CN111991398A - Application of benzopyrazines compound in preparation of SOST protein inhibitor - Google Patents
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
The invention belongs toThe field of medicine, in particular to application of a benzopyrazines compound in preparing an SOST protein inhibitor. The application of the benzo pyridazine compound in preparing the SOST protein inhibitor is characterized in that the benzo pyridazine compound has the following structure shown in the general formula I:
. In the general formula I, Q1And Q2Each independently selected from hydrogen, halogen, straight or branched chain alkyl, cycloalkyl, trihaloalkyl, alkoxy, - (CO) R1and-S (O)2)R2Any one of (a); wherein R is1And R2Each independently selected from C1‑C2A linear alkyl or amino group; q3Selected from any one of hydrogen, halogen, cycloalkyl, trihaloalkyl and alkoxy. The invention provides the application of the benzopyrazines compound in the preparation of the SOST protein inhibitor for the first time, and in-vitro animal experiments in the embodiment of the invention prove that the compound can effectively reverse the diseases mediated by SOST protein abnormality. Provides an effective treatment method and a novel therapeutic drug for clinically treating the diseases mediated by the SOST protein abnormality.
Description
Technical Field
The invention belongs to the field of medicines, relates to a new medical application of a benzo-pyridazine compound, and particularly relates to an application of the benzo-pyridazine compound in preparation of an SOST protein inhibitor.
Background
Sclerostin (SOST, Sclerostin) is a negative regulator of bone formation and is specifically expressed mainly by osteoblasts. Mutations or aberrant expression of SOST are associated with a range of bone diseases. Loss-of-function mutations such as SOST can lead to severe sclerosteosis. While SOST protein is obviously up-regulated in bone tissues of patients with osteoarthritis and osteoporosis. Therefore, small molecule drugs or antibodies to SOST protein can increase bone mass by antagonizing SOST function, and thus can be used for the treatment of osteoporosis, osteoarthritis, or diabetic bone disease.
In addition, bone tissue is one of the common metastatic sites of malignant tumor, and no effective treatment means for the bone metastasis of malignant tumor exists at present. Recently, it has been discovered that SOST proteins play a key role in the bone tissue microenvironment for the interaction process between tumor cells and bone cells, and thus modulation of SOST proteins could potentially reverse tumor bone metastasis.
The inventor recently finds that a class of benzopyrazines compounds are small molecule inhibitors of SOST protein and can antagonize the function of the SOST protein, and no related report that the class of benzopyrazines compounds are used as SOST protein inhibitors exists in the prior art.
Disclosure of Invention
The invention aims to provide application of a benzopyrazines compound in preparing SOST protein inhibitors.
In order to achieve the purpose, the invention adopts the following technical scheme.
The application of the benzo pyridazine compound in preparing the SOST protein inhibitor has the following chemical structure general formula I:
wherein Q is1And Q2Each independently selected from hydrogen, halogen, straight or branched chain alkyl, cycloalkyl, trihaloalkyl, alkoxy, - (CO) R1and-S (O)2)R2Any one of the above; r1And R2Each independently selected from C1-C2A linear alkyl or amino group; q3Selected from any one of hydrogen, halogen, cycloalkyl, trihaloalkyl and alkoxy.
A pharmaceutical composition having SOST protein inhibitory activity, comprising the above-mentioned benzopyrazines and derivatives thereof, pharmaceutically acceptable salts, hydrates or solvates thereof and a pharmaceutically acceptable carrier.
The benzopyrazines compound and the derivative thereof, the pharmaceutically acceptable salt, the hydrate, the solvate, the pharmaceutically acceptable carrier or the pharmaceutical composition are applied to the preparation of the drugs for treating the diseases mediated by the SOST protein abnormality.
Further, the diseases include osteoporosis, osteoarthritis, diabetic bone disease, and bone metastasis of malignant tumor.
Furthermore, the malignant tumor mainly comprises breast cancer, lung cancer, ovarian cancer, colon cancer, pancreatic cancer, esophageal cancer, osteosarcoma, renal cancer, cervical cancer, bladder cancer, head and neck cancer, multiple myeloma, brain tumor, prostate cancer, melanoma, gastric cancer, liver cancer, glioma, oral cancer, soft tissue sarcoma, leukemia and lymph cancer.
Further, the medicament is in any pharmaceutically and therapeutically acceptable dosage form.
Further, the drug is in any pharmaceutically therapeutically acceptable dose.
