CN117924252A - Quinazoline-carbazole skeleton derivative and antidiabetic activity thereof - Google Patents
Quinazoline-carbazole skeleton derivative and antidiabetic activity thereof Download PDFInfo
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- CN117924252A CN117924252A CN202410086385.1A CN202410086385A CN117924252A CN 117924252 A CN117924252 A CN 117924252A CN 202410086385 A CN202410086385 A CN 202410086385A CN 117924252 A CN117924252 A CN 117924252A
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- quinazoline
- hydrogen
- carbazole skeleton
- hydroxy
- skeleton derivative
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- SUYCTEJBRSFZCD-UHFFFAOYSA-N 9h-carbazole;quinazoline Chemical group N1=CN=CC2=CC=CC=C21.C1=CC=C2C3=CC=CC=C3NC2=C1 SUYCTEJBRSFZCD-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 230000003178 anti-diabetic effect Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- -1 hydroxy, methoxy Chemical group 0.000 claims abstract description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 32
- 239000001257 hydrogen Substances 0.000 claims abstract description 32
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 26
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 6
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 claims description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- ONCCWDRMOZMNSM-FBCQKBJTSA-N compound Z Chemical compound N1=C2C(=O)NC(N)=NC2=NC=C1C(=O)[C@H]1OP(O)(=O)OC[C@H]1O ONCCWDRMOZMNSM-FBCQKBJTSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
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- 239000004480 active ingredient Substances 0.000 claims description 2
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- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 abstract description 26
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 abstract description 16
- 235000021314 Palmitic acid Nutrition 0.000 abstract description 13
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 abstract description 13
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
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- 238000006243 chemical reaction Methods 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
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- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 4
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- PJRGCJBBXGNEGD-UHFFFAOYSA-N 2-bromo-9h-carbazole Chemical compound C1=CC=C2C3=CC=C(Br)C=C3NC2=C1 PJRGCJBBXGNEGD-UHFFFAOYSA-N 0.000 description 3
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- NIDSRGCVYOEDFW-UHFFFAOYSA-N 1-bromo-4-chlorobutane Chemical compound ClCCCCBr NIDSRGCVYOEDFW-UHFFFAOYSA-N 0.000 description 1
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- LTBWKAYPXIIVPC-UHFFFAOYSA-N 3-bromo-9h-carbazole Chemical compound C1=CC=C2C3=CC(Br)=CC=C3NC2=C1 LTBWKAYPXIIVPC-UHFFFAOYSA-N 0.000 description 1
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- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses quinazoline-carbazole skeleton derivatives with a structure shown in a formula I or pharmaceutically acceptable salts thereof, wherein n=0-6; r 1 is hydrogen, hydroxy, methoxy, trifluoromethyl, halogen; r 2 is hydrogen, hydroxy, methoxy, trifluoromethyl, halogen; r 3 is hydrogen, hydroxy, methoxy, trifluoromethyl, halogen; r 4 is hydrogen, methoxy, hydroxy, trifluoromethyl. The quinazoline-carbazole skeleton derivative disclosed by the invention is used for in-vitro research on the protection effect of Min6 islet beta cells of mice, and all compounds are found to be capable of protecting islet cells from palmitic acid-induced damage and have different degrees of protection effect on islet beta cells. The invention also discloses application of the quinazoline-carbazole skeleton derivative or the pharmaceutically acceptable salt thereof in preparing a medicament for treating diabetes.
Description
Technical Field
The invention relates to a quinazoline-carbazole skeleton derivative, a preparation method thereof and application thereof in preparing a medicament for treating diabetes.
Background
Diabetes mellitus (diabetes mellitus, DM) is one of the most important non-infectious diseases that currently threatens global human health. Preventing and controlling the occurrence and progression of diabetes is an urgent issue.
Antioxidant enzyme levels in islet beta cells are low and susceptible to oxidative stress, while thioredoxin interacting proteins (thioredoxin-INTERACTING PROTEIN, TXNIP) play an important role in maintaining the cellular redox state. In animal models, TXNIP overexpression has been shown to induce apoptosis of pancreatic beta cells, and TXNIP-deficient animals can be protected from diet-induced insulin resistance and type 2 diabetes. Targeting TXNIP not only improves insulin secretion and sensitivity of islet beta cells, but also reduces various complications caused by long-term diabetes, thus regulating TXNIP level can be used as a novel therapeutic strategy for reducing diabetes and complications thereof.
