GB2374009A - Method of treating hair loss - Google Patents

Abstract

Method of treating hair loss in a mammal which comprises administering a compound of the formula <EMI ID=1.1 HE=27 WI=92 LX=654 LY=782 TI=CF> <PC>in which W is O, S, S(O) or S(O)<SB>2</SB>; X is -SR4, -S(O)R4, or -S(O)<SB>2</SB>R4, -S(O)<SB>2</SB>NR5R6; or X is - C(O)NR5R6 provided that -C(O)NR5R6 is located at the 3', 4' or 5' position; Y is O or H<SB>2</SB>; 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, heteroaryloxy, aralkyloxy, cycloalkoxy, heteroaralkoxy or -NR5R6; R2 is hydrogen, halogen, trifluoromethyl, cyano or alkyl; R3 is halogen, trifluoromethyl, cyano 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)<SB>2</SB> 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; or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a said compound.

Description

METHOD OF TREATING HAIR LOSS Summary of the Invention The present invention relates to the treatment of hair loss (baldness) using compounds of formula I

in which W is 0, S, S (O) or S (0) 2 ;

X is-SR4,-S (0) R4,-S (0) 2R4, or-S (0) 2NR5R6 ; or X is-C (0) NR5R6 provided that -C (O) NR5R6is located at the 3'-, 4-or 5'-position ; Y is 0 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, heteroaryloxy, aralkoxy,

cycloalkoxy, heteroaralkoxy or-NR5R6 ; R2 is hydrogen, halogen, trifluoromethyl, cyano or alkyl ; R3 is halogen, trifluoromethyl, cyano 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 alkylen optionally interrupted by 0, S, S (O), S (0) 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 ; and pharmaceutically acceptable salts thereof ; or using pharmaceutical compositions comprising said compounds.

As used herein the term treatment includes prevention.

Detailed Description of the Invention The present invention provides for treating hair loss in mammals, e. g. , reversing hair loss and/or promoting hair growth using compounds defined herein and pharmaceutical compositions comprising such compounds. The class of compounds is disclosed in patent documents WO 0051971, published September 8,2000 and WO 00/58279, published October 5,2000, as thyromimetic agents.

Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances either individually or as part of a larger group).

The term"optionally substituted alkyl" refers to unsubstituted or substituted straight or branched chain hydrocarbon groups having 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4, 4-dimethylpenthyl, octyl and the like. Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more (e. g. , two or three) of the following groups: halo, lower alkenyl, hydroxy, cycloalkyl, alkanol, alkoxy, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, dialkylaminocarbonyl, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfonamido, nitro, cyano, carboxy, alkoxycarbonyl, aryl, aralkyl, aralkoxy, guanidino, heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and the like. Preferred substituents of substituted alkyl, especially of substituted alkyl of variable R1 being substituted alkoxy, are lower alkyl, cycloalkyl, lower alkenyl, benzyl, mono or disubstituted lower alkyl, e. g., ro- (amino, mono-or du-tower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl, a- (lower alkanoyloxy, lower alkoxycarbonyl or du-tower alkylaminocarbonyl)-lower alkyl, such as pivaloyloxy-methyl.

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

The term "halogen" or "halo" refers 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 containing at least one carbon to carbon double bond. Groups having two to four carbon atoms are preferred.

The term"alkylene" refers to a straight chain bridge of 1 to 6 carbon atoms connected by single bonds x is 1 to 6), which may be substituted with 1 to 3 lower alkyl groups.

The term "cycloalkyl" refers to cyclic hydrocarbon groups of 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"atkytamino"and"diatkytamino"refer to (alkyl) NH- and (alkyl) 2N-, respectively.

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 ualkylsulfonyl. refers to al The term"alkoxycarbony ! * refers to alkyl-O-C (O)-.

The term"alkoxycarbonyloxy"refers to alkyl-O-C (O) O-.

The term"alkyl"as referred to in the above definitions relates to optionally substituted alkyl as defined above.

The term"aryl"refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, tetrahydronaphthyl, and biphenyl groups, each of which may optionally be substituted by one to four substituents such as alkyl, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoyl-amino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, alkylthiono, alkyl-sulfonyl, sulfonamido, heterocyclyl and the like.

The term"monocydic aryt"refers to optionally substituted phenyl as described under aryl.

The term "aralkyl" refers to an aryl group bonded directly through an alkyl group, such as benzyl.

The term"araikoxy"refers to an aryl group bonded through an alkoxy group.

The term "arylsulfonyl" refers to aryl-S (Ok.

The term"aroyl"refers to aryl-C (O)-.

The term"heterocyclyl" refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1,2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The heterocyclic group may be attached at a heteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, 2pyridone, N-lower alkyl-pyridone, e. g., N-lower alkyl-2-pyridone, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, S-oxo-thiamorpholinyl S, S-dioxothiamorpholinyl, 1, 3-dioxolane and tetrahydro-1, 1-dioxothienyl, and the like.

Exemplary bicyclic heterocyclic groups include indoxyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo [2, 3-c] pyridinyl, furo [3, 2-b]pyridinyl] or furo[2, 3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3, 4-dihydro4-oxo-quinazolinyl) and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The term"heterocyclyl'includes substituted heterocyclic groups. Substituted heterocyclic groups refer to heterocyclic groups substituted with 1,2 or 3 of the following : (a) alkyl ; (b) hydroxy (or protected hydroxy); (c) halo ; (d) oxo (i. e. = 0) ; (e) amino, alkylamino or dialkylamin ; (f) alkoxy ; (g) cycloalkyl ; (h) carboxy; (i) heterocyclooxy ; alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl ; (k) mercapto; (I) nitro; (m) cyano; (n) sulfonamido, sulfonamidoalkyl or sulfonamidodialkyl ; (o) aryl ; (p) alkylcarbonyloxy ; (q) arylcarbonyloxy ; (r) arylthio ; (s) aryloxy ; (t) alkylthio ; (u) formyl ; (v) aralkyl ; or (w) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino or halo.

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

The term"heteroaryl" refers to an aromatic heterocycle, for example monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,

furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indoxyl, benzthiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl, and the like, optionally substituted by one or more substitutents as described in connection with substituted aryl, e. g., by lower alkyl, lower alkoxy or halo.

The term"heteraryloxy"refers to heteroaryl-O-.

The term"heteroarylsulfonyl" refers to heteroaryl-S (O) 2-, The term"heteroaroyf refers to heteroaryl-C (O)-.

The term"heteroaralkyl"refer to a heteroaryl group bonded through an alkyl group.

Encompassed by the invention are prodrug derivatives, e. g.,, any pharmaceutically acceptable prodrug ester derivatives of the carboxylic acids of the invention (COR1 being carboxy) which are convertible by solvolysis or under physiological conditions to the free carboxylic acids.

Examples of such carboxylic acid esters include esters defined by COR1, and are preferably lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono or disubstituted lower alkyl esters, e. g... the co- (amino, mono-or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the a- (lower alkanoyloxy, lower alkoxycarbonyl or du-tower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxy-methyl ester, and the like conventionally used in the art.

Preferred meanings of R are hydrogen or lower alkyl ; Preferred meanings of R1 are hydroxy, lower alkoxy or aryloxy.

Preferred meanings of R2 are hydrogen, halogen or lower alkyl.

Preferred meanings of R3 are halogen or lower alkyl.

Preferred meanings of R4 are phenyl or phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl.

Preferred meaning of R5 is hydrogen.

Preferred meanings of R6 are 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 (0) 2R4 or-S (0) 2NR5R6 Preferred Y is 0.

Preferred Z is hydrogen or hydroxy.

The integer"n"preferably is zero, 1 or 2.

The compounds of the invention depending on the nature of the substituents, may possess one or more asymmetric centers. The resulting diastereoisomers, enantiomers and geometric isomers are encompassed by the instant invention.

Preferred are the compounds of formula I as defined above with the proviso that when X is-C (O) NR5R6, Z is different from hydrogen.

Preferred are the compounds of formula I in which W is 0 or S; X is-S (0) 2R4 ; R4 being lower alkyl, phenyl or phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluormethyl ; or is-S (0) 2NR5R6 or is-C (O) NR5R6; R5, in each case, being hydrogen or lower alkyl and R6, in each case, being hydrogen, lower alkyl, lower alkyl substituted by NR5R6, 3-to 7-membered cycloalkyl, phenyl, phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluormethyl ; pyridyl or N-lower alkyl-2-pyridone ; or R5 and R6 combined, in each case, being alkylen or alkylen interrupted by 0 or S (Oh which together with the nitrogen atom to which they are attached form a 5-to 7-membered ring; Y is 0 or H2 ; Z is hydrogen or hydroxy; R is hydrogen; R1 is hydroxy, lower alkoxy or NR5R6 ; R5 being hydrogen or lower alkyl and R6 being hydrogen, lower alkyl, lower alkoxy or R5 and R6 combined being alkylen or alkylen interrupted by 0 which together with the nitrogen atom to which they are attached form a 5to 7-membered ring; R2 is hydrogen, halogen or lower alkyl ; R3 is halogen or lower alkyl ; n represents zero, 1 or 2; and pharmaceutically acceptable salts thereof.

