CN108191875B - Compound and application thereof in preparation of medicine for treating immune-related diseases - Google Patents
Compound and application thereof in preparation of medicine for treating immune-related diseases Download PDFInfo
- Publication number
- CN108191875B CN108191875B CN201810044047.6A CN201810044047A CN108191875B CN 108191875 B CN108191875 B CN 108191875B CN 201810044047 A CN201810044047 A CN 201810044047A CN 108191875 B CN108191875 B CN 108191875B
- Authority
- CN
- China
- Prior art keywords
- compound
- mice
- pharmaceutically acceptable
- treatment
- nephritis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of biological medicines, and particularly relates to a compound and application thereof in preparation of a medicine for treating immune-related diseases. The invention discloses an application of a small molecular compound and a medicinal salt thereof or a pharmaceutically acceptable salt thereof or a solvate thereof in treating inflammatory related diseases. The small molecule compound and the medicinal salt or the pharmaceutically acceptable salt or the solvate thereof can effectively inhibit the expression of TNF-alpha in immune cells and promote the expression of IL-10, thereby inhibiting the abnormal activation of the immune system of an organism and playing a role in resisting inflammation, so that the small molecule compound and the medicinal salt or the pharmaceutically acceptable salt or the solvate thereof can be used for preparing medicines for treating immune-related diseases such as enteritis, pneumonia, nephritis, gastritis, hepatitis, arthritis, lupus erythematosus, multiple sclerosis, ankylosing spondylitis and the like.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to a compound, a medicinal salt thereof and application thereof in preparation of related diseases for inhibiting abnormal activation of immune cells, in particular to application in preparation of related immune diseases for treating enteritis, pneumonia, nephritis, gastritis, hepatitis, arthritis, lupus erythematosus, multiple sclerosis, ankylosing spondylitis and the like.
Background
The generalized immune-related diseases refer to the unbalanced immune regulation caused by the combined action of various environmental and genetic factors, and are specifically characterized in that a plurality of immune cells are activated to perform the function of immune response. However, when the immune regulation mechanism of the organism is abnormal, immune cells in the organism can be continuously and abnormally activated to secrete a large amount of inflammatory mediators, and finally, inflammatory-related diseases are induced. The inflammatory reaction and pain associated with immune-related diseases seriously affect the quality of life of patients, and part of immune-related diseases are not cured and even become cancerous. The immune related diseases include enteritis, pneumonia, nephritis, gastritis, hepatitis, arthritis, lupus erythematosus, multiple sclerosis, ankylosing spondylitis, etc. In the process of the occurrence of immune-related diseases, a plurality of immune cells are abnormally activated and secrete a large amount of inflammatory factors, such as interleukin 1 beta (IL-1 beta), interleukin 6(IL-6), tumor necrosis factor alpha (TNF-alpha) and the like, wherein the TNF-alpha plays the most obvious role in proinflammatory, can promote tissue damage and further activate macrophages and T helper cells (TH1/TH17) so as to stimulate inflammatory response. In addition, interleukin 10(IL-10) has the effects of inhibiting abnormal activation of macrophages, promoting proliferation of regulatory T cells (Tregs), regulating immune response and inhibiting inflammation. However, the existing therapeutic drugs for immune-related diseases mainly focus on salicylic acid preparations, glucocorticosteroids, immunosuppressants and the like, the therapeutic targets of the drugs are not clear, the side effects are large, and the drugs are easy to relapse after being stopped. Therefore, from the pathogenesis of the diseases, the research on safe and effective medicaments can simultaneously up-regulate the expression of the inflammatory factors, and the inhibition of the expression of the proinflammatory factors is very important for the treatment of immune-related diseases.
The series of compounds related to the application belong to a brand new class of compounds, and the application of the compounds similar to the compounds in the preparation of the compounds for inhibiting immune cell abnormal activation related diseases is not available, in particular the application in the preparation of immune related diseases such as enteritis, pneumonia, nephritis, gastritis, hepatitis, arthritis, lupus erythematosus, multiple sclerosis, ankylosing spondylitis and the like. Therefore, the exploratory discovery of the functions of the related compounds has important application value.
Disclosure of Invention
The problem to be solved by the invention is to find a series of small molecular compounds and medicinal salts thereof which can effectively inhibit the proinflammatory factor TNF-alpha and promote the anti-inflammatory factor IL-10.
The invention relates to a compound with a general formula (1) as follows:
the general formula of the small molecular compound and the pharmaceutically acceptable salt thereof is as follows:
characterized in that the specific substituents of said compounds are as defined in any one of the following items # 1 to # 102:
1#:n＝0；X1＝O；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
2#:n＝1；X1＝O；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
3#:n＝2；X1＝O；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
4#:n＝3；X1＝O；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
5#:n＝4；X1＝O；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
6#:n＝5；X1＝O；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
7#:n＝6；X1＝O；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
8#:n＝0；X1＝N；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
9#:n＝0；X1＝S；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
10#:n＝1；X1＝N；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
11#:n＝1；X1＝S；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
12#:n＝2；X1＝N；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
13#:n＝2；X1＝S；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
14#:n＝3；X1＝N；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
15#:n＝3；X1＝S；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
16#:n＝4；X1＝N；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
