JP2002540189A - Diaryl derivatives and their use as medicaments - Google Patents

Abstract

(57) [Summary] Compound of formula (I) Wherein, W is, O, S, S (O) or S _(O) is _2; X is, -SR4, -S (O) R4 , -S (O) 2 R4 or -S (O) ₂ NR5R6, or X is -C (O) NR5R6, provided that -C (O) NR5R6 is located at the 3'-, 4'- or 5'-position; O or H ₂ ; Z is hydrogen, halogen, hydroxy, optionally substituted alkoxy, aralkoxy, acyloxy or alkoxycarbonyloxy; R is hydrogen, halogen, trifluoromethyl, lower alkyl or R1 is hydroxy, optionally substituted alkoxy, aryloxy, heteroaryloxy, aralkoxy, cycloalkoxy, heteroaralkoxy or- 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 Is independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R5 and R6 combine to optionally form O, S, S ( O), S (O) ₂ or an alkylene having NR7 inserted, forming a 5- to 7-membered ring with the nitrogen atom to which they are attached; n is 0 or an integer of 1 to 4 A pharmaceutically acceptable salt thereof; a pharmaceutical composition comprising the compound; related to thyroid hormone imbalance Patient, e.g., hypothyroidism and Koshin, obesity, methods of prevention and treatment of osteoporosis and depression; method of reducing as well as LDL cholesterol and Lp (a) levels in mammals using such compounds.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel compounds of the formula I

Embedded image Wherein, W is, O, S, S (O) or S _(O) is _2; X is, -SR4, -S (O) R4 , -S (O) 2 R4 or -S (O) ₂ NR
5R6 or X is -C (O) NR5R6, provided that-
C (O) NR5R6 is 3 '- located 4'- or 5'-position; Y is O or _{H 2;} Z is hydrogen, halogen, hydroxy, optionally may be substituted R is hydrogen, halogen, trifluoromethyl, lower alkyl or cycloalkyl; R1 is hydroxy, optionally substituted alkoxy, aryloxy, hetero. Aryloxy, aralkoxy, cycloalkoxy, heteroaralkoxy or -NR5R6; R2 is hydrogen, halogen or alkyl; R3 is halogen or alkyl; R4 is optionally substituted alkyl, aryl, aralkyl. ,
R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; R5 and R6 Are combined to form O, S, S (O
), S (O) ₂ or alkylene with NR7 inserted, forming a 5- to 7-membered ring with the nitrogen atom to which they are attached; n represents 0 or an integer from 1 to 4] And a pharmaceutically acceptable salt thereof.

The compounds of the present invention are thyroid hormone analogs that can be used to prevent and / or treat diseases related to thyroid hormone imbalance, such as hypothyroidism and hyperactivity, obesity, osteoporosis and depression. is there. The compounds of the present invention are, in particular, lipid-lowering substances that enhance the clearance of cholesterol from the circulation, in particular the clearance of cholesterol in the form of low density lipoprotein (LDL). They up-regulate, inter alia, LDL receptor function in mammalian liver. Thus, they are useful for reducing total cholesterol plasma levels in mammals, especially for reducing LDL-cholesterol levels. In addition, such compounds also reduce lipoprotein (a) [Lp (a)] levels, an elevated, independent cardiovascular risk factor in mammals. The compounds of the present invention are therefore useful for the prevention and / or treatment of obstructive cardiovascular conditions associated with hyperlipidemia and hyperlipoproteinosis in mammals, such as atherosclerosis and coronary heart disease. Can be

The present invention provides compounds of formula I, pharmaceutical compositions containing such compounds, and methods of using such compounds. The definitions of the various terms used to describe the compounds of the invention are listed below.
These definitions apply to the terms as used throughout the specification (unless otherwise limited in specific instances, individually or as part of a larger group).

The term “optionally substituted alkyl” refers to unsubstituted or substituted straight-chain or branched hydrocarbon groups having 1 to 20, preferably 1 to 7 carbon atoms. . Examples of unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like. Substituted alkyl groups may include one or more (eg, 2 or 3) of the following groups: halo, lower alkenyl,
Hydroxy, cycloalkyl, alkanoyl, alkoxy, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, dialkylaminocarbonyl, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfonamide Including alkyl groups substituted by nitro, cyano, carboxy, alkoxycarbonyl, aryl, aralkyl, aralkoxy, guanidino, heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl, etc. Are not limited to these. Preferred substituents for substituted alkyl, especially substituted alkyl of the variable R1, which is substituted alkoxy, are lower alkyl, cycloalkyl, lower alkenyl, benzyl, mono- or disubstituted lower alkyl, for example ω- (amino, mono- or di- Lower alkylamino, carboxy, lower alkoxycarbonyl) -lower alkyl, α- (lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl) -lower alkyl, for example pivaloyloxy-methyl.

[0005] The term "lower alkyl" refers to an alkyl group as defined above having 1 to 7, preferably 1 to 4 carbon atoms. The terms "halogen" or "halo" refer to fluorine, chlorine, bromine and iodine. The term "alkenyl" refers to any of the above alkyl groups having at least 2 carbon atoms and further comprising at least one carbon-carbon double bond. Groups having 2 to 4 carbon atoms are preferred.

The term “alkylene” is a straight-chain bridge of 1 to 6 carbon atoms connected by a single bond (eg, — (CH ₂ ) x —, where x is 1 to 6). And it can be substituted with one to three lower alkyl groups. The term "cycloalkyl" refers to a cyclic hydrocarbon group having 3 to 8 carbon atoms. The term "alkoxy" refers to alkyl-O-. The term "acyl" refers to alkanoyl, aroyl, heteroaroyl, arylalkanoyl or heteroarylalkanoyl. The term "alkanoyl" refers to alkyl-C (O)-. The term "alkanoyloxy" refers to alkyl-C (O) -O-. The term "alkylamino" and "dialkylamino", respectively (alkyl) NH- and _(alkyl) 2 N-a say. The term "alkanoylamino" refers to alkyl-C (O) -NH-. The term "alkylthio" refers to alkyl-S-. The term "alkylthiono" refers to alkyl-S (O)-. The term "alkylsulfonyl" refers to alkyl-S (O) _2- . The term "alkoxycarbonyl" refers to alkyl-OC (O)-. The term "alkoxycarbonyloxy" refers to alkyl-OC (O) O-. The term "alkyl" in the above definition refers to an optionally substituted alkyl group as defined above.

[0007] The term "aryl" refers to mono- or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, for example, phenyl, naphthyl, tetrahydronaphthyl, and biphenyl groups; Each optionally having 1 to 4 substituents,
For example, alkyl, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoyl-amino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, alkyl-thiono, alkyl-sulfonyl , Sulfonamide, heterocyclyl and the like.

The term “monocyclic aryl” refers to an optionally substituted phenyl as described for aryl. The term "aralkyl" refers to an aryl group, such as benzyl, directly attached to an alkyl group. The term "aralkoxy" refers to an aryl group attached to an alkoxy group. The term "arylsulfonyl" refers to aryl-S (O) _2- . The term "aroyl" refers to aryl-C (O)-.

The term “heterocyclyl” refers to an optionally substituted, fully saturated or unsaturated, aromatic or non-aromatic cyclic group, eg,
A 7- to 7-membered monocyclic, a 7- to 11-membered bicyclic, or a 10- to 15-membered tricyclic ring system comprising at least one heteroatom in a ring containing at least one carbon atom. Having. Each ring of the heterocyclic group containing a heteroatom may have one, two or three heteroatoms selected from nitrogen, oxygen and sulfur. Here, nitrogen and sulfur heteroatoms may also be oxidized if desired. Heterocyclic groups can be attached at a heteroatom or carbon atom.

Examples of monocyclic heterocyclic groups are pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolyl, isothiazolyl, isothiazolyl, isothiazolyl, isothiazolyl, thiazolyl, isothiazolyl, thiazolyl, isothiazolyl, thiazolyl, isothiazolyl, thiazolyl, isothiazolyl, thiazolylyl, thiazolylyl, isothiazolyl, isothiazolyl, thiazolyl, isothiazolyl, thiazolyl, isothiazolyl, thiazolyl, isothiazolyl, thiazolyl, isothiazolyl, thiazolyl, isothiazolyl Azolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl,
Piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, 2-pyridone, N-lower alkyl-pyridone, such as N- Lower alkyl-
2-pyridone, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, S-oxo-thiamorpholinyl,
S, S-dioxo-thiamorpholinyl, 1,3-dioxolan, tetrahydro-1,1-dioxothienyl and the like.

Examples of bicyclic heterocyclic groups are indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl , Benzopyranyl, cinnolinyl, quinoxanilyl, indazolyl, pyrrolopyridyl, flopyridinyl (eg
2,3-c] pyridinyl, furo [3,2-b] -pyridinyl] or furo [2,3-b] pyridinyl),
And dihydroisoindolyl, dihydroquinazolinyl (eg, 3,4-dihydro-4-oxo-quinazolinyl) 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. A substituted heterocyclic group is
(A) Alkyl; (b) hydroxy (or protected hydroxy); (c) halo; (d) oxo (ie, = (E) amino, alkylamino or dialkylamino; (f) alkoxy; (g) cycloalkyl; (h) carboxy; (i) heterocyclooxy; (j) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl (K) mercapto; (l) nitro; (m) cyano; (n) sulfonamide, sulfonamidoalkyl or sulfonamidodialkyl; (o) aryl; (p) alkylcarbonyloxy; (q) arylcarbonyloxy; (s) aryloxy; (t) alkylthio; (u) formyl (V) aralkyl; or (w) alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkylamino, aryl substituted with dialkylamino or halo. The term "heterocyclooxy" refers to a heterocyclic group attached through an oxygen bridge.

The term “heteroaryl” refers to aromatic heterocycles, such as mono- or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, Pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl and the like, optionally one or more substituents as described for substituted aryl, for example lower alkyl , Lower alkoxy or halo. The term "heteroaryloxy" refers to heteroaryl-O-. The term "heteroarylsulfonyl" refers to heteroaryl-S (O) _2- . The term "heteroaroyl" refers to heteroaryl-C (O)-. The term "heteroaralkyl" refers to a heteroaryl group linked through an alkyl group.

For example, any pharmaceutically acceptable prodrug ester derivative of a carboxylic acid (COR1 is carboxy) of the present invention, wherein the carboxylic acid is converted to its free carboxylic acid by solvolysis or under physiological conditions. Convertible prodrug ester derivatives are also included in the present invention.

Examples of such carboxylic esters include the esters defined by COR ₁ , preferably lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as , Ω- (amino, mono- or di-lower alkylamino, carboxy,
Lower alkoxycarbonyl) -lower alkyl ester, α- (lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)
-Lower alkyl esters, such as, for example, pivaloyloxy-methyl esters, which are commonly used in the art.

R is preferably hydrogen or lower alkyl; R1 is preferably hydroxy, lower alkoxy or aryloxy. R2 is preferably hydrogen, halogen or lower alkyl. R3 is preferably halogen or lower alkyl. R4 is preferably phenyl or phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl. R5 is preferably hydrogen. R6 is preferably phenyl or phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl.

Preferred W is O. Preferred X is, -S _(O) 2 R4 or _-S (O) 2 NR5R6. Preferred Y is O. Preferred Z is hydrogen or hydroxy. The integer "n" is preferably 0, 1 or 2.

The compounds of the present invention may have one or more asymmetric centers, depending on the nature of the substituent. The diastereoisomers, enantiomers and geometric isomers obtained fall within the scope of the present invention. Compounds of formula I as defined above wherein X is -C (O) NR5R6 and Z is different from hydrogen are preferred. Compounds of formula I [wherein, W is O or S; X is -S _(O) 2 R4 (where, R4 is a lower alkyl, phenyl,
Or phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl);
Alternatively, _-S (O) 2 NR5R6 or -C (O) NR5R6 (wherein, R5 is, in each case, hydrogen or lower alkyl, R6 is in each case hydrogen, lower alkyl, substituted by NR5R6 Phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, 3- to 7-membered cycloalkyl, phenyl, lower alkyl, lower alkoxy, halogen and trifluoromethyl; pyridyl or N-lower alkyl Alternatively, R5 and R6 are linked, in each case an alkylene or an alkylene having O or S (O) ₂ inserted, together with the nitrogen atom to which they are attached. form a 5- to to 7 membered ring); Y is O or _{H 2;} Z is hydrogen or hydroxy R is hydrogen; R1 is hydroxy, lower alkoxy or NR5R6, wherein R5
Is hydrogen or lower alkyl, R6 is hydrogen, lower alkyl, lower alkoxy, or R5 and R6 are bonded to alkylene or O-inserted alkylene, and they are bonded to each other. R2 is hydrogen, halogen or lower alkyl; R3 is halogen or lower alkyl; n is 0, 1 or 2 And pharmaceutically acceptable salts thereof are preferred.

Compound of Formula IA

Embedded image Wherein, W is O or S; X _{is, -SR4, -S (O) R4} , -S (O) 2 R4, -S (O) 2 NR5R
Is 6 or -C (O) NR5R6; Y is O or _{H 2;} Z is hydrogen, halogen, hydroxy, alkoxy, aralkoxy, is acyloxy or alkoxycarbonyloxy; R1 is hydroxy, lower alkoxy or R2 is hydrogen, halogen or lower alkyl; R3 is halogen or lower alkyl; R4 is optionally substituted alkyl, aryl, aralkyl,
R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R5 is heteroaryl or heteroaralkyl. And R6 combine to optionally form O,
S, S (O), S (O) ₂ or NR7 is an inserted alkylene which forms a 5- to 7-membered ring with the nitrogen atom to which it is attached; n is 0, 1 or 2 And pharmaceutically acceptable salts thereof are preferred. Compounds of Formula IB

Embedded image [In the formula, _{X, -S (O) 2 R4,} -S (O) 2 NR5R6 or -C (O) NR5R
Z is hydroxy, lower alkanoyloxy or lower alkoxy; R1 is hydroxy or lower alkoxy; R2 and R3 are lower alkyl; R4 is aryl; R5, R6 and R7 Is independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R5 and R6 are linked to optionally form O,
An alkylene optionally intervened by S, S (O), S (O) ₂ ,
Alternatively, NR7 forms a 5- to 7-membered ring with the nitrogen atom to which they are attached.] And pharmaceutically acceptable salts thereof are more preferred.

Compound of Formula IC

Embedded image [Wherein, X is a -S _(O) 2 R4 or _-S (O) 2 NR5R6; substituted R5, R6 and R7 are independently hydrogen, optionally; R4 is a monocyclic aryl Or R5 and R6 are linked to form CH ₂ C
_{(Where, Q} is, CH 2, O, NR7, S, S (O) or S _(O) a _{2) H 2 -Q-CH 2} CH 2 A, the nitrogen atom to which they are attached And a pharmaceutically acceptable prodrug ester thereof; and a pharmaceutically acceptable salt thereof.

A compound of formula IC wherein X is S (O) ₂ R 4 and R 4 is phenyl optionally substituted by lower alkyl, halo, lower alkoxy or trifluoromethyl; pharmaceutically acceptable Particularly preferred are salts thereof; and prodrug derivatives thereof.

A pharmaceutically acceptable salt of any of the acidic compounds of the present invention is a salt formed with a base,
That is, cationic salts, for example, alkali and alkaline earth metal salts, for example, sodium, lithium, potassium, calcium, magnesium, and ammonium salts, for example, ammonium, trimethylammonium, diethylammonium, and tris- (hydroxymethyl)- It is a methyl-ammonium salt.

Similar acid addition salts can be, for example, salts of mineral acids, organic carboxylic acids, and organic sulfonic acids, such as hydrochloric acid, methanesulfonic acid, maleic acid, provided that basic groups such as, for example, Pyridyl is also limited to a part of the structure.

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

Embedded image Wherein R 2 and R 3 have the meanings as defined herein and W is oxygen (prepared according to methods well known in the literature). Converting to the fluoromethylsulfonyl ester, treating the latter with lithium chloride in an inert solvent such as N-methylpyrrolidone, N, N-dimethylformamide or dimethylsulfoxide;
Compounds of formula III may be formed.

Embedded image For compounds of formula III

Embedded image By reacting an appropriately substituted phenol or thiophenol of formula V,

Embedded image Wherein R is as defined herein, X ′ and Z ′ are X and Z as defined herein, or X ′ and Z ′ are a base, such as hydroxyl A group capable of converting to X and Z in an inert solvent such as N-methylpyrrolidone, N, N-dimethylformamide or dimethylsulfoxide in the presence of sodium or potassium carbonate at ambient or elevated temperature, respectively. ] Can be converted to a compound of formula IV. Compounds of formula V can be obtained by the methods described herein or in the art.

Alternatively, the compound of formula IV is a bis-aryliodonium tetrafluoroborate of formula VI

Embedded image Wherein R, X and Z ′ have the previously defined meanings and have a phenol or thiophenol of formula II. Wherein W is oxygen or sulfur as described in the art.], For example, in the presence of a copper catalyst and a base such as triethylamine in an inert solvent such as dichloromethane. be able to.

Compounds of formula IV where Z ′ is alkoxy or aralkoxy can be converted to compounds of formula IV where Z ′ is hydroxy by methods well known in the art, for example, when Z ′ is especially a methoxy group, Hydrogen acid or boron trihalide, such as boron trichloride or boron tribromide, or when Z ′ is especially a benzyloxy group, is treated with hydrogen in the presence of a catalyst, such as palladium on carbon. Can be converted using:

Compounds of the present invention wherein X is S (O) ₂ NR5R6 may, for example, be prepared by first converting a compound of formula IV
Wherein R and X ′ are hydrogen, X ′ is located at 3 ′ position, Z ′ is hydrogen, alkoxy or aralkoxy and X ′ is located at 4 ′ position, an organic solvent, For example, treatment with chlorosulfonic acid in dichloromethane produces a compound of formula VII.

Embedded image Wherein Z ′ is as defined above. Compounds of formula VII wherein Z ′ is hydroxy are substituted with a protected hydroxyl group such as alkanoyloxy, alkoxycarbonyloxy or trialkylsyloxy. Certain compounds of formula VII may be converted using methods and conditions well known in the art.

Compounds of formula VII wherein Z ′ is alkoxy, aralkoxy, alkanoyloxy, alkoxycarbonyl-oxy or trialkylsyloxy are converted to compounds of formula VII
Compound of I

Embedded image Wherein Z ′ has the previously defined meaning. In a chlorinating agent such as oxalyl chloride or thionyl chloride, and in an inert solvent such as dichloromethane or tetrahydrofuran, a suitable amount of N′N′— It can be converted by reacting in the presence of dimethylformamide.

The compound of formula VIII can be converted to a primary or secondary amine of formula R5R6NH, where
R5 and R6 have the meanings defined herein] with an organic solvent such as dichloromethane in the presence of a base such as N-methylmorpholine or triethylamine to give a compound of formula IX.

Embedded image A compound of the formula IX, wherein Z ′ has the previously defined meaning,
Wherein Z ′ is hydroxy] can be converted using methods and conditions well known in the art or as set forth herein. Nitro-substituted compounds of formula IV, such as amines of compounds of formula IX, for example amines of formula X

Embedded image Conversion to can be achieved according to methods described in the art. In a polar solvent such as ethanol or tetrahydrofuran, for example with hydrogen, in the presence of a catalyst such as palladium on carbon.

The resulting amine, eg, of Formula X, is converted to an acylating agent, eg, ethyl oxalyl chloride, ethyl malonyl chloride, ethyl succinyl chloride, or ethyl bromoacetic acid, with a base, eg, N-methylmorpholine or triethylamine. In the presence,
Treatment in an organic solvent such as dichloromethane, tetrahydrofuran or N, N-dimethylformamide gives a compound of formula I, for example a compound of formula XI

Embedded image Wherein R 1 is alkoxy, Y is oxygen or H ₂ , Z ′ is Z as defined herein, or Z ′ is a group convertible to Z, and n is 0 to 4 Which is an integer of Compounds of formula I wherein R1 is alkoxy, for example, condensing a compound of formula X with an acylating agent, such as dimethyl or diethyl oxalate, at elevated temperature using an acylating agent as reagent and solvent Can be manufactured by

A compound of formula I wherein R 1 is, for example, alkoxy or aryloxy can be converted to an organic solvent, for example ethanol or using an aqueous base, for example an alkali metal carbonate (ester) or hydroxide. Hydrolysis to the compound of formula I wherein R1 is hydroxy can be carried out in tetrahydrofuran according to the usual methods.

Similarly, other compounds of formula IV wherein X ′ and Z ′ are X and Z as defined herein, or X ′ and Z ′ can be converted to X and Z, respectively. Is a compound of formula XII

Embedded image Is converted by the method described herein or a modification thereof. Further, if desired, the compound is converted to the corresponding compound of formula I by converting X ′ and Z ′ to X and Z, respectively. For example, a compound in which X ′ = COOH is
Is C (O) NR5R6 to the corresponding amide of formula I according to methods well known in the art. Similarly, a compound in which COR ₁ is COOH is a compound in which COR ₁ is CONOH.
It can be converted to a compound that is R ₅ R ₆ .

Starting compounds and intermediates, including functional groups such as amino, thiol, carboxyl, and hydroxy groups, which are converted to the compounds of the present invention in the manner described herein, can be prepared by the usual methods common in synthetic organic chemistry. If desired. Protected amino, thiol, carboxyl and hydroxy groups can be converted to free amino, thiol, carboxyl and hydroxy groups under mild conditions without breaking the molecular framework or other undesirable side reactions It is.

The purpose of introducing a protecting group is to protect the functional group from unwanted reactions with reaction components under the conditions used to effect the desired chemical change. The need and choice of protecting groups for a particular reaction is known to those skilled in the art, and the nature of the functional groups to be protected (hydroxy, amino, etc.), the structure of the molecule in which the substituent is a part, and Depends on stability and reaction conditions.

Well-known protecting groups that are compatible with such conditions and with the introduction and removal of well-known protecting groups are described, for example, in JFW McOmie, “Protective Groups in Organic Chemistry”,
Plenum Press, London, New York, 1973, TW Greene, `` Protective Groups in
Organic Synthesis ", Wiley, New York, 1991.

In the methods cited herein, the reactive functional derivatives of carboxylic acids include, for example, anhydrides (especially mixed anhydrides), acid halides, acid azides, lower alkyl esters, and those activated. Represents an ester of The mixed anhydride is preferably pivalic acid in such form, or a hemiester of lower alkyl (ethyl, isobutyl) carbonic acid; the acid halide is, for example, chloride or bromide; the activated ester is For example, succinimide, phthalimide or 4-nitrophenyl ester; lower alkyl esters are, for example, methyl or ethyl esters.

The above reaction is carried out according to standard methods, preferably in the presence or absence of a diluent, a catalyst, a condensing agent or other substance which is preferably inert to the solvent and its solvent and / or an inert atmosphere. And at low temperature, room temperature or high temperature (preferably near the boiling point of the solvent used) at atmospheric pressure or high pressure. Preferred solvents, catalysts and reaction conditions are given in the accompanying illustrative examples.

The present invention further comprises any variation of the present method, wherein the intermediate product obtained in any of the steps is used as a starting material to perform the remaining steps, or Formed in situ under the reaction conditions, or the reaction components are used in the form of their salts or optically pure enantiomers.

The compounds of the invention and intermediates can be converted into each other according to methods generally known per se. The invention also relates to any novel starting materials and methods for the preparation.

Depending on the choice of starting materials and methods, the novel compounds may be in some form of the possible isomers or mixtures thereof, for example, substantially pure geometric (cis or trans)
It may be an isomer, an optical isomer (enantiomer), a racemate, or a mixture thereof. The possible isomers or mixtures thereof fall within the scope of the present invention.

