Chiral aryl propionic acid derivative as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a chiral aryl propionic acid derivative as well as a pharmaceutical composition and application thereof. The chiral aryl propionic acid derivative has antipyretic, analgesic and anti-inflammatory effects. The chiral aryl propionic acid derivative is shown as a formula (I), wherein the definition of each group is shown in the specification. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to, but is not limited to, the technical field of medicinal chemistry, and particularly relates to a chiral arylpropionic acid derivative, its pharmaceutical composition and uses. Background Art

[0002] Loxoprofen Sodium, chemical name: Sodium 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionate, is the first propionic acid type prodrug non-steroidal anti-inflammatory drug (NSAIDs), developed by Sankyo Co., Ltd. in Japan. Loxoprofen Sodium tablets were launched in Japan in July 1986, with the trade name: Loxonin, and were launched in China in 1999. The original research Chinese trademark name is "Lesong". The marketed drug dosage forms are tablets, capsules, fine granules, patches, and gels. Among the marketed drug dosage forms of various types, the form of the API selected is loxoprofen sodium dihydrate.

[0003]

[0004] Loxoprofen is a prodrug with weak activity. After oral administration, it needs to be metabolized by the liver to be converted into its active ingredient to exert its therapeutic effect. Loxoprofen is considered to be metabolized by carbonyl reductase in the skin and subcutaneous muscle tissues after topical administration. Loxoprofen has 2 chiral centers and 4 chiral isomers. Currently, loxoprofen sodium is marketed as a racemate. Regarding the difference in the pharmacodynamic effects of the four isomers of loxoprofen, there is no literature report. After oral administration of loxoprofen, it is rapidly absorbed. The plasma concentrations of loxoprofen and its metabolites reach their peaks after 30 - 50 minutes, and the plasma protein binding rates are 97% and 93% respectively; after a single topical administration of 1% loxoprofen (100 mg), 10% of the dose is transferred into the body within 12 hours.

[0005] After metabolism, the carbonyl group of loxoprofen is reduced to a hydroxyl group. At this time, the structure will contain 3 chiral centers and will have 8 isomers. The trans-OH metabolite is one of the metabolites. Regarding the specific difference in the pharmacodynamic effects of the corresponding diastereoisomers of its in-vivo active metabolite containing 3 chiral centers, there is also no literature report. Summary of the Invention

[0006] The inventors of the present invention have developed a chiral arylpropionic acid derivative, which has more excellent analgesic and anti-inflammatory effects and can reduce the convulsion side effects caused by combination with quinolone drugs.

[0007] One aspect of the present invention provides a chiral arylpropionic acid derivative, tautomer, solvate, or its pharmaceutically acceptable salt as shown in (I):

[0008]

[0009] In formula (I),

[0010] R a is selected from H, C1-C8 alkyl, or wherein,

[0011] the above-mentioned R c1 and R c2 are each independently H, C1-C8 alkyl;

[0012] R d is selected from hydrogen, wherein,

[0013] R1, R2 or R 2a are each independently H, C1-C8 alkyl, or R1 and R2 together with the connected nitrogen atom form a ring;

[0014] A - represents an acceptable inorganic or organic anion;

[0015] R b is selected from wherein,

[0016] the above-mentioned R c1 and R c2 are each independently H, C1-C8 alkyl;

[0017] n1 is selected from 1, 2, or 3;

[0018] n2 is selected from 0, 1, or 2; when n2 is zero, R3 is directly connected to the oxygen atom, and at this time R a is wherein, R c1 、R c2 and R d are as defined above;

[0019] R3 is selected from wherein,

[0020] the above-mentioned n3 is selected from 1, 2, 3, 4, or 5;

[0021] R 4a 、R 4b or R5 are each independently H, C1-C8 alkyl, or R 4a and R 4b together with the connected nitrogen atom form a ring;

[0022] A - represents an acceptable inorganic or organic anion;

[0023] In some embodiments, the present invention provides a chiral arylpropionic acid derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof as shown in formula (II):

[0024]

[0025] The definitions of the substituents in formula (II) are as described in formula (I).

[0026] In some embodiments, the present invention provides a chiral arylpropionic acid derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof as shown in formula (III):

[0027]

[0028] The definitions of the substituents in formula (III) are as described in formula (I).

[0029] In some embodiments, in the above formulas (I)-(II), R a is hydrogen.

