CN111217752A - Aryl pyrazole compound and application thereof - Google Patents

Aryl pyrazole compound and application thereof Download PDF

Info

Publication number
CN111217752A
CN111217752A CN202010088352.2A CN202010088352A CN111217752A CN 111217752 A CN111217752 A CN 111217752A CN 202010088352 A CN202010088352 A CN 202010088352A CN 111217752 A CN111217752 A CN 111217752A
Authority
CN
China
Prior art keywords
halogen
substituted
hydroxyl
alkyl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202010088352.2A
Other languages
Chinese (zh)
Inventor
余颖聪
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wenzhou Peoples Hospital
Original Assignee
Wenzhou Peoples Hospital
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wenzhou Peoples Hospital filed Critical Wenzhou Peoples Hospital
Priority to CN202010088352.2A priority Critical patent/CN111217752A/en
Publication of CN111217752A publication Critical patent/CN111217752A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Pulmonology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Urology & Nephrology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dermatology (AREA)
  • Psychology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses an arylpyrazole compound, which has the following structure:

Description

Aryl pyrazole compound and application thereof
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to an arylpyrazole compound and application thereof, wherein the arylpyrazole compound has selective PDE4B inhibitory activity.
Background
Phosphodiesterases (PDEs) are the only family of super enzymes in the body that can hydrolyze cAMP and cGMP. The PDEs family, as a basic regulator of second messenger cyclic nucleotides, is involved in the regulation of various physiological functions in the human body, such as cell growth, differentiation and migration, gene expression, mediator secretion, ion channel action, and the like. Also, because of their complexity, diversity and wide tissue distribution, PDEs are increasingly being used as new important drug targets for the treatment of a variety of diseases. The PDEs inhibitor regulates the concentration level of cAMP and cGMP in cells by inhibiting the activity of PDEs, thereby influencing the physiological process of conduction of the PDEs inhibitor and achieving the aim of treating diseases.
The human genome encodes 11 PDE families (PDE1 to PDE11) releasing a series of PDE isozymes, of which PDE type 4 (PDE4) is one of the major cAMP catabolic enzymes present in many inflammatory, immune cells. PDE4 inhibitors have been used clinically in a wide range of applications. For example, the potent PDE4 inhibitor roflumilast (roflumilast) is recognized and used as a therapeutic agent for Chronic Obstructive Pulmonary Disease (COPD), and is effective for interstitial pneumonia (idiopathic pulmonary fibrosis, etc.) in animal models. In addition, the PDE4 inhibitor, apleside (apremilast), can be used for treating arthritic psoriasis and psoriasis vulgaris. In addition, studies have shown that some of the PDE4 inhibitors have a certain therapeutic effect on depression, parkinson's disease, learning and memory disorders, and alzheimer's disease, as well as a variety of centrally acting compounds (see non-patent document 1: expertopin. investig. drugs, 11, 1-13, 2002, non-patent document 6: BMCMedicine, 11, 96, 2013).
However, most current PDE4 inhibitors such as roflumilast, apremilast, and the like often exhibit side effects such as vomiting, nausea, and the like. Studies have shown that there are four isoenzymes for the PDE4 enzyme, PDE4A, PDE4B, PDE4C, PDE4D, and that compounds with selective PDE4B enzyme inhibitory activity and no inhibitory effect on PDE4D are able to exhibit better anti-inflammatory activity with reduced side effects (Jin and Conti (2002) Proc Natl Acad Sci USA,99, 7628-7633). The inhibition of the PDE4D enzyme may induce gastrointestinal side effects such as vomiting and nausea. Therefore, the development of an inhibitor having high selectivity for the PDE4B subtype is of great clinical significance.
Disclosure of Invention
The invention aims to provide a novel arylpyrazole compound which has the selective inhibition effect on PDE4B and weaker effect on PDE4D, so that the novel arylpyrazole compound has better pharmacodynamic property and smaller side effect and has potential effects of treating arthritis, asthma, chronic obstructive pulmonary disease, senile dementia, depression and the like. Meanwhile, the invention also provides a preparation method of the compound, which is scientific, reasonable, simple and feasible.