Preferred are the compounds of formula IA

in which W is 0 or S ; X is-SR4,-S (0) R4,-S (0) 2R4,-S (0) 2NR5R6 or-C (0) NR5R6; Y is 0 or H2 ; Z is hydrogen, halogen, hydroxy, alkoxy, aralkoxy, acyloxy or alkoxycarbonyloxy ; R1 is hydroxy, lower alkoxy or aryloxy ; R2 is hydrogen, halogen or lower alkyl ; R3 is halogen or lower alkyl ; R4 is optionally substituted alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl ; R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl ; or R5 and R6 combined are alkylen optionally interrupted by 0, S, S (O), S (0) 2 or NR7 which together with the nitrogen atom to which they are attached form a 5-to 7-membered ring; n represents zero, 1 or 2; and pharmaceutically acceptable salts thereof.

Further preferred are the compounds of formula B

in which

X is-S (0) 2R4,-S (0) 2NR5R6 or-C (O) NR5R6 ; 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 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl ; or R5 and R6 combined are alkylene optionally

interrupted by 0, S, S (O), S (Oh 2 or NR7 which together with the nitrogen atom to which they are attached form a 5-to 7-membered ring; and pharmaceutically acceptable salts thereof.

Preferred are compounds of formula 1, IA and IB, and pharmaceutically acceptable salts thereof, wherein X is-S (0) 2R4 or-S (0) z NR5R6.

Most preferred are the compounds of formula IC

in which X is-S (0) 2R4 or-S (0) 2NR5R6 ; R4 is monocyclic aryl ; R5, R6 and R7 are independently hydrogen, optionally substituted alkyl or aryl ; or R5 and R6 combined are CH2CH2-Q-CH2CH2 wherein Q is CH2, 0, NR7, S, S (O) or S (Oh which together with the nitrogen atom to which they are attached from a 6-membered ring; pharmaceutically acceptable prodrug esters thereof; and pharmaceutically acceptable salts thereof.

Particularly preferred are the compounds of formula IC wherein X is S (0) 2R4 and R4 is phenyl optionally substituted by lower alkyl, halo, lower alkoxy or trifluormethyl ; pharmaceutically acceptable salts thereof; and prodrug derivatives thereof.

Pharmaceutically acceptable salts of any acidic compounds of the invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris- (hydroxymethyl) -methylammonium salts.

Similarly acid addition salts, such as of mineral acids, organic carboxylic, and organic sulfonic acids e. g., hydrochloric acid, methanesulfonic acid, maleic acid, are possible provided a basic group, such as pyridyl, constitutes part of the structure.

Compounds of formula I may be prepared from appropriately substituted phenols of formula 11

wherein R2 and R3 have meaning as defined herein and W is oxygen (prepared according to methods well-know in the literature) by first converting such to e. g. , a trifluoromethylsulfonyl ester, and treating the latter with lithium chloride in an inert solvent such as N-methyl-pyrrolidone, N, N-dimethylformamide or dimethylsulfoxide to form compounds of formula III

Compounds of formula'" can be converted to compounds of formula IV

by reaction with appropriately substituted phenols or thiophenol of formula V

wherein R has meaning as defined herein, X'and Z'represent X and Z as defined herein, or X'and Z'are groups convertible to X and Z respectively, in the presence of a base such as sodium hydride or potassium carbonate in an inert solvent such as N-methylpyrrolidone, N, N-dimethylformamide or dimethylsulfoxide at ambient or elevated temperature. Compounds of formula V can be obtained using methodologies described herein or in the art.

Alternatively, compounds of formula IV can be obtained by condensing bis-aryl iodonium tetrafluoroborates of formula VI

in which R, X'and Z'are as defined above, with phenols or thiophenol of formula II wherein W is oxygen or sulfur as described in the art, e. g, in the presence of a copper catalyst and a base such as triethylamine in an inert solvent such as dichloromethane.

Compounds of formula IV wherein Z'is alkoxy or aralkoxy can be converted to compounds of formula IV wherein Z'is hydroxy according to methods well-know in the art, e. g. , using acid such as hydrobromic acid or a boron trihalide, such as boron trichlorid or boron tribromide when Z'is in particular a methoxy group or using hydrogen in the presence of a catalyst such as palladium on carbon when Z'is in particular a benzyloxy group.

Compounds of the invention wherein X is S (0) zNR5R6 may be prepared by, for example, first treating compounds of formula IV, wherein R and X'are hydrogen and X'is located at the 3'position, and Z'is hydroxy, alkoxy or aralkoxy and Z'is located at the 4' position, with chlorosulfonic acid in an organic solvent such as dichloromethan to produce compounds of formula VII

wherein Z'is as defined above. Compounds of formula Vt ! in which Z'is hydroxy, may be converted to compounds of formula vil wherein Z'is a protected hydroxyl group such as alkanoyloxy, alkoxycarbonyloxy or trialkylsiloxy using methods and conditions well-know in the art.

Compounds of formula VII wherein Z'is alkoxy, aralkoxy, alkanoyloxy, alkoxycarbonyl-oxy or trialkylsiloxy can be converted to compounds of formula VIII

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

A reaction of compounds of formula VH) with primary or secondary amines of formula R5R6NH wherein R5 and R6 are as defined herein in the presence of a base such as Nmethyl-morpholine or triethylamine in an organic solvent such as dichloromethan affords compounds of formula IX

Compounds of formula IX wherein Z'is as defined above can be converted to compounds of formula IX wherein Z'is hydroxy using methods and conditions well-know in the art or as illustrated herein.

Conversion of nitro substituted compounds of formula IV, for example those of formula IX, to amines of e. g. , formula X

can be achieved according to methods described in the art, e. g. , with hydrogen in the presence of a catalyst such as palladium on carbon in a polar solvent such as ethanol or tetrahydrofuran.

Any resulting amines, for example those of formula X, can be treated with acylating agents such as ethyl oxalyl chloride, ethyl malonyl chloride, ethyl succinyl chloride or ethyl bromoacetate in the presence of a base such as N-methylmorpholine or triethylamine in an organic solvent such as dichloromethane, tetrahydrofuran or N, N-dimethylformamide to form compounds of formula 1, e. g. , those of formula XI

wherein R1 is alkoxy, Y is oxygen or H2, Z'represents Z as defined herein or Z'is a group convertible to Z and n represents an integer from zero to four. Compounds of formula I wherein R1 is alkoxy can also be prepared by condensing e. g. , compounds of formula X with acylating agents such as dimethyl or diethyl oxalate at elevated temperature using the acylating agent both as a reagent and a solvent.

Compounds of formula I wherein R1 is e. g., alkoxy or aryloxy can be hydrolyzed to compounds of formula I wherein R1 is hydroxy according to conventional methods, e. g., using an aqueous base such as an alkali metal carbonate or hydroxide in an organic solvent such as ethanol or tetrahydrofuran.

Similarity, other compounds of formula IV wherein, X'and Z'represent X and Z as defined herein or X'and Z'are groups convertible to X and Z respectively are converted to compounds of formula XII

in a manner illustrated herein or by modifications thereof and, if necessary, said compounds are converted to the corresponding compounds of formula 1, by converting X'and Z'to X and Z respectively. For example, compounds wherein X'= COOH are converted to the corresponding amides of formula I wherein X is C (O) NR5R6 according to methods well known in the art. Similarly compounds wherein COR1 is COOH can be converted to compounds wherein COR1 is CONRsR6.

The starting compounds and intermediates which are converted to the compounds of the invention in a manner described herein, functional groups present, such as amino, thiol, carboxyl, and hydroxy groups, are optionally protected by conventional protecting groups that are common in preparative organic chemistry. Protected amino, thiol, carboxyl, and hydroxy groups are those that can be converted under mild conditions into free amino, thiol, carboxyl and hydroxy groups without the molecular framework being destroyed or other undesired side reactions taking place.

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

Well-known protecting groups that meet these conditions and their introduction and removal are described, for example, in J. F. W. McOmie,"Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, T. W. Greene,"Protective Groups in Organic Synthesis", Wiley, New York, 1991.

In the processes cited herein, reactive functional derivatives of carboxylic acids represent, for example, anhydrides (especially mixed anhydrides), acid halides, acid azides, lower alkyl esters, and activated esters thereof. Mixed anhydrides are preferably such from pivalic acid, or a lower alkyl (ethyl, isobutyl) hemiester of carbonic acid; acid halides are for example chlorides or bromides; activated esters for example succinimido, phthalimido or 4nitrophenyl esters; lower alkyl esters are for example the methyl or ethyl esters.

The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluent, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures (preferably at or near the boiling point of the solvents used), and at atmospheric or super-atmospheric pressure. The preferred solvents, catalysts and reaction conditions are set forth in the appended illustrative examples.

Depending on the choice of starting materials and methods, the compounds may be in the form of one of the possible isomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, optical isomers (antipodes), racemates, or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure geometric or optical isomers, diastereoisomers, racemates, for example by chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e. g. , by separation of the diastereoisomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. The carboxylic acid intermediates can thus be resolved into their optical antipodes e. g. , by fractional crystallization of d-or t- (alpha-methylbenzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabietylamine, brucine or strychnine)-salts. Racemic products can also be resolved by chiral chromatography, e. g., high pressure liquid chromatography using a chiral adsorbent.

Finally, the compounds are either obtained in the free form, or as a salt thereof if salt forming groups are present.

Acidic compounds may be converted into salts with pharmaceutically acceptable bases, e. g. , an aqueous alkali metal hydroxide, advantageously in the presence of an ethereal or alcoholic solvent, such as a lower alkanol. From the solutions of the latter, the salts may be precipitated with ethers, e. g., diethyl ether. Resulting salts may be converted into the free compounds by treatment with acids. These or other salts can also be used for purification of the compounds obtained.

