WO2011063602A1 - Use of 5-substituted-2, 4-thiazolidinediones in preparation of medicaments for modulating insulin-like growth factor 1 receptor - Google Patents

Abstract

Use of 5-substituted-2, 4-thiazolidinediones of formula (I) or pharmaceutically acceptable salts thereof in preparation of the medicaments for modulating insulin-like growth factor 1 receptor (IGFlR). The compounds of the present invention can inhibit the activity of IGFlR kinase and can be used to treat cancer.

Description

 FIELD OF THE INVENTION The present invention relates to the field of medicinal chemistry and pharmacotherapeutics. In particular, the present invention relates to the use of a 5-substituted-2,4-thiazolidinedione compound for the preparation of a medicament for the treatment of a cancer-related disease, which has a strong cell which inhibits the insulin-like growth factor 1 receptor protein. Endo-tyrosine kinase activity, with potential for the treatment of tumor or cancer diseases. BACKGROUND OF THE INVENTION Cancer is a major ailment that seriously endangers human health. There are 9 million people with cancer every year in the world, and 6 million people die of cancer. The annual number of cancers in China is about 1.2 million. The number of people who die of cancer every year is more than 900,000, and the number of patients to be treated exceeds 1.5 million. Overcoming cancer difficulties is a major task for medical workers.

 The drugs that have been studied and applied for a long time are targets for the use of cancer cells as drugs. Therefore, cytotoxic drugs have always been the main drugs for treating cancer, but the problem of side effects of such anticancer drugs has not been solved. With the development of biotechnology and the development of combinatorial chemistry, high-throughput screening, etc., the search for anticancer drugs has gradually entered the stage of targeting specific proteins. Among them, the important role of protein tyrosine kinases in cancer cell proliferation It has become an attractive target for cancer treatment. Protein tyrosine kinase (PTK) plays an important role in tumorigenesis, and it is known that more than half of proto-oncogenes express proteins with PTK activity. The role of protein tyrosine kinases is to transfer the phosphate group of ATP to a specific tyrosine residue of a functional protein that regulates cell growth, proliferation and differentiation.

The insulin-like growth factor (IGF) system plays an important role in the formation and development of tumors. The IGF system includes insulin-like growth factor, insulin-like growth factor receptor, insulin-like growth factor binding protein and its hydrolase. Among them, the insulin-like growth factor type I receptor (IGF1R) is the most important, and this receptor mediates the main physiological functions of IGF. IGF1R is a tyrosine kinase transmembrane protein that binds to its ligand and promotes cell proliferation and inhibits apoptosis. Recent studies have shown that IGF1R is up-regulated in many malignant tumors (such as breast cancer, hepatocellular carcinoma, colorectal cancer, etc.), and is closely related to malignant transformation, infiltration, and metastasis of tumor cells. IGF1R contains a 706 amino acid alpha subunit and a 626 amino acid beta subunit. The α and β subunits form an α-β half receptor through a disulfide bond, and the two α-β half receptors are further linked by a disulfide bond to form a mature β-α-α-β tetramer. The alpha subunit is located extracellularly and has a cysteine-rich region that specifically binds to IGF1, while the beta subunit is distributed across the membrane, with extracellular regions, transmembrane regions, and tyrosine kinase-containing activities. Intracellular region. The target site for tyrosine kinase catalytic subunit and kinase action is located in the cytoplasmic portion of the beta subunit.

 IGF1R mediates a number of signaling pathways within cells. IGF1R binds to its ligand (insulin growth factor I and insulin growth factor II) and initiates two signal transduction pathways: 1 phosphatidylinositol-3-kinase (ΡΙ3Κ)-Akt pathway; 2 mitogen-activated protein kinase ( MAPK) pathway. The main process is: IGFIRa subunit binds to its ligand, causing an allosteric effect between the two α, β subunits of the receptor molecule, allowing the tyrosine base at the C-terminus of the β subunit to rapidly autophosphorylate and activate The activity of IGF1R's tyrosine kinase then rapidly signals the various substrates in the cell, causing multiple site phosphorylation of insulin receptor substrate 1 (IRS1), which in turn forms IRS1, GRB2 and ornithine exchange. A complex of factors (or ras activating factor, SOs), IRS1-GRB2-SOS leads to activation of the GTP-binding protein ras, activation of ras into a phosphorylation and activation of MAP kinase/ERK, and ERK transmits signals to the nucleus, Start the mitosis process. Simultaneous phosphorylation of IRS1 activates PIP3 kinase, which initiates a PIP3-mediated pathway that transmits cell growth signals. In addition, there are reports in the literature (Mat. Rev. Drug Discovery 2005, 4, 988- 1004). The IGFIRp subunit can also directly interact with the P85 subunit of phosphatidyl-3,4,5-triphosphate (P IP3 ) kinase after autophosphorylation. Combine and activate its activity.

