Patent ID: 12201635

DETAILED DESCRIPTION

In order to make the objects, technical solution and advantages of the present invention more apparent, the present invention is further described in detail with reference to specific embodiments.

Example 1

This example is directed to the multi-target kinase inhibitors (I-1), (I-2), (I-3), (I-4), (I-5), and (I-6) of the present invention and methods for preparing the same, wherein the general structural formula of the multi-target kinase inhibitors is shown in formula (I):

wherein R is selected from the following formula (a), formula (b), formula (c), formula (d), formula (e) and formula (f):

The method for preparing the multi-target kinase inhibitor comprises the following steps.

(1) Preparation of compound 4-((6,7-dimethoxyquinazolin-4-yl)oxy)aniline [Compound (IV)] 4-aminophenol [Compound (III)] (3.46 g, 31.2 mmol), NaOH (1.26 g, 31.2 mmol) and 50 mL of dimethyl sulfoxide were added into a 250 mL three-neck flask, mixed and stirred. 50 mL of dimethyl sulfoxide was mixed with 4-chloro-6,7-dimethoxyquinazoline [Compound (II)] (5 g, 22.3 mmol), and added into the above reaction solution. After the dropwise addition, the reaction solution was heated to 120° C. and reacted for 2 h. Then the reaction mixture was cooled to 15-20° C., and poured into 100 mL of ice water. When the temperature was controlled to be 15-30° C., the resultant mixture was added with 20 mL of ethyl acetate and filtered under vacuum with stirring for solid separation. The solid was washed with 20 mL of ethanol once, and dried under vacuum at 40° C. for 12 h to give 4.12 g off-white solid (62.14%), namely Compound (IV).

(2) Preparation of phenyl(4-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)carbamate [Compound (VI)]

Phenyl chloroformate [Compound (V)] (1.64 g, 0.0105 mol) was slowly added to an ice-cooled solution of 4-((6,7-dimethoxyquinazolin-4-yl)oxy)aniline [Compound (IV)] (2.97 g, 0.01 mol) and potassium carbonate (1 g, 0.012 mol) in acetone (30 mL). After the addition, the water-water bath was removed. The reaction mixture was stirred at room temperature for 30 min, and added with methanol (20 mL). An inorganic salt solid was separated from the reaction solution, and the organic layer filtrate was concentrated and finally washed with ethyl acetate (10 mL) to give Compound (VI) in the form of a white powder (3.58 g, 85.85% yield).

(3) Preparation of multi-target kinase inhibitor [Compound (I-1)]

The prepared Compound (VI) (2.01 g, 5 mmol) was dissolved in dimethylformamide (20 mL), added with cyclopropylamine [Compound (VII-1)] (0.43 g, 7.5 mmol), and stirred at 80° C. for 2 h. Then the reaction mixture was cooled to 15-20° C., and poured into 50 mL of ice water. When the temperature was controlled to be 15-30° C., the resultant mixture was filtered under vacuum for solid separation. The solid was washed with water (20 mL) once, washed with acetonitrile (20 mL) once, and dried under vacuum to give the multi-target kinase inhibitor [Compound (I-1)] in the form of a powdery solid (1.25 g, 62.8% yield).

In the above preparation method, the structural formulas of the compounds are as follows:

In this example, the multi-target kinase inhibitor was further characterized by NMR spectroscopy and mass spectrometry, and the results are as follows:lEINMR (400 MHz, DMSO-d6): δ 8.52 (s, 1H), 8.39 (brs, 1H), 7.53 (s, 1H), 7.50 (m, 1H), 7.47 (m, 1H), 7.36 (s, 1H), 7.17 (m, 1H), 7.14 (m, 1H), 6.42 (d, J=2.6 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 2.55 (m, 1H), 0.64 (m, 2H), 0.42 (m, 2H). ESI-MS (m/z): 381 [M+H]+.

