Pharmaceutical composition for treating prostate diseases and glandular nodules and application thereof

Abstract

The invention belongs to the technical field of preparation and application of small molecule drugs, and particularly relates to a pharmaceutical composition for treating prostate diseases and glandular nodules and application of the pharmaceutical composition. The pharmaceutical composition comprises a heterocyclic compound with the structure shown in the formula I or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier of the heterocyclic compound; # imgabs0 # wherein at least one of X1, X2, X3 and X4 is a nitrogen atom, and the remainder is a carbon atom; x5 is an oxygen atom or a carbon atom; and X6 is a nitrogen atom or a carbon atom.

Description

Technical Field

[0001] The present invention belongs to the technical field of small molecule drug preparation and application, and specifically relates to a drug composition for treating prostate diseases and glandular nodules and its application. Background Art

[0002] Prostatitis is clinically divided into acute prostatitis, chronic prostatitis and asymptomatic prostatitis. Chronic prostatitis is clinically divided into chronic bacterial prostatitis and chronic non-bacterial prostatitis / chronic pelvic pain syndrome. For a long time, the treatment drugs for prostatitis have always had the disadvantage of slow onset of effect. In addition, they can only play some local anti-inflammatory effects during the treatment process, and have no substantial effect on eliminating the inflammation of the entire prostate gland. Summary of the invention

[0003] The purpose of the present invention is to provide a pharmaceutical composition for treating prostate diseases to solve the problems raised in the background technology.

[0004] According to a first aspect of an embodiment of the present invention, there is provided a pharmaceutical composition for treating prostate diseases, the pharmaceutical composition comprising a heterocyclic compound having a structure of the following formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;

[0005]

[0006] Among them, X 1 , X 2 , X 3 and X 4 At least one of them is a nitrogen atom and the rest are carbon atoms;

[0007] X 5 is an oxygen atom or a carbon atom; X 6 is a nitrogen atom or a carbon atom;

[0008] R 1 is hydrogen, a halogen atom, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a C1-C10 alkyl group, a C2-C10 alkenyl group, a C1-C10 alkoxy group, a C3-C12 cycloalkyl group or a 3-12 membered heterocyclic group;

[0009] Ar 1 It is a C3-C12 cycloalkyl, a C5-C12 aryl, a 3-12-membered heterocycloalkyl or a 5-12-membered heteroaryl; the C3-C12 cycloalkyl, C5-C12 aryl, a 3-12-membered heterocycloalkyl or a 5-12-membered heteroaryl is optionally substituted by one or more halogen atoms, amino, nitro, hydroxyl, carboxyl, cyano, C1-C5 alkyl, C2-C5 alkenyl or C1-C5 alkoxy.

[0010] In one aspect of the embodiments of the present invention, the heterocyclic compound is a compound having the structure of the following formula II:

[0011]

[0012] Among them, R 1 is hydrogen, a halogen atom, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a C1-C10 alkyl group, a C2-C10 alkenyl group, a C1-C10 alkoxy group, a C3-C12 cycloalkyl group or a 3-12 membered heterocyclic group;

[0013] Ar 1 It is a C3-C12 cycloalkyl, a C5-C12 aryl, a 3-12-membered heterocycloalkyl or a 5-12-membered heteroaryl; the C3-C12 cycloalkyl, C5-C12 aryl, a 3-12-membered heterocycloalkyl or a 5-12-membered heteroaryl is optionally substituted by one or more halogen atoms, amino, nitro, hydroxyl, carboxyl, cyano, C1-C5 alkyl, C2-C5 alkenyl or C1-C5 alkoxy.

[0014] In one aspect of the embodiments of the present invention, the heterocyclic compound is a compound having the structure of the following formula III:

[0015]

[0016] Among them, Ar 1 It is a C3-C12 cycloalkyl, a C5-C12 aryl, a 3-12-membered heterocycloalkyl or a 5-12-membered heteroaryl; the C3-C12 cycloalkyl, C5-C12 aryl, a 3-12-membered heterocycloalkyl or a 5-12-membered heteroaryl is optionally substituted by one or more halogen atoms, amino, nitro, hydroxyl, carboxyl, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl or C1-C5 alkoxy.

