CN111875594A - Indazole heterocycles having phosphodiesterase 4B inhibitory activity - Google Patents
Indazole heterocycles having phosphodiesterase 4B inhibitory activity Download PDFInfo
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- CN111875594A CN111875594A CN202010703992.XA CN202010703992A CN111875594A CN 111875594 A CN111875594 A CN 111875594A CN 202010703992 A CN202010703992 A CN 202010703992A CN 111875594 A CN111875594 A CN 111875594A
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- substituted
- aryl
- carboxyl
- mono
- indazole
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- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
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- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
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- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 1
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- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
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- 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
- A61P17/00—Drugs for dermatological disorders
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- 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
- A61P17/06—Antipsoriatics
-
- 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
- A61P25/22—Anxiolytics
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- 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]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a compound containing an indazole heterocyclic skeleton and application thereof, belonging to the field of pharmaceutical chemistry. The compound containing indazole heterocyclic skeleton has good inhibitory activity on PDE4B, can be used as a PDE4B inhibitor, and is used for preparing medicaments for preventing or treating diseases related to PDE4B, including medicaments for treating inflammation-related diseases such as chronic obstructive pulmonary disease, asthma, dermatitis and psoriasis, and medicaments for treating central nervous diseases such as Alzheimer's disease, anxiety and cognition.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an indazole heterocyclic compound with phosphodiesterase 4B inhibitory activity.
Background
Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable and treatable disease characterized by persistent respiratory symptoms and airflow limitation, usually due to airway and/or alveolar abnormalities caused by significant exposure to toxic particles or gases. Currently, COPD is the fourth most fatal disease in the world, with over 300 million people dying from COPD each year, accounting for about 6% of the worldwide deaths (Global initial for chronic structural diseases, updated 2019). According to the latest statistics, chronic obstructive pulmonary disease has become the third chronic disease in China, which is second to hypertension and diabetes, and about 1 million patients with chronic obstructive pulmonary disease (Lancet.2018; 391(10131):1706-1717) exist. With the increasing air pollution and the aging population, the prevalence rate of COPD is continuously increased in recent years, which not only causes long-term pain and affliction to patients, but also causes heavy economic burden to families and society.
The conventional chronic obstructive pulmonary disease treatment drugs which are commonly used clinically can be divided into bronchodilators and anti-inflammatory drugs according to the pharmacological activity of the drugs. The bronchodilators are the dominant, and include long-acting and short-acting muscarinic receptor antagonists such as ipratropium bromide and tiotropium bromide, long-acting and short-acting beta 2-adrenoceptor agonists, and combinations of bronchodilators and anti-inflammatory glucocorticoids. However, these treatment regimens only improve COPD symptoms, reduce acute exacerbation rates and reduce mortality, provide relief from COPD symptoms, and are not radical, resulting in an inevitable, sustained decline in lung function. Therefore, there is an urgent need for specific therapeutic drugs for COPD in the clinic, and the research and discovery of novel therapeutic drugs for COPD are still hot spots at present.
Since COPD is a complex and comprehensive disease, a variety of mechanisms are involved in the pathogenesis, including inflammatory response, oxidative stress, mitochondrial dysfunction, aging, protease-antiprotease imbalance, and the like, which are interconnected and interact to form the complexity, persistence, and refractory of COPD. Intensive research and development has been conducted on the inflammatory mechanism of COPD. Phosphodiesterase 4 (PDE 4) is widely expressed in a variety of inflammatory and immune cells, and specifically hydrolyzes Cyclic adenosine monophosphate (cAMP), which plays an important role in inflammatory responses. The PDE4 inhibitor can increase cAMP level in vivo, inhibit release of inflammatory factor, promote production of anti-inflammatory mediator, and exert anti-inflammatory effect by inhibiting hydrolysis of PDE 4. The Roflumilast is clinically used for treating COPD, has obvious anti-inflammatory effect, and can inhibit monocytes, macrophages, T cells and the like from releasing inflammatory mediators such as TNF-alpha, interleukin, chemotactic factors and the like. However, the serious side effects of nausea, vomiting and the like exist in the inhibitor, so that the clinical application of the PDE4 inhibitor is limited. A large number of researches show that in human body, subtype B of phosphodiesterase 4 (PDE4B) is related to inflammatory reaction and is involved in the release of various inflammatory mediators in the body, and subtype D is closely related to the generation of side effects such as nausea and vomiting, so that a new idea is provided for finding a PDE4 inhibitor with low side effect, namely, designing a selective PDE4B inhibitor can reduce the influence of the side effect and promote further clinical application.