In the study of beta cell activity, small molecule inhibitors of bispecific tyrosine phosphorylation regulated kinase 1A (bispecific tyrosine phosphorylation-regulated kinase 1A, DYRK 1A) have received increasing attention. In human islet organoid experiments Barzowska et al demonstrated that DYRK1A inhibitors were effective in promoting beta cell proliferation, enhancing long-term insulin secretion, and balancing glucagon. Multiple sets of experimental data relating to DYRK1A and pancreatic β -cell proliferation showed that mice developed severe glucose intolerance and a reduction in the number of β -cell proliferation when DYRK1A was single-fold deficient, ultimately developing diabetes. Thus, DYRK1A inhibitors may result in enhanced β -cell proliferation, one of the effective targets for antidiabetic therapy.
In summary, the inventors hope to be able to develop a quinazoline-carbazole backbone derivative targeting DYRK1A and TXNIP for the treatment of diabetes.
Disclosure of Invention
Based on TXNIP and DYRK1A being very good double targets for treating diabetes, the inventor synthesizes a series of quinazoline-carbazole skeleton derivatives through the design concept of multi-target drug design and combinatorial chemistry, explores the influence of the quinazoline-carbazole skeleton derivatives on diabetes, and discovers that the quinazoline-carbazole skeleton derivatives have anti-diabetes activity.
Quinazoline-carbazole skeleton derivative shown in structural formula I or pharmaceutically acceptable salt thereof:
Wherein n=an integer of 0 to 6;
R 1 is selected from hydrogen, hydroxy, methoxy, trifluoromethyl, halogen; r 2 is selected from hydrogen, hydroxy, methoxy, trifluoromethyl, halogen; r 3 is selected from hydrogen, hydroxy, methoxy, trifluoromethyl, halogen; r 4 is selected from hydrogen, methoxy, hydroxy.
Preferably, n=an integer from 0 to 3; r 1 is selected from hydrogen, bromine; r 2 is selected from hydrogen, bromine; r 3 is selected from hydrogen, hydroxy; r 4 is selected from hydrogen.
More preferably, n=1, R 1 is selected from bromine, R 2 is selected from hydrogen, R 3 is selected from hydrogen, and R 4 is selected from hydrogen; n=2, 3, R 1 is selected from hydrogen, R 2 is selected from hydrogen, R 3 is selected from hydroxy, R 4 is selected from hydrogen.
Specifically, the quinazoline-carbazole skeleton derivative is selected from compounds with the following structures:
the invention also aims to provide a preparation method of the quinazoline-carbazole skeleton derivative, which comprises the following synthetic route:
wherein: n and R 1、R2、R3、R4 are as described above.
Comprising the following steps:
Step (1), using DMF as a reaction solvent, 4-hydroxy quinazoline as a substrate, potassium carbonate as an acid binding agent, and reacting the 4-hydroxy quinazoline with the formula under alkaline conditions Reacting the compound at normal temperature to generate a formula intermediate A;
And (2) heating and refluxing the intermediate A and the compound Z to react by taking DMF as a reaction solvent, potassium carbonate as an acid binding agent and KI as a catalyst, so as to generate the quinazoline-carbazole skeleton derivative shown in the formula I.
In step (1), 4-hydroxy quinazoline is reacted withThe molar ratio of (2) is 1:2-1:3.
The molar ratio of the 4-hydroxy quinazoline to the potassium carbonate is 1:3-1:5.
After the reaction is finished, water is added into the reaction solution according to the volume ratio of the reaction solvent to water of 1:10, crystallization is precipitated, and suction filtration is carried out, thus obtaining an intermediate A.
In the step (2), the molar ratio of the intermediate A to the compound Z is 1:1-1:1.2.
The mol ratio of the intermediate A to the potassium carbonate is 1:2.8-1:3.
The mass ratio of the KI to the intermediate A is 3:100-4:100.