[0030] In some embodiments, in the above formulas (I)-(II), R b is selected from wherein

[0031] the above n1 is selected from 1, 2, or 3; preferably, n1 is 1;

[0032] n2 is selected from 1 or 2; preferably, n2 is 1;

[0033] R c1 and R c2 are each independently H, C1-C8 alkyl; preferably, R c1 and R c2 are both hydrogen;

[0034] R3 is selected from wherein

[0035] the above n3 is selected from 1, 2, 3, 4, or 5; preferably, n3 is selected from 2 or 3;

[0036] R 4a and R 4b are each independently H, C1-C8 alkyl, or R3 and R4 together with the connected nitrogen atom form a ring; preferably, either R 4a and R 4b is hydrogen and the other is simultaneously C1-C8 alkyl, or R 4a and R 4b are both C1-C8 alkyl; more preferably, R 4a and R 4b are both methyl, R 4aand R 4b are both ethyl, R 4a and R 4b are both isopropyl;

[0037] R5 is selected from H, C1-C8 alkyl; preferably, R5 is selected from methyl, ethyl, or isopropyl;

[0038] A - represents an acceptable inorganic or organic anion; preferably, A - is selected from halide ion, perhalate, nitrate, sulfate, hydrosulfide, sulfite, phosphate, hydrogen phosphate, C1-C8 alkyl carboxylate, C1-C8 alkyl sulfonate, C1-C8 alkyl sulfate, C1-C8 aryl sulfonate; more preferably, A - is selected from sulfate, phosphate, acetate, propionate, chloride, bromide; more preferably, A - is selected from acetate, chloride, bromide.

[0039] In some embodiments, in the above formulas (I)-(III), R a is wherein,

[0040] the above R c1 and R c2 are each independently H, C1-C8 alkyl; preferably, R c1 and R c2 are both H, R c1 and R c2 are both C1-C8 alkyl, or R c1 and R c2 any one of them is H and the other is C1-C8 alkyl; more preferably, R c1 and R c2 any one of them is H and the other is methyl;

[0041] R d is selected from hydrogen, wherein,

[0042] the above R1, R2 or R 2a are each independently H, C1-C8 alkyl, or R1 and R2 together with the connected nitrogen atom form a ring; preferably, the above R1 and R2 are each independently H, C1-C8 alkyl, or R1 and R2 together with the connected nitrogen atom form a ring; preferably, preferably, either R1 or R2 is hydrogen and the other is simultaneously C1-C8 alkyl, or R1 and R2 are both C1-C8 alkyl; more preferably, R1 and R2 are both methyl, or R1 and R2 are both ethyl;

[0043] R 2aselected from H, C1-C8 alkyl; preferably, R5 is selected from methyl, or ethyl;

[0044] A - represents an acceptable inorganic or organic negative ion; preferably, A - is selected from halide ion, perhalate, nitrate, sulfate, hydrogen sulfide ion, sulfite, phosphate, hydrogen phosphate, C1-C8 alkyl carboxylate, C1-C8 alkyl sulfonate, C1-C8 alkyl sulfate, C1-C8 aryl sulfonate; more preferably, A - is selected from sulfate, phosphate, acetate, propionate, chloride ion, bromide ion; more preferably, A - is selected from acetate, chloride ion, bromide ion.

[0045] In some embodiments, in the above formulas (I)-(III), R b is R3; wherein,

[0046] R3 is selected from wherein,

[0047] the above n3 is selected from 1, 2, 3, 4, or 5; preferably, n3 is selected from 2, or 3;

[0048] R 4a and R 4b are each independently H, C1-C8 alkyl, or R 4a and R 4b together with the connected nitrogen atom form a ring; preferably, R 4a and R 4b either one is hydrogen and the other is simultaneously C1-C8 alkyl, or R 4a and R 4b are both C1-C8 alkyl; more preferably, R 4a and R 4b are both methyl, R 4a and R 4b are both ethyl, R 4a and R 4b are both isopropyl;

[0049] R5 is selected from H, C1-C8 alkyl; preferably, R5 is selected from methyl, ethyl, or isopropyl;

[0050] A - represents an acceptable inorganic or organic negative ion; preferably, A - is selected from halide ion, perhalate, nitrate, sulfate, hydrogen sulfide ion, sulfite, phosphate, hydrogen phosphate, C1-C8 alkyl carboxylate, C1-C8 alkyl sulfonate, C1-C8 alkyl sulfate, C1-C8 aryl sulfonate; more preferably, A -Selected from sulfate, phosphate, acetate, propionate, chloride, bromide; more preferably, A - Selected from acetate, chloride, bromide.

[0051] In an embodiment of the present application, the pharmaceutically acceptable salt includes an inner salt of the chiral arylpropionic acid derivative in the present invention. The inner salt refers to the formation of a salt within the molecule when the molecule contains both a carboxyl group and an amino group, and the same molecule carries both a positive charge and a negative charge;

[0052] In an embodiment of the present application, the pharmaceutically acceptable salt includes an intermolecular salt of the chiral arylpropionic acid derivative in the present invention. The intermolecular salt refers to the formation of a salt between different molecules when the chiral arylpropionic acid derivative molecule contains both a carboxyl group and an amino group.

[0053] In some embodiments, the above-mentioned chiral arylpropionic acid derivative, tautomer, solvate, or pharmaceutically acceptable salt provided by the present invention is selected from the following compounds:

[0054]

[0055]

[0056]

[0057] On the other hand, in some embodiments, the present invention provides a pharmaceutical composition comprising the above-mentioned chiral arylpropionic acid derivative, tautomer, solvate, or pharmaceutically acceptable salt.

[0058] In some embodiments, the present invention discloses a pharmaceutical composition comprising the compound, tautomer, solvate, or pharmaceutically acceptable salt described in the present invention as an active ingredient or the main active ingredient, supplemented with a pharmaceutically acceptable carrier.

