Chiral arylpropionic acid derivatives and their drug compositions and their use

Abstract

The present invention discloses a chiral arylpropionic acid derivative and a pharmaceutical composition thereof, as well as its use. The chiral arylpropionic acid derivative is represented by formula (I), and the details of the definition of each group are described in the specification. The chiral arylpropionic acid derivative has antipyretic, analgesic and anti-inflammatory effects, and the compound according to the present invention has high activity and can be administered locally, and is expected to reduce the dosage and side effects. [Formula 1] TIFF2025513495000059.tif31129

Description

[Technical Field]

[0001] The present invention relates to, but is not limited to, the art of drug chemistry, and more particularly to chiral arylpropionic acid derivatives, drug compositions thereof, and their use. [Background technology]

[0002] Loxoprofen sodium, whose chemical name is 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionate sodium, is the first propionic acid precursor-type nonsteroidal anti-inflammatory drug (NSAID). Developed and researched by Nippon Sankyo Co., Ltd., loxoprofen sodium tablets were marketed in Japan in July 1986 under the trade name Loxonin, and marketed in China in 1999, with JAKEN JA Pharmaceutical's Chinese trademark name being "Lesong". The commercially available drug is available in various dosage forms, including tablets, capsules, granules, patches, and gels, and loxoprofen sodium dihydrate was selected as the API for these various dosage forms. [ka]

[0003] Loxoprofen is a weakly active prodrug that requires metabolism in the liver after oral administration, and its therapeutic effect is exerted once it is converted to the active ingredient. After local administration, loxoprofen is thought to be metabolized by carbonyl reductase in the skin and subcutaneous muscle tissue. Loxoprofen has two chiral centers and four chiral isomers, and currently, loxoprofen sodium is marketed as a racemic mixture. However, the differences in the pharmacological effects of the four isomers of loxoprofen have not been reported in the literature. After oral administration, loxoprofen is rapidly absorbed, and the plasma concentrations of loxoprofen and its metabolites reach peak levels 30-50 minutes later, with plasma protein binding rates of 97% and 93%, respectively. A single local administration of 1% loxoprofen (100 mg) resulted in 10% of the dose being transferred into the body within 12 hours.

[0004] After loxoprofen is metabolized, the carbonyl group is reduced to a hydroxyl group, resulting in a structure containing three chiral centers and eight isomers, with the trans-OH metabolite being one of the active metabolites. The specific differences in pharmacological effects of the diastereoisomers corresponding to the active metabolite containing the three chiral centers have not been reported in the literature.

[0005] We will conduct detailed studies on several isomers and then develop efficient, fast-acting nonsteroidal anti-inflammatory drug derivatives through structural modification. [Overview of the project]

[0006] The inventors have developed a chiral arylpropionic acid derivative having antipyretic, analgesic, and anti-inflammatory effects. The compound according to the present invention is expected to have superior anti-rheumatic effects, enabling reduced dosage and fewer side effects, and was unexpectedly found to have high distribution in joint areas. Further research has shown that when applied topically to the skin, synovial fluid distribution and therapeutic effects are better, and it can be used as a topically administered nonsteroidal anti-inflammatory drug. [Modes for carrying out the invention]

[0007] One aspect of the present invention provides a chiral arylpropionic acid derivative represented by formula (I), a tautomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. [ka] In equation (I), R1 is H, or one or more [ka] Substitution or non-substitution [ka] It is selected from, R2 is H, or substituted or unsubstituted by one or more [Chemical Formula] , and is selected from [Chemical Formula] , provided that when R1 is hydrogen, R2 is not hydrogen, Y2 is O, N(R6) or S, n1, n2, n3, n4, n5 and n6 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, R3, R4 and R5 are each independently H, a C1-C20 hydrocarbon group, or a C1-C20 alkylcarbonyl group, or R3 and R4 together with the nitrogen atom to which they are bonded form a ring, R6 is H or a C1-C20 hydrocarbon group, A - represents an acceptable inorganic or organic anion.

[0008] In an embodiment of the present application, the hydrocarbon group includes an alkane group, an olefin group or an alkyne group, and also includes a heterocyclic group, an aryl group or a heteroaryl group.

[0009] In an embodiment of the present application, the hydrocarbon group includes a linear, branched or cyclic hydrocarbon group.

[0010] ​In embodiments of this application, the C1-C20 hydrocarbon group means a saturated or unsaturated aliphatic hydrocarbon containing 1 to 20 carbon atoms, and includes C1-C20 alkane groups, C2-C20 olefin groups, and C2-C20 alkyne groups. For example, this includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, ethynyl, propenyl, propynyl, allyl, 2-methyl-2-butenyl, 2-butenyl (-CH2-CH=CH-CH3), 3-butenyl (-CH2-CH2-CH=CH2), 4-pentenyl (-CH2-CH2-CH2-CH=CH2), 2-methyl-2-pentenyl (-CH2-C(CH3)=CH-CH2-CH3), and 5-vinyl (-CH2CH2CH2CH=CH2).

