WO2022199289A1 - 新型雄激素受体降解剂、制备方法和医药用途 - Google Patents
新型雄激素受体降解剂、制备方法和医药用途 Download PDFInfo
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- REIFWJGDIKRUSB-UHFFFAOYSA-N 5-bromo-8-methylquinoline Chemical compound C1=CN=C2C(C)=CC=C(Br)C2=C1 REIFWJGDIKRUSB-UHFFFAOYSA-N 0.000 description 1
- FELNBLNDYLAJLB-UHFFFAOYSA-N 5-bromo-8-nitroquinoline Chemical compound C1=CN=C2C([N+](=O)[O-])=CC=C(Br)C2=C1 FELNBLNDYLAJLB-UHFFFAOYSA-N 0.000 description 1
- CYJZJGYYTFQQBY-UHFFFAOYSA-N 5-bromoisoquinoline Chemical compound N1=CC=C2C(Br)=CC=CC2=C1 CYJZJGYYTFQQBY-UHFFFAOYSA-N 0.000 description 1
- GYCPLYCTMDTEPU-UHFFFAOYSA-N 5-bromopyrimidine Chemical compound BrC1=CN=CN=C1 GYCPLYCTMDTEPU-UHFFFAOYSA-N 0.000 description 1
- CHODTZCXWXCALP-UHFFFAOYSA-N 5-bromoquinoline Chemical compound C1=CC=C2C(Br)=CC=CC2=N1 CHODTZCXWXCALP-UHFFFAOYSA-N 0.000 description 1
- DAYKHFAZOORREQ-UHFFFAOYSA-N 5-bromoquinoline-8-carbonitrile Chemical compound C1=CC=C2C(Br)=CC=C(C#N)C2=N1 DAYKHFAZOORREQ-UHFFFAOYSA-N 0.000 description 1
- ZTEATMVVGQUULZ-UHFFFAOYSA-N 6-bromoisoquinoline Chemical compound C1=NC=CC2=CC(Br)=CC=C21 ZTEATMVVGQUULZ-UHFFFAOYSA-N 0.000 description 1
- NOYFLUFQGFNMRB-UHFFFAOYSA-N 6-bromoquinoxaline Chemical compound N1=CC=NC2=CC(Br)=CC=C21 NOYFLUFQGFNMRB-UHFFFAOYSA-N 0.000 description 1
- KABRXLINDSPGDF-UHFFFAOYSA-N 7-bromoisoquinoline Chemical compound C1=CN=CC2=CC(Br)=CC=C21 KABRXLINDSPGDF-UHFFFAOYSA-N 0.000 description 1
- DPRIHFQFWWCIGY-UHFFFAOYSA-N 8-bromoisoquinoline Chemical compound C1=NC=C2C(Br)=CC=CC2=C1 DPRIHFQFWWCIGY-UHFFFAOYSA-N 0.000 description 1
- 101150029129 AR gene Proteins 0.000 description 1
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- 239000007836 KH2PO4 Substances 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
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- 241000699670 Mus sp. Species 0.000 description 1
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- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
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- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
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- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
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- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
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- 239000001963 growth medium Substances 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
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- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
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- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 210000000064 prostate epithelial cell Anatomy 0.000 description 1
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- RJSRSRITMWVIQT-UHFFFAOYSA-N quinolin-6-amine Chemical compound N1=CC=CC2=CC(N)=CC=C21 RJSRSRITMWVIQT-UHFFFAOYSA-N 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
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- 235000020183 skimmed milk Nutrition 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- TZRQZPMQUXEZMC-UHFFFAOYSA-N tert-butyl n-(2-bromoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCBr TZRQZPMQUXEZMC-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Definitions
- the invention relates to the field of medicinal chemistry, in particular to a series of novel androgen receptor degrading agents, a preparation method and medical use thereof.
- Prostate cancer is a malignant tumor that occurs in male prostate epithelial cells and is one of the most common cancers in men.
- Androgen receptor (AR) is a member of the nuclear receptor family. AR contains four main regions: N-terminal active transcriptional control region (N-terminal domain, NTD), DNA binding domain (DNA binding domain, DBD) ), the hinge region, and the C-terminal ligand binding domain (LBD). AR has been an important target for prostate cancer therapy since Huggins and Hodges discovered that androgens promote prostate cancer growth in the early 1940s.
- ADT androgen deprivation therapy
- CRPC castration-resistant prostate cancer
- AR mutation is another important cause of castration resistance. Most mutations occur in the LBD region of AR, which also provides a mechanistic explanation for the development of resistance to antiandrogen drugs. Mutations in the AR-LBD region can induce the transition from AR antagonists to AR agonists, leading to further tumor progression.
- AR splice variants are also one of the mechanisms leading to castration resistance.
- Alternative splicing is a regulatory process in normal cells that allows a single gene to encode multiple proteins using different combinations of exons and introns during expression.
- Splice variants are the active products obtained after alternative splicing of mRNA.
- more than 20 different ARVs have been identified, of which several clinically important are splice variants lacking the LBD region, such as AR-V7 and ARv567es. Compared with full-length AR, these ARVs lack the LBD region, so AR antagonists cannot bind to it and cannot prevent ARVs from transcriptional activation.
- AR degraders are a class of compounds that can reduce the level of AR protein. Unlike AR antagonists, AR degraders do not directly occupy the cavity of AR, but reduce AR through some mechanism of action, such as the ubiquitination degradation mechanism. Therefore, AR degraders are promising to overcome the resistance mechanisms commonly seen in current AR-targeted therapies.
- the object of the present invention is to provide a novel androgen receptor degrading agent with the structure of general formula I or general formula II, its pharmaceutically acceptable salt or its prodrug.
- R 1 represents CN or NO 2 ;
- R 2 represents a monosubstituted or polysubstituted benzene ring, nitrogen-containing heterocycle, fused ring or nitrogen-containing fused heterocycle;
- R 3 represents H, a mono- or poly-substituted benzene ring, a nitrogen-containing heterocycle, a fused ring or a nitrogen-containing fused heterocycle.
- Reactants and reaction conditions a) K2CO3, DMF, 45°C, 7h; b) NaH, BrCH2COOEt, rt, 2h ; c ) CH3OH, K2CO3 , rt10h ,; d ) HATu , DIPEA,DMF,rt,overnight.
- Reactants and reaction conditions a) NaH, BrCH 2 COOEt, rt, 2h; b) CH 3 OH, K 2 CO 3 , rt 10h,; c) EDC.HCl, DMAP, CH 2 Cl 2 , rt, overnight; d )NaH, BrCH2CH2NHBoc ,rt,5h;e) CF3COOH , CH2Cl2 ,ice bath,0.5h; f )Pd2 ( dba )3 , t-BuONa,BINAP,toluene,110°C, 12h; g) Pd 2 (dba) 3 , t-BuONa, X-phos, toluene, 110°C, 12h; h) Pd 2 (dba) 3 , Cs 2 CO 3 , Xphos, toluene, 50°C, 12h; i )Pd 2 (dba) 3 ,C
- a pharmaceutical composition comprising the novel androgen receptor degrading agent having the structure of general formula I or general formula II according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof or a prodrug thereof, and a pharmacy an acceptable carrier.
- the androgen receptor-related disease is abnormal androgen-dependent cell proliferation, prostate cancer, hirsutism, or androgenetic alopecia.
- Pharmacological experiments show that the degrading agent of the present invention has good anti-prostate cancer activity, and is especially suitable for preparing medicines for treating androgen receptor-related diseases such as prostate cancer.
- Figure 1 shows the degradation ability of compounds 38d, 38e and Enzalutamide to AR at the same concentration
- Figure 2 shows the degradation ability of compounds 38d, 38e and Enzalutamide on AR at different concentrations
- Figure 3 shows the degradation ability of compounds 38d, 38m, 38t, 38k, 38j, 38i and Enzalutamide on AR at the same concentration
- Figure 4 shows the degradation ability of compound 38k and Enzalutamide on AR at different concentrations.
- Mass spectrum was measured with Agilent 1946A-MSD mass spectrometer (ESI-MS); 1 H NMR nuclear magnetic resonance was measured with Bruker AV 300MHz or 400MHz nuclear magnetic resonance instrument (the solvent used was deuterated DMSO or deuterated CDCl 3 , TMS was the internal standard, chemical The displacement ⁇ is in ppm).
- the raw material 28 (8 g, 24 mmol) was dissolved in 30 mL of anhydrous DMF, then NaH (1.44 g, 63 mol) was slowly added under an ice bath, the ice bath was removed, and the reaction was carried out at room temperature for 2 h, and then bromine was added to the reaction system.
- Ethyl acetate (5.3 ml, 3 mmol) was heated to 55 °C and reacted for 7 h. TLC showed that the reaction of the raw materials was complete, and the heating was stopped.
- the raw material 29 (5 g, 16.8 mmol) was dissolved in dry DMF, NaH (604.8 mg, 25.2 mmol) was slowly added under ice bath conditions, the temperature was allowed to rise to room temperature, and the reaction was carried out for 2 h. Subsequently, N-tert-butoxycarbonylbromoethylamine (4.1 g, 18.5 mmol) was added, and the temperature was raised to 55° C. for 7 h. The TLC dot plate showed that the reaction of the raw materials was complete, and the heating was stopped.
- the raw materials 37 120 mg, 0.35 mmol
- 2-bromonaphthalene 150 mg, 0.7 mmol
- sodium tert-butoxide 115 mg, 0.52 mmol
- Pd 2 (dba) 3 16 mg, 0.0175 mmol
- X-phos 12 mg, 0.0175 mmol
- the raw material 37 (240 mg, 0.7 mmol), 3-bromoquinoline (300 mg, 1.4 mmol) was dissolved in 5 mL of toluene, followed by the addition of sodium tert-butoxide (330 mg, 1.05 mmol), Pd2(dba)3 (32 mg, 0.035 mmol) and BINAP (30 mg, 0.035 mmol).
- the temperature was raised to 110°C, and the reaction was overnight. TLC spotting found that the reaction of the raw materials was completed, and the heating was stopped.
- the raw material 37 120 mg, 0.35 mmol
- 4-bromoquinoline 150 mg, 0.7 mmol
- sodium tert-butoxide 115 mg, 0.52 mmol
- Pd 2 (dba) 3 16 mg, 0.0175 mmol
- X-phos 12 mg, 0.0175 mmol
- the raw material 37 120 mg, 0.35 mmol
- 5-bromoquinoline 150 mg, 0.7 mmol
- cesium carbonate 228 mg, 0.7 mmol
- Pd 2 (dba) 3 16 mg, 0.0175 mmol
- X-phos 12 mg, 0.0175 mmol
- the raw materials 37 (240 mg, 0.7 mmol), 6-bromoquinoline (150 mg, 0.7 mmol) were dissolved in 3 mL of toluene, followed by the addition of cesium carbonate (456 mg, 1.4 mmol), Pd 2 (dba) 3 ( 32 mg, 0.035 mmol) and X-phos (24 mg, 0.035 mmol).
- cesium carbonate (456 mg, 1.4 mmol)
- Pd 2 (dba) 3 32 mg, 0.035 mmol
- X-phos 24 mg, 0.035 mmol
- the raw material 11 (240 mg, 0.7 mmol), 7-bromoquinoline (150 mg, 0.7 mmol) was dissolved in 3 mL of toluene, followed by the addition of cesium carbonate (456 mg, 1.4 mmol), Pd 2 (dba) 3 ( 32 mg, 0.035 mmol) and X-phos (24 mg, 0.035 mmol).
- cesium carbonate (456 mg, 1.4 mmol
- Pd 2 (dba) 3 32 mg, 0.035 mmol
- X-phos 24 mg, 0.035 mmol
- the raw material 37 120 mg, 0.35 mmol
- 7-bromoquinoline 150 mg, 0.7 mmol
- cesium carbonate 228 mg, 0.7 mmol
- Pd 2 (dba) 3 16 mg, 0.0175 mmol
- X-phos 12 mg, 0.0175 mmol
- the starting material 37 120 mg, 0.35 mmol
- 5-bromo 8-fluoroquinoline 158 mg, 0.7 mmol
- cesium carbonate 228 mg, 0.7 mmol
- Pd 2 (dba ) 3 16 mg, 0.0175 mmol
- X-phos 12 mg, 0.0175 mmol
- the raw material 37 120 mg, 0.35 mmol
- 1-bromoisoquinoline 150 mg, 0.7 mmol
- cesium carbonate 228 mg, 0.7 mmol
- Pd 2 (dba) 3 16 mg, 0.0175 mmol
- X-phos 12 mg, 0.0175 mmol
- the raw material 37 120 mg, 0.35 mmol
- 3-bromoisoquinoline 150 mg, 0.7 mmol
- cesium carbonate 228 mg, 0.7 mmol
- Pd 2 (dba) 3 16 mg, 0.0175 mmol
- X-phos 12 mg, 0.0175 mmol
- the raw material 37 120 mg, 0.35 mmol
- 4-bromoisoquinoline 150 mg, 0.7 mmol
- cesium carbonate 228 mg, 0.7 mmol
- Pd 2 (dba) 3 16 mg, 0.0175 mmol
- X-phos 12 mg, 0.0175 mmol
- the raw material 37 120 mg, 0.35 mmol
- 5-bromoisoquinoline 150 mg, 0.7 mmol
- cesium carbonate 228 mg, 0.7 mmol
- Pd 2 (dba) 3 16 mg, 0.0175 mmol
- X-phos 12 mg, 0.0175 mmol
- the raw material 37 120 mg, 0.35 mmol
- 6-bromoisoquinoline 150 mg, 0.7 mmol
- cesium carbonate 228 mg, 0.7 mmol
- Pd 2 (dba) 3 16 mg, 0.0175 mmol
- X-phos 12 mg, 0.0175 mmol
- the raw material 37 120 mg, 0.35 mmol
- 7-bromoisoquinoline 150 mg, 0.7 mmol
- cesium carbonate 228 mg, 0.7 mmol
- Pd 2 (dba) 3 16 mg, 0.0175 mmol
- X-phos 12 mg, 0.0175 mmol
- the raw material 37 120 mg, 0.35 mmol
- 8-bromoisoquinoline 150 mg, 0.7 mmol
- 3 mL of toluene 3 mL
- cesium carbonate 228 mg, 0.7 mmol
- Pd 2 (dba) 3 16 mg, 0.0175 mmol
- X-phos 12 mg, 0.0175 mmol
- the raw material 37 120 mg, 0.35 mmol
- 5-bromopyrimidine 110 mg, 0.7 mmol
- cesium carbonate 228 mg, 0.7 mmol
- Pd 2 (dba) 3 16 mg , 0.0175 mmol
- X-phos 12 mg, 0.0175 mmol
- the raw material 37 120 mg, 0.35 mmol
- 2-bromopyrimidine 110 mg, 0.7 mmol
- cesium carbonate 228 mg, 0.7 mmol
- Pd 2 (dba) 3 16 mg , 0.0175 mmol
- X-phos 12 mg, 0.0175 mmol
- the raw material 37 120 mg, 0.35 mmol
- 6-bromoquinoxaline 150 mg, 0.7 mmol
- cesium carbonate 228 mg, 0.7 mmol
- Pd 2 (dba) 3 16 mg, 0.0175 mmol
- X-phos 12 mg, 0.0175 mmol
- Human prostate cancer cell 22RV1 (Nanjing KGI Biotechnology Company).
- BioTek microplate reader Boton Instrument Co., Ltd., USA. ; Inverted microscope (Nikon Ts100, Japan); CO2 incubator (ESCO).
- PBS Weigh 8.0g NaCl, 0.13g Na2HPO4 12H2O, 0.06g KH2PO4, 0.4g KCl, and 0.35g NaHCO3 respectively, add 1mL ultrapure water to dissolve them, add NaOH to adjust pH to 7.4, and then autoclave, Store at 4°C.
- trypsin digestion solution Weigh 0.25 g of trypsin, add 100 mL of ultrapure water to fully dissolve, filter with 0.22 ⁇ m microporous filter, and store at -20°C.
- RPMI1640 medium Weigh 13.3g RPMI1640 medium powder and 2.0g NaHCO3 respectively, add 100mL ultrapure water to fully dissolve, then add 10% double antibody, filter with 0.22 ⁇ m microporous membrane, and add 10% fetal bovine serum when using , stored at 4°C.
- Cell recovery Take the cryovial containing the cells out of the liquid nitrogen tank, immediately place it in a constant temperature water bath at 37 degrees Celsius, shake it repeatedly by hand to thaw it, pour the cells into the culture flask, and add 5.5 mL of medium (containing 10 % fetal bovine serum), transferred to a centrifuge tube, centrifuged at 2000 r/min for 3 minutes, discarded the supernatant, added fresh medium and repeatedly pipetted several times, and transferred to a culture flask for culture.
- medium containing 10 % fetal bovine serum
- RPMI1640 medium containing the cells was cultured in a 5% CO2, 37°C incubator, and the passage was started when the cells covered 80%-90% of the bottom of the bottle. During passage, first pour out the medium in the culture flask, wash twice with PBS, then add 2-3 mL of 0.25% trypsin solution, digest at 37 °C for 3 minutes, observe the cells turn round under the microscope, add 2 mL of fresh Digestion was terminated in RPMI1640 medium (containing 10% fetal bovine serum). Pour off the liquid in the culture flask, wash twice with PBS, add 6 mL of fresh medium, repeatedly pipet and beat evenly, evenly divide it into two culture flasks, and continue culturing.
- RPMI1640 medium containing 10% fetal bovine serum
- Cell cryopreservation collect cells in logarithmic growth phase, add trypsin solution to digest, centrifuge, discard supernatant, add serum-free cryopreservation solution, repeat pipetting several times, and transfer to cryopreservation tube. Put the cryovial into a freezing box, place it in a -80°C refrigerator overnight, and take it out the next day and put it in a liquid nitrogen tank. Record the cell name, date of cryopreservation, and storage location.
- the drugs were serially diluted with medium to 100 ⁇ mol/L, 20 ⁇ mol/L, 2 ⁇ mol/L, 0.2 ⁇ mol/L and then added to 96-well plates, 100 ⁇ L per well, and three replicate wells were set for each concentration.
- the control group was added with the corresponding concentration of the medium containing the vehicle, and the same volume of blank medium was added to the zero-adjusted well, placed in a 5% CO2, 37C incubator for 4 days, and the medium was replaced every two days.
- Add 20 ⁇ L MTT (5 mg/mL) to each well, mix well, and incubate for 4 h in a 5% CO2, 37C incubator in the dark.
- Inhibition rate [(average OD value of control group-average OD value of experimental group)/(average OD value of control group-average OD value of blank control group)] ⁇ 100%.
- the prostate cancer cell line 22RV1 is a human prostate cancer epithelial cell line derived from xenografts (serial passages in mice with castration-induced prostate cancer regression and recurrence after their paternal androgen-dependent CWR22 grafting).
- the growth of 22RV1 cells is androgen-sensitive and the AR splice variant is highly expressed, making this cell line resistant to enzalutamide.
- the anti-proliferative effect of the compound on the 22RV1 cell line was tested under the condition of administering 0.1 ⁇ M testosterone, and it could be investigated whether the target compound could produce cell proliferation-inhibiting effect through anti-androgen effect.
- the most active compounds 38d and 38k were selected for Western Blot experiments to detect whether the synthesized target compounds have AR and AR-V7 degradation effects.
- An equal amount of the above-mentioned protein solution was added to the sample wells of the gel, ready for electrophoresis, wherein the voltage of the stacking gel was 75V, and the voltage of the separating gel was 120V. The electrophoresis was terminated until the bromophenol blue just ran out, and the mold was transferred.
- the band of the target protein was stripped off, attached to a PVDF membrane, transferred to the PVDF membrane by electrophoresis, and then blocked with 5% skim milk on a decolorizing shaker for 1 h.
- the primary antibody was added, incubated overnight at 4°C, and then washed three times with TBST for 5 min each.
- Secondary antibodies were added, incubated at room temperature for 30 min, and then washed three times with TBST for 5 min each.
