CN113149978A - Intermediate compound, preparation method and application thereof - Google Patents
Intermediate compound, preparation method and application thereof Download PDFInfo
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- CN113149978A CN113149978A CN202110153542.2A CN202110153542A CN113149978A CN 113149978 A CN113149978 A CN 113149978A CN 202110153542 A CN202110153542 A CN 202110153542A CN 113149978 A CN113149978 A CN 113149978A
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- Prior art keywords
- compound
- hydrogen
- cancer
- alkyl
- radical
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
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- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 36
- -1 hydroxy, mercapto Chemical class 0.000 claims description 36
- 150000002431 hydrogen Chemical class 0.000 claims description 31
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 13
- 229910052805 deuterium Inorganic materials 0.000 claims description 13
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 125000001475 halogen functional group Chemical group 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 9
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
The invention discloses an intermediate compound, a preparation method and application thereof. The synthesized intermediate compound is used for preparing targeted anticancer drugs, such as inhibitors of CDK4, CDK6, DYRK2 and the like, and is used for preventing and/or treating cancers or tumor-related diseases, including breast cancer, prostatic cancer, lung cancer, multiple myeloma, leukemia, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer and human glioma. The intermediate compound of the invention has simple preparation conditions, high reaction yield and stable performance.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to an intermediate compound, a preparation method and application thereof.
Background
The cell cycle dependent kinase 6(CDK6) is a serine/tyrosine kinase that regulates the transition of the cell cycle from G1 to S phase. Cyclin (cyclin) D binds CDK6 and activates CDK6 in the early stages of the G1 phase of the cell cycle, forming a cyclin D-CDK6 complex that promotes retinoblastoma protein (Rb) phosphorylation. Phosphorylation of Rb results in the release of the transcription factor E2F, facilitating the transition of the cell cycle from G1 to S phase. The up-regulation of protooncogene CDK6 accelerates the progression from G1 to S phase in the cell cycle, thereby promoting cell division and cell proliferation. Therefore, inhibition of CDK6 could inhibit the transition of the cell cycle from G1 to S phase, resulting in antiproliferative and anticancer effects. However, the currently marketed CDK6 inhibitors Palbociclib, Rbociclib and Abemaciclib are highly toxic and have developed resistance.
The dual specificity tyrosine phosphorylation regulated kinase (DYRK) and CDK belong to CMGC family, and play important regulation and control roles in cell cycle and cell proliferation. DYRK2 regulates phosphorylation of cell cycle dependency Rpt3-T25, promotes degradation of CDK inhibitors such as p21 and p27, and promotes progression of the cell cycle from G1 stage to S stage. Inhibition of DYRK2 may also slow the progression of the cell cycle from G1 to S phase, resulting in anti-proliferative and anti-cancer effects.
The targeted drug has the characteristics of strong drug effect and good safety, but due to the complexity and integrity of the cancer, when the drug with a single target point inhibits one passage of the cancer, the related passage is activated so as to compensate the inhibited passage, and the drug resistance of the drug is generated. By utilizing the synergistic effect of CDK6 and DYRK2, a series of compounds are designed to simultaneously target CDK6 and DYRK2, the anticancer activity of the compounds is improved by inhibiting DYRK2 and simultaneously blocking a compensatory pathway of CDK6, and the drug resistance which is easily generated by CDK6 single-target drugs is reduced.
Disclosure of Invention
The purpose of the invention is as follows: the invention provides an intermediate compound for preparing a targeted anticancer drug. The invention also provides a preparation method and application of the intermediate compound. The intermediate compounds of the invention are useful for the synthesis of dual target inhibitors of CDK6 and DYRK 2.
The technical scheme is as follows: the invention provides an intermediate compound shown as a general formula (I):
wherein the content of the first and second substances,
R1selected from hydrogen, deuterium, halogen, hydroxy, mercapto, cyano, nitro, C1-C8Alkyl, halo C1-C8Alkyl radical, C1-C8Alkoxy radical, C3-C8Cycloalkyl radical, C6-C10Aryl radical, C3-C10Heteroaryl group, C4-C8Heterocyclyl radical, -C0-8-NR4R5;
R2Selected from hydrogen, deuterium, halogen, hydroxy, mercapto, cyano, nitro, C1-C8Alkyl radical, C3-C8A cycloalkyl group;
the R is4、R5Each independently selected from hydrogen, deuterium and C1-C8Alkyl, halo C1-C8Alkyl radical, C1-C8Alkoxy or C3-C8A cycloalkyl group.
Preferably, said R is1Is hydrogen, C1-C8Alkyl or-C0-8-NR4R5Wherein R is4、R5Selected from hydrogen, C1-C8Alkyl or C3-C8A cycloalkyl group; r2Is hydrogen or halogen.
Preferably, said R is1Is hydrogen, C1-C3Alkyl or-NR4R5Wherein R is4、R5Selected from hydrogen, C1-C3Alkyl, cyclopentane or cyclohexane; r2Is hydrogen or F.
Preferably, said R is1Selected from: hydrogen, methyl or-NR4R5Wherein R is4、R5Selected from hydrogen, methyl, ethyl or cyclopentane; the R is2Is F.
Preferably, said R is1Selected from: hydrogen, methyl or-NR4R5Wherein R is4Selected from hydrogen, methyl, ethyl or cyclopentane, the R5Selected from hydrogen, methyl, ethyl; the R is2Is F.
The compound is selected from I-1 to I-5:
the invention also provides a preparation method of the intermediate compound, which is characterized in that the compound (A) and the compound (B) are subjected to coupling reaction under the action of a palladium catalyst to prepare a compound (I):
wherein the content of the first and second substances,
R1selected from hydrogen, deuterium, halogen, hydroxy, mercapto, cyano, nitro, C1-C8Alkyl, halo C1-C8Alkyl radical, C1-C8Alkoxy radical, C3-C8Cycloalkyl radical, C6-C10Aryl radical, C3-C10Heteroaryl group, C4-C8Heterocyclyl radical, -C0-8-NR4R5;
R2Selected from hydrogen, deuterium, halogen, hydroxy, mercapto, cyano, nitro, C1-C8Alkyl radical, C3-C8A cycloalkyl group;
the R is4、R5Each independently selected from hydrogen, deuterium and C1-C8Alkyl, halo C1-C8Alkyl radical, C1-C8Alkoxy or C3-C8A cycloalkyl group.
Preferably, the molar ratio of compound (a) to compound (B) is 1:1 to 1.5; the reaction temperature is 75-85 ℃.
Preferably, the reaction solvent is selected from ethylene glycol dimethyl ether.
The application of the intermediate compound in preparing the anti-cancer drugs is disclosed. The anticancer drugs such as CDK4, CDK6, DYRK2 and other inhibitors are used for preventing and/or treating cancers or tumor-related diseases. Cancers include breast cancer, prostate cancer, lung cancer, multiple myeloma, leukemia, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, and human glioma.
The application of the intermediate in preparing an anticancer drug CDK6 and DYRK2 dual-target inhibitor is disclosed, namely the anticancer drug CDK6 and DYRK2 dual-target inhibitor.
The CDK6 and DYRK2 double-target inhibitor has a structural general formula as follows:
x is selected from O, (CH)2)nC (O), NH or S (O)2N is 0 or 1;
R3selected from hydrogen, deuterium, C1-C8Alkyl, halo C1-C8Alkyl radical, C1-C8Alkoxy radical, C3-C8Cycloalkyl, -C0-8-S(O)2R6、 -C0-8-C(O)OR7(ii) a Wherein R is6、R7Each independently selected from hydrogen and C1-C8Alkyl, halo C1-C8Alkyl radical, C3-C8A cycloalkyl group.
