CN110833553A - Use of pyrazolopyrimidine derivatives for the treatment of Arthus response - Google Patents
Use of pyrazolopyrimidine derivatives for the treatment of Arthus response Download PDFInfo
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- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical class C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 title claims abstract description 29
- 230000004044 response Effects 0.000 title claims description 8
- 208000000104 Arthus reaction Diseases 0.000 claims abstract description 24
- 206010053614 Type III immune complex mediated reaction Diseases 0.000 claims abstract description 24
- 210000002966 serum Anatomy 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 16
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- 238000002360 preparation method Methods 0.000 claims description 11
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
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- 108090001061 Insulin Proteins 0.000 claims description 2
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- 239000003242 anti bacterial agent Substances 0.000 claims description 2
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- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
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- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 3
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- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
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- 239000004359 castor oil Substances 0.000 description 1
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- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
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- 229940092253 ovalbumin Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
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- 229960005367 tetanus antitoxin Drugs 0.000 description 1
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- 231100000827 tissue damage Toxicity 0.000 description 1
- 208000025883 type III hypersensitivity disease Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 210000000264 venule Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
Abstract
The invention relates to the technical field of medicaments, in particular to application of pyrazolopyrimidine derivative in treatment of Arthus reaction. The Arthus reaction is associated with the binding of antigen and antibody to form an immune complex. The pyrazolopyrimidine derivative can obviously relieve the skin red and swollen symptom, reduce the expression level of immune complexes and IL-2 in serum, and generate a good treatment effect on Arthus reaction.
Description
Technical Field
The invention relates to the technical field of medicaments, in particular to application of pyrazolopyrimidine derivative in treatment of Arthus reaction.
Background
The Arthus reaction was discovered by Arthus in 1903 and is also known as the Arthur reaction. The mechanism of occurrence is: the xenogeneic serum of former several injections stimulates the organism to produce a large amount of antibodies, when injecting the same antigen again, because the antigen constantly is permeated in the blood vessel by subcutaneous, corresponding antibody in the blood flow is outwards dispersed by the vascular wall, and both meet in the vascular wall, form precipitative immune complex, deposit on venule vascular wall basement membrane, lead to necrotizing vasculitis even ulcer. When arthus phenomenon occurs locally, anaphylactic shock can be caused if alloantigens are injected intravenously. It is reported that the injection of penicillin, rabies vaccine, tetanus antitoxin and other drugs can cause Arthus reaction to different degrees, and is one of the clinically common type III hypersensitivity diseases. In addition, Arthus reactions are also frequent in Systemic Lupus Erythematosus (SLE) 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 derivatives are reported for the treatment of acute myeloid leukemia and psoriasis, and the use of the pyrazolopyrimidine derivatives for the treatment of Arthus response is not available.
Pyrazolopyrimidine derivative of formula I
Disclosure of Invention
To overcome the deficiencies of the prior art, the present invention provides the use of pyrazolopyrimidine derivatives in the treatment of Arthus reaction.
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 drug for treating Arthus reaction
Preferably, the Arthus reaction is manifested by an elevated level of immune complexes in serum.
Preferably, the Arthus reaction is manifested by an elevated serum IL-2 level.
Preferably, the Arthus response is caused by lupus erythematosus.
Preferably, the Arthus reaction is associated with the binding of an antigen and an antibody to form an immune complex.
Preferably, the antigens include endogenous antigens and exogenous antigens.
Preferably, the exogenous antigens include: antibiotics, vaccines, insulin.
Preferably, the pharmaceutically acceptable salts include hydrochloride, sulfate, mesylate, phosphate.
The invention also provides application of a pharmaceutical composition in preparing a medicament for treating Arthus reaction, 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 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.
The Arthus reaction is a type III allergy and is mainly characterized in that free antigen is combined with a corresponding antibody to form an Immune Complex (IC), and if the IC cannot be cleared in time, the IC can be deposited locally to cause a series of chain reactions to cause tissue damage. Clinical findings indicate that SLE patients have increased serum IL-2 levels, enhanced Th cell function, reduced Ts cell function, and enhanced B cell function, and maintain the production of large amounts of autoantibodies and immune complexes.
The pyrazolopyrimidine derivative is originally an FLT3 inhibitor, and researches show that the pyrazolopyrimidine derivative can obviously relieve the red and swollen symptoms of skin, reduce the expression level of immune complexes and IL-2 in serum, and has a good treatment effect on Arthus reaction.
Compared with the prior art, the method has the following advantages:
the pyrazolopyrimidine derivative provided by the invention is a novel drug for treating Arthus reaction, not only expands the drug selectivity of the existing Arthus reaction treatment and provides more drug choices for effective treatment of the Arthus reaction, but also further expands the application range of the pyrazolopyrimidine derivative as an FLT3 inhibitor.
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 Arthus response in rats
1. Experimental animals: SD rats, clean grade, sex and sex, body mass (200 + -20) g, purchased from Beijing Huafukang Biotech GmbH.
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.
3. establishing a model: according to Xutaiyun, published in 2002 as pharmacological experimental methodology, each rat is injected intramuscularly 0.5mL each week for 6 times, the former 3 times are ovalbumin-complete Freund's adjuvant, and the latter 3 times are ovalbumin-incomplete Freund's adjuvant.
4. Animal grouping and administration: on the last to the day of allergy, 70 SD rats were divided into 14 groups of 14 groups, each group consisting of a model group, a pyrazolopyrimidine derivative high dose group (hereinafter referred to as a high dose group), a pyrazolopyrimidine derivative medium dose group (hereinafter referred to as a medium dose group), a pyrazolopyrimidine derivative low dose group (hereinafter referred to as a low dose group), and a positive drug group, according to the physical mass. 10mL/kg of mixed solution of an ELE solution and distilled water in a volume ratio of 1:3 is administered to a model group by intragastric administration, 12mg/kg/d (1.2mg/mL of liquid medicine) of a pyrazolopyrimidine derivative is administered to a high-dose group by intragastric administration, 6mg/kg/d (0.6mg/mL of liquid medicine) of the pyrazolopyrimidine derivative is administered to a medium-dose group by intragastric administration, 3mg/kg/d (0.3mg/mL of liquid medicine) of the pyrazolopyrimidine derivative is administered to a low-dose group by intragastric administration, and 0.005g/kg/d of prednisone is administered to a positive-dose group. The preparation is administered by gavage 1 time daily (10mL/kg), and is administered continuously for 10 days. On day 10, the backs were injected intradermally with 1% ovalbumin, 0.2mL per spot.
5. Detecting the index
(1) The diameter of the local skin redness was observed at each spot 2, 4, 6, 8, 12, 24h after antigen challenge.
(2) After 24h of antigen attack, blood is taken from the eyeballs of the rats in each group, and the content of serum circulating immune complex is determined according to a polyethylene glycol method.
(3) The IL-2 level in the serum of rats was determined by Radioimmunoassay (RIA) according to the procedures described in the IL-2 detection kit.
6. The statistical method comprises the following steps: processing data by SPSS17.0, expressing measurement data by mean + -standard deviation, comparing measurement data among multiple groups by t test, and comparing count data by χ test2And (6) checking. P<A difference of 0.05 is statistically significant.
7. Results of the experiment
(1) Comparison of Back skin redness and swelling diameter at different times
TABLE 1 comparison of Back skin redness and swelling diameter at different times
P <0.05 compared to model group and △ P <0.05 compared to positive group.
As shown in table 1, after 2h antigen challenge, the dorsal skin of each group of rats showed hyperemia and hemorrhage, indicating that a rat Arthus response model had developed. Compared with the model group, the red and swollen diameters of the back skin of the high-dose group and the middle-dose group at the time point within the range of 2-12 h are obviously reduced (P is less than 0.05); the low dose group showed a significant reduction in the diameter of the red skin on the back (P <0.05) at 12h, with only a tendency to decrease at other time points. The above results also show that the degree of reduction of the skin redness diameter on the back of rats by the pyrazolopyrimidine derivative of the invention is positively correlated with the dose.
Compared with the positive medicine group, the time points of the high-dose group have no significant difference (P is more than 0.05) within the range of 2-12 h.
(2) Effect on serum immune complexes and IL-2
TABLE 2 Effect on serum immune complexes and IL-2
P <0.05 compared to model group and △ P <0.05 compared to positive group.
As shown in table 2, the high dose group, the medium dose group and the low dose group all significantly reduced the level of IL-2 in the serum of rats (P <0.05) compared to the model group; the high-dose group and the medium-dose group can obviously reduce the content of immune complexes in serum (P <0.05), and the low-dose group only shows a reduction trend. The results show that the reduction effect of the pyrazolopyrimidine derivative on serum immune complexes and IL-2 is positively correlated with the dosage.
Compared with the positive medicine group, the effects of the high and medium dose groups on the serum immune complex and the IL-2 content have no significant difference (P is more than 0.05).
Conclusion
The pyrazolopyrimidine derivative has a good treatment effect on Arthus reaction, can remarkably relieve the red and swollen symptoms of skin, and reduces the expression levels of immune complexes and IL-2 in serum.
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 and hydrate thereof in preparation of drug for treating Arthus reaction
2. The use according to claim 1, wherein the Arthus reaction is manifested as an elevated level of immune complexes in serum.
3. The use according to claim 1, wherein the Arthus response is manifested by an increase in serum IL-2 levels.
4. The use according to claim 1, wherein the Arthus response is caused by lupus erythematosus.
5. The use according to claim 1, wherein the Arthus reaction is associated with the binding of an antigen and an antibody to form an immune complex.
6. The use of claim 5, wherein the antigens comprise endogenous and exogenous antigens.
7. The use of claim 6, wherein the exogenous antigen comprises: antibiotics, vaccines, insulin.
8. Use according to claim 1, wherein the pharmaceutically acceptable salts comprise hydrochloride, sulfate, mesylate, phosphate.
9. Use of a pharmaceutical composition comprising a pyrazolopyrimidine derivative of formula i, as defined in claim 1, or a pharmaceutically acceptable salt or hydrate thereof, as an active ingredient, and a pharmaceutically acceptable excipient for the preparation of a medicament for the treatment of Arthus reaction.
10. The use according to claim 9, wherein the pharmaceutical composition is an injection preparation, an oral preparation, an external preparation, a sustained-release preparation, or a controlled-release 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 a controlled release formulation, a sustained release formulation, an immediate release formulation.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112843066A (en) * | 2021-02-04 | 2021-05-28 | 广西中恒创新医药研究有限公司 | Composition containing pyrazolopyrimidine derivative with good solubility and use thereof |
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| CN106568938A (en) * | 2016-10-11 | 2017-04-19 | 宁夏医科大学总医院 | Application of DKK1 in serum to diagnosis of systemic lupus erythenlatosus nephritis |
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- 2018-08-15 CN CN201810928269.4A patent/CN110833553A/en active Pending
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| CN102423314A (en) * | 2011-11-26 | 2012-04-25 | 济南环肽医药科技有限公司 | Medicine for treating immunological liver injury or immunological liver fibrosis |
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