CN106470981B - The new derivatives, preparation method and application of 2- [3- cyano-4-isobutoxy phenyl] -4- methylthiazol-5-formic acid - Google Patents
The new derivatives, preparation method and application of 2- [3- cyano-4-isobutoxy phenyl] -4- methylthiazol-5-formic acid Download PDFInfo
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- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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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
Technical field
The invention belongs to field of medicaments, more particularly it relates to 2- [3- cyano-4-isobutoxy phenyl] -4- first
Base thiazole -5- formic acid derivates and its salt, its stereoisomer, and include at least a kind of such as formula (I) compound or its salt or
Pharmaceutical formulations of its stereoisomer as active constituent, and preventing and treating the application in antihyperuricemic disease.
Background technique
Gout is one group of syndrome caused by human body purine metabolic disturbance, and hyperuricemia is one in its pathological development
Stage.According to pathogenic factor, primary gout and secondary gout two types can be classified as.
Primary gout has apparent Family inherited inclination, is apt to occur in the middle-aged and the old, and onset peak is 30~50 years old, about
95% is male, and 5% women is often to fall ill after menopause.The cause of disease of primary gout mainly includes two aspects:
(1) inherent cause clinical findings, gout have apparent Family inherited inclination, and patient with gout relatives merge asymptomatic height
The recall rate of uricacidemia is apparently higher than non-patient with gout.Gout and other metabolic diseases with genetic predisposition are (fat, high
Blood pressure, hyperlipidemia, diabetes etc.) it is in close relations.Having found out causes uric acid to generate in excessive purine metabolism, causes the work of enzyme
Sexually revise the hereditary basis of enzyme gene mutation.
(2) environmental factor overeating, to indulge in excessive drinking, eat rich in purine food be excessively urarthritis acute attack
Common cause.The improvement of socioeconomic status, the metabolic diseases illness rate such as obesity, hypertension increase, and also make the illness rate of gout
Increase.
Secondary gout onset caused by secondary gout is removed because of congenital Fanconi-de Toni syndrome and chronic renal failure
Slowly outer, a lot of diseases are more anxious.The cause of disease of secondary gout is main including the following three aspects:
(1) after causing internal uric acid to generate the excessive cause of disease such as leukaemia, lymthoma progressive stage, especially chemotherapy, true property
Red blood cell count(RBC) increase disease etc..After severe trauma, crush injury, major operation.
(2) causing kidney uric acid that the reduced cause of disease such as severe hypertension, eclampsia is discharged causes renal blood flow to reduce, and influences uric acid
Filtration；Renal failure caused by any reason；Congenital Fanconi-de Toni syndrome, model can syndrome, Bartter syndromes etc.；
The metabolic disorder of tubular secretion uric acid is influenced, such as ethylism, hungry excessive, ketoacidosis, lactic acidosis can draw
It plays organic acid content in blood to increase, inhibits the secretion of renal tubule uric acid；Some drugs can cause hyperuricemia, such as ethamine fourth
Alcohol.
(3) factor for influencing the variation of blood uric acid concentration uses the pre-renal dehydration of diuretic therapy, severe for a long time, keeps blood dense
Contracting increases blood uric acid concentration.
Primary gout clinical manifestation has apparent Family inherited inclination, and according to disease progression feature, the gout course of disease can divide
For following 4 phase: the asymptomatic hyperuricemia phase；Acute attack stage；The asymptomatic intermittent phase；Chronic phase.Main clinical manifestation has
Following several respects:
(1) generation of asymptomatic hyperuricemia is very hidden attacks, and initial stage is that interruption occurs, and is in gradually duration, is more than
Physical examination or because being not intended to find when other diseases are medical.
(2) acute gouty arthritis this be gout most feature and common symptom, onset is hurried, a few hours it
Interior affected joints may occur in which apparent red and swollen, heat pain, often in night-time attack, wake up because of joint severe pain, local joint is because of pain
Cannot touch, in addition cannot lid sheet, limitation of activity.It is secondly other of brothers with foot the first plantar toe for most predilection site
Minor articulus, ankle, knee, wrist, elbow, shoulder joint initial stage are mostly simple joint lesion, and two sides alternately occur, and the later period can be multi-joint lesion,
Occur simultaneously or successively.Overeating is drunk beyond one's capacity, fatigue, infection, wound, operation, wound, periarticular compression, and shoes are carried out not
Suitable wait can be risk factor.Acute attack symptom continues a Zhou Yu more, then gradually alleviates.After local joint redness subsides,
There can be skin itch, peel, pigmentation.Stage of attack, constitutional symptom can have fever, out of strength, increased heart rate, headache etc..
(3) gout intermittent phase gout intermittent phase refers to the interphase of acute gouty arthritis breaking-out twice, short then several weeks, long
Then many decades.Once in a while again without breaking-out after the 1st acute arthritis of some patients, majority is from long to short.The intermittent phase state of an illness is opposite
Steadily, also known as stationary state.Some patientss can have discomfort after former affected joints activity, can be relieved after rest.Can still there be high urine
Acidaemia is influenced by diet and treatment condition, and serum uric acid level is unstable.
(4) the chronic long-term hyperuricemia of gravel gout fails to correct, and it is soft that urate crystal can be deposited on extensively joint
Bone, synovial membrane, ligament, subcutaneous, kidney, gradually form urate calculi, physiological function that is heavy then influencing deposition fabric.It is part of
It after established calculus uric acid obtains control, can still melt, reduce, even disappear completely, this is more special for gouty calculus
Lapse to.
(5) subcutaneous tophus tubercle is deposited on subcutaneous formation by urate crystal, is apt to occur in helix, (toe refers on joint periphery
Between joint, knee joint, elbow joint, wrist joint etc.), tubercle differs in size, and sesame as low as 1~2 centimetre of major tubercle greatly, boundary is not advised
Then, matter is hard, and table superficial part position is in yellow-white.With the tubercle of perienchyma clear-cut, no tenderness, but as merged bacterium infection can
There are perienchyma's redness, tenderness, there is ulceration mouth more.Needle adopts out stone composition or ulceration secretion microscopy is urate crystal.
(6) joint tissue fibrosis and tophus caused by the repeated multiple times acute arthritis of gouty arthritis,chronic is broken out
In articular cartilage, the deposition of synovial membrane, ligament, makes lesion joint gradually damaged deformation, lose motor function.Toe, interphalangeal joint,
Ankle, knee, wrist joint are vulnerable to tired.
(7) the 2 kinds of forms that are deposited with of chronic gouty nephropathy and kidney stone urate crystal in kidney, including uric acid secretion
Uric acid in renal tubule apurinic acid mineralization (uric acid concentration is normal in medullary interstitium, renal tubule) caused by excretion is insufficient and renal tubule
Excessive concentration cannot be discharged in time and uric acid mineralization in the renal tubule that is detained.Chronic Uric-acid Nephropathy can be in both uric acid kidneys
Occur on the basis of interior deposition pattern, for majority after the acute gouty arthritis of recurrent exerbation, minority can be only long-term
Occur on the basis of hyperuricemia.
The clinical manifestation of secondary gout be before hyperuricemia occurs mostly secondary disease Clinical symptoms.Except because congenital
Property Fanconi-de Toni syndrome and chronic renal failure caused by secondary gout onset it is slowly outer, a lot of diseases are more anxious.With high lithemia
Mass formed by blood stasis and a large amount of lithates deposited in renal tubule cause acute renal failure be it is common, serum Uric Acid Concentration can > 1mmol/L,
Urine uric acid increased significantly, visible a large amount of urate crystals in arena, under even visible mirror or gross hematuria.Patient can have urodynia,
The symptoms such as lumbago, Nausea and vomiting, oliguresis or anuria.
The treatment of gout includes two aspects, i.e. two aspects of anti-inflammatory analgetic and reduction blood uric acid, the former is mark, Hou Zhewei
This, symptomatic treatment in acute condition achievees the purpose that treating both manifestation and root cause of disease, and therefore, corresponding drug includes following two categories:
One, anti-inflammatory analgetic class drug
(1) colchicin is a kind of alkaloid extracted in colchici cormus, plays the role of preventing cell mitogen, can
Inhibit the chemotactic of inflammatory cell and reduce inflammatory factor release, there is unique anti-inflammatory disappear for the gouty arthritis of acute attack
Swollen effectiveness, can alleviate symptom within short a few hours.
(2) such types of drugs of non-steroidal anti-inflammatory drugs is more, not only orally available, local topical, it is possible to use suppository, mainly
Local soft tissue redness, heat pain when by inhibiting tissue to mitigate the breaking-out of gout acute arthritis to the inflammatory reaction that uric acid deposits
And general reaction, on serum uric acid level mostly without influence.
(3) Adrenal Glucocorticoid experimental study break out symptom especially severe, or to colchicin intolerant to
Receptor can use small prednisone, dexamethasone, to mitigate the inflammatory reaction of tissue.
Two, anti-trioxypurine drugs
The generation of internal uric acid is related with purine metabolism, and in the final step of purine metabolism, hypoxanthine is in xanthine
Xanthine is generated under the action of oxidoreducing enzyme (XOR), further generates uric acid, inhibits the activity of the enzyme that can effectively subtract
The generation of oliguresis acid.Anti-trioxypurine drug, which mainly passes through, to be inhibited internal uric acid to generate and the discharge of uric acid in blood is promoted to play drop urine
Sour effect, key agents have following several:
(1) the probenecid medicine can inhibit renal tubule to the re-absorption of lithate, to increase discharge of the uric acid from kidney, fit
For blood uric acid height, the patient with gout of uric acid discharge capacity < 3.6mmol/d (< 600mg/d) is urinated.
(2) Benzbromarone (narcaricin) is benzofuran analog derivative, by inhibiting proximal tubular to the weight of uric acid
The excretion of uric acid is absorbed and promoted, does not obstruct the metabolism of purine nucleotides.It is main that (intrahepatic metabolism, bile are discharged by gastrointestinal tract
Discharge), suitable for urinating the patient with gout of uric acid discharge capacity < 3.6mmol/d, it can also be used to the slight raised Renal function in early period of inosine
Infull patient with gout.
(3) Allopurinol is xanthine oxidase inhibitor, can inhibit hypoxanthine and is changed into xanthine and switchs to uric acid again, from
And reduce the synthesis of uric acid.Excessive primary or secondary patient with gout is generated suitable for itself uric acid.
(4) Febuxostat has significant inhibiting effect, thus its work for reducing uric acid to the XOR of oxidized form and reduced form
With more powerful, lasting, therefore this product can be used for treating the chronic hyperuricemia of gout.
Over 30 years, allopurinol is clinically drug of the only one for inhibiting uric acid to generate, and the Huang as gout
Golden therapeutic agent is widely used in clinic, and original achievement is achieved in the treatment of antigout.Febuxostat is newest at present grinds
The XOR inhibitor of system passes through and acts on the oxidizing ferment highly selectively, reduces internal uric acid synthesis, reduces uric acid concentration,
To effectively treat ventilation disease.Compared with other purine, Febuxostat has a clear superiority: allopurinol is only to reduced form
XOR has inhibiting effect, and Febuxostat has significant inhibiting effect to the XOR of oxidized form and reduced form, thus it reduces urine
The effect of acid is more powerful, lasting
However, since Febuxostat mainly passes through the effect for inhibiting uric acid to generate performance anti-trioxypurine, the mechanism to play a role
More single, the effect of anti-trioxypurine is still not ideal enough, there is the space further increased, thus, development efficacy is more excellent, safety more
Good Febuxostat derivative clinically still has very important significance.
Summary of the invention
The purpose of the present invention is to provide a kind of logical formula (I) compound represented, its stereoisomer or pharmaceutical salt:
Wherein,
Linker is selected from chemical bond, alkyl, alkyloxycarbonyl, alkylaminoalkyl group or alkylaminoalkyl group oxygroup carbonyl
Base；Wherein, the carbonyl in the alkyloxycarbonyl or alkylaminoalkyl group Epoxide carbonyl is respectively individually optional further by alkane
Replaced base, alkoxy or oxygroup alkyl；
P is selected from aryl or heteroaryl；Wherein the H in the aryl or heteroaryl respectively it is individually optional further by one or
Replaced multiple alkyl, aryl alkyl, xenyl alkyl, aryl-acyl, heteroaroyl, amino-sulfonyl or halogen；Wherein
The heteroaryl in aryl, heteroaroyl in the aryl alkyl or aryl-acyl, the amino or biphenyl in amino-sulfonyl
Xenyl in base alkyl is respectively individually optional further replaced one or more alkyl, halogen, tetrazole radical；
The heteroaryl is selected from pyridyl group, furyl, purine radicals, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidine radicals, pyrroles
Base, quinazolyl, quinolyl, quinazinyl, imidazole radicals, indazolyl, indolinyl, indyl, diazosulfide base, different benzo
Furyl, isochroman base, iso-dihydro-indole-group, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, phenodiazine
Miscellaneous naphthalene, oxadiazoles, oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridyl, quinoxalinyl, tetrahydro isoquinolyl, tetrahydro
Quinolyl, tetrazole radical, thiadiazolyl group, thiazolyl, thio chromanyl, thienyl, triazolyl, different thiophene benzo dihydro pyrrole
It mutters base, benzimidazolyl, benzodioxane base, benzo dioxepine base, benzodioxole group, benzo
Furyl, benzofuraxan base, benzothiazolyl, benzoxadiazole, benzoxazinyl-, benzoxazolyl, benzimidazolyl, benzo
Morpholinyl, the miscellaneous di azoly of benzo selenium, benzothienyl, carbazyl, chromanyl or imidazo [1,2-a] pyridyl group；
The halogen is selected from fluorine, chlorine, bromine or iodine.
As the preferred solution of the invention, the logical formula (I) compound represented, its stereoisomer or pharmaceutical salt:
Wherein,
The Linker is chemical bond, C1-C5 alkyl, C1-C5 alkyloxycarbonyl, C1-C5 alkyl amino C1-C5 alkyl
Or C1-C5 alkyl amino C1-C5 alkyloxycarbonyl；Wherein the C1-C5 alkyloxycarbonyl or C1-C5 alkyl amino C1-
Carbonyl in C5 alkyloxycarbonyl is optionally further replaced by C1-C5 alkyl, C1-C5 alkoxy or oxygroup C1-C5 alkyl；
The P is phenyl or heteroaryl；Wherein in the phenyl or heteroaryl H optionally by one or more C1-C5 alkyl,
Phenyl C1-C5 alkyl, xenyl C1-C5 alkyl, phenylacyl, heteroaroyl, amino-sulfonyl or halogen replace；Wherein institute
State the phenyl in phenyl C1-C5 alkyl or phenyl acyl group, the heteroaryl in heteroaroyl, the amino in amino-sulfonyl, connection
Xenyl in phenyl C1-C5 alkyl is optionally further replaced by one or more alkyl, halogen or tetrazole radical；
The heteroaryl is selected from pyridyl group, furyl, purine radicals, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidine radicals, pyrroles
Base, quinolyl, quinazinyl, imidazole radicals, indazolyl, indolinyl, indyl, isobenzofuran-base, isoindolyl, isoquinolin
Base, isothiazolyl, isoxazolyl, oxazolyl, phenazinyl, tetrazole radical, thiadiazolyl group, thiazolyl, thienyl, triazolyl, benzo
Imidazole radicals, benzofuranyl, benzothiazolyl, benzimidazolyl, benzo morpholinyl, the miscellaneous di azoly of benzo selenium, benzopyrrole base
Or benzothienyl；
The halogen is selected from fluorine, chlorine or bromine.
As the further preferred scheme of the present invention, the logical formula (I) compound represented, its stereoisomer or pharmaceutically acceptable
Salt:
Wherein,
The Linker is chemical bond, C1-C5 alkyl, C1-C5 alkyloxycarbonyl, C1-C5 alkyl amino C1-C5 alkyl
Or C1-C5 alkyl amino C1-C5 alkyloxycarbonyl；Wherein the C1-C5 alkyloxycarbonyl or C1-C5 alkyl amino C1-
Carbonyl in C5 alkyloxycarbonyl is optionally further replaced by C1-C5 alkyl, C1-C5 alkoxy or oxygroup C1-C5 alkyl；
The P is phenyl or heteroaryl；Wherein in the phenyl or heteroaryl H optionally by one or more methyl, ethyl,
N-propyl, isopropyl, normal-butyl, phenyl formoxyl, heteroaroyl, diphenylmethyl, amino-sulfonyl or halogen replace；Its
Described in phenyl, the xenyl in diphenylmethyl, the amino in amino-sulfonyl or heteroaroyl in phenyl formoxyl
In heteroaryl optionally further replaced by one or more methyl, ethyl, n-propyl, isopropyl, halogen, tetrazole radical；
The heteroaryl be selected from furyl, benzofuranyl, thienyl, benzothienyl, pyrrole radicals, benzopyrrole base,
Imidazole radicals, benzimidazolyl, pyrazolyl, benzopyrene oxazolyl, pyridyl group or pyrimidine radicals；
The halogen is selected from fluorine, chlorine or bromine.
As scheme specifically preferred according to the invention, the logical formula (I) compound represented, its stereoisomer or pharmaceutical
Salt:
Wherein,
The Linker be chemical bond, methylene, 1,1- ethylidene, 1,2- ethylidene,
The P is
The present invention, which leads to formula (I) compound, to be existed in the form of stereoisomer, including all geometric isomers, optics
Isomers and its mixture.The present invention, which leads to formula (I) compound, can also contain one or more asymmetric carbon atoms, and therefore
It can show optical siomerism and/or diastereo-isomerism.Routine techniques, such as chromatography or fractional crystallization equal part can be used
From enantiomter.Required optical isomer can not also will cause by suitable optically active starting material
Racemic or difference to the reaction (i.e. ' chiral pond ' method) under conditions of (solid) isomerization, select suitable starting material and
The reaction of ' chiral auxiliary ' (is split, including dynamic resolution) by derivatization, and conventional separate mode such as chromatographic isolation
Mapping derivative out, or by anti-with suitable chiral reagent or chiral catalyst under the conditions of to known to those skilled in the art
It answers, obtains or isolate after reacting corresponding isomers, all stereoisomers and its mixture are all included in the present invention
In the range of
The compound of the present invention can also show tautomerism, all tautomeric forms and its mixture also by
It is included within the scope of the invention.
It is as follows that the present invention leads to preferred compound shown in formula (I):
The present invention also provides the preparation methods of logical formula (I) compound, in a suitable solvent, formula (2) compound and formula
(3) compound reacts under conditions of in the presence/absence of activator obtains formula (I) compound,
P-Linker-X
Formula (3)
Wherein P, Linker are as defined above, and X indicates the halogens such as H, hydroxyl or chlorine, bromine, iodine.
It is acetonitrile, acetone, tetrahydrofuran, methylene chloride, chloroform, carbon tetrachloride, first that the suitable solvent, which is selected from,
Or mixtures thereof amide, n,N-Dimethylformamide, dimethyl sulfoxide, ethyl acetate, methyl acetate.
The activator is selected from thionyl chloride, oxalyl chloride, dicyclohexylcarbodiimide, 1- (3- dimethylamino-propyl) -3-
One or more of ethyl-carbodiimide hydrochloride, p-nitrophenol or allyl alcohol.
In the preparation process of logical formula (I) compound, formula (2) compound can will be carboxylic acid activated under activator effect
For acyl chlorides, activated amide or active ester.
Specifically, the carboxylic acid in formula (2) compound is reacted with thionyl chloride or oxalyl chloride generates acyl chlorides, Huo Zheyu
Active carbodiimide, such as dicyclohexylcarbodiimide, i.e. DCC or 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide
The reaction activation of hydrochloride, i.e. EDC, or active ester is formed with alcohol or phenol, such as react with p-nitrophenol or allyl alcohol.
It is partially the compound of commercialization in formula (3) compound, can directly uses, another part is needed commodity
The reagent of change can just be obtained by the simple derivatization of this field routine, such as monoesters.
Currently preferred formula (I) compound shown in table 1 is obtained using above-mentioned preparation method.
The synthesis of 1 formula of table (I) compound
The present invention also provides logical formula (I) compound or its salts or its stereoisomer to prepare xanthine oxidoreductase enzyme
(XOR) application in inhibitor.Further, lead to formula (I) compound or its salt or its stereoisomer to prevent and treat in preparation
Application in hyperuricemia disease medicament.
Logical formula (I) compound or its salt of the present invention or its stereoisomer can be used for preparing various administration routes
Dosage form, the form including emulsion, solution, suspension, aerosol and dry powder formulations carry out local administration (such as to skin or to lung
And/or air flue)；Or with tablet, capsule, syrup, powder or particle as carried out Formulations for systemic administration by oral administration；Or with solution or suspension
Form carry out parenteral administration；Or carry out subcutaneous administration；Or per rectum is administered in the form of suppository；Or cutaneous penetration.
Logical formula (I) compound of the present invention or its salt or its stereoisomer pharmaceutically, compared with Febuxostat,
Anti-trioxypurine activity is higher, safety is more preferable.
Specific embodiment
The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..
The preparation of 1 F1-1 of embodiment
The preparation of 1.1 p- [(dipropyl amino) sulfonyl] chlorobenzoyl chlorides
P- [(dipropyl amino) sulfonyl] benzoic acid of 2.85g is added into the toluene of 25ml, 1ml chlorine is then added
Change sulfoxide, is concentrated to dryness after then flowing back 2 hours at 50 DEG C, obtains the flaxen solid of 3.12g, be directly used in next
Step reaction.
The preparation of 1.2 p- [(dipropyl amino) sulfonyl] glycol dibenzoate monoesters
The ethylene glycol of p- [(dipropyl amino) sulfonyl] chlorobenzoyl chloride of 3.12g, 10g are added to 50ml tetrahydrofuran
In, it is stirred at room temperature and 2ml triethylamine is added under stiring after ten minutes, stop reaction after then react 2 hours at 50 DEG C, decompression is dense
Be reduced to it is dry, product with 50ml ethyl acetate dissolve after, 3 × 10ml is successively washed respectively with saturated salt solution and water, then with anhydrous
It is concentrated under reduced pressure into constant weight after sodium sulphate is dry, obtains white powdery solids 2.84g, yield 87.4%.
1H-NMR (400MHz, d6DMSO): δ 8.28-8.30 (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).
The preparation of 1.3 2- [3- chloro -4- isobutoxy phenyl] -4- methylthiazol -5- formyl chloride
2- [3- cyano-4-isobutoxy phenyl] -4- methylthiazol-5-formic acid of 3.16g is added to the dichloro of 25ml
In methane, 1ml thionyl chloride is then added, is concentrated to dryness after then flowing back 2 hours at 50 DEG C, obtains the yellowish of 3.39g
The solid of color is directly used in and reacts in next step.
The preparation of 1.4 F1-1
By p- [(dipropyl amino) sulfonyl] the first and second diol monoester of benzene of 1.2 steps above, the acyl chlorides of 1.3 steps
It is added in 50ml tetrahydrofuran, is stirred at room temperature and 2ml triethylamine is added under stiring after ten minutes, then reaction 2 is small at 50 DEG C
When after stop reaction, be concentrated to dryness, product with 50ml ethyl acetate dissolve after, successively respectively washed with saturated salt solution and water
3 × 10ml obtains white powdery solids 2.84g, through column chromatography then to be concentrated under reduced pressure into constant weight after anhydrous sodium sulfate drying
4.16g, yield 71.3%.
1H-NMR (400MHz, d6DMSO): 8.17- δ 8.19 (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).
The preparation of 2 compound F2-1 of embodiment
The preparation of p- [(dipropyl amino) sulfonyl] the benzoic acid N- methyl-N- ethoxy ethyl ester of 2.1 intermediates
By p- [(dipropyl amino) sulfonyl] benzene of the 3.13g prepared according to method described in 1.1 steps in embodiment 1
Formyl chloride, 35g diethanol amine be added in 50ml tetrahydrofuran, be stirred at room temperature after ten minutes under stiring be added tri- second of 2ml
Amine stops reaction after then reacting 2 hours at 50 DEG C, is concentrated to dryness, after product is dissolved with 50ml ethyl acetate, with saturation
7 × 10ml of brine It obtains white powdery solids 2.65g then to be concentrated under reduced pressure into constant weight after anhydrous sodium sulfate drying,
Yield 76.3%.
1H-NMR (400MHz, d6DMSO): δ 8.24-8.26 (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).
The preparation of 2.2 compound F2-1
By 2- [the 3- cyano-4-isobutoxy benzene of the 3.34g prepared according to method described in 1.3 steps in embodiment 1
Base] -4- methylthiazol -5- formyl chloride, above-mentioned 2.1 step preparation ester be added 100ml tetrahydrofuran in, then be added 2ml tri-
Ethamine, 50 DEG C are stirred to react TLC monitoring in 2 hours and stop reaction after completion of the reaction, are concentrated to dryness, product is with 50ml acetic acid second
After ester dissolution, 3 × 10ml is successively washed respectively with saturated salt solution and water, then to be concentrated under reduced pressure into perseverance after anhydrous sodium sulfate drying
Weight, obtains white powdery solids 2.84g, the 4.29g chromatographed through column, yield 66.3%.
1H-NMR (400MHz, d6DMSO): 8.05- δ 8.22 (m, 4H), 7.86-7.88 (d, 2H), 7.01-7.03 (d,
1H), 4.91-4.94 (wide cutting edge of a knife or a sword, 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).
The preparation of 3 compound F3-1 of embodiment
The preparation of 3.1 2- methyl -2- (4- (4- chlorobenzene formacyl) phenoxy group) propionyl chloride
The preparation of the method referring to described in step 1.1 in embodiment 1, is directly used in and reacts in next step.
3.2 intermediate 2- methyl -2- (4- (4- chlorobenzene formacyl) phenoxy group) propionic acid N- methyl-N- ethoxy ethyl ester
Preparation
The method referring to described in step 2.1 in embodiment 1 is prepared into white solid, yield 81%.
1H-NMR (400MHz, d6DMSO): δ 7.53-7.66 (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).
The preparation of 3.3 compound F3-1
The method referring to described in embodiment 1 2.2, the product of product and 3.2 steps that 3.1 steps are respectively adopted prepare mesh
Product is marked, is white solid, yield 64%.
1H-NMR (400MHz, d6DMSO): 8.16 (d, 1H), 8.07-8.10 (d, 1H), δ 7.68-7.76 (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).
The preparation of 4 compound F4-1 of embodiment
The preparation of 4.1 intermediates
The method referring to described in step 1.2 in embodiment 1, is respectively adopted the product and ethylene glycol of 3.1 steps in embodiment 3
Reaction prepares target product, is white solid, yield 85%.
1H-NMR (400MHz, d6DMSO): δ 7.51-7.65 (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).
The preparation of 4.2 F4-1
By 4.1 steps of 2- [3- cyano-4-isobutoxy phenyl] -4- methylthiazol-5-formic acid of 3.16g, 3.62g
30ml DMF is added after the mixing of the N of intermediate and 2.69g, N- dicyclohexylcarbodiimide, stops after reaction being stirred at room temperature 2 hours
Reaction, reaction system is filtered, and 400ml ethyl acetate, after saturated common salt water washing 3 times, column layer are then added into filtrate
Analyse 1.09g white object product.
1H-NMR (400MHz, d6DMSO): δ 8.0-8.12 (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).
The preparation of 5 compound F5-1 of embodiment
To the tetrahydrofuran of 0-5 DEG C of the bromo- 4- hydroxyphenyl -2- ethyl -3- benzofuran base-ketone (4.24g) of 3,5- bis-
In (30ml) solution be added equivalent sodium hydride (70%, 0.01mol), after being stirred at room temperature 1 hour be added equivalent such as step
2- [3- cyano-4-isobutoxy phenyl] -4- methylthiazol -5- formyl chloride of rapid 1.3 preparation, then at room temperature by reaction solution
Stirring 8 hours, then obtains solid after evaporated under reduced pressure solvent, washing recrystallizes to obtain white solid, yield 57% with dehydrated alcohol.
1H-NMR (400MHz, d6DMSO): δ 8.26-8.27 (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.
The preparation of 6 compound F6-1 of embodiment
By the N, N '-two of 2- [3- cyano-4-isobutoxy phenyl] -4- methylthiazol-5-formic acid and equivalent of 1 equivalent
After reaction is stirred at room temperature 30 minutes in carbodicyclo hexylimide (DCC) in dimethylformamide, the 2- butyl -4- of equivalent is added
Chloro- 1- [[2 '-(1H-TETRAZOLE -5- base) [1,1 '-xenyl] 4- yl] methyl]-H- imidazoles -5- methanol monopotassium salt, it is anti-at 70 DEG C
Stopping in 4 hours is answered to react.Organic phase, concentration gained are extracted to obtain with ethyl acetate after washing away dimethylformamide with saturated salt solution
Solid is with the white product of column chromatographic purifying, yield 64%.
1H-NMR (400MHz, d6DMSO): δ 7.95 (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).
The preparation of 7 compound F7-1 of embodiment
The preparation of 7.1 intermediates
In being added dropwise in 1 hour into the mixture of 0-5 DEG C of acetaldehyde (3ml), anhydrous zinc chloride and dioxane (10ml)
Enter the dioxane solution of p- [(dipropyl amino) sulfonyl] chlorobenzoyl chloride (10.3mmol) prepared such as step 1.1, then will
Reaction solution is stirred at room temperature 16 hours, is then extracted with ether, 5% sodium bicarbonate solution and water wash respectively.Then with
The crude product being concentrated to get is obtained into the grease of yellow, yield 43% with column chromatographic purifying.
1H-NMR (400MHz, d6DMSO): δ 8.25-8.27 (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).
The preparation of 7.2 F7-1
By the potassium carbonate of 2- [3- cyano-4-isobutoxy phenyl] -4- methylthiazol-5-formic acid and 0.5 equivalent of 1 equivalent
It is stirred to react 30 minutes with the potassium iodide of 0.24 equivalent in dimethylformamide, by the dimethyl formyl of the product in 6.1 steps
Amine aqueous solution is slowly added dropwise in reaction flask, and then flow back at 100 DEG C the reaction of stopping in 4 hours.Dimethyl is washed away with saturated salt solution
Organic phase is extracted to obtain with ethyl acetate after formamide, obtained solid is concentrated with the white product of column chromatographic purifying, yield 67%.
1H-NMR (400MHz, d6DMSO): δ 8.12-8.19 (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).
Embodiment 8 is directed to and gives exogenous uric acid while the medicine efficacy screening of uricolytic rat model being inhibited to test
1, materials and methods
1.1 experimental animal
SPF grades SD rat 170,150~180 grams of weight, male, Animal adaptability is raised 1 week, observes body surface sign,
Free water and feeding.All cage tools pass through 121 DEG C of sterilization treatments, and feed is irradiated sterilization treatment, water sterilization treatment it is pure
Water.
1.2 test drug
Screening compounds code name: totally 7 compounds are (later referred to as " F series compound " or " tested by F1-1~F7-1
Drug "), positive control drug: Febuxostat.
1.3 reagents and drug
Oteracil Potassium Oxonic acid), uric acid (Uric), sodium carboxymethylcellulose (CMC), uric acid (UA) measure reagent
Box.
1.4 laboratory apparatus
Uric acid (UA) detection uses U.S. MULTISKAN MK3 microplate reader, Italian BASA-18 full-automatic biochemical analysis
Instrument.
1.5 groupings and administration
170 male SD rats are randomly divided into Normal group, model group, F series compound low dose group and high agent
Amount group, dosage are respectively 12 and 24mg/kg, and positive drug Febuxostat 24mg/kg group gives test medicine using stomach-filling.
2, experimental method and operating procedure: Normal group does not give any drug, remaining each group takes orally give oxygen piperazine daily
Sour potassium 1.5g/kg+ uric acid 0.15g/kg (being dissolved in 0.5% sodium carboxymethylcellulose), gavages 1 time according to quantity on time daily, amounts to 14
Its is before experiment and 14 days eye sockets of modeling take blood 0.5ml, separates serum, measures serum uric acid.It takes orally and fills after modeling success
Stomach gives test medicine and positive drug 7 days, respectively 2 hours after administration the 4th day, takes rat orbital vein blood 1ml,
3500RPM, 15min take the content of supernatant detection serum uric acid.