17#:n＝4；X1＝S；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
18#:n＝5；X1＝N；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
19#:n＝5；X1＝S；X2＝H；X33＝H；R2＝H；R3＝H；R4＝H；
20#:n＝6；X1＝N；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
21#:n＝6；X1＝S；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
22#:n＝0；X1＝N；X2＝F；X3＝H；R2＝H；R3＝H；R4＝H；
23#:n＝0；X1＝N；X2＝Cl；X3＝H；R2＝H；R3＝H；R4＝H；
24#:n＝0；X1＝N；X2＝Br；X3＝H；R2＝H；R3＝H；R4＝H；
25#:n＝0；X1＝N；X2＝I；X3＝H；R2＝H；R3＝H；R4＝H；
26#:n＝0；X1＝N；X2＝F；X3＝F；R2＝H；R3＝H；R4＝H；
27#:n＝0；X1＝N；X2＝F；X3＝Cl；R2＝H；R3＝H；R4＝H；
28#:n＝0；X1＝N；X2＝F；X3＝Br；R2＝H；R3＝H；R4＝H；
29#:n＝0；X1＝N；X2＝F；X3＝I；R2＝H；R3＝H；R4＝H；
30#:n＝0；X1＝S；X2＝F；X3＝H；R2＝H；R3＝H；R4＝H；
31#:n＝0；X1＝S；X2＝Cl；X3＝H；R2＝H；R3＝H；R4＝H；
32#:n＝0；X1＝S；X2＝Br；X3＝H；R2＝H；R3＝H；R4＝H；
33#:n＝0；X1＝S；X2＝I；X3＝H；R2＝H；R3＝H；R4＝H；
34#:n＝0；X1＝S；X2＝F；X3＝F；R2＝H；R3＝H；R4＝H；
35#:n＝0；X1＝S；X2＝F；X3＝Cl；R2＝H；R3＝H；R4＝H；
36#:n＝0；X1＝S；X2＝F；X3＝Br；R2＝H；R3＝H；R4＝H；
37#:n＝0；X1＝S；X2＝F；X3＝I；R2＝H；R3＝H；R4＝H；
38#:n＝0；X1＝O；X2＝F；X3＝H；R2＝H；R3＝H；R4＝H；
39#:n＝0；X1＝O；X2＝Cl；X3＝H；R2＝H；R3＝H；R4＝H；
40#:n＝0；X1＝O；X2＝Br；X3＝H；R2＝H；R3＝H；R4＝H；
41#:n＝0；X1＝O；X2＝I；X3＝H；R2＝H；R3＝H；R4＝H；
42#:n＝0；X1＝O；X2＝F；X3＝F；R2＝H；R3＝H；R4＝H；
43#:n＝0；X1＝O；X2＝F；X3＝Cl；R2＝H；R3＝H；R4＝H；
44#:n＝0；X1＝O；X2＝F；X3＝Br；R2＝H；R3＝H；R4＝H；
45#:n＝0；X1＝O；X2＝F；X3＝I；R2＝H；R3＝H；R4＝H；
46#:n＝0；X1＝N；X2＝F；X3＝F；R2＝Ph；R3＝H；R4＝H；
47#:n＝0；X1＝O；X2＝F；X3＝F；R2＝Ph；R3＝H；R4＝H；
48#:n＝0；X1＝S；X2＝F；X3＝F；R2＝Ph；R3＝H；R4＝H；
49#:n＝0；X1＝N；X2＝F；X3＝F；R2＝Ph；R3＝Ph；R4＝H；
50#:n＝0；X1＝O；X2＝F；X3＝F；R2＝Ph；R3＝Ph；R4＝H；
51#:n＝0；X1＝S；X2＝F；X3＝F；R2＝Ph；R3＝Ph；R4＝H；
52#:n＝0；X1＝N；X2＝F；X3＝F；R2＝Ph；R3＝Ph；R4＝Ph；
53#:n＝0；X1＝O；X2＝F；X3＝F；R2＝Ph；R3＝Ph；R4＝Ph；
54#:n＝0；X1＝S；X2＝F；X3＝F；R2＝Ph；R3＝Ph；R4＝Ph；
55#:n＝0；X1＝N；X2＝F；X3＝Cl；R2＝Ph；R3＝H；R4＝H；
56#:n＝0；X1＝O；X2＝F；X3＝Br；R2＝Ph；R3＝H；R4＝H；
57#:n＝0；X1＝S；X2＝F；X3＝I；R2＝Ph；R3＝H；R4＝H；
58#:n＝0；X1＝N；X2＝F；X3＝Cl；R2＝Ph；R3＝Ph；R4＝H；
59#:n＝0；X1＝O；X2＝F；X3＝Br；R2＝Ph；R3＝Ph；R4＝H；
60#:n＝0；X1＝S；X2＝F；X3＝I；R2＝Ph；R3＝Ph；R4＝H；
61#:n＝0；X1＝N；X2＝F；X3＝Cl；R2＝Ph；R3＝Ph；R4＝Ph；
62#:n＝0；X1＝O；X2＝F；X3＝Br；R2＝Ph；R3＝Ph；R4＝Ph；
63#:n＝0；X1＝S；X2＝F；X3＝I；R2＝Ph；R3＝Ph；R4＝Ph；
64#:n＝0；X1＝N；X2＝F；X3＝F；R2＝H；R3＝Ph；R4＝H；
65#:n＝0；X1＝O；X2＝F；X3＝F；R2＝H；R3＝Ph；R4＝H；
66#:n＝0；X1＝S；X2＝F；X3＝F；R2＝H；R3＝Ph；R4＝H；
67#:n＝0；X1＝N；X2＝Cl；X3＝F；R2＝H；R3＝Ph；R4＝H；
68#:n＝0；X1＝O；X2＝Br；X3＝F；R2＝H；R3＝Ph；R4＝H；
69#:n＝0；X1＝S；X2＝I；X3＝F；R2＝H；R3＝Ph；R4＝H；
70#:n＝0；X1＝N；X2＝F；X3＝Cl；R2＝H；R3＝Ph；R4＝H；
71#:n＝0；X1＝O；X2＝F；X3＝Br；R2＝H；R3＝Ph；R4＝H；
72#:n＝0；X1＝S；X2＝F；X3＝I；R2＝H；R3＝Ph；R4＝H；
73#:n＝0；X1＝N；X2＝F；X3＝F；R2＝H；R3＝H；R4＝Ph；
74#:n＝0；X1＝O；X2＝F；X3＝F；R2＝H；R3＝H；R4＝Ph；
75#:n＝0；X1＝S；X2＝F；X3＝F；R2＝H；R3＝H；R4＝Ph；
76#:n＝0；X1＝N；X2＝Cl；X3＝F；R2＝H；R3＝H；R4＝Ph；
77#:n＝0；X1＝O；X2＝Br；X3＝F；R2＝H；R3＝H；R4＝Ph；
78#:n＝0；X1＝S；X2＝I；X3＝F；R2＝H；R3＝H；R4＝Ph；
79#:n＝0；X1＝N；X2＝F；X3＝Cl；R2＝H；R3＝H；R4＝Ph；
80#:n＝0；X1＝O；X2＝F；X3＝Br；R2＝H；R3＝H；R4＝Ph；
81#:n＝0；X1＝S；X2＝F；X3＝I；R2＝H；R3＝H；R4＝Ph；
82#:n＝0；X1＝N；X2＝F；X3＝F；R2＝t-Bu；R3＝H；R4＝H；
83#:n＝0；X1＝O；X2＝F；X3＝F；R2＝t-Bu；R3＝H；R4＝H；
84#:n＝0；X1＝S；X2＝F；X3＝F；R2＝t-Bu；R3＝H；R4＝H；
85#:n＝0；X1＝N；X2＝F；X3＝F；R2＝Me；R3＝H；R4＝H；
86#:n＝0；X1＝O；X2＝F；X3＝F；R2＝Me；R3＝H；R4＝H；
87#:n＝0；X1＝S；X2＝F；X3＝F；R2＝Me；R3＝H；R4＝H；
88#:n＝0；X1＝N；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝H；
89#:n＝0；X1＝O；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝H；
90#:n＝0；X1＝S；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝H；
91#:n＝0；X1＝N；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝Me；
92#:n＝0；X1＝O；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝Me；
93#:n＝0；X1＝S；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝Me；
94#:n＝0；X1＝N；X2＝F；X3＝F；R2＝H；R3＝H；R4＝Me；
95#:n＝0；X1＝O；X2＝F；X3＝F；R2＝H；R3＝H；R4＝Me；
96#:n＝0；X1＝S；X2＝F；X3＝F；R2＝H；R3＝H；R4＝Me；
97#:n＝0；X1＝N；X2＝F；X3＝F；R2＝H；R3＝H；R4＝t-Bu；
98#:n＝0；X1＝O；X2＝F；X3＝F；R2＝H；R3＝H；R4＝t-Bu；
99#:n＝0；X1＝S；X2＝F；X3＝F；R2＝H；R3＝H；R4＝t-Bu；
100#:n＝0；X1＝N；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝t-Bu；
101#:n＝0；X1＝O；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝t-Bu；
102#:n＝0；X1＝S；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝t-Bu。
or a pharmaceutically acceptable salt or solvate thereof.
"pharmaceutically acceptable salts" are products comprising the salt-forming reaction of a compound of formula (1) with an acid, including inorganic acid salts such as hydrochloride, hydrobromide or sulfate salts, and the like; organic acid salts such as acetate, lactate, succinate, fumarate, maleate, citrate, benzoate, mesylate, or p-toluate salts, and the like.
A pharmaceutical composition containing a compound according to the invention, which comprises as active ingredient a therapeutically effective amount of a compound according to general formula (1), in free form or in pharmaceutically acceptable salt form; one or more pharmaceutically acceptable carrier substances and/or diluents.
The technical scheme of the invention is not limited to the following method, and the scheme is as follows:
synthetic methods for the compounds:
a25 ml round bottom flask was charged with the different starting materials corresponding to compounds # 1-102: heterocyclic compound (0.85mmol) and tetrahydrofuran (3.0mL), wherein the heterocyclic compound (0.85mmol) can be various heterocycles such as imidazole, azole, furan, thiazole and the like or ring-fused compounds thereof. LDA (lithium diisopropylamide) (2M in THF (tetrahydrofuran), 0.47mL) was added at-78 ℃. Then a solution of a chiral imine (0.5mmol) at-78 deg.C, which may be fluoromethyl imine, fluoroethyl imine, trifluoromethyl substituted N-t-butylsulfinyl imine or other imine compound of different substituents, in tetrahydrofuran (2.0 mL). The mixture was then stirred for 2 hours. After the reaction was complete, the reaction was quenched with saturated NH4Cl (3.0 mL). Then extracting with ethyl acetate, and finally separating by column chromatography to obtain the corresponding 1-102# compound.
Unless otherwise indicated, the following terms used in the claims and specification have the following meanings:
"pharmaceutically acceptable salts" and "pharmaceutically acceptable salts" are salts comprising a compound of formula (1) reacted with an acid, and refer to those salts that retain the biological effectiveness and properties of the parent compound, and include: inorganic acid salts such as hydrochloride, hydrobromide or sulfate; organic acid salts such as acetate, lactate, succinate, fumarate, maleate, citrate, benzoate, mesylate, or p-toluate salts, and the like.
"pharmaceutical composition" refers to a mixture of one or more compounds described herein, or their pharmaceutically acceptable salts and prodrugs, with other chemical components, such as pharmaceutically acceptable carriers and excipients, the purpose of the pharmaceutical composition being to facilitate administration of the compound to an organism.