The protein sequences of the four isoform catalytic domains of PDE4 are highly homologous, and inhibitors acting on the catalytic domains do not produce isoform selectivity, whereas most classical PDE4 inhibitors have been reported to act on the catalytic domain. A novel PDE4 inhibitor action mode reported in recent years, wherein the inhibitor acts with a catalytic domain and a regulatory sequence simultaneously, so that the regulatory sequence can stabilize the closed conformation of protein, prevent cAMP from entering and play an inhibiting role, and researches show that the PDE4B and 4D have amino acid difference on the regulatory sequence, and the inhibitor can be designed to generate subtype selectivity based on the difference. Therefore, based on the difference of two amino acids of PDE4B Leu674/PDE4D Gln594 on the downstream regulatory sequence CR3(Conserved Region 3), it is expected that subtype B selectivity will be achieved, while maintaining activity and reducing side effects of inhibitors.
Accordingly, the invention develops design and synthesis research on PDE4B inhibitors aiming at a regulatory sequence CR3, and designs and synthesizes a compound with PDE4B inhibition activity.
Disclosure of Invention
The invention aims to provide a compound containing indazole heterocyclic skeleton and having phosphodiesterase 4B inhibition activity and application thereof.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
a substituted indazole heterocyclic compound is a compound shown as a formula I or an optical isomer, an enantiomer, a diastereomer, a racemate, a racemic mixture or a pharmaceutically acceptable salt or prodrug thereof,
wherein:
R1is selected from one of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 carboxyl, C1-C3 difluoromethyl, C1-C3 trifluoromethyl or substituted benzyl, wherein the substituent of the benzyl in the substituted benzyl is selected from F, Cl, Br, I, CF3CN, hydroxyl, methoxyl, methyl, amino, nitryl, sulfydryl, carboxyl, ethenyl, C4-C8 straight-chain alkyl or branched-chain alkyl, aryl, heterocyclic radical;
R2is aryl or heterocyclic aryl, the aryl is selected from unsubstituted, mono-substituted or poly-substituted phenyl, naphthyl or biphenyl, the mono-substituted or poly-substituted substituent is selected from halogen, cyano, nitro, hydroxyl, amino, carboxyl, carbomethoxy or carbethoxy, the heterocyclic aryl is selected from unsubstituted, mono-substituted or poly-substituted pyrimidine, imidazole, pyrazole, pyridine, triazole, thiazole, indole, indazole or benzimidazole, and the mono-substituted or poly-substituted substituent is selected from halogen, cyano, nitro, hydroxyl, amino, carboxyl, carbomethoxy or carbethoxy;
w, X, Y is selected from C, N, O or S, Z is C or N, and the position of X substituent is selected from ortho, para or meta of W;
R3selected from C1-C6 alkyl, C2-C6 carboxyl, phenyl, heterocyclic aryl or benzyl, wherein the phenyl, heterocyclic aryl and benzyl are unsubstituted, mono-substituted or di-substitutedThe substituted, mono-substituted or di-substituted substituent is selected from F, Cl, Br, I, CF3CN, hydroxyl, methoxyl, methyl, amino, nitryl, sulfydryl, carboxyl, ethenyl, C4-C8 straight-chain alkyl or branched-chain alkyl, aryl, heterocyclic radical.
Further, the compound is selected from the following compounds:
the application of the compound serving as a PDE4B inhibitor in preparing medicines for preventing and/or treating diseases related to PDE 4B.
The PDE 4B-related diseases include inflammatory diseases and central nervous diseases.
The inflammatory diseases include chronic obstructive pulmonary disease, asthma, dermatitis, psoriasis; the central nervous system disorder includes Alzheimer's disease, anxiety resistance, and cognition improvement.
The substituted indazole heterocyclic compound is proved to have good inhibitory activity on PDE4B through modern pharmacological scientific research, and is applicable to diseases related to PDE 4B.
