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CN112552287B - Indole derivative pharmaceutical preparation and preparation method thereof - Google Patents

Indole derivative pharmaceutical preparation and preparation method thereof Download PDF

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CN112552287B
CN112552287B CN202011481659.5A CN202011481659A CN112552287B CN 112552287 B CN112552287 B CN 112552287B CN 202011481659 A CN202011481659 A CN 202011481659A CN 112552287 B CN112552287 B CN 112552287B
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indole derivative
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indole
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CN112552287A (en
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霍志强
黄巧萍
唐睿
柏小娟
李东凤
戴信敏
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Beijing Huashi Jingheng Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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Abstract

The invention relates to an indole derivative pharmaceutical preparation and a preparation method thereof, wherein the indole derivative pharmaceutical preparation comprises an indole derivative or a pharmaceutically acceptable salt thereof, a filler, a disintegrant, a binder and a lubricant. The indole derivative has a structure shown in formula I:
Figure DDA0002838303100000011
wherein R is1Selected from substituted or unsubstituted phenyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted five-membered ring, substituted or unsubstituted six-membered ring, or R1And together with the nitrogen atom adjacent thereto form a five-membered heterocyclic group or a six-membered heterocyclic group; when R is1Selected from substituted or unsubstituted five-membered rings containing up to 2 heteroatoms; when R is1Selected from substituted or unsubstituted six-membered rings containing up to 2 heteroatoms. The invention achieves the purpose of treating tumors by inhibiting the activity of Aurora-A kinase, and the medicinal preparation has high dissolution rate, good dissolution effect and high bioavailability.

Description

Indole derivative pharmaceutical preparation and preparation method thereof
Technical Field
The invention relates to an indole derivative pharmaceutical preparation and a preparation method thereof, belonging to the technical field of chemical medicine.
Background
Aurora-A is a member of Aurora protein kinase family, is a serine/threonine kinase which plays an important role in the cell proliferation process, participates in a plurality of processes of cell mitosis, including processes of cell G2/M conversion, mitotic spindle assembly, chromatid separation, cytoplasm division and the like, and plays an important role in regulating and controlling the cell mitotic process. Abnormal expression of Aurora-a can lead to amplification of cellular centrosomes, aneuploidy of the genome and chromosomal instability. Since Aurora-a is expressed abnormally in many types of tumors, Aurora-a is a potential target for the treatment of the tumors of interest.
The research of antitumor drugs by taking Aurora-A kinase as a target is more and more emphasized by people, Aurora-A kinase is expressed and activated in mitosis and is ineffective to non-proliferative cells, while the proliferation speed of most normal cells in a human body is not high, so that the Aurora-A kinase inhibitor belongs to targeted antitumor drugs.
Therefore, the research on the pharmaceutical preparation of the Aurora-A kinase inhibitor is of great significance.
Disclosure of Invention
The invention provides an indole derivative pharmaceutical preparation and a preparation method thereof, and the specific technical scheme is as follows:
an indole derivative pharmaceutical preparation, comprising an indole derivative or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers;
the indole derivative has a structure shown in formula I:
Figure BDA0002838303090000011
wherein R is1Selected from substituted or unsubstituted phenyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted five-membered ring, substituted or unsubstituted six-membered ring, or R1And together with the nitrogen atom adjacent thereto form a five-membered heterocyclic group or a six-membered heterocyclic group;
when R is1Selected from substituted or unsubstituted five-membered rings containing up to 2 heteroatoms;
when R is1Selected from substituted or unsubstituted six-membered rings containing heteroatomsThe number of the cells is at most 2.
As an improvement of the technical scheme, the indole derivative pharmaceutical preparation comprises the following components in parts by mass:
Figure BDA0002838303090000021
the sum of the mass parts of the components is 100 parts.
As an improvement of the technical scheme, the indole derivatives are selected from any one of the following compounds in formula 1-formula 24, and the structural formula is as follows:
Figure BDA0002838303090000022
Figure BDA0002838303090000031
Figure BDA0002838303090000041
Figure BDA0002838303090000051
Figure BDA0002838303090000061
Figure BDA0002838303090000071
as an improvement of the technical scheme, the filler is one or more of microcrystalline cellulose, starch, mannitol and lactose.
