CN112190581B - Application of pyrrolidine-2-ketone compound in preparation of multiple myeloma related medicines - Google Patents

Application of pyrrolidine-2-ketone compound in preparation of multiple myeloma related medicines Download PDF

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CN112190581B
CN112190581B CN202011215542.2A CN202011215542A CN112190581B CN 112190581 B CN112190581 B CN 112190581B CN 202011215542 A CN202011215542 A CN 202011215542A CN 112190581 B CN112190581 B CN 112190581B
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pyrrolidin
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高剑
姚若斯
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Xuzhou Medical University
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Abstract

The invention relates to application of pyrrolidine-2-ketone compounds in preparation of medicines related to multiple myeloma, belongs to the fields of pharmaceutical chemistry and pharmacotherapeutics, and has an obvious enzyme inhibition effect on c-Myc protein. The compound shown in the formula I, the isomer or the pharmaceutically acceptable salt thereof can be applied to the preparation of medicines related to multiple myeloma.
Figure DDA0002760217240000011

Description

Application of pyrrolidine-2-ketone compound in preparation of multiple myeloma related medicines
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry and pharmacotherapeutics, and particularly relates to an application of pyrrolidine-2-ketone compounds in preparation of medicines related to multiple myeloma, in particular to an application of medicines related to c-Myc inhibitors.
Background
Multiple Myeloma (MM) is a common plasma cell malignancy in the blood system, and is frequently found in middle-aged and elderly people, accounting for about 13% of tumors in the blood system. In recent years, with the maturation of hematopoietic stem cell transplantation technology, the emergence of first-line therapeutic drugs such as immunomodulators and proteasome inhibitors has led to an increase in the survival of patients with multiple myeloma, but the patients have not yet been completely cured. Tumor resistance is an important issue limiting the outcome of treatment for this disease. Therefore, the method has important clinical practical significance for deeply exploring the drug resistance mechanism of MM and developing small molecule drugs based on new targets.
c-Myc is an important transcription factor, and is also an oncogene, the abnormal expression of which plays an important role in the progression of various solid and hematologic tumors. In 2008, Chesi et al, through c-Myc animal model experiments, demonstrated for the first time that c-Myc gene activation is a key event for MGUS to MM transition in immunoglobulin yet unknown significance. Subsequently, gene chip (22 cases of MGUS and 101 cases of MM) analysis showed that the c-Myc gene was activated in 67% of MM patients. Recent studies found that 40% of MM patients had c-Myc overexpression, whereas multivariate regression analysis indicated that c-Myc overexpression was positively correlated with the shorter life-time (OS) of MM. Meanwhile, it has been found that an abnormality or deletion of chromosome 8p21 region 8 is one of the major mechanisms of MM resistance: aberrant expression of c-Myc (at region 8p 21) induces resistance of MM to Bortezomib (BTZ). Thus, targeting the transcription factor c-Myc is a promising strategy for cancer treatment. However, existing c-Myc inhibitors are not druggable due to the disorder of c-Myc homodimers and heterodimers, and the hysteresis of key interaction sites. Therefore, the development of the specific targeting c-Myc small molecule inhibitor is expected to provide theoretical and experimental basis for accurate clinical treatment of relapsed/refractory myeloma.
Disclosure of Invention
The invention aims to provide a 4- (1- (2-phenoxyethyl) -1H-benzo [ d ] imidazole-2-yl) pyrrolidine-2-ketone compound (pyrrolidine-2-ketone compound for short) on the basis of the prior art, which has good c-Myc protein function inhibition effect and can be used for preparing medicines related to multiple myeloma.
Another object of the present invention is to provide a pharmaceutical composition comprising the above mentioned compound, isomer or pharmaceutically acceptable salt thereof as an active ingredient or a main active ingredient, in combination with a pharmaceutically acceptable carrier.
The technical scheme of the invention is as follows:
the application of the compound shown in the formula I, isomers or pharmaceutically acceptable salts thereof in preparing medicines related to multiple myeloma,
Figure BDA0002760217220000021
wherein,
R1represents C1-C4Alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, said substituted phenyl or substituted benzyl being optionally mono-or polysubstituted with the following substituents: hydroxy, nitro, carboxyl, cyano, amino, halogen, C1-C4Alkyl or C1-C4An alkoxy group;
n represents an integer of 1 to 3;
R2represents hydrogen, C1-C4Alkyl radical, C1-C4Alkoxy, hydroxy, nitro or amino.