 IGF1R binds to its ligand and promotes mitosis and anti-apoptosis. It is not required for cells to grow under normal conditions, but it must be in the absence of cells or in the growth of tumor transplanters. Indispensable role. Studies have shown (J. Med. Chem., 2009, 52, 4981-5004) that IGF1R is closely associated with transformation, proliferation, metastasis, and radioresistance in many malignancies. This makes IGF1R a very attractive target for targeted tumor therapy.

Studies on small molecule inhibitors of IGF1R have been reported abroad (J. Med. Chem., 2009, 52, 4981-5004), such as benzimidazole pyridines, isoquinolinediones, and pyrrolopimidines. The compound of the parent nucleus has an effect of inhibiting the activity of IGF1R tyrosine kinase. However, most of these compounds are designed by pharmaceutical chemists based on experience. In the present invention, we use a virtual screening method in computer-aided drug design to screen 230,000 molecular structures in the specs commercial chemical database, purchase and test the inhibitory activity against IGF1R, and finally find a class 5 provided by the present invention. The substituted-2,4-thiazolidinedione compound has a good activity of inhibiting the catalytic activity of the IGF1R kinase domain. Thiazolidinedione compounds have been widely reported in the literature and patents (rrew in Investigational Drugs, 2003, 4, 406-411 ) has a strong inhibitory effect on peroxisome proliferator receptor gamma (PPARy) activity, and its representative drug rosiglitazone has been marketed for the treatment of type 2 diabetes. First-line drugs. The novel 5-substituted-2,4-thiazolidinedione compounds we have discovered have activity for inhibiting the catalysis of the IGF1R kinase domain, and there has been no report on the use of the compounds of the present invention in the preparation of a medicament for cancer-related diseases. This has broadened the field of clinical treatment of such compounds. Disclosure of the Invention An object of the present invention is to provide a novel 5-substituted-2,4-thiazolidinedione compound having a function of inhibiting the insulin-like growth factor 1 receptor (IGF1R) or a pharmaceutically acceptable salt thereof (structural formula) Use as shown in I) in the manufacture of a medicament for cancer-related diseases.

 The compound of the present invention can be used as a small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF1R) to block the growth, proliferation and differentiation of tumor cells by blocking its catalytic activity, thereby blocking the life cycle of tumor cells. Therefore, it can be developed into a new anti-tumor drug.

 The present invention provides a 5-substituted-2,4-thiazolidinedione compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

among them,

 X is selected from 0, N or S;

 B is a benzene ring, a 5 or 6 membered aromatic heterocyclic ring;

 The wavy line indicates the Z-type and E-type geometric isomers of the double bond;

R ₀ , , R ₂ , R ₃ , R ₄ and R _{5 are the} same or different and are each independently selected from the group consisting of: hydrogen, C _r C ₆ linear or branched saturated or unsaturated hydrocarbon group (optionally containing one) Or a plurality of substituents selected from the group consisting of 3⁄4, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, alkoxy, decyl and dC ₄ acyl groups and chains Containing one or more C _r C ₄ alkane groups selected from 0 and S), a C ₃ -C ₇ saturated or unsaturated cycloalkane group, a halogen, a cyano group, a nitro group, a hydroxyl group, Hydroxymethyl, dC ₄ alkoxy, dC ₄ unsaturated alkoxy, carboxy, ester, trifluoromethyl, trifluoromethoxy, sulfonyl, decyl, 3-7 membered heterocyclyl, benzyl, An aromatic group or a 5-7 membered aromatic heterocyclic ring, or any two adjacent groups of R _r R ₅ may be bonded to form a ring, which may be selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, hydroxy Substituting one or more substituents of a group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, a dC ₄ alkoxy group, a fluorenyl group, and a dC ₄ acyl group; and it may contain one or more hetero atoms;

In the above technical solution, according to R. The substituents or groups represented by Ri, R ₂ , R ₃ , R ₄ , R ₅ and R ₆ , the compounds of the formula I provided by the invention include their enantiomers, diastereoisomers Constructs, racemates, and combinations thereof.

