CN106008488A - Cyan indoles derivative and preparation method and use thereof - Google Patents

Cyan indoles derivative and preparation method and use thereof Download PDF

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

Abstract

The invention relates to a cyan indoles derivative and a pharmaceutical composition containing the compound. The compound or the pharmaceutical composition can be used for inhibiting activity of xanthine oxidase and/or urate anion transporter-1. The invention further relates to a method for preparing the compound and the pharmaceutical composition, and use of the compound and the pharmaceutical composition in treatment or prevention of diseases, which are related to relatively high uric acid value in blood, of mammals, particularly human beings.

Description

Cyanoindole analog derivative and its production and use
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to a compounds, the pharmaceutical composition comprising described compound, And their preparation method and purposes, wherein said compound or pharmaceutical composition have suppression xanthine oxidase and/or The purposes of urate anion transport body-1 activity, and can be used for prevention or treatment and the higher relevant disease of uric acid level in blood.
Background technology
Uric acid is the end metabolite eventually of mankind's purine compound.In human body, uric acid is mainly through renal excretion, and it is drained Amount accounts for nearly 2/3rds of total excretion.When uric acid produces too much or acatharsia, uric acid accumulation is made to cause in blood in human body in Uric acid concentration raises, and then causes hyperuricemia.Under normal purine diet state, non-twice fasting blood uric acid level on the same day Male is higher than 420 μm ol/L, and women is higher than 360 μm ol/L, is hyperuricemia.Hyperuricemia can be categorized as (1) uric acid Generating many types of, (2) urate excretion not good figure and (3) mixed type, this type of classification diagnosis contributes to finding the disease of hyperuricemia Cause also gives immunotherapy targeted autoantibody.
Along with uric acid concentration supersaturation in blood, uric acid sodium salt initially forms crystallization and is deposited on synovium of joint, synovial bursa, cartilage And in hetero-organization, when internal uric acid level generation Rapid Variable Design, local wound cause tiny crystals release or urate crystals 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 the formation of acute attack arthritis, tophus, tophaceous chronic arthritis, uric acid Salt nephropathy and uric acid lithangiuria, severe one may occur in which joint deformity and renal insufficiency.Additionally, gout also with hypertension, generation Thank to relevant (the Terkeltaub RA.Clinical of various disease conditions such as syndrome, hyperlipemia, diabetes and insulin resistant 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 the serious metabolic diseases of harm human health；There is data to suggest that, about 5%- The Patients with Hyperuricemia of 12% finally develops into gout.Uric acid is hyperuricemia and the material base of gout generation, therefore, Reduce uric acid concentration in blood and can be used for preventing or treating hyperuricemia and gout, and reduction is suffered from other hyperuricemias and leads to The risk of wind complication.
At present, the medicine reducing uric acid level has suppression uricopoiesis medicine and uricosuric drug.
Uric acid is derived from diet and takes in and the purine bodies of endogenous synthesis, and it is finally to aoxidize xanthine by xanthine oxidase And generate.So xanthine oxidase (Oxanthine oxidase) is considered an important target of suppression uricopoiesis medicine Point.The other purine of existing uricopoiesis depressant is in the news the various diseases that can effectively treat hyperuricemia and be induced by.
On the other hand, the hyperuricemia of about 90% is to be caused by underexcretion, and uric acid is main in the excretion of kidney Including 4 processes: the heavily absorption of the filtration of glomerule, renal tubules and collecting tubule, renal tubules and collecting tubule are secreted and after secretion Heavily absorption, each process is to have been participated in by corresponding albumen, and the most only the uric acid of 8%-12% excretes (Liu Ruo Rosy clouds, Zang Luping, Wu Xinrong, Shandong medicine [J], the 28th phase of volume 52 in 2012).Urate anion transport body-1 (URAT1) It is to be positioned at proximal tubular cell brush border side by what Enomoto etc. found, participates in the uric acid heavily suction at kidney proximal tubule A kind of transmembrane transporter received.Mankind URAT1 (hURAT1), by the SLC22A12 gene code on Chromosome 11q13, contains 10 exons and 9 introns, by 555 amino acid residues, 12 transmembrane structure the and be positioned at-NH of cell interior2With- COOH end forms.Research finds that the SLC22A12 gene that kidney Hypouricemia patient carries is undergone mutation, and loses coding The ability of URAT1 maturation protein, 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), it is significant and closely related with the regulation and control of uric acid level in blood to the uric acid weight absorption function of kidney.Therefore, tool The material having URAT1 inhibitory activity can promote the excretion of uric acid in blood, higher with uric acid level in blood relevant for treating and preventing Disease, including hyperuricemia, gout, tophus, gouty arthritis, hyperuricemia dependency nephropathy, urinary tract Calculus etc..
Existing relevant report claims, by allopurinol with have medicine for improving uric acid excretion and ratio is used in combination is used alone allopurinol tool There is more preferably fall blood uric acid effect (S Takahashi, Ann.Rheum.Dis., 2003,62,572-575).Therefore, by promoting Urate excretion medicine and being used in combination of uricopoiesis depressant can obtain the single drug inaccessiable therapeutic effect of institute and keep away Exempt from corresponding risk, such as, for urate excretion not good figure hyperuricemia, be used alone uricosureic agent and likely cause The risk of lithangiuria, is therefore used in combination uricopoiesis depressant and can obtain the higher therapeutic effect of expection.
Xanthine oxidase can be suppressed to suppress again URAT1 medicine, more preferable therapeutic effect will be provided for patient, simultaneously More convenient than drug combination.This kind of medicine has become as treatment hyperuricemia, gout and the disease relevant to hyperuricemia Sick research and development focus.
Brief summary of the invention
Hereinafter some aspects of the present invention are only summarized, it is not limited to this.These aspects and other parts are later There is more complete explanation.All lists of references in this specification are incorporated in this by entirety.Work as the disclosure of the specification With quote document variant time, be as the criterion with the disclosure of the specification.
The invention provides a class and there is xanthine oxidase and/or the compound of URAT1 inhibitory activity, for prevention or Treatment and the higher relevant disease of uric acid level in blood, such as hyperuricemia, tophus, gouty arthritis and antihyperuricemic Nephropathy that disease is relevant and urinary calculus etc.；The compounds of this invention can suppress xanthine oxidase and/or URAT1's well Activity, has excellent physicochemical property and pharmacokinetic property simultaneously.
The preparation method that present invention provides these compounds and the pharmaceutical composition that comprises these compounds and make By these compounds or the method for the above-mentioned disease of medicine composite for curing mammal, the especially mankind.
Specifically:
On the one hand, the present invention relates to the stereoisomerism of compound shown in a kind of compound as shown in formula (I) or formula (I) Body, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable Salt or its prodrug,
Wherein:
Q is key ,-CH2-,-C (=O)-or-S (=O)2-；
W ring isWherein, E ring is carbocyclic ring, heterocycle, aromatic ring or hetero-aromatic ring；
Each R independently be D-atom, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano group, alkyl, thiazolinyl, alkynes Base, haloalkyl, alkoxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (=O)-cycloalkyl ,-C (=O)-heterocyclic radical ,-C (=O)-aryl ,-C (=O)-heteroaryl ,-L1-S (=O)r-L2-RA, cycloalkyl-alkyl, aryl alkyl, heteroaryl alkyl or carboxylic Base；Wherein, each R is individually optionally by 1,2,3,4 or 5 RxReplace；
RAFor alkyl, thiazolinyl, alkynyl, haloalkyl, alkoxyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl；
Each RxIndependently be hydroxyl, oxo (=O), halogen atom, amino, nitro, cyano group, alkyl, alkoxyl or alkyl halide Base；
R1、R2、R3、R4And R5It is each independently hydrogen atom, D-atom, halogen atom, hydroxyl, amino, nitro, cyano group, alkane Base, haloalkyl, alkoxyl, aryl or heteroaryl；Wherein, each R1、R2、R3、R4And R5Individually optionally by 1,2 or 3 RyTake Generation；
Each RyIndependently be hydroxyl, oxo (=O), halogen atom, amino, nitro, cyano group, alkyl, alkoxyl or carboxyl；
M is 0,1,2,3,4 or 5；
R is 0,1 or 2；
L1For key ,-O-or-NH-；
L2For key ,-O-or-NH-；With
Condition is,
W ring is not
In some embodiments, W ring isWherein, E ring is 5-8 unit carbocyclic ring, 5-8 unit heterocycle, phenyl ring Or 5-8 unit hetero-aromatic ring；R and m has implication as described in the present invention.
In other embodiments, W ring is Or
Wherein, each X1And X2Independently be-S (=O)t-,-Se-,-O-,-NH-or-CH2-, each t independently be 0,1 or 2； Each Y1And Y2Independently be N or CH；R and m has implication of the present invention.
In other embodiment, W ring is OrWherein, R and m has implication of the present invention.
In some embodiments, each R independently be D-atom, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyanogen Base, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxyl, C3-6Cycloalkyl, C1-6Heterocyclic radical, C6-10Virtue Base, C1-5Heteroaryl ,-C (=O)-C3-6Cycloalkyl ,-C (=O)-C1-6Heterocyclic radical ,-C (=O)-C6-10Aryl ,-C (=O)-C1-5 Heteroaryl ,-L1-S (=O)r-L2-RA、C3-6Cycloalkyl-C1-6Alkyl, C6-10Aryl-C1-6Alkyl, C1-5Heteroaryl-C1-6Alkyl or Carboxyl；Wherein, each R is individually optionally by 1,2,3,4 or 5 RxReplace；
RAFor C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxyl, C3-6Cycloalkyl, C1-6Heterocycle Base, C6-10Aryl or C1-5Heteroaryl；
Each RxIndependently be hydroxyl, oxo (=O), halogen atom, amino, nitro, cyano group, C1-6Alkyl, C1-6Alkoxyl or C1-6Haloalkyl.
In other embodiments, each R independently be D-atom, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, Nitro, cyano group, methyl, ethyl, n-pro-pyl, isopropyl, the tert-butyl group, vinyl, acetenyl, propargyl, difluoromethyl, fluoroform Base, methoxyl group, ethyoxyl, isopropoxy, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, benzene Base, naphthyl, furyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, thiazolyl, pyridine radicals, pyrimidine radicals, triazol radical, four nitrogen Oxazolyl ,-C (=O)-cyclopropyl ,-C (=O)-cyclohexyl ,-C (=O)-phenyl ,-C (=O)-thienyl ,-C (=O)-imidazoles Base, ethylsulfonyl, Cvclopropvlmethvl, benzyl, thienyl methyl or carboxyl；Wherein, each R is individually optionally by 1,2,3,4 or 5 Individual RxReplace；
Each RxIndependently be hydroxyl, oxo (=O), fluorine, chlorine, bromine, iodine, amino, nitro, cyano group, methyl, methoxyl group or three Methyl fluoride.
In some embodiments, R1、R2、R3、R4And R5Be each independently hydrogen atom, D-atom, halogen atom, hydroxyl, Amino, nitro, cyano group, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl, C6-10Aryl or C1-5Heteroaryl；Wherein, each R1、R2、 R3、R4And R5Individually optionally by 1,2 or 3 RyReplace；
Each RyIndependently be hydroxyl, oxo (=O), halogen atom, amino, nitro, cyano group, C1-6Alkyl, C1-6Alkoxyl or Carboxyl.
In other embodiments, R1、R2、R3、R4And R5Be each independently hydrogen atom, D-atom, fluorine, chlorine, bromine, Iodine, hydroxyl, amino, nitro, cyano group, methyl, ethyl, trifluoromethyl, methoxyl group, phenyl, naphthyl, pyrrole radicals, pyrazolyl, imidazoles Base, thiazolyl, thienyl, oxazolyl, tetrazole base, pyridine radicals or pyrimidine radicals；Wherein, each R1、R2、R3、R4And R5Individually optional Ground is by 1,2 or 3 RyReplace；
Each RyIndependently be hydroxyl, oxo (=O), fluorine, chlorine, bromine, iodine, cyano group, methyl, isopropyl, methoxyl group or carboxyl.
On the other hand, the invention provides a kind of compound, it is the structure of one of:
Or it is its stereoisomer, several What isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or front Medicine.
On the other hand, the present invention relates to a kind of pharmaceutical composition, it comprises compound disclosed by the invention.
In certain embodiments, pharmaceutical composition of the present invention comprise further pharmaceutically acceptable excipient, Carrier, adjuvant or combinations thereof.
In further embodiments, pharmaceutical composition of the present invention, comprise other preventions or treatment height further Nephropathy that hyperuricemia, tophus, gouty arthritis are relevant with hyperuricemia and the medicine of urinary calculus, described medicine Thing be colchicine, NSAID (non-steroidal anti-inflammatory drug), glucocorticoid, suppression uricopoiesis medicine, uricosureic agent, urine basifier or it Combination in any.
On the other hand, the present invention relates to compound disclosed by the invention or the compositions purposes in preparing medicine, described Medicine is used for preventing or treating mammal, including hyperuricemia, tophus, gouty arthritis and the metabolic arthritis of the mankind Nephropathy that mass formed by blood stasis is relevant and urinary calculus.
On the other hand, the present invention relates to compound disclosed by the invention or the compositions purposes in preparing medicine, described Medicine is used for reducing uric acid level in blood.