[0017] In one aspect of the embodiment of the present invention, preferably, Ar 1 for

[0018]

[0019] Said

[0020] Optionally substituted by one or more halogen atoms, amino, nitro, hydroxyl, carboxyl, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl or C1-C5 alkoxy.

[0021] In one aspect of the embodiments of the present invention, the heterocyclic compound is a compound having the following structures of Formula III-A to Formula III-F;

[0022]

[0023]

[0024] Among them, R 2 It is a C1-C5 alkyl, a C2-C5 alkenyl or a C1-C5 alkoxy.

[0025] In one aspect of the embodiments of the present invention, the heterocyclic compound is at least one of the following compounds 1 to 14;

[0026]

[0027]

[0028]

[0029] In one aspect of the embodiments of the present invention, the heterocyclic compound is prepared by the following steps: Step 1:

[0030]

[0031] Step 2:

[0032]

[0033] Step 3:

[0034]

[0035] Step 4:

[0036]

[0037] Step 5:

[0038]

[0039] In one aspect of the embodiment of the present invention, the boronic acid group of the raw material B may also be a boronic acid pinacol ester group.

[0040] In one aspect of the embodiments of the present invention, the heterocyclic compound is Compound 5, Compound 6 or Compound 13.

[0041] In one aspect of the embodiments of the present invention, the prostate disease is prostatitis and / or prostate hyperplasia.

[0042] In one aspect of the embodiments of the present invention, the prostate disease is prostate cancer.

[0043] According to a second aspect of an embodiment of the present invention, there is provided use of the aforementioned pharmaceutical composition in treating prostate diseases and glandular nodules, wherein the pharmaceutical composition is used alone or in combination with other drugs.

[0044] In one aspect of an embodiment of the present invention, the combined use is combined with surgery, one or more Western medicines, Chinese herbal medicine, radiotherapy, gene therapy or biological regulators.

[0045] According to a third aspect of an embodiment of the present invention, there is provided use of the aforementioned pharmaceutical composition as an effective ingredient in the preparation of a drug for treating prostatitis and / or prostatic hyperplasia, wherein the pharmaceutical composition is used alone or in combination with other drugs.

[0046] In one aspect of an embodiment of the present invention, the combined use is combined with surgery, one or more Western medicines, Chinese herbal medicine, radiotherapy, gene therapy or biological regulators.

[0047] Compared with the prior art, the present invention has the following beneficial effects:

[0048] It can be seen from the above embodiments that the pharmaceutical composition for treating prostate diseases and glandular nodules provided by the present invention can effectively antagonize the proliferation of prostate cancer cells LNCaP and 22RV1, and can selectively regulate the activity of androgen receptor (AR), inhibit the nuclear translocation of AR, thereby blocking the interaction between AR and DNA, and further characterizing the activity against prostate tumor cells.

[0049] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention. DETAILED DESCRIPTION

[0050] In order to make the purpose, technical scheme and advantages of the present invention clearer, the technical scheme of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all the embodiments. The relevant embodiments described herein are illustrative and are used to provide a basic understanding of the present invention. The embodiments of the present invention should not be interpreted as limiting the present invention.

[0051] For simplicity, only some numerical ranges are specifically disclosed herein. However, any lower limit can be combined with any upper limit to form an unspecified range; and any lower limit can be combined with other lower limits to form an unspecified range, and any upper limit can be combined with any other upper limit to form an unspecified range. In addition, each separately disclosed point or single value can itself be combined as a lower limit or upper limit with any other point or single value or with other lower limits or upper limits to form an unspecified range.

[0052] In this article, the terms "comprises", "comprising" or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device that includes a series of elements includes not only those elements, but also includes other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of more restrictions, an element defined by the sentence "comprising a ..." does not exclude the presence of other identical elements in the process, method, article or device that includes the element.

