CN1345309A

CN1345309A - Diaryl derivatives and their use as medicaments

Info

Publication number: CN1345309A
Application number: CN00805693A
Authority: CN
Inventors: P·J·库克拉
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 1999-03-29
Filing date: 2000-03-27
Publication date: 2002-04-17
Also published as: BR0009431A; PL349355A1; EP1165502A1; CZ20013449A3; NO20014702L; RU2001126579A; CA2361016A1; WO2000058279A1; TR200102225T2; IL144637A0; KR20010105394A; SK13812001A3; JP2002540189A; PE20001587A1; CO5160290A1; NO20014702D0; MXPA01009843A; HUP0200588A2; HK1042692A1; NZ514062A

Abstract

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

Description

Diaryl derivatives and as the purposes of medicine

The present invention relates to new compound and the pharmacologically acceptable salt thereof of formula I Wherein

W is O, S, S (O) or S (O) ₂

X is-SR4 ,-S (O) R4 ,-S (O) ₂R4 or-S (O) ₂NR5R6; Perhaps X is-C (O) NR5R6, and condition is-and C (O) NR5R6 is positioned at 3 ', 4 '-or 5 '-position;

Y is O or H ₂

Z is alkoxyl group, aralkoxy, acyloxy or the alkoxy-carbonyl oxy of hydrogen, halogen, hydroxyl, selectivity replacement;

R is hydrogen, halogen, trifluoromethyl, low alkyl group or cycloalkyl;

R1 be the alkoxyl group that replaces of hydroxyl, selectivity, aryloxy, heteroaryloxy, aralkoxy, cycloalkyloxy, assorted aralkoxy or-NR5R6;

R2 is hydrogen, halogen or alkyl;

R3 is halogen or alkyl;

R4 is alkyl, aryl, aralkyl, heteroaralkyl or the heteroaryl that selectivity replaces;

R5, R6 and R7 are alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or the heteroaralkyl that hydrogen, selectivity replace independently of one another; Perhaps to lump together be optionally by O, S, S (O), S (O) for R5 and R6 ₂Or the alkylidene group of NR7 interruption, the nitrogen-atoms that this alkylidene group is connected with them lumps together and forms 5 to 7 yuan of rings;

N represents 0 or 1 to 4 integer.

Compound of the present invention is to intend thyroid, can be used for preventing and/or treating and Triiodothyronine imbalance diseases associated, for example thyroprivia and hyperthyroidism, obesity, osteoporosis and dysthymia disorders.Specifically, compound of the present invention is a lipid-lowering agent, and it can strengthen the removing of the cholesterol removing from blood circulation, particularly low-density lipoprotein (LDL) form of cholesterol.They can also be to the ldl receptor function of adjusted mammalian liver.Therefore, they can be used for reducing mammiferous total plasma cholesterol level, particularly reduce the LDL-cholesterol level.In addition, this compound can also reduce the level of the lipoprotein (a) [Lp (a)] that has raise in Mammals, and it is an independently cardiovascular risk factors.Therefore, compound of the present invention is used in and prevents and/or treats the obstructive cardiovascular disorder that relates to hyperlipidaemia and hyperlipoproteinemia, for example atherosclerosis and coronary heart disease in the Mammals.

The method that the invention provides formula I compound, contains the pharmaceutical composition of described compound and use described compound.

What below list is the definition of describing the used various terms of The compounds of this invention.These definition are applicable to term used in the whole specification sheets (unless individually or as the part of macoradical more it being limited separately) under specific situation.

Term " alkyl that selectivity replaces " is meant the alkyl of the straight or branched that contains 1 to 20 carbon atom, preferred 1 to 7 carbon atom that does not replace or replace.The example of unsubstituted alkyl comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, isohexyl, heptyl, 4,4-dimethyl amyl group, octyl group etc.The alkyl that replaces includes but are not limited to; the alkyl that is replaced by one or more (for example two or three) following groups: halogen; low-grade alkenyl; hydroxyl; cycloalkyl; alkanoyl; alkoxyl group; the alkoxyl group alkoxyl group; alkanoyloxy; amino; alkylamino; dialkyl amido; dialkyl amino carbonyl; alkanoyl amino; sulfydryl; alkylthio; the alkyl sulfide carbonyl; alkyl sulphonyl; aryl sulfonyl; heteroarylsulfonyl; sulfonamido; nitro; cyano group; carboxyl; alkoxy carbonyl; aryl; aralkyl; aralkoxy; guanidine radicals and heterocyclic radical, described heterocyclic radical comprises indyl; imidazolyl; furyl; thienyl; thiazolyl; pyrrolidyl; pyridyl; pyrimidyl; piperidyl; morpholinyl etc.The alkyl that replaces, particularly when variable R 1 is the alkoxyl group of replacement, the substituting group of the substituted alkyl of variable R 1 is low alkyl group, cycloalkyl, low-grade alkenyl, benzyl, list or dibasic low alkyl group preferably, for example ω-(amino, single or two-low-grade alkyl amino, carboxyl, elementary alkoxy carbonyl)-low alkyl group, α-(lower alkane acyloxy, elementary alkoxy carbonyl or two-low-grade alkyl amino carbonylic)-low alkyl group, for example new pentane acyloxy alkyl-methyl.

Term " low alkyl group " be meant contain 1 to 7, preferred 1 to 4 carbon atom above-mentioned.

Term " halogen " or " halogen " are meant fluorine, chlorine, bromine and iodine.

Term " alkenyl " is meant the abovementioned alkyl that contains at least two carbon atoms and contain at least one carbon-carbon double bond.The group that preferably contains 2 to 4 carbon atoms.

Term " alkylidene group " be meant by the bridge of the straight chain of singly linked 1 to 6 carbon atom (for example-(CH ₂) _x-, wherein x is 1 to 6), it can be replaced by 1 to 3 low alkyl group.

Term " cycloalkyl " is meant the cyclic hydrocarbon group of 3 to 8 carbon atoms.

Term " alkoxyl group " is meant alkyl-O-.

Term " acyl group " is meant alkanoyl, aroyl, 4-hetaroylpyrazol, Arylalkanoyl or heteroaryl alkanoyl.

Term " alkanoyl " be meant alkyl-C (O)-.

Term " alkanoyloxy " is meant alkyl-C (O)-O-.

Term " alkylamino " and " dialkyl amido " are meant (alkyl) NH-and (alkyl) respectively ₂N-.

Term " alkanoyl amino " is meant alkyl-C (O)-NH-.

Term " alkylthio " is meant alkyl-S-.

Term " alkyl sulfide carbonyl " be meant alkyl-S (O)-.

Term " alkyl sulphonyl " is meant alkyl-S (O) ₂-.

Term " alkoxy carbonyl " be meant alkyl-O-C (O)-.

Term " alkoxy-carbonyl oxy " is meant alkyl-O-C (O) O-.

More than the term of being mentioned in the definition " alkyl " relates to the alkyl that selectivity defined above replaces.

Term " aryl " is meant that the part at ring contains the monocycle or the two cyclic aromatic series alkyl of 6 to 12 carbon atoms; for example phenyl, naphthyl, tetralyl and xenyl, these groups all can optionally for example alkyl, halogen, hydroxyl, alkoxyl group, alkanoyl, alkanoyloxy, amino, alkylamino, dialkyl amido, alkanoyl-amino, sulfydryl, alkylthio, nitro, cyano group, carboxyl, carboxyalkyl, alkoxy carbonyl, alkyl sulfide carbonyl, alkyl-alkylsulfonyl, sulfonamido, heterocyclic radical etc. replace by 1 to 4 substituting group.

Term " monocyclic aryl " is meant the defined phenyl in aryl that selectivity replaces.

Term " aralkyl " is meant directly by alkyl bonded aryl, for example benzyl.

Term " aralkoxy " is meant by alkoxyl group bonded aryl.

Term " aryl sulfonyl " is meant aryl-S (O) ₂-.

Term " aroyl " be meant aryl-C (O)-.

Term " heterocyclic radical " is meant the saturated or undersaturated aromatic series selectivity replacement, complete or non-aromatic cyclic group, for example 4 to 7 yuan monocycle, 7 to 11 yuan two the ring or 10 to 15 yuan three the ring ring systems, this cyclic group contains at least one heteroatoms in the ring of at least one carbon atoms.Each ring that contains heteroatomic heterocyclic group can contain 1,2 or 3 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, and nitrogen wherein and sulfur heteroatom can also be optionally oxidized.Heterocyclic group can be connected on heteroatoms or the carbon atom.

The example of monocyclic heterocycles group comprises pyrrolidyl, pyrryl, pyrazolyl, azetidinyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidyl oxazolyl oxazolidinyl isoxazoline-3-yl isoxazolyl, thiazolyl, thiadiazolyl group, thiazolidyl, isothiazolyl, the isothiazole alkyl, furyl, tetrahydrofuran base, thienyl oxadiazole base, piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxo azepines base, the azepines base, the 4-piperidone base, pyridyl, the 2-pyridone, N-low alkyl group-pyridone, N-low alkyl group-2-pyridone for example, pyrazinyl, pyrimidyl, pyridazinyl, THP trtrahydropyranyl, morpholinyl, the parathiazan base, S-oxo-parathiazan base, S, S-dioxo-parathiazan base, 1,3-dioxolane and tetrahydrochysene-1,1-dioxo thienyl etc.

The example of bicyclic heterocycles group comprises indyl, benzothiazolyl benzoxazolyl, benzothienyl, quinuclidinyl, quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl-, benzopyranyl, the indolizine base, benzofuryl, chromene ketone group (chromonyl), the tonka bean camphor base, benzopyranyl, the cinnolines base, quinoxalinyl, indazolyl, pyrrolopyridinyl, (for example furo [2 for the furo pyridyl, 3-c] pyridyl, furo [3,2-b] pyridyl] or furo [2,3-b] pyridyl), dihydro-iso indolyl, dihydroquinazoline base (for example 3,4-dihydro-4-oxo-quinazolyl) etc.

