CN114306255B

CN114306255B - Methyl ketone derivative pharmaceutical preparation and preparation method thereof

Info

Publication number: CN114306255B
Application number: CN202111665901.9A
Authority: CN
Inventors: 李玲; 秦旭航; 白荣光; 戴信敏
Original assignee: Beijing Xinkaiyuan Pharmaceuticals Co Ltd
Current assignee: Beijing Xinkaiyuan Pharmaceuticals Co Ltd
Priority date: 2021-12-30
Filing date: 2021-12-30
Publication date: 2023-05-23
Anticipated expiration: 2041-12-30
Also published as: CN114306255A

Abstract

The invention relates to the technical field of medicines, and provides a methyl ketone derivative medicinal preparation and a preparation method thereof. The methyl ketone derivative has a structure shown in formula I:

wherein R is ₁ Represents a substituted or unsubstituted phenyl or an aromatic heterocyclic group. The methyl ketone derivative pharmaceutical preparation provided by the invention is used as a PKC inhibitor for treating cancers, and has small side effects. The methyl ketone derivative pharmaceutical preparation has high dissolution rate and good dissolution effect.

Description

Methyl ketone derivative pharmaceutical preparation and preparation method thereof

Technical Field

The invention relates to a methyl ketone derivative pharmaceutical preparation and a preparation method thereof, belonging to the technical field of chemical medicines.

Background

Protein Kinase C (PKC), a group of phospholipid-dependent protein serine/threonine kinases, was first discovered in 1977 and was widely distributed in mammalian organs, tissues and cells to play an important role in regulating metabolic growth, proliferation and differentiation of cells. It forms together with protein kinase a and protein kinase G the serine/threonine protein kinase AGC (PKA, PKG and PKC) superfamily.

PKC consists of a single polypeptide chain whose structure consists of 4 conserved regions of high homology (C1-C4) and 5 variable regions of low homology (V1-V5), which play a role in the recognition and activation of a particular PKC isoform. Thus, different subtypes are selectively activated under different external stimuli. To date, isozymes have been classified into 4 major classes (12 subtypes) according to their structure, properties, and activators, respectively: traditional PKCs and novel PKCs. Traditional PKCs include pkcα, βi, βii and γ subtypes. Novel PKCs include pkcδ, epsilon, η, θ and μ subtypes. Normally, PKC is in an inactive state; PKC is activated when subjected to an external stimulus. Activated PKC phosphorylates serine/threonine of various proteins, thereby affecting secretion of various internal and external glands, release of neurotransmitters, apoptosis, myocardial contraction, and regulation of metabolic pathways, etc.

A series of studies have shown that: the occurrence and progression of various diseases are associated with abnormal expression of PKC. Such as: there is a significant increase in pkcα expression in human breast, colon, liver cells; abnormal expression of pkcα, pkcβii, pkcδ was found in thyroid lesion cells; the expression of pkcβ is increased in prostate and colon cancer cells, while the expression is decreased in bladder cancer. Furthermore, pkcα expression is increased in highly differentiated bladder, prostate and endometrial cancer cells.

Therefore, the development of novel potent PKC inhibitors is of great importance for the treatment of tumors.

Disclosure of Invention

The researchers of the invention find that the compound shown as the formula I has anti-tumor activity and can be used for treating cancers. Therefore, the invention aims to provide a methylketone derivative pharmaceutical preparation with a structure shown in formula I and a preparation method thereof, wherein a compound shown in formula I and various derivatives thereof have anti-tumor pharmacological activity, and the specific technical scheme is as follows:

the invention provides a methyl ketone derivative pharmaceutical preparation, which comprises methyl ketone derivatives or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers;

the methyl ketone derivative has a structure shown in formula I:

wherein R is ₁ Represents a substituted or unsubstituted phenyl or an aromatic heterocyclic group.