[0053] In the description herein, unless otherwise specified, “above” and “below” include the number.

[0054] Unless otherwise specified, the terms used in the present invention have the commonly known meanings generally understood by those skilled in the art. Unless otherwise specified, the numerical values ​​of the various parameters mentioned in the present invention can be measured using various measurement methods commonly used in the art (for example, they can be tested according to the methods given in the embodiments of the present invention).

[0055] The term "about" is used to describe and illustrate small changes. When used in conjunction with an event or situation, the term may refer to an example in which the event or situation occurs precisely and an example in which the event or situation occurs very approximately. For example, when used in conjunction with a numerical value, the term may refer to a range of variation of less than or equal to ±10% of the numerical value, such as less than or equal to ±5%, less than or equal to ±4%, less than or equal to ±3%, less than or equal to ±2%, less than or equal to ±1%, less than or equal to ±0.5%, less than or equal to ±0.1%, or less than or equal to ±0.05%. In addition, amounts, ratios, and other numerical values ​​are sometimes presented in this article in a range format. It should be understood that such a range format is for convenience and simplicity, and should be flexibly understood to include not only numerical values ​​explicitly designated as range limits, but also all individual numerical values ​​or subranges encompassed within the range, as if each numerical value and subrange were explicitly designated.

[0056] A list of items connected by the terms "at least one of," "at least one of," "at least one of," or other similar terms may mean any combination of the listed items. For example, if items A and B are listed, the phrase "at least one of A and B" means only A; only B; or A and B. In another example, if items A, B, and C are listed, the phrase "at least one of A, B, and C" means only A; or only B; only C; A and B (excluding C); A and C (excluding B); B and C (excluding A); or all of A, B, and C. Item A may contain a single component or multiple components. Item B may contain a single component or multiple components. Item C may contain a single component or multiple components.

[0057] In the present invention, the term "alkyl" refers to an aliphatic hydrocarbon group, which can be straight or branched. Branched refers to one or more lower alkyl groups, such as methyl, ethyl or propyl, attached to a linear alkyl chain. "Lower alkyl" refers to a group containing about 1 to about 6 carbon atoms in the chain, which can be straight or branched.

[0058] In the present invention, the term "alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which can be straight or branched. Branched refers to one or more lower alkyl groups, such as methyl, ethyl or propyl, attached to a linear alkenyl chain. "Lower alkenyl" refers to a group containing about 2 to about 6 carbon atoms in the chain, which can be straight or branched.

[0059] In the present invention, the term "amino" refers to a -NR'R" group. The amino group may be optionally substituted. In an unsubstituted amino group, R' and R" are hydrogen. In a substituted amino group, R' and R" may each independently be, but are not limited to, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, sulfonyl, alkenyl, alkanoyl, aryl, arylalkyl or heteroaryl, provided that R' and R" are not both hydrogen. In a substituted amino group, R' and R" may be cyclized to form a cyclic amino group, such as a pyrrolidinyl or piperidinyl group. Such cyclic amino groups may incorporate other heteroatoms, for example to form piperazine or morpholine groups. Such cyclic amino groups may be optionally substituted, for example, by amino, hydroxyl or oxo groups.

[0060] In the present invention, the term "alkoxy" refers to -O-alkyl. Alkoxy can refer to a straight chain, branched or cyclic, saturated or unsaturated oxy-hydrocarbon chain, including, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and pentoxy. Alkoxy can be optionally substituted with one or more alkoxy substituents ("substituted alkoxy").

[0061] In the present invention, the term "cycloalkyl" refers to a non-aromatic mono- or polycyclic ring system containing about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms, and the preferred cycloalkyl ring contains about 5 to about 7 ring atoms. The cycloalkyl group may be optionally substituted with one or more "ring system substituents", which may be the same or different and are defined as above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Non-limiting examples of suitable polycyclic cycloalkyls include 1-decalin, norbornyl, adamantyl, etc.