After the reaction is finished, ethyl acetate and water are added into the reaction liquid, extraction is carried out, an organic layer is taken, the organic layer is dried by anhydrous Na 2SO4, reduced pressure concentration is carried out, the volume ratio of petroleum ether to acetone=5:1-7:1V/V is taken as an eluent, and the quinazoline-carbazole skeleton derivative shown in the formula I is obtained through separation and purification by silica gel column chromatography.
The inventor researches the protection effect of the quinazoline-carbazole skeleton derivative on the in vitro Min6 islet beta cells of mice, and discovers that all the compounds can protect islet cells from being damaged by palmitic acid, and have different degrees of protection effect on islet beta cells.
The invention also provides application of the quinazoline-carbazole skeleton derivative or the pharmaceutically acceptable salt thereof in preparing medicines for treating diabetes.
A pharmaceutical composition is prepared from the quinazoline-carbazole skeleton derivative or pharmaceutically acceptable salt thereof serving as an active ingredient and pharmaceutically acceptable auxiliary materials into a pharmaceutically acceptable preparation.
The invention has the beneficial effects that:
the quinazoline-carbazole skeleton derivative is synthesized through the 2-step reaction, the reaction condition is mild, the repetition is easy, and the yield is high.
The invention discovers the islet beta cell protection activity of the quinazoline-carbazole skeleton derivative for the first time, is an ideal islet beta cell chemical entity for protecting, is a novel chemical entity for potentially treating diabetes, and has important significance for researching and developing antidiabetic drugs.
Detailed Description
The technical scheme of the present invention will be described in further detail with reference to specific examples, but the present invention is not limited to the following examples.
The synthetic routes for compounds HZ-1 to HZ-8 are as follows:
Example 1
Preparation of Compound A1-Compound A3
4- (3-Chloropropoxy) quinazoline (Compound A1)
2.00G (13.68 mmol) of 4-hydroxy quinazoline and 5.70g (41.24 mmol) of K 2CO3 are taken in a 100mL eggplant-shaped bottle, 10mL of DMF is added for dissolution, 2.70mL (27.37 mmol) of 1-bromo-3-chloropropane is taken and added into the eggplant-shaped bottle, the reaction is carried out at normal temperature for 1h, and TLC monitors that the reaction is complete. 100mL of water was added to the reaction system, and a large amount of white crystals were precipitated, followed by suction filtration under reduced pressure to give compound A1 as white crystals, 2.39g, and a yield of 91.97%.
mp：206～209℃；1H NMR(400MHz,CDCl3)δ：8.33(1H,dd,J＝8.0,0.9Hz,H-8),8.11
(1H,s,H-3),7.78(1H,dt,J＝17.6,4.4Hz,H-2),7.65～7.72(1H,m,H-1),4.21(2H,t,J＝6.7Hz,OCH2-),3.62(2H,t,J＝6.0Hz,CH2Cl-),2.33～2.40(2H,m,2H,-CH2-);ESI-MS m/z:223.1[M+H]+.
4- (4-Chlorobutoxy) quinazoline (Compound A2)
2.00G (13.68 mmol) of 4-hydroxy quinazoline and 5.70g (41.24 mmol) of K 2CO3 are added into a 100mL eggplant-shaped bottle, 10mL of DMF is added for dissolution, 3.15mL (27.37 mmol) of 1-bromo-4-chlorobutane is added dropwise into the eggplant-shaped bottle, the reaction is carried out for 1h at normal temperature, and TLC monitors that the reaction is complete. 100mL of water was added to the reaction mixture, and the mixture was allowed to stand, and a large amount of white crystals were precipitated, and the mixture was suction-filtered under reduced pressure to give compound A2 as white crystals (2.47 g) in a yield of 93.90%.
mp：214～219℃；1H NMR(400MHz,CDCl3)δ8.31(1H，dd,J＝8.0,1.0Hz,H-8),
7.95～8.15(1H,m,H-3),7.67～7.79(1H,m,H-2),7.50～7.61(1H,m,H-6),7.49～7.52(1H,m,H-1),3.96～4.07(2H,m,OCH2-),3.60～3.69(2H,m,CH2Cl),2.01～2.12(2H,m,-CH2-),1.85～1.92(2H,m,-CH2-);ESI-MS m/z:237.1[M+H]+.
