Alternative hydroxypyrimidine xanthine oxidase inhibitors, their preparation methods and pharmaceutical uses

Abstract

This invention belongs to the field of pharmaceutical technology and relates to substituted hydroxypyrimidine xanthine oxidase inhibitors, their preparation methods, and pharmaceutical uses. Specifically, it discloses substituted hydroxypyrimidine compounds of formula (I), their physiologically acceptable salts, methods for preparing said compounds, pharmaceutical formulations containing said compounds, and the use of said compounds in the preparation of drugs for the prevention and treatment of diseases related to hyperuricemia.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to substituted hydroxypyrimidine compounds of general formula (I), and their physiologically acceptable salts. It also relates to the use of these compounds in the treatment of diseases related to xanthine oxidase, methods of using them for treatment, and pharmaceutical compositions containing said compounds. Background Technology

[0002] Xanthine oxidase is a metabolic enzyme widely found in mammals, responsible for oxidizing hypoxanthine to xanthine, which is further oxidized to uric acid. When uric acid accumulates excessively in the body, it leads to hyperuricemia. Hyperuricemia is not only a direct cause of gout but is also associated with various metabolic and chronic diseases. Hyperuricemia has now become the second most common metabolic disease after diabetes, and its incidence is showing an increasing trend year by year.

[0003] The level of uric acid in the body is regulated by both uric acid production and excretion. Both excessive uric acid production and reduced excretion will cause an increase in blood uric acid levels. When the concentration of uric acid exceeds its solubility in the blood, urate crystals will form, which will then deposit in joints or soft tissues, causing inflammation and triggering gout.

[0004] Currently, the treatment of hyperuricemia mainly employs three approaches: xanthine oxidase inhibitors to reduce uric acid production, urate transporter inhibitors to promote uric acid excretion, and urokinase to convert uric acid into a water-soluble substance for accelerated excretion. Xanthine oxidase (XO) is a crucial enzyme regulating the uric acid production pathway, and XO inhibitors play a vital role in the treatment of hyperuricemia. Currently, only allopurinol, febuxostat, and tobistat are available as XO inhibitors, and all have relatively serious adverse reactions. Therefore, it is essential to continue developing XO inhibitors with better efficacy and lower side effects.

[0005] The present invention aims to provide a novel substituted hydroxypyrimidine compound with high xanthine oxidase inhibitory activity, which can be used to treat hyperuricemia and gout. Summary of the Invention

[0006] The object of the present invention is to provide a substituted hydroxypyrimidine compound of formula (I) or a physiologically acceptable salt thereof.

[0007] Another object of the present invention is to provide a method for preparing a substituted hydroxypyrimidine compound of formula (I) or a physiologically acceptable salt thereof.

[0008] Another object of the present invention is to provide the use of a substituted hydroxypyrimidine compound of formula (I) or a physiologically acceptable salt thereof in the preparation of a xanthine oxidase inhibitor, and in the preparation of a medicament for the prevention and / or treatment of hyperuricemia or gout.

[0009] To achieve the objectives of this invention, the following technical solution is adopted:

[0010] The first aspect of the present invention is to provide a substituted hydroxypyrimidine compound or a physiologically acceptable salt thereof represented by the following general formula (I).

[0011]

[0012] Wherein, R is a mono- or poly-substituted group on the benzene ring, selected from hydrogen, halogen, trifluoromethyl; n is 2, 3, 4 or 5; X is selected from C1-C6 alkyl-substituted amino groups, C3-C6 cycloalkyl-substituted amino groups, piperidinyl, piperazinyl, N-methylpiperazinyl and morpholinyl; Y is selected from O, S or NH.

[0013] The preferred compounds are those represented by general formula (IA) or their physiologically acceptable salts:

[0014]

[0015] Wherein, R is a mono- or poly-substituted group on the benzene ring, selected from hydrogen, halogen, or trifluoromethyl; n is 2, 3, 4, or 5.

[0016] The preferred compounds are those represented by the general formula (IB) or their physiologically acceptable salts:

[0017]

[0018] Wherein, R is a mono- or poly-substituted group on the benzene ring, selected from hydrogen, halogen, or trifluoromethyl; n is 2, 3, 4, or 5.