[0059] In yet another aspect, in some embodiments, the present invention provides the use of the above-mentioned pharmaceutical composition in anti-inflammatory analgesics.

[0060] In some embodiments, the present invention provides a pharmaceutical composition containing the above-mentioned composition for treating any condition in humans or animals that can be treated with non-steroidal anti-inflammatory drugs; conditions treatable with non-steroidal anti-inflammatory drugs include: toothache, headache, arthritis and other inflammatory pains, fever, cancer, dysmenorrhea, low back pain, scapulohumeral periarthritis, cervical-shoulder-wrist syndrome, diabetic neuropathy, and acute migraine, bone loss, sunburn.

[0061] In some embodiments, the present invention provides a pharmaceutical composition containing the above-mentioned composition for treating any eye inflammation disease in humans or animals, treating ocular pain after corneal surgery, treating glaucoma, or treating ear inflammation and / or pain conditions.

[0062] On the other hand, in some embodiments, the chiral arylpropionic acid derivatives of the present invention can be formulated into pharmaceutical compositions and administered to patients in a variety of suitably selected administration routes, including parenteral and topical administration routes, such as skin topical preparations, ophthalmic preparations, inhalation preparations, etc.

[0063] In some examples of the present invention, the chiral arylpropionic acid derivatives of the present invention and lactose are mixed and pulverized to prepare an inhalant.

[0064] In some examples of the present invention, the chiral arylpropionic acid derivatives of the present invention, an appropriate amount of surfactant and osmotic pressure regulator are dissolved together to prepare a solution for inhalation.

[0065] In some examples of the present invention, the chiral arylpropionic acid derivatives of the present invention and an appropriate amount of surfactant, etc. are jointly prepared into a skin topical preparation.

[0066] In some examples of the present invention, the chiral arylpropionic acid derivatives of the present invention and suitable excipients, etc. are jointly prepared into ophthalmic preparations, tablets, and capsules.

[0067] The compounds of the present invention have stronger analgesic activity and have more excellent inhibitory effects on the inflammatory factors IL-6 and IL-8 induced by INF-α in human rheumatoid arthritis fibroblast-like synoviocytes (HFLS-RA);

[0068] When the disclosed compounds of the present invention are used in combination with lomefloxacin, they can reduce or avoid the convulsion side effects and death risk of combined use with lomefloxacin, indicating that the compounds of the present invention have good prospects for reducing or avoiding the convulsion side effects of combined use with quinolone drugs.

[0069] Definition:

[0070] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears in this text, it is intended to refer to its corresponding product or its active ingredient.

[0071] Certain compounds of the present invention can exist in non-solvated form or solvated form, such as hydrate, ethanolate form. Generally, the solvated form is equivalent to the non-solvated form and is included within the scope of the present invention.

[0072] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0073] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents found in the present invention with relatively non-toxic acids or bases. When a compound of the present invention contains a relatively acidic functional group, the base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include salts of aluminum, sodium, potassium, calcium, manganese, iron, ammonium, organic amines, or magnesium, or similar salts. When a compound of the present invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, where the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, where the organic acids include, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, and similar acids; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can thus be converted into either base or acid addition salts.

[0074] The term "alkyl" denotes a saturated aliphatic hydrocarbon group, including straight-chain and branched-chain groups. The alkyl group can be substituted or unsubstituted. When it is a substituted alkyl group, the substituent is preferably one or more, more preferably 1 - 3, and most preferably 1 or 2 substituents.

[0075] The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and is non-toxic and side-effect-free to the host or patient. Representative carriers include water, oils, vegetables and minerals, paste bases, lotion bases, ointment bases, etc. These bases include suspending agents, thickening agents, transdermal promoters, etc.

[0076] The numerical ranges mentioned in this application, such as "C1 - C8", mean that the group can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 8 carbon atoms. Description of the Drawings Figure 1Test chart of the inhibitory effect of the compound of Example 12 on acetic acid-induced pain in mice Detailed implementation mode

[0077] The following examples can enable those skilled in the art to understand the present invention more comprehensively, but do not limit the present invention in any way. The structures of all compounds are determined by MS or 1 H NMR.

[0078] Example 1: Preparation of compound ZJT1

[0079] Reaction formula:

[0080]

[0081] Preparation method:

[0082] Step 1: Synthesis of compound ZJT1-1

[0083] Add compound ZJT1-SM (90 g, 365.8 mmol, 1 eq) to ethyl acetate (700 mL), then add S-phenethylamine (20.7 g, 170.8 mmol, 0.5 eq), stir at room temperature for 4 hours, then filter, wash the filter cake with ethyl acetate (200 mL × 3), and vacuum dry the filter cake at 45 °C for 6 hours to obtain 60 g of crude ZJT1-1. Then recrystallize twice with a mixed solvent of toluene and methanol (1:1) to obtain compound ZJT1-1 (30 g), with a yield of 47.8%. ESI-MS(-): m / z = 245.34.

