Hydroxyprolyl-serine compounds, their preparation and use

Abstract

The application belongs to the technical field of medicine, and relates to a hydroxyprolyl-serine compound and a preparation method thereof, and further relates to a pharmaceutical composition containing the compound and application of the compound in treating dry eye syndrome. The application provides a hydroxyprolyl-serine compound in different stereoisomer forms, a preparation method of the hydroxyprolyl-serine compound, a pharmaceutical composition containing the hydroxyprolyl-serine compound, and application of the hydroxyprolyl-serine compound in different stereoisomer forms in preparing a DED treatment drug. The structure of the hydroxyprolyl-serine compound or a salt thereof is as follows.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a hydroxyprolyl-serine compound and a preparation method thereof, and further relates to a pharmaceutical composition containing the compound and application of the compound in treating dry eye. BACKGROUND

[0002] Dry eye disease (DED) is a common ocular surface disease, and the main pathological mechanisms include tear film instability, increased tear osmotic pressure, ocular surface inflammation and damage, and abnormal nerve sensation. The main clinical manifestations are ocular dryness, foreign body sensation, blurred vision and the like, and severe dry eye disease can lead to corneal ulcer and even blindness. At present, dry eye disease is classified into tear deficiency type, lipid abnormality type, mucin abnormality type, tear dynamics abnormality type and mixed type dry eye disease according to the main component or functional abnormality of the tear.

[0003] At present, the main treatment methods for dry eye disease in China are drug therapy and surgical treatment. The commonly used clinical treatment drugs mainly include artificial tear and immunosuppressant, such as sodium hyaluronate eye drops, glucocorticoid eye drops and cyclosporine eye drops. For mild dry eye disease, the treatment effect of artificial tears is good; for moderate dry eye disease, surgical treatment (such as punctal plug embolization and tarsorrhaphy) or local application of immunosuppressant eye drops is adopted for enhanced treatment; for severe dry eye disease, systemic anti-inflammatory or immunosuppressant drug treatment is often required. However, the existing various treatment drugs and methods have some disadvantages: artificial tears can only temporarily relieve the symptoms of ocular discomfort and cannot cure the disease; long-term use of immunosuppressant drugs can produce serious side effects, such as systemic immunosuppression; surgical treatment is traumatic and the postoperative effect is uncertain, and therefore cannot be widely applied in clinical practice. Therefore, it is necessary to develop a safe and effective drug for treating dry eye disease.

[0004] Anti-L-hydroxyprolyl-L-serine is a dipeptide isolated from an anti-hepatitis drug injection, has three chiral carbon atoms, and exists in eight stereoisomers. According to the literature, anti-L-hydroxyprolyl-L-serine has the potential to treat autoimmune hepatitis, and the mechanism of action is as follows: (1) enhancing the free radical scavenging capacity of liver tissue, inhibiting the lipid peroxidation damage of hepatocytes; (2) reducing the aggregation of inflammatory cells in the inflammation and tissue damage area; (3) inhibiting the release of inflammatory cytokines. At present, there is no report on the use of anti-L-hydroxyprolyl-L-serine for treating DED.

[0005] In recent years, the research of chiral drugs has become a hot spot in the development of new drugs. Anti-L-hydroxyprolyl-L-serine is composed of two amino acids, anti-L-hydroxyproline and L-serine, in which hydroxyproline has two chiral carbon atoms and serine has one chiral carbon atom. The stereochemical configuration of chiral drugs is closely related to the drug efficacy, and it is particularly important to study the pharmacodynamic differences between the enantiomers of chiral drugs. Therefore, investigating the relationship between anti-L-hydroxyprolyl-L-serine, its stereoisomers and the efficacy of DED can lay a foundation for the development of safe and efficient DED treatment drugs. SUMMARY

[0006] In view of the defects of the prior art, the present application provides hydroxyprolyl-serine compounds with different stereochemical configurations, preparation methods thereof and pharmaceutical compositions containing the compounds, and the use of the hydroxyprolyl-serine compounds with different stereochemical configurations in the preparation of DED treatment drugs.

