EP0548291A1 - Pyridylthio or pyridyloxy alkanoic acids - Google Patents

Abstract

The invention relates to alkanoic acid compounds having pyridyl and arylthio or alkylthio substituents, or their oxygen analogs, useful as antagonists of leukotrienes.

Description

PYRIDYLTHIO or PYRIDYLOXY ALKANOIC ACIDS

BACKGROUND OF THE INVENTION Scope of the Invention This invention relates to certain substituted pyridyl alkanoic acids and their derivatives which are leukotriene antagonists and thus useful in treating diseases caused by or involving leukotrienes. Detailed Background of the Invention

"Slow Reacting Substance of Anaphylaxis" (SRS-A) has been shown to be a highly potent bronchoconstricting substance which is released primarily from mast cells and basophils on antigenic challenge. SRS-A has been proposed as a primary mediator in human asthma. SRS-A, in addition to its pronounced effects on lung tissue, also produces permeability changes in skin and may be involved in acute cutaneous allergic reactions. Further, SRS-A has been shown to effect depression of ventricular contraction and potentiation of the cardiovascular effects of histamine.

The discovery of the naturally occurring leukotrienes and their relationship to SRS-A has reinforced interest in SRS-A and other arachidonate metabolites. SRS-A derived from mouse, rat, guinea pig and man have all been characterized as mixtures of leukotriene-C4 (LTC4), leukotriene-D4 (LTD4) and leukotriene-E4 (LTE4). Leukotrienes are a group of eicosanoids formed from arachidonic acid metabolism via the lipoxygenase pathway. These lipid derivatives originate from LTA4 and are of two types: (1) those containing a sulfido- peptide side chain (LTC4, LTD4, and LTE4), and (2) those that are nonpeptidic (LTB4). Leukotrienes comprise a group of naturally occurring substances that have the potential to contribute significantly to the pathogenesis of a variety of inflammatory and ischemic disorders. The pathophysiological role of leukotrienes has been the focus of recent intensive studies.

As summarized by Left, A.M., Biochemical Pharmacology. 35. 2, 123-127 (1986) both the peptide and non-peptide leukotrienes exert microcirculatory actions, promoting leakage of fluid across the capillary endothelial membrane in most types of vascular beds. LTB4 has potent chemotactic actions and contributes to the recruitment and adherence of mobile scavenger cells to the endothelial membrane. LTC4, LTD4 and LTE4 stimulate a variety of types of muscles. LTC4 and LTD4 are potent bronchoconstrictors and effective stimulators of vascular smooth muscle. This vasoconstrictor effect has been shown to occur in pulmonary, coronary, cerebral, renal, and mesenteric vasculatures.

Leukotrienes have been implicated in a number of pulmonary diseases. Leukotrienes are known to be potent bronchoconstrictors in humans. LTC4 and LTD4 have been shown to be potent and selective peripheral airway agonists, being more active than histamine. [See Drazen, J.M. et al., Proc. Nat'l. Acad. Sci. USA. 77, 7, 4354-4358 (1980).] LTC4 and LTD4 have been shown to increase the release of mucus from human airways in. vitro. [See Marom, Z. et al., Am. Rev. Respir. Pis.. 126, 449-451 (1982).] The leukotriene antagonists of the present invention can be useful in the treatment of allergic or non- allergic bronchial asthma or pulmonary anaphylaxis.

Leukotrienes have been identified in the nasal secretions of allergic subjects who underwent in. vivo challenge with specific antigen. The release of the leukotrienes was correlated with typical allergic signs and symptoms. [See Creticos, P.S. et al., New England J. of Med.. 310. 25, 1626-1629 (1984).] This suggests that allergic rhinitis is another area of utility for leukotriene antagonists. Leukotrienes have also been directly or indirectly implicated in a variety of non-pulmonary diseases in the ocular, dermatologic, cardiovascular, renal, trauma, inflammatory, carcinogenic and other areas.

Another area of utility for leukotriene antagonists is in the treatment of cardiovascular diseases. Since peptide leukotrienes are potent coronary vasoconstrictors, they are implicated in a variety of cardiac disorders including arrhythmias, conduction blocks and cardiac depression. Synthetic leukotrienes have been shown to be powerful myocardial depressants, their effects consisting of a decrease in contractile force and coronary flow. The cardiac effects of LTC4 and LTD4 have been shown to be antagonized by a specific leukotriene antagonist, thus suggesting usefulness of leukotriene antagonists in the areas of myocardial depression and cardiac anaphylaxis. [See Burke, J.A., et al., J. Pharmacology and Experimental Therapeutics. 221. 1, 235-241 (1982).]

Leukotriene antagonists can also be useful in the area of renal ischemia or renal failure. Badr et al. have shown that LTC4 produces significant elevation of mean arterial pressure and reductions in cardiac output and renal blood flow, and that such effects can be abolished by a specific leukotriene antagonist. [See Badr, K.R. et al., Circulation Research. 54. 5, 492-499 (1984).] Leukotrienes have also been shown to have a role in endotoxin-induced renal failure and the effects of the leukotrienes selectively antagonized in this model of renal injury. [See Badr, K.F., et al., Kidnev International. 30. 474-480 (1986).] LTD4 has been shown to produce local glomerular constrictor actions which are prevented by treatment with a leukotriene antagonist. [See Badr, K.F. et al., Kidnev International. 29. 1 , 328 (1986).] LTC4 has been demonstrated to contract rat glomerular mesangial cells in culture and thereby effect intraglomerular actions to reduce filtration surface area. [See Dunn, M.J. et al., Kidney International. 27, 1, 256 (1985).] Thus another area of utility for leukotriene antagonists can be in the treatment of glomerulonephritis. Cysteinyl leukotrienes have also been shown to undergo enterohepatic circulation, and thus are indicated in the area of inflammatory liver disease. [See Denzlinger, C. et al., Prostaglandins Leukotrienes and Medicine. 21. 321-322 (1986).] Leukotrienes can also be important mediators of inflammation in inflammatory bowel disease. [See Peskar, B.M. et al., Agents and Actions. 18. 381-383 (1986).] Leukotriene antagonists thus can be useful in the treatment of inflammatory liver and bowel disease.

Other areas in which leukotriene antagonists can have utility because leukotrienes are indicated as mediators include prevention of premature labor [See Clayton, J.K. et al., Proceedings of the BPS. 573P, 17-19 Dec. 1984]; treatment of migraine headaches [See Gazzaniga, P.P. et al., Abstracts Int'l Conf. on Prostaglandins and Related Comp.. 121, Florence, Italy (June 1986)]; and treatment of gallstones [See Doty, J.E. et al., Amer. J. of Surgery. 145. 54-61 (1983) and Marom, Z. et al., Amer. Rev. Respir. Pis.. 126. 449-451 (1982). By antagonizing the effects of LTC4, LTD4 and LTE4 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, including human or animals, in which leukotrienes are a key factor.

SUMMARY OF THE INVENTION This invention relates to compounds of formula (I): where neither of the two pyridyl substituents are substituted on the pyridyl nitrogen, or a pharmaceutically acceptable salt thereof wherein X is O or S(0)_q where q is 0, 1 or 2 with the proviso that Ri is not alkylthio or phenylthioalkyl when q is 1 or 2;

Rl is Cδ to Ci3 alkyl, Cη to C12 alkoxy, Cη to C12 alkylthio, C10 to C1 2 1-alkynyl, 10-undecynyloxy, 11 -dodecynyl, phenyl-C4 to C1 0 alkyl, phenyl-C3 to C9 alkoxy, phenylthio-C3 to C9 alkyl, phenyl-C3 to C 9 alkylthio with each phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, C\ to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to CJ Q alkyl, trifluoromethyl-C to C1 2 alkyl or cyclohexyl-C4 to C10 alkyl;

Y is R2, CH(R3)(CH2)_mR2- CH(R₃)-tetrazol-5-yl, or tetrazol-5-yl; R2 is -COR4 where R4 is -OH, -OE where E is a pharmaceutically acceptable cation or a pharmaceutically acceptable ester-forming group, -CN, -SO3H, -SO2NH2, -NHSO2R6, -CH(NH )COR4, or -CONHCH2COR4, or R2 is -CON(R5)2 where R5 is H, Ci to C6 alkyl, phenylCi-Cβalkyl, or the two R5 groups are combined to form a cyclic group having 3 to 5 carbons;

R3 is hydrogen, methyl, C\ to C4 alkoxy, fluoro or hydroxy;

R6 is Ci to Cio-alkyl, phenyl or substituted phenyl; m is 0, 1, or 2;

R is -(CH2)_nD, -(CH2)_nArD where n is 0-6, Ar is phenyl or substituted phenyl, thienyl, pyridyl, imidazolyl, tetrazol-5-yl or thiazolyl and D is -(CH2).R2. where 1 is 10-3, or tetrazol-5-yl.

This invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier or diluent.

