CN106008488B - Cyanoindole analog derivative and its preparation method and application - Google Patents

Cyanoindole analog derivative and its preparation method and application Download PDF

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CN106008488B
CN106008488B CN201610339146.8A CN201610339146A CN106008488B CN 106008488 B CN106008488 B CN 106008488B CN 201610339146 A CN201610339146 A CN 201610339146A CN 106008488 B CN106008488 B CN 106008488B
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compound
alkyl
independently
cyano
atom
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CN106008488A (en
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黄常伟
王晓军
杨新业
马发城
潘圣强
吴俊文
熊绍辉
郭蕊
张英俊
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
    • C07D421/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The present invention relates to a kind of cyanoindole analog derivatives, and the pharmaceutical composition comprising such compound；The compound or pharmaceutical composition can be used for inhibiting the activity of xanthine oxidase and/or lithate anion transport body -1.The invention further relates to the method for preparing this kind of compound and pharmaceutical composition and they treat or prevent mammal, the especially mankind the purposes with the higher related disease of uric acid level in blood.

Description

Cyanoindole analog derivative and its preparation method and application
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to a kind of compound, the pharmaceutical composition for including the compound, And their preparation method and purposes, wherein the compound or pharmaceutical composition have inhibit xanthine oxidase and/or - 1 active purposes of lithate anion transport body, and can be used for preventing or treat and the higher related disease of uric acid level in blood.
Background technology
Uric acid is the metabolite last eventually of mankind's purine compound.In human body, uric acid is mainly through kidney excretion, excretion Amount accounts for nearly 2/3rds of total excretion.When uric acid generates excessive or acatharsia, uric acid accumulation is made to cause in human body in blood Uric acid concentration increases, and then leads to hyperuricemia.Under normal purine diet state, non-empty stomach serum uric acid level twice on the same day Male is higher than 420 μm of ol/L, and women is higher than 360 μm of ol/L, as hyperuricemia.Hyperuricemia can be classified as (1) uric acid Many types of, (2) uric acid excretion not good figure and (3) mixed type were generated, such classification diagnosis helps to find the disease of hyperuricemia Cause simultaneously gives immunotherapy targeted autoantibody.
With uric acid concentration supersaturation in blood, uric acid sodium salt, which initially forms, to be crystallized and is deposited on synovium of joint, synovial bursa, cartilage And its in hetero-organization, when quickly variation occurs for internal uric acid level, local trauma causes tiny crystals release or urate crystals When albumen coating changes, causes repeated relapsing inflammatory reaction, then induce gout.Gout refers in particular to acute feature arthritis Include mainly acute attack arthritis, tophus formation, tophaceous chornic arthritis, uric acid with chronic gout stone disease Salt nephrosis and uric acid lithangiuria, severe one may occur in which joint deformity and renal insufficiency.In addition, gout also with hypertension, generation Thank to related (the Terkeltaub RA.Clinical of the various diseases such as syndrome, hyperlipidemia, diabetes and insulin resistance practice.Gout[J].N Engl J Med.2003,349:1647-1655；Schlesinger N,Schumacher HR Jr.Gort:can management be improved？[J].Curr Opin Rheumatol.2001,13:240-244).
Hyperuricemia and gout are to endanger the serious metabolic disease of human health；There is data to suggest that about 5%- 12% Patients with Hyperuricemia finally develops into gout.Uric acid is the material base that hyperuricemia and gout occur, therefore, It reduces uric acid concentration in blood and can be used for preventing or treat hyperuricemia and gout, and reduce and suffer from other hyperuricemias and lead to The risk of wind complication.
Uric acid is inhibited to generate medicine and uricosuric drug currently, the drug for reducing uric acid level has.
Uric acid is originated from the purine bodies of diet intake and endogenous synthesis, is finally to aoxidize xanthine by xanthine oxidase And it generates.So xanthine oxidase (Oxanthine oxidase) is considered an important target for inhibiting uric acid to generate drug Point.Existing uric acid generates the other purine of depressant and is reported the various diseases that can effectively treat hyperuricemia and be induced by it.
On the other hand, about 90% hyperuricemia is caused by underexcretion, and uric acid is main in the excretion of kidney Including 4 processes：After the filtration of glomerulus, the reabsorption of renal tubule and concetrated pipe, renal tubule and concetrated pipe secretion and secretion Reabsorption, each process be by corresponding albumen participate in complete, finally the only uric acid of 8%-12% excretes (Liu Ruo Rosy clouds, Zang Luping, Wu Xinrong, Shandong medicine [J], the 28th phase of volume 52 in 2012).Lithate anion transport body -1 (URAT1) It is to be located at proximal tubular cell brush border side by discoveries such as Enomoto, participates in again suction of the uric acid in kidney proximal tubule A kind of transmembrane transporter received.Mankind URAT1 (hURAT1) is contained by the SLC22A12 gene codes on Chromosome 11q13 10 exons and 9 intrones, by 555 amino acid residues, 12 transmembrane structures and the-NH positioned at cell interior2With- The ends COOH form.Research finds that the SLC22A12 genes that renal Hypouricemia patient carries mutate, and loses coding The ability of URAT1 maturation proteins, thereby determine that URAT1 be renal Hypouricemia Disease-causing gene (Enomoto, Kimura H, Chairoungdua A,et al.Molecular identification of a renal urate anion exchanger that regulates blood urate levels[J].Nature,2002,417(6887):447- 452) it, is of great significance to the uric acid reabsorption function of kidney and closely related with the regulation and control of uric acid level in blood.Therefore, have There is the substance of URAT1 inhibitory activity that can promote the excretion of uric acid in blood, it is higher related with uric acid level in blood for treating and preventing Disease, including hyperuricemia, gout, tophus, urarthritis, hyperuricemia correlation nephropathy, urinary tract Calculus etc..
Existing relevant report claims, and is used in combination by Allopurinol and with medicine for improving uric acid excretion than Allopurinol tool is used alone There is more preferably blood uric acid effect (S Takahashi, Ann.Rheum.Dis., 2003,62,572-575).Therefore, pass through rush Uric acid excretion medicine and uric acid generate being used in combination for depressant and can obtain the inaccessiable therapeutic effect of single drug institute and keep away Exempt from corresponding risk, for example, good figure hyperuricemia, exclusive use uricosureic agent are not possible to cause for uric acid excretion The risk of lithangiuria, therefore uric acid is used in combination generates depressant and can obtain expected higher therapeutic effect.
It can inhibit xanthine oxidase but also inhibit URAT1 drugs, better therapeutic effect will be provided for patient, simultaneously It is more more convenient than drug combination.This kind of drug has become treatment hyperuricemia, gout and with the relevant disease of hyperuricemia The research and development focus of disease.
Brief summary of the invention
Only summarize some aspects of the present invention below, it is not limited to this.These aspects and other parts are later There is more complete explanation.All bibliography in this specification are incorporated in this by whole.Work as the disclosure of the specification When variant with citation, it is subject to the disclosure of the specification.
The present invention provides a kind of compound with xanthine oxidase and/or URAT1 inhibitory activity, for preventing or Treatment and the higher related disease of uric acid level in blood, such as hyperuricemia, tophus, urarthritis and antihyperuricemic The related nephropathy of disease and urolithiasis etc.；The compounds of this invention can inhibit xanthine oxidase and/or URAT1's well Activity, while there is excellent physicochemical property and pharmacokinetic property.
Pharmaceutical composition present invention provides the preparation method of these compounds and comprising these compounds and make With these compounds or the method for the above-mentioned disease of medicine composite for curing mammal, the especially mankind.
Specifically：
On the one hand, the present invention relates to the alloisomerisms of one kind compound as shown in formula (I) compound represented or formula (I) Body, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, ester are pharmaceutically acceptable Salt or its prodrug,
Wherein：
Q is key ,-CH2,-C (=O)-or-S (=O)2-；
W rings areWherein, E rings are carbocyclic ring, heterocycle, aromatic ring or hetero-aromatic ring；
Each R independently is D-atom, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, alkyl, alkenyl, alkynes Base, halogenated alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-C (=O)-naphthenic base ,-C (=O)-heterocycle ,-C (=O)-aryl ,-C (=O)-heteroaryl ,-L1- S (=O)r-L2-RA, cycloalkyl-alkyl, aryl alkyl, heteroaryl alkyl or carboxylic Base；Wherein, each R is individually optionally by 1,2,3,4 or 5 RxSubstitution；
RAFor alkyl, alkenyl, alkynyl, halogenated alkyl, alkoxy, naphthenic base, heterocycle, aryl or heteroaryl；
Each RxIt independently is hydroxyl, oxo (=O), halogen atom, amino, nitro, cyano, alkyl, alkoxy or alkyl halide Base；
R1、R2、R3、R4And R5It is each independently hydrogen atom, D-atom, halogen atom, hydroxyl, amino, nitro, cyano, alkane Base, halogenated alkyl, alkoxy, aryl or heteroaryl；Wherein, each R1、R2、R3、R4And R5Individually optionally by 1,2 or 3 RyIt takes Generation；
Each RyIt independently is hydroxyl, oxo (=O), halogen atom, amino, nitro, cyano, alkyl, alkoxy or carboxyl；
M is 0,1,2,3,4 or 5；
R is 0,1 or 2；
L1For key ,-O- or-NH-；
L2For key ,-O- or-NH-；With
Condition is,
W rings are not
In some embodiments, W rings areWherein, E rings are 5-8 members carbocyclic ring, 5-8 circle heterocyclic rings, phenyl ring Or 5-8 member hetero-aromatic rings；R and m has meaning as described in the present invention.
In other embodiments, W rings are Or
Wherein, each X1And X2It independently is-S (=O)t,-Se- ,-O- ,-NH- or-CH2, each t independently is 0,1 or 2； Each Y1And Y2It independently is N or CH；R and m has meaning of the present invention.
In other embodiment, W rings are OrWherein, R and m has meaning of the present invention.
In some embodiments, each R independently is D-atom, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyanogen Base, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Alkoxy, C3-6Naphthenic base, C1-6Heterocycle, C6-10Virtue Base, C1-5Heteroaryl ,-C (=O)-C3-6Naphthenic base ,-C (=O)-C1-6Heterocycle ,-C (=O)-C6-10Aryl ,-C (=O)-C1-5 Heteroaryl ,-L1- S (=O)r-L2-RA、C3-6Naphthenic base-C1-6Alkyl, C6-10Aryl-C1-6Alkyl, C1-5Heteroaryl-C1-6Alkyl or Carboxyl；Wherein, each R is individually optionally by 1,2,3,4 or 5 RxSubstitution；
RAFor C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Alkoxy, C3-6Naphthenic base, C1-6Heterocycle Base, C6-10Aryl or C1-5Heteroaryl；
Each RxIt independently is hydroxyl, oxo (=O), halogen atom, amino, nitro, cyano, C1-6Alkyl, C1-6Alkoxy or C1-6Halogenated alkyl.
In other embodiments, each R independently be D-atom, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, Nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tertiary butyl, vinyl, acetenyl, propargyl, difluoromethyl, fluoroform Base, methoxyl group, ethyoxyl, isopropoxy, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, benzene Base, naphthalene, furyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, thiazolyl, pyridyl group, pyrimidine radicals, triazol radical, four nitrogen Oxazolyl ,-C (=O)-cyclopropyl ,-C (=O)-cyclohexyl ,-C (=O)-phenyl ,-C (=O)-thienyl ,-C (=O)-imidazoles Base, ethylsulfonyl, Cvclopropvlmethvl, benzyl, thienyl methyl or carboxyl；Wherein, each R is individually optionally by 1,2,3,4 or 5 A RxSubstitution；
Each RxIt independently is hydroxyl, oxo (=O), fluorine, chlorine, bromine, iodine, amino, nitro, cyano, methyl, methoxyl group or three Methyl fluoride.
In some embodiments, R1、R2、R3、R4And R5Be each independently hydrogen atom, D-atom, halogen atom, hydroxyl, Amino, nitro, cyano, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C6-10Aryl or C1-5Heteroaryl；Wherein, each R1、R2、 R3、R4And R5Individually optionally by 1,2 or 3 RySubstitution；
Each RyIt independently is hydroxyl, oxo (=O), halogen atom, amino, nitro, cyano, C1-6Alkyl, C1-6Alkoxy or Carboxyl.
In other embodiments, R1、R2、R3、R4And R5Be each independently hydrogen atom, D-atom, fluorine, chlorine, bromine, Iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, trifluoromethyl, methoxyl group, phenyl, naphthalene, pyrrole radicals, pyrazolyl, imidazoles Base, thiazolyl, thienyl, oxazolyl, tetrazole base, pyridyl group or pyrimidine radicals；Wherein, each R1、R2、R3、R4And R5It is individually optional Ground is by 1,2 or 3 RySubstitution；
Each RyIt independently is hydroxyl, oxo (=O), fluorine, chlorine, bromine, iodine, cyano, methyl, isopropyl, methoxyl group or carboxyl.
On the other hand, the present invention provides a kind of compounds, are the structure of one of：
Or it is its stereoisomer, several What isomers, tautomer, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or preceding Medicine.
On the other hand, the present invention relates to a kind of pharmaceutical compositions, and it includes compounds disclosed by the invention.
In some embodiments, pharmaceutical composition of the present invention further include pharmaceutically acceptable excipient, Carrier, adjuvant or combination thereof.
In further embodiments, pharmaceutical composition of the present invention includes further that other preventions or treatment are high The drug of uricacidemia, tophus, urarthritis, related with hyperuricemia nephropathy and urolithiasis, the medicine Object be colchicin, non-steroidal anti-inflammatory drugs, glucocorticoid, inhibit uric acid generate medicine, uricosureic agent, urine basifier or it Arbitrary combination.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Drug is for preventing or treating mammal, including the hyperuricemia of the mankind, tophus, urarthritis and high lithemia The related nephropathy of mass formed by blood stasis and urolithiasis.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Drug is for reducing uric acid level in blood.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Activity of the drug for inhibiting xanthine oxidase and/or lithate anion transport body -1 in study subject.
On the other hand, the present invention relates to the methods of the preparation, separation and purifying of formula (I) described compound.
Biological results show that compound provided by the invention can be used as preferable xanthine oxidase and/or uric acid - 1 inhibitor of salt anionic transporter.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, in any embodiment of either side of the present invention, any technical characteristic can be adapted for other realities The technical characteristic in scheme is applied, as long as they are not in contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method and material described herein Trample the present invention.The present invention is not limited to method described herein and material.The one of the document, patent and the similar material that are combined Or more it is different from the application or in the case of contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be subject to the application.
It will further be appreciated that certain features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also in combination be provided in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with any suitable sub-portfolio in single embodiment.
Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise stated, following definition used herein should be applied.For purposes of the present invention, chemical element with Periodic table of elements CAS editions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can join It examines " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley&Sons,New York:Description in 2007, entire contents are incorporated herein by reference.
There is apparent conflict unless otherwise indicated or in context, article " one " used herein, " one (kind) " " described " is intended to include "at least one" or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one Component be taken into account in the embodiment of the embodiment and use or use.
Term " study subject " used in the present invention refers to animal.The typical animal is mammal.It is tested right As, such as also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by It is people to try object.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.
Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded otherwise Content.
" stereoisomer " refers to having identical chemical constitution, but atom or the group spatially different change of arrangement mode Close object.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..
" chirality " be with its mirror image cannot be overlapped property molecule；And " achirality " refer to can be overlapped with its mirror image Molecule.
" enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.
" diastereoisomer " refer to there are two or multiple chiral centers and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral quality and reactivity.Diastereoisomer is mixed Such as electrophoresis and chromatography, such as HPLC can be operated by high resolution analysis to detach by closing object.
Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley&Sons, Inc., New York, 1994.
Many organic compounds exist with optical active forms, i.e., they, which have, makes the plane of linearly polarized light rotate Ability.When describing optically active compound, indicate molecule about one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols rotated for linearly polarized light caused by appointed compound, Wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter:50 mixtures Referred to as racemic mixture or racemic modification, when chemical reaction or in the process without stereoselectivity or stereospecificity when, It may occur in which such case.
Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer It is excessive.
According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Chiral synthon or chiral reagent can be used to prepare for optically active (R)-or (S)-isomers, or be torn open using routine techniques Point.If compound contains, there are one double bonds, and substituent group may be E or Z configurations；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or trans configuration.
The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.
Can the racemic modification of any gained final product or intermediate be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is detached by its diastereoisomeric salt to acquisition.Racemic production Object can also be detached by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, Jacques is can refer to, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, such as General formula compound above, or as special example inside embodiment, subclass, and a kind of compound that the present invention is included.
In general, " substituted " expression of term is taken to one or more of structure hydrogen atom by specific substituent group Generation.Unless otherwise indicated, the group of a substitution can at various substitutable position of that group be carried out there are one substituent group Substitution.When more than one position can be replaced by one or more substituent groups selected from specific group in given structural formula, So substituent group can replace at various locations identical or differently.
Term " unsubstituted " indicates specified group without substituent group.
Term " optionally by ... replace " can exchange use, i.e., with term " unsubstituted or by ... replace " The structure is unsubstituted or is replaced by one or more substituent groups of the present invention.Substituent group packet of the present invention It includes, but is not limited to D, F, Cl, Br, I, N3、CN、NO2、OH、SH、NH2, oxo (=O), alkyl, halogenated alkyl, alkenyl, alkynyl, Alkoxy, naphthenic base, heterocycle, aryl, heteroaryl, cycloalkyl-alkyl, aryl alkyl, heteroaryl alkyl or carboxyl, etc..
In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both may be used To refer among the different groups, not influencing mutually, can also indicating in phase between expressed specific option between the same symbol In same group, do not influenced mutually between expressed specific option between the same symbol.
It is disclosed according to radical species or range in the substituent group of each section of this specification, disclosed compound of present invention.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each section of the present invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then is respectively represented it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.
Terminology used in the present invention " alkyl " or " alkyl group " indicate the linear chain or branched chain univalent hydrocarbyl group of saturation, Wherein, the alkyl group can optionally be replaced by the substituent group that one or more present invention describe.Unless in addition in detail Illustrate, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-12 carbon atom；Another In embodiment, alkyl group contains 3-12 carbon atom；In another embodiment, alkyl group contains 1-6 carbon atom； In yet another embodiment, alkyl group contains 1-4 carbon atom.
The example of alkyl group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n- Pr、-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,- CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tertiary butyl (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyls (- CH (CH3)CH2CH2CH3), 3- amyls (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl-1s-butyl (- CH2CH2CH(CH3)2), 2- first Base -1- butyl (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3) CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyls (- C (CH3)2CH2CH2CH3), 3- first Base -2- amyls (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyls (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- penta Base (- C (CH3)(CH2CH3)2), 2- methyl -3- amyls (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..
Term " alkylidene " indicates to remove two obtained saturations of hydrogen atom from the linear chain or branched chain alkyl of saturation Bivalent hydrocarbon radical group.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In one embodiment, alkylene Base group contains 1-6 carbon atom；In another embodiment, alkylidene group contains 1-4 carbon atom；In another embodiment party In case, alkylidene group contains 1-3 carbon atom；Also in one embodiment, alkylidene group contains 1-2 carbon atom.This The example of sample includes methylene (- CH2), ethylidene (- CH2CH2), isopropylidene (- CH (CH3)CH2) etc..
Term " alkenyl " indicates linear chain or branched chain monovalent hydrocarbon, wherein at least one carbon-to-carbon sp2Double bond, wherein described Alkenyl group can optionally be replaced by one or more substituent groups described in the invention comprising " cis " and " trans " Positioning, or " E " and " Z " positioning.In one embodiment, alkenyl group includes 2-12 carbon atom；In another implementation In scheme, alkenyl group includes 3-12 carbon atom；In another embodiment, alkenyl group includes 2-6 carbon atom；Again In one embodiment, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (- CH =CH2), allyl (- CH2CH=CH2) etc..
Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one carbon- Tri- keys of carbon sp, wherein the alkynyl group can optionally be replaced by one or more substituent groups described in the invention.? In one embodiment, alkynyl group includes 3-12 carbon atom；In another embodiment, alkynyl group includes that 2-6 carbon is former Son；In yet another embodiment, alkynyl group includes 2-4 carbon atom.The example of alkynyl group includes, but is not limited to, second Alkynyl (- C ≡ CH), propargyl (- CH2C ≡ CH), 1- propinyls (- C ≡ C-CH3) etc..
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more The substituent group that the present invention describes is replaced.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH3)3), 1- amoxys (n- amoxys ,-OCH2CH2CH2CH2CH3), 2- amoxys (- OCH (CH3) CH2CH2CH3), 3- amoxys (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- fourths Oxygroup (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (- OCH2CH(CH3)CH2CH3), etc..
Term " halogenated alkyl " indicates that alkyl group is replaced by one or more halogen atoms, and wherein alkyl group has Meaning as described in the present invention, such example includes, but is not limited to, trifluoromethyl, 2,2,3,3- tetra- fluoropropyls, difluoro first Oxygroup, trifluoromethoxy, trifluoromethyl amino etc..
Term " naphthenic base " indicates containing 3-12 ring carbon atom, monovalent or multivalence saturation monocyclic, bicyclic or tricyclic System.In one embodiment, naphthenic base includes 7-12 ring carbon atom；In yet another embodiment, naphthenic base includes 3-8 Ring carbon atom；In yet another embodiment, naphthenic base includes 3-6 ring carbon atom.The group of naphthene base can independently not It is substituted or is replaced by one or more substituent groups described in the invention.
Term " carbocyclic ring " or " carbocylic radical " indicate that unit price or the nonaromatic of multivalence are satisfied containing 3-12 ring carbon atom And/or the unsaturated monocycle in part, bicyclic or three-ring system.Carbon bicyclic group includes spiral shell carbon bicyclic group and condensed carbon bicyclic group, properly Carbocylic radical group include, but is not limited to, naphthenic base, cycloalkenyl group and cycloalkynyl radical.In one embodiment, carbocylic radical includes 3- 8 ring carbon atoms；In yet another embodiment, carbocylic radical includes 3-6 ring carbon atom.The example of carbocylic radical group further wraps It includes, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyls, 1- cyclopenta -2- alkenyls, 1- cyclopenta -3- alkenyls, hexamethylene Base, 1- cyclohexyl -1- alkenyls, 1- cyclohexyl -2- alkenyls, 1- cyclohexyl -3- alkenyls, cyclohexadienyl, suberyl, cyclooctyl, Cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..The carbocylic radical group can it is independently unsubstituted or by One or more substituent groups described in the invention are replaced.
Term " heterocycle " and " heterocycle " are used interchangeably here, all refer to the saturation comprising 3-12 annular atom or portion Point undersaturated nonaromatic unit price or multivalence monocyclic, bicyclic or tricyclic, wherein at least one annular atom be selected from nitrogen, sulphur, oxygen, Phosphorus, silicon and selenium atom.Unless otherwise stated, heterocycle can be connect by carbon atom with other groups in molecule, can also be led to It crosses nitrogen-atoms to connect with other groups in molecule, and-CH2Group can be substituted optionally by-C (=O)-.The sulphur atom of ring can To be optionally oxidized to S- oxides.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compounds.The example of heterocycle Include, but are not limited to：Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- pyrrolins Base, 3- pyrrolinyls, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuryl, tetrahydrochysene Thienyl, dihydrothiophene, 1,3- dioxies cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranoses, 4H- pyranoses, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, alkyl dioxins, dithianyl, thioxanes Base, high piperazine base, homopiperidinyl, Diazesuberane base, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, phenodiazine It is miscellaneousBase, sulphur azepineBase, 2- oxa- -5- azabicyclos [2.2.1] hept- 5- bases, 2- oxo-pyrrolidines base, oxo -1,3- thiazoles It is alkyl, 2- piperidone bases, 3,5- dioxy piperazines piperidinyl and hybar X base, sulfolane base, 1,1- dioxothiomorpholinyls, different Oxazole -3 (2H) -one, 1,5- dihydro-2 h-pyrrole -2- ketone, 1,2- dihydro -3H- pyrazoles -3- ketone, isothiazole -3 (2H) -one -1, 1- dioxide, isothiazole -3 (2H) -one, 1,2- selenazoles -3 (2H) -one, oxazole -2 (3H) -one, pyrimidine -2,4 (1H, 3H)-two Ketone, 2H-1,3- oxazines -2,4 (3H)-diketone, isothiazole -1- monoxide, pyridine -2 (1H) -one, 2,3- dihydros -4H-1,3- Oxazines -4 (3H) -one, pyrrolidine-2,5-dione, 1,2- dioxoles, 2,3- dihydro isothiazole -1,1- dioxide, 2,3- dihydro-isoxazoles, 2,3- dihydropyridines -4 (1H) -one, etc..The heterocyclyl groups can optionally by one or Multiple substituent groups described in the invention are replaced.
Term " hetero atom " refers to O, S, N, P, Si and Se, includes the form of any oxidation state of N, S and P；Primary, secondary, tertiary amine With the form of quaternary ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N is (as 3,4- dihydro-2 h-pyrrole bases In N), NH (as the NH in pyrrolidinyl) or NR (NR in the pyrrolidinyl replaced as N-).
Term " halogen " or " halogen atom " refer to fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (I).
Term " cyano " refers to-CN.
Term " nitro " refers to-NO2。
Term " amino " refers to-NH2。
Term " hydroxyl " refers to-OH.
Term " aryl " indicates to contain 6-14 annular atom or the monocycle of 6-12 annular atom or 6-10 annular atom, double The carbocyclic ring system of ring or tricyclic, wherein at least one ring is aromatic, and there are one or remaining of multiple attachment points and molecule Part is connected.Term " aryl " can be exchanged with term " aromatic rings " and be used.In one embodiment, aryl is by 6-10 ring It is former molecular, and wherein at least contain the carbocyclic ring system there are one aromatic rings.The example of aryl group may include phenyl, naphthalene And anthryl.The aryl group can be replaced by one or more substituent groups described in the invention individually optionally.
Term " heteroaryl " indicate containing 5-12 annular atom or the monocycle of 5-10 annular atom or 5-6 annular atom, Bicyclic or tricyclic, wherein at least one ring is aromatic, and at least one ring includes 1 to 4 hetero atom for being selected from O, N and S, There are one or multiple attachment points be connected with molecule rest part.Term " heteroaryl " can be with term " hetero-aromatic ring " or " heteroaromatic Compound ", which exchanges, to be used.The heteroaryl groups are optionally replaced by one or more substituent groups described in the invention.? In one embodiment, heteroaryl is comprising 1,2, the 3 or 4 heteroatomic 5-12 annular atom for being independently selected from O, N and S composition Heteroaryl；In another embodiment, heteroaryl is the heteroatomic 5-6 ring for being independently selected from O, N and S comprising 1,2,3 or 4 Former molecular heteroaryl.
The example of heteroaryl groups includes, but is not limited to, 2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyls, 2- oxazolyls, 4- oxazolyls, 5- oxazoles Ji, oxadiazolyls (such as 1,2,3- oxadiazolyls, 1,2,5- oxadiazolyls, 1,2,4- oxadiazolyl), oxatriazoles base (such as 1,2,3, 4- oxatriazoles base), 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, isothiazolyl, 2- thiadiazolyl groups (such as 1,3,4- thiadiazolyl groups, 1,2,3- thiadiazolyl groups, 1,2,5- thiadiazolyl groups), thiatriazole base (such as 1,2,3,4- thiatriazoles base), tetrazole radical (such as 2H-1,2, 3,4- tetrazole radicals, 1H-1,2,3,4- tetrazole radicals), triazolyl (such as 2H-1,2,3- triazolyls, 1H-1,2,4- triazolyls, 4H-1, 2,4- triazolyls), 2- thienyls, 3- thienyls, 1H- pyrazolyls (such as 1H- pyrazole-3-yls, 1H- pyrazoles -4- bases, 1H- pyrazoles - 5- yls), 1,2,3- thio biphospholes base, 1,3,4- thio biphospholes base, 1,2,5- thio biphospholes base, N- pyrrole radicals, 2- pyrrole radicals, 3- Pyrrole radicals, 2- pyridyl groups, 3- pyridyl groups, 4- pyridyl groups, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, pyridazinyl (such as 3- pyridazines Base, 4- pyridazinyls), 2- pyrazinyls, triazine radical (such as 1,3,5- triazines), tetrazine base (such as 1,2,4,5- tetrazines, 1,2,3,5- tetra- Piperazine)；Also include below bicyclic, but it is bicyclic to be not limited to these：Benzimidazolyl, benzofuranyl, benzothienyl, indoles Base (such as 2- indyls), purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinolyls), isoquinolyl (such as 1- isoquinolines Quinoline base, 3- isoquinolyls or 4- isoquinolyls), imidazo [1,2-a] pyridyl group, pyrazolo [1,5-a] pyridyl group, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1,2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1, 5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridyl group, etc..
Term " cycloalkyl-alkyl ", " aryl alkyl " and " heteroaryl alkyl " indicates " naphthenic base " respectively, " aryl " and " miscellaneous Aryl " group is connect by alkyl with molecule rest part, wherein " naphthenic base ", " aryl " and " heteroaryl " group has such as this The invention meaning.
No matter term " carboxyl " is single use or is used in conjunction with other terms, such as " carboxyl ", expression-CO2H；Term No matter " carbonyl " is single use or is used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", indicated-(C=O)-.
As described in the invention, substituent group draws one and is keyed to the member ring systems formed on the ring at center (such as formula b institutes Show) it represents substituent group any commutable position on the ring and can replace.For example, formula b represent substituent R can be on C rings It is monosubstituted or polysubstituted on any possible substituted position, as shown in formula c1~formula c17.
As described in the invention, one connects member ring systems (as shown in the formula d) generation for being keyed to and being formed on the center of ring Table connecting key can be connected any attachable position in member ring systems with molecule rest part.Formula d represents any possibility on D rings The position of connection can be connected with molecule rest part.
As described in the present invention, substituent R is keyed to the member ring systems formed on the ring at center by one and represents substituent R It any on coupled ring may only may replace or any rational position is replaced.Take up an official post for example, formula e represents A rings What possible substituted position can be replaced by R, as shown in formula f, formula g, formula h and formula i.
When term " blocking group " or " PG " refer to a substituent group and other reacted with functional groups, commonly used to resistance It is disconnected or protect special functionality.It is connected with amino group to block for example, " blocking group of amino " refers to a substituent group Or the functionality of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyls (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent group of base is used for blocking or protecting the functionality of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl Blocking group " refers to that the substituent group of carboxyl is used for blocking or protecting the functionality of carboxyl, general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group can refer to document：T W.Greene,Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed by pro-drug or is influenced for precursor structure through enzymatic conversion in blood or tissue in blood.This hair Bright pro-drug compounds can be ester, and ester can be as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C1-C24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, you can be acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.It is completely begged for about pro-drug By following documents can be referred to：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change Closing the metabolite of object can be identified by technology well-known in the art, and activity can be retouched by such as the present invention It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, being restored, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. recorded.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, inorganic acid salt Such as hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetate, oxalates, maleate, Tartrate, citrate, succinate, malonate, or handed over by other methods described in the books or literature such as ion Method is changed to obtain these salt.Other pharmaceutically acceptable salts include adipate, alginates, ascorbate, aspartic acid Salt, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, Digluconate, lauryl sulfate, esilate, formates, fumarate, gluceptate, phosphoglycerol Salt, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactic acid Salt, laruate, lauryl sulfate, malate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palm fibre Palmitic acid hydrochlorate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearic acid Salt, rhodanate, tosilate, undecylate, valerate, etc..Salt obtained by an appropriate base includes alkali metal, Alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The compound that the present invention is also intended to contemplate the group of any included N is formed Quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Alkali or alkaline earth metal salt packet Include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises that appropriate, nontoxic ammonium, quaternary ammonium salt are put down with anti- The amine cation that the ion that weighs is formed, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8 Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to that one or more solvent molecules are formed by association with the compound of the present invention Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
When the solvent is water, term " hydrate " can be used.In some embodiments, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In other embodiments, a compounds of this invention point Son can be combined with more than one hydrone, such as dihydrate, in further embodiments, a compounds of this invention Molecule can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remains with The biological effectiveness of the compound of nonhydrated form.
As used in the present invention any disease of term " treatment " or illness, refer to it is all can slow down, interrupt, preventing, Control or the progress for stopping disease or illness, but not necessarily indicate that the symptom of all diseases or illness all disappears, also include To the prophylactic treatment of the symptom, especially it is being easy in the patient with such disease or obstacle.Some are implemented wherein Scheme middle finger improves disease or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).Another In some embodiments, " treatment " refers to mitigation or improves at least one body parameter, including the body that may not be discovered by patient Body parameter.In other embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (example Such as stablize the parameter of body) or above-mentioned two aspect adjusting diseases or illness.In other embodiments, " treatment " refer to prevention or Postpone breaking-out, generation or the deterioration of disease or illness.
Term " therapeutically effective amount " as used in the present invention or " treatment effective dose " are the lifes for referring to cause individual Object or medicinal response (such as enzyme or protein active are reduced or inhibit, or improve symptom, alleviate illness, slow down or postpone disease Disease development, or prevent disease etc.) the compounds of this invention amount.In a non-limiting embodiment, " treatment has term Effect amount " refers to effectively being measured to following situations when applying the compounds of this invention to individual：(1) alleviate at least partly, press down System prevents and/or improves (i) to be mediated by xanthine oxidase or lithate anion transport body -1 (URAT1), or (ii) with Xanthine oxidase or -1 activity of lithate anion transport body are related, or (iii) cloudy by xanthine oxidase or lithate The conditions or diseases of the abnormal activity characterization of ion transport body -1；Or (2) reduce or inhibit xanthine oxidase or lithate The activity of anion transport body -1；Or (3) reduce or inhibit the table of xanthine oxidase or lithate anion transport body -1 It reaches.In another embodiment, term " therapeutically effective amount " refers to working as to cell or organ or acellular organism substance or being situated between When matter is applied, -1 activity of xanthine oxidase or lithate anion transport body can be reduced or inhibited at least partly；Or extremely The effective the compounds of this invention for partially reducing or inhibiting xanthine oxidase or lithate anion transport body -1 to express Amount.
Term compound " giving " and " administration " compound as used in the present invention should be understood as to its of needs Body provides the prodrug of the compound of the present invention or the compounds of this invention.It should be appreciated that those skilled in the art are by using effective The compounds of this invention treatment of amount suffers from the patient or prophylactically patient of the treatment with this obstacle of this obstacle at present, can be with Uric acid concentration in blood is had an impact.
Term " composition " as used in the present invention refers to the product and specified amount of the predetermined component comprising specified amount Predetermined component the spawn that directly or indirectly generates of combination.With the meaning of the relevant this term of pharmaceutical composition Include the product comprising active constituent (single either multiple) and the inert fraction (single or multiple) for forming carrier, Yi Jiyou Any two or Multiple components mixing, it is compound or aggregation, either by one or more ingredient breakdowns or by it is one or more at Point other kinds of reaction or interaction and the spawn that directly or indirectly generates.Therefore, pharmaceutical composition of the present invention It include any composition prepared by mixing the compounds of this invention with pharmaceutical acceptable carrier.
Pharmaceutical composition, preparation and the administration of the compounds of this invention
The present invention provides a kind of pharmaceutical composition, and it includes listed chemical combination in disclosed compound of present invention, such as embodiment Object；With pharmaceutically acceptable excipient, carrier, adjuvant, solvent or combination thereof.
The present invention provides treatment, prevents or improve the method for disease or illness, including give safe and effective amount includes this The combination medicine of disclosure of the invention compound and one or more therapeutically active agents.Wherein, combination medicine include it is one or more its He prevents or treatment hyperuricemia, tophus, urarthritis, nephropathy related with hyperuricemia and urolithiasis Drug.
Other preventions or treatment hyperuricemia, tophus, urarthritis, kidney related with hyperuricemia barrier The drug with urolithiasis is hindered to include but not limited to：Colchicin, non-steroidal anti-inflammatory drugs, glucocorticoid, inhibit uric acid generate medicine, Uricosureic agent, urine basifier or their arbitrary combination.
The others treat hyperuricemias, tophus, urarthritis, kidney related with hyperuricemia Obstacle and the drug of urolithiasis are colchicin, Indomethacin, Etoricoxib, Diclofenac, brufen, rofecoxib, fill in and Former times cloth, Meloxicam, prednisone, succinic acid hydrogenation cortisone, Allopurinol, probenecid, sulfinpyrazone, Benzbromarone, former times difficult to understand are fast Alcohol, Febuxostat, recombined Aspergillus flavus bacteruria acid oxidase, Pegylation recombination urate oxidase, Sodium Bicarbonate Tablets, citric acid Potassium sodium mixture or their arbitrary combination.
The amount of compound refers to that can effectively detect to inhibit biological sample or patient in pharmaceutical composition disclosed by the invention The amount of internal xanthine oxidase and/or lithate anion transport body -1.The dosage of active component can in the present composition To change, still, the amount of active component must can obtain the amount of appropriate dosage forms.Active component can be to provide optimal drug The dosage of effect delivers medicine to the patient (animal and people) for needing this treatment.Selected dosage is imitated depending on desired treatment Fruit depends on administration route and duration for the treatment of.Dosage will be different with patient, this depends on the attribute of disease and serious journey Degree, the weight of patient, the specific diet of patient, drug used at the same time and it will be recognized by those skilled in the art it is other Factor.Dosage range is usually each patient about 0.5mg to 1.0g daily, can be administered in the form of single dose or multi-agent.At one In embodiment, dosage range is each patient about 0.5mg to 500mg daily；It is that each patient is every in another embodiment Its about 0.5mg to 200mg；It is each patient about 5mg to 50mg daily in still another embodiment.
It will also be appreciated that certain compounds of the present invention can exist and be used to treat in a free form, or if it is suitable When can exist in the form of its pharmaceutically acceptable derivates.Pharmaceutically acceptable derivates include pharmaceutically acceptable Prodrug, salt, ester, these esters salt, or when patient in need is administered of the present inventionization can be directly or indirectly provided Close any other adduct or derivative of object or its metabolite or residue.
Drug disclosed by the invention or pharmaceutical composition can prepare and be packaged as (bulk) form in bulk, wherein extractable peace Complete a effective amount of formula (I) compound represented, then gives patient with powder or syrup form.In general, being arrived with daily 0.0001 Dosage level between 10mg/kg weight is administered to patient to obtain to xanthine oxidase and/or lithate anion transport The effective antagonism of body -1.Alternatively, pharmaceutical composition disclosed by the invention can prepare and be packaged as unit dosage forms, wherein each Physically discrete unit contains formula (I) compound represented of safe and effective amount.When being prepared with unit dosage forms, the present invention is public The pharmaceutical composition opened can usually contain, for example, 0.5mg's to 1g or 1mg to 700mg or 5mg to 100mg is disclosed by the invention Compound.
When the pharmaceutical composition of the present invention also contains one or more other activearms in addition to containing the compounds of this invention The compound weight ratio of timesharing, the compounds of this invention and the second active component can change and depending on the effective of each component Dosage.In general, using each effective dose.Thus, for example, when the compounds of this invention is mixed with another medicament, this hair Bright compound and the weight ratio of another medicament generally range from about 1000:1 to about 1:1000, for example, about 200:1 to about 1: 200.The mixture of the compounds of this invention and other active components generally also within the above range, but in each case, all The effective dose of each active component should be used.
" pharmaceutically acceptable excipient " used in the present invention means related to form of administration or pharmaceutical composition consistency Pharmaceutically acceptable material, mixture or solvent.Each excipient mixing when must with pharmaceutical composition it is other at Split-phase is held, and interaction the effect of to avoid that can substantially reduce disclosed compound of present invention when administering to a patient and can cause not It is the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, each excipient must be pharmaceutically acceptable, example Such as, there is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected specific dosage form.In addition, can be according to them in group The specific function in object is closed to select pharmaceutically acceptable excipient.For example, may be selected to can help to produce equal one dosage type low temperature Certain pharmaceutically acceptable excipient.The certain pharmaceutically acceptable figurations that can help to produce stabilizer type may be selected Agent.Contribute to carry or transport when may be selected to administer to a patient disclosed compound of present invention from an organ of body or part to Another organ of body or partial certain pharmaceutically acceptable excipient.Certain medicines of enhancing patient compliance may be selected Acceptable excipient on.
Suitable pharmaceutically acceptable excipient includes following kind of excipient：Diluent, filler, adhesive, Disintegrant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, is rectified lubricant Taste agent, odor mask, colorant, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilization Agent, surfactant and buffer.Technical staff can be appreciated that certain pharmaceutically acceptable excipient can provide more than one Function, and provide alternative function, this depends in preparation existing in how much excipient and preparation there are which other Excipient.
Technical staff grasps the knowledge and skills of this field, so that they can select the suitable of the appropriate amount for the present invention Pharmaceutically acceptable excipient.Additionally, there are resources obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
In Remington:The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation Known technology, the respective content of these documents are incorporated by reference into the present invention.Except any such as because generating any undesirable life Object acts on, or with interaction occurs for any other ingredient in harmful way and pharmaceutically acceptable composition and with the present invention Outside the incompatible any commonly employed carrier of open compound, pays close attention to its application and belong to the scope of the present invention.
Pharmaceutical composition disclosed by the invention is prepared using technology and methods well known by persons skilled in the art.This field The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。
Therefore, on the other hand, the present invention relates to the technique for preparing pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, adjuvant or combination thereof, the technique include mix it is various at Point.Include the pharmaceutical composition of disclosed compound of present invention, can be mixed under such as environment temperature and atmospheric pressure to prepare.
Compound disclosed by the invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.Example Such as, dosage form includes the dosage form that those are suitable for following administration route：(1) it is administered orally, such as tablet, capsule, caplet agent, ball Agent contains tablet, pulvis, syrup, elixir, suspension, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, suspension and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) it sucks, such as aerosol, solution and dry powder doses；(6) local administration, for example, it is cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gelling agent.
In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention can be with It is configured to nose administration dosage form.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. Also in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.
Pharmaceutical composition provided by the invention can with compressed tablets, develop piece, chewable pastille, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are with the substance packet for being resistant to hydrochloric acid in gastric juice effect but dissolving or being disintegrated in intestines The compressed tablets of clothing, to prevent the acidic environment of active ingredient contacts stomach.Enteric coating includes, but are not limited to aliphatic acid, fat Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Sugar coated tablet is the compacting that sugar-coat surrounds Piece can be conducive to cover taste or smell beastly and can prevent tablet from aoxidizing.Thin membrane coated tablet is with water-soluble The compressed tablets of thin layer or the film covering of substance.Film coating includes, but are not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses general characteristic identical with sweet tablet.It is multiple Tabletting is the compressed tablets by being prepared more than a press cycles, including multilayer tablet and pressed coated or dry coating tablet.
Tabules can be by one kind that powder, crystallization or granular active constituent are individual or are described with the present invention Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrant, controlled release polymer, profit Lubrication prescription, diluent and/or colorant.Fumet and sweetener are particularly useful when forming chewable tablets and pastille.
Pharmaceutical composition provided by the invention can be provided with soft capsule or hard capsule, can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, one section It fills in another section, therefore encloses active constituent completely.Soft elastic capsules (SEC) are soft, spherical shell, such as gelatin shell, It is plasticized by the way that glycerine, sorbierite or similar polyalcohol is added.Soft gelatin shell can include the pre- preventing microorganism life of preservative It is long.Suitable preservative be as described in the present invention those, including methyl hydroxybenzoate and propylben and sorbic acid.This Liquid, semisolid and the solid dosage forms that invention provides can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution in propene carbonate, vegetable oil or triglycerides and suspension.Including the capsule of such solution can be such as in the U.S. Patent U.S.Pat.Nos.4,328,245；Preparing described in 4,409,239 and 4,410,545.The capsule can also be adopted With coating as is known to persons skilled in the art, so as to improve or maintain the dissolution of active constituent.
Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of which liquid is thoroughly dispersed in pellet form in another liquid, It can be oil-in-water type or water-in-oil type.Emulsion may include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifier and Preservative.Suspension may include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions may include pharmaceutically may be used The acetal of receiving, for example, low alkyl group aldehyde two (low alkyl group) acetals, such as acetaldehyde diethyl acetal；With tool there are one or it is more The water-soluble solvent of a hydroxyl, such as propylene glycol and ethyl alcohol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and can also include preservative.For liquid dosage form, for example, the solution in polyethylene glycol It can be diluted with enough pharmaceutically acceptable liquid-carriers such as water, to be accurately, conveniently administered.
Other useful liquid and semisolid dosage form include, but are not limited to include active constituent provided by the invention and two level Change those of mono- or poly- alkylene glycol dosage form, described mono- or poly- alkylene glycol includes：1,2- dimethoxymethane, diethylene glycol (DEG) Dimethyl ether, triglyme, tetraethylene glycol dimethyl ether, polyethylene glycol -350- dimethyl ether, polyethylene glycol -550- dimethyl ether, poly- second The approximate average molecular weight of glycol -750- dimethyl ether, wherein 350,550,750 finger polyethylene glycol.These preparations can be further Including one or more antioxidant, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propylgallate, vitamin E, hydrogen Quinone, Hydroxycoumarin, ethanol amine, lecithin, cephalin, ascorbic acid, malic acid, sorbierite, phosphoric acid, bisulfites, coke Sodium sulfite, thio-2 acid and its ester and dithiocarbamate.
Where appropriate, can be by the dosage unit preparations microencapsulation of oral medication.It can also be prepared into extending or tie up Hold the composition of release, such as by being coated by microparticle material or be embedded in polymer, wax or the like.
Combination of oral medication provided by the invention can also be carried in the form of liposome, micella, microballoon or nanometer system For.Micella dosage form can be prepared with the method that U.S.Pat.No.6,350,458 is described.
Pharmaceutical composition provided by the invention can be provided with the granule and pulvis of non-effervesce or effervesce, to be reconstructed into Liquid dosage form.The pharmaceutically acceptable carrier and excipient used in non-effervescent or pulvis may include dilution Agent, sweetener and wetting agent.The pharmaceutically acceptable carrier and excipient used in effervescent or pulvis can wrap Include organic acid and carbon dioxide source.
Colorant and flavoring agent can be used in all above-mentioned dosage forms.
Compound disclosed in this invention can also be combined with the soluble polymer as target medicine carrier.It is such Polymer includes polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl asparagus fern acyl Amine phenol or the oxide polylysine of palmitoyl residues substitution.In addition, compound disclosed in this invention can in reality A kind of Biodegradable polymeric used in the control release of existing drug combines, for example, polylactic acid, poly-epsilon-caprolactone, poly- Hydroxybutyric acid, polyorthoester, polyacetals, poly- dihydropyran, the crosslinking of polybutylcyanoacrylate and hydrogel or amphiphilic block are total Polymers.
Pharmaceutical composition provided by the invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
Pharmaceutical composition provided by the invention can be common with the other active constituents that will not damage expected therapeutic effect Prepare, or with the substance co-formulation that is acted on expected from supplement.
Pharmaceutical composition provided by the invention can be by injection, infusion or implantation parenteral administration, for part or entirely Body is administered.As the parenteral administration that uses of the present invention includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
Pharmaceutical composition provided by the invention can be configured to any dosage form suitable for parenteral administration, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection Body form.Such dosage form can according to conventional method known to the technical staff in pharmaceutical science field come prepare (referring to Remington:The Science and Practice of Pharmacy, ibid).
The pharmaceutical composition for being intended for parenteral administration may include one or more pharmaceutically acceptable carriers and Excipient includes, but are not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and the dispersion of object growth Agent, wetting agent or emulsifier, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent And inert gas.
Suitably include, but are not limited to containing transporter：Water, brine, physiological saline or phosphate buffered saline (PBS) (PBS), Sodium chloride injection, Ringers injections, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers injections.Non- transporter includes, but are not limited to fixed oil, castor oil, corn oil, the cottonseed of plant origin The middle chain of oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soya-bean oil, hydrogenated vegetable oil, hydrogenated soybean oil and coconut oil Triglycerides and palm seed oil.Water miscibility carrier includes, but are not limited to the poly- second of ethyl alcohol, 1,3-BDO, liquid two Alcohol (such as Liquid Macrogol and polyethylene glycol 400), propylene glycol, glycerine, n-methyl-2-pyrrolidone, N, N- dimethylacetamides Amine and dimethyl sulfoxide.
Suitable antimicrobial or preservative include, but are not limited to phenol, cresols, mercurial, benzyl alcohol, chlorobutanol, Methyl p-hydroxybenzoate and propylparaben, thimerosal, benzalkonium chloride (such as benzethonium chloride), methyl hydroxybenzoate and Propylben and sorbic acid.Suitable isotonic agent includes, but are not limited to sodium chloride, glycerine and glucose.Suitable buffer Include, but are not limited to phosphate and citrate.Suitable antioxidant is such as those of present invention description, including sulfurous acid Hydrogen salt and sodium metabisulfite.Suitable local anesthetic includes, but are not limited to procaine hydrochloride.Suitable suspending agent and point Powder is such as those of present invention description, including sodium carboxymethylcellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. Suitable emulsifier includes those of present invention description, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene moves back Tax sorbitol monooleate 80 and triethanolamine oleate ester.Suitable sequestering agent or chelating agent include, but are not limited to EDTA. Suitable pH adjusting agent includes, but are not limited to sodium hydroxide, hydrochloric acid, citric acid and lactic acid.Suitable complexing agent includes, but unlimited In cyclodextrin, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-β-cyclodextrin, Sulfobutylether-beta-cyclodextrin and sulfobutyl group Ether 7- beta-cyclodextrins (CyDex,Lenexa,KS)。
Pharmaceutical composition provided by the invention can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multi-dose parenteral administration must include antibacterial or fungistatic concentrations anti-micro- Biological agent.All parenteral administrations all must be it is sterile, as known in the art and practice.
In one embodiment, pharmaceutical composition is provided with instant sterile solution.In another embodiment, drug Composition is provided with sterile dried soluble product, including freeze-dried powder and hypodermic tablet, and carrier is used before use Reconstruct.In yet another embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In yet another embodiment, medicine Compositions are formulated into the sterile dry insolubility product reconstructed with carrier before use.Also in one embodiment, Pharmaceutical composition is formulated into instant without bacterial emulsion.
Pharmaceutical composition can be configured to suspension, solid, semisolid or thixotropic liquid, be used as the reservoir administration of implantation. In one embodiment, pharmaceutical composition disclosed in this invention is dispersed in solid interior matrix, be insoluble to body fluid but The external polymeric membrane that the active constituent in pharmaceutical composition diffuses through is allowed to be surrounded.
Suitable internal matrix include polymethyl methacrylate, poly- butyl methacrylate, plasticising or it is unplasticizied Polyvinyl chloride, the nylon of plasticising, the polyethylene terephthalate of plasticising, the polyethylene terephthalate of plasticising, natural rubber, Polyisoprene, polyisobutene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, poly- diformazan silica Alkane, silicone carbonate copolymer, the hydrogel of ester of hydrophilic polymer such as acrylic acid and methacrylic acid, collagen, crosslinking The polyvinyl acetate of the partial hydrolysis of polyvinyl alcohol and coach.
Suitable external polymeric membrane includes polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate copolymerization Object, ethylene/vinyl acetate copolymer, silicone rubber, dimethyl silicone polymer, neoprene, haloflex, polychlorostyrene second Alkene, the copolymer of ethlyene dichloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer are poly- to benzene two Formic acid second diester, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol trimer and Ethylene/vinyl ethoxy-ethanol copolymer.
On the other hand, pharmaceutical composition disclosed in this invention can be configured to be suitable for any dose to patient's inhalation Type, such as dry powder doses, aerosol, suspension or liquid composite.In one embodiment, pharmaceutical composition disclosed in this invention Object can be configured to be suitable for the dosage form with dry powder doses to patient's inhalation.In yet another embodiment, disclosed in this invention Pharmaceutical composition can be configured to be suitable for the dosage form by sprayer to patient's inhalation.Pass through the dry powder of inhalation delivery to lung Composition generally comprise fine powdered compound disclosed in this invention and it is one or more it is fine powdered pharmaceutically Acceptable excipient.Pharmaceutically acceptable excipient be especially suitable for dry powder doses is known to those skilled in the art Dawn comprising lactose, starch, mannitol and mono-, two- and polysaccharide.Fine powder can be for example, by being micronized and grinding preparation It obtains.In general, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D50Value is (for example, with swashing What optical diffraction method measured) it defines.
Aerosol can be prepared by the way that compound disclosed in this invention to be suspended or dissolved in liquefied propellant.It is suitble to Propellant include chlorohydrocarbon, hydro carbons and other liquid gas.Representative propellant includes：Arcton 11 (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1- difluoros Ethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, Perfluorinated butane, perflenapent, butane, iso-butane and pentane.Including the aerosol of compound disclosed in this invention usually passes through Metered dose inhaler (MDI) administers to a patient.Such device dawn known to those skilled in the art.
Aerosol may include pharmaceutically acceptable excipient that is additional, being used by MDIs, such as surface-active Agent, lubricant, cosolvent and other excipient, with improve preparation physical stability, improve valve characteristic, improve dissolubility, Or improve taste.
Discontinuous patch agent can be prepared by being suitable for the pharmaceutical composition of cutaneous penetration, it is intended that be kept with the epidermis of patient It is in close contact the time of an elongated segment.For example, the delivering active ingredients from patch agent can be permeated by ion, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for local administration pharmaceutical composition can be formulated into ointment, cream, suspension, lotion, pulvis, Solution, paste, gelling agent, spray, aerosol or finish.For example, ointment, cream and gelling agent can use water or oil Matrix, and suitable thickener and/or gelling agent and/or solvent configure.Such matrix may include water, and/or oily example Such as liquid-liquid paraffin and vegetable oil (such as peanut oil or castor oil) or solvent such as polyethylene glycol.Made according to medium property Thickener and gelling agent include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, poly- carboxylic second Alkene and cellulose derivative and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.
Lotion can use water or oil matrix to prepare, and generally also contain one or more emulsifying agents, stabilizer, dispersion Agent, suspending agent or thickener.
Externally-applied powder can be molded in the presence of any suitable powder matrix such as talcum powder, lactose or starch.Drops It can be formulated with the water comprising one or more dispersing agents, solubilizer, suspending agent or preservative or non-aqueous matrix.
Topical formulations can be by being administered using one or many daily in affected part；The impermeable plastic wound dressing for covering skin is preferential It is used.Adhesiveness store system can realize continuous or extended administration.
The purposes of the compounds of this invention and composition
Compound or pharmaceutical composition disclosed in this invention can be used for preparing for treating, prevent, improve, control or Mitigate mammal, including the treatment hyperuricemia of the mankind, tophus, urarthritis, related with hyperuricemia The drug of nephropathy and urolithiasis can be used for preparing for inhibiting xanthine oxidase and/or uric acid salt anionic to turn Transport other the active drugs of body -1.
Specifically, the amount of compound effectively can detectably inhibit xanthine oxidase in the composition of the present invention And/or lithate anion transport body -1, the compound of the present invention, which can be used as, prevents or treats mankind's hyperuricemia, gout The drug of stone, urarthritis, related with hyperuricemia nephropathy and urolithiasis.
The compound of the present invention or composition can be applied to, but be not limited to, and use the compound of the present invention or combination The effective quantity of object administers to a patient to prevent, treat or mitigate mammal, including the hyperuricemia of the mankind, tophus, pain Wind arthritis, nephropathy related with hyperuricemia and urolithiasis.
The compound of the present invention and pharmaceutical composition to human treatment in addition to beneficial to other than, applying also for veterinary treatment and doting on Mammal in the animal of object, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat.? This, the compound of the present invention includes its pharmaceutically acceptable derivates.
General synthesis step
For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only The method that the practice present invention is provided.
Usually, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment is for being further illustrated this The content of invention.
The professional of fields will be recognized that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and other methods for the preparation of the compounds of the present invention are considered as the model in the present invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention It is completed by method of modifying, such as protection interference group appropriate, by using other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Tenglong Chemical Reagent Co., Ltd. and Haiyang Chemical Plant, Qingdao's purchase It can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
NMR spectrum is recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometers, with CDC13、DMSO-d6、 CD3OD or acetone-d6For solvent (as unit of ppm), use TMS (0ppm) or chloroform (7.26ppm) as reference standard.When going out When existing multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, bimodal), t (triplet, three Weight peak), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, it is double double Peak), dt (doublet of triplets, double triplets).Coupling constant is indicated with hertz (Hz).
The determination condition of Algorithm (MS) data is：6120 level four bars HPLC-M (column models of Agilent： Zorbax SB-C18,2.1x30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase：5%-95% (contains 0.1% first The CH of acid3CN) (containing the H of 0.1% formic acid2O the ratio in)), using electron spray ionisation (ESI), at 210nm/254nm, use UV is detected.
Compound purity is measured using high performance liquid chromatography (HPLC), uses Agilent 1260HPLC (column models： Agilent zorbax Eclipse Plus C18), it is used in combination DAD detectors to detect, is finally calculated using area normalization method To compound purity.
The use of brief word below is through the present invention：
CDC13Deuterochloroform；
CD3OD deuterated methanols；
CDI N, N'- carbonyl dimidazoles；
DMAP 4-dimethylaminopyridine；
DMF N,N-dimethylformamides；
DMSO dimethyl sulfoxide (DMSO)s；
DMSO-d6Deuterated dimethyl sulfoxide；
G grams；
D days
H hours；
Min minutes；
Mmol mMs；
M moles every liter；
DEG C degree Celsius；
H2SO4Sulfuric acid；
HATU 2- (7- azos benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters；
NBS N-bromosuccinimide bromines；
MeCN、CH3CN acetonitriles；
MeOH methanol；
ML, ml milliliters；
RT, rt, r.t. room temperature；
Rpm rpms；
The typical synthesis step of disclosed compound of present invention is prepared as shown in following synthetic schemes.Unless otherwise stated, E、R1、R2、R3、R4、R5, each R and m there is definition as described in the present invention.
Synthetic schemes 1
Wherein, L indicates leaving group；
Compound (a) generates compound (I) after being reacted with compound (b).Include as the L leaving groups indicated but unlimited In halogen atom, mesyl oxygroup, to Methyl benzenesulfonyl base oxygroup etc..
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
Embodiment 1:1- (3- oxo -2,3- dihydrobenzos [d] isoxazole -6- bases) -1H- indole -3-formonitriles
First step 4- fluoro- 2- (methoxymethoxy) methyl benzoate
By the fluoro- 2 hydroxybenzoic acid methyl esters (3.7g, 22mmol) of 4-, n,N-diisopropylethylamine (11mL, 66mmol) and Dichloromethane (50mL) be added 250mL single port bottles in, at 0 DEG C, into reaction bulb be added dropwise chloromethyl methyl ether (7.3mL, 43mmol), after being added dropwise, under nitrogen protection, 16h is stirred at room temperature in reaction mixture.Solvent is removed under reduced pressure, into residue Saturated aqueous ammonium chloride (200mL) is added, water phase is extracted with ethyl acetate (100mL × 2), merges organic phase.Organic phase is used Saturated salt solution (100mL) washs, and anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure.Residue is through silica gel column chromatography (acetic acid second Ester/petroleum ether (v/v)=1/20), obtain title compound (faint yellow solid, 4.67g, 99%).
Second step 4- (3- cyano-1 H-indol -1- bases) -2- (methoxymethoxy) methyl benzoate
By 4- fluoro- 2- (methoxymethoxy) methyl benzoate (4.6g, 21mmol), 1H- indole -3-formonitriles (3.1g, 22mmol), cesium carbonate (14g, 43mmol) and anhydrous DMF (20mL) are added in 100mL single port bottles, and reaction mixture is protected in nitrogen Under shield, 18h is stirred at 80 DEG C.Reaction mixture is cooled to room temperature, saturated aqueous ammonium chloride is added into reaction bulb (150mL), water phase are extracted with ethyl acetate (100mL × 2), merge organic phase.Organic phase is washed with saturated salt solution (100mL) It washs, anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure.Residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/ 5) title compound (yellow solid, 4.87g, 69%), is obtained.
MS(ES-API,pos.ion)m/z:337.1[M+1]+。
Third walks 4- (3- cyano-1 H-indol -1- bases) -2 hydroxybenzoic acid methyl esters
By 4- (3- cyano-1 H-indol -1- bases) -2- (methoxymethoxy) methyl benzoate (5.0g, 15mmol), first Alcohol (50mL) and tetrahydrofuran (50mL) are added in 250mL single port bottles, and concentrated hydrochloric acid (3mL, 36%) is then added into reaction bulb, Reaction mixture stirs 8h at 70 DEG C.Reaction mixture is cooled to room temperature, saturated aqueous ammonium chloride is added into reaction bulb (150mL), water phase are extracted with ethyl acetate (100mL × 2), merge organic phase.Organic phase is washed with saturated salt solution (100mL) It washs, anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure.Residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/ 5) title compound (faint yellow solid, 2.85g, 65%), is obtained.
MS(ES-API,pos.ion)m/z:293.0[M+1]+。
4th step 4- (3- cyano-1 H-indol -1- bases)-N, 2- dihydroxy benzoyl amines
By 4- (3- cyano-1 H-indol -1- bases) -2 hydroxybenzoic acid methyl esters (1.56g, 5.34mmol), methanol (25mL) With tetrahydrofuran (25mL) be added 100mL single port bottles in, then sequentially added into reaction bulb hydroxylamine hydrochloride (445mg, 6.40mmol) aqueous solution (6.4mL) and sodium hydroxide (1.07g, 26.8mmol), reaction mixture is stirred at room temperature for 24 hours.Subtract Pressure removes solvent, and water (100mL) is added into residue, the pH of system is then adjusted to 8 with dilute hydrochloric acid, water phase ethyl acetate (100mL × 2) extract, and merge organic phase.Organic phase is washed with saturated salt solution (100mL), anhydrous sodium sulfate drying, filtering, It is concentrated under reduced pressure.Residue is through silica gel column chromatography (ethanol/methylene (v/v)=1/50), and obtaining title compound, (yellow is solid Body, 1.0g, 64%).