The methyl ketone derivative provided by the invention is selected from any one of the compounds in the following formulas 1-17, and has the following structural formula:

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the invention provides a methyl ketone derivative pharmaceutical preparation, which comprises the following components in parts by mass:

further, the filler is one or more of microcrystalline cellulose, lactose and mannitol.

Further, the disintegrating agent is one or more of sodium carboxymethyl starch, crosslinked sodium carboxymethyl cellulose, crosslinked povidone and low-substituted hydroxypropyl cellulose.

Further, the lubricant is one or more of sodium stearyl fumarate, magnesium stearate, micro silica gel and talcum powder.

The preparation method of the methyl ketone derivative pharmaceutical preparation comprises the following steps:

step 1, sieving a methyl ketone derivative raw material for later use;

step 2, weighing methyl ketone derivatives, filler and disintegrating agent, and putting into a three-dimensional mixer for mixing;

step 3, adding a lubricant into the mixed material, and mixing by adopting a three-dimensional mixer;

step 4, pressing the mixed materials into tablets by adopting a rotary tablet press;

and 5, packaging the sheet by adopting aluminum plastic.

step 1, sieving a methyl ketone derivative raw material for later use;

step 3, putting the uniformly mixed materials into a dry granulator, feeding and converting the materials into 5HZ, tabletting and converting the materials into 15HZ, granulating and converting the materials into 50HZ, and preparing granules by using a screen with the aperture of 1.2 mm;

step 4, adding a lubricant into the mixed material, and mixing by adopting a three-dimensional mixer;

step 5, pressing the mixed materials into plain tablets by adopting a rotary tablet press;

and step 6, putting the pressed plain tablets into a high-efficiency coating machine for coating. Coating with coating solution with 10% solid content prepared from Opadry gastric-soluble film coating powder of Callery company, and controlling the weight gain of the coating to 2-4%;

and 7, packaging the sheet by adopting aluminum plastic.

The methyl ketone derivative pharmaceutical preparation is prepared into oral dosage forms, such as tablets.

The application of the methyl ketone derivative pharmaceutical preparation as a PKC inhibitor in preparing medicaments for treating or preventing tumors.

Further, the tumor is selected from: skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, kidney cancer, cervical cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytoma, meningioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, seminoma, chondrosarcoma, myosarcoma, fibrosarcoma.

Further, the preparation method of the methyl ketone derivative with the structure shown in the formula I provided by the invention comprises the following steps:

dissolving the compound II and the compound III in a reaction solvent, cooling to 0-10 ℃, adding alkali, heating to 25-50 ℃, and carrying out heat preservation reaction to obtain an intermediate IV; the reaction solvent is at least one of tetrahydrofuran, dioxane, toluene and N, N-dimethylformamide (English is abbreviated as DMF); the alkali is at least one of sodium hydride, sodium tert-butoxide, potassium tert-butoxide and lithium hexamethylamide.

Step two, synthesis of intermediate VI

Dissolving the intermediate IV in a reaction solvent, cooling to-80-0 ℃, reacting under the action of alkali, adding the compound V, reacting for 1-3 hours at a constant temperature, heating to room temperature, and reacting for 0.5-1.5 hours at room temperature to obtain an intermediate VI; the reaction solvent is at least one of tetrahydrofuran (THF for short), dioxane, toluene and methyl tertiary butyl ether; the base is at least one of n-butyllithium (abbreviated as BuLi in English), sec-butyllithium and tert-butyllithium.

Step three, synthesis of intermediate VII

Reacting the intermediate VI in a reaction solvent under the action of acid to obtain an intermediate VII; wherein the reaction temperature is 0-40 ℃; the acid is at least one of trifluoroacetic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, hydrochloric acid, ethanol solution of hydrogen chloride, and ethyl acetate solution of hydrogen chloride (the English of ethyl acetate is abbreviated as EA); the reaction solvent is at least one of tetrahydrofuran, dioxane, toluene, acetonitrile and ethyl acetate.