Any resulting mixture of isomers may be converted into pure geometric or optical isomers, diastereoisomers, racemates, for example, by chromatography and chromatography, based on the physicochemical differences in their constituents. And / or separated by fractional crystallization.

Any resulting racemic end product or intermediate may be resolved into optical enantiomers by known methods, for example, resolution of its diastereoisomeric salt (optically active acid or base). ) To release optically active acidic or basic compounds. Thus, the carboxylic acid intermediate can be converted to, for example, d- or l.
-(Alpha-methylbenzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabietylamine, bricine or strychnine)-can be separated into its optical enantiomers by fractional crystallization. Racemic products can be resolved by chiral chromatography, for example, high performance liquid chromatography using a chiral adsorbent. Finally, the compounds of the invention are obtained in free form or as salts thereof, if salt-forming groups are present.

The acidic compounds of the present invention can be advantageously converted to the salts with a pharmaceutically acceptable base, such as the hydrochloride salt of an aqueous alkali metal, in the presence of an ethereal or alcoholic solvent, such as a lower alkanol. From the latter solution, the salt can be precipitated with an ether, such as diethyl ether. The resulting salt can be converted to the free compound by treatment with an acid. These or other salts can also be used for purification of the resulting compound.

Compounds of the present invention having a basic group can be converted into acid addition salts, especially pharmaceutically acceptable salts. These can be used, for example, with inorganic acids, for example mineral acids, for example sulfuric acid, phosphoric acid or hydrohalic acids, or organic carboxylic acids (for example, unsubstituted or substituted with halogen, for example (C _1- C ₄ ) -alkanecarboxylic acids), for example acetic acid, for example dicarboxylic acids which are saturated or unsaturated, for example oxalic acid, succinic acid, maleic acid or fumaric acid, for example hydroxycarboxylic acids, for example glycolic acid; Lactic, malic, tartaric or citric acid, for example,
Amino acids, for example, aspartic acid or glutamic acid, or organic sulfonic acids, for example, (C ₁ -C ₄ ) -alkylsulfonic acid (eg, methanesulfonic acid) or unsubstituted or substituted (eg, by halogen) arylsulfonic acids Formed.

In view of the close relationship between the free compounds and the compounds in the form of their salts, whatever the compounds mentioned herein are, if they are possible or appropriate in the context,
The corresponding salt is also contemplated. Compounds, including their salts, can be obtained in the form of their hydrates, or may include other solvents used for their crystallization.

The pharmaceutical compositions of the present invention may be used for the treatment of thyroid hormone imbalance disorders such as hypothyroidism and hyperactivity, obesity, osteoporosis, depression, and especially for obstructive cardiovascular conditions (hyperlipidemia). Suitable for the treatment and / or prevention of hypertension and hyperlipoproteinemia), for example, for enteral, e.g., oral or rectal, transdermal and parenteral administration to mammals, including humans. It is something. The pharmaceutical composition of the invention comprises an effective amount of a pharmacologically active compound of the invention, alone or with one or more pharmaceutically acceptable carriers.

The pharmacologically active compounds of the present invention are useful for the manufacture of pharmaceutical compositions which contain an effective amount thereof in combination or admixture with excipients or carriers suitable for enteral or parenteral application. It is. The active ingredient may be selected from a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) lubricants such as silica, talc, stearic acid, its magnesium or calcium salts and / or Or polyethylene glycol; for tablets, c) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; optionally, d) disintegrants, such as Tablets or gelatin capsules containing starch, agar, alginic acid or its sodium salt, or an effervescent mixture; and / or e) absorbents, dyes, flavors and sweeteners are preferred. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are conveniently formulated from fatty emulsions or suspensions. The compositions may be sterile and / or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, and / or buffers. In addition, they may contain other therapeutically valuable substances. The compositions are each formulated according to the usual mixing, granulating or coating methods. Such compositions may contain about 0.1-75%, preferably about 1-50%, of the active ingredient.

Formulations suitable for transdermal applications include an effective amount of a compound of the present invention together with a carrier. Advantageous carriers include absorbable pharmaceutically acceptable solvents to assist passage through the skin of the host. The transdermal device includes a backing, a reservoir containing the compound, optionally with a carrier, and, optionally, a rate-controlling barrier for delivering the compound of the host's skin at a controlled and predetermined rate over an extended period of time. And a bandage including a portion for fixing the device to the skin.

A unit dosage form for a mammal of about 50 to 70 kg may contain about 0.01 mg to 10 mg of the active ingredient. The form of administration of the active compound depends on the type, body weight, age and individual condition of the warm-blooded animal (mammal), the form of administration and the compound involved.

The problem solved by the present invention is to provide pharmacologically effective lipid-lowering substances that lower plasma cholesterol levels in mammals. The compounds of the present invention, LDL receptor activity up-regulation and LDL cholesterol triiodothyronine showing enhanced LDL cholesterol clearance from the circulation (T ₃₎ shows a strong binding to nuclear receptors. Accordingly, the compounds of the present invention are particularly useful in mammals as hypocholesterolemic substances for treating and preventing obstructive cardiovascular conditions associated with hypercholesterolemia by reducing total and LDL cholesterol plasma levels. is there. The present invention further provides a method for the preparation of a medicament, particularly a medicament useful for treating and preventing obstructive cardiovascular conditions associated with hypercholesterolemia by reducing plasma levels of total and LDL cholesterol. It also relates to the use of the compounds of the invention.

The compounds of the present invention also reduce lipoprotein (a) levels and therefore Lp (a
) Is useful in the treatment and prevention of obstructive cardiovascular conditions. Preferred are selective thyroid hormone analog lipid-lowering substances of the present invention that have substantially no undesirable cardiac side effects with thyroid hormone.

The properties cited above are demonstrated in in vitro and in vivo tests, conveniently using mammals such as mice, rats, dogs, monkeys or isolated organs, tissues and specimens thereof. The compounds may be applied in vitro in solution, eg, preferably in the form of an aqueous solution, in vivo enterally, parenterally, conveniently intravenously, eg, as a suspension or aqueous solution. In vitro doses may range from about ^10-7 molar to ^10-11 molar. In vivo dosage forms range from about 0.1 to 1000 micrograms / kg, preferably from about 0.5 to 300 micrograms / kg, and conveniently from about 1 to 100 micrograms / kg, depending on the route of administration. May be.

The compounds of the present invention bind to the triiodothyronine (T ₃ ) receptor and are therefore useful as mammalian thyroid hormone agonists. The binding of in vitro T ₃ nuclear receptor, to demonstrate in the following manner. Rat liver nuclear and plasma membrane preparations were prepared using Sprague-Dawley (CD) rats (Charles R
iver Labs) by fractional centrifugation with minor modifications to those described in Emmelot at al (Methods in Enzymology 31:75, Part A, 1974). The nuclear fraction obtained from the 275 × g pellet was analyzed by Spndler et al (J. Biol. Chem. 250: 4118, 197
Further purification as outlined by 5).

The new test compounds are assayed for binding to the nucleus by the method of Spindler et al (J. Biol. Chem. 250: 4118, 1975). The nuclei were incubated at 22 ° C with 0.3 nM [ ¹²⁵ I]-
L- triiodothyronine _{(L-T 3)} and incubated. Parallel incubation in addition to the nuclei and radioactive L-T _3, the test compound at various concentrations or 3
carried out in a tube containing either a non-radioactive L-T ₃ of [mu] M. The latter is used as a criterion for non-specific binding. Binding of the radioactive to the nucleus caused the reaction mixture to
After centrifugation at 0 × g for 7 minutes, the obtained pellet is washed and measured. The amount of the amount of the specifically bound _{^{[125 I] -L-T 3}} , and non-specific binding (excess (3 [mu] M) non-radioactive L-T ₃ and incubated with nuclei of radioactivity contained in the pellets after) Is determined by subtracting The concentration of 50% of the ^[125 I] test compound to inhibit the specific binding of _{-L-T 3 (IC 50)} , bound specifically to the test compound at various concentrations ^[125 I] _{-L-T 3} Is determined on the graph from the reciprocal plot of.

Cholesterol-reducing activity is quantified in rats as follows. Male Sprague-Dawley rats (230-250 g) (Taconic Farms) were freed for two weeks on a water and high cholesterol diet (1.5% cholesterol and 0.5% cholic acid) before and during the 7-day treatment period. To maintain. Groups of animals are treated orally for 7 consecutive days by gavage with vehicle alone or test compound. After the last dose, the animals are fasted for 18 hours and blood is collected. Blood samples were centrifuged at 2500 rpm for 10 minutes, total cholesterol and LD
Plasma is prepared for L and HDL cholesterol concentration determination. HDL value is L
Quantification after DL / VLDL sedimentation (Warnick and Albers, 1978). Diagnostic reagent kit for cholesterol (Sigma Chemical Co., St. Louis)
, MO). The analysis is performed on a Bio-Mek automated workstation. The LDL / VLDL fraction is sedimented by the following method: 0.3
5 mL of plasma is aliquoted into Eppendorf tubes, into which 12 μL of 2M manganese chloride, 11.2 μL of sodium heparin (Porcine Intestinal, 5000 units / mL),
And 8.3 μL of normal saline are added. The sample is vortexed vigorously and placed on ice for 15 minutes, then centrifuged at 1300 rpm for 10 minutes at 4 ° C. and the supernatant is analyzed enzymatically for cholesterol. The HDL cholesterol concentration is adjusted by taking the dilution into account and multiplying the supernatant cholesterol value by 1.09. L
DL / VLDL cholesterol levels are obtained by subtracting HDL cholesterol from total cholesterol.

Cholesterol-lowering activity can be evaluated in dogs with normal blood fed cholesterol levels by administering the test compound orally for 5 days according to the method described above. Cholesterol and Lp (a) reducing activity can be assessed in normolipidemic cynomolgus monkeys as follows:

Adult male and female cynomolgus monkeys (Macaca fascicularis) weighing 3-7 kg
). Animals are housed individually and a standard chow diet (P
urina 5047) supplemented with fresh fruits and vegetables. Each animal will be unrestrained and will move to their respective dosing regime after the washout period. Test compounds are dissolved in ethanol, absorbed into fruit pulp and administered orally. Animals are 8
The test compound is taken once a day for a treatment period ranging from day to day 28. Blood samples are taken as a baseline after an overnight fast and at the end of the study. A blood sample (3 ml) is collected from the femoral vein of a mechanically restrained sedative-free animal into a Vanutainer tube (containing EDTA). Blood is centrifuged at 2000 rpm for 20 minutes at 4 ° C. Aliquot plasma samples and store at -70 ° C until analysis. Plasma concentrations of total cholesterol (TC) and triglycerides (TG) were determined using a commercial kit (S
Quantification by enzymatic method using igma Diagnostics). High density lipoprotein cholesterol (HDL-C) concentration is measured after sedimentation of apo B-containing lipoprotein. The plasma of cynomolgus monkeys fasted by the chow diet has a negligible amount of cholesterol in the very low density lipoprotein, so the low density lipoprotein cholesterol (LDL-C) concentration is calculated by subtracting HDL-C from TC.

Assays are performed on 96-well microtiter plates and read on a microplate spectrophotometer (Dynatech MR 5000). The plasma concentration of Lp (a) is quantified by a commercial Lp (a) ELISA (Perlmmune, Inc.) using control and reference Lp (a) standards. The Lp (a) ELISA uses a monoclonal antibody against apolipoprotein (a) for capture and a polyclonal antibody against apolipoprotein B for detection. The test is Lp (a)
And does not measure free apo (a), apoB or plasminogen. Quantification of Lp (a) is not affected by apo (a) size. Lp (a) plasma concentrations are reported as milligrams of total Lp (a) weight. Samples from each test
Test once by experiment.