"solvate" is a compound according to the invention, or a salt thereof, which corresponds to the features of general formula (1) and which also includes stoichiometric or non-stoichiometric amounts of solvents containing non-covalent intermolecular force bonding. When the solvent is water, the solvate is a hydrate.
"hydrate" means a solid crystalline substance formed during the interaction of a compound according to the invention, which corresponds to the characteristics of formula (1), with water.
Further, another object of the present invention is to provide the use of the above compound in an immunomodulatory drug. The invention first exemplifies the immunomodulatory activity of the compounds at the immune cell level in vitro. Immune cell types as used herein include, but are not limited to, macrophages, dendritic cells, granulocytes, T cells, B cells, NK cells, and mast cells. Immune cells herein are derived from animals including, but not limited to: mice and rats; domesticated animals include, but are not limited to, cats and dogs; and other animals such as but not limited to cattle, sheep, pigs, and horses; primates are for example but not limited to monkeys and humans. The measurement of the level of cytokines secreted by mouse immune cells is a widely accepted and accepted in vitro model for the measurement of anti-inflammatory drug activity, and also provides reference to immune cells from other biological populations such as, but not limited to, humans. The anti-inflammatory results of the synthesized compounds in the mouse macrophage cell line of the present invention are shown in table 1. The above objects are achieved by in vitro cell level bioactivity assay experiments, but the following examples should not be viewed as limiting the functional scope of this compound.
The small molecule compounds of the present invention can be administered orally, intravenously, nasally, rectally, or any other means that can deliver an effective amount of the active agent. Suitable dosages are those which give the desired final amount. Different dosages may be required to treat different diseases. An effective amount of the agent is an amount that results in a significant reduction in the reduction of the inflammatory response.
Researchers with routine skill will be able to determine the most effective dosage and timing of administration of the agents provided by the present invention, taking into account the mode of administration, drug metabolism, and other pharmacokinetic parameters such as drug distribution, clearance, etc.
Further, the present invention provides the use of said compounds for the preparation of an immunomodulatory drug, as said compounds of the invention may be based on molecular mechanisms to exert immunomodulatory effects. Thus, the immune-related diseases include autoimmune diseases such as arthritis, nephritis, enteritis, lupus erythematosus, multiple sclerosis, ankylosing spondylitis, and the like, and inflammatory diseases caused by viral and microbial infections such as hepatitis, pneumonia, gastritis, and the like.
This invention is exemplified by models of related immune diseases in vivo in various models of animals. Animals herein include, but are not limited to: mice and rats; domesticated animals include, but are not limited to, cats and dogs; and other animals such as but not limited to cattle, sheep, pigs, and horses; primates are for example but not limited to monkeys and humans. In vivo assays of enteritis, pneumonia, nephritis, gastritis, hepatitis, lupus erythematosus, multiple sclerosis, ankylosing spondylitis models in mice, and arthritis models in rats are widely recognized and accepted models of in vivo drug activity assays, as well as providing reference to other organisms such as, but not limited to, humans. It is a further object of the present invention to provide a method for treating immune related diseases such as inflammatory bowel disease, pneumonia, nephritis, gastritis, hepatitis, arthritis, lupus erythematosus, multiple sclerosis, ankylosing spondylitis, by administering a biologically active amount of the following compounds:
the following examples are intended to illustrate specific details of this invention and should not be construed as limitations on the scope of the invention's functionality.
The DMSO solution injection preparation of the compound of the invention is applied to the treatment of inflammatory bowel diseases:
1. a TNBS inflammatory bowel disease model was established by enema of BALB/C mice with a 50% ethanol solution of trinitrobenzene sulfonic acid (TNBS).
2. The prepared DMSO solution injection preparation of the compound is injected into the abdominal cavity while a TNBS inflammatory bowel disease model is established, so that the inflammatory bowel disease is treated.
3. Mice were measured daily after treatment and sacrificed 3 days after treatment, colon tissues were taken and histological damage scores and IL-10 and TNF- α inflammatory factor levels were determined.
The DMSO solution injection preparation of the compound of the invention is applied to the pneumonia treatment:
1. a BALB/C mouse is anesthetized by pentobarbital sodium, and a physiological saline solution containing Lipopolysaccharide (LPS) is instilled through nasopharynx to establish an LPS nasal cavity inhalation type mouse acute pneumonia model.
2. The prepared DMSO solution injection preparation of the compound is injected into the abdominal cavity while an acute pneumonia model induced by LPS is established, so that pneumonia is treated.
3. Mice were sacrificed 2 days after treatment and lung tissue was pathologically sectioned for histological lesion scoring and determination of IL-10 and TNF- α inflammatory factor levels.
The DMSO solution injection preparation of the compound of the invention is applied to the treatment of nephritis:
1. selecting a normal ICR mouse, taking a mouse kidney tissue, preparing kidney homogenate, and carrying out intraperitoneal injection on the healthy ICR mouse by combining LPS + kidney homogenate to establish a mouse acute nephritis model.
2. The prepared DMSO solution injection preparation of the compound is injected into the abdominal cavity while an acute nephritis model induced by LPS is established, so that nephritis is treated.
3. Mice were sacrificed 2 days after treatment and kidney tissue was pathologically sectioned for histological scoring and determination of IL-10 and TNF- α inflammatory factor levels.
The DMSO solution injection preparation of the compound of the invention is applied to the treatment of gastritis:
1. selecting normal healthy BALB/C mice, fasting, performing intragastric administration with sodium bicarbonate solution, administering helicobacter pylori after intragastric administration for 15min, and repeating the above operations on 3 rd and 5 th days of experiment to establish a mouse gastritis model.
2. The prepared DMSO solution injection preparation of the compound is injected into the abdominal cavity while a gastritis model caused by helicobacter pylori is established, so that the gastritis is treated.
3. Mice were sacrificed 4 weeks after model building, gastric tissues were taken for pathological sectioning, histological scoring and determination of IL-10 and TNF-alpha inflammatory factor levels.
The DMSO solution injection preparation of the compound of the invention is applied to the treatment of hepatitis:
1. d-galactosamine and LPS are injected into the abdominal cavity of an ICR mouse to establish a mouse hepatitis model.
2. The prepared DMSO solution injection preparation of the compound is injected into the abdominal cavity while a hepatitis model is established, so as to treat hepatitis.
3. After 5 days of treatment, the mice were sacrificed, liver tissues were selected for measurement of IL-10 and TNF-alpha inflammatory factor levels, and blood of the mice was taken to measure glutamate pyruvate transaminase activity therein to determine liver functions.
The DMSO solution injection preparation of the compound of the invention is applied to the treatment of Rheumatoid Arthritis (RA):
1. adjuvant arthritis model (CFA) was established using a complete Freund's adjuvant injected subcutaneously in the right plantar aspect of C57BL/6 mice.
2. Two weeks after adjuvant induction, mice were treated for arthritis by intraperitoneal injection of a DMSO solution of the compound of the present invention.
3. The mice were sacrificed two weeks after treatment, the degree of ankle swelling of the mice was observed at the end of the treatment, the joint disease was scored, the right foot of the mice was taken as a joint tissue section, and the treatment effect was evaluated by pathological scoring.
The invention relates to an application of a DMSO solution injection preparation of a compound in lupus erythematosus treatment, which comprises the following steps:
1. MRL/lpr spontaneous lupus mice were selected as disease models.
2. Lupus erythematosus is treated by administering the compound of the present invention every two weeks after the initial intraperitoneal injection of a DMSO solution of the compound at the age of 6 weeks in MRL/lpr mice.
3. Mice were sacrificed at 22 weeks of age in MRL/lpr mice, and the protein content in the urine and urea nitrogen content in the serum and IL-10 and TNF-alpha inflammatory factor levels in the blood were measured at the end of the treatment.
The DMSO solution injection preparation of the compound of the invention is applied to the treatment of multiple sclerosis:
1. combined with pertussis toxin tail vein injection, incomplete Freund's adjuvant, mycobacterium tuberculosis and Myelin Oligomeric Glycoprotein (MOG), subcutaneously injected into C57/B6 mice to establish a mouse multiple sclerosis model (EAE).
2. The DMSO solution of the compound is injected into the abdominal cavity when a mouse model is established, so that the multiple sclerosis is treated.
3. The mice were sacrificed 25 days after treatment, and the treatment effect was evaluated by scoring the mice behavior at the end of the treatment. The DMSO solution injection preparation of the compound of the invention is applied to the treatment of Ankylosing Spondylitis (AS):
1. human cartilage protein, incomplete Freund's adjuvant, complete Freund's adjuvant in combination with subcutaneous injection of BALB/C mice.
2. Six weeks after model establishment, mice were injected intraperitoneally with DMSO of the compound of the present invention, and administered once every four weeks to treat ankylosing spondylitis.
Mice were sacrificed at 3.36 weeks, spinal columns of the mice were histologically stained and scored to assess treatment efficacy, and spinal tissues were examined for IL-10 and TNF- α inflammatory factor levels.
Fourth, detailed description of the invention
EXAMPLE 1 Synthesis of Compounds No. 1-102 of the present application
A25 ml round bottom flask was charged with the different starting materials corresponding to compounds # 1-102: heterocyclic compound (0.85mmol) and tetrahydrofuran (3.0mL), wherein the heterocyclic compound (0.85mmol) can be various heterocycles such as imidazole, azole, furan, thiazole and the like or ring-fused compounds thereof. LDA (2M in THF,0.47mL) was added at-78 ℃. A solution of a chiral imine (0.5mmol) in tetrahydrofuran (2.0mL), which may be fluoromethyl imine, fluoroethyl imine, trifluoromethyl substituted N-t-butylsulfinyl imine or other imine compound of different substituents, was then added at-78 deg.C. The mixture was then stirred for 2 hours. After the reaction was complete, the reaction was quenched with saturated NH4Cl (3.0 mL). Then extracting with ethyl acetate, and finally separating by column chromatography to obtain the corresponding 1-102# compound.
Starting materials involved in the Synthesis of Compounds Nos. 11 to 102
EXAMPLE 2 screening of the anti-inflammatory Activity of the series of Compounds of the present application on mouse macrophages
The series of compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare test stock solutions (100mg/ml), and mouse macrophage cell line (ANA-1) was cultured in RPMI 1640 culture medium containing 10% fetal bovine serum. When the cell growth density of ANA-1 reaches 70% -80%, collecting cells, preparing cell suspension, inoculating 200 μ l of cell suspension (cell density of 2 × 104/ml) into each well of 96-well culture plate, culturing at 37 deg.C and 100% relative humidity in 5% CO2 incubator for 24h, and grouping according to the following treatment: DMSO group (medium treatment with 1% DMSO); DMSO + LPS group (1 μ g/ml LPS +1 ‰ DMSO culture medium treatment); DMSO + LPS + the compound of the invention group (containing 1. mu.g/ml LPS and 100. mu.g/ml the compound of the invention containing a culture treatment with a final DMSO concentration of 1 ‰.) each group had 5 more wells, and after 12 hours of the above-mentioned each group, cell supernatants were collected and the levels of TNF-. alpha.and IL-10 in the cell supernatants were measured by enzyme-linked immunosorbent assay (ELISA). As shown in tables 2 and 3, the series of compounds can inhibit the secretion of TNF-alpha by macrophages and can promote the expression of IL-10, which indicates that the series of compounds can inhibit the activation of macrophages, wherein the 75# compound has the highest inhibition efficiency, and therefore, the subsequent in vivo examples are carried out in 75 #.
TABLE 2 Effect of a series of compounds of the present application on TNF- α expression levels in mouse peritoneal macrophages
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
Represents P ≤ 0.05, compared with DMSO + LPS control group.
TABLE 3 Effect of a series of compounds of the present application on IL-10 expression levels in mouse peritoneal macrophages
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test. Represents P ≤ 0.05, compared with DMSO + LPS control group.
EXAMPLE 375 # Compound treatment of TNBS-induced enteritis model in mice
Dissolving the 75# compound by DMSO to prepare 200mg/mL mother solution for later use, and further diluting the 75# compound mother solution by water to the concentration required by injection before intraperitoneal injection. A trinitrobenzene sulfonic acid (TNBS) enteritis model of mice is established according to a method reported in the literature, namely 30 female BALB/C mice are taken, the weight of the female BALB/C mice is 16-18g, 0.1mL of TNBS solution (dissolved in 50% ethanol) is filled, the dose of TNBS is 2.5mg/kg of the weight of the female BALB/C mice, and the female BALB/C mice are randomly divided into two groups, namely a 75# compound treatment group and a control group on the day of modeling, and are respectively treated. The 75# compound treatment group was administered with the 75# compound by intraperitoneal injection at 50mg/kg, and the control group was administered with a corresponding amount of aqueous DMSO solution once a day. The model was sacrificed 3 days after establishment, and diseased colon tissue was taken for histological lesion scoring and detection of IL-10 and TNF- α cytokine levels.
(one) histological lesion scoring
Fixing part of colon tissue, performing HE staining, making pathological sections, observing under a microscope (Nikon TE2000U), scoring histological damage, scoring each section by two pathologists in a double-blind manner, averaging, and scoring standard shown in Table 4.
TABLE 4 colitis histological damage criteria
(II) cytokine assay
A part of the diseased colon tissue was excised and weighed, 1mL of physiological saline was added per 100mg of colon tissue, homogenized, centrifuged at 8000rpm and 4 ℃ for 10min, and the supernatant was collected. IL-10 and TNF-. alpha.cytokine levels in colon tissue were measured using a commercial ELISA kit (available from R & D, USA).
From table 5, it can be seen that the intraperitoneal injection of compound # 75 can effectively alleviate the colitis attack of mice, and the colon tissue damage of the treatment group is obviously lower than that of the control group, and is in certain dose dependence. Cytokine levels are also an important measure of tissue inflammation. As can be seen from Table 6, the level of the proinflammatory factor TNF-alpha in the treated group is obviously lower than that in the control group, and the level of the inhibin IL-10 in the treated group is obviously higher than that in the control group. Therefore, the 75# compound can inhibit the damage of colon tissues by inhibiting the inflammatory response of the intestinal tissues, thereby effectively controlling the development of colitis and relieving disease damage.
TABLE 575 administration of Compounds for treatment of enteritis Colon histology scores in mice
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05, and is compared with control group
TABLE 675 # COMPOUNDS ADMINISTRATION OF COLON TISSUE INFLAMMATORY FACTOR TEST FOR TREATING ANESTINATIVE DISEASES IN SMALL
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05, and is compared with control group
EXAMPLE 475 # Compound treatment of LPS-induced murine pneumonia model
Dissolving the 75# compound by DMSO to prepare 200mg/mL mother solution for later use, and further diluting the 75# compound mother solution by water to the concentration required by injection before intraperitoneal injection. A mouse pneumonia model caused by LPS is established according to a method reported in the literature, namely 30 male BALB/C mice are taken, and the weight of the mice is 16-18 g. Firstly, using 22mg/mL sodium pentobarbital physiological saline solution, and injecting the solution into the abdominal cavity according to the dosage of 50 mu l of each mouse until the mouse enters a deep anesthesia state. The nasopharynx was instilled with 167. mu.g/mL LPS physiological saline solution, and 60. mu.L of each mouse was instilled. Mice were then randomized into two groups, 75# compound treated and control, and given treatment separately. The 75# compound treatment group was administered with the 75# compound by intraperitoneal injection at 50mg/kg, and the control group was administered with a corresponding amount of aqueous DMSO solution once a day. The model was sacrificed 2 days after establishment, and diseased lung tissue was taken for histological damage scoring and detection of IL-10 and TNF- α cytokine levels.
(one) histological lesion scoring
Fixing part of lung tissue, performing HE staining, making pathological sections, observing under a microscope (Nikon TE2000U), scoring histological damage, scoring each section by two pathologists in a double-blind manner, averaging, and scoring standard shown in the following table 7.
TABLE 7 Lung injury Pathology Scoring criteria
(II) cytokine assay
A part of the diseased lung tissue was excised and weighed, 1mL of physiological saline was added per 100mg of lung tissue, homogenized, centrifuged at 8000rpm at 4 ℃ for 10min, and the supernatant was collected. IL-10 and TNF-. alpha.cytokine levels in lung tissue were measured using a commercial ELISA kit (purchased from R & D, USA).
From table 8, it can be seen that the intraperitoneal injection of the compound # 75 can effectively relieve the pneumonia attack of mice, and the lung tissue damage of the treatment group is obviously lower than that of the control group and is in certain dose dependence. Cytokine levels are also an important measure of tissue inflammation. As can be seen from Table 9, the level of the proinflammatory factor TNF-alpha in the treated group is significantly lower than that in the control group, and the level of the inhibin IL-10 in the treated group is significantly higher than that in the control group. Therefore, the 75# compound can inhibit lung tissue injury by inhibiting lung tissue inflammatory reaction, thereby effectively controlling the development of pneumonia and relieving disease damage.