Step four, synthesis of the compound I

And (3) carrying out condensation reaction on the intermediate VII and the compound VIII in a reaction solvent under the action of alkali to obtain the compound I. Wherein the reaction temperature is 20-50 ℃; the base is at least one selected from potassium carbonate, cesium carbonate, sodium carbonate, triethylamine, and diisopropylethylamine (abbreviated as DIEA in english); the reaction solvent is at least one of dichloromethane, N-dimethylformamide and tetrahydrofuran.

The synthesis method of the methyl ketone derivative with the structure shown in the formula I has the advantages of few byproducts, high yield and great application value in the synthesis reaction process.

The pharmaceutical preparation provided by the invention comprises a methyl ketone derivative with a structure shown in a formula I or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or diluents.

The pharmaceutical preparation provided by the invention can be prepared into various common dosage forms, such as tablets, pills, capsules, granules, oral solutions, oral suspensions, oral emulsions, injections and the like according to a conventional preparation method in the pharmaceutical field. Is convenient for clinical use to a patient and is administered to the patient by a variety of common modes of administration, such as oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes).

Some terms involved in the expression of the present invention are defined as follows:

by "pharmaceutically acceptable salts" is meant those salts which retain the biological effectiveness and properties of the parent compound. The salt comprises: acid addition salts obtained by reaction of the free base of the parent compound with an inorganic acid or with an organic acid; such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid, and the like; such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, malonic acid, etc.; preferably hydrochloric acid or (L) -malic acid; or when the acid protons present in the parent compound are replaced with metal ions, such as alkali metal ions, alkaline earth metal ions, or aluminum ions, or coordinated with an organic base; such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

"substituted" means that 1, 2 or more hydrogen atoms in a molecule are replaced by other different atoms or molecules, including 1, 2 or more substitutions on a co-or an ectopic atom in the molecule. The "aromatic heterocycle" is a heterocycle with flat structural characteristics, wherein atoms in the ring form a ring-closed conjugated system, the molecule is planar, the upper side and the lower side of the plane are provided with annular delocalized electron clouds, and the number of P electrons in the conjugated system accords with the shock rule. For example: pyridine, furan ring, thiazole ring, pyrimidine ring, and the like.

The compounds of the invention may have one or more asymmetric centers; the compounds can thus be prepared as individual (R) -stereoisomers or (S) -stereoisomers or as mixtures thereof. Unless otherwise indicated, descriptions or names of particular compounds in the specification and claims are intended to include individual enantiomers and racemic or other mixtures thereof. Methods for determining stereochemical configuration and isolating stereoisomers are well known in the art (see discussion in chapter 4 of "Advanced Organic Chemistry", 4 th edition, J.March, john Wiley and Sons, new York, 1992). Thus, the present invention also encompasses any stereoisomers, their corresponding enantiomers (d-and l-isomers or (+) and (-) isomers), and diastereomers and mixtures thereof, having the ability to inhibit PKC activity and is not limited to any one stereoisomer.

The invention has the advantages that:

(1) The methyl ketone derivative pharmaceutical preparation can be used as a PKC inhibitor for treating cancers, and has small side effect;

(2) The methyl ketone derivative pharmaceutical preparation has high dissolution rate and good dissolution effect.

Detailed Description

The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.

Example 1

A compound represented by formula 1: (9- (1- (2-fluorobenzyl) piperidin-4-yl) -9H-carbazol-4-yl) (1-methyl-1H-indol-3-yl) methyl ketone; the synthetic reaction formula is as follows:

the first step: compound 1a (48.9 g,200.0 mmol), compound 1b (52.6 g,200.0 mmol) was dissolved in DMF (300 mL), cooled to 0deg.C, sodium hydride (12.0 g,300.0 mmol) was added in portions, the temperature was raised to 25deg.C after the addition, the reaction was monitored by TLC, water (200 mL) was added to quench the reaction after the reaction was completed, extraction was performed with ethyl acetate (400 mL. Times.2), and the organic layer was dried, concentrated, and separated by column chromatography to give 43.2g of an off-white solid (compound 1 c) in a yield of 50.5%.