4- (5-Chloropentyloxy) quinazoline (Compound A3)
2.00G (13.68 mmol) of 4-hydroxyquinazoline and 5.70g (41.24 mmol) of K 2CO3 are added into a 100mL eggplant-shaped bottle, 10mL of DMF is added for dissolution, 3.73mL (27.36 mmol) of 1-bromo-5-chloropentane is added dropwise for reaction at normal temperature for 1h, and TLC monitors that the reaction is complete. 100mL of water was added to the reaction mixture, the mixture was allowed to stand, a large amount of white crystals were precipitated, and the mixture was suction-filtered under reduced pressure to obtain 2.82g of white crystals, with a yield of 94.05%.
mp 221～22℃；1H NMR(400MHz,CDCl3)δ：8.31(1H,dd,J＝8.0,1.1Hz,H-8),8.05(1H,
d,J＝5.9Hz,H-3),7.75～7.84(2H,m,H-2,H-6),7.52～7.61(1H,m,H-1),4.02(2H,t,J＝7.4Hz,OCH2-),3.55(2H,t,J＝6.5Hz,CH2Cl),1.83(4H,dd,J＝14.9,7.1Hz,-CH2-CH2-),1.56-1.64(2H,m,-CH2-CH2-);ESI-MS m/z:251.0[M+H]+.
Example 2
2-Bromo-9- (3- (quinazolin-4-yloxy) propyl) -9H-carbazole (Compound HZ-1)
100Mg (0.45 mmol) of compound A1 and 111mg (0.50 mmol) of 2-bromocarbazole were dissolved in 5mL of the solution, 186mg (1.35 mmol) of K 2CO3 mg and 3mg of KI were added, and the mixture was refluxed for 8 hours at 120℃and the reaction was complete by TLC. After adding 30mL of ethyl acetate to the reaction system and extracting with water (30 mL. Times.3), the organic layer was dried over anhydrous Na 2SO4 and concentrated under reduced pressure; silica gel column chromatography (petroleum ether: acetone=5:1V/V) gave compound HZ-1 as white crystals, 179.28mg, 92.2% yield.
mp：117～119℃；1H NMR(400MHz,CDCl3)δ：8.33(1H,d,J＝7.8Hz,H-8),8.15(1H,s,
H-3),7.97～8.11(2H,m,Ph-H),7.96(2H,t,J＝8.6Hz,H-2,H-6),7.79(1H,t,J＝7.6Hz,Ph-H),7.61(1H,s,H-1),7.56(1H,s,Ph-H),7.51～7.59(1H,m,Ph-H),7.38(2H,dd,J＝11.7,6.5Hz,Ph-H),4.46(2H,t,J＝6.9Hz,CH2N-),3.95～4.13(2H,m,-CH2-),2.44(2H,dd,J＝12.9,5.4Hz,-CH2-);ESI-MS m/z:244.0[M+H]+.
Example 3
3-Bromo-9- (3- (quinazolin-4-yloxy) propyl) -9H-carbazole (Compound HZ-2)
100Mg (0.45 mmol) of compound A1 and 111mg (0.50 mmol) of 3-bromocarbazole were dissolved in 5mL of DMF, and K 2CO3 mg (1.35 mmol) and 3mg KI were added thereto, and the mixture was refluxed for 8 hours at 120℃and the reaction was complete by TLC. After adding 30mL of ethyl acetate to the reaction system and extracting with water (30 mL. Times.3), the organic layer was dried over anhydrous Na 2SO4 and concentrated under reduced pressure; silica gel column chromatography (petroleum ether: acetone=5:1V/V) gave compound HZ-2 as white crystals, 185.56mg, 95.7% yield.
mp：123～126℃;1H NMR(400MHz,CDCl3)δ：8.31(1H,s,H-8),8.19(1H,s,Ph-H),8.06(1H,s,H-3),7.77(2H,d,J＝8.5Hz,H-2,H-6),7.69(1H,d,J＝7.7Hz,Ph-H),7.54(1H,s,Ph-H),7.52(1H,s,H-1),7.46(1H,s,Ph-H),7.42(1H,s,Ph-H),7.39(1H,s,Ph-H),7.28(1H,s,Ph-H),4.44(2H,dd,J＝8.6,5.1Hz,CH2N-),4.00～4.12(2H,m,CH2O-),2.40(2H,t,J＝5.7Hz,-CH2-);ESI-MS m/z:432.0[M+H]+.