Detailed Description
To further illustrate the present invention, a series of examples are given below, which are purely illustrative and are intended to be a detailed description of the invention only and should not be understood as limiting the invention.
Example 1
Preparation of 3- ((3- (5-chlorothien-2-yl) -1-isopropyl-1H-indazol-5-yl) amino) propionic acid (I-1)
Step 1. Synthesis of 3-bromo-1-isopropyl-5-nitro-1H-indazole
1.00g (4.14mmol) of 3-bromo-5-nitro-1H-indazole and 331.2mg (8.28mmol) of sodium hydride (content: 60%) are added to a 250mL eggplant-shaped bottle, 120mL of anhydrous N, N-dimethylformamide is added under ice-bath conditions to dissolve the mixture, the mixture is stirred for 0.5H and then moved to room temperature, 446. mu.L (4.54mmol) of 2-iodopropane is added, and the reaction is stirred at room temperature for 24H. The reaction solution was quenched by adding 3 times the volume of water, extracted with ethyl acetate several times, the organic phases were combined and washed with water for 2 times, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated, and then subjected to sand preparation and column chromatography purification (petroleum ether: dichloromethane: 4:1) to obtain 435mg of a white solid with a yield of 41.4%.
1H-NMR(500MHz,DMSO-d6):8.44(d,1H),8.28(dd,J＝9.3,2.0Hz,1H),8.02(d,J＝9.3Hz,1H),5.14(m,1H),1.51(d,J＝6.6Hz,6H).
Step 2. Synthesis of 3- (5-chlorothiophene-2-yl) -1-isopropyl-5-nitro-1H-indazole
510.0mg (2.00mmol) of the starting material was placed in a 50mL two-necked round-bottomed flask, and 486.0mg (3.00mmol) of 5-chlorothiophene-2-boronic acid and 37.0mg (0.05mmol) of [1,1' -bis (diphenylphosphino) ferrocene were added]Palladium dichloride (Pd (dppf) Cl2) Dissolving the mixture in 16mL of toluene and 8mL of methanol, and adding Na2CO3424mg (4.00mmol), vacuum pumping 10min with a water pump, nitrogen protection and reflux at 110 ℃. After about 14h the starting material was reacted by TLC. The reaction mixture was filtered with suction, and the filtrate was purified by column chromatography (petroleum ether: dichloromethane: 8:1) to obtain 295mg of a yellow solid in a yield of 46.0%.
1H-NMR(400MHz,CDCl3):8.91(dd,J＝2.1,0.6Hz,1H),8.29(dd,J＝9.3,2.1Hz,1H),7.50(d,J＝9.3Hz,1H),7.44(d,J＝3.9Hz,1H),7.02(d,J＝3.9Hz,1H),4.88(m,1H),1.64(d,J＝6.7Hz,6H).
Step 3, synthesizing 3- (5-chlorothiophene-2-yl) -1-isopropyl-1H-indazole-5-amine
200mg (0.80mmol) of the starting material was placed in a 100mL eggplant type bottle, 148mg (2.64mmol) of reduced iron powder and 353mg (6.60mmol) of ammonium chloride were added thereto, and the mixture was dissolved in 8mL of ethanol and 4mL of water and reacted at 80 ℃ for about 1 hour. TLC detection raw material has completely reduced, filter insoluble impurities, filtrate with dichloromethane extraction 3 times, combined organic phase, anhydrous sodium sulfate after drying concentrated, drying, weighing, crude product about 165mg, yield about 90%.
Step 4. Synthesis of 3- ((3- (5-chlorothien-2-yl) -1-isopropyl-1H-indazol-5-yl) amino) propionic acid (I-1)
165mg of the crude product from the previous step was taken out and placed in a 10mL round-bottom flask, and 45. mu.L (0.66mmol) of acrylic acid and 4mL of toluene were added and dissolved, followed by stirring and refluxing at 110 ℃. After 24 hours of reaction, the reaction was stopped by detecting the remaining portion of the starting material by TLC. Transferring the reaction solution to a 100mL eggplant-shaped bottle, adding 6mL toluene for dilution, adding a large amount of dilute sodium hydroxide solution, adjusting the pH of the reaction solution to be alkaline, stirring uniformly, standing for layering, and taking the lower-layer water phase. The aqueous phase was washed 2 times with toluene and 2 times with diethyl ether. Adding 15% diluted hydrochloric acid into the water phase, adjusting pH to 5-6, allowing the water phase to become turbid, extracting with ethyl acetate for 3 times, mixing the organic phases, drying with anhydrous sodium sulfate, concentrating, and recrystallizing to obtain solid of about 30mg with yield of about 12.5%.
