WO2013023615A1

WO2013023615A1 - Use of vanillic acid glycoside derivatives for treating systemic autoimmune disease

Info

Publication number: WO2013023615A1
Application number: PCT/CN2012/080261
Authority: WO
Inventors: 殷红; 董俊兴
Original assignee: 中国医学科学院药物研究所
Priority date: 2011-08-16
Filing date: 2012-08-16
Publication date: 2013-02-21
Also published as: CN102949404B; CN102949404A

Abstract

Disclosed in the present invention is the use of vanillic acid glycoside derivatives as shown in formula (I) in preparing a medicine for treating a systemic autoimmune disease. Preferably the systemic autoimmune disease is selected from systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, Sjogren's syndrome of mouth and eye, and polymyositis.

Description

Use of vanillic acid derivatives in the treatment of systemic autoimmune diseases FIELD OF THE INVENTION The present invention relates to the novel use of vanillic acid glucosides in the treatment of autoimmune diseases such as systemic lupus erythematosus. Background technique

Autoimmune diseases refer to autologous antibodies and/or T lymphocytes against autoantigens caused by the body's immune response to its own components, causing damage to its tissues or cells and dysfunction. And systemic autoimmune diseases, including systemic lupus erythematosus, due to the deposition of antigen-antibody complexes on the blood vessel wall and other causes of multiple organ damage.

(Systemic Lupus Erythematosus, SLE), Rheumatoid Arthritis (RA), Systemic Sclerosis (SSc), Oral Dryness Syndrome (SS), etc. Take the more serious systemic lupus erythematosus as an example. SLE is an autoimmune disease that can affect the skin and systemic multiple systems. The exact cause is not clear. The disease is more common in young women, and the condition often appears alternately. The incidence rate in China is about 70/100,000, and more than 50% of confirmed cases are damaged by vital organs such as liver and kidney. SLE can not be cured, but it can effectively relieve the disease after treatment. Commonly used treatments are: 1) Hydroxychloroquine: For mild cases with only skin involvement. 2) Glucocorticoid: Hormone standard course of treatment for acute, fulminant cases, or major organ involvement, is currently the main drug for the treatment of this disease. 3) Immunosuppressive agents: mainly used for recurrence of diseases after hormone reduction, or effective side effects of excessive hormonal effects, and severe side effects, as well as cases of lupus nephritis and lupus encephalopathy that are difficult to control with hormone alone. The long-term use of existing immunosuppressive agents can cause bone marrow suppression, reduce the body's anti-infective power, and often affect sugar and lipid metabolism to varying degrees. Therefore, therapeutic drugs with small side effects and strong targeting are considered to be the future development direction. In 2011, the US FDA approved belimumab (bel imumab) for the treatment of active, autoantibody-positive lupus erythematosus (SLE), becoming the first approved SLE-line therapy in 56 years since hydroxychloroquine. According to the analysis, there are more than 2.2 million SLE patients in China, India and Mexico alone, and only a very small number of patients can afford expensive biotherapeutics. Therefore, inexpensive glucocorticoids and immunosuppressants will be the mainstay of SLE. The drug to be treated continues to exist. New, small-molecule immunosuppressive agents with clear mechanisms of action, precise efficacy, and small side effects are not only clinically needed, but also benefit SDL patients and other systemic autoimmune diseases. Vanillic acid glucoside has been isolated in plants such as plum, but other biological activities have not been reported except for antioxidant activity. It was discovered by chance that the vanillin compounds have immunosuppressive activity. Subsequent preparation of compounds by plant extraction and chemical synthesis, after structural confirmation, was used in pharmacological experiments to demonstrate its therapeutic potential for the treatment of systemic autoimmune diseases.

Summary of the invention

The technical problem to be solved by the present invention is to provide a novel drug for treating systemic autoimmune diseases, which has excellent curative effect and low toxic and side effects.

In order to solve the technical problem of the present invention, the present invention adopts the following technical scheme: Specifically, it provides preparation of a vanillin derivative represented by the formula (I), and proves that it is in the treatment of systemic autoimmune diseases by pharmacological experiments. Application potential

COORi

R ₃ ,

o

o.