As an improvement of the technical scheme, the disintegrating agent is one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone and low-substituted hydroxypropyl cellulose.
As an improvement of the technical scheme, the adhesive is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose and povidone.
As an improvement of the technical scheme, the lubricant is one or more of sodium stearyl fumarate, magnesium stearate, aerosil and talcum powder.
The preparation method of the indole derivative pharmaceutical preparation comprises the following steps:
step 1, screening indole derivative raw materials for later use;
step 2, weighing the adhesive according to the prescription amount, preparing the adhesive and water into an adhesive solution, weighing the indole derivatives, the filler, the disintegrant and the adhesive solution, and mixing to prepare wet granules;
step 3, drying the prepared wet granules, controlling the moisture content to be 2-4%, and then finishing the granules;
step 4, adding a lubricant into the granules after finishing, and mixing by adopting a three-dimensional mixer;
and 5, preparing the mixed granules into tablets, granules or capsules.
As an improvement of the technical scheme, when the indole derivative pharmaceutical preparation is a tablet, in the preparation process, the pressed plain tablet is coated by coating liquid, and the weight gain of the coating is controlled to be 2-3%.
As an improvement of the technical scheme, the preparation method of the indole derivative pharmaceutical preparation comprises the following steps:
step 1, screening indole derivative raw materials for later use;
step 2, weighing indole derivatives, a filling agent, a disintegrating agent and an adhesive, and putting into a three-dimensional mixer for mixing;
step 3, adding a lubricant into the uniformly mixed mixture in the three-dimensional mixer and mixing again;
and 4, pressing the mixed materials into tablets.
The indole derivative can be prepared into any one of tablets, capsules and granules for treating or preventing tumors, wherein the tumors are 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, uterine body cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytic cancer, meningioma, Hodgkin lymphoma, non-Hodgkin lymphoma, acute lymphatic leukemia, chronic lymphatic leukemia, acute myeloid leukemia, chronic granulocytic leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, seminoma, chondrosarcoma, myosarcoma and fibrosarcoma.
The invention has the beneficial effects that:
1) the indole derivative medicinal preparation can achieve the aim of treating tumors by inhibiting the activity of Aurora-A kinase.
2) The indole derivative medicinal preparation has high dissolution rate, good dissolution effect and high bioavailability.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
A compound of formula 1: a process for the preparation of 4- (3- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) ureido) benzamide, having the formula:
Figure BDA0002838303090000081
the first step is as follows:
compound 1a (27.6g, 100.0mmol), compound 1b (12.8g, 100.0mmol), diisopropylethylamine (DIEA, 25.8g, 200.0mmol), HATU (45.6g, 120.0mmol) were dissolved in DMF (200mL), stirred at room temperature for 12 hours, monitored by TLC, cooled to room temperature after completion of the reaction, quenched with 200mL of water, extracted with ethyl acetate (300 mL. times.2), the organic layers combined, dried, concentrated, and isolated by column chromatography to give 28.5g of an off-white solid (compound 1c) with a yield of 73.8%.
The second step is that:
compound 1c (28.0g, 72.5mmol) was dissolved in ethyl acetate (EtOAc, 100mL), and an ethyl acetate solution of hydrogen chloride (50mL) was added at room temperature, and the reaction was stirred at room temperature for 4 hours, during which time a solid gradually precipitated, which was filtered and dried to give 23.8g of a white solid (compound 1d) with a yield of 91.7%.
The third step:
compound 1d (358mg, 1.0mmol), compound 1e (136mg, 1.0mmol), triethylamine (Et)3N, 303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (DCM, 300mL), the reaction was stirred overnight at room temperature, monitored by TLC, and after completion of the reaction, directly concentrated and isolated by column chromatography to give 246mg of an off-white solid (compound 1) in 54.9% yield and ESI (+) m/z ═ 449.2.
