CN115246783A - 1,3-cyclohexanedione compound and pharmaceutical composition and application thereof - Google Patents
1,3-cyclohexanedione compound and pharmaceutical composition and application thereof Download PDFInfo
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- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
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- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
The invention belongs to the field of pharmaceutical chemistry and chemical synthesis, and particularly relates to a1,3-cyclohexanedione compound, a pharmaceutical composition and an application thereof, wherein the structural formula of 1,3-cyclohexanedione compound is shown as a formula I. 1,3-Ring of the present inventionThe hexanedione compound not only has good water solubility and stability, but also has better inhibitory activity on LDHA at molecular level and cell level, and shows the compound with anti-tumor activity in vivo.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry and chemical synthesis, and particularly relates to a1,3-cyclohexanedione compound, and a pharmaceutical composition and application thereof.
Background
In 1920, warburg, a german scientist, proposed that tumor cells differ from normal cells and break down glucose for capacitation mainly by glycolysis even under aerobic conditions, and this aerobic glycolysis phenomenon of tumor cells is called the "Warburg" effect. An important common feature of the "Warburg" effect of tumor cells is the production of large amounts of lactate. The main reasons for this are the increased utilization of glucose by tumor cells and the metabolism mainly by glycolysis, leading to the accumulation of lactic acid, the end product of the glycolytic pathway. Lactic acid has multiple biological functions, not only promotes the proliferation and metastasis of tumor cells and the formation of new blood vessels, but also is closely related to the immune escape of the tumor cells, so that the accumulation of lactic acid can remodel the microenvironment of tumors. Therefore, lactic acid not only influences the killing effect of the chemotherapeutic drugs on tumor cells, but also influences the activity-mediated immunosuppression microenvironment of immune cells, and has important influence on the immunotherapy of tumors.
Lactate Dehydrogenase (LDH), one of the key enzymes in the glycolysis process, is responsible for converting pyruvate and NADH to lactate and NAD + [Pharmacology&Therapeutics,2009,121(1):29)]. LDH is a reversible catalytic enzyme, existing in tetramer form, composed of two peptide chains (LDHA, LDHB), respectively. MccBland et al [ Cancer Research,2012,72 (22): 5812]Screening and evaluating candidate oncogenes of triple negative breast cancer by adopting a comprehensive gene analysis method, and determining that LDHB is an important gene of triple negative breast cancer and the triple negative breast cancer depends on glycolysis. LDHA is mainly expressed in hypoxic environments such as skeletal muscle, liver and lymphoid tissues, and hardly expressed in normoxic tissues [ Current medical Chemistry,2010,17 (7)]. LDHA expression is also up-regulated in various tumor cells as a result of hypoxic microenvironment and mitochondrial gene mutation [ Oncology,2009,77 (5): 285-292]. Brand et al [ Cell Metabolism,2016,24 (5): 657-671]Through the statistical analysis of a large number of clinical samples, the expression of the LDHA in the tumor cells is found to be positively correlated with the malignancy degree and inversely correlated with the prognosis of patients. Meanwhile, statistical analysis of records was performed on individuals completely lacking the LDHA subtype, and no other obvious diseases except myoglobin urinary under vigorous anaerobic exercise were considered [ Internal Medicine,1995,34 (5): 326]. Therefore, LDHA has the potential to become a potential molecular target for tumor therapy. Previous studies by Le et al have demonstrated [ PNAS,2010,107 (5): 2037-2042]LDHA silencing may lead to an increased rate of apoptosis of lymphoma cells associated with oxidative stress. In the study of Wang et al [ Breast Cancer Research&Treatment,2012,131(3):791-800]It was demonstrated that LDHA overexpression is closely related to breast tumor size, and LDHA inhibition also leads to increased mitochondrial pathway apoptosis by ROS production in Estrogen Receptor (ER) positive and negative cell lines, as well as significantly slower growth rates for xenograft tumors of both breast cancers.
Therefore, the compound capable of inhibiting the activity of LDHA has the potential to become an anti-tumor medicament or a pharmaceutical composition. In recent years, there has been some development in the study of small molecule inhibitors of LDHs. IC of the compound GNE-140 on LDHA 50 In terms of 3nM [ Nature Chemical biology,2016,12 (10): 779]. Although the compound has higher inhibitory action on LDHA enzyme, the anti-tumor efficacy of the compound in vivo efficacy experiments is lower.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a1,3-cyclohexanedione compound.
The second purpose of the invention is to propose a pharmaceutical composition containing the compound.
The third invention of the present invention is to propose the use of the above compound and pharmaceutical composition.
In order to achieve the purpose of the invention, the technical scheme is as follows:
the invention relates to a1,3-cyclohexanedione compound, a stereochemical isomer or a pharmaceutically acceptable salt thereof, wherein the structural formula of the 1,3-cyclohexanedione compound is shown as a formula I:
wherein, the first and the second end of the pipe are connected with each other,
ar is substituted or unsubstituted phenyl, the substituted phenyl is phenyl substituted by 1 to 3 substituents R ', the substituents R' are same or different and are selected from halogen, cyano, halogen-substituted C1-C6 alkyl, C1-C6 alkyl or C1-C6 alkoxy, preferably halogen, cyano, perhalo-substituted C1-C3 alkyl, C1-C3 alkyl or C1-C3 alkoxy, more preferably halogen, cyano, trifluoromethyl, methyl, methoxy;
x is hydrogen or halogen, preferably chlorine;
R 1 selected from hydrogen or C1-C3 alkyl;
R 2 selected from C1-C3 alkylene;
R 3 selected from substituted or unsubstituted C6-C14 aryl, C4-C12 heteroaryl, said substituted substituents being selected from halogen, halogen-substituted C1-C6 alkyl, preferably halogen or C1-C3 alkyl, more preferably halogen or methyl.