(I)

Wherein: selected from H, CH ₃ , CH ₂ CH ₃ or M, M is selected from alkali metal or alkaline earth metal; R ₂ is H, C1-6 fluorenyl; C1-6 alkyl substituted acyl;

Preferred alkali metals are selected from Li, Na or K. Preferred alkaline earth metals are selected from the group consisting of Mg, Ca or Ba.

Preferably a C1-6 alkyl group selected from _{_{_{CH 3, CH 2 CH 3,}}} CH 2 CH 2 CH 3.

Preferred C1-6 alkyl substituted acyl group selected from _{_{_{COCH 3, COCH 2 CH 3,}}} COCH 2 CH 2 CH 3. The selected compound of formula I is selected from the group consisting of:

Vanillic acid glucoside vanillic acid galactoside

Vanillic acid riboside vanillic acid arabinoside

Vanillic acid rhamnoside. The compound of the above formula I can be synthesized by a conventional phytochemical method or synthetically by a conventional medicinal method. For example, vanillic acid and monosaccharide are used as raw materials, and are synthesized by a conventional organic chemical method. The systemic autoimmune diseases described in the present invention include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, dry mouth syndrome, polymyositis. The present invention demonstrates by pharmacological test that the compound represented by Formula I can significantly inhibit the proliferation of mouse spleen T and sputum lymphocytes cultured in vitro, significantly inhibit the occurrence of delayed hypersensitivity in mice, and can significantly reduce the active DNA-induced system. Serum anti-ds-DNA antibody levels in lupus erythematosus-like mice reduce the deposition of IgG immune complexes in renal tissue and renal tissue damage. Therefore, the compound of formula I can be used as a new immunosuppressant for the treatment of systemic autoimmune diseases, especially systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, dry mouth syndrome, multiple Myositis.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 Effect of vanillic acid glucoside on the proliferation of mouse spleen lymphocytes

Figure 2. Vanillic acid glucoside improves renal pathological damage in SLE syndrome-like mice (HE, 100X)

A1 normal control group, animal kidney tissue is basically normal; A2~A3 model group, diffuse injury of renal tissue, glomerulonephritis is serious;

B1 prednisolone 5mg/Kg body reorganization, pathological improvement of lupus nephritis; B2~ B3 vanillic acid glucoside 1. broad 3. 3mg/Kg body reorganization, pathological damage of lupus nephritis. Figure 3. Vanillic acid glucoside reduces IgG immune complex deposition in kidney tissue of SLE syndrome-like mice ΑΓΑ3 model group animal kidney tissue diffuse injury, glomerular hyperplasia, mesangial cells, capillaries and renal tubules, strong fluorescence of blood vessels (++++); B1 prednisolone 5mg/Kg group, small kidney Ball, renal tubules slightly fluorescent (+), small vessel moderate fluorescence (+~++); B2 vanillic acid glucoside 1. lmg/Kg group, glomerular, tubular microfluorescence (+), small vessel moderate Fluorescence (+~++); B3 vanillic acid glucoside 3. 3mg/Kg group, strong fluorescence in small blood vessels, mild fluorescence of glomeruli and renal tubules (++). DETAILED DESCRIPTION OF THE INVENTION Various aspects and features of the present invention are specifically illustrated by the preferred embodiments of vanillic acid glucoside and vanillic acid glucoside methyl ester in the compounds of formula I, in conjunction with the accompanying drawings. Those skilled in the art should understand that these examples are for illustrative purposes only and do not limit the scope of the invention. The scope of the invention is limited only by the claims. Various modifications and improvements may be made to the various aspects of the invention without departing from the scope of the appended claims. For example, the replacement of vanillic acid glucose used in the examples with other compounds of formula I is understood and attained by one of ordinary skill in the art.

In addition, it should be noted that the various materials and reagents used in the following examples are all materials and reagents commonly used in the art, unless otherwise specified, and can be obtained by conventional commercial means; the methods used are well known to those skilled in the art. The usual method.