Compounds having basic groups can be converted into acid addition salts, especially pharmaceutically acceptable salts. These are formed, for example, with inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric or hydrohalic acid, or with organic carboxylic acids, such as (Ci--atkanecarboxytic acids which, for example, are unsubstituted or substituted by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, succinic, maleic or fumaric acid, such as hydroxy-carboxylic acids, for example glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or with organic sulfonic acids, such as (C1-C4) -alkyl-sulfonic acids (for example methanesulfonic acid) or arylsulfonic acids which are unsubstituted or substituted (for example by halogen). Preferred are salts formed with hydrochloric acid, methanesulfonic acid and maleic acid.

In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.

The pharmaceutical compositions for the treatment of hair loss according to the invention are those suitable for topical, enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, and comprise an effective amount of a pharmacologically active compound defined herein, alone or in combination with one or more pharmaceutically acceptable carriers or excipients. Such formulations include tablets and gelatin capsules comprising the active ingredient together with a) diluents, e. g.,, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine ; b) lubricants, e. g.,, silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol ; for tablets also c) binders, e. g.,, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone ; if desired d) disintegrants, e. g... starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbants, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized 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 also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and typically contain about 0.01 to 25%, preferably about 0.1 to 10%, of the active ingredient.

Suitable formulations for transdermal application include an effective amount of a compound of the invention with carrier. Advantageous carriers include absorbable pharmaco-logically acceptable solvents to assist passage through the skin of the host.

Characteristically, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like. The carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, tragacanth and sodium alginate ; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.

Other compositions useful for attaining systemic delivery of the active ingredient include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol ; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

The compounds may also be topically administered. The carrier of the topical composition preferably aids penetration of the present compounds into the skin to reach the environment of the hair follicle. Topical compositions of the present invention may be in any form including, for example, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Said topical compositions typically contain about 0. 01% to about 10% of active compound, preferably 0.01 to 5% w/w.

Topical compositions containing the active compound may contain a variety of carrier materials well known in the art, such as, for example, water, alcohols, aloe vera gel, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, and the like.

Other materials suitable for use in topical carriers include, for example, emollient, solvents, humectants, thickeners and powders. Examples of each of these types of materials, which can be used singly or as mixtures of one or more materials, are as follows : Emollient, such as stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1, 2-diol, butane-1, 3-diol, mink oil, cetyl alcohol, iso-propyl isostearate, stearic acid, iso-butyl palmitat, isocetyl stearate, oleyl alcohol, isopropyllaurate, hexyllaurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, iso-propyl myristate, iso-propyl palmitat, iso-propyl stearate, butyl stearate,

polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyllinoleate, lauryllactate, myristyllactate, decyl oleate, and myristyl myristate; propellants, such as propane, butane, iso-butane, dimethyl ether, carbon dioxide, and nitrous oxide; solvents, such as ethyl alcohol, methylene chloride, iso-propanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran; humectants, such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin ; and powders, such as chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically modified magnesium aluminium silicate, organically modified montmorillonite clay, hydrated aluminium silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, and ethylene glycol monostearate.

The compounds used in the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamin or phosphatidylcholines.

The compositions used in the present invention may also optionally comprise an activity enhancer. The activity enhancer can be chosen from a wide variety of molecules which can function in different ways to enhance hair growth effects of a compound described herein. Particular classes of activity enhancers include other hair growth stimulants and penetration enhancers.

Non-limiting examples of activity enhancers (hair growth stimulants) which may be used in the compositions herein, including both systemic and topical compositions, include, for example minoxidil and finasteride, most preferably minoxidil.

Non-limiting examples of penetration enhancers which may be used in the compositions herein include, for example, 2-methyl propan-2-01, propan-2-o1, ethyl-2- hydroxypropanoate, hexan-2, 5-diol, POE (2) ethyl ether, di (2-hydroxypropyl) ether, pentan2, 4-diol, acetone, POE (2) methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-l-ol, 1,4-dioxane, tetrahydrofuran, butan-1, 4-diol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol,

lauryl alcohol, dioctyl adipate, dicapryl adipate, d-isopropyl adipate, d-isopropyl sebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl myristate, dimethyl azelate, butyl myristate, dibutyl succinate, didecyl phthalate, decyl oleate, ethyl caproate, ethyl salicylate, iso-propyl palmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, iso-propyl isostearate, butyllaurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl salicylate, 2-hydroxypropanoic acid, 2-hyroxyoctanoic acid, dimethyl sulphoxide, N, N-dimethyl acetamide, N, N-dimethyl formamide, 2-pyrrolidone, 1 methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1, 5-dimethyl-2-pyrrolidone, I-ethyl-2- pyrrolidone, phosphine oxides, sugar esters, tetrahydrofurfural alcohol, urea, diethyl-m- toluamide, and, l-dodecylazacyloheptan-2-one.

The present invention further relates to kits comprising a compound and/or composition herein and information and/or instructions by words, pictures, and/or the like, that use of the kit will provide treatment for hair loss in mammals (particularly humans) including, for example, arresting and/or reversing hair loss and/or promoting hair growth.

In addition or in the alternative, the kit may comprise a compound and 1 or composition herein and information and/or instructions regarding methods of application of the compound and/or composition, preferably with the benefit of treating hair loss in mammals.

A unit dosage for a mammal of about 50 to 70 kg may contain between about 0.01 mg and 10 mg of the active ingredient. The dosage of active compound is dependent on the species of warm-blooded aninial (mammal), the body weight, age and individual condition, on the form of administration, and on the compound involved. Topical compositions comprise about 0. 01% to 10% of the active ingredient, preferably 0. 01% to 5%.

Preferred active ingredients are the most selective thyromimetic agents described herein which are substantially free of undesirable cardiac side effects associated with thyroid hormones, e. g.,, the compounds of examples 26 and 28, or prodrug derivatives thereof.

The above-cited properties are demonstrable in vitro and in vivo tests, using advantageously mammals, e. g... mice or rats. Said compounds can be applied topically in the form of solutions, or systemically, either enterally, parenterally, advantageously intravenously, e. g. , as a suspension or in aqueous solution. The systemic dosage may range depending on the route of administration, between about 0. 1 and 1000 micrograms/kg, preferably between about 0.5 and 300 micrograms/kg, advantageously between about 1 and 100 micrograms/kg. Topically the active ingredient is administered at a concentration of about 0. 01% to about 10% by weight.

The active ingredients bind to the triodoethyronine (Ta) receptor and are thus useful as thyroid hormone agonists in mammals.

The in vitro binding to T. nuclear receptors is determined as follows : Rat liver nuclei and plasma membrane preparations are obtained from Sprague Dawley (CD) rats (Charles River Labs. ) by differential centrifugation as described by Emmelot at al (Methods in Enzymology 31: 75, Part A, 1974) with minor modificatons. The nuclear fraction obtained from the 275 x g pellet is further purified as generally described by Spindler et al (J. Biol. Chem. 250: 4118, 1975).

The novel test compounds are assayed for binding to the nuclei by the method of Spindle et al (J. Biol. Chem. 250: 4118, 1975). The nuclei are incubated at 22 C with 0.3 125 nM of [ I]-L-triiodothyronine (L-T3). Parallel incubations are conducted with tubes containing, in addition to the nuclei and radioactive L-T3, either various concentrations of the test compounds or 3 M of nonradioactive L-Tg. The latter is used as a measure of nonspecific binding. The radio-activity bound to the nuclei is determined following centrifugation of the reaction mixture at 800 x g for 7 minutes and washing of the pellet 125 obtained. The amount of { < ]-L-Tg specificai) y bound is determined by subtracting the amount nonspecifically bound (radioactivity contained in the nuclear pellet following incubation with excess (3 uM) non-radioactive L-T. The concentration of test compound 125 which inhibits the specific binding of [I]-L-T3 by 50 percent (IC50) is determined graphically 125 from the reciprocal plot of the specifically bound [I]-L-T3 versus the various concentrations of the test compound.

The Telogen Conversion Assay measures the potential of a test compound to convert mice in the resting stage of the hair growth cycle ("telogen"), to the growth stage of the hair growth cycle ("anagen").

The Telogen Conversion Assay herein below is used to screen compounds for potential hair growth by measuring melanogenesis.

Three groups of 44 day-old C3H mice are utilized : a vehicle control group, a positive control group, and a test compound group, wherein the test compound group is administered a compound used in the method of the present invention. The length of the assay is at least 19 days with 15 treatment days (wherein the treatment days occur Mondays through Fridays). Day 1 is the first day of treatment. Most studies will end on Day 19, but may be carried out to Day 24 if the melanogenesis response looks positive, but occurs slowly. Typically the test compound is administered at a concentration of 0.1% (e. g. , 0.5 ml) in a suitable vehicle comprising e. g. , a mixture of ethanol, propylene glycol and isosorbide dimethyl ether.

The mice are treated topically Monday through Friday on their lower back (base of tail to the lower rib). A pipettor and tip are used to deliver the solution to each mouse's back.

The solution is applied slowly while moving hair on the mouse to allow the application to reach the skin.

While each treatment is being applied to the mouse topically, a visual grade of from 0 to 4 will be given to the skin color in the application area of each animal. As a mouse converts from telogen to anagen, its skin color will become more bluish-black.