Example 2
A compound of formula 2: a process for the preparation of 4- (3- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) ureido) -N, N-dimethylbenzamide according to the formula:
Figure BDA0002838303090000091
compound 1d (358mg, 1.0mmol), compound 2a (164mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred overnight at room temperature, monitored by TLC, and after completion of the reaction, concentrated directly and isolated by column chromatography to give 312mg of an off-white solid (compound 2) in 65.4% yield ESI (+) m/z-478.2.
Example 3
A compound of formula 3: a process for the preparation of 4- (3- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) ureido) benzenesulfonamide, having the formula:
Figure BDA0002838303090000101
compound 1d (358mg, 1.0mmol), compound 3a (172mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred at room temperature overnight, monitored by TLC, and after completion of the reaction, concentrated directly and isolated by column chromatography to give 226mg of an off-white solid (compound 3) in 46.7% yield ESI (+) m/z 485.2.
Example 4
A compound of formula 4: a process for the preparation of 1- (4-acetylphenyl) -3- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) urea, of the formula:
Figure BDA0002838303090000102
compound 1d (358mg, 1.0mmol), compound 4a (135mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred overnight at room temperature, monitored by TLC, and after completion of the reaction, directly concentrated and isolated by column chromatography to give 268mg of an off-white solid (compound 4) in 59.9% yield ESI (+) m/z-448.2.
Example 5
A compound of formula 5: a process for the preparation of N- (4- (3- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) ureido) phenyl) acetamide having the formula:
Figure BDA0002838303090000111
compound 1d (358mg, 1.0mmol), compound 5a (150mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred overnight at room temperature, monitored by TLC, and after completion of the reaction, concentrated directly and isolated by column chromatography to give 282mg of an off-white solid (compound 5) in 61.0% yield (ESI (+) m/z 463.2).
Example 6
A compound of formula 6: a process for the preparation of N- (4- (3- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) ureido) phenyl) methanesulfonamide having the formula:
Figure BDA0002838303090000112
compound 1d (358mg, 1.0mmol), compound 6a (186mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred overnight at room temperature, monitored by TLC, and after completion of the reaction, directly concentrated and isolated by column chromatography to give 305mg of an off-white solid (compound 6) in 61.2% yield ESI (+) m/z-499.2.
Example 7
A compound of formula 7: a process for the preparation of 1- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3- (4-methoxyphenyl) urea, according to the formula:
Figure BDA0002838303090000121
compound 1d (358mg, 1.0mmol), compound 7a (123mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred overnight at room temperature, monitored by TLC, and after completion of the reaction, concentrated directly and isolated by column chromatography to give 228mg of an off-white solid (compound 7) in 52.4% yield ESI (+) m/z-436.2.
Example 8
A compound represented by formula 8: a process for the preparation of 4- (3- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) ureido) pyridine-2-carboxamide having the formula:
Figure BDA0002838303090000122
compound 1d (358mg, 1.0mmol), compound 8a (137mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred overnight at room temperature, monitored by TLC, and after completion of the reaction, concentrated directly and isolated by column chromatography to give 247mg of an off-white solid (compound 8) in 55.1% yield and ESI (+) m/z 449.2.
Example 9
A compound of formula 9: a process for the preparation of 1- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3- (4-fluorophenyl) urea according to the formula:
Figure BDA0002838303090000131
compound 1d (358mg, 1.0mmol), compound 9a (150mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred at room temperature overnight, monitored by TLC, and after completion of the reaction, concentrated directly and isolated by column chromatography to give 244mg of an off-white solid (compound 9) in 57.7% yield and ESI (+) m/z 424.2.
Example 10
A compound according to formula 10: a process for the preparation of 1- (4-chlorophenyl) -3- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) urea according to the formula:
Figure BDA0002838303090000132
compound 1d (358mg, 1.0mmol), compound 10a (127mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred at room temperature overnight, monitored by TLC, and after completion of the reaction, directly concentrated and isolated by column chromatography to give 266mg of an off-white solid (compound 10) in 60.5% yield (ESI (+) m/z ═ 440.2).