 The term "hydrocarbyl" as used herein refers to an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl group having from 1 to 10 carbon atoms.

The term "aromatic Ar" as used herein means phenyl, substituted phenyl, naphthyl or biphenyl, wherein the substituent is a linear or branched hydrocarbon group selected from 3⁄4, CC ₆ , cyano, nitrate 1-4 groups of acyl group of amino group, amino group, hydroxyl group, hydroxymethyl group, trifluoromethyl group, trifluoromethoxy group, carboxyl group, alkoxy group, fluorenyl group, d-do thioalkyl group and C _r C ₄ group.

 The term "heterocyclyl", unless otherwise indicated, refers to a single or fused ring structure, which may be aromatic or non-aromatic in nature, and which preferably contains from 3 to 20 ring atoms, more preferably from 5 to 8 ring atoms, of which at least 1 and preferably up to 4 are heteroatoms. Examples of the heterocyclic group include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, Pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl and benzofuranyl.

 The term "heteroatom" as used herein includes oxygen, sulfur and nitrogen. When the hetero atom is nitrogen, the nitrogen atom may be substituted with a group such as hydrogen or a Crdo alkyl group.

The term "aromatic heterocycle" as used herein refers to those heterocyclic groups which have aromatic character as described above. In the present specification, when the term "alkyl" is used alone or as a suffix, it has a linear or branched structure. These groups may contain up to 10, preferably up to 6, and more preferably up to 4 carbon atoms. Likewise, the terms "alkenyl" and "alkynyl" have an unsaturated straight or branched chain structure containing from 2 to 10, preferably from 2 to 6 carbon atoms. The cyclic moiety such as a cycloalkyl group, a cycloalkenyl group and a cycloalkynyl group are similar in nature and have at least 3 carbon atoms, preferably 3 to 20 carbon atoms, more preferably 3 to 7 carbon atoms. The term "alkoxy" refers to an alkyl group attached to an oxygen atom as described above, Alkenyl, alkynyl. The term "thioalkyl" refers to an alkyl, alkenyl, alkynyl group attached to a sulfur atom as described above.

 The term "halogen" as used herein includes fluoro, chloro, bromo and iodo.

 The "pharmaceutically acceptable salt" described in the present specification specifically includes the compound provided by the present invention and formic acid, acetic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, propionic acid, malonic acid, succinic acid, An organic acid such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid or citric acid or a salt formed with an acidic base such as aspartic acid or glutamic acid and then formed with an inorganic base such as sodium, potassium or calcium. , aluminum salts and ammonium salts, or salts with organic bases, such as methylamine salts, ethylamine salts, ethanolamine salts, etc.; or with lysine, arginine, ornithine and other basic amino acids to form esters and then A mineral acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid forms a salt.

 A preferred embodiment of the invention is that the compound has the formula shown by the formula (Π):

X is preferably selected as 0, S;

 Y is selected from 0, S, N; wavy lines represent Z-type and E-type geometric isomers of double bonds;

R _{6 is} selected from an aromatic Ar or a 5-7 membered aromatic heterocyclic ring, wherein the 5-7 membered aromatic heterocyclic ring contains 1-2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, which may be selected from halogens, Halogenated C _r C ₃ alkyl, C _r C ₃ alkyl, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, dC ₃ alkoxy and aryl Ar Replaced by one or more of the groups. Another preferred embodiment of the invention is that the compound has the structural formula of formula (III):

X is selected from 0, s; the wavy line indicates the Z-type and E-type geometric isomers of the double bond;

_{R 7, R 8, R 9} , R 1 () and R _u may be the same or different, are each independently hydrogen, C _r C straight or branched chain ₆ saturated or unsaturated hydrocarbon, C ₃ -C ₇ of Saturated or unsaturated cycloalkane, halogen, cyano, nitro, hydroxy, hydroxymethyl, carboxy, ester, trifluoromethyl, trifluoromethoxy, sulfonyl, decyl, dC ₄ alkoxy, dC ₄ unsaturated alkoxy, C _r C ₆ carboxyalkoxy, dC ₆ ester alkoxy, CC ₆ carboxyalkyl, dC ₆ ester alkyl, 3-7 membered cycloalkyl or heterocyclic, benzyl , benzyloxy, aryl or 5-7 membered aromatic heterocyclic ring, or any two adjacent groups of R ₇ -R _u may be joined to form a ring, the ring may be optionally substituted and it may comprise one or more Hetero atom

