SK13812001A3 - Diaryl derivatives and their use as medicaments - Google Patents

Abstract

Compounds of formula (I) in which W is O, S, S(O) or S(O)2; X is -SR4, -S(O)R4, or -S(O)2R4, -S(O)2NR5R6; or X is -C(O)NR5R6 provided that -C(O)NR5R6 is located at the 3', 4' or 5' position; Y is O or H2; Z is hydrogen, halogen, hydroxy, optionally substituted alkoxy, aralkoxy, acyloxy or alkoxycarbonyloxy; R is hydrogen, halogen, trifluoromethyl, lower alkyl or cycloalkyl; R1 is hydroxy, optionally substituted alkoxy, aryloxy, heteroarylocy, aralkyloxy, cycloalkoxy, heteroaralkoxy or -NR5R6; R2 is hydrogen, halogen or alkyl; R3 is halogen or alkyl; R4 is optionally substituted alkyl, aryl, aralkyl, heteroaralkyl or heteroaryl; R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R5 and R6 combined are alkylene optionally interrupted by O, S, S(O), S(O)2 or NR7 which together with the nitrogen atom to which they are attached form a 5- to 7- membered ring; n represents zero or an integer from 1 to 4; pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising said compounds; a method to prevent and treat diseases associated with an imbalance of thyroid hormones, such as hypo-and hyperthyroidism, obesity, osteoporosis and depression; and, a method of lowering LDL cholesterol and Lp(a) levels in mammals using such compounds.

Description

Diaryl derivatives, their use in the preparation of a medicament and pharmaceutical compositions containing them

Technical field

The invention relates to novel compounds which have a thromimetic effect and can be used for the prevention and / or treatment of diseases associated with thyroid hormone imbalances such as hypo- and hyperthyrodism, obesity, osteoporosis and depression. The compounds of the invention further have a hypolipidemic effect which increases the removal of cholesterol from the circulation, in particular the removal of cholesterol in the form of low-density lipoproteins. The compounds further reduce elevated levels of lipoprotein (a), which is an independent cardiovascular risk factor. The invention further relates to the preparation of pharmaceutical compositions containing these compounds and their use as medicaments.

SUMMARY OF THE INVENTION

The present invention provides novel compounds of formula (I)

R in which

W is an oxygen atom, a sulfur atom, an S (O) group or an O atom

S (O) ₂

X is -SR ⁴ , -S (O) R 7 *, -S (O) R 7, -

-S (O) ₂ NR ^with R ⁶ , or X is -C (O) NR -R ^e , wherein the -C (O) NR ⁵ R ^{6 group} is located at the 3'-, 4'- or 5 'positions -.

Y is an oxygen atom or there are two hydrogen atoms,

Z is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted alkoxy group, an arylalkoxy group, an acyloxy group or an alkoxycarbonyloxy group,

R is a hydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkyl group or a cycloalkyl group,

R * is hydroxy, optionally substituted alkoxy, aryloxy, heteroaryloxy, arylalkoxy, cycloalkoxy, heteroarylalkoxy or -NR ⁵ R ⁶ ,

R ² is H, halogen or alkyl,

R ³ is a halogen atom or an alkyl group,

R 'is an optionally substituted alkyl, aryl, arylalkyl, heteroarylalkyl or heteroaryl group,

R ³ , R ⁶ and R ⁷ are independently of one another and are hydrogen, optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or

R ⁵ and R ⁶ together form an alkylene group, optionally interrupted by oxygen, sulfur, S (O), S (O) 2 or NR ⁷ , which together with the nitrogen atom to which they are attached form 5- to 7- a membered ring, n is 0 or an integer from 1 to 4, and pharmaceutically acceptable salts thereof.

The compounds of the invention have a thyromimetic effect and can be used for the prevention and / or treatment of diseases associated with thyroid hormone imbalances such as hypo- and hyperthyrodism, obesity, osteoporosis and depression. In particular, the compounds according to the invention have a hypolipidemic effect which increases the removal of cholesterol from the circulation, in particular the removal of cholesterol in the form of low density lipoproteins (LDL). They are thus useful for lowering total plasma cholesterol levels in mammals, particularly for lowering LDL-cholesterol levels. The compounds further reduce elevated levels of lipoprotein (a) [Lp (a)], which are an independent cardiovascular risk factor in mammals. The compounds of the invention can therefore be used for the prevention and / or treatment of occlusive cardiovascular conditions resulting from hyperlipidemia and hyperlipoproteinaemia, such as atherosclerosis and coronary heart disease in mammals.

The invention relates to compounds of formula I, to pharmaceutical compositions containing them, and to a method of using the compounds.

The following are definitions of various terms used to describe the invention. These definitions apply to the terms used in the description (unless otherwise indicated, in specific cases either individually or as part of a larger group).

The term optionally substituted alkyl refers to unsubstituted or substituted, unbranched or branched hydrocarbon groups having 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. Examples of unsubstituted alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like. Substituted alkyl groups include, but are not limited to, alkyl groups substituted with one or more (e.g., two or three) substituents selected from the group consisting of: halogen atoms, lower alkenyl, hydroxyl, cycloalkyl, alkanoyl, alkoxy, alkyloxyalkoxy, alkanoyloxy amino, alkylamino, dialkylamino, dialkylaminocarbonyl, alkanoylamino, thiol, alkylthio, alkylthio, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkyl, sulfonamide, alkoxy, carboxylic acid, nitro, carboxylic acid, nitro, arylalkoxy, guanidino, heterocyclyl, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridy Preferred substituents in, for example, substituted alkyls, especially when the substituted alkyl group of R ¹ is a substituted alkoxy group, are lower alkyl, cycloalkyl, lower alkenyl, benzyl, mono or a disubstituted lower alkyl group, e.g. an in- (amino, mono- or di-lower alkylamino, carboxyl, lower alkoxycarbonyl) lower alkyl group, and a- (lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl) lower alkyl group such as a pivaloyloxymethyl group.

The term lower alkyl includes alkyl groups as described above having 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms.

The term halogen or halo includes fluorine, chlorine, bromine and iodine.

The term alkenyl includes any of the aforementioned alkyl groups containing at least 2 carbon atoms and further comprising at least one double bond. Preferred are groups containing two to four carbon atoms.

The term alkylene means a straight chain bridge of 1 to 6 atoms linked by single bonds (e.g. - (Cth) -) - wherein x is 1 to 6, which may be further substituted with lower alkyl groups of 1 to 3 carbon atoms.

The term cycloalkyl means a cyclic hydrocarbon group of 3 to 8 carbon atoms.

The term alkoxy means an alkyl-O- group.

The term alkanoyl means an alkyl-C (O) - group.

The term alkanoyloxy means an alkyl-C (O) -O- group.

The terms alkylamino and dialkylamino mean the (a15 alkyl) NH- group and the (alkyl) zN- group.

The term alkanoylamino means an alkyl-C (O) -NH- group.

The term alkylthio means an alkyl-S- group.

The term alkylthiono means an alkyl-S (O, -) group.

The term alkylsulfonyl means an alkyl-S (O) 2- group.

The term alkoxycarbonyl means an alkyl-O-C (O) - group.

The term 'alkoxycarbonyloxy' means an alkyl-O-C (O) -O- group.

The term alkyl in the above definitions refers to an optionally substituted alkyl as defined above.

The term aryl means monocyclic or bicyclic aromatic hydrocarbon groups of 6 to 12 carbon atoms in one ring moiety such as phenyl, naphthyl, tetrahydronaphthyl and biphenyl, each of which may optionally be substituted with one to four substituents selected from the group consisting of alkyl; halogen, hydroxyl, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, nitro, cyano, carboxyalkyl, sulfonyl, thioxy, a heterocyclyl group, and the like.

The term monocyclic aryl means optionally substituted phenyl as described under aryl.

The term aralkyl means an aryl group directly bonded via an alkyl group such as benzyl.

The term aralkoxy means an aryl group linked through an alkoxy group.

The term arylsulfonyl means aryl-S- (O) _2. The term aroyl means aryl-C (O) -.

The term heterocyclyl means an optionally substituted fully saturated or unsaturated aromatic or non-aromatic cyclic group, for example monocyclic of 4 to 7 members, bicyclic of 7 to 11 members, or tricyclic of 10 to 15 members in a ring system having at least one ring heteroatom, and which contains at least one carbon atom. Each heteroatom-containing heterocyclic group ring may have 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic group may be attached via a heteroatom or a carbon atom.

Examples of monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolidyl, oxazolidinyl, isoxazolyl, thiazolyl, thiazol, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrolidinyl, 2-cxoazep, 2-cxoazep, 2-cxoazep. a piperidonyl group, a pyridyl group, a 2-pyridone group, a N-lower alkylpyridone group, e.g. - lower alkyl 2-pyridone, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, S-oxo-thiamorpholinyl, S, S-dioxo-thiamorpholinyl, 1,3-dioxalane and tetrahydro-1,1-dioxothienyl and the like.

Examples of bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzolylinyl, indolizinyl, indolizinyl, indolizinyl, indolizinyl, a quinolinyl group, a quinoxalinyl group, an indazclyl group, a pyrrolopyridyl group, a furopyridinyl group (such as a furo [2,3-c] pyridinyl group, a furo- [3,2-b] pyridinyl group or a furo- [2,3-b] pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as

3,4-dihydro-4-oxo-quinazolinyl) and the like.

Examples of tricyclic heterocyclic groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, zantenyl, and the like.

The term heterocyclyl includes substituted heterocyclic groups. Substituted heterocyclic groups are heterocyclic groups substituted with 1, 2 or 3 substituents selected from the group consisting of:

(a) an alkyl group, (b) a hydroxyl group (or a protected hydroxyl group), (c) halogen atoms, (d) oxo (i.e., = O), (e) amino, alkylamino or dialkylamino, (f) alkoxy (g) cycloalkyl, (h) carboxyl, (i) heterocyclooxy, (j) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl, (k) mercapto, (1) nitro, (m) cyano, (n) ) sulfonamido, sulfonaminoalkyl or sulfonamido-dialkyl, (o) aryl, (p) alkylcarbonyloxy, (q) arylcarbonyloxy, (r) arylthio, (s) aryloxy, (t) alkylthio, (u) formyl), (u) arylalkyl, or (w) an aryl group substituted with an alkyl group, a cycloalkyl group, an alkoxy group, a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, or a halogen atom.

The term heterocyclooxy means a heterocyclic group bonded through an oxygen bridge.

The term heteroaryl means aromatic heterocycles, for example, monocyclic or bicyclic substituents such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyrracinyl pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzethienyl, quinolinyl, isoquinolinyl, benzimidacolyl groups

Also, benzofuryl and the like, optionally substituted with one or more substituents described in connection with a substituted aryl group, for example substituted with a lower alkyl, a lower alkoxy or a halogen atom.

The term heteroaryl-oxy means a heteroaryl-O- group.

The term heteroarylsulfonyl means heteroaryl-S (O) ₂ The term heteroaroyl means heteroaroyl-C (0)

The term heteroaralkyl means a heteroaryl group bonded via an alkyl group.

The invention also includes derivatives which are useful as prodrugs, e.g. pharmaceutically acceptable prodrugs such as carboxylic acid esters. according to the invention (COR ¹ represents a carboxyl group) which are converted to the corresponding free acids by solvolysis under physiological conditions.

Examples of these carboxylic acid esters defined as COR ¹ are preferably lower alkyl esters, lower alkenyl esters, benzyl esters, mono or disubstituted lower alkyl esters, e.g. m- (amino, mono- or di- lower alkylamino, carboxy, lower alkoxycarbonyl) -lower alkyl esters, α- (lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkyl aminocarbonyl) -lower alkyl esters such as pivaloyloxymethyl ester and the like esters commonly used in the art.

A preferred value for R is a hydrogen atom or a lower alkyl group.

It prefers that R ¹ is OH, lower alkcxylová group and aryloxy group.

It prefers ^R: is hydrogen, halogen or lower alkyl.

It prefers R ³ is halogen or lower alkyl.

We prefer R ⁴ is phenyl or phenyl substituted one or more by a substituent selected from a lower alkyl, lower alkoxy, halogen and trifluoromethyl.

A preferred value for R ⁵ is hydrogen.

A preferred value for R ⁶ is a phenyl group or a phenyl group substituted with one or more sustituents selected from the group consisting of lower alkyl, halogen atoms and trifluoromethyl.

A preferred value for W is an oxygen atom.

A preferred value for X is -S (O) ₂ R ⁴ or -S (O) ₂ NR ⁵ R ⁶ .

A preferred value for Y is an oxygen atom.

A preferred value for Z is a hydrogen atom or a hydroxyl group.

A preferred value for n is zero, 1 or 2.

Depending on the type of substance, the compounds of the invention may contain one or more asymmetric centers. The resulting diastereomers, enanriomers and geometric isomers are included within the scope of the present invention.

Preferred are compounds of formula (I) as defined above, provided that when X is -C (O) NR ⁵ R ⁶ , Z is not hydrogen.

Preferred are compounds of formula I wherein W is O or S,

X is -S (O) 2 R ', wherein R ⁴ is lower alkyl, phenyl, or phenyl substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl, or is -S (O) 2 NR ⁵ R®, or is -C (O) NR ⁵ R ^6, wherein in each case R ⁵ is hydrogen or lower alkyl and R ⁶ is in each case hydrogen, lower alkyl, lower alkyl substituted ^with NR ⁶ R, 3- to 7-membered cycloalkyl, phenyl, phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl, or a group pyridylcvá N-lower alkyl-2-pyridone or

R ⁵ and R ⁶ together form an alkylene group or an alkylene group interrupted by an oxygen atom or a S (O) 2 group which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring.

Y is an oxygen atom or a hydrogen atom,

Z is a hydrogen atom or a hydroxyl group,

R is a hydrogen atom,

R ¹ is a hydroxyl group, a lower alkoxy group, or an NR group ^with R ^e where R ⁵ is a hydrogen atom, a lower alkyl group and R ⁶ is a hydrogen atom, a lower alkyl group, a lower alkoxy group or R ⁵ and R ⁶ together form an alkylene group a group or alkylene group interrupted by an oxygen atom and together with the nitrogen atom to which they are attached form a 5- to 7-membered ring,

R ² is hydrogen, halogen or lower alkyl,

R ³ is halogen or lower alkyl, n is zero, 1 or 2, and pharmaceutically acceptable salts thereof.

Preferred are compounds of formula IA

(IA) in which

W is an oxygen atom or a sulfur atom,

X is -SR ⁴ , -S (O) R ⁴ ', -StOzR' ¹ , -S (O) _: NR ⁵ R ⁶ , or -C'O) NR ⁵ R ⁶ ,

Y is an oxygen atom or two hydrogen atoms,

Z is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, an arylalkyl group, an acyloxy group or an alkoxycarbonyloxy group,

R ¹ is a hydroxyl group, a lower alkoxy group or an aryloxy group,

R is a hydrogen atom, a halogen atom or a lower alkyl group,

R ³ is a halogen atom or a lower alkyl group,

R ⁴ is an optionally substituted alkyl, aryl, arylalkyl, hetercaryl or heteroarylalkyl group,

R ^3, R ^e and R ⁷ are each independently -H, substituted alkyl, cycloalkyl, aryl, arylalkyl, hetercarylcvé or heteroarylalkyl; or

R ⁵ and R ^e together form an alkylene group, optionally interrupted by oxygen, sulfur, S (O), 3 (O; or NR ⁷⁾ , which together with the nitrogen atom to which they are attached form a 5- to 7-membered a ring, n is zero, 1 or 2, or a pharmaceutically acceptable salt thereof.

Further preferred are compounds of formula IB

R

R '

O (IB) in which

X is -S (O) ₂ R ⁴ , -S (O) ₂ NR ⁵ R ⁶ , or -C (O) NR ⁵ R ⁶ ,

Z is a hydroxyl group, a lower alkanoyloxy group, or a lower alkoxy group,

R ¹ is a hydroxyl group or a lower alkoxy group,

R ² and R ³ are lower alkyl groups,

R ⁴ is aryl,

R ⁵ , R ⁶ and R ⁷ are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or

R ⁵ and R ^e together form an alkylene group, optionally interrupted by an oxygen atom, a sulfur atom, an S (O) group, an S (O) ₂ group or an NR ⁷ group, which together with the nitrogen atom to which they are attached form 5- to 7- or a pharmaceutically acceptable salt thereof.

Most preferred are compounds of formula IC

HO

ΌΗ

X (IC) in which

X is -S (O) ₂ R ⁴ or -S (O) ₂ NR ³ R ⁶ R 'is a monocyclic aryl group.

R ⁶ together form a CH 2 CH 2 -Q-CH ₂ CH ₂ group, wherein Q is CH ₂ , oxygen, NR ⁷ , sulfur, S (O) or S (O) 2, which together with the nitrogen atom to which they are attached form a six-membered ring, or a pharmaceutically acceptable salt thereof.

Particularly preferred are compounds of formula IC wherein X is S (O) ₂ R ⁴ and R is a phenyl group optionally substituted by a lower alkyl group, a lower alkoxy group or a trifluoromethyl group, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Pharmaceutically acceptable salts are salts of any acidic compound of the invention formed with a base, namely with alkali metal cations, alkaline earth metal cations such as sodium salts, potassium salts, calcium salts, magnesium salts as well as salts with an ammonium cation such as ammonium salts, trimethylammonium salts, diethylammonium salts, and tris- (hydroxymethyl) -methylammonium salts.

If a basic group is included in the structure, such as a pyridyl group, acid addition salts such as mineral acids, organic carboxylic acids, and organic sulfonic acids such as chlorofluoric acid, methanesulfonic acid, and maleic acid can likewise be prepared.

Compounds of formula I may be prepared from appropriately substituted phenols of formula II

wherein R ² and R ³ (prepared by methods such as those described above and W is commonly known in the literature) have a trifluoromethylsulfonyl ester oxygen atom first by subsequent reaction with lithium chloride in an inert organic solvent such as N-methylpyrrolidone, Ν, Ν -dimethylformamide or dimethyl sulfoxide to give a compound of formula III

(III)

The compound of formula III can be converted to the compound of formula 17

by reaction with appropriately substituted phenols or thiophenols of formula V

in which R is as defined above, X 'and Z' have the same meaning when X and Z are as defined above, or X * and Z 'are groups convertible to X and Z, optionally in a base such as sodium hydride or potassium carbonate, in an inert organic solvent such as N-methylpyrrolidone, N, N -dimethylformamide or dimethylsulfoxide at room temperature or three elevated temperature.

Compounds of formula V may be prepared by methods known in the literature.

Alternatively, compounds of formula IV may be prepared by condensation of cis-aryl-iodo-tetrafluoroborate of formula VI

R

r (VI) wherein R, X * and Z 'are as defined above, with phenols or thiophenols of formula II wherein H is oxygen or sulfur, by literature procedures, for example, by reaction in the presence of a copper catalyst and a base such as is triethylamine, in an inert organic solvent such as dichloromethane.

Compounds of formula IV wherein Z 'is an alkoxy or arylalkoxy group may be converted to compounds of formula IV wherein Z' is a hydroxyl group by methods commonly known in the literature, for example using hydrobromic acid or boron trihalide such as boron trichloride or boron tribromide, especially when Z 'is a methoxy group, or by using hydrogen in the presence of a catalyst such as palladium on carbon, especially when Z' is a benzyl group.

Compounds of the invention wherein X is -S (C (R >N'R '*) may be prepared, for example, by first reacting a compound of formula IV wherein R and X' are hydrogen and X * is located at the 3 'and Z' positions is a hydroxyl group, an alkoxy group or an arylalkoxy group and Z 'is located at the 4' position by reaction with chlorosulfonic acid in an organic solvent such as dichloromethane to give a compound of formula VII

OH (VII) wherein Z 'is as defined above. Compounds of formula VII wherein Z 'is a hydroxyl group can be converted to compounds of formula VII' where Z 'is a protected hydroxyl group such as an alkanoyloxy group, an alkoxycarbonylcyl group or a trialkylsiloxy group using methods commonly known in the literature.

Compounds of formula VII wherein Z 'is alkoxy, arylalkoxy, alkanoyloxy, alkoxycarbonyloxy or trialkylsiloxy may be converted to compounds of formula VIII

(VIII) wherein Z 'is as defined above, by reaction with a chlorinating agent such as oxalyl chloride or thionyl chloride in an inert organic solvent such as dichloromethane or tetrahydrofuran in the presence of a catalytic amount of Ν, Ν-dimethylformamide.

Reaction of compounds of formula VIII with primary or secondary amines of the formula R ^S R ^S NH, wherein R ^a and R ^f are as defined above, in the presence of a base such as N-mezylrr.orfolin or triethylamine, in an organic solvent such as dichloromethane AKC , compounds of formula IX are prepared.

Compounds of formula (IX) wherein X 'is as defined above may be converted to compounds of formula (IX) wherein Z * is a hydroxyl group by methods and conditions commonly known in the literature.

Conversion of nitro-substituted compounds of formula IV, for example compounds of formula IX, to the corresponding amines, for example compounds of formula X

R

H _and N

R (X) may be carried out by methods commonly known in the literature, for example by reduction with hydrogen in the presence of a catalyst such as palladium on carbon in a polar solvent such as ethanol or tetrahydrofuran.

Any of the amines thus formed, for example amines of formula X, may be reacted with acylating agents such as oxalyl chloride, ethyl malonyl chloride, ethylsuccinyl chloride or ethyl bromoacetate in the presence of a base such as N-methylmorpholine or triethylamine in an inert organic solvent such as dichloromethane, tetrahydrofuran or N, N-dimethylformamide to form compounds of formula 1, for example compounds of formula XI

(XI) wherein R ¹ is an alkoxy group, Y is an oxygen atom or two hydrogen atoms, Z 'is Z as defined above, or Z' is a group convertible to Z and n is an integer from zero to four. Compounds of formula I wherein R ¹ is an alkoxy group can be prepared by condensing, for example, compounds of formula X with acylating agents such as dimethyl oxalate or diethyl oxalate at elevated temperature and using the acylating agent as reagent and solvent.

Compounds of formula I wherein R ¹ is, for example, an alkoxy or arylcyl group may be hydrolysed to the corresponding compounds of formula I wherein R is a hydroxyl group by procedures commonly known in the literature, for example using an aqueous base such as alkali metal carbonates or hydroxides alkali metals, in an organic solvent such as ethanol or tetrahydrofuran.

Similarly, other compounds of formula IV wherein X * and Z 'are X and Z as defined above, or X' and Z 'are groups convertible to X and Z are converted to compounds of formula XII

(XII) by the methods described above or by modifications thereof, and if necessary, these compounds can be converted to the corresponding compounds of formula I, optionally by converting X 'and Z * to X and Z. For example, compounds wherein X' = COOH are converted to the corresponding compounds. amides of the formula I wherein X is C (O; NR ⁵ R ^', by methods known from the literature. Similarly compounds wherein COR * is COOH may be converted to compounds wherein COR ^1, CONR ^{with R6.}

The starting compounds and prepared intermediates which are converted to the compounds of the invention by the methods described above have functional groups present, such as amino, thiol, carboxyl and hydroxyl groups, optionally protected with protecting groups which are common in preparative organic chemistry. Protected amino, thiol, carboxyl, and hydroxyl groups are those that can be converted under mild conditions to free amino, thiol, carboxyl, and hydroxyl groups without destroying the structure or other side reactions.

The purpose of introducing protecting groups is to protect the functional groups from undesired reactions with the reactants under the conditions used for the desired chemical transformation. The needs and choice of protecting groups for a particular reaction are known to those skilled in the art and depend on the type of functional group to be protected (hydroxyl group, amino group and the like), the structure and stability of the molecule whose substituent is to be protected and the reaction conditions.

Protective groups that achieve these conditions are well known and whose introduction and removal is described, for example, in J.F.W.McOmie, Protective Groups in Organic Chemistry

Plenum Press, London, New York, 1973, and T. W. Greene, Protective

Groups in Organic Synthesis by Hiley, New York, 1991.

In the above procedures, reactive functional derivatives of carboxylic acids are, for example, anhydrides (especially mixed anhydrides), acid halides, acid azides, lower alkyl esters and their activated esters. Preferred mixed anhydrides are anhydrides with pivalic acid or lower alkyl (ethyl, isobutyl, half-esters of carbonic acid, acid halides are for example chlorides or bromides, activated esters are for example succinimidoesters, phthalimidoesters or 4-nitrophenyl esters, lower alkyl esters such as methyl or ethyl ester.

The reactions mentioned above are carried out by standard methods in the presence or absence of a diluent, preferably one which is inert against the reactants and which is a solvent of the catalyst, condensation or other reagent optionally and / or under inert atmosphere, at low temperature, room temperature or at elevated temperature (preferably at or near the boiling point of the solvent used) and at atmospheric pressure or at elevated pressure. Preferred solvents, catalysts and reaction conditions are set forth in the appended examples.

The invention further encompasses any variant of the processes described in which the intermediate obtained at any stage is used as the starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under reaction conditions or in which the reaction components are used in the form of their salts or optically pure antipodes.

The compounds of the invention and intermediates thereof can also be converted into each other by conventional methods.

The invention also relates to novel starting materials and processes for their preparation.

Depending on the choice of starting materials and preparation methods, the novel compounds may exist in the form of one of the possible isomers or in the form of mixtures, for example as substantially pure geometric (trans or cis) isomers, as optical isomers (antipodes), racemates or mixtures thereof . Said possible isomers or mixtures thereof are within the scope of the invention.

Any mixture of isomers may be separated based on physicochemical differences of the components into pure geometric or optical isomers, diastereomers, racemates, for example by chromatography and / or fractional crystallization.

The resulting racemates of the resulting products can be resolved into the optical antipodes by known methods, for example by separating their diastereomeric salts obtained with an optically active acid or base and releasing the optically active basic or acidic compound. Thus, the carboxyl group-containing intermediates can be resolved into optical antipodes, for example, by fractional crystallization of salts with d- or 1- (α-methylbenzylamine, tinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabietylamine, brucine or strychnine). Racemic products may also be resolved by chiral chromatography, for example, high pressure liquid chromatography using chiral absorbents.

Finally, the compounds of the invention may be obtained either in the free form or in the form of a salt if the salt-forming group present is present.

The acid compounds of the invention can be converted to salts with pharmaceutically useful bases, for example by reaction with aqueous alkali metal hydroxide, preferably in the presence of an etheric or alcoholic solvent such as a lower alkanol. Salts can be precipitated from the streams using ethers such as diethyl ether. The resulting salts can be converted to the free compounds by treatment with an acid. These or other salts can also be used to purify the prepared compounds.

Compounds of the invention having basic groups can be converted into acid addition salts, especially pharmaceutically acceptable salts. These are formed, for example, by reaction with inorganic acids such as mineral acids, such as sulfuric acid, phosphoric acid or hydrohalic acid, or with organic carboxylic acids, such as (C 1 -C 4 -alkanecarboxylic acids), which may for example be unsubstituted or substituted by halogen, such as is, for example, acetic acid, saturated or unsaturated dicarboxylic acids, for example glycolic acid, lactic acid, malic acid, tartaric acid or citric acid or amino acids, for example aspartic acid or glutamic acid, or with organic sulphonic acids such as (C 1 -C 3). alkylsulfonic acids (e.g. methanesulfonic acid) or arylsulfonic acids which are unsubstituted or substituted (e.g. halogen), preferably salts formed with hydrochloric acid, methanesulfonic acid or malic acid.

Because of the close relationship between the free compounds and the salt forms, whenever reference is made in this context to a compound, it is also meant the corresponding salt, if possible and responsible in the circumstances.

The compounds, including salts, may also be prepared in the form of hydrates, or may include solvents used in crystallization.

The pharmaceutical compositions of the invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including humans, for the treatment of diseases associated with thyroid hormone imbalance such as hypo- and hyperthyroidism, obesity, osteoporosis, depression and in particular for the treatment and / or prevention of occlusive cardiovascular conditions which are caused by hyperlipidemia and hyperlipoproteinemia, and which comprise an effective amount of a pharmacologically active compound of the invention, either alone or in combination with a pharmaceutically acceptable carrier.

The pharmacologically active compounds of the invention are useful for the manufacture of pharmaceutical compositions comprising an effective amount thereof in association with or in admixture with an excipient or carrier suitable for enteral or parenteral administration. Preferred are tablets and gelatin capsules containing the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, lubricants, for example silica gel, talc, stearic acid and its magnesium or calcium salts and / or or polyethylene glycol, for the manufacture of tablets, also together with c) binders, for example, magnesium aluminum silicate, starch, paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, optionally with dicarbonate; disintegrants, for example starch, agar, alginic acid or its sodium salt, or effervescent mixtures and / or absorbents, colorants, flavors and sweeteners, preferably the injectable compositions are aqueous isotonic solutions or suspensions and the suppositories are preferably prepared from fat emulsions or suspensions . These compositions may be sterilized and / or contain additives such as preservatives, stabilizers, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and / or buffers. In addition, they may also contain other therapeutically active substances. These compositions are prepared by conventional methods of mixing, granulating and coating, respectively, and contain about 0.1 to 75%, preferably 1 to 50%, of the active ingredient.

Suitable formulations for transdermal administration include an effective amount of a compound of the invention with a carrier. Suitable carriers are absorbable pharmacologically usable solvents that allow the skin to pass through the host. A typical transdermal dosage form is a bandage comprising a support portion, a reservoir containing the active compound, optionally with a carrier, optionally containing a barrier to control application of the active agent to the host skin at a controllable and predetermined rate for a longer time.

A unit dosage for mammals of about 50 to 70 kg may contain in the range of about 0.01 mg to 10 mg of the active ingredient. The dose of the active ingredient is dependent on the species of warm-blooded animal (humans), body weight, age and individual condition, the route of administration and the compound employed.

A problem solved by the present invention is the preparation of a pharmacologically active hypolipidemic agent for lowering plasma cholesterol levels in mammals. The compounds of the invention effectively bind to the triiodothyronine (T3) receptor in the nucleus, which is responsible for regulating the activity of the LDL receptor and increasing the clearance of LDL-cholesterol from the blood vessel. The compounds of the invention are also particularly useful in mammals as hypochclesteremic agents for the treatment and prevention of occlusive cardiovascular conditions in which hypercholisteremia contributes by lowering total cholesterol and LDL-chclesterol levels in plasma. The invention further relates to the use of the compounds according to the invention for the preparation of medicaments, in particular medicaments useful for the treatment and prevention of occlusive cardiovascular conditions in which hypercholesteremia is involved by lowering total cholesterol and LDL-cholesterol levels in plasma.

The compounds of the invention also reduce lipoprotein (a) levels and are thus useful in the treatment and prevention of occlusive cardiovascular conditions in which Lp (a ‘) is implicated.

The selective thromimetic hypolipidemic agents of the invention are preferably and substantially free of cardiovascular side effects having thyroid hormones.

Said properties are demonstrated by in vitro and in vivo assays using preferably in mammals, for example mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. These compounds may be administered in vitro in the form of solutions, for example preferably in the form of an aqueous solution and in vivo, either enterally, parenterally or preferably intravenously, for example as a suspension or in the form of an aqueous solution. For in vitro testing, the dose may range from 10 ^-7 molar to 10 ^-11 molar concentration. For in vivo tests, the dose is dependent on the mode of administration and may range between 0.1 and 1000 micrograms / kg, preferably between 0.5 and 300 micrograms / kg, most preferably between 1 and 100 micrograms / kg.

The compounds of the invention bind to the triiodothyronine (T ₃ ) receptor and are thus useful as a thyroid hormone agonist in mammals.

In vitro binding to the T ₃ receptors of the nucleus is determined as follows:

Membrane preparations from the nucleus and plasma are prepared from rat liver obtained from Sprague-Dawley (CD) rats (Charles River Labs) by differential centrifugation as described by Emmelot et al., (Methods in Enzymology 31, 75, Vol. 19, 19-4). ) and the procedure was slightly modified. The core fraction obtained from the 275xg pellet is further purified as generally described in Spindler et al. .J. Biel. Chem., 250, 4118 (1975).

The novel compounds of the invention are traveling to the nucleus binding by the method described by Spindler et al. (J. Biol. Chem., 250, 4118, 1975). The nuclei are incubated at 22 ^e C with 0.3 nM of ^[125 J] -L-trijočotyror.ínu _IL-T3). Parallel incubations are performed in tubes that contain either different concentrations of test compounds or 3 μΜ of non-radioactive L-T3 in addition to the nuclear preparation and radioactive L-TS. Non-radioactive L-T3 is used as a measure of non-specific binding. Nuclear-bound radioactivity is determined after centrifugation of the reaction mixture at 800 xg for 7 minutes and washing of the obtained pellets. The amount of specifically bound [* ^{: 5} J] -L-Tj is determined by subtracting the amount of non-specific bound (radioactivity contained in the nuclear pellet after incubation with an excess (3 μΜ) of non-radioactive L-T3). The concentration of test compound that inhibits the specific binding of [ ^{? 5} J] -L-T3 by 50 percent (IC 50) is determined graphically from a reciprocal plot of specifically bound [ ¹²⁵ J] -L-T 3 versus different concentrations of test compound.

The cholesterol lowering effect in rats is determined as follows:

Male Sprague-Dawley rats (230 g-25C g) are bred two weeks before and 7 days during the test, ad libizum access to water and a high cholesterol diet (1.5% cholesterol and 0.5% cholic acid). Groups of animals are orally administered for 7 consecutive days either alone or together with the test compound. After the last dose, the animals are fasted for 18 hours and bled. Blood samples are centrifuged at 2500 rpm for 10 minutes and plasma is prepared to determine total cholesterol as well as LDL and HDL cholesterol concentrations. HDL values are determined after LCL / VLDL precipitation (Warnick and Albers, 1978). All samples are analyzed enzymatically for cholesterol using a diagnostic kit (Sigma Chemical Co., St-Louis MO). The analyzes are performed in a Bio-MEK automatic workstation. LDL / VLDL fractions were precipitated as follows: aliquots of C, 35 ml of plasma were placed in Eppendrf tubes and 1 μΐ 2M magnesium chloride, 11.2 μί sodium heparin (Porcir. Inzestinal, 5000 units / ml) and 8.3 were added. μΐ of normal saline. The samples are then mixed and placed on ice for 15 minutes, then centrifuged at 4'C for 10 minutes at 1300 rpm. The HDL cholesterol concentration is adjusted for dilution by multiplying the cholesterol value in the supernatant by 1.09. LDL / VLDL values are obtained by subtracting HLD cholesterol from total cholesterol.

The cholesterol lowering effect can also be determined in normocholesterolimic dogs fed a regular diet and following the procedure described earlier after administration of test compounds for 5 days.