M.P.165-168℃,1H-NMR(300MHz,DMSO-d6)：7.50(d,J＝9.0Hz,1H),7.43(d,J＝3.9Hz,1H),7.17(d,J＝3.9Hz,1H),6.91(d,J＝9.1Hz,1H),6.84(s,1H),4.87(m,1H),3.33(t,J＝7.0Hz,2H),2.56(t,J＝6.6Hz,2H),1.46(d,J＝6.6Hz,6H).
Example 2
Preparation of 3- ((3- (5-chlorothien-2-yl) -1-isopropyl-1H-indazol-5-yl) amino) butanoic acid (I-2)
Referring to the synthesis of I-1, about 16mg of solid was obtained with a yield of about 12.8%.
M.P.170-172℃,1H-NMR(300MHz,DMSO-d6):8.07–7.62(m,2H),7.38(d,J＝3.7Hz,2H),7.13(d,J＝3.8Hz,1H),4.89(dt,J＝12.8,6.1Hz,1H),3.85(s,1H),2.68(d,J＝15.8Hz,1H),2.55–2.40(m,1H),1.37(d,J＝6.4Hz,6H),1.20(d,J＝5.9Hz,3H)；ESI-MS(m/z):378.1[M+H]+,376.1[M-H]-.
Example 3
Preparation of 3- ((3- (5-chlorothien-2-yl) -1-isopropyl-1H-indazol-5-yl) amino) -2-methylpropanoic acid (I-3)
Referring to the synthesis of I-1, about 9mg of solid was obtained with a yield of about 7.2%.
M.P.170-174℃,1H-NMR(300MHz,DMSO-d6):7.50(d,J＝9.0Hz,1H),7.42(d,J＝3.8Hz,1H),7.16(d,J＝3.8Hz,1H),6.94(d,J＝9.1Hz,1H),6.87(s,1H),4.87(m,1H),3.51(s,1H),3.11(dd,J＝12.7,6.3Hz,1H),2.71(dd,J＝12.9,6.5Hz,1H),1.46(d,J＝6.5Hz,6H),1.24(d,J＝9.2Hz,3H)；ESI-MS(m/z):378.2[M+H]+,376.2[M-H]-.
Example 4
Preparation of (3- (5-chlorothien-2-yl) -1-isopropyl-1H-indazol-5-yl) glycine (I-4)
Step a. Synthesis of (3- (5-chlorothien-2-yl) -1-isopropyl-1H-indazol-5-yl) glycine ethyl ester
About 190mg of the crude product was taken and placed in a 15mL round-bottom flask, and 65mg (0,79mmol) of sodium acetate and 83. mu.L (0.79mmol) of ethyl chloroacetate were added thereto, dissolved in 6mL of ethanol, and the reaction was heated with stirring at 120 ℃. After 24h of reaction, TLC detection shows that the raw materials still remain, and the reaction is stopped. The reaction mixture was spun to dryness, and then subjected to sand purification by column chromatography (petroleum ether: ethyl acetate: 16:1 and 8:1) to obtain 120mg of a pale yellow solid with a yield of 48.1%.
Step b. Synthesis of (3- (5-chlorothien-2-yl) -1-isopropyl-1H-indazol-5-yl) glycine (I-4)
A15 mL round-bottom flask was charged with 120mg (0.32mmol) of the starting material and 60mg (1.28mmol) of sodium hydroxide, dissolved in 3mL of methanol and 2mL of water, and stirred at 50 ℃. After 2h of reaction TLC check that the starting material has been hydrolysed. Adding 15% diluted hydrochloric acid to adjust pH to neutral, separating out solid, filtering, dissolving again, and recrystallizing to obtain pure product about 20mg with yield of 17.9%.
