CN116535361A - Substituted hydroxypyrimidine xanthine oxidase inhibitor and preparation method and pharmaceutical application thereof - Google Patents

Substituted hydroxypyrimidine xanthine oxidase inhibitor and preparation method and pharmaceutical application thereof Download PDF

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CN116535361A
CN116535361A CN202210094766.5A CN202210094766A CN116535361A CN 116535361 A CN116535361 A CN 116535361A CN 202210094766 A CN202210094766 A CN 202210094766A CN 116535361 A CN116535361 A CN 116535361A
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肖志艳
叶菲
程瀚增
田金英
杨亚军
李雪晨
杨颖�
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
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    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom

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Abstract

The invention belongs to the technical field of medicines, and relates to a substituted hydroxypyrimidine xanthine oxidase inhibitor, a preparation method and a pharmaceutical application thereof.

Description

Substituted hydroxypyrimidine xanthine oxidase inhibitor and preparation method and pharmaceutical application thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to substituted hydroxypyrimidine compounds in a general formula (I) and physiologically acceptable salts thereof. The use of these compounds in the treatment of xanthine oxidase-related diseases, as well as to methods for their use in therapy, and to pharmaceutical compositions containing them.
Background
Xanthine oxidase is a metabolic enzyme that is widely found in mammals and is responsible for the oxidation of hypoxanthine to xanthine and further to uric acid. However, hyperuricemia is caused when uric acid is excessively accumulated in the body. Hyperuricemia is not only a direct cause of gout, but is also associated with a variety of metabolic and chronic diseases. Hyperuricemia has now become the second most metabolic disease next to diabetes mellitus and has a rising trend year by year.
Uric acid levels in the body are regulated by both uric acid production and uric acid excretion, either in excess uric acid production or reduced uric acid excretion, which leads to elevated blood uric acid levels. When uric acid concentration exceeds its solubility in blood, urate crystals are generated and deposited in joints or soft tissues, causing inflammatory reactions and gout.
At present, three main means are adopted for treating hyperuricemia: inhibitors of uric acid-producing xanthine oxidase, inhibitors of urate transporter that promote uric acid excretion, and urokinase that accelerates the excretion of uric acid by converting uric acid into a readily water-soluble substance. Xanthine Oxidase (XO) is an important enzyme regulating uric acid production pathways, and XO inhibitors play a central role in the treatment of hyperuricemia. The XO inhibitors currently on the market are only allopurinol, febuxostat and tobipstat, and have serious adverse reactions. Therefore, there is a need to continue to develop XO inhibitors with better efficacy while having lower side effects.
The invention aims to provide a novel substituted hydroxypyrimidine compound which has higher xanthine oxidase inhibition activity and can be used for treating hyperuricemia and gout.
Disclosure of Invention
The invention aims at providing a substituted hydroxypyrimidine compound shown in a formula (I) or physiologically acceptable salt thereof.
It is another object of the present invention to provide a process for preparing substituted hydroxypyrimidines of formula (I) or a physiologically acceptable salt thereof.
It is a further object of the present invention to provide the use of substituted hydroxypyrimidines of formula (I) or a physiologically acceptable salt thereof for the preparation of xanthine oxidase inhibitors and for the preparation of a medicament for the prevention and/or treatment of hyperuricemia or gout.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a substituted hydroxypyrimidine compound represented by the following general formula (I) or a physiologically acceptable salt thereof,
wherein R is a single or multiple substituent group on the benzene ring and is selected from hydrogen, halogen and trifluoromethyl; n is 2,3,4 or 5; x is selected from C 1 -C 6 Alkyl-substituted amino, C 3 -C 6 Cycloalkyl-substituted amino, piperidinyl, piperazinyl, N-methylpiperazinyl, and morpholinyl; y is selected from O, S or NH.
Preferred compounds are those of formula (IA) or a physiologically acceptable salt thereof:
wherein R is a single or multiple substituent group on the benzene ring and is selected from hydrogen, halogen and trifluoromethyl; n is 2,3,4 or 5.
Preferred compounds are those of formula (IB) or a physiologically acceptable salt thereof:
wherein R is a single or multiple substituent group on the benzene ring and is selected from hydrogen, halogen and trifluoromethyl; n is 2,3,4 or 5.
Preferred compounds are those of the general formula (IC):
wherein R is a single or multiple substituent group on the benzene ring and is selected from hydrogen, halogen and trifluoromethyl; n is 2,3,4 or 5.
Preferred compounds are those of the general formula (ID) or a physiologically acceptable salt thereof:
wherein R is a single or multiple substituent group on the benzene ring and is selected from hydrogen, halogen and trifluoromethyl; n is 2,3,4 or 5.
The most preferred compounds are those selected from the group consisting of:
according to a second aspect of the present invention, there is provided a method for synthesizing the compound of the first aspect, comprising the steps of:
the compound of formula II reacts with the compound of formula III to obtain a compound of formula IV, and the compound of formula IV reacts with cyano compound and urea, thiourea or guanidine to generate a compound of formula I:
wherein R, n, X, Y is as defined in claim 1.
According to a third aspect of the present invention, there is provided a pharmaceutical composition comprising an effective amount of any one of the substituted hydroxypyrimidines of the first aspect of the present invention, and a physiologically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is selected from the group consisting of tablets, capsules, granules, solutions, emulsions, pills and injections.
For the preparation of medicaments, the compounds of the general formula (I) can be admixed in a known manner with suitable pharmaceutical carrier substances, fragrances, flavourings and colours in a known manner and formulated as tablets or coated tablets or suspended or dissolved in water or oil with other additional substances. The compounds of the present invention may be administered orally or parenterally. The oral administration can be tablet, capsule, granule, solution, emulsion, pill, and parenteral administration can be injection. These formulations are prepared according to methods well known to those skilled in the art. Adjuvants used for the manufacture of tablets, capsules, granules, pills are conventional adjuvants such as starch, gelatin, acacia, silica, polyethylene glycol, solvents for liquid dosage forms such as water, ethanol, propylene glycol, vegetable oils such as corn oil, peanut oil, olive oil, etc. Other adjuvants may also be present in the formulations containing the compounds of the invention, such as surfactants, lubricants, disintegrants, preservatives, flavouring agents, pigments and the like.
According to a fourth aspect of the present invention there is provided the use of a substituted hydroxypyrimidine compound of the first aspect or a physiologically acceptable salt thereof in the preparation of a xanthine oxidase inhibitor.
The fourth aspect of the technical scheme of the invention also provides the application of the substituted hydroxypyrimidine compound or the physiologically acceptable salt thereof in preparing a medicament for preventing and/or treating hyperuricemia and gout.
Pharmacological studies show that the compound of the general formula II has the activity of inhibiting xanthine oxidase, and can effectively reduce the blood uric acid level in vivo, thereby achieving the purpose of treatment.
The beneficial technical effects are as follows:
xanthine oxidase inhibitors are the main uric acid lowering drugs used clinically. The compound related by the invention has a large structural difference from the existing medicines and has obvious xanthine oxidase inhibition effect. Wherein, the inhibition activity of most compounds to xanthine oxidase at the concentration of 10 mu M exceeds 90%, which is equivalent to the activity of febuxostat of similar clinical products.
Detailed Description
The invention is further illustrated below with reference to examples, which are not intended to limit the scope of the invention.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS) or High Resolution Mass Spectrometry (HRMS). NMR displacements (δ) are given in parts per million (ppm). The melting point (m.p.) is the melting point given in degrees celsius, the temperature being uncorrected. Column chromatography generally uses 200-300 mesh silica gel. NMR was performed using JEOL ECZ-400S and INOVA-500MHz in DMSO-d as the solvent 6 Internal standard is TMS and chemical shifts are given in ppm. The MS was determined using an Agilent LC/MSD TOF LC/MS.
Example 1: TM-1
a) To a 100mL round bottom flask was added 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), DMF (15 mL), stirring at 80℃for 12h, the solvent was distilled off after completion of the reaction, the residue was dissolved in water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, the solvent was removed by swirling, and dried for further use.
b) Sequentially adding the above materials into a 100mL round bottom flaskThe product, ethyl cyanoacetate (399 mg,3 mmol), guanidine hydrochloride (280 mg,3 mmol), sodium acetate (408 mg,3 mmol), pyridine (8 mL) were reacted at 120℃and the reaction was complete by TLC, the solvent was removed by spinning, the residue was dissolved in water, extracted with ethyl acetate, the organic phases were combined, and the solvent was removed by spinning, followed by elution with 1M dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated brine, methanol/dichloromethane gradient (0% methanol-15% methanol) to give 59mg of a pale yellow solid. 206-208 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):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 O 3 N 5 Cl 2 :424.09377.
example 2: TM-2
The preparation was carried out in a similar manner to example 1, except that 3, 5-dichloro-4-hydroxybenzaldehyde in example 1 was replaced with 3-chloro-4-hydroxybenzaldehyde. 47mg of white solid was obtained. 192-194 ℃ in m.p.; 1 H NMR(400MHz,DMSO-d 6 ):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 O 3 N 5 Cl:390.13274.
example 3: TM-3
The preparation was carried out in a similar manner to example 1, except that 3, 5-dichloro-4-hydroxybenzaldehyde in example 1 was replaced with 3-fluoro-4-hydroxybenzaldehyde, to obtain 89mg of a black solid. 132-134 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):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 O 3 N 5 F:374.16229.
example 4: TM-4
The preparation was carried out in analogy to example 1, except that 3, 5-dichloro-4-hydroxybenzaldehyde was used instead of 3, 5-dichloro-4-hydroxybenzaldehyde in example 1. 60mg of a pale yellow solid was obtained. 218-220 ℃ in m.p.; 1 H NMR(400MHz,DMSO-d 6 ):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＝8.7Hz,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 O 3 N 5 Br:434.08223.
example 5: TM-5
The preparation was carried out in a similar manner to example 1, except that 3, 5-dichloro-4-hydroxybenzaldehyde in example 1 was replaced with 3-iodo-4-hydroxybenzaldehyde. 78mg of a pale yellow solid was obtained. 237-238 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):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),6.86(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 O 3 N 5 I:482.06836.
example 6: TM-6
The preparation was carried out in a similar manner to example 1, except that 4-hydroxy-3-trifluoromethylbenzaldehyde was used instead of 3, 5-dichloro-4-hydroxybenzaldehyde in example 1. 132mg of a pale yellow solid was obtained. 238-239 ℃ at m.p.; 1 H NMR(400MHz,DMSO-d 6 ):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 O 3 N 5 F 3 :424.15910.
example 7: TM-7
The preparation was carried out in a similar manner to example 1, except that 3, 5-difluoro-4-hydroxybenzaldehyde was used instead of 3, 5-dichloro-4-hydroxybenzaldehyde in example 1. 47mg of pale yellow solid was obtained. 236-238 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):δ11.79(s,1H),8.21(s,1H),7.59(d,J＝8.4Hz,2H),7.01(s,1H)，4.27(t,J＝6.2Hz,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 O 3 N 5 F 2 :392.15287.
example 8: TM-8
The preparation was carried out in analogy to example 1, except that 3, 5-dichloro-4-hydroxybenzaldehyde was used instead of 3, 5-dichloro-4-hydroxybenzaldehyde in example 1. 38mg of a pale yellow solid was obtained. 163-166 ℃ in m.p.; 1 H NMR(400MHz,DMSO-d 6 ):δ11.83(s,1H),8.24(s,1H)，8.09(s,2H),7.01(s,1H)，4.09(t,J＝6.4Hz,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] + ,calcd for C 18 H 20 O 3 N 5 Br [81] Br:513.99069.
example 9: TM-9
The preparation was carried out in analogy to example 1, except that 3, 5-dichloro-4-hydroxybenzaldehyde in example 1 was replaced by 3-bromo-5-fluoro-4-hydroxybenzaldehyde. 44mg of pale yellow solid was obtained. 206-208 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):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 O 3 N 5 BrF:452.07281.
example 10: TM-10
The preparation was carried out in analogy to example 1, except that 3, 5-dichloro-4-hydroxybenzaldehyde in example 1 was replaced by 3-bromo-5-chloro-4-hydroxybenzaldehyde. 41mg of a pale yellow solid was obtained. 156-159 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):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 O 3 N 5 [81] BrC l1 :470.04121.
example 11: TM-11
The preparation is similar to example 1, except that N- (3-chloropropyl) dibutyl is usedThe amine replaces the N- (3-chloropropyl) morpholine in example 1. 48mg of a pale yellow solid was obtained. 169-172 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):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 O 2 N 5 Cl 2 :466.17711.
example 12: TM-12
The preparation was carried out in analogy to example 1, except that N- (3-chloropropyl) morpholine in example 1 was replaced by N- (3-chloropropyl) piperidine hydrochloride. 13mg of a pale yellow solid was obtained. 146-149 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):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 O 2 N 5 Cl 2 :422.11451.
example 13: TM-13
The preparation was similar to example 1, except that thiourea was used instead of guanidine in example 1. 13mg of a pale yellow solid was obtained. 194.6-196.4 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):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 O 3 N 4 Cl 2 S:441.05494.
example 14: TM-14
The preparation is similar to example 1, except that urea is used instead of guanidine in example 1. 15mg of a pale yellow solid was obtained. 228.1-230.7 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):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 O 4 N 4 Cl 2 :425.07779.
example 15: TM-15
The preparation was carried out in analogy to example 1, except that N- (3-chloropropyl) morpholine in example 1 was replaced by N- (3-chloropropyl) dibutylamine. 48mg of a pale yellow solid was obtained. 169-172 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):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 O 2 N 5 Cl 2 :466.17711.
pharmacological experiments
Experimental example 1: inhibition of xanthine oxidase by the compounds of the invention
The method comprises the following steps:
the inhibition of xanthine oxidase by each compound at a specific concentration was determined by colorimetry using febuxostat as a positive control.
The specific method comprises the following steps: test samples were dissolved in DMSO to prepare 10mM stock solutions. The effect of each compound on the hydrolysis of Xad-catalyzed Xanthine (XAN) was measured at 37℃and pH7.4 using 96-well plates. The reaction system contains 10 mu mol.L -1 3U/L XOD (vsNo addition of the control group, 0.01% DMSO instead) and buffer (3.5 mM KH 2 PO 4 ,15.2mM K 2 HPO 4 0.25mM EDTA, and 50. Mu.M XAN, pH 7.4). And detecting the luminosity of uric acid serving as a product at the wavelength of 293nm by adopting an enzyme-labeled instrument to determine the Xad-catalyzed Xanthine (XAN) hydrolysis, and calculating the inhibition rate according to the OD value.
Results:
the final concentration of the above-mentioned compounds was measured to be 10. Mu. Mol.L -1 Inhibition of xanthine oxidase at the time and determination of IC of a part of the compounds 50 Values. The results are shown in Table 1:
TABLE 1 inhibition of xanthine oxidase by Compounds
ND: not measured.