The specific technical scheme of the invention is as follows:
an arylpyrazole compound having the following structure:
Figure BDA0002382840110000021
wherein, R represents H, linear or branched alkyl of C1-C8 substituted by one or more of H, hydroxyl, halogen, cycloalkyl of C1-C8 substituted by one or more of H, hydroxyl, alkyl and halogen, phenyl or benzyl substituted by one or more of H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyl and cyano, and R is not methyl.
Preferably, R represents H, linear or branched alkyl of C1-C6 substituted by one or more of H, hydroxyl, halogen, cycloalkyl of C1-C6 substituted by one or more of H, hydroxyl, alkyl of C1-C6, halogen, phenyl substituted by one or more of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, and R is not methyl.
More preferably, said R represents H, -CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2OH、-CH2CH2OH、-CH(OH)CH3、-CH2CH2CH2OH、-CH(CH2OH)CH3、-CH(OH)CH2CH3、
Figure BDA0002382840110000022
Figure BDA0002382840110000023
X represents F, Cl, Br, I.
The embodiment of the invention discloses the following arylpyrazole compounds:
Figure BDA0002382840110000031
the invention also aims to provide a preparation method of the arylpyrazole compound, which comprises the following steps:
(1) the 3 ', 5' -dihydroxy acetophenone and 3, 4-dihydro-2H-pyran are subjected to addition reaction in the presence of pyridine p-toluenesulfonate to generate an intermediate 4,
Figure BDA0002382840110000032
(2a) carrying out substitution reaction on p-hydroxybenzaldehyde and R 'Br or R' I under the alkaline condition to obtain an intermediate 6,
Figure BDA0002382840110000033
r' represents a linear or branched alkyl group of C1-C8 substituted by one or more of H, hydroxyl, halogen, a cycloalkyl group of C1-C8 substituted by one or more of H, hydroxyl, alkyl, halogen, a phenyl or benzyl group substituted by one or more of H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyl, cyano;
the alkaline condition can be selected from common organic base and/or inorganic base, such as anhydrous potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, etc., which can make phenolic hydroxyl group easier to alkylate.
Or (2b) carrying out addition reaction on p-hydroxybenzaldehyde and 3, 4-dihydro-2H-pyran in the presence of pyridine p-toluenesulfonate to generate an intermediate 7,
Figure BDA0002382840110000041
(3) reacting the intermediate 4 with the intermediate 6 or 7 under alkaline conditions, then reacting the intermediate product in the presence of pyridine p-toluenesulfonate to obtain an intermediate 8,
Figure BDA0002382840110000042
r represents H, linear or branched alkyl of C1-C8 substituted by one or more of H, hydroxyl and halogen, cycloalkyl of C1-C8 substituted by one or more of H, hydroxyl, alkyl and halogen, phenyl or benzyl substituted by one or more of H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyl and cyano.
The alkaline condition can be selected from common organic base and/or inorganic base, such as anhydrous potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, etc.
(4) Reacting the intermediate 8 with acethydrazide to obtain a compound 1,
Figure BDA0002382840110000043
preferably, the reaction solvent in the step (1) is dichloromethane, the reaction solvent in the step (2a) is DMF, and the reaction solvent in the step (2b) is dichloromethane; the reaction solvent in the step (3) is absolute methanol; and (4) the reaction solvent is absolute methanol.
Preferably, the acid is used as a catalyst to catalyze the reaction. Such as acetic acid, p-toluenesulfonic acid, and the like.
The preparation method comprises the following steps:
(1) 3 ', 5' -dihydroxyacetophenone, 3, 4-dihydro-2H-pyran, pyridine p-toluenesulfonate (PPTs), were mixed and heated. Preferably, after the reaction is completed, the layers are separated by 10% sodium hydroxide and dichloromethane, and the lower organic layer is removed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under pressure to give intermediate 4.
(2) P-hydroxybenzaldehyde, R 'Br or R' I, anhydrous potassium carbonate (K)2CO3) Anhydrous N, N-Dimethylformamide (DMF), mixed and heated. Preferably, after the reaction is completed, the layers are separated by 10% sodium hydroxide and dichloromethane, and the lower organic layer is removed. Several layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under pressure to give intermediate 6.
