CN101190894A - Fatty acid synthetic enzyme inhibitor and medical preparation use thereof - Google Patents

Fatty acid synthetic enzyme inhibitor and medical preparation use thereof Download PDF

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Publication number
CN101190894A
CN101190894A CNA2006101147935A CN200610114793A CN101190894A CN 101190894 A CN101190894 A CN 101190894A CN A2006101147935 A CNA2006101147935 A CN A2006101147935A CN 200610114793 A CN200610114793 A CN 200610114793A CN 101190894 A CN101190894 A CN 101190894A
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Prior art keywords
oxo
carboxylic acid
benzyloxies
pyrroles
dihydro
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Chinese (zh)
Inventor
李松
于红
张学辉
王莉莉
肖军海
郑志兵
钟武
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Institute of Pharmacology and Toxicology of AMMS
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Institute of Pharmacology and Toxicology of AMMS
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Priority to CNA2006101147935A priority Critical patent/CN101190894A/en
Priority to PCT/CN2006/003402 priority patent/WO2008061399A1/en
Publication of CN101190894A publication Critical patent/CN101190894A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/38—2-Pyrrolones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The invention relates to a compound of a general formula I, which is capable of inhibiting synthetase of fatty acid FabH and the medical salt or hydrate thereof. The definition of each substitute group of the general formula I is stated in the manual book. The invention also relates to a preparation method of the compound of the general formula I and comprises medical compositions of the compound of the general formula I or the medical salt or hydrate thereof as well as the application of the compound used for preparing an inhibitor for the synthetase of fatty acid. The compound is also applicable in medical treatment of bacterial infection.

Description

Fatty acid sythetase inhibitor and pharmaceutical applications thereof
Technical field
The present invention relates to pyrrole derivative and pharmacologically acceptable salt thereof as fatty acid sythetase inhibitor (FabH), its preparation method contain their pharmaceutical composition, and described compound is used to prepare the purposes of fatty acid sythetase inhibitor.
Background technology
In all biological organisms, fatty acid biological synthetic (fatty acidbiosynthesis) all is an essential process.Prokaryotic organism and Eukaryotic fatty acid biological are synthetic be by fatty acid synthetase (fatty acid synthase, FAS) catalysis is finished, although their route of synthesis basically identical, the structure of biosynthesizing device but has nothing in common with each other.Catalysis fatty acid biological synthetic enzyme cording has two types (FAS I and FAS II).FAS I is present in Mammals and the yeast, and wherein whole enzymic activitys all is coded in respectively on the polypeptide chain, and each step lipid acid building-up reactions all is to be finished by this big proteic difference in functionality territory catalysis.FAS II is present in bacterium and the plant, and it is made up of a series of little isolating albumen, and each step lipid acid building-up reactions is all finished by distinct single functional enzyme catalysis.The uniqueness of mycobacterium just is that it has FAS I and FAS II simultaneously, and FAS I relates to the biosynthesizing of basic lipid acid, and FAS II relates to the synthetic of compound cell envelope fat (as mycolic acid).Therefore, selectivity suppresses the inhibitor of the single functional enzyme of FAS II system, might develop into extensive pedigree antibiotic (Payne DJ, Warren PV, Holmes DJ, etal.Drug Discov Develop, 2001,6 (10): 537-544; Heath RJ, WhitebSW, Rock CO.Prog Lipid Res, 2001,40:467-497).
Single functional enzyme FabH of FAS II system is a substrate with acetyl-CoA, is that the synthetic carbochain of lipid acid prolongs the round-robin initiation factor, extensively is present in the bacterium.Simultaneously, this round-robin final product palmityl-ACP produces feedback inhibition again to FabH.Therefore, FabH is important fatty acid biological synthetic enzyme, simultaneously the still crucial point of adjustment in the whole route of synthesis.As seen, FabH plays a part necessary in the bacterium fatty acid biological is synthetic and regulates (Heath RJ, Rock CO.J Biol Chem, 1996,271 (4): 1833-1836; Revill WP, Bibb MJ, ScheuAK, et al.J Bacteriol, 2001,183:3526-3530).
Because the chemical sproof appearance of germ presses for the exploitation novel antibacterial medicine different with existing drug mechanism.Still do not act on the antimicrobial drug of fatty acid biosynthetic pathway on the market, therefore, fatty acid sythetase inhibitor is expected to develop into novel extensive pedigree antibiotic.
Summary of the invention
According to an aspect of the present invention, the present invention relates to compound or its all possible isomer or the pharmacologically acceptable salt or the hydrate of general formula I:
Figure A20061011479300071
Wherein:
Q is CH 2O or NH;
R 1Be aryl;
R 2Be aryl, C 3-10Alkyl or C 4-8Cycloalkyl.
Term used herein " aryl " is meant phenyl, or by hydroxyl, halogen, nitro, CF 3, methylene-dioxy, C 1-6Alkyl, C 1-6Substituting groups such as alkoxyl group one or polysubstituted phenyl.
Term used herein " C 3-10Alkyl " be meant straight or branched alkyl with 3-10 carbon atom, it includes but not limited to n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl etc.Optional hydroxyl, carboxyl, halogen and the C of being selected from of this group 1-6The substituting group of alkoxyl group replaces.
Term used herein " cycloalkyl " is meant the ring with 4-8 carbon atom, and it includes but not limited to cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.
Compound of the present invention can comprise one or more asymmetric centers, and can exist with racemic modification and optical activity form.All these racemic modifications or enantiomorph include within the scope of the present invention.
Compounds more of the present invention can form solvate in this case with solvent crystallization or recrystallization, and they include within the scope of the present invention.
Compound of the present invention is purpose with medicinal, is appreciated that they preferably provide with pure form, at least 60% purity for example, and more suitably 75%, better 85%, best at least 98% purity (% is meant weight percent).
According to another aspect of the present invention, the present invention relates to contain the pharmaceutical composition of above-mentioned compound of Formula I, it comprises compound or its all possible isomer or the pharmacologically acceptable salt or the hydrate of general formula I of the present invention, and at least a pharmaceutically acceptable carrier or vehicle.
According to another aspect of the present invention, the invention still further relates to the method for the above-mentioned compound of Formula I of preparation.
According to a further aspect of the present invention, the present invention relates to the purposes that described compound is used to prepare fatty acid sythetase inhibitor, this fatty acid sythetase inhibitor can be used as the antimicrobial drug of treatment gram-positive microorganism and negative bacterium infection.
The invention still further relates to treatment animal and human's gram-positive microorganism and the method that negative bacterium infects, this method comprises the animal that these needs are arranged, the The compounds of this invention that comprises the human therapy significant quantity.
Preferred The compounds of this invention is selected from:
1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-heptyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-octyl group-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-hexyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-furans-2-ylmethyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-(2-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-(3-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-(3-trifluoromethyl-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-(4-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-cyclohexyl methyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-benzo [1,3] dioxolane-5-ylmethyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-benzyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-(3-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-benzo [1,3] dioxolane-5-ylmethyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-heptyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-(2-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-cyclohexyl methyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-octyl group-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-(3-trifluoromethyl-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-furans-2-ylmethyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-(4-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-pyrrolin-3-carboxylic acid;
4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-1-(3-trifluoromethyl-benzyl)-2,5-pyrrolin-3-carboxylic acid;
1-benzo [1,3] dioxolane-5-ylmethyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-pyrrolin-3-carboxylic acid;
1-cyclohexyl methyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-pyrrolin-3-carboxylic acid; With
4-[4-(2,6-two chloro-benzyloxies)-aniline]-1-octyl group-5-oxo-2,5-pyrrolin-3-carboxylic acid;
Or its pharmacologically acceptable salt or hydrate.
According to the present invention, wherein Q is CH 2The formula of O (I) compound can be prepared by following scheme 1 described synthetic route:
Scheme 1
Figure A20061011479300111
a)NaH，DMF；b)NaBH 4，CH 3OH；c)C 2H 5ONa，C 2H 5OH；d)Ph 3P，DEAD，THF；e)NaOH，CH 3OH。
Specifically, with R wherein 1Define as above-mentioned general formula I, X is the formula R of halogen 1CH 2X benzyl halide (scheme 1-1) and p-Hydroxybenzaldehyde (scheme 1-2) are raw material, handle in sodium hydride/DMF and stir (5-0 ℃, 0.5 hour), generate compound scheme 1-3; Then, with hydride reducer (as sodium borohydride) reduction scheme 1-3 in solvent (as methyl alcohol), obtain compound 4 (scheme 1-4); Under rare gas element such as nitrogen protection, make formula R 2CH 2Addition reaction takes place in X primary amine (scheme 1-5) and ethyl propenoate (scheme 1-6) under stirring at room, under reflux temperature condensation reaction takes place with oxalic acid diethyl ester (scheme 1-7) then in sodium ethylate-ethanol alkaline system, through acidic hydrolysis, make pyrrole derivative 8 (scheme 1-8) again.Utilize catalyzer (as triphenyl phosphorus and diethylazodicarboxylate) to make compound 4 and compound 8 in solvent (as THF), carry out condensation and slough 1 molecular water, make compound 9 (scheme 1-9); Make compound 9 and alkali (as sodium hydroxide) saponification in solvent (as methyl alcohol), obtain wherein R 1And R 2As the defined compound of above-mentioned general formula I (scheme 1-10).