 A further preferred embodiment of the invention is that the compound has the structural formula shown in formula IV:

X is selected from 0, S; The wavy line indicates the Z-type and E-type geometric isomers of the double bond;

_{R 12, R 13, R 14} , R 15 and R ₁₆ may be the same or different, are each independently hydrogen, C _r C linear or branched, saturated or unsaturated hydrocarbon group _6, C ₃ -C ₇ saturated or Unsaturated cycloalkane, halogen, cyano, nitro, hydroxy, hydroxymethyl, carboxy, ester, trifluoromethyl, trifluoromethoxy, sulfonyl, decyl, dC ₄ alkoxy, dC ₄ Saturated alkoxy group, C _r C ₆ carboxyalkoxy group, dC ₆ ester alkoxy group, C _r C ₆ carboxyalkyl group, dC ₆ ester alkyl group.

 detailed description

 The invention will be further illustrated in the following examples. These examples are only intended to illustrate the invention, but are not intended to limit the invention in any way. All parameters in the examples, as well as the remaining descriptions, are by mass unless otherwise indicated.

 Example 1

 The compounds provided by the present invention were obtained by virtual screening by computer aided drug design methods. The invention comprehensively utilizes structure-based pharmacophore matching and receptor-based molecular docking method to perform virtual screening of SPECS compound database (230,000 chemical molecular structures) of SPECS Chemical Company of the Netherlands, and finally selects the compound provided by the invention. Specific examples 1 to 75.

 (1) The SPECS database was coarsely screened based on the structure-based pharmacophore matching method.

Based on the complex crystal structure of IGF1R and its small molecule inhibitor BMI (PDB database number 20 J9), LigandScout was used to generate a pharmacophore model that can characterize the interaction mode between IGF1R and BMI. Using the model as a question model, the three-dimensional structure in the specs small molecule database was matched by the pharmacophore module in Di _SCOve rySt _U rdi _O 2.0, and finally a total of 3326 molecular structures with matching scores higher than 0.0 were retained.

 (2) The specs database is rescreened based on the molecular docking method of the acceptor structure.

The crystal structure of the complex of IGF1R and its small molecule inhibitor BMI (PDB database No. 20 J9) was used as a receptor, and the 3326 compound structures screened in (1) were docked into the receptor by Glide docking software. The docking mode was Glide. "Extremely accurate mode" (XP mode), of course Then, GlideGscore was used to sort and match each compound docking mode. After careful analysis and analysis of the docking binding mode of each compound with IGF-1R, 75 compounds were finally selected for in vitro test to inhibit IGF-1R activity. All compounds were tested. Both were purchased from SPECS (www.specs.net) in the Netherlands.

 Example 2

 In vitro inhibitory effect of the compounds provided by the present invention on insulin-like growth factor 1 receptor (IGF1R) kinase activity

 Material:

The tyrosine kinase used in the experiment was obtained by expression and purification using an insect baculovirus expression system. Poly(Glu, Tyr) _4: i is a product of Sigma (St Louis, MO, USA); ATP, OPD is Amresco (Solon, Ohio, USA); anti-phosphotyrosine monoclonal antibody PY99 is Santa Cruz The product of the company (Santa Cruz, CA, USA); horseradish peroxidase-labeled goat anti-mouse IgG is a product of Calbiochem (Darmstadt, Germany); the ELISA plate is a product of Corning (New York, USA).

 Method:

 The biological activity test method is a tyrosine kinase activity test based on enzyme-linked immunofluorescence analysis.

(1) pre-coated the ELISA plate with a 20 g/ml enzyme reaction substrate Poly(Glu, Tyr) _4:1 ;

(2) ATP solution diluted with reaction buffer (final concentration 5 M), different concentrations of test compound or DMSO control, and test tyrosine kinase were placed in the wells of the substrate coated with the substrate. The reaction was shaken at 37 ° C for 1 hour. Reaction buffer formulation: HEPES (pH 7.4) 50 mM, MgCl ₂ 50 mM, MnCl ₂ 0.5 mM, Na ₃ VO ₄ 0.2 mM, DTT 1 mM.