Or mixing p-hydroxybenzaldehyde, 3, 4-dihydro-2H-pyran, and pyridine p-toluenesulfonate (PPTs), and heating. Preferably, after the reaction is completed, the layers are separated by 10% sodium hydroxide and dichloromethane, and the lower organic layer is removed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under pressure to give intermediate 7.
(3) Intermediate 4, intermediate 6 or 7, anhydrous methanol was dissolved and 4% sodium hydroxide was slowly added dropwise to give a white solid. After the reaction was completed, filtration was carried out to obtain a solid (which may be further dried). Dissolving the solid and PPTs in absolute ethyl alcohol, stirring and heating for reaction. Preferably, after the reaction is finished, the solvent is evaporated under reduced pressure, water and dichloromethane are used for layering, an organic layer is taken, and the solvent is evaporated under reduced pressure to obtain an intermediate 8.
(4) Mixing the intermediate 8 and acethydrazide, adding absolute ethyl alcohol to dissolve, dripping acetic acid for a few drops, stirring, and carrying out reflux reaction. Further preferably, the reaction is completed. And taking out the reaction solution, evaporating the solvent under reduced pressure, layering the reaction solution by using water and ethyl acetate, taking an organic layer, and performing rotary evaporation to obtain the compound 1.
Another object of the present invention is to provide an application of an arylpyrazole compound in the preparation of PDE4 inhibitor, wherein the arylpyrazole compound has the following structure:
Figure BDA0002382840110000051
wherein, R represents H, linear or branched alkyl of C1-C8 substituted by one or more of H, hydroxyl and halogen, cycloalkyl of C1-C8 substituted by one or more of H, hydroxyl, alkyl and halogen, phenyl or benzyl substituted by one or more of H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyl and cyano.
Preferably, R represents H, linear or branched alkyl of C1-C6 substituted by one or more of H, hydroxyl, halogen, cycloalkyl of C1-C6 substituted by one or more of H, hydroxyl, alkyl of C1-C6, halogen, phenyl substituted by one or more of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, and R is not methyl.
More preferably, said R represents H, -CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2OH、-CH2CH2OH、-CH(OH)CH3、-CH2CH2CH2OH、-CH(CH2OH)CH3、-CH(OH)CH2CH3、
Figure BDA0002382840110000052
Figure BDA0002382840110000061
X represents F, Cl, Br, I.
The arylpyrazoles have selective PDE4B enzyme inhibitory activity and no inhibitory activity on PDE 4D.
The above PDE4 inhibitors are useful for the treatment of asthma, chronic bronchitis, chronic obstructive pulmonary disease, eosinophilic granuloma, benign or malignant proliferative skin diseases, endotoxic shock, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, respiratory distress syndrome, diabetes insipidus, allergic rhinitis, conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft-versus-host disease, gastric acid hypersecretion, bacterially, fungally or virally induced sepsis or septic shock, inflammation and cytokine mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle atrophy, depression, memory disorders, acute and chronic neurodegenerative disorders, Parkinson's disease, Alzheimer's disease, spinal cord trauma, craniocerebral injury or multiple sclerosis.
The invention has the advantages that:
the arylpyrazole compound with the structure shown in the general formula 1 has good selective PDE4 inhibition activity, has weak inhibition effect on PDE4D, and can show more excellent pharmacodynamic performance and less side effect compared with the traditional PDE4 inhibitor. The compound can be used for preparing medicines for treating arthritis, asthma, chronic obstructive pulmonary disease, senile dementia, depression and the like.
Detailed Description
The technical solution of the present invention will be described in detail with reference to the following examples. The following examples illustrate but do not limit the synthesis of the compounds of formula 1. In an embodiment, the arylpyrazole compound includes the compounds shown below:
Figure BDA0002382840110000062
example 1: preparation of Compound a
(1) Preparation of intermediate 4
Figure BDA0002382840110000071