[0007] The present application is realized by the following technical solutions:

[0008] The present application first provides a hydroxyprolyl-serine compound or a salt thereof having the following structure:

[0009]

[0010] The present application further provides a hydroxyprolyl-serine compound or a salt thereof having the following structure:

[0011]

[0012] The present application also provides a preparation method of the hydroxyprolyl-serine compound:

[0013] The preparation method of the hydroxyprolyl-serine compound comprises the following steps:

[0014] First step: dissolve compound I, compound II and N,N'-dicyclohexyl carbodiimide (DCC) in a reaction solvent, fill with nitrogen, react at 25-30℃, rotary evaporation, and obtain compound III, the molar ratio of compound I and compound II being 0.1-10:1.

[0015] Second step: dissolve compound III and compound IV in a reaction solvent containing N,N-diisopropyl ethylamine (DIPEA), react at 25-30℃ for 2-24h, and obtain compound V; the molar ratio of compound III and compound IV being 0.1-10:1.

[0016] Third step: dissolve compound V in different acids to obtain the target compound M.

[0017] The reaction solvent in the first step is one or more of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylacetamide, or a combination of two or more thereof.

[0018] The reaction solvent in the second step is one or more of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylacetamide, or a combination of two or more thereof.

[0019] The acid in the third step is one or more of hydrochloric acid, acetic acid, formic acid, maleic acid, lactic acid, carbonic acid, trifluoroacetic acid, phosphoric acid, p-toluenesulfonic acid, or a combination of two or more thereof.

[0020] The synthetic route is as follows:

[0021]

[0022] The reaction solvent in the first step is one or more of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylacetamide, or a combination of two or more thereof. The reaction solvent in the first step is one or more of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylacetamide, or a combination of two or more thereof.

[0023] The reaction solvent in the first step is one or more of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylacetamide, or a combination of two or more thereof. The reaction solvent in the first step is one or more of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylacetamide, or a combination of two or more thereof. The reaction solvent in the first step is one or more of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylacetamide, or a combination of two or more thereof. The reaction solvent in the first step is one or more of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylacetamide, or a combination of two or more thereof.

[0024] a: N,N'-dicyclohexyl carbodiimide (DCC), reaction solvent (dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylacetamide);

[0025] b: N,N-diisopropyl ethylamine (DIPEA), reaction solvent (dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylacetamide);

[0026] c: acid: hydrochloric acid, acetic acid, formic acid, maleic acid, lactic acid, carbonic acid, trifluoroacetic acid, phosphoric acid, p-toluenesulfonic acid.

[0027] According to the different configurations of the reactants, one of the following compounds is obtained: (A) trans-4-L-hydroxyprolyl-L-serine, (B) trans-4-L-hydroxyprolyl-D-serine, (C) trans-4-D-hydroxyprolyl-L-serine, (D) trans-4-D-hydroxyprolyl-D-serine, (E) cis-4-L-hydroxyprolyl-L-serine, (F) cis-4-L-hydroxyprolyl-D-serine, (G) cis-4-D-hydroxyprolyl-L-serine, (H) cis-4-D-hydroxyprolyl-D-serine, as shown in the following schemes:

[0028]

[0029] The application further provides a pharmaceutical composition comprising the hydroxyprolyl-serine compound or salt thereof and a pharmaceutically acceptable carrier or excipient.

[0030] The application provides use of the hydroxyprolyl-serine compound or salt thereof in the preparation of a drug for treating dry eye.

[0031] The application further provides use of the pharmaceutical composition in the preparation of a drug for treating dry eye.

[0032] The application has the following beneficial effects: based on the fact that hydroxyproline has two chiral carbon atoms and serine has one chiral carbon atom, due to the stereoselectivity difference in the interaction between chiral drugs and the body, the stereoisomer of the chiral drug is closely related to pharmacodynamics. The application reacts four different compounds III with two different compounds IV to form eight different hydroxyprolyl-serine compounds, and investigates the effects of different enantiomers on DED. In the benzalkonium chloride (BAC)-induced dry eye model of rats, the eight different hydroxyprolyl-serine compounds have different effects on DED. Among them, the treatment effect of the compound of Example 1 and the compound of Example 8 is the best, that is, it can significantly improve the dry eye symptoms, increase the tear secretion of rats, and reduce the corneal fluorescein staining score, thereby achieving good therapeutic effect and providing the possibility for effective treatment of DED. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 It is a single crystal X-ray diffraction characterization diagram of the compound of Example 1.