The compound shown in the formula I, the isomer or the pharmaceutically acceptable salt thereof can be used for preparing medicaments related to c-Myc inhibitors.
Because the name of the invention is too long and the number of words exceeds 40 words, the invention simply refers to the 4- (1- (2-phenoxyethyl) -1H-benzo [ d ] imidazole-2-yl) pyrrolidine-2-ketone compound as the pyrrolidine-2-ketone compound.
In a preferred embodiment, R1Represents phenyl, substituted phenyl, benzyl, substituted benzyl, said substituted phenyl or substituted benzyl being optionally mono-or polysubstituted with the following substituents: methyl, ethyl, methoxy, ethoxy, hydroxy, fluoro, chloro or bromo.
In a more preferred embodiment, R1Represents phenyl, substituted phenyl, benzyl, substituted benzyl, said substituted phenyl or substituted benzyl being optionally mono-or polysubstituted with the following substituents: methyl, ethyl, methoxy, ethoxy, fluoro or chloro.
In a preferred embodiment, n represents 1 or 2.
In a preferred embodiment, R2Represents hydrogen, methyl, ethyl, methoxy or ethoxy.
In a more preferred embodiment, R2Represents hydrogen, methyl, ethyl or methoxy.
In a particularly preferred embodiment, R1Represents phenyl, substituted phenyl, benzyl, substituted benzyl, said substituted phenyl or substituted benzyl being optionally mono-or polysubstituted with the following substituents: methyl, ethyl, methoxy, ethoxy, fluoro or chloro; n represents 1 or 2; r2Represents hydrogen, methyl, ethyl or methoxy.
Further, in the compound, isomer, or pharmaceutically acceptable salt thereof represented by formula I, the compound is selected from the group consisting of:
Figure BDA0002760217220000031
Figure BDA0002760217220000041
Figure BDA0002760217220000051
wherein the above mentioned compounds are named as follows:
1 compound designation 1-benzyl-4- (1- (2- (2- (2, 4-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) pyrrolidin-2-one;
2 compound designation 1- (4-ethylphenyl) -4- (1- (2- (p-tolyloxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) pyrrolidin-2-one;
3 compound name 4- (1- (2- (2, 5-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (4-ethoxyphenyl) pyrrolidin-2-one;
4 compound name 4- (1- (2- (3, 4-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (p-tolyl) pyrrolidin-2-one;
5 nomenclature of the Compound 4- (1- (2- (2, 6-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (4-ethylphenyl) pyrrolidin-2-one
Compound 6 is named 1- (3, 5-dimethylphenyl) -4- (1- (2- (m-tolyloxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) pyrrolidin-2-one;
compound designation 4- (1- (2- (2, 5-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (m-tolyl) pyrrolidin-2-one;
compound 8 is named 1- (4-ethylphenyl) -4- (1- (2- (o-tolyloxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) pyrrolidin-2-one;
9 nomenclature of the Compound 4- (1- (2- (2, 3-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (m-tolyl) pyrrolidin-2-one
Compound 10 is named 4- (1- (2- (2, 6-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (m-tolyl) pyrrolidin-2-one;
11 compound designation 4- (1- (2- (2, 6-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (4-ethoxyphenyl) pyrrolidin-2-one;
12 compound name 4- (1- (2- (2, 6-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (4-methoxyphenyl) pyrrolidin-2-one;
13 compound designation 1- (3-chlorophenyl) -4- (1- (2- (o-tolyloxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) pyrrolidin-2-one;
14 compound designation 1- (2, 6-dimethylphenyl) -4- (1- (2- (o-tolyloxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) pyrrolidin-2-one;
compound 15 is named 4- (1- (2- (2, 4-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (p-tolyl) pyrrolidin-2-one;
compound 16 is named 4- (1- (2- (2, 6-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (p-tolyl) pyrrolidin-2-one;
17 compound name 4- (1- (2- (4-ethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (4-methoxyphenyl) pyrrolidin-2-one;
18 compound designation 4- (1- (2- (2, 6-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (2-ethoxyphenyl) pyrrolidin-2-one;
compound designation 1- (m-tolyl) -4- (1- (2- (p-tolyloxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) pyrrolidin-2-one;
20 compound name 4- (1- (2- (2, 3-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (4-methoxyphenyl) pyrrolidin-2-one;
21 compound designation 1- (4-chlorophenyl) -4- (1- (2- (2- (2, 6-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) pyrrolidin-2-one;
22 nomenclature of the Compound 1- (3-chlorophenyl) -4- (1- (2- (2- (2, 6-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) pyrrolidin-2-one
23 compound designation 4- (1- (2- (2, 4-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (4-fluorophenyl) pyrrolidin-2-one;
compound 24 is named 1- (3-chlorophenyl) -4- (1- (2- (2- (2, 5-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) pyrrolidin-2-one;
25 name of compound 4- (1- (2- (3, 5-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (m-tolyl) pyrrolidin-2-one;
26 name of compound 1- (4-ethylphenyl) -4- (1- (2-phenoxyethyl) -1H-benzo [ d ] imidazol-2-yl) pyrrolidin-2-one;
27 name of the compound 4- (1- (2- (4-methoxyphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (m-tolyl) pyrrolidin-2-one;
28 name of compound 1- (4-chlorophenyl) -4- (1- (2- (2- (2, 4-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) pyrrolidin-2-one;
29 name of compound 1- (2, 5-dimethylphenyl) -4- (1- (2- (o-tolyloxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) pyrrolidin-2-one;
30 compound designation 4- (1- (2- (2, 5-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (3-methoxyphenyl) pyrrolidin-2-one;
31 the compound is named 4- (1- (2- (2, 4-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -1- (4-methoxyphenyl) pyrrolidin-2-one.