The intermediate of the invention is synthesized into the double-target inhibitor by the following method:
the invention also discloses application of the double-target inhibitor in preparing a medicament for preventing and/or treating cancer or tumor-related diseases. Cancer or tumor-related diseases include breast cancer, prostate cancer, lung cancer, multiple myeloma, leukemia, stomach cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, and human glioma.
Has the advantages that: (1) the intermediate of the invention has stable chemical property, can be preserved for a long time without being shaded at room temperature, and has simple preparation condition and high reaction yield. (2) The target final products CDK6 and DYRK2 double-target inhibitors can be obtained by using the intermediate of the invention through only one-step reaction. (3) The intermediate of the invention is crucial for synthesizing the target final product CDK6 and DYRK2 double-target inhibitor.
Drawings
FIG. 1 is a graph of weight change according to the present invention;
FIG. 2 is the HE staining results of the present invention;
FIG. 3 is a graph of the results of the tumor volume test of the present invention.
Detailed Description
Example 1: synthesis of intermediate (I)
(1) Synthesis of 6- (2-chloro-5-fluoropyrimidin-4-yl) benzothiazole (I-1)
Step one, synthesis of 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzothiazole: 6-Bromobenzothiazole (0.43g, 2.0mmol) was dissolved in DMF (10mL) and pinacol boronate (0.53g,2.1mmol), Pd (dppf) Cl was added2(22mg,0.06 mmol), potassium acetate (0.59g,6.0mmol), argon was replaced three times, and the reaction was heated to 80 ℃ for 24 hours. Cooling, filtering, concentrating, and purifying with rapid silica gel column to obtain white solid 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzothiazole (0.47g, 90% yield).
1HNMR(300MHz,CDCl3)δ9.07(s,1H),8.46(s,1H),8.14(d,J=8.2Hz,1H),7.94(dd,J= 8.2,1.1Hz,1H),1.38(s,12H)。
Step two, synthesis of 6- (2-chloro-5-fluoropyrimidin-4-yl) benzothiazole (I-1): the compound 2, 4-dichloro-5-fluoropyrimidine (0.23 g,1.4mmol) was weighed into a 250mL three-necked flask, after whichAdding Pd (PPh)3)2Cl2(21mg,0.03mmol), sodium carbonate (0.27g, 2.5mmol), ethylene glycol dimethyl ether (10mL) and H2O (0.25mL), argon was replaced three times and the mixture was heated to 80 ℃. The compound 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzothiazole (0.26g,1.0mmol) is dissolved in ethylene glycol dimethyl ether (5mL), and is dripped into a three-neck flask for reaction for 16 hours. Cooled, filtered, concentrated, and purified on a flash silica gel column to give 6- (2-chloro-5-fluoropyrimidin-4-yl) benzothiazole (0.22g, 82% yield) as a yellow solid.1HNMR(300MHz,CDCl3)δ9.17(s,1H),8.84(d,J=1.7 Hz,1H),8.58(d,J=3.1Hz,1H),8.37–8.24(m,2H)。
(2) Synthesis of 6- (2-chloro-5-fluoropyrimidin-4-yl) -2-methylbenzothiazole (I-2)
Referring to the synthesis method of the compound (I-1), the yields were 90% and 84%, respectively, to finally obtain a yellow solid I-2.1H NMR(400 MHz,CDCl3)δ8.70(d,J=1.9Hz,1H),8.55(d,J=3.1Hz,1H),8.28–8.25(m,1H),8.07(d,J=8.6 Hz,1H),2.90(s,3H)。
(3) Synthesis of 6- (2-chloro-5-fluoropyrimidin-4-yl) -N-cyclopentylbenzothiazol-2-amine (I-3)
Step one, synthesizing 6-bromo-N-cyclopentyl benzothiazole-2-amine: 6-bromo-2-chlorobenzothiazole (0.50g,2.0mmol) was dissolved in DMSO (10mL), cyclopentylamine (0.19g,2.2mmol) and N-ethyldiisopropylamine (0.39g,3.0mmol) were added, argon was replaced three times, and the mixture was heated to 80 ℃ for 12 hours. Cooled, filtered, concentrated and purified on flash silica gel to give 6-bromo-N-cyclopentylbenzothiazol-2-amine (0.53g, 90% yield) as a white solid.1H NMR(400MHz,CDCl3)δ7.68(d,J=1.7Hz,1H),7.38– 7.33(m,2H),6.28(s,1H),3.98–3.93(m,1H),2.14–2.04(m,2H),1.72–1.54(m,6H)。
Step two, synthesis of 6- (2-chloro-5-fluoropyrimidin-4-yl) -N-cyclopentylbenzothiazol-2-amine (I-3): referring to the synthesis method of the compound (I-1), the yields were 88% and 83%, respectively, to finally obtain a yellow solid I-3.1H NMR(400MHz,CDCl3)δ8.49 (d,J=1.9Hz,1H),8.46(d,J=3.5Hz,1H),8.17–8.14(m,1H),7.58(d,J=8.6Hz,1H),5.88(s, 1H),4.13–4.07(m,1H),2.19–2.11(m,2H),1.77–1.61(m,6H)。
(4) Synthesis of 6- (2-chloro-5-fluoropyrimidin-4-yl) -N, N-dimethylbenzothiazol-2-amine (I-4)
Step one, synthesis of 6-bromo-N, N-dimethylbenzothiazole-2-amine: 4-bromo-2-iodoaniline (0.60g,2.0mmol), sodium dimethyldithiocarbamate dihydrate (0.72g,4.0mmol), copper acetate (0.36g,2.0mmol) and potassium carbonate (0.55g,4.0 mmol) were weighed out and dissolved in DMF (10mL) and heated to 120 ℃ for 6 h. Cooled, filtered, concentrated and purified on a flash silica gel column to give 6-bromo-N, N-dimethylbenzothiazol-2-amine (0.44g, 85% yield) as a white solid.1H NMR(400MHz,CDCl3)δ7.69(d,J= 1.9Hz,1H),7.41–7.35(m,2H),3.20(s,6H)。
Step two, synthesis of 6- (2-chloro-5-fluoropyrimidin-4-yl) -N, N-dimethylbenzothiazol-2-amine (I-4): reference Synthesis method of Compound (I-1), yields 88% and 80%, finally obtained was I-4 as a yellow solid.1H NMR(400MHz,CDCl3)δ8.49(d,J= 1.9Hz,1H),8.45(d,J=3.6Hz,1H),8.17–8.14(m,1H),7.62(d,J=8.7Hz,1H),3.27(s,6H)。
(5) Synthesis of 6- (2-chloro-5-fluoropyrimidin-4-yl) -N, N-diethylbenzothiazol-2-amine (I-5)
Step one, synthesis of 6-bromo-N, N-diethylbenzothiazole-2-amine: 4-bromo-2-iodoaniline (0.60g,2.0mmol), sodium diethyldithiocarbamate trihydrate (0.90g,4.0mmol), copper acetate (0.36g,2.0mmol) and potassium carbonate (0.55g,4.0 mmol) were weighed out and dissolved in DMF (10mL) and heated to 120 ℃ for 6 h. Cooled, filtered, concentrated and purified on a flash silica gel column to give 6-bromo-N, N-dimethylbenzothiazol-2-amine (0.46g, 80% yield) as a white solid.