[0034] Figure 2 It is a drug administration scheme diagram of the compounds of Examples 1-8.

[0035] Figure 3 It is a comparison diagram of tear secretion of DED rats treated with the compounds of Examples 1-8 on the 14th day of the experiment (7 days after treatment).

[0036] Figure 4 It is a diagram of the corneal fluorescein sodium staining score of DED rats treated with the compounds of Examples 1-8 on the 14th day of the experiment (7 days after treatment).

[0037] Figure 5 It is a diagram of the microscopic observation of the corneal fluorescein sodium staining of DED rats treated with the compounds of Examples 1-8 on the 14th day of the experiment (7 days after treatment): (A) normal control group; (B) model group; (C) diquafosol sodium group; (D-K) Example 1-8 compound group. DETAILED DESCRIPTION

[0038] Example 1: Preparation of trans-4-L-hydroxyprolyl-L-serine (compound A):

[0039]

[0040] First step: Compound I-1, compound II, N,N'-dicyclohexyl carbodiimide (DCC) were dissolved in tetrahydrofuran, filled with nitrogen, reacted at 25°C for 2h, rotary evaporation, to obtain compound III-1;

[0041] Second step: Compound III-1 was dissolved in dichloromethane containing N,N-diisopropyl ethylamine (DIPEA), reacted at 25°C for 2h, the solvent was evaporated under reduced pressure, the residue was diluted with dichloromethane, washed with 5% aqueous phosphoric acid solution, water solution, saturated brine solution in turn, suction filtered, the filtrate was mixed with silica gel, and column chromatography was performed on silica gel with dichloromethane and methanol (100:1-1:100) gradient elution, the column chromatography product was collected and concentrated to obtain compound V-1;

[0042] Third step: Compound V-1 was dissolved in hydrochloric acid, suction filtered, washed, and freeze-dried to obtain compound A (trans-4-L-hydroxyprolyl-L-serine).

[0043] Example 2: Preparation of trans-4-L-hydroxyprolyl-D-serine (compound B):

[0044]

[0045] First step: Compound I-1, compound II, N,N'-dicyclohexyl carbodiimide (DCC) were dissolved in tetrahydrofuran, filled with nitrogen, reacted at 25°C for 2h, rotary evaporation, to obtain compound III-1;

[0046] Second step: Compound III-1 was dissolved in dichloromethane containing N,N-diisopropyl ethylamine (DIPEA), reacted at 25°C for 2h, the solvent was evaporated under reduced pressure, the residue was diluted with dichloromethane, washed with 5% aqueous phosphoric acid solution, water solution, saturated brine solution in turn, suction filtered, the filtrate was mixed with silica gel, and column chromatography was performed on silica gel with dichloromethane and methanol (100:1-1:100) gradient elution, the column chromatography product was collected and concentrated to obtain compound V-1;

[0047] Third step: Compound V-2 was dissolved in hydrochloric acid, suction filtered, washed, and freeze-dried to obtain compound B (trans-4-L-hydroxyprolyl-D-serine).

[0048] Example 3: Preparation of trans-4-D-hydroxyprolyl-L-serine (compound C):

[0049]

[0050] First step: Compound I-2, compound II, N,N'-dicyclohexyl carbodiimide (DCC) were dissolved in tetrahydrofuran, filled with nitrogen, reacted at 25°C for 2h, rotary evaporation, to obtain compound III-2;

[0051] Second step: Compound III-2 was dissolved in dichloromethane containing N,N-diisopropyl ethylamine (DIPEA), reacted at 25°C for 2h, the solvent was evaporated under reduced pressure, the residue was diluted with dichloromethane, washed with 5% phosphoric acid aqueous solution, water solution, saturated brine solution in turn, suction filtered, the filtrate was mixed with silica gel, chromatographed on silica gel column, eluted with dichloromethane and methanol (100:1-1:100) gradient, the column chromatography was collected, concentrated, to obtain compound V-3;

[0052] Third step: Compound V-3 was dissolved in hydrochloric acid, suction filtered, washed, freeze-dried to obtain compound C (trans-4-D-hydroxyprolyl-L-serine).

