CN114984011A - Application of pyrrolopyridine compound in preparation of medicine for treating lupus - Google Patents
Application of pyrrolopyridine compound in preparation of medicine for treating lupus Download PDFInfo
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention belongs to the field of medicines, and particularly relates to application of a pyrrolopyridine compound in preparation of a medicine for treating lupus. The research of the invention finds that the pyrrolopyridine compound can effectively treat lupus and complications thereof, and can obtain a synergistic effect by combining the pyrrolopyridine compound with glucocorticoid.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to the technical field of lupus treatment.
Background
Lupus Erythematosus (LE) is a typical autoimmune disease, which is a disease of accumulating multiple organs and systems of the whole body such as skin, joints, muscles, kidneys, cardiovascular system, blood, central nerves, etc. due to various autoantibodies produced by cellular and humoral immune dysfunction. If effective intervention is not timely obtained in the lupus crisis, the life of a patient can be endangered, and one of the keys of treatment of the lupus crisis is that the lupus crisis quickly induced and relieved.
The current clinical treatment scheme is like a double-edged sword, although the method can control the disease development on one hand and is also accompanied with a plurality of drug toxicity effects on the other hand. For example, long-term application of glucocorticoid can cause damage to digestive tract, secondary Cushing syndrome infection and the like; the use of large doses of glucocorticoids can lead to disorders of the thalamoceptophyseal-adrenal axis. Immunosuppressive agents often cause bone marrow suppression, impairment of liver and kidney functions, secondary infection, and the like. The research and development of the targeted monoclonal antibody biological preparation well solve the problem of non-target effect, and show good treatment effect in clinical tests, but also have some safety problems; and as biological agents, the price is expensive; in addition, the occurrence and development of lupus erythematosus disease involve multiple systems and multiple factors, and the targeted therapy of a single target has limited curative effect. Exploring more efficient and less non-target effect therapeutic drugs has important practical significance and development prospects for LE treatment.
Disclosure of Invention
In view of the above problems, the present invention aims to provide an application of a pyrrolopyridine compound in the preparation of a drug for treating lupus.
A second object of the present invention is to provide an active ingredient and a drug for treating lupus, which comprise a pyrrolopyridine compound.
Application of pyrrolopyridine compounds in preparation of medicines for treating lupus, wherein the pyrrolopyridine compounds have the function of
A compound of the structure of formula 1;
in the formula 1, R is C1-C6 carboxylic acid and salt thereof, C2-C10 ester, C2-C10 amide, sulfonic acid and salt thereof.
The research of the invention shows that the compound with the structure of the formula 1 is helpful for relieving the symptoms and complications of lupus.
In the invention, the pyrrolopyridine compound is a compound with a structure of formula 1-A:
in the application of the invention, the lupus is at least one of systemic lupus erythematosus, discoid lupus erythematosus and cutaneous lupus erythematosus; preferably systemic lupus erythematosus. The research of the invention shows that the compound shown in the formula 1 can effectively relieve the symptoms and complications of systemic lupus erythematosus.
Preferably, the application is to use the pyrrolopyridine compound in preparation of a medicament for inhibiting at least one of Tfh, Th1 and antibody secreting cells from differentiating; and/or inhibiting secretion of at least one of autoantibody dsDNA antibodies, IFN- β and IFN- γ; and/or promote Treg,CD4 + T cells,B cells are differentiated into at least one drug for treating lupus.
In the invention, the compound shown in the formula 1 can effectively inhibit Tfh cell differentiation, Th1 cell differentiation, antibody secretion B cell, interferon secretion, autoantibody generation, Treg cell differentiation and Treg cell differentiationCD4 + T cell ratio promotionB cell ratio functions, thus effectively relieving lupus symptoms and complications.
The application of the pyrrolopyridine compound is used for preparing the medicine for treating kidney injury caused by lupus.
The application of the pyrrolopyridine compound is to prepare the medicine for treating the lymph and/or spleen hyperplasia caused by lupus.
The preferred application of the invention is that the pyrrolopyridine compound and the glucocorticoid are combined to prepare the medicine for treating lupus. In the invention, the pyrrolopyridine compound and the glucocorticoid are combined, so that a combined synergistic effect can be realized, and a better treatment effect can be obtained.
The application of the invention combines the pyrrolopyridine compound with pharmaceutically acceptable auxiliary materials to prepare any pharmaceutically acceptable dosage form; preferably, the dosage form is an external preparation, an oral preparation or an injection preparation.