Claims (11)

1. A substituted hydroxypyrimidine compound represented by the following general formula (I) or a physiologically acceptable salt thereof,
wherein,,
r is a single or multiple substituent group on benzene ring, selected from hydrogen, halogen and trifluoromethyl;
n is 2,3,4 or 5;
x is selected from C 1 -C 6 Alkyl-substituted amino, C 3 -C 6 Cycloalkyl-substituted amino, piperidinyl, piperazinyl, N-methylpiperazinyl, and morpholinyl;
y is selected from O, S or NH.
2. The compound of claim 1, or a physiologically acceptable salt thereof, wherein the compound is of formula (IA):
wherein,,
r is a single or multiple substituent group on benzene ring, selected from hydrogen, halogen and trifluoromethyl;
n is 2,3,4 or 5.
3. The compound of claim 1, or a physiologically acceptable salt thereof, wherein the compound is of formula (IB):
wherein,,
r is a single or multiple substituent group on benzene ring, selected from hydrogen, halogen and trifluoromethyl;
n is 2,3,4 or 5.
4. The compound of claim 1, or a physiologically acceptable salt thereof, wherein the compound is of formula (IC):
wherein,,
r is a single or multiple substituent group on benzene ring, selected from hydrogen, halogen and trifluoromethyl;
n is 2,3,4 or 5.
5. The compound of claim 1, or a physiologically acceptable salt thereof, wherein the compound is of formula (ID):
wherein,,
r is a single or multiple substituent group on benzene ring, selected from hydrogen, halogen and trifluoromethyl;
n is 2,3,4 or 5.
6. A compound according to claim 1, or a physiologically acceptable salt thereof, wherein the compound is selected from the group consisting of:
7. a process for the preparation of a compound according to any one of claims 1 to 6, comprising the steps of:
the compound of formula II reacts with the compound of formula III to obtain a compound of formula IV, and the compound of formula IV reacts with cyano compound and urea, thiourea or guanidine to generate a compound of formula I:
wherein R, n, X, Y is as defined in claim 1.
8. A pharmaceutical combination comprising an effective amount of a compound according to any one of claims 1 to 6, or a physiologically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
9. The pharmaceutical composition of any one of claims 8, wherein the pharmaceutical composition is selected from the group consisting of tablets, capsules, granules, solutions, emulsions, pills, and injections.
10. Use of a compound according to any one of claims 1 to 6, or a physiologically acceptable salt thereof, for the preparation of a xanthine oxidase inhibitor.
11. Use of a compound according to any one of claims 1 to 6, or a physiologically acceptable salt thereof, for the preparation of a medicament for the prophylaxis and/or treatment of hyperuricemia or gout.
CN202210094766.5A 2022-01-26 2022-01-26 Substituted hydroxypyrimidine xanthine oxidase inhibitor and preparation method and pharmaceutical application thereof Pending CN116535361A (en)

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