Example 11
A compound of formula 11: a process for the preparation of 1- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3- (4-fluoro-3-methoxyphenyl) urea, of the formula:
Figure BDA0002838303090000141
compound 1d (358mg, 1.0mmol), compound 11a (141mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred at room temperature overnight, monitored by TLC, and after completion of the reaction, the mixture was directly concentrated and column chromatography was carried out to give 238mg of an off-white solid (compound 11) in 52.5% yield (ESI (+) m/z 454.2).
Example 12
A compound of formula 12: a process for the preparation of 1- (2, 4-difluorophenyl) -3- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) urea according to the formula:
Figure BDA0002838303090000142
compound 1d (358mg, 1.0mmol), compound 12a (129mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred overnight at room temperature, monitored by TLC, and after completion of the reaction, directly concentrated and isolated by column chromatography to give 245mg of an off-white solid (compound 12) in 55.6% yield and ESI (+) m/z 442.2.
Example 13
A compound of formula 13: a process for the preparation of 1- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3- (6-fluoropyridin-3-yl) urea, of the formula:
Figure BDA0002838303090000151
compound 1d (358mg, 1.0mmol), compound 13a (112mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred at room temperature overnight, monitored by TLC, and after completion of the reaction, concentrated directly and isolated by column chromatography to give 219mg of an off-white solid (compound 13) in 51.7% yield and ESI (+) m/z 425.2.
Example 14
A compound of formula 14: a process for the preparation of 1- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3- (pyrimidin-5-yl) urea according to the formula:
Figure BDA0002838303090000152
compound 1d (358mg, 1.0mmol), compound 14a (95mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred at room temperature overnight, monitored by TLC, and after completion of the reaction, concentrated directly and isolated by column chromatography to give 223mg of an off-white solid (compound 14) in 54.8% yield (ESI (+) m/z: 408.2).
Example 15
A compound according to formula 15: a process for the preparation of 1- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3- (2-methoxypyridin-4-yl) urea according to the formula:
Figure BDA0002838303090000161
compound 1d (358mg, 1.0mmol), compound 15a (124mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred overnight at room temperature, monitored by TLC, and after completion of the reaction, concentrated directly and isolated by column chromatography to give 255mg of an off-white solid (compound 15) in 58.5% yield ESI (+) m/z 437.2.
Example 16
A compound according to formula 16: a process for the preparation of 1- (benzo [ d ] [1,3] dioxolan-5-yl) -3- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) urea according to the formula:
Figure BDA0002838303090000162
compound 1d (358mg, 1.0mmol), compound 16a (137mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred at room temperature overnight, monitored by TLC, and after completion of the reaction, the reaction was directly concentrated and column chromatography gave 288mg of an off-white solid (compound 16) in 64.1% yield (ESI (+) m/z 450.2).
Example 17
A compound according to formula 17: a process for the preparation of 1- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3- (1-methylpiperidin-4-yl) urea according to the following reaction scheme:
Figure BDA0002838303090000171
compound 1d (358mg, 1.0mmol), compound 17a (114mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), stirred at room temperature overnight, monitored by TLC, and after completion of the reaction, concentrated directly and isolated by column chromatography to give 258mg of an off-white solid (compound 17) in 60.6% yield ESI (+) m/z-427.2.
Example 18
A compound according to formula 18: a process for the preparation of N- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) morpholine-4-carboxamide, of the formula:
Figure BDA0002838303090000172
compound 1d (358mg, 1.0mmol), compound 18a (87mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred at room temperature overnight, monitored by TLC, and after completion of the reaction, concentrated directly and isolated by column chromatography to give 280mg of an off-white solid (compound 18) in 70.0% yield (ESI (+) m/z 400.2).
Example 19
A compound according to formula 19: a process for the preparation of 1- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3- (1-acetylpiperidin-4-yl) urea according to the formula:
Figure BDA0002838303090000181
compound 1d (358mg, 1.0mmol), compound 19a (142mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred overnight at room temperature, monitored by TLC, and after completion of the reaction, directly concentrated and isolated by column chromatography to give 265mg of an off-white solid (compound 19) in 58.4% yield ESI (+) m/z 455.2.