The invention also provides a pharmaceutical active composition for treating lupus, which comprises the compound shown in the formula 1 and glucocorticoid;
preferably, the dosage ratio (for example, mass ratio) of the compound of formula 1 to the glucocorticoid is 1-3: 1.
the invention also provides a medicine for treating lupus, which comprises the active composition with a pharmaceutically effective amount.
Preferably, the medicament contains pharmaceutically acceptable auxiliary materials. Preferred medicaments are in pharmaceutically acceptable dosage forms. The dosage form is any one dosage form of granules, tablets, capsules, sprays, injections, suspensions, emulsions and the like.
The invention has the beneficial effects that:
1. the compound of formula 1 can reduce the proportion of Tfh, Th1 and antibody secreting B cells in draining lymph nodes; increase the number of Tregs in the draining lymph node,CD4 + (ii) a T-cell,the proportion of B cells; inhibition of IFN- β, IFN- γ, anti-dsDNA production; can be used for treating lupus, relieving lupus symptom and preventing complications.
2. The compound of the formula 1 and the glucocorticoid are combined to realize synergy, so that better lupus treatment effect can be obtained,
drawings
FIG. 1 is a graph showing that formula 1-A of example 1 inhibits Tfh differentiation better than various reference drugs;
FIG. 2 is a graph showing that formula 1-A of example 1 inhibits IL-21 production better than various reference drugs;
FIG. 3 is a graph showing that formula 1-A of example 2 promotes Treg differentiation better than various reference drugs;
FIG. 6 is a schematic representation of the promotion of formula 1-A in example 5Differentiation of CD4+ T into Treg cells;
FIG. 7 is a graph of formula 1-A in example 6 improving renal damage in lupus and decreasing the renal damage score;
FIG. 8 is a graph of the improvement in splenic lymph node hyperplasia of formula 1-A in example 6;
FIG. 9 is a graph showing that formula 1-A in example 6 reduces the proportion of Tfh cells in draining lymph nodes;
FIG. 10 is a graph showing that formula 1-A in example 6 reduces the proportion of Th1 cells in draining lymph nodes;
FIG. 11 is a graph of formula 1-A in example 6 reducing the proportion of antibody secreting B cells in draining lymph nodes;
FIG. 12 is a graph of formula 1-A increasing the proportion of Treg cells in draining lymph nodes in example 6;
FIG. 13 is an elevation of formula 1-A in draining lymph nodes of example 6CD4 + The proportion of T cells;
FIG. 14 is an elevation of formula 1-A in draining lymph nodes of example 6The proportion of B cells;
FIG. 15 shows that formula 1-A inhibits IFN- β production in example 6;
FIG. 16 shows that formula 1-A inhibits IFN- γ production in example 6;
FIG. 17 is a graph of the inhibition of anti-dsDNA production by formula 1-A of example 6;
FIG. 18 shows that the combination of formula 1-A and the glucocorticoid prednisolone in example 7 can better inhibit CD8 in Draining Lymph Node (DLN) than the use of prednisolone alone + Differentiation of TEM cells;
FIG. 19 shows that the combination of formula 1-A and the glucocorticoid polamonylone in example 7 can better inhibit CD8 in draining lymph nodes than the combination of polamonylone alone + Differentiation of TCM cells;
FIG. 20 shows that the combination of formula 1-A and the glucocorticoid prednisolone of example 7 can better maintain CD8 in draining lymph node than the combination of prednisolone alone + The initial state of the T cell, i.e.CD8 + A T cell;
FIG. 21 shows that the combination of formula 1-A and the glucocorticoid polamonylone in example 7 can better inhibit CD4 in draining lymph nodes than the use of polamonylone alone + Differentiation of TEM cells;
FIG. 22 shows that the combination of formula 1-A and the glucocorticoid prednisolone in example 7 can better inhibit CD4 in draining lymph nodes than the single use of prednisolone + Differentiation of TCM cells;
FIG. 23 shows that the combination of formula 1-A of example 7 with the glucocorticoid prednisolone can better maintain CD4 in draining lymph nodes than the use of prednisolone alone + The initial state of the T cell, i.e.CD4 + A T cell;
FIG. 24 shows that the combination of formula 1-A and the glucocorticoid prednisolone in example 7 can better inhibit CD4 in spleen than the single use of prednisolone + Differentiation of TCM cells;
FIG. 25 shows that the combination of formula 1-A and prednisolone as glucocorticoid in example 7 can inhibit the differentiation of ASC in draining lymph node;
FIG. 26 shows that the combination of formula 1-A and prednisolone of glucocorticoid in example 7 can better inhibit the differentiation of memory B cells in draining lymph nodes than the combination of prednisolone;
FIG. 27 shows that the combination of formula 1-A of example 7 with the glucocorticoid prednisolone can better maintain the initial state of B cells in draining lymph nodes than the use of prednisolone alone;