The example of tricyclic heterocyclic group comprises carbazyl, benzindole base, phenanthroline base, acridyl, phenanthridinyl, xanthenyl etc.

Term " heterocyclic radical " comprises the heterocyclic group of replacement.The heterocyclic group that replaces is meant the heterocyclic group that is replaced by 1,2 or 3 following group:

(a) alkyl;

(b) hydroxyl (or hydroxyl of protection);

(c) halogen;

(d) oxo (promptly=O);

(e) amino, alkylamino or dialkyl amido;

(f) alkoxyl group;

(g) cycloalkyl;

(h) carboxyl;

(i) heterocyclic oxy group;

(j) carbalkoxy, unsubstituted elementary alkoxy carbonyl for example;

(k) sulfydryl;

(l) nitro;

(m) cyano group;

(n) sulfonamido, sulfonamido alkyl or sulfonamido dialkyl group;

(o) aryl;

(p) alkyl-carbonyl oxygen base;

(q) aryl carbonyl oxygen base;

(r) arylthio;

(s) aryloxy;

(t) alkylthio;

(u) formyl radical;

(v) aralkyl; Or

(w) aryl that is replaced by alkyl, cycloalkyl, alkoxyl group, hydroxyl, amino, alkylamino, dialkyl amido or halogen.

Term " heterocyclic oxy group " is meant by oxo bridge bonded heterocyclic group.

Term " heteroaryl " is meant heteroaromatic, for example monocycle or aryl bicyclic, for example pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolyl, isoquinolyl, benzimidazolyl-, benzofuryl etc., it is optionally replaced at the substituting group described in the aryl that replaces by one or more, is for example replaced by low alkyl group, lower alkoxy or halogen.

Term " heteroaryloxy " is meant heteroaryl-O-.

Term " heteroarylsulfonyl " is meant heteroaryl-S (O) ₂-.

Term " 4-hetaroylpyrazol " be meant heteroaryl-C (O)-.

Term " heteroaralkyl " is meant by alkyl bonded heteroaryl.

The present invention also comprises prodrug derivant, the pharmaceutically acceptable prodrug ester derivative of carboxylic acid for example of the present invention (COR1 is a carboxyl), and this derivative can change into the free carboxylic acid by solvolysis or under physiological condition.

The example of described carboxylicesters comprises by COR ₁Defined ester, preferred lower alkyl esters, cycloalkyl ester, low-grade alkenyl ester, benzyl ester, list or dibasic lower alkyl esters, for example ω-(amino, single or two-low-grade alkyl amino, carboxyl, lower alkoxycarbonyl)-lower alkyl ester, α-(lower alkane acyloxy, lower alkoxycarbonyl or two-low-grade alkyl amino carbonylic)-lower alkyl esters, for example ester commonly used in this area such as new pentane acyloxy-methyl esters.

R preferably represents hydrogen or low alkyl group;

R1 preferably represents hydroxyl, lower alkoxy or aryloxy.

R2 preferably represents hydrogen, halogen or low alkyl group.

R3 preferably represents halogen or low alkyl group.

R4 preferably represents phenyl or the phenyl that is replaced by one or more substituting groups that are selected from low alkyl group, lower alkoxy, halogen and trifluoromethyl.

R5 preferably represents hydrogen.

R6 preferably represents phenyl or the phenyl that is replaced by one or more substituting groups that are selected from low alkyl group, lower alkoxy, halogen and trifluoromethyl.

W is O preferably.

X preferably-S (O) ₂R4 or-S (O) ₂NR5R6.

Y is O preferably.

Z is hydrogen or hydroxyl preferably.

Integer " n " preferably 0,1 or 2.

According to substituent character, compound of the present invention can have one or more asymmetric centers.Formed diastereomer, enantiomorph and geometrical isomer include within the scope of the invention.

Preferred formula I compound defined above, condition be when X be-during C (O) NR5R6, Z is not a hydrogen.

Preferably suc as formula I compound and pharmacologically acceptable salt thereof, wherein

W is O or S;

X is-S (O) ₂R4; R4 is low alkyl group, phenyl or the phenyl that replaced by one or more substituting groups that are selected from low alkyl group, lower alkoxy, halogen and trifluoromethyl; Perhaps X is-S (O) ₂NR5R6 or-C (O) NR5R6; Wherein R5 is hydrogen or low alkyl group, the low alkyl group that R6 is hydrogen, low alkyl group, replaced by NR5R6,3 to 7 yuan of cycloalkyl, phenyl, the phenyl that replaced by one or more substituting groups that are selected from low alkyl group, lower alkoxy, halogen and trifluoromethyl; Pyridyl or N-low alkyl group-2-pyridone; Perhaps

It is alkylidene group or by O or S (O) that R5 and R6 lump together ₂The alkylidene group that is interrupted, the nitrogen-atoms that described alkylidene group is connected with them lump together and form 5 to 7 yuan of rings;

Y is O or H ₂

Z is hydrogen or hydroxyl;

R is a hydrogen;

R1 is hydroxyl, lower alkoxy or NR5R6; R5 is hydrogen or low alkyl group, and R6 is hydrogen, low alkyl group, lower alkoxy, and perhaps to lump together be alkylidene group or the alkylidene group that is interrupted by O for R5 and R6, and the nitrogen-atoms that described alkylidene group is connected with them lumps together and forms 5 to 7 yuan of rings;

R2 is hydrogen, halogen or low alkyl group;

R3 is halogen or low alkyl group;

N represents 0,1 or 2.

The compound of preferred formula IA and pharmacologically acceptable salt thereof; Wherein

W is O or S;

X is-SR4 ,-S (O) R4 ,-S (O) ₂R4 ,-S (O) ₂NR5R6 or-C (O) NR5R6;

Y is O or H ₂

Z is hydrogen, halogen, hydroxyl, alkoxyl group, aralkoxy, acyloxy or alkoxy-carbonyl oxy;

R1 is hydroxyl, lower alkoxy or aryloxy;

R2 is hydrogen, halogen or low alkyl group;

R3 is halogen or low alkyl group;

R4 is alkyl, aryl, aralkyl, heteroaryl or the heteroaralkyl that selectivity replaces;

R5, R6 and R7 are alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or the heteroaralkyl that hydrogen, selectivity replace independently of one another; Perhaps to lump together be optionally by O, S, S (O), S (O) for R5 and R6 ₂Or the alkylidene group of NR7 interruption, the nitrogen-atoms that described alkylidene group is connected with them lumps together and forms 5 to 7 yuan of rings;

N represents 0,1 or 2.

The further preferably compound of formula IB and pharmacologically acceptable salt thereof:

Wherein

X is-S (O) ₂R4 ,-S (O) ₂NR5R6 or-C (O) NR5R6;

Z is hydroxyl, lower alkane acyloxy or lower alkoxy;

R1 is hydroxyl or lower alkoxy;

R2 and R3 are low alkyl groups;

R4 is an aryl;

R5, R6 and R7 are alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or the heteroaralkyl that hydrogen, selectivity replace independently of one another; Perhaps to lump together be optionally by O, S, S (O), S (O) for R5 and R6 ₂Or the alkylidene group of NR7 interruption, the nitrogen-atoms that described alkylidene group is connected with them lumps together and forms 5 to 7 yuan of rings.

Compound, its pharmaceutically useful prodrug ester and pharmacologically acceptable salt thereof of first-selected formula IC;

Wherein

X is-S (O) ₂R4 or-S (O) ₂NR5R6;

R4 is a monocyclic aryl;

R5, R6 and R7 are the alkyl or aryl that hydrogen, selectivity replace independently of one another; Perhaps to lump together be CH for R5 and R6 ₂CH ₂-Q-CH ₂CH ₂, wherein Q is CH ₂, O, NR7, S, S (O) or S (O) ₂, described CH ₂CH ₂-Q-CH ₂CH ₂The nitrogen-atoms that is connected with them lumps together and forms 6 yuan of rings.

Especially preferably wherein X is S (O) ₂R4 and R4 are optionally by formula IC compound, its pharmacologically acceptable salt and the prodrug derivant thereof of the phenyl of low alkyl group, halogen, lower alkoxy or trifluoromethyl replacement.

The pharmacologically acceptable salt of any acidic cpd of the present invention is the salt that forms with alkali, be cationic salts, for example an alkali metal salt and alkaline earth salt, for example sodium, lithium, potassium, calcium, magnesium salts, and ammonium salt, for example ammonium, trimethyl ammonium, diethyl ammonium and three-(hydroxymethyl)-methyl-ammonium salt.

When in structure, having basic group such as pyridyl, can also form for example acid salt of hydrochloric acid, methylsulfonic acid, toxilic acid etc. of mineral acid, organic acid and organic sulfonic acid.

Formula I compound can be from oxybenzene compound (according to known method preparation the document) preparation of the suitable replacement of formula II:

Wherein R2 and R3 have defined implication herein; W is an oxygen; the preparation method is as follows: at first convert it into for example trifluoromethyl sulfonyl ester; then with this ester with lithium chloride at inert solvent for example N-methyl-pyrrolidone, N, handle forming the formula III compound in dinethylformamide or the methyl-sulphoxide

The formula III compound can be transformed by the following method accepted way of doing sth IV compound:

With the oxybenzene compound of the suitable replacement of formula III compound and formula V or thiophenol compound alkali for example sodium hydride or salt of wormwood in the presence of at inert solvent for example N-Methyl pyrrolidone, N, under the temperature of room temperature or rising, react in dinethylformamide or the methyl-sulphoxide Wherein R has implication defined herein, X ' and Z ' expression X and Z defined herein, and perhaps X ' and Z ' they are respectively the groups that can change into X and Z.Formula V compound can make with the method for putting down in writing in this paper or this area.

