N-(Benzenesulfonyl)amide derivatives and preparation methods and uses thereof

Abstract

The present invention discloses an N-(benzenesulfonyl)amide derivative, a preparation method and use thereof. Specifically, the present invention discloses a compound represented by formula (I) or its tautomer, isotope label, pharmaceutically acceptable salt, and a preparation method and use thereof. The compound of the present invention has the biological activity of inhibiting multiple targets of COX-2, TRPV1, and 5-LOX, and can be effectively used for anti-inflammatory and analgesic.

Description

Technical Field

[0001] The present invention provides a class of N-(benzenesulfonyl)amide derivatives and a preparation method and use thereof. The compounds of the present invention have the biological activity of inhibiting cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and TRPV1 multiple targets, and can be used as anti-inflammatory and / or analgesic drugs. Background Art

[0002] Pain is one of the most common clinical symptoms. Due to its complex pathological mechanism, it has become an urgent need to be met in clinical practice. Currently, commonly used analgesics in clinical practice include opioids and nonsteroidal anti-inflammatory drugs. Nonsteroidal anti-inflammatory drugs mainly achieve analgesic effects by inhibiting cyclooxygenase (COX) in the arachidonic acid metabolic pathway. In addition to COX, the arachidonic acid metabolic pathway also involves lipoxygenase (LOX) and cytochrome P450 enzymes. The above key enzymes and major metabolites are closely related to the development and regression of inflammation and pain. In the lipoxygenase family, 5-lipoxygenase is most closely related to inflammation and pain. Studies have shown that COX-2 and 5-LOX present a compensatory mechanism in the process of amino acid metabolism, and inhibiting one of the pathways will cause the activation of the other pathway. Therefore, simply inhibiting the activity of COX-2 or 5-LOX cannot achieve very good therapeutic effects. In addition, the gastrointestinal side effects of nonsteroidal anti-inflammatory drugs are very obvious, which has become the main factor limiting their clinical use. Therefore, developing an anti-inflammatory and / or analgesic drug with multi-pathway inhibition, high efficiency and low toxicity has high clinical value.

[0003] With the development of related disciplines and the application of new technologies, research on various receptors related to pain transmission and their selective ligands has made certain progress. With the successful cloning of transient receptor potential vanilloid subtype 1 (TRPV1, also known as vanilloid receptor or capsaicin receptor), a new target for the treatment of pain has been found. TRPV1 is one of the members of the non-selective cation channel protein family of transient receptor potential, mainly expressed on the nociceptors of primary afferent sensory neurons, and plays a very critical role in the initiation of neuroinflammatory response and the transduction process of pain. At present, TRPV1 has become an important new analgesic drug target. TRPV1 antagonists can directly block receptors, inhibit the conduction of pain signals from peripheral nerves to central nerves, block various pathological states associated with receptors, and play an analgesic effect. However, the TRPV1 antagonists currently developed (such as ABT-102, AMG 517) cause the body temperature of subjects to rise in clinical trials, which is a very fatal side effect. At present, there is no TRPV1 antagonist that has been successfully marketed.

[0004] In order to solve the defects of the anti-inflammatory and / or analgesic drugs in the prior art, it is urgent to provide a drug with good anti-inflammatory and / or analgesic effect, few side effects and high bioavailability. Summary of the invention

[0005] In order to overcome the defects of the prior art, the present invention provides a compound represented by formula (I):

[0006]

[0007] or a tautomer, an isotopically enriched product, or a pharmaceutically acceptable salt thereof, wherein R1 is as defined herein.

[0008] On the other hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I) or its tautomer, isotope label, pharmaceutically acceptable salt, and pharmaceutically acceptable salt.

[0009] In another aspect, the present invention provides use of the compound represented by formula (I) or its tautomers, isotope-enriched products, and pharmaceutically acceptable salts in the preparation of drugs for preventing and / or treating inflammatory diseases or relieving pain.