In a second aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from 1,3-cyclohexanediones, as described above, a stereochemically isomeric form thereof, or a pharmaceutically acceptable salt thereof, preferably comprising a pharmaceutically acceptable carrier or excipient.
In a third aspect, the present invention relates to a lactate dehydrogenase inhibitor, comprising one or more of the 1,3-cyclohexanedione compounds, stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 6.
The fourth aspect of the present invention relates to the application of 1,3-cyclohexanedione compound, a stereochemically isomeric form or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition, wherein the application comprises: the application of the compound in preparing anti-tumor drugs and in preparing drugs for treating cancers caused by immune escape.
The technical scheme of the invention at least has the following technical effects:
the 1,3-cyclohexanedione compound disclosed by the invention has good water solubility and stability, has good inhibitory activity on LDHA at a molecular level and a cell level, and shows an anti-tumor activity in vivo.
Drawings
Figures 1 and 2 are bar graphs of the effect of compounds of the invention on lactate secretion in HN12 cells;
FIG. 3 is a graph comparing the in vivo antitumor activity against melanoma graft tumor B16F 10.
Detailed Description
To make the features and effects of the present invention comprehensible to those having ordinary knowledge in the art, general description and definitions are made with respect to terms and phrases mentioned in the specification and claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
In this document, the terms "comprising," "including," "having," "containing," or any other similar term, are intended to be open-ended franslational phrase (open-ended franslational phrase) and are intended to cover non-exclusive inclusions. For example, a composition or article comprising a plurality of elements is not limited to only those elements recited herein, but may include other elements not expressly listed but generally inherent to such composition or article. In addition, unless explicitly stated to the contrary, the term "or" is intended to mean an inclusive "or" rather than an exclusive "or". The terms "comprising," "including," "having," "containing," and variations thereof, are to be construed as specifically disclosed and encompass both closed and semi-closed conjunctions "consisting of …" and "consisting essentially of …".
The following detailed description is merely exemplary in nature and is not intended to limit the invention or the application thereof. Furthermore, there is no intention to be bound by any theory presented in the preceding prior art or the summary of the invention or the following detailed description or examples.
The "alkyl group" in the present invention represents saturated straight-chain and branched-chain alkyl groups in a specific number of atoms, and specific examples thereof include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and tert-pentyl groups. The "C1 to C6 alkyl group" represents a saturated straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and specific examples thereof include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. Halogen-substituted C1-C6 alkyl means that at least one hydrogen atom on C1-C6 alkyl is substituted by halogen, and perhalo-substituted C1-C3 alkyl means that all hydrogen atoms on C1-C3 alkyl are substituted by halogen.
The "C1-C3 alkylene" in the present invention represents a saturated straight-chain or branched alkylene group having 1 to 3 carbon atoms, and specifically includes, but is not limited to, methylene (-CH) 2 -) ethylene (-CH 2 -CH 2 -、
) Propylene (-CH) 2 -CH 2 -CH 2 -)。
The "C1-C6 alkoxy group" in the present invention represents all linear or branched alkoxy groups having 1 to 6 carbon atoms, and specific examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy groups.
The term "aryl" denotes a substituent having the structural properties of an aromatic ring, preferably a "C6-C14 aryl", which denotes an aryl group having 6-14 carbon atoms. For example, including but not limited to phenyl, substituted phenyl, naphthyl, substituted naphthyl, anthracenyl, and the like; more preferably, it is a "C6-C8 aryl".
The term "heteroaryl" refers to a monocyclic or polycyclic group having 5 to 14 ring atoms, each ring containing 4 to 6 atoms, of which one or more heteroatoms selected from N, O or S, the remainder being carbon. "heteroaryl" has some aromaticity. Preferred heteroaryl herein is "C2-C9 heteroaryl" which means heteroaryl having 2 to 9 carbon atoms, including for example, but not limited to, furyl, substituted furyl, benzofuryl, substituted benzofuryl, thienyl, substituted thienyl, benzothienyl, substituted benzothienyl, indolyl, substituted indolyl, isoindolyl, substituted isoindolyl, pyrrolyl, substituted pyrrolyl, thiazolyl, substituted thiazolyl, oxazolyl, substituted oxazolyl, pyrazolyl, substituted pyrazolyl, imidazolyl, substituted imidazolyl, pyranyl, substituted pyranyl, pyridazinyl, substituted pyridazinyl, pyrazinyl, substituted pyrazinyl, pyrimidinyl, substituted pyrimidinyl, pyridyl, substituted pyridyl, quinolinyl, substituted quinolinyl, isoquinolinyl, carbazolyl, substituted carbazolyl, and the like. More preferably, the heteroaryl group is a "C2-C5 heteroaryl group", and the heteroatom is more preferably a nitrogen atom.
The halogen in the invention represents fluorine, chlorine, bromine and iodine.
By "pharmaceutically acceptable salt" is meant a compound of formula (I) which retains the desired biological activity with minimal toxic side effects. The pharmaceutically acceptable salts may be obtained directly during the preparation and purification of the compound or indirectly by reacting the free acid or free base of the compound with another suitable base or acid.