[0011] In embodiments of this application, the hydrocarbon group includes a C2-C20 heterocyclic group, where the heterocyclic group means that the heterocycle contains one or more atoms selected from at least oxygen, nitrogen, and sulfur, such as oxyranyl, azilidinyl, thyranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, This includes, but is not limited to, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranil, tetrahydropyranil, hexahydrothiopyranil, hexahydropyrimidinil, oxazinyl, thiadinyl, thioxanil, homopiperazinil, homopiperidinil, azepanil, oxepanil, thiepanil, oxazepanil, diazepanil, 1,4-diazepanil, thiazepanil, tetrahydrothiopyranil, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinone, oxazolidinonil, etc.

[0012] In embodiments of this application, the hydrocarbon group includes, but is not limited to, benzene, naphthalene, anthracene, or biphenyl.

[0013] In embodiments of this application, the hydrocarbon group includes, but is not limited to, a heteroaryl group and includes pyrimidine, furan, thiazole, thiophene, pyridine, pyrrole, and imidazole.

[0014] In embodiments of this application, a pharmaceutically acceptable salt means any form based on the chiral arylpropionic acid derivative used in the present invention, which is ionic, or charged and coupled to a counterion (anion or cation), or present in solution.

[0015] In embodiments of this application, pharmaceutically acceptable salts include salts formed with a chiral arylpropionic acid derivative according to the present invention and an anion, the anion including, but not limited to, fluoride ions, chloride ions, bromide ions, iodide ions, acetate ions, benzoate ions, citrate ions, tartrate ions, oxalate ions, malate ions, ascorbic acid ions, fumarate ions, and the like.

[0016] In embodiments of this application, pharmaceutically acceptable salts include intramolecular salts formed from the chiral arylpropionic acid derivatives according to the present invention, where an intramolecular salt means that a salt is formed within a molecule when both a carboxyl group and an amine group are present in the molecule, and the same molecule has both positive and negative charges.

[0017] In embodiments of this application, pharmaceutically acceptable salts include intermolecular salts of chiral arylpropionic acid derivatives according to the present invention, where intermolecular salt means that a salt is formed between different molecules when both a carboxyl group and an amine group are present in the molecule of the chiral arylpropionic acid derivative.

[0018] In some embodiments, R1 is hydrogen, and R2 is one or more [ka] Replaced by [ka] That is the case.

[0019] In some embodiments, R2 is hydrogen, and R1 is one or more [ka] Replaced by [ka] That is the case.

[0020] In some embodiments, R1 is one or more [ka] Replaced by [ka] And R2 is one or more [ka] Replaced by [ka] That is the case.

[0021] In some embodiments, R1 is one or more [ka] Replaced by [ka] And R2 is, [ka] That is the case.

[0022] In some embodiments, R1 is [ka] And R2 is one or more [ka] Replaced by [ka] That is the case.

[0023] In some embodiments, when R1 or R2 is not hydrogen, the substituent [ka] This may involve substituting hydrogen at terminal carbons or substituting hydrogen at non-terminal carbons.

[0024] In some embodiments, R3 and R4 are both H.

[0025] In some embodiments, R3 and R4 are both C1-C20 hydrocarbon groups or C1-C20 alkylcarbonyl groups, preferably both are C1-C6 hydrocarbon groups or C1-C6 alkylcarbonyl groups, and more preferably both are C1-C6 alkyl groups.

[0026] In some embodiments, R3 is H, and R4 is a C1-C20 hydrocarbon group or a C1-C20 alkylcarbonyl group, preferably R4 is a C1-C6 hydrocarbon group, and more preferably R4 is a C1-C6 alkyl group.

[0027] In some embodiments, R4 is H, and R3 is a C1-C20 hydrocarbon group or a C1-C20 alkylcarbonyl group, preferably R3 is a C1-C6 hydrocarbon group, and more preferably R3 is a C1-C6 alkyl group.

[0028] In some embodiments, R3 and R4 together form a ring with the bonded nitrogen atom, and the nitrogen atom and R3 and / or R4 may be bonded by a normal carbon-nitrogen bond or by an amide bond. The ring formed by both R3 and R4 and the bonded nitrogen atom may be a 4-membered ring, a 5-membered ring, a 6-membered ring, or a 7-membered ring.

[0029] In some embodiments, R3, R4, and R5 are all H.

[0030] In some embodiments, R3 and R4 are both C1-C20 hydrocarbon groups or C1-C20 alkylcarbonyl groups, and R5 is H. Preferably, R3 and R4 are both C1-C6 hydrocarbon groups or C1-C6 alkylcarbonyl groups, and R5 is H. More preferably, R3 and R4 are both C1-C6 alkyl groups, and R5 is H.