And a second step of: intermediate 1c (42.8 g,100.0 mmol) was dissolved in tetrahydrofuran (500 mL), cooled to-78deg.C, n-butyllithium (120 mmol, 1N) was added, stirred for 1 hour, then compound 1d (21.8 g,100.0 mmol) was added, after 2 hours of incubation, the temperature was raised to room temperature and reacted at room temperature for 1 hour, TLC monitored the reaction, saturated ammonium chloride was added after the reaction was completed to quench the reaction, extracted with ethyl acetate (500 mL. Times.2), the organic layer was concentrated, and column chromatography was separated to give 31.4g of an off-white solid (compound 1 e) in 61.9% yield.

And a third step of: compound 1e (31.0 g,61.1 mmol) was dissolved in ethyl acetate (300 mL), 100mL of ethyl acetate solution of hydrogen chloride was added at room temperature, the reaction was stirred at room temperature, TLC was monitored, after the reaction was completed, filtration was performed, and the filter cake was dried to give 23.5g of an off-white solid (compound 1 f) in 94.5% yield.

Fourth step: compound 1f (443 mg,1.0 mmol), compound 1g (87 mg,1.0 mmol) and DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was monitored by TLC under stirring at room temperature, after the reaction was completed, water quenching was added, the organic layer was concentrated, and the column chromatography was separated to give 334mg of an off-white solid (compound 1) in a yield of 64.9%. ESI (+) m/z=516.2.

The structural formula of the compound 1 is shown as formula 1, namely the corresponding structural formula of the corresponding compound with the serial number 1; other compounds and the like.

Example 2

A compound represented by formula 2: (9- (1- (3-fluorobenzyl) piperidin-4-yl) -9H-carbazol-4-yl) (1-methyl-1H-indol-3-yl) methyl ketone; the synthetic reaction formula is as follows:

compound 1f (443 mg,1.0 mmol), compound 2a (188 mg,1.0 mmol) and DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was stirred at room temperature, monitored by TLC, after the reaction was completed, water was added to quench the reaction, the organic layer was concentrated, and column chromatography was performed to obtain 298mg of an off-white solid (compound 2) in a yield of 57.9% and ESI (+) m/z=516.2.

Example 3

A compound represented by formula 3: (9- (1- (4-fluorobenzyl) piperidin-4-yl) -9H-carbazol-4-yl) (1-methyl-1H-indol-3-yl) methyl ketone; the synthetic reaction formula is as follows:

compound 1f (447 mg,1.0 mmol), compound 3a (188 mg,1.0 mmol) and DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was stirred at room temperature, monitored by TLC, after the reaction was completed, water was added to quench the reaction, the organic layer was concentrated, and column chromatography was performed to obtain 322mg of an off-white solid (compound 3) in a yield of 62.5% and ESI (+) m/z=516.2.

Example 4

A compound represented by formula 4: (9- (1- (3-methoxybenzyl) piperidin-4-yl) -9H-carbazol-4-yl) (1-methyl-1H-indol-3-yl) methyl ketone; the synthetic reaction formula is as follows:

compound 1f (443 mg,1.0 mmol), compound 4a (200 mg,1.0 mmol), DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was stirred at room temperature, monitored by TLC, after the reaction was completed, water was added to quench the reaction, the organic layer was concentrated, and the white solid (compound 4) 198mg was isolated by column chromatography in 37.6% yield, ESI (+) m/z= 528.2.

Example 5

A compound represented by formula 5: (1-methyl-1H-indol-3-yl) (9- (1- (pyridin-2-ylmethyl) piperidin-4-yl) -9H-carbazol-4-yl) methanone; the synthetic reaction formula is as follows:

compound 1f (443 mg,1.0 mmol), compound 5a (171 mg,1.0 mmol) and DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was stirred at room temperature, monitored by TLC, after the reaction was completed, water was added to quench the reaction, the organic layer was concentrated, and the white solid (compound 5) 209mg was isolated by column chromatography in a yield of 42.0% and ESI (+) m/z=499.2.