Example 4
9- (3- (Quinazolin-4-yloxy) propyl) -9H-carbazol-4-ol (Compound HZ-3)
100Mg (0.45 mmol) of compound A1 and 82mg (0.45 mmol) of 4-hydroxycarbazole were dissolved in 5mL of DMF, and K 2CO3 mg (1.35 mmol) and 3mg KI were added thereto, and the mixture was refluxed for 8 hours at 120℃and the reaction was complete by TLC. After adding 30mL of ethyl acetate to the reaction system and extracting with water (30 mL. Times.3), the organic layer was dried over anhydrous Na 2SO4 and concentrated under reduced pressure; silica gel column chromatography (petroleum ether: acetone=6:1V/V) gave compound HZ-3 as a yellow solid, 148.19mg, 89.3% yield.
mp：145～149℃；1H NMR(400MHz,CDCl3)δ：8.47(1H,d,J＝9.3Hz,OH-),8.30(1H,
d,J＝7.8Hz,H-8),8.07(1H,s,Ph-H),8.04(1H,s,H-3),7.75(2H,m,H-2,H-6),7.67(1H,d,J＝7.8Hz,Ph-H),7.54(1H,s,H-1),7.52(1H,d,J＝7.9Hz,Ph-H),7.40～7.54(2H,m,Ph-H),7.08(1H,d,J＝8.1Hz,Ph-H),6.64(1H,d,J＝8.0Hz,Ph-H),4.42(2H,s,CH2N-),4.30(2H,s,CH2O-),2.53(2H,s-CH2-);ESI-MS m/z:370.1[M+H]+.
Example 5
2-Bromo-9- (4- (quinazolin-4-yloxy) butyl) -9H-carbazole (Compound HZ-4)
Compound A2 (100 mg,0.42 mmol) and 2-bromocarbazole (94 mg,0.42 mmol) were dissolved in 5mL DMF, K 2CO3 mg (1.26 mmol) and 3mg KI were added, heated to reflux at 120℃for 8h, and TLC monitored to be complete. After adding 30mL of ethyl acetate to the reaction system and extracting with water (30 mL. Times.3), the organic layer was dried over anhydrous Na 2SO4 and concentrated under reduced pressure; silica gel column chromatography (petroleum ether: acetone=5:1V/V) gave compound HZ-4 as white crystals, 168.19mg, 94.5% yield.
mp：152～157℃。1H NMR(400MHz,CDCl3)δ：8.33(1H,d,J＝7.6Hz,H-8),8.13(1H,
s,H-3),8.04～8.15(2H,m,Ph-H),7.92(2H,dd,J＝8.2,4.7Hz,H-2,H-6),7.69(1H,d,J＝8.1Hz,Ph-H),7.57(1H,s,H-1),7.55(1H,s,Ph-H),7.52(1H,d,J＝7.7Hz,Ph-H),7.33～7.41(2H,m,Ph-H),4.33(2H,t,J＝6.7Hz,CH2N-),3.95(2H t,J＝7.0Hz,CH2O-),1.95(2H,dd,J＝15.0,6.8Hz,-CH2-CH2N-),1.86(2H,dd,J＝9.2,5.9Hz,CH2-CH2O-);ESI-MS m/z:446.0[M+H]+.