[0019] Preferred compounds are those represented by general formula (IC) or their physiologically acceptable salts:

[0020]

[0021] Wherein, R is a mono- or poly-substituted group on the benzene ring, selected from hydrogen, halogen, or trifluoromethyl; n is 2, 3, 4, or 5.

[0022] The preferred compounds are those represented by general formula (ID) or their physiologically acceptable salts:

[0023]

[0024] Wherein, R is a mono- or poly-substituted group on the benzene ring, selected from hydrogen, halogen, or trifluoromethyl; n is 2, 3, 4, or 5.

[0025] The most preferred compound is a compound or a physiologically acceptable salt thereof, characterized in that the compound is selected from:

[0026]

[0027]

[0028] The second aspect of the present invention is to provide a method for synthesizing the compound described in the first aspect, comprising the following steps:

[0029] Compound II reacts with compound III to yield compound IV, which then reacts with cyano compounds and urea, thiourea, or guanidine to generate compound I.

[0030]

[0031] The definitions of R, n, X, and Y are the same as those in claim 1.

[0032] A third aspect of the present invention is to provide a pharmaceutical composition, characterized in that the pharmaceutical composition contains an effective dose of any substituted hydroxypyrimidine compound described in the first aspect of the present invention, its physiologically acceptable salt, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is selected from tablets, capsules, granules, solutions, emulsions, pills, and injections.

[0033] To prepare a pharmaceutical formulation, the compound of general formula (I) can be mixed with a suitable pharmaceutical carrier substance, flavoring agent, flavoring agent, and pigment by known methods, and prepared into tablets or coated tablets, or suspended or dissolved in water or oil with other additives. The compounds of this invention can be administered orally or non-gastrointestinally. Oral administration can be in the form of tablets, capsules, granules, solutions, emulsions, or pills; non-gastrointestinal dosage forms include injections. These formulations are prepared according to methods well known to those skilled in the art. Excipients used in the manufacture of tablets, capsules, granules, and pills are conventional adjuvants, such as starch, gelatin, gum arabic, silica, and polyethylene glycol; solvents used in liquid dosage forms include, for example, water, ethanol, propylene glycol, and vegetable oils such as corn oil, peanut oil, and olive oil. Formulations containing the compounds of this invention may also contain other adjuvants, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, and pigments.

[0034] The fourth aspect of the present invention is to provide the use of the substituted hydroxypyrimidine compounds or their physiologically acceptable salts described in the first aspect in the preparation of xanthine oxidase inhibitors.

[0035] The fourth aspect of the present invention also provides the use of the substituted hydroxypyrimidine compounds or their physiologically acceptable salts described in the first aspect in the preparation of drugs for the prevention and / or treatment of hyperuricemia and gout.

[0036] Pharmacological studies have shown that the compound of general formula II of the present invention inhibits the activity of xanthine oxidase and can effectively reduce the level of blood uric acid in the body, thereby achieving the purpose of treatment.

[0037] Beneficial technical effects:

[0038] Xanthine oxidase inhibitors are the main uric acid-lowering drugs used clinically. The compounds involved in this invention differ significantly in structure from existing drugs and exhibit significant xanthine oxidase inhibitory activity. Most of these compounds show an inhibitory activity of over 90% against xanthine oxidase at a concentration of 10 μM, comparable to that of febuxostat, a clinically relevant product. Detailed Implementation

[0039] The invention will be further described below with reference to the embodiments, but these embodiments do not limit the scope of the invention.

[0040] The structure of the compounds was determined by nuclear magnetic resonance (NMR), mass spectrometry (MS), or high-resolution mass spectrometry (HRMS). NMR shifts (δ) are given in parts per million (ppm). Melting points (mp) are given in °C, uncorrected for temperature. Column chromatography typically uses 200–300 mesh silica gel. NMR measurements were performed using a JEOL ECZ-400S and INOVA-500MHz instrument with DMSO-d6 as the solvent and TMS as the internal standard. Chemical shifts are given in ppm. MS measurements were performed using an Agilent LC / MSDTOF liquid chromatography-mass spectrometry system.

[0041] Example 1: TM-1

[0042]

[0043] a) Add 3,5-dichloro-4-hydroxybenzaldehyde (382 mg, 2 mmol), N-(3-chloropropyl)morpholine (360 mg, 2.2 mmol), potassium carbonate (414 mg, 3 mmol), potassium iodide (33 mg, 0.2 mmol), and DMF (15 mL) to a 100 mL round-bottom flask. Stir at 80 °C for 12 h. After the reaction is complete, evaporate the solvent, dissolve the residue in water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, remove the solvent by evaporation, and dry for later use.

[0044] b) In a 100 mL round-bottom flask, the above product, ethyl cyanoacetate (339 mg, 3 mmol), guanidine hydrochloride (280 mg, 3 mmol), sodium acetate (408 mg, 3 mmol), and pyridine (8 mL) were added sequentially. The reaction was carried out at 120 °C. The reaction was monitored by TLC until complete. The solvent was removed by evaporation, the residue was dissolved in water, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed sequentially with 1 M dilute hydrochloric acid solution, saturated sodium bicarbonate solution, and saturated brine, followed by a methanol / dichloromethane gradient elution (0% methanol - 15% methanol). The solvent was removed by evaporation to give 59 mg of a pale yellow solid. mp: 206-208 °C; 1 H NMR (400MHz, DMSO-d6): δ11.77(s,1H),8.31(s,1H),7.91(s,2H),7.03(s,1H),4.13(t,J=6.3Hz,2H), 3.58(t,J=4.5Hz,4H),2.55(d,J=7.2Hz,2H),2.41(brs,4H),1.96(m,2H); HR-MS:m / z=424.09534[M+H] + calcd for C 18 H 20 O3N5Cl2:424.09377.

[0045] Example 2: TM-2

[0046]

[0047] The preparation method is similar to that of Example 1, except that 3,5-dichloro-4-hydroxybenzaldehyde is used instead of 3,5-dichloro-4-hydroxybenzaldehyde in Example 1. 47 mg of a white solid was obtained. mp: 192-194℃; 1 H NMR (400MHz, DMSO-d6): δ11.70(s,1H),8.15(s,1H)7.91(d,J=2.2Hz,1H),7.86(m,1H),7.29(d,J=8.8Hz,1H),7.17(s,1H),4. 20(t,J=6.3Hz,2H),3.61–3.54(m,4H),2.46(t,J=7.2Hz,2H),2.37(d,J=4.4Hz,4H),1.93(m,2H); HR-MS: m / z=390.13419[M+H] + calcd for C 18 H 21 O3N5Cl: 390.13274.

[0048] Example 3: TM-3

[0049]

[0050] The preparation method is similar to that of Example 1, except that 3,5-dichloro-4-hydroxybenzaldehyde is used instead of 3-fluoro-4-hydroxybenzaldehyde in Example 1, yielding 89 mg of a black solid. mp: 132-134℃; 1 H NMR (400MHz, DMSO-d6): δ11.64(s,1H),8.19(s,1H),7.71(m,1H),7.67(m,1H),7.31(t,J=8.7Hz,1H),7.01(s,1H),4. 18(t,J=6.4Hz,2H),3.61–3.54(m,4H),2.46(overlap,2H),2.40(brs,4H),1.93(m,2H); HR-MS: m / z=374.16312[M+H] + calcd for C 18 H 21 O3N5F:374.16229.

[0051] Example 4: TM-4

[0052]

[0053] The preparation method is similar to that of Example 1, except that 3,5-dichloro-4-hydroxybenzaldehyde is used instead of 3-bromo-4-hydroxybenzaldehyde in Example 1. 60 mg of a pale yellow solid is obtained. mp: 218-220℃; 1 H NMR (400MHz, DMSO-d6): δ11.65(s,1H),8.18(s,1H),8.06(d,J=2.2Hz,1H),7.90(dd,J=8.7,2.2Hz,1H),7.25(d,J=8.7H z,1H),7.00(S,1H),4.19(t,J=6.2Hz,2H),3.63–3.53(m,4H),2.40(brs,4H),1.93(m,2H); HR-MS: m / z=434.08383[M+H] + calcd for C 18 H 21 O3N5Br: 434.08223.