The embodiment of the invention provides a1,3-cyclohexanedione compound, a stereochemical isomer or a pharmaceutically acceptable salt thereof, wherein the structural formula of the compound is shown as a formula I:
wherein, the first and the second end of the pipe are connected with each other,
ar is substituted or unsubstituted phenyl, the substituted phenyl is phenyl substituted by 1 to 3 substituents R ', the substituents R' are same or different and are selected from halogen, cyano, halogen-substituted C1-C6 alkyl, C1-C6 alkyl or C1-C6 alkoxy, preferably halogen, cyano, perhalo-substituted C1-C3 alkyl, C1-C3 alkyl or C1-C3 alkoxy, more preferably halogen, cyano, trifluoromethyl, methyl, methoxy;
x is hydrogen or halogen, preferably chlorine;
R 1 selected from hydrogen or C1-C3 alkyl, preferably hydrogen or methyl;
R 2 selected from C1-C3 alkylene;
R 3 selected from substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted C4-C12 heteroaryl, said substituted substituents being selected from halogen, halogen substituted C1-C6 alkyl, preferably halogen or C1-C3 alkyl, more preferably halogen or methyl.
In one embodiment, the 1,3-cyclohexanedione compounds of the present invention, a stereochemically isomeric or pharmaceutically acceptable salt thereof is selected from the group consisting of compounds as shown in IA:
wherein R is 41 、R 42 Each independently selected from halogen, cyano, perhalo-substituted C1-C3 alkyl, C1-C3 alkyl or C1-C3 alkoxy, preferably halogen, cyano, trifluoromethyl, methyl or methoxy, more preferably chlorine;
X、R 1 、R 2 、R 3 as defined in formula I, preferably R 3 Is selected from substituted or unsubstituted C6-C8 aryl or substituted or unsubstituted C4-C8 heteroaryl, and the substituted substituent is selected fromFrom halogen, halogen-substituted C1-C3 alkyl, preferably halogen or methyl; more preferably R 3 Selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl or substituted or unsubstituted pyrazinyl, said substituted substituents being selected from halogen, halogen-substituted C1-C3 alkyl, preferably halogen or methyl.
In one embodiment, the 1,3-cyclohexanediones, stereochemically isomeric forms, or pharmaceutically acceptable salts thereof of the present invention are selected from the group consisting of compounds as shown in IA 1:
X、R 1 、R 41 、R 42 as described in formula IA;
R 21 selected from hydrogen or methyl;
R 31 selected from halogen, halogen substituted C1-C6 alkyl, C1-C6 alkyl; preferably halogen or C1-C3 alkyl, more preferably halogen or methyl;
n is an integer of 0 to 5.
In one embodiment, the 1,3-cyclohexanediones, stereochemically isomeric forms, or pharmaceutically acceptable salts thereof of the present invention are selected from the group consisting of compounds as shown in IA 2:
X、R 1 、R 41 、R 42 as described in formula IA;
R 21 selected from hydrogen or methyl;
R 31 selected from halogen, halogen substituted C1-C6 alkyl, C1-C6 alkyl; preferably halogen or C1-C3 alkyl, more preferably halogen or methyl;
m is an integer of 0 to 4.
In one embodiment, the 1,3-cyclohexanediones, stereochemically isomeric forms, or pharmaceutically acceptable salts thereof of the present invention are selected from the group consisting of compounds as shown in IA 3:
X、R 1 、R 41 、R 42 as described in formula IA;
R 21 selected from hydrogen or methyl;
R 31 selected from halogen, halogen substituted C1-C6 alkyl, C1-C6 alkyl; preferably halogen or C1-C3 alkyl, more preferably halogen or methyl;
p is an integer of 0 to 3.
In one embodiment, the 1,3-cyclohexanediones, stereochemically isomeric forms, or pharmaceutically acceptable salts thereof of the present invention are selected from the group consisting of compounds as shown in IA 4:
X、R 1 、R 41 、R 42 as described in formula IA;
R 21 selected from hydrogen or methyl;
R 31 selected from halogen, halogen substituted C1-C6 alkyl, C1-C6 alkyl; preferably halogen or C1-C3 alkyl, more preferably halogen or methyl;
q is an integer of 0 to 7.
In one embodiment, the 1,3-cyclohexanediones, stereochemically isomeric forms, or pharmaceutically acceptable salts thereof, of the present invention are selected from the group consisting of compounds as represented by IA4a or IA4 b:
X、R 1 、R 41 、R 42 、R 21 、R 31 q is as described for formula IA 4.
In one embodiment, with R 21 The carbon atoms attached are of the R or S type, and preferably of the R type.
In one embodiment, the compound of formula I of the present invention is selected from the compounds represented by the following structural formulae:
in some embodiments, the 1,3-cyclohexanediones, stereoisomers, or pharmaceutically acceptable salts thereof of the present invention may exist as crystalline hydrates or solvates. These crystalline hydrates or solvates are also included within the scope of the present invention.
According to the present invention, stereoisomers include tautomers, meso forms, racemates, enantiomers, diastereomers.
Upon knowing the structure of the compounds of the invention, one skilled in the art can design and synthesize the compounds of the invention using reactions known in the art. Therefore, a specific production method for synthesizing the compound of the present invention is not particularly limited as long as the compound of the present invention can be obtained. The preparation can be carried out by adopting the following reaction flow:
wherein X, R 21 、R 22 、R 1 、R 2 、R 3 As defined above.
A second aspect of the embodiments of the present invention provides a pharmaceutical composition, which comprises a therapeutically effective amount of the 1,3-cyclohexanedione compound, a stereochemically isomeric form thereof, or a pharmaceutically acceptable salt thereof, preferably a pharmaceutically acceptable carrier or excipient.
Experiments prove that the compound provided by the invention has lactate dehydrogenase inhibition activity, including inhibitory activity on LDHA, so that a third aspect of the embodiment of the invention provides a lactate dehydrogenase inhibitor, which comprises the 1,3-cyclohexanedione compound, one or more of stereoisomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.