Perhaps, formula IV compound can be by being that phenol or the thiophenol compound condensation of the formula II of oxygen or sulphur makes with the diaryl iodine a tetrafluoro borate of formula VI and W wherein,

Wherein R, X ' and Z ' as defined above, condensation reaction is carried out according to method described in the art, for example, copper catalyst and alkali for example triethylamine in the presence of for example carry out in the methylene dichloride at inert solvent.

Wherein Z ' is that the formula IV compound of alkoxyl group or aralkoxy can change into wherein that Z ' is the formula IV compound of hydroxyl according to method well known in the art, for example, when Z ' is methoxyl group, use acid as Hydrogen bromide or boron trihalides, for example boron trichloride or boron tribromide; Perhaps when Z ' is benzyloxy, use hydrogen in the presence of catalyzer such as palladium carbon, to transform.

Wherein X is S (O) ₂The The compounds of this invention of NR5R6 can prepare by the following method: for example, at first will be wherein R and X ' be that hydrogen and X ' are positioned at 3 ', Z ' be hydroxyl, alkoxyl group or aralkoxy and Z ' be arranged in 4 ' formula IV compound and chlorsulfonic acid organic solvent for example methylene dichloride react production VII compound Wherein Z ' as defined above.Wherein Z ' is that the formula VII compound of hydroxyl can change into the hydroxyl formula VII compound of alkanoyloxy, alkoxycarbonyloxy or trialkylsiloxy for example that Z ' wherein is protection with method well known in the art and condition.

Wherein Z ' be alkoxyl group, aralkoxy, alkanoyloxy, alkoxycarbonyloxy or trialkylsiloxy formula VII compound can by with chlorination reagent for example oxalyl chloride or thionyl chloride inert solvent for example in methylene dichloride or the tetrahydrofuran (THF), at the N of catalytic amount, the existence of dinethylformamide reaction down transforms accepted way of doing sth VIII compound Wherein Z ' as defined above.

With the primary amine of formula VIII compound and formula R5R6NH or secondary amine (wherein R5 and R6 in the literary composition definition) alkali for example N-methyl-morpholine or triethylamine in the presence of at organic solvent reaction production IX compound in the methylene dichloride for example.

Z ' wherein formula IX compound as defined above can change into the formula IX compound that Z ' is a hydroxyl according to the description of this paper with method well known in the art and conditioned disjunction.

The formula IV compound V (for example compound of formula IX) that nitro is replaced changes into the reaction of the amine of formula X for example can be according to method described in the art, for example with hydrogen catalyzer for example palladium carbon in the presence of for example finish in ethanol or the tetrahydrofuran (THF) at polar solvent.

Formed amine; the compound of formula X for example; can with acylating reagent for example ethyl oxalyl chloride, ethyl malonyl chloride, Ethyl Succinyl Chloride or ethyl bromoacetate alkali for example N-methylmorpholine or triethylamine in the presence of at organic solvent for example methylene dichloride, tetrahydrofuran (THF) or N; handle in the dinethylformamide and form formula I compound, for example compound of formula XI Wherein R1 is an alkoxyl group, and Y is oxygen or H ₂, Z ' defined herein Z of expression or Z ' they are the groups that can change into Z, n represents 0 to 4 integer.Wherein R1 be alkoxyl group formula I compound can also by will be for example formula X compound and acylating reagent for example dimethyl oxalate or oxalic acid diethyl ester at elevated temperatures condensation prepare, the acylating reagent while wherein is as reactant and solvent.

Wherein R1 is that the formula I compound of for example alkoxyl group or aryloxy can be according to ordinary method, and for example for example alkaline carbonate or oxyhydroxide for example are hydrolyzed into wherein in ethanol or the tetrahydrofuran (THF) at organic solvent that R1 is the formula I compound of hydroxyl with aqueous alkali.

Equally, wherein X ' and Z ' expression defined herein X and Z or X ' and Z ' are respectively that other formula IV compound that can change into the group of X and Z can change form according to method described herein or its and transforms accepted way of doing sth XII compound:

As needs, can be by with X ' with Z ' changes into X respectively and Z changes into corresponding formula I compound with described compound.For example, wherein the compound of X '=COOH can change into wherein that X is the acid amides of the corresponding formula I of C (O) NR5R6 according to method well known in the art.COR wherein ₁The similar compound that is COOH can change into wherein COR ₁Be CONR ₅R ₆Compound.

The starting compound that is used for changing into The compounds of this invention and the existing functional group of intermediate according to method as herein described for example amino, sulfydryl, carboxyl and hydroxyl can be optionally with the preparation organic compound in GPF (General Protection False base commonly used protect.The amino of protection, to dredge base, carboxyl and hydroxyl be that those can change into free amino, dredge base, carboxyl and hydroxyl and can saboteur's structure or cause the group of other undesired side reaction under the condition of gentleness.

The purpose of introducing protecting group is to prevent that functional group and reactant from undesired reaction taking place under the condition of carrying out required chemical conversion.For concrete reaction; the selection of base and the protecting group of whether needing protection is well known to a person skilled in the art, it depend on claimed functional group character (hydroxyl, amino etc.), contain structure and the stability and the reaction conditions of this substituent molecule.

The method that satisfies the known protecting group of these conditions and introducing thereof and remove is recorded in; J.F.W.McOmie for example, " protecting group in the organic chemistry (Protective Groupsin Organic Chemistry) ", Plenum Press; London; New York, 1973, T.W.Greene; " protecting group in the organic synthesis (Protective Groups inOrganic Synthesis) "; Wiley, New York, 1991.

In reaction as herein described, the active functional group derivative of carboxylic acid represents, for example acid anhydrides (particularly mixed acid anhydride), carboxylic acid halides, acid azide, lower alkyl esters and activatory ester thereof.Mixed acid anhydride is the acid anhydrides of PIVALIC ACID CRUDE (25) preferably, or the low alkyl group of carbonic acid (ethyl, isobutyl-) half ester; Carboxylic acid halides is for example acyl chlorides or acylbromide etc.; The activatory ester is for example succinimido, phthaloyl imino or 4-nitro phenyl ester; Lower alkyl ester is for example methyl esters or ethyl ester etc.

Above-mentioned reaction is according to the method for routine, there are or do not exist thinner (preferably to the reactant inertia and can dissolve the thinner of this reactant), catalyzer, condensing agent or described other reagent and/or under inert atmosphere, in the temperature of low temperature, room temperature or rising (preferably be in or near the boiling point of solvent for use), under normal pressure or high pressure, carry out.Preferred solvent, catalyzer and reaction conditions are described in embodiment subsequently.

The present invention comprises that also the various of the inventive method change form, and wherein, the midbody product that can obtain in its any stage is as raw material and carry out subsequently step; Perhaps, under reaction conditions, form raw material on the spot; Perhaps, reactant is used with the form of its salt or the pure enantiomorph of optically-active.

Compound of the present invention and intermediate can also transform mutually according to known method.

The invention still further relates to new raw material and preparation method thereof.

According to selected raw material and method, new compound can be one of possible isomer or its mixture, for example, pure basically geometrical isomer (along or anti-), optically active isomer (enantiomorph), racemic modification or its mixture.Above-mentioned possible isomer or its mixture include within the scope of the invention.

Formed isomer mixture can become purified geometry or optically active isomer, diastereomer, racemic modification according to the physical chemistry differential liberation of its each composition, for example, and by the method for chromatogram and/or fractional crystallization.

The racemic modification of formed end product or intermediate can split into optically active enantiomorph by currently known methods, for example, it is separated with the acid or the alkali formation diastereoisomeric salt of opticity, discharges the acidity or the basic cpd of optically active then.Therefore, can the carboxylic acid intermediate be split into its optically active enantiomorph by for example fractional crystallization d-or 1-(α-Jia Jibianji amine, Cinchonidune, cinchonine, quinine, Quinidine, ephedrine, dehydroabietylamine, Bu Luxin or Strychnine)-salt.Racemic product can also be by chiral chromatography, for example use the high pressure liquid chromatography of chiral sorbent to split.

At last, compound of the present invention can obtain with the free form, perhaps, if there is salt forming group, obtains with the form of its salt.

Can be with acidic cpd of the present invention with pharmaceutically acceptable alkali, for example aqueous alkali metal hydroxide transforms salify, preferably ether or alcoholic solvent for example low-level chain triacontanol in the presence of carry out.Can with salt with ether for example ether from alcoholic solution, be precipitated out.Resulting salt can be by changing into free cpds with acid treatment.These and other salt also can be used for the resulting compound of purifying.

The The compounds of this invention that has base can change into acid salt, particularly pharmacologically acceptable salt.These salt can form with for example mineral acid such as sulfuric acid, phosphoric acid or haloid acid; Or with organic carboxyl acid (C for example unsubstituted or that replaced by halogen ₁-C ₄)-paraffinic acid such as acetate, saturated or undersaturated di-carboxylic acid such as oxalic acid, succsinic acid, toxilic acid or fumaric acid, hydroxycarboxylic acid such as oxyacetic acid, lactic acid, oxysuccinic acid, tartrate or citric acid, amino acid such as aspartic acid or L-glutamic acid form; Or with the organic sulfonic acid that does not replace or replace (for example being replaced) by halogen as (C ₁-C ₄)-alkylsulphonic acid (for example methylsulfonic acid) or aryl sulfonic acid form.The preferred salt that forms with hydrochloric acid, methylsulfonic acid and toxilic acid.

Consider the substantial connection between the compound of free cpds and salt form, when mentioning a kind of compound in this article, also comprise corresponding salt, condition is that this is possible or suits in this case.

Compound, comprise its salt, form that can also its hydrate obtains, and perhaps is included in other used in its crystallization solvent.

Pharmaceutical composition of the present invention is suitable for to Mammals, comprises people's enterally administering (for example oral or rectal administration), treats and Triiodothyronine imbalance diseases associated through skin and parenteral admin, for example thyroprivia and hyperthyroidism, obesity, osteoporosis, dysthymia disorders, particularly be used for treating and/or preventing the obstructive cardiovascular disorder relevant with hyperlipidemia and hyperlipoproteinemia, said composition contains the pharmaceutical active compounds of the present invention of significant quantity or the mixture of itself and one or more pharmaceutically acceptable carrier.

Pharmaceutical active compounds of the present invention can be used for producing pharmaceutical composition, and described pharmaceutical composition contains the pharmaceutical active compounds of significant quantity and is applicable to the vehicle of enteron aisle or parenteral application or the mixture of carrier.Preferred tablet and capsule, they contain activeconstituents and a) thinner, for example lactose, glucose, sucrose, N.F,USP MANNITOL, sorbyl alcohol, Mierocrystalline cellulose and/or glycine; B) lubricant, for example silicon-dioxide, talcum, stearic acid, its magnesium salts or calcium salt and/or polyoxyethylene glycol; For tablet, also contain c) tackiness agent, for example neusilin, starch paste, tragakanta, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone; As needs, also contain d) disintegrating agent, for example starch, agar, alginic acid or its sodium salt or effervescent mixture; And/or e) sorbent material, tinting material, seasonings and sweeting agent.Preferred aqueous isotonic solution of injectable composition or suspension, suppository is preferably used fatty emulsion or suspension preparation.Described composition can be aseptic and/or contain sanitas, stablizer, wetting agent or emulsifying agent, dissolution accelerator, is used to regulate assistant agents such as the salt of osmotic pressure and/or buffer reagent.In addition, they also can contain other medicative material.Described composition is according to the mixing of routine, granulation or coating method preparation, and contain have an appointment 0.1 to 75%, preferred about 1 to 50% activeconstituents.

Be used for containing the The compounds of this invention and the carrier of significant quantity through the suitable formulations that skin is used.Preferred carrier comprises that absorbable acceptable solvent is to help the skin by the host.Representational transcutaneous device is a bandage, it comprises back sheet, contain compound and optionally carrier bank, be used in a long time carrying the selective rate key-course of compound and device being fixed on instrument on the skin to host's skin with control and predetermined speed.

Be used for about 50 to 70kg mammiferous unitary dose and can contain 0.01mg to the 10mg activeconstituents of having an appointment.The dosage of active compound depends on kind, body weight, age and individual condition, form of medication and the used compound of warm blooded animal (Mammals).

Problem solved by the invention has provided the effective lipid-lowering agent that can reduce the mammalian plasma cholesterol levels.Compound of the present invention can be effectively and triiodothyronine (T ₃) center receptors bind (this is the symbol of ldl receptor activity to adjusted) and strengthen the LDL-cholesterol from the circulation removing.Therefore, compound of the present invention is particularly suitable for being used as hypocholesterolemic agents in Mammals, is used for always in the blood plasma treating the obstructive cardiovascular disorder relevant with hypercholesterolemia with prevention with the LDL-cholesterol levels by reducing.The invention still further relates to compound of the present invention in the purposes of preparation in the medicine, especially for treating the medicine of the obstructive cardiovascular disorder relevant with hypercholesterolemia with prevention by reducing total and LDL-cholesterol levels in the blood plasma.

Compound of the present invention also can reduce lipoprotein (a) level, therefore can be used for the treatment obstructive cardiovascular disorder relevant with Lp (a) with prevention.

Preferred the selectivity of the present invention of the unfavorable cardiac side effects relevant with Triiodothyronine to intend the Tiroidina lipid-lowering agent basically.

For example mouse, rat, dog, monkey or stripped organ pipe, tissue and prepared product thereof confirmed with Mammals during above-mentioned character was tested in vitro and in vivo.Described compound can be used outward with the form body of solution, preferred aqueous solutions; Use in the body by enteron aisle, parenteral, preferred intravenously for example carries out with the form of the suspension or the aqueous solution.External dosage can be from about 10 ^-7Mole is to 10 ^-11Volumetric molar concentration.Dosage is according to the difference of route of administration in the body, can be from about 0.1 to 1000mg/kg, preferred about 0.5 to 300mg/kg, preferably from about 1 to 100mg/kg.

Compound of the present invention can with triiodothyronine (T ₃) receptors bind, therefore can in Mammals, be used as the Triiodothyronine agonist.

With T ₃The external combination of center acceptor is measured according to following description:

According to the differential centrifugation (Methods in Enzymology 31:75, Part A, 1974) of descriptions such as Emmelot and change slightly, make rat liver nuclear and plasma membrane prepared product from Sprague Dawley (CD) rat (Charles River Labs.).To be further purified from the method that the nuclear part that 275 xg settlings obtain is described according to (J.Biol.Chem.250:4118,1975) such as Spindler.

By combining of the new test compounds of the methods analyst of (J.Biol.Chem.250:4118,1975) such as Spindler and nuclear.To examine under 22 ℃ and 0.3nM[ ¹²⁵I]-L-triiodothyronine (L-T ₃) insulation together.Use except containing nuclear and radioactivity L-T ₃Outside also contain the test compounds or the 3 μ M on-radiation L-T of various concentration ₃Test tube carry out parallel insulation.The latter is used for measuring non-specific binding.Reaction mixture with centrifugal 7 minutes of 800xg and after washing resulting settling, is measured and nuclear bonded radioactivity.Deduct non-specific binding amount (with excessive (3 μ M) on-radiation L-T ₃Be incubated back contained radioactivity in the nuclear settling together) record [ ¹²⁵I]-L-T ₃Specificity bonded amount.With the mapping method from specificity in conjunction with [ ¹²⁵I]-L-T ₃Record among the figure reciprocal to the various concentration of test compounds inhibition [ ¹²⁵I]-L-T ₃Specificity in conjunction with reaching the concentration (IC of 50% o'clock test compounds ₅₀).

Cholesterol-lowering activity is measured according to following being described in the rat:

At treatment first two weeks and in 7 days by a definite date treatment phase, make the male Sprague-Dawley rat (230-250g) (Taconic Farms) can be arbitrarily near water and high-cholesterol diet (1.5% cholesterol and 0.5% cholic acid).With the animal of grouping by gavage separately with carrier or the administration of test compounds continuous oral 7 days.After the last administration, with animal fasting blood sampling then in 18 hours.Blood sample is used to measure total cholesterol and LDL and HDL cholesterol concentration with centrifugal 10 minutes of 2500 rpm with preparation blood plasma.Separate out the back at LDL/VLDL and measure HDL value (Warnick and Albers, 1978).All samples is all used diagnostic kit, and (Sigma Chemical Co., St.Louis MO) analyze cholesterol by enzyme catalysis.Analysis is carried out on the automatic workstation of Bio-Mek.Separate out the LDL/VLDL part in the following way: branches such as 0.35mL blood plasma are added in the Eppendorf tube, to wherein adding 12 μ L 2M magnesium chlorides, 11.2 μ L heparin sodiums (PorcineIntestinal, 5000 units/mL) and 8.3 μ L physiological saline.Sample vortex vibration was placed on ice 15 minutes then, under 4 ℃ centrifugal 10 minutes then with 1300 rpm, then by the enzyme catalysis cholesterol in the clear liquid analytically.Multiply by the 1.09 HDL cholesterol concentrations that calculate diluent by cholesterol value with supernatant liquor.From total cholesterol, deduct the value that the HDL cholesterol calculates the LDL/VLDL cholesterol.

Cholesterol-lowering activity can also be assessed by the oral administration test compounds in the normal dog of the blood cholesterol of feeding conventional food according to the method described above in 5 days.

Decreasing cholesterol and Lp (a) activity can be measured in the normal Cynomolgus monkey of blood fat as follows:

Operating weight is bull and the female Cynomolgus monkey (Macacafascicularis) of 3-7kg.Animal is raised separately and fed with conventional monkey food (Purina 5047), and additional fresh fruit and vegetables.Each animal is all as self contrast, is one section and washes out the phase after dosage regimen each time.Test compounds is dissolved in ethanol, is infiltrated up in the fruit slurry oral administration then.Every day, to the animals administer test compounds once the treatment phase was 8 to 28 days.Obtaining blood sample behind the overnight fasting and when research finishes.From getting blood with the femoral vein of not obeying ataractic animal of mechanical means constraint and blood sample (3ml) being collected in the Vacutainer pipe (containing EDTA).With blood under 4 ℃ centrifugal 20 minutes with 2000 rpm.The plasma sample five equilibrium is preserved until analyzing down in-70 ℃ then.Measure the plasma concentration of total cholesterol (TC) and triglyceride level (TG) with commercial reagents box (Sigma Diagnostics) by enzymatic process.After separating out the lipoprotein that contains apoB, measure high density lipoprotein cholesterol (HDL-C) concentration.Since contain in the fasting blood plasma of the Cynomolgus monkey of edible food can the amount of ignoring vldl, therefore can calculate low density lipoprotein cholesterol (LDL-C) concentration by from TC, deducting HDL-C.Test is carried out in 96 hole titer plate, with its reading in micro plate spectrophotometer (Dynatech MR 5000).(Perlmmune Inc.) measures the plasma concentration of Lp (a), uses the test kit contrast and with reference to Lp (a) standard substance by commercial Lp (a) ELISA.Lp (a) ELISA adopts the monoclonal antibody of anti-lipophorin (a) to catch and adopts the polyclonal antibody of anti-apolipoprotein B to detect.This test is specific for Lp (a), can not measure free apo (a), apoB or Profibrinolysin.The influence that quantitatively is not subjected to apo (a) size to Lp (a).Lp (a) plasma concentration is represented with the milligram number of total Lp (a) material.The sample of each research is only analyzed once.

