N-arylpyrazole compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses an N-aryl pyrazole compound and a pharmaceutical composition and application thereof.The structure of the compound is shown in the formula I. The N-aryl pyrazole compound further comprises pharmaceutically acceptable salt of the N-aryl pyrazole compound, the N-aryl pyrazole compound exerts obvious inhibitory activity on COX-2 or PDE4 or the COX-2 or the PDE4 or the COX-2 or the PDE4 or the COX-2 or the PDE4 or the COX-2 or the PDE4 at the micromolar concentration level, the inhibition rate reaches 50% or above, and the N-aryl pyrazole compound has an exact structure-function relationship; as a single-target or double-target inhibitor drug, the compound has a wide application range. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to an N-aryl pyrazole compound and a pharmaceutical composition and application thereof, and in particular to an N-aryl pyrazole compound which can be prepared as a multi-target inhibitor drug and a pharmaceutical composition and application thereof. Background Art

[0002] Cyclic nucleotide phosphodiesterases (PDEs) are a class of enzymes that uniquely hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) into 5'-AMP and 5'-GMP. The cAMP and cGMP signaling systems regulate the function of many physiological processes, such as the central nervous, cardiovascular, and immune systems. PDE4 is the most diverse family of PDEs, abundantly expressed in most cells, and its main physiological function is to hydrolyze cyclic adenosine monophosphate (cAMP) into 5'-AMP. PDE4 molecules are involved in a variety of physiological processes, including brain function, monocyte and macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, and myocardial contractility.

[0003] PDE4 is the target of many inflammatory diseases, such as immune and inflammatory diseases including pneumonia, dermatitis, atopic dermatitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylosis, autoimmune inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), sepsis, multiple sclerosis, etc.; cardiovascular and cerebrovascular diseases including atherosclerosis, ischemia-reperfusion injury, ischemic stroke, vascular cognitive dysfunction, etc.; mental illnesses including depression, anxiety, etc.; neurodegenerative diseases including Alzheimer's disease, idiopathic Parkinson's disease, etc.; respiratory diseases including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary edema, lung injury, etc. In particular, PDE4 inhibitors are already on the market for the treatment of chronic obstructive pulmonary disease, atopic dermatitis, psoriatic arthritis, and plaque psoriasis; they are in the clinical research stage for the treatment of central nervous system and neurological diseases such as depression, Alzheimer's disease, ischemic stroke, and cognitive dysfunction; there are also a large number of research reports and technical patents in other immune, inflammatory diseases, cardiovascular and cerebrovascular diseases, mental and neurodegenerative diseases, and respiratory diseases.

[0004] Although PDE4 inhibitors have great potential for the treatment of the above diseases, there are only a limited number of PDE4 inhibitors currently on the market, including roflumilast for the treatment of COPD, apremilast for the treatment of psoriasis, and cleborole for the treatment of atopic dermatitis. Therefore, new PDE4 inhibitors have huge clinical demand and huge market prospects.

[0005] Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used drugs in clinical practice and can be used for anti-inflammatory, analgesic and antipyretic effects in a variety of clinical diseases. NSAIDs include non-selective NSAIDs and COX-2 selective NSAIDs / COX-2 selective inhibitors, the latter of which have lower gastrointestinal side effects than non-selective NSAIDs. COX-2 selective inhibitors can be used to treat immune and inflammatory diseases associated with the COX-2-PGE2 signaling pathway, including psoriatic arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylosis and other inflammatory diseases with pain, and can be used in combination with other anti-inflammatory drugs including disease-modifying antirheumatic drugs (DMARDs) and biologics. Although NSAIDs can improve the inflammation, pain and stiffness symptoms of arthritis within hours, they cannot change the course of the disease or slow the progression of joint damage. Summary of the invention

[0006] Objectives of the invention: The first objective of the present invention is to provide an N-aryl pyrazole compound, the second objective is to provide a pharmaceutical composition comprising the N-aryl pyrazole compound, and the third objective is to provide applications of the compound and its pharmaceutical composition.

[0007] Technical solution: The N-aryl pyrazole compound of the present invention has a structure of formula I, and also includes a pharmaceutically acceptable salt thereof:

[0008]

[0009] in:

[0010] R1 is C1-C4 alkyl, C1-C4 alkoxy, 3-6 membered cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy;

[0011] R2 is hydrogen, halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy;

[0012] R3 is hydrogen, halogen, cyano, nitro, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy;

[0013] R4 is hydrogen, halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy;

[0014] R5 is S(O)2-(C1-C4 alkyl), S(O)2-(C1-C4 alkylamino), (CH2) n CN, (CH2) n COOH, (CH2) n CONH-OH, n=0-4.