Pulmonary histology score of mice on administration of compound # TABLE 875 for treatment of pneumonia
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05, and is compared with control group
TABLE 975 test of lung tissue inflammatory factor levels in mice administered with the compound for the treatment of pneumonia
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05, and is compared with control group
EXAMPLE 575 injectable formulations of Compounds for the treatment of nephritis
Dissolving the 75# compound by DMSO to prepare 200mg/mL mother solution for later use, and further diluting the 75# compound mother solution by water to the concentration required by injection before intraperitoneal injection. A mouse nephritis model is established according to a method reported in a literature, namely an ICR male mouse is taken, the weight is 16-18g, the kidney is taken, 1ml of physiological saline is added into each 100mg of tissue for tissue homogenization, and the kidney tissue homogenate is prepared. Then, Lipopolysaccharide (LPS) is used for intraperitoneal injection according to the dosage of 300 mu g/kg in combination with 50 mu l of kidney homogenate tissue fluid, and an acute nephritis model is established. The mice were then randomized into two groups, 75# compound treatment and control, and given treatment separately. The 75# Compound treatment group was administered with the 75# Compound 75# compound by intraperitoneal injection at 50mg/kg, and the control group was administered with a corresponding amount of aqueous DMSO solution once a day. The model was sacrificed 2 days after establishment, and diseased kidney tissue was taken for histological damage scoring and detection of IL-10 and TNF- α cytokine levels.
(one) histological lesion scoring
Fixing part of kidney tissues, performing HE staining, making pathological sections, observing under a microscope (Nikon TE2000U), and scoring histological injuries according to the following scoring standards: degree of tubulointerstitial injury, dilation, necrosis, atrophy according to protein casts and renal tubules: inflammatory cell infiltration: the degree of interstitial fibrosis was assessed on a 0-3 point scale for each parameter (0: normal, 1: mild impaired, 2: moderate impaired, 3: severe impaired), and each section was scored by two pathologists on a double-blind basis and averaged.
(II) cytokine assay
A part of the diseased kidney tissue was excised and weighed, 1mL of physiological saline was added per 100mg of kidney tissue, homogenized, centrifuged at 8000rpm at 4 ℃ for 10min, and the supernatant was collected. IL-10 and TNF-. alpha.cytokine levels in kidney tissue were measured using a commercial ELISA kit (purchased from R & D, USA).
It can be seen from table 10 that the intraperitoneal injection of the compound # 75 can effectively relieve the nephritis attack of the mice, and the renal tissue injury of the treatment group is obviously lower than that of the control group and is in certain dose dependence. Cytokine levels are also an important measure of tissue inflammation. As can be seen from Table 11, the level of the proinflammatory factor TNF-alpha in the treated group is significantly lower than that in the control group, and the level of the inhibin IL-10 in the treated group is significantly higher than that in the control group. Therefore, the 75# compound can inhibit the kidney tissue injury by inhibiting the inflammatory reaction of the kidney tissue, thereby effectively controlling the development of nephritis and relieving the disease damage.
TABLE 1075 compound administration treatment nephritis mice renal tubule histology score
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05, and is compared with control group
TABLE 1175 # Compound administration for nephritis mice Kidney tissue inflammatory factor level assay
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05, and is compared with control group
EXAMPLE 675 # Compound injectable formulations for the treatment of gastritis
Dissolving the 75# compound by DMSO to prepare 200mg/mL mother solution for later use, and further diluting the 75# compound mother solution by water to the concentration required by injection before intraperitoneal injection. A mouse gastritis model is established according to a method reported in the literature, namely BALB/C male mice are taken, and the weight of the mice is 16-18 g. Fasting was carried out for 24h, 0.25ml of 0.2mol/L sodium bicarbonate solution was perfused using a gastric tube, and after 15min helicobacter pylori strains (109CFU/ml, 0.5ml) were perfused, and the above procedure was repeated on days 3 and 5 of the experiment. Mice were then randomized into two groups, 75# compound treated and control, and given treatment separately. The 75# compound treatment group was administered with the 75# compound by intraperitoneal injection at 50mg/kg, and the control group was administered with a corresponding amount of aqueous DMSO solution once a week. The model was sacrificed 4 weeks after establishment, and diseased stomach tissue was taken for histological lesion scoring and detection of IL-10 and TNF- α cytokine levels.
(one) histological lesion scoring
Fixing part of stomach tissue, performing HE staining, making pathological sections, observing under a microscope (Nikon TE2000U), scoring histological damage according to the scoring standard shown in the following table 12, scoring each section by two pathologists in a double-blind manner, and taking an average value.
TABLE 12 pathological scoring criteria for gastric lesions
(II) cytokine assay
A portion of the diseased stomach tissue was excised and weighed, 1mL of physiological saline was added per 100mg of stomach tissue, homogenized, centrifuged at 8000rpm and 4 ℃ for 10min, and the supernatant was collected. IL-10 and TNF-. alpha.cytokine levels in gastric tissue were measured using a commercial ELISA kit (available from R & D, USA).
From table 13, it can be seen that intraperitoneal injection of compound # 75 can effectively alleviate the gastritis attack of mice, and the gastric tissue damage of the treatment group is significantly lower than that of the control group, and is in a certain dose dependence. Cytokine levels are also an important measure of tissue inflammation. From Table 14, it can be seen that the level of the proinflammatory factor TNF-alpha in the treated group is significantly lower than that in the control group, and the level of the inhibin IL-10 in the treated group is significantly higher than that in the control group. Therefore, the 75# compound can inhibit the gastric tissue injury by inhibiting the inflammatory reaction of the gastric tissue, thereby effectively controlling the development of the gastritis and relieving the disease damage.
Table 1375 # Compound dosing treatment gastritis mice gastric histology score
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05, and is compared with control group
TABLE 1475 # Compound administration for the treatment of gastritis mice gastric tissue inflammatory factor level assay
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05, and is compared with control group
EXAMPLE 775 use of injectable formulations of Compounds for the treatment of hepatitis
Dissolving the 75# compound by DMSO to prepare 200mg/mL mother solution for later use, and further diluting the 75# compound mother solution by water to the concentration required by injection before intraperitoneal injection. A mouse hepatitis model is established according to a literature report method, namely a female ICR mouse is taken and is aged for 6-8 weeks. D-galactosamine of 700mg/kg body weight and LPS of 250ng/kg body weight are carefully weighed, and then are injected into the abdominal cavity to establish a mouse severe hepatitis model. Mice were then randomized into two groups, 75# compound treated and control, and given treatment separately. After the model was established for 1 hour, the 75# compound-treated group was intraperitoneally administered with 50mg/kg of the 75# compound, and the control group was administered with a corresponding amount of DMSO aqueous solution 1 time a day. The mice are sacrificed after the model is established for 5 days, the liver tissues of the mice are taken for the level measurement of the inflammatory factors, and the blood of the mice is taken for the activity measurement of the glutamic-pyruvic transaminase.
Measurement of glutamate pyruvate transaminase Activity
The transaminase level in the plasma of mice was detected using the kit from Nanjing Biotechnology, using the procedures described with reference to the kit instructions.
(II) cytokine assay
A part of diseased liver tissue was excised and weighed, 1mL of physiological saline was added per 100mg of liver tissue, homogenized, centrifuged at 8000rpm at 4 ℃ for 10min, and the supernatant was collected. IL-10 and TNF-. alpha.cytokine levels in liver tissue were measured using a commercial ELISA kit (purchased from R & D, USA).
It can be seen from table 15 that intraperitoneal injection of compound # 75 can effectively alleviate the onset of hepatitis in mice, and the damage of liver tissues in the treatment group is significantly lower than that in the control group. Cytokine levels are also an important measure of tissue inflammation. As can be seen from Table 16, the level of the proinflammatory factor TNF-alpha in the treated group is significantly lower than that in the control group, and the level of the inhibin IL-10 in the treated group is significantly higher than that in the control group. Therefore, the 75# compound can inhibit the liver tissue injury by inhibiting the liver tissue inflammatory reaction, thereby effectively controlling the development of hepatitis and relieving the disease damage.