Example 20
A compound represented by formula 20: a process for the preparation of 1- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3- (4-oxocyclohexyl) urea, of the formula:
Figure BDA0002838303090000182
compound 1d (358mg, 1.0mmol), compound 20a (113mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred at room temperature overnight, monitored by TLC, and after completion of the reaction, concentrated directly and isolated by column chromatography to give 301mg of an off-white solid (compound 20) in 70.8% yield ESI (+) m/z 426.2.
Example 21
A compound of formula 21: a process for the preparation of 1- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3- (1-methylpyrrolidin-3-yl) urea according to the formula:
Figure BDA0002838303090000191
compound 1d (358mg, 1.0mmol), compound 21a (100mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred overnight at room temperature, monitored by TLC, and after completion of the reaction, concentrated directly and isolated by column chromatography to give 275mg of an off-white solid (compound 21) in 66.7% yield ESI (+) m/z 413.2.
Example 22
A compound represented by formula 22: a process for the preparation of N- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3-oxopyrrolidine-1-carboxamide having the following reaction formula:
Figure BDA0002838303090000192
compound 1d (358mg, 1.0mmol), compound 22a (85mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), stirred at room temperature overnight, monitored by TLC, and after completion of the reaction, directly concentrated and isolated by column chromatography to give 295mg of an off-white solid (compound 22) in 74.3% yield (ESI (+) m/z: 398.2).
Example 23
A compound according to formula 23: a process for the preparation of 1- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3- (3-oxocyclopentyl) urea according to the formula:
Figure BDA0002838303090000193
compound 1d (358mg, 1.0mmol), compound 23a (99mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred overnight at room temperature, monitored by TLC, and after completion of the reaction, directly concentrated and isolated by column chromatography to give 322mg of an off-white solid (compound 23) in 78.3% yield ESI (+) m/z-412.2.
Example 24
A compound represented by formula 24: a process for the preparation of 1- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3- (tetrahydro-2H-pyran-4-yl) urea, of the formula:
Figure BDA0002838303090000201
compound 1d (358mg, 1.0mmol), compound 24a (101mg, 1.0mmol), triethylamine (303mg, 3.0mmol) and CDI (162mg, 1.0mmol) were dissolved in dichloromethane (300mL), the reaction was stirred overnight at room temperature, monitored by TLC, and after completion of the reaction, concentrated directly and isolated by column chromatography to give 302mg of an off-white solid (compound 24) in 73.1% yield and ESI (+) m/z 414.2.
Example 25
The experimental procedure for the in vitro activity test of Aurora-a kinase is as follows:
adding 10 mu L of reaction solution, 10 mu L of LAurora-A kinase, 10 mu L of substrate, 10 mu L of solution of compound to be detected and 10 mu L of LATP solution into a 96-well plate in sequence, mixing uniformly and incubating for 30 minutes; then 10. mu.L of kinase reaction stop solution was added to each well plate, followed by 10. mu.L of phospho-histone H3 antibody to each well plate, 100. mu.L of LHRP-antibody chelator solution after incubation for 60 minutes at 25 ℃, followed by 100. mu.L of TMB substrate for 10 minutes at 25 ℃, and finally 100. mu.L of ELISA stop solution to each well plate, and 450nm readings were recorded with an ELISA detector, and IC was calculated using the drug-free solvent as a blank control50The specific data are shown in table 1:
TABLE 1
Figure BDA0002838303090000202
Figure BDA0002838303090000211
A＜50nM，50nM≤B≤500nM，500nM＜C。
Example 26
Formulation 1 (Components in wt%)
Figure BDA0002838303090000212
The indole derivative described in this example was selected from the product of example 13: 1- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3- (6-fluoropyridin-3-yl) urea as indole derivative.
The preparation method of the indole derivative medicine tablet comprises the following steps:
step 1, screening indole derivative raw materials for later use.
And 2, weighing the indole derivatives, the microcrystalline cellulose, the croscarmellose sodium and the hydroxypropyl cellulose according to the formula amount in the formula 1, and putting the weighed indole derivatives, the microcrystalline cellulose, the croscarmellose sodium and the hydroxypropyl cellulose into a three-dimensional mixer to mix for 30min at a rotating speed of 10 r/min.
