CN106470981B

CN106470981B - The new derivatives, preparation method and application of 2- [3- cyano-4-isobutoxy phenyl] -4- methylthiazol-5-formic acid

Info

Publication number: CN106470981B
Application number: CN201480078912.9A
Authority: CN
Inventors: 王海勇; 孙天宇; 陈晓峰
Original assignee: Xiangbei Welman Pharmaceutical Co Ltd
Current assignee: Xiangbei Welman Pharmaceutical Co Ltd
Priority date: 2014-06-23
Filing date: 2014-06-23
Publication date: 2019-05-07
Anticipated expiration: 2034-06-23
Also published as: CN106470981A; WO2015196323A1

Abstract

The present invention provides compound shown in a kind of logical formula (I) or its salt or its stereoisomer pharmaceutically.When being applied to logical formula (I) compound or its salt or its stereoisomer to prevent and treat hyperuricemia, there is more preferably than Febuxostat anti-trioxypurine effect and more preferably safety.

Description

Novel derivative of 2- [ 3-cyano-4-isobutoxyphenyl ] -4-methylthiazole-5-carboxylic acid, preparation method and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a 2- [ 3-cyano-4-isobutoxyphenyl ] -4-methylthiazole-5-carboxylic acid derivative, a salt thereof, a stereoisomer thereof, a pharmaceutical preparation at least comprising a compound shown as a formula (I) or a salt thereof or a stereoisomer thereof as an active ingredient, and application of the pharmaceutical preparation in preventing and treating hyperuricemia diseases.

Background

Gout is a group of syndromes caused by purine metabolic abnormality of human body, and hyperuricemia is a stage in the development of the pathological changes. It can be classified into primary gout and secondary gout according to the cause of the disease.

The primary gout has obvious family genetic tendency, is good for middle-aged and elderly people, has the peak disease of 30-50 years old, is about 95 percent male, and is usually developed after menopause in 5 percent female. The etiology of primary gout mainly includes two aspects:

(1) the genetic factors are clinically seen, gout has obvious family genetic tendency, and the detection rate of symptomatic hyperuricemia of gout patients is obviously higher than that of non-gout patients. Gout is closely related to other metabolic diseases with genetic tendency (obesity, hypertension, hyperlipidemia, diabetes, etc.). The genetic basis of mutations in the enzyme gene that cause alterations in the activity of the enzyme in purine metabolism leading to overproduction of uric acid has been ascertained.

(2) Environmental factors such as binge eating, alcohol drinking and excessive ingestion of purine-rich food are common causes of acute episodes of gouty arthritis. The improvement of social and economic conditions, the increase of the prevalence rate of metabolic diseases such as obesity and hypertension, and the increase of the prevalence rate of gout.

Secondary gout is slow in onset of disease due to congenital renal tubular dysfunction and chronic renal failure, and is more acute in onset of disease. The etiology of secondary gout mainly comprises the following three aspects:

(1) causes of excessive uric acid production in vivo, such as leukemia, lymphoma in the advanced stage, especially after chemotherapy, polycythemia vera, etc. Severe trauma, crush injury, major post-surgery.

(2) Causes of the kidney uric acid discharge reduction, such as severe hypertension and eclampsia, causes the kidney blood flow reduction and affects the filtration of uric acid; renal failure of any cause; congenital renal tubular dysfunction, fangke's syndrome, barter's syndrome, etc.; metabolic abnormalities affecting the uric acid secretion of renal tubules, such as ethanol poisoning, hunger excess, ketoacidosis, lactic acidosis and the like can cause the increase of the content of organic acids in blood and inhibit the uric acid secretion of renal tubules; some drugs can cause hyperuricemia, such as ethambutol.

(3) The factors influencing the change of the blood uric acid concentration are treated by diuretic for a long time and are severely dehydrated before the kidney, so that the blood is concentrated and the blood uric acid concentration is increased.

The clinical manifestations of primary gout have obvious family genetic tendency, and the gout course can be divided into the following 4 stages according to the progressive characteristics of the disease: asymptomatic hyperuricemia period; acute attack phase; asymptomatic rest periods; the chronic stage. The main clinical manifestations are as follows:

(1) the asymptomatic hyperuricemia occurs quite insidiously, is intermittent in the initial stage and is gradually persistent, and is more than that discovered unintentionally during physical examination or diagnosis due to other diseases.

(2) Acute gouty arthritis is the most characteristic and common symptom of gout, starts an acute disease, can cause obvious red swelling and hot pain of affected joints within a few hours, often attacks at night, is awakened due to severe pain of the joints, can not touch the local joints due to pain, even can not cover a bed sheet, and is limited in activity. The first metatarsophalangeal part of the foot is the best hair part, and the second metatarsophalangeal part is the other facet joints, ankle, knee, wrist, elbow and shoulder joints of the hand and foot. Overeating, over drinking, fatigue, infection, trauma, surgery, trauma, pressure around joints, and shoe discomfort can all be the inducing factors. Acute attack symptoms last for more than one week and then gradually remit. After the local redness and swelling of the joints subside, there may be itching, peeling and pigmentation of the skin. The general symptoms during the attack period can be fever, hypodynamia, accelerated heart rate, headache, etc.

(3) Gout intermittent period the gout intermittent period is the interval of two episodes of acute gouty arthritis, the short period is several weeks, and the long period is decades. Occasionally, some patients have no onset after the 1 st acute arthritis, and most of them have a long to short duration. The intermittent disease is relatively stable, also called as a static state. Some patients may have discomfort after the original affected joint moves and can be relieved after rest. Hyperuricemia still exists, and the blood uric acid level is unstable under the influence of diet and treatment conditions.