(4) Preparation of multi-target kinase inhibitor [Compound (I-2)]

The prepared Compound (VI) (2.01 g, 5 mmol) was dissolved in dimethylformamide (20 mL), added with cyclobutylamine [Compound (VII-2)] (0.53 g, 7.5 mmol), and stirred at 80° C. for 2 h. Then the reaction mixture was cooled to 15-20° C., and poured into 50 mL of ice water. When the temperature was controlled to be 15-30° C., the resultant mixture was filtered under vacuum for solid separation. The solid was washed with water (20 mL) once, washed with acetonitrile (20 mL) once, and dried under vacuum to give the multi-target kinase inhibitor [Compound (I-2)] in the form of a powdery solid (1.38 g, 64.8% yield).

In the above preparation method, the structural formulas of the compounds are as follows:

In this example, the multi-target kinase inhibitor was further characterized by NMR spectroscopy and mass spectrometry, and the results are as follows:1H NMR (400 MHz, DMSO-d6): δ 8.50 (s, 1H), 8.37 (brs, 1H), 7.51 (s, 1H), 7.48 (m, 1H), 7.45 (m, 1H), 7.34 (s, 1H), 7.15 (m, 1H), 7.13 (m, 1H), 6.40 (d, J =2.6 Hz, 1H), 4.25 (m, 1H) 3.96 (s, 3H), 3.94 (s, 3H), 2.35 (m, 2H), 1.92 (m, 2H), δ 1.73 (m, 2H). ESI-MS (m/z): 395 [M+H]+.

(5) Preparation of multi-target kinase inhibitor [Compound (I-3)]

The prepared Compound (VI) (2.01 g, 5 mmol) was dissolved in dimethylformamide (20 mL), added with cyclopentylamine [Compound (VII-3)] (0.64 g, 7.5 mmol), and stirred at 80° C. for 2 h. Then the reaction mixture was cooled to 15-20° C., and poured into 50 mL of ice water. When the temperature was controlled to be 15-30° C., the resultant mixture was filtered under vacuum for solid separation. The solid was washed with water (20 mL) once, washed with acetonitrile (20 mL) once, and dried under vacuum to give the multi-target kinase inhibitor [Compound (I-3)] in the form of a powdery solid (1.19 g, 60.6% yield).

In the above preparation method, the structural formulas of the compounds are as follows:

In this example, the multi-target kinase inhibitor was further characterized by NMR spectroscopy and mass spectrometry, and the results are as follows:1H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 8.44 (brs, 1H), 7.53 (s, 1H), 7.50 (m, 1H), 7.47 (m, 1H), 7.36 (s, 1H), 7.17 (m, 1H), 7.14 (m, 1H), 6.42 (d, J=2.6 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.78 (m, 1H), 1.68 (m, 2H), 1.49 (m, 2H), 1.40 (m, 2H), 1.20 (m, 2H). ESI-MS (m/z): 409 [M+H]+.

(6) Preparation of multi-target kinase inhibitor [Compound (I-4)]

The prepared Compound (VI) (2.01 g, 5 mmol) was dissolved in dimethylformamide (20 mL), added with vinylamine [Compound (VII-4)] (0.32 g, 7.5 mmol), and stirred at 80° C. for 2 h. Then the reaction mixture was cooled to 15-20° C., and poured into 50 mL of ice water. When the temperature was controlled to be 15-30° C., the resultant mixture was filtered under vacuum for solid separation. The solid was washed with water (20 mL) once, washed with acetonitrile (20 mL) once, and dried under vacuum to give the multi-target kinase inhibitor [Compound (I)] in the form of a powdery solid (1.01 g, 58.8% yield).

In the above preparation method, the structural formulas of the compounds are as follows:

In this example, the multi-target kinase inhibitor was further characterized by NMR spectroscopy and mass spectrometry, and the results are as follows:1H NMR (400 MHz, DMSO-d6): δ 8.78 (s, 1H), 8.61 (brs, 1H), 7.41 (s, 1H), 7.50 (m, 1H), 7.47 (m, 1H), 7.31 (s, 1H), 7.18 (m, 1H), 7.15 (m, 1H), 6.42 (d, J=2.6 Hz, 1H), 6.05 (m, 1H), 5.61 (d, 1H), 4.04 (d, 1H), 3.98 (s, 3H), 3.96 (s, 3H). ESI-MS (m/z): 367 [M+H]+.

