SK16992000A3 - Benzothiophenes, benzofurans, and indoles useful in the treatment of insulin resistance and hyperglycemia - Google Patents

Abstract

This invention provides compounds of Formula (I) wherein Ar is (a), (b) or (c). A, B, C, D, E, X, Y, Z<1> and Z<2> are as defined in the description, or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.

Description

Technical field

The invention relates to compounds which are useful for the treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and for the treatment of ischemic diseases of small and large blood vessels.

BACKGROUND OF THE INVENTION

It has long been known that insulin resistance is widespread in individuals with glucose intolerance. Reaven et al (American Journal of Medicine 60, 80 (1976)) used concomitant infusion of glucose and insulin (insulin-glucose staple technique) and oral glucose tolerance tests to demonstrate that insulin resistance exists in a group of non-obese, non-ketonic individuals. These individuals were on the edge of glucose tolerance up to clear hyperglycemia. The diabetic groups in these studies included both insulin dependent (IDDM) as well as insulin independent (NIDDM) individuals.

At the same time, with persistent insulin resistance, more easily detectable hyperinsulinemia occurs, which can be measured by accurately determining the insulin concentration in the circulating plasma of an individual. Hyperinsulinemia may be present as a result of insulin resistance in both obese and / or diabetic (NIDDM) individuals and / or in glucose intolerance individuals, as well as in IDDM individuals as a result of insulin overdose compared to normal physiological hormone release by the endocrine pancreas.

The association of hyperinsulinemia with obesity and large blood vessel ischemic disease (e.g., atherosclerosis) is confirmed by numerous experimental, clinical and epidemiological studies (reviewed by Sout, Metabolism 34, 7 (1985) and in more detail by Pyoral et al., Diabetes / Metabolism Reviews 3, 463 ( 1987)). Statistically significant increases in plasma insulin after 1 hour and 2 hours ···························· ··· ··· ··· ··· ·· ···· ·· ··· ·· ···

-2 hours after oral glucose loading correlate with an increased risk of coronary heart disease.

Since most of these studies do in fact exclude diabetic subjects, the data on the risk of atherosclerotic disease in relation to diabetes are not numerous, but are the same as those of non-diabetic subjects (Pyorala et al.). However, the incidence of atherosclerotic diseases in disease and mortality statistics in the diabetic population exceeds that of the non-diabetic population (Pyorala et al; Jarret, Diabetes / Metabolism Reviews 5, 547 (1989); Harris et al., Mortality from diabetes in Diabetes in America, 1985 ).

Independent risk factors for obesity and hypertension in atherosclerotic diseases are also associated with insulin resistance. Using a combination of insulin-glucose technique, labeled glucose infusion and indirect calorimetry, it has been shown that insulin resistance of characteristic hypertension is localized in peripheral tissues (essentially muscle) and directly correlates with the severity of hypertension (DeFronzo and Ferrannini, Diabetes 14). 1991)). Insulin resistance in obese hypertension generates hyperinsulinemia which is induced as a mechanism to limit further weight gain by thermogenesis; however, insulin also increases the renal re-absorption of sodium and promotes the sympathetic nervous system in the kidneys, heart and vascular system, causing hypertension.

Insulin resistance is currently considered to be a common consequence of a disorder in the insulin signaling receptor system, in the position following insulin binding to the receptor. The accumulated scientific evidence regarding insulin resistance in major tissues that respond to insulin (muscle, liver, fat) strongly confirms that the defect of insulin signal transduction is in the initial step in this cascade, particularly in the insulin receptor kinase activity, which appears to be as reduced (review by Haring, Diabetology 34, 848 (1991)).

Protein-tyrosine phosphatases (PTPs) are very important in regulating protein phosphorylation. The interaction of insulin with its receptor results in the phosphorylation of certain tyrosine molecules in the receptor protein and thus activation of the kinase receptor. PTPase dephosphorylates the activated insulin receptor and thus attenuates tyrosine kinase activity. PTPases may also modulate the post-receptor

-3 ·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Signaling by catalyzing the dephosphorylation of insulin receptor kinase cell substrates. Said enzymes that appear to be in close association with the insulin receptor to presumably regulate insulin receptor kinase activity include PTP1B, LAR, PTPα and SH-PTP2 (Goldstein BJ, J. Cellular Biochemistry 48, 33 (1992); Goldstein BJ, Receptor 3 , 1-15 (1993), Ahmad F. and Goldstein BJ, Biochem Biophys Acta 1248, 57-69 (1995).

McGuire et al (Diabetes 40, 939 (1991)) have shown that non-diabetic subjects intolerant to glucose exhibit significantly elevated levels of PTP -ase activity in muscle tissue compared to normal individuals and that insulin infusion fails to suppress PTP -ase activity unlike insulin sensitive individuals.

Meyerovitch et al. (J. Clinical Invest. 84, 976 (1989)) observed significantly increased PTPase activity in the liver of two rodent IDDM models, genetically diabetic BB rat and STZ-induced rat. Sredy et al. (Metabolism 44, 1074 (1995)) observed a similar increase in PTPase activity in the liver of obese, diabetic ob / ob mice, a rodent genetic model of NIDDM.

The compounds of this invention have been shown to inhibit rat liver microsomes and human-derived recombinant PTPase-1B (hPTP-1B) in vitro. Then, the compounds are useful in the treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels.

Riedi B. et al (EP 693 491 A1) discloses oxazolodinone A as antibacterial

(A)

NHAc ·····················

-4 · · ····································

Bridges A. et al. (EP 568 289 A2) discloses thiothiophenamidine B as a urokinase inhibitor.

(B)

Chen H. M. et al. (Indian J. Chem., Sect B: Org. Chem. Include. Med. Chem. 35B, (12) 1304-1307 (1996)) disclosed Compound C.

Guirguis N. R. et al. (J. Prakt. Chem. 332 (3): 414-418 (1990)) described Compound D.

···································

5Guirguis NR et al. (Liebigs Ann. Chem. 1003-1011 (1985)) described benzothiophenes E. Thiophenes E (R ¹ = CO 2 H) have also been described by Dubroeucq M. et al (EP 248 734 A1).

Kuroda T. et al. (J. Org. Chem. 59, 7353-7357 and J. Chem. Soc., Chem. Commun. 1635-1636 (1991)) have described benzothiophenes F.

Hashem A. I. (J. Prakt. Chem. 319, 689-692 (1977)) described benzofuran G.

-6 ·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • · ·· ·

Akao Y. et al. (Japan Kokai Tokkyo Koho JP 04 016 854 A2 (Japanese Patent, CA: 117: 36570) discloses six compounds containing a 4-aryl-naphtho [2,3b] thiophene ring system. These compounds were cyclobutylenediyl dimers of said ring system. prepared as electrophotographic photoreceptors.

(H)

Konopelski J. P. et al. (Synlett, 609-611 (1996)) describe indole I.

(D · · · · · · · · · · · · · · · · · · · · ·

Molina P. et al. (Tetrahedron 50, 5027-5036 (1994) and Tetrahedron Lett. 34, 2609-2812 (1993)) disclose indole derivatives J.

Napolitano A. et al. (Tetrahedron 45, 6749-6760 (1989)) disclose indole K.

Dryhurst G. et al. (J. Am. Chem. Soc. Hl., 719-726 (1989)) disclose compound L.

(L)

-8 ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · »· others (Tetrahedron 43: 431-434 (1987)) disclose compound M.

SUMMARY OF THE INVENTION

The present invention provides benzothiophenes, benzofurans and Formula I indoles in which Ar is

(a) (b)

ABOUT)

A is hydrogen, halogen or OH;

B and D independently of one another are hydrogen, halogen, -CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, hydroxyalkyl of 1 to 6 atoms · · ·····························································

-9 carbon, C 6 -C 12 hydroxyaralkyl, C 3 -C 8 cycloalkyl, nitro, amino, -NR ¹ R ^1a , -NR ¹ COR ^1a , -NR ¹ CO 2 R ^1a , cycloalkylamino of 3 to 8 carbon atoms, morpholino , furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, -COR ^1b , or -OR;

R is H, alkyl of 1 to 6 carbon atoms, COR ^1, - (CH 2) nCO2R ^1, -CH (R ¹⁾ CO 2 R ^1, -SO 2 R ^1, - (CH 2) m CH (OH) CO ₂ R ^1, - (CH 2) m COCO2R ^1, - (CH 2) _m CH = CHCO ₂ R ^1, or - (CH 2) m O (CH ₂₎ OC0 ₂ R ^1;

R ¹ is hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl of 6 to 12 carbon atoms, aryl, or -CH ₂ CO ₂ R ¹ ';

R ¹ 'is hydrogen or alkyl of 1 to 6 carbon atoms;

E is S, SO, SO ₂ , O, or NR ^1c ;

X is hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, -CN, aryl, aralkyl of 6 to 12 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, hydroxyaralkyl of 6 to 12 carbon atoms , C 1 -C 6 perfluoroalkyl, C 1 -C 6 alkoxy, aryloxy, arylalkoxy, nitro, amino, -NR ² R ^2a , -NR ² COR ^2a , cycloalkylamino of 3 to 8 carbon atoms, morpholino, alkylsulfanyl of 1 up to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl, -OCH ₂ CO ₂ R ^2b , or -COR ^2c ;

Y is hydrogen, halogen, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, hydroxyaralkyl of 6 to 12 carbon atoms, -OR ³ , -SR ³ , -NR ³ R ^3a , -COR ^3b , morpholino, or piperidino;

R ^1a , R ^1c , R ² , R ^2a , R ³ , R ^3a independently of one another are each hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl of 6 to 12 carbon atoms, or aryl;

R ^1b is alkyl of 1 to 6 carbon atoms or aryl;

R ^2b is hydrogen, alkyl of 1 to 6 carbon atoms;

R ^2e and R ^3b independently of each other are each C 1 -C 6 alkyl, aryl, or C 6 -C 12 aralkyl;

C is hydrogen, halogen or -OR ⁴ ;

R ⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, -CH (R ⁵ ) W, -C (CH ₃ ) 2 CO ₂ R ⁶ ,

5-thiazolidine-2,4-dione, -CH ^(R7) (CH2) mCO2R ^6, -COR ^6, -PO3 ^(R6) 2, -SO ₂ R ^6,

10- _{(CH2) p} CH (OH) CO ₂ R ^6, - (CH 2) PCOCO2R ^6, - (CH 2) _p CH = CHCO ₂ R ^6, or - _(CH2) pO _{(CH2) q CO2} R ⁶ ;

R ⁵ is hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl of 6 to 12 carbon atoms, aryl, -CH ₂ (1H-imidazol-4-yl), -CH ₂ (3-1H-indolyl), - CH ₂ CH ₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), -CH ₂ CH ₂ (1-oxo-1,3-dihydro-isoindol-2-yl), -CH ₂ (3-pyridyl), -CH ₂ CO ₂ H, or - (CH ₂ ) _n G;

or

G is -NR ^6a R ^7a , -NR ^6a COR ^7a , HN0

W is -CO ₂ R ⁶ , -CONH 2, -CONHOH, -CN, -CONH (CH 2) 2 CN, -5-tetrazole, -PO 3 (R ⁶ ) 2, -CH ₂ OH, -CONR ^6b CHR ^7b , -CH ₂ NR ^6b CHR ^7b CO 2 R ⁶ , -CH 2 OCHR ^7b CO 2 R ⁶ , -CH ² Br, or -CONR ^6b CHR ^7b CO ² R ⁶ ;

R ^6, R ⁶³ · R ^7, R ⁷ independently of one another are each hydrogen, alkyl of 1 to 6 carbon atoms, or aryl;

R ^6b is hydrogen or -COR ^6c ;

R ^6c is alkyl of 1 to 6 carbon atoms or aryl;

R ^7b is hydrogen, alkyl of 1 to 6 carbon atoms, or hydroxyalkyl of 1 to 6 carbon atoms;

Z ¹ and Z ² independently of each other are each hydrogen, halogen, -CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, nitro, amino, -NR ¹ R ^1a , -NR ¹ COR ^1a , C 3 -C 8 cycloalkylamino, morpholino, or OR ⁸ ; or Z ¹ and Z ² may together form a diene unit of the formula -CH = CR ⁹ -CR ¹⁰ = CR ¹¹ -;

R ⁸ is hydrogen, alkyl of 1 to 6 carbon atoms, or aryl;

R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, aryl, halogen, hydroxy, or alkoxy of 1 to 6 carbon atoms; m is 1 to 4;

n is 1 or 2;

p is 1 to 4;

q is 1 to 4;

or a pharmaceutically acceptable salt thereof;

These are useful in the treatment of metabolic disorders associated with insulin resistance or hyperglycaemia.

Pharmaceutically acceptable salts may be formed with organic and inorganic acids such as acetic acid, propionic acid, lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid (±) -a- hydroxyphenylacetic acid), malic acid, phthalic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid and the like known compounds of the present invention, a basic moiety such as R ⁵ is -CH ₂ (3-pyridyl), or when Y is morpholine or the compound contains similar basic moieties. Salts may also be formed with organic or inorganic bases, preferably salts with alkali metal bases such as sodium, lithium or potassium if the compound of the invention contains carboxylic or phenolic moieties.

Alkyl includes both straight and branched chain moieties. Halogen means bromine, chlorine, fluorine and iodine. It is preferred that the aryl portion of the aryl or aralkyl substituent is phenyl or naphthyl; most preferred is phenyl. The aryl moiety may be optionally mono-, di-, or tri- substituted with a substituent selected from the group consisting of C 3 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, halogen, alkoxycarbonyl C 2 -C 7 alkyl, C 1 -C 6 alkylamino and a dialkylamino group in which each alkyl group has 1 to 6 carbon atoms, nitro, cyano, -CO ₂ H, C 2 -C 7 alkylcarbonyloxy and alkylcarbonyl groups having 2 to 7 carbon atoms.

Said compounds of the invention may contain an asymmetric carbon atom and some of these compounds may contain one or more asymmetric centers and may therefore form optical isomers and diastereomers. Without being bound by stereochemistry, Formula I of the present invention includes optical isomers and diastereomers; the invention further includes racemic compounds

And separated enantiomerically pure Ra S stereoisomers; the invention further includes other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.

The compounds of the invention may be atropisomers due to possible restriction or small rotation around the aryl-tricyclic or aryl-bicyclic single bond. If another chiral center is present in the molecule, diastereomers exist and can be detected by NMR or other analytical technique. Without being bound by the general formula I of the compound of the invention, the atropisomeric stereochemistry is included, the invention encompasses all atropisomers (enantiomers of diastereomers; as well as racemic, resolved, pure diastereomers and mixtures of diastereomers) and pharmaceutically acceptable salts thereof.

Preferred compounds of the invention include compounds of Formula I

in which

A is hydrogen or halogen;

B and D are each independently of the other hydrogen, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, branched alkyl, cycloalkyl of 3 to 8 carbon atoms, nitro or -OR;

R is hydrogen or alkyl of 1 to 6 carbon atoms;

E is sulfur or oxygen;

X is hydrogen, halogen, alkyl of 1 to 6 carbon atoms, -CN, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, aryloxy, arylalkoxy, nitro, amino, -NR ² R ^2a , -NR ² COR ^2a , cycloalkylamino, morpholino, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl;

······························

-13 ·· ···· ·· ··· ·· ···

R ¹ , R ^1a , R ² , R ^2a , R ³ and R ^3a independently of one another are hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl of 6 to 12 carbon atoms, or aryl;

Y is hydrogen, halogen, -OR ³ , -SR ³ , -NR ³ R ^3a , or morpholine;

C is hydrogen, halogen, or -OR ⁴ ;

R ⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, -CH (R ⁵ ) W, -C (CH ₃ ) ₂ CO ₂ R ⁶ , -5-thiazolidine-2,4-dione, -CH (R ⁷ ) (CH2) mCO2R ^6, -COR ^6, -PO3 ^(R6) _2, -SO ₂ R ^6, - (CH2) PCH (OH) CO 2 R ^6, - (CH 2) _p COCO ₂ R ^6, - (CH 2) GC = CHCO ² R ⁶ , or - (CH 2) _p O (CH ₂ ) _q CO ₂ R ⁶ ;

R ⁵ is hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl of 6 to 12 carbon atoms, aryl, -CH ₂ (1/7-imidazol-4-yl), -CH ₂ (3-1 / 7-indoles) -CH ₂ CH ₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), -CH ₂ CH ₂ (1-oxo-1,3-dihydro-isoindol-2-yl), or -CH ₂ (3-pyridyl);

W is -CO ₂ R ⁶ , -CONH 2, -CONHOH, or -5-tetrazole, or -CONR ^6b CHR ^7b CO ₂ R ⁶ ; R ⁶ , R ⁶³ ', R ⁷ , R ^7a and R ^7b independently of one another are hydrogen, alkyl of 1 to 6 carbon atoms, or aryl;

Z ¹ and Z ² independently of each other are each hydrogen, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, nitro, amino, -NR ¹ R ^1a , -NR ¹ COR ^1a , C 3 -C 8 cycloalkylamino, morpholino, or -OR ⁸ ; or Z ¹ and Z ² may together form a diene unit of the formula -CH = CR ⁹ -CR ¹⁰ = CH-;

R ⁹ and R ¹⁰ are each, independently of one another, hydrogen or alkyl of 1 to 6 carbon atoms; p is 1 to 4; q is 1 to 4;

or a pharmaceutically acceptable salt thereof.

More preferred compounds of the invention are compounds of the general invention

-14 ·· ·· ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

A is hydrogen;

B and D each independently of one another are halogen, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, or cycloalkyl of 3 to 8 carbon atoms;

E is sulfur or oxygen;

X is hydrogen, halogen, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, -CN, alkoxy of 1 to 6 carbon atoms, aryloxy, aryloxy of 6 to 12 carbon atoms, arylsulfanyl;

Y is hydrogen, or -NR ¹ R ² or morpholine;

R ¹ and R ² each independently of one another are hydrogen or alkyl of 1 to 6 carbon atoms, aralkyl of 6 to 12 carbon atoms, or aryl;

C is -OR ⁴ ;

R ⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, -CH (R ⁵ ) W, or -5-thiazolidine-2,4-dione; R ⁵ is hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl of 6 to 12 carbon atoms, aryl, -CH ₂ (3-1H-indolyl), -CH ₂ CH ₂ (1,3-dioxo-1,3- dihydro-isoindol-2-yl), or -CH ₂ CH ₂ (1-oxo-1,3-dihydro-isoindol-2-yl);

W is CO ₂ R ⁶ , -CONH 21 -CONHOH, 5-tetrazole, -PO 3 (R ⁶ ) 2 or -CONR ⁶ CHR ⁶ CO ₂ R ⁶ ;

R ⁶ is hydrogen or alkyl of 1 to 6 carbon atoms;

Z ¹ and Z ² together form the diene unit of the formula -CH = CH-CH = CH-;

or a pharmaceutically acceptable salt thereof.

Even more preferred compounds of the invention include:

(1) (R) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] 3-phenyl- propionic acid;

(2) (ft) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-ethyl-phenoxy] -3 phenyl-propionic acid;

3) (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl-propionic acid;

4) (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-fluorophenoxy] -3-phenyl-propionic acid;

·················

- 15 ··· ··· · · ···············

5) [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenoxy] -acetic acid;

6) acid, (/?) - 2- [2-bromo-4- _{(9-bromo-2-I,} 3-dimethyl-naphtho [2 ₁ 3-b] thiophen-4-yl) -6-sec-phenoxy] - 3-phenylpropionic acid;

7) (R) -2- [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-isopropylphenoxy] -3 phenyl-propionic acid;

(8) (R) -2- [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-cyclopentyl-phenoxy] -3 phenyl-propionic acid;

9) (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-isopropyl-phenoxy] -3-phenyl-propionic acid ;

10) (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-cyclopentyl-phenoxy] -3-phenyl-propionic acid;

(11) (R) -2- [2,6-dibromo-4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3- phenyl-propionic acid;

12) The acid (R) -2- [2,6-dibromo-4- _{(9-bromo-2-one} 3-dimethyl-naphtho [2 ₁ 3-b] thiophen-4-yl) -phenoxy] 4-phenyl butyric acid;

13) (S) -2- [2,6-dibromo-4- (9-bromo-2,3-dinnetyl-naphtho [2 _l 3-b] thiophen-4-yl) -phenoxy] 4-phenyl butyric acid;

14) 2- [2 _I 6-dibromo-4- (9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho [2,3-b] thiophen-4-yl) phenoxy] -3 phenyl-propionic acid;

15) (R) -2- [2,6-dibromo-4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -propionic acid;

16) [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-nitro-phenoxy] -3-phenyl-propionic acid;

17) 2,6-dibromo-4- _{(9-bromo-2-one} 3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol;

18) 2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2 _L 3-b] thiophen-4-yl) -2-nitro-phenol;

19) (R) -2- [2,6-dibromo-4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] - 3-phenylpropionic acid;

20) (R) -2- [2,6-dibromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -phenoxy] -3-phenyl-propionic acid;

·······························

-16 ·· ···· ·· ··· ·· ·

21) acid (2 /?) - 2- [4- _{(9-bromo-2-one} 3-dimethyl-naphtho _[2) 3-b] thiophen-4-yl) -2,6-diisopropyl-phenoxy] -3-phenyl -propionic;

22) (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenoxy] 3-phenyl acid -propionic;

23) {(2 R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl acid propionylamino} -acetic acid;

24) {(2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenoxy] -3-phenyl acid propionylamino} -acetic acid;

or a pharmaceutically acceptable salt thereof.

The compounds of this invention can be prepared according to the schemes below from commercially available starting materials or starting materials that can be prepared using procedures reported in the literature. These schemes illustrate a process for preparing representative compounds of the invention.

Scheme 1

D

(II)

The preparation of 2,3-dimethylthiophene (II: E is S) is carried out in Scheme I from commercially available 3-methylthiophene-carboxaldehyde under the conditions reported by Wolf, and ·

-17 • · · · · ·············

Kishner (using hydrazine followed by KOH / ethylene glycol at reflux). Compound (II: E is S or O) is reacted with one to 1.3 molar equivalents of an alkyllithium reagent such as n-butyllithium, most preferably in an aprotic solvent such as THF in a temperature range of -78 ° C to room temperature under a protective atmosphere an inert gas such as nitrogen or argon to form a 2-lithiated thiophene or furan derivative. This lithium analog is reacted in situ with one or more molar equivalents of benzaldehyde, generally at a temperature range of -78 ° C to room temperature; a reaction time of 5 minutes to three hours to give a compound of formula (III: Q = OH; E is S or O). The hydroxyl group (Q = OH) of (III) can be removed by any of a reduction method such as hydrogenation using a palladium catalyst to give a compound of formula (III: Q = H; E is S or O), but removal is preferably by Nutaitis method and others (Org. Prep. and Proceed. Int. 23: 403-41 (1991)), wherein compound (III: Q = OH; E is S or O) is mixed with one to ten molar equivalents of sodium borohydride in a suitable solvent such as ether, THF or dichloromethane at 0 ° C to room temperature and one to fifty mol equivalents of trifluoroacetic acid are slowly added over 15 minutes to 3 hours; to give a compound of formula (III: Q = H; E is S or O). The 2-lithium analog of compound (II: E is S or O) is optionally reacted with one or more molar equivalents of a benzyl halide such as benzyl bromide (PhCH 2 Br) at a temperature range of -78 ° C to room temperature to directly obtain a compound of formula (III: Q = H; E is S or O).

Compounds of formula (III: Q = H; E is S or O) can be acylated with one or more molar equivalents of commercially available benzoic acid chloride of formula (IV: A, B, C, D is H or OMe; with a combination of A, B, C , D wherein at least one OMe group, but no more than three OMe groups) to form an acylated derivative of formula (V: A, B, C, D is H or OMe; with a combination wherein at least one OMe group is, but not more than three OMe groups; E is S or O). Acylation is most readily accomplished by using 1 to 5 mole equivalents of a Lewis acid catalyst, such as tin tetrachloride or aluminum chloride, in the form of a Lewis acid catalyst.

An inert solvent, for example in dichloromethane, 1,2-dichloroethane or carbon disulphide, generally in the temperature range from -78 ° C to room temperature.

The cyclization of compounds of formula (V: A, B, C, D is hydrogen or OMe; with a combination in which at least one OMe group but no more than three OMe groups; E is S or O) is generally best accomplished using 1-7 10 equivalents of a strong Lewis acid such as trihaloborane, most preferably tribromoborane. The reaction is preferably carried out at -78 ° C with warming to room temperature or heating to 50 ° C in a halogen-carbon solvent such as dichloromethane under an inert atmosphere such as nitrogen or argon. These processes not only cause cyclization and aromatization associated with water loss, but also demethylation of the attached methoxy moieties to give compounds of formula (Ia: A, B, C, D is hydrogen or OH; with a combination in which at least one OMe is, but not more than three OMe groups; E is S or O).

By analogous reactions to Scheme I, compounds of formula (Ia) may be prepared: (Ia: A is H; B, D is alkyl of 1 to 6 carbon atoms or fluorine; C is OH; E is S or O) from the starting compound of formula (III) Q is H; E is S or O) and the corresponding benzoic acid chloride (IV: A is H; B, D is alkyl of 1 to 6 carbon atoms or fluorine; C is OMe). Said benzoic acid chloride (IV: A is H; B, D is C 1 -C 6 alkyl or fluoro; C is OMe) is prepared from benzoic acid by conventional methods using reagents such as oxalyl chloride and thionyl chloride. The starting benzoic acid for the preparation of benzoic acid chloride (IV: A is H; B, D is alkyl of 1 to 6 carbon atoms or fluorine; C is OMe) is commercially available or can be prepared by known methods. For example, the starting acidic material for the preparation of benzoic acid chloride (IV: A is H; B, D is isopropyl; C is OMe) can be prepared using a modified Schuster method (Schuster et al., J. Org. Chem. 53, 5819 (1988)) . Thus, commercially available 2,6-diisopropylphenol is brominated at the 4-position (bromine / acetic acid), methylated (iodomethane / potassium carbonate / DMF), reacted with n-butyllithium to halogen exchange, and the resulting organolithium is reacted with carbon dioxide to form acid 3 5-diisopropyl-4-methoxy benzoic acid.

-19 ····································

Scheme 2

Additional derivatives of compounds of Formula I may be prepared in Scheme 2 by the following methods. The phenol of formula (Ib: B, D, X is H; C is OH; E is S or O) (Scheme 2) can be suitably iodinated to the diiodophenol of formula (Ib: B, D, is I; X is H; C is OH E is S or O) using at least two molar equivalents of iodine in the presence of two or more molar equivalents of an alkali metal hydroxide such as NaOH in an alcoholic solvent such as methanol at a temperature ranging from -20 ° C to room temperature. Similarly, a mono iodophenol of formula (Ib: B is I; D, X are H; C is OH; E is S or O) can be prepared from a phenol of formula (Ib: B, D, X are H; C is OH; E is S or O) (Scheme 2) using 1 to 1.5 molar equivalents of iodine in the presence of at least one molar equivalent of an alkali metal hydroxide such as NaOH in an alcoholic solvent such as methanol at a temperature ranging from -20 ° C to room temperature. Said mono-iodophenol (Ib: B is I; D, X are H; C is OH; E is S or O) or diiodophenol (Ib: B, D, are I; X is H; C is OH; E is S or O ) can be converted to the corresponding methyl ether derivatives of formula (Ib: B is I; D is H; C is OMe; E is S or O) or (Ib: B, D are I; X is H; C is OMe; E is S or O) reacting the phenol moiety with a suitable methylating agent, for example one or more molar equivalents of methyl iodide or dimethylsulfate, and using a base such as an alkali carbonate or hydroxide such as potassium carbonate or sodium hydroxide in a suitable solvent such as THF; · ··· ··· ··· ··· ··· ···

-20 • · ····································

DMF or DMSO. The reaction is generally carried out at temperatures ranging from 0 ° C to 60 ° C.

Said mono-iodo derivative of formula (1b: B is I; D, X are H; C is OH; E is S or O) or a diiodomethyl ether of formula (1b: B, D, are I; X is H; C is OH; E is S or O) can be reacted with one or more mole equivalents of copper (I) cyanide in the case of a mono-iodine analog or with two or more mole equivalents of copper (I) cyanide in the case of a diiodo derivative to form a monocyanomethyl ether of formula (1b); OMe; E is S or O) or a dicyanomethyl ether of formula (1b: B, D are CN; X is H; C is OMe; E is S or O). The cyano derivative reaction is generally carried out at temperatures ranging from 100 ° C to 250 ° C using polar aprotic solvents such as DMF, 1-methyl-2-pyrrolidone or HMPA. Quinoline or pyridine may also be used. Said mono or dicyanomethoxy analogs of formula (1b: B is CN; D is H or CN; X is H; C is OMe; E is S or O) can be converted to the corresponding mono or dicyanophenol analogs of formula (1c: B is CN; D is H or CN; X is H; E is S or O) (Scheme 2) using conventional demethylation methods, for example using one or more molar equivalents of bromide or boron trichloride in dichloromethane at -78 ° C to room temperature; in excess pure pyridinium hydrochloride at 190 to 280 ° C; in hydrobromic acid in acetic acid at 0 ° C to 50 ° C; in excess of trimethylsilyl bromide or trimethylsilyl iodide in dichloromethane, carbon tetrachloride or acetonitrile at -78 ° C to 50 ° C; by reaction with lithium iodide in pyridine or quinoline at temperatures from 100 ° C to 250 ° C and with one or more molar equivalents of ethyl, methyl or isopropyl mercaptan in the presence of one or more molar equivalents of Lewis acid, for example aluminum chloride or boron trifluoride in solvent; is dichloromethane at temperatures ranging from -78 to 50 ° C.

Said mono iodomethyl ether derivative of formula (1b: B is I; X, D are H; C is OMe; E is S or O) or a diiodomethyl ether derivative of formula (1b: B, D are I; X is H; C is OMe; E is S or O) (Scheme 2) can be reacted with one or more molar equivalents of cuprous bromide in the case of a mono-iodine derivative and with two or more molar equivalents of cuprous bromide in the case of a diiodo derivative for · · ·

The formation of a monobromomethyl ether of formula (Ib: B is Br; D is H; C is OMe; E is S or O) or dibromomethyl ether of formula (Ib: D is Br; X is H; C is OMe; E is S or O). The bromine / iodine exchange reaction is generally carried out at temperatures ranging from 100 ° C to 250 ° C using polar aprotic solvents such as DMF, 1-methyl-2-pyrrolidone or HMPA. Quinoline or pyridine may also be used. Said mono or dibromo analogs of formula (Ib: B is Br; D is H or Br; X is H; C is OMe; E is S or O) can be converted to the corresponding mono- or dibromophenol analogs of formula (Ib: B is Br; D is H or Br; X is H; E is S or O) (Scheme 2) using conventional demethylation procedures, for example using one or more molar equivalents of bromide or boron trichloride in dichloromethane at -78 ° C to room temperature; in excess pure pyridinium hydrochloride at 190 to 280 ° C; in hydrobromic acid in acetic acid at 0 ° C to 50 ° C; in excess of trimethylsilyl bromide or trimethylsilyl iodide in dichloromethane, carbon tetrachloride or acetonitrile at -78 ° C to 50 ° C; by reaction with lithium iodide in pyridine or quinoline at temperatures from 100 ° C to 250 ° C and with one or more molar equivalents of ethyl, methyl or isopropyl mercaptan in the presence of one or more molar equivalents of Lewis acid such as aluminum chloride or boron trifluoride in a solvent such as is dichloromethane at temperatures ranging from -78 to 50 ° C.

Scheme 3

·· ·· · · · · · · · · · · · · · · ·

-22 ·· · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Additional derivatives of compounds of formula I may be prepared according to Scheme 3 by the following methods. Compounds of formula (Id: B, C, D are H or OH; in combination B, C, and D is at least one OH group; E is S or O) (Scheme 3) can be acylated on phenol oxygen using one or more equivalents a suitable acylating agent to form compounds of formula (Id: B, C, D are hydrogen or OCOR; in combination B, C, D is at least one OCOR; R is alkyl of 1 to 6 carbon atoms, aryl; E is S or O ). Generally, the acylating agent is an alkyl (C 1 -C 6) or aryl carboxylic anhydride or alkyl (C 1 -C 6) or aryl carboxylic acid anhydride. The reaction is carried out under conventional conditions, for example using pyridine as a solvent in the presence or absence of a co-solvent such as dichloromethane, at 0 ° C to room temperature. Acylated phenols of formula (Id: B, C, D are H or OCOR; in combination B, C, D is at least one OCOR; R is alkyl of 1 to 6 carbon atoms, aryl; E is S or O) can then be brominated at the 9-position a naphthol [2,3-b] thiophene or naphthol [2,3-b] furan ring to form acylated bromophenols of formula (1e: B, C, D are H or OCOR; in combination B, C, D is at least one OCOR group; R is alkyl of 1 to 6 carbon atoms, aryl; X is Br; E is S or O) (Scheme 3). The bromination reaction is generally performed in the dark in the presence of a catalytic amount of ferric chloride in an inert solvent such as dichloromethane or carbon tetrachloride at temperatures ranging from -78 ° C to room temperature.

Phenols of formula (Id: B, D are alkyl of 1 to 6 carbon atoms; C is OH; E is S or O) can be brominated at the 9-position with naphthol [2,3-b] thiophene or naphthol [2, 3-b] furan ring to form bromophenols of formula (1e: B, D are C 1 -C 6 alkyl; C is OH; X is Br; E is S or O) (Scheme 3). The bromination reaction is generally carried out with 1 to 1.3 molar equivalents of molecular bromine in the dark in the presence of a catalytic amount of ferric chloride in an inert solvent such as dichloromethane or carbon tetrachloride at temperatures ranging from -78 ° C to room temperature.

The acyl group is then from the acylated bromophenols of formula (Ie: B, C, D are H or OCOR; in combination B, C, D is at least one OCOR; R is alkyl with

· · • · · · • · ·· · • · ·· ·· · • · ·· • · • • • · • · · · · ···· · · · · · ·· ··

up to 6 carbon atoms, aryl; X is Br; E is S or O) is removed to form bromophenols of formula (Ie: B, C, D are H or OH; in combination B, C, D is at least one OH group; X is Br; E is S or O) (Scheme 3 ) under normal reaction conditions. These conditions include an aqueous solution of a base using one or more molar equivalents of an alkali metal hydroxide such as sodium hydroxide in water with a co-solvent such as THF, dioxane or an alcohol of 1 to 6 carbon atoms such as methanol, or mixtures of THF and alcohol with 1 to 6 carbon atoms at temperatures ranging from 0 ° C to 40 ° C. Acid conditions may also be used; under these conditions, the compound is reacted with one or more molar equivalents of a mineral acid such as hydrochloric acid or sulfuric acid in water in the presence or absence of a co-solvent such as THF at temperatures ranging from room temperature to 80 ° C.

Acylated phenols of formula (Id: B, C, D are H or OCOR; in combination of B, C, D with at least one OCOR; R is alkyl of 1 to 6 carbon atoms, aryl; E is S or O) can be nitrated to forming nitro compounds of formula (Ie: B, C, D are H or OCOR; in combination B, C, D is at least one OCOR group; R is alkyl of 1 to 6 carbon atoms, aryl; X is NO _Z ; E is S or O) (Scheme 3). Dilute nitric acid at temperatures ranging from 0 ° C to room temperature is suitable for this conversion. Nitro compounds of formula (Ie: B, C, D are H or OCOR; C and D cannot simultaneously be H; R is alkyl of 1 to 6 carbon atoms, aryl; X is NO ₂ ; E is S or O) can be further reduced to a primary amine of formula (1e: B, C, D are H or OCOR; in combination B, C, and D is at least one OCOR; R is alkyl of 1 to 6 carbon atoms, aryl; X is NH ₂ ; E is S or O) a suitable reducing agent such as catalytic hydrogenation using palladium or a palladium catalyst, stannous chloride in aqueous hydrochloric acid or ethyl acetate. Acyl in compounds of formula (Ie: B, C, D are H or OCOR; in combination B, C, and D is at least one OCOR; R is alkyl of 1 to 6 carbon atoms, aryl; X is NO ₂ or NH ₂ ; E is S or O) can be removed by conventional methods under conventional conditions.

Said acylated bromophenols of formula (Ie: B, C, D are H or OCOR; in combination B, C, D is at least one OCOR group; R is alkyl of 1 to 6 carbon atoms

-24 • atoms, aryl; X is Br; E is S or O) (Scheme 3) can be converted to acylated cyanophenols of formula (Ie: B, C, D are H or OCOR; in combination B, C, D is at least one OCOR; R is alkyl of 1 to 6 carbon atoms; aryl; X is CN; E is S or O) by reaction with one or more molar equivalents of copper cyanide. The reaction to cyano derivatives is generally carried out at temperatures ranging from 100 ° C to 250 ° C in a polar aprotic solvent such as DMF, 1-methyl-2-pyrrolidone or HMPA. Quinoline or pyridine may also be used. The acyl group of a compound of formula (Ie: B, C, D is H or OCOR; in combination

B, C, D at least one group is OCOR; R is alkyl of 1 to 6 carbon atoms, aryl; X is CN; E is S or O) is often liberated under cyanoderivative reaction conditions to produce cyanophenols of formula (Ie: B, C, D are H or OH; in combination B,

C, D at least one group is OH; X is CN; E is S or O). The release of the acyl group to form cyanophenols (Ie: B, C, D are H or OH; in combination B, C, D at least one group is OH; X is CN; E is S or O) is most easily accomplished by adding one or more molar alkali metal hydroxide equivalents in water to the reaction mixture containing (Ie: B, C, D are H or OCOR; in combination B, C, D at least one group is OCOR; R is alkyl of 1 to 6 carbon atoms, aryl; X; E is S or O) before further processing. The acyl group may also be removed from the isolated acylated cyanophenols of formula (Ie: B, C, D are H or OCOR; in combination B, C, D at least one group is OCOR; R is alkyl of 1 to 6 carbon atoms, aryl; X is CN; E is S or O) to form cyanophenols of formula (Ie: B, C, D are H or OH; in combination B, C, D at least one group is OH; X is CN; E is S or O) in conventional reaction conditions. These conditions include an aqueous base solution consisting of one or more molar equivalents of an alkali metal hydroxide such as sodium hydroxide and water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol, or mixtures of THF and a lower alcohol at temperatures ranging from 0 ° C to 40 ° C. Acid reaction conditions may also be used, wherein the compound is reacted with one or more equivalents of a mineral acid such as hydrochloric acid or sulfuric acid in water in the presence or absence of a co-solvent such as THF at temperatures ranging from room temperature to 80 ° C.

·················

-25 • · · ······································

Compounds of formula (Id: B, C, D are H or OH; in combination B, C, D at least one group is OH; E is S or O) (Scheme 3) can be sulfonylated on phenol oxygen using one or more molar moieties equivalents of a suitable sulfonylating agent to form sulfonic acid esters of formula (Id: B, C, D are H or OSO ₂ R; in combination B, C, D at least one group is OSO ₂ R; R is alkyl of 1 to 6 carbon atoms, aryl; E is S or O). The sulfonylating agent is generally an alkyl (C 1 -C 6) - or aryl sulfonic anhydride or an alkyl (C 1 -C 6) - or aryl sulfonic acid anhydride. The reaction is carried out under conventional conditions, for example in a pyridine medium as a solvent, in the presence or absence of a co-solvent such as dichloromethane, in a temperature range of 0 ° C to room temperature.

Sulfonic acid esters of formula (Id: B, C, D are H or OSO ₂ R; in combination B, C, D at least one group is OSO ₂ R; R is alkyl of 1 to 6 carbon atoms, aryl; E is S or O) can be treated with an iodinating agent to introduce the iodine into the 9-position of the naphthol [2,3-b] thiophene or naphthol [2,3-b] furan ring to form the iodosulfonic acid esters of formula (Ie: B, C, D are H or OSO ₂ R; in combination B, C, D at least one group is OSO ₂ R; R is alkyl of 1 to 6 carbon atoms, aryl; X is I; E is S or O). Suitable iodizing agents include a mixture of 0.7 or more molar equivalents of molecular iodine and 0.25 molar equivalents of iodic acid in admixture with THF and 80% aqueous acetic acid with a small amount of concentrated sulfuric acid at temperatures ranging from room temperature to 80 C. The sulfonic ester group may then be of iodosulfonic acid esters of formula (Ie: B, C, D are H or OSO ₂ R; in combination B, C, D at least one group is OSO ₂ R; R is alkyl of 1 to 6 atoms carbon, aryl; X is I; E is S or O) to remove iodophenols of formula (Ie: B, C, D are H or OH; in combination B, C, D at least one group is OH; X is I; E is S or O) (Scheme 3), using conventional conditions. These conditions include an aqueous base solution consisting of one or more molar equivalents of an alkali metal hydroxide such as sodium hydroxide and water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol, or mixtures of THF and a lower alcohol at temperatures ranging from room to 110 ° C.

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

-26 ··· ··· ··· ·· ··················

Iodosulfonic acid esters (If: C, D are H or OSO ₂ R; C, D cannot be both H; R is alkyl of 1 to 6 carbon atoms, aryl; E is S or O) are common starting materials for the preparation of other compounds of Formula I as depicted in Scheme 4 and as set forth below. Compounds of formula (If: C, D are H or OSO ₂ R; C, D cannot both be H; R is alkyl of 1 to 6 carbon atoms, aryl; E is S or O) can be reacted with a reactant that catalyzes exchanging the iodine atom in (If) with a lower perfluoroalkyl group to form a compound of formula (Ig: C, D are H or OSO ₂ R; C, D cannot be both H; R is alkyl of 1 to 6 carbon atoms, aryl; X is E is S or O) (Scheme 4). The reagent and conditions for said exchange include reaction (If) in anhydrous medium with one to ten molar equivalents of sodium perfluorocarboxylate (RCO ₂ Na; R is perfluoroalkyl) and one to five molar equivalents of cuprous iodide in an inert high boiling solvent such as DMF, DMA or 1-methyl-2-pyrrolidone, at temperatures ranging from 140 ° C to 200 ° C. Optionally, a compound of formula (Ig: C, D are H or OSO ₂ R; C, D cannot both be H; R is C 1 -C 6 alkyl, aryl; X is lower perfluoroalkyl; E is S or O) can be prepared from compounds of formula (If: C, D are H or OSO ₂ R; C, D cannot both be H; R is alkyl of 1 to 6 carbon atoms, aryl; E is S or O) by reacting the latter compound with one to ten molar perfluoroalkyl iodide equivalents and one to five molar equivalents of activated Cu ° in an inert high boiling solvent such as DMF, DMA or 1-methyl-2-pyrrolidone at a temperature of

• ·· ·· · · ·

The temperature range is from 140 ° C to 200 ° C. Optionally still, a compound of formula (If: C, D are H or OSO ₂ R; C, D cannot be both H; R is alkyl of 1 to 6 carbon atoms, aryl; E is S or O) can be reacted with 0.5 up to two molar equivalents of bis (trifluoromethyl) mercury and two to four molar equivalents of activated Cu ° in an inert high boiling solvent such as DMF, DMA or 1-methyl-2-pyrrolidone at a temperature ranging from 140 ° C to 200 ° C to form compounds of formula (Ig: C, D are H or OSO ₂ R; C, D cannot both be H; R is alkyl of 1 to 6 carbon atoms, aryl; X is lower CF ₃ ; E is S or O).

The alkyl derivatives at the 9-position of a compound of formula (Ig: C, D are H or OSO ₂ R; C, D cannot both be H; R is alkyl of 1 to 6 carbon atoms, aryl; X is alkyl of 1 to 6 carbon atoms; E is S or O) (Scheme 4) can be prepared by reacting a compound of formula (If: C, D are H or OSO ₂ R; C, D cannot be both H; R is alkyl of 1 to 6 carbon atoms, aryl; S or O) with three or more molar equivalents of lower tetraalkyl tin in the presence of a palladium catalyst, for example 1 to 10 mol% of bis (triphenylphosphine) palladium (II) chloride in a suitable solvent such as DMF, DMA or 1-methyl-2-pyrrolidone in the range of 140 ° C to 200 ° C.

The sulfonic ester group of sulfonic acid esters of formula (Ig: C, D are H or OSO ₂ R; C, D cannot both be H; R is alkyl of 1 to 6 carbon atoms, aryl; X is alkyl of 1 to 6 carbon atoms or lower perfluoroalkyl; E is S or O) can then be removed under conventional reaction conditions to give phenols of formula (Ig: C, D are H or OH; C, D cannot both be H; X is C 1 -C 6 alkyl or lower perfluoroalkyl; E is S or O). These conditions include an aqueous base solution consisting of one or more molar equivalents of an alkali metal hydroxide such as sodium hydroxide and water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol, or mixtures of THF and a lower alcohol at temperatures ranging from room temperature to 110 ° C.

The alkoxy derivatives at the 9-position of the compound of formula (Ig: C, D are H or OH; C, D cannot both be H; X is C 1 -C 6 alkoxy; E is S or O) can be prepared by reacting a compound of formula (If : C, D are H or OSO ₂ R; C, D cannot be both H; R is alkyl of 1 to 6 carbon atoms, aryl; E is S or O); ···························

• · ··

-28times or more molar equivalents of an alkali metal lower alkoxide such as sodium methoxide in the presence of a copper or copper catalyst, for example 1 to 10 mol% of copper (I) chloride in a suitable solvent such as DMF, DMA or 1-methyl-2-pyrrolidone at a temperature in the range of from 80 ° C to 180 ° C. Under these reaction conditions, the sulfonic acid group of formula (1f: C, D are H or OSO ₂ R; C, D cannot both be H; R is alkyl of 1 to 6 carbon atoms, aryl; E is S or O).

The sulfanyl derivatives at the 9-position of a compound of formula (Ig: C, D are H or OH; C, D cannot both be H; X is C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl ; E is S or O) can be prepared by reacting a compound of formula (1f: C, D are H or OSO ₂ R; C, D cannot be both H; R is alkyl of 1 to 6 carbon atoms, aryl; E is S or O ) with one or more molar equivalents of a suitable C 1 -C 6 alkylthiol, arylthiol, thiopyridine or 2- N, N -dimethylaminoethyl mercaptan with one or more molar equivalents of an alkali metal hydroxide such as sodium hydroxide, with one or more molar equivalents equivalents of copper or copper catalyst such as cuprous oxide in a suitable solvent such as DMF, DMA or 1-methyl-2-pyrrolidone at a temperature in the range of from 100 ° C to 180 ° C. Under these reaction conditions, the sulfonic acid group of formula (1f: C, D are H or OSO ₂ R; C, D cannot both be H; R is alkyl of 1 to 6 carbon atoms, aryl; E is S or O).

(Ih)

(H) ··

Other derivatives of compounds of Formula I in Scheme 5 can be prepared by the following methods. Phenols of formula (Ih: A is H or OH; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2H, N-dimethylaminoethylsulfanyl; E is S or O) can be brominated in two positions to form dibromophenols of formula (Ii: A is H or OH; B, D are Br; X is H, halogen, alkyl (C 1 -C 6), CN, lower perfluoroalkyl, (C 1 -C 6) alkoxy, aralkoxy, nitro, (C 1 -C 6) alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2-W, N-dimethylaminoethylsulfanyl; E is S or O) using at least two molar equivalents of molecular bromine in a suitable solvent such as acetic acid. One to fifty molar equivalents of the acetic acid salt, for example potassium or sodium acetate, may also be used as the co-reactant in this reaction, although the presence of the co-reactant is not directly required.

Phenols of formula (Ih: A is H; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- (N, N -dimethylaminoethylsulfanyl; E is S or O) can be (mono) nitrated to phenols of formula (Ii: A is H; B is NO ₂ ; D is H; X is H, halogen, alkyl s C 1 -C 6, CN, lower perfluoroalkyl, C 1 -C 6 alkoxy, aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2-N, N -dimethylaminoethylsulfanyl; E is S or O) Easily using ferric nitrate in a solvent (lower alcohol).

Nitro compounds of formula (II: A is H; B is NO ₂ ; D is H; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl having 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2H, N-dimethylaminoethylsulfanyl; E is S or O) can be reduced to amino compounds of formula (Ii: A is H; B is NH ₂ ; D is H; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; is S or O) preferably using tin (II) chloride in ethyl acetate at 40 to 100 ° C, or hydrazine and montmorillonite clay in ethanol at 40 to 100 ° C.

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

-30N-Compounds of formula (Ii: A is H; B is NO ₂ ; D is H; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2 H, N -dimethylaminoethylsulfanyl; E is S or O) can also be brominated to compounds of formula (II: A is H; B is NO ₂ ; D is Br; X; is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-A, N, -N- E is S or O) using at least 2 molar equivalents of molecular bromine in a suitable solvent such as acetic acid. One to fifty molar equivalents of the acetic acid salt, for example potassium or sodium acetate, may also be used as the co-reactant in this reaction, although the presence of the co-reactant is not directly required. Bromo-nitro compounds of formula (II): A is H; B is NO ₂ ; D is Br; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy , nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; E is S or O) can be reduced to bromoamino compounds of formula (II: A is H; B is NH ₂ ; D is Br; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- / V, (N-dimethylaminoethylsulfanyl; E is S or O), most preferably tin tetrachloride in ethyl acetate at 40 to 100 ° C, or hydrazine and montmorillonite clay in ethanol at 40 to 100 ° C.

Amino compounds of formula (II): A is H; B is NH ₂ ; D is H or Br; X is H, halogen, C 1 -C 6 alkyl, CN, lower perfluoroalkyl, C 1 -C 6 alkoxy, aralkoxy, nitro , C 1-6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2-N, N -dimethylaminoethylsulfanyl; E is S or O) can be acylated with one or more equivalents of a suitable acylating agent of formula (LG) COR ^1a or (LG) CO 2 R ^1a (wherein LG is a displaceable group such as Cl for an alkyl halide or chloroformate, or OCOR ^1a or OCO 2 R ^1a for an anhydride or mixed anhydride, etc .; R ^1a is an alkyl of 1 to 6 carbon atoms, aralkyl and aryl) to give compounds of formula (IIa) A is H; B is NHCOR ^1a or NHCO ₂ R ^1a ; D is H or Br; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms; ·

I · · «·· ··········

-31 aralkoxy, amino, (C 1 -C 6) alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- (N, N -dimethylaminoethylsulfanyl); E is S or O; R ^1a is alkyl of 1 to 6 carbon atoms, aralkyl and aryl). The acylation may be carried out in the presence of one or more equivalents of a suitable base, for example an alkali metal hydroxide, alkali metal carbonate or bicarbonate, or in the presence of an organic amine base such as triethylamine or pyridine and in the presence or absence of a suitable solvent such as chloroform, dichloromethane, THF, dioxane. and water, or mixtures of these solvents and in the presence or absence of a catalyst such as 4- (N, N-dimethylpyridine).

The dibromo-bisphenols of formula (II: A is OH; B, D are Br; X is H; E is S or O) can be further brominated at the 9-position of naphtho [2,3-b] thiophene or naphtho [2,3-b of a furan ring to form bisphenols of formula (Ii: A is OH; B, D, X are Br; E is S or O). This bromination is generally carried out using 1 to 13 molar equivalents of light-free molecular bromine in the presence of a catalytic amount of ferric chloride in an inert solvent such as dichloromethane or carbon tetrachloride at a temperature ranging from -78 ° C to room temperature.

Scheme 6

(lj) (lk)

Additional derivatives of compounds of Formula I in Scheme 6 can be prepared by the following methods. Phenols of formula (1j: C is H; D is OH; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, ·· • · ··

-32 aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2 H, N-dimethylaminoethylsulfanyl; E is S or O) can be brominated to the first stage to form bromophenols of formula (Ik: A and B are H; C is Br; D is OH; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, (C 1 -C 6) alkoxy, aralkoxy, nitro, (C 1 -C 6) alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- (N, N -dimethylaminoethylsulfanyl; E is S or O) using at least one molar equivalent of molecular bromine in a suitable solvent such as acetic acid, or brominate to the second stage to form dibromophenols of formula (Ik: B is H; A and C are Br; D is OH; X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, (C 1 -C 6) alkoxy, aralkoxy, nitro, (C 1 -C 6) alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- (N, N -dimethylaminoethylsulfanyl; E is S or O) using at least two molar equivalents of molecular bromine in a suitable solvent , for example in acetic acid. Similarly, bisphenols of formula (Ij: C and D are OH; X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; E is S or O) to monobromo derivatives to give a mixture of bromobisphenols of formula (Ik: A is H; B is Br; C and D are OH; X is halogen, alkyl C 1 -C 6, CN, lower perfluoroalkyl, C 1 -C 6 alkoxy, aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2-N, N -dimethylanninoethylsulfanyl; E is S or O) a (Ik: A is Br; B is H; C and D are OH; X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl; 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; E is S or O) using at least one molar equivalents a molecular bromine substituent in a suitable solvent such as acetic acid. The resulting mixture can be separated into pure monobromo products by conventional methods.

· · ·

-33 · 9 * 9 • * * * * * 33 * 33 9 9 9 33 33 33 33

· ·

9 9

Scheme 7

Additional derivatives of compounds of Formula I in Scheme 7 can be prepared by the following methods. Phenols of formula (II: B is H; A and C are H or Br; D is OH; X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; E is S or O) can be acylated with one or more molar equivalents of an alkyl haloacetate of formula (X ² CHR ^{6 and} CO ₂ R ⁶ wherein X ² is Cl, Br or iodine and R ⁶ is alkyl of 1 to 6 carbon atoms, R ^6a is H) and one or more molar equivalents of an alkali metal carbonate such as potassium carbonate in a polar aprotic solvent such as DMF to give the product of formula (Im: B is H; AC is H or Br; X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; R ⁶ is alkyl of 1 to 6 atoms and R ^6a is H; E is S or

ABOUT).

Optionally, bisphenols of formula (II: A and B are H or Br; C and D are OH; X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; E is S or O) dialkylated with two or more molar equivalents of alkyl haloacetate of formula (X ² CHR ^{6 and} CO ₂ R ⁶ ) ··························

Where X ² is Cl, Br, or iodine and R ⁶ is alkyl of 1 to 6 carbon atoms; R ^6a is H) and with two or more alkali metal carbonate equivalents such as potassium carbonate in a polar aprotic solvent such as DMF to give dialkylated esters of formula (Im: A, B are H or Br; C is OCH ² CO ² R ⁶ ; X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; ⁶ is alkyl of 1 to 6 carbon atoms, R ^6a is H, E is S or O).

Phenols of formula (II: B is H or halogen; A is H or halogen; C is H; Br or alkoxy of 1 to 6 carbon atoms; D is OH; X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, (C 1 -C 6) alkoxy, aralkoxy, nitro, (C 1 -C 6) alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; E is S or O) optionally reacted with 2-hydroxycarboxylic ester acids of formula CH (OH) (R ^6a ) CO ₂ R ⁶ wherein R ⁶ and R ^6a are C 1 -C 6 alkyl, aralkyl, aryl) to form esters of formula (Im: B is H or halogen; A is H or halogen; C is H, Br, or an alkoxy group having 1 to 6 carbon atoms; X is halogen, alkyl having 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy having 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl having 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; E is S or O) under the conditions used for Mit sunobu reactions (see Oyo Mitsunobu Synthesis 1 to 27 (1981) for a review). Other co-reactants required to carry out the Mitsunobu reaction include one or more molar equivalents of an alkyl (C 1 -C 6) azodicarboxylate diester such as diethyldiazocarboxylate or diisopropylazodicarboxylate and one or more molar equivalents of a triarylphosphine such as triphenylphosphine in a suitable solvent, e.g. , benzene or toluene at a temperature ranging from -20 to 120 ° C.

Monoesters of formula (Im: A and B are H or halogen; C is H, Br or a C 1 -C 6 alkoxy group; X is halogen, C 1 -C 6 alkyl, CN, lower perfluoroalkyl, C 1 -C 6 alkoxy carbon atoms, aralkoxy, nitro, (C 1 -C 6) alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2-N, N -dimethylaminoethylsulfanyl; R ⁶ and R ^6a are C 1 -C 6 alkyl, aralkyl or aryl groups

·· ·· • · · ·

9 · · · · ·

-35skupiny; E is S or O) as well as the diesters of formula (Im: A and B are H or Br; C is OCH ² CO 2 R ⁶ ; X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms , aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2-N, N -diethylaminoethylsulfanyl; R ⁶ is C 1-6 alkyl, R ^6a is H; E is S or O) convert them to their analogous carboxylic acids under conventional reaction conditions to form monocarboxylic acids of formula (Im: A and B are H or halogen; C is H, Br, or a C 1 -C 6 alkoxy group, X is halogen, C 1 -C 6 alkyl (C 6 -C 6), CN, lower perfluoroalkyl, (C 1 -C 6) alkoxy, aralkoxy, nitro, (C 1 -C 6) alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; R ⁶ is H; R ^6a is alkyl of 1 to 6 carbon atoms, aralkyl or aryl; E is S or O) and to the dicarboxylic acids of formula (Im: A and B are H or Br; C is OCH ₂ CO ₂ H; X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; R ⁶ and R ^6a are H; E is S or O). Reaction conditions for carrying out these transformations include an aqueous base solution consisting of one or more molar equivalents of an alkali metal hydroxide such as sodium hydroxide in water and a co-solvent such as THF, dioxane or a lower alcohol such as methanol, or a mixture of THF and lower. alcohol at a temperature ranging from 0 to 40 ° C.

Scheme 8

(In)

-36 ·· ·· · · · ·

9 9

9999 »

·· · · ·· ·

Additional derivatives of compounds of Formula I in Scheme 8 can be prepared by the following methods. Acetates of formula (In: X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- / V N, N-dimethylaminoethylsulfanyl; Y is H; E is S or O) may be reacted with a halogenating agent, more particularly with an agent that causes the benzylic type of bromination or chlorination such as one or more molar equivalents of N -bromosuccinimide, N-chlorosuccinimide or sulfuryl chloride to form haloacetates of formula (In: X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- N, N-dimethylaminoethylsulfanyl; Y is Cl, Br; E is S or O). This reaction is readily carried out in a suitable solvent, for example dichloromethane or carbon tetrachloride at a temperature ranging from 0 ° C to room temperature.

Said haloacetates of formula (In: X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- / N, N-dimethylaminoethylsulfanyl; Y is Cl, Br; E is S or O) can react with one or more molar equivalents of nucleophiles such as alkoxides (MOR ¹ ), sulfides (MSR ¹ ) or amines (NHR ¹ R ² ) (wherein M is an alkali metal such as Na, Li, or K; R ¹ , R ² are C 1 -C 6 alkyl, aryl or aralkyl groups) in a suitable solvent such as THF, DMF or dichloromethane to give compounds of formula (In X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- (V, R) Y is OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, an alkyl group having 1; C1 to 6, aryl or aralkyl; E is S or O). During the reaction of compounds of formula (In: X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2 -N, N-dimethylaminoethylsulfanyl; Y is Cl, Br; E is S or O) with nucleophiles there can be concomitant loss of the acetyl group to give compounds of formula (L 1: B and D are H; X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 · · · · · · · · · · · · · · · · · · · · · · ·

-37 carbon atoms, aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; Y is OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl; E is S or O).

Compounds of formula (In: X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-A) N is dimethylaminoethylsulfanyl; Y is OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, C 1 -C 6 alkyl, aryl or aralkyl; E is S or O) can be deacetylated to form compounds of formula (IO: B and D are H; X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- (N, N -dimethylaminoethylsulfanyl) Y is Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, an alkyl group having 1 to 6 carbon atoms, aryl or aralkyl; E is S or O). Reaction conditions for deacetylation include an aqueous base solution consisting of one or more molar equivalents of a base such as sodium hydroxide, water and a co-solvent such as THF, dioxane or a lower alcohol such as methanol, or a mixture of THF and lower alcohol at a temperature ranging from 0 ° C to 40 ° C. It is also possible to use acidic conditions in which said compound reacts with one or more molar equivalents of a mineral acid such as hydrochloric acid or sulfuric acid in an aqueous medium in the presence or absence of a co-solvent such as THF at a temperature ranging from room temperature to 80 ° C.

Compounds of formula (Ia: B and D are H; X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, Y is Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, (C 1 -C 6) alkyl, aryl, or aralkyl; the group; E is S or O) can be brominated in two positions to form dibromophenols of the formula (L 1: B and D are Br; X is halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms , aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2 N, N -dimethylaminoethylsulfanyl; Y is Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, · *,,,,,,,, · · ·

-38 alkyl of 1 to 6 carbon atoms, aryl or aralkyl; E is S or O) using at least two molar equivalents of molecular bromine in a suitable solvent, for example acetic acid. One to fifty molar equivalents of an acetic acid salt such as sodium or potassium acetate may also be used as a co-solvent in this reaction, although the presence of acetate is not necessary.

Scheme 9

Additional derivatives of compounds of Formula I in Scheme 9 can be prepared by the following methods. Phenols of formula (Ip: B, D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² wherein R ¹ and R ² are H, C 1 -C 6 alkyl, aryl or aralkyl; E is S or O) can be alkylated with one or more molar equivalents of an alkyl haloacetate of formula (X ² CH ² CO ² R ⁶ wherein X ² is Cl , Br, or iodine and R ⁶ is an alkyl group having 1 to 6 carbon atoms) and one or more molar equivalents of an alkali metal carbonate such as potassium carbonate in a polar aprotic solvent such as DMF to form an alkylated product of formula (Iq: B, D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl 1 with 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy with 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl φφ φφφφφφφφφφφφφφφφφφφ

-39φφ φφφφ s s s s s s s s s s 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1ryryryryryryry aryryryryryryryryryryryryryry; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl; W is CO ₂ R ⁶ ; R ⁵ is H; R ⁶ is C 1 -C 6 alkyl; E is S or O).

Phenols of formula (Ip: B, D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy C 1 -C 6, aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2 H, N-dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, (C 1 -C 6) alkyl, aryl or aralkyl (E is S or O) may be reacted with a 2-hydroxycarboxylic acid ester of formula CH (OH) (R ⁵ ) CO 2 R ⁶ wherein R ⁵ is H, (C 1 -C 6) alkyl, aralkyl, aryl, -CH 2 (1H-imidazol-4-yl), -CH ₂ (3-1 H -indolyl), -CH ₂ CH ₂ (1) , 3-dioxo-1,3-dihydro-isoindol-2-yl), -CH ₂ CH ₂ (1-oxo-1,3-dihydro-isoindol- ₂ -yl), -CH ₂ (3-pyridyl), -CH ₂ CO 2 R ⁶ , R ⁶ is C 1 -C 6 alkyl) to form esters of formula (Iq: B is H, halogen, CN, C 1 -C 6 alkyl, aryl, aralkyl, nit X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- / V, / \ / - ethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen atoms, aryl or aralkyl; W is CO 2 R ^6; R ⁵ is H, (C 1 -C 6) alkyl, aralkyl, aryl, -CH 2 (1 H -imidazol-4-yl), -ΟΗ 2 (3-1 H -indolyl), -CH 2 CH 2 (1,3-dioxo) -1,3-dihydro-isoindol-2-yl), -CH ₂ CH ₂ (1-oxo-1,3-dihydro-isoindol-2-yl), -CH ₂ (3-pyridyl), -CH ₂ CO ² R ⁶ , R ⁶ is C 1 -C 6 alkyl; E is S or O) under the conditions used for Mitsunobu reactions (see Oyo Mitsunobu Synthesis 1 to 27 (1981) for review). Other co-reactants needed to perform the Mitsunobu reaction include one or more molar equivalents of an alkyl (C 1 -C 6) azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of a triarylphosphine, for example triphenylphosphine in a suitable solvent, benzene or toluene at a temperature ranging from -20 to 120 ° C.

·························

-40 • · · · · · ··············

2-Hydroxycarboxylic acid ester of formula CH (OH) (R ⁵ ) CO ² R ⁶ wherein R ⁵ is H, C 1 -C 6 alkyl, aralkyl, aryl, -CH 2 (1H-imidazol-4-yl), -CH ₂ (3-1H-indolyl), -CH ₂ CH ₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), -CH ₂ CH ₂ (1-oxo-1,3-dihydro-isoindol-2) -yl), -CH ₂ (3-pyridyl), -CH ₂ CO ₂ R ⁶ , R ⁶ is an alkyl group having 1 to 6 carbon atoms) is commercially available or can be prepared from commercially available carboxylate precursors under conventional esterification conditions reactions. (SH +) - 2-Hydroxy-1-oxo-3-dihydro-2-isoindolinebutyric acid methyl ester can be prepared from (S) - (+) - 2-hydroxy-1,3-dioxo-2-isoindolinebutyric acid methyl ester by sequential treatment with 1) sodium borohydride in a THF-water mixed medium; 2) trifluoroacetic acid in chloroform; 3) triethylsilane in trifluoroacetic acid; and 4) aqueous sodium bicarbonate solution. 3- (Pyridin-3-yl) -phenyl-lactic acid ethyl ester can be prepared by the two-step procedure of BA Lefker, WA Snake, PJ McGarry (Tetrahedron Lett., 35, 5205-5208 (1994)) from commercially available 3-pyridinecarboxaldehyde and ethyl chloroacetate.

Esters of formula (Iq: B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy C 1 -C 6, aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen atoms, aryl or aralkyl; W is CO ₂ - tert -Bu; R ⁵ is H; E is S or O) can be treated with one or more molar equivalents of a strong base such as lithium diisopropylamide in a suitable solvent, for example in THF at a temperature ranging from -78 ° C to room temperature. In this reaction step, the anion is formed in position and to the ester carbonyl. The resulting anion is mixed with one or more molar equivalents of an alkyl halide of formula X ² R ⁵ (where X ² is halogen; R ⁵ is an alkyl or aralkyl group), allowed to warm to room temperature to form the alkylated ester of formula (Iq: B and D). X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy , nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- (N, N -dimethyl-41-) -

· · • · • · · · • · • · · • · • · • · · • · · • · • · • · • é · • • · • · ···· · · · · · · ·

aminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen atoms, aryl or aralkyl; W is CO ₂ -terc-Bu; R ⁵ is an alkyl and aralkyl group; E is S or O).

Esters of formula (Iq: B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy C 1 -C 6, aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen atoms, aryl or aralkyl; W is CO ² R ⁶ ; R ⁵ is H, alkyl of 1 to 6 carbon atoms, aralkyl, aryl, -CH 2 (1); (7-imidazol-4-yl), -CH ₂ (3-1 / 7-indolyl), -CH ₂ CH ₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), -CH ₂ CH ₂ (1-oxo-1,3-dihydro-isoindol- ₂ -yl), -CH ₂ (3-pyridyl), -CH ₂ CO ₂ R ⁶ , R ⁶ is an alkyl group having 1 to 6 carbon atoms; S or O) can be converted to their analogous carboxylic acids of formula (Iq: B and D are H, halogen, CN, (C 1 -C 6) alkyl, aryl, and X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N , Ndimetylaminoetylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen atoms, aryl or aralkyl; W is CO 2 H; R ⁵ is H, (C 1 -C 6) alkyl, aralkyl, aryl, -CH 2 (1/7-imidazol-4-yl), -CH ₂ (3-1 / 7-indolyl), -CH ₂ CH ₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), -CH ₂ CH ₂ (1-oxo-1,3-dihydro-isoindol-2-yl), -CH ₂ (3-pyridyl), -CH ₂ CO ₂ H; E is S or O). Reaction conditions that allow this reaction include an aqueous base solution consisting of one or more molar equivalents of an alkali metal hydroxide such as sodium hydroxide in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol, or mixtures of THF and lower. alcohol at a temperature in the range of 0 ° C to 40 ° C. Optionally, acidic reaction conditions may be used in which said carboxylic acid ester of formula (Iq) reacts with one or more equivalents of a mineral acid such as hydrochloric acid or sulfuric acid in water in the presence or absence of a co-solvent such as THF at a temperature in the range from room temperature to 80 ° C. On the transformation of the above mentioned, the process of the above mentioned. ·· ·

Optionally, other reaction conditions can also be selected for the acid ester. Other reaction conditions include reacting said carboxylic ester of formula (Iq) with one or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at -78 ° C to room temperature; with one or more molar equivalents of hydrobromic acid in acetic acid at 0 ° C to 50 ° C; with one or more molar equivalents of trimethylsilyl bromide or trimethylsilyl iodide in dichloromethane, carbon tetrachloride or acetonitrile at -78 ° C to 50 ° C; with one or more molar equivalents of lithium iodide in pyridine or quinoline at a temperature ranging from 100 ° C to 250 ° C.

Phenols of formula (Ip: B and D are H, halogen, CN, (C 1 -C 6) alkyl, aryl, aralkyl, nitro; X is H, halogen, (C 1 -C 6) alkyl,

CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen atoms, aryl or aralkyl; E is S or O) can be alkylated with one or more molar equivalents of diethyl trifluoromethylsulfonyloxymethylphosphanate (DP Phillion and SS Andrew, Tetrahedron Lett. 1477-1480 (1986)) and with one or more molar equivalents of an alkali metal hydride such as sodium hydride in a suitable solvent, for example in THF or DMF to give the diethyl phosphonate product of formula (Iq: B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 atoms carbon, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; Y is H,

Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen atoms, aryl or aralkyl; E is S or O).

Phenols of formula (Ip: B and D are H, halogen, CN, (C 1 -C 6) alkyl, aryl, aralkyl, nitro; X is H, halogen, (C 1 -C 6) alkyl,

CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen atoms, aryl or aralkyl; E is an S or O) can react with the diester

-43 2-hydroxyphosphonic acid of formula CH (OH) (R ⁵ ) PO3 (R) -43 · · · · · · · · · · · · · · · · · ⁶ ) 2, (R ⁵ is H, alkyl of 1 to 6 carbon atoms, aralkyl, aryl; R ⁶ is alkyl of 1 to 6 carbon atoms) to form phosphonic acid diesters of formula (Iq: B and D are H, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, (C 1 -C 6) alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, C 1 -C 6 alkyl, aryl or aralkyl; W is PO 3 (R ⁶ ) ₂ ; R ⁵ is H, C 1 -C 6 alkyl, aralkyl, aryl, R ⁶ is C 1 -C 6 alkyl E is S or O) under the conditions used for Mitsunobu reactions (see Oyo Mitsunobu Synthesis 1 to 27 (1981) for a review). Other co-reactants required to carry out the Mitsunobu reaction include one or more molar equivalents of an alkyl (C 1 -C 6) azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of a triarylphosphine, for example triphenylphosphine in a suitable solvent such as benzene or toluene at a temperature ranging from -20 to 120 ° C.

2-Hydroxyphosphonic acid diester of formula CH (OH) (R ⁵ ) PO 3 (R ⁶ ) 2, (R ⁵ is H, alkyl of 1 to 6 carbon atoms, aralkyl, aryl, R ⁶ is alkyl of 1 to 6 carbon atoms ) may be prepared by reacting a dialkyl phosphonate of formula HP (O) (OR ⁶ ) 2 (R ⁶ is C 1 -C 6 alkyl) with an aldehyde of formula R ⁵ CHO (R ⁵ is C 1 -C 6 alkyl, aryl, aralkyl ) under normal reaction conditions.

Phosphonic acid diesters of formula (Iq: B and D are H, halogen, CN, C 1 -C 6 alkyl, aryl, aralkyl, nitro; X is H, halogen, C 1 -C 6 alkyl, CN, lower perfluoroalkyl , alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, (C 1 -C 6) alkyl, aryl or aralkyl; W is PO ₃ (R ⁶ ) 2; R ⁵ is H, (C 1 -C 6) alkyl, aralkyl, aryl, R ⁶ is an alkyl group having 1 to 6 carbon atoms; E is S or O) can be converted to their analogous phosphonic acid groups;

-44 · acids (Iq: B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- / Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen atoms, aryl or aralkyl; W is PO 3 H 2 R ⁵ is H, C 1 -C 6 alkyl, aralkyl, aryl, R ⁶ is H, C 1 -C 6 alkyl; E is S or O). In this conversion reaction of said phosphonic acid diester of formula (Iq), conditions may be used in which said diester reacts with one or more molar equivalents of a mineral acid such as hydrochloric acid or sulfuric acid in water in the presence or absence of a co-solvent such as THF, at a temperature ranging from 40 ° C to 100 ° C. Optionally, various other reaction conditions can be used to convert said diester to the acid of formula (Iq). These conditions include reacting said phosphonic diester of formula (Iq) with two or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at -78 ° C to room temperature; with one or more molar equivalents of hydrobromic acid in acetic acid at 0 ° C to 50 ° C; with two or more molar equivalents of trimethylsilyl bromide or trimethylsilyl iodide in dichloromethane, carbon tetrachloride or acetonitrile at -78 ° C to 50 ° C; with two or more molar equivalents of lithium iodide in pyridine or quinoline at a temperature ranging from 60 ° C to 250 ° C.

Esters of formula (Iq: B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy C 1 -C 6, aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2-N, N -dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen atoms, aryl or aralkyl; W is CO ² R ⁶ ; R ⁵ is H, alkyl of 1 to 6 carbon atoms, aralkyl, aryl, -CH 2 ( 1H-imidazol-4-yl), -CH ₂ (3-1H-indolyl), -CH ₂ CH ₂ (1-oxo-1,3-dihydro-isoindol-2-yl), -CH ₂ (3-pyridyl) , R ⁶ is an alkyl group having 1 to 6 carbon atoms; E is S or O) can be converted to amide analogs thereof

· · · · • · • · · • · • · • · · • · · • · · • · • • • • • • • • · • • · · · ···· · · · · · ·· ·

primary carboxylic acids of formula (Iq: B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl , alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen atoms, aryl or aralkyl; W is CONH 2; R ⁵ is H, alkyl of 1 to 6 carbon atoms, aralkyl, aryl, -CH 2 (1A-imidazole) -4-yl), -CH ₂ (3-1 / 7-indolyl), -CH ₂ CH ₂ (1-oxo-1,3-dihydro-isoindol-2-yl), -CH ₂ (3-pyridyl) E is S or O) reacting the ester starting material with ammonia gas dissolved in a solvent (lower alcohol) such as methanol or ethanol at a temperature in the range of 0 ° C to 100 ° C.

Carboxylic acids of formula (Iq: B and D are H, halogen, CN, (C 1 -C 6) alkyl, aryl, aralkyl, nitro; X is H, halogen, (C 1 -C 6) alkyl, CN, lower perfluoroalkyl, (C 1 -C 6) alkoxy, aralkoxy, nitro, (C 1 -C 6) alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- (N) -dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen atoms, aryl or aralkyl; W is CO 2 H; R ⁵ is H, alkyl of 1 to 6 carbon atoms, aralkyl, aryl, -CH 2 (1H-imidazol-4-yl), -CH ₂ (3-1H-indolyl), -CH ₂ CH ₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), -CH ₂ CH ₂ (1-oxo-1,3-dihydroisoindol-2-yl), -CH ₂ (3-pyridyl); E is S or O) can optionally be converted to their carboxylic acid amide analogs of formula (Iq: B and D are H, halogen, CN, (C 1 -C 6) alkyl, aryl, aralkyl, nitro; X is H, halogen, (C 1 -C 6) alkyl, CN, EXAMPLE perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, Ndimetylaminoetylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen atoms, aryl or aralkyl; W is CONH 2, CONHOH, CONH (CH 2) 2 CN; R ⁵ is H, (1-6C) alkyl, aralkyl, aryl, -CH 2 (1H-imidazol-4-yl), -CH ₂ (3-1H-indolyl), -CH ₂ CH ₂ (1,3 -dioxo-1,3-dihydro-isoindol-2-yl) -CH ₂ CH ₂ (1-oxo-1,3-dihydro-isoindol-2-yl) -CH ₂ (3-pyridyl); E is S or O). This conversion can be accomplished by conventional methods used to convert a carboxylic acid into a carboxylic acid amide. These ways

· · · · • · • · · • · · • · · • · • · • • • • • • • • • • • • • • • • · · · ···· • • · · · · · •

include converting an acid to an activated acid form and reacting with one or more molar equivalents of the desired amine. In this group, amines include ammonia in the form of ammonium hydroxide, hydroxylamine and 2-aminopropionitrile. Methods for activating a carboxylic acid include reacting said acid with one or more molar equivalents of oxalyl chloride or thionyl chloride to form the carboxylic acid chloride, in a suitable solvent, for example, in dichloromethane, chloroform or diethyl ether. The reaction is often catalyzed by the addition of small amounts (0.01 to 0.1 molar equivalents) of dimethylformamide. Other methods of activating a carboxylic acid include reacting said acid with one or more molar equivalents of dicyclohexylcarbodiimide in the presence or absence of one or more molar equivalents of hydroxybenzotriazole in a suitable solvent, for example dichloromethane or dimethylformamide, at a temperature ranging from 0 ° C to 60 ° C.

Phenols of formula (Ip: B and D are H, halogen, CN, C 1 -C 6 alkyl, aryl, aralkyl, nitro; X is H, halogen, C 1 -C 6 alkyl, CN, lower perfluoroalkyl, alkoxy (1-6C) aralkoxy, nitro, (1-6C) alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; Y is H, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, C 1 -C 6 alkyl, aryl or aralkyl; W is CO 2 H; R ⁵ is H, C 1 -C 6 alkyl, aralkyl or aryl; E is S or O) can be alkylated with one or more molar equivalents of haloacetonitrile of formula (X ² CH ² CH, where X ² is Cl, Br or iodine) and with one or more molar equivalents of an alkali metal carbonate such as potassium carbonate in a polar aprotic solvent such as DMF to form nitriles of formula (Iq: B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl ; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen atoms, aryl or aralkyl; W is CN; R ⁵ is H; E is S or O).

-47 ············································ ··· ·· ··· ··

Optionally, carboxylic acid amide analogs of formula (Iq: B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen, aryl or aralkyl; W is CONH 2; R ⁵ is H, alkyl of 1 to 6 carbon atoms, aralkyl, aryl , -CH 2 (1 H -imidazol-4-yl), -CH 2 (3-1 H -indolyl), -CH 2 CH 2 (1,3-dioxo-1,3-dihydro-isoindol-2-yl), -CH 2 CH 2 (1- oxo-1,3-dihydro-isoindol-2-yl), -CH 2 (3-pyridyl); E is S or O) converted to the corresponding nitrile analogs of formula (Iq: B and D are H, halogen, CN, alkyl C 1 -C 6, aryl, aralkyl, nitro; X is H, halogen, C 1 -C 6 alkyl, CN, lower perfluoroalkyl, C 1 -C 6 alkoxy, aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- (N, N -dimethylaminoethylsulfanyl); Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen atoms, aryl or aralkyl; W is CN; R ⁵ is H, (C 1 -C 6) alkyl, aralkyl, aryl, -CH 2 (1 H -imidazol-4-yl), -CH ₂ (3-1Hindolyl), -CH ₂ CH ₂ ( 3-dioxo-1,3-dihydro-isoindol-2-yl) -CH ₂ CH ₂ (1-oxo-1,3-dihydroisoindol-2-yl) -CH ₂ (3-pyridyl); E is S or O) using reactants that dehydrate the primary carboxamide function to a nitrile function. The set of conditions for carrying out this conversion comprises reacting said primary carboxylic acid amide with one or more molar equivalents of trifluoroacetic anhydride and two or more molar equivalents of pyridine in a suitable solvent, for example dioxane, at a temperature ranging from 60 ° C to 120 ° C.

Nitrile analogs of formula (Iq: B and D are H, halogen, CN, (C 1 -C 6) alkyl, aryl, aralkyl, nitro; X is H, halogen, (C 1 -C 6) alkyl, CN, lower perfluoroalkyl, C 1-6 alkoxy, aralkoxy, nitro, C 1-6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² wherein R ¹ and R ² are H, (C 1 -C 6) alkyl, aryl or aralkyl; W is CN; R ⁵ is H, (C 1 -C 6) alkyl, aralkyl, aryl, -CH ₂ (1H-imidazol-4-yl), -CH ₂ (3-1H-48) · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Indolyl), -CH ₂ CH ₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), -CH ₂ CH ₂ (1- oxo-1,3-dihydroisoindol-2-yl), -CH ₂ (3-pyridyl); E is S or O) can be converted to the tetrazoles of formula (Iq: B and D are H, halogen, CN, alkyl having 1; up to 6 carbon atoms, ar X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2 - / V, / V-dimetylanninoetylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 hydrogen atoms, aryl or aralkyl; W is 5-tetrazole; R ⁵ is H, (C 1 -C 6) alkyl, aralkyl, aryl, -CH ₂ (1 H -imidazol-4-yl), -CH ₂ (3-1H-indolyl), -CH ₂ CH ₂ (1,3-dioxo-1,3-dihydroisoindol-2-yl), -CH ₂ CH ₂ (1-oxo-1,3-dihydro-isoindol-2-yl), -CH ₂ (3-pyridyl); E is S or O) by reacting a nitrile function with one or more molar equivalents of trimethylaluminium and with one or more molar equivalents of trimethylsilyl azide in a suitable solvent, for example benzene or toluene, at a temperature ranging from 60 ° C to 120 ° C. The nitrile functionality may optionally be reacted with one or more molar equivalents of ammonium azide in a suitable solvent, for example dimethylformamide, at a temperature ranging from 60 ° C to 160 ° C.

Scheme 10

Other derivatives of the compounds of formula I in Scheme 10 can be prepared by the following methods. Phenols of the formula (Ir: B, D are H, halogen, CN, alkyl of 1 to 6).

-49 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-A, N Ndimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl; E is S or O) can be reacted with one or more molar equivalents of (bis) trimethylsilylamide lithium at a temperature ranging from -78 ° C to room temperature and the lithium salt can then be further reacted with one or more molar equivalents of 5-bromothiazolidin-2, 4-dione (prepared according to Zaska et al., J. Med. Chem. 33, 1418-1423 (1990)) using a suitable solvent such as THF in a protective inert atmosphere at a temperature ranging from -78 ° C to room temperature under to form compounds of formula (Is: R ⁴ is (R, S) -5-thiazolidine-2,4-dione; B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X; is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- (V, N) - Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, an alkyl group having from 1 to 6 carbon atoms; carbon atoms, aryl or aralkyl; E is S or O).

Optionally, the phenols of formula (Ir: B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, (C 1 -C 6) alkoxy, aralkoxy, nitro, (C 1 -C 6) alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , where R ¹ and R ² are H, C 1 -C 6 alkyl, aryl or aralkyl; E is S or O) react with one or more molar equivalents of tetrazole and di-tert-butyl; N-Diethylphosphoramidate in THF at room temperature followed by the addition of one or more molar equivalents of meta-chlorobenzoic acid at -40 ° C according to the method of JW Perich and RB Johns, Synthesis, 142-144 (1988) affords phosphate diesters of formula (Is: R). ⁴ is P (O) (tert -Bu) ₂ ; B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethyl · · ·················

-50 · sulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl; E is S or O). The phosphate diesters are then treated with one or more molar equivalents of hydrochloric acid in a suitable solvent, for example dioxane, to form phosphonic acids of formula (Is: R ⁴ is P (O) (OH) ₂ ; B and D are H, halogen, CN X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms; 6 is C, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, an alkyl group of 1; C1 to 6, aryl or aralkyl; E is S or O).

Phenols of formula (Ir: B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy C 1 -C 6, aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2 H, N-dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, C 1 -C 6 alkyl, aryl or aralkyl; E is S or O) can be converted to carboxylic acids of formula (Is: R ⁴ is C 1 H ⁶ CO 3 H 5; B and D are H X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, (C 1 -C 6) alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, (C 1 -C 6) alkyl; E, S or O) by treatment with two or more molar equivalents of solid sodium hydroxide followed by one or more molar equivalents of 1,1,1-trichloro-2-methyl-2-propanol terahydrate in the presence of a large excess of acetone , which also serves as a solvent.

Phenols of formula (1r: B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of C 1 -C 6 aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- (N, N -dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, an alkyl group of 1 to 6 atoms;

-51 carbon, aryl or aralkyl group; E is S or O) can be converted to carboxylic acids of formula (Is: R ⁴ is CH ₂ CH ₂ CO ₂ H; B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl; E is S or O) one or more molar equivalents of potassium tert-butoxide in a suitable solvent, for example THF.

Phenols of formula (Ir: B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy C 1 -C 6, aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; Y is H,

Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl; E is S or O) can be reacted with a 3-hydroxycarboxylic acid ester of formula CH (OH) (R ⁷ ) CH ₂ CO ₂ R ⁶ (R ⁷ is H or C 1 -C 6 alkyl; R ⁶ is C 1 -C 6 alkyl; To form esters of formula (Is: B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; Y is H,

Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl; E is S or O) under the conditions of the Mitsunobu reaction (for a review, see Oyo Mitsunobu Synthesis 1 to 27 (1981)). Other coreactants required to carry out the Mitsunobu reaction include one or more molar equivalents of an alkyl (C 1 -C 6) azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of a triarylphosphine, for example triphenylphosphine in a suitable solvent such as toluene at a temperature ranging from -20 to 120 ° C.

• · ··················

-52 • · ·····································································

A 3-hydroxycarboxylic acid ester of the formula CH (OH) (R ⁷ ) CH ₂ CO ₂ R ⁶ (R ⁷ is hydrogen or C 1 -C 6 alkyl; R ⁶ is C 1 -C 6 alkyl) is commercially available or may be prepared from commercially available carboxyl precursors under conventional esterification conditions.

Esters of formula (1s: B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy C 1 -C 6, aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl; E is S or O) can be converted to acids of formula (1s: R ⁴ is (R) -CH (R ⁷ ) CH ₂ CO ₂ H; B and D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy C 1 -C 6, aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² wherein R ¹ and R ² are H, an alkyl group having 1 to 6 carbon atoms , aryl or aralkyl group; E is S or O) by several conventional procedures involving reacting an ester of formula (1s) with two or more molar equivalents of a mineral acid such as hydrochloric acid or sulfuric acid in one or more solvents such as water, THF or dioxane at a temperature in the range of 40 to 120 ° C. Optionally, other reaction conditions that result in the conversion of said ester to the acid (Is) may be used. These include the reaction of esters of formula (1s) with two or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at -78 ° C to rooms; with two or more molar equivalents of hydrobromic acid in acetic acid at 0 ° C to 50 ° C; with two or more molar equivalents of trimethylsilyl bromide or trimethylsilyl iodide in dichloromethane, carbon tetrachloride or acetonitrile at -78 ° C to 50 ° C; with two or more molar equivalents of lithium iodide in pyridine or quinoline at a temperature ranging from 60 ° C to 250 ° C.

Nitrophenols of formula (Ir: B is NO ₂ ; D is H or Br; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, · · ···························

-53 nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; Y is H, Cl, Br, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl; E is S or O) can be alkylated with one or more molar equivalents of an alkyl halide or aralkyl halide of formula (XR ⁴ wherein X is Cl, Br or iodine and R ⁴ is C 1-6 alkyl, aralkyl) and with one or more molar moieties alkali metal carbonate equivalents such as potassium carbonate in a polar aprotic solvent such as DMF to give an alkylated product of formula (Is: B is NO ₂ ; D is H or Br; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N, N-dimethylaminoethylsulfanyl; Y is H, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, C 1 -C 6 alkyl, aryl or aralkyl; E is S or O; R ⁴ is C 1 -C 6 alkyl, aralkyl).

Nitro compounds of formula (Is: B is NO ₂ ; D is H or Br; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 Y is H, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, an alkyl group having 1 to 6 carbon atoms, C 1 -C 6 alkyl, arylsulfanyl, pyridylsulfanyl, 2A, N-dimethylaminoethylsulfanyl; aryl or aralkyl; E is S or O; R ⁴ is C 1-6 alkyl, aralkyl may be reduced to the amino compounds of formula (Is: B is NH ₂ ; D is H or Br; X is H, halogen C 1 -C 6 alkyl, CN, lower perfluoroalkyl, C 1 -C 6 alkoxy, aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2 N, N -dimethylaminoethylsulfanyl; Y is H , oR ^1, SR ^1, NR ¹ R ^2, wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl; E is s or O, R ⁴ is alkyl of 1 to 6 carbon atoms, aralkyl) most readily using tin dichloride in ethyl acetate at 40 to 100, or hydrazine plus montmorillonite clays in ethanol at 40 to 100 ° C.

Amino compounds of formula (Is: B is NH ₂ ; D is H or Br; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 up to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-54 · V · 4 · 2-5 · V · V · V · V Y is H, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl, E is S or O; R ⁴ is alkyl of 1 to 6 carbon atoms, aralkyl) can be alkylated with one or more molar equivalents of an alkyl haloacetate of formula (X ² CHR ^{6 a} CO 2 R ^6, wherein X ² is Cl, Br or I and R ⁶ is alkyl of 1 to 6 carbon atoms, R ^6a is H) and with one or more molar equivalents of an alkali metal carbonate such as potassium carbonate in a polar aprotic solvent such as DMF to form an alkyl the product of formula (Is: B is NCHR ^{6 and} CO ² R ⁶ ; R ⁶ is alkyl of 1 to 6 carbon atoms; R ^6a is a radical or alkyl of 1 to 6 carbon atoms; D is H or Br; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-A, N Ndimethylaminoethylsulfanyl; Y is H, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl; E is S or O; R ⁴ is C 1 -C 6 alkyl, aralkyl). These esters can be converted to carboxylic analogs using conventional procedures to give carboxylic acids of formula (Is: B is NCHR ^{6 and} CO ₂ H; R ^6a is hydrogen or alkyl of 1 to 6 carbon atoms; D is H or Br; X is H, halogen C 1 -C 6 alkyl, CN, lower perfluoroalkyl, C 1 -C 6 alkoxy, aralkoxy, nitro, C 1 -C 6 alkylsulfanyl, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; Y is H, OR ¹ , SR ¹ , NR ¹ R ² , wherein R ¹ and R ² are H, C 1 -C 6 alkyl, aryl or aralkyl; E is S or O; R ⁴ is C 1 -C 6 alkyl; 6 carbon atoms, aralkyl group). Conditions for carrying out this reaction include an aqueous base solution containing an alkali metal hydroxide, for example sodium hydroxide in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol, or a mixture of THF and a lower alcohol at a temperature ranging from 0 ° C to 40 ° C.

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

-55 ··· ··· ············································

Additional derivatives of compounds of Formula I in Scheme 11 can be prepared by the following methods. Compounds of formula (It: B, D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy Y is Cl, Br, OR ¹ , wherein R ¹ is H, alkyl of 1 to 6 carbon atoms, aryl or aralkyl, R ⁵ is hydrogen, alkyl of 1 to 6 carbon atoms, 1-6 carbon atoms, aralkoxy, nitro; R ⁶ is H, alkyl of 1 to 6 carbon atoms) can be converted to their sulfoxide derivatives of formula (I 1: n is 1; B, D are H, halogen, CN, alkyl of 1 to 6 carbon atoms) X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro; Y is Cl, Br, OR ¹ , wherein R ¹ is H, C 1 -C 6 alkyl, aryl or aralkyl R ⁵ is hydrogen, C 1 -C 6 alkyl, aryl or aralkyl and; R ⁶ is H, an alkyl group having 1 to 6 carbon atoms) by reaction with one molar equivalent of an oxidizing agent such as m-chloroperbenzoic acid in dichloromethane at a temperature ranging from -20 ° C to 40 ° C, or with peracetic acid in acetic acid and water at a temperature ranging from room temperature to 100 ° C.

Compounds of formula (It: B, D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy From 1 to 6 carbon atoms, aralkoxy, nitro; Y is Cl, Br, OR ¹ , where <RTIgt;

-56 ··· ··· ··································

R ¹ is H, (C 1 -C 6) alkyl, aryl or aralkyl; R ⁵ is hydrogen, C 1 -C 6 alkyl, aryl or aralkyl; R ⁶ is H, alkyl of 1 to 6 carbon atoms) can be converted to their sulfone derivatives of formula (lu: n is 2; B, D are H, halogen, CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl, X is H, halogen, alkyl of 1 to 6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1 to 6 carbon atoms, aralkoxy, nitro; Y is Cl, Br, OR ¹ , wherein R ¹ is H, alkyl (C 1 -C 6) aryl or aralkyl; R ⁵ is hydrogen, C 1 -C 6 alkyl, aryl or aralkyl; R ⁶ is H, C 1 -C 6 alkyl) using two or more molar moieties; equivalents of an oxidizing agent such as m-chloroperbenzoic acid in dichloromethane at -20 to 60 ° C, or peracetic acid in acetic acid and water at a temperature ranging from room temperature to 100 ° C.

The compounds of the invention are useful for the treatment of metabolic disorders associated with insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. The compounds of the present invention are therefore particularly useful for the treatment or inhibition of diabetes II. type. The compounds of the invention are also useful for the control of glucose levels in disorders such as type I diabetes.

The ability of the compounds of the invention to treat or inhibit disorders related to insulin resistance or hyperglycemia has been demonstrated by testing the representatives of said compounds of the invention using two standard pharmacological (in the following) test procedures to determine PTPase inhibition.

Inhibition of tri-phosphorylated insulin receptor of dodecaphosphopeptide dephosphorylation by rat liver protein-tyrosine phosphatases (PTPs)

This standard pharmacological assay procedure determines the inhibition of hepatic microsomal PTPase activity in a rat using phosphotyrosyl dodecapeptide as a substrate corresponding to the 11421163 insulin receptor kinase domain, phosphorylated at tyrosine residues 1146, 1150 and 1151. The following is briefly summarized and the results used.

·· ·· ·· · ·· · · · · · · · ·

-57 ··· ··· ··· ·· ···· ·· ··· ·· ···

Preparation of microsomal fraction

Rats (male Sprague-Dawley rats (Charles River, Kingston, NY, USA) weighing 100-150 g, bred on a rodent diet (Purina)) were sacrificed by carbon dioxide asphyxiation and subjected to bilateral thoracotomy. The liver was collected and washed with cold aqueous salt solution (0.85% w / v) and weighed. The tissue was homogenized on Tad in 10 volumes of Buffer A and microsomes were isolated by the Meyerovitch method [Meyerovitch J., Rothenberg P., Shechter Y., Bonner-Weir S., Kahn CR, Vanadate normalizes hyperglycemia in two mouse models of non- insulin-dependent diabetes mellitus, J. Clin. Invest. 87, 1286-1294 (1991) and Alberts B., Bray D., Lewis J., Raff M., Roberts K., Watson JD (editors) Molecular Biology of the Cell, New York, Garland Publishing, Inc., 1989 ]; this method has been slightly modified. To remove all tissue debris, the homogenized liver was filtered through tissue and then centrifuged at 10,000 x g for 20 minutes at 40 ° C. The supernatant was decanted and centrifuged for 60 minutes at 40 ° C at 100,000 x g. The pellets, microsomes and small vesicles were re-dispersed in: 20 mM tris-HCl (pH 7.4), 50 mM 2-mercaptoethanol, 250 mM EDTA, 10 mM EGTA, 2 mM AEBSF, 0.1 mM TLCK, 0.1 mM TPCK, 0.5 mM benzamidine, 25 pg.ml ¹ leupeptin, 5 pg.ml ¹ pepstatin A, 5 pg.ml ¹ H5B antipaine, 5 pg.ml ¹ chymostatin, 10 pg.ml ¹ aprotinin (buffer A) to a final concentration of approximately 850 pg protein per ml. Protein concentration was determined by the Pierce Coomassie Plus Protein Assay method using crystalline bovine serum albumin as a standard (Pierce Chemical Co., Rockford, IL, USA).

Measurement of PTPase activity

The malachite green and ammonium molybdate method described by Lanzetta PA, Alvarez LJ, Reinach PS, Candia OA was used, and a method for determining nanomole amounts of inorganic phosphates was used and adapted for plate reader (Anal. Biochem. 100: 95-97 (1979)). This procedure was used to detect nanomole amounts of phosphates released by rat hepatic microsomal PTPases, using a dodecaphosphopeptide synthesized by AnaSpec, Inc., (San Jose, CA, USA) as substrate, said TRDIYETDYYRK peptide, corresponding to catalytic domain 1142 ·· ·· ··········

-58 ··· ··· φ φ φ ·· ···············

The 1153 insulin receptor is phosphorylated tyrosine at tyrosine residues 1146, 1150 and 1151. The microsomal fraction (83.25 gl) was preincubated for 10 minutes at 37 ° C in the presence or absence of test compound (6.25 μΙ) and with 305.5 μΙ HEPES (81.83 mM) reaction buffer, pH 7.4. The peptide substrate (10.5 μΙ) with a final concentration of 50 μΜ was allowed to warm to 37 ° C in a LabLine Multi-Block Heater equipped with a titration adapter. A pre-incubated microsomal preparation (39.5 μΙ) in the presence or absence of drug was added to induce a dephosphorylation reaction; the reaction was carried out at 37 ° C for 30 minutes. The reaction was terminated by the addition of 200 μΙ stop reagent (malachite green - ammonium molybdate Tween 20; MG / AM / Tw). The stop reagent contained 3 parts of a 0.45% malachite green hydrochloride solution, 1 part of a 4.2% solution of ammonium molybdate tetrahydrate in 4 M HCl and 0.5% Tween 20. Blank experiments were prepared by adding 200 μΙ MG / AM / Tw to substrate followed by 39.5 g of pre-incubated membrane in the presence or absence of drug. The color was allowed to develop at room temperature for 30 minutes. The absorbance at 650 nm was then determined using a plate reader (Molecular Devices). Samples and blank experiments were prepared in quadruplicate. The effect of 50 μΜ (final concentration) of drug concentration was considered as the criterion for inhibition of microsomal PTPases.

calculation

PTPase activities were expressed relative to the standard potassium phosphate curve as nanomoles of phosphate released per minute per milligram of protein. PTP -ase inhibition of the test compound was calculated as a percentage of the control. A four parameter non-linear logistic regression of PTPase activities using SAS 6.08 PROC NLIN was used to determine IC ₅₀ values of test compounds. All compounds were administered at a concentration of 50 μΜ. Using the representative compounds of the present invention, the following values were found.

····························

-59 ··· ··· · · ···················

Example % change relative to control sample 9 -49.80 19 -30.40 20 2.13 21 -63.12 22 -28.57 23 -26.11 24 -65.31 29 -83.54 30 -60.32 31 -63.42 32 -89.41 33 -61.92 34 -63.01 35 -58.85 36 -67.00 37 -49.83 38 -57.74 40 -83.88 41 -39.60 42 -63.41 43 -78.84 44 -68.50 45 -94.50 46 -91.00 47 -68.48 48 -44.69 49 -89.36 50 -81.27 52 -87.66 53 -81.83 Phenylarzine oxide (reference standard) -57.06

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

-60 ·· ···· ·· ··· ·· ···

Inhibition of triphosphorylated insulin receptor of dodecaphosphopeptide dephosphorylation by hPTPIB

This standard pharmacological assay procedure determines the inhibition of rat recombinant tyrosine protein phosphatase (PTP1B) activity using a phosphotyrosyl dodecapeptide as a substrate corresponding to the 1142-1163 insulin kinase receptor domain phosphorylated on tyrosine residues 1146, 1150 and 1151. Further, the procedure is described below. and the results achieved.

Human recombinant PTP1B was prepared as described by Goldstein (see Goldstein et al., Mol. Cell. Biochem. 109, 107 (1992)). The enzyme preparation was used in microtubes containing 500-700 pg.mľ ¹ protein in 33 mM Tris-HCl, 2 mM EDTA, 10% glycerol and 10 mM 2-mercaptoethanol.

Measurement of PTPase activity

The malachite green and ammonium molybdate method described by Lanzetta P. A. et al. (Lanzetta et al., Anal. Biochem. 100, 95-97 (1979)) was used. A method for determining nanomolar amounts of inorganic phosphates was used and adapted to the plate reader; this procedure was used to detect nanomolar amounts of phosphates released by the action of recombinant PTP1B. A dodecaphosphopeptide custom synthesized by AnaSpec, Inc., (San Jose, CA, USA) was used as the substrate. Said TRDIYETDYYRK peptide, corresponding to the catalytic domain 1142-1153 of the insulin receptor, is phosphorylated tyrosine at tyrosine residues 1146, 1150 and 1151. Recombinant rPTPIB was diluted with buffer (pH 7.4, containing 33 mM Tris-HCl, 2 mM EDTA and 50 mM bTA) mercaptoethanol) to give an approximate activity of 1,000 to 2,000 nanomoles per minute per milligram of proptein. Dilute enzyme (83.25 μΙ) was preincubated for 10 minutes at 37 ° C in the presence or absence of test compound (6.25 mL) and with 305.5 mL of 81.83 mM HEPES reaction buffer (pH 7.4). The peptide substrate (10.5 ml) at a final concentration of 50 mM was allowed to warm up in a LabLine Multi-Block Heater,

-61 with t tit t adapter. A pre-incubated recombinant enzyme preparation (39.5 ml) in the presence or absence of drug was added to induce a dephosphorylation reaction. The reaction lasted 30 minutes at 37 ° C. The reaction was terminated by the addition of 200 mL of malachite green ammonium molybdate solution - Tween 20 (stop reagents, MG / AM / Tw). The stop reagent contained 3 parts of a 0.45% malachite green hydrochloride solution, 1 part of a 4.2% solution of ammonium molybdate terahydrate in 4 M HCl and 0.5% Tween 20. Blank experiments were prepared by adding 200 ml of MG / AM / Tw to substrate followed by 39.5 ml of pre-incubated enzyme in the presence or absence of drug. The color was allowed to develop at room temperature for 30 minutes. The absorbance at 650 nm was then determined using a plate reader (Molecular Devices). Samples and blank experiments were prepared in quadruplicate.

calculation

PTPase activities were expressed relative to the standard potassium phosphate curve as nanomoles of phosphate released per minute per milligram of protein. Inhibition of recombinant PTP1B by the test compound was calculated as a percentage of the control phosphatase sample. A four parameter non-linear logistic regression of PTPase activities using SAS 6.08 PROC NLIN was used to determine the IC 50 values of the test compounds. All compounds were administered at a concentration of 50 μΜ. Using representative compounds of the present invention, the following values were found.

Example IC50 (μΜ) 9 0,539 19 0,697 21 0,381 23 0743 29 0,115 30 0,869 31 0,049 32 0,060 33 0,029 34 0,100

-62 ·· ·· ·· · t · t · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

35 0,273 36 1.34 37 0,352 38 0,299 39 1.74 40 0,110 41 0,729 42 0,089 43 0,171 44 0,237 45 0,203 46 1.19 47 0,095 48 0,083 49 0,384 50 0,457 51 2.21 52 0,287 53 0,204 54 0,982 55 0,059 56 0,489 57 1.90 59 2.20 60 1.51 61 0,164 62 0,028 63 0,138 64 0.39 65 0.36 68 0,080 70 0.33 71 1.19 72 0.48 76 0.45 78 0.27

····················

-63 ··· ··· ······································

79 0.78 83 0.13 88 0.32 Phenylarzine oxide (reference standard) 39.7 sodium ortho-vanadate (reference standard) 244.8 Ammonium molybdate tetrahydrate (reference standard) 8.7

The blood glucose lowering effect of the compounds of the invention was demonstrated by standard in vivo procedures in (ob / ob) mice. The test procedures and results obtained are set out below.

Insulin-independent diabetic (NIDDM) syndrome can typically be characterized by obesity, hyperglycemia, abnormal insulin secretion, hyperinsulinemia, and insulin resistance. Genetically obese-hyperglycemic ob / ob mice exhibit many of these abnormalities and are therefore considered a suitable model for screening hypoglycaemic agents for the treatment of NIDDM [Coleman D., Diabetology 14, 141-148 (1978)].

In each test procedure, mice [male or female ob / ob (C57 B1 / 6J) and their poor relatives (ob / + or + / +, Jackson Laboratories) aged 2 to 5 months (10 to 65 g)] of similar age grouped by body weight into 4 groups of 10 mice each. Mice were housed in 5 cages on normal rodent feeding and ad libitum water. Test substances were administered to mice daily with feed (dispersed in 0.5 ml 0.5% methylcellulose); or dissolved in drinking water, or mixed with food. The dosages of the compounds administered ranged from 2.5 to 200 mg per kilogram of body weight per day. The dose was calculated based on weekly weighing. Ciglitazone (5- (4- (1-methylcyclohexylmethoxy) benzyl) -2,4-dione) was administered as a positive control, see Chang A., Wyse B., Gilchrist B., Peterson T. and Diana A., Diabetes 32, 830 to 838 (1983) at a dose of 100 mg.kg ^-1 day ^-1 which caused a significant reduction in plasma glucose.

On the morning of days 4, 7 and 14, 2 drops of blood (approximately 50 μί) were collected into tubes containing sodium fluoride from the tail vein or after head separation.

·····························

-64 ··· ··· ··· ·· ···· ··· ·· ···

In those experiments in which the compound was administered daily with feed, blood samples were taken at 0 and 4 hours after compound administration. Plasma was isolated by centrifugation and glucose concentration was determined enzymatically on Abbott V.P. Analyzer.

For each mouse, the percentage change in plasma glucose at day 4, 7, or 14 relative to the mean plasma glucose of the vehicle-only mouse was calculated. To determine significant differences between the plasma glucose values of the control group and the experimental groups administered with the individual compounds, a method of analysis of variations was used by Dunette's comparative test (CMSSAS v. 5.18).

The results in the table below show that the compounds of the invention are antihyperglycaemic agents because they lower glucose levels in diabetic mice.

Example Dose (mg.kg ¹ ) % change in glucose from support % change in insulin from support 29 100 -48.63 -89.59 29 25 -38.18 -80.50 29 10 -18.6 (3) -48.11 32 25 -15.68 (a) -48.35 33 25 -21.10 (3) -39.3 35 25 -25,58 -2.98 (a) 40 100 -28.20 -90.80 42 25 -32.5 b 43 25 -45.2 b 44 25 -17.2 b 48 25 -20.1 b 49 10 -35.1 b 61 10 -32.8 (0 b ciglitazone (reference standard) 100 -43 -39

(a) - no significant activity at this dose (p <0.05) (b) - not determined (c) - measured at time 0.

• Φ φ φ · · φ φ φ φ φ φ φ

-65φφφ φφφ φ • Φ φφφφ φφ φφφ φφ

Based on the results of standard pharmacological testing procedures with representatives of the compounds of the present invention, these compounds have been shown to inhibit PTPase activity and lower blood glucose levels in diabetic mice and are therefore useful in the treatment of metabolic disorders associated with insulin resistance or hyperglycemia, typically associated with with obesity or glucose intolerance. In particular, the compounds of the invention are useful for treating the inhibition of type II diabetes and for modulating glucose levels in disorders such as type I diabetes. The term modulation is used herein to maintain glucose levels within clinically normal ranges.

Effective administration of these compounds may be in a daily dosage of from about 1 mg.kg ^"1 to about 250 mg.kg" ^1, which may be administered daily in a single dose or in two or more divided doses. Dosages may be administered by any means suitable for directing the active compounds into the recipient's bloodstream, including oral administration, by implants, parenteral (including intravenous, intraperitoneal and subcutaneous injections), rectal, vaginal and transdermal administration. For the purposes of the present invention, transdermal administration means all modes of administration through the body surface and internal lining of the body openings, including epithelial and mucosal tissues. Administration can be accomplished with the compounds of this invention or their pharmaceutically acceptable salts in the form of solutions, creams, foams, patches, suspensions, and suppositories (rectal or vaginal).

Pharmaceutical compositions for oral administration containing the active compounds of the invention may be in any of the oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral fluids, suspensions or solutions. The capsules may contain mixtures of the active compounds with an inert filler and / or diluent such as pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweeteners, powdered celluloses such as crystalline and microcrystalline celluloses, flour, gelatin, gums and Similarly. Suitable tablet formulations may be prepared by conventional compression, wet granulation or dry granulation techniques using pharmaceutically acceptable diluents, binders, lubricants, tablet disintegrants, dispersants, or stabilizers. ··· · ···· ···· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-66 including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, calcium carbonate, complex silicate silicate sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugars. Oral pharmaceutical compositions may employ standard sustained release formulations or time-release formulations to influence the rate of absorption of the active compound (s). Suppository pharmaceutical compositions can be prepared using conventional materials, including cocoa butter, in the presence or absence of waxes to influence the melting point of the suppository and glycerol. Water-soluble suppository bases, for example polyethylene glycols of different molecular weights, may also be used.

The dose, dosage regimen, and mode of administration of these compounds will likely vary with the disease and the individual being treated and will depend upon the judgment of the attending physician. It is preferred that the administration of one or more compounds begin with low doses and will increase until the desired effect is achieved.

The preparation of representatives of the compounds of this invention is described in the following procedures.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

2,3-dimethyl-thiophen

A mixture of 3-methylthiophene-carboxaldehyde (20 g, 0.159 mol), hydrazine hydrate (31 ml) and diethylene glycol (72 ml) was refluxed for 20 minutes. After cooling to below 100 ° C, potassium hydroxide (22.9 g, 0.408 mol) was added and the reaction mixture was heated at 125-130 ° C for 1.5 hours. The reaction mixture was then cooled to room temperature and water was added. The aqueous mixture was extracted with ether and the ether phase was washed with 5% aqueous HCl and then brine. After drying (magnesium sulphate) the solvent a was removed

-67 ·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · The oily residue was purified by flash chromatography (using pentane as eluent) to give the title compound as an oil (15.81 g, 89%).

¹ H NMR (CDCl 3): δ 6.97 (d, 1H, J = 8 Hz); 6.77 (d, 1H, J = 8Hz); 2.35 (s, 3H); 2.14 (s, 3H).

Example 2

4,5-dimethyl-thiophen-2-yl- (phenyl) -methanol

To a solution of 2,3-dimethylthiophene (5.0 g, 44.6 mol) in THF (100 mL) was added dropwise n-butyllithium (19.6 mL, 49 mL) at -78 ° C under a dry nitrogen atmosphere under stirring. 1 mmol, 2.5 N solution in hexane). The solution was then warmed to 0 ° C for 30 minutes and re-cooled to -78 ° C; then benzaldehyde (5.0 mL, 49.1 mmol) was added. After an additional 45 minutes, saturated aqueous ammonium chloride solution was added and the reaction mixture was partitioned between water and ether. The ether phase was washed with brine and concentrated. The resulting oily residue was triturated with petroleum ether to give the title compound as a white solid (7.77 g, 80%).

¹ H NMR (CDCl 3): δ 7.45 (ddd, J = 8,1,1 Hz, 2H); 7.37 (ddd, J = 8.8, 1 Hz, 2H); 7.3 (m, IH); 6.57 (s, 1 H); 6.93 (s, 1 H, OH); 2.29 (s. 3H); 2.05 (s, 3H).

MS (EI): (M ⁺ ) 218 (45% M- ¹ ).

analysis:

Calcd for C 13 H 14 OS 71.52% C, 6.46% H, 0.00% N;

Found: C, 71.41; H, 6.42; N, 0.09.

Example 3

2-Benzyl-4,5-dimethi Itiophene

To a suspension of 4,5-dimethylthiophen-2-yl- (phenyl) -methanol (7.7 g, 35.3 mmol), sodium borohydride (6.67 g, 177 mmol) and ether (600 mL) at 0 ° Trifluoroacetic acid was added dropwise with stirring over 60 minutes. After an additional 1.5 hours, the reaction mixture was added to a 10% aqueous solution of sodium hydroxide (600 ° C) (600 ° C).

(68 ml) and stirred for 30 minutes. Then the layers were separated and the ether phase was washed with 10% aqueous sodium hydroxide solution, brine and dried (magnesium sulfate). The ether phase was concentrated to give the title compound (6.73 g, 94%) as an oil.

¹ H NMR (CDCl 3): δ 7.33-7.19 (m, 5H); 6.47 (s, 1 H); 4.03 (s, 2 H); 2.77 (s, 3H); 2.06 (s, 2 H).

MS (EI): (M ⁺ ) 202 (45% M ^- 1).

Example 4 (2-Benzyl-4,5-dimethylthiophen-3-yl) - (4-methoxyphenyl) -methanone

To a solution of 2-benzyl-4,5-dimethylthiophene (6.6 g, 32.62 mmol), anyzoyl chloride (methoxybenzoyl chloride, 5.90 g, 34.6 mmol) and dichloromethane (120 mL) under a dry nitrogen tin tetrachloride (4.6 mL, 71.76 mmol) was added dropwise over 10 minutes with stirring at -78 ° C. After 5 hours at -78 ° C, the reaction mixture was slowly warmed to room temperature over two hours. The reaction mixture was mixed with water and extracted with ether. The ether extract was washed with saturated aqueous sodium bicarbonate solution and brine. The solvent was removed and the resulting solid was triturated with ether to give the title compound (9.62 g, 88%) as an off-white solid, mp 85-86 ° C.

¹ H NMR (CDCl 3): δ 7.80 (ddd, J = 8.8, 1 Hz, 2H); 7.24 to 7.10 (m, 5H); 7.92 (ddd, J = 8.8, 1 Hz, 2H); 3.93 (s, 2 H); 3.88 (s, 3H); 2.28 (s, 3H); 1.90 (s, 3H).

MS (EI): (M ⁺ ) 336 (100%, M- ¹ ).

analysis:

Calcd for C 21 H 20 O 2 S 74.97%, H 5.99%, N 0.00%;

H, 6.02; N, 0.05%.

Example 5

4- (2,3-naphtho [2,3-b] thiophen-4-yl) -phenol

-69 ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Fresh boron tribromide (20 mL, 212 mmol) was added dropwise to a (2-benzyl-4,5-dimethylthiophen-3-yl) - (4-methoxyphenyl) -methanone solution under stirring under dry nitrogen at -78 ° C with stirring. (9.40 g, 27.9 mmol) in dichloromethane (95 mL). The solution was then allowed to warm to ambient temperature and stirred for 4 hours. Then the reaction mixture was cooled to 0 ° C and carefully diluted with water and the solvent was removed. Additional water was added and the resulting solid was filtered, washed with water and triturated with petroleum ether to give the title compound (8.23 g, 97%) as a light purple solid, mp 165-168 ° C; C.

¹ H NMR (DMSO-d 6): δ 9.62 (s, 1H); 8.43 (s, 1 H); 7.94 (d, J = 8Hz, 1H); 7.43 (m, 2 H); 7.32 (ddd, J = 8.1, Hz, 1H); 7.11 (d, J = 8Hz, 2H); 6.90 (d, J = 9Hz, 2H); 2.39 (s, 3H); 1.61 (s, 3H).

MS (EI): 304 (100%, M-1).

Example 6

Acetic acid 4- (2,3-dimethylnaphtho [2,3-b] thiophen-4-yl) -phenyl ester

To a solution of 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (2.0 g, 6.57 mmol) in pyridine (8.6 mL) at 0 ° C was added. acetic anhydride (0.68 mL, 7.20 mmol) was added with stirring. After 17 hours, the reaction mixture was added to 5% aqueous HCl and the resulting solid was filtered off, washed with 5% aqueous HCl, water and triturated with petroleum ether. It was then dried in vacuo to give the title compound (1.99 g, 88%) as a white solid, mp 147-150 ° C.

¹ H NMR (DMSO-d 6): δ 8.49 (s, 1H); 7.94 (d, J = 8Hz, 1H); 7.46 (ddd, J = 8.6, 2 Hz, 1H); 7.38 (ddd, J = 8.1, 1 Hz, 1H); 7.39 to 7.34 (m, 2H); 7.28 (d, J = 8Hz, 2H); 6.90 (d, J = 9Hz, 2H); 2.40 (d, J = 1Hz, 3H); 2.34 (s, 3H); 1.57 (d, J = 1Hz, 3H).

MS (EI): 346 (90%, M-1), 304 (100%).

analysis:

Calcd for C22H18O2S: C, 76.27; H, 5.34; N, 0.00;

Found: C, 75.88; H, 5.04; N, 0.28.

-70Example 7

Acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester

To a solution of acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester (1.87 g, 5.41 mmol) and ferric chloride (50 mg, 0.31 mmol) A solution of bromine (0.326 mL, 6.15 mmol) in dichloromethane (47 mL) was added dropwise over 15 minutes at -78 ° C in a dry nitrogen atmosphere under dichloromethane (47 mL). After 10 minutes, dilute aqueous sodium bisulfite was added and the reaction mixture was partitioned between water and ether. The ether phase was washed with brine and concentrated to give the title compound (2.09 g, 91%) as a white solid, mp 190-191 ° C.

¹ H NMR (DMSO-d 6): δ 8.20 (d, J = 8 Hz, 1H); 7.65 (ddd, J = 8.7, 1 Hz, 1H); 7.49 (ddd, J = 8.7, 1 Hz, 1H); 7.43 to 7.38 (m, 1H); 7.40 (d, J = 9Hz, 2H); 7.30 (d, J = 9Hz, 2H); 2.43 (d, J = 1Hz, 3H); 2.33 (s, 3H); 1.55 (d, J = 1Hz, 3H).

MS (EI): single bromine isotopic pattern 424 (95%, M1), 426 (100%). analysis:

Calculated for C ₂ 2HI ₇ BrO ₂ S 62.12% C, 4.03% H, 0.00% N;

Found: C, 62.46; H, 4.05; N, 0.09.

Example 8

4- (9-Bromo-2,3-dimethylnaphtho [2,3-b] thiophen-4-yl) -phenol

To a solution of acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester (0.48 g, 1.14 mmol) in THF (15 mL) and methanol (10 mL) was added aqueous sodium hydroxide solution (6.0 mL, 6.0 mmol) with stirring at room temperature. After one hour, the organic solvents were removed, water was added, the reaction mixture was acidified with 10% HCl solution, and the resulting solid was washed with water and triturated in petroleum ether and finally dried in vacuo to give the title compound (0.32). g, 73% of theory) as a white solid, mp 165-168 ° C.

·· ·· ·· ·

-71 · a a a a a a a H H H H H ¹ H NMR (DMSO-d 6) δ: 9.68 (s, 1H); 8.17 (d, J = 8Hz, 1H); 7.62 (ddd, J = 8.6, 1 Hz, 1H); 7.50 (d, J = 8Hz, 1H); 7.44 (ddd, J = 8.7, 1 Hz, 1H); 7.13 (d, J = 9Hz, 2H); 6.91 (d, J = 9Hz, 2H); 2.42 (d, J = 1Hz, 3H); 1.59 (d, J = 1Hz, 3H).

MS (EI): single bromine isotopic pattern 382 (95%, M1), 384 (100%). analysis:

Calcd for CaoHisBrOS 62.67% C, 3.95% H, 0.00% N;

found: C, 62.40; H, 3.91; N, 0.09.

Example 9

2,6-Dibromo-4- (9-bromo-2,3-naphtho [2,3-b] thiophen-4-yl) -phenol

To a solution of 4- (9-bromo-2,3-naphtho _[I, 2 3-b] thiophen-4-yl) -phenol (1.10 g, 2.87 mmol), potassium acetate (2.82 g, 28, 7 mmol) and acetic acid (31 mL) were added dropwise at room temperature with stirring a solution of bromine (0.34 mL, 5.74 mmol) in acetic acid (5 mL). After stirring for 1.5 hours, water (200 mL) and a small amount of sodium bisulfite were added. The suspension was filtered and the solid was washed with water, triturated in petroleum ether and dried in vacuo to give the title compound (1.52 g, 88%) as a white solid, mp 172-174 ° C.

¹ H NMR (DMSO-d 6): δ 11.95 (br s, 1H); 10.20 (broad s, 1H); 8.19 (ddd, J = 8.1, 1 Hz, 1H); 7.65 (ddd, J = 8.6, 1 Hz, 1H); 7.59 (s, 2 H); 2.44 (d, J = 1Hz, 3H); 1.90 (s, 3H); 1.64 (d, J = 1Hz, 3H).

MS (+ FAB): three bromine isotopic pattern 538 (40%), 540 (100%), 542 (90%), 544 (50%).

analysis:

Calcd for C22Hi3Br OS.C2H _{3 4} O 2 43.95% C, 2.85% H, 0.00% N;

found: C, 44.13; H, 2.66; N, 0.12.

Example 10

Methanesulfonic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester

-72 ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

To a cooled (ice) solution of 4- (2,3-dimethylnaphtho [2,3-b] thiophen-4-yl) -phenol (3.00 g, 9.86 mmol) and pyridine (4.0 mL, 49 mL), 3 mmol, 5 equivalents) in methylene chloride (24 mL) was added dropwise methylsulfonyl chloride (1.14 mL, 14.8 mmol, 1.5 equivalents). The cooling bath was then removed and the reaction mixture was stirred at room temperature for about 38 hours; then water (150 ml) was added, the mixture was acidified with 10% hydrochloric acid solution and extracted with ether. The extracts were combined and washed with brine. Silica gel was added and the solvents were removed. The adsorbate was purified by flash chromatography (45/55 petroleum ether / ethyl acetate) to give the title compound (3.02 g, 80%).

NMR (CDCl ₃ ): δ 8.30 (s, 1H); 7.90 (d, J = 8Hz, 1H); 7.50 to 7.40 (m, 5H); 7.38-7.28 (m, 1H); 3.26 (s, 3H); 2.50 (s. 3H); 1.61 (s, 3H).

Example 11

Methanesulfonic acid 4- (9-iodo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester

To a solution of methanesulfonic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester (3.00 g, 7.84 mmol) in tetrahydrofuran (31.5 mL), 80% aqueous acetic acid (16 mL) and concentrated sulfuric acid (0.87 mL) were added iodine (1.59 g, 6.27 mmol, 0.8 equivalents) and iodic acid (0.414 g, 2.35) at room temperature. mmol, 0.9 equivalents). The reaction mixture was stirred at room temperature for 12 days. The mixture was then poured into dilute aqueous sodium bisulfite solution (200 mL) and the organic portion was extracted with ether (2 x 200 mL). Silica gel was added to the combined extracts. The solvents were removed and the adsorbate was flash chromatographed (90/10 petroleum ether / ethyl acetate) without purification. The material was purified by high pressure liquid chromatography to yield the starting material (30.5%) and the title compound (0.835 g, 30%) as a white solid, mp 212-213 ° C.

NMR (DMSO-d 6): δ 8.09 (d, J = 8 Hz, 1H); 7.64 to 7.58 (m, 1H); 7.54 to 7.42 (m, 5H); 7.43 (d, J = 8Hz, 1H); 3.47 (s, 3H, SO 3 CH 3); 2.42 (s, 3H); 1.50 (s, 3H).

MS (EI): [M +] 508 (100%).

·· ··

-73Analýza:

Calcd for C 21 H 17 O 3 S 2 C, 49.61; H, 3.37; N, 0.00%;

Found: C, 49.44; H, 3.52; N, 0.03.

Example 12

4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) -phenol

To a suspension of methanesulfonic acid 4- (9-iodo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester (0.620 g, 1.22 mmol) and cuprous oxide (0.192 g, 1, Thiophenol (0.270 mL, 2.68 mmol) and finely triturated sodium hydroxide (0.107 g, 2.68 mmol) were added under stirring under dry argon under an atmosphere of dry argon (34 mmol) in anhydrous N, N-dimethylformamide (10 mL). The vessel was sealed and heated to 155 ° C for 9.5 hours. After stirring at room temperature for about eight hours, the reaction mixture was poured into water, acidified with hydrochloric acid, and the organic portion was extracted into ether. The extracts were combined, filtered, washed with water and concentrated. The yellow solid residue was dissolved in dioxane (8ml) and sodium hydroxide solution (2.5M solution, 4.5ml) was added. The vial was sealed and heated to 102 ° C. After completion of the reaction (TLC analysis), the mixture was cooled to room temperature, diluted with water, acidified with hydrochloric acid. The organic portion was extracted with ether, silica gel was added to the combined extracts and the solvents were removed. The adsorbate was flash chromatographed (90/10 to 85/15 petroleum ether / ethyl acetate gradient) and the solvents were removed using benzene and petroleum ether to give the title compound (0.426 g, 85%) as a white solid. .

NMR (DMSO-d 6): δ 9.70 (s, 1H, OH); 8.40 (d, J = 8Hz, 1 H); 7.56 to 7.51 (m, 2H); 7.44 to 7.40 (m, 1H); 7.25 to 7.12 (m, 5H); 7.02 (d, J = 7Hz, 2H); 6.93 (d, J = 9Hz, 2H); 3.67 (s, 3H), 1.62 (s, 3H).

MS (EI): [M +] 412 (100%).

analysis:

Calcd for C26H20OS2: C, 75.69; H, 4.89; N, 0.00;

Found: C, 74.98; H, 4.86; N, 0.13%.

-74Example 13

2,6-Dibromo-4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) -phenol

To a suspension of 4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) -phenol (0.414 g, 1.00 mmol) and potassium acetate (0.982 g, 10.0 mmol) in glacial acetic acid (24 mL) was added dropwise over 10 min at room temperature a solution of bromine (0.114 mL, 2.21 mmol) in glacial acetic acid (2.50 mL). Complete dissolution occurred and a precipitate formed. After stirring for 2 hours, the reaction was quenched by addition of dilute aqueous sodium bisulfite solution and pouring into water (100 mL); the mixture was acidified with 10% hydrochloric acid solution and extracted with ether. The extracts were washed with water; after separating the layers and standing overnight, silica gel was added and the solvents were removed. The adsorbate was flash chromatographed (90/10 petroleum ether / ethyl acetate) to give the title compound (0.391 g, 58%) as an off-white solid.

NMR (DMSO-d 6): δ 10.25 (s, 1H, OH); 8.42 (d, J = 8Hz, 1H); 7.65 (s, 2 H); 7.60 to 7.47 (m, 3H); 7.24 to 7.19 (m, 3H); 7.15 to 7.00 (m, 2H); 2.39 (s, 3H); 1.62 (s, 3H).

Example 14

Acetic acid 4- (9-bromo-2-chloromethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester

To a solution of acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester (4.00 g, 9.4 mmol) in methylene chloride (41 mL), Cooled in an ice bath, sulfuryl chloride (0.76 mL, 10.3 mmol) was added dropwise over 10 minutes. After stirring for 1 hour on the ice-cooled reaction mixture, the reaction was quenched by addition of water (100 mL) and diluted with diethyl ether. After filtration, the layers were allowed to separate. Silica gel was added to the organic layer and the solvents were removed. The adsorbate was flash chromatographed (90/10 to 80/20 petroleum ether / ethyl acetate gradient) to give the title compound (2.57 g, 59%) as a white solid.

NMR (DMSO-d 6): δ 8.23 (d, J = 8 Hz, 1H); 7.71 (dd, J = 8.1 Hz, 1H); 7.55 to 7.43 (m, 4H); 7.33 to 7.30 (m, 2H); 5.09 (s, 2 H); 2.39 (s, 3H); 1.66 (s, 3H).

-75Example 15

4 - ((9-Bromo-3-methyl-2-morpholin-4-yl) methyl-naphtho [2 ₁ 3-b] thiophen-4-yl) -phenol

To a solution of acetic acid 4- (9-bromo-2-chloromethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester (1.20 g, 2.61 mmol) in anhydrous water. N, N -dimethylformamide (12 mL) was added potassium carbonate (1.08 g, 7.83 mmol, 3 equivalents) and morpholine (0.683 mL, 7.83 mmol, 3 equivalents) at room temperature under a dry nitrogen atmosphere. ). The mixture was stirred for 1.75 hours and then an additional equivalent of morpholine (0.227 mL) was added; the mixture was further stirred for 0.5 h and then two more equivalents of morpholine (0.50 mL) were added. The mixture was then stirred for an additional hour and then diluted with water (125 mL) and the organic portion was extracted with diethyl ether (400 mL). After separation of the layers, silica gel was added to the organic layer. The solvents were evaporated and the adsorbate was flash chromatographed (gradient 75/25 to 70/30 petroleum ether / ethyl acetate) to give the title compound (1.00 g, 82%) as a white solid, m.p. Mp 250-251 ° C. NMR (DMSO-d 6): δ 9.69 (s, 1H); 8.18 (d, J = 8Hz, 1H); 7.63 (ddd, J = 8.7, 1 Hz, 1H); 7.51 to 7.42 (m, 2H); 7.13 (d, J = 8Hz, 2H); 6.91 (d, J = 8Hz, 2H); 3.71 (s, 2 H); 3.60 (t, J = 5Hz, 4H); 2.50 to 2.48 (m, 4H); 1.65 (s, 3H).

MS (EI): [M +] monobromo isotopic pattern 467 (10%), 469 (10%). analysis:

Calcd for C ₂₄ H ₂₂ BrNO ₂ S 61.53% C, 4.73% H, 2.99% N;

Found: C, 61.53; H, 4.88; N, 3.01.

Example 16

4- (9-Bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) phenyl acetate

To a suspension of 4- (9-bromo-2-chloromethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -phenylacetate (1.27 g, 2.76 mmol) and potassium carbonate (1.146 g) Dimethyl amine (0.86 mL, 8.29 mmol) was added in anhydrous N, N-dimethylformamide (15 mL) under a dry nitrogen atmosphere at room temperature. After stirring for 3 hours, an additional portion of dimethylamine (0.50 mL, 4.83 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours; the reaction mixture was then held overnight

-76 at -14 ° C. The reaction mixture was diluted with water (100 mL) after stirring for another 5 hours at room temperature. The organic portion was extracted into ether. The extracts were combined, silica gel was added and the solvent was removed. The adsorbate was flash chromatographed (gradient 85/15 to 80/20 petroleum ether / ethyl acetate) to give the title compound (0.332 g, 26%) as a yellow solid.

NMR (CHCl 3): δ 8.29 (d, J = 8 Hz, 1H); 7.54 to 7.51 (m, 2H); 7.36 to 7.30 (m, 1H); 7.20 (d, J = 8Hz, 2H); 6.96 (m, 2 H); 3.90 to 3.65 (broad s, 2H); 2.80 to 2.45 (broad s, 4H); 1.69 (s, 3H); 1.26 to 1.00 (broad s, 6H).

MS (EI): M + M / Z 453 present one bromine, 301 (58%), 302 (16%), 303 (7%), 382 (100%), 383 (54%), 384 (14%), 453 (30%); 455 (30%);

MS [(+) ESI +: [M + H] = 496 (65%), single bromine isotopic pattern; High Resolution MS: calculated mass of 496.09459 for C 25 H 31 N 3 O 3 Cl [M + H], determined 496.09407, mass deviation 0.52 mmu;

analysis:

Calcd for C ₂₄ H ₂₄ BrNOS 63.43% C, 5.32% H, 3.08% N;

Found: C, 62.23; H, 5.11; N, 2.75.

Example 17

4- (9-Bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -phenol

To a solution of 4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -phenyl acetate 90.676 g, 1.36 mmol) in tetrahydrofuran (18 mL) and methanol (12 mL) was added aqueous sodium hydroxide solution (1 M, 1.63 mL) dropwise at room temperature. After stirring for one hour, the solvents were removed. The residue was mixed with water (50 mL) and acidified with 10% hydrochloric acid. The organic impurities were extracted with ether and a white solid formed at the interface of the two phases. The sticky solid was filtered off, triturated with acetic acid and concentrated. The title compound was dissolved in tetrahydrofuran and methanol and treated with a saturated aqueous sodium bicarbonate solution. After stirring for 20 minutes, the mixture was diluted with water and stirred for 10 minutes. The organic fraction shall be

-77 ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Extracted with ether. The ether layer was washed with brine and concentrated to give the title compound (0.490 g, 79%) as a yellow solid.

NMR (DMSO-d 6): δ 9.69 (s, 1H, OH); 8.18 (d, J = 8Hz, 1H); 7.63 to 7.59 (m, 1H); 7.51 to 7.43 (m, 2H); 7.14 (d, J = 8Hz, 2H); 6.91 (d, J = 8Hz, 2H); 3.73 (s, 2 H); 2.58 to 2.50 (m, 4H); 1.63 (s, 3H); 1.01 (t, J = 7Hz, 6H).

Example 18

2,6-Dibromo-4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -phenol

To a solution of 4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -phenol (0.462 g, 1.07 mmol) in acetic acid (9 parts glacial acetic acid) with 1 part water, 10 mL) was added a solution of bromine (0.115 mL, 2.24 mmol, 2.2 equivalents) in acetic acid (9 parts glacial acetic acid with 1 part water, 4 mL). The reaction mixture was stirred for 1.5 hours and then quenched by the addition of dilute aqueous sodium bisulfite. The reaction mixture was then diluted with water and the organic portion was extracted into ether. The insoluble solid was decanted and stirred overnight in ether. The ether was removed and the resulting solid (0.162 g, 0.265 mmol) was dissolved in tetrahydrofuran (100 mL) and sodium hydroxide solution (0.265 mL, 1 M aqueous solution, 0.265 mmol) was added dropwise. After stirring for 20 minutes, the solvents were removed and the residue was slurried in water (100 mL). The water was removed by decantation and the residue was stirred overnight in petroleum ether. Then the solvent was removed. The residue was dissolved in a mixture of tetrahydrofuran and ether and silica gel was added. The solvents were removed and the adsorbate was flash chromatographed (75/25 petroleum ether / ethyl acetate) to give the title compound (0.113 g, 17%) as a white solid.

NMR (DMSO-d 6): δ 10.3 to 10.1 (broad s, 1H, OH); 8.20 (d, J = 8Hz, 1H); 7.66 to 7.63 (m, 1H); 7.60 (s, 2 H); 7.50 to 7.48 (m, 2H); 3.76 (s, 2 H); 3.28 to 2.60 (m, 4H); 1.02 (t, J = 7Hz, 6H);

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

-78 ·· ························

MS + FAB: M + @ m / Z 609/611/613/615 Three bromine characteristics 536 (22%), 538 (68%), 540 (80%), 541 (52%), 611 (22%), 613 ( 22%).

analysis:

Calcd for C ₂₄ H 22 Br ₃ NOS 47.08% C, 3.62% H, 2.29% N;

Found: C, 47.21; H, 3.69; N, 2.21.

Example 19

2,6-Dibromo-4- (9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho [2,3-b] thiophen-4-yl) -phenol

To a solution of 4- (9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (0.854 g, 1.82 mmol) in acetic acid / water 9/1 (17 mL) was added a solution of bromine (0.207 mL, 4.01 mmol) in acetic acid / water 9/1 (1 mL). After stirring for 3 hours, the reaction mixture was diluted with water (200 mL) and the organic portion was extracted several times with diethyl ether. The extracts were combined, concentrated and evaporated with benzene to give a quantitative yield of the title compound as a yellow solid (1.18 g), mp 237-240 ° C.

NMR (pyridine-d 6): δ 8.43 (dd, J = 8.1 Hz, 1H); 7.81 (s, 2 H); 7.71 (d, J = 8Hz, 1H); 7.62 (m, IH); 7.50 (m, IH); 6.20 to 5.30 (broad s, 1H); 3.78 (t, J = 5Hz, 4H); 3.70 (s, 2 H); 2.55 (t, J = 4Hz, 4H); 1.78 (s, 3H);

MS (EI): [M +], triple bromine isotopic pattern, 622 (8%), 624 (18%), 626 (19%), 628 (8%).

analysis:

Calcd for C ₂₄ H ₂₀ Br ₃ NO ₂ S 46.03% C, 3.22% H, 2.24% N;

H, 3.31; N, 2.05.

Example 20

4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-nitro-phenol

To a mixture of 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-phenol (1.98 g, 5.17 mmol) and ferric nitrate heptahydrate (2 (09 g, 5.17 mmol) was added ethanol (40 mL) and the resulting dark blue solution was heated in a 45 ° C oil bath for 14 h. The reaction mixture was poured into dilute HCl and extracted with ether.

Silica gel was then added to the ether phase and the solvent was removed. The adsorbate was flash chromatographed (95/5 petroleum ether / ethyl acetate) to give the title compound (1.63 g, 74%) as an orange solid, mp 183-185 ° C.

NMR (DMSO-d 6): δ 11.31 (s, 1H); 8.21 (d, J = 8Hz, 1H); 7.85 (d, J = 2Hz, 1 H); 7.66 (ddd, J = 8.6, 1 Hz, 1H); 7.54 (dd, J = 8.2 Hz, 1H); 7.48 (dd, J = 7.1 Hz, 1H); 7.29 (d, J = 8Hz, 1H); 6.91 (d, J = 9Hz, 2H); 2.44 (d, J = 1Hz, 3H); 1.61 (d, J = 1Hz, 3H).

MS (EI): single bromine isotopic pattern 427 (95%, M1), 429 (100%). analysis:

Calcd for C ₂₀ H ₄ BrNO ₃ S 56.09% C, 3.29% H, 3.27% N;

H, 3.15; N, 3.23.

Example 21

2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-nitro-phenol

To a suspension of 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-nitro-phenol (0.20 g, 0.467 mmol), potassium acetate (0.228 g) A solution of bromine (0.040 mL, 0.756 mmol) in acetic acid (0.5 mL) was added dropwise with stirring. After 10 minutes, water was added and the reaction mixture was extracted with ether. Silica gel was added to the ether phase and the solvent was removed. The adsorbate was flash chromatographed (gradient 95/5 to 85/15) to give the title compound (0.141 g, 60%) as a yellow solid, mp 129-130 ° C.

NMR (DMSO-d 6): δ 11.30 (s, 1H); 8.22 (d, J = 8Hz, 1H); 8.03 (s, 1 H); 7.96 (s, 1 H); 7.67 (quintplet, J = 4 Hz, 1H); 7.51 (d, J = 4Hz, 2H); 2.45 (s, 3H); 1.65 (s, 3H).

MS (EI): double bromine isotopic pattern 505 (40%), 507 (100%), 509 (50%).

analysis:

Calcd for C ₂₀ H ₁₃ Br ₂ NO ₃ S 47.36% C, 2.58% H, 2.76% N;

found: 47.18% C, 2.55% H, 2.63% N.

-80 ·· ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 22

2-Amino-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol

A procedure similar to that described in Tetrahedron Letters 1990, pages 1181 to 1182 was used. To a solution of 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-nitrophenol (0.608) g, 1.42 mmol), anhydrous hydrazine (0.276 mL, 8.95 mmol) and ethanol (4.2 mL) were added montmorillonite clay K10 (425 mg) and the suspension was heated at 85 ° C for 30 min. The reaction mixture was then cooled to room temperature, water was added and the mixture was extracted with ether. The ether phase was dried and concentrated to give the title compound (0.576 g, 100%) as a white solid, mp 173-175 ° C.

NMR (DMSO-d 6): δ 9.26 (s, 1H); 8.14 (dd, J = 8.1 Hz, 1H); 7.63 to 7.58 (m, 2H); 7.42 (ddd, J = 8.6, 1 Hz, 1H); 6.78 (d, J = 8Hz, 1H); 6.54 (d, J = 2Hz, 1 H); 6.35 (dd, J = 8.2 Hz, 1H); 4.67 (broad s, 2H); 2.42 (s, 3H); 1.69 (s, 3H).

MS (+ FAB): single bromine isotope pattern 398 (30%, M + H), 400 (30%, M + H).

analysis:

Calcd for C ₂₀ H ₆ BrNOS 60.31% C, 4.05% H, 3.52% N;

Found: C 61.36, H 4.08, N 3.25.

Example 23

2-Amino-6-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol

A procedure similar to that described in Tetrehedron Letters 1990, pages 1181 to 1182 was used. To a solution of 2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2 -nitrophenol (1.2 g, 2.37 mmol), anhydrous hydrazine (1 mL) and ethanol (7.2 mL) were added montmorillonite clay K10 (1.4 g) and the suspension was heated at 85 ° C for 1 hour. The reaction mixture was then cooled to room temperature and concentrated. The residue was flash chromatographed twice (first eluting with ether, second eluting with 4/1 petroleum ether / acetate). · · ··

-81 ··· ··· ··· ································ natý Ethyl) to give the title compound (0.741 g, 66%) as a white solid. substances.

NMR (DMSO-d 6): δ 8.16 (ddd, J = 8,1,1 Hz, 1H); 7.65 to 7.60 (m, 2H); 7.47 (ddd, J = 8.6, 1 Hz, 1H); 6.65 (d, J = 2Hz, 1 H); 6.57 (d, J = 2Hz, 1 H); 2.43 (d, J = 1Hz, 3H); 1.73 (d, J = 1Hz, 3H).

MS (M-1): double bromine isotopic pattern 475 (50%, M + H), 477 (100%, M + H), 479 (50%, M + H).

analysis:

Calcd for C ₂₀ H 15 Br ₂ NOS 50.34% C, 3.17% H, 2.94% N;

H, 3.35; N, 2.72.

Example 24

[2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-nitro-phenoxy] -acetic acid

To a suspension of potassium carbonate (0.223 g, 1.61 mmol), [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-nitro-phenol (0.400 g, 0.789 mmol) in DMF (2.8 mL) was added methyl bromoacetate (0.150 mL, 1.58 mmol) with stirring. After 15 hours, the reaction mixture was poured into water and extracted with ethyl acetate. Silica gel was added to the acetate phase and the solvent was removed. The adsorbate was flash chromatographed (9/1 petroleum ether / ethyl acetate) to give the title compound (0.305 g, 67%) as a yellow solid. This solid (0.050 g, 0.086 mmol) was dissolved in 1: 1 THF: methanol and treated with aqueous potassium hydroxide solution (1.0 M solution, 0.30 mL, 0.30 mmol). After 25 minutes, the reaction mixture was diluted with water, acidified with 10% aqueous HCl and extracted with ether. The ether phase was dried (sodium sulfate), concentrated and recrystallized from petroleum ether / ether to give the title compound (0.025 g, 51%) as a white solid, mp 228-229 ° C.

NMR (DMSO-d 6): δ 8.23 (d, J = 9 Hz, 1H); 8.14 (d, J = 2Hz, 1 H); 8.04 (d, J = 2Hz, 1 H); 7.69 (ddd, J = 8.7, 1 Hz, 1H); 7.54 (ddd, J = 8.7, 1 Hz, 1H); 7.48 (d, J = 8Hz, 1H); 4.87 (d, J = 6Hz, 1H); 4.82 (d, J = 6Hz, 1H); 2.46 (s, 3H); 1.62 (s, 3H).

················

-82 ·· ················

MS (+ FAB): double bromine isotope pattern 563 (40%), 565 (100%), 567 (50%).

analysis:

Calcd for C ₂₂ H ₁₅ Br ₂ NO ₅ S 46.75% C, 2.68% H, 2.48% N;

Found: C, 45.18; H, 2.66; N, 2.38.

Example 25

(S) -2-Hydroxy-3-phenylpropionic acid methyl ester

A solution of commercially available (S) -2-hydroxy-3-phenylpropionic acid (5.0 g, 30.1 mmol) and p-toluenesulfonic acid hydrate (1 g) in methanol (125 mL) was heated under reflux for 17 h. reflux and water was removed using a 3A molecular sieve. The solution was concentrated and the residue was dissolved in ether. The ethereal solution was washed with saturated sodium bicarbonate solution, brine and concentrated to give the title compound (5.32 g, 98%) as a white solid.

NMR (CDCl ₃ ): δ 7.36-7.20 (m, 5H); 4.47 (ddd, J = 5.6, 7 Hz, 1H); 3.78 (s, 3H); 3.14 (dd, J = 5, 14 Hz, 1H); 2.97 (dd, J = 7, 14 Hz); 2.69 (d, J = 6Hz, 1H).

Example 26

(S) -2-4 [Nitrobenzoyl] -4-phenylbutyric acid ethyl ester

To a cooled (ice bath) solution of commercially available (R) -2-hydroxy-4-phenylbutyric acid ethyl ester (1.86 mL, 9.60 mmol), pnitrobenzoic acid (6.42 g, 38.4 mmol, 4 equivalents) and triphenylphosphine (10.07 g, 38.4 mmol, 4 equivalents) in anhydrous tetrahydrofuran (110 mL) was added dropwise over 40 min diethyl azocarboxylate (6.05 mL, 38.4 mmol, 4 equivalents) while the reaction temperature was the mixture was maintained between 4 and 5 ° C. The mixture was then stirred for an additional hour at 4 to 5 ° C, then the ice bath was removed and the solution was allowed to warm to room temperature and stirred at this temperature for 5 days. The solvents were removed and the residue was redissolved in a mixture of ether and ethyl acetate (600 mL), silica gel (200 mL) was added and the solvents were removed. The adsorbate has been processed ································ ·· ·· ··· ·· ·

Flash chromatography (80/20 to 70/30 petroleum ether / ethyl acetate gradient) to give the title compound (4.03 g) as a yellow oil.

NMR (CDCl 3): δ 8.30 (d, J = 9 Hz, 2H); 8.18 (d, J = 9Hz, 2H); 7.38 to 7.18 (m, 5H);

5.28 (t, J = 2Hz, 1 H); 4.23 (q, J = 7Hz, 2H); 2.85 (t, J = 8Hz, 2H); 2.40 to 2.33 (m,

2H); 1.29 (t, J = 7Hz, 3H).

MS [(+)] FAB &lt; + &gt;: [M + H] m / z = 358.

Example 27

(S) -2-Hydroxy-4-phenylpropionic acid ethyl ester

To a suspension of potassium cyanide (0.176 g, 2.70 mmol) in absolute ethanol (43 mL) was added dropwise over 0.5 h a solution of (S) -2-4 [nitrobenzoyl] -4-phenylbutyric acid ethyl ester (3, 5, 86 g, 10.8 mmol) in absolute ethanol (38 mL). The reaction mixture was stirred for 2.25 hours, then the solvent was removed and the residue was diluted with water and acidified with dilute hydrochloric acid. The organic portion was extracted with ether. Silica gel (60 mL) was added to the combined extracts and the solvent was removed. The adsorbate was flash chromatographed, eluent (gradient 90/10 to 80/20 petroleum ether / ethyl acetate) and solvents were removed by distillation with benzene to give the title compound (1.67 g, 74%) as a white solid. yellow oily substance.

NMR (CDCl 3): δ 7.38-7.16 (m, 5H); 4.30 to 4.10 (m, 3H); 2.9-2.6 (m, 3H); 2.2-1.9 (m, 2H); 1.15 (t, J = 4Hz, 3H).

[α] _D ²⁵ + 178.23 ° at 10.98 mg / ml ¹ CHCl ³ Example 28

(R) -2- [2,6-Dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3-phenyl- propionic acid

To a solution of 2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (0.60 g, 1.00 mmol) and methyl ester (S) -2-hydroxy-3-phenylpropionic acid (0.300 g, 1.67 mmol), triphenylphosphine (0.437 g, 1.67 mmol) and benzene (5 mL) were added to ··· · ··· ··· ·· · · · · · ·

Diethyl azodicarboxylate (0.262 mL, 1.67 mmol) was added dropwise with stirring. The solution was then heated at 80 ° C in an oil bath for 6 hours. After cooling to room temperature, the reaction mixture was diluted with ether and silica gel (30 mL) was added. Then the reaction mixture was concentrated and the adsorbate on silica gel was flash chromatographed (95/5 petroleum ether / ethyl acetate) to give the title compound (0.76 g, 97%) as a white solid at temperature mp 174-175 ° C.

NMR (DMSO-d 6): δ 8.21 (ddd, J = 8,1,1 Hz, 1H); 7.74 (d, J = 2Hz, 1 H); 7.73 (d, J = 2Hz, 1 H); 7.67 (ddd, J = 8.6, 1 Hz, 1H); 7.53 (ddd, J = 8.7, 1 Hz, 1H); 7.43 (d, J = 8Hz, 1H); 7.35 to 7.24 (m, 5H); 5.11 (dd, J = 7.6 Hz, 1H); 3.61 (s, 3H); 3.43 (dd, J = 13.6 Hz, 1H); 2.44 (d, J = 1Hz, 3H); 1.60 (d, J = 1Hz, 3H).

MS (+ FAB): three bromine isotopic pattern 700 (20%), 702 (70%), 704 (75%), 706 (25%).

analysis:

Calcd for C 30 H 23 Br ₃ O ₃ S 51.23% C, 3.30% H, 0.00% N;

Found: C, 51.52; H, 3.36; N, 0.12.

Example 29

(R) -2- [2,6-Dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3-phenyl-propionic acid

To a solution of (R) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3-phenyl- propionic acid (0.699 g, 0.99 mmol) in THF (12 mL) / methanol (7 mL) was added aqueous potassium hydroxide solution (1 M solution, 2.00 mL, 2.00 mmol) with stirring. After three hours, the solution was concentrated, diluted with water (100 mL) and acidified with 10% aqueous HCl. The solid was filtered, washed with water and triturated in petroleum ether, dried in vacuo to give the title compound (0.645 g, 94%) as a white solid with [α] _D ²⁵ = + 14.29 ° at 8.75 mg / ml ¹ CHCl ₃ .

NMR (DMSO-d 6): δ 8.19 (d, J = 8 Hz, 1H); 7.66 (ddd, J = 8.7, 1 Hz, 1H); 7.61 (s, 2 H); 7.52 (ddd, J = 8.7, 1 Hz, 1H); 7.41 (d, J = 8Hz, 1H); 7.38 to 7.20 (m, 5H); 5.27 «· ···················

-85 (t, J = 7Hz, 1H); 3.37 (dd, J = 14.6 Hz, 1H); 3.28 (dd, J = 14.7 Hz, 1H); 2.43 (s, 3H); 1.59 (s, 3H).

MS (+ FAB): triple bromine isotopic pattern 686 (20%), 688 (75%), 690 (75%), 692 (25%).

analysis:

calcd for C 9 H ₂ O ₂ IBR _{3 3} S 50.53% C, 3.07% H, 0.00% N;

found: 50.04% C, 3.11% H, 0.05% N.

Example 30

(R) -2- [2,6-Dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -propionic acid

To a solution of 2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (0.300 g, 0.554 mmol), commercially available methyl ester ( S) - (-) - Milky (0.078 mL, 0.831 mmol) and triphenylphosphine (0.218 g, 0.831 mmol) in dry benzene (5 mL) were added dropwise over 10 min under dietary nitrogen in 0.1 mL of nitrogen under protective nitrogen. ml, 0.831 mmol). The reaction mixture was then heated to reflux for 4 hours; at room temperature was stirred for an additional 24 hours. It was then diluted with diethyl ether and mixed with silica gel. The solvents were removed and the adsorbate was flash chromatographed (75/25 petroleum ether / methylene chloride) to give a white solid (0.283 g, 81%). To a solution of this solid (0.260 g, 0.415 mmol) in tetrahydrofuran (9 mL) and methanol (3 mL) was added dropwise aqueous potassium hydroxide solution (1 M solution, 0.498 mL, 0.498 mmol) dropwise at room temperature. After stirring for 1.5 hours, the solvents were removed. The residue was mixed with water and acidified with a 10% aqueous hydrochloric acid solution. Diethyl ether was added and after stirring for 10 minutes, the two phases were shaken well and allowed to separate. The organic phase was washed with brine, concentrated and distilled off with petroleum ether to give the title compound (0.257 g, 99%) as a white solid, mp 224-225 ° C.

······························ · 9

-86NMR (DMSO-d6): δ 13.09 to 13.06 (broad s, 1H, COOH); 8.20 (d, J = 8Hz, 1H); 7.75 (s, 2 H); 7.67 (ddd, J = 8.7, 12 Hz, 1H); 7.55 to 7.47 (m, 2H); 5.02 (q, J = 7Hz, 1H); 2.44 (s, 3H); 1.62 (s, 3H); 1.56 (d, J = 6Hz, 3H).

MS (+ FAB): three-bromine isotope pattern 609.7 (30%), 611.8 (75%), 613.8 (100%), 615.7 (35%).

High resolution MS [(+ FAB) + of] the weight of the C ₂ 3Hi Br3O ₇ S _3: 609.84485, measured 609.85789, mass deviation 13.04 mmu.

analysis:

Calcd for C ₂₃ H 17 Br ₃ O ₃ S 45.05% C, 2.79% H, 0.00% N;

H, 2.69; N, 0.38.

Example 31

(S) -2- [2,6-Dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -4-phenyl-butyric acid

The title compound was prepared from 2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (Example 9) and the commercially available ethyl ester of ( ft) -2-hydroxy-4-phenylbutyl as described in Example 30. The product was a white solid, mp 176-177 ° C.

[<x] D ²⁵ = + 7.58 ° ⁽¹ in 10,652 mg ml CHCl _3).

NMR (DMSO-d 6): δ 13.0 (br s, 1H, COOH); 8.21 (ddd, J = 8.7, 1 Hz, 1H); 7.73 (s, 2 H); 7.67 (ddd, J = 8.7, 1 Hz, 1H); 7.52 (ddd, J = 8.7, 1 Hz, 1H); 7.46 (m, IH); 7.32 to 7.28 (m, 2H); 7.24 to 7.18 (m, 3H); 5.03 (t, J = 6Hz, 1H); 2.95 (m, IH); 2.72 (m, IH); 2.44 (s, 3H); 2.28 (m, 2 H); 1.61 (s, 3H).

MS (+ FAB): [M +], triple bromine isotopic pattern 700 (30%), 702 (100%), 704 (75%), 706 (40%).

analysis:

Calcd for C ₃₀ H ₂₃ Br ₃ O ₃ S 51.23% C, 3.30% H, 0.00% N;

found 51.15% C, 3.13% H, 0.00% N.

······························

-87 • · · · · · · · · · · · · · · · · · · · · · ·

Example 32

(R) -2- [2,6-Dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -4-phenyl-butyric acid

The title compound was prepared from 2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (Example 9) and (S) ethyl ester. -2-hydroxy-4-phenylbutyric acid (Example 27) as described in Example 30. The product was a white solid.

[a] ²⁵ _D = -12.187 ° (9.929 mg mL in CHCl _3).

NMR (DMSO-d 6): δ 13.24 (s, 1H); 8.21 (d, J = 8Hz, 1H); 7.73 (s, 2 H); 7.67 (ddd, J = 8.7, 1 Hz, 1H); 7.52 to 7.45 (m, 2H); 7.32 to 7.28 (m, 2H); 7.24 to 7.20 (m, 3H); 5.02 (d, J = 6Hz, 1H); 2.99 to 2.86 (m, 1H); 2.72 to 2.65 (m, 1H); 2.45 (s, 3H); 2.30 to 2.20 (m, 2H); 1.61 (s, 3H).

MS (+ FAB): [M +], triple bromine isotopic pattern 700 (30%), 702 (100%), 704 (90%), 706 (55%).

analysis:

Calcd for C 30 H 23 Br ₃ O ₃ S 51.23% C, 3.30% H, 0.00% N;

Found: C, 51.33; H, 3.33; N, 0.29.

Example 33

(R) -2- [2,6-Dibromo-4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3-phenyl-propionic acid

The title compound was prepared from 2,6-dibromo-4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) -phenol (Example 13) and (S) methyl ester. 2-hydroxy-3-phenylpropionic (Example 25) as described in Example 30. The product was a white solid.

Optical rotation [α] _D ²⁵ = -22.84 ° (at 10.088 mg · ml ^-1 CHCl ₃ ).

NMR (DMSO-d ₆ ): δ 13.13 (br s, 1H); 8.42 (d, J = 8Hz, 1H); 7.75 (t, J = 2Hz, 2H); 7.58 (ddd, J = 8.7, 1 Hz, 1H); 7.50 (ddd, J = 8.7, 1 Hz, 1H); 7.44 (d, J = 8Hz,

-88 ·· ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ··· ·· ·

1H); 7.37 to 7.19 (m, 7H); 7.15 to 7.11 (m, 1H); 7.03 to 7.00 (m, 2H); 5.22 (t, J = 7Hz, 1H); 3.37 to 3.28 (m, 2H); 2.39 (s, 3H); 1.62 (s, 3H).

MS (EI): [M +], Two bromine isotopic pattern 716 (10%), 718 (20%), 720 (10%).

analysis:

Calcd for C 35 H 26 Br ₂ O ₃ S 2 58.50% C, 3.65% H, 0.00% N;

Found: C, 58.77; H, 3.94; N, 0.16.

Example 34

(R) -2- [2,6-Dibromo-4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -propionic acid

The title compound was prepared from 2,6-dibromo-4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) -phenol (Example 13) and commercially available methyl ester of ( The S) - (-) - milk process was as described in Example 30. The product was a white solid, mp 237-239 ° C.

Optical rotation [α] D ²⁵ = - 1.99 ° (at 10.051 mg.ml ^-1 CHCl ₃ ).

NMR (DMSO-d 6): δ 13.2 (broad s, 1H, COOH); 8.43 (d, J = 8Hz, 1H); 7.80 (s, 2 H); 7.62 to 7.58 (d, J = 8Hz, 1H); 7.56 to 7.50 (m, 2H); 7.23 to 7.13 (m, 3H); 7.04 to 7.01 (m, 2H); 5.03 (quartet, J = 7 Hz, 1H); 2.40 (s, 3H); 1.63 (s, 3H); 1.57 (d, J = 8Hz, 3H).

MS (EI): [M +], double bromine isotopic pattern 640 (47%), 642 (100%), 644 (56%).

analysis:

Calcd for C29H22Br2O S2 ₃ 54.22% C, 3.45% H, 0.00% N;

H, 3.33; N, 0.05%.

Example 35

2- [2,6-dibromo-4- (9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3-phenyl-propionic acid ····························

-89 ··· ··· ··· ·· ··················

The title compound was prepared from dibromo-4- (9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (Example 19) and commercially available methyl ester S - (-) - lactic acid according to the procedure described in Example 30. The product was in the form of a yellow solid having an optical rotation of [α] _D ²⁵ = + 26.512 ° at 10.184 mg.ml ^-1 DMSO.

NMR (pyridine-d ₅ ): δ 8.41 (d, J = 9 Hz, 1H); 7.84 (dd, J = 3.1 Hz, 2H); 7.70 (d, J = 7Hz, 2H); 7.43 to 7.32 (m, 6H); 5.89 (t, J = 7Hz, 1H); 3.88 (dq, 2 H); 3.77 (t, J = 7Hz, 4H); 3.66 (s, 2 H); 2.53 (s, 4H); 1.70 (s, 3H).

MS (+ FAB): [(M + H) ⁺ ], triple bromine isotopic pattern 772 (20%), 774 (35%), 776 (45%); High resolution MS, calculated 771.93674 for C33H29NO4SBR3 as [M + H]; mass 771.93954, weight difference 2.80 mmu.

analysis:

Calcd for C ₃ H 28 Br ₃ NO ₄ S 51.18% C, 3.64% H, 1.81% N;

Found: C, 51.57; H, 3.86; N, 1.73.

Example 36

2- [2,6-Dibromo-4- (9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -propionic acid

The title compound was prepared from dibromo-4- (9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (Example 19) and methyl ester of ( S) -2-hydroxy-3-phenylpropionic (Example 25) as described in Example 30. The product was in the form of a yellow solid having an optical rotation of [α] _D ²⁵ = + 13.84 ° at 10.043 mg / ml DMSO .

NMR (pyridine-d 6): δ 8.42 (d, J = 8 Hz, 1H); 7.88 (s, 2 H); 7.63 (m, 2 H); 7.41 (m, IH); 5.61 (q, J = 4Hz, 1H); 3.78 (t, J = 4Hz, 4H); 3.70 to 3.63 (m, 3H); 2.56 (s, 4H); 1.97 (d, J = 7Hz, 3H); 1.71 (s, 3H).

MS (+ FAB): [(M + H) ⁺ ], triple bromine isotopic pattern 696 (35%), 698 (100%), 700 (80%), 702 (40%).

· ·

-90 ·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · ·

analysis:

calcd for C 7 H ₂ 4 Br ₂ NO _{3 4} S.HCI 44.14% C, 3.43% H, 1.91% N;

Found: C, 44.94; H, 3.85; N, 1.83.

Example 37

(R) -2- [2,6-Dibromo-4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3-phenyl- propionic acid

The title compound was prepared from 2,6-dibromo-4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -phenol (Example 18) and methyl ester of ( S) -2-hydroxy-3-phenylpropionic (Example 25) as described in Example 30. The product was a white solid.

NMR (DMSO-d 6): δ 13.3 (broad band, 1H); 8.20 (d, J = 8Hz, 1H); 7.70 (s, 2 H); 7.66 (ddd, J = 8.7, 1H, 1H); 7.51 (ddd, J = 8.7, 1 Hz, 1H); 7.40 to 7.25 (m, 6H); 5.21 (t, J = 7Hz, 1H); 3.75 (s, 2 H); 3.32 (dd, J = 4.3 Hz, 2H); 2.55 (q, J = 7Hz, 4H); 1.63 (s, 3H); 1.02 (t, J = 7Hz, 6H).

MS (+ FAB): [(M + H) ⁺ ] @ ⁺ m / z, 758, triple bromine isotopic pattern 758 (25%), 760 (80%), 762 (75%), 764 (35%), 689 ( 100%).

Analytical HPLC, Primesphere 5C-18 column, eluting with 62% acetonitrile after 15 minutes, gave a purity of 97.8%.

High Resolution MS MAS (FAB) + ve: Calculated mass 759.95556 for the formula C 33 H 31 NO ₃ Br ₃ as [M + H]; determined mass 759.97370, weight difference 18.14 mmu.

Example 38

[2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-nitrophenoxy] -3-phenylpropionic acid

The title compound was prepared from 2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-nitro-phenol (Example 21) and methyl ester ( S) -2 ······································

Hydroxy-3-phenylpropionic (Example 25) as described in Example 30. The product was a white solid, m.p. 243-245 ° C. C.

NMR (DMSO-d 6): δ 11.30 (br s, 1H); 8.23 and 8.22 (2d, J = 3Hz, 1H); 8.06, 8.04 (2d, J = 3Hz, 1H); 7.95 (t, J = 2Hz, 1 H); 7.68 (m, IH); 7.56 to 7.50 (m, 1H); 7.45 (d, J = 8Hz, 1H); 7.34-7.24 (m, 6H); 5.28, 5.22 (2t, J = 6Hz, 1H); 3.40-3.23 (m, 2H); 4.82 (d, J = 6Hz, 1H); 2.46 (s, 3H); 1.59, 1.57 (2s, 3H).

MS (+ FAB): double bromine isotopic pattern 653, 655, 657.

analysis:

Calcd for C 29 H ₂₁ Br ₂ NO ₅ S 53.15% C, 3.23% H, 2.14% N;

H, 3.73; N, 2.04.

Example 39

2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-isopropyl-phenol

Reaction Step 1

2-Isopropyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol

In a similar manner to Example 49 for reaction step 1, from 3-isopropyl-p-anisic acid (3.0 g, 16.5 mmol, RN-33537-78-9), oxalyl chloride (1.7 mL, N, N-dimethylformamide (2 drops), 2,3-dimethyl-5-benzylthiophene (4.0 g, 19.8 mmol), tin tetrachloride (2.1 mL, 18.2 mmol) and anhydrous methylene chloride (65 mL) gave the compound (6.5 g) as a dark red oil which was used without further purification.

In a similar manner to Example 49 for reaction step 2, from (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (3-isopropyl-4-methoxy-phenyl) -methanone (6.5 g, 17.8 mmol), boron tribromide (9.4 mL, 99 mmol) and methylene chloride (75 mL) gave the title compound (1.7 g, 27%) as a yellow solid.

NMR (DMSO-d 6): δ 9.49 (s, 1H); 8.42 (s, 1 H); 7.94 (d, IH); 7.47 to 7.32 (m, 3H); 7.01 (s, IH); 6.93 (s, 2 H); 3.32 (m, 1H); 2.39 (s, 3H); 1.19 (d, 6H).

···················

-92 ··· ··· ·································

Reaction Step 2

Acetic acid 2-isopropyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester

In a similar manner to that described in Example 49 for reaction step 3, z

2-Isopropyl-4- (2-, 3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (0.5 g, 1.4 mmol), acetic anhydride (0.17 mL) , 1.8 mmol) and pyridine (3.5 mL) gave the title compound (0.48 g, 86%) as a white solid.

NMR (DMSO-d 6): δ 8.49 (s, 1H); 8.00 to 7.96 (d, 1H); 7.48 to 7.31 (m, 4H); 7.20 (s, 2 H); 3.10 (septet, 1H); 2.40 (s, 3H); 2.37 (s, 3H); 1.56 (s, 3H); 1.16 (d, 6H).

Reaction Step 3

Acetic acid 2-isopropyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester In a similar manner to that described in Example 49 for reaction step 4,

Acetic acid 2-isopropyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester (0.38 g, 0.97 mmol), ferric chloride (8 mg, 0.051 mmol, bromine (0.055 mL, 1.1 mmol) and methylene chloride (5 mL) gave the title compound (0.40 g, 88%) as a white solid.

NMR (DMSO-d ₆ ): δ 8.20 (d, 1H); 7.67 to 7.62 (m, 1H); 7.52 to 7.43 (m, 2H); 7.34 (d, IH); 7.22 (m, 2 H); 3.09 (septet, 1H); 2.43 (s, 3H); 2.37 (s, 3H); 1.54 (s. 3H); 1.16 and 1.15 (two d, 6H, rotating isomers).

MS (EI): [M ⁺ ], single bromine isotopic pattern, 466, 468.

analysis:

Calcd for C 28 H 33 BrCl 2 S 64.24% C, 4.96% H, 0.00% N;

H, 4.90; N, 0.06.

Reaction Step 4

2-Isopropyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol

In a similar manner to that described in Example 49 for reaction step 5, z

Acetic acid 2-isopropyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester (0.39 g, 0.83 mmol), aqueous solution potassium hydroxide (1.0 mL of 1 M solution, 1.0 mmol), tetrahydrofuran (14 mL), and methanol (8.5 mL) were prepared in the title. ··· ·· ···· ··

-93% (0.35 g, 99% of theory) as a creamy solid, &lt; tb &gt; ______________________________________ &lt; tb &gt; ______________________________________ &lt; tb &gt;

NMR (DMSO-d 6): δ 9.56 (s, 1H); 8.17 (d, IH); 7.64 to 7.60 (ddd, 1H); 7.53 to 7.52 (d, 1H); 7.46 to 7.42 (ddd, 1H); 7.03 (d, IH); 6.97 to 6.91 (m, 2H); 3.31 to 3.28 (m,

1H); 2.42 (s, 3H); 1.58 (s, 3H); 1.16 (d, 6H).

MS (EI): [M ⁺ ], single bromine isotopic pattern, 424, 426.

analysis:

Calcd for (% H) BrOS 64.94% C, 4.98% H, 0.00% N;

H, 4.99; N, 0.03.

Reaction Step 5

2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-isopropyl-phenol

To a suspension of 2-isopropyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (0.35 g, 0.81 mmol) and potassium acetate ( 0.80 g, 8.11 mmol) in glacial acetic acid (11 mL) was added dropwise a solution of bromine (0.05 mL,

0.97 mmol) in glacial acetic acid (1.5 mL). 1 ml of acetic acid was used to rinse the pipette and bromine container. The reaction mixture was stirred at room temperature for 4 hours and then quenched by the addition of a small amount of dilute sodium bisulfite solution and diluted with water (100 mL). The white solid was collected using a glass filter crucible, washed well with water and dried (Na ₂ SO ₄ ) to give the title compound (0.40 g, 98%) as a white solid, m.p. Mp 162 ° C.

NMR (DMSO-d 6): δ 9.20 (s, 1H); 8.19 (d, IH); 7.66 to 7.61 (m, 1H); 7.49 to 7.48 (m, 2H); 7.35 (d, IH); 7.13 (d, IH); 3.40 (septet, 1H); 2.42 (s, 3H); 1.60 (s, 3H); 1.16 (d, 6H).

MS (+ FAB): [M ⁺ H], double bromine isotopic pattern, 502 (12%), 504 (30%), 506 (18%).

analysis:

Calcd for C23H20B2O2S 54.78% C, 4.00% H, 0.00% N;

found: 53.67% C, 3.84% H, 0.03% N.

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

-94 ··· ··· ··························································

Example 40

(R) -2- [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-isopropyl-phenoxy] -3-phenyl-propionic acid

Reaction Step 1

(2 R) -2- [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-isopropyl-phenoxy] -3-methyl ester phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 6, z

2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-isopropyl-phenol (0.36 g, 0.72 mmol), methyl ester (S) -2-hydroxy-3-phenylpropionic acid (0.19 g, 1.1 mmol), triphenylphosphine (0.28 g, 1.1 mmol), diethyl azodicarboxylate (0.17 mL, 1.1 mmol) and of anhydrous benzene (4.0 mL) by heating in an oil bath (80 ° C) for 4.5 hours afforded the title compound (0.27 g, 56%) as a white solid.

NMR (DMSO-d 6): δ 8.20 (d, 1H); 7.70 to 7.60 (m, 1H); 7.60 to 7.40 (m, 2H); 7.40 to 7.20 (m, 7H); 5.07 and 4.95 (two triplets, 1H, rotating isomers); 3.60 and 3.56 (two s, 3H, rotating isomers); 3.40-3.20 (m, 3H); 2.45 and 2.43 (two singlets, 3H, rotating isomers); 1.59 and 1.53 (two singlets, 3H, rotating isomers); 1.20 to 1.00 (m, 6H).

Reaction Step 2

(2R) -2- [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-isopropyl-phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 7, (2fi) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophene) methyl ester -4-yl) -6-isopropyl-phenoxy] -3-phenyl-propionic acid (0.26 g, 0.52 mmol), aqueous potassium hydroxide solution (1.1 mL, 1 M solution, 1.1 mmol), terahydrofuran ( 6 mL) and methanol (2 mL) gave the title compound (0.23 g, 68%) as a white solid, which had an optical rotation of [.alpha.] D @ ²⁵ = + 38.9 DEG at 6.970 mg. .ml ' ¹ CHCI ₃ .

NMR (DMSO-d ₆ ): δ 13.1 (br s, 1H); 8.19 (d, IH); 7.68 to 7.62 (m, 1H); 7.53 to 7.44 (m, 2H); 7.40 to 7.38 (m, 1H); 7.35 to 7.30 (m, 4H); 7.29 to 7.23 (m, 2H); 5,00 ··· ···············

-95 ··· (m, 1H); 3.55 (septet, 1H); 3.35 (m, 2 H); 2.42 and 2.43 (two singlets, 3H, rotating isomers); 1.57 and 1.52 (two singlets, 3H, rotating isomers); 1.14 to 1.03 (m, 6H).

MS (+ FAB): [M ⁺ ], double bromine isotopic pattern, 650 (15%), 652 (30%), 654 (21%).

analysis:

Calcd for C 32 H 28 Br ₂ O ₃ S 58.91% C, 4.33% H, 0.00% N;

Found: C, 58.72; H, 4.45; N, 0.10.

Example 41

(R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-isopropyl-phenoxy] -3-phenyl-propionic acid

Reaction Step 1

(R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-isopropyl-phenoxy] -3-phenyl-propionic acid methyl ester

In a similar manner to that described in Example 49 for reaction step 6, z

4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-isopropyl-phenol (0.30 g, 0.87 mmol), (S) -2-hydroxymethyl ester -3-phenylpropionic (0.62 g, 3.5 mmol), triphenylphosphine (0.91 g, 3.5 mmol), diethyl azodicarboxylate (0.54 mL, 3.5 mmol) and anhydrous benzene (7.0 mL) Heating in an oil bath (85 ° C) for 18 h afforded the title compound (0.18 g, 41%) as a yellow oil.