(4) Chronic gravelly gout is not corrected for long-term hyperuricemia, urate crystals can be widely deposited on articular cartilage, synovium, ligament, subcutaneous tissues and kidney to gradually form urate calculi, and the physiological function of deposited tissues is seriously influenced. After part of formed calculus uric acid is controlled, the calculus uric acid can still be ablated, reduced and even completely disappeared, which is a more special outcome of gouty calculus.

(5) The subcutaneous tophus nodules are formed by depositing urate crystals in the subcutaneous part, are well generated around earrings and joints (toes, interphalangeal joints, knee joints, elbow joints, wrist joints and the like), have different sizes, are 1-2 cm large nodules of sesame seeds, have irregular boundaries and are hard, and are yellowish white on superficial parts. The nodules well-defined with the surrounding tissue are not painful to touch, but if they are associated with bacterial infection, they may cause red swelling and tenderness of the surrounding tissue, often with lacerated wounds. Taking out calculus components or breaking secretion by needle puncture, and microscopically examining to obtain urate crystals.

(6) The fibrosis of joint tissues and the deposition of tophus on articular cartilage, synovial membrane and ligaments caused by repeated acute arthritis attacks of chronic gouty arthritis cause the pathological joints to gradually damage and deform and lose the motion function. The joints between the toes and fingers, and the ankle, knee, and wrist joints are susceptible to fatigue.

(7) There are 2 types of deposits of urate crystals in the kidney of chronic gouty nephropathy and kidney stones, including the extra-tubular urate deposits (mesenchyme and normal concentration of uric acid in the kidney tubule) caused by insufficient excretion of uric acid secretion and the intra-tubular urate deposits which are retained because the concentration of uric acid in the kidney tubule is too high and cannot be discharged in time. Chronic uric acid nephropathy can occur on the basis of these two forms of intrarenal deposition of uric acid, most following repeated episodes of acute gouty arthritis, and a few on the basis of only long-term hyperuricemia.

The clinical manifestations of secondary gout are the clinical features of secondary disease before hyperuricemia occurs. Except for the slow onset of secondary gout caused by congenital renal tubular dysfunction and chronic renal failure, the onset of secondary gout is more acute. Hyperuricemia and acute renal failure caused by the deposition of a large amount of urate in renal tubules are common, the concentration of blood uric acid can be more than 1mmol/L, the urinary uric acid is obviously increased, a large amount of urate crystals can be seen in urinary sediment, and hematuria under an occasional microscope or naked eyes can be seen. The patient may have symptoms such as odynuria, low back pain, nausea, vomiting, oliguria or anuresis.

The gout treatment comprises two aspects, namely inflammation diminishing, pain relieving and blood uric acid reducing, wherein the former is the main aspect, the latter is the main aspect, the emergency treatment is the main aspect, and the purpose of treating both symptoms and root causes is achieved, so that the corresponding medicines comprise the following two types:

anti-inflammatory and analgesic medicine

(1) Colchicine is an alkaloid extracted from colchicine bulb, has effects of preventing cell mitosis, inhibiting inflammatory cell chemotaxis and reducing inflammatory factor release, has unique anti-inflammatory and detumescence effects on acute gout arthritis, and can relieve symptoms in short several hours.

(2) The non-steroidal anti-inflammatory drugs have a plurality of varieties, can be orally taken, locally and externally applied, can also be used as suppositories, mainly relieve local soft tissue redness and swelling, thermal pain and general reaction when gout acute arthritis attacks by inhibiting the inflammatory reaction of tissues to uric acid deposition, and have no influence on the serum uric acid level.

(3) In cases where the onset of acute gouty arthritis is particularly severe, or in cases where colchicine intolerance is experienced, small and medium doses of prednisone and dexamethasone may be used to reduce the inflammatory response of the tissues.

Medicine for reducing uric acid

In the final step of purine metabolism, hypoxanthine is used to generate xanthine under the action of Xanthine Oxidoreductase (XOR), and further generate uric acid, so that the generation of uric acid can be effectively reduced by inhibiting the activity of the enzyme. The uric acid reducing medicine mainly exerts the effect of reducing uric acid by inhibiting the generation of uric acid in vivo and promoting the discharge of uric acid in blood, and the main medicines comprise the following medicines:

(1) the probenecid can inhibit reabsorption of urate by renal tubule, thereby increasing discharge of uric acid from kidney, and is suitable for gout patients with high blood uric acid and urinary uric acid discharge amount less than 3.6mmol/d (less than 600 mg/d).

(2) Benzbromarone (gout and hydrangea) is a benzofuran derivative, promotes the excretion of uric acid by inhibiting the reabsorption of uric acid by a proximal renal tubule, and does not hinder the metabolism of purine nucleotide. Is mainly discharged through gastrointestinal tract (intrahepatic metabolism and bile discharge), is suitable for gout patients with urinary acid discharge amount less than 3.6mmol/d, and can also be used for gout patients with early renal insufficiency with slightly increased inosine.

(3) Allopurinol is a xanthine oxidase inhibitor, and can inhibit the conversion of hypoxanthine into xanthine and then into uric acid, thereby reducing the synthesis of uric acid. Is suitable for patients with primary or secondary gout with excessive uric acid generation.

(4) Febuxostat has obvious inhibiting effect on the XOR of an oxidized form and a reduced form, so that the effect of reducing uric acid is stronger and more durable, and the febuxostat can be used for treating chronic hyperuricemia of gout.