FIG. 28 is a graph showing that the combination of formula 1-A and prednisolone as a glucocorticoid in example 7 can promote the differentiation of antibody Tregs in the spleen better than that of prednisolone;
Detailed Description
Example 1: tfh, IL-21 inhibition in vitro
100ml of peripheral blood was collected from healthy volunteers, PBMC was isolated by Ficoll, and anti-human CD28 was added to a 24-well plate coated with anti-human CD3 one night in advance. Adding solvent (DMSO), formula 1-A, or several reference drugs (Moliblesib, I-BET762 carboxylic acid, BET-BAY002, PROTAC BET-binding motif 2, BI-9564, (S) -JQ-35), respectively, to a final concentration of 1 μ M, culturing at 37 deg.C for 3 days, collecting the culture supernatant, and detecting the concentration of IL-21 with human IL-21ELISA detection kit; harvest cells the proportion of Tfh in CD4+ T cells was measured using flow cytometry. Compared with a control group and various reference drugs, the formula 1-A can inhibit the secretion of IL-21 more effectively; and can inhibit Tfh differentiation more effectively, and the results are shown in figures 1 and 2. IL-21 and Tfh play an important role in promoting the occurrence and development of lupus erythematosus, and more reference medicaments in the formula 1-A have better potential treatment effects.
Example 1 human IL-21ELISA kits were purchased from warames, wuhan, anti-human CD3 and anti-human CD28 were purchased from whirlpool, usa, and flow antibodies were purchased from BD.
Example 2: in vitro Treg cell differentiation study
100ml of peripheral blood was collected from healthy volunteers, PBMC was isolated by Ficoll, and anti-human CD28 was added to a 24-well plate coated with anti-human CD3 one night in advance. The proportion of Treg cells in CD4+ T cells was measured by flow cytometry after culture at 37 ℃ for 3 days with the final concentration of 1. mu.M, added with vehicle (DMSO), formula 1-A, or several reference drugs (Alobesib, PFI-1, (Rac) -BAY1238097, Y06036, respectively). The formula 1-a can promote the differentiation of tregs more effectively than the control group and various reference drugs, and the results are shown in fig. 3. Treg cells play a role in suppressing immune response, can suppress the differentiation of a plurality of cells playing a role in promoting the occurrence and development of lupus erythematosus, are beneficial to the alleviation and treatment of diseases, and more reference medicaments in the formula 1-A have better potential treatment effects.
Example 2 anti-human CD3 and anti-human CD28 were purchased from May whirlpool, and the flow antibody was purchased from BD.
Example 3: effect of formula 1-A on Tfh-induced differentiation
Separating and extracting 150ml of peripheral blood of 3 healthy volunteers, separating PBMC of each volunteer by using lymphocyte separation liquid Ficoll, and then using a person who is gentle and gentleCD4+ sorting magnetic beads from whichCD4+ T cells (according to kit instructions) were added to 10% FBS RPMI 1640 medium containing anti-human CD28, IL-6, IL-12, IL-21, TGF-. beta.and cultured in 24-well cell culture plates previously coated with anti-human CD3, the cell density of the plates being 1X 10 6 The Tfh ratio was measured by flow-assay at 3 days/ml after culture. The Tfh differentiation rate was significantly decreased in the experimental group (formula 1-A) compared to the control group (DMSO) (FIG. 4).
The reagent consumables are as follows:
human beingCD4 sorting magnetic beads, anti-human CD28, anti-human CD3, LS columns were purchased from America and whirlpool;
IL-6, IL-21, IL-12, and TGF-beta are all available from Beijing Yi Qiao Shenzhou science and technology, Inc.;
flow-through antibodies were purchased from BD, specifically CD4: FITC, CXCR5: PE, PD-1: PE-CY 7.
Example 4: effect of formula 1-A on Th1 induced differentiation
Separating and extracting 150ml of peripheral blood of 3 healthy volunteers, separating PBMC of each volunteer by using lymphocyte separation liquid Ficoll, and then using a person who is gentle and gentleCD4+ sorting beadsCD4+ T cells (according to kit instructions) were cultured in a 24-well cell culture plate previously coated with anti-human CD3 in RPMI 1640 medium containing 10% FBS for anti-human CD28, IL-4, IL-2, IL-12, at a cell density of 1X 10 6 Ml, 3 days later the ratio of Th1 was flow-tested. The differentiation rate of Th1 was significantly reduced in the experimental group (formula 1-a) compared to the control group (DMSO) (fig. 5). A significant increase in Th1 levels in lupus erythematosus patients compared to healthy controls; th1 also aggravates disease progression by producing IFN- γ secretion. The formula 1-A can relieve the disease by inhibiting the differentiation of Th 1.
