CN106946851B - A drug used to prevent and treat kidney stones - Google Patents

Abstract

The invention discloses a pyrimidinedione compound of chemical formula I and pharmaceutically acceptable salts, prodrugs and solvates thereof. Pharmacological tests show that the pyrimidinedione compound of the chemical formula I of the present invention can significantly reduce the rate of kidney stones and kidney calcium content, serum urea nitrogen and serum creatinine, can significantly improve the kidney coefficient, and has good preventive and therapeutic effects on kidney stones .

Description

A drug used to prevent and treat kidney stones

technical field

The invention relates to the technical field of medicine, and the invention discloses medicines for preventing and treating kidney stones.

Background technique

Kidney stones refer to stones that occur in the renal calices, renal pelvis, and the junction of the renal pelvis and ureter. Most of them are located in the renal pelvis and calices, and renal parenchymal stones are rare. Plain radiographs show that there are single or multiple round, oval or obtuse triangular dense shadows in the renal area, with high and uniform density and smooth edges, but some are not smooth and mulberry-shaped . Stones in any part of the urinary system can originate in the kidney. According to the different stone components, kidney stones can be divided into calcium oxalate stones, calcium phosphate stones, uric acid (uric acid salt) stones, ammonium magnesium phosphate stones, cystine stones and purine stones. Kidney stones are caused by the imbalance of colloid and crystal metabolism in the body, and are related to factors such as infection, nutritional metabolism disorder, foreign bodies in the urinary system, urine stasis, and geographical climate. Symptoms, it is easy to cause gout and diabetes, hypertension, acute pyelonephritis, chronic renal failure, uremia and other diseases that seriously affect health and life, and the clinical incidence has increased in recent years.

At present, extracorporeal impact lithotripsy (ESWL) or other stone removal techniques are mostly used clinically. Although this method can discharge the calculus, it has many side effects, and the residual rate and recurrence rate of the calculus are very high. According to statistics, the recurrence risk of kidney stones reaches 50% within 5 years, 67% within 9 years, and 75% within 25 years. Therefore, it is very necessary to find an effective treatment method.

Contents of the invention

The object of the present invention is to provide a medicine with preventive and therapeutic effects on kidney stones.

According to one aspect of the present invention, the present invention provides a pyrimidinedione compound, and pharmaceutically acceptable salts, prodrugs and solvates thereof.

According to another aspect of the present invention, another object of the present invention is to provide a preparation method of the pyrimidinedione compound, and pharmaceutically acceptable salts, prodrugs and solvates thereof.

According to another aspect of the present invention, another object of the present invention is to provide the application of the pyrimidinedione compound, and pharmaceutically acceptable salts, prodrugs and solvates thereof in the preparation of medicaments for Prevention and treatment of kidney stones.

According to another aspect of the present invention, another object of the present invention is to provide a compound comprising one or more of the pyrimidinedione compounds, and pharmaceutically acceptable salts, prodrugs and solvates thereof pharmaceutical composition.

The pyrimidinedione compound according to the present invention is represented by the following chemical formula I:

[chemical formula I]

In formula I,

W ₁ and W ₂ may be the same or different, each independently selected from: N or CR ₁ ;

A is selected from: substituted or unsubstituted C1-6 alkylene, substituted or unsubstituted C3-6 cycloalkylene, substituted or unsubstituted C6-12 arylene, wherein the substituent is C1-6 alkane group, C3-6 cycloalkyl or halogen, and one or more -CH ₂ - in A may optionally be replaced by a group selected from -NH-, -O- or -S-, provided that No two groups selected from -NH-, -O- or -S- can be linked together;

Each R1 is independently selected from _: H, halogen, C1-6 alkyl optionally substituted by halogen or OH, CN, OH, amino, C1-6 alkoxy, C2-6 alkynyl, C2-6 alkenyl , C3-6 cycloalkyl, C1-6 alkylamino, formyl, COOH, COOR ₂ , COR ₂ , CONR ₂ R _2a , -NHCOR ₂ , -NHSO ₂ R ₂ , heterocycloalkyl, aryl, hetero Aryl, C1-6 alkylsulfonyl, arylsulfonyl or heteroarylsulfonyl _; R2 and _R2a are each independently selected from C1-6 alkyl, C3-6 cycloalkyl or heterocycloalkyl, Alternatively, R ₂ and R _2a form a 3-7 membered heterocycloalkyl group together with the N atom they are connected to;

Hy represents heteroaryl optionally substituted by one or more substituents independently selected from H, halogen, C1-6 alkyl optionally substituted by halogen or OH, CN, OH , amino, C1-6 alkoxy, C2-6 alkynyl, C2-6 alkenyl, C3-6 cycloalkyl, C1-6 alkylamino, formyl, COOH, COOR ₃ , COR ₃ , CONR ₃ R _3a , -NHCOR ₃ , -NHSO ₃ R ₃ ; R ₃ and R _3a are each independently selected from C1-6 alkyl, C3-6 cycloalkyl or heterocycloalkyl, or, R ₃ and R _3a and their The connected N atoms together form a 3-7 membered heterocycloalkyl group;

n represents 0, 1, 2 or 3.

In a preferred embodiment, W ₁ and W ₂ are each independently selected from: N.

In a preferred embodiment, W ₁ is selected from N and W ₂ is selected from CR ₁ .

In a preferred embodiment, A is selected from: substituted or unsubstituted C1-6 alkylene.

In a preferred embodiment, A is selected from: -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ OCH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ -.

In a preferred embodiment, A is selected from: 1,4-cyclohexylene.

In a preferred embodiment, the heteroaryl represented by Hy is 5 to 10 membered, preferably 5 or 6, containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen as ring atoms, and the remaining ring atoms are carbon. Elementary aryl.

Preferred compounds of the present invention are:

In a preferred embodiment of the present invention, the present invention provides that the pharmaceutically acceptable salt of the pyrimidinedione compound of chemical formula I is selected from base addition salts and acid addition salts. Preferably, the base addition salt is selected from sodium salts, potassium salts, calcium salts, lithium salts, magnesium salts, zinc salts, ammonium salts, tetramethylammonium salts, tetraethylammonium salts, triethylamine salts, triethylamine salts, Methylammonium, ethylamine, diethanolamine, arginine or lysine; or an acid addition salt selected from hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate or p-toluenesulfonate.

The present invention also includes isotopically labeled compounds of the present invention which are isotopically labeled unless one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature. The compounds are the same as those described herein. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ¹⁸ F and ³⁶ Cl.

In the present invention, there is no specific limitation on the prodrug of the compound of the present invention, as long as it can be metabolized into the compound of the present invention in the living body, including without limitation esters, such as methyl ester, ethyl ester and the like.

In the present invention, the solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol.

Group definition

Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms is preferred, and an alkyl group having 1 to 6 carbon atoms is more preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Amylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4- Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3- Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof.

The term "alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- -butenyl etc. C2-10 alkenyl is preferred, C2-6 alkenyl is more preferred, and C2-4 alkenyl is most preferred.

The term "alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl etc. C2-10 alkynyl is preferred, C2-6 alkynyl is more preferred, and C2-4 alkynyl is most preferred.

The term "cycloalkyl" refers to a saturated monocyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably a cycloalkyl ring comprising 3 to 10 carbon atoms, most preferably Cycloalkyl rings contain 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., preferably cyclopropyl.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6 to 10 membered, more preferably Phenyl and naphthyl, most preferably phenyl.

The term "heteroaryl" refers to a 5 to 14 membered aryl group having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen as ring atoms and the remaining ring atoms being carbon. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetra Azolyl, tetrazole, etc.

The term "heterocycloalkyl" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably the heterocyclyl ring contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably the heterocyclyl ring contains 3 to 10 ring atoms, more preferably the heterocyclyl ring contains 5 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, dihydrofuranyl, tetrahydrofuranyl Wait. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

pharmaceutical composition

The term "pharmaceutical composition" used refers to: containing at least one pyrimidinedione compound of chemical formula I according to the present invention and pharmaceutically acceptable salts and prodrugs thereof formulated with pharmaceutically acceptable excipients and solvate compositions. Typical pharmaceutical compositions are: powder, tablet, granule, capsule, solution, emulsion, suspension, injection, spray, aerosol, powder mist, lotion, liniment, ointment, hard Ointments, pastes, patches, etc.

The term "excipient" used in the present invention refers to: anti-adhesive agents, antioxidants, binders, coating agents, tableting aids, disintegrants, lubricants, emulsifiers and the like. Typical excipients are: butylated hydroxytoluene, calcium carbonate, calcium phosphate, calcium stearate, croscarmellose, crospovidone, citric acid, crospovidone, cysteine, ethyl Hydroxypropyl Cellulose, Gelatin, Hydroxypropyl Cellulose, Hydroxypropyl Methyl Cellulose, Lactose, Magnesium Stearate, Maltitol, Mannitol, Methionine, Methyl Cellulose, Methylparaben, Polyethylene Glycol Alcohol, sodium citrate, sorbitol, starch, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin C, vitamin E, xylitol, etc.

Synthetic method of the present invention

The pyrimidine diketone compound of chemical formula I of the present invention can be prepared by the following method:

step one:

This step comprises reacting a compound of formula II with a compound of formula III and a palladium catalyst, a base in an inert solvent to prepare a compound of formula IV.

Solvents used in this step can be alcohols such as methanol, ethanol, isopropanol, etc.; aromatics such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride; nitrile solvents, Such as acetonitrile; ether solvents, such as tetrahydrofuran, 1,4-dioxane; or their mixed solvents. The solvent is preferably 1,4-dioxane.

The base used in this step can be hydroxide such as sodium hydroxide, potassium hydroxide; carbonate such as sodium carbonate, potassium carbonate, cesium carbonate; bicarbonate such as sodium bicarbonate, potassium bicarbonate. The base is preferably a carbonate, more preferably potassium carbonate.

Step two:

This step comprises reacting a compound of formula V with a compound of formula VI and a base, a catalyst in an inert solvent to prepare a compound of formula VII.

Solvents used in this step can be alcohols such as methanol, ethanol, isopropanol, etc.; aromatics such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride; nitrile solvents, Such as acetonitrile; or their mixed solvents. The solvent is preferably acetonitrile.

The base used in this step can be a hydroxide such as sodium hydroxide, potassium hydroxide; a carbonate such as sodium carbonate, potassium carbonate; a bicarbonate such as sodium bicarbonate, potassium bicarbonate; an acetate such as Sodium acetate or potassium acetate. The base is preferably bicarbonate, more preferably potassium bicarbonate.

The catalyst used in this step may be a cuprous salt, such as cuprous iodide.

Step three:

This step comprises reacting a compound of formula IV with a compound of formula VII and a base in an inert solvent to prepare a compound of formula I.

Solvents used in this step can be alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxy ethyl alcohol, diethylene glycol, or glycerin; aromatic hydrocarbons, such as benzene, toluene, or xylene; halogenated hydrocarbons, such as chloroform, methylene chloride; or their mixed solvents. The solvent is preferably an aromatic hydrocarbon, more preferably toluene.

The base used in this step can be hydroxide such as sodium hydroxide, potassium hydroxide; carbonate such as sodium carbonate, potassium carbonate, cesium carbonate; bicarbonate such as sodium bicarbonate, potassium bicarbonate. The base is preferably a carbonate, more preferably cesium carbonate.

In the above steps, W ₁ , W ₂ , A, R ₁ , Hy, n are defined as above, X ₁ and X ₂ may be the same or different, and each is independently selected from halogen, preferably chlorine or bromine.

Beneficial effect

The pyrimidinedione compound of the present invention can significantly reduce the rate of kidney stones and kidney calcium content, serum urea nitrogen and serum creatinine, can significantly increase the coefficient of kidney, and has good preventive and therapeutic effects on kidney stones.

Detailed ways

Hereinafter, the present invention is described in more detail to facilitate understanding of the present invention.

Example 1: 1-(3-(2,4-dioxo-6-(pyridin-2-yl)-3,4-dihydropyrimidin-1(2H)-yl)propyl)-3-( pyrimidin-2-yl)urea (compound 1)

Step 1. Add 6-chloropyrimidine-2,4(1H,3H)-dione (0.29g, 2.0mmol), pyridin-2-ylboronic acid (0.30g, 2.2mmol), tetra (Triphenylphosphine)palladium (29mg, 0.025mmol), K ₂ CO ₃ (0.33g, 2.4mmol), under nitrogen protection, add 1,4-dioxane (10mL), water (2mL), 45 ℃ reaction 4h. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate and separated by silica gel column chromatography, eluted with petroleum ether/ethyl acetate 20:1 to obtain a light yellow solid 6-(pyridin-2-yl)pyrimidine - 2,4(1H,3H)-dione, which is 0.28 g of a light yellow solid, with a purity of 98% and a yield of 74%. ESI-MS: 190.05 [M+H] ⁺ .

Step 2: Mix 1,3-dibromopropane (1.00g, 5.0mmol), KHCO ₃ (1.03g, 7.5.0mmol), CuI (0.095g, 0.5mmol) and toluene (50ml) together and heat under stirring to 80°C, then slowly add a solution of 1-(pyrimidin-2-yl)urea (0.69g, 5.0mmol) in toluene (30ml) dropwise, the dropwise addition was completed in 1 hour, and stirred under reflux for 6 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain 1.07 g of white crystal 1-(3-bromopropyl)-3-(pyrimidin-2-yl)urea with a purity of 97% and a yield of 85% . ESI-MS: 259.01 [M+H] ⁺ .

Step 3: Mix 6-(pyridin-2-yl)pyrimidine-2,4(1H,3H)-dione (0.19g, 1.0mmol), 1-(3-bromopropyl)-3-(pyrimidine-2 A mixture of urea (0.28g, 1.1mmol), potassium carbonate (0.28g, 2mmol) in acetonitrile (30mL) was stirred at 60°C for 12h, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography and purified with petroleum Elution with ether/ethyl acetate 4:1 gave 1-(3-(2,4-dioxo-6-(pyridin-2-yl)-3,4-dihydropyrimidine-1(2H) as a white solid -yl)propyl)-3-(pyrimidin-2-yl)urea 0.30 g, purity 99%, yield 81%.

ESI-MS: 368.14[M+H] ⁺

Elemental analysis: theoretical value/measured value, C (55.58/55.42), H (4.66/4.74), N (26.69/26.61), O (13.07/13.23)

¹ H NMR (400MHz, DMSO-D6) δ11.99(s, 1H), 9.92(s, 1H), 8.42(m, 3H), 7.41-7.48(m, 3H), 6.98(q, 1H), 6.57 (s, 1H), 6.04 (s, 1H), 4.01 (t, 2H), 3.31 (t, 2H), 1.74 (m, 2H).

Following a similar method, the following compounds were synthesized:

Pharmacological Test Example: The Preventive and Therapeutic Effects of the Target Compound on Kidney Calculus

1. Effects of Compounds 1-4 on Kidney Stones and Kidney Parameters in Rats

60 male Wistar rats weighing 180-220 g were randomly divided into seven groups, namely control group, model group, and compound 1-5 groups (collectively referred to as experimental groups). Rats in each group were fed with normal diet and distilled water. The five groups of rats in the model group and the experimental group were fed 2 mL/rat with 1% ethylene glycol (EG)+2% ammonium chloride (AC) every day. Administration was given at the beginning of modeling, once a day for eight consecutive weeks. As the positive control group, the traditional Chinese medicine Shenshitong Granules was selected as the positive control drug, and 3g/kg was intragastrically administered every day. The experimental group was given 20mg/kg orally every day. One hour after the last administration, the animals were anesthetized with pentobarbital sodium, and blood was collected from the abdominal aorta to detect the blood urea nitrogen and creatinine levels, the kidneys were collected to detect the kidney coefficient, the left kidney was collected to measure the calcium content in the kidney, and the right kidney was used for pathological examination. Measure the stone rate. The experimental results were analyzed using SPSS statistical software.