[0031] In some embodiments, R3, R4, and R5 are all C1-C20 hydrocarbon groups or C1-C20 alkylcarbonyl groups, preferably all are C1-C6 hydrocarbon groups, and more preferably all are C1-C6 alkyl groups.

[0032] In some embodiments, R3 and R4 together form a ring with the bonded nitrogen atom, and R5 is H or a C1-C20 hydrocarbon group, of which the nitrogen atom and R3 and / or R4 may be bonded by a normal carbon-nitrogen bond or by an amide bond. The ring formed by both R3 and R4 and the bonded nitrogen atom may be a 4-membered ring, a 5-membered ring, a 6-membered ring, or a 7-membered ring.

[0033] In some embodiments, Y2 is always O, or N(R6), or S.

[0034] In some embodiments, Y2 is N(R6) or S.

[0035] In some embodiments, Y2 is N(R6) or O.

[0036] In some embodiments, Y2 is O, or N(R6), or S.

[0037] In some embodiments, R6 is H.

[0038] In some embodiments, R6 is a C1-C20 hydrocarbon group, preferably a C1-C6 hydrocarbon group, and more preferably a C1-C6 alkyl group.

[0039] In some embodiments, n1, n2, and n3 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and preferably each independently 0, 1, 2, 3, or 4.

[0040] In some embodiments, n1, n2, and n3 are all 0.

[0041] In some embodiments, n4, n5, and n6 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and preferably each independently 0, 1, 2, 3, or 4.

[0042] In some embodiments, n4, n5, and n6 are all 0.

[0043] In some embodiments, A -The group is selected from halogen ions, perhalate groups, nitrate groups, sulfate groups, hydrogen sulfate groups, sulfite groups, phosphoric acid groups, hydrogen phosphate groups, C1-C8 alkyl acid groups, C1-C8 alkyl sulfonic acid groups, C1-C8 alkyl sulfate groups, and C1-C8 aryl sulfonic acid groups.

[0044] In some more specific embodiments, A - It is preferable that the group be selected from sulfate groups, phosphate groups, acetate groups, propionic acid groups, chloride ions, and bromide ions.

[0045] In some embodiments, R1 is hydrogen and R2 is one or more [ka] Replaced by [ka] In this case, under appropriate conditions, the chiral arylpropionic acid derivative according to the present invention may form an intramolecular salt or an intermolecular salt.

[0046] In some embodiments, R1 is hydrogen and R2 is one or more [ka] Replaced by [ka] In this case, under appropriate conditions, the chiral arylpropionic acid derivative according to the present invention may form a salt with other anions, which are as described above.

[0047] In some embodiments, R2 is hydrogen and R1 is one or more [ka] Replaced by [ka] In this case, under appropriate conditions, the chiral arylpropionic acid derivative according to the present invention may form a salt with other anions, which are as described above.

[0048] In some embodiments, R1 is one or more [ka] Replaced by [ka] And R2 is one or more [ka] Replaced by [ka] In this case, under appropriate conditions, the chiral arylpropionic acid derivative according to the present invention may form a salt with other anions, which are as described above.

[0049] In some embodiments, the chiral arylpropionic acid derivatives provided by the present invention are [ka] Alternatively, a selection is made from its pharmaceutically acceptable salts.

[0050] In another embodiment, the present invention provides a drug composition containing the above-mentioned chiral arylpropionic acid derivative, its tautomer, solvate, or pharmaceutically acceptable salt thereof.

[0051] The present invention discloses a drug composition comprising a compound described in the present invention, its tautomer, solvate, or a pharmaceutically acceptable salt thereof as an active ingredient or main active ingredient, and a pharmaceutically acceptable carrier.

[0052] The chiral arylpropionic acid derivative according to the present invention can be prepared as a medicinal composition to be administered to a patient according to a plurality of suitable administration methods, including topical skin preparations, ophthalmic preparations, inhalation preparations, and other methods of extra-gastrointestinal local administration.

[0053] In some examples of the present invention, an inhalation preparation is obtained by mixing the chiral arylpropionic acid derivative according to the present invention with lactose and grinding the mixture.

[0054] In some examples of the present invention, the chiral arylpropionic acid derivative according to the present invention is dissolved together with an appropriate amount of surfactant and an osmotic pressure adjusting agent to form an inhalation solution.

[0055] In some examples of the present invention, a chiral arylpropionic acid derivative according to the present invention is used together with an appropriate amount of a surfactant or the like to form a topical skin preparation.

[0056] In some examples of the present invention, a chiral arylpropionic acid derivative according to the present invention is used together with an appropriate adjuvant to form an ophthalmic formulation.

[0057] In a third aspect, the compounds according to the present invention have high bioavailability when administered intra- or extra-gastrointestinally and are rapidly converted into active ingredients, and are particularly effective when administered cutaneously or orally.