In a 100mL round bottom flask, 3 ', 5' -dihydroxyacetophenone (1.52g, 10mmol), 3, 4-dihydro-2H-pyran (1.68g, 20mmol), pyridine p-toluene sulfonic acid (PPTs, 0.13g, 0.5mmol) were added, mixed, dichloromethane (50mL) was added, dissolved, magnetically stirred, and reacted at 40 ℃ for 24H, then stopped. The reaction mixture was collected, and the mixture was partitioned between 10% sodium hydroxide (50mL) and dichloromethane (50mL) to obtain a lower organic layer. The extracted liquid was washed with 30mL of saturated brine for 2 times, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 4(3.12g, yield 97.5%).1H NMR(500MHz，CDCl3)δ7.26(s，2H),6.93(s，1H),5.58(s,2H),3.81(q，3H),3.62(t,2H),2.55(s,3H),1.98-1.90(m,4H),1.60-1.52(m,4H),1.52-1.48(m,4H)。
(2) Preparation of intermediate 7
Figure BDA0002382840110000072
In a 100mL round bottom flask, p-hydroxybenzaldehyde (1.22g, 10mmol), 3, 4-dihydro-2H-pyran (0.84g, 10mmol), PPTs (0.13g, 0.5mmol) were added, mixed, and dichloromethane (50mL) was added, dissolved, magnetically stirred, and the reaction was stopped after 24H at 40 ℃. The reaction mixture was collected, and the mixture was partitioned between 10% sodium hydroxide (50mL) and dichloromethane (50mL) to obtain a lower organic layer. The extracted liquid was washed with 30mL of saturated brine for 2 times, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 7(1.93g, yield 93.7%).1H NMR(500MHz，CDCl3)δ9.87(s，1H),7.70(d，2H,J＝8.1Hz),7.10(d,2H,J＝8.1Hz),5.60(s，1H),3.78-3.60(m，2H)，1.98(t，2H),1.62-1.56(m，2H),1.72-1.65(m，2H)。
(3) Preparation of intermediate 8
Figure BDA0002382840110000081
In a round bottom flask, add intermediate 4(3.2g, 10mmol), intermediate 76(2.1g, 10mmol), add anhydrous methanol (100mL), dissolve with stirring, and slowly drop 4% sodium hydroxide (8mL) to yield a white precipitate. And continuously refluxing and reacting for 24 hours, and filtering to obtain a solid. The reaction was dissolved in absolute ethanol (8mL), PPTs (0.13g, 0.5mmol), and stirred at 50 ℃ for 22h to complete the reaction. The solvent was evaporated under reduced pressure, the mixture was separated with ether and water, the upper organic layer was taken and the solvent was evaporated under reduced pressure to give compound 8(2.18g, 85.2% yield).1H NMR(500MHz,CDCl3)δ10.10(s,1H),9.56(s,2H),7.80(d,2H,J＝8.7Hz),7.79-7.49(m,2H)，6.70-7.02(m,4H),6.49(s,1H)。
(4) Preparation of product a
Figure BDA0002382840110000082
In a round-bottomed flask, intermediate 8(2.56g, 10mmol), acethydrazide (9) (1.0g, 20mmol) were added, mixed, added with anhydrous ethanol (100mL), dissolved, and 3 drops of acetic acid were added dropwise, stirred, condensed at 85 ℃ under reflux, and the reaction was stopped after 40 hours. The reaction mixture was taken out, the solvent was evaporated under reduced pressure, the mixture was separated from water with ethyl acetate, and the upper organic layer was taken out, rotary evaporated and separated by column chromatography to give Compound a (2.39g, 89.2% yield). ESI MS:267.1[ M + H ]]+1,1H NMR(500MHz,CDCl3)δ9.87(s,1H),9.58(s,1H),9.29(s,2H),7.62(d,2H,J＝8.0Hz),6.80(m,3H),6.66(m,2H),6.19(s,1H)。
Example 2: preparation of Compound b
(1) Intermediate 4 was prepared as in example 1
(2) Preparation of intermediate 6
Figure BDA0002382840110000083
In a 100mL round bottom flask, p-hydroxybenzaldehyde (1.22g, 10mmol), 2-bromoethanol (1.25g, 10mmol), K2CO3(069g, 5mmol), mixing, adding DMF (50mL), dissolving, magnetically stirring, reacting at 40 ℃ for 24h, and stopping. The reaction mixture was collected, and the mixture was partitioned between 10% sodium hydroxide (50mL) and dichloromethane (50mL) to obtain a lower organic layer. The extracted liquid was washed with 30mL of saturated brine for 2 times, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 6(1.35g, yield 81.3%).1H NMR(500MHz，CDCl3)δ9.86(s，1H),7.72(d，2H,J＝8.3Hz),7.17(d,2H,J＝8.2Hz),3.93(m，3H),3.82(m，3H)，3.21(m，1H)。
(3) Preparation of intermediate 8 and final product b referring to example 1, the overall yield of product b is 53.2%
Figure BDA0002382840110000091
ESI MS:313.3[M+H]+1,1H NMR(500MHz,CDCl3)δ9.87(s,1H),9.58(s,1H),9.29(s,2H),7.62(d,2H,J＝8.0Hz),6.80(m,3H),6.66(m,2H),6.19(s,1H),3.95(m,3H),3.83(m,3H)，3.22(m,1H)。
Example 3: preparation of Compound c
The synthesis was carried out according to the procedure for the preparation of compound b of example 2, using ethyl bromide instead of 2-bromoethanol for the preparation of intermediate 6, with an overall yield of compound c of 60.9%. The structural formula is as follows:
Figure BDA0002382840110000092