For 30 years, allopurinol is the only medicine for inhibiting the generation of uric acid clinically, and is widely used in clinic as a gold treatment medicine for gout, and achieves unusual achievement in gout resisting treatment. Febuxostat is an XOR inhibitor newly developed at present, and effectively treats ventilation diseases by acting on oxidase highly selectively, reducing in vivo uric acid synthesis and reducing uric acid concentration. Compared with allopurines, febuxostat has obvious advantages: allopurinol only has an inhibiting effect on reduced XOR, and febuxostat has a remarkable inhibiting effect on oxidized and reduced XOR, so that the effect of reducing uric acid is stronger and more durable

However, the febuxostat mainly exerts the effect of reducing uric acid by inhibiting the production of uric acid, the mechanism of action is single, the effect of reducing uric acid is still not ideal, and the space for further improvement is provided, so that the development of the febuxostat derivative with better curative effect and better safety still has very important significance clinically.

Disclosure of Invention

The invention aims to provide a compound shown as a general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

wherein,

linker is selected from the group consisting of a bond, alkyl, alkyloxycarbonyl, alkylaminoalkyl or alkylaminoalkyloxycarbonyl; wherein the carbonyl group of said alkyloxycarbonyl or alkylaminoalkyloxycarbonyl is each independently optionally further substituted with alkyl, alkoxy, or oxyalkyl;

p is selected from aryl or heteroaryl; wherein each H in the aryl or heteroaryl is independently optionally further substituted with one or more alkyl, arylalkyl, diphenylalkyl, arylacyl, heteroarylacyl, aminosulfonyl, or halogen; wherein aryl in arylalkyl or arylacyl, heteroaryl in heteroarylacyl, amino in aminosulfonyl or biphenyl in biphenylalkyl are each independently optionally further substituted with one or more alkyl, halo, tetrazolyl;

the heteroaryl group is selected from the group consisting of pyridyl, furyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinolizinyl, imidazolyl, indazolyl, indolinyl, indolyl, benzothiadiazolyl, isobenzofuryl, isobenzodihydropyranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazole, oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thiochromyl, thienyl, triazolyl, isothiabenzodihydropyranyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl, benzofuranyl, benzofurazanyl, quinoxalinyl, indolyl, quinoxalinyl, and indazolyl, Benzothiazolyl, benzooxadiazole, benzoxazinyl, benzoxazolyl, benzimidazolyl, benzomorpholinyl, benzoselenadiazolyl, benzothienyl, carbazolyl, chromanyl, or imidazo [1, 2-a ] pyridyl;

the halogen is selected from fluorine, chlorine, bromine or iodine.

As a preferred embodiment of the present invention, the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein,

the Linker is a chemical bond, C1-C5 alkyl, C1-C5 alkyloxycarbonyl, C1-C5 alkylamino C1-C5 alkyl or C1-C5 alkylamino C1-C5 alkyloxycarbonyl; wherein the carbonyl group in the C1-C5 alkyloxycarbonyl group or C1-C5 alkylamino C1-C5 alkyloxycarbonyl group is optionally further substituted by C1-C5 alkyl, C1-C5 alkoxy or oxy C1-C5 alkyl;

p is phenyl or heteroaryl; wherein H in said phenyl or heteroaryl is optionally substituted by one or more C1-C5 alkyl, phenyl C1-C5 alkyl, biphenyl C1-C5 alkyl, phenylacyl, heteroarylacyl, aminosulfonyl, or halogen; wherein the phenyl C1-C5 alkyl or phenyl in phenylacyl, heteroaryl in heteroarylacyl, amino in aminosulfonyl, biphenyl in biphenyl C1-C5 alkyl is optionally further substituted with one or more alkyl, halogen or tetrazolyl;

the heteroaryl group is selected from pyridyl, furyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolyl, quinolizinyl, imidazolyl, indazolyl, indolinyl, indolyl, isobenzofuryl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, oxazolyl, phenazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzimidazolyl, benzomorpholinyl, benzoselenadiazolyl, benzopyrolyl, or benzothienyl;

the halogen is selected from fluorine, chlorine or bromine.

As a further preferred embodiment of the present invention, the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein,

p is phenyl or heteroaryl; wherein H in said phenyl or heteroaryl is optionally substituted with one or more methyl, ethyl, n-propyl, isopropyl, n-butyl, phenylformyl, heteroarylacyl, biphenylmethyl, aminosulfonyl, or halo; wherein the phenyl in the phenylformyl group, the biphenyl in the biphenylmethyl group, the amino in the aminosulfonyl group or the heteroaryl in the heteroarylacyl group are optionally further substituted by one or more methyl, ethyl, n-propyl, isopropyl, halogen, tetrazolyl;

the heteroaryl group is selected from furyl, benzofuryl, thienyl, benzothienyl, pyrrolyl, benzopyrolyl, imidazolyl, benzimidazolyl, pyrazolyl, benzopyrazolyl, pyridyl or pyrimidinyl;

the halogen is selected from fluorine, chlorine or bromine.

As a particularly preferred embodiment of the present invention, the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein,

the Linker is a chemical bond, methylene, 1-ethylene, 1, 2-ethylene,

P is

The compounds of formula (I) of the present invention can exist in the form of stereoisomers, including all geometric isomers, optical isomers and mixtures thereof. The compounds of general formula (I) according to the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical isomerism and/or diastereoisomerism. Enantiomers can be separated using conventional techniques, such as chromatography or fractional crystallization. The desired optical isomers may also be separated from the corresponding enantiomers by reaction of suitable optically active starting materials under conditions which do not result in racemisation or epimerisation (i.e. the 'chiral pool' method), by reaction of a suitable starting material with a 'chiral auxiliary', by derivatization (i.e. resolution, including dynamic resolution), and by conventional separation means such as chromatography, or by reaction with a suitable chiral reagent or chiral catalyst under conditions known to those skilled in the art, to obtain or after reaction, all stereoisomers and mixtures thereof being included within the scope of the present invention.

The compounds of the invention may also exhibit tautomerism, and all tautomeric forms and mixtures thereof are also included within the scope of the invention.

Preferred compounds of the invention of formula (I) are as follows:

the invention also provides a process for the preparation of a compound of formula (I), by reacting a compound of formula (2) with a compound of formula (3) in the presence/absence of an activating agent in a suitable solvent to give a compound of formula (I),

P-Linker-X

formula (3)

Wherein P, Linker is as defined above, and X represents H, hydroxy or halogen such as chlorine, bromine, iodine, etc.

The suitable solvent is selected from acetonitrile, acetone, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, formamide, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, methyl acetate or mixtures thereof.

The activating agent is selected from one or more than two of thionyl chloride, oxalyl chloride, dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, p-nitrophenol or allyl alcohol.

In the preparation process of the compound of the general formula (I), the compound of the formula (2) can activate carboxylic acid into acyl chloride, active amide or active ester under the action of an activating agent.

In particular, the carboxylic acid of the compound of formula (2) is reacted with thionyl chloride or oxalyl chloride to form an acid chloride, or is activated by reaction with an activated carbodiimide, such as dicyclohexylcarbodiimide, i.e. DCC, or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, i.e. EDC, or forms an activated ester with an alcohol or phenol, e.g. with p-nitrophenol or allyl alcohol.

Some of the compounds of formula (3) are commercial compounds and can be used as such, while others require simple derivatization of already commercial reagents, such as monoesters, as is conventional in the art.

The preferred compounds of formula (I) according to the invention shown in Table 1 were obtained by the above-mentioned preparation method.

TABLE 1 Synthesis of Compounds of formula (I)

The invention also provides application of the compound of the general formula (I) or salt or stereoisomer thereof in preparing Xanthine Oxidoreductase (XOR) inhibitors. Further, the application of the compound of the general formula (I) or the salt or the stereoisomer thereof in preparing the medicine for preventing and treating the hyperuricemia disease.

The compounds of formula (I) or salts or stereoisomers thereof according to the invention may be used for the preparation of dosage forms for various routes of administration, including topical administration (e.g. to the skin or to the lungs and/or airways) in the form of emulsions, solutions, suspensions, aerosols and dry powder formulations; or systemically administering in the form of tablets, capsules, syrups, powders or granules, e.g., orally; or parenterally in the form of a solution or suspension; or subcutaneous administration; or rectally in the form of suppositories; or transdermal administration.

Compared with febuxostat, the uric acid reducing activity of the compound with the general formula (I) or the pharmaceutically salt or the stereoisomer thereof is higher and the safety is better.

Detailed Description

The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

Example 1 preparation of F1-1

1.1 preparation of p- [ (dipropylamino) sulfonyl ] benzoyl chloride

2.85g of p- [ (dipropylamino) sulfonyl ] benzoic acid was added to 25ml of toluene, followed by addition of 1ml of thionyl chloride, followed by reflux at 50 ℃ for 2 hours and concentration under reduced pressure to dryness to give 3.12g of a pale yellow solid, which was used directly in the next reaction.

1.2 preparation of ethylene glycol p- [ (dipropylamino) sulfonyl ] benzoate

3.12g of p- [ (dipropylamino) sulfonyl ] benzoyl chloride and 10g of ethylene glycol were added to 50ml of tetrahydrofuran, stirred at room temperature for 10 minutes, then 2ml of triethylamine was added under stirring, then the reaction was stopped after 2 hours at 50 ℃, concentrated to dryness under reduced pressure, the product was dissolved in 50ml of ethyl acetate, then washed with 3 × 10ml of saturated brine and water, then dried over anhydrous sodium sulfate and concentrated to constant weight under reduced pressure, to obtain 2.84g of a white powdery solid with a yield of 87.4%.

¹H-NMR(400MHz，d⁶DMSO)：δ8.28-8.30(d，2H)，8.03-8.05(d，2H)，4.41-4.44(t，2H)，4.01-4.04(t，2H)，3.19-3.20(t，4H)，1.43-1.44(m，4H)，0.94-0.96(t，6H)。

Preparation of 32- [ 3-chloro-4-isobutoxyphenyl ] -4-methylthiazole-5-carbonyl chloride

3.16g of 2- [ 3-cyano-4-isobutoxyphenyl ] -4-methylthiazole-5-carboxylic acid was added to 25ml of dichloromethane, then 1ml of thionyl chloride was added, and then after refluxing at 50 ℃ for 2 hours, concentration under reduced pressure was carried out to dryness to obtain 3.39g of a pale yellow solid which was directly used for the next reaction.

1.4 preparation of F1-1

Adding the p- [ (dipropylamino) sulfonyl ] benzyl ethylene glycol monoester obtained in the step 1.2 and the acyl chloride obtained in the step 1.3 into 50ml of tetrahydrofuran, stirring for 10 minutes at room temperature, adding 2ml of triethylamine under stirring, reacting for 2 hours at 50 ℃, stopping the reaction, concentrating under reduced pressure to dryness, dissolving the product with 50ml of ethyl acetate, washing with saturated brine and water by 3 x 10ml respectively, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to constant weight to obtain 2.84g of white powdery solid, 4.16g of the solid subjected to column chromatography, wherein the yield is 71.3%.

