SI9200314A - COMPOUNDS FOR TREATMENT OF DISEASES CONCERNING LEUKOTRIEN DISEASES - Google Patents

Abstract

This invention relates to certain benzyl sulfides and amines useful as leukotriene antagonists, to a process for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of diseases, particularly those related to leukotrienes.

Description

SMITHKLINE BEECHAM CORPORATION

Compounds for the treatment of leukotriene-related diseases

Scope of the invention

This invention relates to certain compounds containing a substituted pyridyl group linked to a substituted phenyl group by an alkyl or heteroatom-containing chain, and to their use for the treatment of diseases originating from or related to leukotrienes, particularly leukotriene B ₄ . As such, they are useful for antagonizing the effects of leukotrienes.

Background of the invention

A family of biologically active lipids known as leukotrienes exhibit pharmacological effects on the respiratory, cardiovascular, and gastrointestinal systems. Leukotrienes are broadly divided into two subclasses, the peptidoleukotrienes (leukotrienes C ₄ , D ₄ , and E ₄ ) and the dihydroxyleukotrienes (leukotriene B ₄ ). The present invention relates primarily to the hydroxylleukotrienes (LTBs), but is not limited to this specific group of leukotrienes.

Leukotrienes are critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic and inflammatory diseases, including asthma, adult respiratory distress syndrome, cystic fibrosis, psoriasis and inflammatory bowel disease.

LTB ₄ has been shown to be a mediator of inflammation in vivo. It has also been associated with airway hyperresponsiveness in dogs and has been found in elevated concentrations in lung lavages from humans with severe lung function disorders.

By antagonizing the effects of LTB ₄ or other pharmacologically active mediators on an end organ, e.g. airway smooth muscle, the compounds and pharmaceutical compositions of the invention are useful in the treatment of subjects, including humans or animals, in which leukotrienes are a factor.

Brief summary of the invention

The invention relates to novel benzyl sulfides of formula I

or an N-oxide or pharmaceutically acceptable salt, wherein ZO is, NH, NCH ₃ or S(O) wherein q is 0,1 or 2, m is 0-5;

R is a C _x to C^-aliphatic radical, an unsubstituted or substituted phenyl C^C^-aliphatic radical, wherein the substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl and halo, or RC ₁ -C ₂₀ -aliphatic radical-Ο-, or R is an unsubstituted or substituted phenyl C ₁ -C ₁₀ -aliphatic radical-O-, wherein the substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl and halo;

R _x is -(C _x -C ₅ -aliphatic radical)R ₄ , -(C _x -C ₅ -aliphatic radical)CHO, (C _x -C ₅ -aliphatic radicaljC^ORg, -R ₄ , -CH ₂ OH or CHO;

R ₂ is H, halo, lower alkyl, lower alkoxy, -CN, -(CH^R,,, -CH(NH ₂ )(R ₄ ) or -(CH ₂ ) _n R ₉ , where n is 0 - 5 and where R ₉ is -N(R ₇ ) ₂ , where each R _? is independently H or an aliphatic group of 1 to 10 carbon atoms, or an acyl of 1 to 6 carbon atoms or a cycloalkyl-(CH ₂ ) _n -group of 4 to 10 carbon atoms, where n is 0-3, or both R _? groups form a ring having 4 to 6 carbons; or

R ₃ is hydrogen, lower alkyl, lower alkoxy, halo, -CN, -COR ₅ , -NHCONH ₂ or -OH;

1 1 2S2 each R ₄ group is independently -COR ₅ , where R ₅ is -OH, a -OR ₆ group forming a pharmaceutically acceptable ester, or -OX, where X is a pharmaceutically acceptable cation, or R ₅ is -N(R ₇ ) ₂ , where each R _? is independently H, or an aliphatic group having 1 to 10 carbon atoms or a cycloalkyl-(CH ₂ ) _n -group having 4 to 10 carbon atoms, where n is 0-3, or both R _? groups form a ring having 4 to 6 carbons, or R ₄ is sulfonamide or amide or tetrazol-5-yl; and R _g is hydrogen, C^-C^-alkyl or C^-C^acyl, provided that R ₂ and R ₃ are not 2,6-dihalo, 2,6-di(lower alkyl), 2,6-di(lower alkoxy) or

2,6-dicyano.

Another aspect of this invention comprises pharmaceutical compositions comprising these compounds and a pharmaceutically acceptable carrier.

The treatment of diseases associated with or caused by leukotrienes, particularly LTB ₄ or related pharmacologically active mediators, in an end organ is within the scope of the present invention. This treatment can be carried out by administering one or more compounds of formula I alone or in combination with a pharmaceutically acceptable carrier.

Also included within the scope of this invention are processes for preparing these compounds, comprising

a) salt formation or

b) hydrolyzing the ester to form a salt or acid,

c) ester formation,

d) amide formation,

e) oxidation of thio ether,

f) forming a compound of formula I by treating a 6-halomethylpyridyl compound with the appropriate mercaptobenzoate or hydroxybenzoate.

Detailed description of the invention

In describing this invention and explaining in detail what the inventors believe to be their invention herein, we use the following definitions.

Aliphatic includes saturated and unsaturated radicals. This includes normal and branched chains, saturated or mono- or poly-unsaturated chains, where both double and triple bonds may be present in any combination. The term lower alkyl means an alkyl group having 1 to 6 carbon atoms in any isomeric form, and in particular normal or

1 1 292 linear form. Lower alkoxy means a lower alkyl-O- group. Halo means fluoro, chloro, bromo or iodo. Acyl means a radical having a terminal carbonyl carbon.

When referring to a substituted phenyl ring, it is intended that the ring may be substituted with one or more of the substituents listed, as may be compatible with chemical synthesis. The multiple substituents may be the same or different, as where all three are chloro groups, or a combination of chloro and alkyl groups, and further where this latter combination may have different alkyl radicals in the chloro/alkyl substituent pattern.

The term pharmaceutically acceptable ester-forming group in R ₂ and R ₃ includes all esters that can be formed from the acid function(s) that may be present in these compounds. The resulting esters will be esters that are acceptable in their application in pharmaceutical use. This is to say that the mono- or diesters will retain the biological activity of the parent compound and will not have an adverse or deleterious effect in their application and use in the treatment of disease. Such esters are, for example, esters formed with one of the following radicals: C 1 -C ₆ alkyl, phenyl C 1 -C 6 alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl or thienylglycyloxymethyl. The most preferred ester-forming radicals are those where _R3 is alkyl, especially alkyl of 1 to 10 carbons, (i.e., CH2CH2-, where n is 0-9, or phenylCH2-, where n is 0-4.

When referring to R ₂ as an amine, this includes the radical -NH ₂ and mono- or dialkylate derivatives of this radical -NH ₂ . Preferred alkylated amines are mono- or disubstituted amines with 1 to 6 carbons. When referring to R ₂ as an amide, this includes all acylated derivatives of the radical -NH ₂ . Preferred amines are those with 1 to 6 carbons.

If an acidic group is present, amides may be formed. The most preferred amides are those where -R ₆ is hydrogen or alkyl of 1 to 6 carbon atoms. Diethylamide or dimethylamide is particularly preferred.

This invention is intended to encompass pharmaceutically acceptable salts of the compounds herein. These salts will be salts that are acceptable in their administration or pharmaceutical use. By this is meant that the salt will retain the biological activity of the parent compound and that the salt will not have adverse or deleterious effects in its administration and use in the treatment of disease.

Pharmaceutically acceptable salts are prepared in a standard manner in a suitable solvent.

ί 111292

The parent compound is reacted in a suitable solvent with an excess of organic or inorganic acid, in the case of acid addition salts, or with an excess of organic or inorganic base, if R ₄ is -OH.

N-oxides can also be prepared using selected oxidizing agents. These oxides are useful as intermediates in the preparation of compounds of formula I and have useful pharmaceutical efficacy in themselves. Accordingly, N-oxides of formula I can be administered to a subject susceptible to, or caused by, a disease associated with, or suffering from, LTB ₄ or similar leukotrienes.

If a combination of substituents in a compound of the invention results in a chiral center or some other form of isomeric center, all forms of such isomers are included herein. These compounds may be used as a racemic mixture or the racemates may be separated and the individual enantiomers used alone. Olefins may have the cis or trans configuration (E or Z); either or both are useful in the practice of this invention.

As leukotriene antagonists, these compounds can be used in the treatment of various diseases related to leukotrienes, in particular LTB ₄ , or whose origin or effects are attributed to them. It is therefore expected that these compounds can be used in the treatment of allergic diseases, such as those of a pulmonary or non-pulmonary nature. These compounds will be useful, for example, in antigen-induced anaphylaxis, for the treatment of asthma and allergic rhinitis, psoriasis or irritable bowel disease, eye diseases such as uveitis and allergic conjunctivitis.

Preferred compounds are those where ZO or S(O) _q ; m is 0-3; n is 0-2; R is alkoxy of 8 to 15 carbon atoms or unsubstituted or substituted phenyl Cj-Cj-aliphatic radical-O-; and Rj is -(Cj-Cj-aliphatic radical)R ₄ or -(Cj-Cj-aliphatic radical)CH ₂ OR _g . More preferred compounds in the context of this invention are those where R ₁ R ₄ is CH=CH- and R ₂ is -COR ₅ or -NHSO ₂ CF ₃ . Another set of preferred compounds are anilines, those where R ₂ is -N(R ₇ ) ₂ , especially those where R _? is hydrogen. A third set of preferred compounds are those where R ₂ and R ₃ are both hydrogen.

The most preferred compounds are 1-fluoro-3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzene, lithium salt;

111292

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzene, lithium salt;

3-[2-thia-3-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzene, lithium salt;

2-[2-thia-3-[2-(2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridylethyl]benzene, lithium salt;

1-fluoro-4-[2-thia-3-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzene, lithium salt;

1-fluoro-4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzene, lithium salt;

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridylethyl]benzoic acid;

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridylethylbenzoic acid;

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid;

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy]-6-pyridyl]ethyl]benzoic acid;

3-[1-dioxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy]-6-pyridyl]ethyl]benzoic acid;

2-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy]-6-pyridyl]ethyl]benzoic acid, lithium salt;

N-[3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy]-6-pyridyl]ethyl]phenyl]trifluoromethanesulfonamide,

N-[3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethylphenyltrifluoromethanesulfonamide, ' 111202 7

N-[3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethyl]phenyl]trifluoromethanesulfonamide,

N-[3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy]-6-pyridyl] ethyl]phenyl]phenylsulfonamide,

N-[3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethyl]phenyl]phenylsulfonamide,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy]-6-pyridyl]ethyl]benzoic acid,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethyl]benzoic acid,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octan-1-yl]-6-pyridyl]ethyl]benzoic acid,

4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoic acid,

4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzoic acid,

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoic acid,

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzoic acid,

3-[2-thia-3-[2-(2-carboxyethanyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoic acid,

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]N,N-dimethylbenzamide, lithium salt,

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]/ 111 propyl]N,N-dimethylbenzamide, lithium salt,

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-phenylbutyloxy]-6-pyridyl]propyl]benzoic acid,

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-phenyloctyloxy]-6-pyridyl]propyl]benzoic acid,

3-[2-thia-3-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzoic acid,

4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenylacetic acid,

4-[2-oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoic acid,

3-[2-oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoic acid,

4-[2-oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenylacetic acid,

3-[2-dioxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoic acid,

5-[3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propylphenyltetrazole,

- [1-oxa-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethylaniline,

5-carboxy-3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl ethyl] aniline,

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethylaniline,

1 1 2S2

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-[8-(4-trifluoromethylphenyl)octyloxy]-6-pyridyl]ethylaniline,

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-[8-(4-trifluoromethylphenyl)octyloxy]-6-pyridyl]ethyl]aniline, lithium salt,

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-phenyloctyloxy)-6-pyridyl]ethyl]aniline, lithium salt,

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-fluorophenyl)octyloxy)-6-pyridyl]ethyl]aniline,

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-phenyl)octyloxy)-6-pyridyl]ethyl]aniline,

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline,

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6-pyridyl]ethyl]aniline, lithium salt,

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6-pyridyl]ethyl janinline, lithium salt,

3-[1-Dioxythia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6-pyridyl]ethylaniline, lithium salt,

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]propyl N,N-dimethylaniline,

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethylaniline,

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethylN,N-dimethylaniline,

3-[1-dioxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]

1112 92 ίο ethyl]aniline, (E)-sodium 3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(phenylthio)methyl]-2-pyridinyl]

2-propenoate, (E)-lithium 3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(3,4-dichlorophenylthio)methyl]-2-pyridinyl]-2-propenoate, (E)-lithium 3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(4-chlorophenylthio)methyl]-2-pyridinyl]-2-propenoate, (E)-Sodium 3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(4-fluorophenylthio)methyl]-2-pyridinyl]-2-propenoate, (E)-Lithium 3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(2-chlorophenylthio)methyl]-2-pyridinyl]-2-propenoate, (E)-Sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(2-chlorophenylthio)methyl]-2-pyridinyl]-2-propenoate, (E)-Sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(2-methylphenylthio)methyl]-2-pyridinyl]-2-propenoate, (E)-Sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(3-chlorophenylthio)methyl]-2-pyridinyl]-2-propenoate, (E)-Sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(2-methoxyphenylthio)methyl]-2-pyridinyl]-2-propenoate, (E)-Sodium 3-[3-[4-(4-Methoxyphenyl)butoxy]-6-[(2,4-dichlorophenylthio)methyl]-2-pyridinyl]-2-propenoate, (E)-Sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(2-bromobenzylthio)methyl]-2-pyridinyl]-2-propenoate, (E)-Sodium 3-[3-[4-(4-Methoxyphenyl)butoxy]-6-[(2-cyano-6-chlorophenylthio)methyl]-2-pyridinyl]-2-propenoate.

111292

Synthesis

There are several methods for preparing these compounds. One general procedure involves the preparation of

of a 6-(halomethyl)pyridyl adduct and then condensing this fragment with an appropriate mercaptan or alcohol to give compounds where Z is sulfur or oxygen. Typically, functional groups, such as acid groups, will be protected; each acid group may be derivatized in some manner to render it unreactive. After the condensation reaction, the protecting groups may be removed to provide the parent functionality, e.g., the acid. Further modifications of these reactive groups may be carried out, such as salt, amide, ester, etc. formation. Sulfonamides are prepared from the appropriate amines by literature methods. Tetrazoles are prepared from the appropriate acid halide, e.g., acid chloride, by literature methods.

The following reaction schemes provide a more detailed illustration of the chemistry for the preparation of these compounds. Scheme I outlines a method for preparing the substituted phenylalkyl end, which is R.

Scheme I

Pd(Ph ₃ P) ₂ CI ₂

OSi ^l BuPhc

Pd-C

MeO

1112 22

The starting alcohol, represented here by 3-octyn-1-ol, is commercially available (Lancaster Synthesis). To move the triple bond to the w-carbon, KH and 1,3-diaminopropane are combined and stirred until a homogeneous mixture is obtained. This can be done at or around room temperature. This mixture is then cooled, preferably to about 0°C, after which the alcohol is added. Stirring is then started at about room temperature and stirred for about 15 to 20 hours. Water is added to quench the reaction and the product is obtained.

The protection of the alcohol is carried out by forming a silyl ether, shown here as t-butyldiphenylsilyl ether. Other silyl ethers can be used. The alcohol is dissolved in a polar solvent, e.g. dimethylformamide, the imidazole is added, and then the desired silane. All this is carried out under an inert atmosphere, such as argon. Room temperature is acceptable for carrying out the reaction.

The addition of the phenyl group is carried out in a dry environment using an amine as solvent and an inert atmosphere. To a flask containing a solvent, such as triethylamine, under argon, is added the silyl ether, followed by a halophenyl compound, e.g. iodoanisole, a palladium catalyst (Ph ₃ P) ₂ PdCl ₂ and CuI, both in catalytic amounts. Heat is used to effect the reaction; usually a temperature of up to about 50°C will suffice. Usually 2 or more hours, up to 6, but often about 4 at elevated temperature, will suffice to complete the reaction.

The triple bond is then saturated, preferably by catalytic hydrogenation. For example, the silyl ether can be dissolved in a saturated solvent, such as an alcohol, a heavy metal catalyst (Pd-C) added, and the mixture placed under H ₂ for a time sufficient to reduce the triple bond. Typically, the reaction will be complete after 2 to 6 hours of stirring.

The alcohol is recovered by treating the silyl ether with a fluoride source, such as tetrabutylammonium fluoride. The reactants are combined at a slightly reduced '* Š-* temperature, e.g. 0°C, and the reaction is then allowed to proceed at or about room temperature. The reaction may take several hours to complete. The product is recovered by extraction.

The conversion of the alcohol to the iodo compound is carried out using phosphine, imidazole and I ₂ . In practice, this conversion is carried out by adding a molar excess of triphenylphosphine, e.g. a threefold excess of imidazole, to a solution of the alcohol under argon, followed by iodine. The materials are combined at room temperature, and the reaction vessel can then be heated briefly, 10 minutes to 1 hour, to 50 to 70°C to complete the reaction. Standard procedures are then used to recover and purify the product.

Scheme II illustrates an alternative procedure for making R groups.

Scheme II

While the methoxyphenyl compound is discussed here, this series of steps and reagents can be used to prepare other substituted - w-phenylaliphatic groups, denoted by R. The starting materials, benzaldehydes, are commercially available or can be readily prepared by known methods.

To prepare the acid, first the alkylsilazide is added to an inert solvent under an inert atmosphere. The phosphonium salt is then added. This addition can be carried out at or around room temperature. After brief stirring - this mixture is usually a suspension - the benzaldehyde is slowly added at a temperature around room temperature. A slight molar excess of the phosphonium salt is used. After a further brief stirring at a temperature around room temperature, the reaction is quenched with water. The solution is acidified and the acid is extracted with a suitable organic solvent. Additional procedures can be used if desired to

1 1 2 G2 separation and purification.

The alcohol is prepared by reducing the acid using a reducing agent. Lithium aluminum hydride or similar reducing agents may be used, and the conditions may be varied as necessary to effect the reduction.

The tosylate is prepared in an inert solvent using a base such as pyridine. Suitable conditions include carrying out the reaction at or around room temperature for a period of 1 to 5 hours. Other leaving groups that function similarly to the tosylate can be prepared and will be useful as a means of forming the R moiety.

These procedures can be used to prepare a complete spectrum of radicals represented by R, where R has a terminal phenyl group, including substituted phenylaliphatic radicals.

Benzyl mercaptans or analogous compounds, where m is 1 or greater than 1, are commercially available or can be prepared by the process of Scheme III.

Scheme III

^x Jf^-co ₂ R s JI h ₂ n nh ₂ "ΛΪ> ^β X= Cl, Br R= alkyl Alcohol Br' ^HS J0-CO ₂ H Acid - ^HS, ^0- ^co 2Me

The starting materials, haloalkylbenzoates, are commercially available or can be prepared by methods known in the art. Thiourea is added to a solution of the haloalkylbenzoate at or around room temperature. Any suitable solvent can be used, e.g.

acetone. Under these conditions, a precipitate of thiouronium salts should form. The precipitate is collected and dissolved in water and the pH is adjusted to about 10.5 with a base, e.g. with NaOH solution.

1 1 202

Then we begin with refluxing for 1 to 4 hours. The product is then obtained as the free acid by some other separation and purification process. The esterification is then carried out by mixing the acid with the alcohol, bubbling through a solution of HCl, and allowing the resulting solution to stand for no more than a few days; two days is usually sufficient to complete the reaction.

Compounds of formula I in which Z is oxygen can be prepared by the sequence of steps set forth in Scheme IV.

Scheme IV

1. MΓ1Ο21 CH ₂ CI ₂

2. C ₁₂ H ₂₅ l, K ₂ CO ₃ Η ₂₅ Ο ₁₂ Ογ^

3. (Ph) ₃ PCHCO ₂ Me _Μ θ _θ2 θ^4 _Ν ^ΟΗ ₃

1. MCPBA, CH ₂ CI ₂

2. TFAA, DMF

3. _{K2CO3 ,} MeOH

4. SOCI ₂

H ₂₅ Ci ₂ O MeOgC^

COoMe

N CH ₂ CI HCH

1. LiOH.THF, MeOH 2. H ⁺

^JDO ₂ H ho ₂ c^

H

25^12

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The starting material is available from Aldrich. It is treated with a mild oxidizing agent, such as _MnO2 , to oxidize the 2-hydroxyethyl group to the corresponding aldehyde. The R group is then formed. In this case, the ether is prepared under basic conditions using a halogen intermediate. The tosylate prepared according to Scheme III can also be used at this stage. The introduction of the acid function at position 2 is carried out with the triphenylphosphoranylidene reagent. The acetate form is discussed here, but other similar reagents can be used. The N-oxide is then formed with a peroxy acid. Trifluoroacetic anhydride is used to oxidize the methyl group at position 6. This hydroxymethyl group is then converted with thionyl chloride to the corresponding halide (in the form of the hydrohalide), in this case the chloride. The alkyl hydroxybenzoate is then reacted with

6-chloromethyl compounds in the presence of tetrabutylammonium iodide and a weak base. The resulting diester can be hydrolyzed to the salt or then acidified to give the free acid. An oxidant can be used to regenerate the N-oxide, and the N-oxide can then be treated with a base to hydrolyze the esters. The esters can be converted to salts, free acids, or other derivatives. Catalytic hydrogenation can be used to reduce the double bond in the R _t group described herein.

Scheme V illustrates a method for preparing compounds in which Z is S and m is 0.

1112 02

Scheme V

^MCPBA aq LiOH

MeOH

1112 92

The starting hydrochloride is described in Scheme IV. Instead of treating the hydrochloride with an alcohol, the mercapto analog of the hydroxybenzoate described above is used. The resulting thioether can be hydrolyzed to give the salt or further treated to give the free acid, from which other derivatives of the carboxyl function, including alcohols and aldehydes, can be prepared. The double bond in the R _x group can also be reduced catalytically using a heavy metal catalyst and hydrogen.

After the thioether has been prepared, the sulfone and sulfoxide can be prepared by treating the thioether with an oxidizing agent. Peroxyacid or another oxidizing agent can be used.

A method for preparing compounds in which R is alkyl or substituted alkyl is set forth in Scheme VI.

Scheme VI

HO,

HO ₂ ^CR n

MeO ₂ C^N^

2. Tf ₂ O/Pyridine _MeQc ^ _N

1. DIBAL_

2. (C ₆ H ₅ ) ₃ PCHCO ₂ Me MeO ₂ C

Pd(OAc) ₂ /dppf/DMF

1. MCPBA

2. TFAA, DMF _r

3. Tf ₂ O, pyridine

4. Pd(OAc) ₂ , dppf MeOH, CO

_MeO2C

1112 92

In this scheme, 2-hydroxypicolinic acid is converted to an alkyl ester using the appropriate alcohol and acid to catalyze the reaction. The hydroxyl group is then converted to a trifluoromethylsulfonate using trifluoromethanesulfonic anhydride and a base, e.g. pyridine. The lipid end is attached using the appropriate alkyl catechol boronate under palladium coupling conditions. For example, 1-iododecene and catechol borane are reacted to form the alkyl catechol boronate. An alkylation reaction is then carried out using Pd(OAc) ₂ . The ester is reduced to the corresponding aldehyde with a hydride, such as diisobutylaluminum hydride (DIBAL). A Wittig olefination is then carried out, e.g. using methyl(triphenylphosphoranylidene)acetate. The resulting pyridyl methyl acrylate is then oxidized with an oxidizing agent, such as 3-chloroperoxybenzoic acid, to the N-oxide. This oxide is then converted with trifluoroacetic anhydride to 2-pyridone. The trifluoromethylsulfonate is then formed using trifluoromethanesulfonic anhydride and pyridine. Carbomethylation is then carried out using Pd(OAc) ₂ , a simple alcohol, and carbon monoxide. Selective reduction of the pyridyl ester (using a hydride such as NaBH ₄ in a low molecular weight alcohol) gives 2-(hydroxymethyl)pyridine. This compound is treated with thionyl chloride to form

6-chloromethyl compound. This intermediate is converted to ethers or thioethers of formula I in the same manner as shown in Schemes IV - VI.

Pharmaceutical compositions of the invention comprise a pharmaceutical carrier or diluent and an amount of a compound of formula (I). The compound may be present in an amount that produces a physiological response, or it may be present in a smaller amount such that the user will have to take two or more units of the composition to achieve the intended treatment. These compositions may be formulated as solid, liquid or gaseous forms, or may be converted from one of these three forms to another at the time of administration, such as when a solid is administered as an aerosol or when a liquid is administered as a spray or aerosol.

The nature of the formulation and pharmaceutical carrier or diluent will, of course, depend on the intended route of administration, e.g. parenteral, topical, oral or by inhalation.

For parenteral administration, the pharmaceutical preparation will be in the form of a sterile injectable liquid, as an ampoule or a suspension in an aqueous or non-aqueous liquid.

For topical administration, the pharmaceutical preparation will be in the form of a cream, ointment, salves, lotion, paste, and drops suitable for administration into the eye, ear, or nose.

1112

For oral administration, the pharmaceutical preparation will be in the form of a tablet, capsule, powder, pellet, lozenge, syrup, liquid, or emulsion.

When using a pharmaceutical preparation in the form of a solution or suspension, examples of suitable pharmaceutical carriers or diluents include water for aqueous systems, ethanol, glycerin, propylene glycol, corn germ oil, cottonseed oil, peanut oil, sesame oil, liquid paraffins and mixtures thereof with water for non-aqueous systems, lactose, kaolin and mannitol for solid systems, and dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide for aerosol systems. In addition to the pharmaceutical carrier or diluent, these preparations may also contain other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not adversely affect the therapeutic effect of these preparations.

The pharmaceutical preparations thus described are prepared according to the usual techniques of a pharmaceutical chemist, as is applicable to the desired end product.

Preparations for the treatment of psoriasis may be in the form of oral or topical preparations. Preparations for topical use are preferred. Examples of preferred topical preparations are ointments, creams, salves, lotions, pastes and the like. Aerosols may also be used. These dosage forms will contain between 0.01 and 5% by weight of the active ingredient.

Typically, the compound of formula I is administered, i.e., administered to the subject in a composition comprising a non-toxic amount sufficient to cause the symptoms of the disease state to be prevented. If administered orally, the dosage of the composition is selected to be in the range of 50 mg to 1000 mg of active ingredient for each administration. For convenience, equal doses will be administered 1 to 5 times daily, with a daily dosage regimen of about 50 mg to about 5000 mg being selected. If a topical composition is used, the amount used will depend on the size of the affected area and the severity and degree to which the disease, e.g. psoriasis, has progressed.