A fourth aspect of an embodiment of the present invention provides a use of the above compound or pharmaceutical composition, the use comprising: the application in preparing anti-tumor drugs and the application in preparing drugs for treating cancers caused by immune escape;
specifically, the tumor includes melanoma and mesothelioma, and the cancer includes lung cancer, liver cancer, kidney cancer, acute leukemia, prostate cancer, thyroid cancer, skin cancer, colon cancer, rectal cancer, pancreatic cancer, ovarian cancer, breast cancer, myelodysplastic syndrome, esophageal cancer and gastrointestinal cancer.
The embodiment of the invention also provides a method for inhibiting lactate dehydrogenase, an anti-tumor method and a method for treating cancer caused by immune escape. The method comprises administering an effective amount of the 1,3-cyclohexanedione compound described above, or a stereoisomer, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described above, to a subject in need of such treatment.
Preparation examples:
the starting materials described below are commercially available products or are prepared by methods known in the art or according to the methods described herein.
The structure of the compound was determined by Mass Spectrometry (MS). MS was measured using a Thermo Finnigan LCQ-Deca XP model (ESI) liquid chromatography-mass spectrometer. ISCO is used for separating and purifying product by column chromatography
Rf 75 can be used for preparing chromatograph rapidly, and the carrier is 200-300 mesh silica gel of Qingdao ocean chemical plant.
Preparation of Compound 1
The reaction equation is as follows:
step 1: preparation of intermediate 1-1
4-Chlorobenzeneacetic acid (50g, 293.10mmol) was dissolved in concentrated sulfuric acid (250 mL) and stirred, and a solid potassium nitrate (31.11g, 307.75mmol) was added thereto while cooling on ice, and the mixture was allowed to stand at room temperature and stirred for 1 hour. After completion of the reaction, the reaction mixture was poured into an ice-water mixture (300 mL) and stirred, extracted twice with ethyl acetate (300 mL), the organic phases were combined, washed with saturated brine (400 mL), the separated organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give intermediate 1-1 (49 g of a pale yellow solid, yield 77.55%). 1H NMR (400MHz, chloroform-d) Δ 7.83 (m, 1H), 7.53 (m, 1H), 7.45 (m, 1H), 3.72 (s, 2H).
Step 2: preparation of intermediate 2-1
Intermediate 1-1 (49g, 227.28mmol) was dissolved in ethanol (500 mL) and stirred, and concentrated sulfuric acid (50 mL) was added dropwise while cooling on ice. Heated to reflux and stirred for 5 hours. After the completion of the reaction, the solvent was evaporated by thin layer chromatography, extracted with ethyl acetate (300 mL), washed once with water (300 mL) and saturated brine (300 mL), the separated organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give intermediate 2-1 (46 g of yellow oil, yield 83.07%). 1H NMR (600mhz, dmso-d 6) δ 8.01 (m, 1H), 7.73 (m, 1H), 7.63 (m, 1H), 4.11 (q, J =7.1hz, 2h), 3.85 (s, 2H), 1.20 (t, J =7.1hz, 3h).
And step 3: preparation of intermediate 3-1
Intermediate 2-1 (44g, 180.59mmol) was dissolved in ethanol/water (v/v =5, 1, 450ml) and stirred, ammonium chloride (10.63g, 198.65mmol) and iron powder (30.26g, 541.78mmol) were added, respectively, heated to 85 degrees celsius and stirred for 1 hour. After the reaction was completed, most of the solvent was distilled off, extracted with ethyl acetate (400 mL), washed once with water (400 mL) and saturated brine (400 mL), respectively, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and the column was loaded with 200-300 mesh silica gel, and the eluent was purified with a petroleum ether/ethyl acetate system with a polarity gradient of petroleum ether/ethyl acetate (v/v) =10 to 5:1 to obtain intermediate 3-1 (31 g of brown oil, 83.34% yield). MS (ESI) 214.04 (M + H). 1H NMR (400mhz, chloroform-d) δ 7.18 (d, J =8.1hz, 1h), 6.70 (m, 1H), 6.60 (dd, J =8.1,2.1hz, 1h), 4.14 (q, J =7.1hz, 2h), 4.04 (s, 2H), 3.49 (s, 2H), 1.25 (t, J =7.1hz, 3h).
And 4, step 4: preparation of intermediate 4-1
The intermediate 3-1 (10g, 46.8mmol) was dissolved in hydrochloric acid (6N, 100mL) and stirred, a sodium nitrite solution (3.55g, 20mL, 51.48mmol) was added dropwise over ice, stirring was carried out at 0 ℃ for 30 minutes, and then the mixed solution was slowly added dropwise to a potassium ethylxanthate solution (9 g,100mL, 56.116mmol) at a system temperature of not more than 5 ℃ and reacted for 30 minutes. The reaction mixture was extracted with ether (200 mL), washed with saturated brine (200 mL), the organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated to dryness.
The above system was dissolved in ethanol (200 mL), heated to reflux, and potassium hydroxide (11.03g, 196.57mmol) was added to react for 30 minutes. After the completion of the reaction, the solvent was evaporated by thin layer chromatography, water (100 mL) was added, the mixture was neutralized to acidity with hydrochloric acid (1N), extracted with ethyl acetate (200 mL), washed once with saturated brine (200 mL), the separated organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Loading the column with 200-300 mesh silica gel, eluting with a petroleum ether/ethyl acetate system, with a polarity gradient of petroleum ether-petroleum ether/ethyl acetate =2:1, intermediate 4-1 was isolated (yellow solid 6g, yield 63.26%). MS (ESI) 200.78 (M-H) -.
