CN110833547A - Use of pyrazolopyrimidine derivatives for the treatment of rheumatoid arthritis - Google Patents
Use of pyrazolopyrimidine derivatives for the treatment of rheumatoid arthritis Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The pyrazolopyrimidine derivative has a good treatment effect on rheumatoid arthritis, can remarkably reduce the levels of proinflammatory factors such as TNF- α, IL-1 β, IL-6, IL-17 and the like in serum, improves the content level of the anti-inflammatory factor IL-10 in serum, inhibits infiltration and erosion of inflammatory cells on bone and joints, and has a good protection effect on bone joints.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of pyrazolopyrimidine derivative in treating rheumatoid arthritis.
Background
Rheumatoid Arthritis (RA) is a chronic autoimmune disease that increases the risk of joint deformity and disability, and is characterized by joint bone destruction or bone erosion in the early stages of the disease. A number of basic studies have demonstrated that the local, persistent inflammatory process of joints, including synovitis, is one of the major causes of bone destruction in RA patients.
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 pyrazolopyrimidine derivative has no application in treating rheumatoid arthritis.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides the application of the pyrazolopyrimidine derivative in treating rheumatoid arthritis.
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 drugs for treating rheumatoid arthritis
Preferably, the rheumatoid arthritis is manifested by an increase in the level of proinflammatory cytokines in the serum.
Preferably, the proinflammatory cytokines include TNF- α, IL-1 β, IL-6, IL-17.
Preferably, the rheumatoid arthritis is manifested by a decrease in the level of anti-inflammatory cytokines in the serum.
Preferably, the anti-inflammatory cytokines include IL-4, IL-10.
Preferably, the rheumatoid arthritis is manifested by infiltration of inflammatory cells in the joint tissue.
Preferably, the rheumatoid arthritis is manifested by lymphocyte infiltration in joint tissues.
Preferably, the rheumatoid arthritis manifests itself as a synovitis lesion.
Preferably, the rheumatoid arthritis manifests itself as bone resorption, dissolution, destruction.
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 rheumatoid arthritis, 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.
TNF- α was present in relatively high amounts in both inflammatory tissue and synovial fluid in RA patients, as demonstrated in other previous studies
TNF- α can promote the production of cytokines including IL-1, IL-6, IL-8, etc., promote the release of chemokines such as MCP-1, etc., and promote other types of inflammatory diseasesTNF- α can up-regulate synuclein and adhesion molecules, promote activation of endothelial cells, induce angiogenesis formation, and TNF- α can also activate osteoclasts, resulting in destruction of bone mass at inflammatory joint sites of RA patients.
IL-6 has multiple roles in inflammation, and can promote migration of neutrophils to an inflammation site through autocrine action, induce the neutrophils to release hydrolase and other active mediators, and cause damage to RA tissues and joints. IL-6 can promote the expression of VEGF, induce the formation of pannus and promote angiogenesis. IL-6 can also promote the proliferation of synovial cells by increasing expression of RANKL, and promote secretion of MMPs by synovial cells, leading to destruction of articular cartilage. IL-6 is closely related to the systemic inflammatory response. Systemic symptoms associated with RA, such as fever, fatigue, anemia, are all associated with IL-6.
RA bone destruction is closely related to osteoclast hyperactivity caused by synovitis, and in this inflammatory process, the action of IL-17 can be said to be central. Broadly speaking, IL-17 is produced by activated CD4+ and CD8+ lymphocytes, natural killer T cells and the like, and can induce the expression of various chemokines, proinflammatory factors and matrix metalloproteinases, thereby stimulating the generation and development of inflammation. IL-17 was therefore evaluated as a potent cytokine that promotes synovitis. In particular to the effect on osteoclasts, IL-17 can promote osteoclast formation and osteoclast differentiation, wherein IL-17 acts on supporting cells of osteoclast differentiation, such as synovial fibroblasts and osteoblasts, so that the cells express RANKL and further promote osteoclast differentiation; induction of osteoclast hyperfunction: IL-17 can also trigger osteoclast hyperfunction through a wide range of proinflammatory and other cytokine pathways.