Example 6
9- (4- (Quinazolin-4-yloxy) butyl) -9H-carbazol-4-ol (Compound HZ-5)
100Mg (0.42 mmol) of compound A2 and 77mg (0.42 mmol) of 4-hydroxycarbazole were dissolved in 5mL of DMF, K 2CO3 mg (1.26 mmol) and 3mg KI were added, and the mixture was heated under reflux at 120℃for 8h, and the completion of the reaction was monitored by TLC. After adding 30mL of ethyl acetate to the reaction system and extracting with water (30 mL. Times.3), the organic layer was dried over anhydrous Na 2SO4 and concentrated under reduced pressure; silica gel column chromatography (petroleum ether: acetone=6:1V/V) gave compound HZ-5 as a pale yellow solid, 152.60mg, 94.2% yield.
mp：118～122℃。1H NMR(400MHz,CDCl3)δ：8.35(1H,t,J＝7.0Hz,-OH),8.29(1H,t,
J＝15.9Hz,H-8),8.09(1H,s,Ph-H),8.05(1H,d,J＝29.1Hz,H-3),7.83～7.92(2H,m,H-2,H-6),7.60～7.72(1H,m,Ph-H),7.54(1H,t,J＝5.7Hz,H-1),7.42～7.50(1H,m,Ph-H),7.33～7.39(3H,m,Ph-H),7.25(1H,d,J＝7.8Hz,Ph-H),4.25(d,J＝45.6Hz,2H),4.14(2H,d,J＝4.7Hz,2H),2.17(2H,d,J＝4.5Hz,CH2-),1.63(s,2H,CH2-);ESI-MS m/z:384.1[M+H]+.
Example 7
2-Bromo-9- (5- (quinazolin-4-yloxy) pentyl) -9H-carbazole (Compound HZ-6)
100Mg (0.40 mmol) of compound A3 and 89mg (0.40 mmol) of 2-bromocarbazole were dissolved in 5mL of DMF, and K 2CO3 mg (1.19 mmol) and 3mg KI were added thereto and heated under reflux at 120℃for 8h. TLC monitored reaction was complete. After adding 30mL of ethyl acetate to the reaction system and extracting with water (30 mL. Times.3), the organic layer was dried over anhydrous Na 2SO4 and concentrated under reduced pressure; silica gel column chromatography (petroleum ether: acetone=6:1v/V) gives compound HZ-6 as white crystals, 162.14mg, yield 93.10%.
mp：152～157℃；1H NMR(400MHz,CDCl3)δ：8.33(1H,s,H-8),8.06(1H,d,J＝5.8Hz,
H-3),7.94(1H,s,Ph-H),7.76～7.80(2H,m,Ph-H),7.56(2H,t,J＝14.3Hz,H-2,H-6),7.47(1H,d,J＝13.5Hz,H-1),7.41(1H,d,J＝6.2Hz,Ph-H),7.34(1H,s,Ph-H),7.27(2H,d,J＝14.4Hz,Ph-H),4.18(2H,m,CH2N-),3.78(2H,dd,J＝17.7,7.3Hz,CH2O-),2.00～2.31(4H,m,-CH2),1.50(2H,dd,J＝34.2,26.6Hz,-CH2-);ESI-MS m/z:460.0[M+H]+.
Example 8
9-4- (Quinazolin-4-yloxy) butyl) -9H-carbazole (Compound HZ-7)
100Mg (0.42 mmol) of compound A2 and 70mg (0.42 mmol) of carbazole were dissolved in 5mL of DMF, K 2CO3 mg (1.26 mmol) and 3mg of KI were added, and the mixture was heated under reflux at 120℃for 8h, and TLC was monitored to be complete. After adding 30mL of ethyl acetate to the reaction system and extracting with water (30 mL. Times.3), the organic layer was dried over anhydrous Na 2SO4 and concentrated under reduced pressure; silica gel column chromatography (petroleum ether: acetone=7:1v/V) gave compound HZ-7 as yellow crystals, 147.91mg, yield 95.43%.
mp：126～130℃;1H NMR(400MHz,CDCl3)δ：8.34～8.28(1H,m,H-8),8.17(1H,s,Ph-H),8.11(1H,s,Ph-H),8.03(1H,d,J＝6.1Hz,H-3),7.75(2H,dd,J＝14.3,6.3Hz,H-2,H-6),7.71～7.64(1H,m,Ph-H),7.60(1H,d,J＝5.8Hz,Ph-H),7.55(1H,d,J＝6.3Hz,H-1),7.52(1H,s,Ph-H),7.47(1H,s,Ph-H),7.21(2H,s,Ph-H),4.90(2H,d,J＝13.7Hz,CH2N-),3.96(2H,d,J＝13.6Hz,CH2O-),1.98(2H,s,-CH2-),1.85(2H,s,-CH2-);ESI-MS m/z:345.1[M+H]+.