Included within the scope of this disclosure is a method for treating a disease mediated by LTB ₄ , comprising administering a therapeutically effective amount of a compound of formula I, preferably in the form of a pharmaceutical composition, to a subject. For example, included within the scope of this disclosure is the prevention of an inflammatory response resulting from psoriasis by administering

- 111 2C2 effective amounts of the compound of formula I. Administration may be carried out in dosage units at suitable intervals or in single doses as required. This method will normally be used when relief of symptoms is specifically required. However, the method is also useful as a continuous or prophylactic treatment. It is within the skill of the art to determine by routine experimentation from the above dosage range the effective dosage to be administered, taking into account factors such as the severity of the condition or disease being treated, etc.

Pharmaceutical compositions and methods for their use also include the combination of a compound of formula I with Hj-blockers, wherein the combination comprises a sufficient amount of both compounds for the treatment of antigen-induced respiratory anaphylaxis or similar allergic reactions. Representative Hj-blockers useful herein include cromolyn sodium, compounds from the ethanolamine class (diphenhydramine), ethylenediamine (pyrilamine), alkylamine (chlorpheniramine), piperazines (chlorcyclizine) and phenothiazines (promethazine). Hj-blockers such as 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-[(6-methylpyrid-3-yl)methyl]-4-pyrimidone are particularly useful in this invention.

Biological tests

The specificity of antagonistic activity of several compounds of the invention is demonstrated by the relatively low levels of antagonism against agonists such as potassium chloride, carbachol, histamine and PGF ₂ .

The affinity of the compounds used in the method of the invention for receptor binding is measured by the ability of the compounds to bind to the [ ³ H]-LTB ₄ binding sites on human U937 cells. The antagonistic activity of the compounds used in the method of the invention against LTB ₄ is measured by their ability to antagonize in a dose-dependent manner the LTB _4- induced calcium influx measured with fura-2, a fluorescent calcium probe. The methods used are as follows.

U-937 cell culture conditions

U-937 cells were obtained from Dr. John Bomalaski (Medical College of PA) and Dr. John Lee (SmithKline Beecham Corp., Dept. of Immunology) and cultured in RPMI-1640 medium supplemented with 10% (v/v) heat-inactivated fetal calf serum in a humidified environment of 5% CO ₂ and 95% air at 37°C. The cells were

1112

ŽjMi were grown in both T-flasks and Spinner culture. To distinguish between DMSO-treated U937 cells and macrophage-like cells, cells were seeded at a concentration of ΙχΙΟ ⁵ cells/ml in supernatant medium with 1.3% DMSO and incubated for 4 days. Cell densities were generally 0.75 -1.25 χ 10 ⁶ cells/ml and were harvested by centrifugation at 800 x g for 10 minutes.

Preparation of the fraction enriched with U-937 cell membranes

The harvested U-937 cells were washed with 50 mM Tris-HCl, pH 7.4 at 25°C containing 1 mM EDTA (buffer A). The cells were resuspended at a concentration of 5 χ 10 ⁷ cells/ml in buffer A and disrupted by cavitation with nitrogen for 10 min using a Parr bomb at 52.75 bar. The pelleted cell preparation was centrifuged for 10 min at 1000 x g. The supernatant was centrifuged for 30 min at 50,000 x g. The pellet was washed twice with buffer A. The pellet was resuspended with approximately 3 mg membrane protein/ml in 50 mM Tris-HCl, pH 7.4 at 25°C and aliquots were snap frozen and stored at -70°C.

Binding of [ ^3H1 - _LTB4 to membrane receptors U-937

[ ³ H]-LTB4 binding assays were performed at 25°C in 50 mM Tris-HCl (pH 7.5) buffer containing 10 mM CaCl2, 10 mM MgCl^ [ ³ H]-LTB4, a membrane protein of U937 cells (standard conditions) in the presence or absence of various concentrations of LTB ₄ or test compounds. Each experimental point represents the average of three determinations. Total and nonspecific binding of [ ³ H]-LTB4 was determined in the absence or presence of 2 mM unlabeled LTB4. Specific binding was calculated as the difference between total and nonspecific binding. Radioligand competition experiments were performed under standard conditions using approximately 0.2 nM [ ³ H]-LTB4, 20-40 mg of U-937 cell membrane protein, increasing concentrations of _LTB4 (0.1 mM to 10 mM) or other competitive ligands (0.1 mM to 30 mM) in a reaction volume of 0.2 ml and incubated for 30 min at 25°C. Unbound radioligand and competitive drugs were separated from membrane-bound ligand by vacuum filtration. Membrane-bound radioactivity on the filters was determined by liquid scintillation spectrometry.

Saturation binding experiments were performed for U-937 cells under standard conditions, using 15 to 50 mg of U-937 membrane protein and increasing concentrations of [ ³ H]-LTB ₄ (0.02-2.0 nM) in a reaction volume of 0.2 ml and a 30-minute incubation at 22°C. In a separate series of incubation tubes, LTB ₄ (2 mM) was included,

C 1 1 1 202 to determine non-specific binding. Data from saturation binding experiments were analyzed by computer-aided least squares nonlinear curve fitting analysis and further analyzed by the Scatchard method.

FURA-2 uptake into differentiated U-937 cells

The harvested cells were resuspended at 2 x ¹⁰⁶ cells/ml in Krebs-Ringer-Hensilet buffer containing 0.1% BSA (RIA grade), 1.1 mM _MgSO4 , 1.0 mM CaCl2 _and 5 mM HEPES (pH 7.4, buffer B). The diacetomethoxy ester of FURA-2 (FURA-2/AM) was added to a final concentration of 2 mM and the cells were incubated in the dark for 30 minutes at 37°C. The cells were centrifuged at 800 xg for 10 minutes and resuspended at 2 x ¹⁰⁶ cells/ml in fresh buffer B and incubated at 37°C for 20 minutes to allow complete hydrolysis of the captured ester. The cells were centrifuged at 800 xg for 10 minutes and resuspended in cold fresh buffer B at 5 x ¹⁰⁶ cells/ml. Cells were kept on ice in the dark until used for fluorescence measurements.

Fluorescence measurements - calcium mobilization

Fluorescence of U-937 cells containing FURA-2 was measured using a fluorometer designed by the Johnson Foundation Biomedical Instrumentation Group. The fluorometer was equipped with temperature control and a magnetic stirrer under the cuvette holder. The wavelengths were set at 339 nm for excitation and 499 nm for emission. All experiments were performed at 37°C with constant stirring.

U-937 cells were diluted with fresh buffer (B) to a concentration of 1 χ 10 ⁶ cells/ml and stored in the dark on ice. Aliquots (2 ml) of the cell suspension were placed in 4 ml cuvettes and the temperature was raised to 37°C (and maintained in a 37°C water bath for 10 min). The cuvettes were transferred to a fluorometer and fluorescence was measured approximately 1 min before the addition of stimulants or antagonists and monitored approximately 2 min after the stimulus. Agonists and antagonists were added as 2 ml aliquots.

Antagonists were first added to the cells in a fluorometer to determine potential agonist activity. After about 1 min, 10 nM LTB ₄ (near maximal effective concentration) was added and the maximal Ca ² mobilization [Ca ²⁺ ]j was calculated using the following formula: [Ca ²⁺ li = 224i^ ^m ^ ⁿ jFmax-F

1112 92

F was a measurement of the maximum relative fluorescence of the sample. Fmax was determined by lysing the cells with 10 ml of 10% Triton X-100 (final concentration 0.02%). After Fmax was determined, 67 ml of 100 mM EDTA solution (pH 10) was added to completely chelate Ca ²⁺ and quench the FURA-2 signal to obtain Fmin. The [Ca ²⁺ ]j level for 10 nM LTB4 in the absence of antagonist was 100% and the basal [Ca ²⁺ ] 4 was 0%. The IC ₅₀ concentration is the concentration of antagonist that blocks 50% of the [Ca ²⁺ ] mobilization induced by 10 nM LTB4. The EC50 for the increase in [Ca ²⁺ ]i mobilization induced by LTB ₄ was the concentration at half the maximal increase. The K for calcium mobilization was determined using the formula

ICso

Who

1Ψ [LTB4] [EC50]

With the described experiments, the concentration of LTB ₄ was 10 nM and the EC _J0 was 2 nM.

Specific implementation forms

The following examples are provided to illustrate how to prepare and use the compounds of the invention. These examples are merely examples and are not intended to limit the scope of the invention in any way. For a definition of what is reserved to the inventors herein, reference is made to the claims.

Example 1

8-(4-Methoxyphenyl)octan-1-(4-toluenesulfonate)1(a)7-octyn-1-ol

35% KH in mineral oil (27 g, 240 mmol) under argon was washed with hexane and treated dropwise with 1,3-diaminopropane. The mixture was stirred at room temperature until homogeneous. The flask was cooled to 0°C and 3-octyn-1-ol (10 g, 79 mmol, Lancaster Synthesis) was added slowly. The reaction mixture was then stirred at room temperature for 18 h. The reaction was quenched with H ₂ O (50 ml) and the product was extracted into ether. The organic layer was washed with 10% HCl (3x15 ml) and brine and dried (MgSO ₄ ). Evaporation gave the title compound, which was used without further purification. *H NMR (90 MHz, CDC^ d 3.65 (t, J=5Hz, 2H, OCH ₂ ), 2.23 (m, 2H, CH ₂ ), 2.0 (m, IH, acetylenic), 1.7-1.2 (m, 8H, (CH^; IR (pure (u^ 3350,2930,2125 cm ^{4 )} .

111292 1(b) 7-octyne-1-f-butyldiphenylsilyl ether

7-Octyn-1-ol (3.8 g) was dissolved in dimethylformamide (10 ml) and treated with i-butylchlorodiphenylsilane (10.2 ml, 33 mmol) and imidazole (3.65 g, 45 mmol) at 0°C. The reaction mixture was stirred at 0°C for 10 min and at room temperature for 3 h. Water was added and the product was extracted into ethyl acetate. The ethyl acetate extract was washed with H ₂ O and brine and dried (Na^O*). The solvent was evaporated and the residue was purified by flash column chromatography ( _SiO2 , hexanes) to give a yellow oil. ¹ H NMR (250 MHz, _CDCl3 ) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 3.63 (t, 2H, _OCH2 ), 2.23 (m, 2H, _CH2 ), 1.97 (t, 1H, acetylenic), 1.6-1.3 (m, 8H, (CH^), 1.05 (s, 9H, ί-butyl); IR (film) _Umax 3321,2940,2125 ^cm4 .

1(c) 8-(4-Methoxyphenyl)-7-octyne-1-i-butyldiphenylsilyl ether

In a flame-dried flask, under an argon atmosphere, was placed 4-iodoanisole (5.34 g, 22 mmol) in triethylamine (50 mL), followed by the addition of 7-octyne-1-butyldiphenylsilyl ether (9.84 g, 27 mmol), (Pl^P^PdC^ (350 mg, 0.44 mmol), and CuJ (200 mg, 0.88 mmol). The resulting mixture was heated at 50°C for 4 h. After cooling to room temperature, the reaction mixture was filtered and the solvent was evaporated. The residue was partitioned between ethyl acetate and H^O and the organic layer was collected, washed with brine, and dried _{( Na2SO4} ). The solvent was evaporated and the residue was purified by flash column chromatography ( _SiO2 , 1% ethyl acetate in hexanes) to give an oil: Ή NMR (250 MHz, CDC1 ₃ ) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH ₃ ), 3.7 (t, 2H, OCH ₂ ), 2.4 (t, 2H, CH ₂ ), 1.7-1.3 (m, 8H, (CH 2 ), 1.05 (s, 9H, i-butyl).

1(d) 8-(4-Methoxyphenyl)octane-1-i-butyldiphenylsilyl ether

To 8-(4-methoxyphenyl)-7-octyne-1-butyldiphenylsilyl ether (2.16 g, 4.6 mmol) in ethanol (10 mL) and ethyl acetate (10 mL) was added 5% Pd/C (100 mg). The mixture was exposed to H ₂ at 52.7 bar for 4 h. The reaction mixture was filtered through Celite and the solvent was evaporated to give an oil: Ή NMR (250 MHz, CDC1 ₃ ) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH ₃ ), 3.6 (t, 2H, OCH ₂ ), 2.5 (t, 2H, benzyl), 1.75-1.3 (m, 12H, (CH ₂ ) ₆ ), 1.0 (s, 9H, i-butyl).

1 1 2 02 l(e) 8-(4-methoxyphenyl)octan-1-ol

8-(4-Methoxyphenyl)octane-1-butyldiphenylsilyl ether (2.18 g, 4.6 mmol) in tetrahydrofuran (20 mL) was cooled to 0°C and treated with tetrabutylammonium fluoride (14 mL, 14 mmol, 1M in tetrahydrofuran). The cooling bath was removed and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried (Na^SO^. The solvent was evaporated and the residue was purified by flash column chromatography ( _SiO2 , 0-20% ethyl acetate in hexanes) to give a white solid. ^! H NMR (250 MHz, _CDCl3 ) δ 7.15 (d, 2H, aryl), 6.86 (d, 2H, aryl), 3.85 (s, 3H, _OCH3 ), 3.68 (t, 2H, _OCH2 ), 2.62 (t, 2H, benzylic), 1.75-1.3 (m, 12H, ((¾)^.

(f) 8-(4-Methoxyphenyl)octane-1-(4-toluenesulfonate)

6-(4-Methoxyphenyl)octan-1-ol (5.91 g, 25 mmol) was dissolved in dry CHCl3 (100 mL) under an argon atmosphere and cooled to 0°C. To this was added pyridine (2.5 mL, 30 mmol) _and 4-toluenesulfonyl chloride (5.4 g, 28 mmol). The reaction mixture was stirred at 0°C for 20 min and at room temperature for 24 h. The reaction solution was washed with _H2O and brine and dried ( _Na2SO4 ). The solvent was evaporated and the residue was purified by flash column chromatography ( _SiO2 , 0-10% ethyl acetate in hexanes) to give a white solid. Ή NMR (250 MHz, _CDCl3 ) δ 7.79 (d, 2H, aryl), 7.35 (d, 2H, aryl), 7.09 (d, 2H, aryl) 6.82 (d, 2H, aryl) 4.04 (s, 2H, _OCH2 ), 3.8 (s, 3H, _OCH3 ), 2.55 (t, 2H, benzylic), 2.46 (s, 3H, _CH3 ), 1.75-1.15 (m, 12H, ( _CH2 ) ₆ ).

Example 2

6-(4-Methoxyphenyl)hexane-1-(4-toluenesulfonate)

2(a) 5-Hexyne-1-Z-butyldiphenylsilyl ether

5-Hexyn-1-ol (3 g, 30 mmol, Aldrich) was dissolved in dimethylformamide (10 mL) and treated with i-butylchlorodiphenylsilane (10.2 mL, 33 mmol) and imidazole (3.65 g, 45 mmol) at 0°C. The reaction mixture was stirred at 0°C for 10 min and at room temperature for 3 h. Water was added and the product was extracted into ethyl acetate. The ethyl acetate extract was washed with H ₂ O and brine and dried (Na ₂ SO ₄ ). The solvent was evaporated and the residue was purified by flash column chromatography (SiO ₂ , hexanes) to give a yellow oil: ^X H NMR (250 MHz, CDCl ₃ ) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 3.65 (t,

1112 huh?

2H, OCH ₂ ), 2.2 (m, 2H, CH ₂ ), 1.9 (t, IH, acetylenic), 1.7 (m, 4H, CH ₂ CH ₂ ), 1.05 (s, 9H, i-butyl).

2(b) 6-(4-Methoxyphenyl)-5-hexyne-1-i-butyldiphenylsilyl ether

In a flame-dried flask under argon atmosphere, 4-iodoanisole (5.34 g, 22 mmol) in triethylamine (50 mL) was placed and then 5-hexyne-1-butyldiphenylsilyl ether (8.83 g, 27 mmol), (Ph ₃ P) ₂ PdCl ₂ (350 mg, 0.44 mmol) and CuI (200 mg, 0.88 mmol) were added. The resulting mixture was heated at 50°C for 4 h. After cooling to room temperature, the reaction mixture was filtered and the solvent was evaporated. The residue was partitioned between ethyl acetate and _H2O and the organic layer was collected, washed with brine and dried (Na2SO4). The solvent was evaporated and the residue was purified by flash column chromatography ( _SiO2 , 1% ethyl acetate in hexanes) to give an oil: NMR (250 MHz, _CDCl3 ) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, _OCH3 ), 3.7 (t, 2H, _OCH2 ), 2.4 (t, 2H, _CH2 ), 1.7 (m, 4H, _CH2 - _CH2 ), 1.05 (s, 9H, i-butyl).

2(c) 6-(4-Methoxyphenyl)hexane-1-i-butyldiphenylsilyl ether

To 6-(4-methoxyphenyl)-5-hexyne-1-butyldiphenylsilyl ether (2.0 g, 4.6 mmol) in ethanol (10 mL) and ethyl acetate (10 mL) was added 5% Pd/C (100 mg). The mixture was exposed to H ₂ at 52.7 bar for 4 h. The reaction mixture was filtered through Celite and the solvent was evaporated to give an oil: Ή NMR (250 MHz, CDC1 ₃ ) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH ₃ ), 3.6 (t, 2H, OCH ₂ ), 2.5 (t, 2H, benzyl) 1.55 (m, 4H, CH ₂ -CH ₂ ), 1.3 (m, 4H, CH ₂ -CH ₂ ), 1.0 (s, 9H, /-butyl).

2(e) 6-(4-Methoxyphenyl)hexan-1-ol

6-(4-Methoxyphenyl)hexane-1-butyldiphenylsilyl ether (2.0 g, 4.6 mmol) in tetrahydrofuran (20 mL) was cooled to 0°C and treated with tetrabutylammonium fluoride (14 mL, 14 mmol, 1M in tetrahydrofuran). The cooling bath was removed and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate, washed with Na2SO4 and brine _, and dried ( _Na2SO4 ). The solvent was evaporated and the residue was purified by flash column chromatography (SiO ₂ , 0-20% ethyl acetate in hexanes) to give a white solid: ^J H NMR (250 MHz, CDCl ₃ ) δ 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH ₃ ), 3.65 (t, 2H, OCH^, 2.55 (t, 2H, benzylic) 1.6 (m, 4H, C^-CHj), 1.4 (m, 4H, CH^CH^).

1112

2(f) 6-(4-methoxyphenyl)hexane-1-(4*toluenesulfonate)

6-(4-Methoxyphenyl)hexan-1-ol (5.36 g, 25 mmol) was dissolved in dry CH ₂ -Cl ₂ (100 mL) under an argon atmosphere and cooled to 0° C. Pyridine (2.5 mL, 30 mmol) and 4-toluenesulfonyl chloride (5.4 g, 28 mmol) were added. The reaction mixture was stirred at 0° C. for 20 min and at room temperature for 24 h. The reaction solution was washed with _H2O and brine and dried (Na^O^. The solvent was evaporated and the residue was purified by flash column chromatography ( _SiO2 , 0-10% ethyl acetate in hexanes) to give a white solid: ¹ H NMR (250 MHz, _CDCl3 ) δ 1.6-1.3 (m, 8H, CH^), 2.4 (s, 3H, _CH3 ), 2.5 (t, 2H, benzylic) 3.8 (s, 3H, _OCH3 ), 4.0 (t, 2H, OCH^), 6.80 (d, 2H, aryl), 7.0 (d, 2H, aryl), 7.3 (d, 2H, aryl), 7.8 (d, 2H, aryl).

Example 3

E-6-(4-methoxyphenyl)-1-(4-toluenesulfonate)-5-hexene

3(a) E-4-methoxyphenyl-5-hexenoic acid

To a freshly prepared solution of lithium hexamethyldisilazide (64 mmol) in tetrahydrofuran (30 mL) was added a suspension of (4-carboxybutyl)triphenylphosphonium bromide (17.6 g, 30 mmol) in tetrahydrofuran (45 mL) under an argon atmosphere at room temperature. The reaction mixture was stirred for 15 min, during which time an orange-red color of the ylide developed. A solution of

4-anisaldehyde (4.5 g, 30 mmol) in tetrahydrofuran (30 mL) and stirring was continued for 20 min. The reaction was quenched with _H2O (50 mL) and diluted with ether (30 mL). The aqueous layer was acidified to pH 1.0 with 3N HCl and the product was extracted into ethyl acetate (3X50 mL). The combined organic layers were dried ( _MgSO4 ) and the product was purified by flash column chromatography ( _SiO2 , 1% _methanol in _CH2Cl2 ) to give the E-olefin as a solid: ^X H NMR (200 MHz, _CDCl3 ) δ 7.3 (d, 2H, aryl), 6.8 (d, 2H, aryl) 6.3 (d, 1H, olefin), 6.0 (m, 1H, olefin), 3.8 (s, 3H, _OCH3 ), 2.3 (m, 4H, allylic and C^COJ, 1.8 (q, 2H, _CH2 ).

3(b)E-4-Methoxyphenyl-5-hexen-1-ol

E-4-Methoxyphenyl-5-hexenoic acid (1.1 g, 5.0 mmol) in dry ether (10 ml) was slowly added to a suspension of LiAlH ₄ (240 mg, 6.0 mmol) in ether (10 ml) under an argon atmosphere. The reaction mixture was refluxed for 45 minutes. After cooling to room temperature' 1 1 1 2 ε 2

At 3°C, the reaction mixture was quenched with _H2O (10 mL) and then with _{6N H2SO4} (7 mL). Ethyl acetate (20 mL) was added and the organic layer was separated and dried ( _MgSO4 ); evaporation gave a white crystalline solid: mp 65-66°C; ¹ H NMR (200 MHz, _CDCl3 ) δ 7.2 (d, 2H, aryl), 6.8 (d, 2H, aryl) 6.3 (d, 1H, olefin), 6.1 (m, 1H, olefin), 3.8 (s, 3H, _OCH3 ), 3.6 (t, 2H, _OCH2 ), 2.2 (q, 2H, allylic), 1.5 (m, 4H, _CH2 - _CH2 ); Anal.: calcd. for _C13H18O2 : C _75.65 ; H 8.80, found: _C 75.45; H 8.95; MS (Cl): 207 (M+H).

3(c) E-6-(4-methoxyphenyl)-1-(4-toluenesulfonate)-5-hexene

E-4-Methoxyphenyl-5-hexen-1-ol (1.6 g, 7.0 mmol) was dissolved in dry CH ₂ Cl ₂ (50 mL) under an argon atmosphere and treated with 4-toluenesulfonyl chloride (7.0 g, 36 mmol) and pyridine (3 mL). The reaction solution was stirred at room temperature for 3.5 hours. Water (40 mL) was added to the reaction mixture and the organic layer was separated and dried (MgSO ₄ ). The product was purified by flash column chromatography (SiO ₂ , 10% ethyl acetate in hexane) to give an oil: ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.8 (d, 2H, aryl), 7.3 (d, 2H, aryl), 7.2 (d, 2H, aryl) 6.8 (d, 2H, aryl), 6.2 (d, 2H, aryl). IH, olefin), 6.0 (m, IH, olefin), 4.1 (t, 2H, OCH ₂ ), 3.8 (s, 3H, OCH ₃ ), 2.4 (s, 3H, CH ₃ ), 2.1 (q, 2H, allylic), 1.6 (m, 4H, CHfCHJ; MS (Cl): 361 (M+H).

Example 4 1-iodo-8-(4-methoxyphenyl)octane

4(a) 7-Octyn-1-ol. Potassium hydride (35%-ene) in mineral oil (27 g, 240 mmol) under argon was washed with hexane and treated dropwise with 1,3-diaminopropane. The mixture was stirred at room temperature until homogeneous. The flask was cooled to 0°C and 3-octyn-1-ol (10 g, 79 mmol, Lancaster Synthesis) was added slowly. The reaction mixture was then stirred at room temperature for 18 h. The reaction mixture was quenched with H ₂ O (50 ml) and the product was extracted into ether. The organic layer was washed with 10% HCl and brine and dried (MgSO ₄ ). Evaporation gave the title product as a colorless oil, which was used without further purification ^: H NMR (90 MHz, CDCl ₃ ) δ 3.65 (t,J=5Hz, 2H, O-CH ₂ ), 2.23 (m, 2H, CH ₂ ), 2.0 (m, 1H, acetylene), 1.7-1.2 (m, 8H, CH^; IR (neat) n _max 3350,2930,2125 cm' ¹ .

4(b) 7-Octyn-1-i-butyldiphenylsilyl ether. To a cooled (0°C) solution of 7-octyn-1-ol (9.3 g,

73.7 mmol) in dimethylformamide (DMF) (70 ml) was added under an argon atmosphere, followed by i-butylchlorodiphenylsilane (21 ml, 81 mmol) dropwise. The reaction mixture was then stirred at room temperature for 2 h. The reaction solution was diluted with _Et2O and washed with _H2O and brine and dried ( _MgSO4 ). Purification by flash column chromatography ( _SiO2 , 3% EtOAc in hexane) gave the product as a colorless oil: ¹ H NMR (250 MHz, _CDCl3 ) S δ,δ (d, 4H, aryl), 7.4 (m, 6H, aryl), 3.63 (t, 2H, O- _CH2 ), 2.23 (m, 2H, _CH2 ), 1.97 (t, 1H, acetylenic), 1.6-1.3 (m, 8H, CH^), 1.05 (s, 9H, ί-butyl); ER (film) n _max 3321.2940, 2125 ^cm4 .

4(c) 8-(4-Methoxyphenyl)-7-octyne-1-r-butyldiphenylsilyl ether. To a flame-dried flask containing triethylamine (140 ml) was added under an argon atmosphere:

4-Iodoanisole (13.3 g, 56.9 mmol), 7-octyne-1-butyldiphenylsilyl ether (24.9 g, 68.3 mmol), catalyst (PhjP^PdCLj (793 mg, 1.13 mmol) and CuJ (431 mg, 2.27 mmol). The resulting mixture was heated at 50°C for 4 h. After cooling to room temperature, the reaction mixture was filtered, the solid was washed with Et ₂ O and the solvent was evaporated. The residue was diluted with Et ₂ O and washed with 5% HCl, H ₂ O, NaHCO ₃ and brine and dried (MgSO ₄ ). Purification by flash column chromatography (SiO ₂ , 2% EtOAc in hexane) gave the product as an orange oil: ^X H NMR (250 MHz, CDCl ₃ ) 8 Ί,Ί (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH ₃ ), 3.7 (t, 2H, O-CH ₂ ), 2.4 (t, 2H, CH^, 1.7-1.3 (m, 8H, CH ₂ ) ₄ ), 1.05 (s, 9H, f-butyl).