I

The cholesterol and Lp (a) lowering effect can be determined in normolipemic cynomolgus monkeys, as follows:

Adult male and female macaques (Macaca fascicularis) weighing 3-7 kg are used. Animals are housed individually and fed with a standard monkey food (Purina 5074) supplemented with fresh fruit and vegetables. Each animal serves as its own control and each dosing regimen is followed by a washout period. Test compounds are dissolved in ethanol, soaked in fruit and administered orally. Animals are given a single dose of test compound per day during treatment ranging from 8 to 28 days. Blood samples are taken after fasting overnight at the beginning and end of the study. Blood samples (3 ml) are collected from the femoral vein into Vacutainer tubes (containing EDTA). The blood is centrifuged for 20 minutes at 2C00 rpm and 4'C. Plasma samples are aliquoted and stored at -70 ° C until analysis. Plasma levels of total cholesterol (TC) and triglycerides (TG) are determined by enzymatic methods using commercial diagnostic kits (Sigma Diagnostic,. High density lipoprotein and bound cholesterol (HDL-C) concentrations are measured after precipitation of apoB-containing lipoproteins. Because the plasma of the starving macaque monkeys on the diet contains only negligible amounts of low density lipoprotein, the concentration of low density lipoprotein and bound cholesterol (LDL-C) is calculated by subtracting HDL-C from TC. well microtiter plate readings are read with a microplate spectrophotometer (DynatechMR 5000) The plasma concentration of Lp (a) is determined by a commercial Lp (a) ELISA (Permmune, Inc.) using a control set and a reference Lp (a) standard. a) ELISA uses monoclonal antibodies against apolipoprotein (a) to capture and detect polyclo The antibody is specific for Lp (a) and does not measure free apo (a), apoB or plasminogen. Lp (a) quantification is unaffected by apo (a) size. The plasma concentration of Lp (a) is reported in milligrams of total Lp (a) mass. Samples from each study are tested in one run.

To illustrate the invention, the compound of Example 26 shows an IC _{50 of} about 0.17 nM in the T ₃ core receptor binding assay, the compound of Example 28 shows an IC _{53 of} about 0.13 nM, the compound of Example 35 shows an IC 50 of about 1.00 nM, and the compound of Example 39 exhibits an IC 50 of about 0.04 nM. Furthermore, the compound of Example 26 significantly reduced serum cholesterol at a daily dose of 20 micrograms (pg) / kg orally in rats and 10 μς / kg orally in dogs. Furthermore, the levels of Lp'a) in normolipaemic macaques decrease c by about 40% when treated for 4 weeks, with Compound 26 administered at a daily oral dose of 75 μς / kg.

The examples below serve to illustrate the invention in more detail and are not to be construed as limiting the invention in any way. Temperatures are given in degrees Celsius. Unless otherwise stated, all evaporations are carried out under reduced pressure, preferably at about 2 to 13.6 kPa. the structure of the resulting products, intermediates and starting materials is confirmed by standard analytical methods such as microanalysis and spectroscopic characteristics (e.g., MS, 1R, NMR). The abbreviations used are the same as those used in the literature.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

N- {4- [3- (2,2-Dimethylpropylsulfamoyl) -4-hydroxy] -3,5-dimethylphenyl] oxamic acid

HO.

A. 3,5-Dimethyl-4- (4'-methoxyphenoxy) nitrobenzene

A suspension of sodium hydride (NaH, 60% dispersion in mineral oil, 64.11 g, 1.603 mol) in 350 mL of t-methylpyrrolidone (HMP) was cooled to O'C and a solution of 4-methoxyphenol (208.4 mL) was added over 30 minutes. The mixture was warmed to room temperature and after 30 minutes 4-chloro-3,5-dimethylnitrobenzene (283.2 g, 1.526 mol, prepared according to the procedure described in Yokoyama et al., EP) was added. The reaction mixture was cooled to room temperature and quenched by the addition of water (1500 mL). The suspension was cooled to 0 ° C, stirred for 30 minutes, filtered, the filter cake was washed with water. The crude product in ethyl acetate (2100 mL) and activated carbon (42.6 g) were heated to boiling and the solids were filtered hot through celite, and the filtrate was concentrated under reduced pressure to about 800 mL and the resulting slurry was stirred. Cool to 0 ° C and stir for 30 minutes .The product is filtered off under vacuum, washed with cold ethanol. The product was dried in vacuo to give 3,5-dimethyl-4- (4'-methoxyphenoxy) nitrobenzene: NMR (CDCl3): 2.22 (s, 6H), 3.78 (s, 3H), 6.68 (d, 2H, J = 8.7), 6.82 (d, 2H, J = 8.7), 8.02 (s, 2H).

B. 3,5-Dimethyl-4- (4'-hydroxyphenoxy) nitrobenzene

A mixture of the title compound of Part A, 3,5-dimethyl-430

- (4'-methoxyphenoxy) nitrobenzene, (164 g, 60 mmol), acetic acid (AcOH, 100 mL) and aqueous 48% hydrobromic acid (HBr, 100 mL) were heated at 120 ° C for 16 h. The mixture was cooled to room temperature, diluted with water (200 mL), and the precipitated product was filtered off by vacuum filtration, washed with water and hexane and dried in vacuo. To give 3,5-dimethyl-4- (4'-hydroxyphenoxy) nitrobenzene: NMR (CDC1 _3): 2.22 (s, 6H), 6.62 (d, 2H, J = 8.7), 6 77 (d, 2H, c = 8.7),

8.0 (s, 2 H).

C. 5- (2,6-Dimethyl-4-nitrophenoxy) -2-hydroxybenzenesulfonic acid

A solution of the title compound of Part B, 3,5-dimethyl-4- (4'-hydroxyphenoxy) nitrobenzene (7.86 g, 30.35 mmcl) in 150 mL of dichloromethane (CH 2 Cl 2) was allowed to react at room temperature. with chlorosulfonic acid (2.4 mL, 36.42 mmol ·). After 16 hours, the reaction mixture was concentrated and the residue was dissolved in a small amount of methylene chloride (about 5 mL). The product is precipitated by addition of an aqueous chloride solution, filtered in vacuo, washed with water, hexane and diethyl ether and dried under vacuum. It will be obtained

5- (2, 6-dimethyl-4-nitrophenoxy) -2-hydrcxyber.ténsulfónová acid: NMR (DMSO-d _e): 2.18 (s, 6H), 6.67 to 6, = 3 (m, 3 H 1: 1 (s, 2H), 10.07 (s, 1H).

D. 2-Benzyloxy-5- (2,6-dimethyl-4-nitrophenoxy) benzenesulfonic acid cesium salt

A solution of the title compound of Part C, 5- (2,6-dimethyl-4-nitrophenoxy) -2-hydroxybenzenesulfonic acid (6.78 g, 20 mmol) in 100 mL of THF (THF) and 50 mL of N, N-dimethylformamide ( DMF) was treated with cesium carbonate (15.6 g, 48 mmol) and benzyl bromide (7.1 mL, 60 mmol) at room temperature, and the reaction mixture was then heated at 75 ° C for hodín8 hours, then the reaction mixture was stirred at room temperature. The reaction mixture was cooled to room temperature, quenched with aqueous 1N hydrochloric acid (HCl, 100 mL) and tetrahydrofuran was evaporated from 31. The precipitated product is filtered off in vacuo, washed with water, diethyl ether, ethyl acetate and methylene chloride and dried to give the cesium salt of 2-benzyloxy-5- (2,6-dimethyl-4-nitrophenoxy) benzenesulfonic acid: NMR (DMSO-d6): 2 18 (s, 6H), 5.10 (s, 2H), 6.74 (dd, 1H, J = 8.7; 3.8), 6.97 (d, 1H, J = 8.7) 7.11 (d, 1H, J = 3.8), 7.23-7.39 (m, 3H), 7.59 (d, 2H, J = 7.5), 8.12 (s, 2H).

E. 2-Benzyloxy-5- (2,6-dimethyl-4-nitrophenoxy) benzenesulfonyl chloride

A suspension of the title compound of Part D, 2-Benzyloxy-5- (2,6-dimethyl-4-nitrophenoxy) -benzenesulfonic acid cesium salt (9.9 g, 20 mmol) in 200 mL of dichloromethane was treated with dimethylformamide (3, 2, 2, 3, 4, 5, 10). 1 mL, 40 mmol) then oxalyl chloride (3.5 mL, 40 mmol) was added at room temperature over 30 min and the reaction was further stirred for 1 h. Dilute with ethyl ether (200 mL) and wash with water, brine, dry over anhydrous sodium sulfate, and concentrate. The product was washed with ethyl ether (5 mL) and dried in vacuo to give 2-benzyloxy-5- (2,6-dimethyl-4-nitrophenoxy) benzenesulfonyl chloride: NMR (CDCl3): 2.24 (s, 2H), 5.31 (s, 2H), 7.02 (dd, 1H, J = 8.7, 3.8), 7-, 32-7.47 m, 4H), 7.52 (d, 2K, J = 7, 5), 8.05 (s, 2H).

F. 2-Benzyloxy-5- (2, c-dimethyl-4-nitrophenoxy) -N- (2,2-dimethylpropyl) benzenesulfonamide

A solution of the title compound of Part E, 2-benzyloxy-5- (2,6-dimethyl-4-nitrophenoxy) benzenesulfonyl chloride (1.12 g,

2.5 mmol) in 20 ml of dichloromethane was gradually treated at room temperature with N-methylmorpholine (550 ml, 5 mmol) and neopentylamine (442 ml, 3.75 mmol; after 6 hours) the mixture was partitioned between water and ethyl acetate, phase is washed with aqueous 1N hydrochloric acid, brine and dried over anhydrous sodium sulfate to give 2-benzyloxy-5- (2,6-dimethyl-4-nitrophenoxy) -AZ- (2,2-dimethylpropyl, benzenesulfonamide): NMR (CDCl3) 0.76 (s, bH), 2.22 (s, 6H), 2.58 (d, 2H, J = 7.5), 4.82 (t, 1H, J = 7.5) .

5.18 (s, 2H), 6.88 (dd, 1H, J = 9; 3.7), 7.03 (d, 1H, J = 9), 7.33-7.51 (m, 6H) ), 8.04 (s, 2H).

G. 5- (4-Amino-2,6-dimethylphenoxy) -2-benzyloxy-N- (1,2-dimethylpropyl) benzenesulfonamide

A mixture of the title compound of Part F, 2-benzylcxy-5- (2,6-dimethyl-4-nitrophenoxy) -N- (2,2-dimethylpropyl) benzenesulfonamide (1.22 g, 2.45 mmol) and palladium on charcoal (10 wt% 250 mg) in 40 ml tetrahydrofuran was stirred under hydrogen atmosphere for 8 hours. The catalyst was removed by filtration under vacuum through a pad of Celite, washed with tetrahydrofuran, and the filtrate and wash were combined and concentrated. The residue is suspended in dichloromethane, the product is filtered off under vacuum, washed with dichloromethane and dried. To give 5- (4-amino-2,6-dimethyl-phenoxy) ^{-2-benzyloxy-T} and - (2,2-dimethylpropyl) benzenesulfonamide: NMR (DMSO-d _e): 0.80 Is, 9H), 2, 55 (d, 2H, J = 7.5), 4.90 (broad s, 2H), 6.31 (s, 2H., 6.87 (broad s, 2H)).

S, 1H), 6.93 (broad s, 2H), 6.97 (t, 1H, J = 7.5), 10.13 · 3.1%.

