CN110833554B - Use of pyrazolopyrimidine derivatives for the treatment of autoimmune thyroid disorders - Google Patents
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Abstract
The invention relates to the technical field of medicines, in particular to application of pyrazolopyrimidine derivative in treating autoimmune thyroid diseases. The pyrazolopyrimidine derivative has a good treatment effect on autoimmune thyroid diseases, can remarkably reduce the levels of thyroid hormones such as T3, T4, FT3 and FT4 in serum, remarkably reduce the levels of antibodies TMAB and TGAb in serum, and effectively improve the lymphocyte infiltration condition in thyroid tissues. The treatment effect of the pyrazolopyrimidine derivative on autoimmune thyroid diseases is equivalent to that of thyroxine or prednisone.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of pyrazolopyrimidine derivative in treating autoimmune thyroid diseases.
Background
Autoimmune thyroid disease (AITD) accounts for 30% of all auto-aggressive diseases, an organ-specific autoimmune disease. Among them, Chronic Lymphocytic Thyroiditis (CLT) and Graves Disease (GD) are the most common. The former is also called Hashimoto Thyroiditis (HT), and is characterized in that high-titer thyroid autoantibodies exist in serum and are accompanied with infiltration of thyroid lymphocytes to gradually destroy glands, and finally clinical hypothyroidism and thyroid tissue fibrosis are caused. At present, the pathogenesis of the human or animal with genetic susceptibility is generally considered to be that under the action of pathogenic factors such as environment, diet and infection, the immune function is disordered due to the defect of immune monitoring and the occurrence of self tolerance, so that the immune response aiming at the thyroid gland is generated, and the destruction of the thyroid gland is caused to cause diseases.
Currently, there is no exact effective treatment for HT. Only when hypothyroidism occurs during Hashimoto's thyroiditis, alternative therapy, i.e., treatment with thyroid hormone supplementation, is used, but this approach does not solve the problem etiologically, and does not have immunomodulatory effects and does not reduce higher levels of thyroid autoantibodies. Recently, even though glucocorticoid is used for immune regulation, such as in the early stage of hashimoto thyroiditis, prednisone tablets can significantly reduce the sTSH level, TGAb and TPOAb titer and can significantly reduce the thyroid volume. However, the application of glucocorticoid has great disadvantages, and studies show that the short-term (6 months) use of glucocorticoid has good effect, but the rebound rate of glucocorticoid is obviously increased after the drug is stopped, and the long-term or large-dose use has large side effect and poor tolerance of patients. Thus, glucocorticoids have also been limited in their clinical use in the treatment of HT. The Experimental Autoimmune Thyroiditis (EAT) model is a major animal model of autoimmune thyroid disease.
The pyrazolopyrimidine derivative (formula I) is a small molecule inhibitor targeted on FLT3 kinase, is a novel compound independently developed by the applicant, and the patent of the compound is granted in China, the United states, Japan and other areas at present.
Only the pyrazolopyrimidine derivative is reported to treat acute myelogenous leukemia and psoriasis at present, and the application of the pyrazolopyrimidine derivative in treating autoimmune thyroid diseases is not seen.
Pyrazolopyrimidine derivative of formula I
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides the application of the pyrazolopyrimidine derivative in treating autoimmune thyroid diseases.
The purpose of the invention can be realized by the following technical scheme:
application of pyrazolopyrimidine derivative shown as formula I or pharmaceutically acceptable salt and hydrate thereof in preparation of medicine for treating autoimmune thyroid diseases
Preferably, the autoimmune thyroid disorder is manifested by elevated serum levels of thyroid hormone.
Preferably, the thyroid hormones include T3, T4, FT3, FT 4.
Preferably, the autoimmune thyroid disorder is manifested by elevated serum levels of thyroid antibodies.
Preferably, the thyroid antibody comprises TGAb, TMAb.
Preferably, the autoimmune thyroid disorder is manifested by lymphocyte infiltration in thyroid tissue.
Preferably, the autoimmune thyroid disease comprises hashimoto's thyroiditis, subacute thyroiditis, indolent thyroiditis, postpartum thyroiditis, chronic lymphocytic thyroiditis, graves' disease.
Preferably, the pharmaceutically acceptable salts include hydrochloride, sulfate, mesylate, phosphate.