The pyrazolopyrimidine derivative is originally an FLT3 inhibitor, and researches show that the pyrazolopyrimidine derivative has a good treatment effect on rheumatoid arthritis, can remarkably reduce the levels of proinflammatory factors such as TNF- α, IL-1 β, IL-6, IL-17 and the like in serum, improves the content level of the anti-inflammatory factor IL-10 in the serum, inhibits infiltration and erosion of inflammatory cells on bone and joints, and has a good protection effect on bone joints.
Compared with the prior art, the method has the following advantages:
the pyrazolopyrimidine derivative provided by the invention is a novel medicament for treating rheumatoid arthritis, not only expands the selectivity of the existing medicament for treating rheumatoid arthritis and provides more medicament choices for the effective treatment of the rheumatoid arthritis, but also further expands the application range of the pyrazolopyrimidine derivative as an FLT3 inhibitor.
Drawings
FIG. 1 is a photograph of the hind ankle joint of a rat in a blank control group.
FIG. 2 is a model group rat hind ankle joint X-ray film.
FIG. 3 shows a X-ray photograph of the hind ankle joint of rats in the methotrexate group.
FIG. 4 is a X-ray photograph of the hind ankle joint of a rat in a high dose group of pyrazolopyrimidine derivative.
FIG. 5 is a X-ray photograph of the hind ankle joint of a rat in a low dose group of pyrazolopyrimidine derivative.
Fig. 6 is a photograph of the hind ankle joint tempo of rats in the blank control group.
FIG. 7 is a photograph showing the ankle joint beats of the hind paw of the rat in the model group.
Fig. 8 is a photograph of the hind ankle joint beats of rats in the methotrexate group.
Figure 9 is a photograph of the hind ankle joint beats of the pyrazolopyrimidine derivative high dose group rats.
FIG. 10 is a photograph of the ankle joint rhythm of the hind paw of a low dose group of pyrazolopyrimidine derivative.
FIG. 11 shows the HE staining results (100-fold) of the hindfoot ankle tissue of rats in the blank control group.
FIG. 12 shows the HE staining results (100-fold) of the hind ankle tissue of model rats.
FIG. 13 shows HE staining results (100-fold) of tissues of hind ankle of rats in the methotrexate group.
FIG. 14 shows HE staining results (100-fold) of rat hind ankle tissue in high dose groups of pyrazolopyrimidine derivative.
FIG. 15 shows HE staining results (100-fold) of rat hind ankle tissues in a low dose group of pyrazolopyrimidine derivatives.
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 study on rheumatoid arthritis model rats
1. Experimental animals: clean SD rats, female, with a body mass of 180-220 g, purchased from Beijing Wintolite laboratory animal technologies, Inc.
2. Experimental materials: pyrazolopyrimidine derivative was synthesized by the inventors. 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. immunogenic bovine type ii collagen (Chondrex, inc).
3. Animal grouping, modeling and administration: all animals were randomized into the following groups: blank control group, model group, methotrexate group (5mg/kg/week), pyrazolopyrimidine derivative high dose group (hereinafter referred to as high dose group, 12mg/kg/d, 1.2mg/mL drug solution), pyrazolopyrimidine derivative low dose group (hereinafter referred to as low dose group, 6mg/kg/d, 0.6mg/mL drug solution), and 15 individuals per group. Except for the blank control group, rats of each group were immunized 1 st time and injected intradermally with 0.2ml of prepared collagen emulsion containing 200. mu.g of bovine type II collagen on the left side of the tail root. The immunization was performed 1 time on day 7 after the initial immunization, and the injection site was in the right flank of the tail root, and the injection dose was 0.2ml of collagen emulsion containing 200. mu.g of bovine type II collagen. The administration by gavage is started on the 14 th day after the primary immunization, the administration is continued for 6 weeks, and 10mL/kg of mixed solution of the ELE solution and distilled water in the volume ratio of 1:3 is administered by gavage in the blank control group and the model control group.