Example 6

A compound of formula 6: (1-methyl-1H-indol-3-yl) (9- (1- (pyridin-3-ylmethyl) piperidin-4-yl) -9H-carbazol-4-yl) methanone; the synthetic reaction formula is as follows:

compound 1f (443 mg,1.0 mmol), compound 6a (171 mg,1.0 mmol) and DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was stirred at room temperature, monitored by TLC, after the reaction was completed, water was added to quench the reaction, the organic layer was concentrated, and the white solid (compound 6) was isolated by column chromatography as 240mg in 48.2% yield, ESI (+) m/z=499.2.

Example 7

A compound of formula 7: (1-methyl-1H-indol-3-yl) (9- (1- (pyridin-4-ylmethyl) piperidin-4-yl) -9H-carbazol-4-yl) methanone; the synthetic reaction formula is as follows:

compound 1f (443 mg,1.0 mmol), compound 7a (171 mg,1.0 mmol), DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was stirred at room temperature, monitored by TLC, after the reaction was completed, water was added to quench the reaction, the organic layer was concentrated, and the white solid (compound 7) was separated by column chromatography to yield 265mg, 53.2% ESI (+) m/z=499.2.

Example 8

A compound of formula 8: (9- (1- ((6-methoxypyridin-2-yl) methyl) piperidin-4-yl) -9H-carbazol-4-yl) (1-methyl-1H-indol-3-yl) methyl ketone; the synthetic reaction formula is as follows:

compound 1f (443 mg,1.0 mmol), compound 8a (201 mg,1.0 mmol), DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was stirred at room temperature, monitored by TLC, after the reaction was completed, water was added to quench the reaction, the organic layer was concentrated, and the column chromatography was separated to give 302mg of an off-white solid (compound 8) in a yield of 57.2% and ESI (+) m/z=529.2.

Example 9

A compound of formula 9: (1-methyl-1H-indol-3-yl) (9- (1- (pyrimidin-2-ylmethyl) piperidin-4-yl) -9H-carbazol-4-yl) methyl ketone; the synthetic reaction formula is as follows:

compound 1f (443 mg,1.0 mmol), compound 9a (172 mg,1.0 mmol) and DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was stirred at room temperature, monitored by TLC, after the reaction was completed, water was added to quench the reaction, the organic layer was concentrated, and the column chromatography was separated to give 340mg of an off-white solid (compound 9) in a yield of 68.1% and ESI (+) m/z=500.2.

Example 10

A compound of formula 10: 2- ((4- (4- (1-methyl-1H-indole-3-carbonyl) -9H-carbazol-9-yl) piperidin-1-yl) methyl) benzamide; the synthetic reaction formula is as follows:

compound 1f (443 mg,1.0 mmol), compound 10a (213 mg,1.0 mmol) and DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was stirred at room temperature, monitored by TLC, after the reaction was completed, water was added to quench the reaction, the organic layer was concentrated, and column chromatography was performed to obtain 339mg of an off-white solid (compound 10) with a yield of 62.8% and ESI (+) m/z= 541.2.

Example 11

A compound of formula 11: 3- ((4- (4- (1-methyl-1H-indole-3-carbonyl) -9H-carbazol-9-yl) piperidin-1-yl) methyl) benzamide; the synthetic reaction formula is as follows:

compound 1f (443 mg,1.0 mmol), compound 11a (213 mg,1.0 mmol) and DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was stirred at room temperature, monitored by TLC, after the reaction was completed, water was added to quench the reaction, the organic layer was concentrated, and column chromatography was performed to obtain 315mg of an off-white solid (compound 11) in a yield of 58.3% and ESI (+) m/z= 541.2.

Example 12

A compound of formula 12: 4- ((4- (4- (1-methyl-1H-indole-3-carbonyl) -9H-carbazol-9-yl) piperidin-1-yl) methyl) benzamide; the synthetic reaction formula is as follows:

compound 1f (443 mg,1.0 mmol), compound 12a (213 mg,1.0 mmol) and DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was stirred at room temperature, monitored by TLC, after the reaction was completed, water was added to quench the reaction, the organic layer was concentrated, and column chromatography was performed to obtain 355mg of an off-white solid (compound 12) in a yield of 65.7% and ESI (+) m/z= 541.2.

Example 13

A compound of formula 13: 2- ((4- (4- (1-methyl-1H-indole-3-carbonyl) -9H-carbazol-9-yl) piperidin-1-yl) methyl) benzonitrile; the synthetic reaction formula is as follows:

compound 1f (443 mg,1.0 mmol), compound 13a (195 mg,1.0 mmol), DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was stirred at room temperature, monitored by TLC, after the reaction was completed, water was added to quench the reaction, the organic layer was concentrated, and the white solid (compound 13) 361mg was isolated by column chromatography in yield 69.2% ESI (+) m/z= 523.2.

Example 14

A compound of formula 14: 3- ((4- (4- (1-methyl-1H-indole-3-carbonyl) -9H-carbazol-9-yl) piperidin-1-yl) methyl) benzonitrile; the synthetic reaction formula is as follows:

compound 1f (443 mg,1.0 mmol), compound 14a (195 mg,1.0 mmol), DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was stirred at room temperature, monitored by TLC, after the reaction was completed, water was added to quench the reaction, the organic layer was concentrated, and the white solid (compound 14) 354mg was isolated by column chromatography in 67.8% yield, ESI (+) m/z= 523.2.

Example 15

A compound represented by formula 15: 4- ((4- (4- (1-methyl-1H-indole-3-carbonyl) -9H-carbazol-9-yl) piperidin-1-yl) methyl) benzonitrile; the synthetic reaction formula is as follows:

compound 1f (443 mg,1.0 mmol), compound 15a (195 mg,1.0 mmol), DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was stirred at room temperature, monitored by TLC, after the reaction was completed, water was added to quench the reaction, the organic layer was concentrated, and column chromatography was performed to obtain 319mg of an off-white solid (compound 15) in a yield of 61.1% and ESI (+) m/z= 523.2.

Example 16

A compound of formula 16: (9- (1- ((6-methoxypyridin-3-yl) methyl) piperidin-4-yl) -9H-carbazol-4-yl) (1 methyl-1H-indol-3-yl) methanone; the synthetic reaction formula is as follows:

compound 1f (443 mg,1.0 mmol), compound 16a (201 mg,1.0 mmol), DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was stirred at room temperature, monitored by TLC, after the reaction was completed, water was added to quench the reaction, the organic layer was concentrated, and column chromatography was performed to obtain 355mg of an off-white solid (compound 16) with a yield of 67.2% and ESI (+) m/z=529.2.

Example 17

A compound of formula 17: (9- (1- (benzo [ d ] [1,3] dioxolan-5-ylmethyl) piperidin-4-yl) -9H-carbazol-4-yl) (1-methyl-1H-indol-3-yl) methanone; the synthetic reaction formula is as follows:

compound 1f (443 mg,1.0 mmol), compound 17a (214 mg,1.0 mmol), DIEA (194 mg,1.5 mmol) were dissolved in dichloromethane (40 mL), the reaction was stirred at room temperature, monitored by TLC, after the reaction was completed, water was added to quench the reaction, the organic layer was concentrated, and column chromatography was performed to obtain 317mg of an off-white solid (compound 17) in a yield of 58.6% and ESI (+) m/z=542.2.

Biological evaluation test

This example shows that Sotrastaurin is an existing PKC inhibitor by examining the inhibition of PKC alpha (PKC theta) kinase by the compounds 1 to 17 prepared in examples 1 to 17.

Any one of the compounds 1 to 17 was dissolved in dimethyl sulfoxide (DMSO for short) to prepare a compound solution, 25. Mu.L of the compound solution and 10. Mu.L of PKCα (PKCθ) and 15. Mu.L of a mixed solution [20mM Tris-buffer, pH7.4,0.1% BSA (200. Mu.g/mL), 10mM Mg (NO) were added to a 96-well plate ₃ ) ₂ 10mM ATP and 3750Bq of ³³ P-ATP]. Incubation was carried out in an incubator at 30℃for 15 minutes, and stop reaction solution (10. Mu.L of 0.5M Na) ₂ EDTA, pH 7.4), and then 50. Mu.L of the mixture was pipetted onto the pre-moistened phosphocellulose plate. Unbound ATP was washed with 100. Mu.L double distilled water. The phosphocellulose plates were washed 2 times in 0.5% phosphoric acid, followed by 1 time in ethanol, then dried and placed in Omnifilter and counted in Topcount radiometer, and the IC of compounds 1 to 17 was calculated ₅₀ . The results are shown in Table 1:

TABLE 1

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Wherein, the compound number 1 corresponds to the compound 1, and the others are the same.

As can be seen from Table 1, compounds 1 to 17 all have a certain inhibition effect on PKC alpha (PKC theta) kinase, wherein the IC50 value of compounds 1 to 3, 5 to 7, 9 to 12 and 14 to 17 on PKC alpha is less than 10nM; compounds 1-2, compounds 4-6, compounds 11-13, compound 15, compound 17 have IC50 values for PKC theta of less than 10nM. Example 18

Formula 1 (components in wt.%)

In this example, the filler is microcrystalline cellulose, the disintegrant is sodium carboxymethyl starch, and the lubricant is sodium stearyl fumarate.

The methyl ketone derivative described in this example was selected from the product of example 4: (9- (1- (3-methoxybenzyl) piperidin-4-yl) -9H-carbazol-4-yl) (1-methyl-1H-indol-3-yl) methanone as PKC inhibitor.

The preparation method of the methylketone derivative pharmaceutical tablet comprises the following steps:

step 1, sieving the methyl ketone derivative raw material for later use.

And 2, weighing the methyl ketone derivative, the filler and the disintegrating agent, and putting the mixture into a three-dimensional mixer for mixing for 20min at 15 r/min.

And 3, adding 1.0% of lubricant into the mixed material, and mixing for 5min at 15r/min by adopting a three-dimensional mixer.

And 4, pressing the mixed materials into tablets by using a rotary tablet press.

And 5, packaging the sheet by adopting aluminum plastic.

Example 19

Formula 2 (components in wt.%)

The methyl ketone derivative described in this example was selected from the products of example 5: (1-methyl-1H-indol-3-yl) (9- (1- (pyridin-2-ylmethyl) piperidin-4-yl) -9H-carbazol-4-yl) methanone as a PKC inhibitor.

step 1, sieving the methyl ketone derivative raw material for later use.

And 3, putting the uniformly mixed materials into a dry granulator, feeding and converting the materials into 5HZ, tabletting and converting the materials into 15HZ, granulating and converting the materials into 50HZ, and preparing granules by using a screen with the aperture of 1.2 mm.

And step 4, adding 1.0% of lubricant into the mixed material, and mixing for 5min at 15r/min by adopting a three-dimensional mixer.

And 5, pressing the mixed materials into plain tablets by adopting a rotary tablet press.

And 6, putting the pressed plain tablets into a high-efficiency coating machine for coating, adopting the Opadry series gastric-soluble film coating powder of the Karaoke company to prepare coating liquid with the solid content of 10 percent for coating, and controlling the weight gain of the coating to be 2-4 percent.

And 7, packaging the sheet by adopting aluminum plastic.

Example 20

Formula 3 (components in wt.%)

In this example, the filler is lactose, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.