[0054] Example 5: TM-5

[0055]

[0056] The preparation method is similar to that of Example 1, except that 3,5-dichloro-4-hydroxybenzaldehyde is used instead of 3-iodo-4-hydroxybenzaldehyde in Example 1. 78 mg of a pale yellow solid is obtained. mp: 237-238℃; 1 H NMR (400MHz, DMSO-d6): δ11.64(s,1H),8.25(d,J=2.2Hz,1H),8.14(s,1H),7.92(dd,J=8.6,2.2Hz,1H),7.12(d,J=8.7Hz,1H),6.8 6(s,1H), 4.17(t,J=6.0Hz,2H),3.58(brs,4H),2.52(overlap,2H),2.42(overlap,4H),1.94(m,2H); HR-MS: m / z=482.06772[M+H] + calcd for C 18 H 21 O3N5I:482.06836.

[0057] Example 6: TM-6

[0058]

[0059] The preparation method is similar to that of Example 1, except that 4-hydroxy-3-trifluoromethylbenzaldehyde is used instead of 3,5-dichloro-4-hydroxybenzaldehyde in Example 1. 132 mg of a pale yellow solid was obtained. mp: 238-239℃; 1 H NMR (400MHz, DMSO-d6): δ11.67(s,1H),8.30(s,1H),8.15(m,1H),8.09(m,1H),7.41(d,J=8.8Hz,1H),6.93(s,1H),4.25 (t,J=6.1Hz,2H),3.59–3.54(m,4H),2.48–2.43(overlap,2H),2.38(brs,4H),1.92(m,2H); HR-MS: m / z=424.15939[M+H] + calcd for C 19 H 21 O3N5F3:424.15910.

[0060] Example 7: TM-7

[0061]

[0062] The preparation method is similar to that of Example 1, except that 3,5-dichloro-4-hydroxybenzaldehyde is used instead of 3,5-difluoro-4-hydroxybenzaldehyde in Example 1. 47 mg of a pale yellow solid is obtained. mp: 236-238℃; 1 H NMR (400MHz, DMSO-d6): δ11.79(s,1H),8.21(s,1H),7.59(d,J=8.4Hz,2H),7.01(s,1H),4.27(t,J=6.2H z,2H),3.62–3.49(m,4H),2.46(t,J=7.3Hz,2H),2.36(s,4H),1.87(m,2H); HR-MS: m / z=392.15253[M+H] + calcd for C 18 H 20 O3N5F2:392.15287.

[0063] Example 8: TM-8

[0064]

[0065] The preparation method is similar to that of Example 1, except that 3,5-dibromo-4-hydroxybenzaldehyde is used instead of 3,5-dichloro-4-hydroxybenzaldehyde in Example 1. 38 mg of a pale yellow solid is obtained. mp: 163-166℃; 1 H NMR (400MHz, DMSO-d6): δ11.83(s,1H),8.24(s,1H),8.09(s,2H),7.01(s,1H),4.09(t,J=6.4H z,2H),3.60–3.54(m,4H),2.54(s,2H),2.39(s,4H),1.98(m,2H); HR-MS: m / z=513.99200[M+H] + ,calcdfor C 18 H 20 O3N5Br

[81] Br:513.99069.

[0066] Example 9: TM-9

[0067]

[0068] The preparation method is similar to that of Example 1, except that 3,5-dichloro-4-hydroxybenzaldehyde is used instead of 3-bromo-5-fluoro-4-hydroxybenzaldehyde in Example 1. 44 mg of a pale yellow solid is obtained. mp: 206-208℃; 1H NMR (400MHz, DMSO-d6): δ12.07(s,1H),8.14(s,1H),7.93–7.89(m,1H),7.29(s,1H),7.76(m,1H),4.23(t,J= 6.2Hz,2H),3.59–3.52(m,4H),2.47(overlap,2H),2.35(brs,4H),1.90(m,2H); HR-MS: m / z=452.07379[M+H] + calcd for C 18 H 20 O3N5BrF:452.07281.