[0062] In the present invention, the term "heterocyclyl" refers to a non-aromatic saturated monocyclic or polycyclic ring system containing about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, wherein one or more of the ring atoms in the ring system is an element other than carbon, such as nitrogen, oxygen or sulfur, either alone or in combination. There are no adjacent oxygen and / or sulfur atoms in the ring system, and preferred heterocycles contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name indicates that at least one nitrogen, oxygen or sulfur atom is present as a ring atom, respectively. The heterocyclyl may optionally be substituted with one or more "ring system substituents", which are the same or different, as defined herein. The nitrogen or sulfur atom of the heterocyclyl may optionally be oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0063] In the present invention, the term "aryl" refers to an aromatic monocyclic or polycyclic ring system. The aryl group may be optionally substituted with one or more "ring system substituents", which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

[0064] In the present invention, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system in which one or more of the ring atoms is an element other than carbon, such as nitrogen, oxygen or sulfur, either alone or in combination, preferably containing about 5 to about 6 ring atoms. The "heteroaryl" may be optionally substituted with one or more "ring system substituents", which may be the same or different, as defined herein. The prefix aza, oxa or thia before the heteroaryl root name indicates that at least one nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The nitrogen atom of the heteroaryl may be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryl groups include pyridinyl, pyrazinyl, furanyl, thiophenyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, 2,3-naphthyridinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothiophenyl, quinolinyl, imidazolyl, thienopyridinyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridinyl, imidazopyridinyl, isoquinolinyl, benzazaindolyl, 1,2,4-triazinyl, benzothiazolyl, and the like.

[0065] The present invention will be further described below in conjunction with the examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0066] Embodiment 1

[0067] Preparation of compound 1:

[0068] Step 1:

[0069]

[0070] Take 5-chloropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (395.2 mg, 2 mmol), use N, N-dimethylformamide to dissolve it in a 50 mL single-mouth bottle, add HATU (912 mg, 2.4 mmol) and DL-phenylglycinol (330.8 mg, 2.4 mmol) at room temperature, add DIPEA (645.0 mg, 5 mmol) dropwise, and after the addition is completed, react at room temperature for 2 hours; after the reaction is completed, the solvent is removed by rotation, and the mixture is purified by silica gel (ethyl acetate / petroleum ether=1 / 2) to obtain 430.8 mg of intermediate A-1 (5-chloro-N-(2-hydroxy-1-phenylethyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide).

[0071] Step 2:

[0072]

[0073] The intermediate A-1 (5-chloro-N-(2-hydroxy-1-phenylethyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide) (430.8 mg, 1.36 mmol) and triethylamine (404.76 mg, 4 mmol) were dissolved in tetrahydrofuran, stirred at 0°C for 5 minutes, and then p-toluenesulfonyl chloride (610.1 mg, 3.2 mmol) was slowly added dropwise to the reaction system. After the addition was completed, the temperature was raised to room temperature and the reaction was carried out at room temperature for 6 hours. The reaction of the raw material was complete as detected by LC-Ms. ​​The solvent was removed by rotation, and the mixture was extracted three times with ethyl acetate and water. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was removed by rotation to obtain a yellow crude product (intermediate B-1).

[0074] Step 3:

[0075]

[0076] All the crude products obtained in the previous step were dissolved in 40 mL of tetrahydrofuran solution, and DIPEA (1160 mg, 9 mmol) was added. The temperature was raised to 80 ° C. and the reaction was carried out at this temperature for 12 hours. The reaction of the raw materials was monitored by LC-Ms. ​​The solvent was removed from the reaction solution by vortexing, and ethyl acetate and water were added for extraction three times. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was dried by vortexing, and purified using silica gel (ethyl acetate / petroleum ether = 1 / 2) to obtain a light yellow solid (intermediate C-1, 2-(5-chloropyrazolo[1,5-a]pyrimidin-2-yl)-4-phenyl-4,5-dihydrooxazole) 319 mg.

