WO2006029575A1

WO2006029575A1 - NOVEL α-ALKYLOXY PROPIONIC ACIDS, THEIR PREPARATION METHODS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND THEIR USES

Info

Publication number: WO2006029575A1
Application number: PCT/CN2005/001483
Authority: WO
Inventors: Zongru Guo; Jun Feng; Fengming Chu; Yanshen Guo; Ying Lu; Piaoyang Sun; Yunshu Zhou; Kaihong Yuan; Yongjiang Chen
Original assignee: Institute Of Mataria Medica, Chinese Academy Of Medical Sciences; Jiangsu Hengrui Medicine Co., Ltd.
Priority date: 2004-09-17
Filing date: 2005-09-16
Publication date: 2006-03-23

Abstract

The present invention provides novel α-alkyloxy propionic acids of the formula: (I), stereo-, optical isomers and racemates thereof, as well as physiologically acceptable salts, solvates and crystalline forms thereof, their preparation methods, pharmaceutical compositions containing them, and the uses of the compounds in treating clinical conditions associated with insulin resistance.

Description

Novel α-alkoxypropionic acid compound, preparation method thereof and pharmaceutical composition and use thereof

This invention relates to novel α-alkoxypropionic acids of the general formula I, as well as their tautomers, enantiomers, diastereomers and physiologically acceptable salts. The use of these compounds in the treatment of diabetes, also relates to methods for their use, and pharmaceutical compositions containing the compounds. Background technique

The incidence of diabetes is on the rise globally. The number of people with diabetes accounts for about 2.3% of the world's total population, and is growing at a rate of 4-5%. The mortality rate of diabetes is high, for humans. Life health poses a serious threat (John M. Nuss et al. ANNUAL REPORTS IN MEDICINAL CHEMISTRY, 2000, Vol. 35, 211-218). Diabetes is usually divided into two categories: type I diabetes and type II diabetes. Type I diabetes (insulin-dependent diabetes mellitus, IDDM) is an immune disease in which pancreatic β-cell function is absent, and insulin-secreting cells are damaged, resulting in lower than normal plasma insulin levels. Type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM) is a disease caused by peripheral insulin resistance and needs to be treated by drugs that increase the body's sensitivity to insulin. In 1990, Issemann and Green reported the discovery of peroxisome proliferator-activated receptor (PPAR) (Issemann, I., Green, S. Nature, 1990, 347, 645-650) and divided it into α. Three types of γ, δ (David, J. et al., Cell, 1995, Vol. 83, 835-839). Molecular pharmacology studies have shown that PPAR/ is an important target for the treatment of type 2 diabetes drugs. Studies have shown that thiazolidinediones (TZDs) have a high affinity for PPAR/y and act by activating ΡΡΑΙΙγ after entering the body (Shao D et al. J Biol Chem, 1997, 272, 21473). PPAR is in the nucleus and is a member of the nuclear receptor superfamily. After entering the nucleus, the TZDS compound binds to the ligand binding region of the PPARY C-terminus (Ligand Binding Domin, LBD), activates PPARy, and activates factor II at the end of the sequence. Activating fonction-2, AF-2) changes in conformation, and activated PPARy and activated RXR (retinoic acid X receptor) bind to form a heterodimer and then recognize its peroxisome proliferator-responsive element (PPRE) The function of the DNA Binding Domain (DBD) and the target gene-specific DNA sequence (AGGACT) to activate the target gene, regulate the transcription of the target gene, control protein synthesis, and produce different biological effects. . The first commercially available thiazolidinedione anti-type 2 diabetes drug was troglitazone, which was marketed by Sankyo in 1996. Takeda's pioglitazone and Sike's rosiglitazone were also marketed in 1999. In addition to the severe hepatotoxicity of troglitazone, it was discontinued, and the other two drugs were listed. At the forefront of the world's best-selling drugs To this target, scientists have developed new PPARy agonists and resolved the crystal structure of ligand-receptor complexes. Thiazolidinedione compounds, isoxazole-3,5-dione compounds, 1,3-dicarboxylic acid compounds, α-substituted carboxylic acid compounds, L-tyrosine compounds, etc. Very good combination.

With further research, there has been an updated understanding of PPAR receptor ligands. Clinical application shows that selective PPARY agonists such as rosiglitazone and pioglitazone have side effects that cause obesity and cause cardiovascular disease while treating diabetes and lowering blood sugar. The mechanism of action of lipid-lowering drugs such as clofibrate is Because of the agitation of PPARa receptors, it lowers blood lipids and reduces obesity. Therefore, the simultaneous stimulation of PPARY and PPARa substances should be a therapeutic drug for a new generation of type 2 diabetes that produces fewer side effects. A typical dual agonist such as AZ242, which is an et-substituted phenylpropionic acid compound, binds to PPAR and ΡΡΑΙΙγ with EC _5Q of Ι.ΟμΜ and 0.2 μΜ, respectively, and promotes gene transcription with ED ₅ o of 1.2 μΜ and 1.3 μΜ, respectively. . It is effective in reducing blood fat and losing weight when treating diabetes. It has now entered the clinical phase III study. The present invention is directed to the design of dual agonists that synthesize PPAR _Y and c. According to the structure of PPAR receptor, a virtual compound library was constructed by computer simulation using virtual simulation method. The DOCK virtual screening was used to screen out the theoretically strong compounds from the virtual database, and the compounds were synthesized and evaluated. Its activity. Summary of the invention

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel α-nonoxypropionic acid compound of the formula I.

Another object of the present invention is to provide a process for producing an α-pyroxypropionic acid compound represented by Formula I and an analog thereof. A further object of the invention is to provide the use of a compound of formula I for stimulating a peroxisome proliferator-activated receptor (PPAR) and for use in a medicament for the treatment of a disease associated with PPAR.

In order to accomplish the object of the present invention, the present invention employs the following technical solutions: In particular, the present invention relates to a compound of formula I and its racemate, enantiomer, physiologically acceptable salt, solvate And crystalline form,

Where: -

B is selected from the group consisting of a carbocyclic ring having 5 or 6 carbon atoms and a heterocyclic ring number 1-4 (wherein the hetero atoms may be the same or different, and the hetero atom is selected from oxygen, nitrogen or sulfur).

Preferred B is selected from the group consisting of a carbon ring of 6 carbon atoms and a heterocyclic ring containing a hetero atom, '

More preferably, B is selected from the group consisting of a benzene ring and a hetero ring containing a nitrogen atom; n is selected from an integer of 1 to 4,

Preferably n is selected from 2 or 3,

More preferably n is selected from 2;

X is selected from 0, S, NH, CH ₂ , CH(OH), CO or -CH=CH-,

Preferred X is selected from the group consisting of 0, S, NH, CO

More preferably X is selected from O;

Rl is selected from the group consisting of hydrogen, halogen, cyano, -6 alkyl, C ₆ methoxy, Q- ₆ alkylthio, carboxy, alkoxycarbonyl, R7NHCO-

(R7 is selected from H, C _1-6 fluorenyl), CF ₃ ,

Preferred R1 is selected from the group consisting of hydrogen, halogen, cyano, -6 alkyl, d- ₆ methoxy, carboxy, R7NHCO- (R7 is selected from _C1-4 fluorenyl), more preferably R1 is selected from hydrogen, halogen, Cyano, alkyl, C _1-4 alkoxy, carboxy,

Most preferably R1 is selected from the group consisting of hydrogen, bromine, cyano, C _1-3 fluorenyl, C _1-3 alkoxy, carboxy,

R2 is selected from the group consisting of hydrogen, halogen, d. ₆ alkyl, C _1-6 alkoxy, d- ₆ alkylthio, CF ₃ , Preferred R2 is selected from the group consisting of hydrogen, CM alkyl, d. ₄ alkoxy,

Most preferably R2 is selected from the group consisting of hydrogen, methyl, _-3 alkyl,

YR3 is located in the ortho, meta or para position and is different from A.

Wherein Y is selected from the group consisting of 0, S, C _1-6 alkyl,

Y is selected from the group consisting of 0, S, C _1-3 thiol, .

More preferably Y is selected from 0, s,

Most preferably Y is selected from 0;

R3 is selected from the group consisting of hydrogen, d- ₆ alkyl, -6 alkoxy, d- ₆ thiol

Preferred R3 is selected from the group consisting of hydrogen, d- ₃ fluorenyl, C _1-3 alkoxy, C _W thiol

More preferably, R3 is selected from the group consisting of hydrogen, methyl, methoxy;

A selected from

Located in the ortho, meta or para position,

Preferably located in the meta or para position,

Medium,

R4 is selected from H, C _r6 fluorenyl, and preferably R4 is selected from H;

R5 is selected from the group consisting of H, C ₁₂ alkyl, . ₁₂ decyloxy, _{-12 12} cyclodecyl, C _3-12 cyclodecyloxy, halogen substituted alkoxy or cyclodecyloxy, or various substitutions and positions Different aryloxy or aryloxyoxy groups,

Preferred R5 is selected from the group consisting of H, C _1-6 alkyl, C _1-6 alkoxy, C _3-12 cyclodecyl, C _3. ₁₂ cycloalkoxy,

More preferred R5 is selected from methoxy, ethoxy, phenoxy, naphthoxy, tetrahydronaphthalene group, tolyl group, methoxyphenyl, CF _3,

R6 is selected from the group consisting of hydrogen, hydroxy, -6 alkoxy, C ₃ _-8 cycloalkoxy, H ₂ , NHR7, R8R9, NHOH, NHORIO (R7-10 is selected from the group consisting of ₄ fluorenyl).

Preferred R6 is selected from hydroxy, NHOH, C _1-4 alkoxy, C ₃ - ₈ cycloalkyl group,

More preferably R6 is selected from the group consisting of hydroxyl, NHOH, for the purpose of the present invention, preferred compounds include, but are not limited to, compounds of formula IA

IA

Wherein R1 is selected from the group consisting of hydrogen, -6 alkyl, d- ₆ alkoxy, cyano, carboxy, halogen;

R2 is selected from the group consisting of hydrogen, halogen, _.6 alkyl, d. ₆ alkoxy;

Y is selected from S, 0

R3 is selected from the group consisting of hydrogen, _-6 alkyl, d- ₆ methoxy;

R4 is selected from the group consisting of H, Q-6 alkyl;

R5 is selected from a ₆ -alkoxy group, a substituted or unsubstituted phenoxy group (the substituent on the benzene ring is selected from a C ₆ fluorenyl group, a Q 6 fluorenyloxy group), a naphthyloxy group, a tetrahydronaphthyloxy group;

R6 is selected from hydroxy, hydroxy, NHOH, C ₆ alkoxy, C ₃ - ₈ cycloalkyl group. For the purposes of the present invention, more preferred compounds include, but are not limited to, the compounds of formula IAA-

IAA

among them, .

R1 is selected from the group consisting of hydrogen, methyl, methoxy, cyano, carboxyl, halogen;

R2 is selected from the group consisting of hydrogen and methyl;

Y is selected from S, 0;

R3 is selected from the group consisting of hydrogen and methoxy;

R5 is selected from -6 alkoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from -6 fluorenyl, -6 alkoxy), naphthyloxy, tetrahydronaphthyloxy;

R6 is selected from the group consisting of hydroxyl groups and NHOH;

R11 is selected from the group consisting of d-3 alkyl and -3 alkoxy. For the purposes of the present invention, more preferred compounds include, but are not limited to, the compounds of formula IAB:

among them,

Rl is selected from the group consisting of hydrogen, methyl, methoxy, cyano, carboxyl, halogen;

R2 is selected from the group consisting of hydrogen and methyl;

Y is selected from S, 0;

R3 is selected from the group consisting of hydrogen and methoxy;

R5 is selected from the group consisting of d- ₆ methoxy, substituted or unsubstituted *oxy (substituents on the phenyl ring are selected from - ₆ fluorenyl, d- ₆ alkoxy), naphthyloxy, tetrahydronaphthyloxy;

R6 is selected from the group consisting of hydroxyl groups and NHOH;

R11 is selected from the group consisting of fluorenyl and -3 alkoxy. For the purpose of the present invention, preferred compounds include, but are not limited to, compounds as shown in Formula IB.

Wherein R1 is selected from the group consisting of hydrogen, C ₆ fluorenyl, - ₆ decyloxy, cyano, carboxy, halogen;

R2 is selected from the group consisting of hydrogen, halogen, Q. ₆ alkyl, d. ₆ methoxy;

Y is selected from S, 0

R3 is selected from the group consisting of hydrogen, -6 fluorenyl, and d- ₆ alkoxy;

R4 is selected from the group consisting of H and d-6 fluorenyl;

R5 is selected from the group consisting of d- ₆ alkoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from -6 alkyl, Q- ₆ methoxy), naphthyloxy, tetrahydronaphthyloxy;

R6 is selected from hydroxyl, hydroxyl, d- ₆ embankment group, C ₃ - ₈ cycloalkyl group. For the purposes of the present invention, preferred compounds include, but are not limited to, compounds as shown in Formula IC

R2 is selected from the group consisting of hydrogen, halogen, C ₆ fluorenyl, C _W alkoxy;

Y is selected from S, 0

R3 is selected from the group consisting of hydrogen, Q- ₆ alkyl, Q- ₆ methoxy;

R4 is selected from the group consisting of H, Ct- ₆ alkyl;

R5 is selected from the group consisting of d- ₆ alkoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from _-6 alkyl, d- ₆ alkoxy), naphthyloxy, tetrahydronaphthyloxy;

R6 is selected from hydroxyl, hydroxyl, Ci- ₆ alkoxy, C ₃ - ₈ cycloalkyl group embankment. For the purposes of the present invention, preferred compounds include, but are not limited to, compounds of the formula ID

Wherein R1 is selected from the group consisting of hydrogen, C ₆ alkyl, - ₆ decyloxy, cyano, carboxy, halogen;

R2 is selected from the group consisting of hydrogen, halogen, Ci.6 alkyl, _.6 methoxy;

Y is selected from S, 0

R3 is selected from hydrogen, - ₆ alkyl with, -6 alkoxy;

R4 is selected from the group consisting of H, _-6 alkyl;

R5 is selected from the group consisting of d- ₆ methoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from C ₆ alkyl, _-6 alkoxy), naphthyloxy, tetrahydronaphthyloxy;

R6 is selected from hydroxy, hydroxy, - ₆ alkoxy, C ₃ - ₈ cycloalkyl group embankment. For the purposes of the present invention, preferred compounds include, but are not limited to, compounds as shown in Formula IE

Wherein R1 is selected from the group consisting of hydrogen, Q- ₆ fluorenyl, d- ₆ alkoxycyano, carboxy

R2 is selected from the group consisting of hydrogen, halogen, C _w fluorenyl, C _w decyloxy; Y is selected from s, o

R3 is selected from the group consisting of hydrogen, - ₆ fluorenyl, - ₆ alkoxy;

R4 is selected from the group consisting of H, d-6 alkyl;

R5 is selected from the group consisting of d- ₆ alkoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from - ₆ fluorenyl, d- ₆ alkoxy), naphthyloxy, tetrahydronaphthyloxy;

R6 is selected from hydroxyl, hydroxyl, d- ₆ alkoxy, C ₃ - ₈ cycloalkyl group embankment. Preferred compounds include, but are not limited to, compounds of formula IF for the purposes of the present invention.

Wherein R1 is selected from the group consisting of hydrogen, -6 alkyl, - ₆ decyloxy, cyano, carboxy, halogen;

R2 is selected from the group consisting of hydrogen, halogen, C^ fluorenyl, CL ₆ decyloxy;

Y is selected from S and 0.

R3 is selected from the group consisting of hydrogen, C _R6 alkyl, d- ₆ methoxy;

R4 is selected from the group consisting of H, C _R6 alkyl;

(Substituted on the benzene ring is selected from Q-6 alkyl with, Q- ₆ embankment yloxy) -6 embankment group selected from R5, a substituted or unsubstituted phenoxy, naphthyloxy, tetrahydronaphthalene group;

R6 is selected from hydroxyl, hydroxyl, d- ₆ alkoxy, C ₃ - ₈ cycloalkyl group embankment. For the purposes of the present invention, preferred compounds include, but are not limited to, the compounds of formula IG:

Wherein R1 is selected from the group consisting of hydrogen, d- ₆ fluorenyl, -6 fluorenyloxy, cyano, carboxy, halogen;

R2 is selected from the group consisting of hydrogen, halogen, .6 fluorenyl, Ci. ₆ alkoxy;

Y is selected from S, 0

R3 is selected from the group consisting of hydrogen, d- ₆ alkyl, -6-decyloxy;

R4 is selected from the group consisting of H, _-6 alkyl;

R5 is selected from - ₆ methoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from C ₆ fluorenyl, Q-6 fluorenyloxy), naphthyloxy, tetrahydronaphthyloxy;

R6 is selected from hydroxyl, hydroxyl, d- ₆ alkoxy, C ₃ - ₈ cycloalkyl group. 05 001483 For the purposes of the present invention, preferred compounds include, but are not limited to, the compounds of formula IH:

IH

Wherein R1 is selected from the group consisting of hydrogen, d- ₆ alkyl, -6 methoxy, cyano, carboxy, halogen;

R2 is selected from the group consisting of hydrogen, halogen, .6 alkyl, C decyloxy;

Y is selected from S, 0

R3 is selected from the group consisting of hydrogen, d- ₆ alkyl, d- ₆ alkoxy;

R4 is selected from the group consisting of H and -6 fluorenyl;

R5 is selected from a ₆ -alkoxy group, a substituted or unsubstituted phenoxy group (the substituent on the benzene ring is selected from the group consisting of Q- ₆ -yl, Q- ₆ alkoxy), naphthyloxy, tetrahydronaphthyloxy;

R6 is selected from hydroxyl, hydroxyl, d-6 alkoxy, C ₃ - ₈ cycloalkyl group.

The halogens described in the present invention are fluorine, chlorine and bromine. The invention also provides a process for the preparation of a compound of the invention, which comprises reacting a compound of the formula IV with a compound of the formula V, a compound of the formula VI, and a compound of the formula W to form a compound of the formula ffl, which is subsequently reacted by hydrolysis, reduction or the like. A compound of formula K or X; or a compound of formula VI and a compound of formula W are first condensed, followed by a compound of formula IV and a compound of formula V to form a compound of formula Vff1, followed by a reaction of hydrolysis, reduction or the like to form a compound of formula Κ or X.

VII

Wherein Α, Β, X, Y, Rl, R2, R3, R4, R5, R6, n are as defined in claim 1, and 卩, Q represent Departing group

The P and Q are selected from the group consisting of -OH and halogen.

The condensation of V and VI is carried out by the action of a base using tetrabutylammonium bromide as a catalyst.

The condensation of IV and (V + VI) is carried out in the action of a base.

The condensation of (IV + V + VI ) and VII is carried out in the presence of potassium t-butoxide.

The hydroxamic acid derivative is prepared by reacting the corresponding acid with isobutyl chloroformate in the presence of triethylamine, followed by the addition of a hydroxylamine methanol solution.

The reduction reaction is hydrogenation using Pd/C.

Optically pure isomers of the compound of formula I can be prepared using racemic unresolved or optically active starting materials in the synthesis.

The invention therefore also relates to a pharmaceutical composition comprising as an active ingredient a compound of the invention and a conventional pharmaceutical excipient or adjuvant. The pharmaceutical composition of the present invention usually contains 0.1 to 95% by weight of the compound of the present invention.

Pharmaceutical compositions of the compounds of the invention can be prepared according to methods well known in the art. When used for this purpose, the compounds of the invention may be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants, if desired, in a suitable form or dosage for use as a human or veterinary drug. form.

The compound of the present invention or a pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as orally, muscle, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum.

The administration route of the compound of the present invention or a pharmaceutical composition containing the same can be administered by injection. Injections include intravenous, intramuscular, subcutaneous, intradermal, and acupoint injections.

The dosage form can be a liquid dosage form or a solid dosage form. For example, the liquid dosage form may be a true solution type, a colloid type, a microparticle dosage 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, and the like.

The compounds of the present invention can be formulated into common preparations, sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.

In order to form a unit dosage form into tablets, various carriers well known in the art can be widely used. Examples of the carrier are, for example, a diluent and an absorbent such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid. Aluminum, etc.; wetting agent and binder, such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, sugar, honey, glucose solution, gum arabic, gelatin, carboxymethyl cellulose Sodium, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents, such as dried starch, alginate, agar powder, brown algae Powder, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors, such as sucrose, Tristearate, cocoa butter, hydrogenated oil, etc.; absorption enhancers such as quaternary ammonium salts, sodium decyl sulfate, etc.; lubricants such as talc, silica, corn starch, stearates, Boric acid, liquid paraffin, polyethylene glycol, and the like. Tablets may also be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.

For example, in order to prepare a drug delivery unit into a pellet, various carriers known in the art can be widely used. Examples of the carrier are, for example, a diluent and an absorbent such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc, etc.; binders such as gum arabic, tragacanth, Gelatin, ethanol, honey, liquid sugar, rice paste or batter; etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfonate, methyl cellulose, ethyl cellulose, and the like.

For example, in order to encapsulate the administration unit, the active ingredient compound of the present invention is mixed with the various carriers described above, and the resulting mixture is placed in a hard gelatin capsule or soft capsule. The active ingredient of the compound of the present invention can also be formulated into a microcapsule, suspended in an aqueous medium to form a suspension, or can be enclosed in a hard capsule or used as an injection.

For example, the compound of the present invention is formulated into an injectable preparation such as a solution, a suspension solution, an emulsion, or a lyophilized powder injection, which may be aqueous or non-aqueous, and may contain one and/or more drugs. A pharmaceutically acceptable carrier, diluent, binder, lubricant, preservative, surfactant or dispersing agent. For example, the diluent may be selected from the group consisting of water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, and the like. Further, in order to prepare an isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and a conventional cosolvent, a buffer, a pH adjuster or the like may be added. These excipients are commonly used in the field.

In addition, coloring agents, preservatives, perfumes, flavoring agents, sweeteners or other materials may also be added to the pharmaceutical preparations as needed.

The pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect. The dosage of the pharmaceutical composition of the compound of the present invention depends on many factors such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the number of administrations, For therapeutic purposes, the therapeutic dose of the present invention can vary widely. In general, the dosages of the pharmaceutical ingredients employed in the present invention are well known to those skilled in the art. The prophylactic or therapeutic effect of the present invention can be accomplished by appropriately adjusting the amount of the actual drug contained in the final formulation of the compound composition of the present invention to achieve its therapeutically effective amount. A suitable dosage range per day of the compound of the present invention is from 0. 001 to 150 mg/kg body weight, preferably from 0.1 to 100 mg/kg body weight, more preferably from 1 to 60 mg/kg body weight, most preferably 2 — 30mg/Kg body weight. The above dosages may be in the form of a single dose or divided into several, for example Administration in two, three or four dosage forms is limited by the clinical experience of the administering physician and the dosing regimen including the use of other therapeutic means.

The total dose required for each treatment can be divided into multiple or single dose administrations. The compounds or compositions of this invention may be administered alone or in combination with other therapeutic or symptomatic agents and adjusted in dosage. Pharmacological studies have shown that the compound of the formula I of the present invention has an activity of activating PPAR, and for type II diabetes caused by insulin resistance, the compound can improve the body's sensitivity to insulin, thereby achieving therapeutic purposes.

In addition, with further research, PPAR agonists have been found to have effects on many diseases such as hypertension, hyperlipidemia, atherosclerosis, inflammation, and tumors, and PPAR agonists can treat diseases associated with them. Detailed ways

The invention is further illustrated by the following examples, but these examples do not limit the scope of the invention. The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS) or high resolution mass spectrometry (HRMS). The NMR shift (δ) is given in parts per million (ppm). Mp is the defect given by Ό, and the temperature is not corrected. Column chromatography generally uses 200-300 mesh silica gel as a carrier. The NMR measurement was performed using INOVA-500, the solvent was determined to be CDC1 ₃ , DMSO-D ₆ , the internal standard was TMS, and the chemical shift was given in ppm. The measurement of MS was carried out using a VG-ZAB-2F 200C mass spectrometer.

Abbreviation:

TLC: thin layer chromatography;

DMSO: dimethyl sulfoxide;

CDC13: deuterated chloroform;

DMF: Ν, Ν'-dimethylformamide;

Min: minute; h: hour.

Example 1

2-methoxy-344-"2-" fluorenyl) ethoxy 1phenyl} acrylic acid

a) ethyl methoxyacetate

Methoxyacetic acid (38.4 ml, 0.5 mol) was dissolved in 200 ml of ethanol, 2% (calculated by methoxyacetic acid) of 4 g of crystalline ferric sulfate and 0.5 ml of concentrated sulfuric acid were added, and the mixture was heated to reflux for 20 hours, and the reaction was monitored by TLC. end. Stop the reaction, concentrate to remove most of the 005 001483 Ethanol, distilled under reduced pressure, afforded 32 g of colorless liquid, yield 54%. (Acros: 44-45.4 ° C / 9mraHg)

b) 4-(2-bromoethoxy)benzaldehyde

P-hydroxybenzaldehyde (97.696g, 0.9mol), 1,2-dibromoacetamidine (156ml, 1.8mol) and a catalytic amount of tetrabutylammonium bromide were mixed and placed in a 500ml three-necked flask. The oil bath was heated to 100 ° C, and a pre-formulated 10% aqueous sodium hydroxide solution (42 g, 1.05 mol) was added dropwise. After the addition, the reaction was continued for 7 hours, and the reaction was monitored by TLC. The reaction mixture was poured into water, extracted with EtOAc EtOAc (EtOAc m. Ethyl ester = 7:1 gave a white solid, 105 g, yield 57.3%.

c) 4-[2-(1-indolyl)ethoxy]benzaldehyde

Bismuth (2.67 g, 22.8 mmol) and powdered potassium hydroxide (1.919 g, 34.2 mmol) were dissolved in 20 ml of dimethyl sulfoxide, and after 10 minutes, 4-(2-bromoethoxy)benzaldehyde was added ( 5.74 g, 25 mmol), reacted at room temperature for 3 hours, and the reaction was monitored by TLC. The reaction mixture was poured into water, EtOAc was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj :1, obtained white solid 3.326g, yield 55%, mp: 92.8~93.6. C.

'HNMRCCDCb, 300MHz) δ ppm: 9.863(s, 1H, CHO), 7.79 l(d, 2H, J=8.7Hz, ArH), 7.64 l(d, 1H, J=8.1Hz, ArH), 7.413(d , 1H, J=8.1Hz, ArH), 7.256(d, 1H, J=7.2Hz, ArH), 7.207(d, 1H, J=3.3Hz, ArH), 7.128(d, 1H, J-7.2Hz, ArH), 6.935(d, 2H, J=8.7Hz, ArH), 6.528(d, 1H, J=3.3Hz, ArH), 4.572(t, 2H, J=8.4Hz, -OCH2-), 4.359(t , 2H, J=8.4Hz, -NCH ₂ -)

d) 2-methoxy-3{4-[[2-(l-fluorenyl)ethoxy]phenyl]acrylic acid

4-[2-(1-Indolyl)ethoxy]benzaldehyde (2.122 g, 8 mmol) and ethyl methoxyacetate (0.945 g, 8 mmol) were dissolved in 20 ml of dry DMF under ice bath 8 ml of a solution of potassium tert-butoxide in t-butanol (concentration of 1 mol/L) was slowly added dropwise, and the mixture was stirred at room temperature for 4 hours to complete the reaction. The reaction mixture was adjusted to pH=7 with glacial acetic acid, poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate (MgSO4jjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 52.6 %.

0.8 g of this compound was dissolved in 30 ml of ethanol, 20 ml of 10% aqueous solution of sodium hydroxide was added, and the mixture was heated under reflux for 3 hours. The solvent was evaporated, hydrochloric acid was adjusted to pH=1, poured into water, and extracted with ethyl acetate. Drying over anhydrous sodium sulfate, EtOAc EtOAc (EtOAcjjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH C c

1H NMR (DMS0, 300 ΜΗζ) δ ppm: 7.67 l (d, 2H, J = 8.7 Hz, ArH), 7.562-7.512 (t, 2H, ArH), 7.415 (d, 1H, J = 3.3 Hz, ArH), 7.132 (t, 1H, J=7.5Hz, ArH), 7.006 (t, 1H, J=7.5Hz, ArH), 6.904(d, 2H, J=8.7Hz, ArH), 6.853(s, 1H, =CH- ), 6.430 (d, 1H, J = 3.3 Hz, ArH), 4.586 (t, 2H, J = 5.1 Hz, -OCH ₂ -), 4.316 (t, 2H, J = 5.1 Hz, -NCH ₂ -), 3.647(s, 3H, OCH ₃ ) T N2005/001483

MS (FAB): 338 (M+1), 337 (M), 144,130

HRMS (FAB): C ₂₀ Hi ₉ NO ₄ (M), found: 337.132339 (M), Calculated: 337.131408 (M) Example 2:

2-ethoxy-3-{4-"2-(1" fluorenyl)ethoxy 1phenyl}acrylic acid

a) Ethoxyethyl acetate

Ethoxyacetic acid (28.3 ml, 0.3 mol) was dissolved in 200 ml of ethanol to give ethyl ethoxyacetate as a colorless liquid (yield: 70.6%). (Acros: 156 ° C)

b) 2-ethoxy-3-{4-[ ^2- (1-indolyl)ethoxy]phenyl}acrylic acid

Prepared according to the procedure described in Example Id), 4-[2-(1-indolyl)ethoxy]benzaldehyde (1.592 g, 6 mmol) and ethyl acetate (0.872 g, 6.6 irnnol) The title compound was 391 mg of white crystals, mp. mp. 134-147.

lHNMR (DMSO, 300MHz) δ ppm: 7.705 (d, 2H, J = 8.7 Hz, ArH), 7.560-7.510 (t, 2H, ArH), 7.453 (d, IH, J-3.3HZ, ArH), 7.130 ( t, IH, J=7.8Hz, ArH), 7.005(t, IH, J-7.8Hz, ArH), 6.900(d, 2H, J=8.7Hz, ArH), 6.858(s, IH, =CH-) , 6.428(d, IH, J=3.3Hz, ArH), 4.568(t, 2H, J=5.1Hz, -OCH ₂ -), 4.314(t, 2H, J=5.1Hz, -NCH ₂ -), 3.902 (q, 2H, J=7.2Hz, OCH ₂ -), 1.231(t, 3H, J=7.2Hz, -CH ₃ )

MS (FAB): 352 (M+1), 351 (M), 144,130

HRMS (FAB): C ₂₁ H ₂ iN0 ₄ (M), found: 35 U 44 875 (M), Calculated: 35U47058 (M) Example 3:

2-phenoxy-3-{4-"2-(l-fluorenyl)ethoxy 1phenyl}acrylic acid

a) Ethyl phenoxyacetate

Phenol (9.882 g, 105 mmol) and anhydrous potassium carbonate (20.73 g, 150 mmol) were dissolved in 50 ml of acetone, and ethyl chloroacetate (10.75 ml, 100 ml) was slowly added dropwise at room temperature, and the reaction was continued at room temperature. After 8 hours, TLC monitored the reaction completely. The reaction mixture was filtered, and the solvent was evaporated, evaporated, evaporated, evaporated. (136°C/19ramHg) N2005/001483 b) 2-phenoxy-3-{4-[2-(1-indolyl)ethoxy]phenyl}acrylic acid

The title was prepared by the method described in Example Id) using 4-[2-(1-indolyl)ethoxy]benzaldehyde (366 mg, 1.38 mmol) and ethyl phenoxyacetate (249 mg, 1.38 mmol). The compound is 107 mg of white crystals, the yield of condensation and hydrolysis is 25%, mp: 147.2-149.7 ° C o

1H NMR (CDC1 ₃ , 300 ΜΗζ) δ ppm: 7.617 (d, 2H, J = 8.7 Hz, ArH), 7.414-7.213 (m, 6H, ArH), 7.173 (d, 1H: J = 3.3 Hz, ArH), 7.103 (t, IH, J=7.5Hz, ArH), 7.052(s, IH, =CH-), 7.00 l(t, IH, J-7.5Hz, ArH), 6.783(d, 2H, J=8.7Hz, ArH), 6.495 (d, IH, J = 3.3 Hz, ArH), 4.508 (t, 2H, J = 5.7 Hz, -OCH ₂ -), 4.263 (t, 2H, J = 5.7 Hz, -NCH ₂ -)

MS (EI): 399(M), 144,130 Example 4:

2-phenoxy-3-i4-f2-(l-fluorenyl)ethoxy 1phenyl) propylene hydroxamic acid

a) Hydroxylamine methanol solution

Hydroxylamine hydrochloride (139 mg, 2 mmol) was dissolved in 5 ml of anhydrous methanol, and an equivalent of potassium hydroxide solid was added. After stirring at room temperature for 10 minutes, the precipitated solid was filtered off and the filtrate was taken.

b) 2-phenoxy-3-{4-[2-(1-indolyl)ethoxy]phenyl}propene hydroxamic acid

2-Phenoxy-3-{4-[2-(1-indolyl)ethoxy]phenyl}acrylic acid (200 mg, 0.5 mmol) and triethylamine (55 mg, 0.5 mmol) were dissolved in 10 ml of tetrahydrofuran. Isobutyl chloroformate (68rrig, 0.5mmol) was slowly added dropwise, stirring was continued for 10 minutes, the precipitated solid was filtered off, and then the pre-formed hydroxylamine methanol solution was added to the filtrate at one time. The reaction was completely monitored by TLC, and the reaction was carried out conventionally. The residue was separated on a white solid (yield: m.

300MHZ) δ ppm: 10.975(s, IH, -OH), 8.982(s, IH, -OH), 7.533-7.493(dd, 4H, ArH), 7.377(d, IH, ArH), 7.295(t, 2H , ArH), 7.105(t, IH, ArH), 7.029-6.939(m, 5H, ArH, =CH-), 6.838(d, 2H, J 9.0Hz, ArH), 6.404(d, IH, ArH), 4.527 (t, 2H, J = 5.4 Hz, -OCH ₂ -), 4.263 (t, 2H, J = 5.4 Hz, -NCH ₂ -). MS (ESI): 415 (M+1), 102 Example 5 :

2-fa-naphthyloxy)-3-{4-"2-indolyl-indenyl)ethoxy 1phenyl)acrylic acid

a) α_Naphthyloxyacetate

According to the procedure described in Example 3a), a light brown solid of ethyl phthalocyanate, 15.324 g, was obtained from ct-naphthol (14.417 g, 100 mmol), yield 66.6%.

b) 2-(α-naphthyloxy)-3-{4-[2-(1-indolyl)ethoxy]phenyl}acrylic acid

4-[2-(1-indolyl)ethoxy]benzaldehyde (1.592 g, 6 mmol) and ethyl α-naphthyloxyacetate (1.52 g, 6.6 mmol) according to the procedure of Example Id) The title compound was obtained as white crystal 543mg, mp.

115-117 ° C c

'HNMR (DMSO, 300 MHZ) δ ppm: 8.312-8.280 (m, 1H, ArH), 7.912-7.880 (m, 1H, ArH), 7.569-7.459 (m, 7H, ArH), 7.338 (d, 1H, J =3.3Hz, ArH), 7.280(t, 1H, ArH), 7.222(s, 1H, =CH-), 7.104(t, 1H, ArH), 6.968(t, 1H, ArH), 6.778(d, 2H , ArH), 6.690(d, 1H, ArH), 6.378(d, 1H, J=3.3Hz, ArH), 4.484(t, 2H, J=5.4Hz, -OCH ₂ -), 4.218(t, 2H, J=5.4Hz, -NCH ₂ -).

MS (FAB): 450 (M+1), 144, 130 Example 6:

2-Π3-naphthyloxy)-3-{4-"2-(lB fluorenyl)ethoxy 1 phenyl acrylate

a) β-naphthyloxyacetate

According to the method described in Example 3a), β-naphthol (47.58 _g , 330 mmol) of a white solid β-naphthylacetate 54 g was obtained in a yield of 7 U.

b) 2-(β-naphthyloxy)-3-{4-Γ2-(1-indenyl)ethoxy 1phenyl }acrylic acid

According to the method described in Example Id), 4-[2-(1-indolyl)ethoxy]benzaldehyde (2.918 g, llmmol) and β-naphthyloxyacetate (2.763 g, 12 mmol) were obtained. -(β-naphthyloxy)-3-{4-[2-(1-indolyl)ethoxy]phenyl}ethyl acrylate, while giving another white solid, 57 mg, yield 1.0%, mp : 119.7-121.9 ° C, the compound is 2-(β-naphthyloxy)-3-{4-[2-(1-indolyl)ethoxy]phenyl}-butyl acrylate, ¹ H NMR (CDC1 ₃ , 300MHz) δ ppm: 7.819-7.789(m, 2H, ArH), 7.666-7.591(m, 4H, ArH), 7.412-7.088(m, 9H, ArH, -CH=), 6.767(d, 2H, ArH), 6.48 l(d, 1H, ArH), 4.491(t, 2H, -C3⁄4), 4.247(t, 2H, -CH ₂ ), 1.316(s, 9H, 3 X -CH ₃ ). MS (EI): 505(M). N2005/001483 Hydrolysis of ethyl 2-(β-naphthyloxy)-3-{4-[2-(l,indolyl)ethoxy]phenyl}acrylate to give the title compound as white crystals. g, condensation, hydrolysis two-step yield of 52.8%, mp: 200-210 ° C.

^MRCCDCls, 300MHz) δ ppm: 7.829-7.767(t, 2H, ArH), 7.646(d, 2H, J=8.7Hz, ArH), 7.613-7.063(m, 11H, ArH), 6.770(d, 2H, J=8.7Hz, ArH), 6.478(d, 1H, ArH), 4.49 l(t, 2H, J=5.7Hz, -OCH ₂ -), 4.249(t, 2H, J=5.7Hz, -NCH ₂ - )

MS (FAB): 450 (M+1), 449 (M), 144, 130 Example 7:

2-φ-naphthyloxy)-344-"2-α-fluorenyl)ethoxy 1phenyl}propionic acid

Ethyl 2-(β-naphthyloxy)-3-{4-[2-(1′ 哚哚)ethoxy]phenyl}acrylate obtained in 6b) was dissolved in 50 ml of absolute ethanol. And add 1 teaspoon of 10% Pd/C (100mg), medium pressure hydrogenation (pressure is 3.5bar), heat to 70V with heating jacket, continuous reaction for 2 days, separation by atmospheric pressure column chromatography (PE: EA= 4:1), the product 2-(β-naphthyloxy)-3-{4-[2-(lH fluorenyl)ethoxy]phenyl}propanoic acid ethyl ester 580 mg, yield 58%. Mp: 76-81 ° C. Take 280 mg of the compound directly for hydrolysis, dissolve it in 50 ml of ethanol, add 20 ml of 10% aqueous solution of sodium hydroxide, heat to reflux for 3 hours, distill off the solvent, adjust the pH of the hydrochloric acid solution. The title compound is obtained as a beige solid, 176 mg, EtOAc, EtOAc, EtOAc, EtOAc The yield was 62.5%, mp: 102-104 °C.

1HNMR (DMS0, 300MHz) S ppm: 7.727 (t, 2H, ArH), 7.63 l (d, 1H, ArH), 7.506 (d, 2H, J = 8.7 Hz, ArH), 7.377 (d, 1H, J = 3.3Hz, ArH), 7.350(d, IH, ArH), 7.260(t, 1H, ArH), 7.193(d, 2H, ArH), 7.128-6.959(m, 4H, ArH), 6.747(d, 2H, J = 8.7 Hz, ArH), 6.403 (d, IH, J-3.3 Hz, ArH), 4.726-4.698 (m, IH, -OCH-), 4.505 (t, 2H, J = 5.1 Hz, -OCH ₂ - ), 4.198(t, 2H, J=5.1Hz, -NCH ₂ -), 3.144-2.979(m, 2H; ArCH ₂ -)

MS (FAB): 452 (M+1), 451 (M), 185, 144, 130, 93 Example 8:

2-(3-methylphenoxy)-3-ί442-(2-methyl-1-indolyl)ethoxylphenyl)acrylic acid

a) 4-[2-(2-Methyl-1-fluorenyl)ethoxy]benzaldehyde

4-[2-(2-methyl-1′′ fluorenyl)ethoxy]benzaldehyde was obtained by the method described in Example lc) using 2-methylindole (13.12 g, 100 mmol). The needle-like solid was 7.534 g, and the yield was 27%.

'HNMRCDMSO, 300MHZ) δ ppm: 9.825(s, IH, CHO), 7.803(d, 2H, J=8.7Hz, ArH), 7.460(d, IH, J=8.1Hz, ArH), 7.396(d, IH , J=8.1Hz, ArH), 7.034(t, IH, J=8.1Hz, ArH), 7.034(d, 2H, J=8.7Hz, ArH), 6.958(t, IH, J=8.1Hz, ArH) , 6.194(s, IH, ArH), 4.544(t, 2H, J= 5.4Hz, -OCH ₂ -), 4.362(t, 2H, J=5.4Hz, -NCH ₂ -) ₅ 2.468(s, 3H, -CH ₃ )

b) 2-(3-Methylphenoxy)-3-{4-[2-(2-methylindolyl)ethoxy]phenyl}acrylic acid

4-[2-(2-Methyl-fluorenyl)ethoxy]benzaldehyde (0.978 g, 3.5 mmol) and ethyl 3-methylphenoxyacetate were used as described in Example Id) The title compound was obtained as white crystals (yield: 147 mg, hexane, mp. </RTI> </RTI> <RTIgt;

'HNMR (DMSO, 300 MHZ) δ ppm: 12.937 (s, IH, -COOH), 7.598 (d, 2H, J = 9.0 Hz, ArH), 7.410 (d, IH, ArH), 7.380 (d, IH, ArH ), 7.303(s, IH, ArH), 7.158(t, IH, ArH), 7.023(t, IH, ArH), 6.935(s, IH, ArH), 6.849(d, 2H, J=9.0Hz, ArH ), 6.819(d, IH, ArH), 6.740(s, IH, =CH-), 6.69 l(dd, IH, ArH), 6.166(s, IH, ArH), 4.483(t, 2H, J=5.1 Hz, -OCH ₂ -), 4.240(t, 2H, J=5.1Hz, -NCH ₂ -), 2.425(s, 3H, -CH ₃ ), 2.243(s, 3H, -CH ₃ )

MS (ESI): 428 (M+1), 326, 308 (100), 250, 203

HRMS (FAB): C ₂₇ H ₂₅ N0 ₄ (M), found: 427.176712 (M), Calculated: 427.178359 (M) Example 9:

2-(3-methylphenoxy)-344-"2-(2-methyl-1" fluorenyl)ethoxy 1phenyl)propionic acid

2-(3-methylphenoxy)-3-{4-[2-(2-methyl-1-indolyl)ethoxy]phenyl obtained in 8b) according to the method described in Example 7. The title compound was obtained as a pink solid (yield: 212 mg, mp: 76-78).

°C.

!HNMR^DMSO, 300ΜΗζ) δ ppm: 7.440-7.357 (m, 2H, ArH), 7.170 (d, IH, ArH), 7.110-7.007 (m, 3H, ArH), 6.944 (t, IH, ArH), 6.779-6.562(m, 5H, ArH), 6.179(s, IH, ArH), 4.782-4.765(m, IH, -OCH-), 4.482(t, 2H, -OCH2-), 4.187(t, 2H, -NCH ₂ -), 3.042-3.015 (m, 2H, ArCH ₂ -), 2.407 (s, 3H, -CH ₃ ), 2.203 (s, 3H, -CH ₃ ) MS (ESI): 430 (M+1), 368, 326 (100), 308

HRMS (FAB): C ₂₇ H ₂₇ N0 ₄ (M), found: 429. 192 307 (M), Calculated: 429.194009 (M) Example 10:

2-[4-methoxyphenoxy]-3-ί4-Γ2-(~2-methyl-1′′ fluorenyl)ethoxy 1phenyl }propionic acid

4-[2-(2-methyl-1-indolesulfonyl)ethoxy]benzaldehyde (2.235 g, 8 mmol) and 4-methoxyphenoxyacetic acid were used according to the procedure of Example 8 and Ethyl ester (1.85 g, 8.8 mmol) mp. mp.

¹ H NMR (DMSO, 300 ΜΗζ) δ ppm: 7.428 (d, 1H, ArH), 7.387 (d, 1H, ArH), 7.168 (d, 2H, ArH), 7.033 (t, 1H, ArH), 6.944 (t, 1H, ArH), 6.798-6.704(m, 6H, ArH), 6.178(s, 1H, ArH), 4.709-4.666(m, 1H, -OCH-), 4.482(t, 2H, J=5.1Hz, - OCH ₂ -), 4.188 (t, 2H, J = 5.1 Hz, -NCH ₂ -), 3.643 (s, 3H, -OCH ₃ ), 3.084-2.948 (m, 2H, ArCH ₂ -), 2.447 (s, 3H, -CH ₃ )

MS (FAB): 446 (M+l), 445 (M, 207, 158, 144, 115, 93 Example 11:

2-(β-naphthyloxy)-3- -[2-(2-methyl-1-indenyl)ethoxy phenyl acrylate

4-[2-(2-Methyl-1-fluorenyl)ethoxy]benzaldehyde (2.79 g, 10 mmol) and β-naphthyloxyacetate (2.532 g) according to the procedure of Example Id) The title compound was obtained as a brown solid 192 mg, mp. C.

iHNMR MSO, 300MHz) δ ppm: 7.864-7.810(m, 2H, ArH), 7.713(d, 1H, ArH), 7.556(d, 1H, ArH), 7.457-7.302(m, 4H, ArH, 1 X= CH-), 7.252(dd, 1H, ArH), 7.177-7.145 (m, 2H, ArH), 7.004(t, 1H, ArH), 6.919(t, 1H, ArH), 6.795(d, 2H, ArH) , 6.144(s, 1H, ArH), 4.453(t, 2H, J-5.1Hz, -OCH ₂ -), 4.197(t, 2H, J=5.1Hz, -NCH ₂ -), 2.402(s, 3H, -CH ₃ )

MS (FAB): 464 (M+l), 463(M), 158, 144 Example 12

2-ίβ-naphthyloxy)-3-ί4-Γ2-(2-methyl-1-B fluorenyl)ethoxy 1phenyl}propionic acid

2-(β-naphthyloxy)-3-{4-[2-(2-methyl-1′′ fluorenyl)ethoxy]phenyl}acrylic acid obtained in the same manner as in Example 7 The title compound was obtained as a white fine needle crystal (yield: 102 mg). C.

¹ H NMR (DMSO, 300 ΜΗζ) δ ppm: 7.757-7.697 (m, 2H, ArH), 7.64 l (d, IH, ArH), 7.424-7.344 (m, 3H, ArH), 7.264 (t, IH, ArH) , 7.186(d, 2H, J=8.4Hz, ArH), 7.061-6.994(m, 3H, ArH), 6.930(t, IH, ArH), 6.734(d, 2H, J=8.4Hz, ArH), 6.163 (s, IH, ArH), 4.689-4.670(m, IH, -OCH-), 4.458(t, 2H, J=5.1Hz, -OCH ₂ -), 4.160(t, 2H, J=5.1Hz, - NCH ₂ -), 3.134-2.941 (m, 2H, ArCH ₂ -), 2.427 (s, 3H, -CH ₃ ).

MS (FAB): 466 (M+l), 465(M), 158, 144

Example 13

2-ethoxy-3-{4-"2-(1-(7-azaindenyl)ethoxy)phenyl 1 acrylate

a) 4-[2-(1-(7-Azaindole))ethoxy]benzaldehyde

4-[2-(1-(7-Azaindenyl))ethoxyxo,benzaldehyde was obtained according to the procedure described in Example lc) using 7-azaindole (2.363 g, 20 mmol). White solid 4.057g, yield 76.2%, mp: 68-70 °C o

¹ H NMR (DMSO, 300 ΜΗζ) δ ppm: 9.833 (s, IH, CHO), 8.245 (d, 2H, ArH), 7.961 (d, IH, ArH), 7.814 (d, 2H, J = 8.7 Hz, ArH) , 7.625(d, IH, J=3.3Hz, ArH), 7.097(d, 2H, J=8.7Hz, ArH), 7.082(d, IH, ArH), 6.476(d, IH, J=3.3Hz, ArH ), 4.675(t, 2H, J=5.1Hz, -OCH ₂ -), 4.473(t, 2H, J=5.1Hz, -NCH ₂ -) b) 2-ethoxy-3-{4-[2 -(l-(7-azaindenyl)ethoxy)phenyl]acrylic acid

4-[2-(1-(7-Azaindenyl))ethoxy]benzaldehyde (1.622 g, 6 mmol) and ethyl ethoxyacetate (0.872 g, The title compound was obtained as a white solid (yield: 147 mg, mp.

^MRiDMSO^OOMHz) δ ppm: 8.246(d, IH, J=4.8Hz, ArH), 7.962(d, IH, J=7.8Hz, ArH), 7.705(d, 2H, J=8.7Hz, ArH), 7.608(d, IH, J=3.6Hz, ArH), 7.088(dd, IH, J=7.8Hz, J=4.8Hz, ArH), 6.926(d, 2H, J=8.7Hz, ArH), 6.857(s , IH, =CH-), 6.472(d, IH, J=3.6Hz, ArH), 4.642(t, 2H, J=5.4Hz, -OCH ₂ -), 05 001483

4.379 (t, 2H, J = 5.4 Hz, -NCH ₂ -), 3.905 (q, 2H, J = 6.9 Hz, -OCH ₂ -), 1.233 (t, 3H, -CH ₃ ).

MS (FAB): 353 (M+l), 352(M), 145, 93

_{HRMS (FAB): C 20 H} 21 N 2 O 4 (M + l), found: 353.152184 (M + 1), calc: 353.150132 (M + 1) Example 14:

2-ethoxy-3-indole-indole 2-indole-(7-azaindenyl)ethoxy)phenylpropionic acid

Prepared by the method described in Example 7 using 2-ethoxy-3-{4-[2-(1-(7-aza-indolyl)-ethoxy)phenyl]ethyl acrylate obtained in 13 The title compound was obtained as a white fine needle-like solid (187 mg, yield: 66.9%).

'HNMRCDMSO, 300 MHZ) δ ppm: 8.246 (dd, 1H, J = 5.1 Hz, J = 1.5 Hz, ArH), 7.959 (dd, IH, J = 7.5 Hz, J = 1.5 Hz, ArH), 7.606 (d, IH, J=3.3Hz, ArH), 7.090(d, 2H, J=8.7Hz, ArH), 7.076(d, IH, J=7.5Hz, ArH), 6.805(d, 2H, J=8.7Hz, ArH ), 6.470(d, IH, J=3.3Hz, ArH), 4.620(t, 2H, J=5.4Hz, -OCH ₂ -), 4.300(t, 2H, J=5.4Hz, -NCH ₂ -), 3.927-3.883(q, IH, -OCH-), 3.502-3.209(m, 2H, ArCH2-), 2.878-2.721(m, 2H, -OC3⁄4-), 1.008(t, 3H, -CH ₃ ).

MS (FAB): 355 (M+l), 246, 185, 137, 93

HRMS (FAB): C ₂₀ H ₂₃ N ₂ O ₄ (M+l), Found: 355.165161 (M+1), Calculated: 355·165782 (Μ+1) Example 15:

2-(4-methylphenoxy)-3-{442-(1-(7-azaindenyl)ethoxy)phenyl 1 acrylate

4-[2-(1-(7-Azaindenyl))ethoxy]benzaldehyde (0.932 g, 3.5 mmol) and 4-methylphenoxyacetic acid B as described in Example Id) The title compound (1.02 g, 5.25 mmol) was obtained.

¹ H NMR (DMSO, 300 ΜΗζ) δ ppm: 8.225 (d, IH, ArH), 7.942 (dd, IH, ArH), 7.609 (d, 2H, J = 8.7 Hz, ArH), 7.577 (d, IH, J = 3.3Hz, ArH), 7.304(s, IH, =CH-), 7.102-7.052(m, 3H, ArH), 6.905(d, 2H, J=8.7Hz, ArH), 6.806(d, 2H, ArH) , 6.449(d, 1H, J=3.3Hz, ArH), 4.613(t, 2H, J=5.4Hz, -OCH ₂ -), 4.354(t, 2H, J=5.4Hz, -NCH ₂ -), 2.216 (s, 3H, -CH ₃ ) MS (ESI): 415 (M+1), 397, 353 (100), 326, 203

_{HRMS (FAB): C 25 H} 23 N 2 0 4 (M + l), found: 415.165710 (M + 1), calc: 415.165782 (M + 1) Example 16:

2-(4-Methylphenoxy)-3-{442-(l-(7-azaindenyl)ethoxy)phenylpropanoic acid

2-(4-Methylphenoxy)-3-{4-[2-(1-(7-aza-d-decyl)ethoxy)benzene obtained in 15 according to the method described in Example The title compound was obtained as a white solid (yield: 174 mg,yield,yield,yield 37%, mp: 109-115. C.

¹ H NMR (DMSO, 300 ΜΗζ) δ ppm: 8.240 (d, IH, ArH), 7.953 (d, IH, ArH), 7.593 (d, IH, J = 3.3 Hz, ArH), 7.177 (d, 2H, ArH) , 7.087(d, IH, ArH), 7.071(d, IH, ArH), 7.014(d, IH, ArH), 6.837-6.794(m, 2H, ArH), 6.689(d, 2H, ArH), 6.459( d, IH, J=3.3Hz, ArH), 4,780-4.738(m, ΙΗ, -OCH-), 4.612(t, 2H, J-5.4Hz, -OC3⁄4-), 4.300(t, 2H, J=5.4 Hz, -NCH ₂ -), 3.058-3.021 (m, 2H, ArC3⁄4-), 2.176(s, 3H, -CH ₃ ) MS (ESI): 417 (M+1, 100), 385, 353, 311

_{HRMS (FAB): C 25 H} 25 N 2 0 4 (M + l), found: 417.180962 (M + 1), calc: 417.181433 (M + 1) Example 17:

2-ethoxy-3-{4-"2-(5-methoxyberyl)ethoxy 1phenyl}acrylic acid

a) 4-[2-(1-(5-methoxyindole))ethoxy]benzaldehyde

4-[2-(1-(5-Methoxyindole))ethoxy]benzaldehyde was obtained according to the procedure described in Example lc) using 5-methoxyindole (4.415 g, 30 mmol). White solid 2.412 g, yield 33.9 %, mp: 96-98 °C.

¹ H NMR (DMSO, 300 ΜΗζ) δ ppm: 9.833 (s, IH, CHO), 7.819 (d, 2H, J = 8.7 Hz, ArH), 7.449 (d, IH, J = 8.7 Hz, ArH), 7.367 (d , IH, J=3.3Hz, ArH), 7.059(d, 2H, J=8.7Hz, ArH), 7.023(d, IH, J=2.4Hz, ArH), 6.773(dd, IH, J=8.7Hz, J=2.4Hz, ArH), 6.338(d, IH, J=3.3Hz, ArH), 4.55 l(t, 2H, J=5.1Hz, -OCH ₂ -), 4.378(t, 2H, J=5.1Hz , -NCH ₂ -), 3.727(s, 3H, -OCH ₃ )

b) 2-ethoxy-3-{4-[2-(5-methoxy benzhydryl)ethoxy]phenyl}acrylic acid 4-[2-(1-(5-methoxyindole)ethoxy)benzaldehyde (590 mg, 2 mmol) and ethyl acetate (396 mg, 3mmd) Ethyl 2-ethoxy-3-{4-[2-(5-methoxyberhydryl)ethoxy]phenyl}acrylate 316 mg, yield 38.6%.

^MRCDMSO, 300MHz) δ ppm: 7.720(d, 2H, ArH), 7.440(d, IH, ArH), 7.358(d, IH, ArH), 7.023(d, IH, ArH), 6.905(d, 2H, ArH), 6.872(s, IH, -CH=), 6.772(dd, IH, ArH), 6.332(d, IH, ArH), 4.519(t, 2H, -CH ₂ ), 4.292(t, 2H, - CH ₂ ), 4.190(q, 2H, -CH ₂ ), 3.895(q, 2H, -CH ₂ ), 3.729(s, 3H, -CH ₃ ), 1.277-1.218(m, 6H, 2X-CH ₃ ) .

Hydrolysis of ethyl 2-ethoxy-3-{4-[2-(5-methoxy beuterinyl)ethoxy]phenyl}enoate to give the title compound as a white solid 146mg It is 78.4%, mp: 167-170 °C.

'HNMR (DMSO, 300 MHZ) δ ppm: 7.707 (d, 2H, ArH), 7.440 (d, IH, ArH), 7.358 (d, IH, ArH), 7.023 (d, IH, ArH), 6.896 (d, 2H, ArH), 6.856(s, IH, -CH=), 6.772(dd, IH, ArH), 6.332(d, IH, ArH), 4.517(t, 2H, -CH ₂ ), 4.288(t, 2H , -C3⁄4), 3.907(q, 2H, -CH ₂ ), 3.729(s, 3H, -OCH ₃ ), 1.233(t, 3H, -CH ₃ )

HRMS (FAB): C ₂₂ H ₂₃ N0 ₅ (M), Found: 381.159950 (M), Calculated: 381.157623 (M) Example 18:

2-(β-naphthyloxy)-3-{4-[2-(5-methoxy-1-indenyl)ethoxy]phenyl}acrylic acid

4-[2-(1-(5-methoxyindole))ethoxy]benzaldehyde (1.181 g, 4 mmol) and ethyl β-naphthyloxyacetate (1.013) according to the procedure of Example Id) The title compound was obtained as a pale yellow solid (yield: 431 mg, mp.

^MRCDMSO, 300MHz) δ ppm: 7.926(d, IH, ArH), 7.873(d, IH, ArH), 7.795(d, 1H, ArH), 7.673(d, 2H, J=8.7Hz, ArH), 7.472 -7.243(m, 6H, ArH), 7.001 (d, IH, J=2.4Hz, ArH), 6.878(d, 2H, J=8.7Hz, ArH), 6.739(dd, IH, J=9Hz, J= 2.4Hz, ArH), 6.300(d, 1H, J=3.3Hz, ArH), 4.471 (t, 2H, J=5.1Hz, -OCH ₂ -), 4.245(t, 2H, J=5.1Hz, -NCH ₂ -), 3.708(s, 3H, OCH ₃ ).

MS (FAB): 480 (M+1), 479 (M), 185, 174, 160, 93

_{HRMS (FAB): C 30 H} 26 NO (M + 1), Found: 480.181594 (M + 1), calc: 480.181098 (M + 1) Example 19:

2-ethoxy-3-{4-[2-(5-cyano-1"!! 3⁄4yl)ethoxy]phenyl}propionic acid T N2 05/001483

a) 5-cyano-1-anthracene-ethanol

In a 250 ml eggplant bottle, 5-cyanoguanidine (14.2 g, 100 mmol) and potassium hydroxide (8.4 g, 150 mmol) were dissolved in 40 ml of DMSO, stirred for 10 minutes, then 2-bromoethanol was added thereto, and the temperature was raised. The reaction mixture was stirred at 40 ° C for 6 hours. The reaction mixture was poured into water, ethyl acetate was evaporated, ethyl acetate was evaporated. g, yield 55%, mp: 76-77 °C.

b) 5-cyano-1-anthracene-ethanol mesylate

In a 100 ml eggplant bottle, 5-cyano-1 -indole-ethanol (1.368 g, 7.3 mmol), triethylamine (1.336 g, 13.2 mmol) was dissolved in 20 ml of dichloromethane, and a drop was added thereto. The sulfonyl chloride (1.515 g, 13.2 mmol) was stirred at room temperature for 4 hours. The reaction was completed. The methylene chloride was evaporated and evaporated. The petroleum ether was recrystallized to give an orange-yellow solid: 1.367 g, yield 70.4%, mp: 106-108.

c) Ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate

2-Ethoxy-3-(4-hydroxyphenyl) was obtained by the method described in Example 10 using 4-benzyloxybenzaldehyde (10.61 g, 50 mmol) and ethyl ethoxyacetate (6.872 g, 52 mmol). Ethyl propionate, a colorless liquid of 3.575 g, a two-step yield of condensation and reduction of 30.2%.

d) 2-ethoxy-3-{4-[2-(5-cyano-1-yl)ethoxy]phenyl}propionic acid

Add 5-cyano-1-indenyl-ethanol mesylate (529 mg, 2 mmol), ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (477 mg) to a 100 ml eggplant bottle. 2 mmol), potassium carbonate (829 mg, 6 mmol) and magnesium sulfate (144 mg, 1.2 mmol), and then dissolved in 20 ml of anhydrous acetonitrile, heated under reflux for 10 hours, and the reaction was monitored by TLC. The reaction was completed, the mixture was filtered, and the filtrate was concentrated. EtOAc evaporated. -1-(Indolyl) ethoxy]phenyl}propanoic acid ethyl ester 730 mg, yield 89.8%, the compound was dissolved in ethanol / 10% sodium hydroxide solution to give the title compound, white solid 378 mg, yield 56%. M.p.: 133-139 ° C.

1H NMR (DMSO, 300 ΜΗζ) δ ppm: 8.063 (s, 1H, ArH), 7.741 (d, 1H, ArH), 7.624 (d, 1H, ArH), 7.476 (d, 1H, ArH), 7.073 (d, 2H , J=8.7Hz, ArH), 6.738(d, 2H, J=8.7Hz, ArH), 6.597(d, 1H, ArH), 4.610(t, 2H, J=5.1Hz, -OCH ₂ -), 4.24 l(t, 2H, J=5.1Hz, -NCH ₂ -), 3.904-3.863(m, 1H, CH), 3.514-3.188(m, 2H, -CH ₂ ), 2.866-2.705(m, 2H, - CH ₂ ), 0.990(t, 3H, -CH ₃ ).

MS (ESI): 377 (M-1, 100), 331 Example 20: ■■zz

(ooi)£6 'si£ '(n) ςβ Ί+η)ζη: (aw)

(3⁄4D "ΆΖ ^£ P) 086'∑; ^£ (-3⁄4DM- 3⁄4Z ^ Z '(HO- '- 3⁄4DO" 3⁄4ε

XWY 'HI ^C P)S6S-9 '(H-iV 'HZ 'P)Z9 9 '(WY 'HZ '(H-iV 'Ηΐ 3⁄4Α68·9 '(H-iV 'Ηζ ^tiVL XWY ^C UZ ') 6\ L %WV 'HI 'PP)69 B WV 'HI 'P) £S9"- '( V 'ΗΪ 'Ρ)6£ί WY 'Ηΐ 's)990'8 '(HO 'HI 's) £96'8 '(HO- 3⁄41 's)S6 /0I: uidd § (ZH OOE 'OS I) 顺NH^

°aow-9£i

:' chu Ό _/ο9 - _9ς

m Ίζζ '96£ '(οοι 'ι-νόςζρ: (evj) sn

ΉΖ '^ 8· ε90·ε '(- 3⁄4DN- 'mi^=[ 3⁄4z ^ιτ '(H - 'HI ' ^TS^ '(- 3⁄4DO- 'ΖΗΓ5=Γ 'ΗΣ; 3⁄466S '(HJV 'HI ' p)06S'9 'toy 3⁄417 'ρ)εε ·9 w 3⁄4ΐ εο8·9 'tov Ήΐ7 'u szu r ' (IV 'HI

⁽ P) £LVL '(H-iV 'Ηΐ 'P)0Z9'L XWY 3⁄4l 'P)9£ "Z- '(ffV 3⁄4ΐ 's)8S0'8: ^dd 9 (z brain 00ε 'OSWayai^M ^

°〇. Σει-εει :'d'm '%9'9S ? Lai Wei

^zpt ^ ^ '啄w迩^本舍i (i ^omui 'i oos)^? ^邈 M (爱*3⁄43⁄4 ) -ε-

f oo fine _{0 /} cage O (ydLseLSVtL - -^ (M) o Siw- M^ ^c (n)o ^z K ^zz H ^oi D: (evd) vmi

Ziz 'VLZ ΧΕ.ο-ι+η)ίς ⁽ (n)£L Χι+η)πρ: (avj) sn

•(-3⁄4DM- 'zHl"S=r 'ΉΖ ^tZ

'(- 3⁄4D0- 3⁄4Γ5=Γ ⁽ HZ 3⁄496S '(WY 3⁄4ΐ ^e P)99S'9 '(ffV 'mf =[ 'HZ 'P)8W9 %WY 3⁄49

■^)9ZZ-L-19VL '(ffV 3⁄4l 'P)£8S '(ffV 3⁄4i/8=i 'HZ 'Ρ)059· '(P V 'HI ^ZI L %WY 'HI

'V)LLL'L

°. H "d-ui '%VLZ

邈 3⁄43⁄4 3⁄4 oblique love 3⁄42 ( 1&1 10 3⁄4» Bu 蓥

69 ΐ '(H0_I+W) 17 '( )£ ,17 SM

3⁄42 S9rt7 '(- 3⁄40O-

3⁄4∑; 3⁄4A6S '(ffV 3⁄4ΐ 'P)09S'9 XWY 3⁄4£1 ' ) /9-60/: '(ffV 'HI

'Ηΐ 8 8 inch 1 £ '8 : wdd 9 (zH NtOOE 'OS CI) er leg j

°0. 8 inches II: 'd'ui '%Γ8ΐ

-υ f«3⁄4§fl3⁄4

SZ.S6Z0/900Z: OW N2005/001483

5-cyano-1-indole-methanesulfonate (793 mg, 3 mmol) and 2-(β-5,6,7,8-tetrahydronaphthyloxy)-based procedure as described in Example 19 Ethyl 3-(4-hydroxyphenyl)propanoate (llOOmg, 3.3 mmol) gave 2-(β-5,6,7,8-tetrahydronaphthyloxy)-3-{4-[ Ethyl 2-(5-cyano-1-indenyl)ethoxy]phenyl}propanoate 1010 mg, yield 66.7%, which was directly hydrolyzed to give the title compound. 613 mg, yield 64%, mp: 76-81.

'HNMRCDMSO, 300 MHZ δ ppm: 8.062 (s, IH, ArH), 7.732 (d, IH, ArH), 7.623 (d, IH, ArH), 7.460 (d, IH, ArH), 7.156 (d, 2H, ArH), 6.854(d, IH, ArH), 6.757(d, 2H, ArH), 6.595(d, IH, ArH), 6.497(d, IH, ArH), 6.450(s, IH, ArH), 4.658( m, IH, -CH), 4.608(t, 2H, -OCH ₂ -), 4.249(t, 2H, -NCH ₂ -), 3.028-2.971(m, 2H, -CH ₂ ), 2.564(s, 4H , -CH ₂ ), 1.640(s, 4H, -CH ₂ )

MS (FAB): 481 (M+1), 480 (M), 435, 169 (100), Example 25:

2-methoxy-3-{4-"2-(5-cyano-1-indenyl)ethoxy 1-3-methoxyphenyl}acrylic acid

a) 4-(2-Bromoethoxy)-3-methoxybenzoic acid

4-(2-Bromoethoxy)-3-methoxybenzaldehyde was obtained from vanillin (22.82 g, 0.15 mol) according to the procedure of Example lb), white solids: 16.702 g, yield 43% , mp: 61.7-63.6 °C.

b) 3-methoxy-4-[2-(5-cyano-1"indolyl)ethoxy]benzaldehyde

According to the procedure described in Example lc), 5-cyanoguanidine (4.265 g, 30 mmol) and 4-(2-bromoethoxy)-3-methoxybenzaldehyde (8.550 g, 33 mmol) -Methoxy-4-[2-(5-cyano-1-indenyl)ethoxy]benzaldehyde, 7.532 g of a yellow solid, yield 78.4%, mp: 139-141 °C.

'HNMR (DMSO, 300 MHZ) δ ppm: 9.803 (s, IH, CHO), 8.064 (d, IH, ArH), 7.806 (d, IH, J = 8.7 Hz, ArH) _; 7.630 (d, 1H, J = 3.3Hz, ArH), 7.518-7.463 (m, 2H, ArH), 7.35 l(d, IH, ArH), 7.112(d, IH, J=8.7Hz, ArH): 6.611(d, IH, J=3.3 Hz, ArH), 4.682(t, 2H, J=5.1Hz, -OCH ₂ -), 4.402(t, 2H, J=5.1Hz, -NCH ₂ -), 3.776(s, 3H, -OCH ₃ ) PT/CN2005/001483 c) 2-Methoxy-3-{4-[2-(5-cyanophosphonyl)ethoxy]- ³ -methoxyphenyl}acrylic acid

3-methoxy-4-[2-(5-cyanophosphonyl)ethoxy]benzaldehyde (3.20 g, 10 mmol) and ethyl methoxyacetate (m. The title compound was obtained as a white solid (yield: 71 mg, mp.

1H NMR (DMSO, 300MHz) 5 ppm: 8.069 (s, IH, ArH), 7.795 (t, 1H, ArH), 7.633 (d, IH, J = 3.3 Hz, ArH), 7.492 (d, IH, ArH), 7.395 (s, IH, ArH), 7.258(d, 2H, ArH), 6.911(d, IH, ArH), 6.855(s, IH, =CH-), 6.610(d, IH, J=3.3Hz, ArH ), 4.642(t, 2H, J=5.1Hz, -OCH ₂ -), 4.310(t, 2H, J=5.1Hz, -NCH ₂ -), 3.698(s, 3H, OCH ₃ ), 3.66 l(t , 3H, OCH ₃ ).

MS (FAB): 393 (M+1), 392 (M), 375 (M-OH), 347 (M-COOH), 169, 158, 155

_{HRMS (FAB): C 22 H} 20 N 2 O 5 (M), found: 392.137398 (M), calc: 392.137222 (M) Example 26:

2-(β-naphthyloxy)-3-{4-"2-(5-cyanophosphonyl)ethoxy 1-3-methoxyphenylacrylic acid

3-methoxy-4-[2-(5-cyano-1-B-fluorenyl)ethoxy]benzaldehyde (3.20 g, 10 mmol) and β-naphthalene were used according to the procedure of Example Id) Ethyl oxyacetate (2.533 g, ll mmol) gave the title compound, 257 mg of white solid, mp. C.

'HNMRCDMSO, 300 MHZ) δ ppm: 8.037 (s, IH, ArH), 8.037-6.563 (m, 15H, ArH, 1 X-CH-), 4.574 (t, 2H, J-5.1Hz, -OCH ₂ -) , 4.222(t, 2H, J=5.1Hz, -NCH ₂ -), 3.532(s, 3H, -OCH ₃ ).

MS (FAB): 504 (M+1), 503 (M), 185, 169, 93

HRMS (FAB): C ₃₁ H ₂₄ N ₂ 0 ₅ (M), Found: 504·166855 (Μ), Calculated: 504·168522 (Μ) Example 27:

2-(4-methylphenoxy)-3-{4-"3-(5-cyano-1-indenyl)propoxy 1phenyl}acrylic acid

a) 4-(3-Bromopropoxy)benzaldehyde Using p-hydroxybenzaldehyde (18.318 g, 0.15 mol), 1,3-dibromopropane (30.6 ml, 0.3 mol) according to the procedure of Example lb), 4-(3-bromopropoxy)benzene Formaldehyde, white solid 20.387 g, yield 56%.

b) 4-[3-(5-Cyano-1-indolyl)propoxy]benzaldehyde

4-[3- was prepared according to the procedure described in Example lc) using 5-cyanoguanidine (14.216 g, 100 mmol) and 4-(3-bromopropoxy)benzaldehyde (26.741 g, llOmmol 1). (5-Cyano-fluorenyl)propoxy]benzaldehyde gave 21.648 g of a yellow solid, yield 71.1%, mp: 94-96.

'HNMRODMSO, 300MHZ) δ ppm: 9.848(s, IH, CHO), 8.078(d, IH, ArH), 7.834(d, 2H, J=8.7Hz, ArH), 7.683(d, 1H, J=8.4Hz , ArH), 7.596(d, IH, J=3.3Hz, ArH), 7.429(dd, IH, J=8.4Hz, J-1.5Hz, ArH), 7.063(d, 2H, J=8.7Hz, ArH) , 6.598(d, 1H, J=3.3Hz, ArH), 4.429(t, 2H, J=6.6Hz, -OCH ₂ -), 3.992(t, 2H, J=6.6Hz, -NCH ₂ -), 2.38 (m, 2H, -CH ₂ -)

c) 2-(4-Methylphenoxy)-3-{4-[3-(5-cyano-l-H fluorenyl)propoxy]phenyl}acrylic acid

4-[3-(5-Cyano-1-H-fluorenyl)propoxy]benzaldehyde (4.565 g, 15 mmol) and ethyl 4-methylphenoxyacetate as described in Example Id) The title compound was obtained as a white solid (yield: 267 mg, hexane, mp.: 147-151).

'HNMRCDMSO, 300MHz) δ ppm: 8.059(s, IH, ArH), 7.657-7.608(m, 4H, ArH), 7.555(d, IH, J=3.3Hz, ArH), 7.404(d, IH, ArH) , 7.321(s, IH, =CH-), 7.099(d, 2H, ArH), 6.876(d, 2H, ArH), 6.820(d, 2H, ArH), 6.578(d, IH, J=3.3Hz, ArH), 4.378(t, 2H, J=6.3Hz, -OCH ₂ -), 3.874(t, 2H, J=6.3Hz, -NCH ₂ -), 2.224(s, 3H, -CH ₃ ), 2.175( t, 2H, -CH ₂ -).

MS (FAB): 453 (M+l), 452 (M), 436 (M+l-OH), 435 (M-OH), 185, 183, 155, 93 Example 28 _:

2-(3-methylphenoxy 3-{4-"3 5-cyano-1-indenyl)propoxy 1phenyl}acrylic acid

4-[3-(5-Cyano-1-propenyl)propoxy]benzaldehyde (3.348 g, ll mmol) and ethyl 3-methylphenoxyacetate (2.331 g) according to the procedure of Example Id) The title compound was obtained as a white solid (yield: 22.5 %, mp: 101-107

°C.

'HNMRC DMSO^OOMHz) δ ppm: 8.063 (s, 1H, ArH), 7.609 (d, IH, ArH), 7.528 (d, IH, J = 3.3 Hz, ArH), 7.380 (dd, IH, ArH), 7.330 (s, IH, ArH), 7.261-7.216(m, 3H, ArH), 7.157(t, IH, ArH), 6.897-6.858(m, 13⁄4 ArH), 6.813(d, IH, ArH), 6.750(s , IH, =CH-), 6.700(dd, IH, ArH), 6.576(d, IH, J=3.3Hz, ArH), 4.352(t, 2H, J=6.3Hz, -OCH ₂ -), 3.789(t, 2H, J=6.3Hz, -NCH ₂ -), 2.227(s, 3H, -CH ₃ ), 2.143(t, 2H _: -CH ₂ -).

MS (FAB): 453 (M+l), 452 (M), 435 (M-OH), 183, 155, 115 Example 29:

2-(β-naphthyloxy)-3-{4-"3-(5-cyano-1-indenyl)propoxy 1phenyl}acrylic acid

4-[3-(5-Cyanocylinyl)propoxy]benzaldehyde (4.565 g, 15 mmol) and β-naphthyloxyacetate (3.569 g, 15.5 mmol) according to the procedure of Example Id) The title compound was obtained as a white solid, 113 mg, mp. C.

¹ H NMR (DMSO, 300 ΜΗζ) δ ppm: 8.046 (d, IH, ArH), 7.924 (d, IH, ArH), 7.866 (d, IH, ArH), 7.793 (d, IH, ArH), 7.675 (d, 2H, J=8.7Hz, ArH), 7.629(d, IH, ArH), 7.536(d, IH, J=3.3Hz, ArH), 7.541-7.250(m _; 6H, ArH, 1 X=CH-), 6.874(d, 2H, J=8.7Hz, ArH), 6.560(d, IH, J=3.3Hz, ArH), 4.358(t, 2H, J=6.3Hz, -OCH2-), 3.859(t, 2H, J = 6.3 Hz, -NCH ₂ -), 2.157 (t, 2H, J = 6.3 Hz, -CH ₂ -).

MS (FAB): 489 (M+l), 488 (M), 472 (M+l-OH), 471 (M-OH), 274 Example 30:

2-(β-naphthyloxy 3-{3-methoxy 4-"3-(5-cyano-l-fluorenyl)propoxy 1phenyl}acrylic acid

a) 3-methoxy-4-(3-bromopropoxy)benzaldehyde

According to the procedure of Example lb), vanillin (22.82 g, 0.15 mol), 1,3-dibromopropane (30.6 ml, 0.3 mol) gave 23.346 g of white solid, yield 57%, mp: 51.2 -52.4 °C.

b) 3-methoxy-4-[3-(5-cyanophosphonyl)propoxy]benzaldehyde

Prepared according to the procedure described in Example lc) using 5-cyanoguanidine (4.265 g, 30 mmol) and 3-methoxy-4-(3-bromopropoxy)benzaldehyde (9.013 g, 33 mmol) -Methoxy-4-[3-(5-cyanophosphonyl)propoxy]benzaldehyde, 8.9 g of a yellow solid, yield 88.7%, mp: 87-89. C.

¹ H NMR (DMSO, 300 MHz) δ ppm: 9.821 (s, IH, CHO), 8.067 (d, IH, ArH), 7.672 (d, IH, ArH), 7.584 (d, IH, ArH), 7.501-7.436(m, 2H, ArH), 7.410(d, IH, ArH), 7.062(d, 1H, ArH), 6.600(d, IH, ArH), 4.406(t, 2H, J =6.6Hz, -OC3⁄4-), 3.966(t, 2H, J=6.6Hz, -NCH ₂ -), 3.875(s, 3H, -OC ), 2.247(m, 2H, -CH ₂ -) c) 2 -(β-naphthyloxy)-3-{3-methoxy 4-[3-(5-cyano-1-indenyl)propoxy]phenyl}acrylic acid

3-methoxy-4-[3-(5-cyano-1-B-fluorenyl)propoxy]benzaldehyde (3.344 g, 10 mmol) and β-naphthalene were used according to the procedure of Example Id) Ethyl oxyacetate (2.533 g, ll mmol) afforded the title compound. C.

'HNMR (DMSO, 300 MHZ) δ ppm: 8.044 (s, 1H, ArH), 7.926 (d, IH, ArH), 7.865 (d, IH, ArH), 7.793 (d, IH, ArH), 7.630 (d, IH, ArH), 7.535 (d, IH, ArH), 7.467-7.243 (m, 8H, ArH, 1 X-CH-), 6.857 (d, IH, ArH), 6.557 (d, IH, ArH), 4.340 (t, 2H, J=6.0Hz, -OCH ₂ -), 3.837(t, 2H, J=6.0Hz, -NCH ₂ -), 3.817(s, 3H, -OCH3), 2.152(t, 2H, - CH ₂ -).

MS (FAB): 519 (M+l), 518 (M), 502 (M+1-OH), 501 (M-OH), 376, 183, 155 Example 31:

2-(4-Tolyloxy 3-{4-"3-(5-carboxy-1-indenyl)propoxy 1phenyl}acrylic acid

Add ethyl 2-(4-tolyloxy)-3-{4-[3-(5-cyanocyano)propyloxy]phenyl}acrylate (400 mg) to a 100 ml eggplant bottle. The title compound was obtained as a white solid (yield: 46.6%). M.p.: 208-216 °C.

'HNMRCDMSO, 300 MHZ) δ ppm: 8.200 (s, IH, ArH), 7.674 (d, IH, ArH), 7.628 (d, 2H, ArH), 7.503 (d, IH, ArH), 7.443 (d, IH, J=3.3Hz, ArH), 7.32 l(s, IH, =CH-), 7.097(d, 2H, ArH), 6.897(d, 2H, ArH), 6.820(d, 2H, ArH), 6.563(d , IH, J=3.3Hz, ArH), 4.351(t, 2H, J=6.3Hz, -OCH ₂ -), 3.885(t, 2H, J=6.3Hz, -NCH2-), 2.221(s, 3H, -CH ₃ ), 2.178(t, 2H, J=6.3Hz, -CH ₂ -).

MS (FAB): 472 (M+l), 471 (M), 455 (M+l-OH), 454 (M-OH), 436, 173, 130 Example 32:

2-(β-naphthyloxy 3-{4-|~3-(5-carboxy-1-indenyl)propoxy 1phenyl}propene ...

Ethyl 2-(β-naphthyloxy)-3-{4-[3-(5-cyanophosphonyl)propoxy]phenyl}acrylate (200 mg) was obtained according to the procedure of Example 30 The title compound was obtained to give a white solid (yield: mp.

'HNMR (DMSO, 300 MHZ) δ ppm: 8.194 (d, IH, ArH), 7.933 (d, IH, ArH), 7.875 (d, IH, ArH), 7.804 (d, IH, ArH), 7.706-7.661 ( m, 3H, ArH), 7.502(d, IH, ArH), 7.453-7.259(m, 6H, ArH, 1 X=CH-), 6.906(d, 2H, J=8.7Hz, ArH), 6.556(d , 1H, ArH), 4.341 (t, 2H, J=6.0Hz, -OCH ₂ -), 3.871(t, 2H, J=6.0Hz, -NCH ₂ -), 2.169(t, 2H, J=6.0Hz , -CH ₂ -).

MS (FAB): 508 (M+l), 507 (M), 491 (M+l-OH), 490 (M-OH), 472, 174, 130 Example 33: '

2_ethoxy _344_『2-(5-bromofluorenyl)ethoxy 1phenyl}acrylic acid

a) 4-[2-(5-bromo-1"indolyl)ethoxy]benzaldehyde

4-[2-(2-) was prepared according to the procedure described in Example lb) using 5-bromoindole (5.328 g, 27 mmol) and 4-(2-bromoethoxy)benzaldehyde (6.54 g, 28.5 mmol). 5-bromo-1-indenyl)ethoxy]benzaldehyde, white solid 5.62 g (yield 59.9%), mp: 70-72

°C.

^MRCDMSO, 300MHz) δ ppm: 9.83 l(s, IH, CHO), 7.811(d, 2H, J=8.7Hz, ArH), 7.715(d, IH, J=1.5Hz, ArH), 7.560(d, IH, J=8.7Hz, ArH), 7.488(d, IH, J=3.3Hz, ArH), 7.247(dd, IH, J-8.7Hz, J=1.5Hz, ArH), 7.049(d, 2H, J =8.4Hz, ArH), 6.434(d, IH, J=3.3Hz, ArH), 4.544(t, 2H, J-4.8Hz, -OCH2-), 4.396(t, 2H, J=4.8Hz, -NCH ₂ -)

b) 2-Ethoxy-3-{4-[2-(5-bromo-1-indolyl)ethoxy]phenyl}acrylic acid

4-[2-(5-Bromo-1-indolyl)ethoxy]benzaldehyde (1.721 g, 5 mmol) and ethyl ethoxyacetate (0.661 g, 5 mmol). The title compound was obtained, 326 mg of white squamous crystals, condensed and hydrolyzed in a two-step yield of 15.2%, mp: 164-166. . .

'HNMR (DMSO, 300 MHZ) δ ppm: 7.700 (d, IH, J = 8.7 Hz, ArH), 7.700 (d, 2H, J = 8.7 Hz, ArH), 7.547 (d, IH, J = 8.7 Hz, ArH ), 7.474 (d, IH, J = 3.3 Hz, ArH), 7.240 (dd, IH, J = 8.7 Hz, J = 1.8 Hz, ArH), 6.883 (d, 2H, J = 8.7 Hz, ArH), 6.852 (s, IH, =€H-), 6.432(d, IH, J=3.3Hz, ArH), 4.569(t, 2H, J=5.1Hz, -OCH ₂ -), 4.304(t, 2H, J= 5.1 Hz, -NCH ₂ -), 3.904 (q, 2H, J = 6.9 Hz, OCH ₂ -), 1.231 (t, 3H, J = 7.2 Hz, -CH ₃ ).

MS (FAB): 432 (M, +1), 431 (M,), 430 (M+1), 429 (M), 247, 143 PT/CN2005/001483

_{HRMS (FAB): C 21 H} 20 BrNO 4 (M), found: 429.059204 (M), calc: 429 · 057569 (Μ) Example 34:

2-(β-naphthyloxy)-3-{4-Γ2-(5-bromo-indolyl)ethoxy 1phenyl }acrylic acid

Prepared according to the procedure of Example Id), using 4-[2-(5-bromo-bromomethyl)ethoxy]benzaldehyde (1.377 g, 4 mmol) and EtOAc (0.921 g, 4 mmol) The title compound was obtained to give a white solid (lOOmg), condensed, and hydrolyzed in a two-step yield of 15.04%, mp: 124-126 °C.

^MR DMSO, 300MHz) δ ppm: 7.909(d, IH, ArH), 7.857(d, IH, ArH), 7.775(d, IH, ArH), 7.680(d,

IH, ArH), 7.65 l(d, 2H, J=8.7Hz, ArH), 7.511-7.182(m, 4H, ArH, 1 X=CH-), 6.390(d, IH, ArH),

4.520 (t, 2H, J = 5.1 Hz, -OCH ₂ -), 4.258 (t, 2H, J = 5.1 Hz, -NCH ₂ -).

MS (FAB): 530 (M'+1), 529 (M,), 528 (M+1), 527 (M), 247, 143

_{HRMS (FAB): C 29 H} 22 BrN0 4 (M), found: 527.073547 (M), calc: 527.073220 (M) Example 35:

2-fa-naphthyloxy 3--"3-(5-bromo-1-indolyl)propoxy 1phenyl}acrylic acid

a) 4-[3-(5-Bromo-indolyl)propoxy]benzaldehyde

4-[3-" was prepared according to the procedure described in Example lb) using 5-bromoindole (5.77 g, 29.4 mmol) and 4-(3-bromopropoxy)benzaldehyde (7.7 g, 31.7 mmol). (5-Bromo-1-indenyl)propoxy]benzaldehyde, 5.46 g of a yellow oil, yield 51.8%.

b) 2-(c-Naphthyloxy)-3-{4-[3-(5-bromoindolyl)propoxy]phenyl}acrylic acid

The title was prepared according to the procedure of Example Id) using 4-[3-(5-bromo-bromo-propyl)propoxy]benzaldehyde (1.79 g, 5 mmol) and ethyl acetate (1.151 g, 5 mmol) The compound obtained 250 mg of white granular crystals, and the yield of the condensation and hydrolysis was 8.11%, mp: 144-148 °C.

'HNMRCDMSO, 300 MHZ) δ ppm: 8.322-8.290 (m, IH, ArH), 7.893-7.860 (m, IH, ArH), 7.683 (d, 1H, ArH), 7.548-7.389 (m, 6H, ArH), 7.360(d, IH, J=3.0Hz, ArH), 7.277(t, IH, ArH), 7.151(dd, IH, ArH), 05 001483

7.028(s, IH, =CH-), 6.770(d, 2H, ArH), 6.669(d, IH, ArH), 6.375(d, IH, J=3.3Hz, ArH), 4.273(t, 2H _; J = 6.3 Hz, -OCH2-), 3.798 (t, 2H, J = 6.3 Hz, -NCH ₂ -), 2.105 (t, 2H, J = 6.3 Hz, -CH ₂ -).

MS (FAB): 544 (M, +1), 543 (M,), 542 (M+1), 541 (M), 157, 115 Example 36:

2-(β-naphthyloxy)-3-{3-"2-(1-indolyl)ethoxy 1phenyl}acrylic acid

a) 3-[2-(1-indolyl)ethoxy]benzaldehyde

3-[2-(1-吲哚) was prepared according to the method described in Example lb) using hydrazine (4.686 g, 40 mmol) and 3-(2-bromoethoxy)benzaldehyde (10. 078 g, 44 mmol). Ethyloxy]benzaldehyde, 3 g of colorless liquid (yield 28.3%).

!HNMRiDMSO, 300 ΜΗζ) δ ppm: 9.917 (s, IH, CHO), 7.563 (d, IH, ArH), 7.524 (d, IH, J = 7.5 Hz, ArH), 7.481-7.464 (d, 2H, ArH) , 7.432(d, IH, J=3.3Hz, ArH), 7.359(d, 1H, J=2.4Hz, ArH), 7.225-7.185(m, IH, ArH), 7.136(t, IH, J=7.2Hz , ArH), 7.007 (t, IH, J-7.5Hz, ArH), 6.43 l(d, IH, J=3.3Hz, ArH), 4.594(t, 2H, J=5.4Hz, -OCH ₂ -), 4.370(t, 2H, J=5.4Hz, -NCH ₂ -)

c) 2-(β-naphthyloxy)-3-{3-[2-(l-fluorenyl)ethoxy]phenyl}acrylic acid

3-[2-(1-indolyl)ethoxy]benzaldehyde (1.061 g, 4 mmd) and β-naphthyloxyacetate (1.658 g, 7.2 mmol) according to the procedure described in the method of the formula Id). The title compound was obtained as a white solid 224 n.

'HNMR (DMSO, 300 MHZ) δ ppm: 7.890 (t, 2H, ArH), 7.790 (d, IH, ArH), 7.495-7.364 (m, 5H, ArH), 7.323-7.195 (m, 6H, ArH, - CH=), 7.036(t, IH, ArH), 6.955(t, 1H, ArH), 6.859(d, 1H, ArH), 6.346(d, 1H: ArH), 4.483(t, 2H, -CH ₂ ) , 4.176(t, 2H, -CH ₂ )

Pharmacological Experiments Experimental Example 1: In vitro receptor-ligand binding assay

The obtained new compound was assayed with human PPAR α, PPAR Y by Biacore 3000 instrument (Biacore AB, Rapsgatan 7, S-754 50 Uppsala, Sweden) using surface plasmon resonance (SPR, Surface Plasmon Resonance) analysis method. The binding constant Kd of the body binding region (Table 1).

SPR technology: as shown in Figure 1: Its detection principle is:

Surface Plasmon Resonance (SPR) Biochemical analyzer is a new biochemical analysis system based on the principle of physical optics - surface plasmon resonance. The position of the absorption peak of the SPR changes as the refractive index of the liquid phase on the metal surface of the chip changes, and the change in the refractive index is related to the quality and characteristics of the biomolecules bound to the surface of the chip. By monitoring the change in the peak-to-peak position (characteristic value) of the SPR absorption, the biological reaction occurring on the metal surface can be monitored in real time. It has the property of detecting the bonding and resolution reaction of the surface of the metal film in a fast and real-time manner without marking.

Some of the compounds of the present invention were tested for the binding rate to PPARY by the above method, and the results are shown in the following table -

NA: No Activity ND: No Detection Lab 2: In Vitro Cell Filtering

The resulting compound is screened for activity to activate the PPARy receptor.

1) Principles of screening models:

Using a reporter gene approach, a screening model for screening PPARy activators in live cells was designed using the principle that PPARY activation activates its downstream gene transcription. First, a reporter gene plasmid was constructed, and the PPARY receptor DNA-binding sequence (PPRE) was inserted upstream of the luciferase gene, and the expression of the luciferase gene was regulated by the PPARY receptor. The reporter gene plasmid and the PPARY receptor are simultaneously transferred into a cell. When a PPARY activator is present in the cell culture medium, the PPARy receptor is activated, and the activated receptor can induce the expression of the luciferase gene. The yield of luciferase can be detected by its luminescent substrate. such, The intensity of activation of the PPARy receptor by the compound can be seen by observing the intensity of the luminescence. In order to correct the experimental error caused by factors such as transfection efficiency, cell inoculation amount and compound toxicity, GFP plasmid was also co-transfected as an internal reference. The luminescence values of all the test wells were corrected by GFP value in the analysis of the experimental results. The positive control in the trial used the international anti-type 2 diabetes "standard" drug rosiglitazone. The test results are expressed as relative activation multiples, and the solvent control has a value of 1, and the larger the value, the higher the activation ability.

2) Experimental process for screening models'

Seed cells and transfection on the first day:

Liver cancer cell line: 20000 / well lOOul system.

The plasmid was transferred to the cells with FUGENE6.

Dosing the next day

The original lOOul medium was aspirated and replaced with 190 ul of fresh medium.

Drug concentration (M) 10

Lul join

▼

Volume of culture medium (ul) 49 Add the amount of cells after mixing (ul) 10 Corresponding final concentration (M) 10

On the third day, Luciferase intensity and GFP intensity were measured (internal parameters for correcting transfection efficiency)

2) Experimental results:

Compound induction factor compound induction multiple

Example 1 4.861 Example 19 2.6302

Example 2 5.176 Example 20 ND

Example 3 2.9438 Example 21 ND

Example 4 ND Example 22 2.2781

Example 5 2.3018 Example 23 4.8491

Example 6 4.3018 Example 24 ND

Example 7 1.2308 Example 25 3.1953

Example 8 5.8817 Example 26 3.6805

Example 9 2.6953 Example 27 2.3255

Example 10 1.8284 Example 28 1.6095

Example 11 5.8699 Example 29 2.2929

Example 12 1.3373 Example 30 2.8758

Example 13 7.4586 Example 31 1.2249

Example 14 5.5267 Example 32 1.0799

Example 15 5.4675 Example 33 6.6686 Example 16 5.0947 Example 34 5.0414

Example 17 ND Example 35 2.3906

Example 18 5.1066 Example 36 ND

Rosiglitazone 7.3003

NA: No Activity ND: No Detection

The experimental results show that 24 of the 30 compounds tested have more than twice the activation of PPARY receptors under the uniform concentration of ΙΟμπιοΙ/L, and 2 of them have the ability to activate PPARY receptors. The glitazone is quite. Experimental Example 3:

PPAR agonists have effects on many diseases such as hypertension, hyperlipemia, atherosclerosis, inflammation, tumors, and the like, and some of the compounds of the present invention are selected for screening for anticancer activity.

The selection of drugs for killing cancer cells was determined by MTT assay in vitro. The MTT assay is based on the metabolic reduction of 3-(4, 5-dimethylthiazol-2-yl)-2, 5-dipHenyl tetrazol iura bromide (MTT). In this experiment, human colon cancer cells, human fibrosarcoma cells, human prostate cancer cells, human breast cancer cells, and the like, which are highly expressed by PPAR, were selected. Experiments have found that Example 4 has a good inhibitory effect on human colon cancer cells, human fibrosarcoma cells, and human prostate cancer cells.

Human colon cancer cell line HT29 was selected for in vivo experiments.

Example 6 has an inhibitory effect on the growth of HT29 in vivo -

Experimental Example 4: In vitro live fine j screening

From the experimental example 2, 23 compounds with better activity were selected to measure the transcriptional activation experiments of multi-concentration levels of the transfected PPARa/γ gene, and EC _{5C was} calculated according to the relative activation multiples at different concentrations. The semi-effective concentration (EC ₅₀ ) is one of the important indicators for measuring the pharmacological effects of compounds. In this model screening, the activation of the receptor at six different concentrations was observed, and the pharmacological properties of the compound were more comprehensively analyzed. The iterative calculation was performed according to the following formula to fit the concentration of the compound. ) = + ^ ~~ r At the same time, the relative maximum activation intensity of each sample was calculated by taking the maximum activation multiple of the positive drug as 100%. The maximum activation strength of the sample is shown in the table below. The results of the measurement are shown in the table, and the activity is represented by EC _{5 ()} , and the unit is 10 - ⁶ m _O l / L.

1. Transcriptional Activation Experiment of Compound on ΡΡΑϊΙγ Model

The method is as described above.

2. Transcriptional activation experiments of compounds on PPARa model

Using a reporter gene approach, a screening model for screening PPARa activators in live cells was designed using the principle that PPARa binds to a ligand to activate its downstream gene transcription. The ligand binding domain (LBD) of the PPARa receptor was ligated together with the DNA binding domain (DBD) of the GAL4 protein to construct a fusion plasmid. The fusion protein expressed by the plasmid can activate GAL4 DNA in the presence of PPARa ligand. Binding to the expression of genes downstream of the sequence. When the hybrid receptor plasmid and the reporter gene plasmid containing the GAL4 DNA-binding sequence are simultaneously transferred into the cell, the activated receptor can induce the expression of the luciferase gene, and the luciferase production can pass through the luminescent substrate. detected. Thus, the intensity of activation of the PPARa receptor by the compound can be known by observing the intensity of the luminescence. In order to correct the experimental error caused by factors such as transfection efficiency, cell inoculation amount and compound toxicity, GFP plasmid was also co-transfected as an internal reference. The luminescence values of all the test wells were corrected by GFP value in the analysis of the experimental results. The positive control in the trial used the internationally accepted control drug WY14643. The test results are expressed as relative activation multiples, and the value of the solvent control is 1. The higher the value, the higher the activation capacity.

PPARy PPARa

No.

ΕΟ ₅₀ (μΜ) % MAX ΕΟ ₅₀ (μΜ) % MAX

Rosiglitazone 闘 KM) 3.63 19

WY-14643 ND ND 20 100

Example 1 6.31 10 26

Example 2 1.48 Off 6.16 42

Example 3 ND ND ND So

Example 4 ND ND ND II

Example 5 ND ND ND M

Example 6 3.55 I 7.41 9

Example 7 ND ND ND

Example 8 2 circle 5.24 8

Example 9 6.03 14 5.24 11

Example 10 ND ND ND country

Example 11 2.24 Off 4.07 14 Example 12 ND ND ND II

I S

Example 13 B 3.63 i

Example 14 0,75

Example 15 3.46 37

Example 16 5.37 47 2.57 37

Example 17 4.9 3.89 38

Example 18 1.91 8 10 18

Example 19 ND ND ND

Example 20 ND ND ND

Example 21 ND ND ND MP

Example 22 ND ND ND D

Example 23 4.47 65 ia ia

Example 24 ND ND ND 3⁄4

Example 25 6.61 38 4.26 11

Example 26 6.03 28 ia ia

Example 27 ND ND ND diagram

Example 28 ND ND ND

Example 29 ND ND ND

Example 30 5.5 47 ia ia

Example 31 5.5 47 ia ia

Example 32 5.5 47 ia ia

Example 33 1.2 - Ί 2.57 W

Example 34 2.95 II 4.16 9

Example 35 ND ND ND

Example 36 ND ND ND M)

EXAMPLES 4.9 4.9 β.9 ia ia

Example 7 2.75 • l 5.75 Figure

Example 17' 5.01 43 6.6 9

Note: The gray part of the table indicates that the EC ₅ o of this value is less than ΙμΜ or the maximum activation intensity is greater than 50% of the positive drug.

Claims

Rights request

1. A compound of the formula I and its racemates, enantiomers, physiologically acceptable salts, solvates and crystalline forms,

In the formula:

n is selected from an integer of 1 to 4,

X is selected from 0, S, NH, CH ₂ , CH(OH), CO or -CH=CH-,

Rl is selected from hydrogen, halo, cyano, C! - ₆ alkyl with 0! - ₆ alkoxy, - ₆ alkylthio, carboxy, alkoxycarbonyl, R7NHCO-

(R7 is selected from H, C _1-6 alkyl), CF ₃ ,

R2 is selected from the group consisting of hydrogen, halogen, C _]-6 alkyl, C _1-6 decyloxy, -6 trace thio, CF ₃ ,

Y is selected from the group consisting of 0, S, C _1-6 thiol,

R3 is selected from the group consisting of hydrogen, d- ₆ ' fluorenyl, d- ₆ alkoxy, d-6 thiol,

A is in the ortho, meta or para position and is selected from

R4 is selected from the group consisting of H, C; - ₆ alkyl,

R5 is selected from H, C _W2 alkyl, C _{1 -I} 2 alkoxy, _3⁄4 _-12 cycloalkyl, C _3-i2 cycloalkoxy, halogen substituted alkoxy or cycloalkoxy, or various substitutions Different or different positions of aryloxy or aryloxyl groups,

R6 is selected from hydrogen, hydroxy, C -6 alkoxy, C ₃ -! ₈ _{cycloalkoxy, NH 2, NHR7, R8R9,} HOH, NHOR10 (7-10 selected from alkyl with C _6).

The compound according to claim 1, wherein B is selected from the group consisting of a carbon ring of 6 carbon atoms and a heterocyclic ring containing one hetero atom.

3. A compound according to claim 2, characterized in that B is selected from the group consisting of a benzene ring and a hetero ring containing a nitrogen atom.

4. A compound according to claim 1, characterized in that n is selected from 2 or 3.

5. A compound according to claim 4, characterized in that n is selected from 2.

6. A compound according to claim 1, characterized in that the preferred X is selected from the group consisting of 0, S, NH, C0.

7. A compound according to claim 6 wherein X is selected from zero.

8. A compound according to claim 1, wherein, Rl is selected from hydrogen, halo, cyano, C ₆ alkyl with, -6 alkoxy, carboxy, R7NHC0- (R7 is selected from C _1-4 alkyl).

9. A compound according to claim 8, wherein, Rl is selected from hydrogen, halo, cyano, C _M alkyl group, the CM embankment group, a carboxyl group.

10. A compound according to claim 9, characterized in that R1 is selected from the group consisting of hydrogen, bromine, cyano, C _W decyl, d- ₃ alkoxy, carboxy.

11. The compound according to claim 1, wherein, R2 is selected from hydrogen, C ^ alkyl, d. ₆ embankment group.

12. A compound according to claim 11 wherein R2 is selected from the group consisting of hydrogen, methyl, d-3 fluorenyl.

13. The compound according to claim 12, wherein, Y is selected from 0, S, d ~ C ₃ alkyl group.

14. A compound according to claim 13 wherein Y is selected from the group consisting of 0, S.

15. A compound according to claim 14 wherein Y is selected from the group consisting of zero.

16. A compound according to claim 1, characterized in that R3 is selected from the group consisting of hydrogen, _.3 alkyl, d- ₃ methoxy, Q.3 alkylthio.

17. A compound according to claim 16 characterized in that R3 is selected from the group consisting of hydrogen, methyl and methoxy.

18. A compound according to claim 1 wherein R4 is selected from the group consisting of H.

19. A compound according to claim 1 wherein R5 is selected from the group consisting of H, ₆ fluorenyl, d- ₆ methoxy, and. _3. ₁₂ fluorenyl, C ₃ . ₁₂ cyclodecyloxy, CF ₃ .

20. The compound according to claim 19, wherein, R5 is selected from methoxy, ethoxy, phenoxy, naphthoxy, tetrahydronaphthalene group, tolyl group, methoxyphenyl, CF _3.

21. The compound according to claim 1, wherein, R6 is selected from hydroxy, NHOH, _ ₃ alkoxy, C ₃ - ₈ cycloalkyl group.

22. A compound according to claim 21, characterized in that R6 is selected from the group consisting of hydroxyl groups, NHOH.

23. A compound according to claim 1 wherein fragment A is in the meta or para position.

24. The compound of claim 1 wherein said halogen is fluorine, chlorine and bromine.

25. The compound of claim 1 wherein said compound is as shown by IA

Wherein R1 is selected from the group consisting of hydrogen, -6 alkyl, d- ₆ methoxy, cyano, carboxy, halogen;

R2 is selected from the group consisting of hydrogen, halogen, d. ₆ alkyl, d. ₆ methoxy;

Y is selected from S, 0

R3 is selected from the group consisting of hydrogen, _-6 yards, and d- ₆ alkoxy groups;

R4 is selected from the group consisting of H and Ci- ₆ fluorenyl;

R5 is selected from the group consisting of d- ₆ methoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from - ₆ fluorenyl, d- ₆ methoxy), naphthyloxy, tetrahydronaphthyloxy;

R6 is selected from light, hydroxy, NHOH, d- ₆ embankment group, C ₃ - ₈ cycloalkyl group embankment.

26. The compound of claim 25, wherein said compound is as shown by IAA

IAA

among them,

R2 is selected from the group consisting of hydrogen and methyl;

Y is selected from S, 0;

R3 is selected from the group consisting of hydrogen and methoxy;

R5 is selected from the group consisting of d- ₆ methoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from the group consisting of Q-6 fluorenyl, -6 alkoxy), naphthyloxy, tetrahydronaphthyloxy;

R6 is selected from the group consisting of hydroxyl groups and NHOH;

R11 is selected from the group consisting of _-3 alkyl, d- ₃ decyloxy.

27. The compound of claim 26, wherein said compound is as shown by IAB

among them, Rl is selected from the group consisting of hydrogen, methyl, methoxy, cyano, carboxyl, halogen;

R2 is selected from the group consisting of hydrogen and methyl;

Y is selected from S, 0;

R3 is selected from the group consisting of hydrogen and methoxy;

R5 is selected from -6 alkoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from the group consisting of Q- ₆ fluorenyl, -6 fluorenyloxy), naphthyloxy, tetrahydronaphthyloxy;

R6 is selected from the group consisting of hydroxyl groups and NHOH;

R11 is selected from the group consisting of Q-3 alkyl and Q- ₃ alkoxy.

28. The compound of claim 1 wherein said compound is as shown in IB

Wherein R1 is selected from the group consisting of hydrogen, d- ₆ alkyl, d- ₆ methoxy, cyano, carboxy, halogen;

R2 is selected from the group consisting of hydrogen, halogen, d. ₆ alkyl, . ₆ alkoxy;

Y is selected from S, 0

R3 is selected from the group consisting of hydrogen, -6 alkyl, d-6 alkoxy; 'R4 is selected from H, _Cr6 alkyl;

R5 is selected from a _Cr6 alkoxy group, a substituted or unsubstituted phenoxy group (the substituent on the benzene ring is selected from the group consisting of -6-mercapto, d-- _6- methoxy), naphthyloxy, tetrahydronaphthyloxy;

R6 is selected from hydroxyl, hydroxyl, embankment -6 alkoxy, C ₃ - ₈ cycloalkyl group.

29. The compound of claim 1 wherein said compound is as shown by the IC

Wherein R1 is selected from the group consisting of hydrogen, _-6 alkyl, Q- ₆ alkoxy, cyano, carboxy, halogen; R2 is selected from the group consisting of hydrogen, halogen, C _W alkyl, d. ₆ alkoxy;

Y is selected from S, 0

R3 is selected from the group consisting of hydrogen, _Cr6 fluorenyl, and d- ₆ methoxy;

R4 is selected from the group consisting of H and _-6 fluorenyl;

R5 is selected from the group consisting of -6 alkoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from the group consisting of _Cr6 alkyl, _-6 decyloxy), naphthyloxy, tetrahydronaphthyloxy;

R6 is selected from hydroxy, hydroxy, - ₆ alkoxy, C ₃ - ₈ cycloalkyl group.

30. The compound of claim 1, wherein said compound is as indicated by ID

ID wherein R1 is selected from the group consisting of hydrogen, C decyl, d- ₆ methoxy, cyano, carboxy, halogen;

R2 is selected from the group consisting of hydrogen, halogen, C^alkyl, C^ alkoxy;

Y is selected from S, 0

R3 is selected from the group consisting of hydrogen, C, _-6 fluorenyl, d- ₆ decyloxy;

R4 is selected from the group consisting of H and _-6 fluorenyl;

R5 is selected from - ₆ methoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from - ₆ alkyl, Q- ₆ alkoxy), naphthyloxy, tetrahydronaphthyloxy;

R6 is selected from hydroxy, hydroxy, - ₆ embankment alkoxy, C ₃ - ₈ cycloalkyl group embankment.

The compound of claim 1, wherein said compound is as shown in IE

Wherein, Rl is selected from hydrogen, C _r6 alkyl, C ₆ embankment, cyano, carboxy, halogen;

R is selected from the group consisting of hydrogen, halogen, d. ₆ alkyl, d. ₆ alkoxy;

Y is selected from S, 0

R3 is selected from the group consisting of hydrogen, d- ₆ alkyl, _Cr6 alkoxy;

R4 is selected from the group consisting of H, -6 alkyl;

R5 is selected from a C ₆ alkoxy group, a substituted or unsubstituted phenoxy group (the substituent on the benzene ring is selected from a -6 alkyl group, a ₆ alkoxy group), a naphthyloxy group, a tetrahydronaphthyloxy group;

R6 is selected from hydroxy, hydroxyalkyl, -6 alkoxy, C ₃ - ₈ cycloalkyl group.

32. The compound of claim 1, wherein said compound is as shown by IF

Wherein R1 is selected from the group consisting of hydrogen, _Cr6 fluorenyl, d- ₆ alkoxy, cyano, carboxy, halogen;

R2 is selected from the group consisting of hydrogen, halogen, C^ fluorenyl, C^ alkoxy;

Y is selected from S, 0

R3 is selected from the group consisting of hydrogen, d- ₆ alkyl, d- ₆ methoxy;

R4 is selected from the group consisting of H and -6 fluorenyl;

33. The compound of claim 1 wherein said compound is as shown by IG

Wherein R1 is selected from the group consisting of hydrogen, d- ₆ fluorenyl, Cr ₆ decyloxy, cyano, carboxy, halogen; R2 is selected from the group consisting of hydrogen, halogen, d. ₆ alkyl, Q- ₆ methoxy;

Y is selected from S, 0

R3 is selected from the group consisting of: _-6- alkyl, - _6- decyloxy;

R4 is selected from the group consisting of H, -6 alkyl;

R5 is selected from a -6 alkoxy group, a substituted or unsubstituted phenoxy group (the substituent on the benzene ring is selected from a -6 alkyl group, a - ₆ methoxy group), a naphthyloxy group, a tetrahydronaphthyloxy group;

R6 is selected from hydroxyl, hydroxyl, d- ₆ alkoxy, C ₃ - ₈ cycloalkyl group.

34. The compound of claim 1 wherein said compound is as shown by IH

IH

Wherein R1 is selected from the group consisting of hydrogen, _-6 fluorenyl, d- ₆ alkoxy, cyano, carboxy, halogen;

R2 is selected from the group consisting of hydrogen, halogen, d. ₆ fluorenyl, d. ₆ decyloxy;

Y is selected from S, 0

R3 is selected from the group consisting of hydrogen, d- ₆ alkyl, -6 alkoxy;

R4 is selected from the group consisting of H, d- ₆ fluorenyl;

R5 is selected from the group consisting of d- ₆ methoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from d- ₆ alkyl, -6 alkoxy), naphthyloxy, tetrahydronaphthyloxy;

R6 is selected from hydroxy, hydroxy, C _r6 alkoxy, C ₃ - ₈ cycloalkyl group embankment.

35. The compound of claim 1 wherein said compound comprises -

2-methoxy-3-{4-[2-(1-indolyl)ethoxy]phenyl}acrylic acid

2-ethoxy-3-{4-[2-(1-indolyl)ethoxy]phenyl}acrylic acid

2-phenoxy-3-{4-[2-(1-indolyl)ethoxy]phenyl}acrylic acid

2-phenoxy-3-{4-[2-(1-indolyl)ethoxy]phenyl}propene hydroxamic acid

2-(α-naphthyloxy)-3-{4-[2-(1-indolyl)ethoxy]phenyl}acrylic acid

2-(β_naphthyloxy)-3-{4-[2-(1-indolyl)ethoxy]phenyl}acrylic acid

2-(β-naphthyloxy)-3-{4-[2-(1-13⁄4|fluorenyl)ethoxy]phenyl}propionic acid

2-(3-methylphenoxy)-3-{4-[2-(2-methylberyl)ethoxy]phenyl}acrylic acid 2-(3-methylphenoxy)-3-{4-[2-(2-methyl-1′′ fluorenyl)ethoxy]phenyl}propanoic acid

2-(4-methoxyphenoxy)-3-{4-[2-(2-methyl-1-indolyl)ethoxy]phenyl}propionic acid

2-(β-naphthyloxy)-3-{4-[2-(2-methyl-1-indolyl)ethoxy]phenyl }acrylic acid

2-(β-naphthyloxy)-3-{4-[2-(2-methyl-1--1-indolyl)ethoxy]phenyl}propionic acid

2-ethoxy-3-{4-[2-(1-(7-aza-n-ytyl)ethoxy)phenyl]acrylic acid

2-ethoxy-3-{4-[2-(1-(7-azaindenyl)ethoxy)phenyl]propanoic acid

2-(4-Methylphenoxy)-3-{4-[2-(1-(7-azaindenyl)ethoxy)phenyl]acrylic acid

2- (4-methylphenoxy) - ³ - {4- [2- (1- (indol-7-yl) ethoxy) phenyl] propionic acid

2-ethoxy-3-{4-[2-(5-methoxy-1-indenyl)ethoxy]phenyl}acrylic acid

2-(β-naphthyloxy)-3-{4-[2-(5-methoxy-1-indenyl)ethoxy]phenyl}acrylic acid

2-ethoxy-3-{4-[2-(5-cyanophosphonyl)ethoxy]phenyl}propionic acid

2-phenoxy-3-{4-[2-(5-cyanophosphonyl)ethoxy]phenyl}propionic acid

2-phenoxy-3-{4-[2-(5-cyanophosphonyl)ethoxy]phenyl}propoxyhydroxamic acid

2-(ct-naphthyloxy)-3-{4-[2-(5-cyano-1-(indolyl)ethoxy]phenyl}acrylic acid

2-(β-naphthyloxy)-3-{4-[2-(5-cyanophosphonyl)ethoxy]phenyl}acrylic acid

2-(β-5,6,7,8-tetrahydronaphthyloxy)-3-{4-[2-(5-cyano-1'indolyl)ethoxy]phenyl}propionic acid

2-methoxy-3-{4-[2-(5-cyanobenzyl)ethoxy]-3-methoxyphenyl}acrylic acid

2-(β-naphthyloxy)-3-{4-[2-(5-cyano-1-indenyl)ethoxy]-3-methoxyphenyl}acrylic acid

2-(4-methylphenoxy)-3-{4-[3-(5-cyano-1-indolyl)propoxy]phenyl}acrylic acid

2-(3-methylphenoxy)-3-{4-[3-(5-cyano-1-(indolyl)propoxy]phenyl}acrylic acid

2-(β-naphthyloxy)-3-{4-[3-(5-cyano-1-indolyl)propoxy]phenyl}acrylic acid

2-(β-naphthyloxy)-3-{3-methoxy 4-[3-(5-cyanophosphonyl)propoxy]phenyl}acrylic acid

2-(4-Tolyloxy)-3-{4-[3-(5-carboxy-1-indolyl)propoxy]phenyl}acrylic acid

2-(β-naphthyloxy)-3-{4-[3-(5-carboxy-1-indolyl)propoxy]phenyl}acrylic acid

2-ethoxy-3-{4-[2-(5-bromoindolyl)ethoxy]phenyl}acrylic acid

2-(β-naphthyloxy)-3-{4-[2-(5-bromoindolyl)ethoxy]phenyl}acrylic acid

2-(c-naphthyloxy)-3-{4-[3-(5-bromo-1-indolyl)propoxy]phenyl}acrylic acid

2-(β_naphthyloxy)-3-{3-[2-(1′′ fluorenyl)ethoxy]phenyl}acrylic acid.

36. A process for the preparation of a compound according to claims 1-35, characterized in that VII

Wherein A, B, X, Y, R1, R2, R3, R4, R5, R6, n are as defined in claim 1, and P and Q represent a leaving group;

The product of the reaction of the compound of the formula IV with the compound of the formula V, the compound of the formula VI, and the compound of the formula W are condensed to form a compound of the formula VII, followed by hydrolysis, reduction or the like to form a compound of the formula K or X;

Or

The compound of formula VI and the compound of formula W are first condensed, and the compound of formula IV is combined with the compound of formula V to form a compound of the formula, followed by VII. The reaction of hydrolysis, reduction or the like produces a compound of the formula X or X.

The method according to claim 36, wherein said P, Q is from - ΟΗ, halogen.

The process according to claim 36, wherein the condensation of V and VI is carried out by using tetrabutylammonium bromide as a catalyst under the action of a base.

The process according to claim 36, wherein the condensation of IV and (V + VI ) is carried out by the action of a base.

The process according to claim 36, wherein the condensation of (IV + V + VI ) and VII is carried out in the presence of potassium t-butoxide.

The process according to claim 36, wherein the hydroxamic acid derivative is prepared by reacting the corresponding acid with isobutyl chloroformate in the presence of triethylamine, and then adding a hydroxylamine methanol solution.

A method according to claim 36, wherein said reducing reaction is hydrogenation using Pd/C.

43. A pharmaceutical composition comprising a compound of any of claims 1-35 and a pharmaceutically acceptable carrier. The use of a compound according to claims 1-35 for the preparation of a medicament for the treatment of diabetes. The use of a compound according to claims 1-35 for the preparation of a medicament for the treatment of cancer. A compound according to claims 1-35 for use in the treatment of diabetes.

A compound according to claims 1-35 for use in the treatment of cancer.