4. The detection indexes comprise (1) the measurement of the level of inflammatory factors, wherein the groups are fasted after the last 1 times of gastric lavage, blood is taken on the 2 nd day, the groups are killed after blood is taken by adopting a femoral artery bloodletting method, the blood is kept stand for 2h, the blood is centrifuged at 3000r/min for 10min, and supernatant is taken, and the contents of TNF- α, IL-1 β, IL-6, IL-10 and IL-17 in serum are measured by adopting an ELISA method.
(2) And (3) examination of a hindfoot ankle joint X-ray film: each group of rats is sacrificed to take materials, the lower section and the foot of the integral tibia of each group of rats are taken out by an operation method, skin and superficial muscles are carefully stripped, each sample is labeled in time, a hind ankle joint is taken immediately to shoot an X-side slice, and the swelling degree of the hind foot soft tissue, the clear degree of the joint clearance, the integrity of the joint and the damage condition of the joint bone of the rat are observed.
(3) The hind feet and ankle joints of the rats with rheumatoid arthritis are generally observed: the skin color, skin temperature, skin infection condition, hind foot movement and ankle joint swelling condition of each group of rats are continuously observed.
(4) And (4) performing conventional HE staining and observing the pathological tissue morphology.
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) Effect on serum levels of inflammatory factors
TABLE 1 Effect on serum levels of inflammatory factors
| Group of | TNF-α(pg/mL) | IL-1β(pg/mL) | IL-6(pg/mL) | IL-10(pg/mL) | IL-17(pg/mL) |
| Blank control group | 26.38±5.75 | 21.86±6.48 | 42.60±10.26 | 1325.7±102.3 | 110.86±10.13 |
| Model set | 215.72±35.42* | 65.23±15.92* | 175.41±25.36* | 418.2±132.6* | 165.84±20.41* |
| Methotrexate group | 126.81±21.60△ | 46.18±5.28△ | 126.75±18.16△ | 688.5±86.4△ | 136.45±15.18△ |
| High dose group | 78.40±15.35△ | 25.92±8.73△ | 84.72±15.82△ | 1126.4±125.8△ | 124.71±16.37△ |
| Low dose group | 135.78±26.72△ | 39.77±9.45△ | 148.29±20.14 | 629.3±110.5△ | 148.30±12.62 |
P <0.05 compared to the blank control group and △ P <0.05 compared to the model group.
As shown in Table 1, compared with the model group, the high-dose group and the low-dose group can both significantly reduce the levels of TNF- α and IL-1 β in the serum of rats (P <0.05), and simultaneously can both significantly increase the level of IL-10 in the serum of rats (P < 0.05). The high-dose group can significantly reduce the levels of IL-6 and IL-17 in the serum of rats (P <0.05), and the low-dose group only shows a reduction trend and has no statistical significance.
(2) Examination result of hindfoot ankle joint X-ray film
As shown in FIG. 1, the blank control group showed normal results, no swelling of soft tissues, clear joint spaces, intact joints and no destruction of bone.
As shown in figure 2, the model group has severe soft tissue swelling and bone absorption and dissolution phenomena, joint structures of tibia, talus and calcaneus are seriously damaged, and joints are basically damaged.
As shown in fig. 3 and 5, the methotrexate group and the low dose group showed joint structural destruction, osteolysis and soft tissue swelling, but at a reduced level compared to the model group.
As shown in fig. 4, the high dose group significantly retained and protected the joint structure from erosion, without the appearance of significant soft tissue swelling.
(3) General observation results of hind paw and ankle joint of rat
As shown in fig. 6, the rats in the blank control group all appeared normal.
As shown in FIG. 7, the rats in the model group generally had high skin temperature of hind feet, red skin, obvious swelling of soft tissues, rigid joints, no load bearing, and erythema and ulcer on a few feet.
As shown in fig. 8 and 10, the methotrexate group and the low dose group were improved overall, but high hind foot skin temperature, redness of the skin, and swelling of the joints were still observed.
As shown in FIG. 9, the skin of the rats in the high dose group was significantly reduced, the redness and swelling of the joints disappeared, the swelling was not significant, and the movement was smooth as compared with the other groups.
(4) HE staining results
As shown in fig. 11, the blank control group stained normally, cartilage was pink-stained, bone color was darker, joint space was smooth and clear, and no inflammatory cells were present in the joint space.