The methyl ketone derivative described in this example was selected from the products of example 10: 2- ((4- (4- (1-methyl-1H-indole-3-carbonyl) -9H-carbazol-9-yl) piperidin-1-yl) methyl) benzamide as PKC inhibitor.

step 1, sieving the methyl ketone derivative raw material for later use.

And 7, packaging the sheet by adopting aluminum plastic.

Example 21

Formula 4 (components in wt.%)

In this example, the filler was mannitol, the disintegrant was crospovidone, and the lubricant was colloidal silicon dioxide.

The methyl ketone derivative described in this example was selected from the product of example 15: 4- ((4- (4- (1-methyl-1H-indole-3-carbonyl) -9H-carbazol-9-yl) piperidin-1-yl) methyl) benzonitrile as PKC inhibitor.

step 1, sieving the methyl ketone derivative raw material for later use.

And 7, packaging the sheet by adopting aluminum plastic.

Dissolution test experiments were performed on the pharmaceutical formulations provided in examples 18-21.

Dissolution was measured by reference to dissolution and release rate measurement (second method of the fourth rule 0931 of chinese pharmacopoeia 2020).

Instrument: high performance liquid chromatograph and dissolution tester.

Dissolution medium: ph=6.8 phosphate buffer solution.

Volume of dissolution medium: 900mL, rotational speed: 50r/min.

Sampling time: 5min, 10min, 15min, 20min, 30min, 45min, and 60min.

The formulations corresponding to examples 18 to 21 were prepared according to the dissolution and release rate measurement method (second method of the fourth rule 0931 of the year 2020 edition of chinese pharmacopoeia) using a phosphate buffer solution with ph=6.8 as a dissolution medium at a rotation speed of 50 rpm, and the solution was taken according to the sampling time for measurement.

The dissolution profile results for examples 18-21 and the reference formulation in ph=6.8 phosphate buffered solution medium are shown in table 2.

TABLE 2

	Time (min)	5	10	15	20	30	45	60
									Example 18	Self-made product (%)	15.0	45.2	66.5	77.1	85.9	95.6	98.9
Example 19	Self-made product (%)	33.2	60.8	75.8	85.3	95.0	97.6	101.2
									Example 20	Self-made product (%)	25.6	55.3	70.0	80.0	90.2	96.8	99.5
Example 21	Self-made product (%)	24.3	50.9	69.5	79.2	88.5	96.2	99.5

As can be seen from Table 2, the methylketone derivative has excellent dissolution effect when being prepared into tablets, and can reach more than 85% in vitro dissolution within 30min and more than 90% in 45min, and the dissolution rate is high.

The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.

Claims

1. A pharmaceutical formulation of a methylketone derivative, characterized in that: comprises the following components in parts by mass:

the sum of the components is 100 parts;

the methyl ketone derivative is selected from any one of the following compounds in the formulas 1-17, and the structural formula is as follows:

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2. the pharmaceutical preparation of methyl ketone derivatives according to claim 1, wherein the filler is one or more of microcrystalline cellulose, lactose and mannitol.

3. The pharmaceutical preparation of methyl ketone derivatives according to claim 1, wherein the disintegrating agent is one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose.

4. The methylketone derivative pharmaceutical preparation according to claim 1, wherein the lubricant is one or more of sodium stearyl fumarate, magnesium stearate, colloidal silica, and talc.

5. The method for preparing a methylketone derivative pharmaceutical preparation according to claims 1 to 4, comprising the steps of:

step 1, sieving a methyl ketone derivative raw material for later use;

and 5, packaging the sheet by adopting aluminum plastic.

6. The method for preparing a methylketone derivative pharmaceutical preparation according to claims 1 to 4, comprising the steps of:

step 1, sieving a methyl ketone derivative raw material for later use;

step 6, putting the pressed plain tablets into a high-efficiency coating machine for coating; coating with coating solution with 10% solid content prepared from Opadry gastric-soluble film coating powder of Callery company, and controlling the weight gain of the coating to 2-4%;

and 7, packaging the sheet by adopting aluminum plastic.