M.P.130-133℃,1H-NMR(300MHz,DMSO-d6):7.52(d,J＝9.1Hz,1H),7.41(d,J＝3.9Hz,1H),7.18(d,J＝3.9Hz,1H),6.99(dd,J＝9.0,2.0Hz,1H),6.80(d,J＝1.7Hz,1H),4.88(m,1H),3.92(s,2H),1.46(d,J＝6.6Hz,6H)；ESI-MS(m/z):348.1[M-H]-.
Example 5
Preparation of 1- ((3- (5-chlorothien-2-yl) -1-isopropyl-1H-indazol-5-yl) carbamoyl) cyclopropane-1-carboxylic acid (I-5)
Step a. Synthesis of 1- ((3- (5-chlorothien-2-yl) -1-isopropyl-1H-indazol-5-yl) carbamoyl) cyclopropane-1-carboxylic acid (I-5)
A50 mL round-bottom flask was charged with 22mg (0.165mmol) of 1, 1-dicyclopropyldarboxylic acid and 23. mu.L (0.165mmol) of triethylamine, dissolved in anhydrous tetrahydrofuran, and the reaction was stirred for 0.5h under ice-bath. Add slowly 12. mu.L (0.165mmol) of thionyl chloride and continue the reaction for 0.5 h. 48mg (0.165mmol) of the starting material dissolved in anhydrous tetrahydrofuran was slowly added dropwise thereto, followed by reaction for 2 hours. TLC detects that the raw materials react completely, spin-dries the reaction solution, adds toluene to dissolve, then adds a large amount of dilute sodium hydroxide solution, adjusts the pH of the reaction solution to alkalinity, stirs evenly and then stands for layering, and takes the lower aqueous phase. The aqueous phase was washed 2 times with toluene and 2 times with diethyl ether. Adding 15% diluted hydrochloric acid into the water phase, adjusting pH to 5-6, allowing the water phase to become turbid, extracting with ethyl acetate for 3 times, mixing the organic phases, drying with anhydrous sodium sulfate, concentrating, and recrystallizing to obtain solid 25mg with yield of 37.5%.
M.P.140-144℃,1H-NMR(300MHz,DMSO-d6):10.74(s,1H),8.46(s,1H),7.74(d,J＝9.1Hz,1H),7.56(dd,J＝9.1,1.5Hz,1H),7.40(d,J＝3.9Hz,1H),7.23(d,J＝3.9Hz,1H),4.99(m,1H),1.48(m,10H)；ESI-MS(m/z):402.1[M-H]-.
Example 6
Preparation of 3- ((3- (5-chlorothien-2-yl) -1- (2, 2-difluoroethyl) -1H-indazol-5-yl) amino) propionic acid (I-6)
Step a. Synthesis of 3-bromo-1- (2, 2-difluoroethyl) -5-nitro-1H-indazole
1.00g (4.14mmol) of 3-bromo-5-nitro-1H-indazole, 273. mu.L (6.20mmol) of 1, 1-difluoro-2-iodoethane and 1.14g (8.26mmol) of potassium carbonate were put in a 250mL eggplant-shaped bottle, dissolved in 100mL of anhydrous acetonitrile, and reacted for 24 hours with stirring under reflux. The TLC detected the reaction was almost complete, the reaction was filtered and then directly made into sand, purified by column chromatography (petroleum ether: dichloromethane: 4:1) to give about 850mg of a pale yellow solid with 67.1% yield.
1H-NMR(300MHz,Chloroform-d):8.63(dd,J＝2.1,0.6Hz,1H),8.38(dd,J＝9.3,2.1Hz,1H),7.55(d,J＝9.3Hz,1H),6.19(tt,J＝55.1,4.2Hz,1H),4.75(td,J＝13.4,4.2Hz,2H).