Example 1. Vanillic acid glucoside has obvious inhibitory effect on mouse spleen!\ B lymphocyte proliferation in vitro 1. 1 Materials and methods

Clean grade BALB /c mice, male, body weight (19 ± 2) g, purchased from the Experimental Animal Center of the Chinese Academy of Medical Sciences. LPS, ConA, DMS0, MTT Sigma products. RPMI 1640 complete medium contains penicillin 100 U/L, streptomycin 100 U/L, glutamine 2 mM and 10% fetal bovine serum. The mice were sacrificed by cervical dislocation, the spleen was aseptically taken, and the sputum lymphocyte suspension was prepared as usual. The cells were adjusted with 8×107 L, 0.1 mL/well, and 96-well plates were incubated with RPMI 1640 complete medium. ConA-were added (final concentration of 2. 5mg / L) or LPS (final concentration of 10mg / L), and vanilla sour grapes glucoside (final concentration ^{^{1X10- 9 - 1X10- 5 mol / L}} ), each concentration 6 duplicate holes. Incubate in a 37 ° C, 5% CO ₂ incubator. After 44 hours, MTT (5 g/L) 10 L was added to each well, and incubation was continued for 4 h. After centrifugation, the supernatant was gently aspirated, DMSO 100 L was added, and the absorbance at 570 nm was measured by a microplate reader.

1.2 Test results

Glycosides vanilla sour grapes on ConA-induced proliferation of T lymphocytes pi in mice significantly inhibited, the inhibition rate at a concentration 1X10- ^9, 1X10- ⁶ and 1X10- ⁵ mol / L, respectively 71%, 48% and 57% (p<0.05, see Table 1 and Figure 1). Proliferation glycosides vanilla sour grapes on LPS induced mouse B lymphocytes askance also has a certain extent, 1X10 - 1X10- ⁷ mol / 24% -29% inhibition (see Table 2 and FIG. 1) at a concentration of L. Table 1 Effect of vanillic acid glucoside on CoA-induced proliferation of mouse spleen T-lymphocytes Group A570nm (Mean+SD, n=6) Inhibition rate % Control group 0.840±0.214

10" ¹⁰ M group 0.803 ± 0 · 250 4.5

10" ⁹ M group 0.244 ± 0 · 145 *** 70.9

10" ⁸ M group 0.783 ± 0 · 156 6.8

10" ⁷ M group 0.687 ± 0 · 272 18.3

10" ⁶ M group 0.438 ± 0 · 353 47.8

10" ⁵ M group 0.362 ± 0 · 153 ** 57.0

(**ρ<0· 01, ***ρ<0· 001 vs. control group) Table 2 Effect of vanillic acid glucoside on LPS-induced proliferation of mouse spleen B-lymphocytes Group A570nm (Mean+SD, η=6) Inhibition rate % Control group 0.420 ±0.093

10" ¹⁰ M group 0.319 ± 0 · 103 24.0

10" ⁹ M group 0.313 ± 0 · 126 25.4

10" ⁸ M group 0.316 ± 0.140 24.7 10" ⁷ M group 0 · 297 ± 0 · 071 * 29.3

10" ⁶ M group 0.380 ± 0.150 9.6

(*p<0.05 vs control group) Example 2. Vanillic acid glucoside has a significant inhibitory effect on delayed hypersensitivity in mice 2.1 Materials and methods

Balb/c mice, male, 18-20 g, purchased from the Experimental Animal Center of the Chinese Academy of Medical Sciences. Randomly grouped, 3 in each group, and began to experiment after one week of adaptive feeding. Sensitized mBSA (Sigma) plus normal saline for injection to 5 mg/mL, fully emulsified with an equal volume of Freund's complete adjuvant (CFA, Sigma). In addition to the normal control group, each mouse was intradermally injected with an emulsifier of 100 μl. On the 5th day after administration of sensitization, daily intragastric administration was carried out, 0.2 ml/10 g body weight, for 3 consecutive times. Normal and model control groups were given distilled water, test drug vanillic acid glucoside 1.1, 3.3, 10, 20 mg / Kg body weight 4 dose groups, positive drug indomethacin 3.3, 10 mg / Kg body weight 2 dose groups. Two hours after the last administration, the mice were injected intradermally with 25 μl of normal saline and intradermally injected with mBSA (5 mg/mL) 25 μl. After 24 hr, the animals were sacrificed by neck dissection, and the left and right lower limbs were weighed to calculate the degree of swelling (m _g /10 _g body weight) and swelling inhibition rate. At the same time, the thymus and spleen were weighed and the organ index was calculated.