This invention also relates to pharmaceutical compositions for inhibiting antigen-induced respiratory anaphylaxis comprising an effective amount of a compound of formula (I) alone or in combination with a pharmaceutically acceptable excipient; an Hi blocker may also be present in this composition. A method of treating a disease in which leukotrienes are a factor which method comprises administering to a subject in need thereof an effective amount of a compound of claim 1 alone or in combination with a pharamceutically acceptable excipient. DETAILED DESCRIPTION OF THE INVENTION

The following descriptions and definitions are used to set out and explain this invention.

Pharmaceutically acceptable esters may be formed from those compounds having a carboxylic acid function. Such an ester, or diester as the case may be, will be any ester which, as with pharmacuetically acceptable salts, gives an ester which retains the activity of the parent compound and does not impart to the parent acid any unacceptable untoward pharmacological or toxic effects in the context of its intended use and application. While it is expected that any carboxylic acid ester may be used, it is preferred to employ certain esters derived from the following radicals: C_\ to Cβ alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl. The compounds of the present invention, depending on their atomic components, are capable of forming pharmaceutically acceptable salts with acids and bases according to procedures well known in the art. Such salts are those which match the activity of the parent compound and do not exhibit untoward or deleterious activity. Acceptable acids include inorganic and organic acids, such as hydrochloric, sulfuric, methanesulfonic, benzenesulfonic, p- toluenesulϊόnic acid and acetic acid. Bases include organic and inorganic bases, such as ammonia, arginins, organic amines, alkali metal bases and alkaline earth metal bases. Piperazine and ethylenediamine salts are particularly useful in this invention. Also preferred are the dipotassium, disodium, magnesium, zinc, and calcium salts of the diacid compounds of formula (I). Pharmaceutically acceptable cations are the same as the just recited base-derived pharmaceutically acceptable salts. A preferred subgeneric class of compounds of this invention are those where the two pyridyl substituents are interchangeably in the 2 and 3 positions and X is S or O. More preferred are those compounds where X is S, Y is -R2 or CH(R3)(CH₂)_mR2 where R2 is -COOH, R3 is H or -OH and m is 0 and R is -(CH₂)_nD where n is 1, 2, or 3, or R is -(CH2)_πArD where n is 0 or 1 and Ar is phenyl or tetrazol-5-yl. For each of these sub-groups, the preferred Ri groups are Cη to Cχ2 alkylthio, C to C13 - alkyl, phenyl-C3 to C9 -alkylthio and phenyl-C4 to C10 -alkyl.

The more preferred compounds are exemplified by the following compounds:

3-(2-carboxyphenylthio)-3-[3-(2-(8-phenyloctyl))pyridyl] - propionic acid;

3-(2-carboxyphenylthio)-3-[3-(2-(8-phenyloctyl))pyridyl] -2- hydroxypropionic acid; 4-(carboxymethylthio)-4-[3-(2-(8-phenyloctyl))pyridyl] butyric acid;

3-[(tetrazol-5-yl)methylthio]-3-[3-(2-(8-phenyloctyl))pyridyl] - propionic acid;

2-hydroxy-3-[(tetrazol-5-yl)methylthio]-3-[3-(2-(8- phenyloctyl))pyridyl]propionic acid;

3-(2-carboxyphenylthio)-3-[3-(2-(8-phenyloctyl))pyridyl]- propionic acid;

3-(carboxymethylthio)-3-[3-(2-(8-phenylthiooctylthio))- pyridyl]propionic acid; 3-(4-carboxy-2-methoxyphenylmethyithio)-3-[3-(2-(6- phenyloxyhexyloxy))pyridyl]propionic acid;

3"(2-carboxyethylthio)-3-[3-(2-(7-phenylheρtylthio))pyridyl] - propionic acid;

3-(2-carboxyethylthio)-3-[3-(2-(7-phenyIheptyloxy))pyridyl] - 2-hydroxypropionic acid;

3-(2-carboxyethylthio)-3-[3-(8,8,8-trifluorooctyl))pyridyl]- propionic acid;

2-hydroxy-3-(5-tetrazolylmethylthio)-3-[3 -(2-(8- phenyloctyl))pyridyl]propionic acid; 3-(5-tetrazolylmethylthio)-3-[3-(2-(8-phenyloctyl))pyridyl] - propionic acid;

2-hydroxy-3-(2-carboxyethylthio)-3-[3-(2-(8-phenyloctyl))- pyridyl]propionic acid;

2-hydroxy-3-(4-carboxyphenylthio)-3-[3 -(2-(8-phenyloctyl))- pyridyl]propionic acid;

2-hydroxy-3-([4-carboxy-2-fluorobenzyl]thio)-3- [3-(2-(8- phenyloctyl))pyridyl]propionic acid;

3-(3-carboxymethylthio)-3-[3-(2-(8-phenyloctyl))-pyridyl] -2- hydroxypropionic acid; 3-(5-tetrazolylmethylthio)-3-[3-(2-(8,8.,8~trifluorooctyl))- pyridyl]-2-methoxypropionic acid;

2-hydroxy-3-(4-carboxy-2-methoxyphenylmethylthio)-3-[3-(2- (10,10,10-trifluorodecy loxy))pyridyl]propinoic acid; 2-hydrox-3-(4-carboxyphenylmethylthio)-3-[3-(2-(4,4,4- trifluorobutylthio))pyridyl]ypropionic acid;

2-hydroxy-3-(2-fluoro-4-carboxyphenylmethylthio)-3-[3-(2- (8-phenyloctyl))phenyl]propionic acid;

2-methoxy-3-(4-carboxyphenylthio)-3-[3-(2-(6- phenylthiohexylthio))-pyridyl]propionic acid;

2-hydroxy-3-(4-hydroxyphenylthio)-3-[3-(2-(6-phenyl- hexyloxy))pyridyl]propionic acid;

2-methoxy-3-(4-carboxyphenylmethylthio)-3-[3-(2-(8- phenyloctyl)pyridyl]propionic acid; 2-methyl-3-(carboxymethylthio)-3-[3-(2-(7- phenyloxyheptyloxy)-pyridyl]propionic acid;

2-(2-carboxyphenylthio)-2-[3-(2-(8-phenyloctyl))- pyridyl] acetic acid;

2-(carboxymethylthio)-2-[3-(2-(8-phenyloctyl))pyridyl] acetic acid;

2-(3-carboxyphenylmethylthio)-2-[3-(2-(7-phenyl- heρtylthio))pyridyl] acetic acid;

2-(carboxymethylthio)-2-[3-(2-(7-phenylthioheρtylthio)- pyridyl] acetic acid; 2-(carboxymethylthio)-2-[3-(2-(6-phenylhexyloxy)- pyridyl] acetic acid;

2-(carboxymethylthio)-2-[3-(2-(6-phenyloxyhexyloxy))- pyridyl] acetic acid; and

2-(2-(tetrazol-5-yl)ethylthio)-2-[3-(2-(8-phenyloctyl))pyridyl]- acetic acid.

In addition, the oxy analogues of each of these thioethers is a preferred embodiment of this invention.

The nitrogen of the pyridyl ring may be oxidized to the nitrous oxide form by means of an appropriate oxidant. Such oxides will be limited to those compounds of formula (I) where D is O or S(0)₂-

Some of the compounds of formula (I) contain one or two asymmetric centers. This leads to the possibility of two or four stereoisomers for each such compound. The present invention includes all such stereoisomers, racemates, or mixtures thereof. The compounds of formula (I) wherein. Y is COR2 where R2 is -OH or ^"an ester are conveniently prepared from an aldehyde precursor of formula (II)

wherein R\ is described above. A compound of formula (II) is treated with trimethylsilyl cyanide in the presence of zinc iodide at low temperatures in an inert solvent to form the trimethylsilyl-protected cyanohydrin. Treatment of this with gaseous . hydrogen chloride in methanol provides the methyl 2-hydroxyacetate derivative which is converted to the 2-chloroacetate with thionyl chloride. This valuable intermediate is then reacted with a substituted thiol selected to give, a compound of formula (I). The ester may be hydrolyzed to give the salt or the free acid.

The compounds of formula (I) wherein Y is CH2COR2 or

CH(R3)COR4 wherein R4 is OH or an ester, R3 is H, methyl, or alkoxy are prepared by reacting the appropriate aldehyde of the formula (II) and an esterified bromoacetate, conveniently t-butyl bromoacetate, with a mixture of diethyl aluminum chloride, zinc dust and a catalytic amount of cuprous bromide at low temperatures in an inert solvent to give the esterified 3-hydroxypropionate derivative which is reacted directly with a substituted thiol in trifluoroacetic acid. Alternatively, a mixture of trimethyl borate and zinc in tetrahydrofuran may be used to prepare the 3-hydroxypropionate derivative. Alternatively an aldehyde of formula (II) may be reacted at low temperature with the α-lithio salt prepared from an esterified α-halo acetic acid, conveniently t-butylacetate, in an inert solvent to give the esterified 3-hydroxypropionate derivative. By employing an esterified 2- bromopropionate in the above reaction with an aldehyde (II), the compounds of formula (I) wherein Y is CH(CH3)COR4 where R4 is OH or an ester are obtained.

Alternatively, the compounds of the formula (I) wherein Y is CH(R3)COR4 wherein R4 is OH or an ester and R3 is H, methyl, alkoxy, or fluoro are prepared from a propenoate precursor of the following structural formula (III):

wherein Rj is described above, R4 is an alkyl ester protective group, such as t-butyl, and Rχ ι is H, methyl, alkoxy, or fluoro. A compound of formula (III) is reacted with a mixture of alkali metal alkoxide, such as sodium methoxide, and substituted thiol or alcohol to give and ester of formula (I) which can be saponified to obtain a salt or the acid.

The propenoate precursors of formula (III) are prepared from the corresponding aldehydes of formula (II) by general procedures such as reaction with an alkyl (triphenylphosphoranylidene)acetate or by conversion of the aldehyde to a 3-hydroxypropionate derivative, as described above, followed by an elimination reaction to form the double bond. Additionally, the propenoate precursor is obtained from a 3-methanesulfonyloxypropionate derivative by treatment with triethylamine.

The compounds of formula (I) wherein Y is CH(OH)(CH2)_nCOR4 where R₄ is OH or an ester are prepared from an epoxide precursor of the following structural formula (IV)

wherein Rj, and n are described above, and R4 is lower alkoxy. A compound of formula (IV) is reacted in a protic solvent with triethylamine and a substituted thiol or alcohol selected to give the diester of formula (I). This diester can be hydrolyzed to the salt or the free acid by conventional means, for ezample basic hydrolysis.

The epoxide precursors of formula (IV) where n is 2 are prepared by reaction of the Grignard derivative of a bromopyridine compound of formula (IX):

with acrolein to give the corresponding enol derivative which is treated with a trialkylorthoacetate, followed by epoxidation using m-chloroperbenzoic acid.

The epoxide precursors of formula (IV) where n is 0 are prepared by reaction of an aldehyde of formula (II) with a lower alkyl chloroacetate and an alkali metal alkoxide, such as sodium methoxide. The compounds for formula (I) wherein Y is CH(OH)CH2COOH can also be prepared from an ester of formula (V) where R is -(CH2)2 OR4 and Y is CH(OH)CH₂COR4:

wherein R4 is lower alkyl. A compound of formula (V) is reacted with sodium hydride in an inert solvent followed by reaction with a substituted benzyl bromide to yield a product of formula (I).

The compounds of the formula (I) wherein Y is -(CH2)3COR are prepared from the lactone precursor of formula (VI)

where Ri is described above. A compound of formula (VI) is reacted with a mixture of zinc iodide and a substituted thiol in an inert solvent or with a substituted thiol in trifluoroacetic acid to give, after removal of any ester protective group, a compound of formula (I).

The tetrahydro-4H-pyran-2-one precursors of formula (VI) are prepared by reaction of the Grignard derivative of the bromopyridine compound of formula (IV) with chloro titanium tri-isopropoxide followed by reaction with 5-oxovalerate alkyl ester.

The aldehydes of the formula (II) are known or readily prepared utilizing the general procedures described below. The aldehyde precursors to the compounds of formula (I) wherein Ri is, for example, an alkyl radical containing 8-13 carbons are prepared from ethyl nicotinate-2-carboxaldehyde by reaction with the appropriate alkyltriphenylphosphonium bromide followed by catalytic reduction. The ester is then reacted with lithium aluminium hydride in tetrahydrofuran followed by reaction with manganese dioxide in methylene chloride to give the corresponding 2- alky 1-3 -formy lpyridine.

The ethyl nicotinate-2-carboxaldehyde precursor is prepared from the commercially available ethyl-2-methylnicotinate by reaction with selenium dioxide or benzene selenic anhydride.

The alkylthio containing aldehyde precursors of the compounds of formula (I) are prepared from 2-mercapto-3-carboxypyridine. The acid is reacted with an alkyl halide in an appropriate aprotic solvent such as dimethylformamide in the presence of potassium carbonate, followed by addition of diazomethane to yield a 2-alkylthio-3- carbomethoxypyridine. The ester is then reacted with lithium aluminum hydride in tetrahydrofuran followed by reaction with oxalyl chloride in dimethylsulfoxide and triethylamine in methylene chloride to yield the corresponding 2-alkylthio-3-formy lpyridine. The heteroaryl mercaptan precursors necessary to prepare the compounds of formula (I) are known compounds and are conveniently prepared employing standard chemical reactions. The mercapto derivatives of these precursors are prepared according to known methods. These mercaptans are reacted as described above to yield compounds of formula (I).

The compound of formula (I) containing an ester function at the Y position are prepared from the corresponding diacid compound having a carboxylic acid group at the Y and R positions of formula (I) by reacting the diacid with an appropriately alcohol according to processes known in the art. The compounds of formula (I) containing an ester function at the R position are prepared from the above described corresponding diacid compound by reacting the diacid with an alcohol in the presence of an acid catalyst according to processes known in the art. Appropriate modifications of the general processes disclosed, and as further described in the Examples provided hereinbelow, furnish the various compounds defined by formula (I).

A process for the preparation of the compounds of formula (I) of known chirality comprises reacting a diester with a strong base to generate a thiol which is then reacted with an alkylating agent or Michael acceptor to yield the desired compound.

An appropriate diester, for example one having an -OH group on the Y substitutuent, is treated with a suitable strong base such as sodium methoxide, sodium hydride, sodium amide, or lithium diisopropyl amide. The reaction is conducted in an aprotic solvent such as tetrahydrofuran, dimethylsulfoxide, or

N,N-dimethylformamide at ambient temperature and pressure. This gives an intermediate of known chirality. Such a thiol is then reacted with an alkylating agent or Michael acceptor to yield a compound of formula (I). Suitable alkylating agents include alkyl halides such as alkyl bromide or alkyl iodide. Benzyl halides are especially suitable to prepare compounds of Formula (I). The reaction is conducted in an aprotic solvent at ambient temperature and pressure. Suitable Michael acceptors include compounds which undergo nucleophilic addition. Examples include compounds containing carbonyl, carboalkoxy, or cyano groups conjugated with a double or triple bond. Carbonyl compounds or alkynes represented by the following structural formulae are especially suitable.

Here R13, R14, and Ri6 are independently selected from hydrogen or C i -βalkyl; and R15 and R17 are independently selected from H, aryl, or Cι_6alkyl. The reaction is conducted in an aprotic solvent at ambient temperature and pressure.

The leukotriene antagonist activity of the compounds of this invention is measured by the ability of the compounds to inhibit the leukotriene induced contraction of guinea pig tracheal tissues in vitro. The following methodology was employed:

In vitro: Guinea pig (adult male albino Hartley strain) tracheal spiral strips of approximate dimensions 2 to 3 mm cross-sectional width and 3.5 cm length were bathed in modified Krebs buffer in jacketed 10 ml tissue bath and continuously aerated with 95% 02/5% C02- The tissues were connected via silk suture to force displacement transducers for recording isometric tension. The tissues were equilibrated for 1 hr., pretreated for 15 minutes with meclofenamic acid (ImM) to remove intrinsic prostaglandin responses, and then pretreated for an additional 30 minutes with either the test compound or vehicle control. A cumulative concentration-response curve for LTD4 on triplicate tissues was generated by successive increases in the bath concentration of the LTD4. In order to minimize intertissue variability, the contractions elicited by LTD4 were standardized as a percentage of the maximum response obtained to a reference agonist, carbachol (lOmM).

Calculations: The averages of the triplicate LTD4 concentration- response curves both in the presence and absence of the test compound were plotted on log graph paper. The concentration of

LTD4 needed to elicit 30% of the contraction elicited by carbachol was measured and defined as the EC30. The -log Kβ value for the test compound was determined by the following equations:

1. EC30 (presence of test compound) / EC30 (presence of vehicle control) equals the dose ratio which equals X, and

2. Kg = concentration of test compound/(X-l).

The compounds of this invention possess antagonist activity against leukotrienes, primarily leukotriene D4. The antagonist activity of represen-tative compounds of this invention is listed^' in Table I. The -log Kg values were calculated from the above proto¬ col. Where compounds were tested more than once, the -log Kg values represent the current average data.

Pharmaceutical compositions of the present invention comprise a pharmaceutical carrier or diluent and an amount of a compound of formula (I) or a pharmaceutically acceptable salt, such as an alkali metal salt thereof, sufficient to produce inhibition of the effects of leukotrienes, such as symptoms of asthma and other hypersensitivity diseases.

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, cottonseed oil, peanut oil, sesame oil, liquid paraffins 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 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 compositions.

The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, i.e. orally, parenterally, topically or by inhalation. In general, particularly for the prophylactic treatment of 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 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 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 solution or an aqueous or nonaqueous liquid suspension.

For topical administration, the pharmaceutical composition will be in the form of a cream or ointment. Usually a compound of formula I is administered to an animal subject in a composition comprising a nontoxic amount of the compound sufficient to produce an inhibition of the symptoms of an allergic response. When employed in this manner, the dosage of the composition is selected from the range of from 1 μg to 700 mg. of active ingredient for each administration. For convenience, equal doses will be administered 1 to 4 times daily with the daily dosage regimen being selected from about 1 μg. to about 2800 mg. per day. The pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product.

Included within the scope of this disclosure is the method of inhibiting the symptoms of an allergic response resulting from a mediator release which comprises administering to an animal subject a therapeutically effective amount for producing said inhibition of a compound of formula I, preferably in the form of an antagonist in amounts sufficient to inhibit antigen-induced respiratory anaphylaxis. The above-defined dosage of a compound of formula I is conveniently employed for this purpose and the known effective dosage for the histamine Hi -receptor antagonist. The methods of administration described above for the single active ingredient can similarly be employed for the combination with a histamine Hj -receptor antagonist.

The following examples illustrate the preparation of the compounds of this invention and their incorporation into pharmaceutical compositions and as such are not to be considered as limiting the invention set forth in the claims appended hereto. All examples list temperature in degrees centigrade.

EXAMPLE 1 2-Hvdroxy-3-f2-carboxyethylthio )-3-(2-r3-f7- phenylheptylthioΗpyridvDpropionic acid, dipotassium salt 1 (a) 3-(7-PhenylheptylthioV2-(^'carbomethoxy)pyridine 2-Carboxy-3-mercaptopyridine (4.5g, .029M) was dissolved in

15 ml of dry dimethylformamide and warmed to 80°. K2CO3 (5.6g,

.041M) was added cautiously in 3 portions to avoid extensive foaming. The reaction was stirred for 5 minutes at 90° and 7-phenyl-l- bromoheptane (7.7 g, 0.32M) was added dropwise. After stirring at 100-110° for 3-1/2 hours, the reaction was cooled to room temperature and stirred overnight.

The reaction mixture was then poured into a stirred mixture of water and ethyl acetate and the pH adjusted to 2.0 with 3N HC1. The organic layer was separated and the aqueous was extracted twice more with ethyl acetate. The combined extracts were washed twice with water and dried over MgSθ4. This mixture was filtered and concentrated to a volume of 100 ml. This solution was added dropwise at 0° to an ethereal solution of diazomethane (prepared in the usual manner from l -methyl-3-nitro-l -nitrosoguanidine (6.0 g, .04 M), KOH (6.5g, .124 M) and Et2θ/H₂0, 120/30ml). 15 ml of methanσl was added to facilitate solubilizing the pyridine carboxylic acid. After stirring 16 hours at room temperature, the deep red solution was evaporated to an oil and purified by flash chromatography (Baker Siθ2, 20% ethyl acetate/hexane) to yield the titled compound.

1 (b) 2-Hydroxymethyl-3-(7-phenylheptylthio)pyridine

The compound of Example 1 (a) (7.1 lg, 0.22M) was dissolved in 125 ml of dry tetrahydrofuran under an argon atmosphere and cooled to 0°. Diisobutyl aluminum hydride (33.6 ml, 1.5m in toluene, .05 M) was added dropwise and the solution was stirred and allowed to warm to room temperature overnight. The reaction mixture was then cooled in an ice bath, quenched by addition of 10% aqueous NH4CI solution; allowed to warm to room temperature, and warmed for 10 minutes at 35°.

This mixture was extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed once with H2O, once with 5% NaHCθ3 and once with brine, and dried over MgS04.

Filtration and evaporation of the solvent yielded the titled compound. Thin layer chromatography (Siθ2, 40% ethylacetate/hexane) indicated essentially a single material.

1 (c) 2-Formyl-3-(7-phenylheptylthio )pyridine

To a solution of DMSO (228 ml, .035 M) in 100 ml of dry methylene chloride under an Ar atmosphere at 78° oxallyl chloride (1.54 ml, .017 M) was added neat. This solution was stirred 10 minutes at 78°, warmed briefly to 60°, recooled to -78° and the compound of example 1(b) (4.85 g, .0158M) was added in 15 ml of dry methylene chloride. The reaction was stirred at -78° for 20 minutes, then at -60° for 5 minutes and recooled to -78°. Triethylamine (11 ml, .079 M) dissolved in 15 ml methylene chloride was added over a period of 2 minutes and the cooling bath was removed. After the reaction mixture had warmed to room temperature, 100 ml of 10% ammonium chloride solution was added. The methylene chloride layer was separated and washed once with 10% ammonium chloride once with water, once with 5% sodium bicarbonate, once with brine and dried over MgS04. Filtration and evaporation yielded a red oil which was further purified by flash chromatography (Baker Siθ2, 28% ethyl acetate/hexane) to yield the titled compound. l fd^ Methyl 2.3-eρoxy-3-(^'2-r3-f7-phenylheρtylthio^')l- pyridyOpropanoate

The compound of example 1(c) (2.63 g, 8.4 mm) was dissolved in 25 ml of dry methylene chloride and methyl chlofoacetate (1.04 ml, 11.76 mm) added. The solution was cooled to -15° (ice/methanol bath) under an argon atmosphere and sodium methoxide solution (2.27 ml, 25% in methanol) was added dropwise. The reaction was stirred at -15° for 5 minutes and allowd to warm to room temperature. NaCl precipitated from solution as the reaction warmed. After stirring at room temperature for 1-1/2 hours the reaction was quenched by addition of pH 7.0 standard buffer solution (Thomas Scientific). The methylene chloride was evaporated and the cloudy aqueous solution was extracted 3 times with ethyl acetate. The ethyl acetate solution is washed once with water, once with 5% aqueous NaHCθ3, once with brine and dried over MgS04. Filtration and evaporation of the ethyl acetate solution, and flash chromatogrphy (Baker Siθ2, 20% ethyl acetate/hexane) of the resultant oil yielded the titled compound.

1 (e) Methyl 2-hvdroxy-3-(2-rcarbomethoxy1ethylthioV3-f2-r3-f7- phenylheptylthioΗpyridyPpropanoate

The compound of example 1(d)- (2.1 g, 5.45 mm) was dissolved in 2 ml methanol and stirred under an Ar atmosphere. A solution of triethylamine (3.0 ml, 21.82 mm) and 3-mercaptopropionate (1.21 ml, 10.91 mm) in 3 ml of methanol was added. After stirring 16 hours at room temperature the methanol and triethylamine were evaporated and the residual oil was dissolved in ethyl acetate. This solution was washed once with water, once with 5% NaHC03, once with brine and dried over MgSθ4- Thin layer chromatography (Siθ2, 35% ethyl acetate/hexane) and NMR indicated a mixture of regioisomers resulting from opening of the epoxide by the thiol at both the 2 and 3 positions. NMR indicated approximately 55% of the α-hydroxy ester and 45% of the benzylic alcohol.

Filtrating and evaporating the ethyl acetate yielded a yellow oil. This oil was dissolved in 9 ml methanol, and 1.25 ml of 25% sodium methoxide (in methanol) solution was added dropwise. After stirring 1 -1/2 hours, thin layer chromatography indicated that most of the undesired regioisomer had undergone the retro aldol condensation. The reaction was quenched by the addition of 5 ml of 5% aqueous ammonium chloride solution. The mixture was diluted with water and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed once with water, once with brine and dried over MgS©4. Filtration and evaporation of the ethyl acetate solution yielded an oil which was further purified by flash chromatography (Baker Siθ2, 20% ethyl acetate/hexane) to yield the titled compound.

Iff) 2-Hvdroxy-3-('2-carboxyethylthioV3-(2-r3-( 7-phenyl- heptylthioΗpyridyDpropionic acid, dipotassium salt

The compound of example 1(e) (.96 g, 1.9 mm) was dissolved in 15 ml of methanol and stirred under an Ar atmosphere. KOH (.375 g, 5.7 mm) in 5 ml of water was added dropwise. After stirring for 2 hours, the reaction mixture was diluted with water and the solution was washed twice with ethyl acetate. The aqueous was then layered with ethyl acetate and acidified with 3N HC1 to pH 2.0. The organic layer was separated and the aqueous layer was extracted once with ethyl acetate. The acidic organic extracts were combined and washed once with water, once with brine and dried over MgSθ4. Filtration and evaporation of the solvent yielded a yellow oil. The oil was dissolved in a few ml of water with KHCO3 (1.52 g, 15.2 mm) and flash chromatographed (Baker RP-18, eluted using a step gradient - 100% H2O, 200 ml; 40% MeOH/H₂0, 200 ml; 50% MeOH/H2θ; 100 ml; 60% MeOH/H2θ, 100 ml). The desired material eluted in the 40% MeOH/H2θ fractions were evaporated to yield a film, reconstituted in distilled water and lyophilized to yield an amorphous white solid. 1H-NMR at 250 MHz(D2θ, ref=HOD=4.60;) δ: 8.12 (d,lp), 7.68(d,lp),

6.90-7.28(m,6p), 4.78(d,lp), 4.23(d,lp), 2.68-2.95(m,2p), 2.52- 2.65(t,2p), 2.32-2.48(t,2p), 2.1-2.32 (m,2p), 1.3-1.55 (m,4p), .95- 1.3(m,6p) (m,4p), .95-1.3(m,6p).

EXAMPLE 2^" 2-Hvdroxy-3-f2-carboxyethylthioV3-f3-[2-f7-phenyl- heptylthio pyridvPpropionic acid, dipotassium salt 2(a) 2-r7-Phenylheptylthio^')-3-caτboxypyridine

2-Mercapto-3-carboxypyridine (8 g, .052 M) was dissolved in 25 ml dimethylformamide, and treated with K2CO3 (9.97 g, 0.722 M) and 7-phenyl-l-bromoheptane in the same manner as in example 1(a). Esterification with diazomethane in the same manner as in Example 1(a) (l-methyl-3-nitro-l-nitrosoguanidine, 10.6 g, 0722m; KOH, 14.28g, .216m; Et2θ/H2θ: 200 ml/50ml) provided the titled compound. 2(b) 2-(7-Phenylheptylthio)-3-hydroxymethy lpyridine

The compound of Example 2(a) (16 g, .049M) was dissolved in 200 ml of dry tetrahydrofuran and treated with di-isobutyl aluminum hydride (100 ml, 1.5 M in toluene, 0.15M) in the same manner as Example 1(b) to yield the titled compound.

2(c ι- 2-(8-PhenylheptylthioV3-formyrpyridine

The compound of Example 2(b) (13.75 g, .0447 M) was reacted with DMSO (6.45 ml, .0984 M), oxalyl chloride (4.1 ml, .047 mm) and triethylamine (31 ml, .224 M) in 300 ml dry methylene chloride in in the same manner as Example 1(c) to afford the captioned compound. 2(ά) Methyl 2.3-epoxy-3-r2-α-phenylheptylthio )pyridyll- propanoate

The compound of Example 2(c) (11 g, .035 M) was dissolved in 100 ml dry methylene chloride and reacted with methylchloroacetate (4.25 ml; .049 M) and sodium methoxide solution (9.46 ml, .042 M,

25% in MeOH) in the same manner as Example 1(d). The crude product was purified by flash chromatography (Baker Siθ2, 25% ethyl acetate/hexane) to yield the titled compound.

2(e) Methyl 2-hvdroxy-3-(2-[carbomethoxy1ethylthioV3-(^"3-r2-(7- phenylheptylthio^'πpyridyDpropanoate

The compound of Example 2(d) (8.68 g, 22.5 mm) was dissolved in 8 ml of methanol and treated with methyl-3-mercapto propionate (5 ml, 45 mm) and triethylamine (12.5 ml, 90 mm) in the same manner as Example 1(e). The retro aldol condensation to degrade the undesired regioisomer was accomplished by the same method by dissolving the crude product in 16 ml MeOH and treating it with sodium methoxide solution (25% NaOMe/methanol, 5.14 ml, 22.5 mm). Final purification was accomplished by flash chromatography. (Baker Siθ2, 18% ethyl acetate/hexane) to provide the titled compound. 2ffl 2-Hvdroxy-3-f2-carboxyethylthioV3-f3-r2-( 7-phenyl- heptylthioΗpyridvπpropionic acid, dipotassium salt

The compound of Example 2(e) was dissolved in 21 ml of methanol under an Ar atmosphere and treated dropwise with a solution of KOH (58g, 8.85 mm) in 7 ml of water. After 4 hours the reaction was diluted with water, layered with ethyl acetate and acidified to pH 2.0. The organic layer was separated and the aqueous extracted twice with ethyl acetate. The combined organic extracts were washed once with water, once with brine and dried over MgSθ4.

Filtration and evaporation of the solvent yielded a crude oil which was flash chromatographed (Baker Siθ2, step gradient, 3-4% methanol/chloroform - 1% trifluoroacetic acid) to yield a colorless oil. The oil was dissolved in 6 ml of H2O with KHCO3 (2.36 g, 23.6 mm) and flash chromatographed (Baker R-P 18,step gradient, 100% H2O , 250 ml; 100 ml each of 40%, 50%, 60%, 70%, and 80% methanol/H2θ).

Fractions containing the product were pooled and evaporated to a glass. This glass was resuspended in H2O and lyophilized to yield the titled compound as a hygroscopic powder, mp 255-257 with dec. iH-NMR at 250 MHz (CD3OD, ref = CHD2OD = 3.47;) δ: 8.16 (d of d, lp), 8.02(d of d, lp), 6.9-7.18 (m,6p), 4.68 (d, lp, J=4Hz), 4.23(d,lp,J=4Hz), 2.93-3.2 (m,2p), 2.63(t,2p), 2.5(t,2p), 2.35 (t,2p), 1.45-1.65 (broad m, 4p), 1.1-1.43 (broad m, 6p).

EXAMPLE 3 2-Hvdroxy-3-f2-carboxyethylthioV3-(^'3-r2-(undecylthio^,)l- pyridyDpropionic acid

3Ca) 2-CUndecylthioV3-(^'carbomethoxy^')pyridine

2-Mercapto-3-carboxypyridine (6.0 g, 0.39 M) is dissolved in 30 ml dry dimethylformamide and reacted with sodium carbonate (7.5 g, .054 M) and 1-bromoundecane (10.5g, .045 M) in essentially the same manner as Example 1(a).

After stirring for 2-1/2 hours at 100°, the reaction was cooled and poured into 400 ml of ice water. The solution was layered with ethyl acetate and adjusted to pH 2.0 and 2N HC1. The organic layer was separated and the aqueous was extracted twice with ethyl acetate. The combined organic extracts were washed, once with IN HC1, once with H2O, once with brine and dried over MgSθ4- Filtration and evaporation of this solution yielded a yellow solid. This solid was warmed and triturated with diethyl ether/hexane, cooled and filtered to yield the 2-(undecylthio)pyridine-2-carboxylic acid. The pyridine carboxylic acid prepared as above, 6.25 g, was dissolved in ethyl acetate/acetone and added dropwise to an excess of diazome thane in diethyl ether at 0°. Methanol was added to the ethereal solution to effect solubilization of the acid. After stirring 1/2 hour at 0°, the reaction was allowed to warm to room temperature. After 1-1/2 hour at room temperature, the solvent was evaporated jn vacuo and the oily residue was chromatographed over silica gel using the flash method (Baker Siθ2, 10% ethyl acetate/hexane.

3fl_Λ 3-Hydroxymethyl-2-undecylthiopyridine The compound of Example 3(a) (3.0g, 9.68 mm) was dissolved in methylene chloride and cooled to -78° under an argon atmosphere with stirring. A small amount of the ester precipitated at this low temperature. Di-isobutyl aluminum hydride (14.5 ml, 21.78 mm; 1.5 M in toluene) was added dropwise. The reaction was stirred at -78°C for 1/2 hour and placed in a freezer at -20°. After 16 hours the reaction was warmed to room temperature and stirred for 3 hours additional. Thin layer chromatography indicated all starting material had been consumed and one major new product formed (Siθ2, 30% ethyl acetate/hexane, uv+). 10% Aqueous sodium hydroxide (6 ml) was added dropwise. The reaction mixture was stirred 40 minutes at room temperature and filtered. The filter cake was washed with methylene chloride (2x) and the filtrate was washed with H2O (2x), brine (lx) and dried over MgS04. Filtration and evaporation of the solvent yielded a white solid which was essentially homogenous by thin layer chromatography. 3(c) S-Formyl^-fundecylthio ipyridine

The compound of Example 3(a) (2.0g, 7.2mm) was oxidized using the procedure of Example 1(c) using dimethyl sulfoxide (1.2 g, 1.1 ml, 15.6 mm), oxallyl chloride (.99 g, 68 ml, 7.8 mm) and triethylamine (3.58 g, 4.59 ml, 35.5 mm) in 100 ml methylene chloride. This yielded the titled compound. 3Cd) Methyl 2.3-epoxy-3-f3-[2-undecylthio1pyridyl )pτopanόate

The compound of Example 3(c) (1.55 g, 5.29 mm) was reacted with methyl chloroacetate (.84 g, .65 ml, 7.4 mm) and sodium methoxide (.337 g, 6.24 mm; 1.43 ml of 25% sodium methoxide in methanol) in 65 ml methylene chloride according to the procedure of Example 1(d). Flash chromatography (Baker Siθ2- 10% ethyl acetate/hexane) yielded the titled product. 3(e) Methyl 2-hvdroxy-3-C2-rcarborne.thoxylethylthioV3-G-r2- undecylthiolpyridyPpropanoate

The compound of Example 3(d) (1.6 g, 4.38 mm) was dissolved in 3 ml methanol and a solution of methyl-3-mercaptopropionate (1.05 g, 9.67 ml, 8.76 mm) and triethylamine (1.77 g, 2.45 ml, 17.52 mm) in 2 ml MeOH was added. The reaction mixture was stirred at room temperature under an argon atmosphere for 48 hours. The solvent was evaporated to yield an oil. The oil was flash chromatographed (Baker Siθ2, 15% ethyl acetate/hexane) to yield the desired isomer. 3 ^• 2-Hvdroxy-3-r2-carboxyethylthioV3-(^'3-r2-undecylthiol- pyridvDpropionic acid, dipotassium salt.

The compound of Example 3(c) (270 mg, .557 mm) was dissolved in 2.5 ml of methanol and potassium hydroxide (110 mg. 1.67 mm) in 1 ml water was added dropwise. The reaction was stirred at room temperature for 2 hours, the methanol was evaporated and the reaction mixture was diluted with water, washed with diethylether (2x), layered with ethyl acetate and acidified to pH 2.0 with dilute HC1. The organic layer was separated and the aqueous was extracted with ethyl acetate (2x). The combined organic extracts were washed with water (lx), brine (lx) and dried over MgSθ4. This material was flash chromatographed (Baker Siθ2, 3.5% methanol/chloroform - 3.5% trifluoroacetate acid) to yield an oil. The oil was further dissolved in 1 ml H2O and treated with 230 mg (8 eq) of potassium hydrogen carbonate. The resulting solution was applied to a column of octadecyl silane silica gel (Baker ODS) and eluted sequentially with water (200 ml), 60% methanol/H2θ (125 ml) and 70% methanol/H2θ(100 ml).

The fractions containing the desired material which eluted with 60% methanol/water, were combined, evaporated under vaccum to a small volume, reconstituted with water and lyophilized to yield white hygroscopic powder. 1H-NMR of free acid at 250 MHZ (CDCI3 REF=TMS-0): δ 8.38 (d of d, lp), 8.15 (broad s, 4p; OH's), 8.0 (d of d, lp), 7.08 (d of d, lp), 4.73 (d, lp), 1.53-1.75 (m, 2p) 1.05-1.50 (broad m, 18p).

Example 4 2-Hvdτoxy-3- ( 3-r2-(8-phenyloctvnipyridyl ) -3-f 2- carboxyethylthio)propionic Acid 4Ca) Methyl 2.3-epoxy-3-f 3-r2-C8-phenylocty1^>)lpyridvU propionate. To a solution of 2-(8-phenyloctyl)-3-formylpyridine (0.92 g, 3.1 mmol) in methylene chloride (9 mL) was added methyl chloroacetate (0.47 g, 4.4 mmol). The solution was then cooled to -15°C and kept under an argon atmosphere. Sodium methoxide (0.84 mL of 25 wt. % in methanol, 3.1 mmol) was added dropwise and stirring was continued for 5 min at -15°C. After warming to room temperature and stirring for 2 hours, a pH 7 buffer solution was added to the reaction mixture. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic extract was washed successively with H2O, 5% aqueous NaHCθ3 and brine and dried (MgSθ4). The solvent was removed in vacuo, and the residue was purified by flash chromatography eluting with 30% ethyl acetate/petroleum ether to afford the desired epoxide. 4fb Methyl 2-hvdroxy-3-(3-[2-f8-phenyloctvnipyridvn -3-(^'2- carbomethoxyethylthio)propionate

Methyl 2,3-epoxy-3-{3-[2-(8-phenyloctyl)]pyridyl}propionate (0.64 g, 1.7 mmol) was dissolved in methanol under an argon atmosphere. To this was added a solution of methyl 3-mercaptopropionate (0.42 g, 3.5 mmol) and triethylamine (0.7 g, 7.0 mmol) in methanol. The resulting solution was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dissolved in CH2CI2 and washed successively with H2O, 5% aqueous NaHC03 and saturated aqueous NaCl and dried (MgSθ4). The solvent was removed under reduced pressure, and the residue was purified by HPLC to afford the desired alcohol. CIMS , isobutane (m/e) : 488 (M+H). -\(c) 2-Hvdroxy-3-f 3-r2-f8-phenyloctvmpyridvn-3-(2- carboxyethylthio^propionic acid, dipotassium salt. To a solution of methyl 2-hydroxy-3-{3-[2-(8- phenyloctyl)]pyridyl} -3-(2-carbomethoxyethylthio)propionate (120 mg, 0.3 mmol) in methanol (12 mL) under an argon atmosphere was added dilute aqueous KOH, and the resulting mixture was stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure, and the residue was partitioned between H2O and ethyl acetate. The organic extract was washed with H2O and dried (MgSθ4). The solvent was removed in vacuo, and the residue was triturated with methylene chloride. The solid which precipitated was filtered and washed with diethyl ether to afford the diacid. FAB MS (m/ e) : 460.2 (M+H). Example 5

3- { 3-[2-(8-Phenyloctyl)]pyridyl } -3-(2-carboxyethylthio)- propionic Acid 5(a) Methyl 2-Cyano-5-methoxypentadienoate.

To a solution of malonaldehyde bis(dimethyl acetal) (24.6 g, 0.149 mol) in acetic anhydride (50 mL) was added ZnCl2 (0.14 g, 0.001 mol). After heating the resulting mixture at reflux, methyl cyanoacetate (9.9 g, 0.10 mol) was added dropwise, and the reaction mixture was heated at reflux overnight. The mixture was allowed to cool to room temperature, filtered and concentrated under reduced pressure. The semi-solid residue was triturated with diethyl ether/petroleum ether. The solid was removed by filtration, dissolved in ether and decolorized. Removal of the solvent under reduced pressure yielded a semi-solid residue^" which was triturated with ditehyl ether/petroleum ether to provide the desired product, m.p. 95 - 97⁰C. 5(b) 2-Bromo-5-carbomethoxypyridine.

A solution of methyl 2-cyano-5-methoxypentadienoate (1.6 g, 9.58 mmol) in acetic acid (8 mL) under an argon atmosphere was warmed to 40° C, and acetic acid (16 mL) saturated with HBr was added dropwise, maintaining the temperature at 40° C. Following the addition the reaction mixture was heated to 50° C for 30 min and then allowed to cool to room temperature. The solid which precipitated was filtered, washed with ether and treated with 5% aqueous Na2Cθ3. The oil which separated was dissolved in diethyl ether, washed with H2O and dried. After treating with decolorizing charcoal, the solvent was removed in vacuo to provide an amber oil . 5(c l-Phenyl-1.7-octadiyne.

A solution of phenylacetylene (3.19 g, 31.3 mmol) in tetrahydrofuran (63 mL) under an argon atmosphere was cooled to - 5°C, and n-butyl lithium (12.5 mL of 2.5 M solution, 31.3 mmol) was slowly added, followed by HMPT in tetrahydrofuran. To the resulting dark purple solution was added at 0°C, l-hex-5-ynyl-p- toluenesulfonate (7.9 g, 31.3 mmol) in tetrahydrofuran (32 mL). The resulting solution was stirred at 0°C for 1 hour, allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into H2O and extracted with ether. The organic extract was dried (MgSθ4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 15% diethyl ether/petroleum ether to provide the desired material. 5(d) 2-(8-Phenylocta-1.7-diynyl)-3-carbomethoxypyridine.

To a solution of 2-bromo-3-carbomethoxypyridine (3.5 g, 17.3 mmol) and l-phenyl-l,7-octadiyne (2.5 g, 13.7 mmol) in triethylamine (50 mL) were added bis(triphenylphosphine)palladium chloride (0.19 g, 0.27 mmol) and copper iodide (26 mg, 0.14 mmol). The resulting mixture was heated at 80° C under an argon atmosphere for 2 hours and allowed to cool to room temperature. The solvent was removed in vacuo, and diethyl ether was added to the residue. After treatment with decolorizing charcoal, the solvent was removed in vacuo, and the residue was purified by flash chromatography eluting with 30% diethyl ether/petroleum ether to provide the desired product.

5(e) 2-(8-Phenyloctyl)-3-carbomethoxypyridine. To a solution of 2-(8-phenylocta-l,7-diynyl)-3- carbomethoxypyridine (1.0 g, 3.1 mmol) in ethyl acetate (50 mL) was added 10% palladium on activated carbon (0.2 g). The resulting mixture was purged with argon and then stirred under hydrogen at atmospheric pressure for 15 min. The mixture was filtered and concentrated under reduced pressure to provide the desired product. 5(e) 2-f 3-r2-(8-Phenyloctyl)1 ) -3-hvdroxymethylpyridine.

To a solution of 2-(8-phenyloctyl)-3-carbomethoxypyridine (1.0 g, 3.1 mmol) in toluene (20 mL) at -78°C under an argon atmosphere was added dropwise DiBAL (12.3 mL of 1M solution, 12.3 mmol). The resulting mixture was stirred at -78° C for 1 hour, then allowed to warm to room temperature and stirred for several hours. Methanol was slowly added, and the mixture was stirred an additional 15 min. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in CH2CI2 and dried (MgSθ4). Removal of the solvent provided the alcohol which was used without further purification. 5(d) 2-(8-Phenyloctyl)-3-formylpyridine.

To a solution of 2-{3-[2-(8-phenyloctyl)] } -3- hydroxymethy lpyridine prepared above in methylene dichloride (30 mL) was added Mnθ2 (8~g), and the resulting mixture was stirred at room temperature under an argon atmosphere for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether and treated with decolorizing charcoal. The solvent was removed in vacuo and azeotropically treated with toluene (2x) to provide the desired aldehyde. 5(f) f-Butyl 3-hvdroxy-3- f 3-[2-(8-phenyloctyl)1pyridyl ) propionate.

To a solution of di-isopropyl amine (0.36 g, 3.6 mmol) in tetrahydrofuran (5~mL) at -78°C under an argon atmosphere was added dropwise n-butyl lithium (1.42 mL of 2.5 M solution, 3.6 mmol), and the resulting solution was stirred for 5 min. A solution of f-butyl acetate (0.41 g, 3.6 mmol) in tetrahydrofuran (5 mL) was added dropwise. After stirring at -78°C for 1 hour, a solution of 2-(8- phenyloctyl)-3-formylpyridine (0.7 g, 2.4 mmol) in tetrahydrofuran (5 mL) was added dropwise. The mixture was stirred at -78°C for 1 hour, then allowed to warm to room temperature and stirred overnight. Saturated aqueous NH4CI was added, and the mixture was extracted with diethyl ether. The organic extract was washed with H2O and dried. Removal of the solvent in vacuo provided the desired material. 5(g) f-Butyl 3-(3-r2-(8-phenyloctyl)1pyridyl ) cinnamate.

To a solution of f-butyl 3-hydroxy-3- [3-[2-(8-phenyloctyl)]- pyridyl} propionate (0.5 g, 1.2 mmol) and triethylamine (0.38 g, 3.6 mmol) in CH2CI2 (10 mL) at -10°C under an argon atmosphere was added dropwise methanesulfonyl chloride (0.21 g, 1.8 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 48 hours The solvent was removed in vacuo. The residue was dissolved in CH2CI2, washed successively with H2O, 3 N HC1 and H2O and dried (MgS04). Removal of the solvent in vacuo provided the epoxide.

5(h) r-Butyl 3-f 3-r2-(8-phenyloctylϊlpyridyl) -3-(2- carbomethoxythio)propionate.

To a solution of t-butyl 3-{3-[2-(8-phenyloctyl)]pyridyl}- cinnamate (0.4 g, 1.0 mmol) and methyl 3-mercaptopropionate (0.7 g, 5.9 mmol) in methanol (5 mL) at 0°C was added triethylamine (1.19-g, 11.8 mmol). The resulting solution was allowed to warm to room temperature and stirred under an argon atmosphere overnight. The solvent was removed in vacuo. The residue was d-ssolved in CH2CI2, washed with H2O and dried. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with 20% ethyl acetate/hexanes to provide the mixed ester. 5(i) 3-f 3-r2-(8-Phenyloctyl)1pyridvn -3-(2-caτboxyethylthio)- propionic acid, dipiperazine salt.

A solution of f-butyl 3- {3-[2-(8-phenyloctyl)]pyridyl} -3-(2- carbomethoxyethylthio)propionate (0.4 g, 0.8 mmol) in 3 N HC1 (20 mL) was heated to reflux overnight. The solution was concentrated under reduced pressure, and the residue was azeotropically treated with toluene (2x). The residue was dissolved in methanol and dried. The solvent was removed in vacuo , the residue was dissolved in isopropyl alcohol and treated with 1 M piperazine. The mixture was stirred for 2 hours at room temperature and filtered to provide a fine white powder which was recrystallized from isopropyl alcohol. FAB MS (m/z) : 444 (M+H).

Example 6 2-Methoxy-3-r4-carboxyphenylthio1 -3- f 3-r2-(7- phenylheptvPthiolpyridyl . propionic acid

6a) 2.3-Epoxy-3-(3-r2-(7-phenylheptyl)thio1pyridvπ -ρropionamide.

To a saturated solution of ammonia in ethanol (50 mL) at -20°C was added dropwise a solution of methyl 2,3-epoxy-3-{3-[2-(7- phenylheptyl)thio]pyridyl}propanoate (2.0 g, 5.2 mmol) in benzene (5 mL). The resulting mixture was allowed to slowly warm to room temperature and stirred overnight. The solvent was removed in vacuo to provide a white solid which was used without further purification.

6(b) 2-Hvdroxy-3-r4-(carbomethoxyl)phenylthio1 -3- f 3-[2-(7- phenylheptvDthiolpyridyl ) -propionamide. To a solution of 2,3-epoxy-3-{3-[2-(7- phenylheptyl)thio]pyridyl} propionamide (0.54 g, 1.5 mmol) in THF (10 mL) at -10°C under an argon atmosphere was added titanium isopropoxide (1.46 g, 5.1 mmol), followed by the dropwise addition of a solution of methyl 4-mercaptobenzoate (0.37 g, 2.2 mmol) and NaH (10 mg of a 50% oil dispersion, 0.21 mmol) in THF (5 mL). The resulting mixture was stirred at 0°C for 90 min, then partitioned between Et2θ and saturated aqueous^" Na2S04 and filtered through Celite. The organic phase was dried (MgSθ4) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel), eluting with Et2θ to afford a glassy solid.

90 MHz NMR (CDCI3) : δ 8.25 (dd, IH, J = 4 Hz, J = 1 Hz); 7.95 (dd, IH, J = 7 Hz, J = 1 Hz); 7.85 (d, 2H, J = 8 Hz); 7.35 (d, 2H, J = 8 Hz); 7.20 (br s, 5H); 6.88 (dd, IH, J = 9 Hz, J = 3 Hz); 6.50 (br s, IH); 6.08 (br s, IH); 5.28 (d, IH, J = 3 Hz); 4.70 (d, IH, J = 6 Hz); 4.50 (dd, IH, J = 6 Hz, J = 3 Hz); 3.82 (s, 3H); 3.18 (m, 2H); 2.54 (t, 2H, J = 7 Hz); 1.80 - 1.20 (m, 10H).

6(c) Methyl 2-hvdroxy-3-r4-(carbomethoxyl)phenylthio1-3- f 3-T2-(7- phen ylheptyPthiol -pyridyl Ipropanoate. 3-[4-(carbomethoxyl)phenylthio]-2-hydroxy-3- { 3-[2-(7- phenylheptyl)thio]pyridyl} propionamide (0.44 g, 0.8 mmol) in methanol (100 mL) was treated with 25% aqueous HCl (5 mL), and the resulting solution was heated to reflux overnight. Potassium carbonate was added; the mixture was decanted and concentrated under reduced pressure. The residue was partitioned between EtOAc and 5% aqueous NaHC03. The organic phase was washed with saturated aqueous NaCl and dried (MgSθ4). Removal of the solvent in vacuo provided a colorless oil. 90 MHz NMR (CDCI3) : δ 8.20 (d, IH, J = 4 Hz); 7.90 (m, 2H);

7.50 - 6.80 (m, 9H); 5.20 (d, IH, J = 5 Hz); 4.60 (d, IH, J = 3 Hz); 3.80 (s, 3H); 3.65 (s, 3H); 3.20 (m, 2H); 2.60 (t, 2H, J = 5 Hz); 1.80 - 1.20 (m, 10H). 6(d) Methyl 2-methoxy-3-r4-(carbomethoxyl)phenylthiol-3-( 3-r2- (7-phenylheptyl)thio1 -pyridyl ) propanoate.

To a solution of methyl 3-[4-(carbomethoxyl)phenylthio]-2- hydroxy-3-[3-[2-(7-phenylheptyl)thio]pyridyl}propanoate (0.10 g, 0.18 mmol) in 1:10 DMF/THF (4.5 mL) at 0°C under an argon . atmosphere was added NaH (17 mg of 50% oil dispersion, 0.36 mmol), followed by methyl iodide (23 μL, 0.36 mmol). The resulting solution was allowed to warm to room temperature and stirred overnight. The solution was concentrated in vacuo, and the residue was partitioned between H2O and CH2CI2. The organic phase was dried (MgSO- and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel) eluting with 10% Et2θ/ hexanes provided a colorless oil.

90 MHz NMR (CDCΪ3) : δ 8.3tf (dd, IH, J = 5 Hz, J = 1 Hz); 7.80 (m, 2H); 7.30 (d, IH, J = 8 Hz), 7.20 (br s, 5H); 6.90 (dd, IH, J = 7 Hz, J = 4 Hz); 5.20 (d, IH, J = 5 Hz); 4.20 (d, IH, J = 5 Hz); 3.87 (s, 3H); 3.65 (s, 3H); 3.40 (s, 3H); 3.20 (m, 2H); 2.60 (t, 2H, J = 7 Hz); 1.90 - 1.20 (m, 10H).

6(e) 2-Methoxy-3-r4-carboxyphenylthiol-3- . 3-r2-(7- phenylheptyDthiolpyridyπpropionic acid.

A solution of methyl 3-[4-(carbomethoxyl)phenylthio]-2- methoxy-3-{3-[2-(7-phenylheptyl)thio]pyridyl} propanoate (70 mg, 0.14 mmol) and NaOH (32 mg, 0.80 mmol) in 1 :1 H2O/ CH3OH (2 mL) was allowed to stir at room temperature for 36 hours. The solution was concentrated in vacuo to remove CH3OH, and the pH was adjusted to 3-4 with 3 N HCl. The resulting precipitate was collected by filtration and dried. The amorphous solid (60 mg) was treated with piperazine (1 eq), yielding a white solid, m.p. 182°C .

90 MHz NMR (CDCI3) : δ 8.42 (dd, IH, J = 5 Hz, J = 1 Hz); 7.90 (m, 2H); 7.50 (d, IH, J = 8 Hz); 7.25 (br s, 5H); 7.20 (m, 3H); 5.32 (d, IH, J = 6 Hz); 4.30 (d, IH, J = 6 Hz); 3.45 (s, 3H); 3.23 (t, 2H, J = 6 Hz); 2.58 (t,^' 2H, J = 7 Hz); 1.90 - 1.20 (m, 10H).

Example 7 2-Hvdroxy-3-r4-(carboxyρhenyl)thiol-3- ( 3-r2-(7- phenylheptyPthiolpyridyl Ipropionic acid.

7(a) 2-Hvdroxy-3-r4-(carboxyphenyl)thio1-3- f 3-r2-(7- phenylheptyDthiolpyridyl Ipropionic acid.

A solution of methyl 3-[4-(carbomethoxyl)phenylthio]-2- hydroxy-3-{3-[2-(7-phenylheptyl)thio]pyridyl}propanoate (0.12 g, 0.2 mmol) and NaOH (40 mg, 1.0 mmol) in 1 : 3 H2O/ CH3OH (4 mL) was allowed to stir at room temperature for 36 hours. The solution was concentrated in vacuo, and the pH was adjusted to 3-4 with 3 N HCl. The mixture was extracted with CHCI3 (2x), and the combined organic extracts were dried (MgSO_ . Removal of the solvent in vacuo provided a glassy solid.

90 MHz NMR (CDCI3) : δ 8.40 (dd, IH, J = 6 Hz, J = 1 Hz); .8.00 - 7.00 (m, 11H); 5.20 (d, IH, J = 7 Hz); 4.70 (d, IH, J = 7 Hz); 3.30 (t, 2H, J = 8 Hz); 2.60 (t, 2H, J = 8 Hz); 1.90 - 1.20 (m, 10H).

Treatment of the above material with piperazine (1 eq) provided a salt. m.p. 204 - 6°C .

Example 8 2-(4-Carboxyphenoxy)-2-[3-(2-undecylthio)pyτidyl] acetic acid 8(i) methyl 2-chloro-2-[3-(2-undecylthio)pyridylacetate. The title compound is prepared from 3-formyl-2- (undecylthio)pyridine [3(c)] following the procedure given in U.S. Patent No. 4,820,719 for the preparation of methyl 2-chloro-2-(2- dodecylphenyl)acetate from 2-dodecylbenzaldehyde. ^{• •} 8(ii) 2-(4-Carboxyphenoxy)-2-r3-(2-undecylthio)pyridyllacetic acid. The title compound is prepared from methyl 2-chloro-2-[3-(2- undecylthio)pyridylacetate by reaction with methyl

4-hydroxybenzoate and potassium carbonate in dimethylformamide followed by saponification of the diester.

Example 9 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.

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

Tablets

Ingredients Per Tablet Per 10.000 Tablets

1. Active ingredient

(Cpd of Form. I) 40.0mg 400. Og

2. Corn Starch 20.0mg 200. Og 3. Alginic acid 20.0mg 200. Og

4. Sodium alginate 20.0mg 200. Og

5. Mg stearate 1.3 mg 13. Og

101.3 mg 1013. Og

Procedure for tablets:

Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender. Step 2 Add sufficient water portion-wise 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. 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 110°F

(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.

Suppositories:

In gredients Per Supp. Per 1000 Supp.

1. Formula I compound 40.0 mg 40 Og Active ingredient

2. Polyethylene Glycol 1350.0 mg 1,350 Og 1000

3. polyethylene glycol

4000 450.0 mg 450 Og 1840.0 mg 1,840 Og

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. Step 3. Pour the molten mass from Step 2 into supository moulds and chill. Step 4. Remove the suppositories from moulds and wrap.

Claims

What is claimed is:

1. A compound of formula (I)

where neither of the two pyridyl substituents are substituted on the pyridyl nitrogen, or a pharmaceutically acceptable salt thereof wherein

X is O or S(0)q where q is 0, 1 or 2 with the proviso that Ri is not alkylthio or phenylthioalkyl when q is 1 or 2;

Rj is Cδ to C13 alkyl, Cη to Cj2 alkoxy, Cη to C12 alkylthio, Ci rj to C12 1-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to C10 alkyl, phenyl-C3 to C9 alkoxy, phenylthio-C3 to C9 alkyl with each phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, Ci to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to Cχo alkyl, trifluoromethyl-Cγ to C12 alkyl or cyclohexyl- C4 to Cχo alkyl;

Y is R2, CH(R3)(CH2)_mR2- CH(R3)-tetrazol-5-yl, or tetrazol-5-yl;

R2 is -COR4 where R4 is -OH, -OE where E is a pharmaceutically acceptable cation or a pharmaceutically acceptable ester-forming group, -CN, -SO3H, -SO2NH2, -NHSO2R6, -CH(NH₂)COR , or -CONHCH2COR4, or R₂ is -CON(Rs)2 where R5 is H, Ci to CO alkyl, phenylCi-Cβalkyl, or the two R5 groups are combined to form a cyclic group having 3 to 5 carbons;

R3 is hydrogen, methyl, C\ to C4 alkoxy, fluoro or hydroxy;

R6 is Ci to Cio-alkyl, phenyl or substituted phenyl; m is 0, 1, or 2;

R is -(CH2)_nD_> -(CH2)_nArD where n is 0-6, Ar is phenyl or substituted phenyl, thienyl, pyridyl, imidazolyl, tetrazol-5-yl or thiazolyl and D is -(CH2)ιR2. where 1 is 0-3, or tetrazol-5-yl.

2. A compound of claim 1 where X is S or S(0)2.

3. A compound of claim 2 where R is -(CH2)_nD where n is 1 or 2, Y is -COR4 or -CH(R₃)(CH2)_mCOR4 where m is 0 or 1 and R3 is -OH or H.

4. A compound of claim 3 which is 2-hydroxy-3-(2- carboxyethylthio)-3-[2-(3-(7-phenylheptylthio))pyridyl]propionic acid or a pharmaceutically acceptable salt thereof.

5. A compound of claim 3 which is 2-hydroxy-3-(2- carboxyethylthio)-3-[3-(2-(7-phenylheptylthio)pyridyl]propionic acid or a pharmaceutically acceptable salt thereof.

6. A compound of claim 3 which is 3-(2-carboxyethylthio)-3- [3-(2-(8-phenyloctyl))pyridyl]propionic acid or a pharmaceutically acceptable salt thereof.

7. A compound of claim 3 which is 2-hydroxy-3-(2- carboxyethylthio)-3-[2-(3-(8-phenyloctyl))pyridyl]propionic acid, 2- hydroxy-3-(2-carboxyethylthio)-3-[2-(3-(8-phenyloctyl))- pyridyl] propionic acid, or a pharmaceutically acceptable salt thereof.

8. A compound of claim 3 which is 3-(2-carboxyethylthio)-3- [2-(3-(8-phenyloctyl))pyridyl]propionic acid, 3-(2-carboxyethylthio)- 3-[3-(2-(8-phenyloctyl))pyridyl]propionic acid, or a pharmaceutically acceptable salt thereof.

9. A compound of claim 3 which is 2-hydroxy-3-(2- carboxyethylthio)-3-[3-(2-(undecylthio)pyridyl]propionic acid or a pharmaceutically acceptable salt thereof.

10. A compound of claim 1 where R is -(CH2)_nArD where n is 1 or 2 and Ar is phenyl, and Y is -CH2(R3)COR4 where R3 is H, OH or methoxy.

11 A compound of claim 10 which is 2-hydroxy-3-(4- carboxyphenylthio)-3-[3-(2-(8-phenyloctyl))pyridyl]propionic acid, 2- hydroxy-3-([4-carboxy-2-fluorobenzyl]thio)-3-[3 -(2-(8- phenyloctyl)pyridyl]propionic acid, 2-methoxy-3-[4- (carboxyphenyl)thio]-3- {3-[2-(7-phenylheptyl)thio]pyridyl } propionic acid, 2-methoxy-3-(4-carboxybenzylthio)-3-[3-(2-(8- phenyloctyl)pyridyl]propionic acid, 2-hydroxy-3-[4- (carboxyphenyl)thio] -3- { 3 -[2-(7-phenylheptyl)thio]pyridyl ] propionic acid, or a pharmaceutically acceptable salt thereof.

12. A compound of claim 1 where X is O, Y is COR4 or

CH(R3)(CH2)_mCOR4 where R3 is H or -OH and m is 0 or 1, and R is -(CH2)_nD- or -(CH2)_nArD where n isl or 2.

13. A compound of claim 12 which is 2-hydroxy-3-(2- carboxyethyloxy)-3-[3-(2-(8-phenyloctyl))pyridyl]propionic acid or 2-hydroxy-3-(2-carboxyethyloxy)-3-[2-(3-(8-phenyloctyl))- pyridyl] propionic acid, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

15. A composition of claim 14 in a form suitable for administration orally, parenterally, topically or by inhalation.

16. A composition of claim 14 which contains an Hi blocker.

17. A pharmaceutical composition for inhibiting antigen- induced respiratory anaphylaxis comprising a pharmaceutical carrier or diluent and nontoxic amounts sufficient to produce said inhibition of a compound of claim 1 and an histamine Hj -receptor antagonist.

18. A method of treating a disease in which leukotrienes are a factor which method comprises administering to a subject in need thereof an effective amount of a compound of claim 1 alone or in combination with a pharamceutically acceptable excipient.