[0059] In T ₃ nuclear receptor binding assay, the compound of Example 26 of the present invention is about 0.17
indicates nM of _{IC 50,} the compound of Example 28 showed an _{IC 50} of approximately 0.13 nM, the compound of Example 35 showed an _{IC 50} of approximately 1.00 nm, the compound of Example 39 of about 0.04nM Shows the IC ₅₀ . In addition, the compound of Example 26 had a concentration of about 20 micrograms (μg) / kg po in rats and about 10 μg / kg po in dogs.
Daily administration significantly reduces serum cholesterol. In addition, Lp (a) levels in normolipidemic cynomolgus monkeys were measured at 75 μg / kg daily with the compound of Example 26
Approximately 40% reduction after 4 weeks of treatment with an oral dose of.

The following examples are intended to illustrate the invention and should not be construed as limiting. The temperature is in degrees Celsius. Unless otherwise stated, all evaporations are under reduced pressure, preferably between about 15 and 100 mmHg (= 20-133 mba).
r). The structures of the final products, intermediates, and starting materials are standard analytical methods,
For example, confirmation by microanalysis and spectroscopic properties (eg, MS, IR, NMR). The abbreviations used are conventional in the art.

Example 1 N- {4- [3- (2,2-dimethylpropylsulfamoyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid

Embedded image A. 3,5-Dimethyl-4- (4'-methoxyphenoxy) nitrobenzene A suspension of sodium hydroxide in 350 mL of N-methylpyrrolidone (NMP) (NaH; 60% dispersion in mineral oil; 64.11 g, 1 .603 mol) at 0 ^° C.
And treated with a solution of 4-methoxyphenol (208.4 g, 1.679 mol) for 30 minutes. After 30 minutes the mixture was warmed to room temperature (RT) and 4-chloro-3,5-dimethylnitrobenzene (283.2 g, 1.526 mol; Yo)
(prepared by the method described in EP580550 by Koyama et. al.) and add the reaction at 120 ^° C. for 2 hours. The reaction was cooled to room temperature and water (
(1500 mL). The suspension was cooled to 0 ^° C., stirred for 30 minutes and filtered, washing the filtered solid with water and drying under reduced pressure. Crude product, ethyl acetate (Et
OAc; 2100 mL) and charcoal (42.6 g) are heated to reflux and the solids are removed by filtration through celite while hot. The filtrate is concentrated under reduced pressure to about 800 mL,
The suspension obtained is cooled to 0 ^° C. and stirred for 30 minutes. The product was collected by vacuum filtration, washed with cold EtOAc, dried under reduced pressure and 3,5-dimethyl-4- (4 ′
- methoxyphenoxy) as _{nitrobenzene: NMR (CDCl 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 compounds of the title A, 3,5-dimethyl-4- (4′-methoxyphenoxy) nitrobenzene (16.4 g, 60 mmol), acetic acid (AcOH ; 100m
L) and a 48% aqueous solution of hydrobromic acid (HBr; 100 mL) at 120 ^° C. for 16 hours.
Heat for hours. The mixture was cooled to room temperature, diluted with water (200 mL) and the precipitated product was collected by vacuum filtration, washed with water and hexane, dried under reduced pressure,
Obtain dimethyl-4- (4′-hydroxyphenoxy) nitrobenzene: NMR (CD
Cl ₃ ) 2.22 (s, 6H), 6.62 (d, 2H, J = 8.7), 6.77 (d, 2H, J = 8.7), 8.0 (s, 2H)
.

C. 5- (2,6-dimethyl-4-nitrophenoxy) -2-hydroxybenze
Sulfonic acid A solution of the compound of title B, ie, 150 mL of dichloromethane (CH₂Cl ₂ 3,5-Dimethyl-4- (4'-hydroxyphenoxy) nitrobenze in
(7.86 g, 30.35 mmol) was added to chlorosulfonic acid (2.4 mL,
36.42 mmol) at room temperature. After 16 hours, the reaction mixture was concentrated,
Leave a small amount of CH₂Cl₂(About 5 mL). Bring the product to brine (100 mL)
And precipitated by filtration, collected by vacuum filtration, water, hexane and diethyl ether.
-Tel (Et₂O), dried under reduced pressure and 5- (2,6-dimethyl-4-
Obtain nitrophenoxy) -2-hydroxy-benzenesulfonic acid: NMR (DMSO-d ₆ ) 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 solution of the compound of the title C, ie 100 mL of tetrahydrofuran (THF)
And 5- (2,6-) in 50 mL of N, N-dimethylformamide (DMF)
Dimethyl-4-nitrophenoxy) -2-hydroxy-benzenesulfonic acid (6
. 78 g, 20 mmol) and cesium carbonate (15.6 g, 48 mmol) and
And benzyl bromide (7.1 mL, 60 mmol) at room temperature, and ^o Heat at C for 48 hours. The reaction mixture was cooled to RT and 1N aqueous hydrochloric acid (HCl
; 100 mL) and the THF is evaporated. The precipitated product is removed by vacuum filtration.
And collect, water, Et₂O, EtOAc and CH₂Cl₂Wash, dry, 2
-Benzyloxy-5- (2,6-dimethyl-4-nitrophenoxy) benzene
Sulfonic acid and cesium salt are obtained: 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) salt
Suspension of the compound of the title D, ie 200 mL CH₂Cl₂2-benzy in
Luoxy-5- (2,6-dimethyl-4-nitrophenoxy) -benzenesulfo
Acid, cesium salt (9.9 g, 20 mmol) was added to DMF (3.1 mL, 40 m
mol) and oxalyl chloride (3.5 mL, 40 mmol) in 30 mL.
Add at room temperature over minutes. The reaction mixture was further stirred for 1 hour and Et 2 ₂ Diluted with O (200 mL), washed with water and brine, and dried over anhydrous sodium sulfate (N
a₂SO₄) And concentrate. Et the product₂Wash with O (5 mL) and
And dried with 2-benzyloxy-5- (2,6-dimethyl-4-nitro-pheno).
Xy) to obtain benzenesulfonyl chloride: NMR (CDCl_Three) 2.24 (s, 6H), 5.31 (s, 2H)
, 7.02 (dd, 1H, J = 8.7, 3.8), 7.10 (d, 1H, J = 8.7), 7.32-7.47 (m, 4H), 7.
52 (d, 2H, J = 7.5), 8.05 (s, 2H).

F. 2-benzyloxy-5- (2,6-dimethyl-4-nitrophenoxy)-
N-(2,2-dimethylpropyl) solution of the compound of benzenesulfonamide The title E, i.e. 20mL in _CH 2 Cl ₂ in 2-benzyloxy-5- (2,6-dimethyl-4-nitrophenoxy) - chloride Benzenesulfonyl (1.12 g, 2.5 mmol) was added sequentially to N-methylmorpholine (
NMM; 550 mL, 5 mmol) and neopentylamine (442 mL, 3
. 75 mmol) at room temperature. After 6 hours, the mixture was partitioned between water and EtOAc, the organic solution was washed with 1N aqueous HCl and brine, dried over anhydrous Na ₂ SO ₄ , concentrated and concentrated to 2-benzyloxy-5- (2,6-dimethyl- 4-nitrophenoxy)-N-(2,2-dimethylpropyl) benzenesulfonic - give the _{amide: NMR (CDCl 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-dimethylphenoxy) -2-benzyloxy-
N- (2,2-dimethylpropyl) benzenesulfonamide A mixture of compounds of the title F, ie 2-benzyloxy in 40 mL of THF.
C-5- (2,6-dimethyl-4-nitrophenoxy) -N- (2,2-dimethyl
Propyl) benzenesulfonamide (1.22 g, 2.45 mmol) and
Activated carbon (10 wt.%; 250 mg) on a hydrogen atmosphere (H₂, 1a
tm) for 8 hours. The catalyst was removed by vacuum filtration through Celite,
Wash with THF and concentrate the combined filtrates and washes. CH left₂Cl₂During ~
And the product is collected by vacuum filtration, CH₂Cl₂Wash, dry, 5
-(4-amino-2,6-dimethyl-phenoxy) -2-benzyloxy-N-
Obtain (2,2-dimethylpropyl) benzene-sulfonamide: NMR (DMSO-d ₆ ) 0.80 (s, 9H), 1.90 (s, 6H), 2.55 (d, 2H, J = 7.5), 4.90 (br s, 2H), 6.31 (s
, 2H), 6.87 (br s, 1H), 6.93 (br s, 2H), 6.97 (t, 1H, J = 7.5), 10.13 (s, 1H
).

H. N- {4- [3- (2,2-Dimethylpropylsulfamoyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} -oxamic acid A solution of the compound of the title G, ie, in 10 mL of THF. 5- (4-amino-
2,6-Dimethylphenoxy) -2-benzyloxy-N- (2,2-dimethylpropyl) benzenesulfonamide (750 mg, 1.98 mmol) was cooled to 0 ^° C. and NMM (545 mL, 4.96 mmol) and Treat sequentially with ethyl oxalyl chloride (442 mL, 3.96 mmol). The reaction is warmed to RT and after 1 hour quenched with water. The mixture is partitioned between water and EtOAc, the organic solution is washed with aqueous 1N HCl and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue is dissolved in 10 mL of THF and treated with a 1N aqueous solution of lithium hydroxide (LiOH; 1.8 mL, 1.8 mmol) at room temperature. One hour later,
The reaction is quenched with 1N aqueous HCl and the product is transferred to an EtOAc layer, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The product and hexane, then triturated with Et ₂ O, and dried under vacuum, N- {4- [3- (2,2- dimethylpropyl - sulfamoyl) -4-hydroxyphenoxy] -3,5-dimethyl Obtain phenylperoxamidic acid: NMR (CDCl ₃ ) 0.89 (s, 9H), 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] ^- .

The following compounds are prepared similarly.

[Table 1]

[0070]

[Table 2]

[0071]

[Table 3]

Example 23 N- {4- [3- (4-Fluorophenylsulfamoyl) -4-hydroxyphenylsulfamoyl] -3,5-dimethylphenyl} oxamic acid

Embedded image The title compound isExamplePrepared as in 1: NMR (DMSO-d₆) 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; ESI-MS 489 [M-1]^-, 508 [M + NH_Four] ⁺ .

Example 24 N- {4- [3- (4-Fluorophenylsulfamoyl) phenoxy] -3,
5-dimethylphenyl dioxamidic acid

Embedded image The title compound is as in Example 1: NMR (DMSO-d ₆ ) 1.91 (s, 6H), 6.73-6.74 (m
, 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)
, 10.75 (s, 1H); IR (KBr) 1161, 1223, 1509, 1697; ESI-MS 457 [M-1] ^- , 476 [M
NH _4] ^{+ +.}

Example 25 N- {4- [3- (4-Fluorophenylsulfamoyl) -4-hydroxyphenoxy] -3-methylphenyl} oxamic acid

Embedded image Produced as in Example 1 the title _{compound: 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 = 2.4), 9.98 (s, 1H), 10.69 (s, 1H), 10.72 (s, 1H), 10.75 (s
IR (KBr) 1326, 1487, 1506, 1692; ESI-MS 457 [M-1] ^- .

Example 26 (2) N- {4- [3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid

Embedded imageA. 4-fluorobenzenesulfinic acid 4-fluorobenzene in 50 mL of THF (distilled over Na-benzophenone)
A solution of sensulfonyl chloride (2 g, 10.28 mmol) was added to 0%^oCool to C
And add sodium borohydride (1.9 g, 51.4 mmol) little by little
. Reactant 0^oStir at C for 2 hours and warm to room temperature, after 2 hours, water (5 mL)
And quench. Evaporate the solvent and add the aqueous residue to a 6N HCl aqueous solution
And acidify. The product is dissolved in EtOAc, washed with brine and dried over anhydrous Na.₂S
O₄And 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 159 [M-1]^-.