The invention also provides application of the pharmaceutical composition in preparing a medicament for treating autoimmune thyroid diseases, which is characterized in that the pharmaceutical composition comprises pyrazolopyrimidine derivative shown as the formula I or pharmaceutically acceptable salt or hydrate thereof as an active ingredient and a pharmaceutically acceptable excipient.
Preferably, the pharmaceutical composition is an injection preparation, an oral preparation, an external preparation, a sustained release preparation, or a controlled release preparation.
Preferably, the oral preparation comprises tablets, granules and capsules.
Preferably, the pharmaceutical composition is a controlled release formulation, a sustained release formulation, an immediate release formulation.
Normal human Thyroglobulin (TG) and Thyroid Microsomes (TM) exist in thyroid gland cells, are not secreted or leaked to blood abundantly, even if a small amount of the normal human thyroglobulin and the thyroid microsomes overflow to peripheral blood circulation, antibodies are not induced to be generated, when chronic inflammation occurs, thyroid gland cells are damaged, TG and TM are released to blood, and an immune system is stimulated to generate corresponding antibodies, and TGAb and TMAb are important bases for clinical diagnosis, treatment and prognosis of HT.
The autoimmune thyroiditis has long course and complicated disease, can be manifested as hyperthyroidism in early stage, and can slowly decline along with the course of disease development, manifested as thyroid hormone secretion disorder, i.e. the thyroid hormones triiodothyronine (T3), total thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4) and the like in serum are obviously increased.
The pyrazolopyrimidine derivative is originally an FLT3 inhibitor, and researches show that the pyrazolopyrimidine derivative has a good treatment effect on autoimmune thyroid diseases, can remarkably reduce the levels of T3, T4, FT3, FT4 and other thyroid hormones in serum, remarkably reduce the levels of antibodies TMAB and TGAb in serum, and effectively improve the lymphocyte infiltration condition in thyroid tissues. The treatment effect of the pyrazolopyrimidine derivative on autoimmune thyroid diseases is equivalent to that of thyroxine or prednisone.
Compared with the prior art, the method has the following advantages:
the pyrazolopyrimidine derivative provided by the invention is a novel drug for treating autoimmune thyroid diseases, not only expands the drug selectivity of the existing drug for treating autoimmune thyroid diseases and provides more drug choices for the effective treatment of the diseases, but also further expands the application range of the pyrazolopyrimidine derivative as an FLT3 inhibitor.
Drawings
FIG. 1 is a graph (100-fold) showing HE staining of thyroid tissue in mice in the blank control group.
FIG. 2 is a graph (100-fold) showing HE staining of thyroid tissue in a mouse in a model group.
FIG. 3 is a graph (100-fold) showing the HE staining of thyroid tissue in thyroxine-containing mice.
FIG. 4 is a graph (100-fold) showing HE staining of thyroid tissue in prednisone mice.
FIG. 5 HE staining pattern (100 fold) of mouse thyroid tissue in high dose group of pyrazolopyrimidine derivatives.
FIG. 6 HE staining pattern (100 fold) of thyroid tissue in dose groups of mice in pyrazolopyrimidine derivatives.
FIG. 7 HE staining pattern (100 fold) of thyroid tissue in low dose groups of mice with pyrazolopyrimidine derivative.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Example 1 Effect on thyroid pathological structures and levels of hormones and antibodies in EAT mice
1. Experimental animals: ICR mice, female, with the body mass of 18-22 g, purchased from Beijing Wintolite laboratory animal technologies, Inc.
2. Experimental materials: pyrazolopyrimidine derivative was synthesized by the inventors. Mixing castor oil with ethanol 1:1, passing through a sterile filter membrane of 0.22 mu m to obtain an ELE solution, weighing a certain mass of pyrazolopyrimidine derivative powder, dissolving the powder by using the ELE solution, adding a certain volume of sterilized water after the powder is completely dissolved, and uniformly mixing for later use. The volume ratio of the ELE solution to the sterile water is 1: 3. porcine thyroglobulin (PTg, sigma). High iodine aqueous solution (0.64g potassium iodide in 1L distilled water). Preparation of complete Freund adjuvant: mixing liquid paraffin and emulsifier lanolin in a ratio of 5:3 to obtain incomplete Freund's adjuvant; adding inactivated BCG vaccine into the prepared incomplete adjuvant to ensure that the inactivated BCG vaccine is completely dispersed to obtain Freund's complete adjuvant; mixing the prepared antigen and adjuvant at a ratio of 1:1, and grinding to obtain emulsion antigen with final concentration of adjuvant-containing antigen 0.25 mg/ml.
