CZ20004482A3 - Novel derivatives and analogs of 3-arylpropionic acid - Google Patents

Abstract

3-arylpropionic acid derivatives and analogues thereof having the general formula I and their stereo and optical isomers and racemates, as well as pharmaceutically acceptable salts, solvates and crystalline forms thereof. Methods for their preparation are described, pharmaceutical compositions containing them, and the use of these compounds in clinical conditions associated with insulin resistance.

Description

Technical field

The present invention relates to certain novel 3-aryl-2-hydroxypropionic acid derivatives and analogs, a process for the preparation of such compounds having utility in clinical conditions associated with insulin resistance, methods of their therapeutic use, and pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

Insulin resistance, defined as reduced sensitivity to insulin action throughout the body or in individual tissues such as skeletal muscle, myocardium, adipose tissue and liver, is prevalent in many individuals with or without diabetes mellitus. Insulin resistance syndrome, IRS, refers to a set of manifestations including insulin resistance accompanying hyperinsulinemia, possibly non-insulin dependent diabetes mellitus (NIDDM), arterial hypertension, central (visceral) obesity, dyslipidemia observed as impaired lipoprotein VL levels usually characterized by elevated lipoprotein VL concentrations very low density) and reduced HDL (high density lipoprotein) concentrations and reduced fibrinolysis.

Recent epidemiological research has documented that individuals with insulin resistance are at a significantly increased risk of cardiovascular morbidity and mortality, particularly by being affected by myocardial infarction and stroke. In non-insulin-dependent diabetes mellitus

·· · »·· 99 *

·. · 9 9 9 9. 9 9 9 · ·· «· e 9 * 9 · 9 · 9 · ₉ • 9φ · · · · 9« «• 9 99 9999 9" * 9 causing these related conditions atherosclerosis up to 80% of all deaths.

In clinical medicine, there is currently limited attention to the need to increase insulin sensitivity in the IRS (insulin resistance syndrome) and thus to correct dyslipidemia, which is considered to be the cause of the accelerated progression of atherosclerosis.

Furthermore, there is currently no available pharmacotherapy to adequately control metabolic disorders accompanying IRS. So far, NIDDM has been focused on correcting impaired management of disease-associated carbohydrate metabolism. Stimulation of endogenous insulin secretion through secretagogues such as sulfonylureas and, if necessary, by administration of exogenous insulin, are methods often used to normalize blood sugar, but which, if they do, further enable insulin resistance and do not modify other IRS manifestations or reduce cardiovascular morbidity and mortality. In addition, such treatment involves a significant risk of hypoglycaemia with associated complications.

Other therapeutic strategies have focused on abnormalities in glucose metabolism or uptake, including biguanides such as metformin, or glucosidase inhibitors such as acarbose. Although these agents are to some extent effective, their limited clinical effect is accompanied by side effects.

The new therapeutic strategy involves the use of insulin sensitizing agents, such as thiazolidinediones, which at least partially mediate their effects through agonist action at nuclear receptors.

· * · »-

-3 Ciglitazone is a prototype in this class. In the animal model of the IRS, these compounds appear to modulate insulin resistance and accompany hypertriglyceridaemia and hyperinsulinemia, as well as hyperglycemia in diabetes, by improving insulin sensitivity by acting on the transport and control of lipid fate, resulting in an increased effect of insulin in skeletal muscle, liver and adipose tissue.

The use of ciglitazone, as well as the thiazolidinediones described later, has been discontinued in clinical development allegedly due to unacceptable toxicity or due to inadequate efficacy. Thus, there is a need for new and improved compounds with insulin sensitizing properties.

BACKGROUND OF THE INVENTION

Compounds of formula

and certain derivatives thereof disclosed in US Patent No. 5,306,726 and WO 91/19702 are reported to be useful as hypoglycemic and hypocholesterolemic agents;

232,945 are reported to be useful in the treatment of hypertension.

-4AU 650 429 discloses structurally related compounds but which have claimed different properties: possess diuretic, antihypertensive, anti-platelet aggregation and antilipoxygenase properties.

EP 139 421 discloses compounds having the ability to lower blood lipid and sugar levels. These compounds include troglitazone, a compound that has entered the market for the treatment of NIDDM (non-insulin dependent diabetes) or reduced glucose tolerance.

WO 97/31907 discloses compounds claimed to have blood glucose lowering activity and thus useful in the treatment and / or prophylaxis of hyperglycemia and dyslipidemia, and are particularly useful in the treatment of type II diabetes.

These compounds are also claimed to be useful in the treatment and / or prophylaxis of other diseases including type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension and cardiovascular diseases, in particular atherosclerosis.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I

D '[CH ₂ ] _n -CH ₂ -O

D 'and their stereo- and optical isomers and racemates, as well as their pharmaceutically acceptable salts, solvates and crystalline forms, in which:

A is placed in the ortho, metha or para position and represents

R ³ R ¹ II

-CC-COR ' ₂ RR ² or

R ³ RII

C = C-COR where

R is hydrogen,

-OR ^a , wherein R ^a represents a hydrogen atom, an alkyl, an aryl or an alkaryl,

-NR ^a R ^b wherein R ^a and R ^b are identical or different and R has ^the meaning defined above and R ^b represents hydrogen, alkyl, aryl, alkaryl, cyano,

-OH, -O-alkyl, -Oaryl, O-alkaryl, -COR ^c or -SO ₂ R ^d , where R ^c is hydrogen, alkyl, aryl or alkaryl and R ^d is alkyl, aryl or alkaryl,

R ¹ is alkyl, aryl, alkene, alkyne, cyano,

-OR ^e where R ^e is alkyl, acyl, aryl or alkaryl, -O- [CH ₂ ] _m -OR ^f where R ^f is hydrogen, alkyl, acyl, aryl or alkaryl and _m is an integer of 1 to 8,

-OCONR ^and R ^c , where R ^a and R ^c are as defined above, -SR ^d , wherein R ^d is as defined above,

-SO ₂ NR ^a R ^f , where R ^f and R ^a are as defined above,

-SO ₂ OR ^a , where R ^a is as defined above, -COOR ^d , wherein R ^d is as defined above,

R ² is hydrogen, halogen, alkyl, aryl or alkaryl,

R ³ and R ⁴ are the same or different and each represents hydrogen, alkyl, aryl or alkaryl, n is an integer from 1 to 6 located in the ortho, meta or para position and represents

-OSO ₂ R ^d , where R ^d is as defined above, -OCONR ^f R ^a , where R ^f and R ^a are as defined above,

-NR ^c COOR ^d , where R ^c and R ^d are as defined above,

-NR ^c COR ^a , where R ^c and R ^a are as defined above, -NR ^c R ^d , where R ^c and R ^d are as defined above, -NR ^c SO ₂ R ^d , where R ^c and R ^d are as defined above as defined above,

-NR ^c CONR ^a R ^k , wherein R ^a , R ^c and R ^k are the same or different and each represents a hydrogen atom, an alkyl, an aryl or an alkaryl,

-NR ^c CSNR ^and R ^k , wherein R ^a , R ^c and R ^k are the same or different and each represents hydrogen, alkyl, aryl or alkaryl,

-SO ₂ R ^d , where R ^d is as defined above,

-SOR ^d , where R ^d is as defined above,

-SR ^C , where R ^c is as defined above,

-7 · · · * * * * *. · »· · · 1 ..

... ... · · i · · · · · · · · · · · ·. -SC> 2NR ^and R ^f , where R ^f and R ^a are as defined above,

-SC 1 OR ³ , wherein R ^a is as defined above,

-CN,

-CONR ^c R ^a , wherein R ^c and R ^a are as defined above,

D 'is located in the ortho, meta or para position and represents a hydrogen atom, alkyl, acyl, aryl, alkaryl, halogen atom, -CN, -NO ₂ , -NR ^f R ^b , where R ^f and R ^b are as defined above ,

-0R ^f , where R ^f is as defined above,

-OSO ₂ R ^d , where R ^d is as defined above,

D is located in the ortho, meta or para position and represents a hydrogen atom, alkyl, acyl, aryl, alkaryl, halogen atom, -CN, -NO ₂ , -NR ^f R ^b , wherein R ^f and R ^b are as defined above,

-0R ^f , where R ^f is as defined above,

-OSO ₂ R ^d , wherein R ^d is as defined above.

For ease of reference, the definitions of Formula I above are designated as defined in Category A. Unless otherwise stated, throughout the present application, the definitions of the various substituents have the meaning defined in the Category.

AND.

Surprisingly, the compounds of the formula are effective in conditions associated with insulin resistance.

Category A2: in one embodiment, the present invention does not comprise (S) -2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid and 3- [4- / 2- (4-tertiary) .-butoxycarbonylaminophenyl) ethoxy / phenyl] -8-

»· · 4 « • · 4 4 4 4 4 ♦ « «4 4 4 • * 4 · * 4 4 4 * · 4 • 4 4 4 • 4 4 • · 4 4 4 4 «44 4 4 4

- (S) -2-ethoxypropane.

Category A3: preferred compounds of the present invention are compounds having the general formula I wherein A is located in the meta or para position and represents

R ³ R ¹¹ -CC-COR f IR ⁴ R ² in which

R is hydrogen,

-OR ^a , where R ^a is as defined in category A, -NR ^and R ^b , where R ^a and R ^b are the same or different and R ^a is as defined in category A and R ^b is hydrogen, alkyl, aryl, alkaryl, cyano, -OH,

-O-alkyl or -O-alkaryl,

Yippee cyano, -OR ^d , where R ^d is as defined in category A, -O- [CH ₂ ] _m -OR ^a , where m and R ^a are as defined in category A, Yippee hydrogen or alkyl, Yippee hydrogen or alkyl, Yippee hydrogen atom, Yippee an integer of 1 to 3,

• ·

-94 · •

4 «• 3 •

4 4 4

4 • 4 ·

4

4 4 • 4

4444

D is located in the ortho, meta or para position and represents

-OSO2R ^d , where R ^d is as defined in category A,

-OCONR ^and R ^c , where R ^a and R ^c are as defined in category A,

-NR ^c COOR ^d , where R ^c and R ^d are as defined in category A,

-NR ^c COR ^a , where R ^c and R ^a are as defined in category A,

-NR ^c R ^d , where R ^c and R ^d are as defined in category A,

-NR ^c SO 2 R ^d , where R ^c and R ^d are as defined in category A,

-NR ^c CONR ^k R ^c , where R ^a , R ^c and R ^k are as defined in category A,

-NR ^c CSNR ^and R ^k , where R ^a , R ^c and R ^k are as defined in category A,

-SO ₂ R ^d , where R ^d is as defined in category A, -SR ^C , where R ^c is as defined in category A, -CN,

-CONR ^and R ^c , where R ^a and R ^c are as defined in category A,

D 'is located in the ortho, meta or para position and represents a hydrogen atom, an alkyl, an alkaryl, a halogen atom, -CN or -NO ₂ ,

-OR ^h where R ^h is hydrogen or alkyl;

D is located in the ortho, meta or para position and represents a hydrogen atom, an alkyl, an alkaryl, a halogen atom, -CN, or -NO 2;

-OR ^h where R ^h is as defined above.

Category A4: other preferred compounds of the present invention are those of category A3 wherein

And it's placed in a meta or para position,

R is -OR ^a , wherein R ^a is hydrogen, alkyl or alkaryl,

-NHR ^b where R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl,

R ¹ is -O-alkyl,

R ² is hydrogen or alkyl,

R ³ is hydrogen or alkyl,

R ⁴ is a hydrogen atom, n is an integer of 1 to 3,

D is located in the ortho, meta or para position and represents

-NR ^c COOR ^d , where R ^c and R ^D are as defined in category A,

D 'is a hydrogen atom,

D is hydrogen.

Category A5: other preferred compounds * ·

- 11 according to wherein

And is

R is

R ¹ is

R ² is

R ³ is n is

D is according to where

According to the invention, the compounds of category A4 are placed in para position,

-OH, -O-alkyl or -O-alkaryl, -NH ₂ , NHO-alkaryl or -NHCN,

-O-alkyl, preferably -O-lower alkyl, hydrogen, hydrogen, integer 1, located in para position and represents

-NR ^h COOR ^d , where R ^d is as defined in the category

A and R ^h represent hydrogen or alkyl.

Category A6: other preferred compounds of the present invention are those of category A5,

-NR ^j COO-alkyl where R is hydrogen and lower alkyl.

Category A7: other preferred compounds of the present invention are those of category A3,

A is placed in meta or para position, ·· · * ·· ··

•Her! · »..». «, • 9 · 9 · 9 · -12 - ······· ♦ ·. ·; ··· ·· 9 «9999 R is -OR ^a , where R ^a is hydrogen, alkyl or alkaryl, -NHR ^b , wherein R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl, R ¹ is -O-alkyl, R ² is hydrogen or alkyl, R ³ is hydrogen or alkyl, R ⁴ is hydrogen atom, n j e an integer of 1 to 3, D is located in the ortho, meta or para position and represents -NR ^c COR ^a , where R ^c and R ^a are as defined in category A, D 'is hydrogen atom, D is hydrogen atom.

Category A8: other preferred compounds of the present invention are those of category A7, wherein

And is placed in para position, R j e -OH, -O-alkyl or -O-alkaryl, -NH ₂ , -NHO-alkaryl or -NHCN, R ¹ is -O-alkyl, preferably -O-lower alkyl,

- 13 * · ··· • • 99

Yippee atom hydrogen, Yippee atom hydrogen, Yippee whole number 1,

D is located in the para position and represents -NR ^h COR ^d where

R ^d is as defined in Category A and R ^h is hydrogen or alkyl.

Category A9: other preferred compounds of the present invention are those of category A8 wherein

D is -NHCOR ^d , where R ^d is as defined in the category

AND.

Category A10: other preferred compounds of the present invention are those of category A3 wherein

And it's placed in a meta or para position,

R is -OR ^a , wherein R ^a is hydrogen, alkyl or alkaryl,

-NHR ^b where R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl,

R ¹ is -O-alkyl,

R ² is hydrogen,

R ³ is hydrogen or alkyl,

- 14R ⁴ is hydrogen, n is an integer of 1 to 3,

D is located in the ortho, meta or para position and represents -SC> 2R ^d , where R ^d is as defined in category A

D 'is a hydrogen atom,

D is hydrogen.

Category A11: Other preferred compounds of the present invention are those of category A10 wherein

And it's placed in a para position,

R is -OH, -O-alkyl or -O-alkaryl, -NH ₂ ,

-NHO-alkaryl or -NHCN,

R ¹ is -O-alkyl, preferably -O-lower alkyl,

R ³ is a hydrogen atom, n is an integer of 1,

D is located in para position and represents -SO ₂ R ^d , where R ^d is as defined in category A.

Category A12: other preferred compounds of the present invention are those of category A3,

• ·

-15 • · · where

And it's placed in a meta or para position,

R is -OR ^a , wherein R ^a is hydrogen, alkyl or alkaryl,

-NHR ^b where R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl,

R ¹ is -O-alkyl,

R ² is hydrogen,

R ³ is hydrogen or alkyl,

R ⁴ is a hydrogen atom, n is an integer of 1 to 3,

D is located in the ortho, meta or para position and represents -SR ^d , where R ^d is as defined in category A,

D 'is a hydrogen atom,

D is hydrogen.

Category A13: other preferred compounds of the present invention are those of category A12 wherein

And it's placed in a para position,

-OH, -O-alkyl, -O-alkaryl,

- 16 9 9 9 9 9 9

9 9 9 ••• 9 9 9 9

-NH ₂ , -NHO-alkaryl or -NHCN,

R ¹ is -O-alkyl, preferably -O-lower alkyl,

R ³ is a hydrogen atom, n is an integer of 1,

D is located in para position and represents -SR ^d , where R ^d is as defined in category A.

Category A14: other preferred compounds of the present invention are those of category A3 wherein

And it's placed in a meta or para position,

R is -OR ^a , wherein R ^a is hydrogen, alkyl, alkaryl,

-NHR ^b where R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl,

Yippee -O-alkyl, Yippee hydrogen or alkyl, Yippee hydrogen or alkyl, Yippee hydrogen atom, Yippee an integer of 1 to 3,

• 9 9 9999 9 1 9 9 9 9 ¹ 9 9 9 9 9 99 9999 99 D is situated in the ortho, meta or para position and represents -OCONR ^a R ^c, wherein R ^a and R ^c are as defined in Category A, D 'is hydrogen atom, D is hydrogen atom.

9

Category A15: other preferred compounds of the present invention are those of category A14, wherein

And is placed in para position, R j e -OH, -O-alkyl, -O-alkaryl, -NH ₂ , -NHO-alkaryl, -NHCN, R ² is hydrogen atom, R ³ is hydrogen atom, n j e integer 1, D j e located in para position and represents -OCONHR ^d , where R ^d is as defined in category A.

Category 16: other preferred compounds of the present invention are those of category A15, wherein

R ¹ is -O-alkyl, preferably -O-lower alkyl,

D is < ₉ · -18- -18- · -OCONHalkyl.

Category A17: other preferred compounds of the present invention are those of category A3 wherein

And is Placed in meta or para position R j e -OR ^a , where R ^a is hydrogen, alkyl, alkaryl, -NHR ^b , wherein R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl, R ¹ is -O-alkyl, R ² is hydrogen or alkyl, R ³ is hydrogen or alkyl, R ⁴ is hydrogen atom, n j e an integer of 1 to 3, D j e located in the ortho, meta or para position and represents -NR ^c SO 2 R ^d , where R ^c and R ^d are as defined in category A, D ¹ is hydrogen atom and D is hydrogen atom.

Category A18: other preferred compounds of the present invention are those of category A17, wherein

And it's placed in a para position,

R is -OH, -O-alkyl, -O-alkaryl,

-NH ₂ , -NHO-alkaryl or -NHCN,

R ² is hydrogen,

R ³ is a hydrogen atom, n is an integer of 1,

D is located in para position and represents

-NR ^h SO ₂ R ^d , where R ^d is as defined in the category

A and R ^h are hydrogen or alkyl.

Category A19: other preferred compounds of the present invention are those of category A18, wherein

R ¹ is -O-alkyl, preferably -O-lower alkyl,

D is -NR ^h SO 2 alkyl, wherein R ^h is as defined above.

Category A20: other preferred compounds of the present invention are those of category A3 wherein

And it's placed in a meta or para position,

R is -OR ^a , where R ® is hydrogen, alkyl or alkylaryl,

4 • 4 4

-20-NHR ^b , wherein R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl,

R ¹ is -O-alkyl,

Yippee atom hydrogen or alkyl Yippee atom hydrogen or alkyl Yippee atom hydrogen, Yippee whole 1 to 3,

D is located in the ortho, meta or para position and represents

-NR ^c R ^d , where R ^c and R ^d are as defined in category A,

D 'is a hydrogen atom,

D is hydrogen.

Category A21: other preferred compounds of the present invention are those of category A20, wherein

And it's placed in a para position,

R is -OH, -O-alkyl, -O-alkaryl,

-NH ₂ , -NHO-alkaryl or -NHCN,

R ² is hydrogen,

-21 R ³ is a hydrogen atom, n is an integer of 1,

D is located in para position and represents

NR ^h R ^d , where R ^d is as defined in category A a

R ^h is hydrogen or alkyl.

Category A22: other preferred compounds of the present invention are those of category A21, wherein

R ¹ is -O-alkyl, preferably -O-lower alkyl,

D is -NR ^h alkyl, wherein R ^h is hydrogen or alkyl.

Category A23: other preferred compounds of the present invention are those of category A3 wherein

And it's placed in a meta or para position,

R is -OR ^a , wherein R ^a is hydrogen, alkyl or alkaryl,

-NHR ^b where R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl,

Yippee -O-alkyl, Yippee hydrogen or alkyl, Yippee hydrogen or alkyl, Yippee hydrogen atom,

«Fl

-22 • fl • n • n is an integer from 1 to 3,

D is located in the ortho, meta or para position and represents

-NR ^c CONR ^and R ^k , where R ^a , R ^c and R ^k are as defined in category A,

D 'is a hydrogen atom,

D is hydrogen.

Category A24: other preferred compounds of the present invention are those of category A23 wherein

And it's placed in a para position,

R is -OH, -O-alkyl, -O-alkaryl,

-NH ₂ , -NHO-alkaryl or -NHCN,

R ² is hydrogen,

R ³ is a hydrogen atom, n is an integer of 1,

D is located in para position and represents

-NHCONHR ^d , where R ^d is as defined in category A.

Category A25: other preferred compounds

-23 of the present invention are compounds of category A24, wherein

R ¹ is -O-alkyl, preferably -O-lower alkyl,

D is -NHCONHalkyl.

Category A26: other preferred compounds of the present invention are those of category A3 wherein

And it's placed in a meta or para position,

R is -OR ^a , wherein R ^a is hydrogen, alkyl or alkaryl,

-NHR ^b where R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl,

R ¹ is -O-alkyl,

R ² is hydrogen or alkyl,

R ³ is hydrogen or alkyl,

R ⁹ is a hydrogen atom, n is an integer of 1 to 3,

D is located in the ortho, meta or para position and represents

-NR ^c CSNR ^and R ^k , where R ^a , R ^c and R ^k are as defined in category A,

D 'is a hydrogen atom,

·

D is hydrogen.

Category A27: other preferred compounds of the present invention are those of category A26 wherein

And is placed in para location R ¹ is -OH, -O-alkyl, -O-alkaryl, -NH ₂ , -NHO-alkaryl or -NHCN, R ² is hydrogen atom, R ³ is hydrogen atom, n is integer 1, D j e placed in para -NHCSNHR ^d , where category A. position a represents R ^d has the meaning defined in Category A28: other preferred compounds

according to the present invention are compounds of category A27, wherein

R ¹ is -O-lower alkyl,

D is -NHCSNHalkyl.

Category A29: other preferred compounds

According to the present invention, there are compounds of category A3 wherein

And it's placed in a meta or para position,

R is -OR ^a , wherein R ^a is hydrogen, alkyl, alkaryl,

-NHR ^b where R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl,

R ¹ is -O-alkyl,

R ² is hydrogen or alkyl,

R ³ is hydrogen or alkyl,

R ⁴ is a hydrogen atom, n is an integer of 1 to 3,

D is located in the ortho, meta or para position and represents

-OSO ₂ R ^d , where R ^d has the meaning defined in the category

AND,

D 'is a hydrogen atom,

D is hydrogen.

Category A30: other preferred compounds of the present invention are those of category A2 9 where they are located in para position,

-26 * *

R is -OH, -O-alkyl, -O-alkaryl,

-NH ₂ , -NHO-alkaryl or -NHCN,

R ² is hydrogen,

R ³ is a hydrogen atom, n is an integer of 1,

D is placed in para position and represents

-OSO ₂ alkyl or -OSO ₂ alkaryl.

Category A31: other preferred compounds of the present invention are those of category A30 wherein

R ¹ is -O-alkyl, preferably -O-lower alkyl,

D is -OSO ₂ alkyl.

Category A32: other preferred compounds of this invention are 2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid, 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid, 2-ethoxy-3- [4- / 2- (4-methanesulfonylphenyl) ethoxy / phenyl] propanoic acid, • 2-ethoxy-3- [4- / 2- ( 4-methylsulfanylphenyl) ethoxy / phenyl] propanoic acid, 2-ethoxy-3- [4- / 2- (4-isobutyrylaminophenyl) ethoxy / phenyl] propanoic acid, 3- [4- / 2- (4-tert- butylcarbamoyloxyphenyl) ethoxy / phenyl] -2-ethoxypropanoic acid, 2-ethoxy-3- [4- / 2- (4-methanesulfonylaminophenyl) ethoxy / phenyl] propanoic acid,

N-cyano-2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanamide,

N-benzyloxy-2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanamide,

2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanamide, 2-ethoxy-3- [4- / 3- (3-methanesulfonyloxyphenyl) propoxy / phenyl] propanoic acid ethyl ester, 2 -ethoxy-3- [4- / 2- (4- (2-propanesulfonyloxy) phenyl] / ethoxy) phenyl] propanoic acid 3- [4- / 2- (4- (tert-butoxycarbonyl (methyl) amino)) phenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid, (S) -2-ethoxy-3- [4- / 2- (4- (methoxycarbonylamino) phenyl) ethoxy / phenyl] propanoic acid,

-29 »· • 4 4 4

• 4

4 4 4 ethyl 2-ethoxy-3- [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-methoxyphenyl] -2-ethoxypropanoic acid, methyl 3- [4- / 2- (4- tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid (S) -2-ethoxy-3- [4- / 2- (4- (phenylsulfonyl) phenyl / ethoxy) phenyl propane and, where applicable, their stereo- and optical isomers and racemates, as well as their pharmaceutically acceptable salts, solvates and crystalline forms.

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

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

When R ¹ represents an alkyl group, preferred alkyls are alkyl groups having from 2 to β carbon atoms.

When the substituent OR ^a represents an alkaryl group, the preferred alkaryl is benzyl.

* ·

-29 · · <. 29. 29...

• · · · · · · · · · · ·

As used herein, the term "pharmaceutically acceptable salts" is intended to include, but is not limited to, basic salts such as alkali metal, alkaline earth metal, aluminum, zinc and bismuth salts, ammonium salts, basic amino acid salts, and organic amine salts.

In the specification and the appended claims, a given chemical formula or name encompasses all its stereo- or optical isomers or racemates (except for Category A2 compounds), as well as mixtures of different proportions of the individual enantiomers where such isomers and enantiomers exist, as well as its pharmaceutically acceptable salts and solvates thereof, such as hydrates. Isomers may be resolved using conventional techniques such as chromatography or fractional crystallization. Enantiomers can be isolated by resolution of the racemate, for example, by fractional crystallization, resolution or HPLC. Diastereomers may be isolated by resolution of mixtures of isomers, for example, by fractional crystallization, HPLC, or flash chromatography. Alternatively, stereoisomers may be prepared by chiral synthesis from chiral starting materials under conditions that will not result in racemization or epimerization, or by derivatization with a chiral reagent. All stereoisomers are within the scope of this invention.

The following definitions apply throughout the specification and the appended claims.

Unless otherwise indicated or indicated, the term alkyl refers to a straight or branched, substituted or unsubstituted alkyl group having from 1 to 6;

4) 9 carbon atoms or a cyclic alkyl having from 3 to 6 carbon atoms. The term lower alkyl refers to 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 alkyl and lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight or branched pentyl and hexyl, as well as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Unless otherwise indicated or indicated, the term alkoxy refers to O-alkyl, wherein alkyl is as defined above.

Unless otherwise indicated or indicated, the term halogen atom means fluorine, chlorine, bromine or iodine.

Unless otherwise indicated or indicated, the term aryl refers to 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 indicated or indicated, the term substituted refers to an alkyl or aryl group as defined above that is substituted with one or more alkyls, alkoxy groups, halogen atoms, amino groups, thiols, nitro groups, hydroxy groups, acyls, aryl or cyano groups.

Unless otherwise indicated or indicated, the term alkaryl means

-31 y

- (C) -aryl

I ⁿ

Wherein n is an integer from 1 to 6 and

R ^r and R ¹ are identical or different and each represents a hydrogen atom or an alkyl or aryl group as defined above.

Unless otherwise indicated or indicated, the term "acyl" refers to a group

O

-CR ¹ where

R ¹ is hydrogen, alkyl, alkoxy, aryl and alkaryl as defined above.

Unless otherwise indicated and indicated, the terms "alkenyl and" alkynyl denote a straight or branched, substituted or unsubstituted unsaturated hydrocarbon group having one or more double or triple bonds and having a maximum of 6 carbon atoms, preferably 3 carbon atoms.

Unless otherwise indicated and indicated, the term "protecting groups (R ^p )" refers to a protecting group as described in the standard text "Protecting Groups in Organic".

-32 Synthesis, 2nd Edition (1991), Greene and Wuts. The protecting group may also be a polymeric resin, such as Wang's resin or 2-chlorotrityl chloride resin.

Methods of preparation

The compounds of this invention may be prepared as outlined below by any of the methods A to J. However, the invention is not limited to these methods, but the compounds may also be prepared as described in the prior art for structurally related compounds.

A. Compounds of the invention of formula I wherein R ² and R ⁴ are hydrogen may be prepared by a condensation reaction, such as a Knoevenagel or Wittig reaction, from a compound of formula II

with a general compound formulas III or IV R ¹ H ₂ C - COR III or and: L-P-CH-COR, 3/1.

IV ^L R ¹ in which formulas

D, D ', D, n, R, R ¹ and R ³ have the meaning as in category A and

L ² = L ³ are phenyl or

-33L ¹ = L ² are 0R ^d (where R ^d is as defined in category

A) a

L ³ is = O and, if desired, followed by reduction of the obtained double bond and deprotection.

Al. In the condensation step, approximately equimolar amounts of reagents are mixed in the presence of a base such as sodium acetate, piperidine acetate, LDA or potassium tert-butoxide to give a compound of formula I wherein A is an unsaturated moiety. This step may be carried out in the presence of an inert solvent or in the absence of a solvent, in which case the temperature must be sufficiently high to at least partially melt the reaction mixture, the preferred temperature being in the range of from 100 to 250 ° C.

It is sometimes necessary to add a dehydrating agent such as p-toluenesulfonic acid to achieve double bond formation.

In such a typical reaction, the aldehyde or ketone starting material and compound of formula III are combined in approximately equimolar amounts and a molar excess, preferably 1- to 5-fold, of anhydrous sodium acetate, and the mixture is heated to melt if necessary under vacuum. . The compound of formula (I) wherein A is an unsaturated moiety can then be isolated by mixing with water and acetone, followed by filtration of the formed precipitate. The crude product can, if desired, be purified, for example, by recrystallization or standard chromatographic techniques.

This reaction can also conveniently be carried out in a solvent such as toluene in the presence of piperidine acetate. The reaction mixture was maintained at reflux using a Dean-Stark trap to remove water. The solution is then cooled and the olefin product is isolated and purified by standard procedures.

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

A2. The reaction can also be carried out in the presence of titanium tetrachloride and pyridine in an inert solvent such as chloroform.

A3. The condensation step can also be performed as a Wittig-type reaction (cf. Comprehensive Organic Synthesis, Vol. 1, pp. 755-781, Pergamon Press) or according to the procedure described in the experimental section.

Approximately equimolar amounts of reagents II and IV are mixed in the presence of a base such as tetramethylguanidine or potassium carbonate in a 1- to 5-fold excess. This reaction can be carried out in the presence of an inert solvent such as dichloromethane or isopropanol, at a suitable temperature (-10 to +60 ° C) and for a sufficient time.

The compound of formula II is prepared by condensation of a compound of formula V

V with a compound of formula IV

D

VI in which formulas

D, D ', D, on R ³ have the meaning as in category A, for example under alkylation conditions or by Mitsunobu reaction (Tsunoda, Tetr. Lett., 34, 1639 - 1642 (1993)) if desired followed by treatment of D groups as described in the experimental section.

The group R ¹ may be -OH or a leaving group such as a halogen atom, a sulfonate or a trifluoromethanesulfonate.

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

Compounds of formula (III), (IV), (V) or (VI) are either commercially available or can be prepared by standard procedures known to those skilled in the art from commercial

• *

36 available starting materials or procedures described in the experimental section.

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

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

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

B. Compounds of the Invention of Formula I wherein A = -CR ³ R ⁴ -CR ¹ R ² -COR where R ⁴ is hydrogen may be prepared by reacting a carbonyl compound of Formula II

-37 · · · · · · · · · · · · · · · · · · · · · · · · · · ·

with a compound of formula VII

R ¹

AND

H-C-COR

Vil in which formulas

D, D ', D, n, R ¹ and R ³ are as in category A and R ² is alkyl, aryl or alkaryl, followed by dehydroxylation and, if necessary, deprotection.

In the reaction, a 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 boron trifluoride etherate.

The reaction may be carried out as described in the experimental section or by standard procedures known to those skilled in the art.

Compounds of formula (VII) are either commercially available or can be prepared by standard procedures.

C. Compounds of the invention of formula I wherein

• ·

9

A = CR ³ R ⁴ -CR ¹ R ² -COR, may be prepared by an alkylation reaction with a compound of formula VIII

where

X is a leaving group, such as a halogen atom, sulfonates or trifluoromethanesulfonates, with a compound of formula VII

R ¹

AND

H-C-COR

Welcome in which samples

D, D ', D, n, R, R ¹ , R ² , R ³ and R ⁴ are as in category A and, if desired, followed by deprotection.

In the alkylation step, a 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 for a suitable time. The reaction can be carried out as described 9

in examples or standard procedures known in the literature (Synth. Comm., 19 (788), 1167-1175 (1989)).

A compound of formula VIII can be prepared from an alcohol of formula IX

where

D, D ', D, n, R ³ and R ⁴ are as in Category A, using standard procedures or as described in the experimental section.

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

D. Compounds of the present invention of Formula I may be prepared by reacting a compound of Formula V 'CH ₂ d-4R

D * • 9

• 9 9 • 99

with a compound of formula X

HO in which samples

D, D ', · D, n, and A have the same meaning as in category A and

R ¹ is -OH or a leaving group such as a halogen atom, a sulfonate or a trifluoromethanesulfonate, either by an alkylation reaction or a Mitsunobu reaction, if necessary, by removing the protecting groups.

Compounds of formula X can be prepared according to Procedure A from commercially available starting materials and compounds of formula III or IV.

Dl. The leaving group R ¹ in the alkylation reaction may be a sulfonate such as mesylate, nosylate or tosylate, or a halogen atom such as bromine or iodine. Compounds of formula V and X, in approximately equimolar amounts or with an excess of one of the compounds, are heated to reflux 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 heated to reflux for a necessary period of time, usually from 0.5 to 24 hours, the working up usually involving filtration to remove the solid salt, evaporation and extraction with water and an organic solvent such as dichloromethane, ethyl acetate or diethyl ether.

The crude product is purified, if desired, e.g.

-41 ·· · »· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·. . . .

• ·. . ...

·· ·· ···· ·· ...

recrystallization or standard chromatographic procedures.

D2. The Mitsunobu reaction is carried out according to standard procedures.

In a conventional Mitsunobu reaction, a compound of formula V wherein R ¹ is hydroxy is mixed with a compound of formula X in approximately equimolar amounts or with an excess of one of the compounds in an inert solvent such as chloroform, dichloromethane or tetrahydrofuran. A slight molar excess of azodicarboxylate (1-4 equivalents) such as DEAD or ADDP and phosphine (1-4 equivalents) such as tributylphosphine or triphenylphosphine are added and the reaction mixture is stirred at a sufficiently high temperature, for example room temperature, and after sufficient for a long time (1 to 24 hours) to obtain a crude product which can be worked up according to standard literature procedures and, if desired, purified, eg, by standard chromatographic procedures.

E. Compounds of the Invention of Formula I wherein A = -CR ³ R ⁴ -CR ¹ R ² -COR wherein

R, R ² , R ³ and R ⁴ are as in category A and

R ¹ is -0R ^e , where R ^e is as in category A,

-0- [CH ₂ ] _m ^- 0R ^f , where m and R ^f are as in category A,

-OCONR ^and R ^c , where R ^a and R ^c have the meaning as in the category

A, can be prepared by converting a compound of formula XI

· 99 · © ·· · · · · · · · · · ·

999 999 9999

9 9 9 9 9 • ·· 99 9900 99

R ³ X

D

C - C - COR XI IIR ⁴ R ² in which

D, D ', D, n, R ² , R ² , R ³ and R ⁴ are as in category A and X is -OH followed, if necessary, by deprotection.

The reaction may be carried out as an alkylation reaction, a Mitsunobu reaction, an esterification reaction or a reaction with isocyanates. The alkylation reaction can be carried out using various alkylating agents, such as an alkyl halide.

The esterification reaction can be carried out using various acylating agents such as Cl-CO-R ^d (where R ^d is as in category A) and the Mitsunobu reaction can be carried out using an alcohol such as phenol. The reactions may be carried out according to procedures known to those skilled in the art or as described in the Examples.

A compound of formula XI can be prepared by reacting a compound of formula V ^^ [CH ₂ ] _n -CH ₂ -R '

0 'with a compound of formula XII • fl ··

XI!

Fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl Fl

D, D ', D, n, R, R ² , R ^3, and R ⁴ are as in category A and R ¹ is -OH or a leaving group such as halogen, sulfonate or trifluoromethanesulfonate, and X is

-OH, followed, if necessary, by deprotection.

The reaction may be carried out as described above or by standard procedures known to those skilled in the art.

The compound of formula (XII) may be prepared according to literature procedures from commercially available starting materials.

F. Compounds of formula I wherein A is CR ³ R ⁴ -CR ¹ R ² -COR and R, R ² , R ³ and R ⁴ are as in category A and R ¹ is -SR ^d , where R ^d has as defined in category A, can be prepared by reacting a compound of formula XIII

in which i

-44 9 C 9

999 · 9 · 90

99999 9 9 99 9

9 9 9 9 ·

999 9 0 99 999 · »

D, D ', D, n, R, R ² , R ³ and R ⁴ are as defined in category A and X' is a halogen atom, a thiol in a substitution reaction. The reaction may be carried out according to procedures known to those skilled in the art or described in the examples.

Compound (XIII) can be prepared according to Procedure D from either commercially available starting materials or starting materials prepared by standard procedures from commercially available starting materials.

G. Compounds of the Invention of Formula I wherein D is -OSO ₂ R ^d , -SR ^C , OCONR ^f R ^a , -NR ^c COOR ^d , -NR ^c COR ^a , NR ^c R ^d , -NR ^c CONR. ^and R ^k , NR ^c SO ₂ R ^d and -NR ^c CSNR ^and R ^k , where R ^a , R ^c , R ^d , R ^f , R ^g and R ^k are as in category A, may be prepared by reaction of a compound of the general formula of formula XIV

in which

D ', D, and A are as in category A and X ¹ = -OH,

-SH or -NR ^C H, with a suitable reagent such as a sulfonyl halide, isocyanate, acyl halide, chloroformate, anhydride or alkyl halide, in an inert solvent such as dichloromethane or toluene and, if necessary, in the presence of a base such as 4, triethylamine or pyridine, and optionally subsequent deprotection.

The reaction may be carried out according to procedures known to one skilled in the art or as described in the examples.

H. Compounds of formula I wherein R is -OH may be prepared from a compound of formula

I, where R is -OR ^p , where R ^p is. a protecting group such as an alkyl, aryl, alkaryl or polymeric resin such as a Wang resin or a 2-chlorotrityl chloride resin by removing the protecting group by hydrolysis. Hydrolysis can be accomplished by a field of standard procedures either under basic or acidic conditions.

I. A compound of this invention of formula I wherein R is -NR ^a R ^b, may be prepared from compounds of formula I wherein R is -OH with a compound HNR ^a R ^b in the presence of a peptide coupling system (e.g. EDC, DCC, HBTU, TBTU or PyBop or oxalyl chloride in DMF), a suitable base (e.g. pyridine, DMAP, TEA or DiPEA) and a suitable organic solvent (e.g. dichloromethane, acetonitrile or DMF) according to methods known to one skilled in the art or as described in the examples.

J. Compounds of this invention of formula I wherein D is -SO ₂ R ^d or -SOR ^d where R ^d is as defined in category A may be prepared by oxidation of a compound of formula XV,

D '

XV • 00 · 0

♦ ♦ 0

-46 in which

D ', D, and A are as in category A and X ² is -SOR ^d , where R ^d is as defined in category A, with oxidizing agents such as m-chloroperoxybenzoic acid or hydrogen peroxide in an inert solvent such as is dichloromethane, optionally followed by deprotection.

The reaction may be carried out according to standard procedures or as described in the experimental section.

The compounds of this invention can be isolated from their reaction mixtures using conventional procedures.

One skilled in the art will recognize that to obtain the compounds of this invention in an alternative and in some cases more convenient manner, the above steps may be performed in a different order in each process and / or the individual reactions may be performed in other steps of the overall process (ie chemical transformation). can be carried out on intermediates other than those associated with a particular reaction).

In any of the foregoing Preparations A to J, where necessary, hydroxy, amino or other reactive groups may be protected using the protecting group R ^p described in the standard text "Protective Groups in Organic Synthesis, 2nd Edition (1991), Greene and Wuts. The protecting group ^Rp may also be a resin, such as Wang's resin or 2-chlorotrityl-47 chloride resin. The deprotection and deprotection may take place before or after any of the reaction steps described above. Protecting groups may be removed according to procedures well known to those skilled in the art.

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

Pharmaceutical preparations

The compounds of this invention will usually be administered by oral, parenteral, intravenous, intramuscular, subcutaneous or other injection, buccal, rectal, vaginal, transdermal and / or nasal and / or inhalation routes, in the form of pharmaceutical compositions containing the active ingredient either as a free an acid or a pharmaceutically acceptable addition salt with an organic or inorganic base, in a pharmaceutically acceptable dosage form. Depending on the disorder and the patient to be treated and the route of administration, the compositions may be administered at various dosages.

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 atherosclerosis, such as hypertension, hyperlipidemia, dyslipidemia, diabetes and obesity.

Suitable dosages of the compounds of this invention for therapeutic use in humans are about 0.0001 to 100 mg / kg

Body weight, preferably 0.001 to 10 mg / kg body weight.

Accordingly, in a further aspect of the present invention there is provided a pharmaceutical composition comprising any of the compounds of the present invention or pharmaceutically acceptable derivatives thereof in admixture with pharmaceutically acceptable excipients, diluents and / or carriers.

Pharmacological properties

The present compounds of formula I are adapted for the prophylaxis and / or treatment of clinical conditions associated with reduced insulin sensitivity (insulin resistance) and accompanying metabolic disorders. These clinical conditions include, but are not limited to, abdominal obesity, arterial hypertension, hyperinsulinemia, hyperglycemia, non-insulin dependent diabetes mellitus (NIDDM), and dyslipidemia characteristic of insulin resistance. This dyslipidemia, also known as the atherogenic lipoprotein profile of phenotype B, is characterized by slightly elevated levels of unesterified fatty acids, elevated triglycerides of very low density lipoproteins (VLDL), low cholesterol levels of high density lipoproteins (HDL), and the presence of small, dense lipoproteins low density (LDL). Treatment with the present compounds is expected to reduce cardiovascular morbidity and atherosclerosis-related mortality. These cardiovascular disease states include macroangiopathy causing myocardial infarction, cerebrovascular disease, and peripheral arterial insufficiency at the extremities of the limbs. Due to its insulin sensitizing effect, the compounds of formula (I) are:

-49 suggests that it slows down the progress of clinical conditions associated with chronic hyperglycemia in diabetes such as microangiopathy causing renal disease and retinal damage. Furthermore, these compounds may be useful in the treatment of various conditions associated with insulin resistance outside the cardiovascular system, such as polycystic ovarian syndrome.

DETAILED DESCRIPTION OF THE INVENTION

¹ H NMR and ¹³ C NMR measurements were performed on BRUKER ACP 300 or Varian UNITY plus 400, 500 or 600 spectrometers operating at ¹ H 300, 400, 500 or 600 MHz and at ¹³ C 75, 100, 125 or 150 MHz.

Unless otherwise stated, chemical shifts are given in ppm with solvent as internal standard.

Example 1

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 warm to room temperature, then stirred at room temperature, followed by thin layer chromatography. The reaction mixture was filtered. The filtrate is washed with water, the phases are separated and the organic phase is dried

Sodium sulphate and evaporated in vacuo to give 28 g (yield).

%) Of 2- (4-methanesulfonyloxyphenyl) ethyl methanesulfonate.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.85 (s, 3H), 3.05 (t, 2H), 3.15 (s, 3H), 4.35 (s, 2H), 7 2 (dm, 2H); 7.23 (dm, 2H).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 34.8, 37.3, 69, 6, 122.2, 130.5,

135.8, 148.1.

(b) 4- [2- (4-Formylphenoxy) ethyl] phenyl methanesulfonate

2- (4-Methanesulfonyloxyphenyl) ethyl methanesulfonate (30 g, 0.102 mol) was dissolved in acetonitrile and slowly added to a mixture of p-hydroxybenzaldehyde (31.1 g, 0.253 mol) and potassium carbonate (41.46 g, 0.3 mol) ) in acetonitrile and held at reflux until 2- (4-methanesulfonyloxyphenyl) ethyl methanesulfonate was consumed. The salts are filtered off, the solvent is evaporated off under vacuum, dichloromethane is added. The organic phase was washed with water and evaporated. Purification by silica gel chromatography using dichloromethane as eluent gave 21.6 g (66% yield) of 4- [2- (4-formylphenoxy) ethyl] phenyl methanesulfonate.

¹ H-NMR (400 MHz, CDCl 3): δ 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).

¹³ C-NMR (100 MHz, CDCl 3): δ 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- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] acrylic acid ethyl ester

-51 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

To a solution of 4- [2- (4-formylphenoxy) ethyl] phenyl methanesulfonate (4.49 g, 14.0 mmol) and (1,2-diethoxy-2-oxoethyl) (triphenyl) phosphine chloride (5.62 g, 13, 1 mmol) in chloroform (50 mL) was slowly added tetramethylguanidine (1.73 g, 15.0 mmol) at 0 ° C. After stirring overnight at room temperature, the solvent was evaporated in vacuo. When diethyl ether was added to the residue, triphenylphosphine oxide began to crystallize as white crystals, which were filtered off.

The filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate in heptane (gradient 1.25 to 100%) as eluents. The crude product crystallizes on standing. Recrystallization yielded

2.18 g (35% yield) of 2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] acrylic acid ethyl ester as white crystals.

1 H-NMR (500 MHz, CDCl ₃ ): δ 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 = 7Hz), 4.2 (t, 2H, J = 6.8Hz), 4.28 (q, 2H, J = 7Hz), 6.87 (dm, 2H, J = 9Hz) , 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 ): δ 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 / phenyl] propanoic acid ethyl ester

2-Ethoxy-3- [4- / 2- (4-methane-52) • 9 9 9 9 9 9 9 9 ··· 9 9999 9 9 · 99 ·· · φ

99999 9 9 99 9 9 9 9 9 9 99 9999 99 9 sulfonyloxyphenyl) ethoxy / phenyl] acrylic acid (1.47 g, 3.38 mmol) was hydrogenated at atmospheric pressure in ethyl acetate (50 mL) for 3 h. ml) using palladium on carbon (0.74 g, 5%) as a catalyst. The reaction mixture was filtered through diatomaceous earth, dried over magnesium sulfate, and the solvent was evaporated in vacuo to give 1.44 g (98% yield) of 2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl ethyl ester. Propane.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.16 (t, 3H, J = 7 Hz), 1.23 (t,

3H, J = 7Hz), 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 (m, 1H), 3.94-3.98 (m, 1H), 4.12-4.19 (m, 4H), 6.8 (dm, 2H, J = 8.8

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, undifferentiated).

¹³ C-NMR (125 MHz, CDCl ₃ ): δ 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

2-Ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid

Lithium hydroxide hydrate (0.12 g, 2.82 mmol) dissolved in water (10 mL) was slowly added to a solution of 2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in Example 1d) (1.12 g, 2.56 mmol) 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.

-53 ♦ ·· ·· ·· · 4 · 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 · 44 43 4 ··· 44 ·

The residue was acidified with hydrochloric acid (2M) and extracted 3 times with ethyl acetate. The combined organic phases were dried over magnesium sulfate. Evaporation of the solvent gave 1 g (96% yield) of 2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl] propanoic acid.

1 H-NMR (500 MHz, CDCl 3): δ 1.17 (t, 3H, J = 7 Hz), 2,912.99 (m, 1H), 3.03-3.11 (m, 3H), 3, 12 (s, 3H), 3.39-3.47 (m, 1 H), 3.57-3.64 (m, 1 H), 4.01-4.06 (m, 1 H), 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, CDCl ₃ ): δ 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

N-Cyano-2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanamide

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) was added DCC ( 0.444 g, 2.15 mmol) and N-hydroxysuccinimide (0.247 g, 2.15 mmol) at 0 ° C. After stirring overnight at room temperature, the precipitate was filtered off 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 onto potassium bisulfate (1M, 20 mL) and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and the solvent was evaporated. Chromatography

-54 • 9 99 99 99 ·· · 9 9 ·· ••• 99 9 9 99 9

99 9999 99 9 crude product on silica gel using ethyl acetate: heptane: acetic acid (10: 10: 1) as eluent to give 0.755 g (yield 89%) of N-cyano-2-ethoxy-3- [4- (2 - (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanamide.

¹ H NMR (500 MHz, CD ₃ OD): δ 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 1H, 3.22 (m, 1H), 3.17 (s, 3H), 3.07 (t, J = 6.6Hz, 2H), 2.86 (dd, J = 13.9Hz) 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

N-Benzyloxy-2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl / ethoxy) phenyl] propanoamide

To a solution of 2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid (described in the example)

2) (1.65 g, 4.04 mmol) in acetonitrile (25 mL) at 0 ° C were added DCC (1 g, 4.85 mmol) and N-hydroxysuccinimidic acid (0.56 g, 4.85) mmol). After 1 hour, the precipitate was filtered off and diisopropylethylamine (1.82 g, 14.1 mmol) and benzylhydroxylamine (1.24 g, 8.08 mmol) dissolved in acetonitrile were 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 over magnesium sulfate. The solvent was evaporated and the crude product was purified by silica gel chromatography using ethyl acetate: heptane (gradient 10 to 100% ethyl acetate) as eluent to give 1.36 g (yield 66%) of N-benzyloxy-2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] -55 • fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.01 (t, 3H, J = 7.1 Hz), 2.822.90 (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, 1H).

¹³ C-NMR (100 MHz, CDCl 3): δ 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

2-Ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanamide

Mixtures of 2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid (described in the example)

2) (2.9 g, 7.1 mmol) and benzotriazol-1-yl-oxy-tris-pyrrolidine phosphonium hexafluorophosphate (3.7 g, 7.1 mmol) in DMF (30 mL) were bubbled with ammonia (gaseous) for 3 hours at room temperature. Water and ethyl acetate were added. The phases are separated, the organic phase is washed with water, dried over magnesium sulphate and the solvent is evaporated off under vacuum. The crude product was crystallized in diethyl ether to give 2.5 g (86% yield) of a white powder of 2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanamide.

¹ H-NMR (300 MHz, CDCl 3): δ 1.13 (t, 3H, J = 6.8 Hz), 2.802.90 (m, 1H), 3.05-3.14 (m, 6H), 3.36-3.56 (m, 2H), 3.84-56 9 9 9 9 9 9 9 9 9 99 99 9999 99

3.91 (m, 1H), 4.14 (t, 2H, J = 5 Hz), 5.38 (s broad, 1 NH) 6.42 (s broad, 1 NH), 6.80 (dm, 2H) J = 8.8 Hz, unresolved), 7.15 (dm, 2H, J = 8.8 Hz, unresolved), 7, ΙΟΙ, 27 (m, 2H), 7.34 (dm, 2H, J = 8.1 Hz, undifferentiated).

¹³ C-NMR (75 MHz, CDCl ₃ ): δ 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

2-Cyano-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] acrylic acid ethyl ester

A mixture of 4- [2- (4-formylphenoxy) ethyl] phenyl methanesulfonate (described in Example 1b) (2 g, 6.24 mmol), ethyl cyanoacetate (1.41 g, 12.48 mmol) and sodium acetate (1.34 g). (15.6 mmol) was heated to 120 ° C. The mixture, which melts on heating, is then allowed to cool. Dichloromethane was added, the solution was washed with water and brine. The organic phase was dried over sodium sulfate, filtered and the solvent was evaporated in vacuo. Chromatography of the crude product on silica gel using heptane: ethyl acetate (gradient 9: 1 to 1: 1) as eluent followed by crystallization gave 1.98 g (yield 77%) of 2-cyano-3- [4- / 2-] ethyl ester. (4-methanesulfonyloxyphenyl) ethoxy / phenyl] acrylic.

¹ H-NMR (400 MHz, CDCl 3): δ 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 = 9Hz, unresolved), 7.32 (dm, 2H, J = 9Hz, unresolved), 7.97 (dm, 2H, J = 9)

-57Hz, unresolved), 8.15 (s, 1H).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 14.2, 34.9, 37, 4, 62, 4, 68.6,

99.6, 115.2, 116.1, 122.1, 124.6, 130.5, 133.6, 137.3, 148.0, 154.3, 162.8, 163.1.

Example 7

2-Cyano-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester

A mixture of 2-cyano-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] acrylic acid ethyl ester (described in Example 6) (1.69 g, 4.07 mmol) and diethyl-1,4-dihydro The 2,6-dimethyl-3,5-pyridinedicarboxylate (2.06 g, 8.14 mmol) was slowly warmed to above 190 ° C under vacuum and then allowed to cool to room temperature. The crude product was purified by silica gel chromatography using heptane: ethyl acetate (gradient 2: 1 to 1: 1) as eluent to give 1.55 g (yield 91%) of 2-cyano-3- [4- / 2- (ethyl) ester. (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propane.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.17 (t, 3H, J = 7 Hz), 2,963.16 (m, 6H), 3.66-3.72 (m, 1H), 4 0.05 (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 (m, 4H), 7.25 (dm, 2H, J = 8.5 Hz, unresolved).

¹³ C-NMR (100 MHz, CDCl 3): δ 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- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid

A mixture of 2-cyano-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy) phenyl] propanoic acid ethyl ester (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 at room temperature for 30 min. 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 over sodium sulfate, filtered and evaporated in vacuo. The crude product was purified by crystallization in diisopropyl ether to give 0.56 g (yield 67%) of 2-cyano-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl] propanoic acid.

1 H-NMR (500 MHz, CDCl ₃ ): δ 3.02-3.3 (m, 7H), 3.7-3.8 (m,

1H), 4.15 (t, 2H, J = 6.7Hz), 6.8-6-9 (m, 2H), 7.15-7.27 (m, 4H), 7.27-7 4 (m, 2H); 8.67 (s, 1H, OH).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 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- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] acrylic acid

2-Cyano-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] acrylic acid ethyl ester (described in the example)

6) (0.201 g, 0.483 mmol), lithium hydroxide (0.04 g, 1.67

Mmol (2.3 mL) and water (2.3 mL) were stirred at 40 ° C for 23 h. Additional water was added, the methanol was removed by evaporation in vacuo and the mixture was acidified using magnesium bisulfate. The mixture was extracted with ethyl acetate and the organic phase was dried over sodium sulfate, filtered and evaporated in vacuo. The crude products were purified by preparative HPLC using acetonitrile (30-60% gradient): 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- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] acrylic acid and 21.8 mg of 2-cyano-3- [4- 2- (4-hydroxyphenyl / ethoxy) phenyl] acrylic.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 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).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 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

2- [4- / 2- (4-Methanesulfonyloxyphenyl / ethoxy) benzylidene] malonic acid dimethyl ester

To dry tetrahydrofuran (50.8 mL) was added a solution of titanium tetrachloride (4.82 g, 25.4 mmol) and carbon tetrachloride (6.33 mL) at 0 ° C under argon. To the mixture is added a solution of 4- [2- (4-formylphenoxy) ethyl] -60 9 9 9 9 99 0999 00 phenyl methanesulfonate ( described in Example 1b) (4.07 g,

12.7 mmol) in dry tetrahydrofuran (6.35 mL) followed by dimethyl malonate (1.68 mL, 12.7 mmol). Finally, pyridine (4.02 g, 50.8 mmol) in tetrahydrofuran (8.9 mL) 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 is washed with water and the aqueous phase is extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate, filtered and evaporated in vacuo to give 5.34 g (97% yield) of dimethyl 2- [4-] dimethyl ester.

- [2- (4-methanesulfonyloxyphenyl) ethoxy] benzylidene] malonic acid.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.12 (t, 2H, J = 7), 3.14 (s,

3H), 3.84 (s, 3H), 3.87 (s, 3H), 4.2 (t, 2H, J = 7Hz), 6.9 (dm, 2H, J = 9Hz, unresolved) 7.24 (dm, 2H, J = 9 Hz, unresolved), 7.31-7.41 (m, 4H), 7.7 (s, 1H).

¹³ C-NMR (100 MHz, CDCl 3): δ 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

2- [4- / 2- (4-Methanesulfonyloxyphenyl) ethoxy / benzyl] malonic acid dimethyl ester

2- [4- / 2- (4-Methanesulfonyloxyphenyl) ethoxy / benzylidene] malonic acid dimethyl ester (described in Example 10) (2.31 g, 5.32 mmol) was hydrogenated at atmospheric pressure in ethyl acetate (140 h) for 2.5 h. ml) and acetic acid (5 ml) using palladium on carbon (0.8 g) as a catalyst and then filtered through hyflo. Evaporate the solvent in vacuo, add dichloromethane and dilute hydrogen solution.

-61- Sodium carbonate and the phases are separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to give 2.35 g (yield 100%) of 2- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / benzyl] malonic acid dimethyl ester.

1 H-NMR (400 MHz, CDCl ₃ ): δ 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).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 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

2-Ethoxy-3- [3- (3- / 4-methanesulfonyloxyphenyl) propoxy / phenyl] propanoic acid ethyl ester (a) 3- (3-Benzyloxyphenyl) -2-ethoxyacrylic acid ethyl ester

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) was added slowly tetramethylguanidine (6.5 g, 56.6 mmol) was added at 0 ° C. After stirring overnight at room temperature, the solvent was evaporated in vacuo. Diethyl ether was added and the insoluble material was filtered off. The filtrate was washed with sodium bicarbonate solution, dried

The magnesium sulfate was filtered, and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography using tetrahydrofuran (0.5%) in dichloromethane as eluent. The remaining aldehyde was removed by stirring with sodium bisulfite in water and diethyl ether for 2 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.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.4 (m, 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).

¹³ C-NMR (75 MHz, CDCl ₃ ): δ 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) 2-Ethoxy-3- (3-hydroxyphenyl) propanoic acid ethyl ester

3- (3-Benzyloxyphenyl) -2-ethoxyacrylic acid ethyl ester (10.4 g, 31.8 mmol) was hydrogenated at atmospheric pressure in ethyl acetate using palladium on carbon (dry, 10%) as a catalyst. The reaction mixture was filtered through diatomaceous earth and the solvent was evaporated in vacuo. The starting material is not completely consumed, so the hydrogenation is repeated to give 7 g (92% yield) of 2-ethoxy-3- (3-hydroxyphenyl) propanoic acid ethyl ester.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 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).

¹³ C-NMR (75 MHz, CDCl ₃ ): δ 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) propyl methanesulfonate

3- (4-Methanesulfonyloxyphenyl) propyl methanesulfonate was synthesized using the same procedure as in Example 1a from 3- (4-hydroxyphenyl) -1-propanol.

1 H-NMR (400 MHz, CDCl ₃ ): δ 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, CDCl 3): δ 31.7, 32.1, 38.4, 38.5, 69.8,

123.2, 131.1, 140.9, 148.7.

(e) 2-Ethoxy-3- [3- (3- / 4-methanesulfonyloxyphenyl) propoxy / phenyl] propanoic acid ethyl ester

3- (4-Methanesulfonyloxyphenyl) propyl methanesulfonate (1.905 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 heated to reflux for 5 hours, then the solvent was evaporated in vacuo and water was added. The mixture was extracted twice with dichloromethane, dried over sodium sulfate, filtered and the solvent was evaporated in vacuo. Purification by silica gel chromatography eluting with diethyl ether / petroleum ether (gradient 33% to 100% diethyl ether) gave 1.80 g (yield 65%) of 2-ethoxy-3- [3- (3- / 4-methanesulfonyloxyphenyl) propoxy ethyl ester. [phenyl] propane.

-64 • · · · · · · · · · · · · 4 "· • · · · · ·· ···· ^X H-NMR (400 MHz, CDC1 _3): 8 1.17 (t, 3H, J = 7Hz), 1.24 (t, 3H, J = 7.3Hz), 2.05-2.14 (m, 2H), 2.84 (t, 2H, J = 7.5Hz) 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 = 6Hz), 4.0-4.05 (m,

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).

¹³ C-NMR (100 MHz, CDCl 3): δ 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- [3- (3- / 4-methanesulfonyloxyphenyl / propoxy) phenyl] ethyl ester propane (described in Example 12d) (0.889 g, 1.97 mmol) in tetrahydrofuran (9 mL). After stirring at room temperature for 5 hours, 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 (IM), and extracted with ethyl acetate and dichloromethane. The organic phases were combined, dried over sodium sulfate, filtered and the solvent was evaporated in vacuo to give 0.91 g of 2-ethoxy-3- [3- (3- (4-methanesulfonyloxyphenyl) propoxy / phenyl] propanoic acid.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.20 (t, 3H, J = 7.1 Hz), 2.052.15 (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 (m, 2H), 3.95 (t, 2H, J = 6.1

-65 • 9 9

99 9 9 9 • 9 9999

Hz), 4.09-4.14 (m, 1H), 6.77-6.81 (m, 2H), 6.82 (dm, 1H, J = 7.81 Hz, unresolved), 7,197.29 (m, 5 H).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 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

3 - [- 4- (2- / 4-Methanesulfonyloxyphenyl) ethoxy / phenyl] -2-methoxypropanoic acid methyl ester (a) 3- (4-Benzyloxyphenyl) -2-methoxypropanoic acid methyl ester

To a solution of 3- (4-benzyloxyphenyl) -2-hydroxypropanoic acid methyl ester (2.0 g, 6.98 mmol) in dry dichloromethane (20 mL) was added silver oxide (2.43 g, 10.5 mmol), molecular weight sieves (0.4 nm, 2 g) and methyl iodide (2.97 g,

20.9 mmol). The reaction mixture was maintained at reflux for 72 hours, filtered through diatomaceous earth and washed with water. The organic phase was dried (MgSO4) and evaporated in vacuo to give 1.93 g (92% yield) of 3- (4-benzyloxyphenyl) -2-methoxypropanoic acid methyl ester oil.

1 H-NMR (500 MHz, CDCl 3): δ 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, 2H, J = 8.6 Hz, unresolved), 7.29-7.35 (m, 1H), 7.35-7.40 (m, 2H), 7.407.43 (m, 2H) ).

-66 ··· ♦ ···· · · ·· ·····. . . .

(B) Methyl 3- (4-hydroxyphenyl) -2-methyl ester -methoxypropane

3- (4-Benzyloxyphenyl) -2-methoxypropanoic acid methyl ester (1.91 g, 6.36 mmol) was hydrogenated in methanol (30 mL) using palladium on carbon (5%, wet, 0.9 g) as a catalyst. The mixture was filtered through diatomaceous earth and the filtrate was evaporated in vacuo to give 1.16 g (87% yield) of 3- (4-hydroxyphenyl) -2-methoxypropanoic acid methyl ester.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 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 broad,

1OH), 6.77 (dm, 2H, J = 8.3 Hz, unresolved), 7.11 (dm, 2H, J = 8.3 Hz, unresolved).

(c) 3- [4- / 2- (4-Methanesulfonyloxyphenyl) ethoxy / phenyl] -2-methoxypropanoic acid methyl ester

3- (4-Hydroxyphenyl) -2-methoxypropanoic acid methyl ester is alkylated with 2- (4-methanesulfonyloxyphenyl) ethyl methanesulfonate (described in Example 1a) using the same procedure as in Example 1 (b) to give 3- [4- / 2-methyl ester] - (4-methanesulfonyloxyphenyl) ethoxy / phenyl] -2-methoxypropanoic acid.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 2.9-3.0 (m, 2H), 3.09 (t, 2H, J = 6.7 Hz), 3.13 (s, 3H) 3.34 (s, 3H), 3.72 (s, 3H), 3.903-95 (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, unresolved), 7.22 (dm, 2H, J = 8.6 Hz, unresolved),

7.33 (dm, 2H, J = 8.6 Hz, unresolved).

-61Example 15

3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] -2-methoxypropanoic acid

3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] -2-methoxypropanoic acid methyl ester (described in Example 14) was hydrolyzed using the same procedure as in Example 2 to afford 3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] -2-methoxypropanoic acid.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 2.91-2.99 (m, 1H), 3.03-3.10 (m, 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 (s broad, 1H).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 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, 1.482 mmol) was dissolved in dry dichloromethane (10 mL). Silver oxide was added

-68 ··· · ··· · · · 9 · ·

99999 9 9 99 9

9

999 99 99 9999 99 9 (1.717 g, 7.41 mmol) then hexyl iodide (0.943 g, 4.45 mmol) is added slowly. The reaction mixture was stirred at room temperature for 3 hours, then molecular sieves (0.4 nm) were added and the reaction mixture was stirred for 4 more days and then filtered. The solvent was evaporated and suctioned at 60 ° C for 5 hours to give 0.48 g (87% yield) of 3- (4-benzyloxyphenyl) -2-hexyloxypropanoic acid methyl ester.

³ H-NMR (400 MHz, CDCl ₃ ): δ 0.88 (t, 3H), 1.18-1.34 (m, 6H),

2H), 2.91-3.10 (m, 2H), 3.22-3.29 (m, 1H ) 1H), 3.72 (s, 3H); 3.95-4.02 (m, 1 H), 5, 05 / (dm, 2H, J = 8.8Hz , undifferentiated), 7, 16 (dm,

2H, J = 8.8 Hz, unresolved), 7.307.46 (m, 5H) ¹³ C-NMR (100 MHz, CDCl 3): δ 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,

129.6, 130.4, 137.1, 157.6, 173.0.

(b) 2-Hexyloxy-3- (4-hydroxyphenyl) propanoic acid methyl ester

2-Hexyloxy-3- (4-hydroxyphenyl) propanoic acid methyl ester was prepared from 3- (4-benzyloxyphenyl) -2-hexyloxypropanoic acid methyl ester in ethyl acetate using the same procedure as described in Example 14b.

¹ H-NMR (400 MHz, CDCl 3): δ 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 (s broad, 1H, OH).

-69 ·· ·· ·· ·· ·· · · · · · · ··· ····· ·· • · · · · · · ··· ·· "·· ···· · ¹³ · C-NMR (100 MHz, CDCl ₃ ): δ 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- (methyl) methyl ester 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propane

2-Hexyloxy-3- (4-hydroxyphenyl) propanoic acid methyl ester (0.33 g, 1.19 mmol) and 2- (4-methanesulfonyloxyphenyl) ethanol (0.2578 g, 1.19 mmol) were dissolved in dichloromethane ( 5 mL) under argon. Add azodicarbonyldipiperidine (0.451 g, 1.789 mmol) followed by the addition of triphenylphosphine (0.375 g, 1.423 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 an additional 18 hours and then filtered. The filtrate was washed with water, sodium bicarbonate solution, diluted with potassium hydrogen sulphate solution and brine, dried over sodium sulfate and evaporated. Chromatography of the residue on silica gel using heptane: ethyl acetate (2: 1 to 1: 1) as eluent gave 0.381 g (67% yield) of 2-hexyloxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] methyl ester. Propane.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.86 (t, 3H), 1.16-1.32 (m, 1.46-1.58 (m, 2H), 2.90-3 1.01 (m, 2H); 3.10 (t, 2H, J)

Hz), 3.14 (s, 3H), 3.21-3-28 (m, 1H), 3.5 J = 358 (m

3.72 (s, 3H), 3.95-4.0 (m, 1H), 4.15 (t, 2H, J = 6.8

6.81 (dm, 2H, J = 8.8 Hz, unresolved), 7.14 (dm, 2H,

6H), = 6.8, 1H), Hz),

J =

8.8 Hz, unresolved, 7.24 (dm, 2H, J = 8.3 Hz, unresolved), 7.35 (dm, 2H, J = 8.3 Hz, unresolved).

• 44 «44 4 4 4 4 4 4 4 4 '44 4 4 4 444 4 4 · 4 4 4 • 4 4 • 4 4 4 4 • 4 44 4 4 4444 • 4 4

ⁿ C-NMR (100 MHz, CDC1 _3): δ 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 / phenyl] propanoic acid

Lithium hydroxide hydrate (0.036 g, 0.85 mmol) dissolved in water (2.6 mL) was slowly added at room temperature to a solution of 2-hexyloxy-3- [4- (2- (4-methanesulfonyloxyphenyl) ethoxy) methyl ester. phenyl] propane (described in Example 16) (0.37g, 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 is acidified with potassium bisulfate (1M) until the pH is less than 2 and then extracted with ethyl acetate. The organic phase is washed with brine and dried. Evaporation to remove the solvent gave 0.349 g (97.5%) of 2-hexyloxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl] propanoic acid.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.88 (t, 3H, J = 6.8 Hz), 1.181.34 (m, 6H), 1.48-1.60 (m, 2H) 2.94-2.97 (m, 1H), 3.063.13 (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, 7.1 (dm, 2H, J = 8.8 Hz, unresolved), 7.24 (dm, 2H, J = 8.3 Hz, unresolved), 7.35 (dm, 2H, J) = 8.3Hz, undifferentiated).

ni · ··· · · · · · · · / * · · · · · ··· ·· ·· ·· ·· ···· · ¹³ C-NMR (100 MHz, CDC1 _3): δ 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

2-Ethoxy-3- [4- / 2- (3-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester (a) 2- (3-Methanesulfonyloxyphenyl) ethyl methanesulfonate

Methanesulfonyl chloride (9.09 g, 79.6 mmol) was slowly added to a solution of 3-hydroxyphenethyl alcohol (5 g, 36.2 mmol) and triethylamine (12.5 mL, 90.5 mmol) in dichloromethane at -10 ° C. The reaction mixture was stirred overnight at room temperature and then the solid material was filtered off. The filtrate was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, and the solvent was evaporated in vacuo to give 9.3 g (87% yield) of 2- (3-methanesulfonyloxyphenyl) ethyl methanesulfonate.

(b) 2-Ethoxy-3- [4- / 2- (3-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester

2-Ethoxy-3- [4- / 2- (3-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester was synthesized using the same procedure as in Example 1 (b) from 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (described in Example 20b) and 2- (3-methanesulfonyloxyphenyl) ethyl methanesulfonate.

Example 19

-72 • · · 0 0 0 ····· · · · · ·

9 9 0 · · ·· 99 9900 99 9

2-Ethoxy-3- [4- / 2- (3-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid

2-Ethoxy-3- [4- / 2- (3-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid was synthesized from 2-ethoxy-3- [4- / 2- (3-methanesulfonyloxyphenyl) ethoxy / phenyl] ethyl ester propane (described in Example 18) using the same procedure as in Example 2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.34 (m, 1H), 7.24 (m, 2H), 7.15 (m, 3H), 6.81 (d, J = 8, 6 Hz, 2H), 4.16 (t, J = 7 Hz, 2H), 4.03 (dd, J = 7.7 and 4.3 Hz, 1H), 3.61 (m, 1 Η), 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 = 7.0Hz, 3H).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 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

2-Ethoxy-3- [4- / 2- (2-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester (a) 2- (2-triethanesulfonyloxyphenyl) ethyl methanesulfonate

Methanesulfonyl chloride (9 g, 79 mmol) was slowly added to a stream 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 warm to room temperature and then poured onto a mixture of hydrochloric acid and ice. The phases are separated and the organic phase is washed with a solution

-73 9 9 9 9

Sodium chloride, dried and the solvent is evaporated. The residue crystallized on standing to give 9.4 g (89% yield) of 2- (2-methanesulfonyloxyphenyl) ethyl methanesulfonate.

¹ H NMR (300 MHz, CDCl ₃ ): δ 2.85 (s, 3H), 3.15 (t, 2H), 3.25 (s, 3H), 4.4 (t, 2H), 7, 2-7.35 (m. 4H).

¹³ C NMR (100 MHz, CDCl ₃ ): δ 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

3- (4-Benzyloxyphenyl) -2-ethoxyacrylic acid ethyl ester (described in Example 38a) (62 g, 0.19 mol) was hydrogenated in ethyl acetate (400 mL) at atmospheric pressure using palladium on carbon (10%) as a catalyst . The mixture was filtered through diatomaceous earth and evaporated in vacuo to give 45.6 g (100% yield) of 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester.

¹ H-NMR (600 MHz, CDCl ₃ ): δ 1.17 (t, 3H, J = 7Hz), 123 (t, 3H, J = 7Hz), 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 = 7Hz), 5.97 (s, 10H), 6.74 (dm, 2H, J = 8.5Hz, unresolved), 7.08 (dm, 2H, J = 8) , 5 Hz, undifferentiated).

¹³ C-NMR (125 MHz, CDCl ₃ ): δ 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- [4- / 2- (2-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester

-744 4 4 · 4 4 · 4 4 4 • · <· 4 · · 4 · · 4 4 ·· * · · 4

2-Ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester is alkylated with 2- (2-methanesulfonyloxyphenyl) ethyl methanesulfonate using the same procedure as in Example 1 (b) to give the ethyl ester of 2-ethoxy-3- [4 / 2- (2-methanesulfonyloxyphenyl) ethoxy / phenyl] propane.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.2 (2xt, 6H) 2.85 (d, 2H), 3.07 (m, 2H), 3.15 (s, 3H), 3.25 -3.38 (m, 1 H), 3.5-3.65 (m, 1 H), 3.9-4.0 (m, 1 H), 4.15 (m, 2 H), 6.77 (d) , 2H), 7.1-7.45 (unresolved m, 6H).

Example 21

2-Ethoxy-3- [4- / 2- (2-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid

2-Ethoxy-3- [4- / 2- (2-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in Example 20) is hydrolyzed using the same procedure as in Example 2 to give 2-ethoxy-3- [4- 2- (2-methanesulfonyloxyphenyl) ethoxy / phenyl] propane.

¹ H NMR (400 MHz, CDCl ₃ ): δ 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 (m, 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, Δ (t, J = 7.0 Hz, 3H).

¹³ C NMR (100 MHz, CDCl ₃ ): δ 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, O, 15.0.

-75 · · · · · · · · ·

Example 22

2-Ethoxy-3- [3- (2- / 4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester (a) 4- [2- (3-Formylphenoxy) ethyl] phenylmethanesulfonate

3-Hydroxybenzaldehyde is alkylated with 2- (4-methanesulfonyloxyphenyl) ethyl methanesulfonate (described in Example 1a) using the same procedure as in Example 1b to give 4- [2- (3-formylphenoxy) ethyl] phenyl methanesulfonate.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.12 (t, 2H, J = 6.7 Hz), 3.13 (s, 3H), 423 (t, 2H, J = 6.7 Hz) 7.13-7.18 (m, 1H), 7.227.26 (m, 2H), 7.32-7.38 (m, 3H), 7.40-7.47 (m, 2H), 9.95 (s, 1 H).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 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) 2-Ethoxy-3- [3- (2- / 4-methanesulfonyloxyphenyl) ethoxy / phenyl] acrylic

2-Ethoxy-3- [3- (2- / 4-methanesulfonyloxyphenyl) ethoxy / phenyl] acrylic acid ethyl ester was synthesized from 4- [2- (3-formylphenoxy) ethyl] phenyl methanesulfonate and (1,2-diethoxy-2- oxoethyl) (triphenyl) phosphonium chloride using the same procedure as in Example 1c.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.34 (2x, 6H, J = 7 Hz), 3,043.09 (m, 5H), 3.99 (q, 2H, J = 7 Hz), 4.15 (t, 2H, J = 7Hz), 4.27 (apparently q, 2H, J = 7Hz), 6.8-6.85 (m, 1H), 6.92

-76 • · · 4 4 44 • 44444 4 4 «4 4 • 4 4 4 4 4

444 44 44 4444 44 4 (s, 1 H), 7.1-7.25 (m, 3H), 7.28-7.33 (m, 3H), 7.39-7.42 (m,

1H).

¹³ C-NMR (100 MHz, CDCl 3): δ 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.

(b) 2-Ethoxy-3- [3- (2- / 4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester

2-Ethoxy-3- [3- (2- / 4-methanesulfonyloxyphenyl) ethoxy / phenyl] acrylic acid ethyl ester (3.69 g, 8.50 mmol) was hydrogenated at atmospheric pressure in ethyl acetate (70 mL) for 3.5 h. and acetic acid (0.5 mL) using palladium on carbon catalyst and then filtered through hyflo. The solvent is evaporated in vacuo, dichloromethane is added and the water phase is separated. The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to give 3.45 g (93% yield) of 2-ethoxy-3- [3- (2- / 4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester.

1 H-NMR (500 MHz, CDCl 3): δ 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 (with, 3H), 3,31-3,39 (m, 1H), 3.56-3.64 (m, 1 H), 3, 98-4.02 (m, 1H), 4,13-4,20 (m, 4H), 6.73-6.85 (m, 3H,) 3, 15-7,25 (m, 3H), 7.34 (dm, 2H, J = 8.6 Hz, undifferentiated)

¹³ C-NMR (100 MHz, CDCl 3): δ 14.2, 15.0, 35.1, 37.2, 39.3, 60.8, 68.0, 80.1, 112.7, 115, 6, 121.9 (overlapping signals), 129.2, 130.5, 138.0, 138.8, 147.8, 158.5, 172.5,

Example 23 ·· ... φφ φφ Φ · · · φ φ φ φ φ

2-Ethoxy-3- [3- (2- / 4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid

Lithium hydroxide hydrate (0.175 g, 4.18 mmol) in water (5 mL) was slowly added to a solution of 2-ethoxy-3- [3- (2- / 4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in of Example 22) (1.66 g, 3.80 mmol) in tetrahydrofuran (17 mL) at 0 ° C. After stirring at room temperature for 2 hours, 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 over sodium sulfate, filtered and the solvent was evaporated in vacuo to give 1.5 g (96.5% yield) of 2-ethoxy-3- [3- (2- / 4-methanesulfonyloxyphenyl) acid]. ethoxy / phenyl] propane.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.13 (t, 3H, J = 7 Hz), 2,912.98 (m, 1H), 3.03-3.09 (m, 3H), 3 10.09 (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, J = 7.5 Hz), 7.14-7.23 (m, 3H), 7.31 (dm, 2H,

J = 8.56 Hz, unresolved), 10.91 (s broad, 1H, OH).

¹³ C-NMR (125 MHz, CDCl ₃ ): δ 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

2-Ethoxy-3- [4- / 3- (3-methanesulfonyloxyphenyl) propoxy / phenyl] propanoic acid ethyl ester

-78 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · (A) 3- (3-Methanesulfonyloxyphenyl) propyl methanesulfonate

Methanesulfonyl chloride (4.77 g, 41.8 mmol) in dichloromethane (20 mL) is 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 was allowed to reach room temperature and the solid material was filtered off. The filtrate was washed with sodium bicarbonate solution (3 times) and brine, dried over magnesium sulfate and the solvent was evaporated in vacuo. Purification by silica gel chromatography using dichloromethane / methanol (gradient 0 to 8% methanol) afforded 4.22 g (yield 69%) of 3- (3-methanesulfonyloxyphenyl) propyl methanesulfonate.

1 H-NMR (300 MHz, CDCl ₃ ): δ 2.0 (m, 2H), 2.7 (t, 2H), 2.9 (s, 3H), 3.1 (s, 3H), 4, 15 (t, 2H), 7.06-7.15 (m, 3H), 7.27.3 (m, 1H).

¹³ C-NMR (75 MHz, CDCl 3): δ 30.3, 31.2, 37.3, 37.4, 68, 9,

119.8, 122.1, 127.6, 130.1, 143.0, 149.4.

(c) 2-Ethoxy-3- [4- / 3- (3-methanesulfonyloxyphenyl) propoxy / phenyl] propanoic acid ethyl ester

2-Ethoxy-3- (4-hydroxyphenylpropanoic acid ethyl ester (described in Example 20b) is alkylated with 3- (3-methanesulfonyloxyphenyl) propyl methanesulfonate using the same procedure as in Example 1 (b) to obtain 2-ethoxy-3- [ethyl ester] 4- [3- (3-ethanesulfonyloxyphenyl) propoxy] phenyl] propane.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.15 (t, 3H), 1.2 (t, 3H), 2.1 (quintet, 2H), 2.8 (t, 2H), 2 95 (d, 2H); 3.05 (s, 3H);

-79 ·· · ♦ ·· ·· · 9 · 9 9 9 9 • 999 9 9 ··· 9 9 · ··· «· ·

3.3-3.4 (m, 1H), 3.55-3.65 (m, 1H), 3.85-4.0 (m, 3H), 4.15 (q, 2H), 6, Δ (d, 2H), 7.1-7.22 (m, 5H), 7.35 (t, 1H).

¹³ C-NMR (75 MHz, CDCl 3): δ 14.2, 15.1, 30.6., 31.9, 37.2,

38.4, 60.8, 66.2, 66.5, 80.4, 114.2, 119.5, 122.0, 127.6,

129.3, 129.9, 130.4, 144.2, 149.4, 157.6, 172.5.

Example 25

2-Ethoxy-3- [4- / 3- (3-methanesulfonyloxyphenyl / propoxy) phenyl] propanoic acid

2-Ethoxy-3- [4- / 3- (3-methanesulfonyloxyphenyl) propoxy / phenyl] propanoic acid ethyl ester (described in Example 24b) was hydrolyzed using the same procedure as in Example 2 to give 2-ethoxy-3- [ 4- [3- (3-methanesulfonyloxyphenyl) propoxy] phenyl] propane.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.15 (t, 3H), 2.1 (quintet, 2H), 2.85 (t, 2H), 2.9-3.07 (m, 2H), 3.1 (s, 3H), 3.37-3.47 (m, 1H), 3.57-3.67 (m, 1H), 3.95 (t, 2H), 4.05 (m, 1H), 6.8 (d,

2H), 7.1-7.2 (m, 5H), 7.35 (t, 1H).

¹³ C-NMR (75 MHz, CDCl 3): δ 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-propanesulfonyloxy) phenyl) ethoxy / phenyl] propanoic acid ethyl ester (a) 3- [4- / 2- (4-Benzyloxyphenyl / ethoxy) ethyl ester -80 · · · 80 80 * * * * * 80 80 80 80 80 80 80 80 80 80 80 80 80 Phenyl] -2-ethoxypropanoic acid

Azodicarbonyldipiperidine (7.5 g, 30 mmol) was added to 2-ethoxy-3- (4-hydroxyphenyl) 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 overnight at room temperature, the solvent was evaporated in vacuo and diethyl ether was added. The solid material was filtered off after 1 hour and the filtrate was evaporated in vacuo. Purification by silica gel chromatography using ethyl acetate: dichloromethane as eluent gave 10 g (75% yield) of 3- [4- / 2- (4-benzyloxyphenyl / ethoxy) phenyl] -2-ethoxypropanoic acid ethyl ester.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.16-1.30 (m, 6H), 2.95 (d, 2H),

3.05 (t, 2H), 3.3-3.42 (m, 1H), 3.58-3.7 (m, 1H), 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).

¹³ C-NMR (75 MHz, CDCl 3): δ 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) 2-Ethoxy-3- [4- / 2- (4-hydroxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester

3- [4- / 2- (4-Benzyloxyphenyl / ethoxy) phenyl] -2-ethoxypropanoic acid ethyl ester (16 g, 35.6 mmol) was hydrogenated at atmospheric pressure in ethyl acetate (300 mL) using palladium on carbon (dry) , 10%) as a catalyst. The mixture is filtered through diatomaceous earth and

-8] • ······· · · · · · · · · · · · · · · · · · · · · · · · · · · · evaporate in vacuo to give 11.2 g (88% yield) of 2-ethoxy-3- [4- / 2- (4-hydroxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.1-1.30 (m, 6H), 2.9-3.05 (m,

4H), 3.3-3.45 (m, IH), 3,55-3, 70 (m, IH), 4.0 (m, 1H), 4.1 (t, 2H), 4.02 (q, 2H), 6.5 (p wide, 1OH) , 6.75-5.85 (m, 4H), 7.05-7.2 (m, 4H).

¹³ C-NMR (75 MHz, CDCl 3): δ 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 / phenyl] propanoic acid ethyl ester

Triethylamine (0.64 g, 6.28 mmol) was slowly added to a solution of 2-ethoxy-3- [4- / 2- (4-hydroxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester (1.5 g, 4.18) mmol) in dry dichloromethane (20 mL). After cooling to 0 ° C, isopropylsulfonyl chloride (0.9 g, 6.28 mmol) was added slowly. The reaction mixture was stirred at room temperature overnight, water was added and the mixture was extracted with dichloromethane. The organic phase was washed with hydrochloric acid (1M) and sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo to give 1.75 g (yield 90%) of 2-ethoxy-3- [4- / 2- (4- ( 2-propanesulfonyloxy) phenyl) ethoxy / phenyl] propane.

¹ H-NMR (500 MHz, CDCl ₃ ); 3H, J = 7Hz), 1.55 (d, 3.08 (t, 2H, J = 7Hz), 1H), 3.55-3.64 (m, IH), δ 1.16 ( t, 3H, J = 7Hz), 1.22 (t, 6H, J = 6.7Hz), 2.92-2.96 (m, 2H), 3.31-3.38 (m, 1H) ), 3.41-3.50 (m, 3.94-3, 98 (m, 1H), 4.11-4-19 (m,

-82 • fl • fl fl • fl fl fl

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, 2H, J = 8.6 Hz, unresolved).

Example 27

2-Ethoxy-3- [4- / 2- (4- (2-propanesulfonyloxy) phenyl) ethoxy / phenyl] propanoic acid

2-Ethoxy-3- [4- / 2- (4- (2-propanesulfonyloxy) phenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in Example 26) was hydrolyzed using the same procedure as in Example 2 to obtain 2-ethoxy acid -3- [4- / 2- (4- (2-propanesulfonyloxy) phenyl) ethoxy / phenyl] propane.

T-NMR (500 MHz, CDCl ₃ ): δ 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 (m, 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, unresolved), 7.96 (s broad, 1H).

¹³ C-NMR (125 MHz, CDCl ₃ ): δ 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, 157.5, 175.7.

Example 28

2-Ethoxy-3- [4- / 2- (4- (4-nitrobenzenesulfonyloxy) phenyl) ethoxy / phenyl] propanoic acid ethyl ester

2-Ethoxy-3- [4- / 2- (4-hydroxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in the example)

26b) is esterified with 4-nitrobenzenesulfonyl chloride using the same procedure as in Example 26 (c) to give 2-ethoxy-3- [4- / 2- (4- (4-nitrobenzenesulfonyloxy) phenyl) ethoxy / phenyl] propanoic acid ethyl ester.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.16 (t, 3H, J = 7 Hz), 1.23 (t,

3H, J = 7Hz), 2.92-2.97 (m, 2H), 3.05 (t, 3H, J = 5.5Hz),

3.30-3.39 (m, 1H), 3.54-3.65 (m, 1H), 3.93-3.99 (m, 1H),

4.12 (t, 2H, J = 6.8Hz), 4.16 (q, 2H, J = 7Hz), 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).

Example 29

2-Ethoxy-3- [4- / 2- (4- (4-nitrobenzenesulfonyloxy) phenyl) ethoxy / phenyl] propanoic acid

2-Ethoxy-3- [4- / 2- (4- (4-nitrobenzenesulfonyloxy / phenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in Example 28) was hydrolyzed according to the same procedure as in Example 2 to give 2-ethoxy-3 acid. - [4- (2- (4- (4-Nitrobenzenesulfonyloxy / phenyl) ethoxy) phenyl] propane.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.16 (t, 3H, J = 7 Hz), 2,913.01 (m, 1H), 3.01-3.08 (m, 2H), 3 , 37-3.45 (m, 1H), 3.583.66 (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 H2, unresolved) 7.23 (dm, 2H, J = 8.6 Hz, unresolved), 8.02 (dm, 2H, J = • ·

9.1 Hz, unresolved), 8.34 (dm, 2H, J = 9.1 Hz, unresolved), 9.56 (s broad, 1H).

¹³ C-NMR (125 MHz, CDCl ₃ ): δ 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

2-Ethoxy-3- [4- / 2- (4-phenylmethanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester

2-Ethoxy-3- [4- / 2- (4-hydroxy-phenyl) -ethoxy / -phenyl] -propanoic acid ethyl ester (described in Example 26b) (0.54 g, 1.5 mmol) was dissolved in dichloromethane (15 mL) and added. triethylamine (0.23 g, 0.31 mL, 2.25 mmol). 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 stirred overnight. Water was added, the organic layer was separated and the aqueous phase was extracted with dichloromethane. The organic phase is washed with hydrochloric acid (1 Μ), a stream of sodium bicarbonate and sodium chloride. Drying over sodium sulfate and evaporation gave a light yellow oil.

The crude product was purified by flash chromatography on silicate. The compound was eluted with heptane: ethyl acetate (9: 1 followed by 1: 1). The pure fractions were combined and evaporated to give 0.55 g (71%) of 2-ethoxy-3- [4- (2- (4-phenylmethanesulfonyloxyphenyl) ethoxy) phenyl] propanoic acid ethyl ester.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 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 (m,

1H), 3.98 (t, 1H), 4.14 (t, 2H), 4.19 (q, 2H), 4.52 (s, 4)

-852H), 6.82 (d, 2H), 7.08 (d, 2H), 7.17 (d, 2H), 7.29 (d, 2H),

2H), 7.40-7.53 (m, 5H).

¹³ C-NMR (75 MHz, CDCl ₃ ): δ 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.

Example 31

2-Ethoxy-3- [4- / 2- (4-phenylmethanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid

2-Ethoxy-3- [4- / 2- (4-phenylmethanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in Example 30) (0.21 g, 0.41 mmol) was dissolved in tetrahydrofuran (4 mL) and Lithium hydroxide (0.021 g, 0.48 mmol) 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 over magnesium sulfate and evaporation gave 0.184 g (92%) of 2-ethoxy-3- [4- / 2- (4-phenylmethanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid as an oil.

1 H-NMR (500 MHz, CDCl ₃ ): δ 1.20 (t, 3H), 2.94-3.01 (dd,

1H), 3.06-3.11 (m, 3H), 3.41-3.52 (m, 1H), 3.58-3.69 (m, 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 ): δ 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

2-Ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] butanoic acid ethyl ester (a) 3- (4-Benzyloxyphenyl) -2-ethoxy-3-methacrylic acid ethyl ester

LHMDS (11 mL, 11 mmol, 1 M 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 was stirred for 1.5 hours and then allowed to warm to 2 ° C. 1- (3-Benzyloxyphenyl) ethanone (2.3 g, 10 mmol) dissolved in tetrahydrofuran was added slowly and the resulting mixture was stirred at room temperature overnight. 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 was evaporated in vacuo. Double purification by chromatography using ethyl acetate: heptane as eluent afforded 0.6 g (yield 18%) of 3- (4-benzyloxyphenyl) -2-ethoxy-3-methylacrylic acid ethyl ester as a mixture of Z and E isomers, which was purification used in the next step.

Major isomer ¹ H-NMR (500 MHz, CDCl ₃ ): δ 0.99 (t, 3H, J = 7 Hz), 1.37 (t, 3H, J = 7 Hz), 2.13 (s, 3H) ), 3.88 (q, 2H, J = 7Hz), 4.0 (q, 2H, J = 7Hz), 5.11 (s, 2H), 6.94 (dm, 2H, J = 9) Hz, unresolved), 7.11 (dm, 2H, J = 9 Hz, unresolved), 7.337.50 (m, 5H).

(b) 3- (4-Hydroxyphenyl) -2-ethyl ester

Μ

-87 ···· ethoxybutane

3- (4-Benzyloxyphenyl) -2-ethoxy-3-methyl-acrylic acid ethyl ester (1.58 g, 4.64 mmol) was hydrogenated at atmospheric pressure in ethyl acetate (20 mL) using palladium on carbon (wet) as a catalyst. After filtration through diatomaceous earth, the solvent was evaporated in vacuo to give (1.1 g, 94% yield) of 3- (4-hydroxyphenyl) -2-ethoxybutanoic acid ethyl ester as a mixture of diastereomers.

Major isomer 1 H-NMR (500 MHz, CDCl ₃ ): δ 1.77 (t, 3H, J = 7 Hz), 1.25 (t, 3H, J = 7 Hz), 1.32 (d, 3H, J = 7Hz), 3.17 (quintet, 1H, J = 7Hz), 3.29-3.38 (m, 1H), 3.60-3.68 (m, 1H), 3, 88-3.92 (m, 2H), 4.18 (q, 2H, J = 7Hz), 5.2 (s broad, 1H), 6.716.77 (m, 2H), 7.11-7, 16 (m, 2 H).

(c) 2-Ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] butanoic acid ethyl ester

3- (4-Hydroxyphenyl) -2-ethoxybutanoic acid ethyl ester is alkylated with 2- (4-methanesulfonyloxyphenyl) ethyl methanesulfonate (described in Example 1a) using the same procedure as in Example 1 (b) to obtain 2-ethoxy-3- ethyl ester [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] butane as a mixture of diastereomers.

Major isomer ¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.15 (t, 3H, J = 7 Hz), 1.24 (t, 3H, J = 7 Hz), 1.31 (d, 3H) , J = 7 Hz), 2.99-3.20 (m, 6H).

-88 ·· ··· «

3.28-3.35 (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, undifferentiated).

Example 33

2-Ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] butanoic acid

2-Ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] butanoic acid ethyl ester (described in Example 32) is hydrolyzed using the same procedure as in Example 2 to give 2-ethoxy-3- [ 4- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl] butane as a mixture of diasteromers.

Major isomer ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.20 (t, 3H, J = 8 Hz), 1.37 (d, 3H, J = 7.2 Hz), 3.06-3 15 (m, 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): δ 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) phenyl] propanoic acid (a) 4- (2-Benzyloxyphenyl) -3-buten-1-ol

2-Benzyloxybenzaldehyde (8 g, 37 mmol), (3-hydroxypropyl) triphenylphosphonium bromide (19.5 g, 47 mmol) and potassium carbonate (6.6 g, 48 mmol) were combined in isopropanol. The reaction mixture was maintained at reflux overnight, then filtered and the filtrate was evaporated. Chromatography using ethyl acetate: dichloromethane (up to 5%) as eluent afforded 8.4 g (87.6%) of 4- (2-benzyloxyphenyl-3-buten-1-ol). - (2-Benzyloxyphenyl) -3-buten-1-ol.

¹ H-NMR (300 MHz, CDCl ₃ ) major isomer: δ 1.9-2.05 (b, 1H, OF ~, 2.43-2.6 (m, 2H), 3.7-3.8 (m, 2H), 5.2 (s, 21H), 6.26.3 (m, 1H), 6.85-7.5 (m, 10H, unresolved).

¹ H-NMR (300 MHz, CDCl 3) minor isomer: δ 1.9-2.05 (b, 1H, OH), 2.43-2.6 (m, 2H), 3.7-3.8 ( m, 2H), 5.2 (s, 2H), 5.75.8 (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 was hydrogenated in ethanol using the same procedure as in Example 20b.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 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 (s broad, 1H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 26, 4, 29, 6, 31.5, 62.8, 115, 6, 120.5, 127.1, 128.8, 130.3 , 154.0.

(c) 4- (2-Methanesulfonyloxyphenyl) butyl methanesulfonate

4- (2-Methanesulfonyloxyphenyl) butyl methanesulfonate was synthesized from 4- (2-hydroxyphenyl) butanol using the same procedure as in Example 18a.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 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 ): δ 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- [4- (4- / 2-methanesulfonyloxyphenyl / butoxy) phenyl] propanoic acid ethyl ester

2-Ethoxy-3- [4- (4- (2-methanesulfonyloxyphenyl / butoxy) phenyl] propanoic acid ethyl ester was synthesized using the same procedure as in Example 1b from 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester ( described in Example 20b) and 4- (2-methanesulfonyloxyphenyl) butyl methanesulfonate.

(e) 2-Ethoxy-3- [4- (4- / 2-methanesulfonyloxyphenyl / butoxy) phenyl] propanoic acid

2-Ethoxy-3- [4- (4- (2-methanesulfonyloxyphenyl / butoxy) phenyl] propanoic acid ethyl ester (2.7 g, 5.8 mmol) was dissolved in tetrahydrofuran: water (1: 3, 100 mL). Add lithium hydroxide (0.36 g, 8.7 mmol) dissolved

-9] in a small amount of water. The reaction 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 is extracted with sodium hydroxide solution (1M, 30 ml). The aqueous phase was cooled, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated to give 2 g (79% yield) of 2-ethoxy-3- [4- (4- (2-methanesulfonyloxyphenyl / butoxy) phenyl] propanoic acid.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.2 (t, 3H), 1.86 (tn, 4H), 2.81 (t, 2H), 2.94-3.0 (m, 1H), 3.06-3.11 (m, 1H), 3.2 (s, 3H), 3.43-3.48 (m, 1H), 3.6-3.65 (m, 1H) 4.0 (t, 3H), 4.95 4.08 (m, 1H), 6.84 (d, 2H), 7.17 (d, 2H), 7.25-7.28 (m,

2H), 7.32-7.35 (m, 2H).

¹³ C-NMR (100 MHz, CDCl 3): δ 152, 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- (methylsulfonyloxyphenyl) ethoxy] -2-nitrophenyl] propanoic acid methyl ester (a) 3- (4-Benzyloxy-2-nitrophenyl) -2-oxopropanoic acid

Potassium ethoxide (505 g, 6 mol) was added to a solution of ethanol (710 mL) and diethyl ether (4.8 L) and the mixture was cooled to 0 ° C. 4- (Benzyloxy) -1-methyl-2-nitrobenzene (639.8 g, 3 mol) dissolved in diethyloxalate (900 g, 6.16 mol) and toluene (1500 mL) were added slowly over 30 minutes.

• ·

The reaction mixture was stirred at 0 ° C for 3 hours and then allowed to stand overnight. After 5 days at room temperature, the reaction mixture was filtered and the filter cake was washed with diethyl ether (2 L). The cake was then treated with water (10 L), sodium hydroxide solution (5 M, 0.8 L) and extracted 3 times with diethyl ether (3 x 3 L). The aqueous phase was cooled and acidified with hydrochloric acid: water (1: 1, 0.9 L) in two steps with stirring. First, to a pH of 5, the reaction mixture is then stirred for 1 hour before acidification continues to pH 2. The reaction mixture is cooled in an ice: sodium chloride bath. Filtration after 1 hour gave 849.5 g (89.8%) of 3- (4-benzyloxy-2-nitrophenyl) -2-oxopropanoic acid.

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 4.33 (s, 2H), 5.21 (s, 2H), 7.32-7.36 (m, 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

3- (4-Benzyloxy-2-nitrophenyl-2-oxopropanoic acid (40 g, 0.127 mol) was dissolved in methanol (300 mL) and hydrochloric acid (conc., 10 mL) was added with stirring. The mixture was heated to reflux for 5 hours and then evaporated to dryness, dichloromethane and water were added and the phases were separated. to give 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, CDCl 3): δ 3.93 (s, 3H), 4.46 (s, 2H), 5.14 (s, 2H), 7.22 (broad, 2H), 7, 36-7.45 (m, 5H); 7.79 (s, 1H).

(c) 3- (4-Benzyloxy-2-nitrophenyl) -2-hydroxypropanoic acid methyl ester

3- (4-Benzyloxy-2-nitrophenyl) -2-oxopropanoic acid methyl ester (4.1 g, 12.4 mmol) was dissolved in methanol (60 mL). Sodium borohydride (0.5 g, 13.12 mmol) was added portionwise with stirring. TLC (silica gel, ethyl acetate: heptane, 1: 1) after one hour showed the remaining starting material and formation of the byproduct. The reaction mixture was then cooled in an ice bath and additional sodium borohydride (0.2 g, 5.26 mmol) was added. The mixture was then stirred at 0 ° C until the starting 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 is washed with brine and dried over magnesium sulphate 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 oil product.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.86 (d, J = 6Hz, 1H, OH), 3.12 (dd, J = 14.8Hz, 1H), 3.47 (dd) J = 14.4 Hz (1H), 3.79 (s, 3H), 4.45-4.51 (m, 1H), 6.10 (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), 7.54 (d, J = 2) (7 Hz, 1H).

(d) 2-Ethoxy-3- (4-benzyloxy-2-nitrophenyl) propanoic acid methyl ester

-94 • i · 2 .......

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Dissolve 3- (4-benzyloxy-2-nitrophenyl) -2-hydroxypropanoic acid methyl ester (1.86 g, 5.6 mmol) in dichloromethane (24 mL). Were added molecular sieves (1,0.10 ^-7 m, 1.9 g). Then, with stirring, silver oxide (1.96 g, 8.4 mmol) is added, followed by the addition of iodoethane (1.63 mL,

20.4 mmol). After stirring at room temperature for 6 days, the reaction was not complete by TLC, so additional silver oxide and iodoethane were added. The reaction mixture was stirred for 3 more days, then filtered through diatomaceous earth and the filtrate was evaporated to dryness. Chromatography of the crude product on silica gel using a gradient of ethyl acetate in heptane as eluent gave 1.6 g of an oil (80% yield) of 2-ethoxy-3- (4-benzyloxy-2-nitrophenyl) propanoic acid methyl ester.

@ ¹ H-NMR (400 MHz, CDC1 _3): δ 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 = 8.5 Hz) 1H), 7,36-7 45 (m, 5H), 7.55 (d , J = 2.5 Hz, 1H).

(e) 2-Ethoxy-3- (4-hydroxy-2-nitrophenyl) propanoic acid methyl ester

2-Ethoxy-3- (4-benzyloxy-2-nitrophenyl) propanoic acid methyl ester (1.5 g, 4.06 mmol) was dissolved in dichloromethane (8 mL) and dimethylsulfide (8 mL) was added. Boron trifluoride diethyl etherate (5.0 mL, 40.6 mmol) was added with stirring. The reaction mixture was stirred at room temperature for 4 hours and then poured into water and additional dichloromethane was added.

The phases were separated and the organic phase was washed with water and brine and dried over magnesium sulfate. Evaporation to remove the solvent gave 1.04 g (95% yield).

2-Ethoxy-3- (4-hydroxy-2-nitrophenyl) propanoic acid methyl ester.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.15 (t, J = 7 Hz, 3H), 3.26 (dd, 1H), 1H), 1H),

J = 14, 7.5 Hz, 1H), 3.34-3.42 (m, 2H), 3.58-3.66 (m,

3.77 (s, 3H), 4.19 (dd, J = 7.5, 5.5 Hz, 1H), 6.38 (s, 6.96 (dd, J = 8.5, 2.5) Hz, 1H /, 7.22 (d, J = 8.5 Hz, 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 (1.04 g, 3.86 mmol), and potassium carbonate (1.07 g, 7.75 mmol) was combined in acetonitrile (approximately 100 mL). The reaction mixture was heated to reflux for 6 hours and was incomplete by TLC. Another portion of 2- (4-methanesulfonyloxyphenyl) 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 are separated and the organic phase is washed with brine, dried over magnesium sulphate and evaporated. Chromatography of the crude product on silica gel with ethyl acetate / heptane as eluent gave 1.47 g (81% yield) of 2-ethoxy-3- [4- / 2- (4-methylsulfonyloxyphenyl) ethoxy] -2-nitrophenyl] propanoic acid methyl ester .

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.12 (t, J = 7 Hz, 3H), 3.14 (t,

J = 7Hz, 2H), 3.16 (s, 3H), 3.21 (dd, J-14, 8Hz, 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); 06 (dd, J

-964 ·· = 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,

Example 36

2-Ethoxy-3- [4- / 2- (4-methylsulfonyloxyphenyl / ethoxy) -2-nitrophenyl] propanoic acid

2-Ethoxy-3- [4- / 2- (4-methylsulfonyloxyphenyl) ethoxy-2-nitrophenyl] propanoic acid methyl ester (described in Example 35) (0.8 g, 1.71 mmol) was dissolved in tetrahydrofuran (8 mL). A solution of lithium hydroxide monohydrate (0.086 g, 2.05 mmol) in water (8 mL) was added with stirring, and the reaction mixture was stirred at room temperature for 5 hours, then evaporated to remove tetrahydrofuran and extracted with diethyl ether, acidified to pH. The organic phase was washed with water and brine and dried over magnesium sulfate, and the solvent was evaporated to give 0.72 g (93% yield) of 2-ethoxy-3- acid. [4- / 2- (4-methylsulfonyloxyphenyl) ethoxy] -2-nitrophenyl] propane.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 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, 1Ή),

3.36-3.43 (m, 1H), 3.48 (dd, J = 14.5 Hz, 1H), 3.59-3.66 (m, 1H), 4.15 (dd, J = 8.5 Hz (1H), 422 (t, J = 6.5 Hz,

2H), 7.06 (dd, J = 8.5, 2.5 Hz, 1H), 7.25 (d, J = 8.5 Hz,

2H), 7.30 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.5 Hz, 2H) and 7.43 (d, J = 2.5 Hz, 1H) .

-97 ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 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 (2C), 134.33, 137.29, 147.94, 150.22, 157.93 and 175.41.

Example 37

2-Ethoxy-3- [4- / 2- (3-methoxy-4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid (a) 2-Ethoxy-3- [4- / 2- (3-methoxy-4methanesulfonyloxyphenyl) ethyl ester ethoxy / phenyl] propane

2- [3-Methoxy-4- (methylsulfonyloxy) phenyl] ethyl methanesulfonate (described in WO 98/57941) (1.6 g, 4.9 mmol) was dissolved in acetonitrile. Potassium carbonate (1 g, 7.2 mmol) was added, followed by the addition of 2-ethoxy-3- (4-hydroxyphenyl) popanoic acid ethyl ester (described in Example 20b) (1 g, 4.2 mmol). 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 is dried over sodium sulphate and evaporated. NMR showed formation of the corresponding styrene product and the reaction was incomplete, so the crude product was redissolved in acetonitrile and additional 2- [3-methoxy-4- (methylsulfonyloxy) phenyl] ethyl methanesulfonate (0.5 g, 1.5) was added. mmol). The mixture was refluxed for a further 2 hours and then evaporated. The residue was redissolved in diethyl ether and washed with water. The organic phase is dried over magnesium sulphate and evaporated. Chromatography of the crude product gave 1 g of a mixture which, according to NMR, contained 60% (0.68 g, 34.7% yield) of 2-ethoxy-3- [4- / 2- (3-methoxy-98) ethyl ester. · · · · · · · · ·

4-methanesulfonyloxyphenyl) ethoxy / phenyl] propane and 40% (0.32 g) of 2- [3-methoxy-4- (methylsulfonyloxy) phenyl] ethyl methanesulfonate. This mixture was used in the next step without further purification.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 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 (m, 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 / phenyl] propanoic acid

2-Ethoxy-3- [4- / 2- (3-methoxy-4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester was hydrolyzed using the same procedure as in Example 3 to give 2-ethoxy-3- [4- (2- (3-methoxy-4-methanesulfonyloxyphenyl) ethoxy) phenyl] propane.

¹ H-NMR (600 MHz, CDCl ₃ ): δ 1.16 (t, 3H), 2.92-2.97 (m, 1H), 3.30-3.09 (m, 3H), 3, 16 (s, 3H), 3.39-3.45 (m, 1H), 3.573.63 (m, 1H), 3.87 (s, 3H), 4.01-4.05 (m, 1H) , 4.15 (t,

2H), 6.81 (d, 2H, J = 7.8Hz), 6.87 (d, 1H, J = 7.8Hz),

6.93 (s, 1 H), 7.15 (d, 2 H, J = 7.8 Hz), 7.22 (d, 1 H, J =

7.8 Hz).

¹³ C-NMR (150 MHz, CDCl ₃ ): δ 15.2, 35.9, 67.0, 68.4, 79.9, 114.0, 114.6, 121.7,

137.2, 139.3, 151.4, 157.8, 176.0.

38.0, 38.4, 56.2, 124.6, 129, 1, 130.8,

Example 38

-99 • · · · · · · ·

3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid ethyl ester (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 mol) dissolved in chloroform (800 mL) at 0 ° C. After stirring overnight at room temperature, the reaction mixture was stirred at room temperature. 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 solution and dried over magnesium sulfate. The procedure was repeated once and then the crude product was stirred overnight with saturated aqueous sodium bisulfite solution. The solid material was filtered off, the product was extracted with diethyl ether, dried over magnesium sulfate and the solvent was evaporated in vacuo to give 85 g (yield 73%) of 3- (4-benzyloxyphenyl) -2-ethoxyacrylic acid ethyl ester.

¹ H-NMR (300 MHz, CDCl 3): δ 1.35 (m, 6H), 4.0 (q, 2H), 4.3 (q, 2H), 5.05 (s, 2H), 6, 95 (s + m unresolved, 1 + 3H), 7.37.45 (m, 5H), 7.75 (d, 2H).

¹³ C-NMR (125 MHz, CDCl ₃ ): δ 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

-íoo ··· · * · · ·· «

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 overnight at room temperature, the solvent was evaporated in vacuo to give 8 g (yield 94%) of 4- (2-hydroxyethyl) phenylcarbamic acid tert-butyl ester.

1 H-NMR (400 MHz, DMSO-d ₆ ): δ 1.5 (s, 9H), 2.65 (dd, 2H), 3.55 (dd, 2H), 4.6 (s, broad, 1OH), 7.1 (unresolved, 2H), 7.35 (unresolved, 2H), 9.1 (s, 1 NH).

¹³ C-NMR (100 MHz, DMSO-d6): δ 28.3, 38.6, 62.5, 78.9, 118.3, 129.1, 133.2, 136.6, 153.0.

(c) 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid ethyl ester tert-butyl 4- (2-hydroxyethyl) phenylcarbamic acid ester (1.03 g, 4, 34 mmol) and 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (described in Example 20b) (1.03 g, 4.34 mmol) were dissolved in dichloromethane under argon at room temperature. Azodicarbonyldipiperidine (1.65 g, 6.5 mmol) was added followed by triphenylphosphine (1.37 g, 5.2 mmol). After stirring at room temperature for 6 hours, the solvent was evaporated in vacuo. Purification by silica gel chromatography eluting with heptane: ethyl acetate (2: 1) afforded 1.78 g (yield 89%) of 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] - ethyl ester. 2-ethoxypropanoic.

1 H-NMR (400 Wiz, CDCl ₃ ): δ 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 (m, 1H),

- 101 • · * 9 9 99 9 t 99 · 99 9 • 9 999 999 9 99 «9 9 9 9 9

3.95-4.0 (m, 1Η), 4.11 (t, 2Η, J = 7.1 Hz), 4.17 (q, 2Η, J = 7 Hz), 6.60 (s, 1NH) 6.81 (dm, 2H, J = 8.3 Hz, unresolved), 7.15 (dm, 2H, J = 8.3 Hz, unresolved), 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 ): δ 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

3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid

Lithium hydroxide hydrate (77 mg, 1.85 mmol) in water (5.5 mL) was slowly added to a solution of 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2- ethyl ester ethoxypropane (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 a freezer for 4 days. Tetrahydrofuran was removed by evaporation in vacuo. Additional water was added and the mixture acidified to pH 1 with hydrochloric acid. The product was extracted with ethyl acetate, washed twice with water, dried over sodium sulfate, filtered and the solvent was evaporated in vacuo to give 0.712 g (98.7% yield) of acid 3. - [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.18 (t, 3H, J = 7 Hz), 1.54 (s, 9H), 2.93-3.10 (m, 4H), 3 36-3.45 (m, 1H); 3.60-3.69 (m, 1H);

1H), 4.02-4.07 (m, 1H), 4.12 (t, 2H, J = 7Hz), 6.83 (dm, •)

- 102 2H, J = 8.8 Hz, unresolved), 7.15-7.23 (m, 4H), 7.27-7.34 (m, 2H), 10.28 (s broad, 1NH).

¹³ C-NMR (100 MHz, CDCl 3): δ 15.4, 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

3- [4- / 2- (4- (tert-butoxycarbonyl (methyl) amino) phenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid (a) 2- [4- (tert-Butoxycarbonylamino)] tert-Butyl 4- (2-hydroxyethyl) phenylcarbamic acid phenyl ester (described in Example 38b) (170 g, 0.716 mol) was suspended in dichloromethane (1.7 L) and placed in an ice bath. Pyridine (113 g, 1.43 mol) was added to give a clear yellow solution. p-Toluenesulfonyl chloride (205 g, 1.07 mol) was dissolved in dichloromethane (850 mL) and added slowly to the reaction mixture with stirring over 45 minutes. The reaction mixture was allowed to reach room temperature overnight. The solution was then washed with water (4 x 1 L) and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to a weight of 440 g. The remaining yellowish oil was slowly poured into heptane (1.6 L) with vigorous stirring. After about 20 seconds, the oil begins to crystallize. The heavy precipitate was filtered off, washed with heptane (200 ml) and dried in vacuo at 40 ° C overnight. 274 g (97.8% yield) of crude 2- [4- (tert-butoxycarbonylamino) phenyl] ethyl 4-methylbenzenesulfonate are obtained.

- 103 »103 103 103 103 ((((((((((((((((((((103 103 103 103

A sample of the crude product (8 g) was recrystallized from ethanol (30 ml) and water (3 ml) to give 7.1 g (88.8% yield) of pure 2- [4- (tert-butoxycarbonylamino) phenyl] ethyl- Of 4-methylbenzenesulfonate.

T-NMR (500 MHz, CDCl ₃ ): δ 1.55 (s, 9H), 2.47 (s, 3H), 2.93 (t, 2H, J = 7.0 Hz), 4.20 (s) t, 2H, J = 7.0 Hz), 6.45 (s,

1NH), 7.05 (d, 2H), 7.24-7.34 (m, 4H), 7.72 (d, 2H).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 21.6, 28.3, 34.7, 70.7, 80.5,

118.7, 127.8, 129.4, 129.7, 130.7, 133.0, 137.2, 144.6,

152.7.

(c) 2- [4- (tert-Butoxycarbonyl (methyl) amino / phenyl] ethyl-4-methylbenzenesulfonate)

2- [4- (tert-Butoxycarbonylamino) phenyl] ethyl 4-methylbenzenesulfonate (0.5 g, 1.28 mmol) was dissolved in tetrahydrofuran (10 mL). Add iodomethane (0.906 g, 6.38 mmol) 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 to give 0.52 g (96.5% yield) of 2- [4- (tert-butoxycarbonyl (methyl) amino) phenyl] ethyl 4-methylbenzenesulfonate.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 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) 3- (4-Benzyloxyphenyl) -2-ethoxypropanoic acid ethyl ester

- 104 «· * 4 · 4« 4 «* 4 4 4 · 4 4 · 4 · 4 •• 4 44

4444 · · · · * 4 4 4 4 4 ··· 44 44 44 444 4 4 4

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 a catalyst in methanol (20 mL).

The crude product was purified by chromatography using heptane: ethyl acetate (5: 1) as eluent to give 50 mg (yield 10%) of 3- (4-benzyloxyphenyl) -2-ethoxypropanoic acid ethyl ester.

¹ H NMR (300 MHz, CDCl ₃ ): δ 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, 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 = 6.8Hz, 3H).

¹³ C NMR (75 MHz, CDCl ₃ ): δ 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 g, 177 mmol) dissolved in water (150 mL) was added to a solution of 3- (4-benzyloxyphenyl) -2-ethoxypropanoic acid ethyl ester (23.25 g,

70.8 mmol) in dioxane (150 mL). After stirring overnight at room temperature, 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 evaporated in vacuo to give 21.1 g (yield 99.2%) of 3- (4-benzyloxyphenyl) -2-ethoxypropanoic acid.

- 105 999 9 ^X H NMR (300 MHz, CDC1 _3): 6 1.15 (t, 3H), 2.9-3.1 (m, 2H), 3.35-3.45 (m, 1H) 3.6-3.7 (m, 1H); 3.95-3.41 (m, 1H); 5.05 (s, 2H); 6.95 (d, 2H); 7.2 (d) 2 H, 7.25-7.5 (m, 5H).

¹³ C NMR (75 MHz, CDCl ₃ ): δ 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) 3- (4-Benzyloxyphenyl) - (S) -2-ethoxy-N (2-hydroxy- (R) -1-phenethyl) propanamide and 3- (4-benzyloxyphenyl) - (R) -2-ethoxy-N (2-hydroxy- (R) -1-phenethyl) propanamide

EDC (2.03 g, 10.61 mmol), diisopropylethylamine (1.84 mL, 10.61 mmol) and HOBtxH 2 O (1.43 g, 10.61 mmol) were added to a solution of 3- (4-benzyloxyphenyl) acid. -2-ethoxypropanoic (2.92 g, 9.74 mmol) in dry dichloromethane (30 mL) cooled and ice bath. After 30 minutes the ice bath was removed and (R) -phenylglycine (1.46 g, 10.61 mmol) was added. After stirring overnight at room temperature, ethyl acetate (100 mL) was added and the mixture was washed with potassium bisulfate (1 N), saturated sodium bicarbonate solution, sodium carbonate solution and water. The organic phase was dried over sodium sulfate, filtered and the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography using ethyl acetate: heptane to afford

1.5 g (37% yield) of 3- (4-benzyloxyphenyl) - (S) -2-ethoxy-N- (2-hydroxy- (R) -1-phenethyl) propanamide and 1.25 g (31% yield) 3- (4-Benzyloxyphenyl) - (R) -2-ethoxy-N- (2-hydroxy- (R) -1-phenethyl) propanamide.

3- (4-Benzyloxyphenyl) - (S) -2-ethoxy-N- (2-hydroxy- (R) -1-)

(phenethyl) propanamide

- 106 9 · · 106 106 106 106 106 106 106 106 106 106 106 9 9 9 9 9 9 9 9 9 9 9 9 9

1 H-NMR (400 MHz, CDCl ₃ ): δ 7.43-7.27 (m, 8H), 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, J = 6.8 Hz, 2H), 3.15 (dd, J = 14.2 and 3.9 Hz) , t H), 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 ): δ 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.

3- (4-Benzyloxyphenyl) - (R) -2-ethoxy-N- (2-hydroxy- (R) -1-phenethyl) propanamide ¹ H-NMR (400 MHz, CDCl ₃ ): δ 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 (m, 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).

¹³ C NMR (100 MHz, CDCl 3): δ 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-Benzyloxyghenyl) -2- (S) -ethoxypropanoic acid

3- (4-Benzyloxyphenyl) - (S) -2-ethoxy-N- (2-hydroxy- (R) -1-phenethyl) propanamide (8.9 g, 21.22 mmol) 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

- 107 ····· · · ♦ · »....

Ethyl Acetate. The organic phase was washed with brine, dried over sodium sulfate and the solvent was evaporated in vacuo to give 6.85 g of a mixture of 3- (4-benzyloxyphenyl) 2- (S) -ethoxypropanoic acid and (S) -2-ethoxy-3- (4-hydroxyphenyl) propane was used without further purification.

¹ H NMR (400 MHz, CDCl ₃ ): δ 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), 2.98 (dd, J = 14.2 and 7.8 Hz, 1H), 1.19 (t, J = 8.8

Hz, 3H).

(g) 3- (4-Benzyloxyphenyl) -2- (S) -ethoxypropanoic acid ethyl ester

Hydrogen chloride (gaseous) was bubbled through a solution of 3- (4-benzyloxyphenyl) -2- (S) -ethoxypropanoic acid (6.85 g, 22.8 mmol) in ethanol (400 mL). Thionyl chloride (2 mL, 27.4 mmol) was added slowly and the reaction mixture was 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) propanoic acid ethyl ester, which was used without further purification. cleaning.

¹ H NMR (300 MHz, CDCl ₃ ): δ 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, 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 = 7.2Hz, 3H), 1.18 (t, J = 6.8Hz, 3H).

- 108 * 94 · 94 4 9 ·· · ’

9 9 4 9 9 9 · · · ·

9 9 9 9 9

995 499 4999 9

9 9 4

999 99 99 9999 · 999 ¹³ C NMR (75 MHz, CDCl 3): δ 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

3- (4-Benzyloxyphenyl) -2- (S) -ethoxypropanoic acid (7.13 g, 21.7 mmol) was hydrogenated at atmospheric pressure in ethyl acetate (70 mL) for 2 hours using palladium on carbon catalyst. Purification by silica gel chromatography using toluene: ethyl acetate as eluent gave 3.83 g (76% yield in 3 steps) of (S) -2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester.

1 H-NMR (400 MHz, CDCl ₃ ): δ 1.18 (t, 3H, J = 6.8 Hz), 1.24 (t, 3H, J = 7 Hz), 2.96 (d, 2H, J = 6.5 Hz), 3.34-3.43 (ra, 1H), 3.57-3.66 (m, 1H), 4.00 (t, 1H, 6.5 Hz), 4.18 (q, 2 H,

J = 7 Hz), 5.30 (s, 10H), 6.74 (dm, 2H, J = 8.5 Hz, undifferentiated), 7.10 (dm, 2H, J = 8.5 Hz, undifferentiated) ).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 14.2, 15.0, 38.4, 60.9, 66, 2, 80.4, 115.1, 129.0, 130.5, 154 , 5, 172.7.

(i) 3- [4- / 2- (4- (tert-butoxycarbonyl (methyl) amino) phenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid

The sodium hydroxide (0.044 g, 1.1 mmol) was triturated and dissolved in DMSO (10 mL). Add (S) -2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (0.2 g, 0.84 mmol) and stir the mixture for 10 min before adding 2- [4- tert -butoxycarbonyl ( methyl) amino / phenyl] ethyl 4-methylbenzenesulfonate

109 (0.34 g, 0.84 mmol). The reaction mixture was stirred at room temperature for 4 hours and then all starting materials were consumed by LC-MS to form the corresponding ester. Water (10 mL), tetrahydrofuran (5 mL) and sodium hydroxide (0.9 g, 22.5 mmol) were added and the mixture was stirred overnight and then evaporated. The residue is 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 over sodium sulfate and evaporated. The crude product was chromatographed with dichloromethane-methanol (95: 5) as eluent. The product, which is an oil, is dissolved in water and a small amount of ethanol and acetonitrile. The solution was cooled with liquid nitrogen. Lyophilization for 3 days afforded a pure solid, 0.19 g (51% yield) of 3- [4- / 2- (4- (tert-butoxycarbonyl (methyl) amino) phenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic as white solids.

¹ H-NMR (500 MHz, CD ₃ OD): δ 1.10 (t, 3H), 1.45 (s, 9H) 2.86 (m, 1H); 3.01-3.04 (m, 3H), 3.21 (s, 3H), 3.32 (m, 1H), 3.63 (m, 1H), 3.93 (m, 1H); 1H), 4.12 (m, 2H). 6.80 (d, 2H), 7.16-7.20 (m, 4H), 7.28 (d, 2H).

¹³ C-NMR (125.7 MHz, CDCl ₃ ): δ 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) 3- [4- / 2- (4-tert- butoxycarbbo-110 nylaminophenyl) ethoxy / phenyl] - (S) -2- ethoxypropane

2- [4- (tert-Butoxycarbonylamino) phenyl] ethyl methanesulfonate (described in Example 40a) (52.9 g, 0.168 mmol), (S) -2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (described in Example 40h) (40 g, 0.168 mmol) and potassium carbonate (69.5 g, 0.503 mmol) were combined in acetonitrile (1200 mL) and refluxed overnight. Another portion of 2- [4- (tert-butoxycarbonylamino) phenyl] ethyl methanesulfonate (2.5 g, 7.9 mmol) was added. The reaction mixture is maintained at reflux for an additional 8 hours, then filtered. Evaporation of the filtrate gave 76.6 g of 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl] - (S) -2-ethoxypropanoic acid ethyl ester.

This batch of 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid ethyl ester (76.6 g) was combined with another batch of ethyl 3- [4- [2- (4-tert-butoxycarbonylaminophenyl)ethoxy/phenyl]-(S)-2- ethoxypropanoic acid (74.1 g)] and purified twice by flash chromatography on silica gel. First toluene was used as eluent followed by methanol and then toluene with ethyl acetate (2-5%) was used. 69.9 g of pure 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl] - (S) -2-ethoxypropanoic acid ethyl ester are obtained.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.16 (t, 3H), 1.22 (t, 3H), 1.51 (s, 9H), 2.94 (d, 2H), 3 O 2 (t, 2H), 3.31-3.38 (m, 1H),

3.55-3.63 (m, 1H), 3.95 (t, 1H), 4.10 (t, 2H), 4.16 (q,

2H), 6.45 (s broad, 1H), 6.8 (d, 2H), 7.13 (d, 2H), 7.13 (d, 2H), 7.19 (d, 2H), 7.29 (d, 2 H).

- 111 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 · 44 (b) 3- [4- / 2- (4-Aminophenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid ethyl ester hydrochloride

Trifluoroacetic acid (12 mL, 0.0706 mol) was added to a solution of 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid ethyl ester (30 g, 0.065) mol) in dichloromethane (150 mL). The reaction mixture was stirred overnight at room temperature and then washed 3 times with water. The organic phase is dried over magnesium sulphate and evaporated. ¹ H-NMR of the product showed 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- [4- [2- (4-aminophenyl) ethoxy] phenyl] - (S) -2-ethoxypropanoic acid hydrochloride.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.14 (t, J = 7 Hz, 3H), 1.20 (t,

J = 7Hz, 3H), 2.91-2-93 (m, 2H), 3.02 (t, J = 7Hz, 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 = 7 Hz, 2H), 4.14 (q, J = 7 Hz,

2H), 6.76 (d, J = 8.8Hz, 2H), 7.12 (d, J = 8.8Hz, 2H),

7.27 (d, J = 8.3 Hz, 2H); 7.45 (d, J = 8.3 Hz, 2H).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 14.18, 15.02, 35.22, 38.40,

60.77, 66.16, 68.00, 80.31, 114.29 (20), 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) ethoxy / phenyl] propanoic acid ethyl ester

3- [4- / 2- (4 · 99) 99 99 99 · 9 9 · 9

-112999 9 9 9 9 99 · 9 • 9 9 9 9 9 9 ··· 99 9 · 9999 99 999

(aminophenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid (0.55 g,

1.4 mmol) was dissolved in tetrahydrofuran (5 mL) and methyl chloroformate (0.534g, 5.68 mmol) was added slowly. The reaction mixture was continuously checked by HPLC and after 6 days all starting material was consumed. Water was added to the mixture, the tetrahydrofuran was evaporated and the residue was extracted 3 times with ethyl acetate. The organic phase was dried (MgSO4) and evaporated to give 0.525 g (90.2%) of (S) -2-ethoxy-3- [4- / 2- (4- (methoxycarbonylamino) phenyl / ethoxy] phenyl) ethyl ester. propane.

¹ H-NMR (600 MHz, CDCl ₃ ): δ 1.15 (t, 3H), 1.22 (t, 3H); 2.90-2.97 (m, 2H), 3.03 (t, 2H); , 31-3, 37 (m, 1H); 55- 3.62 (m, IH), 3.77 (s, 3H), 3.95 ( q, 1H) , 4.11 (t, 3H) r 4.16 (q, 2H). 6, 60 (broad, NH), 6.80 (d, 2H), 7.13 (d, 2H), 7.21 (d, 2H), 7.32 (d wide, 2H)

C-NMR (150 MHz, CDCl ₃ ): δ 14.4, 15.5, 35.3, 38.7, 45.2,

52.5, 61.0, 66.4, 68.9, 80, 6, 114.5, 129, 5 129, 8 130, 6 _Z

157.8, 172.8, 179.7.

Example 42

(S) -2-Ethoxy-3- [4- / 2- (4- (methoxycarbonylamino) phenyl) ethoxy / phenyl] propanoic acid

(S) -2-Ethoxy-3- [4- / 2- (4- (methoxycarbonylamino) phenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in Example 41) (0.52g, 1.25 mmol) was dissolved in tetrahydrofuran (10 mL) and lithium hydroxide (0.034 g, 1.42 mmol) dissolved in water (2 mL) was added slowly. The reaction mixture was stirred overnight, hydrochloric acid (1 L, 1 mL) was added and the tetrahydrofuran was evaporated. The residue is extracted.

3 times with ethyl acetate. The organic phase was dried over magnesium sulphate and evaporated to give 0.47 g (99% yield) of (S) -2-ethoxy-3- [4- / 2- (4- (methoxycarbonylamino) phenyl) ethoxy / phenyl] acid. propane.

¹ H-NMR (600 MHz, CDCl ₃ ): δ 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 (s broad, 2H).

¹³ C-NMR (150 MHz, CDCl 3): δ 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-butoxycarbonylamino) phenyl) ethoxy / phenyl] -2-ethylsulfanylpropanoic acid methyl ester (a) 3- (4-Benzyloxyphenyl) -2-ethylsulfanylpropanoic acid methyl ester

Potassium hydroxide (0.092 g, 1.64 mmol) was dissolved in methanol. Ethanethiol (0.133 g, 2.14 mmol) and 3- (4-benzyloxyphenyl) -2-chloropropanoic acid methyl ester (0.5 g, 1.64 mmol) 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 is purified by addition of activated carbon in methanol. The mixture was stirred for 15 minutes and the charcoal was filtered off. Evaporation of the solvent gave 0.47 g (86.7% yield) of 3- (4-benzyloxyphenyl) -2-ethylsulfanylpropanoic acid methyl ester.

¹ H-NMR (400 MHz, CDCl 3): δ 1.23 (t, 3H), 2.63 (m, 2H),

2.90 (m, 1 H), 3.14 (m, 1 H), 3.50 (m, 1 H), 3.67 (s, 3H),

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-ethylsulfanylpropanoic acid methyl ester (0.37 g, 1.12 mmol) was dissolved in dichloromethane (3.5 mL). Dimethyl sulfide (3 mL) was added, followed by the addition of boron trifluoride etherate (1.6 g, 11 mmol). The reaction mixture was stirred at room temperature for 3 hours and then quenched with water (3 mL). Additional dichloromethane was added and the phases were separated. The organic phase was washed twice with brine and dried over sodium sulfate. Evaporation of the solvent gave 0.2 g (74.3% yield) of ethylsulfanyl-3- (4-hydroxyphenyl) propanoate.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 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-butoxycarbonylamino) phenyl) ethoxy / phenyl] -2-ethylsulfanylpropanoic acid methyl ester

Sodium hydroxide (0.045 g, 1.25 mmol) was triturated and added to DMSO (10 mL). Add 2-ethylsulfanyl-3- (4-hydroxyphenyl) propanoic acid methyl ester (0.21 g, 0.87 mmol), followed by the addition of 2- / 4- (tert-butoxycarbonylamino) phenyl] ethyl 4-methylbenzenesulfonate (described in Example 40a) (0.342, 0.87 mmol). The reaction mixture was stirred at room temperature for 3 hours, then all starting according to LC-MS

- 115 • 99 99 ·· 99 · 9 9 9 9 9 9 9 • 99 9 9 9 9 9

99999 9 9 99 9

9 9 9 9 9

999 99 99 9999 99 9 materials consumed. Water (10 mL) and tetrahydrofuran (5 mL) were added and stirring was continued overnight. The reaction mixture was then exposed to diethyl ether and water and dilute hydrochloric acid was added to prevent foaming. The phases are separated and the organic phase is washed. 3 times with water. The aqueous phases were combined and washed once more with diethyl ether. All organic phases were combined, dried over sodium sulfate and evaporated.

Chromatography in ether: petroleum ether (1: 9 and 1: 3) afforded 0.18 g (41.4% yield) of 3- [4 / 2- (4- (tert-butoxycarbonylamino) phenyl) ethoxy] methyl ester. phenyl] -2-, ethylsulfanylpropanoic.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.22 (t, 3H), 1.51 (s, 9H), 2.61 (m, 2H), 2.89 (m, 1H), 3 1.01 (t, 2H); 3.12 (m, 1H); 3.48 (m, 1H);

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).

¹³ C-NMR (100 MHz, CDCl 3): δ 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.

Example 44

3- [4- / 2- (4- (tert-butoxycarbonylamino) phenyl) ethoxy / phenyl] -2-ethylsulfanylpropanoic acid

Sodium hydroxide (0.14 g, 3.5 mmol) was triturated and added to DMSO (15 mL). 2-Ethylsulfanyl-3- (4-hydroxyphenyl) propanoic acid methyl ester (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- (target- 116 • 99 99 99 ··

9 9 9 9 ·· · 9 · 9 999 9 9 · 9 9 9 9 9 9 9 9 9

999 99 99 9999 99 9 butoxycarbonylamino) phenyl] ethyl 4-methylbenzenesulfonate (described in Example 40a) (0.342 g, 0.87 mmol). 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.

Most solvents are evaporated. The residue is treated with diethyl ether and water and the phases are separated. The organic phase is dried over sodium sulphate and evaporated. Chromatography of the residue on silica gel using a petroleum ether / diethyl ether gradient system (90:10, 75:25, 25.75 and 0: 100) afforded 0.41 g (34% yield) of 3- [4- / 2- (4-chloro-4-yl) -acetic acid. - (tert-butoxycarbonylamino) phenyl) ethoxy / phenyl] -2-ethylsulfanylpropanoic.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 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, 2H);

1H), 3.96 (m, 2H), 6.68 (d, 2H), 7.03 (d, 2H), 7.10 (d, 2H)

2H), 7.23 (d, 2H).

Example 45

3- [4- / 2- (4-tert-Butoxycarbonylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid benzyl ester

3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid (described in Example 39) (1 g, 2.33 mmol) was dissolved in a solution of dichloromethane and triethylamine (0.235 g). (2.56 mmol) and cooled to 0 ° C. Benzyl chloroformate (0.4 g, 2.33 mmol) was added, followed by DMAP (0.28 g, 2.33 mmol) after 10 minutes. The reaction mixture was stirred at room temperature overnight and then extracted with a saturated solution of sodium bicarbonate, potassium hydrogen sulfate (0.5

- 117

000 • 00 ·· ················ 0 · 0 0 0 0 • «· 00 0 00 0 000 000 0000 0 0 0 0 0 0 0 0

M) and brine. The organic phase is dried over sodium sulphate and evaporated. Chromatography on silica gel using dichloromethane with methanol (1%) as eluent gave 0.36 g (29.7%) of 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2-benzyl ester -ethoxypropane.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 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 (s broad, 1H), 6.8 (d, 2H), 7.12 (d, 2H), 7.23 (d, 2H), 7.25-7.38 (m, 7H) ).

¹³ C-NMR (100 MHz, CD ₃ OD): δ 14.2, 27.6, 34.9, 38.2, 65, 9,

66.4, 68.7, 76.6, 80.3, 114.3, 118.8, 128.15, 1282, 128.3,

128.8, 129.2, 130.3, 133.0, 135.8, 137.7, 154.2, 158.0,

172.8.

Example 46 tert-Butyl- [4- / 2- (4- (2-ethoxy-3-oxopropyl) phenoxy) ethyl / phenylcarbamate]

3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid ethyl ester (described in Example 38) (3.78g, 8.2 mmol) was dissolved 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, followed by chromatography. on a thin layer. After 4 hours, another portion of DIBAL (15.9 mL, 19 mmol) was added. The reaction mixture was quenched with aqueous ammonium chloride solution, resulting in a strong precipitation. The mixture was filtered through hyflo and the filtrate was evaporated. Evaporate again

- 118 • Μ * · ·. · · ····· ♦ ·· ·

9 ·· ·· · · · ···· ^«1 dissolved in ethyl acetate and chromatography on silica gel with ethyl acetate: heptane (gradient 12.5 to 100% ethyl acetate) afforded 0.9 g (26.3% yield) of tert. Butyl- [4- [2- (4- (2-ethoxy-3-oxopropyl / phenoxy) ethyl] phenylcarbamate].

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.19 (t, 3H), 1.53 (s, 9H),

2.80-2.86 (m, 1H, 2.90-2.96 (m, 1H, 3.04 (t, 2H), 3.40- 3.50 (m, 1H), 3.55-3.66 (m, ÍH), 3,79-3,84 (m, 1H), 4.13 (t, 2H), 6.51 (s broad, 1H) , 8, 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): δ 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 47 tert-Butyl- [4- / 2- (4- (3- (benzyl (ethyl) amino) -2-ethoxy-3-propyl) phenoxy) ethyl] phenylcarbamate]

3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid (described in Example 39) (6.09 g, 14.2 mmol) was dissolved in acetonitrile (150 mL) and the solution was cooled to 0 ° C. Add DCC (3.51 g, 17 mmol), HO-Su (1.96 g, 17 mmol) and DIPEA (2.2 g, 17 mmol) and before adding N-ethylbenzylamine (2.72 g, 17 mmol) ) was stirred for 15 minutes. The reaction mixture was stirred overnight and then filtered and evaporated. To the resulting oil was added hydrochloric acid (2 M, 200 mL) and the resulting mixture was then extracted 3 times with ethyl acetate. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulphate and evaporated.

- 1199 «9 9 · ·· ··

999 9 9 9 · · 99 99 99 99 99

I 99999

9 9 9 9 9

999 99 99

Chromatography of the residue on silica gel with heptane: ethyl acetate (1.25 to 100%) using a gradient elution procedure afforded 5.32 g (68.5% yield) of tert-butyl- [4- / 2- (4- (3- (benzyl (ethyl) amino (-2-ethoxy-3-propyl) phenoxy) ethyl / phenylcarbamate].

¹ H-NMR (400 MHz, CDCl 3): δ 1.17 (t, 3H), 1.63 (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).

¹³ C-NMR (100 MHz, CDCl 3): δ 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 48

3- [3- / 2- (tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid ethyl ester (a) 2- [4- (tert-Butoxycarbonylamino) phenyl] ethylmethanesulfonate tert-butyl ester 4- ( 2-hydroxyethyl) phenylcarbamic acid (described in Example 38b) (2.46 g, 1038 mmol) was dissolved in dichloromethane (21 mL). Triethylamine (2.17 mL, 15.6 mmol) was added and the mixture was stirred for 20 minutes and then cooled in an ice bath. Methanesulfonyl chloride (1.25 g, 10.9 mmol) was added slowly. The reaction mixture was stirred for 3.5 hours and the precipitate formed was filtered off. The filtrate was evaporated and the residue was redissolved in ethyl acetate. The newly formed precipitate was filtered off and the filtrate was evaporated. Silica gel chromatography using heptane: ethyl-120 • 9 9 9 9 9 · 9 «9 ·

9 9 9 9 9

999 9 · 99 9999 99 9 acetate (2: 1, 1: 1) to give 3 g (100% yield)

2- [4- (tert-butoxycarbonylamino) phenyl] ethyl methanesulfonate.

^{Σ Η-NMR} (400 MHz, CDC1 _3): δ 1.52 (s, 9H), 2.87 (s, 3H), 3.01 (t, 2H), 4.39 (t, 2H), 7 16 (d, 2H, J = 8.45 Hz), 6.45 (s broad, 1H), 7.33 (d, 2H, J = 8.45 Hz).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 28.2, 34.8, 37.1, 70.2, 80.3, 118.6, 129.2, 130.5, 137.3, 152 , 6.

(b) 3- [3- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid ethyl ester

2-Ethoxy-3- (3-hydroxyphenyl) propanoic acid ethyl ester (0.76 g, 3.2 mmol) was dissolved in acetonitrile (30 mL). Add potassium carbonate (0.53 g, 3.8 mmol), followed by the addition of 2- [4- (4-tert-butoxycarbonylamino) phenyl] ethyl methanesulfonate (1 g, 3.2 mmol). The reaction mixture was heated to reflux for 4.5 hours and then additional 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 (MgSO4) and evaporated.

Chromatography on silicate using ethyl acetate: hexane (1: 4) as eluent gave 0.8 g (54.6% yield) of 3- [3- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] ethyl ester -2-ethoxypropanoic acid.

The product is lyophilized before use in the next step.

- 121 ····· * · · · · 9 9 9 9 9 9 9 9

994 94 44 4994 9 9 499 ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.17 (t, 3H), 1.32 (t, 3H), 1.52 (s, 9H), 2.98 (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,

2H), 6.51 (s broad, 1H), 6.76 (d, 1H, J = 7.98 Hz), 6.796.85 (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).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 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

3- [3- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid

3- [3- / 2- (4-tert-Butoxycarbonylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid ethyl ester (described in Example 48) (0.8g, 1.74 mmol) was dissolved in tetrahydrofuran (15 mL) . Lithium hydroxide hydrate (0.073 g, 1.74 mmol) dissolved in water (5 mL) was added slowly. The reaction mixture was stirred at room temperature for 4.5 hours. Additional lithium hydroxide hydrate (0.036 g, 0.87 mmol) was added and stirring was continued for 2 additional hours. Tetrahydrofuran was carefully evaporated and a large amount of water was added. The pH was adjusted to about 12 with sodium hydroxide (2M) and the solution was extracted with ethyl acetate. The aqueous phase is cooled to less than 10 ° C, acidified with potassium bisulfate (1 M) and extracted with ethyl acetate. The organic phase was washed with water and dried over sodium sulfate. Evaporation gave 0.53 g (70.9% yield) of 3- [3- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl] -2-ethoxypropanoic acid.

- 122 -

1 H-NMR (400 MHz, CDCl ₃ ): δ 1.17 (t, 3H), 1.53 (s, 9H),

2.94-3.13 (m, 4.06-4.09 (m, 6.85 (m, 3H)),

4H), 3.39-3.47 (m, 1H), 4.13 (t, 2H), 7.17-7.23 (m, 3H),

1H), 3.58-3.66 (m, 1H), 6.58 (broad, 1H), 6.777, 26-7.32 (m, 2H).

¹³ C-NMR (100 MHz, CDCl 3): δ 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

3- [4- / 2- (4- (tert-butoxycarbonylamino) phenyl) ethoxy / phenyl] -2-ethoxy-2-methylpropanoic acid (a) 3- (4-Benzyloxyphenyl) -2-ethoxy-3 ethyl ester -hydroxy-2-methylpropanoic acid

Diisopropylamine (1.1 mL, 7.78 mmol) and dry tetrahydrofuran (35 mL) were combined and cooled to -78 ° C under a nitrogen atmosphere. N-Butyllithium (1.6 M in hexane, 4.7 mL, 7.52 mmol) was added slowly and the reaction stirred for 15 minutes. Ethyl 2-ethoxypropionate was dissolved in a small amount of dry tetrahydrofuran and slowly added to the LDA mixture. The solution was stirred at low temperature for 30 minutes, then 4-benzyloxybenzaldehyde was added, followed by addition of saturated ammonium chloride solution (20 mL) after 2 minutes. The mixture was allowed to warm to room temperature and the layers were 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 over 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

-1231.63 g (68% yield) of 3- (4-benzyloxyphenyl) -2-ethoxy-3-hydroxy-2-methylpropanoic acid ethyl ester.

1 H-NMR (400 MHz, CDCl 3): δ 1.18 (t, 3H, J = 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, 1H); 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 ): δ 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-2-methylpropanoic acid ethyl ester

3- (4-Benzyloxy-phenyl) -2-ethoxy-3-hydroxy-2-methyl-propanoic acid ethyl ester (0.358 g, 1 mmol) and triethylsilane (0.32 mL, 2 mmol) were dissolved in dry dichloromethane (4 mL) and cooled to 0 ° C, then boron trifluoride etherate (0.284 g, 2 mmol) was added. The reaction mixture was then stirred at 0 ° C for 2.5 hours and then quenched by the addition of saturated sodium bicarbonate solution (10 mL) and dichloromethane (10 mL). The aqueous layer was extracted 3 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-methylpropanoate.

1 H-NMR (400 MHz, CDCl 3): δ 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, J =

8.7 Hz), 7.28-7.45 (m, 5H)

- 124 • * · · · · «·· · fl · • fl • fl flfl flfl flfl flfl flflflfl flfl · ¹³ C-NMR (100 MHz, CDC1 _3): δ 14.2, 15.7, 20.3 , 44.2, 60.0,

60.8, 70.0, 80.8, 114.3, 127.5, 127.9, 128.5, 128.7, 131.4,

137.2, 157.6, 174.2.

(c) 2-Ethoxy-3- (4-hydroxyphenyl) -2-methylpropanoic acid ethyl ester

3- (4-Benzyloxyphenyl) -2-ethoxy-2-methylpropanoic acid ethyl ester (0.34 g, 0.99 mmol) was hydrogenated at atmospheric pressure in ethyl acetate for 18 h using palladium on carbon (0.05 g) as a catalyst and then filtered through hyflo. The solvent was evaporated to give 0.249 g (98% yield) of 2-ethoxy-3- (4-hydroxyphenyl) -2-methylpropanoic acid ethyl ester.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.21 (t, 3H, J = 7.0 Hz), 1.23 (t, 3H, J = 7.1 Hz), 1.32 (s 3H), 2.95 (s, 2H), 3.38-3.54 (m, 2H), 4.14 (dq, 2H, J = 7.1), 6.70 (d, 2H, J = 8.8 Hz), 7.04 (d, 2H, J = 8.8 Hz).

¹³ C-NMR (100 MHz, CDCl 3): δ 14.2, 15, 6, 20.3, 44.2, 60.4,

60.9, 80.8, 114.8, 128.2, 131.5, 154.5, 174.4.

(d) 3- [4- / 2- (4- (tert-butoxycarbonylamino) phenyl) ethoxy / phenyl] -2-ethoxy-2-methylpropanoic acid

Sodium hydroxide (0.105 g, 2.63 mmol) was triturated and dissolved in DMSO (8 mL). To 4 ml of this solution is added

2- [4- (tert-butoxycarbonylamino) phenyl] ethyl 4-methylbenzenesulfonate (described in Example 40a) (0.515 g 1.326 mmol) and 2-ethoxy-3- (4-hydroxyphenyl) 2-methylpropanoic acid ethyl ester (0.331 g) (1.326 mmol) and the mixture was stirred at rt

- 125 • 4 4 4 4

4 · 4 4 4 4 · 4 44 44 4444 44 4 Stir overnight. Add the remaining volume (4 mL) of sodium hydroxide solution and water (1 mL). A precipitate formed which was dissolved by addition of tetrahydrofuran (1 mL). The mixture was allowed to stand overnight and then evaporated. The residue was redissolved in dichloromethane and water and the phases separated. The aqueous phase was extracted once more with dichloromethane, acidified with hydrochloric acid (1 M), extracted several times with ethyl acetate and diethyl ether. The organic phases are combined, dried over magnesium sulphate and evaporated. Purification of the crude product by flash chromatography and preparative HPLC afforded 0.103 g (17.1% yield) of the acid.

3- [4- / 2- (4- (tert-butoxycarbonylamino) phenyl) ethoxy / phenyl] -2-ethoxy-2-methylpropanoic acid.

¹ H-NMR (600 MHz, CDCl ₃ ): δ 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, J = 6.9 Hz), 6.55 (broad, 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 (broad, 1H).

¹³ C-NMR (75 MHz, CDCl ₃ ): δ 15.5, 20.9, 28.3, 35.1, 42.3,

59.5, 68.6, 80.6, 81.0, 114.2, 118.8, 127.5, 129.4, 131.1,

132.9, 136.7, 153.0, 157.8, 176.1.

Example 51

2-Ethoxy-3- [4- / 2- (4-methylcarbamoyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester

Methyl isocyanate (70 mg, 1.22 mmol) was slowly added to a mixture of triethylamine (180 mg, 1.17 mmol) and 2-ethoxy-3- [4- / 2- (4-hydroxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in Example 26b) (418 mg,

• 126. 9 · · 9 9 9 9 · 9 • 99 9 9 99 9 9 99 • 9 99 9 99 • 99999 9 9 99 9 • 9 9 9 9 9 9

9 9 99 99

1.17 mmol) in dichloromethane (5 mL). After stirring at room temperature for 2.5 hours, excess methyl isocyanate was evaporated in vacuo and water and dichloromethane were added. The phases are separated.

Water and potassium hydrogen sulphate (1 M) were added to the organic phase. The phases are separated, the organic phase is evaporated in vacuo and the residue is purified by chromatography on silica using toluene: diethyl ether (gradient 4: 1 to 3: 1) as eluent to give 229 mg (yield 47%) of 2-ethoxy-ethyl ester. 3- [4- / 2- (4-methylcarbamoyloxyphenyl) ethoxy / phenyl] propane.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 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, J = 7.0 Hz), 3.35-3.43 (m, 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), 5.25 (m, 1H), 6.84 (dm, 2H, J = 8.6 Hz, unresolved), 7.18 (dm, 2H, J = 8.6 Hz, unresolved), 7.28 (dm, 2H, J = 8.3 Hz, unresolved).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 14.1, 14.9, 27.5, 35.0, 38.3, 60.6, 66.0, 68.4, 80.2, 114 , 2, 121.4, 129.2, 129.6, 130.2, 135.1, 149.6, 155.3, 157.4, 172.4.

Example 52

3- [4- / 2- (4- (Benzyloxycarbonylamino) phenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid ethyl ester

3- [4- / 2- (4-Aminophenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid ethyl ester hydrochloride (described in Example 41b) (0.6 g, 1.67 mmol), triethylamine (0, 17 g,

1.67 mmol) and benzyl chloroformate (0.28 g, 1.67 mmol) were combined in tetrahydrofuran. The reaction mixture was stirred at temperature

- 127 -

• 44 • 4 · • • 4 • • t • 4 4 4 • • 4 • · · · • · • 4 4 4 • • · • • 4 4 • • · 4 4 • · • · · 4 • 4 •

room overnight and then evaporate. The residue is treated with sodium bicarbonate solution and diethyl ether. The organic phase is dried over magnesium sulphate and evaporated. The starting material remained according to the NMR spectrum. Thus, the residue is dissolved in tetrahydrofuran and triethylamine and benzyl chloroformate is added. The reaction mixture was stirred at room temperature then evaporated. Working up as described above yields a crude product which is purified by preparative HPLC (Kromasil C8, 7 µιη, 50x250 mm) using acetronitrile (70-100%) in ammonium acetate buffer (pH

7) 0.180 g (22% yield) of 3- [4- / 2- (4- (benzyloxycarbonylamino) phenyl) ethoxy] phenyl] - (S) -2-ethoxypropanoic acid ethyl ester is obtained as mobile phase.

¹ H-NMR (600 MHz, CDCl ₃ ): δ 1.16 (t, 3H), 1.22 (t, 3H), 2.94 (d, 2H), 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 (s broad, 1H), 6.8 (d, 2H), 7.13 (d, 2H), 7.21 (d, 2H), 7.3-7.41 (m, 7H).

¹³ C-NMR (150 MHz, CDCl ₃ ): δ 153, 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

3- [4- / 2- (4- (Benzyloxycarbonylamino) phenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid

3- [4- / 2- (4- (Benzyloxycarbonylamino) phenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid ethyl ester (described in Example 52) (0.16 g, 0.32 mmol) was dissolved in

- 128-

9 99 ·· · · 99 • 9 9 9 99 9 9 9 • • • 9 9 9 • 9 • 9 9 9 9 • 9 9 9 • • · • 9 • 999 9 99 9 9

tetrahydrofuran and lithium hydroxide (9 mg, 0.38 mmol) dissolved in water (1 mL) was added. The resulting mixture was stirred overnight. Add hydrochloric acid (1M, 1 mL). The tetrahydrofuran was evaporated and the aqueous residue was extracted 3 times with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated to give 0.14 g (92.8% yield) of 3- [4- / 2- (4- (benzyloxycarbonylamino) phenyl) ethoxy] phenyl] - (S) -2-ethoxypropanoic acid. .

¹ H-NMR (600 MHz, CDCl ₃ ): δ 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).

¹³ C-NMR (150 MHz, CDCl ₃ ): δ 15.3, 35.4, 38.1, 67.0, 67.3,

68.9, 80.1, 114.7, 119.2, 128.5, 128.6, 128.8, 129, 0,

129.8, 130.7, 136.3, 153.9, 157.9, 175.5.

Example 54

3- [4- / 2- (4-tert-butoxycarbonylaminophenyl / ethoxy) -3-methoxyphenyl] -2-ethoxypropanoic acid (a) 3- (4-Benzyloxy-3-methoxyphenyl) -2-ethoxyacrylic acid ethyl ester

4-Benzyloxy-3-methoxybenzaldehyde (7 g, 28.8 mmol) and (1,2-diethoxy-2-oxoethyl) (triphenyl) phosphonium chloride (13.6 g, 31 mmol) were dissolved in isopropanol and the reaction mixture was cooled to -10 ° C. Potassium carbonate (6 g, 43 mmol) was added. The resulting mixture was stirred overnight and allowed to reach room temperature. The reaction mixture was filtered and the filtrate was evaporated. The residue was added

- 129 · · 129 129 129 129 129 129 129 129 · 129 129 129 129 129 129 129 129 129 129 129 129 129 129 Diethyl ether and the resulting mixture was stirred for a while, then the insoluble material was filtered off. The filtrate was washed with potassium bicarbonate solution and water, dried over magnesium sulfate and evaporated. Isopropyl ether was added to the residue. Triphenylphosphine oxide precipitated, was filtered off 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. Since the product is not sufficiently pure, it is mixed with petroleum ether, the insoluble material is filtered off and the filtrate is evaporated to give 4 g (38% yield) of pure 3- (4-benzyloxy-3-methoxyphenyl) -2-ethoxyacrylic acid ethyl ester.

1 H-NMR (300 MHz, CDCl ₃ ): δ 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), 72.7-7.5 (m, 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 palladium on carbon (dry, 5%). The reaction mixture was filtered through diatomaceous earth. 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, CDCl ₃ ): δ 1.16 (t, 3H), 1.23 (t, 3H), 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 (s broad, 1H), 6.72 (m, 1H), 6.76-6.85 (m, 2H).

- 130-

• ·· • · · • 4 • · ·· • · ·· • · · • · ·· • · · • • · · • · • · • • · · »·· ·· ···· ·· »

¹³ C-NMR (150 MHz, CDCl ₃ ): δ 14.4, 15, 3, 39, 2, 56, 0, 61.0,

66.4, 80.7, 112.4, 114.3, 122.2, 129.3, 144.6, 146.4,

172.8.

(c) 3- [4- / 2- (4-tert-butoxycarbonyl aminophenyl / ethoxy) -3-methoxyphenyl] -2-ethoxypropanoic acid ethyl ester

Dissolve 3- (4-benzyloxy-3-methoxyphenyl) -2-ethoxypropanoic acid ethyl ester (0.5 g, 1.86 mmol) in acetonitrile and add potassium carbonate (0.53 g, 3.91 mmol). Add 2- [4- (tert-butoxycarbonylamino) phenyl] ethyl 4-methylbenzenesulfonate (described in Example 40a) (0.755 g, 1.92 mmol). The resulting mixture was stirred and kept at reflux overnight, then filtered and the filtrate was evaporated. The residue was treated with sodium hydroxide (0.5 M) and diethyl ether. The phases are separated and the organic phase is dried over magnesium sulphate. Evaporation gave 0.7 g (77.2% yield) of 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy) -3-methoxyphenyl] -2-ethoxypropanoic acid ethyl ester.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 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), 3.583.7 (m, 1H), 3.87 (s, 3H), 3.98 (t, 1H), 4, 13-4.25 (m, 4H), 6.48 (s broad, 1H), 6.78-6.87 (m, 3H), 7.12 (d, 2H), 7.277.35 (m, 2H) ).

(d) 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy) -3-methoxyphenyl] -2-ethoxypropanoic acid

Dissolve 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl / ethoxy) -3-methoxyphenyl] -2-ethoxypropanoic acid ethyl ester (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 stirred overnight. Water was added and the tetrahydrofuran was evaporated. The remaining aqueous residue was extracted once with diethyl ether, acidified with potassium bisulfate and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate. Evaporation gave 0.5 (76% yield) of 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl / ethoxy) -3-methoxyphenyl] -2-ethoxypropanoic acid.

¹ H-NMR (400 MHz, CD ₃ OD): δ 1.12 (t, 3H), 1.49 (s, 9H),

2.8 2—2.89 (m, 1H), 2.92-3.0 (m, 3H) , 3.31-3.38 (m, 1H), 3.54-3.63 (m, 1H), 3.78 (s, 3H), 3, 97-4.02 (m, 1H) , 4,07- 4.13 (m, 2H). 6.74 (m, 2H). 6, 8 (m, 1H), 7.17 (d, 2H), 7.29 (d, 2H), 8.75 (s broad, 1H)

¹³ C-NMR (100 MHz, CD ₃ OD): δ 14.2, 27.6, 34.9, 38.5, 55.4,

65, 9, 70.2, 79.5, 80.1, 113, 9, 114.0, 118.8, 121.8, 129.1,

130.8, 132.9, 137.6, 147.3, 149.5, 154.3, 174.9.

Example 55

3- [3- / 2- (4-tert-butoxycarbonylaminophenyl / ethoxy) -4-methoxyphenyl] -2-ethoxypropanoic acid

3- [3- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy] -4-methoxyphenyl] -2-ethoxypropanoic acid was synthesized according to the procedure described in Example 54.

¹ H-NMR (400 MHz, CD ₃ OD): δ 1.1 (t, 3H), 1.5 (s, 9H), 2.82.88 (m, 1H), 2.91-3.02 (m, 3H), 3.32-3.37 (m, 1H), 3.533.61 (m, 1H), 3.76 (s, 3H), 3.95 (m, 1H), 4.1- 4.15 (m, 2Η),

- 132 • ·· · * ·· ····

6.77 (m, 1H), 6.81-6.85 (m, 2H), 7.19 (d, 2H), 7.3 (d, 2H), 8.75 (s broad, 1H).

¹³ C NNIR (100 MHz, CD ₃ 0D): δ 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 / oxy] carbonylamino) phenyl] ethoxy / phenyl] propanoic acid (a) Acid hydrochloride 3 - [4- / 2- (4-aminophenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid

To a solution of 3- [4- / 2- (4-aminophenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid hydrochloride (described in Example 41b) (15 g, 42 mmol) in tetrahydrofuran (100 mL) was added water (200 mL). Lithium hydroxide (3.4 g, 84 mmol) dissolved in a small amount of water was added with stirring and then the reaction mixture was stirred overnight at room temperature. 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 is dried over magnesium sulfate. Evaporation gave 6.4 g of 3- [4- / 2- (4-aminophenyl) ethoxy] phenyl] - (S) -2-ethoxypropanoic acid hydrochloride. The acidic aqueous phase mentioned above was neutralized with sodium hydroxide to a pH of about 5 and extracted with dichloromethane. The organic phase is dried over magnesium sulphate and evaporated. This gives an additional 1.4 g of the desired product. Total

9 fc · 9 9 9 9 · 9 «99 9« · · · · 9 • 9 · «9

9 «·

The yield of 3- [4- / 2- (4-aminophenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid hydrochloride is 7.8 g (50.8%).

¹ H-NMR (500 MHz, CD ₃ OD): δ 1.12 (t, J = 7 Hz, 3H), 2.85 (dd, J = 14.8 Hz, 1H), 2.94 (t, J = 7Hz, 2H), 2.97 (dd, J = 14, 4.5Hz, 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).

ⁿ C-NMR (125 MHz, CD ₃ OD): δ 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 (2C), 144.82, 159.10, 176.35.

(b) (S) -2-Ethoxy-3- [4- (2- [4 - ([[4- (tert-butyl) cyclohexyl / oxy] carbonylamino) phenyl] ethoxy) phenyl] propanoic acid

3- [4- / 2- (4-Aminophenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid hydrochloride (0.2 g, 0.547 mmol) and sodium bicarbonate (0.05 g, 0.595 mmol) were combined. in tetrahydrofuran (5 mL), stirred at room temperature for 20 minutes, and then 4-tert-butylcyclohexylchloroformate (0.131 g, 0.599 mmol) was added. The reaction mixture was stirred at room temperature overnight and then a little additional 4-tert was added. -butylcyclohexylchloroformate, since the reaction is not complete by HPLC. The reaction mixture was stirred for 2 additional 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 over magnesium sulfate and the solvent was evaporated. Chromatography on silica gel (Isolute, SI) using dichloromethane: heptane (1: 1) followed by dichloromethane followed by methanol: dichloromethane (1:99) gave 0.28 g as eluents. ·· ·· · «« · · «and ·· · · ··

-Π4- .. ¹ ····· ¹ ······ · ···· •. (93% yield) (S) -2-ethoxy-3 [4- (2- [4 - ([/ 4- ( tert-butyl) cyclohexyl (oxy) carbonylamino) phenyl] ethoxy) phenyl] propane.

¹ H-NMR (400 MHz, CD ₃ OD): δ 0.86 (s, 9H), 0.99-1.18 (m, 3H),

1.10 (t, J = 7 Hz, 3H), 1.35 (dd, broad, J = 24, 12 Hz,

2H), 1.83 (d, broad, J = 12 Hz, 2H), 2.08 (d, broad, J =

12 Hz, 2H), 2.83 (dd, J = 1) 4.5, 8 P Iz, 1H), 2.92-2.98 (m, 3H), 3, 29-3, 36 (m, 1H); 53-3,61 (m, 1H), 3.97 (dd, J = 8, 4.5 Hz, 1H, 4.08 (t, J = 7H) Hz, 2H) , 4 , 48-4.56 (m, 1H) , 6.79 (d, J = 8.6 Hz), 7.12 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H) a 7, 32 (d, J = 8.5) Hz). ¹³ c-nmr (100 MHz, CD ₃ OD): δ 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 (20, 134.40, 138.57, 155.80, 159, 06, 176, 05 /

Example 57

(S) -2-Ethoxy-3- [4- / 2- (4- (phenoxycarbonylamino) phenyl) ethoxy / phenyl] propanoic acid ethyl ester

3- [4- / 2- (4-Aminophenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid ethyl ester hydrochloride (described in Example 41b) (0.55 g, 1.4 mmol) was dissolved in tetrahydrofuran ( 5 ml). Phenylchloroformate (0.675 g, 3 mmol) was added slowly. The reaction mixture was stirred at room temperature and continuously checked by HPLC and after 3 days all starting material was consumed. Water was added, tetrahydrofuran was evaporated and the residue was extracted 3 times with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated. Purification of the crude product by preparative HPLC (Kromasil

- 135φ Φ · · · Φ · Φ · · · · · Φ · · · ·

C8, 7 µm, 50x250 mm) using acetronitrile (70%) ammonium acetate buffer (pH 7) as the mobile phase gave 0.46 g (96.3% yield) of (S) -2-ethoxy-3 ethyl ester - [4- (2- (4- / phenoxycarbonylamino) phenyl) ethoxy / phenyl] propanoic ^X H-NMR (300 MHz, CDC1 _3): δ 1.18 (t, 3H), 1.24 (s, 9H) 2.96 (d, 2H), 3.07 (t, 2H), 3.31-3.41 (m, 1H), 3.55-3.68 (m,

1H), 3.98 (t, 2H), 4.10-4.23 (m, 4H), 6.83 (d, 2H), 6.96 (s broad, NH), 7.12-7, 31 (m, 9H), 7.37-7.45 (m, 4H), ¹³ C-NMR (75 MHz, CDCl 3): δ 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) Benzyl (-2- (2-methoxyethoxy) 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). Benzyl bromide (15.3 g, 89 mmol) dissolved in dichloromethane (150 mL) was added. The reaction mixture was refluxed for 4 hours. After separation, the organic phase is dried over magnesium sulphate and evaporated. Chromatography using dichloromethane as eluent gave 17.5 g (94%) of benzyl (2- (2-methoxyethoxy) acetate).

¹ H-NMR (500 MHz, CD ₃ OD): δ 3.41 (s, 3H), 3.62 (t, 2H), 3.77 (t, 2H), 4.24 (s, 2H), 5.23 (s, 2H); 7.31-7.45 (m, 5H).

- 136 -

(b) (2) -3- [4- (Benzyloxy) phenyl] -2- (2-methoxyethoxy) -2-propenoic acid benzyl ester

4- (Benzyloxy) benzaldehyde (3.00 g, 14.0 mmol) and benzyl- (2- (2-methoxyethoxy) 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) dissolved in dry tetrahydrofuran (10 mL) was added slowly and the reaction mixture was stirred at -20 overnight.

Deň: 32 ° C. Quench the reaction with acetic acid (0.85 g, 14.0 mmol). The crude product was isolated, redissolved in toluene, and maintained at reflux temperature with p-toluenesulfonic acid (0.24 g, 1.4 mmol) overnight, while the water was digested into a Dean-Stark trap. The solution was cooled, washed with sodium bicarbonate, dried over magnesium sulfate and evaporated. Purification of the crude product by preparative HPLC (Kromasil C8, 10 µπι, 50x500 mm) using acetronitrile (50-70%) in ammonium acetate buffer (pH 7) as the mobile phase afforded 1.83 g (29% yield) of benzyl ester. (2) -3- [4- (benzyloxy) phenyl] -2- (2-methoxyethoxy) -2-propenoic acid.

¹ H-NMR (500 MHz, CD ₃ OD): δ 3.36 (s, 3H), 3.65-3.72 (m, 2H), 4.09-4.17 (m, 2H), δ 11 (s, 2H), 5.30 (s, 2H), 6.98 (d,

2H), 7.05 (s, 1H), 7.32-7.50 (m, 10H), 7.81 (d, 2H).

(c) 3- (4-Hydroxyphenyl) -2- (2-methoxyethoxy) propanoic acid

(2) -3- [4- (Benzyloxy) phenyl] -2- (3-methoxyethoxy) -2-propenoic acid benzyl ester (1.75 g, 4.2 mmol) was hydrogenated in methanol (50 mL) at atmospheric pressure for

The use of palladium on carbon (5%) as a catalyst. The mixture was filtered through diatomaceous earth and evaporated in vacuo to give 0.83 g (88% yield) of (4-hydroxyphenyl) -2- (2-methoxyethoxy) propanoic acid.

¹ H-NMR (500 MHz, CD ₃ OD): δ 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, 1H);

2H).

(d) 3- (4-Hydroxyphenyl) -2- (2-methoxyethoxy) propanoic acid methyl ester

3- (4-Hydroxyphenyl) -2- (2-methoxyethoxy) propanoic acid (0.80 g, 3.1 mmol) was dissolved in methanol saturated with hydrochloric acid and kept at reflux for 2 hours. The mixture was evaporated in vacuo to give 0.84 g (99% yield) of 3- (4-hydroxyphenyl) -2- (2-methoxyethoxy) propanoic acid methyl ester.

¹ H-NMR (500 MHz, CD ₃ OD): δ 2, 97-3.02 (m, 2H), 3.34 (s, 3H), 3.50-3.57 (m, 4H), 3 13 (s, 3H), 4.08-4.17 (m, 1H), 6.75 (d, 2H), 7.11 (d, 2H).

(c) 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2- (2-methoxyethoxy) propanoic acid methyl ester

2- [4- (tert-Butoxycarbonyl (methyl) amino / phenyl] ethyl 4-methylbenzenesulfonate (described in Example 40a) (0.50 g, 1.26 mmol), 3- (4-hydroxyphenyl) methyl ester - 2- (2-methoxyethoxy) propane (0.32g, 1.26 mmol) and potassium carbonate (0.35 g, 2.64 mmol) were combined in acetonitrile (20 mL) and the mixture was maintained at room temperature overnight

-138 • t 9 · 9 · · · · · ·

9 99 999 reverse flow. Water was added, the acetonitrile was evaporated and the residue was extracted 3 times with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated. Purification of the crude product by preparative HPLC (Kromasil C8, 7 µm, 50x250 mm) using acetronitrile (50-70%) ammonium acetate buffer (pH 7) as the mobile phase afforded 0.34 g (58% yield) of methyl 3- ester. [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2- (2-methoxyethoxy) propane.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 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 (s broad, NH), 6, 82 (d, 2H), 7.15 (d, 2H), 7.21 (d, 2H), 7.32 (d, 2H).

¹³ C-NMR (125 MHz, CDCl ₃ ): δ 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

3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2- (2-methoxyethoxy) propanoic acid methyl ester (described in Example 58) (0.26 g, 0.55 mmol) was dissolved 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 at room temperature for 2 hours and then evaporated. The residue was redissolved in diethyl ether and hydrochloric acid (2M) and extracted

-139fl se. The organic phase was dried over magnesium sulfate and evaporated to give 0.236 g (92% yield) of 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) -ethoxy] phenyl] -2- (2-methoxyethoxy) propanoic acid.

¹ H-NMR (600 MHz, CDCl ₃ ): δ 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 (d broad, 2H).

¹³ C-NMR (125 MHz, CDCl 3): δ 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, 174.6.

Example 60

3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid methyl ester

3- [4- / 2- (4-tert-butoxycarbonylamino-phenyl) ethoxy / phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid methyl ester was synthesized using the same procedure as in Example 62 (a) from 3- (4-hydroxyphenyl) -2- (2,2,2-trifluoroethoxy) propanoic acid methyl ester and 4- (2-hydroxyethyl) phenylcarbamic acid tert-butyl ester (described in Example 38b).

¹ H-NMR (300 MHz, CD ₃ OD): δ 1.54 (s, 9H), 2.95-3.12 (m, 4H),

3,63-3,74 (m, ΙΗ), 3.75 (with, 3H), 3.95-4.04 (m, 1H), 4 12 (t, 3H); 1,16- -4.22 (m, 1H), 6, 59 (with wide, NH) , 6.83 (d, 2H), 7.14 (d, 2H), 7.21 (d, 2H), 7.32 (t, 2 H).

- 140 ¹³ C-NMR (75 MHz, CD ₃ OD): δ 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) (0.27 g, 0, Dissolve 52 mmol) in tetrahydrofuran and water (2: 1), add lithium hydroxide (0.015 g, 0.62 mmol) and stir the reaction overnight. Water was added and the 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 is dried over magnesium sulfate. Evaporation gave 0.22 g (85% yield) of the acid

3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy / phenyl] -2- (2,2,2-trifluoroethoxy) propane.

¹ H-NMR (500 MHz, CD ₃ OD): δ 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 (m, 1H);

4.23 (q, 1 H), 6.84 (d, 2 H), 7.18 (d, 2 H), 7.22 (d, 2 H),

7.31 (m, 2 H).

¹³ C-NMR (125 MHz, CD ₃ OD): δ 28.7, 35.42, 38.5, 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 62 • 4

4

- 140 «4 · · · *

44444 · ··

4 4 4 4 4

444 44 44 4444

2-Ethoxy-3- [4- / 2- (4-methanesulfonylaminophenyl) ethoxy / phenyl] propanoic acid ethyl ester (a) 3- [4- / 2- (4-aminophenyl) ethoxy) phenyl] -2-ethoxypropanoic acid ethyl ester

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) were dissolved in dichloromethane ( 35 ml) under argon at room temperature. Azodicarbonyldipiperidine (3.85 g, 15.2 mmol) was added followed by triphenylphosphine (3.20 g, 12.2 mmol). After stirring at room temperature for 1 minute, dichloromethane (30 mL) was added and after 21 hours the solvent was evaporated in vacuo. Purification by silica gel chromatography using heptane: ethyl acetate (3: 2) as eluent gave 3.12 g (86% yield) of 3- [4- / 2- (4-aminophenyl) ethoxy / phenyl] -2- ethoxypropane.

1 H-NMR (400 MHz, CDCl ₃ ): δ 1.18 (t, 3H, J = 7 Hz), 1.24 (t,

3H, J = 7Hz), 2.95-3.02 (m, 4H), 3.31-3.42 (m, 1H), 3.583.67 (m, 3H), 3.96-4.02 (m, 1H), 4.10 (t, 2H, J = 7Hz),

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, unresolved).

¹³ C-NMR (100 MHz, CDCl 3): δ 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- [4- / 2- (4-methanesulfonylaminophenyl) ethoxy / phenyl] propanoic acid ethyl ester

- 142 • »

Triethylamine (0.544 g, 2.99 mmol) then methanesulfonyl chloride (0.392 g, 2.99 mmol) were added to a solution of 3- [4- / 2- (4-aminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid ethyl ester ( 0.89 g, 2.49 mmol) in dichloromethane (8.9 mL) at 0 ° C. After stirring at room temperature for 20 hours, the reaction mixture was poured onto a mixture of hydrochloric acid and ice. Dichloromethane is added, the phases are separated and the organic phase is washed with water, dried over sodium sulfate, filtered and the solvent is evaporated off under vacuum. Purification by silica gel chromatography eluting with heptane: ethyl acetate (3: 2) afforded 0.78 g (72% yield) of 2-ethoxy-3- [4- / 2- (4-methanesulfonylaminophenyl) ethoxy / phenyl] ethyl ester. Propane.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.18 (t, 3H, J = 7Hz), 1.25 (t, 3H, J = 7Hz), 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), 3.984-03 (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).

¹³ C-NMR (125 MHz, CDCl ₃ ): δ 14.1, 15.0, 35.0, 38.3, 39.0,

60.7, 66.1, 68.3, 80.2, 114.2, 121.2, 129.3, 130.1, 130.3,

135.1, 135.7, 157.4, 172.5.

Example 63

2-Ethoxy-3- [4- / 2- (4-methanesulfonylaminophenyl) ethoxy / phenyl] propanoic acid

2-Ethoxy-3- [4- (2- / 4-methane-143-sulfonylaminophenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in Example 62) (0.554 g, 1.27 mmol) was dissolved in tetrahydrofuran ( 5.7 ml). Lithium hydroxide hydrate (0.137 g, 3.26 mmol) was dissolved in water and added portionwise over 30 minutes at room temperature. The reaction mixture was stored in a refrigerator overnight. The tetrahydrofuran was evaporated in vacuo. The aqueous residue was washed with ethyl acetate, acidified to pH 1-2 with hydrochloric acid (1M) and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated in vacuo to give 0.54 g (100% yield) of 2-ethoxy-3- [4- (2- (4-methanesulfonylaminophenyl) ethoxy)]. phenyl] propane.

1 H-NMR (400 MHz, CDCl ₃ ): δ 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 (m, 6H), 7.40 (s, 1NH), 9.02 ( s broad, 1H).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 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

(S) -2-Ethoxy-3- [4- / 2- (4- (methylsulfonyl (methyl) amino) phenyl) ethoxy / phenyl] propanoic acid ethyl ester (a) (S) -2-Ethoxy-3- ethyl ester [4- / 2- (4- (methylsulfonylamino) phenyl) ethoxy / phenyl] propane

3- [4- / 2- (4-aminophenyl) -144 acid hydrochloride ethoxy / phenyl - (S) -2-ethoxypropanoic acid (described in Example 41b) (0.45 g, 1.26 mmol), dichloromethane (10 mL), methanesulfonyl chloride (0.216 g, 1.88 mmol) and triethylamine (0.318 g,

3.14 mmol) was added at 0 ° C and stirred at 0 ° C for 3 hours then at room temperature overnight.

The reaction mixture was poured into ethyl acetate (50 mL). The triethylamine hydrochloride salt was filtered off and the filtrate was evaporated. The residue was redissolved and extracted with ethyl acetate and water. The organic phase is washed once more with water, dried over sodium sulphate and evaporated. Chromatography with diethyl ether: petroleum ether (1: 3, 1: 1, 3: 1) as eluent gave 0.18 g (32.8% yield) of (S) -2-ethoxy-3- [4- / 2-ethyl ester]. - (4- (methylsulfonylamino) phenyl) ethoxy / phenyl] propane.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.21 (t, 3H), 1.28 (t, 3H), 2.99 (m, 2H), 3.04 (s, 3H), 3 11 (m, 2H); 3.39 (m, 1H); 3.64 (m, 1H); 4.01 (m, 1H); 4.15-4.25 (m, 4H); 84 (d, 2H), 7.17 7.23 (m, 4H), 7.30-7.35 (m, 2H).

(c) (S) -2-Ethoxy-3- [4- / 2- (4- (methylsulfonyl (methyl) amino) phenyl) ethoxy / phenyl] propanoic acid ethyl ester

(S) -2-Ethoxy-3- [4- / 2- (4- (methylsulfonylamino) phenyl) ethoxy / phenyl] propanoic acid ethyl ester (0.17 g, 0.39 mmol) was dissolved 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 diethyl ether and water. The organic phase is washed once more with water, dried over sodium sulphate and evaporated. Chromatography with ethyl acetate: petroleum ether (1: 1) afforded 0.098 g (55.8% yield) of the ethyl ester.

- 145 • 99 999 9 · · · _w 9 9 9 9 · ·

(S) -2-ethoxy-3- [4- / 2- (4- (methylsulfonyl (methyl) amino) phenyl) ethoxy / phenyl] propanoic acid.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.16 (t, 3H), 1.23 (t, 3H), 2.84 (s, 3H), 2.94 (m, 2H), 3 0.08 (m, 2H), 3.31 (s, 3H), 3.36 (m,

1H), 3.60 (m, 1H), 3.96 (m, 1H), 4.10-4.20 (m, 4H), 6.80

of (d, 2H), 7.14 (d, 2H), 7.31 (m, 4H). ¹³ c-nmr (75, 4 MHz, CDC1 _3): δ 14.1, 15, 1, 35.0-35.5 (2C), 38,0-38 7 (2C) 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) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid

3- [4- / 2- (4-Aminophenyl) ethoxy) phenyl] - (S) -2-ethoxypropanoic acid hydrochloride (described in Example 56a) (0.2 g, 0.547 mmol) and sodium bicarbonate (0.06 g) ,

0.6 mmol) was combined 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 over magnesium sulfate and the solvent was evaporated. Chromatography on silica gel (Isolute, SI) using dichloromethane and then methanol (2%) in dichloromethane as eluent afforded 0.28 g (89% yield) of 3- [4- / 2- (4 -) -

- (2,4,5-trichlorobenzenesulfonylamino) phenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic.

- 146-

@ 1 H-NMR (500 MHz, CDCl3) .delta z, CDi 0l ₃ ): δ 1, 21 (t, J = 7) Hz, 3H), 2.98 (dd, J = 14.5, 7.5 Hz, ÍH), 3.03 (t, J = 6.5 Hz, 2H), 3.09 (dd, J = 14.5, 4,5 Hz, ÍH), 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 = 7Hz) 2H), 6.81 (d, J = 8 Hz, 2H), 7.10 (d, J = ⁸ Hz, 2H), 7.17 (d, J = 8Hz, 2H), 7.21 (d, J = 8Hz, 2H) , 7.29 (s, 1H), 7, 63 (s, 1H) and 8.10 (with, ÍH).

¹³ C-NMR (125 MHz, CDCl ₃ ): δ 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

3- [4- / 2- (4-Benzylsulfonylaminophenyl) ethoxy / phenyl] -2- (S) -ethoxypropanoic acid ethyl ester

3- [4- / 2- (4-Aminophenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid ethyl ester hydrochloride (described in Example 41b) (0.5 g, 1.27 mmol) was dissolved in dichloromethane ( 10 mL) and triethylamine (0.39 mL, 2.8 mmol) was added. The mixture was cooled to 0 ° C and 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 is added and the phases are separated. The organic phase is washed with water, dried over magnesium sulphate and evaporated. Chromatography of the residue on silica gel using ethyl acetate / heptane as eluent gave 0.245 g (38% yield) of 3- [4- / 2- (4-benzylsulfonylaminophenyl) ethoxy] phenyl] -2- (S) -ethoxypropanoic acid ethyl ester.

• 9 0

- 147 • 99 9 '''H-NMR (600 MHz, CDC1 _3): δ 1.16 (t, J = Ί Hz, 3H), 1.15 (t,

Hz, 3H), 2.91-2.97 (m, 2H) , 3.06 (t, J = 7Hz, 2H) 3.37 (m, 1H), 3.57-3.62 (m, 1H) , 3.96 (dd, J = 8.6Hz, 4, 13- -4.17 (m, 4H) 4.29 (with, 2H) 6, 82 (d, 8.4 Hz, 2 H),

7.10 (d, J = 8.4Hz, 2H), 7.15 (d, J = 9Hz, 2H), 7.24-7.26 (m, 4H) and 7.30-7.32 (m, 3 H).

¹³ C-NMR (150 MHz, CDCl ₃ ): δ 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 (20, 130.35 (20, 130.78 (20, 135.12, 135.22, 157.43, 172.50.

Example 67

3- [4- / 2- (4-Benzylsulfonylaminophenyl) ethoxy / phenyl] -2- (S) -ethoxypropanoic acid

3- [4- / 2- (4-Benzylsulfonylaminophenyl) ethoxy / phenyl] -2- (S) -ethoxypropanoic acid ethyl ester (described in Example 66) (0.15 g, 0.29 mmol) was dissolved in tetrahydrofuran (2). ml). Add lithium hydroxide (0.0084 g, 0.35 mmol) in water (2 mL). The reaction mixture was stirred at room temperature. After 6 hours, the reaction mixture was checked by TLC (silica gel, ethyl acetate: heptane = 50:50) and the reaction was found not to be complete. Lithium hydroxide (about 0.01 g) was added, the reaction mixture was stirred overnight and the tetrahydrofuran was evaporated. The remaining rotzoc is extracted with diethyl ether. The aqueous phase was acidified with hydrochloric acid (1%) to a pH of about 2 and extracted twice with ethyl acetate. The organic phases were combined, dried over magnesium sulfate and the solvent was evaporated. Chromatography of the residue on silica gel (Isolute, SI) using dichloromethane followed by dichloromethane: methanol (98: 2) as •

99

9 «« f A A

The yield of 0.125 g (88% yield) of 3- [4-] acid is obtained in 9 9 9 9 of the eluent. (2- (4-Benzylsulfonylaminophenyl) ethoxy) phenyl] -2- (S) -ethoxypropanoic acid.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 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, J = 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 MHz, CDCl ₃ ): δ 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 (20, 130.44 (2C), 130.81 (20, 135.10, 135.21, 157.57, 175.78).

Example 68

2-Ethoxy-3- [4- / 2- (4-isobutyrylaminophenyl) ethoxy / phenyl] propanoic acid ethyl ester (a) N- [4- (2-hydroxyethyl) phenyl] isobutyramide

2-Methylpropanoic anhydride (24.15 g, 153 mmol) was slowly added to a warm solution of 4-aminophenethyl alcohol (21 g, 153 mmol) in acetone (200 mL). The reaction mixture was refluxed for 1 hour, and then additional 2-methylpropanoic 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 in dichloromethane: heptane gave 30.7 g (yield 0.97%) of N- [4- (2-hydroxyethyl) phenyl] isobutyramide as white crystals.

0

- 149 «00 • 0 0 0 β '· 0 0 • 0 V 0 · * 0 ** 0 • · · 0 0

0 H-NMR (400 MHz, acetone-d ₆ ): δ 1.20 (d, 6H, J = 6.7 Hz), 2.54-2.64 (m, 1H), 2.80 (t, 2H, J = 7Hz), 3.40 (t, 1H, J = 5.6Hz), 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 broad, 1 NH).

(b) 2-Ethoxy-3- [4- / 2- (4-isobutyrylaminophenyl) ethoxy / phenyl] propanoic acid ethyl ester

2-Ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (described in Example 20b) (0.71 g, 2.97 mmol) dissolved in dichloromethane (5 mL) was added to a mixture of N- [4- (2- hydroxyethyl) phenyl] isobutyramide (0.5 g, 2.47 mmol), azodicarbonyldipiperidine (0.75 g, 2.97 mmol) and triphenylphosphine (0.78 g, 2.97 mmol) in dichloromethane (15 mL). After stirring at room temperature overnight, the reaction mixture was filtered and the solvent was evaporated in vacuo. vacuum. The residue was purified by silica gel chromatography using heptane: ethyl acetate (gradient 3: 1 to 1: 1) as eluent to afford 0.69 g (yield 65%) of 2-ethoxy-3- [4- / 2- ( 4-isobutyrylaminophenyl) ethoxy / phenyl] propane.

¹ H NMR (500 MHz, CDCl ₃ ): δ 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), 4.11 (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 = 7.1Hz, 2H), 2.94 (m, 2H), 2.50 (septet, J = 6.9Hz, 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

- 150 2-Ethoxy-3- [4- / 2- (4-isobutyrylaminophenyl) ethoxy / phenyl] propanoic acid

2-Ethoxy-3- [4- / 2- (4-isobutyrylaminophenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in Example 68) was hydrolyzed using the same procedure as in Example 2 to give 2-ethoxy-3- [ 4- [2- (4-isobutyrylaminophenyl) ethoxy] phenyl] propane.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.46 (d, 8.3 Hz, 2H), 7.37 (s,

NH, 1H), 7.20 (d, J = 8.3Hz, 2H), 7.13 (d, J = 8.5Hz,

2H), 6.79 (d, J = 8.5Hz, 2H), 4.11 (m, 2H), 4.02 (dd, J =

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 (m, 1H), 1.23 (d, J = 6.9 Hz, 6H), 1.14 (t, J = 7.0 Hz, 3H).

¹³ C-NMR (75 MHz, CDCl ₃ ): δ 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

(S) -2-Ethoxy-3- [4- / 2- (4-isobutyrylaminophenyl) ethoxy / phenyl] propanoic acid ethyl ester (a) (S) -2-Ethoxy-3- [4- / 2- ( 4-isobutyrylaminophenyl) ethoxy / phenyl] propane

Azodicarbonyldipiperidine (0.99 g, 3.93 mmol) and triphenylphosphine (1.03 g, 3.93 mmol) were added to a solution of N- [4- (2-hydroxyethyl) phenyl] isobutyramide (described in Example 68a) (0). (79 g, 3.93 mmol) and (S) -2- • ethyl ester

4

I · · · «

- 150 4 · ·

-ethoxy-3- (4-hydroxyphenyl) propane (described in Example 40h) (0.78 g, 3.27 mmol) in dry dichloromethane (25 mL). After stirring at room temperature overnight, additional N- [4- (2-hydroxyethyl) phenyl] isobutyramide, azodicarbonyldipiperidine (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 silica gel chromatography eluting with heptane: ethyl acetate (2: 1) afforded 1.22 g (87% yield) of (S) -2-ethoxy-3- [4- / 2- (4-isobutyrylaminophenyl) ethyl ester. ethoxy / phenyl] propane.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.17 (t, 3H, J = 7 Hz), 1,201.26 (m, 9H), 2.55 (quintet, 1H, J = 6.7 Hz) 1.95-2.98 (m, 2H), 3.03 (t, 2H, J = 7Hz), 3.33-3.41 (m, 1H), 3.57-3.65 ( m, 1H), 3.98-4.02 (m, 1H), 4.12 (t, 2H, J = 7Hz), 4.17 (q, 2H, J = 7Hz), 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): δ 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

(S) -2-Ethoxy-3- [4- / 2- (4-isobutyrylaminophenyl) ethoxy / phenyl] propanoic acid

(S) -2-Ethoxy-3- [4- / 2- (4-isobutyrylaminophenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in Example 70) was hydrolyzed using the same procedure

152 (as in Example 2 to obtain (S) -2-ethoxy-3- [4- / 2- (4-methanesulfonylphenyl) ethoxy / phenyl] propane).

1 H-NMR (500 MHz, CDCl ₃ ): δ 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), 3.66-3 66 (m, 1H), 4.01-4.06 (m, 1H), 4.12 (t, 2H, J = 7Hz), 6.80 (dm, 2H, J = 8.8Hz, 7.14 (dm, 2H, J = 8.8 Hz, undifferentiated), 7.22 (dm, 2H, J = 8.3 Hz, undifferentiated), 7.31 (s broad, 1NH), 7 47 (dm, 2H, J = 8.3 Hz, unresolved).

¹³ C-NMR (125 MHz, CDCl ₃ ): δ 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

2-Ethoxy-3- [4- / 2- (4- (isobutyryl-N-methylamino) phenyl) ethoxy / phenyl] propanoic acid ethyl ester

2-Ethoxy-3- [4- / 2- (4-methylaminophenyl / ethoxy) phenyl] propanoic acid (described in Example 99) (0.477 mg, 1.28 mmol) was dissolved in a solution of isobutyric anhydride (2 mL) and pyridine (4 mL) and the reaction mixture was stirred at room temperature for 2 h. Toluene was added and evaporated in vacuo. Purification of the crude product by silica gel chromatography using heptane: ethyl acetate (1: 1) as eluent gave 0.44 g (78% yield) of 2-ethoxy-3- [4- / 2- (4- (isobutyryl- N-methylamino) phenyl) ethoxy / phenyl] propane.

1 H-NMR (400 MHz, CDCl 3): δ 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 = J)

• »· · · ♦ · 9 ·« • «·· · 0 0 · ₉ • · · * * * ♦ ♦ * ·· · ·· · 9000 90

J = 7.1 and 6.1 Hz, 1H),

3H), 3.11 (t, J = 7.1)

J = 6.7 Hz, 1H), 1.23 Hz, 3H), 1.03 (d, J =

- 153-

8, 6 Hz, 2H), 4.17 (m, 4H), 3.97 (dd 3, 60 (m, 1H), 3.35 (m, 1H), 3.23 (s Hz, 2H), 2.95 (m, 2H). 2.52 (septet (t, J = 7.1 Hz, 3H), 1 16 (t, J = 6) 6.7 Hz, 6H).

Example 73

2-Ethoxy-3- [4- / 2- (4- (isobutyryl-N-methylamino) phenyl) ethoxy / 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] ethyl ester [phenyl] propane (described in Example 72) (435 mg, 0.98 mmol) in tetrahydrofuran (6 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified to pH 4 with hydrochloric acid (2M). 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 over sodium sulfate and the solvent was evaporated in vacuo to give 398 mg (yield 98%) of 2-ethoxy-3- [4- / 2- (4- (isobutyryl-N-methylamino) phenyl) ethoxy] phenyl Propane.

1 H-NMR (300 MHz, CDCl ₃ ): δ 1.02 (d, 6H, J = 6.6 Hz), 1.16

(t, 3H, J = 7Hz) 2.49 (quintet, IH, 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, IH), 3.94-4.06 (m, 1H), 4.17 (t, 2H, J = 6.6) Hz), 6 82 (dm, 2H, J = 8.4Hz , undifferentiated), 7.05-7.22 (m, 4H), 7, 33 (dm, 2H, J = 8Hz, undifferentiated).

- 154 ¹³ C-NMR (75 MHz, CDCl ₃ ): δ 15.1, 19.6, 38.0, 66, 6, 68.2, 79.8, 114.4, 127.2, 138.3 , 142.4, 157.5, 175.3, 178.0.

• «·· *. ·. · ·.

• · * ·· ··· ··· ♦ »·· ···. . · ...

31, 0, 35, 3, 37.6

129.3, 130.4, 130.5,

Example 74

(S) -2-Ethoxy-3- [4- / 2- (4- (2,2-diphenylacetylamino) phenyl) ethoxy / phenyl] propanoic acid hydrochloride

3- [4- / 2- (4-Aminophenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid hydrochloride (described in Example 56a) (0.2 g, 0.547 mmol) and sodium bicarbonate (0.05 g) (0.6 mmol) was combined in tetrahydrofuran (5 mL) and stirred at room temperature for 20 minutes. Add 2,2-diphenylacetyl chloride (0.151 g, 0.656 mmol). 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 over magnesium sulfate and the solvent was evaporated. Chromatography on silica gel (Isolute, SI) using dichloromethane as eluent gave the crude product and further purification on silica gel using dichloromethane with methanol (0.5-10%) as eluent gave 0.18 g (63% yield) of the acid ( S) -2-ethoxy-3- [4- / 2- (4- (2,2-diphenylacetylamino) phenyl) ethoxy / phenyl] propane.

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 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 = 8.6Hz, 2H), 7.10 (d, J =

8.6 Hz, 2H), 7.21-7.25 (m, 4H), 7.30-7.36 (m, 8H), 7.54 (d,

J = 8.3 Hz, 2H) and 10.42 (s, 1H).

- 1554 · · «» • · 4 4 · 4 9 4 44 • 44 4

44 444 4 · 4444 «4 4 ¹³ C-NMR (125 MHz, DMSO-d _6): δ 16.23, 34.59, 37.95, 57.42,

64.65, 68.22, 80.32, 114.14 (2C), 119.43 (2C), 126.96 (2C), 128.51 (4C), 128.71 (4C), 129.34 (20, 130.32 (20,

130.48, 133.62, 137.54, 140.20 (2C), 156.97, 169.89, 174.2 (found by GHMHC).

Example 75

3- [4- / 2- (4- (4- (tert-butyl) benzoyl) aminophenyl) ethoxy / phenyl] -2- (S) -ethoxypropanoic acid

3- [4- / 2- (4-Aminophenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid hydrochloride (described in Example 56a) (0.2 g, 0.547 mmol) was dissolved in tetrahydrofuran (5 mL) . Sodium bicarbonate (0.053 g, 0.631 mmol) was added and the mixture was stirred for a while. Add 4-tert-butylbenzoyl chloride (0.118 g, 0.6 mmol). 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 is dried over magnesium sulphate and the solvent is evaporated. Chromatography of the residue on silica gel (Isolute, SI) using dichloromethane: heptane (1: 1), dichloromethane and finally methanol: dichloromethane (1:99) as eluent gave 0.238g (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): δ 1.11 (t, J = 7 Hz, 3H), 1.35 (s, 9H), 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 (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 =

- 156 · · 9 · · 9 9 9 9 ♦ · 9 9 19

8.3 Hz, 2H) and 7.86 (d, J = 8.8 Hz, 2H).

¹³ C-NMR (150 MHz, CD ₃ OD): δ 15.31, 31.56 (3C), 35.80, 36.23,

39.32, 67.12, 69.79, 81.29, 115.37 (2C), 122.44 (2C),

126.51 (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

3- [4- / 2- (4- (4- [tert-Butyl] benzoyl) aminophenyl) ethoxy / phenyl] -2- (S) -ethoxypropanoic acid

3- [4- / 2- (4-Aminophenyl) ethoxy) phenyl] - (S) -2-ethoxypropanoic acid hydrochloride (described in Example 56a) (0.2 g, 0.547 mmol) was dissolved in tetrahydrofuran (5 mL) ). Sodium bicarbonate (0.053 g, 0.631 mmol) was added and the mixture was stirred for a while. Add 4-tert-butylbenzoyl chloride (0.118 g, 0.6 mmol). 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 over magnesium sulfate and the solvent was evaporated. Chromatography of the residue on silica gel (Isolute, SI) using dichloromethane: heptane (1: 1), followed by dichloromethane and finally methanol: dichloromethane (1:99) as eluent gave 0.238g (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): δ 1.11 (t, J = 7 Hz, 3H), 1.35 (s, 9H), 2.85 (dd, J = 14.8 Hz, 1H), 2.96 (dd, J = 14.5Hz, 1H), 3.04 (t, J = 7Hz, 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 = 8.3Hz, 2H), 7.14 (d, J = 8.3Hz, 2H),

- 157Φ φ φ «« φ 9

Φ ΦΦΦΦ Φ φ

ΦΦΦ ΦΦ ΦΦ ΦΦΦΦφ φ

7.29 (d, J = 8.3Hz, 2H); 7.54 (d, J = 8.8 Hz, Hz, 2H). 2H), 7.60 (d, J = 8.3 Hz, 2H) and 7.86 (d, J = 8.8) ¹³ c-nmr (150 MHz, CD ₃ OD): δ 15.31, 31.56 (3C), 35.80, 36.23, 39,32, 67.12 , 69.79, 81.29, 115.37 (2C) , 122.44 (2C), 126, 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 77

2- (S) -Ethoxy-3- [4- / 2- (4- (formylamino) phenyl) ethoxy / phenyl] propanoic acid ethyl ester

Formic acid (0.0585 g, 1.27 mmol) was dissolved in dichloromethane (2 mL). To the solution was added imidazole (0.0874 g, 1.27 mmol), followed by the addition of triethylamine (0.353 mL, 2.54 mmol). The mixture was stirred for a while, then oxalyl chloride (0.161 g, 1.27 mmol) in dichloromethane (2 mL) was added slowly. The resulting mixture was stirred for 30 minutes. To the reaction mixture was added a mixture of 3- [4- / 2- (4-aminophenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid ethyl ester hydrochloride (described in Example 41b) (0.5 g, 1.27 mmol). ) and triethylamine (0.176 mL, 127 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature overnight. Water is added and the phases are separated. The organic phase was washed with water, dried over magnesium sulphate and the solvent was evaporated. Chromatography of the residue on silica gel (Isolute, SI) using heptane followed by ethyl acetate: heptane (5%) followed by ethyl acetate: heptane (10%) followed by ethyl acetate: heptane (25%) as eluents gave 0.230 g (47% yield). ) 2- (S) -ethoxy-3- [4- / 2- (4- (formylamino) phenyl) ethoxy / phenyl] propanoic acid ethyl ester.

• © 9 9 9 · * φ »··· <9 9 9 φ φ 9 φ

- 158 »• 999 · .9 99 9 9 9 9 9 9 9 99 99 9 9 9999 99 9 ¹ H-NMR (600 MHz, CDCl ₃ tautomers): δ 1.14 (t, J = 7 Hz,

3H), , 1, 21 (t, with small clefts, J = 7 Hz, 3H), 2,90-2, 97 (m, 2H) OF 3.01 3, 05 (m, 2H); 3.32-3.37 (m, 1H); 3,56-3,6 1 (m, 1H) of 3, 96 (d d, J = 7.6, 5.6 Hz, 1H), 4.09-4 , 09-4,17 (m, 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, 2H), J = 7.22 (d, J = 8.4 Hz, 1H) OF 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): δ 14.09, 14.95, 34.98 (35.09), 60.72, 66.07, 68.29 (68.44), 80, 20, 114.23 (2C),

118.93 (120.05, 2C), 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

(S) -2-Ethoxy-3- [4 - [(4- (formylamino) phenethyl) oxy / phenyl] propanoic acid

3- [4- / 2- (4-Aminophenyl) ethoxy) phenyl] - (S) -2-ethoxypropanoic acid hydrochloride (described in Example 56a) (0.115 g, 0.314 mmol) in tetrahydrofuran (3 mL) was mixed with the mixture. formic acid (0.5 mL) and acetic anhydride (0.3 mL). The resulting mixture was stirred at room temperature overnight. The tetrahydrofuran was evaporated. Ethyl acetate and water were added to the residue. The phases are separated. The organic phase was washed with brine, dried over magnesium sulfate and the solvent was evaporated. Chromatography of the residue on silica gel (Isolute, SI) using dichloromethane followed by methanol: dichloromethane (1%) followed by methanol: dichloromethane (2%) as eluent gave 0.07 g.

- 159 ••• «0 · 0 00 · 0 0 0 0 0 0 0 0 0 ·· 00 0 * 0000 90,000 (62% yield) (S) -2-ethoxy-3- [4 - / (4 - (formylamino) phenethyl) oxy / phenyl] propane.

¹ H-NMR tautomers (500 MHz, CDCl ₃ ): δ 1.21 (t, J = 7 Hz,

3H), 2.97-3.12 (m, 4H), 3.43-3.49 (m, 1H), 3.64-3.71 (m,

1H), 4.07-4.10 (dd, J = 7.5, 4.5 Hz, 1H), 4.12-4.17 (m,

2H), 6.82-6.86 (m, 2H), 7.07 (d, J = 8.3 Hz, 2H one tautomer), 7.18-7.21 (m, 2H), 7.26 (d, J = 8.3 Hz, 2H one tautomer), 7.30 (d, J = 8.3 Hz, 2H one tautomer), 7.52 (d, J = 8.3 Hz, 2H one tautomer) 7.85 (s, 1H one tautomer), 8.37 (s, 1H one tautomer), 8.64 (d, J = 11.4)

Hz, 1H one tautomer), 9.12 (d, J = 11.4 Hz, 1H one tautomer).

¹³ C-NMR tautomers (125 MHz, CDCl ₃ ): δ 14.99, 35.05 (35.15), 37.93, 66.53, 68.29 (68.44), 79.78, 114, 34 (2C), 119.15 (120.22, 2C), 128.94 (129.04), 129.50 (130.22, 2C),

130.42 (130.44, 2C), 134.75 (135.20), 135.93, 157.48 (157.54), 159.68 (163.71), 175.75.

Example 79

2- [4- / 2- (4-Phenylsulfanylphenyl) ethoxy / benzyl] butanoic acid methyl ester (a) 2- (4-Hydroxybenzyl) butanoic acid methyl ester

2 - [(4-hydroxyphenyl) methylene] butanoic acid (10.48 g, 54.5 mmol) was heated at reflux in a solution of sulfuric acid (1%) in methanol (150 mL) for 24 h. 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 over magnesium sulfate and the solvent was evaporated.

- 160flf flflfflfflfflfflfflflflfflf evaporate under vacuum. The crude product (9 g, 43.6 mmol) was used directly in the next step without further purification and identification.

Hydrogenate in methanol using palladium on carbon (5%, 3 g) as a catalyst. The mixture was filtered through diatomaceous earth and the solvent was evaporated. Purification by silica gel chromatography using dichloromethane: methanol (gradient of 0.5 to 100% methanol) as eluent gave 6.8 g (yield 60% over 2 steps) of 2- (4-hydroxybenzyl) butanoate.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.91 (t, 3H, J = 7.7 Hz), 1.551.84 (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 = 8.4Hz), 6.99 (d, 2H, J = 8.4Hz).

¹³ C-NMR (100 MHz, CDCl 3): δ 11.73, 25.09, 37.31, 49.57,

51.47, 115.22, 115.2.2, 129.87, 129.87, 131.26, 154.21,

176.55.

(b) 2- [4- / 2- (4-Phenylsulfanylphenyl) ethoxy / benzyl] butanoic acid methyl ester

2- (4-Phenylsulfanylphenyl) ethanol (0.5 g, 2.17 mmol), azodicarbonyldipiperidine (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 overnight at room temperature, additional azodicarbonyldipiperidine (0.33 g) and additional triphenylphosphine (0.34 g) were added. The solid material was after 2 hours

- 00 00 00 00 00 00 000 000 00 00 0 000 00000 0 0 00 0 0 0 0 0 0 0 0 0 000 00 00 00 0000 00 000 filtered and the filtrate evaporated in vacuo. Purification by silica gel chromatography using heptane: ethyl acetate (5: 1) as eluent gave 0.638 g (yield 70%) of 2- [4- / 2- (4-phenylsulfanylphenyl) ethoxy / benzyl] butanoic acid methyl ester.

³ H NMR (400 MHz, CDCl ₃ ): δ 7.33-7.20 (m, 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 = 7.3Hz, 3H).

Example 80

2- [4- / 2- (4-Phenylsulfanylphenyl) ethoxy / benzyl] butanoic acid

Sodium hydroxide (3 mL, 1 M) was added slowly to a solution of 2- [4- / 2- (4-phenylsulfanylphenyl) ethoxy / benzyl] butanoic acid methyl ester (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. Lithium hydroxide (50 mg) was added and the mixture was stirred at 70 ° C for 24 h. The reaction mixture was acidified with hydrochloric acid (6M), water (20 ml) was added and the product was extracted with ethyl acetate (2 x 25 ml), washed with water (25 ml), dried over sodium sulfate and the solvent evaporated in vacuo to give 0, 53 g (93% yield) of the desired product.

1 H-NMR (400 MHz, CDCl ₃ ): δ 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),

- 162 ····· · · · · · · · · · · · · · · · · · · · · · · · ·

2.93 (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).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 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

2-Ethoxy-3- [4- / 2- (4-methylsulfanylphenyl) ethoxy / phenyl] propanoic acid ethyl ester

2- (4-Methylsulfanylphenyl) ethanol was reacted with 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (described in Example 20b) using the same procedure as in Example 38 (c) to obtain 2-ethoxy ethyl ester -3- [4- / 2- (4-methylsulfanylphenyl) ethoxy / phenyl] propane.

¹ H-NMR (400 MMHz, CDCl ₃ ): δ 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 (m, 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 (m, 4H).

Example 82

2-Ethoxy-3- [4- / 2- (4-methylsulfanylphenyl) ethoxy / phenyl] propanoic acid

2-Ethoxy-3- [4- / 2- (4-methylsulfanylphenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in Example 81) was hydrolyzed using the same procedure as in Example

- 163 •••• 8 9 10 11 12 ·

9 9 9 9 9

999 99 99

2, except that dioxane is used instead of tetrahydrofuran to obtain 2-ethoxy-3- [4- / 2- (4-methylsulfanylphenyl) ethoxy] phenyl] propanoic acid.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.19 (t, 3H), 2.49 (s, 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 ): δ 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- [4- / 2- (4-Methylsulfanylphenyl) ethoxy / phenyl] -2-phenoxypropanoic acid methyl ester (a) 3- (4-Benzyloxyphenyl) -2-phenoxypropanoic acid methyl ester

3- (4-Benzyloxyphenyl) -2-hydroxypropanoic acid methyl ester was reacted with phenol using the same procedure as in Example 38 (c) to give 3- (4-benzyloxyphenyl) -2-phenoxypropanoic acid methyl ester.

¹ H-NMR (400 MHz, CDCl 3): δ 3.21 (m, 2H), 3.70 (s, 3H), 4.80 (dd, 1H, J = 5.4 Hz, 7.3 Hz) 5.31 (s, 2H), 6.86 (dm, 2H, J = 7.8 Hz, unresolved), 6.96 (m, 3H), 7.25 (m, 4H),

7.38 (m, 5H).

(b) 3- (4-Hydroxyphenyl) -2-phenoxypropanoic acid methyl ester · · · · · • ·

- 164 ··· t · · · · · · · · · · · · · · ·

3- (4-Benzyloxyphenyl) -2-phenoxypropanoic acid methyl ester (0.47 g, 1.3 mmol) was hydrogenated in ethyl acetate (20 mL) using palladium on carbon (18 mg, 5%) as a catalyst at atmospheric pressure and at room temperature for 23 hours. Since the reaction is very slow, the catalyst is converted to palladium hydroxide, ethanol (95%, 10 mL) is added and the pressure is raised to 400 kPa. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated in vacuo to give 0.34 g (yield 95%) of 3- (4-hydroxyphenyl) -2-phenoxypropanoic acid methyl ester.

1 H-NMR (400 MHz, CDCl 3): δ 3.19 (m, 2H), 3.72 (s, 3H), 4.79 (dd, 1H, J = 5.4 Hz, 7.3 Hz) 6.76 (dm, 2H, J = 8.3 Hz, unresolved), 6.85 (dd, 2H, J = 1.0 Hz, 8.8 Hz), 6.97 (m,

1H), 7.16 (dm, 2H, J = 8.8 Hz, unresolved), 7.27 (m, 2H).

(c) 3- [4- / 2- (4-Methylsulfanylphenyl) ethoxy / phenyl] -2-phenoxypropanoic acid methyl ester

3- (4-Hydroxyphenyl) -2-phenoxypropanoic acid methyl ester was reacted with 2- (4-methylsulfanylphenyl) ethanol using the same procedures as in Example 38 (c) to give 3- [4- / 2- (4-methylphenyl) methyl ester. (methylsulfanylphenyl) ethoxy / phenyl] -2-phenoxypropanoic acid.

1 H-NMR (400 MHz, CDCl 3): δ 2.50 (s, 3H), 3.07 (t, 2H, J =

7.0 Hz), 3.2 (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

- 165 ·······························

3- [4- / 2- (4-Methylsulfanylphenyl) ethoxy / phenyl] -2-phenoxypropanoic acid

3- [4- / 2- (4-Methylsulfanylphenyl) ethoxy / phenyl] -2-phenoxypropanoic acid methyl ester (described in Example 83) was hydrolyzed using the same procedure as in Example 2 to afford 3- [4- / 2- (4-methylsulfanylphenyl) ethoxy / phenyl] -2-phenoxypropanoic acid.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 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): δ 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

(S) -2-Ethoxy-3- [4- / 2- (4- (phenylsulfanyl) phenyl) ethoxy / phenyl] propanoic acid ethyl ester

2- [4- (Phenylsulfanyl) phenyl] -1-ethanol (1.22 g,

5.12 mmol), triphenylphosphine (2 g, 7.6 mmol) and 1,1 '- (azodicarbonyl) dipiperidine were dissolved in dichloromethane (15 mL).

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 at room temperature. The solid material was filtered off and the solvent was evaporated. Chromatography of the residue on silica gel using ethyl acetate: petroleum ether (40 to 60 ° C), (1:99, 5:95 and 10:90) gave 1.24 g (47% yield).

Φ φ · · φ «• · • • • • • · • φ φ φ φ φ φ φ φ

- (S) -2-ethoxy-3- [4- / 2- (4- (phenylsulfanyl) phenyl) ethoxy] phenyl] propanoic acid ethyl ester.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.21 (t, 3H), 1.28 (t, 3H), 3.00 (m, 2H), 3.11 (m, 2H), 3 40 (m, 1H), 3.65 (m, 1H), 4.01 (m, 1H), 4.16-4.24 (m, 4H), 6.86 (d, 2H), 7 19 (d, 2H); 7.26 7.38 (m, 9H).

Example 86

(S) -2-Ethoxy-3- [4- / 2- (4- (phenylsulfanyl) phenyl) ethoxy / phenyl] propanoic acid

(S) -2-Ethoxy-3- [4- / 2- (4- (phenylsulfanyl) phenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in Example 85) (0.55 g, 1.22 mmol) was dissolved 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. Aqueous hydrochloric acid is added to the solution until the pH is 1. The solvent is evaporated and the residue is redissolved in water and diethyl ether. The phases were separated and the organic layer was washed once with water and dried over sodium sulfate. The solvent was evaporated. Chromatography of the residue on silica gel using diethyl ether: ethanol (95: 5) as eluent gave 0.40 g (78% yield) of (S) -2-ethoxy-3- [4- / 2- (4- (phenylsulfanyl) acid). (phenyl) ethoxy / phenyl] propane.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.18 (t, 3H), 2.97 (m, 1H), 3.07 (m, 3H), 3.42 (m, 1H), 3 63.8 (m, 1H), 4.04 (m, 1H), 4.15 (m, 2), 6.83 (d, 2H), 7.17 (d, 2H), 7.20-7 26 (m, 3H); 7.26-7.35 (m, 6H).

• · ·

- 167-

0 ··

Example 87

2-Ethoxy-3- [4- / 2- (4-methanesulfonylphenyl) ethoxy / phenyl] propanoic acid ethyl ester

3-Chloroperoxybenzoic acid (0.73 g, 4.20 mmol) was added to a solution of 2-ethoxy-3- [4- / 2- (4-methylsulfanylphenyl) ethoxy / phenyl] propanoic acid ethyl ester (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 over sodium sulfate, filtered and the solvent was evaporated in vacuo. Purification by silica gel chromatography eluting with heptane: ethyl acetate (1: 1) afforded 0.399 g (56% yield) of 2-ethoxy-3- [4- / 2- (4-methanesulfonylphenyl) ethoxy / phenyl] propanoic acid ethyl ester.

³ H NMR (600 MHz: CDCl 3): δ 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, J =

8.7 Hz, 2H), 4.19 (t, J = 6.5 Hz, 2H), 4.17 (m, 2H), 3.96 (dd, J = 7.4 and 5.8 Hz, 1H), 3.60 (m, IH), 3.34 (m, IH),

3.17 (t, J = 6.5 Hz, 2H), 3.05 (s, 3H), 2.96 (m, 2H), 1.23 (t, J = 7.1, 3H), 1 16 (t, J = 7.0Hz, 3H).

Example 88

2-Ethoxy-3- [4- / 2- (4-methanesulfonylphenyl) ethoxy / phenyl] propanoic acid

Lithium hydroxide hydrate (57 mg, 1.37 mmol) dissolved in water (2 mL) was added to a solution of 2-ethoxy-3- [4- / 2- (4-methanesulfonylphenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in of Example 87) (384 mg, 0.91 mmol) in tetrahydrofuran (6 mL). After stirring at room temperature for 2 hours, additional lithium hydroxide hydrate (30 mg) dissolved in water (1 mL) was added. The reaction mixture was stirred at room temperature for 4 additional hours. The reaction mixture was acidified with hydrochloric acid (2M) to pH 4. 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 over sodium sulfate and the solvent was evaporated in vacuo. Purification by silica gel chromatography eluting with heptane: ethyl acetate: acetic acid (10: 10: 1) afforded 0.307 g (yield 86%) of 2-ethoxy-3- [4- / 2- (4-methanesulfonylphenyl) ethoxy]. [phenyl] propane as a pale yellow oil which crystallizes under vacuum drying.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.16 (t, 3H, J =

3, 10 (m, 5H) 3.16 (t, 2H) J = 5.4 Hz), 3, 3,53- -3.66 (m, 1H), 3,98-4, 07 / (m, 1H), 4.18 Hz), 6, 76-6, 85 (m, 2H), 7 10- 7.20 (m, 2H). 2H), 7.86-7.96 (m, 2H).

Hz), 2.8736-3.48 (m, 1H), (t, 2H, J = 6.4 7.46-7.55 (m, ¹³ C-NMR (75 MHz, CDCl 3): δ 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 / phenyl] propanoic acid ethyl ester

(S) -2-Ethoxy-3- [4- (2- (4- (phenylsulfanyl) phenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in Example 85) (0.6 g, 1.33 mmol) was dissolved in methylene chloride (10 mL), 3-chloroperbenzoic acid was added and the solution was stirred at 60 ° C for 2 h, partitioned between water and diethyl ether, washed 3 times with water, dried over sodium sulfate and the solvent was evaporated. Chromatography of the residue on an elution gradient of diethyl ether: petroleum ether (40-60 ° C) 33:67, 50:50 and 67:33 gave 0.31 g (yield 48%) of · (S) -2-ethoxy-3 ethyl ester. - [4- / 2- (4- (phenylsulfonyl) phenyl) ethoxy / phenyl] propane.

Example 90

(S) -2-Ethoxy-3- [4- / 2- (4- (phenylsulfonyl) phenyl) ethoxy / phenyl] propanoic acid

(S) -2-Ethoxy-3- [4- / 2- (4- (phenylsulfonyl) phenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in Example 89) (0.34 g, 0.70 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL). To the solution was added lithium hydroxide (0.022 g, 0.092 mmol) and the solution was stirred at room temperature overnight. Aqueous hydrochloric acid is added until the pH is 3-4, the solvent is evaporated to a small volume. The remaining product was partitioned between water and diethyl ether. The aqueous layer was extracted once with diethyl ether. The organic phase was dried over sodium sulfate and the solvent was evaporated. The crude product is chromatographed on an elution gradient (99: 1, 95: 5 and 90:10). The product is isolated as a viscous oil. The oil was dissolved in water and acetonitrile and frozen with liquid nitrogen. Lyophilization for 24 hours gave 0.18 g (56% yield) of the acid

- 170 «9 · · · · 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 (S) -2-Ethoxy-3- [4- / 2- (4- (phenylsulfonyl) phenyl) ethoxy) phenyl] propane.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.07 (t, 3H), 2.83-2.95 (m, 1H), 2.95-3.10 (m, 3H), 3.303, 44 (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).

¹ H-NMR (500 MHz, CDCl 3): δ 1.15 (t, 3H), 1.22 (t, 3H), 2.93 (m, 2H), 3.11 (t, 2H), 3, 37 (m, 1H), 3.62 (m, 1H), 3.98 (m, 1H), 4.14-4.22 (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, 2 H).

Example 91

3- [4- / 2- (4-tert-Butylcarbamoyloxyphenyl) ethoxy / phenyl] -2-ethoxypropanoic acid ethyl ester tert -Butyl isocyanate (0.14 g, 1.4 mmol) is slowly added to a solution of ethyl 2- ethoxy-3- [4- / 2- (4-hydroxyphenyl) ethoxy / phenyl) propanoic acid (described in Example 26b) (0.5 g, 1.4 mmol) in toluene (5 mL) and then stirred overnight. The crude mixture was purified by silica gel chromatography using ethyl acetate: heptane (gradient 1.25 to 80% ethyl acetate) as eluent to give 0.13 g (yield 20%) of 3- [4- / 2- (4-tert-butyl) ethyl ester. n-butylcarbamoyloxyphenyl) ethoxy / phenyl] -2-ethoxypropanoic acid.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.16 (t, 3H, J = 7Hz), 1.20 (t, 3H, J = 7Hz), 1.38 (s, 9H), 2.92-2.99 (m, 2H), 3.05 (t, 2H, J = 7Hz), 3.31-3.38 (m, 1H), 3.55-3.64 (m, ÍH),

- 171 9 9 * · * * * * * * * * * * * * * * * * * * * * * * · · 1

3.94-3.99 (m, 1Η), 4.0 (t, 2Η, J = 7Hz), - 4.16 (q, 2H, J =

Hz), 5.10 (s broad, NH), 6.80 (dm, 2H, J = 8.5 Hz, unresolved), 7.05 (dm, 2H, J = 8.5 Hz, unresolved), 7 14 (dm, 2H, J = 8.5 Hz, unresolved), 7.25 (dm, 2H, J = 8.5 Hz, unresolved).

¹³ C-NMR (125 MHz, CDCl 3): δ 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 92

3- (4- / 2- (4-tert-butylcarbamoyloxyphenyl) ethoxy / phenyl] -2-ethoxypropanoic acid

3- [4- / 2- (4-tert-butylcarbamoyloxyphenyl) ethoxy / phenyl] -2-ethoxypropanoic acid ethyl ester (described in Example 91) is hydrolyzed using the same procedure as in Example 2 to give 3- [4- [2- (4-tert-butylcarbamoyloxyphenyl) ethoxy] phenyl-2-ethoxypropanoic.

1 H-NMR (400 MHz, CDCl ₃ ): δ 1.17 (t, 3H, J = 7 Hz), 1.32 (s, 9H), 2.90-2.97 (m, 2H), 3, Δ (t, 2H, J = 7 Hz), 3.40-3.50 (m, 1H), 3.53-3.65 (m, 1H), 4.03 (m, 1H), 4.10 (t, 2H, J =

6.79 (dm, 2H, J = 8.5 Hz, unresolved), 6.81 (dm,

2H, J = 8.5 Hz, unresolved), 7.11-7.16 (m, 4H).

Example 93

3- [4- / 2- (4-Benzylcarbamoyloxyphenyl) ethoxy / phenyl] -2-ethoxypropanoic acid ethyl ester

2-Ethoxy-3- [4- / 2- (4-hydro-fl.) -Ethyl ester

-172 Flf Flf Flf Flf Flf Flf Flf Flf Flf Flf Phylphenyl) ethoxy / phenyl] propane (described in Example 26b) (0.36g, 1.0 mmol) was dissolved in dry dichloromethane (25 mL) and benzyl isocyanate (0.20 g, 0.185 mL, 1.5 mmol) was added, followed by 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 solution and brine, dried over sodium sulfate and evaporated to give 0.4 g (81%) of crude 3- [4- / 2- (4-benzylcarbamoyloxyphenyl) ethoxy / phenyl] ethyl ester. -2-ethoxypropanoic. The crude material was purified by reverse phase preparative HPLC using an acetonitrile: water: ammonium acetate gradient as the mobile phase. Fractions containing pure product were combined and the acetonitrile was evaporated in vacuo. The residue was dissolved in dichloromethane, washed with water, dried over sodium sulfate and evaporated to give 0.23 g (48%) of pure 3- [4- / 2- (4-benzylcarbamoyloxyphenyl) ethoxy] phenyl] -2- ethoxypropane.

@ 1 H-NMR (300 MHz, CDC1 _3): δ 1,19 (t, 3H) 1.25 (t, 3H), 2.97 (d, 2H) 3.08 (t, 2H); , 31-3,4 4 (m , 1 6), 3.56-3, 69 (m, 1H), 3 99 (t, 1 H), 4.14 (t, 2H) , 4, 18 (q, 2H), 4, 45 (s, 2H), 6 83 (d, 2H), 7.11 (d, 2H) , 7, 17 (d, 2H), 7 29 (d, 2H), 7 32-7.42 (m, 5 H). ⁿ C-NMR (75 MHz, CDCl 3): δ 14,2 , 15 , 0, 35.1, 38.4 , 45,1, 60.7, 6 16, 1, 68.4, 80.3, 114,2, 121, 4, 127.4 127 5, 128.6, 129,2, 129.7, 130.2, 135 , 2, 137 , 9, 149 , 5, 154.6, 157,3,

172.4.

Example 94

2-Ethoxy-3- [4- / 2- (4-phenylcarbamoyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester

- 173 · ♦ t * ► »9 I ·· 9 ·

2-Ethoxy-3- [4- / 2- (4-phenylcarbamoyloxyphenyl) ethoxy / phenyl] propanoic acid ethyl ester was prepared as described in Example 93, starting from ethyl 2-ethoxy-3- [4- / 2- (4-hydroxyphenyl) ethoxy / phenyl] propanoic (0.18 g, 0.5 mmol) (described in Example 26b), phenyl isocyanate (0.18 g, 0.16 mi, 1.5 mmol) and triethylamine (0, 22 mL, 1.6 mmol) in dry dichloromethane (25 mL).

Preparative reverse phase HPLC using an acetonitrile: water: ammonium acetate gradient as the mobile phase afforded 0.073 g (30%) of pure 2-ethoxy-3- [4- (2- / 4-phenylcarbamoyloxyphenyl) ethoxy / phenyl] ethyl ester. propane.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.19 (t, 3H), 1.25 (t, 3H), 2.98

(d, 2H) , 3 , 10 (t, 2H) 3.34-3.43 (m, 1H), 3.58-3.68 (m, IH), 4 00 (t, IH), 4, 16 (t, 2H), 4.19 (q, 2H), 6.84 (d, 2H), 7 11 (t, IH), 7, 16 (d, 2H); 7.17 (d, 2H); 7.32 (d, 2H), 7 35 (t, 2H), 7, 46 (d, 2H), 7.08 (s broad, 1H) ) · ¹³ c-nmr (10 0.6 MHz, CDCl ₃ ): δ 14.2, 15.0, 35, 1, 38.4, 60,8, 66.2, 6 • 8.5 , 80 , 4, 114 , 3, 118.7, 121.6, 123.8, 129, 1, 129.3 129,9, 130 , 4, 135, θ, 137.38, 149.1, 151.7, 157.5, 17 2.5.

Example 95

3- [4- / 2- (4 - ((Benzylamino) carbonylamino) phenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid

3- [4- / 2- (4-Aminophenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid hydrochloride (described in Example 5c) (0.2 g, 0.547 mmol) and sodium bicarbonate (0.053 g) (0.631 mmol) was combined in tetrahydrofuran (5 mL) and stirred at room temperature for 20 minutes. Benzyl isocyanate is added

-174 ····· · · · · · · · · · · · ·

9 ··· 99 99 9 9 9 (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 over magnesium sulfate and the solvent was evaporated. Chromatography on silica gel (Isolute, SI) using dichloromethane and then methanol (1%) in dichloromethane as eluent gave 0.19 g (75% yield) of 3- [4- / 2- (4 - ((benzylamino) carbonylamino) acid). (phenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic.

¹ H-NMR (500 MHz, CDC1 ₃₎ : δ 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, 1 H) , 4.06 (dd, J = 7,5, 4.5 Hz, 1H), 4.10 (t, J = 7 Hz)

2H), 4, 43 (d, J = 4.5 Hz, 2H) 5.30 (broad, 1H), 6.78 (d, J = 8.5 Hz , 2H ), 7.02 (wide, 1H), 7.14 (d, J = 8.5 Hz, 2H), 7, 18 (d, J = 8.5 Hz, 2H) 7.21 (d, J = 8.5Hz, 2H) 7.26 -7, 35 (m, 5H).

¹³ C-NMR (125 MHz, CDCl ₃ ): δ 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 (2C), 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) amino) phenyl) ethoxy] phenyl] propanoic acid

3- [4- / 2- (4-Aminophenyl) ethoxy) phenyl] - (S) -2-ethoxypropanoic acid hydrochloride (described in Example 56a) (0.2 g, 0.547 mmol) was dissolved in tetrahydrofuran (5 mL) .

-175 ··· · · · · · 9 9 9 9 9 9 9 9 9

Sodium bicarbonate (0.051 g, 0.607 mmol) was added and the mixture was stirred for a while. Add 4- (trifluoromethylthio) phenyl isocyanate (0.126 g, 0.575 mmol). 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 and the phases were separated. The organic phase was dried over magnesium sulfate and the solvent was evaporated. Chromatography of the residue on silica gel (Isolute,

SI) using dichloromethane, methanol: dichloromethane (1:99) and then methanol: dichloromethane (2:98) as eluent gave 0.17g (57% yield) of (S) -2-ethoxy-3- [ 4- [2- (4 - (([4- (trifluoromethyl) sulfanyl / anilino / carbonyl) amino) phenyl) ethoxy] phenyl] propane.

¹ H-NMR (400 MHz, CD ₃ OD): δ 1.09 (t, J = 7 Hz, 3H), 2.84 (dd, J = 14.8 Hz, 1H), 2.93-2, 98 (m, 3H), 3.28-3.36 (m, 1H), 3.53-3.60 (m, 1H), 3.97 (dd, 8.5 Hz, 1H), 4.08 (t, J = 7.5Hz, 2H), 6.77 (d, J = 8.5Hz, 2H), 7.12 (d, J = 8.5Hz, 2H), 7.20 (d J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz,

2H), 7.54 (s, 4H).

¹³ C-NMR (125 MHz, CD ₃ OD): δ 15.31, 36, 11, 39.30, 67, 12,

69.82, 81.28, 115.34 (2C), 117.06, 120.40 (2C), 120.76 (2C), 130.47 (2C), 130.70, 131.17 (q, J = 305 Hz), 131.41 (2C), 134.77, 138.35, 138.55 (2C), 143.93, 154.82, 159.04, 176.12.

Example 97

3- [4- / 2- (4 - ((tert-butylamino) carbonyl) aminophenyl) ethoxy / phenyl] -2- (S) -ethoxypropanoic acid

3- [4- / 2- (4-Aminophenyl) -176-

• • 0 9 9 9 • 4 ·· « • 9 · 9 · • • • 8 «·« M · • · 9 · 9 ··· 98 9

ethoxy) phenyl] - (S) -2-ethoxypropanoic acid (described in Example 56a) (0.2 g, 0.547 mmol) and sodium bicarbonate (0.053 g, is 0.631 mmol) were combined in tetrahydrofuran (5 mL) and at room temperature is stirred for 20 minutes. Add 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 over magnesium sulfate and the solvent was evaporated. Chromatography on silica gel (Isolute, SI) using heptane: dichloromethane (50%) followed by dichloromethane followed by methanol: dichloromethane (1%) as eluent gave 0.15 g (64% yield) of 3- [4- / 2- (4 - ((tert-butylamino) carbonyl) aminophenyl) ethoxy / phenyl] -2 (S) -ethoxypropanoic acid.

¹ H-NMR (600 MHz, CD ₃ OD): δ 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), 3.293.34 (m, 1H), 3.54-3.59 (m, 1H), 3.96 (dd, J = 8.4, 5 Hz, 1H), 4.06 (t, J = 7Hz, 2H), 6.78 (d, J = 8.4Hz, 2H), 7.11 (d, J = 8.4Hz, 2H) 7.14 (d, J = 8.4 Hz, 2H) and 7.22 (d, J = 8.4 Hz, 2H).

¹³ C-NMR (150 MHz, CDCl ₃ ): δ 15.31, 29, 66 (3C), 36.08, 39.31, 51.04, 67.11, 69.94, 81.29, 115, 35 (2C), 120.18 (2C)

130.31 (2C), 130.69, 131.40 (2C), 133.56, 139.35, 157.46, 159.06 and 176.07.

Examples 98 and 99

2-Ethoxy-3- [4- / 2- (4-methylaminophenyl) ethoxy / phenyl] propanoic acid ethyl ester and 3- [4- / 2- (4-dimethylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid ethyl ester

- 177 · · e 177 177 177 - 177 177 177 177 e 177 177 177 177 177 177

Formaldehyde (0.273 mL, 3.36 mmol, 37% in water) and palladium on carbon (100 mg, 10%) were added to a solution of 3- [4- / 2- (4-aminophenyl) ethoxy] ethyl ester (phenyl) -2-ethoxypropanoic acid (described in Example 62a) (0.96 g, 2.69 mmol) in ethyl acetate (15 mL) and then hydrogenated at atmospheric pressure for 4 hours at room temperature. Filtration through diatomaceous earth and purification by silica gel chromatography using heptane: ethyl acetate (gradient 4: 1 to 1: 1) as eluent gave 0.49 g (49% yield) of 2-ethoxy-3- [4- / ethyl] ethyl ester. 2- (4-methylaminophenyl) ethoxy / phenyl] propanoic acid and 0.24 g (yield 23%) of 3- [4- / 2- (4-dimethylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid ethyl ester.

2-Ethoxy-3- [4- / 2- (4-methylaminophenyl) ethoxy / phenyl] propanoic acid ethyl ester

¹ H-NMR (400 MHz , CDCl 3): δ 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).

¹³ C-NMR (100 MHz, CDCl 3): δ 172, 6, 157.7, 147.9, 130, 3, 129.7, 129.1, 126.8, 114.3, 112.6, 80, 5, 69.2, 66.2, 60.7, 38.5, 34.9, 30.9, 15.1, 14.2.

3- [4- / 2- (4-Dimethylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid ethyl ester ¹ H-NMR (500 MHz, CD 3 OD): δ 7.12 (d, J = 8.6 Hz, 2H) 7.10 (d, J = 8.6Hz, 2H), 6.80 (d, J = 8.6Hz, 2H), 6.75 (d, J

- 1780 0 '00 · 0 00 0

0 0 0 0 0 0 • 0000 0 0 0 0 0 0

0 0 0 0 0 0 «00 00

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 (m, 1H), 2.93 (t, J = 7.0 Hz, 2H), 2.91 (m, 2H), 2.87 (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- [4- / 2- (4-dimethylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid ethyl ester (described in the 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 (2M) to pH 5. Tetrahydrofuran was evaporated in vacuo, water (5 mL) was added and the mixture was extracted with ethyl acetate (10 + 5 mL), dried over sodium sulfate and the solvent evaporated in vacuo. Purification by filtration on silica gel afforded 180 mg (84% yield) of 3- [4- / 2- (4-dimethylaminophenyl) ethoxy] phenyl] -2-ethoxypropanoic acid.

1 H-NMR (600 MHz, CDCl ₃ ): δ 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 (m, 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).

- 179 0 0 0 0 0 0 0 00 00 00 0000 00 000 ¹³ C-NMR (150 MHz, CDCl 3): δ 174.9, 157.8, 149 , 4, 130.4,

129, 6, 128.6, 126, 6, 114.4, 113.3, 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 / S) -propyl / amino) phenyl] ethoxy [phenyl] propane

3-Phenyl-3- (4-methylphenyl) propionaldehyde (0.166g, 0.57 mmol) was dissolved in tetrahydrofuran (3 mL) and sulfuric acid (4M, 0.041 mL, 0.164 mmol) was added with stirring, followed by addition of acid hydrochloride 3- [4- / 2- (4aminophenyl) ethoxy / phenyl] - (S-2-ethoxypropanoic acid (described in Example 56a) (0.2 g, 0.547 mmol) dissolved in tetrahydrofuran (2 mL). After cooling to 0 ° C in an ice bath, sodium borohydride (0.042 g, 1.10 mmol) was added and the cooling bath was removed and 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 over magnesium sulfate, and then the solvent was evaporated. 0.13 g (40% yield) of (S) -2-ethoxy acid was obtained -3- [4- / 2- / 4- (3 - [(4-methylphenyl) sulfonyl] -3-phenyl- (R / S) -propyl / amino) phenyl] ethoxy / phenyl] propane.

1 H-NMR (500 MHz, CDCl ₃ ): δ 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 (m, 1H), 3.43-3.50 (m,

- 180 • ····· · · · · · · · · · · · · · · ·

1H), 3.56-3.63 (m, 1H), 4.04-4.10 (m, 3H) ',' 4 * 24 '(d', 'j =' 10.6, 3.9) Hz, 1H), 6.45 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 7.11-7.20 (m, 4H), 7.25-7.34 (m, 5H), 7.39 (d, J = 8.5 Hz, 2H).

¹³ C-NMR (125 MHz, CDCl ₃ ): δ 15.03, 21.58, 27.99, 34.89,

37.68, 41.48, 66.77, 69.04, 69, 15, 79, 79, 113, 12 (2C),

114.41 (2C), 127.25, 128.57 (20, 128.88 (2C), 129.00 (2C), 129.24 (20, 129.79 (20, 129.83 (20, 130)) 44 (20, 132.31, 134.18, 144.46, 147.27, 157.82, 174.05).

Example 102

(S) -2-Ethoxy-3- [4- / 2- (4- (3,3,3-trifluoro-2-methyl (R / S) propylamino) phenyl) ethoxy / phenyl] propanoic acid

2- (Trifluoromethyl) propionaldehyde (0.0724 g, 0.574 mmol) was dissolved 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-] acid hydrochloride. [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 is 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 and dried over magnesium sulfate. The solvent was then evaporated. Nan Silica gel (Isolute, SI) using dichloromethane and then 1% methanol in dichloromethane as eluent to give 0.13 g (40% • · · · · · · · · · · _1O1 ·· ·· ···· ♦ - 1 11- ······· · · ····· · · · · 4 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · () 2-ethoxy-3- [4- / 2- (4- (3,3,3-trifluoro-2-methyl- (R / S) -propylamino) phenyl) ethoxy / phenyl] propane.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.20 (t, J = 7 Hz, 3H), 1.22 (d,

J = 7Hz, 3H) , 2.51-2.61 (m, 1 H), 2.98 (dd, J = 14.5, 8 Hz, · 1H), 3.01 (t, J = 7Hz, 2H), 3.08 (dd, J = 14.5, 4 Hz, 1H) 3.16 (dd, J = 14.7 Hz, 1H), 3,41- 3.47 (m, IH), 3.52 (dd, J = 14, 5.6 Hz, 1H), 3.61-3 67 (m, 1H); 4.06 (dd, J) = 8.4 Hz, 1H), 4.12 (t, J = 7Hz, 2H), 6.61 (d, J = 8Hz, 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 ): δ 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 = 279 Hz), 128 , 65,

129.93 (2C), 130.39 (2C), 145.62, 157.74, 176.24.

Example 103

3- [4- / 2- (4-Cyanophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid ethyl ester

Ethyl 3- [4- / 2- (4-cyanophenyl) ethoxy) phenyl] -2-ethoxypropanoate was synthesized using the same procedure as in Example 38 (c) using 2-ethoxy-3- (4-hydroxyphenyl) ethyl ester of propane (described in Example 20b) (6.62 g, 27.78 mmol) and p-cyanophenethyl alcohol (2.73 g, 18.52 mmol). The reaction was stopped after 2 hours. Purification by silica gel chromatography using dichloromethane first and then petroleum ether diethyl ether as eluents gave a mixture of products and starting material, which was dissolved in ethyl acetate and washed

- 182 · · · · ·

99 9 9 9 9

9

9 99 9 99 9 9 9 sodium hydroxide (IN) solution. The organic phase was washed with water, dried over sodium sulfate, filtered and the solvent was evaporated to give 4.23 g (yield 62%) of 3- [4- / 2- (4-cyanophenyl) ethoxy] phenyl] -2-ethoxypropanoic acid ethyl ester.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.16 (t, 3H, J = 7 Hz), 1.23 (t, 3H, J = 7 Hz), 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), 4.144.26 (m, 4H), 6.8 (dm, 2H, J = 8.6 Hz, unresolved), 7.15 (dm, 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, CDCl ₃ ): δ 14.1, 15.0, 35.8, 38.4, 60.7, 66.1, 67.5, 80.2, 110.3, 114 , 2, 118.8, 129.66, 129.74,

130.4, 132.1, 144.2, 157.2, 172.4.

Example 104

3- [4- / 2- (4-Cyanophenyl) ethoxy / phenyl] -2-phenylsulfanylpropionic acid ethyl ester

Ethyl 3- (4-hydroxyphenyl) -2-phenylsulfanylpropanoate was reacted with p-cyanophenethyl alcohol using the same procedure as in Example 38 (c) to give 3- [4- (2- (4-cyanophenyl) ethoxy) ethyl ester. phenyl] -2-phenylsulfanylpropionic.

¹ H-NMR (600 MHz, CDCl 3): δ 1.08 (t, 3H) 2.99 (dd, 1H), 3,1-3,2 (m, 3H), 3.84 (dd, 1H), 3.97-4.07 (m, 2H), 4.16 (t, 2H), 6 77 ( dm, 2H, J = 8.7 Hz, undifferentiated) 7.10 (dm, 2H) J = 8.4 Hz, undifferentiated) 7,26- 7.31 (m, 3H). 7.39 (dm, 2H)

-183 ··· 9 · 9 · 9 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··

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] -2-phenylsulfanylpropanoic acid

3- [4- / 2- (4-Cyanophenyl) ethoxy / phenyl] -2-phenylsulfanylpropionic acid ethyl ester (described in Example 104) was hydrolyzed using the same procedure as in Example 2 to give 3- [4- / 2- (4-cyanophenyl) ethoxy / phenyl] -2-phenylsulfanylpropanoic acid.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 2.96-3.2 (m, 1H), 3.07-3.14 (m, 3H), 3.77-3.83 (m, 1H) 4.14 (t, 2H, J = 6.5 Hz), 6.78 (dm,

2H, J =

Hz, unresolved), 7.10 (dm, 2H, J = 8.8 Hz, unresolved), 7.23-7.28 (m, 3H), 7.35 (dm, 2H, J = 8.3 Hz) 7.38-7.43 (m, 2H), 7.56 (dm, 2H, J = 8.3 Hz, unresolved).

¹³ C-NMR (125 MHz, CDCl ₃ ): δ 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 / phenyl] propanoic acid ethyl ester (a) 4- [2- (4-Formylphenoxy) ethyl] benzonitrile p-Hydroxybenzaldehyde (24.9 g, 203.8 mmol) was added

-184 dissolved in dichloromethane (dry). Add ADDP (47.2 g, 187 mmol), followed by addition of triphenylphosphine (49 g, 187 mmol). The reaction mixture was stirred at room temperature for 45 minutes and then p-cyanophenethyl alcohol (25 g, 110 mmol) dissolved in a small amount of dichloromethane (dry) was added portionwise over 1 hour. The reaction mixture was stirred at room temperature overnight, filtered and evaporated. Chromatography of the residue on silica gel using ethyl acetate: heptane as eluent gave 9.7 g (22.7% yield) of 4- [2- (4-formylphenoxy) ethyl] benzonitrile.

1 H-NMR (400 MHz, CDCl ₃ ): δ 3.21 (t, 2H), 430 (t, 2H), 6.99 (d, 2H), 7.42 (d, 2H), 7.63 (d, 2H), 7.84 (d, 2H), 9.89 (s, 1H).

¹³ C-NMR (100 MHz, CDCl ₃ ): δ 36.2, 69, 4, 110.8, 116.5,

120.4, 131.3, 131.6, 133.33, 133.73, 145.8, 164.8, 192.8, (b) 4- [2- (4-formylphenoxy) ethyl] benzoic acid

4- [2- (4-Formylphenoxy) ethyl] benzonitrile (9.7 g,

38.6 mmol) was heated to reflux in sulfuric acid (150 ml) and water (150 ml) for 1 hour. Evaporation gave 10 g (100% yield) of 4- [2- (4-formylphenoxy) ethyl] benzoic acid.

1 H-NMR (500 MHz, DMSO-d ₆ ): δ 3.13 (t, 2H), 4.33 (t, 2H), 7.12 (d, 2H), 7.46 (d, 2H) 7.85 (d, 2H), 7.89 (d, 2H), 9.86 (s, 1H).

(c) 4- [2- (4-Formylphenoxy) ethyl] -N-isopropylbenzamide

4- [2- (4-Formylphenoxy) ethyl] benzoic acid

- 185 »(8.11 g, 30) - 185 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 mmol) 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 is washed with potassium hydrogen sulphate (0.3 Μ), water and brine and dried over sodium sulfate. Evaporation gave 8 g (85.6% yield) of 4- [2- (4-formylphenoxy) ethyl] -N-isopropylbenzamide.

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ 1.13 (d, 6H), 3.06 (t, 2H),

3.45 (m, 1 H), 4.22 (t, 2 H), 6.94 (d, 2 H), 7.36 (d, 2 H), 7.61 (d, 2 H), 7.77 (d) 2 H, 8.11 (d, 1 H), 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) (triphenylphosphonium chloride) (3 g, 7 mmol) were dissolved in chloroform. The reaction mixture was cooled in an ice bath. Tetramethylguanidine (1 g, 8.7 mmol) was added portionwise. The reaction mixture was stirred over the weekend and then the solvent was evaporated. The residue was dissolved in ethyl acetate and the precipitated triphenylphosphine oxide was filtered off. The filtrate was evaporated. The crystals are obtained by freezing the solution of the residue in ethanol: water. The crystals were filtered and washed with a very cold ethanol: water mixture to give 1.2 g (44.1% yield) of 2-ethoxy-3- [4- (2- (4- (isopropylaminocarbonyl) phenyl) ethoxy) ethyl ester]. phenyl] acrylic.

-186-

• ·· 4 4 9 4 44 4 44 • 4 4 · • • · • 499 4 4 4 9 • · • 4 4 4 9 « • • 44 44 4 9 4444 ·· •

1 H-NMR (400 MHz, CDCl ₃ ): δ 1.27 (d, 6H), 1.37 (t, 6H), 3.15 (t, 2H), 3.98 (q, 2H), 4 22 (t, 2H), 4.29 (m, 3H), 5.93 (s broad, 1H), 6.88 (d, 2H), 6.96 (s, 1H), 7.35 (d) 2 H, 7.69-7.76 (m, 4H).

¹³ C-NMR (100.6 MHz CDCl ₃ ): δ 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.

(c) 2-Ethoxy-3- [4- / 2- (4- (isopropylaminocarbonyl) phenyl) ethoxy / phenyl] propanoic acid ethyl ester

2-Ethoxy-3- [4- / 2- (4- (isopropylaminocarbonyl) phenyl) ethoxy / phenyl] acrylic acid ethyl ester was hydrogenated using the same procedure as in Example 1 (d) to give 2-ethoxy-3 ethyl ester - [4- / 2- (4- (isopropylaminocarbonyl) phenyl) ethoxy / phenyl] propane.

1 H-NMR (400 MHz, CDCl 3): δ 1.17 (t, 3H), 1.21-1.28 (m, 9H), 2.95 (d, 2H), 3.12 (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 (s broad, 1H), 6.8 (d, 2H), 7.14 (d, 2H), 7.33 (d, 2H), 7.71 (d, 2 H).

¹³ C-NMR (100 MHz, CDCl 3): δ 15.3, 16, 1, 24.0, 36.7, 39.6,

42.9, 61.8, 67.3, 69.2, 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) ethoxy / phenyl] propanoic acid • 4

- 187 • · 4 9 '9 · ··· * 9 * · _{0 φ} • 9 9 9 4 4 · ·· 44 9949

2-Ethoxy-3- [4- / 2- (4- (isopropylaminocarbonyl) phenyl) ethoxy / phenyl] propanoic acid ethyl ester (described in Example 106) (1 g, 2.34 mmol) was dissolved in tetrahydrofuran (10 mL) . Lithium hydroxide (0.056 g, 2.34 mmol) dissolved in water (6 mL) was added portionwise over 20 minutes. The reaction mixture was stirred at room temperature for 3 hours and then diluted with water, followed by careful evaporation of tetrahydrofuran. The remaining aqueous phase was extracted once with diethyl ether, then acidified and extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried over sodium sulfate and evaporated. The residue was dissolved in methanol (10 mL) and sodium hydroxide (0.109 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.

¹ H-NMR (400 MHz, D ₂ O): δ 1.04 (t, 3H), 1.2 (d, 6H), 2.732.81 (m, 1H), 2.88-2.97 (m 3H), 3.22-3.31 (m, 1H), 3.453.55 (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 (140 MHz, D ₂ O): δ 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- (4 - ([(2- (methylsulfanyl) anilino) carbothioyl / amino) phenyl) ethoxy] phenyl] propanoic acid

3- [4- / 2- (4-Aminophenyl) ethoxy / phenyl] - (S) -2-ethoxypropanoic acid hydrochloride (described in Example 56a)

Dissolve -188 (0.2 g, 0.547 mmol) in tetrahydrofuran (5 mL). Sodium bicarbonate (0.053 g, 0.631 mmol) was added and the mixture was stirred for a while. Then 2- (methylthio) phenyl isocyanate (0.108 g, 0.596 mmol) was added. The reaction mixture was stirred overnight and then evaporated to dryness. Chromatography of the residue on silica gel using dichloromethane followed by methanol in dichloromethane (2%, 4%, 10% and 20%) as eluent afforded 0.21 g (75% yield) of (S) -2-ethoxy-3- [ 4- [2- (4 - ([(2- (methylsulfanyl) anilino) carbothioyl / amino) phenyl) ethoxy] phenyl] propane.

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ 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),

3.423 (m, 1H), 3.82 (dd, J = 8.5Hz, 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) .

¹³ C-NMR (150 1MHz, DMSO-d _6): δ 15.29, 15, 49, 34.88, 38.11, 65.22, 68.46, 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 / oxy) phenyl] propanoic acid (a) Benzyl (2-isopropoxyacetate)

Benzyl (2-isopropoxyacetate) is synthesized with 9 ί 9 9 9 β β β β β

120 * · · ·· ·? · Α Ι Ι???? Α Α Α Α Α Α Α Using the same procedure as in Example 58a from isopropoxyacetic acid.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.23 (d, J = 6 Hz, 6H), 3,683.75 (m, 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 benzyl (2-isopropoxyacetate) using the same procedure as in Example 58b.

¹ H-NMR mixtures of E and Z isomers (400 MHz, CDCl 3): δ 1.31 (d, J =

Hz, 6H of one isomer), 1.32 (d, J = 6 Hz, 6H of one isomer), 4.45-4.53 (m, 1H), 5.10 (s, 2H), 5.31 (s (2H of one isomer), 5.32 (s, 2H of one isomer), 6.98-7.01 (m, 2H), 7.07 (s, 1H of one isomer), 7.08 (s, 1H of one isomer) 7.35-7.47 (m, 10H), 7.81-7.85 (m, 2H).

¹³ C-NMR (100 MHz, CDCl 3): δ 22.41 (2C), 66, 60, 69, 85, 74.31, 114.53 (2C), 124.64, 126.79, 127.38 ( 2C), 127.94, 128.10 (2C), 128.15, 128.50 (4C), 131.84 (2C), 135.89, 136.62, 141.64, 159.08, 164, 81

(c) 3- (4-Hydroxyphenyl) -2-isopropoxypropanoic acid

3- (4-Hydroxyphenyl) -2-isopropoxypropanoic acid was synthesized from benzyl [3- [4- (benzyloxy) phenyl] -2-isopropoxy-2-propenoate] using the same procedure as in Example 58c.

«*

- 190Λ 9 9 9 9 9 9 9 »9 9 9 9 9 9 9 9 9

999 99 99 9999 99 9 ^X H-NMR (500 MHz, CDC1 _3): δ 1.08 (d, J = 6 Hz, 3H), 1.21 (d,

J = 6Hz, 3H), 2.93 (dd, J = 14.8Hz, 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

Methyl 3- (4-hydroxyphenyl) -2-isopropoxypropanoate was synthesized using the same procedure as in Example 58d from 3- (4-hydroxyphenyl) -2-isopropoxypropanoic acid.

1 H-NMR (500 MHz, CDCl ₃ ): δ 1.00 (d, J = 6 Hz, 3H), 1.18 (d,

J = 6 Hz, 3H), 2.90 (dd, J = 14, 8.5 Hz, IH), 2.98 (dd, J = 14.5 Hz, IH), 3.50-3.57 ( m, 1H), 3.74 (s, 3H), 4.07 (dd, J = 8.5, 5 Hz, 1H), 6.78 (d, J = 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

2-Isopropoxy-3- [4- / 2- (4-methylsulfonyloxyphenyl) ethoxy / phenyl] propanoic acid methyl ester is synthesized from 3- (4-hydroxyphenyl) -2-isopropoxypropanoic acid methyl ester and 2- (4-methanesulfonyloxyphenyl) ethyl methanesulfonate ( as described in Example 1b) using the same procedure as in Example 58e.

¹ H-NMR (500 MHz, CDCl 3): δ 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 = 7Hz, 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 = 7Hz, 2H), 6.83 (d, J = 8.6Hz, 2H), 7, 17

• ·

191 ► 9 9 • 9 9 9

(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 ): δ 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] propanoic acid

2-Isopropoxy-3- [4- / 2- (4-methylsulfonyloxyphenyl) ethoxy / phenyl] propanoic acid methyl ester (0.1 g, 0.229 mmol) was dissolved in tetrahydrofuran (2 mL). Add lithium hydroxide (0.006 g, 0.25 mmol) in water (2 mL).

The reaction mixture was stirred at room temperature for 8 hours.

The tetrahydrofuran was evaporated. The remaining aqueous solution was extracted with diethyl ether. The aqueous solution was then acidified with hydrochloric acid (1%) to about pH 2 and extracted twice with ethyl acetate. The organic phases were combined and dried over magnesium sulfate. The solvent was evaporated to give 0.085 g (88% yield) of 2-isopropoxy-3- [4- / 2- (4-methylsulfonyloxyphenyl) ethoxy] phenyl] propanoic acid.

¹ H-NMR (400 MHz, CDCl 3): δ 0.99 (d, J = 6 Hz, 3H), 1.15 (d,

J = 6Hz, 3H), 2.88 (dd, J = 13.6, 8.3Hz, 1H), 3.01-3.11 (m, 3H), 3.11 (s, 3H), 3.49-3.58 (m, 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).

¹³ C-NMR (100 MHz, CDCl 3): δ 21, 68, 22.16, 35.07, 37.21,

38.29, 68.12, 73.12, 77.73, 114.28 (2C), 121.89 (2C),

- 192 • 0 · 00 · * 00 0

0 · 0 · 00 0 0 0 «« * 0 0 0 0 0 000 * 0 0 0 fj 0 i 0 0 0 | 4

0 «· · * * * í> 0

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 this invention was tested in obese diabetic Umea ob / ob mice. Groups of mice receive the test compound via lavage once daily for 7 days. On the last day of the experiment, the animals are anesthetized 2 hours after dosing in the un-fed state and blood is collected from the incised artery. Plasma is analyzed for glucose, insulin and triglyceride concentrations. A group of obese mice not treated with test substances serves as a control.

The weight of the mice is measured before and after the experiment and the weight gain achieved is compared to the weight gain of the control animals. Individual values for glucose, insulin, and triglceride levels in mice from the test group are expressed as a percentage of the corresponding values in the control group.

The desired "therapeutic effect" is calculated as the average percentage reduction of the three variables - glucose, insulin and triglyceride levels below that in control animals. The therapeutic effect of the test compounds of this invention is compared to that of a prior art compound troglitazone administered lavage at an oral dose of 100 gmol / kg for 7 days.

The above effects of the test compounds of this invention compared to troglitazone when administered at the same oral dosages show increased potency and efficacy of the claimed compounds.

9

9)

- 1939 f 9 9 9 99 9

9 9 9 9 999 9 9 9 9 9 9 9 9 99 9999

Abbreviations

LDA lithium diisopropylamide

LHMDS lithiumhexamethyldisilylamine

DMF dimethylformamide

DEAD diethylazodicarboxylate

ADDP azodicarbonyldipiperidine

DMSO dimethylsulfoxide

EDO 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide DCC dicyclohexylcarbodiimide

HBTU O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate

TBTU O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate

PyBop benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate

TEA triethylamine

DiPEA diisopropylethylamine

TLC thin layer chromatography

THF tetrahydrofuran

HOBtxH ₂ O 1-hydroxybenzotriazole hydrate t triplet with singlet d doublet q quartet m multiplet «0 · · · · · · · · · · · · · · · · · · · · · · · · · · · «0 0 • 0 · · · · · · · ·

Claims (41)

A compound of formula i D ' D 'and its stereo- and optical isomers and racemates, as well as its pharmaceutically acceptable salts, solvates and crystalline forms, in which: A is placed in the ortho, metha or para position and represents R ³ R ¹ III - C-C —COR R ³ R ¹ I i or —C —C —COR R ⁴ R ² where R is hydrogen, -OR ^a, wherein R ^a is hydrogen, alkyl, aryl or alkaryl, -NR ^a R ^b wherein R ^a and R ^b are identical or different and R has ^the meaning defined above and R ^b represents hydrogen, alkyl, aryl, alkaryl, cyano, -OH, -O-alkyl, -Oaryl, O-alkaryl, -COR ^c or -SO ₂ R ^d , where R ^c is hydrogen, alkyl, aryl or alkaryl and R ^d is alkyl, aryl or alkaryl, * ♦> ·· ·· -195 -:: • · «· · · · Φ · · · «« R ¹ is alkyl, aryl, alkenyl, alkynyl, cyano, -0R ^e wherein R ^e is alkyl, acyl, aryl, or alkaryl, -0- _{[CH2] m} ^- 0R ^f wherein R ^f represents hydrogen, alkyl, acyl, aryl, or alkaryl and m represent an integer of 1 to 8, -OCONR ^and R ^c , where R ^a and R ^c are as defined above, -SR ^d , where R ^d is as defined above, -SO ₂ NR ^and R ^f , where R ^f and R ^a are as defined above, -SO ₂ OR ^a , where R ^a is as defined above, -COOR ^d , wherein R ^d is as defined above, R ² is hydrogen, halogen, alkyl, aryl, or alkaryl, R ³ and R ⁴ are the same or different and each represents hydrogen, alkyl, aryl or alkaryl, n j e an integer of 1 to 6, D j e located in the ortho, meta or para position and represent -OSO ₂ R ^d , where R ^d is as defined above, -OCONR ^f R ^a , where R ^f and R ^a are as defined above, -NR ^c COOR ^d , where R ^c and R ^d are as defined above, -NR ^c COR ^a, wherein R ^c and R ^a are as defined above, -NR ^c R ^d wherein R ^c and R ^d are as defined shits -NR ^c SO 2 R ^d, wherein R ^c and R ^d are as defined above, - 196 - • 9> • · · 9 • · 9 9 9 9 9 99 9 • · • · · · 9 · 9 9 ♦ 9 • • · 9 « 9 9 9 9 9 • • • 9 9 -NR ^c CONR ^a R ^k , wherein R ^a , R ^c and R ^k are the same or different and each represents a hydrogen atom, an alkyl, an aryl or an alkaryl, -NR ^c CSNR ^and R ^k , wherein R ^a , R ^c and R ^k are the same or different and each represents hydrogen, alkyl, aryl or alkaryl, -SO ₂ R ^d , where R ^d is as defined above, -SOR ^d , where R ^d is as defined above, -SR ^C , where R ^c is as defined above, -SO ₂ NR ^a R ^f , where R ^f and R ^a are as defined above, -SO ₂ OR ^a , where R ^a is as defined above, -CN, -CONR ^c R ^a , wherein R ^c and R ^a are as defined above, D 'is located in the ortho, meta or para position and represents a hydrogen atom, alkyl, acyl, aryl, alkaryl, halogen atom, -CN, -NO ₂ , -NR ^f R ^b , where R ^f and R ^b are as defined above , -0R ^f , where R ^f is as defined above, -OSO ₂ R ^d , where R ^d is as defined above, D is located in the ortho, meta or para position and represents a hydrogen atom, alkyl, acyl, aryl, alkaryl, halogen atom, -CN, -NO ₂ , -NR ^f R ^b , where R ^f and R ^b are as defined above , -0R ^f , where R ^f is as defined above, -OSO ₂ R ^d , wherein R ^d is as defined above. A compound according to claim 1 except (S) -2-ethoxy- 3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid and 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl] - (S) -2-ethoxypropanoic acid. A compound according to claim 1 or 2, wherein A is located in the meta or para position and represents R ³ R ¹ -C-C — COR R ⁴ R ² in which R is hydrogen, -OR ^a , where R ^a is as defined in claim 1, -NR ^a R ^b , wherein R ^a and R ^b are the same or different and R ^a is as defined in claim 1 and R ^b is hydrogen, alkyl, aryl , alkaryl, cyano, -OH, -O-alkyl or -O-alkaryl, R ¹ is cyano, -OR ^d , wherein R ^d is as defined in claim 1, -0- _[CH2] ^{m-0R, and} wherein R ^and m are as defined in claim 1, R ² is hydrogen or alkyl, R ³ is hydrogen or alkyl, R ⁴ is a hydrogen atom, n is an integer of 1 to 3, D is located in the ortho, meta or para position and represents -SO 2 R ^d , wherein R ^d is as defined in claim 1 _y - 198 • 0 9 49 44 ·· 4 4 4 4 4 44> >·· 499 99 9 99 • 9 99 9 9 9 9 99 9 0 0 0 0 0 0 0 00 09 09 44 44 444 44 4 -OCONR ^and R ^c , wherein R ^a and R ^c are as defined in claim 1, -NR ^c COOR ^d , wherein R ^c and R ^d are as defined in claim 1, -NR ^c COR ^a , wherein R ^c and R ^a are as defined in claim 1, -NR ^c R ^d , wherein R ^c and R ^d are as defined in claim 1, -NR ^c SO ₂ R ^d , wherein R ^c and R ^d are as defined in claim 1, -NR ^c CONR ^and R ^k , wherein R ^a , R ^c and R ^k are as defined in claim 1, -NR ^c CSNR ^and R ^k , wherein R ^a , R ^c and R ^k are as defined in claim 1, -SO ₂ R ^d , wherein R ^d is as defined in claim 1, SR ^C , wherein R ^c is as defined in claim 1, -CN, -CONR ^c R ^a, wherein R ^a and R ^c are as defined in claim 1, D 'is located in the ortho, meta or para position and represents a hydrogen atom, an alkyl, an alkaryl, a halogen atom, -CN or -NO ₂ , -OR ^h where R ^h is hydrogen or alkyl; D is located in the ortho, meta or para position and represents a hydrogen atom, an alkyl, an alkaryl, a halogen atom, -CN or -NO ₂ , -OR ^h where R ^h is as defined above. The compound of claim 3, wherein And it's placed in a meta or para position, - 199- • flflflfl Flfl flfl ···· R is -OR ^a , where R ^a is hydrogen, alkyl or alkaryl, -NHR ^b , wherein R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl, R ¹ is -O-alkyl, R ² is hydrogen or alkyl, R ³ is hydrogen or alkyl, R ⁴ is hydrogen atom, n j e an integer of 1 to 3, D is located in the ortho, meta or para position and represents -NR ^c COOR ^d wherein R ^c and R ^d are as defined in claim 1, D 'is hydrogen atom, D is hydrogen atom. fl · The compound of claim 4, wherein And is placed in para position, R j e -OH, -O-alkyl or -O-alkaryl, -NH ₂ , NHO-alkaryl or -NHCN, R ¹ is -O-alkyl, preferably -O-lower alkyl, R ² is hydrogen atom, 9 9 4 4 9 9 9 9 9 ^t - ^vv ··· · «· 9 4 9 9 9 9 9 4 4 9 99 9 99 9 9 9 9 99 9 9 R ³ is hydrogen atom, n is integer 1, D is located in para position and represents -NR ^h COOR ^d , wherein R ^d is as defined in claim 1 and R ^h is hydrogen or alkyl. The compound of claim 5, wherein D j e -NR ^{j is} COO-alkyl, wherein R ^j is hydrogen and lower alkyl. The compound of claim 3, wherein And is Placed in meta or para position R j e -OR ^a , where R ^a is hydrogen, alkyl or alkaryl, -NHR ^b , wherein R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl, R ¹ is -O-alkyl, R ² is hydrogen or alkyl, R ³ is hydrogen or alkyl, R ⁴ is hydrogen atom, n is an integer of 1 to 3, · T - ^ ^{ν 1} '··························· D is located in the ortho, meta or para position and represent -NR ^c COR ^a , wherein R ^c and R ^a are as defined in claim 1, D 'is hydrogen atom, D is hydrogen atom. The compound of claim 7, wherein And is placed in para position, R j e -OH, -O-alkyl or -O-alkaryl, -NH ₂ , NHO-alkaryl or -NHCN, R ¹ is -O-alkyl, preferably -O-lower alkyl, R ² is hydrogen atom, R ³ is hydrogen atom, n is integer 1, D j e located in para position and represents -NR ^h COR ^d , wherein R ^d is as defined in claim 1 and R ^h represents hydrogen or alkyl. The compound of claim 8, wherein NHCOR ^d , wherein R ^d is as defined in claim 1. • · ♦ φφφφ ·· _ΛΛΛ ·· · * φφφφ φ. 202 - ······· · ····· · · ·> φ φ φ φ φ The compound of claim 3, wherein And is Placed in meta or para position R is -OR ^a , where R ^a is hydrogen, alkyl or alkaryl, -NHR ^b , wherein R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl, R ¹ is -O-alkyl, R ² is hydrogen atom, R ³ is hydrogen or alkyl, R ⁴ is hydrogen atom, n is an integer of 1 to 3, D is situated in the ortho, meta or para position and represents -SO 2 R ^d, wherein R ^d is as defined in claim 1 D 'is hydrogen atom, D is hydrogen atom. The compound of claim 10, wherein And it's placed in a para position, -OH, -O-alkyl or -O-alkaryl, -NH ₂ , -NHO-alkaryl or -NHCN, • 99 99 '·· 99 ·· · · · · · · · - 204 - ·· «···· • 9 9 9 9 9 9 R ¹ is 99 99 99 9999 99 -O-alkyl, preferably -O-lower alkyl, R ³ is hydrogen atom, n is integer 1, D is located in para position and represents -SO ₂ R ^d , where R ^d . has the meaning defined in claim 1. The compound of claim 3, wherein And is Placed in meta or para position R is -OR ^a , where R ^a is hydrogen, alkyl or alkaryl, -NHR ^b , wherein R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl, R ¹ is -O-alkyl, R ² is hydrogen atom, R ³ is hydrogen or alkyl, R ⁴ is hydrogen atom, n j e an integer of 1 to 3, D j e located in the ortho, meta or para position and represents -SR ^d , wherein R ^d is as defined in claim 1, D 'is hydrogen atom, -204 • 9 · 9 · 49 · 4 4 4 4 4 4 4 · 4 944 499 4449 9 4 4 4 9 4 444 44 44 9444 44 494 D is hydrogen. The compound of claim 12, wherein And it's placed in a para position, R is -OH, -O-alkyl, -O-alkaryl, -NH ₂ , -NHO-alkaryl or -NHCN, R ¹ is -O-alkyl, preferably -O-lower alkyl, R ³ is a hydrogen atom, n is an integer of 1, D is located in the para position and represents -SR ^d , wherein R ^d is as defined in claim 1. The compound of claim 3, wherein And it's placed in a meta or para position, R is -OR ^a , wherein R ^a is hydrogen, alkyl, alkaryl, -NHR ^b where R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl, R ¹ is -O-alkyl, R ² is hydrogen or alkyl, R ³ is hydrogen or alkyl, R ⁴ is a hydrogen atom, 99 · 99 *) 999ί ···· 999 * - 9999999 • ····· · · · • «« 9 99 99 99 9999 99 n is an integer of 1 to 3, D j e located in the ortho, meta or para position and represents -OCONR ^and R ^c , wherein R ^a and R ^c are as defined in claim 1, D 'is hydrogen atom, D is hydrogen atom. The compound of claim 14, wherein And is placed in para position, R j e -OH, -O-alkyl, -O-alkaryl, -NH ₂ , -NHO-alkaryl, -NHCN, R ² is hydrogen atom, R ³ is hydrogen atom, n is integer 1, D j e located at the para position and represents -OCONHR ^d , wherein R ^d is as defined in claim 1. The compound of claim 15, wherein R ¹ is -O-alkyl, preferably -O-lower alkyl, -OCONH-alkyl. -206 • <9 99 99 ·· • 99 9 9 99 9 9 99 99 99 99 9,99999 9 9,999 9 9 9 9 9 9 999 99 99 The compound of claim 3, wherein And it's placed in a meta or para position, R is -OR ^a , wherein R ^a is hydrogen, alkyl, alkaryl, -NHR ^b where R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl, R ¹ is -O-alkyl, R ² is hydrogen or alkyl, R ³ is hydrogen or alkyl, R ⁴ is a hydrogen atom, n is an integer of 1 to 3, D is located in the ortho, meta or para position and represents -NR ^c SO ₂ R ^d , wherein R ^c and R ^d are as defined in claim 1, D 'is hydrogen and D is hydrogen. The compound of claim 17, wherein And it's placed in a para position, Rje -OH, -O-alkyl, -O-alkaryl, -NH ₂ , -NHO-alkaryl or -NHCN; 00 4 · 000 0 1 0 0 1 000 00 ·· 1118 -207 • 0 • · 0 00 0 R ² is hydrogen atom, R ³ is hydrogen atom, n is integer 1, D is located in para position and represents -NR ^h SO ₂ R ^d , wherein R ^d is as defined in claim 1 and R ^h is hydrogen or alkyl. The compound of claim 18, wherein R ¹ is -O-alkyl, preferably -O-lower alkyl, D is -NR ^h SO ₂ alkyl, wherein R ^h is hydrogen or alkyl. The compound of claim 3, wherein And it's placed in a meta or para position, R is -OR ^a , wherein R ^a is hydrogen, alkyl or alkylaryl, -NHR ^b where R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl, Yippee -O-alkyl, Yippee hydrogen or alkyl, Yippee hydrogen or alkyl, Yippee hydrogen atom, Yippee an integer of 1 to 3, t is a * »t • · · 0 0 0 · 0 0 - 208 - 000000 0 000 * 0 0 0 0 0 0 0 0 * 0 0 000 * 0 · * 0000 00 D j e located in the ortho, meta or para position and represents -NR ^c R ^d , wherein R ^c and R ^d are as defined in claim 1, D 'is hydrogen atom, D is hydrogen atom. The compound of claim 20, wherein And is placed in para position, R is -OH, -O-alkyl, -O-alkaryl, -NH ₂ , -NHO-alkaryl or -NHCN, R ² is hydrogen atom, R ³ is hydrogen atom, n is integer 1, D j e located in para position and represents NR ^h R ^d , wherein R ^d is as defined in claim 1 and R ^h is hydrogen or alkyl. The compound of claim 21, wherein R ¹ is -O-alkyl, preferably -O-lower alkyl, -NR ^h alkyl wherein R ^h is hydrogen or alkyl • * -209 * fl · · fl fl fl flfl · · · fl flfl fl * flflfl • flflfl · · · flfl fl "fl flfl • · flflfl ··· ·· ·· ···· flfl flflfl The compound of claim 3, wherein And it's placed in a meta or para position, R is -OR ^a , wherein R ^a is hydrogen, alkyl or alkaryl, -NHR ^b where R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl, R ¹ is -O-alkyl, R ² is hydrogen or alkyl, R ³ is hydrogen or alkyl, R ⁴ is a hydrogen atom, n is an integer of 1 to 3, D is located in the ortho, meta or para position and represents -NR ^c CONR ^and R ^k , wherein R ^a , R ^c and R ^k are as defined in claim 1, D 'is a hydrogen atom, D is hydrogen. The compound of claim 23, wherein And it's placed in a para position, R is -OH, -O-alkyl, -O-alkaryl, -NH ₂ , -NHO-alkaryl or -NHCN, »·». »· · · · - 210 - ···· ** · * · * ^ ^l · ·· ··· & · · · · · · · • ···· * <44 · ·· · 4 · R ² is hydrogen atom, R ³ is hydrogen atom, n is integer 1, D is placed in para position and poses -NHCONHR ^d , wherein R ^d is as defined in claim 1. The compound of claim 24, wherein R ¹ is -O-alkyl, preferably -O-lower alkyl, D is -NHCONHalkyl. The compound of claim 3, wherein Ά je Placed in meta or para position R j e -OR ^a , where R ^a is hydrogen, alkyl or alkaryl, -NHR ^b , wherein R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl, R ¹ is -O-alkyl, R ² is hydrogen or alkyl, R ³ is hydrogen or alkyl, R ⁴ is hydrogen atom, n j e an integer of 1 to 3, • ·· ·· 9 0 9 -211- · * ♦ · * <* · i · • 999 «·· · · 9 9 · • »· · 9 9 9 9 • 99 99 99 9999 99 999 D j e located in the ortho, meta or para position and represent -NR ^c CSNR ^and R ^k , wherein R ^a , R ^c and R ^k are as defined in claim 1, D 'is hydrogen atom, D is hydrogen atom. The compound of claim 26, wherein And is placed in para position, R ¹ is -OH, -O-alkyl, -O-alkaryl, -NH ₂ , -NHO-alkaryl or -NHCN, R ² is hydrogen atom, R ³ is hydrogen atom, n j e integer 1, D j e located in para position and represents -NHCSNHR ^d , wherein R ^d is as defined in claim 1. The compound of claim 27, wherein R ¹ is -O-lower alkyl, D is -NHCSNH-alkyl. 212 • 9 9 9 9 9 9 fc D is -NHCSNH-alkyl The compound of claim 3, wherein And it's placed in a meta or para position, R is -OR ^a , wherein R ^a is hydrogen, alkyl, alkaryl, -NHR ^b where R ^b is hydrogen, alkyl, alkaryl, cyano, -O-alkyl or -O-alkaryl, R ¹ is -O-alkyl, R ² is hydrogen or alkyl, R ³ is hydrogen or alkyl, R ⁴ is a hydrogen atom, n is an integer of 1 to 3, D is located in the ortho, meta or para position and represents -OSO 2 R ^d , wherein R ^d is as defined in claim 1, D 'is a hydrogen atom, D is hydrogen. The compound of claim 29, wherein And it's placed in a para position, R is -OH, -O-alkyl, -O-alkaryl, -213 ··· »· 4 9 · 9 9 · 9 9 · 9 -NH ₂ , -NHO-alkaryl or -NHCN, R ² is hydrogen atom, R ³ is hydrogen atom, n j e integer 1, D j e placed para position and poses -OSO ₂ -alkyl or -OSO ₂ -alkaryl. The compound of claim 30, wherein R ¹ is -O-alkyl, preferably -O-lower alkyl, D is -OSO ₂ alkyl. A compound according to any one of the preceding claims which is 2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanoic acid, 3- [4- / 2- (4-tert- butoxycarbonylaminophenyl) ethoxy / phenyl] -2-ethoxypropanoic acid, 2-ethoxy-3- [4- / 2- (4-methanesulfonylphenyl) ethoxy / phenyl] propanoic acid, 2-ethoxy-3- [4- / 2- (4 -methylsulfanylphenyl) ethoxy / phenyl] propane, -214 2-ethoxy-3- [4- / 2- (4-) -acetic acid -214 isobutyrylaminophenyl) ethoxy / phenyl] propanoic acid, 3- [4- / 2- (4-tert-butylcarbamoyloxyphenyl) ethoxy / phenyl] -2-ethoxypropanoic acid ethyl ester, 2-ethoxy-3- [4- / 2- (4 -methanesulfonylaminophenyl) ethoxy / phenyl] propane, cyan-2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanamide, N-benzyloxy-2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanamide, 2-ethoxy-3- [4- / 2- (4-methanesulfonyloxyphenyl) ethoxy / phenyl] propanamide, 2-ethoxy-3- [4- / 3- (3-methanesulfonyloxyphenyl) propoxy / phenyl] propanoic acid ethyl ester, 2 -ethoxy-3- [4- / 2- (4- (2-propanesulfonyloxy) phenyl / ethoxy) phenyl] propanoic acid 3- [4- / 2- (4- (tert-butoxycarbonyl (methyl) amino) phenyl) (ethoxy / phenyl) - (S) -2-ethoxypropanoic acid, (S) -2-ethoxy-3- [4- / 2- [4- (methoxycarbonylamino) phenyl] ethoxy / phenyl] propanoic acid, 2-ethoxy ethyl ester -3- [4- / 2- (4-methylcarbamoyloxyphenyl) ethoxy / phenyl] propane, - 215 - 3- [4- / 2- (4- (benzyloxycarbonylamino) phenyl) ethoxy / phenyl] - (-) - - - - - - - - - S) -2-ethoxypropanoic acid, 3- [4- / 2- (4-tert-butoxycarbonylaminophenyl / ethoxy) -3-methoxyphenyl] -2-ethoxypropanoic acid, 3- [4- / 2- (4-tert-butyl) methyl ester (butoxycarbonylaminophenyl) ethoxy / phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid, (S) -2-ethoxy-3- [4- / 2- (4- (phenylsulfonyl) phenyl / ethoxy) phenyl] propane and, where applicable, its stereo- and optical isomers and racemates, as well as its pharmaceutically acceptable salts, solvates and crystalline forms. A compound according to any one of the preceding claims, wherein the compound is one of the possible isomers. 34. A process for the preparation of a compound according to claim 1, wherein: a) condensing a compound of formula II R ³ with a compound of formula III or IV, R H ₂ C-COR iii ¹² -p-ch-cor ^iv or -216 • 9 9 9 9 9 9,990 «99 999 99 99 9999 99 999 in which formulas D, D ', D, n, R, R ¹ and R ³ are as defined in claim 1 a L ¹ = L ² = L ³ are phenyl or L ¹ = L ² are OR ^d (wherein R ^d is as defined in claim 1) and L ³ is = O and, if desired, followed by reduction of the obtained double bond and deprotection to form a compound of formula I, wherein R ² and R ⁴ are hydrogen or b) reacting the carbonyl compound of the formula II with a compound of the formula VII R ¹ I H-C-COR AND R ² Vil in which formulas D, D ', D, n, R ¹ and R ³ are as defined in claim 1 a R ² is alkyl, aryl or alkylaryl, followed by dehydroxylation and then, if necessary, deprotecting to form a compound of formula I wherein A is -CR ³ R ⁴ -CR ¹ R ² -COR where R ⁴ is hydrogen, or c) reacting a compound of formula VIII D— (D * -CH ₂ -O— D ” R AND C-X Vlil AND R ⁴ with a compound of formula VII R ¹ H-C-COR AND R ² VII in which formulas D, D ', D, n, R, R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1 and, X is a leaving group, followed, if desired, by deprotection to form a compound of the general formula of formula I wherein A is -CR ³ R ⁴ -CR ¹ R ² -COR or d) reacting a compound of the general formula V -218P D 'with a compound of formula X HIM D in which formulas D, D ', D, n, and A are as defined in claim 1 and R ¹ is -OH or a leaving group, whereupon deprotecting, if necessary, or e) converting a compound of formula XI wherein: D, D ', D, n, R, R ² , R ³ and R ⁴ are as defined in claim 1 and X is -OH followed, if necessary, by deprotection to form a compound of formula I, wherein: A is -CR ³ R ⁴ -CR ¹ R ² -COR where -219 • * 9 9 9 9 0 0 0 00 0 0 000 90 00 0 909 00940 0 4 04 9 « 9 0 9 0 0 0 0 • 09 9 «090 ··« 40 R ¹ is -OR ®, wherein R ^e is as defined in claim 1, -O- [0Η _{2] m} -OR ^f, wherein m and ^Rf are as defined in claim 1, -OCONR ^and R ^c , wherein R ^a and R ^c are as defined in claim 1, f) reacting a compound of formula XIII in which formula D, D ', D, n, R, R ² , R ³ and R ⁴ are as defined in claim 1 and X' is a halogen atom to form a compound of formula I, wherein: And is R ¹ is g) se -CR ³ R ⁴ -CR ¹ R ² -COR where -SR ^d , wherein R ^d is as defined in claim 1, reacts with a compound of formula XIV X ¹ O D ' XIV D -220flflfl flflflfl ·· • flflfl flflflfl flflfl • flfl flfl · ·· • flfl · ·· · flflfl flfl flfl flfl flfl flfl flfl fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll D ', D, n and A are as defined in claim 1 a X ¹ is -OH, SH or NR ^C H, to form a compound of formula I wherein D is -OSO ₂ R ^d , -SR ^C , OCONR ^f R ^a , -NR ^c COOR ^d , -NR ^c COR ^a , -NR ^c R ^d , -NR ^c CONR ^a R ^k , NR ^c SO ₂ R ^d a -NR ^c CSNR ^a R ^k , where R ^a , R ^c , R ^d , R ^f , R ⁹ and R ^k are as defined in claim 1 or h) hydrolyzing a compound of formula I wherein R is OR ^P where R ^p is a protecting group to form a compound of formula I wherein R is -OH, or i) reacting a compound of formula I wherein R is -OH with a compound HNR ^a R ^b, wherein R ^a and R ^b are as defined in claim 1 for producing a compound of formula I wherein R is ^and HNR R ^b , or j) oxidizing a compound of formula XV And, if necessary, followed by deprotection, in which formula D ', D, n and A are as defined in claim 1 a X ² is -SOR ^d or -SR ^d , wherein R ^d is as defined in the claim 1 to form a compound of formula I wherein D is -SO ₂ R ^d or -SOR ^d , whereupon, if desired, the compound obtained by any one of processes a) to j) is converted to the stereoisomer, its pharmaceutically acceptable salt and / or or a solvate thereof, such as a hydrate. The method of claim 34, wherein the compound of any one of claims 2 to 33 is prepared. A compound according to any one of claims 1 to 33 for use in therapy. A pharmaceutical composition comprising a compound according to any one of claims 1 to 33 as an active ingredient, optionally together with an acceptable carrier, excipient and / or diluent. Use of a compound according to any one of claims 1 to 33 for the manufacture of a medicament for the prophylaxis or treatment of clinical conditions associated with insulin resistance. -2229 99 ·· ·· ·· 98 9 · 9 ··· 999 99 99 99 9,99999 9 9 · · · 9 9 9 9 9 9 999 99 99 A method for the prophylaxis and / or treatment of clinical conditions associated with insulin resistance, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 33 to a mammal in need of such prophylaxis and / or treatment. 40. The method of claim 39, wherein the prophylaxis and / or treatment of clinical conditions associated with insulin resistance is the prophylaxis and / or treatment of dyslipidemia in such conditions. 41. The method of claim 39, wherein the prophylaxis and / or treatment of clinical conditions associated with insulin resistance is the prophylaxis and / or treatment of non-insulin dependent diabetes mellitus. A pharmaceutical composition for use in the prophylaxis and / or treatment of clinical conditions associated with insulin resistance, characterized in that the active ingredient is a compound according to any one of claims 1 to 33.