[0084] Step 2: Synthesis of compound ZJT1-2

[0085] Add compound ZJT1-1 (15 g, 40.8 mmol) to a mixed solvent of ethyl acetate (50 mL) and water (65 ml), then adjust the pH to 2-3 with 2N hydrochloric acid, then stir at room temperature for 1 hour, separate the layers, extract the aqueous phase with ethyl acetate (80 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (150 mL), dry with sodium sulfate, and rotary evaporate to obtain compound ZJT1-2 (9.7 g), with a yield of 96.4%. ESI-MS(-): m / z = 245.36.

[0086] Step 3: Synthesis of compound ZJT1-3

[0087] Compound ZJT1-2 (9.2 g, 37.39 mmol, 1 eq) was added to a mixed solvent of methanol (15 ml) and tetrahydrofuran (20 ml). The system was cooled to 0 °C, and then sodium borohydride (1 g, 26.43 mmol, 0.7 eq) was added. The system was warmed to room temperature and stirred for 6 hours. TLC detection showed that the reaction was complete. The system was poured into a mixed solution of water (50 ml) and ethyl acetate (50 ml), and the pH was adjusted to 2 - 3 with 2N hydrochloric acid solution. The layers were separated, and the organic phase was washed with water (100 ml) and then with saturated sodium chloride solution (100 mL), dried over sodium sulfate, rotary evaporated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain compound ZJT1-3 (6.35 g) with a yield of 68.5%. ESI-MS(-): m / z = 247.33

[0088] Step 4: Synthesis of compound ZJT1

[0089] Compound ZJT1-3 (6.02 g, 24.3 mmol, 1 eq) was added to ethyl acetate (50 mL) and toluene (20 ml), then vinyl acetate (6.02 g, 72.9 mmol, 3 eq), lipase (0.9 g), and 3A molecular sieve (0.9 g) were added. The system was stirred at room temperature for 24 hours. TLC detection showed that the reaction was complete. The mixture was filtered, and the filtrate was rotary evaporated to dryness. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain ZJT-1 (3.91 g) with a yield of 65%. ESI-MS(-): m / z = 247.26. 1 1H NMR (ppm, 500 MHz, DMSO-d6): δ 12.20 (s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 4.25 (br, 1H), 3.58 - 3.69 (m, 2H), 2.77 (dd, J = 13.5, 5.4 Hz, 1H), 2.28 (dd, J = 13.5, 9.4, 1H), 1.74 - 1.91 (m, 2H) 1.39 - 1.69 (m, 4H), 1.34 (d, J = 7.1 Hz, 3H), 1.12 - 1.13 (m, 1H).

[0090] Example 2: Synthesis of DSC201-01

[0091] Reaction formula:

[0092]

[0093] Preparation method:

[0094] DSC201-01 SM was prepared according to Example 8 of Patent CN116478050B.

[0095] Step 1: Synthesis of DSC201-0101

[0096] Compound DSC201-01SM (782 mg, 2.0 mmol, 1 eq) was added to tetrahydrofuran (50 mL), and then potassium carbonate (552 mg, 4.0 mmol, 2 eq) was added. The system was cooled to 0 °C, and 1-bromoethanol (248 mg, 2.0 mmol, 1 eq) was added. The system was warmed to room temperature and stirred for 2 hours. TLC detection showed that the reaction was basically complete. The mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain compound DSC201-0101 (624 mg) with a yield of 71.6%. ESI-MS(+): m / z = 436.34.

[0097] Step 2: Synthesis of DSC201-01

[0098] Compound DSC201-0101 (435 mg, 1 mmol, 1 eq) was added to dichloromethane (DCM, 40 mL). The system was cooled to 0 °C, and N,N-dimethylglycine (103 mg, 1 mmol, 1 eq) was added. Then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 210 mg, 1.1 mmol, 1.1 eq) was added, and finally 4-dimethylaminopyridine (DMAP, 24 mg, 0.2 mmol, 0.2 eq) was added. The mixture was stirred for 2 hours, and the system was warmed to room temperature and reacted for 8 hours. TLC detection showed that the reaction was basically complete. The system was poured into water (50 mL), and the layers were separated. The aqueous layer was extracted with DCM (20 mL × 3), dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain compound DSC201-01 (392 mg) with a yield of 75.1%. ESI-MS(+): m / z = 521.38.

[0099] Example 3: Synthesis of DSC201-08

[0100] Reaction formula:

[0101]

[0102] Preparation method:

[0103] Step 1: Synthesis of DSC201-0803

[0104] Under nitrogen protection and at 0 °C, chloroformyl chloride (4.9 g, 38.0 mmol) was added to a solution of 2-(diethylamino)ethanol (4.0 g, 34.4 mmol) and pyridine (5.4 g, 68.8 mmol) in dichloromethane (50 mL). After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for an additional 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain DSC201-0803 (3.54 g), with a yield of 49.1%. ESI-MS(+): m / z = 210.15.