As example of the present invention, at T ₃Nuclear receptor in conjunction with the test in, the IC of the about 0.17nM of compound exhibits of embodiment 26 ₅₀Value, the IC of the about 0.13nM of compound exhibits of embodiment 28 ₅₀Value, the IC of the about 1.00nM of compound exhibits of embodiment 35 ₅₀Value, the IC of the about 0.04nM of compound exhibits of embodiment 39 ₅₀Value.In addition, the compound of described embodiment 26 can also significantly reduce serum cholesterol under the dosage in the every day of about 20 micrograms (μ g)/kg oral (rat) and about 10 μ g/kg oral (dog).In addition, with the compound of described embodiment 26 the every day of dosage treatment after 4 weeks, can make Lp (a) level of the normal Cynomolgus monkey of blood fat descend about 40% with 75 μ g/kg.

Following examples are to be used for illustrating of the present invention, and the present invention is not limited to this.Given temperature is degree centigrade.If not otherwise stated, all evaporations are all carried out under reduced pressure, preferably carry out between about 15 and 100 mmHg (=20-133 millibar).The structure of final product, intermediate and raw material is by conventional analytical procedure confirmation, for example trace analysis and spectroscopy feature (for example MS, IR, NMR).Used abbreviation is the routine abbreviation in this area.

Embodiment 1

N-{4-[3-(2,2-dimethyl propyl sulfamyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } oxaminic acid

A.3,5-dimethyl-4-(4 '-methoxyl group phenoxy group) oil of mirbane

With sodium hydride (NaH; 60% mineral oil dispersion liquid; 64.11g 1.603mol) suspension in 350mLN-methyl-2-pyrrolidone (NMP) is cooled to 0 ℃ of adding 4-methoxyphenol (208.4g, 1.679mol) solution in 30 minutes then.Mixture is warming up to room temperature (RT), after 30 minutes, disposable adding 4-chloro-3,5-dimethyl nitrobenzene (283.2g, 1.526mol; The method preparation of in EP580550, describing by Yokoyama etc.) and with reaction solution in 120 ℃ of heating 2 hours.Reaction solution is cooled to room temperature (RT) and water (1500ml) termination reaction.Suspension is cooled to 0 ℃, stirred 30 minutes, filter, wash filter cake with water vacuum-drying then.With crude product, ethyl acetate (EtOAc; 2100ml) and charcoal (42.6g) reflux, remove solid with the diatomite filtered while hot then.Filtrate decompression is concentrated into about 800mL, the suspension that obtains is cooled to 0 ℃ and stirred 30 minutes.Collect product by vacuum filtration, wash then with cold EtOAc that vacuum-drying obtains 3,5-dimethyl-4-(4 '-methoxyl group phenoxy group) oil of mirbane: 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) oil of mirbane

With the compound of title A, 3,5-dimethyl-4-(4 '-methoxyl group phenoxy group) oil of mirbane (16.4g, 60mmol), acetate (AcOH; 100ml) with 48% hydrobromic acid aqueous solution (HBr; Mixture 100ml) was in 120 ℃ of heating 16 hours.Mixture is cooled to room temperature, water (200mL) dilution, the product of separating out is collected in vacuum filtration, and water and hexane wash vacuum-drying then obtain 3,5-dimethyl-4-(4 '-hydroxyphenoxy) oil of mirbane: NMR (CDCl 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-hydroxy benzenesulfonic acid

With the compound of title B, 3,5-dimethyl-4-(4 '-hydroxyphenoxy) oil of mirbane (7.86g, 150mL methylene dichloride (CH 30.35mmol) ₂Cl ₂) (2.4ml 36.42mmol) at room temperature handles solution with chlorsulfonic acid.After 16 hours, reaction mixture is concentrated and resistates is dissolved in a small amount of methylene dichloride (about 5ml).Add salt solution (100mL) and separate out product, vacuum filtration is collected, water, hexane and ether (Et ₂O) wash vacuum-drying then and obtain 5-(2,6-dimethyl-4-nitrophenoxy)-2-hydroxyl-Phenylsulfonic 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) Phenylsulfonic acid, cesium salt

Compound with title C, 5-(2,6-dimethyl-4-nitrophenoxy)-2-hydroxyl-Phenylsulfonic acid (6.78g, 20mmol) at 100mL tetrahydrofuran (THF) (THF) and 50mL N, solution in the dinethylformamide (DMF) cesium carbonate (15.6g, 48mmol) and bromotoluene (7.1ml 60mmol) at room temperature handles, then in 75 ℃ of heating 48 hours.Reaction mixture is cooled to room temperature uses 1N aqueous hydrochloric acid (HCl then; 100ml) termination reaction is steamed then and is removed THF.The product of separating out, water, Et are collected in vacuum filtration ₂O, EtOAc and CH ₂Cl ₂Washing then, drying obtains 2-benzyloxy-5-(2,6-dimethyl-4-nitrophenoxy) Phenylsulfonic acid cesium salt: NMR (DMSO-d ₆) 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) benzene sulfonyl chloride

With the compound of title D, 2-benzyloxy-5-(2,6-dimethyl-4-nitrophenoxy)-Phenylsulfonic acid cesium salt (9.9g, DMF (the 3.1ml of 200mL dichloromethane solution 20mmol), 40mmol) handle, at room temperature in 30 minutes, add then oxalyl chloride (3.5ml, 40mmol).Reaction mixture is continued to stir 1 hour, use ether (200ml) dilution and water and salt water washing then, with anhydrous sodium sulphate (Na ₂SO ₄) drying concentrates then.Product is washed vacuum-drying then with ether (5ml) obtain 2-benzyloxy-5-(2,6-dimethyl-4-nitro-phenoxy group) benzene sulfonyl chloride: NMR (CDCl ₃) 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, the 2-dimethyl propyl) benzsulfamide

With the compound of title E, and 2-benzyloxy-5-(2,6-dimethyl-4-nitrophenoxy)-benzene sulfonyl chloride (1.12g, 20mL dichloromethane solution 2.5mmol) is used N-methylmorpholine (NMM successively; 550ml, 5mmol) (442ml 3.75mmol) at room temperature handles with neo-pentyl amine.After 6 hours, mixture is distributed between water and ethyl acetate, with organic solution 1N aqueous hydrochloric acid and salt water washing, with the concentrated then 2-benzyloxy-5-(2 that obtains of anhydrous sodium sulfate drying, 6-dimethyl-4-nitrophenoxy)-and N-(2, the 2-dimethyl propyl) benzsulfamide: 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-dimethyl phenoxy)-2-benzyloxy-N-(2, the 2-dimethyl propyl) benzsulfamide

With the compound of title F, and 2-benzyloxy-5-(2,6-dimethyl-4-nitrophenoxy)-N-(2, the 2-dimethyl propyl) benzsulfamide (1.22g, 2.45mmol) and palladium/activated carbon (10 wt%; 250mg) mixture in 40mL THF is at nitrogen atmosphere (H ₂, 1atm) stirred 8 hours down.Remove catalyzer with the diatomite vacuum filtration, concentrate with the THF washing and with filtrate and the washings that merges.Resistates is suspended in the methylene dichloride, and product is collected in vacuum filtration, with washed with dichloromethane then drying obtain 5-(4-amino-2,6-dimethyl-phenoxy group)-2-benzyloxy-N-(2, the 2-dimethyl propyl) benzsulfamide: 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-dimethyl propyl sulfamyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl }-oxaminic acid

Compound with title G, 5-(4-amino-2, the 6-dimethyl phenoxy)-2-benzyloxy-N-(2, the 2-dimethyl propyl) benzsulfamide (750mg, 1.98mmol) 10mL THF solution be cooled to 0 ℃ and use NMM (545ml then successively, 4.96mmol) and ethyl oxalyl chloride (442ml, 3.96mmol) processing.Reaction solution is warming up to room temperature and water termination reaction after 1 hour.Mixture is distributed between water and ethyl acetate, organic solution with 1N hydrochloric acid and salt water washing, is concentrated then with anhydrous sodium sulfate drying.Resistates is dissolved in 10mL THF, with 1N lithium hydroxide (LiOH; 1.8ml, 1.8mmol) at room temperature handle.After 1 hour, add in the ethyl acetate, use the salt water washing, concentrate then with anhydrous sodium sulfate drying with 1N hydrochloric acid termination reaction and with product.Successively with hexane and ether development, vacuum-drying obtains N-{4-[3-(2,2-dimethyl propyl sulfamyl)-4-hydroxyphenoxy then with product]-3, the 5-3,5-dimethylphenyl } oxaminic 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] ^-Can make following compound according to similar approach.

??????????6 ????R＝H，R6＝p- ??????MeOC ₆H ₄-	(DMSO-d ₆)：1.90(s，6H)，3.67(s，3H)，6.68 (d，1H，J＝3)，6.73(d，2H，J＝9.00)，6.89-6.99 (m，4H)，7.54(s，2H)，9.58(s，1H)，10.45(s， 1H)，10.64(s，1H)	1209， 1475， 1514， 1688	485[M-1] ^-
??????????6 ????R＝H，R6＝p- ??????MeOC ₆H ₄-		1209， 1475， 1514， 1688	485[M-1] ^-	?????????7 ????R5＝H，R6＝p- ??????FC ₆H ₄CH ₂-	(DMSO-d ₆)：2.02(s，6H)，4.03(d，2H，J＝6.4)， 6.80-6.89(m，3H)，7.01(t，2H，J＝4.0)，7.22 (dd，2H，J＝6.3，8.7)，7.56(s，2H)，7.77(t，1H， J＝6.4)，10.32(s，1H)，10.64(s，1H)	1224， 1481， 1695	487[M-1] ^-
?????????8 ??R5＝Me-，R6＝Ph-	(CDCl ₃)：1.96(s，6H)，3.14(s，3H)，6.54(d， 1H，J＝2.4)，6.84-6.85(m，2H)，6.88-7.03(m， 2H)，7.20-7.28(m，5H)	1209， 1230， 1481， 1691	469[M-1] ^-	?????????7 ????R5＝H，R6＝p- ??????FC ₆H ₄CH ₂-		1224， 1481， 1695	487[M-1] ^-
?????????8 ??R5＝Me-，R6＝Ph-		1209， 1230， 1481， 1691	469[M-1] ^-	?????????9 ??R5＝H，R6＝n-Pr-	(CDCl ₃)：0.87(t，3H，J＝7.5)，1.38-1.56(m， 2H)，2.11(s，6H)，2.94(app?q，2H，J＝7.5)， 5.0(t，1H，J＝7.5)，6.84(d，1H，J＝3)，7.0(d， 1H，J＝9)，7.08(dd，1H，J＝9，3)，7.32(s， 2H)，8.44(br?s，1H)，9.0(br?s，1H)	1214， 1485， 1693， 1751	421[M-1] ^-440 [M+NH ₄] ⁺
?????????10 ??R5＝H，R6＝i-Pr-	(DMSO-d ₆)：0.95(d，6H，J＝7.5)，2.02(s，6H)， 3.2-3.31(m，1H)，6.86(br?s，1H)，6.97(br?s， 2H)，7.06(d，1H，J＝7.5)，7.57(s，2H)，10.32 (br?s，1H)，10.64(br?s，1H)	1209， 1485， 1698， 1742	421[M-1] ^-	?????????9 ??R5＝H，R6＝n-Pr-		1214， 1485， 1693， 1751	421[M-1] ^-440 [M+NH ₄] ⁺
?????????10 ??R5＝H，R6＝i-Pr-		1209， 1485， 1698， 1742	421[M-1] ^-	?????????11 ??R5＝H，R6＝n-Bu-	(DMSO-d ₆)：0.72(t，3H，J＝7.5)，1.1-1.35(m， 4H)，2.03(s，6H)，2.76(app?q，2H，J＝7.5)， 6.87(br?s，1H)，6.97(br?s，2H)，7.1(t，1H，J＝ 7.5)，7.58(s，2H)	1321， 1481， 1691	435[M-1] ^-454 [M+NH ₄] ⁺
?????????12 ??R5＝H，R6＝i-Bu-	(DMSO-d ₆)：0.75(d，6H，J＝8.2)，1.49-1.62 (m，1H)，2.03(s，6H)，2.55(app?t，2H，J＝6.8)， 6.85(br?s，1H)，6.96(br?s，2H)，7.17(t，1H，J＝ 6.8)，7.57(s，2H)，10.25(br?s，1H)，10.61(br?s， 1H)	1209， 1481， 1693， 1762	435[M-1] ^-	?????????11 ??R5＝H，R6＝n-Bu-		1321， 1481， 1691	435[M-1] ^-454 [M+NH ₄] ⁺
?????????12 ??R5＝H，R6＝i-Bu-		1209， 1481， 1693， 1762	435[M-1] ^-	?????????13 ??R5＝H，R6＝t-Bu-	(DMSO-d ₆)：1.02(s，9H)，2.03(s，6H)，6.81- 7.02(m，4H)，7.56(s，2H)，10.20(br?s，1H)， 10.61(br?s，1H)	1204， 1486， 1645， 1754	435[M-1] ^-

Embodiment 23

N-{4-[3-(4-fluorophenyl sulfamyl)-4-hydroxybenzene sulfenyl]-3,5 3,5-dimethylphenyls } oxaminic acid

Title compound prepares according to mode similar to Example 1: NMR (DMSO-d ₆) 2.21 (s, 6H), 6.87 (d, 1H, J=8.3), 6.95-7.12 (m, 6H), 7.65 (s, 2H), 9.99 (s, 1H), 10.73 (s, 1H), 10.97 (s, 1H); IR (KBr) 1163,1506,1690; ESI-MS 489[M-1] ^-, 508[M+NH ₄] ⁺

Embodiment 24

N-{4-[3-(4-fluorophenyl sulfamyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid

Title compound prepares according to mode similar 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] ⁺

Embodiment 25

N-{4-[3-(4-fluorophenyl sulfamyl)-4-hydroxyphenoxy]-the 3-aminomethyl phenyl } oxaminic acid

Title compound prepares according to mode similar to Example 1: NMR (DMSO-d ₆) 2.06 (s, 3H), 6.65 (d, 1H, J=8.8), 6.92-7.18 (m, 7H), 7.55 (m, 7H), 7.55 (dd, 1H, J=8.8,2.4), 7.70 (d, 1H, J=2.4), 9.98 (s, 1H), 10.69 (s, 1H), 10.72 (s, 1H), 10.75 (s, 1H); IR (KBr) 1326,1487,1506,1692; ESI-MS 457[M-1] ^-

Embodiment 26

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } oxaminic acid

A.4-fluorobenzene-sulfinic acid

With 4-fluorobenzene SULPHURYL CHLORIDE (2g, 50mL THF 10.28mmol) (from the Na-benzophenone, distilling) solution be cooled to 0 ℃ add then in batches sodium borohydride (1.9g, 51.4mmol).The reaction solution stirring was warming up to room temperature in 2 hours then, after 2 hours, water (5ml) termination reaction.Steaming desolventizes, and adds 6N hydrochloric acid with the aqueous residue acidifying.Product is added in the ethyl acetate, use the salt water washing, concentrate then with anhydrous sodium sulfate drying and obtain 4-fluorobenzene-sulfinic 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-(4-fluorobenzene alkylsulfonyl) benzene-1, the 4-glycol

With the compound of title A, and 4-fluorobenzene-sulfinic acid (3g, 10mL aqueous solution 18.75mmol) at room temperature joins 1, and (1.93g is in 30mL dichloromethane solution 17.86mmol) for the 4-benzoquinones.After 4 hours, the product separate out is collected in vacuum filtration, with cold washed with dichloromethane then vacuum-drying obtain 2-(4-fluorobenzene alkylsulfonyl) benzene-1,4-glycol: 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, 1 H); ESI-MS 267[M-1] ^-

C.4-(2,6-dimethyl-4-nitrophenoxy)-2-(4-fluorobenzene alkylsulfonyl) phenol

With the compound of title B, 2-(4-fluorobenzene alkylsulfonyl) benzene-1, the 4-glycol (1.2g, 4.48mmol) in 0 ℃ next time property join NaH (60% mineral oil dispersion liquid; 0.39g, in 15mL NMP suspension 9.86mmol).Mixture is warming up to room temperature, after 30 minutes, adds 4-chloro-3, (1g 5.38mmol) and with reaction solution heated 1 hour in 120 ℃ the 5-dimethyl nitrobenzene.Reaction solution is cooled to room temperature and uses 1N aqueous hydrochloric acid termination reaction.Mixture is distributed between water and ethyl acetate,, concentrate then with anhydrous sodium sulfate drying with organic solution water and salt water washing.Through silica gel chromatography (eluent; EtOAc/ hexane-1/2/1/1) obtains 4-(2,6-dimethyl-4-nitrophenoxy)-2-(4-fluoro-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-dimethyl phenoxy)-2-(4-fluorobenzene alkylsulfonyl) phenol

With the compound of title C, and 4-(2,6-dimethyl-4-nitrophenoxy)-2-(4-fluoro-benzenesulfonyl) phenol (0.69g, 1.65mmol) and palladium/activated carbon (10wt%; 69mg) mixture in 10mL ethanol and 10mL methylene dichloride is at nitrogen atmosphere (H ₂, 1atm) stirred 6 hours down.Remove catalyzer with the diatomite vacuum filtration; mixture washing with 1/1 ethanol and methylene dichloride; the filtrate and the concentrated vacuum-drying then of washings that merge are obtained 4-(4-amino-2,6-dimethyl phenoxy)-2-(4-fluorobenzene alkylsulfonyl)-phenol: NMR (DMSO-d ₆) 1.93 (s, 6H), 4.92 (s, 2H), 6.34 (s, 2H), 6.85 (d, 1H, J=9), 7.00 (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-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } ethyl oxamide

With the compound of title D, (0.64g, 1.65mmol) mixture with the 2mL oxalic acid diethyl ester heated 3 hours in 180 ℃ 4-(4-amino-2,6-dimethyl phenoxy)-2-(4-fluorobenzene alkylsulfonyl) phenol.With reaction solution be cooled to room temperature then vacuum steam to remove oxalic acid diethyl ester.Through silica gel chromatography (eluent; EtOAc/ hexane-1/3? 2/3) obtain N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } ethyl oxamide: 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), 7.87-7.93 (m, 2H), 8.87 (br s, 1H); ESI-MS 486[M-1] ^-

F.N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } oxaminic acid

With the compound of title E, N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyl-phenoxy group]-3, the 5-3,5-dimethylphenyl } ethyl oxamide (773mg, 15mL ethanolic soln 1.58mmol) 1N aqueous sodium hydroxide solution (NaOH; 4.75ml, 4.75mmol) at room temperature handle.After 1 hour, add in the ethyl acetate, use the salt water washing, concentrate then with anhydrous sodium sulfate drying with 1N aqueous hydrochloric acid (5.5ml) termination reaction and with product.Product is developed vacuum-drying then with ether obtains N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } oxaminic acid: NMR (DMSO-d ₆) 2.06 (s, 6H), 6.88 (d, 1H, J=9), 7.03 (dd, 1H, J=9,3), 7.13 (d, 1H, J=3), 7.43 (app t, 2H, J=9), 7.61 (s, 2H), 7.94 (dd, 2H, J=9,5), 10.5 (s, 1H), 10.69 (s, 1H); IR (KBr) 1240,1481,1685,1764; ESI-MS 458[M-1] ^-

Make following compound in a comparable manner.