[0058] The compound according to the present invention has superior anti-rheumatoid arthritis effects. The compound according to the present invention significantly suppresses the proliferation of INF-α-induced human fibroblastoid synovial cell rheumatoid arthritis (HFLS-RA), and also significantly suppresses the expression of inflammatory cytokines, exhibiting higher activity and is expected to enable a reduction in dosage and side effects.

[0059] Furthermore, it was unexpectedly discovered that the compound according to the present invention exhibits high distribution in joint areas after oral administration. Further research has shown that topical application to the skin results in better synovial fluid distribution and therapeutic effect, making it suitable for use as a topically administered nonsteroidal anti-inflammatory drug.

[0060] In a fourth aspect, the present invention provides the use of the above-mentioned chiral arylpropionic acid derivative, its tautomers, and pharmaceutically acceptable salts thereof as nonsteroidal anti-inflammatory drugs, mainly for anti-inflammatory and analgesic purposes for conditions such as arthritis, rheumatoid arthritis, lower back pain, periarthritis of the shoulder joint, and cervicobrachial syndrome, as well as for anti-inflammatory and analgesic purposes after surgery, and for antipyretic and analgesic purposes for acute respiratory inflammation. [Brief explanation of the drawing]

[0061] [Figure 1] This shows a comparison of the distribution of Control 1, Control 2, and compounds DSC4813 and DSC4821 according to the present invention in the joint area. [Examples]

[0062] The following examples may help those skilled in the art to better understand the present invention, but they do not limit the invention in any way. The structures of all compounds are as measured by MS or 1 It is determined by 1H NMR.

[0063] Example 1 Synthesis of the trans-OH compound The trans-OH compound was synthesized by referring to the literature (Mandai, T. and T. Yamakawa (2000). “An Efficient Synthesis of (2S)-2-[4-((1R,2S)-2-Hydroxycyclopentylmethyl)phenyl]propionic Acid.” Synlett 2000(06):0862-0864.). Its mp was 87-88°C, [MH] - The result was 247.16. 1 H NMR(300MHz,CDCl3)δ:1.20-1.32(m,1H),1.41-1.82(m,7H),1.88-2.06(m,2H), 2.46(dd,1H),2.75(dd,1H),3.69(q,1H),3.86-3.95(m,1H),7.10-7.24(m,4H).

[0064] Example 2: Synthesis of DSC4801 [Chemistry]

[0065] 0.8 g of trans-OH compound was added to 10 mL of N,N-dimethylformamide (DMF), the temperature of the reaction system was lowered to 0° C., 1.01 g of compound 1 (2-bromo-N,N-diethylethanamine hydrobromide) and 0.85 g of sodium carbonate were added, and the reaction system was stirred for 18 hours. Water was added to precipitate a solid, which was filtered, 20 mL of dichloromethane was added to the solid, water was added for liquid separation, the organic phase was concentrated to dryness, purified by silica gel column to obtain 0.72 g of compound DSC4801. The yield was 64%, [M+H] + = 348.33. 1 H NMR (300 MHz, CDCl3) δ: 0.95 (t, 6H), 1.19-1.30 (m, 1H), 1.41-1.71 (m, 6H), 1.75-1.85 (m, 1H), 1.94-2.14 (m, 2H), 2.44 (dd, 1H), 2.51 (m, 4H), 2.78 (m, 3H), 3.74 (q, 1H), 3.86-4.05 (m, 1H), 4.26 (t, 2H), 7.11-7.21 (m, 4H).

[0066] Example 3 Synthesis of DSC4804 [Chemistry]

[0067] 0.45 g of compound DSC4801, 0.15 g of pyridine and 10 mL of acetonitrile were added into a reaction flask, and the reaction mixture was heated to 35° C. 0.2 g of acetic anhydride was added at 35-40° C., and then the reaction was allowed to proceed at 50° C. for 4 hours. The reaction system was concentrated to dryness, cooled to room temperature, 15 mL of dichloromethane and 15 mL of water were added, liquid separation was performed, and the organic phase was concentrated to dryness. Purification by silica gel column gave 0.39 g of compound DSC4804. The yield was 77%, [M+H] + = 390.19. 1H NMR(300 MHz, CDCl3)δ:1.08(t,6H),1.17-1.30(m,1H),1.45-1.86(m,7H),1.94-2.11(m,5H),2.49(dd, 1H),2.53(m,4H),2.75(m,3H),3.76(q,1H),3.81-3.98(m,1H),4.3(t,2H),7.07-7.20(m,4H).

[0068] Example 4: Synthesis of DSC4807 [ka]

[0069] Synthesis of Compound 2 1.0 g of the trans-OH compound was added to 10 mL of N,N-dimethylformamide (DMF), the temperature of the reaction system was lowered to 0°C, 0.83 g of benzyl bromine and 0.55 g of sodium carbonate were added, and the reaction system was stirred for 3 hours. Water was added to precipitate the solid, which was filtered, 20 mL of dichloromethane was added to the solid, water was added and liquid-liquid was separated, the organic phase was concentrated to dry, and purified by silica gel column to obtain 1.12 g of compound 2. The yield was 82%, and [M+H] + The result was 339.10.