Example 9
9- (5- (Quinazoline-4-epoxy) pentyl) -9H carbazole (Compound HZ-8)
100Mg (0.40 mmol) of compound A3 and 67mg (0.40 mmol) of carbazole were dissolved in 5mL of DMF, and catalyst K 2CO3 mg (1.19 mmol) and 3mg KI were added thereto, and the mixture was refluxed for 8 hours at 120℃and the reaction was complete by TLC. After adding 30mL of ethyl acetate to the reaction system and extracting with water (30 mL. Times.3), the organic layer was dried over anhydrous Na 2SO4 and concentrated under reduced pressure; silica gel column chromatography (petroleum ether: acetone=7:1V/V) gave compound HZ-8 as white crystals, 142.64mg, 93.82% yield.
mp：132～136℃；1H NMR(400MHz,CDCl3)δ：8.43(1H,s,H-8),8.16(1H,d,J＝5.8Hz,
H-3),7.84(1H,s,Ph-H),7.66～7.74(2H,m,Ph-H),7.54～7.61(2H,t,J＝14.3Hz,H-2,H-6),7.43(1H,d,J＝13.5Hz,pH-H),4.81(2H,d,J＝33.7Hz,CH2N-),3.91(2H,d,J＝68.6Hz,CH2O-),2.00(2H,s,-CH2-),1.95(2H,s,-CH2-);ESI-MS m/z:367.1[M+H]+.
TABLE 1 quinazoline-carbazole skeleton derivatives of the present invention
Example 10
Protection effect of quinazoline-carbazole skeleton derivative on islet beta cells under stimulation of palmitic acid
(1) Principle of experiment
Insulin secreted by islet cells can exert a hypoglycemic effect. Therefore, the hypoglycemic medicine has islet cell protection effect. Palmitic acid induced islet beta cell apoptosis is a common model of diabetes damage in vitro. And judging whether the compound has a protective effect on islet beta cells by comparing the cell activities of the compound and a palmitic acid injury model.
(2) Cell culture and passage
The cells were cultured at 37℃in an incubator containing 5% CO 2, and when the cell fusion reached 80%, passage of the cells was possible. The complete medium was aspirated and washed twice with PBS buffer, 1mL of 0.25% EDTA-containing pancreatin was added, and after 1.5min of digestion, the complete medium (DMEM medium+1% triple antibody+10% foetal calf serum) was added to blow the cells in suspension. Centrifuging at 1000r/min for 5min, discarding supernatant to collect cells, adding fresh culture medium into cell sediment, re-suspending, spreading into T25 culture flask, and culturing in cell incubator.
(3) Preparation of the solution
10% Bovine Serum Albumin (BSA): precisely weighing 1.0g of BSA powder, fully dissolving with PBS buffer solution, fixing volume to 10mL, filtering, sterilizing, packaging, and preserving at-20deg.C for use.
Preparation of Palmitic Acid (PA) working solution: accurately weighing 30.77mg of PA powder, adding 1mL of absolute ethyl alcohol for ultrasonic dissolution or heating and dissolving in water bath at 60 ℃, adding 3mL of 50nmol/L NaOH solution to prepare 30mmol/L working solution, filtering and sterilizing, and preparing the solution immediately after use. Immediately before use, the cells were diluted 1:100 in DMEM medium containing 0.55%fattyacid free-BSA.
Preparation of compound solution: respectively precisely weighing the compounds, adding dimethyl sulfoxide dissolved compounds to prepare 100mmol/L storage solution, diluting with PBS buffer solution to obtain 1mmol/L working solution, and preserving at-20deg.C for use; immediately before use, the working solution was diluted to 10. Mu. Mol/L in DMEM medium without BSA.