??????33 ??R4＝n-Bu-	(DMSO-d ₆)：0.81(t，3H，J＝7.2)，1.24-1.36(m， 2H)，1.41-1.51(m，2H)，2.04(s，6H)，3.37(t， 2H，J＝7.2)，6.88(d，1H，J＝3)，7.08(dd，1H， J＝9，3)，7.15(d，1H，J＝3)，7.00-7.10(m， 2H)，7.57(s，2H)，10.67(s，2H)	1205， 1488， 1694	420[M-1] ^-439 [M+NH ₄] ⁺
??????33 ??R4＝n-Bu-		1205， 1488， 1694	420[M-1] ^-439 [M+NH ₄] ⁺	??????34 ??R4＝i-Pr-	(DMSO-d ₆)：1.11(d，6H，J＝7)，2.03(s，6H)， 3.66-3.75(m，1H)，6.88(d，1H，J＝3)，)，7.02 (d，1H，J＝3)，7.08(dd，1H，J＝9，3)，7.57(s， 2H)，10.65(s，2H)	1229， 1354， 1480， 1688， 1761	406[M-1] ^-425 [M+NH ₄] ⁺

Embodiment 35

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } malonamic acid

Title compound is according to preparing with embodiment 26 similar modes: 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 472[M-1] ^-

Embodiment 36

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } succinamic acid

Title compound is according to preparing with embodiment 26 similar modes: NMR (DMSO-d ₆) 2.04 (s, 6H), 2.50-2.56 (m, 4H), 6.87 (d, 1H, J=9), 7.01 (dd, 1H, J=9,3), 7.12 (d, 1H, J=3), 7.39-7.45 (m, 4H), 7.93 (dd, 2H, J=8.8,5.2), 9.93 (s, 1H), 10.5 (br s, 1H), 12.1 (s, 1H); IR (KBr) 1480,1659,1717; ESI-MS 486[M-1] ^-

Embodiment 37

3-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3,5-3,5-dimethylphenyl amino } propionic acid

Title compound is according to preparing with embodiment 26 similar modes: 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] ^-

Embodiment 38

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-the 3-aminomethyl phenyl } oxaminic acid

Title compound is according to preparing with embodiment 26 similar modes: 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) 1234,1495,1697; ESI-MS 444[M-1] ^-

Embodiment 39

N-{3,5-two bromo-4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy] phenyl } oxaminic acid

Title compound is according to preparing with embodiment 26 similar modes: 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] ^-

Embodiment 40

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } oxamide

Title compound is according to preparing with embodiment 26 similar modes: NMR (DMSO-d ₆) 2.06 (s, 6H), 6.88 (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 497[M-1] ^-, 475[M+NH ₄] ⁺

Embodiment 41

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl]-N '-propyl group-oxamide

Title compound is according to preparing with embodiment 26 similar modes: ES-MS 499[M-1] ^-, 518[M+NH ₄] ⁺

Embodiment 42

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl }-N ' sec.-propyl-oxamide

Embodiment 43

N-butyl-N '-and 4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl }-oxamide

Title compound is according to preparing with embodiment 26 similar modes: ES-MS 513[M-1] ^-, 515[M+1] ⁺, 532[M+NH ₄] ⁺

Embodiment 44

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl }-N '-(2-methoxy ethyl) oxamide

Title compound is according to preparing with embodiment 26 similar modes: ES-MS 517[M+1] ⁺

Embodiment 45

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl }-2-morpholine-4-base-2-oxo ethanamide

Title compound is according to preparing with embodiment 26 similar modes: ES-MS 527[M-1] ^-, 529[M+1] ⁺, 546[M+NH ₄] ⁺Embodiment 46

N-{4-[4-hydroxyl-3-(piperidines-1-carbonyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid

A.5-(2,6-dimethyl-4-nitrophenoxy)-2-(2-methoxy ethoxy methoxyl group) phenylformic acid 2-methoxy ethoxy methyl esters

With NaH (60% mineral oil dispersion liquid; 1.32g 50mL NMP suspension 33mmol) is cooled to 0 ℃ of disposable then adding 2, and the 5-resorcylic acid (1.54g, 10mmol).Mixture is warming up to room temperature, after 30 minutes, disposable adding 4-chloro-3, (2.41g 13mmol) and with reaction solution heated 3 hours in 120 ℃ 5-dimethyl-oil of mirbane.Reaction solution is cooled to room temperature and add 2-methoxy ethoxy Methochloride (2.85ml, 25mmol).Stir after 30 minutes, mixture is poured in the water and with product added in the ether.With organic solution salt water washing, concentrate then with anhydrous sodium sulfate drying.Through silica gel chromatography (eluent; EtOAc/ hexane-1/2 → 3/2) obtains 5-(2,6-dimethyl-4-nitrophenoxy)-2-(2-methoxy ethoxy methoxyl group) phenylformic acid 2-methoxy ethoxy methyl esters: 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-dimethyl phenoxy)-2-(2-methoxy ethoxy methoxyl group) phenylformic acid 2-methoxy ethoxy methyl esters

With the compound of title A, and 5-(2,6-dimethyl-4-nitrophenoxy)-2-(2-methoxyl group-oxyethyl group methoxy base) phenylformic acid 2-methoxy ethoxy methyl esters (3.2g, 6.68mmol) and palladium/activated carbon (10wt%; 320mg) (H2 1atm) stirred 3 hours down the mixture in the 50mL ethyl acetate in nitrogen atmosphere.Remove catalyzer with the diatomite vacuum filtration, wash with ethyl acetate, the filtrate and the concentrated vacuum-drying then of washings that merge are obtained 5-(4-amino-2,6-dimethyl phenoxy)-2-(2-methoxy ethoxy methoxyl group) phenylformic acid 2-methoxyl group-oxyethyl group methyl esters: NMR (CDCl ₃) 2.07 (s, 6H), 3.37 (s, 3H), 3.40 (s, 3H), 3.52-3.62 (m, 4H), 3.83-3.92 (m, 4H), 5.26 (s, 2H), 5.52 (s, 2H), 6.60 (s, 2H), 6.80 (dd, 1H, J=8.3,3), 7.13 (d, 1H, J=8.3), 7.24 (d, 1H, J=3).C.5-[4-(oxyethyl group oxalyl group amino)-2, the 6-dimethyl phenoxy]-2 hydroxybenzoic acid

Compound with title B, 5-(4-amino-2, the 6-dimethyl phenoxy)-2-(2-methoxyl group-oxyethyl group methoxy base) phenylformic acid 2-methoxy ethoxy methyl esters (2.83g, 6.3mmol) 20mL THF solution be cooled to 0 ℃ and use NMM (2.1ml then successively, 18.9mmol) and ethyl oxalyl chloride (0.915ml, 8.19mmol) processing.After 15 minutes, mixture is distributed between ethyl acetate and water,, concentrate then with anhydrous sodium sulfate drying with organic solution salt water washing.Resistates is dissolved in 30mL ethanol adds 20mL 6N hydrochloric acid then.With mixture stirring at room 16 hours, remove ethanol then under reduced pressure.With resistates water (100ml) dilution, solid is collected in vacuum filtration, washes with water dry then.Obtain 5-[4-(oxyethyl group oxalyl group amino)-2,6-dimethyl phenoxy with the acetonitrile recrystallization]-2 hydroxybenzoic acid: NMR (DMSO-d ₆) 1.31 (t, 3H, J=7), 2.06 (s, 6H), 4.30 (q, 2H, J=7), 6.88-6.97 (m, 2H), 7.08 (dd, 1H, J=9,3), 7.54 (s, 2H), 10.7 (s, 1H).D.N-{4-[4-hydroxyl-3-(piperidines-1-carbonyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid

With the compound of title C, 5-[4-(oxyethyl group oxalyl group amino)-2,6-dimethyl phenoxy]-2 hydroxybenzoic acid (37mg; 0.1mmol) 1mL DMF solution with NMM (55 μ L; 0.5mmol) and 1, (32mg 0.2mmol) at room temperature handles 1 '-carbonyl dimidazoles.Reaction mixture in 60 ℃ of heating 1 hour, is cooled to room temperature then and adds piperidines (24 μ L), 0.24mmol).After 16 hours, (333 μ L 0.5mmol) handle with the 1.5N LiOH aqueous solution with reaction solution.Mixture was stirred 30 minutes, use trifluoroacetic acid (TFA then; 100 μ L) termination reaction.Product is passed through HPLC purifying (moving phase; Acetonitrile-water contains 0.1% trifluoroacetic acid) obtain N-{4-[4-hydroxyl-3-(piperidines-1-carbonyl) phenoxy group]-3,5 3,5-dimethylphenyls } oxaminic acid: NMR (DMSO-d ₆) 1.34-1.63 (m, 6H), 2.06 (s, 6H), 3.30 (br s, 4H), 6.36 (d, 1H, J=2.3), 6.67 (dd, 1H, J=8.3,2.3), 6.80 (d, 1H, J=8.3), 7.53 (s, 2H), 9.38 (br s, 1H), 10.6 (s, 1H); ESI-MS 413[M+1] ⁺

Embodiment 47

N-{4-[4-hydroxyl-3-(morpholine-4-carbonyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid

Title compound is according to preparing with embodiment 46 similar modes: ESI-MS 415[M+1] ⁺

Embodiment 48

N-[4-(3-cyclohexyl carboxyamide base-4-hydroxyphenoxy)-3, the 5-3,5-dimethylphenyl] oxaminic acid

Title compound is according to preparing with embodiment 46 similar modes: ESI-MS 427[M+1] ⁺Embodiment 49

N-{4-[4-hydroxyl-3-(2-methoxy ethyl formamyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid

Title compound is according to preparing with embodiment 46 similar modes: ESI-MS 403[M+1] ⁺

Embodiment 50

N-{4-[4-hydroxyl-3-(2-morpholine-4-base-ethylamino formyl radical) phenoxy group]-3,5 3,5-dimethylphenyls }-oxaminic acid

Title compound is according to preparing with embodiment 46 similar modes: ESI-MS 458[M+1] ⁺

Embodiment 51

N-{4-[4-hydroxyl-3-(pyridin-3-yl formamyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid

Title compound is according to preparing with embodiment 46 similar modes: ESI-MS 422[M+1] ⁺

Embodiment 52: example of formulations: can contain the 100mg active substance according to following description preparation; N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy for example]-3, the 5-3,5-dimethylphenyl } hard gelatin capsule of oxaminic acid: form (1000 capsules) activeconstituents 100.0g lactose 250.0g Microcrystalline Cellulose 30.0g sodium lauryl sulphate 2.0g Magnesium Stearate 8.0g

Is that the sieve of 0.2mm joins in the freeze dried activeconstituents with sodium lauryl sulphate by size of mesh.With two kinds of composition thorough mixing.Being the sieve adding lactose of 0.6mm then by size of mesh, is the sieve adding Microcrystalline Cellulose of 0.9mm subsequently by size of mesh.Then these compositions are continued to mix 10 minutes.Be the sieve adding Magnesium Stearate of 0.8mm at last by size of mesh.Continue to mix after 3 minutes, the resulting preparation of 390mg is filled in No. 0 hard gelatin capsule.