[0015] Preferably, in the structure:

[0016] R1 is C1-C4 alkyl, 3-6 membered cycloalkyl, C1-C4 haloalkyl;

[0017] R2 is hydrogen, halogen, C1-C4 alkoxy;

[0018] R3 is hydrogen, halogen, cyano;

[0019] R4 is hydrogen or halogen;

[0020] R5 is S(O)2-(C1-C4 alkyl), (CH2) n CN, (CH2) n COOH, (CH2) n CONH-OH, n=0-4.

[0021] Further preferably, in the structure:

[0022] R1 is methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, trifluoromethyl;

[0023] R2 is hydrogen, chlorine, fluorine, or methoxy;

[0024] R3 is hydrogen, chlorine, fluorine, or cyano;

[0025] R4 is hydrogen or chlorine;

[0026] R5 is S(O)2CH3, CH2CN, (CH2) n COOH, (CH2) n CONH-OH, n=0 or 1.

[0027] More preferably, in the structure:

[0028] R2, R3, and R4 are all chlorine;

[0029] R5 is S(O)2CH3, CH2CN, CH2COOH, CONH-OH.

[0030] Specifically, the N-aryl pyrazole compound of the present invention is selected from any of the following compounds:

[0031]

[0032]

[0033] Among them, the pharmaceutically acceptable salt is a salt formed by the N-aryl pyrazole compound and any base selected from the following: alkali metal ion base (NaOH, KOH, NaOCH2CH3, KOCH2CH3, etc.), alkaline earth metal ion base (Ca(OH)2, Mg(OH)2), organic amine (triethylamine, trimethylamine, diethylamine, diisopropylamine, piperidine, morpholine, pyrrolidine, etc.), ammonia (ammonia gas, ammonia water, organic solution containing ammonia), basic amino acids (lysine, arginine, histidine, etc.), nitrogen-containing unsaturated ring compounds (pyridine, 4-dimethylaminopyridine, piperazine, pyrrole, imidazole, pyrazole, thiazole, triazole, etc.).

[0034] "Pharmaceutically acceptable salts" refer to salts of compounds prepared from compounds having specific substituents and relatively non-toxic bases, which can be obtained by contacting the free form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent to obtain a base addition salt. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. Preferably, the salt is contacted with a base in a conventional manner and the parent compound is separated to regenerate the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as different solubility in polar solvents.

[0035] "Pharmaceutically acceptable salts" can be synthesized from parent compounds containing acid radicals by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid form with a stoichiometric amount of an appropriate base in water or an organic solvent or a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0036] Since PDE4 inhibitors are used clinically to reduce PsA inflammation and slow down the progression of the disease, they can promote the increase of intracellular cAMP, prevent the synthesis of the pro-inflammatory cytokine TNF-α, and increase the anti-inflammatory cytokine IL-10. Therefore, the compounds designed by the present invention are good strategies for treating chronic inflammatory arthritis as dual inhibitors of COX-2 and PDE4. They can be used as both NSAIDS and DMARDs, which can reduce pain and inflammatory symptoms and slow down the progression of the disease. In addition, the compounds designed by the present invention are multi-target NSAIDS, which have the value of reducing inflammation, relieving pain, and delaying the progression of arthritis.

[0037] The pharmaceutical composition of the present invention comprises the N-aryl pyrazole compound and a pharmaceutically acceptable carrier.

[0038] "Pharmaceutically acceptable carrier" can be an excipient widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipient can be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipient can include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0039] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0040] The pharmaceutical composition of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical composition of the present invention can also be a controlled release or sustained release dosage form (e.g., liposomes or microspheres). Examples of solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of preparations for parenteral administration include, but are not limited to, solutions for injection, dry powder preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0041] The N-aryl pyrazole compound or the pharmaceutical composition of the present invention is used to prepare COX-2 inhibitors and PDE4 inhibitors. More preferably, the drug is a PDE4 / COX-2 dual-target inhibitor drug.

[0042] Specifically, the drug is used to prepare a drug for preventing and / or treating immune diseases, inflammatory diseases, cardiovascular and cerebrovascular diseases, respiratory diseases, central mental diseases, and central nervous system diseases related to the COX-2-PGE2 and PDE4-cAMP signaling pathways.

[0043] Among them, when R5 is a methylsulfonyl group, the compound is a COX-2 inhibitor and can be used as a non-steroidal anti-inflammatory drug to treat immune and inflammatory diseases related to the COX-2-PGE2 signaling pathway, including psoriatic arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylosis and other inflammatory diseases accompanied by pain.