3, statistical procedures
Data mean soil standard deviationIt indicates, using Excel 7.0 and SPPS 13.0for windows
Software is analyzed, and comparison among groups are examined with q, is compared before and after medication and is examined with self pair t, and it is aobvious that P < 0.001 indicates that difference has
Meaning.
4, experimental result
As seen from Table 2, after continuous gavage gives Oteracil Potassium 1.5g/kg+ uric acid 0.15g/kg 14 days, each modeling group is big
Mouse serum uric acid increases 3-6 times than blank control group, compared with value before modeling and blank control group, difference highly significant
(p < 0.001), no significant difference between each modeling group.
Influence of the 2 F series compound of table to uricacidemia rat uric acid content
N=10*P < 0.05,**P < 0.01,***P < 0.001 and model group ratio.
Exogenous uric acid is given by foundation while inhibiting uricolytic rat uricacidemia model, to F series chemical combination
Object carries out drug screening, and reduces serum uric acid effect with positive drug Febuxostat and be compared, the results show that F seriation
The effect that object is significantly reduced serum uric acid is closed, wherein low dose group is suitable with positive control drug effect, and high dose group
It is superior to positive control drug, and has dose-effect relationship.
Embodiment 9 adds uricolytic enzyme inhibitor to cause mouse hyperuricemia animal model for a large amount of purine substances
Medicine efficacy screening experiment
1, materials and methods
1.1 experimental animal
SPF grades KM mouse 340,20-24 grams of weight, male, Animal adaptability is raised 3 days, observes body surface sign, freely
Drinking-water and feeding.All cage tools pass through 121 DEG C of sterilization treatments, and feed is irradiated sterilization treatment, the pure water of water sterilization treatment.
1.2 test drug
Screening compounds code name: totally 7 compounds are (later referred to as " F series compound " or " tested by F1-1-F7-1
Drug "), positive control drug: Febuxostat.
1.3 reagents and drug
Oteracil Potassium (Oxonic acid), hypoxanthine (Hypoxanthine), uric acid (UA) assay kit.
1.4 laboratory apparatus
Uric acid (UA) detection uses U.S. MULTlSKAN MK3 microplate reader, Italian BASA-18 full-automatic biochemical analysis
Instrument.
1.5 groupings and administration
340 male KM mouse are randomly divided into Normal group, model group, F series compound low dose group and high agent
Amount group (dosage is respectively 17 and 34g/kg), positive drug Febuxostat 34mg/kg group, is given tested using stomach-filling by every group 20
Drug.
2, experimental method and operating procedure:
Normal group does not give any drug, the daily Intraperitoneal injection of hypoxanthine 500mg/kg of remaining each group and subcutaneous injection
Uricase inhibitor Oteracil Potassium 50mg/kg is used cooperatively, continuous 7d.Before experiment and after modeling 7d, every group takes 2-3
Mouse goes eyeball to take blood 0.5ml, separates serum, serum uric acid is measured, as mouse normal serum uric acid level and modeling
Mice serum uric acid level.Test medicine and Febuxostat 4 days are given in stomach-filling after modeling success, small in last 1 time administration 2 respectively
When, it goes eyeball to take blood 0.5ml, 4000RPM, 20min, takes the content of supernatant detection serum uric acid.
3, statistical procedures
Data mean soil standard deviationIt indicates, using 13.0 for windows of Excel 7.0 and SPPS
Statistical software is analyzed, and comparison among groups are examined with q, is compared before and after medication and is examined with self pair t, and P < 0.001 indicates difference
There is significant meaning.
4, experimental result
The influence that 3 F based compound of table generates uricacidemia mouse uric acid
N=10*P < 0.05,**P < 0.01,***P < 0.001 and model group ratio
By establishing a large amount of purine uric acid while inhibiting uricolytic mouse uricacidemia model, to F series chemical combination
Object carries out drug screening, and compared with positive drug Febuxostat reduces serum uric acid effect.The results show that with model group phase
Than Febuxostat is significantly reduced the effect of serum uric acid with F series compound, wherein most of F series chemical combination
The effect of the reduction serum uric acid of object is better than positive control drug, and has dose-effect relationship.
Embodiment 10 is for the uricolytic mouse model medicine efficacy screening experiment of inhibition
1, materials and methods
1.1 experimental animal
SPF grades KM mouse 170,22-26 grams of weight, male.Animal adaptability is raised 3 days, observes body surface sign, freely
Drinking-water and feeding.All cage tools pass through 121 DEG C of sterilization treatments, and feed is irradiated sterilization treatment, the pure water of water sterilization treatment.
1.2 test drug
Screening compounds code name: totally 7 compounds are (later referred to as " F series compound " or " tested by F1-1-F7-1
Drug "), positive control drug: Febuxostat.
1.3 reagents and drug
Oteracil Potassium (Oxonic acid), uric acid (UA) assay kit.
1.4 laboratory apparatus
Uric acid (UA) detection uses U.S. MULTISKAN MK3 microplate reader, Italian BASA-18 full-automatic biochemical analysis
Instrument
1.5 groupings and administration
170 male KM mouse are randomly divided into Normal group, model group, F series compound low dose group and high agent
Amount group (dosage is respectively 17 and 34g/kg), positive drug Febuxostat 34mg/kg group, is given tested using stomach-filling by every group 10
Drug.
2, experimental method and operating procedure
Normal group does not give any drug, and stomach-filling is given after the intraperitoneal injection of remaining each group Oxonic Acid sylvite 300mg/kg, 1h
Test medicine is given, 2h goes eyeball to take blood 1ml after administration, is centrifuged 4000RPM, 20min, and serum is taken to measure uric acid content.