(7) Preparation of multi-target kinase inhibitor [Compound (I-5)]

The prepared Compound (VI) (2.01 g, 5 mmol) was dissolved in dimethylformamide (20 mL), added with tetrahydropyrrole [Compound (VII-5)] (0.53 g, 7.5 mmol), and stirred at 80° C. for 2 h. Then the reaction mixture was cooled to 15-20° C., and poured into 50 mL of ice water. When the temperature was controlled to be 15-30° C., the resultant mixture was filtered under vacuum for solid separation. The solid was washed with water (20 mL) once, washed with acetonitrile (20 mL) once, and dried under vacuum to give the multi-target kinase inhibitor [Compound (I-5)] in the form of a powdery solid (1.26 g, 66.4% yield).

In the above preparation method, the structural formulas of the compounds are as follows:

In this example, the multi-target kinase inhibitor was further characterized by NMR spectroscopy and mass spectrometry, and the results are as follows:1H NMR (400 MHz, DMSO-d6): δ 8.52 (s, 1H), 8.39 (brs, 1H), 7.53 (s, 1H), 7.50 (m, 1H), 7.47 (m, 1H), 7.36 (s, 1H), 7.17 (m, 1H), 6.42 (d, J=2.6 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.25 (m, 4H), 1.70 (m, 4H). ESI-MS (m/z): 395 [M+H]+.

(8) Preparation of multi-target kinase inhibitor [Compound (I-6)]

The prepared Compound (VI) (2.01 g, 5 mmol) was dissolved in dimethylformamide (20 mL), added with piperidine [Compound (VII-6)] (0.64 g, 7.5 mmol), and stirred at 80° C. for 2 h. Then the reaction mixture was cooled to 15-20° C., and poured into 50 mL of ice water. When the temperature was controlled to be 15-30° C., the resultant mixture was filtered under vacuum for solid separation. The solid was washed with water (20 mL) once, washed with acetonitrile (20 mL) once, and dried under vacuum to give the multi-target kinase inhibitor [Compound (I-6)] in the form of a powdery solid (1.27 g, 65.1% yield).

In the above preparation method, the structural formulas of the compounds are as follows:

In this example, the multi-target kinase inhibitor was further characterized by NMR spectroscopy and mass spectrometry, and the results are as follows:1H NMR (400 MHz, DMSO-d6): δ 8.53 (s, 1H), 8.40 (brs, 1H), 7.55 (s, 1H), 7.51 (m, 1H), 7.48 (m, 1H), 7.38 (s, 1H), 7.18 (m, 1H), 6.42 (d, J=2.6 Hz, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.77 (m, 4H), 1.59 (m, 2H), 1.53 (m, 4H). ESI-MS (m/z): 409 [M+H]+.

Example 2

In this example, the inhibitory activities of the multi-target kinase inhibitors described herein against RET, VEGFR3, and PDGFRA were investigated.

(I) Procedures

1. The compounds to be detected were accurately weighed and added into DMSO to form stock solutions, which were then diluted to desired concentrations with a buffer to give solutions of the compounds to be detected.

2. An RET or VEGFR3 or PDGFRA kinase solution, corresponding substrate solutions of Z′-LYTE, a buffer or a compound to be detected and ATP were added into a 384 reaction vessel, and reacted at room temperature for 1 h.

3. To each well was added a fluorescence enhancer, followed by incubation at room temperature for 1 h.

4. Data were read separately using a fluorescence analyzer.

(II) Data Processing

1. The relative inhibitory rate for each well was calculated according to a formula.

2. Active samples were diluted and tested for relative inhibitory rates, and the inhibitory rates IC50were calculated by plotting in the software Xlfit.

(III) Results

The experimental results are shown in Table 1:

TABLE 1Inhibitory activities of multi-target kinase inhibitorsagainst kinases RET, VEGFR3 and PDGFRAIC50(nM)ExperimentalCompoundRETVEGFR3PDGFRAproceduresI-1123060Z'-LYTEI-23716308Z'-LYTEI-385962Z'-LYTEI-4266552Z'-LYTEI-5102213124Z'-LYTEI-6251328632Z'-LYTE