ESI MS:297.7[M+H]+1,1H NMR(500MHz,CDCl3)δ9.97(s,1H),9.52(s,1H),9.23(s,2H),7.66(d,2H,J＝8.0Hz),6.83(m,3H),6.61(m,2H),6.13(s,1H),3.82(m,2H),1.31(m,3H)。
example 4: preparation of Compound d
Check-up was performed with reference to the preparation of compound b of example 2, using benzyl bromide instead of 2-bromoethanol in the preparation of intermediate 6, with an overall yield of compound d of 63.1%. The structural formula is as follows:
Figure BDA0002382840110000093
ESI MS:359.1[M+H]+1,1H NMR(500MHz,CDCl3)δ9.91(s,1H),9.57(s,1H),9.23(s,2H),7.66-7.51(m,5H),6.81(m,3H),6.72-6.63(m,4H),6.11(s,1H),4.72(s,2H)。
example 5: preparation of Compound e
Checking was performed with reference to the preparation of compound b of example 2, 2-bromopropane was used instead of 2-bromoethanol in the preparation of intermediate 6, and the overall yield of compound e was 49.3%. The structural formula is as follows:
Figure BDA0002382840110000101
ESI MS:311.3[M+H]+1,1H NMR(500MHz,CDCl3)δ9.98(s,1H),9.47(s,1H),9.13(s,2H),7.69(d,2H,J＝8.1Hz),6.85(m,3H),6.60(m,2H),6.17(s,1H),3.91(m,1H),1.33(m,6H)。
example 6: preparation of Compound f
Checking was performed with reference to the preparation of compound b of example 2, using bromocyclopropane instead of 2-bromoethanol in the preparation of intermediate 6, with an overall yield of compound f of 52.6%. The structural formula is as follows:
Figure BDA0002382840110000102
ESI MS:309.6[M+H]+1,1H NMR(500MHz,CDCl3)δ9.88(s,1H),9.41(s,1H),9.11(s,2H),7.77(d,2H,J＝8.3Hz),6.75(m,3H),6.61(m,2H),6.12(s,1H),2.41(m,1H),0.79(m,2H),0.52(m,2H)。
example 7: preparation of control Compounds
To better illustrate the importance of the position and type of the substituents in formula 1 according to the invention on the activity of PDE4B, compounds D1, D2 and D3 were synthesized by reference to the methods of the above examples and examined for their activity on PDE4 and PDE 4D.
Figure BDA0002382840110000103
Figure BDA0002382840110000111
Example 8: PDE4B and PDE4D inhibitory Activity studies of the products obtained in examples 1-7
The experimental method comprises the following steps: the main step references Yong-xian Shao, J.Med.chem.2014,57, 10304-10313. By using3H-cAMP was used as a substrate to test the inhibitory activity of compounds against PDE 4B/D. Buffer was added to 384 well plates with 50mM Tris-HCl, pH 8.0,10mM MgCl test buffer2And 1mM DTT. Then, the prepared arylpyrazole compound (1 nM-1000 nM), PDE4B or 4D (50-200ng/mL) and3H-cAMP (20nM) was added to the buffer. Incubate at room temperature for 15 min, add 0.2M ZnSO4The reaction was terminated with 0.2N Ba (OH)2Precipitate out3Reaction product of H-cAMP, unreacted3H-cAMP was left in the supernatant and the radioactivity (cpm values) of the supernatant was measured using a Sigma LS1801 scintillation machine. The inhibitory activity of the arylpyrazole compounds is expressed by the hydrolysis rate of H-cAMP. Each compound was tested at 8 different concentrations to calculate half maximal Inhibitory Concentration (IC)50Value), repeat the test 3 times, and nonlinear regression calculated its IC50 value. A positive control was tested with Rolipram as PDE4B/D enzyme activity.
Inhibitory Activity of the Compounds of Table 1 on PDE4B/D
Figure BDA0002382840110000112
Specific IC from the above table50The data show that the compound of the invention has strong inhibitory action on PDE4B, and has potential effects on treating arthritis, asthma, chronic obstructive pulmonary disease, senile dementia, depression and the like. Meanwhile, compared with the positive control Rolipram, the compound greatly reduces the inhibition effect on PDE4D, so that clinically induced gastrointestinal side effects such as vomit, nausea and the like are smaller. The comparative compounds D1, D2 and D3 have the same structural skeletons as those of the compounds of the present invention, but they have the same structuresThe position or the type of the substituent group is changed, and the inhibitory activity and the selectivity of the PDE4B of the compound are obviously reduced.
While the present invention has been illustrated by the foregoing specific embodiments, it is not to be construed as limited thereby, but is to cover the general aspects of the foregoing disclosure. Various modifications and embodiments can be made without departing from the spirit and scope of the invention.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and their concepts should be equivalent or changed within the technical scope of the present invention.

Claims (10)

1. An arylpyrazole compound characterized by having the following structure:
Figure FDA0002382840100000011
wherein, R represents H, linear or branched alkyl of C1-C8 substituted by one or more of H, hydroxyl, halogen, cycloalkyl of C1-C8 substituted by one or more of H, hydroxyl, alkyl and halogen, phenyl or benzyl substituted by one or more of H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyl and cyano, and R is not methyl.
2. The arylpyrazole compounds according to claim 1, wherein R represents H, a linear or branched alkyl group of C1-C6 substituted by one or more of H, hydroxy, halogen, an alkyl group of C1-C6, a cycloalkyl group of C1-C6 substituted by one or more of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, a haloalkyl group of C1-C6, hydroxy, cyano, and R is not methyl.
3. The article of claim 1, IIArylpyrazoles, characterized in that R represents H, -CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2OH、-CH2CH2OH、-CH(OH)CH3、-CH2CH2CH2OH、-CH(CH2OH)CH3、-CH(OH)CH2CH3、
Figure FDA0002382840100000012
Figure FDA0002382840100000013
Figure FDA0002382840100000014
X represents F, Cl, Br, I.
4. The arylpyrazole compound according to claim 1, which has the following structural formula:
Figure FDA0002382840100000015
5. the process for the preparation of arylpyrazoles according to any of claims 1-4, characterized in that it comprises the following steps:
(1) the 3 ', 5' -dihydroxy acetophenone and 3, 4-dihydro-2H-pyran are subjected to addition reaction in the presence of pyridine p-toluenesulfonate to generate an intermediate 4,
Figure FDA0002382840100000021
(2)
(2a) the p-hydroxybenzaldehyde and R 'Br or R' I are subjected to substitution reaction under the alkaline condition to obtain an intermediate 6,
Figure FDA0002382840100000022
r' represents a linear or branched alkyl group of C1-C8 substituted by one or more of H, hydroxyl, halogen, a cycloalkyl group of C1-C8 substituted by one or more of H, hydroxyl, alkyl, halogen, a phenyl or benzyl group substituted by one or more of H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyl, cyano;
or (2b) carrying out addition reaction on p-hydroxybenzaldehyde and 3, 4-dihydro-2H-pyran in the presence of pyridine p-toluenesulfonate to generate an intermediate 7,
Figure FDA0002382840100000023
(3) reacting the intermediate 4 with the intermediate 6 or 7 under alkaline conditions, then reacting the intermediate product in the presence of pyridine p-toluenesulfonate to obtain an intermediate 8,
Figure FDA0002382840100000024
r represents H, linear or branched alkyl of C1-C8 substituted by one or more of H, hydroxyl, halogen, cycloalkyl of C1-C8 substituted by one or more of H, hydroxyl, alkyl and halogen, phenyl or benzyl substituted by one or more of H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyl and cyano;
(4) reacting the intermediate 8 with acethydrazide under the catalysis of acid to obtain a compound 1,
Figure FDA0002382840100000031
6. the method according to claim 5, wherein the reaction solvent in the step (1) is dichloromethane, the reaction solvent in the step (2a) is DMF, and the reaction solvent in the step (2b) is dichloromethane; the reaction solvent in the step (3) is absolute methanol; and (4) the reaction solvent is absolute methanol.
7. The process according to claim 5, wherein the acid is acetic acid and/or p-toluenesulfonic acid.
8. The application of an arylpyrazole compound in preparing a PDE4 inhibitor, wherein the arylpyrazole compound has the following structure:
Figure FDA0002382840100000032
wherein, R represents H, linear or branched alkyl of C1-C8 substituted by one or more of H, hydroxyl and halogen, cycloalkyl of C1-C8 substituted by one or more of H, hydroxyl, alkyl and halogen, phenyl or benzyl substituted by one or more of H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyl and cyano.
9. Use according to claim 8, characterized in that the arylpyrazoles have selective PDE4B enzyme inhibitory activity and no inhibitory activity on PDE 4D.
10. The use according to claim 9, wherein the PDE4 inhibitor is for the treatment of asthma, chronic bronchitis, chronic obstructive pulmonary disease, eosinophilic granuloma, benign or malignant proliferative skin diseases, endotoxic shock, septic shock, ulcerative colitis, Crohn's disease, myocardial and brain reperfusion injury, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, respiratory distress syndrome, diabetes insipidus, allergic rhinitis, conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft-versus-host disease, hyperchlorhydria, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle atrophy, depression, memory disorders, acute and chronic neurodegenerative disorders, parkinson's disease, alzheimer's disease, spinal cord trauma, craniocerebral injury or multiple sclerosis.
CN202010088352.2A 2020-02-12 2020-02-12 Aryl pyrazole compound and application thereof Pending CN111217752A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010088352.2A CN111217752A (en) 2020-02-12 2020-02-12 Aryl pyrazole compound and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010088352.2A CN111217752A (en) 2020-02-12 2020-02-12 Aryl pyrazole compound and application thereof

Publications (1)

Publication Number Publication Date
CN111217752A true CN111217752A (en) 2020-06-02

Family

ID=70826235

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010088352.2A Pending CN111217752A (en) 2020-02-12 2020-02-12 Aryl pyrazole compound and application thereof

Country Status (1)

Country Link
CN (1) CN111217752A (en)

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004080972A1 (en) * 2003-03-12 2004-09-23 Vertex Pharmaceuticals Incorporated Pirazole modulators of atp-binding cassette transporters
WO2006124687A1 (en) * 2005-05-12 2006-11-23 University Of Medicine And Dentistry Of New Jersey Opioid receptor subtype-selective agents
WO2008045663A2 (en) * 2006-10-06 2008-04-17 Kalypsys, Inc. Aryl-substituted heterocyclic pde4 inhibitors as antiinflammatory agents
WO2008131148A1 (en) * 2007-04-19 2008-10-30 The Trustees Of The University Of Pennsylvania Diphenyl-heteroaryl derivatives and their use for binding and imaging amyloid plaques
WO2009143150A2 (en) * 2008-05-19 2009-11-26 Burnham Institute For Medical Research Intestinal alkaline phosphatase modulators and uses thereof
WO2011009484A1 (en) * 2009-07-22 2011-01-27 Novartis Ag Arylpyrazoles and arylisoxazoles and their use as pkd modulators
JP2011042591A (en) * 2009-08-19 2011-03-03 Kowa Co 3,5-bisaryl pyrazole compound and erythropoietin production promoter containing the same as active ingredient
US20160213780A1 (en) * 2015-01-22 2016-07-28 Vanderbilt University Methods for use of small molecule activators of hem-y / protoporphyrinogen oxidase (ppo)
CN110698403A (en) * 2019-09-29 2020-01-17 温州市人民医院 Trisubstituted pyrazole derivative and application thereof
CN111170925A (en) * 2020-01-09 2020-05-19 常州大学 Phthalimide compound serving as PDE2/4 dual inhibitor and preparation method thereof

