3, 5-dibromo-4-hydroxybenzenesulfonamide compound as well as synthesis method and application thereof

Abstract

The invention discloses a 3, 5-dibromo-4-hydroxybenzenesulfonamide compound as well as a synthesis method and application thereof, the compound has the following structural general formula: R is one of the following: R1 is H, C1-C4 alkyl, trifluoromethyl or difluoromethyl, and R2 is H, C1-C4 alkyl or halogen. The 3, 5-dibromo-4-hydroxybenzenesulfonamide compound designed and synthesized by the invention is a novel compound and can be used for treating diseases related to gout.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of 3,5-dibromo-4-hydroxybenzenesulfonamide compound and its synthesis method and application. BACKGROUND

[0002] Gout is a kind of joint disease caused by uric acid deposition in vivo, and the formation of gout is closely related to the metabolic disorder of uric acid. Uric acid is decomposed from purine material, and purine exists in all tissues of the body. Uric acid is excreted with urine through kidney after blood decomposition, and when uric acid excretion is insufficient, the content of uric acid in vivo is increased, thereby causing gout. URAT1 is a kind of organic anion transporter protein, and the content of uric acid in vivo is increased by reabsorbing uric acid. Therefore, inhibiting the activity of URAT1 can reduce the reabsorption of uric acid, thereby reducing the content of uric acid in vivo, and playing an important role in treating gout. At present, the drugs for treating gout mostly have some side effects such as greater toxicity, so it is of great significance to develop more efficient URAT1 inhibitors for treating gout. SUMMARY

[0003] In view of the above technical problems existing in the prior art, the purpose of the present application is to provide a kind of 3,5-dibromo-4-hydroxybenzenesulfonamide compound and its synthesis method and application. The 3,5-dibromo-4-hydroxybenzenesulfonamide compound provided by the present application can be used as urate transporter protein 1 (URAT1) inhibitor for treating gout related diseases.

[0004] The technical scheme adopted by the present application is as follows:

[0005] A kind of 3,5-dibromo-4-hydroxybenzenesulfonamide compound, the compound has the following general structure:

[0006]

[0007] Among them, R is one of the following:

[0008]

[0009] Among them, R1 is H, C1-C4 alkyl, trifluoromethyl or difluoromethyl, and R2 is H, C1-C4 alkyl or halogen.

[0010] The synthesis method of the 3,5-dibromo-4-hydroxybenzenesulfonamide compound comprises the following steps:

[0011]

[0012] The steps of the synthesis route include:

[0013] Step 1: Using sodium p-hydroxybenzenesulfonate as shown in Formula 1 as a raw material, under the action of inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate and potassium carbonate or organic bases such as pyridine, diisopropylethylamine and triethylamine, it undergoes a nucleophilic substitution reaction with benzyl bromide as shown in Formula 2 to obtain compound 3.

[0014] Step 2: Compound 3 undergoes chlorosulfonation with thionyl chloride under the catalysis of DMF to give compound 4;

[0015] Step 3: Under the action of inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate and potassium carbonate or organic bases such as pyridine, diisopropylethylamine and triethylamine, compound 4 and compound 5 undergo a condensation reaction to obtain compound 6;

[0016] Step 4: Compound 6 undergoes debenzylation under the action of trifluoroacetic acid to give compound 7;

[0017] Step 5: Compound 7 undergoes a bromination reaction with sodium bromide in the presence of hydrogen peroxide to obtain target compound 8;

[0018] The structural formula of compound 5 is RH, and the group R in structural formula RH is the same as the substituent R in target compound 8.

[0019] This invention also discloses the use of the aforementioned class of 3,5-dibromo-4-hydroxybenzenesulfonamide compounds and their pharmaceutically acceptable salts as URAT1 inhibitors.

[0020] This invention also discloses the use of the aforementioned class of 3,5-dibromo-4-hydroxybenzenesulfonamide compounds and their pharmaceutically acceptable salts in the preparation of medicaments for treating URAT1-mediated gout-related diseases.

[0021] The beneficial effects achieved by this invention are: the 3,5-dibromo-4-hydroxybenzenesulfonamide compounds designed and synthesized by this invention are a new type of compound that can be used to treat gout-related diseases. Detailed Implementation

[0022] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0023] 1. Preparation of intermediates and target compounds:

[0024] Example 1: p-Phenylacetylbenzenesulfonic acid (3)

[0025]

[0026] 0.025 mol of sodium p-hydroxybenzenesulfonate (compound 1), 5 mL of isopropanol, 10 mL of 3 mol / L NaOH aqueous solution, and 5.2 g (0.030 mol) of benzyl bromide (compound 2) were added to a reaction flask. After the addition was complete, the reaction mixture was reacted at 75 °C for 8 h. After the reaction was completed, the reaction solution was cooled to room temperature, acidified with dilute hydrochloric acid, filtered, and the filter cake was washed successively with water and isopropanol. The mixture was then dried under vacuum to obtain 5.0 g of p-phenylmethoxybenzenesulfonic acid, compound 3, with a yield of 74.5%.

[0027] Example 2: p-Phenylacetyl chloride (4)

[0028]

[0029] 5.0 g (0.019 mol) of compound 3 and 20 mL of anhydrous DMF were added to a reaction flask. 2.6 g (0.022 mol) of thionyl chloride was slowly added dropwise at room temperature. After the addition was complete, the reaction mixture was allowed to react at room temperature for 1 h. After the reaction was completed, the reaction mixture was slowly poured into ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 3.4 g of compound 4, with a yield of 62.9%.

[0030] Example 3: 5-((4-(benzyloxy)phenyl)sulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6a)

[0031]

[0032] 120 mg (0.42 mmol) of compound 4, 5 mL of dichloromethane, 59.0 mg (0.42 mmol) of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine 5a, and 128 mg (1.26 mmol) of triethylamine were added to a reaction flask. The mixture was reacted at room temperature for 2 h after the addition was complete. After the reaction was completed, the reaction solution was poured into water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 150 mg of compound 6a, with a yield of 92.6%.

[0033] Example 4: 5-((4-(benzyloxy)phenyl)sulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6b)

[0034]

[0035] The synthesis method of compound 6b is the same as in Example 3, except that 4,5,6,7-tetrahydrothieno[3,2-c]pyridine 5a is replaced with an equimolar amount of 4,5,6,7-tetrahydrofurano[3,2-c]pyridine 5b. The reaction yields compound 6b in 86.5%.

[0036] Example 5: 5-((4-(benzyloxy)phenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (6c)

[0037]

[0038] The synthesis method of compound 6c is the same as that in Example 3, except that 4,5,6,7-tetrahydrothieno[3,2-c]pyridine 5a is replaced with an equimolar amount of 4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine 5c. The final reaction yields compound 6c with a yield of 84.7%.

[0039] Example 6: 7-((4-(benzyloxy)phenyl)sulfonyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (6d)

[0040] The synthesis method of compound 6d is the same as in Example 3, except that 4,5,6,7-tetrahydrothieno[3,2-c]pyridine 5a is replaced with an equimolar amount of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 5d. The final reaction yields white solid 6d in 81.2% yield.

[0041] Example 7: 1-((4-(benzyloxy)phenyl)sulfonyl)-1H-benzo[d]imidazolium (6e)

[0042]

[0043] The synthesis steps of compound 6e were the same as in Example 3, except that 4,5,6,7-tetrahydrothieno[3,2-c]pyridine 5a was replaced with an equimolar amount of 1H-benzo[d]imidazolium 5e, and the reaction temperature was increased to 40°C. The final reaction yielded compound 6e with a yield of 60.8%.

[0044] Example 8: 4-(benzyloxy)-N-(2,2-difluorobenzo[d][1,3]dioxolane-5-yl)benzenesulfonamide (6f)

[0045]

[0046] The synthesis steps of compound 6f were the same as in Example 3, except that 4,5,6,7-tetrahydrothieno[3,2-c]pyridine 5a was replaced with an equimolar amount of 2,2-difluorobenzo[d][1,3]dioxolane-5-amine. The final reaction yielded compound 6f in 71.8% yield.

[0047] Example 9: 4-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)sulfonyl)phenol (7a)

[0048]

[0049] 81.0 mg (0.21 mmol) of compound 6a, 10 mL of toluene, and 1 mL of trifluoroacetic acid were added to a reaction flask. The mixture was refluxed for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature and then poured into water. The solution was adjusted to weakly acidic pH with saturated NaHCO3 solution, extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 53 mg of compound 7a, with a yield of 87.0%.