B. 2- a solution of (4-fluoro-benzenesulfonyl) compounds of benzene-1,4-diol The title A, i.e. in the water of 10 mL 4-fluorobenzene sulfinic acid (3g, 18.75mmol) and, 30 mL of _CH 2 Cl _To a solution of 1,4 benzoquinone (1.93 g, 17.86 mmol) in ₂ at room temperature. After 4 hours, the precipitated product was collected by vacuum filtration, washed with cold CH ₂ Cl _2, and concentrated under reduced pressure, 2- (4-fluoro-benzenesulfonyl) - benzene -
Obtain _{1,4-diol: NMR (DMSO-d 6)} 6.73 (d, 1H, J = 9), 6.92 (dd, 1H, J =
9, 3), 7.31 (d, 1H, J = 3), 7.41 (app t, 2H, J = 9), 7.96 (dd, 2H, J = 9,
5), 9.41 (s, 1H), 10.05 (s, 1H); ESI-MS 267 [M-1] ^- .

4- (2,6-dimethyl-4-nitrophenoxy) -2- (4-fluorobenzenesulfonyl) phenol Compound of title B, 2- (4-fluorobenzenesulfonyl) benzene-1,
4-diol (1.2 g, 4.48 mmol) was added to NaH in 15 mL of NMP.
(60% dispersion in mineral oil; 0.39 g, 9.86 mmol) is added in portions at 0 ^° C. to the suspension. The mixture was warmed to room temperature and after 30 minutes, 4-chloro-3,5-dimethylnitrobenzene (1 g, 5.38 mmol) was added and the reaction was cooled to 120 ^° C.
And heat for 1 hour. Cool the reaction to room temperature and quench with 1N aqueous HCl. The mixture was partitioned between water and EtOAc, the organic solution was washed with water and brine, anhydrous N
Dry over a ₂ SO ₄ and concentrate. Chromatography on silica (eluent; Et
OAc / hexane-1 / 2/2/1) to give 4- (2,6-dimethyl-4).
- nitrophenoxy) -2- (4-fluoro - obtaining benzenesulfonyl) _{phenol: NMR (CDCl 3) 2.11 (} 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- (4-fluorobenzenesulfonyl) phenol Compound of title C, ie, 4- (2,6-dimethyl-4-nitrophenoxy)-
2- (4-fluoro-benzenesulfonyl) phenol (0.69 g, 1.6
5 mmol) and activated carbon on palladium (10wt%;. 69mg mixtures) in of _CH 2 Cl ₂ EtOH and 10mL of 10mL, stirred for 6 hours in a hydrogen atmosphere _(H 2, 1 atm). The catalyst was removed by vacuum filtration through celite, washing with 1/1-mixture of EtOH and _CH 2 Cl _2, concentrated and the combined filtrate and washings, and dried under reduced pressure, 4- (4-Amino-2 , 6-Dimethylphenoxy) -2- (4-fluorobenzenesulfonyl) -phenol is obtained: NM
R (DMSO-d ₆ ) 1.93 (s, 6H), 4.92 (s, 2H), 6.34 (s, 2H), 6.85 (d, 1H, J = 9), 7.0
0 (dd, 1H, 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, 1H), 10.4 (s, 1H).

E. N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid ethyl ester The compound of the title D, ie, 4- (4-amino-2,6 -Dimethylphenoxy)
-2- (4-Fluoro-benzenesulfonyl) phenol (0.64 g, 1.
A mixture of 65 mmol) and 2 mL of diethyl oxalate is heated at 180 ^° C. for 3 hours. The reaction is cooled to room temperature and the diethyl oxalate is removed under reduced pressure. Chromatography on silica (eluent; EtOAc / Hexane-1 / 3-? 2/3)
) Is carried out, and N- {4- [3- (4-fluoro-benzenesulfonyl) -4-
[Hydroxyphenoxy] -3,5-dimethylphenyldioxamate ethyl ester is obtained: 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), 7.40 (s, 2H), 7.87-7.9
3 (m, 2H), 8.87 (br s, 1H); ESI-MS 486 [M-1] ^- .

F. N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid The compound of the title E, ie, N- {4- [3- (4-fluoro Benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethylphenyl {oxamic acid ethyl ester (773 mg, 1.58 mmol) in 15 mL of EtOH
The solution in the above was added to a 1N aqueous sodium hydroxide solution (NaOH; 4.75 mL, 4.7).
5 mmol) at room temperature. After 1 hour, the reaction was washed with 1N aqueous HCl (5.
(5 mL), transfer the product to EtOAc, wash with brine, dry over anhydrous Na ₂ SO ₄ and concentrate. The product was triturated with Et ₂ O, and dried under vacuum, N- {4- [
3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3
To give the 5-dimethylphenyl} oxamic _{acid: NMR (DMSO-d 6)} 2.06 (s, 6H), 6.8
8 (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, 2H, J = 9,5), 10.5 (s, 1H), 10.69 (s, 1H
); IR (KBr) 1240, 1481, 1685, 1764; ESI-MS 458 [M-1] ^- .

The following compounds are prepared similarly.

[Table 4]

[0082]

[Table 5]

Example 35 N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} malonamic acid

Embedded image Prepared analogously to the title compound of 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), 10.18 (s, 1H), 10.55 (s,
1H), 12.6 (br s, 1H); IR (KBr) 1142, 1239, 1485, 1623, 1654, 1736; ESI-MS 4
72 [M-1] ^- .

Example 36 N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} succinamic acid

Embedded image Prepared analogously to the title compound of Example _{26: NMR (DMSO-d 6} ) 2.04 (s, 6H), 2.5
0-2.56 (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), 10.5 (b
rs, 1H), 12.1 (s, 1H); IR (KBr) 1480, 1659, 1717; ESI-MS 486 [M-1] ^- .

Example 37 3- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenylamino} -propionic acid

Embedded image To prepare the title compound in the same manner as in Example _{26: NMR (MeOH-d 4} ) 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
.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, 1675; ESI-MS 460 [M + 1] ⁺ , 458 [M-1] ^- .

Example 38 N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3-methylphenyl} oxamic acid

Embedded image Prepared analogously to the title compound of Example _{26: NMR (DMSO-d 6} ) 2.18 (s, 3H), 6.
90 (d, 1H, J = 9), 6.92 (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), 7.74 (d, 1H, J =
3), 7.97 (dd, 2H, J = 9,5), 10.67 (s, 1H), 10.71 (s, 1H); IR (KBr) 1234, 149
5, 1697; ESI-MS 444 [M-1] ^- .

Example 39 N- {3,5-dibromo-4- [3- (4-fluorobenzenesulfonyl)-
4-Hydroxyphenoxy] phenyl dioxamic acid

Embedded image The title compound is prepared as 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 (m, 2H), 8.27 (s, 2H), 10.74 (s, 1H), 11.15 (s, 1H); IR (KBr) 1290
, 1454, 1484, 1589, 1695; ESI-MS 588 [M-1] ^- .

Example 40 N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxalamide

Embedded image Prepared analogously to the title compound of Example _{26: NMR (DMSO-d 6} ) 2.06 (s, 6H), 6.8
8 (d, 1H, 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), 8.29 (br s,
1H), 10.49 (s, 1H), 10.58 (s, 1H); IR (KBr) 1141, 1250, 1481, 1676; ESI-MS 4
97 [M-1] ^- , 475 [M + NH ₄ ] ⁺ .

Example 41 N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} -N'-propyl-oxalamide

Embedded image The title compound is similarly prepared as in Example 26: ES-MS 499 [M-1] ^- , 518
[M ⁺ NH _4] +.

Example 42 N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} -N'-isopropyl-oxalamide

Embedded image The title compound is prepared as in Example 26: ES-MS 499 [M-1] ^- , 518 [M + NH ₄ ] ⁺ .

Example 43 N-butyl-N '-{4- [3- (4-fluorobenzenesulfonyl) -4-
[Hydroxyphenoxy] -3,5-dimethylphenyl} -oxalamide

Embedded image The title compound is prepared as in 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

Embedded image The title compound is prepared as in Example 26: ES-MS 517 [M + 1] ⁺ .

Example 45 N- {4- [3- (4-Fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} -2-morpholin-4-yl-2-oxoacetamide

Embedded image The title compound is prepared as in 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

Embedded image A. 5- (2,6-Dimethyl-4-nitrophenoxy) -2- (2-methoxyethoxymethoxy) benzoic acid 2-methoxyethoxymethyl ester Sodium NaH in 50 mL of NMP (60% dispersion in mineral oil; 32g
, 33 mmol) was cooled to 0 ^° C. and 2,5-dihydroxybenzoic acid (
(1.54 g, 10 mmol) are added in small portions. The mixture was warmed to room temperature and after 30 minutes, 4-chloro-3,5-dimethyl-nitrobenzene (2.41 g, 13 mmol)
1) is added in portions and the reaction is heated at 120 ^° C. for 3 hours. The reaction was cooled to room temperature and 2-methoxyethoxymethyl chloride (2.85 mL, 25 mmol)
Is added. After stirring 30 minutes, the mixture was poured into water, transferring the product into Et ₂ O. Wash the organic solution with brine, dry over anhydrous Na ₂ SO ₄ and concentrate. Chromatography on silica (eluent; EtOAc / hexane-1 / 2 → 3/2)
Obtain 5- (2,6-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.
02 (s, 2H).

B. 5- (4-amino-2,6-dimethylphenoxy) -2- (2-methoxyethoxymethoxy) benzoic acid 2-methoxyethoxymethyl ester The compound of title A, namely 5- (2,6-dimethyl-4-nitro) Phenoxy)
2- (2-methoxy-ethoxymethoxy) benzoic acid 2-methoxyethoxymethyl ester (3.2 g, 6.68 mmol) and palladium on activated carbon (10
wt. %; 320 mg) in 50 mL of EtOAc in a hydrogen atmosphere (
H _2, 1 atm) and stirred for 3 h. The catalyst was removed by vacuum filtration through celite, washed with EtOAc, the combined filtrates and washes were concentrated, dried under reduced pressure, and 5- (4-amino-2,6-dimethylphenoxy) -2- (2 -Methoxyethoxymethoxy) benzoic acid 2-methoxy-ethoxymethyl ester is obtained: NM
R (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 The compound of title B, i.e., 5- (4-amino-2,6-dimethylphenoxy) -2- (2-methoxy-ethoxymethoxy) benzoic acid 2-methoxyethoxymethyl ester (2.83 g) , 6.3 mmol) in 20 mL of THF was cooled to 0 ^° C. and treated sequentially with NMM (2.1 mL, 18.9 mmol) and ethyl oxalic chloride (0.915 mL, 8.19 mmol). I do. Fifteen
After minutes, the mixture was partitioned between EtOAc and water, the organic solution was washed with brine and anhydrous N
Dry over a ₂ SO ₄ and concentrate. Dissolve the residue in 30 mL EtOH and add 20 mL
Of 6N HCl aqueous solution is added. The mixture is stirred at room temperature for 16 hours and the EtOH is removed under reduced pressure. Dilute the residue with water (100 mL) and collect the solid by vacuum filtration, wash with water and dry. By crystallization from acetonitrile, 5-
Obtain [4- (ethoxyoxalyl-amino) -2,6-dimethylphenoxy] -2-hydroxybenzoic _{acid: NMR (DMSO-d 6)} 1.31 (t, 3H, J = 7), 2.06 (s, 6H), Four.
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 compound of the title C, ie, 5- [4- (ethoxyoxalylamino) -2. ,
6-dimethylphenoxy] -2-hydroxybenzoic acid (37 mg, 0.1 mmol
A solution of 1) in 1 mL of DMF is treated with NMM (55 μL, 0.5 mmol) and 1,1′-carbonyldiimidazole (32 mg, 0.2 mmol) at room temperature. The reaction mixture is heated at 60 ^° C. for 1 hour, then cooled to room temperature and piperidine (24 μL, 0.24 mmol) is added. After 16 hours, the reaction was
Treat with aqueous LiOH (333 μL, 0.5 mmol). The mixture is stirred for 30 minutes and the reaction is quenched with trifluoroacetic acid (TFA; 100 μL). The product is purified by HPLC (mobile phase; acetonitrile-water containing 0.1% trifluoroacetic acid) and N- {4- [4-hydroxy-3- (piperidine-1-carbonyl)].
Phenoxy] -3,5-dimethylphenyl dioxamic acid is 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), 6.6
7 (dd, 1H, J = 8.3, 2.3), 6.80 (d, 1H, J = 8.3), 7.53 (s, 2H), 9.38 (br s, 1
H), 10.6 (s, 1H); ESI-MS 413 [M + 1] ⁺ .

Example 47 N- {4- [4-Hydroxy-3- (morpholine-4-carbonyl) phenoxy] -3,5-dimethylphenyl} oxamic acid

Embedded image The title compound is prepared as in Example 46: ESI-MS 415 [M + 1] ⁺ .

Example 48 N- [4- (3-Cyclohexylcarbamoyl-4-hydroxyphenoxy)-
3,5-Dimethylphenyl] oxamic acid The title compound is prepared as in Example 46: ESI-MS 427 [M + 1] ⁺ .

Example 49 N- {4- [4-Hydroxy-3- (2-methoxyethylcarbamoyl) phenoxy] -3,5-dimethylphenyl} oxamic acid

Embedded image The title compound is prepared as in Example 46: ESI-MS 403 [M + 1] ⁺ .

Example 50 (ii) N- {4- [4-hydroxy-3- (2-morpholin-4-yl-ethylcarbamoyl) phenoxy] -3,5-dimethylphenyl} -oxamic acid

Embedded image The title compound is prepared as in Example 46: ESI-MS 458 [M + 1] ⁺ .

Example 51 N- {4- [4-Hydroxy-3- (pyridin-3-ylcarbamoyl) phenoxy] -3,5-dimethylphenyl} oxamic acid

Embedded image The title compound is prepared as in Example 46: ESI-MS 422 [M + 1] ⁺ .

Example 52: Formulation example: 100 mg of active substance, for example N- {4- [3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid A hard gelatin capsule containing, for example, is prepared as follows: Composition (per 1000 capsules) Active ingredient 100.0 g Lactose 250.0 g Microcrystalline cellulose 30.0 g Sodium lauryl sulfate 2.0 g Magnesium stearate 8.0 g

The sodium lauryl sulfate is added to the lyophilized active ingredient through a sieve with a mesh size of 0.2 mm. Mix both components well. Then, lactose was first passed through a sieve having a mesh size of 0.6 mm, and then microcrystalline cellulose was passed through a 0.1 mm mesh.
Add through a 9 mm mesh size sieve. Immediately mix the components thoroughly for another 10 minutes. Finally, the magnesium stearate is added through a sieve with a mesh size of 0.8 mm. After mixing for an additional 3 minutes, each of the resulting 3
90 mg of the formulation are filled into size 0 hard gelatin capsules.

[Procedure amendment]

[Submission Date] January 25, 2002 (2002.2.125)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Contents of correction]

[Claims]

Embedded image Wherein, W is, O, S, S (O) or S (O) is _2; X is, -SR4, -S (O) R4 , -S (O) 2 R4 or -S (O) ₂ NR5R6
Or X is -C (O) NR5R6, provided that -C (O) N
R5R6 is 3 '- located 4- or 5'-position; Y is O or _{H 2;} Z is hydrogen, halogen, hydroxy, optionally substituted optionally alkoxy, aralkoxy, acyloxy Or R is hydrogen, halogen, trifluoromethyl, lower alkyl or cycloalkyl; R1 is hydroxy, optionally substituted alkoxy, aryloxy, heteroaryloxy, aralkoxy, R2 is hydrogen, halogen or alkyl; R3 is halogen or alkyl; R4 is optionally substituted alkyl, aryl, aralkyl,
R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; R5 and R6 Are combined, and if desired, O, S, S (O)
, S (O) ₂ or NR7 is an inserted alkylene, which forms a 5- to 7-membered ring with the nitrogen atom to which they are attached; n represents 0 or an integer of 1 to 4] A compound, or a pharmaceutically acceptable salt thereof.

Embedded image Wherein, W is O or S; X is, -SR4, -S (O) R4 , -S (O) 2 R4, is -S (O) ₂ NR5R6 or -C (O) NR5R6 Y is O or H ₂ ; Z is hydrogen, halogen, hydroxy, alkoxy, aralkoxy, acyloxy or alkoxycarbonyloxy; R 1 is hydroxy, lower alkoxy or aryloxy; R 2 is hydrogen, R3 is halogen or lower alkyl; R4 is optionally substituted alkyl, aryl, aralkyl,
R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R5 is heteroaryl or heteroaralkyl. And R6 combine to optionally form O,
S, S (O), S (O) ₂ or NR7 is an inserted alkylene which forms a 5- to 7-membered ring with the nitrogen atom to which it is attached; n is 0, 1 or 2 Or a pharmaceutically acceptable salt thereof.

Embedded image [In the formula, X, -S (O) ₂ R4, is -S (O) ₂ NR5R6 or -C (O) NR5R6; Z is hydroxy, is lower alkanoyloxy or lower alkoxy; R1 is hydroxy R2 and R3 are lower alkyl; R4 is aryl; R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, Is aralkyl, heteroaryl, or heteroaralkyl; or R5 and R6 are linked to optionally form O,
S, S (O), S (O) ₂ or an alkylene having NR7 inserted therein, together with the nitrogen atom to which they are attached, a 5- to 7-membered ring wherein optionally from oxygen, nitrogen and sulfur Which may contain selected additional heteroatoms). Or a pharmaceutically acceptable salt thereof.

Embedded image [Wherein, X is a -S (O) ₂ R4 or -S (O) ₂ NR5R6; substituted R5, R6 and R7 are independently hydrogen, optionally; R4 is a monocyclic aryl Or R5 and R6 are linked to form CH ₂ C
(Where, Q _is, CH 2, O, NR7, S, S (O) or S (O) a _{2) H 2 -Q-CH 2} CH 2 A, the nitrogen atom to which they are attached And a pharmaceutically acceptable prodrug ester thereof; or a pharmaceutically acceptable salt thereof.

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0001

[Correction method] Change

[Contents of correction]

The present invention provides compounds of formula I

Embedded image Wherein, W is, O, S, S (O) or S (O) is _2; X is, -SR4, -S (O) R4 , -S (O) 2 R4 or -S (O) ₂ NR5R6
Or X is -C (O) NR5R6, provided that -C (O) N
R5R6 is 3 '- located 4'- or 5'-position; Y is O or _{H 2;} Z is hydrogen, halogen, hydroxy, optionally substituted optionally alkoxy, aralkoxy, R is hydrogen, halogen, trifluoromethyl, lower alkyl or cycloalkyl; R1 is hydroxy, optionally substituted alkoxy, aryloxy, heteroaryloxy, aralkoxy R2 is hydrogen, halogen or alkyl; R3 is halogen or alkyl; R4 is optionally substituted alkyl, aryl, aralkyl. ,
R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; R5 and R6 Are combined, and if desired, O, S, S (O)
, S (O) ₂ or NR7 is an inserted alkylene, which forms a 5- to 7-membered ring with the nitrogen atom to which they are attached; n represents 0 or an integer of 1 to 4] The present invention relates to novel compounds and pharmaceutically acceptable salts thereof.

[Procedure amendment 3]

[Document name to be amended] Statement

[Correction target item name] 0004

[Correction method] Change

[Contents of correction]

The term “optionally substituted alkyl” refers to unsubstituted or substituted straight-chain or branched hydrocarbon groups having 1 to 20, preferably 1 to 7, carbon atoms. Say. Examples of unsubstituted alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl,
Includes isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like. A substituted alkyl group can be one or more (eg, 2 or 3) of the following groups: halo, lower alkenyl, hydroxy, cycloalkyl, alkanoyl, alkoxy, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino,
Dialkylaminocarbonyl, alkanoylamino, thiol, alkylthio,
Alkylthiono, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfonamide, nitro, cyano, carboxy, alkoxycarbonyl, aryl, aralkyl, aralkoxy, guanidino, heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, Including, but not limited to, alkyl groups substituted by pyrimidyl, piperidyl, morpholinyl, and the like. Preferred substituents of substituted alkyl, especially substituted alkyl of variable R1 being substituted alkoxy are lower alkyl, cycloalkyl, lower alkenyl, benzyl, mono- or disubstituted lower alkyl, for example ω- (amino, mono- or di-substituted). Lower alkylamino, carboxy, lower alkoxycarbonyl) -lower alkyl, α- (lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl) -lower alkyl, for example pivaloyloxy-methyl.

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0006

[Correction method] Change

[Contents of correction]

The term “alkylene” is a straight-chain bridge of 1 to 6 carbon atoms connected by a single bond (eg, — (CH ₂ ) x —, wherein x is 1 to 6. Yes,
It can be substituted with one to three lower alkyl groups. The term "cycloalkyl" refers to a cyclic hydrocarbon group having 3 to 8 carbon atoms. The term "alkoxy" refers to alkyl-O-. The term "acyl" refers to alkanoyl, aroyl, heteroaroyl, arylalkanoyl or heteroarylalkanoyl. The term "alkanoyl" refers to alkyl-C (O)-. The term "alkanoyloxy" refers to alkyl-C (O) -O-. The terms "alkylamino" and "dialkylamino" each refer to (alkyl)
NH- and _(alkyl) 2 N-a say. The term "alkanoylamino" refers to alkyl-C (O) -NH-. The term "alkylthio" refers to alkyl-S-. The term "alkylthiono" refers to alkyl-S (O)-. The term "alkylsulfonyl" refers to alkyl-S (O) _2- . The term "alkoxycarbonyl" refers to alkyl-OC (O)-. The term "alkoxycarbonyloxy" refers to alkyl-OC (O) O-. The term "alkyl" in the above definition refers to an optionally substituted alkyl group as defined above.

[Procedure amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0009

[Correction method] Change

[Contents of correction]

The term “heterocyclyl” refers to an optionally substituted, fully saturated or unsaturated, aromatic or non-aromatic cyclic group, eg,
4- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 10- to 15-membered tricyclic ring systems, which contain at least one ring in a ring containing at least one carbon atom.
Has two heteroatoms. Each ring of the heterocyclic group containing a heteroatom is a nitrogen atom,
It may have one, two or three heteroatoms selected from oxygen and sulfur atoms. Here, nitrogen and sulfur heteroatoms may also be oxidized if desired. Heterocyclic groups can be attached at a heteroatom or carbon atom.

[Procedure amendment 6]

[Document name to be amended] Statement

[Correction target item name] 0018

[Correction method] Change

[Contents of correction]

The compounds of the present invention may have one or more asymmetric centers, depending on the nature of the substituent. The diastereoisomers, enantiomers and geometric isomers obtained fall within the scope of the present invention. Compounds of formula I as defined above wherein X is -C (O) NR5R6 and Z is different from hydrogen are preferred. Wherein, W is O or S; X is -S (O) is ₂ R4 (where, R4 is consisting of lower alkyl, phenyl or lower alkyl, lower alkoxy, halogen and trifluoromethyl phenyl and is) or substituted by one or more substituents selected from the group; or a NR5R6 -S (O) ₂ NR5R6 or -C (O) (wherein, R
5 is in each case hydrogen or lower alkyl, R6 is in each case hydrogen, lower alkyl, lower alkyl substituted by NR5R6, 3- to 7-membered cycloalkyl, phenyl, lower alkyl, lower alkoxy, halogen And phenyl substituted by one or more substituents selected from the group consisting of: trifluoromethyl; pyridyl or N-lower alkyl-2-pyridone; or R5 and R6 are linked, in each case: an alkylene which alkylene or O or S (O) ₂ are inserted, they form a 5- to 7-membered ring together with the nitrogen atom bonded); Y is a O or H ₂ Z is hydrogen or hydroxy; R is hydrogen; R1 is hydroxy, lower alkoxy or NR5R6 (Where R5
Is hydrogen or lower alkyl, R6 is hydrogen, lower alkyl, lower alkoxy, or R5 and R6 are bonded to alkylene or O-inserted alkylene, and they are bonded to each other. R2 is hydrogen, halogen or lower alkyl; R3 is halogen or lower alkyl; n is 0, 1 or 2 Certain compounds of formula I and pharmaceutically acceptable salts thereof are preferred.