[0077] Step 4:

[0078]

[0079] 2-(5-chloropyrazolo[1,5-a]pyrimidin-2-yl)-4-phenyl-4,5-dihydrooxazole (319 mg, 1.068 mmol) was dissolved in anhydrous dichloromethane, 2,3-dichloro-5,6-dicyanobenzoquinone (600 mg, 2.64 mmol) and 4A molecular sieves (250 mg) were added, and the reaction was carried out at room temperature for 4 hours; the reaction of the raw materials was monitored by LC-Ms; after the reaction was completed, the filter was filtered, and the filter cake was washed twice with anhydrous dichloromethane, and the solvent was removed by rotation to obtain 289 mg of yellow oily compound intermediate D-1 (2-(5-chloropyrazolo[1,5-a]pyrimidin-2-yl)-4-phenyloxazole).

[0080] Step 5:

[0081]

[0082] To a single-mouth bottle, add 150 mg (0.5 mmol) of intermediate D-1 (2-(5-chloropyrazolo[1,5-a]pyrimidin-2-yl)-4-phenyloxazole), then add 1-methyl-1H-pyrazole-4-boronic acid (100 mg, 0.8 mmol), 1,4-dioxane (15 mL) and water (5 mL), add potassium carbonate (90 mg, 0.65 mmol) under stirring at room temperature, add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (12 mL) and 1,4-dioxane (15 mL). g, 0.016mmol), argon was replaced 3 times, the temperature was raised to 100℃, the reaction was carried out for 6 hours, the mixture was naturally cooled to room temperature, the solvent was evaporated under reduced pressure, ethyl acetate and water were added to the residue for extraction, the liquids were separated, the organic phase was washed with water until neutral, anhydrous sodium sulfate was added for drying, and the mixture was filtered. The solvent was evaporated from the filtrate under reduced pressure and then purified using silica gel (ethyl acetate / petroleum ether=1 / 2) to obtain compound 1: 2-(5-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-4-phenyloxazole 24mg.

[0083] Embodiment 2

[0084] The steps of Example 2 are basically the same as those of Example 1, except that Example 2 uses an equimolar amount of 1-cyclopropylpyrazole-4-boric acid pinacol ester to replace the 1-methyl-1H-pyrazole-4-boric acid used in Example 1; the product structure of Example 2 is shown below:

[0085]

[0086] Embodiment 3

[0087] The steps of Example 3 are basically the same as those of Example 1, except that, in Example 3, an equimolar amount of 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester is used to replace the 1-methyl-1H-pyrazole-4-boric acid used in Example 1; the product structure of Example 3 is shown below:

[0088]

[0089] Embodiment 4

[0090] The steps of Example 4 are basically the same as those of Example 1, except that an equal molar amount of 5-pyrimidineboronic acid is used in Example 4 to replace the 1-methyl-1H-pyrazole-4-boronic acid used in Example 1; the product structure of Example 4 is shown below:

[0091]

[0092] Embodiment 5

[0093] The steps of Example 5 are basically the same as those of Example 1, except that an equal molar amount of 2-methoxypyrimidine-5-boric acid is used in Example 5 to replace the 1-methyl-1H-pyrazole-4-boric acid used in Example 1; the product structure of Example 5 is shown below:

[0094]

[0095] Embodiment 6

[0096] The steps of Example 6 are basically the same as those of Example 1, except that Example 6 uses an equimolar amount of (1-methyl-1H-1,2,4-triazol-3-yl)boric acid to replace the 1-methyl-1H-pyrazole-4-boric acid used in Example 1; the product structure of Example 6 is shown below:

[0097]

[0098] Embodiment 7

[0099] The steps of Example 7 are basically the same as those of Example 1, except that an equimolar amount of (4-methyl-4H-1,2,4-triazol-3-yl)boric acid is used in Example 7 to replace the 1-methyl-1H-pyrazole-4-boric acid used in Example 1; the product structure of Example 7 is shown below:

[0100]

[0101] Embodiment 8

[0102] The steps of Example 8 are basically the same as those of Example 1, except that an equal molar amount of 1H-pyrazole-4-boric acid is used in Example 8 to replace the 1-methyl-1H-pyrazole-4-boric acid used in Example 1; the product structure of Example 8 is shown below:

[0103]

[0104] Embodiment 9

[0105] The steps of Example 9 are basically the same as those of Example 1, except that an equal molar amount of pyridine-3-boric acid is used in Example 9 to replace the 1-methyl-1H-pyrazole-4-boric acid used in Example 1; the product structure of Example 9 is shown below:

[0106]

[0107] Embodiment 10

[0108] The steps of Example 10 are basically the same as those of Example 1, except that an equal molar amount of 2-methoxy-5-pyridineboronic acid is used in Example 10 to replace the 1-methyl-1H-pyrazole-4-boronic acid used in Example 1; the product structure of Example 10 is shown below:

[0109]

[0110] Embodiment 11

[0111] The steps of Example 11 are basically the same as those of Example 1, except that an equal molar amount of 1H-pyrrolo[2,3-B]pyridine-4-boric acid is used in Example 11 to replace the 1-methyl-1H-pyrazole-4-boric acid used in Example 1; the product structure of Example 11 is shown below:

[0112]

[0113] Embodiment 12

[0114] The steps of Example 12 are basically the same as those of Example 1, except that an equimolar amount of (1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boric acid is used in Example 12 to replace the 1-methyl-1H-pyrazole-4-boric acid used in Example 1; the product structure of Example 12 is shown below:

[0115]

[0116] Embodiment 13

[0117] The steps of Example 13 are basically the same as those of Example 1, except that an equimolar amount of isothiazole-4-boric acid pinacol ester is used in Example 13 to replace the 1-methyl-1H-pyrazole-4-boric acid used in Example 1; the product structure of Example 13 is shown below:

[0118]

[0119] Embodiment 14

[0120] The steps of Example 14 are basically the same as those of Example 1, except that, in Example 14, 3,5-dimethyl-isothiazole-4-boric acid pinacol ester is used in an equal molar amount to replace the 1-methyl-1H-pyrazole-4-boric acid used in Example 1; the product structure of Example 14 is shown below:

[0121]

[0122] Pharmacological experiments:

[0123] The cell proliferation assay kit (CCK 8) was used to evaluate the in vitro antiproliferative effects of compounds 1-14 on LNCaP and 22RV1 cells. The experimental steps were as follows: LNCaP or 22RV1 cells (1×10 4 Cells) were inoculated in 96-well plates in rmi 1640 medium supplemented with 10% fetal bovine serum; after incubation at 37°C for 24 hours, the cells were treated with compounds of different concentrations for 24 hours, and then 10 μl CCK8 solution was added to each well, and the incubation continued for 2 hours. The absorbance at 450 nm was measured using an enzyme reader (BioTek enzyme reader). The calculation formula for cell viability (%) is: cell viability (%) = (AS Ab) (Ac Ab) × 100, where AS, Ac, and Ab represent the absorbance of different concentrations of drug wells, control wells, and blank wells, respectively. The test results of cell proliferation antagonism showed that compounds 5, 6, and 13 can effectively antagonize the proliferation of prostate cancer cells LNCaP and 22RV1.

[0124] Those skilled in the art will readily appreciate other embodiments of the present invention after considering the specification and practicing the disclosure disclosed herein. The present invention is intended to cover any variations, uses or adaptations of the present invention that follow the general principles of the present invention and include common knowledge or customary technical means in the art that are not disclosed by the present invention.