Step b. Synthesis of 3- (5-chlorothien-2-yl) -1- (2, 2-difluoroethyl) -5-nitro-1H-indazole
486.0mg of raw material was placed in a 50mL two-necked round-bottomed flask, 386.0mg (2.38mmol) of 5-chlorothiophene-2-boronic acid, 337mg (3.18mmol) of sodium carbonate and 35.0mg (0.05mmol) of [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (Pd (dppf) Cl2) were added, the mixture was dissolved in 16mL of toluene and 8mL of methanol, Na2CO 3337 mg (3.18mmol) was added, the mixture was evacuated by a water pump for 10min, and the mixture was refluxed at 110 ℃ under nitrogen protection. After about 20h the starting material was reacted by TLC. The reaction mixture was filtered, the filtrate was washed with sand, and purified by column chromatography (petroleum ether: dichloromethane: 8:1) to give a yellow solid (200 mg) in a yield of 36.7%.
1H-NMR(300MHz,Chloroform-d):8.63(dd,J＝2.1,0.6Hz,1H),8.38(dd,J＝9.3,2.1Hz,1H),7.55(d,J＝9.3Hz,1H),6.19(tt,J＝55.1,4.2Hz,1H),4.75(td,J＝13.4,4.2Hz,2H).
Step c, synthesizing 3- (5-chlorothien-2-yl) -1- (2, 2-difluoroethyl) -1H-indazol-5-amine
100mg (0.30mmol) of the above-mentioned raw material was put in a 100mL eggplant type bottle, 67mg (1.20mmol) of reduced iron powder and 214mg (4.0mmol) of ammonium chloride were added thereto, and the mixture was dissolved in 8mL of ethanol and 4mL of water and reacted at 80 ℃ for about 1 hour. TLC detection raw material has completely reduced, filter insoluble impurities, filtrate with dichloromethane extraction 3 times, combined organic phase, anhydrous sodium sulfate drying after concentration, drying, weighing, crude product about 85mg, yield about 90%.
Step d. Synthesis of 3- ((3- (5-chlorothien-2-yl) -1- (2, 2-difluoroethyl) -1H-indazol-5-yl) amino) propanoic acid (I-6)
85mg of the crude product from the previous step was taken out and placed in a 10mL round-bottom flask, 18. mu.L (0.27mmol) of acrylic acid and 4mL of toluene were added and dissolved, and the reaction was stirred at 110 ℃ and refluxed. After 24 hours of reaction, the reaction was stopped by detecting the remaining portion of the starting material by TLC. Transferring the reaction solution to a 100mL eggplant-shaped bottle, adding 6mL toluene for dilution, adding a large amount of dilute sodium hydroxide solution, adjusting the pH of the reaction solution to be alkaline, stirring uniformly, standing for layering, and taking the lower-layer water phase. The aqueous phase was washed 2 times with toluene and 2 times with diethyl ether. Adding 15% diluted hydrochloric acid into the water phase, adjusting pH to 5-6, allowing the water phase to become turbid, extracting with ethyl acetate for 3 times, mixing the organic phases, drying with anhydrous sodium sulfate, concentrating, and recrystallizing to obtain solid of about 10mg with yield of about 9.0%.
M.P.180-182℃1H-NMR(300MHz,DMSO-d6):7.57–7.48(m,2H),7.20(d,J＝3.9Hz,1H),6.96(d,J＝9.1Hz,1H),6.87(s,1H),6.40(tt,J＝54.9,3.6Hz,1H),4.86(td,J＝15.0,2.9Hz,2H),3.32(s,2H),2.56(t,J＝6.6Hz,2H)；ESI-MS(m/z):386.1[M+H]+,384.0[M-H]-.
Example 7
Preparation of 3- ((3- (5-chlorothien-2-yl) -1- (2,2, 2-trifluoroethyl) -1H-indazol-5-yl) amino) propionic acid (I-7)
Referring to the synthesis of I-6, about 11mg of solid was obtained with a yield of about 9.7%.
M.P.168-170℃1H-NMR(300MHz,DMSO-d6)7.64–7.54(m,2H),7.22(d,J＝3.9Hz,1H),7.02(dd,J＝9.1,1.7Hz,1H),6.94(s,1H),5.40(q,J＝9.1Hz,2H),3.36(t,J＝6.7Hz,2H),2.57(t,J＝6.7Hz,2H)；ESI-MS(m/z):404.2[M+H]+,402.1[M-H]-.
Example 8
Preparation of 3- ((3- (5-chlorothien-2-yl) -1-isopropyl-1H-indazol-5-yl) amino) propionic acid (I-8)
Referring to the synthesis of I-1, about 25mg of solid was obtained with a yield of about 13.8%.
M.P.164-166℃,1H-NMR(300MHz,DMSO-d6):7.66(d,J＝9.0Hz,1H),7.51(d,J＝3.9Hz,1H),7.41(s,1H),7.22(m,2H),4.42(q,J＝7.1Hz,2H),3.45(t,J＝6.9Hz,2H),2.65(t,J＝6.9Hz,2H),1.39(t,J＝7.2Hz,3H)；ESI-MS(m/z):350.2[M+H]+,348.1[M-H]-.
Example 9
Preparation of 3- ((3- (3-chlorophenyl) -1-isopropyl-1H-indazol-5-yl) amino) propionic acid (I-9)
Referring to the synthesis of I-1, about 28mg of solid was obtained with a yield of about 15.1%.
M.P.170-171℃1H-NMR(300MHz,DMSO-d6):7.97–7.77(m,4H),7.58(t,J＝8.0Hz,1H),7.52–7.45(m,1H),7.41(d,J＝8.3Hz,1H),5.07(p,J＝6.5Hz,1H),3.52(t,J＝7.0Hz,2H),2.71(t,J＝7.0Hz,2H),1.54(d,J＝6.6Hz,6H)；ESI-MS(m/z):358.2[M+H]+,356.2[M-H]-.
Example 10
Preparation of (3- (5-chlorothien-2-yl) -1- (2, 2-difluoroethyl) -1H-indazol-5-yl) glycine (I-10)
Referring to the synthesis of I-4, a solid was obtained in a yield of about 24mg of 25.9%.
M.P.173-175℃,1H-NMR(300MHz,DMSO-d6):7.64(d,J＝9.2Hz,1H),7.54(d,J＝3.5Hz,1H),7.22(d,J＝8.3Hz,3H),6.42(t,J＝54.7Hz,1H),4.91(t,J＝15.0Hz,2H),4.07(s,2H).
Example 11
Preparation of 3- (5- ((carboxymethyl) amino) -3- (5-chlorothien-2-yl) -1H-indazol-1-yl) propionic acid (I-11)
Referring to the synthesis of I-4, about 30mg of solid was obtained with a yield of 28.2%.
M.P.111-115℃,1H-NMR(300MHz,DMSO-d6):7.67(dd,J＝9.0,4.1Hz,1H),7.51(d,J＝4.0Hz,1H),7.41(d,J＝10.0Hz,1H),7.29(d,J＝9.0Hz,1H),7.23(d,J＝3.9Hz,1H),4.61(t,J＝6.5Hz,2H),4.12(s,2H),2.93(t,J＝6.5Hz,2H).
Example 12
Preparation of (3- (5-chlorothien-2-yl) -1- (3- (methoxycarbonyl) benzyl) -1H-indazol-5-yl) glycine (I-12)
Referring to the synthesis of I-4, about 30mg of solid was obtained in 24.8% yield.
1H-NMR(300MHz,DMSO-d6):7.84(d,J＝8.3Hz,2H),7.70(d,J＝9.1Hz,1H),7.54(d,J＝4.0Hz,1H),7.46(dd,J＝4.6,1.9Hz,2H),7.39(s,1H),7.26(dd,J＝9.8,2.6Hz,2H),5.73(s,2H),4.11(s,2H)；HRMS(ESI-TOF):called for C21H16ClN3O4S[M+H]+441.0550,found 442.0627.
Example 13
Preparation of 1- ((3- (5-chlorothien-2-yl) -1- (2, 2-difluoroethyl) -1H-indazol-5-yl) carbamoyl) cyclopropane-1-carboxylic acid (I-13)
Referring to the synthesis of I-5, about 30mg of solid was obtained with a yield of 25.8%.
M.P.152-155℃,1H-NMR(300MHz,DMSO-d6):10.76(s,1H),8.54–8.46(m,1H),7.76(d,J＝9.1Hz,1H),7.62(dd,J＝9.1,1.8Hz,1H),7.47(d,J＝4.0Hz,1H),7.27(d,J＝3.9Hz,1H),6.46(tt,J＝54.7,3.4Hz,1H),4.97(td,J＝15.2,3.2Hz,2H),1.47(d,J＝3.2Hz,4H)；HRMS(ESI-TOF):called for C18H14ClF2N3O3S[M+H]+425.0412,found 426.0487.