The reagent consumables are as follows:
human beingCD4 sorting magnetic beads, anti-human CD28, anti-human CD3, LS columns were purchased from America and whirlpool;
IL-4, IL-2, IL-12 were purchased from Beijing Yiqiao Shenzhou science and technology, Inc.;
flow-through antibodies were purchased from BD, specifically CD4: FITC, IFN-. gamma.: PE-CY 7.
Example 5: effect of formula 1-A on Treg-induced differentiation
Separating and extracting 150ml of peripheral blood of 3 healthy volunteers, separating PBMC of each volunteer by using lymphocyte separation liquid Ficoll, and then using a person who is gentle and gentleCD4+ sorting beadsCD4+ T cells (according to kit instructions) were added to 10% FBS RPMI 1640 medium containing anti-human CD28, IL-2, TGF-. beta.and cultured in 24-well cell culture plates previously coated with anti-human CD3, the cell density of the plates was 1X 10 6 /ml, the proportion of tregs was flow-detected after 3 days (fig. 6). The experimental group (formula 1-a) showed a significant increase in the rate of Treg differentiation compared to the control group (DMSO).
The reagent consumables are as follows:
human beingCD4 sorting magnetic beads, anti-human CD28, anti-human CD3, LS columns were purchased from America and whirlpool;
IL-2, TGF-beta are both available from Beijing Yi Qiao Shenzhou science and technology, Inc.;
flow-through antibodies were purchased from BD, specifically CD4: FITC, CD 25: APC, CD 127: percep-cy 5.5.
Example 6: therapeutic Effect of formula 1-A on spontaneously lupus mice
12-week-old mice (MRL/lpr, Beijing sbefu) were randomly divided into two groups, a control group (6) and an experimental group (6), and the mice were gavaged with the suspension of formula 1-A at a daily dose of 10mg/kg, and the control group was gavaged with the same dose of vehicle. After 6 weeks of administration, mice were sacrificed and their body weights, spleen and lymph node weights were measured according to the guidance of the animal ethics committee; separately grinding and sieving spleen and lymph node of mouse to obtain single cell, and flow analyzing Tfh in spleen lymph node
(CD4+ CXCR5+ PD-1+), Treg (CD4+ CD25+ FOXP3+), Th1(CD4+ IFN-. gamma. +, antibody secreting B cells,CD4 + (ii) a T-cell,the proportion of B cells; taking a left kidney fixed embedding section, observing the damage degree of glomeruli under a microscope after HE staining, and calculating a score; ELISA was used to measure IFN-. gamma.IFN-. beta.anti-dsDNA levels in serum (see FIGS. 7-17, following the instructions for each kit). Tfh, Th1, antibody secreting B cells, glomerular lesion score, IFN-. gamma., IFN-. beta.and anti-dsDNA were all able to aggravate the disease or to positively correlate with the disease condition, whereas Treg cells,(ii) a CD4+ T cell,b cells are negatively associated with or have a remitting effect on the disease.
The flow-type antibody and the reagent for flow-type analysis are purchased from BD company, and specifically comprise:
CD4, Percp-CY5.5, IFN-gamma PE-CY7, CXCR5, PE-CY7, PD-1, PE, CD25BB515, FOXP3, APC, CD 19: APC-CY7, B220: PE-CY7, IgD: FITC, CD 138: APC, CD4: PE, CD44: APC-CY7, CD62L: PE-CY 7; fixing a nuclear membrane breaking reagent and fixing a membrane breaking reagent.
ELISA kits were purchased from Huamei organisms.