[0044] When R5 is cyano or acetic acid, the compound is a PDE4 inhibitor and can be used as a drug for preventing and / or treating immune and inflammatory diseases, cardiovascular and cerebrovascular diseases, respiratory diseases, central mental illnesses and central nervous system diseases related to the PDE4-cAMP signaling pathway. The PDE4-cAMP signaling pathway-related immune and inflammatory diseases mainly include pneumonia, dermatitis, atopic dermatitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylosis, autoimmune inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), sepsis, and multiple sclerosis; the related cardiovascular and cerebrovascular diseases mainly include atherosclerosis, ischemia-reperfusion injury, ischemic stroke, and vascular cognitive dysfunction; the related respiratory diseases include asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary edema, and lung injury; the central mental illness and central nervous system diseases include depression, anxiety, Alzheimer's disease, and idiopathic Parkinson's disease.

[0045] When R5 is a hydroxamic acid group, the compound is a PDE4 / COX-2 dual-target inhibitor and can be used as a drug for preventing and / or treating immune and inflammatory diseases, cardiovascular and cerebrovascular diseases, respiratory diseases, central mental illnesses and central nervous system diseases related to the PDE4-cAMP and COX-2-PGE2 signaling pathways. The immune and inflammatory diseases related to the PDE4-cAMP and COX-2-PGE2 signaling pathways mainly include pneumonia, dermatitis, atopic dermatitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylosis, autoimmune inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), sepsis, multiple sclerosis, etc.; the related cardiovascular and cerebrovascular diseases mainly include atherosclerosis, ischemia-reperfusion injury, ischemic stroke, and vascular cognitive dysfunction; the related respiratory system diseases include asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary edema, and lung injury; the central mental diseases and central nervous system diseases include depression, anxiety, Alzheimer's disease, and idiopathic Parkinson's disease.

[0046] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0047] The compounds all showed inhibitory activity against COX-2 or PDE4 or both at micromolar concentration levels, with an inhibition rate of more than 50%, and had a definite structure-activity relationship. As single-target or dual-target inhibitor drugs, they have a wide range of applications. DETAILED DESCRIPTION

[0048] The technical solution of the present invention is further described below in conjunction with embodiments.

[0049] Example 1

[0050]

[0051] 3-Methyl-1-phenyl-1H-pyrazole-5-ol (3 mmol) was dissolved in acetonitrile, 4-bromomethylbenzylsulfone (3 mmol) was added, triethylamine (9 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate / water, the organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated under low pressure, and finally separated by silica gel column chromatography to obtain the product. 1 H NMR (300MHz, DMSO) δ7.97(d,J=8.3Hz,2H),7.73(d,J=8.1Hz,2H),7.70-7.63(m,2H),7.46( t,J=7.9Hz,2H),7.28(t,J=7.4Hz,1H),5.80(s,1H),5.37(s,2H),3.24(s,3H),2.16(s,3H).

[0052] Example 2

[0053]

[0054] 3-Ethylmethyl-1-phenyl-1H-pyrazole-5-ol (3 mmol) was dissolved in acetonitrile, 4-bromomethylbenzylsulfone (3 mmol) was added, triethylamine (9 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate / water, the organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated under low pressure, and finally separated by silica gel column chromatography to obtain the product. 1 H NMR (300MHz, DMSO) δ7.97(d,J=8.3Hz,2H),7.73(d,J=8.3Hz,2H),7.68(dd,J=8.6,1.2Hz,2H),7.46(t,J=7.9Hz, 2H),7.28(t,J=7.4Hz,1H),5.87(s,1H),5.37(s,2H),3.24(s,3H),2.56(q,J=7.6Hz,2H),1.19(t,J=7.6Hz,3H).

[0055] Example 3

[0056]

[0057] 3-Isopropyl-1-phenyl-1H-pyrazole-5-ol (3 mmol) was dissolved in acetonitrile, 4-bromomethylbenzylsulfone (3 mmol) was added, triethylamine (9 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate / water, the organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated under low pressure, and finally separated by silica gel column chromatography to obtain the product. 1 HNMR(400MHz,DMSO)δ8.08-7.88(m,2H),7.82-7.70(m,2H),7.68(dd,J=8.6,1.2Hz,2H),7.50-7.41(m,2H),7 .27(t,J=7.4Hz,1H),5.91(s,1H),5.37(s,2H),3.24(s,3H),2.84(h,J=6.9Hz,1H),1.23(s,3H),1.21(s,3H).