And 4, step 4: preparation of intermediate 5-1
2,6-dichlorobenzaldehyde (50g, 285.70mmol) was dissolved in acetone (250 mL) and stirred, and sodium hydroxide solution (w/w =8%,214ml, 428.55mmol) was added dropwise to the solution in ice bath and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off by thin layer chromatography, methylene chloride was added and the mixture was extracted (300 mL), washed with saturated brine (300 mL), the separated organic phase was dried over anhydrous sodium sulfate, filtered and the solvent was evaporated. Loading the column with 200-300 mesh silica gel, eluting with petroleum ether/ethyl acetate system, with a polarity gradient of petroleum ether-petroleum ether/ethyl acetate (v/v) =50, and isolating intermediate 5-1 (40 g yellow solid, yield 65.1%). 1 H NMR(400MHz,Chloroform-d)δ7.61(d,J＝16.7Hz,1H),7.37(d,J＝8.0Hz,2H),7.21(t,J＝8.1Hz,1H),6.82(d,J＝16.7Hz,1H),2.43(s,3H)。
And 5: preparation of intermediate 6-1
Dissolving a methanol solution of sodium methoxide (28.18mL, 147.86mmol) in methanol (250 mL) and stirring, adding diethyl malonate (20.67 mL (135.54 mmol), stirring at normal temperature for 30 minutes, adding V (26.6g, 123.21mmol), heating to reflux and stirring for 3 hours, then adding a sodium hydroxide solution (2N, 154mL, 308.03mmol), continuing to reflux for 1 hour, cooling to room temperature, adding concentrated hydrochloric acid (46.21mL, 554.46mmol) under ice bath, heating to reflux and stirring for 1 hour again, cooling to room temperature, extracting the reaction solution with ethyl acetate (300 mL) for 2 times, combining the organic phases, washing with saturated brine (500 mL), separating the organic phase, drying with anhydrous sodium sulfate, evaporating to dryness, pulping with ethyl acetate (200 mL) for 30 minutes, and filtering to obtain an intermediate 6-1 (white solid, 28g yield 88.39%). MS (ESI) 257.07 (M + H); 1H NMR (400MHz, DMSO-d 6) Δ 11.39 (s, 1H), 7.50 (s, 2H), 7.33 (t, J =8.1Hz, 1H), 5.33 (M, 1H), 4.27-4.16 (M, 1H), 3.24 (s, 2H), 2.23 (s, 2H).
Step 6: preparation of intermediate 7-1
Intermediate 6-1 (6.34g, 24.67mmol) was dissolved in DMF (200 mL) and stirred, intermediate 4-1 (5 g, 24.67mmol) and solid potassium carbonate (8.52g, 61.68mL) were added, respectively, and the mixture was heated to 80 ℃ and stirred overnight. After the end of the reaction, the solvent was evaporated by thin layer chromatography. The reaction was neutralized to pH =4 with 1N dilute hydrochloric acid solution, extracted twice with ethyl acetate/isopropanol (v/v =10, 1, 200 mL), the organic phases were combined, washed with saturated brine (300 mL), the separated organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness, and the reaction mixture was neutralized with petroleum ether/ethyl acetate 1: solvent 1 was slurried for 2 hours and filtered to give intermediate 7-1 (10 g of white solid, 88.5% yield). MS (ESI) 455.1 (M-H) -; 1 H NMR(400MHz,DMSO-d6)δ7.51(m,2H),7.39–7.26(m,2H),6.94(m,1H),6.75(m,1H),4.45–4.32(m,1H),3.59–3.44(m,4H),3.17(s,2H),2.55–2.44(m,2H)。
and 7: preparation of Compound 1
Intermediate 7-1 (1g, 2.19mmol) was dissolved in DMF (50 mL) and stirred, and (R) -alpha-methylbenzylamine (265.90mg, 2.19mmol), HATU (1g, 2.63mmol) and DIEA (573. Mu.l, 3.29 mmol) were added, respectively, and stirred at room temperature overnight. Monitoring the reaction by thin layer chromatographyAfter the completion of the reaction, the solvent was evaporated to dryness, the extract was extracted with dichloromethane (100 mL), washed with water (100 mL), 1N diluted hydrochloric acid (100 mL) and saturated brine (100 mL), respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness, a column was loaded on 200-300 mesh silica gel, the eluent was dichloromethane/ethyl acetate system with a polarity gradient of dichloromethane/ethyl acetate (v/v) = 5:1-1:1, and the compound 1 was isolated (860 mg of pale yellow solid, yield 69.9%). MS (ESI) 558.0473 (M-H) -; 1 H NMR(400MHz,DMSO-d 6 )δ8.48(d,J＝8.1Hz,1H),7.52(m,2H),7.39–7.25(m,5H),7.25–7.17(m,1H),6.92(dd,J＝8.1,2.1Hz,1H),6.79(m,1H),4.97–4.73(m,1H),4.50–4.35(m,1H),3.57(m,3H),3.47–3.30(m,4H),2.56(m,1H),1.34(d,J＝7.0Hz,3H)。
preparation of Compound 2
The same as the synthesis method of the compound 1, the intermediate 7-1 is taken as a common raw material to be condensed with 2- (aminomethyl) -5-methylpyrazine to obtain a compound 2.MS (ESI) 560.0366 (M-H) -. 1 H NMR(400MHz,Chloroform-d)δ8.36(m,2H),7.42–7.27(m,3H),7.18(t,J＝8.0Hz,1H),7.05(m,1H),6.64(m,1H),4.54–4.41(m,3H),3.69(m,2H),3.56(s,2H),2.67(dd,J＝17.5,4.7Hz,2H),2.52(s,3H),1.43–1.23(m,2H)。
Preparation of Compound 3
The same method as the method for preparing the compound 1 is used for condensing the intermediate 7-1 which is taken as a common raw material with 2-pyridine methylamine to obtain a compound 3.MS (ESI) 545.0273 (M-H) -; 1 H NMR(400MHz,DMSO-d 6 )δ8.65(m,1H),8.49(m,1H),7.74(m,1H),7.51(m,2H),7.34(m,2H),7.30–7.16(m,2H),6.99(m,1H),6.83(m,1H),4.36(d,J＝5.8Hz,2H),3.66–3.43(m,6H),3.15(m,1H),2.58m,1H)。
preparation of Compound 4
The same method as the method for preparing the compound 1 is adopted, and the intermediate 7-1 is taken as a common raw material to be condensed with N-methylbenzylamine to obtain a compound 4.MS (ESI) 558.0466 (M-H) -; 1 H NMR(400MHz,Chloroform-d)δ7.41–7.26(m,6H),7.22–7.08(m,3H),7.07–6.92(m,2H),4.57(s,1H),4.49–4.45(m,1H),3.66(m,4H),2.95(m,2H),2.87(s,2H),2.65(m,3H)。
preparation of Compound 5
The same as the process for preparing Compound 1, whereinThe intermediate 7-1 is a common raw material and is condensed with 2-amine methylpyrazine to obtain a compound 5.MS (ESI) 546.0228 (M-H) -; 1 H NMR(600MHz,Chloroform-d)δ8.53–8.38(m,3H),7.40–7.30(m,2H),7.26(d,J＝7.9Hz,1H),7.17(t,J＝8.0Hz,1H),7.05–6.99(m,2H),6.83(m,1H),4.53(d,J＝5.5Hz,2H),4.47(m,1H),3.74–3.63(m,2H),3.55(s,2H),3.13(q,J＝7.4Hz,1H),2.66(dd,J＝17.5,4.7Hz,2H)。
preparation of Compound 6
The same method as the method for preparing the compound 1 is used for condensing the intermediate 7-1 which is taken as a common raw material with (R) -1- (1-naphthyl) ethylamine to obtain a compound 6.MS (ESI) 608.0619 (M-H) -;1H NMR (400mhz, chloroform-d) δ 8.03 (d, J =8.3hz, 1h), 7.84-7.80 (m, 1H), 7.76 (dd, J =6.8,2.7hz, 1h), 7.55-7.27 (m, 7H), 7.18 (t, J =8.0hz, 1h), 7.05 (m, 1H), 7.00 (dd, J =8.0,2.2hz, 1h), 5.89 (q, J =7.1hz, 1h), 5.77 (d, J =8.3hz, 1h), 4.44 (m, 1H), 3.67 (s, 2H), 3.53-3.37 (m, 2H), 2.63 (s, 2H), 1.61 (d, J = 6.3h), 1.25 (s, 1H).
Preparation of Compound 7
The same method as the method for preparing the compound 1 is used for condensing the intermediate 7-1 which is taken as a common raw material with (R) - (+) -1- (2-naphthyl) ethylamine to obtain the compound 7.MS (ESI) 608.0617; 1 H NMR(400MHz,DMSO-d 6 )δ8.60(d,J＝8.0Hz,1H),7.86(m,3H),7.75(m,1H),7.48(m,5H),7.39–7.26(m,2H),6.96(m,1H),6.83(m,1H),5.07(m,1H),4.49–4.35(m,1H),3.59(m,2H),3.42(m,3H),2.65–2.53(m,2H),1.44(d,J＝7.0Hz,3H).
preparation of Compound 8
The same method as the method for preparing the compound 1 is used for condensing the intermediate 7-1 which is taken as a common raw material with (R) -1- (3-bromophenyl) ethylamine to obtain a compound 8.MS (ESI) 635.957 (M-H) -; 1 H NMR(400MHz,Chloroform-d)δ7.41–7.28(m,5H),7.22–7.07(m,4H),7.01(m,1H),6.10(d,J＝7.8Hz,1H),5.14–4.85(m,1H),4.60–4.34(m,1H),3.67(m,2H),3.46(m,2H),2.80(s,1H),2.65(m,2H),1.40(d,J＝7.0Hz,3H)。
preparation of Compound 9
The same method as the method for preparing the compound 1 is used for condensing the intermediate 7-1 which is taken as a common raw material with (R) -1- (4-bromophenyl) ethylamine to obtain a compound 9.MS (ESI) 635.9576 (M-H) -; 1 H NMR(400MHz,DMSO-d 6 )δ8.52(d,J＝7.8Hz,1H),7.50(m,3H),7.40–7.28(m,2H),7.22(d,J＝8.2Hz,2H),6.93(m,1H),6.80(m,1H),4.85(t,J＝7.2Hz,1H),4.50–4.30(m,1H),3.70–3.50(m,3H),3.39(m,3H),2.66–2.52(m,2H),1.32(d,J＝7.0Hz,3H)。
pharmacological test example:
experimental example 1 determination of inhibitory Activity of Compounds on LDHA enzyme
The establishment of the LDHA molecular enzyme activity method is a report of a reference [ Dragovich PS et al.Bioorg Med Chem Lett.2014,24 (16): 3764-71.384], and concretely comprises the following steps: a reaction system of 10 mu L is arranged in each hole of a hole plate, and comprises 50mM HEPES (pH = 7.2), 0.01% (volume ratio) TritonX-100, 0.1mg/mL Bovine Gamma Globulin (BGG), 2mM DTT, 50 mu M NADH, LDHA enzyme diluted in a gradient way and 50 mu M pyruvic acid, the reaction system is configured in a dark place, and the enzyme activity is reflected by measuring the change of the NADH content. The excitation wavelength of NADH is 340nm and the emission wavelength is 480nm, fluorescence is detected by using a Synergy H1 multifunctional enzyme-labeled instrument of Bio-tek company, the excitation wavelength is 340nm and the emission wavelength is 480nm, a change curve of the fluorescence value within 10min is drawn, a flat section of the change curve is taken to calculate the slope so as to represent the enzyme catalysis reaction rate, then an enzyme concentration-reaction rate curve is drawn, and the maximum enzyme concentration in a linear interval is taken as the optimum concentration of LDHA enzyme in the subsequent experiment.