Example 7: therapeutic effect of formula 1-A in combination with glucocorticoid prednisolone (Pred) on mice with lupus erythematosus
12-week-old spontaneous lupus model mice (MRL/lpr, Beijing sbefu) are randomly divided into two groups, a nylon-splashing group (6) and a synergistic group (6) of formula 1-A and nylon-splashing, the nylon-splashing group is drenched with nylon-splashing suspension at a dose of 5mg/kg per day, and the synergistic group is drenched with nylon-splashing suspension at a dose of 5mg/kg and 10mg/kg per day. After 6 weeks of administration, mice were sacrificed and their body weights, spleen and lymph node weights were measured according to the guidance of the animal ethics committee; separately grinding and sieving spleen and lymph node of mouse to obtain single productCell, flow analysis of TEM CD8+ T (CD44+ CD62L-CD8+), TCM CD8+ T (CD44+ CD62L + CD8+) in lymph nodes,CD8+T(CD44-CD62L+CD8+),TEM CD4+T(CD44+CD62L-CD4+),TCM CD4+T(CD44+CD62L+CD4+),CD4+ T (CD44-CD62L + CD4+), antibody secreting cells ASC (B220-IgD-CD138+), memory B cells (B220+ CD138+ IgD-),b cells (B220+ CD138-IgD +); and the proportion of TCM 4+ T CD44+ CD62L + CD4+) cells and Tregs (CD4+ CD25+ FOXP3+) in the spleen. TEM CD8+ T cells, TCM CD8+ T cells, TEM CD4+ T cells, TCM CD4+ T cells, antibody secreting cells, memory B cells can aggravate diseases or have positive correlation with diseases, and Treg cells,(ii) a CD8+ T cell,(ii) a CD4+ T cell,b cells were negatively associated with or had a remitting effect on the disease (results are shown in fig. 18-28).
The flow-type antibody and the reagent for flow-type analysis are purchased from BD company, and specifically comprise:
CD4: PE, CD8: Percp-CY5.5, CD44: APC-CY7, CD62L: PE-CY 7; CD 19: APC-CY7, B220: PE-CY7, IgD: FITC, CD 138: APC; CD4: percp-cy5.5, CD 25: BB515, FOXP3, APC; fixing the reagent for breaking nuclear membrane and fixing the reagent for breaking envelope membrane.
Claims (10)
1. The application of the pyrrolopyridine compound in preparing the medicine for treating lupus is characterized in that the pyrrolopyridine compound is a compound with a structure shown in a formula 1;
in the formula 1, R is C1-C6 carboxylic acid and salt thereof, C2-C10 ester, C2-C10 amide, sulfonic acid and salt thereof.
3. the use of claim 1, wherein the lupus is at least one of systemic lupus erythematosus, discoid lupus erythematosus, and cutaneous lupus erythematosus.
4. The use according to claim 1, wherein the pyrrolopyridine compound is used for the preparation of a medicament for inhibiting at least one of Tfh, Th1, antibody-secreting cell differentiation; and/or inhibiting secretion of at least one of autoantibody dsDNA antibodies, IFN- β and IFN- γ; and/or promote Treg,CD4 + T cells, a,B cells are differentiated into at least one drug for treating lupus.
5. The use of claim 1, wherein the pyrrolopyridine compound is used for the manufacture of a medicament for treating kidney damage caused by lupus.
6. The use according to claim 1, wherein the pyrrolopyridines are used for the preparation of a medicament for the treatment of lupus-induced lymphoproliferative and/or splenic hyperplasia.
7. The use according to any one of claims 1 to 6, wherein the pyrrolopyridine compound is used in combination with a glucocorticoid for the manufacture of a medicament for the treatment of lupus.
8. The use of claim 1, wherein the pyrrolopyridine compound is combined with a pharmaceutically acceptable excipient to prepare any pharmaceutically acceptable dosage form;
preferably, the dosage form is an external preparation, an oral preparation or an injection preparation.
9. A pharmaceutically active composition for the treatment of lupus, comprising a compound of formula 1 as described in claim 1 and a glucocorticoid;
preferably, the dosage ratio of the compound shown in the formula 1 to the glucocorticoid is 1-3: 1.
10. a medicament for treating lupus, comprising a pharmaceutically effective amount of the active composition of claim 9;
preferably, the medicament contains pharmaceutically acceptable auxiliary materials;
preferably, the medicament is in a pharmaceutically acceptable dosage form, such as an injectable formulation.
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Citations (3)
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CN105073747A (en) * | 2013-03-15 | 2015-11-18 | 普莱希科公司 | Heterocyclic compounds and uses thereof |
CN111194318A (en) * | 2017-10-13 | 2020-05-22 | 普莱希科公司 | Solid forms of compounds for modulating kinases |
WO2021175432A1 (en) * | 2020-03-04 | 2021-09-10 | Boehringer Ingelheim International Gmbh | Method for administration of an anti cancer agent |
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CN105073747A (en) * | 2013-03-15 | 2015-11-18 | 普莱希科公司 | Heterocyclic compounds and uses thereof |
CN111194318A (en) * | 2017-10-13 | 2020-05-22 | 普莱希科公司 | Solid forms of compounds for modulating kinases |
WO2021175432A1 (en) * | 2020-03-04 | 2021-09-10 | Boehringer Ingelheim International Gmbh | Method for administration of an anti cancer agent |
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