3. Animal grouping, modeling and administration: all mice were randomly divided into 7 groups, namely a blank control group, a model group, a thyroxine group (10mg/kg/d), a prednisone group (25. mu.g/kg/d), a pyrazolopyrimidine derivative high dose group (hereinafter referred to as a high dose group, 16mg/kg/d, 1.6mg/mL of liquid medicine), a pyrazolopyrimidine derivative medium dose group (hereinafter referred to as a medium dose group, 8mg/kg/d, 0.8mg/mL of liquid medicine), a pyrazolopyrimidine derivative low dose group (hereinafter referred to as a low dose group, 4mg/kg/d, 0.4mg/mL of liquid medicine), and 15 mice per group. Except for the blank control group, mice in each group were injected subcutaneously at multiple points with PTg (0.25mg/ml) of complete Freund's adjuvant antigen for a total of 0.2ml for 2 consecutive weeks, once a week. Each mouse was injected subcutaneously with PTg (0.25mg/ml) of incomplete Freund's adjuvant antigen 0.2ml starting at week 3 for 3 consecutive weeks, once a week. Each group was given daily high iodine water, except for the blank control group. Meanwhile, each administration group is subjected to intragastric administration according to 10ml/kg body weight, mixed liquor of an ELE solution and distilled water in a volume ratio of 1:3 is subjected to intragastric administration in a blank control group and a model control group, and fasting is performed after the last administration.
4. Detection indexes are as follows: (1) determination of hormone, antibody levels: after the experiment is finished, blood is taken from the orbit of the mouse, the mouse is placed at room temperature for 20min, centrifuged at 2500r/min for 10min, and serum is taken. Serum triiodothyronine (T3), total thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), thyroglobulin antibody (TGAb), thyroid microsomal antibody (TMAb) were measured by radioimmunoassay.
(2) Pathological structure observation: taking thyroid gland tissue, fixing with formalin, taking materials conventionally, dehydrating, embedding paraffin, making into slices of 4 mu m, performing HE staining, reading the slices by a pathology professional under an optical microscope, and observing pathological histological change conditions of the thyroid gland of the mouse.
5. The statistical method comprises the following steps: data were processed using SPSS17.0, the measured data were expressed as mean. + -. standard deviation, comparisons between groups were analyzed using one-way anova, and differences of P <0.05 were statistically significant.
6. Results of the experiment
(1) Histopathological examination results
As shown in figure 1, the blank control group had consistent size and dense arrangement of thyroid acini, with the cavities filled with colloid, and no lymphocyte infiltration in and around the acini.
As shown in FIG. 2, most thyroid glands in the model group exhibited different degrees of acinar dilatation, thin gum in acinar cavities, partial acinar destruction, obvious lymphocyte infiltration in acinar and interstitium, lymphoid follicle formation in severe cases, and more eosinophil infiltration in few cases.
As shown in figure 3, the thyroxine lesions were significantly reduced compared to the model group, most of them were substantially recovered to normal, occasionally infiltrated by interstitial lymphocytes, and a small part of thyroid gland body had thin glia in the gonadal cavity with lymphocyte infiltration.
As shown in fig. 4, the lesions of the prednisone group were significantly reduced compared to the model group, and similar to the thyroxine group, most of them were recovered to normal, with occasional infiltration of interstitial lymphocytes, and a small part of thyroid gland corpus gonad dilated with thin glia in the glandular cavity accompanied with infiltration of lymphocytes.
As shown in FIGS. 5 to 7, the high, medium and low dose groups were reduced compared to the model group, and there were cases where lymphoid follicles were formed in the thyroid gland, and there were cases where the thyroid gland was dilated, and the glandular cavities were thin in collagen, and were destroyed, with much infiltration of lymphocytes. The rest basically returns to normal, and interstitial lymphocyte infiltration is occasionally seen.
(2) Effect on serum thyroid hormone levels in mice
TABLE 1 Effect on serum thyroid hormone levels in mice
P <0.05 compared to control blank; compared with the model group, the Delta P is less than 0.05.