[0053] Example 4: Preparation of trans-4-D-hydroxyprolyl-D-serine (compound D):

[0054]

[0055] First step: Compound I-2, compound II, N,N'-dicyclohexyl carbodiimide (DCC) were dissolved in tetrahydrofuran, filled with nitrogen, reacted at 25°C for 2h, rotary evaporation, to obtain compound III-2;

[0056] Second step: Compound III-2 was dissolved in dichloromethane containing N,N-diisopropyl ethylamine (DIPEA), reacted at 25°C for 2h, the solvent was evaporated under reduced pressure, the residue was diluted with dichloromethane, washed with 5% phosphoric acid aqueous solution, water solution, saturated brine solution in turn, suction filtered, the filtrate was mixed with silica gel, chromatographed on silica gel column, eluted with dichloromethane and methanol (100:1-1:100) gradient, the column chromatography was collected, concentrated, to obtain compound V-4;

[0057] Third step: Compound V-4 was dissolved in hydrochloric acid, suction filtered, washed, freeze-dried to obtain compound D (trans-4-D-hydroxyprolyl-D-serine).

[0058] Example 5: Preparation of cis-4-L-hydroxyprolyl-L-serine (compound E):

[0059]

[0060] First step: Compound I-3, compound II, N,N'-dicyclohexyl carbodiimide (DCC) were dissolved in tetrahydrofuran, filled with nitrogen, reacted at 25°C for 2h, rotary evaporation, to obtain compound III-3;

[0061] Second step: Compound III-3 was dissolved in dichloromethane containing N,N- diisopropylethylamine (DIPEA), and reacted at 25°C for 2h. The solvent was evaporated under reduced pressure, and the residue was diluted with dichloromethane, washed with 5% phosphoric acid aqueous solution, water, and saturated brine in sequence, filtered, and the filtrate was mixed with silica gel and subjected to silica gel column chromatography with dichloromethane and methanol (100:1-1:100) as eluent in gradient mode. The column chromatography product was collected and concentrated to obtain compound V-5.

[0062] Third step: Compound V-5 was dissolved in hydrochloric acid, filtered, washed, and freeze-dried to obtain compound E (cis-4-L-hydroxyprolyl-L-serine).

[0063] Example 6: Preparation of cis-4-L-hydroxyprolyl-D-serine (compound F):

[0064]

[0065] First step: Compound I-3, compound II, and N,N'-dicyclohexylcarbodiimide (DCC) were dissolved in tetrahydrofuran, and nitrogen was filled in. The mixture was reacted at 25°C for 2h, and rotary evaporation was performed to obtain compound III-3.

[0066] Second step: Compound III-3 was dissolved in dichloromethane containing N,N- diisopropylethylamine (DIPEA), and reacted at 25°C for 2h. The solvent was evaporated under reduced pressure, and the residue was diluted with dichloromethane, washed with 5% phosphoric acid aqueous solution, water, and saturated brine in sequence, filtered, and the filtrate was mixed with silica gel and subjected to silica gel column chromatography with dichloromethane and methanol (100:1-1:100) as eluent in gradient mode. The column chromatography product was collected and concentrated to obtain compound V-5.

[0067] Third step: Compound V-6 was dissolved in hydrochloric acid, filtered, washed, and freeze-dried to obtain compound F (cis-4-L-hydroxyprolyl-D-serine).

[0068] Example 7: Preparation of cis-4-D-hydroxyprolyl-L-serine (compound G):

[0069]

[0070] First step: Compound I-4, compound II, and N,N'-dicyclohexylcarbodiimide (DCC) were dissolved in tetrahydrofuran, and nitrogen was filled in. The mixture was reacted at 25°C for 2h, and rotary evaporation was performed to obtain compound III-4.

[0071] Second step: compound III-4 was dissolved in dichloromethane containing N,N- diisopropylethylamine (DIPEA), and reacted at 25°C for 2h. The solvent was evaporated under reduced pressure, and the residue was diluted with dichloromethane, washed with 5% phosphoric acid aqueous solution, water, and saturated brine in sequence, filtered, and the filtrate was mixed with silica gel, and chromatographed on a silica gel column with dichloromethane and methanol (100:1-1:100) as eluents in gradient mode. The column chromatography product was collected, concentrated, and compound V-7 was obtained.

