NZ238426A

NZ238426A - Phenyl-methylene-thio (or -sulphinyl, -sulphonyl, -amino or -methylamino) substituted pyridine derivatives and medicaments

Info

Publication number: NZ238426A
Application number: NZ238426A
Authority: NZ
Inventors: Robert A Daines; William D Kingsbury
Original assignee: Smithkline Beecham Corp
Priority date: 1990-06-07
Filing date: 1991-06-06
Publication date: 1994-11-25
Also published as: EP0593464A1; AU655428B2; ZA914322B; CA2083957A1; HUT64747A; MX26167A; TW221809B; MA22195A1; EP0593464A4; AU8189691A; KR930700102A; FI925545A; HU9203867D0; WO1991018601A1; PL290587A1; JPH05507492A; IL98387A0; CN1058015A; JPH07116150B2; FI925545A0

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £38426 4 23842 no Lwut^: .7-6-fo Complete Specification Filad: C!a«s: fa(ferZlJ.V'/if Publication Date: . .?.5.H.QV. .W...... ! P.O. Journal, No: /3.$>. •j >fi % f I" 1 f- ^'3 iHVl? NEW ZEALAND PATENTS ACT, 1953 No.: Date: N.Z. patskt G^rjca 6 JUN1991_,f COMPLETE SPECIFICATION PYRIDYL-BENZOIC ACID DERIVATIVES FOR TREATING LEUKOTRIENE-RELATED DISEASES pXK/ We, SMITH KLINE JtikvVTN^ /Phllft-^elUVvLoi. r^pHfvL '-King of Prusci-a, ■* SMITHKLINE BEECHAM CORPORATION of/ 700 Swodoland Road, /IQlOl Pennsyl vania/-49406-, United States of America, a corporation organized under the laws of the Commonwealth of Pennsylvania, one of the United States of America, hereby declare the invention for which we pray that a patent may be granted to ixie</us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (followed by page la) # 238426 Benzoic Acid Derivatives Scope of the Invention This invention relates to amine, ether or thioether linked 5 pyridyl-benzoic acid derivatives which are useful for treating diseases associated with leukotrienes. These compounds are particularly useful in treating diseases attributable to hydroxyleukotrienes, especially LTB4 and LTB4-agonist active substances. Background of the Invention 10 The family of bioactive lipids known as the leukotrienes exert pharmacological effects on respiratory, cardiovascular and gastrointestinal systems. The leukotrienes are generally divided into two sub-classes, the peptidoleukotrienes (leukotrienes C4, D4 and E4) and the hydroxyleukotrienes (leuk'otriene B4). This invention is 15 primarily concerned with the hydroxyleukotrienes (LTB) but is not limited to this specific group of leukotrienes. The peptidoleukotrienes are implicated with the biological response associated with the "Slow Reacting Substance of Anaphylaxis" (SRS-A). This response has been expressed in vivo as 20 prolonged bronchoconstriction, in cardiovascular effects such as coronary artery vasoconstriction and numerous other biological responses. The pharmacology of the peptidoleukotrienes include smooth muscle contractions, myocardial depression, increased vascular permeability and enhanced mucous production. 25 By comparison, LTB4 exerts its biological effects through stimulation of leukocyte and lymphocyte functions. It stimulates chemotaxis, chemokinesis and aggregation of polymorphonuclear leukocytes (PMNs). It is critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic, and 30 inflammatory diseases including asthma, adult respiratory distress syndrome, cystic fibrosis, psoriasis, and inflammatory bowel disease. Leukotriene B4 (LTB4) was first described by Borgeat and Samuelsson in 1979, and later shown by Corey and co-workers to be 5(S),12(R)-dihydroxy-(Z,E,E,Z)-6,8,10,14-eicosatetraenoic acid. HO .. . OH V^^^ODOH . 35 Fig. I 238 426 w * It is a product of the arachidonic acid cascade that results from the enzymatic hydrolysis of LTA4 (Figure I). It has been found to be produced by mast cells, polymorphonuclear leukocytes, monocytes and macrophages. LTB4 has been shown to be a potent stimulus in 5 vivo for PMN leukocytes, causing increased chemotactic and chemokinetic migration, adherence, aggregation, degranulation, superoxide production and cytotoxicity. The effects of LTB4 are mediated through distinct receptor sites on the leukocyte cell surface which exhibit a high degree of stereospecificity. Pharmacological 10 studies on human blood PMN leukocytes indicate the presence of two classes of LTB4-specific receptors that are separate from receptors specific for the peptide chemotactic factors. Each of the sets of receptors appear to be coupled to a separate set of PMN leukocyte functions. Calcium mobilization is involved in both mechanisms. 15 LTB4 has been established as an inflammatory mediator in vivo. It has also been associated with airway hyperresponsiveness in the dog as well as being found in increased levels in lung lavages from humans with severe pulmonary dysfunction. In addition, as with the other leukotrienes, LTB4 has been implicated in inflammatory bowel 20 disease, rheumatoid arthritis, gout, and psoriasis. By antagonizing the effects of LTB4, or other pharmacologically active mediators at the end organ, for example airway smooth muscle, the compounds and pharmaceutical compositions of the instant invention are valuable in the treatment of diseases in subjects, 25 including human or animals, in which leukotrienes are a key factor. Some of these compounds may also inhibit the 5-lipoxygenase enzyme or may be LTD4 antagonists. SUMMARY OF THE INVENTION The compounds of this invention are represented by formula (I) 30 FU (I) or an N-oxide, or a pharmaceutical^ acceptable salt thereof, where T is S(0)n where n is 0, 1 or 2, O, NH or NCH3; ^ <r. -O * <r>\ c-.v- 3 238426 R is Ci to C20"aliphatic, unsubstituted or substituted phenyl Ci to Cio-aliphatic where substituted phenyl has one or more substituents selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is Ci to C20-aliphatic-O-, or R is unsubstituted or substituted phenyl Cj to Cio-aliphatic-O- where substituted phenyl has one or more substituents selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo; Rj is -(Cj to C5 aliphatic)R4, -(C1 to C5 aliphatic)CHO, -(Ci to C5 aliphatic)CH20R8, -R4, -CH2OH, or CHO; f R2 is hydrogen or -COR5 where R5 is -OH, a pharmaceutically acceptable ester-forming group or -OX where X is a pharmaceutically acceptable cation, or R5 is -N(R7)2 where R7 is H, an aliphatic group of 1 to 10 carbon atoms, or a cycloalkyl-(CH2)n- group, of 4 to 10 carbons where n is 0-3 or both R7 groups, together with the nitrogen atom to which they are attached, form a ring having 4 to 6 carbons, or R2 is -CH(NH2)(R4) or an amine, an amide or a sulfonamide; R3 is hydrogen, lower alkoxy, halo, -CN, COR5, NHCONH2, or OH; R4 is -COR5 where R5 is -OH, a pharmaceutically acceptable ester-forming group or -OX where X is a pharmaceutically acceptable cation, or R5 is -N(R7)2 where R7 is H, an aliphatic group, of 1 to 10 carbon atoms, or a cycloalkyl-(CH2)n" group of 4 to 10 carbons v.'iiere n is 0-3 or both R7 groups, together with the nitrogen atom to which they are attached, form a ring having 4 to 6 carbons; and R8 is hydrogen, Ci to C6 alkyl, or Ci to C6-acyl. In another aspect, this invention covers pharmaceutical compositions containing the instant compounds and a pharmaceutically acceptable excipient. Treatment of diseases related to or caused by leukotrienes, particularly LTB4, 6r related pharmacologically active mediators at the end organ are within the scope of this invention. This treatment can be effected by administering one or more of the compounds of formula I alone or in combination with a pharmaceutically acceptable excipient. In yet another aspect, this invention relates to a method for making a compound of formula I which method is illustrated in the Reaction Schemes given below and in the Examples set forth in specification. # 2 3 8 4? " DETAILED DESCRIPTION OF THE INVENTION The following definitions are used in describing this invention and setting out what the inventors believe to be their invention herein. 5 "Aliphatic" is intended to include 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 phrase "lower alkyl" means an alkyl group of 1 to 6 carbon atoms in any isomeric form, but 10 particularly the normal or linear form. "Lower alkoxy" means the group lower alkyl-O-. "Halo" means fluoro, chloro, bromo or iodo. "Acyl" means the radical having a terminal carbonyl carbon. When reference is made to a substituted phenyl ring, it is meant that the ring can be substituted with one or more of the named 15 substituents as may be compatible with chemical synthesis. Multiple substituents may be the same or different, such as where there are three 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. 20 The phrase "a pharmaceutically acceptable ester-forming group" in R2 and R3 covers all esters which can be made from the acid function(s) which may be present in these compounds. The resultant esters will be ones which are acceptable in its application to a pharmaceutical use. By that it is meant that the mono or diesters will 25 retain the biological activity of the parent compound and will not have an untoward or deleterious effect in their application and use in treating diseases. Such esters are, for example, those formed with one of the following radicals: Ci to C6 alkyl, phenyl Ci-C6alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl, 30 pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl. The most preferred ester-forming radicals are those where R3 is alkyl, particularly alkyl of 1 to 10 carbons, (ie CH3-(CH2)n_ where n is 0-9), or phenyl-(CH2)n- where n is 0-4. 35 When R2 is referred to as being an amine, that includes the radical -NH2 and mono- or dialkylate derivatives of this -NH2 radical. Preferred alkylated amines are the mono- or disubstituted amines having 1 to 6 carbons. When R2 is referred to as being an amide, that i 23 3 42 includes all acylate derivatives of the NH2 radical. The preferred amides are those having 1 to 6 carbons. Where there is an acid group, amides may be formed. The most preferred amides are those where -Rg is hydrogen or alkyl of 1 to 6 5 carbon atoms. Particularly preferred is the diethylamide. Pharmaceutically acceptable salts of the instant compounds are intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the 10 parent compound and the salt will not have untoward or deleterious effects in its application and use in treating diseases. Pharmaceutically acceptable salts are prepared in a standard manner, in a suitable solvent. The parent compound in a suitable solvent is reacted with an excess of an organic or inorganic acid, in the 15 case of acid addition salts, or an excess of organic or inorganic base in the case where R4 is OH. Representative acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, succinic acid or methanesulfonic acid. Cationic salts are readily prepared from alkali metal bases such as sodium, potassium, calcium, 20 magnesium, zinc, copper or the like and ammonia. Organic bases include the mono or disubstituted amines, ethylene diamine, piperazine, amino acids, caffeine, tromethamine, tris compounds and the like. N-oxides may also be prepared by means of selected oxidizing 25 agents. These oxides are useful as intermediates in preparing the compounds of formula I and have useful pharmaceutical activity in and of themselves. Hence one can administer the N-oxides of formula I to a subject who is susceptible to or is suffering from a disease related to or caused by LTB4 or similar leukotrienes. 30 If by some combination of substituents, a chiral center is created or another form of an isomeric center is created in a compound of this invention, all forms of such isomer(s) are intended to be covered herein. These compounds may be used as a racemic mixture or the racemates may be separated and the individual 35 enantiomer used alone. As leukotriene antagonists, these compounds can be used in treating a variety of disease assoicated with or attributing their origin or affect to leukotrienes, particularly LTB4. Thus it is expected that these compounds can be used to treat allergic diseases such of a pulmonary and non-pulmonary nature. For example these compounds will be useful in antigen-induced anaphylaxis. They are useful in treating asthma and allergic rhinitis. Ocular diseases such as uveitis, and allergic conjunctivitis can also be treated with these compounds. The preferred compounds of this invention are those where R is alkoxy, particularly alkoxy of 8 to 15 carbon atoms or substituted or unsubstituted phenyi-Ci to Cio-aliphatic-O-; Ri is-(Ci to C5 aliphatic)R4 or -(Ci to C5 aliphatic)CH20R8, and R2 is -COOH or -N(A)(B) where A is H, or alkyl of 1 to 6 carbons and B is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons or -SO2R9 where R9 is -CF3, Ci to C6 alkyl or phenyl. The more preferred compounds of this invention are those where R is-alkoxy of 8 to 15 carbon atoms or alkoxy-substituted phenyl C\ to Cs-alkoxy; Rj is COR5, -CH2CH2COR5CH: -CH=CH-COR5; and R2 is -COOH or a sulfonamide, particularly -NHSO2CF3. Another set of preferred compounds are the analines, those where R2 is N(R7)2, particularly where R7 is hydrogen. The most preferred compounds are set out in Figure II. Figure II CH2-T R Ri R2 H25C12-O- *HOOC-CH=CH- /n-COOH tf H25C12-O- *HOOC-CH=CH- p-COOH II H25C12-O- *HOOC-CH=CH- o-COOH > o*s\ H25C12-O- *HOOC-CH=CH- m-COOH II H25C12-O- *HOOC-CH=CH- p-COOH II H25C12-O- *HOOC-CH=CH- o-COOH > o2sx H25C12-0-. *HOOC-CH=CH- w-COOH I L 6 8 4 2 6 H25C12-O- *HOOC-CH=CH- m-COOH N-oxide °\ CH30-Ph-(CH2)8-0- *HOOC-CH=CH- m-COOH N-oxide \ H25C12-0- *HOOC-CH=CH- w-COOH * Trans configuration. In each of the compounds, the methylene carbon of the T groups is substituted on the pyridyl ring. Synthesis 5 These compounds may be made by the starting materials, intermediates and reagents set out in the following reaction flow charts. These flow charts are intended to act as a road map to guide one from known starting materials to the desired products. These specific starting materials, intermediates and reagents are only given 10 to illustrate the general case and are not intended to limit the chemistry illustrated thereby. Reagents, intermediates, temperatures, solvents, reaction times, work-up procedures all may be varied to accomodate differences and optimize the particular conditions for making a particular compound. Such variations will be apparent to a 15 chemist or will not require more than minimal experimentation to optimize conditions and reagents for a particular step. The preparation of certain precursors needed for making the R group are given in scheme 1. These compounds are made by forming the R group first, then 20 preparing the intermediate form of the R\ group and finally coupling the phenyl containing the R2 group with the pyridyl ring. Thereafter the Ri and R2 groups may be further modified as desired. These reaction schemes as set out in this order. Scheme 1 illustrates means for making intermediates useful for preparing the R 25 group which are not commercially available. Scheme 2 itself illustrates how to form the R group and thereafter how to further synthesize these compounds once the R group is formed. # 8 238426 Scheme 1(a) A /=\ (Ph)3P=CH(CH2)3C02-w H3CO-< CHO ch3°^ // uaih4 TsCl pyr- ^ ^ ^ ,OTs cH3oH^/r 10 (c) While the methoxyphenyl compound is illustrated here, this series of steps and reagents may be used to make other substituted-w-phenylaliphatic groups denoted by R. The starting material, the benzaldehydes, are commercially available or can be readily made by « 15 known methods. To make the acid (a), first an alkylsilazide is added to an inert solvent under an inert atmosphere. Then the phosphonium salt is added. This addition can be done at room temperature or thereabouts. After a brief period of mixing, this mixture is usually a 20 suspension, the benzaldehyde is added slowly at about room temperature. A slight molar excess of the phosphonium salt is employed. After an additional brief period of stirring at about room temperature, the reaction is quenched with water. The solution is acidified and the acid extracted with a suitable organic solvent. 25 Further separatory and purification procedures may be employed as desired. The alcohol (b) is made by reducing the acid using a reducing agent. Lithium aluminum hydride or similar reducing agents may be employed, and conditions may be varied as needed to effect the 30 reduction. The tosylate (c) is prepared in an inert solvent employing a base such as pyridine. Suitable conditions include carrying out the reaction at room temperature or thereabouts for a period of 1 to 5 hours. Other leaving groups similar in function to the tosylate may be 35 prepared and will be useful as a means for forming the R moiety. i 10 238426 Reaction Scheme 1(b) outlines one method for making an alkoxyphenylalkyl R group. This method could be used to make other R groups where phenyl is the w group on the alphatic chain, including substituted phenyl-containing groups. Scheme 1(b) ^ v OH KAPA * KA ». ^ ^ OH t-Bu(Ph)2SiCl (a) H3CO-Ph-I ; n njCVJTU-l j y ss—(CH2)nOSi(Ph)2-t-Bu ► H3CO—^ J—sss— (CH2)nOSi(Ph)2-t-Bu (b) Pd [(Ph)3P]2Cl2 (c) H2, Pd-C /=\ Bu4NF _ ► H3CO-6 y— (CH2)n+20Si(Ph)2-t-Bu _ ► (d) H3CO-<k jj (CH2)n+2-OH TsC1 ^ H3CO—L V-(CH2)n+2-OTs Pyr N—f Ce) (f) 15 In those instances where an w-yn-l-ol is not commercially available, it can be prepared from a corresponding 3-yn-l-ol by treating the alcohol with a strong base. Here an alkali metal amide is used. The alcohol is then protected in order to add the desired phenyl group at the terminal triple bond. A silyl ether is formed in this 20 instance; it illustrates the general case. A halo-substituted-phenyl adduct is used to add the phenyl group at the triple bond. At this point, the triple bond can be reduced, most conveniently by catalytic means, eg. palladium-on-carbon under hydrogen. Alternatively, the triple bond could be retained and the intermediate carried on through 25 to the tosylate as illustrated. The silyl group is removed and the resulting alcohol is converted to the tosylate or another group which is sufficiently reactive so as to form an ether in the synthesis of these compound. Compounds of formula I where T is an ether can be made by the 30 sequence of steps given in Scheme 2. i 10 o u ■ft .J Scheme 2 HO HO. )0n 1. Mn02, CH2CI2 2. C12H25I, K2CO3 N^CH a (ph)3PCHC02Me 1. MCPBA, CH2CI2 2.TFAA, DMF 3. K2C03, MeOH 4. SOCI2 ^25^12^ H25Ci90, Me02C^^N^CH3 (2a) HO^^ XO* MeOgC^s^ N CH2CI HCI (n-Bu)4N I", K2C03 (2b) 10 15 20 1. LiOH, THF, MeOH H25C120 2. H+ 0Nv^s^C02Me U H02C co2h MCPBA 1. LiOH 2. H+ COoMe COoH (2e) The starting material is available from Aldrich. It is treated with a mild oxidizing agent such as Mn02 to oxidize the 2-hydroxyethyl group to the corresponding aldehyde. The R group is then formed. In this case an ether is prepared under basic conditions using an a-halo intermediate. A tosylate made as per Scheme 1, can also be used in this step. Introducing the acid function at position 2 (2a) is accomplished by means of a triphenylphosphoranylidene reagent. The acetate form is illustrated here but other similar reagents could be used. The N-oxide is then formed by means of a peroxy acid. Trifluoroacetic anhydride is used to oxidize the 6-position methyl group. This hydroxymethyl group is then converted 11 2 3 8 4 2 6 to the corresponding halide (2b), (in the hydrohalide form) in this case the chloride, by means of thionyl chloride. An alkyl hydroxybenzoate is then reacted with the 6-chloromethyl compound in the presence of tetrabutylammonium iodide and a weak base. The resulting diester (2c) can be hydrolyzed to the salt or, further, acidified to give the free acid (2d). An oxidant can be used to regenerate the N-oxide (2e) which can then be treated with base to hydrolyze the esters (2f). Esters can be converted to salts, the free acids and other derivatives. Catalytic hydrogenation can be used to reduce the double bond in the Ri group described here. To make compounds where T is a thioether, the sequence given in Scheme 3 can be used. Scheme 3 H25C12O Me02C HCL (2b) CS2CO3 Bu4NI H25Ci20 CI DMF HSv^ T| jfC02Me Mc02C K? (3a) T> • C02Me MCPBA CH2C12 H25Ci20 Me02C aq LiOH THF H C 0 MeOH h25<-12u (3b) (3c) (3b) MCPBA CH2C12 °^^C"c°2mc Mc02C ~o (3d) C02Me 12 23 8 42 8 aq. LiOH THF h2.~ -H02C MeOH 0=S XJ-co* (3e) The starting hydrochloride is described in Scheme 2. Instead of treating the hydrochloride with an alcohol, in this instance the mercapto analog of the hydroxybenzoate described above is used. The resulting thioether (3a) can be hydrolyzed to give the salt or treated further to give the free acid from which other derivatives of the carboxyl function can be prepared, including alcohols and aldehydes. Also, the double bond in the Ri group can be reduced by catalytic means using a heavy metal catalyst and hydrogen. Once the thioether is prepared, the sulfone (3b, 3c) and sulfoxide (3d, 3e) can be prepared by treating the thioether with an oxidizing agent. A peroxy acid or other oxidizing agent can be used. A method for making compounds where R is alkyl or subsituted alkyl is given in Scheme 4. HO Scheme 4 1 .HCI/MeOH TfO ho2C^N Pd(OAc)2 / dppf / DMF R 1.DIBAL 1. MCPBA Me02C 2. (C6H5)3PCHC02Me Me02C^^N 2. TFAA. DMF y? 3. Tf20, pyridine 4. Pd(OAc)2, dppf MeOH, CO (4b) (4c) t 1 o i... £ 13 r M8O2C N' (4d) 1. NaBH/i, MeOH C02Me 2. SOCI2 H02C <°»"si0rCO2H ho2c (4f) O- O^.COsH (40) In this Scheme, 2-hydroxypicolinic acid is converted to the alkyl ester using the corresponding alcohol and an acid to catalyze the reaction. The hydroxyl group is then converted to the 10 trifluoromethysulfonate (4a) by means of trifluoromethanesulfonic anhydride and a base, e.g. pyridine. The lipid tail 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. Then the alkylation 15 reaction is effected using Pd(OAc)2 giving the compound 4b. The ester is reduced to the corresponding aldehyde with a hydride such as diisobutylaluminum hydride (DIBAL). A Wittig olefination is then carried out using, for example, methyl(triphenylphosphoranylidene)-acetate. The resulting pyridyl ethyl acrylate (4C) is then oxidized to 20 the N-oxide with an oxidizing agent such as 3-chloroperoxybenzoic acid. This oxide is then rearranged to the 2-pyridone with trifluoroacetic anhydride. A trifluoromethylsulfonate is then formed using trifluoromethanesulfonic anhydride and pyridine. Carbomethylation is then effected by means of Pd(OAc)2, a simple 25 alcohol, and carbon monoxide (4d). Selectively reducing the pyridyl-ester (using a hydride such as NaBH4 in a low molecular weight alcohol) yields the 2-(hydroxymethyl)-pyridine. This compound is treted with thionyl chloride to form the 6-chloromethyl compound of JF 14 238426 formula 4e. This intermediate, the aliphatic equivalent of 2b, is transformed to the ethers (4e) for thioether (4c) of formula I in the same manner as is illustrated in Schemes 2 and 3. Compounds where the linking group is an amine can be made by the procedure illustrated in Scheme 5. Scheme 5 10 15 20 25 t-BOCHN MeO.C^V^ N XI NaH, DMF MsOoC t-BOCHN J (2b, 4e) (5a) 1.TFA 2. LiOH 3. H+ H02C (5b) The starting chloro compound can be prepared as per the same starting material in Schemes 2 and 3. The 6-chloromethyl compound is reacted with a t-BOC-protected amine or another protected amine or an unprotected amine, where R2 is preferably a ester group such as a caTbomethoxy group. Sodium hydride in dimethylformamide will affect the amine formation. The ester groups may then be hydrolyzed with a base to obtain the salt and the t-BOC protecting group removed by acidification (if utilized). This procedure is particularly useful for making compounds where the atom of the R group bonded to pyridyl is carbon or oxygen. Formulations Pharmaceutical compositions of the present invention comprise a pharmaceutical carrier or diluent and an amount of a compound of the formula (I) or a pharmaceutically acceptable salt, such as an alkali metal salt thereof, sufficient to produce the inhibition of the effects of leukotrienes. 9 ViZ*L 15 When the pharmaceutical composition is employed in the form of a solution or suspension, examples of appropriate pharmaceutical ^ carriers or diluents include: for aqueous systems, water; for non aqueous systems, ethanol, glycerin, propylene glycol, corn oil, 5 cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide. Also, in addition to the pharmaceutical carrier or diluent, the instant 10 compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions. 15 The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by inhalation. In general, particularly for the prophylactic treatment of 20 asthma, the compositions will be in a form suitable for administration by inhalation. Thus the compositions will comprise a suspension or solution of the active ingredient in water for administration by means of a conventional nebulizer. Alternatively the compositions will comprise a suspension or solution of the active ingredient in a 25 conventional liquified propellant or compressed gas to be administered from a pressurized aerosol container. The compositions may also comprise the solid active ingredient diluted with a solid diluent for administration from a powder inhalation device. In the above compositions, the amount of carrier or diluent will vary but 30 preferably will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingredient. For parenteral administration the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or 35 an aqueous or nonaqueous liquid suspension. For topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, pastes, and drops suitable for administration to the eye, ear, or nose. / 16 238426 For oral administration the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion. Usually a compound of formula I is administered to a subject in 5 a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a factor. When employed in this manner, the dosage of the composition ^ is selected from the range of from 50 mg to 1000 mg of active ingredient for each administration. For convenience, equal doses will 10 be administered 1 to 5 times daily with the daily dosage regimen being selected from about 100 mg to about 5000 mg. The pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product. 15 Included within the scope of this disclosure is the method of treating a disease mediated by LTB4 which comprises administering to a subject a therapeutically effective amount of a compound of formula I, preferably in the form of a pharmaceutical composition. For example, inhibiting the symptoms of an allergic response resulting 20 from a mediator release by administration of an effective amount of a compound of formula I is included within the scope of this disclosure. a The administration may be carried out in dosage units at suitable intervals or in single doses as needed. Usually this method will be practiced when relief of symptoms is specifically required. However, 25 the method is also usefully carried out as continuous or prophylactic treatment. It is within the skill of the art to determine by routine experimentation the effective dosage to be administered from the dose range set forth above, taking into consideration such factors as the degree of severity of the condition or disease being treated, and so 30 forth. Pharmaceutical compositions and their method of use also include the combination of a compound of formula I with Hi blockers where the combination contains sufficient amounts of both compounds to treat antigen-induced respiratory anaphylaxis or 35 similar allergic reaction. Representative Hi blockers useful here include cromolyn sodium, compounds from the ethanolamines (diphenhydramine), ethylenediamines (pyrilamine), the alkylamines (chlorpheniramine), the piperazines (chlorcyclizine), and the I 5 10 15 20 25 30 17 2 3 4 2 5 phenothiazines (promethazine). Hi 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 aspect of the invention. Bioassavs The specificity of the antagonist activity of a number of the compounds of this invention is demonstrated by relatively low levels of antagonism toward agonists such as potassium chloride, carbachol, histamine and PGF2- The receptor binding affinity of the compounds used in the method of this invention is measured by the ability of the compounds to bind to [3H]-LTB4 binding sites on human U937 cell membranes. The LTB4 antagonists activity of the compounds used in the method of this invention is measured by their ability to antagonize in a dose dependent manner the LTB4 elicited calcium transient measured with fura-2, the fluorescent calcium probe. The methods employed were as follows: U937 Cell Culture Conditions U937 cells were obtained from Dr. John Bomalaski (Medical College of PA) and Dr. John Lee (SK&F, Dept. of Immunology) and grown in RPMI-1640 medium supplemented with 10% (v/v) heat inactivated fetal calf serum, in a humidified environment of 5% CO2, 95% air at 37°°C. Cells were grown both in T-flasks and in Spinner culture. For differentiation of the U937 cells with DMSO to monocyte-like cells, the cells were seeded at a concentration of 1 x 105 cells/ml in the above medium with 1.3% DMSO and the incubation continued for 4 days. The cells were generally at a density of 0.75-1.25 x 106 cells/ml and were harvested by centrifugation at 800 x g for 10 min. Preparation of U937 Cell Membrane Enriched Fraction Harvested U937 cells were washed with 50 mM Tris-HCl, pH 7.4@25°°C containing 1 mM EDTA (buffer A). Cells were resuspended in buffer A at a concentration of 5 x 107 cells/ml and disrupted by nitrogen cavitation with a Parr bomb at 750 psi for 10 min. at 0°°C. The broken cell preparation was centrifuged at 1,000 x g for 10 min. The supernatant was centrifuged at 50,000 x g for 30 min. The pellet was washed twice with buffer A. The pellet was resuspended at about 3 mg membrane protein/ml with 50mM Tris-HCl, pH 