[Procedure amendment 7]

[Document name to be amended] Statement

[Correction target item name] 0019

[Correction method] Change

[Contents of correction]

Formula IA

Embedded image Wherein, W is O or S; X is, -SR4, -S (O) R4 , -S (O) 2 R4, is -S (O) ₂ NR5R6 or -C (O) NR5R6 Y is O or H ₂ ; Z is hydrogen, halogen, hydroxy, alkoxy, aralkoxy, acyloxy or alkoxycarbonyloxy; R 1 is hydroxy, lower alkoxy or aryloxy; R 2 is hydrogen, R3 is halogen or lower alkyl; R4 is optionally substituted alkyl, aryl, aralkyl,
R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R5 is heteroaryl or heteroaralkyl. And R6 combine to optionally form O,
S, S (O), S (O) ₂ or NR7 is an inserted alkylene which forms a 5- to 7-membered ring with the nitrogen atom to which it is attached; n is 0, 1 or 2 Is preferable, and a pharmaceutically acceptable salt thereof. Formula IB

Embedded image [In the formula, X, -S (O) ₂ R4, is -S (O) ₂ NR5R6 or -C (O) NR5R6; Z is hydroxy, is lower alkanoyloxy or lower alkoxy; R1 is hydroxy R2 and R3 are lower alkyl; R4 is aryl; R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, Is aralkyl, heteroaryl, or heteroaralkyl; or R5 and R6 are linked to optionally form O,
Alkylene optionally intervened by S, S (O), S (O) ₂ , or NR7 forming a 5- to 7-membered ring with the nitrogen atom to which they are attached. And pharmaceutically acceptable salts thereof are more preferred.

[Procedure amendment 8]

[Document name to be amended] Statement

[Correction target item name] 0020

[Correction method] Change

[Contents of correction]

Formula IC

Embedded image [Wherein, X is a -S (O) ₂ R4 or -S (O) ₂ NR5R6; substituted R5, R6 and R7 are independently hydrogen, optionally; R4 is a monocyclic aryl Or R5 and R6 are linked to form CH ₂ C
(Where, Q _is, CH 2, O, NR7, S, S (O) or S (O) a _{2) H 2 -Q-CH 2} CH 2 A, the nitrogen atom to which they are attached And a pharmaceutically acceptable prodrug ester thereof; and a pharmaceutically acceptable salt thereof.

[Procedure amendment 9]

[Document name to be amended] Statement

[Correction target item name] 0023

[Correction method] Change

[Contents of correction]

Similarly, the acid addition salt can be, for example, a salt of a mineral acid, an organic carboxylic acid, and an organic sulfonic acid such as hydrochloric acid, methanesulfonic acid, maleic acid, provided that a basic group such as And pyridyl also constitute a part of the structure.

[Procedure amendment 10]

[Document name to be amended] Statement

[Correction target item name] 0024

[Correction method] Change

[Contents of correction]

The compound of formula I has the formula II

Embedded image Wherein R 2 and R 3 have the meanings as defined herein, and W is oxygen (
Prepared according to methods well known in the literature)]. First, a compound of formula II is converted to, for example, a trifluoromethylsulfonyl ester, the latter being converted to lithium chloride in an inert solvent such as N-methylpyrrolidone, N, N-dimethylformamide or dimethylsulfoxide. Process,
Formula III

Embedded image Can be formed. Compounds of formula III have the formula V

Embedded image Wherein R is as defined herein, X ′ and Z ′ represent X and Z as defined herein, or X ′ and Z ′ are bases, such as hydroxyl A group that can be converted to X and Z in an inert solvent such as N-methylpyrrolidone, N, N-dimethylformamide or dimethylsulfoxide in the presence of sodium or potassium carbonate at ambient temperature or elevated temperature, respectively. By reacting an appropriately substituted phenol or thiophenol of formula IV

Embedded image Can be converted to a compound of the formula Compounds of formula V can be obtained by the methods described herein or in the art.

[Procedure amendment 11]

[Document name to be amended] Statement

[Correction target item name] 0025

[Correction method] Change

[Contents of correction]

Alternatively, the compound of formula IV has the formula VI

Embedded image Wherein R, X and Z ′ have the previously defined meanings and have a phenol or thiophenol of formula II. Wherein W is oxygen or sulfur as described in the art.] With an inert solvent such as a copper catalyst and a base such as triethylamine in an inert solvent such as It can be obtained by condensation in dichloromethane.

[Procedure amendment 12]

[Document name to be amended] Statement

[Correction target item name] 0027

[Correction method] Change

[Contents of correction]

A compound of the present invention wherein X is S (O) ₂ NR5R6 is, for example, firstly a compound of formula IV wherein R and X ′ are hydrogen and X ′ is located at the 3 ′ position. , Z ′ is hydrogen, alkoxy or aralkoxy and X ′ is located at the 4 ′ position) with chlorosulfonic acid in an organic solvent such as dichloromethane to give a compound of formula VII

Embedded image Wherein Z ′ has the meaning as defined above. Methods and conditions well known in the art can be used to convert compounds of formula VII where Z 'is hydroxy to compounds of formula VII where Z' is a protected hydroxyl group such as alkanoyloxy, alkoxycarbonyloxy or trialkylsyloxy. Can be used to convert.

[Procedure amendment 13]

[Document name to be amended] Statement

[Correction target item name] 0028

[Correction method] Change

[Contents of correction]

Compounds of formula VII wherein Z ′ is alkoxy, aralkoxy, alkanoyloxy, alkoxycarbonyl-oxy or trialkylsyloxy are converted to compounds of formula VII
I

Embedded image Wherein Z ′ is as defined above, with a chlorinating agent such as oxalyl chloride or thionyl chloride in an inert solvent such as dichloromethane or tetrahydrofuran in a catalytically appropriate amount of N ′.
It can be converted by reacting in the presence of N'-dimethylformamide.

[Procedure amendment 14]

[Document name to be amended] Statement

[Correction target item name] 0029

[Correction method] Change

[Contents of correction]

The compound of formula VIII is converted to a primary or secondary amine of formula R5R6NH, wherein
R5 and R6 have the meanings defined herein] with an organic solvent such as dichloromethane in the presence of a base such as N-methylmorpholine or triethylamine to give a compound of formula IX

Embedded image Is obtained. Compounds of formula IX, wherein Z 'has the previously defined meanings, and compounds of formula IX, wherein Z' is hydroxy, are well known in the art or described herein. It can be converted using methods and conditions. Nitro-substituted compounds of formula IV, for example compounds of formula IX, for example of formula X

Embedded image To an amine can be achieved according to methods described in the art. In a polar solvent such as ethanol or tetrahydrofuran, for example with hydrogen, in the presence of a catalyst such as palladium on carbon.

[Procedure amendment 15]

[Document name to be amended] Statement

[Correction target item name] 0030

[Correction method] Change

[Contents of correction]

The resulting amine, eg, of Formula X, is converted to an acylating agent, eg, ethyl oxalyl chloride, ethyl malonyl chloride, ethyl succinyl chloride, or ethyl bromoacetic acid, with a base, eg, N-methylmorpholine or triethylamine. In the presence,
Treatment in an organic solvent such as dichloromethane, tetrahydrofuran or N, N-dimethylformamide gives a compound of formula I, for example a compound of formula XI

Embedded image Wherein R 1 is alkoxy, Y is oxygen or H ₂ , Z ′ is Z as defined herein, or Z ′ is a group convertible to Z, and n is 0 to 4 Which is an integer of the formula: Compounds of formula I wherein R1 is alkoxy, for example, condensing a compound of formula X with an acylating agent, such as dimethyl or diethyl oxalate, at elevated temperature using an acylating agent as reagent and solvent Can be manufactured by

[Procedure amendment 16]

[Document name to be amended] Statement

[Correction target item name] 0032

[Correction method] Change

[Contents of correction]

Similarly, other compounds of formula IV wherein X ′ and Z ′ are X as defined herein
And X ′ and Z ′ are groups which can be converted into X and Z, respectively.
With the formula XII

Embedded image To the compound of formula (I) by the method given herein or a variation thereof. further,
If desired, the compound is converted to the corresponding compound of formula I by converting X 'and Z' to X and Z, respectively. For example, a compound where X '= COOH is converted to the corresponding amide of Formula I where X is C (O) NR5R6 according to methods well known in the art. Similarly, a compound in which COR ₁ is COOH is a compound in which COR ₁ is COH.
It can be converted to a compound that is ONR ₅ R ₆ .

[Procedure amendment 17]

[Document name to be amended] Statement

[Correction target item name] 0033

[Correction method] Change

[Contents of correction]

The functional groups contained in the starting compounds and intermediates, such as amino, thiol, carboxyl, and hydroxy groups, which are converted to the compounds of the present invention in the manner described herein, can be synthesized by conventional methods common in preparative organic chemistry. If desired. Protected amino, thiol, carboxyl and hydroxy groups can be converted to free amino, thiol, carboxyl and hydroxy groups under mild conditions without breaking the molecular framework or other undesirable side reactions It is.

[Procedure amendment 18]

[Document name to be amended] Statement

[Correction target item name] 0036

[Correction method] Change

[Contents of correction]

In the method cited herein, the reactive functional derivative of the carboxylic acid may be, for example, an anhydride (especially a mixed anhydride), an acid halide, an acid azide, a lower alkyl ester,
And activated esters thereof. The mixed anhydride is preferably pivalic acid in such form, or a lower alkyl (ethyl, isobutyl) hemiester of carbonic acid; the acid halide is, for example, chloride or bromide; the activated ester is For example, succinimide, phthalimide or 4-nitrophenyl ester; lower alkyl esters are, for example, methyl or ethyl esters.

[Procedure amendment 19]

[Document name to be amended] Statement

[Correction target item name] 0044

[Correction method] Change

[Contents of correction]

Compounds of the present invention having a basic group can be converted into acid addition salts, especially pharmaceutically acceptable salts. These can be used, for example, with inorganic acids, for example mineral acids, for example sulfuric acid, phosphoric acid or hydrohalic acids, or organic carboxylic acids (for example unsubstituted or halogen-substituted, for example (C _1- C ₄ ) -alkanecarboxylic acid
), E.g., acetic acid, e.g., a saturated or unsaturated dicarboxylic acid, e.g., oxalic acid, succinic acid, maleic acid or fumaric acid, e.g., a hydroxycarboxylic acid, e.g., glycolic acid, lactic acid, malic acid, tartaric acid or Citric acid, for example
Amino acids, such as aspartic acid or glutamic acid, or organic sulfonic acids, such as (C ₁ -C ₄ ) -alkylsulfonic acid (eg, methanesulfonic acid) or aryl unsubstituted or substituted (eg, by halogen) Formed with sulfonic acid.