[0050] Example 10: 4-((6,7-dihydrofurano[3,2-c]pyridin-5(4H)-yl)sulfonyl)phenol (7b)

[0051]

[0052] The synthesis steps of compound 7b are the same as in Example 9, except that compound 6a is replaced with an equal molar amount of compound 6b. The final reaction yields compound 7b with a yield of 64.6%.

[0053] Example 11: 4-((1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)sulfonyl)phenol (7c)

[0054]

[0055] The synthesis steps of compound 7c are the same as in Example 9, except that compound 6a is replaced with an equal molar amount of compound 6c. The final reaction yields compound 7c with a yield of 81.5%.

[0056] Example 12: 4-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)sulfonyl)phenol (7d)

[0057]

[0058] The synthesis steps of compound 7d are the same as in Example 9, except that compound 6a is replaced with an equal molar amount of compound 6d. The final reaction yields compound 7d with a yield of 76.4%.

[0059] Example 13: 4-((1H-benzimidazol-1-yl)sulfonyl)phenol (7e)

[0060]

[0061] The synthesis steps of compound 7e are the same as in Example 9, except that compound 6a is replaced with an equal molar amount of compound 6e. The final reaction yields compound 7e with a yield of 69.3%.

[0062] Example 14: N-(2,2-difluorobenzo[d][1,3]dioxolane-5-yl)-4-hydroxybenzenesulfonamide (7f)

[0063]

[0064] The synthesis steps of compound 7f are the same as in Example 9, except that compound 6a is replaced with an equal molar amount of compound 6f. The final reaction yields compound 7f with a yield of 49.3%.

[0065] Example 15: 2,6-Dibromo-4-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)sulfonyl)phenol (8a)

[0066]

[0067] 56.0 mg (0.19 mmol) of compound 7a, 2 mL of acetic acid, 39.0 mg (0.38 mmol) of sodium bromide, and 65.0 mg (0.57 mmol) of 30% hydrogen peroxide were added to a reaction flask. The mixture was reacted at room temperature for 4 h. After the reaction was completed, the reaction solution was poured into water and adjusted to weak acidity with saturated NaHCO3 solution. The solution was extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 34 mg of 8a, with a yield of 39.1%. 1 HNMR(400MHz,DMSO-d6)δ11.20(s,1H),7.86(s,2H),7.01(d,J=6.2Hz,1H),6.52(d,J=6 .2Hz,1H),4.48(s,2H),3.74(t,J=6.8Hz,2H),2.75(t,J=6.8Hz,2H).ESI-MS:m / z[M+H] + 454.

[0068] Example 16: 2,6-Dibromo-4-((6,7-dihydrofurano[3,2-c]pyridin-5(4H)-yl)sulfonyl)phenol (8b)

[0069]

[0070] The synthesis steps of compound 8b are the same as in Example 15, except that compound 7a is replaced with an equal molar amount of compound 7b, and the reaction yields compound 8b in 35.3%. 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),7.83(s,2H),7.54(d,J=5.8Hz,1H),6.38(d,J=5 .8Hz,1H),4.42(s,2H),3.62(t,J=6.2Hz,2H),2.56(t,J=6.2Hz,2H).ESI-MS:m / z[M+H] + 438.

[0071] Example 17 2,6-Dibromo-4-((1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)sulfonyl)phenol

[0072]

[0073] The synthesis steps of compound 8c are the same as in Example 15, except that compound 7a is replaced with an equal molar amount of compound 7c. The final reaction yields compound 8c with a yield of 40.1%. 1 H NMR (400MHz, DMSO-d6) δ11.78(s,1H),11.12(s,1H),7.84(s,2H),6.54(d,J=5.3Hz,1H),5.92 (d,J=5.3Hz,1H),4.35(s,2H),3.58(t,J=6.0Hz,2H),2.74(t,J=6.0Hz,2H).ESI-MS:m / z[M+H] + 437.

[0074] Example 18: 2,6-Dibromo-4-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)sulfonyl)phenol (8d)

[0075]

[0076] The synthesis steps of compound 8d are the same as in Example 15, except that compound 7a is replaced with an equal molar amount of compound 7d. The final reaction yields compound 8d with a yield of 63.5%. 1 HNMR (400MHz, DMSO-d6) δ11.12(s,1H),7.88(s,2H),4.53(s,2H),4.18(t,J=6.0Hz,2H),3.62(t,J=6.0Hz,2H).ESI-MS:m / z[M+H] + 507.

