CA2089728A1 - Pyridylthio or pyridyloxy alkanoic acids - Google Patents

Pyridylthio or pyridyloxy alkanoic acids

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Publication number
CA2089728A1
CA2089728A1 CA002089728A CA2089728A CA2089728A1 CA 2089728 A1 CA2089728 A1 CA 2089728A1 CA 002089728 A CA002089728 A CA 002089728A CA 2089728 A CA2089728 A CA 2089728A CA 2089728 A1 CA2089728 A1 CA 2089728A1
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Prior art keywords
pyridyl
compound
propionic acid
phenyloctyl
hydroxy
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Abandoned
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CA002089728A
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French (fr)
Inventor
James S. Frazee
John G. Gleason
Ralph F. Hall
Charles M. Kinzig
Irene N. Uzinskas
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SmithKline Beecham Corp
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Individual
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

This invention relates to alkanoic acid compounds having pyridyl and arylthio or alkylthio substituents, or their oxygen analogs, which are useful as leukotriene antagonists.

Description

WO 92/051~6 2 0 8 9 7 2 ~ Pcr/usg1/o6q94 PYRIDYLTHIO or PYRIDYLOXY ALKANOIC ACIDS
BACKGROUND OF T~ ~VEN I`ION
Scope of the Invention This invention relates to certain substituted pyridyl alkanoic acids and their derivatives which are leukotriene antagonists and thus useful in ~reating diseases caused by or involving leukotrienes.
Detailed Background of ~e Tnvention "Slow Reacting Substance of Anaphylaxis'l (SRS-A) has been 10 shown to be a highly potent bronchoconstric~ing substance which is released primarily from mast cells and basophils on an~igenic 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 15 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
2 0 arachidonate metabolites. SRS-A derived from mouse, rat, guinea pig and man have all been characteri~ed as mixtures of leukotriene-C4 (LTC4), leukotriene-D4 (LTI:)4) and leukotriene-E4 (LTE4).
Leukotrienes are a group of eicosanoids formed ~rom arachidonic acid metabolism via the lipox~genase pathway. These 25 lipid derivatives originate from LTA4 and are of two types: (1) those con~aining a sul~ldo- peptide side chain (LTC4, LTD4, and LTE4), and (2) those that are nonpeptidic (LTB4). I,eukotrienes comprise a group of naturally occurring substances that have the potential to contribute significantly to the pathogenesis of a variety of inflammatory and
3 0 ischemic disorders. The pathophysiological role of leukotrienes has been the focus of recent intensive studies.
As summarized by Left, A.M., Biochemical Pharmacolo~y, 35, 2, I23-127 (1986) both the peptide and non-peptide leulcotrienes exert microcirculatory actions, promoting leakage of fluid across the 3 ~ 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 ~he endothelial membrane.
LTC4, LTD4 and LTE4 s~imulate a variety of types of muscles. LTC4 and LTD4 are potent bronchoconstrictors and effective stimulators of Wo 92/05156 Pcr/ussl/o6~94 208972~ ~ 2 -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. etal., 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, ~. et al., Am. ReY.
Respir. Dis., 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 chailenge 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, 2~, 1626-1629 (1984).] This suggests that allergic rhinitis is another area of utility for leukotriene antagonists.
2 0 Leukotrienes have also been directly or indirectly implicated in a Yariety 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 2 5 treatment of cardiovascular diseases. Since peptide leukotrienes are potent coronary vasoconstrictors, they are implicated in a variety of cardiac disorders including alThythmias, conduction blocks and cardiac depression. Synthetic leuko~rienes have been shown to be powerful myocardial depressants, their effects consiseing 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 ~eukotriene antagonists in the areas of myocardial depression and cardiac anaphylaxis. [See Burke, J.A., etal., J. Pharmacologv 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 208972~ I
WO 92/0s1~6 Pcr/ussl/o6494 . !
abolished by a s~ecific leukotriene antagonist. [See Badr, K.R. et al., ~rculation Research, 54, 5, 492-4~9 (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 S renal injury. [See Badr, K.F., etal., 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. etal., _dnev Internationa1, 29, 1, 328 (1986).] LTC4 has been demonstrated to contract rat glomerular mesangial cells in culture and thereby ef~ect intraglomerular actions to reduce filtration surface area.~See Dunn, M.J. et al., Kidney Tn-ternational, 27, 1, 256 (1985).] Thus another area of utility for leulcotriene 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. etal.9 Prostaglandins LeukotriQnes and Medicine, 21, 321-322 ~1986).] Leukotrienes can also be important mediators of inflammation in inflammatory bowel disease. [See Peskar, B.M. etal., A~ents and Actions, 18, 381-383 2 0 (1986).] Leukotriene antagonists thus can be useful in the treatment of inflammatory liver and bowel disease.
Other areas in whi~h leukotriene antagonists can-have utility because leukotrieDes are indicated as mediators include prevention of premature labor [See Clayton, J.K. etal., Proceedirl~s of the BPS, 573P, 17-19 Dec. 1984]; treatment of migraine headaches [See Gazzaniga, P.P. et al., Abstracts Tnt'l Conf. on Prosta~landins and Related Comp., 121, Florence, ltaly (June 1986)~; and treatment of gallstones [See Doty, J.E. etal., Amer. J._of SurgerY, 145, 54~61 (1983) and Marom, Z.
etal., Amer. Rev. Re~pir. Dis., 126, 449-451 (19~2).
3 0 By antagoni~ing the effects of LTC4, LTD4 and LTE4 or other pharmacologically active mediators at the end organ, for example, airway smoo~h muscle, the compounds and pharmaceutical composi~ions of the instant invention are valuable in the treatment of diseases in subjects, including human or animals, in which 3 5 leukotrienes are a key factor.
SUMMARY OF THE ~VENTTON
This invention relates to compounds of forrnula (I):

wo 92/05156 Pcr/us91/o6494 20~9728 - 4 ~ -x ,R

R
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(O)q where q is 0, 1 or 2 with the proviso that R1 is not alkylthio or phenylthioalkyi when q is 1 or 2;
Rl is C~ to C13 alkyl, C7 to C12 alkoxy, C7 to C12 alkylthio, Clo to C12 1-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to C1o alkyl, phenyl-C3 to Cg alkoxy, phenylthio-C3 to Cg alkyl, phenyl-C3 to C g alkylthio with` each phenyl optionally mono substituted with bromo, chloro, trifluorome~hyl, Cl to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to Clo alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl-C4 to Clo alkyl;
Y is R2, CH(R3)(CH2)mR2, CH(R3)-tetrazol-5-yl, or tetra~ol-S-yl;
R2 is -COR4 where R4 is -OH, -OE where E is a pharrnaceutically acceptable cation or a pharmaceutically acceptable ester-forming group, -CN, -SO3H, -S02NH2, -NHS02R6, -CH(NH2)COR4, or -CONHCH2COR4, or R2 is -CON(Rs)2 where Rs is H, Cl to C6 alkyl, phenylCl-C6alkyl, or the two Rs groups are combined to form a cyclic 2 0 group having 3 to 5 carbons;
R3 is hydrogen, methyl, Cl to C4 alkoxy, fluoro or hydroxy;
R6 is Cl to Clo-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 2 5 substitu~ed phenyl, thienyl, pyridyl, imidazolyl, tetrazol-S-yl or thiazolyl and D is -(CH2)1R2, 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 3 0 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 H
3 5 blocker may also be present in this composition.