 (3) After the reaction was completed, the liquid in the well was discarded, and the plate was washed three times with a potassium ion-free PBS solution (T_PBS) containing 0.1% Tween-20.

(4) An anti-tyrosine phosphorylation antibody PY99 (antibody was diluted 1:500 with BSA 5 mg/ml in T-PBS solution) was added, and the reaction was carried out for 30 minutes at 37 ° C on a shaker. The plate was washed three times with T-PBS. (5) Horseradish peroxidase-labeled goat anti-mouse IgG (antibody diluted 1:1000 in BSA 5 mg/ml T-PBS solution) was added, and the reaction was shaken at 37 ° C for 30 minutes. The plate was washed three times with T-PBS.

(6) Add 2 mg/ml of OPD chromogenic solution (diluted with 0.1 M citric acid-sodium citrate buffer containing 0.03% 3⁄4 O ₂ ), and react at 25 ° C until the color develops.

(7) Add 2M 3⁄4SO ₄ 50 1/well to stop the reaction.

 (8) VERSAmax reading with a tunable wavelength microplate reader with a wavelength of 492 nm. The inhibition rate of the sample is obtained by the following formula:

 Sample inhibition rate % = [1 - (compound OD value - no enzyme control well OD value) / (compound OD value - no enzyme control well OD value)] x l00%

(9) The experiment was repeated 3 times or more, and the IC _5Q value of each compound was calculated by the Logit method.

 The activity test results are shown in Table 1:

Table 1 provides a compound of the invention on half of human IGF1R inhibitory protein Inhibitory concentration IC ₅₀ values

 Screening method: enzyme-linked immunosorbent assay (ELISA)

 Tyrosine kinase: insulin-like growth factor 1 receptor (IGF1R)

 Duration: lh

Evaluation of results: Invalid: ₅₀ >100·0μΜ;

 Valid: Ιθ5ο <100.0μΜο

 In vitro half-inhibitory concentration of IGF1R kinase activity

10 Sample number structure results evaluation IC ₅₀ (μΜ)

7 . Effective 5.4

^HN

8 00; valid 4.4

9 effective 0.09

10 effective 1.7

11 effective 64.4 Sample number structure results evaluation IC ₅₀ (μΜ)

12 effective 0.64

 /

^Η

 13 Valid 9.0

TM

14 effective 16.0

15 Valid 5.5

_HN

16 valid 55.7 Sample number structure results evaluation IC ₅₀ (μΜ)

17 effective 0.42

 18 effective 15.0

_HN

 0

19 effective 6.0

20 active 8.0

21 Valid 5.1

样品编号 结构 结果评定 IC₅₀ (μΜ) 22 effective 2.5

Sample number structure results evaluation IC ₅₀ (μΜ)

23 <ΧΧ' is valid 6.9

^ΗΝ

24 effective 14.9

25 Effective 11.1

26 effect 9.0

 -jiS has

27 effective 12.1

28 Effective 8.0 Sample number structure results evaluation IC ₅₀ (μΜ)

29 effective 0.4

30 effective 15.0

31 ~: Effective 63.0

丫^c ^

 32 Valid 10.2

.

33 valid 95.0

k

 34 Valid 68.2

样品编号 结构 结果评定 IC₅₀ (μΜ) _HN

Sample number structure results evaluation IC ₅₀ (μΜ)

42 ~. Effective 24.50

43 Valid 6.32.

^^^^^^^^^^^^^

 44 Valid 10.23

45 effective 16.0

46 effective 0.21

/

47 effective 0.45 Sample number structure results evaluation IC ₅₀ (μΜ)

48 effective 36.8

49 effective 9.02

50 effective 5.23

51 > X Xh Effective 0.20

52 effective 1.56

 Y

 53 effective 1.20

 Y

54 effective 0.86 Sample number structure results evaluation IC ₅₀ (μΜ)

55 effective 5.45

s 丫.