[0070] Synthesis of Compound 3 1.0 g of compound 2, 0.3 g of pyridine, and 20 mL of anhydrous dichloromethane were added to a reaction flask. The temperature of the reaction mixture was lowered to 0°C, and 0.66 g of bromoacetyl bromide was added. The reaction system was allowed to react at room temperature for 12 hours. Water was added and the mixture was separated. The organic phase was concentrated to dry and purified by silica gel column chromatography to obtain 1.06 g of compound 3. The yield was 78%, and [M+H] + The result was 459.21.

[0071] Synthesis of Compound 4 0.2 g of the compound diethylaminoethanol and 15 mL of anhydrous tetrahydrofuran were added to the reaction flask. The temperature of the reaction system was lowered to 0°C, 0.05 g of sodium hydride (60%) was added, and the reaction system was stirred for 30 minutes. 0.71 g of compound 3 was added, and the reaction mixture was heated to 35°C and reacted for 4 hours. The reaction system was concentrated to dry. The mixture was cooled to room temperature, 15 mL of dichloromethane and 15 mL of water were added, and the mixture was separated. The organic phase was concentrated to dry and purified by silica gel column chromatography to obtain 0.63 g of compound 4. The yield was 75%, and [M+H] + The result was 496.34.

[0072] Synthesis of compound DSC4807 0.5 g of compound 4 was mixed with 1.19 g of 10% palladium-carbon, 10 mL of methanol was added to the reaction system, a hydrogen gas balloon was attached, and the reaction system was heated to 30°C and reacted for 8 hours. The reaction system was filtered, the filtrate was concentrated to dry, and purified by silica gel column chromatography to obtain 0.36 g of compound DSC4807. The yield was 88%, [MH] - The result was 404.29.

[0073] Example 5: Synthesis of DSC4806 [ka]

[0074] Synthesis of Compound 6 Compound 6 was synthesized by referring to the method described in the literature ("Characterization of N,N-dimethylamino acids by electrospray ionization-tandem mass spectrometry." J. Mass Spectrom. 2015, 50, 771-781).

[0075] Synthesis of Compound 7 1.2 g of compound 6 and 30 mL of ethanol were added to a reaction flask. 10 mL of 2N sodium hydroxide solution was added to the reaction system, and 1.51 g of benzyl bromide was added while vigorously stirring. After the reaction system was allowed to react at room temperature for 2 hours, concentrated hydrochloric acid was added to adjust the pH to neutral, the solid was precipitated, filtered, the filter cake was washed sequentially with water and ethanol, and the reaction system was dried to obtain 1.48 g of compound 7. The yield was 77%. [MH] - The result was 238.25.

[0076] Synthesis of compound 8 1.2 g of compound 7 and 15 mL of dichloromethane were added to a reaction flask. 1 g of thionyl chloride was added to the reaction system, and the mixture was reacted at room temperature for 3 hours. The reaction system was concentrated to dry, and 30 mL of dichloromethane was added again. The mixture was concentrated to dry. 15 mL of dichloromethane and 1 mL of triethylamine were added to the reaction system, and 1.74 g of compound DSC4801 was added. The reaction system was heated to 40°C and reacted for 5 hours. The mixture was concentrated to dry and purified by silica gel column to obtain 1.83 g of compound 8. The yield was 64%, and [M+H] + The result was 569.33.

[0077] Synthesis of compound DSC4806 0.25 g of 5% palladium-carbon was added to 0.6 g of compound 8, 10 mL of methanol was added to the reaction system, a hydrogen gas balloon was attached, and the reaction system was heated to 30°C and reacted for 8 hours. The reaction system was filtered, the filtrate was concentrated to dry, and purified by silica gel column to obtain 0.43 g of compound DSC4806. The yield was 85%, and [M+H] + The result was 479.29.

[0078] Example 6: Synthesis of DSC4815 and DSC4816 [ka]

[0079] Synthesis of compound DSC4815 Under the protection of nitrogen gas, at room temperature, 20 mL of tetrahydrofuran and 2.6 g of compound DSC4801 were sequentially added to a reaction flask, followed by the slow addition of 8 mL of tetrahydrofuran solution containing 0.54 g of chloroethane. After the addition was complete, the mixture was heated to reflux and reacted for 30 minutes. After the reaction was complete, the temperature was lowered to 0-10°C, filtered, dried, and the crude product was obtained. Recrystallization in a methanol / acetone mixed solvent yielded 1.33 g of compound DSC4815. The yield was 43%, [M+H] + The result was 376.03.