In a preferred embodiment, in the compound, isomer, or pharmaceutically acceptable salt thereof represented by formula I, the compound is selected from the group consisting of:
Figure BDA0002760217220000071
Figure BDA0002760217220000081
the compound, the isomer or the pharmaceutically acceptable salt thereof provided by the invention can be used for preparing medicines related to multiple myeloma, and the compound has an obvious inhibition effect on c-Myc protein.
In a preferred embodiment, the present invention provides a pharmaceutical composition, which comprises the compound, isomer or pharmaceutically acceptable salt thereof of the present invention as an active ingredient or a main active ingredient, together with a pharmaceutically acceptable carrier. Further, the pharmaceutical composition can be prepared into a liquid preparation or a solid preparation. Furthermore, the pharmaceutical composition can be prepared into injections, oral liquids, granules, tablets, powders or capsules.
Unless otherwise indicated, the following terms used in the specification and claims have the meanings discussed below:
"alkyl" means a saturated aliphatic radical of 1 to 20 carbon atoms, including straight and branched chain radicals (a numerical range referred to herein, e.g., "1 to 20", means that the radical, in this case alkyl, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). Alkyl groups having 1 to 4 carbon atoms are referred to as lower alkyl groups. When a lower alkyl group has no substituent, it is referred to as unsubstituted lower alkyl. More preferably, the alkyl group is a medium size alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, and the like. Preferably, the alkyl group is a lower alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, or the like. Alkyl groups may be substituted or unsubstituted. When substituted alkyl, the substituent is preferably one or more, more preferably 1 to 3, most preferably 1 or 2 substituents.
"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
"hydroxy" means an-OH group.
"cyano" means a-CN group.
"nitro" means-NO2A group.
"amino" means-NH2A group.
"carboxyl" means a-COOH group.
"alkoxy" means-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
(1) salts with acids are obtained by reaction of the free base of the parent compound with inorganic acids including hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid and the like, or with organic acids including acetic acid, trifluoroacetic acid, propionic acid, acrylic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, benzoic acid, hydroxybenzoic acid, γ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, cinnamic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, aspartic acid, stearic acid, mandelic acid, succinic acid or malonic acid and the like.
(2) The acidic protons present in the parent compound are replaced with metal ions such as alkali metal ions, alkaline earth metal ions or aluminum ions, or are complexed with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, quinine, and the like.
"pharmaceutical composition" refers to the combination of one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, with another chemical ingredient, such as a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration process to an animal.
By adopting the technical scheme of the invention, the advantages are as follows:
the 4- (1- (2-phenoxyethyl) -1H-benzo [ d ] imidazole-2-yl) pyrrolidine-2-ketone compound provided by the invention has an obvious inhibition effect on c-Myc protein, has good c-Myc inhibition activity, and can be used for preparing medicines related to multiple myeloma.
Drawings
FIG. 1 shows the effect of the Luciferase reporter activity assay compound on the activity of the target c-Myc protein at a concentration of 10. mu.M.
Detailed Description
To further illustrate the present invention, a series of examples are given below, which are purely illustrative and are intended to be a detailed description of the invention only and should not be understood as limiting the invention.
