Deuterated derivatives of Lanifibranor

Abstract

To provide a deuterated derivative of Lanifibranor.SOLUTION: Provided is a deuterated derivative of Lanifibranor, particularly a derivative used for a treatment that is specifically a treatment of a fibrotic disease.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to deuterated derivatives of Lanifibranor, particularly for use in therapy, particularly in the treatment of fibrotic diseases. [Background technology]

[0002] Lanifibranol or 4-(1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloro-indol-2-yl)butanoic acid is a PPAR receptor agonist useful for use in the treatment of systemic sclerosis (SSc) and non-alcoholic steatohepatitis (NASH). In particular, Lanifibranol is described together with other indole derivatives in US Pat. No. 5,399,433, and is described for use in the prevention or treatment of hypertriglyceridemia, hypercholesterolemia, and more generally for the restoration of normal parameters during disruptions of lipid and carbohydrate metabolism, as well as in the treatment of endothelial dysfunction, inflammatory diseases, or neurodegeneration.

[0003] The advantages of using deuterated molecules as a means to alter metabolism by improving metabolic stability and, in some cases, cell permeability are known (Non-Patent Documents 1-5, Patent Documents 2 and 3). The synthesis of deuterated pharmaceuticals has also been described in several publications (Non-Patent Documents 6 and 7).

[0004] However, the effect of hydrogen replacement with deuterium on the metabolism of chemicals is still unpredictable, and it is recognized that for many authors deuteration of pharmaceuticals is not considered a reliable means of regulation (Non-patent Documents 8-10). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2007 / 026097 [Patent Document 2] International Publication No. 2017 / 136375 [Patent Document 3] International Publication No. 2018 / 039521 [Non-patent literature]

[0006] [Non-Patent Document 1] Maehr&al.,J.Med.Chem.2013,56,3878-3888 [Non-Patent Document 2] Kerekes et al.,J.Med.Chem.2011,54,201-210 [Non-Patent Document 3] Harbeson&Tung,Medchem News 2014,2 9-22 [Non-Patent Document 4] Gant,J.Med.Chem.2014,57,3595-3611 [Non-Patent Document 5] DeWitt&Maryanoff,Biochemistry 2018,57,472-473 [Non-Patent Document 6] Modutwa&al.,J.Label Compd.Radiopharm 2010,53 686-692 [Non-Patent Document 7] Junk et al., J. Label Compd. Radiopharm 1997, 39 625-630 [Non-Patent Document 8] Foster, AB, Adv Drug Res 1985,14:1-40 [Non-Patent Document 9] Fisher,MB et al,Curr Opin Drug Discov Devel,2006,9:101-09 [Non-Patent Document 10] Katsnelson,Nature Medicine 2013,19 6 656 Summary of the Invention [Means for solving the problem]

[0007] The present invention relates to a compound of formula (I):

[0008] [ka]

[0009] The present invention relates to a deuterated derivative of lanifibranor represented by the formula: (wherein, among the above R1 to R7, at least one group is a deuterium atom (D), and the other groups are hydrogen atoms (H).

[0010] The present invention also relates to compositions, in particular pharmaceutical compositions, comprising at least one deuterated derivative of formula (I).

[0011] The present invention also relates to deuterated derivatives of formula (I) for use in therapy, particularly in the treatment of fibrotic diseases. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The present invention relates to a compound of formula (I):

[0013] [ka]

[0014] (wherein at least one group among R1 to R7 is a deuterium atom, and the other groups are hydrogen atoms), as well as a deuterated derivative of lanifibranor, and a pharma- ceutically acceptable salt and solvate thereof.

[0015] According to the first embodiment of the present invention, at least R1 is D.

[0016] In particular, the deuterated derivative of Lanifibranor is 4-(1-(2-deuterio-1,3-benzothiazol-6-yl)sulfonyl)-5-chloro-1H-indol-2-yl)butanoic acid.

[0017] According to another embodiment of the present invention, at least one group among R2 to R7 is D. More preferably, at least one group among R2 and R3, and / or at least one group among R4 and R5, and / or at least one group among R6 and R7 is D. Even more preferably, R2, R3, R4, R5, R6, and R7 are D.