As can be seen from Table 1, the levels of T3 and T4 in the serum of mice can be significantly reduced in the high, medium and low dose groups (P is less than 0.05) compared with the model group; the high and medium dose groups can significantly reduce the levels of FT3 and FT4 in serum (P <0.05), and the low dose group only shows a reduction trend and has no statistical significance. Compared with thyroxine, the pyrazolopyrimidine derivative of the present invention has superior lowering effect on FT3 and T3 than thyroxine. Compared with prednisone, the pyrazolopyrimidine derivative of the present invention has a better lowering effect on T3 than prednisone.
(3) Effect on EAT mouse thyroid antibodies
TABLE 2 Effect on EAT mouse thyroid antibodies
| Group of | TMAb(ng/mL) | TGAb(ng/mL) |
| Blank control group | 15.62±5.6 | 14.75±6.09 |
| Model set | 92.87±17.2* | 95.83±22.3* |
| Thyroxine group | 65.73±15.4△ | 58.62±17.8△ |
| Prednisone group | 64.21±14.3△ | 61.78±16.4△ |
| High dose group | 61.30±12.6△ | 62.95±12.8△ |
| Middle dose group | 70.14±13.8△ | 74.28±10.5△ |
| Low dose group | 82.96±10.6 | 86.91±19.6 |
P <0.05 compared to control blank; compared with the model group, the Delta P is less than 0.05.
As shown in table 2, compared with the model group, the high and medium dose groups both significantly reduced the levels of the antibodies TMAb and TGAb in the serum of the mice (P <0.05), and the low dose group showed only a reduction trend and had no statistical significance. Compared with thyroxine or prednisone, the pyrazolopyrimidine derivative of the invention has the same effect of reducing antibody TMAB, TGAb as thyroxine or prednisone.
Conclusion
The pyrazolopyrimidine derivative has a good treatment effect on autoimmune thyroid diseases, can remarkably reduce the levels of thyroxine hormones such as T3, T4, FT3, FT4 and the like in serum, remarkably reduce the levels of antibodies TMAB and TGAb in the serum, and effectively improve the lymphocyte infiltration condition in thyroid tissues. The treatment effect of the pyrazolopyrimidine derivative on autoimmune thyroid diseases is equivalent to that of thyroxine or prednisone.
Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that many modifications and improvements can be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (12)
1. Application of pyrazolopyrimidine derivative shown as formula I or pharmaceutically acceptable salt thereof in preparation of medicines for treating autoimmune thyroid diseases
2. Use according to claim 1, wherein the autoimmune thyroid disease is manifested as an increase in serum thyroid hormone levels.
3. Use according to claim 2, wherein the thyroid hormones comprise T3, T4, FT3, FT 4.
4. Use according to claim 1, wherein the autoimmune thyroid disease is manifested as elevated serum levels of thyroid antibodies.
5. The use of claim 4, wherein the thyroid antibody comprises TGAb, TMAb.
6. Use according to claim 1, characterized in that the autoimmune thyroid disease is manifested by an infiltration of lymphocytes in the thyroid tissue.
7. The use according to claim 1, wherein the autoimmune thyroid disorder comprises subacute thyroiditis, indolent thyroiditis, postpartum thyroiditis, chronic lymphocytic thyroiditis, Graves' disease.
8. Use according to claim 1, wherein the pharmaceutically acceptable salts comprise hydrochloride, sulfate, mesylate, phosphate.
9. Use of a pharmaceutical composition for the preparation of a medicament for the treatment of autoimmune thyroid disorders, wherein the pharmaceutical composition comprises a pyrazolopyrimidine derivative of formula i or a pharmaceutically acceptable salt thereof as claimed in claim 1 as an active ingredient, and a pharmaceutically acceptable excipient.
10. The use according to claim 9, wherein the pharmaceutical composition is an injection preparation, an oral preparation or an external preparation.
11. The use according to claim 10, wherein the oral formulation comprises tablets, granules, capsules.
12. The use according to claim 9, wherein the pharmaceutical composition is an immediate release formulation, a sustained release formulation, a controlled release formulation.
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| CN103930425B (en) * | 2012-05-14 | 2016-04-27 | 华东理工大学 | Pteridinone derivative and the application as EGFR, BLK, FLT3 inhibitor thereof |
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