Measurement of plasma Glu-alanine transaminase Activity in mice with hepatitis treated by administration of Compound # in Table 1575
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05, and is compared with control group
TABLE 1675 test for the level of inflammatory factors in liver tissue of mice on hepatitis after administration of the Compound
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05, and is compared with control group
EXAMPLE 875 # Compound injectable formulations for treatment of rheumatoid arthritis
Dissolving the 75# compound by DMSO to prepare 200mg/mL mother solution for later use, and further diluting the 75# compound mother solution by water to the concentration required by injection before intraperitoneal injection. A mouse CFA type arthritis model is established according to a literature report method, namely an adjuvant type arthritis model is established by taking 30 female C57BL/6 mice with the weight of 16-18g and injecting 20 mu l of complete Freund's adjuvant into the right plantar area of the mouse subcutaneously. Two weeks after adjuvant induction, mice were randomized into 2 groups, i.e., 75# compound treated and control groups, and given treatment separately. The 75# compound treatment group was administered with the 75# compound by intraperitoneal injection at 50mg/kg, and the control group was administered with the corresponding amount of aqueous DMSO solution 1 time every two days. The mice were sacrificed two weeks after treatment, the right paw of the mice was taken at the end of the treatment as a joint tissue section, the treatment effect was evaluated by pathological scoring, and the joint tissue of the mice was taken for the measurement of the level of inflammatory factors.
(one) pathological scoring of mouse joints
Animals were sacrificed 4 weeks after administration, ankle and knee joints were taken, fixed with 4% formaldehyde for 24 hours, sectioned by embedding, HE stained, and pathological changes were observed by microscope. Microscopic (Nikon TE2000U) arthritic score criteria: 0 minute: joints have normal structures such as joint spaces, cartilage, bone, synovial tissue, and the like. 1 minute: vacuolization and mild joint inflammation in the joint tissue with synovial hyperplasia, an increase in the number of blood vessels, and a small foci of inflammatory cells, with mild destruction of cartilage and no erosive destruction of bone being seen. And 2, dividing: the joint has obvious cartilage erosion damage, moderate joint inflammation, pannus formation, no bone damage and no joint structure damage. And 3, dividing: there is severe pannus formation, extensive cartilage erosion destruction, visible bone destruction, and destruction of joint structures. The arthritis pathological score (AS) is the sum of the pathological scores of all joints of each mouse, each foot does not exceed 3 points, and the total score does not exceed 12 points.
(II) cytokine assay
A part of the diseased joint tissue was excised and weighed, 1mL of physiological saline was added per 100mg of the joint tissue, homogenized, centrifuged at 8000rpm at 4 ℃ for 10min, and the supernatant was collected. IL-10 and TNF-. alpha.cytokine levels in joint tissues were measured using a commercial ELISA kit (available from R & D, USA).
TABLE 1775 therapeutic effect of compound administration on rheumatoid arthritis
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05
TABLE 1875 test of cytokine levels in articular tissue of mice administered with arthritis
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05
As shown in Table 17, the 75# compound can obviously inhibit joint damage such as local edema, tissue swelling and joint deformation of joints of rats. On the other hand, the compound 75# treatment group can be found to have only slight synovial hyperplasia and occasionally a small amount of inflammatory cell infiltration in the local joint through histological scoring. As shown in Table 18, it can be seen that the level of the proinflammatory factor TNF- α in the treated group is significantly lower than that in the control group, and the level of the anti-inflammatory factor IL-10 in the treated group is significantly higher than that in the control group. The 75# compound can inhibit the joint tissue damage by inhibiting the joint inflammatory reaction, thereby effectively controlling the development of arthritis and relieving the disease damage.
Example 975 application of Compound injection formulation to treatment of Lupus erythematosus
Dissolving the 75# compound by DMSO to prepare 200mg/mL mother solution for later use, and further diluting the 75# compound mother solution by water to the concentration required by injection before intraperitoneal injection. MRL/lpr spontaneous lupus mice were selected as disease models, i.e., 40 MRL/lpr mice, weighing 16-18g, were randomly divided into two groups, i.e., 75# compound-treated group and control group, and treated separately. The 75# compound treatment group was administered with the 75# compound by intraperitoneal injection at 50mg/kg, and the control group was administered with a corresponding amount of aqueous DMSO. MRL/lpr mice were dosed at 6 weeks of age, every 2 weeks and mice were sacrificed at week 22. And (3) measuring the protein content in the urine of the mouse and the urea nitrogen content in the serum of the mouse at the end of treatment, and evaluating the treatment effect according to the indexes.
(1) Determination of protein content in mouse urine
The protein content in the mouse urine was determined using a commercial protein quantification kit (Nanjing institute of bioengineering).
(2) Determination of Urea Nitrogen and content in mouse serum
Blood was collected from the orbit and the urea nitrogen content in the mouse serum was determined using a commercial kit (Nanjing institute of bioengineering). IL-10 and TNF-. alpha.cytokine levels in blood were measured using a commercial ELISA kit (available from R & D, USA).
As shown in table 19, the 75# compound was effective in reducing the protein content in the urine and the urea nitrogen content in the serum of mice, and this result indicates that the 75# compound was effective in alleviating the onset of glomerulonephritis caused by lupus. As shown in Table 20, it can be seen that the level of the proinflammatory factor TNF- α in the treated group is significantly lower than that in the control group, and the level of the anti-inflammatory factor IL-10 in the treated group is significantly higher than that in the control group. The 75# compound can effectively control the development of lupus and alleviate the disease damage by inhibiting the systemic inflammatory response.
TABLE 1975 # Compounds therapeutic Effect on lupus erythematosus
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05
TABLE 2075 # Compound administration for serum cytokine level detection in treatment of lupus erythematosus
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05
EXAMPLE 1075 use of Compound in the treatment of multiple sclerosis
Dissolving the 75# compound by DMSO to prepare 200mg/mL mother solution for later use, and further diluting the 75# compound mother solution by water to the concentration required by injection before intraperitoneal injection. The mouse EAE model was established according to literature reports, i.e., 40 mice C57BL/6 were treated and injected caudally with 200ng diphtheria toxin, while mice were injected subcutaneously with an emulsion containing 500ng Mycobacterium tuberculosis, 100. mu.l incomplete Freund's adjuvant, and 300. mu.g MOG. After 48 hours 200ng of diphtheria toxin was re-injected in the tail vein. Mice were randomized into two groups, 75# compound treated and control, and given treatment separately. The 75# compound treatment group was administered with the 75# compound by intraperitoneal injection at 50mg/kg, and the control group was administered with a corresponding amount of aqueous DMSO solution once every 3 days. The behavior of the mice was observed 25 days after the treatment, and the treatment effect was evaluated by scoring. The scoring criteria were as follows: score 0, no symptoms; 1 minute, tail weakness; 2 min, hind limb paresis; 3 min, hemiplegia; 4 points, paralysis of forelimbs; and 5 points of total paralysis or death. Blood from mice was collected and IL-10 and TNF-. alpha.cytokine levels in the blood were measured using a commercially available ELISA kit (available from R & D, USA).
As shown in table 21, the results of behavioral scoring for EAE model mice treated with compound # 75 were significantly higher than those of the model group. As shown in Table 22, it can be seen that the level of the proinflammatory factor TNF- α in the treated group is significantly lower than that in the control group, and the level of the anti-inflammatory factor IL-10 in the treated group is significantly higher than that in the control group. The 75# compound can effectively control the development of EAE and alleviate disease damage by inhibiting the systemic inflammatory response.
TABLE 2175 # Compound administration of efficacy in EAE model
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05
TABLE 2275 test for EAE cytokine levels by administration of Compound #
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05
EXAMPLE 1175 # Compound for use in the treatment of Ankylosing Spondylitis (AS)
Dissolving the 75# compound by DMSO to prepare 200mg/mL mother solution for later use, and further diluting the 75# compound mother solution by water to the concentration required by injection before intraperitoneal injection. The procedure reported in the literature was followed to establish ankylosing spondylitis in mice, each mouse was injected subcutaneously with complete Freund's adjuvant containing 100. mu.g of human cartilage protein, and repeated once at weeks 3 and 5, respectively, wherein the complete Freund's adjuvant was replaced with incomplete Freund's adjuvant at week 5. At 6 weeks after model establishment, mice were randomized into two groups, i.e., 75# compound treated and control, and given treatment separately. The 75# compound treatment group was administered with the 75# compound by intraperitoneal injection at 50mg/kg, and the control group was administered with a corresponding amount of aqueous DMSO solution once a week. Mice were sacrificed at 36 weeks, and the spinal column of the mice was histologically stained and scored to evaluate the effect of the treatment. The scoring criteria were as follows: 1 point, inflammation at the attachment site, accumulation of inflammatory cells in the spinal disc; 2 min, disc 50% fusion; dividing by 3, and fusing all the spinal discs; 4 points, cartilage/bone glue. Blood from mice was collected and IL-10 and TNF-. alpha.cytokine levels in the blood were measured using a commercially available ELISA kit (available from R & D, USA).