wo 92/05156 2 0 8 9 7 2 ~ P~USg!~06494 A method of treating a disease in which leukotrienes are a factor which method comprises administering ~o a subject in need thereof an effective amount of a compound of clairn 1 alone or in combination with a pharamceuticall y acceptable excipient.
S DETAILED DESCRIl'TIQN OF THE INVEN~ON
- The ~ollowing descrip~ions 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 10 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 irnpart to the parent acid any unacceptable un~oward pharmacological or toxic effects in the context of its intended use and application. While it is expected 15 that any carboxylic acid ester may be used, it is preferred ~o employ certain esters deriYed from the following radicals: Cl to C6 alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl.
2 0 The compounds of the present invention, depending on ~heir atomic components, are capable of forming pharmaceutically acceptable salts wi~h acids and bases according to procedures well known in the art. Such salts are those which match the activity of ~he parent compound and do not exhibit untoward or deleterious activity.
2 5 Acceptable acids include inorganic and organic acids, such as hydrochloric, sulfllric, methanesulfonic, benzenesulfonic, p-toluenesulfonic acid and acetic acid. Bases iDclude organic and inorganic bases, such as ammonia, arginin, organic amines, alkali metal bases and alkaline earth metal bases. Piperazine and 3 0 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).
Pharrnaceutically acceptable cations are the same as the just recited base-derived pharmaceutically acceptable salts.
3 5 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)nArD

WO 92/05t56 Pcr/uss1/o6494 20~97~
where n is 0 or 1 and Ar is phenyl or tetrazol-5-yl. .For each of these sub-groups, the preferred R1 groups are C7 to C12 alkyl~hio, C8 to C13-alkyl, phenyl-C3 to Cg-alkylthio and phenyl-C4 to Clo-alkyl.
The more preferred compounds are exemplified by the following 5 compounds:
3-(2-carboxyphenylthio)-3-[3-(2-(8-phenyloctyl))pyridyl]-propionic acid;
3-(2-carboxyphenylthio)-3-[3-(2-(8-phenyloctyl))pyridyl] -2-hydroxypropionic acid;
1 0 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-f2-(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;
2 0 3-(4-carboxy-2-methoxyphenylmethylthio)-3-[3-(2-(6-phenyloxyhexyloxy))pyridyl]propionic acid;
3-(2-carboxyethylthio)-3 -~3 -(2-(7-phenylheptylthio))pyridyl] -propionic acid;
3-(2-carboxyethylthio)-3 -[3-(2-(7-phenylheptyloxy))pyridyl] -2 ~ 2-hydroxypropionic acid;
3-(2-carboxyethylthio)-3-[3-(8,8,8-~riMuorooctyl))pyridyl] -propionic acid;
2-hydroxy-3-(5-tetrazolylmethylthio)-3-[3 -(2-(8-phenyloctyl))pyridyl]propionic acid;
3 0 3-(~-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))-3 5 pyridyl]propionic acid;
2-hydroxy-3-([4-carboxy-2-fluorobenzyl]thio)-3-[3-(2-(8-phenyloctyl))pyridyllpropionic acid;
3-(3-carboxymethylthio)-3-[3-(2-(8-phenyloctyl))-pyridyll -~ -hydroxypropionic acid;

WO 9~/051s6 Pcr/uss1/o6494 ~ 20~972~ - 7 ~

3-(~ -tetrazolylmethylthio)-3-[3 -(2-(8 ,8.,8~trifluorooctyl))-pyridyl]-2-methoxypropionic acid;
2-hydroxy-3 -(4-carboxy-2-methoxyphenylmethylthio)-3 - ~3 -(2-( l 0, l 0,1 0-trifluorodecyloxy~)pyridyl] propin oic ac id;
2-hydrox-3-(4-carboxyphenylmethylthio)-3-[3-(2-(4,4,4-- trifluorobutylthio))pyridyl]ypropionic acid;
2-hydroxy-~ -fluoro-4-carboxyphenylmethylthio)-3-[3-(2-(8-phenyloctyl))p~yl]propionic acid;
2-methoxy-3.-(4-carboxyphenylthio)-3-[3-(2-(6-- 1 û 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;
l 5 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 2 0 acid;
2-(3 -carboxyphenylmethylthio)-2-[3-(2-(7 -phenyl-heptylthio))pyridyl]acetic acid;
2-(carboxymethylthio)-2-[3-(2-(7-phenylthioheptylthio3-pyridyl]acetic acid;
2 5 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] -3 0 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 fonnula (I) where D is O or S()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 presen~ invention includes all such stereoisomers, racemates, or mixtures thereof.

WO 92/05156 ~ 0 89 7~ PcrtlJss1/o6494 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) OHC

S R, (II) wherein Rl is described above. A compound of forrnula (II) is treated with trimethylsilyl cyanide in the presence of zinc iodide at low temperatures in an inert solvent to form the trimethylsilyl-protec~ed l 0 cyanohydrin. Treatment of this with gaseous hydrogen chloride in methanol provides the methyl 2-hydroxyacetate derivative which is converted ~o 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 l 5 salt or the free acid.
The compounds of forrnula (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, 2 0 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 2 5 used to prepare the 3-hydroxypropionate derivative. Alternatively an aldehyde of formula (II) may be reacted at low temperature with - the ~-lithio salt prepared from an esterified a-halo acetic acid, conveniently t-butylacetate, in an inert solvent to give the esterified 3-hydroxypropionate derivative. By employing an esterified 2-3 0 bromopropionate in the above reaction with an aldehyde (II), thecompounds of formula (I) wherein Y is CH(CH3)COR4 where R~, is OH or - an ester are obtained.
Alternatively, the compounds of the forTnula (I) wherein Y is CH(R3)COR4 wherein R4 is OH or an ester and R3 is H, methyl, all;oxy, 3 ~ or fluoro are prepared from a propenoate precursor of the following structural formula (III):

wo 92/05156 2 0 8 9 7 ~ ~ Pcr/us91/o6494 ~,~COR~

R, (III) wherein Rl is described above, R4 ;s an alkyl ester protective group, such as t-butyl, and Rll is H, methyl, aLkoxy, or fluoro. A compound S 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 l 0 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 15 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) (CH2)mc N~\
R1 (IV) wherein Rl, and n are described above, and R4 is lower alkoxy. A
compound of formula (IV) is reac~ed in a protic solvent with 2 5 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 0 compound of formula (IX):