H. N- {4- [3- (2,2-Dimethyl-propylsulfamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl] -oxamic acid

A solution of the title compound of Part G, 2-benzyloxy-5- (2,6-dimethyl-4-nitrophenoxy) -N- (2,2-dimethylpropyl benzenesulfonamide (750 mg, 1.98 mmol) in 10 mL of tetrahydrofuran The reaction mixture was cooled to C ° C and treated with N-methylmorpholine (545 mL, 4.96 mmol; and ethyloxylyl chloride (442 mL, 3.96 mmol). The reaction was allowed to warm to room temperature and was stirred for 1 h. The mixture was partitioned between water and ethyl acetate, the organic solution was washed with aqueous 1N hydrochloric acid solution, brine, dried over sodium sulfate and concentrated. The residue was dissolved in 10 ml of tetrahydrofuran and treated with aqueous 1N lithium hydroxide solution (LiOH, 1.8 ml, 1.8 mmol: After 1 hour, the reaction is quenched with aqueous 1N hydrochloric acid, the product is taken up in ethyl acetate, washed with brine, dried over sodium sulfate and concentrated by evaporation. ethyl ether and dried in vacuo to give N- (4- [3- (2,2 -dimetylpropylsulfamoyl) -4-hydroxy-phenoxy] -3,5-dimetylfenylloxámová acid: NMR (CDC1 _3): 0.89 (s, 9 H), 2.13 (s, 6H), 2.70 (d, 2H, J = 7.5), 5.22 (t, 1H, J = 7.5), 6.84 (d, 1H, J = 3.7), 7.04 (d, 1H, J = 8.7), 7.15 (dd, 1H, J = 8.7; 3.7), 7.33 (s, 2H), 8.54 (broad s, 1H), 9.18 (s, 1H).

IR (KBr) 1759, 1693, ESI-MS 449 [M-1].

The following compounds can be prepared in a similar manner:

1 0 * R * with γύ ΎΎ δ ^H Example # R ^s , R ® NMR IR (KBr) ESI-MS 2 R- - H, R ⁴ - Ph- (DMSO-d 6): 1.91 (s, 6H), 6.79-6.99 (m, 6H), 7.11-7.17 (m, 2H), 7.55 (s, 2H), 9.99 (s, 1H), 10.46 (s, 1H). ), 10.52 (s, IH) 1207, 1481, 1689 455 [M1] ^- 3 R ³ -H, R * = p-FCiH- (DMSO-dd: 1-91 (s, 6H), 6.72 (d, 1H, J = 3.0), 6.89-7.03 (m, 6H, 7.55 (S, 2H), 9.96 (s, 1H), 10.54 ( S, IH), 10.66 (s, IH). 1207, 1481, 1508, 1693 473 [Ml] ^- 4 R - H, R * - O - FC _e H ₄ - (MeOH-dJ: 1.98 (s, 6H), 6.81 (d, 1H, J = 2.6), 6.87-7.14 (m, 5H), 7.36 (td, 1H, J = 7.9, 1.9), 7.46 (s, 2H). ) 1209, 1481, 15C0, 1659 473 [Ml] ^- 5 R ^: = H, R® = m-FCiH, - (DMSO-d 6): 1.97 (s, 6H), 6.75-6.84 (m, 4H), 6.92 (d, 1H, J = 8.8), 7.04 (dd, IH, J = 8.8, 3.1), 7.20 (app q, IH, J = 7.0), 7.58 (s, 2H), 10.35 (s, IH), 10.59 (s, IH), 10.66 (s, IH). 1238 1475, 1706 473 [Ml] ^- 6 R - H, R ® = p-MeOC _t H ₄ - (DMSO-d 6): 1.90 (s, 6H), 3.67 (s, 3H), 6.68 (d, 1H, J = 3), 6.73 (d, 2H, J = 9.00), 6.89-6.99 (m, 4E), 7.54 (s, 2H), 9.58 (s, IH), 10.45 (s, IH), 10.64 (s, IH) 1209, 1475, 1514 1683 485 [M-1] '

7 R ⁵ = H, R ¹ = p-FC 2 CH · .- (DMSO-dJ: 2.02 (s, 6H), 4.03 (d, 2H, J = 6.4), 6.80-6.89 (m, 3H), 7.01 (t, 2H, J = 4.0), 7.22 (dd, 2H, J = 6.3, 8.7), 7.56 (s, 2H), 7.77 (t, 1H, J = 6.4), 10.32 (s, IH), 10.64 (s, IH) 1224 1481, 1695 487 [M-I] + 8 R ⁵ = Me-, R * ¹ = Ph- (CDCl3): 1.96 (s, 6H), 3.14 (s, 3H), 6.54 (d, 1H, J = 2.4), 6.846.85 (m, 2H), 6.88-7.03 (m, 2H), 7.20-7.28 (m, 5H); 1209, 1230 1481, 1691 469 [M-I] + 9 (CDCl3): 0.87 (t, 3H, J = 7.5); 1.38-1.56 (m, 2H); 2.11 (s. 6H); 1214, 1485, 421 [Ml] ^- R ⁵ -H, R ^e = n-Pr- 2.94 (app q, 2H, J = 7.5), 5.0 (t, 1H, J = 7.5), 6.84 (d, IH, J = 3, 7.0 (d, IH, J * = 9), 7.08 (dd, IH, J = 9, 3), 7.32 (s, 2H), 8.44 (s, IH), 9.0 (s, IH) 1693, 1751 440 [M + NH,] - 10 R ⁵ = H, R ® = i-Pr- (DMSO-d 6): 0.95 (d, 6H, J = 7.5), 2.02 (s, 6H), 3.2-3.31 (m, 1H), 6.86 (Sir, s), 6.97 (Sir, s) 2H), 7.06 (d, 1H, J = 7.5), 7.57 (s, 2H), 10.32 (broad s, 1H), 10.64 (broad s, 1H) 1209, 1485, 1698 1742 421 [M-I] - 11 (DMSO-d 6): 0.72 (t, 3H, J 7.5), 1.1-1.35 (m, 4H), 2.03 (s, 6H), 1321 1481, 435 [M-I] + R = H, R ^f = n-Bu- 2.76 (acp q, 2H, J = 7.5), 6.87 (broad s, 1H), 6.97 (broad s, 2H), 7.1 (t, 1H, J = 7.5), 7.58 (s, 2H) 1691 454 :: - i + nh.] ', 1 1 1 12 R ⁵ = H, R = i-BU (DMSO-d6): 0.75 (d, 6H, J = 8.2), 1.49-1.62 (m, 1H), 2.03 (s, 6H), 2.55 (acc t, 2H, J = 6.8), 6.85 (Sir); 6.96 (broad s, 2H), 7.17 (t, 1H, J = 6.8), 7.57 (s, 1H); 2H), 10.25 (broad s, IH), 10.61 (broad s, IH) 1209, 1481, 1693, 1762 435 [M-I] + 1 1 1 1 13 R · = H, R '= tert-Bu- (DMSO-d 6): 1.02 (s, 9H), 2.03 (s, 6H), 6.81-7.02 (m, 4H), 7.56 (s, 2H), 10.20 (broad s, 1H), 10.61 (broad s) s, IH) 1204 1486. 1645 1754 435 [Ml] ^- 14 R ^H, R ^N - Cyclohexyl (CDCl3): 1.06-1.32 (m, 5H); 1.73 (m, 5H), 2.01 (s, 6H), 3.023.14 (m, 1 H, 5.05 (d, 1H, J = 7.5), 6.62 (d, IH, J = 3), 6.97 (d, IH, J = 9), 7.10 (dd, IH, J) » 9, 3), .32 (s, 2H), 8.52 (broad s, IH), 9.06 (broad s, IH) 1209, 1481, 1695 1741 461 [M-I] +

15 R ⁵ - Me-, R ¹ * = Me- (MeOH-d6): 2.07 (s, 6H, 2.64 (s, 6H), 6.86-6.94 (m, 3 H), 7.39 (s, 2H) 1234, 1486. 1685 407 [M] ^- · R 16, R '= - _(CH) 4- (MeOH-dJ: 1.76-1.80 (m, 4H, 2.08 (s, 6H)), 3.21-3.29 (m, 4H), 6.886.95 (m, 3H), 7.40 (s, 2H). 1230 1479 1693 433 [Ml] ^- 17 R 5, R 6 = - _{(CH) S} - (MeOH-dJ): 1.49-1.58 (m, 6H), 2.13 (s, 6H), 3.08-3.10 (m, 4H), 6.927.02 (m, 3H), 7.53 (s, 2H). 1207, 1481, 1658 447 [M1] ^- 18 R ⁵ = H, R 1 · = MeOCH _: CH 1 (CDC1 _3): 6.2 (s, 6H), 3.3 (t, 2H, J - 5.5), 3.22 (s, 3H), 3:35 (t, 2H, J = 5.5), 6.85 (br. S, 2H ,, 6.97 (broad s, 1H), 7.34 (s, 2H) 1218, 1483, 1689 437 [Ml] ^- 19 R, R ' ^: = - (CH ₌ ) 10 (CH 2) _: - (MeOH-dJ: 2.13 (s, 6H)), 3.12 (t, 4H, J = 6), 3.68 (t, 4H, J = 6), 6.95-7.03 (m, 3H), 7.54 (s, 2H) 1479 1711, 1745 449 [M-l] ’ 20 R ¹ , R ^? = - (CH) SO _(CH): - (CDCl3): 2.12 (s, 6H), 3.10-3.13 (m, 4 H), 3.74-3.76 (m, 4 H), 6.926.99 (m, 3 H), 7.41 (s, 2H) 1209, 1481, 1697 497 [M-1] - 21 R ^; -H, R '= 3-Pyridyl (DMSO-d 6): 1.95 (s, 6H), 6.81 (d, 1H, J = 3), 6.92 (d, 1H, J = 9), 7.00 (dd, IH, J = 9, 3), 7.26 ( dd, IH, J = 8.5), 7.41-7.45 (m, IH), 7.56 (s, 2H), 8.21 (dd, IH, J = 5, 1.5), 8.27 (d, IH, J = 2.5) 10.34 (s, IH), 10.66 (s, IH). 1481, 1500 1689 473 [Ml] ^- i i 22 R ⁵ H, R ⁶ = -O = ° Me (DMSO-d 6): 1.88 (s, 6H), 3.75 (s, 3H), 6.64-6.69 (m, 2H), 6.93 (d, IH, J = 9, 6.99 (dd, IH, J = 9, 2.5), 7.32 (dd, IH, J = 9, 2.5), 7.53 (s, 2H), 7.77 (d, IH, J = 2.5), 9.74 (s, IH); 10.56 (s, IH); 10.61 (s, IH) 488 [M + l] ’ J

Example 23

N- {4- [3- (i-fluorophenylsulfamoyl) -4-hydroxyphenylsulfaryl] -3,5-dimethylphenylloxamic acid

The title compound was prepared according to the procedure for EXAMPLE 1: NMR (DMSO-d 6): 2.21 (8.66), 6.87 (d, 1H, J = 8.3), 6.95-7.12 ( m, 6H), 7.65 (s, 2H), 9.9S.'s, 1H), 10.73 (s, 1H), 10.97 (s, 1H),

IR (KBr) 1163, 1506, 1630, 4S9 [M-1] ‘, 488 [M + N 6] +.

Example 24

N- {4- [3- (4-Fluorophenylsulfamoyl) phenoxy] -3,5-dimethylphenyl} oxamic acid

The title compound was prepared according to the procedure for EXAMPLE 1: NMR (DMSO-d6: 1.91 (5.66), 6.73-6.74 (m, 1H), 6.95-7.00 (m, 2H), 7.04-7.10 (m, 26), 21.2 (dd, 1H, J = 8.2, 2.4), 7.35 (d, 1H, J = 8.0) 7.52 (app, 1H, J = 3.0: 7.5S: s, 2H), 10.21 (s, 1H), 10.75 s, 1H), IR (KBr) 1161, 1223, 15C9, 1637, 457 [M < -1 >], 476 [M + NH < + >].