Wherein Q is that formula (I) compound of NH can be prepared by the synthetic route described in the following scheme 2:
Scheme 2
a)C 2H 5ONa，C 2H 5OH；b)SnCl 2，C 2H 5OH；c)C 2H 5ONa，C 2H 5OH；d)AcOH；e)NaHCO 3，THF，C 2H 5OH。
Specifically, under reflux temperature, make 2,6-dichloro bromobenzyl (scheme 2-1) and paranitrobenzaldehyde (scheme 2-2) react in sodium ethylate-ethanol alkaline system, generate compound 3 (scheme 2-3); Then, with reductive agent (as tin protochloride) reducing compound 3 in solvent (as ethanol), obtain compound 4 (scheme 2-4); Under rare gas element such as nitrogen protection, make formula R 2CH 2Addition reaction takes place in X primary amine (scheme 2-5) and ethyl propenoate (scheme 2-6) under stirring at room, under reflux temperature condensation reaction takes place with oxalic acid diethyl ester (scheme 2-7) then in sodium ethylate-ethanol alkaline system, through acidic hydrolysis, make pyrrole derivative 8 (scheme 2-8) again.Utilize catalyzer (as acetic acid) to make compound 4 and compound 8 condensations and slough 1 molecular water, make compound 9 (scheme 2-9); Make compound 9 and alkali (as sodium bicarbonate) saponification in solvent (as THF and ethanol), obtain wherein R 2Compound of Formula I (scheme 2-10) as defined above.
Therefore, the preparation method of general formula of the present invention (I) compound can be summarized as follows:
For Q wherein is CH 2The formula of O (I) compound, this method may further comprise the steps:
(1) with R wherein 1As above general formula I defines, X is the formula R of halogen 1CH 2X benzyl halide and p-Hydroxybenzaldehyde are raw material, handle in sodium hydride/DMF under-5-0 ℃ and stir 0.5 hour; In solvent such as methyl alcohol, reduce the scheme products therefrom with hydride reducer such as sodium borohydride then;
(2) under rare gas element such as nitrogen protection, make wherein R 2The as above defined formula R of general formula I 2CH 2Addition reaction takes place in X primary amine and ethyl propenoate under stirring at room, under reflux temperature condensation reaction takes place with oxalic acid diethyl ester in sodium ethylate-ethanol alkaline system then, make again product experience acidic hydrolysis;
(3) utilize catalyzer such as triphenyl phosphorus and diethylazodicarboxylate to make step (1) and step (2) product carry out condensation and slough 1 molecular water in solvent such as THF, and make it the saponification in solvent such as methyl alcohol with alkali such as sodium hydroxide, obtaining wherein, Q is CH 2O, and R 1And R 2Compound of Formula I as defined above;
Perhaps,
For Q wherein is formula (I) compound of NH, and this method may further comprise the steps:
(1) under reflux temperature, make 2,6-dichloro bromobenzyl and paranitrobenzaldehyde react in sodium ethylate-ethanol alkaline system, then, reduce products therefrom with reductive agent such as tin protochloride in solvent such as ethanol;
(2) under rare gas element such as nitrogen protection, make wherein R 2The as above definition R of general formula I institute 2CH 2Addition reaction takes place in X primary amine and ethyl propenoate under stirring at room, under reflux temperature condensation reaction takes place with oxalic acid diethyl ester in sodium ethylate-ethanol alkaline system then, makes products therefrom experience acidic hydrolysis again;
(3) utilize catalyzer such as acetic acid to make the product condensation that step (1) and step (2) obtain and slough 1 molecular water, make it the saponification in solvent such as THF and ethanol with alkali such as sodium bicarbonate again, obtaining wherein, Q is NH, R 1And R 2General formula (I) compound as defined above.
The compound of general formula I of the present invention or its pharmaceutically useful salt can use separately; or use with the form of pharmaceutical composition with pharmaceutically useful carrier or vehicle; when using with the form of pharmaceutical composition; usually with the compound of Formula I of the present invention of effective dose or its pharmacologically acceptable salt or hydrate and one or more pharmaceutically acceptable carrier or thinner in conjunction with making suitable administration form or dosage form, this program comprises by suitable manner component mixing, granulation, compression or dissolving.Therefore, the invention provides pharmaceutical composition, it comprises compound, its all possible isomer or its pharmacologically acceptable salt or the hydrate and at least a pharmaceutically useful carrier of general formula I.
The pharmaceutical composition of The compounds of this invention can following aspect any-mode grant: in oral, spraying suction, rectal administration, intranasal administration, vagina administration, topical, parenterai administration such as subcutaneous, vein, intramuscular, intraperitoneal, the sheath, in the ventricle, in the breastbone or intracranial injection or input, or by a kind of reservoir medication of outer planting, wherein preferred oral, intramuscular injection, intraperitoneal or intravenously application method.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration.Form of administration can be liquid dosage form, solid dosage.Liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other formulations are tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder, inclusion compound, implants, patch, liniment etc. for example.
Can also contain carrier commonly used in the pharmaceutical composition of the present invention, pharmaceutically acceptable carrier described here is including, but not limited to ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein such as human serum protein, buffer substance such as phosphoric acid salt, glycerine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloided silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, wool grease etc.The content of carrier in pharmaceutical composition can be 1 weight %-98 weight %, accounts for 80 weight % usually greatly.For simplicity, local anesthetic, sanitas, buffer reagents etc. can directly be dissolved in the carrier.
Oral tablet and capsule can contain vehicle such as tackiness agent, as syrup, and gum arabic, sorbyl alcohol, tragacanth, or polyvinylpyrrolidone, weighting agent is as lactose, sucrose, W-Gum, calcium phosphate, sorbyl alcohol, Padil, lubricant, as Magnesium Stearate, talcum, polyoxyethylene glycol, tripoli, disintegrating agent, as yam starch, or acceptable dibutyl phthalate, as bay sodium alkoxide vitriol.Tablet can be with known method dressing on the pharmacopedics.
Oral liquid can be made the suspension of water and oil, solution, and emulsion, syrup or elixir also can be made dry product, with preceding make up water or other suitable medium.This liquid preparation can comprise conventional additive, as suspension agent, and sorbyl alcohol, Walsroder MC 20000S, dextrose syrup, gel, Natvosol, carboxymethyl cellulose, aluminium stearate gel, hydrogenant food oils, emulsifying agent, as Yelkin TTS, sorb gathers candy list oleate, Sudan Gum-arabic; Or nonaqueous carrier (may comprise edible oil), as Prunus amygdalus oil, grease such as glycerine, ethylene glycol, or ethanol; Sanitas is as methyl p-hydroxybenzoate or propyl ester, Sorbic Acid.Can add seasonings or tinting material as needs.
Suppository can comprise conventional suppository base, as cocoa butter or other glyceryl ester.
Stomach is offerd medicine outward, and liquid formulation is made by compound and a kind of disinfectant carrier usually.The first-selected water of carrier.Different according to selected carrier and drug level, compound had both dissolved in and also can be made into aaerosol solution in the carrier, and was earlier that compound is soluble in water when making injection solution, packed into after the filter-sterilized and sealed in bottle or the ampoule.
When topical application, The compounds of this invention can be made suitable ointment, lotion, or the form of creme, and wherein activeconstituents suspends or is dissolved in one or more the carrier.Wherein the operable carrier of ointment formulation is including, but not limited to mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion and creme includes but not limited to: mineral oil, and sorbitan monostearate, polysorbate60, the n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
According to the difference of administering mode, can contain weight ratio 0.1% in the component, or the active ingredient of weight ratio 10-60% more suitably.But when comprising unitary dose in the component, each unit preferably comprises 50-500 milligram activeconstituents.Different according to route of administration and administration frequency, the suitable therapeutic dose that is used to be grown up is 100-3000 milligram every day, as 1500 milligrams of every days.This dosage is corresponding to 1.5-50 milligram/kg/day, and proper dosage is 5-20 milligram/kg/day.
Must recognize, the best dosage of compound of Formula I and be at interval by compound property with such as form, approach and the position of administration and external conditionss such as the specific Mammals decision of being treated, and this best dosage can be determined with routine techniques.Must recognize also simultaneously that the best course of treatment, promptly compound of Formula I is at the nominal dosage of every day in the time, available method well known in the art is determined.
Embodiment
Following specific embodiment is the preferred embodiments of the invention, and it should not be construed as the present invention is constituted any restriction.
Fusing point is measured with SRY-1 type fusing point instrument, and thermometer is not calibrated.Mass spectrum is measured by MicromassZabSpec high resolution mass spectrometer (resolving power 1000) and API 3000 series connection quadrupole mass spectrometers.1H NMR is measured by JNM-ECA-400 SUPERCONDUCTING NMR instrument, operating frequency 400MHz.
Embodiment 1.1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 4-(2,6-two chloro-benzyloxies)-phenyl aldehyde
With 20mmol 2,6-dichloro bromobenzyl and 17mmol p-Hydroxybenzaldehyde are dissolved among the DMF of 14mL, are cooled to 0 ℃, stir down to add 20mmol 60%NaH, continue to stir 0.5h, remove ice bath, stirring at room 0.5h.In reaction solution impouring 140mL frozen water, ethyl acetate extraction, washing, anhydrous MgSO 4Dry.Concentrate, the gained crude product gets white crystals through purification by silica gel column chromatography (petrol ether/ethyl acetate wash-out), and mp 75-77 ℃, yield 93.2%. 1H-NMR(d 6-DMSO)δ：5.35(s，2H，-CH 2O)，5.27(d，2H，J＝8.6Hz，Ar-H)，7.50(m，1H，Ar-H)，7.60(m，2H，Ar-H)，7.90(d，2H，J＝8.6Hz，Ar-H)，9.90(s，1H，-CHO).
Step 2 4-(2,6-two chloro-benzyloxies)-phenylcarbinol
30mmol 4-(2,6-two chloro-benzyloxies)-phenyl aldehyde is dissolved in the methyl alcohol of 45mL, under 28-30 ℃ of condition, slowly drips the 18mmol NaBH of preparation in advance 4, 0.6mL 2N NaOH and water 5.4mL solution altogether, continue to stir 0.5h.Add 6N HCl and be neutralized to pH 4, concentrate, ether extraction, washing, anhydrous sodium sulfate drying.Concentrate, get product, need not promptly can be used for next step reaction by purifying.
Step 3 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
50mmol benzylamine and 50mmol ethyl propenoate are dissolved in the ethanol of 20mL, feed nitrogen, stirring at room 24h.Add 50mmol oxalic acid diethyl ester and alcohol sodium solution (sodium Metal 99.5 52mmol/20mL dehydrated alcohol) then, reflux 1h.Cooling concentrates, and adds 400mL water and 6mL concentrated hydrochloric acid.Filter, the thick product of gained ethanol/water recrystallization gets white crystals, and mp 137-139 ℃, yield 78.5%.
Step 4 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
With 7mmol 4-(2,6-two chloro-benzyloxies)-phenylcarbinol, 7mmol 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester and 7.7mmol triphenyl phosphorus are dissolved among the 30mL THF, be cooled to 0 ℃, drip the 7mmol diethylazodicarboxylate (DEAD) and the 8mL THF solution of preparation in advance, room temperature reaction spends the night.Concentrate, crude product gets white solid, yield 76.6% through purification by silica gel column chromatography (petrol ether/ethyl acetate/methanol-eluted fractions). 1H-NMR(CDCl 3)δ：1.28(t，3H，J＝7.0Hz，-CH 3)，3.86(s，2H，2-CH 2)，4.21(q，2H，J＝7.0Hz，-OCH 2CH 3)，4.62(s，2H，1-NCH 2)，5.27(s，2H，-CH 2O)，5.76(s，2H，-CH 2O)，6.99(d，2H，J＝8.6Hz，Ar-H)，7.20-7.37(m，8H，Ar-H)，7.42(d，2H，J＝8.6Hz，Ar-H).
Step 5 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
With 2mmol 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester is dissolved in the methyl alcohol of 100mL, adds 25mmol1N NaOH solution then, room temperature reaction 3h.In reaction solution impouring 250mL water, ether extraction, water layer is transferred pH 1-2 with concentrated hydrochloric acid, ethyl acetate extraction, washing, anhydrous sodium sulfate drying.Concentrate, the crude product re-crystallizing in ethyl acetate gets white crystals, 162 ℃ of dp, yield 26.4%. 1H-NMR(d 6-DMSO)δ：3.88(s，2H，2-CH 2)，4.57(s，2H，1-NCH 2)，5.23(s，2H，-CH 2O)，5.58(s，2H，-CH 2O)，7.06(d，2H，J＝8.7Hz，Ar-H)，7.20(m，2H，Ar-H)，7.29(m，1H，Ar-H)，7.33(m，2H，Ar-H)，7.37(d，2H，J＝8.7Hz，Ar-H)，7.47(m，1H，Ar-H)，7.56(m，2H，Ar-H)，12.85(s，1H，-COOH).ESI MS(m/z)：496(M +-1).
Embodiment 2.4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-heptyl-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-heptyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 3, substitute benzylamine with heptyl amice, get white crystals, mp 124-126 ℃, yield 75.8%.
Step 2 4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-heptyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 1-heptyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2, and 5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester gets white solid, and mp 89-90 ℃, yield 75.1%. 1H-NMR(CDCl 3)δ：0.86(t，3H，-CH 3)，1.27-1.33(m，11H，-4CH 2CH 3，-OCH 2CH 3)，1.56(m，2H，-CH 2)，3.43(t，2H，1-NCH 2)，3.95(s，2H，2-CH 2)，4.24(q，2H，J＝7.2Hz，-OCH 2CH 3)，5.26(s，2H，-CH 2O)，5.74(s，2H，-CH 2O)，6.98(d，2H，J＝8.6Hz，Ar-H)，7.24(m，1H，Ar-H)，7.35(d，2H，Ar-H)，7.40(d，2H，J＝8.6Hz，Ar-H).
Step 3 4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-heptyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-heptyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, crude product dehydrated alcohol recrystallization, get white crystals, 125 ℃ of dp, yield 15.3%. 1H-NMR(d 6-DMSO)δ：0.85(t，3H，-CH 3)，1.24(m，8H，-4CH 2)，1.51(m，2H，-CH 2)，3.36(t，2H，1-NCH 2)，3.97(s，2H，2-CH 2)，5.22(s，2H，-CH 2O)，5.56(s，2H，-CH 2O)，7.04(d，2H，J＝8.6Hz，Ar-H)，7.35(d，2H，J＝8.6Hz，Ar-H)，7.47(m，1H，Ar-H)，7.56(m，2H，Ar-H)，12.81(s，1H，-COOH).ESI MS(m/z)：504(M +-1).
Embodiment 3.4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-octyl group-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-octyl group-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 3, substitute benzylamine with octylame, get white crystals, mp 121-123 ℃, yield 78.3%.
Step 2 4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-octyl group-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 1-octyl group-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2, and 5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester gets white solid, and mp 78-79 ℃, yield 75.8%. 1H-NMR(CDCl 3)δ：0.87(t，3H，-CH 3)，1.26-1.33(m，13H，-5CH 2CH 3，-OCH 2CH 3)，1.56(m，2H，-CH 2)，3.43(t，2H，1-NCH 2)，3.95(s，2H，2-CH 2)，4.24(q，2H，J＝7.0Hz，-OCH 2CH 3)，5.26(s，2H，-CH 2O)，5.74(s，2H，-CH 2O)，6.98(d，2H，J＝8.4Hz，Ar-H)，7.24(m，1H，Ar-H)，7.35(d，2H，Ar-H)，7.40(d，2H，J＝8.4Hz，Ar-H).
Step 3 4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-octyl group-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-octyl group-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, crude product dehydrated alcohol recrystallization, get white crystals, 109 ℃ of dp, yield 12.9%. 1H-NMR(d 6-DMSO)δ：0.84(t，3H，-CH 3)，1.24(m，10H，-5CH 2)，1.51(m，2H，-CH 2)，3.33(t，2H，1-NCH 2)，3.97(s，2H，2-CH 2)，5.22(s，2H，-CH 2O)，5.56(s，2H，-CH 2O)，7.04(d，2H，J＝9.0Hz，Ar-H)，7.35(d，2H，J＝9.0Hz，Ar-H)，7.47(m，1H，Ar-H)，7.55(m，2H，Ar-H)，12.80(s，1H，-COOH).ESI MS(m/z)：518(M +-1).
Embodiment 4.4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-hexyl-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-hexyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 3, substitute benzylamine with hexylamine, get white crystals, mp 132-134 ℃, yield 69.3%.
Step 2 4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-hexyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 1-hexyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2, and 5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester gets white solid, and mp 58-59 ℃, yield 74.2%. 1H-NMR(CDCl 3)δ：0.88(t，3H，-CH 3)，1.29-1.33(m，9H，-3CH 2CH 3，-OCH 2CH 3)，1.56(m，2H，-CH 2)，3.44(t，2H，1-NCH 2)，3.95(s，2H，2-CH 2)，4.24(q，2H，J＝7.0Hz，-OCH 2CH 3)，5.26(s，2H，-CH 2O)，5.74(s，2H，-CH 2O)，6.98(d，2H，J＝8.6Hz，Ar-H)，7.24(m，1H，Ar-H)，7.35(d，2H，Ar-H)，7.40(d，2H，J＝8.6Hz，Ar-H).
Step 3 4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-hexyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-hexyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, crude product dehydrated alcohol recrystallization, get white crystals, 136 ℃ of dp, yield 20.4%. 1H-NMR(d 6-DMSO)δ：0.85(t，3H，-CH 3)，1.24(m，6H，-3CH 2)，1.51(m，2H，-CH 2)，3.34(t，2H，1-NCH 2)，3.97(s，2H，2-CH 2)，5.22(s，2H，-CH 2O)，5.56(s，2H，-CH 2O)，7.04(d，2H，J＝8.6Hz，Ar-H)，7.35(d，2H，J＝8.6Hz，Ar-H)，7.47(m，1H，Ar-H)，7.56(m，2H，Ar-H)，12.81(s，1H，-COOH).ESI MS(m/z)：490(M +-1).
Embodiment 5.4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-furans-2-ylmethyl-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-furans-2-ylmethyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 3, substitute benzylamine with furans-2-base-methylamine, get white crystals, mp 132-134 ℃, yield 74.8%.
Step 2 4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-furans-2-ylmethyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 1-furans-2-ylmethyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get white solid, mp 87-89 ℃, yield 75.1%. 1H-NMR(CDCl 3)δ：1.30(t，3H，J＝7.0Hz，-CH 3)，3.96(s，2H，2-CH 2)，4.23(q，2H，J＝7.0Hz，-OCH 2CH 3)，4.61(s，2H，1-NCH 2)，5.26(s，2H，-CH 2O)，5.74(s，2H，-CH 2O)，6.28(d，1H，J＝3.0Hz，furan-H)，6.33(dd，1H，J＝3.0Hz，furan-H)，6.99(d，2H，J＝8.6Hz，Ar-H)，7.25(m，1H，Ar-H)，7.35(m，3H，Ar-H，furan-H)，7.41(d，2H，J＝8.6Hz，Ar-H).
Step 3 4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-furans-2-ylmethyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-furans-2-ylmethyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, the crude product re-crystallizing in ethyl acetate, get white crystals, 146 ℃ of dp, yield 21.2%. 1H-NMR(d 6-DMSO)δ：3.91(s，2H，2-CH 2)，4.58(s，2H，1-NCH 2)，5.23(s，2H，-CH 2O)，5.56(s，2H，-CH 2O)，6.38(d，1H，J＝3.3Hz，furan-H)，6.42(dd，1H，J＝3.3Hz，furan-H)，7.05(d，2H，J＝8.6Hz，Ar-H)，7.37(d，2H，J＝8.6Hz，Ar-H)，7.45(m，1H，Ar-H)，7.56-7.63(m，3H，Ar-H，furan-H)，12.90(s，1H，-COOH).ESIMS(m/z)：486(M +-1).
Embodiment 6.1-(2-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-(2-chloro-benzyl)-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 3, substitute benzylamine with 2-chloro-benzylamine, get white crystals, mp165-166 ℃, yield 76.0%.
Step 2 1-(2-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 1-(2-chloro-benzyl)-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get white solid, mp 99-100.5 ℃, yield 44.7%. 1H-NMR(CDCl 3)δ：1.29(t，3H，J＝7.0Hz，-CH 3)，3.90(s，2H，2-CH 2)，4.22(q，2H，J＝7.0Hz，-OCH 2CH 3)，4.76(s，2H，1-NCH 2)，5.27(s，2H，-CH 2O)，5.76(s，2H，-CH 2O)，6.99(d，2H，J＝8.6Hz，Ar-H)，7.16-7.27(m，4H，Ar-H)，7.36-7.39(d，3H，Ar-H)，7.42(d，2H，J＝8.6Hz，Ar-H).
Step 3 1-(2-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 1-(2-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, crude product dehydrated alcohol recrystallization, get white crystals, 167 ℃ of dp, yield 23.9%. 1H-NMR(d 6-DMSO)δ：3.71(s，2H，2-CH 2)，4.57(s，2H，1-NCH 2)，5.22(s，2H，-CH 2O)，5.47(s，2H，-CH 2O)，7.06(d，2H，J＝8.6Hz，Ar-H)，7.09(dd，1H，Ar-H)，7.32(dd，2H，Ar-H)，7.35(d，2H，J＝8.6Hz，Ar-H)，7.45-7.49(m，2H，Ar-H)，7.56(m，2H，Ar-H).ESIMS(m/z)：530(M +-1).
Embodiment 7.1-(3-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-(3-chloro-benzyl)-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 3, substitute benzylamine with 3-chloro-benzylamine, get white crystals, mp134-135 ℃, yield 79.2%.
Step 2 1-(3-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 1-(3-chloro-benzyl)-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get white solid, mp 130-131 ℃, yield 52.9%. 1H-NMR(CDCl 3)δ：1.29(t，3H，J＝7.0Hz，-CH 3)，3.87(s，2H，2-CH 2)，4.22(q，2H，J＝7.0Hz，-OCH 2CH 3)，4.59(s，2H，1-NCH 2)，5.27(s，2H，-CH 2O)，5.76(s，2H，-CH 2O)，7.00(d，2H，J＝8.7Hz，Ar-H)，7.09(m，1H，Ar-H)，7.21-7.28(m，4H，Ar-H)，7.36(d，2H，Ar-H)，7.42(d，2H，J＝8.7Hz，Ar-H).
Step 3 1-(3-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 1-(3-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, crude product dehydrated alcohol recrystallization, get white crystals, 148 ℃ of dp, yield 16.4%. 1H-NMR(d 6-DMSO)δ：3.71(s，2H，2-CH 2)，4.57(s，2H，1-NCH 2)，5.22(s，2H，-CH 2O)，5.47(s，2H，-CH 2O)，7.02(d，2H，J＝8.7Hz，Ar-H)，7.09(dd，1H，Ar-H)，7.32(dd，2H，Ar-H)，7.35(d，2H，J＝8.7Hz，Ar-H)，7.45-7.49(m，2H，Ar-H)，7.56(m，2H，Ar-H).ESIMS(m/z)：530(M +-1).
Embodiment 8.1-(3-trifluoromethyl-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-(3-trifluoromethyl-benzyl)-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 3, substitute benzylamine with 3-trifluoromethyl-benzylamine, get white crystals, mp 156-158 ℃, yield 78.2%.
Step 2 1-(3-trifluoromethyl-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 1-(3-trifluoromethyl-benzyl)-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get white solid, mp 117-119 ℃, yield 41.9%. 1H-NMR(CDCl 3)δ：1.27(t，3H，J＝7.2Hz，-CH 3)，3.88(s，2H，2-CH 2)，4.22(q，2H，J＝7.2Hz，-OCH 2CH 3)，4.67(s，2H，1-NCH 2)，5.27(s，2H，-CH 2O)，5.76(s，2H，-CH 2O)，7.00(d，2H，J＝8.6Hz，Ar-H)，7.23(m，1H，Ar-H)，7.36-7.49(m，7H，Ar-H)，7.56(d，1H，Ar-H).
Step 3 1-(3-trifluoromethyl-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 1-(3-trifluoromethyl-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, the crude product re-crystallizing in ethyl acetate, get white crystals, 163 ℃ of dp, yield 11.4%. 1H-NMR(d 6-DMSO)δ：3.95(s，2H，2-CH 2)，4.67(s，2H，1-NCH 2)，5.23(s，2H，-CH 2O)，5.58(s，2H，-CH 2O)，7.05(d，2H，J＝8.6Hz，Ar-H)，7.37(d，2H，J＝8.6Hz，Ar-H)，7.46-7.68(m，7H，Ar-H)，12.89(s，1H，-COOH).ESI MS(m/z)：564(M +-1).
Embodiment 9.1-(4-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-(4-chloro-benzyl)-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 3, substitute benzylamine with 4-chloro-benzylamine, get white crystals, mp164-167 ℃, yield 75.5%.
Step 2 1-(4-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 1-(4-chloro-benzyl)-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get white solid, mp 91-93 ℃, yield 39.1%. 1H-NMR(CDCl 3)δ：1.27(t，3H，J＝7.1Hz，-CH 3)，3.85(s，2H，2-CH 2)，4.21(q，2H，J＝7.1Hz，-OCH 2CH 3)，4.58(s，2H，1-NCH 2)，5.27(s，2H，-CH 2O)，5.75(s，2H，-CH 2O)，7.00(d，2H，J＝8.4Hz，Ar-H)，7.14(d，2H，J＝8.4Hz，Ar-H)，7.25(m，1H，Ar-H)，7.30(d，2H，J＝8.4Hz，Ar-H)，7.36(m，2H，Ar-H)，7.41(d，2H，J＝8.4Hz，Ar-H).
Step 3 1-(4-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 1-(4-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, the crude product re-crystallizing in ethyl acetate, get white crystals, 173 ℃ of dp, yield 21.0%. 1H-NMR(d 6-DMSO)δ：3.90(s，2H，2-CH 2)，4.56(s，2H，1-NCH 2)，5.23(s，2H，-CH 2O)，5.58(s，2H，-CH 2O)，7.06(d，2H，J＝8.6Hz，Ar-H)，7.23(d，2H，J＝8.4Hz，Ar-H)，7.37(d，2H，J＝8.6Hz，Ar-H)，7.40(d，2H，J＝8.4Hz，Ar-H)，7.46(m，1H，Ar-H)，7.56(m，2H，Ar-H).ESI MS(m/z)：530(M +-1).
Embodiment 10.1-cyclohexyl methyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-cyclohexyl methyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 3, substitute benzylamine with cyclohexyl-methylamine, get white crystals, mp174-177 ℃, yield 80.8%.
Step 2 1-cyclohexyl methyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 1-cyclohexyl methyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get white solid, mp 118-120 ℃, yield 80.8%. 1H-NMR(CDCl 3)δ：0.95(m，2H，Cyclohexane-H)，1.17(m，3H，Cyclohexane-H)，1.31(t，3H，J＝7.2Hz，-CH 3)，1.58-1.74(m，6H，Cyclohexane-H)，3.26(d，2H，1-NCH 2)，3.96(s，2H，2-CH 2)，4.24(q，2H，J＝7.2Hz，-OCH 2CH 3)，5.26(s，2H，-CH 2O)，5.74(s，2H，-CH 2O)，6.98(d，2H，J＝8.6Hz，Ar-H)，7.22(m，1H，Ar-H)，7.35(d，2H，Ar-H)，7.40(d，2H，J＝8.6Hz，Ar-H).
Step 3 1-cyclohexyl methyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 1-cyclohexyl methyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, crude product dehydrated alcohol recrystallization, get white crystals, 148 ℃ of dp, yield 11.9%. 1H-NMR(d 6-DMSO)δ：0.88(m，2H，Cyclohexane-H)，1.16(m，3H，Cyclo-hexane-H)，1.54(m，6H，Cyclohexane-H)，3.18(d，2H，1-NCH 2)，3.97(s，2H，2-CH 2)，5.22(s，2H，-CH 2O)，5.55(s，2H，-CH 2O)，7.04(d，2H，J＝8.6Hz，Ar-H)，7.35(d，2H，J＝8.6Hz，Ar-H)，7.45(m，1H，Ar-H)，7.55(m，2H，Ar-H)，12.78(s，1H，-COOH).ESIMS(m/z)：502(M +-1).
Embodiment 11.1-benzo [1,3] dioxolane-5-ylmethyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-benzo [1,3] dioxolane-5-ylmethyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 3, with benzo [1,3] dioxolane-5-base-methylamine substitutes benzylamine, white crystals, mp 146-148 ℃, yield 78.1%.
Step 2 1-benzo [1,3] dioxolane-5-ylmethyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 1-benzo [1,3] dioxolane-5-ylmethyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2, and 5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester gets white solid, mp 112-115 ℃, yield 86.1%. 1H-NMR(CDCl 3)δ：1.27(t，3H，J＝7.0Hz，-CH 3)，3.84(s，2H，2-CH 2)，4.21(q，2H，J＝7.0Hz，-OCH 2CH 3)，4.52(s，2H，1-NCH 2)，5.27(s，2H，-CH 2O)，5.75(s，2H，-CH 2O)，5.95(s，2H，-OCH 2O-)，6.68-6.77(m，3H，Ar-H)，6.99(d，2H，J＝8.7Hz，Ar-H)，7.25(m，1H，Ar-H)，7.36(d，2H，Ar-H)，7.36(d，2H，Ar-H)，7.42(d，2H，J＝8.7Hz，Ar-H).
Step 3 1-benzo [1,3] dioxolane-5-ylmethyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 1-benzo [1,3] dioxolane-5-ylmethyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, the crude product re-crystallizing in ethyl acetate gets white crystals, 163 ℃ of dp, yield 14.2%. 1H-NMR(d 6-DMSO)δ：3.86(s，2H，2-CH 2)，4.46(s，2H，1-NCH 2)，5.23(s，2H，-CH 2O)，5.57(s，2H，-CH 2O)，5.99(s，2H，-OCH 2O-)，6.70-6.88(m，3H，Ar-H)，7.05(d，2H，J＝8.6Hz，Ar-H)，7.37(d，2H，J＝8.6Hz，Ar-H)，7.45(m，1H，Ar-H)，7.55(m，2H，Ar-H)，12.81(s，1H，-COOH).ESI MS(m/z)：540(M +-1).
Embodiment 12.1-benzyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 4-(3,5-two fluoro-benzyloxies)-phenyl aldehyde
With 24mmol 3,5-difluoro bromobenzyl and 20mmol p-Hydroxybenzaldehyde are dissolved among the DMF of 16mL, are cooled to 0 ℃, stir down to add 24mmol 60%NaH, continue to stir 0.5h, remove ice bath, stirring at room 0.5h.In reaction solution impouring 170mL frozen water, ethyl acetate extraction, washing, anhydrous MgSO 4Dry.Concentrate, get product, need not promptly can be used for next step reaction by purifying.
Step 2 4-(3,5-two fluoro-benzyloxies)-phenylcarbinol
20mmol 4-(3,5-two fluoro-benzyloxies)-phenyl aldehyde is dissolved in the methyl alcohol of 30mL, under 28-30 ℃ of condition, slowly drips the 12mmol NaBH of preparation in advance 4, 0.4mL 2N NaOH and water 3.6mL solution altogether, continue to stir 0.5h.Add 6N HCl and be neutralized to pH 4, concentrated, add 100mL water, stir 4h, filter, washing, drying gets white crystals, yield 85.8%.
Step 3 1-benzyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, substitute 4-(2,6-two chloro-benzyloxies)-phenylcarbinol with 4-(3,5-two fluoro-benzyloxies)-phenylcarbinol, get white solid, mp 108-110 ℃, yield 40.8%. 1H-NMR(CDCl 3)δ：1.27(t，3H，J＝7.0Hz，-CH 3)，3.86(s，2H，2-CH 2)，4.20(q，2H，J＝7.0Hz，-OCH 2CH 3)，4.61(s，2H，1-NCH 2)，5.04(s，2H，-CH 2O)，5.74(s，2H，-CH 2O)，6.73(m，1H，Ar-H)，6.91(d，2H，J＝8.6Hz，Ar-H)，6.96(m，2H，Ar-H)，7.20-7.36(m，5H，Ar-H)，7.40(d，2H，J＝8.6Hz，Ar-H).
Step 4 1-benzyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 1-benzyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, the crude product re-crystallizing in ethyl acetate, get white crystals, 157 ℃ of dp, yield 20%. 1H-NMR(d 6-DMSO)δ：3.87(s，2H，2-CH 2)，4.56(s，2H，1-NCH 2)，5.15(s，2H，-CH 2O)，5.56(s，2H，-CH 2O)，7.01(d，2H，J＝8.9Hz，Ar-H)，7.17-7.37(m，10H，Ar-H)，12.83(s，1H，-COOH).ESI MS(m/z)：464(M +-1).
Embodiment 13.1-(3-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-(3-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 4-(3,5-two fluoro-benzyloxies)-the alternative 4-(2 of phenylcarbinol, 6-two chloro-benzyloxies)-and phenylcarbinol, with 1-(3-chloro-benzyl)-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get white solid, mp 94-95 ℃, yield 77.0%. 1H-NMR(CDCl 3)δ：1.28(t，3H，J＝7.2Hz，-CH 3)，3.87(s，2H，2-CH 2)，4.21(q，2H，J＝7.2Hz，-OCH 2CH 3)，4.58(s，2H，1-NCH 2)，5.04(s，2H，-CH 2O)，5.73(s，2H，-CH 2O)，6.73(m，1H，Ar-H)，6.92(d，2H，J＝8.6Hz，Ar-H)，6.96(m，2H，Ar-H)，7.09(m，1H，Ar-H)，7.20-7.28(m，3H，Ar-H)，7.40(d，2H，J＝8.6Hz，Ar-H).
Step 2 1-benzyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 1-(3-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, the crude product re-crystallizing in ethyl acetate, get white crystals, 146 ℃ of dp, yield 16.9%. 1H-NMR(d 6-DMSO)δ：3.92(s，2H，2-CH 2)，4.57(s，2H，1-NCH 2)，5.15(s，2H，-CH 2O)，5.55(s，2H，-CH 2O)，7.01(d，2H，J＝8.7Hz，Ar-H)，7.17-7.38(m，9H，Ar-H)，12.75(s，1H，-COOH).ESI MS(m/z)：498(M +-1).
Embodiment 14.1-benzo [1,3] dioxolane-5-ylmethyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-benzo [1,3] dioxolane-5-ylmethyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 4-(3,5-two fluoro-benzyloxies)-the alternative 4-(2,6-two chloro-benzyloxies) of phenylcarbinol-phenylcarbinol, with 1-benzo [1,3] dioxolane-5-ylmethyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2, and 5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester gets white solid, mp 99-100.5 ℃, yield 69.8%. 1H-NMR(CDCl 3)δ：1.27(t，3H，J＝7.0Hz，-CH 3)，3.84(s，2H，2-CH 2)，4.20(q，2H，J＝7.0Hz，-OCH 2CH 3)，4.51(s，2H，1-NCH 2)，5.04(s，2H，-CH 2O)，5.73(s，2H，-CH 2O)，5.94(s，2H，-OCH 2O-)，6.68-6.76(m，4H，Ar-H)，6.91(d，2H，J＝8.6Hz，Ar-H)，6.96(m，2H，Ar-H)，7.39(d，2H，J＝8.6Hz，Ar-H).
Step 2 1-benzo [1,3] dioxolane-5-ylmethyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 1-benzo [1,3] dioxolane-5-ylmethyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, the crude product re-crystallizing in ethyl acetate gets white crystals, 172 ℃ of dp, yield 18.9%. 1H-NMR(d 6-DMSO)δ：3.85(s，2H，2-CH 2)，4.45(s，2H，1-NCH 2)，5.15(s，2H，-CH 2O)，5.55(s，2H，-CH 2O)，6.00(s，2H，-OCH 2O-)，6.71(dd，1H，Ar-H)，6.80(d，1H，Ar-H)，6.86(d，1H，Ar-H)，7.00(d，2H，J＝8.6Hz，Ar-H)，7.19(m，3H，Ar-H)，7.35(d，2H，J＝8.6Hz，Ar-H)，12.82(s，1H，-COOH).ESI MS(m/z)：508(M +-1).
Embodiment 15.4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-heptyl-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-heptyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 4-(3,5-two fluoro-benzyloxies)-the alternative 4-(2 of phenylcarbinol, 6-two chloro-benzyloxies)-and phenylcarbinol, with 1-heptyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get white solid, mp 75-77 ℃, yield 69%. 1H-NMR(CDCl 3)δ：0.86(t，3H，-CH 3)，1.27-1.32(m，11H，-4CH 2CH 3，-OCH 2CH 3)，1.57(m，2H，-CH 2)，3.43(t，2H，1-NCH 2)，3.95(s，2H，2-CH 2)，4.24(q，2H，J＝7.0Hz，-OCH 2CH 3)，5.03(s，2H，-CH 2O)，5.71(s，2H，-CH 2O)，6.72(m，1H，Ar-H)，6.90(d，2H，J＝8.6Hz，Ar-H)，6.96(m，4H，Ar-H)，7.38(d，2H，J＝8.6Hz，Ar-H).
Step 2 4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-heptyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-heptyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, crude product dehydrated alcohol recrystallization, get white crystals, 122 ℃ of dp, yield 14.7%. 1H-NMR(d 6-DMSO)δ：0.85(t，3H，-CH 3)，1.24(m，8H，-4CH 2)，1.50(m，2H，-CH 2)，3.34(t，2H，1-NCH 2)，3.96(s，2H，2-CH 2)，5.14(s，2H，-CH 2O)，5.53(s，2H，-CH 2O)，6.99(d，2H，J＝8.6Hz，Ar-H)，7.16-7.22(m，3H，Ar-H)，7.33(d，2H，J＝8.6Hz，Ar-H)，12.80(s，1H，-COOH).ESI MS(m/z)：472(M +-1).
Embodiment 16.1-(2-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-(2-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 4-(3,5-two fluoro-benzyloxies)-the alternative 4-(2 of phenylcarbinol, 6-two chloro-benzyloxies)-and phenylcarbinol, with 1-(2-chloro-benzyl)-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get white solid, mp 88-90 ℃, yield 71.6%. 1H-NMR(CDCl 3)δ：1.29(t，3H，J＝7.0Hz，-CH 3)，3.90(s，2H，2-CH 2)，4.21(q，2H，J＝7.0Hz，-OCH 2CH 3)，4.76(s，2H，1-NCH 2)，5.04(s，2H，-CH 2O)，5.73(s，2H，-CH 2O)，6.73(m，1H，Ar-H)，6.91(d，2H，J＝8.6Hz，Ar-H)，6.96(m，2H，Ar-H)，7.18-7.27(m，3H，Ar-H)，7.37(m，1H，Ar-H)，7.42(d，2H，J＝8.6Hz，Ar-H).
Step 2 1-(2-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 1-(2-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, the crude product re-crystallizing in ethyl acetate, get white crystals, 167 ℃ of dp, yield 24.2%. 1H-NMR(d 6-DMSO)δ：3.90(s，2H，2-CH 2)，4.66(s，2H，1-NCH 2)，5.15(s，2H，-CH 2O)，5.56(s，2H，-CH 2O)，7.01(d，2H，J＝8.6Hz，Ar-H)，7.17-7.50(m，9H，Ar-H)，12.87(s，1H，-COOH).ESI MS(m/z)：498(M +-1).
Embodiment 17.1-cyclohexyl methyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-cyclohexyl methyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 4-(3,5-two fluoro-benzyloxies)-the alternative 4-(2 of phenylcarbinol, 6-two chloro-benzyloxies)-and phenylcarbinol, with 1-cyclohexyl methyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get white solid, mp 106-108 ℃, yield 82.2%.
Step 2 1-cyclohexyl methyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 1-cyclohexyl methyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, crude product anhydrous diethyl ether recrystallization, get white crystals, 150 ℃ of dp, yield 21.6%. 1H-NMR(d 6-DMSO)δ：0.88(m，2H，Cyclohexane-H)，1.15(m，3H，Cyclo-hexane-H)，1.54(m，6H，Cyclohexane-H)，3.18(d，2H，1-NCH 2)，3.96(s，2H，2-CH 2)，5.14(s，2H，-CH 2O)，5.53(s，2H，-CH 2O)，6.99(d，2H，J＝8.6Hz，Ar-H)，7.16(m，3H，Ar-H)，7.33(d，2H，J＝8.6Hz，Ar-H)，12.79(s，1H，-COOH).ESI MS(m/z)：470(M +-1).
Embodiment 18.4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-octyl group-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-octyl group-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 4-(3,5-two fluoro-benzyloxies)-the alternative 4-(2 of phenylcarbinol, 6-two chloro-benzyloxies)-and phenylcarbinol, with 1-octyl group-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get white solid, mp 70-72 ℃, yield 71.7%. 1H-NMR(CDCl 3)δ：0.87(t，3H，-CH 3)，1.26-1.32(m，13H，-5CH 2CH 3，-OCH 2CH 3)，1.55(m，2H，-CH 2)，3.43(t，2H，1-NCH 2)，3.95(s，2H，2-CH 2)，4.24(q，2H，J＝7.0Hz，-OCH 2CH 3)，5.03(s，2H，-CH 2O)，5.71(s，2H，-CH 2O)，6.75(m，1H，Ar-H)，6.90(d，2H，J＝8.6Hz，Ar-H)，6.94(m，2H，Ar-H)，7.38(d，2H，J＝8.6Hz，Ar-H).
Step 2 4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-octyl group-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-octyl group-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, crude product dehydrated alcohol recrystallization, get white crystals, 116 ℃ of dp, yield 11.4%. 1H-NMR(d 6-DMSO)δ：0.84(t，3H，-CH 3)，1.18(m，10H，-5CH 2)，1.50(m，2H，-CH 2)，3.33(t，2H，1-NCH 2)，3.96(s，2H，2-CH 2)，5.14(s，2H，-CH 2O)，5.53(s，2H，-CH 2O)，6.99(d，2H，J＝8.7Hz，Ar-H)，7.18(m，3H，Ar-H)，7.33(d，2H，J＝8.7Hz，Ar-H)，12.80(s，1H，-COOH).ESIMS(m/z)：586(M +-1).
Embodiment 19.1-(3-trifluoromethyl-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-(3-trifluoromethyl-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 4-(3,5-two fluoro-benzyloxies)-the alternative 4-(2,6-two chloro-benzyloxies) of phenylcarbinol-phenylcarbinol, with 4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-heptyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2, and 5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester gets white solid, mp 114-116 ℃, yield 74.9%. 1H-NMR(CDCl 3)δ：1.26(t，3H，J＝7.2Hz，-CH 3)，3.88(s，2H，2-CH 2)，4.21(q，2H，J＝7.2Hz，-OCH 2CH 3)，4.67(s，2H，1-NCH 2)，5.04(s，2H，-CH 2O)，5.74(s，2H，-CH 2O)，6.73(m，1H，Ar-H)，6.91(d，2H，J＝8.7Hz，Ar-H)，6.95(m，2H，Ar-H)，7.40(d，2H，J＝8.7Hz，Ar-H)，7.45-7.57(m，4H，Ar-H).
Step 2 1-(3-trifluoromethyl-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 1-(3-trifluoromethyl-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, crude product anhydrous diethyl ether recrystallization, get white crystals, 147 ℃ of dp, yield 16.3%. 1H-NMR(d 6-DMSO)δ：3.94(s，2H，2-CH 2)，4.66(s，2H，1-NCH 2)，5.15(s，2H，-CH 2O)，5.55(s，2H，-CH 2O)，7.00(d，2H，J＝8.4Hz，Ar-H)，7.17(m，3H，Ar-H)，7.35(d，2H，J＝8.4Hz，Ar-H)，7.51-7.68(m，4H，Ar-H)，12.85(s，1H，-COOH).ESI MS(m/z)：532(M +-1).
Embodiment 20.4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-furans-2-ylmethyl-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-furans-2-ylmethyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 4-(3,5-two fluoro-benzyloxies)-the alternative 4-(2 of phenylcarbinol, 6-two chloro-benzyloxies)-and phenylcarbinol, with 1-furans-2-ylmethyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get white solid, mp 98-100 ℃, yield 94.0%.
Step 2 4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-furans-2-ylmethyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-furans-2-ylmethyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, crude product anhydrous diethyl ether recrystallization, get white crystals, 134 ℃ of dp, yield 16.7%. 1H-NMR(d 6-DMSO)δ：3.90(s，2H，2-CH 2)，4.57(s，2H，1-NCH 2)，5.14(s，2H，-CH 2O)，5.53(s，2H，-CH 2O)，6.38(m，2H，furan-H)，7.00(d，2H，J＝8.6Hz，Ar-H)，7.17(m，3H，Ar-H)，7.34(d，2H，J＝8.6Hz，Ar-H)，7.62(m，1H，furan-H)，12.87(s，1H，-COOH).ESIMS(m/z)：454(M +-1).
Embodiment 21.1-(4-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-(4-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 1 step 4, with 4-(3,5-two fluoro-benzyloxies)-the alternative 4-(2 of phenylcarbinol, 6-two chloro-benzyloxies)-and phenylcarbinol, with 1-(4-chloro-benzyl)-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get white solid, mp 115-116 ℃, yield 63.0%. 1H-NMR(CDCl 3)δ：1.27(t，3H，J＝7.0Hz，-CH 3)，3.85(s，2H，2-CH 2)，4.21(q，2H，J＝7.0Hz，-OCH 2CH 3)，4.58(s，2H，1-NCH 2)，5.04(s，2H，-CH 2O)，5.72(s，2H，-CH 2O)，6.73(m，1H，Ar-H)，6.91(d，2H，J＝8.6Hz，Ar-H)，6.95(m，2H，Ar-H)，7.14(d，2H，J＝8.4Hz，Ar-H)，7.29(d，2H，J＝8.6Hz，Ar-H)，7.39(d，2H，J＝8.4Hz，Ar-H).
Step 2 1-(4-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 1 step 5, with 1-(4-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, the crude product re-crystallizing in ethyl acetate, get white crystals, 171 ℃ of dp, yield 18.2%. 1H-NMR(d 6-DMSO)δ：3.89(s，2H，2-CH 2)，4.55(s，2H，1-NCH 2)，5.15(s，2H，-CH 2O)，5.55(s，2H，-CH 2O)，7.01(d，2H，J＝8.6Hz，Ar-H)，7.17(m，3H，Ar-H)，7.23(d，2H，J＝8.6Hz，Ar-H)，7.35(d，2H，J＝8.6Hz，Ar-H)，7.39(d，2H，J＝8.6Hz，Ar-H)，12.84(s，1H，-COOH).ESI MS(m/z)：498(M +-1).
Embodiment 22.1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 11,3-two chloro-2-(4-nitro-Phenoxymethyl)-benzene
With 10mmol 2,6-dichloro bromobenzyl and 10mmol p-NP join in the alcohol sodium solution (sodium Metal 99.5 10mmol/10mL dehydrated alcohol), reflux 2h, and cooling concentrates.Add water 20mL, filter, washing gets faint yellow solid 2.8g, yield 96.5%.
Step 2 4-(2,6-two chloro-benzyloxies)-aniline
With 6.7mmol 1,3-two chloro-2-(4-nitro-Phenoxymethyl)-benzene and 33.6mmol tin protochloride are dissolved in the 67mL ethanol, stir reflux 5h.Cooling is evaporated to driedly, adds the 80mL ethyl acetate in resistates, uses NaHCO 3Transfer pH value of solution 7-8, leach insolubles, with ethyl acetate repetitive scrubbing filter residue, merging filtrate, washing, anhydrous Na 2SO 4Dry.Concentrate, get faint yellow oily thing, need not can carry out next step reaction by purifying.
Step 3 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
With 7.2mmol 4-(2,6-two chloro-benzyloxies)-aniline and 7.2mmol 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester (embodiment 1 step 3 product) is dissolved in the 10mL Glacial acetic acid, stirs reflux 4h.Cooling carefully splashes into NaHCO with reaction solution 3In the saturated aqueous solution, ethyl acetate extraction, washing, anhydrous Na 2SO 4Dry.Concentrate, the gained crude product gets faint yellow solid through purification by silica gel column chromatography, and mp 105-107 ℃, yield 58.6%. 1H-NMR(CDCl 3)δ：0.99(t，3H，J＝7.0Hz，-CH 3)，3.95(m，4H，2-CH 2，-OCH 2CH 3)，4.62(s，2H，1-NCH 2)，5.19(s，2H，-CH 2O)，6.93(d，2H，J＝8.9Hz，Ar-H)，7.01(d，2H，J＝8.9Hz，Ar-H)，7.26-7.39(m，5H，Ar-H)，7.45(m，1H，Ar-H)，7.55(m，2H，Ar-H)，8.63(s，1H，-NH).
Step 4 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
With 4mmol 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester is dissolved in 51mL tetrahydrofuran (THF) and the 17mL ethanol, stirs down, adds 20mmol 5%Na HCO 3The aqueous solution, reflux 48h.Cooling in reaction solution impouring 200mL water, is transferred pH1-2 with 2N hydrochloric acid, ethyl acetate extraction, washing, anhydrous Na 2SO 4Dry.Concentrate, gained crude product re-crystallizing in ethyl acetate gets the off-white color solid, 155 ℃ of dp, yield 63.4%. 1H-NMR(d 6-DMSO)δ：3.93(s，2H，2-CH 2)，4.60(s，2H，1-NCH 2)，5.18(s，2H，-CH 2O)，6.92(d，2H，J＝8.9Hz，Ar-H)，7.03(d，2H，J＝8.9Hz，Ar-H)，7.25-7.38(m，5H，Ar-H)，7.45(m，1H，Ar-H)，7.56(m，2H，Ar-H)，8.55(s，1H，-NH)，12.35(s，1H，-COOH).ESI MS(m/z)：481(M +-1).
Embodiment 23. 4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-1-(3-trifluoromethyl-benzyl)-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-1-(3-trifluoromethyl-benzyl)-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to embodiment 22 steps 3, with 1-(3-trifluoromethyl-benzyl)-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester (embodiment 8 step 1 products) substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get white solid, mp71-73 ℃, yield 53.4%. 1H-NMR(CDCl 3)δ：1.21(t，3H，J＝7.0Hz，-CH 3)，3.95(s，2H，2-CH 2)，4.16(q，2H，J＝7.0Hz，-OCH 2CH 3)，4.69(s，2H，1-NCH 2)，5.25(s，2H，-CH 2O)，6.97(d，2H，J＝8.9Hz，Ar-H)，7.11(d，2H，J＝8.9Hz，Ar-H)，7.22(m，1H，Ar-H)，7.35(d，2H，Ar-H)，7.46-7.57(m，4H，Ar-H)，8.16(s，1H，-NH).
Step 2 4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-1-(3-trifluoromethyl-benzyl)-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to embodiment 22 steps 4, with 4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-1-(3-trifluoromethyl-benzyl)-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester gets yellow crystal, 170 ℃ of dp, yield 25.3%. 1H-NMR(d 6-DMSO)δ：3.99(s，2H，2-CH 2)，4.70(s，2H，1-NCH 2)，5.18(s，2H，-CH 2O)，6.92(d，2H，J＝8.9Hz，Ar-H)，7.07(d，2H，J＝8.9Hz，Ar-H)，7.44-7.68(m，7H，Ar-H)，8.53(s，1H，-NH)，12.35(s，1H，-COOH).ESI MS(m/z)：549(M +-1).
Embodiment 24. 1-benzo [1,3] dioxolane-5-base-methyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-benzo [1,3] dioxolane-5-base-methyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to implementing sharp 22 steps 3, with 1-benzo [1,3] dioxolane-5-base-methyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester (embodiment 14 step 1 products) substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get yellow solid, mp 101-103 ℃, yield 59.6%. 1H-NMR(CDCl 3)δ：1.20(t，3H，J＝7.0Hz，-CH 3)，3.93(s，2H，2-CH 2)，4.15(q，2H，J＝7.0Hz，-OCH 2CH 3)，4.54(s，2H，1-NCH 2)，5.26(s，2H，-CH 2O)，5.95(s，2H，-OCH 2O-)，6.75(m，3H，Ar-H)，6.97(d，2H，J＝8.9Hz，Ar-H)，7.11(d，2H，J＝8.9Hz，Ar-H)，7.23(m，1H，Ar-H)，7.36(d，2H，Ar-H)，8.12(s，1H，-NH).
Step 2 1-benzo [1,3] dioxolane-5-base-methyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to implementing sharp 22 steps 4, with 1-benzo [1,3] dioxolane-5-ylmethyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get yellow solid, 168 ℃ of dp, yield 57.4%. 1H-NMR(d 6-DMSO)δ：3.91(s，2H，2-CH 2)，4.48(s，2H，1-NCH 2)，5.18(s，2H，-CH 2O)，6.00(s，2H，-OCH 2O-)，6.74-6.89(m，3H，Ar-H)，6.92(d，2H，J＝8.9Hz，Ar-H)，7.37(d，2H，J＝8.9Hz，Ar-H)，7.44(m，1H，Ar-H)，7.55(m，2H，Ar-H)，8.50(s，1H，-NH)，12.35(s，1H，-COOH).ESI MS(m/z)：525(M +-1).
Embodiment 25.1-cyclohexyl methyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 1-cyclohexyl methyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to implementing sharp 22 steps 3,1-cyclohexyl methyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester (embodiment 10 step 1 products) substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get white solid, mp 157-159 ℃, yield 46.6%. 1H-NMR(CDCl 3)δ：0.94(m，2H，Cyclohexane-H)，1.17(m，6H，-CH 3，Cyclohexane-H)，1.64(m，6H，Cyclohexane-H)，3.29(d，2H，1-NCH 2)，4.05(s，2H，2-CH 2)，4.14(q，2H，J＝7.0Hz，-OCH 2CH 3)，5.24(s，2H，-CH 2O)，6.94(d，2H，J＝8.9Hz，Ar-H)，7.08(d，2H，J＝8.9Hz，Ar-H)，7.22(m，1H，Ar-H)，7.35(d，2H，Ar-H)，8.02(s，1H，-NH).
Step 2 1-cyclohexyl methyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to implementing sharp 22 steps 4, with 1-cyclohexyl methyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester gets yellow solid, 189 ℃ of dp, yield 48.8%. 1H-NMR(d 6-DMSO)δ：0.88(m，2H，Cyclohexane-H)，1.16(m，3H，Cyclo-hexane-H)，1.60(m，6H，Cyclohexane-H)，3.22(d，2H，1-NCH 2)，4.02(s，2H，2-CH 2)，5.16(s，2H，-CH 2O)，6.90(d，2H，J＝8.9Hz，Ar-H)，6.99(d，2H，J＝8.9Hz，Ar-H)，7.44(m，1H，Ar-H)，7.55(m，2H，Ar-H)，8.45(s，1H，-NH)，12.32(s，1H，-COOH).ESI MS(m/z)：487(M +-1).
Embodiment 26.4-[4-(2,6-two chloro-benzyloxies)-aniline]-1-octyl group-5-oxo-2, the preparation of 5-dihydro-1H-pyrroles-3-carboxylic acid
Step 1 4-[4-(2,6-two chloro-benzyloxies)-aniline]-1-octyl group-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester
According to implementing sharp 22 steps 3, with 4-(2,6-two chloro-benzyloxies)-aniline and 1-octyl group-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester (embodiment 3 step 1 products) substitutes 1-benzyl-4-hydroxyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester, get the off-white color solid, mp 68-70 ℃, yield 47.5%. 1H-NMR(CDCl 3)δ：0.85(t，3H，-CH 3)，1.19-1.29(m，13H，-5CH 2CH 3，-OCH 2CH 3)，1.57(m，2H，-CH 2)，3.44(t，2H，1-NCH 2)，4.03(s，2H，2-CH 2)，4.15(q，2H，J＝7.2Hz，-OCH 2CH 3)，5.24(s，2H，-CH 2O)，6.94(d，2H，J＝8.9Hz，Ar-H)，7.08(d，2H，J＝8.9Hz，Ar-H)，7.26(m，1H，Ar-H)，7.35(d，2H，Ar-H)，8.01(s，1H，-NH).
Step 2 4-[4-(2,6-two chloro-benzyloxies)-aniline]-1-octyl group-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid
According to implementing sharp 22 steps 4, with 4-[4-(2,6-two chloro-benzyloxies)-aniline]-1-octyl group-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester substitutes 1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid, ethyl ester gets faint yellow solid, 146 ℃ of dp, yield 52.8%. 1H-NMR(d 6-DMSO)δ：0.83(t，3H，-CH 3)，1.25(m，10H，-5CH 2)，1.54(m，2H，-CH 2)，3.35(t，2H，1-NCH 2)，4.02(s，2H，2-CH 2)，5.18(s，2H，-CH 2O)，6.90(d，2H，J＝8.9Hz，Ar-H)，6.99(d，2H，J＝8.9Hz，Ar-H)，7.44(m，1H，Ar-H)，7.55(d，2H，Ar-H)，8.45(s，1H，Ar-H)，12.33(s，1H，-COOH).ESI MS(m/z)：503(M +-1).
The biological activity of The compounds of this invention can be estimated with the following method:
Embodiment 27
The withered grass mycobacterium is gone down to posterity on 125 white horse with a black mane Wen egg slant mediums, cultivated 4-5 days.Get a little inoculation in liquid nutrient medium (contain 0.5% peptone, 0.3% extractum carnis, 2.0% glycerine, the pH value is 7.0-7.2), in 37 ℃, 220rpm jolts 24h, measures the optical density value (OD of 600nm wavelength on enzyme connection instrument 600nm), to OD 600nmBe 0.5-0.6.Inoculate 1.0% bacterium liquid and (contain 0.5% peptone in the calibrating substratum, 0.3% yeast extract paste, 1.2% agar, the pH value is 7.0-7.4) in, pave plate, after treating that flat board solidifies, add the tablet that diameter is 0.7cm in spacing distance greater than 3.0cm, tablet contain concentration be 0.5mM treat SCREENED COMPOUND 100 μ L, simultaneously, if 0.5mM positive compound 1-(6-chloro-3, the 4-methylenedioxy benzyl)-2-carboxyl-5-(2, the 6-dichloro-benzyloxy) indoles (Daines RA, Pendrak I, Sham K, et al.First X-ray cocrystal ctructure of a bacterial FabH condensingenzyme and a small molecule inhibitor achieved using rationaldesign and homology modeling [J] .J Med Chem, 2003,46:58.), 0.1mM vazadrine and blank solvent DMSO contrast.Behind 37 ℃ of cultivation 48h, observe inhibition zone, measure each compound antibacterial circle diameter, ask average test-results 5 times.Test-results is listed in table 1.
Table 1 compound is to the restraining effect of Mycobacterium phlei
Compound Average diameter of inhibition zone (cm) Compound Average diameter of inhibition zone (cm)
Positive compound 2.2 Positive compound 2.2
The vazadrine 2.3 The vazadrine 2.3
Embodiment 1 0.6 Embodiment 14 0.9
Embodiment 2 1.7 Embodiment 15 0.5
Embodiment 3 2.0 Embodiment 16 0.8
Embodiment 4 1.5 Embodiment 17 0.8
Embodiment 5 1.3 Embodiment 18 0.7
Embodiment 6 1.6 Embodiment 19 0.6
Embodiment 7 1.8 Embodiment 20 0.6
Embodiment 8 2.0 Embodiment 21 0.7
Embodiment 9 1.7 Embodiment 22 1.8
Embodiment 10 1.7 Embodiment 23 2.0
Embodiment 11 1.3 Embodiment 24 2.1
Embodiment 12 0.8 Embodiment 25 0.8
Embodiment 13 1.6 Embodiment 26 1.4

Claims (7)

1. the compound of general formula I, its all possible isomer or its pharmaceutically useful salt or hydrate:
Figure A2006101147930002C1
Wherein:
Q is CH 2O or NH;
R 1Be aryl;
R 2Be aryl, C 3-10Alkyl or C 4-8Cycloalkyl.
Wherein " aryl " is meant phenyl, or by hydroxyl, halogen, nitro, CF 3, methylene-dioxy, C 1-6Alkyl, C 1-6Alkoxy substituent one or polysubstituted phenyl.
2. the compound of claim 1, it is selected from:
1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-heptyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-octyl group-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-hexyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-1-furans-2-ylmethyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-(2-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-(3-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-(3-trifluoromethyl-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-(4-chloro-benzyl)-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-cyclohexyl methyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-benzo [1,3] dioxolane-5-ylmethyl-4-[4-(2,6-two chloro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-benzyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-(3-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-benzo [1,3] dioxolane-5-ylmethyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-heptyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-(2-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-cyclohexyl methyl-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-octyl group-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-(3-trifluoromethyl-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-1-furans-2-ylmethyl-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-(4-chloro-benzyl)-4-[4-(3,5-two fluoro-benzyloxies)-benzyloxy]-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylic acid;
1-benzyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-pyrrolin-3-carboxylic acid;
4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-1-(3-trifluoromethyl-benzyl)-2,5-pyrrolin-3-carboxylic acid;
1-benzo [1,3] dioxolane-5-base-methyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-pyrrolin-3-carboxylic acid;
1-cyclohexyl methyl-4-[4-(2,6-two chloro-benzyloxies)-aniline]-5-oxo-2,5-pyrrolin-3-carboxylic acid; With
4-[4-(2,6-two chloro-benzyloxies)-aniline]-1-octyl group-5-oxo-2,5-pyrrolin-3-carboxylic acid;
Or its pharmacologically acceptable salt or hydrate.
3. the preparation method of claim 1 general formula (I) compound,
For Q wherein is CH 2The formula of O (I) compound, this method may further comprise the steps:
(1) with R wherein 1As claim 1 general formula I define, X is the formula R of halogen 1CH 2X benzyl halide and p-Hydroxybenzaldehyde are raw material, handle in sodium hydride/DMF under-5-0 ℃ and stir 0.5 hour; In solvent such as methyl alcohol, reduce the scheme products therefrom with hydride reducer such as sodium borohydride then;
(2) under rare gas element such as nitrogen protection, make wherein R 2As the defined formula R of claim 1 general formula I 2CH 2Addition reaction takes place in X primary amine and ethyl propenoate under stirring at room, under reflux temperature condensation reaction takes place with oxalic acid diethyl ester in sodium ethylate-ethanol alkaline system then, make again product experience acidic hydrolysis;
(3) utilize catalyzer such as triphenyl phosphorus and diethylazodicarboxylate to make step (1) and step (2) product carry out condensation and slough 1 molecular water in solvent such as THF, and make it the saponification in solvent such as methyl alcohol with alkali such as sodium hydroxide, obtaining wherein, Q is CH 2O, R 1And R 2As the defined compound of Formula I of claim 1;
Perhaps,
For Q wherein is formula (I) compound of NH, and this method may further comprise the steps:
(1) under reflux temperature, make 2,6-dichloro bromobenzyl and paranitrobenzaldehyde react in sodium ethylate-ethanol alkaline system, then, reduce products therefrom with reductive agent such as tin protochloride in solvent such as ethanol;
(2) under rare gas element such as nitrogen protection, make wherein R 2As the defined formula R of claim 1 general formula I 2CH 2Addition reaction takes place in X primary amine and ethyl propenoate under stirring at room, under reflux temperature condensation reaction takes place with oxalic acid diethyl ester in sodium ethylate-ethanol alkaline system then, makes products therefrom experience acidic hydrolysis again;
(3) utilize catalyzer such as acetic acid to make the product condensation that step (1) and step (2) obtain and slough 1 molecular water, make it the saponification in solvent such as THF and ethanol with alkali such as sodium bicarbonate again, obtaining wherein, Q is NH, R 1And R 2As the defined general formula of claim 1 (I) compound.
4. pharmaceutical composition, it comprises according to the compound of Formula I of claim 1 or its all possible isomer or pharmacologically acceptable salt or hydrate, and at least a pharmaceutically acceptable carrier or vehicle.
5. the compound of Formula I of claim 1 is used to prepare the purposes for the treatment of fatty acid sythetase inhibitor.
6. the compound of Formula I of claim 1 is used to prepare the purposes of the medicine for the treatment of infectation of bacteria.
7. treat the method for infectation of bacteria, this method comprises formula (I) compound of the claim 1 that the patient treatment of these needs significant quantity is arranged.
CNA2006101147935A 2006-11-23 2006-11-23 Fatty acid synthetic enzyme inhibitor and medical preparation use thereof Pending CN101190894A (en)

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