The following examples illustrate the compounds used in the invention including their preparation and formulation and are not to be construed as being limitations thereon.

Temperatures are given in degrees Centrigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 and 100 mmHg (= 20133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e. g., microanalysis and spectroscopic characteristics (e. g.,

MS, IR, NMR). Abbreviations used are those conventional in the art.

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

A. 3, 5-Dimethyl-4- (4'-methoxyphenoxy) nitrobenzene A suspension of sodium hydride (NaH; 60% dispersion in mineral oil ; 64.11 g, 1.603 mol) in 350 mL of N-methylpyrrolidone (NMP) is cooled to OOC and treated with a solution of 4-methoxyphenol (208.4 g, 1.679 mol) over 30 min. The mixture is warmed to room temperature (RT) and after 30 min, 4-chloro-3, 5-dimethyinitrobenzene (283.2 g, 1.526 mol ; prepared by the method described by Yokoyama et. al. in EP580550) is added in one portion and the reaction is heated at 120oC for 2 h. The reaction is cooled to room temperature (RT) and quenched with water (1500 mL). The suspension is cooled to 0 C, stirred for 30 min, then filtered and the filtercake is washed with water and dried in vacuo. The crude product, ethyl acetate (EtOAc; 2100 mL) and charcoal (42.6 g) were heated to reflux and the solids were removed by filtration through celite while hot. The filtrate is concentrated under reduced pressure to ca. 800 mL and the resulting suspension is cooled to OOC and stirred for 30 min. The product is collected by vacuum filtration, washed with cold EtOAc and dried in vacuo to afford 3, 5-dimethyl-4- (4'-methoxyphenoxy) nitrobenzene: NMR (CDCI3) 2.22 (s, 6H),

3. 78 (s, 3H), 6. 68 (d, 2H, J = 8. 7), 6. 82 (d, 2H, J = 8. 7), 8. 02 (s, 2H).

B. 3, 5-Dimethyl-4- (4'-hydroxyphenoxy) nitrobenzene A mixture of the title A compound, 3, 5-dimethyl-4- (4'-methoxyphenoxy) nitrobenzene (16.4 g, 60 mmol), acetic acid (AcOH ; 100 mL) and aqueous 48% hydrobromic acid (HBr; 100 mL) is heated at 120oC for 16 h. The mixture is cooled to RT, diluted with water (200 mL) and the precipitated product is collected by vacuum filtration, washed with water and hexanes and dried in vacuo to afford 3, 5-dimethyl-4- (4'-hydroxyphenoxy) nitrobenzene: NMR (CDCI3) 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-hydroxybenzenesulfonic acid A solution of the title B compound, 3, 5-dimethyl-4- (4'-hydroxyphenoxy) nitrobenzene (7.86 g, 30.35 mmol) in 150 mL of dichloromethan (CH2Ciz) is treated with chlorosulfonic acid (2.4 mL, 36.42 mmol) at RT. After 16 h, the reaction mixture is concentrated and the residue is dissolved in small amount of CH2CI2 (ca. 5 mL). The product is precipitated by addition of brine (100mL), collected by vacuum filtration, washed with water, hexanes and diethyl ether (Et2O) and dried in vacuo to give 5- (2, 6-dimethyl-4-nitrophenoxy)-2-hydroxy- benzenesulfonic acid: NMR (DMSO-d6) 2.18 (s, 6H), 6.67-6. 83 (m, 3H), 8.1 (s, 2H), 10.07 (s, 1H).

D. 2-Benzyloxy-5- (2, 6-dimethyl-4-nitrophenoxy) benzenesulfonic acid, cesium salt A solution of the title C compound, 5- (2, 6-dimethyl-4-nitrophenoxy)-2-hydroxy- benzenesulfonic acid (6.78 g, 20 mmol) in 100 mL of tetrahydrofuran (THF) and 50 mL of N, N-dimethylformamide (DMF) is treated with cesium carbonate (15.6 g, 48 mmol) and benzyl bromide (7.1 mL, 60 mmol) at RT, then heated at 75 C for 48 h. The reaction mixture is cooled to RT and quenched with aqueous 1N hydrochloric acid (HCI ; 100 mL), and THF is evaporated. The precipitated product is collected by vacuum filtration, washed with water, Et2O, EtOAc and CH2CI2 and dried to afford 2-benzyloxy-5- (2, 6-dimethyl-4nitrophenoxy) benzenesulfonic acid, cesium salt : NMR (DMSO-d6) 2.18 (s, 6H), 5.10 (s, 2H), 6.74 (dd, 1H, J = 8.7, 3.8), 6.97 (d, 1H, J = 8.7), 7.11 (d, 1H, J = 3.8), 7.23-7. 39 (m, 3H), 7.59 (d, 2H, J = 7.5), 8.12 (s, 2H).

E. 2-Benzyloxy-5- (2, 6-dimethyl-4-nitrophenoxy) benzenesulfonyl chloride A suspension of the title D compound, 2-benzyloxy-5- (2, 6-dimethyl-4-nitrophenoxy)- benzenesulfonic acid, cesium salt (9.9 g, 20 mmol) in 200 mL of CH2CI2 is treated with DMF (3.1 mL, 40 mmol), then oxalyl chloride (3.5 mL, 40 mmol) is added over 30 min at RT. The reaction mixture is stirred for 1 h further, then diluted with Et2O (200 mL) and washed with water and brine, dried over anhydrous sodium sulfate (Na2SO4) and concentrated. The product is washed with Et2O (5 mL) and dried in vacuo to afford 2-benzyloxy-5- (2, 6-dimethyl-

4-nitro-phenoxy) benzenesulfonyl chloride : NMR (CDC13) 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) benzenesulfonamide A solution of the title E compound, 2-benzyloxy-5- (2, 6-dimethyl-4-nitrophenoxy)- benzenesulfonyl chloride (1.12 g, 2.5 mmol) in 20 mL of CH2CI2 is treated sequentially with N-methylmorpholine (NMM; 550 mL, 5 mmol) and neopentylamine (442 mL, 3.75 mmol) at RT. After 6 h, the mixture is partitioned between water and EtOAc, and the organic solution

is washed with aqueous 1 N HCI and brine, dried over anhydrous Na2SO4 and concentrated to afford 2-benzyloxy-5- (2, 6-dimethyl-4-nitrophenoxy)-N- (2, 2-dimethylpropyl) benzenesulfonamide : NMR (CDCis) 0. 78 (s, 9H), 2. 22 (s, 6H), 2. 58 (d, 2H, J = 7. 5), 4. 82 (t, 1 H, 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-hydroxy-N- (2, 2-dimethylpropyl) benzene sulfonamide A mixture of the title F compound, 2-benzy) oxy-5- (2, 6-dimethy)-4-nitrophenoxy)-N- (2, 2dimethylpropyl) benzenesulfonamide (1.22 g, 2.45 mmol) and palladium on activated carbon (10 wt. %; 250 mg) in 40 mL of THF is stirred under hydrogen atmosphere (H2, 1 atm) for 8 h. The catalyst is removed by vacuum filtration through celite, washed with THF and the combined filtrate and washings are concentrated. The residue is suspended in CH2CI2 and

the product is collected by vacuum filtration, washed with CH2CI2 and dried to give 5- (4amino-2, 6-dimethyl-phenoxy)-2-hydroxy-N- (2, 2-dimethyl propyl) benzenesu) fonamide : NMR (DMSO-d6) 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-Dimethylpropy ! sulfamoyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl}oxamic acid A solution of the title G compound, 5- (4-amino-2, 6-dimethytphenoxy)-2-hydroxy-N- (2, 2dimethylpropyl) benzenesulfonamide (750 mg, 1. 98 mmol) in 10 mL of THF is cooled to OOC and treated sequentially with NMM (545 mL, 4. 96 mmol) and ethyl oxalyl chloride (442 mL, 3. 96 mmol). The reaction is warmed to RT and after 1 h, quenched with water. The mixture is partitioned between water and EtOAc and the organic solution is washed with aqueous 1 N HCI and brine, dried over anhydrous Na2SC and concentrated. The residue is dissolved in 10 mL of THF, then treated with aqueous 1 N lithium hydroxide (LiOH ; 1. 8 mL, 1. 8 mmol) at RT. After 1 h, the reaction is quenched with aqueous 1 N HCI and the product is taken up in EtOAc, washed with brine, dried over anhydrous NazS04 and concentrated. The product is triturated with hexanes, then with Et2O and dried in vacuo to afford of N- {4- [3- (2, 2dimethy) ropy)-su) famoyi)-4-hydroxyphenoxy]-3, 5-dimethyipheny)} oxamicacid : NMR (CDC13) 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, 1 H) ; I R (KBr) 1759, 1693 ; ESI-MS 449 [M-1].

The following additional compounds may be similarly prepared.

h : 00 j DC R5 : plI S'l Ho i : c OH"6 n Y W , IN Example No. NMR IR (KBr) ESI-MS R5, R6

2 (DMSO-d6) : 1.91 (s, 6H), 6.79-6. 99 (m, 6H), 1207,455 [M-1)7. 11-7.17 (m, 2H), 7.55 (s, 2H), 9.99 (s, 1H), 1481, R5 = H, R6 = Ph-10. 46 (s, 1H), 10.52 (s, 1H) 1689 3 (DMSO-de) : 1.91 (s, 6H), 6.72 (d, 1H, J = 3. 0), 1207,473 [M-1]6. 89-7.03 (m, 6H), 7.55 (s, 2H), 9.96 (s, 1 H), 1481, R5 = H, R6 = p-FC6H4- 10.54 (s, 1H), 10.66 (s, 1H) 1508, 1693 4 (MeOH-d4): 1.98 (s, 6H), 6.81 (d, 1H, J = 2.6), 1209, 473 [M-1]6. 87-7.14 (m, 5H), 7.36 (td, 1H, J = 7. 9,1. 9), 1481, R5 = H, R6 = o-FC6H4- 7.46 (s, 2H) 1500, 1689 5 (DMSO-d6) : 1.97 (s, 6H), 6.75-6. 84 (m, 4H), 1238,473 [M-1 6. 92 (d, 1H, J=8. 8), 7.04 (dd, 1H, J=8. 8,1475, R5 = H, R6 = m-FCeH4-3. 1), 7.20 (app q, 1 H, J = 7. 0), 7.58 (s, 2H), 1706 10.35 (s, 1H), 10.59 (s, 1H), 10.66 (s, 1H) 6 (DMSO-d6): 1.90 (s, 6H), 3.67 (s, 3H), 6.68 1209, 485 [M-1 (d, 1H, J = 3), 6.73 (d, 2H, J = 9.00), 6.89-6. 991475, R = H, R6 = p- (m, 4H), 7.54 (s, 2H), 9.58 (s, 1H), 10.45 (s, 1514, MeOC6H4- 1H), 10.64 (s, 1H) 1688 7 (DMSO-de) : 2.02 (s, 6H), 4.03 (d, 2H, J = 6. 4), 1224,487 [M-1 6. 80-6.89 (m, 3H), 7.01 (t, 2H, J = 4. 0), 7.22 1481, R5 = H, R6 = p- (dd, 2H, J = 6. 3,8. 7), 7.56 (s, 2H), 7.77 (t, 1 H, 1695 FCeH4CH2-J = 6. 4), 10.32 (s, 1H), 10.64 (s, 1H) 8 (CDCl3): 1.96 (s, 6H), 3.14 (s, 3H), 6.54 (d, 1209, 469 [M-1]1 H, J = 2.4), 6.84-6. 85 (m, 2H), 6.88-7. 03 (m, 1230, R5 = Me-, R6 = Ph- 2H), 7.20-7. 28 (m, 5H) 1481, 1691 9 (CDO3) : 0.87 (t, 3H, J = 7. 5), 1.38-1. 56 (m, 1214,421 [M-1]2H), 2.11 (s, 6H), 2.94 (app q, 2H, J = 7. 5), 1485, R5 = H, R6 = n-Pr- 5.0 (t, 1H, J=7. 5), 6.84 (d, 1H, J=3), 7.0 (d, 1693,440 1H, J = 9), 7.08 (dd, 1H, J = 9, 3), 7.32 (s, 1751 [M+NH4]+ 2H), 8.44 (br s, 1H), 9.0 (br s, 1 H) 10 (DMSO-d6) : 0.95 (d, 6H, J = 7. 5), 2.02 (s, 6H), 1209, 421 [M-1]3. 2-3.31 (m, 1 H), 6.86 (br s, 1 H), 6.97 (br s, 1485, R5= H, R6=i-Pr-H), 7.06 (d, 1 H, J = 7. 5), 7.57 (s, 2H), 10.32 1698, (br s, 1H), 10.64 (br s, 1 H) 1742 11 (DMSO-d6): 0.72 (t, 3H, J = 7. 5), 1.1-1. 35 (m, 1321, 435 [M-1]4H), 2.03 (s, 6H), 2.76 (app q, 2H, J = 7. 5), 1481, R5 = H, R6 = n-Bu-6. 87 (br s, 1H), 6.97 (br s, 2H), 7.1 (t, 1H, J = 1691 454 7.5), 7.58 (s, 2H) [M+NH4]+

12 (DMSO-d6) : 0.75 (d, 6H, J : : 8. 2), 1.49-1. 62 1209, 435 [M-1] (m, 1H), 2.03 (s, 6H), 2.55 (app t, 2H, J = 6. 8), 1481, R5 = H, R6 = i-Bu-6. 85 (br s, 1 H), 6.96 (br s, 2H), 7.17 (t, 1H, J = 1693, 6. 8), 7.57 (s, 2H), 10.25 (brs, 1H), 10.61 (br s, 1762 1H) 13 (DMSO-d6) : 1.02 (s, 9H), 2.03 (s, 6H), 6.81- 1204, 435 [M-1]7. 02 (m, 4H), 7. 56 (s, 2H), 10.20 (br s, 1 H), 1486, R5 = H, R6 = t-Bu- 10.61 (brs,1H) 1645, 1754 14 (CDCI3) : 1.06-1. 32 (m, 5H), 1.50-1. 73 (m, 1209, 461 [M-1] 5H), 2.01 (s, 6H), 3.02-3. 14 (m, 1H), 5.05 (d, 1481, R5 = H, R6 = Cyclohexyl 1H, J = 7.5), 6.82 (d, 1 H, J = 3), 6.97 (d, 1 H, J 1695, = 9), 7.10 (dd, 1H, J = 9, 3), 7.32 (s, 2H), 8.52 1741 (brs, 1H), 9.06 (brs, 1H) 15 (MeOH-d4): 2.07 (s, 6H), 2.64 (s, 6H), 6. 86- 1234, 407 [M-1] 6. 94 (m, 3H), 7.39 (s, 2H) 1486, R5 = Me-, R6 = Me- 1685 16 (MeOH-d4): 1.76-1. 80 (m, 4H), 2.08 (s, 6H), 1230, 33 [M-1r 3.21-3. 29 (m, 4H), 6.88-6. 95 (m, 3H), 7.40 (s, 1479, R5, R6 = -(CH2)4- 2H) 1693 17 (MeOH-d4): 1.49-1. 58 (m, 6H), 2.13 (s, 6H), 1207, 447 [M-1]' 3.08-3. 10 (m, 4H), 6.92-7. 02 (m, 3H), 7.53 (s, 1481, R5, R6=- (CH2) s- 2H) 1658 18 (CDCI3) : 2.06 (s, 6H), 3.03 (t, 2H, J = 5.5), 1218, 437 [M-1]3.22 (s, 3H), 3.35 (t, 2H, J = 5. 5), 6.85 (br s, 1483, R5 = H, R6 2H), 6.97 (br s, 1H), 7.34 (s, 2H) 1689 MeOCH2CH219 (MeOH-d4): 2.13 (s, 6H), 3.12 (t, 4H, J=6), 1479, 449 [M-1r 3.68 (t, 4H, J = 6), 6.95-7. 03 (m, 3H), 7.54 (s, 1711, R5, R6= 2H) 1745 - (CH2) 20 (CH2) 220 (CDCl3): 2.12 (s, 6H), 3. 10-3. 13 (m, 4H), 3.74- 1209, 497 [M-1]3.76 (m, 4H), 6.92-6. 99 (m, 3H), 7.41 (s, 2H) 1481, R5, R6= 1697 -(CH2)2SO2(CH2)2

21 (DMSO-d6) : 1. 95 (s, 6H), 6. 81 (d, 1 H, J = 3), 1481, 473 [M-116. 92 (d, 1 H, J = 9), 7. 00 (dd, 1 H, J = 9, 3), 1500, R5 = H, R6 = 3-Pyridyl 7. 26 (dd, 1 H, J = 8, 5), 7. 41-7. 45 (m, 1H), 7. 56 1689 (s, 2H), 8. 21 (dd, 1 H, J = 5, 1. 5), 8. 27 (d, 1 H, J = 2. 5), 10. 34 (s, 1H), 10. 66 (s, 1H) 22 (DMSO-d6) : 1. 88 (s, 6H), 3. 75 (s, 3H), 6. 64- 488 [M+ 1 r 6. 69 (m, 2H), 6. 93 (d, 1 H, J = 9), 6. 99 (dd, 1 H, /==\ J = 9, 2. 5), 7. 32 (dd, 1 H, J = 9, 2. 5), 7. 53 (s, 2H), 7. 77 (d, 1 H, J = 2. 5), 9. 74 (s, 1 H), 10. 56 Me (s, 1H), 10. 61 (s, 1H)

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

The title compound is prepared similarly to Example 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, 1 H) ; IR (KBr) 1163, 1506, 1690 ; ESI-MS 489 [M-1]-, 508 [M+NH4t.

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

The title compound is similarly to Example 1 : NMR (DMSO-d6) 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.

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

The title compound is prepared similarly to Example 1: NMR (DMSO-d6) 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]'.

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

A. 4-Fluorobenzenesulfinic acid A solution of 4-fluorobenzenesulfonyl chloride (2 g, 10.28 mmol) in 50 mL of THF (distilled from Na-benzophenone) is cooled to OoC and sodium borohydride (1.9 g, 51. 4 mmol) is added portionwise. The reaction is stirred at 0 C for 2 h, then warmed to RT, and after 2 h, quenched with water (5 mL). The solvent is evaporated and the aqueous residue is acidified by addition of aqueous 6N HCI. The product is taken up in EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated to give 4-fluorobenzenesulfinic acid: NMR (DMSO-d6) 7.12 (app t, 2H, J = 8.3), 7.5 (dd, 2H, J = 8.3, 6); ESI-MS 159 [M-1r.