[Procedure amendment 20]

[Document name to be amended] Statement

[Correction target item name] 0073

[Correction method] Change

[Contents of correction]

Example 24 N- {4- [3- (4-Fluorophenylsulfamoyl) phenoxy] -3,5-dimethylphenyl} oxamic acid

Embedded image The title compound is analogous to Example _{1: NMR (DMSO-d 6} ) 1.91 (s, 6H), 6.73-6.74 (m
, 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)
, 10.75 (s, 1H); IR (KBr) 1161, 1223, 1509, 1697; ESI-MS 457 [M-1] ^- , 476 [M
NH _4] ^{+ +.}

[Procedure amendment 21]

[Document name to be amended] Statement

[Correction target item name] 0077

[Correction method] Change

[Contents of correction]

C. 4- (2,6-dimethyl-4-nitrophenoxy) -2- (4-fluorobenzenesulfonyl) phenol Compound of title B, 2- (4-fluorobenzenesulfonyl) benzene-1,4
- diol (1.2g, 4.48mmol), NaH in NMP in 15 mL (60% dispersion in mineral oil; 0.39 g, 9.86 mmol) is added portionwise at ^{0 o} C to a suspension of. The mixture is warmed to room temperature and after 30 minutes, 4-chloro-3,5-dimethylnitrobenzene (1 g, 5.38 mmol) is added and the reaction is heated at 120 ^° C. for 1 hour. Cool the reaction to room temperature and quench with 1N aqueous HCl. The mixture was partitioned between water and EtOAc, the organic solution was washed with water and brine, and anhydrous Na ₂ SO ₄
Dry and concentrate. Chromatography on silica (eluent; EtOAc / hexane-1 / 2/1/1) was performed to give 4- (2,6-dimethyl-4-nitrophenoxy) -2- (4-fluoro-benzenesulfonyl). ) To obtain phenol: NMR (C
DCl ₃ ) 2.11 (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).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4453 A61K 31/4453 31/5375 31/5375 A61P 3/04 A61P 3/04 3/06 3 / 06 5/14 5/14 9/00 9/00 9/10 101 9/10 101 19/10 19/10 25/24 25/24 C07C 311/29 C07C 311/29 317/22 317/22 323/67 323/67 C07D 213/75 C07D 213/75 213/76 213/76 295/12 295/12 Z 295/18 295/18 Z (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ , TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR , BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT , RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZWF terms (reference) 4C055 AA01 AA03 AA04 BA01 BA02 BA42 CA02 CA52 CA53 CB04 CB08 CB16 DA01 4C086 AA01 AA02 AA03 BC17 BC21 BC73 MA01 MA04 NA 14 ZA12 ZA36 ZA45 ZA70 ZA97 ZC06 ZC33 ZC35 4C206 AA01 AA02 AA03 GA13 GA31 JA13 JA20 MA01 MA04 MA12 NA14 ZA12 ZA36 ZA45 ZA70 ZA97 ZC06 ZC33 ZC35 4H006 AA01 AA03 AB23 BJ30 BM30 BT30 BM30 TB10 BM30

Claims (10)

[Claims] 1. A compound of the following formula: Wherein, W is, O, S, S (O) or S _(O) is _2; X is, -SR4, -S (O) R4 , -S (O) 2 R4 or -S (O) ₂ NR
5R6 or X is -C (O) NR5R6, provided that-
C (O) NR5R6 is 3 '- located 4- or 5'-position; Y is O or _{H 2;} Z is hydrogen, halogen, hydroxy, optionally substituted optionally alkoxy R is hydrogen, halogen, trifluoromethyl, lower alkyl or cycloalkyl; R1 is hydroxy, optionally substituted alkoxy, aryloxy, heteroaryl Oxy, aralkoxy, cycloalkoxy, heteroaralkoxy or -NR5R6; R2 is hydrogen, halogen or alkyl; R3 is halogen or alkyl; R4 is optionally substituted alkyl, aryl, aralkyl,
R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; R5 and R6 Are combined to form O, S, S (O
), S (O) ₂ or alkylene with NR7 inserted, forming a 5- to 7-membered ring with the nitrogen atom to which they are attached; n represents 0 or an integer from 1 to 4] Or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein X is -C (O) NR5R and Z is not hydrogen. 3. A compound of formula I [wherein, W is O or S; X is -S _(O) 2 R4 (where, R4 is a lower alkyl, phenyl,
Or phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl);
Alternatively, _-S (O) 2 NR5R6 or -C (O) NR5R6 (wherein, R5 is, in each case, hydrogen or lower alkyl, R6 is in each case hydrogen, lower alkyl, substituted by NR5R6 Phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, 3- to 7-membered cycloalkyl, phenyl, lower alkyl, lower alkoxy, halogen and trifluoromethyl; pyridyl or N-lower alkyl Alternatively, R5 and R6 are linked and in each case alkylene or alkylene with O or S (O) ₂ inserted, and together with the nitrogen atom to which they are attached, 5 - forming a through 7-membered ring); Y is O or H _2; Z is Oh hydrogen or hydroxy R is hydrogen; R1 is hydroxy, lower alkoxy or NR5R6, wherein R5
Is hydrogen or lower alkyl, R6 is hydrogen, lower alkyl, lower alkoxy, or R5 and R6 are bonded to alkylene or O-inserted alkylene, and they are bonded to each other. R2 is hydrogen, halogen or lower alkyl; R3 is halogen or lower alkyl; n is 0, 1 or 2 ] The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof. 4. A compound of the formula Wherein, W is O or S; X _{is, -SR4, -S (O) R4} , -S (O) 2 R4, -S (O) 2 NR5R
Is 6 or -C (O) NR5R6; Y is O or _{H 2;} Z is hydrogen, halogen, hydroxy, alkoxy, aralkoxy, is acyloxy or alkoxycarbonyloxy; R1 is hydroxy, lower alkoxy or R2 is hydrogen, halogen or lower alkyl; R3 is halogen or lower alkyl; R4 is optionally substituted alkyl, aryl, aralkyl,
R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R5 is heteroaryl or heteroaralkyl. And R6 combine to optionally form O,
S, S (O), S (O) ₂ or NR7 is an inserted alkylene which forms a 5- to 7-membered ring with the nitrogen atom to which it is attached; n is 0, 1 or 2 The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof. 5. The formulas of the compounds [In the formula, _{X, -S (O) 2 R4,} -S (O) 2 NR5R6 or -C (O) NR5R
Z is hydroxy, lower alkanoyloxy or lower alkoxy; R1 is hydroxy or lower alkoxy; R2 and R3 are lower alkyl; R4 is aryl; R5, R6 and R7 Is independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R5 and R6 are linked to optionally form O,
S, S (O), S (O) ₂ or alkylene with NR7 inserted, with a 5- to 7-membered ring together with the nitrogen atom to which they are attached; (where optionally oxygen, nitrogen and sulfur Which may include additional heteroatoms selected from
A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof. 6. A compound of the formula [Wherein, X is a -S _(O) 2 R4 or _-S (O) 2 NR5R6; substituted R5, R6 and R7 are independently hydrogen, optionally; R4 is a monocyclic aryl Or R5 and R6 are linked to form CH ₂ C
_{(Where, Q} is, CH 2, O, NR7, S, S (O) or S _(O) a _{2) H 2 -Q-CH 2} CH 2 A, the nitrogen atom to which they are attached And a pharmaceutically acceptable prodrug ester thereof; or a pharmaceutically acceptable salt thereof. 7. A compound of claim 6 wherein X is S (O) ₂ R 4 wherein R 4 is phenyl optionally substituted by lower alkyl, halo, lower alkoxy or trifluoromethyl. Or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable prodrug ester thereof. 8. The compound of claim 1, wherein: N- {4- [3- (2,2-dimethylpropylsulfamoyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid; N- [4- (4-hydroxy-3-phenylsulfamoylphenoxy) -3,
N- {4- [3- (4-fluorophenylsulfamoyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamidic acid; N- {4-} 3- (2-fluorophenylsulfamoyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamic acid; N- {4- [3- (3-fluorophenylsulfamoyl) -4-hydroxyphenoxy]- N- {4- [3- [4-hydroxy-4- (4-methoxyphenylsulfamoyl) phenoxy] -3,5-dimethylphenyl} oxamidic acid; 3- (4-fluorobenzylsulfamoyl) -4-hydroxy-
N- {4- [4-hydroxy-3- (methylphenylsulfamoyl) phenoxy] -3,5-dimethylphenyl} oxamidic acid; N- [4- (4-hydroxy-3-propylsulfamoylphenoxy) -3,
5-dimethylphenyl] oxamic acid; N- [4- (4-hydroxy-3-isopropylsulfamoylphenoxy)-
3,5-dimethylphenyl] 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,
N- {4- [4-hydroxy-3- (pyrrolidone-1-sulfonyl) phenoxy] -3,5-dimethylphenyl} oxamidic acid; N- {4- [4-hydroxy- 3- (piperidine-1-sulfonyl) phenoxy] -3,5-dimethylphenyl} oxamidic acid; N- {4- [4-hydroxy-3- (2-methoxyethylsulfamoyl) phenoxy] -3,5- N- {4- [4-hydroxy-3- (morpholin-4-sulfonyl) phenoxy] -3,5-dimethylphenyl} oxamidic acid; N- {4- [3- (dioxo N- {4- [4-thiomorpholine-4-sulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamidic acid; Droxy-3- (pyridone-3-ylsulfamoyl) phenoxy] -3,5-dimethylphenyl} oxamidic 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-hydroxyphenylsulfamoyl] -3, 5-dimethylphenyl} oxamidic acid; N- {4- [3- (4-fluorophenylsulfamoyl) phenoxy] -3,
N- {4- [3- (4-fluorophenylsulfamoyl) -4-hydroxyphenoxy] -3-methylphenyl} oxamidic acid; N- {4- [3- (4 N- [4- (3-benzenesulfonyl-4-hydroxyphenoxy) -3,5; -fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyldioxamate;
N- {4- [3- (4-chlorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} oxamidic acid; N- {4- [4-hydroxy-3- (Toluene-4-sulfonyl) phenoxy] -3,5-dimethylphenyl {oxamic acid; N- {4- [4-hydroxy-3- (4-methoxybenzenesulfonyl) phenoxy] -3,5-dimethyl-phenyl} Oxamic acid; N- {4- [4-hydroxy-3- (4-trifluoromethylbenzenesulfonyl) phenoxy] -3,5-dimethylphenyl} oxamic acid; N- [4- (4-hydroxy-3-methane Sulfonylphenoxy) -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} oxamidic acid N- {4- [3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} malonamic acid; N- {4- [3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5- N- {4- [3- (4-dimethylphenyl} succinamic acid; 3- {4- [3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenylamino} propionic acid; N- {3,5 fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3-methylphenyl} oxamidic acid Dibromo -4 [3- (4-fluoro-benzenesulfonyl) -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'-propyl-oxalamide; N- {4- [3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3 , 5-Dimethylphenyl} -N′-isopropyl-oxalamide; 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- N- {4- [3- (4-fluorobenzenesulfonyl) -4-hydroxyphenoxy] -3,5-dimethylphenyl} -2-morpholin-4-yl-2-oxoacetamide; 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-dimethylphenyldioxamidic acid; N {4- [4-hydroxy-3- (morpholine-4-carbonyl) phenoxy] -3,5-dimethylphenyl} oxamic acid; N-r4- (3- cyclohexylcarbamoyl-4-hydroxyphenoxy) -
3,5-dimethylphenyl] oxamic acid; N- {4- [4-hydroxy-3- (2-methoxyethylcarbamoyl) phenoxy] -3,5-dimethylphenyl} oxamidic acid; N- {4- [4- Hydroxy-3- (2-morpholin-4-yl-ethylcarbamoyl) phenoxy] -3,5-dimethylphenyl} oxamic acid; and N- {4- [4-hydroxy-3- (pyridin-3-ylcarbamoyl) A) phenoxy] -3,5-dimethylphenyldioxamidic acid; or a pharmaceutically acceptable salt thereof. 9. Use of a compound according to any one of claims 1 to 8, which is associated with hyperlipidemia and hyperlipoproteinemia for the prevention and treatment of diseases associated with thyroid hormone imbalance. For the prevention and treatment of obstructive cardiovascular conditions,
Pharmaceutical for preventing and treating hypothyroidism and hyperthyroidism, obesity, osteoporosis and depression, for reducing total cholesterol plasma levels and LDL cholesterol levels, and for preventing and treating atherosclerosis and coronary heart disease Use for the formulation of. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.