Step two, synthesis of 6- (2-chloro-5-fluoropyrimidin-4-yl) -N, N-diethylbenzothiazol-2-amine (I-5): reference Synthesis method of Compound (I-1), yields 90% and 82%, finally obtained was I-5 as a yellow solid.1H NMR(300MHz,CDCl3)δ8.44(dd,J= 8.8,2.7Hz,2H),8.13(d,J=8.6Hz,1H),7.58(d,J=8.7Hz,1H),3.61(q,J=7.2Hz,4H),1.32(t,J=7.2Hz,6H)。
The intermediate compound I-1-I-5 prepared by the embodiment of the invention has unchanged performance after being stored for more than 6 months at normal temperature in a non-light-shielding environment.
Example 2: synthesis of intermediate (B)
(6) Synthesis of (6-aminopyridin-3-yl) (4-ethylpiperazin-1-yl) methanone (B-1)
6-Aminonicotinic acid (0.28g,2.0mmol), N, N' -carbonyldiimidazole (0.39g,2.4mmol) were weighed out and dissolved in DMF (5mL) and reacted at 70 ℃ for 10min, stirred at room temperature for 1h, N-ethylpiperazine (0.46g,4.0mmol) was added, reacted overnight at room temperature, concentrated and purified on silica gel to give the compound 6-aminopyridin-3-yl) (4-ethylpiperazin-1-yl) methanone (0.40g, 85% yield).1H NMR (300MHz,CDCl3)δ8.19–8.17(m,1H),7.57–7.54(m,1H),6.51–6.48(m,0.9Hz,1H),4.79(s, 2H),3.73–3.60(m,4H),2.49–2.42(m,6H),1.13–1.08(m,3H)。
(7) Synthesis of 5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-amine (B-2)
2-amino-5-formylpyridine (0.32g,2.6mmol) and N-ethylpiperazine (0.45g,3.9mmol) were dissolved in 1, 2-dichloroethane (20mL) and stirred at room temperature for 2h, followed by addition of sodium triacetoxyborohydride (0.87g,4.1mmol) and stirring at room temperature for 8 h. Quenching was performed by addition of 1M NaOH (30mL), extraction with DCM (20mL × 3), drying over anhydrous sodium sulfate, concentration and column chromatography (DCM/MeOH ═ 10:1) gave compound 5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-amine (0.52g, 91%).1HNMR(300MHz,CDCl3) δ7.94(d,J=2.3Hz,1H),7.40(dd,J=8.3,2.4Hz,1H),6.46(d,J=8.3Hz,1H),4.57(s,2H),3.36(s, 2H),2.47–2.37(m,10H),1.07(t,J=7.2Hz,3H)。
(8) Synthesis of t-butyl 4- ((6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (B-3)
Synthesis method of reference Compound (B-2), yield was 89%.1HNMR(300MHz,CDCl3):δ7.94(d,J=2.3 Hz,1H),7.40(dd,J=8.4,2.3Hz,1H),6.48(d,J=8.4Hz,1H),4.54(s,2H),3.40(t,J=5.1Hz,4H), 3.36(s,2H),2.35(t,J=5.1Hz,4H),1.45(s,9H)。
(9) Synthesis of t-butyl 4- (6-aminonicotinoyl) piperazine-1-carboxylate (B-4)
Synthesis method of reference Compound (B-1), yield was 87%.1H NMR(300MHz,CDCl3)δ8.18(d,J=2.2Hz, 1H),7.56(dd,J=8.5,2.2Hz,1H),6.51(d,J=8.5Hz,1H),4.76(s,2H),3.65–3.56(m,4H),3.48– 3.42(m,4H),1.48(s,9H)。
(10) Synthesis of t-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate (B-5)
Step one, synthesizing tert-butyl 4- (6-nitropyridine-3-yl) piperazine-1-carboxylate: 5-bromo-2-nitropyridine (0.41g,2.0 mmol), tert-butylpiperazine-1-carboxylate (0.48g,2.6mmol) and triethylamine (0.41g,4.0mmol) were weighed out and dissolved in DMSO (5mL), heated to 60 ℃ and reacted for 18 h. The mixture was cooled, filtered, concentrated and purified by flash silica gel column to give tert-butyl 4- (6-nitropyridin-3-yl) piperazine-1-carboxylate (0.49g, 80% yield).1H NMR(400MHz,CDCl3)δ8.17–8.13(m,2H),7.22(dd,J =9.2,3.1Hz,1H),3.66–3.64(m,4H),3.49–3.46(m,4H),1.49(s,9H)。
Step two, synthesizing tert-butyl 4- (6-aminopyridine-3-yl) piperazine-1-carboxylate: tert-butyl 4- (6-nitropyridin-3-yl) piperazine-1-carboxylate (0.31g,1.0mmol), reduced iron powder (0.17g,3.0mmol) and ammonium chloride (0.49g,9.0mmol) were weighed out and dissolved in 70% ethanol (10mL) and heated to 70 ℃ for 6 h. Cooled, filtered, concentrated and purified on a flash silica gel column to give the compound tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate (0.24g, 85% yield).1H NMR(300MHz,CDCl3)δ7.78(d,J= 2.9Hz,1H),7.17(dd,J=8.8,2.9Hz,1H),6.49(d,J=8.8Hz,1H),4.19(s,2H),3.59–3.55(m,4H), 2.98–2.94(m,4H),1.48(s,9H)。
(11) Synthesis of 5- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridin-2-amine (B-6)
Synthesis method of reference Compound (B-2), yield was 90%.1H NMR(400MHz,CDCl3)δ8.10–7.79(m,1H), 7.40(d,J=8.3Hz,1H),6.57(s,1H),4.55(s,2H),3.41(s,2H),3.22(t,J=4.9Hz,4H),2.77(s,3H), 2.53(t,J=5.0Hz,4H)。
(12) Synthesis of Ethyl 4- ((6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (B-7)
Synthesis method of reference Compound (B-2), yield was 86%.1H NMR(400MHz,CDCl3)δ7.87(d,J=2.2Hz, 1H),7.43(dd,J=8.5,2.3Hz,1H),6.51(d,J=8.5Hz,1H),5.71(s,2H),4.12(q,J=7.1Hz,2H), 3.46(t,J=5.1Hz,4H),3.36(s,2H),2.37(t,J=5.1Hz,4H),1.25(t,J=7.1Hz,3H)。
(13) Synthesis of 5- ((4-isopropylpiperazin-1-yl) methyl) pyridin-2-amine (B-8)
Synthesis method of reference Compound (B-2), yield was 81%.1H NMR(400MHz,CDCl3)δ7.88(d,J=2.2Hz, 1H),7.43(dd,J=8.4,2.2Hz,1H),6.48(d,J=8.4Hz,1H),4.95(s,2H),3.39(s,2H),2.88–2.80(m, 1H),2.72–2.51(m,8H),1.10(d,J=6.6Hz,6H)。
(14) Synthesis of (6-aminopyridin-3-yl) (4-isopropylpiperazin-1-yl) methanone (B-9)
Synthesis method of reference Compound (B-1), yield was 85%.1H NMR(300MHz,CDCl3)δ8.18(s,1H),7.55 (d,J=8.4Hz,1H),6.49(dd,J=8.6,2.1Hz,1H),4.86(s,2H),3.67–3.61(m,4H),2.77–2.71(m, 1H),2.55–2.51(m,4H),1.05(d,J=6.0Hz,6H)。
Example 3: synthesis of dual target inhibitors
(1) Synthesis of (6- ((4- (benzothiazol-6-yl) -5-fluoropyrimidin-2-yl) amine) pyridin-3-yl) (4-ethylpiperazin-1-yl) methanone (NO. 1):
the compounds 6- (2-chloro-5-fluoropyrimidin-4-yl) benzothiazole (133mg,0.5mmol) and 6-aminopyridin-3-yl) (4-ethylpiperazin-1-yl) methanone (141mg,0.6mmol) were dissolved in dioxane (5mL) and Pd was added2(dba)3(23mg,0.025mmol), Xantphos (58mg,0.1mmol), cesium carbonate (326mg,1.0mmol), argon replacement three times, heating to 100 ℃ and reaction for 12h. Cool, filter and concentrate column chromatography (DCM to DCM/MeOH ═ 10:1) to give compound (6- ((4- (benzothiazol-6-yl) -5-fluoropyrimidin-2-yl) amine) pyridin-3-yl) (4-ethylpiperazin-1-yl) methanone (88mg, 38% yield).1H NMR(300MHz,CDCl3)δ9.68(s, 1H),9.15(s,1H),8.76–8.75(m,1H),8.61–8.58(m,2H),8.52(dd,J=8.7,0.9Hz,1H),8.33–8.26 (m,2H),7.86(dd,J=8.7,2.3Hz,1H),3.80–3.61(m,4H),2.51–2.44(m,6H),1.12(t,J=7.2Hz, 3H)。
(2) Synthesis of 4- (benzothiazol-6-yl) -5-fluoro-N- (5- (piperazin-1-yl) pyridin-2-yl) pyrimidin-2-amine hydrochloride (NO. 2):
synthesis of tert-butyl 4- (6- ((4- (benzothiazol-6-yl) -5-fluoropyrimidin-2-yl) amine) pyridin-3-yl) piperazine-1-carboxylate:
synthesis of reference Compound (NO.1), yield was 47%.1H NMR(400MHz,CDCl3)δ9.15(s,1H),8.77 –8.76(m,1H),8.45(d,J=3.4Hz,1H),8.33–8.26(m,3H),8.04–8.02(m,2H),7.38(dd,J=9.1, 3.0Hz,1H),3.63–3.60(m,4H),3.11–3.09(m,4H),1.49(s,9H)。
Tert-butyl 4- (6- ((4- (benzothiazol-6-yl) -5-fluoropyrimidin-2-yl) amine) pyridin-3-yl) piperazine-1-carboxylate is reacted for 2h at 0 ℃ by introducing HCl gas. After the reaction was completed, concentration was carried out to obtain a compound, which was 4- (benzothiazol-6-yl) -5-fluoro-N- (5- (piperazin-1-yl) pyridin-2-yl) pyrimidin-2-amine hydrochloride in 100% yield.1H NMR(400MHz,DMSO-d6)δ11.43(s,1H), 9.60(s,1H),9.33(s,2H),8.91(s,1H),8.87(d,J=3.3Hz,1H),8.33–8.23(m,2H),8.07(d,J=9.4 Hz,1H),8.01(d,J=2.9Hz,1H),7.85(d,J=9.4Hz,1H),3.44(t,J=5.1Hz,4H),3.27–3.25(m, 4H)。
(3) Synthesis of 4- (benzothiazol-6-yl) -5-fluoro-N- (5- ((4-isopropylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (NO. 3):
synthesis of reference Compound (NO.1), yield was 48%.1H NMR(400MHz,CDCl3)δ9.15(s,1H),8.78 (d,J=1.6Hz,1H),8.48(d,J=3.5Hz,1H),8.38(dd,J=8.5,0.8Hz,1H),8.35–8.32(m,1H),8.30 –8.27(m,1H),8.25–8.23(m,2H),7.73(dd,J=8.6,2.3Hz,1H),3.50(s,2H),2.68–2.44(m,9H), 1.06(d,J=6.5Hz,6H)。
(4) Synthesis of (6- ((5-fluoro-4- (2-methylbenzothiazol-6-yl) pyrimidin-2-yl) amine) pyridin-3-yl) (piperazin-1-yl) methanone hydrochloride (NO. 4):
synthesis of tert-butyl 4- (6- ((5-fluoro-4- (2-methylbenzothiazol-6-yl) pyrimidin-2-yl) amine) nicotinoyl) piperazine-1-carboxylate:
synthesis of reference Compound (NO.1), yield was 40%.1H NMR(400MHz,CDCl3)δ9.11(s,1H),8.63 (s,1H),8.55–8.51(m,3H),8.24(d,J=8.6Hz,1H),8.09(dd,J=8.7,3.3Hz,1H),7.86(dt,J=8.9, 2.6Hz,1H),3.67–3.46(m,8H),2.91(s,3H),1.48(s,9H)。
Referring to the synthesis method of the compound (No.2), hydrochloride of (6- ((5-fluoro-4- (2-methylbenzothiazol-6-yl) pyrimidin-2-yl) amine) pyridin-3-yl) (piperazin-1-yl) methanone was synthesized in a yield of 100%.1H NMR(300MHz,DMSO-d6)δ12.04(s,1H),9.85(s, 2H),8.92(d,J=2.9Hz,1H),8.81(s,1H),8.60(s,1H),8.28(d,J=9.1Hz,1H),8.21(d,J=8.7Hz, 1H),8.13(d,J=8.6Hz,1H),8.06(d,J=9.0Hz,1H),3.83–3.77(m,4H),3.20–3.14(m,4H),2.88 (s,3H)。
(5) Synthesis of (6- ((4- (2- (cyclopentylamine) benzothiazol-6-yl) -5-fluoropyrimidin-2-yl) amine) pyridin-3-yl) (4-isopropylpiperazin-1-yl) methanone (NO. 5):
synthesis of reference Compound (NO.1), yield was 48%.1H NMR(400MHz,CDCl3)δ9.04(s,1H),8.52 –8.39(m,4H),8.05(dd,J=8.4,1.9Hz,1H),7.85(dt,J=8.6,2.2Hz,1H),7.64(dd,J=8.6,1.8Hz, 1H),6.19(s,1H),4.09–4.04(m,1H),3.73–3.62(m,4H),2.79–2.75(m,1H),2.60–2.55(m,4H), 2.18–2.13(m,2H),1.78–1.64(m,6H),1.08(d,J=6.6Hz,6H)。
(6) Synthesis of (6- ((4- (2- (dimethylamine) benzothiazol-6-yl) -5-fluoropyrimidin-2-yl) amine) pyridin-3-yl) (4-ethylpiperazin-1-yl) methanone (NO. 6):
6- (2-chloro-5-fluoropyrimidin-4-yl) -N, N-dimethylbenzothiazol-2-amine (154mg,0.5mmol) and 6-aminopyridin-3-yl) (4-ethylpiperazin-1-yl) methanone (141mg,0.6mmol) were dissolved in dioxane (5mL), and Pd was added2(dba)3(23mg,0.025mmol), BINAP (31mg,0.05mmol), sodium tert-butoxide(96mg,1.0mmol), argon was replaced three times, heated to 100 ℃, reacted for 12h, cooled, filtered and concentrated to column chromatography (DCM-DCM/MeOH ═ 10:1) to give the compound (6- ((4- (2- (dimethylamino) benzothiazol-6-yl) -5-fluoropyrimidin-2-yl) amine) pyridin-3-yl) (4-ethylpiperazin-1-yl) methanone (139mg, 55% yield).1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.69(d,J=3.8Hz,1H),8.52(d,J=2.0Hz,1H),8.35 (d,J=2.4Hz,1H),8.31(d,J=8.7Hz,1H),8.06(d,J=8.6Hz,1H),7.86(dd,J=8.6,2.4Hz,1H), 7.59(d,J=8.6Hz,1H),3.59–3.47(m,4H),3.21(s,6H),2.44–2.34(m,6H),1.01(t,J=7.1Hz, 3H)。
(7) Synthesis of (6- ((4- (2- (dimethylamine) benzothiazol-6-yl) -5-fluoropyrimidin-2-yl) amine) pyridin-3-yl) (4-isopropylpiperazin-1-yl) methanone (NO. 7):
synthesis of reference Compound (NO.1), yield was 44%.1H NMR(400MHz,CDCl3)δ8.73(s,1H),8.52 –8.48(m,2H),8.45–8.44(m,2H),8.16–8.13(m,1H),7.85(dd,J=8.7,2.4Hz,1H),7.65(d,J= 8.6Hz,1H),3.75–3.63(m,4H),3.27(s,6H),2.79–2.75(m,1H),2.62–2.55(m,4H),1.08(d,J= 6.5Hz,6H)。
(8) Synthesis of (6- ((4- (2- (diethylamine) benzothiazol-6-yl) -5-fluoropyrimidin-2-yl) amine) pyridin-3-yl) (4-ethylpiperazin-1-yl) methanone (NO. 8):
synthesis of reference Compound (NO.1), yield was 44%.1H NMR(300MHz,CDCl3)δ8.56(s,1H),8.50 (d,J=8.7Hz,1H),8.47(d,J=2.3Hz,1H),8.43–8.41(m,2H),8.13(dd,J=8.7,1.7Hz,1H),7.84 (dd,J=8.7,2.4Hz,1H),7.62(d,J=8.6Hz,1H),3.80–3.60(m,8H),2.54–2.47(m,6H),1.33(t,J =7.1Hz,6H),1.13(t,J=7.1Hz,3H)。
(9) Synthesis of N, N-diethyl-6- (2- ((5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) amine) -5-fluoropyrimidin-4-ylbenzothiazol-2-amine (NO. 9):
synthesis of reference Compound (NO.1), yield was 38%.1H NMR(400MHz,CDCl3)δ8.69(s,1H),8.43 –8.39(m,3H),8.29(d,J=2.3Hz,1H),8.15–8.12(m,1H),7.71(dd,J=8.6,2.3Hz,1H),7.62(d,J =8.6Hz,1H),3.63(q,J=7.2Hz,4H),3.50(s,2H),2.53–2.42(m,10H),1.33(t,J=7.1Hz,6H), 1.10(t,J=7.2Hz,3H)。
(10) Synthesis of N, N-diethyl-6- (5-fluoro-2- ((5- (piperazin-1-ylmethyl) pyridin-2-yl) amine) pyrimidin-4-yl) benzothiazol-2-amine hydrochloride (NO. 10):
synthesis of tert-butyl 4- ((6- ((4- (2- (diethylamine) benzothiazol-6-yl) -5-fluoropyrimidin-2-yl) amine) pyridin-3-yl) methyl) piperazine-1-carboxylic acid ester:
synthesis method of reference Compound (I-1), yield was 48%.1H NMR(400MHz,CDCl3)δ8.45(s,1H),8.43 –8.39(m,3H),8.26(d,J=2.2Hz,1H),8.15–8.12(m,1H),7.73(d,J=8.2Hz,1H),7.62(d,J=8.6 Hz,1H),3.63(q,J=7.1Hz,4H),3.51(s,2H),3.46–3.44(m,4H),2.44–2.41(m,4H),1.46(s,9H), 1.33(t,J=7.1Hz,6H)。
Synthesis of N, N-diethyl-6- (5-fluoro-2- ((5- (piperazin-1-ylmethyl) pyridin-2-yl) amine) pyrimidin-4-yl) benzothiazol-2-amine hydrochloride:
synthesis method of reference Compound (NO.2), yield was 100%.1H NMR(400MHz,DMSO-d6)δ11.71(s,1H), 9.94(s,2H),8.80(d,J=3.6Hz,1H),8.65(d,J=2.2Hz,1H),8.56(d,J=1.8Hz,1H),8.42(dd,J= 8.9,2.2Hz,1H),8.11–8.08(m,1H),8.01(d,J=8.9Hz,1H),7.65(d,J=8.6Hz,1H),4.51(s,2H), 3.63(q,J=7.1Hz,4H),3.50–3.44(m,8H),1.26(t,J=7.1Hz,6H)。
(11) Synthesis of (6- ((4- (2- (diethylamine) benzothiazol-6-yl) -5-fluoropyrimidin-2-yl) amine) pyridin-3-yl) (piperazin-1-yl) methanone (NO. 11):
synthesis of tert-butyl 4- (6- ((4- (2- (diethylamine) benzothiazol-6-yl) -5-fluoropyrimidin-2-yl) amine) nicotinoyl) piperazine-1-carboxylate:
synthesis of reference Compound (NO.1), yield was 40%.1H NMR(400MHz,CDCl3)δ8.99(s,1H),8.53 (dd,J=8.7,0.8Hz,1H),8.51(dd,J=2.4,0.9Hz,1H),8.45(d,J=3.8Hz,1H),8.42(d,J=1.9Hz, 1H),8.15–8.12(m,1H),7.84(dd,J=8.8,2.4Hz,1H),7.64(d,J=8.6Hz,1H),3.67–3.61(m,8H), 3.50–3.47(m,4H),1.48(s,9H),1.34(t,J=7.1Hz,6H)。
Synthesis of (6- ((4- (2- (diethylamine) benzothiazol-6-yl) -5-fluoropyrimidin-2-yl) amine) pyridin-3-yl) (piperazin-1-yl) methanone:
synthesis method of reference Compound (NO.2), yield was 100%.1H NMR(400MHz,DMSO-d6)δ11.78(s,1H), 10.03(s,1H),9.88(s,2H),8.83(d,J=3.6Hz,1H),8.60(d,J=1.8Hz,1H),8.58(d,J=2.1Hz,1H), 8.23(dd,J=8.9,2.2Hz,1H),8.13–8.07(m,2H),7.71(d,J=8.6Hz,1H),3.86–3.78(m,3H),3.67 (q,J=7.1Hz,4H),3.19–3.15(m,3H),1.27(t,J=7.1Hz,6H)。
(12) Synthesis of (6- ((4- (2- (diethylamine) benzothiazol-6-yl) -5-fluoropyrimidin-2-yl) amine) pyridin-3-yl) (4-isopropylpiperazin-1-yl) methanone (NO. 12):
synthesis of reference Compound (NO.1), yield was 47%.1H NMR(300MHz,CDCl3)δ9.69(s,1H),8.60 (d,J=2.3Hz,1H),8.54(d,J=8.7Hz,1H),8.50(d,J=3.7Hz,1H),8.41(s,1H),8.12(d,J=8.6Hz, 1H),7.86(dd,J=8.7,2.3Hz,1H),7.62(d,J=8.6Hz,1H),3.77–3.59(m,8H),2.78–2.72(m,1H), 2.59–2.54(m,4H),1.32(t,J=7.1Hz,6H),1.07(d,J=6.4Hz,6H)。
Third, biological evaluation experiment
(1) CDK6 kinase activity analysis and detection method
The experiment was carried out using the Lance Ultra method from Perkinelmer. In the assay plate, protein kinase, Ulight-labeled polypeptide substrate, ATP and compound were mixed and the reaction was incubated. Thereafter, EDTA was added to terminate the reaction, and an europium (Eu) chelate-labeled antibody was added to carry out detection. The experiment was analyzed by an Envision instrument from PerkinElmer in the TR-FRET format. After excitation at 320/340nm, fluorescent signals at 665nm and 615nm can be emitted. Eu can be transferred to the adjacent fluorescent substance ULight receptor, and the emitted light is detected.
Measured IC50The values are shown in table 1 below, and it can be seen from the experimental results that the compounds of the examples of the present invention have a strong inhibitory activity against CDK6 kinase activity.
TABLE 1 IC of the Compounds of the invention on CDK6 kinase Activity50Measured value
Compound (I) | IC50(nM) | Compound (I) | IC50(nM) | Compound (I) | IC50(nM) |
NO.1 | 144 | NO.5 | 74 | NO.9 | 15 |
NO.2 | 129 | NO.6 | 18 | NO.10 | 45 |
NO.3 | 175 | NO.7 | 57 | NO.11 | 39 |
NO.4 | 93 | NO.8 | 14 | NO.12 | 8 |
(2) DYRK2 kinase activity analysis and detection method
The compounds of the invention were tested for DYRK2 kinase inhibitory activity. The method is briefly described as follows (see: Banerjee S, Wei T, Wang J, et al. inhibition of product-specific phosphorylation-regulated kinase 2 tissues 26S protease-amplified genetic improvement [ J ]. Proceedings of the National Academy of Sciences,2019,116(49): 24881-24891):
1) different concentrations of compound were added to 384-well plates, the wells were re-plated, followed by DYRK2 protein, the substrates Woodtide (KKISGRLSPIMTEQ) and33p-gamma ATP, mixing evenly;
2) incubation for 30 minutes at room temperature;
3) the reaction was stopped with 0.5M (3%) orthophosphoric acid solution and then transferred to a P81 plate, followed by washing with 50mM orthophosphoric acid solution;
4)IC50results were calculated using GraphPad Prism software.
Measured IC50The values are shown in table 2 below, and it can be seen from the experimental results that the example compounds of the present invention have strong inhibitory activity against DYRK2 kinase activity.
TABLE 2 IC of Compounds of the invention on DYRK2 kinase Activity50Measured value
Compound (I) | IC50(nM) | Compound (I) | IC50(nM) | Compound (I) | IC50(nM) |
NO.1 | 35 | NO.5 | 106 | NO.9 | 197 |
NO.2 | 85 | NO.6 | 9 | NO.10 | 290 |
NO.3 | 263 | NO.7 | 16 | NO.11 | 39 |
NO.4 | 27 | NO.8 | 14 | NO.12 | 15 |
(3) Measurement of inhibition of proliferation of various cancer cells
The inhibition of cell proliferation of 14 cells of a compound on human breast cancer (MCF-7, triple negative breast cancer MDA-MB-231) cell line, multiple myeloma (RPMI8226) cell line, leukemia (K562) cell line, gastric cancer (MGC-803) cell line, ovarian cancer (SK-OV-3) cell line, colon cancer (HT-29) cell line, liver cancer (HepG2) cell line, pancreatic cancer (Panc-1) cell line, human glioma (U251) cell line, lung cancer (A-549, non-small cell lung cancer NCI-H1299) cell line, and prostate cancer (PC-3, Du-145) cell line, etc. was tested by the following method.
The experimental steps are as follows:
the inhibition of the proliferation of various cancer cells by the compound is measured according to the MTT method, and the half inhibition concentration IC of the cell proliferation inhibition activity of the compound is obtained50。
1) Cells in logarithmic growth phase were grown at 1X 105cells/well were seeded in 96-well plates at 37 ℃ with 5% CO2Culturing under the condition that the cells are 90% fused, and then incubating for 2h by using serum-free DMEM medium or RPMI-1640 medium or L-15 medium or F12K medium or MEM medium or F-12 medium or IMDM medium to synchronize the cells (each cell adopts the corresponding medium);
2) to the plates 100. mu.L of a solution of the test compound in different concentrations diluted in a gradient was added and the plates were incubated at 37 ℃ in 5% CO2Incubating for 72 hours under incubator conditions;
3) 4h before the end of incubation, 20. mu.L of MTT solution (5mg/mL) was added to each well. After incubation is finished, discarding supernatant of each well, adding 150 mu L DMSO into each well, oscillating on a cell oscillator for 10min, and measuring OD (optical density) by using an enzyme-labeling instrument after crystals are fully dissolved570The inhibition rate is (control group OD value-experimental group OD value)/control group OD value × 100%;
4) after data were obtained, GraphPad Prism 6 was fitted to obtain IC50。
The compound No.6 and a marketed drug CDK4/6 inhibitor Palbociclib are tested for the proliferative activity of various cancer cells, and the IC is measured50The values are shown in Table 3. It can be seen that the compound No.6 has 14 cell proliferation inhibition effects on human breast cancer (MCF-7, triple negative breast cancer MDA-MB-231) cell lines, multiple myeloma (RPMI8226) cell lines, leukemia (K562) cell lines, stomach cancer (MGC-803) cell lines, ovarian cancer (SK-OV-3) cell lines, colon cancer (HT-29) cell lines, liver cancer (HepG2) cell lines, pancreatic cancer (Panc-1) cell lines, human glioma (U251) cell lines, lung cancer (A-549, non-small cell lung cancer NCI-H1299) cell lines, prostate cancer (PC-3, Du-145) cell lines and the like, and the proliferation inhibition effects on the 14 cells are obviously stronger than that of the commercial CDK4/6 inhibitor Palbociclib.
TABLE 3. formation ofCompound (I) inhibits cell proliferation activity IC in a variety of cancers50
(4) Acute toxicity assay for compounds
The test animals were: an ICR mouse; 18-22 g; half of a female and a half of a male; the number of the devices is 40.
Group dose setting: (1) control group: perfusing into normal saline with equal amount for administration for 1 time, wherein the administration is carried out on 10 mice, and the mice are half female and half male; (2) 2500mg/kg group: the stomach-filling medicine is administrated for 1 time, 10 mice are administrated, and the male and female are half each; (3)5000mg/kg group: the stomach-filling medicine is administrated for 1 time, 10 mice are administrated, and the male and female are half each; (4)10000mg/kg group: the gastric lavage drug is administered for 1 time, 10 mice, and male and female halves.
TABLE 4 groups of dose settings
Laboratory environment: the room temperature is 24 +/-2 ℃, and the relative humidity is 60-70%. Observation indexes are as follows: the test drug (compound No.6) was administered 1 time at the dose shown in table 4, and the toxic symptoms and death of the mice were recorded and dead animals were necropsied. The observation period was 14 days. The results show that: within 12h after each group of mice was administered, no abnormality was observed in the animals. No animal death was observed within 24h of administration, and no animal death was observed after 14 days of administration. No other obvious abnormalities were observed.
The body weight change is shown in figure 1, compared with the control group, 2500mg/kg, 5000mg/kg and 10000mg/kg of the gavage administration have no obvious toxic reaction.
The HE staining result is shown in FIG. 2, and the compound No.6 has no obvious toxicity to the major organs such as heart, liver, spleen, lung and kidney.
(5) Compound pharmacokinetic assay
Weighing a test sample, placing the test sample in a sterile vial, adding 250 mu LDMSO, adding 10 mu L methanesulfonic acid, dissolving, adding 4.78mL 5% glucose injection, performing ultrasonic treatment and shaking to mix uniformly to prepare a test sample solution of 2mg/mL, and taking the solution as an intragastric administration preparation. Separately, 0.5mL of 2mg/mL sample solution was added to 4.5mL of 5% glucose injection, and the mixture was shaken and mixed to prepare 0.2mg/mL sample solution as an intravenous injection preparation.
TABLE 5 pharmacokinetic parameter records
(6) Determination of anti-lung cancer Activity of Compounds
The drug is compound NO.6 and a marketed drug CDK4/6 inhibitor Palbociclib. The cell strain is human non-small cell lung cancer cell strain A-549 which is cultured in RPMI-1640 culture medium containing 10% fetal bovine serum. The tested animals are SPF BALB/c nude mice; male; each group had 5. The drug dose settings are as in table 6.
TABLE 6 drug dose configuration
The preparation method of the medicine comprises the following steps:
compound No.6(150 mg/kg): 30mg of the powder of the compound to be tested is weighed and dissolved in 2mL of normal saline to prepare the medicine with the concentration of 15mg/mL, and the medicine is orally administrated by gastric gavage, and the administration volume is 0.2mL20 g.
Compound No.6(300 mg/kg): 60mg of the powder of the compound to be tested is weighed and dissolved in 2mL of normal saline to prepare the medicine with the concentration of 30mg/mL, and the medicine is orally taken and administered by gastric gavage, and the administration volume is 0.2mL/20 g.
Palbociclib (150 mg/kg): 30mg of the powder of the compound to be tested is weighed and dissolved in 2mL of normal saline to prepare the medicine with the concentration of 15mg/mL, and the medicine is orally taken and administered by gastric gavage, and the administration volume is 0.2mL/20 g.
The experimental method comprises the following steps: the nude mouse lung cancer transplantation tumor model is established by inoculating a human lung cancer cell strain A549 to axillary subcutaneous tissues of nude mice. A549 cells in logarithmic growth phase are taken and inoculated to the right axillary subcutaneous of 30 nude mice under the aseptic condition, and the inoculation amount of the cells is 5 multiplied by 106One/only. Measuring the diameter of the transplanted tumor by using a vernier caliper until the tumor grows to 80mm3On the left and right, 20 tumor-bearing nude mice with good growth state and uniform tumor size were selected and randomly divided into 4 groups, 5 mice in each group, namely, a model group, a compound No.6(150mg/kg) low dose group, a compound No.6(300mg/kg) high dose group, and a positive drug Palbociclib (150mg/kg) group. The tested drug compound NO.6 is administrated by intragastric administration in a low-dose and high-dose group and the positive drug Palbociclib, the administration is carried out once in 2 days, and the administration is carried out by intragastric administration in a model group for solvent control with equal volume. The antitumor effect of the test substance is dynamically observed by using a method for measuring the tumor size. The number of tumor diameters was measured every other day, and the weight of the nude mice was measured simultaneously with the tumor diameter. Mice were sacrificed on day 22, and tumor mass was surgically removed and fixed with 10% formaldehyde and stored in liquid nitrogen for further use.
The experimental results show that: the test drug compound No.6(150mg/kg) low dose group and the compound No.6(300mg/kg) high dose group showed relative tumor proliferation rates T/C (%) of 44.8% and 35.9% and tumor growth inhibition rates of 55.2% and 64.1% respectively, as compared with the model group. The positive drug Palbociclib is administrated by intragastric administration at the dose of 150mg/kg, the relative tumor proliferation rate T/C (%) is 39.6%, and the tumor inhibition rate is 60.4%.
Therefore, the test drug prepared from the compound NO.6 has obvious inhibition effect on the growth of the xenograft tumor of the nude mouse of the human lung cancer A549, and the effect is better than that of the positive control drug Palbociclib.
(7) Determination of anti-prostate cancer (PC3) Activity of Compounds
The drug is compound NO.6 and a marketed drug CDK4/6 inhibitor Palbociclib. The cell strain is human prostatic cancer PC-3 cell. The tested animals are SPF BALB/c nude mice; male; each group had 8. The drug dose settings are as in table 7.
TABLE 7 drug dose configuration
The preparation method of the medicine comprises the following steps:
compound No.6(100 mg/kg): 20mg of the powder of the compound to be tested is weighed and dissolved in 2mL of normal saline to prepare the medicine with the concentration of 10mg/mL, and the medicine is orally administrated by gastric gavage, and the administration volume is 0.2mL20 g.
Compound No.6(200 mg/kg): 40mg of the powder of the compound to be tested is weighed and dissolved in 2mL of normal saline to prepare the medicine with the concentration of 20mg/mL, and the medicine is orally administrated by gastric gavage, and the administration volume is 0.2mL20 g.
Palbociclib (100 mg/kg): 20mg of the powder of the compound to be tested is weighed and dissolved in 2mL of normal saline to prepare the medicine with the concentration of 10mg/mL, and the medicine is orally administrated by gastric gavage, and the administration volume is 0.2mL20 g.
The experimental method comprises the following steps: the nude mouse transplantation tumor model of human prostate cancer is established by inoculating human prostate cancer PC-3 cells to the axillary subcutaneous part of nude mouse. Inoculating PC-3 cells in logarithmic growth phase into right axillary subcutaneous tissue of 40 nude mice under aseptic condition, wherein the inoculation amount of the cells is 5 × 106One/only. Measuring the diameter of the transplanted tumor by using a vernier caliper until the tumor grows to 90mm3On the left and right, 32 tumor-bearing nude mice with good growth state and uniform tumor size were selected and randomly divided into 4 groups of 8 mice, i.e., a model group, a compound No.6(100mg/kg) low dose group, a compound No.6(200mg/kg) high dose group, and a positive drug Palbociclib (100mg/kg) group. The test drug compound NO.6 is administrated by intragastric administration in low dose and high dose groups and the positive drug Palbociclib, once a day, and the model group is administrated by intragastric administration with equal volume of solvent control. The antitumor effect of the test substance is dynamically observed by using a method for measuring the tumor size. The tumor diameter was measured every other day, and the weight of the nude mice was measured at the same time as the tumor diameter. Mice were sacrificed on day 29 and surgery was performedStripping tumor blocks, fixing with 10% formaldehyde, and storing in liquid nitrogen.
The experimental results show that: the test drug compound No.6(100mg/kg) low dose group and the compound No.6(200mg/kg) high dose group showed relative tumor proliferation rates T/C (%) of 35.7% and 23.4% and tumor growth inhibition rates of 64.3% and 76.6% respectively, as compared with the model group. The positive drug Palbociclib is administrated by intragastric administration at the dose of 100mg/kg, the relative tumor proliferation rate T/C (%) is 35.5%, and the tumor inhibition rate is 64.5%.
Therefore, the test drug prepared from the compound NO.6 has obvious inhibition effect on the growth of the human prostate cancer PC3 nude mouse xenograft tumor, and the effect is better than that of a positive control drug Palbociclib.
(8) Determination of the Activity of Compounds against prostate cancer (Du-145)
The drugs are compound No.6, the marketed drug CDK4/6 inhibitor Palbociclib and the first line prostate cancer treatment drug Enzalutamide. The cell line is human prostatic cancer Du-145 cells. The tested animals are SPF BALB/c nude mice; male; each group had 10. The drug dose settings are as in table 8.
TABLE 8 drug dose configuration
The preparation method of the medicine comprises the following steps:
compound No.6(100 mg/kg): 20mg of the powder of the compound to be tested is weighed and dissolved in 2mL of normal saline to prepare the medicine with the concentration of 10mg/mL, and the medicine is orally taken and administered by gastric gavage, and the administration volume is 0.2mL/20 g.
Compound No.6(200 mg/kg): 40mg of the powder of the compound to be tested is weighed and dissolved in 2mL of normal saline to prepare the medicine with the concentration of 20mg/mL, and the medicine is orally taken and administered by gastric gavage, and the administration volume is 0.2mL/20 g.
Palbociclib (100 mg/kg): 20mg of the powder of the compound to be tested is weighed and dissolved in 2mL of normal saline to prepare the medicine with the concentration of 10mg/mL, and the medicine is orally taken and administered by gastric gavage, and the administration volume is 0.2mL/20 g.
Enzalutamide (100 mg/kg): 20mg of the powder of the compound to be tested is weighed and dissolved in 2mL of normal saline to prepare the medicine with the concentration of 10mg/mL, and the medicine is orally taken and administered by gastric gavage, and the administration volume is 0.2mL/20 g.
The experimental method comprises the following steps: the model of human prostate cancer nude mouse transplantation tumor is established by inoculating human prostate cancer Du-145 cells into the axillary subcutaneous of nude mouse. Du-145 cells in logarithmic growth phase are taken and inoculated under the right axillary fossa of 60 nude mice under the aseptic condition, and the inoculation amount of the cells is 5 multiplied by 106One/only. Measuring the diameter of the transplanted tumor by using a vernier caliper until the tumor grows to 90mm3On the left and right, 50 tumor-bearing nude mice with good growth status and uniform tumor size were selected and randomly divided into 5 groups of 10 mice each, namely, a model group, a compound No.6(100mg/kg) low dose group, a compound No.6(200mg/kg) high dose group, a positive drug Palbociclib (100mg/kg) group, and a positive drug Enzalutamide (100mg/kg) group. The test drug compound NO.6 is administrated by intragastric administration in a low-dose and high-dose group, a positive drug group Palbociclib and a positive drug group Enzalutamide, and is administrated once a day, and a model group is administrated by intragastric administration with a solvent control with equal volume. The antitumor effect of the test substance is dynamically observed by using a method for measuring the tumor size. The tumor diameter was measured every other day, and the weight of the nude mice was measured at the same time as the tumor diameter. Control mice were sacrificed on day 35, and tumor mass was surgically removed and fixed with 10% formaldehyde and stored in liquid nitrogen for further use. The remaining mice were sacrificed on day 49, and tumor mass was surgically removed and fixed with 10% formaldehyde and stored in liquid nitrogen for further use.
The experimental results are shown in fig. 3: the low dose group of test compound No.6(100mg/kg) inhibited tumor growth better than the positive drug Palbociclib (100mg/kg), the low dose group of test compound No.6(100mg/kg) and the positive drug Enzalutamide (100mg/kg) group inhibited tumor growth similarly, the high dose group of compound No.6(200mg/kg) inhibited tumor growth significantly better than the positive drug Palbociclib (100mg/kg) and the positive drug Enzalutamide (100mg/kg), and decreased tumor volume starting on day 31.
Therefore, the test drug prepared from the compound NO.6 has obvious inhibition effect on the growth of the xenograft tumor of the nude mouse with the human prostatic cancer Du-145, and the effect is better than that of a positive control drug CDK4/6 inhibitor Palbociclib and a first-line prostatic cancer treatment drug Enzalutamide.
Claims (10)
1. An intermediate compound of formula (I) wherein:
wherein the content of the first and second substances,
R1selected from hydrogen, deuterium, halogen, hydroxy, mercapto, cyano, nitro, C1-C8Alkyl, halo C1-C8Alkyl radical, C1-C8Alkoxy radical, C3-C8Cycloalkyl radical, C6-C10Aryl radical, C3-C10Heteroaryl group, C4-C8Heterocyclyl radical, -C0-8-NR4R5;
R2Selected from hydrogen, deuterium, halogen, hydroxy, mercapto, cyano, nitro, C1-C8Alkyl radical, C3-C8A cycloalkyl group;
the R is4、R5Each independently selected from hydrogen, deuterium and C1-C8Alkyl, halo C1-C8Alkyl radical, C1-C8Alkoxy or C3-C8A cycloalkyl group.
2. The intermediate compound of claim 1, wherein:
the R is1Is hydrogen, C1-C8Alkyl or-C0-8-N R4R5Wherein R is4、R5Selected from hydrogen, C1-C8Alkyl or C3-C8A cycloalkyl group; r2Is hydrogen or halogen.
3. The intermediate compound of claim 1, wherein:
the R is1Is hydrogen, C1-C3Alkyl or-NR4R5Wherein, in the step (A),R4、R5selected from hydrogen, C1-C3Alkyl, cyclopentane or cyclohexane; r2Is hydrogen or F.
4. The intermediate compound of claim 1, wherein:
the R is1Selected from: hydrogen, methyl or-NR4R5Wherein R is4、R5Selected from hydrogen, methyl, ethyl or cyclopentane; the R is2Is F.
5. The intermediate compound of claim 1, wherein:
the R is1Selected from: hydrogen, methyl or-NR4R5Wherein R is4Selected from hydrogen, methyl, ethyl or cyclopentane, the R5Selected from hydrogen, methyl, ethyl; the R is2Is F.
7. a process for the preparation of an intermediate compound as claimed in claim 1, characterized in that: preparing a compound (I) from a compound (A) and a compound (B) through a coupling reaction under the action of a palladium catalyst:
wherein the content of the first and second substances,
R1selected from hydrogen, deuterium, halogen, hydroxy, mercapto, cyano, nitro, C1-C8Alkyl, halo C1-C8Alkyl radical, C1-C8Alkoxy radical, C3-C8Cycloalkyl radical, C6-C10Aryl radical, C3-C10Heteroaryl group, C4-C8Heterocyclyl radical, -C0-8-NR3R4;
R2Selected from hydrogen, deuterium, halogen, hydroxy, mercapto, cyano, nitro, C1-C8Alkyl radical, C3-C8A cycloalkyl group;
the R is4、R5Each independently selected from hydrogen, deuterium and C1-C8Alkyl, halo C1-C8Alkyl radical, C1-C8Alkoxy or C3-C8A cycloalkyl group.
8. The process for preparing an intermediate compound according to claim 7, wherein the molar ratio of the compound (A) to the compound (B) is 1:1 to 1.5; the reaction temperature is 75-85 ℃.
9. The process for preparing an intermediate compound as claimed in claim 7, wherein the reaction solvent is selected from ethylene glycol dimethyl ether.
10. Use of the intermediate compound of claim 1 for the preparation of a targeted anticancer drug.
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