3, statistical procedures
Data mean soil standard deviationIt indicates, unites using Excel 7.0 and SPPS13.0 for windows
Meter software is analyzed, and comparison among groups are examined with q, is compared before and after medication and is examined with self pair t, and P < 0.001 indicates that difference has
Significant meaning.
4, experimental result
Influence of the 4 F series compound of table to uricacidemia mice serum uric acid content
N=10*P < 0.05,**P < 0.01,***P < 0.001 and model group ratio
Inhibit uricolytic mouse uricacidemia model by establishing, to the progress drug screening of F series compound, and with
Positive drug Febuxostat reduces the comparison of serum uric acid effect.The results show that Febuxostat and F series compound have significantly
Reduction serum uric acid effect, wherein F1-1, F2-1, F3-1, F7-1 reduce serum uric acid effect be better than Febuxostat,
And there is dose-effect relationship.Other compounds of the present invention are measured using identical method and all have significant reduction serum
The effect of uric acid.
The experiment of 11 given the test agent Oral Acute Toxicity of embodiment
Given the test agent:
Given the test agent (Febuxostat, F1-1, F2-1, F3-1, F4-1, F5-1, F6-1, F7-1).
Preparation method: suspension is made into the grinding of 0.2% compound.
Animal subject:
ICR mouse.
Weight: 18-22g.
Number of animals: 200.
Dosage setting:
Trial test shows that Febuxostat has certain toxicity, and 1600mg/kg dosage can cause some animals dead, and compound
F1-1, F2-1, F3-1, F4-1, F5-1, F6-1, F7-1 toxicity very little, lower 4/4 mouse of 1600mg/kg dosage have no obvious poison
Property symptom, also without animal dead.On the basis of preliminary experiment, each tested material formal test dosage setting is as follows:
The setting of each tested material formal test dosage of table 5
* maximum to match concentration.
Administration route
Gastric infusion (ig).
Test method
Test room environmental: 24 ± 2 DEG C of room temperature, relative humidity 60~70%.
Observation index: compound is made into the drug of respective concentration by above-mentioned dosage according to administration volume by proportional diluted method
Solution etc. holds ig and is administered once, and the various poisoning symptoms of record mouse and death condition, dead animal perform an autopsy on sb..
Observation period: 14 days.
Test result
1. abnormal response: mouse ig Febuxostat, F1-1, F2-1, F3-1, F4-1, F5-1, F6-1, F7-18 compounds
Afterwards within 12h, only Some Animals appearance activity is reduced in Febuxostat high dose group in each dosage group, has no other exceptions.It gives
F1-1, F2-1, F3-1, F4-1, F5-1, F6-1, F7-1 dosage group have no animal dead, Febuxostat part high dose in medicine 24
There is death successively in group animal dead, subsequent groups of animals, and each group surviving animals have no dead after administration the 8th day.Dead animal
And the rarely seen activity of surviving animals reduces and syntexis, has no that other are obvious abnormal.
2. autopsy findings: the visible bilateral renal lighter of high dose dead animal postmortem, the retention of urine, other organs are not
See obvious exception, observation finishes surviving animals postmortem and shows that each internal organs are normal, and F1-1, F2-1, F3-1, F4-1, F5-1, F6-
1, the surviving animals postmortem of F7-1 compound group is showed no obvious internal organs abnormal change.
3. the cause of death: after Febuxostat is administered in mouse, final cachexia may be led to due to the toxicity of urinary system
And it dies.
The death condition and LD of mouse ig compound50Value.
The LD of 6 mouse ig compound of table50Value (uses Bliss method[1]It calculates)
Brief summary: compared with Febuxostat, the safety of compound F1-1, F2-1, F3-1, F4-1, F5-1, F6-1, F7-1
It is superior to Febuxostat.Using identical method measure other compounds of the present invention all have good safety and.
Above embodiment be only preferred embodiments of the present invention will be described, not to the scope of the present invention into
Row limits, and without departing from the spirit of the design of the present invention, those of ordinary skill in the art make technical solution of the present invention
All variations and modifications out, should fall within the scope of protection determined by the claims of the present invention.
Claims (7)
1. a kind of compound, its stereoisomer or pharmaceutical salt, which is characterized in that the compound structure is following structures
One of formula:
2. the preparation method of compound described in claim 1, which is characterized in that existed by formula (2) compound and formula (3) compound
Compound described in claim 1 is obtained in the presence/absence of reaction under conditions of activator；
Wherein formula (2) structural formula of compound is as follows:
Formula (3) structural formula of compound is one of following compound structures:
3. preparation method according to claim 2, which is characterized in that solvent is selected from acetonitrile, acetone, tetrahydrofuran, dichloro
Methane, chloroform, carbon tetrachloride, formamide, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, methyl acetate or
Its mixture.
4. preparation method according to claim 2, which is characterized in that the activator is selected from thionyl chloride, oxalyl chloride, two
In carbodicyclo hexylimide, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, p-nitrophenol or allyl alcohol
It is one or more kinds of.
5. a kind of pharmaceutical composition, which is characterized in that compound described in the claim 1 including effective dose.
6. pharmaceutical composition according to claim 5, which is characterized in that the dosage form of described pharmaceutical composition is selected from tablet, glue
Capsule, syrup, powder, granule, emulsion, solution.
7. compound described in claim 1 or its pharmaceutical salt or its stereoisomer are preparing the suppression of xanthine oxidoreductase enzyme
Application in preparation.
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