[0105] Step 2: Synthesis of DSC201-0802

[0106] ZJT1 (2.48 g, 10 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and diphenylmethyl diazomethane (2.91 g, 15 mmol) was added thereto under an ice bath. The reaction was carried out at 0 °C for 30 minutes. The system was concentrated to dryness under reduced pressure to remove the solvent, and DSC201-0802 (3.9 g) was obtained, with a yield of 94.1%. ESI-MS(+): m / z = 415.34.

[0107] Step 3: Synthesis of DSC201-0801

[0108] DSC201-0802 (3.9 g, 9.4 mmol) was dissolved in acetonitrile (30 mL). Under an ice bath, potassium carbonate (2.07 g, 15 mmol) and DSC201-0803 (2.94 g, 14 mmol) were added successively. After reacting at room temperature for 3 h, the mixture was filtered and concentrated, and column chromatography was performed to obtain DSC201-0801 (4.3 g), with a yield of 77.9%. ESI-MS(+): m / z = 588.45.

[0109] Step 4: Synthesis of DSC201-08

[0110] DSC201-0801 (0.59 g, 1.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated to dryness, 30 mL of water and 30 mL of ethyl acetate were added, and the pH value of the aqueous phase was adjusted to about 7 with saturated sodium bicarbonate. The mixture was shaken and separated. The aqueous phase was further extracted with ethyl acetate twice (30 mL x 2), the organic layers were combined, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was subjected to column chromatography to obtain DSC201-08 (0.3 g), with a yield of 71.7%. ESI-MS(-): m / z = 420.34.

[0111] Example 4: Synthesis of DSC201-10

[0112] Reaction formula:

[0113]

[0114] Preparation method:

[0115] Step 1: Synthesis of DSC201-1002

[0116] Under nitrogen protection and at 0 °C, chloroformyl chloride (4.9 g, 38.0 mmol) was added to a dichloromethane (50 mL) solution of 3-diethylamino-1-propanol (4.47 g, 34.1 mmol) and pyridine (5.4 g, 68.8 mmol). After the addition was complete, the reaction mixture was allowed to warm to room temperature and react for an additional 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain DSC201-1002 (3.6 g), with a yield of 47.2%. ESI-MS(+): m / z = 224.13.

[0117] Step 2: Synthesis of DSC201-1001

[0118] DSC201-0802 (3.9 g, 9.4 mmol) was dissolved in acetonitrile (30 mL). Under an ice bath, potassium carbonate (2.07 g, 15 mmol) and DSC201-1002 (3.13 g, 14 mmol) were added sequentially. After reacting at room temperature for 3 h, the mixture was filtered and concentrated, and column chromatography was performed to obtain DSC201-1001 (3.8 g), with a yield of 67.2%. ESI-MS(+): m / z = 602.38.

[0119] Step 3: Synthesis of DSC201-10

[0120] DSC201-1001 (0.61 g, 1.0 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. It was concentrated to dryness, 30 mL of water and 30 mL of ethyl acetate were added, and the pH of the aqueous phase was adjusted to about 7 with saturated sodium bicarbonate. The mixture was shaken and separated. The aqueous phase was further extracted with ethyl acetate twice (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was subjected to column chromatography to obtain DSC201-10 (0.22 g), with a yield of 50.5%. ESI-MS(-): m / z = 434.24.

[0121] Example 5: Synthesis of DSC201-12 and DSC201-16

[0122] Reaction formula:

[0123]

[0124] Preparation method:

[0125] Step 1: Synthesis of DSC201-12

[0126] Dissolve DSC201-08 (0.31 g, 0.744 mmol) in ethanol (5 mL), add dicyclohexylcarbodiimide (0.3 g, 1.45 mmol) and 4-dimethylaminopyridine (DMAP, 0.01 g). After reacting at room temperature for 3 h, concentrate to remove ethanol. Add dichloromethane (50 mL), wash with saturated brine (50 mL), dry the organic phase with anhydrous sodium sulfate and concentrate. Column chromatography gives DSC201-12 (0.24 g) with a yield of 71.8%. ESI-MS(+): m / z = 450.32.

[0127] Step 2: Synthesis of DSC201-16

[0128] Dissolve DSC201-12 (0.45 g, 1 mmol) in dichloromethane (10 mL), add acetic acid (70 mg, 1.1 mmol). After stirring for 10 minutes, evaporate the solvent under reduced pressure. Pulverize the residue with methyl tert-butyl ether and filter to obtain DSC201-16 (0.33 g) with a yield of 64.8%. ESI-MS(+): m / z = 450.35.

[0129] Example 6: Synthesis of DSC201-14

[0130] Reaction formula:

[0131]

[0132] Preparation method:

[0133] Dissolve DSC201-08 (0.42 g, 1 mmol) in dichloromethane (10 mL), add acetic acid (70 mg, 1.1 mmol). After stirring for 10 minutes, evaporate the solvent under reduced pressure. Pulverize the residue with methyl tert-butyl ether and filter to obtain DSC201-14 (0.37 g) with a yield of 77.1%. ESI-MS(-): m / z = 420.26.