Compounds with an ICso of less than 100 nM are considered capable of effectively inhibiting activities of target proteins. As can be seen from the experimental results in Table 1, the half-inhibitory concentrations of the multi-target kinase inhibitors provided herein against the targets are at nanomolar levels; the half-inhibitory concentrations of the multi-target kinase inhibitors (I-1), (I-3) and (I-4) against kinases RET, VEGFR3 and PDGFRA are all below 100 nM, and the half-inhibitory concentrations of the multi-target kinase inhibitor (I-2) against kinases RET and VEGFR3 are both below 100 nM. Therefore, the multi-target kinase inhibitors (I-1), (I-3) and (I-4) provided herein can effectively inhibit the enzymatic activities of RET, VEGFR3 and PDGFRA, and the multi-target kinase inhibitors (I-2) can effectively inhibit the enzymatic activities of RET and VEGFR3. It can be seen that the multi-target kinase inhibitors synthesized herein have most of the IC50within 100 nM, and are proved to have good druggability by in vitro experiments.

Example 3

In this example, the in vivo anti-tumor activity (liver cancer/esophageal cancer) of the multi-target kinase inhibitor [Compound (I-1)] was investigated according to the requirements in Guidelines for Pharmacodynamics of Anti-tumor Drugs. The experimental procedures and results are as follows:

(I) Experimental Procedures

Tumor models of nude mice were established using SA/MC-7721 heptoma cells and KYSE 410 esophageal cancer cells that meet modeling conditions. The modeled mice were divided into 5 groups: a model group, a Compound (I-1) 5 mg/kg group, a Compound (I-1) 10 mg/kg group, a Compound (I-1) 20 mg/kg group, and a positive control group (sorafenib or cabozantinib). Administration was performed from the day of grouping that was counted as day 1 and for 21 consecutive days, and the 21st day was counted as day21. Tumor volumes were measured twice a week during the period of administration for statistical test. The test results are shown inFIG.1andFIG.2.

(II) Results

Two groups of experiments for the tumor inhibitory effect of the multi-target kinase inhibitor [Compound (I-1)] on mice with SMMC-7721 liver cancer and mice with KYSE 410 esophageal cancer have similar test results, and the analysis of the results shows that: compared with the model group, the experimental groups at the dosages of 5 mg/kg, 10 mg/kg and 20 mg/kg and the positive control group presented lower tumor volumes; analysis of variance of the tumor volumes on day21 showed significant difference (P<0.0001), suggesting that Compound (I-1) provided herein has the same noticeable inhibitory effect on liver cancer as the positive control group does; compared with the positive control group, the experimental groups at the dosages of 10 mg/kg and 20 mg/kg presented lower tumor volumes, suggesting that Compound (I-1) provided herein has stronger in vivo anti-tumor activity than the positive drugs sorafenib and cabozantinib when at low dosage.

Example 4

In this example, the formulation and preparation process for tablets each containing 50 mg of the multi-target kinase inhibitor (I-1) are provided:

TABLE 2Formulation for 1000 tablets containingmulti-target kinase inhibitor (I-1)Contents in weightContent/TabletAmount ofComponentpercentages (%)(mg/Tablet)prescription (g)I-110.0050.0050.00Lactose75.00375.00375.00Polyvinyl-5.0025.0025.00pyrrolidoneLow-substituted5.0025.0025.00hydroxypropylcelluloseSodium3.0015.0015.00croscarmelloseSilica1.005.005.00Magnesium1.005.005.00stearateTotal100.00500.00500.00(1000 tablets in total)

The preparation process of the above tablets comprises the following steps.

1. The multi-target kinase inhibitor (I-1) was ultra-micronized and sieved with a sieve of more than 300 mesh to give a micronized powder starting material having a particle size D90controlled to be less than 50 μm, and the other excipients of the prescription were pre-treated by passing through a 60-mesh sieve; and 50 g of sieved multi-target kinase inhibitor starting material, 375 g of lactose, 25 g of polyvinylpyrrolidone, 25 g of low-substituted hydroxypropyl cellulose and 15 g of sodium croscarmellose were well mixed in a three-dimensional mixer to prepare a pre-mixed material.

2.5 g of magnesium stearate and 5 g of silica were added to the obtained pre-mixed material to give a mixed powder, the mixed powder was fully mixed in a three-dimensional mixer, the tablet weight range of tableting was determined according to the content results of the intermediate detection, and the mixture was tableted using a rotary tablet press to give the tablets.

Example 5

In this example, the formulation and preparation process for dispersible tablets each containing 50 mg of the multi-target kinase inhibitor (I-1) are provided:

TABLE 3Formulation for 1000 dispersible tablets containingmulti-target kinase inhibitor (I-1)Contents in weightContent/TabletAmount ofComponentpercentages (%)(mg/Tablet)prescription (g)I-110.0050.0050.00Microcrystalline17.5087.5087.50celluloseLactose52.50262.50262.50Polyvinyl-3.0015.0015.00pyrrolidoneLow-substituted10.0050.0050.00hydroxypropylcelluloseSodium5.0025.0025.00croscarmelloseSilica1.005.005.00Magnesium1.005.005.00stearateTotal100.00500.00500.0(1000 tablets in total)

The preparation process of the above dispersible tablets comprises the following steps.

1. The multi-target kinase inhibitor (I-1) was ultra-micronized and sieved with a sieve of more than 300 mesh to give a micronized powder starting material having a particle size D90 controlled to be less than 50 μm, and the other excipients of the prescription were pre-treated by passing through a 60-mesh sieve; 50 g of sieved multi-target kinase inhibitor starting material, 87.5 g of microcrystalline cellulose, 262.5 g of lactose, 15 g of polyvinylpyrrolidone, 50 g of low-substituted hydroxypropyl cellulose and 25 g of sodium croscarmellose were well mixed in a three-dimensional mixer to give a pre-mixed material.

2.5 g of magnesium stearate and 5 g of silica were added to the obtained pre-mixed material to give a mixed powder, the mixed powder was fully mixed in a three-dimensional mixer, the tablet weight range of tableting was determined according to the content results of the intermediate detection, and the mixture was tableted using a rotary tablet press to give the dispersible tablets.

Example 6

In this example, the formulation and preparation process for dispersible tablets each containing 25 mg of the multi-target kinase inhibitor (I-1) are provided:

TABLE 4Formulation for 1000 dispersible tablets containingmulti-target kinase inhibitor (I-1)Contents in weightContent/TabletAmount ofComponentpercentages (%)(mg/Tablet)prescription (g)I-110.0025.0025.00Microcrystalline17.5043.7543.75celluloseLactose52.50131.25131.25Polyvinyl-3.007.507.50pyrrolidoneLow-substituted10.0025.0025.00hydroxypropylcelluloseSodium5.0012.5012.50croscarmelloseSilica1.002.502.50Magnesium1.002.502.50stearateTotal100.00250.00250.00(1000 tablets in total)

The preparation process of the above dispersible tablets comprises the steps as in Example 5.

Example 7

In this example, the formulation and preparation process for dispersible tablets each containing 10 mg of the multi-target kinase inhibitor (I-1) are provided:

TABLE 5Formulation for 1000 dispersible tablets containingmulti-target kinase inhibitor (I-1)Contents in weightContent/TabletAmount ofComponentpercentages (%)(mg/Tablet)prescription (g)I-110.0010.0010.00Microcrystalline17.5017.5017.50celluloseLactose52.5052.5052.50Polyvinyl-3.003.003.00pyrrolidoneLow-substituted10.0010.0010.00hydroxypropylcelluloseSodium5.005.005.00croscarmelloseSilica1.001.001.00Magnesium1.001.001.00stearateTotal100.00100.00100.00(1000 tablets in total)

The preparation process of the above dispersible tablets comprises the steps as in Example 5.

Example 8

In this example, the formulation and preparation process for dispersible tablets each containing 5 mg of the multi-target kinase inhibitor (I-1) are provided:

TABLE 6Formulation for 1000 dispersible tablets containingmulti-target kinase inhibitor (I-1)Contents in weightContent/TabletAmount ofComponentpercentages (%)(mg/Tablet)prescription (g)I-11.005.005.00Microcrystalline20.50102.50102.50celluloseLactose58.50292.50292.50Polyvinyl-3.0015.0015.00pyrrolidoneLow-substituted10.0050.0050.00hydroxypropylcelluloseSodium5.0025.0025.00croscarmelloseSilica1.005.005.00Magnesium1.005.005.00stearateTotal100.00500.00500.00(1000 tablets in total)

The preparation process of the above dispersible tablets comprises the steps as in Example 5.

Example 9

In this example, the formulation and preparation process for sustained-release tablets each containing 250 mg of the multi-target kinase inhibitor (I-1) are provided:

TABLE 7Formulation for 1000 sustained-release tabletscontaining multi-target kinase inhibitor (I-1)Contents in weightContent/TabletAmount ofComponentpercentages (%)(mg/Tablet)prescription (g)I-150.00250.00250.00Hydroxypropyl17.5087.5087.50methylcelluloseSodium alginate22.50112.50112.50Polyvinyl-3.0015.0015.00pyrrolidoneSodium5.0025.0025.00croscarmelloseSilica1.005.005.00Magnesium1.005.005.00stearateTotal100.00500.00500.00(1000 tablets in total)

The preparation process of the above dispersible tablets comprises the following steps.

1. The multi-target kinase inhibitor (I-1) was ultra-micronized and sieved with a sieve of more than 300 mesh to give a micronized powder starting material having a particle size D90controlled to be less than 50 μm, and the other excipients of the prescription were pre-treated by passing through a 60-mesh sieve; and 250 g of sieved multi-target kinase inhibitor (I-1), 87.5 g of hydroxypropyl methylcellulose, 112.5 g of sodium alginate, and 15 g of polyvinylpyrrolidone were well mixed in a high-efficiency mixing granulator, and added with a 30% aqueous solution of ethanol to give a soft material, the soft material was dried and granulated, and added with 25 g of sodium croscarmellose, and then the resulting mixture was well mixed in a three-dimensional mixer to give a pre-mixed material.

2.5 g of magnesium stearate and 5 g of silica were added to the obtained pre-mixed material to give a mixed powder, the mixed powder was fully mixed in a three-dimensional mixer, the tablet weight range of tableting was determined according to the content results of the intermediate detection, and the mixture was tableted using a rotary tablet press to give the sustained-release tablets containing the multi-target kinase inhibitor.

Example 10

In this example, the formulation and preparation process for capsules each containing 50 mg of the multi-target kinase inhibitor (I-1) are provided:

TABLE 8Formulation for 1000 capsules containingmulti-target kinase inhibitor (I-1)Contents in weightContent/TabletAmount ofComponentpercentages (%)(mg/Tablet)prescription (g)I-120.0050.0050.00Microcrystalline67.00167.50167.50celluloseLactose10.4526.0026.00Silica1.503.753.75Magnesium1.002.502.50stearateSodium dodecyl0.050.250.25sulfateTotal100.00250.00250.00(1000 capsulesin total)

The preparation process of the above capsules comprises the following steps.

1. The multi-target kinase inhibitor (I-1) was ultra-micronized and sieved with a sieve of more than 300 mesh to give a micronized powder starting material having a particle size D90controlled to be less than 50 μm, and the other excipients of the prescription were pre-treated by passing through a 60-mesh sieve; 50 g of sieved multi-target kinase inhibitor starting material, 167.5 g of microcrystalline cellulose, and 26 g of lactose were well mixed in a three-dimensional mixer to give a pre-mixed material.

2. 2.5 g of magnesium stearate and 3.75 g of silica were added to the obtained pre-mixed material to give a mixed powder, the mixed powder was fully mixed in a three-dimensional mixer, the filling amount weight range was determined according to the content results of the intermediate detection, and capsules were filled using an automatic capsule filler to give the capsules containing the multi-target kinase inhibitor.

Example 11

In this example, the formulation and preparation process for granules each containing 50 mg of the multi-target kinase inhibitor (I-1) are provided:

TABLE 9Formulation for 1000 pouches of granulescontaining multi-target kinase inhibitor (I-1)Contents in weightAmount/PouchAmount ofComponentpercentages (%)(mg/Pouch)prescription (g)I-110.0050.0050.00Sucrose67.20336.00336.00Gum arabic5.0025.0025.00Tragacanth10.0050.0050.00Low-substituted5.0025.0025.00hydroxypropylcelluloseSilica1.507.507.50Magnesium1.005.005.00stearateVanillin0.100.500.50Orange0.201.001.00powderyessenceTotal100.00500.00500.00(1000 pouchesin total)

The preparation process of the above granules comprises the following steps.