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Abstract
本发明公开了具有通式I或通式II结构的新型雄激素受体降解剂、制备方法和医药用途。经药理实验证明该类化合物具有良好的抗前列腺癌活性,特别适用于制备治疗雄激素受体相关疾病如前列腺癌等的药物。
Description
本发明涉及药物化学领域,特别涉及一系列新型雄激素受体降解剂及其制备方法和医药用途。
前列腺癌是发生于男性前列腺上皮细胞的恶性肿瘤,是男性中最常见的癌症之一。雄激素受体(Androgen receptor,AR)是核受体家族成员之一,AR包含四个主要区域:N端活性转录控制区域(N-terminal domain,NTD),DNA结合区域(DNA binding domain,DBD),铰链区以及C末端的配体结合区(Ligand binding domain,LBD)。自从Huggins和Hodges在20世纪40年代早期发现雄激素促进前列腺癌生长以来,AR一直是前列腺癌治疗的重要靶点。
目前,雄激素剥夺疗法(Androgen deprivation therapy,ADT)是临床上前列腺癌治疗的首选方法。大多数晚期前列腺癌患者最初对ADT有效,但是经过1~2年后,几乎所有的前列腺癌患者都将逐渐发展为去势抵抗性前列腺癌(Castration-resistant prostate cancer,CRPC)。研究显示,CRPC的发生与AR表达增加密切相关,而AR表达增加主要归因于AR基因序列扩增。AR突变是导致去势抵抗发生的另一重要原因。大多数突变都发生在AR的LBD区,这也为抗雄激素药物的耐药性形成提供了机制上的解释。AR-LBD区突变能够诱导AR拮抗剂向AR激动剂转变,导致肿瘤进一步恶化。AR剪接变异体(AR splice variants,ARVs)也是导致去势抵抗发生的机制之一。选择性剪接是正常细胞中的一个调控过程,它允许单个基因在表达过程中使用不同的外显子和内含子组合来编码多种蛋白质。剪接变异体是mRNA经选择性剪接后所得到的活性产物。目前,已有20多种不同的ARVs被发现,其中具有重要临床意义的几种是缺少LBD区的剪接变异体,如AR-V7和ARv567es。与全长AR相比,这些ARVs缺少LBD区,因此AR拮抗剂无法与其结合,无法阻止ARVs进行转录激活。因此,发展新型的AR靶向疗法可能为对当前疗法产生抵抗的前列腺癌患者带来福音。AR降解剂是一类能够降低AR蛋白水平的化合物,与AR拮抗剂不同,AR降解剂并不是直接占据AR的空腔,而是通过某些作用机制,如泛素化降解机制,来降低AR蛋白,因此AR降解剂有希望克服目前AR靶向治疗中常见的耐药机制。
发明内容
发明目的:本发明目的是提供具有通式I或通式II结构的新型雄激素受体降解剂、其药学上可接受的盐或其前药。
技术方案:本发明通式的化合物结构如下:
其中R
1代表CN或者NO
2;
其中R
2代表单取代或多取代的苯环、含氮杂环、稠环或含氮稠杂环;
其中R
3代表H、单取代或多取代的苯环、含氮杂环、稠环或含氮稠杂环。
本发明部分、优选的化合物结构及编号如下:
药理实验及实验实施例中化合物的代号等同于以上代号所对应的化合物结构。
34a-34h
反应物和反应条件:a)K
2CO
3,DMF,45℃,7h;b)NaH,BrCH
2COOEt,r.t.,2h;c)CH
3OH,K
2CO
3,r.t.10h,;d)HATu,DIPEA,DMF,r.t.,overnight.
35a-35h,38a-38w
反应物和反应条件:a)NaH,BrCH
2COOEt,r.t.,2h;b)CH
3OH,K
2CO
3,r.t.10h,;c)EDC.HCl,DMAP,CH
2Cl
2,r.t.,overnight;d)NaH,BrCH
2CH
2NHBoc,r.t.,5h;e)CF
3COOH,CH
2Cl
2,ice bath,0.5h;f)Pd
2(dba)
3,t-BuONa,BINAP,toluene,110℃,12h;g)Pd
2(dba)
3,t-BuONa,X-phos,toluene,110℃,12h;h)Pd
2(dba)
3,Cs
2CO
3,Xphos,toluene,50℃,12h;i)Pd
2(dba)
3,Cs
2CO
3,X-phos,toluene,110℃,12h.
上述合成路线中将R
2、R
3、R
4中不同杂环以及杂环上取代基进行变化,即可获得通式I或通式II结构的化合物。
一种药物组合物,其包含权利要求1至4中任一项的具有通式I或通式II结构的新型雄激素受体降解剂、其药学上可接受的盐或其前药,及药学上可接受的载体。
具有通式I或通式II结构的新型雄激素受体降解剂、其药学上可接受的盐或其前药在制备治疗雄激素受体相关疾病药物中的用途。
进一步地,雄激素受体相关疾病为依赖于雄激素的细胞异常增殖、前列腺癌、多毛症或雄激素脱发。
有益效果:本发明的降解剂经药理实验证明该类化合物具有良好的抗前列腺癌活性,特别适用于制备治疗雄激素受体相关疾病如前列腺癌等的药物。
图1为化合物38d,38e和Enzalutamide在相同浓度下对AR的降解能力;
图2为化合物38d,38e和Enzalutamide在不同浓度下对AR的降解能力;
图3为化合物38d,38m,38t,38k,38j,38i和Enzalutamide在相同浓度下对AR的降解能力;
图4为化合物38k和Enzalutamide在不同浓度下对AR的降解能力。
化合物合成以及结构确证中所用到的试剂以及仪器的来源;
质谱用Agilent1946A-MSD型质谱仪测定(ESI-MS);
1H NMR核磁共振采用Bruker AV300MHz或400MHz型核磁共振仪测定(使用的溶剂为氘代DMSO或氘代CDCl
3,TMS为内标,化学位移δ单位为ppm)。实验中柱层析采用100-200或200-300目柱层析硅胶(青岛海洋化工厂),洗脱剂为石油醚(60-90℃)、乙酸乙酯、二氯甲烷、甲醇等,薄层层析采用GF254薄层层析硅胶(青岛海洋化工厂),所用化学试剂均为市售化学纯或分析纯产品,除特别说明外,试剂未经处理直接使用。
实施例1
5,5-二甲基-3-(4-硝基--3(三氟甲基)苯基)咪唑烷-2,4-二酮(28)的合成
氮气保护条件下,将化合物26(5g,0.024mol),5,5-二甲基海因(6.15g,0.048mol)溶于20mL DMF中,随后加入(6.6g,0.048mol)无水碳酸钾,升温至40℃反应7h,TLC点板显示原料反应完全,停止加热,待反应冷却至室温后,将反应液倒入冰水中,抽滤,干燥得淡黄色固体8g,不经过纯化,直接下投。
实施例2
5,5-二甲基-3-(4-氰基--3(三氟甲基)苯基)咪唑烷-2,4-二酮(29)的合成
氮气保护条件下,将化合物27(5g,0.026mol),5,5-二甲基海因(6.66g,0.052mol)溶于20mL DMF中,随后加入(7.15g,0.052mol)无水碳酸钾,升温至40℃反应7h,TLC点板显示原料反应完全,停止加热,待反应冷却至室温后,将反应液倒入冰水中,抽滤,干燥得白色固体,不经过纯化,直接下投。
实施例3
2-(5,5-二甲基-3-(4-硝基-3-(三氟甲基)苯基)-2,4-二氧杂咪唑啉-1-基)乙酸乙酯(30)的合成
氮气保护条件下,将原料28(8g,24mmol)溶于30mL无水DMF,随后冰浴下缓慢加入NaH(1.44g,63mol),移去冰浴,室温反应2h,随后向反应体系中加入溴乙酸乙酯(5.3ml,3mmol),升温至55℃反应7h。TLC显示原料反应完全,停止加热,待反应冷却至室温,将反应液倒入冰水中,抽滤,干燥得粗品,经柱层析纯化得淡黄色固体6.5g,收率67.2%。
1H NMR(400MHz,CDCl
3)δ8.09(d,J=7.5Hz,1H),8.02(s,1H),7.61(dd,J=7.4,1.6Hz,1H),4.19(q,J=8.0Hz,2H),3.92(s,2H),1.47(s,6H),1.25(t,J=8.0Hz,3H)。
实施例4
2-(5,5-二甲基-3-(4-氰基-3-(三氟甲基)苯基)-2,4-二氧杂咪唑啉-1-基)乙酸乙酯(31)的合成
氮气保护条件下,将化合物29(8g,25mmol)溶于30mL无水DMF,随后冰浴下缓慢加入NaH(1.53g,67mol),移去冰浴,室温反应2h,随后向反应体系中加入溴乙酸乙酯(5.3ml,3mmol),升温至55℃反应7h。TLC显示原料反应完全,停止加热,待反应冷却至室温,将反应液倒入冰水中,抽滤,干燥得粗品,经柱层析纯化得到米白色固体3.7g。ESI-MS m/z:378[M+Na]
+。
实施例5
2-(5,5-二甲基-3-(4-硝基-3-(三氟甲基)苯基)-2,4-二氧杂咪唑啉-1-基)乙酸(32)的合成
将化合物30(6.5g,0.021mol)溶解在50mL甲醇中,加入13mL40%NaOH水溶液,室温搅拌过夜,TLC点板显示原料反应完全,浓缩反应液,加入4N HCl调节PH 至3~4,乙酸乙酯萃取三次,合并有机层,有机层用饱和食盐水洗3次,加入无水硫酸镁干燥10分钟,过滤得滤液,滤液旋干得粗品,经柱层析得淡黄色固体6g,收率76.1%。ESI-MS m/z:398[M+Na]
+。
实施例6
2-(5,5-二甲基-3-(4-氰基-3-(三氟甲基)苯基)-2,4-二氧杂咪唑啉-1-基)乙酸(33)的合成
将化合物31(6.5g,0.022mol)溶解在50mL甲醇中,加入14mL40%NaOH水溶液,室温搅拌过夜,TLC点板显示原料反应完全,浓缩反应液,加入4N HCl调节PH至3~4,乙酸乙酯萃取三次,合并有机层,有机层用饱和食盐水洗3次,加入无水硫酸镁干燥10分钟,过滤得滤液,滤液旋干得粗品,经柱层析米白色固体3.7g。ESI-MS m/z:378[M+Na]
+。
实施例7
2-(5,5-二甲基-3-(4-硝基-3-(三氟甲基)苯基)-2,4-二氧代咪唑啉-1-基)-N-(吡啶-3-基)乙酰胺(34a)的合成
氮气保护的条件下,将化合物32(100mg,0.26mmol)溶解在3mL无水DMF中,加入429μL DIPEA,197mg HATu,室温反应半小时,随后加入3-氨基吡啶(30mg,0.312mmol),室温搅拌过夜。TLC点板显示原料反应完全,加水淬灭反应,乙酸乙酯萃取三次,合并有机相,饱和氯化铵洗两次,饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,过滤得滤液,滤液旋干得粗品,经柱层析得淡黄色粉末75mg,收率64.1%。Data for 34a:m.p.:220-222℃;
1H NMR(400MHz,CDCl
3)δ9.61–9.42(m,1H),8.69–8.53(m,1H),8.30(dt,J=4.8,2.7Hz,1H),8.17–8.11(m,1H),8.09–8.03(m,1H),8.02–7.93(m,2H),7.26(ddd,J=13.0,7.8,4.0Hz,1H),4.18(d,J=3.8Hz,2H),1.68–1.38(m,6H).
13C NMR(101MHz,CDCl
3)δ174.25,166.13,153.79,145.87,145.04,140.84,135.89,134.97,128.85,127.66,126.05,124.57,124.12,122.87,62.34,51.83,43.48,22.97.HRMS(ESI)m/z calcd for C
19H
16F
3N
5O
5[M+H]
+452.1176,found 452.1172。
实施例8
2-(5,5-二甲基-3-(4-硝基-3-(三氟甲基)苯基)-2,4-二氧代咪唑啉-1-基)-N-(吡啶-2-基)乙酰胺(34b)的合成
氮气保护的条件下,将化合物32(100mg,0.26mmol)溶解在3mL无水DMF中,加入429μL DIPEA,197mg HATu,室温反应半小时,随后加入2-氨基吡啶(30mg,0.312mmol),室温搅拌过夜。TLC点板显示原料反应完全,加水淬灭反应,乙酸乙酯萃取三次,合并有机相,饱和氯化铵洗两次,饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,过滤得滤液,滤液旋干得粗品,经柱层析得得白色粉末59mg,收率50.4%。Data for 34b:m.p.:92-94℃;
1H NMR(400MHz,DMSO-d
6)δ10.84–10.63(m,1H),8.53–8.00(m,5H),7.84(ddt,J=39.9,15.7,7.9Hz,1H),7.30–7.05(m,1H),4.52–4.08(m,2H),1.66–1.44(m,6H).
13C NMR(101MHz,DMSO)δ175.14,167.47,153.45,152.07,148.50,145.72,138.79,136.66,131.47,131.35,127.04,125.47,120.11,113.96,62.26,43.12,22.67.HRMS(ESI)m/z calcd for C
19H
16F
3N
5O
5[M+H]
+452.1176,found 452.1174。
实施例9
2-(5,5-二甲基-3-(4-硝基-3-(三氟甲基)苯基)-2,4-二氧代咪唑啉-1-基)-N-(吡啶-3-基甲基)乙酰胺(34c)的合成
氮气保护的条件下,将化合物32(100mg,0.26mmol)溶解在3mL无水DMF中,加入429μL DIPEA,197mg HATu,室温反应半小时,随后加入3-氨甲基吡啶(34 mg,0.312mmol),室温搅拌过夜。TLC点板显示原料反应完全,加水淬灭反应,乙酸乙酯萃取三次,合并有机相,饱和氯化铵洗两次,饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,过滤得滤液,滤液旋干得粗品,经柱层析得淡黄色粉末77mg,收率63.6%。Data for 34c:m.p.:76-78℃;
1H NMR(400MHz,CDCl
3)δ8.38(d,J=4.7Hz,1H),8.33(s,1H),8.05(s,1H),7.92(p,J=1.7Hz,2H),7.64–7.58(m,2H),7.57–7.53(m,1H),7.21(ddd,J=7.7,4.9,2.1Hz,1H),4.52–4.27(m,2H),4.04(d,J=2.2Hz,2H),1.51(d,J=2.3Hz,6H).
13C NMR(101MHz,CDCl
3)δ174.28,167.59,153.55,148.74,148.59,145.76,135.95,133.87,128.72,125.96,124.07,123.83,62.20,43.01,41.05,22.93.HRMS(ESI)m/z calcd for C
20H
18F
3N
5O
5[M+H]
+466.1332,found 466.1328。
实施例10
2-(5,5-二甲基-3-(4-硝基-3-(三氟甲基)苯基)-2,4-二氧代咪唑啉-1-基)-N-(吡啶-2-基甲基)乙酰胺(34d)的合成
氮气保护的条件下,将化合物32(100mg,0.26mmol)溶解在3mL无水DMF中,加入429μL DIPEA,197mg HATu,室温反应半小时,随后加入2-氨甲基吡啶(34mg,0.312mmol),室温搅拌过夜。TLC点板显示原料反应完全,加水淬灭反应,乙酸乙酯萃取三次,合并有机相,饱和氯化铵洗两次,饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,过滤得滤液,滤液旋干得粗品,经柱层析得淡黄色粉末53mg,收率43.8%。Data for 34d:m.p.:174-175℃;
1H NMR(400MHz,CDCl
3)δ8.50(dt,J=4.7,2.3Hz,1H),8.20(t,J=2.4Hz,1H),8.07(dd,J=8.8,2.3Hz,1H),8.02(d,J=8.8Hz,1H),7.70(tt,J=7.7,2.2Hz,1H),7.45(d,J=6.3Hz,1H),7.29(t,J=3.9Hz,1H),7.24(dd,J=7.4,4.8Hz,1H),4.61(dd,J=4.9,2.7Hz,2H),4.13(d,J=2.6Hz,2H),1.56(d,J=2.6Hz,6H).HRMS(ESI)m/z calcd for C
20H
18F
3N
5O
5[M+Na]
+488.1152,found 488.1150。
实施例11
2-(5,5-二甲基-3-(4-氰基-3-(三氟甲基)苯基)-2,4-二氧代咪唑啉-1-基)-N-(吡啶-3-基)乙酰胺(34e)的合成
氮气保护的条件下,将化合物33(100mg,0.27mmol)溶解在3mL无水DMF中,加入450μL DIPEA,207mg HATu,室温反应半小时,随后加入3-氨基吡啶(32mg,0.33mmol),室温搅拌过夜。TLC点板显示原料反应完全,加水淬灭反应,乙酸乙酯萃取三次,合并有机相,饱和氯化铵洗两次,饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,过滤得滤液,滤液旋干得粗品,经柱层析得白色粉末34mg,收率30.3%。Data for34e:m.p.:95-96℃;
1H NMR(400MHz,CDCl
3)δ9.12(s,1H),8.60(d,J=2.5Hz,1H),8.34(d,J=4.7Hz,1H),8.17–8.07(m,2H),8.01(dd,J=8.5,2.2Hz,1H),7.92(d,J=8.5Hz,1H),7.29(d,J=5.6Hz,1H),4.19(s,2H),1.59(s,6H).
13C NMR(101MHz,CDCl
3)δ174.15,166.03,153.89,145.37,140.99,136.14,135.42,134.68,128.03,127.53,124.00,123.00,120.53,115.01,108.42,62.38,43.86,23.06.
13C NMR(101MHz,CDCl
3)δ174.43,167.20,155.42,153.52,148.88,137.09,135.99,128.85,125.97,124.35,122.70,122.17,77.37,62.27,44.31,43.16,23.02.HRMS(ESI)m/z calcd for C
20H
16F
3N
5O
3[M+H]
+432.1278,found 432.1276。
实施例12
2-(5,5-二甲基-3-(4-氰基-3-(三氟甲基)苯基)-2,4-二氧代咪唑啉-1-基)-N-(吡啶-2-基)乙酰胺(34f)的合成
氮气保护的条件下,将化合物33(100mg,0.27mmol)溶解在3mL无水DMF中,加入450μL DIPEA,207mg HATu,室温反应半小时,随后加入2-氨基吡啶(32mg, 0.33mmol),室温搅拌过夜。TLC点板显示原料反应完全,加水淬灭反应,乙酸乙酯萃取三次,合并有机相,饱和氯化铵洗两次,饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,过滤得滤液,滤液旋干得粗品,经柱层析得白色粉末48mg,收率42.8%。Data for34f:m.p.:228-230℃;
1H NMR(400MHz,CDCl
3)δ8.85(s,1H),8.30(dd,J=4.8,2.2Hz,1H),8.21–8.13(m,2H),8.05(dd,J=8.3,2.2Hz,1H),7.94(d,J=8.4Hz,1H),7.75(td,J=8.4,8.0,2.0Hz,1H),7.15–7.04(m,1H),4.24(s,2H),1.60(d,J=1.6Hz,6H).
13C NMR(101MHz,DMSO)δ175.15,167.48,153.32,152.10,148.51,137.13,136.64,131.46,130.23,124.24,120.13,115.66,113.97,107.25,62.23,43.00,22.69.HRMS(ESI)m/z calcd for C
20H
16F
3N
5O
3[M+H]
+432.1278,found 432.1274。
实施例13
2-(5,5-二甲基-3-(4-氰基-3-(三氟甲基)苯基)-2,4-二氧代咪唑啉-1-基)-N-(吡啶-3-基甲基)乙酰胺(34g)的合成
氮气保护的条件下,将化合物33(100mg,0.26mmol)溶解在3mL无水DMF中,加入429μL DIPEA,197mg HATu,室温反应半小时,随后加入3-氨甲基吡啶(36mg,0.33mmol),室温搅拌过夜。TLC点板显示原料反应完全,加水淬灭反应,乙酸乙酯萃取三次,合并有机相,饱和氯化铵洗两次,饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,过滤得滤液,滤液旋干得粗品,经柱层析得白色粉末57mg,收率49.2%。Data for 34g:m.p.:84-85℃;
1H NMR(400MHz,CDCl
3)δ8.47(d,J=4.9Hz,1H),8.42(s,1H),8.09(d,J=2.0Hz,1H),7.96(dd,J=8.4,2.1Hz,1H),7.87(d,J=8.4Hz,1H),7.64(dt,J=7.8,1.9Hz,1H),7.26(dd,J=8.2,5.2Hz,1H),7.17(t,J=6.0Hz,1H),4.45(d,J=6.0Hz,2H),4.05(s,1H),1.54(s,5H).
13C NMR(101MHz,CDCl
3)δ174.20,167.49,153.60,148.86,136.20,135.86,135.35,133.70,133.37,127.92,123.80,122.88,115.00,108.26,62.23,43.26,41.16,23.02.HRMS(ESI)m/z calcd for C
21H
18F
3N
5O
3[M+H]
+446.1434,found 446.1429。
实施例14
2-(5,5-二甲基-3-(4-氰基-3-(三氟甲基)苯基)-2,4-二氧代咪唑啉-1-基)-N-(吡啶-2-基甲基)乙酰胺(34h)的合成
氮气保护的条件下,将化合物33(100mg,0.26mmol)溶解在3mL无水DMF中,加入429μL DIPEA,197mg HATu,室温反应半小时,随后加入2-氨甲基吡啶(36mg,0.33mmol),室温搅拌过夜。TLC点板显示原料反应完全,加水淬灭反应,乙酸乙酯萃取三次,合并有机相,饱和氯化铵洗两次,饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,过滤得滤液,滤液旋干得粗品,经柱层析得白色粉末63mg,收率54.4%。Data for 34h:m.p.:158-160℃;
1H NMR(400MHz,CDCl
3)δ8.61–8.33(m,1H),8.17(d,J=2.1Hz,1H),8.03(dd,J=8.5,2.0Hz,1H),7.93(d,J=8.4Hz,1H),7.69(td,J=7.7,1.8Hz,1H),7.47(t,J=5.0Hz,1H),7.28(s,1H),7.22(dd,J=7.5,5.0Hz,1H),4.60(d,J=5.0Hz,2H),4.12(s,2H),1.55(s,6H).
13C NMR(101MHz,CDCl
3)δ174.25,166.13,153.79,145.87,145.04,140.84,135.89,134.97,128.85,127.66,126.05,124.57,124.12,122.87,120.15,62.34,53.50,43.48,22.97.HRMS(ESI)m/z calcd for C
21H
18F
3N
5O
3[M+H]
+446.1434,found 446.1431.
实施例15
N-([[1,1'-联苯]-3-基)-2-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-2,4-二氧代咪唑啉-1-基乙酰胺(35a)的合成
氮气保护的条件下,将化合物33(150mg,0.43mmol)溶解于无水二氯甲烷中,加入DMAP(10mg,0.087mmol),EDC.HCl(91mg,0.47mmol)室温反应5分钟, 随后加入3-联苯胺(80mg,0.47mmol),室温过夜反应,TLC检测原料反应完全,加入水淬灭反应,乙酸乙酯萃取三次,有机相用饱和氯化铵洗两次,饱和食盐水洗涤三次,旋干过柱得白色固体37mg,收率17.9%。Data for 35a:m.p.:173-174℃;
1H NMR(300MHz,CDCl
3)δ8.68(s,1H),8.21(s,1H),8.08–8.00(m,2H),7.95(d,J=8.5Hz,3H),7.77(s,1H),7.63–7.48(m,3H),4.33(s,2H),1.67(s,6H).
13C NMR(75MHz,CDCl
3)δ174.13,166.36,154.18,136.00,135.39,134.09,131.78,128.90,127.97,126.65,126.27,125.68,123.04,120.29,114.97,108.60,62.57,44.78,23.04.HRMS(ESI)m/z calcd for C
25H
19F
3N
4O
3[M+Na]
+503.1301,found 503.1301。
实施例16
N-([[1,1'-联苯]-3-基)-2-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-2,4-二氧代咪唑啉-1-基乙酰胺(35b)的合成
氮气保护的条件下,将化合物33(150mg,0.43mmol)溶解于无水二氯甲烷中,加入DMAP(10mg,0.087mmol),EDC.HCl(91mg,0.47mmol)室温反应5分钟,随后加入3-氨基联苯(79mg,0.47mmol),室温过夜反应,TLC检测原料反应完全,加入水淬灭反应,乙酸乙酯萃取三次,有机相用饱和氯化铵洗两次,饱和食盐水洗涤三次,旋干过柱得粉色固体21mg,收率9.6%。Data for 35b:m.p.:170-172℃;
1H NMR(300MHz,CDCl
3)δ8.24(s,1H),8.21(d,J=1.8Hz,1H),8.05(dd,J=8.4,2.0Hz,1H),7.96(d,J=8.4Hz,1H),7.78(s,1H),7.61(d,J=6.8Hz,2H),7.55–7.36(m,6H),4.20(d,J=11.1Hz,2H),1.65(s,6H).
13C NMR(75MHz,CDCl
3)δ174.16,165.45,153.96,142.36,140.38,137.60,136.09,135.40,129.54,128.84,127.99,127.71,127.17,123.78,122.99,118.70,115.02,62.45,44.53,23.07.HRMS(ESI)m/z calcd for C
27H
21F
3N
4O
3[M-H]
-505.1493,found 505.1492。
实施例17
2-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-2,4-二氧杂咪唑啉-1-基)-N-(萘-1-基)乙酰胺(35c)的合成
氮气保护的条件下,将化合物33(150mg,0.43mmol)溶解于无水二氯甲烷中,加入EDC.HCl(91mg,0.47mmol)和HOBt(64mg,0.47mmol)室温反应5分钟,随后加入1-萘胺(80mg,0.47mmol)和DIPEA(86μL,0.52mmol),室温过夜反应,TLC检测原料反应完全,加入水淬灭反应,乙酸乙酯萃取三次,有机相用饱和氯化铵洗两次,饱和食盐水洗涤三次,旋干过柱得白色固体66mg,收率30.3%。Data for 35c:m.p.:182-184℃;
1H NMR(300MHz,CDCl
3)δ8.24–8.16(m,2H),8.06(dd,J=8.4,2.1Hz,1H),7.98(d,J=8.5Hz,6H),7.59(d,J=7.8Hz,2H),7.47(t,J=7.5Hz,1H),7.38(dd,J=8.4,6.0Hz,1H),4.21(s,2H),1.66(s,6H).
13C NMR(75MHz,CDCl
3)δ174.15,165.40,154.01,140.20,137.89,136.37,136.08,135.42,128.87,128.00,127.74,127.36,126.86,123.07,120.29,115.00,108.55,106.57,62.49,44.61,23.09.HRMS(ESI)m/z calcd for C
27H
21F
3N
4O
3[M-H]
-505.1492,found 505.1485。
实施例18
2-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-2,4-二氧杂咪唑啉-1-基)-N-(喹啉-3-基)乙酰胺(35d)的合成
氮气保护的条件下,将化合物33(150mg,0.43mmol)溶解于无水二氯甲烷中,加入DMAP(10mg,0.087mmol),EDC.HCl(91mg,0.47mmol)室温反应5分钟,随后加入3-氨基喹啉(68mg,0.47mmol),室温过夜反应,TLC检测原料反应完全,加入水淬灭反应,乙酸乙酯萃取三次,有机相用饱和氯化铵洗两次,饱和食盐水洗涤三 次,旋干过柱得淡黄色固体28mg,收率13.5%。Data for 35d:m.p.:106-107℃;
1H NMR(300MHz,CDCl
3)δ9.43–9.12(m,1H),8.77(d,J=2.4Hz,1H),8.67(d,J=2.5Hz,1H),8.16(d,J=2.0Hz,1H),8.06–7.96(m,2H),7.90(d,J=8.5Hz,1H),7.71(dd,J=8.2,1.5Hz,1H),7.63(ddd,J=8.4,6.9,1.5Hz,1H),7.51(ddd,J=8.1,6.9,1.2Hz,1H),4.25(s,2H),1.61(s,6H).
13C NMR(75MHz,CDCl
3)δ174.14,166.14,153.98,145.02,143.60,136.08,135.42,133.86,131.19,128.80,128.57,128.03,127.81,127.57,124.40,123.00,114.98,108.45,62.42,43.95,23.10.HRMS(ESI)m/z calcd for C
24H
18F
3N
5O
3[M+H]
+482.1434,found 482.1430。
实施例19
2-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-2,4-二氧杂咪唑啉-1-基)-N-(喹啉-4-基)乙酰胺(35e)的合成
氮气保护的条件下,将化合物33(150mg,0.43mmol)溶解于无水二氯甲烷中,加入DMAP(10mg,0.087mmol),EDC.HCl(91mg,0.47mmol)室温反应5分钟,随后加入4-氨基喹啉(68mg,0.47mmol),室温过夜反应,TLC检测原料反应完全,加入水淬灭反应,乙酸乙酯萃取三次,有机相用饱和氯化铵洗两次,饱和食盐水洗涤三次,旋干过柱得淡黄色固体45mg,收率21.7%。Data for 35e:m.p.:108-109℃;
1H NMR(300MHz,CDCl
3)δ9.47(s,1H),8.89(d,J=5.1Hz,1H),8.33(d,J=5.1Hz,1H),8.22–8.14(m,2H),8.09–7.95(m,3H),7.79(t,J=7.6Hz,1H),7.64(t,J=7.7Hz,1H),4.36(s,2H),1.68(s,6H).
13C NMR(101MHz,CDCl
3)δ173.81,166.54,154.58,151.08,148.81,140.22,135.82,135.45,129.69,127.99,126.90,123.00,119.35,114.86,110.65,62.77,45.54,23.02.HRMS(ESI)m/z calcd for C
24H
18F
3N
5O
3[M+H]
+482.1434,found 482.1435。
实施例20
2-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-2,4-二氧杂咪唑啉-1-基)-N-(喹啉-5-基)乙酰胺(35f)的合成
氮气保护的条件下,将化合物33(150mg,0.43mmol)溶解于无水二氯甲烷中,加入DMAP(10mg,0.087mmol),EDC.HCl(91mg,0.47mmol)室温反应5分钟,随后加入5-氨基喹啉(68mg,0.47mmol),室温过夜反应,TLC检测原料反应完全,加入水淬灭反应,乙酸乙酯萃取三次,有机相用饱和氯化铵洗两次,饱和食盐水洗涤三次,旋干过柱得淡黄色固体31mg,收率14.9%。Data for 35f:m.p.:174-175℃;
1H NMR(300MHz,CDCl
3)δ8.97(dd,J=4.3,1.5Hz,1H),8.85(s,1H),8.32(d,J=8.6Hz,1H),8.19(d,J=2.1Hz,1H),8.08–7.98(m,3H),7.94(d,J=8.4Hz,1H),7.73(t,J=8.1Hz,1H),7.48(dd,J=8.6,4.2Hz,1H),4.32(s,2H),1.67(s,6H).
13C NMR(101MHz,CDCl
3)δ174.07,166.56,154.18,150.43,148.33,136.05,135.38,133.78,133.46,132.01,130.00,129.28,127.97,127.53,123.01,122.97,121.26,121.19,114.95,108.48,62.54,44.48,23.07.HRMS(ESI)m/z calcd for C
24H
18F
3N
5O
3[M+H]
+482.1434,found 482.1429。
实施例21
2-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-2,4-二氧杂咪唑啉-1-基)-N-(喹啉-6-基)乙酰胺(35g)的合成
氮气保护的条件下,将化合物33(150mg,0.43mmol)溶解于无水二氯甲烷中,加入DMAP(10mg,0.087mmol),EDC.HCl(91mg,0.47mmol)室温反应5分钟,随后加入5-氨基喹啉(68mg,0.47mmol),室温过夜反应,TLC检测原料反应完全,加入水淬灭反应,乙酸乙酯萃取三次,有机相用饱和氯化铵洗两次,饱和食盐水洗涤三次,旋干过柱得白色固体54mg,收率26.1%。Data for 35g:m.p.:112-114℃;
1H NMR(400 MHz,CDCl
3)δ9.28(d,J=68.3Hz,1H),8.81(t,J=5.5Hz,1H),8.31(d,J=2.8Hz,1H),8.16(d,J=5.3Hz,1H),8.01(dq,J=19.1,9.8,8.9Hz,3H),7.88(t,J=9.6Hz,1H),7.56(dd,J=9.0,2.5Hz,1H),7.37(dd,J=8.3,4.5Hz,1H),4.24(s,2H),1.59(d,J=7.9Hz,6H).
13C NMR(101MHz,CDCl
3)δ174.23,165.86,153.87,149.42,145.24,136.17,135.37,129.79,128.74,127.98,123.28,121.83,120.55,116.49,115.05,108.27,62.35,43.98,23.07.HRMS(ESI)m/z calcd for C
24H
18F
3N
5O
3[M+H]
+482.1434,found 482.1436。
实施例22
2-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-2,4-二氧杂咪唑啉-1-基)-N-(喹啉-8-基)乙酰胺(35h)的合成
氮气保护的条件下,将化合物33(150mg,0.43mmol)溶解于无水二氯甲烷中,加入DMAP(10mg,0.087mmol),EDC.HCl(91mg,0.47mmol)室温反应5分钟,随后加入6-氨基喹啉(68mg,0.47mmol),室温过夜反应,TLC检测原料反应完全,加入水淬灭反应,乙酸乙酯萃取三次,有机相用饱和氯化铵洗两次,饱和食盐水洗涤三次,旋干过柱得白色固体60mg,收率29.0%。Data for 35h:m.p.:179-180℃;
1H NMR(300MHz,CDCl
3)δ10.28(s,1H),8.81(dd,J=4.3,1.6Hz,1H),8.75(dd,J=6.0,3.1Hz,1H),8.32–8.20(m,2H),8.12(dd,J=8.5,2.1Hz,1H),7.99(d,J=8.4Hz,1H),7.63–7.58(m,2H),7.53(dd,J=8.3,4.3Hz,1H),4.41(s,2H),1.67(s,6H).