7.4 at 25°C and aliquots were rapidly frozen and stored at -70°°C. I 18 238426 Binding of flHI-LTBj. to U397 Membrane Receptors [3H]-LTB4 binding assays were performed at 25°°C, in 50 mM Tris-HCl (pH 7.5) buffer containing 10 mM CaCh, 10 mM MgCl2, [3H]-LTB4, U937 cell membrane protein (standard conditions) in the 5 presence (or absence of varying concentrations of LTB4, or SK&F compounds. Each experimental point represents the means of triplicate determinations. Total and non-specific binding of [3H]-LTB4 were determined in the absence or presence of 2 mM of unlabeled LTB4, respectively. Specific binding was calculated as the difference 10 between total and non-specific , binding. The radioligand competition experiments were performed, under standard conditions, using approximately 0.2 nM [3H]-LTB4, 20-40 mg of U937 cell membrane protein, increasing concentrations of LTB4(0.1 nM to 10 nM) or other competing ligands (0.1 mM to 30 mM) in a reaction volume of 0.2 ml 15 and incubated for 30 minutes at 25°°C. The unbound radioligand and • competing drugs were separated from the membrane bound ligand by a vacuum filtration technique. The membrance bound radioactivity on the filters was determined by liquid scintillation spectrometry. Saturation binding experiments for U937 cells were performed, 20 under standard conditions, using approximately 15-50 mg of U937 membrane protein and increasing concentrations of [3H]-LTB4 (0.02-2.0 mM) in a reaction volume of 0.2 ml and incubation at 22°°C, for 30 minutes. LTB4 (2 mM) was included in a separate set of incubation tubes to determine non-specific binding. The data from the saturation 25 binding experiments was subjected to computer assisted non-linear least square curve fitting analysis and further analyzed by the method of Scatchard. Uptake of Fura-2 by Differentiated U937 Cells Harvested cells were resuspended at 2 x 106 cells/ml in Krebs 30 Ringer Hensilet buffer containing 0.1% BSA (RIA grade), 1.1 mM MgS04, 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 cells incubated in the dark for 30 minutes at 37°°C. The cells were centrifuged at 800 x g for 10 minutes and 35 resuspended at 2 x 106 cells/ml in fresh buffer B and incubated at 37°°C for 20 minutes to allow for complete hydrolysis of entrapped ester. The cells were centrifuged at 800 x g for 10 minutes and resuspended in cold fresh buffer B at 5 x 106 cells/ml. Cells were I 19 2 3 8 4 2 6 maintained on ice in the dark until used for fluorescent measurements. Fluorescent Measurements Calcium Mobilization The fluorescence of fura-2 containing U937 cells was measured 5 with a fluorometer designed by the Johnson Foundation Biomedical Instrumentation Group. Fluorometer is equipped with temperature control and a magnetic stirrer under the cuvette holder. The wave lengths are set at 339 nm for excitation and 499 nm for emission. All experiments were performed at 37°C with constant mixing. 10 U937 cells were diluted with fresh buffer to a concentration of 1 x 106 cells/ml and maintained in the dark on ice. Aliquots (2 ml) of the cell suspension were put into 4 ml cuvettes and the temperature brought up to 37°C, (maintained in 37°C, water bath for 10 min). Cuvettes were transferred to the fluorometer and fluorescence 15 measured for about one minute before addition of stimulants or antagonists and followed for about 2 minutes post stimulus. Agonists and antagonists were added as 2 ml aliquots. Antagonists were added first to the cells in the fluorometer in order to detect potential agonist activity. Then after about one 20 minute 10 nM LTB4 (a near maximal effective concentration) was added and the maximal Ca2+ mobilization [Ca2+]i was calculated using the following formula: [Ca2+]i = 224fF-Fminl 25 {Fmax-F} F was the maximum relative fluorescence measurement 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 30 100 mM EDTA solution (pH 10) was added to totally chelate the Ca2 + and quench the fura-2 signal and obtain the Fmin. The [Ca2+]i level for 10 nM LTB4 in the absence of an antagonist was 100% and basal [Ca2+]i was 0%. The IC50 concentration is the concentration of antagonist which blocks 50% of the 10 nM LTB4 induced [Ca2+]i 35 mobilization. The EC50 for LTB4 induced increase in [Ca2+]i mobilization was the concentration for half maximal increase. The Ki for calcium mobilization was determined using the formula: 9 20 238426 _IC5Q_ Kl" [LTB4I 1 [EC50] With the experiments described, the LTB4 concentration was 10 nM and the EC50 was 2 nM. Several of the compounds of this invention were tested in one or more of the aforementioned assays. Results for those tests are given in Figure III; average results are given where more than one test was done. 10 15 Figure III Binding. IC<q. (Kfl. mM U-937 PMN Ca-Mobilization U-937 PMN Structure Membrane Whole Cell Whole cell ICjj. mM % Asonist « 7o Agonist Ex 1 14.0(4.6) 0.75 0.29 0.85 0 0 Ex 2 0.9 • 0.34 1.0 0 0 Ex 3 12.0(3.9) 2.1 0.58 1.3 0 0 Ex 4 10.5(3.3) 2.3 - 1.5 .0 - Ex 5(h) >100 6.2 2.4 0.58 0 0 Ex 5(j) 52.5(16.6) 0.97 0.72 1.0 0 0 20 Examples The following are a set of examples which are given to illustrate how to make and use the compounds of this invention. These Examples are just that, examples, and are not intended to circumscribe or otherwise limit the scope of this invention. Reference is made to the claims for defining what is reserved to the inventors by this document. Example A 8-(4-MethoxvphenvOoctan-l -(4-toluenesulfonate) ACl) 7-Octvn-l-ol. 35% KH in mineral oil (27g, 240mmol) under an argon atmosphere was washed with hexane and treated dropwise with 1,3-25 diaminopropane. The mixture was stirred at room temperature until it became homogeneous. The flask was cooled to 0°C and 3-octyn-l-ol (lOg, 79mmol, Lancaster Synthesis) was slowly added. The reaction was then stirred at room temperature for 18 hours. The reaction was 9 253426 21 quenched with H2O (50mL) and the product was extracted into ether. The organic layer was washed with 10% HCI (3X15mL) and brine and dried (MgS04). Evaporation gave the title product which was used without further purification: *H NMR (90MHz, CDCI3) d 3.65 (t, J=5Hz, 5 2H, OCH2), 2.23 (m, 2H, CH2), 2.0 (m, 1H, acetylenic), 1.7-1.2 (m, 8H, (CH2)4); IR (neat) umax 3350, 2930, 2125 cnr*. A(2) 7-Octvn-l-f-butvldiphenvlsilvl ether. 7-Octyn-l-ol (3.8g) was dissolved in dimethylformamide 10 (lOmL) and treated with J-butylchlorodiphenylsilane (10.2mL, 33mmol) and imidazole (3.65g, 45mmol) at 0°C. The reaction was stirred at 0°C for 10 minutes and at room temperature for 3 hours. Water was added and the product was extracted into ethyl acetate. The ethyl acetate extract was washed with H2O and brine and dried 15 (Na2SC>4). The solvent was evaporated and the residue purified by flash column chromatography (silica, hexanes) to give a yellow oil: *H NMR (250MHz, CDCI3) d 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, (CH2H), 1.05 (s, 9H, r-butyl); IR~(film)umax 3321, 2940, 2125 cm"*. 20 A(3) 8-r4-Methoxvphenvn-7-octvn-l-r-butvldiphenv1silvl ether To a flame-dried flask under an argon atmosphere was added 4-iodoanisole (5.34g, 22mmol) in triethylamine (50mL) followed by the addition of 7-octyn-l-t-butyldiphenylsilyl ether(9.84g, 27mmol), 25 (Ph3P)2PdCl2 (350mg, 0.44mmol), and Cul (200mg, 0.88mmol). The resulting mixture was heated at 50°C for 4 hours Upon cooling to room temperature the reaction mixture was filtered and the solvent evaporated. The residue was partitioned between ethyl acetate and H2O and the organic layer was collected and washed with brine and 30 dried (Na2S04). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 1% ethyl acetate in hexanes) to give an oil: ^H NMR (250MHz, CDCI3) d 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), 1.7-1.3 (m, 8H, (CH2M), 1.05 (s, 9H, 35 f-butyl). i 2 3 8 4 2 6 10 22 AC4) 8-(4-MethoxvphenyPoctan-l -r-butvldiphenvlsilvl ether. To 8-(4-methoxyphenyl)-7-octyn-l-t-butyldiphenylsilyl ether (2.16g, 4.6mmol) in ethanol (lOmL) and ethyl acetate (10 mL) was added 5% Pd/C (lOOmg). The mixture was subjected to 75 psi of H2 for 4 hours. The reaction was filtered through Celite and the solvent evaporated to give an oil: *H NMR (250MHz, CDCI3) d 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.6 (t, 2H, OCH2), 2.5 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH2)6), 1.0 (s, 9H, /-butyl). A(5) 8-f4-Methoxvphenvnoctan-l-ol. 8-(4-Methoxyphenyl)octan-l-r-butyldiphenylsilyl ether (2.18g, 4.6mmol) in tetrahydrofuran (20mL) was cooled to 0°C and treated with tetrabutylammonium fluoride (14mL, 14mmol, 1M in 15 tetrahydrofuran). The cooling bath was removed and the reaction was stirred at room temperature for 24 hours. The reaction was diluted with ethyl acetate and was washed with H2O and brine and dried (Na2SC>4). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 0-20% ethyl acetate 20 in hexanes) to give a white solid: NMR (250MHz, CDCI3) d 7.15 (d, 2H, aryl), 6.86 (d, 2H, aryl), 3.85 (s, 3H, OCH3), 3.68 (i, 2H, OCH2), 2.62 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH2)6). A(6) 8-(4-MethoxvphenvOoctan-l -(4-toluenesulfonate). 25 6-(4-Methoxyphenyi)octan-l-ol (5.91 g, 25mmol) was dissolved in dry CH2CI2 (lOOmL) under an argon atmosphere and cooled to 0°C. To this was added pyridine (2.5mL, 30mmol) and 4-toluenesulfonyl chloride (5.4g, 28mmol). The reaction was stirred at 0°C for 20 minutes and at room temperature for 24 hours. The reaction solution 30 was washed with H2O and brine and dried (Na2SC>4). The solvent was evaporated and the residue purified by flash column chromatography (silica, 0-10% ethyl acetate in hexanes) to give a white solid: NMR (250MHz, CDCI3) d 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, 35 2H, benzylic), 2.46 (s, 3H, CH3), 1.75-1.15 (m, 12H, (CH2)6). / 23 238426 Example B 6-(4-MethoxyphenvOhexan-l -("4-toluenesulfonate) B(l) 5-Hexvn-l-/-butvldiphenvlsilvl ether 5 5-Hexyn-l-ol (3g, 30mmol, Aldrich) was dissolved in dimethylformamide (lOmL) and treated with /-butylchlorodiphenylsilane (10.2mL, 33mmol) and imidazole (3.65g, ^ 45mmol) at 0°C. The reaction was stirred at 0°C for 10 minutes and at room temperature for 3 hours. Water was added and the product was 10 extracted into ethyl acetate. The ethyl acetate extract was washed with H2O and brine and dried (Na2S04). The solvent was evaporated and the residue purified by flash column chromatography (silica, hexanes) to give a yellow oil: *H NMR (250MHz, CDCI3) d 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 3.65 (t, 2H, OCH2), 2.2 (m, 2H, CH2), 1.9 (t, 1H, 15 acetylenic), 1.7 (m, 4H, CH2-CH2), 1.05 (s, 9H, /-butyl). B(2) 6-f4-Methoxyphenyn-5-hexyn-l-f-butyldiphenylsilyl ether. To a flame-dried flask under an argon atmosphere was added 4-iodoanisole (5.34g, 22mmol) in triethylamine (50mL) followed by 20 the addition of 5-hexyn-l-/-butyldiphenylsilyl ether (8.83g, 27mmol), (Ph3P)2PdCl2 (350mg, 0.44mmol), and Cul (200mg, O.88mmol). The £ resulting mixture was heated at 50°C for 4 hours. Upon cooling to room temperature the reaction mixture was filtered and the solvent evaporated. The residue was partitioned between ethyl acetate and 25 H2O and the organic layer was collected and washed with brine and dried (Na2SC>4). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 1% ethyl acetate in hexanes) to give an oil: NMR (250MHz, CDCI3) d 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), 30 3.7 (t, 2H, OCH2), 2.4 (t, 2H, CH2), 1.7 (m, 4H, CH2-CH2), 1.05 (s, 9H, /-butyl). B(31 6-f4-Methoxvphenvnhexan-l-/-butvldiphenvlsilvl ether. To 6-(4-methoxyphenyl)-5-hexyn-l-/-butyldiphenylsilyl ether 35 (2.0g, 4.6mmol) in ethanol (lOmL) and ethylacetate (lOmL) was added 5% Pd/C (lOOmg). The mixture was subjected to 75 psi of H2 for 4 hours. The reaction was filtered through Celite and the solvent evaporated to give an oil: NMR (250MHz, CDCI3) d 7.7 (d, 4H, aryl), t 24 a™ \j ^ i iv_, 23342? 7.4 (m, 6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.6 (t, 2H, OCH2), 2.5 (t, 2H, benzylic), 1.55 (m, 4H, CH2-CH2), 1.3 (m, 4H, CH2-CH2), 1.0 (s, 9H, /-butyl). 5 BC4) 6-(4-MethoxyphenyOhexan-l-ol. 6-(4-Methoxyphenyl)hexan-l-/-butyldiphenylsilyl ether (2.0g, 4.6mmol) in tetrahydrofuran (20mL) was cooled to 0°C and treated with tetrabutylammonium fluoride (14mL, 14mmol, 1M in tetrahydrofuran). The cooling bath was removed and the reaction 10 was stirred at room temperature for 24 hours. The reaction was diluted with ethyl acetate and was washed with H2O and brine and dried (Na2SC>4). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 0-20% ethyl acetate in hexanes) to give a white solid: NMR (250MHz, CBCI3) d 7.05 (d, 15 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.65 (t, 2H, OCH2), 2.55 (t, 2H, benzylic), 1.6 (m, 4H, CH2-CH2), 1.4 (m, 4H, CH2-CH2). BCS) 6-(4-Methoxvphenynhexan-l -(4-toIuenesulfonate). 6-(4-Methoxyphenyl)hexan-l-ol (5.36g, 25mmol) was dissolved 20 in dry CH2CI2 (lOOmL) under an argon atmosphere and cooled to 0°C. To this was added pyridine (2.5mL, 30mmol) and 4-toluenesulfonyl chloride (5.4g, 28mmol). The reaction was stirred at 0°C for 20 minutes and at room temperature for 24 hours. The reaction solution was washed with H2O and brine and dried (Na2SC>4). The solvent was 25 evaporated and the residue purified by flash column chromatography (silica, 0-10% ethyl acetate in hexanes) to give a white solid: *H NMR (250MHz, CDCI3) d 1.6-1.3 (m, 8H, (CH2)4), 2.4 (s, 3H, CH3), 2.5 (t, 2H, benzylic), 3.8 (s, 3H, OCH3), 4.0 (t, 2H, OCH2), 6.80 (d, 2H, aryl), 7.0 (d, 2H, aryl), 7.3 (d, 2H, aryl), 7.8 (d, 2H, aryl). 30 Example C E-6-(4-methoxvphenvn-1 -f4-toluenesulfonateV5-hexene CCD E-4-Methoxvphenvl-5-hexenoic acid. 35 To a freshly prepared solution of lithium hexamethyldisilazide (64mmol) in tetrahydrofuran (30mL), under an argon atmosphere, ' was added a suspension of (4-carboxybutyl)triphenylphosphonium bromide (17.6g, 30mmol) in tetrahydrofuran (45mL) at room $ 238426 25 temperature. The reaction was stirred for 15 minutes during which time the orange-red color of the ylide developed. A solution of 4-anisaidehyde (4.5g, 30mmol) in tetrahydrofuran (30mL) was added dropwise and stirring was continued for an additional 20 minutes. 5 The reaction was quenched with H2O (50mL) and diluted with ether (30mL). The aqueous layer was acidified to pH 1.0 with 3N HCI and the product was extracted into ethyl acetate (3X50mL). The combined organic layers were dried (MgSC>4) and the product was purified by flash column chromatography (silica, 1% methanol in CH2CI2) to yield 10 the E-olefin as a solid: *H NMR (200MHz, CDCI3) d 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 CH2 and CH2CC>2), 1.8 (q, 2H, CH2). C(21 E-4-Methoxvphenyl-5-hexen-l-ol. 15 E-4-Methoxyphenyl-5-hexenoic acid (l.lg, 5.0mmol) in dry ether (lOmL) was slowly added to a suspension of UAIH4 (240mg, 6.0mmol) in ether (lOmL) under an argon atmosphere. The reaction mixture was refluxed for 45 minutes. Upon cooling to room temperature the reaction was quenched with H2O (lOmL) followed by 20 6N H2SO4 (7mL). Ethyl acetate (20mL) was added and the organic layer was separated and dried (MgS04); evaporation gave a white crystalline solid: mp. 65-66°C; lH NMR (200MHz, CDCI3) d 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); 25 Anal. Calcd. for C13H18O2: C, 75.65; H, 8.80, found: C, 75.45; H, 8.95; MS (CI): 207 (M+H). C(3) E-6-(4-methoxvphenvn-l -f4-toluenesulfonate)-5-hexene. E-4-Methoxyphenyl-5-hexen-l-ol (1.6g, 7.0mmol) was 30 dissolved in dry CH2CI2 (50mL) under an argon atmosphere and treated with 4-toluenesulfonyl chloride (7.0g, 36mmol) and pyridine (3mL). The reaction solution was stirred at room temperature for 3.5 hours. Water (40mL) was added to the reaction and the organic layer was separated and dried (MgS04). The product was purified by flash 35 column chromatography (silica, 10% ethyl acetate in hexane) to give an oil: !H NMR (200MHz, CDCI3) d 7.8 (d, 2H, aryl), 7.3 (d, 2H, aryl), 7.2 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.2 (d, 1H, olefin), 6.0 (m, 1H, olefin), 9 238426 26 4.1 (t, 2H, OCH2), 3.8 (s, 3H, OCH3), 2.4 (s, 3H, CH3), 2.1 (q, 2H, allylic ), 1.6 (m, 4H, CH2- CH2); MS (CI): 361 (M+H). Example 1 5 3-IT -Oxythia-2-r2-fE-2-carboxyethenyO-3-dodecyloxy-6- pyridyllethyllbenzoic acid, dilithium salt lfa) 3-Hydroxy-6-methyl-2-pyridine carboxaldehvde. 2,6-Lutidine-a2,3-diol (l.Og, 7.18mmol, Aldrich) was suspended 10 in dry CH2CI2 (40mL) and treated with Mn02 (6.1g, 70mmol). The reaction was stirred at room temperature for 6 hours. 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: *H NMR (250MHz, CDCI3): d 10.65 (s, 15 1H, OH), 10.30 (s, 1H, CHO), 7.30 (dd, 2H, 4-pyridyl, 5-pyridyl), 2.55 (s, 3H, CH3). 1(b) 3-Dodecvloxy-6-methyl-2-pyridine carboxaldehvde. 3-Hydroxy-6-methyl-2-pyridine carboxaldehye obtained above 20 was dissolved in dry dimethylformamide (lOmL) and treated with 1-iodododecane (2.1mL, 8.62mmol) and anhydrous K2C03 (3.0g, 21.7mmol) under an argon atmosphere. The reaction was heated at 90° C for lh with vigorous stirring. Upon cooling to room temperature the reaction mixture was poured into ethyl acetate 25 (lOOmL); the ethyl acetate solution was washed with H20 (3X20mL) and brine and dried (MgS04). The solvent was removed under reduced pressure and the crude product was used directly in the next step without further purification: ^H NMR (250MHz, CDCI3): d 10.40 (s, 1H, CHO), 7.30 (m, 2H, 4-pyridyl, 5- pyridyl), 4.07 (t, J=6.5Hz, 2H, 30 0CH2), 2.6 (s, 3H, CH3), 1.85-0.89 (m, 23H, aliphatic). lfc) 2-fE-2-Carboxvmethv1ethenvO-3-dodecvloxv-6-methvlpvridine. 3-Dodecyloxy-6-methyl-2-pyridine carboxaldehyde obtained above was dissolved in dry toluene (12mL) under an argon 35 atmosphere and treated with methyl (triphenylphosphoranylidene)-acetate (5.0g, 15mmol). The reaction was heated for 1 hour at 50°C. Upon cooling to room temperature the reaction was diluted with ethyl acetate (lOOmL) and washed with H20 (2X20mL) and brine and dried I ? ^ £ u ? (MgS04). Purification by flash column chromatography (silica, 7.5% ethyl acetate in petroleum ether) gave a colorless solid: *H NMR (250MHz, CDCI3): d 8.07 (d, J=15.7Hz, 1H, olefin), 7.10 (m, 2H, 4- pyridyl, 5-pyridyl), 7.05 (d, J=15.7Hz, 1H, olefin), 3.98 (t, J=6.6Hz, 2H, 5 OCH2), 3.80 (s, 3H, C02CH3), 2.49 (s, 3H, CH3), 1.88-0.85 (m, 23H, aliphatic). lfd) 2-(E-2-Carboxvmethvlethenyn-3-dodecvloxy-6-methylpyridine N-oxide. 10 2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-methylpyridine (2.15g, 5.95mmol) was dissolved in dry CH2CI2 (20mL) and cooled to 0<*>C; 85% m-chloroperoxybenzoic acid (1.45g, 7.14mmol) was added and the reaction was stirred at 0°C for 30 minutes and at room temperature for 16 hours. The reaction solution was poured into 15 saturated aqueous NaHC03 (20mL). The aqueous phase was extracted with CH2C12 (3X20mL) and the combined CH2CI2 extracts were washed with H2O (20mL) and brine and dried (MgS04). The crude pale yellow solid was used directly in the next step without further purification: *H NMR (250MHz, CDCI3): d 8.23 (d, J=16.2Hz, 1H, 20 olefin), 7.58 (d, J=16.2Hz, 1H, olefin), 7.13 (d, J=8.8Hz, 1H, 5- pyridyl), 6.79 (d, J=8.8Hz, 1H, 4-pyridyl), 4.06 (t, J=6.6Hz, 2H, OCH2), 3.81 (s, 3H, C02CH3), 2.45 (s, 3H, CH3), 1.92-0.85 (m, 23H, aliphatic); MS (CI): 378.2 (M+H). 25 lfe) 2-(E-2-CarboxymethylethenyO-3-dodecyloxy-6-('hydroxy-methvllpvridine. 2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-methylpyridine N-oxide obtained above was suspended in dry dimethylformamide (20mL) and cooled to 0°C under an argon atmosphere. To this was 30 slowly added trifluoroacetic anhydride (8.5mL, 60.2mmol). The reaction was stirred at 0°C for 10 minutes and then at room temperature for 16 hours; thin layer chromatography indicated that two reaction products were present (alcohol and trifluoroacetate). The reaction solution was slowly added to a cooled (0°C) saturated 35 aqueous Na2CC>3 solution (lOOmL). The aqueous solution was extracted with ethyl acetate (2X50mL) and the combined ethyl acetate extracts were washed with H2O (2X20mL) and brine and dried (MgSC>4); the solvent was removed in vacuo. The product mixture was « 233426 28 dissolved in methanol (20mL), treated with anhydrous K2CO3 (500mg), and vigorously stirred for 20 minutes. The reaction was diluted with ethyl acetate (75mL) and washed with H2O (30mL). The aqueous phase was extracted with ethyl acetate (2X20mL) and the 5 combined ethyl acetate extracts were washed with brine (2X20mL) and dried (MgSC>4). Purification by flash column chromatography (silica, 25% ethyl acetate in petroleum ether) gave a colorless solid: lH NMR (250MHz, CDCI3): d 8.09 (d, J=15.8Hz, 1H, olefin), 7.24 (d, J=8.6Hz, 1H, 5-pyridyl), 7.16 (d, J=8.6Hz, 1H, 4-pyridyl), 7.03 (d, 10 J=15.8Hz, 1H, olefin), 4.69 (d, J=4.2Hz, 2H, CH2), 4.03 (t, J=6.6Hz, 2H, OCH2), 3.82 (s, 3H, C02CH3), 3.61 (t, J=4.2Hz, 1H, OH), 1.91-0.85 (m, 23H, aliphatic); MS (CI): 378.3 (M+H). 1(0 2-(E-2-Carboxymethylethenyn-3-dodecyloxy-6-(chloTomethyl)-15 pyridine hydrochloride. 2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-(hydroxymethyl)pyridine (250mg, 0.662mmol) was dissolved in dry toluene (lOmL) under an argon atmosphere and cooled to 0°°C. Thionyl chloride (0.50mL, 6.85mmol) was slowly added and the 20 solution was stirred at 0°C for 30 minutes followed by lh at room temperature. The solvent and excess thionyl chloride were removed at reduced pressure. The crude hydrochloride salt was then used directly in the next step without further purification. 25 Kg) Methyl 3-ri-thia-2-r2-(E-2-carboxymethylethenyO-3-dodecyloxv-6-pvridyllethynbenzoate. 2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-(chloromethyl)pyridine hydrochloride (0.662mmol), prepared as previously described, was dissolved in dry dimethylformamide (lmL) 30 and sequentially treated with methyl 3-mercaptobenzoate (167mg, 0.993mmol), anhydrous CS2CO3 (970mg, 2.98mmol), and tetrabutylammonium iodide (25mg, 0.068mmol) under an argon atmosphere. The reaction was heated at 65°C for 45 minutes. Upon cooling to room temperature the reaction was diluted with ethyl 35 acetate (30mL) and washed with H2O (2X15mL) and brine and dried (MgS04). Purification by flash column chromatography (silica, petroleum ether: CH2Cl2:ethyl acetate, 70: 25: 5) gave a colorless oil: lH NMR (250MHz, CDCI3): d 8.04 (s, 1H, 2-phenyl), 8.03 (d, J=15.7Hz, 29 238426 IH, olefin), 7.81 (d, J=7.9Hz, IH, 4-phenyl), 7.52 (d, J=7.9Hz, 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=15.7Hz, IH, olefin), 4.26 (s, 2H, CH2S), 3.97 (t, J=6.6Hz, 2H, OCH2), 3.90 (s, 3H, C02CH3), 3.81 (s, 3H, CO2CH3), 1.85-0.85 (m, 23H, aliphatic). Proceeding in a similar manner, but substituting the appropriate thiol for 3-mercaptobenzoate, and using known chemistry where appropriate, the following compounds were made: N-[3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]oxamic acid, dilithium salt, 3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]benzene, lithium salt, 3-[l -Thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]anisole, lithium salt, N-[3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]benzene-sulfonamide, dilithium salt N-[3-[l -thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl] ethyl] phenyl] trifluoromethane-sulfonamide, dilithium salt, and 3 - [ 1 -thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)-octyloxy)-6-pyridyl]ethyl]benzoic acid, dilithium salt. 1(h) Methyl 3-ri-oxvthia-2-f2-(E-2-carboxvmethvlethenvI)-3-dodecvloxv-6-pvridvllethvllbenzoate. Methyl 3-[l-thia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate (320mg, 0.606mmol) was dissolved in dry CH2C12 (2.5mL) and cooled to 0°C. 85% m- Chloroperoxybenzoic acid (130mg, 0.64mmol) was added and the solution was stirred for 10 minutes at 0°C. The reaction was diluted with ethyl acetate (60mL) and washed with saturated aqueous NaHCC>3 (2X20mL) and brine and dried (MgSC>4). Purification by flash column chromatography (silica, CH2Cl2:petroleum ether:ethyl acetate, 50:25:25) gave a colorless solid: lH NMR (250MHz, CDCI3): d 8.11 (d, J=7.9Hz, IH, 4-phenyl), 8.10 (s, IH, 2-phenyl), 7.94 (d, J=15.7Hz, IH, olefin), 7.67 (d, J=7.9Hz, IH, 6-phenyl), 7.53 (dd, J=7.9Hz, IH, 5-phenyl), 7.19 (d, J=8.6Hz, IH, 5-pyridyl), 7.14 (d, J=8.6Hz, IH, 4- / ✓ \ 1 ■ 30 7 O " 9 ^ pyridyl), 6.68 (d, J=15.7Hz, IH, olefin), 4.21 (d, J=12.5Hz, IH, CHS), 4.15 (d, J=12.5 Hz, IH, CH'S), 3.99 (t, J=6.6Hz, 2H, OCH2), 3.93 (s, 3H, CO2CH3), 3.81 (s, 3H, CO2CH3), 1.87-0.85 (m, 23H, aliphatic); Anal. Calcd. for C30H41O6NS: C, 66.27; H, 7.60; N, 2.58, found: C, 65.97; H, 5 7.22; N, 2.46; MS (CI): 544.3 (M+H). Ki) 3-11 -Oxvthia-2-r2-(E-2-carboxyethenvn-3-dodecyloxy-6-pyridyllethvllbenzoic acid, dilithium salt Methyl 3-[l-oxythia-2-[2-(E-2-carboxymethylethenyl)-3-10 dodecyloxy-6-pyridyl]ethyl]benzoate (120mg, 0.221mmol) was dissolved in tetrahydrofuran (1.3mL) and methanol (0.66mL) under an argon atmosphere and treated with 1M LiOH (0.66mL, 0.66mmol). The reaction was stirred at room temperature for 18 hours. The tetrahydrofuran and methanol were removed under reduced pressure 15 and the product was purified by Reversed Phased MPLC (RP-18 silica, 10-65% methanol in H20) and isolated by lyophilization to give a colorless amorphous solid: *H NMR (250MHz, CD3OD): d 8.27 (s, IH, 2-phenyl), 8.11 (d, J=7.9Hz, IH, 4-phenyl), 7.77 (d, J=15.7Hz, IH, olefin), 7.60 (d, J=7.9Hz, IH, 6-phenyl), 7.58 (dd, J=7.9Hz, IH, 5-20 phenyl), 7.27 (d, J=8.6Hz, IH, 5-pyridyl), 7.04 (d, J=15.7Hz, IH, olefin), 7.01 (d, J=8.6Hz, IH, 4-pyridyl), 4.33 (d, J=12.5Hz, IH, CHS), 4.25 (d, J=12.5Hz, IH, CH'S), 4.04 (t, J=6.5Hz, 2H, OCH2), 1.88-0.86 (m, 23H, aliphatic); Anal. Calcd. for C28H3506NSLi2 • 2 H2O: 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). 25 Example 2 3-fl -Dioxvthia-2-[2-(E-2-carboxvethenvO-3-dodecvloxv-6-pvridvllethvllbenzoic acid, dilithium salt 30 2fa) Methyl 3-11 -dioxythia-2-f2-(E-2-carboxvmethvlethenvP-3-dodecvloxv-6-pvridvllethvllbenzoate. Methyl 3-[ l-thia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate (107mg, 0.197mmol) was dissolved in dry CH2CI2 (2mL), cooled to 0°C, and treated with 85% m- 35 chloroperoxybenzoic acid (44mg, 0.217mmol). The reaction was stirred at 0°C for 1.5 hours. The reaction was diluted with ethyl acetate (30mL) and washed with saturated aqueous NaHC03 (15mL) and brine and dried (MgS04). The product was purified by flash i 238426 10 31 column chromatogrphy (silica, petroleum ether: CH2Cl2:ethyl acetate, 60:25:15) to give a colorless solid: ]H NMR (250MHz, CDCI3): d 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=15.7Hz, IH, olefin), 7.55 (dd, J=7.7Hz, IH, 5-phenyl), 7.42 (d, J=8.6Hz, IH, 5-pyridyl), 7.21 (d, J=8.6Hz, IH, 4-pyridyl), 6.28 (d, J=15.7Hz, IH, olefin), 4.52 (s, 2H, CH2SC>2), 4.00 (t, J=6.6Hz, 2H, OCH2), 3.92 (s, 3H, C02CH3), 3.78 (s, 3H, C02CH3), 1.87-0.85 (m, 23H, aliphatic); Anal. Calcd. for C30H41O7NS: 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). 2fb) 3-ri-Dioxythia-2-f2-(E-2-carboxyethenyn-3-dodecyloxy-6-pyridyllethvllbenzoic acid, dilithium salt. Methyl 3-[l-dioxythia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate (20, 170mg, 0.303mmol) was 15 dissolved in tetrahydrofuran (3.0mL) and methanol (l.OmL) and treated with 1M LiOH (l.OmL, l.Ommol). The reaction was stirred at room temperature for 24 hours. The tetrahydrofuran and methanol were removed under reduced pressure and the product was purified by Reversed Phased MPLC (RP-18 silica, 10-65% methanol in H2O) 20 and isolated by lyophilization to give a colorless amorphous solid: ^H NMR (250MHz, CD3OD): d 8.40 (s, IH, 2-phenyl), 8.22 (d, J=7.9Hz, IH, 4-phenyl), 7.69 (d, J=7.9Hz, IH, 6-phenyl), 7.67 (d, J=15.7Hz, IH, olefin), 7.53 (dd, J=7.9Hz, IH, 5-phenyl), 7.30 (d, J=8.6Hz, IH, 5-pyridyl), 7.18 (d, J=8.6Hz, IH, 4-pyridyl), 6.85 (d, J=15.7Hz, IH, olefin), 25 4.62 (s, 2H, CH2S02), 4.03 (t, J=6.5Hz, 2H, OCH2), 1.87- 0.86 (m, 23H, aliphatic); Anal. Calcd. for C28H3507NSLi2 • 7/4 H20: C, 58.48; H, 6.74; N, 2.44, found: C, 58.58; H, 6.74; N, 2.67; FAB-MS: (+ve), 544.3 (M+H); (-ve), 536.2 (M-Li). 30 Example 3 4-11 -Oxvthia-2-f2-('E-2-carboxvethenvn-3-dodecvloxv-6- pyridvllethvllbenzoic acid, dilithium salt 4-[ 1 -Oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, dilithium salt, was prepared according to 35 the procedure described for 3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, dilithium salt substituting methyl 4-mercaptobenzoate for methyl 3-mercaptobenzoate. I 10 15 20 25 30 2 3 8 4 r 5 3(a) Methyl 4-fl-thia-2-f2-(E-2-carboxymethylethenvl)-3-dodecyloxv-6-pvridvllethvllbenzoate NMR (250MHz, CDCI3): d 8.05 (d, J=15.7Hz, IH, olefin), 7.90 (d, J=8.5Hz, 2H, aryl), 7.37 (d, J=8.5Hz, 2H, aryl), 7.35 (d, J=8.6Hz, IH, 5- pyridyl), 7.14 (d, J=8.6Hz, IH, 4-pyridyl), 7.01 (d, J=15.7Hz, IH, olefin), 4.29 (s, 2H, CH2S), 3.98 (t, J=6.5Hz, 2H, OCH2), 3.88 (s, 3H, C02CH3), 3.86 (s, 3H, C02CH3), 1.86-0.85 (m, 23H, aliphatic). 3(b) Methyl 4-n-oxythia-2-12-(E-2-carboxvmethvlethenyl)-3-dodecyloxy-6-pyridynethyllbenzoate. mp. 107-109°C; *H NMR (250MHz, CDC13) d 8.13 (d, J=8.5Hz, 2H, aryl), 7.95 (d, J=15.7Hz, IH, olefin), 7.56 (d, J=8.5Hz, 2H, aryl), 7.18 (d, J=8.6Hz, IH, 5-pyridyl), 7.11 (d, J=8.6Hz, IH, 4-pyridyl), 6.62 (d, J=15.7Hz, IH, olefin), 4.22 (d, J=12.5Hz, IH, CHS), 4.13 (d, J=12.5 Hz, IH, CH'S), 4.03 (t, J=6.5Hz, 2H, OCH2), 3.99 (s, 3H, C02CH3), 3.78 (s, 3H, C02CH3), 1.92-0.85 (m, 23H, aliphatic); Anal. Calcd. for C30H4iO6NS: C, 66.27; H, 7.60; N, 2.58, found: C, 65.99; H, 7.55; N, 2.27; MS (CI): 544 (M+H). 3(c) 4-fl -Oxythia-2-f2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridvllethyllbenzoic acid, dilithium salt, mp. 205-207°C (dec.); IH NMR (250MHz, CD3OD): d 8.09 (d, J=8.5Hz, 2H, aryl), 7.78 (d, J=15.7Hz, IH, olefin), 7.59 (d, J=8.5Hz, 2H, aryl), 7.26 (d, J=8.6Hz, IH, 5-pyridyl), 7.07 (d, J=15.7Hz, IH, olefin), 6.98 (d, J=8.6Hz, IH, 4-pyridyl), 4.33 (d, J=12.5Hz, IH, CHS), 4.22 (d, J=12.5Hz, IH, CH'S), 4.04 (t, J=6.5Hz, 2H, OCH2), 1.88-0.86 (m, 23H, aliphatic); Anal. Calcd. for C28H35C>6NSLi2 • 3/2 H20: 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). Example 4 2-fl -Oxvthia-2-[2-(E-2-carboxyethenyl)-3-dodecvloxv-6- pyridyllethyllbenzoic 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-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, dilithium salt, but substituting methyl 2-mercaptobenzoate for methyl 3-mercaptobenzoate. / 33 238426 4(a) Methvl 2-N -thia-2-l"2-(E-2-carboxymethylethenvn-3-dodecyloxv-6-pvridvnethvllbenzoate. NMR (250MHz, CDCI3): d 8.07 (d, J=15.7Hz, IH, olefin), 7.96 (d, J=7.8Hz, IH, 3- phenyl), 7.56 (d, J=7.8Hz, IH, 6-phenyl), 7.43 (d, J=8.6Hz, IH, 5- pyridyl), 7.42 (m, IH, 5 aryl), 7.14 (d, J=8.6Hz, IH, 4-pyridyl), 7.10 (m, IH, aryl), 7.06 (d, J=15.7Hz, IH, olefin), 4.27 (s, 2H, CH2S), 3.98 (t, J=6.6Hz, 2H, OCH2),' 3.91 (s, 3H, C02CH3), 3.83 (s, 3H, C02CH3), 1.86-0.86 (m, 23H, aliphatic). 10 4(b) methyl 2-ri-oxythia-2-r2-(E-2-carboxymethy1ethenyn-3-dodecyloxy-6-pyridyllethvllbenzoate. mp. 60-62°C; *H NMR (250MHz, CDC13): d 8.13 (d, J=7.8Hz, IH, 3-phenyl), 7.87 (d, J=15.7Hz, IH, olefin), 7.68 (d, J=7.8Hz, IH, 6-phenyl), 7.53 (m, 2H, aryl), 7.33 (d, J=8.6Hz, IH, 5-pyridyl), 7.16 (d, J=8.6Hz, IH, 4-pyridyl), 15 6.46 (d, J=15.7Hz, IH, olefin), 4.42 (d, J=12.6Hz, IH, CHS), 4.30 (d, J=12.6Hz, IH, CH'S), 4.03 (s, 3H, C02CH3), 4.0 (t, J=6.6Hz, 2H, OCH2), 3.81 (s, 3H, C02CH3), 1.87-0.85 (m, 23H, aliphatic); Anal. Calcd. for C30H41O6NS: C, 66.27; H, 7.60; N, 2.58, found: C, 66.37; H, 7.67; N, 2.56; MS (CI): 544 (M+H). 20 4(c) 2-ri-oxvthia-2-r2-(E-2-carboxyethenyn-3-dodecyloxv-6-pyridyllethyllbenzoic acid, dilithium salt, mp. 235°C (dec); ^H NMR (250MHz, CD3OD): d 8.07 (d, J=7.8Hz, IH, 3-phenyl), 7.76 (d, J=7.8Hz, IH, 6-phenyl), 7.71 (d, J=15.7Hz, IH, olefin), 7.53 (m, 2H, aryl), 7.31 (s, 25 2H, pyridyl), 6.92 (d, J=15.7Hz, IH, olefin), 4.72 (d, J=12.6Hz, IH, CHS), 4.12 (d, J=12.6Hz, IH, CH'S), 4.05 (t, J=6.5Hz, 2H, OCH2), 1.88-0.86 (m, 23H, aliphatic); FAB-MS: (+ve), 528.3 (M+H). In addition, by subsituting the appropriate reagents and intermediates for those recited in 4(a) - 4(c), and by using chemistry 30 available in the art, the following compounds were made: 3 - [ 1 -oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzoic acid, dilithium salt, N-[3-[l -oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]phenyl]trifluoromethanesulfonamide, dilithium salt, 35 N-[3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4- methoxyphenyl)octyloxy)-6-pyridyl] ethyl] phenyl] trifluoro-methanesulfonamide, dilithium salt, 34 238426 N-[3-[l-oxythia-2~[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]-benzenesulfonamide, dilithium salt 3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]anisole, lithium salt, 3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzene, lithium salt 3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-trifluoromethylphenyl)octyloxy)-6-pyridyl]ethyl]aniline, lithium salt, 3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-phenyloctyloxy)-6-pyridyl]ethyl]aniline, lithium salt, and 3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-fluorophenyl)octyloxy)-6-pyridyl]ethyl]aniline, lithium salt. Example 5 3-T1 -Oxa-2-r2-('E-2-carboxyethenvn-3-dodecvloxv-6-pvndvllethvnbenzoic acid, dilithium salt 5(a) Methyl 3-1"! -oxa-2-r2-(E-2-carboxymethv1ethenvn-3-dodecvl-oxy-6-pvridvnethvllbenzoate. 2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-(chloromethyl)pyridine hydrochloride, prepared as per Example 1(a) -1(f), was dissolved in dry dimethylformamide (2mL) and treated sequentially with methyl 3-hydroxybenzoate (152mg, l.OOmmol, Aldrich), anhydrous K2CO3 (500mg, 3.62mmol), and tetrabutylammonium iodide (24.4mg, 0.066mmol) under an argon atmosphere. The reaction was heated at 90°C for 1 hour. Upon cooling to room temperature the reaction was diluted with ethyl acetate (50mL) and washed with H2O (3X15mL) and brine and dried (MgS04). Purification by flash column chromatography (silica, CH2CI2: petroleum ether: ethyl acetate, 50:48:2) gave a colorless solid: NMR (250MHz, CDCI3): d 8.09 (d, J=15.8Hz, IH, olefin), 7.69 (s, IH, 2- phenyl), 7.65 (d, J=7.9Hz, IH, 4- phenyl), 7.44 (d, J=8.6Hz, IH, 5-pyridyl), 7.34 (dd, J=7.9Hz, IH, 5-phenyl), 7.22 (d, J=8.6Hz, IH, 4-pyridyl), 7.16 (d, J=7.9Hz, IH, 6-phenyl), 7.07 (d, J=15.8Hz, IH, olefin), 5.18 (s, 2H, CH2), 4.02 (t, J=6.6Hz, 2H, OCH2), 3.91 (s, 3H, C02CH3), 3.82 (s, 3H, CO2CH3), 1.90-0.88 (m, 23H, aliphatic): Anal. Calcd. for C30H41O6N • 1/8 mole toluene: C, 70.88; H, 8.09; N, 2.68, found: C, 70.98; H, 8.19; N, 2.64; MS (CI): 512.4 (M+H). / 2 3 8-25 35 5(b) 3-T1 -Oxa-2-f2-(E-2-carboxyethenyO-3-dodecyloxy-6-pyridvllethynbenzoic acid, dilithium salt. Methyl 3-[l-oxa-2-[2-(E-2-carboxymethylethenyl)-3-5 dodecyloxy-6-pyridyl]ethyl]benzoate (80mg, 0.156mmol) was dissolved in tetrahydrofuran (1.34mL) and methanol (0.50mL) and treated with 1M LiOH (0.50mL, 0.50mmol). The reaction was stirred at room temperature for 20 hours. The tetrahydrofuran and methanol were removed at reduced pressure and the product was 10 purified by Reversed Phased MPLC (RP-18 silica, 10-65% methanol in H2O) and isolated by lyophilization to give a colorless amorphous solid: lH NMR (250MHz, CD3OD): d - 7.81 (d, J=15.7Hz, IH, olefin), 7.62 (s, IH, 2-phenyl), 7.56 (d, J=7.9Hz, IH, 4-phenyl), 7.44 (d, J=8.6Hz, IH, 5-pyridyl), 7.40 (d, J=8.6Hz, IH, 4-pyridyl), 7.26 (dd, 15 J=7.9Hz, IH, 5- phenyl), 7.07 (d, J=15.7Hz, IH, olefin), 7.05 (d, J=7.9Hz, IH, 6- phenyl), 5.13 (s, 2H, CH2), 4.07 (t, J=6.5Hz, 2H, OCH2), 1.89-0.89 (m, 23H, aliphatic); Anal. Calcd. for C28H3506NLi2 • 5/2 H20: 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). 20 5(c) 3-fl -Oxa-2-r2-(E-2-carboxvethenvl)-3-dodecvloxv-6-pyridvllethvllbenzoic acid. N-oxide. dilithium salt. Methyl 3-T1 -oxa-2-r2-(E-2-carboxvmethvlethenvl)-3-25 dodecvloxv-6-pyridvllethvllbenzoate. N-oxide. Methyl 3-[l-oxa-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl] ethyl] ben zoate (130mg, 0.254mmol) was dissolved in dry CH2CI2 (1.5mL), cooled to 0°C, and treated with 85% m-chloroperoxybenzoic acid (57mg, 0.28mmol). The reaction was stirred at 0°C for 10 minutes and then 30 for 20 hours at room temperature. The reaction was diluted with ethyl acetate (30mL) and washed with saturated aqueous NaHC03 (15mL), H20 (lOmL), and brine and dried (MgS04). The product was purified by flash column chromatography (silica, CH2C12." petroleum ether: ethyl acetate, 50: 40: 10) to give a colorless solid. 1H NMR 35 (250MHz, CDCI3): d 8.24 (d, J=16.2Hz, IH, olefin), 7.71 (d, J=8.0Hz, IH, 4-phenyl), 7.68 (s, IH, 2-phenyl), 7.60 (d, J=16.2Hz, IH, olefin), 7.46 (d, J=9.0Hz, IH, 5-pyridyl), 7.38 (dd, J=8.0Hz, IH, 5-phenyl), 7.22 (d, J=8.0Hz, IH, 6-phenyl), 6.9 (d, J=9.0Hz, IH, 4-pyridyl), 5.32 (s, 2H, / 36 238 4 26 CH2), 4.10 (t, J=6.6Hz, 2H, OCH2), 3.92 (s, 3H, C02CH3), 3.83 (s, 3H, C02CH3), 1.94-0.88 (m, 23H, aliphatic); Anal.Calcd. for C30H41O7N: 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). 5 5(d) 3-1"! -Oxa-2-r2-(E-2-carboxyethenyl)-3-dodecvloxy-6-pyridyllethyllbenzoic acid. N-oxide. dilithium salt. Methyl 3-[l-oxa-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate, N-oxide (llOmg, 0.208mmol) 10 was dissolved in tetrahydrofuran (2mL) and methanol (0.65mL) and treated with 1M LiOH (0.65mL). The reaction was stirred at room temperature for 20 hours. The tetrahydrofuran and methanol were removed under reduced pressure and the product was purified by Reversed Phase MPLC (RP-18 silica, 10-65% methanol in H20) and 15 isolated by lyophilization to give a colorless amorphous solid. *H NMR (250MHz, CD3OD): d 7.99 (d, J=16.2Hz, IH, olefin), 7.64 (s, IH, 2- phenyl), 7.60 (d, J=8.0Hz, IH, 4-phenyl), 7.52 (d, J=9.0Hz, IH, 5-pyridyl), 7.45 (d, J=16.2Hz, IH, olefin), 7.30 (d, J=9.0Hz, IH, 4-pyridyl), 7.29 (dd, J=8.0Hz, IH, 5-phenyl), 7.08 (d, J=8.0Hz, IH, 6-phenyl), 5.30 20 (s, 2H, CH2), 4.17 (t, J=6.6Hz, 2H, OCH2), 1.95-0.86 (m, 23H, aliphatic); Anal. Calcd. for C28H3507NLi2 • 3H20: 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). Proceeding in a similar manner, but substituting the appropriate 25 intermediates, the following compounds were made: 3 - [ 1 -oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)-octyloxy)-6-pyridyl]ethyl]benzoic acid, N-oxide, dilithium salt, 3-[l-oxa-2-[2-(E,E-4-carboxybuta-l,3-dienyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzoic acid, N-oxide, 30 dilithium salt, 3-[ l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)-nonyloxy)-6-pyridyl]ethyl]benzoic acid, N-oxide, dilithium salt, N-[ 3 - [ 1 -oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]e thy 1] phenyl] trifluoromethane-35 sulfonamide, N-oxide, dilithium salt, 4-methoxy-3-[ 1 -oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzoic acid, dilithium salt, 37 2 3 G 4 2 N-[3-[ 1 -oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]acetamide, N-oxide, lithium salt, 3 - [ 1 -oxa-2-[2-(E-2-carboxyethenyl)-3-(7-(4-methoxybenzyl-sulfonyl)heptyloxy)-6-pyridyl]ethyl]benzoic acid, N-oxide, dilithium salt, 3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(7-(4-methoxyphenyl-sulfonyl)heptyloxy)-6-pyridyl]ethyl]benzoic acid, N-oxide, dilithium salt, 3-[l-oxa-2-[2-(E-2-diethylphosphonoethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, N-oxide, lithium salt, N-[3-[l -oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]oxamic acid, dilithium salt, N-[6-methoxy-3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)oc tyloxy)-6-pyridyl] ethyl] phenyl] trif luoromethane-sulfonamide, N-oxide, dilithium salt, N-[6-methoxy-3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)oc ty loxy)-6-pyridy l]ethyl] phenyl] trif luoromethane-sulfonamide, dilithium salt, N-[3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]phenyl]oxamic acid, N-oxide, dilithium salt, 3-[l-oxa-2-[2-(E-2-ethylphosphonoethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, N-oxide, dilithium salt, 3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]benzene, lithium salt, 3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]phenylurea, lithium salt, 3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]benzonitrile, lithium salt, 3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]phenol, lithium salt, and 3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]benzamide, lithium salt. 238426 38 Example 6 3-fl -Oxa-2-r2-(E-2-carboxyethenvl)-3-(8-(4-methoxvphenynoctvloxy V6-pyridyllethynaniline lithium salt 5 6(a) 7-Octvn-l-ol. 35% KH in mineral oil (27g, 240mmol) under an argon atmosphere was washed with hexane and treated dropwise with 1,3-diaminopropane. The mixture was stirred at room temperature until it became homogeneous. The flask was cooled to 0° C and 3-octyn-l-ol (lOg, 79mmol, Lancaster Synthesis) was slowly 10 added. The reaction was then stirred at room temperature for 18 hours. The reaction was quenched with H2O (50mL) and the product was extracted into ether. The organic layer was washed with 10% HCI and brine and dried (MgSC>4). Evaporation gave 9.73g (97%) of product as a colorless oil which was used without further purification: 15 lH NMR (90MHz, CDCI3) d 3.65 (t, J=5Hz, 2H, O-CH2), 2.23 (m, 2H, CH2), 2.0 (m, IH, acetylenic), 1.7-1.2 (m, 8H, (CH2)4); IR (neat) nmax 3350, 2930,. 2125 cnr*. 6(b) 7-Octvn-l-Ibutvldiphenvlsilvl ether. To a cooled (0° C) solution 20 of 7-octyn-l-ol (9.3g, 73.7mmol) in DMF (70mL) under an argon atmosphere was added imidazole (7.5g, llOmmol) followed by the dropwise addition of lbutylchlorodiphenylsilane. The reaction was then stirred at room temperature for 2 hours. The reaction solution was diluted with Et20 and washed with H2O and brine and dried 25 (MgSCU). Purification by flash column chromatography (silica, 3% EtOAc in hexane ) provided 24.9g (93%) as a colorless oil: !H NMR (250MHz, CDCI3) d 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 3.63 (t, 2H, O-CH2), 2.23 (m, 2H, CH2), 1.97 (t, IH, acetylenic), 1.6-1.3 (m, 8H, (CH2)4), 1.05 (s, 9H, lbutyl); IR (film) nmax 3321, 2940, 2125 cnr*. 30 6(c) 8-(4-Methoxyphenvl)-7-octvn-l-Ibutvldiphenvlsilvl ether. To a flame dried flask containing triethylamine (140mL) under an argon atmosphere was added 4-iodoanisole (13.3g, 56.9mmol), 7-octyn-l-lbutyldiphenylsilyl ether (24.9g, 68.3mmol), (Ph3P)2PdCl2 35 catalyst (793mg, 1.13mmol), and Cul (431mg, 2.27mmol). The resulting mixture was heated at 50° C for 4 hours. Upon cooling to room temperature the reaction mixture was filtered, the solids were washed with Et20 and the solvent was evaporated. The residue was 10 15 20 30 2 3 0 4 2 5 diluted with Et20 and washed with 5% HCI, H2O, NaHC03, and brine and dried (MgSCU). Purification by flash column chromatography (silica, 2% EtOAc in hexane) gave 30g (93%) as an orange oil: *H NMR (250MHz, CDCI3) d 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, 0-CH2), 2.4 (t, 2H, CH2), 1.7-1.3 (m, 8H, (CH2)4), 1.05 (s, 9H, tbutyl). 6(d) 8-(4-Methoxyphenvl)octan-l-Ibutyldiphenvlsilvl ether. 8-(4-Methoxyphenyl)-7-octyn-l-lbutyldiphenylsilyl ether (30g, 63.7mmol) was dissolved in EtOH (125mL) and EtOAc (125mL) and treated with 5% Pd-C catalyst (3g). The reaction was vigorously stirred under an H2 atmosphere (balloon pressure) for 4 hours. The reaction mixture was filtered through a pad of celite and the solvent was evaporated. The resulting pale yellow oil was pure by nmr analysis and was used directly for the next step: JH NMR (250MHz, CDCI3) d 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, 0-CH2), 2.5 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH2)6), 1.0 (s, 9H, 'butyl). 6(e) 8-(4-Methoxvphenynoctan-l-ol. To a cooled (0° C) solution of 8-(4-methoxyphenyl)octan-l-tbutyldiphenylsilyl ether (63mmol) was added tetrabutylammonium fluoride (70mL, 70mmol; 1M solution in THF). The cooling bath was removed and the reaction was stirred at room temperature for 4.5 hours. The solvent was evaporated and the residue was dissolved in Et20. This was washed with H2O, 5% HCI, NaHC03, and brine and dried (MgS04). Purification by flash column chromatography (silica, 30% EtOAc in hexane) gave 12.6g (85%; two steps) as a colorless solid: !H NMR (250MHz, CDCI3) d 7.15 (d, 2H, aryl), 6.86 (d, 2H, aryl), 3.85 (s, 3H, OMe), 3.68 (t, 2H, 0-CH2), 2.62 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH2)6); MS (CI): 254.2 (M+NH4); mp 47-49 °C. 6(f) l-Iodo-8-(4-methoxyphenynoctane. To a stirred solution of 8-(4-methoxyphenyl)octan-l-ol (12.3g, 52mmol) in dry toluene (200mL) under an argon atmosphere was added triphenylphosphine (17.8g, 67.6mmol) and imidazole (10.6g, 156mmol). After the imidazole had dissolved I2 (17.lg, 67.6mmol) was added. The reaction was then heated at 65 °C for 30 minutes. Upon cooling to 40 23 8 4 2 6 room temperature the reaction was concentrated to 1/4 volume. The remaining solution was diluted with Et20 and washed with H2O and brine and dried (MgSC>4). The solvent was removed and the resulting residue was dissolved in CH2CI2 and applied to a flash 5 chromatography column (silica). Elution with 2% EtOAc in hexane provided 16.3g (90%) of product as a colorless oil (slight contamination with triphenylphosphine): *H NMR (250MHz, CDCI3) d 7.08 (d, J=8.6Hz, 2H, aryl), 6.82 (d, J=8.6Hz, 2H, aryl), 3.78 (s, 3H, OMe), 3.17 (t, J=7.4Hz, 2H, I-CH2), 2.54 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, 10 CH2), 1.60 (m, 2H, CH2), 1.31 (m, 8H, aliphatic); MS (CI): 364.2 (M+NH4). 