Claims

1. the compound or pharmaceutically acceptable salt thereof of following formula

Wherein

W is O, S, S (O) or S (O) ₂

X is-SR4 ,-S (O) R4 ,-S (O) ₂R4 or-S (O) ₂NR5R6; Perhaps X be positioned at 3 '-, 4 '-or 5 '-position-C (O) NR5R6;

Y is O or H ₂

R is hydrogen, halogen, trifluoromethyl, low alkyl group or cycloalkyl;

R2 is hydrogen, halogen or alkyl;

R3 is halogen or alkyl;

N represents 0 or 1 to 4 integer.

2. the compound of claim 1, condition be, when X be-during C (O) NR5R6, Z is not a hydrogen.

3. claim 1 or 2 described formula I compound or pharmaceutically acceptable salt thereofs, wherein

W is O or S;

Y is O or H ₂

Z is hydrogen or hydroxyl;

R is a hydrogen;

R2 is hydrogen, halogen or low alkyl group;

R3 is halogen or low alkyl group;

N represents 0,1 or 2.

4. claim 1 or 2 compound, this compound is a following formula: compound;

Wherein

W is O or S;

X is-SR4 ,-S (O) R4 ,-S (O) ₂R4 ,-S (O) ₂NR5R6 or-C (O) NR5R6;

Y is O or H ₂

R1 is hydroxyl, lower alkoxy or aryloxy;

R2 is hydrogen, halogen or low alkyl group;

R3 is halogen or low alkyl group;

N represents 0,1 or 2;

Or its pharmacologically acceptable salt.

5. claim 1 or 2 compound, this compound is a following formula: compound:

Wherein

X is-S (O) ₂R4 ,-S (O) ₂NR5R6 or-C (O) NR5R6;

Z is hydroxyl, lower alkane acyloxy or lower alkoxy;

R1 is hydroxyl or lower alkoxy;

R2 and R3 are low alkyl groups;

R4 is an aryl;

R5, R6 and R7 are alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or the heteroaralkyl that hydrogen, selectivity replace independently of one another; Perhaps to lump together be optionally by O, S, S (O), S (O) for R5 and R6 ₂Or the alkylidene group of NR7 interruption, the nitrogen-atoms that described alkylidene group is connected with them lumps together and forms 5 to 7 yuan of rings; Described ring optionally contains another heteroatoms that is selected from oxygen, nitrogen and sulphur;

Or its pharmacologically acceptable salt.

6. following formula: compound, its pharmaceutically useful prodrug ester and pharmacologically acceptable salt thereof:

Wherein

X is-S (O) ₂R4 or-S (O) ₂NR5R6;

R4 is a monocyclic aryl;

7. the compound of claim 6, wherein X is S (O) ₂R4 and R4 are the phenyl that is optionally replaced by low alkyl group, halogen, lower alkoxy or trifluoromethyl; Its pharmacologically acceptable salt or its pharmaceutically useful prodrug ester.

8. the compound of claim 1, described compound is selected from:

N-{4-[3-(2,2-dimethyl propyl sulfamyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-[4-(4-hydroxyl-3-phenyl sulfamoyl phenoxyl)-3, the 5-3,5-dimethylphenyl] oxaminic acid;

N-{4-[3-(4-fluorophenyl sulfamyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-{3-(2-fluorophenyl sulfamyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-[3-(3-fluorophenyl sulfamyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-[4-hydroxyl-3-(4-p-methoxy-phenyl sulfamyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-[3-(4-luorobenzyl sulfamyl)-4-hydroxyl-phenoxy group]-3,5-3,5-dimethylphenyl oxaminic acid;

N-{4-[4-hydroxyl-3-(aminomethyl phenyl sulfamyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-[4-(4-hydroxyl-3-propyl group sulfamyl phenoxy group)-3, the 5-3,5-dimethylphenyl] oxaminic acid

N-[4-(4-hydroxyl-3-sec.-propyl sulfamyl phenoxy group)-3, the 5-3,5-dimethylphenyl] oxaminic acid;

N-[4-(3-butyl sulfamyl-4-hydroxyphenoxy)-3, the 5-3,5-dimethylphenyl] oxaminic acid

N-[4-(4-hydroxyl-3-isobutyl-sulfamyl phenoxy group)-3, the 5-3,5-dimethylphenyl] oxaminic acid;

N-[4-(3-tertiary butyl sulfamyl-4-hydroxyphenoxy)-3, the 5-3,5-dimethylphenyl] oxaminic acid;

N-[4-(3-cyclohexyl sulfamyl-4-hydroxyphenoxy)-3, the 5-3,5-dimethylphenyl] oxaminic acid;

N-[4-(3-dimethylamino alkylsulfonyl-4-hydroxyphenoxy)-3, the 5-3,5-dimethylphenyl] oxaminic acid;

N-{4-[4-hydroxyl-3-(tetramethyleneimine-1-alkylsulfonyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-[4-hydroxyl-3-(piperidines-1-alkylsulfonyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-[4-hydroxyl-3-(2-methoxy ethyl sulfamyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-[4-hydroxyl-3-(morpholine-4-alkylsulfonyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-[3-(dioxo parathiazan-4-alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl) oxaminic acid;

N-{4-[4-hydroxyl-3-(pyridin-3-yl sulfamyl) phenoxy group]-3, the 5-3,5-dimethylphenyl) oxaminic acid;

N-{4-[4-hydroxyl-3-(1-methyl-6-oxo-1,6-dihydropyridine-3-base sulfamyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-[3-(4-fluorophenyl sulfamyl)-4-hydroxybenzene sulfenyl]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-[3-(4-fluorophenyl sulfamyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-[3-(4-fluorophenyl sulfamyl)-4-hydroxyphenoxy]-the 3-aminomethyl phenyl } oxaminic acid;

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-[4-(3-benzenesulfonyl-4-hydroxyphenoxy)-3, the 5-3,5-dimethylphenyl] oxaminic acid;

N-{4-[3-(4-chlorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-[4-hydroxyl-3-(toluene-4-alkylsulfonyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-[4-hydroxyl-3-(4-anisole alkylsulfonyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-[4-hydroxyl-3-(4-trifluoromethyl benzenesulfonyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-[4-(4-hydroxyl-3-methylsulfonyl phenoxy group)-3, the 5-3,5-dimethylphenyl] oxaminic acid;

N-{4-[3-(butane-1-alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-[4-hydroxyl-3-(propane-2-alkylsulfonyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } malonamic acid;

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } succinamic acid;

3-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3,5-3,5-dimethylphenyl amino } propionic acid;

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-the 3-aminomethyl phenyl } oxaminic acid;

N-{3,5-two bromo-4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy] phenyl } oxaminic acid;

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl } oxamide;

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl }-N '-propyl group-oxamide;

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl }-N '-sec.-propyl-oxamide;

N-butyl-N '-and 4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl }-oxamide;

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl }-N '-(2-methoxy ethyl) oxamide;

N-{4-[3-(4-fluorobenzene alkylsulfonyl)-4-hydroxyphenoxy]-3, the 5-3,5-dimethylphenyl }-2-morpholine-4-base-2-oxo ethanamide;

N-{4-[4-hydroxyl-3-(piperidines-1-carbonyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-[4-hydroxyl-3-(morpholine-4-carbonyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-[4-(3-cyclohexyl carboxyamide base-4-hydroxyphenoxy)-3, the 5-3,5-dimethylphenyl] oxaminic acid;

N-{4-[4-hydroxyl-3-(2-methoxy ethyl formamyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

N-{4-[4-hydroxyl-3-(2-morpholine-4-base-ethylamino formyl radical) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid; With

N-{4-[4-hydroxyl-3-(pyridin-3-yl formamyl) phenoxy group]-3, the 5-3,5-dimethylphenyl } oxaminic acid;

Or its pharmacologically acceptable salt.

9. any described compound is used to prepare the purposes of medicine in the claim 1 to 8, wherein, described medicine can be used for prevention and treatment and Triiodothyronine imbalance diseases associated, be used to prevent the obstructive cardiovascular disorder relevant with hyperlipidemia and hyperlipoproteinemia with treatment, be used for prevention and treatment thyroprivia and hyperthyroidism, obesity, osteoporosis and dysthymia disorders, be used to reduce total blood plasma cholesterol level and LDL-cholesterol levels and be used for prevention and treatment atherosclerosis and coronary heart disease.

10. the pharmaceutical composition that contains any described compound and pharmaceutically acceptable carrier in the claim 1 to 8 for the treatment of significant quantity.