13C NMR(75MHz,CDCl
3)δ174.44,165.23,153.45,148.49,138.28,136.62,136.34,135.39,133.53,128.10,128.01,127.31,123.10,122.45,121.92,116.86,115.05,108.46,108.44,62.26,44.01,23.15.HRMS(ESI)m/z calcd for C
24H
18F
3N
5O
3[M+Na]
+504.1254,found 504.1252。
实施例23
叔丁基(2-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-2,4-二氧杂咪唑啉-1-基)乙基)氨基甲酸酯(36)的合成
氮气保护下,将原料29(5g,16.8mmol)用干燥的DMF溶解,冰浴条件下缓慢加入NaH(604.8mg,25.2mmol),温度允许升至室温,反应2h。随后加入N-叔丁氧羰基溴乙胺(4.1g,18.5mmol),温度升至55℃反应7h。TLC点板显示原料反应完全,停止加热,待反应冷却至室温,将反应液倒入冰水中,抽滤,干燥得粗品,经柱层析纯化得白色固体3.3g。收率44.6%。
1H NMR(400MHz,CDCl
3)δ8.14–7.80(m,1H),7.47(dd,J=7.5,1.5Hz,1H),6.18–5.68(m,1H),3.65(t,J=7.0Hz,2H),3.43(td,J=7.1,6.0Hz,2H),1.43(d,J=7.7Hz,15H)。
实施例24
4-(3-(2-氨基乙基)-4,4-二甲基-2,5-二氧杂咪唑啉-1-基)-2-(三氟甲基)苄腈(37)的合成
将化合物36(3.3g,7.5mmol)溶于二氯甲烷中,冰浴条件下缓慢加入三氟乙酸10mL,维持冰浴反应半小时,TLC检测发现原料反应完全,将反应液浓缩至干,用4M NaOH溶液调至碱性,二氯甲烷萃取三次,合并有机相,饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,有机层旋干得泡沫状固体,红外灯下干燥得粗品2.7g。ESI-MS m/z:363[M+Na]
+。
实施例25
4-(4,4-二甲基-3-(3-(喹啉-2-基氨基)乙基)-2,5-二氧代咪唑啉-1-基)-2-(三氟甲基)苄腈(38a)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),2-溴萘(150mg,0.7mmol)溶解于3mL甲苯中,随后加入叔丁醇钠(115mg,0.52mmol),Pd
2(dba)
3(16mg,0.0175 mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得淡黄色粉末43mg,收率26.3%。Data for 38a:m.p.:172-173℃;
1H NMR(300MHz,CDCl
3)δ8.21(s,1H),8.00(q,J=8.4Hz,2H),7.70(q,J=8.3,7.3Hz,3H),7.43(t,J=7.5Hz,1H),7.29(d,J=11.9Hz,2H),7.01–6.84(m,2H),3.85–3.52(m,4H),1.59(s,6H).
13C NMR(75MHz,CDCl
3)δ174.45,153.85,145.01,145.01,136.29,135.39,135.12,129.34,128.09,127.76,127.66,126.59,125.93,123.16,122.34,117.82,115.09,108.44,103.97,62.17,43.28,39.57,23.49.HRMS(ESI)m/z calcd for C
24H
21F
3N
4O
2[M+Na]
+489.1508,found 489.1507。
实施例26
4-(4,4-二甲基-2,5-二氧-3-(2-(喹啉-3-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38b)的合成
氮气保护条件下,将原料37(240mg,0.7mmol),3-溴喹啉(300mg,1.4mmol)溶解于5mL甲苯中,随后加入叔丁醇钠(330mg,1.05mmol),Pd2(dba)3(32mg,0.035mmol)和BINAP(30mg,0.035mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得白色粉末56mg,收率17.1%。Data for 38b:m.p.:146-147℃;
1H NMR(400MHz,DMSO-d
6)δ10.24(s,1H),9.35(d,J=2.6Hz,1H),8.41–8.27(m,1H),8.21(d,J=2.6Hz,1H),8.17(d,J=8.7Hz,1H),8.06(d,J=8.7Hz,1H),7.94(d,J=8.3Hz,1H),7.89(d,J=8.0Hz,1H),7.57(dt,J=22.9,7.2Hz,2H),4.06(t,J=7.7Hz,2H),3.70(t,J=7.6Hz,2H),1.49(s,6H).
13C NMR(101MHz,DMSO)δ174.35,157.36,144.53,143.86,143.02,136.79,134.66,131.80,128.97,128.24,127.92,127.81,127.49,122.82,119.78,117.50,116.34,101.71,60.08,42.57,40.37,22.41.HRMS(ESI)m/z calcd for C
24H
20F
3N
5O
2[M+H]
+468.1641,found 468.1638。
实施例27
4-(4,4-二甲基-2,5-二氧代-3-(2-(喹啉-4-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38c)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),4-溴喹啉(150mg,0.7mmol)溶解于3mL甲苯中,随后加入叔丁醇钠(115mg,0.52mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得淡黄色粉末41mg,收率25.1%。Data for 38c:m.p.:156-158℃;
1H NMR(300MHz,DMSO-d
6)δ10.39(s,1H),8.90(d,J=4.7Hz,1H),8.37(s,1H),8.20(d,J=8.7Hz,1H),8.13(d,J=8.6Hz,1H),8.04(d,J=8.4Hz,1H),7.97(d,J=8.4Hz,1H),7.76(t,J=7.7Hz,1H),7.52–7.42(m,2H),4.07(t,J=7.4Hz,2H),3.78(t,J=7.5Hz,2H),1.54(s,6H).
13C NMR(75MHz,DMSO)δ174.41,158.01,153.84,153.01,151.12,149.53,145.30,144.63,136.87,130.04,129.62,126.00,125.37,124.42,122.78,117.42,116.36,116.05,60.07,45.86,22.53.HRMS(ESI)m/z calcd for C
24H
20F
3N
5O
2[M+H]
+468.1641,found 468.1635。
实施例28
4-(4,4-二甲基-2,5-二氧代-3-(2-(喹啉-5-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38d)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),5-溴喹啉(150mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得淡黄色粉末39mg,收率23.8%。Data for 38d:m.p.:201-202℃;
1H NMR(300MHz,DMSO-d
6)δ8.83(dd,J=4.1,1.5Hz,1H),8.56(d,J=8.6Hz,1H),8.37(d,J=8.4Hz,1H),8.25(d,J=2.0Hz,1H),8.10(dd,J=8.4,2.0Hz,1H),7.57(t,J=8.0Hz,1H),7.44(dd,J=8.6,4.2Hz,1H),7.27(d,J=8.4Hz,1H),6.75(d,J=7.7Hz,1H),6.63(d,J=5.7Hz,1H),3.76–3.54(m,4H),1.49(s,6H).
13C NMR(101MHz,CDCl
3)δ174.19,154.73,150.22,149.25,143.23,136.14,135.38,130.27,128.95,128.05,123.12,119.64,118.75,118.33,114.93,108.58,103.55,62.34,44.97,39.35,23.47.HRMS(ESI)m/z calcd for C24H20F3N5O2[M+H]+468.1641,found 468.1635。
实施例29
4-(4,4-二甲基-2,5-二氧代-3-(2-(喹啉-6-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38e)的合成
氮气保护条件下,将原料37(240mg,0.7mmol),6-溴喹啉(150mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(456mg,1.4mmol),Pd
2(dba)
3(32mg,0.035mmol)和X-phos(24mg,0.035mmol)。升温至50℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得浅绿色粉末36mg,收率11.0%。Data for 38e:m.p.:159-160℃;
1H NMR(300MHz,DMSO-d
6)δ8.53(d,J=4.2Hz,1H),8.38(d,J=8.4Hz,1H),8.25(s,1H),8.11(d,J=8.4Hz,1H),8.01(d,J=8.3Hz,1H),7.77(d,J=9.0Hz,1H),7.34(dd,J=8.3,4.2Hz,1H),7.28–7.20(m,1H),6.91–6.84(m,1H),3.57(dt,J=22.0,6.5Hz,4H),1.50(s,6H).
13C NMR(75MHz,DMSO)δ175.18,153.40,146.74,145.76,142.84,137.25,136.66,133.69,131.82,130.48,124.57,122.01,115.72,107.28,101.90,62.24,41.66,22.98.HRMS(ESI)m/z calcd for C
24H
20F
3N
5O
2[M+H]+468.1641,found 468.1636。
实施例30
4-(4,4-二甲基-2,5-二氧代-3-(2-(喹啉-7-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38f)的合成
氮气保护条件下,将原料11(240mg,0.7mmol),7-溴喹啉(150mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(456mg,1.4mmol),Pd
2(dba)
3(32mg,0.035mmol)和X-phos(24mg,0.035mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得淡黄色粉末81mg,收率22.1%。Data for 38f:m.p.:198-199℃;
1H NMR(300MHz,CDCl
3)δ8.76(dd,J=4.4,1.8Hz,1H),8.16(d,J=2.0Hz,1H),8.07–7.90(m,3H),7.60(d,J=8.8Hz,1H),7.15(dd,J=8.1,4.3Hz,1H),7.06(d,J=2.3Hz,1H),6.94(dd,J=8.8,2.4Hz,1H),4.85(t,J=5.0Hz,1H).3.84–3.56(m,4H),1.54(s,6H).
13C NMR(75MHz,CDCl
3)δ174.34,154.00,150.68,148.27,136.25,135.68,135.33,128.96,128.03,123.07,122.06, 118.58,117.65,108.46,104.48,62.20,43.26,39.39,23.46.HRMS(ESI)m/z calcd for C
24H
20F
3N
5O
2[M+H]
+468.1641,found 468.1666。
实施例31
4-(3-(2-(二(喹啉-6-基)氨基)乙基)-4,4-二甲基-2,5-二氧杂咪唑啉-1-基)-2-(三氟甲基)苄腈(38g)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),6-溴喹啉(150mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得淡黄色粉末25mg,收率12.0%。Data for 38g:m.p.:180-181℃;
1H NMR(300MHz,CDCl
3)δ8.82(dd,J=4.4,1.6Hz,2H),8.17(d,J=2.0Hz,1H),8.09–7.96(m,5H),7.94(d,J=8.4Hz,1H),7.54(dq,J=4.8,2.7Hz,4H),7.38(dd,J=8.3,4.2Hz,2H),4.35(dd,J=9.3,6.1Hz,2H),3.74(dd,J=9.2,5.9Hz,2H),1.50(s,6H).