A method of treating a disease mediated by abnormal SOST protein, including osteoporosis, osteoarthritis, diabetic bone disease, and bone metastases from malignant tumors; the method comprises administering a therapeutically effective amount of a compound of formula I, or a salt or other form of a pharmaceutically acceptable derivative thereof.
The SOST protein-mediated diseases refer to related diseases caused by significant dysregulation of SOST expression level, and more specifically, diseases such as osteoporosis, osteoarthritis, diabetic bone disease, and malignant tumor bone metastasis.
The preparation of the SOST protein inhibitor comprises the step of combining the compound of the formula I, or the pharmaceutically acceptable salt and the solvate thereof with pharmaceutically common auxiliary materials or carriers to prepare the pharmaceutical composition with the SOST protein inhibitory activity. The pharmaceutical composition can be prepared into tablets, granules, capsules, oral liquid, injection, aerosol and other pharmaceutical preparations; controlled or sustained release dosage forms or nano-formulations known in the modern pharmaceutical industry may also be employed. These choices regarding formulation means and methods are believed to be well within the skill of the art and will not be repeated here.
The terms used in the present invention shall have the following general meanings.
The term "halogen" denotes a halogen substituent, and refers to fluoro (-F), chloro (-Cl), bromo (-Br), or iodo (-I).
The term "straight or branched alkyl" refers to straight or branched alkyl.
Accordingly, the term "C1-C2The straight-chain or branched alkyl group' refers to a straight-chain or branched alkyl group, the number of carbon atoms in the substituent group is 1-2, and the substituent group comprises a methyl group and an ethyl group.
The term "trihaloalkyl" refers to a straight or branched alkyl group substituted with 3 halogen substituents.
The term "cycloalkyl" refers to non-aromatic cycloalkanes, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
The term "alkoxy" refers to a chemical group wherein an alkyl group is attached to an oxygen atom, and typically includes, but is not limited to, methoxy (-OCH)3) Ethoxy (-OC)2H5)。
The term "amino" refers to the group-NH2A group.
Compared with the prior art, the invention has the following beneficial effects.
The invention provides the application of the benzopyrazines compound in the preparation of the SOST protein inhibitor for the first time, and in-vitro animal experiments in the embodiment of the invention prove that the compound can effectively reverse the diseases mediated by SOST protein abnormality. Provides an effective treatment method and a novel therapeutic drug for clinically treating the diseases mediated by the SOST protein abnormality.
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FIG. 1 shows the detection of binding of a representative compound S6 to SOST protein using SPR technique (surface plasmon resonance technique), in which the horizontal axis represents the time of change (S) and the vertical axis represents the intensity of the surface plasmon resonance signal.
FIG. 2 is an in vivo animal experiment of Compound S6 for reversing bone metastasis of breast cancer, wherein the left and right of the first row are a staining pattern of lung tissue of a control group animal and a staining pattern of lung tissue of a compound S6 administration group animal, respectively; the left and right of the second row of the graph are the bone tissue staining graph of the control group animal and the bone tissue staining graph of the compound S6 administration group animal, respectively.
Detailed Description
The present invention will be described more fully hereinafter with reference to the following non-limiting examples, which are provided to illustrate and not to limit the present invention, but to which modifications according to the spirit of the invention may be made, which are within the scope of the appended claims. Terms described herein, such as osteoporosis, osteoarthritis, malignant tumor bone metastasis, and the like, are all scientific terms commonly used in the scientific arts and are not intended to limit the scope of the invention in any way.
The compound represented by the benzopyrazines provided by the invention is S6, and the chemical structural formula is as follows:
example 1 binding of compound S6 to SOST protein was detected using SPR technique.
SPR (surface Plasmon resonance), a surface Plasmon resonance technique, is a common technique for detecting the binding strength of small molecule compounds and target proteins. The experiment was performed on a Biacore T200(GE Healthcare) instrument with His-tagged SOST proteins immobilized on NTA chips. The compound S6 was dissolved in an immobilization buffer containing 5% -DMSO and tested at a flow rate of 30 μ L/min with a contact time of 60S, a dissociation time of 300S, and a solution calibration curve including 4.5-5.8% (v/v) DMSO solvent. After the experiment was completed, analysis was performed using Biacore evaluation software and binding curves were plotted using GraphPad Prism, as shown in fig. 1, and binding constants were calculated. The dissociation constant K of compound S6 for binding to SOST protein was calculateddAt 1.52mM, compound S6 demonstrated better binding to SOST protein, and thus antagonized SOST protein function.