[0018] In particular, the deuterated derivative of Lanifibranor is 4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloro-indol-2-yl]-2,2,3,3,4,4-hexadeuteriobutanoic acid.

[0019] The pharma- ceutically acceptable salts of the deuterated derivatives of the present invention are similar to the pharma- ceutically acceptable salts of Lanifibranor, particularly salts of the acid in combination with a pharma- ceutically acceptable non-toxic inorganic or organic base. As the inorganic base, for example, hydroxides of sodium, potassium, magnesium, or calcium can be used. As the organic base, for example, amines, amino alcohols, basic amino acids such as lysine or arginine, or compounds with a quaternary ammonium function such as betaine or choline can be used.

[0020] The compounds of the present invention are prepared according to conventional methods for the preparation of Lanifibranor, such as those described in US Pat. No. 5,399,323, replacing the non-isotopically enriched intermediates used in these conventional methods with deuterated synthetic intermediates.

[0021] The present invention also relates to a composition comprising a deuterated derivative of the present invention or a salt or solvate thereof, particularly a pharma- ceutically acceptable salt or solvate, and a carrier suitable for use therewith.

[0022] When used in therapy, the composition of the invention will advantageously be a pharmaceutical composition, the carrier comprising conventional pharmacopoeia excipients selected according to the envisaged mode of administration.

[0023] Such compositions are known to those skilled in the art and are described in particular in WO 2015 / 189401 and WO 2015 / 189401.

[0024] For oral administration, e.g. in the form of tablets, capsules, lozenges, gels, syrups, oral suspensions, the pharmaceutical composition of the invention advantageously contains 1 to 1000 mg, e.g. 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 200 mg, 500 mg, or 1000 mg, of the deuterated derivative of formula (I).

[0025] The present invention also relates to a deuterated derivative of formula (I) or a pharma- ceutically acceptable salt or solvate thereof for use in therapy.

[0026] Other therapeutic uses of the deuterated derivatives of the present invention are similar to those known for Lanifibranor and its analogues, such as those described in WO 2015 / 189401 and WO 2015 / 189401.

[0027] Thus, the present invention relates to deuterated derivatives of formula (I) or pharma- ceutically acceptable salts or solvates thereof for use in combating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance, diabetes, or obesity, and cardiovascular diseases resulting from serum lipoprotein imbalances. The compounds of the present invention are also useful as active ingredients of medicaments intended to prevent or treat diseases associated with endothelial dysfunction, atherosclerosis, myocardial infarction, hypertension, cerebrovascular disorders, certain inflammatory diseases (e.g., rheumatoid arthritis), and neurodegeneration (especially Alzheimer's disease or Parkinson's disease, etc.).

[0028] The present invention particularly relates to deuterated derivatives of formula (I) for use in the treatment of fibrotic diseases. In one embodiment, the fibrotic disease is a disorder affecting organs that may develop fibrosis, such as the heart, lungs, liver, kidneys, gastrointestinal tract, skin, muscle, etc. The fibrotic disease is in particular selected from liver fibrosis, fatty liver, non-alcoholic steatohepatitis, chronic kidney disease, pulmonary fibrosis, such as idiopathic pulmonary fibrosis, and systemic sclerosis.

[0029] The present invention also relates to a method for treating the above-mentioned fibrotic diseases in a patient awaiting treatment, said method comprising administering to said patient a deuterated derivative of formula (I), in particular as a pharmaceutical composition comprising said deuterated derivative of formula (I) in a form suitable for the chosen method of administration.

[0030] It is advantageous to predetermine the need for patient treatment by suitable diagnostic methods for detecting the fibrotic disease to be treated, in particular by analyzing the PPAR receptor expression levels in the fibrotic tissue of the patient to be treated. EXAMPLES

[0031] Abbreviation APCI = atmospheric pressure chemical ionization DCM = dichloromethane DMSO = dimethyl sulfoxide eq.=equivalent EtOAc = ethyl acetate EtOH = ethanol h=time HPLC = High Performance Liquid Chromatography LCMS = Liquid Chromatography / Mass Spectrometry MeOH = methanol min=minutes Pd(PPh3)4 = Tetrakis(triphenylphosphine)palladium(0) pTsOH = p-toluenesulfonic acid NMR=nuclear magnetic resonance THF = tetrahydrofuran