4(d) 8-(4-Methoxyphenyl)octane-1-r-butyldiphenylsilyl ether

8-(4-Methoxyphenyl)octyne-1-butyldiphenylsilyl ether (30 g, 63.7 mmol) was dissolved in EtOH (125 mL) and EtOAc (125 mL) and treated with 5% Pd-C catalyst (3 g). The reaction mixture was stirred vigorously under an atmosphere of H ₂ (flask pressure) for 4 h. The reaction mixture was filtered through a pad of Celite and the solvent was evaporated. The resulting light yellow oil was pure by NMR analysis and was used directly in the next step: *H NMR (250 MHz, CDCl ₃ ) δ Ί,Ί (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH ₃ ), 3.6 (t, 2H, O-CH ₂ ), 2.5 (t, 2H, benzyl), 1.75-1.3 (m, 12H, CH^, 1.0 (s, 9H, i-butyl).

4(e) 8-(4-Methoxyphenyl)octan-1-ol. To a cooled (0°C) solution of 8-(4-methoxyphenyl)octane-1r-butyldiphenylsilyl ether (63 mmol) was added tetrabutylammonium fluoride (70 mL, 70 mmol; 1M solution in THF). The cooling bath was removed and the reaction mixture was stirred at room temperature for 4.5 h. The solvent was evaporated and the residue was dissolved in _Et2O . This was washed with _H2O , 5% HCl, _NaHCO3 and brine and dried ( _MgSO4 ). Purification by flash column chromatography ( _SiO2 , 30% EtOAc in hexane) gave the product as a colorless solid: ¹ H NMR (250 h 111292

MHz, CDCLj) δ 7.15 (d, J=8.6Hz, 2H, aryl), 6.86 (d, J=8.6Hz, 2H, aryl), 3.85 (s, 3H, OCH ₃ ), 3.68 (t, J=6.5Hz, 2H, O-CH^, 2.62 (t, J=7.6Hz, 2H, benzyl), 1.75-1.3 (m, 12H, CH 2 ): MS (Cl): 254.2 (M+NH ₄ ); mp 47-49°C.

4(f) l-iodo-8-(4-methoxyphenyl)octane. Triphenylphosphine (17.8 g, 67.6 mmol) and imidazole (10.6 g, 156 mmol) were added to a stirred solution of 8-(4methoxyphenyl)octan-1-ol- (12.3 g, 52 mmol) in dry toluene (200 ml) under an argon atmosphere. After the imidazole had dissolved, J ₂ (17.1 g, 67.6 mmol) was added. The reaction mixture was then heated at 65°C for 30 min. After cooling to room temperature, the reaction mixture was concentrated to 1/4 volume. The remaining solution was diluted with Et ₂ O, washed with H ₂ O and brine, and dried (MgSO ₄ ). The solvent was removed and the resulting residue was dissolved in CH ₂ Cl ₂ and applied to a flash chromatography column (SiO ₂ ). Elution with 2% EtOAc in hexane gave the product as a colorless oil (slight contamination with triphenylphosphine): ¹ H NMR (250 MHz, CDCl ₃ ) δ 7.08 (d, J=8, 6Hz, 2H, aryl), 6.82 (d, J=8.6Hz, 2H, aryl), 3.78 (s, 3H, OCH ₃ ), 3.17 (t, J=7.4Hz, 2H, J-CH ₂ ), 2.54 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH^, 1.60 (m, 2H, CH ₂ ), 1.31 (m, 8H, aliphatic): MS (Cl): 364.2 (M+NH ₄ ).

Example 5

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, dilithium salt l(a) 3-hydroxy-6-methyl-2-pyridine carboxaldehyde

2,6-Lutidine-α2,3-diol (1.0 g, 7.18 mmol, Aldrich) was suspended in dry _CH2Cl2 (40 mL) and treated with _MnO2 (6.1 g, 70 mmol). The reaction mixture was stirred at room temperature for 6 h. _The reaction mixture was filtered through a pad of Celite and the solvent was removed in vacuo. The aldehyde was used directly in the next step without further purification: Ή NMR (250 MHz, CDCl3) δ 10.65 (s, 1H, OH), 10.30 (s, 1H, CHO), 7.30 (dd, 2H, 4-pyridyl, 5-pyridyl), 2.55 (s, 3H, _CH3 ).

5(b) 3-dodecyloxy-6-methyl-2-pyridine carboxaldehyde

The 3-hydroxy-6-methyl-2-pyridine carboxaldehyde obtained above was dissolved in dry dimethylformamide (10 mL) and treated with 1-iodododecane (2.1 mL, 8.62 mmol) and anhydrous I^CO3 (3.0 g, 21.7 mmol) under an argon atmosphere. The reaction mixture was

1 1 222 was heated with vigorous stirring for 1 h at 90°C. After cooling to room temperature, the reaction mixture was poured into ethyl acetate (100 mL); the ethyl acetate solution was washed with H ₂ O (3X20 mL) and brine and dried (MgSO ₄ ). The solvent was removed under reduced pressure and the crude product was used directly in the next step without further purification: Ή NMR (250 MHz, CDCl ₃ ) δ 10.40 (s, 1H, CHO), 7.30 (m, 2H, 4-pyridyl,

5-pyridyl), 4.07 (t, J=6.5 Hz, 2H, OCH ₂ ), 2.6 (s, 3H, CH ₃ ), 1.85-0.89 (m, 23H, aliphatic).

(c) 2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-methylpyridine

The 3-dodecyloxy-6-methyl-2-pyridine carboxaldehyde obtained above was dissolved in dry toluene (12 mL) under an argon atmosphere and treated with methyl (triphenylphosphoranylidene)acetate (5.0 g, 15 mmol). The reaction mixture was heated at 50° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with P^O (2X20 mL) and brine and dried (MgSO ₄ ). Purification by flash column chromatography ( _SiO2 , 7.5% ethyl acetate in petroleum ether) gave a colorless solid: ¹ H NMR (250 MHz, _CDCl3 ) δ 8.07 (d, J=15.7Hz, 1H, olefin), 7.10 (m, 2H, 4-pyridyl, 5-pyridyl), 7.05 (d, J=15.7 Hz, 1H, olefin), 3.98 _{(t, J=6.6 Hz, 2H, OCH2), 3.80 (s, 3H, CO2CH3 ) ,} 2.49 (s, 3H, _CH3 ), 1.88-0.85 (m, 23H, aliphatic).

(d) 2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-methylpyridine N-oxide

2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-methylpyridine (2.15 g, 5.95 mmol) was dissolved in dry CH ₂ Cl ₂ (20 mL) and cooled to 0°C; 85% m-chloroperoxybenzoic acid (1.45 g, 7.14 mmol) was added and the reaction mixture was stirred at 0°C for 30 min and at room temperature for 16 h. The reaction solution was poured into saturated aqueous NaHCO ₃ (20 mL). The aqueous phase was extracted with CH ₂ Cl ₂ (3X20 mL) and the combined CH ₂ Cl ₂ extracts were washed with H ₂ O (20 mL) and brine and dried (MgSO ₄ ). The crude light yellow solid was used directly in the next step without further purification: Ή NMR (250 MHz, CDCl ₃ ) δ 8.23 (d, J=16.2 Hz, 1H, olefin), 7.58 (d, J=16.2 Hz, 1H, olefin), 7.13 (d, J=8.8 Hz, 1H, 5-pyridyl), 6.79 (d, J=8.8 Hz, 1H, 4-pyridyl), 4.06 (t, J=6.6 Hz, 2H, OCH^, 3.81 (s, 3H, O^CH^, 2.45 (s, 3H, CH ₃ ), 1.92-0.85 (m, 23H, aliphatic); MS (Cl): 378.2 (M+H).

111202

5(e) 2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-(hydroxymethyl)pyridine

The 2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-methylpyridine N-oxide obtained above was suspended in dry dimethylformamide (20 mL) and cooled to 0°C under an argon atmosphere. To this was added slowly trifluoroacetic anhydride (8.5 mL, 60.2 mmol). The reaction mixture was stirred at 0°C for 10 min and then at room temperature for 16 h; thin layer chromatography showed that two reaction products (alcohol and trifluoroacetate) were present. The reaction solution was added slowly to a cooled (0°C) saturated aqueous Na2Cl2 solution (100 mL). The aqueous solution was extracted with ethyl acetate (2X50 mL) and the combined ethyl acetate extracts were washed with H2O (2X20 mL) and brine and dried ( _MgSO4 ); the solvent was removed in vacuo. The product mixture was dissolved in methanol (20 mL), treated with anhydrous K^O ₃ (500 mg) and stirred vigorously for 20 min. The reaction mixture was diluted with ethyl acetate (75 mL) and washed with H ₂ O (30 mL). The aqueous phase was extracted with ethyl acetate (2X20 mL) and the combined ethyl acetate extracts were washed with brine (2X20 mL) and dried (MgSO ₄ ). Purification by flash column chromatography ( _SiO2 , 25% ethyl acetate in petroleum ether) gave a colorless solid: NMR (250 MHz, _CDCl3 ) δ 8.09 (d, J=15.8Hz, 1H, olefin), 7.24 (d, J=8.6Hz, 1H, 5-pyridyl), 7.16 (d, J=8.6 Hz, 1H, 4-pyridyl), 7.03 (d, J=15.8Hz, 1H, olefin), 4.69 (d, J=4.2 Hz, 2H, CH^), 4.03 (t, J=6.6 Hz, 2H, _OCH2 ), 3.82 (s, 3H, CCtjCH^), 3.61 (t, J=4.2 Hz, 1H, OH), 1.91-0.85 (m, 23H, aliphatic); MS (CI): 378.3 (M+H).

(f) 2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-(chloromethyl)pyridine hydrochloride

2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-(6-hydroxymethyl)pyridine (250 mg, 0.662 mmol) was dissolved in dry toluene (10 mL) under an argon atmosphere and cooled to 0°C. Thionyl chloride (0.50 mL, 6.85 mmol) was added slowly and the solution was stirred at 0°C for 30 min, then at room temperature for 1 h. The solvent and excess thionyl chloride were removed under reduced pressure. The crude hydrochloride salt was then used directly in the next step without further purification.

5(g) Methyl 3-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridylethyl 1benzoate

2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-(chloromethyl)pyridine hydrochloride (0.662 mmol), prepared as described previously, was dissolved in dry dimethylformamide (1

1 1 ι ml) and treated sequentially with methyl 3-mercaptobenzoate (167 mg, 0.993 mmol), anhydrous Cs ₂ CO ₃ (970 mg, 2.98 mmol) and tetrabutylammonium iodide (25 mg, 0.068 mmol) under an argon atmosphere. The reaction mixture was heated at 65°C for 45 minutes. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with H ₂ O (2X15 mL) and brine and dried (MgSO 4 ). Purification by flash column chromatography (SiO ₂ ), petroleum ether: CH ₂ Cl ₂ :ethyl acetate, 70:25:5) gave a colorless oil: ¹ H NMR (250 MHz, CDCl ₃ ) δ 8.04 (s, IH, 2-phenyl), 8.03 (d, J=15.7Hz, IH, olefin), 7.81 (d, J=7.9Hz, IH, 4-phenyl), 7.52 (d, J=7.9 Hz, IH, 6-phenyl), 7.31 (dd, J=7.9Hz, IH, 5-phenyl), 7.29 (d, J=8.6Hz, IH, 5-pyridyl), 7.12 (d, J=8.6Hz, IH, 4-pyridyl), 6.98 (d, J=15.7 Hz, IH, olefin), 4.26 (s, 2H, CH ₂ S), 3.97 (t, J=6.6 Hz, 2H, OCH ₂ ), 3.90 (s, 3H, CO ₂ CH ₃ ), 3.81 (s, 3H, CO ₂ CH ₃ ), 1.85-0.85 (m, 23H, aliphatic).

Using a similar approach, except that we replaced 3-mercaptobenzoate with a suitable thiol and used known chemistry where applicable, we produced the following compounds:

N-[3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]oxamic acid, dilithium salt,

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzene, lithium salt,

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethylanisole, lithium salt,

N-[3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]benzenesulfonamide, dilithium salt,

N-[3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]phenyl]trifluoromethanesulfonamide, dilithium salt and

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzoic acid, dilithium salt.

5(h) [Methyl 3-[1-oxythia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6pyridyl]ethyl]benzoate

1 1 2 S2

Methyl 3-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate (320 mg, 0.606 mmol) was dissolved in dry CH ₂ Cl ₂ (2.5 mL) and cooled to 0° C. 85% m-chloroperoxybenzoic acid (130 mg, 0.64 mmol) was added and the solution was stirred for 10 min at 0° C. The reaction was diluted with ethyl acetate (60 mL) and washed with saturated aqueous NaHCO ₃ (2X20 mL) and brine and dried (MgSO ₄ ). Purification by flash column chromatography (SiO ₂ ), CH ₂ Cl ₂ :petroleum ether:ethyl acetate, 50:25:25) gave a colorless solid: Ή NMR (250 MHz, CDCl ₃ ) δ 8.11 (d, J=7.9Hz, 1H, 4-phenyl), 8.10 (s, 1H, 2-phenyl), 7.94 (d, J=15.7Hz, 1H, olefin), 7.67 (d, J=7.9Hz, 1H, 6-phenyl), 7.53 (dd, J=7.9 Hz, 1H, 5-phenyl), 7.19 (d, J=8.6Hz, 1H,

5-pyridyl), 7.14 (d, J=8.6 Hz, IH, 4-pyridyl), 6.68 (d, J=15.7Hz, IH, olefin), 4.21 (d, J=12.5 Hz, IH, CHS), 4.15 (d, J=12.5 Hz, IH, CH'S), 3.99 (t, J=6.6 Hz, 2H, OCH ₂ ), 3.93 (s, 3H, CO ₂ CH 3 ), 3.81 (s, 3H, CO ₂ CH ₃ ), 1.87-0.85 (m, 23H, aliphatic). Anal.: calcd. for C₂H₂N₂: C 66.27; H 7.60; N 2.58, found: C 65.97; H 7.22; N 2.46; MS (Cl): 544.3 (M+H).

5(i) 3-yl-oxythia-2-i2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl-1-ethyl-1-benzoic acid, dilithium salt

Methyl 3-[1-oxythia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate (120 mg, 0.221 mmol) was dissolved in tetrahydrofuran (1.3 mL) and methanol (0.66 mL) under argon and treated with 1M LiOH (0.66 mL, 0.66 mmol). The reaction mixture was stirred at room temperature for 18 h. Tetrahydrofuran and methanol were removed under reduced pressure and the product was purified by reverse-phase MPLC (RP-18 _SiO2 , 10-65% methanol in _H2O ) and isolated by lyophilization to give a colorless amorphous solid: *H NMR (250 MHz, _CD3OD ) δ 8.27 (s, 1H, 2-phenyl), 8.11 (d, J=7.9Hz, 1H, 4-phenyl), 7.77 (d, J=15.7Hz, 1H, olefin), 7.60 (d, J=7.9Hz, 1H, 6-phenyl), 7.58 (dd, J=7.9 Hz, 1H, 5-phenyl), 7.27 (d, J=8.6Hz, 1H, 5-pyridyl), 7.04 (d, J=15.7Hz, 1H, olefin), 7.01 (d, J=8.6 Hz, IH, 4-pyridyl), 4.33 (d, J=12.5 Hz, IH, CHS), 4.25 (d, J=12.5 Hz, IH, CH'S), 4.04 (t, J=6.5 Hz, 2H, OCR,), 1.88-0.86 (m, 23H, aliphatic); Anal.: calcd. for C ₂₈ H ₃₅ O ₆ NSLi ₂ . 2 H ₂ O: C 59.68; H 6.97; N 2.49, found: C 59.49; H 6.98; N 2.58; FAB-MS (+ve), 528.5 (M+H).

Example 6

3-[1-dioxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, dilithium salt

Λ 1 1 1 222 37

6(a) Methyl 3-[1-dioxythia-2-i2-(E-2-carboxymethyl-ethenyl)-3-dodecyloxy-6-pyridyl]ethylbenzoate

Methyl-3-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate (107 mg, 0.197 mmol) was dissolved in dry CH ₂ Cl ₂ (2 mL), cooled to 0°C, and treated with 85% m-chloroperoxybenzoic acid (44 mg, 0.217 mmol). The reaction mixture was stirred at 0°C for 1.5 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated aqueous NaHCO ₃ (15 mL), brine, and dried (MgSO ₄ ). The product was purified by flash column chromatography (SiO ₂ , petroleum ether: CH ₂ Cl ₂ :ethyl acetate, 60:25:15) to give a colorless solid: ¹ H NMR (250 MHz, CDCl ₃ ) δ 8.30 (s, IH, 2-phenyl), 8.26 (d, J=7.7Hz, IH, 4-phenyl), 7.83 (d, J=7.7Hz, IH,

6-phenyl), 7.82 (d, J=15.7 Hz, IH, olefin), 7.55 (dd, J=7.7 Hz, IH, 5-phenyl), 7.42 (d, J=8.6 Hz, IH, 5-pyridyl), 7.21 (d, J=8.6 Hz, IH, 4-pyridyl), 6.28 (d, J=15.7 Hz, IH, olefin), 4.52 (s, 2H, CH ₂ SO ₂ ), 4.00 (t, J=6.6 Hz, 2H, OCH ₂ ), 3.92 (s, 3H, CO ₂ CH ₃ ), 3.78 (s, 3H, CO ₂ CH ₃ ), 1.87-0.85 (m, 23H, aliphatic); Anah: Calc. for C^H^C^NS: C 64.38; H 7.38; N 2.50, found: C 64.71; H 7.41; N 2.57; MS (CI): 560.3 (M+H).

6(b) 3-II-dioxythia-2-i2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, dilithium salt

Methyl 3-[l-dioxythia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate (20, 170 mg, 0.303 mmol) was dissolved in tetrahydrofuran (3.0 mL) and methanol (1.0 mL) and treated with 1 M LiOH (1.0 mL, 1.0 mmol). The reaction mixture was stirred at room temperature for 24 h. The tetrahydrofuran and methanol were removed under reduced pressure and the product was purified by reverse-phase MPLC (RP-18 _SiO2 , 10-65% methanol in H^O) and isolated by lyophilization to give a colorless amorphous solid: Ή NMR (250 MHz, _CD3OD ): δ 8.40 (s, 1H, 2-phenyl), 8.22 (d, J=7.9Hz, 1H,

4-phenyl), 7.69 (d, J=7.9Hz, IH, 6-phenyl), 7.67 (d, J=15.7 Hz, IH, olefin), 7.53 (dd, J=7.9Hz, IH, 5-phenyl), 7.30 (d, J=8.6Hz, IH, 5-pyridyl), 7.18 (d, J=8.6 Hz, IH, 5-phenyl).

4-pyridphi), 6.85 (d, J=15.7 Hz, IH, olefin), 4.62 (s, 2H, C^SOJ, 4.03 (t, J=6.5 Hz, 2H, OCH ₂ ), 1.87-0.86 (m, 23H, aliphatic); Anal.: calcd. for C^H^NSL^. 7/4 H ₂ O: C 58.48; N 2.44; N 2.67; 544.3 (M-Li).

1112 02

Example Ί

4-1-oxythia-2-f2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridylethyl]benzoic acid, dilithium salt

4-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, dilithium salt, was prepared according to the procedure described for 3-[l-oxythia-2-[2-(E-2carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, dilithium salt, except that methyl 3-mercaptobenzoate was replaced by methyl 4-mercaptobenzoate.

7(a) Methyl 4-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyl-oxy-6-pyridylethylbenzoate ^X H NMR (250 MHz, CDCl ₃ ); δ 8.05 (d, J=15.7 Hz, IH, olefin), 7.90 (d, J=8.5 Hz, 2H, aryl), 7.37 (d, J=8.5 Hz, 2H, aryl), 7.35 (d, J=8.6Hz, IH, 5-pyridyl), 7.14 (d, J=8.6Hz, IH, 4-pyridyl), 7.01 (d, J=15.7 Hz, IH, olefin), 4.29 (s, 2H, CH ₂ S), 3.98 (t, J=6.5 Hz, 2H, OCH ₂ ), 3.88 (s, 3H, CO ₂ CH ₃ ), 3.86 (s, 3H, CO ₂ CH ₃ ), 1.86-0.85 (m, 23H, aliphatic).

7(b) Methyl 4-[1-oxythia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridylethylbenzoate, m.p. 107-109°C; ^X H NMR (250 MHz, CDCl ₃ ) δ 8.13 (d, J=8.5 Hz, 2H, aryl), 7.95 (d, J=15.7 Hz, IH, olefin), 7.56 (d, J=8.5 Hz, 2H, aryl), 7.18 (d, J=8.6 Hz, IH, 5-pyridyl), 7.11 (d, J=8.6 Hz, 5-pyridyl). J=8.6Hz, IH, 4-pyridyl), 6.62 (d, J=15.7 Hz, IH, olefin), 4.22 (d, J=12.5 Hz, IH, CHS), 4.13 (d, J=12.5 Hz, IH, CH'S), 4.03 (t, J=6.5 Hz, 2H, OCH ₂ ), 3.99 (s, 3H, CO ₂ CH ₃ ), 3.78 (s, 3H, _{CO2CH3 )} , 1.92-0.85 (m, 23H, aliphatic); Anal.: calcd. for C12H13C14NS: C 66.27; H 7.60; N 2.58, found: C 65.99; H 7.55; N 2.27; MS (CI), 544 (M+H).

7(c) 4-tri-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridylethyl]benzoic acid, dilithium salt, mp 205-207°C (decomposition); ^X H NMR (250 MHz, CD ₃ OD) δ 8.09 (d, J=8.5 Hz, 2H, aryl), 7.78 (d, J=15.7 Hz, IH, olefin), 7.59 (d, J=8.5 Hz, 2H, aryl), 7.26 (d, J=8.6 Hz, IH, 5-pyridyl), 7.07 (d, J =15.7 Hz, IH, olefin), 6.98 (d, J=8.6Hz, IH, 4-pyridyl), 4.33 (d, J=12.5 Hz, IH, CHS), 4.22 (d, J=12.5 Hz, IH, CH'S), 4.04 (t, J=6.5 Hz, 2H, OCH^, 1.88-0.86 (m, 23H, aliphatic); Anal.: calc. for C12H13O2NSL13.3/2H2O: C _60.64 ; H 6.91; N 2.53, found: C 60.41; H 6.73; N 2.60; FAB-MS (+ve), 528.5 (M+H).

1 1 202

Example 8

2-yl-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridylethyl]benzoic acid, dilithium salt

2-[l-Oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, dilithium salt, was prepared according to the procedure described for 3-[l-Oxythia-2-[2-(E-2carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, dilithium salt, except that methyl 3-mercaptobenzoate was replaced by methyl 2-mercaptobenzoate.

8(a) Methyl 2-[l-thia-2-r2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridylylbenzoate NMR (250 MHz, CDC1 ₃ ) δ 8.07 (d, J=15.7 Hz, IH, olefin), 7.96 (d, J=7.8 Hz, IH, 3-phenyl), 7.56 (d, J=7.8 Hz, IH, 6-phenyl), 7.43 (d, J=8.6Hz, IH, 5-pyridyl), 7.42 (m, IH, aryl), 7.14 (d, J=8.6Hz, IH, 4-pyridyl), 7.10 (m, IH, aryl), 7.06 (d, J=15.7 Hz, IH, olefin), 4.27 (s, 2H, CH ₂ S), 3.98 (t, J=6.6 Hz, 2H, OCH ₂ ), 3.91 (s, 3H, CC^CH^, 3.83 (s, 3H, CO ₂ CH ₃ ), 1.86-0.86 (m, 23H, aliphatic).

8(b) Methyl 2-[1-oxythia-2-12-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridylethylbenzoate, m.p. 60-62°C;

Ή NMR (250 MHz, CDC1 ₃ ) δ 8.13 (d, J=7.8 Hz, IH, 3-phenyl), 7.87 (d, J=15.7 Hz, IH, olefin), 7.68 (d, J=7.8 Hz, IH, 6-phenyl), 7.53 (m, 2H, aryl), 7.33 (d, J=8.6 Hz, IH, olefin).

5-pyridyl), 7.16 (d, J=8.6Hz, IH, 4-pyridyl), 6.46 (d, J=15.7 Hz, IH, olefin), 4.42 (d, J=12.6 Hz, IH, CHS), 4.30 (d, J=12.6 Hz, IH, CH'S), 4.03 (s, 3H, CO ₂ CH ₃ ), 4.0 (t, J=6.6 Hz, 2H, OCH ₂ ), 3.81 (s, 3H, CO ₂ CH ₃ ), 1.87-0.85 (m, 23H, aliphatic); Anal.: calcd. for C^H^C^NS: C 66.27; H 7.60; N 2.58, found: C 66.37; H 7.67; N 2.56; MS (Cl), 544 (M+H).

8(c) 2-yl-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, dilithium salt, mp 235°C (decomposition); *H NMR (250 MHz, CD ₃ OD) δ 8.07 (d, J=7.8 Hz, IH, 3-phenyl), 7.76 (d, J=7.8 Hz, IH, 6-phenyl), 7.71 (d, J=15.7 Hz, IH, olefin), 7.53 (m, 2H, aryl), 7.31 (s, 2H, pyridyl), 6.92 (d, J=15.7 Hz, IH, olefin), 4.72 (d, J=12.6 Hz, IH, CHS), 4.12 (d, J=12.6 Hz, IH, CH'S), 4.05 (t, J=6.5 Hz, 2H, OCH^, 1.88-0.86 (m, 23H, aliphatic); FAB-MS (+ve), 528.3 (M+H).

In addition, by replacing the reagents and intermediates listed in 4(a) 1 1 1 2 92

4(c), with suitable, and using chemistry available in the art, the following compounds were prepared:

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzoic acid, dilithium salt,

N-[3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethylphenyl]trifluoromethanesulfonamide, dilithium salt,

N-[3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethylphenyljtrifluoromethanesulfonamide, dilithium salt,

N-[3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]benzenesulfonamide, dilithium salt,

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethylanisole, lithium salt,

3-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzene, lithium salt.

Example 9

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, dilithium salt

9(a) Methyl 3-[1-oxa-2-[2-(E-2-carboxymethylethenyl)-3-dodecyl-oxy-6-pyridyl]ethylbenzoate

2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-(chloromethyl)pyridine hydrochloride, prepared according to Example 1(a) - 1(f), was dissolved in dry dimethylformamide (2 mL) and treated sequentially with methyl 3-hydroxybenzoate (152 mg, 1.00 mmol, Aldrich), anhydrous (500 mg, 3.62 mmol) and tetrabutylammonium iodide (24.4 mg,

0.066 mmol) under argon atmosphere. The reaction mixture was heated at 90°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml) and washed with H ₂ O (3x15 ml) and brine and dried (MgSO ₄ ). Flash purification

1 1 222 column chromatography (SiO ₂ , CH ₂ C1 ₂ : petroleum ether;ethyl acetate, 50:48:2) gave a colorless solid: Ή NMR (250 MHz, CDC1 ₃ ) δ 8.09 (d, J=15.8 Hz, IH, olefin), 7.69 (s, IH, 2-phenyl), 7.65 (d, J=7.9 Hz, IH, 4-phenyl), 7.44 (d, J=8.6Hz, IH, 5-pyridyl), 7.34 (dd, J=7.9 Hz, IH, 5-phenyl), 7.22 (d, J=8.6Hz, IH, 4-pyridyl), 7.16 (d, J=7.9 Hz, IH, 6-phenyl), 7.07 (d, J=15.8 Hz, IH, olefin), 5.18 (s, 2H, CH ₂ ), 4.02 (t, J=6.6 Hz, 2H, OCH ₂ ), 3.91 (s, 3H, CO ₂ CH ₃ ), 3.82 (s, 3H, CO ₂ CH ₃ ), 1.90-0.88 (m, 23H, aliphatic). Anal.: calcd. for C^^O^N . 1/8 mole of toluene: C 70.88; H 8.09; N 2.68, found: C 70.98; H 8.19; N 2.64; MS (Cl), 512.4 (M+H).

9(b) 3-[1-Oxa-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridylethylbenzoic acid, dilithium salt.

Methyl 3-[1-oxa-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate (80 mg, 0.156 mmol) was dissolved in tetrahydrofuran (1.34 mL) and methanol (0.50 mL) and treated with 1M LiOH (0.50 mL, 0.50 mmol). The reaction mixture was stirred at room temperature for 20 h. Tetrahydrofuran and methanol were removed under reduced pressure and the product was purified by reverse-phase MPLC (RP-18 _SiO2 , 10-65% methanol in _H2O ) and isolated by lyophilization to give a colorless amorphous solid: Ή NMR (250 MHz, _CD3OD ) δ - 7.81 (d, J=15.7 Hz, IH, olefin), 7.62 (s, IH, 2-phenyl), 7.56 (d, J=7.9 Hz, IH, 4-phenyl), 7.44 (d, J=8.6 Hz, IH, 5-pyridyl), 7.40 (d, J=8.6Hz, IH, 4-pyridyl), 7.26 (dd, J=7.9 Hz, IH, 5-phenyl), 7.07 (d, J=15.7 Hz, IH, olefin), 7.05 (d, J=7.9 Hz, 1H, 6-phenyl), 5.13 (s, 2H, CH ₂ ),

4.07 (t, J=6.5 Hz, 2H, _OCH2 ), 1.89-0.89 (m, 23H, aliphatic); Analytical: calcd. for C2H2NO3. 5/2 _H2O : C 62.22; H 7.46; N 2.59, found: C 62.06; H 7.37; N 2.82; FAB-MS (+ve), 502.3 (M+Li); (-ve), 488.2 (M-Li).

9(c) 3-[1-Oxa-2-12-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridylethyl]benzoic acid, N-oxide, dilithium salt.

Methyl 3-[1-oxa-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridylethylbenzoate, N-oxide. Methyl 3-[1-oxa-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridylethylbenzoate (130 mg, 0.254 mmol) was dissolved in dry CH ₂ Cl ₂ (1.5 mL), cooled to 0°C, and treated with 85% m-chloroperoxybenzoic acid (57 mg, 0.28 mmol). The reaction mixture was stirred at 0°C for 10 min and then at room temperature for 20 h. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with saturated aqueous _NaHCO3 (15 mL), _H2O (10 mL), brine, and dried ( _MgSO4 ). The product was purified by _flash column chromatography ( _SiO2 , _CH2Cl2 :petroleum ether:ethyl acetate, 50:40:10) to give a colorless solid.

Ή NMR (250 MHz, CDCL,) δ 8.24 (d, J=16.2 Hz, IH, olefin), 7.71 (d, J=8.0 Hz, IH,

4-phenyl), 7.68 (s, IH, 2-phenyl), 7.60 (d, J=16.2 Hz, IH, olefin), 7.46 (d, J=9.0 Hz, IH,

5- pyridyl), 7.38 (dd, J=8.0 Hz, IH, 5-phenyl), 7.22 (d, J=8.0 Hz, IH, 6-phenyl), 6.9 (d, J=9.0 Hz, IH, 4-pyridyl), 5.32 (s, 2H, CH ₂ ), 4.10 (t, J=6.6 Hz, 2H, 00^,),3.92 (s, 3H, CO ₂ CH,), 3.83 (s, 3H, CO ₂ CH ₃ ), 1.94-0.88 (m, 23H, aliphatic); Anal: calcd. for Ο^Ο,Ν: C 68.29; H 7.83; N 2.65, found: C 68.27; H 7.82; N 2.66; MS (CI):

528.3 (M+H).

9(d) 3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid. N-oxide, dilithium salt.

Methyl 3-[1-oxa-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate, N-oxide (110 mg, 0.208 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (0.65 mL) and treated with 1 M LiOH (0.65 mL). The reaction mixture was stirred at room temperature for 20 h. The tetrahydrofuran and methanol were removed under reduced pressure and the product was purified by reverse-phase MPLC (RP-18 SiO ₂ , 10-65% methanol in H ₂ O) and isolated by lyophilization to give a colorless amorphous solid. ^X H NMR (250 MHz, CD ₃ OD): δ 7.99 (d, J=16.2 Hz, IH, olefin), 7.64 (s, IH, 2-phenyl), 7.60 (d, J=8.0 Hz, IH, 4-phenyl), 7.52 (d, J=9.0 Hz, IH, 5-pyridyl), 7.45 (d, J=16.2 Hz, IH, olefin), 7.30 (d, J=9.0 Hz, IH, 4-pyridyl), 7.29 (dd, J=8.0 Hz, IH, 5-phenyl), 7.08 (d, J=8.0 Hz, IH, 6-phenyl), 5.30 (s, 2H, CH ₂ ), 4.17 (t, J=6.6 Hz, 2H, OCH ₂ ), 1.95-0.86 (m, 23H, aliphatic); Anal: calcd. for C ₂₈ H ₃₅ O ₇ NLi ₂ . 3H ₂ O: C 59.47; H 7.31; N 2.48, found: C 59.46; H 6.91; N 2.50; FAB-MS (+ve),: 512.2 (M+H); (-ve), 504.5 (M-Li).

Using a similar method, except that we replaced the appropriate intermediates, we produced the following compounds:

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzoic acid, N-oxide, dilithium salt,

1112 02

3-[1-oxa-2-[2-(E,E-4-carboxybuta-1,3-dienyl)-3-(8-(4-methoxyphenyl]octyloxy)-6-pyridyl]ethyl]benzoic acid, N-oxide, dilithium salt,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)nonyloxy)-6-pyridyl]ethyl]benzoic acid, N-oxide, dilithium salt,

N-3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyljphenyljtrifluoromethane-sulfonamide, N-oxide, dilithium salt,

4- Methoxy-3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(7-(4-methoxyphenyl)octyloxy)-6-pyridyl]-ethyl]benzoic acid, dilithium salt,

N-3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenylacetamide, N-oxide, lithium salt.

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(7-(4-methoxybenzyl)sulfonyl)heptyloxy)-6-pyridylethylbenzoic acid, N-oxide, dilithium salt,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(7-(4-methoxyphenyl)sulfonyl)heptyloxy)-6-pyridyl]ethyl]benzoic acid, N-oxide, dilithium salt

3-[1-oxa-2-[2-(E-2-diethylphosphonoethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, 4-oxide, lithium salt,

N-3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]oxamic acid, dilithium salt,

N-[6-methoxy-3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridylethylphenyl]trifluoromethanesulfonamide, N-oxide, dilithium salt,

N-[6-methoxy-3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridylethylphenyl]trifluoromethanesulfonamide, dilithium salt,

N-[3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]phenyl]oxamic acid, N-oxide, dilithium salt,

1112 92

3-[1-oxa-2-[2-(E-2-ethylphosphonoethenyl)-3-dodecyloxy)-6-pyridyl]ethyl]benzoic acid, N-oxide, dilithium salt,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzene, lithium salt,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenylurea, lithium salt,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzonitrile, lithium salt,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenol, lithium salt and

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzamide, lithium salt.

Example 10

3-fl-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethylaniline, lithium salt

10(a) 7-Octyn-1-ol. 35% KH in mineral oil (27 g, 240 mmol) under argon was washed with hexane and treated dropwise with 1,3-diaminopropane. The mixture was stirred at room temperature until homogeneous. The flask was cooled to 0°C and 3-octyn-1-ol (10 g, 79 mmol, Lancaster Synthesis) was added slowly. The reaction mixture was then stirred at room temperature for 18 h. The reaction mixture was quenched with H ₂ O (50 ml) and the product was extracted into ether. The organic layer was washed with 10% HCl and brine and dried (MgSO ₄ ). Evaporation gave a colorless oil which was used without further purification: ^! H NMR (90 MHz, CDC1 ₃ ): δ 3.65 (t, J=5 Hz, 2H, O-CHj), 2.23 (m, 2H CH ₂ ), 2.0 (m, IH, acetylenic), 1.7-1.2 (m, 8H, (CH^); IR (pure) n _mM 3350,2930,2125 cm ⁴ .

10(b) 7-Octyn-1-t-butyl]diphenylsilyl ether. A cooled (0°C) solution of 7-octyn-1-ol (9.3 g,

73.7 mmol) in DMF (70 ml) was added under an argon atmosphere with imidazole (7.5 g, 110 mmol) followed by t-butylchlorodiphenylsilane dropwise. The reaction mixture was then

1112 was stirred at room temperature for 2 h. The reaction solution was diluted with Et ₂ O and washed with H _? O and brine and dried (MgSO ₄ ). Purification by flash column chromatography (SiO ₂ , 3% EtOAc in hexane) gave a colorless oil: NMR (250

MHz, CDClg): δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl) 3.63 (t, 2H, O-CH ₂ ), 2.23 (m, 2H, CHj), 1.97 (t, IH, acetyleneslri), 1.6-1.3 (m, 8H, (CH^) 1.05 (s, 9H, t-butyl);IR (film) n 3321,2940,2125 cm ⁴ .

10(c) 8-(4-methoxyphenyl)-7-octyne-1-t-butyldiphenylsilyl ether

To a flame-dried flask containing triethylamine (140 mL) under argon atmosphere were added 4-iodoanisole (13.3 g, 56.9 mmol), 7-octyne-1-butyldiphenylsilyl ether (24.9 g, 68.3 mmol), catalyst (Ph ₃ P) ₂ PdCl ₂ (793 mg, 1.13 mmol) and CuI (431 mg, 2.27 mmol). The resulting mixture was stirred at 50°C for 4 h. After cooling to room temperature, the reaction mixture was filtered, the solid was washed with Et ₂ O and the solvent was evaporated. The residue was diluted with Et ₂ O and washed with 5% HCl, H ₂ O, NaHCO ₃ and brine and dried (MgSO ₄ ). Purification by flash column chromatography (SiO ₂ , 2% EtOAc in hexane) gave an orange oil: ^J H NMR (250 MHz, CDCl ₃ ): δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl) 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OMe), 3.7 (t, 2H, O-CH ₂ ), 2.4 (t, 2H, CH ₂ ), 1.7-1.3 (m, 8H, (CH^)) 1.05 (s, 9H, t-butyl).

10(d) 8-(4-Methoxyphenyl)octane-1-t-butyldiphenylsilyl ether

8-(4-Methoxyphenyl)-7-octyne-1-t-butyldiphenylsilyl ether (30 g, 63.7 mmol) was dissolved in EtOH (125 mL) and EtOAc (125 mL) and treated with 5% Pd-C catalyst (3 g). The reaction mixture was stirred vigorously under an atmosphere of H ₂ (pumpkin pressure) for 4 h. The reaction mixture was filtered through a pad of Celite and the solvent was evaporated. The resulting light yellow oil was pure by NMR analysis and was used directly for the next step: *H NMR (250 MHz, CDCl ₃ ): δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl) 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OMe), 3.6 (t, 2H, O-CH^, 2.5 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH ₂ ) ₆ ) 1.0 (s, 9H, t-butyl).

10(e) 8-(4-Methoxyphenyl)octan-1-ol

To a cooled (0°C) solution of 8-(4-methoxyphenyl)octane-1-yl-diphenylsilyl ether (63 mmol) was added tetrabutylammonium fluoride (70 mL, 70 mmol; 1M solution in THF). The cooling bath was removed and the reaction mixture was stirred at room temperature.

1 1 2 S2

4.5 hours. The solvent was evaporated and the residue was dissolved in _Et2O . This was washed with _H2O , 5% HCl, _NaHCO3 and brine and dried ( _MgSO4 ). Purification by flash column chromatography ( _SiO2 , 30% EtOAc in hexane) gave a colorless solid: Ή NMR (250 MHz, _CDCl3 ): δ 7.15 (d, 24H, aryl), 6.86 (d, 2H, aryl), 3.85 (s, 3H, OMe), 3.68 (t, 2H, O-CH^, 2.62 (t, 2H, benzylic), 1.75-1.3 (m, 12H, ( _CH2 ) ₆ ) MS (CI): 254.2 (M+ _NH4 ); mp 47-49°C.

10(f) l-iodo-8-(4-methoxyphenyl)octane. Triphenylphosphine (17.8 g, 67.6 mmol) and imidazole (10.6 g, 156 mmol) were added to a stirred solution of 8-(4methoxyphenyl)octan-1-ol (12.3 g, 52 mmol) in dry toluene (200 ml) under an argon atmosphere. After the imidazole had dissolved, J ₂ (17.1 g, 67.6 mmol) was added. The reaction mixture was heated at 65°C for 30 min. After cooling to room temperature, the reaction mixture was concentrated to 1/4 volume. The remaining solution was diluted with Et ₂ O, washed with H ₂ O and brine, and dried (MgSO ₄ ). The solvent was removed and the resulting residue was dissolved in CH ₂ Cl ₂ and applied to a flash chromatography column (SiO ₂ ). Elution with 2% EtOAc in hexane gave a colorless oil (slight contamination with triphenylphosphine): Ή NMR (250 MHz, CDCl ₃ ): δ 7.08 (d, J=8.6 Hz, 2H, aryl), 6.82 (d, J=8.6 Hz, 2H, aryl) 3.78 (s, 3H, OMe), 3.17 (t, J=7.4 Hz, 2H, J-CH ₂ ), 2.54 (t, J=7.6 Hz, 2H, benzylic), 1.85 (m, 2H, CH ₂ ), 1.60 (m, 2H, CI1 ₂ ), 1.31 (m, 8H, aliphatic): MS (CI): 264.2 (M+NH ₄ ).

10(g) 3-hydroxy-6-methyl-2-pyridine carboxaldehyde 2,6-lutidine-α2,3-diol (15 g, 107.8 mmol; Aldrich) was suspended in dry _CH2Cl2 (200 mL) and treated with _MnO2 ( ₄₇ g, 539 mmol). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was filtered through a pad of Celite and the solvent was evaporated. The crude aldehyde was obtained as a yellow-brown solid and was used directly for the next step: ^j H NMR (250 MHz, _CDCl3 ): δ 10.65 (s, 1H, OH), 10.30 (s, 1H, aldehyde), 7.30 (m, 2H,

4,5-pyridyl), 2.55 (s, 3H, methyl).

10(f) 3-[8-(4-methoxyphenyl)octyloxy-6-methyl-2-pyridine carboxaldehyde. To a solution of 1-iodo-8-(4-methoxyphenyl)octane (16.3 g, 47.1 mmol) in dry DMF (45 mL) under argon was added 3-hydroxy-6-methyl-2-pyridine carboxaldehyde (7.7 g, 56.2 mmol) and anhydrous ^003 (32 g, 235 mmol). The reaction mixture was stirred vigorously at 90°C for 1.5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with H ₂ O, aqueous NH ₄ Cl and brine and dried (MgSO ₄ ). Evaporation gave the crude aldehyde as a dark oil, which was used without further purification.

111202

10(g) 2-(E-2-carboxymethylethenyl)-3-f8-(4-methoxyphenyl)octyloxyl-6-methylpyridine.

The 3-[8-(4-methoxyphenyl)octyloxy]-6-methyl-2-pyridine carboxaldehyde obtained above was dissolved in dry toluene (100 mL) under an argon atmosphere and treated with methyl (triphenylphosphoranylidene)acetate (16 g, 48 mmol). The reaction mixture was heated at 50°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with H ₂ O and brine and dried (MgSO 4 ). Purification by flash column chromatography (SiO ₂ , 20% EtOAc in hexane) gave a light yellow oil: ¹ H NMR (250 MHz, CDCl 3 ); δ 8.07 (d, J=15.7 Hz, 1H, olefin), 7.10 (m, 4H, phenyl, 4,5-pyridyl), 7.07 (d, J=15.7 Hz, 1H, olefin), 6.81 (d, J=8.6 Hz, 2H, phenyl), 3.97 (t, J=6.5 Hz, 2H, O-CH ₂ ), 3.79 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.54 (t, J=7.6 Hz, 2H, benzyl), 2.48 (s, 3H, methyl), 1.85 (m, 2H, CH ₂ ), 1.60 (m, 2H, CH ₂ ), 1.37 (m, 8H, aliphatic); mS (Cl): 412.3 (M+H).

10(h) 2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-methylpyridineN-oxide. 2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-methylpyridine (17.1 g, 41.5 mmol) was dissolved in dry CH ₂ Cl ₂ (105 mL) and cooled to 0°C; 50% mCPBA (15.8 g, 45.8 mmol) was added in three portions over 10 min. The cooling bath was removed and the reaction mixture was stirred for 15 h at room temperature. The reaction mixture was poured into aqueous NaHCO ₃ and the product was extracted into CH ₂ Cl ₂ . The organic extract was washed with H ₂ O and brine and dried (MgSO ₄ ). The crude product was obtained as a yellow solid, which was used without further purification.

10(i) 2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine. The 2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-methylpyridine N-oxide obtained above was suspended in dry DMF (130 mL) and cooled to 0°C under an argon atmosphere. Trifluoroacetic anhydride (56 mL, 400 mmol) was added slowly to this. The reaction mixture was maintained at 0°C for 20 min and then at room temperature for 18 h. The reaction solution was added slowly to _a saturated aqueous _Na2CO3 solution and stirred for 1 h. The product was then extracted into EtOAc; the combined organic extracts were washed with _H2O and brine and dried ( _MgSO4 ). Purification by flash column chromatography (SiO ₂ , EtOAc:hexane:CH ₂ Cl ₂ , 30:20:50) gave a waxy solid: Ή NMR (250 MHz, CDCy: δ 8.08 (d, J=15.7 Hz, IH, olefin), 7.23 (d, J=8.6 Hz, IH, 5-pyridyl), 7.16 (d, J=8.6 Hz, IH, 4-pyridyl), 7.09 (d, J=8.6 Hz, 2H, phenyl), 7.03 (d, J=15.7 Hz, IH, olefin), 6.82 (d, J=8.6 Hz, 2H, phenyl), 4.69 (d, J=4.1 Hz, 2H, CHj-OH), 4.01 (t, J=6.5 Hz, 2H, O-CH ₂ ), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.62 (t, J=4.l Hz, IH, OH), 2.55 (t, 3=7.6 Hz, 2H, benzylic), 1.85 (m, 2H, CH^, 1.58 (m, 2H, CH ₂ ), 1.44 (m, 8H, aliphatic); MS (Cl): 428.2 (M+H).

1 1 202 lOfi) 3-Aminophenol t-butylcarbamate. 3-Aminophenol (2.0 g, 18.3 mmol; Aldrich) was dissolved in CH ₂ Cl ₂ (18 mL) and DMF (6 mL) and treated with di-t-butyl dicarbonate (5.0 mL, 21.7 mmol). The reaction mixture was stirred under an argon atmosphere for 18 h. The reaction solution was diluted with EtOAc, washed with H^O and brine, and dried (MgSO ₄ ). Purification by flash column chromatography ( _SiO2 , EtOAc:hexane: _CH2Cl2 , _15:60:25 ) gave a colorless solid: ¹ H NMR (250 MHz, _CDCl3 ): δ 7.15 (m, 2H, aryl), 6.72 ((m, 1H, aryl), 6.53 (m, 2H, aryl OH), 6.0 (s, 1H, NH), 1.54 (s, 9H, t-butyl): MS (CI): 210.2 (M+H); mp 95-97°C.

10(k) 2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-[(3-amino)phenoxymethylpyridine t-butylcarbamate. To a cooled (0°C) solution of SOC1 ₂ (0.51 ml, 7.0 mmol) in dry toluene (2 ml) under an argon atmosphere was added a solution of 2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine (300 mg, 0.70 mmol) in toluene (5 ml). After 5 minutes, the cooling bath was removed and the reaction mixture was stirred for 2 hours at room temperature. The toluene and excess SOC1 ₂ were evaporated. To this was added dry DMF (0.90 mL), 3-aminophenol t-butylcarbamate (209 mg, 1.0 mmol) and anhydrous _{Cs2CO3 (} 1.63 g, 5.0 mmol). The reaction mixture was heated at 90°C under argon for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with _H2O , 10% NaOH, F2O and brine and dried ( _MgSO4 ). Purification by flash column chromatography ( _SiO2 , EtOAc-hexanesCH^CB 7:63:30) gave a colorless oil. ^J H NMR (250 MHz, _CDCl3 ): δ 8.09 (d, J=15.7 Hz, 1H, olefin), 7.44 (d, J=8.6 Hz, 1H, aryl), 7.15 (m, 5H, aryl), 7.05 (d, J« 15.7 Hz, 1H, olefin), 6.90 (m, 1H, aryl), 6.82 (d, J=8.6 Hz, 2H, aryl), 6.65 (m, 1H, aryl), 6.51 (s, 1H, NH), 5.12 (s, 2H, CH2 _- O), 4.0 (t, J=6.5 Hz, 2H, O- _CH2 ), 3.81 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.54 (t, J=7.6 Hz, 2H, benzylic), 1.88 (m, 2H, CH ₂ ), 1.51 (s, 9H, t-butfl), 1.46 (m, 10H, aliphatic).

10(1) 3-[1-oxa-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridylethyliline

2-(E-2-Carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-[(3-amino)phenoxymethyl]pyridine t-butylcarbamate (348 mg, 0.562 mmol) was dissolved in dry _CH2Cl2 (3.0 _mL ) under an argon atmosphere and cooled to 0°C. Anisole (0.09 mL, 0.83 mmol) was added followed by trifluoroacetic acid (0.6 mL). The reaction mixture was stirred for 1 h at 0°C and then for 3 h at room temperature. The reaction mixture was quenched with aqueous _NaHCO3 . The product was extracted into _CH2Cl2 and _the organic extracts were washed with brine and

1 1 2C2 was dried (MgSO ₄ ). Purification by flash column chromatography (SiO ₂ , EtOAc:hexane:CH ₂ Cl ₂ , 20:50:30) gave a light yellow oil: ¹ H NMR (250 MHz, CDCl ₃ ); δ 8.09 (d, J=15.7 Hz, IH, olefin), 7.44 (d, J=8.6 Hz, IH, 5-pyridyl), 7.17 (d, J=8.6 Hz, IH, 4-pyridyl), 7.08 (m, 3H, aryl), 7.05 (d, J=15.7 Hz, IH, olefin), 6.88 (d, J=8.6 Hz, IH, 4-pyridyl). Hz, 2H, aryl), 6.42 (m, IH, aryl), 6.31 (m, IH, aryl), 6.29 (m, IH, aryl), 5.10 (s, 2H, CHj-O), 4.02 (t, J=6.5 Hz, 2H, O-CH ₂ ), 3.81 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.70 (broad singlet, 2H, NH ₂ ), 2.54 (t, J=7.6 Hz, 2H, benzylic), 1.88 (m, 2H, CH ₂ ), 1.62 (m, 2H, CHj ), 1.40 (m, 8H, aliphatic); Analysis: calcd. for C^H^NjOj . 1/2^0: C 70.56; H 7.45; N 5.31, found: C 70.74; H 7.36; N 5.06; MS (Cl),:

519.3 (M+H).

10(m) 3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridylethylaniline, lithium salt. 3-[1-oxa-2-[2-(E-2-carboxymethylethenyl)-3(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (30 mg, 0.0578 mmol) was dissolved in THF (0.36 mL) and MeOH (0.24 mL) and treated with 1.0M LiOH (0.12 mL, 0.12 mmol). The reaction mixture was stirred under argon for 6 h. The solvent was evaporated and the product was purified by reverse-phase MPLC (RP-18 _SiO2 , gradient _H2O -MeOH). Lyophilization gave a colorless amorphous solid: ^X H NMR (250 MHz, d ⁴ MeOH): δ 7.80 (d, J=15.7 Hz, IH, olefin), 7.38 (s, 2H, 4,5-pyridyl), 7.06 (d, J=15.7 Hz, IH, olefin), 7.05 (d, J=8.6 Hz, 2H, phenyl), 6.97 (t, J=8.0 Hz, IH, 5'-phenyl), 6.78 (d, J=8.6 Hz, 2H, phenyl), 6.39 (m, IH, 2'-phenyl), 6.35 (m, 2H, 4',6'-phenyl), 5.04 (s, 2H, CH ₂ -O), 4.04 (t, J=6.5 Hz, 2H, O-CH ₂ ), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6 Hz, 2H, benzylic), 1.85 (m, 2H, CH ₂ ), 1.57 (m, 4H, aliphatic), 1.36 (m, 6H, aliphatic);

Analysis: calcd. for C12H12N12Li.9/ _4H2O : C 65.38; H 7.22; N 5.08, found: C 65.39; H 7.24; N 5.23; MS (FAB),: 511 (M+H), 517 (M+Li).

Example 11

5-Carboxy-3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridylethylaniline, dilithium salt of l(a) 3-amino-5-carboxymethylphenol. A solution of 3-amino-5-hydroxybenzoic acid hydrochloride (1.9 g, 10 mmol; Lancaster Synthesis) in MeOH (50 mL) was bubbled with HCl gas at 0°C for 30 min. The reaction was quenched and allowed to stand for 5 h. The solvent was removed in vacuo and the residue was dissolved in Η _? Ο. The aqueous solution was neutralized with 5% Na ₂ CO ₃ and the product was extracted into EtOAc. The organic solution was then dried (MgSO ₄ ) and evaporated to give 1.5 g (89%) of the ester as

1 1 202 off-white solid, which was used without further purification: ^X H NMR (250 MHz, CDCl ₃ ): δ 6.85 (dd, J=1.9 Hz, IH, aryl), 6.80 (dd, J=1.9 Hz, IH, aryl), 6.30 (dd, J=1.9 Hz, IH, aryl), 3.80 (s, 3H, methyl ester).

ll(b) 3-Amino-5-carboxymethylphenol t-butylcarbamate. A solution of 3-amino-5-carboxymethylphenol (1.5 g, 8.0 mmol) in DMF (8 mL) under argon was treated with di-t-butyldicarbonate (2.1 g, 10 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and washed with H ₂ O and brine and dried (MgSO ₄ ). Recrystallization from Et ₂ O-hexane gave a yellow-brown solid: ^J H NMR (250 MHz, CDCl,): δ 7.35 (dd, J=1.9 Hz, IH, aryl), 7.15 (dd, J=1.9 Hz, IH, aryl), 6.65 (dd, J=1.9 Hz, IH, aryl), 6.45 (s, IH, NH), 3.80 (s, 3H, methyl ester), 1.4 (s, 9H, t-butyl).

ll(c) 2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyloxy-6-yl-3-amino-5-carboxymethyl)phenoxymethyl]pyridine t-butylcarbamate. To a cooled (0°C) solution of SOC1 ₂ (0.34 ml, 4.6 mmol) in dry toluene (1.5 ml) under an argon atmosphere was added a solution of 2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyloxy]-6hydroxy-methylpyridine (197 mg, 0.46 mmol) in toluene (3 ml). After 5 minutes, the cooling bath was removed and the reaction mixture was stirred for 2 hours at room temperature. The toluene and excess SOC1 ₂ were evaporated. Dry DMF (1.0 mL), 3-amino-5-carboxymethylphenol t-butylcarbamate (150 mg, 0.5 mmol) and anhydrous _{Cs2CO3 (} 1.0 g, 3.0 mmol) were added. The reaction mixture was heated at 90°C under argon for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with _H2O , 10% NaOH, _H2O and brine and dried ( _MgSO4 ). Purification by flash column chromatography (SiO ₂ , 20% EtOAc in hexane) gave a colorless oil: NMR (250 MHz, CDCl ₃ ): δ 8.09 (d, J=15.7 Hz, 1H, olefin), 7.55 (dd, J=1.9 Hz, 1H, aryl), 7.09 (dd, J=1.9 Hz, 1H, aryl), 7.46 (d, J=8.6 Hz, 1H, 5-pyridyl), 7.38 (dd, J=1.9 Hz, 1H, aryl), 7.22 (dd, J=8.6 Hz, 1H, 4-pyridyl), 7.12 (d, J=8.6 Hz, 2H, phenyl),

7.07 (d, J=15.7 Hz, IH, olefin), 6.82 (d, J=8.6 Hz, 2H, phenyl), 6.58 (s, IH, NH), 5.16 (s, 2H, CH ₂ -O), 4.04 (t, J=6.5 Hz, 2H, O-CH ₂ ), 3.92 (s, 3H, methyl ester), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.58 (t, J=7.6 Hz, 2H, benzylic), 1.88 (m, 2H, CH ₂ ), 1.55 (s, 9H, t-butyl), 1.46 (m, 10H, aliphatic): MS (Cl): 677 (M+H).

1 1 PL 51 ll(d) 5-Carboxymethyl-3-yl-oxa-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethylaniline. 2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-[(3-amino-5-carboxymethyl)phenoxymethyl]pyridine t-butylcarbamate (200 mg, 0.29 mmol) was dissolved in dry CH ₂ Cl ₂ (3.0 mL) under an argon atmosphere and cooled to 0°C. Anisole (0.05 mL, 0.46 mmol) was added followed by trifluoroacetic acid (0.3 mL). The reaction mixture was stirred for 30 min at 0°C and then for 3.5 h at room temperature. The reaction mixture was quenched with aqueous NaHCO ₃ . The product was extracted into CH 2 Cl 2 and the organic extracts were washed with brine and dried (MgSO ₄ ). Purification by flash column chromatography (SiO ₂ , 25% EtOAc in hexane) gave a colorless oil: ¹ H NMR (250 MHz, CDCl ₃ ): δ 8.09 (d, J=15.7 Hz, 1H, olefin), 7.44 (d, J=8.6 Hz, 1H, 5-pyridyl), 7.17 (d, J=8.6 Hz, 1H, 4-pyridyl), 7.08 (m, 3H, aryl), 7.05 (d, J=15.7 Hz, 1H, olefin), 6.96 (dd, J=1.9 Hz, 1H, aryl), 6.88 (d, J=8.6 Hz, 2H, phenyl), 6.49 (dd, J=1.9 Hz, 1H, aryl), 5.12 (s, 2H, CP^-O), 4.04 (t, J=6.5 Hz, 2H, O-CH ₂ ), 3.92 (s, 3H, methyl ester), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.54 (t, J=7.6 Hz, 2H, benzylic), 1.88 (m, 2H, CH^, 1.62 (m, 2H, CH^, 1.40 ₍ m _{, aliphatic ) .-} calcd.

11(e) 5-carboxy-3-[1-oxa-2-f2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridylethylaniline, dilithium salt

5-Carboxymethyl-3-[1-oxa-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (120 mg, 0.208 mmol) was dissolved in THF (1.0 mL) and MeOH (0.5 mL) and treated with 1.0M LiOH (0.5 mL, 0.5 mmol). The reaction mixture was stirred under argon for 16 h. The solvent was evaporated and the product was purified by reverse-phase MPLC (RP-18 _SiO2 , gradient _H2O -MeOH). Lyophilization gave a colorless amorphous solid: Ή NMR (250 MHz, d ⁴ -MeOH): δ 7.80 (d, J=15.7 Hz, IH, olefin), 7.42 (d, J=8.6 Hz, IH, 5-pyridyl), 7.38 (d, J=8.6 Hz, IH, 4-pyridyl), 7.06 (d, J=15.7 Hz, IH, olefin). olefin), 7.05 (d, J=8.6 Hz, 2H, phenyl), 6.98 (dd, J=1.9 Hz, IH, aryl), 6.92 (dd, J=1.9 Hz, IH, aryl), 6.80 (d, J=8.6 Hz, 2H, phenyl), 6.47 (dd, J=1.9 Hz, IH, aryl), 5.11 (s, 2H, CH ₂ -O), 4.05 (t, J=6.5 Hz, 2H, O-CH ₂ ), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6 Hz, 2H, benzylic), 1.85 (m, 2H, CH ₂ ), 1.57 (m, 4H, aliphatic), 1.36 (m, 6H, aliphatic); Analysis: calcd. for C^H^N^L^ . 21/5H ₂ O: C 58.04; H 6.70; N 4.36, found: C 57.87; H 6.34; N 4.22; MS (FAB): 561 (M+H).

ί 1 h1 2 92

Example 12

3-yl-thia-2-F2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridylethylaniline, lithium salt

12(a) 3-yl-thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)6-pyridyl]ethyl]aniline. To a cooled (0°C) solution of SOC1 ₂ (0.26 ml, 3.5 mmol) in dry toluene (1 ml) under an argon atmosphere was added a solution of 2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine (150 mg, 0.35 mmol) in toluene (2.5 ml). After 5 minutes, the cooling bath was removed and the reaction mixture was stirred for 2 hours at room temperature. The toluene and excess SOC1 ₂ were evaporated. The crude product was dissolved in dry DMF (1 mL) and added to a solution of sodium 3-aminothiophenoxide prepared from 3-aminothiophenol (0.09 mL, 0.84 mmol; Aldrich) and NaH (34 mg, 0.084 mmol; 60%-ene in mineral oil) in DMF (2 mL) under an argon atmosphere. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc, washed with H ₂ O and brine, and dried (MgSO ₄ ). Purification by flash column chromatography ( _SiO2 , 30% EtOAc in hexane) gave a colorless solid: Ή NMR (250 MHz, _CDCl3 ): δ 8.06 (d, J=15.7 Hz, 1H, olefin), 7.27 (d, J=8.6 Hz, 1H, 5-pyridyl), 7.08 (m, 5H, 4-pyridyl, 5'-phenyl, olefin, phenyl), 6.81 (d, J=8.6 Hz, 2H, phenyl), 6.74 (m, 2H, 2',4'-phenyl), 6.46 (ddd, J=8.0, 1.9 Hz, 1H, 6'-phenyl), 4.20 (s, 2H, CH2 _- S), 3.96 (t, J=6.5 Hz, 2H, O- _CH2- ). 3.81 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.65 (broad singlet, 2H, NHj), 2.55 (t, J=7.6 Hz, 2H, benzyl),

1.83 (m, 2H, CH^, 1.60 (m, 2H, _CH2 ), 1.45 (m, 2H, _CH2 ), 1.35 (m, 6H, aliphatic): Analysis: calcd. for C^E^N^S. 1/ _4H2O : C 69.06; H 7.20; N 5.20, found: C 69.02; H 7.16; N 5.21; MS (CI),: 535 (M+H); mp 57-60°C.

12(b) 3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridylethylaniline, lithium salt. 3-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (75 mg, 0.14 mmol) was dissolved in THF (0.56 mL) and MeOH (0.28 mL) and treated with 1.0 M LiOH (0.28 mL, 0.28 mmol). The reaction mixture was stirred under argon for 6 h. The solvent was evaporated and the product was purified by reverse-phase MPLC (RP-18 _SiO2 , gradient F^O-MeOH). Lyophilization gave a colorless amorphous solid: Ή NMR (250 MHz, d ⁴ MeOH): δ 7.76 (d, J=15.7 Hz, IH, olefin), 7.25 (d, J=8.6 Hz, IH, 5-pyridyl), 7.24 (d, J=8.6 Hz, IH, 4-pyridyl), 7.09 (d, J=8.6 Hz, IH, 2H, phenyl), 7.04 (d, J=15.7 Hz, IH, olefinic), 6.97 (dd, J=8.0 Hz, IH, 5'-phenyl), 6.80 (d, J=8.6, Hz, 2H, phenyl), 6.72 (dd, J= 1.9, IH, 2'-phenyl), 6.67 (dd, J=8.0 Hz, IH, 2'-phenyl). 4'-phenyl), 6.51 (ddd, J=8,0,1,9 Hz, λ 1112 02

IH, 6'-phenyl), 4.16 (s, 2H, CH ₂ S), 4.00 (t, J=6.5 Hz, 2H), O-CH ₂ ), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6 Hz, 2H, benzylic), 1.80 (m, 2H, CH^, 1.49 (m, 4H, aliphatic), calcd. for G^H^SLi: 63.05; H 6.72; MS (M+H): 521.

Using a similar method, except that we replaced the intermediates listed here with suitable ones and used chemistry known in the art, we prepared the following compounds:

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6-pyridylethylaniline, lithium salt.

Colorless amorphous solid: ^J H NMR (360 MHz, d ⁶ -DMSO): δ 7.43 (d, J=15.7 Hz, IH, olefin), 7.33 (d, J=8.6 Hz, IH, pyridyl), 7.23 (d, J=8.6 Hz, IH, pyridyl), 7.13 (d, J=8.6 Hz, 2H, phenyl), 6.92 (dd, J=7.8 Hz, IH, 5'-phenyl), 6.86 (d, J=15.7, Hz, IH, olefin), 6.82 (d, J=8.6 Hz, 2H, phenyl), 6.61 (s, IH, 2'-phenyl), 6.51 (d, J=7.8 Hz, IH, 4'-phenyl), 6.37 (d, J=7.8 Hz, IH, 4'-phenyl). 6'-phenyl), 5.10 (broad singlet, 2H, NH ₂ ), 4.16 (s, 2H, CH ₂ -S), 4.01 (t, J=6.5 Hz, 2H), O-CH ₂ ), 3.72 (s, 3H, OMe), 2.58 (t, J=7.6 Hz, 2H, benzylic), 1.71 (m, 4H, aliphatic); Analysis: calcd. for C ₂₆ H ₂₇ N ₂ O ₄ SLi. 1 3/4 H ₂ O: C 62.20; H 6.12; N 5.58: found: C 62.23; H 5.82; N 5.44; MS (ES ⁺ ): 464.3 (M+; free acid); (ES ): 463.0 (MH; free acid);

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-trifluoromethylphenyl)octyloxy)-6-pyridyl]ethylaniline, lithium salt.

Colorless amorphous solid: ^X H NMR (250 MHz, d ⁴ -MeOH): δ 7.78 (d, J= 15.7 Hz, IH, olefin), 7.53 (d, J=8.6 Hz, 2H, phenyl), 7.34 (d, J=8.6 Hz, 2H, phenyl), 7.25 (d, J=8.6 Hz, IH, pyridyl), 7.24 (d, J=8.6 Hz, IH, pyridyl), 7.04 (d, J=15.7, Hz, IH, olefin), 6.97 (dd, J=8.0 Hz, IH, 5'-phenyl), 6.72 (dd, J= 1.9 Hz, IH, 2'-phenyl), 6.67 (ddd, J=8.0, 1.9 Hz, IH, 4'-phenyl), 6.51 (ddd, J=8.0,1.9 Hz, IH, 6'-phenyl), 4.16 (s, 2H,CH ₂ S), 4.01 (t, J=6.5 Hz, 2H, O-CH ₂ ), 2.68 (t, J=7.6 Hz, 2H, benzylic), 1.85 (m, 2H, CH 2 ), 1.68 (m, 2H, CH ₂ ), 1.50 (m, 2H, CHJ, 1.37 (m, 6H, aliphatic); Analysis: calcd for C ₃₀ H ₃₂ F ₃ N ₂ O ₃ SLi. 11/2 H ₂ O: C 60.91; H 5.96; N 4.74: found: C 60.53; H 5.56; N 4.51; MS (ES ⁺ ): 559.0 (M+H; free acid); (ES*): 557.0; (MH; free acid); and

1 1 2 t J

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-phenyl)octyloxy)-6-pyridyl]ethyl]aniline, lithium salt.

Colorless amorphous solid: ¹ H NMR (250 MHz, d ⁴ -MeOH): δ 7.72 (d, J=15.7 Hz, IH, olefin), 7.20 (m, 7H, pyridyl, phenyl), 7.04 (d, J=15.7, Hz, IH, olefin), 6.97 (dd, J=8.0 Hz, IH, 5'-phenyl), 6.72 (dd, J=1.9 Hz, IH, 2'-phenyl), 6.67 (ddd, J=8.0, 1.9 Hz, IH, 4'-phenyl), 6.51 (ddd, J=8.0,1.9 Hz, IH, 6'-phenyl), 4.16 (s, 2^(¾^). 4.02 (t, J=6.5 Hz, 2H, O-CH ₂ ), 2.52 (t, J=7.6 Hz, 2H, benzyl), 1.83 (m, 2H, CH ₂ ), 1.59 (m, 2H, CH ₂ ), 1.50 (m, 2H, CH ₂ ), 1.37 (m, 6H, aliphatic); MS (ES ⁺ ): 491.0 (M+H; free acid); (EC'): 489.0; (MH; free acid);

Example 13

3-tri-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridylethylaniline, lithium salt

13(a) 3-[1-Oxythia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridylethylaniline. To a cooled (-15°C) solution of 3-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (150 mg, 0.28 mmol) in CH2Cl2 (4 mL) under argon was added 85%-one mCPBA (63 mg, 0.31 mmol) in two portions over 15 min. The reaction was maintained at -15°C for a total of 40 min. The reaction mixture was quenched with aqueous _NaHCO3 and the product was extracted into EtOAc. The organic extract was washed with H ₂ O and brine and dried (MgSO 4 ). The product was recrystallized from EtOAc-hexane to give a colorless solid: *H NMR (250 MHz, CDCl ₃ ): δ 8.03 (d, J=15.7 Hz, 1H, olefin), 7.22 (dd, J=8.0 Hz, 1H, 5'-phenyl), 7.15 (m, 2H, 4,5-pyridyl), 7.11 (d, J=8.6 Hz, 2H, phenyl), 6.92 (m, 1H, 2'-phenyl), 6.85 (d, J=15.7 Hz, 1H, olefin), 6.80 (m, 3H, phenyl, 4'-phenyl), 6.73 ddd, J=8.0,1.9 Hz, 1H, 6'-phenyl), 4.12 (s, 2H, CH ₂ -S), 4.00 (t, J=6.5 Hz, 2H, O-CH ₂ ), 3.99 (broad singlet, 2H, NH ₂ ), 3.82 (s, 3H, methyl ester), 3.79 (s, 3H, OMe), 2.56 (t, J=7.6 Hz, 2H, benzyl), 1.85 (m, 2H, CH ₂ ), 1.60 (m, 2H, CH ₂ ), 1.48 (m, 2H, CH ₂ ), 1.36 (m, 6H, aliphatic); Analysis: calcd. for C^H^N^S : C 67.61; H 6.95; N 5.09, found: C 67.73; H 7.17; N 4.82; MS (Cl): 551 (M+H); floor 109-111°C.

13(b) 3-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridylethylaniline, lithium salt. 3-[1-Oxythia-2-[2-(E-2-carboxymethylethenyl)-3(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (109 mg, 0.198 mmol) was dissolved in THF (0.80 mL) and MeOH (0.40 mL) and treated with 1.0M LiOH (0.40 mL, 0.40 mmol). The reaction mixture was stirred under argon for 6 h. The solvent was evaporated and the product was purified by reverse-phase MPLC (RP-18 _SiO2 , gradient _H2O -MeOH). Lyophilization gave a colorless amorphous solid: ² H NMR (250 MHz, d ⁴ -MeOH): δ 7.75 (d, J=15.7 Hz, IH, olefin), 7.28 (d, J=8.6 Hz, IH, 5-pyridyl), 7.15 (dd, J=8.0 Hz, IH, 5'-phenyl), 7.03 (m, 4H, 4-pyridyl). olefin, phenyl), 6.86 (dd, J=1.9 Hz, IH, 2'phenyl), 6.75 (m, 4H, 4',6'-phenyl, phenyl), 4.20 (q, J=13 Hz, 2H, CH ₂ -S), 4.02 (t, J=6.5 Hz, 2H, O-CH ₂ ), 3.72 (s, 3H, OMe), 2.52 (t, J=7.6 Hz, 2H, benzyl), 1.85 (m, 2H, CH ₂ ), 1.53 (m, 4H, aliphatic), 1.37 (m, 6H, aliphatic); Analysis: calcd. for C^H^N^SLi. 2 H ₂ O: C 62.27; H 6.79; N 4.84, found: C 62.13; H 6.89; N 5.01; MS (FAB): 543 (M+H), 537 (M+H); free acid.

Using a similar approach, we have prepared:

3-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)-6-pyridyl]ethyl]aniline, lithium salt

Colorless amorphous solid: *H NMR (250 MHz, d ⁴ -MeOH): δ 7.75 (d, J=15.7 Hz, IH, olefin), 7.28 (d, J=8.6 Hz, IH, pyridyl), 7.20 (d, J=8.6 Hz, IH, pyridyl),

7.12 (d, J=8.6 Hz, 2H, phenyl), 7.06 (s, IH, 2'-phenyl), 7.02 (d, J=7.8 Hz, IH, 4'-phenyl), 6.81 (m, 5H, 5',6'-phenyl, olefin, phenyl), 4.20 (q, J=13 Hz, 2H, CH ₂ -S(O)), 4.02 (t, J=6.5 Hz, 2H, O-CH^, 3.72 (s, 3H, OMe), 2.62 (t, J=7.6 Hz, 2H, benzylic), 1.80 (m, 4H, aliphatic); Analysis: calcd for C ₂₆ H ₂₇ N ₂ O ₅ SLi. 2 5/8 H ₂ O: C 58.50; H 6.09; N 5.25, found: C 58.18; H 5.67; N 5.12; MS (ES ⁺ ): 481.2 (M+H); free acid, (es-): 479.0 (MH; free acid).

3-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-trifluoromethylphenyl)octyloxy-6-pyridyl]ethylaniline, lithium salt.

Colorless amorphous solid: ^J H NMR (250 MHz, d ⁴ -MeOH): δ 7.75 (d, J=15.7 Hz, IH, olefin), 7.53 (d, J=8.6 Hz, 2H, phenyl), 7.34 (d, J=8.6 Hz, 2H, phenyl),

7.24 (d, J=8.6 Hz, IH, pyridyl), 7.18 (d, J=8.6 Hz, IH, pyridyl), 7.04 (d, J=8.0 Hz, IH, 4'-phenyl), 7.02 (d, J=15.7 Hz, IH, olefin), 6.89 (s, IH, 2'-phenyl), 6.78 (m, 2H, 5',6'phenyl), 4.20 (q, J=13 Hz, 2H, CH ₂ -S(O)), 4.02 (t, J=6.5 Hz, 2H, O-CH ₂ ), 2.52 (t,

1 1 2 V56

J=7.6 Hz, 2H, benzyl), 1.88 (m, 2H, CH ₂ ), 1.69 (m, 2H, CH ₂ ), 1.50 (m, 2H, CH ₂ ), 1.39 (m, 6H, aliphatic); Analysis: calcd. for C^H^F^C^SLi. 1 3/4 H ₂ O: C 58.87; H 5.85; N 4.58, found: C 58.92; H 5.55; N 4.48; MS (ES+): 575.2 (M+H); free acid;

3-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(phenyl)octyloxy-6-pyridyl]ethyl]aniline, lithium salt.

Colorless amorphous solid: ² H NMR (250 MHz, d ⁴ -MeOH): δ 7.75 (d, J=15.7 Hz, IH, olefin), 7.20 (m, 7H, pyridyl, phenyl), 7.04 (d, J=8.0 Hz, IH, 4'-phenyl), 7.02 (d, J=15.7 Hz, IH, olefin), 6.89 (s, IH, 2'-phenyl), 6.78 (m, 2H, 5',6'-phenyl), 4.20 (q, J=13 Hz, 2H, CH ₂ -S(O)), 4.02 (t, J=6.5 Hz, 2H, O-CH ₂ ), 2.52 (t, J=7.6 Hz, 2H, benzyl), 1.88 (m, 2H, CH ₂ ), 1.69 (m, 2H, CH^, 1.50 (m, 2H, CHj), 1.39 (m, 6H, aliphatic); Analysis: calcd. for C ₂₉ H ₃₃ N ₂ O ₄ SLi. 1 H ₂ O: C 65.65; H 6.65; N 5.28, found: C 65.62; H 6.39; N 4.90; MS (ES+): 507.0 (M+H); free acid; (ES-): 505.0 (MH; free acid);

3-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-fluorophenyl)octyloxy-6-pyridyl]ethyl]aniline, lithium salt:

Colorless amorphous solid: Ή NMR (250 MHz, d ⁴ -MeOH): δ 7.75 (d, J=15.7 Hz, IH, olefin), 7.30-6.90 (multiplet, 8H, pyridyl, phenyl, olefin, 4'-phenyl), 6.89 (s, IH, 2'phenyl), 6.78 (m, 2H, 5',6'-phenyl), 4.20 (q, J=13 Hz, 2H, CH^O)), 4.02 (t, J=6.5 Hz, 2H, O-CH ₂ ), 2.52 (t, J=7.6 Hz, 2H, benzylic), 1.88 (m, 2H, CH ₂ ), 1.59 (m, 2H, CH^, 1.50 (m, 2H, CH ₂ ), 1.39 (m, 6H, aliphatic); MS (ES+): 525.2 (M+H); free acid; (ES-): 523.0 (MH; free acid).

Example 14

3-fl-dioxythia-2-f2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridylethylaniline, lithium salt

14(a) 3-[1-Dioxythia-2-yl2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridylethylaniline. To a cooled (0°C) solution of 3-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (75 mg, 0.14 mmol) in CH ₂ Cl ₂ (3 mL) under argon was added 85%-ene mCPBA (63 mg, 0.308 mmol). After 1 h, the reaction mixture was quenched with aqueous NaHCO ₃ and the product

P 1 2 02 was extracted into EtOAc. The organic extracts were washed with H ₂ O and brine and dried (MgSO ₄ ). Purification by flash column chromatography ( _SiO2 , 50% EtOAc in hexane) gave a colorless solid: NMR (250 MHz, _CDCl3 ): δ 7.90 (d, J=15.7 Hz, 1H, olefin), 7.39 (d, J=8.6 Hz, 1H, 5-pyridyl), 7.21 (t, J=8.0 Hz, 1H, 5'-phenyl), 7.19 (d, J-8.6 Hz, 1H, 4-pyridyl), 7.11 (d, J=8.6 Hz, 2H, phenyl), 7.03 (m, 2H, 2',4'-phenyl), 6.86 (m, 1H, 6'-phenyl), 6.81 (d, J=8.6 Hz, 2H, phenyl), 6.54 (d, J=15.7 Hz, 1H, olefin), 4.46 (s, 2H, CH ₂ -S), 3.99 (t, J=6.5 Hz, 2H, O-CH ₂ ), 3.86 (broad singlet, 2H, NH^, 3.79 (s, 3H, metU ester), 3.78 (s, 3H, OMe), 2.55 (t, J=7.6 Hz, 2H, benzyl), 1.82 (m, 2H, CH^, 1.60 (m, 2H, CH ₂ ), 1.45 (m, 2H, CH ₂ ), 1.35 (m, 6H, aliphatic); Analysis: calcd. for C^H^N^Sl/S moles C ₆ H ₁₄ : C 66.57; H 7.22; N 4.70, found: C 66.45; H 7.24; N 4.89; MS (Cl): 567 (M+H); floor 92-95°C.

14(b) 3-[1-Dioxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridylethylaniline, lithium salt.

3-[1-Dioxythia-2-[2-(E-2-carboxymethyl-ethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridylethylaniline (51 mg, 0.09 mmol) was dissolved in THF (0.30 mL) and MeOH (0.18 mL) and treated with 1.0M LiOH (0.18 mL, 0.18 mmol). The reaction mixture was stirred under argon for 6 h. The solvent was evaporated and the product was purified by reverse-phase MPLC (RP-18 _SiO2 , gradient _H2O -MeOH). Lyophilization gave a colorless amorphous solid: Ή NMR (250 MHz, ^d4 -MeOH); δ 7.65 (d, J=15.7 Hz, IH, olefin), 7.26 (d, J=8.6 Hz, IH, 5-pyridfl), 7.24 (d, J=8.6 Hz, IH, 4-pyridU), 7.17 (dd, J=8.0 Hz, IH, 5'-phenyl), 7.06 (d, J=8.6 Hz, 2H, phenU), 6.97 (dd, J=1.9 Hz, IH, 2'phenyl), 6.85 (m, 2H, 4',6'-phenyl), 6.78 (d, J=8.6 Hz, 2H, phenyl), 6.75 (d, J=15.7 Hz, IH, olefin), 4.55 (s, 2H, CH ₂ -S), 4.04 (t, J=6.5 Hz, 2H, O-CH,), 1.86 (m, 2H, _CH2 ), 1.55 (m, 4H, aliphatic), 1.37 (m, 6H, aliphatic): MS (FAB): 559 (M+H), 553 (M+H); free acid.

Example 15

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridylethyl]N,N-dimethylaniline, lithium salt

15(a) 3-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridylethyl-NN-dimethylaniline. To a solution of 3-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (75 mg, 0.14 mmol) in acetonitrile (1 mL) was added formaldehyde (0.25 mL, 3.1 mmol, 37% aqueous solution) and NaCNBH ₃ (50 mg, 0.80 mmol). The reaction mixture was stirred at room temperature for 15 min. The reaction solution was neutralized by the addition of glacial acetic acid and stirred for another 2 h. The reaction mixture was diluted with H2O and the product was extracted into EtOAc. The organic layer was washed with _H2O and brine and dried ( _MgSO4 ). Purification by flash column chromatography ( _SiO2 , 20% EtOAc in hexane) gave a light yellow oil: NMR (250 MHz, CDCl,): δ 8.06 (d, J=15.7 Hz, 1H, olefin), 7.35 (d, J=8.6 Hz, 1H, 5-pyridyl), 7.08 (m, 4H, 4-pyridyl, 5'-phenyl, phenyl), 7.04 (d, J=15.7 Hz, 1H, olefin), 6.83 (d, J=8.6 Hz, 2H, phenyl), 6.74 (m, 2H, 2',4'-phenyl), 6.52 (dd, J=8.0,1.9Hz, 1H, 6'-phenyl), 4.23 (s, 2H, ClLj-S), 4.00 (t, J=6.5 Hz, 2H, O-CH ₂ ), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.89 (s, 6H, Me ₂ ), 2.55 (t, J=7.6 Hz, 2H, benzyl), 1.83 (m, 2H, CH^), 1.60 (m, 2H, CH ₂ ), 1.45 (m, 2H, CH ₂ ), 1.35 (m, 6H, aliphatic); MS (CI); 563 (M+H).

15(b) 3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline, lithium salt. 3-[1-thia-2-[2-(E-2-carboxymethyl-ethenyl)-3-(8-(4methoxyphenyl)-octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline (100 mg, 0.178 mmol) was dissolved in THF (0.72 mL) and MeOH (0.36 mL) and treated with 1.0 M LiOH (0.36 mL, 0.36 mmol). The reaction mixture was stirred under argon for 6 h. The solvent was evaporated and the product was purified by reverse-phase MPLC (RP-18 SiO ₂ , gradient H ₂ OMeOH). Lyophilization gave a colorless amorphous solid: ^] H NMR (250 MHz, d ⁴ -MeOH): δ 7.78 (d, J=15.7 Hz, IH, olefin), 7.25 (s, 2H, 4,5-pyridyl), 7.07 (m, 4H, phenyl, olefin, 5'-phenyl), 6.80 (d, J=8.6 Hz, 2H, phenyl), 6.72 (dd, J=1.9 Hz, IH, 2'-phenyl), 6.67 (ddd, J=8.0,1.9Hz, IH, 4'-phenyl), 6.55 (ddd, J=8.0.1.9Hz, IH, 6'-phenyl), 4.20 (s, 2H, CH^S), 4.00 (t, J=6.5 Hz, 2H, O-CH ₂ ), 3.76 (s, 3H, OMe), 2.85 (s, 6H, Me ₂ ), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH ₂ ), 1.55 (m, 4H, aliphatic), 1.33 (m, 6H, aliphatic); Analysis: calcd. for C ₃₂ H ₃₉ N ₂ O ₄ SLi. 5/4 IL,O: C 66.59; H 7.25; N 4.85, found: C 66.50; H 7.01; N 4.75; MS (FAB): 555.2 (M+H).

Example 16

3-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridineethyl]N,N-dimethylaniline, lithium salt

1119 9° 59

16(a) 3-[1-Oxythia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-NN-dimethylaniline. Prepared from 3-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)-octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline by the procedure described for the preparation of 3-[1-oxythia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline. *H NMR (250 MHz, CDCl ₃ ): δ 8.01 (d, J=15.7 Hz, IH, olefin), 7.22 (dd, J=8.0 Hz, IH, 5'-phenyl), 7.17 (d, J=8.6Hz, IH,

5-pyridyl), 7.13 (d, J=8.6Hz, IH, 4-pyridyl), 6.80 (m, 6H, phenyl, 2',4',6'-phenyl, olefin), 4.12 (s, 2H, CH ₂ -S), 4.00 (t, J=6.5 Hz, 2H, O-CH ₂ ), 3.82 (s, 3H, methyl ester), 3.79 (s, 3H, OMe), 2.95 (s, 6H, Me ₂ ), 2.55 (t, J=7.6 Hz, 2H, benzyl), 1.85 (m, 2H, CH^, 1.60 (m, 2H, CH^, 1.48 (m, 2H, CH ₂ ), 1.36 (m, 6H, aliphatic); MS (CI): 579.2 (M+H).

16(b) 3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline, lithium salt. Prepared from 3-[1-oxythia-2-[2-(E-2-carboxymethyl-ethenyl)-3-(8-(4-methoxyphenyl)-octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline according to the procedure described for the preparation of 3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethylaniline, lithium salt. Colorless amorphous solid: ^X H NMR (250 MHz, d ₄ MeOH); δ 7.75 (d, J=15.7 Hz, IH, olefin), 7.31 (dd, J=8.0 Hz, IH, 5'-phenyl), 7.24 (d, J=8.6Hz, IH, 5-pyridyl), 7.03 (m, 3H, 4-pyridyl, phenyl), 6.95 (d, J=15.7 Hz, IH, olefin), 6.80 (m, 4H, aryl), 6.70 (m, IH, aryl), 4.21 (q, J=13Hz, 2H, CH ₂ -S), 4.02 (t, J=6.5 Hz, 2H, O-CH ₂ ), 3.74 (s, 3H, OMe), 2.84 (s, 6H, Me ₂ ), 2.56 (t, J=7.6 Hz, 2H, benzylic), 1.85 (m, 2H, CH ₂ ), 1.53 (m, 4H, aliphatic), 1.37 (m, 6H, aliphatic); MS (FAB): 571.3 (M+H).

Example 17

Preparation of 3-[N-[2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]methylaminobenzoic acid, dilithium salt

The title compound was prepared according to the method outlined above in Scheme 5 by reacting the appropriate t-BOC protected aminobenzoic acid with 2-(E2-carboxymethylethenyl)-3-dodecyloxy)-6-(chloromethyl)-pyridine hydrochloride or a similar intermediate.

Similarly, 3-[N-[2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]methyl]aminobenzoic acid, N-oxide, dilithium salt and

1112 9?

««

3-[N-[2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)-octyloxy)-6-pyridyl]methyl]-N-methylaminobenzoic acid, dilithium salt.

Example 18

4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoic acid, dilithium salt

18(a). 3-Hydroxy-6-methyl-2-pyridine carboxaldehyde. 2,6-lutidine-a ² ,3-diol (15 g, 107.8 mmol; Aldrich) was suspended in dry CH^Cl^ (200 mL) and treated with MnO2 (47 g, 539 mmol). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was filtered through a pad of Celite and the solvent was evaporated. The crude aldehyde was obtained as a brownish yellow solid and used directly for the next step: ^X H NMR (250MHz, CDCl3) δ 10.65 (s, 1H, OH), 10.30 (s, 1H, aldehyde, 7.30 (m, 2H, 4,5-pyridyl), 2.55 (s, 3H, methyl).

18(b). 3-i8-(4-methoxyphenyl)octyloxy-6-methyl-2-pyridine carboxaldehyde. To a solution of 1-iodo-8-(4-methoxyphenyl)octane (16.3 g, 47.1 mmol) in dry DMF (45 mL) under argon was added 3-hydroxy-6-methyl-2-pyridine carboxaldehyde (7.7 g, 56.2 mmol) and anhydrous I^COj (32 g, 235 mmol). The reaction mixture was stirred vigorously at 90°C for 1.5 h. After cooling to room temperature, it was diluted with EtOAc and washed with H ₂ O, aqueous NH ₄ Cl and brine and dried (MgSO ₄ ). Evaporation gave the crude aldehyde as a dark oil, which was used without further purification.

18(c). 2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyloxy]-6-methylpyridine.

3-[8-(4-Methoxyphenyl)octyloxy]-6-methyl-2-pyridine carboxaldehyde obtained above was dissolved in dry toluene (100 mL) under argon atmosphere and treated with methyl (triphenylphosphoranylidene)acetate (16 g, 48 mmol). The reaction mixture was heated at 50°C for 1 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with H ₂ O and brine, and dried (MgSO ₄ ). Purification by flash column chromatography (SiO ₂ , 20% EtOAc in hexane) gave the product as a light yellow oil: ¹ H NMR (250 MHz, CDCl ₃ ) δ 8.07 (d, J=15.7Hz, 1H, olefin), 7.10 (m, 4H, phenyl,

4,5-pyridfl), 7.07 (d, J= 15.7Hz, IH, olefin), 6.81 (d, J=8.6 2H, phenyl), 3.97 (t, J=6.5 Hz, 2H, O-Cl·^), 3.79 (s, 3H, OCH ₃ ), 3.78 (s, 3H, methyl ester), 2.54 (t, J=7.6 Hz, 2H, benzyl), 2.48 (s, 3H, methyl), 1.85 (m, 2H, CH 2 , 1.60 (m, 2H, CH ₂ ), 1.37 (m, 8H, aliphatic); MS (CI): 412.3 (M+H).

t-'< 11 1 2 S 2

18(d). 2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyloxy]-6-methylpyridine N-oxide. (2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-methylpyridine (17.1 g, 41.5 mmol) was dissolved in dry CHCl3 (105 mL) and cooled to 0°C; 50% m-chloroperbenzoic acid (15.8 g, 45.8 mmol) was added in three portions over 10 min. The cooling bath was _removed and the reaction mixture was stirred for 15 h at room temperature. The reaction mixture was poured into aqueous _NaHCO3 and the product was extracted into _CH2Cl2 . The organic extract was washed with _H2O and brine and dried ( _MgSO4 ). The crude product was obtained as a yellow solid and We used it without additional cleaning.

18(e) 2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyloxy]-6-hydroxymethylpyridine. The 2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-methylpyridine N-oxide obtained above was suspended in dry DMF (130 mL) and cooled to 0°C under an argon atmosphere. Trifluoroacetic anhydride (56 mL, 400 mmol) was added slowly to this. The reaction mixture was maintained at 0°C for 20 min and then at room temperature for 18 h. The reaction solution was added slowly to a saturated aqueous Na2O3 solution and stirred for 1 h. The product was then extracted into EtOAc; the combined organic extracts were washed with _H2O and brine and dried ( _MgSO4 ). Purification by flash column chromatography (SiO ₂ , EtOAc:hexane:CH ₂ Cl ₂ , 30:20:50) gave a waxy solid: Ή NMR (250 MHz, CDC1 ₃ ) δ 8.08 (d, J=15.7Hz, IH, olefin), 7.23 (d, J=8.6Hz, IH, 5-pyridyl), 7.16 (d, J=8.6Hz, IH, 4-pyridyl), 7.09 (d, J=8.6Hz, 2H, phenyl), 7.03 (d, J=15.7Hz, IH, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 4.69 (d, J=4.1Hz, 2H, CFL^OH), 4.01 (t, J=6.5 Hz, 2H, O-CH ₂ ), 3.82 (s, 3H, OCH ₃ ), 3.78 (s, 3H, methyl ester), 3.62 (t, J=4.1Hz, IH, OH), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH ₂ ), 1.58 (m, 2H, CH ₂ ), 1.44 (m, 8H, aliphatic); MS (Cl): 428.2 (M+H).

18(f) Methyl 4-[2-thia-3-[2-(E-2-carboxy-methylethenyl)-3-[8-(4-methoxyphenyl)octyloxy-6-pyridylpropyl]benzoate. To a cooled (0°C) solution of SOCl (0.51 ml, 7.0 mmol) in dry toluene (2 ml) under an argon atmosphere was added a solution of

2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine (300 mg, 0.70 mmol) in toluene (5 mL). After 5 min, the cooling bath was removed and the reaction mixture was stirred for 2 h at room temperature. Toluene and excess SOC1 ₂ were evaporated. Dry DMF (2 mL), methyl 4-mercaptomethylbenzoate (180 mg, 0.7 mmol) [prepared from 4-mercaptomethylbenzoic acid (Bader) and methanolic HCl] and anhydrous Cs ₂ CO ₃ (1.63 g, 5.0 mmol) were added. The reaction mixture was heated at 60°C under argon for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with HjO, 10% NaOH, HjO and brine and dried.

1112 02 (MgSO ₄ ). Purification by flash column chromatography ( _SiO2 , 15% EtOAc in hexane) gave a colorless waxy solid: ^X H NMR (250MHz, CDCl3 _δ 8.05 (d, J=15.8Hz, 1H, olefin), 7.93 (d, J=8.6Hz, 2H, phenyl), 7.35 (d, J=8.6Hz, 2H, phenyl), 7.18 (d, J=8.6Hz, 1H, pyridyl), 7.06 (d, J=8.6Hz, 1H, pyridyl), 7.02 (d, J=8.6Hz, 2H, phenyl), 6.98 (d, J=15.8Hz, 1H, olefin), 6.78 (d, J=8.6Hz, 2H, phenyl), 3.92 (t, J=6.5 Hz, 2H, OCH ₂ ), 3.85 s, 3H, methyl ester), 3.75 (s, 3H, OCH ₃ ), 3.72 (s, 3H, methyl ester) 3.64 (s, 2H, SCH ₂ ), 3.59 (s, 2H, SCH ₂ ), 2.49 (t, J=7.6 Hz, 2H, benzylic), 1.78 (m, 2H, CH ₂ ), 1.40 (m, 10H, aliphatic); MS (Cl): 592 (M+H).

18(g) 4-(2-thia-3-i2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridylpropylbenzoic acid, dilithium salt. Methyl 4-[2-thia-3-[2-(E-2carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate (80 mg, 0.13 mmol) was dissolved in tetrahydrofuran (THF) (1.5 mL) and MeOH (1.5 mL) and treated with 1.0M LiOH (0.8 mL, 0.8 mmol). The reaction mixture was stirred under argon for 20 h. The solvent was evaporated and the product was purified by reverse-phase MPLC (RP-18 _SiO2 , gradient _H2O MeOH). Lyophilization gave a colorless amorphous solid: Ή NMR (250MHz, d ⁴ -MeOH) δ 7.87 (d, J=8.6 2H, phenyl), 7.79 (d, J=15.8Hz, IH, olefin), 7.34 (m, 3H, phenyl pyridyl), 7.23 (d, J=8.6Hz, IH, pyridyl), 7.08 (d, J=15.8Hz, IH, olefin), 7.06 (d, J=8.6Hz, 2H, phenyl), 6.80 (d, J=8.6Hz, 2H, phenyl), 4.04 (t, J=6.5 Hz, 2H, OCH ₂ ), 3.74 s, 2H, SCH ₂ ), 3.73 (s, 3H, OCH ₃ ), 3.69 (s, 2H, SCH ₂ ), 2.55 (t, J-7.6 Hz, 2H, benzylic), 1.87 (m, 2H, Cl·^), 1.50 (m, 10H, aliphatic); Analysis: calcd. for C ₃₂ H ₃₅ NO ₆ SLi ₂ . 3H ₂ O: C 61.04; H 6.56; N 2.22; found: C 60.96 H 6.35; N 2.39; MS (FAB): 576 (M+H), 582.3 (M+Li).

Example 19

4-[2-Oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoic acid, dilithium salt

19(a) Methyl 4-[2-oxythia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyloctyloxy]-6-pyridylpropyl]benzoate. Methyl 4-[2-thia-3-[2-(E-2-carboxymethylethenyl)3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate (110 mg, 0.186 mmol) was dissolved in dry CH2Cl2 (4 mL) under an argon atmosphere and cooled to -20°C. To this was added 85% m-chloroperoxybenzoic acid (36 mg, 0.18 mmol) in two portions 15 min apart. 15 min after the second addition, the reaction mixture was stirred for 15 min at -20°C and then quenched with 5% _NaHCO3 . The product was extracted into _CH2Cl2 . ₂ and the organic extracts were dried (MgSO ₄ ). Purification

411222 by flash column chromatography (SiO ₂ , 50% EtOAc in hexane) gave a white solid: Ή NMR (250MHz, CDC1 ₃ ) S 8.10 (d, J=15.8Hz, IH, olefin), 8.07 (d, J=8.6Hz, 2H, phenyl), 7.50 (d, J=8.6Hz, 2H, phenyl). phenyl), 7.28 (d, J=8.6Hz, IH, pyridyl), 7.20 (d, J=8.6Hz, IH, pyridyl), 7.12 (d, J=8.6Hz, 2H, phenyl), 7.07 (d, J=15.8Hz, IH, olefin), 6.83 (d, J=8.6Hz, 2H, phenyl), 4.19 (d, J=8.6Hz, 2H, phenyl). J=12.8Hz, IH, SCH), 4.12 (d, J=12.8Hz, IH, SCH), 4.04 (t, J=6.5 Hz, 2H, OCH ₂ ), 3.94 (s, 3H, methyl ester), 3.92 (m, 2H, SCH ₂ ), 3.83 (s, 3H, OCH ₃ ), 3.79 (s, 3H, methyl ester), 2.56 (t, J=7.6 Hz, 2H, benzylic), 1.87 (m, 2H, CH ₂ ), 1.40 (m, 10H, aliphatic); Analysis: calcd. for CgJVK^S: C 67.19; H 6.80; N 2.30; found: C 66.80 H 7.12; N 2.25; MS (Cl): 608 (M+H).

19(b). 4-[2-oxythia-3-f2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyloctyl-oxy)-6-pyridylpropylbenzoic acid, dilithium salt. Methyl

4-[2-Oxythia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate (90 mg, 0.148 mmol) was dissolved in THF (1.5 mL) and MeOH (1.5 mL) and treated with 1.0M LiOH (0.8 mL, 0.8 mmol). The reaction mixture was stirred under argon for 20 h. The solvent was evaporated and the product was purified by reverse-phase MPLC (RP-18 _SiO2 , gradient _H2O -MeOH). Lyophilization gave a colorless amorphous solid: Ή NMR (250MHz, d ⁴ -MeOH) δ 7.98 (d, J=8.6Hz, 2H, phenyl), 7.81 (d, J=15.8Hz, IH, olefin), 7.40 (d, J=8.6Hz, 2H, phenyl), 7.39 (d, J=8.6Hz, IH, pyridyl). 7.27 (d, J=8.6Hz, IH, pyridyl), 7.09 (d, J= 15.8Hz, IH, olefin), 7.05 (d, J=8.6Hz, 2H, phenyl), 6.77 (d, J=8.6Hz, 2H, phenyl), 4.35 (d, J=12.8Hz, IH, SCH), 4.25 (d, J=12.8Hz, IH, SCH). J=12.8Hz, IH, SCH), 4.06 (m, 4H, OCH ₂ , SCH ₂ ), 3.73 (s, 3H, OCH ₃ , 2.52 (t, J=7.6Hz, 2H, benzylic), 1.86 (m, 2H, CH ₂ ), 1.55 (m, 4H, aliphatic), 1.35 (m, 6H, aliphatic); MS (FAB): 592 (M+H), 500 (M+H); free acid).

Example 20

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxyl-6pyridylpropylbenzoic acid, dilithium salt

20(a) Methyl 3-mercaptomethylbenzoate, To a solution of methyl 3-bromomethylbenzoate (6.9 g, 30 mmol; Lancaster) in dry acetone (10 ml) was added dropwise a solution of thiourea (2.28 g, 30 mmol) in dry acetone (40 ml) at room temperature. After 15 min, the precipitated thiouronium salt was collected by filtration; the solid was washed with acetone and dried. The thiouronium salt was dissolved in H ₂ O (65 ml) and the pH was adjusted to 10.5 by the addition of 10% NaOH. The mixture was refluxed for 2 h. After cooling to £/-4 *f.

_; at room temperature the solution was extracted with EtOAc and the organic layer was discarded. The aqueous solution was acidified to pH 1.5 and extracted three times with EtOAc. The organic extracts were dried (MgSO ₄ ), filtered and the solvent was evaporated. The crude acid was then dissolved in anhydrous MeOH (125 mL), cooled to 0°C and dry HCl gas was bubbled through the solution for 30 min. The reaction mixture was then allowed to stand for 2 days at room temperature. The mixture was concentrated in vacuo and the product was purified by flash column chromatography (SiO ₂ , 5% EtOAc in hexane) to give a colorless oil: Ή NMR (250MHz, CDCl ₃ ) δ 8.00 (s, 1H, 2-phenyl), 7.91 (d, J=7.6Hz, 1H,

6-phenyl), 7.52 (d, J=7.6Hz, IH, 4-phenyl), 7.39 (dd, J=7.6Hz, IH, 5-phenyl), 3.92 (s, 3H, metU ester), 3.78 (d, J=7.7Hz, 2H, SCH ₂ ), 1.79 (t, J=7.7Hz, IH, SH).

20(b). Methyl 3-[2thia-3-i2-(E-2-carboxy-methylethenyl)-3-(8-(4-methoxyphenyl)octyloxy]-6-pyridyl1propyl]benzoate. To a cooled (0°C) solution of SOC1 ₂ (2.5 ml, 35 mmol) in dry toluene (25 ml) under an argon atmosphere was added a solution of

2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethyl-pyridine (1.5 g, 3.5 mmol) in toluene (10 ml). After 5 minutes, the cooling bath was removed and the reaction mixture was stirred for 4 hours at room temperature. Toluene and excess SOC1 ₂ were evaporated. To this was added dry DMF (5 ml), methyl 3-mercaptomethylbenzoate (600 mg,

3.3 mmol) and anhydrous _Cs2CO3 (6.6 g, 20 mmol). _The reaction mixture was heated at 60°C under argon atmosphere for 1.5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with F^O, 10% NaOH, H^O, and brine, and dried (MgSO4). Purification by flash column chromatography ( _SiO2 , 15% EtOAc in hexane) gave a colorless waxy solid: ^J H NMR (250MHz, _CDCl3 ) δ 8.07 (d, J=15.8Hz, 1H, olefin), 7.99 (s, 1H, 2-phenyl), 7.90 (d, J=7.7Hz,

IH, 6-phenyl), 7.54 (d, J=7.7Hz, IH, 4-phenyl), 7.37 (dd, J=7.7Hz, IH, 5-phenyl), 7.28 (d, J=8.6Hz, IH, pyridyl), 7.14 (d, J=8.6Hz, IH, pyridyl), 7.11 (d, J=8.6Hz, 2H, phenyl), 7.08 (d, J=15.8Hz, IH, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 3.99 (t, J=6.5Hz, 2H, OCH ₂ ), 3.91 (s, 3H, methyl ester), 3.81 (s, 3H, OCH ₃ ), 3.78 (s, 3H, methyl ester), 3.71 (s, 2H, SCH ₂ ), 3.68 (s, 2H, SCH ₂ ), 2.55 (t, J=7.6Hz, 2H, benzyl), 1.78 (m, 2H, CH^,

1.5 (m, 10H, aliphatic); MS (Cl): 592.2 (M+H).

20(c). 3-[2-thia-3-(2(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoic acid, dilithium salt. Methyl 3-[2-thia-3-[2(E-2-carboxymethylethenyl)3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate (1.5 g, 2.5 mmol) was dissolved in THF (20 ml) and MeOH (20 ml) and treated with 1.0M LiOH (11.5 ml, 11.5 mmol). The reaction mixture was stirred under argon for 20 h. The solvent was evaporated and the product was purified by reverse-phase MPLC (RP-18 _SiO2 , gradient _H2O1112S2

MeOH). Lyophilization gave a colorless amorphous solid: ^J H NMR (250MHz, d ⁴ -MeOH) δ 7.96 (s, IH, 2-phenyl), 7.85 (d, J=7.7Hz, IH, 6-phenyl), 7.79 (d, J=15.8Hz, IH, olefin), 7.30 (m, 4H, 4,5-phenyl), 4,5-pyridyl. 7.08 (d, J= 15.8Hz, IH, olefin), 7.06 (d, J=8.6Hz, 2H, phenyl), 6.80 (d, J=8.6Hz, 2H, phenyl), 4.04 (t, J=6.5Hz, 2H, OCH ₂ ), 3.74 (s, 2H, SCH ₂ ), 3.73 (s, 3H, OCH ₃ ), 3.69 (s, 2H, SCH ₂ ), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.87 (m, 2H, CH ₂ ), 1.50 (m, 10H, aliphatic); Analysis: calcd. for C 2 NO 2 5/4H ₂ O: C 64.32; H 6.32; N 2.34; found: C 64.28 H 6.24; N 2.32; MS (FAB: 564.2 (M+H); free acid).

If we proceed in a similar manner, except that we replace 8-(4-methoxyphenyl)octan-1-ol with another alcohol, such as 4-(4-methoxyphenyl)butan-1-ol, and prepare or provide the appropriate mercaptan and the appropriate benzoate or aniline, we produce the following compounds:

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6-pyridyl]propyl]benzoic acid, dilithium salt;

2-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]propyl]benzoic acid, dilithium salt;

4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenylacetic acid, dilithium salt;

1-fluoro-3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6-pyridyl]-propyl]benzene, lithium salt;

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6-pyridyl]-propyl]benzene, lithium salt;

1-fluoro-4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzene, lithium salt;

r\

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]aniline, dilithium salt;

N-[3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]-propyl]phenyltrifluoromethanesulfonamide; [Mercaptan, prepared according to the method of Tagawa, H. and Veno, K., Chem Pharm, Buli., 26(5), 1384 (1978)]; and

N-[3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]-propyl]benzene-methanesulfonamide, [Mercaptan, prepared by the method of Luther, E. Chem Ber., 30,1065 (1897)].