¹H-NMR(400MHz，d⁶DMSO)：8.17-δ8.19(m，3H)，8.06-8.09(dd，1H)，7.88-7.90(d，2H)，7.01-7.03(d，1H)，4.65-4.69(m，4H)，3.89-3.91(d，2H)，3.08-3.12(t，4H)，2.77(s，3H)，2.19-2.22(m，1H)，1.52-1.64(m，4H)，1.08-1.10(d，6H)，0.85-0.88(m，6H)。

ESI-MS：m/z628、629、630(M+1)。

EXAMPLE 2 preparation of Compound F2-1

2.1 preparation of intermediate p- [ (dipropylamino) sulfonyl ] benzoic acid N-methyl-N-hydroxyethyl ethyl ester

3.13g of p- [ (dipropylamino) sulfonyl ] benzoyl chloride prepared as described in 1.1 step of example 1, 35g of diethanolamine was added to 50ml of tetrahydrofuran, stirred at room temperature for 10 minutes, then 2ml of triethylamine was added under stirring, and then the reaction was stopped after 2 hours at 50 ℃, concentrated under reduced pressure to dryness, the product was dissolved in 50ml of ethyl acetate, washed with 7X 10ml of saturated saline, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to constant weight to obtain 2.65g of white powdery solid, the yield was 76.3%.

¹H-NMR(400MHz，d⁶DMSO)：δ8.24-8.26(d，2H)，8.08-8.10(d，2H)，4.37-4.40(t，2H)，3.61-3.64(t，2H)，3.15-3.19(t，2H)，2.82-2.85(t，2H)，2.52-2.55(t，4H)，2.11(s，3H)，1.48-1.52(m，4H)，0.96-1.0(t，6H)。

2.2 preparation of Compound F2-1

3.34g of 2- [ 3-cyano-4-isobutoxyphenyl ] -4-methylthiazole-5-carbonyl chloride prepared according to the method described in the step 1.3 of example 1 and the ester prepared in the step 2.1 were added to 100ml of tetrahydrofuran, then 2ml of triethylamine was added, the reaction was stopped after TLC monitoring the completion of the reaction with stirring at 50 ℃ for 2 hours, the reaction was concentrated to dryness under reduced pressure, the product was dissolved in 50ml of ethyl acetate, then 3X 10ml of saturated brine and water were washed in succession, and then dried over anhydrous sodium sulfate and concentrated to constant weight under reduced pressure to obtain 2.84g of a white powdery solid, 4.29g by column chromatography, and the yield was 66.3%.

¹H-NMR(400MHz，d⁶DMSO): 8.05-delta 8.22(m, 4H), 7.86-7.88(d, 2H), 7.01-7.03(d, 1H), 4.91-4.94 (broad peak, 4H), 3.91-3.92(d, 2H), 3.58-3.73(m, 4H), 3.07-3.11(m, 7H), 2.75(s, 3H), 2.19-2.23(m, 1H), 1.51-1.53(m, 4H), 1.09-1.10(d, 6H), 0.86-0.88(t, 6H).

ESI-MS：m/z685、686、687(M+1)。

EXAMPLE 3 preparation of Compound F3-1

Preparation of 3.12-methyl-2- (4- (4-chlorobenzoyl) phenoxy) propionyl chloride

Prepared as described in step 1.1 of reference example 1 and used directly in the next reaction.

3.2 preparation of intermediate N-methyl-N-hydroxyethyl 2-methyl-2- (4- (4-chlorobenzoyl) phenoxy) propanoate

Prepared in 81% yield as white solid according to the procedure described in step 2.1 of example 1.

¹H-NMR(400MHz，d⁶DMSO)：δ7.53-7.66(m，4H)，7.25-7.27(d，2H)，7.08-7.10(d，2H)，4.21-4.24(t，2H)，3.67-3.69(t，2H)，2.61-2.64(t，2H)，2.59(t，2H)，2.34(s，3H)，1.68(s，6H)。

3.3 preparation of Compound F3-1

The product of step 3.1 and the product of step 3.2 were used to prepare the desired product as a white solid in 64% yield, respectively, according to the method described in 2.2 of example 1.

¹H-NMR(400MHz，d⁶DMSO)：8.16(d，1H)，8.07-8.10(d，1H)，δ7.68-7.76(d，4H)，7.42-7.44(d，2H)，7.01-7.03(d，1H)，6.86-6.88(d，2H)，4.70-4.77(d，4H)，3.90-3.92(d，2H)，3.19-3.47(d，4H)，2.73(s，3H)，2.76(s，3H)，2.19-2.23(m，1H)，1.71(s，6H)，1.09-1.10(d，6H)

ESI-MS：m/z：718、720、721、722(M+1)。

EXAMPLE 4 preparation of Compound F4-1

4.1 preparation of intermediates

The desired product was prepared as a white solid in 85% yield by reacting the product of step 3.1 in example 3 with ethylene glycol, respectively, according to the procedure described in step 1.2 in example 1.

¹H-NMR(400MHz，d⁶DMSO)：δ7.51-7.65(m，4H)，7.22-7.24(d，2H)，7.13-7.15(d，2H)，4.28-4.31(t，2H)，3.77-3.80(t，2H)，1.68(s，6H)。

4.2 preparation of F4-1

After 3.16g of 2- [ 3-cyano-4-isobutyloxyphenyl ] -4-methylthiazole-5-carboxylic acid, 3.62g of the intermediate of step 4.1 and 2.69g of N, N-dicyclohexylcarbodiimide were mixed, 30ml of DMF was added, the reaction was stirred at room temperature for 2 hours and then stopped, the reaction system was filtered, 400ml of ethyl acetate was added to the filtrate, and after washing with saturated brine for 3 times, column chromatography was performed to obtain 1.09g of a white target product.