(4) Determination of the protective action of the drug on islet cells under palmitic acid stimulation
When the Min6 cell fusion reached 80%, the cells were uniformly inoculated into 96-well plates and cultured overnight at 37℃in a 5% CO 2 incubator. Setting a PA treatment group (PATREATMENT), namely constructing a cell damage model by using 0.3mmol/L PA; the incubation was continued for 24h with the addition of a compound test solution at a final concentration of 10. Mu. Mol/L, and then Cell viability was determined using CCK8 reagent.
(5) Experimental results
TABLE 2 protective Activity of Compounds against PA stimulated Min6 cells at 10. Mu. Mol/L
As can be seen from table 2, all compounds have different degrees of protection to islet β cells, with cell viability higher than 60%, and higher than PA-stimulated cell damage model (40.1% cell viability). Wherein, the protection effect of the compounds HZ-5 and HZ-6 is higher than 80%, and the cell activities are 88.4% and 82.3%, respectively.
In general, the quinazoline-carbazole skeleton derivatives have different degrees of islet cell protection, and are novel chemical entities for resisting diabetes.
Claims (10)
1. Quinazoline-carbazole skeleton derivative shown in formula I or pharmaceutically acceptable salt thereof:
Wherein: n=0 to 6; r 1 is hydrogen, hydroxy, methoxy, trifluoromethyl, halogen; r 2 is hydrogen, hydroxy, methoxy, trifluoromethyl, halogen; r 3 is hydrogen, hydroxy, methoxy, trifluoromethyl, halogen; r 4 is hydrogen, methoxy, hydroxy, trifluoromethyl.
2. The quinazoline-carbazole skeleton derivative according to claim 1, wherein: n=an integer of 0 to 3; r 1 is selected from hydrogen, bromine; r 2 is selected from hydrogen, bromine; r 3 is selected from hydrogen, hydroxy; r 4 is selected from hydrogen.
3. Quinazoline-carbazole skeleton derivative shown in formula I or pharmaceutically acceptable salt thereof:
Wherein: n=1, R 1 is selected from bromine, R 2 is selected from hydrogen, R 3 is selected from hydrogen, R 4 is selected from hydrogen; n=2, 3, R 1 is selected from hydrogen, R 2 is selected from hydrogen, R 3 is selected from hydroxy, R 4 is selected from hydrogen.
4. A quinazoline-carbazole skeleton derivative or a pharmaceutically acceptable salt thereof, characterized by: the quinazoline-carbazole skeleton derivative is selected from the following compounds:
5. A method for producing a quinazoline-carbazole skeleton derivative according to claim 1, characterized in that: the synthetic route is as follows:
wherein: n and R 1、R2、R3、R4 are as defined in claim 1.
6. The method for producing a quinazoline-carbazole skeleton derivative according to claim 5, wherein: comprising the following steps:
Step (1), using DMF as a reaction solvent, 4-hydroxy quinazoline as a substrate, potassium carbonate as an acid binding agent, and reacting the 4-hydroxy quinazoline with the formula under alkaline conditions Reacting the compound at normal temperature to generate a formula intermediate A;
And (2) heating and refluxing the intermediate A and the compound Z to react by taking DMF as a reaction solvent, potassium carbonate as an acid binding agent and KI as a catalyst, so as to generate the quinazoline-carbazole skeleton derivative shown in the formula I.
7. The method for producing a quinazoline-carbazole skeleton derivative according to claim 6, wherein: in step (1), 4-hydroxy quinazoline is reacted withThe molar ratio of (2) to (3) is 1:2-1:3; the molar ratio of the 4-hydroxy quinazoline to the potassium carbonate is 1:3-1:5.
8. The method for producing a quinazoline-carbazole skeleton derivative according to claim 6, wherein: in the step (2), the molar ratio of the intermediate A to the compound Z is 1:1-1:1.2; the mol ratio of the intermediate A to the potassium carbonate is 1:2.8-1:3;
The mass ratio of the KI to the intermediate A is 3:100-4:100.
9. Use of a quinazoline-carbazole skeleton derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of diabetes.
10. A pharmaceutical composition characterized by: the pharmaceutical composition takes the quinazoline-carbazole skeleton derivative or the pharmaceutically acceptable salt thereof as an active ingredient, and pharmaceutically acceptable auxiliary materials to prepare a pharmaceutically acceptable preparation.
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