WO2008061400A1

WO2008061400A1 - Fatty acid synthase inhibitors and medical uses thereof

Info

Publication number: WO2008061400A1
Application number: PCT/CN2006/003403
Authority: WO
Inventors: Song Li; Hong Yu; Xuehui Zhang; Lili Wang; Junhai Xiao; Zhibing Zheng; Wu Zhong
Original assignee: Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A.
Priority date: 2006-11-23
Filing date: 2006-12-13
Publication date: 2008-05-29
Also published as: CN101190904A

Abstract

The present application discloses compounds of formula (I) and their pharmaceutically acceptable salts or solvates that have fatty acid synthase inhibitory effect (FabH), in which the definitions of the substituents in formula (I) are illuminated as description. The present application also discloses the preparation methods of formula (I), the pharmaceutical compositions containing the present compounds and the uses of the compounds in preparing fatty acid synthase inhibitors. The said compounds may be use for the treatment of bacteria infections.

Description

Fatty acid synthase inhibitor and its pharmaceutical use

The present invention relates to a Y-butyrolactone derivative, a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition containing the same, and the use of the γ-butyrolactone derivative as a fatty acid synthase inhibitor (FabH) . The fatty acid synthase inhibitor can be used as an antibacterial agent for treating Gram-positive and Gram-negative infections. Background technique

Among all biological organisms, fatty acid biosynthesis is a necessary process. The fatty acid biosynthesis of prokaryotes and eukaryotes is catalyzed by fatty acid synthase (FAS). Although their synthetic pathways are basically the same, the structure of biosynthesis is different. There are two types of enzymes that catalyze the biosynthesis of fatty acids (FAS I and FAS II ). FAS I is present in mammals and yeast, where all of the enzymatic activity is encoded in a single polypeptide chain, and each step of the fatty acid synthesis reaction is catalyzed by the different functional domains of this large protein. FAS II is found in bacteria and plants. It consists of a series of small, isolated proteins. Each step of fatty acid synthesis is catalyzed by distinct monofunctional enzymes. The uniqueness of mycobacteria is that it has both FAS I and FAS II, FAS I involves the biosynthesis of essential fatty acids, and FAS II involves the synthesis of complex cell envelope lipids such as mycolic acids. Therefore, selective inhibition of inhibitors of FAS II system monofunctional enzymes may lead to the development of broad-spectrum antibacterial drugs ( Payne DJ, Warren PV, Holmes DJ, et al. Drug Discov Develop, 2001, 6(10): 537-544 Heath RJ, hiteb SW, Rock CO. Prog Lipid Res, 2001, 40: 467-497. ).

The single-function enzyme FabH of the FAS II system, which uses acetyl-CoA as a substrate, is fat. The initial factor of the acid synthesis carbon chain extension cycle is widely present in bacteria. At the same time, the final product of the cycle, cyanoyl-ACP, again produces feedback inhibition of FabH. Therefore, FabH is an important fatty acid biosynthetic enzyme and a key regulatory point in the entire synthetic pathway. It can be seen that FabH plays a necessary and regulatory role in bacterial fatty acid biosynthesis (Heath RJ, Rock CO. J Biol Chera, 1996, 271 (4): 1833-1836; evill WP, Bibb MJ, Scheu AK, et al. J Bacteriol, 2001, 183: 3526-3530. ).

Due to the emergence of drug resistance, it is urgent to develop new antibacterial drugs that have different mechanisms of action from existing drugs. There are no antibacterial agents on the market for fatty acid biosynthesis. Therefore, FabH inhibitors are expected to develop into new broad-spectrum antibacterial drugs. Summary of the invention

According to one aspect of the invention, the invention relates to a compound of formula I, or all possible isomers or pharmaceutically acceptable salts or hydrates thereof:

(I)

among them:

R is selected from aryl, Cw. Alkyl group

As used herein, the term "aryl" refers to phenyl and substituted by hydroxy,, nitro, CF _3, methylenedioxy, d- ₆ alkyl, d- _C6 alkoxy substituted phenyl and the like.

The term "C^alkyl" as used in the present invention means a straight or branched alkyl group having 3 to 10 carbon atoms, which includes, but is not limited to, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. The The group is optionally substituted with a substituent selected from the group consisting of a hydroxyl group, a carboxyl group, a halogen, and a d- ₆ alkoxy group. The compounds of the invention may contain one or more asymmetric centers and may exist as racemates and optically active forms. All such racemates or enantiomers are included within the scope of the invention.

Some of the compounds of the present invention may be crystallized or recrystallized from a solvent, in which case solvates may be formed, all of which are included in the scope of the present invention.

The compounds of the present invention are for pharmaceutical use, it being understood that they are preferably provided in pure form, for example at least 60% pure, more suitably 75%, more preferably 85%, and most preferably at least 98% pure (%) Means weight percent).

According to another aspect of the present invention, the present invention relates to a pharmaceutical composition comprising a compound of the above formula I, which comprises a compound of the formula I of the present invention, or all possible isomers or pharmaceutically acceptable salts or hydrates thereof, and At least one pharmaceutically acceptable carrier or excipient.

According to another aspect of the invention, the invention also relates to a process for the preparation of a compound of the above formula I.

According to a further aspect of the invention, the invention relates to the use of said compound for the preparation of a fatty acid synthase inhibitor, which is useful as an antibacterial agent for the treatment of Gram-positive and Gram-negative infections.

The invention further relates to a method of treating Gram-positive and Gram-negative infections in animals and humans, the method comprising administering to a mammal in need thereof, including a human, a therapeutically effective amount of a compound of the invention. Preferred compounds of the invention are selected from the group consisting of

(2E, 4E)- 2-phenyl-4-[4-(2,6-dichloro-benzyloxy)-phenylhydrazinyl]-5-oxo-tetrahydro-furan-3-carboxylic acid;

(2E, 4E) - 2-(4-Chloro-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-phenylhydrazinyl]-5-oxo-tetrahydro-furan- 3-carboxylic acid; (2E, 4E)- 2 -Benzo[1,3]dioxan-5-yl-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo Generation-tetrahydro-furan-3-carboxylic acid;

(2E, 4E)-2-(4-indolyl-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro-furan 3-carboxylic acid;

(2E, 4£)-2-(3-chloro-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro-furan 3-carboxylic acid;

(2E, 4E) -2- (4-Trifluoromethyl-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro - furan-3-carboxylic acid;

(2E, 48)-2-(6-Chloro-benzo[1,3]di-p-halothylar-5-yl)-4-[4-(2,6-dichloro-benzyloxy)-benzene Methyl]-5-oxo-tetrahydro-furan-3-carboxylic acid;

(2E, 4 ugly)-2-(3-methyl-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro- Furan-3-carboxylic acid;

(2E, 4E) -2- (4-isopropyl-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzoindolyl--5-oxo-tetrahydro- Furan-3-carboxylic acid;

^{(2Z, 4E) - 2 -} (4 - methoxy - phenyl) - 4- [4- (2, 6-dichloro - benzyloxy) - benzylidene〗-5-oxo - tetrahydro - Furan-3-carboxylic acid;

(2E, 4E)-2-(4-methoxy-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-phenylhydrazinyl]-5-oxo-tetrahydro- Furan-3-carboxylic acid;

(2E, 4E)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-2-octyl-5-oxo-tetrahydro-furan-3-carboxylic acid;

(2Z, 4E)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-2-heptyl-5-oxo-tetrahydro-furan-3-carboxylic acid;

(2E, 4E)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-2-heptyl- 5-oxo-tetrahydro-furan-3-carboxylic acid;

(2E, 4Ε)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-2-hexyl-5-oxo-tetrahydro-furan-3-carboxylic acid; (2E, 4E)- ² _( ² -Chloro-4-fluoro-phenyl)-4- [4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro -furan-3-carboxylic acid; and

(2Z, 4E)-2-(2-chloro-4-fluoro-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro - furan-3-carboxylic acid;

Or a pharmaceutically acceptable salt or hydrate thereof; according to the invention, the compound of formula (I) can be prepared by the synthetic route as described in Scheme 1 below:

plan 1

a) NaH, DMF; b) diethyl succinate, CH ₃ 0Na, CH ₃ 0H; c) NaOH; d) SOCl ₂ , CH ₂ C1 ₂ ; e) p-methoxybenzyl alcohol, pyridine, CHC1 ₃ ; f) LDA, THF; g) R-CHO; h) TFA, CH ₂ Cl _2o

Specifically, p-hydroxybenzaldehyde (Scheme 1-1) and 2,6-dichlorobromobenzyl (Scheme 1-2) were treated with sodium hydride/DMF and stirred (-5-0 ° C, 0.5 hours) Compound 3 (Scheme 1-3) is formed; then, Stobbe condensation reaction with diethyl succinate in sodium methoxide-sterol alkaline system is carried out under the protection of an inert gas such as nitrogen, and hydrolysis is carried out by sodium hydroxide. Aryl methylene succinate compound 4 (Scheme 1-4); dehydrating with thionyl chloride at reflux temperature to produce aryl sulfinyl succinic anhydride 5 (Scheme 1-5); catalyzed by pyridine, Esterification of methoxybenzyl alcohol to form monobenzyl ester compound 6 (Scheme 6); with an inert gas such as nitrogen, with another molecule of aldehyde in THF, using LDA as a catalyst, - 78 ° C Next, an Aldol condensation reaction occurs, and Compound 8 (Scheme 1-8) is obtained via Compound 7 (Scheme 1-7); finally, Compound 8 is esterified with TFA/CH ₂ C1 _{2 to} successfully prepare the target compound of the present invention ( Option 1-9).

Therefore, the preparation method of the compound of the general formula (I) of the present invention comprises the following steps:

(1) Treat p-hydroxybenzaldehyde and 2,6-dichlorobenzyl bromide in sodium hydride/DMF at -5 to 0 ° C and stir for 0.5 hours.

(2) Under the protection of an inert gas such as nitrogen, the product of the step (1) and the diethyl succinate are subjected to a Stobbe condensation reaction in a sodium methoxide-methanol basic system, and hydrolyzed by sodium hydroxide to obtain an arylmethylene group. Succinic acid compound;

(3) dehydrating with thionyl chloride at reflux temperature to obtain aryl sulfenyl succinic anhydride;

( ⁴ ) esterification with p-methoxybenzyl alcohol under catalysis of pyridine to form a monobenzyl ester compound;

(5) under the protection of an inert gas such as nitrogen, with an aldehyde of the formula RCH0 wherein R is as defined above in formula I in THF, using LDA as a catalyst, at a reaction temperature of -78 ° C, Aldol condensation reaction occurs;

(6) The product of the step (5) is esterified with TFA/CH ₂ C1 ₂ to obtain the compound of the formula I of the present invention. The compound of the formula I of the present invention or a pharmaceutically acceptable salt thereof may be used singly or in the form of a pharmaceutical composition together with a pharmaceutically acceptable carrier or excipient, when used in the form of a pharmaceutical composition, usually An effective dosage of a compound of the formula I according to the invention, or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable carriers or diluents, in a suitable administration form or dosage form, including the appropriate application The means mix, granulate, compress or dissolve the components. Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula I, all possible isomers thereof, or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable carrier.

The pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, Intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or input, or by means of an explanted reservoir, preferably oral, intramuscular, intraperitoneal or intravenous.

The compound of the present invention or a pharmaceutical composition containing the same can be administered in a unit dosage form. The dosage form can be a liquid dosage form or a solid dosage form. The liquid dosage form may be a true solution, a colloid, a microparticulate form, an emulsion dosage form, or a suspension dosage form. Other dosage forms such as tablets, capsules, dropping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders, inclusions, implants, patches, Rubbing agent, etc.

The pharmaceutical composition of the present invention may further contain a usual carrier, and the pharmaceutically acceptable carrier herein includes, but is not limited to: ion exchanger, alumina, aluminum stearate, lecithin, serum protein such as human serum albumin, buffer. a substance such as phosphate, glycerin, sorbic acid, potassium sorbate, a mixture of partially glycerides of saturated plant fatty acids, water, salt or Electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, carboxymethyl Cellulose sodium, polyacrylate, beeswax, lanolin, and the like. The amount of the carrier in the pharmaceutical composition may range from 1% by weight to 98% by weight. /. , usually about 80% by weight. For convenience, local anesthetics, preservatives, buffers, etc., are directly soluble in the carrier.

Oral tablets and capsules may contain excipients such as binders, such as syrups, gum arabic, sorbitol, tragacanth, or polyvinylpyrrolidone, fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, Aminoacetic acid, a lubricant such as magnesium stearate, talc, polyethylene glycol, silica, a disintegrant such as potato starch, or an acceptable humectant such as sodium lauryl sulfate. The tablets may be coated by methods known in the pharmacy.

The oral solution can be prepared as a suspension of water and oil, a solution, an emulsion, a syrup or a sputum, or as a dry product, supplemented with water or other suitable medium before use. Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible Oils, emulsifiers, such as lecithin, sorbitan monooleate, gum arabic; or non-aqueous carriers (possibly containing edible oils), such as almond oil, oils such as glycerol, ethylene glycol, or ethanol; preservatives, For example, decyl hydroxybenzoate or propyl ester, sorbic acid. Flavoring or coloring agents can be added as needed.

The suppository can comprise a conventional suppository base such as cocoa butter or other glycerides. For parenteral administration, liquid dosage forms are usually made from the compound and a sterile carrier. The carrier is preferred water. Depending on the selected carrier and drug concentration, the compound can be dissolved in the carrier or in a suspension solution. The compound is dissolved in water before being prepared for injection, filtered and sterilized, and then placed in a sealed bottle or ampoule.

When the skin is topically applied, the compound of the present invention can be formulated into a suitable ointment, washed In the form of a cream, or a cream, wherein the active ingredient is suspended or dissolved in one or more carriers. The carrier in which the ointment preparation can be used includes, but is not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polyoxypropylene, emulsifying wax and water; and detergents and creams can be used, including but not limited to : mineral oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Depending on the mode of administration, the components may contain from 0.1% by weight, or more suitably from 10% to 60% by weight of the active ingredient. Where a unit dosage is included in the component, each unit preferably contains from 50 to 500 mg of active ingredient. Depending on the route of administration and the frequency of administration, a suitable therapeutic dose for an adult is 100-3000 grams per day, such as 1500 mg per day. This dose corresponds to 1. 5 - 50 g / kg / day, and the appropriate dose is 5-20 g / kg / day.

It must be recognized that the optimal dosage and interval of administration of the compound of formula I is determined by the nature of the compound and the external conditions such as the form, route and location of administration and the particular mammal being treated, and this optimal administration The dosage can be determined using conventional techniques. It must also be recognized that the optimal course of treatment, i.e., the daily dose of the compound of formula I over a nominal period of time, can be determined by methods well known in the art. detailed description

The following specific examples are preferred embodiments of the invention and are not to be construed as limiting the invention in any way.

The melting point was measured with a SRY-1 type melting point apparatus, and the thermometer was uncorrected. Mass spectra were determined by a Micromas s ZabSpec high resolution mass spectrometer (resolution 1000) and an API 3000 tandem quadrupole mass spectrometer. 1H NMR was measured by a ΠΜ-ECA-400 superconducting NMR instrument at an operating frequency of 4QQMHz. Example 1·(2Ε, 4Ε)- 2-Phenyl-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro-furan- 3- Preparation of carboxylic acid

Step 1 4-(2,6-Dichloro-benzyloxy)-phenylfurfural

20 ol 2,6-dichlorobenzyl bromide and 17 mmol p-hydroxybenzaldehyde were dissolved in 14 mL of DMF, cooled to 0 ° C, 20 匪ol 60 NaH was added with stirring, stirring was continued for 0.5 h, the water bath was removed, and stirred at room temperature. 0.5 h. The reaction solution was poured into 140 mL of water of, extracted with ethyl acetate, washed with water, dried over anhydrous MgS0 _4. After concentrating, the obtained crude material was purified mjjjjjjjjj C, yield 93.? . /. . ¹ !!- NMR - DMS0) δ: 5.35 (s, 2H, -CH ₂ 0) , 5.27 (d 2H, /= 8.6 Hz, Ar-H), 7.50 (m, 1H, Ar-H), 7.60 ( m, 2H, Ar-H), 7.90 (d, 2H, /=8.6Hz, Ar-H), 9.90(s, 1H, -CH0) .

Step 2 2-[4-(2,6-Dichloro-benzyloxy)-benzylidene]-succinic acid, mix 36 mmol of diethyl succinate and sodium methoxide at room temperature (sodium metal 26 mmol) /17 mL of anhydrous methanol), nitrogen was added, heated to reflux, and 18 liters of 4-(2,6-dichloro-benzyloxy)-benzofural in 75 mL of methanol was added dropwise with stirring to continue reflux. 10 h. Then 100 mL of 2N NaOH solution was added and reflux was continued for 11 h and cooled to room temperature. The reaction solution was poured into 400 mL of ice water and extracted with diethyl ether. The aqueous layer was adjusted to pH 1-2 with concentrated hydrochloric acid, ethyl acetate, and washed with water and dried over anhydrous magnesium sulfate. Concentrated to give a white solid, dp 211 ° C, yield 83.5%. ^- NMR (cT ₆ -DMSO) δ: 3.40 (s, 2H, 3-CH ₂ ), 5.27 (s, 2H, -CH ₂ 0) , 7.14 (d, 2H, 7 = 8.9 Hz, Ar-H) , 7.40-7.50 (m, 3H, Ar-H), 7.56 (d, 2H, 7=8.9Hz, Ar-H), 7.70 (s, 1H, =CH), 12.46(brs, 2H, -C00H) .

Step 3 3- [4- (2, 6-Dichloro-benzyloxy)-phenylhydrazinyl]-dihydro-furan-2, 5-dione

Suspension of ramol ² -[ ⁴ -( ² , ⁶ -dichloro-benzyloxy)-benzylidene]-succinic acid in 33 mL of CH ₂ Cl ₂ and adding 130 mmol of thionyl chloride under stirring, heating Reflux 5 h, cool to room temperature. Concentration, filtration, and repeated washing of the solid with benzene and petroleum ether afforded crystals of orange crystals, mp 198-200 ° C, yield 91.8%. NMR {d DMS0) δ: 3.97 (d, 2H, 4-CH ₂ ), 5.32 (s, 2H, -CH ₂ 0), 7.19 (d, 2H, 7 = 8.9 Hz, Ar - H), 7.47 (m) , 1H, Ar-H), 7.57 (m, 2H, Ar-H), 7.63 (t, 1H, =CH), 7.67 (d, 2H, 7 = 8.9 Hz, Ar-H).

Step 4 2-[4-(2,6-Dichloro-benzyloxy)-benzylidene]-succinic acid 4-(4-Methoxy-benzyl) ester

9 mmol 3-[4-( ² , 6-Dichloro-benzyloxy)-benzylidene]-dihydro-furan-2, 5-dione, 24 mmol p-methoxybenzyl alcohol and 18 mmol pyridine was dissolved in 30 mL of chloroform was heated at reflux for 24 h ₀ was cooled, concentrated, the residue was poured into 120 raL10% aqueous hydrochloric acid solution, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate. Concentrated, filtered and washed to give white crystals, mp 165-167 ° C, yield: 85.2%. 'H-NMR (i ₆ -DMS0) δ: 3.52 (s, 2Η, 3-CH ₂ ) , 3.74 (s, 3H, — 0CH ₃ ) , 5.06 (s, 2H, -CH ₂ 0), 5.26 (s , 2H, -CH ₂ 0) , 6.91 (d, 2H, /=8.9Hz, Ar-H) , 7.08 (d, 2H, 7=8.6Hz, Ar-H), 7.28(d, 2H, 7=8.9 Hz, Ar-H), 7.37 (d, 2H, /= 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, -C00H) . Step 5 (2E, 4E)- 2-Phenyl-4-[4-(2,6-dichloro-benzyloxy)-benzylidene] -5-oxo-tetrahydro-furan-3-carboxylic acid

Dissolve 4 mmol of 2-( ⁴ -U,6-dichloro-benzyloxy)-benzylidene]-succinic acid 4-(4-methoxy-benzyl) ester in 40 mL of THF and cool to - 78 ° C, add 12 leg ol LDA, continue to stir for 1.5 h, add 4 ol benzaldehyde 2raL THF solution, continue to stir for 3-8 h. 6 raL of 6N H ₂ S0 ₄ solution was added dropwise, extracted with diethyl ether and dried over anhydrous magnesium sulfate. Concentrated, the residue was dissolved in 25mLCH _₂ Cl _2, followed by addition of 0.3 mL TFA, stirring was continued for 12 h. 20 mL of a NaHCO ₃ aqueous solution was added to the reaction mixture, and the mixture was adjusted to pH 1-2 with concentrated hydrochloric acid, ethyl acetate and evaporated. Thick The crude product was purified by silica gel column chromatography eluting elut elut elut elut elut elut elut elut elut elut elut elut CH) , 5.30(s 2H, — CH ₂ 0), 5.87 (d, 1H, 7=7. OHz, 2—CH), 7.20 (d, 2H, 7=8.7Hz, Ar - H), 7.34-7.59 (m, 9H, Ar-H, =CH), 7.67 (d, 2H, /=8.7Hz, Ar - H), 12.74(s, 1H, - COOH) . FAB MS (m/z): 469 (M ++1). Example 1, (2E, 4E) -2- (4-chloro-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5 -oxo-tetrahydro-furan-3-carboxylic acid

Follow step 5 of Example 1 to replace benzaldehyde with p-chlorobenzaldehyde. The crude product was purified by EtOAcjjjjjjlilili . 'H-NMR - DMS0) δ: 3.63(s, 1H, 3-CH), 5.25(s, 2H, a CH ₂ 0), 5.84(s, 1H, 2—CH), 7.06 (d, 2H, 7 =8.7 Hz, Ar-H), 7.23 (d, 2H, 7=8.4 Hz, Ar-H), 7.41 (d, 2H, 7=8.4 Hz, Ar-H), 7.45-7.57 (ra, 4H, Ar -H, =CH), 7.91 (d, 2H, 7 = 8.7 Hz, Ar-H). ESI MS (m/z): 501 (M ⁺ - 1). Example 3. (2E, 4E)- 2 -Benzo[1,3]dioxan-5-yl-4-[4-(2 6dichloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro-furan-3 -Preparation of carboxylic acid

Follow the procedure of step 5 of Example 1 to replace benzaldehyde with piperonal. The crude product was purified by silica gel column chromatography (methylene chloride / alcohol Yue elution) to give a white solid, dp 205 ° C, a yield of _{15.0 ° / o 0 'H-} NMR (if 6 -DMS0) δ: 3.70 (s, 1H, 3-CH), 5.25 (s, 2H, -CH ₂ 0), 5.75 (s, 1H, 2-CH), 5.97 (d, 2H, -CH ₂ -), 6.69 (m, 2H, Ar- H) , 6.85(d, 1H, 7=8.1Hz, Ar-H) , 7.07 (d, 2H, /=8·6Hz, Ar-H) , 7.44-7.58 (ra, 4H, Ar-H, =CH ), 7.89 (d, 2H, 7=8.6Hz, Ar-H), ESI MS (m/z): 511 (M+- 1). Example 4. (2E, 4E)-2-(4-Mercapto-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo- Preparation of tetrahydro-furan-3-carboxylic acid

Following step 5 of Example 1, parabenzaldehyde was replaced by p-methylbenzaldehyde. The crude product (eluting with petroleum ether / ethyl acetate) was purified by silica gel column chromatography to give a white solid, yield _{18.6% 0 ^ -NMRC ^ -DMSO)} δ: 2.31 (s, 3H, -CH 3), 4.64 (d , 1H, 7=7.3Hz, 3-CH) , 5.30(s, 2H, — CH ₂ 0), 5.83 (d, 2H, 7=7.3Hz, 2-CH) , 7.19(m, 4H, Ar-H ), 7.27 (d, 2H, /=8.4Hz, Ar-H), 7.46— 7.59 (m, 4H, Ar-H, =CH) , 7.66 (d, 2H, 7=9.0Hz, Ar-H), 12.69 (s, 1H, -C00H). ESI MS (m/z): 437 (M ⁺ -COOH). Example 5. (2E, 4E) -2- (3-chloro-phenyl)- 4- [ Preparation of 4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro-furan-3-carboxylic acid

Follow step 5 of Example 1 to replace benzaldehyde with m-chlorobenzaldehyde. The crude product was purified by EtOAcjjjjjjjjj 'H-NMR (i/ ₆ -DMS0) δ: 3.68 (s, 1H, 3-CH) , 5.25 (s, 2H, — CH ₂ 0) , 5.88 (s, 1H, 2-CH) , 7.06 (d , 2H, /=8.6Hz, Ar-H) , 7.26 (in, 2H, Ar-H) , 7.35-7.57 (ra, 6H, Ar-H, =CH) , 7.89 (d, 2H, /=8.6 Hz , ESI MS (m/z): 457 (M ⁺ - COOH). Example ⁶ · (2E, 4E) - ² _( ⁴ -trifluoromethyl-phenyl)- 4- [4 -(2,6-Dichloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro-furan-3-carboxylic acid

Following step 5 of Example 1, substituting benzaldehyde with p-trifluoromethylbenzaldehyde. The crude product was purified by EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , 5.23(s, 2Η, - CH ₂ 0), 5.98(s, 1H, 2-CH) , 7.05 (d, 2H, =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, 7 = 8. 1 Hz, Ar-H). ESI MS (m/z): 491 (M ⁺ - COOH). Example 7. (2E, 4E) - 2-(6-Chloro-benzo[1,3]di-p-decyl-5-yl)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene] -5 -Preparation of oxo-tetrahydro-furan-3-carboxylic acid

Following step 5 of Example 1, 6-chloropiperonal was substituted for benzaldehyde. 3%。 The crude product was purified by EtOAc EtOAc. -NMR 1⁄2-DMS0) δ: 4. 04 (s, 1H, 3-CH) , 5. 28 (d, 2H, -CH ₂ 0), 6. 02 (m, 3H, -CH ₂ -, =CH ) , 6. 68 (s, 1H, 2-CH) , 7. 13 (m, 3H, Ar-H) , 7. 46-7. 60 (in, 4H, Ar-H) , 7. 83 (d , 2H, 7=7. 8Hz, Ar-H), 13. 66 (s, 1H, -C00H) . ESI MS (m/z) : 501 (M - C00H) . Example 8. (2E, 4E) -2- (3-Methyl-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro-furan-3-carboxylic acid Preparation

Following step 5 of Example 1, m-benzaldehyde was replaced by m-benzylbenzaldehyde. The crude was purified by EtOAc EtOAc EtOAc EtOAc C, Yield 14. 0%. 'H-NMR (cT ₆ -DMS0) δ: 2. 32 (s, 3Η, -CH ₃ ) , 4. 66 (d, 1H, /=6. 7Hz, 3-CH), 5. 31 (s, 2H, - CH ₂ 0), 5. 83 (d, 2H, 7=6. 7Hz, 2-CH), 7. 14-7. 30 (m, 6H, Ar-H), 7. 47-7. 51 (in, 1H, Ar-H), 7. 57 (m, 3H, Ar-H), 7. 67 (d, 2H, 7=8. 9Hz, Ar-H), 12. 73 (s, 1H , -C00H) . ESI MS (m/z): 437 (M ⁺ - C00H) . Example 9. (2E, 4E) - 2- (4-isopropyl-phenyl)-4- [4- ( Preparation of 2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro-furan-3-carboxylic acid

Following step 5 of Example 1, substituting benzaldehyde for benzaldehyde. Crude Purification by column chromatography on silica gel eluting elut elut elut elut C, yield 15.8%. - NMR -DMS0) δ: 1.13(d, 6H, - 2CH ₃ ), 2.80(ra, 1H, -CH-) , 3.68(s, 1H, 3-CH) , 5.24 (s, 2H, — CH ₂ 0 ), 5.83(s, 1H, 2-CH) , 7.05 (d, 2H, 7=8.4Hz, Ar-H) , 7.11 (d, 2H, 7=8.1Hz, Ar-H) , 7.19 (d, 2H , /=8. lHz, Ar-H), 7.42-7.57 (in, 4H, Ar-H), 7.90 (d, 2H, 7=8.4Hz, Ar-H) . ESI MS (m/z): 499 (M ⁺ -1) . Example 10. (2Z, 4E)- 2-(4-Methoxy-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzamide Preparation of -5-oxo-tetrahydro-furan-3-carboxylic acid

Following step 5 of Example 1, p-formaldehyde was replaced by p-methoxybenzaldehyde. The crude was purified by EtOAc EtOAc EtOAc EtOAc C, yield 6.2%. - wake up (-DMS0) δ: 3.76(s, 3H, -0CH ₃ ), 4.61 (d, 1H, 7=7.2Hz, 3-CH) , 5.30(s, 2H, -CH ₂ 0) , 5.81 (d , 1H, 7=7.2Hz, 2-CH), 6.94 (d, 2H, 7=8.7Hz, Ar-H), 7.19 (d, 2H, f=9.0Hz, Ar-H) , 7.31 (d, 2H , 7=8.7 Hz, Ar-H), 7.46-7.59 (m, 4H, Ar-H), 7.65 (d, 2H, /=9.0 Hz, Ar-H), 12.71 (s, 1H, -C00H). ESI MS (m/z): 453 (M ⁺ - C00H). Example 11. (2E, 4E)- 2-(4-methoxy-phenyl)-4-[4-(2,6 dichloride Of -benzyloxy)-benzylidene]-5-oxo-tetrahydro-furan-3-carboxylic acid

In accordance with step 5 of Example 1, p-methoxybenzaldehyde was replaced by p-methoxybenzaldehyde. The crude was purified by EtOAc EtOAc EtOAc EtOAc C, yield 17.? . /. . ¹ !!- NMR1⁄2- DMS0) δ: 3.72 (s, 3H, -0CH ₃ ) , 4.08 (s, 1Η, 3-CH) , 5.30(s, 2Η, a CH ₂ 0), 5.80(s, 1H, 2-CH), 6.92 (d, 2H, /=8.9Hz, Ar-H), 7.12 (d, 2H, 7=8.6Hz, Ar-H), 7.21(d, 2H, 7=8.9Hz, Ar- H) , 7.45- 7.58 (m, 4H, Ar-H), 7.75 (d, 2H, /=8.6Hz Ar-H), 13.62 (s, 1H, -C00H). ESI MS (ra/z): 453 (M - COOH). Example 12· (2E, 4E)-4-[4- (2, 6 Preparation of chloro-benzyloxy)-benzylidene]-2-octyl-5-oxo-tetrahydro-furan-3-carboxylic acid

Purify the benzaldehyde with furfural according to step 5 of Example 1. The crude product was purified by m~jjjjjjlililililili ^-NMR (i ₆ -DMS0) 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 ₂ 0) , 7.11 (d, 2H, /=8.6H'z, Ar-H), 7.39 ( s, 1H, =CH), 7.46(m, 1H, Ar-H), 7.56 (d, 2H, Ar-H), 7.80 (d, 2H, 7=8.6Hz, Ar-H) . ESI MS (m /z): 505 (M++ 1). Example 13. (2Z, 4E) -4- [4-(2,6-Dichloro-benzyloxy)-benzylidene]- 2-heptyl- 5- Preparation of oxo-tetrahydro-furan-3-carboxylic acid

Following step 5 of Example 1, octylaldehyde was substituted for benzaldehyde. The crude product was purified by EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -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 2 0), 7.14 (d, 2H, 7 = 8.6Hz, Ar-H), 7.43-7.59 (m, 4H, Ar-H, = CH), 7.64 (d , 2H, 7=8.6Hz, Ar-H) . ESI MS (ra/z): 490 (M++ 1) · Example 14. (2E, 4E)-4-[4-(2,6 Dichloro-benzyl Preparation of oxy)-benzylidenyl]-2-heptyl- 5-oxo-tetrahydro-furan-3-carboxylic acid

Following step 5 of Example 1, octylaldehyde was substituted for benzaldehyde. The crude product was purified by EtOAcjjjjjjjjjj ^{_{! H-NMR (i 6 -DMS0}} ) δ: 0. 82 (t, 3H, -CH 3), 1. 23- 1. 36 (in, 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 ₂ 0), 7. 14 (d, 2H, /=8. 6Hz, Ar-H), 7. 46-7. 58 (m, 4H, Ar-H, =CH) , 7. 72 (d, 2H, /=8. 6Hz, ESI MS (ra/z): 490 (M ⁺ + 1). Example 15. (2E, 4E) -4- [4-(2,6-dichloro-benzyloxy)-benzene Preparation of methyl]-2-hexyl-5-oxo-tetrahydro-furan-3-carboxylic acid

Following the procedure of Example 1, step 5, heptanal was replaced by heptaldehyde. The crude product was purified by chromatography eluting elut elut elut elut elut elut elut elut elut

-NMR -DMS0) δ: 0. 82 (t, 3H, -CH ₃ ), 1. 23- 1. 34 (m, 8H, -4CH ₂ ) , 1. 54 (ra, 2H, — CH ₂ ), 3. 75 (brs, 1H, 3—CH ₂ ), 4. 70 (in, 1H, 2-CH ₂ ) , 5. 28 (s, 2H, —CH ₂ 0), 7. 11 (d, 2H, 7=8. 6Hz, Ar-H), 7. 41-7. 58 (m, 4H, Ar-H, =CH), 7. 79 (d, 2H, /=8. 6Hz, Ar-H). ESI MS (m/z): 477 (M ⁺ + 1). Example 16. (2E, 4E) -2- (2-chloro-4-fluoro-phenyl) -4- [4- (2, 6 Preparation of chloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro-furan-3-carboxylic acid

Following step 5 of Example 1, 2-benz-tetrafluoro-benzaldehyde was substituted for benzaldehyde. The crude product was purified by EtOAc EtOAcjjjjjjjjjjjj CH ₂ ), 5. 25 (s, 2H, -CH ₂ 0) , 6. 16 (s, 1H, 2-CH ₂ ) , 7. 07 (d, 2H, /=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, /=8· 6Ηζ, Ar-H) . ESI MS (m/z): 475 (M ⁺ - C00H). Example 17. (2Z, 4E) - 2- (2-chloro-4-fluoro-phenyl)-4- 4- (2, 6 two Preparation of chloro-benzyloxy)-benzylidene] ^-5 -oxo-tetrahydro-furan-3-carboxylic acid

Following step 5 of Example 1, 2-benz--4-fluoro-benzaldehyde was substituted for benzaldehyde. The crude was purified by EtOAc EtOAc EtOAc EtOAc C, yield 33. S^-NMR-DMSO) δ: 4.63 (d, 1H, 7 = 7.2 Hz, 3-CH ₂ ) 5.30 (s, 2H, -CH ₂ 0), 6.08 (d, 1H, 7 =7.2Hz, 2-CH ₂ ) , 7.21 (d, 2H, /=8.7Hz, Ar-H) , 7.29 (t, 1H, Ar-H) , 7.31-7.62 (m, 6H, Ar-H, = CH), 7.65 (d, 2H, 7 = 8.7 Hz, Ar-H), 12.93 (s, 1H, - C00H). ESI MS (m/z): 475 (M ⁺ - C00H) · Compounds of the invention The biological activity can be evaluated by the following methods:

Example 18

The M. subtilis was passaged on 125 Rovin's egg slant medium and cultured for 4-5 days. A small strain was inoculated in liquid medium (containing 0.5% peptone, 0.3% beef extract, 2.0% glycerol, pH 7.0-7, 2), shaken at 37 ° C, 220 rpm for 24 h, determined on a enzyme-linked instrument The optical density value of the 600 nm wavelength (0D ₆ . . . _nm ) to 0D ₆ . . _Nra is 0.5-0.6. O厘米加直径。 The inoculation of 1.0% of the bacteria in the assay medium (containing 0.5% peptone, 0.3% yeast extract, 1.2% agar, pH 7.0-7.4), slab, after the plate is solidified, at a separation distance greater than 3. Ocm plus diameter to 0.7cm tablet, the tablet having a concentration of 0.5 mM compound ΙΟΟμΙ be screened simultaneously, provided positive 0.5 mM compound 1- (6-chloro - ³ and ⁴ - methylenedioxy-benzyl) -2-carboxy --5- (2,6-Dichlorobenzyloxy) 吲 ( ( Daines RA, Pendrak I, Sham K, et al. First X-ray cocrystal ctructure of a bacterial FabH condensing enzyme and a small molecule inhibitor achieved using rational design and homology modeling [J]. J Med Chem, 2003, 46: 5 8.), 0.1 raM isoniazid and a blank solvent DMSO control. At 37. After 48 hours of C culture, the antibacterial sputum was observed, and the diameter of the antibacterial sputum of each compound was measured. fruit. The test results are shown in Table 1.

Table 1 Inhibition of compounds against Mycobacterium phlei bacteriostatic mean average bacteriostatic average compound

Diameter (cm) Diameter (cm) Positive compound 2. 2 Positive compound 2. 2 Isoniazid 2. 3 Isoniazid 2. 3 Example 1 0. 7 Example 10 1. 7 Example 2 2. 0 Implementation Example 11 1. 7 Example 3 1. 4 Example 12 1. 7 Example 4 0. 9 Example 13 2. 4 Example 6 1. 8 Example 14 2. 1 Example 6 2. 0 Example 15 1. 6 Example 7 1. 8 Example 16 1. 8 Example 8 1. 6 Example 17 2. 5 Example 9 2. 0

Claims

A compound of formula I, all possible isomers thereof or a pharmaceutically acceptable salt or hydrate thereof:

among them:

R is selected from the group consisting of aryl, C ₃ —. alkyl;

The "aryl" refers to phenyl and is hydroxy, ! a phenyl group substituted with a nitro group, a nitro group, a CF ₃ group, a methylenedioxy group, a _δ alkyl group, or an alkoxy group.

2. A compound of claim 1 selected from the group consisting of:

(2E, 4E)- 2-Phenyl-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro-furan-3-carboxylic acid;

(2E, 4E) - ² - ( ⁴ -chloro-phenyl)- ⁴ - [4 -(2, 6-dichloro-benzyloxy)-phenylhydrazinyl]-5-oxo-tetrahydro-furan 3-carboxylic acid;

(2E, 4£) -2-Benzo[1,3]dioxan-5-yl-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5 -oxo-tetrahydro-furan-3-carboxylic acid;

(2E, 4E) -2- (4-indolyl-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro- Furan-3-carboxylic acid;

(2E, 4E) -2-(3-Chloro-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro-furan 3-carboxylic acid;

(2E, 4E) - ² - ( ⁴ -trifluoromethyl-phenyl) -4- [4-(2, 6-dichloro-benzyloxy) - Benzamethylene]-5-oxo-tetrahydro-furan-carboxylic acid;

(2E, 4E)- 2-(6-Chloro-benzo[1,3]di-p-methoxy-n-yl)-4-[4-(2,6-dichloro-benzyloxy)-benzene Methylene]-5-oxo-tetrahydro-furan- ³ -carboxylate;

(2E, 4E) -2- (3- Yue-yl-phenyl) - 4- [4- ^{(2,6-dichloro} - benzyloxy) - benzylidene] -5-oxo - tetrahydro - Furan-3-carboxylic acid;

(2E, 4E)- 2-(4-isopropyl-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetrahydro - furan-3-carboxylic acid;

(2Z, 4E)- 2-(4-Methoxy-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzoindolyl]-5-oxo-tetrahydro - furan-3-carboxylic acid;

(2E, 4E)-2-(4-methoxy-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetraindole - furan-3-carboxylic acid;

(2Z, 4E)- 4 - [4-(2,6-Dichloro-benzyloxy)-benzylidene]-2-heptyl-5-oxo-tetrahydro-furan-3-carboxylic acid;

(2E, 4E)-4-[4-(2,6-Dichloro-benzyloxy)-benzylidene]- 2 -heptyl-5-oxo-tetrahydro-furan-3-carboxylic acid;

(2E, 4E)-4-[4-(2,6-Dichloro-benzyloxy)-phenylhydrazinyl]-2-hexyl-5-oxo-tetrahydro-furan-3-carboxylic acid;

(2E, 4E)- 2-(2-chloro-4-fluoro-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetra Hydrogen-furan-3-carboxylic acid;

(2Z, 4E)- 2-(2-chloro-4-fluoro-phenyl)-4-[4-(2,6-dichloro-benzyloxy)-benzylidene]-5-oxo-tetra Hydrogen-furan-3-carboxylic acid;

Or all possible isomers thereof, or pharmaceutically acceptable salts or hydrates

3. A process for the preparation of a compound of formula (I) according to claim 1, which process comprises Next steps:

5小时,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

(2) Under the protection of an inert gas such as nitrogen, the product of the step (1) and the diethyl succinate are subjected to a Stobbe condensation reaction in a sodium methoxide-methanol basic system, and hydrolyzed by sodium hydroxide to obtain an aromatic fluorenylene group. Succinic acid compound;

(3) dehydrating with thionyl chloride at reflux temperature to obtain arylmethylene succinic anhydride;

(4) an esterification reaction with p-methoxybenzyl alcohol under catalysis of pyridine to form a monobenzyl ester compound;

(5) under the protection of an inert gas such as nitrogen, with an aldehyde of the formula RCH0 wherein R is as defined above in the formula I, in the THF, using LDA as a catalyst, and an Aldol condensation reaction occurs at a reaction temperature of -78 ° C;

(6) The product of the step (5) is esterified with TFA/CH ₂ C1 _{2 to} give the compound of the formula I of the present invention.

4. A pharmaceutical composition comprising a compound of formula I according to claim 1, or all possible isomers or pharmaceutically acceptable salts or hydrates thereof, and at least one pharmaceutically acceptable carrier or excipient.

5. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of a fatty acid synthase.

6. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of bacterial infections.

7. A method of treating a bacterial infection, the method comprising administering to a patient in need thereof A therapeutically effective amount of a compound of formula (I) according to claim 1.