Example 21

3-[2-Oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoic acid, dilithium salt and 3-i2-dioxythia-3-[2-(E-2carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl1propyl]benzoic acid, dilithium salt

21(a). Methyl 3-[2-oxythia-3-r2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxyl-6-pyridylpropylbenzoate and methyl 3-[2-dioxythia-3-[2-(E-2-carboxymethylethenyl)-3-i8-(4-methoxyphenyl)octyloxy]-6-pyridylpropynebenzoate.

Methyl 3-[2-thia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyloxy]-6-pyridyl]propyl]benzoate (150 mg, 0.25 mmol) was dissolved in dry CH ₂ Cl ₂ (5 mL) under an argon atmosphere and cooled to -20°C. To this was added 85% m-chloroperoxybenzoic acid (52 mg, 0.26 mmol) in two portions 15 min apart. After the second addition, the reaction mixture was stirred for 25 min at -20°C and then quenched with 5% NaHCO ₃ . The product was extracted into CH ₂ Cl ₂ and the organic extracts were dried (MgSO ₄ ). Purification by flash column chromatography ( _SiO2 , 20 and 50% EtOAc in hexane) gave the sulfoxide as a white solid and the sulfone as a white solid:

Sulfoxide: Ή NMR (250MHz, CDCL,) δ 8.07 (d, J=15.8Hz, IH, olefin), 8.01 (s,

IH, 2-phenyl), 7.97 (d, J=7.7Hz, IH, 6-phenyl), 7.55 (d, J=7.7Hz, IH, 4-phenyl), 7.46 (dd, J=7.7Hz, IH, 5-phenyl), 7.28 (d, J=8.6Hz, IH, pyridyl), 7.20 (d, J=8.6Hz, IH, pyridyl). 7.07 (d, J=8.6Hz, 2H, phenyl), 7.05 (d, J=15.8Hz, IH, olefin), 6.78 (d, J=8.6Hz, 2H,

1112 *»· k . tno is phenyl), 4.12 (d, J=12.8Hz, IH, SCH), 4.05 (d, J=12.8Hz, IH, SCH), 4.04 (t, J=6.5Hz, 2H, OCH^, 3.94 (s, 3H, methyl ester), 3.92 (m, 2H, SCH ₂ ), 3.83 (s, 3H, OCH ₃ ), 3.79 (s, 3H, methyl ester), 2.56 (t, J=7.6Hz, 2H, benzyl), 1.87 (m, 2H, CH^, 1.40 (m, 10H, aliphatic); Analysis: calc. for C^H^NO^ . 1/4H ₂ O: C 66.70; H 6.83; N 2.29; found: C 66.54; 6.68; N 2.30; MS (Cl): 608.2 (M+H);

Sulfone: Ή NMR (250MHz, CDC1 ₃ ) δ 8.23 (s, IH, 2-phenyl), 8.13 (d, J=15.8Hz, IH, olefin), 8.08 (d, J=7.7Hz, IH, 6-phenyl), 7.74 (d, J=7.7Hz, IH, 4-phenyl), 7.51 (dd, J=7.7Hz, IH, IH, olefin). 5-phenyl), 7.46 (d, J=8.6Hz, IH, pyridyl), 7.24 (d, J=8.6Hz, IH, pyridyl), 7.12 (d, J=8.6Hz, 2H, phenyl), 7.11 (d, J= 15.8Hz, IH, olefin), 6.84 (d, J=8.6Hz, 2H, phenyl), 4.30 (s, 4H, SCH ₂ ), 4.06 (t, J=6.5Hz, 2H, OCH ₂ ), 3.93 (s, 3H, methyl ester), 3.83 (s, 3H, OCH ₃ ), 3.79 (s, 3H, methyl ester), 2.56 (t, J=7.6Hz, 2H, benzylic), 1.9 (m, 2H, CH^, 1.5 (m, 10H, aliphatic); MS (CI): 624.2 (M+H).

21(b). 3-[2-Oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)-octyloxy]-6-pyridylpropyl]benzoic acid, dilithium salt. Methyl 3-[2-oxythia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate (100 mg, 0.165 mmol) was dissolved in THF (1.5 mL) and MeOH (1.5 mL) and treated with 1.0M LiOH (0.8 mL, 0.8 mmol). The reaction mixture was stirred under an argon atmosphere for 20 h. The solvent was evaporated and the product was purified by reverse-phase MPLC (RP-18 SiO ₂ , gradient H ₂ O-MeOH. Lyophilization gave a colorless amorphous solid: ^J H NMR (250MHz, d ⁴ -MeOH) δ 7.95 (m, 2H, 2,6-phenyl), 7.82 (d,

J= 15.8Hz, IH, olefin), 7.40 (m, 2H, 4,5-phenyl), 7.37 (d, J=8.6Hz, IH, pyridyl), 7.29 (d, J=8.6Hz, IH, pyridyl), 7.10 (d, J=15.8Hz, IH, olefin), 7.06 (d, J=8.6Hz, 2H, phenyl), 6.79 (d, J=8.6Hz, 2H, phenyl), 4.36 (d, J= 12.8Hz, IH, SCH), 4.25 (d, J= 12.8Hz, IH, SCH), 4.08 (m, 4H, OCH ₂ , SCH ₂ ), 3.73 (s, 3H, OCH ₃ ), 2.54 (t, J=7.6Hz, 2H, Benzyl), 1.87 (m, 2H, _CH2 ), 1.55 (m, 4H, aliphatic), 1.37 (m, 6H, aliphatic); Analysis: calcd. for _{C32H35NO7SLi2.7} / _4H2O : C61.68; _H6.23 ; _N2.25 ; found: _C61.79 ; H6.10; N2.39; MS (FAB): 592.2 (M+H).

This reaction was also used to prepare 3-[2-oxythia-3-[2-(E-2-carboxyethenyl)3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzoic acid, lithium salt.

21(c). 3-[2-Dioxythia-3-[2-(E-2-carboxyethenyl)-3-i8-(4-methoxyphenyl)-octyloxy-6-pyridyl]propyl]benzoic acid, dilithium salt. Methyl 3-[2-dioxythia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyloxy]-6-pyridyl]propyl]benzoate (20 mg, 0.0321 mmol) was dissolved in THF (0.5 mL) and MeOH (0.5 mL).

1112 (0.5 mL) and treated with 1.0M LiOH (0.2 mL, 0.2 mmol). The reaction mixture was stirred under argon for 20 h. The solvent was evaporated and the product was purified by reverse-phase MPLC (RP-18 _SiO2 , gradient _H2O -MeOH). Lyophilization gave a colorless amorphous solid: Ή NMR (250MHz, d ⁴ -MeOH) δ 8.08 (s, IH, 2-phenyl), 7.96 (d, J=7.7Hz, IH, 6-phenyl), 7.85 (d, J=15.8Hz, IH, olefin), 7.58 (d, J=7.7Hz, IH, 4-phenyl), 7.39 (m, 3H, 5-phenyl, 4,5-pyridyl), 7.13 (d, J=15.8Hz, IH, olefin), 7.08 (d, J=8.6Hz, 2H, phenyl), 6.82 (d, J=8.6Hz, 2H, phenyl), 4.86 (s, 4H, SCH ₂ ), 4.10 (t, J=6.5Hz, SCH 2 ). 2H, OCH ₂ ), 3.75 (s, 3H, OCH ₃ ), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.87 (m, 2H, CH ₂ ), 1.55 (m, 4H, aliphatic), 1.40 (m, 6H, aliphatic); Analysis: calcd. for C ₃₂ H ₃₅ NO _g SLi ₂ .9/4H ₂ O: C 59.30; H 6.14; N 2.16; found: C 59.29 H 6.20; N 2.39; MS (FAB): 608.2 (M+H).

This reaction can also be used to prepare other sulfoxides and sulfones of the invention, including 3-[2-dioxythia-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxy-phenyl)butyl-oxy]-6-pyridyl]propyl]benzoic acid, dilithium salt, and 3-[2-oxythia-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzoic acid, dilithium salt.

Example 22

3-[2-thia-3-[2-(2-carboxyethanyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridylpropylbenzoic acid, dilithium salt

22(a). 2-(2-Carboxymethylethanyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine. 2-(E-2-Carboxymethyl-ethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine (300 mg, 0.702 mmol) was dissolved in MeOH (3 mL) and treated with 5% Pd-C catalyst (30 mg). The reaction mixture was stirred under an atmosphere of H ₂ (flask pressure) for 5 h. The reaction mixture was diluted with CH ₂ Cl ₂ , filtered through Celite, and concentrated. Purification by flash column chromatography (SiO ₂ , EtOAcICF^Cl^hexane, 25:50:25) gave a light yellow oil: ^X H NMR (250MHz, CDC1 ₃ ) δ 7.09 (m, 4H, phenyl, pyridyl), 6.80 (d, J=8.6Hz, 2H, phenyl), 4.62 (s, 2H, CH). ₂ ), 3.93 (t, J=6.5Hz, 2H, OCH^, 3.77 (s, 3H, OCH ₃ ), 3.68 (s, 3H, methyl ester), 3.16 (dd, J=7.3, 7.2Hz, 2H, CH ₂ ), 2.77 (dd, J=7.3, 7.2Hz, 2H, CH ₂ ), 2.54 (t, J=7.6Hz, 2H, benzyl), 1.79 (m, 2H, CH^, 1.57 (m, 2H, CH ₂ ), 1.44 (m, 2H, CH ₂ ), 1.34 (m, 6H, aliphatic); MS (Cl): 430.2 (M+H).

111222

22(b). Methyl 3-[2-thia-3-i2-(2-carboxymethylethanyl)-3-i8-f4-methoxyphenyloxyl-6-pyridylpropylbenzoate. To a cooled (0°C) solution of SOCl ₂ (0.17 ml, 2.33 mmol) in dry toluene (1.5 ml) under an argon atmosphere was added

2-(2-Carboxymethylethanyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine (100 mg, 0.233 mmol). After 5 min, the cooling bath was removed and the reaction mixture was stirred for 1.5 h at room temperature. Toluene and excess SOCl were evaporated. To this were added dry DMF (0.5 ml), methyl 3-mercaptomethylbenzoate (47 mg, 0.258 mmol) and _{anhydrous Cs2CO3} (380 mg, 1.16 mmol). The reaction mixture was heated at 60°C under argon atmosphere for 1 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with _H2 0.10% NaOH, _H2O and brine and dried ( _MgSO4 ). Purification by flash column chromatography (SiO ₂ , EtOAc:CH ₂ Cl ₂ :hexane, 15:25:65) gave a light yellow oil: ^X H NMR (250MHz, CDCl ₃ ) δ 7.99 (s, IH, 2-phenyl), 7.92 (d, J=7.7Hz, IH, 6-phenyl), 7.54 (d, J=7.7Hz, IH,

4-phenyl), 7.37 (dd, J=7.7Hz, IH, 5-phenyl), 7.09 (m, 4H, pyridyl, phenyl), 6.88 (d, J=8.6Hz, 2H, phenyl), 3.93 (t, J=6.5Hz, 2H, OCHj), 3.91 (s, 3H, methyl ester), 3.78 (s, 3H, OCH ₃ ), 3.71 (s, 2H, SCH ₂ ), 3.65 (s, 3H, methyl ester), 3.64 (s, 2H, SCH ₂ ), 3.14 (dd, J=7.3, 7.2Hz, 2H, CH^, 2.79 (dd, J=7.3, 7.2Hz, 2H, CH ₂ ), 2.55 (t, J=7.6Hz, 2H, benzyl), 1.80 (m, 2H, CH ₂ ), 1.58 (m, 2H, CH^, 1.45 (m, 2H, CH ₂ ), 1.34 (m, 6H, aliphatic); Analysis: calcd. for C^H^NO^: C 68.77; H 7.30; N 2.36; found: C 68.87; H 7.21, N 2.17, MS (CI): 594.6 (M+H).

22(c). 3-[2-thia-3-[2-(2-carboxyethanyl)-3-[8-(4-methoxyphenyl)octyl]oxy]-6-pyridyl]propyl]benzoic acid, dilithium salt. Methyl 3-[2-thia-3-[2-(2-carboxymethylethanyl)-3[8-(4-methoxyphenyl)octyl]oxy]-6-pyridyl]propyl]benzoate (116 mg, 0.195 mmol) was dissolved in THF (2.25 mL) and MeOH (0.75 mL) and treated with 1.0 M LiOH (0.75 mL, 0.75 mmol). The reaction mixture was stirred under argon for 20 h. The solvent was evaporated and the product was purified by reverse-phase MPLC (RP-18 SiO ₂ , H ₂ -MeOH gradient). Lyophilization gave a colorless amorphous solid: ^X H NMR (250MHz, d ⁴ -MeOH) δ 7.90 (s, IH, 2-phenyl), 7.83 (d, J=7.7Hz, IH, 6-phenyl), 7.34 (m, 2H, 4,5-phenyl), 7.25 (d, J=8.6Hz, IH, pyridyl), 7.14 (d, J=8.6Hz, IH, 6-phenyl). J=8.6Hz, IH, pyridfl), 7.07 (d, J=8.6Hz, 2H, phenyl), 6.83 (d, J=8.6Hz, 2H, phenyl), 4.01 (t, J=6.5Hz, 2H, OCE^), 3.77 (s, 3H, OCHj), 3.73 (s, 2H, SCH^, 3.71 (s, 2H, SCH ₂ ), 3.07 (dd, J=7.3, 7.2Hz, 2H, CHj), 2.47 (m, 4H, CH^, benzylic), 1.81 (m, 2H, _CH2 ), 1.50 (m, 4H, aliphatic), 1.30 ₍ m, 6H, aliphatic); Analysis: calcd. for _{C32H37NO6SLi2.9} / _4H2O : _C62.18 ; H6.77; N2.27; found: C61.93; H6.48; N2.10; MS (ES) _: 566 (M+H; free acid), 564 (MΗ; free acid).

* e *

1 1 202

In a similar way, we prepared these compounds:

3-[1-thia-2-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyl]oxy]-6-pyridyl]ethyl]benzene, lithium salt;

3-[2-thia-2-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyl]oxy]-6-pyridyl]propyl]benzene, lithium salt and 1-fluoro-4-[2-thia-3-[2-(2-carboxyethanyl)-3'[4-(4-methoxyphenyl)butyl]oxy]-6-pyridyl]propyl]benzene, lithium salt.

Example 23

4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridylpropylphenylacetic acid, dilithium salt

23(a). Methyl 4-mercaptomethylphenylacetate.

4-Bromomethyl-phenylacetic acid (1 g, 4.4 mmol) and thiourea (334 mg, 4.4 mmol) were heated (35-40°C) in acetone (20 ml) until a homogeneous solution was formed. After cooling to room temperature, the thiouronium salt precipitated. The solvent was evaporated and the residue was suspended in H ₂ O (10 ml). The pH was adjusted to 12 with 10% NaOH. The mixture was then refluxed for 2 h. The solution was acidified with 6N HCl and the product was extracted into EtOAc. The organic extracts were washed with H ₂ O and dried (MgSO ₄ ). The crude acid was dissolved in MeOH (20 ml) and treated with conc. H^SO* (0.33 ml). The reaction mixture was refluxed for 1.5 h. After cooling to room temperature, the reaction mixture was diluted with H _? O and the product was extracted into EtOAc. The organic extracts were washed with H ₂ O and dried (MgSO ₄ ). The methyl ester was obtained as an oil; the crude product was used without further purification: ^: H NMR (250MHz, CDCl ₃ ) δ 7.23 (m, 4H, aryl), 3.71 (d, J=7.6Hz, 2H, SCH^, 3.68 (s, 3H, methyl ester), 360 (s, 2H, CH ₂ ), 1.74 (t, J=7.6Hz, IH, SH); IR (filrn)n _max 2570 (SH), 1740 (CO cm ⁴ ).

23(b) Methyl 4-[2-thia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyl]oxyl-6-pyridinepropylphenylacetate. To a cooled (0°C) solution of SOC1 ₂ (0.44 ml, 6.2 mmol) in dry toluene (7 ml) was added under an argon atmosphere.

2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine (270 mg, 0.62 mmol). After 5 minutes, the cooling bath was removed and the reaction mixture

111?

stirred for 2 hours at room temperature. Toluene and excess SOC1 ₂ were evaporated. To this were added dry DMF (3 ml), methyl 4-mercaptomethylphenylacetate (183 mg, 0.93 mmol) and anhydrous Cs ₂ CO ₃ (907 mg, 2.79 mmol). The reaction mixture was heated at 60°C under an argon atmosphere for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with H ₂ 0.10% NaOH, HjO and brine and dried (MgSO ₄ ). Purification by flash column chromatography ( _SiO2 , 20% EtOAc in hexane) gave a light yellow oil: ^X H NMR (250MHz, _CDCl3 ) δ 8.08 (d, J=15.8Hz, IH, olefin), 7.22 (m, 6H, phenyl, pyridyl), 7.12 (d, J=8.6Hz, 2H, phenyl), 7.07 (d, J=15.8Hz, IH, olefin), 6.83 (d, J=8.6Hz, 2H, phenyl), 4.00 (t, J=6.5Hz, 2H, _OCH2 ), 3.82 (s, 3H, methyl ester) 3.78 (s, 3H, _OCH3 ), 3.70 (s, 3H, methyl ester), 3.68 (s, 2H, _SCH2 ), 3.67 (s, 2H, SCH ₂ ), 3.62 (s, 2H, CH ₂ ), 2.55 (t, J=7.6Hz, 2H, benzyl), 1.85 (m, 2H, CH ₂ ), 1.60 (m, 2H, CH ₂ ), 1.50 (m, 2H, CH ₂ ), 1.37 (m, 6H, aliphatic); MS (Cl): 605 (M+H).

23(c). 4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenylacetic acid, dilithium salt. Methyl 4-[2-thia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenylacetate (100 mg, 0.165 mmol) was dissolved in THF (1.4 mL) and MeOH (0.5 mL) and treated with 1.0 M LiOH (0.5 mL, 0.5 mmol). The reaction mixture was stirred under argon for 20 h. The solvent was evaporated and the product was purified by reverse-phase MPLC (RP-18 SiO ₂ , gradient P^OMeOH). Lyophilization gave a colorless amorphous solid: ^X H NMR (250MHz, d ⁴ -MeOH) δ 7.76 (d, J=15.8Hz, IH, olefin), 7.21 (m, 6H, phenyl, pyridyl), 7.06 (d,

J=8.6Hz, 2H, phenyl), 7.05 (d, J=15.8Hz, IH, olefin), 6.77 (d, J=8.6Hz, 2H, phenyl), 4.02 (t, J=6.5Hz, 2H, OCH ₂ ), 3.72 (s, 3H, OCH ₂ ), 3.66 (s, 4H, SCH ₂ ), 3.44 (s, 2H, CH ₂ ), 2.51 (t, J=7.6Hz, 2H, benzylic), 1.86 (m, 2H, CH ₂ ), 1.53 (m, 4H, aliphatic), 1.34 (m, 6H, aliphatic); MS (FAB): 578.2 (M+H); free acid).

Example 24

4-[2-Ioxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridylpropyl]phenylacetic acid, dilithium salt

24(a). Methyl 4-[2-oxythia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyl]oxy]-6-pyridylpropylphenyl1acetate.

* 1112S2

Methyl 4-[2-thia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyl]oxy]6-pyridyl]propyl]phenyl]acetate (171 mg, 0.28 mmol) was dissolved in dry CH ₂ Cl ₂ (5 mL) under an argon atmosphere and cooled to -10°C. To this was added 85% m-chloroperoxybenzoic acid (67 mg, 0.31 mmol) in two portions 15 min apart. After the second addition, the reaction mixture was stirred for 20 min at -10°C and then quenched with aqueous NaHCO ₃ . The product was extracted into EtOAc and the organic extracts were washed with H ₂ O and brine and dried (MgSO ₄ ). Purification by flash column chromatography ( _SiO2 , 30% EtOAc in hexane) gave the sulfoxide as a white solid: Ή NMR (250MHz, _CDCl3 ) δ 8.00 (d, J=15.8Hz, IH, olefin), 7.30 (d, J=8.2Hz, 2H, phenyl), 7.23 (d, J=8.2Hz, 2H, phenyl), 7.20 (d, J=8.6Hz, IH, pyridyl), 7.13 (d, J=8.6Hz, IH, pyridyl), 7.01 (d, J=8.6Hz, 2H, phenyl), 6.98 (d, J=15.8Hz, IH, olefin), 6.76 (d, J=8.6Hz, 2H, olefin), 4.05 (d, J=12.9Hz, IH, SCH), 4.02 (d, J= 12.9Hz, IH, SCH), 3.94 (t, J=6.5Hz, 2H, OCH ₂ ), 3.83 (d, J=12.9Hz, IH, SCH), 3.80 (d, J=12.9Hz, IH, SCH), 3.74 (s, 3H, methyl ester), 3.70 (S, 3H, OCH ₃ ), 3.62 (s, 3H, methyl ester), 3.56 (s, 2H, CH^, 2.47 (t, J=7.6Hz, 2H, benzyl), 1.78 (m, 2H, CH ₂ ), 1.57 (m, 2H, CH ₂ ), 1.39 (m, 2H, CH^, 1.28 (m, 6H, aliphatic); MS (FAB): 622.3 (M+H); mp 87-89°C.

24(b). 4-[2-Oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)-octyl]oxy]6-pyridyl]propylphenyl]acetic acid, dilithium salt. Methyl

4-[2-Oxythia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyl]oxy]-6-pyridyl]propyl]phenyl]acetate (110 mg, 0.177 mmol) was dissolved in THF (1.0 mL) and MeOH (0.53 mL) and treated with 1.0M LiOH (0.53 mL, 0.53 mmol). The reaction mixture was stirred under argon for 20 h. The solvent was evaporated and the product was purified by reverse-phase MPLC (RP-18 _SiO2 , gradient _H2O -MeOH. Lyophilization gave a colorless amorphous solid: ^X H NMR (250MHz, ^d4 -MeOH) δ 7.79 (d, J=15.8Hz, IH, olefin), 7.34 (m, 6H, phenyl, pyridyl), 7.09 (d, J=15.8Hz, IH, olefin), 7.06 (d, J=8.6Hz, 2H, phenyl), 6.79 (d, J=8.6Hz, 2H, phenyl), 4.29 (d, J=12.9Hz, IH, SCH), 4.18 (d, J=12.9Hz, IH, SCH), 4.04 (m, 4H, SCH^ OCHJ), 3.73 (s, 3H, OCR,), 3.48 (s, 2H, CH^, 2.55 (t, J=7.6Hz, 2H, benzyl), 1.85 (m, 2H, CH ₂ ), 1.55 (m, 4H, aliphatic), 1.35 (m, 6H, aliphatic); MS (FAB): 606.3 (M+H), 594.4 (M+H); free acid).

Example 25

3-i2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy-6pyridylpropyl]N,N-dimethylbenzamide, lithium salt e 1 1 1 2 e 2

25(a). 3-[2-thia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyl]oxyl-6-pyridyl]propyl]benzoic acid. To a cooled (0°C) solution of SOC1 ₂ (0.85 ml, 11.7 mmol) in dry toluene (5 ml) was added a solution of

2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyl]oxy]-6-hydroxymethylpyridine (500 mg, 1.17 mmol) in toluene (6 ml). After 5 min, the cooling bath was removed and the reaction mixture was stirred for 2 h at room temperature. Toluene and excess SOC1 ₂ were evaporated. To this was added dry DMF (2 ml), 3-mercaptomethyl-benzoic acid (216 mg, 1.29 mmol) in DMF (2 ml) and anhydrous Cs ₂ CO ₃ (3.8 g, 11.7 mmol). The reaction mixture was heated at 60°C under an argon atmosphere for 6 h. After cooling to room temperature, the reaction mixture was diluted with H ₂ O and washed with EtOAc. The aqueous phase was acidified to pH 1.2 and extracted with EtOAc. The combined organic extracts were washed with H ₂ O and brine and dried (MgSO ₄ ). Purification by flash column chromatography (SiO ₂ , 5% MeOH in CH ₂ C1 ₂ ) gave a light yellow oil: ¹ H NMR (250MHz, CDCl ₃ ) δ 8.07 (d, J=15.7Hz, IH, olefin), 8.05 (s, IH, 2-phenyl), 7.96 (d, J=7.6Hz, IH, 6-phenyl), 7.58 (d, J=7.6Hz, IH, 4-phenyl), 7.39 (dd, J=7.6Hz, IH, 5-phenyl), 7.24 (d, J=8.6Hz, IH, pyridyl), 7.13 (d, J=8.6Hz, IH, pyridyl), 7.08 (d, J=8.6Hz, 2H, phenyl), 7.06 (d, J=15.7Hz, IH, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 4.01 (t, J=6.5Hz, 2H, OCH^), 3.81 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.72 (s, 2H, CH ₂ ), 3.69 (s, 2H, S-CH ₂ ), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH ₂ ), 1.57 (m, 2H, CH^, 1.49 (m, 2H, CH ₂ ), 1.35 (m, 6H, aliphatic).

25(b). 3-[2-[thia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy-6-pyridyl]propyl]N,N-dimethyl]benzamide. 3-[2-[thia-3-[2-(E-2-carboxymethylethenyl)3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoic acid (98 mg, 0.17 mmol) was dissolved in SOCl ₂ (5 ml) and refluxed for 1 hour. Excess SOCl ₂ was removed in vacuo. The resulting acid chloride was dissolved in dry CH^Cl^ (5 ml), cooled to 0°C and treated with triethylamine (52 ml, 0.37 mmol). Diethylamine was then introduced into the reaction mixture via a cold finger (condensator); the reaction mixture was stirred for 15 minutes. The solvent was removed in vacuo and the product was purified by flash column chromatography ( _SiO2 , 35% EtOAc in hexane) to give a light yellow oil: ^X H NMR (250MHz, _CDCl3 ) δ 8.07 (d, J=15.7Hz, 1H, olefin), 7.38 (m, 4H, 4,5,6-phenyl, pyridyl), 7.29 (s, 1H, 2-phenyl), 7.20 (d, J=8.6Hz, 1H, pyridyl), 7.11 (d, J=8.6Hz, 2H, 6-phenyl), 7.03 (d, J=15.7Hz, 1H, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 4.02 (t, J=6.5Hz, 2H, O- _CH2 ), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.70 (s, 2H, S-CH^), 3.68 (s, 2H, S-CH ₂ ), 3.12 (s, 3H, N-Me), 2.97 (s, 3H, N-Me), 2.55 (t, J=7.6Hz, 2H, benzyl), 1.86 (m, 2H, CH ₂ ), 1.6-1.3 (m, 10H, aliphatic).

T - 1 1 1 2 C

25(c). 3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridylpropyl]N,N-dimethylbenzamide, lithium salt. 3-[2-[thia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]N,N-dimethylbenzamide (80 mg, 0.132 mmol) was dissolved in THF (1.5 mL) and MeOH (1.5 mL) and treated with 1.0M LiOH (0.4 mL, 0.4 mmol). The reaction mixture was stirred under argon for 24 h. The solvent was evaporated and the product was purified by reverse-phase MPLC (RP-18 SiO ₂ , gradient H ₂ O-MeOH). Lyophilization gave a colorless amorphous solid: ^! H NMR (250MHz, d ⁴ -MeOH) δ 7.79 (d, J=15.7Hz, IH, olefin), 7.33 (m, 6H, 2,4,5,6-phenyl,

4,5-pyridyl), 7.07 (d, J=8.6Hz, 2H, phenyl), 7.05 (d, J=15.7Hz, olefin), 6.80 (d, J=8.6Hz, 2H, phenyl), 4.03 (t, J=6.5Hz, 2H, O-CH ₂ ), 3.76 (s, 2H, S-CH ₂ ), 3.74 (s, 3H, OMe), 3.69 (s, 2H, S-CH ₂ ), 3.09 (s, 3H, N-Me), 2.97 (s, 3H, N-Me), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.86 (m, 2H, CH ₂ ), 1.54 (m, 4H, aliphatic), 1.36 (m, 6H, aliphatic).

Example 26

5-f3-f2-thia-3-[2-(E-2-carboxyethenyl)-3-f8-(4-methoxyphenyl)octyloxy1-6pyridylpropylphenyltetrazole, dilithium salt

This tetrazole was prepared via the above-described acid chloride according to Duncia, Pierce and Santella, J. Org. Chem., 1991, 56, 2395-2400.

Example 26bis (E)-sodium 3-[3-[4-[4-methoxyphenyl)butyloxyl-6-phenylthiomethyl-2-pyridinyl-2-propenoate

26bis(a) (E)-methyl 3-[3-[4-(4-methoxyphenyl)butyloxyl-6-phenylthiomethyl]-2-pyridinyl]-2-propenoate. Thiophenol (0.017 mL, 0.166 mmol) was dissolved in dry MeCN (0.30 mL) and treated with 2-(E-2-carboxymethylethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-chloromethylpyridine hydrochloride (65 mg, 0.152 mmol) and 1,8diazabicyclo[5.4.[0]undec-7-ene (DBU, 0.08 mL, 0.532 mmol). The reaction mixture was stirred under argon at 50°C for 3 h. The reaction solution was diluted with EtOAc, washed with EtOAc and brine, and dried (MgSO ₄ ). Purification by flash column chromatography ( _SiO2 , EtOAc: _CH2Cl2 : _hexane , 10:15:75) gave a colorless waxy solid: NMR (250MHz, _CDCl3 ) δ 8.04 (d, J=15.7Hz, 1H, vinyl), 7.367.07 (m, 9H, aryl), 6.99 (d, J=15.7Hz, 1H, vinyl), 6.83 (d, J=8.7Hz, 2H, phenyl), 4.21 (s, 2H, CH2 _- S), 3.97 (t, J=6.1Hz, 2H, Cf^O), 3.81 (s, 3H, OMe), 3.78 (s, 3H, methyl

1 1 2 S2 ester), 2.64 (t, J=7.2Hz, 2H, benzylic), 1.81 (m, 4H, CH ₂ CH ₂ ); Analysis: calcd. for C ₂₇ H ₂₉ NO ₄ S.3/8H ₂ O: C 68.95; H 6.38; N 2.98; found: C 68.89; H 6.23; N 2.94; MS (ES): 464.2 (M+H).

If we proceed in a similar manner, but replace the above intermediates with the appropriate chloromethylpyridine and thiophenol or mercaptoalkylphenyl adducts, we can prepare the following compounds:

methyl 3-[3-[8-(4-methoxyphenyl)octyloxy]-6-[(3-carbomethoxybenzylthio)-methyl]2-pyridinyl]-2-propenoate, methyl 3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[phenylthiomethyl]-2-pyridinyl]-2-propenoate.

26bis(b) (E)-Sodium 3-[3-i4-(4-methoxyphenyl)butyloxyl-6-iphenylthiomethyl1-2pyridinyl-2-propenoate. (E)-Methyl 3-[3-[4-(4-methoxyphenyl)-butyloxy]-6[phenylthiomethyl]-2-pyridinyl]-2-propenoate (55 mg, 0.119 mmol) was dissolved in THF (1.0 mL) and MeOH (0.30 mL) and treated with 1.0 M NaOH (0.25 mL, 0.25 mmol). The reaction product was stirred under argon for 20 h. The solvent was evaporated and the product was purified by reverse-phase MPLC (RP-18 SiO ₂ ), gradient L^O-MeOH. Lyophilization gave the title product as a colorless amorphous solid: ^J H NMR (250MHz, d ⁶ DMSO) δ 7.42 (d, J=15.7Hz, IH, vinyl), 7.40-7.20 (m, 7H, aryl), 7.12 (d, J=8.7Hz, 2H, phenyl), 6.83 (d, J=8.7Hz, 2H, phenyl). 6.82 (d, J=15.7Hz, IH, vinyl), 4.26 (s, 2H, CH ₂ -S), 4.01 (t, J=6.lHz, 2H, CH ₂ O), 3.71 (s, 3H, OMe), 2.61 (t, J=7.2Hz, 2H, benzylic), 1.73 (m, 4H, CH ₂ CH ₂ ); Analysis: calcd. for C 12 H 12 NO 12 Na 12 HO: C 64.38; H 5.71; N 2.89; found: C 64.46; H 6.04; N 2.97; MS (ES-): 450.2 (M+H, free acid), (ES): 448.0 (MH, free acid).

If we proceed in a similar manner, we prepared these compounds:

(E)-sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[phenylthiomethyl]-2-pyridyl2-propenoate (E)-lithium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(3,4-dichlorophenylthio)-methyl]-2-pyridinyl-2-propenoate (E)-lithium 3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(4-chlorophenylthio)-methyl]-2pyridinyl-2-propenoate č 1 1 1 2 G 2 (E)-sodium 3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(4-chlorophenylthio)-methyl]-2pyridinyl-2-propenoate (E)-sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(3-chlorobenzylthio)-methyl]-2pyridinyl-2-propenoate (E)-Sodium 3-[3-[4-(4-Methoxyphenyl)butoxy]-6-[(2-chlorobenzylthio)-methyl]-2-pyridinyl-2-propenoate (E)-Sodium 3-[3-[4-(4-methoxyphenyl)butoxy]-6-[(2,4-dichlorobenzylthio)-methyl]-2-pyridinyl-2-propenoate (E)-Sodium 3-[3-[4-(4-Methoxyphenyl)butoxy]-6-[(2-cyano-6-chlorobenzylthio)-methyl]2-pyridinyl-2-propenoate.

Example 27

Pharmaceutical compositions comprising the compounds of the invention may be prepared in a variety of forms and with a variety of carriers. Methods for preparing various compositions may be found in standard literature, such as Remington's Pharmaceutical Sciences, and similar publications and manuals. Specific examples of compositions are set forth below.

Tablets

Ingredients per tablet per 10,000 tablets 1. active ingredient (compound with formula I) 40 mg 400g 2. cornstarch 20 mg 200g 3. alginic acid 20 mg 200g 4. sodium alginate 20 mg 200g 5. magnesium stearate 1.3 mg 13 g

101.3 mg 1013 g

1 1 2 92

Tablet manufacturing process:

Step 1. Mix ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer. Step 2. Add sufficient water to the mixture from Step 1 in portions, mixing thoroughly after each addition. Continue adding water and mixing until the mass has a consistency that allows it to be converted into wet granules.

Stage 3. The wet mass is converted into granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.

Stage 4. The wet granules are then dried in a dryer at 60°C until dry.

Step 5. Grease the dry granules with ingredient number 5.

Stage 6. The greased granules are compressed on a suitable tablet press.

SuDOzitorii: Ingredients on the sup. per 1000 sup. 1. active ingredient, compound of formula I 4.0 mg 40g 2. polyethylene glycol 1000 135.0 mg 1,350 grams 3. polyethylene glycol 4000 45.0 mg 450g 184.0 mg 1.840 grams

Procedure:

Step 1. Melt ingredients No. 2 and No. 3 together and mix until homogeneous. Step 2. Dissolve ingredient No. 1 in the melted mass from Step 1 and mix until homogeneous.

Step 3. Pour the molten mass from step 2 into suppository molds and cool.

Step 4. Remove the suppositories from the molds and wrap them.

Example 28

Inhalation preparation

The compound of formula I, 1 to 10 mg/ml, is dissolved in isotonic saline and sprayed from a nebulizer operating at an air flow adjusted to deliver the desired amount of drug at each pressure.

Example 29

1 1 292

Preparations for topical use

Pharmaceutical compositions comprising the compounds of the invention may be prepared in a variety of forms and with a variety of carriers. Methods for preparing various compositions may be found in standard literature, such as Remington's Pharmaceutical Sciences, and similar publications and manuals. Specific examples of compositions are set forth below.

Ointments

Hydrophilic Vaseline

Ingredients quantity (% w/w) cholesterol 30.0 g stearyl alcohol 30.0 g white wax 78.0 g active ingredient 2.0 g white petrolatum 860.0 g

Stearyl alcohol, white wax and white petrolatum are melted together (e.g. on a steam bath) and cholesterol and active ingredient are added. Start mixing and continue mixing until the solids disappear. Remove the heat source and allow the mixture to solidify and pack into metal or plastic tubes.

Emulsion ointment

Ingredients multiple (% m/m) methylparaben 0.25 grams propylparaben 0.15 sodium lauryl sulfate 10.0 grams active ingredient 5.0g propylene glycol 120.0 grams stearyl alcohol 250.0g white petroleum jelly 250.0g purified water about 1000.0 g

Stearyl alcohol and white petrolatum are combined over heat. The other ingredients are dissolved in water, then this solution is added to the warm (around 50 to 100°C) alcohol/petroleum mixture and stirred until the mixture hardens. It can then be filled into tubes or other suitable packaging form.

Claims (27)

PATENT APPLICATIONS A compound of formula I or N-oxide or a pharmaceutically acceptable salt thereof, wherein ZO, NH, NCH 1 or S (O) _q , wherein q is 0,1 or 2, m is 0-5; R 1 is a C 1 to C 16 -aliphatic radical, unsubstituted or substituted phenyl C _x -C ₁₀ -aliphatic radical, wherein the substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl and halo, or R _{1 is a} C ₁ -C ₄ -aliphatic radical-Ο-, or R is unsubstituted or substituted phenyl C ₁ -C ₁₀ -aliphatic radical-O-, where the substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy , lower alkyl, trihalomethyl and halo; R _x is - (C ₁ -C ₆ -aliphatic radical) R ₄ , - (C ₁ -C ₅ aliphatic radical) CHO, (C ₁ -C ₅ -aliphatic radical) CH ₂ OR ₈ , -R ₄ , -CH ₂ OH or CHO; R ₂ is H, halo, lower alkyl, lower alkoxy, -CN, - (CH ₂ ) _n R ₄ , -C ₄ NH ₄ ) or - (CH ₂ ) _n R ₉ , where n is 0 - 5 and where R _{9 is} -N (R ₇ ) ₂ , where is each R _? independently H or an aliphatic group of 1 to 10 carbon atoms, or an acyl of 1 to 6 carbon atoms or a cycloalkyl- (CH ₂ ) _n -group of 4 to 10 carbons, where n is 0-3, do they form both groups of R _? a ring having 4 to 6 carbons; or R ₃ is hydrogen, lower alkyl, lower alkoxy, halo, -CN-, COR ₅ -, NHCONI I ₂ or -OH; each group R ₄ is independently -COR ₅ , where R _{5 is} -OH, a group -OR ₆ forming a pharmaceutically acceptable ester, or -ΟΧ, where X is a pharmaceutically acceptable cation, or R _{5 is} -N (R ₇ ) ₂ , where is each R _? independently H, or an aliphatic group of 1 to 10 carbon atoms or a cycloalkyl- (CH ₂ ) _n -group of 4 to 10 carbons, where n is 0-3, or form both groups of R _{7 a} ring having 4 to 6 carbons, or R _{4 is} sulfonamide or amide or tetrazol-5-yl; and R _g is hydrogen, C 1 -C 6 alkyl or C 1 -C 4 -acyl, provided that and R 8 is not 2,6-breathing, 2,6-di (lower alkyl), 2,6-di (lower alkoxy) or 2,6-diciano. 2. A pharmaceutical composition comprising an effective amount of a compound of formula I according to claim 1, alone or in combination with a pharmaceutically acceptable carrier. Compound according to claim 1, characterized in that ZS (O) _q , m is 0, R is alkoxy of 8 to 15 carbon atoms or unsubstituted or substituted phenyl-C 1 -C 4 -alkyl-O, Iger is substituted phenyl substituted with fluoro, trifluoromethyl or methoxy; R ₁ is R ₄ CH = CH or R ₄ CH ₂ CH ₂ - and R is -COR _S ah -NHSO ₂ CF ₃ . Compound according to claim 3, characterized in that 3- [1-thia-2- [2- (E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridyl] ethyl] benzoic acid, 3- [1-thia-2- [2- (E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridyl] ethylbenzoic acid, 2- [1-oxythia-2- [2- (E-2-carboxyethenyl) -3-dodecyloxy-6-pyridyl] ethyl] -benzoic acid, 3- [1-thia-2- [2- (E-2-carboxyethenyl) -3-dodecyloxy-6-pyridyl] ethyl] -benzoic acid, 3- [1-oxythia-2- [2- (E-2-carboxyethenyl) -3-dodecyloxy-6-pyridyl] ethyl] -benzoic acid, 3- [1-dioxythia-2- [2- (E-2-carboxyethenyl) -3-dodecyloxy-6-pyridyl] ethyl] -benzoic acid, N- [3- [1-thia-2- [2- (E-2-carboxyethenyl) -3-dodecyloxy-6-pyridyl] ethyl] -phenyl] trifluoromethanesulfonamide, N- [3- [1-thia-2- [2- (E-2-carboxyethenyl) -3- (8- (4-methoxyphenyl) octyloxy-6-pyridyl] ethyl] phenyltrifluoromethanesulfonamide, N- [3- [1-oxythia-2- [2- (E-2-carboxyethenyl) -3- (8- (4-methoxyphenyl) octyloxy-6-pyridyl] ethyl] -phenyl] trifluoromethanesulfonamide, N- [3- [1-oxythia-2- [2- (E-2-carboxyethenyl) -3- (8- (4-methoxyphenyl) octyloxy-6-pyridyl] ethyl] -phenyl] phenylsulfonamide or N- [3- [1-thia-2- [2- (E-2-carboxyethenyl) -3- (8- (4-methoxyphenyl) octyloxy-6-pyridyl] ethyl] -phenylphenylsulfonamide or a pharmaceutically acceptable salt thereof. 5. A compound according to claim 1 wherein ZO, m is 0, R is alkoxy of 8 to 15 carbon atoms or unsubstituted or substituted phenyl-C1-C4-alkyl-O, wherein the substituted phenyl is substituted by fluoro , trifluoromethyl or methoxy, R _t is R ₄ CH = CH or R ₄ CH ₂ CH _{2 -} and R ₂ is -COR ₅ or -NHSO ₂ CF ₃ . Compound according to claim 5, characterized in that 3- [1-oxa-2- [2- (E-2carboxyethenyl) -3-dodecyloxy] -6-pyridyl] ethyl] -benzoic acid or 3- [1 -oxa-2- [2- (E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridyl] ethyl] -benzoic acid or its N-oxide or a pharmaceutically acceptable salt thereof. Compound according to claim 1, characterized in that ZO, m is 0, R is alkoxy of 8 to 15 carbon atoms or unsubstituted or substituted phenf-C 1 -C ₁₀ -alkyl, wherein the substituted phenyl is substituted by fluoro, trifluoromethyl or methoxy. A compound according to claim 7, characterized in that 3- [1-oxa-2- [2- (E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octan-1-yl] - 6-Pyridyl] ethyl] -benzoic acid, its dilithium salt, free acid or other pharmaceutically acceptable salt. S3 A compound according to claim 1, characterized in that Z is NH or NCH ₃ , m is 0, R is alkoxy of 8 to 15 carbon atoms or unsubstituted or substituted phenyl-C 1 -C 4 -alkyl-O, where substituted phenyl substituted with fluoro, trifluoromethyl or methoxy, R _x is R ₄ CH = CH- or R ₄ CH ₂ CH ₂ - and R is -COR ₅ or -NHSO ₂ CF ₃ . Compound according to claim 1, characterized in that ZS (O) _q , wherein q is 0.1 or 2, m is 1-3, R is alkoxy of 8 to 15 carbon atoms, phenyl-C ₄ -C _10- alkyl-O- or substituted phenylC ₄ -C ₁₀ -alkyl-O; R is R ₄ , - (C ₁ -C ₃ -alkyl) R ₄ ah - (C ₂ -C ₃ -alkenyl) R ₄ . A compound according to claim 1, wherein R is alkoxy of 8 to 15 carbon atoms or or substituted phenyl-C ₄ -C ₁₀ -alkyl-O-, wherein the substituted phenyl is substituted with fluoro, trifluoromethyl or methoxy, R _x CH _{2 is} CH ₂ R ₄ or -CH = CHR ₄ and R 2 is - (CH ₂ ) _n R ₄ where n is 0 or 1. A compound according to claim 11, wherein 4- [2-thia-3- [2- (E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridyl] propyl] -benzoic acid, 4- [2-thia-3- [2- (E-2-carboxyethenyl) -3- [4- (4-methoxyphenyl) butyloxy] -6-pyridyl] propyl] -benzoic acid, 3- [2-thia-3- [2- (E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridyl] propyl] -benzoic acid, 3- [2-thia-3- [2- (E-2-carboxyethenyl) -3- [4- (4-methoxyphenyl) butyloxy] -6-pyridyl] propyl] -benzoic acid, 3- [2-thia-3- [2- (2-carboxyethanyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridyl] propyl] -benzoic acid, 3- [2-thia-3- [2- (E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridyl] propyl] -N, N-dimethylbenzamide, lithium salt, 3- [2-thia-3- [2- (E-2-carboxyethenyl) -3- [4- (4-methoxyphenyl) butyloxy] -6-pyridyl] propyl] -N, N-dimethylbenzamide, lithium salt, 3- [2-thia-3- [2- (E-2-carboxyethenyl) -3- [4-phenyl) butyloxy-6-pyridylpropyl] -benzoic acid, dilithium salt, 3- [2-thia-3- [2- (E-2-carboxyethenyl) -3- [8-phenyl) octyloxy] -6-pyridyl] propyl] -benzoic acid, dilithium salt, 3- [2-thia-3- [2- (2-carboxyethanyl) -3- [4- (4-methoxyphenyl) butyloxy] -6-pyridyl] propyl] -benzoic acid, dilithium salt, 4- [2-thia-3- [2 - ((E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridyl] propylphenylacetic acid or 4- [2-oxythia-3- [2 - ((E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridyl propylbenzoic acid, 3- [2-oxythia-3- [2 - ((E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridyl] propylbenzoic acid, 4- [2-oxythia-3- [2 - ((E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridyl propylphenylacetic acid, 3- [2-dioxythia-3- [2 - ((E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridyl] propylbenzoic acid or a pharmaceutically acceptable salt thereof. A compound according to claim 1, wherein ZS (O) _q , wherein q is 0.1 or 2, m is 1-3, R is alkoxy of 8 to 15 carbon atoms, or unsubstituted or substituted phenyl- C ₄ C ₁₀ -alkyl-O-, R _x is CH ₂ CH ₂ R ₄ or -CH = CHR ₄ , Rz is H, halo, lower alkyl, lower alkoxy, -CN and R _{3 is} hydrogen, halo, -CN or lower alkyl, except those compounds where R ₂ and R ₃ are both hydrogen. A compound according to claim 1, wherein R _{4 is} tetrazol-5-yl. A compound according to claim 14, characterized in that it is 5- [3 [2-thia-3- [2- (E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy-6-pyridyl] propylphenyltetrazole, its dilithium salt or other pharmaceutically acceptable salt. A compound according to claim 1 wherein ZO, m is 1-3, R is alkoxy of 8 to 15 carbon atoms or unsubstituted or substituted phenyl-C ₄ -C ₁₀ -alkyl-O- and R ₁ is R ₄ , -CH ^ f ^ R, or -CH = CHR ₄ . A compound according to claim 1 wherein Z is NH or NCH ₃ , m is 1-3, R is alkoxy of 8 to 15 carbon atoms or unsubstituted or substituted phenyl-C ₄ -C ₁₀ -alkyl-O- , where the substituted phenyl is substituted by fluoro, trifluoromethyl or methoxy, and R _: is -CH ₂ CH ₂ R ₄ ah -CH = CHR ₄ . A compound according to claim 1 wherein ZO, m is 0 or 1, R is alkoxy of 8 to 15 carbon atoms or unsubstituted or substituted phenyl-C ₄ -C ₁₀ -alkyl-O-, where substituted phenyl substituted with fluoro, trifluoromethyl or methoxy, and R _t is -CH ₂ CH ₂ R ₄ or -CH = CHR ₄ and R ₂ is -CH _2n R ₉ where n is 0.1 or 2. A compound according to claim 18, characterized in that 3 [1-oxa-2- [2- (E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridyl] ethyl ] aniline, lithium salt or 5-carboxy-3- [1-oxa-2- [2- (E-2-carboxyethenyl) -3- (8- (4methoxyphenyl) octyloxy) -6-pyridyl] ethyl] aniline, its dilithium salt or free acid or another pharmaceutically acceptable salt thereof. A compound according to claim 1 wherein ZS (O) _q , m is 0 or 1, R is alkoxy of 8 to 15 carbon atoms or unsubstituted or substituted phenyl-C 1 -C 4 -alkyl-O-, wherein the substituted phenyl is substituted by fluoro, trifluoromethyl or methoxy, and R ₂ is -CH ₂ CH ₂ R ₄ or -CH = CHR ₄ and R is -CH ^ R 1, where n is 0,1 or 2. A compound according to claim 20, characterized in that 3 [1-thia-2- [2- (E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridyl] ethyl ] aniline, lithium salt; 3 [1-thia-2- [2- (E-2-carboxyethenyl) -3- [4- (4-methoxyphenyl) octyloxy] -6-pyridyl] ethyl] N, N-dimethylaniline, lithium salt, 3 [1-thia-2- [2- (E-2-carboxyethenyl) -3- [4- (4-methoxyphenyl) butyloxy] -6-pyridyl] ethyl] aniline, lithium salt, 3- [1-thia-2- [2- (E-2-carboxyethenyl) -3- (8- (4-trifluoromethylphenyl) octyloxy) -6-pyridyl] Ethanylaniline, lithium salt, 3- [1-thia-2- [2- (E-2-carboxyethenyl) -3- (8-phenyloxyloxy) -6-pyridyl] ethyl] aniline, lithium salt, 3 [2-thia-3- [2- (E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridyl] propyl] N, N-dimethylaniline, lithium salt, 3 [1-oxythia-2- [2- (E-2-carboxyethenyl) -3- [4- (4-methoxyphenyl) butyloxy] -6-pyridyl] ethylaniline, lithium salt, 3 [1-oxythia-2- [2- (E-2-carboxyethenyl) -3- [8- (4-trifluoromethylphenyl) octyloxy] -6-pyridyl heptaniline, lithium salt, 3 [1-oxythia-2- [2- (E-2-carboxyethenyl) -3- [8- (4-fluorophenyl) octyloxy-6-pyridylethylaniline, lithium salt, 3 [1-oxythia-2- [2- (E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridyl] ethylaniline, lithium salt or 3 [1-oxythia-2- [2- (E-2-carboxyethenyl) -3- [8- (phenyloxyloxy] -6-pyridyl] ethyl] aniline, lithium salt, 3 [1-oxythia-2- [2- (E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy-6-pyridylethyl] N, N-dimethylaniline, lithium salt, 3 [1-dioxythia-2- [2- (E-2-carboxyethenyl) -3- [4- (4-methoxyphenyl) butyloxy-6-pyridylethylaniline, lithium salt or 3 [1-dioxythia-2- [2- (E-2-carboxyethenyl) -3- [8- (4-methoxyphenyl) octyloxy] -6-pyridylethyl aniline, lithium salt or their acid or a pharmaceutically acceptable salt thereof. A compound according to claim 1, characterized in that Z is NH or NCH ₃ , m is 0 or 1, R is alkoxy of 8 to 15 carbon atoms or unsubstituted or substituted phenyl -C 1 -C 4 -alkyl-,-, wherein the substituted phenyl is substituted with fluoro, trifluoromethyl or methoxy, and R _{1 is} -CH ₂ CH ₂ R ₄ or -CH = CHR ₄ and R ₂ is - (CH ₂ J 4, where n is 0,1 or 2. A compound according to claim 1, wherein R 1 and R _{3 are} hydrogen. A compound according to claim 23, wherein ZS (O) _q , m is 0 or 1, R is alkoxy of 8 to 15 carbon atoms or unsubstituted or substituted phenyl-C 1 -C 4 -alkyl, wherein it is substituted phenyl substituted with methoxy, fluoro or trifluoromethyl and R _{x is} -CH ₂ CIT ₂ R ₄ or -CH = CHR ₄ . A compound according to claim 24, characterized in that 3 [2-thia-3- [2- (E-2-carboxyethenyl) -3- [4- (4-methoxyphenyl) butyloxy] -6-pyridyl] propyl ] benzene, lithium salt; 3 [2-thia-3- [2- (2-carboxyethanyl) -3- [4- (4-methoxyphenyl) butyloxy] -6-pyridyl] propyl] benzene, lithium salt, or 3 [1-thia-2- [2- (2-carboxyethanyl) -3- [4- (4-methoxyphenyl) butyloxy] -6-pyridyl] propyl] benzene, lithium salt, free acid or other pharmaceutically acceptable salt. A compound according to claim 23, wherein Z is O and m is 0 or 1. A compound according to claim 23, wherein Z is NH or NCH ₃ and m is 0 or 1.