¹H-NMR(400MHz，d⁶DMSO)：δ8.0-8.12(m，2H)，7.62-7.68(m，4H)，7.39-7.41(d，2H)，6.98-7.00(d，1H)，6.84-6.86(d，2H)，4.48-4.52(m，4H)，3.89-3.90(d，2H)，2.86(s，3H)，2.20-2.23(m，1H)，1.70(s，6H)，1.09-1.11(d，6H)。

ESI-MS：m/z：661、662、663、664(M+1)。

EXAMPLE 5 preparation of Compound F5-1

To a 0-5 ℃ solution of 3, 5-dibromo-4-hydroxyphenyl-2-ethyl-3-benzofuranyl-methanone (4.24g) in tetrahydrofuran (30ml) was added an equivalent amount of sodium hydride (70%, 0.01mol), and after stirring at room temperature for 1 hour, an equivalent amount of 2- [ 3-cyano-4-isobutoxyphenyl ] -4-methylthiazole-5-carbonyl chloride prepared in step 1.3 was added, and then the reaction solution was stirred at room temperature for 8 hours, and then the solvent was evaporated under reduced pressure to obtain a solid, which was washed with water, and recrystallized from absolute ethanol to obtain a white solid with a yield of 57%.

¹H-NMR(400MHz，d⁶DMSO)：δ8.26-8.27(d，1H)，8.15-8.18(dd，1H)，8.07(s，2H)，7.51-7.53(d，1H)，7.43-7.45(d，1H)，7.32-7.36(m，1H)，7.25-7.29(m，1H)，7.04-7.07(d，1H)，3.92-3.94(d，2H)，2.92-2.98(q，2H)，2.88(s，3H)，1.30-1.41(m，4H)，1.07-1.12(d，6H)。

ESI-MS：m/z：720、721、722、723、724、725。

EXAMPLE 6 preparation of Compound F6-1

1 equivalent of 2- [ 3-cyano-4-isobutoxyphenyl ] -4-methylthiazole-5-carboxylic acid and an equivalent of N, N ' -Dicyclohexylcarbodiimide (DCC) were reacted with stirring in dimethylformamide at room temperature for 30 minutes, and then an equivalent of 2-butyl-4-chloro-1- [ [2 ' - (1H-tetrazol-5-yl) [1, 1 ' -biphenyl ] 4-yl ] methyl ] -H-imidazole-5-methanol monopotassium salt was added and reacted at 70 ℃ for 4 hours to stop the reaction. Dimethylformamide was washed with saturated saline, and then, an organic phase was extracted with ethyl acetate, and the obtained solid was concentrated to obtain a white product purified by column chromatography, with a yield of 64%.

¹H-NMR(400MHz，d⁶DMSO)：δ7.95(s，1H)，7.80-7.86(m，2H)，7.40-7.45(m，2H)，7.16-7.19(dd，2H)，6.99-7.01(d，2H)，6.89-6.91(d，1H)，6.78-6.80(d，1H)，5.17(s，2H)，5.21(s，2H)，2.57(s，3H)，2.41-2.45(t，2H)，2.18-2.23(m，3H)，1.58-1.64(m，2H)，1.25-1.35(m，3H)，1.09-1.11(d，6H)，0.85-0.89(m，3H)。

ESI-MS：m/z721、722、723、724(M-K+2)。

EXAMPLE 7 preparation of Compound F7-1

7.1 preparation of intermediates

A solution of p- [ (dipropylamino) sulfonyl ] benzoyl chloride (10.3mmol) prepared in step 1.1 in dioxane was added dropwise over 1 hour to a mixture of acetaldehyde (3ml), anhydrous zinc chloride and dioxane (10ml) at 0-5 deg.C, then the reaction was stirred at room temperature for 16 hours, followed by extraction with ether, 5% sodium bicarbonate solution and water washing, respectively. The crude product obtained by concentration was then purified by column chromatography to give a yellow oil in 43% yield.

¹H-NMR(400MHz，d⁶DMSO)：δ8.25-8.27(d，2H)，8.05-8.07(d，2H)，7.11-7.13(q，1H)，3.16-3.18(t，4H)，1.93-1.96(d，3H)，1.43-1.45(m，4H)，0.94-0.98(t，6H)。

7.2 preparation of F7-1

1 equivalent of 2- [ 3-cyano-4-isobutoxyphenyl ] -4-methylthiazole-5-carboxylic acid was reacted with 0.5 equivalent of potassium carbonate and 0.24 equivalent of potassium iodide in dimethylformamide with stirring for 30 minutes, and a dimethylformamide solution of the product in step 6.1 was slowly added dropwise to the reaction flask, followed by refluxing at 100 ℃ for 4 hours to stop the reaction. Dimethylformamide was washed with saturated brine, and then an organic phase was extracted with ethyl acetate, and the obtained solid was concentrated to obtain a white product purified by column chromatography, with a yield of 67%.

¹H-NMR(400MHz，d⁶DMSO)：δ8.12-8.19(m，4H)，7.87-7.90(d，2H)，7.31-7.33(m，1H)，7.00-7.02(d，1H)，3.89-3.91(d，2H)，3.07-3.11(t，4H)，2.77(s，3H)，2.19-2.22(m，1H)，1.75-1.76(d，3H)，1.52-1.57(m，4H)，1.08-1.09(d，6H)，0.85-0.88(m，6H)。

ESI-MS：m/z628、629、630(M+1)。

Example 8 drug efficacy screening experiment for rat model administered with exogenous uric acid while inhibiting uricolysis

1. Materials and methods

1.1 Experimental animals

170 SPF SD rats with weight of 150-180 g are bred in males for 1 week in an adaptive manner, body surface signs are observed, and water and food are freely drunk. Sterilizing all cages at 121 deg.C, sterilizing feed by irradiation, and sterilizing with water.

1.2 test drugs

Screening compound code number: 7 compounds F1-1 to F7-1 (hereinafter referred to simply as "F series compounds" or "test drugs"), positive control drugs: febuxostat.