[0010] Beneficial effects: The compound of the present invention is an N-(phenylsulfonyl)amide derivative that can inhibit multiple targets of COX-2, 5-LOX, and TRPV1, has anti-inflammatory and analgesic activities that are significantly superior to existing drugs, and has stronger water solubility and bioavailability, as well as lower side effects. DETAILED DESCRIPTION

[0011] definition

[0012] As used in this specification, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0013] As used herein, the term "alkyl" refers to a monovalent group of a straight or branched saturated hydrocarbon chain having 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like.

[0014] As used herein, the term "alkenyl" refers to a linear or branched unsaturated hydrocarbon chain monovalent group having 2 to 6 carbon atoms and having a carbon-carbon double bond (e.g., 1, 2 or 3 carbon-carbon double bonds). The term is exemplified by groups such as vinyl (i.e., -CH=CH2), propen-1-yl (i.e., -CH=CHCH3), propen-3-yl (or allyl, i.e., -CH2CH=CH2), propen-2-yl (i.e., -C(CH3)=CH2), butadienyl (including 1,2-butadienyl and 1,3-butadienyl), etc.

[0015] As used herein, the term "alkynyl" refers to a linear or branched unsaturated hydrocarbon chain monovalent group having 2 to 6 carbon atoms and having carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds). The term is exemplified by groups such as ethynyl (i.e., -C≡CH), propargyl (i.e., -CH2C≡CH), propynyl (i.e., -C≡CCH3), etc.

[0016] As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0017] As used herein, the term "alkoxy" refers to an "alkyl-O-" group, wherein alkyl is as defined herein. This term is exemplified by groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

[0018] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen, wherein alkyl is as defined herein. The term is exemplified by the groups trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1,-difluoroethyl, etc.

[0019] As used herein, the term "cycloalkyl" refers to a monoradical saturated group having 3 to 6 carbon atoms as ring atoms. Examples of cycloalkyl include cyclopropane, cyclobutane, cyclopentane, cyclohexane.

[0020] As used herein, the term "heterocyclyl" refers to a monocyclic monoradical saturated group having 5 to 6 ring atoms in the ring, wherein in addition to carbon atoms, the ring atoms also contain at least one heteroatom selected from oxygen, nitrogen and / or sulfur. Examples of heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,3-dioxolane, 1,2-dioxolane, 1,3-dithiolanyl, 1,2-dithiolanyl, 1,2-oxathiolanyl, 1,3-oxathiolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, dithiopyranyl, oxathiolanyl, morpholinyl, etc.

[0021] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to affect treatment as defined below when administered to a mammal in need of such treatment. The therapeutically effective amount will vary with the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art.

[0022] As used herein, the term "tautomer" refers to the coexistence of two (or more) compounds that differ only in the position and electron distribution of one (or more) mobile atoms, such as keto-enol tautomers.

[0023] As used herein, the term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of a given compound and are not biologically or otherwise undesirable. Pharmaceutically acceptable salts can be acid addition salts and / or base addition salts. Acid addition salts can be prepared from inorganic acids and organic acids. Salts derived from inorganic acids include hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, carbonates, bisulfates, hydrogenphosphates, dihydrogenphosphates, bicarbonates, etc.; salts derived from organic acids include formates, acetates, propionates, glycolates, pyruvates, oxalates, malates, malonates, succinates, maleates, fumarates, tartrates, citrates, benzoates, cinnamates, mandelates, methanesulfonates, ethanesulfonates, p-toluenesulfonates, salicylates, lactates, nicotinates, lauryl sulfates, naphthylsulfonates, camphorsulfonates, gluconates, glucuronates, oleates, palmitates, stearates, pamoates, trifluoroacetates, etc. Base addition salts can be formed with inorganic or organic bases. Salts derived from inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, lithium, barium, aluminum salts and the like; salts derived from organic bases include salts formed with various primary, secondary and tertiary amines, for example, ethylamine, diethylamine, n-propylamine, isopropylamine, diethanolamine, meglumine, lysine, piperazine, piperidine, morpholine, tromethamine, choline and the like.

[0024] As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0025] Any formula or structure given herein, including Formula I or any formula disclosed herein, is also intended to represent unlabeled forms of the compounds as well as isotopically labeled forms. These isotopically labeled forms of compounds may also be referred to as "isotopically labeled" or "isotopically enriched analogs." Isotopically labeled compounds have structures depicted herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as, but not limited to, 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Various isotope-labeled compounds of the present invention, for example, compounds into which a radioactive isotope (e.g. 3 H. 13 C and 14 C). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced with deuterium.

[0026] Compound

[0027] In one embodiment, the present invention provides a compound represented by formula (I)

[0028]

[0029] or its tautomers, isotope-labeled substances, pharmaceutically acceptable salts, wherein

[0030] R1 is selected from

[0031] in:

[0032] R2 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkanoyloxy, C1-C6 alkanoylamido, hydroxyl, amino, cyano, nitro, carboxyl;

[0033] R3 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkanoyloxy, C1-C6 alkanoylamido, hydroxyl, amino, cyano, carboxyl;

[0034] R4 is selected from hydrogen or C1-C6 alkyl;

[0035] R5 is selected from C3-C6 cycloalkyl or 5-6 membered heterocyclic group;

[0036] m is an integer selected from 1 to 5;

[0037] n is selected from integers of 0-5.

[0038] In one embodiment, in the compound represented by formula (I) of the present invention or its tautomer, isotope-labeled substance, or pharmaceutically acceptable salt,

[0039] R1 is selected from in:

[0040] R2 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, amino, cyano, nitro, and carboxyl.

[0041] In one embodiment, in the compound represented by formula (I) of the present invention or its tautomer, isotope-labeled substance, pharmaceutically acceptable salt, R1 is selected from in:

[0042] R3 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, amino, cyano, carboxyl;

[0043] R4 is selected from hydrogen or C1-C6 alkyl;

[0044] m is selected from integers of 1 to 3.

[0045] In one embodiment, in the compound represented by formula (I) of the present invention or its tautomer, isotope-labeled substance, pharmaceutically acceptable salt, R1 is selected from in:

[0046] R5 is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,3-dioxolanyl, 1,2-dioxolanyl, 1,3-dithiolanyl, 1,2-dithiolanyl, 1,2-oxathiolanyl, 1,3-oxathiolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, dithiopyranyl, oxathiolanyl, morpholinyl;

[0047] n is selected from integers of 1 to 3.

[0048] In a specific embodiment, the compound represented by formula (I) of the present invention is selected from:

[0049] (E)-3-(4-hydroxy-3-methoxyphenyl)-N-((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)acrylamide;

[0050] 2-(4-isobutylphenyl)-N-((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)propanamide;

[0051] 5-(1,2-dithiolan-3-yl)-N-((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)pentanamide;

[0052] 4-Hydroxy-3-methoxy-N-((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)benzamide;

[0053] or a tautomer, an isotope-labeled substance, or a pharmaceutically acceptable salt thereof.

[0054] In a specific embodiment, the compound of the present invention is selected from:

[0055] Sodium benzoyl((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)amide;

[0056] Sodium (E)(-3-(4-hydroxy-3-methoxyphenyl)acryloyl)((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)amide;

[0057] Sodium (2-(4-isobutylphenyl)propionyl)((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)amide;

[0058] Sodium (5-(1,2-dithiolan-3-yl)pentanoyl)((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)amide;

[0059] Sodium (4-hydroxy-3-methoxybenzoyl)((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)amide;

[0060] Sodium (ethoxycarbonyl)((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)amide.

[0061] Pharmaceutical compositions and administration

[0062] The pharmaceutical composition provided by the present invention comprises the compound of the present invention or its stereoisomer, tautomer, solvate, prodrug, isotope label, pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are known to those skilled in the art, including diluents, lubricants, disintegrants, adhesives, buffers, preservatives, stabilizers, wetting agents, glidants, emulsifiers, colorants, flavoring agents, sweeteners, etc. According to the different routes of administration of the drug, such as oral administration, parenteral administration and rectal administration, the pharmaceutical composition of the present invention can be made in solid form (including but not limited to tablets, capsules, pills, granules, powders, powders, suppositories) or liquid form (including but not limited to solutions, suspensions, emulsions, tinctures, syrups). When the pharmaceutical composition of the present invention is in solid form, the pharmaceutically acceptable carrier generally includes one or more of the following: a) diluents, such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose, etc.; b) lubricants, such as silicon dioxide, talc, stearic acid, polyethylene glycol, etc.; c) binders, such as magnesium aluminosilicate, gelatinized starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, etc.; d) disintegrants, such as starch, alginic acid, agar, corn starch; e) stabilizers, such as antioxidants such as ascorbic acid; f) glidants, such as silicon dioxide; g) flavoring agents, such as mint, methyl salicylate; sweeteners, such as sucrose, saccharin. When the pharmaceutical composition of the present invention is in liquid form, the pharmaceutically acceptable carrier generally includes one or more of the following: a) a diluent, such as water for injection, physiological saline, Ringer's solution, polyethylene glycol, glycerol, propylene glycol, etc.; b) an antioxidant, such as ascorbic acid or sodium bisulfite; c) a buffer, such as acetate, phosphate, etc.

[0063] The effective dose of the compounds of the present invention depends at least on the nature, extent, delivery method and pharmaceutical dosage form of the condition being treated, and will be ultimately determined by the clinician. It can be expected that about 0.0001 to about 100 mg per kilogram of body weight per day; generally about 0.01 to about 10 mg per kilogram of body weight per day; more typically, about 0.01 to about 5 mg per kilogram of body weight per day; most typically about 0.05 to about 0.5 mg per kilogram of body weight per day. For example, the daily candidate dose for an adult of about 70 kg body weight will be in the range of 1 mg to 1000 mg, preferably in the range of 5 mg to 500 mg, and can be administered in the form of a single dose or multiple doses.

[0064] Indications

[0065] The compounds of the present invention have significant anti-inflammatory activity and can be used to treat or prevent inflammation-related diseases, including rheumatoid arthritis, gouty arthritis, osteoarthritis, spondylitis, systemic lupus erythematosus, psoriasis, eczema, subcutaneous inflammation, postpartum inflammation, enteritis, gastritis, inflammatory headache, periarteritis, stroke, ischemia, mental trauma, allergic rhinitis, coronary artery plaque inflammation, inflammation caused by bacteria, inflammation caused by viruses, inflammation caused by surgery, inflammation caused by trauma or gastric ulcer, etc.

[0066] The compounds of the present invention have significant analgesic activity and can be used to treat or prevent pain diseases of various causes, including but not limited to various acute pains and / or chronic pains, such as headaches, toothaches, migraines, visceral pains, neuralgia, etc.

[0067] General synthetic method

[0068] Compounds of the present invention can be prepared using methods disclosed herein and their modified approaches and methods well known in the art. Typical embodiments of compounds according to the present invention can be synthesized using the following general reaction schemes. It is apparent from the description herein that corresponding different products can be obtained by replacing reaction raw materials with other materials having similar structures. Reaction raw materials are typically obtained from commercial sources or synthesized using disclosed methods.

[0069] Reaction process

[0070]

[0071] The specific reaction process is:

[0072] Step 1: Dissolve compound Ia in a suitable solvent, such as methanol / water, then add a base (such as sodium hydroxide), raise the temperature to 60° C. and react for 20 hours to obtain compound Ib as a white solid.

[0073] Step 2: Dissolve compound Ib in a suitable solvent, such as dichloromethane, ethyl acetate, chloroform, etc., add celecoxib (Ic) and a condensation agent (such as DCC / DMAP, etc.) in sequence at room temperature, and react at 35°C for 20 hours under nitrogen protection to obtain compound I.

[0074] Optionally, step 3: dissolve compound I in a suitable solvent (including but not limited to methanol, ethanol, ethanol, DMF, etc.), add a base (such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.), react at 0°C to room temperature for 0.5 hours, and filter to obtain compound I'.

[0075] abbreviation name DCC Dicyclohexylcarbodiimide DCM Dichloromethane DMAP 4-Dimethylaminopyridine EA Ethyl acetate g gram MeCN Acetonitrile mg mg mL ml mmol mmol PE Petroleum ether TLC Thin layer chromatography

[0076] Example 1 Synthesis of Sodium Benzoyl((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)amide (HY-1)

[0077]

[0078] Step 1: Synthesis of compound 1

[0079]

[0080] Celecoxib (2.29 g, 6.00 mmol) was dissolved in DCM (50 mL), and benzoic acid (732 mg, 6.00 mmol), DCC (1.85 g, 9.00 mmol) and DMAP (732 mg, 6.00 mmol) were added at room temperature. The reaction was carried out at room temperature for 2 hours under nitrogen protection, and TLC showed that the reaction was complete. The reaction solution was washed three times with 1N hydrochloric acid solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (SiO2, PE: EA = 5: 1) to obtain a crude product of 1.00 g. The target compound 1 (550 mg, yield 19.0%) was obtained by purification on a preparative plate again (SiO2, DCM: MeOH = 20: 1) as a white solid.

[0081] Step 2: Synthesis of compound HY-1

[0082]

[0083] Compound 1 (550 mg, 1.13 mmol) was dissolved in ethanol (5 mL), and an ethanol solution (5 mL) of sodium hydroxide (45 mg, 1.13 mmol) was added dropwise at 0°C. After the addition, the mixture was kept warm for 0.5 hours, filtered, and the filter cake was washed with ether (5 mL × 1). The filter cake was dried in vacuo to obtain the target compound HY-1 (350 mg, yield 61.0%) as a yellow solid. 1H NMR (400MHz, DMSO-d6)ppm 7.87-7.92(m,4H),7.30-7.40(m,5H),7.18-7.23(m,4H),7.15(s,1H),2.31(s,3H).

[0084] Example 2 Synthesis of Compound (E) (-3-(4-hydroxy-3-methoxyphenyl)acryloyl)((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)amide Sodium (HY-3)

[0085]

[0086] Referring to the synthesis method of Example 1, benzoic acid was replaced by ferulic acid to obtain yellow solid compound HY-3 (375 mg, yield 64.7%). 1 H NMR(400MHz,DMSO-d6)δppm 7.82(d,J=8.4Hz,2H),7.33(d,J=8.8Hz,2H),7.18-7.23(m,4H),7.09-7.15(m,2H),6.92(s,1H) ,6.76(d,J=8.4Hz,1H),6.45(d,J=8.0Hz,1H),6.02(d,J=15.6Hz,1H),3.73(s,3H),2.31(s,1H).

[0087] Example 3 Synthesis of Sodium (2-(4-isobutylphenyl)propionyl)((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)amide (HY-4)

[0088]

[0089] Referring to the synthesis method of Example 1, benzoic acid was replaced by ibuprofen to obtain a white solid compound HY-4 (365 mg, yield 70.3%). 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.65 (d, J = 8.28Hz, 2H), 7.26 (d, J = 8.53Hz, 2H), 7.13-7.22 (m, 5H), 7.06 (d, J = 7.78Hz, 2H), 6.95 (d, J = 8 .03Hz,2H),3.27-3.33(m,1H),2.36(d,J=7.03Hz,2H),2.32(s,3H),1.71-1.81(m,1H),1.16(d,J=7.03Hz,3H),0.84(d,J=6.53Hz,6H).

[0090] Example 4 Synthesis of the compound sodium (5-(1,2-dithiolan-3-yl)pentanoyl)((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)amide (HY-5)

[0091]

[0092] Referring to the synthesis method of Example 1, α-lipoic acid was used to replace benzoic acid to obtain a yellow solid compound HY-5 (451 mg, yield 51.0%). 1 H-NMR (DMSO-d6, 400MHz) δ (ppm): 7.77 (d, J = 8.4Hz, 2H), 7.32 (d, J = 8.4Hz, 2H), 7.22-7.17 (m, 4H), 7.15 (s, 1H), 3.59-3.52 (m, 1H), 3.20-3.0 6(m,2H),2.42-2.34(m,1H),2.32(s,3H),1.92(t,J=7.2Hz,2H),1.86- 1.78(m,1H),1.67-1.47(m,2H),1.44-1.37(m,2H),1.30-1.22(m,2H).

[0093] Example 5 Synthesis of Sodium (4-hydroxy-3-methoxybenzoyl)((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)amide (HY-6)

[0094]

[0095] Referring to the synthesis method of Example 1, benzoic acid was replaced by vanillic acid to obtain a white solid compound HY-6 (323 mg, yield 99.3%). 1 H NMR(400MHz,DMSO-d6)δ(ppm):7.86-7.83(m,2H),7.32-7.29(m,2H),7.26-7.23(m,1 H),7.22-7.17(m,5H),7.23(s,1H),6.03(d,J=8.4Hz,1H),3.62(s,3H),2.30(s,3H).

[0096] Example 6 Synthesis of Sodium (Ethoxycarbonyl)((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)amide (HY-7)

[0097]

[0098] Referring to the synthesis method of Example 1, ethyl bicarbonate was used to replace benzoic acid to obtain a white solid compound HY-7 (0.44 g, yield 79.5%). 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.15 (d, J = 8.4Hz, 2H), 7.33 (d, J = 8.4Hz, 2H), 7.21-7.1 7(m,4H),7.14(s,1H),3.74-3.68(q,J=7.2Hz,2H),2.30(s,3H),1.01(t,J=7.2Hz,3H).

[0099] (IV) Biological activity test

[0100] 1. Inhibitory activity of the compounds of the present invention on TRPV1, COX-2, and 5-LOX

[0101] In order to verify the inhibitory effect of the compound on TRPV1, COX-2, and 5-LOX, celecoxib, the 5-LOX inhibitor zileuton, and the TRPV1 inhibitor N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide (BCTC) were used as positive control drugs, and the inhibitory activity of the final compound HY-1-7 on TRPV1, COX-2, and 5-LOX was tested and analyzed.

[0102] 1.1 TRPV1 In vitro Inhibition Assay

[0103] Add 5 mM EDTA to the Ca 2+ and Mg 2+ TRPV1 aequorin cells (Perkin Elmer, Waltham, MA, USA) were cultured in phosphate-buffered saline-free medium. The cells were pelleted at 1000 g for 2 min and resuspended in Dulbecco's minimal essential medium F12 (density 3*10 5 cells / mL) and incubated in the presence of 5 mM coelenterazine (Promega, Madison, WI, USA) for 4 h in the dark. After loading, cells were diluted with assay buffer to a concentration of 5*10 6 Cells / mL. 20uL of sample solutions of different concentrations (0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5μM) were injected into 384-well plates, and the assay buffer was added to the blank control wells as a reference. The sample solution and cells were incubated for 2.5min, and then the agonist capsaicin (Tocris, UK) and hydrochloric acid solution (pH = 5) were added and detected immediately, and the light emission was recorded at variable times. Then the IC 50 .

[0104] 1.2 In vitro COX-2 inhibition assay

[0105] Set up blank control wells, 100% enzyme activity control wells, positive control drug (celecoxib) control wells and test compound sample wells, and set up two parallel wells for each test compound sample. After incubation at 37°C for 10 minutes, the fluorescence intensity was detected, with an excitation wavelength of 560nm and an emission wavelength of 590nm. The specific operation was carried out according to the instructions of the COX-2 inhibitor screening kit (China Bio-Tech Biotechnology Co., Ltd.). The inhibitory effect of drugs / compounds on COX-2 enzyme activity was studied by measuring the relative fluorescence values ​​(RFU) of compound solutions of different concentrations (0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5 μM).

[0106] Inhibitory activity calculation:

[0107] Inhibition rate (%) = (RFU 100% enzyme activity - RFU sample) / (RFU 100% enzyme activity - RFU blank control) × 100%

[0108] 1.3 5-LOX Inhibition Assay in vitro

[0109] Set up blank control wells, 100% enzyme activity control wells, positive control drug (zileuton) control wells, celecoxib and test compound sample wells, and set up two parallel wells for each test compound sample. After incubation at 37°C for 10 minutes, add 10μL 3,3',5,5'-tetramethylbenzidine (TMB) and 10μL arachidonic acid (AA) to each well to activate the reaction. After incubation at 37°C for 15 minutes, the fluorescence intensity was detected at 450nm using an enzyme reader. The inhibitory effect of drugs / compounds on 5-LOX enzyme activity was studied by measuring the optical density (OD) of compound solutions of different concentrations (0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5μM).

[0110] Inhibitory activity calculation:

[0111] Inhibition rate (%) = (OD 100% enzyme activity - OD sample) / (OD 100% enzyme activity - OD blank control) × 100%

[0112] Table 1 Inhibitory activity of the compounds of the present invention on TRPV1, COX-2, and 5-LOX

[0113]

[0114]

[0115] The above experimental results show that the compounds of the present invention have the biological activity of simultaneously inhibiting the dual targets of COX-2 and 5-LOX. In particular, the compounds HY-3, HY-4 and HY-6 of the present invention have the biological activity of simultaneously inhibiting the multi-targets of TRPV1, COX-2 and 5-LOX.

[0116] 2. Analgesic activity of the compounds of the present invention

[0117] The formalin pain experiment can simulate clinical chronic pain well and is an important chronic pain model. The mouse formalin pain experiment can be divided into two phases, namely 0-5 minutes after injection of formalin (Phase I or Phase I time) and 15-30 minutes (Phase II or Phase II time). The pain mechanisms caused by these two phases are different. Phase I is a direct effect caused by stimulating nociceptors, which can be inhibited by central analgesics such as morphine. Phase II is an inflammatory response mediated by prostaglandins, which can be inhibited by non-steroidal anti-inflammatory agents, steroids and central analgesics.

[0118] 2.1 Reagents and instruments

[0119] Formalin (Xilong Scientific Co., Ltd., batch number: 190603 2), electronic balance (Sartorius Scientific Instrument Co., Ltd., model: Beijing 00000246), 1 mL syringe (Shuguang Jianshi, batch number: 210617), microinjection needle, gavage needle.

[0120] 2.2 Experimental animals and groups

[0121] 40 male ICR mice were provided by Anhui Medical University (Batch No. SCXK 2017-001). The 40 male ICR mice were randomly divided into 4 groups according to their body weight, namely, model control group, positive control celecoxib 20 mg / kg dose group, compound HY-3 20 mg / kg dose group, and HY-6 20 mg / kg dose group. All the mice were intragastrically administered once.

[0122] 2.3 Experimental methods

[0123] Mice were fasted but not allowed to drink water for 12 hours before the experiment. During the formal experiment, mice in each group were given drugs in turn. 0.05 ml of 2% formalin was injected subcutaneously into the dorsum of the right hind paw of the mice 30 minutes after the drug administration. The mice were placed in a glass cover for observation and the total time of licking the injected paw within 0 to 5 minutes and the total time of licking the injected paw within 15 to 30 minutes were recorded.

[0124] 2.4 Experimental Results

[0125] Table 2 Analgesic experimental data of compounds HY-3 and HY-6 of the present invention

[0126]

[0127] a p<0.05, aa p<0.01vs model b p<0.05, bb p<0.01vs positive control

[0128] According to the above table, compared with the model control group, the compounds HY-3 and HY-6 of the present invention can significantly reduce the pain time of phase II (P<0.01) and the pain time of phase I (P<0.05). In particular, compared with the positive control drug celecoxib, the effect of reducing the pain time of phase II by the compound HY-6 of the present invention is significantly better (P<0.01).