On the other hand, the present invention relates to compound disclosed by the invention or the compositions purposes in preparing medicine, described Medicine is for suppressing xanthine oxidase and/or the activity of urate anion transport body-1 in study subject.
On the other hand, the method that the present invention relates to preparation, separation and the purification of formula (I) described compound.
Biological results shows, the compound that the present invention provides can be as preferable xanthine oxidase and/or uric acid Salt anionic transporter-1 inhibitor.
Any embodiment of the either side of the present invention, can be combined with other embodiment, as long as they are not There will be contradiction.Additionally, in any embodiment of either side of the present invention, it is real that arbitrary technical characteristic goes for other Execute this technical characteristic in scheme, as long as they do not have contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspects and The content of his aspect will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
Certain embodiments of the present invention be will now be described in more detail, and the example is by the structural formula enclosed and chemical formula explanation.This Invention intention contains all of replacement, amendment and equivalent technical solutions, and they are included in such as the present invention of claim definition In the range of.Those skilled in the art will appreciate that many similar with the described herein or method of equivalent and material can be used in reality Trample the present invention.The present invention is not limited to method described herein and material.At the document combined, patent and similar material one Or many different from the application or conflicting in the case of (include but not limited to defined term, term application, described Technology, etc.), be as the criterion with the application.
It will further be appreciated that some feature of the present invention, for clearly visible, carry out in multiple independent embodiments Describe but it also may provide in combination in single embodiment.Otherwise, the various features of the present invention, for brevity, Single embodiment is described but it also may individually or with the sub-portfolio being arbitrarily suitable for 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.The all patents that the present invention relates to and public publication are integrally incorporated this by reference Bright.
Unless otherwise indicated, it should apply following definition used herein.For purposes of the present invention, chemical element with Periodic table of elements CAS version, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can be joined Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, New York:2007, entire contents is incorporated herein by.
Context except as otherwise noted or has significantly conflict, article used herein " ", " one (kind) " " described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.Such as, " component " refers to one or more component, it is possible to have more than one Component be taken into account in the embodiment of described embodiment and use or use.
Term used in the present invention " study subject " refers to animal.Typical described animal is mammal.Tested right As, the most also refer to primate (the such as mankind, sex), cattle, sheep, goat, horse, dog, cat, rabbit, rat, little Mus, fish, bird etc..In certain embodiments, described study subject is primate.In other embodiments, described it is subject to Try liking people.
Term used in the present invention " patient " refers to people's (including adult and child) or other animals.Implement at some In scheme, " patient " refers to people.
It is open language that term " comprises ", i.e. includes the content specified by the present invention, but is not precluded from otherwise Content.
" stereoisomer " refers to have identical chemical constitution, but the change that atom or group spatially arrangement mode is different Compound.Stereoisomer includes enantiomer, diastereomer, conformer (rotamer), geometric isomer (cis/trans) isomer, atropisomer, etc..
" chirality " is that have can not the molecule of overlapping character with its mirror image；And " achirality " refer to can be overlapping with its mirror image Molecule.
" enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror image relationship.
" diastereomer " refers to two or more chiral centre and the stereoisomerism of its molecule mirror image the most each other Body.Diastereomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Diastereomer mixes Compound can be separated by high resolution analysis operation such as electrophoresis and chromatograph, such as HPLC.
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 compound exist with optical active forms, and i.e. they have and make the plane of linearly polarized light rotate Ability.When describing optically active compound, prefix D and L or R and S is used to represent that molecule is about one or more hands 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 for (+) or the compound of d be dextrorotation.A kind of concrete stereoisomerism Body is enantiomer, and the mixture of this isomer is referred to as enantiomeric mixture.The 50:50 mixture of enantiomer Be referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereo selectivity or stereospecificity time, May occur in which this situation.
Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can be enriched with raceme or enantiomer Presented in, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration aspect there is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer Excess.
According to starting material and the selection of method, the compounds of this invention can with in possible isomer or they Mixture, the such as form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) is deposited ?.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent to prepare, or use routine techniques to tear open Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing dibasic cycloalkanes in compound Base, the substituent group 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 the purest geometric isomer, enantiomer, diastereomer, such as, by chromatography and/or fractional crystallization Method.
By known method, the racemic modification of any gained end-product or intermediate can be passed through those skilled in the art The method being familiar with splits into optical antipode, e.g., by separating its diastereoisomeric salt obtained.Racemic product Thing can also be separated by chiral chromatogram, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomer can be prepared by asymmetric synthesis, such as, refers to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, as General formula compound above, or as example special inside embodiment, subclass, and the compounds that the present invention is comprised.
It is said that in general, term " substituted " represents that the one or more hydrogen atoms in given structure are taken by concrete substituent group Generation.Unless other aspects show, a substituted group can have a substituent group to carry out in each commutable position of group Replace.When in given structural formula, more than one position can be selected from one or more substituent groups of concrete group and replaced, So substituent group can replace in each position identical or differently.
Term " unsubstituted ", represents and specifies group without substituent group.
Term " optionally by ... replaced ", can with term " unsubstituted or quilt ... replaced " exchange use, i.e. Described structure is unsubstituted or is replaced by one or more substituent groups of the present invention.Substituent group bag of the present invention Include, but be not limited to D, F, Cl, Br, I, N3、CN、NO2、OH、SH、NH2, oxo (=O), alkyl, haloalkyl, thiazolinyl, alkynyl, Alkoxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkyl-alkyl, aryl alkyl, heteroaryl alkyl or carboxyl, etc..
In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode used in the present invention " each ... to independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, and it both may be used To refer in different groups, do not affect mutually between concrete option expressed between same-sign, it is also possible to represent in phase In same group, do not affect mutually between concrete option expressed between same-sign.
At each several part of this specification, the come into the open substituent group of compound of the present invention is open according to radical species or scope.Special Not pointing out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.Such as, term “C1-6Alkyl " refer in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
At each several part of the present invention, describe connection substituent group.When this structure clearly needs linking group, for this Ma Kushi variable cited by group is interpreted as linking group.Such as, if this structure needs linking group and for this The Ma Kushi group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively The alkylidene group connected or arylene group.
Terminology used in the present invention " alkyl " or " alkyl group ", represent saturated straight or branched univalent hydrocarbyl group, Wherein, the substituent group that described alkyl group can optionally be described by one or more present invention replaces.Unless it is the most detailed Illustrating, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-12 carbon atom；At 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 comprises, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-pro-pyl (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 group (-CH (CH3)CH2CH2CH3), 3-amyl group (-CH (CH2CH3)2), 2-methyl-2-butyl (-C (CH3)2CH2CH3), 3-methyl-2-butyl (-CH (CH3)CH(CH3)2), 3-methyl isophthalic acid-butyl (-CH2CH2CH(CH3)2), 2-first Base-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH3) CH2CH2CH2CH3), 3-hexyl (-CH (CH2CH3)(CH2CH2CH3)), 2-methyl-2-amyl group (-C (CH3)2CH2CH2CH3), 3-first Base-2-amyl group (-CH (CH3)CH(CH3)CH2CH3), 4-methyl-2-amyl group (-CH (CH3)CH2CH(CH3)2), 3-methyl-3-penta Base (-C (CH3)(CH2CH3)2), 2-methyl-3-amyl group (-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 remove obtained by two hydrogen atoms from saturated straight or branched alkyl saturated 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；Another embodiment party In case, alkylidene group contains 1-3 carbon atom；The most 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 " thiazolinyl " represents straight or branched monovalent hydrocarbon, at least one of which carbon-to-carbon sp2Double bond, wherein, described Alkenyl group can optionally be replaced by one or more substituent groups described in the invention, and it includes " cis " and " trans " Location, or " E " and the location of " Z ".In one embodiment, alkenyl group comprises 2-12 carbon atom；Implement at another In scheme, alkenyl group comprises 3-12 carbon atom；In another embodiment, alkenyl group comprises 2-6 carbon atom；Again In one embodiment, alkenyl group comprises 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (-CH =CH2), pi-allyl (-CH2CH=CH2) etc..
Term " alkynyl " expression straight or branched monovalent hydrocarbon containing 2-12 carbon atom, at least one of which carbon- Carbon sp tri-key, wherein, described alkynyl group can optionally be replaced by one or more substituent groups described in the invention.? In one embodiment, alkynyl group comprises 3-12 carbon atom；In another embodiment, to comprise 2-6 carbon former for alkynyl group Son；In yet another embodiment, alkynyl group comprises 2-4 carbon atom.The example of alkynyl group includes, but is not limited to, second Alkynyl (-C ≡ CH), propargyl (-CH2C ≡ CH), 1-propinyl (-C ≡ C-CH3) etc..
Term " alkoxyl " represents that alkyl group is connected with molecule remainder by oxygen atom, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.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.Described alkoxy base can be the most one or more The substituent group that the present invention describes is replaced.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1-propoxyl group (n-PrO, n-propoxyl group ,-OCH2CH2CH3), 2-propoxyl group (i-PrO, i-propoxyl group ,-OCH (CH3)2), 1-butoxy (n-BuO, n-butoxy ,-OCH2CH2CH2CH3), 2-methyl-l-propoxyl group (i-BuO, i-fourth oxygen Base ,-OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH3)CH2CH3), 2-methyl-2-propoxyl group (t- BuO, t-butoxy ,-OC (CH3)3), 1-amoxy (n-amoxy ,-OCH2CH2CH2CH2CH3), 2-amoxy (-OCH (CH3) CH2CH2CH3), 3-amoxy (-OCH (CH2CH3)2), 2-methyl-2-butoxy (-OC (CH3)2CH2CH3), 3-methyl-2-fourth Epoxide (-OCH (CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (- OCH2CH(CH3)CH2CH3), etc..
Term " haloalkyl " represents that alkyl group is replaced by one or more halogen atoms, and wherein alkyl group has Implication as described in the present invention, such example comprises, but is not limited to, trifluoromethyl, 2,2,3,3-tetra-fluoropropyls, difluoro first Epoxide, trifluoromethoxy, trifluoromethyl amino etc..
Term " cycloalkyl " represents containing 3-12 ring carbon atom, unit price or the saturated monocycle of multivalence, dicyclo or three rings System.In one embodiment, cycloalkyl comprises 7-12 ring carbon atom；In yet another embodiment, cycloalkyl comprises 3-8 Ring carbon atom；In yet another embodiment, cycloalkyl comprises 3-6 ring carbon atom.Described group of naphthene base can the most not It is replaced or is replaced by one or more substituent groups described in the invention.
Term " carbocyclic ring " or " carbocylic radical " represent satisfies containing the nonaromatic of 3-12 ring carbon atom, unit price or multivalence With or the unsaturated monocycle of part, dicyclo or three-ring system.Carbon bicyclic group includes spiral shell carbon bicyclic group and condenses carbon bicyclic group, properly Carbocylic radical group include, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.In one embodiment, carbocylic radical comprises 3- 8 ring carbon atoms；In yet another embodiment, carbocylic radical comprises 3-6 ring carbon atom.The example of carbocylic radical group wraps further Include, cyclopropyl, cyclobutyl, cyclopenta, 1-cyclopenta-1-thiazolinyl, 1-cyclopenta-2-thiazolinyl, 1-cyclopenta-3-thiazolinyl, hexamethylene Base, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, Ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl, etc..Described carbocylic radical group can the most unsubstituted or quilt One or more substituent groups described in the invention are replaced.
Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to comprising the saturated of 3-12 annular atoms or portion Point undersaturated nonaromatic unit price or multivalence monocycle, dicyclo or three rings, at least one of which annular atoms selected from nitrogen, sulfur, oxygen, Phosphorus, silicon and selenium atom.Unless otherwise indicated, heterocyclic radical can be connected with other groups in molecule by carbon atom, it is also possible to logical Cross nitrogen-atoms to be connected with other groups in molecule, and-CH2-group can be optionally by-C (=O)-replacement.The sulphur atom of ring can To be optionally oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of heterocyclic radical Include, but are not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2-pyrrolin Base, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydrochysene Thienyl, dihydro-thiophene base, 1,3-dioxy cyclopenta, two sulfur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranose, 4H-pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, dithiane base, thiophene alkane Base, homopiperazine base, homopiperidinyl, Diazesuberane base, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, phenodiazine MiscellaneousBase, sulfur azepineBase, 2-oxa--5-azabicyclo [2.2.1] hept-5-base, 2-oxo-pyrrolidine base, oxo-1,3-thiazole Alkyl, 2-piperidone base, 3,5-dioxy piperazine piperidinyl and hybar X base, sulfolane base, 1,1-dioxothiomorpholinyl, different Oxazole-3 (2H)-one, 1,5-dihydro-2 h-pyrrole-2-ketone, 1,2-dihydro-3H-pyrazoles-3-ketone, isothiazole-3 (2H)-one-1, 1-dioxide, isothiazole-3 (2H)-one, 1,2-selenazoles-3 (2H)-one, oxazole-2 (3H)-one, pyrimidine-2,4 (1H, 3H)-two Ketone, 2H-1,3-oxazines-2,4 (3H)-diketone, isothiazole-1-monoxide, pyridine-2 (1H)-one, 2,3-dihydro-4H-1,3- Oxazines-4 (3H)-one, pyrrolidine-2,5-dione, 1,2-dioxole, 2,3-dihydro isothiazole-1,1-dioxide, 2,3-dihydro-isoxazoles, 2,3-dihydropyridine-4 (1H)-one, etc..Described heterocyclyl groups can optionally by one or Multiple substituent groups described in the invention are replaced.
