CZ20013449A3 - Diaryl derivatives and their use as a medicament - 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 and their use as pharmaceuticals

Technical field

The invention relates to novel compounds having thromrometic treatment of diseases such as depression.

Effect, especially low effect and associated can be used for the prevention and / or imbalance of thyroid hormones, hypo- and hyperthyrodism, obesity, osteoporosis and the compounds of the invention further have a hypolipidemic which increases cholesterol clearance from circulation, cholesterol removal in the form of density lipoproteins. Compounds of lipoproteins (a) that further reduce independently elevated levels of cardiovascular risk factor. The invention furthermore relates to pharmaceutical compositions, their use as medicaments.

SUMMARY OF THE INVENTION

The subject of the invention are

R1

relates to the preparation of these compounds and to the novel compounds of formula I

R (i)

in which

W is O, S, S (O) or S (O) ₂ ,

X is -SR ₄ , -S (O) R ₄ , -S (O) ₂ R ₄ , -S (O) ₂ NR ₅ R ₆ , or X is-C (O) NR ₅ R _6, the group -C (O) NR _a R _e is located at the 3'-, 4'-, 5-, or,

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 hydrogen, halogen, trifluoromethyl, lower alkyl or cycloalkyl,

R 1 is hydroxyl, optionally substituted alkoxy, aryloxy, heteroaryloxy, arylalkoxy, cycloalkoxy, heteroarylalkoxy or -NR ₅ R ₅ ,

R ₂ is hydrogen, halogen or alkyl,

R ₃ is a halogen atom or an alkyl group,

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

R _5, R _s and R ₇ are independent of one another and are hydrogen, optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, or

_R and _R 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 a 5- to 7-membered a ring, n is 0 or an integer from 1 to 4, and pharmaceutically acceptable salts thereof.

Β · · * ·

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 of 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. In addition, the compounds also reduce elevated levels of lipoproteins (a) [Lp (a) 1, which are an independent cardiovascular risk factor in mammals. The compounds of the invention can therefore be used for prevention

and / or treatment occlusive cardiovascular conditions, which are as a result of hyperlipidemia and hyperlipoproteinemia , as Yippee atherosklerosa and coronary heart disease in mammals. Invention relates to compounds of general interest formulas AND,

pharmaceutical compositions containing the compounds and methods 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. · ♦ ·:

-4->··:; ! 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, alkylthiol, alkylthio, alkylsulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, , carboxyl, alkoxycarbonyl, aryl, aralkyl, arylalkoxy, guanidino, heterocyclyl such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pirimidyl, piperidyl, morpholinyl and the like. Preferred substituents in, for example, substituted alkyls, especially when the substituted alkyl group in R _T is a substituted alkoxy group, are lower alkyl, cycloalkyl, lower alkenyl, benzyl, mono- or di-substituted lower alkyl, e.g. τσ- (amino) , a mono- or di-lower alkylamino group, a carboxyl group, a lower alkoxycarbonyl) lower alkyl group, an a- (lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl) lower alkyl group such as a pivaloyloxymethyl group.

The term lower alkyl includes alkyl groups described above with 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 above 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 simple bonds (e.g. - (CH ₂ ) _X -, wherein x is 1 to 6, which may be further substituted by 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 a group

(alkyl) NH- and a (alkyl) ₂ N- group, respectively. Expression alkanoylamino means an alkyl-C (O) -NH- group. Expression alkylthio means an alkyl-S- group. Expression alkylthiono means alkyl-S (O) -. Expression alkylsulfonyl means an alkyl-S (O) ₂ - group. Expression alkoxycarbonyl means an alkyl-O-C (O) - group. Expression alkoxycarbonyloxy means a group

alkyl-O-C (O) -O-;

The abovementioned definitions apply as defined above.

The term alkyl in the above optionally substituted alkyl

The term aryl means a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 12 carbon atoms in one group, wherein the ring moieties such as phenyl, naphthyl, tetrahydronaphthyl and biphenyl each may be optionally substituted with one substituent selected from the group consisting of halogen atoms a hydroxyl group, an alkanoyl group, up to four groups, a group, a group, an amino group, a nitro group, an alkanoyl group, a carboxyalkyl alkoxy alkanoyloxy group. aminoalkylamino, dialkylamino, thiol, alkylthiol cyano, carboxyl, alkyl, alkoxycarbonyl, alkylthion, alkylsulfonyl, sulfonamide, heterocyclyl and the like.

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

substituted

The term aralkyl means an aryl group directly linked 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 which is, for example, monocyclic of 4 to 7 members, bicyclic of 7 to 11 members or tricylic of 10 to 15 members in a ring system having at least one ring heteroatom, and which contains at least one carbon atom. Each ring of a heteroatom-containing heterocyclic group 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 via a carbon atom.

Examples of monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, 2-azepidinyl, azepinyl a group, a pyridyl group, a 2-pyridone group, an N-lower alkyl-pyridone group, e.g., an N-lower alkyl 2-pyridone group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, tetrahydropyranyl, morpholinyl, thiamorpholinyl, S-oxo-thiamorpholinyl, S, S-dioxo-thiamorpholinyl, 1,3-dioxalan and tetrahydro-1,1-dioxothienyl and the like.

-8-bicyclic heterocyclic group, benzothiazolyl, at the benzothiazolyl group;

Examples of indolyl groups include a group, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzopyranyl, indolizinyl, benzofuryl a chromonyl group, a coumarinyl group, a benzopyranyl group, a cincholinyl group, a quinoxalinyl group, an indazolyl group, a pyrrolopyridyl group, a furo-pyridinyl group (such as a furo [2,3-c] pyridinyl group, furo [3,2-b] pyridinyl or furo [2,3-b] -pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxoquinazinyl) and the like.

Examples of tricyclic heterocyclic groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl 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 group (ie = 0), (e) amino, alkylamino or dialkylamino, (f) alkoxy, ( g) cycloalkyl,

(H) a carboxyl group, (i) a heterocyclooxy group, (j) an alkoxycarbonyl group, such as an unsubstituted lower alkoxycarbonyl group, (k) a mercapto group, (l) a nitro group, ( m) cyano, (n) sulfonamido, sulfonamidoalkyl or sulfonamido-dialkyl, (o) aryl, (p) alkylcarbonyloxy, (q) arylcarbonyloxy, (r) arylthio, (s) aryloxy, (t) alkylthio, (u) alkylthio, (u) alkylthio, (u) alkylthio, (u) ) formyl, (v) arylalkyl, or (w) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxyl, amino, alkylamino, dialkylamino, or halo.

The term heterocyclooxy refers to a heterocyclic group linked through an oxygen bridge.

The term heteroaryl denotes aromatic heterocycles, for example, monocyclic or bicyclic substituents such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl. pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl,

A -10isoquinolinyl group, a benzimidazolyl group, a benzofuryl group, and the like, optionally substituted with one or more substituents described in connection with a substituted aryl group, e.g., substituted with a lower alkyl, a lower alkoxy, or a halogen atom.

The term heteroaryloxy refers to a heteroaryl-O- group.

The term heteroarylsulfonyl refers to a heteroaryl-S (O) ₂ - group.

The term heteroaroyl denotes a heteroaryl-C (O) - group.

The term heteroaralkyl refers to 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 the carboxylic acid esters of the invention (COR 1 denotes a carboxyl group), which are converted to the corresponding free acids under physiological conditions by solvolysis.

Examples of these carboxylic acid esters defined as COR _r are preferably lower alkyl esters, lower alkenyl esters, benzyl esters, mono or disubstituted lower alkyl esters, e.g., tn- (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 hydrogen or lower alkyl.

Ti 9 ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti tiiti

Preferred values for R _x are hydroxyl, lower alkoxy and aryloxy.

A suitable value for R ₂ is hydrogen, halogen or lower alkyl.

A preferred value for R ₃ is halogen or lower alkyl.

A preferred value for R ₄ is a phenyl group or a phenyl group substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen atoms, and trifluoromethyl.

A preferred value for _R5 is hydrogen.

A preferred value for R ₆ is a phenyl group or a phenyl group substituted with one or more substituents 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 substituents, the compounds of the invention may contain one or more asymmetric centers. The resulting diastereomers, enantiomers and geometric isomers are included within the scope of the present invention.

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

Preferred are compounds of formula I wherein,

• *

-12W is an oxygen or sulfur atom,

X is -S (O) ₂ R ₄ where

R ₄ is a phenyl group or a plurality of phenyl substituents in the group.

4 4 ·

A lower alkyl group, a group substituted by one selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, and a trifluoromethyl group, or the group is hydrogen or lower

-S (O) ₂ NR ₅ R ₆ or

-C (O) NR _a R _e, wherein in both cases R ₅ alkyl group and a hydrogen atom, lower alkyl substituted by NR _S R _S group, a phenyl group with one or more substituent group, is a hydrogen

R ₆ is in each case a lower alkyl group

A 7-membered cycloalkyl group substituted by a group selected from phenyl lower alkyl, lower alkoxy, halogen and trifluoromethyl, pyridyl or N-lower alkyl-2-pyridone, or

R ₅ and R _e 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 hydrogen atoms,

Z is a hydrogen atom or a hydroxyl group,

R is hydrogen,

Rj. is hydroxy, lower alkoxy, or the group NR _{5 R,} where R ₅ is hydrogen, lower alkyl and R _e is hydrogen, lower alkyl, lower alkoxy or _R5 and _R together form an alkylene group or an 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.

Compounds of formula IA are preferred

• 9 99 • 9 9 * 99 9 9 • · 9 · 9 * • • · * 9 9 9 9 • • • • · · • 9 9 • 9 ♦ ·· 9 9 ···  * · 99 9 « 9 9 » 9 · • « • 9 9 · »«

(IA) in which

W is an oxygen atom or a sulfur atom,

X is -SR ₄ , -S (O) R ₄ , -S (O), R ₄ , -S (O) ₂ 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 arylalkoxy group, an acyloxy group or an alkoxycarbonyloxy group,

R ₄ 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,

_{R, R} and R ₇ are independently hydrogen, substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or

R _s and R ₆ together form an alkylene group optionally interrupted by oxygen, sulfur, S (0), S {0) ₂ 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

in which

X is -S (O) ₂ R ₄ , -S (O) ₂ NR ₅ R _e , 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,

R4 is aryl,

R _E , R ₆ and R ₇ are independently 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 to which they are attached form a 5- to 7-membered or a pharmaceutically acceptable salt thereof.

Most preferred are compounds of formula IC

(IC) in which

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

R ₄ is a monocyclic aryl group;

-15R _g 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 pharmaceutically acceptable salts thereof.

Particularly preferred are compounds of formula IC wherein X is S (O) ₂ R ₄ and R 5 is a phenyl group optionally substituted with a lower alkyl group, a lower alkoxy group or a trifluoromethyl group, or a pharmaceutically acceptable salt thereof or prodrug thereof.

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

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

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

(II) wherein R ₂ and R ₃ are as defined above and W is an oxygen atom (prepared by methods commonly known in the literature) by first converting to e.g. trifluoromethylsulfonyl ester followed by reaction with lithium chloride in an inert organic solvent such as N-methylpyrrolidone , N, N-dimethylformamide or dimethyl sulfoxide to give the compound of formula III

can convert to

(III)

(IV) by reaction with the appropriately substituted Formula V substituted phenols or thiophenols

wherein R is as defined above, X 'and Z' have the same meaning as X and Z as defined above or X and Z 'are groups convertible to X and Z, respectively, in the presence of 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 at 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 bis-aryl iodonium tetrafluoroborate of formula VI

(VI) wherein R, X'and Z 'are as defined above, with phenols or thiophenols of the general formula II, wherein W is an oxygen atom or a sulfur atom, according to literature procedures, e.g. by reaction in the presence of a copper catalyst and a base such is triethylamine, in an inert organic solvent such as dichloromethane.

Compounds of formula IV wherein 2 is alkoxy or arylalkoxy may be converted to compounds of formula IV wherein Z is hydroxyl by methods commonly known in the literature, e.g. using hydrobromic acid or boron trihalide such as boron trichloride or bromide boron, 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 -Ξ (O) ₂ NR ₅ R _6j 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'-position and Z' is a hydroxyl group , alkoxy or

The arylalkoxy group and Z ' is located in the 4 ' position by reaction with chlorosulfonic acid in an organic solvent such as dichloromethane to give a compound of formula VII

(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 wherein Z' is a protected hydroxyl group such as an alkanoyloxy, alkoxycarbonyloxy or trialkylsiloxy group using methods commonly known in the literature.

Compounds of formula VII wherein 2 'is alkoxy, arylalkoxy, alkanoyloxy, alkoxycarbonyloxy or trialkylsiloxy may be converted to compounds of formula VIII

(VIII) wherein it 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 N, N-dimethylformamide.

Reaction of compounds of formula VIII with primary or secondary amines of formula R ₅ NH R _G wherein R ₅ and R ₆ have

-19-  * it * it it • · · • · to · • it «· • · to · • it to it • · to to · this to ··· · · • ♦ · meaning given above. At this moment base, as N-methylmorpholine or triethylamine, in organic a solvent such as is dichloromethane, se prepare compounds

of formula IX.

(IX)

Compounds of formula (IX) wherein X is as defined above may be converted to compounds of formula (IX) wherein Z 1 is a hydroxyl group by methods and conditions commonly known in the literature.

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

(X) can 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 those of formula X, may be reacted with acylating agents such as oxalyl chloride, ethyl malonyl chloride, ethyl succinyl 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 I, for example compounds of formula XI

wherein R ₂ 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 1 wherein R _A 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 _x is, for example, an alkoxy or aryloxy group may be hydrolyzed to the corresponding compounds of formula I wherein R _T is a hydroxyl group by procedures known in the literature, for example using an aqueous base such as alkali metal carbonates or hydroxides an alkali metal, 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

according to the methods described above or modifications thereof, and if desired, these compounds can be converted to the corresponding compounds of formula I by conversion of X 'and Z' to X and Z, respectively. For example, compounds wherein X '= COOH are converted to the corresponding amides of formula I wherein X is C (D) NR ₅ R _6th methods commonly known in the literature. Similarly, compounds where COR 1 is COOH can be converted to compounds wherein ΟΟΗ _Τ is CONR _S R ₆ .

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 that are conventional in preparative organic chemistry. Protected amino, thiol, carboxyl, and hydroxyl groups are those that can be converted under mild conditions into 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 unwanted 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, etc.), the structure and stability of the molecule whose substituent is to be protected and the reaction conditions.

-22 you ti titi

Protecting groups which achieve these conditions are well known and their introduction and removal are described, for example, in J.F.W. McOmie, Protective Groups in. Organic Chemistry Plenum Press, London, New York, 1973, and T. W. Green, Protective Groups in Organic Synthesis Wiley, New York, 1991.

In the above processes, 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 pivalic acid anhydrides or lower alkyl (ethyl, isobutyl) semi-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 ester or ethyl ester.

The above reactions are carried out by standard methods in the presence or absence of a diluent, preferably one that is inert to the reactants with a catalyst solvent, condensation respectively and / or inert atmosphere, or at which the other reagent is low, near room temperature. pressure or catalysts or elevated temperature (preferably at or at elevated pressure. Preferred and reaction conditions are given by boiling the solvent used, the atmospheric solvent used in the accompanying examples.

The invention further encompasses any variant of the processes described in which the intermediate obtainable 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

They use the components 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 methods of preparation, the novel compounds of the possible isomers or the substantially pure geometric optical isomers (antipodes), the possible isomers, or may exist in the form of a single mixture, for example as in cis) isomers such as their ( trans or racemates or mixtures thereof.

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 final products can be resolved into the optical antipodes by known methods, for example by resolution of their diastereomeric salts obtained with an optically active acid or base and liberating 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, cinchonidine, quinine, quinidine, ephedrine, dihydroabietylamine, brucine or strychnine). Racemic products can 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 free form or in salt form if the salt-forming group present is present.

The acidic compounds of the invention may be converted into salts with pharmaceutically usable bases, for example by treatment with aqueous alkali metal hydroxide, preferably in the presence of an etheric or alcoholic solvent such as a lower alkanol. Salts may precipitate out of solution using ethers, for example 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.

The compounds according to the invention having basic groups can be converted into acid addition salts, in particular pharmaceutically usable salts. These are formed, for example, by reaction with inorganic acids such as mineral acids, for example sulfuric acid, phosphoric acid or hydrohalic acid, or organic carboxylic acids. such as _(C-C4) alkanecarboxylic acids which may be unsubstituted or substituted for example by halogen, for example acetic acid, saturated or unsaturated dicarboxylic acids, for example glycolic, lactic, malic, tartaric or citric acid or amino acids such as aspartic acid or glutamic acid, or with organic sulfonic acids such as (C 1 -C ₄ ) -alkylsulfonic acids (e.g. methanesulfonic acid) or arylsulfonic acids which are unsubstituted or substituted (e.g., halogen). Salts formed with hydrochloric acid, methanesulfonic acid or malic acid are preferred.

Insight the close relationship between the free compounds and the compounds in the form of salts, whenever reference is made to this

By reference to the compound, this also means the corresponding salt, if possible and corresponding 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 hyperthyroidisms, 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 partenteral administration. Preferred are tablets and gelatin capsules containing the active ingredient together with a diluent, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, b) 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 sc) binders, for example, aluminum magnesium silicate, starch, paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, optionally with d) disintegrants, for example starch, agar or its, or sparkling • · • * · ·

-26 · · 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 Mixtures and / or se absorbents, colorants, flavors and sweeteners.

Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are preferably prepared from fat emulsions or suspensions. These compositions may be sterilized and / or contain ingredients such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and / or buffers. In addition, they may also contain other therapeutically active agents. These compositions are prepared by conventional mixing, granulating and coating methods, 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 passage through the skin of the host. A typical transdermal dosage form is a bandage consisting of a support portion, a reservoir containing the active compound, optionally with a carrier, optionally containing a barrier to control the application of the active agent to the skin of the host in a controllable and

predetermined fastening application speed of unit n. for longer and skin. time and equipment for Unit dose for mammals as 50 to 70 kg can contain between about 0.01 mg up to 10 mg active ingredient. Dose

The active ingredient is dependent on the species of warm-blooded animal (human), body weight, age and individual condition, route of administration and compound used.

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 bind effectively to the triiodothyronine (T ₃ ) receptor in the nucleus, which is responsible for regulating the activity of LDL receptors and

·· • · • » «A «· • · • IN * • · · * • • • » • * • and t • · «  · • · • · • ♦ • • • • • · • · «· • 9

increasing the removal of LDL-cholesterol from the bloodstream. Thus, the compounds of the invention are particularly useful in mammals as hypocholesteremic agents for the treatment and prevention of occlusive cardiovascular conditions in which hypercholisteremia contributes by lowering total cholesterol and LDL-cholesterol 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 reducing plasma cholesterol and LDL-cholesterol levels in plasma,

The compounds of the present invention also lower levels of IIpoprotein (a) and are thus useful for the treatment and prevention of occlusive cardiovascular conditions in which Lp (a) is involved.

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

The above properties are demonstrated by in vitro and in vivo assays using preferably 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 be between 10 ⁷ molar and 10 ¹¹ molar concentrations. In 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.

«0 0 ' «0 0 « 0 * • • 0 • 0 Φ 0 0 · • 00 * 0 • • · Φ • 0 0 • 0 « 0 ♦ 00 0 0 Φ 0 • * • • • « «0 0 0 0000 00 0 ·· 0 · * · 0 «

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

In vitro binding to T ₃ core receptors is determined as follows:

Membrane preparations from 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, Volume A, 1974) and the procedure was slightly modified. The nuclear fraction obtained from the 275xg pellet is further purified as generally described in Spindler et al. (J. Biol. Chem. 250, 4118, 1975).

The novel compounds of the invention are tested for core binding by the method described by Spindler et al. (J. Biol. Chem. 250,

4118, 1975). Nuclei were incubated at 22 ° C with 0.3 nM ^[12S J] -L-triiodothyronine (L-T3). Parallel incubations are performed in tubes containing either different concentrations of test compounds or 3μΜ non-radioactive L-T3 in addition to the nuclear preparation and radioactive L-T3. 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 the specifically bound ^[12S J] -L-T3 is determined by subtracting the amount non-specifically bound (radioactivity contained in the nuclear the pellet following incubation with excess (3μΜ) non-radioactive LT _3). The concentration of test compound that inhibits the specific binding of [ ¹²⁵ J] -L-T3 by 50 percent (IC 50) is determined graphically from a reciprocal diagram of specifically bound [ ¹²⁵ J] -L-T3 versus different concentrations of test compound.

The cholesterol lowering effect in rats is determined as follows.

•

The Sprague-Dawley rats (230g-250g) were bred two weeks before and 7 days during the test under ad libitum 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 250 rpm for 10 minutes and plasma is prepared to determine total cholesterol concentrations as well as LDL and HDL cholesterol. HDL values are determined after LDL / 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 0.35 mL of plasma were placed in Eppendorf tubes and ΙμΒ 2M magnesium chloride, 11.2 qL sodium heparin (Porcin Intestinal, 5000 units / ml) and 8.3 µl were added. normal saline solution. 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 above after administration of the test compounds for 5 days.

Reducing normolipemic monkeys

Adult fascicularis (3-7 cholesterol) are used and Lp (a) can be determined in male cynomolgus and as follows:

female cynomolgus monkeys (Macaca kg. Animals are bred

Animals

-30 ·· ··· «··· ·· individually and fed with a standard monkey food (Purina 5074) supplemented with fresh fruits and vegetables. Each animal serves as its own control and each dosage regimen is followed by a washout period. Tested with ethanol, allowed to soak compounds dissolved in the fruit and applied orally.

Animals are given a single dose of treatment time, which ranges after fasting through the test compounds per day for from 8 to 28 days. Blood samples are taken from the femoral vein overnight at the beginning and at the end of the study. Blood samples (3ml)

Vacutainer tubes (containing EDTA). The blood is centrifuged for 20 minutes at 2000 rpm and 4 ° C. divides into aliquots and stores

Samples up to analysis at -70 ° C. Plasma total cholesterol (TC) and triglyceride (TG) concentrations are determined by enzymatic methods using commercially available high density Sigma lipoprotein diagnostic kits

Diagnostic).

The concentration of α-bound cynomolgus-containing fodder monkeys per feed (HDL-C) is measured after apoB precipitation. Since plasma diet contains only lipoproteins in low lipoproteins starving a negligible amount of cholesterol density, low-density and bound cholesterol concentrations

TC. Assays are performed which are read with a microplate spectrophotometer (DynatechMR 5000).

The plasma concentration of Lp (a) (Permmune, Inc.) is determined by a commercial Lp (a) ELISA using control sets and a reference.

Lp (a) standard. Lp (a) ELISA uses monoclonal antibodies against apolipoprotein (a) for capture and polyclonal antibodies against apolipoprotein specific for Lp (a) and does not measure free apo (a) for detection

B.

The test is apoB or plasminogen. Quantification

Lp (a) is not affected by the size i and apo (a). Plasma concentration of Lp (a) with total Lp (a) mass. Samples reported in milligrams from each study are tested in one run.

-31 • it

To illustrate the invention, the compound of the example exhibits a compound of the T ₃ binding assay compound of the example nuclear receptor

IC _{50 of} about 0.17 nM, according to Example compound

The compound shows an IC ₅₀

5 shows IC _S0 2 in Example 6 hereinafter serum cholesterol at a daily dose of about 0.13 nM, about 1.00 nM and an IC ₅₀ exhibits significantly about 0.04nM.

reduces the micrograms (gg) / kg p.o. in rats and 10μg / kg p.o. in dogs. In addition, Lp (a) levels in normolipaemic monkeys of cvnomolgus decrease n by about 40% when treated for 4 weeks with Compound 26 administered at a daily oral dose of 75 µg / 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 evaporation is carried out under reduced pressure, preferably at about 2 to 13.6 kPa. The structure of the end products, intermediates and starting materials is confirmed by standard analytical methods such as microanalysis and spectroscopic characteristics (e.g., MS,

IR, 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

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

Oil hydride suspension, 64.11 g, sodium (NaH,

60% dispersion in mineral

1.603 mol) in 350 ml

The N-methylpyrrolidone (NMP) was cooled to 0 ° C over time

4-methoxyphenol (208.4

1.679 mol).

at room temperature and added in one minute

4-chloro-3,5-dimethylnitrobenzene (1.526 mol) (283.2 g, as described in Yokoyama et al., EP 580 550), and the reaction mixture was heated to 120 ° C for 2 hours. The suspension was cooled to 0 ° C, stirred for 30 minutes, filtered, the filter cake was washed with water and dried in vacuo. 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. The filtrate was concentrated under reduced pressure to about 800 mL and the resulting suspension was cooled to 0 ° C and stirred for 30 minutes. The product is filtered off under vacuum, washed with cold ethyl acetate and dried under vacuum. To afford 3,5-dimethyl-4- (4'-methoxyphenoxy) nitrobenzene: NMR (CDC1 ₃₎ 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

3,5-dimethyl-4- (4'-methoxyphenoxy) nitrobenzene, mmol), acetic acid (AcOH, 100ml), and aqueous paragraphs (164

A, hydrobromic (HBr, 100 mL) was heated for 16 hours

48% acid at 120 ° C. 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.

-33- .... ... ·· ·· water and hexane and dried in vacuo. Gets with 3,5-dimethyl- 4- (4'-hydroxyphenoxy) nitrobenzene: NMR (CDC1 ₃₎ (d, 2H, J = 8.7), 6.77 (d, 2H, J = 8.7), 8.0 (s, 2H) . 2.22 (s, 6H), 6.62

····

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 mmol) in 150 mL of dichloromethane (CH ₂ C1 ₂₎ was reacted at of 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 the addition of sodium chloride solution, filtered in vacuo, washed with water, hexane and diethyl ether and dried under vacuum. 5- (2,6-dimethyl-4-nitrophenoxy) -2-hydroxybenzenesulfonic acid was obtained: NMR (DMSO-d6) 2.18 (s, 6H), 6.67-6.83 (m, 3H), 8 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) benzenesulfonic acid, (6.78 g, 20 mmol) in 100 mL tetrahydrofuran (THF) and 50 mL

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 48 hours. The reaction mixture was cooled to room temperature, quenched with aqueous 1N hydrochloric acid (HCl, 100 mL) and the tetrahydrofuran evaporated. The precipitated product is vacuum filtered, 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-d ₆₎ 2, 18 (s, 6H), 5.10 (s, 2H), 6.74 (dd, 1H, *)

-340 = 8.7, 3.8), 6.97 (d, 1H, J = 8.7), 7.1 (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, 1 mL, 40 mmol) was then added at room temperature oxalyl chloride (3.5 mL, 40 mmol) at room temperature and the reaction mixture was further stirred for 1 hour. Dilute with ethyl ether (200 mL) and wash with water, anhydrous sodium sulfate, ethyl ether (5 mL), and

2-Benzyloxy-5- (2,6-dimethyl chloride): NMR (CDCl3) 2.24 (s, 3.8), 7.32-7.47 (m, 4H), 7.52 sodium chloride solution, dried and concentrated The product is washed with vacuum drying to give 4-nitro-phenoxy) benzenesulfonyl (2H), 5.31 (s, 2H), 7.02 (dd, 1H, J = 8.7, (d, 2H, J = 7), 5), 8.05 (s, 2H).

F. 2-Benzyloxy-5- (2,6-dimethyl-4-nitrophenoxy) -N- (2,2-dimethylpropyl) benzenesulfonamide

A solution of the title compound of paragraph E,

2-Benzyloxy-5- (2,6-dimethyl-4-nitrophenoxy) benzenesulfonyl chloride (1.12 g, 2.5 mmol) in 20 mL dichloromethane was gradually treated with N-methylmorpholine (550 mL, 5 mmol) at room temperature. ) and neopentylamine (442 mL, 3.75 mmol). After 6 hours the mixture was partitioned between water and ethyl acetate, the organic phase was washed with aqueous 1N hydrochloric acid, brine and dried over anhydrous sodium sulfate. Concentration gave 2-benzyloxy-5- (2,6-dimethyl-4-nitrophenoxy) -N- (2,2-dimethylpropyl) benzenesulfonamide: NMR (CDC1 ₃₎ 0.78 (s, 9H), 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-dimethyl-phenoxy) 2-benzyloxy-N- (2,2-dimethyl-35)

9 ·

9 · · · · ·

9t

9 propyl) benzenesulfonamide

Mixture of the title compound

2-benzyloxy-5- (2,6-dimethyl-4-nitrophenoxy) -N- (2,2-dimethylpropyl) benzenesulfonamide, (1.22 g, 2.45 mmol) and palladium

F, on activated carbon (10 wt%, 250 mg) in 40 mL tetrahydrofuran was stirred in hydrogen atmosphere for 8 hours, removed by vacuum filtration through a column

The catalyst was washed with celite, washed with tetrahydrofuran and concentrated. The residue is filtered off under vacuum, the filtrate and the washing solution are combined and suspended in dichloromethane, the product is washed with dichloromethane and dried. 5- (4-Amino-2,6-dimethyl-phenoxy) -2-benzyloxy-N- (2,2-dimethyl-propyl) -benzenesulfonamide is obtained:

NMR (DMSO-d 6) 0.80 (s, 9H), 2.55 (d, 2H,

6.31 (s, 2H), 6.87 (br s, 1H), 6.93 (br

10.13 (s, 1 H).

H. N- {4- [3- (2,2-dimethylpropylsulfamoyl) -4-hydroxyphenoxy] 3,5-dimethylphenyl} oxamic acid

A solution of the title compound of paragraph G,

2-Benzyloxy-5- (2,6-dimethyl-4-nitrophenoxy) -N- (2,2-dimethylpropyl) benzenesulfonamide (750 mg, 1.98 mmol) in 10 mL tetrahydrofuran was cooled to 0 ° C and mixed se s

N-methylmorpholine (545 mL, 4.96 mmol) and ethyloxalyl chloride (442 mL, 3.96 mmol). The reaction mixture was warmed to room temperature and quenched with water after 1 hour. 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 1 N lithium hydroxide solution (LiOH, 1.8 mL, 1.8 mmol). After 1 hour, the reaction was quenched with aqueous 1N hydrochloric acid, the product was taken up in ethyl acetate, washed with brine, dried over sodium sulfate and concentrated. The product was triturated in hexane, then ethyl ether and dried in ethyl acetate

-36vakuu. N- [4- [3- (2,2-dimethylpropylsulfamoyl) -4 ' -hydroxyphenoxy] -3,5-dimethylphenyl] oxamic acid was obtained: NMR (CDCl3) 0.89 (s9H), 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 (br s, 1H), 9.18 (s, 1H),

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

Similarly, the following compounds may be added:

R5 of Re

2 (DMSO-dJ: 1.91 (s, 6H), 6.79-6.9) 1207, 455 [M-1] - R @ _e (m, 6H), 7.11-7.17 (m, 2H), 7.55 (s, 1481, R ₆ = c ₆ h ₅ - 2H), 9.99 (s, 1H), 10.46 (s, 1H), 10.52 (s, 1H) 1689

3 _(DMSO- d): 1.91 (s, 6H), 6.72 (d, 1H, 1207, 473 [M-1] - r ₅ = h J-3.0), 6.89-7.03 (m, 6H), 7.55 (s, 1481, R _e = p-FC ₆ H ₄ - 2H), 9.96 (s, 1H), 10.54 (s, 1H), 10.66 1508, (S, 1 H) 1693 4 (MeOH-d _4): 1.98 (s, 6H), 6.81 (d, 1H, 1209, 473 [M-1] ' R @ ₅ = H J = 2.6), 6.87-7.14 (m, 5H), 7.36 (td, 1481, R _fi = O-FC ₆ H ₄ 1 H, J = 7.9, 1.9), (s, 1H) 1500, 1689 5 (DMSO-d _e): 1.97 (s, 6H), 6.75 to 6.84 1238, 473 [M-l] ’ r ₅ = h (m, 4H), 6.92 (d, 1H, J = 8.8), 7.04 1475, R _s = m-FC _with H ₄ - (dd, 1H, J = 8.8), 7.20 (app q, 1H, J = 7.0), 7.58 (s, 2H), 10.35 (s, 1H), 10.59 ( s, 1H), 10.66 (s, 1 H) 1706,

«· Φφ

-37 ·· ·

_R 6 H R _E = p-MeOC ₆ 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, 0), 6.89-6.99 (τη, 4H), 7.54 (S, 2H), 9.58 (s, 2H), 10.45 (s, 1H), 10.64 (s, 1H) ) 1209, 1475, 1514, 1688 485 [M-1] 7 (DMSO-d _6): 2.02 (s, 6H), 4.0 3 (d, 2H, 1224, 487 [M-1] - R @ ₅ = H J = 6.4), 6.80-6.89 (m, 3H), 7.01 (t, 1481, _R6 = p-Fc _of H ₄ CH ₂ - 2H, J = 4.0), 7.22 (dd, 2H, J = 6.3, 8.7), 7.56 (s, 2H); 7.7 (t, 1H, J = 6.4); 10.32 (s, 1H); 10.64 (s, 1H) 1695 8 R _s -Me R _e = C ₆ H ₅ - (CDC1 _3): l, 96 (s, 6H), 3.14 (s, 3H), 6.54 (d, 1H, J = 2.4), 6.84 to 6.8 5 (m, 2H 6.88-7.03 (m, 2H), 7.20-7.28 (m, 5H) 469 [M-1] 9 (CDCl3): 0.87 (t, 3H, J = 7.5), 1.38- 1214, 421 [M-l] ’ R _S = H 1.56 (m, 2H), 2.11 (s, 6H), 2.94 (app 1485, R _s = n-Pr- q, 2H, J = 7.5), 5.0 (t, 1H, J = 7.5), 6.84 1693, 440 (d, 1H, J = 3), 7.0 (d, 1H, J = 9), 7.08 (dd, 1H, J = 9.3, 7.32 (s, 2H), 8.44 ( br s, 1H), 9.0 (br s, 1H) 1751 [m + m + ₄ ] ⁺ 10 (DMSO-d _6): 0, 9 5 (d, 1H, J = 7.5), 2.02 1209, 421 [M-l] ’ r ₅ = h (s, 6H), 3.2-3.31 (m, 1H), 6.86 (br 1485, R _s = i-Pr- S, 1H), 6.97 (br s, 2H), 7.06 (d, 1H, J = 7.5), 7.57 (s, 2H), 10.32 (brs, 1 H), 10.64 (s, 1 H) 1698, 1742 11 (DMSO-dJ: 0.72 (t, 1H, J = 7.5), 1.1- 1321, 435 [M-1] ' r ₅ = h 1.35 (m, 4H), 2.03 (s, 6H), 2.76 (app 1481, _R6 = n-Bu- q, 2H, J = 7.5), 6.87 (br s, 1H), 6.97 (br s, 2H), 7.1 (t, 1H, J = 7.5), 7.58 (s, 2H) 1691 454 [M + NHJ *] 12 (DMSO-dJ: 0.75 (d, 1H, J = 8.2), 1.49- 1209, 435 [M-1] - r ₅ = h 1.62 (m, 1H), 2.03 (s, 6H), 2.55 (app 1481, R _s = i -Bu- t, 2H, J = 6.8), 6.96 (br s, 1H), 7.17 1993,

(t, 1Η, J = 6.8), 7.57 (s, 2Η), 10.25 (br 1762 s, 1Η), 10.61 (br s, 1H)

13 (DMSO-d _6): 1.02 (s, 9H), 2.03 (s, 6H), 1204, 435 [M-1] - r ₅ = h 6.81-7.02 (m, 4H), 7.56 (s, 2H), 10.20 1486, _R6 = t-Bu- (br s, 1H), 10.61 (br s, 1H) 1645, 1754 14 (CDC1 _3): 1.06 to 1.32 (m, 5H), 1.50 1209, 461 [M-l] ’ r ₅ = h 1.73 (m, 5H), 2.01 (s, 6H), 3.02-3.14 1481, R ₆ = cycloxexyl (m, 1H), 5.05 (d, 1H, J = 7.5), 6.82 (d, 1H); 1H, J = 3), 6.97 (d, 1H, J = 9), 7.10 (dd, 1H, J = 9.3), 7.32 (s, 2H), 8.52 (br s, 1H), 9.06 (brs, 1H) 1695, 1741

• * ® • · ♦ · , _, Q _ · · * ··· ··· • 4 • v • · • · * · « :: i: i ··· · g · ·· ·· 15 Dec (MeOH-dJ 2.07 (s, 6H), 2.64 (s, 6H), 1234, 407 [M-l] ’ R _s = Me- 6.86-6.94 (m, 3H); 7.39 (s, 2H) 1486, R ₆ = Me- 1685 16 (MeOH-d _4): 1.76-1.80 (m, 4H), 2.08 1230, 433 [M-l] ’ R ₅ = R 8 = - (CH ₂ ) ₄ - (s, 6H), 3.21-3.29 (m, 4H), 6.88-6.95 1479, (m, 3H) 7.40 (s, 2H) 1693 17 (MeOH-d _4): 1.49-1.58 (m, 6H), 2.13 1207, 447 [M-l] ’ R ₅ = R ₆ = - (CH ₂ ) ₅ - (s, 6H), 3.08-3.10 (m, 4H), 6.92-7.02 1481, (m, 3H) 7.53 (s, 2H) 1658 18 (CDC1 _3): 2.06 (s, 6H), 3.03 (t, 2H, J = 1218, 437 [M-l] ’ r ₅ -r ₆ = 5.5.3.22 (s, 3H), 3.35 (t, 2H, J = 5.5), 1483, MeO- (CH ₂ ) ₂ - 6.85 (br s, 2H), 6.97 (br s1H), 7.34 íq · τ τη V ** / t 1689 19 Dec (MeOH-d _4): 2.13 (s, 6H), 3.12 (t, 2H, 1479, 449 [M-l] ’ R ₅ = R ₆ = J = 6), 3.68 (t, 4H, J = 6), 6.95-7.03 (m, 1711, - (CH ₂ ) ₂ O (CH ₂ ) ₂ - 3H), 7.54 (s, 2H) 1745 20 May (CDC1 _3): 2.12 (s, 6H), 3.10 to 3.13 (m, 1209, 497 [M-1] - r ₅ = r ₆ 4H), 3.74-3.76 (m, 4H), 6.92-6.99 1481, - (CH ₂ ) _{2 -} sc (ch ₂ ) ₂ - (m, 3H), 7.41 (s, 2H) 1697 21 (DMSO-d6) = 1.95 (s, 6H), 6.81 (d, 1H, 1481, 473 [M-1] - r ₅ = h J = 3), 6.92 (d, 1H, J = 9), 7.0 (dd, 1H, 1500, J = 9.3), 7.26 (dd, 1H, J = 8.5), 7.41- 1689 R _g = 3-pyridyl 7.45 (m, 1H), 7.56 (s, 2H), 8.21 (dd, 1H, J = 5, 1.5), 8.27 (d, 1H, J = 2.5), 10.34 (s, 1H); 10.66 (S, 1H) 22nd (DMSO-d _6): l, 95 (s, 6H), 3.75 (s, 3H), 488 [M + 1] ^<+> r ₅ -h 6.64-6.6 (m, 2H), 6.93 (d, 1H, J = 9), R _s = 6.99 (dd, 1H, J = 9.5), 7.32 (dd, 1H,

J = 9, 2.5), 7.53 (s, 2H), 7.77 (d, 1H,

J = 2.5), 9.74 (s, 1H), 10.56 (s, 1H),

10.61 (s, 1 H)

Example 23

N- {4- [3- (4-fluorophenylsulfamoyl) -4-hydroxyphenylsulfanyl] 3,5-methylmethylphenyl] oxamic acid

The title compound was prepared as in Example 1: NMR (DMSO-d 6 2.21 (s, 6H), 6.87 (d, 1H, (J = 8.3), 6.95-7.12 ( m, 6H), 7.65 (s, 2H), 9.99 (s, 1H), 10.73 (s, 1H), 10.97 (S, 1H), IR (KBr) 1163, 1506.1690 , 489 [M + 1], 488 [M + NH] ⁺ .

Example 24

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

The title compound was prepared according to Example 1: NMR (DMSO-d ₆₎ l, 91 (s, 6H), 6.73 to 6.74 (τη, 1H)

6.95-7.00 (m, 2H), 7.04-7.10 (m, 2H), 7.21 (dd, 1H, J = 8.2 2.4), 7.35 (d, 1H, J = 8.0), 7.52 (app t, 1H, J = 8.0), 7.59 (s, 2H), 10.21 (s, 1H)

100, 75 (S, 1H), IR (KBr) 1161, 1223, 1509, 1697, 457 [M-1] &lt; - &gt;

Example 25

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

The title compound was prepared according to the procedure for EXAMPLE 1: NMR (DMSO-d 6 2.06 (s, 3H), 6.65 (d, 1H, J = 8.8),

6.92-7.18 (m, 7H), 7.55 (m, 7H), 7.55 (dd, 1H, J = 8, 8, 2.4), 7.70 (d, 1H, J) = 8.0), 9.98 (s, 1H), 10.72 (s, 1H), 10.75 (s, 1H), IR (KBr)

1326,1487,1506,1692, ESI-MS 457 [M-1] ’

-40Example 26

N- {4- [3- (4-fluorobenzenesulfamoyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid

A. 4-Fluorobenzenesulfinic acid

A solution of 4-fluorobenzenesulfonyl chloride (2g, 10, 28mmol) in 50 mL of tetrahydrofuran (distilled from Na-benzophenone) was cooled to 0 ° C and sodium borohydride (1.9 g, 51.4 mmol) was added portionwise. After 2 hours at 0 ° C, warm to room temperature and after 2 hours quench with water (5ml), evaporate the solvent and acidify the aqueous residue by adding aqueous 6N hydrochloric acid, shake product into ethyl acetate, wash with brine, dry anhydrous sodium sulfate and concentrated to give 4-fluorobenzenesulfinic acid: NMR (DMSO-d ₆₎ 7.12 (app t, 2H, J = 8.3, 7.5 (dd, 2H, J = 8.3, 6) , ESI-MS 457 [M +].

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

A solution of the title compound of Part A, 4-fluorobenzenesulfinic acid (3 g, 18.75 mmol) in 10 mL of water was added to a solution of 1,4-benzoquinone (1.93 g, 17.86 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: NMR (DMSO-d6) 6.73 (d, 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-1] -.

C.

4- (dimethyl-4-nitrophenoxy) -2- (fluorobenzenesulfonyl) phenol of paragraph B,

2- (4-fluoro, 4.48 mmol) with one sodium (60% dispersion in ___). · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ·

The title compound benzenesulfonyl) benzene-1,4-diol (1.2 was added to a suspension of mineral oil hydride, 0.39 g, 9.86 mmol) in 15 mL of N-methylpyrrolidone at 0 ° C. The reaction mixture was allowed to warm to room temperature and after 30 minutes 4-chloro-3,5-dimethylnitrobenzene (1g, 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 aqueous 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. Chromatography on silica gel (EtOAc / hexane 1 / 2-1 / 1 to give 4 - (dimethyl-4-nitrophenoxy) -2- (fluorobenzenesulfonyl) phenol: NMR (CDC1 ₃₎ 2, LL (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) in 10 ml of ethanol and 10 ml of dichloromethane is stirred under a hydrogen atmosphere for 6 hours. The catalyst was separated by filtration through a pad of celite, washed with a 1: 1 mixture of ethanol and dichloromethane, and the filtrate and washings were combined, concentrated and dried in vacuo. 4- (4-Amino-2,6-dimethyl-phenoxy) -2- (fluorobenzenesulfonyl) phenol was obtained: NMR (DMSO-d ₆ ) 1.93 (s, 6H), 4.9 (S, 2H), 6.34 (s, 2H), 6.85 (d, 1H, J = 9), 7.0 (dd, 1H, J = 93), 7.12 (d, 1H, J = 3), 7 43 (app t, 2H, J = 9), 7.94 (dd, 2H, J = 9.5), 9.41 (S, 1H), 10.4 (s, 1H).

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

A mixture of the title compound of paragraph D, 4- (4-amino-2,6-dimethyl-phenoxy) -2- (fluorobenzenesulfonyl) phenol,

-42 (0.64 g, 1.65 mmol) and 2 mL of diethyl oxalate were heated at 180 ° C for 3 h. 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) gave 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 (brs, 1H), ESI-MS 486 [M-1] &lt; - &gt;.

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

A solution of the title compound of paragraph E, N- {4- [3- (4-fluorobenzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -oxamic acid ethyl ester (773 mg, 1.58 mmol) in 15 mL of ethanol at room temperature was treated with aqueous 1N sodium hydroxide solution (4.75 mL, 4.75 mmol). After 1 hour, the reaction was quenched by the addition of aqueous 1N hydrochloric acid (5.5 mL) and the product was 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-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid: NMR (DMSO-d _s) 2.06 (s, 6H), 6.88 (d, 1H, J = 9), 7.03 (dd, 1H, J = 93),

7.13 (d, 1H, J = 3), 7.43 (app t, 2H, J = 9), 7.61 (s, 2H), 7.94 (dd, 2H,

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.

v · •

• ti · ti ti

-43We tell you ··· ···· ··· • ti ti ti ti ti ti ti. Ti

Example

IR ESI-MS

r ₄ 27 Mar: (MeOH-d _4): 2.02 (s, 6H), 6.85 (d, 1H, 1209, / 1/1 ημ i 1 ‘ -χ ~ X L 1'1 _L J J = 7), 6.98 (dd, 1H, J = 7.2, 2.3), 7.26 1479, R ₄ = C _e H ₅ - (d, 1H, J = 2.3) 7.53 (s, 2H), 7.55-7.68 (m, 3H), 7.93 (d, 2H, J = 7). 1697 28 (MeOH-dJ: 2.12 (s, 6H), 6.84 (d, 1H, 1207, 474 [M-l] ’ J = 8.3), 6.96 (dd, 1H, J = 8.3, 3), 1479, R ₄ = p-C1C _S H ₄ - 7.24 (d, 1H, J = 3); 7.53 (d, 2H, J = 7.5); 7.58 (s, 2H); 7.90 (d, 2H, J = 7.5). 1697 29 (MeOH-d _4): 2.10 (s, 6H), 2.41 (s, 3H); 1149, 454 [M-1] 6.82 (d, 1H, J = 9), 6.95 (dd, 1H, J = 9), 1207, R ₄ = p-MeC _€ H ₄ 7.19 (d, 1H, J = 3) 7.45 (d, 2H, J = 8.3), 1481 4 76 7.53 (s, 2H); 7.77 (d, 2H, J = 8.3) [M + NH] ⁺ 30 (CDC1 _3): 1.98 (s, 6H), 3.80 (s, 3H); 1209, 470 [M-1] ' 6.80-6.82 (m, 2H); 6.89-6.93 (m, 3H); 1475, R ₄ = p-MeOC ₆ H ₄ - 7.31 (s, 2H); 7.73 (d, 2H, J = 7.2); 1588, 8.73 (br s, 1H), 8.89 (br s, 1H) 1705 31 (DMSO-dJ: 2.07 (s, 6H), 6.89 (d, 1H, 1207, 508 [M-l] ’ J = 9.3), 7.08 (dd, 1H, J = 93), 7.15 1476, R ₄ = p-CF ₃ OC _G H ₄ (d, 1H, J = 3), 7.60 (s, 2H), 7.98 (d, 2H, J = 3), 8.08 (d, 2H, J = 3) 1697 32 (MeOH-d _4): 2.12 (s, 6H), 3.23 (s, 3H); 1205, 378 [M-1] 6.96-7.0 (m, 2H); 7.11 (d, 1H, J = 2.2) 1481, R ₄ = Me- 7.51 (s, 2H). 1687, 1739 33 (DMSO-dJ: 0.81 (t, 3H, J = 7.2), 1.24- 1205, 420 [M-1] ' 1.36 (m, 2H), 1.41-1.51 (m, 2H), 2.04 1488, R ₄ = n-Bu- (s, 6H), 3.3 7 (d, 1H, J = 3), 7.0 8 (dd, 1694 43 9 1H, J = 9.3), 7.15 (d, 1H, J = 3), 7.00- 7.10 (t, 2H), 7.57 (s, 2H), 10.6 7 (s, 2H) [M + NH] ⁺

-44 ······ (DMSO-d ₆ ): 1.1 (d, 6H, J = 7), 2.03 (s, 1229, ₄₀ 6 [M 1] -1)

6H), 3.66-3.75 (m, 1H), 6.88 (d, 1H, J = 1354,

R ₄ = i-Pr 3), 7.02 (d, lH, J = 3), 7.08 (dd, 1H, J = 1480, ⁴²⁵

9, 3), 7.57 (S, 2H), 10.65 (s, 2H) 1688, [M + NH]

1761

Example 35

N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonamic acid

by _% , by xx? r ° r ixa OH The compound mentioned in heading is prepared according to the procedure

described 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 = 93), 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 (br s, 1H),

IR (KBr) 1142, 1239, 1485, 1623, 1654, 1736, ESI-MS 472 [M-1] &lt; + &gt;.

Example 36

N- {4- [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 = 93), 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] +.

-45Example 37

N- {4- [3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenylamino} propionic acid

NMR (MeOH-d ₄ ) 2.06 (s, 6H), 2.65 described in Example 26:

(t, 2H, J = 7)

3.49 (t, 2H, J = 7);

6.82 (d, 1H, J = 9), 6.85 (s, 2H), 6.94 (dd, 1H, J = 9, 3), 7.15 (d, 1H, J = 3), 7 23 (app t, 2H, J = 9), 7.88-7.93 (m, 2H), IR (KBr) 1199, 1493, 1623, 1675, ESI-MS 458 [M] +.

Example 38

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

The title compound was prepared according to the procedure described in Example 26: NMR (DMSO-d _s) 2.18 (s, 3H), 6.90 (d, lH, 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] &lt; - &gt;.

Example 39

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

1 * · ··· < ·· • * ·· 1 · ** • · «· * · • • « «* • ♦ «· • • · ♦ • · ·  * · «« * • r ·> • * · • * • * · 4 · k I • ·

The title compound was prepared according to the procedure for 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), 7.927.97 (m, 2H), 8.27 (s, 2H), 10.74 (s, 1H) IR, 11.15 (s, 1H), IR (KBr)

1290, 1454, 1484, 1589, 1695, ESI-MS 588 [M-1] &lt; - &gt;.

Example 40

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

The title compound was prepared according to the procedure described in Example 26: NMR (DMSO-d _e) 2.06 (s, 6H), 6.88 (d, lH, 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), 7.92-7.96 (m, 2H), 8.0 (br s, 1H) 10.49 (S, 1H), 10 58 (S, 1H), IR (KBr) 1141, 1250, 1481, 1676 ESI-MS

497 [M] + 516 [M + NH] ⁺ .

Example 41

N- [4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl] -N- ^1- propyl oxalamide

-4Ί-

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

Example 42

N- (4- [3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} -N ¹ -isopropyl-oxalamide

The title compound was prepared analogously to Example 26: ES-MS 499 [M-1], 518 [M + NH] +

Example 43

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

O

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

Example 44

N- {4- [3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} -N '- (2-methoxyethyl) oxalamide

The title compound was prepared analogously to Example 26: ES-MS 517 [M + 11].

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 + NH4]

Example 46

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

A. 5- (2,5-Dimethyl-4-nitro-phenoxy) -2- (2-methoxy-ethoxy-methoxy) -benzoic acid 2-methoxy-ethoxymethyl-ester

A suspension of NaH (60¾ 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 is poured into water and the reaction product is taken up in diethyl ether. Organic

-49 · • · '' ':::::::::::::

.: ..... * .......

The 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) afforded 5- (2,5-dimethyl-4-nitrophenoxy) -2 (2-methoxyethoxymethoxy) benzoic acid 2-methoxyethoxymethyl ester: NMR (CDCl ₃ 2) 23 (s, 6H), 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, O 2 (s, 2H).

B. 5- (4-Amino-2,6-dimethyl-phenoxy) -2- (2-methoxy-ethoxy-methoxy) -benzoic acid 2-methoxy-ethoxymethyl-ethyl ester

5- (2,5-Dimethyl-4-nitrophenoxy) -2- (2-methoxyethoxy-

methoxy) -benzoic acids, (3.2 g, 6.68 mmol ) and palladium on activated carbon (10% by weight, 32 mg) in 50 ml ethyl acetate se stirred under an atmosphere of hydrogen during 3 hours. Catalyst se

filtered through a pad of celite in vacuo, washed with ethyl acetate, and the combined filtrate and washings were concentrated in vacuo. 5- (4-Amino-2,6-dimethylphenoxy) -2- (2-methoxyethoxymethoxy) benzoic acid 2-methoxyethoxymethyl ester: NMR (CDCl 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), 6.80 (dd, 1H, J = 8.3, 3), 7.13 (d, 1H, J = 8.3), 7.24 (d, 1H, J = 3)

C. 5- [4- (Ethoxyoxalylamino) -2,6-dimethylphenoxy] -2-hydroxybenzoic acid

A solution of the title compound of paragraph B,

5- (4-Amino-2,6-dimethyl-phenoxy) -2- (2-methoxy-ethoxymethoxy) -benzoic acid 2-methoxy-ethoxymethyl-ester (2.83 g, 6.3 mmol) in 20 mL of tetrahydrofuran was cooled to 0 ° C and then treated sequentially with N-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

-50 thicken. 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 ethanol was evaporated under reduced pressure. The residue was diluted with water (100ml) and the solid was collected by vacuum filtration, washed with water and dried. Crystallization from acetonitrile gave 5- [4- (ethoxyoxalylamino) -2,6-dimethylphenoxy] -2-hydroxybenzoic acid: NMR (DMSO-d6, 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-

-dimethylphenyloxamic acid

The title compound of paragraph C, 5- [4- (ethoxyoxalylamino) -2,6-dimethyl-phenoxy] -2-hydroxybenzoic acid, in 1 ml of dimethylformamide, is treated 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 hour, then cooled to room temperature and piperidine (24 μΐ, 0.24 mmol) was added. After 16 hours, aqueous 1.5 N lithium hydroxide solution (333 μΐ, 0.5 mmol) was added to the reaction mixture. The reaction mixture is stirred for 30 minutes and then quenched with trifluoroacetic acid (100 μΐ). The product was purified by high pressure liquid chromatography (acetonitrile-water with 0.1% trifluoroacetic acid). N- {4- [4-hydroxy-3- (piperidine-1-carbonyl) phenoxy] -3,5-dimethylphenyl] oxamic acid was obtained: NMR (DMSO-d 6, 1.34-1.63 (m, 6H), 2) 06 (s, 6H), 3.30 (br s, 4H), 6.36 (d, 1H, J = 2.3), 6.67 (dd, 1H, 8.3,

2.3), 6.80 (d, 1H, J = 8.3), 7.53 (s, 2H), 9.38 (br s, 1H), 10.6 (S, 1H), ESI- MS: 413 [M + l] ^+.

Example 47

N- {4- [4-Hydroxy-3- (morpholine-1-carbonyl) phenoxy] -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

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

The title compound was prepared according to the procedure for EXAMPLE 46: ESI-MS 403 [M + 1] ⁺ .

Example 50

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

-52 «· · ♦ · ·

Example 46: ESI-MS 458 [M + 1] ^<+> .

Example 51

N- {4- [4-Hydroxy-3- (2-pyridinin-3-ylcarbamoyl) phenoxy] -3,5-dimethylphenyl} oxamic acid

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

Example 52

Formulation Preparation Example: Hard gelatin capsules containing 100 mg of active ingredient, for example N- (4- [3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid, can 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 sulfate 2,0 G magnesium stearate 8.0 G K lyophilized active substance sodium lauryl sulphate is added

sieved through sieves with mesh size 0,2 mm. Both folders are

t * · · blends perfectly. Lactose is then added first using a 0.6 mm sieve and then microcrystalline cellulose using a 0.9 mm sieve. The ingredients are then mixed thoroughly for another 10 minutes. Finally, magnesium stearate is added using a 0.8 mm sieve. After stirring for 3 minutes, 390 mg of the mixture is filled into each 0 size hard gelatin capsule.

Claims (6)

Compounds of the general formula I in which W is oxygen, sulfur, S (O) or a group S (0) ₂ , X is -SR ₄ , -S (O) R ₄ , -S (O) ₂ R ₄ , -S (O) ₂ NR ₅ R ₆ , or X is -C (O) NR ₅ R ₆ , wherein the -C (O) NR ₅ R ₆ is located at the 3'-, 4'-, or 5'- positions, Y is an oxygen atom or there are two hydrogen atoms, Z is hydrogen, halogen, hydroxyl, optionally substituted alkoxy, arylalkoxy, aoyloxy or alkoxycarbonyloxy, R is hydrogen, halogen, trifluoromethyl, lower alkyl or cycloalkyl, R _x is hydroxyl, optionally substituted alkoxy, aryloxy, heteroaryloxy, arylalkoxy, cycloalkoxy, heteroarylalkoxy or -NR ₅ R ₆ , R ₂ is hydrogen, halogen or alkyl, R ₃ is a halogen atom or an alkyl group, R ₄ is an optionally substituted alkyl, aryl, arylalkyl, heteroarylalkyl or heteroaryl group, R ₅ , R ₆ and R ₇ are independently of one another and are hydrogen, optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or _R and R together form _€ alkylene group optionally interrupted by oxygen, sulfur, S (0) S (0) ₂ or NR _7, which together with the nitrogen atom to which they are attached form a 5- to 7-membered a ring, n is 0 or an integer from 1 to 4, or a pharmaceutically acceptable salt thereof. 2. Compounds nndl e L ' claim 1 of the general formula I, in which Z has another meaning than hydrogen atom, if X is a group -C (O) NR ₅ R _6th 3. Compounds according to claims 1 or 2 gener of formula I, ve which W is an oxygen atom or a sulfur atom, X is -S (O) ₂ R ₄ 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) ₂ NR ₅ R ₆ or -C (O) NR ₅ R ₆ wherein R ₅ is in each case hydrogen or lower alkyl and _R phenomenon each case hydrogen, lower alkyl, a lower alkyl group substituted with NR ₅ R _G , a 3- to 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 a lower alkyl-2-pyridone group, or R ₅ and R _s together form in each case an alkylene or alkylene interrupted by O or S (0) ₂ which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring, -56Y is an oxygen atom or two hydrogen atoms, Z is a hydrogen atom or a hydroxyl group, R is hydrogen, R 1 is hydroxyl, lower alkoxy or NR ₅ R ₆ in which R ₅ is hydrogen or lower alkyl and R ₆ is hydrogen, lower alkyl, lower alkoxy or R ₅ and R ₆ together form an alkylene group or an oxygen interrupted alkylene group 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 zero, 1 or 2, or a pharmaceutically acceptable salt thereof. Compounds according to claims 1 or 2 of the general formula IA, R2 (IA) wherein W is an oxygen atom or a sulfur atom, X is -SR _4, -S (O) _R4, -S (O) ₂ R _4, -S (O) ₂ NR _S R _S or -C (O) NR ₅ 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, Rt. 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, -5ΊR ₄ is an optionally substituted alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, R 5, R _e and R, are independently 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) ₇ or NR ₇ , which together with the nitrogen atom to which they are attached form 5- to 7 a membered ring, n is zero, 1 or 2, or a pharmaceutically acceptable salt thereof. in which R2 X is -C (O) NR ₅ R ₆ group, or a t Z is or a lower hydroxyl alkoxy hydroxyl r ₂ group, a lower alkanoyloxy group, a group, a group or a lower alkoxy group, an alkyl group, r ₄ is and R ₃ is lower is an aryl group R ₆ and R ₇ are independently of each other hydrogen atoms, optionally substituted alkyl groups, groups, arylalkyl groups, heteroarylalkyl groups, or R _s and R ₆ taken together is interrupted by oxygen, cycloalkyl, aryl, heteroaryl group or an alkylene group optionally a sulfur atom, a group S (0) S (O) ₂ or NR ₇ , which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring, or a pharmaceutically acceptable salt thereof. Compounds according to claim 6, of the general formula IC, in which X is -S (O) ₂ R ₄ or -S (O) ₂ NR ₅ R ₅ , R ₄ is a monocyclic aryl group, R _s, R ₆ and R ₇ are independently hydrogen, optionally substituted alkyl or aryl group, or R ₅ and R ₆ together form a CH ₂ CH ₂ -Q-CH ₂ CH _2, wherein Q is CH ₂ , an oxygen atom, _NR7, a sulfur atom, a group s (0) or s (0) ₂ which together with the nitrogen atom to which they are attached form a six membered ring, or pharmaceutically usable salts, or pharmaceutically acceptable prodrug ester. 7. Compounds according to claim 6 of formula Ic, wherein Z is S (O) ₂ R _4, and R ₄ is phenyl optionally substituted with lower seekers, halogen, lower alkoxy or trifluoromethyl group or pharmaceutically usable salts, or their pharmaceutically useful ester prodrugs. The compounds of claim 1 which are N- {4- [3- (2,2-Dimethylpropylsulfamoyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid, N- [4- (4-Hydroxy-3-phenylsulfamoylphenoxy) -3,5-dimethylphenyl] oxamic acid, 59N- {4- [3- (4-Fluorophenylsulfamoyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid, N- {4- [3- (2-Fluorophenylsulfamoyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid, N- (4- [3- (3-Fluorophenylsulfamoyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid, N- {4- [4-Hydroxy-3- (4-methoxy-phenylsulfamoyl) -phenoxy] -3,5-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-Hydroxy-3-isopropylsulfamoyl-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid, N- [4- (3-Butylsulfamoyl-4-hydroxyphenoxy) -3,5-dimethylphenyl] oxamic acid, N- [4- (4-Hydroxy-3-isobutylsulfamoylphenoxy) -3,5-dimethylphenyl] oxamic acid, N- [4- (3-t-Butylsulfamoyl-4-hydroxyphenoxy) -3,5-dimethylphenyl] oxamic acid, N- [4- (3-Cyclohexylsulfamoyl-4-hydroxyphenoxy) -3,5-dimethylphenyl] oxamic acid, N- [4- (3-Dimethylsulfamoyl-4-hydroxyphenoxy) -3,5-dimethylphenyl] oxamic acid, N- {4- [4-Hydroxy-3- (pyrrolidine-1-sulfonyl) -phenoxy] -3,5-dimethyl-phenyl} -oxamic acid, N- {4- [4-Hydroxy-3- (piperidine-1-sulfonyl) -phenoxy] -3,5-dimethyl-phenyl} -oxamic acid, N- {4- [4-Hydroxy-3- (2-methoxy-ethylsulfamoyl) -phenoxy] -3,5-dimethyl-phenyl) -oxamic acid, N- {4- [4-Hydroxy-3- (morpholine-4-sulfonyl) phenoxy] -3,5-dimethylphenyl} oxamic acid, 9 9 9 9 « 9 9 • 9 99 -60N- {4- [3- (Dioxothiomorpholine-4-sulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid, N- {4- [4-Hydroxy-3- (pyridin-3-ylsulfamoyl) -phenoxy] -3,5-dimethyl-phenyl} -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-methylphenyl} oxamic acid, N- {4- [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-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid, N- {4- [4-Hydroxy-3- (toluene-4-sulfonyl) -phenoxy] -3,5-dimethyl-phenyl} -oxamic acid, N- {4- [4-Hydroxy-3- (4-methoxybenzenesulfonyl) phenoxy] -3,5-dimethylphenyl} oxamic acid, N- {4- [4-Hydroxy-3- (4-trifluoromethyl-benzenesulfonyl) -phenoxy] -3,5-dimethyl-phenyl} -oxamic acid, N- [4- (4-Hydroxy-3-methanesulfonyl-phenoxy) -3,5-dimethyl-phenyl] -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, -61N- {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-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -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} -4'-propyloxalamide, N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} -1'-isopropyloxalamide, N-Butyl-N '- {4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -oxalamide, N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} -1 '- (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} oxamic acid, N- (4- [4-Hydroxy-3- (morpholine-4-carbonyl) phenoxy] -3,5-dimethylphenyl} oxamic acid, AND. ^r N- [4- (3-Cyclohexylcarbamoyl-4-hydroxyphenoxy) -3,5-dimethylphenyl] oxamic acid, N- {4- [4-Hydroxy-3- (2-methoxyethylcarbamoyl) phenoxy] -3,5-dimethylphenyl} oxamic acid, N- {4- [4-Hydroxy-3- (2-morpholin-4-yl-ethylcarbamoyl) -phenoxy] -3,5-dimethyl-phenyl} -oxamic acid, and N- {4- [4-Hydroxy-3- (pyridin-3-ylcarbamoyl) phenoxy] -3,5-dimethylphenyl} oxamic acid, or a pharmaceutically acceptable salt thereof. • 9 • 9 9 · • 9 Use of the compounds according to any one of claims 1 to 8 for the preparation of medicaments for the prevention and treatment of diseases associated with thyroid hormone imbalance and for the prevention and treatment of occlusive cardiovascular conditions in which it is the cause of hyperlipidemia and hyperlipoproteinemia and for the prevention and treatment of hypo- and hyper- thyroidism, obesity, osteoporosis and depression, for lowering total plasma cholesterol and LDL-cholesterol levels and for preventing and treating 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.