[0129] 3. Bioavailability study of the compounds of the present invention

[0130] Sixteen male SD rats were provided by Shanghai Xipu-Bikai Experimental Animal Co., Ltd. (Batch No.: SCXK2019-0004). Sixteen male SD rats were randomly divided into two groups, with 8 rats in each group. They were fasted for 12 hours but had free access to water. After a single intravenous injection of HY-6 (1 mg / kg) for 5, 10, 15, 30, 45, 60, 90, 120, 240 and 360 minutes, and after a single oral gavage of HY-6 (10 mg / kg) for 10, 20, 30, 45, 60, 90, 120, 240, 360, 720 minutes, 200 μL of blood was collected from the fundus venous plexus in heparin-treated test tubes, and 50 μL of plasma was collected for LC-MS / MS analysis after centrifugation at 8000 rpm for 5 minutes. The obtained blood drug concentration-time data were used to calculate the pharmacokinetic parameters (using the non-compartmental model) using Phoenix WinNonlin 6.3 software.

[0131] Table 3 Pharmacokinetic parameters of compound HY-6 of the present invention

[0132]

[0133]

[0134] The results showed that the oral bioavailability of compound HY-6 was as high as 96.8%, which was significantly better than the positive control celecoxib (the literature reported that its oral bioavailability was between 22-40%). [Abdul Rasool BK, Khalifa A, Abu-Gharbieh E, R., K. Employment of Alginate Floating In Situ Gel for Controlled Delivery of Celecoxib: Solubilization and Formulation Studies. Biomed Res Int. 2020, 1879125]

Claims

1. Compound represented by formula (I) or its tautomer, deuterated substance, or pharmaceutically acceptable salt, wherein R1 is selected from in: wherein R2 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and hydroxyl; wherein R2 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy; R5 is selected from 1,3-dioxolanyl, 1,2-dioxolanyl, 1,3-dithiolanyl, 1,2-dithiolanyl, 1,2-oxathiolanyl, 1,3-oxathiolanyl; n is selected from integers from 0 to 5.

2. The compound according to claim 1 or its tautomer, deuterated substance, or pharmaceutically acceptable salt, wherein R1 is selected from in: R2 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and hydroxy.

3. The compound according to claim 1 or its tautomer, deuterated substance, or pharmaceutically acceptable salt, wherein R1 is selected from in: R2 is selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy.

4. The compound according to claim 1 or its tautomer, deuterated substance, or pharmaceutically acceptable salt, wherein R1 is selected from in: R5 is selected from 1,3-dioxolanyl, 1,2-dioxolanyl, 1,3-dithiolanyl, 1,2-dithiolanyl, 1,2-oxathiolanyl, 1,3-oxathiolanyl; n is selected from integers of 1 to 3.

5. The compound according to claim 1, selected from: (E)-3-(4-hydroxy-3-methoxyphenyl)-N-((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)acrylamide; 5-(1,2-dithiolan-3-yl)-N-((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)pentanamide; 4-Hydroxy-3-methoxy-N-((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)benzamide; or a tautomer, a deuterated substance, or a pharmaceutically acceptable salt thereof.

6. A compound selected from: Sodium (E)(-3-(4-hydroxy-3-methoxyphenyl)acryloyl)((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)amide; Sodium (5-(1,2-dithiolan-3-yl)pentanoyl)((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)amide; Sodium (4-hydroxy-3-methoxybenzoyl)((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)amide.

7. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 6 or its tautomer, deuterated substance, pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

8. Use of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing and / or treating inflammatory diseases.

9. The use according to claim 8, wherein the inflammatory disease comprises rheumatoid arthritis, gouty arthritis, osteoarthritis, spondylitis, systemic lupus erythematosus, psoriasis, eczema, subcutaneous inflammation, postpartum inflammation, enteritis, gastritis, inflammatory headache, periarteritis, allergic rhinitis, coronary artery plaque inflammation, inflammation caused by bacteria, inflammation caused by viruses, inflammation caused by surgery, inflammation caused by trauma or gastric ulcer.

10. Use of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing and / or treating stroke, ischemia or mental trauma.

11. Use of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for analgesia.

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