### ###0156### ###0157### ###0158### ###0159### ###0160### ###0161### ###0162### ###0163### ###0164### ###0165### ###0166### ###0167### ###0168### ###0169### ###0170### ###0171### ###0172### ###0173### ###0174### ###0175### ###0176### ###0177### ###0178### ###0179### ###0180### ###0181### ###0182### ###0183### ###0184### ###0185### ###0186### ###0187### ###0188### ###0189### ###0190### ###0191### ###0192### ###0193### ###0194### ###0195### ###0196### ###0197### ###0198### ###0199### ###0200### ###0201### ###0202### ###0203### ###0204### ###0205### ###0206### ###0207### ###0208### ###0209### ###0210### ###0211### ###0212### ###0213### ###0214### ###0215### ###0216### ###0217### ###0218### ###0219### ###0220### ###0221### ###0222### ###0223### ###0224### ###0225### ###0226### ###0227### ###0228### ###0229### ###0230### ###0231### ###0232### ###0233### ###0234### ###0235### ###0236### ###0237### ###0238### ###0239### ###0240### ###0241### ###0242### ###0243### ###0244### ###0245### ###0246### ###0247### ###0248### ###0249### ###0250### ###0251### ###0252### ###0253### ###0254### ###0255### ###0256### ###0257### ###0258### ###0259### ###0260### ###0261### ###0262### ###0263### ###0264### ###0265### ###0266### ###0267### ###0268### ###0269### ###0270### ###0271### ###0272### ###0273### ###0274### ###0275### ###0276### ###0277### ###0278### ###0279### ###0280### ###0281### ###0282### ###0283### ###0284### ###0285### ###0286### ###0287### ###0288### ###0289### ###0290### ###0291### ###0292### ###0293### ###0294### ###0295### ###0296### ###0297### ###0298### ###0299### ###0300### ###0301### ###0302### ###0303### ###0304### ###0305### ###0306### ###0307### ###0308### ###0309### ###0310### ###0311### ###0312### ###0313### ###0314### ###0315### ###0316### ###0317### ###0318### ###0319### ###0320### ###0321### ###0322### ###0323### ###0324### ###0325### ###0326### ###0327### ###0328### ###0329### ###0330### ###0331### ###0332### ###0333### ###0334### ###0335### ###0336### ###0337### ###0338### ###0339### ###0340### ###0341### ###0342### ###0343### ###0344### ###0345### ###0346### ###0347### ###0348### ###0349### ###0350### ###0351### ###0352### ###0353### ###0354### ###0355### ###0356### ###0357### ###0358### ###0359### ###0360### ###0361### ###0362### ###0363### ###0364### ###0365### ###0366### ###0367### ###0368### ###0369### ###0370### ###0371### ###0372### ###0373### ###0374### ###0375### ###0376### ###0377### ###0378### ###0379### ###0380### ###0381### ###0382### ###0383### ###0384### ###0385### ###0386### ###0387### ###0388### ###0389### ###0390### ###0391### ###0392### ###0393### ###0394### ###0395### ###0396### ###0397### ###0398### ###0399### ###0400### ###0401### ###0402### ###0403### ###0404### ###0405### ###0406### ###0407### ###0408### ###0409### ###0410### ###0411### ###0412### ###0413### ​ ​ ​ ​ 2. The S(+)-pranoprofen derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein ​ ​ ​ 5. The pharmaceutical composition of claim 4, wherein, ​ 6. The pharmaceutical composition of claim 5, wherein, ​ ​ 8. Use according to claim 7, characterized in that, ​ ​

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