[0072] Third step: compound V-7 was dissolved in hydrochloric acid, filtered, washed, and freeze-dried to obtain compound G (cis-4-D-hydroxyprolyl-L-serine).

[0073] Example 8: cis-4-D-hydroxyprolyl-D-serine (compound H):

[0074]

[0075] First step: compound I-4, compound II, and N,N'-dicyclohexylcarbodiimide (DCC) were dissolved in tetrahydrofuran, and nitrogen was filled in, and reacted at 25°C for 2h. The product was obtained by rotary evaporation.

[0076] Second step: compound III-4 was dissolved in dichloromethane containing N,N- diisopropylethylamine (DIPEA), and reacted at 25°C for 2h. The solvent was evaporated under reduced pressure, and the residue was diluted with dichloromethane, washed with 5% phosphoric acid aqueous solution, water, and saturated brine in sequence, filtered, and the filtrate was mixed with silica gel, and chromatographed on a silica gel column with dichloromethane and methanol (100:1-1:100) as eluents in gradient mode. The column chromatography product was collected, concentrated, and compound V-7 was obtained.

[0077] Third step: compound V-8 was dissolved in hydrochloric acid, filtered, washed, and freeze-dried to obtain compound H (cis-4-D-hydroxyprolyl-D-serine).

[0078] The identification information of the compounds in Examples 1-8 is shown in Table 1:

[0079] Table 1. Related information of the compounds in Examples 1-8

[0080]

[0081]

[0082] Example 9: in vivo pharmacodynamic study of SD rats

[0083] Dosing regimen

[0084] With healthy SD rats as model animals, 55 male SD rats with no abnormality on the surface of the eye were randomly divided into 11 groups, 5 rats (10 eyes) in each group, namely: normal control group, model group, positive drug diquafos sodium group, compound of Example 1 group, compound of Example 2 group, compound of Example 3 group, compound of Example 4 group, compound of Example 5 group, compound of Example 6 group, compound of Example 7 group, and compound of Example 8 group.

[0085] The normal control group of rats was not treated, and the remaining 10 groups of rats were eye-dropped with 0.3% benzalkonium chloride (BAC) solution prepared by PBS, 10 μl per eye each time, 2 times a day (9 am, 9 pm), for 14 days, to establish a rat dry eye model.

[0086] The administration scheme was as follows: the positive drug diquafos sodium eye drops, and the solutions (1 mg / ml) of the compounds of Examples 1-8 were eye-dropped according to their groups, 10 μl per eye each time, 4 times a day (11 a.m., 1 p.m., 5 p.m., 7 p.m.), and the administration was started after 7 days of modeling, and lasted for 7 days. The normal control group was not eye-dropped, and the model group was replaced with the same amount of normal saline. The administration scheme is shown in Figure 2 .

[0087] Detection index and method

[0088] Schirmer I test

[0089] Tear secretion detection was performed on the 0th, 7th, and 14th days of the experiment. The lower fornix of the rat was gently pulled, and one end of the phenol red cotton thread, about 1 mm, was folded and placed in the lower fornix at about one-third of the outer corner of the rat. After 1 min, the cotton thread was taken out, and the cornea was not touched during the placement process. The length of the red part of the cotton thread was recorded as the result of the basic tear secretion test (mm). After the dry eye model was successfully established, the amount of basic tear secretion was reduced.

[0090] Corneal fluorescein sodium staining score

[0091] After the Schirmer I test, 8 μl of 1% fluorescein sodium solution was dropped into the conjunctival sac of the rat, and the rat was artificially blinked gently. After 10 min, the excess dye was washed off with sterile normal saline. The head of the rat was placed under a slit lamp microscope, the upper and lower eyelids were separated, and the rat was maintained in an open state. The rat was observed and photographed under a 25X slit lamp cobalt blue light, and evaluated according to the following scoring system: the cornea was divided into 4 quadrants, and the staining degree of each quadrant was scored from 0 to 3 points, with a total score of 0 to 12 points. Dry eye can cause damage to the corneal epithelium, even secondary to keratitis and corneal ulceration. After fluorescein sodium staining, the yellow-green color will appear in the area of the damaged corneal epithelium, and the corresponding corneal fluorescein sodium staining score will be higher.