[0058] Example 4

[0059]

[0060] 3-Cyclopropyl-1-phenyl-1H-pyrazole-5-ol (3 mmol) was dissolved in acetonitrile, 4-bromomethylbenzylsulfone (3 mmol) was added, triethylamine (9 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate / water, the organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated under low pressure, and finally separated by silica gel column chromatography to obtain the product. 1 H NMR (300MHz, DMSO) δ7.97(d,J=8.3Hz,2H),7.72(d,J=8.3Hz,2H),7.66(dd,J=8.6,1.2Hz,2H),7.45(dd,J=8.6,7.2Hz,2H),7. 27(t,J=7.3Hz,1H),5.75(s,1H),5.34(s,2H),3.23(s,3H),1.85(tt,J=8.4,5.0Hz,1H),0.94-0.85(m,2H),0.79-0.62(m,2H).

[0061] Example 5

[0062]

[0063] 3-tert-Butyl-1-phenyl-1H-pyrazole-5-ol (3 mmol) was dissolved in acetonitrile, 4-bromomethylbenzylsulfone (3 mmol) was added, triethylamine (9 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate / water, the organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated under low pressure, and finally separated by silica gel column chromatography to obtain the product. 1 H NMR(300MHz,DMSO)δ7.98(d,J=8.3Hz,2H),7.79-7.71(m,2H),7.68(dd,J=8.6,1.2Hz,2H),7.46( dd,J=8.6,7.2Hz,2H),7.27(t,J=7.4Hz,1H),5.98(s,1H),5.37(s,2H),3.23(s,3H),1.27(s,9H).

[0064] Example 6

[0065]

[0066] 3-Methyl-1-(3-chlorophenyl)-1H-pyrazole-5-ol (3 mmol) was dissolved in acetonitrile, 4-bromomethylbenzylsulfone (3 mmol) was added, triethylamine (9 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate / water, the organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated under low pressure, and finally separated by silica gel column chromatography to obtain the product. 1 HNMR (300MHz, DMSO) δ8.05-7.93(m,2H),7.92-7.63(m,4H),7.49(t,J=8.1Hz,1H),7. 34(ddd,J=8.1,2.1,1.0Hz,1H),5.84(s,1H),5.40(s,2H),3.24(s,3H),2.16(s,3H).

[0067] Example 7

[0068]

[0069] 1-(3-Methoxyphenyl)-3-methyl-1H-pyrazole-5-ol (3mmol) was dissolved in acetonitrile, 4-bromomethylbenzylsulfone (3mmol) was added, triethylamine (9mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate / water, the organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated under low pressure, and finally separated by silica gel column chromatography to obtain the product. 1H NMR (400MHz, DMSO) δ7.97(d,J=8.4Hz,2H),7.73(d,J=8.3Hz,2H),7.58(d,J=8.1Hz,2H),7.35(t,J=8.1Hz ,1H),7.28(ddd,J=8.0,2.0,1.0Hz,1H),5.81(s,1H),5.36(s,2H),3.76(s,3H),3.23(s,3H),2.16(s,3H).

[0070] Example 8

[0071]

[0072] 1-(3,4-dichlorophenyl)-3-methyl-1H-pyrazole-5-ol (3mmol) was dissolved in acetonitrile, 4-bromomethylbenzylsulfone (3mmol) was added, triethylamine (9mmol) was added, and stirred at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate / water, the organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated under low pressure, and finally separated by silica gel column chromatography to obtain the product. 1 H NMR (400MHz, DMSO) δ8.00-7.96(m,2H),7.96-7.90(m,1H),7.78-7.70(m,4H),5.85(s,1H),5.40(s,2H),3.24(s,3H),2.16(s,3H).

[0073] Example 9

[0074]

[0075] 3-Methyl-1-phenyl-1H-pyrazole-5-ol (3 mmol) was dissolved in acetonitrile, 4-bromomethylbenzyl acetonitrile (3 mmol) was added, triethylamine (9 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate / water, the organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated under low pressure, and finally separated by silica gel column chromatography to obtain the product. 1 H NMR (400MHz, CDCl3) δ7.71(dd,J=8.6,1.2Hz,2H),7.48-7.33(m,6H),7.26(t,J=7.4Hz,1H),5.54(s,1H),5.15(s,2H),3.79(s,2H),2.29(s,3H).