WO 92/05156 2 0 89 72 ~ PCl'~US91~!06'194 - 10 - ,~
~, Br R1 (IX) with acrolein to give the corresponding enol derivative which is treated with a trialkylorthoacetate, followed by epoxidation using rn-chloroperbenzoic acid.
The epoxide precursors of formula (IV) where n is û 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 c~n also be prepared from an ester of formula (V) where R is -(CH2)2COR4 and Y is CH(OH)CH2COR4:

~ (CH2)nc02R4 ¢~--CH2CO2R4 R~

wherein R4 is lower alkyl. A compound of formula (V) is reacted with sodium hyd~ide in an ineTt solvent followed by reaction with a substi~uted benzyl bromide to yield a product of formula (I).
The compounds of the forrnula (I) wherein Y is -(CH2)3COR4 aTe 2 0 prepared from the lactone precursor of formula (VI) o oJ~ .

' ~NJ (VI) where Rl is described above. A compound of formula (VI) is reacted 25 with a mixture of zinc iodide and a substituted thiol in an inert solvent or with a substituted thiol in ~rifluoroacetic 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 WO 92/05l56 2 0 8 9 7 2 3 PCr/US91/06494 compound of formula (IV) with chloro titanium tri-isopropoxide followed by reaction with 5-oxovalera~e alkyl ester.
The aldehydes of the forrnula (II) are known or readily prepared utilizing the general procedures described below.
The aldehyde precursors to the compounds of formula (I) wherein Rl is, for example, an alk'yl 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 l O aluminium hydride in tetrahydrofuran followed by reaction with manganese dioxide in methylene chloricle to give the corresponding 2-alkyl-3 -formylpyridine .
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 forrnula (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, 2 0 followed by addition of dia~omethane to yield a 2-alkylthio-3-carbomethoxypyridine. The ester is then reacted with lithium aluminum hydride in tetrahydrofuran followed ~y reaction with oxalyl chloride in dimethylsulfoxide and triethylamine in methylene chloride to yield the corresponding 2-alkylthio-3-formylpyridine.
2 5 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 3 0 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 forrnula (I) by reacting the diacid with an appropriately alcohol according to 3 5 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.

WO 92/05156 PCr/US91/06494 ?~- 12-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 prepara~ion of the compounds of formula (I) of 5 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 substi~utuent, is treated with a suitable strong base such as 10 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 alkyla~ing 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 conduc~ed in an aprotic solvent at 2 0 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 2 5 especially suitable.
R13~<C02R3 H~ _Co2R3 R14 R15 Here R13, R14, and R16 are independently selected *om hydrogen or Cl 6alkyl; and Rls and R17 are independently selected from H, aryl, 3 0 or Cl 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 ~o inhibit the leukotriene inducPd contraction of guinea pig tracheal tissues in vitro.
3 5 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 wo 92/05156 - 13 - pcr/uss1/o6494 tissue bath and continuously aerated with 95% 2/5% C02. The tissues were connected via silk suture to force displacement transducers for recording isometric tension. The tissues were equilibrated for I hr., pretreated for 15 minutes with meclo~Fenamic 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 10 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 l 5 compound were plotted on log graph paper. The concentration of LTD4 needed to elicit 30% of the con~action elici~ed by carbachol was measured and defined as the EC30. The -log KB value for the test compound was determined by the following equations:
l. EC30 (presence of test compound) l EC30 (presence of vehicle 20 control) equals the dose ratio which equals X, and 2. KB = concentration of test compound/(X-I).
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 25 TableI. The -log KB values were calculated from the above proto-col. Where compounds were tested more than once, the -log KB
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 3 0 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 3 5 of a solution or suspension, examples of appropriate pharmaceutical carriers or diluents include: for a~queous 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;

wo 92/0~156 2 0 8 9 7 2 ~ pcr/uss!/o6494 - 1 4 - -~

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 adminis~ration 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 ehe 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 composi~ions may also comprise the solid active ingredient diluted with a solid diluent for administra~ion 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 acti~e ingredient. When the diluent is a solid i~ may be present in lesser, equal or greater amounts than the solid active ingredient.
2 5 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.
3 0 Usually a compound of forrnula 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 I llg to 700 mg. of 3 5 active ingredient for each administration. For convenience, equal doses will be administered I ~o 4 times daily with the daily dosage regimen being selected from about 1 ~Lg. to about 2800 mg. per day.

W~92/05156 208972~15 ~ PCr/VS91/06494 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 5 inhibiting the symptoms of an allergic response resulting from a mediator release which comprises adminis~ering 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.
10 The above-defined dosage of a compound of formula I is conveniently employed for this purpose and the known effective dosage for the his~amine H1-receptor antagonist. The methods of administration described above for the single active ingredient can similarly be employed for the combination with a histamine H1-receptor 1 5 antagonis t.
The following examples illustrate the preparation of the compounds of this invention and their incorporation into phar~naceutical compositions and as such are not to be considered as limiting the invention set forth in the claims appended hereto. All 0 examples list temperature in degrees centigrade.
EXAMPLE_l 2-H~droxy-3-~2-carboxvethvlthio)-3-(2-~3-(7-phenylheptvlthio)lpyridvl?propionic acid. dipotassium ~alt ~ !a~ 3-(7-Phenv!heptvlthio)-2-(carbomethoxv!pyridine 2 5 2-Carboxy-3-mercaptopyridine (4.5g9 .029M) was dissolved in 15 ml of dry dimethylformamide and warmed to 80. K2C03 (5.6g, .041M) was added cautiously in 3 portions to avoid extensive foaming.
The reaction was stirred for ~ minutes at 90 and 7-phenyl-1-bromoheptane (7.7 g, 0.32M) was added dropwise. After stirrin, 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 s~irred mixture of water and ethyl acetate and the pH adjusted to 2.0 with 3N HCl. The organic layer was separated and the aqueous was ex~racted twice more with ethyl acetate. The combined extracts were washed ~wice with water and dried over MgS04. 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-1-nitrosoguanidine (6.0 g, Wo 92/û5156 pcr/us91/o6494 208~72~ 16-.04 M), KOH (6.5g, .124 M) and Et2O/H2O, 120/30ml). 15 ml of methan~l 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 Si02, 2V% ethyl acetate/hexane) to yield the titled compound.
1 ('o~ 2-HvdroxymethY1-3-(7-phen.~Ylhe~cYIthio)pYridine The compound of Example 1 (a) (7.11g, 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 al]owed 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% NaHCO3 and once with brine, and dried over MgSO4.
Filtration and evaporation of the solvent yielded the titled compound.
2 0 Thin layer chromatography (SiO2, 40% ethylacetate/hexane) indicated essentially a single material.
I ~C~ 2-Forrnyl-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 2 5 (1.54 ml, .017 M) was added nea~. This solution was stirred 10 minutes at 78, warmed briefly to 60, recooled to -78 and the compound of example l(b) (4.85 g, .0158M) was added in 15 rnl of dry methylene chloride. The reac~ion was stirred at -78 for 20 minutes, then at -60 for 5 minutes and recooled to -78.
3 0 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 3 5 10% ammonium chloride once with water, once with 5% sodium bicarbonate, once with brine and dried over MgSO4. Filtration and evaporation yielded a red oil which was further puri~led by flash chromatography (Baker SiO2, 28% e~hyl acetate/hexane) to yield the titled compound.

WD 92/û5156 2 ~ ~ ~ 7 2 3 Pcr/us91/06494 li -ICd~_ Mçthyl 2~3-epoxy-3-L2-~3-(7 ~h~ylheptylthio~l-pYridvl!propanoate The compound of example 1 (c) (2.63 g, 8.4 mm) was dissolved in 25 ml of dry methylene chloride and methyl chloroacetate ( 1.04 ml, 5 11.76 mm) added. The solu~ion was cooled to -15 (ice/methanol bath) under an argon atmosphere and sodium methoxide solution (2.27 ml, 2~% in methanol) was added dropwise. The reaction was stirred at -15 for 5 minutes and allowd to warm to room temperature. NaCI precipitated from solution as ~he reaction warmed.
After stirring at room temperature for 1-1/2 hours the reaction was quenched by addition of pH 7.û seandard buffer solution (Thomas ~cientific). 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 waeer, once with 5% aqueous l S NaHC03, once with brine and dried over MgSC)4. Filtration and evaporation of the ethyl acetate solution, and flash chromatogrphy (Baker SiO2, 20% ethyl acetate/hexane) of the resultant oil yielded the titled compound.
l(e) Methyl 2-hydroxY-3-(2-~carbomethoxvlethvlthio!-3-(2-~3-f7-2 0 phenvlheptYlthio~lpxridyl~propanoate The compound of example l (d) (2.1 g, 5.45 mm) was dissolvec3 in 2 ml methanol and stirred under an Ar atmosphere. A solution of triethylamine (3.0 ml, 21.82 mm) asld 3-mercaptopropionate (1.21 ml, 10.91 mm) in 3 ml of methanol was added. After stirring 16 hours at 2 5 room temperature the methanol and triethylamine were evaporated and the residual oil was dissolved in ethyl acetate. This solu~ion was washed once with water, once with 5% N~HC03, once with br~ne and dried over MgS04. Thin layer chromatography (SiO2, 35% ethyl acetate/hexane) and NMR indicated a mixture of regioisomers 3 0 resulting from opening of the epoxide by the thiol at both the 2 and 3 positions. NMR indicated approximately ~5% of the a-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 3 5 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 wo 92/OSl5S PC~/USgl/06494 2089~2~
and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed once ~ith water, once with brine and dried over MgS04. Filtration and evaporation of the ethyl acetate solution yielded an oil which was further purified by flash chromatography (Baker SiO2, 20% ethyl acetate/hexane) to yield the titled compound.
I (f! 2-HYdroxY-3-(2-carboxvethvlthio~2-~3-(7-1phenYI-heptylthio!lpyridYl)propionic acid. dipot~ium salt The compound of example l(e) (.96 g, 1.9 mm) was dissolved in 1 0 lS ml of methanol and stirred under an Ar atmosphere. KOH (.375 g, 5.7 mm) in ~ 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 HCI to pH 2Ø The organic 1 S 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 MgS04. Filtration and evaporation of the solvent yielded a yellow oil. The oil was dissolved in a few ml of water with KHC03 (1.52 g, 15.2 mm) and flash chromatographed (Baker RP-18, eluted using a step gradient -100% H20, 200 ml; 40% MeOH/H20, 200 ml; 50% MeOH/H20; 100 ml;
60% MeOH/H2Q, 100 ml). The desired material eluted in the 40%
MeOH/H20 fractions were evaporated to yield a film, reconstituted in distilled water and lyophilized to yield an amorphous white solid.
lH-NMR at 250 MHz(D20, ref=HOD=4.60;) ~: 8.12 (d,lp), 7.68(d,1p), 6.90-7.28(m,6p), 4.78(d,1p), 4.23(d,1p), 2.68-2.95(m,2p), 2.52-2.65(t,2p), 2.32-2.4B(t,2p), 2.1-2.32 ~m,2p), 1.3-1.55 (m,4p), .95-1.3Sm,6p) (m,4p~, .95-1.3(m,6p).

3 0 2-HydroxY-3-(2-carboxYethYlthio!-3-(3-~2-(7-phenvl-heptylthio!lpyridYl~propionic acid. dipotassium salt 2fa) 2-f7-PhenylheptYlthio)-3-carboxYpyr1dine 2-Mercap~o-3-carboxypyridine (8 g, .052 M) was dissolved in 25 ml dimethylformamide, and treated with K2C03 (9.97 g, 0.722 M) 3 S and 7-phenyl-1-bromoheptane in the same manner as in example 1 (a). Esterification with diazomethane in the same manner as in Example l(a) (l-methyl-3-nitro-1-nitrosoguanidine, 10.6 g, 0722m;
KOH, 14.28g, .216m; Et20/H20: 200 ml/SOml) provided the titled compound.

WO 9~/05156 2 Q g 9 7 2 ~ Pcr/Us9l/o~49q _ - 19:

. 2!b) 2-(7-Phenvlheptvlthio)-3-hvdroxYmethYlpvrid,ine 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, 15 M in toluene, 0.15M) in the same manner as S Example 1 (b) to yield the titled compound.
2(c) _2-C~PhenYlhe~ylthio~-3-for~Ylpvridine The cornpound 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 1 0 the same manner as Example 1 (c) to afford the captioned compound.
2(d~ Methyl 2.3-epoxv-3-L2-(7-phenylheptvlthio)pYridvll-ropan oate The compound of Example 2(c) (11 g, .035 M) was dissolved in 100 ml dry methylene chloride and reac~ed with methylchloroacetate 15 (4.25 ml; .049 M) and sodium methoxide solution (9.46 ml, .042 M, 25% in MeOH) in the same manner as Example l(d). The crude product was purified by flash chromatog~aphy (Baker SiO2, 25% ethyl acetate/hexane) to yield the titled compound.
2(e~ Methvl 2-hvdroxv-~-(2-rcarbomethoxylethYlthio)-3-!3-~2-(7-2 0 phenvlheptYlthio)lpyridYl)propanoate The compound of Example 2(d) (8.6~ g, 22.~ mm) was dissolvedin 8 ml of methanol and treated with methyl-3-mercapto propionate (5 ml, 45 mm) and triethylamine (12.5 ml~ 90 mm) iD the same manner as Example 1 (e). The retro aldol condensation to degrade the 2 5 undesired regioisomer was accomplished by the same me~hod 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 SiO2, 18% ethyl aeetate/hexane) to provide ~he titled compound.
3 0 2(f~ _2-HvdroxY-3-L2-carboxYethvlthio)-3-(3-~2-~7-phenvl-hep~ylthio)lpvridvl)propionic 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 3 5 reaction was diluted with water, layered with ethyl acetate and acidi~led to pH 2Ø 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 MgSO4.
Filtration and evaporation of the solvent yielded a crude oil which WO 92/05156 Pcr/US9l/06494 2 0 (~ 9 7,~ g - 20 -was flash chromatographed (Baker SiO2, step gradient, 3-4%
methanol/chloroform - 1% trifluoroacetic acid) to yield a colorless oil.
The oil was dissolved in 6 ml of H20 with KHC03 (2.36 g, 23.6 mm) and flash chromatographed (Baker R-P 18,step gradient, 100% H20, 250 ml; lO0 ml each of 40%, 50%, 60%, 70%, and 80% methanol/H20).
Fractions containing the product were pooled and evaporated to a glass. This glass was resuspended in H20 and lyophilized to yield the titled compound as a hygroscopic powder. mp 255-257 with dec.
lH-NMR at 250 MHz (CD30D, ref = CHD20D = 3.47;) ~: 8.16 (d of d, lp), 10 8.02(d of d, lp), 6.9-7.18 (m,6p), 4.6B (d, lp, J=4Hz), 4.23(d,1p,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).

2-Hvdroxv-3-(2-carboxvethylthio)-3-(3-r2-(undecylthio)l-pyridYl)propionic acid - 3(a! 2-(Undecvlthio)-3-(carbomethoxylpyridine 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 (lO.Sg, .045 M) in essentially the same 2 0 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 HCl. The organic layer was separated and the aqueous was extracted twice wit~i ethyl 2 5 acetate. The combined organic extracts were washed, once with lN
HCI, once with H20, once with brine and dned over MgS04. Filtration and evaporation of this solution yielded a yellow solid. This solid was warmed and triturated with diethyl e~her/hexane, cooled and filtered to yield the 2-(undecylthio)pyridine-2-carboxylic acid.
3 0 The pyridine carboxylic acid prepared as above, 6.25 g, was dissolved in ethyl acetate/acetone and added dropwise to an excess of diazomethane in diethyl e~her 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.
3 S After 1-1/2 hour at room temperature, the solvent was evaporated i n vacuo and the oily residue was chromatographed over silica gel using the llash method (Baker SiO2, 10% ethyl acetate/hexane.
3(b) 3-T~vdroxymethvl-7-undecvl~hiopvridine wo 92/05156 2 0 8 ~ 7 2 ~ PCr/US9l/û6494 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 srnall amount of the ester precipitated at this low temperature. Di-isobutyl aluminum hydride (14.5 ml, 21.78 mm; 1.5 S M in toluene) was added dropwise. The reaction was stirred at -78C
for 1/2 hour and placed in a freezer at -20. After 16 hours the reaction was warmed to room temperature and stiTTed for 3 hours addi~ional. Thin layer chromatography indicated all starting material had been consumed and one major new product formed (Si02, 30%
10 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 ~llter cake was washed with methylene chloride (2x) and the filtrate was washed with H20 (2x), brine (lx) and dried over MgSO4. Filtration and evaporation of the 15 .solYent yielded a white solid which was essentially homogenous by thin layer chromatography.
;~L~ 3-Form~l-2-~undecYlthio~pYridine The compound of Example 3(a) (2.0g, 7.2rnm) was oxidized using the procedure of Example l(c) using dimethyl sulfoxide (1.2 g, 1.1 ml~
2 0 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.
3(d!,,,. Methvl 2.3-epoxv-3-(3-r2-undecYlthiolpvridvl~propanoate The compound of Example 3(c~ (1.55 g, 5.29 mm) was reacted 2 5 with methyl chloroacetate (.84 g, .6~ 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 l(d). Flash chromatography (Baker SiO2, 10% e~hyl acetate/hexane) yielded the titled product.
3 0 3(e) Methvl 2-hvdroxv-3-C2-~carbomethoxvlethvlthio?-3-(3-r2-undecvlthiolpyridvl)propanoate 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, 2.4~ ml, 17.52 35 mm) in 2 ml MeOH was added. The reaction mixture was stirred at room temperature under an argon atmosphere for 4~ hours. The solven~ was evaporated ~o yield an oil. The oil was flash chromatographed (Baker SiO2, 15% ethyl acetate/hexane) to yield the desired isomer.

WO 92/051~6 ~ a ~ ~ 7 ~ ~ 22 PCr/US91/06494 3(f) 2-~vdrQxy-~-(2-carboxyethylthio~-3-(3-~2-undecyIthiol-pvridvl)propionic 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.
5 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 HCl. The organic layer was separated and the aqueous 10 was extracted with ethyl acetate (2x). The combined organic extracts were washed with water (lx), brine (lx) and dried over MgS04. This material was flash chromatographed (Baker SiO2, 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) 15 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/H20 (125 ml) and 70% methanol/H2O(100 ml).
The fractions containing the desired material which eluted with 2 0 60% methanol/water, were combined, evaporated under vaccum to a small volume, reconstituted with water and Iyophilized to yield white hygroscopic powder. lH-NMR of free acid at 250 MH~; (CDC13 REF=TMS-0): ~ 8.38 (d of d, lp), 8.15 (broad s, 4p; OH's)9 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 2 5 m, 1 8p~.
Example 4 2-~lvdrox~-3-!3-~2-f8-phenyloctvl)lpvridvl )-3-(2-carboxyethvl~hio)propionic Acid
4(a)MethvL 2.3-epoxv-3- t 3-~2-(8-phenvloctvl)lpvridvl ~ propiona~e.
3 0 To a solution of 2-(8-phenyloctyl)-3-formylpyridine t0.9? 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 -15C 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 35 continued for 5 min at -15C. 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 ~Inder reduced pressure and extracted with ethyl acetate. The organic ex~act was washed successively with H2O, 5% aqueous NaHCO3 and WO 92/05156 2 0 8 9 7 2 ~ Pcr/ussl/o6494 - ~3 -brine and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography e~uting with 30% ethyl acetate/petroleum ether to afford the desired epoxide.
4(b) Methyl 2-hvdroxy-3-~3-r2-~8-phenyloctvl)lpyridyl ~ -3-(2-S carbQmethoxvethylthio!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 10 mmol) in methanol. The resulting solution was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dissolved in CH2Ck and washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced 15 pressure, and the residue was purified by HPLC to afford the desired alcohol. CIMS, isobutane (m/e): 488 (M+H).
4(c~ 2-Hvdroxv-3- ~-r~-(8-ph~nvloctYl~l~ridyl~ -3-~2-carboxvethYlthio~propionic acid~ dipQtassium salt.
To a solution of methyl 2-hydroxy-3-{3-[2-(8-20 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 H2 O and 2 5 ethyl acetate. The organic extract was washed with H2O and dried (MgSO4). The solvenL was removed in ~acuo, and ~he 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).
3 0 Example 5 3-{3-[2-(~-Phenyloctyl)]pyridyl) -3-(2-carboxye~hylthio)-propionic Acid
5(a) Methyl 2-Cyano-5-methoxypentadienoate.
To a solution of malonaldehyde bis(dimethyl acetal) (24.6 g, 3~ 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 dro~wise, and the reaction mixture was heated at reflux overrlight. The mixture was allowed to cool to room temperature, filtered and concentrated under reduced wo 92/05156 2 0 ~ 9 7 2 8 PCI/USg1/06494 - 24 - _ pressure. The semi-solid residue was triturated with diethyl ether/petroleum ether. The solid was removed by filtration, dissolved in e~her and decolorized. Removal of the solvent under reduced pressure yielded a semi-sol;d residue- which was triturated 5 with ditehyl ether/petroleum ether to provide the desired product.
m.p. 95 - 97C.
$(b~ 2-Br~mo-S-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 10 warmed to 40~C, and acetic acid (16 mL) saturated wieh HBr was added dropwise, maintaining the tempera~ure at 40C. Following the addition the reaction mixture was heated to 50C for 30 min and then allowed to cool to room temperature. The solid which precipitated was ~lltered, washed with ether and treated with 5% aqueous Na2C03.
15 The oil which separated was dissolved in diethyl ether, washed with H20 and dried. After treating with decolorizing charcoal, the solvent was removed in vacuo to provide an amber oil .
S(C! 1-Phenyl-1~7-octadivne.
A solution of phenylacetylene (3.19 g, 31.3 mmol) in 2 0 tetrahydrofuran (63 mL) under an argon atmosphere was cooled to 5C, 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 0C, l-hex-5-ynyl-p-toluenesulfonate (7.9 g, 31.3 mmol) in tetrahydrofuran t32 mL). The 25 resulting solution was stirred at 0C for 1 hour, allowed ~o warm to room temperature and stirred overnight. The reaction mixture was poured into H20 and extracted with ether. The organic extract was dried ~MgS04), filtered and concentrated under reduced pressure.
The residue was purified by flash chromatography, eluting with 15%
3 0 diethyl ether/petroleum ether to provide the desired material.
5(d) 2-(8-Phenvlocta-l.?-divnvl)-3-carbomethoxypvridine.
To a solution of 2-bromo-3-carbomethoxypyridine (3.5 g, 17.3 mmol) and l-phenyl-1,7-octadiyne (2.5 g, 13.7 mmol) in triethylamine (50 mL) were added bis(triphenylphosphine)palladium 35 chloride (0.19 g, 0.27 mmol) and copper iodide ~26 mg, 0.14 mmol).
The resulting mixture was heated at 80C under an argon atmosphere for 2 hours and allowed to cool to room temperature. l`he solvent was removed in vacuo, and diethyl ether was added to the residue. After treatment with clecolorizing charcoal, the solvent was removed i n
6 2 0 8 9 7 2 ~ PCr/US91/06494 vacuo, and the residue was purified by flash chromatography eluting with 30% diethyl ether/petroleum e ther to provide the desired prod uc t.
5(e! 2-f8-Phenvloct~d)-3-carbomethoxypyridine~
To a solution of 2-t8-phenylocta-1,7-diynyl)-3-carbomethoxypyndine (1.0 g, 3.1 m;mol) in ethyl acetate (50 mL) was added lO~o palladium on activated carbon (0.2 g). The resulting mixture was purged with argon and ~hen stirred under hydrogen at atmospheric pressure for 15 min. The mixture was filtered and concentrated under reduced pressure to provide ~he desired product.
5(e? 2-~3- r2-( 8-Phenvloctvl~ 3-hydroxvmethvlpYridine.
To a solution of 2^(8-phenyloctyl)-3-carbomethoxypyridine ( 1.0 g, 3.1 mmol) in toluene (20 mL) at -78C under an argon atmosphere was added dropwise DiBAL (12.3 mL of lM solu~ion, 12.3 mmol). The resulting mixture was stirred at -78C for 1 hour, then allowed to warm to room temperature and stirred for several hours. Methanol was slowly added, and ~he mixture was stirred an additional 15 nnin.
The re~ction mixture was filtered, and the filtrate was concentra~ed under reduced pressure. The residue was dissolved in CH2CI~ and dried (MgSO4). Removal of the solvent provided the alcohol which was used without fulther purification.
5(d) 2-(8-PhenYloctvl)-3-formYlpyridine.
To a solution of 2-(3-[2-(8-phenyloctyl)]}-3-hydroxymethylpyridine prepared above in methylene dichloride (30 mL) was added MnO2 (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 dissolYed in diethyl ether and treated with decolorizing charcoal. The solvent was removed in vacuo 3 0 and azeotropically treated with toluene ~2x) to provide the desired aldehyde .
~-hYdroxY-3- L3-r2-(8-phenvloctvl~lpvridyl ! propionate.
To a solution of di-isopropyl amine (0.36 g, 3.6 mmol) in tetrahydrofuran (5~mL) at -78C under an argon atmosphere was 3 5 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 t-butyl acetate ~0.41 g, 3.6 mmol) in tetrahydrofuran (5 mL) was added dropwise. After stirring at -78~C for I hour, a solution of 2-(8-phenyloctyl)-3~formylpyridine (0.7 g, 2.4 mmol) in tetrahydrofuran wo 92/05156 Pcr/US91/06494 2 0 8 9 ~ 2 ~ 26 (5 mL) was added dropwise. The mixture was stirred at -78C for 1 hour, then allowed to warm to roorn temperature and stirred overnight. Saturated aqueous NH4CI was added, and the mixture was extracted with diethyl ether. The organic extract was washed with S H20 and dried. Removal of the solvent in vacuo provided the desired material .
5(~2_ t-Butvl 3-~3-~2-~8-~heny!octvl~]pyridyl~cinnamate.
To a solution of t-butyl 3-hydroxy-3-~3-[2-(8-phenyloctyl)]-pyridyl}propionate (0.5 g, 1.2 mmol) and triethylamine (0.38 g, 3.6 10 mmol) in ( H2C12 (10 mL) at -10C 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 rennoved in vacuo. The residue was dissolved in CH2C12, washed successively with H2O, 3 N HCl and 15 H2O and dried (MgSO4). Removal of the solvent in vacuo provided the epoxide .
5!h) t-Butyl 3-~3-r2-(8-phenvloctvl~lpvridvl!-3-(2 carbomçthoxythio!propionate.
To a solution of t-butyl 3-~3-~2-(8-phenyloctyl)]pyridyl}-2 0 cinnamate (0.4 g, 1.0 mmol) and methyl 3-mercaptopropionate (0.7 g, 5.9 mmol) in methanol (5 m~) at 0C was added trie~hylamine (l.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 dissolved in 25 CH2C12, washed with H~O 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-r3-r~-(8-Phenvloctvl)lpvridYl ~ -3-~2-carboxvethvlthio)-3 0 propionic acid. dipiperazine salt.
A solution of t-butyl 3-(3-[2-(8 phenyloctyl)]pyridyl~-3-(2-carbomethoxyethylthio)propionate (0.4 g, 0.8 mmol) in 3 N HCI (20 mL~ was heated tO reflux overnight. The solution was concentrated under reduced pressure, and the residue was azeotropically treated 3 5 with toluene (2x). The residue was dissolved in methanol and dried.
The solvent was removed in Yacuo ~ 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 WO 92tO5156 2 0 ~ 9 7 2 8 PCI'/US91/06494 - 27. -. . .

white powder which was recrystallized from isopropyl alcohol. EA B
MS (m/z): 444 (M+H).
Example_6 2-Methoxv:3-~4-carboxvphenvlthiQ~3- ~3-~2-(7-phenvlheptvlLthiolpvridvllpropionic _acid ___~_~heptvl!~hi~ rid~-,E~o~?ionamide.
To a saturated solution of ammonia in ethanol (~0 mL) at -20C
was added dropwise a solution of methyl 2,3-epoxy-3-f3-[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(~2~Ydroxv-3-r4-(carbomethoxyl!phenvlthio1-3-~3-~2-(7-1 5 phe~n~lhept~l2thio1pyridyl~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 -10C under an argon atmosphere was added titanium isopropoxide (1.46 g, 5.1 mmol), followed by the dropwise addition of 2 0 a solution of methyl 4-mercaptobenzoate (0.37 g, 2.2 mmol) and NaH
tlO mg of a ~0% oil dispersion, 0.21 mmol) in TH~ (5 mL). The resulting mixture was stirred at O"C for 90 min, then partitioned between Et20 and saturated aqueous Na2SO4 and filtered through Celite. The organic phase was dried (MgSO4) and concentrated under 2 5 reduced pressure. The residue was purified by column chromatography (silica gel), eluting with Et2O to afford a glassy solid.
90 MHz NMR (CDC13): ~ 8.25 (dd, lH, J = 4 Hz, J = 1 Hz); 7.95 (dd, lH, 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, lH, J = 9 Hz, J = 3 Hz); 6.50 (br s, lH); 6.08 3 0 (br s, lH); 5.28 (d, lH, J = 3 Hz); 4.70 (d, lH, J = 6 Hz); 4.50 (dd~ lH, J
= 6 Hz, J = 3 ~Iz); 3.82 (s, 3H); 3.l8 (m, 2H); 2.54 (t, 2H, J = 7 Hz);
1.80 - 1.20 (m, lOH).
6(c~ Methvl 2-hxdroxy-3-~4-(carbomethoxyl)phenylthio1-3- ~ 3-r2-(7-envlh~2tyl!thiol-~ridvl !propanoate.
3 5 3-14-(carbomethoxyl)phenylthio] -2-hydroxy-3- { 3-~2-~7-phenylheptyl)thio]pyridyl~propionamide (0.44 g, 0.8 mmol) in methanol (lOû mL~ was treated with 25% aqueous HCI (5 mLj, and ~he resulting solution was heated to reflux overnight. Potassium carbollate was added; the mixture was decanted and concentrated wo 9~/0~156 Pcr/US9l/06494 2~72~ - 28 - ~
-- under reduced pressure. The residue was partitioned between EtOAc and 5% aqueous NaHC03. The organic phase was washed wi~h saturated aqueous NaCl and dried (MgS04). Removal of the solvent in vacuo provided a colorless oil.
90 MHz NMR (CDC13): ~ 8.20 (d, lH, J = 4 Hz); 7.90 (m, 2H);
7.50 - 6.80 (m, 9H); 5.20 (d, lH, J = S Hz); 4.60 (d, lH, 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, 1 OH).
~(d~ Methvl 2-methoxv-3-~4-(carbomethoxYl)phenvlthiol-3-~3-~2-1 0 (7-phenvlheptyl)thiol-pyridYl ~ propanoate.
To a solution of methyl 3-[4-(carbomethoxyl)phenylthio]-2-hydroxy-3-~3-[2-(7-phenylheptyl~thio]pyridyl}propanoa~e (0.10 g, 0.18 mmol) in 1:10 DMF/THF (4.5 mL) at 0C under an argon atmosphere was added NaH (17 mg of 50% oil dispersion, 0.36 mmol), followed by methyl iodide (23 ~lL, 0.36 mmol). The resulting solution was allowed to warrn to room temperature and stilTed overnight. The solution was concentrated in vacuo, and the residue w~s partitioned between H20 and CH2C12. The organic phase was dried (MgS04) and concentrated under reduced pressure. Purification of the residue by 2 0 column chromatography (silica gel) eluting with 10% Et20/ hexanes provided a colorless oil.
90 MHz NMR (CDCI3): ~ 8.3~ (dd, lH, J = 5 Hz, J = 1 Hz); 7.80 (m, 2H); 7.30 (d, lH, J = 8 Hz), 7.20 (br s, 5H); 6.90 (dd, lH, J = 7 Hz, J
= 4 ~); 5.20 (d, lH, J = 5 Hz); 4.20 (d, lH, 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, lOH).
6(e) 2-Meth oxv-3 - ~4-c arbQxvphenyl th i ol -3 - ~ 3 - ~2-(? -phen~eptvl)thiolpvridyl )propionic acid.
A solution of methyl 3-[4-(carbosnethoxyl)phenylthio]-2-3 0 methoxy-3-(3-[2-(7-phenylheptyl)thio]pyridyl}propanoate (70 mg, 0.14 mmol) and NaOH (32 mg, 0.80 mmol) in 1:1 H20/ CH30H (2 mL) was allowed to stir at room temperature for 36 hours. The solution was concentrated in vacuo to remove CH30H, and the pH was adjusted to 3-4 with 3 N HCI. The resulting precipitate was collected by 3 5 filtration and dried. The amorphous solid (60 mg) was tre~ted with piperazine (1 eq), yielding a white solid. m.p. 182C.
90 MHz NMR (CDC13): ~ 8.42 (dd, IH, J = 5 Hz, J = 1 Hz); 7.90 (m, 2H); ?.50 (d, lH, J = 8 Hz); 7.25 (br s, SH); 7.20 (m, 3H); 5.32 (d, Wo 92/~5156 2 ~ ~ 9 7 2 ~ P~/US~1/06494 lH, J = 6 Hz); 4.30 (d, lH, 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-HYdroxy-3-r4-fcarboxyphenyl?thiol-3- ( 3-L2-~7-phenylheptyl~thiolpyridvl)propionic acid~
7(a) ~2-HvdroxY~4-~carboxyphen~lthiol-3- ~ 3-r2-(7-~henvlheptyl)thiolpYridyl !Propionic acid, A solution of methyl 3-[4-carbomethoxyl)phenylthio]-2-hydroxy-3- { 3-[2-(7-phenylheptyl)thio]pyridyl } propanoate (û. 12 g, 0.2 mmol) and NaOH (40 mg, 1.0 mmol) in 1: 3 H2O/ CH30H (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 HCI.
The mixture was extracted with CHC13 (2x), and the combined organic ext}acts were dried (MgS04). Removal of the solvent in vacuo l S provided a glassy solid.
90 MHz ~MR (CDC13): ~ 8.40 (dd, lH, J = 6 Hz, J = 1 Hz); .8.00 -7.00 (m, llH); 5.20 (d, lH, J = 7 Hz); 4.70 (d, lH, 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 ( l eq) provided a salt. m.p. 204 - 6C.
Example 8 2-(4-CarboxYphenoxy! 2-r3-(2-undecvlthio)pyridYllacetic acid
8(i) methvl 2-chloro-2-r3-(2-undecvlthio)pvridylacetate.
The title compound is prepared from 3-formyl-2-2 5 (undecylthio~pyridine [3(c)] following the procedsre given in U.S.
Patent No. 4,820,719 for the preparation of rnethyl 2-chloro-2-(2-dodecylphenyl)acetate from 2-dodecylbenzaldehyde.
8(ii) 2-!4-Carboxvphenoxv)-~-~3-l2-1Jndecylthio)pvridvllacetic acid.
The title compound is prepared from methyl 2-chloro-2-[3-(2-3 0 undecylthio)pyridylacetate by reaction with methyl 4-hydroxybenzoate and potassium carbonate in dimethylformamide followed by saponification of the dies~er.
Example 9 Formulations for pharmaceutical use incorporating compounds 3 5 of the present invention can be prepared in various forms ~nd with numerous excipients. Examples of such formulations are givPn below.
Inha!ant Formulation - 30 - ~_ A compound of formula I, 1 to 10 mglml, is dissolved in isotonic saline and aerosolized from nebulizer operating at an air flow adjusted to deliver the desired amount of drug per use.