B. 2- (4-Fluorobenzenesulfonyl) benzene-1, 4-diol A solution of the title A compound, 4-fluorobenzenesulfinic acid (3 g, 18.75 mmol) in 10 mL of water is added to a solution of 1,4 benzoquinone (1.93 g, 17.86 mmol) in 30 mL of CH2Cl2 at RT. After 4 h, the precipitated product is collected by vacuum filtration and washed

with cold CH2Cl2and dried under vacuum to afford 2- (4-fluorobenzenesulfonyl)-benzene-1, 4diol : NMR (DMSO-d6) 6. 73 (d, 1H, J = 9), 6. 92 (dd, 1 H, 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-1r.

C. 4- (2, 6-Dimethyl-4-nitrophenoxy)-2- (4-fluorobenzenesulfonyl) phenol The title B compound, 2-(4-fluorobenzenesulfonyl)benzene-1,4-diol (1.2 g, 4.48 mmol) is added to a suspension of NaH (60% dispersion in mineral oil ; 0.39 g, 9.86 mmol) in

15 mL of NMP at 0 C in one portion. The mixture is warmed to RT and after 30 min, 4chloro-3, 5-dimethyinitrobenzene (1 g, 5. 38 mmol) is added and the reaction is heated at 120oC for 1 h. The reaction is cooled to RT and quenched with aqueous 1N HO. The mixture is partitioned between water and EtOAc, and the organic solution is washed with water and brine, dried over anhydrous NazS04 and concentrated. Chromatography on silica (eluant ; EtOAc/hexane-1/2/1/1) affords 4-(2,6-dimethyl-4-nitrophenoxy)-2-(4-fluorobenzenesulfonyl) phenol : NMR (CDCI3) 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, 1 H).

D. 4- (4-Amino-2, 6-dimethylphenoxy)-2- (4-fluorobenzenesulfonyl) phenol (a) A mixture of the title C compound, 4-(2,6-dimethy)-4-nitrophenoxy)-2-(4-fluorobenzenesulfonyl) phenol (0.69 g, 1.65 mmol) and palladium on activated carbon (10 wt. %; 69 mg) in 10 mL of EtOH and 10 mL of CH2Ci2 is stirred under hydrogen atmosphere (H2,1 atm) for 6 h. The catalyst is removed by vacuum filtration through celite, washed with a 1/1mixture of EtOH and CH2CI2, and the combined filtrate and washings are concentrated and dried under vacuum to give 4- (4-amino-2, 6-dimethylphenoxy)-2- (4-fluorobenzenesulfonyl)- phenol : NMR (DMSO-d6) 1.93 (s, 6H), 4.92 (s, 2H), 6.34 (s, 2H), 6.85 (d, 1 H, 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-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5dimethylphenyl) oxamic acid ethyl ester E. A mixture of the title D compound, 4-(4-amino-2,6-dimethylphenoxy)-2-(4-fluoro benzenesulfonyl) phenol (0.64 g, 1.65 mmol) and 2 mL of diethyl oxalate is heated at 180oC for 3 h. The reaction is cooled to RT and diethyl oxalate is removed under vacuum. Chromatography on silica (eluat ; EtOAc/hexane-1/3 ? 2/3) affords N- {4- [3-(4-fluoro-benzenesulfonyl)-4-hydroxyphenoxy]-3,5-dimethylphenyl}oxamic acid ethyl ester: NMR (CDO3) 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-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5 dimethylphenyl) oxamic acid A solution of the title E compound, N-{4-[3-(4-fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl}oxamic acid ethyl ester (773 mg, 1.58 mmol) in 15 mL of EtOH is treated with aqueous 1N sodium hydroxide (NaOH ; 4.75 mL, 4.75 mmol) at RT. After 1 h,

the reaction is quenched with aqueous 1 N HCI (5. 5 mL) and the product is taken up in EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated. The product is triturated with Et20 and dried in vacuo to afford N-{4-[3-(4-fluorobenzenesulfonyl)-4hydroxyphenoxy]-3, 5-dimethylphenylloxamic acid : NMR (DMSO-d6) 2. 06 (s, 6H), 6. 88 (d, 1H, J = 9), 7. 03 (dd, 1H, J = 9, 3), 7. 13 (d, 1H, J = 3), 7. 43 (app t, 2H, J = 9), 7. 61 (s, 2H), 7.94 (dd, 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 additional compounds are similarly prepared.

) 0-SP o rY YYR4 s HO, & O Na OH R4 Example NMR IR (KBr) ESI-MS R4 27 (MeOH-d6) : 2. 02 (s, 6H), 6. 85 (d, 1 H, J = 7), 1209, 440 [M-1]' 6. 98 (dd, 1 H, J = 7, 2. 3), 7. 26 (d, 1 H, J = 2. 3), 1479, R4 = Ph-7. 53 (s, 2H), 7. 55-7. 68 (m, 3H), 7. 93 (d, 2H, J 1697 =7) 28 (MeOH-d6) : 2. 12 (s, 6H), 6. 84 (d, 1H, J = 8. 3), 1207, 474 [M-1r 6. 96 (dd, 1 H, J = 8. 3, 3), 7. 24 (d, 1 H, J = 3), 1479, R4 = p-CIC6H4- 7. 53 (d, 2H, J = 7. 5), 7. 58 (s, 2H), 7. 90 (d, 2H, 1697 J = 7. 5) 29 (MeOH-d6) : 2. 10 (s, 6H), 2. 41 (s, 3H), 6. 82 (d, 1149, 454 [M-1 1H, J = 9), 6. 95 (dd, 1H, J = 9, 3), 7. 19 (d, 1H, 1207, .73 R4 = p-MeC6H4-J = 3). 7. 45 (d, 2H, J = 8. 3), 7. 53 (s, 2H), 7. 77 1481 (d, 2H, J = 8. 3) M+NH4t 30 (CDCI3) : 1. 98 (s, 6H), 3. 80 (s, 3H), 6. 80-6. 82 1209, 470 [M-1]' (m, 2H), 6. 89-6. 93 (m, 3H), 7. 31 (s, 2H), 7. 73 1475, R4 = p-MeOC6H4- (d, 2H, J = 7. 2), 8. 73 (br s, 1 H), 8. 89 (br s, 1 H) 1588, 1705 31 (DMSO-d6) : 2. 07 (s, 6H), 6. 89 (d, 1H, J=9), 1207, 508 [M-1]' 7. 08 (dd, 1H, J = 9, 3), 7. 15 (d, 1H, J = 3), 1476, R4 p-CF3C6H4-7. 60 (s, 2H), 7. 98 (d, 2H, J = 3), 8. 08 (d, 2H, J 1697 = 3) 32 (MeOH-d4) : 2. 12 (s, 6H), 3. 23 (s, 3H), 6. 96-7. 01205, 378 [M-1]' (m, 2H), 7. 11 (d, 1 H, J = 2. 2), 7. 51 (s, 2H) 1481, R4=Me-1687, 1739 33 (DMSO-de) : 0. 81 (t, 3H, J = 7. 2), 1. 24-1. 36 (m, 1205, 420 [M-1 OA n R.. H), 1. 41-1. 51 (m, 2H), 2. 04 (s, 6H), 3. 37 (t, 1488, 2H, J = 7. 2), 6. 88 (d, 1 H, J = 3), 7. 08 (dd, 1H, 1694 439 J = 9, 3), 7. 15 (d, 1H, J = 3), 7. 00-7. 10 (m, M+NH 2H), 7. 57 (s, 2H), 10. 67 (s, 2H)

34 (DMSO-d6) : 1. 11 (d, 6H, J = 7), 2. 03 (s, 6H), 1229, 406 [M-1]' 3. 66-3. 75 (m, 1 H), 6. 88 (d, 1 H, J = 3),), 7. 02 1354, (d, 1 H, J=3), 7. 08 (dd, 1 J= 9, 3), 7. 57 (s, 1480, 425 2H), 10. 65 (s, 2H) 1688, M+NH4t 1761

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

The title compound is prepared similarly to Example 26: NMR (DMSO-d6) 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]-.

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

The title compound is prepared similarly to Example 26: NMR (DMSO-d6) 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), 7.397.45 (m, 4H), 7.93 (dd, 2H, J = 8.8, 5.2), 9.93 (s, 1H), 10.5 (brs, 1H), 12.1 (s, 1 H) ; IR (KBr) 1480,1659, 1717; ESI-MS 486 [M-1r.

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

The title compound is prepared similarly to Example 26: NMR (MeOH-d4) 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+1t, 458 [M-1r.

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

The title compound is prepared similarly to Example 26: NMR (DMSO-d6) 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]-.

Example 39 N-{3,5-Dibromo-4-[3-(4-fluorobenzenesulfonyl)-4-hydroxyphenoxy]phenyl}oxamic acid

The title compound is prepared analogously to Example 26: NMR (DMSO-d6) 6.91 (d, 1 H, J = 9), 7.09 (dd, 1 H, J = 9,3), 7.20 (d, 1 H, 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

The title compound is prepared analogously to Example 26 : NMR (DMSO-d6) 2. 06 (s, 6H), 6. 88 (d, 1H, J = 9), 7. 03 (dd, 1H, J = 9, 3), 7. 13 (d, 1H, J = 3), 7. 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, 1 H), 10. 58 (s, 1H) ; IR (KBr) 1141, 1250, 1481, 1676 ; ESI-MS 497 [M-1]", 475 [M+NH4]'.

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

The title compound is prepared analogously to Example 26: ES-MS 499 [M-1]-, 518 [M+NH4]+.

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

The title compound is prepared analogously to Example 26: ES-MS 499 [M-1]-, 518 [M+NH4t.

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

The title compound is prepared analogously to Example 26: ES-MS 513 [M-1]-, 515 [M+1]+, 532 [M+NH4r.

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

The title compound is prepared analogously to Example 26: ES-MS 517 [M+1] +.

Example 45

N- {4- [3- (4-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl}-2morphot ! n-4-yt-2-oxoacetam) de

The title compound is prepared analogously to Example 26: ES-MS 527 [M-1 529 [M+1F, 546 [M+NH4]+.

Example 46

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

A. 5- (2, 6-Dimethyt-4-nitrophenoxy)-2- (2-methoxyethoxymethoxy) benzoic acid 2 methoxyethoxymethyl ester A suspension of sodium NaH (60% dispersion in mineral oil ; 1.32 g, 33 mmol) in 50 mL of NMP is cooled to 0 C and 2,5-dihydroxybenzoic acid (1.54 g, 10 mmol) is added in one portion. The mixture is warmed to room temperature, and after 30 min, 4-chloro-3, 5 dimethyl-nitrobenzene (2.41 g, 13 mmol) is added in one portion and the reaction is heated at 120oC for 3 h. The reaction is cooled to RT and 2-methoxyethoxymethyl chloride (2.85 mL, 25 mmol) is added. After stirring for 30 min, the mixture is poured onto water and the product is taken up in Et2O. The organic solution is washed with brine, dried over anhydrous Na2SO4and concentrated. Chromatography on silica (eluant ; EtOAc/hexane-1/2- 3/2)

affords 5- (2, 6-dimethyi-4-nitrophenoxy)-2- (2-methoxyethoxymethoxy) benzoic acid 2 methoxyethoxymethyl ester: NMR (CDCI3) 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 A mixture of the title A compound, 5-(2,6-dimethyl-4-nitrophenoxy)-2-(2-methoxyethoxymethoxy) 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 is stirred under hydrogen atmosphere (H2, 1 atm) for 3 h. The catalyst is removed by vacuum filtration through celite, washed with EtOAc, and the combined filtrate and washings are concentrated and dried under vacuum to give 5- (4-amino-2, 6-dimethyiphenoxy)-2- (2- methoxyethoxymethoxy) benzoic acid 2-methoxy-ethoxymethyl ester: NMR (CDCI3) 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- (Ethoxyoxalylamlno) -2, 6-dimethylphenoxy]-2-hydroxybenzolc acid A solution of the title B compound, 5-(4-amino-2,6-dimethylphenoxy)-2-(2-methoxyethoxymethoxy) benzoic acid 2-methoxyethoxymethyl ester (2.83 g, 6.3 mmol) in 20 mL of THF is cooled to OoC and treated sequentially with NMM (2.1 mL, 18.9 mmol) and ethyl oxalyl chloride (0.915 mL, 8.19 mmol). After 15 min, the mixture is partitioned between EtOAc and water, and the organic solution is washed with brine, dried over anhydrous Na2S04 and concentrated. The residue is dissolved in 30 mL of EtOH and 20 mL of aqueous 6N HCI is added. The mixture is stirred at RT for 16 h, and EtOH is removed under reduced pressure. The residue is diluted with water (100 mL), and the solid is collected by vacuum filtration, washed with water and dried. Crystallization from acetonitril gives 5-[4-

(ethoxyoxalylamino)-2, 6-dimethylphenoxy]-2-hydroxybenzoic acid : NMR (DMSO-d6) 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, 1 H, J = 9, 3), 7. 54 (s, 2H), 10. 7 (s, 1 H).

D. N- {4- [4-Hydroxy-3- (piperidine-1-carbonyl) phenoxy]-3, 5-dimethylphenyi} oxamic acid A solution of title C compound, 5-[4-(ethoxyoxalylamino)-2,6-dimethylphenoxy]-2hydroxybenzoic acid (37 mg, 0.1 mmol) in 1 mL of DMF is treated with NMM (55 AL, 0.5 mmol) and 1, 1'-carbonyidiimidazole (32 mg, 0.2 mmol) at RT. The reaction mixture is heated at 60 C for 1 h, then cooled to RT and piperidine (24 uL, 0.24 mmol) is added. After 16 h,

the reaction is treated with aqueous 1. 5 N LiOH (333 uL, 0. 5 mmol). The mixture is agitated for 30 min, and the reaction is quenched with trifluoroacetic acid (TFA ; 100 gel). The product is purified by HPLC (mobile phase ; acetonitrile-water with 0. 1% of trifluoroacetic acid) to afford N- {4- [4-hydroxy-3- (piperidine-1-carbony !) phenoxy]-3, 5-dimethyipheny)) oxamic acid: NMR (DMSO-d6) 1.34-1. 63 (m, 6H), 2.06 (s, 6H), 3.30 (br s, 4H), 6.36 (d, 1 H, J = 2.3), 6.67 (dd, 1 H, J = 8. 3,2. 3), 6.80 (d, 1 H, J = 8.3), 7.53 (s, 2H), 9.38 (br s, 1 H), 10.6 (s, 1H) ; ESI MS 413 [M+1r.

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

The title compound is prepared similarly to Example 46: ESI-MS 415 [M+1t.

Example 48 N- [4- (3-Cyclohexylcarbamoyl-4-hydroxyphenoxy)-3, 5-dimethylphenyl] oxamic acid

(i) The title compound is prepared similarly to Example 46: ESI-MS 427 [M+1.

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

The title compound is prepared similarly to Example 46: ESI-MS 403 [M+1] +.

(ii) Example 50

N- {4- [4-Hydroxy-3- (2-morphoHn-4-yl-ethylcarbamoyl) phenoxy]-3, 5dimethy ! phenyt}-oxam ! c ac ! d

The title compound is prepared similarly to Example 46 : ESI-MS 458 [M+1t.

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

The title compound is prepared similarly to Example 46: ESI-MS 422 [M+1] +.

Example 52 A composition for topical administration is made, comprising:

Component Amount Active Ingredient 1% Ethanol 60% Propylene Glycol 20% Dimethyl Isosorbide 19% A human male subject suffering from male pattern baldness is treated by daily topical administration of the above composition for 4-8 weeks to the scalp.

Example 53 A composition for topical administration is made according to the method of Dowton et aI., "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporin A: I. An in vitro Study Using Hairless Mouse Skin", S. T. P. Pharma Sciences. Vol. 3, pp. 404407 (1993), using Novasome 1 for the non-ionic liposomal formulation.

A human male subject suffering from male pattern baldness is treated each day with the above composition for 4-8 weeks, the above composition being administered topically to the scalp.

Claims (12)

1. What is claimed is: 1. A method for the treatment of hair loss which comprises administering to a mammal in need thereof an effective amount of a compound of the formula

   in which W is 0, S, S (O) or S (Oh 2 ; X is -SR4, -S(O)R4, -S(O)2R4, or -S(O)2NR5R6; X is or -C(O)NR5R6 located at the 3'-, 4'- or 5' position; Y is 0 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, heteroaryloxy, aralkoxy,

   cycloalkoxy, heteroaralkoxy or-NR5R6 ; R2 is hydrogen, halogen, trifluoromethyl, cyano or alkyl ; R3 is halogen, trifluoromethyl, cyano 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 alkylen optionally interrupted by 0, S, S (O), S (Oh 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; or a pharmaceutically acceptable salt thereof.
2. 2. A method according to claim 1 in which compound W is O or S; X is -S(O)2R4; R4 being lower alkyl, phenyl or phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluormethyl ; or is -S(O)2NR5R6; or is -C(O)NR5R6 located at the 3', 4'or 5'-position; R5, in each case, being hydrogen or lower alkyl and R6, in each case, being hydrogen, lower alkyl, lower alkyl substituted by NR5R6, 3-to 7-membered cycloalkyl, phenyl, phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluormethyl ; pyridyl or N-lower alkyl-2-pyridone ; or R5 and R6 combined, in each case, being alkylen or alkylen interrupted by 0 or S (Oh which together with the nitrogen atom to which they are attached form a 5-to 7membered ring; Y is 0 or H2 ; Z is hydrogen or hydroxy; R is hydrogen; R1 is hydroxy, lower alkoxy or NR5R6 ; R5 being hydrogen or lower alkyl and R6 being hydrogen, lower alkyl, lower alkoxy or R5 and R6 combined being alkylen or alkylen interrupted by 0 which together with the nitrogen atom to which they are attached form a 5to 7-membered ring; R2 is hydrogen, halogen or lower alkyl ; R3 is halogen or lower alkyl ; and n represents zero, 1 or 2;
3. 3. A method according to claim 1 which comprises administering a compound of the formula

   in which W is O or S; X is-SR4,-S (0) R4,-S (0) 2R4,-S (0) 2NR5R6 or-C (0) NR5R6; Y is 0 or H2 ; Z is hydrogen, halogen, hydroxy, alkoxy, aralkoxy, acyloxy or alkoxycarbonyloxy ; R1 is hydroxy, lower alkoxy or aryloxy ; R2 is hydrogen, halogen or lower alkyl ; R3 is halogen or lower alkyl ; R4 is optionally substituted alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl ; R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl,