The impact of table 1 target compound on rat kidney calculus

Table 2 Effects of target compounds on rat kidney coefficient, renal calcium content, serum creatinine and serum urea nitrogen

Note: Compared with blank control group, *P<0.05, **P<0.01;

The above test results showed that, compared with the control group, the calculus rate of rats in the model group was significantly higher than that of the control group, the kidney coefficient was significantly lower than that of the control group, and the renal calcium content, serum urea nitrogen and serum creatinine were significantly higher than those of the control group, suggesting that calculus Model modeling is successful. Compared with the model group, the calculus rate and renal calcium content, serum urea nitrogen and serum creatinine of rats in the experimental group decreased significantly, while the renal coefficient was significantly increased (P<0.01). Compared with the positive control, the preventive and therapeutic effect of the compound of the invention on kidney stones is equivalent to that of the existing Shenshitong granules. Therefore, the compound of the present invention has good preventive and therapeutic effects on kidney stones.

In summary, the pyrimidinedione compounds of the present invention can significantly reduce the rate of renal calculus and renal calcium content, serum urea nitrogen and serum creatinine, can significantly increase the renal coefficient, and have good preventive and therapeutic effects on renal calculus.

The preferred embodiments of the present invention have been described above, but they are not intended to limit the present invention. Modifications and changes to the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.

Claims (9)

1. A pyrimidinedione compound of chemical formula I and a pharmaceutically acceptable salt thereof: [chemical formula I] In formula I, W ₁ and W ₂ may be the same or different, each independently selected from: N or CR ₁ ; A is selected from: substituted or unsubstituted C1-6 alkylene, substituted or unsubstituted C3-6 cycloalkylene, wherein the substituent is C1-6 alkyl; Each R ₁ is independently selected from H, halogen, amino, C1-6 alkoxy, COR ₂ , CONR ₂ R _2a ; R ₂ and R _2a are each independently selected from C1-6 alkyl groups, or, R ₂ and R _2a together with the N atom they are connected to form a 3-7 membered heterocycloalkyl group; Hy represents a heteroaryl group, which is a 5-membered or 6-membered aryl group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen as ring atoms, and the remaining ring atoms are carbon. The group is optionally substituted by one or more substituents independently selected from H, halogen, C1-6 alkyl; n represents 0, 1, 2 or 3. 2. The pyrimidinedione compound and the pharmaceutically acceptable salt thereof according to claim 1, wherein said W ₁ and W ₂ are each independently selected from: N. 3. The pyrimidinedione compound and its pharmaceutically acceptable salt according to claim 1, wherein said A is selected from: -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH2CH _{( CH3 )} CH2-. 4. The pyrimidinedione compound and the pharmaceutically acceptable salt thereof according to claim 1, wherein said A is selected from: 1,4-cyclohexylene. 5. A pyrimidinedione compound and a pharmaceutically acceptable salt thereof, characterized in that, the pyrimidinedione compound is selected from: 6. A method for preparing the pyrimidinedione compound according to claim 1, said method comprising the following steps: step one: This step comprises making the compound of chemical formula II react with the compound of chemical formula III and palladium catalyst, base in inert solvent to prepare the compound of chemical formula IV; Step two: The step comprises reacting a compound of formula V with a compound of formula VI and a base, a catalyst in an inert solvent to prepare a compound of formula VII; Step three: This step comprises reacting a compound of formula IV with a compound of formula VII and a base in an inert solvent to prepare a compound of formula I; In the above steps, the definitions of W ₁ , W ₂ , A, R ₁ , Hy, and n are as described in claim 1, and X ₁ and X ₂ may be the same or different, each independently selected from halogen. 7. The method according to claim 6, characterized in that X ₁ and X ₂ can be the same or different, and are independently selected from chlorine or bromine. 8. A pharmaceutical composition, which contains at least one pyrimidinedione compound according to any one of claims 1-5 and a pharmaceutically acceptable salt thereof formulated with a pharmaceutically acceptable excipient. 9. The use of pyrimidinedione compounds and pharmaceutically acceptable salts thereof according to any one of claims 1-5 in the preparation of medicines, which are used for preventing and treating kidney stones.