Example 1
Experimental methods and results
First, cell viability experiment
The experimental principle is as follows: the reagent contains WST-8, which is reduced by dehydrogenase in cells to yellow Formazan product (Formazan dye) with high water solubility under the action of electron carrier 1-Methoxy-5-methylphenazinium dimethyl sulfate (1-Methoxy PMS). The amount of formazan produced was proportional to the number of living cells. Therefore, the cell proliferation and toxicity analysis can be directly carried out by utilizing the characteristic.
The experimental steps are as follows:
1. plate paving: taking two humanized myeloma cells RPMI-8226 and U266 in logarithmic growth phase to inoculate a 96-well plate, wherein each well has 100 mu L of cell suspension, and the cell number is 5 multiplied by 103Per well, a blank control group was added with only 100. mu.L of 10% FBS-containing complete medium RPMI-1640, and 3-5 duplicate wells were set for each group.
2. Different concentration gradient small molecule compound treated RPMI-8226 and U266 were placed in cell culture box (37 deg.C, 5% CO)2) Culturing for 24h, adding 5 microliter CCK-8 solution into each well, and continuously culturing for 3 h and detecting by a microplate reader.
3. And (3) detection: and (3) zeroing the blank control group, detecting the absorbance (OD value) at the wavelength of 450nm, repeating for 2-3 times, taking an average value, and calculating the cell inhibition rate of the administered compound.
The experimental results are as follows: as shown in the following table 1, most of the compounds in the invention have obvious cell inhibition effects on RPMI-8226 and U266 cell strains, and especially, the compounds 1, 3,4, 5, 8, 11, 17, 25, 28 and 29 have the strongest inhibition effects, and the effects are obviously better than those of the positive control drug 10074-G5.
TABLE 1 Dual-concentration inhibition ratio (%)
Figure BDA0002760217220000101
Figure BDA0002760217220000111
II, c-Myc protein activity assay
The experimental principle is as follows:
firefly luciferase catalyzes the oxidation of luciferin under conditions of ATP, magnesium ions, oxygen, and the like, to generate bioluminescence, which is then measured by a chemiluminescence apparatus. By using the bioluminescence system, the transcription regulation element of the gene of interest is cloned at the upstream of the firefly luciferase gene to construct a reporter gene plasmid. Then, the cells are transfected, treated with an appropriate drug or the like, lysed, and luciferase activity at 560nm is measured.
The experimental steps are as follows:
1. the NEK293T cells are paved in a 24-well plate on the previous day, c-Myc expression plasmids, Myc-Luc reporter gene plasmids and Renilla internal reference plasmids are transfected on the next day, a fresh culture medium is replaced after 6h, small molecule inhibitors are added for treatment, and the cells are collected after 48 h.
2. The cells were lysed using a cell lysate carried in a Promega kit (product No. E1910), 100. mu.l of the lysate was added to each well and the lysate was pipetted uniformly, and the lysate was lysed by rotating a horizontal shaker at a low speed for 10 minutes.
3. And adding 10 microliters of cell lysate into a 96-well white board per well, adding a firefly luciferase substrate in the solution II according to the ratio of 1:2.5, and reacting for 10 seconds to detect the luciferase activity.
4. Adding Stop & Glo detection solution, stopping first luminescence, starting second luminescence, mixing, and detecting second luminescence value with luminescence detector.
The experimental results are as follows:
as shown in FIG. 1 below, the transcriptional activity of the c-Myc promoter was significantly enhanced in the (c-Myc + c-Myc-Luciferase) group as compared with the Control group. The compounds 1, 3,4, 8, 17, 25, 28 and 29 in the invention can reduce the c-Myc transcription activity, and other 24 compounds which are not listed also have similar functions of reducing the c-Myc transcription activity, especially the compounds 1, 8, 17, 25 and 29 with better anti-tumor cell activity have the most obvious effect of inhibiting the c-Myc promoter transcription activity and are obviously better than the positive control drug 10074-G5. This indicates that the compounds of the present invention exert anti-tumor cell activity by targeting the c-Myc protein. The 4- (1- (2-phenoxyethyl) -1H-benzo [ d ] imidazole-2-yl) pyrrolidine-2-ketone compound is a high-activity c-Myc inhibitor and can be used for preparing medicines related to multiple myeloma.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications of the technical solutions described in the foregoing embodiments are still possible, or some technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Claims (4)

1. Use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of multiple myeloma, wherein the compound is selected from:
Figure FDA0003292233620000011
2. a pharmaceutical composition for treating multiple myeloma, which comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient or a main active ingredient, together with a pharmaceutically acceptable carrier.
3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is formulated as a liquid formulation or a solid formulation.
4. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is formulated as an injection, an oral liquid, a granule, a powder, a tablet or a capsule.
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