Example 14
In vitro PDE4B enzyme inhibition Activity assay
PDE4B enzyme inhibitory activity was assessed by reacting fluorescently labeled cAMP as a substrate with PDE4B1, and measuring the intensity of fluorescence polarization signal of the remaining substrate to indirectly determine the effect of the compound on the enzyme activity. Specific results are shown in table 1.
PDE4B inhibitory Activity of the Compounds of the examples in Table 1
| Name of Compound | 1 μ M inhibition rate | Inhibition rate of 10. mu.M |
| Control group: rolipram | 82％ | 99％ |
| I-1 | 14％ | 52％ |
| I-2 | 20％ | 61％ |
| I-3 | 28％ | 67％ |
| I-4 | 58％ | 89％ |
| I-5 | 32％ | 74％ |
| I-6 | 47％ | 81％ |
| I-7 | 18％ | 49％ |
| I-8 | 38％ | 78％ |
| I-9 | 10％ | 46％ |
| I-10 | 75％ | 94％ |
| I-11 | 62％ | 84％ |
| I-12 | 11％ | 52％ |
| I-13 | 13％ | 49％ |
As shown in the above table, the compounds of the present invention have good PDE4B inhibitory activity.
The above description is only of the preferred embodiments of the present invention, and it should be noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the invention and these are intended to be within the scope of the invention.
Claims (5)
1. A substituted indazole heterocyclic compound characterized by: the structural formula is shown as a formula I,
wherein:
R1is selected from one of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 carboxyl, C1-C3 difluoromethyl, C1-C3 trifluoromethyl or substituted benzyl, wherein the substituent of the benzyl in the substituted benzyl is selected from F, Cl, Br, I, CF3CN, hydroxyl, methoxyl, methyl, amino, nitryl, sulfydryl, carboxyl, ethenyl, C4-C8 straight-chain alkyl or branched-chain alkyl, aryl, heterocyclic radical;
R2is aryl or heterocyclic aryl, the aryl is selected from unsubstituted, mono-substituted or poly-substituted phenyl, naphthyl or biphenyl, the mono-substituted or poly-substituted substituent is selected from halogen, cyano, nitro, hydroxyl, amino, carboxyl, carbomethoxy or carbethoxy, the heterocyclic aryl is selected from unsubstituted, mono-substituted or poly-substituted pyrimidine, imidazole, pyrazole, pyridine, triazole, thiazole, indole, indazole or benzimidazole, and the mono-substituted or poly-substituted substituent is selected from halogen, cyano, nitro, hydroxyl, amino, carboxyl, carbomethoxy or carbethoxy;
w, X, Y is selected from C, N, O or S, Z is C or N, and the position of substituent X is selected from ortho, para or meta of W;
R3is selected from C1-C6 alkyl, C2-C6 carboxyl, phenyl, heterocyclic aryl or benzyl, the phenyl, the heterocyclic aryl and the benzyl are unsubstituted, mono-substituted or di-substituted, and the mono-substituted or di-substituted substituent is selected from F, Cl, Br, I, CF3CN, hydroxyl, methoxyl, methyl, amino, nitryl, sulfydryl, carboxyl, ethenyl, C4-C8 straight-chain alkyl or branched-chain alkyl, aryl, heterocyclic radical.
2. The compound of claim 1, wherein: selected from the following compounds:
3. use of a compound of claim 1 or an optical isomer, enantiomer, diastereomer, racemate, racemic mixture or a pharmaceutically acceptable salt or prodrug thereof for the manufacture of a medicament for the prevention and/or treatment of diseases associated with PDE 4B.
4. Use according to claim 3, characterized in that: the PDE 4B-related diseases include inflammatory diseases and central nervous diseases.
5. Use according to claim 4, characterized in that: the inflammatory diseases include chronic obstructive pulmonary disease, asthma, dermatitis, psoriasis; the central nervous system disorder includes Alzheimer's disease, anxiety resistance, and cognition improvement.
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