[0080] Synthesis of compound DSC4816 1 g of compound DSC4815 and 5 mL of anhydrous ethanol were added to a reaction flask and heated at 50°C. 0.45 g of silver acetate was then added. The reaction mixture was stirred for 3 hours, then filtered by heat, and the filtrate was cooled to approximately 10°C. 13 mL of methyl tert-butyl ether was added, and crystallization was performed to obtain 0.39 g of compound DSC4816. The yield was 37%, and [M+H] + =376.03, [MH] - The result was 59.01.

[0081] Example 7 Synthesis of DSC4821 [ka]

[0082] Synthesis of compound 11 0.18 g of compound diethylamine hydrochloride, 0.5 g of compound 3, and 15 mL of anhydrous tetrahydrofuran were added to a reaction flask. The temperature of the reaction system was lowered to 0°C, 0.7 mL of triethylamine was added, and the reaction mixture was heated to 35°C and reacted for 4 hours. The reaction system was concentrated to dry, cooled to room temperature, 15 mL of dichloromethane and 15 mL of water were added, and the mixture was separated. The organic phase was concentrated to dry and purified by silica gel column chromatography to obtain 0.34 g of compound 11. The yield was 69%, and [M+H] + The result was 452.34.

[0083] Synthesis of compound DSC4821 0.3 g of compound 11 was mixed with 50 mg of palladium-carbon (10%), 10 mL of methanol was added to the reaction system, a hydrogen gas balloon was attached, and the reaction system was heated to 30°C and reacted for 8 hours. The reaction system was filtered, the filtrate was concentrated to dry, and purified by silica gel column chromatography to obtain 0.2 g of compound DSC4821. The yield was 84%, [MH] - The result was 360.29. 1 H NMR(300MHz,CDCl3)δ:0.99(t,6H),1.22-1.30(m,1H),1.37-1.66(m,3H),1.45(d,3H),1.70-1.79(m,1H),1.83 -2.02(m,2H),2.43-2.66(m,6H),2.75(dd,1H),3.15(s,2H),3.65(q,1H),3.76-3.88(m,1H),7.08-7.27(m,4H).

[0084] Example 8: Synthesis of DSC4826 [ka]

[0085] Synthesis of compound 12 0.7 g of compound 2, 1.25 g of p-nitrophenyl chloroformate, 1 mL of triethylamine, and 10 mL of tetrahydrofuran were added to a reaction flask. The reaction system was allowed to react at room temperature for 1 hour. The reaction system was concentrated to dry, extracted with ethyl acetate and water, concentrated to dry the organic phase, and purified by silica gel column chromatography to obtain 0.8 g of compound 12. The yield was 77%, and [M+H] + The result was 504.21.

[0086] Synthesis of compound 13 0.13 g of the compound diethylaminoethanol and 15 mL of anhydrous tetrahydrofuran were added to the reaction flask, the temperature of the reaction system was lowered to 0°C, 65 mg of sodium hydride (60%) was added, and the reaction system was stirred for 30 minutes. 0.55 g of compound 12 was added, the reaction mixture was heated to 35°C and reacted for 4 hours, the reaction system was concentrated to dry, cooled to room temperature, 15 mL of dichloromethane and 15 mL of water were added, liquid-liquid was separated, the organic phase was concentrated to dry, and purified by silica gel column to obtain 0.37 g of compound 13. The yield was 71%, [M+H] + The result was 482.39.

[0087] Synthesis of compound DSC4826 Using the synthesis method for compound DSC4821, 0.18 g of compound DSC4826 was synthesized from compound 13 as a material. The yield was 84%, [MH] - The result was 390.33. 1 H NMR(300MHz,CDCl3)δ:1.01(t,6H),1.22-1.30(m,1H),1.38-1.82(m,7H),1.91-2.06(m,2H),2.46(dd,1H), 2.51-2.55(m,4H),2.75-2.88(m,3H),3.71(q,1H),3.86-3.91(m,1H),4.23-4.25(t,2H),7.05-7.20(m,4H).

[0088] The following compounds according to the examples were synthesized in the same manner as in the above examples, using commercially available compounds or intermediate compounds appropriately synthesized using commercially available compounds.

[0089] [ka]

[0090] Synthesis of comparative examples [ka]

[0091] The synthesis of Control 1 was carried out using the synthesis method of the compound in the example. [M+H] - The result was 317.37. 1 H NMR(300MHz,CDCl3)δ:0.78(t,3H),1.06-1.29(m,3H),1.38-1.76(m,7H),1.81-2.02(m,2H), 2.11(t,2H),2.47(dd,1H),2.79(dd,1H),3.63(q,1H),3.85-3.95(m,1H),7.13-7.27(m,4H).

[0092] Control 2 was sourced from the market.

[0093] For the synthesis of control 3, refer to the examples of this application and the synthesis method described in Chinese Patent No. 103705496.