Example 25 N- {4- [3- (4-Fluoro-phenylsulfamoyl) -4-hydroxy-phenoxy] -3-methyl-phenyl} -oxamic acid

The title compound was prepared according to the procedure for EXAMPLE 1: NMR (DMSO-d 6): 2.16 (8.36), 6.65 (d, 1H, J = 8, B), 6.92-7.18

1692, ESI-MS 457 [M-1].

Example 26

N - {4- [3- (4-Fluorobenzenesulfamoyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl) oxanoic acid

hi

A. 4-Fluorobenzenesulfinic acid

A solution of 4-fluorobenzenesulfonyl chloride (2 g, 10.28 mmol) in 5 mL of tetrahydrofuran (distilled from Na-benzophenone) was cooled to 0 ° C and sodium borohydride (1.9 g,

51.4 mmol). The reaction mixture was stirred at C ° C for 2 hours, warmed to room temperature and after 2 hours quenched by the addition of water (5 mL). The solvent was evaporated and the aqueous residue was acidified by the addition of 5N hydrochloric acid. The product is taken up in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated to give 4-fluorobenzenesulfonic acid: NMR (DMSO-d6): 7.12 (app t, 2H, J = 8.3), Δ (dd, 2H, J = 8.3,

6 ;, ESI-MS 45 [M +] ^- .

B. 2- (4-Fluorobenzenesulfonyl) benzene-1,4-diol

A solution of the title compound A, 4-fluorobenzenesulfonic acid (3 g, 18.75 mmol) in 10 mL of water was added to a solution of 1,4-benzoquinone (1.93 g, 1.86 mmol) in 30 mL of water at room temperature. ml of dichloromethane. After 4 hours, the precipitated product is collected by vacuum filtration and dried under vacuum. 2- (4-fluorobenzenesulfonyl) benzene-1,4-diol was obtained: NMR (DMSO-d 6): 6.73 (δ, 1H, J = 9), 6.92 (dd, 1H, J = 9.3) 7.31 (d, 1H, J = 3), 7.41 (s, 1H), 10.05 (S, 1H), ESI-MS 457 [M] ^- .

C. 4- (Dimethyl-4-nitrophenoxy) -2- (fluorobenzenesulfonyl) phenol

The title compound of Part B, 2- (4-fluorobenzenesulfonyl) benzene-1,4-diol (1.2 g, 4.48 mmol) was added in one portion at 0 ° C to a sodium hydride suspension (60% dispersion in mineral oil). , 0.39 g, 9.86 mmol) in 15 mL of N-methylpyrrolidone. The reaction mixture was allowed to warm to room temperature and after 30 minutes 4-chloro-3,5-dimethylnitrobenzene (1 g, 5.38 mmol) was added and the reaction mixture was heated at 120 ° C for 1 hour. The reaction mixture was then cooled to room temperature and quenched by the addition of 1N hydrochloric acid. The mixture was partitioned between water and ethyl acetate, the organic solution was washed with water, brine, dried over anhydrous sodium sulfate, and concentrated. Silica gel chromatography (eluting with EtOAc / hexane 1 / 2-1 / 1, 4- (dimethyl-4-nitrophenoxy) -2- (benzenesulfonyl) phenol: NMR (CDC1 ₃₎ 2, Q (s, 6H), 6 , 85-6.96 (m, 3H), 7.00 (app t, 2H, J = 9), 7.88 (dd, 2H, J = 9.5),

7.98 (s, 2H), 8.73 (s, 1H).

D. 4- (4-Amino-2,6-dimethylphenoxy) -2- (fluorobenzenesulfonyl) phenol

A mixture of the title compound of Part C, 4- (dimethyl-4-nitrophenoxy) -2- (fluorobenzenesulfonyl) phenol, 0.69 g, 1.65 mmol) and palladium on charcoal (10 wt%, 69 mg, 10 ml of ethanol and 10 ml of dichloromethane are stirred under a hydrogen atmosphere for 6 hours, the catalyst is separated by filtration through a pad of celite, washed with a 1: 1 mixture of ethanol and dichloromethane, the filtrate and washing solution are combined, concentrated and dried in vacuo 4- (4-Amino-2,6-dimethylphenoxy) -2- (fluorobenzenesulfonyl) phenol: NMR (DMSO-d 6): 1.93 (s, 6H), 4.9is, 2H), 6.34 (s, 2H), 6.85 (d, 1 H, J = 9), 7.0 (dd, 1 H, J = 9,

3), 7.12 (d, 1H, J = 3), 7.43 (app t, 2H, J = 9), 7.94 (dd, 2H, J = 9.5), 9.41 (s) 1 H), 10.4 (s, 1 H).

E. N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl] oxamic acid ethyl ester

A mixture of the title compound of Part D, 4- (4-amino-2,6-dimethylphenoxy) -2- (fluorobenzenesulfonyl) phenol (0.64 g, 1.65 mmol) and 2 mL of diethyl oxalate was heated at 180 ° C for 3 hours. C. The reaction mixture was cooled to room temperature and the diethyl oxalate was evaporated in vacuo. Silica gel chromatography (eluting with EtOAc-hexane 1 / 3-2 / 3) affords N- {4- [3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl] oxamic acid ethyl ester: NMR (CDCl ₃ ) 1.46 (t, 3H, J = 7.5), 2.06 (s, 6H), 4.42 (q, 2H, J = 7.5), 6.90-6.98 (m, 3H), 7.22 (app. T, 2H, J-8.3), 7.87-7.93 (m, 2H), 8.87 (broad s, 1H), ESI-MS 486 [M- 1] '.

F. N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl] oxamic acid

A solution of the title compound of Part E, N- {4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl] -oxamic acid ethyl ester (773 mg, 1.58 mmol) in 15 mL of ethanol The mixture was treated with aqueous 1N sodium hydroxide solution (4.75 mL, 4.75 mmol) at room temperature. After 1 hour, the reaction is quenched by the addition of aqueous 1N hydrochloric acid (5.5 ml) and the product is taken up in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated. The product was triturated in ethyl ether and dried in vacuo to give N- {4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxyfencxy] -3,5-dimethyl-phenyl Joxárr.ová acid: NMR _(DMSO-d6): 2, 06 (s, 6H), 6.88 (d, 1H, J = 9), 7.03 dd, 1H, J = 9, 3), 7.13 (d, 1H, J = 3), 7.43 (app t, 2H, J = 9), 7.61 (s, 2H), 7.94 (dd, 2K, J = 9.5), 10.5 (s, 1H), 10.69 (s, 1H), IR 1240, 1481, 1685,

1764, 458 [M-1] < - >.

The following compounds were prepared in a similar manner.

1 ° Ό ΗΟγΧ ΛΛ U. _QH 0 ^H Example R ⁴ NMR IR (KBr) ESI-MS 27 R * = Ph- (MeOH-d _6): 02.02 (s, 6H), 6.85 (d, IH, J = 7), 6.98 (dd, IH, J = 7, 2.3), 7.26 (d, IH, J - 2.3), 7:53 (s, 2H), 7.55-7.68 (m, 3H), 7.93 (d, 2H, J = 7) 1209, 1479 1697 440 [M-1] ' 28 R = p-ClC ₄ H _s - (MeOH-dd: 2.12 (s, 6H)), 6.84 (d, 1H, J = 8.3), 6.96 (dd, 1H, J 8.3, 3), 7.24 (d, 1H, J = 3, 7.53 (d, 2H, J = 7.5), 7.58 (s, 2K)), 7.90 (d, 2H, J = 7.5). 1207, 1479 1697 474 [Ml] ^- 29 R ^: = p-MeC <H · - (MeOH-dJ: 2.10 (s, 6H), 2.41 (s, 3H), 6.82 (d, 1H, J = 9), 6.95 (dd, 1H, J = 9,3), 7.19 (d, 1H, J) = 3), 7.45 (d, 2H, J = 8.3), 53 (s, 2H), 7.77 (d, 2H, J = 8.3). 1149, 1207, 1481 454 [M-1] 473 [MtNH.] 30 R ⁴ = p-MeOC _ŕ H, - (CDCl3: 1.98 (s, 6H)), 3.80 (s, 3H), 6.80-6.82 (m, 2H), 6.89-6.93 (m, 3H), 7.31 (s, 2H), 7.73. 2H, J = 7.2), 8.73 (broad s, IH ;, 8.89 (broad s, IH)) 1209, 1475, 1588, 1705 40 [M-1 / ! 31 R ⁴ = p-CF ³ C 1 H, - (DMSO-d6): 2.07 (s, 6H), 6.89 (d, 1H, J = 9), 7.08 (dd, 1H, J = 9, 3), 7.15 (d, 1H, J = 3), 7.60 (s, 2H), 7.98 (d, 2H, J = 3), 8.03 (d, 2H, J = 3); 1207, 1476 1697 508 [M-1] 32 R ^; => Me- (MeOH-dJ): 2.12 (s, 6H); 3.23 (s, 3H); 6.96-7.0 (m, 2H); 1H, J - 2.2), 7.51 (s, 2H). 1205, 1481, 1687, 1739 378 [M-1] -

33 R '- n-Bu- (DMSO-d 6): 0.81 (t, 3H, J = 7.2), 1.24-1.36 (m, 2 H), 1.41-1.51 (m, 2 H), 2.04 (s, 6H), 3.37 (t, 2H, J = 7.2), 6.88 (d, IH, J = 3), 7.08 (dd, IH, J = 9,3), 7.15 (d, IH, J = 3), 7.00-7.10 (m, 2H), 7.57 (s) (2H), 10.67 (s, 2H) 1205, 1488. 1694 420 [M-1] ^- 439 [M + NH] + 34 R '= i-Pr- (DMSO-d 6): 1.11 (d, 6H, J = 7); 2.03 (s, 6H), 3.66-3.75 (m, 1H), 6.88 (d, 1H, J = 3), 7.02 (d, IH, J = 3, 7.08 (dd, IH, J = 9) 3), 7.57 (s, 2 H), 10.65 (s, 2 H) 1229, 1354, 1480, 1688, 1761 406 [M-1] 425 [M + NH] -

Example 35

N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenyl] -3,5-dimethylphenylImalonamic acid

The title compound was prepared according to the procedure in Example 26: NMR (DMSO-d ₆ ): 2.05 (s, 6H), 3.35 (s, 2H), 6.89 (d, 1H, J = 9) 7.01 (dd, 1H, J = 9, 3), 7.14 (d, 1H, J = 3), 7.39-7.45 (m, 4H), * 7.93 (dd, 2H, J = 8.8, 5.2), 10.55 (s, 1H), 12.6 (broad s, 1H), IR (KBr)

1142, 1239, 1485, 1623, 1654, 1736, ESI-MS 472 [M-1].

Example 36

N- {4- Γ 3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl) succinamic acid

The title compound was prepared according to the procedure in Example 26: NMR (DMSO-d ₆ ): 2.04 (s, 6H), 2.50-2.56 (m, 4H),

6.87 (d, 1H, J = 9), 7.01 (dd, 1H, J = 9, 3), 7.12 (d, 1H, J = 3), 7.39-7.45 (m) 4H), 7.93 (dd, 2H, J = 8.8, 5.2), 9.93 (s, 1H), 12.1 (s, 1H), IR (KBr) 1480, 1623, 1659 , 1717, ESI-MS 486 [M-1] &lt; - &gt;.

Example 37

N- (4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenylamino) propionic acid

The title compound was prepared according to the procedure described in Example 26: NM? (MeOH-dJ: 2.06 (s, 6H), 2.65 (t, 2H, J = 7 ;,);

3.49 (t, 2H, J = 7), 6.82 (d, 1H, J = 9), 6.85 (s, 2H), 6.94dd, 1E, J = 5,

3), 7.15 (d, 1H, J = 3), 7.23 app, 2H, J = 9), 7.88-7.93 (m, 2H), [delta] (KBr 1199, 1493, 1623, 1675, ESI-MS 458 [M] ^- .

Example 38

N- {4- [3- (4-Fluorobentenesulfonyl) -4-hydroxyphenoxy] -3-methylphenyl} oxamic acid

The title compound was prepared as described in Example 26: NMR _(DMSO-d6): 2.18 (s, 3H), 6.90 (d, 1 H, J = 9 '.

5.92 (d, 1H, J = 9), 7.16 (dd, 1H, J = 9.3), 7.34 (d, 1H, J = 3), 7.43 app t, 2H, J = 9), 7.61 (dd, 1H, J = 9.3), 7.97 (dd, 2H, J = 9.5), 10.67; _S , 1H,

10.71 (s, 1H), IR (KBr) 1234, 1495, 1697, ESI-MS 444 [M-1].

Example 39

N- {3,5-Dibromo-4- [3- (4-fluorobenzenesulfonyl) -4-hyaroxyphenoxy]. phenyl} oxamic acid

The title compound was prepared according to the procedure in Example 26: NMR (DMSO-d ₆ ): 6.91 (d, 1H, J = 9), 7.09-dd, 1H,

J = 9.3, 7.20 (d, 1H, J = 3), 7.44 (app t, 2H, J = 8.6), 7.92-7.97 im, 2H;

8.27 (s, 2H), 10.74 (s, 1H), 11.15 (s, 1H), IR (KBr) 1290, 1454, 1484,

1589, 1695, ESI-MS 588 [M] ^- .

Example 40

N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl loxamic acid

The title compound was prepared according to the procedure for EXAMPLE 26: NMR (DMSO-d 6): 2.06 (s, 6H), 6.88 (d, IE, J = 9;

7.03 (dd, 1H, J = 9.3), 7.13 (d, 1H, J = 3), 7.42 (app t, 2H, J = 8.9), 7.66 (s, 2H), 7.52-7.96 (m, 2H), 8.0 (br s, 1H), 10.49 S, 1H),

10.58 (s, 1H), ZC (KBr) 1141, 1250, 1481, 1676, ESI-MS 497] M-1] -,

516 [M + _NH4] +.

Example 41

N- {4- (3- (4-Fluorobenzenesulfonyl; -4-hydroxyphenoxy) -3,5-dimethylphenyl} -N´-propyloxalamide

The title compound was prepared in analogy to the procedure described in Example 26: ES-MS 499 [M-1] + 518 [M + NH ₄ ] -.

Example 42

And ⁷ - {4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3, 5-dimetylfer.yl J N 'izopropyloxalamid

The title compound was prepared analogously to Example 26: ES-MS 499 [M] +, 518 [M + NH ₄ ] +.

Example 43

N-Butyl-N '- {4- [3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxalamide

ABOUT

The title compound was prepared analogously to Example 26: ES-MS 513 [M-1], 515 [M + 1] +, 532 [MtNH ₄ ] +.

Example 44. N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl] -N'- (2-methoxyethyl) oxalamide

Example compound 26: ES-MS 517 [M + 1] +.

is prepared analogously to the pedal

Example 45

N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} -2-morpholin-4-yl-2-oxoacetamide

The title compound was prepared analogously to Example 26: ES-MS 527 [M-1] / 529 [M + 1] *, 546 [M + NH 4 +].

Example 46

N- {4- [4-Hydroxy-3- (piperidine-1-carbonyl) phenoxy] -3,5-dimethylphenyl} oxamic acid

A. 5- (2,5-Dimethyl-4-nitrophenoxy) -2- (2-methoxyethoxymethoxy) benzoic acid 2-methoxyethoxymethyl ester

A suspension of sodium hydride NaH (60% dispersion in mineral oil, 1.32 g, 33 mmol) in 50 mL of N-methylpyrrolidone was cooled to 0 ° C and 2,5-dihydroxybenzoic acid (1.54 g, 10 mmol) was added in one portion. ). The mixture was warmed to room temperature and after 30 minutes 4-chloro-3,5-dimethylnitrobenzene (2.41 g, 13 mmol) was added in one portion. The reaction mixture was cooled to room temperature and 2-methoxyethoxymethyl chloride (2.85 mL, 25 mmol) was added. After stirring for 30 minutes, the mixture was poured into water and the reaction product was taken up in diethyl ether. The organic solution was washed with brine, dried over anhydrous sodium sulfate and concentrated. Silica gel chromatography (eluting with ethyl acetate / hexane 1/2 to 3/2) gave 5- (2,5-dimethyl-4-nitrophenoxy) -2- (2-methoxyethoxymethoxy, benzoic acid 2-methoxyethoxymethyl ester): NMR (CDCl 3): 2.23 (s,

6Η), 3.36 (s, 3H), 3.38 (s, 3H), 3.54-3.60 (m, 4H), 3.80-3.90 (m, 4H),

5.28 (s, 2H), 5.52 (s, 2H), 6.82 (dd, 1H, J = 9.3), 7.17-7.23 (m, 2H), 8.02 ( s, 2H).

B. 5- (4-Amino-2,6-dimethylphenoxy) -2- (2-methoxyethoxymethoxy) benzoic acid 2-methoxyethoxymethyl ester

A mixture of 5- (2,5-dimethyl-4-nitrophenoxy) -2- (2-methoxyethoxymethoxy) benzoic acid 2-methoxyethoxymethyl ester (3.2 g, 6.68 mmol) and palladium on charcoal ( 10% (320 mg) in 50 mL of ethyl acetate was stirred under a hydrogen atmosphere for 3 hours. The catalyst was filtered off under vacuum through a pad of Celite, washed with ethyl acetate, and the combined filtrate and washings were concentrated in vacuo. 2-methoxyethoxymethyl ester is obtained

5- (4-amino-2,6-dimethyl-phenoxy) -2- (2-metcxyetoxymetoxy) benzoate: NMR (CDC1 _3): 2.07 (s, 6H), 3.37 (s, 3H), 3, 40 (s, 3H), 3.52-3.62 (m, 4H), 3.83-3.92 (m, 4H), 5.26 (s, 2H), 5.52 (s, 2H) , 6.60 (s,

2H), 6.70 (dd, 1H, J = 8.3, 3), 7.13 (d, 1H, J = 9.3), 7.24 (d, 1H, J = 3).

C. 5- [4- (ethoxyoxalylamino) -2,6-dimethylphenoxy; -2-hydroxybenzoic acid

A solution of 5- (4-amino-2,6-dimethyl-phenoxy) -2- (2-methoxy-ethoxy-methoxy) -benzoic acid 2-methoxy-ethoxy-methyl ester (2.83 g, 6.3 mmol) in Part B, 20 mL of tetrahydrofuran was cooled to 0 ° C and then treated sequentially with N, m-methylmorpholine (2.1 mL, 18.9 mmol) and ethyloxalyl chloride (0.915 mL, 8.19 mmol). After 15 minutes, the mixture was partitioned between ethyl acetate and water, the organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue is dissolved in 30 ml of ethanol and 20 ml of aqueous 6N hydrochloric acid are added. The mixture was stirred at room temperature for 16 hours, then the ethanol was evaporated under reduced pressure. The residue was diluted with water (100 mL) and the solid was collected by filtration under vacuum, washed with water and dried. Crystallization from acetonitrile gave 5- [4- (ethoxyxalylamino) -2,6-dimethylphenoxy] -2-hydroxybenzoic acid: NMR (DMSO-47)

-de): 1.31 (t, 3H, J = 7), 2.06 (s, 6H), 4.30 (q, 2H, J = 7), 6.88-6.97 (m,

2H), 7.08 (dd, 1H, J-9, 3), 7.54 (s, 2H), 10.7 (s, 1H).

D. N- {4- [4-hydroxy-3- (piperidine-1-carbonyl) phenoxy] -3,5-dimethylphenyl} oxamic acid

The title compound of Part C, 5- [4- (ethoxyoxalylamino, -2,6-dimethylphenoxy) -2-hydroxybenzoic acid, in 1 mL of dimethylformamide was mixed with N-methylmorpholine (55 μΐ, 0.5 mmol) at room temperature. and 1,1'-carbonyldiimidazole (32 mg, 0.2 mmol) The reaction mixture was heated at 60 ° C for 1 h, then cooled to room temperature and piperidine (24 µΐ, 0.24 mmol) was added. aqueous 1.5N lithium hydroxide solution (333 μΐ, 0.5 mmol) was added to the reaction mixture, which was stirred for 30 minutes, then quenched with trifluoroacetic acid (100 μΐ) and purified by HPLC. acetonitrile-water with 0.1% trifluoroacetic acid) to give N- {4-; 4-hydroxy-3- (piperidine-1-carbonyl) phenoxy] -3,5-dimethylphenyl] oxamic acid: NMF.

(DMSO-d6): 1.34-1.63 (m, 6H), 2.06 (s, 6H), 3.30 (broad s, 4H),

I

6.36 (d, 1H, J = 2.3), 6.67 (dd, 1H, J = 5.3, 2.3), 6.80 (d, 1H, J = 8.3),

7.53 (s, 2H), 9.38 (broad s, 1H), 10.6 (s, 1H), ESI-MS 413 [M + 1] +.

Example 47

N- {4- [4-Hydroxy-3- (morpholin-1-carboryl) ferhoxy] -3,5-dimethylphenyl] oxamic acid

The title compound was prepared according to the procedure for EXAMPLE 46: ESI-MS 415 [M + 1] +.

Example 48

N- [4- (3-Cyclohexylcarbamoyl-4-hydroxyphenoxy) -3,5-dimethylphenyl] oxamic acid

The title compound was prepared according to the procedure for Example 46: ESI-MS 427 [M + 1] +.

Example 49

4- [4-Hydroxy-3- (2-methoxyethylcarbamoyl) phenoxy] -3,5-dimethylphenyl} oxamic acid

The title compound of Example 46: ESI-MS 403 [M + 1] +.

is prepared according to the procedure of

Example 50

N- {4- [4-Hydroxy-3- (2-morpholin-4-yl-ethylcarbamoyl) -phenoxy] -3,5-dimethyl-phenyl} -oxamic acid

The title compound was prepared according to the procedure for Example 46: ESI-MS 458 [M + 1] '.

Example 51

N- (4- [4-Hydroxy-3- (2-pyridin-3-ylcarbamoyl) phenoxy] -3,5-diethylphenyl) oxamic acid

The title compound was prepared according to the procedure for EXAMPLE 46: ESI-MS 422 [M + 1] +.

Example 52

Example of formulation preparation

Hard gelatin capsules containing 100 mg of the active ingredient, for example N- {4- [3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid, may be prepared, for example, as follows:

Mixture composition for 1000 capsules active substance 100.0 g lactose 250.0 g microcrystalline cellulose 30.0 g sodium lauryl sulphate 2.0 g magnesium stearate 8.0 g

Sodium lauryl sulfate screened through sieves with a mesh size of 0.2 mm is added to the lyophilized active substance. Both components are mixed perfectly. Lactose is then added first using a 0.6 mm mesh screen and then microcrystalline cellulose using a 0.9 mm mesh screen. The ingredients are then thoroughly mixed for 10 minutes. Finally, magnesium stearate is added using a 0.8 mm sieve. After further mixing for 3 minutes, 390 mg of the mixture is filled into each 0-size hard gelatin capsule.