[0069] Example 10: TM-10

[0070]

[0071] The preparation method is similar to that of Example 1, except that 3,5-dichloro-4-hydroxybenzaldehyde is used instead of 3,5-dichloro-4-hydroxybenzaldehyde in Example 1. 41 mg of a pale yellow solid is obtained. mp: 156-159℃; 1 H NMR (400MHz, DMSO-d6): δ11.70(s,1H),8.31(s,1H),8.05(m,1H),7.97–7.94(m,1H),6.98(s,1H), 4.11(t,J=6. 3Hz, 2H), 3.59 (s, 4H), 2.58 (overlap, 2H), 2.43 (overlap, 4H), 2.04–1.94 (m, 2H); HR-MS: m / z=470.03979[M+H] + calcd for C 18 H 20 O3N5

[81] BrC l1 :470.04121.

[0072] Example 11: TM-11

[0073]

[0074] The preparation method is similar to that of Example 1, except that N-(3-chloropropyl)dibutylamine is used instead of N-(3-chloropropyl)morpholine in Example 1. 48 mg of a pale yellow solid is obtained. mp: 169-172℃; 1H NMR (400MHz, DMSO-d6): δ12.01(s,1H),8.05(s,1H),7.92(s,2H),7.45(s,1H),4.13(t,J=6.3Hz,2H),2.65(t,J=6.4Hz,2H), 2.47–2.39(m,4H),1.92(p,J=6.8,6.3Hz,2H),1.38(m,4H),1.27(m,4H),0.87(t,J=7.3Hz,6H); HR-MS: m / z=466.17804[M+H] + calcd for C 22 H 30 O2N5Cl2:466.17711.

[0075] Example 12: TM-12

[0076]

[0077] The preparation method is similar to that of Example 1, except that N-(3-chloropropyl)piperidine hydrochloride is used instead of N-(3-chloropropyl)morpholine in Example 1. 13 mg of a pale yellow solid was obtained. mp: 146-149℃; 1 H NMR (400MHz, DMSO-d6): δ12.00(s,1H), 8.06(s,1H),7.91(s,2H),7.54(s,1H), 4.11(t,J=6.3Hz,2H), 2.57(t,J=7. 3Hz, 2H), 2.45 (overlap, 4H), 1.97 (p, J=6.7Hz, 2H), 1.52 (m, 4H), 1.39 (m, 6.4Hz, 2H); HR-MS: m / z=422.11487[M+H] + calcd for C 19 H 22 O2N5Cl2:422.11451.

[0078] Example 13: TM-13

[0079]

[0080] The preparation method is similar to that of Example 1, except that thiourea is used instead of guanidine in Example 1. 13 mg of a pale yellow solid was obtained. mp: 194.6-196.4℃; 1H NMR (400MHz, DMSO-d6): δ11.94(s,1H),7.87(s,2H),4.15(t,J=6.0Hz,2H),3.75(s,4H),3.12(m,6H),2.13(m,2H); HR-MS: m / z=441.05441[M+H] + calcd for C 18 H 19 O3N4Cl2S: 441.05494.

[0081] Example 14: TM-14

[0082]

[0083] The preparation method is similar to that of Example 1, except that urea is used instead of guanidine in Example 1. 15 mg of a pale yellow solid was obtained. mp: 228.1-230.7℃; 1 H NMR (400MHz, DMSO-d6): δ11.52(s,1H),7.81(s,2H),4.09(t,J=6.2Hz,2H),3.58(t,J =4.7Hz,4H),2.66(brs,2H),2.54(brs,4H),1.97(m,2H); HR-MS: m / z=425.07932[M+H] + calcd for C 18 H 19 O4N4Cl2: 425.07779.

[0084] Example 15: TM-15

[0085]

[0086] The preparation method is similar to that of Example 1, except that N-(3-chloropropyl)dibutylamine is used instead of N-(3-chloropropyl)morpholine in Example 1. 48 mg of a pale yellow solid is obtained. mp: 169-172℃; 1 H NMR (400MHz, DMSO-d6): δ12.01(s,1H),8.05(s,1H),7.92(s,2H),7.45(s,1H),4.13(t,J=6.3Hz,2H),2.65(t,J=6.4Hz,2H), 2.47–2.39(m,4H),1.92(p,J=6.8,6.3Hz,2H),1.38(m,4H),1.27(m,4H),0.87(t,J=7.3Hz,6H); HR-MS: m / z=466.17804[M+H] +calcd for C 22 H 30 O2N5Cl2:466.17711.