[0076] Example 10

[0077]

[0078] 3-Methyl-1-phenyl-1H-pyrazole-5-ol (3mmol) was dissolved in acetonitrile, 4-bromomethylphenylacetic acid methyl ester (3mmol) was added, triethylamine (9mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate / water, the organic layers were combined, dried with anhydrous Na2SO4, filtered, concentrated at low pressure, and finally separated by silica gel column chromatography to obtain the methyl phenylacetic acid intermediate. The methyl phenylacetic acid intermediate was dissolved in methanol, and NaOH (3eq) aqueous solution was added, and the reaction was hydrolyzed at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate / water, the organic layers were combined, dried with anhydrous Na2SO4, filtered, concentrated at low pressure, and finally separated by silica gel column chromatography to obtain the product. 1 HNMR(300MHz,DMSO)δ7.66(d,J=7.6Hz,2H),7.43(dd,J=8.2,2.6Hz,3H),7.33-7.24 (m,4H),5.81(s,1H),5.20(d,J=2.8Hz,2H),3.60(s,2H),2.17(s,3H),12.43(s,1H).

[0079] Embodiment 11

[0080]

[0081] According to the method of Example 10, 3-methyl-1-(3-chlorophenyl)-1H-pyrazol-5-ol was used to prepare the product. 1 HNMR(300MHz, CDCl3)δ7.79(t,J=2.0Hz,1H),7.67-7.60(m,1H),7.34(q,J=7.9 Hz,5H),7.25-7.16(m,1H),5.54(s,1H),5.13(s,2H),3.67(s,2H),2.27(s,3H).

[0082] Example 12

[0083]

[0084] According to the method of Example 10, 1-(3-methoxyphenyl)-3-methyl-1H-pyrazol-5-ol was used to prepare the product. 1 HNMR (300MHz, DMSO) δ12.30 (s, 1H), 7.46-7.38 (m, 2H), 7.37-7.21 (m, 5H), 6.81 (ddd, J= 8.0,2.5,1.3Hz,1H),5.81(s,1H),5.20(s,2H),3.73(s,3H),3.59(s,2H),2.16(s,3H).

[0085] Embodiment 13

[0086]

[0087] According to the method of Example 10, 1-(3,4-dichlorophenyl)-3-methyl-1H-pyrazol-5-ol was used to prepare the product. 1 HNMR(300MHz,DMSO)δ12.36(s,1H),7.93(t,J=1.5Hz,1H),7.71(d,J=1.4Hz,2H),7.48- 7.39(m,2H),7.30(d,J=8.1Hz,2H),5.86(s,1H),5.24(s,2H),3.58(s,2H),2.16(s,3H).

[0088] Embodiment 14

[0089]

[0090] According to the method of Example 10, 1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-ol was used to prepare the product. 1 HNMR(300MHz,DMSO)δ12.11(s,1H),7.75-7.63(m,2H),7.57-7.46(m,2H),7.41(d,J=8 .0Hz,2H),7.29(d,J=8.0Hz,2H),5.83(s,1H),5.21(s,2H),3.58(s,2H),2.15(s,3H).

[0091] Embodiment 15

[0092]

[0093] According to the method of Example 10, 1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-ol was used to prepare the product. 1 HNMR (300MHz, DMSO) δ12.37 (s, 1H), 7.75-7.53 (m, 2H), 7.41 (d, J = 8.1Hz, 2 H),7.34-7.22(m,4H),5.80(s,1H),5.19(s,2H),3.59(s,2H),2.15(s,3H).

[0094] Example 16

[0095]

[0096] According to the method of Example 10, 1-(3-fluorophenyl)-3-methyl-1H-pyrazol-5-ol was used to prepare the product. 1H NMR (400MHz, DMSO) δ12.37(s,1H),7.57(ddd,J=8.3,2.0,1.0Hz,1H),7.54-7.46(m,2H),7.43(dd,J=8.0,1.9Hz ,2H),7.33-7.27(m,2H),7.08(tdd,J=8.5,2.6,1.0Hz,1H),5.84(s,1H),5.23(s,2H),3.59(s,2H),2.16(s,3H).

[0097] Embodiment 17

[0098]

[0099] According to the method of Example 10, 1-(3-chloro-4-fluorophenyl)-3-methyl-1H-pyrazol-5-ol was used to prepare the product. 1 HNMR (300MHz, DMSO) δ12.38(s,1H),7.84(dd,J=6.7,2.6Hz,1H),7.68(ddd,J=9.1,4.3,2.7Hz,1H),7.51(t ,J=9.1Hz,1H),7.45-7.37(m,2H),7.33-7.26(m,2H),5.84(s,1H),5.22(s,2H),3.59(s,2H),2.16(s,3H).

[0100] Embodiment 18

[0101]

[0102] According to the method of Example 10, 1-(3,5-dichlorophenyl)-3-methyl-1H-pyrazol-5-ol was used to prepare the product. 1 HNMR(300MHz,DMSO)δ12.37(s,1H),7.75(d,J=1.9Hz,2H),7.49(t,J=1.9Hz,1H),7.46- 7.40(m,2H),7.31(d,J=8.1Hz,2H),5.87(s,1H),5.26(s,2H),3.60(s,2H),2.17(s,3H).