[0092] Table 2. Corneal fluorescein sodium staining score

[0093]

[0094] Statistical processing

[0095] The data were processed by GraphPad Prism 8.0, and the data analysis was performed by independent sample t test. The results are shown in Figure 3 and Figure 4 , wherein ### indicates p < 0.005 compared with the normal control group; * indicates p < 0.05 compared with the model group; ** indicates p < 0.01 compared with the model group; and *** indicates p < 0.005 compared with the model group.

[0096] Results

[0097] Table 3. Therapeutic effects of compounds of Examples 1-8 on DED rats

[0098]

[0099]

[0100] Conclusion

[0101] From the results of the above charts, it can be seen that the therapeutic effects of the compounds of Examples 1-8 are different. The results of the basic tear secretion test Figure 3 show that the tear secretion amount is increased to different degrees after treatment with each compound, especially, the tear secretion amount of the compound of Example 1 is closest to the result of the normal group after treatment with the compound, and the tear secretion amount of the compound of Example 8 is not different from the result of the positive control group, and is significantly increased compared with the model group, indicating that they all have the effect of increasing tear secretion; the corneal fluorescein sodium staining score chart Figure 4 and the microscopic observation chart Figure 5 show that the corneal staining of the compound of Example 1 is basically invisible after treatment with the drug, which is equivalent to the results of the positive control group and the normal group, and the compound of Example 8 shows small area of corneal staining (the staining positive in the chart is the bright white area of the cornea), both of which can significantly reduce the corneal fluorescein staining score, and have significant difference compared with the results of the model group. The final results show that: compared with the model group, each compound has the effect of improving the symptoms of dry eye and increasing the tear secretion amount. Especially, the compounds of Example 1 and Example 8 have the best therapeutic effect, which can significantly improve the symptoms of dry eye, increase the tear secretion amount, and reduce the corneal fluorescein staining score, providing the possibility for the clinical treatment of DED.

Claims

1. Use of a hydroxyprolyl-serine compound or a salt thereof in the preparation of a medicament for treating dry eye syndrome, wherein the hydroxyprolyl-serine compound or a salt thereof is prepared by the following method: Step 1: dissolving compound I, compound II and N,N'-dicyclohexylcarbodiimide in a reaction solvent, charging nitrogen, reacting, rotary evaporation to obtain compound III; Step 2: dissolving compound III and compound IV in a reaction solvent containing N,N-diisopropyl ethylamine, reacting to obtain compound V; Step 3: dissolving compound V in an acid to obtain M; wherein, the reaction solvent in Step 1 or Step 2 is dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylacetamide; the acid in Step 3 is hydrochloric acid, acetic acid, formic acid, maleic acid, lactic acid, carbonic acid, trifluoroacetic acid, phosphoric acid, p-toluenesulfonic acid; in Step 1, the molar ratio of compound I and compound II is 0.1-10:1; in Step 2, the molar ratio of compound III and compound IV is 0.1-10:1; one or more of the hydroxyprolyl-serine compound or a salt thereof and a pharmaceutically acceptable carrier or excipient are prepared into a pharmaceutical composition. 。 2. Use according to claim 1, characterized in that:

2. The hydroxyprolyl-serine compound or a salt thereof according to claim 1, wherein the compound is: ###0001### ###0002### ###0003### ###0004### ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### ###0066### ###0067### ###0068### ###0069### ###0070### ###0071### ###0072### ###0073### ###0074### ###0075### ###0076### ###0077### ###0078### ###0079### ###0080### ###0081### ###0082### ###0083### ###0084### ###0085### ###0086### ###0087### ###0088### ###0089### ###0090### ###0091### ###0092### ###0093### ###0094### ###0095### ###0096### ###0097### ###0098### ###0099### ###0100### ###0101### ###0102### ###0103### ###0104### ###0105### ###0106### ###0107### ###0108### ###0109### ###0110### ###0111### ###011 ​ ​ ​ ； ​ To , , , ; To , .

3. Use according to claim 2, wherein the compound is ###0002### ​ 4. The use according to claim 2, wherein ​ 5. The use according to claim 2, wherein the compound is ###00003### or a pharmaceutically acceptable salt thereof. ​ 6. The use according to claim 2, wherein the compound is ###00003### or a pharmaceutically acceptable salt thereof. ​ 7. The use according to claim 1, wherein the compound is ###0002### ​

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