Activity screening of LDHA inhibitors:
similarly, the above reaction system was used, a blank group was set as a group without LDHA, a control group was set as a group without compound, and a positive control group was set as a group GNE-140, each compound in the compound group was diluted from 780nM at a gradient concentration of 3 times, and the reaction system was prepared under a dark condition for detection and measurement was carried out in a SynergyH1 fluorescence microplate reader (see formula 1-1). Drawing a change curve of the fluorescence value within 10min, taking a straight section of the change curve to calculate a slope k, and calculating the enzyme activity inhibition rate:
enzyme activity inhibition rate = [ (k) Control -k Experiment of )/(k Control -k Blank space )]×100％
At half inhibition rate (IC) 50 ) Compounds representing the inhibitory activity of the compound, the inhibition at a concentration of 10. Mu.M of less than 50%, are denoted IC 50 More than 10 mu M, measuring the molecular level enzyme activity inhibition rate of the compound,a compound concentration-enzyme activity inhibition rate curve is prepared, graph pad software is used for drawing and fitting the inhibition rate curve to obtain IC50, and the compound inhibition rate is shown in table 1.
TABLE 1
As can be seen from the experimental data in Table 1, the LDHA enzyme inhibitory activity of the compound of the present invention is lower than that of the positive drug GNE-140.
Example 2 Effect of Compounds on cellular lactate secretion
Step 1: cell culture
Human oral squamous carcinoma cell lines which are determined to be sensitive to glycolysis in earlier work are selected. The cells were in good condition and in logarithmic growth phase, and were obtained from the cell bank of the culture Collection of the Chinese academy of sciences. The cell culture media used were: DMEM (Corning, USA) +10% fetal bovine serum (GIBCO, USA). The cells used in the experiment were all placed at 5% CO 2 95% air, and culturing in a constant temperature incubator at 37 ℃.
Step 2: compound-to-cell lactate secretion assay
The cell lactic acid secretion is detected by adopting a lactic acid determination kit (Nanjing Kangkui, nanjing, A019-2). Head and neck cancer cell HN12 at 1.5X 10 4 Density per well was seeded in 96-well plates, attached overnight, replaced with 180. Mu.L serum-free medium and treated with test compound for 12h (compound concentration 50/25/12.5. Mu.M), solvent control contained 1% DMSO. Preparing an enzyme reaction working solution and a color development solution in advance according to the kit specification, taking a new 96-well plate, adding 2 mu L of cell culture medium supernatant, 100 mu L of enzyme reaction working solution and 20 mu L of color development solution into each well, incubating for 10min in a shaking table at 37 ℃, adding 200 mu L of reaction termination solution, measuring the absorbance value at 530nm on an enzyme label analyzer, calculating the concentration of lactic acid by using an Excel fitting standard curve, and drawing by GraphPad software (with p as the index of P)<0.05). The test results are shown in fig. 1 and 2.
As can be seen from fig. 1 (in which GNE-140, compound 1, compound 3, compound 4, and the like correspond in order from left to right) and fig. 2 (in which GNE-140, compound 6, compound 5, compound 7, compound 8, and compound 9 correspond in order from left to right), the compound of the present invention has a significant inhibitory effect on the amount of lactic acid secretion in head and neck cancer cells HN12, and preferably, compounds 4, 6, 7, 8, and 9 are similar to the inhibitory effect of the positive drug GNE-140.
Example 3 Effect of Compounds on cell proliferation
B16F10 cells were plated at 3X 10 3 Density per well was seeded in 96-well plates and placed in an incubator overnight to allow cells to adhere. The drugs are prepared to proper concentration by normal saline, the drugs are added, 20 mu L/well is added, and the mixture is put into an incubator to be cultured for 72 hours. Adding 20 mu L of CCK-8 staining solution into each well, putting the mixture back to the incubator for incubation for 1.5h, measuring the OD value at 450nm by using a microplate reader, and calculating the inhibition rate.
Inhibition Rate = [1- (OD) Experimental group /OD Control group )]×100％
IC was determined by plotting and fitting inhibition curves to GraphPad software 50 The test results are shown in Table 2.
TABLE 2 proliferation inhibitory Activity of Compounds on B16F10 cells
| Compound (I) | GNE-140 | 6 |
| IC50(μM) | 22.85 | 26.05 |
As can be seen from the experimental data in table 2, the compounds of the present invention have significant inhibitory effects on the proliferation of B16F10 cells.
Example 4 in vivo antitumor Activity of Compounds
B16F10 cells were plated at 1X 10 5 Mice are inoculated subcutaneously in axilla with tumors growing to about 80-100 mm 3 The administration is started by grouping, the administration mode is intratumoral injection administration every day, the drug concentration is 50mg/kg, tumors are weighed every three days, and the average tumor volume of a solvent control group of a mouse is 2000mm 3 As an endpoint. Mapping by GraphPad software (. P.)<0.05)
Tumor inhibition rate = (mean volume of change of control group-mean volume of change of experimental group)/mean volume of change of control group x 100%.
The results of the experiment are shown in FIG. 3.
As can be seen from FIG. 3, compared with the control drug GNE-140, the compound 6 of the present invention has better in vivo anti-tumor activity, and the tumor inhibition rate thereof reaches 48%, while the compound GNE140 has no obvious anti-tumor activity under the same dosage.