2.2 Test results mBSA re-attacks sensitized mice can cause obvious delayed hypersensitivity reaction. Indomethacin (3.3, 10mg/Kg) and vanillic acid glucoside (3.3mg/Kg) have obvious inhibitory effects, inhibition The rates are 34.6, 66.6 and 48.0%, respectively. Indomethacin significantly increased the spleen index of mice, while vanillin glucoside had no significant effect on the thymus and spleen index of mice. See Table 3 for details.

Table 3 Effect of vanillic acid glucoside on delayed hypersensitivity in mice

Swelling degree (mg/10g) swelling inhibition rate thymus index (mg/10g) spleen index (mg/lOg) group

(Mean Shi SD, n=3) (%) (Mean Shi SD, n=3) (Mean Shi SD, n=3) Normal control group 5.4±3· 0 20.7±3· 3 43.7±4· 3 Model control Group 31.8±3· 2 19.2±0· 7 46.5±4· 5 Indomethacin 3.3mg/Kg 20.8±7· 1 * 34.6 15.3±3· 9 55.4±1· 5 * Indomethacin 10. Omg/Kg 10.6±4· 4 ** 66.6 18.5±1· 9 69.1±7· 9 * Vanillic acid glucoside

28.2±14· 7 11.2 20.5±4· 9 45.1±4· 7 1. lmg/Kg

Vanillic acid glucoside

16.5±6· 3 * 48.0 18.7±1· 1 51.2±1· 5 3.3mg/Kg

Vanillic acid glucoside

23.9±4· 8 24.9 17.2±1· 3 52.4±8· 0 10. Omg/Kg

Vanillic acid glucoside

29.4±4· 7 7.5 18.1±4· 5 45.5±5· 0 20. Omg/Kg

(*ρ<0.05, **ρ<0.01 vs model control group)

Example 3. Effect of vanillic acid glucoside on active DNA-induced systemic lupus erythematosus-like mice antibody level and renal tissue damage

3.1 Materials and methods

Spleen lymphocyte activation and genomic DNA extraction BALB /c mice were sacrificed, spleen was aseptically prepared, spleen cell suspension was routinely prepared, trypan blue count (survival rate > 95%), adjusted with RPMI 1640-20% fetal bovine serum The cells were 2X107L, and Con A was added to a final concentration of 3 mg/L. Each bottle of 20 mL was added to the culture flask, and cultured at 37 ° C in a 5% CO 2 incubator. After 48 hours, the cells were removed and centrifuged to collect activated cells. The animal DNA genomic DNA rapid extraction kit (Beijing Boda Tektronix Biogene Technology Co., Ltd.) was used to prepare the active DNA according to the kit procedure. Establishment of a systemic lupus erythematosus-like mouse model in BALB/c mice, 6wk, female. The mice were randomly divided into groups of 6 rats, the model group and the drug group were immunized, and the blank group was not treated. The immunization procedure was: intradermal multiple injection, once every 2 weeks, each time 0. lmg / 0.2mL, a total of 3 times. For the first immunization, the dry powder of DNA was added to physiological saline to 2 mg/mL, and it was fully emulsified with an equal volume of Freund's complete adjuvant and injected. The second immunization with DNA and Freund's incomplete adjuvant emulsifier; the third immunization is a DNA suspension. Blood sputum was taken during sensitization to detect serum anti-ds-DNA antibody levels. On the 8th day after the third immunization, the daily intragastric administration was started, 0.2 mL/10 g body weight, a total of 15 times. The doses administered were vanillic acid glucosides 1.1, 3.3 and 10!^/13⁄4 body weight; the positive control drug prednisolone acetate 5 mg/ _{kg; the} model group and the normal control group were given purified water. After the last administration, the animals were sacrificed by eyeball extraction; the serum test antibody was taken; the thymus, spleen and liver were weighed to calculate the organ index; the kidney was fixed with 4% formaldehyde solution for pathological examination. Anti-ds-DNA antibody detection 96-well microtiter plate (C0STAR), 100 μL of squid dsDNA (Sigma, 50 mg/L) per well was coated at 4 °C overnight, PBS-0.5% Tw _een 20 wash plate, 2 mg /mL BSA-PBS adsorption, after washing the plate, add 100 μL of diluted serum, using goats - Anti-mouse IgG-HRP (eBioscience) and enzyme-linked immunosorbent assay (ELISA) kits (Wuhan Dr.) were used to determine the 450 nm 0D value (Labelters, Labsystems) according to the kit protocol. Renal histopathology The kidneys of the mice were fixed with 4% formaldehyde solution, 5 μ πι paraffin sections, and routinely sectioned. 1) HE staining, routine histopathological examination; 2) Using goat-anti-mouse IgG-FITC (eBioscience), fluorescein examination of renal tissue IgG immune complexes, blind pathology score: 0 = substantially no fluorescence; 1 = Focal glomerular mild fluorescence; 2 = - a certain number of glomerular light moderate fluorescence, renal tubular light moderate fluorescence; 3 = a large number of glomeruli, renal tubules, invasive inflammation cells intensity fluorescence; 4 = The glomerulus is strongly fluorescent in a large area, and the fluorescence shows diffuse glomerular and tubular necrosis.