[0032] Example 1: 4-[5-chloro-1-[(2-deuterio-1,3-benzothiazol-6-yl)sulfonyl)]indol-2-yl]butanoic acid Preparation Example 1: 2-Deuterio-1,3-benzothiazole n-BuLi (37.0 mL, 92.5 mmol, 2.5 eq; 2.5 M in hexane) was added dropwise to a solution of 1,3-benzothiazole (5.0 g, 36.9 mmol, 1.0 eq.) in THF (80 mL) and cooled to -78 °C. After the addition was complete, DO (4 mL, 222 mmol, 6.0 eq.) was added to the reaction mixture at -78 °C. The whole was stirred for 30 min and then allowed to warm to room temperature. The reaction was monitored by LCMS analysis. The reaction mixture was then treated with saturated aqueous NH4Cl solution and the whole was extracted three times with DCM. The combined organic layers were dried over MgSO4, then filtered and evaporated under reduced pressure to give the crude product, which was purified by flash chromatography (eluent: 0 to 40% EtOAc in n-heptane) to give the compound of Preparation 1 (3.22 g, 64% yield) as a brown oil. APCI MS m / z 137 [M+H] + ;HPLC-MS (220-254nm) purity: 99%. 1 H NMR (300MHz DMSO-d6): δ7.46-7.58(2H,m);8.08-8.19(2H,m).

[0033] Preparation Example 2: 2-Deuterio-6-nitro-1,3-benzothiazole 2-Deuterio-1,3-benzothiazole (Preparation Example 1, 2.9 g, 21.3 mmol, 1.0 eq.) was slowly added to a sulfuric acid solution (13 mL) at 0° C., followed by dropwise addition of nitric acid (6.4 mL) while keeping the temperature below 0° C. The reaction mixture was then allowed to warm to room temperature and stirred for 12 hours before being hydrolyzed over an ice-water mixture. The yellow precipitate was filtered off, washed with water and crystallized from ethanol to give the desired product (Preparation Example 2, 1.4 g, 37% yield) as yellow crystals. APCI MS m / z 182 [M+H] + ;HPLC-MS (220-254nm) purity >99%. 1 H NMR (300MHz DMSO-d6): δ8.27-8.38(2H,m); 9.25(1H,d,J=2.3Hz).

[0034] Preparation 3: 2-Deuterio-1,3-benzothiazole-6-amine Tin chloride powder (7.3 g, 38.6 mmol, 3.5 eq.) was added to a solution of the compound of Preparation 2 (2.0 g, 11.0 mmol, 1.0 eq.) in a mixture of EtOH / EtOAc (1:1) (60 mL), and the solution was stirred at room temperature for 4 h. At the end of the reaction, the reaction mixture was filtered through a Celite® cartridge and extracted with a saturated Na2CO3 solution. The combined organic layers were dried over MgSO4, then filtered and evaporated under reduced pressure to give a crude product, which was purified by flash chromatography (eluent: 0 to 20% MeOH in DCM) to give the desired compound (Preparation 3, 970 mg, 58% yield) as brown crystals. APCI MS m / z 152 [M+H] + ;HPLC-MS (220-254nm) purity: 97%. 1 H NMR (300MHz DMSO-d6): δ5.38(2H,s); 6.8(1H,dd,J=8.7Hz and J=2.2Hz);7.11(1H,d,J=2.2Hz);7.7(1H,d,J=8.7Hz).

[0035] Preparation 4: 2-Deuterio-1,3-benzothiazole-6-sulfonyl chloride A solution of thionyl chloride (1.1 mL) in water (4.5 mL) was prepared at 0° C. and stored at 4° C. overnight. To this solution was added copper(I) chloride (0.05 eq.) at −10° C. The compound of Preparation 3 (450 mg, 2.9 mmol, 1.0 eq.) was dissolved in hydrochloric acid (3.5 mL) while keeping the temperature below 25° C., the solution was cooled to −10° C. and then sodium nitrite solution (3.3 mmol, 0.7 mL, 1.1 eq.) was added so that the temperature did not exceed −2° C. The resulting mixture was stirred at −2° C. for 15 minutes and added dropwise to the original aqueous thionyl chloride solution at −5° C. The reaction mixture was then stirred at −5° C. for 3 hours and then hydrolyzed in water. The formed precipitate was filtered and then washed with water to give the desired product (Preparation 4, 255 mg, 37% yield) as light brown crystals. This compound was used in the next step without purification. HPLC-MS (220-254nm) purity: 94%.

