WO2008061399A1

WO2008061399A1 - Fatty acid synthase inhibitor and its use

Info

Publication number: WO2008061399A1
Application number: PCT/CN2006/003402
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. China
Priority date: 2006-11-23
Filing date: 2006-12-13
Publication date: 2008-05-29
Also published as: CN101190894A

Abstract

Formula (I) or its pharmaceutically acceptable salt or hydrate possessing inhibiting fatty acid synthase FabH effect, its preparation, pharmaceutical composition and use of such compound in preparation of a medicament for the treatment of bacterial infections.

Description

Fatty acid synthase inhibitor and its pharmaceutical use

The present invention relates to a pyrrole derivative as a fatty acid synthase inhibitor (FabH), a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition containing the same, and the use of the compound for the preparation of a fatty acid synthase inhibitor. 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 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, Whiteb SW, Rock CO. Prog Lipid Res, 2001, 40: 467-497 ).

The FAS II system's single-function enzyme, FabH, uses acetyl-CoA as a substrate and is the initiator of the carbon chain elongation cycle of fatty acid synthesis, which is widely present in bacteria. At the same time, the The final product of the ring, palmitoyl-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 Chem, 1996, 271 (4): 1833-1836; Revill WP, Bibb MJ, Scheu AK, et a 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, fatty acid synthase inhibitors are expected to develop into new types of 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:

among them:

Q is CH ₂ 0 or dish;

^ is aryl;

R ₂ is aryl, C ₃ - _1Q alkyl or (cycloalkyl).

As used herein, the term "aryl" refers to phenyl, or hydroxy, halogen, nitro, CF _3, methylenedioxy, Albuquerque, d- ₆ alkoxy substituent group or a substituted phenyl . The term "Cw.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. This group being optionally substituted with a substituent selected from hydroxy, carboxy, d- ₆ 1¾ hormone and alkoxy.

The term "cycloalkyl" as used in the present invention refers to a ring having 4 to 8 carbon atoms including, but not limited to, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

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 1-benzyl- 4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydropyrrole-3-carboxylic acid;

4-[4-(2,6-Dichloro-benzyloxy)-benzyloxy]-1-heptyl- 5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid;

4-[4-(2,6-Dichloro-benzyloxy)-benzyloxy]-1-octyl-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid;

4-[4-(2,6-Dichloro-benzyloxy)-benzyloxy]-1-hexyl-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid;

- [4-(2,6-Dichloro-benzyloxy)-benzyloxy]-1-furan-2-ylmethyl-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid ;

1-( ² -Chloro-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole- 3- carboxylic acid;

1-(Chloro-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydropyrrole-3-carboxylic acid;

1- (3-trifluoromethyl-benzyl) - - ⁴ - ^[4 - ^(2, 6-dichloro - benzyloxy) - benzyloxy] -5-oxo-2,5-dihydro-pyrrol - 3-carboxylic acid;

1-(4-Chloro-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole-3- Carboxylic acid

1-cyclohexylmethyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo- 2 5-dihydropyrrole-3-carboxylic acid;

1-Benzo[1,3]di-p-decyl-5-ylmethyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2 , 5-dihydro-1^pyrrole-3-carboxylic acid;

1-benzyl-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydropyrrole-3-carboxylic acid;

1- ⁽³ - chloro - benzyl) -4- [4- (3, ⁵ - difluoro - benzyloxy) - benzyloxy] -5-oxo-2,5-dihydro - pyrrolo --3- carboxylic acid; 1-Benzo[1,3]dioxan-5-ylmethyl-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2, 5-dihydro-I pyrrole-3-carboxylic acid;

4-[4-(3,5-Difluoro-benzyloxy)-benzyloxy]-1-heptyl- 5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid;

1-( ² -Chloro-benzyl)-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole-3- carboxylic acid;

1-cyclohexylmethyl-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2 5 -dihydro-1#-pyrrole-3-carboxylic acid ;

4-[4-(3,5-Difluoro-benzyloxy)-benzyloxy]-1-octyl- 5-oxo-2,5-dihydro-Ipyrrole-3-carboxylic acid;

1-( ³ -trifluoromethyl-benzyl) - ⁴ - [4-(3, 5-difluoro-benzyloxy)-benzyloxy] -5-oxo-2, 5-dihydro-1 ^"pyrrole-3-carboxylic acid;

4- [4- (3, ⁵ - difluoro - benzyloxy) - benzyloxy] -1 - furan-2 - yl methyl - 5-oxo-2,5-dihydro-pyrrol --3- acid ;

1-(4-Chloro-benzyl)-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole- 3- Carboxylic acid

1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo-2,5-dihydropyrrole-3-carboxylic acid;

4-[4-(2,6-Dichloro-benzyloxy)-aniline] 5-oxo- 1-(3-trifluoromethyl-benzyl)-2,5-dihydropyrrole-3- Carboxylic acid

1-Benzo[1,3]dioxan-5-ylmethyl-4 -[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo-2, 5- Dihydropyrrole-3-carboxylic acid;

1-cyclohexylmethyl-4-[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo-2,5-dihydropyrrole-3-carboxylic acid;

4-[4-(2,6-Dichloro-benzyloxy)-aniline]-1-octyl- 5-oxo-2,5-dihydropyrrole-3-carboxylic acid; Or a pharmaceutically acceptable salt or hydrate thereof. According to the invention, compounds of formula (I) wherein Q is CH ₂ 0 can be prepared by the synthetic route described in Scheme 1 below:

plan 1

9 a) NaH, DMF; b) NaBH ₄ , CH ₃ 0H; c) C ₂ H ₅ ONa, C ₂ H ₅ OH; d) Ph ₃ P, DEAD, THF; e) NaOH, CH ₃ 0H.

Specifically, the formula R!CHJ benzyl halide (Scheme 1-1) wherein X is as defined in the above formula I, and X is a halogen, and p-hydroxybenzaldehyde (Scheme 1-2) are used as starting materials in sodium hydride/ Treatment and stirring in DMF (-5-0 ° C, 0.5 hours) to give compound scheme 1-3; then, reduction scheme 1-3 with a hydride reducing agent (such as sodium borohydride) in a solvent (such as methanol), Compound 4 (Scheme 1-4) is obtained; the addition of the formula R ₂ CH ₂ X primary amine (Scheme 1-5) and ethyl acrylate (Scheme 1-6) under stirring with an inert gas such as nitrogen is carried out under stirring at room temperature. Reaction, then with diethyl oxalate (Scheme 1-7) in ethanol A condensation reaction occurs at a reflux temperature in a sodium-ethanol basic system, followed by acidic hydrolysis to obtain a pyrrole derivative 8 (Scheme 1-8). Compound 9 and Compound 8 are condensed in a solvent such as THF using a catalyst such as triphenylphosphine and diethyl azodicarboxylate and 1 molecule of water is removed to obtain Compound 9 (Scheme 1-9) The compound 9 is saponified with a base such as sodium hydroxide in a solvent such as decyl alcohol to give a compound which is 1 ₂₂ as defined in the above formula I (Scheme 1-10). Compounds of formula (I) wherein Q is NH can be prepared by the synthetic route described in Scheme 1 below:

Scenario 2

a) C ₂ H ₅ ONa, C ₂ H ₅ OH; b) SnC l ₂ , C ₂ H ₅ OH ; c) C ₂ H ₅ ONa, C ₂ H ₅ OH ; d) AcOH; e) NaHC0 ₃ , THF , C ₂ H ₅ OH.

Specifically, 2,6-dichlorobromobenzyl (Scheme 2-1) and p-Nitrophenylfurfural (Scheme 2-2) are reacted in a sodium ethoxide-ethanol basic system at reflux temperature to form Compound 3 (Scheme 2-3); Then, Compound 3 is reduced with a reducing agent such as stannous chloride in a solvent such as ethanol to give Compound 4 (Scheme 2 - 4); under an inert gas such as nitrogen, The addition reaction of the formula R ₂ CH ₂ X primary amine (Scheme 2-5) and ethyl acrylate (Scheme 2-6) with stirring at room temperature, and then with diethyl oxalate (Scheme 2-7) in sodium ethoxide A condensation reaction occurs in an ethanol basic system at a reflux temperature, followed by acidic hydrolysis to obtain a pyrrole derivative 8 (Scheme 2-8). Compound 4 and Compound 8 are condensed by a catalyst such as acetic acid and 1 molecule of water is removed to obtain Compound 9 (Scheme 2-9); Compound 9 and a base such as sodium hydrogencarbonate are used in a solvent such as THF and ethanol. Saponification to give a compound of formula I wherein R _{2 is} as defined above (Scheme 2-10).

Thus, the process for the preparation of the compounds of the general formula (I) according to the invention can be summarized as follows: For compounds of the formula (I) wherein Q is CH ₂ 0, the process comprises the steps of:

(1) Take it! 5小时。 Then, as defined by the above formula I, X is a halogen, and the hydroxybenzaldehyde is used as a starting material, and the mixture is stirred at -5 ° C in sodium hydride / DMF and stirred 0. 5 hours; Reduction of the product obtained with a hydride reducing agent such as sodium borohydride in a solvent such as methanol;

(2) Under the protection of an inert gas such as nitrogen, an addition reaction of 11 ₂ of the formula R ₂ CHJ primary amine and ethyl acrylate as defined by the above formula I is carried out under stirring at room temperature, and then with diethyl oxalate in sodium ethoxide - a condensation reaction occurs in an ethanol basic system at reflux temperature, and the product is subjected to acidic hydrolysis;

(3) using a catalyst such as triphenylphosphine and diethyl azodicarboxylate to condense the product of step (1) and step (2) in a solvent such as THF and remove one molecule of water and make it a base Sodium hydroxide is saponified in a solvent such as methanol to give a compound of formula I wherein Q is CH ₂ 0 and R _{2 is} as defined above;

Or,

Wherein Q is NH respect to Formula (I) compound, the method comprising the steps of: (1) at reflux temperature, ^2,6-dichloro benzyl bromide in acetic and p-nitrobenzaldehyde The sodium alkoxide-ethanol is reacted in an alkaline system, and then the resulting product is reduced with a reducing agent such as stannous chloride in a solvent such as ethanol;

(2) Under the protection of an inert gas such as nitrogen, an addition reaction of 11 _{2 of the} formula R ₂ CH ₂ X primary amine and ethyl acrylate as defined by the above formula I is carried out under stirring at room temperature, and then with diethyl oxalate in ethanol a sodium-ethanol alkaline system undergoes a condensation reaction at a reflux temperature, and the resulting product is subjected to acidic hydrolysis;

(3) The product obtained in the step (1) and the step (2) is condensed by using a catalyst such as acetic acid, and 1 molecule of water is removed, and then saponified with a base such as hydrogencarbonate in a solvent such as THF and ethanol to obtain Q as NH. , ! And R ₂ are as defined above for the compound of formula (I). 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 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, pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders, inclusions, implants, patches, wipes, 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. Substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated plant fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts , colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, sodium carboxylate, polyacrylic acid ester, beeswax, lanolin, and the like. The amount of the carrier in the pharmaceutical composition may be 1 part by weight. /. -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, Chloroacetic 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 an elixir, 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 oxime ether, glucose syrup, gel, 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, Such as methyl or propyl paraben 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 applied topically to the skin, the compounds of the invention may be in the form of a suitable ointment, lotion, or 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 grams of active ingredient. Depending on the route of administration and frequency of administration, a suitable therapeutic dose for an adult is 100-3000 mg per day, such as 1500 g 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 dosage of the compound of formula I for a given 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. The mass was determined by a Micromas s ZabSpec high resolution detector (resolution 1000) and an API ³ 000 tandem quadrupole mass spectrometer. 1H NMR was determined by TM-ECA-400 superconducting NMR instrument at an operating frequency of 4Q0 MHz. Example 1. 1-Benzyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid Preparation

Step 1 4- (2,6-Dichloro-kethoxy)-benzaldehyde

0小时后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后后Water bath, stirring at room temperature for Q. 5 h. The reaction solution was poured into 140 mL ice-water, extracted with ethyl acetate, washed with water, dried over anhydrous MgS0 _4. 2%。 Concentration, the resulting crude product was purified by silica gel column chromatography (EtOAc /EtOAc. - 11 ( - DMS0) δ: 5. 35 (s, 2H, - CH ₂ 0) , 5. 27 (d 2H, /= 8. 6Hz, 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, -CHO) .

Step 2 4- (2,6-Dichloro-benzyloxy)-benzyl alcohol

30 mmol of 4-(2,6-dichloro-benzyloxy)-benzaldehyde was dissolved in 45 mL of decyl alcohol, and the pre-formulated 18 mmo l NaBH ₄ was slowly added dropwise at 28-3 CTC. 5小时。 Stirring 0. 5 h. It was neutralized to pH 4 by the addition of 6N HCl, concentrated, extracted with diethyl ether, washed with water and dried over anhydrous sodium sulfate. Concentration gave the product which was used in the next step without purification.

Step 3 1-Benzyl-4-hydroxy-5-oxo-2,5-dihydro- 1^pyrrole-3-carboxylic acid ethyl ester 50 inniol benzylamine and 50 mmol of ethyl acrylate were dissolved in 20 mL of ethanol, passed through a nitrogen atmosphere, and stirred at room temperature for 24 h. Then, 50 mmol of diethyl oxalate and sodium ethoxide solution (metal sodium 52 mraol / 20 mL of absolute ethanol) were added, and the mixture was heated under reflux for 1 h. Cool, concentrate, add 400fflL of water and 6mL of concentrated hydrochloric acid. Filtration, the crude product was recrystallized from ethanol/water to afford white crystals, mp 137-139 ° C, yield 78.5.

Step 4 1-Benzyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid ethyl ester

The 7 mmol 4- (2, ⁶ - dichloro - benzyloxy) - phenyl Yue-ol, 7 so ol 1- benzyl-4-hydroxy - 5-oxo - 2,5-dihydro - 1 - pyrrole - Ethyl 3-carboxylate and 7.7 mmol of triphenylphosphorus were dissolved in 30 mL of THF, cooled to 0 ° C, and pre-formed 7 mraol diethyl azodicarboxylate (DEAD) and 8raLTHF solution were added dropwise at room temperature. overnight. The residue was purified by EtOAc EtOAcjjjjjjj ^- MR (CDCls) δ: 1.28(t, 3H, 7=7. OHz, - CH ₃ ),

3.86 (s, 2H, 2-CH ₂ ) , 4.21 (q, 2H, 7=7. OHz, -OCH ₂ CH ₃ ) , 4.62 (s, 2H, 1-NCH ₂ ) , 5.27(s, 2H, - _{CH 2 0), 5.76 (s} , 2H, -CH 2 0), 6.99 (d, 2H, 7 = 8.6Hz, Ar-H), 7.20-7.37 (in, 8H, Ar-H), 7.42 (d, 2H, 7=8.6Hz, Ar-H).

Step 5 1-Benzyl - ⁴ - [4- (2,6-dichloro - benzyloxy) - benzyloxy] -5-oxo - 2, 5-dihydro-pyrrole-3-carboxylic acid ^

2 mraol 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid The ester was dissolved in 100 mL of methanol, then 25 mmol of IN NaOH solution was added and allowed to react at room temperature for 3 h. The reaction solution was poured into 250 mL of water, and extracted with diethyl ether. The aqueous layer was adjusted to pH 1-2 with concentrated hydrochloric acid, ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The organic layer was crystallized from EtOAc (EtOAc:EtOAc) ^{_{! H-NMR (c / 6}} -DMS0) δ: 3.88 (s, 2H, 2-CH 2),

4.57 (s, 2H, 1-NCH ₂ ), 5.23 (s, 2H, -CH ₂ 0) , 5.58 (s, 2H, — CH ₂ 0), 7. 06 (d, 2H, /=8. 7Hz, Ar-H), 7. 20 (m, 2H, Ar-H), 7. 29 (m, 1H, Ar-H) , 7. 33 (ra , 2H, Ar-H), 7. 37 (d, 2H, 7=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). Example 2. 4- [4-(2,6-dichloro-benzyloxy) Preparation of benzyloxy]-1-heptyl-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid

Step 1 1-Heptyl- 4-hydroxy-5-oxo-2, 5-dihydro-1^-pyrrole-3-carboxylic acid ethyl ester

Substituting benzylamine with heptylamine according to step 3 of Example 1 gave white crystals mp 124-126. C, yield 75. 83⁄4.

Step 2 4-[4-(2,6-Dichloro-benzyloxy)-benzyloxy]-1-heptyl- 5-oxo-2,5-dihydropyrrole-ethyl 3-carboxylate

Substituting 1-heptyl-4-hydroxy-5-oxo-2,5-dihydropyrrole-3-carboxylate for 1-benzyl-4-hydroxy-5-oxo in accordance with step 4 of Example 1. 1%。 The 2,5-dihydro-pyrrole-3-carboxylic acid ethyl ester, a white solid, mp 89-90 ° C, a yield of 75.1%.

'H-NMR (CDCls) δ: 0. 86 (t, 3H, -CH ₃ ) , 1. 27-1. 33 (m, 11H, -4CH ₂ CH ₃ , -OCH ₂ CH ₃ ) , 1. 56 (ra, 2H, — CH ₂ ), 3. 43 (t, 2H, 1—NCH ₂ ), 3. 95 (s, 2H, 2-CH ₂ ) , 4. 24 (q, 2H, 7=7. 2Hz, -0CH ₂ CH ₃ ) , 5. 26 (s, 2H, -CH ₂ 0) , 5. 74 (s, 2H, -CH ₂ 0) , 6. 98 (d, 2H, 7=8. 6Hz , Ar-H) , 7. 24 (m, 1H, Ar-H) , 7. 35 (d, 2H, Ar-H) , 7. 40 (d, 2H, 7=8. 6Hz, Ar-H) .

Step 3 4-[4-(2,6-Dichloro-benzyloxy)-benzyloxy]-1-heptyl-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid

Following step 5 of Example 1, 4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-1-heptyl-5-oxo-2,5-dihydropyrrole-3 - Ethyl carboxylate instead of 1-benzyl 4-[4-(2,6-Dichloro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid ethyl ester, crude ethanol Recrystallization, white crystals, dp 125 ° C, yield 15.3%.

δ: 0.85 (t, 3H, -CH ₃ ) , 1.24 (ra, 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 ₂ 0) , 5.56 (s, 2H, — CH ₂ 0), 7.04 (d, 2H, 7=8.6Hz, Ar-H), 7.35 (d, 2H, 7 = 8.6 Hz, Ar-H), 7.47 (in, 1H, Ar-H), 7.56 (m, 2H, Ar-H), 12.81 (s, 1H, -C00H) . ESI MS ( m/z): 504 (M ⁺ - 1). Example ^3. 4-[4-(2,6-Dichloro-benzyloxy)-benzyloxy]-1-octyl-5-oxo- Preparation of 2,5-dihydro-pyrrole-3-carboxylic acid

Step 1 1-octyl-4-hydroxy-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid ethyl ester

Substituting octylamine for benzylamine according to step 3 of Example 1 gave white crystals, mp 121-123. C, yield 78.3 ₀

Step 2 4-[4-(2,6-Dichloro-benzyloxy)-benzyloxy]-1-octyl- 5-oxo-2,5-dihydropyrrole-3-carboxylate

Substituting ethyl 1-octyl-4-hydroxy-5-oxo-2,5-dihydro-pyrrole-3-carboxylate for 1-benzyl-4-hydroxy-5-oxygen according to step 4 of Example 1. Ethyl 2- 2,5-dihydro-pyrrole-3-carboxylate gave white solid, mp 78-79 ° C, yield 75.8%.

^-NMR (CDC1 ₃ ) δ: 0.87 (t, 3H, -CH ₃ ) , 1.26 - 1.33 (m, 13H, -5CH ₂ CH ₃ , -OCH ₂ CH ₃ ) , 1.56 (ra, 2H, -CH _{2 )} ), 3.43(t, 2H, 1-NCH ₂ ) , 3.95 (s, 2H, 2 - CH ₂ ), 4.24 (q, 2H, /=7.0Hz, an OCH ₂ CH ₃ ), 5.26(s, 2H, — CH ₂ 0), 5.74 (s, 2H, -CH ₂ 0) , 6.98 (d, 2H, 7=8.4Hz, Ar-H) , 7.24 (ra, 1H, Ar-H) , 7.35 (d, 2H , Ar-H), 7.40 (d, 2H, 7=8.4Hz, Ar-H). Step 3 4- [4- (2,6-dichloro - benzyloxy) - benzyloxy] -1-octyl ^--5-- oxo-2,5-dihydro - pyrrolo --3- acid

Following step 5 of Example 1, 4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-1-octyl-5-oxo-2,5-dihydro-1pyrrole - 3-carboxylate in place of 1-benzyl-4- [4- (2,6-dichloro - benzyloxy) - benzyloxy] - _ ^5-oxo-2, ^5-dihydro-1 pyrrol _ 3-carboxylate The crude product was recrystallized from ethanol to give white crystals, dp 109 ° C, a yield of 12. / H-NMR (-DMS0) δ: 0.84 (t, 3H, -CH 3), 1.24 (in, 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 ₂ 0) , 5.56 (s, 2H, -CH ₂ 0) , 7.04 (d, 2H, /=9.0Hz, Ar-H) , 7.35 (d, 2H, /=9.0Hz, Ar-H ), 7.47 (m, 1H, Ar-H), 7.55 (in, 2H, Ar-H), 12.80(s, 1H, -C00H) . ESI MS (ra/z): 518 (M+- 1). Example 4. 4-[4-(2,6-Dichloro-benzyloxy)-benzyloxy]-1-hexyl-5-oxo-2,5-dihydro-1pyrrole-3-carboxylic acid preparation

Step 1 1-Hexyl-4-hydroxy-5-oxo-2,5-dihydro-1#-pyrrole-3-carboxylic acid ethyl ester

Following step 3 of Example 1, substituting hexylamine for benzylamine to give white crystals, mp

132-134 ° C, yield 69.3%.

Step 2 4-[4-(2,6-Dichloro-benzyloxy)-benzyloxy]-1-hexyl- ⁵ -oxo

- 2,5-Dihydro-pyrrole-3-carboxylic acid ethyl ester

Substituting ethyl 1-hexyl-4-hydroxy-5-oxo-2,5-dihydropyrrole-3-carboxylate for 1-benzyl-4-hydroxy-5-oxo- as in Example 1 2,5-Dihydropyrrole-ethyl 3-carboxylate gave a white solid, mp 58-59 ° C, yield: 74.2. .

^-NMR (CDC1 ₃ ) δ: 0.88 (t, 3H, - CH ₃ ), 1.29-1.33 (m, 9H, -3CH ₂ CH ₃

-OCH ₂ CH 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, 7=7.0Hz, -OCH ₂ CH ₃ ) , 5.26 (s, 2H, — CH ₂ 0), 5.74(s, 2H, — CH ₂ 0), 6.98 (d, 2H, 7=8.6Hz, Ar-H), 7.24 (m, 1H, Ar-H), 7.35 (d, 2H, Ar-H), 7.40 (d, 2H, 7=8.6Hz, Ar -H) .

Step 3 4-[4-(2,6-Dichloro-benzyloxy)-benzyloxy]-1-hexyl-5-oxo-2,5-dihydropyrrole-3-carboxylic acid

Following step 5 of Example 1, 4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-1-hexyl-5-oxo-2,5-dihydro- 1^pyrrole Ethyl-3-carboxylate in place of 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2, 5-dihydro-1pyrrole -3 - Ethyl carboxylate, the crude product was recrystallized from anhydrous ethanol to give white crystals, dp 136 ° C, yield 20.4%. ^-NMR - DMS0) δ: 0.85 (t, 3H, -CH ₃ ) , 1.24 (ra, 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 ₂ 0) , 5.56 (s, 2H, —CH ₂ 0), 7.04 (d, 2H, 7=8.6Hz, Ar-H), 7.35 (d, 2H, 7=8.6Hz, Ar-H), 7.47 (m, 1H, Ar-H), 7.56 (m, 2H, Ar-H), 12.81 (s, 1H, — C00H) . ESI MS (m/z): 490 (M+-1). Example 5. 4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-1-furan-2 - Preparation of methyl-5-oxo-2,5-dihydropyrrole-3-carboxylic acid

Step 1 1-furan-2-ylmethyl-4-hydroxy-5-oxo-2,5-dihydropyrrole-ethyl 3-carboxylate

Substituting benzylamine with furan-2-yl-methylamine according to Step 3 of Example 1 gave white crystals, mp 132-134. (:, yield 74.8%.

Step 2 4-[4-(2,6-Dichloro-benzyloxy)-benzyloxy]-1-furan-2-ylmethyl-5-oxo-2,5-dihydro-pyrrole-3 -carboxylic acid ethyl ester

Following step 4 of Example 1, 1-furan-2-ylmethyl-4-hydroxy-5-oxo 2006/003402

- 2,5-Dihydro-pyrrole-ethyl 3-carboxylate in place of 1-benzyl-4-hydroxy- ⁵ -oxo 2,5-dihydropyrrole-3-carboxylate as a white solid, mp 87-89°C, yield 75· r/ H- NMR (CDC1 ₃ ) δ: 1.30 (t, 3H, /= 7. OHz, - CH ₃ ) , 3.96 (s, 2H, 2-CH ₂ ) , 4.23 (q, 2H, 7=7. OHz, -OCH ₂ CH ₃ ) , 4.61 (s, 2H, 1-NCH ₂ ), 5.26(s, 2H, -CH ₂ 0) , 5.74 (s, 2H, - CH ₂ 0) , 6.28 (d, 1H, /=3. OHz, furan-H), 6.33 (dd, 1H, 7=3. OHz, furan-H), 6.99 (d, 2H, 7=8.6Hz, Ar-H), 7.25 (m, 1H, Ar-H), 7.35 (m, 3H, Ar-H, furan-H), 7.41 (d, 2H, 7 = 8.6 Hz, Ar-H).

Step 3 4-[4-(2,6-Dichloro-benzyloxy)-benzyloxy]-1-furan- ² -ylmethyl-5-oxo-2, 5-dihydro-1^- Pyrrole-3-carboxylic acid

Following step 5 of Example 1, 4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-1-furan-2-ylmethyl-5-oxo-2, 5- dihydro - pyrrole - 3-carboxylate in place of 1-benzyl - 4- [4- (2,6-dichloro - benzyloxy) - benzyloxy] - ⁵ - oxo - ^2, ⁵ - two Hydrogen-1^pyrrole-3-carboxylic acid ethyl ester, the crude product was crystallized from ethyl acetate to afford white crystals, dp 146 ° C, yield 221. ^-NMRC^-DMSO) δ: 3.91 (s, 2H, 2-CH ₂ ) , 4.58 (s, 2H, 1-NCH ₂ ), 5.23 (s, 2H, — CH ₂ 0), 5.56 (s, 2H , -CH ₂ 0) , 6.38 (d, 1H, 7=3.3Hz, furan-H), 6.42 (dd, 1H, /=3.3Hz, furan-H) , 7.05 (d, 2H, 7=8.6Hz, Ar-H), 7.37 (d, 2H, /=8.6Hz, Ar-H), 7.45 (ra, 1H, Ar-H), 7.56-7.63 (m, 3H, Ar-H, furan-H), 12.90 (s, 1H, -C00H) . ESI MS (m/z): 486 (M+-1). Example 6. 1- (2-chloro-benzyl) -4- [4- (2, 6- Preparation of chloro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid

Step 1 1-(2-Chloro-benzyl)-4-hydroxy-5-oxo-2,5-dihydro-pyrrole-ethyl 3-carboxylate

Following step 3 of Example 1, substituting 2-chloro-benzylamine for benzylamine gives white crystals. Mp 165-166 ° C, yield 76.0 ° /. .

Step 2 1- (2-Chloro-benzyl) - - ⁴ - ^[4 - (2,6-dichloro - benzyloxy) - benzyloxy] - 5-oxo - 2, 5-dihydro-1 ^ Pyrrole-ethyl 3-carboxylate

Substituting 1-(2-chloro-benzyl) ^-4 -hydroxy- ⁵ -oxo-2,5-dihydro-Ipyrrole-3-carboxylic acid ethyl ester for 1-benzyl- according to step 4 of Example 1. 4-hydroxy - 5-oxo - ^2, ⁵ - dihydro - pyrrole-3-carboxylate as a white solid, mp 99-100.5 ° C, yield _{44.7 0 'H-NMR (CDC1} 3) δ: 1.29(t, 3H, /=7. OHz, -CH ₃ ) , 3.90(s, 2H, 2-CH ₂ ) , 4.22 (q, 2H, 7=7. OHz, -OCH ₂ CH ₃ ) , 4.76( s, 2H, 1-NCH ₂ ) , 5.27 (s, 2H, -CH ₂ 0), 5.76(s, 2H, -CH ₂ 0) , 6.99 (d, 2H, 7=8.6Hz, Ar-H), 7.16-7.27 (m, 4H, Ar-H), 7.36-7.39 (d, 3H, Ar-H), 7.42 (d, 2H, /=8·6Hz, Ar-H).

Step 3 1-(2-Chloro-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]- 5-oxo-2, 5-dihydro-pyrrole- 3-carboxylic acid

Following step 5 of Example 1, 1-(2-chloro-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo- 2, 5 -Dihydro-pyrrole- ³ -carboxylate to replace 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2, 5- The ethyl dihydropyrrole-3-carboxylate was recrystallized from anhydrous ethanol to give white crystals, dp 167 ° C, yield 23.9%. 'H- RC^-DMSO) δ: 3.71 (s, 2H, 2-CH ₂ ), 4.57 (s, 2H, 1-NCH ₂ ), 5.22 (s, 2H, -CH ₂ 0) , 5.47 (s, 2H, -CH ₂ 0) , 7.06 (d, 2H, 7 = 8.6 Hz, Ar-H), 7.09 (dd, 1H, Ar-H), 7.32 (dd, 2H, Ar-H), 7.35 (d, 2H, /=8.6Hz, Ar-H) , 7.45-7.49 (m, 2H, Ar-H), 7.56 (ra, 2H, Ar-H) ESI MS (m / z):. 530 (m + - 1 Example 7. 1-(3-Chloro-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2, 5-di Preparation of Hydropyrrole-3-carboxylic Acid

Step 1 1- (3-chloro - benzyl) -4-hydroxy - _ ^5-oxo-2, ^5-dihydro-1 pyrrol _ -3 - ethyl carboxylate

The benzylamine was replaced by 3-chloro-benzylamine in the step 3 of Example 1 to give white crystals, mp 134-135 ° C, yield: 79.

Step 2 1-(3-Chloro-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2, 5-dihydropyrrole-3 -carboxylic acid ethyl ester

Substituting 1-(3-chloro-benzyl)-4-hydroxy-5-oxo-2,5-dihydropyrrole-3-carboxylate for 1-benzyl-4- as in Example 4, Step 4. Ethyl hydroxy-5-oxo-2,5-dihydropyrrole-3-carboxylate gave a white solid, mp 130 - 1 31. C, yield 52.9%. ^{! H-NMR (CDCls) δ} : 1. 29 (. T, 3H, / = 7 OHz, -CH 3), 3. 87 (s, 2H, 2-CH 2), 4. 22 (q, 2H, 7=7. OHz, -OCH ₂ CH ₃ ) , 4. 59 (s, 2H, 1-NCH ₂ ) , 5. 27 (s , 2H, -CH ₂ 0) , 5. 76 (s, 2H, - CH ₂ 0), 7. 00 (d, 2H, 7=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, /=8. 7Hz, Ar-H).

Step 3 1-(3-Chloro-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydropyrrole-3 -carboxylic acid

Following step 5 of Example 1, 1-(3-chloro-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2,5 -Dihydro- 1 pyrrole-3-carboxylic acid ethyl ester instead of 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo- 2, 5 -Dihydro-pyrrole-ethyl 3-carboxylate, the crude product was crystallised from dry ethyl acetate to afford white crystals. C, Yield 16. 4 o 'H-NMR ^-DMSO) δ: 3. 71 (s , 2Η, 2- CH ₂ ), 4. 57 (s, 2H, I-NCH2) , 5. 22 (s , 2H, -CH ₂ 0) , 5. 47 (s , 2H, — CH ₂ 0), 7. 02 (d, 2H, /=8. 7Hz, Ar-H) , 7. 09 (dd, 1H, Ar-H) , 7. 32 (dd, 2H, Ar-H) , 7. 35 (d, 2H, 7=8. 7Hz, Ar-H) , 7. 45-7. 49 (m, 2H, Ar -H) , 7. 56 (in, 2H, Ar-H) . ES I MS (ra/z): 530 (M+-1) · Example 8. 1- (3-trifluoromethyl-benzyl) - 4- [4- (2, 6-Dichloro-benzyloxy) Of benzyl)-benzyloxy]-5-oxo-2,5-dihydro-1pyrrole-3-carboxylic acid

Step 1 1-(3-Trifluoromethyl-benzyl)-4-hydroxy-5-oxo-2,5-dihydropyrrole-3-carboxylate

The benzylamine was replaced by 3-trifluoromethyl-benzylamine according to Step 3 of Example 1 to give white crystals, mp 156-158 ° C, yield 78.2%.

Step 2 1-(3-Trifluoromethyl-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2, 5-dihydro -1 -pyrrole-ethyl 3-carboxylate

Substituting 1-(3-trifluoromethyl-benzyl)-4-hydroxy-5-oxo-2,5-dihydro-Ipyrrole-3-carboxylic acid ethyl ester in accordance with Step 4 of Example 1 Ethyl benzyl-4-hydroxy-5-oxo-2,5-dihydro-1#-pyrrole-3-carboxylate gave a white solid, ll ll. ^J H-NM (CDC1 ₃ ) δ: 1.27 (t, 3H, /=7.2Hz, -CH ₃ ),

3.88 (s, 2H, 2-CH ₂ ) , 4.22 (q, 2H, 7=7.2Hz, — OCH ₂ CH ₃ ), 4.67 (s, 2H, 1-NCH ₂ ) , 5.27 (s, 2H, -CH ₂ 0) , 5.76 (s, 2H, -CH ₂ 0) , 7.00 (d, 2H, /=8.6Hz, Ar-H), 7.23(m, 1H, Ar-H), 7.36-7.49 (ra, 7H , Ar-H), 7.56 (d, 1H, Ar-H).

Step 3 1-(3-Trifluoromethyl-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2, 5-dihydro Pyrrole-3-carboxylic acid

Following step 5 of Example 1, 1-(3-trifluoromethyl-benzyl)-4- [4-(2,6-dichloro-benzyloxy)-benzyloxy]- 5-oxo- 2,5-Dihydro-pyrrole-ethyl 3-carboxylate in place of 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]- 5-oxo-2 , 5 -Dihydro- 1^ "Pyrrol-3-carboxylic acid ethyl ester, the crude product was crystallized from ethyl acetate to give white crystals, dp 163 ° C, yield 11.4%. ^X H-NM (i3⁄4-DMS0) δ : 3.95 (s, 2Η, 2 - CH ₂ ),

4.67 (s, 2H, 1-NCH ₂ ) , 5.23(s, 2H, — CH ₂ 0), 5.58(s, 2H, — CH ₂ 0), 7.05 (d, 2H, 7=8.6Hz, Ar-H ), 7.37 (d, 2H, 7 = 8.6 Hz, Ar-H), 7.46-7.68 (m, 7H, Ar-H), 12.89 (s, 1H, -C00H) . ESI MS (ra/z): 564 (M ⁺ - 1). Example 9. 1-(4-Chloro-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]- 5-oxo-2, 5-dihydro- Preparation of pyrrole-3-carboxylic acid

Step 1 1-(4-Chloro-benzyl)-4-hydroxy-5-oxo-2,5-dihydropyrrole-3-carboxylate

According to Example 1, Step 3, using 4-chloro - benzyl amine for benzylamine to give white crystals, mp 164- 167 ° C, a yield of 75.5% ₀

Step 2 1-(4-Chloro-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]- 5-oxo-2, 5-dihydropyrrole-3 -carboxylic acid ethyl ester

Substituting 1-(4-chloro-benzyl)-4-hydroxy-5-oxo-2,5-dihydropyrrole-3-carboxylate for 1-benzyl-4- as in Example 4, Step 4. Hydroxy-5-oxo-2,5-dihydro-Ipyrrole-3-carboxylate ethyl ester gave mp 91-93 ° C. . ^-NMR (CDC1 ₃ ) δ: 1.27 (t, 3H, 7 = 7.1 Hz, -CH ₃ ) , 3.85 (s, 2H, 2-CH ₂ ) , 4.21 (q, 2H, 7 = 7.1 Hz, -OCH ₂ CH ₃ ) , 4.58(s, 2H, 1-NCH ₂ ), 5.27(s, 2H, — CH ₂ 0), 5.75(s, 2H, — CH ₂ 0), 7.00 (d, 2H, /=8.4 Hz, Ar-H), 7.14 (d, 2H, 7=8.4Hz, Ar-H), 7.25(m, 1H, Ar-H), 7.30 (d, 2H, /=8.4Hz, Ar-H), 7.36 (ra, 2H, Ar-H), 7.41 (d, 2H, 7=8.4Hz, Ar-H).

Step 3 1-(4-Chloro-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]- 5-oxo-2, 5-dihydro-pyrrole- ³ _carboxylic acid

According to Example 1, step 5, 1- (4-chloro - benzyl) -4- [4- ^(2, ⁶ - dichloro - benzyloxy) - benzyloxy] -5-oxo - 2, 5 -Dihydro-1pyrrole-ethyl 3-carboxylate in place of 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo- 2, 5 Ethyl dihydropyrrole-3-carboxylate, the crude product was crystallized from ethyl acetate to afford white crystals, dp 173 ° C, yield 21.0%. ^-NMIU - DMS0) δ: 3.90(s, 2H, 2-CH ₂ ) , 4.56(s, 2H, 1-NCH ₂ ) , 5.23(s, 2H, -CH ₂ 0) , 5.58 (s, 2H, -CH ₂ 0) , 7.06 (d, 2H, 7=8.6Hz, Ar-H), 7.23 (d, 2H, /=8.4Hz, Ar-H), 7.37 (d, 2H, 7=8.6Hz, Ar-H), 7.40 ( d, 2H, 7=8.4Hz, Ar-H), 7.46 (m, 1H, Ar-H), 7.56 (ra, 2H, Ar-H) . ESI MS(ra/z): 530 (M ⁺ - 1 Example 10. 1-Cyclohexylmethyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]- 5-oxo-2, 5-dihydro-Ipyrrole - Preparation of 3-carboxylic acid

Step 1 1-Cyclohexyldecyl-4-hydroxy-5-oxo-2,5-dihydro-1 pyrazole-3-carboxylate

Substituting benzylamine with cyclohexyl-methylamine according to step 3 of Example 1 gave white crystals mp 174-177. C, yield 80.8% ₀

Step 2 1-Cyclohexylmethyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]- 5-oxo-2, 5-dihydro-pyrrole-3-carboxylic acid Ethyl ester

Substituting 1-cyclohexyldecyl-4-hydroxy-5-oxo-2,5-dihydro-pyrrole-3-carboxylate for 1-benzyl-4-hydroxy-5 as in Example 4, Step 4. - oxo - ^2, 5 - dihydro-pyrrol - 3-carboxylate as a white solid, mp 118- 120 ° C, a yield of 80.8%.

'H-NMR (CDC1 ₃ ) δ: 0.95 (m, 2H, Cyclohexane-H), 1.17 (m, 3H, Cyclohexane-H), 1.31 (t, 3H, 7=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, /= 7.2Hz, -OCH ₂ CH ₃ ) , 5.26 (s, 2H, -CH ₂ 0) , 5.74 (s, 2H, -CH ₂ 0) , 6.98 (d, 2H, /=8.6Hz, Ar-H) , 7.22 (ra, 1H, Ar -H) , 7.35 (d, 2H, Ar-H), 7.40 (d, 2H, /=8.6Hz, Ar-H).

Step 3. 1-Cyclohexylmethyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole-3-carboxy Acid

1 according to the procedure of Example 5, using 1-cyclohexylmethyl-4- [4- (2,6-dichloro - benzyloxy) - benzyloxy] - 5-oxo - 2, ⁵ - dihydro - Pyrrole- ³ -carboxylate ethyl ester instead of 1- Benzyl - 4- [4- (2,6-dichloro - benzyloxy) - benzyloxy] -5-oxo - ^2, ⁵ _ dihydro - 1 - pyrrole-3-carboxylate, a crude product Recrystallization from absolute ethanol gave white crystals, dp 148. (:, yield 11.9%. NMR(oH)MSO) 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-Recommended ₂ ), 3.97 (s, 2H, 2-CH ₂ ) , 5.22(s, 2H, - CH ₂ 0), 5.55 (s, 2H, -CH ₂ 0) , 7.04 ( d, 2H, 7=8.6 Hz, Ar-H), 7.35 (d, 2H, 7=8.6 Hz, Ar-H), 7.45 (ra, 1H, Ar-H), 7.55 (ra, 2H, Ar-H ), 12.78(s, 1H, -C00H) . ESI MS (m/z): 502 (M ⁺ - 1). Example 11. 1 -Benzo[1,3]dioxane-5-yl Preparation of keto-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-1pyrrole-3-carboxylic acid

Step 1 1-Benzo[1,3]dioxane-5-ylmethyl- ⁴ -hydroxy- ⁵ -oxo-2,5-dihydro-pyrrole-3-carboxylic acid ethyl ester

Substituting benzyl [1,3]di-p-methane-5-yl-methylamine for benzylamine according to step 3 of Example 1 gave white crystals, mp 146 - 148 ° C, yield 78. 1%.

Step 2 1-Benzo[1,3]dioxol-5-ylmercapto-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo- 2, 5-Dihydro-1 pyrazole- ³ -carboxylate

Following step 4 of Example 1, 1-benzo[1,3]dioxane-5-ylmethyl-4-hydroxy-5-oxo-2,5-dihydropyrrole-3-carboxylic acid The ester was replaced by ethyl 1-benzyl- ⁴ -hydroxy-5-oxo-2,5-dihydro-pyrrol-3-carboxylate to give a white solid, mp 112-115. 'H-NMR (CDC1 ₃ ) δ: 1.27 (t, 3Η, /=7. OHz, - CH ₃ ), 3.84 (s, 2H, 2-CH ₂ ) , 4.21 (q, 2H, 7=7. OHz , -OCH ₂ CH ₃ ) ,

4.52 (s, 2H, 1-NCH ₂ ), 5.27(s, 2H, -CH ₂ 0) , 5.75 (s, 2H, -CH ₂ 0) ,

5.95 (s, 2H, -0CH ₂ 0-), 6.68-6.77 (ra, 3H, Ar-H), 6.99 (d, 2H, /=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, 7=8. 7Hz, Ar-H) . Step 3 1-Benzo[1,3]dioxane-5 Methyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-1 ^pyrrole- ³ -carboxylate

Following step 5 of Example 1, 1-benzo[1,3]dioxan-5-ylmethyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy] -5-oxo-2,5-dihydro-I pyrrole-ethyl 3-carboxylate in place of 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy] 2%。 -5- oxo- 2,5-dihydro- 1 pyrrole-3-carboxylic acid ethyl ester, the crude product was recrystallized from ethyl acetate. ^-NMR (-DMS0) δ: 3. 86 (s, 2H, 2 - CH ₂ ), 4. 46 (s, 2H, 1-NCH ₂ ), 5. 23 (s, 2H, -CH ₂ 0) , 5. 57 (s, 2H, - CH ₂ 0), 5. 99 (s, 2H, -0CH ₂ 0-) , 6, 70-6. 88 (m, 3H, Ar-H), 7. 05 (d, 2H, /=8. 6Hz, Ar-H), 7. 37 (d, 2H, 7=8. 6Hz, Ar-H), 7. 45 (m, 1H, Ar-H), 7. 55 (m, 2H, Ar-H), 12. 81 (s, 1H, -C00H). ESI MS (m/z): 540 (M ⁺ -1). Example 12. 1-benzyl-4- Preparation of [4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid

Step 1 4- (3, 5-Difluoro-benzyloxy)-benzaldehyde

The mixture was stirred at room temperature. The mixture was stirred at 0. 5 h, the water bath was removed, and the mixture was stirred at room temperature. The mixture was stirred at 0 ° C. Q. 5 h. The reaction solution was poured into 170 mL ice-water, extracted with ethyl acetate, washed with water, dried over anhydrous MgS0 _4. Concentration gave the product which was used in the next step without purification.

Step 2 4- (3,5-Difluoro-benzyloxy)-benzyl alcohol

20 匪ol 4- (3, 5-difluoro-benzyloxy)-benzaldehyde was dissolved in 30 mL of methanol, and the pre-formulated 12 ramol NaB was slowly added dropwise at 28-30 °C. 5小时。 The stirring was continued for 0. 5 h. Add 6N HCl Neutralize to pH 4, concentrate, add 1QOmL of water, stir for 4 h, filter, wash with water, and dry to give white crystals, yield 85.8%.

Step 3 1-Benzyl-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid ethyl ester

Substituting 4-(3,5-difluoro-benzyloxy)-benzyl alcohol for 4-(2,6-dichloro-benzyloxy)-benzyl alcohol according to step 4 of Example 1 gave a white solid m _. 108-110°C, yield 40. Sy H—NM CDCls) δ: 1.27(t, 3H, /=7. OHz, — CH ₃ ), 3.86 (s, 2H, 2-CH ₂ ) , 4.20 (q , 2H, /=7. OHz, -OCH ₂ CH ₃ ) , 4.61 (s, 2H, 1-NCH ₂ ) , 5.04 (s, 2H, a CH ₂ 0) , 5.74 (s, 2H, -CH ₂ 0 ), 6.73 (m, 1H, Ar-H), 6.91 (d, 2H, 7 = 8.6 Hz, Ar-H), 6.96 (ra, 2H, Ar-H), 7.20 - 7.36 (m, 5H, Ar- H), 7.40 (d, 2H, 7=8.6Hz, Ar-H).

Step 4 1-Benzyl-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydropyrrole-3-carboxylic acid

Following step 5 of Example 1, 1-benzyl-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-1pyrrole 3-carboxylate in place of 1-benzyl-4- [4- (2,6-dichloro - benzyloxy) - benzyloxy] - 5-oxo - ^2, ⁵ - dihydro - pyrrole - The ethyl 3-carboxylate was recrystallized from ethyl acetate to give white crystals, dp 157 ° C, yield 20%. ^-NMRi^-DMSO) δ: 3.87 (s, 2H, 2-CH ₂ ), 4.56 (s, 2H, 1 - NCH ₂ ), 5.15 (s, 2H, -CH ₂ 0) , 5.56 (s, 2H , - CH ₂ 0), 7.01 (d, 2H, /=8.9Hz, Ar-H), 7.17-7.37 (m, 10H, Ar-H), 12.83 (s, 1H, -C00H) . ESI MS (m /z): 464 (M ⁺ -1). Example 13. 1-(3-Chloro-benzyl)-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy] - Preparation of 5-oxo-2,5-dihydropyrrole-3-carboxylic acid

Step 1 1-(3-Chloro-benzyl)-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]- 5-oxo-2, 5-dihydro-pyrrole- 3-carboxylate Substituting 4-(3,5-difluoro-benzyloxy)-benzyl alcohol for 4-(2,6-dichloro-benzyloxy)-benzyl alcohol according to step 4 of Example 1, 1-(3- Ethyl chloro-benzyl)-4-hydroxy-5-oxo-2,5-dihydro-pyrrole-3-carboxylate instead of 1-benzyl-4-hydroxy-5-oxo-2, 5-di Hydrogen-pyrrol-3-carboxylate ethyl ester gave white solid, mp 94-95 ° C, mp.: 77. Oyo H-NMR CCD Ch) δ: 1.28 (t, 3H, 7 = 7.2 Hz, - CH ₃ ), 3.87 (s, 2H, 2-CH ₂ ) , 4.21 (q, 2H, J = 1.2 Hz, -OCH ₂ CH ₃ ) , 4.58 (s, 2H, 1-NCH ₂ ) , 5.04 (s, 2H, -CH ₂ 0) , 5.73 (s, 2H, -CH ₂ 0) , 6.73 (in, 1H, Ar-H) , 6.92 (d, 2H, 7=8.6Hz, Ar-H) , 6.96 (ra, 2H, Ar -H), 7.09 (m, 1H, Ar-H), 7.20-7.28 (ra, 3H, Ar-H), 7.40 (d, 2H, 7 = 8.6 Hz, Ar-H).

Step 2 1-Benzyl-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2, 5-dihydropyrrole-3-carboxylic acid

Following step 5 of Example 1, 1-(3-chloro-benzyl)-4- [4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo- ² , ⁵ -Dihydro-I pyrrole- ³ -carboxylate in place of 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy] ^-5 -oxo- ² , ⁵ -Dihydro-:--pyrrole-3-carboxylic acid ethyl ester, the crude product was crystallized from ethyl acetate to afford white crystals, dp 146" C, yield 16.9%. 'H-NMRC^-DMSO) δ: 3.92 ( s, 2H, 2-CH ₂ ), 4.57(s, 2H, 1-NCH ₂ ), 5.15 (s, 2H, — CH ₂ 0), 5.55(s, 2H, -CH ₂ 0) , 7.01 (d, 2H, 7=8.7 Hz, Ar-H), 7.17-7.38 (ra, 9H, Ar-H), 12.75 (s _; 1H, -C00H) . ESI MS (ra/z): 498 (M ⁺ - 1) Example 14. 1-Benzo[1,3]dioxane-5-ylmercapto-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5- Preparation of oxo-2,5-dihydro-pyrrole-3-carboxylic acid

Step 1 1-Benzo[1,3]dioxol-5-ylmethyl-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo- 2, 5-Dihydro-1 pyrazole-3-carboxylate Substituting 4-(3,5-difluoro-benzyloxy)-benzyl alcohol for 4-(2,6-dichloro-benzyloxy)-benzyl alcohol according to step 4 of Example 1, 1-benzo[ 1,3]Dioxane-5-ylmethyl- ⁴ -hydroxy- 5-oxo-2,5-dihydro-pyrrole-3-carboxylate as an alternative to 1-benzyl-4-hydroxy-5 -Oxo-2,5-dihydro-1^"pyrrol-3-carboxylate ethyl ester gave white solid, mp 99-100.5 ° C, yield 69.8%. - awake (CDC1 ₃ ) δ: 1.27 (t , 3H, /=7.0Hz, -CH ₃ ) , 3.84 (s, 2H, 2— CH ₂ ), 4.20 (q, 2H, 7=7.0Hz, -OCH ₂ CH ₃ ) , 4.51 (s, 2H, 1 -NCH ₂ ), 5.04 (s, 2H, -CH ₂ 0) , 5.73 (s, 2H, -CH ₂ 0) , 5.94 (s, 2H, -0CH ₂ 0 -), 6.68-6.76 (m, 4H, Ar-H), 6.91 (d, 2H, /-8.6 Hz, Ar-H), 6.96 (m, 2H, Ar-H), 7.39 (d, 2H, 7 = 8.6 Hz, Ar-H).

Step 2 1-Benzo[1,3]dioxane-5-ylmethyl-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo- 2, 5-dihydropyrrole-3-carboxylic acid

Following step 5 of Example 1, 1-benzo[1,3]dioxane-5-ylmethyl-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy] - 5-Oxo- 2,5-dihydropyrrole-3-carboxylic acid ethyl ester instead of 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5 - oxo - 2, 5-dihydro-pyrrol -I - 3-carboxylate The crude product was recrystallized from ethyl acetate to give white crystals, dp 172 ^D C, a yield of 18.9%. - Legs - Recommended 0) δ: 3.85 (s, 2H, 2 - CH ₂ ), 4.45 (s, 2H, 1 - recommended ₂ ), 5.15(s, 2H, — CH ₂ 0), 5.55 (s, 2H, -CH ₂ 0) , 6.00 (s, 2H, - 0CH ₂ 0-), 6.71 (dd, 1H, Ar-H) , 6.80 (d 1H, Ar-H) , 6.86 (d, 1H, Ar-H) , 7.00 (d, 2H, =8.6Hz, Ar-H) , 7.19 (ra, 3H, Ar-H) , 7.35 (d, 2H, /=8.6Hz, Ar-H) , 12.82(s, 1H, - C00H) . ESI MS (ra/z): 508 (M+-1) · Example 15. 4-[4- (3, 5-difluoro-benzyloxy)-benzyloxy]-1-heptyl- Preparation of 5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid

Step 1 4- [4-(3,5-Difluoro-benzyloxy)-benzyloxy]-1-heptyl- 5-oxo - 2,5-Dihydro-1 ^pyrrole-3-carboxylic acid ethyl ester

Substituting 4-(3,5-difluoro-benzyloxy)-benzyl alcohol for 4-(2,6-dichloro-benzyloxy)-benzenemethanol to 1-heptyl- Ethyl 4-hydroxy- ⁵ -oxo-2,5-dihydro-Ipyrrole-3-carboxylate instead of 1-benzyl-4-hydroxy-5-oxo-2,5-dihydro-pyrrole-3 Ethyl carboxylate gave a white solid, mp 75-77 ° C, yield 69. . ^-NM (CDC1 ₃ ) δ: 0. 86 (t, 3H, -CH ₃ ) , 1. 27-1. 32 (m, 11H, -4CH ₂ CH ₃ , -OCH ₂ CH 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, 7=7. 0Hz, -OCH ₂ CH ₃ ) , 5. 03 (s, 2H, -CH ₂ 0) , 5. 71 (s, 2H, -CH ₂ 0) , 6. 72 (m, 1H, Ar-H) , 6. 90 (d, 2H, 7=8. 6Hz, Ar-H), 6. 96 (m, 4H, Ar-H), 7. 38 (d, 2H, 7=8. 6Hz, Ar-H) .

Step 2 4-[4-(3,5-Difluoro-benzyloxy)-benzyloxy]-1-heptyl- 5-oxo-2,5-dihydro-1#-pyrrole-3-carboxy Acid

Following step 5 of Example 1, 4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-1-heptyl- 5-oxo-2,5-dihydro-1 pyrrole Ethyl-3-carboxylate in place of 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2, 5-dihydro-Ipyrrole 7%。 The carboxylic acid ethyl ester, the crude product was recrystallized from anhydrous ethanol to give white crystals, dp 122 Ό, yield 14.7%. -NMR -DMS0) δ: 0. 85 (t, 3H, - CH ₃ ), 1. 24 (m, 8H, - 4CH ₂ ), 1. 50 (ra, 2H, - CH ₂ ), 3. 34 ( t, 2H, 1- NCH ₂ ), 3. 96 (s, 2H, 2-CH ₂ ) , 5. 14 (s, 2H, -CH ₂ 0) , 5. 53 (s, 2H, -CH ₂ 0 ), 6. 99 (d, 2H, 7=8. 6Hz, Ar-H), 7. 16-7. 22 (ra, 3H, Ar-H), 7. 33 (d, 2H, /=8. _{6Hz s Ar-H), 12.} 80 (s, 1H, -C00H) ESI MS (m / z):. 472 (m + - benzyl) -4 - 1) · Example 16. 1- (2-chloro- -Preparation of [4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole-3-octanoic acid

1 1- (2-Chloro-benzyl)-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy -5-oxo-2,5-dihydro-1 -pyrrole-3-carboxylate

Substituting 4-(3,5-difluoro-benzyloxy)-benzyl alcohol for 4-(2,6-dichloro-benzyloxy)-benzyl alcohol in the step 4 of Example 1, 1-(2- Ethyl chloro-benzyl)-4-hydroxy-5-oxo-2,5-dihydropyrrole-3-carboxylate instead of 1-benzyl-4-hydroxy-5-oxo-2, 5-dihydro Ethyl pyrrol-3-carboxylate, white solid, mp 88-90 ° C,

71.

ΟΗζ, -CH ₃ ) , 3.90(s, 2Η, 2-CH ₂ ) , 4.21 (q, 2Η, 7=7. ΟΗζ, -OCH ₂ CH ₃ ) , 4.76(s, 2Η, 1 - recommended 2), 5.04 (s, 2H, -CH ₂ 0) , 5.73 (s, 2H, -CH ₂ 0) , 6.73 (m, 1H, Ar-H), 6.91 (d, 2H, 7 = 8.6 Hz, 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, /=8.6Hz, Ar-H ) .

Step 2 l-(2-Chloro-benzyl)-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole- 3-carboxylic acid

Following step 5 of Example 1, 1-(2-chloro-benzyl)-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2,5 -Dihydro- 1 pyrrole-3-carboxylic acid ethyl ester instead of 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2, 5 -Dihydropyrrole-ethyl 3-carboxylate, the crude product was crystallized from ethyl acetate to afford white crystals, dp 167 ° C, yield 24.2%. ― NMR - DMS0) δ: 3.90 (s, 2H, 2-CH ₂ ) , 4.66 (s, 2H, 1-NCH ₂ ), 5.15 (s, 2H, - CH ₂ 0), 5.56(s, 2H, - CH ₂ 0) , 7.01 (d, 2H, 7 = 8.6 Hz, Ar-H), 7.17-7.50 (m, 9H, Ar-H), 12.87 (s 1H, -C00H) . ESI MS (m/z) : 498 (M ⁺ -1) . Example 17. 1-Cyclohexylmethyl-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2, Preparation of 5-dihydropyrrole-3-carboxylic acid

Step 11- cyclohexylmethyl - 4- [4- (3, ⁵ - difluoro - benzyloxy) - benzyloxy] - 5-oxo-2,5-dihydro - pyrrolo --3- acid Ethyl ester According to step 4 of Example 1, 4-(3,5-difluoro-benzyloxy)-benzyl alcohol was replaced by 4-(3,5-difluoro-benzyloxy)-benzyl alcohol as 1-cyclohexyl. Methyl 4-hydroxy-5-oxo-2,5-dihydro-pyrrole-3-carboxylate in place of 1-benzyl-4-hydroxy-5-oxo-2,5-dihydropyrrole- Ethyl 3-carboxylate, mp 106-108 ° C, mp.

Step 2 1-Cyclohexylmethyl-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2, 5-dihydro-1^pyrrole-3- Carbohydrate

Following step 5 of Example 1, 1-cyclohexylmethyl-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]- 5-oxo-2, 5-dihydro- pyrrole-3-carboxylate in place of 1-benzyl-4- [4- (2,6-dichloro - benzyloxy) - benzyloxy] _ ^5-oxo-2, ⁵ - dihydro-1 The ethyl pyrrole-3-carboxylate was recrystallized from dry diethyl ether to afford white crystals. C, yield 21.6%. ! H-NMRWs-DMSO) δ: 0.88 (ra, 2H, Cyclohexane-H), 1.15 (m, 3H, Cyclohexane-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 ₂ 0) , 5.53(s, 2H, -CH ₂ 0) , 6.99 (d, 2H, 7=8.6 Hz, Ar-H), 7.16(m, 3H, Ar-H), 7.33 (d, 2H, /=8.6Hz, Ar-H), 12.79(s, 1H, -C00H) . ESI MS (ra/z ): 470 (M+-1). Example 18. 4-[4-(3,5-Difluoro-benzyloxy)-benzyloxy]-1-octyl- ⁵ -oxo-2, 5- Preparation of dihydropyrrole-3-carboxylic acid

Step 1 4- [4- (3, ⁵ - difluoro - benzyloxy) - benzyloxy] -1-octyl - ⁵ - oxo - 2, 5-dihydro --1 ^ "pyrrole-3-carboxamide Ethyl acetate

Substituting 4-(3,5-difluoro-benzyloxy)-benzyl alcohol for 4-(2,6-dichloro-benzyloxy)-benzenemethanol to 1-octyl- according to step 4 of Example 1. Ethyl 4-hydroxy-5-oxo-2,5-dihydro-Ipyrrole-3-carboxylate in place of 1-benzyl-4-hydroxy-5-oxo-2,5-dihydropyrrole-3- The ethyl carboxylate gave a white solid, mp 70-72 ° C, yield 71.7%. ^{! H-NMR (CDC) δ} : 0.87 (t, 3H, -CH 3), 1.26- 1.32 (m, 13H, -5CH 2 CH 3, -OCH 2 CH 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, 7=7.0Hz, -OCH ₂ CH ₃ ) , 5.03 (s, 2H, -CH ₂ 0), 5.71(s, 2H, a CH ₂ 0) , 6.75 (ra, 1H, Ar—H), 6.90 (d, 2H, 7=8.6Hz, Ar—H), 6.94 (m, 2H) , Ar—H), 7.38 (d, 2H, 7=8.6Hz, Ar-H).

Step 2 4-[4-(3,5-Difluoro-benzyloxy)-benzyloxy]-1-octyl-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid

Following step 5 of Example 1, 4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-1-octyl-5-oxo-2, 5-dihydro-1^ Ethyl pyrrol-3-carboxylate in place of 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2, 5-dihydro-I The ethyl pyrrole-3carboxylate was recrystallized from anhydrous ethanol to give white crystals, dp 116 ° C, yield 11.4%. ^- NMR -DMS0) 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 ₂ 0), 5.53(s, 2H, -CH ₂ 0) , 6.99 (d, 2H, /=8.7Hz, Ar-H), 7.18 (m, 3H, Ar-H), 7.33 (d, 2H, 7 = 8.7 Hz, Ar-H), 12.80 (s, 1H, -C00H). ESI MS (m/z): 586 (M ⁺ -1). Example 19. 1-(3-Trifluoromethyl-benzyl)-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5 -Oxo-2,5-dihydro-I pyrrole-3-carboxylic acid preparation

Step 1 1-(3-Trifluoromethyl-benzyl)-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2, 5-dihydro - 1 ^"pyrrole-ethyl 3-carboxylate

Substituting 4-(3,5-difluoro-benzyloxy)-benzyl alcohol for 4-(2,6-dichloro-benzyloxy)-benzyl alcohol according to step 4 of Example 1, 4-[4- Ethyl (3,5-difluoro-benzyloxy)-benzyloxy]-1-heptyl-5-oxo-2,5-dihydropyrrole-3-carboxylate instead of 1-benzyl- 4- Ethyl hydroxy-5-oxo-2,5-dihydro-1pyrrole-3-carboxylate gave a white solid. Nip 114-116. C, yield 74. / H- NMR (CDC1 ₃ ) δ: 1.26 (t, 3H, 7 = 7.2 Hz, -CH ₃ ), 3.88 (s, 2H, 2-CH ₂ ) , 4.21 (q, 2H, /=7.2Hz, — 0CH ₂ CH ₃ ), 4.67 (s, 2H, 1-NCH ₂ ), 5.04 (s, 2H, — CH ₂ 0), 5.74 (s, 2H, — CH ₂ 0),

6.73(m, IH, Ar-H), 6.91 (d, 2H, /=8.7Hz, Ar-H), 6.95 (m, 2H, Ar-H) , 7.40 (d, 2H, 7=8.7Hz, Ar -H) , 7.45-7.57 (m, 4H, Ar-H).

Step 2 l-(3-Trifluoromethyl-benzyl)-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2, 5-dihydro - Pyrrole-3-carboxylic acid

Following step 5 of Example 1, 1-(3-trifluoromethyl-benzyl)-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo- Ethyl 2,5-dihydro-pyrrole-3-carboxylate instead of 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2 , 5 -Dihydro-pyrrole-ethyl 3-carboxylate, the crude product was crystallized from anhydrous diethyl ether to afford white crystals, dp 147 ° C, yield 16.3%. 'H-NMR (cT ₆ -DMS0) δ: 3.94 (s, 2Η, 2-CH ₂ ) , 4.66(s, 2H, 1-NCH ₂ ), 5.15 (s, 2H, — CH ₂ 0) , 5.55 ( s, 2H, -CH ₂ 0) ,

7.00 (d, 2H, 7=8.4Hz, Ar-H), 7.17(ra, 3H, Ar-H), 7.35 (d, 2H, 7=8.4Hz, Ar-H), 7.51-7.68 (ra, 4H , Ar-H), 12.85 (s, IH, -COOH). ESI MS (m/z): 532 (M ⁺ -1). Example 20. 4- [4- (3,5-difluoro-benzyl) Preparation of oxy)-benzyloxy]-1-furan-2-ylmethyl-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid

Step 1 4-[4-(3,5-Difluoro-benzyloxy)-benzyloxy]-1-furan-2-ylindenyl-5-oxo-2,5-dihydro-pyrrole-3 -carboxylic acid ethyl ester

Substituting 4-(3,5-difluoro-benzyloxy)-benzofuran for 4-(2,6-dichloro-benzyloxy)-benzyl alcohol, 1-furan- according to step 4 of Example 1. Ethyl 2-methylmethyl-4-hydroxy-5-oxo-2,5-dihydropyrrole-3-carboxylate instead of 1-benzyl-4-hydroxy-5-oxo-2, 5-dihydro - Pyrrole-3-carboxylate ethyl ester gave white solid, mp 98-100 ° C, yield 94.0%. N2006/003402 Step 2 4- [4-(3,5-Difluoro-benzyloxy)-benzyloxy]-1-furan- ² -ylmethyl-5-oxo-2, 5-dihydro- Pyrrole-3-carboxylic acid

According to Example 1, Step 5, 4- [4- (3, ⁵ - difluoro - benzyloxy) - benzyloxy] -1-furan --2-yl-5-oxo-2,5- dihydro pyrrole - 3-carboxylate in place of 1-benzyl - 4- [4- (2,6-dichloro - benzyloxy) - benzyloxy] - 5-oxo - ^2, 5 - dihydro 7%。 The pyrrole-3-carboxylic acid ethyl ester, the crude product was recrystallized from anhydrous diethyl ether to give white crystals, dp 134 ° C, yield 16.7%. -NMR - DMS0) δ: 3. 90 (s, 2H, 2-CH ₂ ), 4. 57 (s, 2H, 1-NCH ₂ ) , 5. 14 (s, 2H, -CH ₂ 0) , 5 . 53 (s, 2H, — CH ₂ 0),

6. 38 (m, 2H, furan-H), 7. 00 (d, 2H, 7=8. 6Hz, Ar-H), 7. 17 (ra, 3H, Ar-H) , 7. 34 (d , 2H, 7=8. 6Hz, Ar-H) , 7. 62 (ra, 1H, furan-H) 12. 87 (s, 1H, -C00H) . ESI MS (m/z): 454 (M ⁺ - 1) . Example 21. 1-(4-Chloro-benzyl)-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo- 2, 5 -Preparation of dihydro-pyrrole-3-carboxylic acid

Step 1 1-(4-Chloro-benzyl)- 4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2, 5-dihydro-1^ ·pyrrole-ethyl 3-carboxylate

Substituting 4-(3,5-difluoro-benzyloxy)-benzyl alcohol for 4-(3,5-dichloro-benzyloxy)-benzyl alcohol in the presence of step 4 of Example 1, 1--4- Ethyl chloro-benzyl)-4-hydroxy-5-oxo-2,5-dihydro-pyrrole-3-carboxylate instead of 1-benzyl-4-hydroxy-5-oxo- 2, 5-di 0%。 The hydrogen pyrrole- 3 - carboxylic acid ethyl ester, a white solid, mp 115-116 ° C, yield 63. 0%. 'H-NMR (CDC1 ₃ ) δ: 1. 27 (t, 3H, 7=7. OHz, -CH ₃ ) , 3. 85 (s, 2H, 2-CH ₂ ) , 4. 21 (q, 2H , /-7. 0Hz, -OCH ₂ CH ₃ ) , 4. 58 (s, 2H, 1-NCH ₂ ) , 5. 04 (s, 2H, — CH ₂ 0), 5. 72 (s, 2H, -CH ₂ 0) , 6. 73 (m, 1H, Ar-H) , 6. 91 (d, 2H, 7=8. 6Hz, Ar-H) , 6. 95 (ra, 2H, Ar-H) ,

7. 14 (d, 2H, 7=8. 4Hz, Ar-H), 7. 29 (d, 2H, 7=8. 6Hz, Ar-H), 7. 39 (d, 2H, 7=8. 4Hz, Ar-H). Step 2 1-(4-Chloro-benzyl)-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]- 5-oxo-2, 5-dihydro-pyrrole- 3-carboxylic acid

Following step 5 of Example 1, 1-(4-chloro-benzyl)-4- [4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo- 2, 5 -Dihydro-pyrrole-3-carboxylic acid ethyl ester instead of 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo- 2, 5- The dihydropyrrole-ethyl 3-carboxylate was recrystallized from ethyl acetate to give white crystals, dp 171 ° C, yield 18.2%. ^-NMR-DMSO) δ: 3.89 (s, 2H, 2-CH ₂ ), 4.55 (s, 2H, 1-NCH ₂ ), 5.15 (s, 2H, - CH ₂ 0), 5.55 (s, 2H, — CH ₂ 0), 7.01 (d, 2H, 7=8.6Hz, Ar-H), 7.17 (in, 3H, Ar-H), 7.23 (d, 2H, /=8.6Hz, Ar-H), 7.35 (d, 2H, 7=8.6Hz, Ar-H), 7.39 (d, 2H, /=8.6Hz, Ar-H), 12.84 (s, 1H, -C00H) . ESI MS (m/z) : 498 (M ⁺ -1). Example 22. 1-Benzyl-4-[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo-2,5-dihydropyrrole- Preparation of 3-carboxylic acid

Step 1 1, 3-Dichloro-2-(4-nitro-phenoxyindenyl)-benzene

1Q mmol 2,6-dichlorobenzyl bromide and 10 ol p-nitrophenol were added to a sodium ethoxide solution (metal sodium 10 mraol/10 mL absolute ethanol), heated to reflux for 2 h, cooled and concentrated. Add water 20 mL, filter, wash with water to give a pale yellow solid 2.8 g, yield

96.5%.

Step 2 4- (2,6-Dichloro-benzyloxy)-aniline

6.7 ramol of 1, 3-dichloro-2-(4-nitro-phenoxymethyl)-benzene and 33.6 ramol of stannous chloride were dissolved in 67 mL of ethanol, stirred, and heated to reflux for 5 h. Cooled, and concentrated to dryness under reduced pressure, added 80 mL of ethyl acetate to the residue, washed with NaHC0 ₃ solution adjusting pH 7-8, insolubles were filtered off, the filter cake washed repeatedly with ethyl acetate, the combined filtrate washed with water, dried over anhydrous Na ₂ S0 _{4 is} dry. Concentrated to give a light yellow oil that can be carried without purification One step reaction.

Step 3 1-Benzyl-4-[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo- 2 5-dihydropyrrole-ethyl 3-carboxylate

7.2 mraol 4-(2,6-dichloro-benzyloxy)-phenylamine and 7.2 mraol 1-benzyl-4-hydroxy-5-oxo-2,5-dihydro- 1 -pyrrole-3-carboxyl Ethyl acetate (product of Step 3 of Example 1) was dissolved in 10 mL of glacial acetic acid, stirred, and heated to reflux for 4 h. Cooling, the reaction solution was carefully added dropwise a saturated aqueous solution of NaHC0 _3, extracted with ethyl acetate, washed with water and dried over anhydrous Na ₂ S0 _4. Concentration, the obtained crude material was purified mjjjjjjj ^-NMR (CDC1 ₃ ) δ: 0.99 (t, 3H, 7 = 7.0 Hz, -CH ₃ ) , 3.95 (m, 4H, 2-CH ₂ , - OCH ₂ CH ₃ ), 4.62 (s, 2H, 1 -NCH ₂ ), 5.19 (s, 2H, — CH ₂ 0) , 6.93 (d, 2H, 7=8.9Hz, Ar-H) , 7.01 (d, 2H, /-8.9Hz, Ar-H) , 7.26 -7.39 (ra, 5H, Ar-H), 7.45 (ra, 1H, Ar-H), 7.55 (m, 2H, Ar-H), 8.63 (s, 1H, -NH).

Step 4 1-Benzyl-4-[4-(2,6-Dichloro-benzyloxy)-aniline]-5-oxo-2 5-dihydropyrrole-3-carboxylic acid

Dissolve 4 匪ol 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo-2,5-dihydropyrrole-3-carboxylic acid ethyl ester Into 51 raL of tetrahydrofuran and 17 mL of ethanol, 20 mmol of a 5% aqueous solution of NaHC0 _{3 was} added and stirred under reflux for 48 h. After cooling, the reaction solution was poured into 200 mL of water, pH 1 - 2 was adjusted with 2N hydrochloric acid, extracted with ethyl acetate, washed with water and dried over anhydrous Na ₂ SO ₄ . After concentration, the obtained crude material was crystallised from ethyl acetate. -NMR ( - DMS0) δ: 3.93 (s, 2H, 2-CH ₂ ) , 4.60 (s, 2 Η, 1-NCH ₂ ) , 5.18 (s, ₂ Η, — CH ₂ 0), 6.92 (d, 2H, 7=8.9 Hz, Ar-H), 7.03 (d, 2H, 7=8.9 Hz, Ar-H), 7.25-7.38 (m, 5H, Ar-H), 7.45 (m, 1H, Ar-H), 7.56 (ra, 2H, Ar-H), 8.55 (s, 1H, -NH), 12.35 (s, 1H, -C00H) . ESI MS (m/z): 481 (M ⁺ - 1). Example 23. 4-[4-(2,6-Dichloro-benzyloxy)-aniline]-5-oxo-1-(3-trifluoromethyl-benzyl)-2,5-dihydro -1 Preparation of pyrrole-3-carboxylic acid

Step 1 4-[4-(2,6-Dichloro-benzyloxy)-aniline]-5-oxo-1-(3-trifluoromethyl-benzyl)-2, 5-dihydro-I Ethyl pyrrol-3-carboxylate

Following Step 3 of Example 22, 1-(3-trifluorodecyl-benzyl)-4-hydroxy-5-oxo-2,5-dihydropyrrole-3-carboxylate (Step 8) 1 product) instead of 1-benzyl-4-hydroxy-5-oxo-2,5-dihydro-1^"pyrrole-3-carboxylic acid ethyl ester as a white solid, mp 71-73 ° C, yield 53. 4%. ^-NMR (CDC1 ₃ ) δ: 1. 21 (t, 3Η, 7=7. ΟΗζ, — CH ₃ ), 3. 95 (s, 2Η, 2-CH ₂ ) , 4. 16 (q, 2H, /=7. 0Hz, -OCH ₂ CH ₃ ) , 4. 69 (s, 2H, 1-NCH ₂ ) , 5. 25 (s, 2H, -CH ₂ 0) , 6. 97 ( d, 2H, 7=8. 9Hz, Ar-H), 7. 11 (d, 2H, 7=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, IH, -NH).

Step 2 4-[4-(2,6-Dichloro-benzyloxy)-aniline]-5-oxo-1-(3-trifluoromethyl-benzyl)-2, 5-dihydropyrrole- 3-carboxylic acid

Step 4 according to Example 22, 4-[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo-1-(3-trifluoromethyl-benzyl)-2, Ethyl 5-dihydropyrrole-3-carboxylate instead of 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo-2,5-dihydro -1-- pyrrole - 3-carboxylate to give yellow crystals, dp 170 ° C, a yield of 25. A _30-- should wake 0) δ: 3. 99 (s , 2H, 2-CH 2), 4, 70 (s, 2Η, 1-NCH ₂ ) , 5, 18 (s, 2H, -CH ₂ 0), 6. 92 (d, 2H, 7=8. 9Hz, Ar-H) , 7. 07 (d , 2H, 7=8. 9Hz, Ar-H) , 7. 44-7. 68 (ra, 7H, Ar-H) , 8. 53 (s, 1H, -NH) , 12. 35 (s, 1H , -C00H) . ESI MS (m/z): 549 (M ⁺ -1). Example 24. 1-Benzo[1,3]didecane-5-yl-methyl-4-[4 - (2, 6- Preparation of dichloro-benzyloxy)-aniline]-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid Step 1 1-Benzo[1,3]dioxanane-5-yl -methyl 4-[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo-2,5-dihydro-1 pyrazole-3-carboxylate

According to the procedure of step 22, 1-benzo[1,3]di-p-methoxylan-5-yl-methyl-4-hydroxy-5-oxo-2,5-dihydropyrrole-3-carboxy Ethyl acetate (product of Step 1 of Example 14) was replaced by ethyl 1-benzyl-4-hydroxy-5-oxo-2,5-dihydropyrrole-3-carboxylate as a yellow solid, mp 101-103. C, yield 59·6%. ^{_{! H-NMR (CDC1 3)}} δ: 1.20 (t, 3H, /=7.0Hz, - CH 3), 3.93 (s, 2H, 2-CH 2), 4.15 (q, 2H, 1 = 1.0Hz, - OCH ₂ CH ₃ ) , 4.54 (s, 2H, 1-NCH ₂ ) , 5.26(s, 2H, —CH ₂ 0) , 5.95(s, 2H, -0CH ₂ 0-) , 6.75 (ra, 3H, Ar -H) , 6.97 (d, 2H, 7=8.9Hz _: Ar-H) , 7.11 (d, 2H, /=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]dioxane-5-yl-methyl-4-[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo-2 , 5-dihydro-pyrrole-3-carboxylic acid

According to the procedure of Step 22, 1-benzo[1,3]dioxan-5-ylmethyl-4-[4-(2,6-dichloro-benzyloxy)-aniline]-5 -Oxo- 2,5-dihydro-pyrrole-3-carboxylic acid ethyl ester instead of 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo - 2,5-Dihydro-Ipyrrole-ethyl 3-carboxylate gave a yellow solid, mp. -NMR ( - DMS0) δ: 3.91 (s, 2H, 2-CH ₂ ) , 4.48 (s, 2Η, 1-NCH ₂ ) , 5.18 (s, 2H, -CH ₂ 0) , 6.00 (s, 2H, -0CH ₂ 0~) , 6.74-6.89 (m, 3H, Ar-H), 6.92 (d, 2H, /=8.9Hz, Ar-H) , 7.37 (d, 2H, 7=8.9Hz, Ar-H ), 7.44 (ra, 1H, Ar-H), 7.55 (m, 2H, Ar-H),

8.50(s, 1H, -NH), 12.35(s, 1H, -C00H) · ESI MS (m/z): 525 (M ⁺ -1). Example 25. 1-cyclohexylmethyl- 4- [ 4-(2,6-dichloro-benzyloxy)-benzene Preparation of amine]-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid

Step 1 1-Cyclohexylmethyl-4-[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo-2,5-dihydro-pyrrole-carboxylate

Substituting 1-benzyl 1-methylhexylmercapto-4-hydroxy-5-oxo-2,5-dihydro-pyrrole-3-carboxylate (product of step 10 of Example 10) Ethyl 4-hydroxy-5-oxo-2,5-dihydro-17-pyrrole-3-carboxylate gave a white solid, mp 157-159 ° C, yield 46.6%. ^-NMR (CDC1 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, /= 7.0Hz, -OCH ₂ CH ₃ ) , 5.24(s, 2H, — CH ₂ 0), 6.94 (d, 2H, 7 = 8.9Hz, Ar-H), 7.08 (d, 2H, 7 = 8.9Hz, Ar-H), 7.22 (m, 1H, Ar-H), 7.35 (d? 2H, Ar -H) , 8.02 (s, 1H, -NH).

Step 2 1-Cyclohexylmethyl-4-[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo-2,5-dihydropyrrole-3-carboxylic acid

According to the procedure of Step 22, 1-cyclohexylmethyl-4-[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo-2, 5-dihydro- 1# -ethylpyrrol-3-carboxylate in place of 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo-2,5-dihydro-pyrrole- Ethyl 3-carboxylate gave a yellow solid, dp 189 ° C, yield 48.8%. !H-驴(-face 0) 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 ₂ 0) , 6.90 (d, 2H, /=8.9Hz, Ar-H) , 6.99 ( d, 2H, 7=8.9 Hz, Ar-H), 7.44 (m, 1H, Ar-H), 7.55 (in, 2H, Ar-H), 8.45 (s, 1H, -NH), 12.32 (s, 1H, -C00H) . ESI MS (m/z): 487 (M+-1). Example 26. 4- [4- (2, 6-dichloro-benzyloxy)-aniline] -1- octyl -5 - oxygen Preparation of 2,5 dihydro-I pyrrole-3-carboxylic acid

Step 1 4-[4-(2,6-Dichloro-benzyloxy)-aniline]-1-octyl- 5-oxo-2 5-dihydro-pyrrole-3-carboxylate

According to Example 22, step 3, 4-(2,6-dichloro-benzyloxy)-phenylamine and 1-octyl-4-hydroxy-5-oxo-2,5-dihydropyrrole-3-carboxyl Ethyl acetate (Example 3 Step 1 product) was replaced by ethyl 1-benzyl-4-hydroxy-5-oxo-2,5-dihydro-1pyrrole-3-carboxylate as a white solid, mp 68 5%。 The yield was 47. 5%. ^- MR (CDC1 ₃ ) δ: 0. 85 (t, 3H, — CH ₃ ), 1. 19-1. 29 (in, 13H, -5CH ₂ CH ₃ , -OCH ₂ CH 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, 7 = 7 2Hz, -. OCH 2 CH 3), 5. 24 (s, 2H, a _{CH 2 0), 6. 94 (} d, 2H, / = 8 9Hz, Ar -H) , 7. 08 (d, 2H, 7=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-Dichloro-benzyloxy)-aniline]-1-octyl- 5-oxo- 2 5 -dihydro - 1 pyrrole - 3 -isoleic acid

22 Step 4 as described in Lee, to 4- [4- (2,6-dichloro - benzyloxy) - anilino] -1-octyl _ ⁵ - oxo _ ^2, ⁵ - dihydro -1 ^ - pyrrolidin Ethyl-3-carboxylate in place of 1-benzyl-4-[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo-2,5-dihydro-pyrrole-3- 8%。 The carboxylic acid ethyl ester, a pale yellow solid, dp 146 ° C, yield 52.8%. 'H-NMR (d ₆ -dUS0) δ: 0. 83 (t, 3Η, - CH ₃ ), 1. 25 (ra, 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 ₂ 0) , 6. 90 (d, 2H, 7=8. 9Hz, Ar-H) , 6. 99 (d, 2H, /=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, - C00H) . ESI MS (m/z): 503 (M ⁺ - 1) . The biological activity of the compound of the present invention can be evaluated by the following method: Example 27

The M. subtilis was passaged on 125 Rovin's egg slant medium and cultured for 4-5 days. A small strain of bacteria 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 by enzyme-linked instrument The optical density value of the 600 nm wavelength (0D ₆ . . . _nm ) to 0D ₆ . . _Nra is 0.5-0.6. Inoculate 1.0% bacterial solution in the assay medium (containing 0.5% peptone, 0.3% yeast extract, 1.2% agar, pH 7.0-7.4), and lay the plate. After the plate is solidified, the separation distance is greater than 3.0cm and the diameter is A 0.7 cm tablet containing 0.5 mM of the compound to be screened ΙΟΟμΙ. At the same time, a 0.5 mM positive compound 1-(6-chloro-3,4-methylenedioxybenzyl) ^-2 -carboxy-- ^5- ( ^2, ⁶ - dichloro-benzyloxy) indole NEB (Dairies 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 mM isoniazid and a blank solvent DMSO control. After incubating at 37 ° C for 48 h, the bacteriostatic sputum was observed, and the diameter of the inhibition zone of each compound was measured, and the average test result was obtained five times. The test results are shown in Table 1.

Inhibition of compounds against Mycobacterium phlei averaging diameter of bacteriostatic average diameter of bacteriostatic compounds compounds

(era) (cm) positive compound 2. 2 positive compound 2. 2 isoniazid 2. 3 isoniazid 2, 3 Example 1 0. 6 Example 14 0. 9 Example 2 1. 7 Example 15 0 5 Embodiment 3 2. 0 Example 16 0. 8 Example 4 1. 5 Example 17 0. 8 Example 5 1. 3 Example 18 0. 7 Example 6 1. 6 Example 19 0. 6 Example 7 1. 8 Example 20 0. 6 Example 8 2. 0 Example 21 0. 7 Example 9 1. 7 Example 22 1. 8 Example 10 1. 7 Example 23 2. 0 Example 11 1. 3 Example 24 2. 1 Example 12 0. 8 Example 25 0. 8 Example 13 1. 6 Example 26 1, 4

Claims

Rights request

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

among them:

Q is CH ₂ 0 or NH;

^ is aryl;

R ₂ is an aryl group. Alkyl or C ₄ - ₈ cycloalkyl.

Wherein "aryl ,, it refers to phenyl, or hydroxy, halogen, nitro, CF _3, methylenedioxy, ₆ alkyl, D- ₆ alkoxy substituent or a substituted phenyl.

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

1-- benzyl - 4- [4- (2,6-dichloro - benzyloxy) - benzyloxy] _ ⁵ - oxo _ ^2, ⁵ - dihydro - pyrrolo the I --3- acid;

4- [4- (2,6-dichloro - benzyloxy) - benzyloxy] -1-heptyl - 5-oxo - 2, ⁵ - dihydro - pyrrolo --3- acid;

4- [4- (2,6-dichloro - benzyloxy) - benzyloxy] - 1-octyl - 5-oxo - ^2, ^5-dihydro-_ -I-pyrrole-3-carboxylic acid;

4- [4- (2,6-dichloro - benzyloxy) - benzyloxy] -1-hexyl - 5-oxo-2, ⁵ - dihydro - pyrrolo --3- acid;

4-[4-(2,6-Dichloro-benzyloxy)-benzyloxy]-1-furan-2-ylmethyl- ⁵ -oxo Generation-2, 5-dihydro-1^pyrrole-3-carboxylic acid;

1-(2-Chloro-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydropyrrole-3-carboxylate Acid

1-(3-Chloro-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole- 3- Carboxylic acid

1_ (3-trifluoromethyl - benzyl) -4- [4- (2,6-dichloro - benzyloxy) - benzyloxy] - ⁵ - oxo - ² _, _ ^5-dioxo - pyrrole - 3-carboxylic acid;

1-(4-Chloro-benzyl)-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole- 3- Carboxylic acid

1-cyclohexylmethyl-4-[4-(2,6-dichloro-benzyloxy)-decyloxy]-5-oxo-2,5-dihydro-1^-pyrrole-3-carboxylate Acid

1-Benzo[1,3]dioxan-5-ylmethyl-4-[4-(2,6-dichloro-benzyloxy)-benzyloxy]-5-oxo- 2, 5-dihydro-pyrrole-3-carboxylic acid;

1-benzyl 4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-l^pyrrole-3-carboxylic acid;

1-(3-Chloro-benzyl)-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole-3- Carboxylic acid

1-Benzo[1,3]dioxane-5-ylmethyl-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo- 2, 5-dihydro-pyrrole-3-carboxylic acid;

4-[4-(3,5-Difluoro-benzyloxy)-benzyloxy]-1-heptyl-5-oxo-2,5-dihydro-pyrrole-3-carboxylic acid;

1-(2-Chloro-benzyl)-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydropyrrole-3-carboxylate Acid

1-cyclohexylmethyl-4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-1 1pyrrole-3-carboxylic acid ;

4-[4-(3,5-Difluoro-benzyloxy)-benzyloxy]-1-octyl-5-oxo- 2, 5-di Hydrogen - 1 ^"pyrrole-3-carboxylic acid;

1-(3-Trifluoromethyl-benzyl)- 4-[4-(3,5-difluoro-benzyloxy)-benzyloxy]-5-oxo-2,5-dihydro-pyrrole 3-carboxylic acid;

4-[4-(3,5-Difluoro-benzyloxy)-benzyloxy]-1-furan-2-ylindolyl-5-oxo-2,5-dihydropyrrole-3-carboxylic acid ;

4-[4-(2,6-Dichloro-benzyloxy)-aniline]-5-oxo-1-(3-trifluoromethyl-benzyl)-2,5-dihydropyrrole-3- Carboxylic acid

1-Benzo[1,3]dioxane-5-yl-indenyl-4-[4-(2,6-dichloro-benzyloxy)-aniline]-5-oxo- 2, 5 - dihydropyrrole-3-carboxylic acid;

4- [4- (2,6-dichloro - benzyloxy) - anilino] -1-octyl - ⁵ - oxo - ^2, ^{5-dihydro-pyrrol} _ --3- acid;

Or a pharmaceutically acceptable salt or hydrate thereof

3. The method for preparing a compound of the formula (I) according to claim 1,

For wherein Q is CH ₂ 0 in formula (I) compound, the method comprising the steps of:

(1) A CHZ benzyl halide and a hydroxy hydroxybenzaldehyde, wherein X is a halogen, as defined in the formula 1 of claim 1, are used as a starting material, and are treated in sodium hydride/DMF at -5 ° C and stirred. 5 hours; then reducing the product obtained by a reduction scheme with a hydride reducing agent such as sodium borohydride in a solvent such as methanol;

(2) under the protection of an inert gas such as nitrogen, wherein R _{2 is} as defined in formula 1 of claim 1 The defined formula R ₂ CHJ primary amine and ethyl acrylate are subjected to addition reaction under stirring at room temperature, and then condensation reaction is carried out with diethyl oxalate in a sodium ethoxide-ethanol basic system at reflux temperature, and then the product is obtained. Experience acidic hydrolysis;

(3) using a catalyst such as triphenylphosphine and diethyl azodicarboxylate to condense the product of step (1) and step (2) in a solvent such as THF and remove one molecule of water and make it a base Saponification of sodium hydroxide in a solvent such as methanol to give a compound of formula I wherein Q is CH ₂ 0, and 11 ₂ as defined in claim 1;

Alternatively, for a compound of formula (I) wherein Q is NH, the method comprises the steps of:

(1) reacting 2,6-dichlorobenzyl bromide and p-nitrobenzaldehyde in a sodium ethoxide-ethanol basic system at reflux temperature, and then reducing with a reducing agent such as stannous chloride in a solvent such as ethanol Product obtained;

(2) under the protection of an inert gas such as nitrogen, the addition reaction of R ₂ as a primary amine of formula R ₂ CH ₂ X and ethyl acrylate as defined in formula 1 with stirring at room temperature, followed by oxalic acid The ethyl ester is subjected to a condensation reaction in a sodium ethoxide-ethanol basic system at a reflux temperature, and the resulting product is subjected to acidic hydrolysis;

(3) condensing the product obtained in the step (1) and the step (2) with a catalyst such as acetic acid and removing 1 molecule of water, and then saponifying it with a base such as sodium hydrogencarbonate in a solvent such as THF and ethanol to obtain Q therein. For NH, ! ^ and R _{2 are} as defined in claim 1

(I) a compound.

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.