[0087] Pharmacological experiments

[0088] Experimental Example 1: Inhibitory effect of the compounds of the present invention on xanthine oxidase

[0089] method:

[0090] Febuxostat was used as a positive control, and the inhibition rate of each compound on xanthine oxidase at specific concentrations was determined by colorimetry.

[0091] The specific method is as follows: The test sample was dissolved in DMSO to prepare a 10 mM stock solution. The effect of each compound on the XOD-catalyzed hydrolysis of xanthine (XAN) was determined using a 96-well plate at 37℃ and pH 7.4. The reaction system contained 10 μmol·L⁻¹ -1 The compound (final concentration), 3 U / L XOD (no addition to the control group, replaced by 0.01% DMSO), and buffer solution (3.5 mM KH2PO4, 15.2 mM K2HPO4, 0.25 mM EDTA, and 50 μM XAN, pH 7.4) were used. The photometric activity of the product uric acid at 293 nm was measured using an ELISA reader to determine the XOD-catalyzed hydrolysis of xanthine (XAN), and the inhibition rate was calculated based on the OD value.

[0092] result:

[0093] The above compounds were measured at a final concentration of 10 μmol·L⁻¹. -1 The inhibition rate of xanthine oxidase was determined, and the IC50 of some compounds was measured. 50 Values. The results are shown in Table 1:

[0094] Table 1. Inhibitory effects of compounds on xanthine oxidase

[0095]

[0096] ND: Not determined.

Claims

1. A substituted hydroxypyrimidine compound or a physiologically acceptable salt thereof represented by the following general formula (I), （I） in, R is a mono- or poly-substituted group on the benzene ring, selected from hydrogen, halogen, and trifluoromethyl; n is 2, 3, 4 or 5; X is selected from C1-C6 alkyl-substituted amino groups, C3-C6 cycloalkyl-substituted amino groups, piperidinyl, piperazine, etc. N- Methylpiperazinyl and morpholinyl; Y is selected from O, S, or NH.

2. The compound according to claim 1 or a physiologically acceptable salt thereof, characterized in that, The compound described is the compound represented by general formula (IA): (IA) in, R is a mono- or poly-substituted group on the benzene ring, selected from hydrogen, halogen, and trifluoromethyl; n is 2, 3, 4 or 5.

3. The compound according to claim 1 or a physiologically acceptable salt thereof, characterized in that, The compound described is the compound represented by the general formula (IB): (IB) in, R is a mono- or poly-substituted group on the benzene ring, selected from hydrogen, halogen, and trifluoromethyl; n is 2, 3, 4 or 5.

4. The compound according to claim 1 or a physiologically acceptable salt thereof, characterized in that, The compound described is the compound represented by the general formula (IC): (IC) in, R is a mono- or poly-substituted group on the benzene ring, selected from hydrogen, halogen, and trifluoromethyl; n is 2, 3, 4 or 5.

5. The compound according to claim 1 or a physiologically acceptable salt thereof, characterized in that, The compound described is the compound represented by general formula (ID): (ID) in, R is a mono- or poly-substituted group on the benzene ring, selected from hydrogen, halogen, and trifluoromethyl; n is 2, 3, 4 or 5.

6. The compound according to claim 1 or a physiologically acceptable salt thereof, characterized in that, The compounds mentioned are selected from:

7. A method for preparing the compound according to any one of claims 1 to 6, characterized in that, Includes the following steps: Compound II reacts with compound III to yield compound IV, which then reacts with cyano compounds and urea, thiourea, or guanidine to generate compound I. The definitions of R, n, X, and Y are the same as those in claim 1.

8. A drug combination, characterized in that, The drug combination contains an effective dose of the compound as described in any one of claims 1 to 6 or a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

9. The pharmaceutical composition according to claim 8, characterized in that, The pharmaceutical composition is selected from tablets, capsules, granules, solutions, emulsions, pills, and injections.

10. Use of the compound of any one of claims 1 to 6 or a physiologically acceptable salt thereof in the preparation of a xanthine oxidase inhibitor.

11. Use of the compound of any one of claims 1 to 6 or a physiologically acceptable salt thereof in the preparation of a treatment for the prevention and / or treatment of hyperuricemia or gout.

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