[0036] Preparation Example 5: N-(4-chloro-2-iodophenyl)-2-deuterio-1,3-benzothiazole-6-sulfonamide Under argon, 4-chloro-2-iodoaniline (564 mg, 2.2 mmol, 1.0 eq.) was dissolved in anhydrous pyridine (8 mL) and the compound of Preparation 4 (600 mg, 2.5 mmol, 1.15 eq.) was added. The solution was then stirred at room temperature for 2 h. The solvent was evaporated and the crude reaction was purified by flash chromatography (eluent: 0 to 30% EtOAc in n-heptane) to give the desired product (Preparation 5, 0.73 g, 73% yield) as brown crystals. APCI MS m / z 452 [M+H] + ;HPLC-MS (220-254nm) purity: 94%. 1 H NMR (300 MHz DMSO-d6): δ 7.01 (1H, d, J = 8.5 Hz); 7.4 (1H, dd, J = 8.5 Hz and J = 2.3 Hz); 7.82 (1H, dd, J = 8.7 Hz and J = 1.8 Hz); 7.88 (1H, d, J = 2.4 Hz); 8.26 (1H, d, J = 8.7 Hz); 8.6 (1H, d, J = 1.5 Hz); 10.03 (1H, s).

[0037] Preparation 6: 4-[5-chloro-1-[(2-deuterio-1,3-benzothiazol-6-yl)sulfonyl)]indol-2-yl]butanoic acid The compound of Preparation 5 (1.31 g, 2.9 mmol, 1.0 eq.) was dissolved in anhydrous DMF (30 mL) under argon, followed by the addition of 5-hexynoic acid (360 mg, 3.2 mmol, 1.1 eq.), copper iodide (56 mg, 0.3 mmol, 0.1 eq.), Pd(PPh3)4 (168 mg, 0.15 mmol, 0.05 eq.), and triethylamine (606 μL, 4.4 mmol, 1.5 eq.) and the reaction mixture was stirred at 80° C. for 2 h. At the end of the reaction, the mixture was taken up in 1N aqueous hydrochloric acid and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, then filtered and evaporated under reduced pressure to give the crude product, which was purified by flash chromatography (eluent: 0 to 5% MeOH in DCM) to give the desired product (Example 1, 1.05 g, 83% yield) as brown crystals. APCI MS m / z 452[[M+H] + ;HPLC-MS (220-254nm) purity: 94%. 1 H NMR(300MHz DMSO-d6):δ1.86-2.01(2H,m);2.29-2.41(2H,m);3.08(2H,t,J=7.2Hz);6.61(1H,s);7.31(1H,dd,J=8.7Hz and J=2.0Hz);7.51(1H, d,J=2.0Hz);7.84(1H,dd,J=8.7Hz and J=1.8Hz);8.08(1H,d,J=8.7Hz);8.19(1H,d,J=8.7Hz);8.97(1H,d,J=1.8Hz);12.13(1H,s). Deuterium introduction rate by 500MHz NMR analysis: 98%.

[0038] Example 2: 4-[1-(1,3-Benzothiazol-6-ylsulfonyl)-5-chloro-indol-2-yl]-2,2,3,3,4,4-hexadeuteriobutanoic acid Preparation Example 7: 2-(1,1,2,2,3,3,4,4-octadeuterio-4-iodo-butoxy)tetrahydropyran Iodotrimethylsilane (25 g, 125 mmol, 1 eq.) was added to THF-D8 (10 g, 125 mmol, 1 eq.) at 0 °C. After stirring at 0 °C for 2 h, ether (80 mL) and water (20 mL) were added. The mixture was stirred for 3 h and then decanted. The organic layer was then dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude reaction was taken up in DCM (100 mL) at 0 °C, followed by the addition of dihydropyran (12.5 mL, 150 mmol, 1.2 eq.) and pTsOH (50 mg, 0.2 mmol, 0.002 eq.). The reaction mixture was then stirred overnight at 0 °C. The solution was washed successively with saturated NaHCO3 solution (3 × 15 mL), then with brine, then dried over Na2SO4 and concentrated under reduced pressure. The crude reaction was purified by flash chromatography (eluent: 1:20 to 1:5 EtOAc:Hexanes) to give the desired product (Preparation 7, 23 g, 62% yield) as a colorless oil which was used directly in the next step.