[0103] Embodiment 19

[0104]

[0105] According to the method of Example 10, 1-(3-trifluoromethylphenyl)-3-methyl-1H-pyrazol-5-ol was used to prepare the product. 1HNMR (300MHz, DMSO) δ12.36 (s, 1H), 8.03 (s, 2H), 7.75-7.57 (m, 2H), 7.43 (d, J = 7.6 Hz,2H),7.30(d,J=7.8Hz,2H),5.89(s,1H),5.25(s,2H),3.59(s,2H),2.18(s,3H).

[0106] Embodiment 20

[0107]

[0108] According to the method of Example 10, 1-(4-cyanophenyl)-3-methyl-1H-pyrazol-5-ol was used to prepare the product. 1 HNMR (300MHz, DMSO) δ12.41(s,1H),7.91(s,4H),7.44(d,J=7.9Hz,2H),7.30(d,J=7.9Hz,2H),5.89(s,1H),5.25(s,2H),3.60(s,2H),2.17(s,3H).

[0109] Embodiment 21

[0110]

[0111] 3-Methyl-1-phenyl-1H-pyrazole-5-ol (3mmol) was dissolved in acetonitrile, methyl 4-bromomethylbenzoate (3mmol) was added, triethylamine (9mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was extracted with methyl formate / water, the organic layers were combined, dried with anhydrous Na2SO4, filtered, concentrated at low pressure, and finally separated by silica gel column chromatography to obtain the methyl ester intermediate. The methyl ester intermediate was dissolved in methanol, hydroxylamine methanol solution was added, and the reaction was hydrolyzed at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate / water, the organic layers were combined, dried with anhydrous Na2SO4, filtered, concentrated at low pressure, and finally separated by silica gel column chromatography to obtain the product.

[0112] 1 H NMR(300MHz,DMSO)δ11.25(s,1H),9.09(s,1H),7.83-7.75(m,2H),7.71-7.63(m,2H),7.54(d ,J=8.2Hz,2H),7.50-7.38(m,2H),7.34-7.20(m,1H),5.79(s,1H),5.28(s,2H),2.15(s,3H).

[0113] Embodiment 22

[0114]

[0115] According to the method of Example 21, 3-ethyl-1-phenyl-1H-pyrazol-5-ol was used to prepare the product. 1 H NMR (300MHz, DMSO) δ11.09(s,1H),9.12(s,1H),7.78(d,J=7.9Hz,2H),7.67(d,J=8.0Hz,2H),7.54(d,J=7.9Hz,2H), 7.44(t,J=7.8Hz,2H),7.26(t,J=7.4Hz,1H),5.86(s,1H),5.28(s,2H),2.51(d,J=2.0Hz,2H),1.19(t,J=7.6Hz,3H).

[0116] Embodiment 23

[0117]

[0118] According to the method of Example 21, 3-trifluoromethyl-1-phenyl-1H-pyrazol-5-ol was used to prepare the product. 1 H NMR (400MHz, DMSO) δ11.25(s,1H),9.08(s,1H),7.98(d,J=7.7Hz,1H),7.78(d,J=7.8Hz,2H), 7.68(d,J=7.9Hz,2H),7.55(d,J=8.0Hz,3H),7.43(t,J=7.2Hz,1H),6.56(s,1H),5.39(s,2H).

[0119] Embodiment 24

[0120]

[0121] According to the method of Example 21, 3-isopropyl-1-phenyl-1H-pyrazol-5-ol was used to prepare the product. 1 H NMR (300MHz, DMSO) δ11.26(s,1H),9.09(s,1H),7.78(d,J=8.2Hz,2H),7.71-7.64(m,2H),7.55(d,J=8.2Hz,2H),7.4 4(t,J=7.9Hz,2H),7.26(t,J=7.4Hz,1H),5.90(s,1H),5.28(s,2H),2.84(p,J=6.9Hz,1H),1.23(s,3H),1.21(s,3H).

[0122] Embodiment 25

[0123]

[0124] According to the method of Example 21, 3-cyclopropyl-1-phenyl-1H-pyrazol-5-ol was used to prepare the product. 1 H NMR (300MHz, DMSO) δ11.25(s,1H),9.10(s,1H),7.77(d,J=7.9Hz,2H),7.65(d,J=7.8Hz,2H),7.53(d,J=8.0Hz,2H),7.44(t,J= 7.9Hz,2H),7.25(t,J=7.3Hz,1H),5.74(s,1H),5.25(s,2H),1.85(tt,J=8.4,4.9Hz,1H),0.94-0.84(m,2H),0.75-0.62(m,2H).