13C NMR(75MHz,CDCl
3)δ174.22,153.32,149.00,144.83,136.22,135.39,135.00,130.96,129.47,127.99,125.37,123.00,121.80,114.95,108.51,61.99,50.80,37.79,23.42.HRMS(ESI)m/z calcd for C
33H
25F
3N
6O
2[M+H]
+595.2063,found 595.2500。
实施例32
4-(3-(2-(二(喹啉-7-基)氨基)乙基)-4,4-二甲基-2,5-二氧杂咪唑啉-1-基)-2-(三氟甲基)苄腈(38h)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),7-溴喹啉(150mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得淡黄色粉末66mg,收率31.7%。Data for 38h:m.p.:244-245℃;
1H NMR(300MHz,DMSO-d
6)δ8.85(dd,J=4.3,1.7Hz,1H),8.40(d,J=8.4Hz,1H),8.31(dd,J=8.3,1.8Hz,1H),8.24(d,J=2.0Hz,1H),8.10(dd,J=8.4,2.0Hz,1H),7.95(d,J=8.9Hz,1H),7.78(d,J=2.3Hz,1H),7.50(dd,J=8.9,2.4Hz,1H),7.43(dd,J=8.2,4.3Hz,1H),4.37(t,J=7.1Hz,1H),3.79(t,J=7.4Hz,1H),1.47(s,3H).HRMS(ESI)m/z calcd for C
33H
25F
3N
6O
2[M+H]
+595.2063,found 595.2600。
实施例33
4-(4,4-二甲基-2,5-二氧代-3-(2-(8-硝基喹啉-5-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38i)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),5-溴8-硝基喹啉(177mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得黄色粉末22mg,收率13.4%。Data for 38i:
1H NMR(300MHz,DMSO-d
6)δ9.14–9.06(m,1H),8.83(d,J=8.6Hz,1H),8.42(dd,J=20.4,8.5Hz,2H),8.30(s,1H), 8.21–8.12(m,1H),7.88(s,1H),7.71(dd,J=8.5,4.0Hz,1H),6.85(d,J=9.0Hz,1H),3.82–3.70(m,4H),1.55(s,J=3.1Hz,6H).ESI-MS m/z:535[M+Na]
+。
实施例34
4-(4,4-二甲基-2,5-二氧代-3-(2-(8-氰基喹啉-5-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38j)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),5-溴8-氰基喹啉(163mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得淡黄色粉末31mg,收率18.9%。Data for 38j:
1H NMR(300MHz,DMSO-d
6)δ9.00(dd,J=4.2,1.4Hz,1H),8.72(dd,J=8.7,1.6Hz,1H),8.38(d,J=8.4Hz,1H),8.23(d,J=1.9Hz,1H),8.15–8.04(m,2H),7.70–7.55(m,2H),6.82(d,J=8.4Hz,1H),3.66(p,J=6.0Hz,4H),1.47(s,6H).ESI-MS m/z:515[M+Na]
+。
实施例35
4-(4,4-二甲基-2,5-二氧代-3-(2-(8-氟喹啉-5-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38k)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),5-溴8-氟喹啉(158mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得深黄色粉末37mg,收率22.6%。Data for 38k:
1H NMR(300MHz,DMSO-d
6)δ8.91(dd,J=4.2,1.5Hz,1H),8.61(dt,J=8.8,1.7Hz,1H),8.37(d,J=8.4Hz,1H),8.24(d,J=2.0Hz,1H),8.10(dd,J=8.4,2.0Hz,1H),7.56(dd,J=8.6,4.2Hz,1H),7.43(dd,J=11.0,8.5Hz,1H),6.64(dd,J=8.6,3.7Hz,1H),6.49(t,J=5.5Hz,1H),3.61(dt,J=25.8,6.6Hz,4H),1.49(s,6H).ESI-MS m/z:493[M+Na]
+。
实施例36
4-(4,4-二甲基-2,5-二氧代-3-(2-(8-甲基喹啉-5-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38l)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),5-溴8-甲基喹啉(155mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得黄色粉末55mg,收率33.5%。Data for 38l:
1H NMR(300MHz,DMSO-d
6)δ8.88(dd,J=4.1,1.5Hz,1H),8.59–8.50(m,1H),8.38(d,J=8.3Hz,1H),8.25(d,J=1.9Hz,1H),8.10(d,J=8.6Hz,1H),7.51–7.39(m,2H),6.66(d,J=7.8Hz,1H),6.42(d,J=5.5Hz,1H),3.64(d,J=6.4Hz,2H),3.55(d,J=6.5Hz,2H),1.49(s,9H)。
实施例37
4-(4,4-二甲基-2,5-二氧-3-(2-(异喹啉-1-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38m)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),1-溴异喹啉(150mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得淡黄色粉末18mg,收率11.0%。Data for 38m:
1H NMR(300MHz,DMSO-d
6)δ8.36(d,J=8.4Hz,1H),8.26–8.16(m,2H),8.09(dd,J=8.4,2.0Hz,1H),7.93(d,J=5.8Hz,1H),7.74(d,J=8.1Hz,1H),7.64(q,J=6.6,5.9Hz,2H),7.52(ddd,J=8.4,6.8,1.4Hz,1H),6.95(d,J=5.8Hz,1H),3.83(q,J=6.3Hz,2H),3.63(t,J=6.6Hz,2H),1.49(s,6H)。
实施例38
4-(4,4-二甲基-2,5-二氧-3-(2-(异喹啉-3-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38n)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),3-溴异喹啉(150mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得淡黄色粉末35mg,收率21.4%。Data for 38n:
1H NMR(300MHz,DMSO-d
6)δ10.35(s,1H),9.18(s,1H),8.40(d,J=12.7Hz,2H),8.28–8.19(m,1H),8.07(dd,J=18.0,8.4Hz,2H),7.84(d,J=8.4Hz,1H),7.67(t,J=7.5Hz,1H),7.49(t,J=7.5Hz,1H),4.20(t,J=8.0Hz,2H),3.68(t,J=7.9Hz,2H),1.51(s,6H)。
实施例39
4-(4,4-二甲基-2,5-二氧-3-(2-(异喹啉-4-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38o)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),4-溴异喹啉(150mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得淡黄色粉末16mg,收率9.7%。Data for 38o:
1H NMR(300MHz,DMSO-d
6)δ8.61(s,1H),8.37(d,J=8.4Hz,1H),8.25(s,1H),8.20–8.06(m,2H),8.04–7.90(m,2H),7.77–7.59(m,2H),6.46(s,1H),3.71–3.61(m,4H),1.49(s,6H)。
实施例40
4-(4,4-二甲基-2,5-二氧-3-(2-(异喹啉-5-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38p)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),5-溴异喹啉(150mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得深黄色粉末22mg,收率13.3%。Data for 38p:
1H NMR(300MHz,DMSO-d
6)δ9.17(s,1H),8.44(d,J=6.0Hz,1H),8.37(d,J=8.4Hz,1H),8.25(d,J=2.0Hz,1H),8.11(dd,J= 8.3,2.0Hz,1H),7.99(d,J=6.1Hz,1H),7.52(t,J=7.9Hz,1H),7.32(d,J=8.1Hz,1H),6.91(d,J=7.7Hz,1H),6.61(t,J=5.4Hz,1H),3.69–3.57(m,4H),1.50(s,6H)。
实施例41
4-(4,4-二甲基-2,5-二氧-3-(2-(异喹啉-6-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38q)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),6-溴异喹啉(150mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得深黄色粉末22mg,收率13.3%。Data for 38q:
1H NMR(300MHz,DMSO-d
6)δ8.92(s,1H),8.38(d,J=8.4Hz,1H),8.28–8.19(m,2H),8.11(dd,J=8.4,2.0Hz,1H),7.83(d,J=8.9Hz,1H),7.46(d,J=5.8Hz,1H),7.11(dd,J=8.9,2.2Hz,1H),6.82(d,J=2.2Hz,1H),6.73(s,1H),3.58(t,J=5.6Hz,4H),1.50(s,6H)。
实施例42
4-(4,4-二甲基-2,5-二氧-3-(2-(异喹啉-7-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38r)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),7-溴异喹啉(150mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得黄色粉末25mg,收率15.1%。Data for 38r:
1H NMR(300MHz,DMSO-d
6)δ8.99(s,1H),8.38(d,J=8.4Hz,1H),8.25(d,J=1.9Hz,1H),8.17(s,1H),8.11(dd,J=8.4,2.0Hz,1H),7.72(d,J=8.9Hz,1H),7.59(d,J=5.1Hz,1H),7.26(dd,J=8.9,2.2Hz,1H),7.01(d,J=2.3Hz,1H),6.47(t,J=5.5Hz,1H),3.63–3.51(m,4H),1.49(s,6H)。
实施例43