[0039] Preparation Example 8: 2-(1,1,2,2,3,3,4,4-octadeuteriohex-5-ynoxy)tetrahydropyran A solution of lithium acetylide (19.94 g, 186.3 mmol, 1 eq.) in freshly distilled DMSO (60 mL) was added dropwise to a solution of the compound of Preparation 7 (30 g, 102.7 mmol, 0.55 eq.) in DMSO (30 mL) at 5° C. The resulting solution was stirred for 2 h and then hydrolyzed with NH4Cl solution at 0° C. The mixture was then extracted with hexane and washed with copper sulfate (5%, 20 mL) solution and then with brine (20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the desired product (Preparation 8, 10.7 g, 55% yield) as a yellow oil. This product was used directly in the next step without purification.

[0040] Preparation Example 9: 1,1,2,2,3,3,4,4-Octadeuteriohex-5-yn-1-ol To a solution of the compound of Preparation 8 (10.7 g, 56.2 mmol, 1 eq.) in a mixture of THF (12.5 mL) and MeOH (350 mL) at 0° C., pTsOH (360 mg, 1.82 mmol, 0.03 eq.) was added in small portions and the resulting reaction mixture was stirred overnight. The mixture was then washed with saturated NaHCO3 solution (3×15 mL) and brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude reaction was purified by flash chromatography (eluent: 1:20 to 1:5 EtOAc:Hexanes) to give the desired product (Preparation 9, 5 g, 82% yield) as a colorless oil. This product was used directly in the next step.

[0041] Preparation Example 10: 2,2,3,3,4,4-Hexadeuteriohex-5-ynoic acid To a stirred solution of the compound of Preparation 9 (9.25 g, 87 mmol, 1 eq.) in acetone (87 mL) was added Jones reagent (a solution of CrO3 (17.45 g, 174.5 mmol, 2 eq.) in 10N H2SO4 (218 mL)) at 0° C. over 5 min. The reaction mixture was then stirred for 1 h and concentrated under reduced pressure. Ether (130 mL) and water (4 mL) were immediately added. The resulting solid was filtered off and the filtrate was extracted with ether (6×100 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product (Preparation 10, 9.17 g, 89% yield) as an orange oil. This product was used directly in the next step without purification.

[0042] Preparation Example 11: 4-[1-(1,3-Benzothiazol-6-ylsulfonyl)-5-chloro-indol-2-yl]-2,2,3,3,4,4-hexadeuteriobutanoic acid A mixture of benzothiazole-6-sulfonic acid (4-chloro-2-iodo-phenyl)-amide (16 g, 35.5 mmol, 1 eq.), hex-5-ynoic acid (Preparation Example 10, 5.2 g, 44 mmol, 1.24 eq.), copper iodide (335 mg, 1.75 mmol, 0.05 eq.), dichlorobis(triphenylphosphine)palladium (1.24 g, 1.72 mmol, 0.05 eq.), triethylamine (130 mL), and N,N-dimethylformamide (130 mL) was stirred at 110° C. for 1 h under nitrogen. The reaction mixture was then diluted with 1M HCl solution and extracted with ethyl acetate. Insoluble matter was filtered off, and the filtrate was dried over Na2SO4 and then concentrated under reduced pressure. The crude reaction was purified by flash chromatography and then recrystallized from DCM to give the desired product (Example 2, 2.3 g, 15% yield) as a white solid. Deuterium incorporation by 500 MHz NMR analysis: >99%. 1 H NMR (400 MHz, DMSO-d6) δ 6.62 (1H, d, J = 0.6 Hz), 7.32 (1H, dd, J = 8.9 and 2.2 Hz), 7.57 (1H, d, J = 2.1 Hz), 7.85 (1H, dd, J = 8.7 and 2.1 Hz), 8.10 (1H, d, J = 8.9 Hz), 8.20 (1H, d, J = 8.7 Hz), 8.99 (1H, s), 9.66 (1H, s), 12.15 (1H, s).