[0125] Embodiment 26

[0126]

[0127] According to the method of Example 21, 3-tert-butyl-1-phenyl-1H-pyrazol-5-ol (3 mmol) was used to prepare the product. 1 H NMR(300MHz,DMSO)δ11.26(s,1H),9.09(s,1H),7.82-7.74(m,2H),7.72-7.63(m,2H),7.55(d ,J=8.2Hz,2H),7.49-7.39(m,2H),7.33-7.10(m,1H),5.96(s,1H),5.28(s,2H),1.27(s,9H).

[0128] Embodiment 27

[0129]

[0130] According to the method of Example 21, 1-(3-chlorophenyl)-3-methyl-1H-pyrazol-5-ol was used to prepare the product. 1 HNMR(300MHz,DMSO)δ7.89-7.71(m,3H),7.69(d,J=8.1Hz,1H),7.55(d,J=7.9Hz,2H) ,7.48(t,J=8.2Hz,1H),7.32(d,J=8.0Hz,1H),5.83(s,1H),5.31(s,2H),2.16(s,3H).

[0131] Embodiment 28

[0132]

[0133] According to the method of Example 21, 1-(3-chlorophenyl)-3-ethyl-1H-pyrazol-5-ol was used to prepare the product. 1 HNMR (400MHz, DMSO) δ11.19(s,1H),9.08(s,1H),7.79(d,J=8.0Hz,2H),7.75(t,J=2.1Hz,1H),7.69(dd,J=8.2,2.1Hz,1H),7.56(d,J =8.0Hz,2H),7.47(t,J=8.1Hz,1H),7.32(dd,J=8.0,2.1Hz,1H),5.89(s,1H),5.31(s,2H),2.57-2.51(m,2H),1.19(t,J=7.6Hz,3H).

[0134] Embodiment 29

[0135]

[0136] According to the method of Example 21, 1-(3-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-5-ol was used to prepare the product.

[0137] 1 H NMR (300MHz, DMSO) δ11.27(s,1H),9.10(s,1H),7.82-7.76(m,3H),7.70(ddd,J=7.9,2. 1,1.3Hz,1H),7.56(dd,J=8.1,2.3Hz,3H),7.53-7.48(m,1H),6.61(s,1H),5.42(s,2H).

[0138] Embodiment 30

[0139]

[0140] According to the method of Example 21, 1-(3-methoxyphenyl)-3-trifluoromethyl-1H-pyrazol-5-ol was used to prepare the product. 1 H NMR (300MHz, DMSO) δ11.27(d,J=1.7Hz,1H),9.10(d,J=1.9Hz,1H),7.83-7.74(m,2H),7.56(d,J=8.2Hz,2H),7 .48-7.39(m,1H),7.29-7.22(m,2H),7.00(ddd,J=8.4,2.3,1.2Hz,1H),6.58(s,1H),5.39(s,2H),3.78(s,3H).

[0141] Embodiment 31

[0142]

[0143] According to the method of Example 21, 1-(3,4-dichlorophenyl)-3-trifluoromethyl-1H-pyrazol-5-ol was used to prepare the product. 1 H NMR (300MHz, DMSO) δ11.28(s,1H),9.11(s,1H),8.00(d,J=2.3Hz,1H),7.91-7.68(m,4H),7.57(d,J=8.1Hz,2H),6.63(s,1H),5.44(d,J=11.6Hz,2H).

[0144] Example 32: Evaluation of the in vitro PDE4 enzyme activity and COX-2 activity inhibitory activity of the example compounds

[0145] 1. Experimental methods

[0146] PDE4 enzyme activity inhibition test method: The specific operation is based on the instruction manual of the kit IMAP FP Explorer Kit (MOLECULAR DEVICES, Cat. No. R8124, Lot. No. 3171238). Add the buffer containing PDE4B1 (BPS, Cat. No. 60041, Lot. No. 90520) to the 384-well plate containing the test compound DMSO solution and incubate at room temperature for 15 minutes. Then add the FAM-cAMP substrate solution to the reaction liquid plate containing enzyme activity and compound, and incubate at room temperature for 60 minutes. Finally, add the stop buffer and incubate at room temperature for 1 hour. The test was performed using a multifunctional microplate reader (PerkinElmer EnVision), and the fluorescence signal test used an excitation wavelength of 485nM and an emission wavelength of 530nM. The negative control test used a buffer without PDE4B1 enzyme, and each test sample was tested twice in parallel.

