CN101190904A - Fatty acid synthetic enzyme inhibitor and medical preparation use thereof - Google Patents
Fatty acid synthetic enzyme inhibitor and medical preparation use thereof Download PDFInfo
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- CN101190904A CN101190904A CNA2006101147920A CN200610114792A CN101190904A CN 101190904 A CN101190904 A CN 101190904A CN A2006101147920 A CNA2006101147920 A CN A2006101147920A CN 200610114792 A CN200610114792 A CN 200610114792A CN 101190904 A CN101190904 A CN 101190904A
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- C07—ORGANIC CHEMISTRY
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The invention relates to a compound of general formula I which can inhibit synthase (FabH) of fatty acid and medicinal salt or hydrate thereof and the substituent group in the general formula I is defined as the instruction. The invention also relates to a preparation method of the compound of the general formula I, which consists of the medical composition of the compound of the general formula I or the medicinal salt or the hydrate thereof as well as the purpose that the compound which can be used for curing bacterial infection is used for preparing fatty acid synthase inhibitor.
Description
Technical field
The present invention relates to gamma-butyrolactone derivative and pharmaceutically useful salt thereof, its preparation method contain their pharmaceutical composition, and described gamma-butyrolactone derivative is as the purposes of fatty acid sythetase inhibitor (FabH).This fatty acid sythetase inhibitor can be as the antimicrobial drug of treatment Gram-positive and negative bacterium infection.
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.Do not act on the antimicrobial drug of fatty acid biosynthetic pathway on the market, therefore, the FabH 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:
Wherein:
R is selected from aryl, C
3-10Alkyl;
Term used herein " aryl " is meant phenyl and by hydroxyl, halogen, nitro, CF
3, methylene-dioxy, C
1-6Alkyl, C
1-6The phenyl that alkoxyl group etc. replace.
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.
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:
(2E, 4E)-2-phenyl-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(4-chloro-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-benzo [1,3] dioxolane-5-base-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(4-methyl-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(3-chloro-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(4-trifluoromethyl-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(6-chloro-benzo [1,3] dioxolane-5-yl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(3-methyl-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(4-sec.-propyl-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2Z, 4E)-2-(4-methoxyl group-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(4-methoxyl group-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-2-octyl group-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2Z, 4E)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-2-heptyl-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-2-heptyl-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-2-hexyl-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(2-chlorine 4-fluoro-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid; With
(2Z, 4E)-2-(2-chlorine 4-fluoro-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
Or its pharmacologically acceptable salt or hydrate;
According to the present invention, formula (I) compound can be prepared by the synthetic route described in the following scheme 1:
Scheme 1
A) NaH, DMF; B) diethyl succinate, CH
3ONa, CH
3OH; C) NaOH; D) SOCl
2, CH
2Cl
2E) p-methoxybenzyl alcohol, pyridine, CHCl
3F) LDA, THF; G) R-CHO; H) TFA, CH
2Cl
2
Specifically, with p-Hydroxybenzaldehyde (scheme 1-1) and 2, (5-0 ℃, 0.5 hour) handled and stirred to 6-dichloro bromobenzyl (scheme 1-2) in sodium hydride/DMF, generates compound 3 (scheme 1-3); Then, under rare gas element such as nitrogen protection, with ethyl succinate the Stobbe condensation reaction taking place in sodium methylate-methyl alcohol alkaline system, through sodium hydroxide hydrolysis, makes aryl methylene succinic acid compound 4 (scheme 1-4); Under reflux temperature,, make aryl methylene succinyl oxide 5 (scheme 1-5) with the sulfur oxychloride dehydration; Under pyridine catalysis,, generate single benzyl ester compound 6 (scheme 1-6) with p-methoxybenzyl alcohol generation esterification; Under rare gas element such as nitrogen protection, with the aldehyde of another molecule in THF, utilize LDA to be catalyzer, under-78 ℃, the Aldol condensation reaction takes place, make compound 8 (scheme 1-8) through compound 7 (scheme 1-7); At last, compound 8 is through TFA/CH
2Cl
2Esterlysis successfully makes target compound of the present invention (scheme 1-9).
Therefore, the preparation method of general formula of the present invention (I) compound may further comprise the steps:
(1)-5-0 ℃ under, with p-Hydroxybenzaldehyde and 2,6-dichloro bromobenzyl is handled in sodium hydride/DMF and was stirred 0.5 hour,
(2) under rare gas element such as nitrogen protection, be that the Stobbe condensation reaction takes place in sodium methylate-methyl alcohol alkaline system the product and the ethyl succinate of step (1), through sodium hydroxide hydrolysis, make the aryl methylene succinic acid compound;
(3) under reflux temperature,, make the aryl methylene succinyl oxide with the sulfur oxychloride dehydration;
(4) under pyridine catalysis,, generate single benzyl ester compound with p-methoxybenzyl alcohol generation esterification;
(5) under rare gas element such as nitrogen protection, with R wherein as above the aldehyde of the defined formula RCHO of general formula I in THF, utilize LDA to be catalyzer, under-78 ℃ of temperature of reaction, the Aldol condensation reaction takes place;
(6) step (5) product is through TFA/CH
2Cl
2Esterlysis makes formula I compound of the present invention.
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. (2E, 4E)-2-phenyl-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-preparation of 5-oxo-tetrahydrochysene-furans-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 2-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-Succinic Acid
Under the room temperature, mix 36mmol diethyl succinate and sodium methoxide solution (sodium Metal 99.5 26mmol/17mL anhydrous methanol), feed nitrogen, be heated to backflow, stir down, drip 18mmol4-(2,6-two chloro-benzyloxies)-and the 75mL methanol solution of phenyl aldehyde, continue backflow 10h.Add 100mL 2N NaOH solution then, continue backflow 11h, be cooled to room temperature.In the frozen water with reaction solution impouring 400mL, ether extraction, water layer is transferred pH 1-2 with concentrated hydrochloric acid, ethyl acetate extraction, washing, anhydrous magnesium sulfate drying.Concentrate, get the off-white color solid, 211 ℃ of dp, yield 83.5%.
1H-NMR(d
6-DMSO)δ：3.40(s，2H，3-CH
2)，5.27(s，2H，-CH
2O)，7.14(d，2H，J＝8.9Hz，Ar-H)，7.40-7.50(m，3H，Ar-H)，7.56(d，2H，J＝8.9Hz，Ar-H)，7.70(s，1H，＝CH)，12.46(brs，2H，-COOH).
Step 3 3-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-dihydro-furan-2, the 5-diketone
With 13mmol 2-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-Succinic Acid is suspended in 33mLCH
2Cl
2In, stirring adding 130mmol sulfur oxychloride down, reflux 5h is cooled to room temperature.Concentrate, filter,, get the orange crystallization with benzene and sherwood oil repetitive scrubbing solid, mp 198-200 ℃, yield 91.8%.
1H-NMR(d
6-DMSO)δ：3.97(d，2H，4-CH
2)，5.32(s，2H，-CH
2O)，7.19(d，2H，J＝8.9Hz，Ar-H)，7.47(m，1H，Ar-H)，7.57(m，2H，Ar-H)，7.63(t，1H，＝CH)，7.67(d，2H，J＝8.9Hz，Ar-H).
Step 4 2-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-Succinic Acid 4-(4-methoxyl group-benzyl) ester
With 9mmol 3-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-dihydro-furan-2,5-diketone, 24mmol p-methoxybenzyl alcohol and 18mmol pyridine are dissolved in the 30mL chloroform, reflux 24h.Cooling concentrates, in residuum impouring 120mL 10% aqueous hydrochloric acid, and ethyl acetate extraction, washing, anhydrous magnesium sulfate drying.Concentrate, filter, washing gets white cotton-shaped crystallization, and mp 165-167 ℃, yield 85.2%.
1H-NMR(d
6-DMSO)δ：3.52(s，2H，3-CH
2)，3.74(s，3H，-OCH
3)，5.06(s，2H，-CH
2O)，5.26(s，2H，-CH
2O)，6.91(d，2H，J＝8.9Hz，Ar-H)，7.08(d，2H，J＝8.6Hz，Ar-H)，7.28(d，2H，J＝8.9Hz，Ar-H)，7.37(d，2H，J＝8.6Hz，Ar-H)，7.48(m，1H，Ar-H)，7.57(m，2H，Ar-H)，7.73(s，1H，＝CH)，12.64(s，1H，-COOH).
Step 5 (2E, 4E)-2-phenyl-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid
With 4mmol 2-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-Succinic Acid 4-(4-methoxyl group-benzyl) ester is dissolved among the 40mLTHF, is cooled to-78 ℃, drip 12mmol LDA, continue to stir 1.5h, drip the 2mL THF solution of 4mmol phenyl aldehyde, continue to stir 3-8h.Slowly drip 6mL 6N H
2SO
4Solution, ether extraction, anhydrous magnesium sulfate drying.Concentrate, residuum is dissolved in 25mL CH
2Cl
2In, add 0.3mL TFA then, continue to stir 12h.In reaction solution, add 20mL NaHCO
3The aqueous solution is transferred pH 1-2 with concentrated hydrochloric acid, ethyl acetate extraction, washing, anhydrous magnesium sulfate drying.Concentrate, the gained crude product gets white solid, 239 ℃ of dp, yield 25.5% through purification by silica gel column chromatography.
1H-NMR(d
6-DMSO)δ：4.68(d，1H，J＝7.0Hz，3-CH)，5.30(s，2H，-CH
2O)，5.87(d，1H，J＝7.0Hz，2-CH)，7.20(d，2H，J＝8.7Hz，Ar-H)，7.34-7.59(m，9H，Ar-H，＝CH)，7.67(d，2H，J＝8.7Hz，Ar-H)，12.74(s，1H，-COOH).FAB MS(m/z)：469(M
++1).
Embodiment 2. (2E, 4E)-2-(4-chloro-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid
According to embodiment 1 step 5, substitute phenyl aldehyde with 4-chloro-benzaldehyde.Crude product gets white solid, 291 ℃ of dp, yield 18.5% through purification by silica gel column chromatography (methylene chloride wash-out).
1H-NMR(d
6-DMSO)δ：3.63(s，1H，3-CH)，5.25(s，2H，-CH
2O)，5.84(s，1H，2-CH)，7.06(d，2H，J＝8.7Hz，Ar-H)，7.23(d，2H，J＝8.4Hz，Ar-H)，7.41(d，2H，J＝8.4Hz，Ar-H)，7.45-7.57(m，4H，Ar-H，＝CH)，7.91(d，2H，J＝8.7Hz，Ar-H).ESI MS(m/z)：501(M
+-1).
Embodiment 3. (2E, 4E)-2-benzo [1,3] dioxolane-5-base-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-preparation of 5-oxo-tetrahydrochysene-furans-3-carboxylic acid
According to embodiment 1 step 5, substitute phenyl aldehyde with piperonylaldehyde.Crude product gets white solid, 205 ℃ of dp, yield 15.0% through purification by silica gel column chromatography (methylene chloride wash-out).
1H-NMR(d
6-DMSO)δ：3.70(s，1H，3-CH)，5.25(s，2H，-CH
2O)，5.75(s，1H，2-CH)，5.97(d，2H，-CH
2-)，6.69(m，2H，Ar-H)，6.85(d，1H，J＝8.1Hz，Ar-H)，7.07(d，2H，J＝8.6Hz，Ar-H)，7.44-7.58(m，4H，Ar-H，＝CH)，7.89(d，2H，J＝8.6Hz，Ar-H)，ESI MS(m/z)：511(M
+-1).
Embodiment 4. (2E, 4E)-2-(4-methyl-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-preparation of 5-oxo-tetrahydrochysene-furans-3-carboxylic acid
According to embodiment 1 step 5, substitute phenyl aldehyde with p-tolyl aldehyde.Crude product gets white solid, yield 18.6% through purification by silica gel column chromatography (petrol ether/ethyl acetate wash-out).
1H-NMR(d
6-DMSO)δ：2.31(s，3H，-CH
3)，4.64(d，1H，J＝7.3Hz，3-CH)，5.30(s，2H，-CH
2O)，5.83(d，2H，J＝7.3Hz，2-CH)，7.19(m，4H，Ar-H)，7.27(d，2H，J＝8.4Hz，Ar-H)，7.46-7.59(m，4H，Ar-H，＝CH)，7.66(d，2H，J＝9.0Hz，Ar-H)，12.69(s，1H，-COOH).ESI MS(m/z)：437(M
+-COOH).
Embodiment 5. (2E, 4E)-2-(3-chloro-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-preparation of 5-oxo-tetrahydrochysene-furans-3-carboxylic acid
According to embodiment 1 step 5, substitute phenyl aldehyde with m chlorobenzaldehyde.Crude product gets white solid, yield 17.5% through purification by silica gel column chromatography (methylene chloride wash-out).
1H-NMR(d
6-DMSO)δ：3.68(s，1H，3-CH)，5.25(s，2H，-CH
2O)，5.88(s，1H，2-CH)，7.06(d，2H，J＝8.6Hz，Ar-H)，7.26(m，2H，Ar-H)，7.35-7.57(m，6H，Ar-H，＝CH)，7.89(d，2H，J＝8.6Hz，Ar-H).ESIMS(m/z)：457(M
+-COOH).
Embodiment 6. (2E, 4E)-2-(4-trifluoromethyl-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-preparation of 5-oxo-tetrahydrochysene-furans-3-carboxylic acid
According to embodiment 1 step 5, so that trifluoromethylated benzaldehyde is substituted phenyl aldehyde.Crude product gets white solid, 272 ℃ of dp, yield 16.6% through purification by silica gel column chromatography (methylene chloride wash-out).
1H-NMR(d
6-DMSO)δ：3.69(s，1H，3-CH)，5.23(s，2H，-CH
2O)，5.98(s，1H，2-CH)，7.05(d，2H，J＝8.1Hz，Ar-H)，7.26(m，2H，Ar-H)，7.44-7.56(m，6H，Ar-H，＝CH)，7.70(d，2H，Ar-H)，7.89(d，2H，J＝8.1Hz，Ar-H).ESI MS(m/z)：491(M
+-COOH).
Embodiment 7. (2E, 4E)-2-(6-chloro-benzo [1,3] dioxolane-5-yl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-preparation of 5-oxo-tetrahydrochysene-furans-3-carboxylic acid
According to embodiment 1 step 5, substitute phenyl aldehyde with 6-chlorine piperonylaldehyde.Crude product gets white solid, 198 ℃ of dp, yield 19.3% through purification by silica gel column chromatography (methylene chloride wash-out).
1H-NMR(d
6-DMSO)δ：4.04(s，1H，3-CH)，5.28(d，2H，-CH
2O)，6.02(m，3H，-CH
2-，＝CH)，6.68(s，1H，2-CH)，7.13(m，3H，Ar-H)，7.46-7.60(m，4H，Ar-H)，7.83(d，2H，J＝7.8Hz，Ar-H)，13.66(s，1H，-COOH).ESI MS(m/z)：501(M
+-COOH).
Embodiment 8. (2E, 4E)-2-(3-methyl-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-preparation of 5-oxo-tetrahydrochysene-furans-3-carboxylic acid
According to embodiment 1 step 5, substitute phenyl aldehyde with a tolyl aldehyde.Crude product gets white solid, 234 ℃ of dp, yield 14.0% through purification by silica gel column chromatography (petrol ether/ethyl acetate wash-out).
1H-NMR(d
6-DMSO)δ：2.32(s，3H，-CH
3)，4.66(d，1H，J＝6.7Hz，3-CH)，5.31(s，2H，-CH
2O)，5.83(d，2H，J＝6.7Hz，2-CH)，7.14-7.30(m，6H，Ar-H)，7.47-7.51(m，1H，Ar-H)，7.57(m，3H，Ar-H)，7.67(d，2H，J＝8.9Hz，Ar-H)，12.73(s，1H，-COOH).ESIMS(m/z)：437(M
+-COOH).
Embodiment 9. (2E, 4E)-2-(4-sec.-propyl-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-preparation of 5-oxo-tetrahydrochysene-furans-3-carboxylic acid
According to embodiment 1 step 5, substitute phenyl aldehyde with cumic aldehyde.Crude product gets white solid, 282 ℃ of dp, yield 15.8% through purification by silica gel column chromatography (methylene chloride wash-out).
1H-NMR(d
6-DMSO)δ：1.13(d，6H，-2CH
3)，2.80(m，1H，-CH-)，3.68(s，1H，3-CH)，5.24(s，2H，-CH
2O)，5.83(s，1H，2-CH)，7.05(d，2H，J＝8.4Hz，Ar-H)，7.11(d，2H，J＝8.1Hz，Ar-H)，7.19(d，2H，J＝8.1Hz，Ar-H)，7.42-7.57(m，4H，Ar-H)，7.90(d，2H，J＝8.4Hz，Ar-H).ESI MS(m/z)：499(M
+-1).
Embodiment 10. (2Z, 4E)-2-(4-methoxyl group-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-preparation of 5-oxo-tetrahydrochysene-furans-3-carboxylic acid
According to embodiment 1 step 5, substitute phenyl aldehyde with aubepine.Crude product gets white solid, 253 ℃ of dp, yield 6.2% through purification by silica gel column chromatography (methylene chloride wash-out).
1H-NMR(d
6-DMSO)δ：3.76(s，3H，-OCH
3)，4.61(d，1H，J＝7.2Hz，3-CH)，5.30(s，2H，-CH
2O)，5.81(d，1H，J＝7.2Hz，2-CH)，6.94(d，2H，J＝8.7Hz，Ar-H)，7.19(d，2H，J＝9.0Hz，Ar-H)，7.31(d，2H，J＝8.7Hz，Ar-H)，7.46-7.59(m，4H，Ar-H)，7.65(d，2H，J＝9.0Hz，Ar-H)，12.71(s，1H，-COOH).ESI MS(m/z)：453(M
+-COOH).
Embodiment 11. (2E, 4E)-2-(4-methoxyl group-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-preparation of 5-oxo-tetrahydrochysene-furans-3-carboxylic acid
According to embodiment 1 step 5, substitute phenyl aldehyde with aubepine.Crude product gets white solid, 184 ℃ of dp, yield 17.2% through purification by silica gel column chromatography (methylene chloride wash-out).
1H-NMR(d
6-DMSO)δ：3.72(s，3H，-OCH
3)，4.08(s，1H，3-CH)，5.30(s，2H，-CH
2O)，5.80(s，1H，2-CH)，6.92(d，2H，J＝8.9Hz，Ar-H)，7.12(d，2H，J＝8.6Hz，Ar-H)，7.21(d，2H，J＝8.9Hz，Ar-H)，7.45-7.58(m，4H，Ar-H)，7.75(d，2H，J＝8.6Hz，Ar-H)，13.62(s，1H，-COOH).ESI MS(m/z)：453(M
+-COOH).
Embodiment 12. (2E, 4E)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-preparation of 2-octyl group-5-oxo-tetrahydrochysene-furans-3-carboxylic acid
According to embodiment 1 step 5, substitute phenyl aldehyde with aldehyde C-9.Crude product gets white solid, 239 ℃ of dp, yield 16.2% through purification by silica gel column chromatography (methylene chloride wash-out).
1H-NMR(d
6-DMSO)δ：0.82(t，3H，-CH
3)，1.22(br，12H，-6CH
2)，1.51(br，2H，-CH
2)，3.70(br，1H，3-CH
2)，4.69(t，1H，2-CH
2)，5.28(s，2H，-CH
2O)，7.11(d，2H，J＝8.6Hz，Ar-H)，7.39(s，1H，＝CH)，7.46(m，1H，Ar-H)，7.56(d，2H，Ar-H)，7.80(d，2H，J＝8.6Hz，Ar-H).ESI MS(m/z)：505(M
++1).
Embodiment 13. (2Z, 4E)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-preparation of 2-heptyl-5-oxo-tetrahydrochysene-furans-3-carboxylic acid
According to embodiment 1 step 5, substitute phenyl aldehyde with octanal.Crude product gets white solid, 215 ℃ of dp, yield 6.0% through purification by silica gel column chromatography (methylene chloride wash-out).
1H-NMR(d
6-DMSO)δ：0.85(t，3H，-CH
3)，1.23-1.49(m，10H，-5CH
2)，1.70(m，2H，-CH
2)，4.23(brs，1H，3-CH
2)，4.60(m，1H，2-CH
2)，5.29(s，2H，-CH
2O)，7.14(d，2H，J＝8.6Hz，Ar-H)，7.43-7.59(m，4H，Ar-H，＝CH)，7.64(d，2H，J＝8.6Hz，Ar-H).ESI MS(m/z)：490(M
++1).
Embodiment 14. (2E, 4E)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-preparation of 2-heptyl-5-oxo-tetrahydrochysene-furans-3-carboxylic acid
According to embodiment 1 step 5, substitute phenyl aldehyde with octanal.Crude product gets white solid, 236 ℃ of dp, yield 15.6% through purification by silica gel column chromatography (methylene chloride wash-out).
1H-NMR(d
6-DMSO)δ：0.82(t，3H，-CH
3)，1.23-1.36(m，10H，-5CH
2)，1.57(m，2H，-CH
2)，3.97(brs，1H，3-CH
2)，4.69(m，1H，2-CH
2)，5.29(s，2H，-CH
2O)，7.14(d，2H，J＝8.6Hz，Ar-H)，7.46-7.58(m，4H，Ar-H，＝CH)，7.72(d，2H，J＝8.6Hz，Ar-H).ESI MS(m/z)：490(M
++1).
Embodiment 15. (2E, 4E)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-preparation of 2-hexyl-5-oxo-tetrahydrochysene-furans-3-carboxylic acid
According to embodiment 1 step 5, substitute phenyl aldehyde with enanthaldehyde.Crude product gets white solid, 206 ℃ of dp, yield 14.3% through purification by silica gel column chromatography (methylene chloride wash-out).
1H-NMR(d
6-DMSO)δ：0.82(t，3H，-CH
3)，1.23-1.34(m，8H，-4CH
2)，1.54(m，2H，-CH
2)，3.75(brs，1H，3-CH
2)，4.70(m，1H，2-CH
2)，5.28(s，2H，-CH
2O)，7.11(d，2H，J＝8.6Hz，Ar-H)，7.41-7.58(m，4H，Ar-H，＝CH)，7.79(d，2H，J＝8.6Hz，Ar-H).ESI MS(m/z)：477(M
++1).
Embodiment 16. (2E, 4E)-2-(2-chlorine 4-fluoro-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-preparation of 5-oxo-tetrahydrochysene-furans-3-carboxylic acid
According to embodiment 1 step 5, substitute phenyl aldehyde with 2-chloro-4-fluoro-phenyl aldehyde.Crude product gets white solid, 268 ℃ of dp, yield 29.0% through purification by silica gel column chromatography (methylene chloride wash-out).
1H-NMR(d
6-DMSO)δ：3.65(s，1H，3-CH
2)，5.25(s，2H，-CH
2O)，6.16(s，1H，2-CH
2)，7.07(d，2H，J＝8.6Hz，Ar-H)，7.11-7.21(m，2H，Ar-H)，7.44-7.57(m，5H，Ar-H，＝CH)，8.07(d，2H，J＝8.6Hz，Ar-H).ESI MS(m/z)：475(M
+-COOH).
Embodiment 17. (2Z, 4E)-2-(2-chlorine 4-fluoro-phenyl)-4-[4-(2,6 two chloro-benzyloxy)-Ben Yajiaji]-preparation of 5-oxo-tetrahydrochysene-furans-3-carboxylic acid
According to embodiment 1 step 5, substitute phenyl aldehyde with 2-chloro-4-fluoro-phenyl aldehyde.Crude product gets white solid, 213 ℃ of dp, yield 33.8% through purification by silica gel column chromatography (methylene chloride wash-out).
1H-NMR(d
6-DMSO)δ：4.63(d，1H，J＝7.2Hz，3-CH
2)，5.30(s，2H，-CH
2O)，6.08(d，1H，J＝7.2Hz，2-CH
2)，7.21(d，2H，J＝8.7Hz，Ar-H)，7.29(t，1H，Ar-H)，7.31-7.62(m，6H，Ar-H，＝CH)，7.65(d，2H，J＝8.7Hz，Ar-H)，12.93(s，1H，-COOH).ESI MS(m/z)：475(M
+-COOH).
The biological activity of the compound that the present invention relates to can be estimated with the following method:
Embodiment 18
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 | 0.7 | Embodiment 10 | 1.7 |
| Embodiment 2 | 2.0 | Embodiment 11 | 1.7 |
| Embodiment 3 | 1.4 | Embodiment 12 | 1.7 |
| Embodiment 4 | 0.9 | Embodiment 13 | 2.4 |
| Embodiment 6 | 1.8 | Embodiment 14 | 2.1 |
| Embodiment 6 | 2.0 | Embodiment 15 | 1.6 |
| Embodiment 7 | 1.8 | Embodiment 16 | 1.8 |
| Embodiment 8 | 1.6 | Embodiment 17 | 2.5 |
| Embodiment 9 | 2.0 |
Claims (7)
1. the compound of general formula I, its all possible isomer or its pharmacologically acceptable salt or hydrate:
Wherein:
R is selected from aryl, C
3-10Alkyl;
Described " aryl " is meant phenyl and by hydroxyl, halogen, nitro, CF
3, methylene-dioxy, C
1-6Alkyl, C
1-6The phenyl that alkoxyl group replaces.
2. claim 1 compound, it is selected from:
(2E, 4E)-2-phenyl-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(4-chloro-phenyl)-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-benzo [1,3] dioxolane-5-base-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(4-methyl-phenyl)-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(3-chloro-phenyl)-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(4-trifluoromethyl-phenyl)-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(6-chloro-benzo [1,3] dioxolane-5-yl)-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(3-methyl-phenyl)-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(4-sec.-propyl-phenyl)-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2Z, 4E)-2-(4-methoxyl group-phenyl)-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(4-methoxyl group-phenyl)-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-2-octyl group-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2Z, 4E)-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-2-heptyl-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-2-heptyl-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-2-hexyl-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
(2E, 4E)-2-(2-chlorine 4-fluoro-phenyl)-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid; With
(2Z, 4E)-2-(2-chlorine 4-fluoro-phenyl)-4-[4-(2,6-two chloro-benzyloxies)-Ben Yajiaji]-5-oxo-tetrahydrochysene-furans-3-carboxylic acid;
Or its all possible isomer, or pharmacologically acceptable salt or hydrate.
3. the preparation method of claim 1 general formula (I) compound, this method may further comprise the steps:
(1)-5-0 ℃ under, with p-Hydroxybenzaldehyde and 2,6-dichloro bromobenzyl is handled in sodium hydride/DMF and was stirred 0.5 hour,
(2) under rare gas element such as nitrogen protection, be that the Stobbe condensation reaction takes place in sodium methylate-methyl alcohol alkaline system the product and the ethyl succinate of step (1), through sodium hydroxide hydrolysis, make the aryl methylene succinic acid compound;
(3) under reflux temperature,, make the aryl methylene succinyl oxide with the sulfur oxychloride dehydration;
(4) under pyridine catalysis,, generate single benzyl ester compound with p-methoxybenzyl alcohol generation esterification;
(5) under rare gas element such as nitrogen protection, with R wherein as above the aldehyde of the defined formula RCHO of general formula I in THF, utilize LDA to be catalyzer, under-78 ℃ of temperature of reaction, the Aldol condensation reaction takes place;
(6) step (5) product is through TFA/CH
2Cl
2Esterlysis obtains compound of Formula I of the present invention.
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.
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| PCT/CN2006/003403 WO2008061400A1 (en) | 2006-11-23 | 2006-12-13 | Fatty acid synthase inhibitors and medical uses thereof |
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