And 3, adding magnesium stearate into the mixed materials in the three-dimensional mixer, and mixing for 5min at the rotating speed of 10 r/min.
And 4, pressing the mixed materials into tablets by adopting a rotary tablet press.
And 5, packaging the tablets by adopting aluminum plastic.
Example 27
Formulation 2 (Components in wt%)
Figure BDA0002838303090000213
The indole derivative described in this example was selected from the product of example 15: 1- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3- (2-methoxypyridin-4-yl) urea as indole derivative.
The preparation method of the indole derivative medicine tablet comprises the following steps:
step 1, screening indole derivative raw materials for later use.
Step 2, weighing povidone K30 according to the prescription of the formula 2 and preparing the povidone K30 and water into povidone K30 water solution; weighing indole derivatives, microcrystalline cellulose and crospovidone, putting into a wet mixing granulator, mixing for 5min, adding povidone K30 water solution, preparing into wet granules, granulating, and sieving with 18 mesh sieve.
And 3, drying the wet particles by adopting a fluidized bed to obtain dry particles, keeping the air inlet temperature of the fluidized bed at 50-70 ℃, keeping the material temperature at 30-40 ℃, controlling the moisture of the dry particles to be 2-4%, and then finishing the particles.
And 4, adding the superfine silica gel powder into the dried dry particles, and mixing for 5min at the speed of 10r/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, preparing coating liquid with the solid content of 10% by adopting Opadry series film coating powder of Carekon company, and controlling the coating weight to be increased by 2-3%.
And 7, packaging the coated tablets by adopting aluminum plastic.
Example 28
Formulation 3 (Components in wt%)
Figure BDA0002838303090000221
The indole derivative described in this example was selected from the product of example 22: n- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3-oxopyrrolidine-1-carboxamide as indole derivative.
The preparation method of the indole derivative medicine capsule comprises the following steps:
step 1, screening indole derivative raw materials for later use.
Step 2, weighing hydroxypropyl cellulose according to the prescription amount of the formula 3, and preparing the hydroxypropyl cellulose and water into a hydroxypropyl cellulose aqueous solution; weighing indole derivatives, corn starch and low-substituted hydroxypropyl cellulose, putting into a high-efficiency wet granulator, mixing for 5min, adding hydroxypropyl cellulose water solution, and preparing into wet granules.
And 3, drying the wet particles by using an oven or a fluidized bed to obtain dry particles, wherein the moisture of the dried dry particles is 2-3%, and then finishing the particles.
And 4, adding the superfine silica gel powder into the finished particles, and mixing by adopting a three-dimensional mixer.
And 5, putting the mixed materials into a capsule filling machine for filling.
And 6, packaging the filled capsules by adopting aluminum plastic.
Example 29
Formulation 4 (Components in wt%)
Figure BDA0002838303090000231
The indole derivative described in this example was selected from the product of example 23: 1- (2- (3- (dimethylamino) piperidine-1-carbonyl) -1H-indol-4-yl) -3- (3-oxocyclopentyl) urea as indole derivative.
The preparation method of the indole derivative drug granules comprises the following steps:
step 1, screening indole derivative raw materials for later use.
Step 2, weighing povidone K30 according to the prescription of the formula 4, and preparing povidone K30 and water into povidone K30 water solution; weighing indole derivatives, lactose, microcrystalline cellulose and sodium carboxymethyl starch, putting into a high-efficiency wet granulator, mixing for 5min, adding polyvidone K30 water solution, and making into wet granule.
And 3, drying the wet particles by adopting a fluidized bed to obtain dry particles, wherein the moisture content of the dried dry particles is 2-4%, and then finishing the particles.
And 4, adding sodium stearyl fumarate into the whole granules, and mixing by adopting a three-dimensional mixer.
And 5, subpackaging the mixed particles by using a particle packaging machine.
Example 30
Dissolution testing experiments were performed on the corresponding formulations in examples 26-29.