[0134] Example 7: Synthesis of DSC201-15

[0135] Reaction formula:

[0136]

[0137] Preparation method:

[0138] Dissolve DSC201-10 (0.44 g, 1 mmol) in hydrogen chloride methanol solution (10 mL). After stirring for 30 minutes, evaporate the solvent under reduced pressure. Pulverize the residue with methyl tert-butyl ether to obtain DSC201-15 (0.31 g) with a yield of 65.8%. ESI-MS(-): m / z = 434.28.

[0139] Example 8: Synthesis of DSC201-18 and DSC201-19

[0140] Reaction formula:

[0141]

[0142] Preparation method:

[0143] Synthesis of compound DSC201-18:

[0144] Under nitrogen protection and at room temperature, successively add tetrahydrofuran (50 mL) and compound DSC201-08 (4.21 g, 10 mmol) to the reaction flask, and then slowly add a tetrahydrofuran solution of chloroethane (20 mL). After addition, heat to reflux and react for 30 minutes. After the reaction is completed, cool to 0 - 10 °C, filter, and dry to obtain the crude product. Recrystallize with a mixed solvent of methanol / acetone to obtain compound DSC201-18 (2.1 g), with a yield of 43.3%. ESI-MS(-): m / z = 449.15.

[0145] Synthesis of compound DSC201-19:

[0146] Successively add ethanol (15 mL) and compound DSC201-18 (2.30 g, 5 mmol) to the reaction flask, heat at 50 °C, and when compound DSC201-18 dissolves, add silver acetate (0.92 g, 5.5 mmol). Stir the reaction mixture for 3 h, perform hot filtration, cool the filtrate to about 10 °C, add 45 ml of methyl tert-butyl ether to crystallize, and obtain compound DSC201-19 (1.64 g), with a yield of 64.4%. ESI-MS(-): m / z = 449.22.

[0147] Example 9: Synthesis of DSC201-24 and DSC201-25

[0148] Reaction formula:

[0149]

[0150] Preparation method:

[0151] Synthesis of compound DSC201-24:

[0152] Compound DSC201-01SM (782 mg, 2.0 mmol, 1 eq) was added to tetrahydrofuran (50 mL), followed by potassium carbonate (552 mg, 4.0 mmol, 2 eq). The system was cooled to 0 °C, and α-chloroethyl acetate (244 mg, 2.0 mmol, 1 eq) was added. The system was warmed to room temperature and stirred for 2 hours. TLC detection showed that the reaction was basically complete. The mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography to obtain compound DSC201-24 (456 mg) with a yield of 47.7%. ESI-MS(+): m / z = 478.42.

[0153] Synthesis of compound DSC201-25:

[0154] DSC201-24 (0.48 g, 1 mmol) was dissolved in dichloromethane (10 mL), and acetic acid (70 mg, 1.1 mmol) was added. After stirring for 10 minutes, the solvent was removed under reduced pressure. The residue was triturated with methyl tert-butyl ether and filtered to obtain DSC201-25 (0.26 g) with a yield of 48.4%. ESI-MS(+): m / z = 478.54.

[0155] Following the same method as the above examples, the following example compounds were synthesized using commercially available compounds or intermediate compounds appropriately synthesized from commercially available compounds.

[0156]

[0157]

[0158] Example 10: Obtaining of control compounds

[0159]

[0160] The above control compound 1 was obtained by referring to Example 8 of Patent 202310412212.X, and control compound 2 was obtained by a simple esterification reaction based on control compound 1.

[0161] Example 11: Effects on cytokine secretion of HFLS-RA cells

[0162] The experiment was divided into a blank control group (without the test article or TNF-α), a TNF-α group (the final concentration of TNF-α for cell incubation was 10 ng / mL), and a test article group (a total of 37 groups, namely Control Compound 1 group, Control Compound 2 group, DSC201-01 group, DSC201-02 group, DSC201-03 group, DSC201-04 group, DSC201-05 group, DSC201-06 group, DSC201-07 group, DSC201-08 group, DSC201-09 group, DSC201-10 group, DSC201-11 group, DSC201-12 group, DSC201-13 group, DSC201-14 group, DSC201-15 group, DSC201-16 group, DSC201-17 group, DSC201-18 group, DSC201-19 group, DSC201-20 group, DSC201-21 group, DSC201-22 group, DSC201-23 group, DSC201-24, DSC201-25 group, DSC201-26 group, DSC201-27 group, DSC201-28 group, DSC201-29 group, DSC201-30 group, DSC201-31 group, DSC201-32 group, DSC201-33 group, DSC201-34 group, and DSC201-35 group. The final concentrations of each test article and TNF-α for cell incubation were 100 μg / mL and 10 ng / mL, respectively).

[0163] HFLS-RA cells in the logarithmic growth phase (purchased from Shanghai Cell Bank) were seeded into a 6-well culture plate at a density of 5×10 4 cells / ml, with an inoculation volume of 2.5 mL per well. After inoculation, the cells were cultured in an incubator at 37°C and 5% CO2 for 2 h. Then, appropriate amounts of each test article solution were added according to the grouping and the final concentration of the test article. Each group was set with 3 replicate wells. After continuing to culture for 48 h, the cell supernatant was collected, and the contents of IL-6 and IL-8 in the supernatant were detected using an ELISA kit (Enzyme-linked Biotechnology, ml028580). The results are shown in Table 1.