Example 2 in vivo animal experiments with compound S6 to reverse breast cancer bone metastasis.
The effect of compound S6 on reversing bone metastasis of breast cancer is verified by using an in vivo animal model. Firstly, BALB/C nude mice (4-6 weeks old) are planted with SCP2 tumor cells (2X 10)6Breast cancer metastatic cell line). The control group was gavaged with DMSO solution, and the administration group was gavaged with DMSO solution of Compound S6 at a dose of 50 mg/kg. After 3 weeks of administration, the control group and the administration group were subjected to bone tissue H&And E, dyeing treatment. The results showed that the bone tissue of the control animals showed significant Osteoporosis (osteoporotis) after the bone metastasis of breast cancer, while the bone tissue of the animals administered with the S6 compound showed OsteoporosisSignificant inhibition was obtained as shown in figure 2. In addition, the results show that the control group animals also showed significant pulmonary metastasis, while the S6 compound-administered group showed significant inhibition of pulmonary metastasis as shown in fig. 2. The results prove that the compound S6 can potentially reverse bone metastasis of malignant tumors by antagonizing SOST protein function, and has potential therapeutic effect on osteoporosis.
Claims (10)
1. The application of the benzo pyridazine compound in preparing the SOST protein inhibitor is characterized in that the chemical structure formula I of the benzo pyridazine compound is as follows:
2. the use according to claim 1, wherein the chemical structure of the benzopyrazines is represented by formula I, wherein Q is3Selected from any one of hydrogen, halogen, cycloalkyl, trihaloalkyl and alkoxy.
3. The use according to claim 1, wherein the chemical structure of the benzopyrazines is represented by formula I, wherein Q is1And Q2Each independently selected from halogen, alkoxy, straight or branched chain alkyl, trihaloalkyl, - (CO) R1and-S (O)2)R2Any one of the above.
4. The use according to claim 1, wherein the chemical structure of the benzopyrazines is as shown in formula I, wherein R is1And R2Each independently selected from C1-C2Linear alkyl or amino.
5. A pharmaceutical composition having an SOST protein inhibitory activity, comprising the benzopyrazines and derivatives thereof, pharmaceutically acceptable salts, hydrates or solvates thereof as claimed in claim 1, and a pharmaceutically acceptable carrier.
6. The use according to claim 1, wherein the use of the benzopyrazines and derivatives thereof, pharmaceutically acceptable salts, hydrates, solvates, pharmaceutically acceptable carriers thereof or the pharmaceutical composition according to claim 5 for the preparation of a medicament for the treatment of diseases mediated by SOST protein abnormalities.
7. The use of claim 6, wherein the disease is selected from the group consisting of osteoporosis, osteoarthritis, diabetic bone disease, and bone metastases from malignant tumors.
8. The use of claim 7, wherein said malignant tumor is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, colon cancer, pancreatic cancer, esophageal cancer, osteosarcoma, renal cancer, cervical cancer, bladder cancer, head and neck cancer, multiple myeloma, brain tumor, prostate cancer, melanoma, gastric cancer, liver cancer, glioma, oral cancer, soft tissue sarcoma, leukemia, and lymphoma.
9. The use of claim 6, wherein the medicament is in any pharmaceutically and therapeutically acceptable dosage form.
10. The use of claim 6, wherein the medicament is in any pharmacotherapeutically acceptable dose.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101379056A (en) * | 2006-01-31 | 2009-03-04 | 捷瑞尼股份公司 | Compounds for the inhibition of integrins and use thereof |
| KR20180032707A (en) * | 2016-09-22 | 2018-04-02 | 경북대학교 산학협력단 | Pharmaceutical composition for prevention or treatment of inflammatory diseases containing integrin inhibitor as an active ingredient |
| CA2984073A1 (en) * | 2017-10-27 | 2019-04-27 | Nuchem Therapeutics Inc. | Inhibitors of polynucleotide repeat-associated rna foci and uses thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101379056A (en) * | 2006-01-31 | 2009-03-04 | 捷瑞尼股份公司 | Compounds for the inhibition of integrins and use thereof |
| KR20180032707A (en) * | 2016-09-22 | 2018-04-02 | 경북대학교 산학협력단 | Pharmaceutical composition for prevention or treatment of inflammatory diseases containing integrin inhibitor as an active ingredient |
| CA2984073A1 (en) * | 2017-10-27 | 2019-04-27 | Nuchem Therapeutics Inc. | Inhibitors of polynucleotide repeat-associated rna foci and uses thereof |
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