6(g) 3-Hydroxv-6-methvl-2-pyridine carboxaldehvde. 2,6-Lutidine-a2,3-diol (15g, 107.8mmol; Aldrich) was suspended in dry CH2C12 15 (200mL) and treated with Mn02 (47g, 539mmol). The reaction was stirred at room temperature for 6 hours. The reaction mixture was filtered through a pad of celite and the solvent was evaporated. The crude aldehyde was obtained as a tan solid and was used directly for the next step: !H NMR (250MHz, CDCI3) d 10.65 (s, IH, OH), 10.30 (s, 20 IH, aldehyde), 7.30 (m, 2H, 4,5-pyridyl), 2.55 (s, 3H, methyl). 6(f) 3-r8-(4-Methoxvphenyl)octyloxyl-6-methyl-2-pyridine carboxaldehvde. To a solution of l-iodo-8-(4-methoxyphenyl)octane (16.3g, 47.1mmol) in dry DMF (45mL) under an argon atmosphere 25 was added 3-hydroxy-6-methyl-2-pyridine carboxaldehyde (7.7g, 56.2mmol) and anhydrous K2CO3 (32g, 235mmol). The reaction was vigorously stirred at 90 °C for 1.5 hours. Upon cooling to room temperature the reaction was diluted with EtOAc and washed with H20, aq NH4CI, and brine and dried (MgS04). Evaporation provided 30 crude aldehyde as a dark oil that was used without further purification. 6(g) 2-(E-2-Carboxvmethvlethenyl)-3-f8-(4-methoxyphenyl)-octvloxyl-6-methylpyridine. 3-[8-(4-Methoxyphenyl)octyloxy]-6-35 methyl-2-pyridine carboxaldehyde obtained above was dissolved in dry toluene (lOOmL) under an argon atmosphere and treated with methyl (triphenylphosphoranylidene)acetate (16g, 48mmol). The reaction was heated for 1 hour at 50° C. Upon cooling to room 10 15 20 30 238-:? temperature the reaction was diluted with EtOAc and washed with H2O and brine and dried (MgS04). Purification by flash column chromatography (silica, 20% EtOAc in hexane) gave 17.2g (88%; from iodide) as a pale yellow oil: *H NMR (250MHz, CDCI3) d 8.07 (d, J=15.7Hz, IH, olefin), 7.10 (m, 4H, phenyl, 4,5-pyridyl), 7.07 (d, J=15.7Hz, IH, olefin), 6.81 (d, J=8.6Hz, 2H, phenyl), 3.97 (t, J=6.5Hz, 2H, O-CH2), 3.79 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.54 (t, J=7.6Hz, 2H, benzylic), 2.48 (s, 3H, methyl), 1.85 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.37 (m, 8H, aliphatic); MS (CI): 412.3 (M+H). 6(h) 2-(E-2-Carboxymethylethenyn-3-r8-r4-methoxyphenyn-octyloxvl-6-methvlpyridine N-oxide. 2-(E-2-CarboxymethyIethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-methylpyridine (17. lg, 41.5mmol) was dissolved in dry CH2CI2 (105mL) and cooled to 0°C; 50% mCPBA (15.8g, 45.8mmol) was added in three portions over 10 minutes. The cooling bath was removed and the reaction was stirred for 15 hours at room temperature. The reaction was poured into aqueous NaHC03 and the product extracted into CH2C12. The organic extract was washed with H2O and brine and dried (MgS04). The crude product was obtained as a yellow solid and was used without further purification. 6(i) 2-('E-2-CarboxymethylethenyO-3-f8-('4-methoxyphenvO-octyloxvl-6-hydroxvmethylpyridine. 2-(E-2-Carboxymethylethenyl)-3. [8-(4-methoxyphenyl)octyloxy]-6-methyl pyridine N-oxide obtained above was suspended in dry DMF (130mL) and cooled to 0 °C under an argon atmosphere. To this was slowly added trifluoroacetic anhydride (56mL, 400mmol). The reaction was maintained at 0°C for 20 minutes followed by 18 hours at room temperature. The reaction solution was slowly added to a solution of saturated aqueous Na2C03 and stirred for 1 hour. The product was then extracted into EtOAc; the combined organic extracts were washed with H2O and brine and dried (MgS04). Purification by flash column chromatography (silica, Et0Ac:hexane:CH2Cl2, 30:20:50) gave 11 g (62%; two steps) as a waxy solid: *H NMR (250MHz, CDCI3) d 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, CH2-OH), 4.01 (t, J=6.5Hz, 2H, 0-CH2), 42 23 8 4 2 5" 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.62 (t, J=4.1Hz, IH, OH), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.58 (m, 2H, CH2), 1.44 (m, 8H, aliphatic); MS (CI): 428.2 (M+H). 5 6(j) 3-Aminophenol Ibutvlcarbamate. 3-Aminophenol (2.0g, 18.3mmol; Aldrich) was dissolved in CH2C12 (18mL) and DMF (6mL) and treated with di-lbutyl dicarbonate (5.0mL, 21.7mmol). The reaction was stirred under an argon atmosphere for 18 hours. The reaction solution was diluted with EtOAc and washed with H20 and 10 brine and dried (MgS04). Purification by flash column chromatography (silica, EtOAc:hexane:CH2Cl2, 15:60:25) gave 3.64g (95%) as a colorless solid: *H NMR (250MHz, CDC13) d 7.15 (m, 2H, aryl), 6.72 (m, IH, aryl), 6.53 (m, 2H, aryl, OH), 6.0 (s, IH, NH), 1.54 (s, 9H, tbutyl); MS (CI): 210.2 (M+H); mp 95-97 °C. 15 6(10 2-(E-2-Carboxymethy1ethenvn-3-f8-(4-methoxyphenvP-octyloxvl-6-r(3-amino)phenoxvmethvllpyridine Ibutvlcarbamate. To a cooled (0 °C) solution of SOCl2 (0.5 lmL, 7.0mmol) in dry toluene (2mL) under an argon atmosphere was added a solution of 2-(E-2-20 carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6- hydroxymethylpyridine (300mg, 0.70mmol) in toluene (5mL). After 5 minutes the cooling bath was removed and the reaction was stirred for 2 hours at room temperature. The toluene and excess SOCl2 were evaporated. To this was added dry DMF (0.90mL), 3-aminophenol 25 tbutylcarbamate (209mg, l.Ommol), and anhydrous Cs2C03 (1.63g, 5.0mmol). The reaction was heated at 90 °C under an atmosphere of argon for 2 hours. Upon cooling to room temperature the reaction was diluted with EtOAc and washed with H20, 10% NaOH, H20, and brine and dried (MgS04). Purification by flash column chromatography 30 (silica, EtOAc:hexane:CH2Cl2, 7:63:30) yielded 348mg (80%) as a colorless oil: JH NMR (250MHz, CDCI3) d 8.09 (d, J=15.7Hz, IH, olefin), 7.44 (d, J=8.6Hz, IH, aryl), 7.15 (m, 5H, aryl), 7.05 (d, J=15.7Hz, IH, olefin), 6.90 (m, IH, aryl), 6.82 (d, J=8.6Hz, 2H, aryl), 6.65 (m, IH, aryl), 6.51 (s, IH, NH), 5.12 (s, 2H, CH2-0), 4.0 (t, J=6.5Hz, 2H, 0-CH2), 35 3.81 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.54 (t, J=7.6Hz, 2H, benzylic), 1.88 (m, 2H, CH2), 1.51 (s, 9H, tbutyl), 1.46 (m, 10H, aliphatic). 43 2 3 8 4 2 e 6(1) 3-ri -Oxa-2-r2-(E-2-carboxymethylethenyO-3-(8-(4-methoxv-phenv Doctv 1 oxy)-6-pyridv 11 ethyl 1 aniline. 2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyloxy]-6-[(3-amino)phenoxy methyl] pyridine lbutylcarbamate 5 (348mg, 0.562mmol) was dissolved in dry CH2CI2 (3.0mL) under an argon atmosphere and cooled to 0°C. Anisole (0.09mL, 0.83mmol) was added followed by trifluoroacetic acid (0.6mL). The reaction was stirred for 1 hour at 0° C and then for 3 hours at room temperature. The reaction was quenched with aqueous NaHCC>3. The product was 10 extracted into CH2CI2 and the organic extracts were washed with brine and dried (MgS04). Purification by flash column chromatography (silica, EtOAc:hexane:CH2CI2, 20:50:30) gave 273mg (94%) as a pale yellow oil: *H NMR (250MHz, CDCI3) d 8.09 (d, J=15.7Hz, IH, olefin), 7.44 (d, J=8.6Hz, IH, 5-pyridyl), 7.17 (d, J=8.6Hz, IH, 4-pyridyl), 7.08 15 (m, 3H, aryl), 7.05 (d, J=15.7Hz, IH, olefin), 6.88 (d, J=8.6Hz, 2H, aryl), 6.42 (m, IH, aryl), 6.31 (m, IH, aryl), 6.29 (m, IH, aryl), 5.10 (s, 2H, CH2-O), 4.02 (t, J=6.5Hz, 2H, 0-CH2), 3.81 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.70 (broad singlet, 2H, NH2), 2.54 (t, J=7.6Hz, 2H, benzylic), 1.88 (m, 2H, CH2), 1.62 (m, 2H, CH2), 1.40 (m, 8H, aliphatic); Analysis 20 calcd for C31H38N2O5 • 1/2 H20: C, 70.56; H, 7.45; N, 5.31; found: C, 70.74; H, 7.36; N, 5.06; MS (CI): 519.3 (M+H). 6(m) 3-Tl-Oxa-2-r2-(E-2-carboxvethenyn-3-(8-(4-methoxvphenvn-octyloxy)-6-pyridyl1ethyl1aniline lithium salt. 3-[l-Oxa-2-[2-(E-2-25 carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (30mg, 0.0578mmol) was dissolved in THF (0.36mL) and MeOH (0.24mL) and treated with 1.0M LiOH (0.12mL, 0.12mmol). The reaction was stirred under an argon atmosphere for 6 hours. The solvent was evaporated and the product purified by 30 Reversed Phased MPLC (RP-18 silica, H20-Me0H gradient). Lyophilization yielded 27mg (93%) as a colorless amorphous solid: !H NMR (250MHz, d4-MeOH) d 7.80 (d, J=15.7I-Iz, IH, olefin), 7.38 (s, 2H, 4,5-pyridyl), 7.06 (d, J=15.7Hz, IH, olefin), 7.05 (d, J=8.6Hz, 2H, phenyl), 6.97 (t, J=8.0Hz, IH, 5'-phenyl), 6.78 (d, J=8.6Hz, 2H, phenyl), 35 6.39 (m, IH, 2'-phenyl), 6.35 (m, 2H, 4\6'-phenyl), 5.04 (s, 2H, CH2-0), 4.04 (t, J=6.5Hz, 2H, 0-CH2), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.57 (m, 4H, aliphatic), 1.36 (m, 6H, aliphatic); Analysis calcd for C3oH35N205Li • 9/4 H2O: C, 65.38; H, 7.22; 5 10 15 20 30 44 23 8 4 2 6' N, 5.08; found: C, 65.39; H, 7.24; N, 5.23; MS (FAB): 511 (M+H), 517 (M+Li). Example 7 5-Carboxv-3-n -oxa-2-r2-(E-2-carboxyethenvl)-3-(8-(4-methoxyphenynoctyloxy)-6-pyridyllethyllaniline. dilithium salt 7(a) 3-Amino-5-carboxymethylphenol. HCI gas was bubbled through a solution of 3-amino-5-hydroxybenzoic acid hydrochloride (1.9g, lOmmol; Lancaster Synthesis) in MeOH (50mL) at 0 °C for 30 minutes. The reaction was stoppered and allowed to sit for 5 hours. The solvent was removed in vacuo and the residue was dissolved in H2O. The aqueous solution was neutralized with 5% Na2C03 and the product was extracted into EtOAc. The organic solution was then dried (MgS04) and evaporated producing 1.5g (89%) of ester as an off-white solid that was used without additional purification: *H NMR (250MHz, CDCI3) d 6.85 (dd, J=1.9Hz, IH, aryl), 6.80 (dd, J=1.9Hz, IH, aryl), 6.30 (dd, J=1.9Hz, IH, aryl), 3.80 (s, 3H, methyl ester). 7(b) 3-Amino-5-carboxymethylphenol Ibutvlcarbamate. A solution of 3-amino-5-carboxymethylphenol (1.5g, 8.0mmol) in DMF (8mL) under an argon atmosphere was treated with di-lbutyldicarbonate (2.1g, lOmmol). The reaction was stirred at room temperature for 16 hours. The reaction was diluted with EtOAc and washed with H20 and brine and dried (MgS04). Recrystallization from Et20 - hexane gave 1.6g (76%) as a tan solid: !H NMR (250MHz, CDCI3) d 7.35 (dd, J=1.9Hz, IH, aryl), 7.15 (dd, J=1.9Hz, IH, aryl), 6.65 (dd, J=1.9Hz, IH, aryl), 6.45 (s, IH, NH), 3.80 (s, 3H, methyl ester), 1.4 (s, 9H, tbutyl). 7(c) 2-(E-2-Car boxy met hv let hen vl)-3-f 8-( 4-methoxyphenvl)-octvl ox vl-6 - \ (3-am in o-5-c arboxv me thvDph en oxv methyl 1 pyridine Ibutvlcarbamate. To a cooled (0 °C) solution of SOCI2 (0.34mL, 4.6mmol) in dry toluene (1.5mL) under an argon atmosphere was added a solution of 2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine (197mg, 0.46mmol) in toluene (3mL). After 5 minutes the cooling bath was removed and the reaction was stirred for 2 hours at room temperature. The toluene and excess SOCl2 were evaporated. To this 9 * • i 1 f 45 was added dry DMF (l.OmL), 3-amino-5-carboxymethylphenol tbutylcarbamate (I50mg, O.5mmol), and anhydrous CS2CO3 (l.Og, 3.0mmol). The reaction was heated at 90 °C under an atmosphere of argon for 2 hours. Upon cooling to room temperature the reaction was 5 diluted with EtOAc and washed with H2O, 10% NaOH, H2O, and brine and dried (MgS04). Purification by flash column chromatography (silica, 20% EtOAc in hexane) yielded 220mg (71%) as a colorless oil: *H NMR (250MHz, CDCI3) d 8.09 (d, J=15.7Hz, IH, olefin), 7.55 (dd, J=1.9Hz, IH, aryl), 7.9 (dd, J=1.9Hz, IH, aryl), 7.46 (d, J=8.6Hz, IH, 5-10 pyridyl), 7.38(dd, J=1.9Hz, IH, aryl), 7.22 (d, J=8.6Hz, IH, 4-pyridyl), 7.12 (d, J=8.6Hz, 2H, phenyl), 7.07 (d, J=15.7Hz, IH, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 6.58 (s, IH, NH), 5.16 (s, 2H, CH2-0), 4.04 (t, J=6.5Hz, 2H, 0-CH2), 3.92 (s, 3H, methyl ester), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.58 (t, J=7.6Hz, 2H, benzylic), 1.88 (m, 2H, 15 CH2), 1.55 (s, 9H, tbutyl), 1.46 (m, 10H, aliphatic); MS (CI): 677 (M+H). 7(d) 5-Carboxvmethvl-3-n -oxa-2-r2-(E-2-carboxymethvlethenyO-3-• (8-f4-methoxyphenvl)octyloxy')-6-pyridy lie thy 11 aniline. 2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-[(3-20 amino-5-carboxymethyl)phenoxymethyl]pyridine lbutylcarbamate (200mg, 0.29mmol) was dissolved in dry CH2CI2 (3.0mL) under an argon atmosphere and cooled to 0 °C. Anisole (0.05mL, 0.46mmol) was added followed by trifluoroacetic acid (0.3mL). The reaction was stirred for 30 minutes at 0°C and then for 3.5 hours at room 25 temperature. The reaction was quenched with aqueous NaHC03. The product was extracted into CH2CI2 and the organic extracts were washed with brine and dried (MgS04). Purification by flash column chromatography (silica, 25% EtOAc in hexane) gave 120mg (72%) as a colorless oil: ]H NMR (250MHz, CDCI3) d 8.09 (d, J=15.7Hz, IH, olefin), 30 7.44 (d, J=8.6Hz, IH, 5-pyridyl), 7.17 (d, J=8.6Hz, IH, 4-pyridyl), 7.08 (m, 3H, aryl), 7.05 (d, J=15.7Hz, IH, olefin), 6.96 (dd, J=1.9Hz, IH, aryl), 6.88 (d, J=8.6Hz, 2H, phenyl), 6.49 (dd, J=1.9Hz, IH, aryl), 5.12 (s, 2H, CH2-O), 4.04 (t, J=6.5Hz, 2H, 0-CH2), 3.92 (s, 3H, methyl ester), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.54 (t, J=7.6Hz, 2H, benzylic), 35 1.88 (m, 2H, CH2), 1.62 (m, 2H, CH2), 1.40 (m, 8H, aliphatic); Analysis calcd for C33H40N2O7 • 1/2 H20: C, 67.67; H, 7.06; N, 4.78; found: C, 67.42; H, 6.96; N, 4.69; MS (CI): 577 (M+H). 23842S 46 7(e) 5-Carboxv-3-n-oxa-2-["2-(E-2-carboxvethenvl)-3-(8-(4-methoxyphenynoctyloxy')-6-pyridyl1ethyllaniline. dilithium salt. 5-Carboxymethyl-3-[l-oxa-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (120mg, 5 0.208mmol) was dissolved in THF (l.OmL) and MeOH (0.5mL) and treated with 1.0M LiOH (0.5mL, 0.5mmol). Thie reaction was stirred under an argon atmosphere for 16 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H20-Me0H gradient). Lyophilization yielded 80mg (69%) as a colorless 10 amorphous solid: *H NMR (250MHz, d4-MeOH) d 7.80 (d, J=15.7Hz, IH, olefin), 7.42 (d, J=8.6Hz, IH, 5-pyridyl), 7.38 (d, J=8.6Hz, IH, 4-pyridyl), 7.06 (d, J=15.7Hz, IH, olefin), 7.05 (d, J=8.6Hz, 2H, phenyl), 6.98 (dd, J=1.9Hz, IH, aryl), 6.92 (dd, J=1.9Hz, IH, aryl), 6.80 (d, J=8.6Hz, 2H, phenyl), 6.47 (dd, J=1.9Hz, IH, aryl), 5.11 (s, 2H, CH2-0), 15 4.05 (t, J=6.5Hz, 2H, 0-CH2), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.57 (m, 4H, aliphatic), 1.36 (m, 6H, aliphatic); Analysis calcd for C3iH34N205Li2 • 21/5 H20: C, 58.04; H, 6.70; N, 4.36; found: C, 57.87; H, 6.34; N, 4.22; MS (FAB): 561 (M+H). 20 Example 8 3-[l-Thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxvphenynoctvloxv)-6-pyridyllethynaniline. lithium salt 8(a) 3-T1 -Thia-2-r2-(E-2-carboxymethylethenvl)-3-(8-(4-methoxv-25 phenyl)octvloxy)-6-pyridynethvnaniline. To a cooled (0° C) solution of SOCl2 (0.26mL, 3.5mmol) in dry toluene (lmL) under an argon atmosphere was added a solution of 2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxy methyl pyridine (150mg, 0.35mmol) in toluene (2.5mL). After 5 minutes the cooling bath was 30 removed and the reaction was stirred for 2 hours at room temperature. The toluene and excess SOCl2 were evaporated. The crude product was dissolved in dry DMF (lmL) and added to a solution of sodium 3-aminothiophenoxide, prepared from 3-aminothiophenol (0.09mL, 0.84mmol; Aldrich) and NaH (34mg, 35 0.084mmol; 60% in mineral oil) in DMF (2mL), under an argon atmosphere. The reaction was stirred at room temperature for 3 hours. The reaction was diluted with EtOAc and washed with H2O and brine and dried (MgS04). Purification by flash column 47 238426 chromatography (silica, 30% EtOAc in hexane) gave 124mg (66%) as a colorless solid: *H NMR (250MHz, CDCI3) d 8.06 (d, J=15.7Hz, IH, olefin), 7.27 (d, J=8.6Hz, IH, 5-pyridyl), 7.08 (m, 5H, 4-pyridyl, 5'-phenyl, olefin, phenyl), 6.81 (d, J=8.6Hz, 2H, phenyl), 6.74 (m, 2H, 5 2\4'-phenyl), 6.46 (ddd, J=8.0, 1.9Hz, IH, 6'-phenyl), 4.20 (s, 2H, CH2-S), 3.96 (t, J=6.5Hz, 2H, O-CH2), 3.81 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.65 (broad singlet, 2H, NH2), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.83 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.45 (m, 2H, CH2), 1.35 (m, 6H, aliphatic); Analysis calcd for C3iH3sN204S • 1/4 H20: C, 69.06; H, 7.20; 10 N, 5.20; found: C, 69.02; H, 7.16; N, 5.21; MS (CI): 535 (M+H); mp 57-60 °C. 8(b) 3-Il-Thia-2-r2-(E-2-carboxyethenyn-3-(8-(,4-methoxyphenyn-octv1oxv)-6-pvridvllethvnaniline. lithium salt. 3-[l-Thia-2-[2-(E-2-15 carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (75mg, 0.14mmol) was dissolved in THF (0.56mL) and MeOH (0.28mL) and treated with l.OM LiOH (0.28mL, 0.28mmol). The reaction was stirred under an argon atmosphere for 6 hours. The solvent was evaporated and the product purified by 20 Reversed Phased MPLC (RP-18 silica, H20-Me0H gradient). •Lyophilization yielded 48mg (66%) as a colorless amorphous solid: *H NMR (250MHz, d^-MeOH) d 7.76 (d, J=15.7Hz, IH, olefin), 7.25 (d, J=8.6Hz, IH, 5-pyridyl), 7.24 (d, J=8.6Hz, IH, 4-pyridyl), 7.09 (d, J=8.6Hz, 2H, phenyl), 7.04 (d, J=15.7Hz, IH, olefin), 6.97 (dd, J=8.0Hz, 25 IH, 5'-phenyl), 6.80 (d, J=8.6Hz, 2H, phenyl), 6.72 (dd, J=1.9Hz, IH, 2'-phenyl), 6.67 (ddd, J=8.0, 1.9Hz, IH, 4-phenyl), 6.51 (ddd, J=8.0, 1.9Hz, IH, 6'-phenyl), 4.16 (s, 2H, CH2-S), 4.00 (t, J=6.5Hz, 2H, 0-CH2), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.80 (m, 2H, CH2), 1.49 (m, 4H, aliphatic), 1.33 (m, 6H, aliphatic); Analysis calcd for 30 C30H35N2O4SLi • 5/2 H20: C, 63.03; H, 7.05; N, 4.90; found: C, 62.67; H, 6.72; N, 4.72; MS (FAB): 527 (M+H), 521 (M+H; free acid). Proceeding in a similar manner, but substituting the appropriate intermediates for those indicated here, and using chemistry well known in the art, the following compounds were prepared: 35 3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-trifluoromethyl- phenyl)octyloxy)-6-pyridyl]ethyl]aniline, lithium salt, 3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-phenyloctyloxy)-6-pyridyl]ethyl]aniline, lithium salt, 238428 48 Example 9 3-1"! -Oxythia-2-r2-(E-2-carboxvethenvl)-3-(8-(4-methoxvphenvl)ootvloxy)-6-pvTidvllethynaniline. lithium salt 5 9(a) 3-T1 -Oxvthia-2-r2-(E-2-carboxymethv1ethenyl)-3-(8-(4-methoxyphenyl)octvloxy)-6-pvridynethyl1 aniline. To a cooled (-15° C) solution of 3-[l-thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (150mg, 0.28mmol) 10 in CH2CI2 (4mL) under an argon atmosphere was added 85% mCPBA (63mg, 0.31mmol) in two portions over 15 minutes. The reaction was maintained at -15 °C for a total of 40 minutes. The reaction was quenched with aq NaHC03 solution and the product extracted into EtOAc. The organic extract was washed with H2O and brine and dried 15 (MgS04). The product was recrystallized from EtOAc - hexane to give 109mg (71%) as a colorless solid: *H NMR (250MHz, CDCI3) d 8.03 (d, J=15.7Hz, IH, olefin), 7.22 (dd, J=8.0Hz, IH, 5'-phenyl), 7.15 (m, 2H, 4,5-pyridyl), 7.11 (d, J=8.6Hz, 2H, phenyl), 6.92 (m, IH, 2'-phenyl), 6.85 (d, J=15.7Hz, IH, olefin), 6.80 (m, 3H, phenyl, 4'-phenyl), 6.73 20 (ddd, J=8.0, 1.9Hz, IH, 6'-phenyl), 4.12 (s, 2H, CH2-S), 4.00 (t, J=6.5Hz, 2H, O-CH2), 3.99 (broad singlet, 2H, NH2), 3.82 (s, 3H, methyl ester), 3.79 (s, 3H, OMe), 2.56 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.48 (m, 2H, CH2), 1.36 (m, 6H, aliphatic); Analysis calcd for C3iH38N205S: C, 67.61; H, 6.95; N, 5.09; found: C, 67.73; H, 25 7.17; N, 4.82; MS (CI): 551 (M+H); mp 109-111 °C. 9(b) 3-N -Oxythia-2-r2-(E-2-carboxyethenvl)-3-(8-(4-methoxy-phenyl)octyloxv)-6-pvridvl1ethvnaniline. lithium salt. 3-[l-Oxythia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-30 6-pyridyl]ethyl]aniline (109mg, 0.198mmol) was dissolved in THF (0.80mL) and MeOH (0.40mL) and treated with l.OM LiOH (0.40mL, 0.40mmol). The reaction was stirred under an argon atmosphere for 6 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H20-Me0H gradient). 35 Lyophilization yielded 78mg (73%) as a colorless amorphous solid: *H NMR (250MHz, d4-MeOH) d 7.75 (d, J=15.7Hz, IH, olefin), 7.28 (d, J=8.6Hz, IH, 5-pyridyl), 7.15 (dd, J=8.0Hz, IH, 5'-phenyl), 7.03 (m, 4H, 4-pyridyl, olefin, phenyl), 6.86 (dd, J=1.9Hz, IH, 2'-phenyl), 6.75 (m, 238426 49 4H, 4\6'-phenyl, phenyl), 4.20 (q, J=13Hz, 2H, CH2-S), 4.02 (t, J=6.5Hz, 2H, 0-CH2), 3.72 (s, 3H, OMe), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.53 (m, 4H, aliphatic), 1.37 (m, 6H, aliphatic); Analysis calcd for C3oH35N205SLi • 2 H20: 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). Proceeding in a similar manner, but substituting l-iodo-8-(4-fluorophenyl)octane for l-iodo-8-(4-methothyphenyl)octane in making 2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyloxy]-6-hydroxymethylpyridine, there was made 3-[l-oxythia-2-[2-(E-2-car boxy ethenyl)-3-( 8-(4-fluorophen yl)octyloxy)-6-pyridyl] -ethyl]aniline, lithium salt. Example 10 3-fl -Dioxvthia-2-f2-('E-2-carboxyethenyn-3-('8-('4-methoxyphenvnoctv1oxvV6-pvridvllethvllaniline. lithium salt lOfa) 3-ri-Dioxvthia-2-f2-("E-2-carboxvmethylethenyn-3-('8-(,4- methoxvphenyl)octvloxv>)-6-pyridvl1ethyl]aniline. To a cooled (0 °C) solution of 3-[l-thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (75mg, 0.14mmol) in CH2CI2 (3mL) under an argon atmosphere was added 85% mCPBA (63mg, 0.308mmol). After 1 hour the reaction was quenched with aq NaHC03 solution and the product extracted into EtOAc. The organic extracts were washed with H2O and brine and dried (MgS04). Purification by flash column chromatography (silica, 50% EtOAc in hexane) gave 52mg (66%) as a colorless solid: *H NMR (250MHz, CDCI3) d 7.90 (d, J=15.7Hz, IH, olefin), 7.39 (d, J=8.6Hz, IH, 5-pyridyl), 7.21 (t, J=8.0Hz, IH, 5'-phenyl), 7.19 (d, J=8.6Hz, IH, 4-pyridyl), 7.11 (d, J=8.6Hz, 2H, phenyl), 7.03 (m, 2H, 2',4'-phenyl), 6.86 (m, IH, 6'-phenyl), 6.81 (d, J=8.6Hz, 2H, phenyl), 6.54 (d, J=15.7Hz, IH, olefin), 4.46 (s, 2H, CH2-S), 3.99 (t, J=6.5Hz, 2H, 0-CH2), 3.86 (broad singlet, 2H, NH2), 3.79 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.82 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.45 (m, 2H, CH2), 1.35 (m, 6H, aliphatic); Analysis calcd for C31H38N2O6S • 1/3 mol CgHu: C, 66.57; H, 7.22; N, 4.70; found: C, 66.45; H, 7.24; N, 4.89; MS (CI): 567 (M+H); mp 92-95 <>C. 238426 50 lOCM 3-fl -Dioxythia-2-r2-(E-2-carboxvethenyn-3-f8-(4- methoxyphenyOoctyloxv)-6-pyridynethyllaniline. lithium salt. 3-[l-Dioxythia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline (51mg, 0.09mmol) 5 was dissolved in THF (0.30mL) and MeOH (0.18mL) and treated with l.OM LiOH (0.18mL, 0.18mmol). The reaction was stirred under an argon atmosphere for 6 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H20-Me0H gradient). Lyophilization yielded 33mg (66%) as a colorless 10 amorphous solid: *H NMR (250MHz, d4-MeOH) d 7.65 (d, J=15.7Hz, IH, olefin), 7.26 (d, J=8.6Hz, IH, 5-pyridyl), 7.24 (d, J=8.6Hz, IH, 4-pyridyl), 7.17 (dd, J=8.0Hz, IH, 5'-phenyl), 7.06 (d, J=8.6Hz, 2H, phenyl), 6.97 (dd, J=1.9Hz, IH, 2'-phenyl), 6.85 (m, 2H, 4',6'-phenyl), 6.78 (d, J=8.6Hz, 2H, phenyl), 6.75 (d, J=15.7Hz, IH, olefin), 4.55 (s, 2H, 15 CH2-S), 4.04 (t, J=6.5Hz, 2H, 0-CH2), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6Hz, 2H, benzylic), 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 11 20 3-11 -Thia-2-r2-(E-2-carboxyethenvn-3-(8-(4- methoxvphenvnoctvloxy V6-pvridv 11 ethyl 1-N.N-di methyl aniline. lithium salt 11(a) 3-f 1 -Thia-2-f2-fE-2-carboxymethvlethenyn-3-f8-(4- 25 methoxvphenyPoctvloxy)-6-pyridvnethyll-N.N-dimethvlaniline. To a solution of 3-[l-thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyllethyl]aniline (75mg, 0.14mmol) in acetonitrile (lmL) was added formaldehyde (0.25mL, 3.1mmol; 37% aqueous solution) and NaCNBH3 (50mg, 0.80mmol). The reaction was 30 stirred at room temperature for 15 minutes. The reaction solution was made neutral by the addition of glacial acetic acid and stirred for an additional 2 hours. The reaction was diluted with H20 and the product extracted into EtOAc. The organic layer was washed with H20 and brine and dried (MgS04). Purification by flash column 35 chromatography (silica, 20% EtOAc in hexane) gave 56mg (72%) as a pale yellow oil: ]H NMR (250MHz, CDC13) d 8.06 (d, J=15.7Hz, IH, olefin), 7.35 (d, J=8.6Hz, IH, 5-pyridyl), 7.08 (m, 4H, 4-pyridyl, 5'-phenyl, phenyl), 7.04 (d, J=15.7Hz, IH, olefin), 6.83 (d, J=8.6Hz, 2H, 51 phenyl), 6.74 (m, 2H, 2\4'-phenyl), 6.52 (dd, J=8.0, 1.9Hz, IH, 6'-phenyl), 4.23 (s, 2H, CH2-S), 4.00 (t, J=6.5Hz, 2H, 0-CH2), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.89 (s, 6H, Me2), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.83 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.45 (m, 2H, CH2), 1.35 (m, 6H, aliphatic); MS (CI): 563 (M+H). 11(b) 3-fl -Thia-2-r2-(E-2-carboxyethenyn-3-(8-(4- methoxyphenyl)octyloxy)-6-pyridyllethyll-N.N-dimethylaniline. lithium salt. 3-[l-Thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline (lOOmg, 0.178mmol) was dissolved in THF (0.72mL) and MeOH (0.36mL) and treated with l.OM LiOH (0.36mL, 0.36mmol). The reaction was stirred under an argon atmosphere for 6 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H20-Me0H gradient). Lyophilization yielded 63mg (64%) as a colorless amorphous solid: NMR (250MHz, d4-MeOH) d 7.78 (d, J=15.7Hz, IH, olefin), 7.25 (s, 2H, 4,5-pyridyl), 7.07 (m, 4H, phenyl, olefin, 5'-phenyl), , 6.80 (d, J=8.6Hz, 2H, phenyl), 6.72 (dd, J=1.9Hz, 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, CH2-S), 4.00 (t, J=6.5Hz, 2H, 0-CH2), 3.76 (s, 3H, OMe), 2.85 (s, 6H, Me2), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.55 (m, 4H, aliphatic), 1.33 (m, 6H, aliphatic); Analysis calcd for C32H39N204SLi . 5/4 H20: 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 12 3-f l-Oxythia-2-r2-(E-2-carboxyethenvn-3-(8-(4-methox vph env Hoctvl ox v)-6-pvrid vile thy n-N.N-dimethvlani line. lithium salt 12fa) 3-fl -Oxythia-2-r2-(E-2-carboxymethvlethenyn-3-(8-(4- methoxvphenynoctyloxy)-6-pyridvllethvll-N.N-dimethyl aniline. Prepared from 3-[l-thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline in 68% yield according to 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 (250MHz, CDCI3) d 8.01 (d, J=15.7Hz, IH, olefin), 7.22 (dd, J=8.0Hz, IH, 5'- 52 238426 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, CH2-S), 4.00 (t, J=6.5Hz, 2H, 0-CH2), 3.82 (s, 3H, methyl ester), 3.79 (s, 3H, OMe), 2.95 (s, 6H, Me2), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.48 (m, 2H, CH2), 1.36 (m, 6H, aliphatic); MS (CI): 579.2 (M+H). 12(b) 3-ri-Oxythia-2-[2-(E-2-carboxyethenyn-3-(8-(4- methoxypheny1)octyloxy)-6-pyridyllethyl1-N.N-di methyl aniline, lithium salt. Prepared from 3-[l-oxythia-2-[2-(E-2-carboxymethyl-ethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline in 70% yield according to the procedure described for the preparation of 3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline, lithium salt. Colorless amorphous solid: !H NMR (250MHz, d4-MeOH) d 7.75 (d, J=15.7Hz, IH, olefin), 7.31 (dd, J=8.0Hz, IH, 5'-phenyl), 7.24 (d, J=8.6Hz, IH, 5-pyridyl), 7.03 (m, 3H, 4-pyridyl, phenyl), 6.95 (d, J=15.7Hz, IH, olefin), 6.80 (m, 4H, aryl), 6.70 (m, IH, aryl), 4.21 (q, J=13Hz, 2H, CH2-S), 4.02 (t, J=6.5Hz, 2H, O-CH2), 3.74 (s, 3H, OMe), 2.84 (s, 6H, Me2), 2.56 (t-, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.53 (m, 4H, aliphatic), 1.37 (m, 6H, aliphatic); MS (FAB): 571.3 (M+H). Example 13 Preparation of 3-fN-r2-[2-(E-2-Carboxyethenyl)-3-(8-(4-methoxvphenv noctyloxy)-6-pyridyl"l methyl! laminobenzoic acid. dilithium salt The captioned compound was prepared according to the method set out in Scheme 5 above by reacting the appropriate r-BOC-protected aminobenzoic acid with 2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-(chloromethyl)-pyridine hydrochloride or a similar intermediate, the captioned compound was prepared. In a similar manner 3-[N-[2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]methyl]]aminobenzoic acid, N-oxide, dilithium salt and 3-[N-[2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]methyl]-N-methyl] aminobenzoic acid, dilithium salt were made. 53 23 8 4 2 6 Example 14 Preparation of Free Acids Any of the salts described in the foregoing Examples may be converted to the free acid by dissolving the salt in water, then adding 5 sufficient acid, for example HCI, to bring down the pH to 7.0 or less will provide the free acid. It, the free acid, will either precipitatate out of solution, or may be extracted, or recovered by other separatory means know in the art. Proceeding in a manner as described in the preceeding twelve 10 Examples, but substituting the appropriate the following Example 15 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with 15 numerous excipients. Means for making various formulations can be found in standard texts such as Remington's Pharmaceutical Sciences, and similar publications and compendia. Specific examples of formulations are given below. 20 Tablets Ingredients Per Tablet Per 10,000 Tablets 1. Active ingredient (Cpd of Form. I) 40 mg 400 g 25 2. Corn Starch 20 mg 200 g 3. Alginic acid 20 mg 200 g 4. Sodium alginate 20 mg 200 g 5. Magnesium stearate 1-3 mg ii-£ 101.3 mg 1013 g 30 Procedure for making tablets: Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender. 35 Step 2 Add sufficient water portionwise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> # 54 238426 Step 3 The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen. Step 4 The wet granules are then dried in an oven at 410°F 5 (60°C) until dry. Step 5 The dry granules are lubricated with ingredient No. 5. Step 6 The lubricated granules are compressed on a suitable tablet press. 10 Suppositories: Ingredients Per Supp. Per 1000 Supp.