4-(4,4-二甲基-2,5-二氧-3-(2-(异喹啉-8-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38s)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),8-溴异喹啉(150mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得深黄色粉末27mg,收率16.3%。Data for 38s:
1H NMR(300MHz,DMSO-d
6)δ9.51(s,1H),8.40(dd,J=15.3,7.0Hz,2H),8.25(d,J=2.0Hz,1H),8.11(dd,J=8.4,2.0Hz,1H),7.65(d,J=5.6Hz,1H),7.57(t,J=7.9Hz,1H),7.12(d,J=8.1Hz,1H),7.01–6.91(m,1H),6.81(d,J=7.7Hz,1H),3.65(m,4H),1.50(s,6H)。
实施例44
4-(4,4-二甲基-2,5-二氧-3-(2-(吡啶-2-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38t)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),2-溴吡啶(110mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175 mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得浅黄色粉末33mg,收率19.2%。Data for 38t:
1H NMR(300MHz,Chloroform-d)δ8.19–8.09(m,2H),8.09–7.91(m,2H),7.45(ddd,J=8.8,7.1,1.9Hz,1H),6.69–6.58(m,1H),6.49(d,J=8.4Hz,1H),4.97(t,J=5.7Hz,1H),3.75(q,J=6.2,5.7Hz,2H),3.66(dd,J=6.8,4.9Hz,2H),1.57(s,6H)。
实施例45
4-(4,4-二甲基-2,5-二氧-3-(2-(嘧啶-5-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38u)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),5-溴嘧啶(110mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得白色粉末27mg,收率15.7%。Data for 38u:
1H NMR(300MHz,DMSO-d
6)δ8.44(s,1H),8.36(d,J=8.4Hz,1H),8.23(d,J=2.3Hz,3H),8.09(dd,J=8.4,2.0Hz,1H),6.38(t,J=5.9Hz,1H),3.49(m,4H),1.48(s,6H)。
实施例46
4-(4,4-二甲基-2,5-二氧-3-(2-(嘧啶-2-基氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38v)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),2-溴嘧啶(110mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得淡黄色粉末33mg,收率19.2%。Data for 38v:
1H NMR(300MHz,DMSO-d
6)δ8.40–8.28(m,3H),8.21(d,J=1.9Hz,1H),8.07(dd,J=8.4,2.0Hz,1H),7.29(t,J=6.0Hz,1H),6.61(t,J=4.8Hz,1H),3.60(q,J=6.4Hz,2H),3.49(t,J=6.5Hz,2H),1.45(s,6H)。
实施例47
4-(4,4-二甲基-2,5-二氧-3-(2-二(喹喔啉-6-基)氨基)乙基)咪唑啉-1-基)-2-(三氟甲基)苄腈(38w)的合成
氮气保护条件下,将原料37(120mg,0.35mmol),6-溴喹喔啉(150mg,0.7mmol)溶解于3mL甲苯中,随后加入碳酸铯(228mg,0.7mmol),Pd
2(dba)
3(16mg,0.0175mmol)和X-phos(12mg,0.0175mmol)。升温至110℃,反应过夜,TLC点板发现原料反应完毕,停止加热,待反应冷却至室温后,加入水淬灭反应,用乙酸乙酯萃取三次,收集有机相,有机相用饱和食盐水洗涤三次,无水硫酸镁干燥10分钟,旋干,过柱得黄色粉末21mg,收率11.7%。Data for 38w:
1H NMR(300MHz,DMSO-d
6)δ8.89(d,J=1.9Hz,2H),8.83(d,J=1.9Hz,2H),8.38(d,J=8.4Hz,1H),8.22(d,J=2.0Hz,1H),8.07(t,J=8.9Hz,3H),7.88(d,J=2.6Hz,2H),7.76(dd,J=9.1,2.6Hz,2H),4.41(t,J=7.3Hz,2H),3.81(t,J=7.3Hz,2H),1.48(s,6H)。
下面是本发明化合物的部分药理学实验及结果:
MTT法测试化合物对前列腺癌细胞株(22RV1)增殖能力的抑制情况
前列腺癌细胞株22RV1抗增殖活性实验
1材料和方法
1)实验材料
(1)细胞系
人前列腺癌细胞22RV1(南京凯基生物技术公司)。
(2)仪器和试剂
BioTek酶标仪(美国伯腾仪器有限公司)。;倒置显微镜(日本尼康Ts100);CO2培养箱(ESCO)。
RPMI1640培养基、双抗(Gibco),优级胎牛血清(Gibco);3-(4,5)-2噻唑-(2,5)-二甲基溴化四氢唑蓝(MTT)(南京凯基生物公司);DMSO(Amresco);其他试剂均为国产分析纯。
2)溶剂的配置方法
PBS:分别称量8.0g NaCl,0.13g Na2HPO4·12H2O,0.06g KH2PO4,0.4g KCl,以及0.35g NaHCO3,加入1mL超纯水将它们溶解,加入NaOH调节pH至7.4,随后进行高压灭菌,置于4℃保存。
0.25%胰酶消化液:称量0.25g胰蛋白酶,加入100mL超纯水充分溶解,用0.22μm微孔过滤器过滤,置于-20℃保存。
RPMI1640培养液:分别称取13.3g RPMI1640培养基粉和2.0g NaHCO3,加入100mL超纯水充分溶解,随后加入10%双抗,使用0.22μm微孔滤膜过滤,使用时加入10%胎牛血清,置于4℃保存。
3)实验方法
(1)细胞培养
细胞复苏:将装有细胞的冻存管从液氮罐中取出,立刻至于37摄氏度恒温水浴锅,用手反复摇晃使其融化,将细胞倒入培养瓶中,加入5.5mL培养基(含10%胎牛血清)稀释,转入离心管中,2000r/min离心3分钟,弃去上清液,加入新鲜的培养基反复吹打几次,移入培养瓶中培养。
细胞传代:人前列腺癌22Rv1细胞是贴壁生长细胞,把含有细胞的RPMI1640培养液置于5%CO2,37℃培养箱中培养,待细胞铺满瓶底80%-90%时开始进行传代。传代时,首先把培养瓶中的培养基倒掉,PBS洗两遍,然后加入2~3mL0.25%胰蛋白酶液,37℃下消化3分钟,显微镜下观察到细胞变圆,加入2mL新鲜的RPMI1640培养基(含10%胎牛血清)终止消化。倒掉培养瓶中的液体,PBS洗两遍,加入6mL新鲜培养基,反复吹打均匀,均分到两个培养瓶中,继续培养。
细胞冻存:收取对数生长期细胞,加入胰蛋白酶溶液消化,离心,弃去上清液,加入无血清冻存液,反复吹打几次,转入冻存管中。将冻存管放入冻存盒中,置于-80℃冰箱过夜,次日取出放入液氮罐中。记录细胞名称,冻存日期以及存放位置。
细胞计数:用75%乙醇溶液将血球计数板擦拭干净,取少量细胞重悬液(约10uL),滴加在计数板上,盖上盖玻片,静置片刻。将计数板放在倒置显微镜下观察,记录计数板中四大格细胞总数,如若细胞压线,只记录上方和左侧的。(细胞数/mL=所得细胞总数/4×104)
(2)MTT检测法
取对数生长期细胞,倒掉旧培养基,加入0.25%胰蛋白酶溶液消化3分钟,显微镜下观察细胞变圆,加入3mL含10%胎牛血清的新鲜RPMI1640培养基终止消化,将溶液转移至离心管,2000r/min离心3分钟,弃去上清。加入2mL培养基将细胞重悬,进 行细胞计数。计数完成后,按照每孔4000~6000个细胞的浓度将细胞种植于96孔板中,每孔100μL。将铺好细胞的96孔板置于37℃,5%CO2培养箱中继续培养24h。用培养基将药物梯度稀释为100μmol/L,20μmol/L,2μmol/L,0.2μmol/L随后将它们加入到96孔板中,每孔100μL,每个浓度设置三个复孔。对照组加入相应浓度的含溶媒的培养基,调零孔加入相同体积的空白培养基,置于5%CO2、37C培养箱孵育4天,每两天更换一次培养基。每孔加入20μL MTT(5mg/mL),混合均匀后,于5%CO2、37C培养箱避光培养4h。将96孔板中的液体移除,每孔加入150μL DMSO,置于微型振荡器上震荡,使底部的结晶完全溶解。随后将96孔板放入酶标仪中检测,于490nm处测定吸光度,绘制曲线并计算药物对细胞的抑制率及IC50。抑制率=[(对照组平均OD值-实验组平均OD值)/(对照组平均OD值-空白对照组平均OD值)]×100%。
化合物对22RV1细胞株的增殖抑制活性结果及分析
前列腺癌细胞系22RV1是来自异种移植(在阉割引起前列腺癌衰退又在其父系的雄性激素依赖型CWR22嫁接后复发的小鼠中连续传代)的人前列腺癌上皮细胞系。22RV1细胞的生长对雄激素敏感,且高表达AR剪接变异体,因此该细胞系对恩杂鲁胺具有抵抗性。在给予0.1μM睾酮的条件下测试化合物对于22RV1细胞株的抗增殖作用,可考察目标化合物是否可通过抗雄激素效应产生细胞增殖抑制作用。
(-表示未测得实验结果)
(3)Western Blot实验
根据MTT实验结果,其中活性最好的化合物38d和38k被挑选出来进行Western Blot实验,以检测所合成的目标化合物是否具有AR和AR-V7降解作用。
实验方法:人前列腺癌22RV1细胞经化合物处理完毕后,弃去培养基,PBS洗涤2-3次,依次加入蛋白酶抑制剂和RIPA裂解液,反复晃动培养板,使细胞与之充分接触,然后用刮子将细胞刮下。将所得的细胞悬液转移至离心管中,于冰上裂解30min,期间可用移液枪反复吹打,促进细胞裂解完全,然后进行离心(4℃,12,000g,10min),上层液即为得到的总蛋白溶液。参照试剂盒的说明书,用BCA蛋白定量检测试剂盒测定蛋白浓度,然后按照蛋白溶液:蛋白上样缓冲液=4:1的比例加入5*蛋白上样缓冲液,并于沸水浴中煮沸15min,准备进行下一步的蛋白分离。将等量的上述蛋白溶液加入到凝胶上样孔中,准备进行电泳,其中浓缩胶的电压为75V,分离胶电压为120V。电泳至溴酚蓝刚跑出即可终止,进行转模。将目的蛋白的条带剥离出来,贴上PVDF膜,通过电泳,转移至PVDF膜上,后用5%脱脂牛奶于脱色摇床上封闭1h。加入一抗,4℃孵育过夜,而后用TBST洗涤三次,每次洗涤时间为5min。加入二抗,室温下孵育30min,而后用TBST洗涤三次,每次洗涤时间为5min。提前于暗室中按照ECLA:ECLB=1:1的比例配置ECL混合溶液,然后将处理好的PVDF膜面朝上放在曝光匣中,加入配置好的ECL混合溶液反应1-2min后弃去反应液,根据显影试剂的发光强度调整曝光条件,开始曝光。扫描所得胶片,用Photoshop整理去色,Alpha软件分析光密度值。
实验结果如图所示,在添加0.1μM睾酮的情况下化合物38d在0.1μM的时候能够明显降解AR,且对AR的降解能力呈梯度增强。在添加0.1μM睾酮的情况下化合物38k能够明显降解AR和AR-V7,且对AR和AR-V7的降解能力呈梯度增强。
Claims (7)
- 根据权利要求1所述的具有通式I或通式II结构的新型雄激素受体降解剂、其药学上可接受的盐或其前药,其特征在于:R 1代表CN或者NO 2;R 2代表单取代或多取代的苯环、含氮杂环、稠环或含氮稠杂环;R 3代表H、单取代或多取代的苯环、含氮杂环、稠环或含氮稠杂环。
- 根据权利要求2所述的具有通式I或通式II结构的新型雄激素受体降解剂、其药学上可接受的盐或其前药,其特征在于:R 1代表CN;R 2代表单取代或多取代的含氮杂环或含氮稠杂环;R 3代表单取代或多取代含氮杂环或含氮稠杂环。
- 一种药物组合物,其包含权利要求1至4中任一项的具有通式I或通式II结构的新型雄激素受体降解剂、其药学上可接受的盐或其前药,及药学上可接受的载体。
- 权利要求1至4中任一项的具有通式I或通式II结构的新型雄激素受体降解剂、其药学上可接受的盐或其前药在制备治疗雄激素受体相关疾病药物中的用途。
- 权利要求6所述的用途,其特征在于:雄激素受体相关疾病为依赖于雄激素的细胞异常增殖、前列腺癌、多毛症或雄激素脱发。
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