Table 2375 # Compounds efficacy in AS model
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05
Table 2475 test for serum cytokine levels in AS model with compound administration therapy
Data are shown as mean ± standard deviation, and significant differences were determined by ANOVA test.
P is less than or equal to 0.05
AS shown in table 23, the performance score of AS model mice treated with compound # 75 was significantly higher than that of the model group. As shown in Table 24, it can be seen that the level of the proinflammatory factor TNF- α in the treated group is significantly lower than that in the control group, and the level of the anti-inflammatory factor IL-10 in the treated group is significantly higher than that in the control group. The 75# compound can effectively control the development of AS and alleviate the disease damage by inhibiting the systemic inflammatory response.
Claims (8)
1. The application of small molecule compounds and pharmaceutically acceptable salts thereof in preparing medicines for inhibiting immune cell activation;
the general formula of the small molecular compound and the pharmaceutically acceptable salt thereof is as follows:
characterized in that the specific substituents of said compounds are as defined in any one of the following items # 1 to # 102:
1#:n＝0；X1＝O；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
2#:n＝1；X1＝O；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
3#:n＝2；X1＝O；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
4#:n＝3；X1＝O；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
5#:n＝4；X1＝O；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
6#:n＝5；X1＝O；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
7#:n＝6；X1＝O；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
8#:n＝0；X1＝N；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
9#:n＝0；X1＝S；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
10#:n＝1；X1＝N；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
11#:n＝1；X1＝S；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
12#:n＝2；X1＝N；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
13#:n＝2；X1＝S；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
14#:n＝3；X1＝N；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
15#:n＝3；X1＝S；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
16#:n＝4；X1＝N；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
17#:n＝4；X1＝S；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
18#:n＝5；X1＝N；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
19#:n＝5；X1＝S；X2＝H；X33＝H；R2＝H；R3＝H；R4＝H；
20#:n＝6；X1＝N；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
21#:n＝6；X1＝S；X2＝H；X3＝H；R2＝H；R3＝H；R4＝H；
22#:n＝0；X1＝N；X2＝F；X3＝H；R2＝H；R3＝H；R4＝H；
23#:n＝0；X1＝N；X2＝Cl；X3＝H；R2＝H；R3＝H；R4＝H；
24#:n＝0；X1＝N；X2＝Br；X3＝H；R2＝H；R3＝H；R4＝H；
25#:n＝0；X1＝N；X2＝I；X3＝H；R2＝H；R3＝H；R4＝H；
26#:n＝0；X1＝N；X2＝F；X3＝F；R2＝H；R3＝H；R4＝H；
27#:n＝0；X1＝N；X2＝F；X3＝Cl；R2＝H；R3＝H；R4＝H；
28#:n＝0；X1＝N；X2＝F；X3＝Br；R2＝H；R3＝H；R4＝H；
29#:n＝0；X1＝N；X2＝F；X3＝I；R2＝H；R3＝H；R4＝H；
30#:n＝0；X1＝S；X2＝F；X3＝H；R2＝H；R3＝H；R4＝H；
31#:n＝0；X1＝S；X2＝Cl；X3＝H；R2＝H；R3＝H；R4＝H；
32#:n＝0；X1＝S；X2＝Br；X3＝H；R2＝H；R3＝H；R4＝H；
33#:n＝0；X1＝S；X2＝I；X3＝H；R2＝H；R3＝H；R4＝H；
34#:n＝0；X1＝S；X2＝F；X3＝F；R2＝H；R3＝H；R4＝H；
35#:n＝0；X1＝S；X2＝F；X3＝Cl；R2＝H；R3＝H；R4＝H；
36#:n＝0；X1＝S；X2＝F；X3＝Br；R2＝H；R3＝H；R4＝H；
37#:n＝0；X1＝S；X2＝F；X3＝I；R2＝H；R3＝H；R4＝H；
38#:n＝0；X1＝O；X2＝F；X3＝H；R2＝H；R3＝H；R4＝H；
39#:n＝0；X1＝O；X2＝Cl；X3＝H；R2＝H；R3＝H；R4＝H；
40#:n＝0；X1＝O；X2＝Br；X3＝H；R2＝H；R3＝H；R4＝H；
41#:n＝0；X1＝O；X2＝I；X3＝H；R2＝H；R3＝H；R4＝H；
42#:n＝0；X1＝O；X2＝F；X3＝F；R2＝H；R3＝H；R4＝H；
43#:n＝0；X1＝O；X2＝F；X3＝Cl；R2＝H；R3＝H；R4＝H；
44#:n＝0；X1＝O；X2＝F；X3＝Br；R2＝H；R3＝H；R4＝H；
45#:n＝0；X1＝O；X2＝F；X3＝I；R2＝H；R3＝H；R4＝H；
46#:n＝0；X1＝N；X2＝F；X3＝F；R2＝Ph；R3＝H；R4＝H；
47#:n＝0；X1＝O；X2＝F；X3＝F；R2＝Ph；R3＝H；R4＝H；
48#:n＝0；X1＝S；X2＝F；X3＝F；R2＝Ph；R3＝H；R4＝H；
49#:n＝0；X1＝N；X2＝F；X3＝F；R2＝Ph；R3＝Ph；R4＝H；
50#:n＝0；X1＝O；X2＝F；X3＝F；R2＝Ph；R3＝Ph；R4＝H；
51#:n＝0；X1＝S；X2＝F；X3＝F；R2＝Ph；R3＝Ph；R4＝H；
52#:n＝0；X1＝N；X2＝F；X3＝F；R2＝Ph；R3＝Ph；R4＝Ph；
53#:n＝0；X1＝O；X2＝F；X3＝F；R2＝Ph；R3＝Ph；R4＝Ph；
54#:n＝0；X1＝S；X2＝F；X3＝F；R2＝Ph；R3＝Ph；R4＝Ph；
55#:n＝0；X1＝N；X2＝F；X3＝Cl；R2＝Ph；R3＝H；R4＝H；
56#:n＝0；X1＝O；X2＝F；X3＝Br；R2＝Ph；R3＝H；R4＝H；
57#:n＝0；X1＝S；X2＝F；X3＝I；R2＝Ph；R3＝H；R4＝H；
58#:n＝0；X1＝N；X2＝F；X3＝Cl；R2＝Ph；R3＝Ph；R4＝H；
59#:n＝0；X1＝O；X2＝F；X3＝Br；R2＝Ph；R3＝Ph；R4＝H；
60#:n＝0；X1＝S；X2＝F；X3＝I；R2＝Ph；R3＝Ph；R4＝H；
61#:n＝0；X1＝N；X2＝F；X3＝Cl；R2＝Ph；R3＝Ph；R4＝Ph；
62#:n＝0；X1＝O；X2＝F；X3＝Br；R2＝Ph；R3＝Ph；R4＝Ph；
63#:n＝0；X1＝S；X2＝F；X3＝I；R2＝Ph；R3＝Ph；R4＝Ph；
64#:n＝0；X1＝N；X2＝F；X3＝F；R2＝H；R3＝Ph；R4＝H；
65#:n＝0；X1＝O；X2＝F；X3＝F；R2＝H；R3＝Ph；R4＝H；
66#:n＝0；X1＝S；X2＝F；X3＝F；R2＝H；R3＝Ph；R4＝H；
67#:n＝0；X1＝N；X2＝Cl；X3＝F；R2＝H；R3＝Ph；R4＝H；
68#:n＝0；X1＝O；X2＝Br；X3＝F；R2＝H；R3＝Ph；R4＝H；
69#:n＝0；X1＝S；X2＝I；X3＝F；R2＝H；R3＝Ph；R4＝H；
70#:n＝0；X1＝N；X2＝F；X3＝Cl；R2＝H；R3＝Ph；R4＝H；
71#:n＝0；X1＝O；X2＝F；X3＝Br；R2＝H；R3＝Ph；R4＝H；
72#:n＝0；X1＝S；X2＝F；X3＝I；R2＝H；R3＝Ph；R4＝H；
73#:n＝0；X1＝N；X2＝F；X3＝F；R2＝H；R3＝H；R4＝Ph；
74#:n＝0；X1＝O；X2＝F；X3＝F；R2＝H；R3＝H；R4＝Ph；
75#:n＝0；X1＝S；X2＝F；X3＝F；R2＝H；R3＝H；R4＝Ph；
76#:n＝0；X1＝N；X2＝Cl；X3＝F；R2＝H；R3＝H；R4＝Ph；
77#:n＝0；X1＝O；X2＝Br；X3＝F；R2＝H；R3＝H；R4＝Ph；
78#:n＝0；X1＝S；X2＝I；X3＝F；R2＝H；R3＝H；R4＝Ph；
79#:n＝0；X1＝N；X2＝F；X3＝Cl；R2＝H；R3＝H；R4＝Ph；
80#:n＝0；X1＝O；X2＝F；X3＝Br；R2＝H；R3＝H；R4＝Ph；
81#:n＝0；X1＝S；X2＝F；X3＝I；R2＝H；R3＝H；R4＝Ph；
82#:n＝0；X1＝N；X2＝F；X3＝F；R2＝t-Bu；R3＝H；R4＝H；
83#:n＝0；X1＝O；X2＝F；X3＝F；R2＝t-Bu；R3＝H；R4＝H；
84#:n＝0；X1＝S；X2＝F；X3＝F；R2＝t-Bu；R3＝H；R4＝H；
85#:n＝0；X1＝N；X2＝F；X3＝F；R2＝Me；R3＝H；R4＝H；
86#:n＝0；X1＝O；X2＝F；X3＝F；R2＝Me；R3＝H；R4＝H；
87#:n＝0；X1＝S；X2＝F；X3＝F；R2＝Me；R3＝H；R4＝H；
88#:n＝0；X1＝N；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝H；
89#:n＝0；X1＝O；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝H；
90#:n＝0；X1＝S；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝H；
91#:n＝0；X1＝N；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝Me；
92#:n＝0；X1＝O；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝Me；
93#:n＝0；X1＝S；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝Me；
94#:n＝0；X1＝N；X2＝F；X3＝F；R2＝H；R3＝H；R4＝Me；
95#:n＝0；X1＝O；X2＝F；X3＝F；R2＝H；R3＝H；R4＝Me；
96#:n＝0；X1＝S；X2＝F；X3＝F；R2＝H；R3＝H；R4＝Me；
97#:n＝0；X1＝N；X2＝F；X3＝F；R2＝H；R3＝H；R4＝t-Bu；
98#:n＝0；X1＝O；X2＝F；X3＝F；R2＝H；R3＝H；R4＝t-Bu；
99#:n＝0；X1＝S；X2＝F；X3＝F；R2＝H；R3＝H；R4＝t-Bu；
100#:n＝0；X1＝N；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝t-Bu；