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004080972A1 (en) * 2003-03-12 2004-09-23 Vertex Pharmaceuticals Incorporated Pirazole modulators of atp-binding cassette transporters
WO2006124687A1 (en) * 2005-05-12 2006-11-23 University Of Medicine And Dentistry Of New Jersey Opioid receptor subtype-selective agents
WO2008045663A2 (en) * 2006-10-06 2008-04-17 Kalypsys, Inc. Aryl-substituted heterocyclic pde4 inhibitors as antiinflammatory agents
WO2008131148A1 (en) * 2007-04-19 2008-10-30 The Trustees Of The University Of Pennsylvania Diphenyl-heteroaryl derivatives and their use for binding and imaging amyloid plaques
WO2009143150A2 (en) * 2008-05-19 2009-11-26 Burnham Institute For Medical Research Intestinal alkaline phosphatase modulators and uses thereof
WO2011009484A1 (en) * 2009-07-22 2011-01-27 Novartis Ag Arylpyrazoles and arylisoxazoles and their use as pkd modulators
JP2011042591A (en) * 2009-08-19 2011-03-03 Kowa Co 3,5-bisaryl pyrazole compound and erythropoietin production promoter containing the same as active ingredient
US20160213780A1 (en) * 2015-01-22 2016-07-28 Vanderbilt University Methods for use of small molecule activators of hem-y / protoporphyrinogen oxidase (ppo)
CN110698403A (en) * 2019-09-29 2020-01-17 温州市人民医院 Trisubstituted pyrazole derivative and application thereof
CN111170925A (en) * 2020-01-09 2020-05-19 常州大学 Phthalimide compound serving as PDE2/4 dual inhibitor and preparation method thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
EMMANUEL BEY ET AL.: "Design, synthesis and biological evaluation of bis(hydroxyphenyl) azoles as potent and selective non-steroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) for the treatment of estrogen-dependent diseases", 《BIOORGANIC & MEDICINAL CHEMISTRY》 *
M. IRSHAD ET AL.: "Aurones and Analogues: Promising Heterocyclic Scaffolds for Development of Antioxidant and Antimicrobial Agents", 《RUSSIAN JOURNAL OF GENERAL CHEMISTRY》 *
贾怀锋: "新查尔酮的制备及吡唑衍生物的合成研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 *

Similar Documents

Publication Publication Date Title
CN109053731B (en) P-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof
CN106660996A (en) Novel 2,5-substituted pyrimidines as PDE4 inhibitors
CN112645869B (en) Preparation method of chlorpheniramine maleate intermediate
CN111943944A (en) Ethylthio-containing pyridine-bis-1, 2, 4-oxadiazole substituted benzamide compound and preparation method and application thereof
JP2024501554A (en) Oxyspiro ring-substituted pyrrolopyrazole derivatives and intermediates thereof and methods for their preparation
WO2015012110A1 (en) Method for manufacturing c-glycoside derivative
CN113234070A (en) Honokiol thioether derivative containing oxazole ring, and preparation method and application thereof
CN111217752A (en) Aryl pyrazole compound and application thereof
CN110240539B (en) Fluorine substituted diphenylethane compound, preparation method and application
KR20060092219A (en) Aminopyridine-derivatives as inductible no-synthase inhibitors
CN111647004B (en) Propenone derivative for removing N-methylofloxacin and preparation method and application thereof
CN111646975B (en) N-methyl lomefloxacin allyl ketone derivative and preparation method and application thereof
CN111170925B (en) Phthalimide compound as PDE2/4 dual inhibitor and preparation method thereof
CN109574830B (en) Rosuvastatin calcium intermediate, and preparation method and application thereof
CN106565657A (en) Hesperetin cinnamate compound with anti-tumor activity and synthetic method thereof
CN106674102A (en) Halogenated quinoline compound and preparation method thereof
CN106045971A (en) Pirfenidone derivative and preparation method thereof
CN101781311A (en) Novel preparation method of platelet aggregation inhibition compound
CN109232572B (en) P-methyl-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof
CN109180675B (en) P-methoxy substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof
CN108707153B (en) D-valine substituted maleimide derivative and preparation method and application thereof
CN110156676B (en) 3, 4-dihydroquinoline-2 (1H) -ketone derivative and preparation method and application thereof
CN109053732B (en) Para-fluorine substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof
CN109232571B (en) P-methylmercapto-substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof
CN112830926B (en) Acrylic ketone derivative of N-acetyl moxifloxacin and preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20200602