3. 2 test results

(1) On the 7th day after the third immunization, the serum anti-ds-DNA antibody levels of all immunized mice were significantly higher than those of the blank control group, indicating successful modeling.

(2) 15 days after the administration, 1.1, 3.3, and 10m _{_g} / K _g body weight of mouse serum anti vanilla sour grapes ds_DNA antibody levels glycoside administered group were 0. 368 ± 0. 047, 0. 303 ± 0. 060, 0. 328 ±0. 053 (0D) , which is significantly lower than the model group 0. 445 ±0. 110 ( p=0. 149, p<0.05 and p<0.05, n=6 , Table 4). Table 4 Effect of vanillic acid glucoside on serum anti-ds-DNA antibody in SLE syndrome-like mice

(*p<0. 05, **p<0. 01 vs model control group)

(3) The results of routine pathological examination of HE showed that the model group had diffuse injury of kidney tissue, glomerular lesions, and lupus nephritis (Fig. 2 A2, A3); vanillic acid glucoside (1. 1, 3. 3 And 10m _g /K _g body weight) and prednisolone (5mg/K _g Body weight) 15 days of administration, can improve the pathological damage of lupus nephritis to varying degrees (Figure 2 Bl-3

(4) Fluorescence examination of renal tissue IgG immune complexes showed that the immunohistochemical score of renal tissue in the model group was 3.2±0.9 (n=6), and the three vanillic acid glucoside administration groups (1.1, 3.3 and The scores of 10m _g /K _g body weight were 1.6±0.7 (n=6), 2.5±0.8 (n=6), 2.8 ± 1.1 (n=2), which decreased compared with the model group. 1. The lmg/Kg dose group improved significantly (p<0.01, Table 5, Figure 3). Table 5 Effect of vanillic acid glucoside on renal tissue immune complex deposition in SLE syndrome-like mice

(**ρ<0·01 vs model control group) The above results indicate that vanillic acid glucoside can significantly reduce serum anti-ds-DNA antibody levels in active DNA-induced systemic lupus erythematosus-like mice, and reduce IgG immune complexes. Deposition in kidney tissue and damage to kidney tissue. In summary, vanillic acid glucoside can significantly inhibit the proliferation of mouse spleen T and sputum lymphocytes in vitro, significantly inhibit the occurrence of delayed hypersensitivity in mice, and can significantly reduce active DNA-induced systemic lupus erythematosus. Syndrome-like mice serum anti-ds-DNA antibody levels reduce the deposition of IgG immune complexes in renal tissue and renal tissue damage. Vanillic acid Glucosin can be used as a new immunosuppressant for the treatment of autoimmune diseases such as systemic lupus erythematosus.

Example 4. Synthesis of vanillic acid glucoside methyl ester 4.1 synthetic route

4.2 Experimental part

In a 100 ml three-necked flask, 20 mL of anhydrous methanol was added, and the mixture was cooled to _15 ° C in an ice salt bath, and 5.2 mL of thionyl chloride was slowly added dropwise. After the dropwise addition was completed, the reaction was further stirred at -15 ° C for 30 minutes. Then, 6.60 g (20 mmol) of 3-methoxy-4-glucosyl-benzoic acid (hydrogluconate) was added to a three-necked flask, and the reaction was stirred at room temperature for three days. Methanol was evaporated under reduced pressure to give a white solid (·························

