CN107089955A - Sulfonic acid amide derivatives and its production and use - Google Patents

Sulfonic acid amide derivatives and its production and use Download PDF

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CN107089955A
CN107089955A CN201710077574.2A CN201710077574A CN107089955A CN 107089955 A CN107089955 A CN 107089955A CN 201710077574 A CN201710077574 A CN 201710077574A CN 107089955 A CN107089955 A CN 107089955A
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alkyl
compound
group
base
deuterium
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CN107089955B (en
Inventor
黄常伟
王晓军
杨新业
马发城
李峥
黄伟明
顾峥
吴族平
张英俊
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D417/02—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
    • C07D417/12—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 linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a class sulphonamide derivatives, and the pharmaceutical composition comprising such compound.The compound or pharmaceutical composition can be used for suppressing lithate anion transport body.The invention further relates to prepare the method for this kind of compound and pharmaceutical composition, and their higher relevant diseases of uric acid level in mammal, the particularly mankind, with blood are treated or prevented purposes.

Description

Sulfonic acid amide derivatives and its production and use
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to a class sulfamide compound or its composition, and its prepare Method and purposes, wherein described compound or composition have the purposes for suppressing lithate anion transport body activity, and can For preventing or treating and the higher relevant disease of uric acid level in blood.
Background technology
Uric acid is the metabolite last eventually of mankind's purine compound.In the mankind, uric acid is mainly through kidney excretion, and it is drained Amount accounts for nearly 2/3rds of total excretion.When uric acid produces excessive or acatharsia, uric acid accumulation is set to trigger in blood in human body in Uric acid concentration is raised, and then causes hyperuricemia.Under normal purine diet state, non-empty stomach serum uric acid level twice on the same day Higher than 420 μm ol/L of male, as higher than 360 μm ol/L of women, hyperuricemia.Hyperuricemia can be categorized 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 is initially formed, crystallizes and is deposited on synovium of joint, synovial bursa, cartilage And its in hetero-organization, cause tiny crystals to discharge or urate crystals when quick change, local trauma occur for internal uric acid level When albumen coating changes, cause repeated relapsing inflammatory reaction, then induce gout.Gout refers in particular to acute feature arthritis With chronic gout stone disease, mainly include acute attack arthritis, tophus formation, tophaceous chornic arthritis, uric acid 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 disease conditions 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, Uric acid concentration can be used for preventing or treating hyperuricemia and gout in reduction blood, and reduction suffers from other hyperuricemias and logical The risk of wind complication.
Research shows that about 90% hyperuricemia is caused by underexcretion, and uric acid is main in the excretion of kidney Including 4 processes：After worry, the reabsorption of renal tubule and concetrated pipe, renal tubule and the concetrated pipe of glomerulus are secreted and secreted Reabsorption, each process be by corresponding albumen participate in complete, finally only 8%-12% uric acid 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) is Proximal tubular cell brush border side is located at by discoveries such as Enomoto, reabsorption of the uric acid in kidney proximal tubule is participated in A kind of transmembrane transporter.SLC22A12 gene codes of the hURAT1 on Chromosome 11q13, contains 10 extrons and 9 Individual introne, by 555 amino acid residues, 12 transmembrane structures and the-NH positioned at cell interior2With-COOH ends composition. Research finds that the SLC22A12 genes that kidney Hypouricemia patient carries are undergone mutation, and loses coding URAT1 maturation proteins Ability, thereby determine that URAT1 be kidney 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), its uric acid to kidney Reabsorption function is significant and closely related with the regulation and control of uric acid level in blood.
Therefore, the material with URAT1 inhibitory activity can promote the excretion of uric acid in blood, in treatment and prevention and blood The higher relevant disease of uric acid level, including hyperuricemia, gout, tophus, urarthritis, hyperuricemia correlation Nephropathy, lithangiuria etc..
This kind of medicine has become treatment hyperuricemia, the research and development heat of gout and the disease related to hyperuricemia Point.
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 overall.Work as the disclosure of the specification With citation it is variant when, be defined by the disclosure of the specification.
The invention provides the compound that a class has URAT1 inhibitory activity, for preparing prevention or treatment with being urinated in blood The higher relevant disease of acid number, such as hyperuricemia, tophus, urarthritis, the kidney relevant with hyperuricemia Obstacle and urolithiasis etc.；The compounds of this invention can suppress URAT1 well, while having excellent physicochemical property and medicine generation Kinetic 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 composition treatment mammal, the especially mankind.
Specifically：
On the one hand, the present invention relates to the alloisomerism of compound shown in compound of the one kind as shown in formula (I) or formula (I) Body, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, ester is pharmaceutically acceptable Salt or its prodrug,
Wherein,
A rings are C6-10Aryl or C1-9Heteroaryl；
B rings are C3-6Cycloalkyl, C2-6Heterocyclic radical, C6-10Aryl or C1-6Heteroaryl；
L is key ,-O- or-NH-；
L0For key or-CH2-；
R is hydrogen, deuterium, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkoxy -C1-6Alkyl, C1-6Alkyl amino-C1-6Alkane Base, C3-6Cycloalkyl, C2-9Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl or C6-10Aryl-C1-6Alkyl；Described C1-6Alkyl, C2-6 Alkenyl, C2-6Alkynyl, C1-6Alkoxy -C1-6Alkyl, C1-6Alkyl amino-C1-6Alkyl, C3-6Cycloalkyl, C2-9Heterocyclic radical, C6-10Virtue Base, C1-9Heteroaryl and C6-10Aryl-C1-6Alkyl can further individually optionally by it is one or more selected from deuterium, oxo (=O), F, Cl, Br, I, hydroxyl, amino, the substituent of nitro and cyano group are replaced；
Each R1It independently is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano group, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynes Base, C1-6Haloalkyl ,-OR4、-NR5R6、-L1- C (=O)-L2-R7、-L3- S (=O)t-L4-R8、C3-8Cycloalkyl, C2-9Heterocycle Base, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl-C1-6Alkyl or C1-9Heteroaryl-C1-6Alkyl, wherein R1Can be optionally further Hydrogen, deuterium, oxo (=O), F, Cl, Br, I, hydroxyl, amino, nitro, cyano group, C are selected from by one or more1-6Alkyl, C1-6Alcoxyl Base, C1-6Haloalkyl, C1-6Halogenated alkoxy and C3-6The substituent of cycloalkyl is replaced；
R4、R5、R6、R7And R8It is each independently hydrogen, deuterium, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Haloalkyl, C3-8Cycloalkyl, C2-9Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl；
L1And L3It is each independently key ,-O- ,-NH- or C1-6Alkylidene；
L2And L4It is each independently key ,-O- ,-NR9- or C1-6Alkylidene；
R9For hydrogen, deuterium, C1-3Alkyl, C1-3Haloalkyl, C3-6Cycloalkyl, C2-6Heterocyclic radical, C6-10Aryl or C1-6Heteroaryl；
T is 0,1 or 2；
R2For hydrogen, deuterium, C1-3Alkyl, C1-3Haloalkyl or C3-6Cycloalkyl；
Each R3It independently is hydrogen, deuterium, oxo (=O), F, Cl, Br, I, hydroxyl, amino, nitro, cyano group or C1-3Alkyl；
M is 0,1,2,3,4 or 5；
N is 0,1,2 or 3；
Condition is, when B rings are phenyl, R1For methyl and m is that 1, L is-O- or-NH-.
In certain embodiments, A rings are
Wherein,
X1For-O- ,-S- or-NH-；
Each X2、X3、X4And X5It independently is CH or N；
X6And X7It is each independently-O- ,-S- ,-NH- or-CH2-。
In further embodiments, A rings are phenyl, naphthyl, 2,3- dihydro -1H- indenes, 1,2,3,4-tetrahydro-naphthalene base, furan Mutter base, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, thiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl, oxadiazolyls, pyrrole Piperidinyl, pyrimidine radicals, pyrazinyl, pyridazinyl, indyl, quinolyl, 1H- benzimidazolyls, benzopyrazoles base, 1,4- benzos two are disliked Alkyl or 1,3- benzo dioxolane bases.
In certain embodiments, B rings be cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, pyrrolidinyl, It is tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, pyrrole radicals, imidazole radicals, furyl, thienyl, thiazolyl, pyridine radicals, phonetic Piperidinyl, phenyl or naphthyl.
In certain embodiments, R be hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, Vinyl, pi-allyl, acetenyl, propargyl, difluoromethyl, trifluoromethyl, the fluoro ethyls of 2,2- bis-, methyl epoxide methyl, ethyl Epoxide methyl, ethyl epoxide ethyl, acetyl group, Acetoxvethyl, acetamidoethyl, cyclopropyl, cyclobutyl, cyclopenta, Cyclohexyl, tetrahydrofuran base, pyrrolidinyl, piperidyl, piperazinyl, phenyl, naphthyl, benzyl, furyl, thienyl, pyridine radicals Or pyrimidine radicals；
Each R1It independently is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano group, methyl, ethyl, n-propyl, isopropyl Base, normal-butyl, isobutyl group, the tert-butyl group, vinyl, acetenyl, difluoromethyl, trifluoromethyl, methoxyl group, ethyoxyl, n-propyl Epoxide, isopropyl epoxide, normal-butyl epoxide, isobutyl group epoxide, tert-butyl group epoxide, phenoxy group, methylamino, ethylamino, isopropyl Amino, dimethylamino, diethylamino, acetyl group, mesyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrochysene furan Mutter base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, furyl, pyrrole radicals, imidazoles Base, pyrazolyl, thienyl, thiazolyl, oxazolyls, pyridine radicals, pyrimidine radicals, indyl, quinolyl, isoquinolyl, phenyl or naphthalene Base, wherein R1Optionally further hydrogen, deuterium, oxo (=O), F, Cl, Br, I, hydroxyl, amino, nitre can be selected from by one or more Base, cyano group, C1-4Alkyl, C1-4Alkoxy, C1-4Haloalkyl, C1-4Halogenated alkoxy and C3-6The substituent of cycloalkyl is replaced.
In certain embodiments, the present invention relates to the compound as shown in formula (II), or the chemical combination shown in formula (II) The stereoisomer of thing, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or prodrug,
Wherein, A, R, each R1, each R3, m and n there is implication as described in the present invention.
On the other hand, the present invention relates to a kind of pharmaceutical composition, the pharmaceutical composition includes formula (I) of the present invention or (II) Described compound, or its stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, generation Thank product, pharmaceutically acceptable salt or their prodrug, and its it is pharmaceutically acceptable carrier, excipient, diluent, auxiliary Agent, medium or combinations thereof.
In certain embodiments, pharmaceutical composition of the present invention, further comprising other preventions or the high urine for the treatment of Acidaemia, tophus, urarthritis, the medicine of the nephropathy relevant with hyperuricemia and urolithiasis, the medicine Medicine, uricosureic agent are generated for colchicin, NSAIDs, glucocorticoid, suppression uric acid, urinate basifier or they Any combination.
On the other hand, the present invention relates to the compound described in formula (I) or (II) or its pharmaceutical composition in medicine is prepared Purposes, the medicine is used to prevent or treat mammal, including the hyperuricemia of the mankind, tophus, gouty joint The scorching, nephropathy relevant with hyperuricemia and urolithiasis.
On the other hand, the present invention relates to the compound described in formula (I) or (II) or its pharmaceutical composition in medicine is prepared Purposes, the medicine be used for reduce uric acid level in blood.
On the other hand, the present invention relates to the compound described in formula (I) or (II) or its pharmaceutical composition in medicine is prepared Purposes, the medicine be used in study subject suppress lithate anion transport body.
On the other hand, the side of preparation, separation and the purifying of the compound included the present invention relates to formula (I) or formula (II) Method.
Biological results show that the compound that the present invention is provided can suppress as preferable lithate anion transport body Agent.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not Contradiction occurs.In addition, in any embodiment of either side of the present invention, any technical characteristic goes 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 enclosed.This Invention is intended to cover all replacement, modification and equivalent technical solutions, and they are included in the present invention defined such as claim In the range of.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method described herein and material Trample the present invention.The present invention is not limited to method described herein and material.The one of the document combined, patent and similar material Or many 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 defined by the application.
It will further be appreciated that some features of the present invention, are clearly visible, carried out in multiple independent embodiments Description, but it is also possible to provide in combination in single embodiment.Conversely, the various features of the present invention, for brevity, It is described in single embodiment, but it is also possible to individually or with arbitrarily suitable sub-portfolio provide.
Unless otherwise indicated, 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 that identical implication.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise indicated, 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 Examine " 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 are obvious conflict, article " one " used herein, " one (kind) " unless otherwise indicated or in context " 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 for example also referring to primate (such as the 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, i.e., including the content specified by the present invention, but be not precluded from otherwise Content.
" stereoisomer " refers to identical chemical constitution, but the spatially different change of arrangement mode of atom or group Compound.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..
" chirality " be with its mirror image can not overlapping property molecule；And " achirality " refer to can be with overlapping with its mirror image Molecule.
" enantiomter " refers to that two of a compound can not isomers that is overlapping but being mutually mirror.
" diastereoisomer " refers to have two or more chiral centres 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 Compound can be by high resolution analysis operation such as electrophoresis and chromatogram, and such as HPLC is separated.
Stereochemical definitions used in the present invention and rule typically 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, rotates the plane of linearly polarized light Ability.When describing optically active compound, represent molecule on 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 represent that compound is left-handed.Prefix is dextrorotation for (+) or d compound.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 during there is no stereoselectivity or stereospecificity when, It may occur in which such case.
Any asymmetric atom (for example, carbon etc.) that the present invention discloses compound can be enriched with racemic or enantiomer Form exist, for example (R)-, (S)-or (R, S)-configuration be present.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 at least 80% enantiomeric excess, at least 90% enantiomeric excess, 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, the form of such as racemic modification and the non-enantiomer mixture quantity of asymmetric carbon atom (this depend on) 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 a double bond, substituent may be E or Z configurations；If containing dibasic cycloalkanes in compound Base, the substituent of cycloalkyl 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.
The racemic modification of any gained end-product or intermediate can be passed through into those skilled in the art with known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Thing can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can be prepared by asymmetric syntheses, for example, Jacques is referred 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 compound described in the invention, of the invention optionally can be replaced by one or more substituents, such as General formula compound above, or as example special inside embodiment, subclass, and the class compound that the present invention is included.
In general, term is " substituted " to represent that institute is taken to one or more of structure hydrogen atom by specific substituent Generation.Unless otherwise indicated, the group of a substitution can have a substituent, in group, each commutable position is carried out Substitution.When more than one position can be selected from one or more substituents of specific group and be replaced in given structural formula, So substituent can be replaced with identical or different in each position.
Term " unsubstituted ", represents specified group without substituent.
Term " optionally by ... replace ", can exchange with term " unsubstituted or by ... replace " and use, i.e., The structure is unsubstituted or replaced by one or more substituents of the present invention.Substituent bag of the present invention Include, but be not limited to D, F, Cl, Br, I, N3、CN、NO2、OH、SH、NH2, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkyl Amino, cycloalkyl, heterocyclic radical, aryl, heteroaryl, etc..
In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode used in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, it both may be used To refer in different groups, do not influence mutually, can also represent in phase between expressed specific option between same-sign In same group, do not influenceed mutually between expressed specific option between same-sign.
In each several part of this specification, the substituent that the present invention discloses compound is disclosed according to radical species or scope.It is special Do not point out, each independent sub-combinations thereof of each member of the present invention including these radical species and scope.For example, term “C1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each several part 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.If for example, the structure needs linking group and for being somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then is represented respectively 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 ", represent the straight or branched univalent hydrocarbyl group of saturation, Wherein, the substituent that the alkyl group can be described optionally by one or more present invention replaces.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 is included, 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), the tert-butyl group (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl groups (- CH (CH3)CH2CH2CH3), 3- amyl groups (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl isophthalic acids-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- amyl groups (- C (CH3)2CH2CH2CH3), 3- first Base -2- amyl groups (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyl groups (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- penta Base (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl groups (- 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 " represents to remove from the straight or branched alkyl of saturation the saturation obtained by two hydrogen atoms 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 " represent straight or branched monovalent hydrocarbon, wherein at least one unsaturation site, that is, have a carbon- Carbon sp2Double bond, wherein, the alkenyl group optionally can be replaced by one or more substituents described in the invention, It includes " cis " and " trans " positioning, or " E " and " Z " positioning.In one embodiment, alkenyl group includes 2-12 Individual carbon atom；In another embodiment, alkenyl group includes 3-12 carbon atom；In another embodiment, alkenyl group Include 2-6 carbon atom；In yet another embodiment, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, But it is not limited to, vinyl (- CH=CH2), pi-allyl (- CH2CH=CH2) etc..
Term " alkynyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a key of carbon-to-carbon sp tri-, wherein, the alkynyl group can be retouched optionally by one or more present invention The substituent stated is replaced.In one embodiment, alkynyl group includes 3-12 carbon atom；In another embodiment, alkynes Base group includes 2-6 carbon atom；In yet another embodiment, alkynyl group includes 2-4 carbon atom.The example of alkynyl group Include, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH2C ≡ CH), 1- propinyls (- C ≡ C-CH3) etc..
Term " alkoxy " represents that alkyl group is connected by oxygen atom with molecule remainder, and wherein alkyl group has Implication 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 that the present invention is described is replaced.
The example of alkoxy base is included, 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 Epoxide (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (- OCH2CH(CH3)CH2CH3), etc..
Term " alkoxyalkyl " represents that alkoxy base is connected by alkyl with molecule remainder, wherein alkoxy base Group and alkyl group have implication as described in the present invention.The alkoxy-alkyl group can be optionally by one or more The substituent of invention description is replaced.The example of alkoxy-alkyl group is included, but is not limited to, methyl epoxide methyl (- CH2OCH3), ethyl epoxide methyl (- CH2OCH2CH3), ethyl epoxide ethyl (- CH2CH2O CH2CH3), etc..
Term " alkyl amino " includes " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino group independently Ground is replaced by one or two alkyl group；The alkyl has implication described in the invention.Some of embodiments are, Alkyl amino is one or two C1-6Alkyl is connected to the alkylamino group of the lower level formed on nitrogen-atoms.Other one A little embodiments are that alkyl amino is one or two C1-4The alkyl of lower level be connected to the alkyl amino formed on nitrogen-atoms Group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but does not limit In, N- methylaminos, N- ethylaminos, N, N- dimethylaminos, N, N- lignocaines etc..
Term " alkylaminoalkyl group " represents that alkylamino group is connected by alkyl with molecule remainder, wherein alkyl Amino group and alkyl group have implication as described in the present invention.The alkylaminoalkyl groups can be optionally by one Or the substituent that multiple present invention are described is replaced.The example of alkylaminoalkyl groups is included, but is not limited to, methylamino Methyl (- CH2NCH3), ethylaminomethyl (- CH2NCH2CH3), ethylaminoethyl (- CH2CH2NCH2CH3), etc..
Term " haloalkyl ", " halogenated alkoxy " or " haloalkylamino " represents alkyl, alkoxy or alkyl amino Group is replaced by one or more halogen atoms, wherein alkyl, and alkoxy or alkylamino group have as described herein Implication, such example is included, but is not limited to, trifluoromethyl, 2,2,3,3- tetra- fluoropropyls, difluoro-methoxy, fluoroform Epoxide, trifluoromethyl amino etc..
Term " cycloalkyl " represents that the saturation of unit price or multivalence is monocyclic, bicyclic or three rings containing 3-12 individual full carbon atoms System.In one embodiment, cycloalkyl includes 7-12 carbon atom；In yet another embodiment, cycloalkyl includes 3-8 carbon Atom；In yet another embodiment, cycloalkyl includes 3-6 carbon atom.The group of naphthene base can be independently unsubstituted Or replaced by one or more substituents described in the invention.Suitable group of naphthene base is included, but is not limited to, ring third Base, cyclobutyl, cyclopenta, cyclohexyl, etc..
Term " carbocyclic ring " or " carbocylic radical " represent that unit price or the nonaromatic of multivalence are satisfied containing 3-12 individual full carbon atoms And/or unsaturated monocyclic, the bicyclic or three-ring system in part.Carbon bicyclic group includes spiral shell carbon bicyclic group and fusion carbon bicyclic group, properly Carbocylic radical group include, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.In one embodiment, carbocylic radical includes 3- 8 carbon atoms；In yet another embodiment, carbocylic radical includes 3-6 carbon atom.The example of carbocylic radical group further comprises, Cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyls, 1- cyclopenta -2- alkenyls, 1- cyclopenta -3- alkenyls, cyclohexyl, 1- cyclohexyl -1- alkenyls, 1- cyclohexyl -2- alkenyls, 1- cyclohexyl -3- alkenyls, cyclohexadienyl, suberyl, cyclooctyl, ring nonyl Base, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..The carbocylic radical group can be independently unsubstituted or by one Or multiple substituents described in the invention are replaced.
Term " heterocyclic radical " and " heterocycle " are used interchangeably here, all referring to the saturation comprising 3-12 annular atom or portion Point undersaturated nonaromatic unit price or multivalence are monocyclic, bicyclic or tricyclic, and wherein at least one annular atom is selected from nitrogen, sulphur and oxygen Atom.Unless otherwise indicated, heterocyclic radical can be connected by carbon atom with other groups in molecule, can also by nitrogen-atoms with Other groups are connected in molecule, and-CH2- group can be optionally by-C (=O)-replacement.The sulphur atom of ring can optionally by It is oxidized to S- oxides.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compounds.The example of heterocyclic radical includes, but does not limit In：Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- pyrrolinyls, 3- pyrrolins Base, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro Thienyl, 1,3- dioxies cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranoses, 4H- pyranoses, four Hydrogen thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, alkyl dioxins, dithiane base, thioxanes base, homopiperazine base, Homopiperidinyl, Diazesuberane base, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulphur azepineBase, 2- oxa- -5- azabicyclos [2.2.1] hept- 5- bases.- CH in heterocyclic radical2- group is by the example bag of-C (=O)-replacement Include, but be not limited to, 2- oxo-pyrrolidines base, oxo -1,3-thiazoles alkyl, 2- piperidone bases, 3,5- dioxy piperazines piperidinyl and phonetic Pyridine diketo.The oxidized example of sulphur atom includes, but not limited to sulfolane base, 1,1- dioxothiomorpholins in heterocyclic radical Base.Described heterocyclyl groups optionally can be replaced by one or more substituents described in the invention.
Term " n former molecular ", wherein n is integer, the number of ring member nitrogen atoms in molecule is typically described, described The number of ring member nitrogen atoms is n in molecule.For example, piperidyl is 6 molecular Heterocyclylalkyls of original, and decahydro naphthyl is 10 originals Molecular carbocylic radical group.
Used term is " undersaturated " in the present invention represents to contain one or more degrees of unsaturation in group.
Term " hetero atom " refers to O, S, N, P and Si, includes the form of any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, for example, N is (as in 3,4- dihydro-2 h-pyrrole bases 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 atoms (Br) or iodine atom (I).
Term " aryl " represented containing 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom is monocyclic, double The full carbocyclic ring system of ring or three rings, wherein, at least one ring is aromatic, and have one or more attachment points and molecule its Remaining part split-phase connects.Term " aryl " can be exchanged with term " aromatic rings " and used.In one embodiment, aryl is by 6-10 Annular atom composition, and wherein at least contains the carbocyclic ring system of an aromatic rings.The example of aromatic yl group can include phenyl, naphthalene Base and anthryl.The aromatic yl group can be replaced with individually optional by one or more substituents described in the invention.
Term " aryl alkyl " represents that aromatic yl group is connected by alkyl group with molecule remainder, wherein aromatic yl group There is implication as described in the present invention with alkyl group.The aromatic yl alkyl group can be optionally by one or more present invention The substituent of description is replaced.The example of aryl alkyl is included, but is not limited to, phenyl methyl, phenylethyl, naphthyl -1- first Base, naphthyl -2- methyl, etc..
Term " heteroaryl " represented containing 5-12 annular atom, or 5-10 annular atom, or 5-6 annular atom it is monocyclic, Bicyclic or three rings, wherein at least one ring is aromatic, and at least one aromatic rings includes one or more hetero atoms, and is had One or more attachment points are connected with molecule remainder.Term " heteroaryl " can be with term " hetero-aromatic ring " or " heteroaromaticization Compound " is exchanged and used.The heteroaryl groups are optionally replaced by one or more substituents described in the invention.One In embodiment, heteroaryl be comprising 1, the heteroatomic 5-12 former molecular heteroaryls that 2,3 or 4 are independently selected from O, S and N Base；In another embodiment, heteroaryl be comprising 1, the heteroatomic 5-6 atom group that 2,3 or 4 are independently selected from O, S and N Into heteroaryl.
The example of heteroaryl groups is included, 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- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 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 following 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] pyridine radicals, pyrazolo [1,5-a] pyridine radicals, 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] pyridine radicals, etc..
Term " heteroaryl alkyl " represents that heteroaryl groups are connected by alkyl group with molecule remainder, wherein heteroaryl Base group and alkyl group have implication as described in the present invention.The heteroarylalkyl group can be optionally by one or many The substituent that the individual present invention is described is replaced.
As described in the invention, a connecting key is connected to member ring systems (as shown in the formula a) generation formed on the center of ring Table connecting key can be connected any attachable position in member ring systems with molecule remainder.Formula a represents any possibility on E rings The position of connection can be connected with molecule remainder.
As described in the invention, substituent draws a key and is connected to the member ring systems formed on the ring at center (such as formula b institutes Show) represent substituent any commutable position on the ring and can replace.For example, formula b represent substituent R can be on G rings It is monosubstituted or polysubstituted on any position that may be substituted, as shown in formula c1~formula c19.