Dissolution is determined by reference to dissolution and release determination methods (second method of 0931, the four general rules of the 2020 edition of Chinese pharmacopoeia).
The instrument comprises the following steps: ultraviolet spectrophotometer and dissolution rate tester.
Dissolution medium: phosphate buffered solution pH 6.8.
Volume of dissolution medium: 900mL, rotation speed: 50 r/min.
Sampling time: 5min, 10min, 15min, 30min, 45 min.
The formulations of examples 26 to 29 were measured according to the dissolution and release rate measurement method using a phosphate buffer solution having a pH of 6.8 as a dissolution medium and a rotation speed of 50 rpm, and the solutions were measured according to the sampling time.
The results of the dissolution profiles of examples 26 to 29 and the reference formulation in phosphate buffered saline at pH 6.8 are shown in table 2:
TABLE 2
Time (min) 5 10 15 30 45
Example 26 From preparation (%) 23.5 42.3 63.2 81.5 94.2
Example 27 From preparation (%) 13.4 30.7 49.6 77.6 91.1
Example 28 From preparation (%) 10.5 26.2 44.5 72.8 88.9
Example 29 From preparation (%) 18.2 42.1 65.5 83.2 95.9
From table 2, it can be seen that: when the indole derivatives are prepared into corresponding tablets, granules or capsules, the indole derivatives have excellent dissolution effect, the in-vitro dissolution rate can reach more than 85% within 45min, the dissolution rate is high, and the bioavailability is good.
In the above examples, compound 1 refers to a compound of formula 1, compound 1a refers to a compound of formula 1a, and so on.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (9)

1. An indole derivative pharmaceutical preparation, which is characterized by comprising an indole derivative or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers;
the indole derivatives are selected from any one of the following compounds 1 to 24, and the structural formula is as follows:
Figure FDA0003172677460000011
Figure FDA0003172677460000021
Figure FDA0003172677460000031
Figure FDA0003172677460000041
Figure FDA0003172677460000051
2. the indole derivative pharmaceutical preparation according to claim 1, comprising the following components in parts by mass:
Figure FDA0003172677460000052
Figure FDA0003172677460000061
the sum of the mass parts of the components is 100 parts.
3. The indole derivative pharmaceutical formulation of claim 2, wherein: the filler is one or more of microcrystalline cellulose, starch, mannitol and lactose.
4. The indole derivative pharmaceutical formulation of claim 2, wherein: the disintegrant is one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose.
5. The indole derivative pharmaceutical formulation of claim 2, wherein: the adhesive is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvidone.
6. The indole derivative pharmaceutical formulation of claim 2, wherein: the lubricant is one or more of sodium stearyl fumarate, magnesium stearate, silica gel micropowder and pulvis Talci.
7. The process for preparing an indole derivative pharmaceutical formulation according to claim 2, comprising the steps of:
step 1, screening indole derivative raw materials for later use;
step 2, weighing the adhesive according to the prescription amount, preparing the adhesive and water into an adhesive solution, weighing the indole derivatives, the filler, the disintegrant and the adhesive solution, and mixing to prepare wet granules;
step 3, drying the prepared wet granules, controlling the moisture content to be 2-4%, and then finishing the granules;
step 4, adding a lubricant into the granules after finishing, and mixing by adopting a three-dimensional mixer;
and 5, preparing the mixed granules into tablets, granules or capsules.
8. The process for preparing an indole derivative pharmaceutical formulation according to claim 7, wherein: when the indole derivative pharmaceutical preparation is a tablet, the pressed tablet is coated by coating liquid in the preparation process, and the weight gain of the coating is controlled to be 2-3%.
9. The process for preparing an indole derivative pharmaceutical formulation according to claim 2, comprising the steps of:
step 1, screening indole derivative raw materials for later use;
step 2, weighing indole derivatives, a filling agent, a disintegrating agent and an adhesive, and putting into a three-dimensional mixer for mixing;
step 3, adding a lubricant into the uniformly mixed mixture in the three-dimensional mixer and mixing again;
and 4, pressing the mixed materials into tablets.
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