As shown in fig. 12, a large number of inflammatory cells appeared in the model group, the inflammatory cells were flaky and deeply blue, the original joint relationship was not clearly resolved, the inflammatory cells severely eroded the bone, the joint space disappeared and was completely infiltrated and filled by the inflammatory cells.
As shown in fig. 13 and 15, the methotrexate group and the low dose group both exhibited a large number of inflammatory cells distributed in the joint space and in cartilage and bone, the joint space was indistinguishable, the inflammatory cells also severely eroded bone, the cartilaginous bone was almost visible, but had been destroyed and almost disappeared, and the joint space was filled with a large number of inflammatory cells.
As shown in figure 14, a small amount of inflammatory cells appeared and distributed sporadically in the joint space, the joint space was normal and clear, the inflammatory cells did not attack the bone severely, and the pink cartilage and the deep red bone were both clear and visible and rarely damaged.
Conclusion
The pyrazolopyrimidine derivative has a good treatment effect on rheumatoid arthritis, can remarkably reduce the levels of proinflammatory factors such as TNF- α, IL-1 β, IL-6 and IL-17 in serum, improves the content level of an anti-inflammatory factor IL-10 in serum, inhibits infiltration and erosion of inflammatory cells to bone and joints, and has a good protection effect on bone joints.
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 (13)
1. Application of pyrazolopyrimidine derivative shown as formula I or pharmaceutically acceptable salt and hydrate thereof in preparation of drugs for treating rheumatoid arthritis
2. The use according to claim 1, wherein the rheumatoid arthritis is manifested by elevated serum proinflammatory cytokine levels.
3. The use according to claim 2, wherein the pro-inflammatory cytokines comprise TNF- α, IL-1 β, IL-6, IL-17.
4. The use according to claim 1, wherein the rheumatoid arthritis is manifested by a decrease in the level of anti-inflammatory cytokines in the serum.
5. The use according to claim 4, wherein said anti-inflammatory cytokines comprise IL-4, IL-10.
6. Use according to claim 1, characterized in that the rheumatoid arthritis is manifested by an infiltration of inflammatory cells or lymphocytes in the joint tissue.
7. Use according to claim 1, characterized in that the rheumatoid arthritis manifests itself as synovitis lesions.
8. Use according to claim 1, characterized in that the rheumatoid arthritis manifests itself in bone resorption, dissolution, destruction.
9. Use according to claim 1, wherein the pharmaceutically acceptable salts comprise hydrochloride, sulfate, mesylate, phosphate.
10. Use of a pharmaceutical composition for preparing a medicament for treating rheumatoid arthritis, wherein the pharmaceutical composition comprises the pyrazolopyrimidine derivative represented by formula i in claim 1, or a pharmaceutically acceptable salt or hydrate thereof, as an active ingredient, and a pharmaceutically acceptable excipient.
11. The use according to claim 10, wherein the pharmaceutical composition is an injection preparation, an oral preparation, an external preparation, a sustained-release preparation, or a controlled-release preparation.
12. The use according to claim 11, wherein the oral formulation comprises tablets, granules, capsules.
13. The use according to claim 10, wherein the pharmaceutical composition is a controlled release formulation, a sustained release formulation, an immediate release formulation.
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| CN101759683A (en) * | 2008-12-25 | 2010-06-30 | 北京美迪赛医药技术有限公司 | Preparation method of hydrindene amide compound, medical composition comprising hydrindene amide compound and application thereof as protein kinase inhibitor |
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| CN101759683A (en) * | 2008-12-25 | 2010-06-30 | 北京美迪赛医药技术有限公司 | Preparation method of hydrindene amide compound, medical composition comprising hydrindene amide compound and application thereof as protein kinase inhibitor |
| CN103446577A (en) * | 2013-09-03 | 2013-12-18 | 庞会心 | Medicine composition for preventing and treating arthritis and application thereof |
| CN107245073A (en) * | 2017-07-11 | 2017-10-13 | 中国药科大学 | 4-（Heteroaromatic replaces）Amino -1H-3- pyrazole carboxamides FLT3 inhibitor and application thereof |
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