[0147] COX-2 enzyme activity test method: The reaction mixture in COX-2 reaction buffer (100mM Tris-HCl, pH 8.0) contains 1.25μg of COX-2 and the indicated amount of control, reference inhibitor or test inhibitor. Add 10μl of DMSO solution of the test compound to 100μl of reaction buffer, and the final concentration of DMSO is 0.5%. After incubation for 10 minutes, add the substrate arachidonic acid (final concentration 200μM, ethanol final concentration 1%) and the colorimetric reagent ADHP (final concentration 100μM) to the reaction solution, and incubate the reaction mixture at room temperature for 5 minutes. The fluorescence signal test uses an excitation wavelength of 535nM and an emission wavelength of 590nM. The negative control test uses a buffer without COX-2 enzyme, and each test sample is subjected to two parallel experiments.

[0148] 2. Experimental results

[0149] Table 1. Inhibitory activity results of the example compounds on PDE4 and COX-2

[0150]

[0151]

[0152]

[0153]

[0154] All compounds showed inhibitory activity against COX-2 or PDE4, or both, at a micromolar concentration level, with an inhibition rate of more than 50%. Among them, when R5 is a mesyl group, the compound is a COX-2 inhibitor, which can be used as a non-steroidal anti-inflammatory drug for the treatment of immune and inflammatory diseases related to the COX-2-PGE2 signaling pathway. When R5 is a cyano group or an acetic acid group, the compound is a PDE4 inhibitor, which can be used as a drug for preventing and / or treating immune and inflammatory diseases, cardiovascular and cerebrovascular diseases, respiratory diseases, central mental diseases and central nervous system diseases related to the PDE4-cAMP signaling pathway. When R5 is a hydroxamic acid group, the compound is a PDE4 / COX-2 dual-target inhibitor, which can be used as a drug for preventing and / or treating immune and inflammatory diseases, cardiovascular and cerebrovascular diseases, respiratory diseases, central mental diseases and central nervous system diseases related to the PDE4-cAMP and COX-2-PGE2 signaling pathways.

Claims

1. An N-aryl pyrazole compound, characterized in that: Having the structure of formula I, and also including pharmaceutically acceptable salts thereof: in: R1 is C1-C4 alkyl, C1-C4 alkoxy, 3-6 membered cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy; R2 is hydrogen, halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; R3 is hydrogen, halogen, cyano, nitro, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; R4 is hydrogen, halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; R5 is S(O)2-(C1-C4 alkyl), S(O)2-(C1-C4 alkylamino), (CH2) n CN, (CH2) n COOH, (CH2) n CONH-OH, n=0-4.

2. The N-aryl pyrazole compound according to claim 1, characterized in that: In the structure: R1 is C1-C4 alkyl, 3-6 membered cycloalkyl, C1-C4 haloalkyl; R2 is hydrogen, halogen, C1-C4 alkoxy; R3 is hydrogen, halogen, cyano; R4 is hydrogen or halogen; R5 is S(O)2-(C1-C4 alkyl), (CH2) n CN, (CH2) n COOH, (CH2) n CONH-OH, n=0-4.

3. The N-aryl pyrazole compound according to claim 2, characterized in that: In the structure: R1 is methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, trifluoromethyl; R2 is hydrogen, chlorine, fluorine, or methoxy; R3 is hydrogen, chlorine, fluorine, or cyano; R4 is hydrogen or chlorine; R5 is S(O)2CH3, CH2CN, (CH2) n COOH, (CH2) n CONH-OH, n=0 or 1.

4. The N-aryl pyrazole compound according to claim 3, characterized in that: In the structure: R2, R3, and R4 are all chlorine; R5 is S(O)2CH3, CH2CN, CH2COOH, CONH-OH.

5. The N-aryl pyrazole compound according to claim 1, characterized in that: Select any of the following compounds:

6. The N-aryl pyrazole compound according to claim 1, characterized in that: The pharmaceutically acceptable salt is a salt formed by the compound and any base selected from the group consisting of an alkali metal ion base, an alkaline earth metal ion base, an organic amine, ammonia, and a basic amino acid.

7. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the N-aryl pyrazole compound according to claim 1 and a pharmaceutically acceptable carrier.

8. Use of the N-aryl pyrazole compound according to claim 1 or the pharmaceutical composition according to claim 7 in the preparation of COX-2 inhibitors and PDE4 inhibitors.

9. The application according to claim 8, characterized in that: The drug is a PDE4 / COX-2 dual-target inhibitor drug.

10. The application according to claim 8, characterized in that: The medicine is used to prepare a medicine for preventing and / or treating immune diseases, inflammatory diseases, cardiovascular and cerebrovascular diseases, respiratory diseases, central mental diseases, and central nervous system diseases related to COX-2-PGE2 and PDE4-cAMP signaling pathways.

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