When term " blocking group " or " PG " refer to a substituent with other reacted with functional groups, commonly used to hinder It is disconnected or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected to block with amino group Or the feature 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 of base is used for blocking or protecting the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl Blocking group " refers to that the substituent of carboxyl is used for blocking or protect the feature 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 description of group typically refers 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 compound shown in formula (I) in vivo. Such conversion is hydrolyzed or is that precursor structure is influenceed through enzymatic conversion in blood or tissue in blood by pro-drug.This hair Bright pro-drug compounds can be ester, in existing invention ester can as pro-drug the phenyl ester class that has, aliphatic (C1-C24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.One for example in the present invention Compound includes hydroxyl, you can be acylated the compound for obtaining prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.On pro-drug begging for completely By may be referred to documents below：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 in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology known to art Adopt and experimentally characterized as stating.Such product can be by, by aoxidizing, being reduced, water to drug compound Solution, amidated, desamido- effect is esterified, degreasing, and enzymatic lysis etc. method is obtained.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention is fully contacted to the metabolite produced by a period of time with mammal.
" 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 art on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed is included, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Other method such as ion-exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, mesylate, 2- naphthalene sulfonates, nicotinic acid Salt, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, spy penta Hydrochlorate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through appropriate alkali Obtained salt includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any included N's The quaternary ammonium salt that the compound of group is formed.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Alkali Metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..It is appropriate, nontoxic that pharmaceutically acceptable salt further comprises Ammonium, quaternary ammonium salt and gegenions formation amine cation, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid Compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention are formed Thing.The solvent for forming solvate is included, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.
When the solvent is water, term " hydrate " can be used.In certain embodiments, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In other embodiment, 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 is remained with The biological effectiveness of the compound of nonhydrated form.
As used in the present invention term " treatment " any disease or illness, refer to it is all can slow down, interrupt, preventing, Control or the progress for stopping disease or illness, but not necessarily represent that the symptom of all diseases or illness all disappears, it also includes To the prophylactic treatment of the symptom, especially in the patient of such disease or obstacle is easily suffered from.Some are implemented wherein Scheme middle finger improves disease or illness (slow down or prevent or mitigate disease or the development of 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 and (for example stablizes perceptible symptom) or physiologically (example Such as stablize the parameter of body) or above-mentioned two aspect regulation 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 trigger individual Thing or medicinal response (for example reduce or inhibitory enzyme or protein active, or improve symptom, alleviate illness, slow down or postpone disease Disease development, or prevention disease etc.) the compounds of this invention amount.In a non-limiting embodiment, " treatment has term Effect amount " refer to when to individual apply the compounds of this invention when, the amount effective to situations below：(1) alleviate at least in part, press down System, prevention and/or improvement (i) are mediated by lithate anion transport body (URAT1), or (ii) and lithate anion transport Body activity is related, or the illness or disease that (iii) is characterized by the abnormal activity of lithate anion transport body；Or (2) drop Activity that is low or suppressing lithate anion transport body；Or (3) reduction or the expression for suppressing lithate anion transport body. In another embodiment, term " therapeutically effective amount " refers to work as to be applied to cell or organ or acellular organism material or medium Used time, it can at least in part reduce or suppress lithate anion transport body activity；Or reduce at least in part or suppress urine The amount for the effective the compounds of this invention that hydrochlorate anion transport body surface reaches.
Term compound " giving " and " administration " compound as used in the present invention should be understood to its of needs Body provides the compound of the present invention or the prodrug of the compounds of this invention.It should be appreciated that those skilled in the art are by using effective The patient current with this obstacle of the compounds of this invention treatment of amount or prophylactically patient of the treatment with this obstacle, can be with Influence is produced on uric acid concentration in blood.
Term " composition " as used in the present invention refers to the product of the predetermined component comprising ormal weight, and ormal weight Predetermined component the spawn that directly or indirectly produces of combination.The implication of this term related to pharmaceutical composition Product including including active component (single or multiple) and the inert fraction (single or multiple) for constituting carrier, Yi Jiyou It is any two or Multiple components mixing, compound or assemble, either by one or more ingredient breakdowns or by one or more into Point other kinds of reaction or interaction and the spawn that directly or indirectly produces.Therefore, pharmaceutical composition of the present invention Including any combinations thing by mixing and preparing with pharmaceutical acceptable carrier by the compounds of this invention.
The description of the compound of the present invention
The invention discloses a class sulfonic acid amide derivatives, its pharmaceutically acceptable salt, pharmaceutical preparation and combinations thereof, Lithate anion transport body inhibitor, the symptom or disease higher to uric acid level in mankind's blood, such as antihyperuricemic can be used as Disease, tophus, urarthritis, the treatment of the nephropathy relevant with hyperuricemia and urolithiasis have potential purposes.
On the one hand, the present invention relates to the alloisomerism of compound shown in compound of the one kind as shown in formula (I) or formula (I) Body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein, A, B, R, L, L0, each R1、R2, each R3, m and n there is implication as described in the present invention.
In certain embodiments, A rings are aryl or heteroaryl.
In certain embodiments, B rings are cycloalkyl, heterocyclic radical, aryl or heteroaryl.
In certain embodiments, L is key ,-O- or-NH-.
In certain embodiments, L0For key or-CH2-。
In certain embodiments, R is hydrogen, deuterium, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylaminoalkyl group, cycloalkanes Base, heterocyclic radical, aryl, heteroaryl or aryl alkyl；Described alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylaminoalkyl group, Cycloalkyl, heterocyclic radical, aryl, heteroaryl and aryl alkyl further can be selected from deuterium, oxo by one or more individually optionally (=O), F, Cl, Br, I, hydroxyl, amino, the substituent of nitro and cyano group are replaced.
In certain embodiments, each R1Independently be hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano group, alkyl, Alkenyl, alkynyl, haloalkyl ,-OR4、-NR5R6、-L1- C (=O)-L2-R7、-L3- S (=O)t-L4-R8, cycloalkyl, heterocyclic radical, Aryl, heteroaryl, aryl alkyl or heteroaryl alkyl, wherein R1Optionally further hydrogen, deuterium, oxygen can be selected from by one or more Generation (=O), F, Cl, Br, I, hydroxyl, amino, nitro, cyano group, alkyl, alkoxy, haloalkyl, halogenated alkoxy and cycloalkyl Substituent replaced；
R4、R5、R6、R7And R8Be each independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic radical, Aryl or heteroaryl；
L1And L3It is each independently key ,-O- ,-NH- or alkylidene；
L2And L4It is each independently key ,-O- ,-NR9- or alkylidene；
R9For hydrogen, deuterium, alkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl；
T is 0,1 or 2.
In certain embodiments, R2For hydrogen, deuterium, alkyl, haloalkyl or cycloalkyl.
In certain embodiments, each R3Independently be hydrogen, deuterium, oxo (=O), F, Cl, Br, I, hydroxyl, amino, nitro, Cyano group or alkyl.
In certain embodiments, m is 0,1,2,3,4 or 5.
In certain embodiments, n is 0,1,2 or 3.
In certain embodiments, compound of the present invention, condition is, when B rings are phenyl, R1It is for methyl and m 1, L is-O- or-NH-.
In certain embodiments, A rings are C6-10Aryl or C1-9Heteroaryl.
In further embodiments, A rings are
Wherein,
X1For-O- ,-S- or-NH-；
Each X2、X3、X4And X5It independently is CH or N；
X6And X7It is each independently-O- ,-S- ,-NH- or-CH2-。
Also in certain embodiments, A rings are phenyl, naphthyl, 2,3- dihydro -1H- indenes, 1,2,3,4-tetrahydro-naphthalene base, furan Mutter base, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, thiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl, oxadiazolyls, pyrrole Piperidinyl, pyrimidine radicals, pyrazinyl, pyridazinyl, indyl, quinolyl, 1H- benzimidazolyls, benzopyrazoles base, 1,4- benzos two are disliked Alkyl or 1,3- benzo dioxolane bases.
In certain embodiments, B rings are C3-6Cycloalkyl, C2-6Heterocyclic radical, C6-10Aryl or C1-6Heteroaryl.
In further embodiments, B rings are cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, pyrrolidines Base, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, pyrrole radicals, imidazole radicals, furyl, thienyl, thiazolyl, pyridine radicals, Pyrimidine radicals, phenyl or naphthyl.
In certain embodiments, R is hydrogen, deuterium, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkoxy -C1-6Alkyl, C1-6 Alkyl amino-C1-6Alkyl, C3-6Cycloalkyl, C2-9Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl or C6-10Aryl-C1-6Alkyl；It is described C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkoxy -C1-6Alkyl, C1-6Alkyl amino-C1-6Alkyl, C3-6Cycloalkyl, C2-9 Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl and C6-10Aryl-C1-6Alkyl further can be selected from by one or more individually optionally Deuterium, oxo (=O), F, Cl, Br, I, hydroxyl, amino, the substituent of nitro and cyano group are replaced.
In further embodiments, R is hydrogen, deuterium, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Alkoxy -C1-4Alkyl, C1-4Alkyl amino-C1-4Alkyl, C3-6Cycloalkyl, C2-6Heterocyclic radical, C6-10Aryl, C1-6Heteroaryl or C6-10Aryl-C1-4Alkyl； Described C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Alkoxy -C1-4Alkyl, C1-4Alkyl amino-C1-4Alkyl, C3-6Cycloalkanes Base, C2-6Heterocyclic radical, C6-10Aryl, C1-6Heteroaryl and C6-10Aryl-C1-4Alkyl can be further individually optionally by one or many The individual substituent selected from deuterium, oxo (=O), F, Cl, Br, I, hydroxyl, amino, nitro and cyano group is replaced.
Also in certain embodiments, R is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary fourth Base, vinyl, pi-allyl, acetenyl, propargyl, difluoromethyl, trifluoromethyl, the fluoro ethyls of 2,2- bis-, methyl epoxide methyl, second Base epoxide methyl, ethyl epoxide ethyl, acetyl group, Acetoxvethyl, acetamidoethyl, cyclopropyl, cyclobutyl, ring penta Base, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, piperidyl, piperazinyl, phenyl, naphthyl, benzyl, furyl, thienyl, pyridine Base or pyrimidine radicals.
In certain embodiments, each R1It independently is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano group, C1-6Alkane Base, C2-6Alkenyl, C2-6Alkynyl, C1-6Haloalkyl ,-OR4、-NR5R6、-L1- C (=O)-L2-R7、-L3- S (=O)t-L4-R8、 C3-8Cycloalkyl, C2-9Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl-C1-6Alkyl or C1-9Heteroaryl-C1-6Alkyl, its Middle R1Optionally further hydrogen, deuterium, oxo (=O), F, Cl, Br, I, hydroxyl, amino, nitro, cyanogen can be selected from by one or more Base, C1-6Alkyl, C1-6Alkoxy, C1-6Haloalkyl, C1-6Halogenated alkoxy and C3-6The substituent of cycloalkyl is replaced；
R4、R5、R6、R7And R8It is each independently hydrogen, deuterium, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Haloalkyl, C3-8Cycloalkyl, C2-9Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl；
L1And L3It is each independently key ,-O- ,-NH- or C1-6Alkylidene；
L2And L4It is each independently key ,-O- ,-NR9- or C1-6Alkylidene；
R9For hydrogen, deuterium, C1-3Alkyl, C1-3Haloalkyl, C3-6Cycloalkyl, C2-6Heterocyclic radical, C6-10Aryl or C1-6Heteroaryl.
In further embodiments, each R1It independently is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano group, C1-4 Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Haloalkyl ,-OR4、-NR5R6、-L1- C (=O)-L2-R7、-L3- S (=O)t-L4-R8、 C3-6Cycloalkyl, C2-6Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl-C1-3Alkyl or C1-9Heteroaryl-C1-3Alkyl, its Middle R1Optionally further hydrogen, deuterium, oxo (=O), F, Cl, Br, I, hydroxyl, amino, nitro, cyanogen can be selected from by one or more Base, C1-4Alkyl, C1-4Alkoxy, C1-4Haloalkyl, C1-4Halogenated alkoxy and C3-6The substituent of cycloalkyl is replaced；
R4、R5、R6、R7And R8It is each independently hydrogen, deuterium, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Haloalkyl, C3-6Cycloalkyl, C2-6Heterocyclic radical, C6-10Aryl or C1-6Heteroaryl；
L1And L3It is each independently key ,-O- ,-NH- or C1-4Alkylidene；
L2And L4It is each independently key ,-O- ,-NR9- or C1-4Alkylidene；
R9For hydrogen, deuterium, methyl, isopropyl, trifluoromethyl, cyclopropyl or phenyl.
Also in certain embodiments, each R1It independently is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano group, first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, vinyl, acetenyl, difluoromethyl, trifluoromethyl, first Epoxide, ethyoxyl, n-propyl epoxide, isopropyl epoxide, normal-butyl epoxide, isobutyl group epoxide, tert-butyl group epoxide, phenoxy group, first Amino, ethylamino, isopropylamino, dimethylamino, diethylamino, acetyl group, mesyl, cyclopropyl, cyclobutyl, ring Amyl group, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, furan Mutter base, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, thiazolyl, oxazolyls, pyridine radicals, pyrimidine radicals, indyl, quinolyl, different Quinolyl, phenyl or naphthyl, wherein R1Can optionally further by it is one or more selected from hydrogen, deuterium, oxo (=O), F, Cl, Br, I, hydroxyl, amino, nitro, cyano group, C1-4Alkyl, C1-4Alkoxy, C1-4Haloalkyl, C1-4Halogenated alkoxy and C3-6Cycloalkanes The substituent of base is replaced.
In certain embodiments, R2For hydrogen, deuterium, C1-3Alkyl, C1-3Haloalkyl or C3-6Cycloalkyl.
In certain embodiments, each R3Independently be hydrogen, deuterium, oxo (=O), F, Cl, Br, I, hydroxyl, amino, nitro, Cyano group or C1-3Alkyl.
In certain embodiments, the present invention relates to the compound as shown in formula (II), or the chemical combination shown in formula (II) The stereoisomer of thing, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or prodrug,
Wherein, A, R, each R1, each R3, m and n there is implication as described in the present invention.
In certain embodiments, the compound of compound of the present invention comprising one of or one of Stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, solvate, hydrate, metabolite, ester, pharmaceutically Acceptable salt or its prodrug, but be not limited to：
Unless otherwise mentioned, the stereoisomer of compound shown in formula (I), solvate, metabolite, salt and pharmaceutically Acceptable prodrug is intended to be included within the scope of the present invention.
On the other hand, the present invention relates to a kind of pharmaceutical composition, the pharmaceutical composition includes formula (I) of the present invention or (II) Described compound, or its stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, generation Thank product, pharmaceutically acceptable salt or their prodrug, and its it is pharmaceutically acceptable carrier, excipient, diluent, auxiliary Agent, medium or combinations thereof.
In certain embodiments, pharmaceutical composition of the present invention, further comprising other preventions or the high urine for the treatment of Acidaemia, tophus, urarthritis, the medicine of the nephropathy relevant with hyperuricemia and urolithiasis, the medicine Medicine, uricosureic agent are generated for colchicin, NSAIDs, glucocorticoid, suppression uric acid, urinate basifier or they Any combination.
On the other hand, the present invention relates to the compound described in formula (I) or (II) or its pharmaceutical composition in medicine is prepared Purposes, the medicine is used to prevent or treat mammal, including the hyperuricemia of the mankind, tophus, gouty joint The scorching, nephropathy relevant with hyperuricemia and urolithiasis.
On the other hand, the present invention relates to the compound described in formula (I) or (II) or its pharmaceutical composition in medicine is prepared Purposes, the medicine be used for reduce uric acid level in blood.
On the other hand, the present invention relates to the compound described in formula (I) or (II) or its pharmaceutical composition in medicine is prepared Purposes, the medicine be used in study subject suppress lithate anion transport body.
On the other hand, the side of preparation, separation and the purifying of the compound included the present invention relates to formula (I) or formula (II) Method.
The present invention disclose compound can containing asymmetric or chiral centre, therefore can different stereoisomer forms deposit .It is contemplated that all stereoisomer forms of compound shown in formula (I) or formula (II), including but not limited to diastereomeric Isomers, enantiomter, atropisomer and geometry (or conformation) isomers, and their mixture such as racemic are mixed Thing, the part as the present invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific is not indicated, then the structure All stereoisomers all consider within the present invention, and disclose compound as the present invention and be included in the invention.When Spatial chemistry is expressed when wedge shape line (solid wedge) or dotted line are indicated in fact of particular configuration, then the alloisomerism of the structure Body clearly and is defined with regard to this.
Compound shown in formula (I) or formula (II) can exist with different tautomeric forms, and all these mutual Tautomeric, is included within the scope of the present invention.
Compound shown in formula (I) or formula (II) can exist in a salt form.In one embodiment, the salt refers to medicine Acceptable salt on.Term " pharmaceutically acceptable " refers to that material or composition must be with other compositions comprising preparation And/or the mammal treated with it is compatible in chemistry and/or in toxicology.In another embodiment, the salt differs Surely it is pharmaceutically acceptable salt, can be used to preparing and/or purifying compound and/or use shown in formula formula (I) or formula (II) In the intermediate of the enantiomer of compound shown in separation Ben Shishi (I) or formula (II).
Pharmaceutically useful acid-addition salts can be disclosed compound and acted on inorganic acid or organic acid and formed by the present invention, such as acetic acid Salt, aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfuric acid Salt, camsilate, chloride/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, Gluconate, glucuronate, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, Lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoic acid Salt, naphthalene sulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid Hydrogen salt/dihydric phosphate, poly- galactolipin hydrochlorate, propionate, stearate, succinate, sulfosalicylate, tartrate, Toluene fulfonate and trifluoroacetate.
The inorganic acid of salt can be obtained by its derivative to be included such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.
The organic acid of salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, butanedioic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..
Pharmaceutically acceptable base addition salts can be disclosed compound and acted on inorganic base or organic base and formed by the present invention.
The inorganic base that salt can be obtained by its derivative includes, the metal of I races to the XII races of such as ammonium salt and periodic table. In some embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.
The organic base of salt can be obtained by its derivative includes primary amine, secondary amine and tertiary amine, and substituted amine includes naturally occurring Substituted amine, cyclic amine, deacidite etc..Some organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.
The officinal salt of the present invention can be synthesized with conventional chemical processes by parent compound, alkalescence or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate etc.) reaction, or by making the free alkali form and chemistry of these compounds It is prepared by the suitable acid reaction of metered amount.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, in appropriate cases, it is necessary to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. For example " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts：Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) in can find the list of the suitable salt of other.
In addition, compound disclosed by the invention including their salt, with their hydrate forms or can also include it The form of solvent (such as ethanol, DMSO, etc.) is obtained, for their crystallization.The present invention discloses compound can be with pharmacy Upper acceptable solvent (including water) inherently or by design forms solvate；Therefore, it is contemplated that including the present invention Open compound solvation and unsolvated form.
Any structural formula that the present invention is provided is also intended to expression these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the formula that there is the compound of isotope enrichment the present invention to provide is described, except one or many Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Include the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In there is radio isotope, such as3H、14C and18F those compounds, or wherein there is non radioactive isotope, such as2H and13C those compounds.The compound of such isotope enrichment can be used for metabolism research (to use14C), Reaction kinetics research (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including medicine or substrate group The single photon emission computed tomography (SPECT) of measure of spread is knitted, or available in the radiotherapy of patient.18The change of F enrichments Compound is especially desirable for PET or SPECT researchs.Compound shown in the formula (I) or formula (II) of isotope enrichment can be with It is suitable by being used described by the embodiment and preparation process in routine techniques or the present invention familiar to the person skilled in the art Isotope labeling reagent substitutes original used unmarked reagent to prepare.
In addition, higher isotope particularly deuterium is (i.e.,2H or D) substitution some treatment advantages can be provided, these advantages are Brought by metabolic stability is higher.For example, Half-life in vivo increase or volume requirements reduction or therapeutic index obtain improving band Come.It should be appreciated that the deuterium in the present invention is counted as the substituent of compound shown in formula formula (I) or formula (II).Same position can be used Plain enrichment factor defines the concentration of such higher isotope particularly deuterium.Term used in the present invention " isotope enrichment because Son " refers to the ratio between the isotope abundance and natural abundance of specified isotope.If the substituent of the compounds of this invention Deuterium is designated as, the compound has at least 3500 (52.5% deuteriums at each specified D-atom for each D-atom specified Incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% deuterium incorporations), At least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporations), at least The same position of 6466.7 (97% deuterium incorporations), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuterium incorporations) Plain enrichment factor.The pharmaceutically useful solvate of the present invention includes such as D that wherein recrystallisation solvent can be isotope substitution2O, third Ketone-d6、DMSO-d6Those solvates.
Pharmaceutical composition, preparation and the administration of the compounds of this invention
The present invention provides a kind of pharmaceutical composition, and it discloses listed chemical combination in compound, such as embodiment comprising the present invention Thing；With pharmaceutically acceptable excipient, carrier, adjuvant, solvent or combinations thereof.
Offer treatment of the invention, prevention improve the method for disease or illness, including give including originally for safe and effective amount The combination medicine of disclosure of the invention compound and one or more therapeutically active agents.Wherein, combination medicine comprising it is one or more its He prevents or treatment hyperuricemia, tophus, urarthritis, the nephropathy relevant with hyperuricemia and urolithiasis Medicine.
Other prevention or treatment hyperuricemias, tophus, urarthritis, the kidney barrier relevant with hyperuricemia The medicine with urolithiasis is hindered to include but is not limited to：Colchicin, NSAIDs, glucocorticoid, suppress uric acid generation medicine, Uricosureic agent, urine basifier or their any combination.
Described others treat hyperuricemias, tophus, urarthritis, the kidney relevant with hyperuricemia Obstacle and the medicine of urolithiasis are colchicin, Indomethacin, Etoricoxib, Diclofenac, brufen, rofecoxib, plug Former times cloth, Meloxicam, prednisone, butanedioic acid hydrogenation cortisone, Allopurinol, probenecid, sulfinpyrazone, Benzbromarone, former times difficult to understand are fast Alcohol, Febuxostat, recombined Aspergillus flavus bacteruria acid oxidase, Pegylation restructuring urate oxidase, Sodium Bicarbonate Tablets, citric acid Potassium sodium mixture or their any combination.
The amount of compound refers to energy effective detection to suppression biological specimen or patient in pharmaceutical composition disclosed by the invention The amount of internal lithate anion transport body.The dosage of active component can change in the present composition, still, active component Amount must can obtain the amount of appropriate dosage forms.Active component can deliver medicine to needs with the dosage for providing optimal drug effect The patient (animal and people) of this treatment.Selected dosage depends on desired therapeutic effect, depending on method of administration and controlling Treat the duration.Dosage will be different with patient, this attribute and the order of severity for depending on disease, the weight of patient, patient Specific diet, medicine used at the same time and it will be recognized by those skilled in the art other factorses.Dosage range is usually Each daily about 0.5mg to 1.0g of patient, can be administered in the form of single dose or multi-agent.In one embodiment, dosage range For the daily about 0.5mg to 500mg of each patient；It is in another embodiment the daily about 0.5mg to 200mg of each patient； It is each patient about 5mg to 50mg daily in still another embodiment.
It will also be appreciated that some compounds of the present invention can exist and for treating in a free form, or it is if suitable When can exist in the form of its pharmaceutically acceptable derivates.Pharmaceutically acceptable derivates include pharmaceutically acceptable Prodrug, salt, ester, the salt of these esters, or can directly or indirectly provide of the present inventionization when patient in need is administered Any other adduct or derivative of compound or its metabolite or residue.
Medicine disclosed by the invention or pharmaceutical composition can prepare and be packaged as (bulk) form in bulk, wherein extractable peace Compound shown in the formula (I) of full effective dose, then gives patient with powder or syrup form.Generally, arrived with daily 0.0001 Dosage level between 10mg/kg body weight is administered to obtain the antagonism effective to lithate anion transport body to patient. Or, pharmaceutical composition disclosed by the invention can prepare and be packaged as unit dosage forms, wherein each physically discrete unit contains There is the compound shown in the formula (I) of safe and effective amount.When being prepared with unit dosage forms, pharmaceutical composition disclosed by the invention is usual It can contain, for example, 0.5mg to 1g or 1mg to 700mg or 5mg to 100mg compound disclosed by the invention.
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 every kind of component Dosage.Generally, using every kind of 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, e.g., from 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 every kind of active component should be used.
" pharmaceutically acceptable excipient " means related to form of administration or pharmaceutical composition uniformity used in the present invention Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with pharmaceutical composition it is other into Split-phase is held, and the interaction of effect of the invention for disclosing compound can be substantially reduced during avoiding that patient is administered and can be caused not It is the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, every kind of excipient must be pharmaceutically acceptable, example Such as, with sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected specific formulation.In addition, can be according to them in group Specific function in compound selects pharmaceutically acceptable excipient.For example, may be selected to can help to produce equal one dosage type low temperature Some pharmaceutically acceptable excipient.The some pharmaceutically acceptable figurations that can help to produce stabilizer type may be selected Agent.May be selected to help to carry when patient be administered or transport it is of the invention disclose compound from an organ of body or partly to Another organ of body or partial some pharmaceutically acceptable excipient.Some medicines of enhancing patient compliance may be selected Acceptable excipient on.
Suitable pharmaceutically acceptable excipient includes following kind of excipient：Diluent, filler, adhesive, Disintegrant, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweetener, rectify Taste agent, odor mask, colouring agent, anticaking agent, NMF, chelating agent, plasticiser, tackifier, antioxidant, preservative, stably Agent, surfactant and buffer.Technical staff can be appreciated that some pharmaceutically acceptable excipient can provide more than one Function, and provide alternative function, this depends in preparation existing in how much excipient and preparation in the presence of those other Excipient.
Technical staff grasps the knowledge and skills of this area, so that they can select the suitable of the appropriate amount for the present invention Pharmaceutically acceptable excipient.Additionally, there are resource 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 is incorporated by reference into the present invention.Except any such as because producing any undesirable life Thing is acted on, or with interaction occurs for any other composition in harmful way and pharmaceutically acceptable composition and with the present invention Outside the incompatible any commonly employed carrier of open compound, pay close attention to its application and belong to the scope of the present invention.
Pharmaceutical composition disclosed by the invention is prepared using technology well known by persons skilled in the art and method.This area 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, assistant agent, solvent or combinations thereof, it is each that the technique includes mixing Plant composition.The pharmaceutical composition of compound is disclosed comprising the present invention, can mix to make under such as environment temperature and atmospheric pressure It is standby.
Compound disclosed by the invention is usually formulated as the formulation for being suitable for that patient is administered by required approach.Example Such as, formulation includes the formulation that those are suitable for following method of administration：(1) it is administered orally, such as tablet, capsule, caplet agent, ball Agent, containing tablet, pulvis, syrup, elixir, supensoid agent, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, supensoid agent and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) suck, such as aerosol, solution and dry powder doses；(6) it is local administration, such as cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gel.
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 formulation.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.
The pharmaceutical composition that the present invention is provided can with compressed tablets, develop piece, chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets are provided.Enteric coatel tablets are with the material bag for being resistant to hydrochloric acid in gastric juice effect but dissolving or being disintegrated in intestines The compressed tablets of clothing, so as to prevent the sour environment of active ingredient contacts stomach.Enteric coating includes, but 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 is surrounded Piece, it can be beneficial to cover taste beastly or smell 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 material.Film coating includes, but not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses and sweet tablet identical general characteristic.It is multiple Tabletting is to pass through compressed tablets prepared by more than one press cycles, including multilayer tablet and pressed coated or dry coating tablet.
Tabules can be by one kind for individually or with the present invention being described in powder, crystallization or granular active component Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrant, controlled release polymer, profit Lubrication prescription, diluent and/or colouring agent.Fumet and sweetener are particularly useful when forming chewable tablets and lozenge.
The pharmaceutical composition that the present invention is provided can be provided with soft capsule or hard shell capsules, and it can be fine by gelatin, methyl Element, starch or calcium alginate is tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is constituted by two sections, one section Fill in another section, therefore enclose active component completely.Soft elastic capsules (SEC) are soft, spherical shell, such as gelatin shell, It is plastified by adding glycerine, sorbierite or similar polyalcohol.Soft gelatin shell can include the pre- preventing microorganism life of preservative It is long.Suitable preservative for as described in the present invention those, including methyl hydroxybenzoate and propylben, and sorbic acid.This Inventing the liquid provided, semi-solid and solid dosage forms can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution and supensoid agent in propene carbonate, vegetable oil or triglycerides.Capsule comprising 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 Coating as is known to persons skilled in the art is used, so as to improve or maintain the dissolution of active component.
The pharmaceutical composition that the present invention is provided 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 another liquid in pellet form, It can be oil-in-water type or water-in-oil type.Emulsion can include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifying agent and Preservative.Supensoid agent can include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions can include pharmaceutically may be used Two (low alkyl group) acetals of the acetal of receiving, such as low alkyl group aldehyde, such as acetaldehyde diethyl acetal；With with one or many The water-soluble solvent of individual hydroxyl, such as propane diols and ethanol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and preservative can also be included.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 the active component provided comprising the present invention and two grades Change those formulations of list-or poly- alkylene glycol, the list-or poly- alkylene glycol include：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 mean molecule quantity 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, monoethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbierite, phosphoric acid, bisulfites, Jiao Sodium sulfite, thio-2 acid and its ester and dithiocarbamate.
Where appropriate, can be by the dosage unit preparations microencapsulation of oral administration.It can also be prepared into extending or tieing up The composition of release is held, such as by the way that microparticle material to be coated or be embedded in polymer, wax or the like.
The combination of oral medication that the present invention is provided can also be carried in the form of liposome, micella, microballoon or nanometer system For.It is prepared by method that micella formulation can be described with U.S.Pat.No.6,350,458.
The pharmaceutical composition that the present invention is provided 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 can include dilution Agent, sweetener and wetting agent.The pharmaceutically acceptable carrier and excipient used in effervescent or pulvis can be wrapped Include organic acid and carbon dioxide source.
Colouring agent and flavor enhancement can be used in all above-mentioned formulations.
Compound disclosed in this invention can also be combined with as the soluble polymer of 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 with reality The class Biodegradable polymeric used in the control release of existing medicine is combined, for example, PLA, poly-epsilon-caprolactone, poly- Hydroxybutyric acid, poe, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and the crosslinking of hydrogel or amphiphilic block are common Polymers.
The pharmaceutical composition that the present invention is provided can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
The pharmaceutical composition that the present invention is provided can with will not to damage other active components of expected therapeutic action common Prepare, or the material co-formulation with the expected effect of supplement.
The pharmaceutical composition that the present invention is provided can be by injection, infusion or implantation parenteral, for local or complete Body is administered.As the parenteral that uses of the present invention include intravenous, intra-arterial, intraperitoneal, intrathecal, intra-ventricle, in urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical composition that the present invention is provided can be configured to any formulation suitable for parenteral, 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 formulation can according to known to the technical staff in pharmaceutical science field conventional method preparing (referring to Remington:The Science and Practice of Pharmacy, ibid).
Be intended for the pharmaceutical composition of parenteral can include one or more pharmaceutically acceptable carriers and Excipient, includes, but not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life The preservative of thing growth, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and scattered Agent, wetting agent or emulsifying agent, 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, salt solution, physiological saline or phosphate buffered saline (PBS) (PBS), Sodium chloride injection, Ringers parenteral solutions, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers parenteral solutions.Non- transporter includes, but not limited to fixed oil, castor oil, corn oil, the cottonseed of plant origin Oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soya-bean oil, hydrogenated vegetable oil, the middle chain of hydrogenated soybean oil and coconut oil Triglycerides and palm seed oil.Water miscibility carrier includes, but not limited to the poly- second two of ethanol, 1,3-BDO, liquid Alcohol (such as Liquid Macrogol and polyethylene glycol 400), propane diols, glycerine, METHYLPYRROLIDONE, N, N- dimethylacetamides Amine and dimethyl sulfoxide.
Suitable antimicrobial or preservative include, but not limited to phenol, cresols, mercurial, phenmethylol, 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 not limited to sodium chloride, glycerine and glucose.Suitable buffer Include, but not limited to phosphate and citrate.Suitable antioxidant is including the sulfurous acid as being described the present invention Hydrogen salt and sodium metabisulfite.Suitable local anesthetic includes, but are not limited to procaine hydrochloride.Suitable suspending agent and point Powder is including sodium carboxymethylcellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone as being described the present invention. Suitable emulsifying agent includes those that the present invention is described, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene is moved 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 does not limit In cyclodextrin, including alpha-cyclodextrin, beta-schardinger dextrin, hydroxypropyl-β-cyclodextrin, Sulfobutylether-beta-schardinger dextrin and sulfobutyl group Ether 7- beta-schardinger dextrins (CyDex,Lenexa,KS)。
The pharmaceutical composition that the present invention is provided can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multiple dose parenteral administration must include antibacterial or fungistatic concentrations anti-micro- Biological agent.All parenteral administrations all must be sterile, as known in the art with practice.
In one embodiment, pharmaceutical composition is provided with instant sterile solution.In another embodiment, medicine Composition is provided with sterile dried soluble product, including freeze-dried powder and hypodermic tablet, and it is using preceding using carrier Reconstruct.In yet another embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In yet another embodiment, medicine The sterile dry insolubility product that compositions are reconstructed before being formulated into use with carrier.Also in one embodiment, Pharmaceutical composition is formulated into instant without bacterial emulsion.
Pharmaceutical composition can be configured to supensoid agent, solid, semisolid or thixotropic liquid, the reservoir administration as implantation. In one embodiment, pharmaceutical composition disclosed in this invention is dispersed in solid interior matrix, its be insoluble to body fluid but The outside polymeric membrane for allowing the active component in pharmaceutical composition to diffuse through is surrounded.
Suitable internal matrix include polymethyl methacrylate, poly- butyl methacrylate, plasticising or it is unplasticizied Polyvinyl chloride, plasticising nylon, plasticising PET, plasticising polyethylene terephthalate, natural rubber, Polyisoprene, polyisobutene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, poly- diformazan silica Alkane, silicone carbonate copolymer, the hydrogel of the 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 outside polymeric membrane includes polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate copolymerization Thing, ethylene/vinyl acetate copolymer, silicone rubber, dimethyl silicone polymer, neoprene, haloflex, polychlorostyrene second Alkene, the copolymer of ethlyene dichloride and vinyl acetate, vinylidene chloride, ethene 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 to any dose to patient's inhalation Type, such as dry powder doses, aerosol, supensoid agent or liquid composite.In one embodiment, drug regimen disclosed in this invention Thing can be configured to be suitable to formulation of the dry powder doses to patient's inhalation.In yet another embodiment, it is disclosed in this invention Pharmaceutical composition can be configured to be suitable to the formulation 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.The pharmaceutically acceptable excipient for being especially suitable for use as dry powder doses is known to those skilled in the art Dawn, it includes lactose, starch, mannitol and single-, two- and polysaccharide.Fine powder can be prepared for example, by being micronized and grinding Obtain.In general, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D50Value is (for example, with sharp The measurement of optical diffraction method) define.
Aerosol can be prepared by the way that compound disclosed in this invention is suspended or dissolved in liquefied propellant.It is adapted to Propellant include chlorohydrocarbon, hydro carbons and other liquid gas.Representational propellant includes：Arcton 11 (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), HFC-134a (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.Aerosol comprising compound disclosed in this invention generally passes through Patient is administered metered dose inhaler (MDI).Such device dawn known to those skilled in the art
Aerosol can include pharmaceutically acceptable excipient that is extra, 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 paster agent can be prepared into 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 paster agent can be permeated by ion, such as General description in Pharmaceutical Research, 3 (6), 318 (1986).
Be suitable for the pharmaceutical composition of local administration can be formulated into ointment, cream, supensoid agent, lotion, pulvis, Solution, paste, gel, spray, aerosol or finish.For example, ointment, cream and gel can use water or oil Matrix, and suitable thickener and/or gel and/or solvent are configured.Such matrix can 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 gel 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 be prepared with water or oil matrix, and generally also contained one or more emulsifying agents, stabilizer, disperseed Agent, suspending agent or thickener.
Externally-applied powder can be molded in the presence of arbitrarily suitable powder matrix such as talcum powder, lactose or starch.Drops It can be formulated with water or non-aqueous matrix comprising one or more dispersants, solubilizer, suspending agent or preservative.
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 Used.Adhesiveness store system can realize continuous or extension administration.
The purposes of the compounds of this invention and composition
Compound or pharmaceutical composition disclosed in this invention can be used for prepare be used for treat, prevent, improving, controlling or Mitigate mammal, including it is the treatment hyperuricemia of the mankind, tophus, urarthritis, relevant with hyperuricemia The medicine of nephropathy and urolithiasis, can be used for preparing other medicines for being used for suppressing lithate anion transport body.
Specifically, the amount of compound effectively can detectably suppress uric acid salt anionic in composition of the invention Transporter, compound of the invention can as prevent or treatment mankind hyperuricemia, tophus, urarthritis, with The medicine of the relevant nephropathy of hyperuricemia and urolithiasis.
The compound or composition of the present invention can apply to, but be not limited to, compound or combination using the present invention Mammal is prevented patient's administration, treats or mitigated to the effective dose of thing, includes hyperuricemia, tophus, the pain of the mankind Wind arthritis, the nephropathy relevant with hyperuricemia and urolithiasis.
The compound and pharmaceutical composition of the present invention applies also for veterinary treatment and doted in addition to beneficial to human treatment Mammal in the animal of thing, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat. This, compound of the invention includes its pharmaceutically acceptable derivates.
General synthesis step
For the description present invention, embodiment is listed below.But it is to be understood that the invention is not restricted to these embodiments, simply The method that the practice present invention is provided.
Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent such as formula (I).Following reaction scheme and embodiment are used to this is further illustrated The content of invention.
The professional of art will be recognized that：Chemical reaction described in the invention can be for suitably preparing perhaps Other compounds of many present invention, and be considered as preparing other methods of compound of the invention in model of the 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 Completed by method of modifying, such as appropriate protection interference group, by using other known reagent except 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 applied to 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 business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all not by being further purified when using, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Teng Long chemical reagent Co., Ltd, and Haiyang Chemical Plant, Qingdao's purchase It can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether is dried to obtain by metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMA and N, N- Dimethylformamide is that drying is used in advance through anhydrous sodium sulfate.
Reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects below Show), reaction bulb all suitable rubber stoppers beyond the Great Wall, substrate is squeezed into by syringe.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 spectrometer, with CDC13、DMSO-d6、 CD3OD or acetone-d6For solvent (in units of ppm), reference standard is used as with TMS (0ppm) or chloroform (7.26ppm).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 represented with hertz (Hz).
The condition determination of Algorithm (MS) data is：Level Four bar HPLC-M (the pillar models of Agilent 6120： Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Mobile phase：5%-95% (contains 0.1% The CH of formic acid3CN) (H of 0.1% formic acid is being contained2O the ratio in)), using electron spray ionisation (ESI), under 210nm/254nm, Detected with UV.
Compound purity is determined using high performance liquid chromatography (HPLC), uses Agilent 1260HPLC (pillar models： Agilent zorbax Eclipse Plus C18), and detected with DAD detectors, it is final to be calculated using area normalization method To compound purity.
The use of brief word below is through the present invention：
CDC13Deuterochloroform；
DMSO-d6Deuterated dimethyl sulfoxide；
G grams
H hours
Min minutes
Mmol mMs
DEG C degree Celsius
MeCN、CH3CN acetonitriles
MeOH methanol
ML, ml milliliters
RT, rt, r.t. room temperature
Rpm rpms
Rt retention times
Prepare the present invention and disclose the typical synthesis step of compound as shown in following synthetic schemes.Unless otherwise indicated, A、B、R、L、L0, each R1、R2, each R3, m and n there is definition as described in the present invention.
Synthetic schemes 1
Compound (6) can be prepared by following process：
Compound (1) obtains compound (2) by bromo-reaction, and subsequent compound (2) obtains with compound (3) reaction cyclization To compound (4), final compound (4) occurs substitution reaction with compound (5) and obtains compound (6).
Synthetic schemes 2
Compound (6a) can be prepared by following process：
Compound (4a) occurs substitution reaction with the compound (5a) that different substituents replace and obtains compound (6a).
The following examples can be so that the present invention will be further described, however, these embodiments should not be used as to this hair The limitation of bright scope.
Embodiment
Embodiment 1:2- (5- chlorothiophene -2- sulfoamidos) -4- cyclopropyl thiazole -5- methyl formates
By 2- amino -4- cyclopropyl thiazole -5- methyl formates (1.98g, 10mmol), pyridine (7.9g, 100mmol) and two Chloromethanes (20mL) is added in 100mL single port bottles, and 5- chlorothiophene -2- sulfonic acid chlorides (2.39g, 11mmol) are added into reaction bulb, 12h is stirred at room temperature in reactant mixture.Reaction solution is concentrated under reduced pressure, residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v) title compound (white solid, 0.80g, 21%)=1/1) is obtained after purification.
MS(ES-API,pos.ion)m/z:379.0[M+1]；
1H NMR(400MHz,CDCl3)δ7.47(s,1H),6.89(s,1H),3.88(s,3H),3.03–2.92(m,1H), 1.22–1.20(m,2H),1.02–1.00(m,2H)。
Embodiment 2:2- (3- cvanobenzenesulfonamides base) -4- cyclopropyl thiazole -5- methyl formates
By 2- amino -4- cyclopropyl thiazole -5- methyl formates (1.98g, 10mmol), pyridine (7.9g, 100mmol) and two Chloromethanes (20mL) is added in 100mL single port bottles, and 3- cyanobenzenesulfonyl chlorides (2.22g, 11mmol), reaction are added into reaction bulb 12h is stirred at room temperature in mixture.Reaction solution is concentrated under reduced pressure, residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/ V)=title compound (white solid, 0.55g, 15%) 1/1) is obtained after purification.
MS(ES-API,pos.ion)m/z:364.0[M+1]；
1H NMR(400MHz,CDCl3) δ 8.21-8.19 (m, 2H), 7.84 (d, J=7.5Hz, 1H), 7.64 (t, J= 7.7Hz,1H),3.89(s,3H),3.06–2.94(m,1H),1.24–1.22(m,2H),1.02–1.00(m,2H)。
Embodiment 3:4- cyclopropyl -2- (4- fluorobenzenesulfonamides base) thiazole -5- methyl formates
By 2- amino -4- cyclopropyl thiazole -5- methyl formates (1.98g, 10mmol), pyridine (7.9g, 100mmol) and two Chloromethanes (20mL) is added in 100mL single port bottles, and 4- fluorophenylsulfonyl chlorides (2.14g, 11mmol) are added into reaction bulb, and reaction is mixed 12h is stirred at room temperature in compound.Reaction solution is concentrated under reduced pressure, residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =title compound (white solid, 1.64g, 46%) 1/1) is obtained after purification.
MS(ES-API,pos.ion)m/z:357.0[M+1]；
1H NMR(400MHz,CDCl3)δ9.42(s,1H),7.96–7.92(m,2H),7.14–7.10(m,2H),3.85 (s,3H),2.97–2.90(m,1H),1.20–1.15(m,2H),0.98–0.94(m,2H)。
Embodiment 4:4- Cvclopropvlmethvls -2- (4- Methyl benzenesulfonyls amido) thiazole -5- methyl formates
The bromo- 4- cyclopropyl -3- oxobutyrates of first step 2-
By 4- cyclopropyl -3- oxobutyrates (3.12g, 20mmol), magnesium perchlorate (1.34g, 6.0mmol) and acetic acid Ethyl ester (50mL) is added in 100mL single port bottles, and reactant mixture is stirred at room temperature after 0.1h, is added in batches into reaction bulb N- bromo-succinimides (3.93g, 22mmol), after adding, 12h is stirred at room temperature in reactant mixture.Add into reaction bulb Enter frozen water (100mL), aqueous phase merges organic phase with ethyl acetate (60mL × 2), organic phase is with saturated aqueous common salt (60mL × 2) Washing, anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure.Residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/ 10) title compound (pale yellowish oil liquid, 4.28g, 91%) is obtained after purification.
MS(ES-API,pos.ion)m/z:236.0[M+2]。
Second step 2- amino -4- Cvclopropvlmethvl thiazole -5- methyl formates
By the bromo- 4- cyclopropyl -3- oxobutyrates (2.35g, 10mmol) of 2-, thiocarbamide (0.84g, 11mmol), carbonic acid Hydrogen sodium (1.68g, 20mmol) and ethanol (80mL) are added in 250mL single port bottles, and reactant mixture stirs 2.5h at 80 DEG C. Reactant mixture is cooled to room temperature, filtered, filtrate decompression concentration.Residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v) title compound (light yellow solid, 1.27g, 60%)=1/4), is obtained after purification.
MS(ES-API,pos.ion)m/z:213.1[M+1]。
3rd step 4- Cvclopropvlmethvls -2- (4- Methyl benzenesulfonyls amido) thiazole -5- methyl formates
By 2- amino -4- cyclopropyl thiazole -5- methyl formates (2.12g, 10mmol), pyridine (7.9g, 100mmol) and two Chloromethanes (20mL) is added in 100mL single port bottles, and 4- toluene sulfonyl chlorides (2.10g, 11mmol), reaction are added into reaction bulb 12h is stirred at room temperature in mixture.Reaction solution is concentrated under reduced pressure, residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/ V)=title compound (white solid, 2.38g, 65%) 1/1) is obtained after purification.
MS(ES-API,pos.ion)m/z:367.1[M+1]；
1H NMR(400MHz,CDCl3) δ 7.84 (d, J=8.1Hz, 2H), 7.29 (d, J=3.2Hz, 2H), 3.85 (s, 3H), 2.96 (d, J=7.2Hz, 2H), 2.43 (s, 3H), 1.03-1.01 (m, 1H), 0.61-0.59 (m, 2H), 0.34-0.32 (m,2H)。
Embodiment 5:4- cyclopropyl -2- (4- fluorobenzene cyclic amides base) thiazole -5- methyl formates
By 2- amino -4- cyclopropyl thiazole -5- methyl formates (1.98g, 10mmol), pyridine (7.9g, 100mmol) and two Chloromethanes (20mL) is added in 100mL single port bottles, and 2- naphthalene sulfonyl chlorides (2.49g, 11mmol), reaction mixing are added into reaction bulb 12h is stirred at room temperature in thing.Reaction solution is concentrated under reduced pressure, residue through silica gel column chromatography (ethyl acetate/petroleum ether (v/v)= 1/1) title compound (white solid, 2.06g, 53%) is obtained after purification.
MS(ES-API,pos.ion)m/z:389.1[M+1]；
1H NMR(400MHz,DMSO-d6) δ 8.50 (s, 1H), 8.20 (d, J=7.6Hz, 1H), 8.10 (d, J=8.7Hz, 1H), 8.02 (d, J=7.7Hz, 1H), 7.84-7.81 (m, 1H), 7.73-7.61 (m, 2H), 3.78 (s, 3H), 2.96-2.77 (m,1H),1.07–1.01(m,4H)。
Embodiment 6:4- cyclopropyl -2- (4- fluorobenzene cyclic amides base) thiazole -5- Ethyl formates
By 2- amino-4-phenyl thiazole -5- Ethyl formates (2.48g, 10mmol), pyridine (7.9g, 100mmol) and dichloro Methane (20mL) is added in 100mL single port bottles, and 4- toluene sulfonyl chlorides (2.10g, 11mmol) are added into reaction bulb, and reaction is mixed 12h is stirred at room temperature in compound.Reaction solution is concentrated under reduced pressure, residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =title compound (white solid, 1.37g, 34%) 1/1) is obtained after purification.
MS(ES-API,pos.ion)m/z:403.1[M+1]；
1H NMR(400MHz,CDCl3) δ 9.40 (s, 1H), 7.84 (d, J=8.3Hz, 2H), 7.58-7.37 (m, 5H), 7.28 (s, 1H), 4.22 (q, J=7.1Hz, 2H), 2.41 (s, 3H), 1.25 (t, J=7.1Hz, 3H).
Embodiment 7:4- cyclohexyl -2- (4- Methyl benzenesulfonyls amido) thiazole -5- Ethyl formates
The bromo- 3- cyclohexyl -3- oxopropanoates of first step 2-
By 3- cyclohexyl -3- oxopropanoates (3.97g, 20mmol), magnesium perchlorate (1.34g, 6.0mmol) and acetic acid Ethyl ester (50mL) is added in 100mL single port bottles, and reactant mixture is stirred at room temperature after 0.1h, is added in batches into reaction bulb N- bromo-succinimides (3.93g, 22mmol), after adding, 12h is stirred at room temperature in reactant mixture.Add into reaction bulb Enter frozen water (100mL), aqueous phase merges organic phase with ethyl acetate (60mL × 2), organic phase is with saturated aqueous common salt (60mL × 2) Washing, anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure.Residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/ 50) title compound (light yellow solid, 4.49g, 81%) is obtained after purification.
MS(ES-API,pos.ion)m/z:278.0[M+2]。
Second step 2- amino -4- cyclohexyl thiazole -5- Ethyl formates
By the bromo- 3- cyclohexyl -3- oxopropanoates (2.77g, 10mmol) of 2-, thiocarbamide (0.84g, 11mmol), carbonic acid Hydrogen sodium (1.68g, 20mmol) and ethanol (80mL) are added in 250mL single port bottles, and reactant mixture stirs 2.5h at 80 DEG C. Reactant mixture is cooled to room temperature, filtered, filtrate decompression concentration.Residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v) title compound (light yellow solid, 0.53g, 21%)=1/2), is obtained after purification.
MS(ES-API,pos.ion)m/z:255.1[M+1]。
3rd step 4- cyclohexyl -2- (4- Methyl benzenesulfonyls amido) thiazole -5- Ethyl formates
By 2- amino -4- cyclohexyl thiazole -5- Ethyl formates (2.54g, 10mmol), pyridine (7.9g, 100mmol) and two Chloromethanes (20mL) is added in 100mL single port bottles, and 4- toluene sulfonyl chlorides (2.10g, 11mmol), reaction are added into reaction bulb 12h is stirred at room temperature in mixture.Reaction solution is concentrated under reduced pressure, residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/ V)=title compound (white solid, 1.80g, 44%) 1/1) is obtained after purification.
MS(ES-API,pos.ion)m/z:409.1[M+1]；
1H NMR(400MHz,CDCl3) δ 7.87 (d, J=8.2Hz, 2H), 7.26 (d, J=8.0Hz, 2H), 4.30 (q, J =7.1Hz, 2H), 3.67-3.63 (m, 1H), 2.41 (s, 3H), 1.80-1.76 (m, 5H), 1.49-1.29 (m, 8H).
Embodiment 8:2- (4- aminomethyl phenyls sulfoamido) -4- (thiophene -2- bases) thiazole -5- Ethyl formates
First step 2- amino -4- (thiophene -2- bases) thiazole -5- Ethyl formates
By 3- oxos -3- (thiophene -2- bases)-ethyl propionate (1.98g, 10mmol), elemental iodine (2.79g, 11mmol), oxygen Change copper (0.875g, 11mmol) and ethanol (40mL) is added in 100mL single port bottles, reactant mixture is stirred at 90 DEG C 8.0h.Then thiocarbamide (0.76g, 10mmol) is added into reaction bulb, reaction system is stirred overnight at 90 DEG C.By reaction mixing Thing is cooled to room temperature, and reaction solution is concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (100mL), aqueous phase second are added into residue Acetoacetic ester (60mL × 2), merges organic phase, and organic phase is washed with saturated aqueous common salt (60mL × 2), anhydrous sodium sulfate drying, mistake Filter, is concentrated under reduced pressure.Residue obtains titled after purification through silica gel column chromatography (ethyl acetate/dichloromethane (v/v)=1/50) Compound (white solid, 0.31g, 12%).
MS(ES-API,pos.ion)m/z:255.0[M+1]。
Second step 2- (4- aminomethyl phenyls sulfoamido) -4- (thiophene -2- bases) thiazole -5- Ethyl formates
By 2- amino -4- (thiophene -2- bases) thiazole -5- Ethyl formates (2.54g, 10mmol), pyridine (7.9g, 100mmol) added with dichloromethane (20mL) in 100mL single port bottles, added into reaction bulb 4- toluene sulfonyl chlorides (2.10g, 11mmol), 12h is stirred at room temperature in reactant mixture.Reaction solution is concentrated under reduced pressure, residue is through silica gel column chromatography (acetic acid second Ester/petroleum ether (v/v)=1/1) title compound (white solid 1.39g, 34%) is obtained after purification.
MS(ES-API,pos.ion)m/z:409.0[M+1]；
1H NMR(400MHz,CDCl3) δ 7.85 (d, J=8.1Hz, 2H), 7.76 (d, J=3.4Hz, 1H), 7.50 (d, J =4.9Hz, 1H), 7.25 (s, 2H), 7.13-7.05 (m, 1H), 4.31 (q, J=7.1Hz, 2H), 2.40 (s, 3H), 1.34 (t, J=7.1Hz, 3H).
Embodiment 9:2- (4- acetylphenyls sulfoamido) -4- cyclopropyl thiazole -5- methyl formates
By 2- amino -4- cyclopropyl thiazole -5- methyl formates (1.98g, 10mmol), pyridine (7.9g, 100mmol) and two Chloromethanes (20mL) is added in 100mL single port bottles, 4- acetylbenzenesulfonyl chlorides (2.41g, 11mmol) is added into reaction bulb, instead Answer mixture that 12h is stirred at room temperature.Reaction solution is concentrated under reduced pressure, residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v) title compound (white solid, 1.98g, 52%)=1/1) is obtained after purification.
MS(ES-API,pos.ion)m/z:381.0[M+1]；
1H NMR(400MHz,DMSO-d6) δ 8.11 (d, J=8.5Hz, 2H), 7.95 (d, J=8.4Hz, 2H), 3.79 (s, 3H),2.97–2.90(m,1H),2.62(s,3H),1.20–1.15(m,2H),0.98–0.94(m,2H)。
Embodiment 10:2- ([1,1'- xenyls] -4- bases sulfoamido) -4- cyclopropyl thiazole -5- methyl formates
By 2- amino -4- cyclopropyl thiazole -5- methyl formates (1.98g, 10mmol), pyridine (7.9g, 100mmol) and two Chloromethanes (20mL) is added in 100mL single port bottles, and 4- phenylbenzene sulfonyl chlorides (2.78g, 11mmol), reaction are added into reaction bulb 12h is stirred at room temperature in mixture.Reaction solution is concentrated under reduced pressure, residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/ V)=title compound (white solid, 2.82g, 68%) 1/1) is obtained after purification.
MS(ES-API,pos.ion)m/z:415.1[M+1]；
1H NMR(400MHz,CDCl3) δ 8.01 (d, J=8.4Hz, 2H), 7.65 (d, J=8.4Hz, 2H), 7.59-7.51 (m,2H),7.49–7.39(m,3H),3.87(s,3H),3.01–2.92(m,1H),1.21–1.16(m,2H),0.99–0.95 (m,2H)。
Embodiment 11:4- cyclopropyl -2- (4- Phenoxyphenyls sulfoamido) thiazole -5- methyl formates
First step 4- cyclopropyl -2- (4- Phenoxyphenyls sulfoamido) thiazole -5- methyl formates
By 2- amino -4- cyclopropyl thiazole -5- methyl formates (1.98g, 10mmol), pyridine (7.9g, 100mmol) and two Chloromethanes (20mL) is added in 100mL single port bottles, 4- phenoxyphenylsulfonyhalides chlorine (2.96g, 11mmol) is added into reaction bulb, instead Answer mixture that 12h is stirred at room temperature.Reaction solution is concentrated under reduced pressure, residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v) title compound (white solid, 3.23g, 75%)=1/2) is obtained after purification.
MS(ES-API,pos.ion)m/z:431.1[M+1]；
1H NMR(400MHz,CDCl3) δ 7.93-7.84 (m, 2H), 7.41 (t, J=7.9Hz, 2H), 7.22 (t, J= 7.4Hz, 1H), 7.07 (d, J=7.7Hz, 2H), 7.00 (t, J=5.8Hz, 2H), 3.87 (s, 3H), 3.01-2.92 (m, 1H), 1.21–1.16(m,2H),0.99–0.95(m,2H).Embodiment 12:4- cyclopropyl -2- (2- methoxyl group -4- aminomethyl phenyl sulphonyl Amido) thiazole -5- methyl formates
By 2- amino -4- cyclopropyl thiazole -5- methyl formates (1.98g, 10mmol), pyridine (7.9g, 100mmol) and two Chloromethanes (20mL) is added in 100mL single port bottles, added into reaction bulb 2- methoxyl group -4- toluene sulfonyl chlorides (2.43g, 11mmol), 12h is stirred at room temperature in reactant mixture.Reaction solution is concentrated under reduced pressure, residue is through silica gel column chromatography (acetic acid second Ester/petroleum ether (v/v)=1/2) title compound (white solid, 0.65g, 17%) is obtained after purification.
MS(ES-API,pos.ion)m/z:383.1[M+1]；
1H NMR(400MHz,CDCl3) δ 7.87 (d, J=8.0Hz, 1H), 6.86 (d, J=8.0Hz, 1H), 6.79 (s, 1H),3.86(s,3H),3.84(s,3H),3.01–2.92(m,1H),2.40(s,3H),1.21–1.16(m,2H),0.99– 0.95(m,2H)。
Embodiment 13:4- cyclopropyl -2- (2,3- dihydro -1H- indenes -5- sulfoamidos) thiazole -5- methyl formates
By 2- amino -4- cyclopropyl thiazole -5- methyl formates (1.98g, 10mmol), pyridine (7.9g, 100mmol) and two Chloromethanes (20mL) add 100mL single port bottles in, added into reaction bulb 2,3- dihydro -1H- indenes -5- sulfonic acid chlorides (2.38g, 11mmol), 12h is stirred at room temperature in reactant mixture.Reaction solution is concentrated under reduced pressure, residue is through silica gel column chromatography (acetic acid second Ester/petroleum ether (v/v)=1/2) title compound (white solid, 1.44g, 38%) is obtained after purification.
MS(ES-API,pos.ion)m/z:379.1[M+1]；
1H NMR(600MHz,DMSO-d6) δ 7.64 (s, 1H), 7.60 (d, J=7.8Hz, 1H), 7.39 (d, J=7.9Hz, 1H),3.78(s,3H),2.93–2.84(m,5H),2.10–2.00(m,2H),1.09–1.01(m,4H)。
Embodiment 14:4- cyclopropyl -2- (4- Methyl benzenesulfonyls amido) thiazole -5- methyl formates
The bromo- 3- cyclopropyl -3- propionic acid methyl esters of first step 2-
By 3- cyclopropyl -3- propionic acid methyl esters (2.84g, 20mmol), magnesium perchlorate (1.34g, 6.0mmol) and acetic acid Ethyl ester (50mL) is added in 100mL single port bottles, and reactant mixture is stirred at room temperature after 0.1h, is added in batches into reaction bulb N- bromo-succinimides (3.93g, 22mmol), after adding, 12h is stirred at room temperature in reactant mixture.Add into reaction bulb Enter frozen water (100mL), aqueous phase merges organic phase with ethyl acetate (60mL × 2), organic phase is with saturated aqueous common salt (60mL × 2) Washing, anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure.Residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/ 10) title compound (pale yellowish oil liquid, 3.98g, 90%) is obtained after purification.
MS(ES-API,pos.ion)m/z:222.0[M+2]。
Second step 2- amino -4- cyclopropyl thiazole -5- methyl formates
By the bromo- 3- cyclopropyl -3- propionic acid methyl esters (2.21g, 10mmol) of 2-, thiocarbamide (0.84g, 11mmol), carbonic acid Hydrogen sodium (1.68g, 20mmol) and ethanol (80mL) are added in 250mL single port bottles, and reactant mixture stirs 2.5h at 80 DEG C. Reactant mixture is cooled to room temperature, filtered, filtrate decompression concentration.Residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v) title compound (pale yellowish oil liquid, 1.31g, 66%)=1/2), is obtained after purification.
MS(ES-API,pos.ion)m/z:199.1[M+1]。
3rd step 4- cyclopropyl -2- (4- Methyl benzenesulfonyls amido) thiazole -5- methyl formates
By 2- amino -4- cyclopropyl thiazole -5- methyl formates (1.98g, 10mmol), pyridine (7.9g, 100mmol) and two Chloromethanes (20mL) is added in 100mL single port bottles, and 4- toluene sulfonyl chlorides (2.10g, 11mmol), reaction are added into reaction bulb 12h is stirred at room temperature in mixture.Reaction solution is concentrated under reduced pressure, residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/ V)=title compound (white solid, 2.29g, 65%) 1/1) is obtained after purification.
MS(ES-API,pos.ion)m/z:353.1[M+1]；
1H NMR(400MHz,CDCl3) δ 7.81 (d, J=8.2Hz, 2H), 7.24 (d, J=8.1Hz, 2H), 3.84 (s, 3H),2.99–2.87(m,1H),2.40(s,3H),1.19–1.11(m,2H),0.96–0.90(m,2H)。
Embodiment 15:4- cyclobutyl -2- (4- aminomethyl phenyls sulfoamido) thiazole -5- methyl formates
The bromo- 3- cyclobutyl -3- oxopropanoates of first step 2-
By 3- cyclobutyl -3- oxopropanoates (3.40g, 20mmol), magnesium perchlorate (1.34g, 6.0mmol) and acetic acid Ethyl ester (50mL) is added in 100mL single port bottles, and reactant mixture is stirred at room temperature after 0.1h, is added in batches into reaction bulb N- bromo-succinimides (3.93g, 22mmol), are added after finishing, 12h is stirred at room temperature in reactant mixture.Into reaction bulb Add frozen water (100mL), aqueous phase merges organic phase with ethyl acetate (60mL × 2), organic phase with saturated aqueous common salt (60mL × 2) wash, anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure.Residue through silica gel column chromatography (ethyl acetate/petroleum ether (v/v)= 1/20) title compound (light brown oily liquids, 4.88g, 98%) is obtained after purification.MS(ES-API,pos.ion)m/z: 250.0[M+2]。
Second step 2- amino -4- cyclobutyl thiazole -5- Ethyl formates
By the bromo- 3- cyclopropyl -3- propionic acid methyl esters (2.49g, 10mmol) of 2-, thiocarbamide (0.84g, 11mmol), carbonic acid Hydrogen sodium (1.68g, 20mmol) and ethanol (80mL) are added in 250mL single port bottles, and reactant mixture stirs 2.5h at 80 DEG C. Reactant mixture is cooled to room temperature, filtered, filtrate decompression concentration.Residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v) title compound (pale yellowish oil liquid, 2.10g, 93%)=1/2), is obtained after purification.
MS(ES-API,pos.ion)m/z:227.1[M+1]。
3rd step 4- cyclobutyl -2- (4- aminomethyl phenyls sulfoamido) thiazole -5- Ethyl formates
By 2- amino -4- cyclobutyl thiazole -5- Ethyl formates (2.26g, 10mmol), pyridine (7.9g, 100mmol) and two Chloromethanes (20mL) is added in 100mL single port bottles, and 4- toluene sulfonyl chlorides (2.10g, 11mmol), reaction are added into reaction bulb 12h is stirred at room temperature in mixture.Reaction solution is concentrated under reduced pressure, residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/ V)=title compound (white solid, 2.17g, 57%) 1/1) is obtained after purification.
MS(ES-API,pos.ion)m/z:381.0[M+1]；
1H NMR(600MHz,CDCl3) δ 7.85 (d, J=8.3Hz, 2H), 7.29 (d, J=8.2Hz, 2H), 4.38-4.31 (m, 1H), 4.27 (q, J=7.1Hz, 1H), 2.40 (s, 2H), 2.34-2.32 (m, 1H), 2.19-2.10 (m, 1H), 2.07- 2.02 (m, 1H), 1.94-1.84 (m, 1H), 1.33 (t, J=7.1Hz, 2H).
Embodiment 16:4- (1- methylcyclopropyl groups) -2- (4- aminomethyl phenyls sulfoamido) thiazole -5- methyl formates
The bromo- 3- of first step 2- (1- methylcyclopropyl groups) -3- propionic acid methyl esters
By 3- (1- methylcyclopropyl groups) -3- propionic acid methyl esters (3.12g, 20mmol), magnesium perchlorate (1.34g, 6.0mmol) added with ethyl acetate (50mL) in 100mL single port bottles, reactant mixture is stirred at room temperature after 0.1h, to reaction N- bromo-succinimides (3.93g, 22mmol) are added in batches in bottle, are added after finishing, reactant mixture is stirred at room temperature 12h.Frozen water (100mL) is added into reaction bulb, aqueous phase merges organic phase, organic phase saturation with ethyl acetate (60mL × 2) Saline solution (60mL × 2) is washed, anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure.Residue through silica gel column chromatography (ethyl acetate/ Petroleum ether (v/v)=1/20) title compound (pale yellowish oil liquid, 4.33g, 92%) is obtained after purification.
MS(ES-API,pos.ion)m/z:236.0[M+2]。
Second step 2- amino -4- (1- methylcyclopropyl groups) thiazole -5- methyl formates
By the bromo- 3- of 2- (1- methylcyclopropyl groups) -3- propionic acid methyl esters (2.35g, 10mmol), thiocarbamide (0.84g, 11mmol), sodium acid carbonate (1.68g, 20mmol) and ethanol (80mL) are added in 250mL single port bottles, and reactant mixture is 80 2.5h is stirred at DEG C.Reactant mixture is cooled to room temperature, filtered, filtrate decompression concentration.Residue is through silica gel column chromatography (acetic acid Ethyl ester/petroleum ether (v/v)=1/2), title compound (light yellow solid, 1.34g, 65%) is obtained after purification.
MS(ES-API,pos.ion)m/z:213.1[M+1]。
3rd step 4- (1- methylcyclopropyl groups) -2- (4- aminomethyl phenyls sulfoamido) thiazole -5- methyl formates
By 2- amino -4- (1- methylcyclopropyl groups) thiazole -5- methyl formates (2.12g, 10mmol), pyridine (7.9g, 100mmol) added with dichloromethane (20mL) in 100mL single port bottles, added into reaction bulb 4- toluene sulfonyl chlorides (2.10g, 11mmol), 12h is stirred at room temperature in reactant mixture.Reaction solution is concentrated under reduced pressure, residue is through silica gel column chromatography (acetic acid second Ester/petroleum ether (v/v)=1/1) title compound (white solid, 2.02g, 55%) is obtained after purification.
MS(ES-API,pos.ion)m/z:367.1[M+1]。
Biological activity test
Test example URAT1 (uric acid anion transport body) inhibitory activity is determined
1) test method
The structure of a.hURAT1 stable expression cell strains
By human URAT 1 plasmid transfection into HEK-293T cells, people is obtained using G418 (Geneticin, Geneticin) URAT1 stable expression cell strains.
B. uric acid, which absorbs, suppresses
Human URAT 1 expression cell is seeded in 96 orifice plates, culture medium is removed after being at least incubated 12h, and with (Cl-)- 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 The 5 μ L compound solutions and 45 μ L of above-mentioned preparation are contained [8- by compound solution14C] uric acid buffer solution mix after added to containing There is in 96 orifice plates of stable transfected cells (i.e. final compound concentration is 20 μM to 0.08nM), while setting buffering fluid apertures (transfection Cell, is added without medicine) and negative hole (non-transfected cell is added without medicine)；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 of supernatant liquid to Isoplate-96 microwell plates, and 150 μ L are added per hole Ultima GoldTMXR, and 600rpm shakes 10min.Use MicroBeta Trilux flickers/luminescence counter (PerkinElmer) count, read [8-14C] uric acid surplus, compound is calculated by following equation and suppresses [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 (%)=[1- (medicine holes14C 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) result of the test
The test result of the compounds of this invention URAT1 inhibitory activity of table 2
Numbering URAT1 IC50(μM)
Embodiment 1 0.222
Embodiment 2 0.138
Embodiment 4 0.135
Embodiment 6 0.085
Embodiment 14 0.025
Embodiment 15 0.288
Embodiment 16 0.108
Conclusion：The compounds of this invention has preferable inhibitory activity to URAT1.
Finally it should be noted that also other modes are used for implementing the present invention.Correspondingly, embodiments of the invention are It will illustratively illustrate, but be not limited to content described in the invention, it is also possible to be made 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, the stereoisomer of its compound shown in the compound or formula (I) shown in formula (I), geometrical isomerism Body, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or it before Medicine,
Wherein：
A rings are C6-10Aryl or C1-9Heteroaryl；
B rings are C3-6Cycloalkyl, C2-6Heterocyclic radical, C6-10Aryl or C1-6Heteroaryl；
L is key ,-O- or-NH-；
L0For key or-CH2-；
R is hydrogen, deuterium, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkoxy -C1-6Alkyl, C1-6Alkyl amino-C1-6Alkyl, C3-6Cycloalkyl, C2-9Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl or C6-10Aryl-C1-6Alkyl；Described C1-6Alkyl, C2-6Alkene Base, C2-6Alkynyl, C1-6Alkoxy -C1-6Alkyl, C1-6Alkyl amino-C1-6Alkyl, C3-6Cycloalkyl, C2-9Heterocyclic radical, C6-10Virtue Base, C1-9Heteroaryl and C6-10Aryl-C1-6Alkyl can further individually optionally by it is one or more selected from deuterium, oxo (=O), F, Cl, Br, I, hydroxyl, amino, the substituent of nitro and cyano group are replaced；
Each R1It independently is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano group, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Haloalkyl ,-OR4、-NR5R6、-L1- C (=O)-L2-R7、-L3- S (=O)t-L4-R8、C3-8Cycloalkyl, C2-9Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl-C1-6Alkyl or C1-9Heteroaryl-C1-6Alkyl, wherein R1Can optionally further by It is one or more to be selected from hydrogen, deuterium, oxo (=O), F, Cl, Br, I, hydroxyl, amino, nitro, cyano group, C1-6Alkyl, C1-6Alcoxyl Base, C1-6Haloalkyl, C1-6Halogenated alkoxy and C3-6The substituent of cycloalkyl is replaced；
R4、R5、R6、R7And R8It is each independently hydrogen, deuterium, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Haloalkyl, C3-8Ring Alkyl, C2-9Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl；
L1And L3It is each independently key ,-O- ,-NH- or C1-6Alkylidene；
L2And L4It is each independently key ,-O- ,-NR9- or C1-6Alkylidene；
R9For hydrogen, deuterium, C1-3Alkyl, C1-3Haloalkyl, C3-6Cycloalkyl, C2-6Heterocyclic radical, C6-10Aryl or C1-6Heteroaryl；
T is 0,1 or 2；
R2For hydrogen, deuterium, C1-3Alkyl, C1-3Haloalkyl or C3-6Cycloalkyl；
Each R3It independently is hydrogen, deuterium, oxo (=O), F, Cl, Br, I, hydroxyl, amino, nitro, cyano group or C1-3Alkyl；
M is 0,1,2,3,4 or 5；
N is 0,1,2 or 3；
Condition is, when B rings are phenyl, R1For methyl and m is that 1, L is-O- or-NH-.
2. compound according to claim 1, wherein, A rings are
Wherein,
X1For-O- ,-S- or-NH-；
Each X2、X3、X4And X5It independently is CH or N；
X6And X7It is each independently-O- ,-S- ,-NH- or-CH2-。
3. compound according to claim 1 or 2, wherein,
A rings are phenyl, naphthyl, 2,3- dihydro -1H- indenes, 1,2,3,4-tetralin base, furyl, pyrrole radicals, imidazole radicals, pyrrole Oxazolyl, thienyl, thiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl, oxadiazolyls, pyridine radicals, pyrimidine radicals, pyrazinyl, rattle away Piperazine base, indyl, quinolyl, 1H- benzimidazolyls, benzopyrazoles base, 1,4- benzdioxans base or 1,3- benzos two dislike cyclopentadienyl Alkyl.
4. compound according to claim 1, wherein,
B rings are cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, pyrrolidinyl, tetrahydrofuran base, piperidyl, piperazine Piperazine base, morpholinyl, pyrrole radicals, imidazole radicals, furyl, thienyl, thiazolyl, pyridine radicals, pyrimidine radicals, phenyl or naphthyl.
5. compound according to claim 1, wherein,
R is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, vinyl, pi-allyl, acetylene Base, propargyl, difluoromethyl, trifluoromethyl, the fluoro ethyls of 2,2- bis-, methyl epoxide methyl, ethyl epoxide methyl, ethyl epoxide second Base, acetyl group, Acetoxvethyl, acetamidoethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrole Cough up alkyl, piperidyl, piperazinyl, phenyl, naphthyl, benzyl, furyl, thienyl, pyridine radicals or pyrimidine radicals；
Each R1It independently is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano group, methyl, ethyl, n-propyl, isopropyl, just Butyl, isobutyl group, the tert-butyl group, vinyl, acetenyl, difluoromethyl, trifluoromethyl, methoxyl group, ethyoxyl, n-propyl epoxide, Isopropyl epoxide, normal-butyl epoxide, isobutyl group epoxide, tert-butyl group epoxide, phenoxy group, methylamino, ethylamino, isopropylamino, Dimethylamino, diethylamino, acetyl group, mesyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, Pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, furyl, pyrrole radicals, imidazole radicals, pyrazoles Base, thienyl, thiazolyl, oxazolyls, pyridine radicals, pyrimidine radicals, indyl, quinolyl, isoquinolyl, phenyl or naphthyl, wherein R1Optionally further hydrogen, deuterium, oxo (=O), F, Cl, Br, I, hydroxyl, amino, nitro, cyanogen can be selected from by one or more Base, C1-4Alkyl, C1-4Alkoxy, C1-4Haloalkyl, C1-4Halogenated alkoxy and C3-6The substituent of cycloalkyl is replaced.
6. compound according to claim 1, it is the compound as shown in formula (II), or the compound shown in formula (II) Stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically may be used The salt or prodrug of receiving,
7. compound according to claim 1, it is for the compound with one of following structural formula or with following structure The stereoisomer of the compound of one of formula, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, generation Product, ester, pharmaceutically acceptable salt or its prodrug are thanked,
8. a kind of pharmaceutical composition, it includes the compound described in claim 1-7 any one and pharmaceutically acceptable Excipient, carrier, adjuvant, solvent or combinations thereof.
9. pharmaceutical composition according to claim 8, it is further comprising other preventions or treatment hyperuricemia, gout Stone, urarthritis, the medicine of the nephropathy relevant with hyperuricemia and urolithiasis, the medicine be colchicin, NSAIDs, glucocorticoid, suppression uric acid generation medicine, uricosureic agent, urine basifier or their any combination.
10. the pharmaceutical composition described in compound or claim 8-9 any one described in claim 1-7 any one exists Prepare the purposes in medicine, the medicine is used to prevent or treat mammal, including the hyperuricemia of the mankind, tophus, Urarthritis, the nephropathy relevant with hyperuricemia and urolithiasis；
Or the medicine is used to reduce uric acid level in blood；
Or the medicine is used in study subject suppress lithate anion transport body.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111632146A (en) * 2020-05-29 2020-09-08 中山大学 Application of OAT inhibitor and oncolytic virus in preparation of antitumor drugs
CN111943957A (en) * 2019-05-17 2020-11-17 中国医学科学院药物研究所 Quinoline formamide compound and preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101208089A (en) * 2005-06-03 2008-06-25 泽农医药公司 Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
WO2008126731A1 (en) * 2007-04-05 2008-10-23 Daiichi Sankyo Company, Limited Aryl derivatives
WO2014170792A1 (en) * 2013-04-19 2014-10-23 Pfizer Limited Sulfonamide derivatives as urat-1 inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101208089A (en) * 2005-06-03 2008-06-25 泽农医药公司 Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
WO2008126731A1 (en) * 2007-04-05 2008-10-23 Daiichi Sankyo Company, Limited Aryl derivatives
WO2014170792A1 (en) * 2013-04-19 2014-10-23 Pfizer Limited Sulfonamide derivatives as urat-1 inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HANIA SHAHID 等: "Investigational drugs for hyperuricemia", 《EXPERT OPINION ON INVESTIGATIONAL DRUGS》 *
吴新荣 等: "抗高尿酸血症药物作用靶点研究进展", 《中国药理学通报》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111943957A (en) * 2019-05-17 2020-11-17 中国医学科学院药物研究所 Quinoline formamide compound and preparation method and application thereof
CN111632146A (en) * 2020-05-29 2020-09-08 中山大学 Application of OAT inhibitor and oncolytic virus in preparation of antitumor drugs
CN111632146B (en) * 2020-05-29 2021-09-28 中山大学 Application of OAT inhibitor and oncolytic virus in preparation of antitumor drugs

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