 56 effective 3.40

57 people. Effective 83.5

58 valid 79.0 s

 s

59 Effective 10.15

60 effective 0.95

样品编号 结构 结果评定 IC₅₀ (μΜ) 61 effective 21.0

Sample number structure results evaluation IC ₅₀ (μΜ)

62 effective 35.64

63 effective 96.0

64 valid 96.21

. Γ

 Person, 〈

 65 valid 56.41

66 effective 4.87

67 effective 3.45

68 effective 80.6 Sample number structure results evaluation IC ₅₀ (μΜ)

69 effective 4.23

70 effective 7.40

 71 effective 43.20

72 effective 26.4

73 Valid 98.2

74 effective 86.5

. IT

75 effective 45.80 Sample number structure results evaluation IC ₅₀ (μΜ)

< . Benzimidazole pyridine effective 0.29

Isoquinolinedione Effective 0.319

 Hey. Bioactivity tests have shown that thiazolidinedione activity is superior or at least equivalent to the previously reported small inhibitors of IGF1R (such as benzimidazoles, isoquinolinediones, see Table 1).

 Industrial applicability

 The 5-substituted-2,4-thiazolidinedione compounds of the present invention have a good effect in inhibiting the activity of the insulin-like growth factor 1 receptor (IGF1R) kinase, and IGF1R plays an important role in the proliferation and differentiation of tumor cells. Promoting action, therefore, the compounds of the invention are useful in the preparation of a medicament for the treatment of neoplastic diseases.

Claims

Rights request 1. A 5-substituted-2,4-thiazolidinedione compound represented by the following formula (I), an enantiomer, a diastereomer, a racemate or a pharmaceutically acceptable compound thereof The use of salt in the preparation of insulin-like growth factor 1 receptor function regulating drugs:

among them,  X is selected from 0, N or S;  B is a benzene ring, a 5 or 6 membered aromatic heterocyclic ring;  The wavy line indicates the Z-type and E-type geometric isomers of the double bond; R ₀ , , R ₂ , R ₃ , R ₄ and R _{5 are the} same or different and are each independently selected from the group consisting of: hydrogen; a straight or branched saturated or unsaturated hydrocarbon group of C _r C ₆ , which may optionally contain one or more groups selected from halo, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, alkoxy, mercapto and C _r C ₄ acyl substituent chain and containing one or more selected from 0 and ₄ in the alkane group dC S; C _r; C ₃ -C ₇ saturated or unsaturated cycloalkane group; halogen; cyano; nitro; hydroxy; hydroxymethyl C ₄ alkoxy; C _r C ₄ unsaturated alkoxy; carboxy; ester; trifluoromethyl; trifluoromethoxy; sulfonyl; fluorenyl; 3-7 membered heterocyclic; benzyl; Or a 5-7 membered aromatic heterocyclic ring; or any two adjacent groups of R _r R ₅ may be bonded to form a ring, which may be selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, Substituting one or more substituents of trifluoromethyl, trifluoromethoxy, carboxy, C _r C ₄ alkoxy, decyl and dC ₄ acyl and which may comprise one or more atom; The aryl group is a phenyl group, a substituted phenyl group, a naphthyl group or a biphenyl group, wherein the substituent is a linear or branched hydrocarbon group selected from halogen, CC ₆ , a cyano group, a nitro group, an amino group, a hydroxyl group, or a hydroxy group. , trifluoromethyl, trifluoromethoxy, carboxy, C _r C ₄ alkoxy, mercapto, thioalkyl CRDO and ₄ C _r C 1-4 acyl groups; The heterocyclic group is an aromatic or non-aromatic single or fused ring structure and contains 3-20 ring-forming atoms, the ring-forming atom includes 1 to 4 hetero atoms, and the heterocyclic group is selected from the group consisting of Furanyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, a pyridazinyl group, a triazinyl group, a quinolyl group, an isoquinolyl group, a quinoxalinyl group, a benzothiazolyl group, a benzoxazolyl group, a benzothienyl group, and a benzofuranyl group; An alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl group up to 10 carbon atoms  The hetero atom is oxygen, sulfur or nitrogen;  The halogen is fluorine, chlorine, bromine or iodine. The use of the 5-substituted-2,4-thiazolidinedione compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for regulating insulin-like growth factor 1 receptor function, wherein The pharmaceutically acceptable salt is a compound of the formula (1) and is selected from the group consisting of formic acid, acetic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, propionic acid, malonic acid, succinic acid, fumaric acid, maleic acid, a salt formed from an organic acid in lactic acid, malic acid, tartaric acid, and citric acid; sodium, potassium, calcium, aluminum or ammonium formed with an acidic base formed from an acidic amino acid selected from aspartic acid and glutamic acid a salt; an ethylamine salt; an ethanolamine salt; or an ester formed with a basic amino acid selected from the group consisting of lysine, arginine, and ornithine, and then selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, a salt formed from a mineral acid in sulfuric acid, nitric acid and phosphoric acid. The use of the 5-substituted-2,4-thiazolidinedione compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for regulating insulin-like growth factor 1 receptor function, wherein The 5-substituted-2,4-thiazolidinedione compound represented by the formula (I) has a structure represented by the following formula (II):