Claims

1. A pharmaceutical composition for treating prostate diseases and glandular nodules, characterized in that: The pharmaceutical composition comprises a heterocyclic compound having the structure of the following formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; wherein at least one of X1, X2, X3 and X4 is a nitrogen atom, and the rest are carbon atoms; X5 is an oxygen atom or a carbon atom; X6 is a nitrogen atom or a carbon atom; R1 is hydrogen, a halogen atom, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a C1-C10 alkyl group, a C2-C10 alkenyl group, a C1-C10 alkoxy group, a C3-C12 cycloalkyl group or a 3-12 membered heterocyclic group; Ar1 is a C3-C12 cycloalkyl, a C5-C12 aryl, a 3-12-membered heterocycloalkyl or a 5-12-membered heteroaryl; the C3-C12 cycloalkyl, C5-C12 aryl, a 3-12-membered heterocycloalkyl or a 5-12-membered heteroaryl is optionally substituted by one or more halogen atoms, amino, nitro, hydroxyl, carboxyl, cyano, C1-C5 alkyl, C2-C5 alkenyl or C1-C5 alkoxy.

2. The pharmaceutical composition for treating prostate diseases and glandular nodules according to claim 1, characterized in that: The heterocyclic compound is a compound having the structure of the following formula II; Wherein, R1 is hydrogen, a halogen atom, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a C1-C10 alkyl group, a C2-C10 alkenyl group, a C1-C10 alkoxy group, a C3-C12 cycloalkyl group or a 3-12 membered heterocyclic group; Ar1 is a C3-C12 cycloalkyl, a C5-C12 aryl, a 3-12-membered heterocycloalkyl or a 5-12-membered heteroaryl; the C3-C12 cycloalkyl, C5-C12 aryl, a 3-12-membered heterocycloalkyl or a 5-12-membered heteroaryl is optionally substituted by one or more halogen atoms, amino, nitro, hydroxyl, carboxyl, cyano, C1-C5 alkyl, C2-C5 alkenyl or C1-C5 alkoxy.

3. The pharmaceutical composition for treating prostate diseases and glandular nodules according to claim 2, characterized in that: The heterocyclic compound is a compound having the structure of the following formula III; Wherein, Ar1 is a C3-C12 cycloalkyl, a C5-C12 aryl, a 3-12-membered heterocycloalkyl or a 5-12-membered heteroaryl; the C3-C12 cycloalkyl, C5-C12 aryl, a 3-12-membered heterocycloalkyl or a 5-12-membered heteroaryl is optionally substituted by one or more halogen atoms, amino, nitro, hydroxyl, carboxyl, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl or C1-C5 alkoxy.

4. The pharmaceutical composition for treating prostate diseases and glandular nodules according to claim 3, characterized in that: The heterocyclic compound is a compound having the following structures of Formula III-A to Formula III-F; Wherein, R2 is a C1-C5 alkyl, a C2-C5 alkenyl or a C1-C5 alkoxy.

5. The pharmaceutical composition for treating prostate diseases and glandular nodules according to any one of claims 1 to 4, characterized in that: The heterocyclic compound is at least one of the following compounds 1 to 14; 6. The pharmaceutical composition for treating prostate diseases and glandular nodules according to any one of claims 3 to 5, characterized in that: The heterocyclic compound is prepared by the following steps: Step 1: Step 2: Step 3: Step 4: Step 5:

7. The pharmaceutical composition for treating prostate diseases and glandular nodules according to claim 5, characterized in that: The heterocyclic compound is compound 5, compound 6 or compound 13.

8. The pharmaceutical composition for treating prostate diseases and glandular nodules according to claim 1, characterized in that: The prostate disease is prostatitis and / or prostate hyperplasia.

9. Use of the pharmaceutical composition for treating prostate diseases and glandular nodules according to any one of claims 1 to 8, characterized in that: The pharmaceutical composition is used alone or in combination with other drugs.

10. Use of the pharmaceutical composition for treating prostate diseases and glandular nodules according to claim 9 in treating prostate diseases and glandular nodules, characterized in that: The combined use is combined with surgical operation, combined with one or more western medicines, combined with Chinese herbal medicine, combined with radiotherapy, combined with gene therapy or combined with biological regulators.

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