Claims (10)

PATENT CLAIMS Compounds of general formula I in which: W is O, S, S (O) or S (O) ₂ X is -SR ^-1, -S (O) R ^J, -S (O) ₂ R ⁴ group, -S (O) NR ^{5 R,} alebc X is -C (O) NR ^a R ^e, the group C (O) NR ⁵ R ⁶ are disposed at positions 3 ', 4' or 5 ' -. Y is an oxygen atom or there are two hydrogen atoms, Z is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted alkoxy group, an arylalkoxy group, an acyloxy group or an alkoxycarbonyloxy group, R is a hydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkyl group or a cycloalkyl group, R is OH, optionally substituted alkoxy, aryloxy, heteroaryloxy groups, aralkoxy, oyklcälkozylová group, heteroarylalkoxylová, or -N? / R ^e, R ² is a hydrogen atom, a halogen atom or an alkyl group, R * is a halogen atom or an alkyl group, R ⁴ is an optionally substituted alkyl, aryl, arylalkyl, hetercarylalkyl or heteroaryl group, R ^a, R ^c Ar are independent of each other and are hydrogen, optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R ⁵ and R ⁶ together form an alkylene group, optionally interrupted by oxygen, sulfur, S (O), S (O) = or NR ⁷ , which together with the nitrogen atom to which they are attached form 5- to 7- a membered ring, n is 0 or an integer from 1 to 4, And pharmaceutically acceptable salts thereof. Compounds according to claim 1, in which Z is other than hydrogen when X is -C (O) NR ^S R 1 Compounds according to claims 1 or 2, of the general formula I, in which W is an oxygen atom or a sulfur atom, X is -S1OjR 'wherein R ⁴ is lower alkyl, phenyl or phenyl substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl, or -S (O) ; NP. ⁼ R ⁶ or -C (O) NR ⁵ R ^6, wherein ^R: is in each case hydrogen or lower alkyl and R ⁶ is in each case hydrogen, lower alkyl, lower alkyl substituted skúpi.za NR ^S R ^E , 3- to C-1 A 7-membered cycloalkyl group, a phenyl group, a phenyl group substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl, pyridyl or lower alkyl-2-pyrionium, or R @ ⁵ and R @ ⁵ in each case form an alkylene group or an alkylene group interrupted by an oxygen atom or an H2O group, which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring, Y is an oxygen atom or there are two hydrogen atoms, Z is a hydrogen atom or a hydroxyl group, R is a hydrogen atom, R ¹ is hydroxyl, lower alkoxy, or NR ⁵ R ⁶ in which R ³ is hydrogen or lower alkyl and R ⁶ is hydrogen, lower alkyl, lower alkoxy or R ³ and R ⁶ together form an alkylene or alkylene group interrupted by an oxygen atom, which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring, R ² is hydrogen, halogen or lower alkyl, R ³ is halogen or lower alkyl, n is zero, 1 or 2, or a pharmaceutically acceptable salt thereof. Compounds according to claims 1 and 2, of the general formula IA in which H is an oxygen or sulfur atom, X is -SR ⁴ , -S (O) R ⁴ , -SfOhR ¹ , -S (C); NR ⁵ R ^6, or -C (O) NR ³ R ⁶ , Y is an oxygen atom or there are two hydrogen atoms, Z is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, an arylalkoxy group, an acyloxy group or an alkoxycarbonyloxy group, R ¹ is a hydroxyl group, a lower alkoxy group or an aryloxy group, R ² is hydrogen, halogen or lower alkyl, R ³ is a halogen atom or a lower alkyl group, R ⁴ is an optionally substituted alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, »m ¹ R, R and R are each independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R ^s and R ⁶ together form an alkylene group, optionally interrupted by O, S, S (0), S (0) ₂ or NR ^7, which, together with the nitrogen atom to which they are attached form a 5- to 7 an o-ring, n is zero, 1 or 2, or a pharmaceutically acceptable salt thereof. Compounds according to claims 1 or 2, of the general formula IB in which X is -S (O) ₂ R ^4, -S (O) JNR ⁵ R ^6, or -C (O) ^NR R®, Z is a hydroxyl group, a lower alkanoyloxy group, or a lower alkoxy group, R * is a hydroxyl group or a lower alkoxy group, ^R: and R ³ are lower alkyl, R ⁴ is an aryl group, R ⁵ , R ⁶ and R ⁷ are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R ⁵ and R 'together form an alkylene group, optionally interrupted by O, S, S (O), S _(0), or NR ^7, which, together with the nitrogen atom to which they are attached form a 5- to 7 member circle; which may optionally contain a further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur; or a pharmaceutically acceptable salt thereof. I Compounds according to claim 5, of the general formula IC, in which X is -S (O) 2 R ⁴ or -S (O) 2 NF. ⁵ R ^e , R 'is a monocyclic aryl group, ^R: R and R ⁷ are each independently hydrogen, optionally substituted alkyl or aryl, or R and R together are CH2CH2-Q-CH2CH2 wherein Q is CH, O, NR ^7, a sulfur atom, a S (O) or a S (O) 2 group, which together with the nitrogen atom to which they are attached form a six-membered ring, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester prodrug thereof. Compounds according to claim 6, of the general formula IC, in which X is a group S (O); R ⁴ and R ⁴ are phenyl optionally substituted by lower alkyl, halogen, lower alkoxy or trifluoromethyl or a pharmaceutically acceptable salt thereof or pharmaceutically usable ester pre-drugs. Compounds according to claim 1 which are N- {4- [3- (2,2-Dimethylpropylsulfamoyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl] oxamic acid, N- [4- (4-Hydroxy-3-phenylsulfamoyl-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid, N-14- [3- (4-Fluorophenylsulfamoyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl] oxamic acid, N- {4- [3- (2-Fluorophenylsulfamoyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl] oxamic acid, N-14- [3- (3-Fluorophenylsulfamoyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl] oxamic acid, I N- {4- [4-Hydroxy-3- (4-methoxy-phenylsulfamoyl) -phenoxy] -3, 6-dimethyl-phenyl-oxamic acid, N- {4- [3- (4-Fluorobenzylsulfamoyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl] oxamic acid, N- {4- [4-Hydroxy-3- (methylphenylsulfamoyl) phenoxy] -3,5-dimethylphenyl] oxamic acid, N- [4- (4-Hydroxy-3-propylsulfamoylphenoxy) -3,5-dimethylphenyl] oxamic acid, N- [4- (4-Cydroxy-3-isopropylsulfamoylphenoxy) -3,5-dimethylphenyl] oxamic acid, N- [4- (3-Sutylsulfamoyl-4-hydroxyphenoxy) -3,5-dimethylphenyl] oxamic acid, N- [4- (4-Cydroxy-3-isobutylsulfamoylphenoxy) -3,5-dimethylphenyl] oxamic acid, N-S '(3- tert -Butylsulfamoyl-4-hydroxyphenoxy) -3,5-dimethylphenyl] oxamic acid, N-S-13-Cyclohexylsulfamoyl-4-hydroxyphenoxy) -3,5-dimethylphenyl] oxamic acid, N - [4- (3-Dimethylsulfamoyl-4-hydroxyphenoxy) -3,5-dimethylphenyl] oxaic acid, N- {4- [4-Hydroxy-3- (pyrrolidine-1-sulfonyl) phenoxy] -3,5-dimethylphenyl} oxamic acid, N- {4- [4-Hydroxy-3- (piperidine-1-sulfonyl) phenoxy] -3,5-dimethylphenyl} oxamic acid, N- {4- [4-Hydroxy-3- (2-methoxyethylsulfamoyl) phenoxy] -3,5-dimethylphenyl) oxamic acid, N- {4- [4-Hydroxy-3- (morpholine-4-sulfonyl) phenoxy] -3,5-dimethylphenyl} oxamic acid, Nl 4- [3- (Dioxotiomorfolir.-4-sulfonyl) -4-hydroxy-phenoxy] -3, 5-dimethyl-phenyl} -oxamic acid, 'I _e N- {4- [4-Hydroxy-3- (pyridin-3-ylsulfamoyl) phenoxy] -3,5-dimethylphenyl} oxamic acid, N- {4- [4-Hydroxy-3- (1-methyl-6-oxo-1,6-dihydropyridin-3-ylsulfamoyl) phenoxy] -3,5-dimethylphenyl} oxamic acid, N - {4- [3- (4-Fluorophenylsulfamoyl) -4-hydroxyphenylsulfanyl] -3,5-dimethylphenyl} oxamic acid, N- {4- [3- (4-Fluorophenylsulfamoyl) phenoxy] -3,5-dimethylphenyl} oxamic acid, N- {4- [3- (4-Fluorophenylsulfamoyl-4-hydroxyphenoxy) -3-ethylphenyl] oxamic acid, N-14- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid, N- [4- (3-Benzenesulfonyl) -4-hydroxyphenoxy) -3,5-dimethylphenyl} oxamic acid, N- {4- [3- (4-Chlorobenzenesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl} -oxamic acid, N-14- [4-Hydroxy-3- (toluene-4-sulfonylphenoxy) -3,5-dimethylphenyl} oxamic acid, N- {4- [4-Hydroxy-3- (4-methoxybenzenesulfonyl) phenoxy] -3,5-dimethylphenyl] oxylic acid, N - {4- [4-Hydroxy-3- (4-trifluoromethylbenzenesulfonyl) phenoxy] -3,5-dimethylphenyl] oxamic acid, N- [4- (4-Hydroxy-3-methanesulfonylphenoxy) -3,5-dimethylphenyl] oxamic acid, N- (4- [3- (Butane-1-sulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl] oxamic acid, N- (4- [4-Hydroxy-3- (propane-2-sulfonyl) phenoxy] -3,5-dimethylphenyl] oxamic acid, N- (4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl] malonic acid, N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl] succinic acid, N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenylamino} propionic acid, N- {4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy; -3-methylphenyl} oxamic acid, N- (3,5-Dibromo-4- [3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] phenyl) oxamic acid, N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxalamide, N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} -N'-propyloxalamide, N- {4- [3- (4-Fluorobenzenesulfonyl, -4-hydroxyphenoxy) -3,5-dimethylphenyl} -N'-isopropyloxalamide, N-Butyl-N '- (4- [3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxalamide, N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl] -N '- (2-methoxyethyl) oxalamide, N- (4- [3- (4-Fluorobenzenesulfonyl, -4-hydroxyphenoxy) -3,5-dimethylphenyl] -2-morpholin-4-yl-2-oxoacetamide, N- {4- [4-Hydroxy-3- (piperidine-1-carbonyl) phenoxy] -3,5-dimethylphenyl loxamic acid, N- {4- [4-Hydroxy-3- (morpholine-4-carbonyl) phenoxy] -3,5-dimethylphenyl loxamic acid, N- [4- (3-Cyclohexylcarbamoyl-4-hydroxyphenoxy) -3,5-dimethylphenyl] oxamic acid, N- {4- [4-Hydroxy-3- (2-methoxyethylcarbamoyl) phenoxy] -3,5-dimethylphenyl loxamic acid, N- {4- [4-Hydroxy-3- (2-morpholin-4-yl-ethylcarbamoyl) -phenoxy] -3,5-dimethyl-phenyl-loxamic acid, and N - {4- [4-Hydroxy-3- (pyridin-3-ylcarbamoyl) phenoxy] -3,5-dinethylphenylloxamic acid, or a pharmaceutically acceptable salt thereof. Use of compounds according to any one of claims 1 to 8 for the preparation of a medicament for the prevention and treatment of diseases associated with thyroid hormone imbalance and for the prevention and treatment of occlusive cardiovascular conditions associated with nyperlipidemia and hyperlipoproteinemia and for the prevention and treatment of hypoa hyperthyroidism, obesity, obesity, and depression, to reduce total plasma cholesterol and LDL-cholesterol levels, and to prevent and treat atherosclerosis and coronary heart disease. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.