[0077] Example 19: 2,6-Dibromo-4-((1H-benzimidazol-1-yl)sulfonyl)phenol (8e)

[0078]

[0079] The synthesis steps of compound 8e are the same as in Example 15, except that compound 7a is replaced with an equal molar amount of compound 7e. The final reaction yields compound 8e with a yield of 41.8%. 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.06(s,1H),7.86(s,2H),7.58-7.49(m,2H),7.26-7.16(m,2H).ESI-MS:m / z[M+H] + 433.

[0080] Example 20: 2,6-Dibromo-N-(2,2-difluorobenzo[d][1,3]dioxolane-5-yl)-4-hydroxybenzenesulfonamide (8f)

[0081]

[0082] The synthesis steps of compound 8f were the same as in Example 15, except that compound 7a was replaced with an equal molar amount of compound 7f. The final reaction yielded compound 8f with a yield of 29.5%. 1 H NMR (400MHz, DMSO-d6) δ11.18(s,1H),9.88(s,1H),7.88(s,2H),6.66-6.58(m,2H),6.42(dd,J=7.2,1.8Hz,1H).ESI-MS:m / z[M+H] + 488.

[0083] 2. Bioactivity testing

[0084] Test Methods: HEK-293 cells expressing URAT1 were conventionally cultured in a 5% CO2, 37℃ cell culture incubator. After digestion with 0.25% trypsin for 3 min, complete culture medium was added to terminate the digestion. Following centrifugation and resuspending, a portion was used for cell propagation, and the remainder was used for cell experiments and compound inhibitory activity testing. Cells were added to the control and experimental groups, but no cells were added to the blank and zero-adjustment groups. After incubation for 48 h, readings were taken using a microplate reader with an excitation wavelength of 490 nm and an emission wavelength of 525 nm, followed by shaking. Inhibition rate (%) = (Control group - Experimental group / Control group - Blank group) × 100%. Survival rate (%) = (Experimental group - Zero-adjustment group / Control group - Zero-adjustment group) × 100%. Benzbromarone was used as the positive compound in the experiment. The test results are shown in Table 1.

[0085] Table 1. Inhibitory activity of the target compound against URAT1

[0086]

[0087]

[0088] a SE: Average of standard error

[0089] The contents described in this specification are merely an enumeration of the implementation forms of the inventive concept, and the scope of protection of this invention should not be regarded as limited to the specific forms described in the embodiments.

Claims

1. A class of 3,5-dibromo-4-hydroxybenzenesulfonamide compounds, characterized in that... The compounds have the following general structural formula: wherein R is one of the following: wherein R1 is H, C1-C4 alkyl, trifluoromethyl or difluoromethyl, and R2 is H, C1-C4 alkyl or halogen.

2. The method of synthesis of a class of 3,5-dibromo-4-hydroxybenzenesulfonamides according to claim 1, characterized in that, The synthetic route is as follows: The steps of the synthetic route include: Step 1: sodium p-hydroxybenzenesulfonate shown in formula 1 is used as a raw material, and a nucleophilic substitution reaction occurs with benzyl bromide shown in formula 2 under the action of a base to obtain compound 3; Step 2: compound 3 undergoes a chlorosulfonylation reaction with dichlorosulfoxide under the catalysis of DMF to obtain compound 4; Step 3: compound 4 undergoes a condensation reaction with compound 5 under the action of a base to obtain compound 6; Step 4: compound 6 is debenzylated under the action of trifluoroacetic acid to obtain compound 7; Step 5: compound 7 undergoes a bromination reaction with sodium bromide under the action of hydrogen peroxide to obtain the target compound 8; wherein the structural formula of compound 5 is R-H, and the group R in the structural formula R-H is the same as the substituent R in the target compound 8.

3. The 3,5-dibromo-4-hydroxybenzenesulfonamide compounds and pharmaceutically acceptable salts thereof as claimed in claim 1 for use as URAT1 inhibitors.

4. The 3,5-dibromo-4-hydroxybenzenesulfonamide compounds and pharmaceutically acceptable salts thereof as claimed in claim 1 for use in the preparation of a medicament for the treatment of a URAT1-mediated gout-related disease.

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