[0164] Table 1. Effects of test articles on the expression of IL-6 and IL-8 inflammatory factors in TNF-α-induced HFLS-RA cells

[0165]

[0166]

[0167] As can be seen from Table 1, compared with the blank control group, TNF-α could significantly induce the expression of inflammatory factors IL-6 and IL-8 in HFLS-RA cells (P<0.001); compared with the TNF-α group, the test article groups (a total of 37 groups) all showed inhibitory effects on the expression of IL-6 and IL-8 inflammatory factors in TNF-α-induced HFLS-RA cells (P<0.001); compared with the control compound 1 group, DSC201-08, DSC201-09, DSC201-10, DSC201-11, DSC201-14, DSC201-15, DSC201-18, DSC201-19, DSC201-20, DSC201-21, DSC201-22, DSC201-23, DSC201-32 and DSC201-33 all showed more excellent inhibitory activities on the expression of IL-6 and IL-8 inflammatory factors in TNF-α-induced HFLS-RA cells (P<0.001), among which DSC201-08, DSC201-14 and DSC201-19 were the most significant, and at the same time, it was shown that the inhibitory activities before and after salification of such structures did not change significantly; compared with the control compound 2 group, DSC201-01, DSC201-02, DSC201-03, DSC201-04, DSC201-05, DSC201-06, DSC201-07, DSC201-12, DSC201-13, DSC201-16, DSC201-17, DSC201-24, DSC201-25, DSC201-26, DSC201-27, DSC201-28, DSC201-29, DSC201-30, DSC201-31, DSC201-34 and DSC201-35 all showed more excellent inhibitory activities on the expression of IL-6 and IL-8 inflammatory factors in TNF-α-induced HFLS-RA cells (P<0.001), among which DSC201-24 and DSC201-25 were the most significant. The overall results showed that the compounds of the present invention could exert anti-inflammatory effects by inhibiting the expression of IL-6 and IL-8 inflammatory factors, and were significantly superior to control compound 1 and control compound 2.

[0168] Example 12: Inhibitory effect of the compounds of the present invention on acetic acid-induced pain in mice

[0169] 54 18-22g SPF female KM mice were divided into 18 groups, 3 animals in each group. 17 test solutions of equal molar concentrations of control compound 1, control compound 2, DSC201-08, DSC201-09, DSC201-10, DSC201-11, DSC201-12, DSC201-14, DSC201-15, DSC201-16, DSC201-18, DSC201-19, DSC201-20, DSC201-24, DSC201-27, DSC201-32 and DSC201-33 were prepared with sterile water for injection and set aside. The test was administered by intraperitoneal injection in mice, with a dosing volume of 0.4 mL / mouse. Equal volumes of sterile water for injection and 17 test sample solutions were respectively administered by intraperitoneal injection to mice in the corresponding groups. Group 1: negative control group, sterile water for injection; Group 2: control compound 1; Group 3: control compound 2; Group 4: DSC201-08; Group 5: DSC201-09; Group 6: DSC201-10; Group 7: DSC201- 11; Group 8: DSC201-12; Group 9: DSC201-14; Group 10: DSC201-15; Group 11: DSC201-16; Group 12: DSC201-18; Group 13: DSC201-19; Group 14: DSC201-20; Group 15: DSC201-24; Group 16: DSC201-27; Group 17: DSC201-32; Group 18: DSC201-33.

[0170] 30 minutes after administration, each mouse in each group was intraperitoneally injected with 0.2 mL of 0.6% glacial acetic acid to establish a mouse pain model. At the same time, the number of twistings of each mouse within 20 minutes was recorded and the average value was calculated. Figure 1 .

[0171] The results showed that the number of twists in each drug-treated group was less than that in the vehicle group; compared with group 2 (control compound 1), group 4 (DSC201-08), group 5 (DSC201-09), group 6 (DSC201-10), group 7 (DSC201-11), group 9 (DSC201-14), group 10 (DSC201-15), group 12 (DSC201-18), group 13 (DSC201-19), group 14 (DSC201-20 ), group 17 (DSC201-32) and group 18 (DSC201-33) had lower writhing times; compared with group 3 (control compound 2), group 8 (DSC201-12), group 11 (DSC201-16), group 15 (DSC201-24) and group 16 (DSC201-27) had lower writhing times; the overall results showed that the compounds disclosed in the present invention have stronger analgesic activity, and the analgesic activity is not significantly affected before and after salt formation.