   aryl, aralkyl, heteroaryl, or heteroaralkyl ; or R5 and R6 combined are alkylen optionally interrupted by 0, S, S (O), S (Oh 2 or NR7 which together with the nitrogen atom to which they are attached form a 5-to 7-membered ring ; n represents zero, 1 to 2 ; or a pharmaceutically acceptable salt thereof.
4. 4. A method according to claim 1 which comprises administering a compound of the formula

   wherein X is -S(O)2R4, -S(O)2NR5R6 or -C(O)NR5R6; Z is hydroxy, lower alkanoyloxy or alkoxy ; R1 is hydroxy or lower alkoxy ; R2 and R3 are lower alkyl ; R4 is aryl ; 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 0, S, S (O), S (Oh 2 or NR7 which together with the nitrogen atom to which they are attached form a 5-to 7-membered ring; which may optionally contain another heteratom selected from oxygen, nitrogen and sulfur ; or a pharmaceutical acceptable salt thereof.
5. 5. A method according to claim 4 which comprises administering a compound wherein X is - S (0) 2R4 or-S (0) 2NR5R6 ; or a pharmaceutically acceptable salt thereof.
6. 6. A method for the treatment of hair loss which comprises administering to a mammal in need thereof a compound of the formula

   wherein X is-S (0) 2R4 or-S (0) 2NR5R6 ; R4 is monocyclic aryl ; R5, R6 and R7 are independently hydrogen, optionally substituted alkyl or aryl ; or R5 and R6 combined are CH2CH2-Q-CH2CH2 wherein Q is CH2, 0, NR7, S, S (O) or S (Oh which together with the nitrogen atom to which they are attached from a 6-membered ring; or a pharmaceutically acceptable prodrug ester thereof; or a pharmaceutically acceptable salt thereof.
7. 7. A method according to claim 6 wherein X is S (OhR4 and R4 is phenyl optionally substituted by lower alkyl, halo, lower alkoxy or trifluormethyl ; or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable prodrug ester thereof.
8. 8. A method according to claim 6 in which the compound is selected from:

   N- [4- (4-Hydroxy-3-pheny) sutfamoy) phenoxy)-3, 5-dimethytpheny)] oxamicacid ; N- [4- (4-Hydroxy-3-isopropy) su) famoy) phenoxy)-3, 5-dimethytpheny)] oxarnic acid ; N-[ 4- (4-Hydroxy-3-isobutylsulfamoylphenoxy) -3, 5-dimethylphenyl]oxamic acid ; and N- {4 [3- (4-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyt} oxamic acid ; or a pharmaceutically acceptable salt thereof ; or a pharmaceutically acceptable prodrug ester thereof.
9. 9. A method according to claim 6 in which the compound is : N- {4 [3- (4-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl} oxamic acid ; or a pharmaceutically acceptable salt thereof ; or a pharmaceutically acceptable prodrug ester thereof.
10. 10. A method according to claim 1 in which the compound is selected from : N- {4- [3- (2, 2-Dimethylpropy) sulfamoyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl} oxamic acid ; N- [4- (4-Hydroxy-3-phenyisu ! famoyiphenoxy)-3, 5-dimethytpheny)] oxamicacid ; N- {4- [3- (4-Fluorophenyisulfamoyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl} oxamic acid ; N- {4- {3- (2-Fluorophenylsulfamoyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl) oxamic acid ; N- {4- [3- (3-Fluorophenylsulfamoyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl} oxamic acid ; N- {4- [4-Hydroxy-3- (4-methoxyphenylsulfamoyl) phenoxy]-3, 5-dimethylphenyl} oxamic acid ; N- {4- [3- (4-Fluorobenzylsulfamoyl)-4-hydroxy-phenoxy]-3, 5-dimethylphenyl} oxamic acid ; N- {4- [4-Hydroxy-3- (methylphenylsulfamoyl) phenoxy]-3, 5-dimethylphenyl} oxamic acid ; N- [4- (4-Hydroxy-3-propy) su) famoy) phenoxy)-3, 5-dimethy) pheny)] oxamicacid ; N- [4- (4-Hydroxy-3-isopropylsulfamoylphenoxy)-3, 5-dimethylphenyl] oxamic acid ; N- [4- (3-Buty) su) famoy)-4-hydroxyphenoxy)-3, 5-dimethy) pheny)] oxamicacid ; N- [4- (4-Hydroxy-3-isobuty) su) famoy) phenoxy)-3, 5-dimethy) pheny)] oxamicacid ; N- [4- (3-t-Buty) su) famoy)-4-hydroxyphenoxy)-3, 5-dimethy) pheny)] oxamicacid ; N-[ 4- (3-Cyclohexylsulfamoyl-4-hydroxyphenoxy) -3, 5-dimethylp henyl]oxamic acid ;

    N- [4- (3-Dimethylsulfamoyl-4-hydroxyphenoxy)-3, 5-dimethylphenyl] oxamic acid ; N- {4- [4-Hydroxy-3- (pyrrolidine-1-sulfonyl) phenoxy]-3, 5-dimethylphenyl} oxamic acid ; N- {4- [4-Hydroxy-3- (piperidine-1-sulfonyl) phenoxy]-3, 5-dimethylphenyl} oxamic acid ; N- {4- [4-Hydroxy-3- (2-methoxyethylsulfamoyl) phenoxy]-3, 5-dimethylpheny)} oxamic acid ; N- {4- [4-Hydroxy-3- (morpholine-4-sulfonyl) phenoxy]-3, 5-dimethylpheny)} oxamic acid ; N- {4- [3- (Dioxothiomorpholine-4-sulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl} oxamic acid ; N- {4- [4-Hydroxy-3- (pyridin-3-ylsulfamoyl) phenoxy]-3, 5-dimethylpheny)} oxamic acid ; N- {4- [4-Hydroxy-3- (1-methyl-6-oxo-1, 6-dihydropyridin-3-ylsulfamoyl) phenoxy]-3, 5dimethylphenyl) oxamic acid ; N- {4- [3 (4-Fluorophenylsulfamoyl)-4-hydroxyphenylsulfanyl]-3, 5-dimethylphenyl} oxamic acid ; N- {4- [3- (4-Fluorophenylsulfamoyl) phenoxy]-3, 5-dimethylphenyl} oxamic acid ; N- {4- [3- (4-Fluorophenyisulfamoyl)-4-hydroxyphenoxy]-3-methylpheny)) oxamic acid ; N- {4- [3- (4-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl} oxamic acid ; N- [4- (3-Benzenesuifonyt-4-hydroxyphenoxy)-3, 5-dimethy) pheny)] oxamicacid ; N- {4- [3- (4-Chlorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyt} oxamic acid ; N- {4- [4-Hydroxy-3- (toluene-4-sulfonyl) phenoxy]-3, 5-dimethylpheny)} oxamic acid ; N- {4- [4-Hydroxy-3- (4-methoxybenzenesulfonyl) phenoxy]-3, 5-dimethyl-pheny)) oxamic acid ; N- {4- [4-Hydroxy-3- (4-trifluoromethylbenzenesulfonyl) phenoxy]-3, 5-dimethylpheny)} oxamic acid ; N- [4- (4-Hydroxy-3-methanesu) fony) phenoxy)-3, 5-dimethy) pheny)] oxamicacid ; N- {4- [3- (Butane-1-sulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl} oxamic acid ; N- {4- [4-Hydroxy-3- (propane-2-sulfonyl) phenoxy]-3, 5-dimethylphenyl} oxamic acid N- {4- [3- (4-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl} malonamic acid ; N- {4- [3- (4-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl} succinamic acid ; 3- {4- [3- (4-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenylamino} propionic acid ; (2) N- {4- [3- (4-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3- methylphenyl} oxamic acid;

    N- (3, 5-Dibromo-4 [3- (4-fluorobenzenesulfonyl)-4-hydroxyphenoxy] phenyl} oxamic acid ; N- {4- [3- (4-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl} oxalamide ; N- {4- [3- (4-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl}-N'-propyloxalamide ; N- {4- [3- (4-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl}-N'-isopropyloxalamide ; N-Butyl-N'- {4- [3- (4-fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl}oxalamide ; N- (4- [3- (4-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl}-N'- (2methoxyethyl) oxalamide ; N- {4- [3- (4-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5-dimethylphenyl}-2-morpholin-4-yl2-oxoacetamide ; N- {4- [3- (4-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3, 5-dimethyl phenyl}-2-morpholin-4-yl2-oxoacetamide ; N- {4- [4-Hydroxy-3- (piperidine-1-carbonyl) phenoxy]-3, 5-dimethylphenyl) oxamic acid ; N- {4- [4-Hydroxy-3- (morpholine-4-carbonyl) phenoxy]-3, 5-dimethylphenyl} oxamic acid ; N- [4- (3-Cyc) ohexy) carbamoy)-4-hydroxyphenoxy)-3, 5-dimethytpheny)] oxamicacid ; N- {4- [4-Hydroxy-3- (2-methoxyethy) carbamoy)) phenoxy]-3, 5-dimethy) pheny)) oxamicacid ; 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) phenoxy]-3, 5-dimethylphenyl) oxamic acid ; or a pharmaceutically acceptable salt thereof.
11. 11. A method according to claim 1 in which the compound is administered as a pharmaceutical formulation comprising a said compound.
12. 12. A method according to claim 11 in which the compound is administered as a topical pharmaceutical formulation.