NMR (DMSO-d 6): δ 8.40 (s, 1H); 7.90 (d, IH); 7.50 to 7.20 (m, 6H); 7.20 to 7.00 (m, 6H); 7.20 to 7.00 (m, 3H); 7.00 to 6.80 (m, 2H); 5.20 (t, IH); 3.65 and 3.63 (two s, 3H, rotating isomers); 3.30 to 3.20 (m, 3H); 2.40 (s, 3H); 1.50 (s. 3H); 1.15 (two doublets, 3H, rotating isomers), 1.05 (two doublets, 3H, rotating isomers).

Reaction Step 2

(R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-isopropyl-phenoxy] -3-phenyl-propionic acid ·· ·· · e ·· • · · · ·······

-96 • · · · · · · · · · · · · · · · · · · · · · · ·

In a similar manner to that described in Example 49 for reaction step 7, (ft) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2- isopropyl-phenoxy] -3-phenyl-propionic acid (0.18 g, 0.35 mmol), aqueous potassium hydroxide solution (0.71 mL, 1M solution, 0.71 mmol), tetrahydrofuran (6 mL), and methanol (2 mL). mL) afforded the title compound (0.072 g, 41%) as a white solid.

NMR (DMSO-d 6): δ 13.10 (br s, 1H); 8.43 (d, IH); 7.49 (dd, IH); 7.46 to 7.29 (m, 7H); 7.28 to 7.22 (m, 1H); 7.10 to 7.03 ((m, 2H); 6.89 to 6.85 (m, 1H); 5.07 (m, 1H); 3.40 to 3.19 (m, 3H); 2 38 and 2.37 (two singlets, 3H, rotating isomers) 1.53 and 1.51 (two singlets, 3H, rotating isomers), 1.15 and 1.14 (two doublets, 3H, rotating isomers); 1.03 (d, 3H).

MS (EI): [M +] 494.

analysis:

Calcd for C 32 H 30 O 3 S 77.70% C, 6.11% H, 0.00% N;

Found: C, 75.71; H, 6.29; N, 0.03.

Example 42

(R) -2- [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-sec-butylphenoxy] -3-phenyl acid propionic acid

Reaction Step 1

2-sec-Butyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol

In a similar manner to that described in Example 49 for reaction step 1, 3-sec-butyl-p-anisic acid (3.0 g, 14.4 mmol) was prepared as described in M. Derenberg and P. Hodge, Tetrahedron Lett. 1971, 3825-3828; DG Davies et al., J. Chem. Soc. (C) 1971, 455-460), oxalyl chloride (1.4 mL, 15.8 moles), N, N-dimethylformamide (2 drops) 2,3-dimethyl-5-benzylthiophene (3.5 g, 16.6 mmol), tin tetrachloride (1.5 mL, 15.8 mmol) and anhydrous methylene chloride (92 mL) prepared the compound (6.2 g). ) in the form of an oily substance which was used further without purification.

In a similar manner to that described in Example 49 for reaction step 1, the reaction is carried out in a manner similar to that described in Example 49.

-97 (2-Benzyl-4,5-dimethylthiophen-3-yl) - (3-se / r- butyl-4-methoxy-phenyl) -methanone (6.2 g, 15.8 mmol), boron tribromide (7.1 mL, 74.8 mmol) and methylene chloride (54 mL) gave the title compound (2.34). g, 41% of theory) as a solid.

MS (EI): [M &lt; + &gt;] 360.

Reaction Step 2

2- [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-sec-butyl phenol

In a similar manner to that described in Example 39 for reaction step 6, from 2-seph-butyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (2.34) g, 6.5 mmol), bromine (0.69 mL, 13 mmol), potassium acetate (6.4 g, 65 mmol) and glacial acetic acid (65 mL) gave the title compound (0.63 g, 19 mmol). % of the theoretical yield) as a solid.

MS (EI): [M ⁺ ], two bromine isotopic pattern, 516 (50%), 518 (100%), 520 (55%).

Reaction Step 3

(R) -2- [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-tert-butylphenoxy] -3- phenyl-propionic acid

In a similar manner to Example 49 for reaction step 6, 2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) - 6-se-t-butylphenol (0.63 g, 1.2 mmol), (S) -2-hydroxy-3-phenylpropionic acid methyl ester (0.44 g, 2.4 mmol), triphenylphosphine (0, 64 g, 2.4 mmol), diethyl azodicarboxylate (0.38 mL, 2.4 mmol) and anhydrous benzene (2.4 mL) at room temperature after 5 days of reaction gave an oil (0.60 g, 72%) ), which was used without further purification.

In a similar manner to that described in Example 49 for reaction step 7, (R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophene) methyl ester -4-yl) -6-sec-butyl-phenoxy] -3-phenyl-propionic acid (0.55 g, 0.73 mmol), aqueous potassium hydroxide solution (1.6 mL, 1 M solution, 1.6 mmol), tetrahydrofuran (7.5 mL) and methanol (2.5 mL) was prepared as a solid foam (0.26 g, 48%).

·····························

-98 ·· ···· ·· ··· ·· ···

MS (EI): [M ⁺ ], double bromine isotopic pattern, 664 (14%), 666 (26%), 668 (14%).

analysis:

Calcd for C 50 H 50 B 5 O 5 S 59.47% C, 4.54% H, 0.00% N;

found: C 59.44, H 4.81, N 0.03.

Example 43

(R) -2- [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-ethyl-phenoxy] 3-phenyl acid propionic acid

Step 1 (2-Benzyl-4,5-dimethyl-thiophen-3-yl) - (3-ethyl-4-methoxy-phenyl) -methanone

In a similar manner to that described in Example 49 for reaction step 1, from 3-ethyl-p-anisic acid (5.0 g, 27.7 mmol; RN-22934-35-6), oxalyl chloride (2.7 mL, 30.5 mmol), N, N-dimethylformamide (2 drops), 2,3-dimethyl-5-benzylthiophene (6.7 g, 33.2 mmol), tin tetrachloride (3.6 mL, 30.5 mmol) and anhydrous methylene chloride (177 mL) gave the title compound (5.2 g, 51%) as an oil.

¹ H NMR (DMSO-d 6): δ 7.59 to 7.54 (m, 2H); 7.25 to 7.11 (m, 3H); 7.09 to 7.04 (m, 3H); 3.87 (s, 3H); 3.84 (s, 2 H); 2.57 (q, 2 H); 2.26 (s, 3H); 1.82 (d, 3H); 1.10 (t, 3H). MS (+ FAB): [M + H] 365.

analysis:

Calcd for C23H24O2S: C, 75.79; H, 6.64; N, 0.00;

Found: C, 75.34; H, 6.72; N, 0.00%.

Reaction Step 2

2-ethyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol

In a similar manner to Example 49 for reaction step 2, from (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (3-ethyl-4-methoxy-phenyl) -methanone (6.1 g, 16.7 mmol), boron tribromide (7.1 mL, 75.4 mmol) and methylene chloride (58 mL) gave the title compound (2.6 g, 46%) as a solid.

······································ 9 9 9 9 9 9

-999 9 9 9 9 9 9 9 9

9999 99 999 99 999

NMR (DMSO-d 6): δ 9.49 (s, 1H); 8.42 (s, 1 H); 7.93 (d, IH); 7.43 (m, IH); 7.33 (m, 1H); 7.02 to 6.90 (m, includes singlet at δ 6.94, 3H); 2.73 to 2.52 (complex m, ABX characteristic, 2H, rotating isomers); 2.40 (s, 3H); 1.62 (s, 3H); 1.15 (t, 3 H). MS (EI): [M +] 332.

Reaction Step 3

(R) -2- [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-ethyl-phenoxy] -3-phenyl-methyl ester propionate

In a similar manner to that described in Example 39 for reaction step 6, 2-ethyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (2.6 g, 7.8 mmol, bromine (0.83 mL, 15.7 mmol), potassium acetate (7.7 g, 78.5 mmol), and glacial acetic acid (78 mL) gave the title compound (0.73 g). ) in the form of a solid which was used without further purification.

In a similar manner to that described in Example 49 for reaction step 6, z

2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-ethyl-phenol 2-methyl ester (0.73 g, 1.5 mmol) (S) -2-hydroxy-3-phenylpropionic acid methyl ester (0.54 g, 3.0 mmol), triphenylphosphine (0.78 g, 3.0 mmol), diethyl azodicarboxylate (0.47 mL, 3.0 mmol) ) and anhydrous benzene (3.0 mL) at room temperature after 5 days prepared an oil (0.58 g, 60%).

NMR (DMSO-d 6): δ 8.19 (d, 1H); 7.65 (m, IH); 7.54 to 7.22 (m, includes singlet at δ 7.32, 9H); 5.09 and 5.01 (two t, 1H, rotating isomers), 3.60 and 3.56 (two s, 3H, rotating isomers), 3.45-3.25 (complex m, 2H, rotating isomers) 2.78 to 2.50 (complex m, ABX characteristic, 2H); 2.42 and 2.43 (two s, 3H, rotating isomers); 1.59 and 1.54 (two s, 3H, rotating isomers); 1.09 and 1.07 (two t, 3H, rotating isomers.

Reaction Step 4

(R) -2- [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-ethyl-phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 7, from (R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] methyl ester) Thiophen-4-yl) -6-ethyl-phenoxy] -3-phenyl-propionic acid (0.41 g, 0.63 mmol), aqueous hydroxide solution

-100 «Potassium (1.3 ml, 1 M solution, 1.3 mmol) ), tetrahydrofuran (4.5 ml) and methanol (1.5 ml) gave the title compound (0.38 g, 95%) as a light yellow solid.

NMR (DMSO-d 6): δ 13.05 (br s, 1H); 8.20 (d, IH); 7.65 (m, IH); 7.54 to 7.18 (m, 9H); 5.05 (m, 1 H), 3.33 (m, 2 H); 2.90 to 2.50 (complex m, ABX characteristic, 2H); 2.43 and 2.41 (two s, 3H, rotating isomers), 1.58 and 1.53 (two s, 3H); rotational isomers); 1.10 and 1.09 (two t, 3H, rotating isomers).

MS (-ESI): [M-H], double bromine isotopic pattern, 635 (44%), 637 (100%), 639 (62%).

analysis:

Calcd for C3iH 6 Br ₂ S ₂ O ₃ 58.32% C, 4.11% H, 0.00% N;

found: 58.11% C, 4.32% H, 0.18% N.

Example 44

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-isopropyl-phenoxy] -3-phenyl-propionic acid

Reaction Step 1

(2 R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-isopropyl-phenoxy] -3-phenyl- propionic acid

In a similar manner to that described in Example 49 for reaction step 6, z

4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-isopropyl-phenol (0.26 g, 0.67 mmol), methyl ester ( S) -2-hydroxy-3-phenylpropionic (0.32 g, 1.8 mmol), triphenylphosphine (0.46 g, 1.8 mmol), diethyl azodicarboxylate (0.28 mL, 1.8 mmol) and anhydrous benzene (7.0 mL) in an oil bath (90 ° C) for 4 h afforded the title compound (0.15 g, 38%) as a white solid.

NMR (DMSO-d 6): δ 8.18 (m, 1H); 7.66 to 7.58 (m, 1H); 7.50 to 7.40 (m, 2H); 7.40 to 7.30 (m, 4H); 7.30 to 7.20 (m, 1H); 7.14 to 7.04 (m, 2H); 6.92 to 6.87 (m, 1H); 5.27 (t, 1H); 3.70 and 3.65 (two singlets, 3H, rotating isomers); 3.40-3.20 (m, 3H);

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

- 101 • · ·······················

2.40 (s, 3H); 1.49 (s, 3HJ); 1.15 and 1.13 (two doublets, 3H, rotating isomers), 1.06 and 1.04 (two doublets, 3H, rotating isomers).

Reaction Step 2

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-isopropyl-phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 7, from (2 R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophene-4) methyl ester -yl) -2-isopropyl-phenoxy] -3-phenyl-propionic acid (0.15g, 0.25 mmol), aqueous potassium hydroxide solution (0.50 mL, 1 M solution, 0.50 mmol), tetrahydrofuran (6 ml) and methanol (2 ml) gave the title compound (0.14 g, 95%) as a white solid.

NMR (DMSO-d 6): δ 13.14 (br s, 1H); 8.18 to 8.15 (m, 1H); 7.64 to 7.58 (m, 1H);

7.48-7.31 (m, 6H); 7.30 to 7.22 (m, 1H); 7.11 to 7.04 (m, 2H); 6.90 to 6.85 (m, 1H); 3.39 to 3.18 (m, 3H); 2.41 and 2.40 (two singlets, 3H, rotating isomers); 1.51 a

1.49 (two singlets, 3H, rotating isomers); 1.15 and 1.14 (two doublets, 3H, rotating isomers); 1.04 and 1.03 (two doublets, 3H, rotating isomers);

MS (EI): [M +], single bromine isotopic pattern, 572/574.

analysis:

Calcd for C ₃₂ H ₂ 9Br O ₃ S 67.01% C, 5.10% H, 0.00% N;

Found: C, 67.19; H, 5.47; N, 0.18.

Example 45

(R) -2- [2-Cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3-phenyl-propionic acid

Step 1 (2-Benzyl-4,5-dimethyl-thiophen-3-yl) - (3-cyclopentyl-4-methoxy-phenyl) -methanone

To a suspension of 3-cyclopentyl-β-anisic acid (5.0 g, 22.7 mmol, RN59216-82-9) in anhydrous methylene chloride (60 mL) was added oxalyl chloride (2.4 mL, 27.2 mmol) and N N-dimethylformamide (2 drops); worked in the protective

-102 ············· II 9 · 9 99 9 9 9 9 at room temperature. After stirring for 1.5 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in carbon disulfide (32 mL) and the resulting solution was added to 2,3-dimethyl-5-benzylthiophene (5.1 g, 25.0 mmol). Tin tetrachloride (2.9 ml, 25.0 mmol) was added under nitrogen atmosphere at -78 ° C; the reaction mixture was then stirred at room temperature for 4 hours. Then, the reaction solution was poured onto a mixture of ice and water (200 mL) and extracted with diethyl ether (200 mL). The diethyl ether layer was washed twice with sodium bicarbonate solution and once with brine. Concentration under reduced pressure and chromatography with petroleum ether / ethyl acetate (95/5) gave the title compound (4.8 g, 52%) as an amber oil.

NMR (DMSO-d 6): δ 7.61 to 7.54 (m, 2H); 7.24 to 7.14 (m, 3H); 7.08 to 7.02 (m, 3H); 3.87 (s, 3H); 3.84 (s, 2 H); 3.42 to 3.30 (m, 1H); 2.26 (s, 3H); 2.00 to 1.85 (m, 2H); 1.81 (s, 3H); 1.74 to 1.58 (m, 4H); 1.48 to 1.36 (m, 2H).

MS (EI): [M &lt; + &gt;] 404.

analysis:

Calcd for C 2 ₆ H ₂ 8 O ₂ S 77.19% C, 6.98% H, 0.00% N;

Found: C, 76.26; H, 7.24; N, 0.04.

Reaction Step 2

2-Cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol

To (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (3-cyclopentyl-4-methoxy-phenyl) -methanone (4.8 g, 11.7 mmol) in anhydrous methylene chloride (70 mL) Boron tribromide (3.6 mL, 37.6 mmol) was added dropwise over 20 minutes at -78 ° C under nitrogen. The reaction mixture was then stirred at room temperature for 22 hours. It was then poured onto a mixture of ice and water (600 ml) and extracted with diethyl ether (800 ml). The diethyl ether layer was washed twice with water (500 mL) and once with brine (500 mL). Concentration under reduced pressure and chromatography with petroleum ether / ethyl acetate (97/3) gave the title compound (3.4 g, 78%) as a white solid, mp 156-158 ° C.

································

-103 ··· ··· ·· ♦ · ···· ·· ··· ·· ·

NMR (DMSO-d 6): δ 9.48 (s, 1H); 8.42 (s, 1 H); 7.93 (d, IH); 7.46 to 7.41 (m, 2H); 7.35 to 7.30 (m, 1H); 7.00 (s, 1 H); 6.95 to 6.90 (m, 2H); 3.38 to 3.28 (m, 1H); 2.39 (s, 3H); 1.99 to 1.90 (m, 2H); 1.68 to 1.47 (m, 6H); 1.60 (s, 3H).

MS (EI): [M +] 372.

analysis:

Calcd

% C, 80.60;% H, 6.49;% N; % C, 80.39;% H, 6.43;% N, 0.04.

Reaction Step 3

(R) -2- [2-Cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3-phenyl-propionic acid methyl ester

In a similar manner to Example 49f, from 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (0.40 g, 1.1 mmol) (S) -2-hydroxy-3-phenylpropionic acid methyl ester (0.29 g, 1.6 mmol), triphenylphosphine (0.42 g, 1.6 mmol), diethyl azodicarboxylate (0.25 mL, 1.6 mmol) ) and anhydrous benzene (6.0 mL) in an oil bath (80 ° C) for 6 hours, afforded the title compound (0.26 g, 46%) as a white solid.

NMR (DMSO-d 6): δ 8.44 (s, 1H); 7.94 (d, IH); 7.43 to 7.26 (m, 8H); 7.08 to 7.01 (m, 2H); 6.88 to 6.85 (m, 1H); 5.24 (dd, IH); 3.70 and 3.66 (two singlets, 3H, rotating isomers); 3.42 to 3.20 (m, 3H); 2.38 (s, 3H); 2.02 to 1.30 (m, including singlet at δ 1.52, 11H).

Reaction Step 4

(R) -2- [2-Cyclopenty-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3-phenyl-propionic acid

In a manner similar to that described in Example 49 for Step 7, (R) -2- [2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -acetate 1-Phenoxy] -3-phenyl-propionic acid (0.22 g, 0.41 mmol), aqueous potassium hydroxide solution (0.82 mL, 1 M solution, 0.82 mmol), tetrahydrofuran (12 mL) and methanol (4 mL) title compound (0.21 g, 95%) as a white solid.

····························

-104 · · · ·········································

Optical rotation [α] _D ²⁵ - 8.19 ° (at 8.549 mg · ml ¹ CHCl ₃ ).

NMR (DMSO-d 6): δ 13.10 (br s, 1H); 8.43 (d, IH); 7.93 (m, IH); 7.43 to 7.20 (m, 8H); 7.07 to 7.02 (m, 1H); 6.88 to 6.84 (m, 1H); 5.03 and 5.07 (two dd, 1H, rotating isomers); 3.39 to 3.17 (m, 3H); 2.38 and 2.37 (two singlets, 3H, rotating isomers); 1.90 (m, IH); 1.76 (m, IH); 1.70 to 1.32 (m, includes two singlets at δ 1.54 and 1.52 (rotating isomers) 9H).

MS (EI): [M +] 520.

analysis:

Calcd for C ₃₄ H ₃₂ O ₃ S 78.43% C, 6.19% H, 0.00% N;

Found: C, 77.96; H, 6.40; N, 0.02.

Analysis of the major component (96.9%) was determined by HPLC analysis.

Example 46

(R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl-propionic acid

Reaction Step 1

(Ft) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -phenyl-propionic acid methyl ester

In a similar manner to that described in Example 49 for step 6, 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenol (0.40 g, 1) (2 mmol), (S) -2-hydroxy-3-phenylpropionic acid methyl ester (0.49 g, 2.7 mmol), triphenylphosphine (0.71 g, 2.7 mmol), diethyl azodicarboxylate (0.36 mL, 2.7 mmol) and anhydrous benzene (13 mL) by heating in an oil bath (70-86 ° C) for 10 h to afford the title compound (0.24 g, 40%) as a white solid.

NMR (DMSO-d 6): δ 8.44 (s, 1H); 7.94 (d, IH); 7.45 to 7.39 (m, 2H); 7.35 to 7.30 (m, 5H); 7.28 to 7.24 (m, 1H); 6.96 (s, 2 H); 4.77 (t, IH); 3.56 (s, 3H); 3.34 to 3.25 (m, 2H); 2.39 (s, 3H); 2.22 (s, 3H); 2.17 (s. 3H); 1.56 (m, 3H).

MS (EI): [M +] 494.

• • · · · · • · · · · · · · · • • • · • • • • • • • • • • • • • • · · ···· · · · · · · · •

-105 Analysis:

Calcd for C 32 H 30 O 3 S 77.70% C, 6.11% H, 0.00% N;

Found: C, 76.53; H, 5.85; N, 0.08.

Reaction Step 2

(R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl-propionic acid

In a similar manner to Example 49 for step 7, from (R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-methyl ester, 6-dimethyl-phenoxy] -3-phenyl-propionic acid (0.23 g, 0.46 mmol), aqueous potassium hydroxide solution (0.91 mL, 1 M solution, 0.91 mmol), tetrahydrofuran (12 mL) and methanol ( 4mL) gave the title compound (0.19g, 86%) as a white solid.

Optical rotation [α] D ²⁵ = + 33.04 ° (at 10.170 mg.ml, ¹ MeOH).

NMR (DMSO-d 6): δ 12.9 (br s, 1H); 8.44 (s, 1 H); 7.94 (d, IH); 7.45 to 7.40 (m, 2H); 7.35 to 7.22 (m, 6H); 6.95 (s, 2 H); 4.70 (t, IH); 3.25 (d, 2 H); 2.38 (s, 3H); 2.24 (s. 3H); 2.22 (s, 3H); 1.56 (s, 3H).

MS (EI): [M +] 480.

analysis:

Calcd for C 31 H 28 O 3 S 77.47% C, 5.87% H, 0.00% N;

Found: C, 76.23; H, 5.77; N, 0.03.

Analysis of the major component (94.6%) was determined by HPLC analysis.

Example 47

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-cyclopentyl-phenoxy] -3-phenyl-propionic acid

Reaction Step 1

Acetic acid 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester

To 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl (2.8 g, 7.5 mmol) in anhydrous pyridine (20 mL) at room temperature and protection ······················

Acetic acid anhydride (0.92 mL, 9.8 mmol) was added dropwise to a nitrogen atmosphere. the reaction mixture was then placed in the freezer. After 41 hours, the reaction mixture was diluted and acidified to pH 1 with 10% aqueous hydrochloric acid. The mixture was then extracted with diethyl ether (500 mL), the diethyl ether layer was washed with 5% aqueous hydrochloric acid (100 mL), twice. water (100 mL) and brine (100 mL) and dried (MgSO ₄ ). Concentration under reduced pressure gave the title compound (3.1 g, 98%) as a white solid.

NMR (DMSO-d 6): δ 8.48 (s, 1H); 7.97 (d, IH); 7.47 to 7.43 (m, 1H); 7.38 to 7.36 (m, 2H); 7.28 (s, 1H); 7.19 (d, 2H); 3.14 (q, IH); 2.40 (s, 3H); 2.37 (s, 3H); 1.99 to 1.91 (m, 2H); 1.69 to 1.40 (m, 6H); 1.56 (s, 3H).

MS (EI): [M +] 414.

analysis:

Calcd for C ₂₇ H ₂₆ O ₂ S 78.23% C, 6.32% H, 0.00% N;

Found: C, 77.68; H, 6.39; N, 0.04.

Reaction Step 2

Acetic acid 2-cyclopentyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester

To acetic acid 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester (2.9 g, 7.7 mmol) in anhydrous methylene chloride (68 ml) ferric chloride (66 mg, 0.41 mmol) was added. The reaction mixture was placed under a nitrogen atmosphere in a light-free space and cooled to -78 ° C. Bromine (0.44 mL, 8.5 mmol) in anhydrous methylene chloride (11 mL) was added dropwise over 15 minutes. After stirring at -78 ° C for 45 min, the reaction was quenched by addition of dilute sodium bisulfite solution and poured into water (200 mL). The mixture was extracted with diethyl ether (300 mL), and the diethyl ether layer was washed with water and then brine. Concentration under reduced pressure and chromatography with petroleum ether / ethyl acetate gave the title compound (2.7 g, 79%) as a white solid.

·················

- 107 ·· ···············

NMR (CDCl 3): δ 8.28 (d, 1H); 7.58 to 7.52 (m, 2H); 7.39 to 7.34 (m, 1H); 7.29 (d, 1H); 7.18 (dd, 1H); 7.14 and 7.13 (d, 1H); 3.18 (q, IH); 2.44 (s, 3H); 2.40 (s, 3H); 2.06 to 2.02 (m, 2H); 1.75 to 1.45 (m, includes singlet at δ 1.60, 9H).

MS (EI): [M +], single bromine isotopic pattern 492/494.

analysis:

Calcd for C2 ₇ H ₂ 5BrO ₂ S 65.72% C, 5.11% H, 0.00% N;

H, 4.96; N, 0.00%.

Reaction Step 3

2-Cyclopentyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol

To a solution of acetic acid 2-cyclopentyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester (2.7 g, 5.4 mmol) in tetrahydrofuran (88 mL) and methanol (30 mL) were added dropwise aqueous potassium hydroxide solution (6.5 mL, 1 M solution, 6.5 mmol) dropwise at room temperature. After stirring for 1.5 hours, the reaction mixture was concentrated under reduced pressure. The residue was mixed with water (200 mL) and acidified to pH 1 with 10% aqueous hydrochloric acid. The solution was extracted with diethyl ether (300 mL) and the diethyl ether layer was washed twice with water and dried (Na ₂ SO 4). Concentration under reduced pressure gave the title compound (2.4 g, 100%) as a white solid.

NMR (DMSO-d ₆ ): δ 9.54 (s, 1H); 8.16 (d, IH); 7.61 (m, IH); 7.52 (s, 1 H); 7.43 (m, IH); 7.03 (s, 1H); 6.93 (m, 2H); 3.32 (m, IH); 2.41 (s, 3H); 1.94 (m, 2 H); 1.58 (s, 3H); 1.72 to 1.42 (m, 6H).

MS (EI): [M +], single bromine isotope pattern, 450/452.

analysis:

Calculated for C 5 H _{2 2} 3BrOS 66.52% C, 5.13% H, 0.00% N;

Found: C, 67.17; H, 5.25; N, 0.04.

Reaction Step 4

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-cyclopentyl-phenoxy] -3-phenyl-propionic acid methyl ester · · ····················

-108 ·· ···· ·· ··· ·· ···

In a similar manner to that described in Example 49 for reaction step 6, z

4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-cyclopentyl-phenol (0.40 g, 0.89 mmol), methyl ester of (S) 2-hydroxy-3-phenylpropionic acid (0.48 g, 2.7 mmol), triphenylphosphine (0.70 g, 2.7 mmol), diethyl azodicarboxylate (0.42 mL, 2.7 mmol) and anhydrous benzene (6 ml) by heating in an oil bath (85 ° C) for 4.5 hours to give the title compound (0.19 g, 34%) as a white solid.

NMR (DMSO-d 6): δ 8.17 (d, 1H); 7.64 to 7.59 (m, 1H); 7.45 to 7.40 (m, 2H); 7.38 to 7.24 (m, 5H); 7.10 to 7.03 (m, 2H); 6.90 to 6.86 (m, 1H); 5.28 to 5.24 (m, 1H); 3.70 and 3.66 (two singlets, 3H, rotating isomers); 3.40-3.24 (m, 3H); 2.40 (s, 3H); 1.95-1.30 (m, 8H), 1.49 (s, 3H).

MS (EI): [M +], single bromine isotope pattern 612/614.

Reaction Step 5

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-cyclopentyl-phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 7, (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -acetate -2-cyclopentyl-phenoxy] -3-phenyl-propionic acid (0.18 g, 0.30 mmol), aqueous potassium hydroxide solution (0.39 mL of 1 M solution, 0.39 mmol), tetrahydrofuran (6 mL) and methanol (2 mL) gave the title compound (0.15 g, 84%) as a white solid.

NMR (DMSO-d 6): δ 13.12 (br s, 1H); 8.18 to 8.15 (m, 1H); 7.64 to 7.58 (m, 1H); 7.47 to 7.22 (m, 7H); 7.10 to 7.04 (m, 2H); 6.89 to 6.86 (m, 1H); 5.10 to 5.03 (m, 1H); 3.32 to 3.18 (m, 3H); 2.40 (s, 3H); 1.90 (m, IH); 1.76 (m, IH); 1.70 to 1.30 (m, includes two singlets at δ 1.51 and 1.50 (rotating isomers), 9H).

MS (-ESI): [M-H], single bromine isotopic pattern, 597/599.

analysis:

Calcd for C 34 H 31 BrO 3 S 68.11% C, 5.21% H, 0.00% N;

found: 68.10% C, 5.31% H, 0.01% N.

······························································ I ·

-109 ·· ···· ·· ··· ·· ···

Example 48

(R) -2- [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-cyclopentyl-phenoxy] -3-phenyl-propionic acid

Reaction Step 1

2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-cyclopentyl-phenol

To a suspension of 2-cyclopentyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) phenol (2.0 g, 4.4 mmol) and potassium acetate (4.4 g, 44.3 mmol) in glacial acetic acid (60 mL) was added dropwise a solution of bromine (0.27 mL, 5.3 mmol) in glacial acetic acid (8 mL) over 17 min. . The thick reaction mixture was diluted with glacial acetic acid (20 mL). After stirring at room temperature for 2 hours, the reaction mixture was poured into water (500 mL). The solution was extracted once with diethyl ether (250 mL) and then with 100 mL of diethyl ether. The combined extracts were washed twice with water (100 mL). Concentration under reduced pressure and chromatography with petroleum ether / ethyl acetate (98/2) followed by trituration in petroleum ether gave the title compound (1.2 g, 52%) as a white solid, m.p. Mp 5-191 ° C.

NMR (DMSO-d 6): δ 9.19 (s, 1H); 8.18 (d, IH); 7.65 to 7.61 (m, 1H); 7.50 to 7.47 (m, 2H); 7.33 (d, IH); 7.11 (d, IH); 3.42 (q, IH); 2.43 (s, 3H); 2.00 to 1.97 (m, 2H); 1.69 to 1.46 (m, 6H); 1.60 (s, 3H).

MS (EI): [M +], double bromine isotopic pattern, 528 (100%), 532 (52%). analysis:

Calcd for C ₂₅ H ₂₂ Br ₂ OS 56.62% C, 4.18% H, 0.00% N;

H, 4.12; H, 0.05%.

Reaction Step 2

(2R) -2- [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-cyclopentyl-phenoxy] -3-phenyl- propionic acid

To a solution of 2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-cyclopentyl-phenol (1.2 g, 2, (2 mol), (S) -2-hydroxy-3-phenylpropionic acid methyl ester (0.60 g, 3.3 mmol) and triphenylphosphine (0.87 g, 3.3 mmol) in anhydrous benzene (20 mL) in protective nitrogen atmosphere at room temperature is dropwise

-110-

• · · • · · • · · · • · · · · • · • • • • • • · • • • • · · • • · · • ···· • · · • • · · · • · ·· •

diethyl azodicarboxylate (0.52 mL, 3.3 mmol) was added. After 5 hours at room temperature, the reaction mixture was mixed with adsorbent (silica gel) and chromatographed with petroleum ether / ethyl acetate (95/5) to give the title compound (1.2 g, 86%) as a white solid. mp 167-168.5 ° C.

NMR (CDCl 3): δ 8.28 (m, 1H); 7.58 to 7.47 (m, 2H); 7.41 to 7.36 (m, 2H); 7.34 to 7.25 (m, 5H); 7.18 (m, IH); 5.11 and 5.02 (two dd, 1H, rotating isomers), 3.66 and 3.63 (two s, 3H, rotating isomers); 3.58 to 3.33 (m, 3H); 2.44 and 2.43 (two s, 3H, rotating isomers); 2.20 (m, IH); 1.95 (m, IH); 7.75 to 1.32 (m, include two singlets at δ 1.63 and 1.69 (rotating isomers), 9H).

MS (EI): [M +], 2-bromo isotopic pattern, 690 (46%), 692 (100%). analysis:

Calcd for C 35 H ₃ Br ₂ O ₃ S 60.70% C, 4.66% H, 0.00% N;

H, 4.64; N, 0.01%.

Reaction Step 3

(2 R) -2- [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-cyclopentyl-phenoxy] -3-phenyl-acid propionic acid

To a solution of (2R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-cyclopentyl-phenoxy] methyl ester - 3-phenyl-propionic acid (1.0 g, 1.5 mmol) in tetrahydrofuran (30 mL) and methanol (10 mL) was added dropwise an aqueous potassium hydroxide solution (3.0 mL, 1 M solution, 3 mL) at room temperature. 0 mmoles). After 4 hours, the reaction mixture was concentrated under reduced pressure. The residue was stirred with water (100 mL) and acidified with a 10% aqueous hydrochloric acid solution. After stirring for 15 minutes, the solid was filtered and washed with water / methanol (95/5). The solid was dried under vacuum at 50 ° C for 18 h to give the title compound (0.99 g, 100%) as a white solid.

Optical rotation [α] _D ²⁵ = + 38.44 ° (at 9.624 mg · ml · ¹ MeOH).

NMR (DMSO-d 6): δ 13.01 (br s, 1H); 8.19 (d, IH); 7.67 to 7.62 (m, 1H); 7.54-7.22 (m, 9H); 4.92 (m, IH); 3.46 (m, IH); 3.34 (m, 2 H); 2.42 and 2.41 (two singlets, ·· ·· ·· ·············

- 111 · (rotating isomers), 1.99 (m, 1H); 1.98 (m, IH); 1.72 to 1.27 (m, includes two s at δ 1.57 and 1.53 (rotating isomers), 6H);

MS (-ESI): [M-H], double bromine isotopic pattern, 675 (72%) 677 (100%), 679 (66%).

Analysis calculated for C34H FIG _{2 3 3} 0 C <60.19% C, 4.46% H, 0.00% N;

H, 4.35; N, 0.04.

Example 49

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl-propionic acid

Step 1 (2-Benzyl-4,5-dimethyl-thiophen-3-yl) - (4-methoxy-3,5-dimethyl-phenyl) -methanone

To a suspension of 3,5-dimethyl-p-anisic acid (15.2 g, 84.4 mmol, RN21553-46-8) in anhydrous methylene chloride (200 mL) was added oxalyl chloride (9.6 mL) at room temperature under a nitrogen atmosphere. ml, 110 mmol) and Ν, im-dimethylformamide (5 drops). After two hours the solvent was removed. The residue was dissolved in anhydrous methylene chloride (200 mL) and added to 2,3-dimethyl-5-benzylthiophene (17.1 g, 84.4 mmol) under nitrogen atmosphere. To the reaction mixture cooled to -78 ° C was added tin tetrachloride (10.8 mL, 92.8 mmol) quickly. The cooling bath (-78 ° C) was then removed and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured onto ice-water (1 L) and the resulting mixture was extracted once with diethyl ether (700 mL) and once with 400 mL of diethyl ether. The combined diethyl ether extracts were washed with ice water (500 mL), dilute sodium bicarbonate solution (500 mL), water (500 mL), brine (1 liter) and then dried (Na ₂ SO 4). Concentration under reduced pressure gave the title compound (25.2 g, 82%) as a yellow oil.

NMR (DMSO-d ₆ ): δ 7.40 (s, 2H); 7.24 to 7.15 (m, 3H); 7.06 (d, 2 H); 3.83 (s, 2 H); 3.70 (s, 3H); 2.28 (s, 3H); 2.26 (s, 6H); 1.83 (s, 3H).

·······················

-112 • · ··· ·············

Reaction Step 2

4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenol

Under a nitrogen atmosphere and cooling to -78 ° C, to (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (4-methoxy-3,5-dimethyl-phenyl) -methanone (25.2 g) was added. , 69.2 mmol) in anhydrous methylene chloride (420 mL) was added boron tribromide (20.9 mL, 221 mmol) dropwise over 16 min and the resulting mixture was stirred at -78 ° C for 1.5 h. The cooling bath (-78 ° C) was then removed and the mixture was stirred at room temperature for 4 hours. The mixture was then poured onto a mixture of ice and water (1 liter) containing a little sodium bisulfite, and the resulting mixture was extracted with diethyl ether (1 liter each, 300 ml each). The combined diethyl ether extracts were washed twice with water (1 liter), brine (1 liter) and then dried (Na 2 SO 4). Concentration under reduced pressure gave a dark residue, which was combined with the remainder of the process again with (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (4-methoxy-3,5-dimethylphenyl) -methanone. (13.9 g, 38.1 mmol) and boron tribromide (11.5 mL, 122 mmol). Adsorption on silica gel and chromatography with petroleum ether / ethyl acetate (90/10) gave a dense amber foam residue, identified as

2,6-Dimethyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (24.0 g, 67% of theory)

NMR (DMSO-d 6): δ 8.41 (s, 2H); 7.93 (d, IH); 7.49 to 7.39 (m, 2H); 7.34-7.28 (m, 1H); 6.87 (s, 2 H); 2.38 (s, 3H); 2.23 (s, 6 H); 1.62 (s, 3H);

MS (EI): [M +] 332.

Reaction Step 3

Acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenyl ester

To a solution of 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenol (24.0 g,

72.2 mmol) in pyridine (200 mL) under a nitrogen atmosphere at 0 ° C was added dropwise acetic anhydride (8.9 mL, 93.9 mmol) dropwise over 10 min. After 45 minutes at 0 ° C, the reaction mixture was placed in the freezer for 18 hours, then removed and stirred for 2 hours with cooling in an ice bath, which was allowed to warm freely to room temperature. The reaction mixture was then poured into water (1 liter) and acidified to pH 1 with 10% hydrochloric acid. The resulting mixture was extracted with diethyl ether, which was washed with 10% acid. ···· ··· · · · · · · · ·

-113 ·· ···· ··· ·· ·· · HCl (1 L), twice with water (1 L), brine (700 ml) and dried _(MgSO4). Concentration under reduced pressure and chromatography with petroleum ether / ethyl acetate (97/3) gave the title compound (22.4 g, 79%) as a cream solid.

NMR (CDCl ₃ ): δ 8.26 (s, 1H); 7.87 (d, IH); 7.58 (d, IH); 7.44 to 7.40 (m, 1H); 7.33 to 7.29 (m, 1H); 7.07 (s, 2 H); 2.42 (s, 3H); 2.41 (s, 3H); 2.23 (s, 6 H); 1.67 (s, 3H). MS (EI): [M +] 374.

analysis:

Calcd for C24H22O2S: C, 76.97; H, 5.92; N, 0.00;

Found: C, 76.17; H, 5.75; N, 0.22.

Reaction Step 4

Acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenyl ester Solution of 4- (2,3-dimethyl-naphtho [ 2,3-b] thiophen-4-yl) -2,6-dimethylphenyl acetic acid ester (10.0 g, 26.7 mmol) and ferric chloride (0.23 g, 1.4 mmol) in anhydrous methylene chloride (231 mL) was stored in a light-protected environment at -78 ° C under nitrogen. A solution of bromine (1.5 mL, 29.4 mmol) in anhydrous methylene chloride (38 mL) was added dropwise over 50 minutes. After 30 minutes, the reaction was quenched by addition of dilute sodium bisulfite solution and dilution with water. The mixture was then extracted with diethyl ether. The diethyl ether layer was washed twice with water, brine and dried (MgSO ₄ ). Concentration under reduced pressure and chromatography with petroleum ether / ethyl acetate (97/3 then 97/5) gave the title compound (6.7 g, 55%) as a white solid.

NMR (DMSO-d ₆ ): δ 8.27 (d, 1H); 7.56 to 7.52 (ddd, 1H); 7.38 to 7.34 (ddd, 1H); 7.06 (s, 2 H); 2.43 (s, 3H); 2.41 (s, 3H); 2.22 (s, 6 H); 1.64 (s, 3H).

MS (EI): [M +], single bromine isotope pattern, 452/454.

analysis:

Calcd for C24H21BrO2S 63.58% C, 4.67% H, 0.00% N;

Found: C, 63.41; H, 4.45; N, 0.08.

················

- 114 ··· ··· ··· ·· ············ · ···

Reaction Step 5

4- (9-bromo-2,3-dimethyl-naphtho [2,3-bjtiofén-4-yl) -2,6-dimethyl-phenol

To a solution of acetic acid 4- (9-bromo-2 ₁ 3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenyl ester (6.5 g, 14.3 mmol) Aqueous potassium hydroxide solution (17.2 mL, 1 M solution, 17.2 mmol) was added dropwise at room temperature in tetrahydrofuran (240 mL) and methanol (80 mL). After stirring at room temperature for 4 hours, the reaction mixture was stored in a freezer for 18 hours. After removal from the freezer, the mixture was stirred and allowed to warm to room temperature. Additional portions of aqueous potassium hydroxide solution (41.5 mL, 1 M solution, 41.5 mmol), tetrahydrofuran (50 mL) and methanol (10 mL) were added. The mixture was diluted with water (500 mL), acidified with 10% aqueous hydrochloric acid, and extracted with diethyl ether. The diethyl ether layer was washed twice with water (500 mL) and dried (MgSO ₄ ). Concentration under reduced pressure gave a residue which was adsorbed on silica gel. Chromatography with petroleum ether / ethyl acetate (97/3 then 95/5) gave the title compound (5.5 g, 93%) as a white solid foam.

NMR (CDCl 3): δ 8.41 (s, 1H); 8.16 (d, IH); 7.64 to 7.54 (m, 2H); 7.46 to 7.40 (m, 1H); 6.89 (s, 2 H); 2.41 (s, 3H); 2.23 (s, 6 H); 1.60 (s, 3H).

MS (-ESI): [M-H], single bromine isotope pattern, 409/411.

Reaction Step 6

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl-propionic acid methyl ester

To a solution of 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenol (5.0 g, 12.1 mmol), methyl ester (S) -2-hydroxy-3-phenylpropionic acid (3.3 g, 18.3 mmol) and triphenylphosphine (4.8 g, 18.3 mmol) in anhydrous benzene (50 mL) under nitrogen atmosphere at room temperature diethyl azodicarboxylate (2.6 mL, 18.3 mmol) was added dropwise over 25 minutes. The reaction mixture was heated with stirring for 2 hours and then stirred at room temperature for 3 days. The crude reaction mixture was adsorbed onto silica gel and chromatographed with petroleum ether / ethyl acetate ((95/5) to give the title compound (4.5 g, 65%) as a white solid foam.

·· · ·· · · · · · · ·

-115 «• · 11 11 11 11 11 11 11 11 11 11

NMR (DMSO-d 6): δ 8.18 (d, 1H); 7.64 (ddd, IH); 7.53 to 7.43 (m, 2H); 7.38 to 7.24 (m, 5H); 7.00 (s. 2H); 4.80 (t, IH); 3.58 (s, 3H); 3.31 (m, 2 H); 2.42 (s, 3H); 2.24 (s. 3H); 2.19 (s, 3H) 1.55 (s, 3H).

MS (EI): [M +], single bromine isotopic pattern, 572/574.

analysis:

Calcd for C 32 H 29 BrO ₃ S 67.01% C, 5.10% H, 0.00% N;

Found: C, 66.33; H, 5.09; N, 0.09.

Analytical HPLC determined the content of the major component (94.39%).

Reaction Step 7

(2 R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl-propionic acid

To a solution of (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl- propionic acid (3.1 g, 5.4 mmol) in tetrahydrofuran (125 mL) and methanol (41 mL) was added dropwise an aqueous potassium hydroxide solution (6.5 mL, 1 M solution, 6.5 mmol) at room temperature. . After 1.5 hours at room temperature, the reaction mixture was stored in a freezer for 18 hours. After removal from the freezer, the mixture was allowed to warm to room temperature with stirring. A further portion of aqueous potassium hydroxide solution (19.5 mL, 1 M solution, 19.5 mmol) was added and the mixture was stirred at room temperature for 9.5 hours. Concentration under reduced pressure gave a residue which was diluted with water (1 liter). The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid and extracted with diethyl ether (700 mL). The diethyl ether layer was washed twice with water (500 mL) and then dried (Na ₂ SO ₄ ). Concentration under reduced pressure and chromatography on silica gel (treated with 2% phosphoric acid in methanol) with petroleum ether / ethyl acetate (90/10 then 86/14) gave the title compound (1.9 g, 64%). ) in the form of a white rigid foam.

Optical rotation [α] D ²⁵ = + 33.38 ° (at 10.035 mg · ml- ¹ MeOH).

NMR (DMSO-d 6): δ 12.90 (broad singlet, 1H); 8.17 (d, IH); 7.63 (ddd, IH); 7.50 to 7.43 (m, 2H); 7.36 to 7.23 (m, 5H); 6.97 (s, 2 H); 4.71 (t, IH); 3.25 (d, 2 H); 2.41 (s, 3H); 2.24 (s. 3H); 2.21 (s, 3H); 1.54 (s, 3H).

·· ···· ·· ··· ·· ·

-116MS (EI): [M +], single bromine isotope pattern, 558/560.

Analysis calculated for C ₃₁ H ₂₇ BrO ₃ S 66.55% C, 4.86% H, 0.00% N;

Found: C, 65.91; H, 5.05; N, 0.09.

Analytical HPLC determined the content of the major component (99.5%).

Example 50

(R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenoxy] -3-phenyl-propionic acid

Step 1 (2-Benzyl-4,5-dimethyl-thiophen-3-yl) - (2,5-diisopropyl-4-methoxy-phenyl) -methanone

In a similar manner to that described in Example 49 for reaction step 1, oxalyl chloride (2.2 g) from 3,5-diisopropyl 1β-anisic acid (5.0 g, 21.2 mmol, RN-117439-59-5). ml, 25.4 mmol), N, N-dimethylformamide (2 drops), 2,3-dimethyl-5-benzylthiophene (4.3 g, 21.2 mmol), tin tetrachloride (5.0 mL, 42.7 mmol) and anhydrous methylene chloride (82 mL) gave the title compound (4.1 g, 45%) as a yellow oil.

NMR (DMSO-d 6): δ 7.47 (s, 2H); 7.23 to 7.12 (m, 3H); 7.02 to 6.99 (m, 2H); 3.86 (s, 2 H); 3.73 (s, 3H); 3.31 to 3.20 (m, 2H); 2.27 (s. 3H); 1.82 (s, 3H); 1.15 (d, 12H).

MS (EI): [M +] 420.

Reaction Step 2

2,6-Diisopropyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol

In a similar manner to Example 49 for reaction step 2, from (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (3,5-diisopropyl-4-methoxy-phenyl) -methanone ( 4.3 g, 10.1 mmol), boron tribromide (3.1 mL, 32.4 mmol) and methylene chloride (60 mL) gave the title compound (1.2 g, 30%) as a yellow foam. .

NMR (DMSO-d 6): δ 8.42 (s, 1H); 8.24 (s, 1 H); 7.94 (d, IH); 7.48 to 7.32 (m, 3H); 6.90 (s, 2 H); 3.45 to 3.35 (m, 2H); 2.38 (s, 3H); 1.57 (s. 3H); 1.15 (d, 12H).

MS (- ESI): [M-H] 387.

······················

-117 ·· ···· ·· ··· ·· ·

Reaction Step 3

(2R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-ifenoxy] -3-phenyl-propionic acid methyl ester

In a similar manner to Example 49 for reaction step 6, from 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-isopropyl-phenol (0.33 g, 0.84 mmol), (S) -2-hydroxy-3-phenylpropionic acid methyl ester (1.5 g, 8.3 mmol), triphenylphosphine (2.2 g, 8.3 mmol), diethyl azodicarboxylate (1.3 mL) , 8.3 mmol) and anhydrous benzene (9.0 mL) was heated in an oil bath (85 ° C) for 18 h to afford the title compound (0.11 g, 24%) as an oil.

NMR (DMSO-d 6): δ 8.45 (s, 1H); 7.96 (d, IH); 7.50 to 7.25 (m, 8H); 7.03 (s, 2 H); 4.54 (t, 1 H); 3.56 (s, 3H); 3.40 to 3.18 (m, 4H); 2.38 (s, 3H); 1.51 (s, 3H); 1.14 and 1.13 (two doublets, 6H, rotating isomers); 1.07 and 1.04 (two doublets, 6H, rotating isomers).

MS (EI): [M &lt; + &gt;] 550.

Reaction Step 4

(2 R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 7, (2R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) - 2,6-diisopropylphenoxy] -3-phenyl-propionic acid (0.11 g, 0.20 mmol), aqueous potassium hydroxide solution (0.39 mL, 1 M solution, 0.39 mmol), terahydrofuran (3 mL) and of methanol (1 mL) gave the title compound (0.10 g, 98%) as a white solid.

NMR (DMSO-d 6): δ 12.97 (br s, 1H); 7.96 (d, 1H); 7.47 to 7.25 (m, 8H); 7.04 (s, 2 H); 4.47 (t, IH); 3.41 to 3.30 (m, 2H); 3.28 to 3.23 (m, 2H); 2.40 (s, 3H); 1.53 (s, 3H); 1.15 (d, 6H); 1.08 (d, 6H).

MS (EI): [M &lt; ⁺ &^gt;] 536

analysis:

Calcd for C 35 H 36 O 3 S 78.32% C, 6.76% H, 0.00% N;

··················

-118% H, 6.86%, -0.11% N. Found: C, 77.12; H, 6.86;

Analytical HPLC determined the content of the major component (93.2%).

Example 51

(R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-fluoro-phenoxy] -3-phenyl-propionic acid

Step 1 (2-Benzyl-4,5-dimethyl-thiophen-3-yl) - (3-fluoro-4-methoxy-phenyl) -methanone

In a similar manner to Example 49 for reaction step 1, from 3-fluoro-p-anisic acid (10.0 g, 58.8), oxalyl chloride (6.2 mL, 71.0 mmol), N, N-dimethylformamide (12 drops), 2,3-dimethyl-5-benzylthiophene (11.9 g, 58.8 mmol), tin tetrachloride (10.3 mL, 88.0 mmol) and anhydrous methylene chloride (130 mL) gave the title compound as a white solid. compound (7.53 g, 68%) as a yellow solid.

MS (+ ESI): [M + H] 355.

analysis:

Calcd for C ₂ H ₁₉ FO ₂ S 71.16% C, 5.40% H, 0.00% N;

Found: C, 70.01; H, 5.43; N, -0.06.

Reaction Step 2

2-Fluoro-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol

In a similar manner to Example 49 for reaction step 2, from (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (3-fluoro-4-methoxy-phenyl) -methanone (7.5 g, 21.2 mmol), boron tribromide (7.0 mL, 74.3 mmol) and methylene chloride (88 mL) gave the title compound (6.7 g, 99%) as a yellow foam.

MS (ESI): [M &lt; + &gt;] 322.

analysis:

Calcd for C ₂₀ H ₅ FOS 74.51% C, 4.69% H, 0.00% N;

Found:% C, 73.96;% H, 4.94;

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

-119 ·· ···· ·· ··· ··

Reaction Step 3

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-fluoro-phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 6, from 2-fluoro-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (1.00 g, 3.1 mmol), (S) -2-hydroxy-3-phenylpropionic acid methyl ester (0.67 g, 3.7 mmol), triphenylphosphine (0.98 g, 3.7 mmol), diethyl azodicarboxylate (0.59 mL) , 3.7 mmol) and anhydrous benzene (20 mL) by heating in an oil bath (85 ° C) for 5 h afforded the title compound (0.86 g) as a white solid, which was used without further purification.

In a similar manner to that described in Example 49 for reaction step 7, (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -acetate -2-fluorophenoxy] -3-phenyl-propionic acid (0.86 g, 1.8 mmol), aqueous potassium hydroxide solution (3.6 mL, 1 M solution, 3.6 mmol), terahydrofuran (12 mL), and methanol (4 mL) gave the title compound (0.41 g, 63%) as a white solid, which had an optical rotation of [α] _D ²⁵ + 0.87 ° at 11.473 mg.m ^{-1 1} MeOH.

MS (EI): [M ⁺ ] 470.

analysis:

Calcd for C ₂₉ H ₂₃ FO ₃ S 74.02% C, 4.93% H, 0.00% N;

Found: C, 73.95; H, 5.22; N, 0.12.

Example 52

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-fluoro-phenoxy] -3-phenyl-propionic acid

Reaction Step 1

Acetic acid 2-fluoro-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester

In a similar manner to that described in Example 49 for reaction step 3, from 2-fluoro-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (1.0 g, 3.1 mmol), acetic anhydride (0.36 mL, 3.8 mmol), and pyridine (7.5 mL) were prepared in the title. ··· ·········· ·

-120 e · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · a substance which was used further without further purification.

NMR (DMSO-d 6): δ 8.49 (s, 1H); 8.00 to 7.96 (d, 1H); 7.48 to 7.31 (m, 4H); 7.20 (s,

2H); 3.10 (septet, 1H); 2.40 (s, 3H); 2.37 (s, 3H); 1.56 (s, 3H); 1.16 (d, 6H).

In a similar manner to that described in Example 49 for reaction step 4, z

Acetic acid 2-fluoro-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester (1.1 g, 2.9 mmol), ferric chloride (24.8 mg, 0.15 mmol), bromine (0.16 mL, 3.2 mmol) and methylene chloride (12 mL) gave the title compound (0.86 g, 67%) as a white solid.

MS (EI): [M ⁺ ], single bromine isotopic pattern, 442/444.

Reaction Step 2

2-Fluoro-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol

In a similar manner as described in Example 49 for reaction step 5, 2-fluoro-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester was substituted acetic acid (0.29 g, 0.65 mmol), aqueous potassium hydroxide solution (0.79 mL, 1 M solution,

0.79 mmol), tetrahydrofuran (12 mL) and methanol (7.5 mL) gave the title compound (0.3 g, 100%) as a solid, off-white solid.

MS (EI): [M ⁺ ], single bromine isotope pattern, 400/402.

Reaction Step 3

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-fluoro-phenoxy] -3-phenyl-propionic acid methyl ester

In a similar manner to that described in Example 49 for reaction step 6, from 2-fluoro-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (0). (29 g, 0.72 mmol), (S) -2-hydroxy-3-phenylpropionic acid methyl ester (0.19 g, 1.1 mmol), triphenylphosphine (0.28 g, 1.1 mmol), of diethyl azodicarboxylate (0.17 mL, 1.1 mmol) and anhydrous benzene (5.0 mL) gave the title compound (0.23 g, 58%) as a white solid.

MS (EI): [M ⁺ ], single bromine isotope pattern, 562/564.

-121 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ···

Reaction Step 4

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-fluoro-phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 7, from (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophene-4-) methyl ester yl) -2-fluorophenoxy] -3-phenyl-propionic acid (0.23 g, 0.41 mmol), aqueous potassium hydroxide solution (0.50 mL, 1 M solution, 0.50 mmol), terahydrofuran (6 mL) and methanol (2 mL) gave the title compound (0.17 g, 74%) as a white solid.

MS (EI): [M ⁺ ], single bromine isotope pattern, 548/550.

analysis:

calcd for C ₂₉ H22BrFO ₃ S 63.39% C, 4.04% H, 0.00% N;

Found: C, 62.14; H, 4.29; N, 0.16.

Analysis of the major component (82.5%) was determined by HPLC analysis.

Example 53

[4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenoxy] -acetic acid

Reaction Step 1

Acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenyl ester

In a similar manner to that described in Example 49 for reaction step 3, from 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenol (3.0 g, 13.7 mmol), acetic anhydride (1.68 mL, 17.8 mmol) and pyridine (85 mL) gave the title compound (5.37 g, 91%) as a white solid. mp 243-245 ° C.

NMR (DMSO-d ₆ ): δ 8.49 (s, 1H); 7.98 (d, IH); 7.49 to 7.39 (m, 3H); 7.16 (s, 2 H); 3.01 (septet, 1H); 2.43 (s, 3H); 2.41 (s, 3H); 1.56 (s, 3H); 1.16 (d, 12H).

MS (EI): [M &lt; ⁺ &^gt;] 430.

analysis:

Calculated for C ₂ eH ₃ o0 ₂ S 78.10% C, 7.02% H, 0.00% N;

Found: C, 77.95; H, 7.04; N, 0.07.

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

The content of the main component (99.3%) was determined by HPLC analysis.

Reaction Step 2

Acetic acid 4- (9-bromo-2,3-dimethylnaphtho [2,3-b] thiophen-4-yl) -2,6-diisopropylphenyl ester

In a similar manner to that described in Example 49 for reaction step 4, acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenyl ester ( 0.80 g, 18.5 mmol), ferric chloride (16 mg, 0.1 mmol), bromine (0.13 mL, 2.6 mmol) and methylene chloride (19 mL) gave the title compound (0.53 g, 56% of theory) as a white solid.

NMR (DMSO-d 6): δ 8.21 (d, 1H); 7.68 to 7.62 (m, 1H); 7.60 to 7.42 (m, 2H); 7.18 (s, 2 H); 3.00 (septet, 2H); 2.42 (s, 6H); 1.53 (s, 3H); 1.14 (d, 12H).

Reaction Step 3

4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenol

In a similar manner to that described in Example 49 for reaction step 5, 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenyl acetic acid ester (0.52 g, 1.0 mmol), aqueous potassium hydroxide solution (1.64 mL of 1 M solution, 1.64 mmol), tetrahydrofuran (18.5 mL), and methanol (11.5 mL) were prepared. The title compound (0.45 g, 95% of theory) as a cream solid having a melting point of 212-216 ° C.

NMR (DMSO-d 6): 8.30 (s, 1H); 8.17 (d, IH); 7.61 (ddd, IH); 7.53 (d, IH); 7.44 (ddd, IH); 6.92 (s, 2 H); 3.41 (septet, 2H); 2.41 (s, 3H); 1.55 (s, 3H); 1.15 (d, 12H).

MS (EI): [M ⁺ ], single bromine isotope pattern, 466/468.

analysis:

Calcd for C ₂₆ H ₂ 7Bros 66.80% C, 5.82% H, 0.00% N;

Found: C, 66.17; H, 5.63; N, 0.06.

Reaction Step 4

[4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenoxy] -acetic acid methyl ester

-123 -

· · • · · · • · ·· · • · · · · • · · • · • • · · • · · · ···· ·· ··· • e ·

A solution of 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenol (0.42 g, 0.89 mmol), methyl bromoacetate ( 0.36 mL, 3.8 mmol), and potassium carbonate (0.42 g, 3.0 mmol) in anhydrous N, N -dimethylformamide (3.5 mL) were stirred at room temperature for 2 days under a protective atmosphere. nitrogen. The reaction mixture was then diluted with water and extracted with diethyl ether. Concentration under reduced pressure and chromatography with petroleum ether / ethyl acetate (95/5) gave the title compound (0.42 g, 87%) as a white solid. NMR (DMSO-d 6): 8.20 (d, 1H); 7.66 to 7.61 (m, 1H); 7.48 (d, 2 H); 7.11 (s, 2 H); 4.56 (s, 2 H); 3.77 (s, 3H); 3.42 to 3.27 (m, 2H); 2.42 (s, 3H); 1.51 (s, 3H); 1.18 and 1.16 (two doublets, 12H).

Reaction Step 5

[4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenoxy] -acetic acid

In a similar manner to that described in Example 49 for reaction step 7, [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6- diisopropylphenoxyacetate (0.40 g, 0.74 mmol), aqueous potassium hydroxide solution (0.89 mL, 1 M solution, 0.89 mmol), terahydrofuran (6 mL), and methanol (2 mL) were prepared as described above. compound (0.37 g, 95%) as a white solid, mp 228-231 ° C.

NMR (DMSO-d 6): δ 12.98 (br s, 1H); 8.19 (d, IH); 7.65 to 7.61 (m, 1H); 7.47 (d, 2 H); 7.10 (s, 2 H); 4.44 (s, 2 H); 3.40 (septet, 2H); 2.41 (s, 3H); 1.51 (s, 3H); 1.18 and 1.16 (two doublets, 12H).

MS (EI): [M ⁺ ], single bromine isotope pattern, 524/526.

analysis:

Calcd for C 28 H 29 BrO 3 S 64.00% C, 5.56% H, 0.00% N;

found 63.32% C, 5.39% H, 0.01% N.

HPLC analysis determined the major component content (96%).

Example 54

(2 R) -2- [2,6-Dibromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -phenoxy] -3-phenyl-propionic acid;

·································

-124a · · ··· · · · ··· ·· ··· ··

Reaction Step 1 (2-Benzyl-4,5-dimethyl-furan-3-yl) - (4-methoxy-3,5-dibromo-phenyl) -methanone

In a similar manner to that described in Example 49 for reaction step 1, z

3-dibromo-β-anisic acid (8.0 g, 25.8 mmol), oxalyl chloride (2.48 mL, 28.4 mmol), N, N -dimethylformamide (2 drops), 2,3- dimethyl 5-benzylfuran (5.77 g, 31.0 mmol), tin tetrachloride (3.30 mL, 28.4 mmol), and anhydrous methylene chloride (165 mL) gave the title compound (2.92 g, 24%). theoretical yield) as a solid.

NMR (DMSO-d 6): δ 7.81 (s, 2H); 7.28 to 7.14 (m, 3H); 7.04 (d, 2 H); 3.86 (s, 3H); 3.84 (s, 2 H); 2.19 (s, 3H); 1.81 (s, 3H).

MS (EI): [M ⁺ ], two bromine isotopic pattern, 476 (25%), 478 (50%); 480 (25%).

Reaction Step 2

4- (2,3-Dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-dibromophenol

In a similar manner to Example 49 for reaction step 2, from (2-benzyl-4,5-dimethyl-furan-3-yl) - (4-methoxy-3,5-dibromo-phenyl) -methanone (2). , 52 g, 5.30 mmol), boron tribromide (3.79 mL, 40.0 mmol) and methylene chloride (18 mL) gave the title compound (0.93), which was used without further purification.

NMR (DMSO-d 6): δ 10.19 (br s, 1H); 8.01 (d, IH); 7.98 (s, IH); 7.56 (s, 2 H); 7.51 (d, IH); 7.44 (ddd, IH); 7.36 (ddd, IH); 2.39 (s, 3H); 1.62 (s, 3H).

MS (-ESI): [M-H], double bromine isotopic pattern, 443 (63%), 445 (100%); 447 (63%).

Reaction Step 3

(2 R) -2- [2,6-Dibromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -phenoxy] -3-phenyl-propionic acid methyl ester

In a similar manner to that described in Example 49 for reaction step 6, z

4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-dibromo-phenol (0.88 g, 1.97 mmol), methyl ester of ( S) -2-hydroxy-3-phenylpropionic (0.71 g, 3.94 φ φ • • • • · · ·)

- 125 · · φ · mm · · · olu · olu · mm · mm mm mm olu mmol), triphenylphosphine (1.03 g, 3.94 mmol), diethyl azodicarboxylate (0.62 mL, 3.94 mmol) and anhydrous benzene (3.9 mL) at room temperature gave the title compound (0.15 g, 96%) as a solid.

NMR (DMSO-d 6): δ 8.04 (d, 1H); 8.03 (s, 1 H); 7.71 (s, 2 H); 7.51-7.24 (m, 8H); 5.11 (dd, IH); 3.63 (s, 3H); 3.53 to 3.35 (two overlapping quartets, ABX characteristic, 2H); 2.41 (s, 3H); 1.60 (s, 3H).

MS (EI): [M +], two bromine isotopic pattern, 606 (52%), 608 (100%); 610 (52%).

Reaction Step 4

(2R) -2- [2,6-Dibromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 7, from (2R) -2- [2-bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-) methyl ester yl) -phenoxy] -3-phenyl-propionic acid (0.25 g, 0.41 mmol), aqueous potassium hydroxide solution (0.82 mL, 1 M solution, 0.82 mmol), terahydrofuran (3.0 mL) and methanol (1 mL) gave the title compound (0.24 g, 100%) as a white solid.

NMR (DMSO-d 6): δ 13.11 (br s, 1H); 8.02 (d, IH); 8.01 (s, 1 H); 7.66 (s, 2 H); 7.49 to 7.21 (m, 8H); 5.19 (t, IH); 3.36 (m, 2 H); 2.39 (s, 3H); 1.58 (s, 3H).

MS (EI): [M ⁺ ], double bromine isotopic pattern, 592 (50%), 594 (100%), 596 (50%).

analysis:

calcd for C 9 H _{2 2 2} 2 Br O4 58.61% C, 3.73% H, 0.00% N;

H, 4.01; N, 0.05%.

Example 55

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-1-phenoxy] -3-phenyl acid propionic acid

-126 »· ·· ··

9 · · · · ·

9 9 9 9

9

9 • · · · · · · · · · · · ·

Reaction Step 1

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenoxy] -3-phenyl- propionic acid

In a similar manner to that described in Example 49 for reaction step 6, 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl- phenol (0.46 g, 0.98 mmol), (S) -2-hydroxy-3-phenylpropionic acid methyl ester (0.70 g, 3.9 mmol), triphenylphosphine (1.02 g, 3.9 mmol) diethyl azodicarboxylate (0.62 mL, 3.9 mmol) and anhydrous benzene (1.0 mL) by heating in an oil bath (90 ° C) for 24 h afforded the title compound (0.20 g, 32%). in the form of a white solid.

NMR (DMSO-d 6): δ 8.19 (d, 1H); 7.65 to 7.60 (m, 1H); 7.50 to 7.40 (m, 2H); 7.38-7.27 (m, 5H); 7.06 (s, 2 H); 4.55 (t, 1 H); 3.55 (s, 3H); 3.35 to 3.19 (m, 4H); 2.41 (s, 3H); 1.49 (s, 3H); 1.13 (d, 6H); 1.06 and 1.04 (two doublets, 6H, rotating isomers).

Reaction Step 2

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 7, (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -acetate -2,6-diisopropyl-phenoxy] -3-phenyl-propionic acid (0.20 g, 0.3 mmol), aqueous potassium hydroxide solution (1.2 mL, 1 M solution, 1.2 mmol), terahydrofuran ( 3 mL) and methanol (1 mL) gave the title compound (0.18 g, 93%) as a white solid, mp 222-226 ° C.

NMR (DMSO-d 6): δ 13.0 (br s, 1H); 8.20 (d, IH); 7.64 (ddd, IH); 7.48 to 7.46 (m, 2H); 7.38-7.27 (m, 5H); 7.06 (s, 2 H); 4.48 (t, IH); 3.40-3.26 (m, 4H); 2.42 (s, 3H); 1.50 (s. 3H); 1.14 (d, 6H); 1.07 (d, 6H).

MS (-ESI): [M-H], single bromine isotopic pattern, 558/560.

analysis:

Calcd for C 6 H 8 BrO 6 S 68.28% C, 5.73% H, 0.00% N;

Found: C, 68.15; H, 5.83; N, 0.03.

The content of the main component (100%) was determined by analytical HPLC.

- 127 ·· ·· ·· · · · · · · ·

9 · · · ·············

Example 56 [3-Bromo-5- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-hydroxy-phenyl] -carbamic acid tert-butyl ester

A solution of 2-amino-6-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (0.382 g, 0.801 mmol) and di-tert- of butyl dicarbonate (0.191 g, 0.875 mmol) in THF (0.83 mL) was heated at 70 ° C for 15 h. The reaction mixture was then diluted with ether and silica gel was added. The ether was removed and the adsorbate was flash chromatographed (9/1 petroether / ethyl acetate) to give the title compound (0.447 g, 98%) as a white solid, mp 205-207 ° C. .

NMR (DMSO-d 6): δ 9.61 (s, 1H); 8.55 (2, 1 H); 8.19 (d, J = 8 Hz, 1H); 7.65 (ddd, J = 8.6, 2 Hz, 1H); 7.52 to 7.46 (m, 3H); 7.27 (d, J = 2Hz, 1 H); 2.44 (d, J = 1Hz, 3H); 1.67 (d, J = 1Hz, 3H); 1.40 (s, 9H).

MS (EI): [MH], double bromine isotopic pattern, 575 (20%, M +), 577 (50%, M +), 579 (20%, M +), 519 (50%, M + H-tertBu), 521 (100%, M + H-tertBu), 523 (55%, M + H-tertBu).

analysis:

Calcd for C 2 H _{5 2} 3 Br ₂ NO ₃ S 52.01% C, 4.02% H, 2.43% N;

H, 3.84; N, 2.28.

Example 57

9-Bromo-4- (3-bromo-methoxy-5-nitro-phenyl) -2,3-dimethyl-naphtho [2,3-b] thiophene

To a solution of 9-bromo-4- (3-bromo-methoxy-5-nitro-phenyl) -2,3-dimethyl-naphtho [2,3-b] thiophene (0.600 g, 1.183 mmol) in DMF (8 mL) iodomethane (0.22 mL, 3.55 mmol) and potassium carbonate (0.490 g, 3.55 mmol) were added under stirring at room temperature. After 7 hours, an additional portion of iodomethane (0.1 mL, 1.61 mmol) was added and the suspension was stirred for an additional 17 hours. The reaction mixture was then poured into water and extracted with ether. Silica gel was added. The ether was removed and the adsorbate was flash chromatographed (95/5 petroleum ether / ethyl acetate) to give the title compound as a white solid.

-128 99 999 compound (0.416 g, 67% of theory) as a yellow solid having a yellow solid. mp 204-205 ° C.

NMR (DMSO-d 6): δ 8.23 (d, J = 2 Hz, 1H); 8.04 (d, J = 2Hz, 1 H); 7.69 (ddd, J = 8.6, 1 Hz, 1H); 7.53 (ddd, J = 8.6, 1 Hz, 1H); 7.47 (d, J = 8Hz, 1H); 4.05 (s. 3H); 2.45 (d, J = 1Hz, 3H); 1.62 (d, J = 1Hz, 3H).

MS (FAB +): double bromine isotopic pattern, 519, 521, 523.

analysis:

Calcd for C ₂₁ H ₁₅ Br ₂ NO ₃ S 48.39% C, 2.90% H, 2.69% N;

H, 2.69; N, 2.58.

Example 58

3-Bromo-5- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-methoxy-phenylamine

A suspension of 9-bromo-4- (3-bromo-methoxy-5-nitro-phenyl) -2,3-dimethyl-naphtho [2,3-b] thiophene (0.372 g, 0.714 mmol), stannous chloride (805 mg, 3.57 mmol) and ethyl acetate (4 mL) was heated to 70 ° C until the reactants dissolved. After 30 minutes, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and silica gel was added. The ethyl acetate was removed and the adsorbate was flash chromatographed (4/1 petroleum ether / ethyl acetate) to give the title compound (0.324 g, 92%) as a white solid, m.p. 198-200 ° C. C.

NMR (DMSO-d 6): δ 8.18 (d, J = 8 Hz, 1H); 7.64 (ddd, J = 8.6, 1H, 1H); 7.58 (d, J = 8 Hz, 1H); 7.50 (ddd, J = 8.6, 1 Hz, 1H); 6.70 (d, J = 2Hz, 1 H); 6.64 (d, J = 2Hz, 1 H); 5.46 (s, 1 H); 3.80 (s, 3H); 2.44 (d, J = 1Hz, 3H); 1.73 (d, J = 1Hz, 3H).

MS (EI): double bromine isotopic pattern, 489 (50%, M +), 491 (100%, M +), 493 (60%, M +).

analysis:

Calcd for C ₂₁ H ₁₇ Br ₂ NOS 51.34% C, 3.49% H, 2.85% N;

H, 3.43; N, 2.71.

··· · ··· · ·• e ···· · · ·

-1299 ·· ············································································

Example 59

[3-Bromo-5- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-methoxy-phenylamino] -acetic acid methyl ester

To a suspension of 3-bromo-5- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-methoxyphenylamine (0.260 g, 0.529 mmol) and potassium carbonate (0.411 g) 3.00 mmol) in DMF (1.7 mL) was added methyl bromoacetate (0.285 mL, 3.01 mmol) with stirring at room temperature. After two days, an additional portion of methyl bromoacetate (0.135 mL, 1.5 mmol) was added and the reaction stirred for one more day. It was then poured into water and the solid was filtered and washed with water. The solid was triturated in petroleum ether and dried at 60 ° C under vacuum to give the title compound (0.212 g, 71%) as a white solid, mp 194-198 ° C.

NMR (DMSO-d 6): δ 8.17 (dd, J = 8.1 Hz, 1H); 7.63 (ddd, J = 8.6, 1 Hz, 1H); 7.53 to 7.45 (m, 2H); 6.77 (d, J = 2Hz, 1 H); 6.54 (d, J = 2Hz, 1 H); 6.10 (t, J = 7Hz, 1H); 3.97 (dd, J = 7.4 Hz, 2H); 3.83 (s, 3H); 3.52 (s, 3H); 2.43 (s, 3H); 1.69 (s, 3H). MS (FAB +): double bromine isotopic pattern, 561, 563, 565.

analysis:

Calcd for C ₂₄ H 21 Br ₂ NO ₃ S 51.17% C, 3.76% H, 2.49% N;

Found: C, 50.43; H, 3.63; N, 2.53.

Example 60

[3-Bromo-5- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-methoxy-phenylamino] -acetic acid

To a solution of [3-bromo-5- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-methoxy-phenylamino] -acetic acid methyl ester (0.180 g, 0.320 mmol) in THF (2.5 mL) was added aqueous potassium hydroxide solution (0.64 mL, 1 M solution, 0.64 mmol) with stirring at room temperature. After 4 hours the solvent was removed and water was added. The suspension was acidified and extracted with ether. Silica gel was added. The ether was removed and the adsorbate was flash chromatographed (gradient: 7/3 petroleum ether / ethyl acetate to 9/1 ethyl acetate / methanol) to give the title compound.

9 · · · · · · ·

The compound (0.112 g, 64%) was obtained as a white solid, m.p. > 190 ° C ( dec).

NMR (DMSO-d 6): δ 8.16 (d, J = 8 Hz, 1H); 7.63 (ddd, J = 8.6, 1 Hz, 1H); 7.56 (d, J = 8Hz, 1H); 7.48 (ddd, J = 8.6, 1 Hz, 1H); 6.72 (d, J = 2Hz, 1 H); 6.43 (d, J = 2Hz, 1 H); 5.74 (broad s, 1H); 3.83 (s, 3H); 3.46 (s, 2 H); 2.42 (s, 3H); 1.71 (s, 3H).

MS (FAB +): double bromine isotopic pattern, 547, 549, 551.

analysis:

Calcd for C ₂₃ H ₁₉ Br ₂ NO ₃ S 50.29% C, 3.49% H, 2.55% N;

H, 3.73; N, 2.26.

Example 61

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenoxy] -3-phenyl-propionic acid

Step 1 (2-Benzyl-4,5-dimethyl-thiophen-3-yl) - (4-methoxy-3,5-diethylphenyl) methanone

In a similar manner to that described in Example 49 for reaction step 1, z

3,5-diethyl-β-anisic acid (9.45 g, 45.4 mmol, prepared by the method of J. Lipowitz and T. Cohen, J. Org. Chem. 30, 3891-3894 (1965); CK Bradsher et al. J. Am. Chem. Soc., 76, 2357-2362 (1954), CK Brasher et al., Org., Prep. Proced. Int. 18, 2213-2215 (1986), oxalyl chloride (4.4 ml, 49). , 9 mmol), N, N -dimethylformamide (2 drops), 2,3-dimethyl-5-benzylthiophene (11.0 g, 54.5 mmol), tin (II) chloride (5.8 mL, 49.9 mmol) ) and anhydrous methylene chloride (291 mL) gave the title compound (17.7 g, 99%) as an oil.

NMR (DMSO-d ₆ ): δ 7.43 (s, 2H); 7.24 to 7.11 (m, 3H); 7.07 to 7.01 (m, 2H); 3.85 (s, 2 H); 3.70 (s, 3H); 2.62 (q, 4H); 2.26 (s, 3H); 1.83 (s, 3H); 1.14 (t, 6 H).

Reaction Step 2

4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenol

-131 ·· ··································

In a similar manner to Example 49 for reaction step 2, from (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (4-methoxy-3,5-diethyl-phenyl) -methanone (17). , 67 g, 45.0 mmol), boron tribromide (12.8 mL, 135.4 mmol) and methylene chloride (90 mL) gave the title compound (16.6 g), which was used in the next work without purification.

NMR (DMSO-d ₆ ): δ 8.41 (s, 1H); 8.31 (s, 1 H); 7.93 (d, IH); 7.47 (d, IH); 7.42 (ddd, IH); 7.32 (ddd, IH); 6.86 (s, 2 H); 2.76 to 2.56 (complex m, ABX characteristic, 4H); 2.39 (s, 3H); 1.60 (s, 3H); 1.14 (t, 6 H).

MS (+ ESI): [M] &lt; + &gt; 360.

Reaction Step 3

Acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenyl ester

In a similar manner to Example 49 for reaction step 3, from 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenol (16.6 g, 46 mmol), acetic anhydride (5.66 mL, 59.9 mmol), pyridine (92 mL) and methylene chloride (92 mL) prepared a residue which was triturated in acetone / hexane (1/1) to give title compound (6.85 g, 37%) as a solid.

NMR (DMSO-d 6): δ 8.47 (s, 1H); 7.97 (d, IH); 7.49 to 7.34 (m, 3H); 7.11 (s, 2 H); 2.60 to 2.46 (m, 4H); 2.40 (two overlapping s, 6H); 1.59 (s. 3H); 1.13 (t, 6 H).

MS (+ ESI): [M + H] 403;

analysis:

Calcd for C 26 H 28 Cl 2 S 77.57%, H 6.51%, N 0.00%;

Found: C, 76.46; H, 6.60; N, 0.19.

Reaction Step 4

Acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenyl ester

In a similar manner to that described in Example 49 for reaction step 4, acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenyl ester ( 1.0 g, 2.5 mmol), ferric chloride (20 mg, 0.12 mmol), bromine (2.7 mL, 2.7 mmol) and

Methylene chloride (25 mL) gave the title compound (1.2 g, 100%) as a solid.

NMR (DMSO-d 6): δ 8.20 (d, 1H); 7.68 to 7.61 (m, 1H); 7.49 (d, 2 H); 7.13 (s, 2 H); 2.60 to 2.47 (m, 4H); 2.42 (s, 3H); 2.40 (s, 3H); 1.56 (s, 3H); 1.13 (t, 6 H). MS (+ APCI): [M + H], single bromine isotopic pattern, 481/483.

analysis:

Calcd for C ₂₆ H ₂₅ BrO ₂ S 64.86% C, 5.23% H, 0.00% N;

found: C 63.06, H 5.13, N 0.03.

Reaction Step 5

4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenol

In a similar manner to that described in Example 49 for reaction step 5, from 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenyl ester acetic acid (1.0 g, 2.1 mmol), aqueous potassium hydroxide solution (2.5 mL, 1 M solution, 2.5 mmol), tetrahydrofuran (29.7 mL) and enough methanol to form a homogeneous solution were prepared in the title compound (0.83 g, 91%) as a solid.

NMR (DMSO-d 6): δ 8.36 (s, 1H); 8.16 (d, IH); 7.61 (ddd, 1H); 7.55 (d, IH); 7.44 (ddd, IH); 6.88 (s, 2 H); 2.76 to 2.56 (complex m, ABX characteristic, 4H); 2.41 (s, 3H); 1.58 (s, 3H); 1.14 (t, 6 H).

MS (+ APCI): [M + H], single bromine isotope pattern, 439/441.

Reaction Step 6

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenoxy] -3-phenyl-propionic acid methyl ester

In a similar manner to Example 49 for reaction step 6, from 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenol (0.83 g, 1.89 mmol), (S) -2-hydroxy-3-phenylpropionic acid methyl ester (2.72 g, 15.0 mmol), triphenylphosphine (3.96 g, 15.0 mmol), diethyl azodicarboxylate (2.36 mL, 15.0 mmol) and anhydrous benzene (40.0 mL) at room temperature gave the title compound (0.74 g, 65%) as a solid.

9 9

-133 ·· ·· ···· ·· ·· ·· ·

NMR (DMSO-d 6): δ 8.18 (d, 1H); 7.66 to 7.60 (m, 1H); 7.48 to 7.44 (m, 2H); 7.37 to 7.23 (m, 5H); 7.01 (s, 2 H); 4.69 (t, IH); 3.55 (s, 3H); 3.29 (m, 2 H); 2.74 to 2.45 (m, 4H); 2.41 (s, 3H); 1.53 (s, 3H); 1.09 and 1.08 (two t, 6H).

MS (+ APCI): [M + H], single bromine isotope pattern, 601/603

Reaction Step 7

(2 R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 7, (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -acetate -2,6-diethylphenoxy] -3-phenyl-propionic acid (0.70 g, 1.16 mmol), aqueous potassium hydroxide solution (2.3 mL, 1 M solution, 2.3 mmol), terahydrofuran (11, 6 mL) and enough methanol to give a homogeneous solution of the solids and recrystallized from hexane / acetone to afford the title compound (0.15 g, 22%) as a white solid.

NMR (DMSO-d 6): δ 12.91 (br s, 1H); 8.18 (d, IH); 7.63 (ddd, IH); 7.51 to 7.42 (m, 2H); 7.36-7.22 (m, 5H); 7.00 (s. 2H); 4.62 (t, IH); 3.25 (d, 2 H); 2.74 (complex m, ABX characteristic, 1H); 2.66 (complex m, ABX characteristic, 2H); 2.55 (complex m, ABX characteristic, 1H); 2.41 (s, 3H); 1.53 (s, 3H); 1.10 (t, 6H).

MS (-ESI): [M-H], single bromine isotope pattern, 585/587.

analysis:

Calcd for C ₃₃ H ₃₁ BrO ₃ S 67.46% C, 5.32% H, 0.00% N;

Found: C, 66.84; H, 5.24; N, 0.13.

Example 62

{(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl-propionylamino} - acid

(2 R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl-propionic acid ( 0.5 g, 0.89 mmol), 1- (3-dimethyl) hydrochloride, · · · · ··· ··· ··· ···

-134 aminopropyl) -3-ethylcarbodiimide (0.34 g, 1.77 mmol), glycine ethyl ester hydrochloride (0.24 g, 1.72 mmol), potassium carbonate (0.50 g, 3.62 mmol) and methylene chloride (6 mL) were stirred at room temperature. After three days, the reaction mixture was diluted with methylene chloride, washed twice with water, once with brine, and then dried (Na ₂ SO ₄ ). Adsorption on silica gel and chromatography with hexane / ethyl acetate (75/25) gave a solid (0.4 g), which was treated with potassium hydroxide (1.11 mL, 1 M solution, 1.11 mmol), tetrahydrofuran ( 8.9 ml) and sufficient methanol to form a homogeneous solution. After 24 hours at room temperature, the reaction mixture was diluted with diethyl ether, washed once with aqueous hydrochloric acid (1 M solution), twice with water, once with brine, and then dried (Na ₂ SO ₄ ). Concentration under reduced pressure and recrystallization from hexane / ethyl acetate gave a white solid (0.20 g, 36%).

NMR (DMSO-d 6): δ 12.58 (br s, 1H); 8.53 (t, IH); 8.18 (d, IH); 7.64 (ddd, IH); 7.52 to 7.43 (m, 2H); 7.34 to 7.19 (m, 5H); 6.92 (s, 2 H); 4.87 (t, IH); 3.88 to 3.70 (two overlapping quartets, ABX characteristic, 2H); 3.31 to 3.10 (two overlapping quartets, ABX characteristic, 2H); 2.43 (s, 3H); 2.23 (s. 3H); 2.19 (s, 3H); 1.56 (s, 3H).

MS (+ APCI): [M + H], single bromine isotopic pattern, 616/618.

analysis:

Calcd for C ₃ H ₃ BrNO ₄ S 64.29% C, 4.90% H, 2.27% N;

Found: C, 63.97; H, 4.48; N, 2.03.

Example 63

{(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenoxy] -3-phenyl-propionylamino] - acid

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenoxy] -3-phenyl- propionic acid (0.48 g, 0.82 mmol), oxalyl chloride (0.071 g, 0.81 mmol) and benzene (16.3 mL) were stirred at room temperature for 40 minutes. Glycine ethyl ester hydrochloride (0.14 g, 1.0 mmol) and potassium carbonate (0.36 g, 2.6) were added.

-135 ·············); the resulting mixture was stirred at room temperature overnight. The reaction mixture was adsorbed onto silica gel and chromatographed with hexane / ethyl acetate (90/10) to give a solid (0.17 g) which was further treated with potassium hydroxide (1.32 mL, 1.0 M solution, 1.32 mmol), tetrahydrofuran (10 mL) and enough methanol to give a homogeneous solution. After stirring at room temperature for about 30 minutes, the reaction mixture was diluted with diethyl ether, washed once with 1 M aqueous hydrochloric acid solution, once with water, once with brine, and then dried (Na ₂ SO ₄ ). The solution was concentrated under reduced pressure, the residue was dissolved in methylene chloride and dried (Na ₂ SO ₄ ). Concentration under reduced pressure gave a white solid (0.14 g, 26%).

NMR (DMSO-d ₆ ): δ 12.51 (br s, 1H); 8.49 (t, IH); 8.17 (d, IH); 7.62 (ddd, IH); 7.46 (d, 2 H); 7.32 to 7.17 (m, 5H); 6.95 (s, 1 H); 6.94 (s, 1 H); 4.73 (t, IH); 3.85 to 3.68 (two overlapping quartets, ABX characteristic, 2H); 3.30 to 3.10 (two overlapping quartets, ABX characteristic, 2H); 2.80 to 2.50 (complex m, ABX characteristic, 4H); 2.41 (s, 3H); 1.54 (s. 3H); 1.06 (t, 6 H).

MS (-ESI): [M-H], single bromine isotopic pattern, 642/644.

analysis:

Calcd for C 8 H 11 BrNCl 2 C 65.21, H 5.32, N 2.17;

H, 5.36; N, 2.07.

Example 64

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3-phenyl-propionic acid

Reaction Step 1

(2 R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3-phenyl-propionic acid methyl ester

In a similar manner to that described in Example 49 for reaction step 6, from 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (5.13 g, (S) -2-hydroxy-3-phenylpropionic acid methyl ester (4.8 g, 26.6 mmol), triphenylphosphine (7.0 g, 26.7 mmol), diethyl azodicarboxylate (4.2 mL) (26.7 mmol) and anhydrous.

-136 and benzene (74.0 mL) at room temperature prepared the title compound (74.0 mL) at room temperature. 4.8 g (66% of theory) as a solid.

NMR (DMSO-d 6): δ 8.17 (d, J = 8 Hz, 1H); 7.62 (ddd, J = 1.6, 8 Hz, 1H); 7.50 to 7.20 (m with doublet included at δ 7.22 (J = 8 Hz), 9H); 7.01 (d, J = 8Hz, 2H); 5.25 (dd, J = 5.7 Hz, 1H); 3.67 (s, 3H); 3.25 (complex m, ABX characteristic, 2H); 2.41 (s, 3H); 1.51 (s, 3H).

MS (+ APCI): [M + H] ⁺ , monobromo isotope pattern, 545/547.

analysis:

Calcd for C 30 H 25 BrO ₃ S 66.06% C, 4.62% H, 0.00% N;

Found: C, 66.15; H, 4.82; N, -0.11.

Reaction Step 2

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 7, from (2 R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophene-4) methyl ester -yl) -phenoxy] -3-phenyl-propionic acid (0.6 g, 1.10 mmol), aqueous potassium hydroxide solution (1.3 mL, 1 M solution, 1.3 mmol), terahydrofuran (15.7 mL), and sufficient methanol to give a homogeneous solution gave the title compound (0.58 g, 99%) as a solid.

NMR (DMSO-d6): δ 13.14 (broad s, 1H); 8.17 (d, J = 8Hz, 1H); 7.62 (ddd, J = 1.6, 8 Hz, 1H); 7.48 to 7.20 (m containing doublet at δ 7.22 (J = 8 Hz), 9H); 7.00 (d, J = 8Hz, 2H); 5.08 (dd, J = 5.8 Hz, 1H); 3.32 to 3.15 (two overlapping quartets, ABX characteristic, 2H); 2.41 (s, 3H); 1.53 (s, 3H).

MS (+ APCI): [M + H] ⁺ , single bromine isotopic pattern, 531/533.

analysis:

calcd for C 9 H ₂₃ BrO ₂ S ₃ 65.54% C, 4.36% H, 0.00% N;

Found: C, 65.51; H, 4.61; N, 0.09.

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

-137 • · · ·························

Example 65

(2S) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl-propionic acid

Reaction Step 1

(2S) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl-propionic acid methyl ester

In a similar manner to Example 49 for reaction step 6, from (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenol (10 (4 g, 25.4 mmol), (S) -2-hydroxy-3-phenylpropionic acid methyl ester (13.7 g, 76.0 mmol), triphenylphosphine (20.0 g, 76.3 mmol), diethyl azodicarboxylate ( 12.0 mL, 76.2 mmol) and anhydrous THF (139 mL) at room temperature gave the title compound (8.66 g, 59%) as a sticky foam. Optical rotation [α] ²⁵ D = - 44.19 ° (at 9.188 mg.ml ^-1 MeOH).

NMR (DMSO-d 6): δ 8.18 (d, J = 8 Hz, 1H); 7.62 (ddd, J = 2.6, 8 Hz, 1H); 7.51 to 7.42 (m, 2H); 7.36 to 7.23 (m, 5H); 6.98 (s, 2 H); 4.78 (t, J = 7Hz, 1H); 3.56 (s, 3H); 3.29 (m, 2 H); 2.41 (s, 3H); 2.22 (s, 3H); 2.17 (s. 3H); 1.54 (s, 3H).

MS (+ APCI): [M + H], single bromine isotopic pattern, 573/575.

analysis:

Calcd for C ₃ H 29 BrO ₃ S 67.01% C, 5.10% H, 0.00% N;

Found: C, 66.72; H, 4.86; N, 0.12.

Reaction Step 2

(2S) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 7, (2S) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -acetate -2,6-dimethyl-phenoxy] -3-phenyl-propionic acid (4.0 g, 6.97 mmol), aqueous potassium hydroxide solution (8.4 mL, 1 M solution, 8.4 mmol), terahydrofuran ( 99.6 ml) and enough methanol to produce a homogeneous solution prepared a solid product. Recrystallization from 2% ethyl acetate in hexane gave the title compound (1.45 g, 37%) as a white solid.

-138 ° C Melting point 134-139 ° C and optical rotation [α] ²⁵ = - 35.86 ° (at 10.040 mg.ml ^-1 MeOH).

NMR (DMSO-d ₆ ): δ 12.91 (br s, 1H); 8.17 (d, J = 8Hz, 1H); 7.63 (ddd, J = 2.6, 8 Hz, 1H); 7.52 to 7.42 (m, 2H); 7.37 to 7.21 (m, 5H); 6.97 (s, 2 H); 4.72 (t, J = 7Hz, 1H); 3.25 (d, J = 7Hz, 2H); 2.41 (s, 3H); 2.25 (s. 3H); 2.22 (s, 3H); 1.54 (s, 3H).

MS (-ESI): [MH] ⁺ , single bromine isotopic pattern, 557/559.

analysis:

Calcd for C ₃ H ₂ 7BrO ₃ S 66.55% C, 4.86% H, 0.00% N;

Found: C, 66.17; H, 4.87; N, 0.01%.

Example 66

(2R) -2- [4- (9-Bromo-2,3-dimethyl-1-oxo-1H-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethylphenoxy] - 3-phenylpropionic acid

From a solution of (2 R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl -propionic (0.5 g, 0.89 mmol), glacial acetic acid (6.6 mL) and 30% aqueous hydrogen peroxide solution (1.0 mL, 9.8 mmol) gave a suspension which was immediately diluted with water and extracted with diethyl ether. Chromatographic purification with methanol / methylene chloride afforded the title compound (0.12 g, 23%) as a light yellow solid having an optical rotation [α] ²⁵ D = + 29.57 ° (at 7.88 mg.ml) ^'1 MeOH).

NMR (DMSO-d 6): δ 13.10 (br s, 1H); 8.28 (d, J = 8Hz, 1H); 7.74 (ddd, J = 1.7, 8 Hz, 1H); 7.63 (ddd, J = 1.7, 8 Hz, 1H); 7.39 (d, J = 8Hz, 1H); 7.36 to 7.18 (m, 5H); 7.01 (s, IH); 6.89 (s, 1 H); 4.69 (t, J = 7Hz, 1H); 3.23 (m, 2 H); 2.24, 2.21, 2.20 and 2.18 (4 s, mixture of sulfoxide diastereomers, 6H); 2.17 (s. 3H); 1.42 (s, 3H).

MS (-APCI): [M-H], single bromine isotopic pattern, 573/575.

analysis:

Calcd for C ₃ H ₂₇ BrO ₄ S 64.70% C, 4.73% H, 0.00% N;

found: 64.18% C, 4.44% H, -0.03% N.

Analytical HPLC revealed two major peaks (45.16%, 47.72%), a mixture of sulfoxide diastereomers.

-139 ·· ·······························

Example 67

(R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenoxy] -3-phenyl-propionic acid

Reaction Step 1

(2R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenoxy] -3-phenyl-propionic acid methyl ester

In a similar manner to that described in Example 49 for reaction step 6, z

4- (2,3-Dimethyl-naphtho [2 ₁ 3-b] thiophen-4-yl) -2,6-diethyl-phenol (0.84 g, 2.23 mmol), (S) -2-methyl ester -hydroxy-3-phenylpropionic (3.36 g, 18.6 mmol), triphenylphosphine (4.8 g, 18.3 mmol), diethyl azodicarboxylate (2.92 mL, 18.5 mmol) and anhydrous benzene (75 mL) at room temperature, the title compound (0.50 g, 42%) was obtained as a solid.

NMR (DMSO-d 6): δ 8.44 (s, 1H); 7.94 (d, J = 8Hz, 1H); 7.48 to 7.22 (m, 8H); 6.99 (s, 2 H); 4.69 (t, J = 7Hz, 1H); 3.55 (s, 3H); 3.27 to 3.22 (two overlapping dd, J = 6, 13 Hz, 2H); 2.70 to 2.40 (complex m, ABX characteristic, 4H); 2.38 (s, 3H); 1.53 (s, 3H); 1.10 and 1.09 (two overlapping triplets, J = 8 Hz, 6H).

MS (+ APCI): [M + H], 523;

Reaction Step 2

(2R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 7, from (2R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-methyl ester. 6-diethyl-phenoxy-3-phenyl-propionic acid (0.46 g, 0.88 mmol), aqueous potassium hydroxide solution (1.1 mL, 1 M solution, 1.1 mmol), terahydrofuran (12.6 mL), and sufficient methanol to give a homogeneous solution gave the title compound (0.43 g, 89%) as a white solid.

NMR (DMSO-d 6): δ 12.91 (br s, 1H); 8.44 (s, 1 H); 7.94 (d, J = 8Hz, 1H); 7.47 to 7.22 (m, 8H); 6.98 (s, 2 H); 4.61 (t, J = 7 Hz, 1H); 3.25 (d, J = 7Hz, 2H); 2.72 (complex m, ABX characteristic, 1H); 2.66 (two overlapping quartets, J = 8 ·· ·· ··· · · · ·······

- 140 ·· ·················

Hz, 2H); 2.55 (complex m, ABX characteristics, 1H); 2.38 (s, 3H); 1.10 and 1.09 (two overlapping triplets, J = 8 Hz, 6H).

MS (- ESI): [M-H], 507.

analysis:

Calcd for C ₃ H 32 O ₃ S · 0.6H ₂ O C 76.30, H 6.44, N 0.00%;

Found: C, 76.44; H, 6.49; N, 0.04.

Example 68

{(2 R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenoxy] -3-phenyl-propionylamino} -acetic acid

In a similar manner to Example 63, from (2R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl-phenoxy] -3-phenyl-propionic acid (0.27 g, 0.53 mmol), oxalyl chloride (0.046 g, 0.53 mmol), N, N-dimethylformamide (two drops), benzene (9 mL), glycine ethyl ester hydrochloride (0.18 g, 1.29 mmol) and potassium carbonate (0.46 g, 3.33 mmol) at room temperature prepared a solid which was adsorbed onto silica gel and chromatographed with hexane / ethyl acetate (90/10). The resulting solid (0.18 g) was treated with potassium hydroxide (2.34 mL, 1 M solution, 2.34 mmol), tetrahydrofuran (10 mL) and enough methanol to form a homogeneous solution. The title compound (0.10 g, 33% of theory) was obtained as a pale yellow solid.

NMR (DMSO-d 6): δ 12.52 (br s, 1H); 8.48 (t, J = 6Hz, 1H); 8.43 (s, 1 H); 7.94 (d, J = 8Hz, 1H); 7.48 to 7.16 (m, 8H); 6.93 (s, 2 H); 4.73 (t, J = 7Hz, 1H); 3.79 and 3.73 (two overlapping dd, J = 6.17 Hz, 2H); 3.24 (dd, J = 7, 14 Hz, 1H); 3.15 (dd, J = 7.14 Hz, 1H); 2.80 to 2.50 (complex m, ABX characteristic, 4H); 2.39 (s, 3H); 1.07 (t, J = 8Hz, 6H).

MS (+ APCI): [M + H] +, 566.

analysis:

Calcd for C35H _{3 4} 5 NO S.0,6H ₂ O 74.31% C, 6.24% H, 2.48% N;

Found: C, 74.11; H, 6.69; N, 2.24.

····························

-141 ··· ··· ··· ·· ···· ·· ··· ·· ···

Example 69

4- (2,3-Dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-diethyl-phenol

Step 1 (2-Benzyl-4,5-dimethyl-furan-3-yl) - (4-methoxy-3,5-diethyl-phenyl) -methanone

In a similar manner to that described in Example 49 for reaction step 1, starting from 3,5-diethyl-β-anisic acid (10.66 g, 51.2 mmol) prepared in three steps from

4-bromo-2,6-diethylaniline by the method of J. Lipowitz and T. Cohen, J. Org. Chem. 30.

3891-3894 (1965); C. K. Bradsher et al., J. Am. Chem. Soc. 76, 2357-2362 (1954); J. Alexandra, Org., Prep. Proced. Int. 18, 2213-2215 (1986)), oxalyl chloride (4.9 mL, 56.2 mmol), N, N-dimethylformamide (2 drops), 2,3-dimethyl-5-benzylfuran (11.4 g, 61, 2 mmol), tin tetrachloride (6.6 mL, 56.4 mmol) and anhydrous methylene chloride (198 mL) gave the title compound (22 g,> 100%) as an oil.

NMR (DMSO-d 6): δ 7.42 (s, 2H); 7.29 to 7.21 (m, 3H); 7.04 (d, J = 7Hz, 2H); 3.82 (s, 2 H); 3.74 (s, 3H); 2.61 (quartet, J = 8 Hz, 4H); 2.19 (s, 3H); 1.83 (s, 3H); 1.13 (t, J = 8Hz, 6H).

Reaction Step 2

4- (2,3-Dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-diethyl-phenol

In a similar manner to Example 49 for reaction step 2, from (2-benzyl-4,5-dimethyl-furan-3-yl) - (4-methoxy-3,5-diethyl-phenyl) -methanone (22). g), boron tribromide (36.8 mL, 389 mmol) and methylene chloride (180 mL) at reflux for four hours to afford the title compound (3.09 g, 17.5%) as an off-white solid. solids.

NMR (DMSO-d ₆ ): δ 8.29 (s, 1H); 7.96 (d, J = 8Hz, 1H); 7.90 (s, 1 H); 7.57 (d, J = 8Hz, 1H); 7.39 (ddd, J = 1.7, 8 Hz, 1H); 7.29 (ddd, J = 1.7, 8 Hz, 1H); 6.89 (s, 1 H);

2.75 to 2.55 (complex m, ABX characteristic, 4H); 2.36 (s, 3H); 1.55 (s, 3H);

1.15 (t, J = 8Hz, 6H).

MS (EI): [M &lt; + &gt;] 344.

·· ·· • · · ·

% H, 7.02%; N, 0.00%;

H, 7.11; N, 0.05%.

• · · ···················

analysis:

calcd for C24H24O2 as determined

Example 70

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-diethyl-phenoxy] -3-phenyl-propionic acid

Reaction Step 1

Acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-diethyl-phenyl ester

In a similar manner to that described in Example 49 for reaction step 3, from 4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-diethyl-phenol (1.75 g, 5.1 mmol), acetic anhydride (0.62 mL, 6.6 mmol) and pyridine (10.2 mL) gave the compound (2.23 g) as a solid which was used without further purification. .

In a similar manner to that described in Example 49 for reaction step 4, acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-diethyl-phenyl ester ( 2.23 g, 5.8 mmol), ferric chloride (247 mg, 0.29 mmol), bromine (0.34 mL, 6.4 mmol, and methylene chloride (58 mL) gave the title compound (0.29 g). , 10% of the theoretical yield) as a solid.

NMR (DMSO-d ₆ ): δ 8.26 (d, J = 8 Hz, 1H); 7.64 (ddd, J = 1.7, 8 Hz, 1H); 7.59 (d, J = 9Hz, 1H); 7.48 (ddd, J = 1.7, 8 Hz, 1H); 7.16 (s, 2 H); 2.54 and 2.53 (two overlapping quartets, J = 7 Hz, 4H); 2.44 (s, 3H); 2.42 (s, 3H); 1.54 (s. 3H); 1.14 (t, J = 7Hz, 6H).

MS (EI): [M ⁺ ], single bromine isotopic pattern, 464, 466.

Reaction Step 2

4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-diethyl-phenol

In a similar manner to that described in Example 49 for reaction step 5, acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -phenyl ester (0, 29 g, 0.62 mmol), aqueous potassium hydroxide solution (0.75 mL, 1 M solution, 0.75 mmol), tetrahydrofuran (8.9 mL) and enough methanol to form a homogeneous • · · · · · · · · · ·

The title compound (0.26 g, 100%) was obtained as a solid.

NMR (DMSO-d 6): δ 8.36 (s, 1H); 8.21 (d, J = 8Hz, 1H); 7.63 (d, J = 8Hz, 1H); 7.59 (ddd, J = 1.7, 8 Hz, 1H); 7.41 (ddd, J = 1.7, 8 Hz, 1H); 6.91 (s, 2 H); 2.69 and 2.62 (two overlapping quartets, J = 7 Hz, 4H); 2.41 (s, 3H); 1.55 (s, 3H); 1.14 (t, J = 7Hz, 6H).

MS (EI): [M ¹ ], ^single bromine isotope pattern, 422/424.

Reaction Step 3

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-diethyl-phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 6, from 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-diethyl-phenol (0.26 g, 0.64 mmol), (S) -2-hydroxy-3-phenylpropionic acid methyl ester (1.38 g, 7.06 mmol), triphenylphosphine (1.98 g, 7.55 mmol), diethyl azodicarboxylate (1.2 mL, 7.62 mmol) and anhydrous benzene (0.85 mL) by heating at 100 ° C for 36 h prepared the compound (0.15 g, 39%) which was used without further purification.

In a similar manner to that described in Example 49 for reaction step 7, (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -acetate -2,6-diethylphenoxy] -3-phenyl-propionic acid (0.15 g, 0.25 mmol), aqueous potassium hydroxide solution (0.98 mL, 1 M solution, 0.98 mmol), terahydrofuran (2, 5 mL) and enough methanol to give a homogeneous solution gave the title compound (0.1 g, 71%) as a white solid.

NMR (DMSO-d 6): δ 12.96 (br s, 1H); 8.23 (d, J = 8Hz, 1H); 7.66 (m, 1H); 7.64 to 7.53 (m, 2H); 7.43 to 7.30 (m, 5H); 7.02 (s, 2 H); 4.61 (t, J = 7 Hz, 1H); 3.25 (d, J = 7Hz, 2H); 2.82 to 2.52 (complex m, ABX characteristic, 4H); 2.41 (s, 3H); 1.49 (s, 3H); 1.11 and 1.10 (two overlapping triplets, J = 7 Ht, 6H).

MS (-ESI): [M-H], single bromine isotopic pattern, 569/571.

analysis:

Calcd for C 33 H 31 BrO 4 69.35% C, 5.47% H, 0.00% N;

found: 69.93% C, 5.84% H, 0.19% N.

································

-144 • • e · · · · · · · · · · · · · · · · · · ·

The content of the main component (98.3%) was determined by analytical HPLC.

Example 71

(R) -2- [2-Cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -propionic acid

Reaction Step 1

(2R) -2- [2-Cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -propionic acid methyl ester

In a similar manner to that described in Example 49 for reaction step 6, from 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (0.80 g, 2.2 mmol), (S) - (-) - lactic acid methyl ester (0.24 g, 3.3 mmol), triphenylphosphine (0.84 g, 3.2 mmol), diethyl azodicarboxylate (0.51 mL, 3 mmol) , 2 mmol) and anhydrous benzene (5.0 mL) by heating (90 ° C) gave the title compound (0.67 g, 68%) as a white solid, mp 65-66 ° C. .

NMR (DMSO-d 6): δ 8.46 (s, 1H); 7.96 (d, J = 8Hz, 1H); 7.50 to 7.30 (m, 3H); 7.14 (m, 1H); 7.09 and 7.08 (two dd, J = 2.8 Hz, isomers, 1H); 6.95 and 6.92 (two d, J = 8 Hz, isomers, 1H); 5.14 and 5.11 (two quartets, J = 7 Hz, isomers, 1H); 3.75 and 3.70 (two s, isomers, 3H); 3.43 (m, IH); 2.41 (s, 3H); 2.00 (m. 2H); 1.77 to 1.50 (m containing doublet (J = 7 Hz) at δ 1.61 and singlet at δ 1.57, 12H).

MS (EI): [M &lt; + &gt;] 458.

analysis:

Calcd for C29H30O3S 75.95% C, 6.59% H, 0.00% N;

Found: C, 74.93; H, 6.55; N, -0.09%.

Reaction Step 2

(R) -2- [2-Cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -propionic acid

In a similar manner to that described in Example 49 for reaction step 7, from (R) -2- [2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophene-4-) methyl ester yl) phenoxy] propionic acid (0.60 g, 1.3 mmol), aqueous potassium hydroxide solution ··· ·················

-145 (1.98 mL, 1 M solution, 1.98 mmol), tetrahydrofuran (9 mL), and methanol ( 3 mL) gave the title compound (0.55 g, 95%) as a white solid.

Optical rotation [α] _D ²⁵ = + 7.95 ° (at 10.068 mg · mľ ¹ MeOH).

NMR (DMSO-d 6): δ 13.02 (broad s, 1H); 8.46 (s, 1 H); 7.96 (d, J = 8Hz, 1H); 7.50 to 7.30 (m, 3H); 7.13 and 7.12 (two doublets, J = 2 Hz, isomers, 1H); 7.11 and 7.09 (two dd, J = 2.8 Hz, isomers, 1H); 6.93 and 6.91 (two doublets, J = 8 Hz, isomers, 1H); 4.95 (q, J = 7Hz, 1H); 3.44 (m, IH); 2.41 (s, 3H); 2.00 (m. 2H); 1.79 and 1.50 (m, including doublet (J = 7 Hz) at δ 1.60 and singlet at δ 1.58, 12H).

MS (EI): [M +], 444.

analysis:

Calcd for C28H28O3S 75.64% C, 6.35% H, 0.00% N;

Found: C, 74.10; H, 6.32; N, -0.09.

The content of the main component (99.99%) was determined by analytical HPLC.

Example 72

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-cyclopentyl-phenoxy] -propionic acid

In a similar manner to that described in Example 49 for reaction step 6, from 2-cyclopentyl-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (0 (37 g, 0.99 mmol), (S) - (-) - lactic acid methyl ester (0.75 g, 7.9 mmol), triphenylphosphine (2.1 g, 8.0 mmol), diethyl azodicarboxylate (1, 0.15 mmol, 0.75 g, 7.9 mmol) 23 mL, 7.8 mmol) and anhydrous benzene (1.0 mL) was heated to 90 ° C for 18 h to afford the title compound (0.20 g, 28%) as a solid which was used as is without further purification.

In a similar manner to that described in Example 49 for reaction step 7, (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -acetate ) -2-cyclopentyl-phenoxy] -propionic acid (0.20 g, 0.37 mmol), aqueous potassium hydroxide solution (0.74 mL, 1M solution, 0.74 mmol), tetrahydrofuran (3.7 mL) and enough · · ······································

-146 methanol to give a homogeneous solution of the title compound (0.18 g, 95%) as an off-white solid .

NMR (DMSO-d 6): δ 13.00 (br s, 1H); 8.18 (d, J = 8 Hz, 1H); 7.63 (m, IH); 7.50 to 7.40 (m, 2H); 7.14 and 7.13 (two doublets, J = 2 Hz, isomers, 1H); 7.10 and 7.09 (two dd, J = 2.8 Hz, isomers, 1H); 6.93 and 6.91 (two doublets, J = 8 Hz, isomers, 1H); 4.94 (q, J = 7Hz, 1H); 3.41 (m, IH); 2.42 (s, 3H); 1.98 (m, 2 H); 1.78 to 1.46 (m, including two doublets (J = 7 Hz, isomers) at δ 1.59 and 1.58, and a singlet at δ 1.54.12H).

MS (-ESI): [M-H], single bromine isotopic pattern, 521/523.

analysis:

Calcd for C ₂ H _{2 e} 7BrO ₃ S 64.24% C, 5.20% H, 0.00% N;

found: 64.11% C, 5.62% H, 0.10% N.

Example 73

4- [4- (9-Bromo-2,3-dimethylnaphtho [2,3-b] thiophen-4-yl) -2-cyclopentylphenoxy] butyric acid

Reaction Step 1

4- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-cyclopentyl-phenoxy] -butyric acid methyl ester

A solution of 2-cyclopentyl-4- (9-bromo-2,3-dimethylnaphtho [2,3-b] thiophen-4-yl) phenol (0.30 g, 0.81 mmol), 4-bromobutyric acid methyl ester ( 1.5 ml, 13.0 mmol), 60% sodium hydride (0.09 g, 2.3 mmol), potassium carbonate (1.0 g, 7.2 mmol) and anhydrous benzene were heated at 100 ° C for 36 hours C. Chromatographic purification with hexane / ethyl acetate gave the title compound (0.23 g, 52%) as a solid.

MS (EI): [M +], monobromo characteristic, 550/552.

NMR (DMSO-d 6): δ 8.18 (d, J = 8 Hz, 1H); 7.62 (ddd, J = 2.6, 8 Hz, 1H); 7.50 to 7.41 (m, 2H); 7.16 and 7.04 (m, 3H); 4.11 (m, 2 H); 3.63 (s, 3H); 3.31 (quintet, J = 8 Hz, 1H); 2.57 (t, J = 7Hz, 2H); 2.42 (s, 3H); 2.07 (quintet, J = 7 Hz, 2H); 1.95 (m, 2 H); 1.74 to 1.45 (m, including singlet at δ 1.56, 9H).

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

-147 • · β ··· ·· ······ ·· ··· ··

Reaction Step 2

4- [4- (9-Bromo-2,3-dimethylnaphtho [2,3-b] thiophen-4-yl) -2-cyclopentylphenoxy] butyric acid

In a similar manner to that described in Example 49 for reaction step 7, 4- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2- cyclopentylphenoxy] -butyrate (0.23 g, 0.42 mmol), aqueous potassium hydroxide solution (1.66 mL, 1 M solution, 1.66 mmol), tetrahydrofuran (9.2 mL) and enough methanol to form a homogeneous solution to give the title compound (0.22 g, 100%) as an off-white solid.

NMR (DMSO-d ₆ ): δ 12.15 (br s, 1H); 8.18 (d, J = 8Hz, 1H); 7.62 (ddd, J = 2.6, 8 Hz, 1H); 7.51 to 7.41 (m, 2H); 7.14 to 7.05 (m, 3H); 4.10 (m, 2H); 3.37 (m, 1H); 2.48 (t, J = 7Hz, 1H); 2.41 (s, 3H), 2.04 (quintet, J = 7 Hz, 2H); 1.96 (m, 2 H); 1.72 to 1.44 (m including singlet at δ 1.56, 9H); 1.58 and 1.53 (two s, 3H).

MS (-ESI): [M-H] -, single bromine isotopic pattern, 535/537.

analysis:

Calcd for C 29 H ₂ 9BrO ₃ S 64.80% C, 5.44% H, 0.00% N;

found: 64.20% C, 5.50% H, 0.03% N.

Example 74

2-Cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -phenol

In a similar manner to that described in Example 49 for reaction step 1, from 3-cyclopentyl-β-anisic acid (10.0 g, 45.4 mmol; RN-59216-82-9), oxalyl chloride (4.4 mL, 50.4 mmol), N, N-dimethylformamide (2 drops), 2,3-dimethyl-5-benzylfuran (10.1 g, 54.2 mmol), tin tetrachloride (5.8 mL, 49.6 mmol) and anhydrous methylene chloride (183 mL) gave the compound (18.8 g) as an oil which was used without further purification.

In a similar manner to Example 49 for reaction step 2, from (2-benzyl-4,5-dimethyl-furan-3-yl) - (3-cyclopentyl-4-methoxy-phenyl) -methanone (18.8 g, 368 mmol), boron tribromide (34.8 mL, 368 mmol), and methylene chloride (167 mL) ··· ········· ·

-148 DEG C. for 2 hours at 50 DEG-55 DEG C. to give the title compound (1.56 g, 9.6% of theory); yield) in the form of a light brown solid.

NMR (DMSO-d 6): δ 9.46 (s, 1H); 7.96 (d, J = 8Hz, 1H); 7.90 (s, 1 H); 7.54 (d, J = 8Hz, 1H); 7.39 (ddd, J = 1.7, 8 Hz, 1H); 7.29 (ddd, J = 1.7, 8 Hz, 1H); 7.04 (d, J = 2Hz, 1 H); 6.97 (dd, J = 2.8 Hz, 2H); 6.91 (d, J = 8Hz, 1H); 3.38 to 3.26 (m, 1H); 2.36 (s, 3H); 1.96 (m, 2 H); 1.74 to 1.44 (m including singlet at δ 1.55, 9H).

MS (EI): [M +] 356.

analysis:

Calcd for C 25 H 24 O 2 84.24% C, 6.79% H, 0.00% N;

Found: C, 83.48; H, 6.71; N, 0.04.

Example 75

Acetic acid 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -phenyl ester

In a similar manner to that described in Example 49 for reaction step 3, from 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -phenol (4.81 g, 13.5 mmol), acetic anhydride (1.60 mL, 17.0 mmol) and pyridine (27 mL) and methylene chloride (27 mL) yielded a residue which was chromatographed with hexane / ethyl acetate to prepare the title compound. compound (0.92 g, 17%) as a solid.

NMR (DMSO-d 6): δ 8.00 (d, J = 8 Hz, 1H); 7.97 (s, 1H); 7.42 (ddd, J = 1.7, 8 Hz, 1H); 7.34 (ddd, J = 1.7, 8 Hz, 1H); 7.30 (d, J = 2Hz, 1 H); 7.22 (dd, J = 2.8 Hz, 1H); 7.19 (d, J = 8Hz, 1H); 3.14 (m, IH); 2.37 (s, 3H); 2.36 (m, 2 H); 1.74 to 1.44 (m including singlet for δ 1.52, 9H).

MS (+ ESI): [M + H] &lt; ^{+ &gt};, 399.

analysis:

Calcd for C27H26O3 81.38% C, 6.58% H, 0.00% N;

Found: C, 80.76; H, 6.65; N, 0.05%.

Example 76

(R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-ethyl-phenoxy] -propionic acid

-149 ·· ················

In a similar manner to that described in Example 49 for reaction step 6, from 2-ethyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol (1.47 g, 4.42 mmol), (S) -2-hydroxy-3-phenylpropionic acid methyl ester (4.78 g, 26.5 mmol), triphenylphosphine (6.96 g, 26.5 mmol), diethyl azodicarboxylate (4.18 mL) , 26.5 mmol) and anhydrous benzene (8.8 mL) gave the compound (0.16 g) as a solid which was used without further purification.

In a similar manner to that described in Example 49 for reaction step 7, from (R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-methyl ester -ethyl-phenoxy] -3-phenyl-propionic acid (0.16 g, 0.32 mmol), aqueous potassium hydroxide solution (0.65 mL, 1 M solution, 0.65 mmol), tetrahydrofuran (3.2 mL) and enough of methanol to give a homogeneous solution gave the title compound (0.10 g, 63%) as a yellow foam.

NMR (DMSO-d 6): δ 13.11 (br s, 1H); 8.43 (d, J = 2Hz, 1 H); 7.93 (d, J = 2Hz, 1 H); 7.48 to 7.20 (m, 8H); 7.10 to 7.00 (m, 2H); 6.86 (dd, J = 4.9 Hz, 1H); 5.08 and 5.04 (two dd, J = 4.8 Hz, isomers, 1H); 3.42 (m, ABX characteristic, 2H); 2.75 to 2.52 (complex m, ABX characteristic, isomers, 2H); 2.38 (s, 3H); 1.56 and 1.54 (two s, isomers, 3H); 1.08 and 1.06 (two t, J = 7 Hz, 3H).

MS (EI): [M] 480.

analysis:

Calcd for C 31 H 28 O 3 S 77.47% C, 5.87% H, 0.00% N;

Found: C, 74.55; H, 5.87; N, 0.20.

Example 77

(R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-ethyl-phenoxy] -3-phenyl-propionic acid

Reaction Step 1 Acetic acid (R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-ethyl-phenyl] ester

In a similar manner to that described in Example 49 for reaction step 3, from 2-ethyl-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -phenol (1.4 g, 4.2 mmol), acetic anhydride (0.52 mL, 5.5 mmol) and pyridine (8.4 mL) gave a residue which was

-150 chromatographed with hexane / acetate hexane / ethyl acetate -150 · · oval chromatograf oval oval oval 50 oval oval oval oval oval oval oval oval oval oval oval ethyl acetate to give the title compound (1.62 g, > 100% of theory) as a solid.

NMR (DMSO-d 6): NMR (DMSO-d 6): δ 8.49 (s, 1H); 7.97 (d, J = 9Hz, 1H); 7.50 to 7.43 (m, 1H); 7.40 to 7.35 (m, 2H); 7.27 (s, 1 H); 7.21 (s, 2 H); 2.57 (two overlapping quartets, J = 8 Hz, 2H); 2.40 (s, 3H); 2.37 (s, 3H); 1.58 (s, 3H); 1.13 (t, J = 8Hz, 3H).

MS (EI): [M +], 374.

analysis:

Calcd for C24H22O2S: C, 76.97; H, 5.92; N, 0.00;

Found: C, 75.72; H, 5.92; N, 0.03.

Reaction step 2 Acetic acid [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-ethyl-phenyl] ester

In a similar manner to that described in Example 49 for reaction step 4, z

Acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-ethyl-phenyl ester (1.53 g, 4.1 mmol), ferric chloride (41 mg, 0.22 mmol, bromine (0.23 mL, 4.5 mmol) and methylene chloride (35 mL) gave the title compound (0.48 g, 26%) as a solid.

NMR (DMSO-d 6): δ 8.21 (d, J = 9 Hz, 1H); 7.65 (ddd, J = 2.6, 8 Hz, 1H); 7.57-7.40 (m, 2H); 7.30 (s, 1 H); 7.23 (s, 2 H); 2.56 (two overlapping quartets, J = 8 Hz, 2H); 2.43 (s, 3H); 2.37 (s, 3H); 1.56 (s, 3H); 1.13 (t, J = 8Hz, 3H).

Reaction Step 3

4- (9-bromo-2,3-naphtho [2,3-b] thiophen-4-yl) -2-ethylphenol

In a similar manner to that described in Example 49 for reaction step 5, z

Acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-ethyl-phenyl ester (1.5 g, 3.33 mmol), aqueous solution potassium hydroxide (4.0 mL, 1 M solution, 4.0 mmol), tetrahydrofuran (55 mL), and methanol (37 mL) gave the title compound (1.4 g,> 100%) as a green foam. .

NMR (DMSO-d 6): δ 9.55 (s, 1H); 8.21 (d, J = 9Hz, 1 H); 7.62 (ddd, J = 1.7, 8 Hz, 1H); 7.54 (d, J = 8Hz, 1H); 7.44 (ddd, J = 1.7, 8 Hz, 1H); 7.05 to 6.87 (m, 3H);

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

-151 ·· ···· ·· ··· ·· ···

2.60 (complex m, ABX characteristic, 2H); 2.41 (s, 3H); 1.59 (s. 3H); 1.13 (t, J = 8Hz, 3H).

Reaction Step 4

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-ethyl-phenoxy] -3-phenyl-propionic acid methyl ester

In a similar manner to that described in Example 49 for reaction step 6, from 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-ethyl-phenol (0). (45 g, 1.16 mmol), (S) -2-hydroxy-3-phenylpropionic acid methyl ester (0.31 g, 1.72 mmol), triphenylphosphine (0.45 g, 1.72 mmol), diethyl azodicarboxylate ( 0.27 mL, 1.71 mmol) and anhydrous benzene (5 mL) was heated to 90 ° C for 18 h to afford the title compound (0.22 g, 33%) as a glassy residue.

NMR (DMSO-d 6): δ 8.22 (d, J = 9 Hz, 1H); 7.66 (ddd, J = 3.6, 8 Hz, 1H); 7.59-7.22 (m, 7H); 7.20 to 7.02 (m, 2H); 6.92 (dd, J = 2.8 Hz, 1H); 5.31 (m, IH); 3.74 to 3.70 (two s, isomers, 3H); 3.32 (m, 2 H); 2.64 (complex m, 2H); 2.45 (s, 3H); 1.55 (s, 3H); 1.12 and 1.10 (two t, J = 7 Hz, isomers, 3H).

Reaction Step 5

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-ethyl-phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 7, (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -acetate -2-ethylphenoxy] -3-phenyl-propionic acid (0.22 g, 0.38 mmol), aqueous potassium hydroxide solution (0.46 mL, 1 M solution, 0.46 mmol), terahydrofuran (15 mL), and methanol (5 mL) gave the title compound (0.19 g, 90%) as a white solid.

Optical rotation [α] D ²⁵ = + 1.55 ° (at 8.396 mg · ml · ¹ MeOH).

NMR (DMSO-d 6): δ 13.15 (br s, 1H); 8.17 (dd, J = 4.9 Hz, 1H); 7.66 to 7.58 (m, 1H); 7.50 to 7.21 (m, 1H); 7.50 to 7.21 (m, 7H); 7.11 to 7.04 (m, 2H); 6.88 (dd, J = 4.9 Hz, 1H); 5.09 and 5.06 (two dd, J = 4.8 Hz, isomers, 1H); 3.24 (complex m,

-152 ·· ·······················

ASBX characteristic, 2H); 2.66 and 2.56 (two overlapping quartet doublets, ABX characteristic, isomers, 2H); 2.42 and 2.40 (two s, isomers, 3H); 1.53 and 1.52 (two s, isomers, 3H); 1.08 and 1.06 (two t, J = 8 Hz, isomers, 3H).

MS (EI): [M +], single bromine isotope pattern, 558/560.

analysis:

Calcd for C 18 H 20 BrO 6 S 66.54% C, 4.86% H, 0.00% N;

Found: C, 66.91; H, 5.28; N, -0.07.

Example 78

2-Bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6-ethyl-phenol

In a similar manner to that described in Example 49 for reaction step 1, from 3-bromo-5-ethyl-p-anisic acid (4.95 g, 19.1 mmol), oxalyl chloride (1.8 mL, 20.6 mmol) N, N -dimethylformamide (2 drops), 2,3-dimethyl-5-benzylfuran (4.3 g, 23.1 mmol), tin tetrachloride (2.5 mL, 21.4 mmol) and anhydrous methylene chloride (72 mL) gave an oil (7.85 g) which was used further without purification. In a similar manner to Example 49 for reaction step 2, from (2-benzyl-4,5-dimethyl-furan-3-yl) - (3-bromo-5-ethyl-4-methoxy-phenyl) -methanone (7). , 85 g, 18.4 mmol), boron tribromide (13.2 mL, 14.0 mmol) and methylene chloride (63 mL) by heating at 50 ° C for 2 h afforded the title compound (0.85 g, 12%) ) as a white solid.

NMR (DMSO-d 6): δ 9.17 (s, 1H); 7.99 (d, J = 8Hz, 1H); 7.95 (s, 1 H); 7.52 (d, J = 8Hz, 1H); 7.42 (ddd, J = 1.7, 8 Hz, 1H); 7.37 to 7.30 (m, 2H); 7.10 (d, J = 2Hz, 1 H); 2.80 to 2.60 (complex m, ABX characteristic, 2H); 2.37 (s, 3H); 1.59 (s. 3H); 1.15 (t, J = 8Hz, 3H).

MS (EI): [M +], single bromine isotopic pattern, 394/396.

analysis:

Calcd for C22H18BrO2 66.85% C, 4.84% H, 0.00% N;

found: 67.07% C, 4.85% H, 0.05% N.

-153 ································

Example 79

(R) -2- [2-Bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6-ethyl-phenoxy] -3-phenyl-propionic acid

Reaction Step 1

(R) -2- [2-Bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6-ethyl-phenoxy] -3-phenyl-propionic acid methyl ester

In a similar manner to that described in Example 49 for reaction step 6, from 2-bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6-ethyl-phenol (0). (30 g, 0.76 mmol), (S) -2-hydroxy-3-phenylpropionic acid methyl ester (0.54 g, 3.0 mmol), triphenylphosphine (0.80 g, 3.1 mmol), diethyl azodicarboxylate ( 0.48 mL, 3.0 mmol) and anhydrous benzene (1.0 mL) was heated to 100 ° C for 12 h to afford the title compound (0.37 g, 88%) as a solid.

NMR (DMSO-d 6): δ 8.02 (d, J = 8 Hz, 1H); 7.99 (s, IH); 7.54 to 7.22 (m, 10H); 5.08 and 5.02 (two dd, J = 6.8 Hz, isomers, 3H); 3.60 and 3.57 (two s, isomers, 3H); 3.47 to 3.30 (m, 2H); 2.80 to 2.52 (complex m, ABX characteristic, isomers, 2H); 2.40 and 2.39 (two s, isomers, 3H); 1.58 and 1.53 (two s, isomers, 3H); 1.12 and 1.10 (two t, J = 8 Hz, isomers, 3H).

MS (EI): [M +], single bromine isotope pattern, 556/558

Reaction Step 2

(R) -2- [2-Bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6-ethyl-phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 7, from (2 R) -2- [2-bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4) methyl ester -yl) -6-ethylphenoxy] -3-phenyl-propionic acid (0.34 g, 0.61 mmol), aqueous potassium hydroxide solution (1.2 mL, 1 M solution, 1.2 mmol), terahydrofuran (6, 0 mL) and enough methanol to give a homogeneous solution gave the title compound (0.31 g, 94%) as a white foam.

NMR (DMSO-d 6): δ 8.01 (d, J = 8 Hz, 1H); 7.97 (d, J = 2Hz, 1 H); 7.48 (d, J = 9Hz, 2H); 7.46 to 7.22 (m, 9H); 7.20 (dd, J = 2.6 Hz, 1H); 5.03 (m, IH); 3.35 (m, 2 H);

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

-154 ·· ···· ·· ·· ·· ···

2.94 to 2.55 (complex m, ABX characteristic, 2H); 2.38 and 2.36 (two s, isomers, 3H); 1.56 and 1.51 (two s, isomers, 3H); 1.11 and 1.10 (two t, J = 7 Hz, 3H isomers).

MS (EI): [M +], single bromine isotopic pattern, 542/544.

analysis:

Calcd for C ₃ iH27BrO ₄ 68.51% C, 5.01% H, 0.00% N;

Found: C, 68.22; H, 5.42; N, 0.10.

Example 80

4- [2-Bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6-ethyl-phenoxy] -butyric acid

Reaction Step 1

4- [2-Bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6-ethyl-phenoxy] -butyric acid methyl ester

A solution of 2-bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6-ethyl-phenol (0.30 g, 0.76 mmol), 60% sodium hydride (33 mg, 0.83 mmol), 4-bromobutyric acid methyl ester (0.44 mL, 3.82 mmol) and anhydrous benzene (1.0 mL) was heated at 100 ° C for 6 h. Then a further portion of methyl 4-bromobutyrate (0.45 mL, 3.91 mmol) and potassium carbonate (0.5 g, 3.62 mmol) were added and the reaction mixture was heated again at 100 ° C for 6 hours. The crude reaction mixture was chromatographed using hexane / ethyl acetate to give the title compound (0.31 g, 82%) as a solid.

NMR (DMSO-d 6): δ 8.00 (d, J = 8 Hz, 1H); 7.98 (s, IH); 7.48 (d, J = 8Hz, 1H); 7.46 (d, J = 2Hz, 1 H); 7.43 (ddd, J = 1.7, 8 Hz, 1H); 7.35 (ddd, J = 1.7, 8 Hz, 1H); 7.26 (d, J = 2Hz, 1 H); 4.03 (dd, J = 6.9 Hz, 1H); 3.98 (dd, J = 6.9 Hz, 1H); 3.63 (s, 3H); 2.74 (quartet d, J = 7.15 Hz, 1H); 2.69 (quartet d, J = 7.15 Hz, 1H); 2.62 (t, J = 7Hz, 2H); 2.38 (s, 3H); 2.09 (quintet, J = 7 Hz, 2H); 1.56 (s, 3H); 1.18 (t, J = 7Hz, 3H).

MS (EI): [M +], single bromine isotopic pattern, 494/496.

·· · ·· · · · · · · · · · · ·

-155 ·· ·························

Reaction Step 2

4- [2-Bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6-ethyl-phenoxy] -butyric acid

In a similar manner to that described in Example 49 for reaction step 7, 4- [2-bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6- ethyl-phenoxy] butyric (0.31 g, 0.63 mmol), aqueous potassium hydroxide solution (1.25 mL, 1 M solution, 1.25 mmol), terahydrofuran (6.3 mL) and enough methanol to obtain a homogeneous solution (0.26 g, 87%) of the title compound as a white foam.

NMR (DMSO-d 6): δ 12.15 (br s, 1H); 8.01 (d, J = 8Hz, 1H); 7.98 (s, 1H); 7.48 (d, J = 8Hz, 1H); 7.46 (d, J = 2Hz, 1 H); 7.42 (ddd, J = 1.7, 8 Hz, 1H); 7.35 (ddd, J = 1.7, 8 Hz, 1H); 7.26 (d, J = 2Hz, 1 H); 4.04 (dd, J = 6.9 Hz, 1H); 3.98 (dd, J = 6.9 Hz, 1H); 2.74 (d quartet, J = 7.15 Hz, 1H); 2.71 (d quartet, J = 7.15 Hz, 1H); 2.53 (t, J = 7Hz, 2H); 2.38 (s, 3H); 2.38 (s, 3H); 2.06 (quintet, J = 7 Hz, 2H); 1.56 (s, 3H); 1.19 (t, J = 7Hz, 3H).

MS (-ESI): [M-H] -, single bromine isotopic pattern, 479/481.

analysis:

Calcd for C 26 H 28 BrO 4 64.87% C, 5.23% H, 0.00% N;

Found: C, 64.94; H, 5.23; N, 0.08.

Example 81

4- [2-Bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6-ethyl-phenoxy] -butyramide, 0.4 hydrate

4- [2-Bromo-4- (2,3-dimethyl-naphtho [2,3-b] furo-4-yl) -6-ethyl-ifenoxy] -butyric acid solution (60 mg, 0.12) oxalyl chloride (10.8 µL, 0.12 mmol), N, N-dimethylformamide (2.0 µL) and methylene chloride (1.0 mL) were stirred at room temperature for 2.5 hours. A saturated solution of ammonia in acetonitrile (5 mL) was then added and the resulting mixture was stirred at room temperature for two days. Concentration under reduced pressure gave a residue which was dispersed in 3% ethanol in water (31 mL) and stirred at room temperature for 18 hours. The cloudy solution was filtered, the filter was washed thoroughly with water and air dried to give the title compound.

156% of the title compound (52.6 mg, 88%) as an off-white solid.

NMR (DMSO-d 6): δ 8.00 (d, J = 8 Hz, 1H); 7.98 (s, IH); 7.49 (d, J = 8Hz, 1H); 7.45 (d, J = 2Hz, 1 H); 7.43 (ddd, J = 1.7, 8 Hz, 1H); 7.35 (ddd, overlapping with broad s, J = 1.7, 8 Hz, 2H); 7.25 (d, J = 2Hz, 1 H); 6.79 (broad s, 1H); 4.01 (dd, J = 6.9 Hz, 1H); 3.96 (dd, J = 6.9 Hz, 1H); 2.75 (d quartet, J = 7.15 Hz, 1H); 2.71 (d quartet, J = 7.15 Hz, 1H); 2.38 (s, 3H); 2.35 (t, J = 7Hz, 3H); 2.04 (quintet, J = 7 Hz, 2H); 1.56 (s, 3H); 1.19 (t, J = 7Hz, 3H).

MS (+ ESI): [M + H] +, single bromine isotopic pattern, 480/482.

analysis:

calculated for 0 _{2 26} 6Η ΒγΝ0 ₃ .0.4 H ₂ O 64.04% C, 5.54% H, 2.87% N;

Found: C, 64.01; H, 5.43; N, 2.89.

Example 82

4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -2-ethyl-phenol

Reaction step 1 (2-Benzyl-4,5-dimethyl-furan-3-yl) - (4-methoxy-3-ethyl-phenyl) -methanone

In a similar manner to Example 49 for reaction step 1, from 3-ethyl-p-anisic acid (5.0 g, 27.7 mmol), oxalyl chloride (2.7 mL, 31.0 mmol), Λ / N-dimethylformamide (2 drops), 2,3-dimethyl-5-benzylfuran (6.2 g, 33.3 mmol), tin tetrachloride (3.6 mL, 30.8 mmol) and anhydrous methylene chloride (177 mL) of the title compound (7.24 g, 75%) as an oil.

NMR (DMSO-d 6): δ 7.61 (dd, J = 2.8 Hz, 1H); 7.54 (d, J = 2Hz, 1 H); 7.28 to 7.13 (m, 3H); 7.09 to 7.03 (m, 3H); 3.86 (s, 3H); 3.82 (s, 2 H); 2.55 (q, J = 7Hz, 2H); 2.16 (s, 3H); 1.78 (s, 3H); 1.08 (t, J = 7Hz, 3H).

Reaction Step 2

4- (2,3-Dimethyl-naphtho [2,3-b] furan-4-yl) -2-ethyl-phenol ··· ·········· · · · · · ·

-157 ··· ··· ··· ·· ···· ·· ··· ·· ···

In a similar manner to Example 49 for reaction step 2, from (2-benzyl-4,5-dimethyl-furan-3-yl) - (4-methoxy-3-ethyl-phenyl) -methanone (7.0 g, 20.1 mmol), boron tribromide (14.4 mL, 152.3 mmol) and methylene chloride (69 mL) gave the title compound (0.61 g, 9.6%) as an off-white solid. substances.

NMR (DMSO-d ₆ ): δ 9.45 (s, 1H); 7.97 (d, J = 8Hz, 1H); 7.90 (s, 1 H); 7.55 (d, J = 8)

Hz, 1H); 7.39 (ddd, J = 1.7, 8 Hz, 1H); 7.29 (ddd, J = 1.7, 8 Hz, 1H); 7.02 (d, J = 2H)

Hz, 1H); 6.98 (dd, J = 2.8 Hz, 1H); 6.91 (d, J = 8Hz, 1H); 2.63 (d quartet, J = 7.14

Hz, 1H); 2.58 (d quartet, J = 7.14 Hz, 1H); 2.36 (s, 3H); 1.56 (s, 3H); 1.14 (t, J 8)

Hz, 6H).

MS (EI): [M +] 316.

Example 83

(R) -2- [4- (9-Bromo- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-propyl-phenoxy] -3-phenyl-propionic acid

Step 1 (2-Benzyl-4,5-dimethyl-thiophen-3-yl) - (4-methoxy-3-propyl-phenyl) -methanone

In a similar manner to Example 49 for reaction step 1, from 3-propyl-p-anisic acid (3.0 g, 15.4 mmol), oxalyl chloride (1.48 mL, 17.0 mmol), Λ / N-dimethylformamide (2 drops), 2,3-dimethyl-5-benzylthiophene (3.75 g, 18.5 mmol), tin tetrachloride (1.99 mL, 17.0 mmol) and anhydrous methylene chloride (99 mL) of the title compound (2.11 g, 38%) as an oil.

NMR (DMSO-d 6): δ 7.58 (dd, J = 2.8 Hz, 1H); 7.53 (d, J = 2Hz, 1 H); 7.25 to 7.11 (m, 3H); 7.10 to 7.03 (m, 3H); 3.86 (s, 3H); 3.84 (s, 2 H); 2.54 (t, J = 7Hz, 2H); 2.26 (s, 3H); 1.81 (s, 3H); 1.51 (sextet, J = 7Hz, 2H); 0.87 (t, J = 7Hz, 3H).

MSD (EI): [M +] 378.

Reaction Step 2

4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-propyl-phenol

-158 ··· ··· · ····················

In a similar manner to Example 49 for reaction step 2, from (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (4-methoxy-3-propyl-phenyl) -methanone (2.70). g, 7.1 mmol), boron tribromide (5.12 mL, 54.2 mmol) and methylene chloride (24.5 mL) gave the title compound (1.77 g, 71%) as a solid.

NMR (DMSO-d 6): δ 9.44 (s, 1H); 8.42 (s, 1 H); 7.93 (d, J = 8Hz, 1H); 7.50 to 7.25 (m, 3H); 7.50 to 7.25 (m, 3H); 7.05 to 6.88 (m, 3H); 2.61 (m, IH); 2.52 (m, 1H); 2.39 (s, 3H); 1.70 to 1.50 (m includes singlet for δ 1.63, 5H); 0.88 (t, J = 7Hz, 3H).

MS (EI): [M +] 346.

Reaction Step 3

Acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-propyl-phenyl ester

In a similar manner to that described in Example 49 for reaction step 3, z

4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-propyl-phenol (1.3 g, 3.8 mmol), acetic anhydride (0.46 ml, 4.9 mmol) and pyridine (7.5 mL) gave a residue which was purified by chromatography with hexane / ethyl acetate to give the title compound (0.81 g, 56%) as a solid.

NMR (DMSO-d 6): δ 8.50 (s, 1H); 7.98 (d, J = 9Hz, 1H); 7.51 to 7.44 (m, 1H); 7.40 to 7.36 (m, 2H); 7.26 (s, 1 H); 7.23 (s, 2 H); 2.55 (m, 2 H); 2.42 (s, 3H); 2.38 (s, 3H); 1.64 to 1.53 (m including singlet for δ 1.61, 5H); 0.88 (t, J = 7Hz, 3H).

MS (EI): [M +], 388.

Reaction Step 4

Acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-propyl-phenyl ester

In a similar manner to that described in Example 49 for reaction step 4, z

Acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-propyl-phenyl ester (0.80 g, 2.1 mmol), ferric chloride (16.7 g) mg, 0.10 mmol), bromine (0.12 mL, 2.3 mmol) and methylene chloride (21 mL) gave the title compound (0.38 g, 39%) as a solid.

NMR (DMSO-d 6): δ 8.20 (d, J = 9 Hz, 1H); 7.65 (ddd, J = 1.6, 8 Hz, 1H); 7.48 (ddd, J = 1.6, 8 Hz, 1H); 7.43 (d, J = 8Hz, 1H); 7.28 (s, 1 H); 7.23 (s, 2 H); 2.53 (m, 2 H);

····························

-159 • 9 · ··· ·· ············

2.43 (s, 3H); 2.36 (s, 3H); 1.63 to 1.50 (m including singlet for δ 1.57, 5H); 0.86 (t, J = 7Hz, 3H).

MS (EI): [M ⁺ ], single bromine isotopic pattern, 466, 468.

Reaction Step 5

(2R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-propyl-phenoxy] -3-phenyl-propionic acid

In a similar manner to that described in Example 49 for reaction step 5, from the 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-propyl-phenyl ester acetic acid (0.36 g, 0.77 mmol), aqueous potassium hydroxide solution (0.92 mL, 1 M solution, 0.92 mmol), tetrahydrofuran (11.4 mL) and methanol (7.6 mL) prepared a solid. 4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-propyl-phenol which was used further without further purification.

In a similar manner to Example 49 for reaction step 6, from 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-propyl-phenol (0). (77 mmol), (S) -2-hydroxy-3-phenylpropionic acid methyl ester (1.12 g, 6.2 mmol), triphenylphosphine (1.60 g, 6.1 mmol), diethyl azodicarboxylate (0.96 mL, 6.1 mmol) and anhydrous benzene (2.5 mL) was heated to 85 ° C for three days to prepare solid (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3- b] thiophen-4-yl) -2-propyl-phenoxy] -3-phenyl-propionic acid, which was used further without purification.

In a similar manner to that described in Example 49 for reaction step 7, (2R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -acetate -2-propylphenoxy] -3-phenyl-propionic acid (0.23 g, 0.39 mmol), aqueous potassium hydroxide solution (0.93 mL, 1 M solution, 0.93 mmol), terahydrofuran (4.6 mL) ) and sufficient methanol to give a homogeneous solution of the title compound (0.17 g, 74%) as a yellow foam.

NMR (DMSO-d 6): δ 13.15 (br s, 1H); 8.18 (d, J = 3.9 Hz, 1H); 7.67 to 7.59 (m, 1H); 7.50 to 7.23 (m, 7H); 7.52-7.40 (m, 2H); 6.88 (dd, J = 5.8 Hz, 1H); 5.15 to 5.02 (m, 1H); 3.24 (m, 2 H); 2.73 to 2.53 (m, 2H); 2.42 (s, 3H); 1.60 to 1.40 (m including two singlets for δ 1.56 and 1.54, isomers, 5H); 0.87 and 0.85 (two t, J = 7 Hz, isomers, 3H).

MS (EI): [M +], single bromine isotopic pattern, 572/574.

····························

-160 ·· ···· ·· ··· ·· ·

Example 84 [9-bromo-4- _{(4-methoxy-3-I,} 5-dimethylphenyl) -3-methylnaphtho [2 _L 3-b] thien-2-yl] methyl ester

A solution of 4- (9-bromo-2 ₁ 3-dimethyl-naphtho [2,3-b] thiophen-4-yl-2,6-dimethyl-anisole (2.0 g, 4.7 mmol) of sulfuryl chloride (0 , 42 mL, 5.3 mmol), diisopropylethylamine (0.90 mL, 5.2 mmol), and anhydrous methylene chloride (24 mL) was stirred at 0 ° C for 2 h. , once with brine and then dried (Na 2 SO _4). Concentration under reduced pressure gave a residue, which was immediately treated with sodium acetate (1.2 g, 14.6 mmol) and / V, / V-dimethylformamide (16 After 24 hours, the reaction mixture was diluted with diethyl ether, washed three times with water, once with brine, and then dried (Na ₂ SO ₄ ) to give a residue which was chromatographed with hexane / ethyl acetate to yield a residue. The title compound (0.36 g, 27% of theory) was obtained as a yellow foam.

NMR (DMSO-d 6): δ 8.41 (s, 1H); 8.21 (d, J = 9Hz, 1 H); 7.68 (ddd, J = 2.6, 8 Hz, 1H); 7.57 to 7.45 (m, 2H); 7.05 (s, 2 H); 3.78 (s, 3H); 2.30 (s, 6H); 2.08 (s, 3H); 1.68 (s, 3H).

MS (EI): [M &lt; + &gt;], single-bromine isotopic charkateristics, 482/484.

analysis:

Calculated for C ₂ 5H23BrO ₃ S 62.11% C, 4.80% H, 0.00% N;

H, 4.75; N, 0.04.

Example 85

Acetic acid 4- (9-bromo-2,3-dimethyl) -naphtho [2,3-b] thien-4-yl] -2-methyl-phenyl ester

Reaction Step 1

Acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-methyl-phenyl ester

In a similar manner to that described in Example 49 for reaction step 1, from 3-methyl-p-anisic acid (10 g, 60.2 mmol), oxalyl chloride (5.77 mL, 66 mmol), N, N- dimethylformamide (2 drops), 2,3-dimethyl-5-benzylthiophene (14.6 g, 72.2 mmol), tin tetrachloride (7.75 mL, 66.2 mmol) and anhydrous ·· ·· ·· · · · ···· ···· ··

-161 methylene chloride (300 ml) gave an oil (24.4 g) which was used without further purification.

In a similar manner to Example 49 for reaction step 2, from (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (4-methoxy-3-methyl-phenyl) -methanone (24.4 g), boron tribromide (17.1 mL, 180.9 mmol) and methylene chloride (120 mL) gave a residue which was further treated with acetic anhydride (7.4 mL, 78.4 mmol), pyridine (58 mL, ) and methylene chloride (400 mL) in a similar manner to that described in Example 49 for reaction step 3. Conventional work-up afforded the title compound (9.83 g, 45.5%) as a solid.

NMR (DMSO-d 6): δ 8.48 (s, 1H); 7.97 (d, J = 8Hz, 1H); 7.50 to 7.33 (m, 3H); 7.27 (s, 1 H); 7.21 (s, 2 H); 2.40 (s, 3H); 2.36 (s, 3H); 2.19 (s, 3H); 1.58 (s, 3H).

MS (+ APCI): [M + H] + 361.

Reaction Step 2

Acetic acid 4- (9-bromo-2,3-dimethyl) -naphtho [2,3-b] thien-4-yl] -2-methyl-phenyl ester

In a similar manner to that described in Example 49 for reaction step 4, acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-methyl-phenyl ester (5, 0 g, 13.9 mmol), ferric chloride (0.11 mg, 0.68 mmol), bromine (14.3 mL, 1.07 M solution in carbon tetrachloride, 15.3 mmol) and methylene chloride (63 mL) to give the title compound (5.44 g, 90.7% of theory) as a solid.

NMR (DMSO-d ₆ ): δ 8.20 (d, J = 9 Hz, 1H); 7.65 (ddd, J = 2.6, 8 Hz, 1H); 7,52 to

7.42 (m. 2H); 7.30 (s, 1 H); 7.23 (s, 2 H); 2.43 (s, 3H); 2.36 (s, 3H); 2.20 (s, 3H); 1.56 (s, 3H).

MS (EI): [M ⁺ ], single bromine isotopic pattern, 438/440.

analysis:

Calcd for C23H18BrO2S 62.87% C, 4.36% H, 0.00% N;

H, 3.99; N, 0.10.

Example 86

Acetic acid 4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenyl ester

Reaction Step 1

Acetic acid 4- (9-bromo-2-bromomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenyl ester

In a similar manner to that described in Example 49 for reaction step 4, 4- (2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenyl ester was substituted acetic acid (10.0 g, 26.7 mmol), ferric chloride (0.23 g, 1.42 mmol), bromine (1.51 mL in methylene chloride (38 mL), 29.4 mmol) and methylene chloride (231 mL) ) gave acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenyl ester (6.68 g) and the title compound. (1.60 g) as a yellow solid.

NMR (DMSO-d 6): δ 8.28 (m, 1H); 7.62 to 7.56 (m, 2H); 7.41 to 7.37 (m, 1H); 7.06 (s, 2 H); 4.70 (s, 2 H); 2.42 (s, 3H); 2.24 (s, 6 H); 1.72 (s, 3H).

MS (EI): [M ⁺ ], two-bromine isotopic characteristic, 530/532/534.

analysis:

Calcd for C27H22Cl2O4S: 54.15% C, 3.79% H, 0.00% N;

found: 53.81% C, 3.61% H, 0.10% N.

Reaction Step 2

Acetic acid 4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenyl ester

Acetic acid 4- (9-bromo-2-bromomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenyl ester (1.21 g, 2.27 mmol) ) was treated with diethylamine (0.71 mL, 6.82 mmol), potassium carbonate (0.94 g, 6.82 mmol) and N, N-dimethylformamide (12.1 mL) at room temperature for 1 hour. Then the reaction mixture was poured into water (250 ml), filtered and washed well with water. Drying in air gave the title compound (1.13 g, 94.5%) as a yellow solid.

NMR (DMSO-d 6): δ 8.19 (d, 1H); 7.66 to 7.61 (m, 1H); 7.47 (d, 2 H); 7.13 (s, 2 H); 3.73 (s, 2 H); 2.58 to 2.52 (q, 4H); 2.40 (s, 3H); 2.16 (s, 6H); 1.61 (s, 3H); 1.02 (t, 6 H).

MS (EI): [M ⁺ ], single bromine isotopic pattern, 523/525.

-16364.12% C, 5.77% H, 2.67% N;

% C, 63.30;% H, 5.67;% N, 2.55.

····································

analysis:

Calcd for C ₂₈ H ₃ BrNO ₂ S determined

Example 87

2- [4- (9-Bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl-propionic acid

Reaction Step 1

4- (9-Bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenol

In a similar manner to that described in Example 49 for reaction step 5, 4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenyl acetic acid ester (1.13 g, 2.15 mmol), aqueous potassium hydroxide solution (2.58 mL, 1 M solution, 2.58 mmol), tetrahydrofuran (28 mL) and methanol (28 mL) were prepared as described above. compound (1.0 g, 96%) as a yellow solid.

NMR (DMSO-d ₆ ): δ 8.47 (s, 1H); 8.17 (d, 1H); 7.64 to 7.59 (m, 1H); 7.55 to 7.45 (m, 1H); 7.45 to 7.39 (m, 1H); 6.90 (s, 2 H); 3.72 (s, 2 H); 2.60 and 2.50 (m, 4H); 2.23 (s, 6 H); 1.64 (s, 3H); 1.01 (m, 6H).

Reaction Step 2

(2R) -2- [4- (9-Bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl-methyl ester propionate

In a similar manner to Example 49 for reaction step 6, from 4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethylphenol (0.90 g, 1.87 mmol), (S) -2-hydroxy-3-phenylpropionic acid methyl ester (0.67 g, 3.73 mmol), triphenylphosphine (0.98 g, 3.73 mmol), of diethyl azodicarboxylate (0.59 mL, 3.73 mmol) and anhydrous benzene (10 mL) by heating at 87 ° C for 6 h afforded the title compound (0.46 g, 38%) as a solid.

NMR (DMSO-d 6): δ 8.19 (d, 1H); 7.66 to 7.61 (m, 1H); 7.47 to 7.45 (m, 2H); 7.34 (d, 4H); 7.32 to 7.26 (m, 1H); 7.00 (d. 2H); 4.80 (t, IH); 3.74 (s, 2 H); 3.58 (s, 3H);

·················

-164 ··· ··· ·· ·· ·············

3.36 to 3.25 (m, 2H); 2.55 (q, 4H); 2.24 (s. 3H); 2.19 (s, 3H); 1.59 (s. 3H); 1.03 (t, 6 H).

MS (+ ESI): [M + H] ⁺ , single bromine isotopic pattern, 644/646.

analysis:

Calcd for C 7 H 8 BrNO 3 S 67.07% C, 5.94% H, 2.17% N;

Found: C, 66.73; H, 5.93; N, 2.15.

Reaction Step 3

(2 R) -2- [4- (9-Bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl acid propionic acid

In a similar manner to that described in Example 49 for reaction step 7, (2R) -2- [4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophene-4) methyl ester -yl) -2,6-dimethyl-phenoxy-1-propionic acid (0.35 g, 0.98 mmol), aqueous potassium hydroxide solution (1.95 mL, 1 M solution, 1.95 mmol), terahydrofuran (9 mL) and methanol (3 mL) gave the title compound (0.35 g, > 100%) as a solid.

NMR (DMSO-d 6): δ 12.90 (br s, 1H); 8.19 (d, IH); 7.66 to 7.61 (m, 1H); 7.50 to

7.43 (m, 2 H); 7.37 to 7.31 (m, 4H); 7.28 to 7.24 (m, 1H); 7.00 (s. 2H); 4.72 (t, IH); 3.74 (s, 2 H); 3.38 to 3.25 (m, 2H); 2.60 to 2.53 (q, 4H); 2.26 (s, 3H); 2.23 (s. 3H); 1.60 (s, 3H); 1.02 (t, 6 H).

MS (-ESI): [M-H] -, single bromine isotopic pattern, 628/630.

analysis:

Calcd for C 57 F 57 BrNO 5 S 66.66% C, 5.75% H, 2.22% N;

Found: C, 66.95; H, 5.99; N, 2.26.

Example 88

(2R) -2- [4- (9-Bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenoxy] -3-phenyl-propionic acid

The title compound was prepared in analogy to Example 87 using the appropriate starting materials; the product was a yellow solid.

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

165NMR (DMSO-d6): δ 13.00 (broad s, 1H); 8.18 (d, IH); 7.63 to 7.60 (m, 1H); 7.46 to

7.44 (m. 2H); 7.36 to 7.24 (m, 5H); 7.06 (s, 2 H); 4.46 (t, IH); 3.71 (s, 2 H); 3.38 to 3.34 (m, 2H); 3.25 (d, 2 H); 2.54 (q, 4H); 1.52 (s, 3H); 1.13 (d, 6H); 1.06 (d, 6H); 1.00 (t, 6H).

MS (-ESI): [M-H] -, single bromine isotopic pattern, 684/686.

analysis:

Calcd for C 15 H 18 BrNO 5 S 68.21% C, 6.46% H, 2.04% N;

Found: C, 68.04; H, 6.52; N, 1.92.

Analytical HPLC determined the content of the major component (97.4%).

Claims (43)

PATENT CLAIMS 1. Benzothiophenes, benzofurans or indoles of the general formula I in which Ar is (a) (b) (c) A is hydrogen, halogen or OH; B and D independently of one another are hydrogen, halogen, -CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, hydroxyaralkyl of 6 to 12 carbon atoms, cycloalkyl 3-8 carbon atoms, nitro, amino, -NR ¹ R ^1a , -NR ¹ COR ^1a , -NR ¹ CO 2 R ^1a , C 3 -C 8 cycloalkylamino, morpholino, furan-2-yl, furan-3-yl , thiophen-2-yl, thiophen-3-yl, -COR ^1b , or -OR; R is hydrogen, alkyl of 1 to 6 carbon atoms, -COR ¹ , - (CH 2) n CO ² R ¹ , -CH (R ^1a ) CO ² R ¹ , -SO ² R ¹ , - (CH 2) m CH (OH) CO 2 R ¹ , - ( CH2) COCO ₂ R ^1, - (CH 2) m CH = CHCO2R ^1, or - (CH 2) _m O (CH 2) OCO ₂ R ^1; R ¹ is hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl of 6 to 12 carbon atoms, aryl, or -CH ₂ CO ₂ R ¹ '; R ¹ 'is hydrogen or alkyl of 1 to 6 carbon atoms; E is S, SO, SO ₂ , O, or NR ^1c ; ··············· - 167 ·· ···· ·· ··· ·· ··· X is hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, -CN, aryl, aralkyl of 6 to 12 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, hydroxyaralkyl of 6 to 12 carbon atoms , C 1 -C 6 perfluoroalkyl, C 1 -C 6 alkoxy, aryloxy, arylalkoxy, nitro, amino, -NR ² R ^2a , -NR ² COR ^2a , cycloalkylamino of 3 to 8 carbon atoms, morpholino, alkylsulfanyl of 1 up to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl, -OCH ₂ CO ₂ R ^2b , or -COR ^2c ; Y is hydrogen, halogen, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, hydroxyaralkyl of 6 to 12 carbon atoms, -OR ³ , -SR ³ , -NR ³ R ^3a , -COR ^3b , morpholino, or piperidino; R ^1a , R ^1c , R ² , R ^2a , R ³ , R ^3a independently of one another are each hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl of 6 to 12 carbon atoms, or aryl; R ^1b is alkyl of 1 to 6 carbon atoms or aryl; R ^2b is hydrogen, alkyl of 1 to 6 carbon atoms; R ² ® and R ^3b independently of each other are each C 1 -C 6 alkyl, aryl, or C 6 -C 12 aralkyl; C is hydrogen, halogen or -OR ⁴ ; R ⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, -CH (R ⁵ ) W, -C (CH 3) 2 CO ² R ⁶ , -5-thiazolidine-2,4-dione, -CH (R ⁷ ) (CH 2) _m CO ₂ R ^6, -COR ^6, -PO3 ^(R6) 2, -SO ₂ R ^6, - (CH2) PCH (OH) CO 2 R ^6, - (CH 2) _p COCO ₂ R ^6, - (CH2) PCH = CHCO ² R ⁶ , or - (CH ₂ ) _p O (CH ₂ ) _q CO ₂ R ⁶ ; R ⁵ is hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl of 6 to 12 carbon atoms, aryl, -CH ₂ (1H-imidazol-4-yl), -CH ₂ (3-1H-indolyl), -CH ₂ CH ₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), -CH ₂ CH ₂ (1-oxo-1,3-dihydro-isoindol-2-yl), -CH ₂ (3-pyridyl), -CH ₂ CO ₂ H, or - (CH ₂ ) _n G; G is -NR ^6a R ^7a , -NR ^6a COR ^7a , U LJCH ₂ ) _n or W is -CO ₂ R ⁶ , -CONH 21 -CONHOH, -CN, -CONH (CH 2) 2 CN, -5-tetrazole, -PO 3 (R ⁶ ) 2, -CH ₂ OH, -CONR ^6b CHR ^7b , -CH ₂ NR ^6b CHR ^7b CO 2 R ⁶ , -CH 2 OCHR ^7b CO 2 R ⁶ , -CH ² Br, or -CONR ^6b CHR ^7b CO ² R ⁶ ; -168 ·· ·· ··· ··· ··· R ⁶ , R ^6a , R ⁷ , R ^7a independently of one another are hydrogen, alkyl of 1 to 6 carbon atoms, or aryl; R ^6b is hydrogen or -COR ^6c ; R ^6c is alkyl of 1 to 6 carbon atoms or aryl; R ^7b is hydrogen, alkyl of 1 to 6 carbon atoms, or hydroxyalkyl of 1 to 6 carbon atoms; Z ¹ and Z ² independently of each other are each hydrogen, halogen, -CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, nitro, amino, -NR ¹ R ^1, -NR ¹ COR ^1, cycloalkylamino of 3-8 carbon atoms, morpholino, or -OR ^8; or Z ¹ and Z ² may together form a diene unit of the formula -CH = CR ⁹ -CR ¹⁰ = CR ¹¹ -; R ⁸ is hydrogen, alkyl of 1 to 6 carbon atoms, or aryl; R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, aryl, halogen, hydroxy, or alkoxy of 1 to 6 carbon atoms; m is 1 to 4; n is 1 or 2; p is 1 to 4; q is 1 to 4; or a pharmaceutically acceptable salt thereof. Benzothiophenes, benzofurans or indoles according to claim 1, wherein Ar is in which A is hydrogen or halogen; B and D are each, independently of the other, hydrogen, halogen, -CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, branched alkyl, cycloalkyl of 3 to 8 • · · · ······· -169 carbon, nitro or -OR atoms; R is hydrogen or alkyl of 1 to 6 carbon atoms; E is sulfur or oxygen; X is hydrogen, halogen, alkyl of 1 to 6 carbon atoms, -CN, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, aryloxy, arylalkoxy, nitro, amino, -NR ² R ^2a , -NR ² COR ^2a , cycloalkylamino, morpholino, alkylsulfanyl of 1 to 6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- N, N -dimethylaminoethylsulfanyl; R ¹ , R ^1a , R ² , R ^2a , R ³ and R ^3a independently of one another are hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl of 6 to 12 carbon atoms, or aryl; Y is hydrogen, halogen, -OR ³ , -SR ³ , -NR ³ R ^3a , or morpholine; C is hydrogen, halogen, or -OR ⁴ ; R ⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, -CH (R ⁵ ) W, -C (CH 3) 2 CO ² R ⁶ , -5-thiazolidine-2,4-dione, -CH (R ⁷ ) (CH 2) mCO ₂ R ^6, -COR ^6, -PO3 ^(R6) 2, -SO ₂ R ^6, - (CH2) PCH (OH) CO 2 R ^6, - (CH 2) _p COCO ₂ R ^6, - (CH 2) GC = CHCO2R ⁶ , or - (CH 2) _p O (CH 2) _q CO ₂ R ⁶ ; R ⁵ is hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl of 6 to 12 carbon atoms, aryl, -CH 2 (1 H -imidazol-4-yl), -CH 2 (3-1 H -indoles I), -CH 2 CH 2 (1,3-dioxo-1,3-dihydroisoindol-2-yl), -CH 2 CH 2 (1-oxo-1,3-dihydro-isoindol-2-yl), or -CH 2 (3-pyridyl); W is CO 2 R ^6, -CONH 2, -CONHOH, 5-tetrazole, or a -CONR ^{6 b 7 b} CHR CO ₂ R ^6; R ⁶ , R ^6a ', R ⁷ , R ^7a and R ^7b independently of one another are hydrogen, alkyl of 1 to 6 carbon atoms, or aryl; Z ¹ and Z ² independently of each other are each hydrogen, halogen, -CN, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, nitro, amino, -NR ¹ R ^1, -NR ¹ COR ^1, cycloalkylamino of 3-8 carbon atoms, morpholino, or -OR ^8; or Z ¹ and Z ² may together form a diene unit of the formula -CH = CR ⁹ -CR ¹⁰ ° = CH-; R ⁹ and R ¹⁰ are each, independently of one another, hydrogen or alkyl of 1 to 6 carbon atoms; p is 1 to 4; q is 1 to 4; or a pharmaceutically acceptable salt thereof. ························ - 170 ··· · · · · · · · · · · · Benzothiophenes, benzofurans or indoles according to claim 2, wherein A is hydrogen; B and D each independently of one another are halogen, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 6 to 12 carbon atoms, or cycloalkyl of 3 to 8 carbon atoms; E is sulfur or oxygen; X is hydrogen, halogen, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, -CN, alkoxy of 1 to 6 carbon atoms, aryloxy, aryloxy of 6 to 12 carbon atoms and arylsulfanyl; Y is hydrogen, or -NR ¹ R ² or morpholine; R ¹ and R ² each independently of one another are hydrogen or alkyl of 1 to 6 carbon atoms, aralkyl of 6 to 12 carbon atoms, or aryl; C is OR ⁴ ; R ⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, -CH (R ⁵ ) W, or -5-thiazolidine-2,4-dione; R ⁵ is hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl of 6 to 12 carbon atoms, aryl, -CH ₂ (3-1H-indolyl), -CH ₂ CH ₂ (1,3-dioxo-1,3 -dihydro-isoindol-2-yl), or -CH ₂ CH ₂ (1-oxo-1,3-dihydro-isoindol-2-yl); W is -CO ₂ R ⁶ , -CONH 21 -CONHOH, -5-tetrazole, -PO 3 (R ⁶ ) 2 or -CONR ⁶ CHR ⁶ CO ₂ R ⁶ ; R ⁶ is hydrogen or alkyl of 1 to 6 carbon atoms; Z ¹ and Z ² together form the diene unit of the formula -CH = CH-CH = CH-; or a pharmaceutically acceptable salt thereof. The compound of Claim 1 which is (R) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy acid. -3-Phenyl-propionic or a pharmaceutically acceptable salt thereof. The compound of Claim 1 which is (R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6- ethyl-phenoxy] -3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof. ······························· -171 ·· ···· ·· ··· ·· · The compound of claim 1 which is (R) -2- [4- (9-bromo-2,3-dimethylnaphtho [2,3-b] thiophen-4-yl) -2,6-dimethylphenoxy acid. -3-Phenyl-propionic or a pharmaceutically acceptable salt thereof. (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-fluoro-phenoxy] compound according to claim 1 -3-phenylpropionic or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is [4- (9-bromo-2,3-dimethylnaphtho [2,3-b] thiophen-4-yl) -2,6-diisopropylphenoxy] acetic acid or a pharmaceutically acceptable salt thereof. The compound of Claim 1 which is (R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6- sec-butyl-phenoxy] -3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is (R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6- isopropyl-phenoxy] -3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is (R) -2- [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2- cyclopentyl-phenoxy] -3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-isopropyl-phenoxy] - 3-phenylpropionic or a pharmaceutically acceptable salt thereof. (R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-cyclopentyl-phenoxy] compound according to claim 1 -3-phenylpropionic or a pharmaceutically acceptable salt thereof. - 172 ······················· The compound of claim 1 which is (R) -2- [2,6-dibromo-4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) - phenoxy] -3-phenyl-propionic or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is (R) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy acid. -4-Phenylbutyric acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is (S) -2- [2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy acid. -4-Phenylbutyric acid or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is 2- [2,6-dibromo-4- (9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho [2,3-b] thiophen-4-yl) acid -phenoxy] -3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is (R) -2- [2,6-dibromo-4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) - phenoxy] propionic or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is [2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-nitro-phenoxy] -3- phenylpropionic or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is 2,6-dibromo-4- (9-bromo-2,3-dimethylnaphth [2,3-b] thiophen-4-yl) -phenol or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is 2-bromo-4- (9-bromo-2,3-dimethylnaphtho [2,3-b] thiophen-4-yl) -2-nitro-phenol or a pharmaceutically acceptable salt thereof. -173 ·· ·· ·· ··· · 9 · 9 · 9 · 9 The compound of claim 1 which is (R) -2- [2,6-dibromo-4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) acid. 1-Phenoxy] -3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is (R) -2- [2,6-dibromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -phenoxy] -3- phenylpropionic or a pharmaceutically acceptable salt thereof. (2 R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl- phenoxy] -3-phenyl-propionic or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is (R) -2- [4- (9-bromo-2,3-dimethylanaphth [2,3-b] thiophen-4-yl) -2,6-diethyl- phenoxy] -3-phenyl-propionic or a pharmaceutically acceptable salt thereof. 26. The compound of Claim 1 which is {(2 ft) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2 _I 6-dimethyl phenoxy] -3-phenyl-propionylamino} -acetic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is {(2R) -2- [4- (9-bromo-2,3-dimethylnaphtho [2,3-b] thiophen-4-yl) -2,6-diethylphenoxy] -3 acid -phenyl-propionylamino} acetic acid or a pharmaceutically acceptable salt thereof. (2 R) -2- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3- phenylpropionic or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is (2S) -2- [4- (9-bromo-2,3-dimethylnaphtho [2,3-b] thiophen-4-yl) -2,6-dimethylphenoxy] -3- phenylpropionic or a pharmaceutically acceptable salt thereof. • • • - 174 ·· ······················· 30. The compound of Claim 1 which is {(2 /?) - 2- [4- (2,3-naphtho [2 ₁ 3-b] thiophen-4-yl) -2,6-diethyl-phenoxy] -3-phenyl-propionylamino} -acetic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is (R) -2- [4- (9-bromo-2,3-dimethylnaphtho [2,3-b] furan-4-yl) -2,6-diethyl-] - phenoxy] -3-phenyl-propionic or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is (R) -2- [2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -propionic acid or a pharmaceutical thereof permissible salt. The compound of claim 1 which is (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-cyclopentyl-phenoxy] acid -propionic or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is (R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-ethyl-phenoxy] -3-phenyl -propionic or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is 2-bromo-4- (2,3-dimethyl-naphtho [2,3b] furan-4-yl) -6-ethyl-phenol or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is (R) -2- [2-bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6-ethyl-phenoxy] - 3-phenylpropionic or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-propyl-phenoxy] acid -3-phenylpropionic or a pharmaceutically acceptable salt thereof. -175 ·· ································ (2R) -2- [4- (9-Bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -2,6], according to claim 1 -diisopropyl-phenoxy] -3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is: 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol; 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol; 4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) -phenol; 2,6-dibromo-4- (2,3-dimethyl-9-phenylsulfanyl-naphtho [2,3-b] thiophen-4-yl) -phenol; 4- (9-bromo-3-methyl-2-morpholino-4-yl) methyl-naphtho [2,3-b] thiophen-4-yl) -phenol; Acetic acid 4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -ester; 4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -phenol; 2,6-dibromo-4- (9-bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -phenol; 2.6- dibromo-4- (9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho _[I, 2 3-b] thiophen-4-yl) -phenol; 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-nitro-phenol; 2-amino-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol; 2-amino-6-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenol; [2-Bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-nitro-phenoxy] -acetic acid; (R) -2 - [2,6-dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thien 4-yl) phenoxy] -propanoic acid; 2- [2,6-dibromo-4- (9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -propionic acid; 2-bromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -6-isopropyl-phenol; (R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-isopropyl-phenoxy] -3-phenyl-propionic acid; (R) -2- [2-Cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3-phenyl-propionic acid; (R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl-propionic acid; (R) -2- [4- (2,3-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diisopropyl-phenoxy] -3-phenyl-propionic acid; ··············································· - 176 (R) -2- [4- (2,3-dimethyl-naphtho [2,3-] b] thiophen-4-yl) -2-fluoro-phenoxy] -3-phenyl-propionic acid; (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-ethyl-phenoxy] -3-phenyl-propionic acid; 3-Bromo-5- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-methoxy-phenylamine; or [3-bromo-5- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-methoxy-phenylamino] -acetic acid; (2R) -2- [4- (9-Bromo-2,3-dimethyl-1-oxo-1H-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethylphenoxy] -3 phenyl-propionic acid; (R) -2- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2 ₁ 6-diethyl-phenoxy] -3-phenyl-propionic acid; 4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-diethyl-phenol; 4- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-cyclopentyl-phenoxy] -butyric acid; 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -phenol; Acetic acid 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -phenyl ester; (R) -2- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-ethyl-phenoxy] -3-phenyl-propionic acid; 4- [2-Bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6-ethyl-phenoxy] -butyric acid; 4- [2-Bromo-4- (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -6-ethyl-phenoxy] -butyric acid amide; (2,3-dimethyl-naphtho [2,3-b] furan-4-yl) -2-ethyl-phenol; Acetic acid [9-bromo-4- (4-methoxy-3,5-dimethyl-phenyl) -3-methyl-naphtho [2,3-b] thien-2-yl] -methyl ester; Acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thien-4-yl) -2-methyl-phenyl ester; Acetic acid 4- (9-bromo-2-diethylaminomethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenyl ester; 2- [4- (9-Bromo-2-diethylaminomethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxy] -3-phenyl-propionic acid; or a pharmaceutically acceptable salt thereof. - 177 ································ The compound of claim 1 which is: Acetic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester; Acetic acid 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester; Methanesulfonic acid 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester; Methanesulfonic acid 4- (9-iodo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester; Acetic acid 4- (9-bromo-2-chloromethyl-3-methyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester; (R) -2- [Dibromo-4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxy] -3-phenyl-propionic acid methyl ester; [3-Bromo-5- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-hydroxy-phenyl] -carbamic acid tert-butyl ester; 9-Bromo-4- (3-bromo-methoxy-5-nitro-phenyl-2,3-dimethyl-naphtho [2,3-b] thiophene, or [3-bromo-5- (9-bromo) -methyl ester] -2,3-Dimethyl-1-naphtho [2,3-b] thiophen-4-yl) -2-methoxy-phenylamino-acetic acid. 41. A pharmaceutical composition comprising a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of metabolic disorders associated with insulin resistance or hyperglycemia of a mammal. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for treating or inhibiting type II diabetes in a mammal. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for modulating glucose levels in a mammal.