Term " hetero atom " refers to O, S, N, P, Si and Se, including the form of any oxidation state of N, S and P；Primary, secondary, tertiary amine Form with quaternary ammonium salt；Or the form that in heterocycle, the hydrogen on nitrogen-atoms is replaced, such as, N (as 3,4-dihydro-2 h-pyrrole base In N), NH (NH as in pyrrolidinyl) or NR (NR as in the substituted pyrrolidinyl of N-).
Term " halogen " or " halogen atom " refer to fluorine atom (F), chlorine atom (Cl), bromine atoms (Br) or atomic iodine (I).
Term " cyano group " refers to-CN.
Term " nitro " refers to-NO2。
Term " amino " refers to-NH2。
Term " hydroxyl " refers to-OH.
Term " aryl " represents containing 6-14 annular atoms, or 6-12 annular atoms, or the monocycle of 6-10 annular atoms, double Ring or the carbocyclic ring system of three rings, wherein, at least one ring is aromatic, and has one or more attachment point and molecule remaining Part is connected.Term " aryl " can use with term " aromatic rings " exchange.In one embodiment, aryl is by 6-10 ring Former molecular, and at least a part of which contains the carbocyclic ring system of an aromatic rings.The example of aromatic yl group can include phenyl, naphthyl And anthryl.Described aromatic yl group can be replaced by one or more substituent groups described in the invention individually optionally.
Term " heteroaryl " represents containing 5-12 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms, Dicyclo or three rings, at least one of which ring is aromatic, and at least one ring comprises 1 to 4 hetero atom selected from O, N and S, One or more attachment point is had to be connected with molecule remainder.Term " heteroaryl " can be with term " hetero-aromatic ring " or " heteroaromatic Compound " exchange use.Described heteroaryl groups is optionally replaced by one or more substituent groups described in the invention.? In one embodiment, heteroaryl is to comprise 1,2,3 or 4 heteroatomic 5-12 annular atoms compositions being independently selected from O, N and S Heteroaryl；In another embodiment, heteroaryl is to comprise 1,2,3 or 4 heteroatomic 5-6 rings being independently selected from O, N and S Former molecular heteroaryl.
The example of heteroaryl groups includes, but is not limited to, 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazole radicals, 4-imidazole radicals, 5-imidazole radicals, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-azoles Base, di azoly (such as 1,2,3-di azoly, 1,2,5-di azoly, 1,2,4-di azoly), triazolyl (such as 1,2,3, 4-triazolyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, isothiazolyl, 2-thiadiazolyl group (as 1,3,4-thiadiazolyl group, 1,2,3-thiadiazolyl group, 1,2,5-thiadiazolyl group), thiatriazole base (such as 1,2,3,4-thiatriazole base), tetrazole radical (such as 2H-1,2, 3,4-tetrazole radical, 1H-1,2,3,4-tetrazole radical), triazolyl (such as 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1, 2,4-triazolyl), 2-thienyl, 3-thienyl, 1H-pyrazolyl (as 1H-pyrazole-3-yl, 1H-pyrazoles-4-base, 1H-pyrazoles- 5-yl), 1,2,3-thio biphosphole base, 1,3,4-thio biphosphole base, 1,2,5-thio biphosphole 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 are (such as 3-pyridazine Base, 4-pyridazinyl), 2-pyrazinyl, triazine radical (such as 1,3,5-triazine), tetrazine base is (such as 1,2,4,5-tetrazine, 1,2,3,5-tetra- Piperazine)；Also include following dicyclo, but be not limited to these dicyclos: benzimidazolyl, benzofuranyl, benzothienyl, indole Base (such as 2-indyl), purine radicals, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl are (such as 1-isoquinoline Quinoline base, 3-isoquinolyl or 4-isoquinolyl), 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 " cycloalkyl-alkyl ", " aryl alkyl " and " heteroaryl alkyl " represents " cycloalkyl " respectively, " aryl " and " miscellaneous Aryl " group is connected with molecule remainder by alkyl, wherein " cycloalkyl ", " aryl " and " heteroaryl " group have as Implication described in invention.
Term " carboxyl ", is either used alone and is still used in conjunction, such as " carboxyl ", expression-CO with other terms2H；Term " carbonyl ", is either used alone and is still used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", represent-(C=O)-.
As described in the invention, substituent group draws the member ring systems formed on a ring being bonded the center of receiving (such as formula b institute Show) represent substituent group any commutable position on this ring and can replace.Such as, formula b represent substituent R can be on C ring On any position that may be replaced monosubstituted or polysubstituted, as shown in formula c1～formula c17.
As described in the invention, a connecting key is connected to member ring systems (as shown in the formula d) generation formed in the heart in ring Table connecting key can be connected with molecule remainder any attachable position in member ring systems.Formula d represents any possibility on D ring The position connected all can be connected with molecule remainder.
As described in the present invention, substituent R is represented substituent R by the member ring systems formed on a ring being bonded the center of receiving May only any on coupled ring may replace or any rational position replaces.Such as, formula e represents A ring and takes up an official post The position what may be replaced all can be replaced by R, as shown in formula f, formula g, formula h and formula i.
The when that term " blocking group " or " PG " referring to a substituent group and other reacted with functional groups, it is commonly used to resistance Disconnected or protect special functional.Such as, " blocking group of amino " refers to that a substituent group is connected with amino group and blocks Or amino functional in protection compound, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenes Asia methoxycarbonyl group (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent group of base is used for blocking or protect the functional of hydroxyl, suitable blocking group to include acetyl group and silicyl." carboxyl Blocking group " refer to the substituent group of carboxyl for blocking or protect the functional of carboxyl, general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxyl methyl, 2-is (to toluene Sulfonyl) ethyl, 2-(p-nitrophenyl sulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The description that group is general 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 used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo. Such conversion is hydrolyzed in blood by prodrug or is that precursor structure is affected through enzymatic conversion in blood or tissue.This Bright prodrug compounds can be ester, and in existing invention, ester can have phenyl ester class, aliphatic as prodrug (C1-C24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention one Compound comprises hydroxyl, i.e. can be acylated the compound obtaining prodrug form.Other prodrug form includes Phosphate ester, if these phosphate compounds are that the di on parent obtains.About complete the begging for of prodrug Discuss and 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 that concrete compound or its salt is in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention Adopt as stating and experimentally characterize.Such product can be by passing through oxidation, reduction, water to drug compound Solving, amidated, desamido-effect, esterification, degreasing, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes compound Metabolite, be fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.
" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention.Medicine On, acceptable salt is known to us at art, 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 includes, but is not limited to, inorganic acid salt Example hydrochloric acid salt, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetate, oxalates, maleate, Tartrate, citrate, succinate, malonate, or handed over by additive method such as ion described on books document Method of changing is to obtain these salt.Other pharmaceutically acceptable salts include adipate, alginate, Ascorbate, aspartic acid Salt, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, camsilate, cyclopentyl propionate, Digluconate, lauryl sulfate, esilate, formates, fumarate, gluceptate, phosphoglycerol Salt, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid Salt, laruate, lauryl sulfate, malate, mesylate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, palm fibre Palmitic acid hydrochlorate, pamoate, pectate, persulfate, 3-phenylpropionic acid salt, picrate, pivalate, propionate, stearic acid Salt, rhodanate, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali includes alkali metal, Alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate the compound of the group of any comprised N and is formed Quaternary ammonium salt.Water solublity or oil-soluble or dispersion product can be obtained by quaternization.Alkali metal or alkali salt bag Include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt farther includes suitable, nontoxic ammonium, and quaternary ammonium salt is flat with anti- The amine cation that weighing apparatus ion is formed, such as halogenide, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8 Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecule and the present invention is formed Thing.The solvent forming solvate includes, 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 complex that water is formed.
When described solvent is water, it is possible to use term " hydrate ".In certain embodiments, a compounds of this invention Molecule can combine with a hydrone, such as monohydrate；In other embodiment, a compounds of this invention divides Son can combine with more than one hydrone, such as dihydrate, in further embodiments, and a compounds of this invention Molecule can combine with the hydrone less than, such as semihydrate.It should be noted that hydrate of the present invention remains with The biological effectiveness of the described compound of nonhydrated form.
As used in the present invention any disease or disease " treated " in term, refer to all can to slow down, interrupt, stop, Controlling or stop disease or the progress of disease, but not necessarily representing that the symptom of all diseases or disease all disappears, it also includes Prophylactic treatment to described symptom, especially in easily suffering from the patient of such disease or obstacle.Some are implemented wherein Scheme middle finger improves disease or disease (i.e. slow down or stop or palliate a disease or the development of its at least one clinical symptoms).Separately In some embodiments, " treatment " refers to relax or improve at least one body parameter, including the body may not discovered by patient Body parameter.In other embodiments, " treat " and refer to (such as stablize perceptible symptom) from health or physiologically (example Parameter such as stable health) or above-mentioned two in terms of regulate disease or disease.In other embodiments, " treat " refer to prevention or Postpone disease or the outbreak of disease, occur or deteriorate.
Term " therapeutically effective amount " or " treatment effective dose " refer to cause individual life as used in the present invention Thing or medicinal response (such as reduce or inhibitory enzyme or protein active, or improve symptom, alleviate disease, slow down or postpone disease Sick development, or prevention disease etc.) the amount of the compounds of this invention.In the embodiment of an indefiniteness, " treatment has term Effect amount " refer to when using the compounds of this invention to individuality, amount effective to situations below: (1) is alleviated at least in part, pressed down System, prevent and/or improve (i) to be mediated by xanthine oxidase or urate anion transport body-1 (URAT1), or (ii) with Xanthine oxidase or urate anion transport body-1 activity are relevant, or (iii) is cloudy by xanthine oxidase or urate The disease of the abnormal activity sign of ion transport body-1 or disease；Or (2) reduce or suppress xanthine oxidase or urate The activity of anion transport body-1；Or (3) reduce or suppress xanthine oxidase or the table of urate anion transport body-1 Reach.In another embodiment, term " therapeutically effective amount " refers to work as to cell or organ or acellular organism material or be situated between When matter is used, can reduce or suppress xanthine oxidase or urate anion transport body-1 activity at least in part；Or extremely Partially reduce or suppress the effective the compounds of this invention that xanthine oxidase or urate anion transport body-1 are expressed Amount.
Term compound " gives " and " administration " compound should be understood to needing the individual of its as used in the present invention Body provides compound or the prodrug of the compounds of this invention of the present invention.Will be appreciated that those skilled in the art are by using effectively The compounds of this invention treatment of amount suffers from the patient of this obstacle at present or prophylactically treats the patient suffering from this obstacle, permissible Uric acid concentration in blood is produced impact.
Term " compositions " refers to the product of the predetermined component comprising ormal weight, and ormal weight as used in the present invention The spawn that produces directly or indirectly of the combination of predetermined component.The implication of this term relevant to pharmaceutical composition Including the product of the inert fraction (single or multiple) comprising active component (single or multiple) and composition carrier, Yi Jiyou Any two or Multiple components mixing, compound or gathering, or by one or more ingredient breakdown, or become by one or more Point other kinds of reaction or interaction and the spawn that directly or indirectly produces.Therefore, pharmaceutical composition of the present invention Including any compositions prepared by the compounds of this invention is mixed with pharmaceutically suitable carrier.
The pharmaceutical composition of the compounds of this invention, preparation and administration
The present invention provides a kind of pharmaceutical composition, and it comprises the present invention and comes into the open listed chemical combination in compound, such as embodiment Thing；With pharmaceutically acceptable excipient, carrier, adjuvant, solvent or combinations thereof.
The present invention provides treatment, the method preventing or improving disease or disease, including giving comprising originally of safe and effective amount Disclosure of the invention compound and the combination medicine of one or more therapeutically active agents.Wherein, combination medicine comprises one or more its Nephropathy that his prevention or treatment hyperuricemia, tophus, gouty arthritis are relevant with hyperuricemia and urinary calculus Medicine.
The kidney barrier that other prevention or treatment hyperuricemia, tophus, gouty arthritis are relevant with hyperuricemia Hinder the medicine with urinary calculus to include but not limited to: colchicine, NSAID (non-steroidal anti-inflammatory drug), glucocorticoid, suppression uricopoiesis medicine, Uricosureic agent, urine basifier or their combination in any.
The kidney that described other treatment hyperuricemia, tophus, gouty arthritis are relevant with hyperuricemia The medicine of obstacle and urinary calculus is colchicine, indomethacin, Etoricoxib, diclofenac, ibuprofen, rofecoxib, plug Former times cloth, meloxicam, prednisone, succinic acid hydrocortisone, allopurinol, probenecid, sulphinpyrazone, benzbromarone, former times difficult to understand are fast Alcohol, Febuxostat, recombined Aspergillus flavus bacteriuria acid oxidase, Pegylation restructuring urate oxidase, Sodium Bicarbonate Tablets, citric acid Potassium sodium mixture or their combination in any.
In pharmaceutical composition disclosed by the invention, the amount of compound refers to suppression biological specimen or patient effectively be detected Internal xanthine oxidase and/or the amount of urate anion transport body-1.In the present composition, the dosage of active component can To change, but, the amount of active component must be the amount that can obtain appropriate dosage forms.Active component can be to provide optimal drug The dosed administration of effect is in the patient (animal and people) needing this treatment.Selected dosage depends on desired treatment effect Really, route of administration and treatment persistent period are depended on.Dosage will be different with patient, this attribute depending on disease and serious journey Degree, the weight of patient, the concrete diet of patient, the medicine simultaneously used and it will be recognized by those skilled in the art other Factor.Dosage range is usually about 0.5mg to 1.0g each patient's every day, can be administered with the form of single dose or multi-agent.At one In embodiment, dosage range is about 0.5mg to 500mg each patient's every day；It is that each patient is every in another embodiment It about 0.5mg to 200mg；Still another embodiment is about 5mg to 50mg each patient's every day.
It will also be appreciated that some compound of the present invention can exist in a free form and be used for treating, if or suitable When can be presented in its pharmaceutically acceptable derivates.Pharmaceutically acceptable derivates includes pharmaceutically acceptable Prodrug, salt, ester, the salt of these esters, or when patient in need is administered, can directly or indirectly provide of the present inventionization Compound or its metabolite or any other adduct of residue or derivant.
Medicine disclosed by the invention or pharmaceutical composition can prepare and be packaged as (bulk) in bulk form, wherein can extract peace The compound shown in formula (I) of full effective dose, then gives patient with powder or syrup form.Generally, to arrive every day 0.0001 Dosage level between 10mg/kg body weight, to patient, is administered to obtain xanthine oxidase and/or urate anion transport The effective antagonism of body-1.Or, pharmaceutical composition disclosed by the invention can be prepared and be packaged as unit dosage forms, the most each The most discrete unit contains the compound shown in formula (I) of safe and effective amount.When preparing with unit dosage forms, the present invention is public The pharmaceutical composition opened generally can contain, and such as, 0.5mg's to 1g or 1mg to 700mg or 5mg to 100mg is disclosed by the invention Compound.
When the pharmaceutical composition of the present invention in addition to containing the compounds of this invention possibly together with one or more other activity group Timesharing, the compound weight ratio of the compounds of this invention and the second active component can change and depend on the effective of every kind of component Dosage.Generally, the effective dose of every kind is used.It is therefoie, for example, when the compounds of this invention mixes with another kind of medicament, this Bright compound is typically about 1000:1 to about 1:1000, e.g., from about 200:1 to about 1 with the weight ratio of another kind of medicament: 200.The mixture of the compounds of this invention and other active component the most within the above range, but in each case, all The effective dose of every kind of active component should be used.
The present invention " pharmaceutically acceptable excipient " used means relevant to form of administration or pharmaceutical composition concordance Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient must become with other of pharmaceutical composition when mixing Split-phase is held, and can be substantially reduced the present invention and come into the open the interaction of effect of compound and causing not during to avoid being administered patient It it is the interaction of pharmaceutically acceptable pharmaceutical composition.Additionally, every kind of excipient must be pharmaceutically acceptable, example As, there is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected concrete dosage form.Additionally, can be according to them in group Specific function in compound selects pharmaceutically acceptable excipient.Such as, optional can help to produce equal one dosage type low temperature Some pharmaceutically acceptable excipient.Optional some pharmaceutically acceptable figuration that can help to produce stabilizer type Agent.Optional contribute to time patient is administered carrying or transport the present invention come into the open compound from health organ or part to Another organ of health or some pharmaceutically acceptable excipient of part.Optional some medicine strengthening patient compliance Acceptable excipient on.
Suitable pharmaceutically acceptable excipient includes following kind of excipient: diluent, filler, binding agent, Disintegrating agent, lubricant, fluidizer, granulating agent, coating materials, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweeting agent, rectify Taste agent, odor mask, coloring agent, anticaking agent, wetting agent, chelating agen, plasticiser, viscosifier, antioxidant, preservative, stable Agent, surfactant and buffer agent.Technical staff it can be appreciated that, some pharmaceutically acceptable excipient can provide more than one Function, and alternative function is provided, this depend on preparation exists which there is in how many these excipient and preparation 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 the obtainable resource of a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and be used 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)。
At 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 Dekker, New York discloses the various carriers for configuring pharmaceutically acceptable compositions, and is used for what it was prepared Known technology, the respective content of these documents is incorporated by reference into the present invention.Except any such as because producing any less desirable life Thing effect, or so that other composition any in harmful way and pharmaceutically acceptable compositions occurs to interact and the present invention Outside any commonly employed carrier that compound of coming into the open is incompatible, pay close attention to its application and belong to the scope of the present invention.
Pharmaceutical composition disclosed by the invention uses technology well known by persons skilled in the art and method to prepare.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 prepare the technique of pharmaceutical composition, described pharmaceutical composition comprises the present invention Come into the open compound and pharmaceutically acceptable excipient, carrier, adjuvant or combinations thereof, and this technique includes mixing various one-tenth Point.Comprise the present invention to come into the open the pharmaceutical composition of compound, can mix under such as ambient temperature and atmospheric pressure and prepare.
Compound disclosed by the invention is usually formulated as being adapted to pass through the dosage form that patient is administered by required approach.Example As, dosage form includes that those are suitable for the dosage form of following route of administration: (1) oral administration, such as tablet, capsule, caplet agent, ball Agent, containing tablet, powder, syrup, elixir, suspensoid, solution, Emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, suspensoid and redissolution powder；(3) transdermal administration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) suck, such as aerosol, solution and dry powder doses；(6) topical, such as ointment, ointment, lotion, molten Liquor, paste, spray, foam 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 is permissible It is configured to nose administration dosage form.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. The most in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.
The present invention provide pharmaceutical composition can with compressed tablet, develop sheet, can chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are to dissolve or the material bag of disintegrate in intestinal with being resistant to gastric acid effect The compressed tablet of clothing, thus prevent the sour environment of active ingredient contacts stomach.Enteric coating includes, but not limited to fatty acid, fat Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Coated tablet is the compacting that sugar-coat surrounds Sheet, it can be beneficial to cover taste beastly or abnormal smells from the patient and can prevent tablet from aoxidizing.Thin membrane coated tablet is for using water solublity The compressed tablet that the thin layer of material or thin film cover.Film coating includes, but not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses the general characteristic identical with sweet tablet.Multiple Tabletting is the compressed tablet through preparing more than a press cycles, including multilayer tablet and pressed coated or dry coated tablet.
Tabules can by powder, the one that individually or describes with the present invention of crystallization or granular active component Or prepared by variety carrier or excipient composition, described carrier and excipient include binding agent, disintegrating agent, controlled release polymer, profit Lubrication prescription, diluent and/or coloring agent.Fumet and sweeting agent are particularly useful when forming chewable tablet and lozenge.
The pharmaceutical composition that the present invention provides can provide with soft capsule or hard capsule, and it can be by gelatin, methyl fibre Prepared by dimension element, starch or calcium alginate.Described hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, one section Fill in another section, enclose active component the most completely.SEC (SEC) is soft, spherical shell, such as gelatin shell, It plastifies by adding glycerol, sorbitol or similar polyhydric alcohol.Soft gelatin shell can comprise preservative and carry out prophylaxis of microbial life Long.Suitably preservative be as described in the present invention those, including methyl hydroxybenzoate and propylparaben, and sorbic acid.This Liquid, semisolid and solid dosage forms that invention provides can be encapsulated in capsule.Suitably liquid and semisolid dosage form is included in Solution in Allyl carbonate, vegetable oil or triglyceride and suspensoid.The capsule comprising such solution can be as in the U.S. Patent U.S.Pat.Nos.4,328,245；Preparing described in 4,409,239 and 4,410,545.Described capsule can also be adopted Use coating as is known to persons skilled in the art, thus improve or maintain the dissolution of active component.
The pharmaceutical composition that the present invention provides can provide with liquid and semisolid dosage form, including Emulsion, solution, suspendible Agent, elixir and syrup.Emulsion is two-phase system, and one of which liquid is thoroughly dispersed in another kind of 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.Suspensoid can include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions can include pharmaceutically may be used The acetal accepted, two (low alkyl group) acetal of such as low alkyl group aldehyde, such as acetaldehyde diethyl acetal；With there is one or many The water-soluble solvent of individual hydroxyl, such as propylene glycol and ethanol.Elixir is transparent, the water-alcohol solution of sweet taste.Syrup is dense The aqueous solution of sugar such as sucrose, and also preservative can be comprised.For liquid dosage form, such as, the solution in Polyethylene Glycol Can be with enough pharmaceutically acceptable liquid-carrier such as water dilutions, to be accurately, conveniently administered.
Other useful liquid and semisolid dosage form include, but are not limited to comprise the active component and two grades that the present invention provides Change list-or those dosage forms of poly-alkylene glycol, described list-or poly-alkylene glycol include: 1,2-dimethoxymethane, diethylene glycol Dimethyl ether, triethylene glycol dimethyl ether., tetraethylene glycol dimethyl ether, Polyethylene Glycol-350-dimethyl ether, Polyethylene Glycol-550-dimethyl ether, poly-second Glycol-750-dimethyl ether, wherein 350,550,750 refer to the approximation mean molecule quantity of 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, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfites, Jiao Sodium sulfite, thio-2 acid and ester thereof and dithiocarbamate.
Time suitably, can be by the dosage unit preparations microencapsulation of oral administration.Can also be prepared into extending or dimension Hold the compositions of release, such as by by microparticle material coating or be embedded in polymer, wax or the like.
The combination of oral medication that the present invention provides can also carry with the form of liposome, micelle, microsphere or nanometer system Supply.Micelle dosage form can be prepared by the method that U.S.Pat.No.6,350,458 describes.
The pharmaceutical composition that the present invention provides can provide with non-effervescent or the granule of effervescent and powder, to reconstruct Liquid dosage form.The pharmaceutically acceptable carrier used in non-effervescent granule or powder and excipient can include dilution Agent, sweeting agent and wetting agent.The pharmaceutically acceptable carrier and the excipient that use in effervescent granule or powder can wrap Include organic acid and carbon dioxide source.
Coloring agent and flavoring agent can be used in all above-mentioned dosage forms.
Compound disclosed in this invention can also be combined with the soluble polymer as target medicine carrier.Such Polymer includes polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl Radix Asparagi acyl Amine phenol or the substituted oxide polylysine of palmitoyl residues.Additionally, compound disclosed in this invention can with in reality The class Biodegradable polymeric controlling to use in release of existing medicine combines, such as, polylactic acid, poly-epsilon-caprolactone, poly- Hydroxybutyric acid, poe, polyacetals, poly-dihydropyran, polybutylcyanoacrylate and the crosslinking of hydrogel or amphiphilic block are altogether Polymers.
The present invention provide pharmaceutical composition can be configured to immediately or Modified release dosage forms, including postpone-, slow release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
The pharmaceutical composition that the present invention provides can be common with other active component without compromising on intended therapeutical effect Preparation, or with supplement the material co-formulation of intended effect.
The pharmaceutical composition that the present invention provides can be by injection, infusion or implantation parenteral, for local or complete Body is administered.As the present invention use parenteral include intravenous, intra-arterial, intraperitoneal, sheath in, in ventricle, in urethra, breast In bone, intracranial, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical composition that the present invention provides can be configured to be suitable to any dosage form of parenteral, including solution, mixes Suspension, Emulsion, micelle, liposome, microsphere, nanometer system and being suitable to makes consolidating of solution or suspension the most in a liquid Bodily form formula.Such dosage form can be prepared according to the conventional method known to the skilled person in pharmaceutical science field and (sees 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 anti-micro-life Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer agent, antioxidant, local anesthetic, suspending agent and the dispersion of thing growth Agent, wetting agent or emulsifying agent, chelating agent, sequestering agent or chelating agen, antifreezing agent, cryoprotective agent, thickening agent, pH adjusting agent And noble gas.
Suitably include, but are not limited to containing transporter: water, saline, normal saline or phosphate buffered saline (PBS) (PBS), Sodium chloride injection, Ringers injection, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers injection.Non-transporter includes, but not limited to the fixed oil of plant origin, Oleum Ricini, Semen Maydis oil, Semen Gossypii The middle chain of oil, olive oil, Oleum Arachidis hypogaeae semen, Oleum menthae, safflower oil, Oleum sesami, Oleum Glycines, hydrogenated vegetable oil, hydrogenated soybean oil and Oleum Cocois Triglyceride and palm seed oil.Water miscibility carrier includes, but not limited to ethanol, 1,3 butylene glycol, the poly-second of liquid two Alcohol (such as Liquid Macrogol and PEG400), propylene glycol, glycerol, METHYLPYRROLIDONE, N, N-dimethylacetamide Amine and dimethyl sulfoxide.
Suitably antimicrobial or preservative include, but not limited to phenol, cresol, mercurial, benzyl alcohol, chlorobutanol, Methyl parahydroxybenzoate and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride (such as benzethonium chloride), methyl hydroxybenzoate and Propylparaben and sorbic acid.Suitably isotonic agent includes, but not limited to sodium chloride, glycerol and glucose.Suitably buffer agent Include, but not limited to phosphate and citrate.Suitably antioxidant is as the present invention describes, including sulfurous acid Hydrogen salt and sodium metabisulfite.Suitably local anesthetic includes, but are not limited to procaine hydrochloride.Suitably suspending agent and point Powder is as the present invention describes, including sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. Suitably emulsifying agent includes those that the present invention describes, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene moves back Tax sorbitol monooleate 80 and triethanolamine oleate ester.Suitably sequestering agent or chelating agen includes, but are not limited to EDTA. Suitably pH adjusting agent includes, but are not limited to sodium hydroxide, hydrochloric acid, citric acid and lactic acid.Suitably chelating agent includes, but does not limits In cyclodextrin, including alpha-cyclodextrin, beta-schardinger dextrin-, HP-β-CD, Sulfobutylether-beta-schardinger dextrin-and sulfobutyl group Ether 7-beta-schardinger dextrin-(CyDex,Lenexa,KS)。
The pharmaceutical composition that the present invention provides can be configured to single dose or multiple dose administration.Described single-dose preparations is wrapped It is contained in ampulla, bottle or syringe.Described multiple dose parenteral administration must comprise the anti-micro-of antibacterial or fungistatic concentrations Biological agent.All of parenteral administration must be all aseptic, as known in the art with practice.
In one embodiment, pharmaceutical composition provides with instant sterile solution.In another embodiment, medicine Compositions provides with aseptic dried soluble product, and including freeze-dried powder and hypodermic tablet, it uses carrier before use Reconstruct.In yet another embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In yet another embodiment, medicine The aseptic dry insolubility product that compositions reconstructs with carrier before being formulated into use.The most in one embodiment, Pharmaceutical composition is formulated into the aseptic Emulsion of instant.
Pharmaceutical composition can be configured to suspensoid, solid, semisolid or thixotropic liquid, and the reservoir being used as to implant is administered. In one embodiment, pharmaceutical composition disclosed in this invention is dispersed in solid interior substrate, its be insoluble to body fluid but The outside polymeric membrane allowing the active component in pharmaceutical composition to diffuse through is surrounded.
Be suitable for internal matrix include polymethyl methacrylate, poly-butyl methacrylate, plasticising or unplasticizied Polrvinyl chloride, the nylon of plasticising, the polyethylene terephthalate of plasticising, the polyethylene terephthalate of plasticising, natural rubber, Polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, poly-diformazan silica Alkane, silicone carbonate copolymer, the hydrogel of ester of hydrophilic polymer such as acrylic acid and methacrylic acid, collagen, crosslinking The polyvinyl acetate of the partial hydrolysis of polyvinyl alcohol and coach.
The outside polymeric membrane being suitable for includes polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate copolymerization Thing, ethylene/vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polychlorostyrene second Alkene, ethlyene dichloride gather benzene two with the copolymer of vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer 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, suspensoid or liquid composite.In one embodiment, drug regimen disclosed in this invention Thing can be configured to be suitable to by the dry powder doses dosage form to patient's inhalation.In yet another embodiment, disclosed in this invention Pharmaceutical composition can be configured to be suitable to by the aerosol apparatus dosage form to patient's inhalation.Dry powder by inhalation delivery to lung Compositions generally comprises fine powdered that compound disclosed in this invention is fine powdered pharmaceutically with one or more Acceptable excipient.The pharmaceutically acceptable excipient 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 by such as micronization and grinding preparation Obtain.In general, reduced size of (as micronized) compound can be by the D of about 1 to 10 micron50Value is (such as, with swashing Optical diffraction method is measured) define.
Aerosol can be by being suspended or dissolved in liquefied propellant preparation by compound disclosed in this invention.It is suitable for Propellant include chlorohydrocarbon, hydro carbons and other liquid gas.Representational propellant includes: Arcton 11 (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoro Ethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, Perfluorinated butane, perflenapent, butane, iso-butane and pentane.The aerosol comprising compound disclosed in this invention generally passes through Patient is administered by metered dose inhaler (MDI).Such device dawn known to those skilled in the art.
Aerosol can comprise pharmaceutically acceptable excipient extra, that can be used, such as surface activity by MDIs Agent, lubricant, cosolvent and other excipient, with improve preparation physical stability, improve valve characteristic, improve dissolubility, Or improve taste.
The pharmaceutical composition being suitable for transdermal administration can be prepared as discontinuous paster agent, it is intended that keeps with the epidermis of patient It is in close contact the time of an elongated segment.Such as, delivering active ingredients from paster agent can be permeated by ion, as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for the pharmaceutical composition of topical can be formulated into ointment, ointment, suspensoid, lotion, powder, Solution, paste, gel, spray, aerosol or oil preparation.Such as, ointment, ointment and gel can be with water or oil Substrate, and the thickening agent and/or gel and/or the solvent that are suitable for configure.Such substrate can include, water, and/or oil example Such as liquid-liquid paraffin and vegetable oil (such as Oleum Arachidis hypogaeae semen or Oleum Ricini), or solvent such as Polyethylene Glycol.Make according to medium property Thickening agent and gel include soft paraffin, aluminium stearate, cetearyl alcohol, Polyethylene Glycol, lanoline, Cera Flava, poly-carboxylic second Alkene and cellulose derivative, and/or glyceryl monostearate and/or nonionic emulsifier.
Lotion can be prepared with water or oil matrix, and generally also contains one or more emulsifying agents, stabilizer, dispersion Agent, suspending agent or thickening agent.
Externally-applied powder can molding in the presence of powder the substrate such as Pulvis Talci, lactose or starch being arbitrarily suitable for.Drop Can be formulated with the water or non-aqueous matrix comprising one or more dispersants, solubilizing agent, suspending agent or preservative.
Topical formulations can be by applying one or many to be administered every day in affected part；The impermeable plastic wound dressing covering skin is preferential Used.The administration that adhesiveness store system can realize continuously or extend.
The compounds of this invention and the purposes of compositions
Compound disclosed in this invention or pharmaceutical composition may be used for preparing for treating, prevent, improve, control or Alleviate mammal, relevant with hyperuricemia including the treatment hyperuricemia of the mankind, tophus, gouty arthritis Nephropathy and the medicine of urinary calculus, it is also possible to be used for suppressing xanthine oxidase and/or urate anion to turn for preparation Other medicines of fortune body-1 activity.
Specifically, in the compositions of the present invention, the amount of compound can the most detectably suppress xanthine oxidase And/or urate anion transport body-1, the compound of the present invention can be as prevention or treatment mankind's hyperuricemia, gout Nephropathy that stone, gouty arthritis are relevant with hyperuricemia and the medicine of urinary calculus.
Compound or the compositions of the present invention can apply to, but are not limited to, and use compound or the combination of the present invention Patient is administered and prevents, treat or alleviate mammal by the effective dose of thing, including the hyperuricemia of the mankind, tophus, bitterly Nephropathy that wind arthritis is relevant with hyperuricemia and urinary calculus.
The compound of the present invention and pharmaceutical composition, in addition to useful to human treatment, apply also for veterinary treatment and dote on Mammal in the animal on thing, the animal of introduced variety and farm.The example of other animal includes horse, Canis familiaris L. and cat.? This, the compound of the present invention includes its pharmaceutically acceptable derivates.
General synthesis step
For describing the present invention, it is listed below embodiment.But it is to be understood that the invention is not restricted to these embodiments, simply The method putting into practice the present invention is provided.
Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment are used for being further illustrated by this The content of invention.
The professional of art is it will be appreciated that chemical reaction described in the invention can be used to prepare perhaps suitably Other compounds of many present invention, and it is considered as the model in the present invention for other method of the compound of preparing the present invention Within enclosing.Such as, the synthesis according to the compound of those non-illustrations of the present invention can be successfully by those skilled in the art Completed by method of modifying, as group is disturbed in suitable protection, by utilizing reagent known to other except described in the invention , or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applicable to the preparation of other compounds of the present invention.
The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, the most not through being further purified, unless other aspects show during use.General reagent is western Gansu Province chemical industry from Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Tianjin good fortune chemistry in morning Chemical reagent work, Wuhan Xin Huayuan development in science and technology company limited, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao purchase Can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, normal hexane, N,N-dimethylacetamide and N, N- Dimethylformamide is to be dried in advance through anhydrous sodium sulfate to use.
Hereinafter reaction is usually and overlaps a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb the most suitable rubber closure, substrate is squeezed into by syringe.Glass drying oven is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
NMR (Nuclear Magnetic Resonance) spectrum uses Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer record, with CDC13、DMSO-d6、 CD3OD or acetone-d6For solvent (in units of ppm), with TMS (0ppm) or chloroform (7.26ppm) as reference standard.When going out The when of existing multiplet, by use following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t (triplet, three Weight peak), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double double Peak), dt (doublet of triplets, double triplets).Coupling constant, represents with hertz (Hz).
The condition determination of Algorithm (MS) data is: Agilent 6120 level Four bar HPLC-M (pillar model: Zorbax SB-C18,2.1x30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Phase: 5%-95% is (containing 0.1% first in flowing The CH of acid3CN) at (H containing 0.1% formic acid2O) ratio in), use electron spray ionisation (ESI), under 210nm/254nm, use UV detects.
Compound purity uses high performance liquid chromatography (HPLC) to measure, use Agilent 1260HPLC (pillar model: Agilent zorbax Eclipse Plus C18), and detect with DAD detector, final employing area normalization method calculates To compound purity.
The use of brief word below runs through the present invention:
CDC13Deuterochloroform；
CD3OD deuterated methanol；
CDI N, N'-carbonyl dimidazoles；
DMAP DMAP；
DMF N,N-dimethylformamide；
DMSO dimethyl sulfoxide；
DMSO-d6Deuterated dimethyl sulfoxide；
G gram；
D days
H hour；
Min minute；
Mmol mM；
M mole every liter；
DEG C degree Celsius；
H2SO4Sulphuric acid；
HATU 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester；
NBS N-bromosuccinimide bromine；
MeCN、CH3CN acetonitrile；
MeOH methanol；
ML, ml milliliter；
RT, rt, r.t. room temperature；
Rpm rpm；
The preparation present invention comes into the open the typical synthesis step of compound as shown in following synthetic schemes.Unless otherwise indicated, E、R1、R2、R3、R4、R5, each R and m there is as described in the present invention definition.
Synthetic schemes 1
Wherein, L represents leaving group；
Compound (a) generates compound (I) after reacting with compound (b).The leaving group represented as L includes but does not limits In halogen atom, mesyl epoxide, to Methyl benzenesulfonyl base epoxide etc..
The compound, pharmaceutical composition and the application thereof that there is provided the present invention below in conjunction with embodiment are further described.
Embodiment
Embodiment 1:1-(3-oxo-2,3-dihydrobenzo [d] isoxazole-6-base)-1H-indole-3-formonitrile
First step 4-fluoro-2-(methoxymethoxy) essence of Niobe
By fluoro-for 4-2 hydroxybenzoic acid methyl ester (3.7g, 22mmol), DIPEA (11mL, 66mmol) and Dichloromethane (50mL) adds in 250mL single port bottle, at 0 DEG C, drip in reaction bulb chloromethyl methyl ether (7.3mL, 43mmol), after dropping, reactant mixture under nitrogen protection, is stirred at room temperature 16h.Removal of solvent under reduced pressure, in residue Adding saturated aqueous ammonium chloride (200mL), aqueous phase ethyl acetate (100mL × 2) extracts, and merges organic facies.Organic facies is used Saturated aqueous common salt (100mL) washs, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure.Residue is through silica gel column chromatography (acetic acid second Ester/petroleum ether (v/v)=1/20), obtain title compound (faint yellow solid, 4.67g, 99%).
Second step 4-(3-cyano-1 H-indol-1-base)-2-(methoxymethoxy) essence of Niobe
By fluoro-for 4-2-(methoxymethoxy) essence of Niobe (4.6g, 21mmol), 1H-indole-3-formonitrile (3.1g, 22mmol), cesium carbonate (14g, 43mmol) and dry DMF (20mL) add in 100mL single port bottle, and reactant mixture is protected at nitrogen Protect down, at 80 DEG C, stir 18h.Reactant mixture is cooled to room temperature, in reaction bulb, adds saturated aqueous ammonium chloride (150mL), aqueous phase ethyl acetate (100mL × 2) extracts, and merges organic facies.Organic facies saturated aqueous common salt (100mL) is washed Washing, anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure.Residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/ 5) title compound (yellow solid, 4.87g, 69%), is obtained.
MS(ES-API,pos.ion)m/z:337.1[M+1]+。
3rd step 4-(3-cyano-1 H-indol-1-base)-2 hydroxybenzoic acid methyl ester
By 4-(3-cyano-1 H-indol-1-base)-2-(methoxymethoxy) essence of Niobe (5.0g, 15mmol), first Alcohol (50mL) and oxolane (50mL) add in 250mL single port bottle, then add concentrated hydrochloric acid (3mL, 36%) in reaction bulb, Reactant mixture stirs 8h at 70 DEG C.Reactant mixture is cooled to room temperature, in reaction bulb, adds saturated aqueous ammonium chloride (150mL), aqueous phase ethyl acetate (100mL × 2) extracts, and merges organic facies.Organic facies saturated aqueous common salt (100mL) is washed Washing, anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure.Residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/ 5) title compound (faint yellow solid, 2.85g, 65%), is obtained.
MS(ES-API,pos.ion)m/z:293.0[M+1]+。
4th step 4-(3-cyano-1 H-indol-1-base)-N, 2-dihydroxy benzoyl amine
By 4-(3-cyano-1 H-indol-1-base)-2 hydroxybenzoic acid methyl ester (1.56g, 5.34mmol), methanol (25mL) Add in 100mL single port bottle with oxolane (25mL), be then sequentially added in reaction bulb oxammonium hydrochloride. (445mg, 6.40mmol) aqueous solution (6.4mL) and sodium hydroxide (1.07g, 26.8mmol), reactant mixture is stirred at room temperature 24h.Subtract Pressure removes solvent, adds water (100mL), then with dilute hydrochloric acid, the pH of system is adjusted to 8, aqueous phase ethyl acetate in residue (100mL × 2) extract, and merge organic facies.Organic facies saturated aqueous common salt (100mL) washs, and anhydrous sodium sulfate is dried, and filters, Concentrating under reduced pressure.Residue is through silica gel column chromatography (ethanol/methylene (v/v)=1/50), and (yellow is solid to obtain title compound Body, 1.0g, 64%).
MS(ES-API,pos.ion)m/z:294.1[M+1]+。
5th step 1-(3-oxo-2,3-dihydrobenzo [d] isoxazole-6-base)-1H-indole-3-formonitrile
By 4-(3-cyano-1 H-indol-1-base)-N, 2-dihydroxy benzoyl amine (700mg, 2.39mmol), CDI (1.55g, 9.56mmol), DMAP (58mg, 0.478mmol) and oxolane (30mL) add in 100mL single port bottle, and reaction is mixed Compound stirs 12h at 80 DEG C.Reactant mixture is cooled to room temperature, in reaction bulb, adds saturated aqueous common salt (80mL), aqueous phase Extract by ethyl acetate (40mL × 2), merge organic facies.Organic facies saturated aqueous common salt (60mL) washs, and anhydrous sodium sulfate is done Dry, filter, concentrating under reduced pressure.Residue, through silica gel column chromatography (ethanol/methylene (v/v)=1/200), obtains title compound (pale solid, 300mg, 46%).
MS(ES-API,pos.ion)m/z:276.1[M+1]+。
1H NMR(400MHz,DMSO-d6) δ (ppm) 8.69 (s, 1H), 8.09 (d, J=8.4Hz, 1H), 7.94 (s, 1H), 7.78 7.76 (m, 1H), 7.71 7.69 (m, 1H), 7.62 (dd, J=8.4,1.4Hz, 1H), 7.43 7.38 (m, 2H).
Embodiment 2:1-(3-oxo-2,3-dihydrobenzo [d] [1,2] selenazoles-6-base)-1H-indole-3-formonitrile
The bromo-4-of first step 2-(3-cyano-1 H-indol-1-base) essence of Niobe
By bromo-for 2-4-fluorophenyl carbamate (4.89g, 21mmol), 1H-indole-3-formonitrile (3.1g, 22mmol), carbonic acid Caesium (14g, 43mmol) and dry DMF (30mL) add in 100mL single port bottle, reactant mixture 80 DEG C of stirrings under nitrogen protection 18h.Reactant mixture is cooled to room temperature, in reaction bulb, adds saturated aqueous ammonium chloride (150mL), aqueous phase acetic acid second Ester (100mL × 2) extracts, and merges organic facies.Organic facies saturated aqueous common salt (100mL) washs, and anhydrous sodium sulfate is dried, mistake Filter, concentrating under reduced pressure.Residue, through silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/5), obtains title compound (yellow Solid, 5.7g, 76%).
MS(ES-API,pos.ion)m/z:355.0[M+1]+。
The bromo-4-of second step 2-(3-cyano-1 H-indol-1-base) Benzoylamide
By bromo-for 2-4-(3-cyano-1 H-indol-1-base) essence of Niobe (1.90g, 5.35mmol), oxolane (30mL) methanol solution (40mL, 7M) with ammonia adds in the airtight tube sealing of 50mL, and reactant mixture stirs 15h at 150 DEG C.Will Reactant mixture is cooled to room temperature, organic facies concentrating under reduced pressure.Residue is through silica gel column chromatography (ethanol/methylene (v/v)=1/ 100) title compound (faint yellow solid, 670mg, 37%), is obtained.
MS(ES-API,pos.ion)m/z:340.0[M+1]+。
3rd step 1-(3-oxo-2,3-dihydrobenzo [d] [1,2] selenazoles-6-base)-1H-indole-3-formonitrile
By Hydro-Giene (Water Science). (144mg, 0.76mmol), 1,10-phenanthroline (138mg, 0.76mmol) and dry DMF (20mL) Adding in 100mL single port bottle, reactant mixture is stirred at room temperature 0.5h.Then, in reaction bulb, it is sequentially added into the bromo-4-of 2- (3-cyano-1 H-indol-1-base) Benzoylamide (1.29g, 3.79mmol), selenium powder (360mg, 4.54mmol) and potassium carbonate (1.05g, 7.61mmol), reactant mixture 130 DEG C of stirring 24h under nitrogen protection.Reactant mixture is cooled to room temperature, to Adding saturated aqueous common salt (80mL) in reaction bulb, aqueous phase ethyl acetate (40mL × 2) extracts, and merges organic facies.Organic facies is used Saturated aqueous common salt (60mL) washs, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure.Residue is through silica gel column chromatography (methanol/bis- Chloromethanes (v/v)=1/200), obtain title compound (light yellow solid, 70mg, 5.5%).
MS(ES-API,pos.ion)m/z:340.0[M+1]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)9.36(s,1H),8.71(s,1H),8.35(s,1H),8.01(d,J =8.2Hz, 1H), 7.79 (d, J=6.9Hz, 1H), 7.69 (d, J=7.8Hz, 2H), 7.47 7.38 (m, 2H).
Embodiment 3:1-(3-oxo-2,3-dihydrobenzo [d] isothiazole-6-base)-1H-indole-3-formonitrile
First step 4-bromo-2-fluorobenzamide
Ammonia (100mL, 28%) is added in 250mL single port bottle, in reaction bulb, slowly drips 4-bromo-2-fluorobenzoyl Dichloromethane (50mL) solution of chlorine (5.62g, 23.7mmol), after dropping, reactant mixture is stirred at room temperature 1.0h. Aqueous phase, with dichloromethane (80mL × 2), merges organic facies.Organic facies saturated aqueous common salt (100mL) washs, and anhydrous sodium sulfate is done Dry, filter, concentrating under reduced pressure.Residue, through silica gel column chromatography (ethyl acetate/dichloromethane (v/v)=1/30), obtains titled Compound (white solid, 4.80g, 93%).
MS(ES-API,pos.ion)m/z:218.9[M+2]+。
Second step 2-(benzylthio)-4-brombenzamide
Anhydrous tetrahydro furan (30mL) is added in 100mL two-mouth bottle, at 0 DEG C, in reaction bulb, add sodium hydride (840mg, 21.0mmol), then drips benzyl mercaptan (2.04mL, 17.4mmol) in reaction bulb, and after dropping, reaction is mixed Compound is stirred at room temperature 1h.Reaction mixture is slowly added to another equipped with 4-bromo-2-fluorobenzamide (3.77g, In the anhydrous tetrahydrofuran solution of 30mL 17.3mmol), after dropping, reactant mixture stirs 0.5h at 0 DEG C, then 3h is stirred at 90 DEG C.Reactant mixture is cooled to room temperature, in reaction bulb, adds saturated aqueous ammonium chloride (100mL), Aqueous phase ethyl acetate (80mL × 2) extracts, and merges organic facies.Organic facies saturated aqueous common salt (100mL) washs, anhydrous slufuric acid Sodium is dried, and filters, concentrating under reduced pressure.Residue, through silica gel column chromatography (ethyl acetate/dichloromethane (v/v)=1/10), is marked Topic compound (white solid, 3.6g, 65%).
MS(ES-API,pos.ion)m/z:322.9[M+2]+。
3rd step 6-bromobenzene also [d] isothiazole-3 (2H)-one
2-benzyl-mercapto-4-brombenzamide (5.3g, 16mmol) and dichloromethane (150mL) are added 500mL single port bottle In, in reaction bulb, adding sulfonic acid chloride (3.3g, 24mmol), reactant mixture is stirred at room temperature 3h.Add in reaction bulb Pentane (80mL), the white solid sucking filtration that will separate out, filter cake pentane washs, and is dried, and (white is solid to obtain title compound Body, 3.37g, 89%).
MS(ES-API,pos.ion)m/z:230.9[M+2]+。
4th step 1-(3-oxo-2,3-dihydrobenzo [d] isothiazole-6-base)-1H-indole-3-formonitrile
By 6-bromobenzene also [d] isothiazole-3 (2H)-one (1.15g, 5.0mmol), 1H-indole-3-formonitrile (0.86g, 6.0mmol), potassium carbonate (2.1g, 15mmol), Hydro-Giene (Water Science). (390mg, 2.0mmol), DMG (103mg, 1.0mmol) adding in 50mL single port bottle with dry DMF (20mL), reactant mixture under nitrogen protection, stirs at 200 DEG C 36h.Reactant mixture is cooled to room temperature, in reaction bulb, adds saturated aqueous ammonium chloride (100mL), aqueous phase acetic acid second Ester (80mL × 2) extracts, and merges organic facies.Organic facies saturated aqueous common salt (100mL) washs, and anhydrous sodium sulfate is dried, and filters, Concentrating under reduced pressure.Residue, through silica gel column chromatography (oxolane/ethyl acetate (v/v)=1/10), obtains title compound (yellowish Color solid, 90mg, 6.2%).
MS(ES-API,pos.ion)m/z:292.0[M+1]+。
1H NMR(600MHz,DMSO-d6) δ (ppm) 11.89 (s, 1H), 8.71 (s, 1H), 8.37 (d, J=1.7Hz, 1H), 8.08 (d, J=8.4Hz, 1H), 7.80 7.79 (m, 1H), 7.72 7.71 (m, 2H), 7.45 7.40 (m, 2H).
Embodiment 4:1-(3-oxo-2,3-dihydro-1H-indazole-6-base)-1H-indole-3-formonitrile
First step 4-(3-cyano-1 H-indol-1-base)-2-fluorophenyl carbamate
By 2,4 difluorobenzene methyl formate (2.70g, 15.7mmol), 1H-indole-3-formonitrile (1.85g, 13.0mmol), Cesium carbonate (8.7g, 27mmol) and dry DMF (25mL) add in 100mL single port bottle, reactant mixture under nitrogen protection, 48h is stirred at 80 DEG C.Reactant mixture is cooled to room temperature, in reaction bulb, adds saturated aqueous ammonium chloride (100mL), water Extract by ethyl acetate (80mL × 2) mutually, merge organic facies.Organic facies saturated aqueous common salt (100mL) washs, anhydrous sodium sulfate It is dried, filters, concentrating under reduced pressure.Residue, through silica gel column chromatography (dichloromethane/petroleum ether (v/v)=1/1), obtains title compound Thing (pale red solid, 800mg, 21%).
MS(ES-API,pos.ion)m/z:295.0[M+1]+。
Second step 4-(3-cyano-1 H-indol-1-base)-2-hydrazino-benzoic acid methyl ester
By 4-(3-cyano-1 H-indol-1-base)-2-fluorophenyl carbamate (810mg, 2.8mmol), ethanol (50mL) and Oxolane (100mL) adds in 250mL single port bottle, then adds hydrazine hydrate (5mL, 98%), reaction mixing in reaction bulb Thing stirs 24h at 70 DEG C.Reactant liquor is cooled to room temperature, concentrating under reduced pressure.Residue is through silica gel column chromatography (dichloromethane/stone Oil ether (v/v)=3/1), obtain title compound (light yellow solid, 360mg, 42%).
MS(ES-API,pos.ion)m/z:307.1[M+1]+。
3rd step 1-(3-oxo-2,3-dihydro-1H-indazole-6-base)-1H-indole-3-formonitrile
By 4-(3-cyano-1 H-indol-1-base)-2-hydrazino-benzoic acid methyl ester (350mg, 1.1mmol), methanol (6mL), Oxolane (6mL) and water (6mL) add in 100mL single port bottle, at 0 DEG C, add in reaction bulb Lithium hydrate (140mg, 5.8mmol), reactant mixture stirs 12h at 0 DEG C.Decompression removes organic solvent, adds water (60mL), water in residue Washed once with ether (50mL) mutually.Aqueous phase is 1 with the acidified with citric acid pH value of 10%, extracts by ethyl acetate (40mL × 2), Merge organic facies.Organic facies saturated aqueous common salt (40mL × 2) washs, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure.Residual Thing through silica gel column chromatography (oxolane/dichloromethane (v/v)=1/3), obtain title compound (light yellow solid, 230mg, 77%).
MS(ES-API,neg.ion)m/z:273.1[M-1]-。
1H NMR(400MHz,DMSO-d6)δ(ppm)11.83(s,1H),10.81(s,1H),8.65(s,1H),7.85(d, J=8.5Hz, 1H), 7.78 7.76 (m, 1H), 7.63 7.61 (m, 1H), 7.54 (s, 1H), 7.40 7.36 (m, 2H), 7.24 7.21(m,1H)。
Embodiment 5:1-(1-acetyl group-3-oxo-2,3-dihydro-1H-indazole-6-base)-1H-indole-3-formonitrile
By 1-(3-oxo-2,3-dihydro-1H-indazole-6-base)-1H-indole-3-formonitrile (1.00g, 3.65mmol), pyrrole Pyridine (790mg, 10.0mmol) and toluene (50mL) add in 100mL single port bottle, then add chloroacetic chloride in reaction bulb (310mg, 4.0mmol), reactant mixture is stirred at room temperature 18h.Ethyl acetate (100mL) is added in reaction bulb, organic The most successively with dilute hydrochloric acid (80mL, 2M) and saturated aqueous common salt (80mL) washing, anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure.Residual Stay thing through silica gel column chromatography (ethyl acetate/dichloromethane (v/v)=1/50), obtain title compound (faint yellow solid, 150mg, 13%).
MS(ES-API,pos.ion)m/z:317.1[M+1]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)12.36(s,1H),8.72(s,1H),8.45(s,1H),8.01(d,J =8.4Hz, 1H), 7.80 7.78 (m, 1H), 7.67 7.64 (m, 2H), 7.44 7.39 (m, 2H), 2.60 (s, 3H).
Embodiment 6:1-(1-cyclopropyl formoxyl-3-oxo-2,3-dihydro-1H-indazole-6-base)-1H-indole-3-first Nitrile
By ethylene-acetic acid (88mg, 1.0mmol), HATU (400mg, 1.1mmol), 1-(3-oxo-2,3-dihydro-1H- Indazole-6-base)-1H-indole-3-formonitrile (274mg, 1.0mmol) and DMF (6mL) add in 100mL single port bottle, then to instead Answering and add DIPEA (530 μ L, 3.0mmol) in bottle, reactant mixture is stirred at room temperature 12h.To reaction bulb Middle addition ethyl acetate (80mL), organic facies is washed with saturated sodium bicarbonate aqueous solution (80mL) and saturated aqueous common salt (80mL) successively Washing, anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure.Residue is through silica gel column chromatography (ethyl acetate/dichloromethane (v/v)=1/ 10) title compound (white solid, 60mg, 18%), is obtained.
MS(ES-API,pos.ion)m/z:343.1[M+1]+。
1H NMR(600MHz,DMSO-d6) δ (ppm) 12.34 (s, 1H), 8.69 (s, 1H), 8.44 (d, J=1.6Hz, 1H), 8.02 (d, J=8.4Hz, 1H), 7.79 7.77 (m, 1H), 7.67 7.65 (m, 2H), 7.43 7.39 (m, 2H), 2.97 2.93(m,1H),1.23–1.21(m,2H),1.12–1.09(m,2H)。
Embodiment 7:1-(2-oxo-2,3-dihydrobenzo [d] [1,3] oxazole-6-base)-1H-indole-3-formonitrile
First step 6-bromobenzene also [d] oxazole-2 (3H)-one
By 2-amino-5-bromophenol (2.0g, 10.6mmol), N, N'-carbonyl dimidazoles (1.72g, 10.6mmol) and nothing Water DMF (20mL) adds in 100mL single port bottle, and reactant mixture stirs 20h at 60 DEG C.Reactant mixture is cooled to room Temperature, adds saturated aqueous ammonium chloride (100mL) in residue, and aqueous phase ethyl acetate (60mL × 2) extracts, and merges organic Phase.Organic facies saturated aqueous common salt (60mL) washs, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure.Residue is through silica gel column layer Analysis (ethyl acetate/petroleum ether (v/v)=1/4), obtains title compound (brown solid, 2.26g, 97%).
Second step 1-(2-oxo-2,3-dihydrobenzo [d] [1,3] oxazole-6-base)-1H-indole-3-formonitrile
By 6-bromobenzene also [d] oxazole-2 (3H)-one (1.00g, 4.67mmol), 1H-indole-3-formonitrile (0.797g, 5.60mmol), potassium carbonate (1.93g, 14.0mmol), Hydro-Giene (Water Science). (178mg, 0.94mmol), DMG (96mg, 0.931mmol) and dry DMF (12mL) add in 20mL microwave tube, reactant mixture under nitrogen protection 130 DEG C stir Mix 2h.Reactant mixture is cooled to room temperature, in reaction bulb, adds saturated aqueous ammonium chloride (100mL), aqueous phase acetic acid Ethyl ester (80mL × 2) extracts, and merges organic facies.Organic facies saturated aqueous common salt (100mL) washs, and anhydrous sodium sulfate is dried, mistake Filter, concentrating under reduced pressure.Residue, through silica gel column chromatography (ethyl acetate/dichloromethane (v/v)=1/4), obtains title compound (light Yellow solid, 1.29g, 16%).
MS(ES-API,pos.ion)m/z:276.1[M+1]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)12.00(s,1H),8.54(s,1H),7.81–7.73(m,1H), 7.70 (d, J=1.8Hz, 1H), 7.59 7.51 (m, 1H), 7.44 7.35 (m, 3H), 7.30 (d, J=8.2Hz, 1H).
Embodiment 8:1-(3-hydroxyl-1-aoxidizes benzo [d] isothiazole-6-base)-1H-indole-3-formonitrile
By 1-(3-oxo-2,3-dihydrobenzo [d] isothiazole-6-base)-1H-indole-3-formonitrile (140mg, 0.48mmol) add in 50mL single port bottle with oxolane (12mL), in reaction bulb, then add saturated sodium metaperiodate water Solution (10mL), reactant mixture is stirred at room temperature 7d.Decompression remove oxolane, in residue add water (80mL) and Potassium carbonate (1.0g).Aqueous phase ether (40mL × 2) extracts, then, with dilute hydrochloric acid acidifying pH value to 4, and aqueous phase ethyl acetate (60mL × 2) extract, and merge organic facies.Organic facies saturated aqueous common salt (100mL) washs, and anhydrous sodium sulfate is dried, and filters, subtracts Pressure concentrates.Residue is through silica gel column chromatography (ethyl acetate/dichloromethane (v/v)=1/15), and (white is solid to obtain title compound Body, 60mg, 41%).
MS(ES-API,pos.ion)m/z:308.0[M+1]+。
1H NMR(600MHz,DMSO-d6)δ(ppm)11.68(s,1H),8.76(s,1H),8.56–8.54(m,1H), 8.14 (s, 2H), 7.81 7.80 (m, 1H), 7.73 (d, J=7.9Hz, 1H), 7.48 7.42 (m, 2H).
Embodiment 9:1-(1-cyclopropyl-3-oxo-2,3-dihydro-1H-indazole-6-base)-1H-indole-3-formonitrile
By 1-(3-oxo-2,3-dihydro-1H-indazole-6-base)-1H-indole-3-formonitrile (411mg, 1.5mmol), bromo Cyclopropane (272mg, 2.25mmol), cesium carbonate (980mg, 3.0mmol) and dry DMF (12mL) add in 20mL microwave tube, Under nitrogen protection, 200 DEG C are stirred 1.5h to reactant mixture.Reactant mixture is cooled to room temperature, adds full in reaction bulb With aqueous ammonium chloride solution (100mL), aqueous phase ethyl acetate (80mL × 2) extracts, and merges organic facies.Organic facies saturated common salt Water (100mL) washs, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure.Residue is through silica gel column chromatography (ethyl acetate/dichloromethane Alkane (v/v)=1/30), obtain title compound (faint yellow solid, 40mg, 8.5%).
MS(ES-API,pos.ion)m/z:315.1[M+1]+。
1H NMR(400MHz,DMSO-d6) δ (ppm) 11.03 (s, 1H), 8.67 (s, 1H), 7.83 (d, J=8.5Hz, 1H), 7.79 7.77 (m, 1H), 7.73 (d, J=1.2Hz, 1H), 7.69 7.66 (m, 1H), 7.43 7.40 (m, 2H), 7.29 7.26(m,1H),3.51–3.48(m,1H),1.06–1.02(m,4H)。
Embodiment 10:1-(2,4-dioxo-3,4-dihydro-2H-benzo [e] [1,3] oxazines-7 base)-1H-indole-3-first Nitrile
First step 7-bromo-2H-benzo [e] [1,3] oxazines-2,4 (3H)-diketone
By bromo-for 4-2 hydroxybenzoic acid methyl ester (850mg, 3.93mmol), pyridine (380 μ L, 4.7mmol) and anhydrous acetonitrile (10mL) add in 100mL single port bottle, at 0 DEG C, in reaction bulb, drip ethyl chloroformate (410 μ L, 4.3mmol), dropping After, reactant mixture stirs 0.5h at 0 DEG C, then stirs 14h at 90 DEG C.Reactant mixture is cooled to room temperature, Adding saturated aqueous ammonium chloride (100mL) in residue, aqueous phase ethyl acetate (60mL × 2) extracts, and merges organic facies. Organic facies saturated aqueous common salt (60mL) washs, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure.Residue is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/4), obtains title compound (white solid, 700mg, 74%).
MS(ES-API,pos.ion)m/z:242.9[M+2]+。
Second step 4-(3-cyano-1 H-indol-1-base)-2-Hydroxylbenzamide
By bromo-for 7-2H-benzo [e] [1,3] oxazines-2,4 (3H)-diketone (300mg, 1.24mmol), 1H-indole-3-first Nitrile (210mg, 1.48mmol), potassium carbonate (510mg, 3.72mmol), Hydro-Giene (Water Science). (47mg, 0.248mmol), N, N-dimethyl Glycine (26mg, 0.248mmol) and dry DMF (6mL) add in 20mL microwave tube, reactant mixture under nitrogen protection, 200 DEG C of stirring 2h.Reactant mixture is cooled to room temperature, in reaction bulb, adds saturated aqueous ammonium chloride (100mL), aqueous phase Extract by ethyl acetate (80mL × 2), merge organic facies.Organic facies saturated aqueous common salt (100mL) washs, and anhydrous sodium sulfate is done Dry, filter, concentrating under reduced pressure.Residue, through silica gel column chromatography (ethanol/methylene (v/v)=1/50), obtains title compound (faint yellow solid, 0.117g, 34%).
MS(ES-API,pos.ion)m/z:278.1[M+1]+。
3rd step 1-(2,4-dioxo-3,4-dihydro-2H-benzo [e] [1,3] oxazines-7 base)-1H-indole-3-formonitrile
By 4-(3-cyano-1 H-indol-1-base)-2-Hydroxylbenzamide (110mg, 0.40mmol), pyridine (60 μ L, 0.70mmol) add in 100mL single port bottle with anhydrous acetonitrile (8mL), at 0 DEG C, in reaction bulb, drip ethyl chloroformate (60 μ L, 0.60mmol), after dropping, reactant mixture stirs 0.5h at 0 DEG C, then stirs 24h at 90 DEG C.Will reaction Mixture is cooled to room temperature, adds saturated sodium bicarbonate aqueous solution (80mL) in residue, is filtered by the solid separated out, dry Dry, obtain title compound (yellow solid, 21mg, 17%).
MS(ES-API,neg.ion)m/z:302.0[M-1]-。
1H NMR(600MHz,DMSO-d6) δ (ppm) 8.73 (s, 1H), 8.14 (d, J=8.4Hz, 1H), 7.85 7.69 (m,4H),7.47–7.42(m,2H)。
Embodiment 11:1-(3-oxo-1-(thiophene-2-carbonyl)-2,3-dihydro-1H-indazole-6-base)-1H-indole-3- Formonitrile HCN
By thiophene-2-carboxylic acid (70mg, 0.55mmol), carbonyl dimidazoles (112mg, 0.691mmol), dichloromethane (4mL) adding in 100mL single port bottle with DMF (4mL), reactant mixture is stirred at room temperature 4h.Then add in reaction bulb 1-(3-oxo-2,3-dihydro-1H-indazole-6-base)-1H-indole-3-formonitrile (150mg, 0.547mmol), reactant mixture exists 12h is stirred under room temperature.Adding ethyl acetate (80mL) in reaction bulb, organic facies is successively with dilute hydrochloric acid (80mL, 2M) and saturated Saline solution (80mL) washs, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure.Residue is through silica gel column chromatography (ethyl acetate/bis- Chloromethanes (v/v)=1/10), obtain title compound (white solid, 84mg, 40%).
MS(ES-API,pos.ion)m/z:385.1[M+1]+。
1H NMR(400MHz,DMSO-d6) δ (ppm) 12.59 (s, 1H), 8.76 (s, 1H), 8.61 (d, J=1.5Hz, 1H), 8.38 (dd, J=3.8,1.1Hz, 1H), 8.13 (dd, J=5.0,1.1Hz, 1H), 8.09 (d, J=8.4Hz, 1H), 7.84–7.78(m,1H),7.76–7.70(m,2H),7.49–7.39(m,2H),7.35–7.29(m,1H)。
Embodiment 12:1-(1-benzoyl-3-oxo-2,3-dihydro-1H-indazole-6-base)-1H-indole-3-formonitrile
By benzoic acid (67mg, 0.55mmol), N, N'-carbonyl dimidazoles (112mg, 0.691mmol), dichloromethane (4mL) adding in 100mL single port bottle with DMF (4mL), reactant mixture is stirred at room temperature 4h.Then add in reaction bulb 1-(3-oxo-2,3-dihydro-1H-indazole-6-base)-1H-indole-3-formonitrile (150mg, 0.547mmol), reactant mixture exists 12h is stirred under room temperature.Adding ethyl acetate (80mL) in reaction bulb, organic facies is successively with dilute hydrochloric acid (80mL, 2M) and saturated Saline solution (80mL) washs, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure.Residue, through silica gel column chromatography (dichloromethane), obtains To title compound (light yellow solid, 65mg, 31%).
MS(ES-API,pos.ion)m/z:379.1[M+1]+。
1H NMR(400MHz,DMSO-d6)δ(ppm)12.43(s,1H),8.76(s,1H),8.59(s,1H),8.05(d,J =8.4Hz, 1H), 7.98 (d, J=7.4Hz, 2H), 7.81 (d, J=7.3Hz, 1H), 7.72 7.71 (m, 2H), 7.64 7.62 (m,1H),7.56–7.54(m,2H),7.47–7.40(m,2H)。
Biological activity test
Test example 1 XO (xanthine oxidase) inhibitory activity measures
1) test method
Compound buffer (50mM potassium dihydrogen phosphate) 2.5 times dilute a series of concentration, from 2000nM to 0.524nM, adds to 384 orifice plates with the amount in 30 μ L/ holes；Every hole adds 30 μ L concentration afterwards is the xanthine oxidase of 21mU/mL Changing enzyme, 3000rpm is centrifuged room temperature oscillation incubation 10min after 1min；Then every hole adds the substrate (Huang that 30 μ L concentration are 600 μMs Purine)；Buffer disposal hole (without compound, add same concentrations enzyme and substrate) and negative control hole are set simultaneously (without chemical combination Thing and enzyme, add same concentrations substrate).PHERAstar FS microplate reader is used to read the suction at 290nm after incubated at room 5min Shading value, uses GraphPad Prism after the suppression ratio by following equation computerized compound suppression xanthine oxidase activity 5 calculate IC50Value, concrete outcome is shown in Table 1.
Suppression ratio (%)=[1-(ODDrug treating hole-ODNegative control hole)/(ODBuffer disposal hole-ODNegative control hole)]×100
2) result of the test
The test result of table 1 the compounds of this invention XO inhibitory activity
Numbering IC50(nM)
Embodiment 1 29.7
Embodiment 3 50.9
Embodiment 4 12.0
Embodiment 10 12.8
Conclusion: the compounds of this invention has preferable inhibitory activity to XO.
Test example 2 URAT1 (uric acid anion transport body-1) inhibitory activity measures
1) test method
The structure of a.hURAT1 stable expression cell strain
By in human URAT 1 plasmid transfection to HEK-293T cell, G418 (Geneticin, Geneticin) is used to obtain people URAT1 stable expression cell strain.
B. uric acid absorbs suppression
Human URAT 1 express cell is seeded in 96 orifice plates, at least hatches and remove culture medium after 12h, and with (Cl-)- Free HBSS buffer solution cell；The four times of dilutions of compound buffer obtain a series of from 200 μMs to 0.8nM concentration 5 μ L compound solutions and the 45 μ L of above-mentioned preparation are contained [8-by compound solution14C] uric acid buffer mixing after add to containing There is in 96 orifice plates of stable transfected cells (i.e. final compound concentration be 20 μMs to 0.08nM), buffering fluid apertures (transfection is set simultaneously Cell, is added without medicine) and negative hole (non-transfected cell is added without medicine)；Hatch removal buffer after 5min, and use for 37 DEG C Buffer solution cell, every hole adds 50 μ L lysis buffers (100mM NaOH solution), is cracked by cell, and 600rpm shakes Shake 10min.1000rpm is centrifuged 5min, pipettes 45 μ L of supernatant liquid to Isoplate-96 microwell plate, and every hole adds 150 μ L Ultima GoldTMXR, and 600rpm shakes 10min.Use MicroBeta Trilux flicker/luminescence counter (PerkinElmer) counting, reads [8-14C] uric acid surplus, suppresses [8-by following equation computerized compound14C] uric acid suction By XLfit computed in software IC after the suppression ratio received50Value, the IC recorded50Value is shown in Table 2.
Suppression ratio (%)=[1-(medicine hole14C picked-up-negative hole14C absorbs)/(buffering fluid apertures14C picked-up-negative hole14C Picked-up)] × 100；
Wherein, negative hole is not for inoculate transfectional cell hole.
2) result of the test
The test result of table 2 the compounds of this invention URAT1 inhibitory activity
Numbering IC50(μM)
Embodiment 3 0.250
Embodiment 5 0.069
Embodiment 6 0.048
Embodiment 9 0.200
Embodiment 10 0.496
Embodiment 12 0.195
Conclusion: the compounds of this invention has preferable inhibitory activity to URAT1.
Pharmacokinetic Evaluation
Test method
Weigh after SD Rat Septal curfew is eaten 15 hours, carry out random packet, test-compound preparation solvent according to body weight For 5%DMSO+5%Solutol+90%Saline.For the test group of intravenous administration, give 1mg/kg to experimental animal Dosage；For the test group of oral administration, experimental animal is given the dosage of 5mg/kg.Then, it is 0,0.083 at time point (only intravenous injection group), 0.25,0.5,1.0,2.0,5.0,7.0 and 24 hours extracting vein bloods (about 0.2mL), be placed in EDTAK2Anti- In solidifying pipe, it is centrifuged 2 minutes at 11000rpm, collects blood plasma, and preserve at-20 DEG C or-70 DEG C until carrying out LC/MS/MS and dividing Analysis.Measure each time point blood plasma drug concentration, calculate pharmacokinetic parameters according to pharmaceutical concentration-time curve.
The pharmacokinetic property of the compounds of this invention passes through above experimental test, has good pharmacokinetics special Levy.
Finally it should be noted that also have other modes to be used for implementing the present invention.Correspondingly, embodiments of the invention are To 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 Amendment or the equivalents added in the claims.All publications or patent cited in the present invention all will be as these Bright list of references.

Claims (10)

1. a compound, it is the stereoisomer of compound shown in the compound shown in formula (I) or formula (I), geometrical isomerism Body, tautomer, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or it before Medicine,
Wherein:
Q is key ,-CH2-,-C (=O)-or-S (=O)2-；
W ring isWherein, E ring is 5-8 unit carbocyclic ring, 5-8 unit heterocycle, phenyl ring or 5-8 unit hetero-aromatic ring；
Each R independently be D-atom, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano group, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxyl, C3-6Cycloalkyl, C1-6Heterocyclic radical, C6-10Aryl, C1-5Heteroaryl ,-C (=O)- C3-6Cycloalkyl ,-C (=O)-C1-6Heterocyclic radical ,-C (=O)-C6-10Aryl ,-C (=O)-C1-5Heteroaryl ,-L1-S (=O)r-L2- RA、C3-6Cycloalkyl-C1-6Alkyl, C6-10Aryl-C1-6Alkyl, C1-5Heteroaryl-C1-6Alkyl or carboxyl；Wherein, each R is individually optional Ground is by 1,2,3,4 or 5 RxReplace；
RAFor C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxyl, C3-6Cycloalkyl, C1-6Heterocyclic radical, C6-10 Aryl or C1-5Heteroaryl；
Each RxIndependently be hydroxyl, oxo (=O), halogen atom, amino, nitro, cyano group, C1-6Alkyl, C1-6Alkoxyl or C1-6Halogen Substituted alkyl；
R1、R2、R3、R4And R5It is each independently hydrogen atom, D-atom, halogen atom, hydroxyl, amino, nitro, cyano group, C1-6Alkane Base, C1-6Haloalkyl, C1-6Alkoxyl, C6-10Aryl or C1-5Heteroaryl；Wherein, each R1、R2、R3、R4And R5Individually optional ground quilt 1,2 or 3 RyReplace；
Each RyIndependently be hydroxyl, oxo (=O), halogen atom, amino, nitro, cyano group, C1-6Alkyl, C1-6Alkoxyl or carboxyl；
M is 0,1,2,3,4 or 5；
R is 0,1 or 2；
L1For key ,-O-or-NH-；
L2For key ,-O-or-NH-；With
Condition is,
W ring is not
Compound the most according to claim 1, wherein, W ring is
Wherein, each X1And X2Independently be-S (=O)t-,-Se-,-O-,-NH-or-CH2-, each t independently be 0,1 or 2；Each Y1 And Y2Independently be N or CH.
Compound the most according to claim 1, wherein, W ring is
Compound the most according to claim 1, wherein, each R independently be D-atom, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano group, methyl, ethyl, n-pro-pyl, isopropyl, the tert-butyl group, vinyl, acetenyl, propargyl, difluoro Methyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, Pyrrolidinyl, phenyl, naphthyl, furyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, thiazolyl, pyridine radicals, pyrimidine radicals, three Nitrogen oxazolyl, tetrazole base ,-C (=O)-cyclopropyl ,-C (=O)-cyclohexyl ,-C (=O)-phenyl ,-C (=O)-thienyl ,-C (=O)-imidazole radicals, ethylsulfonyl, Cvclopropvlmethvl, benzyl, thienyl methyl or carboxyl；Wherein, each R individually optional ground quilt 1,2,3,4 or 5 RxReplace；
Each RxIndependently be hydroxyl, oxo (=O), fluorine, chlorine, bromine, iodine, amino, nitro, cyano group, methyl, methoxyl group or fluoroform Base.
Compound the most according to claim 1, R1、R2、R3、R4And R5Be each independently hydrogen atom, D-atom, fluorine, chlorine, Bromine, iodine, hydroxyl, amino, nitro, cyano group, methyl, ethyl, trifluoromethyl, methoxyl group, phenyl, naphthyl, pyrrole radicals, pyrazolyl, Imidazole radicals, thiazolyl, thienyl, oxazolyl, tetrazole base, pyridine radicals or pyrimidine radicals；Wherein, each R1、R2、R3、R4And R5Independent Optionally by 1,2 or 3 RyReplace；
Each RyIndependently be hydroxyl, oxo (=O), fluorine, chlorine, bromine, iodine, cyano group, methyl, isopropyl, methoxyl group or carboxyl.
Compound the most according to claim 1, has a structure of one of:
Or it is its stereoisomer, several What isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or front Medicine.
7. a pharmaceutical composition, it comprises the compound described in claim 1-6 any one, and pharmaceutically acceptable tax Shape agent, carrier, adjuvant or combinations thereof.
Pharmaceutical composition the most according to claim 7, it comprises other preventions or treatment hyperuricemia, gout further Nephropathy that stone, gouty arthritis are relevant with hyperuricemia and the medicine of urinary calculus, described medicine be colchicine, NSAID (non-steroidal anti-inflammatory drug), glucocorticoid, suppression uricopoiesis medicine, uricosureic agent, urine basifier or their combination in any.
9. the compound described in claim 1-6 any one or the pharmaceutical composition described in claim 7-8 any one exist Preparing the purposes in medicine, described medicine is used for preventing or treating mammal, including the hyperuricemia of the mankind, tophus, Nephropathy that gouty arthritis is relevant with hyperuricemia and urinary calculus.
10. the compound described in claim 1-6 any one or the pharmaceutical composition described in claim 7-8 any one exist Preparing the purposes in medicine, described medicine is used for reducing uric acid level in blood；
Or described medicine is for suppressing urate anion transport body-1 and/or the activity of xanthine oxidase.
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CN108727267B (en) * 2017-05-26 2022-05-13 江苏新元素医药科技有限公司 URAT1 inhibitor and application thereof
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
CN111072647A (en) * 2019-12-11 2020-04-28 沈阳药科大学 3-substituted indole-5-oxo-4, 5-dihydro-1, 2, 4-oxadiazole compound and application thereof
CN111617305A (en) * 2020-04-23 2020-09-04 杭州千芝雅卫生用品有限公司 Preparation method of skin-friendly liquid absorbing material
CN111617305B (en) * 2020-04-23 2021-05-11 杭州千芝雅卫生用品有限公司 Preparation method of skin-friendly liquid absorbing material
CN112778316B (en) * 2021-01-29 2022-03-25 中国医科大学 N- (indole-5-yl) bicyclic aromatic amide compound and preparation method and application thereof
CN112778316A (en) * 2021-01-29 2021-05-11 中国医科大学 N- (indole-5-yl) bicyclic aromatic amide compound and preparation method and application thereof
WO2022220636A1 (en) * 2021-04-16 2022-10-20 주식회사 엘지화학 Oral formulation containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid
WO2022265382A1 (en) * 2021-06-15 2022-12-22 주식회사 엘지화학 Pharmaceutical composition comprising 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid
WO2022265378A1 (en) * 2021-06-15 2022-12-22 주식회사 엘지화학 Pharmaceutical composition comprising 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid
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