The above embodiments are merely exemplary in nature and are not intended to limit the claimed embodiments or the application or uses of such embodiments. In this document, the term "exemplary" represents "as an example, instance, or illustration. Any exemplary embodiment herein is not necessarily to be construed as preferred or advantageous over other embodiments.
In addition, while at least one exemplary embodiment or comparative example has been presented in the foregoing detailed description, it should be appreciated that a vast number of variations are possible. It should also be appreciated that the embodiments described herein are not intended to limit the scope, applicability, or configuration of the claimed subject matter in any way. Rather, the foregoing implementations will provide those of ordinary skill in the art with a convenient road map for implementing the described embodiment or embodiments. Further, various changes may be made in the function and arrangement of elements without departing from the scope defined in the claims, which includes known equivalents and all foreseeable equivalents at the time of filing this patent application.
Claims (10)
1. A1,3-cyclohexanedione compound, a stereochemical isomer or a pharmaceutically acceptable salt thereof, wherein the structural formula of the 1,3-cyclohexanedione compound is shown as formula I:
wherein the content of the first and second substances,
ar is substituted or unsubstituted phenyl, the substituted phenyl is phenyl substituted by 1 to 3 substituents R ', the substituents R' are same or different and are selected from halogen, cyano, halogen-substituted C1-C6 alkyl, C1-C6 alkyl or C1-C6 alkoxy, preferably halogen, cyano, perhalo-substituted C1-C3 alkyl, C1-C3 alkyl or C1-C3 alkoxy, more preferably halogen, cyano, trifluoromethyl, methyl, methoxy;
x is hydrogen or halogen, preferably chlorine;
R 1 selected from hydrogen or C1-C3 alkyl;
R 2 selected from C1-C3 alkylene;
R 3 selected from substituted or unsubstituted C6-C14 aryl, or substituted or unsubstituted C4-C12 heteroaryl, said substituted substituents being selected from halogen, halogen substituted C1-C6 alkyl, preferably halogen or C1-C3 alkyl, more preferably halogen or methyl.
2. The 1,3-cyclohexanedione compound of claim 1, a stereochemically isomeric form, or a pharmaceutically acceptable salt thereof, wherein the compound has the structural formula IA:
wherein R is 41 、R 42 Each independently selected from halogen, cyano, perhalo-substituted C1-C3 alkyl, C1-C3 alkyl or C1-C3 alkoxy, preferably halogen, cyano, trifluoromethyl, methyl or methoxy, more preferably chlorine.
3. The 1,3-cyclohexanedione compound of claim 2, a stereochemically isomeric form, or a pharmaceutically acceptable salt thereof, wherein the compound has the structural formula IA1, IA2, IA3, or IA 4:
R 21 are respectively selected from hydrogen or methyl;
R 31 respectively selected from halogen, halogen substituted C1-C6 alkyl and C1-C6 alkyl; preferably halogen or C1-C3 alkyl, more preferably halogen or methyl:
n is an integer of 0 to 5;
m is an integer of 0 to 4;
p is an integer of 0 to 3;
q is an integer of 0 to 7.
4. The 1,3-cyclohexanedione compound of claim 3, a stereochemically isomeric form, or a pharmaceutically acceptable salt thereof, wherein the IA4 compound has the structural formula IA4a or IA4 b:
5. the 1,3-cyclohexanedione compound, its stereochemically isomeric form, or a pharmaceutically acceptable salt thereof as claimed in claim 3 or 4, wherein R and R are 21 The carbon atoms attached are of the R or S type, preferably the R type.
6. The 1,3-cyclohexanedione compound, a stereochemically isomeric form, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5, wherein the compound of formula I is selected from the compounds of the following structural formula:
7. a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from 1,3-cyclohexanediones, a stereochemically isomeric form thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6, preferably comprising a pharmaceutically acceptable carrier or excipient.
8. A lactate dehydrogenase inhibitor comprising one or more of the 1,3-cyclohexanediones, stereoisomers or pharmaceutically acceptable salts thereof of any one of claims 1-6, or a pharmaceutical composition according to claim 7.
9. Use of a1,3-cyclohexanedione compound of any of claims 1-6, a stereochemically isomeric or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 7, comprising: the application of the compound in preparing anti-tumor drugs and in preparing drugs for treating cancers caused by immune escape.
10. The use of claim 9, wherein the tumors comprise melanoma and mesothelioma, and the cancers comprise lung cancer, liver cancer, kidney cancer, acute leukemia, prostate cancer, thyroid cancer, skin cancer, colon cancer, rectal cancer, pancreatic cancer, ovarian cancer, breast cancer, myelodysplastic syndrome, esophageal cancer, and gastrointestinal cancer.
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| CN111285850A (en) * | 2018-12-06 | 2020-06-16 | 中国科学院上海药物研究所 | Isoindoline compounds, preparation method thereof, pharmaceutical composition and application thereof |
| CN111434654A (en) * | 2019-01-11 | 2020-07-21 | 四川大学 | Triazole hexanone biaryl (hetero) ring derivative and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111285850A (en) * | 2018-12-06 | 2020-06-16 | 中国科学院上海药物研究所 | Isoindoline compounds, preparation method thereof, pharmaceutical composition and application thereof |
| CN111434654A (en) * | 2019-01-11 | 2020-07-21 | 四川大学 | Triazole hexanone biaryl (hetero) ring derivative and preparation method and application thereof |
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| MENGYAN DU 等: "Development of a novel lactate dehydrogenase A inhibitor with potent antitumor activity and immune activation", 《CANCER SCIENCE》, vol. 113, pages 2974 - 2985 * |
| PETER S. DRAGOVICH 等: "Identification of substituted 3-hydroxy-2-mercaptocyclohex-2- enones as potent inhibitors of human lactate dehydrogenase", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, pages 3764 - 3771 * |
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