1. Formula 1 compound 4.0 mg 40 g Active ingredient

15 2. Polyethylene Glycol 135.0 mg 1,350 g 1000

3. polyethylene glycol 45.0 mg 450 g

4000 184.0 mg 1,840 g

20 Procedure:

Step 1. Melt ingredient No. 2 and No. 3 together and stir until uniform.

Step 2. Dissolve ingredient No. 1 in the molten mass from Step 1 and stir until uniform.

25 Step 3. Pour the molten mass from Step 2 into supository moulds and chill.

Step 4. Remove the suppositories from moulds and wrap.

Inhalation Formulation 30 A compound of formula I, 1 to 10 mg/ml, is dissolved in isotonic saline and aerosolized from a nebulizer operating at an air flow. Adjusted to deliver the desired amount of drug per use.

55

WHAT WE CLAIM IS:

1. A compound of formula (I)

R 2

R3 (I)

or an N-oxide, or a pharmaceutically acceptable salt thereof, where T is S(0)n where n is 0, 1 or 2, O, NH or NCH3;

R is Cj to C20-aliphatic, unsubstituted or substituted phenyl Ci to Cio-aliphatic where substituted phenyl has one or more substituents selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is Ci to C20-aliphatic-O-, or R is unsubstituted or substituted phenyl Cj to Cjo-aliphatic-O- where substituted phenyl has one or more substituents selected from the group, consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo;

Rj is -(Ci to C5 aliphatic)R4, -(Cj to C5 aliphatic)CHOt -(Ci to C5 aliphatic)CH20R8. -R4. -CH2OH, or CHO;

R2 is hydrogen or -COR5 where R5 is -OH, a pharmaceutically acceptable ester-forming group or -OX where X is a pharmaceutically acceptable cation, or R5 is -N(Ry)2 where R7 is H, an aliphatic group of 1 to 10 carbon atoms, or a cycloalkyl-(CH2)n- group of 4 to 10 carbons where n is 0-3 or both R7 groups,together with the nitrogen atom to which they are attached, form a ring having 4 to 6 carbons, or R2 is -CH(NH2)(R4), an amide or a sulfonamide; R3 is hydrogen, lower alkoxy, halo, -CN, NHCONH2, or OH; R4 is -COR5 where R5 is -OH, a pharmaceutically acceptable ester-forming group or -OX where X is a pharmaceutically acceptable cation, or R5 is -N(R7)2 where R7 is H, an aliphatic group of 1 to 10 carbon atoms, or a cycloalkyl-(CH2)n- group of 4 to 10 carbons where n is 0-3 or both R7 groups,together with the nitrogen atom 0

/y to which they are attached, form a ring having 4 to 6 carbons;

//flan d j

Rs is hydrogen, Ci to C6 alkyl, or Ci to C6-acyl. \ c^,

x" 1

2. A compound of claim 1 where R3 is hydrogen.

3. A compound of claim 1 where T is S(0)n where n is 0, 1 or 2.

4. A compound of claim 3 where n is 0.

5. A compound of claim 3 where n is 1 or 2, R is alkoxy of 8 to 15 carbon atoms or unsubstituted or substituted phenyl-Q to Cl0.

238 42.

23 8 4

56

aliphatic-O-; Ri is -(Ci to C5 aliphatic)R4 or -(C\ to C5-aliphatic)CH20R8' and R4 and R8 are as defined in claim 1.

6. A compound of claim 5 where Ri is R5OC-CH=CH- , R2 is -COR 5 or -NHSO2CF3 , and R5 is as defined in claim 1.

7. A compound of claim 6 which is 3-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid or a pharmaceutically acceptable salt thereof.

8. A compound of claim 6 which is 2-[l-dioxythia-2-

[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid or a pharmaceutically acceptable salt thereof.

9. A compound of claim 6 which is 3-[l-dioxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyI]benzoic acid or a pharmaceutically acceptable salt thereof.

10. A compound of claim 6 which is 2-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid or a pharmaceutically acceptable salt thereof.

A compound of claim 1 where T is 0.

12. A compound of claim 11 where R is alkoxy of 8 to 15 carbon atoms or unsubstituted or substituted phenyl-Ci to Cio~ aliphatic-O-; Ri is -(C1 to C5 aliphatic)R4 or -(Ci to C5-aliphatic)CH20Rg' and R4 and Rg are as defined in claim 1.

13- A compound of claim 12 where Rj is R50C-CH=CH- , R2 is -COOH or -NHSO2CF3, and R5 is as defined in claim 1.

14. A compound of claim 13 which is 3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoic acid, its N-oxide or a pharmaceutically acceptable salt thereof.

15. A compound of claim 13 which is 2-[l-oxa-2-[2-E-2-carboxyethenyl) -3- [ (methoxyphenyl )octyloxy]-6-pyridyl ] ethyl ] benzoic acid, its N-oxide or a pharmaceutically acceptable salt thereof.

16. A compound of claim 1 where T is NH or NCH3.

17. A compound of claim 16 where R is alkoxy of 8 to 15 :arbon atoms or unsubstituted or substituted phenyl-Ci to C10-

, iliphatic-O-; Rj is -(Cj to C5 aliphatic)R4 or -(Ci to C5-aliphatic)CH20Rjg> and R4 and Rg are as defined in claim 1. ;

18. A compound of claim 17 where Ri is R5OC-CH=CH- , R2 is -COOH or -NHS02CF3 , and R5 is as defined in claim 1.

57

19. A compound of formula (I)

R3 (I)

or an N-oxide, or a pharmaceutically acceptable salt thereof, where

T is S(0)n where n is 0, 1 or 2, 0, NH, or NCH3;

R is Ci to C20-aliphatic, unsubstituted or substituted phenyl Cl to C10-aliphatic where substituted phenyl has one or more substituents selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is Cj to C20-aliphatic-O-, or R is unsubstituted or substituted phenyl Ci to Cjo-aliphatic-O- where substituted phenyl has one or more substituents selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo;

Rl is -(Ci to C5 aliphatic)R4.-(Ci to C5 aliphatic)CHO, -(Ci to C5 aliphatic)CH20R8, -R4, -CH2OH, or CHO;

R2 is an amine or -CH(NH2)(R4);

R3 is hydrogen, lower alkoxy, halo, -CN, COR5, NHCONH2, or OH;

R4 is -COR5 where R5 is -OH. a nhnrmaceutically acceptable ester-forming group or -OX where X is a pharmaceutically acceptable cation, or R5 is -N(R7)2 where R7 is H, an aliphatic group of 1 to 10 carbon atoms, or a cycloalkyl-(CH2)n- group of 4 to 10 carbons where n is 0-3 or both R7 groups, together with the nitrogen atom to which they are attached, form a ring having 4 to 6 carbons;

and

R8 is hydrogen, Ci to C(, alkyl, or Ci to C6-acyl.

20. A compound of claim 19 where T is O.

21 . A compound of claim 20 where R3 is hydrogen.

22 . A compound of claim 21 which is 3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyllethyljaniline^ lithium salt,or 5-Carboxy-3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline, dilithium salt, an acid thereof or another pharmaceutically acceptable salt thereof.

23. A compound of claim 19 where T is S(0)n where n is 0, 1

or _ r

24. A compound of claim 23. where R3 is hydrogen. 0 Ft^\

25. A compound of claim 24 where n is 0. f(y

238 426

26. A compound of claim 25 which is 3-[l-thia-242-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline, lithium salt, or 3-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline, lithium salt or the free acid thereof or another pharmaceutically acceptable salt thereof.

27. A compound of claim 24 where n is 1.

28'. A compound of claim 27, which is 3-[l -oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octy loxy)-6-pyridyl] -ethyl]aniline, lithium salt, or 3-[ 1 -oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline, lithium salt or the free acid thereof or another pharmaceutically acceptable salt thereof.

29. A compound of claim 23 where n. is 2.

30. A compound of claim 29 where R3 is hydrogen.

31 . A compound of claim 30 which is 3-[l-dioxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octy loxy)-6-pyridyl]-ethyl]aniline, lithium salt or the free acid thereof or another pharmaceutically acceptable salt thereof.

32. A compound of claim 19 where T is NH or NCH3.

33 . A pharmaceutical composition comprising a pharmaceutical carrier or diluent and a compound of any one of claims L to 32.

34 . A pharmaceutical composition according to claim 33 in a form suitable for administration by inhalation, parenteral administration, or oral administration or topical administration.

35. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 or claim 19 in the manufacture of a medicament for preventing or treating a pulmonary disease in which leukotrienes are a factor .

3e. The use'of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 or claim 19 in the

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