[0094] Example 9: Effect on the proliferative activity of HFLS-RA cells Grouping and Sample Concentrations: The experiment was divided into two groups: a blank control group (Group 1 for CCK-8 detection at 0 hours and Group 2 for CCK-8 detection at 72 hours; neither group contained the test product or TNF-α), a TNF-α group (only TNF-α was added without the test product, with a final TNF-α concentration of 10 ng / mL), a test product group (test products were DSC4801-DSC4826 and controls 1-3; the structures of controls 1-3 were based on the synthetic parts of the comparative examples; the final concentrations of each test product and TNF-α for cell incubation were 100 μg / mL and 10 ng / mL, respectively), and a positive control group (final concentrations of methotrexate and TNF-α for cell incubation were 1 μg / mL and 10 ng / mL, respectively).

[0095] Co-incubation: HFLS-RA cells are taken during the logarithmic growth phase, and 3 × 10⁻¹⁶ cells are incubated. 4Cells were inoculated into 96-well culture plates at a density of cells / ml, with an inoculation volume of 100 μL per well. After inoculation, the cells were incubated at 37°C in a 5% CO2 incubator for 24 hours (cell adhesion confluence reached approximately 25%). An appropriate amount of each sample solution was added according to the final concentration of the group and sample, and three duplicate wells were created for each group. Before sample addition (0 hours), CCK-8 detection was performed on group 1, the blank control group, and CCK-8 detection was performed on the remaining groups after incubation in the incubator for 72 hours.

[0096] Detection and Calculation: The culture medium was discarded, and 100 μL of medium containing 10% CCK-8 solution was added to each well. The cultures were incubated at 37°C for 2 hours. Absorbance (OD value) was measured at 450 nm using a microplate reader, and the cell proliferation rate was calculated according to the following formula. The results are shown in Table 1.

[0097] The formula is: Cell proliferation rate = [OD (72h) -OD (0h) ] / OD (0h) It is ×100%, and in the formula, OD (0h) This shows the OD value at 0 hours, OD (72h) This shows the OD value at 72 hours.

[0098] [Table 1]

[0099] As can be seen from Table 1, the TNF-α group significantly promoted the proliferation of HFLS-RA cells compared to the blank control group (P<0.001). The positive control group and the test product groups (compounds DSC4801-DSC4826 and controls 1-3 according to the present invention) were all able to significantly suppress TNF-α-induced HFLS-RA cell proliferation compared to the TNF-α group (P<0.001). The compounds according to the present invention showed a significantly higher level of suppression of TNF-α-induced HFLS-RA cell proliferation compared to control groups 1, 2, and 3 (P<0.001). As a result, it was shown that the compounds according to the present invention can exert an anti-inflammatory effect by suppressing HFLS-RA cell proliferation and are significantly superior to control compounds 1, 2, and 3.

[0100] Example 10: Effects of HFLS on cytokine secretion in RA The experiment was divided into three groups: a blank control group (without test product or TNF-α), a TNF-α group (final TNF-α concentration for cell incubation was 10 ng / mL), and test product groups (a total of eight groups: DSC4801, DSC4807, DSC4810, DSC4813, DSC4821, DSC4826, and control groups 1 and 3, with final concentrations of 100 μg / mL and 10 ng / mL for each test product and TNF-α for cell incubation, respectively).

[0101] HFLS-RA cells were taken during the logarithmic growth phase, and 5 × 10⁻⁶ cells were taken. 4 At a density of individual cells / ml 96 wells The cells were inoculated into culture plates, with an inoculation volume of 200 μL per well. After inoculation, the cells were incubated at 37°C in a 5% CO2 incubator for 2 hours. An appropriate amount of each sample solution was added according to the final concentration of the group and sample, and three duplicate wells were created for each group. After continuing incubation for 48 hours, the cell supernatant was collected, and the content of IL-6 and IL-8 in the supernatant was detected using an ELISA reagent kit. The results are shown in Table 2.

[0102] [Table 2]

[0103] As can be seen from Table 2, TNF-α significantly induces the expression of IL-6 and IL-8 inflammatory factors in HFLS-RA cells compared to the blank control group (P<0.001). The compound according to the present invention significantly suppresses the expression of IL-6 and IL-8 inflammatory factors in HFLS-RA cells induced by TNF-α compared to the TNF-α group, control group 1, and control group 3 (P<0.001). As a result, the compound according to the present invention is shown to exert an anti-inflammatory effect by suppressing the expression of IL-6 and IL-8 inflammatory factors, and is significantly superior to control compounds 1 and 3.

[0104] Example 11 Distribution in joint tissue Thirty-six healthy male SD rats weighing 200 ± 20 g were prepared. They were housed at room temperature of 20-26°C, humidity of 40-70%, and a light-dark cycle of 12 hours / 12 hours, and were allowed to feed freely during this time. After adaptive rearing for three days, the SD rats were randomly divided into four groups (A / B / C / D), with nine rats per group. Within each group, they were further randomly divided into three time groups, with three rats per time group. Each group was orally administered intragastricly by suspension of the test substance (each test substance suspended in 1% MS). Of these, group A received 3 mg / kg of DSC4813, group B received 2.94 mg / kg of DSC4821, group C received 2.47 mg / kg of control 1, and group D received 2 mg / kg of control 2 (loxoprofen). Three rats were anesthetized and executed in each group at 0.5 hours, 1 hour, and 2 hours after administration. The left and right ankle joints were then dissected, the skin around the joints was removed, and tissues around the ankle joints (including medial and lateral collateral ligaments, medial and lateral deltoid ligaments, fascia, tendons, and synovial membrane) were collected and weighed. After cutting, the joint tissue samples were subjected to sonic extraction using 10 mL of methanol. The extraction time was 20 minutes. After extraction, the samples were placed in EP tubes, sealed, and stored at -20°C for measurement. The substances to be measured were detected by LC-MS / MS (trans-OH forms of the compound were detected in groups A / B / C, while loxoprofen and all isomers with the carbonyl group reduced to OH were detected in group D. The results for group D represent the sum of the concentrations of loxoprofen and all isomers with the carbonyl group reduced to OH). The results are shown in Figure 1.

[0105] As can be seen from Figure 1, the compounds DSC4813 and DSC4821 according to the present invention showed significantly improved distribution at joint sites after oral intragastric infusion compared to controls 1 and 2 (P<0.001). Therefore, it was estimated that the compounds DSC4813 and DSC4821 according to the present invention have good anti-arthritis effects and are superior to control compounds 1 and 2.

[0106] The present invention has been disclosed above by preferred embodiments, but these embodiments are not intended to limit the invention. Those skilled in the art can make several modifications and improvements without departing from the spirit and scope of the invention. Therefore, the scope of protection of the present invention is as defined in the claims.

Claims

1. A chiral arylpropionic acid derivative represented by the following formula (I), its tautomer, solvate, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 In formula (I), R １ H is, R ２ is one or more 【Chemistry 2】 Replaced by 【Transformation 3】 And, Y ２ is O, or N(R ６ ), or S, n 4 is 1 or 2, n 5 is 2, n 6 is 0 or 1, R3 and R4 are each independently C1-C20 hydrocarbon groups. R5 is H or a C1-C20 hydrocarbon group. R 6 is H, A － This represents an acceptable inorganic or organic anion.

2. A chiral arylpropionic acid derivative represented by the following formula (I), its tautomer, solvate, or a pharmaceutically acceptable salt thereof. 【Chemistry 4】 In formula (I), R ２ H is, R １ is one or more 【Transformation 5】 Replaced by 【Transformation 6】 And, n1 is 2, n2 is 2, n3 is 0 or 1, Y ２ is O or N(R ６ ), or S, R3 and R4 are independently a C1-C20 hydrocarbon group or a C1-C20 alkylcarbonyl group, and R ３ and R ４ They form a ring with the nitrogen atom they are bonded to, R5 is H or a C1-C20 hydrocarbon group. R 6 is a C1-C20 hydrocarbon group, A － This represents an acceptable inorganic or organic anion.

3. In the formula, R ３ , R ４ and R ５ When is a hydrocarbon group, the hydrocarbon group is a C1-C4 alkane group, the chiral arylpropionic acid derivative according to claim 1 or 2, a tautomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

4. The following formula: 【Transformation 7】 A chiral arylpropionic acid derivative, a tautomer, a solvate, or a pharmaceutically acceptable salt thereof, selected from the compounds represented by or pharmaceutically acceptable salts thereof.

5. The pharmaceutically acceptable salt comprises a salt formed with an anion, wherein the anion comprises at least one selected from the group consisting of fluoride ions, chloride ions, bromide ions, iodide ions, acetate ions, benzoate ions, citrate ions, tartrate ions, oxalate ions, malate ions, ascorbic acid ions, and fumarate ions, according to claim 1, 2, or 4, a chiral arylpropionic acid derivative, a tautomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

6. The pharmaceutically acceptable salt includes an intramolecular salt or an intermolecular salt, the chiral arylpropionic acid derivative according to claim 1, 2, or 4, its tautomer, solvate, or pharmaceutically acceptable salt thereof.

7. A drug composition comprising a chiral arylpropionic acid derivative according to claim 1, 2, or 4, a tautomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

8. Use of the chiral arylpropionic acid derivative according to Claim 1, 2, or 4, its tautomer, solvate, or pharmaceutically acceptable salt thereof in the manufacture of an antipyretic, analgesic, or anti-inflammatory drug.

9. Use of the drug composition according to Claim 7 in the manufacture of an antipyretic, analgesic, and anti-inflammatory drug.

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