5 Tablets IngredientsPer TabletPer 10 000 Tablets 1. Active ingredient (Cpd of Form. I)40.0mg 400.0g 2. Corn Starch20.0mg 200.0g 3. Alginic acid20.0mg 200.0g 4. Sodium alginate20.0mg 200.0g 5. Mg stearate 1.3 m~ 13.0g 101.3 mg 1013.Og Procedure for tablets:
Step 1 Blend ingr dients No. 1, No. 2, No. 3 and No. 4 in a suita~le mixer/blender.
Step 2 Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such addi~ions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.
Step 3 Thç wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen. 5 Step 4 The wet granules are then dried in an oven at 1 1 0F
(60~C) until dry.
Step S The dry granules are lubricated with ingredient No. 5.
Step 6 The lubricated granules are compressed on a suitable tablet press.
Suppositories:

Ingredients Per Supp.Per lO00 Supp.
1. Formula I compound 40.0 mg 40 Og 3 5 Active ingredient 2. Polyethylene Glycol 1350.0mg 1,350 Og 3. polyethylene glycol 4000 450.0 m~ 450 Og WO 92/05156 2 0 8 9 7 2 8 Pcr/US~l/06494 - I

1840.0 mg 1,840 Og Procedure:
Step 1. Melt ingredient No. 2 and No. 3 together and stir until S uniform.
Step 2. Dissolve ingredient No. 1 ;n the molten mass from Step 1 and stir uneil uniform.
Step 3. Pour the molten mass frorn Step 2 into supository moulds and chill.0 Step 4. Remove the suppositories from moulds and wrap.

Claims (18)

What is claimed is:
1. A compound of formula (I) (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(O)q where q is 0, 1 or 2 with the proviso that R1 is not alkylthio or phenylthioalkyl when q is 1 or 2;
R1 is C8 to C13 alkyl, C7 to C12 alkoxy, C7 to C12 alkylthio, C10 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, C1 to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to C10 alkyl, trifluoromethyl-C7 to C12 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(NH2)COR4, or -CONHCH2COR4, or R2 is -CON(R5)2 where R5 is H, C1 to C6 alkyl, phenylC1-C6alkyl, or the two R5 groups are combined to form a cyclic group having 3 to 5 carbons;
R3 is hydrogen, methyl, C1 to C4 alkoxy, fluoro or hydroxy;
R6 is C1 to C10-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)lR2, where l is 0-3, or tetrazol-5-yl.
2. A compound of claim 1 where X is S or S(O)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 is1 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 H1 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 H1-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.
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US5856322A (en) * 1990-10-12 1999-01-05 Merck Frosst Canada, Inc. Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists
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ES2065234B1 (en) * 1992-10-27 1995-09-01 Smithkline Beecham Corp COMPOUNDS TO TREAT DISEASES RELATED TO LEUCOTRENEES.
AR029004A1 (en) * 1999-09-22 2003-06-04 Essential Therapeutics Inc ACID COMPOUND 7-ACILAMINO-3-HETEROARILTIO-3-CEBOEM CARBOXILICO AND ITS USE FOR THE PREPARATION OF AN ANTIBACTERIAL COMPOSITION
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FR2885616B1 (en) * 2005-05-12 2007-06-22 Servier Lab NOVEL PHENYLPYRIDINYLPIPERAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

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US4920131A (en) * 1987-11-03 1990-04-24 Rorer Pharmaceutical Corp. Quinoline derivatives and use thereof as antagonists of leukotriene D4

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MX9101098A (en) 1992-05-04
WO1992005156A1 (en) 1992-04-02
JPH06501019A (en) 1994-01-27
KR930702304A (en) 1993-09-08
EP0548291A1 (en) 1993-06-30
IE913214A1 (en) 1992-02-25
PT98974A (en) 1992-08-31
ZA917261B (en) 1992-09-30
AU8900391A (en) 1992-04-15

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