[0043] Example 3: Pharmacological activity The compounds of the present invention were subjected to biological testing to assess their potential to treat or prevent certain conditions. First, the ability of these compounds to act as activators of the nuclear receptor PPAR was measured.

[0044] The transactivation assay was used as a primary screening test. Cos-7 cells were transfected with plasmids expressing chimeric PPAR-Gal4 (receptors PPARα-Gal4, PPARδ-Gal4, or PPARγ-Gal4) of mouse or human receptors and the reporter plasmid 5Gal4pGL3 TK Luc. The transfection was performed using chemicals (Jet PEI).

[0045] The transfected cells were distributed in 384-well plates and left for 24 hours. After 24 hours, the medium was changed. The products to be tested were added to the medium (final concentration 10 -4 ~3×10 -10 M). After overnight incubation, luciferase expression was measured after addition of "SteadyGlo" according to the manufacturer's instructions (Promega).

[0046] 10 -5 Fenofibric acid (PPARα agonist) at 10 M -8 M GW501516 (PPARδ agonist), and 10 -6 M Rosiglitazone (a PPARγ agonist) was used as a reference.

[0047] Results are expressed as fold induction compared to basal values, which are the % activity of the appropriate reference (reference = 100%). Effect concentration curves and EC 50 was calculated using Assay Explorer (MDL) software.

[0048] [Table 1]

[0049] As can be seen from the above table, the deuterated derivative of lanifibranor activates the three subtypes of PPAR receptors (PPARα, PPARγ, and PPARδ) and has EC 50 The EC values ​​for the two PPAR subtypes were less than 2.5 μM. 50 It is noted that the ratio is less than 100 or greater than 0.01.

[0050] References 1.DeWitt&Maryanoff,Biochemistry 2018,57,472-473 2.Fisher et al,Curr Opin Drug Discov Devel,2006,9:101-09 3. Foster, Adv Drug Res 1985, 14:1-40 4. Gant, J. Med. Chem. 2014, 57, 3595-3611 5.Harbeson&Tung,Medchem News 2014,2 9-22 6. Junk et al., J. Label Compd. Radiopharm 1997, 39 625-630 7. Katsnelson, Nature Medicine 2013, 19 6 656 8. Kerekes et al., J. Med. Chem. 2011, 54, 201-210 9. Maehr et al., J. Med. Chem. 2013, 56, 3878-3888 10.Modutwa&al.,J.Label Compd.Radiopharm 2010,53 686-692 11.WO2007 / 026097 12.WO2015 / 189401 13.WO2017 / 136375 14.WO2018 / 039521

Claims

1. Formula (I): 【Chemistry 1】 (Wherein, R １ ~R ７ wherein at least one group is a deuterium atom and the other groups are hydrogen atoms), or a pharma- ceutically acceptable salt or solvate thereof, The drug is for the prevention or treatment of a disease selected from the group consisting of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance, diabetes, obesity, cardiovascular diseases caused by an imbalance of serum lipoproteins, diseases associated with endothelial dysfunction, atherosclerosis, myocardial infarction, hypertension, cerebrovascular disorders, inflammatory diseases, and neurodegeneration.

2. At least the above R １ The method of claim 1, wherein

3. The agent according to claim 2, which is 4-(1-(2-deuterio-1,3-benzothiazol-6-yl)sulfonyl)-5-chloro-1H-indol-2-yl)butanoic acid.

4. The above R ２ ~R ７ The method of claim 1 , wherein at least one of the groups is D.

5. The above R ２ and R ３ and / or at least one group of the above R ４ and R ５ and / or at least one group of the above R ６ and R ７ The method of claim 4, wherein at least one of the groups is D.

6. The agent according to claim 5, which is 4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloro-indol-2-yl]-2,2,3,3,4,4-hexadeuteriobutanoic acid.

7. The drug according to claim 1, wherein the inflammatory disease is rheumatoid arthritis.

8. The method of claim 1, wherein the neurodegeneration is Alzheimer's disease or Parkinson's disease.

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