Structural confirmation: 1) 3⁄4 丽 δ 2.0 (4Η, -OH), δ 3.41 (1Η, - CH- ), δ 3.47 (1H, _CH -), δ 3.76 (1Η, -CH-) , δ 3.89 (1Η, - CH- ) , δ 5.76 (1Η, - CH- ) , δ 3.47, 3.68 (2Η, - CH ₂ - ) , δ 3.73 (3Η, - CH ₃ 0- ) δ 3.91 (3Η, -C00CH ₃ ) , δ 6.78 (1Η, -ArH) , δ 7.27 (1Η, -ArH) , 7.45 (1Η, -ArH) ; 2) ESI -MS: [M+H]+ 344.8

Example 5 Vanguard glucoside methyl ester has obvious inhibitory effect on the proliferation of mouse spleen T lymphocytes in vitro 5.1 Materials and methods

In the same manner as in Example 1.1, 120 L of acidified isopropanol was added to the MTT color, and the absorption value at 492 nm was measured by a microplate reader. 5.2 Test results

Methyl glycosides vanilla sour grapes on ConA-induced proliferation of mouse T lymphocytes pi significantly inhibited, 1X10- ^12, 1X10- ¹¹ and 1X10- 1 inhibition rate ^(W) 1 / L a concentration of 36%, 26% and 13% (ρ<0· 05, see Table 6).

Proliferation vanilla sour grapes methyl glucoside ^{^{(1X10- 13 _ 1X10- 6 mol /}} L concentration) on LPS induced mouse B lymphocytes askance no significant effect (data not shown). Table 6 Effect of vanguard glucoside methyl ester on CoA-induced proliferation of mouse spleen T-lymphocytes

( *ρ<0. 05, **ρ<0. 01, ***ρ<0. 001 vs. control) Example 6 Vanillyl glucoside methyl ester has an inhibitory effect on delayed hypersensitivity in mice

6. 1 Materials and methods

Same embodiment 2. Part 1

6. 2 Test results Compared with the model control group, vanillic acid glucoside methyl ester (0. 04, 0.2, 1.0, 3. Omg / Kg body weight) has a certain degree of delayed hypersensitivity in mice. Inhibition (inhibition rate 20-30%) had no significant effect on mouse thymus and spleen index (Table 7). Table 7 Effect of vanguard glucoside methyl ester on delayed hypersensitivity in mice

Swelling degree (mg/10g) Swelling inhibition rate Thymus index (mg/10g) Spleen index (mg/10g) Group

(Mean Shi SD, n=3) (%) (Mean Shi SD, n=3) (Mean Shi SD, n=3) Model control group 40.6±8·7 18.1±7·0 65.7±4·6 Vanillic acid Glucoside methyl ester

32.4±5· 4 20.2 22.5±3· 0 58.9±1· 1

0.04mg/Kg

Vanillic acid glucoside methyl ester

32.4±8· 9 20.2 21.4±0· 4 58.4±12· 5 0.2mg/Kg

Vanillic acid glucoside methyl ester

31.6±1· 7 22.1 19.1±2· 6 64.3 ±19· 9 1. Omg/Kg

Vanillic acid glucoside methyl ester

28.0±10.0 31.1 17.6±3· 8 63.0±13· 6 3. Omg/Kg

Claims

Rights request

1. The use of a vanillin derivative as shown in formula (I) for the preparation of a medicament for the treatment of systemic autoimmune diseases;

(I)

Its towel:

Ri is selected from H, CH ₃ , CH ₂ CH ₃ or M, and M is selected from alkali metal or alkaline earth metal;

R ₂ is H, a C1-6 alkyl group; a C1-6 alkyl substituted acyl group;

2. Use according to claim 1, characterized in that the alkali metal is selected from Li, 1^ or .

3. Use according to claim 1, characterized in that the alkaline earth metal is selected from the group consisting of Mg, Ca or Ba.

4. The use according to claim 1, characterized in that, C1-6 alkyl group is selected from the _{_{_{CH 3, CH 2 CH 3,}}} CH 2 CH 2 CH:

5. Use according to claim 1, wherein said acyl group selected from a C1-6 alkyl group COCH _3, COCH ₂ CH:

: Glucoside vanillic acid galactoside

Vanillic acid rhamnoside. The use of any one of claims 1 to 6, wherein the systemic autoimmune disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, dry mouth syndrome, multiple muscles inflammation.