MS(ES-API,pos.ion)m/z:294.1[M+1]+。
5th step 1- (3- oxo -2,3- dihydrobenzos [d] isoxazole -6- bases) -1H- indole -3-formonitriles
By 4- (3- cyano-1 H-indol -1- bases)-N, 2- dihydroxy benzoyl amines (700mg, 2.39mmol), CDI (1.55g, 9.56mmol), DMAP (58mg, 0.478mmol) and tetrahydrofuran (30mL) are added in 100mL single port bottles, and reaction is mixed It closes object and stirs 12h at 80 DEG C.Reaction mixture is cooled to room temperature, saturated salt solution (80mL), water phase are added into reaction bulb It is extracted with ethyl acetate (40mL × 2), merges organic phase.Organic phase is washed with saturated salt solution (60mL), and anhydrous sodium sulfate is dry It is dry, it filters, is concentrated under reduced pressure.Residue obtains title compound through silica gel column chromatography (ethanol/methylene (v/v)=1/200) (pale solid, 300mg, 46%).
MS(ES-API,pos.ion)m/z:276.1[M+1]+。
1H NMR(400MHz,DMSO-d6) δ (ppm) 8.69 (s, 1H), 8.09 (d, J=8.4Hz, 1H), 7.94 (s, 1H), 7.78-7.76 (m, 1H), 7.71-7.69 (m, 1H), 7.62 (dd, J=8.4,1.4Hz, 1H), 7.43-7.38 (m, 2H).
Embodiment 2:1- (3- oxo -2,3- dihydrobenzos [d] [1,2] selenazoles -6- bases) -1H- indole -3-formonitriles
The bromo- 4- of first step 2- (3- cyano-1 H-indol -1- bases) methyl benzoate
By the bromo- 4- fluorophenyl carbamates (4.89g, 21mmol) of 2-, 1H- indole -3-formonitriles (3.1g, 22mmol), carbonic acid Caesium (14g, 43mmol) and anhydrous DMF (30mL) are added in 100mL single port bottles, reaction mixture 80 DEG C of stirrings under nitrogen protection 18h.Reaction mixture is cooled to room temperature, saturated aqueous ammonium chloride (150mL), water phase acetic acid second are added into reaction bulb Ester (100mL × 2) extracts, and merges organic phase.Organic phase is washed with saturated salt solution (100mL), anhydrous sodium sulfate drying, mistake Filter is concentrated under reduced pressure.Residue obtains title compound (yellow through silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/5) Solid, 5.7g, 76%).
MS(ES-API,pos.ion)m/z:355.0[M+1]+。
The bromo- 4- of second step 2- (3- cyano-1 H-indol -1- bases) benzamide
By the bromo- 4- of 2- (3- cyano-1 H-indol -1- bases) methyl benzoate (1.90g, 5.35mmol), tetrahydrofuran The methanol solution (40mL, 7M) of (30mL) and ammonia is added in the closed tube sealings of 50mL, and reaction mixture stirs 15h at 150 DEG C.It will Reaction mixture is cooled to room temperature, and organic phase is concentrated under reduced pressure.Residue is through silica gel column chromatography (ethanol/methylene (v/v)=1/ 100) title compound (faint yellow solid, 670mg, 37%), is obtained.
MS(ES-API,pos.ion)m/z:340.0[M+1]+。
Third walks 1- (3- oxo -2,3- dihydrobenzos [d] [1,2] selenazoles -6- bases) -1H- indole -3-formonitriles
By cuprous iodide (144mg, 0.76mmol), 1,10- phenanthroline (138mg, 0.76mmol) and anhydrous DMF (20mL) It is added in 100mL single port bottles, 0.5h is stirred at room temperature in reaction mixture.Then, the bromo- 4- of 2- are sequentially added into reaction bulb (3- cyano-1 H-indol -1- bases) benzamide (1.29g, 3.79mmol), selenium powder (360mg, 4.54mmol) and potassium carbonate (1.05g, 7.61mmol), reaction mixture stir for 24 hours for 130 DEG C under nitrogen protection.Reaction mixture is cooled to room temperature, to Saturated salt solution (80mL) is added in reaction bulb, water phase is extracted with ethyl acetate (40mL × 2), merges organic phase.Organic phase is used Saturated salt solution (60mL) washs, and anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure.Residue is through silica gel column chromatography (methanol/bis- Chloromethanes (v/v)=1/200), obtain title compound (light yellow solid, 70mg, 5.5%).
MS(ES-API,pos.ion)m/z:340.0[M+1]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)9.36(s,1H),8.71(s,1H),8.35(s,1H),8.01(d,J =8.2Hz, 1H), 7.79 (d, J=6.9Hz, 1H), 7.69 (d, J=7.8Hz, 2H), 7.47-7.38 (m, 2H).
Embodiment 3:1- (3- oxo -2,3- dihydrobenzos [d] isothiazole -6- bases) -1H- indole -3-formonitriles
The bromo- 2- fluorobenzamides of first step 4-
Ammonium hydroxide (100mL, 28%) is added in 250mL single port bottles, the bromo- 2- fluorobenzoyls of 4- are slowly added dropwise into reaction bulb Dichloromethane (50mL) solution of chlorine (5.62g, 23.7mmol), after being added dropwise, 1.0h is stirred at room temperature in reaction mixture. Water phase dichloromethane (80mL × 2), merging organic phase.Organic phase is washed with saturated salt solution (100mL), and anhydrous sodium sulfate is dry It is dry, it filters, is concentrated under reduced pressure.Residue obtains titled through silica gel column chromatography (ethyl acetate/dichloromethane (v/v)=1/30) Close object (white solid, 4.80g, 93%).
MS(ES-API,pos.ion)m/z:218.9[M+2]+。
Second step 2- (benzylthio) -4- brombenzamides
Anhydrous tetrahydro furan (30mL) is added in 100mL two-mouth bottles, at 0 DEG C, sodium hydride is added into reaction bulb Benzyl mercaptan (2.04mL, 17.4mmol) is then added dropwise in (840mg, 21.0mmol) into reaction bulb, and after being added dropwise, reaction is mixed It closes object and 1h is stirred at room temperature.By reaction mixture be slowly added to another equipped with the bromo- 2- fluorobenzamides of 4- (3.77g, In the anhydrous tetrahydrofuran solution of 30mL 17.3mmol), after being added dropwise, reaction mixture stirs 0.5h at 0 DEG C, then 3h is stirred at 90 DEG C.Reaction mixture is cooled to room temperature, saturated aqueous ammonium chloride (100mL) is added into reaction bulb, Water phase is extracted with ethyl acetate (80mL × 2), merges organic phase.Organic phase is washed with saturated salt solution (100mL), anhydrous slufuric acid Sodium is dried, and is filtered, and is concentrated under reduced pressure.Residue is marked through silica gel column chromatography (ethyl acetate/dichloromethane (v/v)=1/10) Inscribe compound (white solid, 3.6g, 65%).
MS(ES-API,pos.ion)m/z:322.9[M+2]+。
Third walks 6- bromobenzenes simultaneously [d] isothiazole -3 (2H) -one
500mL single port bottles are added in 2- benzyl-mercapto -4- brombenzamides (5.3g, 16mmol) and dichloromethane (150mL) In, sulfonic acid chloride (3.3g, 24mmol) is added into reaction bulb, 3h is stirred at room temperature in reaction mixture.It is added into reaction bulb Pentane (80mL) filters the white solid of precipitation, and filter cake is washed with pentane, dry, and obtaining title compound, (white is solid Body, 3.37g, 89%).
MS(ES-API,pos.ion)m/z:230.9[M+2]+。
4th step 1- (3- oxo -2,3- dihydrobenzos [d] isothiazole -6- bases) -1H- indole -3-formonitriles
By 6- bromobenzenes simultaneously [d] isothiazole -3 (2H) -one (1.15g, 5.0mmol), 1H- indole -3-formonitriles (0.86g, 6.0mmol), potassium carbonate (2.1g, 15mmol), cuprous iodide (390mg, 2.0mmol), n,N-Dimethylglycine (103mg, It 1.0mmol) is added in 50mL single port bottles with anhydrous DMF (20mL), reaction mixture under nitrogen protection, stirs at 200 DEG C 36h.Reaction mixture is cooled to room temperature, saturated aqueous ammonium chloride (100mL), water phase acetic acid second are added into reaction bulb Ester (80mL × 2) extracts, and merges organic phase.Organic phase is washed with saturated salt solution (100mL), anhydrous sodium sulfate drying, filtering, It is concentrated under reduced pressure.It is (yellowish to obtain title compound through silica gel column chromatography (tetrahydrofuran/ethyl acetate (v/v)=1/10) for residue Color solid, 90mg, 6.2%).
MS(ES-API,pos.ion)m/z:292.0[M+1]+。
1H NMR(600MHz,DMSO-d6) δ (ppm) 11.89 (s, 1H), 8.71 (s, 1H), 8.37 (d, J=1.7Hz, 1H), 8.08 (d, J=8.4Hz, 1H), 7.80-7.79 (m, 1H), 7.72-7.71 (m, 2H), 7.45-7.40 (m, 2H).
Embodiment 4:1- (3- oxo -2,3- dihydro -1H- indazole -6- bases) -1H- indole -3-formonitriles
First step 4- (3- cyano-1 H-indol -1- bases) -2- fluorophenyl carbamates
By 2,4- difluoro-benzoic acids methyl esters (2.70g, 15.7mmol), 1H- indole -3-formonitriles (1.85g, 13.0mmol), Cesium carbonate (8.7g, 27mmol) and anhydrous DMF (25mL) are added in 100mL single port bottles, reaction mixture under nitrogen protection, 48h is stirred at 80 DEG C.Reaction mixture is cooled to room temperature, saturated aqueous ammonium chloride (100mL), water are added into reaction bulb It is mutually extracted with ethyl acetate (80mL × 2), merges organic phase.Organic phase is washed with saturated salt solution (100mL), anhydrous sodium sulfate It is dry, it filters, is concentrated under reduced pressure.Residue obtains title compound through silica gel column chromatography (dichloromethane/petroleum ether (v/v)=1/1) Object (pale red solid, 800mg, 21%).
MS(ES-API,pos.ion)m/z:295.0[M+1]+。
Second step 4- (3- cyano-1 H-indol -1- bases) -2- hydrazino-benzoic acid methyl esters
By 4- (3- cyano-1 H-indol -1- bases) -2- fluorophenyl carbamates (810mg, 2.8mmol), ethyl alcohol (50mL) and Tetrahydrofuran (100mL) is added in 250mL single port bottles, and hydrazine hydrate (5mL, 98%), reaction mixing are then added into reaction bulb Object stirs for 24 hours at 70 DEG C.Reaction solution is cooled to room temperature, is concentrated under reduced pressure.Residue is through silica gel column chromatography (dichloromethane/stone Oily ether (v/v)=3/1), obtain title compound (light yellow solid, 360mg, 42%).
MS(ES-API,pos.ion)m/z:307.1[M+1]+。
Third walks 1- (3- oxo -2,3- dihydro -1H- indazole -6- bases) -1H- indole -3-formonitriles
By 4- (3- cyano-1 H-indol -1- bases) -2- hydrazino-benzoic acids methyl esters (350mg, 1.1mmol), methanol (6mL), Tetrahydrofuran (6mL) and water (6mL) are added in 100mL single port bottles, at 0 DEG C, be added into reaction bulb lithium hydroxide (140mg, 5.8mmol), reaction mixture stirs 12h at 0 DEG C.Organic solvent is removed under reduced pressure, water (60mL), water are added into residue Mutually it washed once with ether (50mL).Water phase is 1 with 10% acidified with citric acid pH value, is extracted with ethyl acetate (40mL × 2), Merge organic phase.Organic phase is washed with saturated salt solution (40mL × 2), and anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure.Residual Object through silica gel column chromatography (tetrahydrofuran/dichloromethane (v/v)=1/3), obtain title compound (light yellow solid, 230mg, 77%).
MS(ES-API,neg.ion)m/z:273.1[M-1]-。
1H NMR(400MHz,DMSO-d6)δ(ppm)11.83(s,1H),10.81(s,1H),8.65(s,1H),7.85(d, J=8.5Hz, 1H), 7.78-7.76 (m, 1H), 7.63-7.61 (m, 1H), 7.54 (s, 1H), 7.40-7.36 (m, 2H), 7.24- 7.21(m,1H)。
Embodiment 5:1- (1- acetyl group -3- oxo -2,3- dihydro -1H- indazole -6- bases) -1H- indole -3-formonitriles
By 1- (3- oxo -2,3- dihydro -1H- indazole -6- bases) -1H- indole -3-formonitriles (1.00g, 3.65mmol), pyrrole Pyridine (790mg, 10.0mmol) and toluene (50mL) are added in 100mL single port bottles, and chloroacetic chloride is then added into reaction bulb (310mg, 4.0mmol), 18h is stirred at room temperature in reaction mixture.Ethyl acetate (100mL) is added into reaction bulb, it is organic Mutually dilute hydrochloric acid (80mL, 2M) and saturated salt solution (80mL) is used to wash successively, anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure.It is residual Object is stayed through silica gel column chromatography (ethyl acetate/dichloromethane (v/v)=1/50), obtain title compound (faint yellow solid, 150mg, 13%).
MS(ES-API,pos.ion)m/z:317.1[M+1]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)12.36(s,1H),8.72(s,1H),8.45(s,1H),8.01(d,J =8.4Hz, 1H), 7.80-7.78 (m, 1H), 7.67-7.64 (m, 2H), 7.44-7.39 (m, 2H), 2.60 (s, 3H).
Embodiment 6:1- (1- cyclopropyl formoxyl -3- oxo -2,3- dihydro -1H- indazole -6- bases) -1H- indoles -3- first Nitrile
By ethylene-acetic acid (88mg, 1.0mmol), HATU (400mg, 1.1mmol), 1- (3- oxo -2,3- dihydros -1H- Indazole -6- bases) -1H- indole -3-formonitriles (274mg, 1.0mmol) and DMF (6mL) be added in 100mL single port bottles, then to anti- It answers and n,N-diisopropylethylamine (530 μ L, 3.0mmol) is added in bottle, 12h is stirred at room temperature in reaction mixture.To reaction bulb Middle addition ethyl acetate (80mL), organic phase are washed with saturated sodium bicarbonate aqueous solution (80mL) and saturated salt solution (80mL) successively It washs, anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure.Residue is through silica gel column chromatography (ethyl acetate/dichloromethane (v/v)=1/ 10) title compound (white solid, 60mg, 18%), is obtained.
MS(ES-API,pos.ion)m/z:343.1[M+1]+。
1H NMR(600MHz,DMSO-d6) δ (ppm) 12.34 (s, 1H), 8.69 (s, 1H), 8.44 (d, J=1.6Hz, 1H), 8.02 (d, J=8.4Hz, 1H), 7.79-7.77 (m, 1H), 7.67-7.65 (m, 2H), 7.43-7.39 (m, 2H), 2.97- 2.93(m,1H),1.23–1.21(m,2H),1.12–1.09(m,2H)。
Embodiment 7:1- (2- oxo -2,3- dihydrobenzos [d] [1,3] oxazole -6- bases) -1H- indole -3-formonitriles
First step 6- bromobenzenes simultaneously [d] oxazole -2 (3H) -one
By 2- amino -5- bromophenols (2.0g, 10.6mmol), N, N'- carbonyl dimidazoles (1.72g, 10.6mmol) and nothing Water DMF (20mL) is added in 100mL single port bottles, and reaction mixture stirs 20h at 60 DEG C.Reaction mixture is cooled to room Saturated aqueous ammonium chloride (100mL) is added into residue for temperature, and water phase is extracted with ethyl acetate (60mL × 2), is merged organic Phase.Organic phase is washed with saturated salt solution (60mL), and anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure.Residue is through silica gel column layer It analyses (ethyl acetate/petroleum ether (v/v)=1/4), obtains title compound (brown solid, 2.26g, 97%).
Second step 1- (2- oxo -2,3- dihydrobenzos [d] [1,3] oxazole -6- bases) -1H- indole -3-formonitriles
By 6- bromobenzenes simultaneously [d] oxazole -2 (3H) -one (1.00g, 4.67mmol), 1H- indole -3-formonitriles (0.797g, 5.60mmol), potassium carbonate (1.93g, 14.0mmol), cuprous iodide (178mg, 0.94mmol), n,N-Dimethylglycine (96mg, 0.931mmol) and anhydrous DMF (12mL) are added in 20mL microwave tubes, and reaction mixture stirs for 130 DEG C under nitrogen protection Mix 2h.Reaction mixture is cooled to room temperature, saturated aqueous ammonium chloride (100mL), water phase acetic acid are added into reaction bulb Ethyl ester (80mL × 2) extracts, and merges organic phase.Organic phase is washed with saturated salt solution (100mL), anhydrous sodium sulfate drying, mistake Filter is concentrated under reduced pressure.It is (light to obtain title compound through silica gel column chromatography (ethyl acetate/dichloromethane (v/v)=1/4) for residue Yellow solid, 1.29g, 16%).
MS(ES-API,pos.ion)m/z:276.1[M+1]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)12.00(s,1H),8.54(s,1H),7.81–7.73(m,1H), 7.70 (d, J=1.8Hz, 1H), 7.59-7.51 (m, 1H), 7.44-7.35 (m, 3H), 7.30 (d, J=8.2Hz, 1H).
Embodiment 8:1- (3- hydroxyls -1- oxidation benzo [d] isothiazole -6- bases) -1H- indole -3-formonitriles
By 1- (3- oxo -2,3- dihydrobenzos [d] isothiazole -6- bases) -1H- indole -3-formonitriles (140mg, It 0.48mmol) is added in 50mL single port bottles with tetrahydrofuran (12mL), the sodium metaperiodate water of saturation is then added into reaction bulb Solution (10mL), 7d is stirred at room temperature in reaction mixture.Tetrahydrofuran is removed under reduced pressure, into residue be added water (80mL) and Potassium carbonate (1.0g).Water phase is extracted with ether (40mL × 2), then, with dilute hydrochloric acid acidification pH value to 4, water phase ethyl acetate (60mL × 2) extract, and merge organic phase.Organic phase is washed with saturated salt solution (100mL), and anhydrous sodium sulfate drying, filtering subtracts Pressure concentration.Residue is through silica gel column chromatography (ethyl acetate/dichloromethane (v/v)=1/15), and obtaining title compound, (white is solid Body, 60mg, 41%).
MS(ES-API,pos.ion)m/z:308.0[M+1]+。
1H NMR(600MHz,DMSO-d6)δ(ppm)11.68(s,1H),8.76(s,1H),8.56–8.54(m,1H), 8.14 (s, 2H), 7.81-7.80 (m, 1H), 7.73 (d, J=7.9Hz, 1H), 7.48-7.42 (m, 2H).
Embodiment 9:1- (1- cyclopropyl -3- oxo -2,3- dihydro -1H- indazole -6- bases) -1H- indole -3-formonitriles
By 1- (3- oxo -2,3- dihydro -1H- indazole -6- bases) -1H- indole -3-formonitriles (411mg, 1.5mmol), bromo Cyclopropane (272mg, 2.25mmol), cesium carbonate (980mg, 3.0mmol) and anhydrous DMF (12mL) are added in 20mL microwave tubes, Under nitrogen protection, 200 DEG C are stirred 1.5h to reaction mixture.Reaction mixture is cooled to room temperature, is added into reaction bulb full With aqueous ammonium chloride solution (100mL), water phase is extracted with ethyl acetate (80mL × 2), merges organic phase.Organic phase saturated common salt Water (100mL) washs, and anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure.Residue is through silica gel column chromatography (ethyl acetate/dichloromethane Alkane (v/v)=1/30), obtain title compound (faint yellow solid, 40mg, 8.5%).
MS(ES-API,pos.ion)m/z:315.1[M+1]+。
1H NMR(400MHz,DMSO-d6) δ (ppm) 11.03 (s, 1H), 8.67 (s, 1H), 7.83 (d, J=8.5Hz, 1H), 7.79-7.77 (m, 1H), 7.73 (d, J=1.2Hz, 1H), 7.69-7.66 (m, 1H), 7.43-7.40 (m, 2H), 7.29- 7.26(m,1H),3.51–3.48(m,1H),1.06–1.02(m,4H)。
Embodiment 10:1- (- 7 base of 2,4- dioxos -3,4- dihydro -2H- benzos [e] [1,3] oxazines) -1H- indoles -3- first Nitrile
Bromo- 2H- benzos [e] [1,3] oxazines -2,4 (the 3H)-diketone of first step 7-
By the bromo- 2 hydroxybenzoic acid methyl esters (850mg, 3.93mmol) of 4-, pyridine (380 μ L, 4.7mmol) and anhydrous acetonitrile (10mL) is added in 100mL single port bottles, and at 0 DEG C, ethyl chloroformate (410 μ L, 4.3mmol) is added dropwise into reaction bulb, is added dropwise After, reaction mixture stirs 0.5h at 0 DEG C, then stirs 14h at 90 DEG C.Reaction mixture is cooled to room temperature, Saturated aqueous ammonium chloride (100mL) is added into residue, water phase is extracted with ethyl acetate (60mL × 2), merges organic phase. Organic phase is washed with saturated salt solution (60mL), and anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure.Residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/4) obtains title compound (white solid, 700mg, 74%).
MS(ES-API,pos.ion)m/z:242.9[M+2]+。
Second step 4- (3- cyano-1 H-indol -1- bases) -2-Hydroxylbenzamide
By bromo- 2H- benzos [e] [1,3] oxazines -2,4 (the 3H)-diketone (300mg, 1.24mmol) of 7-, 1H- indoles -3- first Nitrile (210mg, 1.48mmol), potassium carbonate (510mg, 3.72mmol), cuprous iodide (47mg, 0.248mmol), N, N- dimethyl Glycine (26mg, 0.248mmol) and anhydrous DMF (6mL) are added in 20mL microwave tubes, reaction mixture under nitrogen protection, 200 DEG C of stirring 2h.Reaction mixture is cooled to room temperature, saturated aqueous ammonium chloride (100mL), water phase are added into reaction bulb It is extracted with ethyl acetate (80mL × 2), merges organic phase.Organic phase is washed with saturated salt solution (100mL), and anhydrous sodium sulfate is dry It is dry, it filters, is concentrated under reduced pressure.Residue obtains title compound through silica gel column chromatography (ethanol/methylene (v/v)=1/50) (faint yellow solid, 0.117g, 34%).
MS(ES-API,pos.ion)m/z:278.1[M+1]+。
Third walks 1- (- 7 base of 2,4- dioxos -3,4- dihydro -2H- benzos [e] [1,3] oxazines) -1H- indole -3-formonitriles
By 4- (3- cyano-1 H-indol -1- bases) -2-Hydroxylbenzamide (110mg, 0.40mmol), pyridine (60 μ L, It 0.70mmol) is added in 100mL single port bottles with anhydrous acetonitrile (8mL), at 0 DEG C, ethyl chloroformate (60 is added dropwise into reaction bulb μ L, 0.60mmol), after being added dropwise, reaction mixture stirs 0.5h at 0 DEG C, is then stirred for 24 hours at 90 DEG C.It will reaction Mixture is cooled to room temperature, and saturated sodium bicarbonate aqueous solution (80mL) is added into residue, and the solid of precipitation is filtered, and is done It is dry, obtain title compound (yellow solid, 21mg, 17%).
MS(ES-API,neg.ion)m/z:302.0[M-1]-。
1H NMR(600MHz,DMSO-d6) δ (ppm) 8.73 (s, 1H), 8.14 (d, J=8.4Hz, 1H), 7.85-7.69 (m,4H),7.47–7.42(m,2H)。
Embodiment 11:1- (3- oxos -1- (thiophene -2- carbonyls) -2,3- dihydro -1H- indazole -6- bases) -1H- indoles -3- Formonitrile HCN
By thiophene -2-carboxylic acid (70mg, 0.55mmol), carbonyl dimidazoles (112mg, 0.691mmol), dichloromethane (4mL) and DMF (4mL) are added in 100mL single port bottles, and 4h is stirred at room temperature in reaction mixture.Then it is added into reaction bulb 1- (3- oxo -2,3- dihydro -1H- indazole -6- bases) -1H- indole -3-formonitriles (150mg, 0.547mmol), reaction mixture exists 12h is stirred at room temperature.Ethyl acetate (80mL) is added into reaction bulb, organic phase uses dilute hydrochloric acid (80mL, 2M) and saturation successively Saline solution (80mL) washs, and anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure.Residue is through silica gel column chromatography (ethyl acetate/bis- Chloromethanes (v/v)=1/10), obtain title compound (white solid, 84mg, 40%).