1.3 reagents and drugs

Oxazinic acid potassium, Uric acid (Uric), sodium carboxymethylcellulose (CMC) and Uric Acid (UA).

1.4 Experimental instruments

Uric Acid (UA) was detected using a US MULTISKAN MK3 enzyme-labeling instrument, BASA-18 full-automatic Biochemical Analyzer, Italy.

1.5 grouping and administration

170 male SD rats are randomly divided into a normal control group, a model group, an F series compound low-dose group and a high-dose group, the doses are respectively 12 mg/kg and 24mg/kg, a positive drug febuxostat 24mg/kg group, and the tested drug is administered by gastric lavage.

2. The experimental method and the operation steps are as follows: the normal control group is not provided with any medicine, the other groups are orally administered with 1.5g/kg of Potassium Oxonate and 0.15g/kg of uric acid (dissolved in 0.5 percent sodium carboxymethylcellulose) every day, and the potassium Oxonate and the uric acid are taken by filling the mixture for 1 time in time every day for 14 days, 0.5ml of blood is taken from the orbit before the experiment and 14 days after modeling, serum is separated, and the content of the uric acid in the serum is determined. After the model building is successful, the tested medicine and the positive medicine are orally administered by gastric lavage for 7 days, 2 hours after the administration day 4, 1ml of orbital venous blood of a rat is adopted, 3500RPM is adopted, 15 minutes are carried out, and the supernatant is taken to detect the content of serum uric acid.

3. Statistical treatment

Mean soil standard deviation for dataThe expression shows that Excel 7.0 and SPPS13.0 for windows software are used for analysis, q test is used for comparison among groups, self-pairing t test is used for comparison before and after medication, and P < 0.001 shows that the difference has significant significance.

4. Results of the experiment

As can be seen from Table 2, after 1.5g/kg of Potassium Oxonate and 0.15g/kg of uric acid are continuously administered by intragastric administration for 14 days, the content of uric acid in serum of rats of each modeling group is increased by 3-6 times compared with that of the blank control group, and compared with the pre-modeling value and the blank control group, the difference is very obvious (p is less than 0.001), and no obvious difference exists among the modeling groups.

TABLE 2 Effect of F series Compounds on uric acid content in uricemic rat

N＝10 ^*p＜0.05，^**p＜0.01，^***p < 0.001 to model group ratio.

The results show that the F series compounds have obvious effect of reducing serum uric acid, wherein the effect of the low-dose group is equivalent to that of a positive control, and the effect of the high-dose group is superior to that of the positive control and has a dose effect relationship.

Example 9 drug efficacy screening experiment for mouse hyperuricemia animal model induced by a large amount of purine substances plus uricase inhibitor

1. Materials and methods

1.1 Experimental animals

340 SPF-grade KM mice with the weight of 20-24 g are male, the animals are bred adaptively for 3 days, the body surface signs are observed, and water and food are freely drunk. Sterilizing all cages at 121 deg.C, sterilizing feed by irradiation, and sterilizing with water.

1.2 test drugs

Screening compound code number: 7 compounds in total (hereinafter referred to as "F series compounds" or "test drugs") F1-1-F7-1, positive control drugs: febuxostat.

1.3 reagents and drugs

Potassium oxonate (Oxonic acid), Hypoxanthine (Hypoxanthine) and Uric Acid (UA) determination kit.

1.4 Experimental instruments

1.5 grouping and administration

340 male KM mice were randomly divided into a normal control group, a model group, a F-series compound low dose group and a high dose group (doses of 17 and 34g/kg, respectively), a positive drug febuxostat 34mg/kg group, and 20 mice per group, and the test drugs were administered by gavage.

2. The experimental method and the operation steps are as follows:

the normal control group is not administered any medicine, and the rest groups are administered by intraperitoneal injection of hypoxanthine 500mg/kg and subcutaneous injection of urate oxidase inhibitor Potassium Oxonate 50mg/kg for 7 days continuously. Before experiment and 7d after model building, each group takes 2-3 mice, removes eyeballs and takes 0.5ml of blood, separates serum, and measures the content of serum uric acid as the normal serum uric acid value of the mice and the serum uric acid value of the model building mice. After the model building is successful, the tested drug and febuxostat are administered by gastric lavage for 4 days, the drug is administered for 2 hours in the last 1 time respectively, 0.5ml of blood is taken after eyeball removal, 4000RPM is used for 20min, and supernatant is taken to detect the content of serum uric acid.

3. Statistical treatment

Mean soil standard deviation for dataThe expression shows that Excel 7.0 and SPPS13.0 for windows statistical software are used for analysis, q test is used for comparison among groups, self-pairing t test is used for comparison before and after medication, and P < 0.001 shows that the difference has significant significance.

4. Results of the experiment

TABLE 3 Effect of F-series Compounds on uric acid production in uricemic mice

N＝10 ^*p＜0.05，^**p＜0.01，^***p < 0.001 to model group ratio

Through establishing a mouse uricemia model in which a large amount of purine uric acid can inhibit the uricolysis at the same time, the F series compounds are subjected to drug screening, and compared with the positive drug febuxostat, the effect of reducing serum uric acid is achieved. The results show that compared with the model group, the febuxostat and the F series compounds have obvious effect of reducing serum uric acid, wherein the effect of reducing serum uric acid of most of the F series compounds is better than that of the positive control drugs, and the F series compounds have a dose-effect relationship.

Example 10 drug efficacy screening experiment for mouse model inhibiting uricolysis

1. Materials and methods

1.1 Experimental animals

SPF grade KM mice 170, weighing 22-26 g, male. Animals were acclimatized for 3 days, observed for body surface signs, and had free access to water and food. Sterilizing all cages at 121 deg.C, sterilizing feed by irradiation, and sterilizing with water.