X is 0 or S; Y is selected from the group consisting of 0, S and Ν; the wavy line indicates the Ζ-type and Ε-type geometric isomers of the double bond; R _{6 is} selected from an aryl group or a 5-7 membered aromatic heterocyclic ring, wherein the 5-7 membered aromatic heterocyclic ring contains 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, optionally selected from halogen One or more of an alkyl group of a halogenated dC ₃ , an alkyl group of CC ₃ , a nitro group, an amino group, a hydroxyl group, a methylol group, a trifluoromethyl group, a trifluoromethoxy group, an alkoxy group, and an aromatic group. Substituted by a group wherein the various groups are as defined in claim 1. The use of the 5-substituted-2,4-thiazolidinedione compound according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for regulating insulin-like growth factor 1 receptor function, wherein The 5-substituted-2-4-thiazolidinedione compound represented by the formula (I) has a structure represented by the following formula (III):

X is selected from 0 and S; the wavy line indicates the Z and E geometric isomers of the double bond; _{R 7, R 8, R 9} , R 1 () and R _u may be the same or different, are each independently hydrogen, C _r C straight or branched chain ₆ saturated or unsaturated hydrocarbon, C ₃ -C ₇ of Saturated or unsaturated cycloalkane, halogen, cyano, nitro, hydroxy, hydroxymethyl, carboxy, ester, trifluoromethyl, trifluoromethoxy, sulfonyl, decyl, dC ₄ alkoxy, dC ₄ unsaturated alkoxy, C _r C ₆ carboxyalkoxy, dC ₆ ester alkoxy, CC ₆ carboxyalkyl, dC ₆ ester alkyl, 3-7 membered cycloalkyl or heterocyclic, benzyl , a benzyloxy group, an aryl group or a 5-7 membered aromatic heterocyclic ring, or any two adjacent groups of R ₇ -R _u may be joined to form a ring which may be substituted and which may comprise one or more Atom; wherein each group is as defined in claim 1. The use of a 5-substituted-2,4-thiazolidinedione compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for regulating insulin-like growth factor 1 receptor function, wherein The 5-substituted-2,4-thiazolidinedione compound represented by the formula (I) has a structure represented by the following formula (IV):

X is selected from 0 and S; the wavy line indicates the Z and E geometric isomers of the double bond; _{R 12, R 13, R 14} , R 15 and R ₁₆ may be the same or different, are each independently hydrogen, C _r C linear or branched, saturated or unsaturated hydrocarbon group _6, C ₃ -C ₇ saturated or Unsaturated cycloalkane, halogen, cyano, nitro, hydroxy, hydroxymethyl, carboxy, ester, trifluoromethyl, trifluoromethoxy, sulfonyl, decyl, dC ₄ alkoxy, dC ₄ defines saturated hydrocarbon group, C _r C ₆ alkoxy, carboxyl, ester group dC ₆ alkoxy, C _r C ₆ carboxyalkyl or dC ₆ alkyl ester group in which the various groups are as in claim 1 . The 5-substituted-2,4-thiazolidinedione compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the preparation of a insulin-like growth factor 1 receptor function-modulating drug Use of the 5-substituted-2,4-thiazolidinedione compound selected from the following compounds 1 to 75:

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C8T00/010ZN3/X3d Z09C90/llOZ OAV Εε

C8T00/010ZN3/X3d Z09C90/llOZ OAV Ιε

C8T00/010ZN3/X3d Z09C90/llOZ OAV

C8T00/010ZN3/X3d Z09C90/llOZ OAV Εε

C8T00/010ZN3/X3d Z09C90/llOZ OAV