MS(ES-API,pos.ion)m/z:385.1[M+1]+。
1H NMR(400MHz,DMSO-d6) δ (ppm) 12.59 (s, 1H), 8.76 (s, 1H), 8.61 (d, J=1.5Hz, 1H), 8.38 (dd, J=3.8,1.1Hz, 1H), 8.13 (dd, J=5.0,1.1Hz, 1H), 8.09 (d, J=8.4Hz, 1H), 7.84–7.78(m,1H),7.76–7.70(m,2H),7.49–7.39(m,2H),7.35–7.29(m,1H)。
Embodiment 12:1- (1- benzoyl -3- oxo -2,3- dihydro -1H- indazole -6- bases) -1H- indole -3-formonitriles
By benzoic acid (67mg, 0.55mmol), N, N'- carbonyl dimidazoles (112mg, 0.691mmol), dichloromethane (4mL) and DMF (4mL) are added in 100mL single port bottles, and 4h is stirred at room temperature in reaction mixture.Then it is added into reaction bulb 1- (3- oxo -2,3- dihydro -1H- indazole -6- bases) -1H- indole -3-formonitriles (150mg, 0.547mmol), reaction mixture exists 12h is stirred at room temperature.Ethyl acetate (80mL) is added into reaction bulb, organic phase uses dilute hydrochloric acid (80mL, 2M) and saturation successively Saline solution (80mL) washs, and anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure.Residue is obtained through silica gel column chromatography (dichloromethane) To title compound (light yellow solid, 65mg, 31%).
MS(ES-API,pos.ion)m/z:379.1[M+1]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)12.43(s,1H),8.76(s,1H),8.59(s,1H),8.05(d,J =8.4Hz, 1H), 7.98 (d, J=7.4Hz, 2H), 7.81 (d, J=7.3Hz, 1H), 7.72-7.71 (m, 2H), 7.64-7.62 (m,1H),7.56–7.54(m,2H),7.47–7.40(m,2H)。
Biological activity test
Test example 1 XO (xanthine oxidase) inhibitory activity measures
1) test method
A series of compound concentration of 2.5 times of buffer solution (50mM potassium dihydrogen phosphates) dilution, from 2000nM to 0.524nM is added to the amount in 30 holes μ L/ in 384 orifice plates；The xanthine oxidase of 30 a concentration of 21mU/mL of μ L is added per hole later Change enzyme, 3000rpm centrifuges room temperature oscillation incubation 10min after 1min；Then it is (yellow that a concentration of 600 μM of substrates of 30 μ L are added per hole Purine)；Buffer solution processing hole (same concentrations enzyme and substrate is added in no compound) and negative control hole (no chemical combination are set simultaneously Same concentrations substrate is added in object and enzyme).It is incubated at room temperature after 5min using the suction at PHERAstar FS microplate reader reading 290nm Shading value uses GraphPad Prism after calculating the inhibiting rate of compound inhibition xanthine oxidase activity by following equation 5 calculate IC50Value, concrete outcome are shown in Table 1.
Inhibiting rate (%)=[1- (ODDrug-treated hole-ODNegative control hole)/(ODBuffer solution handles hole-ODNegative control hole)]×100
2) test result
The test result of 1 the compounds of this invention XO inhibitory activity of table
Number IC50(nM)
Embodiment 1 29.7
Embodiment 3 50.9
Embodiment 4 12.0
Embodiment 10 12.8
Conclusion：The compounds of this invention has preferable inhibitory activity to XO.
2 URAT1 of test example (uric acid anion transport body -1) inhibitory activity measures
1) test method
The structure of a.hURAT1 stable expression cell strains
By in human URAT 1 plasmid transfection to HEK-293T cells, people is obtained using G418 (Geneticin, Geneticin) URAT1 stable expression cell strains.
B. uric acid, which absorbs, inhibits
Human URAT 1 expression cell is seeded in 96 orifice plates, culture medium is removed after being at least incubated 12h, (Cl is used in combination-)- Free HBSS buffer solutions wash cell；The dilution of four times of compound buffer solution obtains a series of from 200 μM to 0.8nM concentration 5 μ L compound solutions of above-mentioned preparation and 45 μ L are contained [8- by compound solution14C] uric acid buffer solution mixing after be added to and contain There is in 96 orifice plates of stable transfected cells (i.e. final compound concentration is 20 μM to 0.08nM), while buffering fluid apertures (transfection is set Cell is added without drug) and negative hole (non-transfected cell is added without drug)；Buffer solution is removed after 37 DEG C of incubation 5min, is used in combination Buffer solution washs cell, and 50 μ L lysis buffers (100mM NaOH solutions) are added per hole, cell is cracked, 600rpm shakes Shake 10min.1000rpm centrifuges 5min, pipettes 45 μ L supernatants to Isoplate-96 microwell plates, 150 μ L are added per hole Ultima GoldTMXR, and 600rpm shakes 10min.Use MicroBeta Trilux flickers/luminescence counter (PerkinElmer) it counts, reads [8-14C] uric acid surplus, compound is calculated by following equation and inhibits [8-14C] uric acid suction IC is calculated by XLfit softwares after the inhibiting rate of receipts50Value, the IC measured50Value is shown in Table 2.
Inhibiting rate (%)=[(the drug holes 1-14C intakes-negative hole14C is absorbed)/(buffering fluid apertures14C intakes-negative hole14C Intake)] × 100；
Wherein, negative hole is not to be inoculated with transfectional cell hole.
2) test result
The test result of 2 the compounds of this invention URAT1 inhibitory activity of table
Number IC50(μM)
Embodiment 3 0.250
Embodiment 5 0.069
Embodiment 6 0.048
Embodiment 9 0.200
Embodiment 10 0.496
Embodiment 12 0.195
Conclusion：The compounds of this invention has preferable inhibitory activity to URAT1.
Pharmacokinetic Evaluation
Test method
It weighs after SD Rat Septal curfews are eaten 15 hours, is grouped at random according to weight, test-compound prepares solvent For 5%DMSO+5%Solutol+90%Saline.For the test group of intravenous injection administration, 1mg/kg is given to experimental animal Dosage；For the test group of oral medication, the dosage of 5mg/kg is given to experimental animal.Then, it is 0,0.083 at time point (only intravenous injection group), 0.25,0.5,1.0,2.0,5.0,7.0 and 24 hours extracting vein bloods (about 0.2mL), are placed in EDTAK2It is anti- It in solidifying pipe, is centrifuged 2 minutes in 11000rpm, collects blood plasma, and preserved at -20 DEG C or -70 DEG C until carrying out LC/MS/MS points Analysis.Each time point blood plasma drug concentration is measured, pharmacokinetic parameters are calculated according to pharmaceutical concentration-time curve.
The pharmacokinetic property of the compounds of this invention has good pharmacokinetics special by the above experimental test Sign.
Finally it should be noted that also other modes are used for implementing the present invention.Correspondingly, the embodiment of the present invention is It will illustratively illustrate, but be not limited to content described in the invention, it is also possible to made by within the scope of the present invention Modification or the equivalents added in the claims.All publications or patent cited in the present invention will all be used as this hair Bright bibliography.

Claims (10)

1. a kind of compound is the stereoisomer of compound shown in formula (I) compound represented or formula (I), geometrical isomerism Body, tautomer or pharmaceutically acceptable salt,
Wherein：
Q is key；
W rings are
Wherein, each X1And X2It independently is-S (=O)t,-Se- ,-O- ,-NH- or-CH2, each t independently is 0,1 or 2；Each Y1 And Y2It independently is N or CH；
Each R independently is D-atom, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Alkoxy, C3-6Naphthenic base, C1-6Heterocycle, C6-10Aryl, C1-5Heteroaryl ,-C (=O)- C3-6Naphthenic base ,-C (=O)-C1-6Heterocycle ,-C (=O)-C6-10Aryl ,-C (=O)-C1-5Heteroaryl ,-L1- S (=O)r-L2- RA、C3-6Naphthenic base-C1-6Alkyl, C6-10Aryl-C1-6Alkyl, C1-5Heteroaryl-C1-6Alkyl or carboxyl；Wherein, each R is individually optional Ground is by 1,2,3,4 or 5 RxSubstitution；
RAFor C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Alkoxy, C3-6Naphthenic base, C1-6Heterocycle, C6-10 Aryl or C1-5Heteroaryl；
Each RxIt independently is hydroxyl, oxo (=O), halogen atom, amino, nitro, cyano, C1-6Alkyl, C1-6Alkoxy or C1-6Halogen Substituted alkyl；
R1、R2、R3、R4And R5It is each independently hydrogen atom, D-atom, halogen atom, hydroxyl, amino, nitro, cyano, C1-6Alkane Base, C1-6Halogenated alkyl, C1-6Alkoxy, C6-10Aryl or C1-5Heteroaryl；Wherein, each R1、R2、R3、R4And R5Individually optional ground quilt 1,2 or 3 RySubstitution；
Each RyIt independently is hydroxyl, oxo (=O), halogen atom, amino, nitro, cyano, C1-6Alkyl, C1-6Alkoxy or carboxyl；
M is 0,1,2,3,4 or 5；
R is 0,1 or 2；
L1For key ,-O- or-NH-；
L2For key ,-O- or-NH-；With
Condition is,
W rings are not
2. compound according to claim 1, wherein W rings are
3. compound according to claim 1, wherein each R independently is D-atom, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tertiary butyl, vinyl, acetenyl, propargyl, difluoro Methyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, Pyrrolidinyl, phenyl, naphthalene, furyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, thiazolyl, pyridyl group, pyrimidine radicals, three Nitrogen oxazolyl, tetrazole base ,-C (=O)-cyclopropyl ,-C (=O)-cyclohexyl ,-C (=O)-phenyl ,-C (=O)-thienyl ,-C (=O)-imidazole radicals, ethylsulfonyl, Cvclopropvlmethvl, benzyl, thienyl methyl or carboxyl；Wherein, each individually optional ground R quilt 1,2,3,4 or 5 RxSubstitution；
Each RxIt independently is hydroxyl, oxo (=O), fluorine, chlorine, bromine, iodine, amino, nitro, cyano, methyl, methoxyl group or fluoroform Base.
4. compound according to claim 1, R1、R2、R3、R4And R5Be each independently hydrogen atom, D-atom, fluorine, chlorine, Bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, trifluoromethyl, methoxyl group, phenyl, naphthalene, pyrrole radicals, pyrazolyl, Imidazole radicals, thiazolyl, thienyl, oxazolyl, tetrazole base, pyridyl group or pyrimidine radicals；Wherein, each R1、R2、R3、R4And R5It is independent Optionally by 1,2 or 3 RySubstitution；
Each RyIt independently is hydroxyl, oxo (=O), fluorine, chlorine, bromine, iodine, cyano, methyl, isopropyl, methoxyl group or carboxyl.
5. compound according to claim 1, the structure with one of：
Or it is its stereoisomer, several What isomers, tautomer or pharmaceutically acceptable salt.
6. a kind of pharmaceutical composition, it includes described in claim 1-5 any one compound and pharmaceutically acceptable tax Shape agent, carrier, adjuvant or combination thereof.
7. pharmaceutical composition according to claim 6 further includes other and prevents or treat hyperuricemia, gout The drug of stone, urarthritis, related with hyperuricemia nephropathy and urolithiasis, the drug be colchicin, Non-steroidal anti-inflammatory drugs, glucocorticoid inhibit uric acid to generate medicine, uricosureic agent, urine basifier or their arbitrary combination.
8. the pharmaceutical composition described in compound or claim 6-7 any one described in claim 1-5 any one exists Prepare the purposes in drug, the drug is used to prevent or treat the hyperuricemia of mammal, tophus, gouty joint Scorching, related with hyperuricemia nephropathy and urolithiasis.
9. purposes according to claim 8, the mammal is the mankind.
10. the pharmaceutical composition described in compound or claim 6-7 any one described in claim 1-5 any one exists The purposes in drug is prepared, the drug is for reducing uric acid level in blood；
Or the drug is used to inhibit the activity of lithate anion transport body -1 and/or xanthine oxidase.
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