1.2 test drugs

1.3 reagents and drugs

Potassium oxonate (Oxonic acid) and Uric Acid (UA) determination kit.

1.4 Experimental instruments

1.5 grouping and administration

170 male KM mice were randomly divided into a normal control group, a model group, a low-dose group and a high-dose group (doses of 17 and 34g/kg, respectively) of F-series compounds, and a positive drug febuxostat 34mg/kg group, 10 mice per group, and the test drugs were administered by gavage.

2. Experimental methods and procedures

The normal control group does not give any medicine, the rest groups are injected with 300mg/kg of oteracil potassium salt in the abdominal cavity, the tested medicine is given after 1h by intragastric administration, the eyeball is removed 2h after administration, 1ml of blood is taken, the centrifugation is carried out at 4000RPM for 20min, and the serum is taken to measure the content of uric acid.

3. Statistical treatment

4. Results of the experiment

TABLE 4 influence of F series of Compounds on serum uric acid content in uricemic mice

N＝10 ^*p＜0.05，^**p＜0.01，^***p < 0.001 to model group ratio

And (3) carrying out drug screening on the F series of compounds by establishing a mouse uricemia model for inhibiting the uricolysis, and comparing the drug screening with the effect of a positive drug febuxostat on reducing serum uric acid. The results show that both the febuxostat and the F series compounds have obvious effect of reducing serum uric acid, wherein the effect of reducing serum uric acid of F1-1, F2-1, F3-1 and F7-1 is better than that of febuxostat, and the febuxostat and the F series compounds have dose-effect relationship. The other compounds have obvious effect of reducing serum uric acid by adopting the same method.

Example 11 test sample oral acute toxicity test

And (3) testing a sample:

test samples (febuxostat, F1-1, F2-1, F3-1, F4-1, F5-1, F6-1, F7-1).

The preparation method comprises the following steps: the suspension was prepared by grinding with 0.2% compound.

The test animals were:

ICR mice.

Weight: 18-22 g.

Number of animals: 200 pieces.

Dose setting:

a preliminary test shows that febuxostat has certain toxicity, the 1600mg/kg dose can cause death of a part of mice, while the compounds F1-1, F2-1, F3-1, F4-1, F5-1, F6-1 and F7-1 have little toxicity, 4/4 mice have no obvious toxicity symptom under 1600mg/kg dose, and no animal death exists. On the basis of the preliminary experiment, the formal test dose setting of each test object is as follows:

TABLE 5 official experimental dose settings for each test article

Maximum dosed concentration.

Route of administration

Gavage (ig).

Test method

Laboratory environment: the room temperature is 24 +/-2 ℃, and the relative humidity is 60-70%.

Observation indexes are as follows: the compound is prepared into a drug solution with corresponding concentration according to the dose and the administration volume by an equal ratio dilution method, the equal volume ig is administrated for 1 time, various poisoning symptoms and death conditions of mice are recorded, and dead animals are subjected to autopsy.

And (3) an observation period: and 14 days.

Test results

1. Abnormal reaction: within 12h after mice ig febuxostat, F1-1, F2-1, F3-1, F4-1, F5-1, F6-1 and F7-18 compounds, only part of animals in the febuxostat high-dose group in each dose group have reduced activity, and other abnormalities are not seen. No animal death was observed in the F1-1, F2-1, F3-1, F4-1, F5-1, F6-1 and F7-1 dose groups within 24 days of administration, the febuxostat fraction high dose groups died, and subsequently, the animals died successively, and no death was observed in the surviving animals of each group after the 8 th day of administration. Dead animals and surviving animals only have reduced activity and emaciation, and no other obvious abnormality is seen.

2. And (4) autopsy results: the dead animals with high dose all have the appearance of bilateral lightening of kidney color and retention of urine on necropsy, other organs have no obvious abnormality, the necropsy of the observed living animals shows that all organs are normal, and the necropsy of the compound groups of F1-1, F2-1, F3-1, F4-1, F5-1, F6-1 and F7-1 has no obvious organ abnormality change.

3. The cause of death: after administration of febuxostat to mice, eventual systemic failure may occur due to urinary toxicity.

Death and LD from mouse ig Compound₅₀The value is obtained.

TABLE 6 LD of mouse ig compounds₅₀Value (by Bliss method)^[1]Calculating)

And (3) knotting: compared with febuxostat, the compounds F1-1, F2-1, F3-1, F4-1, F5-1, F6-1 and F7-1 are superior to febuxostat in safety. The other compounds of the invention have good safety and are determined by the same method.

The above examples are only for describing the preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, and various modifications and improvements made to the technical solution of the present invention by those skilled in the art without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structural formulae:

2. a process for producing a compound of claim 1, which comprises reacting a compound of formula (2) with a compound of formula (3) in the presence/absence of an activator to obtain a compound of claim 1;

wherein the compound of formula (2) has the following structural formula:

the structural formula of the compound of the formula (3) is one of the following compound structures:

3. the method according to claim 2, wherein the solvent is selected from acetonitrile, acetone, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, formamide, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, methyl acetate, and a mixture thereof.

4. The method according to claim 2, wherein the activating agent is one or more selected from the group consisting of thionyl chloride, oxalyl chloride, dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, p-nitrophenol and allyl alcohol.

5. A pharmaceutical composition comprising an effective amount of a compound of claim 1.

6. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is in a dosage form selected from the group consisting of tablets, capsules, syrups, powders, granules, emulsions, and solutions.

7. Use of a compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, for the manufacture of a xanthine oxidoreductase inhibitor.