101#:n＝0；X1＝O；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝t-Bu；
102#:n＝0；X1＝S；X2＝F；X3＝F；R2＝Me；R3＝Me；R4＝t-Bu。
2. the use of a small molecule compound according to claim 1 and pharmaceutically acceptable salts thereof for the manufacture of a medicament for inhibiting activation of immune cells, wherein the immune cells are macrophages.
3. The use of the small molecule compound of claim 1 and pharmaceutically acceptable salts thereof in the preparation of a medicament for inhibiting the expression of TNF- α by immune cells.
4. The use of the small molecule compound of claim 1 and pharmaceutically acceptable salts thereof in the preparation of a medicament for promoting the expression of IL-10 by immune cells.
5. The use of a small molecule compound of claim 1 and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of enteritis, pneumonia, nephritis, gastritis, hepatitis, arthritis, lupus erythematosus, multiple sclerosis, or ankylosing spondylitis.
6. The use of the small molecule compound of claim 1 and pharmaceutically acceptable salts thereof in the manufacture of a medicament for inhibiting TNF- α expression in inflammatory bowel disease, pneumonia, nephritis, gastritis, hepatitis, arthritis, lupus erythematosus, multiple sclerosis, or ankylosing spondylitis, or for promoting IL-10 expression in inflammatory bowel disease, pneumonia, nephritis, gastritis, hepatitis, arthritis, lupus erythematosus, multiple sclerosis, or ankylosing spondylitis.
7. The use of the compound # 75 of claim 1 and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of enteritis, pneumonia, nephritis, gastritis, hepatitis, arthritis, lupus erythematosus, multiple sclerosis, or ankylosing spondylitis.
8. The use of the 75# compound of claim 1, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting TNF- α expression in inflammatory bowel disease, pneumonia, nephritis, gastritis, hepatitis, arthritis, lupus erythematosus, multiple sclerosis, or ankylosing spondylitis, or for promoting IL-10 expression in inflammatory bowel disease, pneumonia, nephritis, gastritis, hepatitis, arthritis, lupus erythematosus, multiple sclerosis, or ankylosing spondylitis.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810004975 | 2018-01-03 | ||
| CN201810004975X | 2018-01-03 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108191875A CN108191875A (en) | 2018-06-22 |
| CN108191875B true CN108191875B (en) | 2020-12-22 |
Family
ID=62589879
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810044047.6A Active CN108191875B (en) | 2018-01-03 | 2018-01-17 | Compound and application thereof in preparation of medicine for treating immune-related diseases |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108191875B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107445979B (en) * | 2017-08-14 | 2019-07-16 | 石家庄学院 | 6- methYl-thiazol and triazole -5- carboxamides derivatives and application |
-
2018
- 2018-01-17 CN CN201810044047.6A patent/CN108191875B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| A novel fluorinated triazole derivative suppresses macrophage activation and alleviates experimental colitis via a Twist1-dependent pathway;Tingyue Tu et al.;《Biochemical Pharmacology》;20180717;第155卷;第275-287页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108191875A (en) | 2018-06-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100552043B1 (en) | Composition for obesity treatment comprising fumagillol derivatives | |
| CN112979743B (en) | Betulinic acid derivative and application thereof | |
| JP5345390B2 (en) | Water-soluble artemisinin derivative, preparation method thereof, pharmaceutical composition and use | |
| JP4891926B2 (en) | Artemisinin derivatives, methods for their preparation, applications and pharmaceutical compositions containing the derivatives | |
| JP2008526953A (en) | Treatment of inflammatory diseases with Praziquantel | |
| EP1970372B1 (en) | Salts of 9-oxoacridine-10-acetic acid with 1-alkylamno-1-desoxy-polyols | |
| CN104066324A (en) | Methods for treating gout flares | |
| CN108191875B (en) | Compound and application thereof in preparation of medicine for treating immune-related diseases | |
| CN114980898A (en) | Methods for treating inflammatory bowel disease | |
| CN111939179A (en) | Application of cobra venom or extract thereof in preparation of medicine for reducing uric acid and/or resisting gouty arthritis | |
| US20210338700A1 (en) | Pharmaceutical use of anemoside b4 against acute gouty arthritis | |
| TWI435727B (en) | Use of modulating secretion of cytokines | |
| TWI439269B (en) | Use of 4-cyclopropylmethoxy-n-(3,5-dichloro-1-oxidopyridin-4-yl)-5-(methoxy)pyridine-2-carboxamide for preparing a medicament for use in the treatment of motor disorders related to parkinson's disease | |
| CA2717495C (en) | Fullerene therapies for inflammation | |
| CN111184706B (en) | Active medicine for preventing and treating cholecystitis and application thereof | |
| KR102128810B1 (en) | Prevention or treatment of uric acid or gout disease | |
| CN112826820B (en) | NLRP3 inhibitor and application thereof | |
| CN115737648B (en) | Application of benzhydryl piperazine compound in treating echinococcosis | |
| CN115645385B (en) | Application of licochalcone B in preparation of medicines for treating and/or preventing type I interferon diseases | |
| CN111635430A (en) | Non-steroid compound, preparation method and application thereof | |
| CN116172994B (en) | Application of anthraquinone derivative in preparation of anti-pancreatitis medicine | |
| CN116444482B (en) | Thiophene-2-carboxylic acid derivative, preparation method and medical application thereof | |
| CN114949242B (en) | Application of selenium-containing compound in preparation of osteoclast differentiation inhibitor | |
| CN109966299B (en) | Application of indole alkaloid in treating allergic rhinitis and pharmaceutical composition thereof | |
| CN113304163B (en) | Application of trifolium pterocarpus santalin in treating arthritis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |