MXPA00011610A - New 3-aryl propionic acid derivatives and analogs - Google Patents

Abstract

Novel 3-aryl proprionic acid derivatives and analogs, having general formula (I) and stereo- and optical isomers and racemates thereof as well as pharmaceutically acceptable salts, solvates and crystalline forms thereof, process for their manufacture, pharmaceutical preparations containing them and the use of the compounds in clinical conditions associated with insulin resistance.

Description

NEW DERIVATIVES OF PROPIONIC AND ANALOGUE 3-ARIL ACID Field of the invention The present invention concerns certain new derivatives of 3-aryl-2-hydroxypropionic acid and the like, to a process for preparing such compounds, which have utility in clinical conditions associated with insulin resistance, to methods for their therapeutic use and to compositions pharmaceuticals that contain them.

BACKGROUND OF THE INVENTION Insulin resistance, defined as the reduction of sensitivity to the actions of insulin in the whole body or in individual tissues such as skeletal muscle, myocardium, fat and predominantly the liver in many individuals with or without diabetes mellitus. The syndrome of resistance to diabetes, IRS, refers to a group of manifestations that include insulin resistance with accompanying hyperinsulinemia, possibly diabetes mellitus not dependent on insulin (NIDDM), hypertension, central obesity (visceral ), dyslipidemia observed as RE.125167 altered lipoprotein levels typically characterized by high concentrations of VLDL (very low density lipoproteins) and high HDL (high lipoproteins) and reduced fibrinolysis.

Recent epidemiological investigations have documented that individuals with insulin resistance are at an enormously increased risk of cardiovascular morbidity and mortality, notably suffering from myocardial infarction and stroke. In diabetes mellitus not dependent on insulin these arteriosclerosis are related to conditions that cause up to 80 - of all deaths.

Currently there is, in clinical medicine only limited awareness of the need to increase insulin sensitivity in IRS and thereby correct the dyslipidemia that is considered to cause the accelerated progress of arteriosclerosis.

In addition, there is currently no pharmacotherapy available to adequately correct the metabolic alterations associated with IRS. To date, the NIDDM treatment has focused on correcting the control of carbohydrate metabolism alterations associated with the disease. The stimuli of endogenous insulin secretion by means of secretagogues, similar to sulfonylureas, and if necessary the administration of exogenous insulin are the methods frequently used to normalize the blood sugar but which will be, if it is something, additionally resistance to the improved insulin and will not correct the other manifestations of IRS nor reduce cardiovascular morbidity and mortality. In addition, such treatments involve a significant risk of hypoglycemia with associated complications.

Other therapeutic strategies have focused on aberrations in the metabolism or absorption of glucose, which include biguanidines, such as metformin, or glucosidase inhibitors, such as acarbose. Although these agents have been efficient to the extent that their limited clinical effect is associated with side effects.

A new therapeutic strategy involves the use of insulin sensitizing agents, such as thiazslidindicetones which, at least in part, mediate their effects via an agonistic action on nuclear receptors. Ciglitazone is the prototype of this class. In animal IRS models these compounds seem to correct insulin resistance and associated hypertriglyceridemia and hyperinsulinemia, as well as hyperglycemia in diabetes, by improving insulin sensitivity via an effect on lipid transport and handling, which lead to the improved action of insulin in skeletal muscle, liver and adipose tissue.

The Ciglitazone as well as the thiazolidindicetones subsequently described in clinical development have either been discontinued according to the reports received, due to unacceptable toxicity or to demonstrate inadequate potency. Therefore there is a need for new and better compounds with insulin sensitizing properties.

Precedents in Matter Compounds of the formula: f > - and certain derivatives of these described in the USA 5 306 726 and WO 91/19702 are mentioned as being useful as hypoglycemic and hypocholesterolemic agents, and in US 5 232 945 it is mentioned that they are "useful in the treatment of hypertension.

AU 650 429 describes structurally related compounds, but claims to have different properties: diuretic, anti-hypertensive, anti-platelet agglomerating and anti-lipoxygenase properties EP 139 421 describes compounds that have the ability to lower lipid and blood sugar levels.

Among these compounds is triglitazone, a compound that has reached the market for the treatment of NIDDM or decreased glucose tolerance.

WO 97/31907 describes compounds that were claimed to demonstrate good blood glucose abatement activity and therefore are used in the treatment and / or prophylaxis or hyperglycemia, dyslipidemia, and used particularly in the treatment of Type II diabetes.

These compounds are also claimed for use in the treatment and / or prophylaxis of other diseases including Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, cardiac dysfunction, diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension and cardiovascular diseases, especially arteriosclerosis .

Description of the invention The invention concerns compounds of the general formula (I): and stereo and optical isomers and racemates thereof as well as pharmaceutically acceptable salts, solvates and crystalline forms thereof, in said formula A, is located in the ortho position, meta or stops and represents R3 R1 1 i R3 R1 - C - C - COR | I o - C = C - COR, R4 R2 where R is hydrogen; -0Ra, wherein Ra represents hydrogen, alkyl, aryl or alkylaryl; -NR3Rb, wherein Ra and Rb are the same or different and Ra is as defined above and R represents hydrogen, alkyl, aryl, alkylaryl, cyano, -OH, -Oalkyl, Oaryl, -Oalkylaryl, -COR ^ or -S0Rd, in where R "represents hydrogen, alkyl, aryl or alkylaryl and Rd represents alkyl, aryl or alkylaryl, R1 is alkyl, aryl, alkene, alkyne, cyano; -ORe, wherein Re is alkyl, acyl, aryl or alkylaryl; [CHc] m-ORf, wherein Rf represents hydrogen, alkyl, acyl, aryl or alkylaryl and m represents an integer 1-8; -0C0NR3Rc, wherein Ra and Rc are as defined above; -SRd, wherein Rd is as was previously defined; -S02NRaRi, wherein Rf and Ra are as defined above; -S02ORa, wherein Ra is as defined above; -COORd, where Rd is as defined above; R 2 is hydrogen, halogen, alkyl, aryl, or alkylaryl, R 3 and R 4 are the same or different and each represents hydrogen, alkyl, aryl, or alkylaryl, n is an integer from 1 to 6; D is located in the ortho, meta or para position and represents -OSO¿Rd, where Rd is as defined above; -COONRíRa, where R1 and Ra are as defined above; -NRcCOORd, where R "and Ra are as previously defined; -NRcCOR% where Rc and Ra are as previously defined; -NRcRd, where Rc and Rd are as defined above; -NRcSO_Rd, where R ~ and Rd are as defined above; -NRcCONRaR, wherein R% Rc and Rl are the same or different and each of them represents a hydrogen, alkyl, aryl, or arylalkyl; -NRÍ ~ CSNRaRr, where Ra, Rr are the same or different and each of them represents a hydrogen, alkyl, aryl or alkylaryl; -S02Rd, where Rd is as defined above; -SOR, where Rd is as defined above; -SR, where R is as defined above; -SO¿NRaRf, where Rf and Ra are as previously defined; -SO¿ORa, where R3 is as defined above; -CN, -CONRcR% where R and Ra are as defined above; D 'is located in the ortho, meta or para position and represents a hydrogen, alkyl, acyl, aryl, alkylaryl, halogen, -CN, -N02, -NRfRb, wherein Rf and Rb are as defined above; -ORf, where Rf is as defined above; -OSO 3.d, where Rd is as defined above; D "is located in the ortho, meta or para position and represents a hydrogen, alkyl, acyl, aryl, alkylaryl, halogen, -CN, -N0_, -NRfR wherein Rf and Rr are as defined above; -ORf, wherein Rf is as defined above -OSO ^ Rd, where Rd c as defined above; For ease of reference the definitions of formula I above will hereinafter be referred to as defined in Category A. Unless stated otherwise, the definitions of the various substituents are those defined in Category A throughout the present application. .

The compounds of the formula I are surprisingly effective under conditions associated with insulin resistance.

Category A2: In one embodiment of the present invention it does not comprise (S) -2-ethoxy-3- [4- (2- {4- [methanesulfononyloxyphenyl] ethoxy) phenyl] propanoic acid, and -. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxyfillyl} - (S) -2-ethoxypropanoic.

Cathode A3: the preferred compounds of the present invention are those of formula I, wherein A is located in the meta position or para and represents, R3 R1 I t -C-C-COR. R4R2 R, is hydrogen; -ORa, where R3 is as defined in category A; -NRaRb, where Ra and Rb are the same or different and R3 is as defined in category A and R represents hydrogen, alkyl, aryl, alkylaryl, cyano , -OH, -Oalkyl or -Oalkylaryl; R1 is cyano; -ORd, where Rd is as defined in category A; -0- [CH;] -. -ORa, where m and Ra are as defined in Category A; R "is hydrogen or alkyl, R3 is hydrogen or alkyl, R4 is hydrogen, n is an integer from 1 to 3, D is located in the ortho, meta or para position and represents -OSORd, where R is equal to the defined in Category A; -OCONRaRc, where Ra and R "are as defined in Category A; -NRCOORd, where R and Rd are as defined in Category A; -NRcCORa, where R '~ and Ra are as defined in Category A; -NRRd, where R "and Rd are as defined in the Category A; -NRS02Rd, where Rc and Rd are as defined in Category A; -NRCONRkR, where Ra, R and R are as defined in Category A; -NRCSNRR, where Ra, R'r and Rk are as defined in Category A; -S02 d, where Rd is as defined in Category A; -SRr, where R ~ is as defined in the Category TO; -CN; -C0NRaRk wherein Ra and R are as defined in Category A, D 'is located in the ortho, meta or para position and represents hydrogen, alkyl, alkylaryl, halogen, -CN or -NO_; -ORh, wherein Rh is hydrogen or alkyl; D "is located in the ortho, meta or para position and represents hydrogen, alkyl, alkylaryl, halogen, -CN or -N0_; -0Rh, wherein R is as defined above.

Category 4 additional preferred compounds of the present invention are those of category A3 in which A is located in the meta or para position; R is, -ORa, wherein Ra is hydrogen, alkyl or alkylaryl; -NHR, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R "is hydrogen or alkyl, R3 is hydrogen or alkyl, R4 is hydrogen, n is an integer from 1 to 3, D is located in the ortho, meta or para position and represents -NRCOORd, where R", and R are as defined in Category A; D 'is hydrogen. D "is hydrogen.

Category A5: preferred additional compounds of the present invention are those of Category A4, wherein A is located in the para position; R is -OH, -Oalkyl or -Oalkylaryl; -NH_, -NHOalkylaryl or -NHCN; R1 is -Oalkyl, preferably -O-lower alkyl; R2 is hydrogen; R3 is hydrogen; n is the integer 1; D is located in the position para, and represents -NRCOOR, where Rd is as defined in Category A and Rh represents hydrogen or alkyl Category A6: Additional preferred compounds of the present invention are those of Category A5, wherein D is -NR'COOalkyl wherein R 1 represents hydrogen and lower alkyl.

Category A7: Additional preferred compounds of the present invention are those of Category A3, where A is located in the meta or para position. R is -ORa, wherein Ra is hydrogen, alkyl or alkylaryl; -NHRb, wherein Rfc is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R is hydrogen or alkyl; R3 is hydrogen or alkyl; R4 is hydrogen; n is an integer from 1 to 3; D is located in the ortho, meta or para position and represents -NRcCORa, where Rc and Ra are as defined in Category A; D 'is hydrogen. D "is hydrogen.

Category A8: Additional preferred compounds of the present invention are those of Category A7 in which A is located in the position for; R is -OH, -Oalkyl or -Oalkylaryl; -NH2, -NHOalkylaryl or -NHCN; R1 is -Oalkyl, preferably -O-lower alkyl; • R2 is hydrogen; R3 is hydrogen; n is the integer 1; D is located in the para position, and represents -NRhCOR, where Rd is as defined in Category A and Rh represents hydrogen or alkyl.

Category A9: additional preferred compounds of the present invention are those of category A8, wherein D is -NHCORd, where Rd is as defined in category A.

Category Al0: Additional preferred compounds of the present invention are those of Category A3, in which A is located in the meta or para position, R is -ORa, wherein Ra is hydrogen, alkyl or alkylaryl; -NHRfc, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl, R2 is hydrogen; R3 is hydrogen or alkyl; R4 is hydrogen; n is an integer from 1 to 3; D is located in the ortho, meta or para position and represents -S02Rd, where R is as defined in the Category TO; D 'is hydrogen; D "is hydrogen.

Category All: Additional preferred compounds of the present invention are those of Category 10, in which A is located in the position for; R is -OH, -Oalkyl or -Oalkylaryl; -NH./ -NHOalkylaryl or -NHCN; R1 is -Oalkyl, preferably -O-lower alkyl; R3 is hydrogen; n is the integer 1; D is located in the position for and represents -S02Rd, where Rd is as defined in Category A.

Category A12: Additional preferred compounds of the present invention are those of Category A3, in which A is located in the meta or para position, R is -OR3, wherein Ra is hydrogen, alkyl or alkylaryl; -NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R2 is hydrogen, R3 is hydrogen or alkyl, R3 is hydrogen; n is an integer from 1 to 3; D is located in the ortho, meta or para position and represents -SRd, where Rd is as defined in the Category TO; D 'is hydrogen; D "is hydrogen.

Category Al3; Additional preferred compounds of the present invention are those of Category A12, wherein A is located in the position for; R is -OH, -Oalkyl, -Oalkylaryl; -NH? -NHOalkylaryl or -NHCN; R1 is -Oalkyl, preferably -O-lower alkyl; . R3 is hydrogen; n is the integer 1; D is located in the position for and represents -SRd, where Rd is as defined in Category A.

Category A14: Additional preferred compounds of the present invention are those of Category A3, in which A is located in the meta or para position, R is -OR% wherein Rd is hydrogen, alkyl, alkylaryl; -NHR, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R- is hydrogen or alkyl; R3 is hydrogen or alkyl; R4 is hydrogen; n is an integer from 1 to 3; D is located in the ortho, meta or para position and represents -OCONRaRc, where Ra and Rr are as defined in Category A; D 'is hydrogen; D "is hydrogen.

Category A15: Additional preferred compounds of the present invention are those of Category A14, wherein A is located in the position for; R is -OH, -Oalkyl, -Oalkylaryl; -NH2, -NHOalkylaryl, -NHCN; R2 is hydrogen; R3 is hydrogen; n is the integer 1; D is located in the position for, and represents -OC0NHRd, where Rd is as defined in Category A.

Category Al6: Additional preferred compounds of the present invention are those of Category A15, in which R1 is -Oalkyl, preferably -O lower alkyl, D is -OCONHalkyl.

Category A17: Additional preferred compounds of the present invention are those of Category A3, in which A is located in the meta or para position, R is -ORa, wherein Ra is hydrogen, alkyl, alkylaryl; -NHR, wherein R is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl, R1 is -Oalkyl, R2 is hydrogen or alkyl; R3 is hydrogen or alkyl, R4 is hydrogen; n is an integer from 1 to 3; D is located in the ortho, meta or para position and represents .NRS02Rd, where Rc and Rd are as defined in category A; D 'is hydrogen; D "is hydrogen.

Category Al8: Additional preferred compounds of the present invention are those of Category Al7, in which A is located in the position for; R is -OH, -Oalkyl, -Oalkylaryl; -NH ^, NHOalkyl aryl or -NHCN; R2 is hydrogen; R3 is hydrogen; n is the integer 1, D is located in the para position, and represents -NRhS02Rd, where Rd is as defined in Category A and Rh is hydrogen or alkyl.

Category A19: Additional preferred compounds of the present invention are those of Category Al8, in which R1 is -Oalkyl, preferably -O-lower alkyl; D is -NRhSO.alkyl wherein Rh is as defined above.

Category A20: Additional preferred compounds of the present invention are those of Category A3, where A is located in the meta or para position; R is -0Ra, wherein R3 is hydrogen, alkyl or alkylaryl; -NHR, wherein Rc is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R2 is hydrogen or alkyl; R3 is hydrogen or alkyl; R4 is hydrogen; n is an integer from 1 to 3; D is located in the ortho, meta or para position and represents -NRcRd, where Rc and Rd are as defined in Category A; D 'is hydrogen; D "is hydrogen.

Category A21: Additional preferred compounds of the present invention are those of the A20 category, in which A is located in the position for; R is -OH, -Oalkyl, -Oalkylaryl; -NH2, -NHOalkylaryl or -NHCN; R2 is hydrogen; R3 is hydrogen; n is the integer 1; D is located in the position para, and represents -NRhRd where Rd is as defined in category A and Rn is hydrogen or alkyl.

Category A22: preferred additional compounds of the present invention are those of Category A21, wherein R1 is -Oalkyl, preferably -O-lower alkyl; D is -NR-alkyl wherein Rh is hydrogen or alkyl.

Category A23: Additional preferred compounds of the present invention are those of Category A3, where A is located in the meta or para position; R is -ORa, wherein Ra is hydrogen, alkyl or alkylaryl; -NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R2 is hydrogen or alkyl; R3 is hydrogen or alkyl; R4 is hydrogen; n is an integer from 1 to 3; D is located in the ortho, meta or para position and represents .NRcCONRaR1 '', where Ra, R and R1 'are as defined in category A; D 'is hydrogen; D "is hydrogen.

Category A24: Additional preferred compounds of the present invention are those of Category A23, wherein A is located in the position for; R is -OH, -Oalkyl, -Oalkylaryl; -NH2, -NHOalkylaryl or -NHCN; R2 is hydrogen; R3 is hydrogen; n is the integer 1; D is located in the position para, and represents - NHCONHR, where Rd is as defined in Category A.

Category A25: Additional preferred compounds of the present invention are those of Category A24, wherein R1 is -Oalkyl, preferably -O-lower alkyl; D is -NHCONHalkyl.

Category A26: Additional preferred compounds of the present invention are those of Category A3, where A is located at the meta or para position; R is -0Ra, wherein Ra is hydrogen, alkyl or alkylaryl; -NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R2 is hydrogen or alkyl; R3 is hydrogen or alkyl; R4 is hydrogen; n is an integer from 1 to 3; D is located in the ortho, meta or para position and represents -NR '~ CSNRaR, where Ra, R "and R1' are as defined in Category A, D 'is hydrogen, D" is hydrogen.

Category A27: Additional preferred compounds of the present invention are those of Category A26, in which A is located in the position for; R is -OH, -Oalkyl, -Oalkylaryl; -ISfflL, -NHOalkylaryl or -NHCN; R2 is hydrogen; R? it is hydrogen; n is the integer 1; D is located in the position para, and represents -NHCSNHR, where Rd is as defined in Category A.

Category A28: Additional preferred compounds of the present invention are those of Category A27, in which Ri is -O lower alkyl. D is -NHCSNHalkyl.

Category A29: Additional preferred compounds of the present invention are those of Category A23, wherein A is located in the meta or para position; R is -ORa, wherein Ra is hydrogen, alkyl, alkylaryl; -NHR, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R2 is hydrogen or alkyl; R3 is hydrogen or alkyl; R4 is hydrogen; n is an integer between 1 and 3; D is located in the ortho, meta or para position and represents -OS02Rd, where Rd is as defined in Category A; D 'is hydrogen; D "is hydrogen.

Category A30: Additional preferred compounds of the present invention are those of Category A29, in which A is located in the position for; R is -OH, -Oalkyl, -Oalkylaryl; -NH_, NHOalkylaryl or -NHCB; R 'is hydrogen; RJ is hydrogen; n is the integer 1; D is located in the para position and represents -OSO ^ alqullo or -OSOnalquilaril.

Category A31: Additional preferred compounds of the present invention are those of Category A30, in which R1 is -Oalkyl, preferably -O-lower alkyl; D is -OSO_ alkyl.

Category A32: Additional preferred compounds of the invention are 2-ethoxy-3- [4- (2. {4-methanesulfonyloxyphenyl) ethoxy) phenyl] propanoic acid; acid 3-. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl} -2-ethoxypropanoic; 2-ethoxy-3- acid. { 4- [2- (4-methanesulfonylphenyl) ethoxy] phenyl} propanoic; 2-ethoxy-3- acid. { 4- [2- (4-methylsulfanylphenyl) ethoxy] phenyljpropanoic acid; 2-ethoxy-3- [4- (2-. {4-isobutyrylaminophenyl) ethoxy) phenyl] propanoic acid; 3-ethyl ester. { 4- [2- (4-tert-butylcarbonyloxyphenyl). ethoxy] phenyl} - 2-ethoxypropanoic; 2-ethoxy-3- acid. { 4- [2- (4-methanesulfonylaminophenyl) ethoxy] phenyl} propanoic; N-cyano-2-ethoxy-3- [4- (2. {4-methanesulfonyloxyphenyl) ethoxy) phenyl] propanoic acid amide; N-benzyloxy-2-ethoxy-3- [4- (2. {4-methanesulfonyloxyphenyl) ethoxy) phenyl] propanoic acid amide; 2-ethoxy-3- [4- (2. {4-methanesulfonyloxyphenyl) ethoxy) phenyl] propanoic acid amide; 2-ethoxy-3-ethyl ester. { 4- [3- (3-methanesulfonyloxyphenyl) propoxy] phenyl} propanoic; 2-ethoxy-3- (4-. {2- [4- (2-propanesulfonyloxy) phenyl] ethoxy} phenyl) propanoic acid; acid 3- [4-. { 2- (4- [tert -butoxycarbonyl (methyl) amino] phenyl) ethoxy} phenyl] - (S) -2-ethoxypropanoic; (S) -2-ethoxy-3- [4-. { 2- [4- (methoxycarbonylamino) phenyl) ethoxy] phenyl} propanoic; 2-ethoxy-3-ethyl ester. { 4- [2- (4-methylcarbamoyloxyphenyl) ethoxy] phenyl} propanoic; acid 3- [4-. { 2- (4- [benzyloxycarbonylamino] phenyl) ethoxy} phenyl] - (S) -2-ethoxypropanoic; acid 3-. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] -3-methoxy phenyl} -2-ethoxypropanoic; 3- [4- (2. {4-tert-Butoxycarbonylaminophenyl) ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid methyl ester; (S) -2-ethoxy-3t (4-. {2- [4- (phenylsulfonyl) phenyl] ethoxy} phenyl) propanoic acid; And, where applicable, the stereo- and optical isomers and the racemates thereof as well as the pharmaceutically acceptable salts, solvates and crystalline forms thereof.

Category A33: Additional preferred compounds of the present invention are compounds that are one of the possible enantiomers.

When the alkyl is included in the substituent D the preferred alkyls are methyl, ethyl, propyl, isopropyl and tertiary butyl.

When the substituent R1 represents an alkyl group, the preferred alkyls are alkyl groups having from 2 to 6 carbon atoms.

When the substituent 0Ra represents an alkylaryl group, the preferred alkylaryl is benzyl.

In the present specification the term "pharmaceutically acceptable salts" is intended to define but not limit base salts such as the alkali metal salts, alkaline earth metal salts, aluminum, zinc and bismuth salts, ammonium salts, salts with amino acids basic, and salts with organic amines.

For all specifications and appended claims, a given chemical formula or name will encompass all stereo and optical isomers and racemates thereof (with the exception of Category 2 compounds), as well as mixtures in different proportions of the enantiomers separate, where such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and solvates thereof such as for example hydrates. The isomers can be separated using conventional techniques, for example, chromatography or fractional crystallization. The enantiomers can be isolated by separation of the racemate for example by fractional crystallization, definition or HPLC. The diastereoisomers can be isolated by separation of mixtures of isomers for example by fractional crystallization, HPLC or flash chromatography. Alternatively, the stereoisomers can be made by chiral synthesis of initial chiral materials under conditions that do not cause racemization or epimerization, or by derivation with a chiral reagent. All stereoisomers are included within the scope of the invention.

The following definitions will apply through all specifications and appended claims.

Unless otherwise stated or indicated, the term "alkyl" denotes a straight or branched substituted or unsubstituted alkyl group having 1 to 6 carbon atoms or a cyclic alkyl having 3 to 6 carbon atoms. The term "lower alkyl" denotes a straight or branched substituted or unsubstituted alkyl group having from 1 to 3 carbon atoms or a cyclic alkyl having 3 carbon atoms. Examples of said lower alkyls and alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl, and straight and branched pentyl and hexyl as well as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Unless stated or indicated otherwise, the term "alkoxy" denotes an O-alkyl group, wherein the alkyl is as defined above.

Unless otherwise stated or indicated, the term "halogen" shall mean fluorine, chlorine, bromine and iodine.

Unless otherwise stated or indicated, the term "aryl" denotes a substituted or unsubstituted phenyl, furyl, thienyl or pyridyl group, or a fused ring system of any of these groups, such as naphthyl.

Unless otherwise stated or indicated, the term "substituted" denotes an alkyl or an aryl group as defined above that is substituted by one or more alkyl, alkoxy, halogen, amino, thiol, nitro, hydroxy, acyl groups , aril, or cyan.

Unless otherwise stated or indicated, the term "alkylaryl" denotes a Rr Where n is an integer from 1 to 6 and Rr and Ri are the same or different and each represents hydrogen or an alkyl or aryl group as defined above.

Unless otherwise stated or indicated, the term "acyl" denotes a group O I -C-R1, wherein R: is hydrogen, alkyl, alkoxy, aryl and alkylaryl as defined above.

Unless stated or indicated otherwise, the terms "alkenyl" and "alkynyl" denote a straight or branched substituted or unsubstituted hydrocarbon group having one or more double or triple bonds and having a maximum of six carbon atoms. , preferably 3 carbon atoms.

Unless otherwise stated or indicated the term "protective group" (Rp) denotes a protecting group as described in the standard texts "Protecting groups in Organic Synthesis", 2a. Edition (1991) by Greene and Wuts. The protecting group may also be a polymeric resin such as Wang resin or 2-clarotrityl chloride resin.

Preparation Methods The compounds of the invention can be prepared as outlined below according to any of the methods AJ- however, the invention is not limited to these methods, the compounds can also be prepared as described for the structurally related compounds in the above in the matter.

A. The compounds of the invention of formula I wherein R2 and R4 are hydrogen can be prepared by a condensation reaction, such as a Knoevenagel or Wittig reaction, of a carbonyl compound of formula II with a compound of formula III or IV in said formulas D, D ', D ", n, R, R * and R" are as defined in Category A and L1 = L2 = L3 are phenyl or L- = L are 0Rd (where Rd is as defined in Category A) and "es = 0, and if desired, followed by the reduction of the double bond obtained and removal of the protective groups.

Al. In the condensation step approximately equimolar amounts of reactants are mixed in the presence of a base, such as sodium acetate, piperidine acetate, LDA or potassium tert-butoxide to provide the compound of formula I wherein a is the unsaturated portion. This step can be carried out in the presence of an inert solvent or in the absence of a solvent in which case the temperature would be sufficiently high to cause at least partial melting of the reaction mixture, such a preferred temperature is in the range of 100. ° C to 250 ° C.

Sometimes it is necessary to add a dehydrating agent such as p-toluenesulfonic acid in order to achieve the formation of the double bond.

In a typical reaction such the starting material, aldehyde or ketone and the compound of formula III are combined in approximately equimolar amounts and molar excess, preferably 1-5 times of anhydrous sodium acetate and the mixture is heated until melted, if necessary to the vacuum The compound of formula I in which A is the unsaturated portion, can then be isolated by mixing with water and acetone, followed by filtration of the formed precipitate. The crude product can be purified if desired, for example by recrystallization or by standard chromatography methods.

This reaction can also be conveniently carried out in a solvent such as toluene in the presence of piperidine acetate. The reaction mixture is refluxed in a Dean-Stark apparatus to remove water. The solution is then cooled and the olefin product is isolated and purified, by standard methods.

The reaction can also be carried out by mixing the aldehyde and the ketone and the compound of formula III in dry tetrahydrofuran, adding potassium tert-butoxide slowly at -20 ° C and quenching the reaction with acetic acid. The crude product is isolated and then dissolved in toluene and refluxed with p-toluenesulfonic acid in a Dean-Stark apparatus to remove the water. The product is then isolated and purified, by standard methods.

A2. The reaction can also be carried out in the presence of titanium (IV) chloride and pyridine in an inert solvent, such as chloroform.

A3. The condensation step could also be carried out as a Wittig-type reaction (see Comprehensive Organic Synthesis, vol.1, p 755-781 Pergamon Press) or as described in the experimental part. Approximately equimolar amounts of reactants II and IV are mixed in the presence of a base such as a potassium carbonate or tetramethylguanidine in a molar excess 1-5 times. This reaction can be carried out in the presence of an inert solvent such as dichloromethane or isopropanol at a suitable temperature (-10 ° C - + 60 ° C) and for a sufficient time.

The compound of formula II is prepared by coupling a compound of formula V with a compound of formula VI in said formulas D, D ', D ", n and R are as defined in Category A, a, for example alkylation conditions or by a Mitsunobu reaction (Tsunoda, Tetr.Lett.34, 1639-42 (1993) , when necessary followed by modifications of the D groups as described in the experimental section The group R 'can be -OH or a displaceable group, such as halogen, sulfonate or triflate.

The alkylation reaction and the Mitsunobu reaction can be carried out as described below or as in the experiment section.

The compounds of formula III, IV, V or VI are either commercially available or can be prepared by standard procedures known to any person skilled in the art from commercially available raw materials or by methods described in the experimental section.

The reduction of the olefin can be effected by using a wide variety of known reduction methods to reduce carbon-carbon double bonds, such as catalytic hydrogenation in the presence of an appropriate catalyst, magnesium or sodium amalgam in a lower alcohol such as methanol, or hydrogen transfer reagents such as diethyl-2,5-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.

The catalytic hydrogenation can be conducted in alcohol, cellosolves, protic polar organic solvents, ethers, lower aliphatic acids, and particularly in methanol, ethanol, methoxyethanol, dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate or acetic acid, either alone or in mixture. Examples of catalysts used include palladium black, palladium or activated carbon, platinum oxide or the Wilkinson catalyst. The reaction can be carried out at different temperatures and pressures depending on the reactivity of the proposed reaction.

In the case of hydrogen transfer reactions with diethyl-2,5-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, equimolar amounts of reactants are mixed and the mixture is heated to melting (140 ° C, 250 ° C). ) in an inert atmosphere or in a vacuum.

B. The compounds of the invention of formula I wherein A = CR3R4-CR1R: -COR, wherein R is hydrogen can be prepared by reacting a carbonyl compound of formula II with a compound of formula VII R * H-C - COR VII R¿ in said formulas D, D ', D ", n, R1 and R3 are as defined in Category A and R2 is alkyl, aryl or alkylaryl, followed by dehydroxylation and if necessary by removal of protecting groups.

In the reaction the compound of formula II is reacted with a compound of formula VII in the presence of a strong base such as LDA in an inert solvent followed by the addition of a dehydroxylating agent such as borotrifluoride etherate. The reaction can be carried out as described in the experimental section or by standard methods known to some experts in the field.

The compound of formula VII is "either commercially available or can be prepared by standard procedures.

C. The compounds of the invention of formula I wherein A = CR:, R4-CR1R "-COR, can be prepared by an alkylation reaction with a compound of formula VIII ? Vile! wherein X is a displaceable group, such as halogen, sulfonates or triflates, in a compound of formula VII, R 1 H-C-COR VI! R¿ In said formulas D, D ', D ", n, R, R :, R, R' and R are as defined in Category A and, if desired, followed by removal of the protecting groups.

In the alkylation step the compound of formula VII is reacted with a compound of formula VIII in the presence of one or more bases such as potassium carbonate, triethylbenzylammonium chloride, sodium hydride, LDA, butyllithium or LHMDS and in an inert solvent such as acetonitrile, DMF or dichloromethane at a suitable temperature and time. The reaction can be carried out as described in the examples or by standard methods known in the literature. (Synth, Comm. 19 (788) 1167-1175 (1989)).

The compound of formula VIII can be prepared from an alcohol of formula IX 1X where D, D ', D ", n, R3 and R4 are as defined in Category A, using standard methods or as described in the experimental section.

The compound of formula IX can be prepared from a compound of formula II either by reduction with a known reducing agent to convert a carbonyl group to a hydroxyl group such as lithium borohydride or sodium borohydride or by reaction with an organometallic compound such as a organolithium or a Grignard reagent by standard methods or as described in the experimental section.

D. The compounds of the invention of formula I can be prepared from a compound of the formula with a compound of formula X in said formulas D, D ', D ", n and A are as defined in Category A, and R- is -OH or a displaceable group such as halogen, sulfonate, triflate, either by an alkylcation reaction or by a Mitsunobu reaction, when necessary followed by removal of protective groups.

The compound of formula X can be prepared according to method A from commercially available starting materials and compounds of formula III and IV.

Dl. In an alkylation reaction the displaceable group R1 may be a sulfonate such as mesylate, nosylate, tosylate, or a halogen, such as bromine or iodine. The compounds of formula V and X, in approximately equimolar amounts or with an excess of one of the compounds are heated at reflux temperature in an inert solvent, such as isopropanol or acetonitrile, in the presence of a base, such as potassium carbonate. or cesium carbonate.

The mixture is refluxed for the necessary time, typically between 0.5 hrs to 24 hrs, the preparation process usually includes filtration, for removal of solid salts, evaporation and extraction with water and an organic solvent such as dichloromethane, ethyl acetate, or ether diethyl The crude product is purified if desired, for example by recrystallization or by standard chromatographic methods.

E. The compounds of the invention of formula I, wherein A is -CR3R4-CR1R2-COR, wherein R, R2, R3 and R4 are as defined in Category A and R1 is -0R, wherein Re is as defined in Category A, -0- [CH;], -ORf, where my Rf are as defined in Category A, -OCONRaRk where Ra and R "are as defined in Category A, can prepared by conversion of a compound of formula XI Where D, D, D ", n, R, R2, R3 and R4 are as defined in Category A and X" is -OH followed, if necessary, by removal of the protecting groups.

The reaction can be carried out as an alkylation reaction, a Mitsunobu reaction, an esterification reaction or by reaction with isocyanates. The alkylation reaction can be carried out using a variety of alkylating agents, such as alkyl halide. The esterification reaction can be carried out using a variety of acylating agents such as Cl-CO-R (wherein Rd is as defined in Category A) and the Mitsunobu reaction can be carried out using an alcohol such as phenol. The reactions can be carried out according to methods known to those skilled in the art as described in the examples.

The compound of formula XI can be prepared by reaction of a compound of formula V with a compound of formula XII Where D, D ', D ", n, R, R-, R, R" are as defined in Category A and R1 is -OH or a displaceable group such as halogen, sulfonate or triflate and X "is - OH followed, if necessary, by removal of protective groups.

The reaction can be carried out as described above or by standard methods known to any person skilled in the art.

The compound of formula XII can be prepared according to literature methods from commercially available starting materials.

F. compounds of the formula I wherein -CRR ^ -CR1R ~ -COR, and R, R2, R? and R4 are as defined in Category A and R1 is -SR4, where Rd is as defined in Category A, can be prepared by reacting a compound of formula XIII wherein D, O ', D ", n, R, R2, R3, R4 are as defined in Category A and X' is halogen, a thiol in a substitution reaction.The reaction may be carried out in accordance with known methods by those skilled in the art as described in the examples.

The compound of formula XIII can be prepared in accordance with method D either from commercially available starting materials or from starting materials prepared by standard procedures from commercially available starting materials.

G. compounds of the invention of formula I wherein D is -OSO_Rd, -SR, -OCONRfR, -NR ~ COORd, -NR "COR% -NR kk -NR" CONRaR ", NRSO_R and .NR ~ CSNRaR '" , wherein R% R ~, R a, R f, R 1 and R 1 'are as defined in Category A, can be prepared by reacting a compound of formula XIV where D ', D ", n and A are as defined in Category A and X1 = -OH, -SH or -NR" H, with a suitable reagent, such as a sulfonhalide, isocyanate, acylhalide, chloroformate, anhydride or alkylhalide in an inert solvent such as dichloromethane or toluene and when necessary in the presence of a base, such as triethylamine or pyridine and eventually followed by removal of the protecting groups.

The reaction can be carried out according to methods known to those skilled in the art or as described in the examples.

H. Compounds of the invention of formula I wherein R is -OH can be prepared from a compound of formula I wherein R is ORp, wherein Rp is a protecting group such as alkyl, aryl, alkylaryl or a polymeric resin such as Wang resin or 2-chlorotrityl chloride resin, by removal of the protecting group by hydrolysis. The hydrolysis can be carried out in accordance with standard methods, either in basic or acidic conditions.

I. The compound of the invention of formula I wherein R is -NRaRb can be prepared by reacting a compound of formula I when R is -OH with a compound of formula HNRaRb in the presence of a peptide coupling system (eg EDC, DCC, HBTU, TBTU or PyBop or oxalilchloride in DMF), an appropriate base (for example (for example pyridine, DMAP, TEA or DiPEA) and a suitable organic solvent (for example dichloromethane, acetonitrile or DMF) according to methods known per se. those skilled in the art or as described in the examples.

J. The compounds of the invention of formula I wherein D is -S02Rd or -SORd, wherein Rd is as defined in Category A, can be prepared by oxidation of a compound of formula XV Where D ', D ", n and A are as defined in Category A and X2 is -S0R or -SRd, where Rd is as defined in Category A with oxidizing agents such as m-chloroperoxybenzoic acid or peroxide of hydrogen in an inert solvent such as dichloromethane eventually followed by removal of the protecting groups.

The reactions can be carried out in accordance with standard procedures or as described in the experimental section.

The compounds of the invention can be isolated from their reaction mixtures using conventional techniques.

Those skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative and sometimes more convenient manner, the individual steps of the aforementioned process can be carried out in a different order, and / or the individual reaction can be carried out in different stage of the global route (for example, the chemical transformation can be carried out with different intermediaries to those previously associated with a particular reaction).

In any of the foregoing methods of preparation from A to J, where necessary, hydroxy, amino or other reactive groups can be protected using a protecting group, RF as described in the standard text "Protective groups in Organic Synthesis", 2a . Ed. (1991) by Greene and Wuts. The protecting group Rp can also be a resin, such as the Wang resin or the 2-chlorotryril chloride resin. The protection and deprotection of the functional groups can take place before or after any of the steps described above. Protective groups can be eliminated according to techniques that are well known to those skilled in the art.

The term "inert solvent" refers to a solvent that does not react with the starting materials, reagents, intermediates or products in a manner that adversely affects the result or the desired product.

Pharmaceutical preparations The compounds of the invention will normally be administered orally, parenterally, intravenously, intramuscularly, subcutaneously or in other forms, injectable, buccal, rectal, vaginal, transdermal and / or via inhalation, in the form of pharmaceutical preparations comprising the ingredient active as either a free acid, or a pharmaceutically acceptable organic or inorganic base addition salt, in a pharmaceutically acceptable dosage form Depending on the disorders and patients to be treated and the route of administration, the compositions may be administered in varying doses .

The compounds of the invention may also be combined with other therapeutic agents that are useful in the treatment of disorders associated with the development and progression of arteriosclerosis such as hypertension, hyperlipidemias, dyslipidemias, diabetes and obesity.

Suitable daily doses of the compounds of the invention in human treatment are approximately 0.0001-100 mg / kg body weight, preferably 0.001-10 mg / kg body weight.

According to a further aspect of the invention there is thus provided a formulation which includes any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, in mixtures with pharmaceutically acceptable adjuvants, diluents and / or vehicles.

Pharmacological Properties The compounds of formula (I) herein will be adapted for the prophylaxis and / or treatment of clinical conditions associated with reduced insulin sensitivity (insulin resistance) and associated metabolic disorders. These clinical conditions will include, but not be limited to, abdominal obesity, hypertension, hyperinsulinemia, hyperglycemia, diabetes mellitus not dependent on insulin (NIDDM) and dyslipidemia that characteristically appear with insulin resistance. This dyslipidemia, also known as the phenotype B profile of atherogenic lipoprotein, is characterized by moderately elevated non-esterified fatty acids, low density lipoprotein triglycerides (VLDL), high density lipoprotein cholesterol (HDL), and the presence of of low density lipoproteins (LDL), small, dense. Treatment with the compounds of the present is expected to decrease the cardiovascular morbidity and mortality associated with arteriosclerosis. These conditions of cardiovascular disease include macro-angiopathies that cause myocardial infarction, cerebrovascular disease and peripheral arterial insufficiency of the lower extremities. Because of their insulin sensitizing effect, the compounds of formula (I) are also expected to reduce the progress of the clinical conditions associated with chronic hyperglycemia in diabetes as well as the micro-angiopathies that cause kidney disease and damage to the retina. In addition, the compounds may be useful in the treatment of various external conditions of the cardiovascular system associated with insulin resistance characteristic of polycystic ovarian syndrome.

Practical examples Determinations of AH NMR and * ~ C NMR were made in a BRUCKER ACP 300 or VARIAN UNITY plus 400, 500 or 600 spectrophotometer, operating at H frequencies of 300, 400, 500 and 600 MHz, respectively, and at frequencies of "C of 75, 100, and 150 MHz, respectively.

Unless established or otherwise indicated, chemical shifts are given in ppm with the solvent as the internal standard.

Example 1. Ethyl 2-ethoxy-3- [4- (2. {4-methanesulfonyloxyphenyl) ethoxy) phenyl] propanoic acid ethyl ester (a) 2- (4-methanesulfonyloxyphenyl) ethyl methanesulfonate P-Hydroxyphenethyl alcohol (15 g, 0.108 mol) was dissolved in dichloromethane. Triethylamine (27.3 g, 0.27 mol) was added followed by the addition of a solution of methanesulfonyl chloride (27.2 g, 0.239 mol) in dichloromethane at 0 ° C. The reaction mixture was allowed to reach room temperature, then stirred at room temperature and followed with TLC. The reaction mixture was filtered. The filtrate was washed with water, the phases were separated and the organic phase was dried with sodium sulfate and evaporated in vacuo to give 28 g (88% yield) of 2- (4-methanesulfonyloxyphenyl) ethyl methanesulfonate.

: H-NMR (400 MHz, CDC15): d 2.85 (s, 3H), 3.05 (t, 2H), 3.15 (s, 3H), 4.35 (s, 2H), 7.2 (dm, 2H), 7.25 (dm) , 2H). 13C-NMR (100MHz; CDCl3): d 34. 8, 37 .3, 69. 6, 122 .2, 130. 5, 135. 8, 148. 1; (b) 4- [2- (4-f ormilf enoxi) ethyl] f enylmetansulfonnate 2- (4-methanesulfonyloxyphenyl) ethyl methanesulfonate (30 g, 0.102 mol) was dissolved in acetonitrile and slowly added to the mixture of p-hydroxybenzaldehyde (31.1 g, 0.255 mol) and potassium cabronate (41.46 g, 0.3 mol) in acetonitrile. and refluxed until 2- (4-methanesulfonyloxyphenyl) ethyl methanesulfonate was consumed. The salts were removed from the filtrate, the solvent was evaporated in vacuo, dichloromethane was added. The organic phase was washed with water and evaporated. Purification by chromatography on silica gel using dichloromethane as eluent gave 21.6 g (66% yield) of 4- [2- (4-formylphenoxy) ethyl] phenyl ethanesulfonate.

^ - MR (400 MHz, CDC1_): 5 3.05-3.15 (t, 2H; s, 3H), 4.2 (t, 2H), 6.95 (dm, 2H), 7.2 (dm, 2H), 7.3 (dm, 2H ), 7.8 (dm, 2H), 9.8 (s, 1H). 13C-NMR (100 MHz, CDC13): d 37.3, 38.3, 63.4, 116.1, 122.1, 129.2, 130.6, 132.6, 138.1, 147.7, 162.6, 191.7. (c) 2-Ethoxy-3-ethyl ester. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy-phenyl} acrylic Tetramethylguanidine (1.73 g, 15.0 moles) was added slowly to a solution of 4- [2- (4-formylphenoxy) ethyl] phenylmethanesulfonate (4.49 g, 14.0 mmol) and (1,2-diethoxy-2-oxoethyl) chloride ( triphenyl) phosphonium (5.62 g, 13.1 mmol) in chloroform (50 ml) at 0 ° C. After stirring at room temperature overnight the solvent was evaporated in vacuo. When the diethyl ether was added to the residue, the triphenylphosphine oxide crystallized as white crystals, which were removed by filtration. The filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate in heptane (gradient 1.25-100%) as eluents). The crude product crystallized at rest. Recrystallization gave 2.18 g (35% yield) of 2-ethoxy-3-ethyl ester. { 4- [methanesulfonyloxy-phenyl) ethoxy] -phenyl} acrylic like white crystals.

^ - MRÍdOO MHz; CDC1¿): d 1.34-1.38 (2t, 2x6H, J = 7 Hz for both), 3.11 (t, 2H, J = 6 HZ), 3.13 (s, 3H), 3.98 (q, 2H, J = 7 HZ ), 4.2 (t, 2H, J = 6.8 Hz), 4.28 (q, 2H, J = 7 Hz), 6.87 (dm, 2H, J = 9 Hz, unresolved), 6.95 (s, 1H), 7.23 ( dm, 2H, J = 9 Hz, unresolved), 7.33 (dm, 2H, J = 9 Hz, unresolved), 7.73 (dm, 2H, J = 9 Hz, unresolved) 13 C-NMR (125 MHz, CDCl 3): d 14.3, 15.5, 35.0, 37.3, 61.0, 67.5, 68.1, 114.4 ', 122.0, 123.8, 126.6, 130.5, 131.7, 137.7, 143.1, 147.9, 159.0, 164.9. (d) 2-Ethoxy-3- [4- (2. {4-methanesulfonyloxyphenyl) ethoxy) phenyljpropanoic acid ethyl ester The ethyl ester of 2-ethoxy-3- acid. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} Acrylic (1.47 g, 3.38 mmol) was hydrogenified for 3 hours at atmospheric pressure in ethyl acetate (50 ml) using Pd / C (0.74 g, 5%) as a catalyst. The reaction mixture was filtered through celite, dried (magnesium sulfate) and the solvent was evaporated in vacuo to give 1.44 g (98% yield) of 2-ethoxy-3- [4-] ethyl ester. { 4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic.

XH-NMR (500 MHz, CDC13): d 1.16 (t, 3H, J = 7 Hz), 1.23 (t, 3H, J = 7 Hz), 2.92-2.96 (m, 2H), 3.09 (t, 2H, J = 6.6 Hz), 3.13- (s, 3H), 3.31-3.38 (m, 1H), 3.56-3.63 (, 1H), 3.94-3.98 (, 1H), 4.12-4.19 (m, 4H), 6.8 ( dm, 2H, J = 8.8 Hz, unresolved), 7.14 (dm, 2H, J = 8.9 Hz, unresolved), 7.22 (dm, 2H, J = 8.9 Hz, unresolved), 7.33 (dm, 2H, J = 8.6 Hz, unresolved). 13 C-NMR (125 MHz; CDC 13): d 14.2, 15.0, 35.1, 37.2, 38.4, 60.7, 66.1, 68.1, 80.3, 114.3, 121.9, 129.5, 130.4, 130.5, 138.0, 147.8, 157.4, 172.5.

Example 2-Ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl) ethoxy) phenyl] propanoic acid Hydrated lithium hydroxide (0.12 g, 2.82 mmol) dissolved in water was added slowly to a solution of 2-ethoxy-3- [4- (2. {4-methanesulfonyloxy-phenyl-phenyl) -phenyl] -propanoic acid ethyl ester. (described in Example Id) (1.12 g, 2.56 mmole) in tetrahydrofuran (30 ml). After stirring at room temperature for 3 hours. Water (50 ml) was added and the tetrahydrofuran was removed by evaporation in vacuo. The residue was acidified with hydrochloric acid (2M), and extracted three times with ethyl acetate. The combined organic phases were dried with magnesium sulfate. Evaporation of the solvent gave 1 g (96% yield) of 2-ethoxy-3- [4- (2. {4-methanesulfonyloxyphenyl) ethoxy) -phenyl] propanoic acid.

^ -NMR (500 MHz, CDC1_): d 1.17 (t 3H, J = 7 Hz), 2.91-2.99 (m, 1H), 3.03-3.11 (m, 3H), 3.12 (s, 3H), 3.39-3.47 (m, 1H), 3.57-3.64 (m, 1H), 4.01-4.06 (1H), 4.14 (t, 2H, J = 6.7 Hz), 6.81 (dm, 2H, J = 8.6 Hz, unresolved), 7.15 (dm, 2H, J = 8.6 Hz, unresolved), 7.22 (dm, 2H, J = 8.6 Hz, unresolved), 7.33 (dm, 2H, J = 8.6 Hz, unresolved). 13 C-NMR (125 MHz; CDC 13): d 15.0, 35.1, 37.2, 37.8, 66.8, 68.1, 79.7, 114.4, 121.9, 128.8, 130.49, 130.52, 137.9, 147.8, 157.5, 169.1.

Example 3. Amide N-cyano-2-ethoxy-3- [4- (2-. {4-methanesulfonyloxyphenyl}. Ethoxy) phenyl] propanoic DCC 0.44 g; 2.15 mmole) and N-hydroxy-succinimide (0.247 g, 2.15 mmole) to a solution of 2-ethoxy-3- [4- (2. {4-methanesulfonyloxyphenyl) ethoxy) phenyl] propanoic acid (described in Example 2) (0.8 g, 1.96 mmol) in acetonitrile (20 ml) at 0 ° C. After stirring at room temperature overnight a precipitate was separated by filtration and diisopropylethylamine (1 ml, 5.88 mmol) and cyanamide (0.165 g, 3.92 mmol) were added. After stirring overnight the reaction mixture was poured into potassium bisulfate (1M, 20 ml) and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried (sodium sulfate) and the solvent was evaporated. Chromatography of the crude product on silica gel using ethyl acetate: heptane; acetic acid (10: 10: 1) as eluent gave 0.755 g (89% yield) of amide N-cyano-2-ethoxy-3- [4- (2-. {4-methanesulfonyloxy-phenyl} ethoxy] ) phenyl] propanoic. 2H NMR (500 MHz, CD50D): d 7.39 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 4.16 (t, J = 6.6 Hz, 2H), 3.79 (dd) , J = 8.6 Hz and 4.5 Hz, 1H), 3.53 (m, lH), 3.22 (m, 1H), 3.17 (s, 3H), 3.07 (t, J = 6.6 Hz, 2H), 2.86 (dd, J = 13.9 Hz and 4.5 Hz, 1H), 2.75 (dd, J = 13.9 Hz and 8.6 Hz, 1H), 1.07 (t, J = 7.0 Hz, 3H).

Example 4. Amide N-benzyloxy-2-ethoxy-3- [4- (2. {4-methanesulfonyloxyphenyl}. Ethoxy) phenyl] propanoic DCC (1 g, 4.85 mmol) and N-hydroxy-succinimide acid (0.56 g, 4.85 mmol) were added to a solution of 2-ethoxy-3- [4- (2. {4-methanesulfonyloxyphenyl)}. ethoxy) phenyl] propanoic acid (described in Example 2) (1.65 g, 4.04 mmol) in acetonitrile (25 ml) at 0 ° C. After 1 hour a precipitate was filtered off (1.82 g, 14.1 mmol) and benzyl hydroxylamine (1.24 g, 8.08 mmol) dissolved in acetonitrile was added. After stirring overnight, hydrochloric acid (2M) was added and the mixture was extracted with diethyl ether. The organic phase was washed with sodium carbonate solution and dried (magnesium sulfate). The solvent was removed and the crude product was purified by chromatography on silica gel using ethyl acetate: heptane (gradient 10-100% ethyl acetate) as eluent to give 1-36 g (66 ° yield) of amide N -benzyloxy-2-ethoxy-3- [4- (2-. {4-methanesulfonyloxy-phenyl-malexy) phenyl] -propanoic acid. 1H-NMR (400 MHz; CDC1: d 1.01 (t, 3H, J = 7.1 Hz), 2.82-2.90 (m, 1H), 3.03-3.11 (m, 3H), 3.12 (s, 3H), 3.36 (q , 2H, J = 7.1 HZ), 3.91-3.96 (m, 1H), 4.13 (t, 2H, J = 6.8 Hz), 4.76 (d, 1H, J = 11.4 Hz), 4.88 (d, 1H, J = 11.4 Hz) 6.79 (dm, 2H, J = 8.8 Hz, unresolved), 7.12 (dm, 2H, J = 8.8 Hz, unresolved), 7.21 (dm, 2H, J = 8.8 Hz, unresolved), 7.27- 7.36 (m, 7H), 8.69 (s, INH). 13 C-NMR (100 MHz; CDCl 3): 5 15.0, 35.1, 37.3, 37.8, 66.7, 68.2, 78.3, 81.0, 114.2, 121.9, 128.5, 128.8, 129.17, 129.23, 130.5, 130.8, 135.0, 138.0, 147.8, 157.5 168.8.

Example 5. Amide 2-ethoxy-3- [4- (2-. {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid.

Ammonia was bubbled through a mixture of 2-ethoxy-3- [4- (2. {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid (written in Example 2) (2.9 g, 7.1 mmol) and benzotriazol-1-yl-oxy-tris-pyrrolidin-phosphonium hexafluorophosphate (3.7 g, 7.1 mmol) in DMF (30 ml) for 3 hours at room temperature. Water and ethyl acetate were added. The phases were separated, the organic phase was washed with water, dried with magnesium sulfate and the solvent was evaporated in vacuo.The crude product was crystallized from diethyl ether to give 2.5 g (86% yield) of white amide powder 2-ethoxy-3- [4- (2-. {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid.

^ -NMR (300 MHz, CDC13): d 1.13 (t, 3H, J = 6.8 Hz), 2.80-2.90 (m, 1 H), 3.05-3.14 (m, 6H) 9 3.36-3.56 (, 2H), 3.84-3.91 (m, 1H), 4.14 (t, 2H, J = 6.5 Hz), 5.38 (s br, 1 NH), 6.42 (s br, 1 NH), 6.80 (dm, 2H, J = 8.8 Hz, unresolved), 7.15 (dm, 2H, J = 8.8 Hz, unresolved), 7.19-7.27 (m, 2H), 7.34 (dm, 2H, J = 8.1 Hz, unresolved). 13 C-NMR (75 MHz; CDCl: d 15.2, 35.2, 37.3, 38.0, 66.6, 68.1, 81.4, 114.2, 122.0, 129.7, 130.58, 130.64, 138.0, 147.8, 157.3, 175.2.

Example 6. Ethyl ester of 2-cyano-3- acid. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} acrylic A mixture "of 4- [2- (4-formylphenoxy) ethyl] phenylmethanesulfonate (described in Example Ib) (2g, 6.24 mmol), ethyl cyanoacetate (1.41 g, 12.48 mmol) and sodium acetate (1.34 g; Immoles) was heated to 120 ° C. The mixture that was melted by heating was allowed to stand for cooling, dichloromethane was added, the solution was washed with water and brine, the organic phase was dried with sodium sulfate, filtered and the The solvent was evaporated in vacuo, chromatography of the crude product over silica gel using heptane: ethyl acetate (gradient 9: 1 to 1: 1) as eluent followed by crystallization gave 1.98 g (77 i yield) of 2-ethyl ester. -cyano-3- { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} acrylic.

-NMR (400 MHz, CDC1_): d 1.37 (t, 3H, J = 7.1 Hz), 3.13 (t 2H, J = 6.8 HZ), 3.13 (s, 3H), 4.24 (t, 2H, J = 6.8 HZ ), 4.35 (q, 2H, J = 7.1 Hz), 6.95 (dm, 2H, J = 9 Hz, unresolved), 7.23 (dm, 2H, J = 9 Hz, unresolved), 7.32 (dm, 2H, J = 9 Hz, unresolved), 7.97 (dm, 2H, J = 9 Hz, unresolved), 8.15 (s, 1H). 13 C-NMR (100 MHz; CDCl 3): d 14.2, 34.9, 37.4, 62.4, 68.6, 99.6, 115.2, 116.1, 122.1, 114.6, 130.5, 133.6, 137.3, 148.0, 154.3, 162.8, 163.1.

Example 7. Ethyl ester of 2-cyano-3- acid. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic A mixture of the ethyl ester of 2-cyano-3- acid. { .4- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} acrylic (described in Example 6) (1.69 g, 4.07 mmol) and diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate (2.06 g, 8.14 mmol) was slowly heated to more than 190 ° C under vacuum and then kept at rest for cooling to room temperature. The crude product was purified by chromatography on silica gel using heptane: ethyl acetate (gradient 2: 1 to 1: 1) as eluent to give 1.55 g (91% yield) of 2-cyano-3-ethyl ester. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic XH-NMR (400 MHz, CDCl 5): d 1.17 (t, 3H, J = 7 Hz), 2.96-3.16 (m, 6H), 3.66-3.72 (m, 1H), 4.05 (t, 2H, J = 6.8 Hz), 4.13 (q, 2H, J = 7 Hz), 6.73 (dm, 2H, J = 8.5 Hz, unresolved), 7.09- 7.19 (, 4H), 7.25 (dm, 2H, J = 8.5 Hz, no solve). 13 C-NMR (100 MHz; CDCl 3): -d 13.4, 34.3, 34.5, 36.7, 39.3, 114.3, 116.0, 121.5, 127.2, 129.6, 130.1, 137.4, 147.5, 157.7, 165.2.

Example 8 ^ 2-cyano-3- acid. { 4- [2-4-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic A mixture of the ethyl ester of 2-cyano-3- acid. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic (described in Example 7) (0.9 g, 2.16 mmol), lithium hydroxide hydrate (0.12 g, 2.86 mmol), methanol (5 mL), water (5 mL) and tetrahydrofuran (10 mL) was stirred for 30 minutes at room temperature. Water was added and the mixture was washed with diethyl ether. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and evaporated in vacuo. The crude product was purified by crystallization from diisopropyl ether to give 0.56 g (67% yield) of 2-cyano-3- acid. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic 1 H-NMR (500 MHz; CDC1¿): d 3.02-3.3 (m, 7H), 3.7-3.8 (m, 1H), 4.15 (t, 2H, J = 6.7 Hz), 6.8-6.9 (, 2H), 7.15-7.27 (m, 4H), 7.27-7.4 (, 2H), 8.67 (s, 1H, OH). 13C-NMR (100 MHz; CDC13): d 34.8, 35.0, 37.3, 39.9, 68.2, 114.9, 115.6, 122.0, 127.0, 130.2, 130.6, 137.8, 147.8, 158.3, 170.0.

Example 9. 2-cyano-3- acid. { 4- [2-methanesulfonyloxyphenyl) ethoxy] phenyl} acrylic Ethyl ester of 2-cyano-3- acid. { 4-methanesulfonyloxyphenyl) ethoxy] phenyl} acrylic (described in Example 6) (0.201 g; 0.483 mmol), lithium hydroxide (0.04 g, 1.67 mmol), methanol (2.3 ml) and water (2.3 ml) were stirred at 40 ° C for 23 hours. More water was added, the methanol was removed by evaporation in vacuo and the mixture was acidified using potassium bisulfate. The mixture was extracted with ethyl acetate and the organic phase was dried (sodium sulfate), filtered and evaporated in vacuo. The crude products were purified on preparative HPLC using acetonitrile (gradient 30-60%): ammonium acetate (0.1 M). The fractions were acidified with potassium bisulfate and then extracted with ethyl acetate. The organic phases were combined and evaporated in vacuo to give 7 mg of 2-cyano-3- acid. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy] -phenyl} Acrylic and 21.8 mg of 2-cyano-3- acid. { 4- [2- (4-hydroxyphenyl) ethoxy] phenyl} -acrylic. aH-NNR (400 MHz, CDC1: d 3.11 (t, 2H, J = 6.8 Hz), 3.12 (s, 3H), 4.23 (t, 2H, J = 6.8 Hz), 6.94 (dm, 2H, J = 9 Hz, unresolved), 7.22 (dm, 2H, J = 8.5 Hz, unresolved), 7.31 (dm, 2H, J = 8.5 Hz, unresolved), 7.95 (dm, 2H, J = 9 Hz, unresolved) , 8.13 (s, 1H). 13C-NMR (100 MHz; CDC1: d 34.9, 37.4, 68.6, 99.6, 115.2, 116.3, 122.1, 124.5, 130.5, 133.6, 137.3, 148.0, 154.7, 162.8, 164.9.

Example 10. Dimethyl ester of 2- acid. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy] benzylidene} malonic A solution of titanium tetrachloride (4.82 g, 25.4 mmol) and carbon tetrachloride (6.35 ml) were added to dry tetrahydrofuran (50.8 ml) at 0 ° C under argon. To the mixture was added a solution of 4- [2- (4-formylphenoxy) ethyl] phenylmethanesulfonate (described in Example Ib) (4.0"? G; 12.7 mmol) in dry tetrahydrofuran (6.35 ml) and then dimethyl malonate ( 1.68 ml, 12.7 mmoles) Finally, pyridine in tetrahydrofuran was added over 3 hours.The reaction mixture was stirred at room temperature for 15 hours, water was added and the mixture was extracted with a mixture of diethyl ether and ethyl acetate. The organic phase was washed with water and the aqueous phase was extracted with dichloromethane, The organic phases were combined, dried (sodium sulfate), filtered and evaporated in vacuo to yield 5.34 g (97% yield) of dimethyl ester. 2- { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy] benzylidin.} malonic acid ^ -NMR (400 MHz, CDC1_): d 3.12 (t, 2H, J = 7), 3.14 (s, 3H), 3.84 (s, 3H), 3.87 (s, 3H), 4.2 (t, 2H, J = 7 Hz), 6.9 (dm, 2H, J = 9 Hz, unresolved), 7.24 (dm, 2H, J = 9 Hz, unresolved), 7.31-7.41 (, 4H), 7.7 (s, 1H). 13 C-NMR (100 MHz; CDCl 3): d 34.9, 37.3, 52.5, 52.6, 68.3, 114.9, 122.0, 122.9, 125.4, 130.5, 131.5, 137.5, 142.4, 147.9, 160.7, 164.8, 167.5.

Example 11. Dimethyl acid 2- ester. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy] benzyl} Malonic acid dimethyl ester 2-. { 4- [2-} 4-methanesulfonyloxyphenyl) ethoxy] benzylidene} Malonic acid (described in Example 10) (2.31 g, 5.32 mmol) was hydrogen for 2.5 hours at atmospheric pressure in ethyl acetate (140 ml) and acetic acid (5 ml) using Pd / C (0.8 g) as catalyst and then it was filtered through hyflo. The solvent was evaporated in vacuo, dichloromethane and dilute sodium bicarbonate solution were added and the phases were separated. The organic phase was washed with brine, dried (sodium sulfate), filtered and evaporated in vacuo to give 2.35 g (100 l yield) of the dimethyl ester of 2- acid. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy] benzyl. { Malonic XH-NMR (400 MHz, CDC1_): d 3.10 (t, 2H, J = 6.6 Hz), 3.14 (s, 3H), 3.17 (d, 2H, J = 7.6 Hz), 3.64 (t, 1H, J = 7.6), 3.71 (s, 6H), 4.15 (t, 2H, J = 6.6 Hz), 6.81 (dm, 2H, J = 8.8 Hz, unresolved), 7.11 (dm, 2H, J = 8.8 Hz, unresolved ), 7.24 (dm, 2H, J = 8.8 Hz, unresolved), 7.34 (dm, 2H, J = 8.8 Hz, unresolved)? 13C-NMR (100 MHz; CDC1 .d 33.9, 35.1, 36.0, 37.3, 52.5, 53.8, 68.2, 114.6, 121.9, 129.8, 130.0, 130.5, 137.9, 147.9, 157.5, 169.2.

Example 12. Ethyl ester of 2-ethoxy-3- acid. { 3- [3- (4-methanesulfonyloxyphenyl) propoxyjiphenyl} propanoic (a) Ethyl 3- (3-benzyloxyphenyl) -2-ethoxyacrylic acid ester Tetramethylguanidine (6.5 g, 56.6 mmol) was slowly added to a solution of 3-benzyloxybenzaldehyde (11.7 g, 55 mmol) and (1,2-diethoxy-2-oxoethyl) (triphenyl) phosphonium chloride (20.1 g, 46.8 mmol. ) in dichloromethane (200 ml) at 0 ° C. After stirring at room temperature overnight the solvent was evaporated in vacuo Diethyl ether was added and the insoluble material was removed by filtration. sodium bicarbonate, dried (magnesium sulfate), filtered and the solvent was evaporated in vacuo.The residue was purified by chromatography on silica gel using tetrahydrofuran (0.5%) in dichloromethane as eluent, the remaining aldehyde was removed by stirring with sodium bisulfite in water and diethyl ether for two days The phases were separated and the organic phase was evaporated in vacuo to give 10.5 g (69% yield) of 3- (3-benzyloxyphenyl) -2-ethoxyacrylic acid ethyl ester . 2H-NMR (300 MHz; CDC1_): d 1.4 (, 6H), 4.02 (q, 2H), 4.32 (q, 2H), 5.12 (s, 2H), 6.97 (unresolved, 2H), 7.3-7.5 ( m, 7H), 7.7 (unresolved, 1H). 13C-NMR (75 MHz; CDC1: d 14.3, 15.6, 61.2, 67.7, 69.9, 115.6, 116.1, 123.2, 123.7, 127.4, 128.0, 128.6, 129.4, 135.0, 137.0, 144.9, 158.8, 164.6. (b) Ethyl ester of 2-ethoxy-3- (3-hydroxyphenyl) propanoic acid The 3- (3-benzyloxyphenyl) -2-ethoxyacrylic acid ethyl ester (10.4 g, 31.8 mmol) was hydrogenatmosed to atmospheric pressure in ethyl acetate using Pd / C (dry, 10 l) as a catalyst. The reaction mixture was filtered through celite and the solvent was evaporated in vacuo. The initial materials were not completely consumed, so the hydrogenation was repeated to give 7 g (92% yield) of 2-ethoxy-3- (3-hydroxyphenyl) propanoic acid ethyl ester. 1H-NMR (300 MHz; CDC1: d 1.15 (t, 3H), 1.22 (t, 3H), 2.95 (m, 2H), 3.4 (m, 1H), 3.6 (m, 1H), 4.05 (m , 1H), 4.15 (q, 2H). 15C-NMR (75 MHz, CDC13): 6 14.1, 15.0, 39.2, 61.2, 66.4, 80.2, 113.9, 116.5, 121.2, 129.4, 137.2, 138.5, 156.0. (c) 3- (4-methanesulfonyloxyphenyl) propylmethanesulfonate 3- (4-Methanesulfonyl-oxyphenyl) propylmethanesulfonate was synthesized using the same method as in Example Ia from 3- (4-hydroxyphenyl) -1-propanol.

^ - MR (400 MHz, CDCI3): d 2.1 (q, 2H), 2.8 (t, 2H), 3.0 (s, 3H), 3.15 (s, 3H), 4.25 (t, 2H), 7.23-7.27 ( m, 4H). 13 C-NMR (100 MHz; CDC1: d 31.7, 32.1, 38.4, 38.5, 69.8, 123.2, 131.1, 140.9, 148.7. (d) 2-Ethoxy-3-ethyl ester. { 3- [3- (4-methanesulfonyloxyphenyl) propoxy] phenyl} propanoic 3- (4-Methanesulfonyloxyphenyl) propylmethanesulfonate (1905 g, 6.18 mmol) dissolved in acetonitrile (13 ml) was added dropwise to a mixture of 2-ethoxy-3- (3-hydroxyphenyl) -propanoic acid ethyl ester (1.47). g, 6.18 mmol) and potassium carbonate (2.56 g, 18.54 mmol) in acetonitrile (15 ml). The mixture was refluxed for 5 hours, then the solvent was evaporated in vacuo and water was added. The mixture was extracted twice with dichloromethane, dried (sodium sulfate), filtered and the solvent evaporated in vacuo. Purification by chromatography on silica gel using diethyl ether / petroleum ether (33% gradient to 100% diethyl ester) gave 1.80 g (65% yield) of 2-ethoxy-3-ethyl ether. { 3- [3- (4-methanesulfonyloxyphenyl) propoxy] phenyl} propanoic ^ -NMR (400 MHz, CDC13): d 1.17 (t, 3H, J = 7 Hz), 1.24 (t, 3H, J = 7.3 Hz), 2.05-2.14 (m, 2H), 2.84 (t, 2H, J = 7.5 Hz), 2.97-3.01, (m, 2H), 3.14 (s, 3H), 3.33-3.42 (m, 1H), 3.58-3.66 (m, 1H), 3.96 (t, 2H, J = 6 Hz), 4.0-4.05 (, 1H), 4.15-4.23 (m, 2H), 6.74-6.87 (m, 3H), 7.17-7.24 (m, 3H), 7.25-7.30 (m, 2H). 13C-NMR (100 MHz; CDC13): d 14.2, 15.0, 30.7, 31.6, 37.2, 39.4, 60.8, 66.2", 66.5, 80.1, 112.8, 115.6, 121.8, 121.9, 129.2, 130.0, 138.8, 141.0, 147.4, 158.8, 172.4.

Example 13. 2-Ethoxy-3- [3- (3. {4-methanesulfonyloxyphenyl) propoxy) phenyl] propanoic acid Lithium hydroxide hydrate (91.1 mg, 2.7 mmol) in water (6.6 ml) was slowly added to a solution of 2-ethoxy-3-ethyl ester. { 3- [3- (4-methanesulfonyloxyphenyl) propoxy] phenyl} propane (described in Example 12d) (0.889 g, 1.97 mmol) in tetrahydrofuran (9 ml). After stirring at room temperature for 5 hours, the tetrahydrofuran was removed by evaporation in vacuo. The residue was washed with diethyl ether and ethyl acetate. The aqueous phase was acidified with potassium bisulfate (1M), and extracted with ethyl acetate and dichloromethane. The organic phases were combined, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 0.91 g of 2-ethoxy-3- [3- (3. {4-methanesulfonyloxyphenyl) acid. propoxy) phenyl] propanoic.

XH-NMR (400 MHz, CDC13): d 1.20 (t, 3H, J = 7.1 Hz), 2.05-2.15 (m, 2H), 2.84 (t, 2H, J = 7.6 Hz), 2.95-3.03, (m , 1H), 3.11-3.17 (m, 4H), 3.46-3.65 (, 2H), 3.95 (t, 2H, J = 6.1 Hz), 4.09-4.14 (m, 1H), 6.77-6.81 (m, 2H) , 6.82 (dm, 1H, J = 7.81 Hz, unresolved), 7.19-7.29 (m, 5H). 13C-NMR (100 MHz; CDC1.,): D 15.0, 30.7, 31.6, 37.3, 38.6, 66.5, 67.0, 79.5, 113.0, 115.6, 121.88, 121.90, 129.4, 130.0, 138.0, 141.0, 147.4, 158.9, 173.9 .

Example 14. Methyl ester of 3- acid. { 4- [2-} 4-methanesulfonyloxyphenyl) ethoxy] phenyl} -2-methoxypropanoic (a) 3- (4-Benzyloxyphenyl) -2-methoxypropanoic acid methyl ester Silver oxide (I) (2.43 g, 10.5 mmol), molecular sieve (4 A °, 2 g) and methyl iodide (2.97 g; . 9 mmol) was added to a solution of 3- (4-benzyloxyphenyl) -2-hydroxypropanoic acid methyl ester (2.0 g, 6.98 mmol) in dry dichloromethane (20 ml). The reaction mixture was refluxed for 72 hours, filtered through celite and washed with water. The organic phase was dried with magnesium sulfate and evaporated in vacuo to give 1.93 g (92% yield) of a 3- (4-benzyloxyphenyl) -2-methoxypropanoic acid methyl ester oil.

^ -NMR (500 MHz, CDC13): d 2.90-3.01 (m, 2H), 3.35 (s, 3H), 3.71 (s, 3H), 3.91-3.96 (m, 1H), 5.04 (s, 2H), 6.90 (dm, 2H, J = 8.6 Hz, unresolved), 7.13 (dm, 9H, J = 8.6 Hz, unresolved), 7.29-7.35 (m, 1H), 7.35-7.40 (m, 2H), 7. 40-7.43 (m, 2H). (b) 3- (4-Hydroxyphenyl) -2-methoxypropanoic acid methyl ester The 3- (4-benzyloxyphenyl) -2-methoxypropanoic acid methyl ester (1.91 g, 6.36 mmol) was hydrogen in methanol (30 ml) using Pd / C (5% humidity, 0.9 g) as a catalyst. The mixture was filtered through celite and the filtrate was evaporated in vacuo to give 1.16 g (87% yield) of ester. 3- (4-hydroxyphenyl) -2-methoxypropanoic acid methyl ester. 1 H-NMR (500 MHz, CDC13): d 2.93-3.03 (m, 2H), 3.38 (s, 3H), 3.75 (s, 3H), 3.94-3.99 (m, 1H), 5.02-5.12 (s) br, 1 OH, 6.77 (dm, 2H, J = 8.3 Hz, unresolved), 7.11 (dm, 2H, J = 8.3 Hz, unresolved). (c) 3- Methyl ester. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy phenyl} -2-methoxypropanoic 3- (4-Hydroxyphenyl) -2.methoxypropanoic acid methyl ester was alkylated with 2- (4-methanesulfonyloxyphenyl) ethyl methanesulfonate (described in Example la) using the same method as in Example 1 (b) to give methyl ester of the acid 3-. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy] -phenyl} -2-methoxypropanoic.

XH-NMR (500 MHz; CDC13): d 2.9-3.0 (, 2H), 3.09 (t, 2H, J = 6.7 Hz), 3.13 (s, 3H), 3.34 (s, 3H), 3.72 (s, 3H) ), 3.90-3.95 (m, 1H), 4.14 (t, 2H, J = 6.7 Hz), 6.80 (dm, 2H, J = 8.6 Hz, unresolved), 7.11 (dm, 2H, J = 8.6 Hz, no solve), 7.22 (dm, 2H, J = 8.6 Hz, unresolved), 7.33 (dm, 2H, J = 8.6 Hz, unresolved).

Example 15. Acid 3-. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy-phenyl} -2-methoxypropanoic.

The methyl ester of 3- acid. { 4- [2-} 4-methanesulfonyloxyphenyl) ethoxy] phenyl} - 2- methoxypropanoic (described in Example 14) was hydrolyzed using the same method as in Example 2 to give 3- acid. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} - 2-methoxypropanoic ^ - MR (500 MHz, CDC13): d 2.91-2.99 (m, 1H), 3.03-3.10 (, 3H), 3.11 (s, 3H), 3.37 (s, 3H), 3.94-3.99 (m, 1H), 4.13 (t, 2H), 6.81 (dm, 2H, J = 8.3 Hz, unresolved), 7.15 (dm, 2H, J = 8.3 Hz, unresolved), 7.21 (dm, 2H, J = 8.3 Hz, 'unresolved), 7.32 (dm, 2H, J = 8.3 Hz, unresolved), 9.36 (bs, H). 13C-NMR (100 MHz, CDC13): d 35.0, 37.1, 37.7, 58.5, 68.1, 81.2, 114.4, 121.9, 128.7, 130.3, 130.5, 137.9, 147.8, 157.5, 176.3.

Example 16. 2-Hexyloxy-3- [4- (2. {4-methanesulfonyloxyphenyl) ethoxy) phenyl] propanoic acid methyl ester (a) 3- (4-Benzyloxyphenyl) -2-hexyloxypropanoic acid methyl ester 3- (4-Benzyloxyphenyl) -2-hydroxypropanoic acid methyl ester (0.4243 g, 1482 mol) was dissolved in dry dichloromethane (10 ml). Silver (I) oxide (1717 g, 7.41 mmol) was added, followed by the slow addition of hexyl iodide (0.943 g, 4.45 mmol). The reaction mixture was stirred at room temperature for 3 hours then molecular sieve (3 A °) was added and the reaction mixture was stirred for a further 4 days and then filtered. The solvent was evaporated and evacuation at 60 ° C for 5 hours gave 0.48 g (87% yield) of 3- (4-benzyloxyphenyl) -2-hexyloxypropanoic acid methyl ester. 1H-NMR (400 MHz; CDC1: d 0.88 (t, 3H), 1.18-1.34 (m, 6H), 1.47-1.60 (m, 2H), 2.91-3.10 (m, 2H), 3.22-3.29 (m, 1H), 3.52-3.59 (m, 1H), 3.72 (s, 3H), 3.95-4.02 (m, 1H), . 05 (s, 2H), 6.91 (dm, 2H, J = 8.8 Hz, unresolved), 7.16 (dm, 2H, J = 8.8 Hz, unresolved), 7.30-7.46 (, 5H). 13C-NMR (100 MHz; CDC1¿): d 14.0, 22.6, 25.6, 29.5, 31.5, 38.5, 51.8, 70.0, 71.0, 80.6, 114.6, 127.5, 127.9, 128. 5, 129. 130.4, 137.1, 157.6, 173.0. (b) 2-Hexyloxy-3- (4-hydroxyphenyl) propanoic acid methyl ester The methyl ester of 2-hexyloxy-3- (4-hydroxyphenyl) propanoic acid was prepared from the methyl ester of 3- (4-benzyloxyphenyl) -2-hexyloxypropanoic acid using the same method as described in Example 14b.

^ - MR (400 MHz, CDCI3): d 0.87 (t, 3H), 1.17-1.33 (m, 6H), 1.46-1.58 (m, 2H), 2.89-3.0 (m, 2H), 3.21-3.30 (m , 1H), 3.51-3.59 (m, 1H), 3.72 (s, 3H), 3.94-4.0 (m, 1H), 6. 75 (dm, 2H, J = 8.8 Hz, unresolved), 7.10 (dm, 2H, J = 8.8 Hz, unresolved), 7.27 (bs, 1H, OH). 13 C-NMR (100 MHz; CDC 13): d 14.0, 22.6, 25.6, 29.5, 31.5, 38.5, 51.8, 71.0, 80.6, 115.1, 129.3, 130.6, 154.3, 173.1. (c) 2-Hexyloxy-3- [4- (2. {4-methanesulfonyloxyphenyl) ethoxy) phenyl] propanoic acid methyl ester 2-Hexyloxy-3- (4-hydroxyphenyl) methylester was dissolved ) propanoic (0.33 g, 1.19 mmol) and 21 2- (4-methanesulfonyloxyphenyl) ethanol (0.2578 g, 1.19 mmol) in dichloromethane (5 ml) under argon. Azodicarbonyl dipiperidine (0.451 g, 1789 mmol) was added followed by the addition of triphenylphosphine (0.375 g, 1423 mmol). The reaction mixture was stirred at room temperature and after 2 hours more dichloromethane (2 ml) was added. The reaction mixture was stirred for another 18 hours and then filtered. The filtrate was washed with water, sodium bicarbonate solution, dilute potassium bisulfate solution and brine, dried with sodium sulfate and evaporated The chromatography of the residue on silica gel using heptane: ethyl acetate (2: 1 to 1 1) as eluent gave 0.381 g of (67% yield) of 2-hexyloxy-3- [4- (2. {4-methanesulfonyloxyphenyl) -ethoxy) phenyl] propanoic acid methyl ester.

XH-NMR (400 MHz; CDC1): d 0.86 (t, 3H), 1.16-1.32 (m, 6H), 1.46-1.58 (m, 2H), 2.90-3.01 (m, 2H), 3.10 (t, 2H, J = 6.8 Hz), 3.14 (s, 3H), 3.21-3.28 (m, 1H), 3.51-3.58 (m, 1H), 3.72 (s, 3H), 3.95-4.0 (m, 1H), 4.15 (t, 2H, J = 6.8 Hz), 6.81 (dm, 2H, J = 8.8 Hz, unresolved), 7.14 (dm, 2H, J = 8.8 Hz, unresolved), 7.24 (dm, 2H), J = 8.8 Hz, unresolved), 7.35 (dm, 2H, J = 8.3Hz, unresolved). 13C-NMR (100 MHz; CDC15): d 14.0, 22.5, 25.5, 29.5, 31.5, 35.1, 37.2, 38.4, 51.7, 68.1, 70.9, 80.5, 114.3, 121.9, 129.5, 130.4, 130.5, 137.9, 147.8, 157.4 172.9.

Example 17. 2-Hexyloxy-3- [4- (2. {4-methanesulfonyloxyphenyl) ethoxy) phenyljpropanoic acid Lithium hydroxide hydrate (0.036 g, 0.85 mmole) dissolved in water (2.6 ml) was added slowly at room temperature to a solution of 2-hexyloxy-3- [4- (2- {4 methanesulfonyloxy-phenyl.} ethoxy) phenyl] propanoic acid (described in Example 16) (0.37 g, 0.77 mmol) in tetrahydrofuran (3.5 ml). The reaction mixture was stirred at room temperature for 3.5 hours and then evaporated to remove tetrahydrofuran. The residue was acidified with potassium bisulfate (1M) until pH < 2 and then extracted with ethyl acetate. The organic phase was washed with brine and dried. Evaporation to remove the solvent gave 0.349 g (97.5% yield) of 2-hexyloxy-3- [4- (2-. {4-methanesulfonyloxyphenyl] -ethoxy) phenyl] propanoic acid. 1 H-NMR (400 MHz, CDCl 5): d 0.88 (t, 3 H, J = 6.8 Hz), 1.18-1.34 (, 6 H), 1.48-1.60 (m, 2 H), 2.94-2.97 (m, 1 H), 3.06 -3.13 (m, 3H), 3.14 (s, 3H), 3.36-3-43 (m, 1H), 3.50-3.57 (m, 1H), 4.02-4.07 (m, 1H), 4.16 (t, 2H, J = 6.5 Hz), 6.82 (dm, 2H, J = 8.8 Hz, unresolved), 7.15 (dm, 2H, J = 8.8 Hz, unresolved), 7.24 (.dm, 2H, J = 8.3 Hz, unresolved ), 7.35 (dm, 2H, J = 8.3 Hz, unresolved). 13 C-NMR (100 MHz CDCl 3): d 13.9, 22.4, 25.4, 29.3, 31.4, 35.0, 37.1, 37.8, 68.0, 71.2, 79.9, 114.2, 121.8, 129.0, 130.4, 130.42, 137.8, 147.8, 157.4, 176.5.

Example 18. Ethyl ester of 2-ethoxy-3- acid. { 4- [2- (3-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic (a) 2- (3-methanesulfonyloxyphenyl) ethyl methanesulfonate D-methanesulfonyl chloride (9.09 g, 79.6 moles) was added slowly to a solution of 3-hydroxyphenethyl alcohol (5 g, 36.2 mmol) and triethylamine 812.5 ml; 90.5 mmol) in dichloromethane at -10 ° C. The reaction mixture was stirred overnight at room temperature and then the solid material was removed by filtration. The filtrate was washed with sodium bicarbonate solution and brine, dried (magnesium sulfate) and the solvent was evaporated in vacuo to give 9.3 g (87 I yield) of 2- (3-methanesulfonyloxyphenyl) -ethylmethanesulfonate. (b) 2-Ethoxy-3-ethyl ester. { 4- [2- (3-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic The ethyl ester of 2-ethoxy-3- acid. { 4- [2- (3-ethanesulfonyloxyphenyl) ethoxy] phenyl} Propanoic acid was synthesized using the same method as in Example 1 (b) from the ethyl ester of 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid (described in Example 20b) and 2- (3-methanesulfonyloxyphenyl) -ethylmethanesulfonate .

Example 19. 2-Ethoxy-3-acid. { 4- [2- (3-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic 2-Ethoxy-3- acid. { 4- [2- (3-methanesulfonyloxyphenyl) ethoxy] phenyl} Propanoic acid was synthesized from the ethyl ester of 2-ethoxy-3- acid. { 4- [2- (3-methanesulfonyloxyphenyl) -ethoxy] phenyl} propane (described in Example 18) using the same method as in Example 2.

XH NMR (400 MHz; CDC13): d 7.34 (, 1H), 7.24 (m, 2H), 7.15 (m, 3H), 6.81 (d, J = 8.6 Hz, 2H), 4.16 (t, J = 6.7 Hz , 2H), 4.03 (dd, J = 7.7 and 4.3 Hz, 1H), 3.61 (, 1H), 3.42 (m, 1H), 3.12 (s, 3H), 3.10 (t, J = 6.7 Hz, 2H), 3.05 (dd, J = 14.2 and 4.3 Hz, 1H), 2.94 (dd J = 14.2 and 7.7 Hz, 1H), 1.16 (t, J = 7.0 Hz, 3H). 13C-NMR (100 MHz; CDC13): d 174.7, 157.5, 149.3, 141.1, 130.5, 129.9, 128.8, 128.0, 122.6, 119.9, 114.4, 79.7, 68.0, 66.8, 37.7, 37.3, 35.4, 15.0.

Example 20. Ethyl ester of 2-ethoxy-3- acid. { 4- [2- (2-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic (a) 2- (2-methanesulfonyloxyphenyl) ethyl methanesulfonate Methanesulfonyl chloride (9 g, 79 mmol) was added slowly to a solution of 2- (2-hydroxyphenyl) ethanol (5 g, 36 mmol) and triethylamine (7.99 g, 79 mmol) in dichloromethane at 10 ° C. The reaction mixture was allowed to reach room temperature and then poured into a mixture of hydrochloric acid and ice. The phases were separated and the organic phase was washed with brine, dried and the solvent was evaporated. The crystallized residue after standing gave 9.4 g (89% yield) of 2- (2-methanesulfonyloxyphenyl) ethyl methanesulfonate.

XH NMR (300 MHz, CDC13): d 2.85 (s, 3H), 3.15 (t, 2H), 3.25 (s, 3H), 4.4 (t, 2H), 7.2-7.35 (m, 4H). 13C NMR (1 0 0 MHz; CDC13): d 30.3, 37.2, 38.5, 69.0, 122.4, 127.6, 128.8, 129.6, 131.8, 147.5. (b) 2-Ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester The 3- (4-benzyloxyphenyl) -2-ethoxy? Acrylic acid ethyl ester (described in Example 38a) (62 g; 0.19 mmol) was hydrogen in ethyl acetate (400 ml) at atmospheric pressure using Pd / C ( 10%) as a catalyst. The mixture was filtered through celite and evaporated in vacuo to give 45.6 g (100% yield) of 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester. aH-NMR (600 MHz, CDCl 3): d 1.17 (t, 3H, J = 7 Hz), 1.23 (t, 3H, J = 7 Hz), 2.95 (d, 2H, J = 6.6 Hz), 3.35-3.42 (m, 1H), 3.58-3.64 (m, 1H), 4.0 (t, 1H, J = 6.6 Hz), 4.17 (q, 2H, J = 7 Hz), 5.97 (s, 10H), 6.74 (dm, 2H, J = 8.5 Hz, unresolved), 7. 08 (dm, 2H, J = 8.5 Hz, unresolved). 13 C-NMR (125 MHz; CDC 13): d 14.0, 14.8, 38.3, 61.0, 66.1, 80.3, 115.1, 128.2, 130-3, 154.8, 173.0. c) 2-Ethoxy-3-ethyl ester. { 4- [2- (2-methanesulfonyloxyphenyl) ethoxy-phenyl} propanoic The ethyl ester of 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid was alkylated with 2- (2-methanesulfonyloxyphenyl) ethyl methanesulfonate using the same method as in example 1 (b) to give the ethyl ester of 2-ethoxy acid -3-. { 4- [2- (2-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic XH NMR (300 MHz, CDC13): d 1.2 (2xt, 6H) 2.85 (d, 2H), 3.07 (m, 2H), 3.15 (s, 3H), 3.25-3.38 (m, 1H), 3.5-3.65 ( m, 1H), 3.9-4.0 (m, 1H), 4.15 (m, 2H); 6.77 (d, 2H), 7.1-7.45 (unresolved m, 6H).

Example 21. 2-Ethoxy-3- acid. { 4- [2- (2-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic The ethyl ester of 2-ethoxy-3- acid. { 4- [2- (2-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic The ethyl ester of 2-ethoxy-3- acid. { 4- [2- (2-methanesulfonyloxyphenyl) ethoxy] phenyl} Propanoic acid (described in example 20) was hydrolyzed using the same method as in example 2 to give 2-ethoxy-3- acid. { 4- [2- (2-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic XH NMR (400 MHz, CDC13): d 7.41 (m, 1H), 7.35 (m, 1H), 7.27 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 4.19 (t, J = 6.8 Hz, 2H), 4.03 (dd, J = 7.7 and 4.3 Hz, 1H), 3.60 (m, 1H), 3.42 (.1H), 3.19 (s, 3H) , 3.18 (t, J = 6.8 Hz, 2H), 3.06 (dd, J = 14.2 and 4.3 Hz, 1H), 2.94 (dd, J = 14.2 and 7.7 Hz, 1H), 1.6 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz; CDC13): d 175.7, 157.5, 147.6, 131.5, 131.4, 130.5, 128.9, 128.1, 127.3, 122.1, 114.4, 79.7, 67.1, 66.8, 38.2, 37.8, 30.0, 15.0.

Example 22. Ethyl ester of 2-ethoxy-3- acid. { 3- [2-4-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic (a) 4- [2- (3-formylphenoxy) ethyl] phenylmethanesulfonate 3-Hydroxybenzaldehyde was alkylated with 2- (4-methanesulfonyloxyphenyl) -ethylmethanesulfonate (described in Example la) using the same method as in Example Ib to give 4- [2- (3-formylphenoxy) ethylphenylmethanesulfonate. 1 H-NMR (400 MHz, CDCl 3): d 3.12 (t, 2 H, J = 6.7 Hz), 3.13; s, 3 H), 4.23 (t, 2 H, J = 6.7 Hz), 7.13-7.18 (m, 1 H) , 7.22-7.26 (m, 2H), 7.32-7.38 (m, 3H), 7.40-7.47 (m, 2H), 9.95 (s, 1H). 13C-NMR (100 MHz; CDC13): d 34.9, 37.2, 68.3, 112.7, 121.7, 121.9, 123.5, 128.6, 130.4, 137.5, 147.8, 159.1, 191.9. (b) Ethyl ether of 2-ethoxy-3-acid. { 3- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} acrylic The ethyl ester of 2-ethoxy-3- acid. { 3- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} Acrylic was synthesized from 4- [2- (3-formylphenoxy) ethyl] phenylmethanesulfonate and (1,2-diethoxy-2-oxoethyl) (triphenyl) phosphonium chloride using the same method as in Example le. 1 H-NMR (400 MHz, CDCl 3): d 1.34 (2xt, 6H, J = 7 Hz), 3.04-3.09 (, 5H), 3.99 (q, 2H, J = 7 Hz), 4.15 (t, 2H) J = 7 Hz), 4.27 (apparently q, 2H, J = 7 Hz), 6.8-6.85 (m, 1H), 6.92 (s, 1H), 7.1-7.25 (m, 3H), 7.28-7.33 (m, 3H ), 7.39-7.42 (m, 1H). 13C-NMR (100 MHz; CDC13): d 14.0, 15.3, 34.7, 36.8, 60.8, 67.4, 67.9, 115.2, 121.7, 122.7, 123.2, 129.1, 130.2, 134.7, 137.6, 144.7, 147.7, 158.3, 164.1. (c) 2-Ethoxy-3-ethyl ester. { 3- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic The ethyl ester of 2-ethoxy-3- acid. { 3- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} Acrylic (3.69 g, 8.50 mmol) was hydrogenified for 3.5 hours at atmospheric pressure in ethyl acetate (70 ml) and acetic acid (0.5 ml) using Pd / C as a catalyst and then filtered through hyflo. The solvent was evaporated in vacuo, dichloromethane and water were added and the phases were separated. The organic phase was dried (sodium sulfate), filtered and evaporated in vacuo to give 3.45 g (93% yield) of 2-ethoxy-3-ethyl ester. { 3- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic ^ - MR (500 MHz- CDC13): d 1.16 (t, 3H, J = 7 Hz), 1.22 (t, 3H, J = 7.1 Hz), 2.95-2.99 (m, 2H), 3.09 (t, 2H, J = 6.7 Hz), 3.13 (s, 3H) 3.31-3.39 (m, 1H), 3.56-3.64 (m, 1H), 3. 98-4.02 (m, 1H), 4.13-4.20 (m, 4H), 6.73-6.85 (m, 3H,), 7. 15-7.25 (m, 3H), 7.34 (dm, 2H, J = 8.6 Hz, unresolved). 13 C-NMR (100 MHz; CDCl 3): d 14.2, 15.0, 35.1, 37.2, 39.3, 60.8, 68.0, 80.1, 112.7, 115.6, 121.9 (superimposed signals), 129.2, 130.5, 138.0, 138.8, 147.8, 158.5, 172.5 .

Example 23. Acdio 2-ethoxy-3-. { 3- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic Lithium hydroxide hydrate was added slowly (0.175 g, 4.18 mmoles) in water (5 ml) to a solution of 2-ethoxy-3-ethyl ester. { 3-. { 2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} propanoic (described in Example 22) (1.66 g, 3.80 mmol) in tetrahydrofuran (17 ml) at 0 ° C. After stirring at room temperature for two hours the tetrahydrofuran was removed by evaporation in vacuo. The residue was extracted with diethyl ether. The aqueous phase was acidified with hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 1.5 g. (96.5% yield) of 2-ethoxy-3- acid. { 3- [2- (4-methanesulfonyloxyphenyl) ethoxy-phenyl} propanoic 1H-NMR (500 MHz, CDC13): d 1.13 (t 3H, J = 7 Hz), 2.91-2.98 (m, 1H), 3.03-3.09 (m, 3H), 3.09 (s, 3H), 3.33- 3.41 (m, 1H), 3.56-3.64 (m, 1H), 4.03-4.08 (m, 1H), 4.13 (t, 2H, J = 6-9 Hz), 6.75 (dd, 1H, J = 8.3, 2.07 Hz), 6.81 (s, 1H), 6.84 (d, 1H, 1 = 7.5 Hz), 7.14-7.23 (m, 3H), 7.31 (dm, 2H, J = 8.56 Hz, unresolved), 10.91 (bs, 1H, OH). 13 C-NMR (125 MHz; CDC1_): d 14.8, 35.0, 37.0, 38.8, 66.4, 67.9, 76.5, 112.7, 115.6, 121.78, 121.81, 129.1, 130.4, 137.8, 138.5, 147.7, 158.4, 176.7.

Example 24. Ethyl ester of 2-ethoxy-3- acid. { 4- [3- (3-methanesulfonyloxyphenyl) propoxy] phenyl} propanoic (a) 3- (3-methanesulfonyloxyphenyl) propylmethanesulfonate Methanesulfonyl chloride (4.77 g, 41.8 mmol) in dichloromethane (20 ml) was slowly added to a solution of 3- (3-hydroxyphenyl) -1-propanol (3.03 g, 19.9 mmol) and triethylamine (6.04 g, 59.7 mmol). in dichloromethane at -20 ° C. The reaction mixture left to reach room temperature and the solid material was removed by filtration. The filtrate was washed with sodium bicarbonate solution (3 times) and brine, dried magnesium sulfate) and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using dichloromethanemethanol (gradient 0-8% methanol) gave 4.22 g (69% yield) of 3- (3-methanesulfonyloxyphenyl) propylmethanesulfonate. 1H-SMR (300 MHz, CDCl 3): d 2.0 (m, 2H), 2.7 (t, 2H), 2.9 (s, 3H), 3.1 (s, 3H), 4.15 (t, .2H), 7.05-7.15 (m, 3H), 7.2-7.3 (m, 1H). 13 C-NMR (75 MHz, CDCl 3): d 30.3, 31.2, 37.3, 37.4, 68.9, 119.8, 122.1, 127.6, 130.1, 143.0,149.4. (b) Ethyl ester of the acid or 2-ethoxy-3-. { 4- [3- (3-methanesulfonyloxyphenyl) propoxy] phenyl} propanoic The 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (described in Example 20b) was rented with 3- (3-methanesulfonyloxyphenyl) propylmethanesulfonate using the same method as in Example 1 (b) to give the 2-ethoxy-3-ethyl ester. { 4- [3- (3-ethanesulfonyloxyphenyl) propoxy] -phenyl propanoic acid.

XH-NMR (300 MHz, CDCl 3): d 1.15 (t, 3H), 1.2 (t, 3H), 2.1 (quintet, 2H), 2.8 (t, 2H), 2.95 (d, 2H), 3.05 (s, 3H), 3.3-3.4 (m, 1H), 3.55-3.65 (m, 1H), 3.85-4.0 (m, 3H), 4.15 (q, 2H), 6.8 (d, 2H), 7.1-7.22 (, 5H) ), 7.35 (t, 1H). 13C-NMR (75 MHz; CDC13): d 14.2, 15.1, 30.6, 31.9, 37.2, 38.4, 60.8, 66.2, 66.5, 80.4, 114.2, 119.5, 121.0, 127.6, 129.3, 129.9, 130.4, 144.2, 149.4, 157.6 172.5 Example 25. 2-Ethoxy-3-acid. { 4- [3- (3-methanesulfonyloxyphenyl) propoxyjiphenyl} propanoic The ethyl ester of 2-ethoxy-3- acid was hydrolysed. { 4- [3- (3-methanesulfonyloxyphenyl) propoxyjiphenyl} propanoicco (described in Example 24b) using the same method as in Example 2 to give 2-ethoxy-3- acid. { 4- [3- (3-methanesulfonyloxyphenyl) propoxyjiphenyl} propanoic ^? - NMR (300 MHz, CDC13): d 1.15 (t, 3H), 2.1 (quintet, 2H), 2.85 (t, 2H), 2.9-3.07 (, 2H), 3.1 (s, 3H), 3.37- 3.47 (m, 1H), 3.57-3.67 fm, 1H), 3.95 (t, 2H), 4.05 (m 1H), 6.8 (d, 2H), 7.1-7.2 (m, 5H), 7.35 (t, 1 HOUR) . 13C-NMR (75 MHz; CDC13): d 15.0, 30.6,, 31.9, 37.3, 37.9, 66.5, 66.7, 79.8, 114.3, 119.5, 122.0, 127.6, 128.8, 129.9, 130.5, 144.2, 149.4, 157.8, 176.4.

Example 26. 2-Ethoxy-3- (4-. {2- [4- (2-propansulphonyloxy) phenyl] -ethoxy} phenyl) propanoic acid ethyl ester (a) Ethyl ester of 3- acid. { 4- [2- (4-benzyloxyphenyl) ethoxy] phenyl} 2-ethoxypropanoic acid Azodicarbonyl dipiperidine (7.5 g, 30 mmol) was added to 2-ethoxy-3- (4-hyd oxyphenyl) propanoic acid ethyl ester (described in Example 20b) (7 g, 30 mmol), 2- ( 4-benzyloxyphenyl) ethanol (6.8 g, 30 mmol) and triphenylphosphine (7.8 g, 30 mmol) dissolved in dichloromethane. After stirring at room temperature overnight the solvent was evaporated in vacuo and diethyl ether was added. The solid material was separated by filtration after one hour and the filtrate was evaporated in vacuo. Purification by chromatography on silica gel using ethyl acetate: dichloromethane as eluent gave 10 g (75% yield) of 3-ethyl ester. { 4- [2- (4-benzyloxyphenyl) ethoxy] phenyl} - 2-ethoxypropanoic.

XH-NMR (300 MHz; CDC13): d 1.15-1.30 (m, 6H), 2.95 (d, 2H), 3.05 (t, 2H), 3.3-3.42 (m, 1H), 3.58-3.7 (m, 1H) 1 4.0 (m, 1H), 4.05-4.25 (m, 4H), 5.05 (s, 2H), 6.85 (d, 2H), 6.95 (d, 2H), 7.1-7.25 (m, 4H), 7.3-7.5 (m , 5H).

X3C-NMR (75 MHz; CDC13): d 14.3, 15.1, 35.0, 38.5, 60. 8, 66.2, 68.9, 70.0, 80.5, 114.4, 114.9, 127.5, 128.0, 128. 6, 129.3, 130.0, 130.4, 130.6, 137.1, 157.5, 157.6, 172.6. b) Ethyl ester of 2-ethoxy-3- acid. { 4- [2- (4-hydroxyphenyl) ethoxy-phenyl} propanoic Hydrogen chloride is acid 3-. { 4- [2- (4-benzyloxyphenyl) ethoxy] phenyl} 2-ethoxypropanoic acid (16 g, 35.6 mmol) at atmospheric pressure in ethyl acetate (300 ml) using Pd / C (dry, 10%) as a catalyst. The mixture was filtered through celite and the solvent was evaporated in vacuo to give 11.2 g (88% yield) of 2-ethoxy-3-ethyl ester. { 4- [2- (4-hydroxyphenyl) ethoxy-phenyl} propanoic 1 H-NMR (300 MHz, CDC13): d 1.1-1.30 (m, 6H), 2.9-3.05 (m, 4H), 3.3-3.45 (m, 1H), 3.55-3.70 (m, 1H), 4.0 (, 1H), 4. 1 (t, 2H), 4.02 (q, 2H), 6.5 (s br, 1 OH), 6.75-6.85 (m, 4H), 7.05-7.2 (m, 4H). 13 C-NMR (75 MHz, CDCl 3): d 14.2, 15.0, 34.9, 38.4, 61.1, 66.3, 69.0, 80.4, 114.4, 115.5, 129.1, 129.8, 130.0, 130.4, 154.7, 157.6, 173.0. (c) 2-Ethoxy-3- (4. {2- [4- (2-propanesulfonyloxy) phenyl] ethoxy} propanoic acid ethyl ester Triethylamine (0.64 sec 6.2. mmoles) to a solution of ethyl ester of 2-ethoxy-3- acid. { 4- [2- (4-hydroxyphenyl) ethoxy] phenyl} propane (1.5 g, 4.18 mmol) in dry dichloromethane (20 ml). After cooling to 0 ° C, isopropyl chloride (0.9 g, 6.28 mmol) was slowly added. The reaction mixture was stirred overnight at room temperature, water was added and the mixture was extracted with dichloromethane. The organic phase was washed with hydrochloric acid (1M) and sodium bicarbonate solution, dried (magnesium sulfate) and evaporated in vacuo to give 1.75 g (90% yield) of 2-ethoxy-3-ethyl ester. - (4- { 2- [4- (2-propanesulfonyloxy) phenyl] ethoxy) phenyl) propanoic acid. 1H-NMR (500 MHz; CDC1_): d 1.16 (t, 3H, J = 7 Hz), 1.22 (t, 3H, J = 7 Hz), 1.55 (d, 6H, J = 6.7 Hz), 2.92-2.96 (m, 2H), 3.08 (t, 2H, 1 = 7 Hz), 3.31-3.38 (m, 1H), 3.41-3.50 (m, 1H), 3.55-3.64 (m, 1H), 3.94-3.98 (m , 1H), 4.11-4.19 (m, 4H), 6.80 (dm, 2H, J = 8.6 Hz, unresolved), 7.14 (dm, 2H, J = 8.6 Hz, unresolved), 7.21 (dm, 2H, J = 8.6 Hz, unresolved), 7.31 (dm, ZH, J = 8.6 Hz, unresolved).

Use 27. 2-Ethoxy-3- (4- [2- [4- (2-propanesulfonyloxy) phenyl] ethoxy] phenyl) propanoic acid.

The ethyl ester of 2-ethoxy-3- (4-. {2- 2- [4- (2-propanesulfonyloxy) phenylamino} phenyl) propanoic acid (described in Example 26) was hydrolyzed using the same method as in Example 2 to give 2-ethoxy-3- (4-. {2- 2- 4- (2-propansulphonyloxy) phenyl] ethoxy} phenyl) propanoic acid.

H --_ MR (500 MHz, - CDC13): d 1.17 (t, 3H, J = 7.2 Hz), 1.54 (d, 6H, J = 6.8 Hz), 2.91-2.98 (m, 1H), 3.03-3.1 ( m, 3H), 3.38-3.52 (m, 2H), 3.55-3.65 (, 1H), 4.01-4.06 (m, 1H), 4.14 (t, 2H, J = 6.9 Hz), 6.81 (dm, 2H, J = 8.6 Hz, unresolved), 7.15 (dm, 2H, J = 8.6 Hz, unresolved), 7.21 (dm, 2H, J = 8.6 Hz, unresolved), 7.31 (dm, 2H, J = 8.6 Hz, sin solve), 7.96 (bs, 1H). 13 C-NMR (125 MHz, CDCl 3): d 15.0, 16.7, 35.1, 37.8, 52.3, 66.8, 68.2, 79.7, 114.4, 121.9, 128.8, 130.4, 130.5, 137. 4, 147.6, 137.5, 175.7.

Example 28. 2-Ethoxy-3- (4-. {2- [4- (4-nitrobenzenesulfonyloxy) phenyl] ethoxy} phenyl) -propanoic acid ethyl ester The ethyl ester of 2-ethoxy-3- acid was esterified. { 4- [2- (4-hydroxyphenyl) ethoxy-phenyl} propane (described in Example 26b) with 4-nitrobenzenesulfonyl chloride using the same method as in example 26 (c) to give the ethyl ester of 2-ethoxy-3- (4-. {2- 2- 4- (4-Nitrobenzenesulfonyloxy) phenyl-ethoxy, phenyl) propanoic acid. 1 H-NMR (400 MHz, CDCl 3): d 1.16 (t, 3 H, 3 = 1 Hz), 1.23 (t, 3 H, J = 7 Hz), 2.92 -2.97 (m, 2 H), 3.05 (t, 3 H, J = 6.5 Hz), 3.30-3.39 (m, 1H), 3.54-3.65 (m, 1H), 3.93-3.99 (, 1H), 4.12 (t, 2H, J = 6.8 Hz), 4.16 (q, 2H, J = 7 Hz), 6.77 (dm, 2H, J = 8.8 Hz, unresolved), 6.93 (dm, 2H, J = 8.8 Hz, unresolved), 7.14 (dm, 2H J = 8.8 Hz, unresolved), 7.23 (dm, 2H, J = 8.8 Hz, unresolved), 8.03 (dm, 2H, J = 8.8 Hz, unresolved), 8.36 (dm, 2H, J = 8.8 Hz, unresolved).

Use 29. 2-Ethoxy-3- (4-. {2- [4- (4-nitrobenzenesulfonyloxy) phenyl] ethoxy} phenyl) -propanoic acid The ethyl ester of 2-ethoxy-3- (4-. {2- [4- (4-nitrobenzenesulfonyloxy) phenyl] ethoxy} phenyl) propanoic acid (described in Example 28) was hydrolyzed by the same method as in Example 2 to give 2-ethoxy-3- (4- {2- (4-nitrobenzenesulfonyloxy) phenyl] ethoxy} phenyl) propanoic acid 1 H-NMR (500 MHz, CDCl 3): d 1.16 (t, 3H) 1 = 7 Hz), 2.91-3.01 (m, 1H), 3.01-3.08 (m, 2H), 3.37-3.45 (m, 1H), 3.58-3.66 (m, 1H), 4.0-4.06 (m, 1H) 4.08-4.14 (m, 2H), 6.78 (dm, 2H, J = 8.6 Hz, unresolved), 6.92 (dm, 2H, J = 8.6 Hz, unresolved), 7.15 (dm, 2H, J = 8.6 Hz, unresolved), 7.23 (dm, 2H, J = 8.6 Hz, unresolved), 8.02 (dm, 2H, J = 9.1 Hz, no solve), 8.34 (dm, 2H, J = 9.1 Hz, unresolved), 9.56 (bs, 1H). 13 C-NMR (125 MHz; CDC 13): d 14.9, 35.0, 37.8, 66.6, 67.9, 79.6, 114.2, 115.3, 121.9, 124.2, 129.0, 129.8, 130.4, 138.3, 140.9, 147.7, 150.8, 157.4, 176.3.

Example 30. Ethyl ester of 2-ethoxy-3- acid. { 4- [2- (4-phenylmetanesuloniloxyphenyl) ethoxy] phenyl} propanoic The ethyl ester of 2-ethoxy-3- acid was dissolved. { 4- [2- (4-hydroxyphenyl) ethoxy-phenyl} propane (described in Example 26b) (0.54 g, 1.5 mmol) in dichloromethane (15 ml), triethylamine (0.23 g, 0.31 ml, 2.25 mmol) was added. The solution was cooled to 0 ° C and benzylsulfonyl chloride (0.43 g, 2.25 mmol) dissolved in dichloromethane (5 ml) was added. The resulting mixture was allowed to reach room temperature and was stirred overnight, the organic layer was separated and the aqueous phase was extracted with dichloromethane. The organic phase was washed with hydrochloric acid (1M), sodium bicarbonate. sodium and brine. After drying with sodium sulphate and evaporation a slightly yellow oil was obtained. The crude product was purified by flash chromatography on silica gel. The compound was eluted with heptane: ethyl acetate (9: 1 followed by 1: 1). The pure fractions were combined and evaporated yielding 0.55 g (71%) of the ethyl ester of 2-ethoxy-3- acid. { 4- [2- (4-phenylmethanesulfonyloxyphenyl) ethoxyjiphenyl} propanoic XH-NMR (300 MHz, CDC13): d 1.18 (t, 3H); 1.25 (t, 3H); 2. 97 (d, 2H); 3.09 (t, 2H); 3.30-3.45 (m, 1H); 3.55-3.70 (, 1H, 3.98 (t, 1H), 4.14 (t, 2H), 4.19 (q, 2H), 4.52 (s, 2H); 6. 82 (d, 2H, 7.08 (d, 2H), - 7.17 (d, 2H), 7.29 (d, 2H), 7.40-7.53 (m, 5H) 13C-NMR (75 MHz, CDC13): d 14.6, 15.4, 35.5, 38.8, 57.0, 61.9, 66.5, 68.5, 80.6, 114.5, 122.2, 127.5, 129.2, 129. 5, 129.7, 130.1, 130.6, 131.1, 137.9, 148.0, 157.6, 172.7 E eg 31. 2-ethoxy-3- acid. { 4- [2- (4-phenyl-ethanesulfonyloxyphenyl) ethoxy-phenyl} propanoic It dissolved the ethyl ester of 2-ethoxy-3- acid. { 4- [2- (4-phenylmethanesulfonyloxyphenyl) ethoxyjiphenyl} propanoic (described in example 30) (0.21 g, 0.41 mmol) in tetrahydrofuran (4 ml) and lithium hydroxide (0.021 g; -0.48 mmol-es) dissolved in water (1 ml) was added dropwise. The resulting solution was stirred at room temperature - overnight and then acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying with magnesium sulfate and evaporation gave 0.184 g (92%) of 2-ethoxy-3- acid. { 4- [2- (4-phenylmethanesulfonyloxy-phenyl) ethoxy-phenyl} propanoic as an oil.

* H-NMR (500 MHz, CDC13): d 1.20 (t, 3H); 2.94-3.01 (dd, 1H); 3.06- 3.13 (m, 3H); 3.41-3.52 (m, 1H); 3.58- 3.69 (, 1H); 4.06 (dd, 1H); 4.15 (t, 2H); 4.53 (s, 2H); 6.84 (d, 2H); 7.09 (d, 2H); 7.18 (d, 2H); 7.31 (d, 2H); 7.44-7.48 (m, 5H) 13 C-NMR (125 MHz, CDCl 3): d 15.3, 35.4.38.1, 57.0, 67.1, 68.5, 80.0, 114.7, 122.2, 127.5, 129.1, 129.2, 129.5, 130.7, 130.8, 131.1, 137.9, 148.1, 157.8, 175.6 Example 32. Ethyl ester of 2-ethoxy-3- acid. { 4-. { 2- (4-methanesulfonyloxyphenyl) ethoxyphihenyl} butanoic (a) Ethyl 3- (4-benzyloxyphenyl) -2-ethoxy-3-methylacrylic acid ethyl ester LHMDS (11 mL, 11 mmol, 1M in tetrahydrofuran) was added to a solution of triethyl 2-ethoxyphosphonoacetate (2.95 g, 11 mmol) in dry tetrahydrofuran (30 mL) at -50 ° C under a nitrogen atmosphere, the mixture stirred for 1.5 hours and then the temperature was allowed to rise to 2 ° C. 1- (3-Benzyloxyphenyl) ethane-ketone (2.3 g, 10 mmol) dissolved in tetrahydrofuran was added slowly and the resulting mixture was stirred overnight at room temperature. Saturated ammonium chloride solution (40 ml) was added and after 1 hour the phases were separated. The aqueous phase was extracted twice with ethyl acetate, the organic phases were combined and the solvent evaporated in vacuo. Purification twice by chromatography using ethyl acetate: heptane as eluent gave 0.6 g (18% yield) of 3- (4-benzyloxyphenyl) -2-ethoxy-3-methylacrylic acid ethyl ester as a mixture of Z-isomers and E, which was used in the next stage without further purification.

Main isomer 1 H-NMR (500 MHz, CDC 13): d 0.99 (t, 3 H, J = 7 Hz), 1.37 (t, 3 H, 1 = 7 Hz), 2.13 (s, 3 H), 3. 88 (q, 2H, J = 7 Hz), 4.0 (q, 2H, J = 7 Hz), 5.11 (s, 2H), 6.94 (dm 2H, J = 9 Hz, unresolved), 7.11 (dm, 2H, J = 9 Hz, unresolved), 7.33-7.50 (, 5H). (b) Ethyl 3- (4-hydroxyphenyl) -2-ethoxybutanoic acid ethyl ester The 3- (4-benzyloxyphenyl) -2-ethoxy-3-methylacrylic acid ethyl ester (1.58 g, 4.64 mmol) was hydrogenated at atmospheric pressure in ethyl acetate (20 ml) using Pd / C (wet) as the catalyst . After filtration through celitee, the solvent was evaporated in vacuo to give (1.1 g, 94% yield) of 3- (4-hydroxyphenyl) -2-ethoxybutanoic acid ethyl ester as a diastomeric mixture.

Main isomer XH-NMR (500 MHz, CDCI3): d 1.17 (t, 3H, J = 7 Hz), 1.23 (t, 3H, J = 7 Hz), 1.32 (d, 3H, J = 7 Hz), 3.17 (quintet, 1H, J = 7 Hz), 3.29-3.38 (m, 1H), 3.60-3.68 (m, 1H), 3.88-3.92 (m, 2H), 4.18 (q, 2H, J = 7 Hz), 5.2 (bs, 10H), 6.71-6.77 (, 2H) 7.11-7.16 (, 2H). (c) 2-Ethoxy-3-ethyl ester. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy-phenyl} butanoic The ethyl ester of 3- (4-hydroxyphenyl) -2-ethoxybutanoic acid was reacted with 2- (4-methanesulfonyloxyphenyl) ethyl methanesulfonate (described in Example la) using the same method as in Example 1 (b) to give the 2-ethoxy-3-ethyl ester. { 4- [2- (4-Methanesulfonyloxyphenyl) -ethoxy-phenyl} -butanoic as a diastereomeric mixture.

Main isomer 1H-NMR (500 MHz, CDC13): d 1.15 (t, 3H, J = 7 Hz), 1.24 (t, 3H, J = 7 Hz), 1.31 (d, 3H, J = 7 Hz), 2.99 -3.90 (, 6H), 3.23-3.35 (m, 1H), 3.58-3.65 (m, 1H), 3.88 (d, 1H, J = 6.5 Hz), 4.14-4.20 (m, 4H), 6.83 ( dm, 2H), J = 8.5 Hz, unresolved), 7.18 (dm, 2H, J = 8.5 Hz, unresolved), 7.25 (dm, 2H, J = 8.5 Hz, unresolved), 7.36 (dm, 2H, J = 8.5 Hz, unresolved).

E pg 33. 2-Ethoxy-3- Acid. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy-phenyl} butanoic The ethyl ester of 2-ethoxy-3- acid was hydrolysed. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy phenyl} butanoic (described in example 32), using the same method as in example 2 to give 2-ethoxy-3- acid. { 4- [2- (4-methanesulfonyloxyphenyl) ethoxy-phenyl} butanoic as a diastereomeric mixture.

Main isomer 1H-NMR (400 MHz, CDC13) d 1.20 (t, 3H, J = 8 Hz), 1.37 (d, 3H, J = 7.2 Hz), 3.06-3.15 (, 5H), 3.15-3.25 (m, 1H), 3.40-3.50 (m, 1H), 3.62-3.72 (m, 1H), 3.93 (d, 1H, J = 5.6 Hz), 4.15 (t, 2H, J = 6.8 Hz), 6.81 (dm,. 2H, J = 8.8 Hz, unresolved), 7.17 (dm, 2H, J = 8, 8 Hz, unresolved), 7.23 (dm, 2H, J = 8, 8 Hz, unresolved), 7.33 (dm, 2H, J = 8, 8 Hz, unresolved). 13 C-NMR (100 MHz, CDCl 3): d 15.0, 17.9, 35.1, 37.2, 41.7, 67.6, 68.1, 83.5, 114.2, 121.9, 129.2, 130.5, 133.5, 138.0.147.8, 157.5, 175.4.

Example 34. 2-Ethoxy-3- [4- (4. {2-methanesulfonyloxyphenyl) butoxy) phenylpropanoic acid (a) 4- (2-benzyloxyphenyl) -3-buten-l-ol 2-Benzyloxybenzaldehyde (8 g, 37 mmol), 3-hydroxypropyl) triphenylphosphonium bromide (19.5 g, 47 mmol) and potassium carbonate (6.6 g, 48 mmol) in isopropanol were mixed. The reaction mixture was refluxed overnight, then filtered and the filtrate was evaporated. Chromatography using ethyl acetate: dichloromethane (up to 5%) as eluent gave 8.4 g (87.6%) of 4- (2-benzyloxyphenyl) -3-buten-1-ol. Both cis- and trans-4- (2-benzyloxyphenyl) -3-buten-ol were formed in accordance with NMR.

XH-NMR (300 MHz; CDC13) of major isomer: d 1.9-2.05 (b, 1H, OH), 2-43-2.6 (, 2H), 3-7-3.8 (m, 2H), 5.2 (s) , 2H), 6.2-6.3 (, 1H), 6.85-7.5 (m, 10H, unresolved) XH-NMR (300 MHz; CDCl 3) of the minor isomer: d 1.9-2.05 (b, 1H, OH), 2.43-2.6 (m, 2H), 3.7-3.8 (, 2H), 5.2 (s, 2H), 5.7 -5.8 (m, 1H), 6.8 (d, 1H, 6.85-7.5 (m, 9H, unresolved). (b) 4- (2-hydroxyphenyl) butanol 4- (2-Benzyloxyphenyl) -3-buten-1-ol is hydrogen in ethanol using the same method as in Example 20b. 1H-MR (300 MHz, CDCl 3): d 1.5-1.73 (m, 4H), 2.65 (t, 2H), 3.65 (t, 2H), 6.75-6.9 (m, 2H), 7.02-7.15 (m, 2H ), 7.4 (bs, 1 H). 13C-NMR (75.5 MHz; CDC13): d 26.4, 29.6, 31.5, 62.8, 115.6, 120.5, 127.1, 128.8, 130.31, 154.0. (c) 4- (2-methanesulfonyloxyphenyl) butylmethanesulfonate The 4- (2-methanesulfononyloxyphenyl) butylmethanesulfonate was synthesized using the same method as in Example 18a from 4- (2-hydroxyphenyl) butanol. 1 H-NMR (300 MHz, CDC13): d 1.7-1.83 (m, 4H), 2.7-2.88 (m, 2H), 2.95 (s, 3H), 3.17. (s, 3H), 4.25 (t, 2H), 7.2-7.3 (m, 4H). 13 C-NMR (75.5 MHz, CDCl 3): d 25.8, 28.6, 29.3, 37.2, • 38.3, 69.8, 122.0, 127.4, 127.6, 130.8, 134.7, 147.5. (d) 2-Ethoxy-3-ethyl ester. { 4- (4- (2-ethanesulfonyloxy-phenyl) -butoxy-phenyl} propanoic acid The ethyl ester of 2-ethoxy-3- acid was synthesized. { 4- (4- (2-methanesulfonyloxyphenyl) butoxyJphenyl) propanoic using the same method as in Example Ib from the ethyl ester of 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid (described in Example 20b) ) and 4- (2-methanesulfonyloxyphenyl) butylmethanesulfonate. (e) 2-Ethoxy-3- [4- (-. {2-methanesulfonyloxyphenyl) butoxy) phenyl] propanoic acid 2-Ethoxy-3 was dissolved. { 4-} 4- (2-methansulfonyloxyphenyl) butoxyJphenyl} propane (2.7 g, 5.8 mmol.) in tetrahydrofuran: water (1: 3, 100 ml), lithium hydroxide (0.36 g, 8.7 mmol) dissolved in a small amount of water was added. The mixture was stirred overnight at room temperature and then evaporated, the residue was redissolved in ethyl acetate and hydrochloric acid (2M> and extracted) After separation the organic phase was extracted with sodium hydroxide (1M, 30M). The aqueous phase was cooled, acidified with hydrochloric acid (conc) and extracted with ethyl acetate.The organic phase was dried with magnesium sulfate and evaporation gave 2 g (79% yield) of 2-ethoxy acid. 3- [4- (4-. {2-Methanesulfonyloxyphenyl} butoxy) phenyl] propanoic acid.

XH-NMR (500 MHz, CDC13): d 1.2 (t, 3H), 1.86 (, 4H), 2.81 (t, 2H), 2.94-3.0 (m, 1H), 3.06-3.11 (, 1H), 3.2 ( s, 3H), 3.43-3.48 (m,! H), 3.6-3.65 (, 1H), 4.0 (t, 3H), 4.95 -4.08 (m, 1H), 6.84 (d, 2H), 7.17 (d, 2H.}., 7.25-7.28 (, 2H), 7.32-7.35 (m, 2H). 13C-NMR (100 MHz, CDC13): d 15.2, 26.7, 29.2, 30.0, 38.0, 38.4, 67.0, 67.7, 80.0, 114.6, 122.2, 127.5, 127.7, 128.8, 130.7, 131.0, 135.3, 147.7, 158.1, 175.8 .

Example 35. 2-Ethoxy-3- [4- (2. {4-mrtylsulfonyloxyphenyl) ethoxy) -2-nitrophenyl-propanoic acid methyl ester (a) 3- (4-Benzyloxy-2-nitrophenyl) -2-oxopropanoic acid Potassium ethoxide (505 g: 6 moles) was added to a solution of ethanol (710 ml) and diethyl ether (4.8 1.) and the mixture was cooled to 0 ° C. 4 (benzyloxy) -l was slowly added. -methyl-2-nitrobenzene (639.8 g, 3 moles) dissolved in diethyl oxalate (900 g, 6.16 moles) and toluene (1500 ml) for 30 minutes The reaction mixture was stirred for three hours at 0 ° C and then it was allowed to stand cold all night.After 5 days at room temperature the reaction mixture was filtered and the filter cake was washed with diethyl ether (2 1) .The cake was then treated with water (10 1) , sodium hydroxide (5M, 0.8 1) and extracted three times with diethyl ether (3 x 3 1). The aqueous phase was cooled and acidified in two stages while stirring with hydrochloric acid: water (1: 1, 0.9 1). First at pH 5 and the reaction mixture was then stirred for 1 hour before continuing the acidification until pH 2.

The reaction mixture was cooled in an ice bath: sodium chloride. Filtration after one hour gave 849.5 g (89.8%.) Of 3- (4-benzyloxy-2-nitrophenyl) -2-oxopropanoic acid. 1H-NM (500 MHz, DMSO-d6) d 4.33 (s, 2H), 5.21 (s, 2H), 7.32-7.36 (, 2H), 7.39-7.50 (m 5H), 7.65 (d, J = 2.6 Hz, 1H) (b) 3- (4-Benzyloxy-2-nitrophenyl) -2-oxopropanoic acid methyl ester The 3- (4-benzyloxy-2-nitrophenyl-2-oxopropanoic acid (40 g, 0.127 mol) was dissolved in methanol (300 mL), hydrochloric acid (conc, 10 mL) was added with stirring. heated to reflux for 3.5 hours and then evaporated to dryness.

Dichloromethane and water were added to the residue and the phases were separated. The organic phase was washed with dilute sodium bicarbonate solution and water, and dried with magnesium sulfate. Filtration through a short column of silica gel and evaporation gave 29.6 g (71% yield) of 3- (4-benzyloxy-2-nitrophenyl) -2-oxopropanoic acid methyl ester as a yellow solid. 1 H-NMR (300 MHz, CDC13): d 3.93 (s, 3H), 4.46 (s, 2H), 5.14 (s, 2H), 7.22 (br, 2H), 7.36-7.45 (m, 5H 7.79 (s, 1 HOUR) . (c) 3- (4-Benzyloxy-2-nitrophenyl) -2-hydroxypropanoic acid methyl ester The 3- (4-benzyloxy-2-nitrophenyl) -2-oxopropanoic acid methyl ester was dissolved. (4.1 g, 12.4 moles) in methanol (60 ml). Sodium borohydride was added (0.5 g, 13.12 mmoles.) In portions with agitation. (silica gel, ethyl acetate: heptane, 1: 1) after one hour showed initial material remaining and the formation of a by-product. The reaction mixture was then cooled in an ice bath and more sodium borohydride (0.2 g, 5.26 mmol) was added. After addition, mixture was stirred at 0 ° C until the initial material was consumed. The reaction mixture was evaporated to dryness. Ethyl acetate and water were added to the residue and the phases were separated. The organic phase was washed with brine and dried with magnesium sulfate and evaporated. Chromatography of the crude product on silica gel using a gradient of ethyl acetate in heptane as eluent gave 2.5 g (61% yield) of 3- (4-benzyloxy-2-nitrophenyl) -2-hydroxypropanoic acid methyl ester. as an oily product.

XH-NMR (300 MHz, CDC13): d 2.86 (d, J = 6 Hz, 1H, OH), 3.12 (dd, J = 14.8 Hz, 1H), 3.47 (dd, J = 14.4 Hz, 1H) , 3.79 (s, 3H), 4.45-4.51 (m, 1H), 5.10 (s, 2H), 7.15 (dd, J = 8.8.2.7 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.35-7.43 (m, 5H) and 7.54 (d, J = 2.7 Hz, 1H). (d) 2-Ethoxy-3- (4-benzyloxy-2-nitrophenyl) propanoic acid methyl ester The 3- (4-benzyloxy-2-nitrophenyl) -2-hydroxypropanoic acid methyl ester (1.86 g, 5.6 mmol) was dissolved in dichloromethane (20 ml). Molecular sieves (4 A °, 1.9 g) were added. Silver (I) oxide (1.96 g, 8.4 mmol) was added while stirring, followed by the addition of iodoethane (1.63, 20.4 mmol.) After 6 days of stirring at room temperature the reaction was not complete. According to the TLC so that more silver (I) oxide and iodoethane was added.The reaction mixture was stirred for three more days, then filtered through celite and the filtrate was evaporated to dryness. on silica gel using a gradient of ethyl acetate in heptane as eluent gave 1.6 g of oil (80% yield) of 2-ethoxy-3- (4-benzyloxy-2-nitrophenyl) propanoic acid methyl ester.

"H-NMR (400, MHz, CDClj): -d 1.13 (t, J = 7 Hz, 3H), 3.23 (dd, J = 14, 8 Hz, 1H), 3.29-3.37 (m, 2H) 3.58- 3.66 (m, 1H), 3.72 (s, 3H), 4.15 (dd, J = 8.4.5 Hz, 1H), 5.12 (s, 2H), 7.15 { Dd, J = 8-5.2.5 Hz, 1H), 7.31 (d, J.5 Hz, 1H), 7.36-7.45 (m, 5H), 7.55 (d, J = 2.5 Hz, 1H). (e.) 2-Ethoxy-3- (4-hydroxy-2-nitrophenyl) methoxylic acid methyl ester The 2-ethoxy-3- (4-benzyloxy-2-nitrophenyl) propanoic acid methyl ester (1.5 g, 4.06 mmol) in dichloromethane (8 ml) was dissolved and dimethylsulfide (8 ml) was added. diethyl boron trifluoride (5.0 ml, 40.6 mmol) with stirring The reaction mixture was stirred at room temperature for 4 hours and then poured into water and more dichloromethane was added.The phases were separated and the organic phase was washed with water and brine and dried with magnesium sulfate The evaporation to remove the solvent gave 1.04 g (95% yield of 2-ethoxy-3- (4-hydroxy-2-nitrophenyl) propanoic acid methyl ester.

^ -NMR (400 MHz, CDC13): d 1.15 (t, 1 = 7 Hz, 3H, 3.26 (dd, J = 14, 7.5 Hz, 1H) 3.34- 3.42 (m, 2H), 3.58-3.66 (m, 1H), 3.77 (s, 3H), 4.19 (dd, J = 7.5, 5.5 Hz, 6.38 (s, 1H), 6.96 (d, J = 8.5, 2.5 Hz, 1H), 7.22 (d, J = 8.5Hz , 1H), 7.37 (d, J = 2.5 Hz, 1H). (f) 2-Ethoxy-3- [4- (2. {4-methylsulfonyloxyphenyl) ethoxy) -2-nitrophenyl] propanoic acid methyl ester 2- (4-methanesulfonyloxyphenyl) ethyl methanesulfonate (1.14 g, 3.87 mmol), 2-ethoxy-3- (4-hydroxy-2-nitrophenyl) propanoic acid methyl ester were mixed. (1.04 g, 3.86 mmol) and potassium carbonate (1.07 g, 7.75 mmol) were mixed in acetonitrile (approximately 100 ml). The reaction mixture was heated to reflux for 6 hours and according to the TLC the reaction was not completed. Another portion of 2- (4-methanesulfonilloxyphenyl) ethyl methanesulfonate (0.2 g, 0.68 mmol) was added. The reaction mixture was heated to reflux overnight, and then evaporated to dryness. Ethyl acetate and water were added to the residue. The phases were separated and the organic phase was washed with brine, dried with magnesium sulfate and evaporated. Chromatography of the crude product on silica gel with a gradient of ethyl acetate / heptane as eluent gave 1.47 g (81% yield) of 2-ethoxy-3- [4- (2- {4- methylsulfonyloxyphenyl, ethoxy) -2-nitrophenyl-Jpropanoic acid.

XH-NMR (400 MHz, CDC13): d 1.12 (t J = 7 Hz, 3H), 3.14 (t, J = 7 Hz, 2H), 3.16 (s, 3H), 3.21 (dd, J = 14, 8 Hz, 1H), 3.30-3.67 (m, 2H), 3.57-3.65 (m, 1H); 3.73 (s, 3H), 4.13 (dd, J = 8, 5 Hz, 1H), 4.22 (t, J = 7 Hz, 2H), 7.06 (dd, J = 8.5, 2.5 Hz, 1H), 7.26 (d, J = 8.5 Hz, 2H), 7.-29 (d, J = 8. 5 Hz, 1H), 7.35 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 2.5 Hz, 1 HOUR) .

Example 36. 2-Ethoxy- [4- (2. {4-methylsulfonyloxyphenyl) ethoxy) -2-nitrophenyl-propanoic acid The 2-ethoxy-3- [4- (2. {4-methylsulfonyloxyphenyl) ethoxy) -2-nitrophenyl-propanoic acid methyl ester was dissolved. (described in Example 35) (0.8 g, 1.71 mmol) in tetrahydrofuran (8 ml). A solution of lithium hydroxide monohydrate (0.086 g, 2.05 mmol) in water (8 ml) was added with stirring. The reaction mixture was stirred at room temperature for 5 hours and then evaporated to remove tetrahydrofuran. The residue was extracted with diethyl ether, acidified to pH ~ 3 with hydrochloric acid (10%.) And extracted with ethyl acetate, the organic phase was washed with water and brine, dried with magnesium sulfate, the solvent was removed and 0.72 g was obtained (93%).

Performance% } of 2-ethoxy-3- [4- (2. {4-methylsulfonyloxyphenyl) ethoxy) -2-nitrophenyl-Jpropanoic acid. 1H-NR (400 MHz, CDC13): d 1.13 (t, J = 7 Hz, 3H), 3.13 (t, J = 6.5 Hz, 2H), 3.15 (s, 3H) .3.23 (dd, J = 14, 8 Hz, 1H), 3.36-3.43 (m, 1H), 3.48 (dd, J = 14, 5 Hz, 1H), 3.59-3.66 (m, lH), 4.15. { dd, J = 8.5 Hz, 1H), 4.22 (t, J = 6.5Hz, 2H), 7.06 (dd, J = 8.5 2.5 Hz, 1 H), 7.25 (d, J = 8.5Hz, 2H), 7.30 (d, J = 8.5Hz, 1H), 7.35 (d, J = 8.5 Hz, 2H) and 7.43 (d, J = 2.5, Hz, 1H). 13 C-NMR (100 MHz, CDCl 3): d 14.89, 34.88, 34.91, 37.33, 67.10, 68.79, 78.31, 110.13, 119.64, 122.09 (2C), 123.30, 130.52 (20), 134.33, 137.29, 147.94, 150.22, 157.93 and 175.41.

Example 37. 2-Ethoxy-3- £ 4- (2. {3-methoxy-4-ethanesulfonyloxyphenyl) ethoxy) -phenyl-propanoic acid (a) 2-Ethoxy-3- [4- (2. {3-methoxy-4-methanesulfonyloxyphenyl) ethoxy) phenyljpropanoic acid ethyl ester 2- [3-methoxy-4-. { methylsulfonyloxo} phenylmethyl methanesulfonate (described in WO 98/57941) (1.6 g, 4.9 mmol) in acetonitrile. Potassium carbonate (1 g, 7.2 mmol) was added followed by the addition of 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (described in Example 20b). { lg; 4.2 mmoles). The reaction mixture was refluxed for 2 hours and then stirred at room temperature for 16 hours. The acetonitrile was evaporated and the residue redissolved in diethyl ether and washed with water. The organic phase was dried with sodium sulfate and evaporated. The NMR demonstrated the formation of the corresponding styrene product and that the reaction was not. Completed so that the crude product was redissolved in acetonitrile and more 2- [3-methoxy-4- (methylsulfonyloxy) phenyl-methyl-methanesulfonate (0.5 g, 1.5 mmol) was added. The mixture was refluxed for 2 more hours and then evaporated. The residue was redissolved in diethyl ether and washed with water. The organic phase was dried with magnesium sulfate and evaporated. Chromatography of the crude product gave 1 g of a mixture that conformed to the NMR contained 60% (0.68 g, 34.7% yield) of the ethyl ester of 2-ethoxy-3- [4- (2. 4-methanesulfonyloxyphenyl) ethoxy) phenyljpropanoic acid and 40% (0.32 g) of 2- [3-methoxy-4-. { methylsulfonyloxy} phenyljetylmethanesulfonate. This mixture was used without further purification in the next step. 1 H-NMR (300 MHz; CDClj): d 1.13 (t, 3H), 1.2 (t, 3H), 2.92 (d, 2H), 2.96-3.1 (m, 2H), 3.13 (s, 3H.), 3.27 (m, 1H), 3. 52-3.67 (, 1H), 3.87 (s, 3H), 3.97 (t, 1H), 4.1-4.2 (m, 4H), 6.78-6.98 (m, 4H, unresolved), 7.1-7.23 (m, 3H, unresolved). (b) 2-Ethoxy-3- [4- (2. {3-methoxy-4-methanesulfonyloxyphenyl) ethoxy) phenylpropanoic acid The ethyl ester of 2-ethoxy-3- [4- (2. {3-methoxy-4-methanesulfonyloxyphenyl) ethoxy) phenyl propanoic acid was hydrolysed using the same method as in Example 13 to give the acid 2 -ethoxy-3- [4- (2-. {3-methoxy-4-methanesulfonyloxyphenyl} ethoxy) phenylpropanoic acid. 1H-NMR (600 MHz, CDC13): d 1.16 (t, 3H), 2.92-2.97 (m, 1H), 3.30-3.09 (, 3H), 3.16 (s, 3H), 3.39-3.45 (m, 1H) , 3. 57-3.63 (m, 1H), 3.87 (s, 3H.}., 4.01-4.05 (m, 1H), 4.15 (t 2H), 6.81 (d, 2H, J = 7.8 Hz), 6.87 (d, 1H, J = 7.8 Hz), 6.93 (s, 1H), 7.15 (d, 2H, J = 7.8 HZ), 7.22 (d, 1H, J = 7.8 Hz). 13C-NMR (150 MHz, CDC13): d 15.2, 35.9, 38.0, 38.4, 56.2, 67.0, 68.4, 79.9, 114.0, 114.6, 121.7, 124.6, 129.1, 130.8, 137.2, 139.3, 151.4, 157.8, 176.0 Example 38. Ethyl ester of 3- acid. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy-phenyl} -2-ethoxypropanoic (a) 3- (.}. 4-Benzyloxyphenyl-2-ethoxyacrylic acid ethyl ester Tetramethylguanidine (42.3 g, 0.37 mol) was slowly added to a solution of 4-benzyloxybenzaldehyde (75.6 g, 0.36 mol) and (1,2-diethoxy-2-oxoethyl) (triphenyl) phosphonium chloride (130 ^ 7 g). 0.304 moles) dissolved in chloroform (800 ml) at 0 ° C. After stirring at room temperature overnight, the solvent was evaporated in vacuo, the residue was dissolved in diethyl ether, the insoluble material was filtered off and the filtrate was washed with sodium bicarbonate and dried (magnesium sulphate) . The procedure was repeated once and thereafter the crude product was stirred overnight with a saturated aqueous solution of sodium bisulfite. The solid material was separated by filtration, the product was extracted with diethyl ether, dried (magnesium sulfate) and the solvent was evaporated in vacuo to give 85 g. (73% yield) of 3- (4-benzyloxyphenyl) -2-ethoxyacrylic acid ethyl ester. 1H-NMR (300 MHz, CDC13): d 1.35 (m, 6H), 4.0 (q, 2H), 4.3 (q, 2H), 5.05 (s, 2H), 6.95 (s + msin solve, 1 + 3H) , 7.3-7.45 (m, 5H), 7.75 (d, 2H). 13C-NMR (125 MHz; CDC13): d 14.4, 15.6, 61.0, 67.5, 70.0, 114.8, 124.0, 126.7, 127.5, 128.1, 128.6, 131.7, 136.7, 143.1. 159.2, 165.0. (b) 4- (2-Hydroxyethyl) phenylcarbamic acid tert-butyl ester Di-tert-butyl dicarbonate (7.95 g, 36 mmol) was added to a mixture of p-aminophenethyl alcohol (5 g, 36 mmol) in tetrahydrofuran at 0 ° C. After stirring at room temperature overnight, the solvent was evaporated in vacuo to give 8 g (94% yield) of 4- (2-hydroxyethyl) phenylcarbamic acid tert-butyl ester. 1 H-NMR (400 MHz, DMSO-d 6): d 1.5 (s, 9H), 2.65 (dd, 2H), 3.55 (dd, 2H), 4.6 (s, br, 1 OH ), 7.1 (unresolved, 2H), 7.35 (unresolved, 2H), 9.1 (s, 1 NH).

X3C-NMR (100 MHz; DMSO-d6): d 28.3, 38.6, 62.5, 78.9, 118.3, 129.1, 133.2, 136.6, 153.0 (c) 3- Ethyl ester. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy-phenyl} -2-ethoxypropanoic The 4- (2-hydroxyethyl) phenylcarbamic acid tert-butyl ester (1.03 g, 4.34 mmol) and the 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester were dissolved. (described in Example 20b) (1.03 g, 4.34 mmol) in dichloromethane under argon at room temperature.

Azodicarbonyl dipiperidine (1.65 g, 6.5 mmol) was added and thereafter triphenylphosphine (1.37 g, 5.2 mmol) After stirring at room temperature for 6 hours the solvent was evaporated in vacuo. silica gel using heptane: ethyl acetate (2: 1) as eluent gave 1.78 g (89% yield) of 3- ({4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] -phenyl) ethyl ester .} -2-ethoxypropanoic acid.

^ -H-NMR (400 MHz, CDC13): d 1.17 (t, 3H, J = 7 Hz), 1.23 (t, 3H, J = 7 Hz), 1.53 (s, 9H), 2.94-2.97 (m, 2H), 3.03 (t, 2H, J = 7.1 Hz), 3.31-3.40 (m, 1H), 3.56-3.65 (, 1H), 3.95-4.0 (m, 1H.), 4.11 (t 2H, J = 7.1 Hz), 4.17 (q, 2H, J = 7 Hz), 6.60 (s, INH), 6.81 (dm, 2H, J = 8.3Hz, unresolved), 7.15 (dm, 2H, J = 8.3 Hz, without solve), 7.20 (dm, 2H, J = 8.3 Hz, unresolved), 7.31 (dm, 2H, J = 8.3 Hz, unresolved). 13 C-NMR (100 MHz, CDCl 3): d 14.1, 15.0, 28.3, 35.0, 38.4, 60.7, 66.1, 68.6, 80.26, 80.32, 114.3, 118.7, 128.2, 129.4, 130.3, 132.8, 136.7, 152.8, 157.5, 172.4 .

Example 39. Acid 3-. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy-phenyl} -2-ethoxypropanoic Lithium hydroxide hydrate (77 mg, 1.85 mol.) In water (5.5 ml) was slowly added to a solution of ethyl ester of 3-. {4- [2- (4-ter- butoxycarbonylaminophenyl) ethoxy-phenyl.} -2-ethoxypropanoic acid (described in Example 38.) (0.77 g, 1.68 mmol) in tetrahydrofuran (7.6 ml) After stirring at room temperature for 4 hours the reaction mixture was stored in freezing for 4 days The tetrahydrofuran was removed by evaporation in vacuo, more water was added and the mixture was acidified with hydrochloric acid to pH 1. The product was extracted with ethyl acetate, washed twice with water, dried (sulfate sodium) was filtered and the solvent evaporated in vacuo to give 0.712 g (98.7% yield) of 3- {4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl}. -2-ethoxypropanoic. 1H-NMR (400 MHz; CDC13): d 1.18 (t, 3H, 3 = 7 Hz), 1.54 (s, 9H), 2.93-3. 1 0 (m, 4H). 3.36-3.45 (m, 1H), 3.60-3.69 (, 1M, 4.02-4.07 (m, 1H), 4.12 (t 2H, J = 7 Hz), 6.83 (dm, 2H), J = 8.8 Hz, unresolved), 7.15-7.23 (m, 4H), 7.27-7.34 (, 2H), 10.28 (bs, INH). 13 C-NMR (100 MHz; CDC 13): d 15. 0, 28.3, 35.2, 38. 0, 66.7, 68. 8, 79. 9, 80.7, 114. 6, 119. 1, 129. 0, 129. 4, 130. 4, 133.1, 136.8, 153.2, 157. 8, 175. 3.

Example 40. Acid 3- [4-. { 2- (4- [tert-butoxycarbonyl (methyl) aminojfenill) ethoxy} phenyl J- (S) -2-ethoxypropanoic (a) 2- [4- (tert-butoxycarbonylamino) phenylJetyl-4-methylbenzenesulfonate The 4- (2-hydroxyethyl) phenylcarbamate ter-butyl ester (described in Example 38b) was suspended (170 g, 0.716 moles) in dichloromethane (1.7 1) and placed in an ice bath. Pyridine (113 g, 1.43 mol) was added to give a light yellow solution. Chloride of p-toluenesulfonyl (205 g, 1.07 mol) was dissolved in dichloromethane (850 ml) and slowly added with stirring to the reaction mixture for 45 minutes. The reaction mixture was maintained until room temperature was reached overnight. The solution was then washed with water (4 x 1 L) and dried with magnesium sulfate. The solvent was evaporated under reduced pressure until the weight was 440 g. The remaining brown oil was poured slowly into heptane (1.6 L) with vigorous stirring. After about 20 seconds the oil began to crystallize. The heavy precipitate was separated from the filtrate, washed with heptane (200 ml) and dried under vacuum at 40 ° C overnight. This procedure gave 274 g (97.8% yield) of 2- [4- (tert-butoxycarbonylamino) phenylJetyl-4-methylbenzenesulfonate.

A sample of the crude product (8g) was recrystallized from ethanol (30 ml) and water (3 ml) to give 7.1 g (88.8% yield) of 2- [4-tert-butoxycarbonylamino) phenyl-Jethyl-4-methylbenzenesulfonate. 1H - S__R (500 .MHz; CDC13): d 1.55 (s, 9H), 2.47 (s, 3H), 2.93 (t, 2H, 1 = 7.0 Hz), 4.20 (t, 2H, J = 7.0 Hz) , 6.45 (s, INH), 7.05 (d, 2H), 7.24-7.34 (m, 4H), 7.72 (d, 2H). 13C-NMR (100 MHz; CDC13): d 91.6, 28.3, 34.7, 70.7, 80.5, 118.7, 127.8, 129.4, 199.7, 130.7, 133.0, 137.2, 144.6, 152.7, (b) It was • dissolved 2- [4-. { tert-butoxycarbonyl (methyl) amino} phenyl Jethyl-4-methylbenzenesulfonate, 2- [4- (tert-butoxycarbonyl) amino) phenyl] ethyl-4-methylbenzenesulfonate (0.5 g, 1.28 mol) in tetrahydrofuran (10 ml). Iodomethane (0.906 g, 6.38 mmol) was added, followed by sodium hydride (0.061 g, 2.54 mmol). The reaction mixture was stirred at room temperature for 3 hours and then evaporated. The residue was extracted with diethyl ether and water. The organic phase was dried and evaporated and 0.52 g (96.5% yield) of 2- [4-tert-butoxycarbonyl (methyl.}. Amino.] Phenyl] ethyl-4-methylbenzenesulfonate was obtained.

^ -NMR (300 MHz, CDC13): d 1.45 (s, 9H), 2.44 (s, 3H), 2.93 (t, 2H), 3.23 (s, 3H), 4.19 (t, 2H), 7.05-7.15 ( m, 4H), 7.30 (d, 2H), 7.71 (d, 2H). (c) Ethyl 3- (4-benzyloxyphenyl) -2-ethoxypropanoic acid ethyl ester The 3- (4-benzyloxyphenyl) -2-ethoxyacrylic acid ethyl ester (described in Example 38a) (0.5 g, 1.5 mmol) was hydrogenated at atmospheric pressure using rhodium on carbon (5%, 50 mg.) As Catalyst in methanol (20 mL) The crude product was purified by chromatography using heptane: ethyl acetate (5: 1) as eluent to give 50 mg (10% yield) of 3- (4-benzyloxyphenyl) ethyl ester -2-ethoxypropanoic acid.

XH NMR (300 MHz, CDC13): d 7.47-7.30 (m, 5H), 7.17 (d, 1 = 8.8, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.06 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 3.98 (t, J = 6.6 Hz, 1H), 3.61 (dq, J = 8.9 and 6.8 Hz, 1H.), 3.36 (dq, J = 8.9 and 6.8 Hz, 1H), 2.97 (d, J = 6.6 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDC13): d 172.6, 157.6, 137.1, 130.4, 129.5, 128.6, 127.9, 127.5, 114.6, 80.4, 70.0, 66.2, 60.8, 38.5, 15.1, 14.2. (d.) 3- (4-benzyloxyphenyl) -2-ethoxypropanoic acid Lithium hydroxide hydrate (7.4, 177 mmol) dissolved in water (150 ml) was added to a solution of 3- (4-benzyloxyphenyl) -2-ethoxypropanoic acid ethyl ester (23.35 g, 70.8 mol) in dioxane (150 mg). ml). After stirring at room temperature overnight the dioxane was evaporated in vacuo, water was added and the mixture was extracted with ethyl acetate. The aqueous phase was acidified with hydrochloric acid (1N) and extracted with ethyl acetate. The organic phase was washed with water and brine, dried and the solvent was evaporated in vacuo to give 21.1 g (99.2% yield) of 3- (4-benzyloxyphenyl) -2-ethoxypropanoic acid.

XH NMR (300 MHz, CDCl 3): d 1.15 (t, 3H), 2.9-3.1 (m, 2H), 3.35-3.45 (m, 1H), 3.6-3.7 (, 1H), 3.95-3.41 (m, 1H ), 5.05 (s, 2H), 6.95 (d, 2H), 7.2 (d, 2H), 7.25-7.5 (m, 5H). 13 C-NMR (75 MHz, CDCl 3): d 15.0, 38.1, 66.6, 70.0, 79.9, 114.7, 127.5, 128.0, 128.6, 129.3, 130.5, 137.1, 157.7, 176.3 (e) Amide 3- (4-benzyloxyphenyl) - (S) -2-ethoxy-N- (2-hydroxy- (R) -1-phenylethyl) propanoic and amide 3- (4-benzyloxyphenyl) - (R) - 2-ethoxy-N- (2-hydroxy- (R) -1-phenylethyl) propanoic EDC (2.03 g, 10.61 mmol), diisiopropylamine (1.84 ml, 10.61 mol) and H0BtxH20 (1.43 g, 10.61 mmol) were added to a solution of 3- (4-benzyloxyphenyl) -2-ethoxypropanoic acid (2.92 g, 9.74 mol). ) in secco dichloromethane (30 ml) cooled on an ice bath. After 30 minutes the ice bath was removed and (R) -phenylglycine (1.46 g, 10.61 mmol) was added. After stirring at room temperature overnight ethyl acetate (100 ml) was added and the mixture was washed with potassium bisulfate (1M), saturated sodium bicarbonate solution, sodium carbonate solution and water. The organic phase was dried (sodium sulfate), filtered and the solvent was evaporated in vacuo.The crude product was purified by chromatography on silica gel using acetate to give 1.5 g (37% yield) of amide 3- (4- benzyloxyphenyl) - (S) -2-ethoxy-N- (2-hydroxy- (R) -1-phenylethyl) propanoic and 1.25 g (31% yield) of amide 3- (-benzyloxyphenyl) - (R) -2 -ethoxy-N- (2-hydroxy- (R) -1-phenylethyl) propanoic.

Amide 3- (4-benzyloxyphenyl) - (S) -2-ethoxy-N- (2-hydroxy- (R) -1-phenylethyl) propanoic 1H NMR (400 MHz; CDC13): d 7.43-7.27 (m, 5H), 7.22 (d, J = 8.3 Hz, 4H), 7.13 (d, NH, J = 7.8 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 5.08 (s, 2H), 5.01 (m, 1H), 3.99 ( dd, J = 6.8 and 3.9 Hz, 1H), 3.69 (m, 2H), 3.50 (q, 1 = 6.8 Hz, 2H), 3.15 (dd, J = 14.2 and 3.9 Hz, 1H), 2.97 (dd, J = 14.2 and 6.8 Hz, 1H), 2.94 (m, OH, 1H), 1.16 (t J = 6.8 Hz, 3H). 13 C NMR (100 MHz; CDCl 3): d 172.3, 157.5, 138.9, 137.0, 130.7, 129.4, 128.6, 128.4, 127.7, 127.6, 127.3, 126.5, 114.4, 81.0, 69.8, 66.3, 66.0, 55.3, 37.8, 15.1.

Amide 3- (4-benzyloxyphenyl) - (R) -2-ethoxy-N- (2-hydroxy- (R) -1-phenylethyl) ropanoica 1H NMR (400 MHz; CDC13): d 7.49-7.20 (m, 9H), 7.13 (d, J = 8.8 Hz, 4H), 7.08 (d, J = 8.3 Hz, 4H), 6.86 (d, J = 8.8 Hz, 1H.}., 5.04 (s, 2H), 5.01 (, 1H), 4.01 (dd, J = 6.8 and 3.9 Hz, 1H), 3.83 (m, 2H), 3.57 (m, 2H), 3.16 (m, OH, 1H), 3.09 (dd, J = 14.2 and 3.9 Hz, 1H), 2.91 (dd, J = 14.2 and 6.8 Hz, 1H), 1. 21 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz; CDC13): d 172.3, 157.4, 138.6, 137.0, 130.6, 129.3, 128.5, 128.4, 127.8, 127.4, 127.3, 126.4, 114.4, 81.1, 69.8, 66.4, 66.1, 54.9, 37.5, 15.1. (f) 3- (4-Benzyloxyphenyl) -2- (S) -ethoxypropanoic acid The amide 3- (-benzyloxyphenyl) - (S) -2-ethoxy-N- (2-hydroxy- (R) -1-phenylethyl) propanoic (8.9 g, 21.22 mmoles) was hydrolyzed with concentrated sulfuric acid (27 ml) in water (104 ml) and dioxane (104 ml) at 90 ° C for 5 hours. The reaction mixture was poured into water (220 ml) and extracted with ethyl acetate. The organic phase was washed with brine, dried (sodium sulfate), and the solvent was evaporated in vacuo to give 6.85 g of 3- (4-benzyloxyphenyl) -2- (S) -ethoxypropanoic acid acid mixture ( S) -2-ethoxy-3- (4-hydroxyphenyl) propanoic which was used without further purification.

XH NMR (400 MHz, CDC13): d 7.47-7.30 (m, 5H), 7.19 (d, J = 8.8, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.10 (s, 2H), 4.06 (dd, J = 7.8 and 4.4 Hz, 1H), 3.64 (dq, J = 9.8 and 6.8 Hz, 1H), 3.44 (dq, J = 9.8 and 6.8 Hz, 1H), 3.09 (dd, J = 14.2 and 4.4 Hz, 1H, 2.93 (dd, J = 14.2 and 7.8 Hz, 1H), 1.19 (t, J = 6.8 Hz, 3H). (g) Ethyl 3- (4-benzyloxyphenyl-2- (S) -ethoxypropanoic acid ethyl ester Hydrogen chloride was bubbled through a solution of 3- (4-benzyloxyphenyl) -2- (S) -ethoxypropanoic acid (6.85 g, 22.8 mol) in ethanol (400 ml). ml; 27.4 immoles) and the reaction mixture refluxed for 2 hours. The solvent was evaporated to give 8 g of a mixture of 3- (4-benzyloxyphenyl) -2- (S) -ethoxypropanoic acid ethyl ester and (S) -2-ethoxy-3- (4-hydroxyphenyl) ethyl ester ) propanoic which were used without further purification.

* H NMR (300 MHz; CDC13): d 7.47-7.30 (m, 5H), 7.17 (d, J = 8.8, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.06 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 3.98 (t, 1 = 6.6 Hz, 1H), 3.61 (dq, J = 8.9 and 6. 8 Hz, 1H), 3.36 (dq, J = 8.9 and 6.8 Hz, 1H), 2.97 (d, J = 6.6 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCI3): 172.6, 157.6, 137.1, 130.4, 129.5, 128.6, 127.9, 127.5, 114.6, 80.4, 70.0, 66.2, 60.8, 38.5, 15.1, 14.2. (h) (S) -2-Ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester The 3- (4-benzyloxyphenyl) -2- (S) -ethoxypropanoic acid (7.13 g, 21.7 mmoles) was hydrogenated at atmospheric pressure for 2 hours in ethyl acetate (70 ml) using Pd / C as a catalyst. purification by chromatography on silica gel using toluene: ethyl acetate as the eluent gave 3.83 g (yield between stages of 76%) of ethyl ester of (S) -2-ethoxy-3- (4-hydroxyphenyl) propanoic acid.

^? - NMR (400 MHz, CDC13): d 1.18 (t 3H, J = 6.8 Hz), 1.24 Ct, 3H, J = 7 Hz), 7.96 (d, 2H, J = 6.5 Hz), 3.34-3.43 (m, 1H), 3. 57-3.66 (m, 1H), 4.00 (t, 1H, 6.5 Hz), 4.18 (q, 2H, J = 7 Hz), 5.30 (s, 1 OH), 6.74 (dm, 2H, J = 8.5 Hz, unresolved), 7. 10 (dm, 2H, J = 8.5 Hz, unresolved). 13 C-NMR (100 MHz, CDCl 3): d 14.2, 15. 0, 38.4, 60. 9, 66.2, 80. 4, 115. 1, 129. 0, 130. 5, 154.5, 172. 7 (i) Acid 3- [4-. { 2- (4- [tert-butoxycarbonyl (methyl) aminoj phenyl) ethoxy} phenyl- (S) -2-ethoxypropanoic Sodium hydroxide (0.44 g, 1.1 mmol) was pulverized and dissolved in DMSO (10 mL). (S) -2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (0.2 g, 0.84 mmol.) Was added and the mixture was stirred for 10 minutes before the addition of 2- [4-. Tert-butoxycarbonyl (methyl) amino} phenyl-keptyl-4-methylbenzenesulfonate (0.34 g, 0.84 mmol) The reaction mixture was stirred at room temperature for 4 hours and then according to LC-MS all the starting materials were The corresponding ester was added and water was added (10 ml), tetrahydrofuran (5 ml) and sodium hydroxide. (0.9 g, 22.5 mol) and the mixture was stirred overnight and then concentrated by evaporation. The residue was treated with ethyl acetate and water. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, dried with sodium sulfate and evaporated. The crude product was chromatographed with dichloromethane: methanol (95: 5) as eluent. The product, an oil, was dissolved in water and a small amount of ethanol and acetonitrile. The solution was cooled with liquid nitrogen. Lyophilization for three days gave a pure solid compound, 0.19 g (51% yield) of 3- [4-. { 2- (4- [tert -butoxycarbonyl (methyl) aminojphenyl) ethoxy} phenyl] - (S) -2-ethoxypropanoic acid as a white solid substance. 1 H-NMR (500 MHz; CD30D): d 1.10 (t, 3M, 1.45 (s, 9H), 2. 86 (m, 1H), 3.01-3.04 (m, 3H), 3.21 (s, 3H), 3.32 (m, 1H), 3.63 (, 1H), 3.93 (m, 1H), 4.12 (m, 2H), 6.80 (d, 9H), 7.16-7.20 (, 4H), 7.28 (d, 2H). 13C-NMR (125.7 MHz; CDC13): d 15.3, 28.6, 36.4, 38.0, 40.4, 66.8, 69.5, 81.5, 115.2, 126.8, 130.3, 131.3, 137.6, 143.2, 156-5, 158.7.

Example 41. (S) -2-Ethoxy-3- (4- [2- {4- (methoxycarbonylamino) phenyl} ethoxy-phenyl) propanoic acid ethyl ester (a) Ethyl ester of 3- acid. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic 2- [4- (tert-butoxycarbonylamino) phenyl] ethyl methanesulfonate (described in Example 40a) (52.9 g, 0.168 mmol), ethyl ester of (S) -2-ethoxy-3- (4-hydroxyphenyl) were mixed propanoic (described in Example 40h) (40 g, 0.168 mol) and potassium carbonate (69.5 g, 0.503 mmol) in acetonitrile (1200 ml) and refluxed overnight. Another portion of 2- [44- (tert-butoxycarbonylamino) phenyl-kemeylmethanesulfonate (2.5 g, 7.9 mole) was added. The reaction mixture was refluxed for an additional 8 hours then filtered. Evaporation of the filtrate gave 76.6 g of ethyl ester of 3- acid. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic.

This batch of 3- ethyl acid ester. { 4- [2-tert-butoxycarbonylanephenyl) ethoxyfenyl} - (S) -2-ethoxypropanoic (76.6 g.) Was combined with another batch of 3- ({4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy-phenyl) - (S) -2-ethoxypropanoic acid ethyl ester (74.1 g) and it was purified twice by flash chromatography on silica gel, first with toluene then with methanol as eluents and the second time with toluene with ethyl acetate (2-5%).

This procedure gave 69.9 g of ethyl ester of 3- acid. { 4 - [- (ter-3- { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic acid. 13H-NMR (400 MHz; CDC13): d 1.16 (t, 3H), 1.22 (t, 3H), 1.51 (s, 9H), 2.94 (d, 2H), 3.02 (t, 2H), 3.31-3.38 (, 1H), 3.55-3.63 (m, 1H), 3.95 (t 1H), 4.10 (t 2H), 4.16 (q, 2H), 6.45 (bs, 1H), 6.8 (d, 2H), 7.13 (d, 2H), 7.13 (d, 2H), 7.19 (d, 2H), 7.29 (d, 2H). (b) 3- Acid ethyl ester hydrochloride. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic Trifluoroacetic acid (12 ml, 0.706 moles) was added to a solution of 3- ethyl ester. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic acid (30 g, 0.65 mol) in dichloromethane (150 ml). The reaction mixture was stirred overnight at room temperature and then washed twice with water. The organic phase was dried with magnesium sulfate and evaporated. The XH-NMR of the product exhibited a mixture of product and starting material. The crude product (27.3 g) was redissolved in ethyl acetate, ethyl acetate saturated with hydrochloric acid (500 ml) was added and the mixture was stirred overnight at room temperature. Evaporation gave 24.7 g (96.5% yield) of 3- hydrochloride. { 4- [2- (aminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic.

XH-NMR (400 MHz, CDC13): d 1.14 (t, J = 7 Hz, 3H), 1.20 (t, J = 7 Hz, 3H), 2.91-2.93 (, 2H), 3.02 (t, J = 7 Hz, 2H), 3.29-3.36 (m, 1H), 3.54-3.61 (m, 1H), 3.94 (dd, J = 7.3, 5.8 Hz, 1H), 4.08 (t, J = 77Hz, 2H), 4.14 ( q, J = 7 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.45 (d, = 8.3 Hz, 2H. 13C_NMR (100 MHz, CDC13): d 14.18, 15.02, 35.22, 38.40, 60.77, 66.16, 68.00, 80.31, 114.29 (2C), 123.39 (2C), 128.16, 129.50, 130.39 (2C), 130.42 (2C), 139.69 , 157.29, 172.53 (c) (S) -2-Ethoxy-3- (4- [2- ({4- (methoxycarbonylamino) phenyl)} ethoxyJphenyl propanoic acid ethyl ester Acid ethyl ester hydrochloride was dissolved 3-. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic (0.55 g, 1.4 mmol) in terahydrofuran (5 mL) and methyl chloroformate (0.534 g, 5.68 mmol) was slowly added. The reaction mixture was checked constantly with HPLC and after 6 days all the initial material was consumed.

Water was added a. the mixture, the tetrahydrofuran was evaporated and the residue was extracted three times with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated and 0.525 g (90.2%) of ethyl ester of acid was obtained.

'(S) -2-Ethoxy-3- (4- [2- {4- (methoxycarbonylamino) phenyl} ethoxyJphenyl) propanoic acid.

XH-NMR (600 MHz, CDC13): d 1.15 (t, 3H), 1.22 (t, 3H), 2.90-2.97 (m, 2H), 3.03 (t, 2H), 3.31-3.37 (m, 1H), 3.55- 3.62 (, 1H), 3.77 (s, 3H), 3.95 (q, 1H), 4.11 (t, 3H), 4. 16 (q, 2H), 6.60 (bs, NH), 6.80 (d, 2H), 7.13 (d, 2H), 7. 21 (d, 2H), 7.37 (be, 2H) 13 C-NMR (150 MHz; CDC13): d 14.4, 15.5, 35.3, 38.7, 45.2, 61.0, 66.4, 68.9, 80.6, 114.5, 129.5, 129.8, 130.6, 157.8, 172.8, 179.7 Example 42. (S) -2-Ethoxy-3- (4- [2-. {4- (methoxycarbonylamino) phenylj-ethoxy-phenyl) propanoic acid The ethyl ester of (S) -2-ethoxy-3- (4- [2- {4-methoxycarbonylamino) phenyl-malexyphenyl) propanoic acid was dissolved (described in example 41) (0.52 g, 1.25 mol) in tetrahydrofuran (10 ml) and slowly added lithium hydroxide (0.034 g, 1.42 mmol) dissolved in water (2 ml). The reaction mixture was stirred overnight, hydrochloric acid (1M, 1 ml) was added and the tetrahydrofuran was evaporated. The residue was extracted three times with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated and 0.47 g (99% yield) of (S) -2-ethoxy-3- [4-. { 2- [4- (methoxycarbonylamino) phenyl) -ethoxy-phenyl} propanoic XH-NMR (600 MHz, CDC13): d 1-16 (t, 3H), 2.91-3.05 (m, 2H), 3.03 (t, 2H), 3.38-3.45 (m, 1H), 3.56-3.63 (m , 1H), 3.77 (s, 3H), 4.03 (q, 1H), 4.11 (t, 3H), 6.80 (d, 2H), 7.14 (d, 2H), 7.21 (d, 2H), 7.30 (bs, 2H). 13 C-NMR (150 MHz; CDCI3): 8 15.3.35.4.38-1.52.6.67.0.68.9.80.0,114.7,129-0, 129.8, 130.7, 157.9, 175.6 Example 43. 3- [4-. { 2- (4- [tert-butoxycarbonylaminojphenyl) ethoxy} phenyl J-2-ethylsulfanylpropanoic acid (a) 3- (4-Benzyloxyphenyl) -2-ethylsulfanyl propanoic acid methyl ester Potassium hydroxide (0.092 g, 1.64 mmol) was dissolved in methanol. Ethanediol (0.133 g, 2.14 mmoles) and 3- (4-benzyloxyphenyl) -2-chloropropanoic acid methyl ester (0.5 g, 1.64 mmoles) were added. The reaction mixture was stirred at room temperature overnight. Diethyl ether (15 ml) was added. The mixture was filtered and evaporated. The residue was purified by the addition of activated carbon in methanol. The mixture was stirred for 15 minutes and the activated carbon was removed by filtration. Evaporation of the solvent gave 0.47 g (86.7% yield) of 3- (4-benzyloxyphenyl) -2-ethylsulfanyl propanoic acid methyl ester. 1 H-NMR (400 MHz, CDC13): d 1.23 (t, 3 H), 2.63 (m, 2 H), 2.90 (m, 1 H), 3.14 (m, 1 H, 3.50 (m, 1 H), 3.67 (s, 3 H ), 5.04 (s, 2H), 6.89 (d, 2H), 7.11 (d, 2H), 7.30-7.45 (m, 5H). (b) 2-Ethylsulfanyl-3- (4-hydroxyphenyl) propanoic acid methyl ester 3- (4-Benzyloxyphenyl) -2-ethylsulfyl propanoic acid methyl ester (0.37 g, 1.12 mmol) was dissolved in dichloromethane (3.5 mL). Dimethylsulfide was added (3 ml), followed by the addition of boron trifluoride etherate (1.6 g, 11 mmol.) The reaction mixture was stirred for 3 hours at room temperature and then quenched with water (3 ml). added more dichloromethane and the phases were separated.The organic phase was washed twice with brine and dried with sodium sulfate.The evaporation of the solvent gave 0.2 g (74.3% yield) of methyl ester of ethylsulfanyl-3- (4-methyl ester). -hydroxyphenyl) propanoic. 1 H-NMR (3QQ MHÍ; CDC13): d 1.23 (t, 3H), 2.62 (q, 2H), 2.90 (m, 1H, 3.11 (m, 1H), 3.51 (m, 1H), 3.68 (s, 3H ), 6.73 (d, 2H), 7.05 (d, 2H). (c) 3- [4-. { 2- (4- [tert-butoxycarbonylaminojphenyl) ethoxy} phenyl J-2-ethylsulfanyl propanoic Sodium hydroxide (0.045 g, 1-25 mmol) was sprayed and added to DMSO (10 ml) Methyl ester of the acid 2-ethylsulfanyl-3- (4-hydroxyphenyl) was added. ) propanoic (0.21 g, 0.87 mmo-Les) followed by the addition of 2- [4- (tert-butoxycarbonylamino) phenyl-Jethyl-4-methylbenzenesulfonate - (described in Example 40a) (0.342 g, 0.87 mmol). The mixture was stirred at room temperature for 3 hours, then all the starting material was consumed according to LC-MS, water (10 ml) and tetrahydrofuran (5 ml) were added and stirring was continued overnight. It was treated with diethyl ether and water and diluted hydrochloric acid was added to prevent foaming, the phases were separated and the organic phase was washed three times with water.The phases were combined and washed once more with diethyl ether. All the organic phases were combined, dried with sodium sulfate and ev they beat Chromatography in petroleum ether (1: 9 and 1: 3) gave 0.18 g (41.4% yield) of methyl 3- [4-. { 2- (4- [tert-butoxycarbonylamino] phenyl) ethoxy} phenyl J-2-ethylsulfanylpropanoic acid.

XH-NMR (400 MHz, CDCl): d 1.22 (t, 3H), 1.51 (s, 9H), 2.61 (m, 2H), 2.89 (m, 1H), 3.01 (t, 2H), 3.12 (m, 1-H), 3.48 (m, -1H), 3.66 (s, 3H), 4.09 (t, 2H), 6.79 (d, 2H), 7.08 (d, 2H), 7.18 (d, 2H), 7.29 ( d, 2H) 13C-NMR (100 MHz; CDC13): d 14.6, .25.9, 28.6, 35.3, 37.3, 48.4, 52.3, 68.9, 80.7, 114.7, 119.0, 129.7, 130.1, 130.4, 133.1, 137.0, 153.0, 157.9, 173.0 E p 44. Acid 3- [4-. { 2- (4- [tert-butoxycarbonylamino) phenyl) ethoxy} phenyl-2-ethylsulfanylpropanoic acid.

Sodium hydroxide (0.14 g, 3.5 mmol) was pulverized and added to DMSO (15 mL). Methyl ester of 2-ethylsulfanyl-3- (4-hydroxyphenyl) propanoic acid acid (described in Example 43b) (0.21 g, 0.87 mmol) was added and the resulting mixture was stirred at room temperature for 10 minutes before the addition of 2 - [4- (tert-butoxycarbonylamino) phenylJethyl-4-methylbenzenesulfonate (described in Example 40a) (0.342 g; 0.87 min.). The reaction mixture was stirred at room temperature for 4 hours. Sodium hydroxide (1.08 g, 2.7 mmol) was dissolved in water (15 ml) and added to the reaction mixture followed by the addition of tetrahydrofuran (5 ml). The reaction mixture was stirred at room temperature overnight. The majority of the solvents evaporated. The residue was treated with diethyl ether and water and the phases were separated. The organic phase was dried with sodium sulfate and evaporated. Chromatography of the residue on silica gel using a petroleum ether gradient system: 'diethyl ester (90:10, 75:25, 25:75 and 0: 100) gave 0.41 g (34% yield) of acid 3 - [4-. { 2- (4- [tert-butoxycarbonylamino phenyl) ethoxy} phenyl J-2-ethylsulfanylpropanoic acid.

XH-NMR (400 MHz, CDC13): d 1.02 (t, 3H), 1.50 (s, 9H), 2. 44 (m, 2H), 2.77 (m, 1H), 2.92 (m, 2H), 3.15 (m, 1H) 3. 44 (m, 1H), 3.96 (m, 2H), 6.68 (d, 2H), 7.03 (d, 2H), 7.10 (d, 2H), 7.23 (d, 2H).

Example 45. Benzyl ester of 3- acid. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy phenyl} '-2-ethoxypropanoic acid The acid was dissolved 3-. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy phenyl} -2-ethoxypropanoic acid (described in example 39) (1 g, 2.33 mmole) in a solution of dichloromethane and triethylamine (0.235 g, 2.56 mmole) and the mixture was cooled to 0 ° C. Benzyl chloroformate (0.4 g, 2.33 mmol) was added followed by addition of "DMAP (0.28 g, 2.33 mmol) after 10 minutes.

The reaction mixture was stirred overnight at room temperature and then extracted with saturated sodium bicarbonate, sodium bisulfate (0.5 M) and brine. The organic phase was dried with sodium sulfate and evaporated. Chromatography on silica gel using dichloromethane with methanol (1%) as eluent gave 0.36 g (29.7%) of 3-benzyl ester. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy-phenyl)} -2-ethoxypropanoic.

XH-NMR (400 MHz, CDC13): d 1.18 (t 3H), 1.53 (s, 9H), 2.98 (d, 2H), 3.07 (t, 2H), 3.32-3.4 (m, 1H), 3.56-3.65 (m, 1H), 4.03 (t 1H), 4.16 (t, 2H), 5.15 (s, 2H), 6.53 (bs, 1H), 6.8, (d, 2H), 7.12 (d, 2H), 7.23 ( d, 2H), 7.25-7.38 (m, 7H). 13C-NMR (100 MHz; CD3OD): d 14.2, 27.6, 34.9, 38.2, 65. 9, 66.4, 68.7, 76.6, 80.3, 114.3, 118.8, 128.13, 128.2, 128. 3, 128.8, 129.2, 130.3, 133.0, 135.8, 137.7, 154.2, 158.0, 172.8.

Example 46. 4- (2- [4-. {2-ethoxy-3-oxopropyl.) Phenoxyethyl) phenylcarbamate tert-butyl ester 3-ethyl ester was dissolved. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy-phenyl] -2-ethoxypropanoic acid (described in Example 38) (3.78 g, 8.2 mmol) in dry dichloromethane and the solution was cooled to -78 ° C. DIBAL (20%, 15.9 ml, 19 mmol) was added slowly.The reaction mixture was stirred at -78 ° C and continued with TLC.After 4 hours another portion of DIBAL (15.9 ml, 19 mmol) was added.

The reaction was quenched with aqueous ammonium chloride and the addition resulted in a heavy precipitate. The mixture was filtered through HyFlo and the filtrate was evaporated. The residue was redissolved in ethyl acetate and chromatography on silica gel with ethyl acetate: heptane (gradient 12.5-100% ethyl acetate) gave 0.9 g (26.3% yield) of tert -butyl-4- (2- [4-. {2-ethoxy-3-oxopropyljphenoxyjet) phenylcarbamate. 1 H-NMR (400 MHz, CDCl 3): 5 1.19 (t, 3 H), 1.53 (s, 9 H), 2. 80-2.86 (m, 1H), 2.90-2.96 (IH), 3.04 (t, 2H), 3.40-3.50. (m, 1H), 3.55-3.66 (m, 1H), 3.79-3.84 (m, 1H), 4.13 (t, 2H), 6.51 (bs,! H), 6.83 (d, 2H), 7.14. { d, 2H), 7.21 (d, 2H), 7.31 (d, 2H), 9.68 (s, 1H) 13 C-NMR (100 MHz, CDCl 3): d 15.5, 28.6, 35.4, 36.1, 66.3, 69.0, 80.7, 85.4, 114.7, 119.0, 128.9, 129.7 , 130.6, 133.1, 137.0, 153.1, 157.9, 204.0.

Example 47. 4- [2- (4-. {3- [benzyl (ethyl) aminoJ-2-ethoxy-3-oxopropyl] phenoxy) -ethyl tert-butylcarbamate.

The acid was dissolved 3-. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy phenyl} -2-ethoxypropanoic acid (described in example 39) (6.09 g, 14.2 mmol) in acetonitrile (150 ml) and the solution was cooled to 0 ° C. DCC (3.51 g, 17 mmol), HO-Su (1.96 g, 17 mmol) and DIPEA (2.2 g, 17 mmol) were added and stirred for 15 minutes before the addition of N-ethylbenzylamine (2.72 g, 17 mmol). ). The reaction mixture was stirred and stirred overnight and then filtered and evaporated. Hydrochloric acid (2 M, 200 ml) was added to the residual oil and the obtained mixture was then extracted three times with ethyl acetate. The organic phase was washed with sodium bicarbonate solution, dried with magnesium sulfate and evaporated.

Chromatography of the residue on silica gel with heptane: ethyl acetate (1.25-100%) using the elution gradient technique gave 5.32 g (68.5% yield) of 4- [2- (4-. {3 - [benzyl (ethyl) aminoJ-2-ethoxy-3-oxopropyl] phenoxy) ethyl-phenylcarbamate tert-butyl. 1H-R (400 MHz, CDC13): d 1.17 (t 3H), 1.53 (s, 9H), 2.94-3-13 (m, 4H), 3-39-3-47 '(m, 1H), 3.58 -3.66 (, 1H), 4.06-4.09 (m, 1H), 4.13 (t, 2H), 6.58 (b, 1H), 6.77-6.85 (m, 3H), 7.17-7.13 (m, 3H), 7.26- 7.32 (m, 2H) 13 C-NMR (100 MHz; CDCl 3): d 15.0, 28.4, 35.2, 38.9, 66.9, 68.8, 79.7, 80.6, 113.2, 116.0, 119.1, 121.9, 129.2, 129.4, 133.2, 136.8, 138.3, 153.1, 158.9, 1774.4.

Example 48. Ethyl ester of 3- acid. { 3- [2- (tert-butoxycarbonylaminophenyl) ethoxy-phenyl} -2-ethoxypropanoic (a) 2- [4- (tert-butoxycarbonylamino) phenyl ethylmetanesulfonate 4- (2-Hydroxyethyl) phenylcarbamic acid tert-butyl ester (described in Example 38b) was dissolved (2.46"g; 10" .3"8 immoles) in dichloromethane (21 ml) Triethylamine (2.17 ml, 15.6 mmol) was added and the mixture was stirred for 20 minutes and then cooled on an ice bath. methanesulfonyl chloride (1.25 g, 10.9 Z5 ~ mmoies). The reaction mixture was stirred for 3.5 hours and the precipitate that formed was separated by filtration. The filtrate was evaporated and the residue redissolved in ethyl acetate. A new precipitate formed and separated by filtration and the filtrate was evaporated. Chromatography on silica gel using heptane: ethyl acetate (2: 1, 1: 1) gave 3 g (100% yield) of 2- [4- (tert-butoxycarbonylamino) phenyl ethylmetanesulfonate.

^ -NMR (400 MHz, CDC13): d 1.52 (s, 9H), 7.87 (s, 3H), 3.01 (t, 2H), 4.39 (t, 2H), 7.16 (d, 2H, J = 8.45 Hz) , 6.45 (bs, 1H), 7.33 (d, 2H, J = 8.45 Hz) 13 C-NMR (100 MHz; CDC 13): d 28.2, 34.8, 37.1, 70.2, 80.3, 118.6, 129.2, 130.5, 137.3, 152.6. (b) 3- Ethyl ester. { 3- [2- (4-tert-butoxycarbonylaminophenyl) ethoxyphihenyl} -2-ethoxypropanoic 2-Ethoxy-3- (3-hydroxyphenyl) propanoic acid ethyl ester (0.76 g, 3.2 mmol) was dissolved in acetonitrile (30 ml). Potassium carbonate was added followed by the addition of 2- [4- (4-tert-butoxycarbonylamino) phenyl-kemeylmethanesulfonate (1 g, 3.2 mmol). The reaction mixture was refluxed for 4.5 hours and then more acetonitrile (20 ml) was added. The mixture was refluxed overnight and then evaporated. The residue was redissolved in water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried with magnesium sulfate and evaporated. Chromatography on silica gel using ethyl acetate: exano (1: 4) as eluent gave 0.8 g (54.6% yield) of 3- ethyl ester. { 3- [2- (4-tert-butoxycarbonylaminophenyl) ethoxyphihenyl} -2-ethoxypropanoic.

The product was lyophilized before being used in the next step.

XH-NMR (400 MHz, CDC13): d 1.17 (t, 3H), 1.32 (t, 3H), 1.52 (s, 9H), 2.93 (d, 2H), 3.04 (t, 2H), 3.32-3.4 ( m, 1H), 3.57-3.65 (m, 1H), 4.01 (t, 1H), 4.13 (t, 2H), 4.18 (q, 9H), 6.51- (bs, 1H), 6.76 (d, 1H, J = 7.98 Hz), 6.79-6.85 (m, 2H), 7.17 (d, 1H, J = 7.97 Hz), 7.2 (d, 2H, J = 8.28 Hz), 7.31 (d, 2H), J = 8.28 Hz) . 13C-NMR (100 MHz; CDC13): d 14.4, 15.3, 28.6, 35.5, 39.6, 61.0, 66.4, 68.9, 80.4, 80.6, 113.0, 115.9, 119.0, 122.0, 129.4, 129.7, 133.2, 137.1, 139.0, 153.1 , 158.9, 172.7.

Example 49. Acid 3-. { 3- [2- (4- tert.-butoxycarbonylaminophenyl). Ethoxyfindyl) -2-ethoxypropanoic acid 3-ethyl ester was dissolved. { 3- [2- (4-tert-butoxycarbonylaminophenyl) ethoxyphihenyl} -2-ethoxypropanoic acid (described in Example 48) (0.8 g, 1.74 mmoles) in tetrahydrofuran (15 ml). Lithium hydroxide hydrate dissolved in water (5 ml) was added slowly. The reaction mixture was stirred at room temperature for 4.5 hours. More lithium hydroxide hydrate (0.036 g, 0.87 mmol) was added and stirring was continued for a further 2 hours.Therhydrofuran was carefully evaporated and a large amount of water was added, the pH was adjusted to approximately 12 with hydroxide Sodium (2M) and the solution was extracted with ethyl acetate.The aqueous phase was cooled to <10 ° C, acidified with potassium bisulfate (1M) and extracted with ethyl acetate. Water and dried with sodium sulfate.The evaporation gave 0.53 g (70.9% yield) of 3-, {3- [3-, 4-tert-butoxycarbonylaminophenyl) ethoxy phenyl} -2-ethoxypropanoic.

XH-NMR (400 MHz, CDC13): d 1.17 (t, 3H), 1.53 (s, 9H, 2.94-3.13 (m, 4H), 3.39-3.47 (m, 1H), 3.58-3.66 (m, 1H) , 4.06-4.09 (m, 1H), 4.13 (t, 2H), 6.58 (b, 1H), 6.77-6.85. (M, 3H), 7.17-7.23 (m, 3H), 7.26-7.32 (m, 2H ) 13C-NMR (100 MHz, CDC13): d 15. 0, 28.4, 35.2, 38. 9, 66.9, 68. 8, 79.7, 80. 6, 113.2, 116. 0, 119. 1, 121.9, 129.2, 129.4, 133.2, 136.8, 138.3, 153.1, 158.9, 174.4 Example 50. Acid 3- [4-. { 2- (4-tert-butoxycarbonylamino-phenyl) ethoxy} Phenyl-2-ethoxy-2-methylpropanoic acid (a) 3- (4-Benzyloxyphenyl) -2-ethoxy-3-hydroxy-2-methyl propanoic acid ethyl ester Di-isopropylamine (1.1 ml, 7.78 mol) and dry tetrahydrofuran (35 ml) were mixed and cooled to -78 ° C under a nitrogen atmosphere. It was added slowly -butyl lithium (1.6 M in hexane, 4.7 ml, 7.52 mmole) and the reaction mixture was stirred for 15 minutes. The ethyl ester of 2-ethoxypropionic acid was dissolved in a small amount of dry tetrahydrofuran and added slowly to the LDA mixture. The solution was stirred for 30 minutes at low temperature and then 4-benzyloxybenzaldehyde was added followed, after 2 minutes by the addition of saturated ammonium chloride solution (20 ml). The mixture was warmed to room temperature and the layers separated. The aqueous phase was extracted twice with ether and the organic phases were combined and washed with hydrochloric acid. (0.3 M, 100 ml) and brine, dried with magnesium sulfate and evaporated. Purification of the residue by chromatography on silica gel using ethyl acetate: toluene (1: 9) with triethylamine (0.1%) as eluent gave 1.63 g (68%) of 3- (4-benzyloxyphenyl) 2-ethoxy acid ethyl ester -3-hydroxy-2-methyl propanoic.

XH-NMR (400 MHz, CDC13): d 1.18 (t, 3H, 1 = 7.0 Hz), 1.26 (t, 3H, 7.1 Hz), 1.41 (s, 3H), 3.26 (br, 1H), 3.44-3.60 (m, 2H), 4.06-4.15 (m, 2H), 4.77 (s, 1M, 5.07 (s, 2H), 6.93 (d, 2H, J = 8.8 Hz), 7.30 (d, 2H, J = 8.8 Hz ), 7.32-7.47 (m, 5H) 13 C-NMR (100 MHz; CDCl 3): d 14.1, 15.6, 17.1, 60.3, 60.8, 69.9, 78.0, 82.9, 114.0, 127.4, 127.8, 128.5, 128.7, 131.5, 137.0, 158.5, 172.4 (b.) 3- (4-Benzyloxyphenyl) -2-ethoxy-3-hydroxy-2-methylpropanoic acid ethyl ester (0.358 g, 1 mmol) and triethylamine (0.32 mL, 2 mmol) were dissolved in dry dichloromethane. (4 ml) and cooled to 0 ° C after which borotrifluoride etherate (0.284 g, 2 mmole) was added.The reaction mixture was then stirred at 0 ° C for 2.5 hours and then quenched by the addition of bicarbonate. saturated sodium (10 ml) and dichloromethane (10 ml) The aqueous layer was extracted three times with diethyl ether The organic phases were combined and dried over sodium sulfate.

Evaporation of the solvent gave 0.349 g (100% yield) of 3- (4-benzyloxyphenyl) -2-ethoxy-2-methyl propanoic acid ethyl ester.

XH-NMR (400 MHz, CDC13): d 1.19-1.26 (m, 6H, 1.31 (s, 3H, 2.97 (s, 2H), 3.38-3.53 (m, 2H), 4.15 (dq, 2H, J = 7.1 ), 5.03 (s, 2H), 6.87 (d, 2H, J = 8.7 Hz), 7.12 (d, 2H, 1 = 8.7 Hz), 7.28-7.45 (m, 5H) 13 C-NMR (100 MHz; CDCl 3): d 14.2, 15.7, 20.3, 44.2, 60.0, 60.8, 70.0, 80.8, 114.3, 127.5, 127.5, 127.9, 129.5, 128.7, 131.4, 137.2, 157.6, 174.2. (c) 2-Ethoxy-3- (4-hydroxyphenyl) -2-methyl propanoic acid ethyl ester The ethyl ester of 3- (4-benzyloxyphenyl) -2-ethoxy-2-methylpropanoic acid (0.34 g, 0.99 mmol) was hydrolyzed for 18 hours at atmospheric pressure in ethyl acetate using Pd / C (0.05 g) as a catalyst. and then it was filtered through HyFlo. The solvent was evaporated and 0.249 g (98% yield) of 2-ethoxy-3- (4-hydroxyphenyl) -2-methylpropanoic acid ethyl ester was obtained. 1 H-NMR (400 MHz, CDCl 3): d 1.21 (t 3 H), J = 7.0 Hz), 1.23 (t, 3 H, J = 7.1 Hz), 1.32 (s, 3 H), 2.95 (s, 2 H), 3.38 -3.54 (m, 2H), 4.14 (dq, 2H, J = 7.1), 6.70 (d, 2H, 3 = 8.8 Hz), 7.04 (d, 9H, J = 8.8 Hz). 13C-NMR (100 MHz; CDC13): d 14.2, 15.6, 20.3, 44.2, 60.0, 60.9, 50.5, 114.8, 128.2, 131.5, 154.5, 174.4. (d) Acid 3- [4-. { 2- (4- [tert-butoxycarbonylamino] phenyl) ethoxy} Phenyl-2-ethoxy-2-methylpropanoic acid Sodium hydroxide (0.105 g, 2.63 mmol) was pulverized and dissolved in DMSO (8 ml). To 4 ml of this solution were added 2- [4- (tert-butoxycarbonylamino) phenylJethyl-4-methylbenzenesulfonate (described in Example 40a) (0.515 g, 1.316 mol) and 2-ethoxy-3- (4-ethyl) ethyl ester -hydroxyphenyl) 2-methyl propanoic acid (0.331 g, 1316 immoles) and the mixture was stirred at room temperature overnight. The remaining volume (4 ml) of sodium hydroxide solution and water (1 ml) was added. The mixture was kept at rest overnight and then evaporated. The residue was redissolved in dichloromethane and water and the phases were separated. The aqueous phase was extracted once more with dichloromethane, acidified with hydrochloric acid (1M), extracted several times with ethyl acetate and diethyl ether. The organic phases were combined, dried with magnesium sulfate and evaporated. Purification of the crude product by flash chromatography and preparative HPLC gave 0.103 g (17.1% yield) of 3- [4-. { 2- (4- [tert-butoxycarbonylaminojphenyl) ethoxy} Phenyl-2-ethoxy-2-methyl-propanoic acid.

^ - M (600 MHz, CDC13): d 1.24 (t, 3H, J = 7.0 Hz), 1.46 (s, 3H), 1.52 (s, 9H), 2.36 (s, 2H), 3.02 (t, 2H, J = 6.9 Hz), 4.10 (t, 2H, 1 = 6.9 Hz), 6.55 (br, 1H), 6.79 (d, 2H) J = 8.6 HZ), 7.08 (d, 2H J = 8.6 Hz), 7.14-7.28 (m, 5H), 7.29 (br, 1H). 13 C-NMR (75 MHz, CDCl 3): d 15.5, 20.9, 28.3, 35.1, 42.3, 59.5, 68.6, 80.6, 81.0, 114.2, 115.9, 127.5, 129.4, 131.1, 132.9, 136.7, 153.0, 157.3, 176.1.

Example 51. Ethyl ester of 2-ethoxy-3- acid. { 4- [2- (4-methylcarbamoyloxyphenyl) ethoxy-phenyl} propanoic Methyl isocyanate (70 mg, 1.22 mmol) was slowly added to a mixture of triethyl amine (180 mg, 1.17 mmol) and 2-ethoxy-3-ethyl ester. { 4- [2- (4-hydroxyphenyl) ethoxy-phenylpropanoic acid (described in Example 26b) (418 mg, 1.17 mmol) in dichloromethane (5 ml). After stirring at room temperature for 2.5 hours the excess methyl isocyanate was evaporated in vacuo and water and dichloromethane were added. The phases separated. Water and potassium bisulfate (1 M) was added to the organic phase. The phases were separated, the organic phase was evaporated in vacuo and the residue was purified by chromatography on silica gel using toluene: diethylether (gradient 4: 1 to 3: 1) as eluent to give 229 mg (47% yield) of ester Ethyl 2-ethoxy-3- acid. { 4- [2- (4-methylcarbamoyloxyphenyl) ethoxy-phenyl} propanoic XH-NMR (400 MHz, CDC13): d 1.2 (t, 3H, J = 7.0 Hz), 1.26 (t, 3H), 2.87 (d, 3H, J = 4.9 Hz), 2.97-3.01 (m, 2H), 3.09 (t, 2H, 1 = 7.0 Hz), 3.35-3.43 (, 1H), 3.59-3.68 (m, 1H), 3. 99-4.03 (m, 1H), 4.16 (t, 2H, J = 7.0 Hz), 4.20 (q, 2H), . 25 (m, INH), 6.84 (dm, 2H, J = 8.6 HZ, unresolved), 7.09 (dm, 2H, J = 8.3 Hz, unresolved), 7.18 (dm, 2H, J = 8.6 Hz, unresolved ), 7.28 (dm, 2H, .J = 8.3 Hz, unresolved). 13C-NMR (100 MHz; CDC13): d 14.1, 14.9, 27.5, 35.0, 38.3, 60.6, 66.0, 68.4, 80.2, 114.2, 121.4, 129.1, 129.6, 130.2, 135.1, 149.6, 155.3, 157.4, 172.4.

Example 52. Ethyl ester of 3- [4-. { 2- (4- [benzyloxycarbonylaminojphenyl) ethoxy} phenyl] - (S) -2-ethoxypropanoic Acid ethyl ester hydrochloride was mixed 3-. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic (described in Example 41b) (0.6 g, 1.67 mmol, triethylamine (0.17 g, 1.67 mmol) and benzylchloroformate (0.28 g, 1.67 mmol) in tetrahydrofuran. The reaction mixture was stirred at room temperature overnight and then evaporated. The residue was treated with sodium bicarbonate solution and diethyl ether. The organic phase was dried with magnesium sulfate and evaporated. According to the NMR spectrum there was initial material remaining. The residue was dissolved in tetrahydrofuran and triethylamine and benzylchloroformate were added. The reaction mixture was stirred at room temperature then evaporated. The treatment described above gave a crude product which by purification with preparative HPLC (Kromasil C8, 7 .m., 50 X 250 mm) using acetonitrile (70-100%) in ammonium acetate buffer (pH 7) as the phase mobile gave 0.180 g (22% yield) of ethyl 3- [4-. { 2- (4- [benzyloxycarbonylamino] phenyl) ethoxy} phenyl] - (S) -2-ethoxypropanoic acid.

XH-NMR (600 MHz, CDC13): d 1.16 (t, 3H), 1.22 (t 3H), 7.94 (d, 9H), 3.03 (t, 2H), 3.32-3.37 (m, 1H), 3.57-3.62 (m, 1H), 3.96 (t, 1H), 4.11 (t, 2H), 4.16 (q, 2H), 5.19 (s, 2H, 6.75 (bs, 1H), 6.8 (d, 2H), 7.13 (d , 2H), 7.21 (d, 2H), 7.3-7.41 (m, 7H). 13C_NMR (150 MHz, CDC13). d 15.3, 15.3, 35.4, 38.7, 61.0, 66.4, 67.2, 68.9, 80.7, 114.6, 119.1, 128.5, 128.6, 128.8, 129.0, 129.8, 130.7, 136.3, 153.9, 157.8, 172.8.

Example 53. Acid 3- [4-. { 2- (4- [benzyloxycarbonylamino] phenyl) ethoxy} phenyl J- (S) -2-ethoxypropanoic The 3- [4-] ethyl ester was dissolved. { 2- (4- [benzyloxycarbonylamino.] Phenyl) ethoxy} phenyl J- (S) -2-ethoxypropanoic acid (described in Example 52) (0.16 g, 0.32 mmol) in tetrahydrofuran and lithium hydroxide (9 mg, 0.38 mmol) dissolved in water (1 ml) was added. The resulting mixture was stirred overnight. Hydrochloric acid (1M, 1 ml) was added. The tetrahydrofuran was evaporated and the remaining aqueous residue was extracted three times with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated to give 0.14 g (92.8% yield) of 3- [4-. { 2- (4- [benzyloxycarbonylamino] -phenyl) ethoxy} phenyl J- (S) -2-ethoxypropanoic.

XH-NMR (600 MHz, CDCl 3): d 1.16 (s, 3H), 2.91-3.08 (m, 4H), 3.38-3.45 (m, 1H), 3.56- 3.64 (m, 1H), 4.00-4.05 (m , 1H), 4.07-4.14 (m, 4H), 5.20 (s, 2H), 6.81 (d, 2H), 7.14 (d, 2H), 7.28-7.42 (m, 7H). 13C-NMR (150 MHz; CDC13): d 15.3, 35.4, 38.1, 67.0, 67.3, 68.9, 50.1, 114.7, 119.21 118.5, 128.6, 128.8, 129.0, 129.8, 130.7, 136.3, 153.9, 157.9, 175.5 Example 54, Acid 3-. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy-3-methoxyphenyl} -2-ethoxypropanoic (a) Ethyl 3- (4-benzyloxy-3-ethoxyphenyl) -2-ethoxyacrylic acid ethyl ester 4-benzyloxy-3-methoxybenzaldehyde was dissolved (7 g; 28. 8 mmol) and (1,2-diethoxy-2-oxoethyl) (triphenyl) phosphonium chloride (13.6 g, 31 mmol) in isopropanol and the reaction mixture was cooled to -10 ° C. D-potassium carbonate (6 g, 43 mmol) was added. The resulting mixture was stirred overnight and the temperature was maintained until room temperature. The reaction mixture was filtered and the filtrate was evaporated. Diethyl ether was added to the residue and the resulting mixture was stirred for a while and then the insoluble material was separated by filtration. The filtrate was washed with portasium bisulfate solution and water, dried with magnesium sulfate and evaporated. Isopropyl ether was added to the residue. Triphenylphosphine oxide precipitated and separated by filtration and the filtrate was evaporated. Chromatography of the residue on silica gel using toluene with ethyl acetate (0.1%, 3% = as eluent gave 5.2 g of 3- (4-benzyloxy-3-methoxyphenyl) -2-ethoxyacrylic acid ethyl ester. it was not sufficiently pure it was stirred with petroleum ether, the insoluble material was separated by filtration and the filtrate was evaporated to give 4 g (38% yield) of 3- (4-benzyloxy-3-methoxyphenyl) ethyl ester - 2-ethoxy acrylic.

^ -NMR (300 MHz, CDC13): d 1.33-1.5 (m, 6H), 3.92 (s, 3H), 4.03 (q, 2H), 4.3 (q, 2H), 5.16 (s, 2H), 6.88 ( d, 1H), 6.96 (s, 1H), 7.2 (d, 1H), 7.27-7.5 (, 6H). (b) 3- (4-Benzyloxy-3-methoxyphenyl) -2-ethoxypropanoic acid ethyl ester 3- (4-benzyloxy-3-methoxyphenyl) -2-ethoxyacrylic acid ethyl ester (5.5 g, 15.4 mmol) was dissolved in ethyl acetate and hydrogenated using Pd / C (5%, dry). The reaction mixture was filtered through celite. Evaporation of the filtrate gave 4 g (97% yield) of 3- (4-benzyloxy-3-methoxyphenyl) -2-ethoxypropanoic acid ethyl ester. 1 H-NMR (600 MHz, CDC13): d 1.16 (t 3 H), 1.23 (t, 3 H), 2. 9 (m, 2H), 3.28-3.36 (m, 1H), 3.55-3.63 (m, 1H), 3.83 (s, 3H), 3.95 (m, 1H), 4.16 (m, 2H), 5.63 (bs, 1H), 6.72 (m, 1H), 6.76-6.85 (m, 2H). 13C-NMR (150 MHz, CDC13): d 14.4, 15.3, 39.2, 56.0, 61.0, 66.4, 80.7, 117.4, 114.3, 122.2, 129.3, 144.6, 146. 4, 172.8 (c) 3- Ethyl ester. { 4- [3- (4-tert-butoxycarbonylaminophenyl) ethoxy] -3-methoxyphenyl} -2-ethoxypropanoic 3- (4-Benzyloxy-3-methoxyphenyl) -2-ethoxypropanoic acid ethyl ester (0.5 g, 1.86 mmol) was dissolved in acetonitrile and potassium carbonate (0.53 g, 3.91 mmol) was added. 2- [4- (tert-Butoxycarbonylamino) phenyl-keptyl-4-methylbenzenesulfonate (described in Example 40a) (0.755 g, 1.92 mmol) was added. The resulting mixture was stirred and refluxed overnight then filtered and the filtrate was evaporated. The residue was treated with sodium hydroxide (0.5 M) and diethyl ether. The phases were separated and the organic phase was dried with magnesium sulfate. Evaporation gave 0.7 g (77.2% yield) of 3- ethyl ester. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy-3-methoxyphenyl} -2-ethoxypropanoic.

XH-NMR (300 MHz, CDC13): d 1.18 (t, 3H), 1.27 (t, 3H), 1.52 (s, 9H), 2.95 (d, 2H), 3.1 (t, 2H), 3.3-3.43 ( m, 1H), 3.58-3.7 (, 1H), 3.87 (s, 3H), 3.98 (t, 1H), 4.13-4.25 (m, 4H), 6.48 (bs, 1H), 6.78-6.87 (, 3H) , 7.12 (d, 2H), 7.27-7.35 (m, 2H) (d) Acid 3-. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxyJ-3-methoxyphenyl} -2-ethoxypropanoic 3-ethyl ester was dissolved. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxyJ-3-methoxyphenyl} -2-ethoxypropanoic acid (0.7 g, 1.34 mmol) in tetrahydrofuran and water (1: 1), lithium hydroxide hydrate (0.09 g, 2.13 mmol) was added and the reaction mixture was stirred overnight. Water was added and tetrahydrofuran was evaporated. The remaining aqueous residue was extracted once with diethyl ether, acidified with d-potassium bisulfate and extracted with ethyl acetate. The organic phase was dried with magnesium sulphite. Evaporation gave 0.5 (76% yield) of 3- acid. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] -3-methoxyphenyl} -2-ethoxypropanoic.

XH-NMR (400 MHz, CD30D): d 1.12 (t, 3H), 1.49 (s, 9H), 2. 82-2.89 (m, 1H), 2.92-3.0 (m, 3H), 3.31-3.38 (m, 1H), 3. 54-3.63 (, 1H), 3.78 (s, 3H), 3.97-4.02 (m, 1H), 4.7- 4.13 (m, 2H), 6.74 (m, 2H), 6.8 (m, 1H), 7.17 (d , 2H), 7.29 (d, 2H), 8.75 (bs, 1H). 13C-NMR (100 MHz; CD3OD): d 14.2, 27.6, 34.9, 38.5, 55.4, 65.9, 70.2, 79.5, 80.1, 113.9, 1 14.0, 118.8, 121.8, 129.1, 130.8, 132.9, 137.6, 147.3, 149.5, 154.3, 174.9.

Example 55, Acid 3-. { 3- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] -4-methoxyphenyl} -2-ethoxypropanoic The 3- acid was synthesized. { [2- (4-tert-butoxycarbonyl inophenyl) ethoxy-4-methoxyphenyl} -2-ethoxypropanoic acid from 3-benzyloxy-4-methoxybenzaldehyde according to the procedure described in example 54.

XH-NMR (400 MHz, CD30D): d 1.1 (t 3H), 1.5 (s, 9H), 2.8-2.88 (m, 1H), 2.91-3.02 (m, 3H), 3.32-3.37 (m, 1H) , 3.53-3.61 (m, 1H), 3.76 (s, 3H), 3.95 (m, 1H), 4.1-4.15 (m, 2H), 6.77 (m, 1H), 6.81-6.85 (m, 2H), 7.19 (d, 2H), 7.3 (d, 2H), 8.75 (bs, 1H). 13C-NMR (100 MHz; CD3OD): d '14.2, 27.6, 34.9, 38.4, 55.5, 65.9, 70.1, 79.5, 80.0, 112.4, 115.4, 118.8, 122.0, 129.2, 130.4, 132.9, 137.6, 148.2, 148.6, 154.2, 174.8.

Example 56. (S) -2-Ethoxy-3- [4-} 2- [4- ([ { 4- (tert-butyl) cyclohexyl.} Oxyjcarbonylamino) -phenylpropaxy) phenyl propanoic (a) 3- Hydrochloride. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic Water (200 ml) was added to a solution of 3-ethyl ester hydrochloride. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic acid (described in Example 41b) (15 g, 42 mmol) in tetrahydrofuran (100 ml). Hydroxide was added. lithium (3.4 g; 84 mol) dissolved in a small amount of water while stirring and then the reaction mixture was stirred at room temperature overnight. The tetrahydrofuran was evaporated and the remaining residue was extracted twice with ethyl acetate. The aqueous phase was acidified with hydrochloric acid (2 M) and extracted with ethyl acetate.

The organic phase was dried with magnesium sulfate. Evaporation gave 6.4 g. of acid hydrochloride 3-. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic. The aqueous phase, from the previous one, was neutralized with sodium hydroxide to pH ~ 5 and extracted with dichloromethane. The organic phase was dried with magnesium sulfate and evaporated. This procedure gave 1.4 g more of the desired product. The total yield of 3- hydrochloride. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic was 7.8 g (50.8%).

^ -NMR (500 MHz, CD3OD): d 1.12 (t, J = 7 Hz, 3H), 2.85 (dd, J = 14.8 Hz, 1N), 2.94 (t, J = 7 Hz, 2H), 2.97 (dd, J = 14.4.5 Hz, 1H), 3.31-3.37 (m, 1H), 3.56-3.62 (m, 1H), 3.98 (dd, J = 8, 4.5 Hz, 1H), 4.08 (t, J) = 7 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H) and 7.14 (d, J = 8.8 Hz, 2H). 13 C-NMR (125 MHz, CD 3 OD): d 15.31, 36.05, 39.37, 67.09, 70.20, 81.49, 115.34 (2C), 117.74 (2C), 130.76 (2C), 130.81. 130. 94,131.41 (20, 144.82,159.10,176.35. (b) (S) -2-Ethoxy-3 [4- (2- [4- ([. {4- (tert-butyl) cyclohexyl} oxyhacrylamino) -phenyl-methoxy) phenyl-propanoic acid 3-hydrochloride was mixed. -. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic acid (0.2 g 0.547 mmol) and sodium bicarbonate (0.05 g, 0.595 mmol) in tetrahydrofuran (5 ml), stirred at room temperature ppr 20 minutes and then chloroformate 4 was added. -tert-butylcyclohexyl (0.131 g, 0.599 mmol) The reaction mixture was stirred at room temperature overnight and then a little more 4-tert-butylcyclohexyl chloroformate was added to the reaction since the reaction had not taken place. The reaction mixture was stirred for a further 2 hours and then evaporated to dryness, ethyl acetate and water were added to the residue and the phases were separated, the organic phase was dried with magnesium sulfate and the solvent was added. The chromatography on silica gel (Isolute, SI) using dichloromethane: heptane (1: 1), followed by dichloromethane, and then methanol: dichloromethane (1:99) as eluents gave 0.28 g (93% yield) of the acid ( S) -2-ethoxy-3 [4- (2- [4- ([ { 4- (tert-butyl) cycloh ex. (oxy oxycarbonylamino) -phenyl) -phenyl-propanoic acid.

JH-NMR (400 MHz, CD3OD): d 0.86 (s, 9H), 0.99-1.18 (m, 3H), 1.10 (t, J = 7Hz, 3H), 1.35 (dd, br, J = 24, 12 Hz , 2H), 1.83 (d, br, J = 12 Hz, 2H), 2.08 (d, br, J = 12 Hz, 2H), 2.83 (dd, J = 14.5, 8 Hz, 1H), 2.92-2.98 ( m, 3H), 3.29-3.36 (m, 1H), 3.53-3.61 (m, 1H, 3.97 (dd, J = 8.45 Hz, 1H, 4.08 (t, J = 7 Hz, 2H), 4.48-4.56 (m, 1H), 6.79 (d, J = 8.5 Hz), 7.12 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H) and 7.32 (d, J = 8.5 Hz). 13C-NMR (100 MHz, CD3OD): d 15.30, 26.63 (2C), 28.04 (3C), 33.07, 33.60 (2C), 36.10, 39.32, 67.13, 69.90, 75.41, 81.30, 115.37 (4C), 120.02, 130.34 (2C), 130.73, 131.42 (2C), 134.40, 138.57, 155.80, 159.06, 176.05.

Example 57. (S) -2-Ethoxy-3- (4-. {2- [4- (phenoxycarbonylamino) phenylJethoxy] -phenyl) propanoic acid ethyl ester The ethyl ester hydrochloride of 3- acid was dissolved. { 4- [2- (4-aminophenyl) ethoxy phenyl} - (S) - 2-ethoxypropanoic (described in Example 41b) (0.55 g, 1.4 mmol) in tetrahydrofuran (5 ml). Phenyl chloroformate (0.675 g, 3 mmol) was added slowly. The reaction mixture was stirred at room temperature and continuously checked with HPLC and after three days all the initial material consumed was present. Water was added, tetrahydrofuran was evaporated and the residue was extracted three times with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated. Purification of the crude product with preparative HPLC (Kromasil C8, 7 μm, 50 x 250 mm) using acetonitrile (70%) in ammonium acetate buffer (pH 7) as the mobile phase gave 0.46 g (96.3% yield) of the ester Ethyl (S) -2-ethoxy-3- (4- { 4- [4- (phenoxycarbonylamino) phenyl} ethoxyJphenyl) propanoic acid. 1 H-NMR (300 MHz, CDCl 3): d 1.18 (t, 3 H), 1.24 (s, 9 H), 2.96 (d, 2 H), 3.07 (t, 2 H), 3.31 - 3.41 (m, 1 H), 3.55- 3.68 (m, 1H), 3.98 (t, 2H), 4.10-4.23 (m, 4H), 6.83 (d, 2H), 6.96 (bs, NH), 7.12-7.31 (m, 9H), 7.37-7.45 ( m, 4H), 13C_-NMR (75 MHz; CDCI3): d 15.5, 28.6, 35.4, 36.1, 66.8, 69.0, 80.7, 85.4, 114.7, 119.0, 128.9, 129.7, 130.6, 133.1, 137.0, 153.1, 157.9, 204.0 Example 58. 3- [4- (2. {4-tert-Butoxycarbonylaminophenyl) ethoxy) phenyl-2- (2-methoxyethoxy) propanoic acid methyl ester (a) 2- (2-methoxyethoxy) benzyl acetate 2- (2-Methoxyethoxy) acetic acid (10 g, 75 mmol) and tetrabutylammonium bromide (25.3 g, 75 mmol) were dissolved in sodium hydroxide solution (2 M, 75 mL, 75 mmol). and added benzyl bromide (15.3 g, 89 mol) dissolved in dichloromethane (150 ml). The reaction mixture was refluxed 4 hours. After separation the organic phase was dried with magnesium sulfate and evaporated. Chromatography using dichloromethane as eluent gave 17.5 g (94%) of benzyl 2- (2-methoxyethoxy) acetate. 1 H-NMR (500 MHz, CD30D): d 3.41 (s, 3H), 3.62 (t 2H), 3.77 (t, 2H), 4.24 (s, 2H), 5.23 (s, 2H), 7.31-7.45 (, 5H). (b) (Z) -3- [4- (Benzyloxy) phenylJ-2- (2-methoxyethoxy) -2-propenoic acid benzyl ester 4- (benzyloxy) benzaldehyde (3.00 g, 14.0 mmol) and 2- (2-methoxyethoxy) benzyl acetate (4.23 g, 17.0 mmol) were dissolved in dry tetrahydrofuran (100 ml) and cooled to -20 ° C. Potassium tert-butoxide (1.91 g, 17.0 mmol) was added, dissolved in dry tetrahydrofuran (10 mL) and the reaction was stirred overnight at -20 ° C. The reaction was quenched with acetic acid (0.85 g; 14.0 mmoles) The crude product was isolated, redissolved in toluene and refluxed overnight with p-toluenesulfonic acid. (0.24 g, 1.4 mmol) in the Dean-Stark apparatus to separate the water. The solution was cooled, washed with sodium bicarbonate, dried with magnesium sulfate and evaporated. Purification of the crude product with preparative HPLC (Kromasil C8, 10 μm, 50 x 500 mm) using acetonitrile (50-70%) in ammonium acetate buffer (pH 7) as the mobile phase gave 1.83 g (29% yield) of (Z) -3- [4- (benzyloxy) phenylJ-2- (2-methoxyethoxy) -2-propenoic acid benzyl ester.

"H-NMR (500 MHz, CD30D): d 3.36 (s, 3H), 3.65-3.72 (m, 2H), 4.09-4.17 (m, 2H), 5.11 (s, 2H), 5.30 (s, 2H) , 6.98 (d, 2H), 7.05 (s, 1H), 7.32-7.50 (m, IOH), 7.81 (d, 2H). (c) The benzyl ester of (Z) -3- [4- (benzyloxy) phenyl-2- (2-methoxyethoxy) -2-propenoic acid (1.75 g, 4.2 mmol) in methanol (50 ml) was hydrolyzed. At atmospheric pressure using Pd / C (5%) as a catalyst, the mixture was filtered through celite and evaporated under vacuum to give 3- (-hydroxyphenyl) -2- (2-methoxyethoxy) propanoic acid 0.83 g (88%). of performance).

^ - MR (500 MHz, CD30D): d 2.90-2.97 (m, 1H), 3.10-3.16 (m, 1H), 3.42 (s, 3H), 3.49- 3.52 (m, 1H), 3.55-3.63 (m , 2H), 3.65-3.72 (m, 1H), 4.12 (q, 1H), 6.74 (d, 2H), 7.10 (d, 2H). (d) 3- (4-Hydroxyphenyl) -2- (2-methoxyethoxy) propanoic acid methyl ester 3- (4-hydroxyphenyl) -2- (2-methoxy) propanoic acid (0.80 g, 3.1 mmol) was dissolved in methanol saturated with hydrochloric acid and refluxed for 2 hours. The mixture was evaporated in vacuo to give 3- (4-hydroxyphenyl) -2- (2-methoxyethoxy) propanoic acid methyl ester 0.84 g (99% yield). 1H-NMR (500 MHz, CD3OD): d 2.97-3.02 (m, 2H), 3.34 (s, 3H), 3.50-3.57 (m, 4H), 3.73 (s, 3H), 4.08-4.17 (, 1H) , 6.75 (d, 2H), 7.11 (d, 2H). (e) 3- [4- (2. {4-tert-Butoxycarbonylaminophenyl) ethoxy) phenyl] -2- (2-methoxyethoxy) propanoic acid methyl ester They were mixed 2- [4-. { tert-butoxycarbonyl (methyl) amino} phenyl] ethyl-4-methylbenzenesulfonate (described in Example 40a) (0.50 g, 1.26 mmol), 3- (4-hydroxyphenyl) -2- (2-methoxyethoxy) propanoic acid methyl ester (0.32 g, 1.26 mol) and Potassium carbonate (0.35 g, 2.64 mmol) was mixed in acetonitrile (20 ml) and refluxed overnight. Water was added, acetonitrile was evaporated and the residue was extracted three times with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated. Purification of the crude product with preparative HPLC (Kromasil C8, 7 μm, 50 x 500 mm) using acetonitrile (50-70%.) In ammonium acetate buffer (pH 7) as mobile phase gave 0.34 g (58%. ) yield of 3- [4- (2. {4-tert-butoxycarbonylaminophenyl) ethoxy) phenyl-2- (2-methoxyethoxy) propanoic acid methyl ester.

XH-NMR (500 MHz, CDC13): d 1.54 (s, 9H), 2.97-3.02 (m, 2H), 3.05 (t, 2H), 3.33 (s, 3H), 3.48-3.55 (m, 4H), 3.72 (s, 3H), 4.09-4.17 (m, 3H), 6.64 (bs, NH), 6.82 (d, 2H), 7.15 (d, 2H), 7.21 (d, 2H), 7.32 (d, 2H) . 13 C-NMR (125 MHz, CDCl 3): d 14.5, 15.5, 28.6, 35.4, 38.7, 52.1, 59.2, 69.0, 70.3, 72.2, 81.3, 114.6, 119.1, 129.4, 129.7, 130.6, 133.1, 137.1, 153.2, 157.9 , 173.0.

Example 59. 3- [4- (2-. {4-tert-Butoxycarbonylaminophenyl)} ethoxy) phenyl-2- (2-methoxyethoxy) propanoic acid Acid 3- [4- (2- {4-tert-butoxycarbonylaminophenyl) ethoxy) phenyl] -2- (2-methoxyethoxy) propanoic acid methyl ester (described in Example 58) (0.26 g) was dissolved.; 0.55 mmoles! in tetrahydrofuran: water (1: 3, 4 ml). Lithium hydroxide (16.0 mg, 0.66 mmol) dissolved in a small amount of water was added. The reaction mixture was stirred for two hours at room temperature and then evaporated. The residue was redissolved in diethyl ether and hydrochloric acid (2M) and extracted. The organic phase was dried with magnesium sulfate and evaporated to give 0.235 g (92% yield) of 3- [4- (2. {4-tert-butoxycarbonylaminophenyl) ethoxy) phenylJ-2- ( 2-methoxyethoxy) propanoic.

H-NMR (500 MHz, CDC13): d 1.46 (s, 9H), 2.83-3.02 (m, 3H), 3.27 (s, 3H), 3.38-3.65 (m, 3H), 3.99 (q, 1H), 4.03-4.10 (m, 2H), 6.75 (d, 2H), 7.08-7.16 (m, 4H), 7.26 (bd, 2H). 13C-NMR (125 MHz; CDC13): d 28.5, 35.2, 38.4, 58.9, 69.0, 70.2, 71.9, 81.1, 114.6, 119.1, 129.6, 130.6, 133.0, 137.1, 153.2, 157.7, 17.6.

Example 60. 3- [4- (2. {4-Tert-Butoxycarbonylaminophenyl) ethoxy) phenyl J-2- (2,2,2-trifluoroethoxy) propanoic acid methyl ester The 3- [4- (2. {4-tert-butoxycarbonylaminophenyl) ethoxy) phenyl-2- (2,2,2-trifluoroethoxy) propanoic acid methyl ester was synthesized using the same method as in Example 62 (a) from 3- (4-hydroxyl) -2- (2,2,2-trifluoroethoxy) propanoic acid methyl ester and 4- (2-hydroxyethyl) phenylcarbamic acid tert -butyl ester described in Example 38b.

^ -N R (300 MHz, CD30D): d 1.34 (s, 9H), 2.95-3.12 (m, 4H), 3.63-3.74 (m, 1H), 3.75 (s, 3H), 3.95-4.04 (m, 1 H), 4. 12 (t 3H), 4.16-4.22 (m, 1H), 6.59 (bs, NH), 6.83 (d, 2H), 7.14 (d, 2H), 7.21 (d, 2H), 7.32 (t 2H). 13C-NMR (75 MHz, CD3OD): d 28.7, 35.42, 38.5, 52.4, 67.9, 68.4, 69.0, 81.7, 114.7, 119.0, 121.9, 125.6, 128.4, 129.7, 130.6, 133.1, 137.0, 153.1, 158.0, 171.5 .

Example 61. 3- [4- (2-. {4-tert-Butoxycarbonylaminophenyl) ethoxy) phenyl-2- (2,2,2-trifluoroethoxy) propanoic acid 3- [4- (2. {4-Tert-Butoxycarbonylaminophenyl) ethoxy) phenyl-2- (2,2,2-trifluoroethoxy) propanoic acid methyl ester (described in Example 60) was dissolved (0.27) g, 0.52 mmole) in tetrahydrofuran and water (2: 1), lithium hydroxide (0.015 g, 0.62 mmol) was added and the reaction mixture was stirred overnight. Water was added and tetrahydrofuran was evaporated. The remaining aqueous residue was extracted once with diethyl ether, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate. Evaporation gave 0.22 g (85% yield) of 3- [4- (2. {4-tert-butoxycarbonylaminophenyl) ethoxy) phenylJ-2- (2,2,2-trifluoroethoxy) propanoic acid.

XH-NMR (500 MHz, CD30D): d 1.47 (s, 3H), 3.01-3.08 (m, 3H), 3.12-3.17 (m, 1H), 3.68-3.78 (m, 1H), 3.98-4.07 (, 1H), 4.23 (q, 1H), 6.84 (d, 2H), 7.18 (d, 2H, 7.22 (d, 2H), 7.31 (m, 2H). 13 C-NMR (125 MHz; CD 3 OD): d 28.7, 35.42, 38.5, 67.9, 68.4, 69.0, 81.7, 114.7, 121.9, 125.6, 128.4, 129.7, 130.6, 133.1, 137.0, 153.1, 158.0, 171.5. 19.0, Example 62. Ethyl ester of 2-ethoxy-3- acid. { 4- [2- (4-methanesulphonylamino) ethoxy-phenyl} propanoic (a) Ethyl ester of 3- acid. { 4- [2- (4-aminophenyl) ethoxy-phenyl} -2-ethoxypropic 4-aminophenethyl alcohol (1.39 g, 10.2 mmol) and 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (described in Example 20b) (2.42 g, 10.2 mmol) in dichloromethane (35) were dissolved. ml) under argon at room temperature, azodicarbonyl dipiperidine (3.85 g, 15.2 mmol) and then triphenylphosphine (3.20 g, 12.2 mmol) was added in. After standing at room temperature for 1 minute, dichloromethane (30 ml) was added. and after 21 hours the solvent was evaporated in vacuo Purification by chromatography on silica gel using heptane: ethyl acetate (3: 2) as eluent gave 3.12 g (86% yield) of 3- ethyl ester. {4- [2- (4-aminophenyl) ethoxy-phenyl) -2-ethoxypropanoic acid. 1H-NMR (400 NIHZ; CDC13): d 1.18 (t, 3H, J = 7 Hz), 1.24 (t, 3H, J = 7 Hz), 2.95-3.02 (m, 4H), 3.31-3.42 (m, 1H), 3.58-3.67 (m, 3H), 3.96-4.02 (m, 1H), 4.10 (t, 2H, J = 7 Hz), 4.13 (q, 2H, J = 7 Hz), 6.66 (dm, 2H ) J = 8.3 Hz, unresolved), 6.83 (dm, 2H, J = 8.3 Hz, unresolved), 7.08 (dm, 2H, J = 8.3 Hz, unresolved), 7.16 (dm, 2H, J = 8.3 Hz ,without resolving) . 13C-NMR (100 MHz; CDC13): d 14.1, 15.0.34.9, 38.4, 60.7, 66.1, 69.0, 80.3, 114.3, 115.2, 127.9, 129.1, 129.7, 130.3, 144.8, 157.6, 172.5. (b) 2-Ethoxy-3-ethyl ester. { 4- [2- (4-methansulfonylaminophenyl) ethoxy-phenyl} propanoic Triethylamine (0.544 g, 2.99 mmol) and then methanesulfonyl chloride (0.392 g) were added.; 2.99 immoles) to a solution of 3- ethyl ester. { 4- [2- (4-aminophenyl) ethoxy-phenyl} -2-ethoxypropanoic acid (0.89 g, 2.49 mol) in dichloromethane (8.9 ml) at 0 ° C. After stirring at room temperature for 20 hours the reaction mixture was poured into a mixture of hydrochloric acid and ice. Dichloromethane was added, the phases were separated and the organic phase was washed with water, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane: ethyl acetate (3: 2) as eluent gave 0.78 g (72% yield) of 2-ethoxy-3-ethyl ester. { 4- [2- (4-methanesulfonylaminophenyl) ethoxyj phenylpropanoic acid. 1H-MR (500 MHz, CDC13): d 1.18 (t, 3H, J = 7 Hz), 1.25 (t, 3H, J = 7 Hz), 2.96-2.99 (m, 2H), 3.01 (s, 3H) , 3.07 (t, 2H, J = 7 Hz), 3.34-3.43 (m, 1H), 3.59-3.66 (m, 1H) 3.98-4.03 (m, 1H), 4.13-4.22 (m, 4H), 6.83 ( dm, 2H, J = 8.8 Hz, unresolved), 7.16 (dm, 2H, J = 8.8 Hz, unresolved), 7.22 (dm, 2H, J = 8.5 Hz, unresolved), 7.28 (dm, 2H, J = 8.5 Hz, unresolved). 13C-NMR (125 MHz; CDC13): d 14.1, 15.0, 35.0, 38.3, 39.0, 60.7, 66.1, 68.3, 80.2, 114.2, 121.2, 129.3, 130.3, 130.1, 130.3, 135.1, 135.7, 157.4, 172.5.

Example 63. 2-Ethoxy-3- Acid. { 4- [2- (4-ethanesulfonylaminophenyl) ethoxy-phenyl} propanoic The ethyl ester of 2-ethoxy-3- acid was dissolved. { 4- [2- (4-methanesulfonylaminophenyl) ethoxyJphenyl} propanoic (described in Example 62) (0.554 g, 1.27 mmol) in tetrahydrofuran (5.7 ml) Lithium hydroxide hydrate (0.137 g, 3.26 mmol) was dissolved in water and added portionwise for 30 minutes at room temperature. The reaction mixture was stored in the refrigerator overnight. The tetrahydrofuran was evaporated in vacuo. The aqueous residue was washed with ethyl acetate, acidified with hydrochloric acid (1M) to pH 1-2 and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (sodium sulfite), filtered and the solvent evaporated in vacuo to give 0.54 g (100% yield) of 2-ethoxy-3- acid. { 4- [2- (4-methanesulfonylaminophenyl) ethoxy-phenyl} propanoic XH-NMR (400 MHz, CDCl 3): d 1.17 (t, 3H), J = 7 Hz), 2.93-3.0 (m, 4H), 3.0-3.09 (m 3H), .3.37-3.47 (m, 1H) , 3.59-3.68 (m, 1H), 4.03-4-08 (m, 1H), 4.12 (t, 2H, J = 7 Hz), 6.82 (dm, 2H, J = 8.8 Hz, unresolved), 7.14- 7.29 (, 6H), 7.40 (s, INH), 9.02 (bs, 1H). 13C-NMR (100 MHz; CDC13): d 14.9, 35.0, 37.8, 39.0, 66. 5, 68.3, 79.6, 114.3, 121.2, 128.8, 130.0, 130.3, 135.1, 135.6, 157.4, 176.3.

Example 64. Ethyl ester of (S) -2-ethoxy-3- [4-. { 2- (4- [methanesulfonyl (methyl) aminojphenyl) ethoxy} phenyl] propanoic (a) Ethyl ester of (S) -2-ethoxy-3- [4-. { 2- (4- [Methylsulfonylamino-phenyl) -ethoxy-phenyl-propionic acid Hydrochloride of 3- (4- [2- (4-aminophenyl) ethoxy-phenyl) - (S) -2-ethoxypropanoic acid ethyl ester (described in Example 41b) (0.45 g, 1.26 mol), dichloromethane ( 10 ml), methanesulfonyl chloride (0.216 g, 1.88 mol) and triethylamine (0.318 g, 3.14 mmol) were mixed at 0 ° C and stirred for 3 hours at that temperature and then at room temperature overnight. The reaction was poured into ethyl acetate (50 ml) The triethylamine hydrochloride salt was separated by filtration and the filtrate was evaporated The residue was redissolved and extracted with ethyl acetate and water The organic phase was washed once more with water , dried with sodium sulfate and evaporated, chromatography with diethyl ether: petroleum ether (1: 3, 1: 1, 3: 1) as eluent gave 0.18 g (32.8% yield) of ethyl ester of the acid (S). ) -2-Ethoxy-3- [4-. {2- (4- [Methylsulfonylamino] phenyl) ethoxy} phenylpropanoic acid.

^ -M (500 MHz, CDC13): d 1.21 (t, 3H), 1.28 (t, 3H), 2.99 (m, 2H), 3.04 (s, 3H), 3.11 (m, 2H), 3.39 (m, 1 HOUR) , 3. 64 (, 1H), 4.01 (, 1H), 4.15-4.25 (m, 4H), 6.84 (d, 2H), 7.17- 7.23 (, 4H), 7.30-7.35 (m, 2H). (b) Ethyl ester of (S) -2-ethoxy-3- [4-. { 2- (4- [Methylsulfonyl (methyl) aminojphenyl) ethoxy} Phenyl-propanoic (S) -2-ethoxy-3- [4-] ethyl ester was dissolved. { 2- (4- [Methylsulfonylamino] phenyl) ethoxy} phenylpropanoic acid (0.17 g, 0.39 mmol) in tetrahydrofuran (10 ml). Iodomethane (0.277 g, 1.95 mmol) and sodium hydride (0.019 g, 0.79 mmol) were added and the reaction mixture was stirred at room temperature for 3 hours and then evaporated, the residue was redissolved and extracted with ether. The organic phase was washed once more with water, dried with sodium sulfate and evaporated, chromatography with ethyl acetate: petroleum ether (1: 1) gave 0.98 g (55.8% yield). ) of (S) -2-ethoxy-3- [4-. {2- (4- [methylsulfonyl (methyl) aminoj phenyl) ethoxy} phenylpropanoic acid ethyl ester.XH-NMR (300 MHz, CDC13): d 1.16 (t, 3H), 1.23 (t, 3H), 2.84 (s, 3H), 2.94 (m, 2H), 3.08 (, 2H), 3.31 (s, 3H) ), 3.36 (m, 1H), 3.60 (m, 1H), 3.96 (m, 1H), 4.10-4.20 (, 4H), 6.80 (d, 2H), 7.14 (d, 2H), 7.31 (m, 4H) ). 13 C-NMR (75.4 MHz, CDCl 3): d 14.1, 15.1, 35.0-35.5 (2C), 38.0-38.7 (90, 60.7, 66.1 68.2, 80.3, 114.2, 126.2, 129.3, 129.8, 130.3, 137.8, 139.6, 157.3 172.3 Example 65. 3- (4- { 2- [4- (2,4,5-trichlorobenzenesulfonylamino) phenyl-amino-phenyl} - phenyl) - (-) -2-ethoxypropanoic acid 3-hydrochloride was mixed. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic acid (described in Example 56a) (0.2 g, 0.547 mol) and sodium bicarbonate (0.05 g, 0.6 mmol) in acetonitrile (10 ml) and stirred at room temperature for 15 minutes. The mixture was then cooled in an ice bath and 2, 4, 5-trichlorobenzenesulfonyl chloride (0.184 g, 0.657 mmol) was added.

After the addition the ice bath was removed and the reaction mixture was heated to reflux for 4 hours and then evaporated to dryness. Ethyl acetate and water were added to the residue and the phases were separated. The organic phase was dried with magnesium sulfate and the solvent was evaporated. Chromatography on silica gel (Isolute, SI) using dichloromethane and then methanol (2%) in dichloromethane as eluent gave 0.28 g (89% yield) of 3- (4-. {2- 2- (2, 4, 5-trichlorobenzenesulfonylamino) phenyl-3-ylxyphenyl-2- (S) -2-ethoxypropanoic acid. 1 H-NMR (500 MHz, CDCl 3): d 1.21 (t, J = 7 Hz, 3H), 2.98 (d, J = 14.5, 7.5 Hz, 1H), 3.03 (t, J = 6.5 Hz, 2H), 3.09 (dd, J = 14.5, 4.5 Hz, 1H), 3.44-3.50 (m, 1H), 3.61-3.67 (m, 1H), 4.08 (dd, J = 7.5, 4.5 Hz, 1H), 4.12 (t, J) = 7 Hz, 2H), 6.81 (d, J = 8 Hz, 2H), 7.10 (d, J = 5 Hz, 2H), 7.17 (d, J = 8 Hz, 2H), 7.21 (d, J = 8 Hz, 2H), 7.29 (s, 1H), 7.63 (s, 1H) and 8.10 (s, 1H). 13 C-NMR (125 MHz, CDCl 3): d 15.0, 35.0, 37.7, 66.8, 68.1, 79.7, 114.4 (2C), 122.1 (2C), 128.8, 129.9, 130.1 (2C), 130.5 (2C), 132.1, 132.8 , 133.0, 133.3, 135.9, 136.7, 138. 2, 157.5, 175.

Example 66. Ethyl ester of 3- [4-. { 2- (4-benzylsulfonylaminophenyl) ethoxy} phenyl J-2- (S) -ethoxypropanoic acid The ethyl ester hydrochloride of 3- acid was dissolved. { 4- [2- (4- aminophenyl) ethoxy phenyl} - (S) -2-ethoxypropanoic acid (described in Example 41b) (0.5 g, 1.27 mmol) in dichloromethane (10 ml) and triethylamine (0.39 ml, 2.8 mmol) was added. The mixture was cooled to 0 ° C, phenylmethanesulfonyl chloride (0.32 g, 1.68 mmol) was added. The reaction mixture was then stirred overnight and the temperature was allowed to reach room temperature. Water was added and the phases were separated. The organic phase was washed with water, dried with magnesium sulfate and evaporated. Chromatography of the residue on silica gel using ethyl acetate / heptane as eluent gave 0.245 g (38% yield) of ethyl 3- [4-. { 2- (4-benzylsulphonylaminophenyl) ethoxy} phenyl J-2- (S) -ethoxypropanoic acid.

^ - MRIDOO MHz, CDC13): d 1.15 (t, J = 7 Hz, 3H), 1.15 (t, J = 7 Hz, 3H), 2.91-2.97 (m, 2H), 3.06 (t.J = 7 Hz, 2H), 3.32-3.37 (m, 1H), 3.57-3.62 (m, 1H), 3.96 (dd, J = 8, 6 Hz, 1H), 4.13-4.17 (m, 4H), 4.29 (s) , 2H), 6.82 (d, 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 9 Hz, 2H), 7.24-7.26 (m, 4H $ and 7.30-7.32 (m, 3H). 13 C-NMR (150 MHz, CDCl 3): d 14.15, 14.99, 35.03, 35.37, 57.31, 60.74, 66.10, 68.36, 80.27, 114.25 (2C), 120.31 (2C), 128.51, 128.74 (2C), 128.80, 129.35, 130.04 (2C), 130.35 (2C), 130.78 (2C), 135.12, 135.22, 157.43, 172.50.

Example 67. Acid 3- [4-. { 2- (4-beneensulfonylaminophenyl) ethoxy} phenyl J-2- (S) -ethoxypropanoic acid The 3- [4-] ethyl ester was dissolved. { 2- (4-Benzenesulfonylaminophenyl) ethoxy} phenylJ-2- (S) -ethoxypropanoic acid (described in Example 66) (0.15 g, 0.29 mmol) in tetrahydrofuran (2 ml). Lithium hydroxide (0.0084 g, 0.35 mmol) in water (2 ml) was added. The reaction mixture was stirred at room temperature. After 6 hours, the reaction was checked by TLC (silica gel, ethyl acetate: heptane (50:50) and was not complete, more lithium hydroxide was added (approx 0.01 g), the reaction mixture was stirred overnight and the tetrahydrofuran was evaporated. The remaining solution was extracted with diethyl ether. The aqueous phase was acidified with hydrochloric acid (1%) to pH ~ 2 and extracted twice with ethyl acetate. The organic phases were combined, dried with magnesium sulfate and the solvent was evaporated. Chromatography of the residue on silica gel (Isolute, SI) using dichloromethane and then dichloromethane: methanol (98: 2) as eluent gave 0.125 g (88% yield) of 3- [4-. { 2- (4-benzylsulfonylaminophenyl) ethoxy} phenyl J-2- (S) -ethoxypropanoic acid.

XH-MR (500 MHz, CDC13): d 1.20 (t, J = 7 Hz, 3H), 2.97 (dd, J = 14, 8 Hz, 1H), 3.07 (dd, J = 14, 4.5 Hz, 1H) , 3.09 (t, J = 7 Hz, 2H), 3.41-3.47 (m, 1H), 3.60-3.66 (m, 1H), 4.05 (dd, J = 8, 4.5 Hz, 1H), 4.18 (t, J = 7 Hz, 2H), 4.33 (s, 2H), 6.86 (d, 1 = 8.5 Hz, 2H), 6.96 (s, 1H), 7.14 (d, J = 8.5 Hz, 2H), 7.27-7.30 (m , 4H) and 7.35-7.37 (m, .3H). 13 C-NMR (125 NHz, CDCl 3): d 14.97, 35.04, 37.83, 57.32, 66.65, 68.36, 79.66, 114.36 (2C), 120.31 (2C), 128.45, 128.76 (2C), 128.83 (2C), 130.07 (2C) ), 130.44 (2C), 130.81 (2C), 135.10, 135.21, 157.57, 175.73.

Example 68. Ethyl ester of 2-ethoxy-3- [4- [2- (4-isobutyrylaminophenyl) ethoxy-phenyl) acid} pro? 2-Methylpropanoic anhydride (24.15 g, 153 mmol) was slowly added to a hot solution of 4-aminophenethyl alcohol (21 g, 153 mmol) in acetone (200 mL). The reaction mixture was refluxed for 1 hour and then more 2-methylpropanoic acid anhydride (1 g) was added. the reflux was continued for 1.5 hours and then the solvent was evaporated in vacuo. Recrystallization of the solid residue from dichloromethane: heptane gave 30.7 g (97% yield) of N- [4- (2-hydroxyethyl) phenyljisobutyramide as white crystals.

XH-NMR (400 MHz; Acetone -d ^ i: d 1.20 (d, 6H, J = 6.7 Hz), 2.54-2.64 (m, 1H), 2.80 (t, 2H, J = 7 Hz), 3.40 (t , 1 OH, J = 5.6 Hz), 3.75-3.80 (m, 2H), 7.13 (dm, 2H, J = 8.5 Hz, unresolved), 7.53 (dm 2H, J = 8.5 Hz, unresolved), 8.77 ( s br, 1 NH). (b) 2-Ethoxy-3-ethyl ester. { 4- [2- (4-isobutyrylaminophenyl) ethoxy-phenyl} propanoic 2-Ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (described in Example 20b) (0.71 g, 2.97 mol) was dissolved in dichloromethane (5 ml) was added to a mixture of N- [4- ( 2-hydroxyethyl) phenyljisobutyramide (0.5 g, 2.47 mmole), azodicarbonyl dipiperidine (0.75 g, 2.95 mmole) and triphenylphosphine (0.78 g, 2.97 mmole) in dichloromethane (15 ml). After stirring at room temperature overnight the reaction mixture was filtered and the solvent evaporated in vacuo. The residue was purified by chromatography on silica gel using heptane: ethyl acetate (gradient 3: 1 to 1: 1) as eluent to give 0.69 g (65% yield) of 2-ethoxy-3-ethyl ester. { 4- [2- (4-isobutyrylaminophenyl) ethoxy-phenyl} propanoic XH NMR (500 MHz, CDC13): d 7.47 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 4.11 (t, J = 7.1 Hz, 2H), 3.96 (dd, J = 7.4 and 6.0 Hz, 1H), 3.59 (m, 1H), 3.34 (m, 1H), 3.04 (t, J = 7.1 Hz, 2H), 2.94 (m, 2H), 2.50 (d, J = 6.9 Hz, 1H), 1.25 (d, J = 6.9 Hz, 6H), 1.22 (t J = 7.1 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H).

Example 69. 2-Ethoxy-3- [4- (2-. {4-isobutyrylaminophenyl) ethoxy) phenylpropanoic acid The ethyl ester of 2-ethoxy-3- acid was hydrolysed. { 4- [2- (4-isobutyrylaminophenyl) ethoxyJphenyl} propanoic (described in example 68) using the same method as in example 2 to give 2-ethoxy-3- [4- (2. {4-isobutyrylaminophenyl) ethoxy) phenylpropanoic acid. ? ll NMR (300 MHz; CDCI3): d 7.46 (d, 8.3 Hz, 2H), 7.37 (s, NH, 1H), 7.2C (d, J = 8.3 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 4.11 (m, 2H), 4.02 (dd, .1 = 7.6 and 4.6 Hz, 1H), 3.60 (dq, J = 9.3 and 7.0 Hz, 1H) , 3.40 (dq, J = 9.3 and 7.0 Hz, 1H, 3.02 (m, 3H), 2.93 (dd, J = 14.1 and 7.7 Hz, 1H), 2.50 (, 1H), 1.23 (d, J = 6.9 Hz, 6H), 1.14 (t, J = 7.0 az, 3H). 13C NMR (75 MHz, CDC13): d 175.5, 175.3, 157.7, 136.4, 134.2, 130.5, 129.5, 128.8, 120.1, 114.4, 79.8, 68.6, 66.7, 37.9, 36.6, 35.2, 19.6, 15.0 Example 70. Ethyl ester of (S) -2-ethoxy-3- acid. { 4- [2- (4-isobutyrylaminophenyl) ethoxyJphenyl} propanoic (a) Ethyl ester of (S) -2-ethoxy-3- acid. { 4- [2- (4-isobutyrylaminophenyl) ethoxy-phenyl} propanoic Azodicarbonyl dipiperidine (0.99 g, 3.93 mmol) and triphenylphosphine (1.03 g, 3.93 mmol) were added to a solution of N- [4- (2-hydroxyethyl) phenyljisobutyramide (described in Example 68a) (0.79 g, 3.93 mmoles) and (S) -2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (described in example 40b) (0.78 g); 3.27 mmoles) in dry dichloromethane (25 ml). After stirring at room temperature overnight more N- [4- (2-hydroxyethyl) phenylj isobutyramide, azodicarbonyl dipiperidine (0.16 g, 0.65 mmol) and triphenylphosphine (0.17 g, 0.65 mmol) were added. After stirring for 24 hours the reaction mixture was filtered and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane: ethyl acetate (2: 1) as eluent gave 1.22 g (87% yield) of ethyl ester of (S) -2-ethoxy-3- acid. { 4- [2- (4-isobutyrylaminophenyl) ethoxy-phenyl} propanoic XH-NMR (400 MHz, CDC13). d 1.17 (t, 3H, J = 7 Hz), 1.20-1.26 (m, 9H), 2.55 (fivefold, 1H, 1 = 6.7 Hz), 2.95-2.98 (m, 2H), 3.03 (t, 2H, J = 7 Hz), 3.33-3.41 (m, 1H), 3.57-3.65 (m, 1H), 3.98-4.02 (m, 1H), 4.12 (t, 2H, J = 7 Hz), 4.17 (q, 2H, J = 7 Hz), 6.82 (dm, 2H, J = 8.6 Hz, unresolved), 7.15 (dm, 2H, J = 8.6 Hz, unresolved), 7.20 (dm, 2H, J = 8.6 Hz, unresolved) , 7.53 (dm, 2H, J = 8.6 Hz, unresolved). 13 C-NMR (100 MHz; CDCl 3): d 14.0, 14.9, 19.4, 35.0, 36.1, 38.2, 60.6, 65.9, 68-4, 80.1, 114.1, 120.0, 129.0, 129.1, 130.1, 133.7, 136.6, 157.3, 172.4 175.6 Example 71. Acid. { S) -2-ethoxy-3- [4- (2-. {4-isobutyrylaminophenyl) ethoxy) phenyljpropanoic acid Hydrolyzed ester of (S) -2-ethoxy-3- acid. { 4- [2- (4-isobutyrylaminophenyl) ethoxyJfenll} propane (described in example 70) using the same procedure as in example 2 to give acid (s) -2-ethoxy-3-. { 4- [2- (4-methanesulfonylphenyl) ethoxy] phenyl} propanoic 2H-NMR (500 MHz, CDC1): d 1.17 (t, 3H, J = 7 Hz), 1.70 (d, 6H, J = 7.3 Hz), 2.45-2.57 (m, 1H), 2.91-2.98 (m, 1H), 3. 01-3.10 (m, 1H), 3.39-3.48 (m, 1H), 3.56-3.65 (m, 1H), 4. 01- 4.06 (m, 1H), 4.12 (t, 2H, J = 7 Hz), 6.80 (dm, 2H, J = 8.8 Hz, unresolved), 7.14 (dm, 2H, J = 8.8 Hz, unresolved), 7.22 (dm 2H, J = 8.3 Hz, unresolved), 7.31 (bs, INH), 7.47 (dm, 2H , J = 8.3 Hz, unresolved). 13 C-NMR (125 MHz, CDCl 3): d 15.0, 19.6, 35.2, 36.6, 37.8, 66.7, 68.6, 79.8, 114.4, 120.0, 128.7, 129.4, 130.4, 134.1, 136.4, 157.7, 174.6, 175.3.

Example 72. Ethyl ester of 2-ethoxy-3- (4-. {2- [4-isobutyryl-N-methylamino) phenylJethoxy acid} phenyl) -propanoic 2-Ethoxy-3-ethyl ester was dissolved. { 4- [2- (4-methylaminophenylaminophenyl) ethoxyJphenyl} propanoic (described in example 99) (0.477 mg, 1.28 mol) in a solution of isobutyric anhydride (2 ml) and pyridine (4 ml) and the reaction mixture was stirred for 2 hours at room temperature. Toluene was added and evaporated in vacuo. Purification of the crude product by chromatography on silica gel using heptane: ethyl acetate (1: 1) as eluent gave 0.44 g (78% yield) of ethyl 2-ethoxy-3- (4- [2- ( 4- (isobutyryl-N-methylamino) phenyl-malexy} phenyl) propanoic acid. 1H NMR (400 MHz, CDC13): d 7.33 (d, J = 8.2 Hz, 2H), 7. 15 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 4.17 (m, 4H), 3.97 (dd, J = 7.1 and 6.1 Hz, 1H), 3. 60 (m, 1H), 3.35 (m, 1H), 3.23 (s, 3H), 3.11 (t, J = 7.1 Hz, .2H), 2.95 (m, 2H), 2.52 (septuplet, J = 6.7 Hz, 1H), 1. 23 (t, J = 7.1 Hz 3H, 1.16 (t, J = 6.9 Hz, 3H, 1.03 (d, J = 6.7 Hz, 6H).

Example 73. 2-Ethoxy-3- (4-. {2- 2- [4- (isobutyryl-N-methylamino) phenylamino] phenyl) -propanoic acid Lithium hydroxide hydrate (62 mg, 1.48 mmol) dissolved in water (2 ml) was added to a solution of 2-ethoxy-3- (4-. {2- [4-isobutyryl-N-methylamino) phenyl] ethoxy} phenyl) -propanoic acid (described in example 72) (435 mg, 0.98 mol) in tetrahydrofuran (6 ml). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with hydrochloric acid (2 M) to pH 4. The tetrahydrofuran was evaporated in vacuo, water (5 ml) was added and the mixture was extracted with ethyl acetate (10 ml). The organic phase was dried (sodium sulfate) and the solvent was evaporated in vacuo to give 398 mg (98% yield) of 2-ethoxy-3- (4-. {2- [4- (isobutyryl-N -methylamino) phenyl] ethoxy.} phenyl) propanoic. 1 H-NMR (300 MHz, CDC13): d 1.02 (d, 61.1, J = 6.6 Hz), 1.16 (t, 3H, J = 7 Hz), 7.49 (quintet, 1H, J = 6.6 Hz), 2.84 -3.15 (m, 4H), 3.22 (s, 3H.), 3.29-3.46 (m, 1H), 3.52-3.69 (m, 1H), 3.94-4.06 (m, 1H), 4.17 (t, 2H, J = 6.6 Hz), 6.82 (dm, 2H, J = 8.4 Hz, unresolved), 7.05-7.22 (m, 4H), 7.33 (dm, 2H, J = 8 Hz, unresolved). 13C-NNM (75 MHz, CDCl 3): d 15.1, 19.6, 31.0, 35.3, 37.6, 38.0, 66.6, 68.2, 79.8, 114.4, 127.2, 129.3, 130.4, 130.5, 138.3, 142.4, 157.5, 175.3, 178.0.

Example 74. 3- Hydrochloride was mixed. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic acid (described in example 56a) (0.2 g; 0.547 mmol) and sodium bicarbonate (0.05 g; 0.6 mmol) in tetrahydrofuran (5 ml) and stirred at room temperature for 20 minutes. 2,2-Diphenylacetyl chloride (0.151 g, 0.656 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then evaporated to dryness. Ethyl acetate and water were added to the residue and the phases were separated. The organic phase was dried with magnesium sulfate and the solvent was evaporated. Chromatography on silica gel (Isolute, SI) using dichloromethane as the eluent gave the crude product and further purification by silica gel column chromatography using dichloromethane with methanol (0.5-10%) as eluent gave 0.18 g (63% yield) of (S) -2-ethoxy-3- [4- (2- {4- (2,2-diphenylacetylamino) phenyl} ethoxy) phenyljpropanoic acid.

XH-NMR (500 MHz, DMSO-d6): d 0.99 (t, J = 7 Hz, 3H), 2.72 (dd, J = 14.3, 8 Hz, 1H), 2.86 (dd, J = 14.3, 4.5 Hz, 1H), 2.93 (t, J = 6.8 Hz, 2H, 3.19-3.25 (m, 1H), 3.48-3.54 (m, 1H), 3.83 (dd, J = 8, 4.5 Hz, 1H), 4.08 (t, J = 6.8 Hz, 2H), 5.17 (s, 1H), 6.78 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 7.21-7.25 (m, 4H), 7.30- 7.36 (m, 5H), 7.54 (d, J = 8.3 Hz, 2H) and 10.42 { S, 1H). 13C_NMR (125 MHz, DMSO-d6): d 15.23, 34.59, 37.95, 57.42, 64.65, 68.22, 80.32, 114.14 (2C), 119.43 (2C), 126. 96 (2C), 128.5K4C), 128.71 (4C), 129.34 (2C), 130.32 (2C), 130. 48, 133.62, 137.54, 140.20 (2C), 156.97, 169.89, 174. 2 (found by GHMBC).

Example 75. Acid 3-. { 4- [2-. { 4- (4- [tert-butylbenzoyl) aminophenyl} ethoxy] phenyl} -2- (S) -ethoxypropanoic acid ? e dissolved 3- acid hydrochloride. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (?) -2-ethoxypropanoic acid (described in Example 56a) (0.2 g, 0.547 mmol.) In tetrahydrofuran (5 ml.) Added sodium bicarbonate (0.053 g, 0.631 mmol) and the mixture was stirred by a 4-tert-Butylbenzoyl chloride (0.118 g, 0.6 mmol) was added.The reaction mixture was stirred overnight and then evaporated to dryness, dichloromethane and water were added to the residue and the phases were separated. The organic phase was dried with magnesium sulfate and the solvent was evaporated, chromatography of the residue over silica gel (Isolute, SI) using dichloromethane: heptane (1: 1), dichloromethane and finally methanol: dichloromethane (1:99) as eluents gave 0.238. g (89% yield) of 3- ({4- [2-. {4- (4- [tert-butyl-benzoyl) aminophenyl} ethoxyJphenyl} -2- (S) -ethoxypropanoic acid. 1H-NMR (400MHz, CD3OD): d 1.11 (t, l = 7Hz, 3H, 1.35 (s, 9H), 2.85 (dd, J = 14, 8 Hz, 1H), 2.96 (dd, J = 14, 5 Hz, 1H), 3.04 (t, J = 7 Hz, 2H), 3.30-3.37 (m, 1H, 3.54-3.61 (m, 1H), 3.98 (dd, J = 8.5 Hz, 1H), 4.15 ( t, J = 7 Hz, 2H), 6.81 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H) and 7.86 (d, j = 8.8 Hz, 2H). 13C-NMR (150 MHz, CD3OD): d 15.31, 31.56 (3C), 35.80, 36.23, 39.32, 67.12, 69.79, 81.29, 115.37 (2C), 122.4 (2C), 116.51 (2C), 128.48 (2C), 130.34 (2C), 130.76, 131.43 (2C), 133.31, 136.24, 138.15, 156.51, 159.06, 168.72, 176.04.

Example 76, Acid 3-. { 4- [2-. { 4- (4- [tert-butylbenzoyl) aminophenyl} ethoxy-phenyl} -2- (?) -ethoxypropanoic acid 3-hydrochloride was dissolved. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (?) -2-ethoxypropanoic acid (described in Example 56 a) (0.2 g, 0.547 mmol) in tetrahydrofuran (5 ml 9) Sodium bicarbonate (0.053 g, 0.631 mmol) was added and the mixture was stirred for a while, and 4-tert-butylbenzoyl chloride (0.118 g, 0.6 mmol) was added in. The reaction mixture was stirred thoroughly. overnight and then evaporated to dryness, and dichloromethane and water were added to the residue and the phases were separated.The organic phase was dried with magnesium sulfate and the solvent was evaporated.The chromatography of the residue on silica gel (Isolute, SI) using dichloromethane: heptane (1: 1), then dichloromethane and finally methanol: dichloromethane (1:99) as eluents gave 0.238 g (89% yield) of 3-. {4- [2-. {4- (4- [tert-butyl-benzoyl) aminophenyl] -ethoxy-phenyl} -2- (S) -ethoxypropanoic acid. 1 H-NMR (400 MHz, CD 3 OD): 5 1.11 (t, J = 7 Hz, 3 H), 1.35 (s, 9 H), 2.85 (dd, J = 14.8 Hz, 1 H), 2.96 (dd, J = 14 , 5 Hz, 1H), 3.04 (t, J = 7 Hz, 2H), 3.30-3.37 (H, 1H, .3.54-3.61 (m, 1H), 3.98 (dd, J = 8, 5 Hz, 1H) , 4.15 (t J = 7 Hz, 2H), 6.81 (d, J = 9.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.54 ( d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H) and 7.86 (d, J = 8.8 Hz, 2H). 13C-NMR (150 MHz, CD3OD): d 15.31, 31.56 (3C), 35.80, 36.23, 39.32, 67.12, 69.79, 81.29, 115.37 (2C), 127.4 (2C), 126.51 £ 2C), 128.48 (2C), 130.34 (2C), 0 130.76, 131.43 (2C), 133.31, 136.24, 138.15, 156.51, 159.06, 168.72, 176.04.

Example 77. Ethyl 2- (S) -ethoxy-3- (4-. {2- [4- (formylamino) phenyl-methoxy} -phenyl) -propanoic acid ethyl ester Formic acid (0.585 g, 1.27 mmol) was dissolved in dichloromethane (2 ml). Imidazole (0.0874 g) was added; 1.27 mmole) in the solution, followed by addition of triethylamine (0.353 ml, 2.54 mmole). The mixture was stirred for a time and then oxalyl chloride (0.161 g, 1.27 mmol) in dichloromethane (2 ml) was added slowly. The resulting mixture was stirred for 30 minutes. A mixture of 3-ethyl ester hydrochloride was added. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic acid (described in example 41b) (0.5 g, 1.27 mol) and triethylamine (0.176 ml, 1.27 mol) in dichloromethane (3 ml) to the reaction mixture. The reaction mixture was stirred at room temperature overnight. Water was added and the phases were separated. The organic phase was washed with water, dried with magnesium sulfate and the solvent was evaporated. Chromatography of the residue on silica gel (Isolute, SI) using heptane, then ethyl acetate / heptane (5%), followed by ethyl acetate / heptane (10%) and then ethyl acetate / heptane (25%) as eluents gave 0.230 g (47% yield) of 2- (S) -ethoxy-3- (4-. {2- [4- (formylamino) phenylJethoxy} -phenyl) propanoic acid ethyl ester. 1 H-NMR (600 MHz, CDC13, tautomers.): D 1.14 (t, J = 7 Hz, 3H), 1.21 (t, with small breaks, J = 7 Hz, 3H), 2.90-2.97 (m, 2H), 3.01-3.05 (m, 2H), 3.32-3.37 (m, 1H, 3.56-3.61 (m, 1H), 3.96 (dd, J = 7.6, 5.6 Hz, 1H), 4.09-4.09-4.17 (, 4H), 6.79 (d, d, J = 8.7, 8.7 Hz, 2H), 7.03 (d, J = 8.4 Hz, 1H), 7.12 (d, d, J = 8.7, 8.4 Hz, 1H), J = 7.22 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.84 and 8.30 (s, s, 1H), 8.41 and 8.65 (d, d, J = 11.1 Hz, 11.5 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3, tautomers: d 14.09, 14.95, 34.98 (35.09), 60.72, 66.07, 68.29 (68.44), 80.20, 114. 23 (2C), 118.93 (129.95.20, 129.12 (129.22), 129.39, 130. 12 (130.28), 2C), 130.26 (2C), 134.56 (135.10), 135.44, 157.36 (157.41), 159.27 (162.63), 172.54.

Example 78. Acid (S) -2-ethoxy-3- (4- { [4- (formylamino) phenethyl) phenyl) propanoic acid 3-hydrochloride was mixed. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic acid (described in example 56a) (0.115 g, 0.314 mol) in tetrahydrofuran (3 ml) with a mixture of formic acid (0.5 ml) and acetic anhydride (0.3 ml). The resulting mixture was stirred at room temperature overnight. Tetrahydrofuran was evaporated. Ethyl acetate and water were added to the residue. The phases separated. The organic phase was washed with brine, dried with magnesium sulfate and the solvent was evaporated. Chromatography of the residue on silica gel (Isolute, SI) using dichloromethane, then methanol / dichloromethane (1 _) followed by methanol / dichloromethane (2%) as eluents gave 0.07 g (62% yield) of (S) -2-ethoxy-3- (4) acid - { [4- (formylamino) phenethyljoxy.] Phenyl) propanoic.

Example 79. 2- Methyl ester. { 4- [2- (4-phenylsulfanylphenyl) ethoxyJ-benzyl} butanoic (a) 2- (4-Hydroxybenzyl) butanoic acid methyl ester The acid 2 - [(4-hydroxyphenyl) methylene-butanoic acid (10.48 g, 54.5 mol) was refluxed 24 hours in a solution of sulfuric acid (1%) in methanol (150 ml). the solvent was evaporated and water (100 ml) was added. The aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, dried (magnesium sulfate) and the solvent evaporated in vacuo. The crude product (9 g, 43.6 mmoles) was used directly in the next step without further purification and identification.

It was hydrogen in methanol using palladium on carbon (5%, 3 g) as a catalyst. The mixture was filtered through celite and the solvent was evaporated. Purification by chromatography on silica gel using dicyro-methanol: methanol (gradient 0.5-100% methanol) as eluent gave 6.8 g (during the two stages, 60% yield) of 2- (4-hydroxybenzyl) -butanoic acid methyl ester .

XH7NMR (400 MHz, CDC13): d 0.91 (4 3H, J = 7.7 Hz), 1.55-1.84 (m, 2H), 2.57 (m, 1H), 2.68 (dd, 1H, J = 6.2 Hz and 6.6 Hz) ,. 2.82 (dd, 1H, J = 6.2 Hz and 6.6 Hz), 3.61 (s, 3H), 5.58 (s, 10H), 6.71 (d, 2H, J = 8.4 Hz), 6.99 (d, 2H, J = 8.4 Hz). 13 C-NMR (100 MHz, CDCl 3): d 11.73, 25.09, 37.31, 49.57, 51.47, 115.22, 115.22, 129.87, 129.87, 131.26, 154.21, 176.55. (b) 2- Methyl ester. { 4- [2- (4-phenylsulfanylphenyl) ethoxyJ-benzyl} butanoic 2- (4-phenylsulfanylphenyl) ethanol (0.5 g, 2.17 mmol), azodicarbonyl dipiperidine (0.66 g, 2.6 mmol) and triphenylphosphine (0.68 g, 2.6 mmol) were dissolved in dichloromethane (20 ml) at room temperature. After stirring for 10 minutes, 2- (4-hydroxybenzyl) butanoic acid methyl ester (0.54 g, 2.6 mmol) dissolved in dichloromethane (5 ml) was added. After stirring at room temperature overnight more azodicarbonyl dipiperidine (0.33 g) and more triphenylphosphine (0.34 g) were added. The solid material was separated by filtration after two hours and the filtrate was evaporated in vacuo. Purification by chromatography on silica gel using heptane: ethyl acetate (5: 1) as eluent gave 0.638 g (70% yield) of 2-methyl ester. { 4- [2- (4-phenylsulfanylphenyl) ethoxyJbenzyl} butanoic 1 H NMR (400 MHz, CDC13): d 7.33-7.20. (, 9H), 7.05 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 8.3 Hz, 2H), 4.13 (t, J = 7.0 Hz, 2H), 3.60 (s, 3H), 3.05 (t, J = 7.0, 2H) 2.86, (dd, J = 13.7 and 8. 4 Hz, 1H), 2.68 (dd, J = 13.7 and 6.5 Hz, 1H), 2.54 (m, 1H), 1. 59 (m, 2H, 0.90 (t, J = 7.3 Hz, 3H).

Example 80. Acid 2-. { 4- [2- (4-phenylsulfanylphenyl) ethoxy J-benzyl} butanoic Sodium hydroxide (3 mL, 1M) was added slowly to a solution of 2- methyl ester. { 4- [2- (4-phenylsulfanylphenyl) ethoxybenzyl} butanoic (described in example 79) (0.59 g, 1.4 mmol) in dioxane (12 ml). the reaction mixture was stirred at room temperature for 12 hours, then at 50 ° C for 4 hours. He added lithium hydroxide (50 mg) and the mixture was stirred at 70 ° C for 24 hours. The reaction mixture was acidified with hydrochloric acid (6 M), water (20 ml) was added and the product was extracted with ethyl acetate (2 x 25 ml), washed with water (25 ml), dried (sulfate sodium) and the solvent was evaporated in vacuo to give 0.53 g (93% yield) of the desired product.

XH NMR (400 MHz, CDC13): d 7.34-7.28 (m, 7H), 7.24 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.15 (t, J = 7.0 Hz, 2H), 3.08 (t, J = 7.0 Hz, 2H), 7.93 (dd, J = 13.9 and 7.7 Hz, 1H), 2.72 (dd, J = 13.9 and 7.0 Hz, 1H), 2.58 (m, 1H), 1.63 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz; CDC13): d 181.3, 157.3, 137.7, 136.3, 133.2, 131.6, 131.3, 130.5, 129.9, 129.8, 129.1, 126.8, 114.5, 68.3, 49.0, 36.9, 35.4, 24.7, 11.6.

Example 81. Ethyl ester of 2-ethoxy-3- acid. { 4- [2- (4-methy1sulfani1feni1) ethoxyjfeni1} propanoic and reacted 2- (4-methylsulfanylphenyl) ethanol with 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (described in Example 20b) using the same method as in Example 38 (c) to give 2-ethoxy-3-ethyl ester. { 4- [2- (4-methylsulfanylphenyl) ethoxy-phenyl} propanoic XH-NMR (400 MHz, CDC13): d 1.17 (t, 3H), 1.24 (t, 3H), 2.49 (s, 3H), 2.94-2.97 (m, 2H), 3.05 (t 2H), 3.32-3.40 (m, 1H), 3.57-3.65 (, 1H), 3.95-3.99 (m, 1H), 4.11-4.21 (t + q, 4H), 6.82 (d, 2H), 7.15 (d, 2H), 7.2- 7.28 (, 4H).

Example 82. 2-Ethoxy-3- Acid. { 4- [2- (4-methylsulfanylphenyl) ethoxy-phenyl} propanoic and hydrolysed 2-ethoxy-3-ethyl ester. { 4- [2- (4-methylsulfanylphenyl) ethoxy-phenyl} propane (described in Example 81.), using the same method as in Example 2 but with dioxane instead of tetrahydrofuran to give 2-ethoxy-3-. {4- [2- (4-methylsulfanylphenyl) ethoxy-phenyl) acid} propanoic.

XH-NMR (400 MHz, CDC13): d 1.19 (t, 3H), 2.49 (5, 3H), 2. 92-2.99 (dd, 1H) 3.03-3.11 (dd + t, 3H), 3.41-3.50 (m, 1H), 3. 59-3.65 (m, 1H), 4.04-4.07 (dd, 1H), 4.14 (t, 2H), 6.83 (d, 2H), 7.16 (d, 2H), 7.20-7.28 (m, 4H). 13 C-NMR (100 MHz; CDCl 3): d 16.1, 17.3, 36.4, 38.8, 68.0, 69.6, 80.9, 115.5, 128.2, 129.7, 130.6, 131.6, 136.4, 137.3, 158.8, 175.9.

Example 83. 3- Methyl ester. { 4- [2- (4-methylsulfanylphenyl) ethoxy-phenyl} -2-phenoxypropanoic (a) 3- (4-Benzyloxyphenyl) -2-phenoxypropanoic acid methyl ester 3- (4-benzyloxyphenyl) -2-hydroxypropanoic acid methyl ester was reacted with phenol using the same method as in example 38 (c) to give 3- (4-benzyloxyphenyl) -2-phenoxypropanoic acid methyl ester. 1 H-NMR (400 MHz-CDC13): d 3.21 (, 2H), 3.70 (s, 3H, 4. 80 (dd, 1H, J = 5.4 Hz, 7.31 Hz), 5.31 (s, 2H), 6.86 (dm, 2H, J = 7.8 Hz, unresolved), 6.96 (, 3H), 7.25 (m, 4H), 7.38 (m, 5H). (b) 3- (4-Hydroxyphenyl) -2-phenoxypropanoic acid methyl ester 3- (4-Benzyloxyphenyl) -2-phenoxypropanoic acid methyl ester (0.47 g, 1.3 mmol) in ethyl acetate (20 ml) was hydrogenated using Pd / C (18 mg) as a catalyst at atmospheric pressure and room temperature. hours, Since the reaction was very slow, the catalyst was changed to palladium hydroxide, ethanol (95%, 10 ml) was added and the pressure was increased to 4 bar. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give 0.34 g (95% yield) of 3- (4-hydroxyphenyl) -2-phenoxypropanoic acid methyl ester. 1 H-NMR (400 MHz, CDC13): d 3.19 (m, 2 H), 3.72 (s, 3 H), 4.79 (dd, 1 H, J = 5.4 Hz, 7.3 Hz), 6.76 (dm, 2 H, J = 8.3 Hz, unresolved), 6.85 (dd, 2H, J = 10 Hz, 8.8 Hz), 6.97 (m, 1H), 7.16 (dm, 2H, J = 8.8 Hz, unresolved), '7.27 (m, 2H ). (c) 3- Methyl ester. { 4- [2- (4-methylsulfanylphenyl) ethoxy-phenyl} -2-phenoxypropanoic 3- (4-Hydroxyphenyl) -2-phenoxypropanoic acid methyl ester was reacted with 2- (4-methylsulfanylphenyl) ethanol using the same methods as in Example 38 (c) to give 3- methyl ester. { 4- [2- (4-methylsulfanylphenyl) ethoxy-phenyl} -2-phenoxy propane.

XH-NMR (400 MHz, CDC13): d 2.50 (s, 3H), 3.07 (t, 2H, J = 7.0 Hz), 3.22 (m, 2H), 3.74 (s, 3H), 4.16 (t, 2H, J = 7.0 Hz), 4.81 (dd, 1H, J = 5.2 Hz, 7.5 Hz), 6.87 (m , 4H), 6.99 (t, 1H, J = 7.5 Hz), 7.26 (m, 8H).

Example 84. Acid 3-. { 4- [2- (4-methylsulfanylphenyl) ethoxy-phenyl} -2-phenoxypropanoic 3-methyl ester was hydrolysed. { 4- [2- (4-methylsulfanylphenyl) ethoxy] phenyl} -2-phenoxypropanoic acid (described in example 83) using the same method as in example 2 to give 3- acid. { 4- [2- (4-methylsulfanyl-f-enyl) ethoxy-enyl} -2-f enoxipropanoic. 1H-MR (400 MHz, CDC13): d 2.50 (s, 3H), 3.07 (t, 2H, J = 7.3 Hz), 3.26 (d, 2H, J = 6.4 Hz), 4.15 (t, 2H, J = 6.8 Hz), 4.84 £ t, 1H, J = 5.4 Hz), 6.88 (m, 4H), 7.05 (dt, 1H, J = 1.0 Hz, 7.3 Hz.,., 7.27 (m, 8H). 13 C-NMR (100 MHz; CDCl 3): d 17.3, 36.3, 39.1, 69.7, 78.7, 115.7, 116.5, 123.2, 128-2, 129.3, 130.6, 130.8, 131.7, 136.4, 137.4, 158.6, 160.0, 177.9.

Example 85. Ethyl ester of (S) -2-ethoxy-3- (4- { 2- [4- (phenylsulfanyl) phenyl-amino-phenyl} -phenyl) propanoic acid 2- [4-phenylsulfanyl) phenyl] -l-ethanol (1.22 g, 5.12 mmol), triphenylphosphine (2 g, 7.6 mmol) and 1,1 '- (azodicarbonyl) dipiperidine in dichloromethane (15 ml) were dissolved. After 10 minutes a solution of (S) -2-ethoxy-3- (4-hydroxyphenyl) propanoic acid (described in Example 40b) in dichloromethane (15 ml) was added and the reaction mixture was stirred overnight the room temperature. The solid material was separated from the filtrate and the solvent was evaporated. Chromatography of the residue on silica gel using ethyl acetate: petroleum ether (40-60%), (1:99, 5:95 and 10:90) gave 1.24 g (47% yield) of ethyl ester of the acid ( S) -2-ethoxy-3- (4- { 2- [4- (phenylsulfanyl) phenyl-phenoxy} phenyl) propanoic acid.

XH-NMR (500 MHz; CDC13): d 1.21 (t, 3H), 1.28 (t, 3H), 3. 00 (, 2H, 3.11 (m, 2H), 3.40 (m, 1H), 3, .65 (m, 1H), 4. 01 (m, 1H), 4.16-4.24 (, 4H), 6.86 (d, 2H), 7.19 (d, 2H.), 7.26-7.38 (m, 9H).

Example 86. (S) -2-Ethoxy-3- (4-. {2- [4- (phenyl-sulphanyl) -phenyl-amino-phenyl} -phenyl) -propanoic acid (S) -2-Ethoxy-3- (4-. {2- 2- [4- (phenylsulfanyl) phenyl-pentaxy} phenyl) propanoic acid ethyl ester (described in Example 85) was dissolved (0.55 g, 1.22 mmoles). ) in tetrahydrofuran (5 ml) and water (5 ml). Lithium hydroxide (0.035 g, 1.46 mmol) was added and the solution was stirred at room temperature for 24 hours Hydrochloric acid in aqueous solution was added to the solution until pH = 1. The solvent was evaporated and the residue redissolved The phases were separated and the organic layer was washed once with water and dried with sodium sulfate, the solvent was evaporated, chromatography of the residue on silica gel using ether: ethanol (95: 5) as The eluent gave 0.40 g (78% yield) of (?) -2-ethoxy-3- (4-. {2- [4- (phenylsulfanyl) phenyl-pentaxy] phenyl) propanoic acid. 1H-NR, (400 MHz, CDC13): d 1.18 (t, 3H), 2.97 (m, 1H), 3. 07 (m, 3H), 3.42 (m, 1H), 3.63 d (m, 1H), 4.04 (m, 1H), 4.15 (m, 2), 6.83 (d, 2H, 7.17 (d, 2H), 7.20-7.26 (, 3H), 7.26-7.35 (m, 6H).

Example 87. Ethyl ester of 2-ethoxy-3- acid. { 4- [2- (4-methanesulfonylphenyl) ethoxyjiphenyl} propanoic 3-Chloroperoxybenzoic acid (0.73 g, 4.20 mmol) was added to a solution of 2-ethoxy-3-ethyl ester. { 4- [2- (4-methylsulfanylphenyl) ethoxyJphenyl} propane (described in example 81) (0.65 g, 1.68 mmol) in dichloromethane (20 ml) at 0 ° C. After stirring at room temperature for 3 hours, water (20 ml) was added. The mixture was extracted with ethyl acetate (20 ml), washed with saturated sodium bicarbonate solution, dried (sodium sulfate) was filtered and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane: ethyl acetate (1: 1) as eluent gave 0.399 g (56% yield) of 2-ethoxy-3-ethyl ester. { 4- [2- (4-methanesulfonylphenyl) ethoxyj phenyl} propanoic slightly contaminated by 3-chloroperoxybenzoic acid.

XH NMR (600 MHz, CDC13): d 7.89 (d, J = 8.3 Hz, 2H, 7.49 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.7 Hz, 2H), 6.80 (d, 1 = 8.7 Hz, 2H), 4.19 (4 J = 6.5 Hz, 2H), 4.17 (m, 2H), 3.96 (dd, J = 7.4 and 5.8 Hz, 1H), 3.60 (m, 1H), 3.34 (m, 1H), 3.17 (t, J = 6.5, 2H), 3.05 (s, 3H), 2.95 (m, 2H), 1.23 (t, J = 7.1, 3H), 1.16 (t, J = 7.0 Hz, 3H) .

Example 88. 2-Ethoxy-3- Acid. { 4- [2- (4-methanesulfonylphenyl). Ethoxyphonyl. Propanoic Lithium hydroxide hydrate (57 mg, 1.37 mmol) was dissolved in water (2 ml) was added to a solution of 2-ethoxy-3-ethyl ester. { 4- [2- (4-methanesulfonylphenyl) ethoxyjiphenyl} propane (described in Example 87) (3384 mg, 0.91 mmol) in tetrahydrofuran (6 ml). After stirring at room temperature for 2 hours more lithium hydroxide hydrate (30 mg) dissolved in water (1 ml) was added. The reaction mixture was stirred at room temperature for a further 4 hours. The reaction mixture was acidified with hydrochloric acid (2 M) to pH 4. The tetrahydrofuran was evaporated in vacuo, water (5 ml) was added and the product was extracted with ethyl acetate (10 ml). The organic phase was washed with water, dried (sodium sulfate) and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane: ethyl acetate: acetic acid (10: 10: 1) as eluent gave 0.307 g (86% yield) of 2-ethoxy-3- acid. { 4- [2- (4-methanesulfonylphenyl) ethoxyjiphenyl} propanoic as a pale yellow oil that crystallizes when dried in vacuum.

XH-NMR (300 MHz, CDC13): d 1.16 (t, 3H, J = 7 Hz), 2.87-3.10 (m, 5H), 3.16 (t, 2H, J = 6.4 Hz), 3.36-3.48 (m, 1H), 3.53-3.66 (m, 1H), 3.98-4.07 (m, 1H), 4.18 (t, 2H, J = 6.4 Hz), 6.75-6.85 (m, 2H), 7.10-7.20 (, 2H, 7.46). -7.55 (m, 2H), 7.86-7.96 (m, 2H). 13C-NMR (75 MHz; CDC13): d 11.4, 35.7, 37.8, 44.6, 66.7, 67.6, 79.8, 114.4, 127.5, 129.0, 129.1, 130.0, 130.6, 145.2, 157.4, 175.4.

Example 89. (S) -2-Ethoxy-3- (4-. {2- [4- (phenylsulfonyl) phenyl] ethoxy] -phenylpropanoic acid ethyl ester Ethyl (!) -2-ethoxy-3- (4-. {2- 2- [4- (phenylsulfanyl) phenylJethoxy} phenylJpropanoic acid ethyl ester (described in Example 85) (0.6 g, 1.33 mmol) was dissolved in Methylene chloride (10 ml) and 3-chloroperbenzoic acid was added The solution was stirred 2 hours at 60 ° C. It was partitioned between water and diethyl ether The organic layer was washed three times with water, dried with sodium sulfate. and the solvent was evaporated, chromatography of the residue, elution gradient with diethyl ester: petroleum ether (40-60 ° C) 33:67, 50:50 and 67:33 gave 0.31 g (38% yield) of ester Ethyl (?) -2-ethoxy-3- (4-. {2- [4- (phenylsulfonyl) phenylj-ethoxy} phenyl) propanoic acid.

Example 90, (S) -2-Ethoxy-3- (4-. {2- [4-. {Phenylsulfonyl) phenyl-malexy acid} phenyl) propanoic (?) -2-Ethoxy-3- (4-. {2- 2- [4- (phenylsulfonyl) phenyl] ethoxy} phenyl) propanoic (described in Example 89) (0.34 g, 0.70 mmol) in THF were dissolved. (5 ml) and water (5 ml). Lithium hydroxide was added to the solution (0.022 g, 0.092 mol) and the solution was stirred overnight at room temperature. He added hydrochloric acid in aqueous solution until pH = 3-4. The solvent was evaporated to a small volume. The remaining product was distributed between water and diethyl ether. The water layer was extracted once with diethyl ether. The organic phase was dried with sodium sulfate and the solvent was evaporated. Chromatography of the crude product, elution gradient1 (99: 1, 95: 5 and 90:10). The product was isolated as a viscous oil. The oil was dissolved in water and acetonitrile and frozen by liquid nitrogen. Freeze drying for 24 hours gave 0.18 g (56% yield) of (?) -2-ethoxy-3- (4-. {2- [4- (phenylsulfonyl) phenyl-pentaxy] phenyl) propanoic acid. 1 H-NMR (400 MHz; CDC13): d 1.07 (t, 3H), 2.83-2.95 (m, 1H), 7.95-3.10 (m, 3H), 3.30- 3.4 (m, 1H), 3.44-3.58 (m, 1H), 3.91-4.01 (m, 1H), 4.02-4.13 (m, 2H), 6.72 (d, 2H), 7.10 (d, 2H), 7.37 (d, 2H), 7.43-7.56 (m, 3H), 7.85 (d, 2H), 7.92 (d, 2H).

IH-NMR (500 MHz; CDC13):? 1.15 (t, 3H), 1.22 (t, 3H), 2.93 (m, 2H), 3.11 (t, 2H), 3.37, (m, 1H), 3.67 (m, 1H), 3.98 (m, 1H), 4.14-4.72 (m, 4H), 6.76 (d, 2H), 7.13 (d, 2H), 7.42 (d, 2H), 7.50 (d, 2H), 7.56-7.62 (m, 1H), 7.91 (d, 2H), 7.97 (d, 2H).

Example 91. Ethyl ester of 3- acid. { 4- [2- (4-tert-butylcarbamoyloxyphenyl) ethoxyfenyl} -2-ethoxypropanoic Tert-butyl isocyanate (0.14 g; 1. 4 mmoles} to a solution of ethyl ester of 2-ethoxy-3- acid. { 4- [2- (4-hydroxyphenyl) ethoxyJphenyl} propane (described in Example 26b) (0.5 g, 1.4 mmol) in toluene (5 ml) and then the reaction mixture was stirred overnight. The crude mixture was purified by chromatography on silica gel using ethyl acetate: heptane (gradient 1.25-80% ethyl acetate) as eluent to give 0.13 g (20% yield) of 3- ethyl ester. { 4- [2- (4-tert-butylcarbamoyloxyphenyl) ethoxyfenyl} -2-ethoxypropanoic.

XH-NMR (500 MHz, CDC13): d 1.16 (t, 3H, J = 7 Hz), 1.20 (t, 3H, J = 7 Hz), 1.38 (s, 9H), 2.92-2.99 (m, 2H) , 3.05 (t, 2H, J = 7 Hz), 3.31-3.38 (m, 1H), 3.55-3.64 (m, 1H), 3.94-3.99 (m, 1H), 4.0 (t, 2H, J = 7 Hz ), 4.16 (q, 2H, J = 7 Hz), 5.10 (bs, NH), 6.80 (dm, 2H, 5 = 8.5 Hz, unresolved), 7.05 (dm, 2H, 3 = 8.5 Hz, unresolved) , 7.14 (dm, 2H, 1 = 8.5 Hz, unresolved), 7.25 (dm, 2H, J = 8.5 Hz, unresolved). 13 C-NMR (125 MHz; CDC 13): d 14.9, 35.0, 37.8, 66.6, 67.9, 79.6, 114.2, 115.3, 191-9, 124.2, 129.0, 129-8, 130.4, 138.3, 140.9, 147.7, 150.8, 157.4 , 176.3.

Example 92, Acid 3-. { 4- [2- (4-tert-butylcarbamoyloxyphenyl) ethoxyfenyl} -2-ethoxypropanoic and hydrolyzed 3-. { 4- [2- (4-tert-Butylcarbamoyloxyphenyl) ethoxy] phenyl} -2-ethoxypropanoic acid (described in Example 91) using the same method as in Example 2 to give 3- acid. { 4- [2- (4-tert-butylcarbamoyloxyphenyl) ethoxyfenyl} -2- ethoxypropanoic.

XH-NMR (400 MHz, CDC13): d 1.17 (t, 3H, J = 7 Hz), 1.32 (s, 9H), 2.90-2.97 (m, 2H), 3.01 (t, 2H, J = 7 Hz) , 3.40-3.50 (m, 1H), 3.53-3.65 (m, 1H), 4.03 (m, 1H), 4.10 (4 2H, J = 7 Hz), 6.79 (dm, 2H, 1 = 8.5 Hz, unresolved), 6.81 (dm, 2H, J = 8.5 Hz, unresolved), 7.11-7.16 (m, 4H).

Example 93. Ethyl ester of 3- acid. { 4- [2- (4-benzylcarbamoyloxyphenyl) ethoxy-phenyl} -2-ethoxy-propanoic 2-Ethoxy-3-ethyl ester was dissolved. { 4- [2- (4-hydroxyphenyl) ethoxy} phenyl } Propanoic acid (described in example 26b) (0.36g, 1.0 mmol) in dry dichloromethane (25 ml) and benzyl isocyanate (0.20 g, 0.185 ml) was added with the addition of triethylamine (0.22 ml, 1.5 mmol). The solution was stirred at room temperature for 3 hours. The dichloromethane phase was washed with dilute acid, sodium bicarbonate and brine, dried with sodium sulfate and evaporated to give 0.4 g (81.3- {4- [2- (4-benzylcarbamoyloxyphenyl) ethyl ester. ) ethoxy-phenyl] -2-ethoxypropanoic acid The crude material was purified on reverse phase preparative HPLC using a gradient of acetonitrile-water-ammonium acetate as the mobile phase.The fractions containing the crude product were combined and the acetonitrile was removed The residue was dissolved in dichloromethane, washed with water, dried with sodium sulfate and evaporated to give 0.23 g (48% yield) of ethyl ester of 3-. {4- [2- ( Pure 4-benzylcarbamoyloxyphenyl) ethoxy-phenyl.} -2-ethoxypropanoic acid.

XH-NMR (500 MHz, CDC13): d 1.16 (t, 3H, J = 7 Hz), 1.20 (t, 3H, J = 7 Hz), 1.38 (s, 9H), 2.92-2.99 (m, 2H) , 3.05 (t, 2H, J = 7 Hz), 3.31-3.38 (m, 1H), 3.55-3.64 (m, 1H), 3.94-3.99 (t, 1H), 4.0 (t, 2H, J = 7 Hz ), 4.16 (q, 2H, J = 7 Hz), 5.10 (bs, NH), 6.80 (dm, 2H, 5 = 8.5 Hz, unresolved), 7.05 (dm, 2H, 3 = 8.5 Hz, unresolved) , 7.14 (dm, 2H, 1 = 8.5 Hz, unresolved), 7.25 (dm, 2H, J = 8.5 Hz, unresolved). 13C-NMR (125 MHz; CDC13): d 14.9, 35.0, 37.8, 66.6, 67.9, 79.6, 114.2, 115.3, 191.9, 124.2, 129.0, 129-8, 130.4, 138.3, 140.9, 147.7, 150.8, 157.4, 176.3 .

Example 94. Ethyl ester of 2-ethoxy-3- acid. { 4- [2-. { 4-phenylcarbamoyloxyphenyl} etoxijfenil} propanoic The ethyl ester of 2-ethoxy-3- acid was prepared. { 4- [2- (4-phenylcarbamoyloxyphenyl) ethoxy-phenyl} propane as described in Example 93 starting from the ethyl ester of 2-ethoxy-3- acid. { 4- [2- (4-hydroxyphenyl) ethoxy-phenyl} propanoic (0.18 g, 0.5 mmol) (described in Example 26b), phenyl isocyanate (0.18 g, 0.16 ml); 1.5 mmol) and triethylamine (0.22 ml); 1.6 mmol) in dry dichloromethane (25 ml).

After preparative reverse phase HPLC using a gradient of acetonitrile-water-ammonium acetate as the mobile phase, 0.073 g (30%) of 2-ethoxy-3-ethyl ester was obtained. { 4- [2- (4-phenylcarbamoyloxyphenyl) ethoxy phenyl} pure propanoic.

^ -NMR (500 MHz, CDC13): d 1.19 (t, 3H); 1.25 (t, 3H); 2. 98 (d, 2H); 3.10 (t, 2H); 3.34-3.43 (, 1H); 3.58-3.68 (m, 1H); 4.00 (t, IH); 4.16 (t, 2H); 4.19 (q, 2H; 6.84 (d, 2H); 7.11 (t, 1H); 7.16 (d, 2H); 7.17 (d, 2H); 7.32 (d, 2H); 7.35 (t, 2H); 7.46 (d, 2H); 7.08 (bs, 1H) 13, -NMR (100.6 MHz, CDCI,): 8 14.2,15-0, 35.1, 38.4, 60.8, 66.2, 68.5, 80.4,114.3, 118.7,121.6,123.8,129.1, 129. 3,129.9,130.4,135.8,137.38,149.1, 151.7,157.5, 172.5 ~ EXAMPLE 95. 3- [4- (2- [4- (. {Benzylamino} carbonylamino) phenylamino) phenyl] - (S) -2-ethoxypropanoic acid 3-Hydrochloride was mixed. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic (described in Example 56a) (0.2 g, 0.547 'immoles) and sodium bicarbonate (0.053 g, 0.631 mmol) in tetrahydrofuran (5 ml) and stirred at room temperature for 20 minutes . He added benzyl isocyanate (0.087 g, 0.653 mmol). The reaction mixture was stirred at room temperature for 5 hours and then evaporated to dryness.

Dichloromethane and water were added to the residue and the phases were separated. The organic phase was dried with magnesium sulfate and the solvent was evaporated, chromatography on silica gel (Isolute,? L) using dichloromethane and then methanol (1%) in dichloromethane as eluent gave 0.19 g (75% yield) of 3- [4- (2- [4- ( { benzylamino.}. carbonylamino) phenyl] - (-) -2-ethoxypropanoic acid.

XH-NMR (500 MHz, CDC13): d 1.19 (t, J = 7 Hz, 3H), 2.97 (dd, J = 14.5, 7.5 Hz, 1H), 3.02 (t, J = 7 Hz, 2H), 3.07 (dd, J = 14.5, 4.5 Hz, 1H), 3.44-3.50 (m, 1H), 3.59-3.65 (m.1H), 4.06 (dd, J = 7.5, 4.5 Hz, 1H), 4.10 (t, J) = 7Hz, 2H), 4.43 (d, J = 4.5Hz, 2H), 5.30 (br, 1H), 6.78 (d, J = 8.5 Hz, 9H), 7.02 (br, 1H), 7.14 (d, J = 8.5 Hz, 2H), 7.1 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 7.26-7.35 (m, 5H). 13C_NMR (125 MHz, CDC13): d 15.01, 35.10, 37.91, 44.09, 66.49, 68.44, 79.81, 114.34 (2C), 121.99 (2C), 127.28, 127.33 (2C), 128.58 (2C), 128.85, 129.79 (2C) ). 130.42 (20, 134.31, 136.41, 138.77, 156.94, 157.53, 175.37.

Example 96. (S) -2-Ethoxy-3- [4- (2- { 4 - [( { 4- [(trifluoromethyl) sulfanyl] anilino] carbonyl) -aminoj phenyl} acid. ethoxy) phenyl] propanoic ? e dissolved 3- acid hydrochloride. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic acid (described in Example 56a) (0.2 g, 0.547 mmol) in tetrahydrofuran (5 ml). Sodium bicarbonate (0.051 g, 0.607 mmole) was added and the mixture stirred briefly. The addition of 4- (trifluoromethylthio) phenyl isocyanate (0.126 g, 0.575 mmol) was added, the reaction mixture was stirred at room temperature for 6 hours and then evaporated to dryness, ethyl acetate and water were added to the residue. The phases were separated, the organic phase was dried with magnesium sulfate and the solvent evaporated, chromatography of the residue over silica gel (Isolute, SI) using dichloromethane, methanol: dichloromethane (1:99) and then methanol: dichloromethane. (2:98) as eluents gave 0.17 g ('57% yield) of the acid (S) -2-ethoxy-3- [4- (2- { 4 - [(. {4- [(trifluoromethyl)] sulfanyl] anilino.} carbonyl) -aminoJphenyl.} ethoxy) phenyl] propanoic acid.

^ -NMR (400 MHz, CD30D): d 1.09 (t, 1 = 7 Hz, 3H), 2.84 (dd, J = 14.8 Hz, 1H), 2.93- 2.98 (m, .2H), 3.28-3.36 (m , 1H), 3.53-3.60 (, 1H), 3.97 (dd, 8, 5 Hz, 1H), 4.08 (t, J = 7.5 Hz, 2H), 6.77 (d, J = 8.5 Hz, 2H), 7.12 ( d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H, 7.35 (d, J = 8.5 Hz, 2H), 7.54 (s, 4H). 13C _NMR (125 MHz, CD30D): d 15.31, 56.11, 39.30, 67.12, 69.82, 81.28, 115.34 () C), 117.06, 120.40 (2C), 120.76 (20, 130.47 (2C), 130.70, 131.17 (q, J = 305 Hz), 131. 4K2C), 134.77, 138.35, 138.55 (2C), 143.93, 154.82, 159.04, 176.12.

E p 97. Acid 3-. { 4- [2- (4 - [(tert-butylamino) carbonyljaminophenyl) ethoxy} phenyl } -2- (?) -ethoxypropanoic acid They mixed 3-hydrochloride. { 4- [2- (4-aminophenyl) ethoxy-phenyl} - (?) -2-ethoxypropanoic acid (described in example 56a) (0.2 g, 0.547 mol) and sodium bicarbonate (0.053 g; 0.631 mmol) in tetrahydrofuran (5 ml) and stirred at room temperature for 20 minutes. He added 4-tert-butyl isocyanate (0.059 g, 0.595 mmol).

The reaction mixture was stirred at room temperature overnight and then evaporated to dryness.

Dichloromethane and water were added to the residue and the phases were separated. The organic phase was dried with magnesium sulfate and the solvent was evaporated.

Chromatography on silica gel (Isolute, SI) using heptane / dichloromethane (50%), then dichloromethane followed by methanol / dichloromethane (1%) as eluents gave 0.15 g (64-% yield) of 3- [. { 4- [2- (4 - [(tert-butylamino) carbonyljaminophenyl) ethoxy] phenyl} -2- (S) -ethoxypropanoic acid.

^ -NMR (600 MHz, CD30D): d 1.10 (t, J = 7 Hz, 3H), 1. 34 (s, 9H), 2.84 (dd, J = 14.8 Hz, 1H), 2.92-2.96 (m, 3H), 3.29-3.34 (m, 1H), 3.54-3.59 (m, 1H), 3.96 ( dd, J = 8, 4.5 Hz, 1H), 4.06 (t, J = 7 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 7.14 ( d, J = 8.4 Hz, 2H) and 7.22 (d, 1 = 8.4 Hz, 2H). 13C-NMR (150 MHz, CDC13): d 15.31, 29.66 (3C), 36.08, 39.31, 51.04, 67.11, 69.94, 81.29, 115.35 (2C), 120.18 (2C), 130.69, 131.40 (20, 133.56, 139.35, 157.46, 159.06 and 176.07 Examples 98 and 99. Ethyl ester of 2-ethoxy-3- { 4- [2- (4-methylaminophenyl) ethoxy-phenylpropanoic acid and ethyl ester of 3-. {4- [2- ( 4-dimethylaminophenyl) ethoxy-phenyl.} -2-ethoxypropanoic acid Formaldehyde (0.273 ml, 3.36 immoles, 37% by weight solution in water and Pd / C (100 mg, 10%) was added to a solution of ethyl ester of 3-. {4- [2- (4- aminophenyl) ethoxyJphenyl.} -2-ethoxypropanoic acid (described in example 62a) (0.96 g, 2.69 mmoles) in ethyl acetate (15 ml) and then hydrogen at atmospheric pressure and at room temperature for 4 hours. through celite and purification by chromatography on silica gel using heptane: ethyl acetate (gradient 4: 1 to 1: 1) as eluent gave 0.49 g (49% yield) 2-ethoxy-3-ethyl ester. 4- [2- (4-methylaminophenyl) ethoxy-phenyl) -propanoic acid and 0.24 g (23% yield) of ethyl 3- ({4- [2- (4-dimethylamphenyl) ethoxy-phenyl) ethyl ester}. -2-ethoxypropanoic.

Ethyl ester of 2-ethoxy-3- acid. { 4- [2- (4-methylaminophenyl) ethoxy-phenyl} propane XH NMR (400 MHz, CDC13): d 7.13 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H). 6.58 (d, J = 8.5 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 4.08 (t, J = 7.4 Hz, 2H), 3.96 (dd, J = 7.3 and 5.9 Hz, 1H), 3.59 (dq, J = 9.2 and 7.0, 1H), 3.34 (dq, J = 9.2 and 7.0 Hz, 1H), 2.98 (t, J = 7.4 Hz, 2H), 2.94 (m, 2H). 13C NMR (100 MHz; CDC13): d 172.6, 157.7, 147.9, 130.3, 129. 7, 129-1, 126.8, 114.3, 1 17.6, SO.S, 69.9, 66.2, 60.7, 38.5, 34.9, 30.9, 15.1, 14.2.

Ethyl ester of 3- acid. { 4- [2- (4-dimethylaminophenyl) ethoxyJphenyl} -2-ethoxypropanoic XH NMR (500 MHz, CD3OD: d 7.12 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.6 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 4.07 (t, J = 7.0 Hz, 2H), 4. 01 (dd, J = 7.5 and 5.7 Hz, 1H), 3.55 (m, 1H), 3.36 (, 1H), 2.93 (t, J = 7.0 Hz, 2H), 2.91 (m, 2H), 2.8 7 (s) , 6H), 1.17 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.0 Hz, 3H).

Example 100. 3- (4- [2- (4-Dimethylaminophenyl) ethoxy-phenyl) -2-ethoxypropanoic acid Lithium hydroxide hydrate (38 mg, 0.90 mmol) dissolved in water (2 ml) was added to a solution of 3- ethyl ester. { 4- [2- (4-dimethylaminophenyl) ethoxyJphenyl} -2-ethoxypropanoic acid (described in Example 99) (232 mg, 0.60 mmol) in tetrahydrofuran (6 ml). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with hydrochloric acid (2 M) to pH 5. The tetrahydrofuran was evaporated in vacuo, water (5 ml) was added and the mixture was extracted with ethyl acetate (10 + 5 ml), dried (sodium sulfate) and the solvent was evaporated in vacuo. Purification by filtration on silica gel gave 180 mg (84 yield) of 3- acid. { 4- [2- (4-dimethylaminophenyl) ethoxy-phenyl} -2-ethoxypropanoic.

XH NMR (600 MHz, CDC13): d 7.15 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 6.81 (d, J = 8.3 Hz, 2H), 6.74 (d, J = 8.3 Hz, 2H), 4.12 (t, J = 7.3 Hz, 2H), 4.03 (m, 1H), 3.59 (m, 1H), 3.42 (, 1H), 3.06 (dd, J = 14.1 and 3.8, 1H-, 2.99 (t, J = 7.3 Hz, 2H), 2.93 (m, 1H), 2.92 (s, 6H), 1.16 (t, J = 7.0 Hz, 3H). 13C NMR (150 MHz; CDCI3): d 174.9, 157.8, 149.4, 130.4, 129.6, 128.6, 126.6, 114.4, 11.3.3, 79.9, 69.1, 66.8, 41.0, 37.8, 34.8, 15.0.

Example 101. (S) -2-Ethoxy-3- (4- { 2- [4- { 3- [(4-methylphenyl) sulfonyl] -3-phenyl (R /?) -propyl} amino) phenylj ethoxy} phenylpropanoic 3-phenyl-3- (4-methylphenyl) propionaldehyde was dissolved (0.166 g, 0.57 mmol.) In tetrahydrofuran (3 mL) and sulfuric acid (4 M, 0.041 mL, 0.164 mmol) was added with stirring followed by the addition of 3-. {4- [2- (4-aminophenyl) ethoxy-phenyl.} - (S) -2-ethoxypropanoic (described in Example 56a) (0.2 g, 0.547 mmol) dissolved in tetrahydrofuran (2 ml). The reaction mixture was stirred for 10 minutes, then cooled to 0 ° C in an ice bath and sodium borohydride (0.042 g, 1.10 mmol) was added. After the addition, the cooling bath was removed. The mixture was stirred overnight and then evaporated to remove tetrahydrofuran. Ethyl acetate and water were added to the residue and the organic phase was separated, washed with brine, dried with magnesium sulfate. The solvent was then evaporated. Chromatography on silica gel (Isolute, SI) using dichloromethane and then methanol (1 %} in dichloromethane as eluent gave 0.13 g (40%) yield) of (?) -2-ethoxy-3- (4-. {2- [4- (. {3- (. {3- 3- [ (4-ethylphenyl) sulfonyl-J-3-phenyl- (R / S) -propyl.}. Amino) phenyl] ethoxy, phenyl) propanoic XH-NMR (500 MHz, CDC13): d 1.18 (t, J = 7 Hz, 3H), 2.39 (s, 3H), 2.39-2.46 (m, 1H), 2.71-2.78 (m, 1H), 2.92- 3.00 (m, 3H.}., 3.05-3.11 (m, 2H), 3.15-3.22 (, 1H), 3.43-3.50 (m, lH), 3.56-3.63 (m, lH), 4-04- .10 (m, 3H), 4.24 (dd, J = 10.6, 3.9Hz, 1H), 6.45 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.5Hz, 2H), 7.11-7.20 (m, 4H), 7.25-7.34 (m, 5H), 7.39 (d, J = 8.5Hz-, 2H). 13C-NMR (125 MHz), CDC13): d 15.03, 21.58, 7.99, 34.89, 37.68, 41.48, 66.77, 69.04, 69.15, 79.79, 113.12 (2C), 114.41 (2C), 127.25, 128.57 (2C), 128.88 (2C), 129.99 (2C), 129.24 (2C), 129.79 (2C), 129.83 (2C), 130.44 (2C), 132.31, 134.18, 144.46, 147.27, 157.82, 174.05.

Example 102. (S) -2-Ethoxy-3- (4-. {2- 2- [4- (3,3,3-trifluoro-2-methyl- (R / c) -propylamino) phenylj ethoxy acid} phenyl) propanoic.

It was dissolved 2- (trifluoromethyl) propionaldehyde (0.0724 g, 0.574 mmol) in tetrahydrofuran (3 ml) and sulfuric acid (4 M, 0.041 ml, 0.164 mol) was added with stirring followed by addition of acid hydrochloride. 3- {4- [2- (4-aminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic acid (described in Example 56a) (0.2 g, 0.547 mmol) dissolved in tetrahydrofuran (2 ml). The reaction mixture was stirred for 10 minutes, then cooled to 0 ° C in an ice bath and sodium borohydride (0.042 g, 1.10 mmol) was added.After addition, the cooling bath was removed.The mixture was stirred overnight and then evaporated to remove tetrahydrofuran.

Ethyl acetate and water were added to the residue and the organic phase was separated, washed with brine, dried with magnesium sulfate. Then the solvent was evaporated. Chromatography on silica gel (Isolute,? L) using dichloromethane and then 1% methanol in dichloromethane as eluent gave 0.13 g (40% yield) of (?) -2-ethoxy-3- (4-. 2- [4- (3, 3, 3-trifluoride-2-methyl- (R / S) -propylamino.}. Phenyl-amino-phenyl) -propanoic acid.

^ -NmR (500. MHz, CDC13): d 1.20 (t J = 7 Hz, 3H), 1.22 (d, J = 7 Hz, 3H), 2.51-2.61 (m, 1H), 2.98 (dd, J = 14.5, 8 HZ, 1H), 3.01 (t, J = 7 Hz, 2H), 3.08 (dd, J = 14.5, 4 Hz, 1H, 3.16 (dd, J = 14, 7 Hz, 1H), 3.41- 3.47 (m, 1H), 3.52 (dd, J = 14, 5.5 Hz, 1H), 3.61-3.67 (m, 1H), 4.06 (dd, J = 8, 4 Hz, 1H), 4.12 (t, J = 7 Hz, 2H), 6.61 (d, J = 8 Hz, 2H), 6.85 (d, J = 8 Hz, 2H), 7.14 (d, J = 8 Hz, 2H), 7.18 (d, J = 8 Hz , 2H). 13 C-NMR (125 MHz, CDCl 3): d 11.43, 14.98, 34.84, 37. 43 (q, J = 25 Hz), 37.89, 43.88, 66.70, 68.99, 79.80, 113. 11 (2C), 114.37 (2C), 127.63, 127.85 (q, J = 279Hz), 128.65, 129.93 (2C), 130.39 (2C), 145.62, 157.74, 176.24.

Example 103 .. Ethyl ester of 3- acid. { 4- [2- (4-cyanophenyl) ethoxy-phenyl} -2-ethoxypropanoic The ethyl ester of acid 3- was synthesized. { 4- [2- (4-cyanophenyl) ethoxyJphenyl} -2-ethoxypropanoic using the same method as in example 38 (c) which used 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (written in Example 20b) (6.62 g, 27.78 mmol) and p-cyanophenethyl alcohol (2.73 g, 18.52 mmol). The reaction mixture was stopped after two hours. Purification by chromatography on silica gel using first dichloromethane and then petroleum ether: diethyl ether as eluents gave a mixture of product and starting material which was dissolved in ethyl acetate and washed with sodium hydroxide (IN). The organic phase was washed with water, dried (sodium sulfate), filtered and the solvent was evaporated to give 4.23 g (62% yield) of 3-ethyl ester. { 4- [2- (4-cyano-phenyl-9-ethoxy] -phenyl] -2-ethoxypropanoic acid.

^ -NMR (400 MHz, CDC13): d 1.16 (t, 3H, J = 7Hz), 1.23 (t, 3H, J = 7Hz), 2.93-2.97 (m, 2H), 3.14 (t, 2H, J = 6.4 Hz), 3.3-3.4 (m, 1H), 3.56-3.65 (m, 3H), 3.94-3.99 (m, 1H), 4.14-4.26 (m, 4H), 6.8 (dm, 2Hm J = 8.6Hz, unresolved), 7.15 8dm, 2H, 'J = 8.6 Hz, unresolved), 7.4 (dm, 2H, J = 8.3 Hz, unresolved), 7.60 (dm, 2H, J = 8.3 Hz, unresolved). 13 C-NMR (100 MHz; CDC 13): d 14.1, 15.0, 35.8, 38.4, 60.7, 66.1, 67.5, 80.2, 119.3, 114.2, 118.8, 129.66, 299.74, 130.4, 132.1, 144.2, 157.2, 172.4.

Example 104. Ethyl ester of 3- acid. { 4- [2- (4-cyanophenyl) ethoxy-phenyl} -2-phenylsulfanylpropionic The ethyl ester of 3- (4-hydroxyphenyl) -2-phenylsulfanylpropanoic acid was reacted with p-cyanophenethyl alcohol using the same method as in Example 38 (c) to give 3- ethyl ester. { 4- [2- (4-cyanophenyl) ethoxyJ} -2-phenylsulfanylpropionic. 1H-N__R (800 MHz); CDCl 3): d 1.08 (t, 3H), 2.99 (dd, 1H), 3.1-3.2 (m, 3H), 3.84 (dd, 1H), 3.97-4.07 (m, 3H), 4.16 (t, 2H), 6.77 (dm, 2H, .7 = 8.7 Hz, unresolved), 7.10 (dm, 2H, J = 8.4 Hz, unresolved), 7.26-7.31 (m, 3H), 7.39 (dm, 2H, J = 8.0 Hz , unresolved), 7.41-7.45 (m, 2H), 7.60 (dm, 2H, J = 8.4 Hz, unresolved) Example 105. 3- [4- [2- (4-Cyanophenyl) ethoxy-phenyl) acid} -2-phenylsulfanylpropanoic The ethyl ester of 3- acid was hydrolysed. { 4- [2- (4-cyanophenyl) ethoxyJphenyl} -2-phenylsulfanylpropionic acid (described in Example 104.), using the same method as in Example 2 to give 3- ({4- [2- (4-cyanophenyl) ethoxy-phenyl) -2-phenylsulfanylpropanoic acid. 1H-NMR (500 MHz, CDC13): d 2.96-3.2 (m, 1H), 3.07-3.14 (m, 3H), 3.77-3.83 (m, 1H), 4.14 (t, 2H, J = 6.5Hz), 6.78 (d, 2H, J = 8.8 Hz, unresolved), 7.10 (dm, 2H, J = 8.8 Hz, unresolved), 7.23-7.28 (m, 3H), 5.35 (dm, 2H, J = 8.3 Hz, unresolved), 7.38-7.43 (, 2H), 7.56 (dm, 2H, J = 8.3 Hz, unresolved) 13 C-NMR (125 MHz; CDCl 3): d 35.7, 36.7, 52.1, 67.5, 110.3, 114.5, 118.8, 128.2, 129.0, 129.70, 129.73, 130.1, 132.1, 132.7, 133.0, 144.1, 157.4, 177.3.

Example 106. 2-Ethoxy-3- [4- (2- (4-isopropylaminocarbonyl) phenyl] -ethoxy) phenyljpropanoic acid ethyl ester (a) 4- [2- (4-formyl phenoxy) ethyl-benzonitrile It dissolved p-hydroxybenzaldehyde (24.9 g, 203.8 mmoles) in dichloromethane (dry). ADDP (47.2 g, 187 mmol) was added followed by the addition of triphenylphosphine (49 g; 187 mmoles) The reaction mixture was stirred at room temperature for 45 minutes and then p-cyanophenethyl alcohol (25 g, 110 mol) dissolved in a small amount of dichloromethane (dry) was added in portions over one hour. The reaction mixture was stirred at room temperature overnight, filtered and evaporated. Chromatography of the residue on silica gel using ethyl acetaate: heptane as eluent gave 9.7 g (22.7% yield) of 4- [2- (4-formylphenoxy) ethyl-benzonitrile.

^ -NMR (400 MHz; CDC13): d 3.21 (t, 2H), 4.30 (t 2H), 6.99 (d, 2H), 7.42 (d, 2H), 7.63 (d, 2H), 7.84 (d, 2H) ), 9.89 (s, 1H). 13C-NMR (100 MHz; CDC13): d 36.2, 69.4, 110.8, 116.5, 120.4, 131.3, 131.6, 133.33, 13 3.73, 145.8, 164.8, 192.8. (b) 4- [2- (4-formylphenoxy) ethylbenzoic acid Reflux 4- [2- (4-formylphenoxy) ethyl-benzonitrile (9.7 g, 38.6 mmol) in sulfuric acid (150 mL) for 1 hour.The evaporation gave 10 g (100% yield) of 4- [2 - (4-formylphenoxy) ethylbenzoic acid. 1 H-NMR (500 MHz, DMSO-d 6): d 3.13 (t, 2 H), 4.33 (t, 2 H), 7.12 (d, 2 H), 7.46 (d, 2 H), 7.85 (d, 2 H), 7.89 (d, 2 H). d, 2H), 9.86 (s, 1H). (c) 4- [2- (4-formylphenoxy) ethyl J-N-isopropyl benzamide 4- [2- (4-Formylphenoxy) ethyl-benzoic acid (8.11 g, 30 mmol), TBTU (10.6 g, 33 mmol) and DMAP (8.1 g, 66 mmol) were dissolved in DMF (85 mL). The reaction mixture was cooled in an ice bath and isopropylamine (12 g, 200 m-noles) dissolved in DMF (100 ml) was added. The reaction mixture was stirred at room temperature overnight. A large amount of water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with potassium bisulfate (0.3 M), water and brine and dried with sodium sulfate. Evaporation gave 8 g (85.6% yield) of 4- [2- (4-formylphenoxy) ethyl] -N-isopropylbenzamide.

XH-NMR (600 MHz; DMSO-d6): d 1.13 (d, 6H), 3.06 (t, 2H), 3.45 (m, 1H), 4.22 (t, 2H), 6.94 (d, 2H), 7.36 (d, 2H), 7.61 (d, 2H), 7.77 (d, 2H), 8.11 (d, 1H) ), 8.22 (s, 1 H). (d) 2-Ethoxy-3- [4- (2- ({4- (isopropylaminocarbonyl) phenyl} ethoxy) phenyl] acrylic acid ethyl ester 4- [2- (4-formylphenoxy) ethyl] -N-isopropylbenzamide (2 g, 6.42 mmol) and (1,2-diethoxy-2-oxoethyl) (triphenyl) phosphonium chloride (3 g, 7 mmol) in chloroform. The reaction mixture was cooled in an ice bath. Tetramethylguanidine (1 g, 8.7 mmol) was added in portions. The reaction mixture was stirred over the weekend then the solvent was evaporated. The residue was dissolved in ethyl acetate and the triphenylphosphine oxide which precipitated was separated by filtration. The filtrate was evaporated. The crystals were obtained by freezing the residue in an ethanol / water solution. The crystals were separated from the filtrate and washed with a very cold mixture of ethanol / water and 1.2 g (44.1% yield) of 2-ethoxy-3- [4- (2-. {4 - (isopropylaminocarbonyl) phenyl} ethoxy] acrylic. 1 H-NMR (400 MHz, CDC13); d 1.27 (d, 6H), 1.37 (t 6H), 3. 15 (t, 2H), 3.93 (q, 2H), 4.22 (t, 2H), 4.29 (m, 3H), . 93 (bs, 1H), 6.88 (d, 2H), 6.96 (s, 1H), 7.35 (d, 2H), 7.69-7.76 (m, 4H). 13C-NMR (100.6 MHz CDC13): d 15.4, 16.6, 24.0, 36.6, 42.9, 62.1, 68.6, 69.2, 115.6, 125.0, 127.7, 128.1, 130.2, 132.8, 134.4, 142.9, 144.2, 160.2, 166.0, 167.5. (e) Ethyl ester of 2-ethoxy-3- acid. { 4- (isopropyl-enecarbonyl) phenyl} ethoxy) phenyl] propanoic Hydrogenated 2-ethoxy-3- [4- (2- {4- (isopropylaminocarbonyl) phenyl} ethoxy) phenyl] acrylic acid ethyl ester using the same method as in Example 1 (d) for to give 2-ethoxy-3- [4- (2- {4- ({isopropylaminocarbonyl)) phenyl ethyl ester} ethoxy) phenyl] propanoic.

XH-NMR (400 MHz, CDC13): d 1.17 (t, 3H), 1.21-1.28 (m, 9H), 2.95 (d, 2H), 3.17 (t, 2H), 3.31-3.39 (m, 1H), 3.56-3.64 (m, 1H), 3.96 (t, 1H), 4.13-4.20 (m, 4H), 4.26-4.32 (m, 1H), 5.95 '(bs, 1H), 6.8 (d, 2H), 7.14 (d, 2H), 7.33 (d, 2H), 7.71 (d, 2H). 13 C-NMR (100 MHz, CDCl 3): d 15.3, 16.1, 24.0, 36.7, 39.6, 42.9, 61.8, 67.3, 69.9, 81.5, 115.4, 128.1. 130.2, 130.6, 131.5, 134.3, 143.1, 158.5, 167.6, 173.6.

Example 107. 2-Ethoxy-3- [4- (2-. {4-isopropylaminocarbonyl) phenyl] acid} -ethoxy) phenyl] propanoic The ethyl ester of 2-ethoxy-3- [4- (2- {4- (isopropylaminocarbonyl) phenyl} ethoxy) phenyl] propanoic acid (described in Example 106.) was dissolved (1 g; 2.34 mmoles) in tetrahydrofuran (10 ml) Lithium hydroxide (0.56 g, 2.34 mol) dissolved in water (6 ml) was slowly added portionwise over 20 minutes, slowly in portions, for 20 minutes. the ambient temperature for 3 hours and then diluted with water, followed by careful evaporation of the tetrahydrofuran.The residual aqueous phase was extracted once with diethyl ether, then acidified and extracted with ethyl acetate. washed with brine, dried with sodium sulfate and evaporated.

The residue was dissolved in methanol (10 ml) and sodium hydroxide (1.09 g, 1.73 mmol) in water (3.5 ml) was added. The solution was evaporated and the residue redissolved in water. Lyophilization gave 0.643 g (65.2% yield) of. { 2-Ethoxy-3- [4- (2- {4- (isopropylaminocarbonyl) phenyl} ethoxy-phenyl] -propanoic acid.

XH-NMR (400 MHz; D20): d 1.04 (t, 3H), 1.2 (d, 6H), 2. 73-2.81 (m, 1H), 2.88-2.97 (m, 3H), 3.22-3.31 (m, 1H), 3. 45-3.55 (m, 1H), 3.86-3.92 (m, 1H), 4.09 (m, 3H), 6.77 (d, 2H), 7.6 (d, 2H), 7.24 (d, 2H), 7.58 (d, 2H). 13 C-NMR (100 MHz; D 20): d 15.3, 22.6, 33.8, 39.3, 43.4, 66.7, 69.6, 83.6, 115.9, 128.3, 130.2, 131.4, 132.3, 133.2, 143.9, 170.5, 181.4.

Example 108. (S) -2-Ethoxy-3- (4-. {2- 2- [4- ( { [2- (Methylsulfanyl) anilino] carbothiol.}. Amino) -phenyl] ethoxy acid}. phenyl) propanoic ? e dissolved the acid hydrochloride 3-. { 4- [2- (4-aminophenyl) ethoxy] phenyl} - (?) -2-ethoxypropanoic acid (described in Example 56a) (0.2 g, 0.547 mmol) in tetrahydrofuran (5 ml). Sodium bicarbonate (0.53 g, 0.631 mmol) was added and the mixture stirred briefly. Then 2- (methylthio) phenyl isocyanate (108 g, 0.596 mol) was added. The reaction mixture was stirred overnight and then evaporated to dryness. Chromatography of the residue on silica gel using dichloromethane and then methanol in dichloromethane (2%, 4%, 10% and 20%) as eluent gave 0.21 g (75% yield) of 2- ()) -2-ethoxy-3- (4- (2- [4- ( { [2- (methylsulfanyl) anilino] carbothiol}. Amino) -phenyl] ethoxy.} phenyl) propanoic.

XH-NMR (600 MHz, DMSO-d6): d 0.96 (t, J = 7 Hz, 3H), 2.35 (s, 3H), 2.70 (dd, J = 14.8 Hz, 1H), - 2.81 (dd, J = 14.5 Hz, 1H), 2.93 (t, J = 6.6 Hz, 2H), 3.18-3.23 (m, 1H), 3.42- 3.47 (m, 1H), 3.82 (dd, J = 3.5 Hz, 1H), 4.08 (t, J = 6.6 Hz, 2H), 6.76 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 7.12 (dd, J = 7.7, 7.4 Hz, 1H) 7.19- 7.26 (m, 4H), 7.31 (d, J = 7.7 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 9.21 (s, 1H) and 9.84 (s, 1H). 13C_NMR (150 MHz, DM? O-d6): d 15.29, 15.49, 34.88, 38.11, 65.22, 63.46, 80.25, 114.52 (2C), 124.37 (2C), 125.42, 126.67, 127.57, 129.14, 129.46 (2C), 130.28, 130.70 (2C), 135.44, 136.47, 136.89, 137.90, 157.34, 174.45, 180.86.

Example 109. 2-isopropoxy-3- [4- (. {4- ({(methylsulfonyl) oxy] phenethyl} -oxi) phenyl] propanoic acid (a) benzyl 2-isopropoxyacetate The benzyl 2-isopropoxyacetate was synthesized using the same method as in Example 58a from isopropoxyacetic acid.

XH-NMR (500 MHz, CDC13): d 1.23 (d, J = 6 Hz, 6H), 3.68-3.75 (, 1H), 4.15 (s, 2H), 5.23 (s, 2H), 7.36-7.41 (m , 5H). (b) benzyl 3- [4- (benzyloxy) phenyl] -2-isopropoxy-2-propenoate Benzyl 3- [4- (benzyloxy) phenyl] -2-isopropoxy-2-propenoate was synthesized from 2- isopropoxyacetate benzyl using the same method as in Example 58b. 1H-NMR of mixture of E and Z isomers (400 MHz, CDC13): d 1.31 (d, J = 6Hz, 6H, 6H of one isomer), 1.32 (d, J = 6Hz, 6H of an isomer), 4.45- 4.53 (m, 1H), 5.10 (s, 2H), 5.31 (s, 2H of an isomer), 5.32 (s, 2H of an isomer), 6.98-7.01 (m, 2H), 7.07 (s, 1 H of a isomer), 7.08 (s, IH of an isomer), 7.35-7.47 (m, 10H), 7.81-7.85 (m, 2H). 13C-NMR (100 MHz; CDC13): d 22.41 (2C), 66.60, 69.85, 74.31, 114.53 (2C), 124.64, 126.79, 127.38 (2C), 127.94, 128.10 (20, 128.15, 128.50 (4C), 131.84 (2C), 135.89, 136.62, 141.64, 159.08, 164.8 1. (c) 3- (4-hydroxyphenyl) -2-isopropoxypropanoic acid 3- (4-Hydroxyphenyl) -2-isopropoxypropanoic acid was synthesized from 3- [4- (benzyloxy) phenyl] -2-isopropoxy-2-propenoate using the same method as in example 58c. aH-NMR (500 MHz, CDC13): d 1.08 (d, J = 6 Hz, 3H, 1.21 (d, J = 6 Hz, 3H), 2.93 (dd, J = 14, 8 Hz, 1H), 3.10 ( dd, J = 14.4 Hz, 1H), 3.56-3.63 (m, 1H), 4.14 (dd, J = 8.4 Hz, 1H), 6.80 (d, J = 8.3 Hz, 2H), 7.15 (d , J = 8.3 Hz, 2H). (d) 3- (4-Hydroxyphenyl) -2-isopropoxypropanoic acid methyl ester The methyl 3- (4-hydroxyphenyl) -2-isopropoxypropanoate was synthesized using the same method as in Example 58d from 3- (4-hydroxyphenyl) -2-isopropoxypropanoic acid.

^ -NMRISOO MHz; CDC13): d 1.00 (d, J = 6 Hz, 3H), 1.18 (d, J = 6 Hz, 3H), 2.90 (dd, J = 14, 8.5 Hz, 1H), 2.98 (dd, J = 14, 5 Hz, 1H), 3.50-3.57 (m, 1H), 3.74 (s, 3H), 4.07 (dd, J = 8.5, 5 Hz, 1H), 6.78 (d, 5 = 8.3 Hz, 2H) and 7.13 ( d, J = 8.3 Hz). (e) 2-Isopropoxy-3- [4- (2. {4-methylsulfonyloxyphenyl) ethoxy) phenyl] propanoic acid methyl ester The 2-isopropoxy-3- [4- (2. {4-methylsulfonyloxyphenyl) ethoxy) phenyl] propanoic acid methyl ester was synthesized from the 3- (4-hydroxyphenyl) -2-isopropoxypropanoic acid methyl ester and 2- (4-methanesulfonyloxyphenyl) ethyl methanesulfonate (described in Example Ib) using the same method as in Example 58e. 1 H-NMR (500 MHz, CDC13): d 0.99 (d, J = 6 Hz, 3H), 1. 17 (t, J = 6 Hz. 3H), 2.90 (dd, J = 13.8, 8.6 Hz, 1H), 2. 97 (dd, J = 13.8, 5 Hz, 1H, 3.12 (t, J = 7 Hz, 2H), 3.15 (s, 3H), 3.50- 3.55 (m, 1H), 3.73 (s, 3H), 4.05 (dd, J = 8.6, 5 Hz, 1H), 4.17 (t, J = 7 Hz, 2H), 6.83 ( d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H). 13 C-NMR (100 MHz, CDCl 3): d 21.40, 22.49, 35.10, 37.23, 38.82, 51.80, 68.13, 72.39, 78.33, 114.20 (2C), 121.90 (2C), 129.62, 130.43 (20, 130.51 (2C), 137.92, 147.80, 157.32, 173.48. (f) 2-isopropoxy-3- [4- (2. {4-methylsulfonyloxyphenyl) ethoxy) phenyl] The 2-isopropoxy-3- [4- (2. {4-methylsulfonyloxyphenyl) ethoxy) phenyl] propanoic acid methyl ester was dissolved. (0.1 g, 0.229 mol) in tetrahydrofuran (2 ml). Lithium hydroxide (0.006 g, 0.25 mmol) in water (2 ml) was added.

The reaction mixture was stirred at room temperature for 8 hours. Tetrahydroguran was evaporated. The remaining water in the solution was extracted with diethyl ether. The aqueous solution was then acidified with hydrochloric acid (1%) to pH ~ 2 and extracted twice with ethyl acetate. X organic phases were combined and dried with magnesium sulfate. The solvent was evaporated and 0.085 g (88% yield) of 2-isopropoxy-3- [4- (2. {4-methylsulfonyloxyphenyl) ethoxy) phenyl] propanoic acid was obtained. 1 H-NMR (400 MHz, CDC13): d 0.99 (d, J = 6 Hz, 3 H), 1.15 (d, J = 6 Hz, 3 H), 2.88 (dd, J = 13.6, 5.3 Hz, 1 H), 3.01 -3.11 (, 3H), 3.11 (s, 3H), 3.49-3.58 (, 1H), 4.07 (dd, J = 8.3.3.9 Hz, 1H), 4.13 (t, J = 6.8 Hz, 2H), 6.80. { d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H) and 7.32 (d, J = 8.3 Hz, 2H). 13C_NMR (100 MHz; CDC13): d 21.68, 22.16, 35.07, 37.21, 3 8.29, 68.12, 73.12, 77.73, 114.28 (2, C), 121.89 (2C), 129.02, 130.49 (2C). 130.57 (2C), 137.89, 147.79, 157.47 and 175.89.

Biological activity The biological activity of the compounds of the invention was tested in obese diabetic mice of the strain Ornea ob / ob. Groups of mice received the test compound by tube feeding once daily for 7 days. On the last day of the experiment the animals were anesthetized 2 hours after the dose in a non-food state and the blood was collected from an artery in which an incision was made. The plasma was analyzed for glucose, insulin and triglycerides concentration. A group of untreated obese diabetic mice of the same age served as control. The weight of the mice was measured before and after the experiment and the weight gain obtained was compared with the weight gain of the control animals. The individual values of glucose, insulin and triglyceride levels of the mice in the test group were expressed as the percentage variation of the corresponding values of the control group.

The desired "therapeutic effect" was calculated as the average percentage reduction of the three glucose, insulin and triglycerides variables lower than the levels in the control animals. The therapeutic effect of the compounds tested according to the invention was compared to the same effect in the troglitazone compound prior to the subject, administered by oral feeding at the oral dose of 100 μmol / kg for 7 days.

The superior effects of the compounds tested according to the invention compared to that of troglitazone when the same oral dose was given demonstrated the increase in potency and efficiency of the claimed compounds.

Abbreviations NIDDM diabetes mellitus non-insulin dependent IRS insulin resistance syndrome VLDL low density lipoprotein HDL high density lipoprotein PPAR peroxisome proliferator peroxisome proliferator LDA lithium diisopropylamide KHMDS lithium hexamethyldisilamine DMF dimeti1for amide DEAD diethyl azodicarboxylate ADDP azodicarbonyl dipiperidine EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide DCC dicyclohexylcarbodiimide HBTU O-benzotriazol-1-yl- N, N, N 'N' -tetramethylammonium hexafluorophosphate TBTU O-benzotriazole-1-yl- N, N ', tetrafluoroborate N '-tetramethyluronium PyBop benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate TEA triethylamine DiPEA diisopropylethylamine TLC thin layer chromatography THF tetrahydrofuran Pd / C palladium on carbon H0BtxH0 1-hydroxybenzotriazole-hydrate t triplet s single d doublet qqint quintoto multipleto br broad DM? O dimethyl sulfoxide DIBAL diisobutyl aluminum hydride It is noted that in relation to this date the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, it is claimed as property in the following:

Claims (42)

1. l.A compound compound of the general formula: and stereo and optical isomers and racemates thereof as well as pharmaceutically acceptable salts, solvates and crystalline forms thereof, which is characterized in that A, is located in the ortho position, meta or stops and represents R3 R1 | | R3 R1! i - C-C - COR 0. | i - c -c 1 I R4 R2 where R is hydrogen; -ORa, wherein Ra represents hydrogen, alkyl, aryl or alkylaryl; -NRaR, wherein Ra and Rb are the same or different and Ra is as defined above and Rb represents hydrogen, alkyl, aryl, alkylaryl, cyano, -OH, -Oalkyl, Oaryl, -Oalkylaryl, -COR ° or -S02Rd, wherein R ° represents hydrogen, alkyl, aryl or alkylaryl and Rd represents alkyl, aryl or alkylaryl, R1 is alkyl, aryl, alkene, alkyne, cyano; -0Re, wherein Re is alkyl, acyl, aryl or alkylaryl; -0- [CH2Jm-ORf, wherein Rf represents hydrogen, alkyl, acyl, aryl or alkylaryl and represents an integer 1-8; -OCONRaRc, where Ra and Rc are as defined above; -SRd, where Rd is as defined above; -S02NRaRf, wherein Rf and Ra are as defined above; -S020Ra, where Ra is as defined above; -C00Rd, where Rd is as defined above; Rz is hydrogen, halogen, alkyl, aryl, or alkylaryl, R3 and R4 are the same or different and each represents hydrogen, alkyl, aryl, or alkylaryl, n is an integer from 1 to 6; D is located in the ortho, meta or para position and represents -0S02Rd, where Rd is as defined above; -COONRfRa, where Rf and Ra are co or defined above; -NR ° COORd, where Rc and Rd are as defined above; -NRcCORa, where Rc and Ra are as defined above; -NRcRd, where Rc and Rd are as defined above; -NRcS02Rd, where Rc and Rd are as defined above; -NRcCONRaRk, wherein Ra, Rc and Rk are the same or different and each represents hydrogen, alkyl, aryl, or arylalkyl; -NRcCSNRaRk, wherein Ra, Rc are the same or different and each represents a hydrogen, alkyl, aryl or alkylaryl; -S02Rd, where Rd is as defined above; -SORd, where Rd is as defined above; -? R °, where Rc is as defined above; -S02NRaRf, wherein Rf and Ra are as defined above; -S02ORa, where Ra is as defined above; -CN, -CONRcRa, where Rc and Ra are as defined above; D 'is located in the ortho, meta or para position and represents a hydrogen, alkyl, acyl, aryl, alkylaryl, halogen, -CN, -N02, -NRfRb, wherein Rf and Rb are as defined above; -0Rf, where Rf is as defined above; -OS02Rd, where Rd is as defined above; D "is located in the ortho, meta or para position and represents a hydrogen, alkyl, acyl, aryl, alkylaryl, halogen, -CN, -N02, -NRfRb wherein Rf and R are as defined above; -ORf, wherein Rf is as previously defined -OS02Rd, where Rd c as defined above;
2. 2. A compound according to claim 1 with the exception of (S) -2-ethoxy-3- (2- [4- (4-methanesulfonyloxyphenyl) ethoxy) phenylpropanoic acid, and 3- acid. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy-phenyl} - (S) -2-ethoxypropanoic.
3. 3. A compound according to claims 1 6 2 wherein A is located in the meta position or stops and represents, where R, is hydrogen; -ORa, wherein Ra is as defined in claim 1; -NRaRb, wherein Ra and Rb are the same or different and Ra is as defined in claim 1 and R represents a hydrogen, alkyl, aryl, alkylaryl, cyano , -OH, -Oalkyl or -Oalkylaryl; R1 is cyano; -ORd, where Rd is as defined in claim 1; -0- [CH2Jm-ORa, where m and Ra are as defined in Category A; R2 is hydrogen or alkenyl; R3 is hydrogen or alkyl; R4 is hydrogen; n is an integer from 1 to 3; D is located in the ortho, meta or para position and represents -OS02Rd, where Rd is as defined in claim 1; -0C0NRaRc, wherein Ra and Rs are as defined in claim 1; -NRcCOORd, wherein Rc and Rd are as defined in claim 1; -NRcCORa, wherein Rc and Ra are as defined in claim 1; NRcRd, wherein Rc and Rd are as defined in claim 1; NRc? 02Rd, wherein Rs and Rd are as defined in claim 1; -NRcCONRaRk, wherein Ra, R ° and Rk are as defined in claim 1; -NRcC? NRaRk, wherein Ra, Rc and Rk are as defined in claim 1; -S02Rd, wherein Rd is as defined in claim 1; -SRC, wherein Rc is as defined in claim 1; -CN; -C0NRaRc, wherein Ra and Rc are as defined in claim 1; D 'is located in the ortho, meta or para position and represents hydrogen, alkyl, alkylaryl, halogen, -CN or -N02; -0Rh, where Rh is hydrogen or alkyl; D "is located in the ortho, meta or para position and represents hydrogen, alkyl, alkylaryl, halogen, -CN or -N02; -ORh, wherein Rh is as above.
4. 4. A compound according to claim 3, characterized in that A is located in the meta or para position; R is -0Ra, wherein Ra is hydrogen, alkyl or alkylaryl; -NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R2 is hydrogen or alkenyl; R3 is hydrogen or alkyl; R4 is hydrogen; n is an integer from 1 to 3; D is located in the ortho position, meta or stops and represents -NRcCOORd, wherein Rc, and Rd are as defined in claim 1; D 'is hydrogen, D "is hydrogen.
5. 5. A compound according to claim 4, characterized in that A is located in the position for; R is -OH, -Oalkyl or -Oalkylaryl; -NH2 / -NHOalkylaryl or -NHCN; R1 is -Oalkyl, preferably -O-lower alkyl; Rz is hydrogen; R3 is hydrogen; N is the integer 1; D is located in the para position, and represents -NRhC00Rd, where Rd is as defined in claim 1 and Rh represents hydrogen or alkyl.
6. 6. A compound according to claim 5, characterized in that, D is -NR ^ COOalkyl, wherein R3 represents hydrogen or lower alkyl.
7. 7. A compound according to claim 3, characterized in that A is located in the meta or para position. R is -ORa, wherein Ra is hydrogen, alkyl or alkylaryl; -NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R2 'is hydrogen or alkyl; R3 is hydrogen or alkenyl; R4 is hydrogen; N is an integer from 1 to 3; D is located in the ortho, meta or para position and represents -NRcCORa, wherein Rc and Ra are as defined in claim 1; D "is hydrogen, D" is hydrogen.
8. 8. A compound according to claim 7, characterized in that, A is located in the position for; R is -OH, -Oalkyl, -Oalkylaryl; -NH2. -NHOalkylaryl or -NHCN; R1 is -Oalkyl, preferably -O-lower alkyl; Rz is hydrogen R3 is hydrogen; n is the integer 1; D is located in the para position and represents NRhCORd, where Rd is as defined in claim 1 and Rh represents hydrogen or alkyl.
9. 9. A compound according to claim 8, characterized in that D is -NHCORd alkyl, wherein Rd is as defined in claim 1.
10. 10. A compound according to claim 3, characterized in that A is located in the meta position or for R is -ORa, wherein Ra is hydrogen, alkyl, alkylaryl; -NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R2 is hydrogen; R3 is hydrogen or alkyl; R4 is hydrogen; n is an integer from 1 to 3; D is located in the ortho, meta or para position and represents -S02Rd, where Rd is as defined in claim 1; D * is hydrogen; D "is hydrogen.
11. 11. A compound according to claim 10, characterized in that A is located in the position for; R is -OH, -Oalkyl, -Oalkylaryl; -NH2, -NHOalkylaryl or -NHCN; R1 is -Oalkyl, preferably-lower alkyl; R3 is hydrogen; n is the integer 1; D is located in the position para, and represents -S02Rd where Rd is as defined in claim 1.
12. 12. A compound according to claim 3, characterized in that A is located in the meta or para position; R is -ORa, wherein Ra is hydrogen, alkyl or alkylaryl; -NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R2 is hydrogen; R3 is hydrogen or alkyl; R4 is hydrogen; n is an integer from 1 to 3; D is located in the ortho, meta or para position and represents -SRd, where Rd is as defined in claim 1; D 'is hydrogen; D "is hydrogen."
13. 13. A compound according to claim 12, characterized in that- A is located in the position for; R is -OH, -Oalkyl, -Oalkylaryl; -NH2. -NHOalkylaryl or -NHCN; R1 is -Oalkyl, preferably -O-lower alkyl; R3 is hydrogen; n is the integer 1; D is located in the para position and represents -SRd, where Rd is as defined in claim 1.
14. 14. A compound according to claim 3, characterized in that A is located in the meta or para position, R is -ORa, wherein Ra is hydrogen, alkyl, alkylaryl; -NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R2 is hydrogen or alkyl; R3 is hydrogen or alkyl; R4 is hydrogen; n is an integer from 1 to 3; D is located in the ortho, meta or para position and represents -0C0NRaRc, where Ra and Rc are as defined in claim 1; D "is hydrogen; D" is hydrogen.
15. 15. A compound according to claim 14, characterized in that A is located in the position for; R is -OH, -Oalkyl, -Oalkylaryl; -NH2, -NHOalkylaryl, -NHCN; R2 is hydrogen; R3 is hydrogen; n is the integer 1; D is located in the position para, and represents -OCONHRd, where R is as defined in claim 1.
16. 16. A compound according to claim 15, characterized in that R1 is -Oalkyl, preferably -O lower alkyl, D is -OCONHalkyl.
17. 17. A compound according to claim 3, characterized in that A is located in the meta or para position, R is -ORa, 'wherein Ra is hydrogen, alkyl, alkylaryl; -NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl, R1 is -Oalkyl, R2 is hydrogen or alkyl; R3 is hydrogen or alkyl, R4 is hydrogen; n is an integer from 1 to 3; D is located in the ortho, meta or para position and represents -NRsS02Rd, wherein Rc and Rd are as defined in claim 1; D 'is hydrogen; D "is hydrogen.
18. 18. A compound according to claim 17, characterized in that A is located in the position for; R is -OH, -Oalkyl, -Oalkylaryl; -NH2, NHOalkylaryl or -NHCN; R2 is hydrogen; R3 is hydrogen; n is the integer 1, D is located in the para position, and represents -NRhS02Rd, where Rd is as defined in claim 1 and Rh is hydrogen or alkyl.
19. 19. A compound according to claim 18, characterized in that R1 is -Oalkyl, preferably -O-lower alkyl; D is -NRhS02alkyl wherein Rh is hydrogen or alkyl,
20. 20. A compound according to claim 3, characterized in that A is located in the meta or para position; R is -ORa, wherein R is hydrogen, alkyl or alkylaryl; -NHRb, wherein R is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R2 is hydrogen or alkyl; R3 is hydrogen or alkyl; R4 is hydrogen; n is an integer from 1 to 3; D is located in the ortho, meta or para position and represents -NRcRd, wherein Rc and Rd are as defined in claim 1; D 'is hydrogen; D "is hydrogen.
21. 21. A compound according to claim 20, characterized in that A is located in the position for; R is -OH, -Oalkyl, -Oalkylaryl; -NH2, -NHOalkylaryl or -NHCN; R2 is hydrogen; R3 is hydrogen; n is the integer 1; D is located in the para position, and represents -NRhRd where Rd is as defined in claim 1 and Rh is hydrogen or alkyl.
22. 22. A compound according to claim 21, characterized in that R1 is -Oalkyl, preferably -O-lower alkyl; D is -NR-alkyl wherein Rh is hydrogen or alkyl.
23. 23. A compound according to claim 3, characterized in that A is located in the meta or para position; R is -ORa, wherein Ra is hydrogen, alkyl or alkylaryl; -NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R2 is hydrogen or alkyl; R3 is hydrogen or alkyl; R4 is hydrogen; n is an integer from 1 to 3; D is located in the ortho, meta or para position and represents .NRcCONRaRk, wherein Ra, Rc and Rk are as defined in claim 1; D 'is hydrogen; Or "it's hydrogen.
24. 24. A compound according to claim 23, characterized in that A is located in the position for; R is -OH, -Oalkyl, -Oalkylaryl; -NH2, -NHOalkylaryl or -NHCN; R2 is hydrogen; R3 is hydrogen; n is the integer 1; D is located in the position para, and represents -NHCONHRd, where Rd is as defined in claim 1.
25. 25. A compound according to claim 24, characterized in that R is -Oalkyl, preferably -O lower alkyl; D is -NHCONHalkyl.
26. 26. A compound according to claim 3, characterized in that A is located in the meta or para position; R is -OR, wherein Ra is hydrogen, alkyl or alkylaryl; -NHRb, wherein Rb is hydrogen, alkenyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R2 is hydrogen or alkyl; R3 is hydrogen or alkyl; R4 is hydrogen; n is an integer from 1 to 3; D is located in the ortho, meta or para position and represents -NRcCSNRaRk, wherein Ra, Rc and R are as defined in claim 1; Df is hydrogen; D "is hydrogen.
27. 27. A compound according to claim 26, characterized in that A is located in the position for; R is -OH, -Oalkyl, -Oalkylaryl; -NH2, -NHOalkylaryl or -NHCN; R2 is hydrogen; R3 is hydrogen; n is the integer 1; D is located in the position para, and represents -NHCSNHRd, where Rd is as defined in claim 1.
28. 28. A composite according to claim 27, characterized in that Ri is -O lower alkyl. D is -NHCSNHalkyl.
29. 29. A compound according to claim 3, characterized in that A is located in the meta or para position; R is -ORa, wherein Ra is hydrogen, alkyl, alkylaryl; -NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl; R1 is -Oalkyl; R2 is hydrogen or alkyl; R3 is hydrogen or alkyl; R4 is hydrogen; n is an integer between 1 and 3; D is located in the ortho, meta or para position and represents -OS02Rd, where Rd is as defined in claim 1; D 'is hydrogen; D "is hydrogen.
30. 30. A compound according to claim 29, characterized in that A is located in the position for; R is -OH, -Oalkyl, -Oalkylaryl; -NH2, NHOalkylaryl or -NHCN; R2 is hydrogen; R3 is hydrogen; n is the integer 1; D is located in the para position and represents -OS02alkyl or -O? 02alkylaryl.
31. 31. A compound according to claim 30, characterized in that R1 is -Oalkyl, preferably -O-lower alkyl; D is -0S02 alkyl.
32. 32. A compound according to any of the preceding claims which is characterized in that it is: 2-ethoxy-3- [4- (2-. {4-methanesulfonyloxyphenyl) ethoxy) phenyl propanoic acid; acid 3-. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl} -2-ethoxypropanoic; 2-ethoxy-3- acid. { 4- [2- (4-methanesulfonylphenyl) ethoxy] pheni1} propanoic; 2-ethoxy-3- acid. { 4- [2- (4-methylsulfanylphenyl) ethoxy] phenyl} propanoic; 2-ethoxy-3- [4- (2-. {4-isobutyrylaminophenyl) ethoxy) phenyl] propanoic acid; 3-ethyl ester. { 4- [2- (4-tert-butylcarbamoyloxyphenyl) ethoxy-phenyl} - 2-ethoxypropanoic; 2-ethoxy-3- acid. { 4- [2- (4-methanesulfonylaminophenyl) ethoxy] phenyl} propanoic; N-cyano-2-ethoxy-3- [4- (2. {4-methanesulfonyloxyphenyl) ethoxy) phenyl] propanoic acid amide; N-benzyloxy-2-ethoxy-3- [4- (2. {4-ethanesulfonyloxyphenyl) ethoxy) phenyl] propanoic acid amide; 2-ethoxy-3- [4- (2. {4-methanesulfonyloxyphenyl) ethoxy) phenylpropanoic acid amide; 2-ethoxy-3-ethyl ester. { 4- [3- (3-methanesulfonyloxyphenyl) propoxy] phenyl} propanoic; 2-ethoxy-3- (4-. {2- 2- [4- (2-propanesulfonyloxy) phenyl] ethoxy} pheny1) propanoic acid; acid 3- [4-. { 2- (4- [tert -butoxycarbonyl (methyl) amino] phenyl) ethoxy} phenyl] - (S) -2-ethoxypropanoic; (S) -2-ethoxy-3- [4-. { 2- [4- (methoxycarbonylamino) phenyl) ethoxyJphenyl} propanoic; 2-ethoxy-3-ethyl ester. { 4- [2- (4-methylcarbamoyloxyphenyl) ethoxy-phenyl} propanoic; acid 3- [4-. { 2- (4- [benzyloxycarbonylamino] phenyl) ethoxy} phenyl- (S) -2-ethoxypropanoic acid; acid 3-. { 4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxyJ-3-methoxyphenyl} -2-ethoxypropanoic; 3- [4- (2. {4-tert-Butoxycarbonylaminophenyl) ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid methyl ester; (S) -2-ethoxy-3- (4-. {2- [4- (phenylsulfonyl) phenyl] ethoxy} phenyl) propanoic acid; and, where applicable, the stereo- and optical isomers and the racemates thereof as well as the pharmaceutically acceptable salts, solvates and crystalline forms thereof.
33. 33. A compound according to any of the preceding claims which is characterized in that the compound is one of the possible enantiomers.
34. 24. A process for preparing a compound according to claim 1, which is characterized by a) condensation of a compound of formula II with a compound of formula III or IV H2C - COR II! L2- P - CH - COR? ? 1 R1 in said formulas D, D ', D ", n, R, R1 and R3 are as defined in claim 1 and L1 = L2 = L3 are phenyls or L1 = L2 are 0Rd (where Rd is as defined in claim 1 and L3 is = 0, and then, if desired, reduce the double bond and remove the protecting groups, for the formation of a compound of formula I wherein R2 and R4 are hydrogen or b) reaction of a carbonyl compound of formula II - ° "with a compound of formula VII H-C - COR Vil 1 in said formulas D, D ', D ", n, R1 and R3 are as defined in claim 1 and R2 is alkyl, aryl or alkylaryl, followed by dehydroxylation and, if necessary, by removal of the protecting groups, for the formation of a compound of formula I, wherein A is -CR ^ -CR ^ -COR, wherein R4 is hydrogen, or c) reaction of a compound of formula VIII with a compound of formula VII R1 HC-COR VII in said formulas D, D ', D ", n, R, R1, R2, R3 and R4 are as defined in claim 1 and X is a displaceable group, then, if necessary, eliminate the protecting groups for the formation of a compound of formula I wherein A is -CR3R4-CR1R2-COR, or d) reaction of a compound of the formula V with a compound of formula X in said formulas D, D ', D ", n, and A are as defined in claim 1 and R1 is -OH or a displaceable group, then, if necessary, removing the protecting groups, or e) conversion of a compound of formula XI in said formula D, D ', D ", n, R, R2, R3 and R4 are as defined in claim 1 and X" is -OH followed, if necessary, by removal of the protecting groups, for the formation of a compound of formula I, wherein -CR3R4-CR1R2-COR, wherein R1 is -ORe, wherein Re is as defined in claim 1, -0- [CH2Jm-ORf, wherein m and Rf are as defined in claim 1, -OCONRR ° , wherein Ra and Rc are as defined in claim 1, f) reaction of a compound of the formula XIII with a thiol, in said formula D, D ', D ", n, R, R2, R3 and R4 are as defined in claim 1 and X' is halogen, for the formation of a compound of the formula I wherein A is -CR3R4-CR1R2-COR, wherein R1.es -SRd, wherein Rd is as defined in claim 1; g) reaction of a compound of the formula XIV with a suitable reagent and continue with the removal of the protecting groups, in said formula D ', D ", n and A are as defined in claim 1 and X1 is -OH, -SH or -NRCH for the formation of a compound of the formula I, wherein D is -0S02Rd, -SRC, -0C0NRfRa, -NRcC00Rd, -NRcC0Ra, -NR > cc-R-da, NRcS02Ra and wherein Ra, Rc, Rd, Rf, R9 and Rk are as defined in claim 1, or h) hydrolysis of a compound of the formula I wherein R is -ORp, wherein Rp is a protecting group, for the formation of a compound of the formula I wherein R is -OH, or i) reaction of a compound of formula I, wherein R is -OH with a compound of the formula HNRaRb, wherein Ra and Rb are as defined in claim 1, for the formation of a compound of formula I wherein R is -NRaRb, or j) oxidation of a compound of the formula XV and if it is necessary to continue with the elimination of the protective groups, in said formula Df, D ", n and A are as defined in claim 1 and X2 is -? ORd or -? Rd where Rd is as defined in claim 1, for the formation of a compound of the formula I wherein D is -? 02Rd or -? 0Rd, then, if desired, the compound obtained according to any of methods a) - j) is converted to a stereoisomer , pharmaceutically acceptable salt and / or solvate, such as hydrate, thereof
35. 35. A process according to claim 34 which is characterized by the preparation of a compound according to any of claims 2-33.
36. 36. A compound according to any of claims 1-33 for use in therapy.
37. 37. A pharmaceutical formulation which is characterized in that it contains a compound according to any of claims 1-33 as an active ingredient optionally together with an acceptable vehicle, adjuvant and / or diluent.
38. 38. The use of a compound according to any of claims 1-33 in the manufacture of a medicament for the prophylaxis and / or treatment of clinical conditions associated with insulin resistance.
39. 39. A method for the prophylaxis and / or treatment of clinical conditions associated with insulin resistance which is characterized in that a therapeutically active amount of a compound according to any of claims 1-33 administered to a mammal in need of such prophylaxis and / or treatment.
40. 40. A method according to claim 39, which is characterized in that prophylaxis and / or treatment of the clinical conditions associated with insulin resistance is the prophylaxis and / or treatment of dyslipidemia under such conditions.
41. 41. A method according to claim 39 which is characterized in that the prophylaxis and / or treatment of the clinical conditions associated with insulin resistance is the prophylaxis and / or treatment of hyperglycemia in diabetes mellitus not dependent on insulin.
42. 42. A pharmaceutical formulation for use in the prophylaxis and / or treatment of clinical conditions associated with insulin resistance which is characterized in that the active ingredient is a compound according to any of claims 1-33.