[0172] Example 13: Experiment on whether convulsions are induced when combined with lomefloxacin

[0173] 96 male Kunming mice at 5 weeks of age were randomly divided into 16 groups, with 6 mice in each group. Before oral administration, the mice were fasted for 18 hours without water deprivation. Grouping and dosing: Group 1 (control compound 1 at 500 mg / kg), Group 2 (control compound 2 at 500 mg / kg), Group 3 (lomefloxacin at 1000 mg / kg), Group 4 (lomefloxacin at 1000 mg / kg + control compound 1 at 500 mg / kg), Group 5 (lomefloxacin at 1000 mg / kg + control compound 2 at 500 mg / kg), Group 6 (lomefloxacin at 1000 mg / kg + DSC201-08 at 500 mg / kg), Group 7 (lomefloxacin at 1000 mg / kg + DSC201-12 at 500 mg / kg), Group 8 (lomefloxacin at 1000 mg / kg + DSC201-14 at 500 mg / kg), Group 9 (lomefloxacin at 1000 mg / kg + DSC201-19 at 500 mg / kg), Group 10 (lomefloxacin at 1000 mg / kg + DSC201-20 at 500 mg / kg), Group 11 (lomefloxacin at 1000 mg / kg + DSC201-24 at 500 mg / kg), Group 12 (lomefloxacin at 1000 mg / kg + DSC201-25 at 500 mg / kg), Group 13 (lomefloxacin at 1000 mg / kg + DSC201-27 at 500 mg / kg), Group 14 (lomefloxacin at 1000 mg / kg + DSC201-29 at 500 mg / kg), Group 15 (lomefloxacin at 1000 mg / kg + DSC201-32 at 500 mg / kg), and Group 16 (lomefloxacin at 1000 mg / kg + DSC201-33 at 500 mg / kg). After dosing, the mice were placed in observation cages and continuously observed for 8 hours. The occurrence of clonic convulsions (CL) and tonic convulsions (TN) was recorded, and the number of mouse deaths (DE) within 24 hours after dosing was continuously recorded. The overall lethality rate of each group was calculated (overall lethality rate = DE / 6, where 6 is the number of animals in each group). The results are shown in Table 2:

[0174] Table 2. Results of the experiment on whether convulsions are induced when combined with lomefloxacin

[0175]

[0176]

[0177] Results: The data of Group 1 - Group 3 showed that during the observation period, the control compound 1, control compound 2, and lomefloxacin alone did not cause convulsions or death in mice; the data of Group 4 and Group 5 showed that whether lomefloxacin was co - administered with control compound 1 or control compound 2, there were mice with clonic and tonic convulsions, and 5 mice died within 24 hours, with a mortality rate as high as 83.3%; the data of Group 6 - Group 16 showed that when the compounds disclosed in the present invention were co - administered with lomefloxacin respectively, only individual groups had 1 mouse with clonic convulsions, no tonic convulsions occurred, and no mice died within 24 hours; the overall results showed that the compounds disclosed in the present invention could reduce or avoid the occurrence of convulsion side effects when used in combination with quinolone drugs.

[0178] Although the present invention has been disclosed above with preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications and improvements without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention shall be defined by the claims.

Claims

1. A chiral arylpropionic acid derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof as shown in (I): In formula (I), R a Selected from H, C1-C8 alkyl, or in, The above R c1 and R c2 Each independently represents H, C1-C8 alkyl; R d Selected from hydrogen, in, R1, R2 or R 2a Each is independently H, C1-C8 alkyl, or R1 and R2 together with the connected nitrogen atom form a ring; A - Represents acceptable inorganic or organic negative ions; R b Selected from in, The above R c1 and R c2 Each independently represents H, C1-C8 alkyl; n1 is selected from 1, 2, or 3; n2 is selected from 0, 1, or 2; when n2 is zero, R3 is directly connected to the oxygen atom, and R a for Among them, R c1 , R c2 and R d As defined above; R3 is selected from in, The above n3 is selected from 1, 2, 3, 4, or 5; R 4a , R 4b or R5 are each independently H, C1-C8 alkyl, or R 4a and R 4b Together with the connected nitrogen atoms, they form a ring; A - Represents acceptable inorganic or organic negative ions.

2. The chiral arylpropionic acid derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof according to claim 1, wherein the structure is as shown in formula (II): in, The above R b Selected from in, The above n2 is selected from 1 or 2; R c1 , R c2 and n1 are as defined in formula (I) of claim 1.

3. The chiral arylpropionic acid derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof according to claim 1, wherein the structure is as follows: in, The above R3, R c1 , R c2 or R d The definition is as defined in formula (I) of claim 1.

4. The chiral arylpropionic acid derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof according to claim 1, selected from the following compounds:

5. The chiral arylpropionic acid derivative according to claims 1 to 4, wherein the pharmaceutically acceptable salt comprises a salt thereof with an anion, wherein the anion is fluoride ion, chloride ion, bromide ion, iodide ion, acetate ion, benzoate ion, citrate ion, tartrate ion, oxalate ion, malate ion, ascorbate ion, or fumarate ion.

6. The chiral arylpropionic acid derivative according to claims 1 to 4, wherein the pharmaceutically acceptable salt thereof comprises an internal salt or an intermolecular salt.

7. A pharmaceutical composition comprising the chiral arylpropionic acid derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.

8. Use of the chiral arylpropionic acid derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, or the pharmaceutical composition according to claim 7 in the preparation of at least one of antipyretic, analgesic and anti-inflammatory drugs.

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