1. The multi-target kinase inhibitor (I-1) was ultra-micronized and sieved with a sieve of more than 300 mesh to give the multi-target kinase inhibitor (I-1) having a particle size D90controlled to be less than 50 μm, and the other excipients of the prescription were pre-treated by passing through a 60-mesh sieve.

2. The sieved multi-target kinase inhibitor (I-1), sucrose, gum arabic and tragacanth were well mixed in a high-efficiency mixing granulator, added with a proper amount of a 30% ethanol solution and well mixed to give a soft material, the soft material was granulated by passing through a 30-mesh sieve, the sieved soft material was dried in a fluidized bed at 50-60° C., and the dried material was sieved with a 30-mesh sieve to give dry granules.

3. A lubricating glidant and a flavoring agent were added to the dry granules to give a mixed powder, and the mixed powder was well mixed in a multi-directional motion mixer, and packaged by using a granule packer to give the granules containing the multi-target kinase inhibitor.

Efficacy Example 1

100 tablets of each sample prepared in Examples 4 and 5 were investigated in vitro for dissolution rates in various dissolution media.

Dissolution tests were performed according to the content homogeneity inspection method of Chapter 0931 in Chinese Pharmacopoeia (Volume IV, 2015 Edition), and the second method was adopted. The volume of a dissolution medium is 900 mL, and the rotating speed is 50 rpm. Purified water, a hydrochloric acid solution with a pH of 1.2, an acetate buffer with a pH of 4.5 and a phosphate buffer with a pH of 6.8 were adopted as the dissolution media, in which except for the hydrochloric acid solution with a pH of 1.2, the other three dissolution media were all added with a 0.5% sodium dodecyl sulfate (abbreviated as “SDS”) surfactant. Dissolution rates of the samples of Examples 4 and 5 in 4 dissolution media were measured by HPLC, and the dissolution data recorded are shown in Table 10, Table 11,FIG.3andFIG.4:

TABLE 10Dissolution rates of the samples of Example 4 in dissolution mediawith different pH valuesTimeMedium5 min10 min15 min20 min30 min45 minpH1.276.3586.7396.3494.3192.1190.21pH4.5 + 0.5% SDS37.4076.5294.3699.1098.5798.95pH6.8 + 0.5% SDS38.4875.7494.41100.68103.58104.02Water + 0.5% SDS44.1980.1595.89100.05102.35102.69

TABLE 11Dissolution rates of the samples of Example 5 in dissolution mediawith different pH valuesTimeMedium5 min10 min15 min20 min30 min45 minpH1.287.1793.6693.9094.2693.2692.18pH4.5 + 0.5% SDS64.9982.9688.9490.8491.7492.14pH6.8 + 0.5% SDS60.7083.2290.8793.3495.6396.20Water + 0.5% SDS61.5882.1191.0994.2096.0996.70

Two groups of multi-target kinase inhibitor samples of Example 4 and Example 5 were investigated in vitro for dissolution rates in various dissolution media, and the results show that the sample of Example 4 had in vitro dissolution rates of no less than 94 in different dissolution media at minute 15, and the sample of Example 5 had in vitro dissolution rates of no less than 88 in different dissolution media at minute 15, indicating that the pharmaceutical composition of the present invention dissolves quickly when prepared into tablets, and the drug release can reach a plateau at minute 15. The results also show downward trends in the dissolution rates of the pharmaceutical composition samples with increasing pH values, and on the other hand, the samples in the forms of a common tablet or dispersible tablet of oral solid preparations are expected to be dissolved in the stomach and absorbed through the upper half of the small intestine of a patient, indicating that the pharmaceutical compositions of the present invention are improved in dissolution rates and in vivo absorption when prepared into tablets by a certain production process. In addition, according to the content of the multi-target kinase inhibitor contained in the pharmaceutical composition as an active ingredient, the pharmaceutical composition only needs to be orally taken once a day by a patient, which greatly improves the compliance of the patient.

Finally, it should be noted that the above examples are only for illustrating the technical solution of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that modifications or equivalent substitutions can be made to the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention.