NO180086B - Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists - Google Patents

Description

The leukotrienes form a group of locally acting hormones, produced in living systems from arachidonic acid. The main leukotrienes are Leukotriene^ B^ (LTB^), LTC4, LTD^ and LTE^. The biosynthesis of these leukotrienes begins with the action of the enzyme 5-lipoxygenase on arachidonic acid to form the epoxide known as !eukotriene> A^ (LTA^), which is converted to the other leukotrienes by enzymatic steps. Further details concerning the biosynthesis as well as the metabolism of the leukotrienes can be found in Leukotrienes and Lipoxygenases, Ed. J. Rokach, Elsevier, Amsterdam (1989). The effects of the leukotrienes in living systems and their contribution to various disease states are also discussed in the book by Rokach.

The prior art describes certain quinoline-containing compounds which have activity as antagonists of the effects of the leukotrienes. Thus EP 318 093 (Merck) describes compounds of structure A. Structure B is described in WO 89/12629 (Rorer).

The present invention relates to unsaturated hydroxyalkyl-quinolinic acids which have activity as leukotriene antagonists, methods for their production, and methods and pharmaceutical formulations for the use of these compounds in mammals (especially humans).

Due to their activity as leukotriene antagonists, the compounds according to the invention are useful as anti-asthmatic agents, anti-allergic agents, anti-inflammatory agents and cytoprotective agents. They are also useful in the treatment of angina, cerebral spasms, glomerular nephritis, hepatitis, endotoxemia, uveitis and transplant rejection.

The invention thus relates to a compound which is characterized by having the formula:

in which

R<1> is halogen;

R<2> is lower alkyl, -CF3, substituted or unsubstituted phenyl, benzyl or 2-phenethyl, or two R<2> groups bonded to the same carbon, can form a cycloalkyl ring with up to 6 members;

R<3> is H or R<2>;

Q<1> is -C(O)OH;

m' is 2 or 3;

p' is 0 or 1;

m + p is 1-5;

and pharmaceutically acceptable salts thereof.

Definitions

The following abbreviations have the indicated meanings:

Et = ethyl

Me = methyl

Bz = benzyl

Ph = phenyl

t-Bu = tert-butyl

i-Pr = isopropyl

n-Pr = normal propyl

c-Hex = cyclohexyl

c-Pr = cyclopropyl

1,1-c-Bu = 1,1-bis-cyclobutyl

1,1-c-Pr = 1,1-bis-cyclopropyl (e.g. HOCH2 (1,1-c-Pr)CH2CO2Me is methyl 1-(hydroxymethyl)cyclopropane acetate)

c- = cyclo

Ac = acetyl

Tz = 1H (or 2H)-tetrazol-5-yl

Th = 2- or 3-thienyl

C3H5 = allyl

c-Pen = cyclopentyl

c-Bu = cyclobutyl

phe = benzenediyl

pye = pyridinediyl

fur = furandiyl

thio = thiophendiyl

DEAD = diethylazocarboxylate

DHP = dihydropyran

DIAD = diisopropylazodicarboxylate

r.t. = room temperature

"Lower alkyl" denotes alkyl groups having from 1 to 7 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopropyl, cyclopropyl-

methyl and the like.

Some of the compounds described here contain one or more asymmetric centers and can thus give rise to diastereoisomers and optical isomers. Present invention

se is intended to include such possible diastereoisomers as well as their racemic and dissolved optically active forms.

Optically active (R) and (S) isomers can be resolved using conventional techniques.

Certain of the compounds described herein contain olefinic double bonds and, unless otherwise indicated,

these are intended to include both E- and Z-geometric isomers.

Salts

The pharmaceutical preparations according to the invention comprise a compound of formula I as an active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and possibly other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminium, ammonium, calcium; copper, iron(III), iron(II), lithium, magnesium, manganese salts, manganese, potassium, sodium,

zinc and ..similar. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine , polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like..

When the compound of the invention is basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid/lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucinic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid , succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Particularly preferred are citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid.

It should be understood that in the discussion of methods of treatment that follows, references to the compounds of formula I are intended to also include the pharmaceutically acceptable salts.

Applicability

The ability of the compounds of formula I to antagonize the effects of the leukotrienes makes them useful for preventing or reversing the symptoms induced by the leukotrienes in a human. This antagonism of the effects of leukotrienes indicates that the compounds and pharmaceutical preparations thereof are useful for treating, preventing or ameliorating in mammals and especially in humans: 1) pulmonary diseases including diseases such as asthma, chronic bronchitis,

and related obstructive respiratory diseases, 2) allergies and allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunctivitis and the like, 3) inflammation such as arthritis or inflammatory bowel disease, 4) pain, 5) skin diseases such as psoriasis, atopic eczema and the like, 6) cardiovascular diseases such as angina, myocardial ischemia, hypertension, platelet aggregation and the like, 7) renal insufficiency arising from ischemia caused by immunological or chemical (cyclosporine) etiology, 8) migraine or cluster headache, 9) ocular conditions such as uveitis, 10) hepatitis resulting from chemical, immunological or infectious stimuli, 11) trauma or shock conditions such as burns, endotoxemia and the like, 12) graft rejection, 13) prevention of side effects associated with therapeutic administration of cytokines such as Interleukin II and tumor necrosis factor, 14) chronic lung diseases such as cystic fibrosis, bronchi tis and other small and large respiratory diseases, and 15) cholecystitis.

The compounds according to the invention can thus also be used to treat or prevent mammalian (especially human) disease states such as erosive gastritis, erosive esophagitis; diarrhea; cerebral spasms; premature birth;

spontaneous abortion; dysmenorrhea; ischemia; harmful agent-induced damage or necrosis of hepatic, pancreatic.,

renal or myocardial tissue; liver parenchymal damage caused by hepatotoxic agents such as CC14 and D-galactosamine; ischemic renal failure; disease-induced hepatic damage; bile-salt-induced pancreatic or gastric injury; trauma- or stress-induced cell damage; and glycerol-induced renal failure. The compounds also exhibit a cytoprotective effect.

The cytoprotective activity of a compound can be observed in both animals and humans by observing the increased resistance of the gastrointestinal mucosa to the

harmful effects of strong irritants, for example 5 the ulcerogenic effect of aspirin or indomethacin. In addition to reducing the effect of non-steroidal anti-inflammatory drugs on the gastrointestinal tract, animal studies show that cytoprotective compounds will prevent

gastric lesions caused by oral administration of strong acids, strong bases, ethanol, hypertonic saline solutions and the like.

Two determinations can be used to measure cytoprotective ability. These provisions are: (A) an ethanol-induced

lesion determination, and (B) an indomethacin-induced ulcer-

L5 determination, and is described in EP 140 684.

Dose ranges

The size of a prophylactic or therapeutic dose of a compound of formula I will of course vary with the species

20 of the severity of the condition to be treated and with the particular compound of formula I and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range for anti-asthmatic, anti-allergic or anti-<25> inflammatory use and in general applications other than cytoprotection lies within the range from 0.001 mg to approx. 100 mg per kg body weight of a mammal, preferably 0.01 mg to approx. 10 mg per kg, and most advantageously 0.1 to 1 mg per kg, in individual or divided doses. On the other hand, it may be <30> necessary to use doses outside these limits in some cases.

For use where a preparation for intravenous administration is used, a suitable dose range for anti-asthmatic,

anti-inflammatory or anti-allergic use from 0.001 mg to <35> approx. 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of formula I per kg body weight per day, and for cytoprotective use from 0.1 mg to approx. 100 mg (preferably from about 1 mg to about 100 mg and preferably from 1 mg to about 10 mg) of a compound of formula I per kg body weight per day.

In the case where an oral preparation is used, is

a suitable dosage range for anti-asthmatic, anti-inflammatory or anti-allergic use, for example from 0.01 mg to approx.

100 mg of a compound of formula I per kg body weight per day, preferably from 0.1 mg to approx. 10 mg per kg, and for cytoprotective use from 0.1 mg to approx. 100 mg (preferably from about 1 mg to about 100 mg and preferably from about 10 mg to about 100 mg) of a compound of formula I per kg body weight per day.

For the treatment of diseases of the eye, ophthalmic preparations for ocular administration comprising 0.001 - 1% by weight solutions or suspensions of the compounds of formula I in an acceptable ophthalmic formulation can be used.

The exact amount of a. compound of formula I for use as a cytoprotective agent will depend, inter alia, on whether it is administered to heal damaged cells or to prevent future damage, on the nature of the damaged cells (eg, gastrointestinal ulceration vs. nephrotic necrosis), and on the nature of the causative agent. An example of the use of a compound of formula I in terms of avoiding future damage would be the co-administration of a compound of formula I with a non-steroidal anti-inflammatory drug that might otherwise cause such damage (eg indomethacin). For such use, the compound of formula I is administered from 30 minutes before and up to 30 minutes after administration of the NSAID. Preferably, it is administered before or simultaneously with the NSAID (for example in a combination dosage form).

Pharmaceutical preparations

Any suitable route of administration may be used to provide a mammal, particularly a human, with an effective dose of a compound of the invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal and similar routes can be used. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like.

The pharmaceutical preparations according to the invention comprise a compound of formula I as an active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and possibly other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.

The preparations include preparations suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions to be treated and on the nature of the active ingredient. They can conveniently be presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical field.

For administration by inhalation, the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation for compressed packets or nebulizers. The compounds can also be given as powders that can be formulated and the powder preparation can be inhaled using an insufflation powder inhalation device. The preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol,

which can be formulated as a suspension or solution of a compound of formula I in suitable propellants, such as fluorocarbons or hydrocarbons.

Suitable topical formulations of the compound of formula I include transdermal devices, aerosols, creams, ointments, lotions, atomizing powders and the like.

In practical use, the compounds of formula I may be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can assume a wide number of forms, depending on the form of the preparation desired for administration, for example oral or parenteral (including intravenous). When preparing the preparations for oral dosage form, any of the usual pharmaceutical media can be used, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, dyes and the like in the case of oral liquid preparations, such as for eg suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, and where the solid oral preparations are preferred in relation to liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are of course used. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

In addition to the usual dosage forms indicated above, the compounds of formula I can also be administered by controlled release agents and/or delivery devices such as those described in US Patents 3,845,770, 3,916,899, 3,536,809, 3,598,123 , 3,630,200 and 4,008,719.

Pharmaceutical preparations according to the invention suitable. for oral administration may be presented as discrete units such as capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such preparations may be prepared by any of the pharmaceutical methods, but all methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more necessary ingredients. In general, the preparations are prepared by uniform and intimate mixing of the active ingredient with liquid carriers or finely divided solid carriers or both, after which, if necessary, the product is shaped into the desired presentation.

For example, a tablet can be produced by pressing or molding, possibly with one or more auxiliary ingredients. Compressed tablets can be prepared by pressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface-active agent or dispersant. Molded tablets are prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Preferably, each tablet contains from 2.5 to approx. 500 mg of active ingredient, and each bag or capsule contains from approx. 2.5 to approx. 500 mg of the active ingredient.

The following are examples of representative pharmaceutical dosage forms for the compounds of formula I:

Combinations with other medicines

In addition to the compounds of formula I, the pharmaceutical preparations according to the invention may also contain other active ingredients, such as cyclooxygenase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), peripheral analgesic agents such as zomepirac diflunisal and the like. The weight ratio between the compound of formula I and the second active ingredient can be varied and will depend on the effective dose of each ingredient. Preferably, an effective dose of each is used. Thus, when, for example, a compound of formula I is combined with an NSAID, the weight ratio between the compound of formula I and the NSAID will generally vary from 1000:1 to 1:1000, preferably 200:1 to 1:200.

Combinations of a compound of formula I and other active ingredients will generally also be within the range indicated above, but in each case an effective dose of each active ingredient must be used.

NSAIDs can be characterized into five groups: (1) propionic acid derivatives; (2) acetic acid derivatives; (3) phenamic acid derivatives; •

(4) oxicam; and

(5) biphenylcarboxylic acid derivatives;

or a pharmaceutically acceptable salt thereof.

The propionic acid derivatives that can be used include: alminoprofen, benoxaprofen, bucloxinic acid, ... carprofen,

fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pir-profen, prano-profen, suprofen, thiaprofenic acid and thioxaprofen. Structurally related propionic acid derivatives with similar analgesic^ and anti-inflammatory properties are also contemplated

to be included within this group.

Thus "propionic acid derivatives" as defined herein are non-narcotic analgesic/non-steroidal anti-inflammatory drugs having a free -CH(CH3)COOH or -CH2CH2COOH group (which may optionally be in the form of a pharmaceutically acceptable salt group, e.g. .eg -CH(CH3)COO~Na<+> or -CH2CH2COO~Na<+>), typically bonded directly or via a carbonyl function to a ring system, preferably to an aromatic ring system.

The acetic acid derivatives that can be used include: indomethacin which is a preferred NSAID, vacemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidomethacin and zomepirac. Structurally related acetic acid derivatives with similar analgesic and anti-inflammatory properties are also intended to be included in this group.

Thus, "acetic acid derivatives" as defined herein are non-narcotic analgesic/non-steroidal anti-inflammatory drugs having a free -CH2COOH group (which may optionally be in the form of a pharmaceutically acceptable salt group, for example -CH2COO~Na<+ >), typically bound directly to a ring system, preferably to an aromatic or heteroaromatic ring system.

The fenamic acid derivatives that can be used include: flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid. Structurally related fenamic acid derivatives with similar analgesic and anti-inflammatory properties are also intended to be included in this group.

Thus, "fenamic acid derivatives" as defined herein are non-narcotic analgesic/non-steroidal anti-inflammatory drugs containing the main structure:

which can carry a number of substituents cg in which the free -COCH group can be in the form of a pharmaceutically acceptable salt group, for example -COO~Na<+>. The biphenylcarboxylic acid derivatives that can be used include: diflunisal and flufenisal. Structurally related biphenyl carboxylic acid derivatives with similar analgesic and anti-inflammatory properties are also intended to be included in this group.

Thus, "biphenylcarboxylic acid derivatives" as defined herein are non-narcotic analgesic/non-steroidal anti-inflammatory drugs containing the main structure:

which may carry a number of substituents, and in which the free -COOH group may be in the form of a pharmaceutically acceptable salt group, for example -CO Na+.

The oxicams which can be used in the present invention include: isoxicam, piroxicam, sudoxicam and tenoxicam. Structurally related oxicams with similar analgesic and anti-inflammatory properties are also intended to be included in this group.

Thus, "oxicams" as defined herein are non-narcotic analgesic/non-steroidal anti-inflammatory drugs having the general formula:

wherein R is an aryl or heteroaryl ring system.

The following NSAIDs can also be used:

amfenac sodium, aminoprofen, anitrazafen, anthrafenin, auranofin, bendazac lysinate, benzydanin, beprozine, broperamol, bufezolac, cinmetacin, ciproquazone, cloximat, dazidamine, deboxamate, delmetacin, detomidine, dexindoprofen, diacerein, di-physalamine, difenpyramid, emorfazone, enfenamic acid, enolicam, epirizol, ether salad, etodolac, etofenamate, fanetizol mesylate, fenclorac, fendosal, fenflumizole, feprazone, floctafenin, flunixin, flunoxaprofen,

fluproquazone, fopirtoline, fosfosal, furcloprofen, glucamethacin, guaimesal, ibuproxam, isofezolac, isonixim, isoprofen,. isoxicam, lefetamine-HCl, leflunomide, lofemizole, lonazolac-calcium, lotifazole, loxoprofen, lysine-clonixinate, meclofenamate-sodium, meseclazone, nabumeton, nictindole, nimesulide, orpanoxine, oxamethacin, oxapadol, _perisoxal-citrate, pimeprofen, pimetacin, piproxen, pyrazolac, pirfenidone, proglumetacin maleate, proquazone, pyridoxiprofen, sudoxicam, talmetacin, talniflumate, tenoxicam, thiazolinobutazone, thielavin B, thiaramide-HCl, tiflamizole, timegadin, tolpadol, tryptamide and ufenamate.

The following NSAIDs, designated by company code number (see for example Pharmaprojects), can also be used: 480156S, AA861, AD1590, AFP802, AFP860, AI77B, AP504,

AU8001, BPPC, BW540C, CHINOIN 127, CN100, EB382,

EL508, F1044, GV3658, ITF182, KCNTEI6090, KME4,

LA2851, MR714, MR897, MY309, ON03144, PR823, PV102,

PV108, R830, RS2131, SCR152, SH440, SIR133, SPAS510,

SQ27239, ST281, SY6001, TA60, TAI-901 (4-benzoyl-1-indanecarboxylic acid), TVX2706, U60257', UR2301 and WY41770.

Finally, NSAIDs that may also be used include the salicylates, specifically acetylsalicylic acid, and phenylbutazones,

and pharmaceutically acceptable salts thereof.

In addition to indomethacin, other preferred NSAIDs are acetylsalicylic acid, diclofenac, fenbufen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, phenylbutazone, piroxicam, sulindac and tolmetin.

Pharmaceutical preparations comprising the compounds of formula I may also contain inhibitors of the biosynthesis of the leukotrienes, such as those described in EP 138 481 (24 April 1985), EP 115 394 (8 August 1984), EP 136 893 (10 April 1985) and EP 140 709 (May 8, 1985).

The compounds of formula I can also be used in combination with leukotriene antagonists such as those described in EP 106 565 (April 25, 1984) and EP 104 885 (April 4, 1984) and others known in the art, such as those described in EP Application Nos. 56,172 (July 21, 1982) and 61,800 (June 10, 1982);

and in British Patent No. 2,058,785 (April 15, 1981).

Pharmaceutical preparations comprising the compounds of formula I may also contain, as the second active ingredient, prostaglandin antagonists such as those described in EP

11,067 (May 28, 1980) or thromboxane antagonists such as those described in US Patent 4,237,160. They may also contain histidine decarboxylase inhibitors such as α-fluoro-methyl-histidine, described in US Patent 4,325,961. The compounds of formula I can also advantageously be combined with

an H^t or H2~ receptor antagonist, such as, for example, acetamazole, aminothiadiazoles described in EP 40 696 (December 2, 1981), benadryl, cimetidine, famotidine, framamine, histadyl, phenergan, ranitidine, terfenadine and similar compounds, such as those which is described in US Patent 4,283,408,

4 362 736 and 4 394 508. The pharmaceutical preparations can also contain a K<+>/H<+>ATP7ase inhibitor such as omeprazole, described in US patent 4 255 431 and the like. The compounds of formula I can also be suitably combined with most cell stabilizing agents, such as

1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane and related compounds described in British Patents 1,144,905 and 1,144,906. Other useful pharmaceutical preparations include the compounds of formula I in combination with serotonin antagonists, such as such as methysergide, the serotonin antagonists described in Nature, Vol. 316, pages 126-131, 1985 and the like.

Other advantageous pharmaceutical preparations include the compounds of formula I in combination with anti-cholinergic agents such as ipratropium bromide, bronchodilators such as the beta-agonist salbutamol, metaproterenol, terbutaline, fenoterol and the like, and anti-asthmatic drugs such as theophylline, choline theophylline and enprophylline, calcium antagonists - the nifedipine, diltiazem, nitrendipine, verapamil, nimodipine, felodipine etc, and the corticosteroids hydrocortisone, methylprednisolone, betamethasone, dexamethasone, beclomethasone and the like.

Preferred connections

Preferred compounds are 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)- propyl)thio)methyl)cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof, and sodium-l-(((l(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-( 2-(2-hydroxy-2-propyl)phenyl)propyl)thio)methyl)cyclopropane acetate or a pharmaceutically acceptable salt thereof.

Synthesis methods

The compounds according to the invention can be prepared. according to the following methods. Temperatures are in degrees Celsius.

Method A

Bromic acid II is treated with 2 equivalents of a base such as n-butyllithium in a suitable solvent such as THF at -100°C, then at -78°C to form III, which reacts with IV (see E'P 206 751, December 30, 1986; EP 318,093, May 31, 1989 and US Patent 4,851,409, July 25, 1989), forming the hydroxy acid V. (When Y = -C=C-, compound IV can also be prepared by the method of Yamanaka et al., Chem. Pharm. Bull., 27, 270-273 (1979) and by Crisp et al., Aust. J. Chem., 42, 279-285 (1989).

V is then esterified using conditions such as methanol/HCl, CH2N2 or MeI/K2CO3 and an organometallic reagent is then added to form the diol VI.

The benzyl alcohol of VI is then reacted with the ethylene IX by: (1) preparation of the chloride by reaction with methanesulfonyl chloride in the presence of triethylamine, and (2) substitution of the chloride by the thiol IX in the presence of a base such as sodium hydride or cesium carbonate under formation of VII. In those cases where Q"<*>" is an ester, hydrolysis with a base such as ; NaOH, LiOH or K2C03 (followed by acidification) the acid VIII.

VII and VIII are both representative of structure I.

Method B

The ketone IV is reduced to the benzylic alcohol

o during the formation of a reagent such as NaBH^. This benzylic alcohol is converted to the benzylic bromide using conditions such as carbon tetrabromide/1,2-bis-(diphenyl-phosphino)ethane, and treatment with triphenylphosphine gives the phosphonium salt X. Using a base such as potassium hexa- 5 methyldisilazide is formed. ylide of X,, and this is added to a lactol. Oxidation of the thus obtained benzylic alcohol. using conditions such as (1) MnO 2 in EtOAc and (2) MnO 2 -/HCN/MeOH gives the ester XI. The thiol IX is then added to XI using a Lewis acid such as AlCl₂ or TiCl₂ to form the thioether XII. Reaction of XII with an organometallic compound such as lithium or a magnesium salt gives, in cases where Q is stable under these conditions, the tertiary alcohol XIII which is representative of structure I.

Method C

The ester XXVII, obtained by Method E, is hydrolysed with a base such as NaOH to form XIV. XIV is reacted with an organometallic compound and chlorotrimethylsilane is added to the reaction mixture to form the hydroxyketone XV. The benzylic alcohol is then reacted with methanesulfonyl chloride in the presence of a base such as triethylamine. The mesylate thus obtained is substituted with the thiolate derivative of IX to form XVI. Finally, an organometallic reaction or a reduction using a reagent such as NaBH^ on XVI gives the alcohol XVIII. Using this method, two different R groups can be added to form a secondary or an unsymmetrical tertiary alcohol.

Method D

The hydroxy acid XVII (included within the definition of XIV) is cyclized to the lactone XXI using a reagent such as 2-chloro-N-methylpyridinium iodide. An organometallic reagent is then added to XXI to form the diol XXII. Finally, the secondary alcohol is substituted with the thiol IX as in Method C, forming the thioester XX.

Method E

The aldehyde XXIII, a derivative of IV, is reacted with an organometallic reagent, and the benzylic alcohol thus obtained is oxidized to XXIV with an oxidizing agent such as activated manganese dioxide. XXIV is then reacted with the iodide XXV in the presence of a base such as lithium diisopropylamine to form the alkylation product XXVI. Reduction with sodium borohydride or addition of an organometallic reagent gives the hydroxyester XXVII, which is then treated as the lactone XXI

in Method D during formation of the thioether XXVIII.

Method F

The enolate of the ketone XXIX, obtained by treating XXIX with a base such as KH or NaH, is reacted with dimethyl carbonate to form the ketoester XXX. XXX is enolized with a base such as NaH and treated with the iodide XXXI, the methyl ester of XXV. The adduct thus obtained is then decarboxylated using conditions such as heating with HCl in acetic acid, forming a mixture of the ester XXXII and the corresponding acid. Esterification of the mixture, using a reagent such as diazomethane or methyl iodide and K^CO^/ gives XXXII, which is then converted to XXXIII or its epimer as described in Method G.

Method G

The hydroxy acid XVII is esterified using conditions such as heating with Mel and K^CO^ or by reaction with diazomethane. Treatment of this hydroxyester with an oxidant such as activated manganese dioxide gives the ketoester XXXIV. The ketone is then reduced using the chiral Oxazaborolidine XXXV in the presence of borane/THF complex. Reaction of the ester with an organometallic reagent gives the diol XXXVI, which is chiral XXII. Protection of the secondary alcohol with tertiary butylchlorodiphenylsilane in the presence of a base such as 4-(dimethylamino)pyridine, protection of the tertiary alcohol

in as the 2-tetrahydropyranyl ether, and removal of the silyl ether gives XXXVII. The chiral center of XXXVII can be inverted to form XXXVIII using conditions such as: (1) treatment with triphenylphosphine, diethylazodicarboxylate and an acid such as R-(-)α-methoxyphenylacetic acid (chiral acid

) improves dissolution), and (2) hydrolysis of the ester thus obtained with a base such as NaOH. Formation of the mesylate and substitution with the thiol IX as in Method C, followed by hydrolysis of the 2-tetrahydropyranyl ether using conditions such as pyridinium p-toluenesulfonate 3 in methanol gives the thioethers XXXIX and XL.

Method H

The bromoaldehyde XLI is reduced with a reagent similar to sodium borohydride, and the resulting benzylic alcohol is protected as the 2-tetrahydropyranyl ether. The Grignard reaction of XVII op XV gives a hydroxy acid, which is then converted to the ketone XLIII as in Method C. Substitution with the thiol IX is then carried out (as in Method C) to form XLIV. An organometallic reagent is then added to this ketone to form a tertiary alcohol. In cases where Q"*"

is an acid, it is protected as the methyl ester using a reagent such as CH.^^. Deprotection of the benzylic alcohol, followed by oxidation with a reagent such as MnC^/ gives the aldehyde XLV. A Wittig reaction with a phosphonium derivative of a substituted 2-(bromomethyl)quinoline, followed by a hydrolysis step when Q is an ester, gives the styrylquinoline

XLVI.

Method I

The phenylacetic acid XLVII is reduced to the alcohol XLVIII using a reagent such as borane in tetrahydrofuran. Formation of the alcoholate with one equivalent of a Grignard reagent, followed by treatment with magnesium gives the dimagnesium salt of XLVIII. This is added to a ketone or an aldehyde using the alcohol XLIX. The bromide L is then formed using conditions such as (1) formation of the mesylate with methanesulfonyl chloride and triethylamine, and (2) substitution of the mesylate with sodium bromide in N,N-dimethylformamide. The dimagnesium salt of L is then formed as previously described, and added to the ketone IV. The adduct LI is then reacted with the thiol IX as in Method C to form LII.

Method J

The ketoester XXX is treated with the iodide LIII and decarboxylated as in Method F. Reduction of the ketone with et

» reagent such as NaBH4 gives the alcohol LIV. When reacted with an organometallic reagent in toluene, the nitrile LIV is converted

to the amine LV. The thiol IX is then added as in Method C, forming LVI. Reaction of an iodide with the amine LVI

gives a secondary or tertiary amine LVII. Both LVI and LVII are representative of structure I.

Method K

Vinyl magnesium bromide or alkyl magnesium bromide is added to the aldehyde derivative of IV to form LVIII. Applying the procedure of R.C. Larock et al.

(Tetrahedron Letters, 30, 6629 (1989), couple the aryl halide LIX to the alcohol LVIII to form LX. When Q 3 is an ester or an alcohol, LX can be converted to LXI or its epimer, a structure representative of Ia , using the procedure of Method G. Also when Q 3 is Q 1 , chiral reduction of the ketone gives LX with XXXV as in Method G, followed by formation of the mesylate and substitution with

the thiol LXII, LXIII, a structure representative of Ib.

Method L

The iodide LXIV is converted to a mixed zinc-copper organometallic reagent which is added to XXIII in the presence of BF2*Et20. This alcohol LXV is converted to a mesylate and displaced with LXII in the presence of a base such as C₂CO₂. Alternatively, the alcohol can be oxidized (Swern type) and reduced using a catalyst such as B-chlorodiisopinocampheylborane (H.C. Brown et al., J. Am. Soc., 1988, 110, 1539) before mesylation and displacement to form LXVII or its enantiomers.

Method M

The tertiary alcohol of LX is first protected with dihydropyran (DHP) and the ketone is then reduced with (-)-B-kloxdiis"opinocamfeyibar.aji: ;. or as in Method G during formation

of LXVIII. The secondary benzylic alcohol is then converted to thiolacetate LXIX using the conditions of Volante (Tetrahedron lett., 22, 3119 (1981)). The thiol ester is cleaved with hydrazine or an alkoxide, and the side chain is added by nucleophilic substitution in the presence of a base such as Cs2C02-Deprotection of the tertiary alcohol gives LXX, the isomer of LXI.

Method N, P, Q and R describe the formation of 1-(mercaptomethyl)cyclopropaneacetic acid and its ester, derivatives which are useful for practicing the invention. Method R is described in detail in Example 161.

Method N

A diester of itaconic acid is cyclopropanated using CH2N2/Pd(OAc)2 (Synthesis, 1981, 714) or Me3SI/n-BULi (J. Org. Chem., (1973), 38, 3942) or.Me2SOI/NaH

(J. Am. Chem. Soc. , (1965), 87, 1353) or the Simmons-Smith conditions (J. March, Advanced Organic Chemistry, 3rd ed., 1985, pp. 772-773). The cyclopropane ring can also be prepared by adding a dihalocarb and reducing the thus obtained dihalocyclopropane. Hydrolysis of the diester and dehydration of the diacid gives the cyclopropanated succinic anhydride. This anhydride can alternatively be prepared directly by cyclopropanation of itaconic anhydride. Reduction with LiAlH^ or NaBH^ (Can. J. Chem., 56, 1524 (1978)) and acidification gives the lactone. The lactone is opened to the bridge master with HBr (Heiv. Chim. Acta. 63, 2508 (1980)), and the bromide substituted with KSH (Chem .Abstr. 58 P11490b) or AcSNa Hydrolysis with KOH gives the mercaptoic acid.

Method P

A cuprate reagent is prepared from a bromomethyl sulfide such as bromomethylbenzyl sulfide by reaction with butyllithium and a copper salt. Alternatively, this reagent is prepared from the tributyltin derivative as shown. 1,4-addition of this cuprate to an α,B-unsaturated cyclopropylidene ester gives the protected (1-mercaptomethyl)cyclopropane acetate. Deprotection with Na/NH^ when Z is a benzyl group, and hydrolysis, gives the mercaptoic acid.

Method Q

2-(bromomethyl)acrylate is reacted with a thiol such as benzyl mercaptan. Reduction of the ester with a reagent such as diisobutyl aluminum hydride gives the primary alcohol. Cyclopropanation of the double bond as in Method N gives 1-(hydroxymethyl)cyclopropanemethylthioether. If the ester

is reduced first, it is then advantageous to carry out the cyclopropane ring with C^^ or by the Simmons-Smith procedure. If ester.en. is to be cyclopropanated first, it is advantageous to use one of the sulfonium reagents in Method N. Mesylation of the primary alcohol, substitution with cyanide, hydrolysis of the nitrile and removal of the Z group (with Na/NH^ when Z is benzyl) gives the desired mercapto acid .

Method R

Diethyl-1,1-cyclopropanedicarboxylate is reduced to the diol with a reagent such as LiAlH^, and monoprotected as, for example, a benzoyl ester. The alcohol is mesylated and substituted for a cyanide group. Hydrolysis and esterification give methyl-1-(hydroxymethyl)cyclopropane acetate. This hydroxyester can also be prepared from the lactone of Method N. The alcohol is mesylated and substituted with a thiol acetate group. This group can alternatively be introduced by the action of thiolacetic acid/triphenylphosphine/diisopropylazodicarboxylate (Tetrahedron Lett., 22, 3119

(1981)) on the hydroxyl group. The thiol is then formed in situ with hydrazine.

In the following forms, Qu =

R<1>, R2, R3, Q<1> are defined as above, and in which

CR3R22 can be the radical of a standard amino acid;

R<4> is halogen, -NO2, -CN, -OR<3>, -SR3, NR<3>R3, NR<3>C(0)R<7>

or R<3>;

R<5> is H, halogen, -NO2, -N3, -CN, -SR<2>, -NR3R<3>, -OR<3>,

lower alkyl or -C(O)R<3>;

R<7> is H or C1-C4 alkyl;

R 16 is H, C 1 -<C> 4 alkyl or OH;

R22 is R<4>, CHR<7>OR<3> or CHR<7>SR<2>;

m is 0-8;

n is 0 or 1;

p is 0-8;

m + n + p is 1-10 when r is 1 and X<2> is 0, S, S(0) or S(0)2; m + n + p is 0-10 when r is 1 and X<2> is CR<3>R16;

m + n + p is 0-10 when r is 0;

m' + n' + p' is 0-10;

r and r' are independently 0 or 1;

s is 0 or 3;

X is independently 0, S, S(0), S(0)2 or CR<3>R16;

Y is -CR<3>=CR<3-> or -C=C-;

Z<1> and Z2 are independently -HET( -R3-R5) -;

HET is the diradical of a benzene, a pyridine, a furan or a thiophene.

Tests for determining biological activity

The compounds of formula I can be tested using the following assays to determine their mammalian leukotriene antagonist activity and their ability to inhibit leukotriene biosynthesis.

The leukotriene antagonist properties of the compounds of the invention were evaluated using the following assays.

LTD^ receptor binding studies in guinea pig lung membranes, guinea pig trachea and in vivo studies in anesthetized guinea pigs

A full description of these three tests is given by T.R. Jones et al., Can. J. Physiol. Pharmacol., 67, 17-29 (1989).

The compounds of formula I were tested using the following assays to determine their mammalian leukotriene biosynthesis inhibitory activity.

Determination of inhibition of 5-lipoxygenase

The activity of 5-lipoxygenase was measured from the conversion of [14 C]-arachidonic acid to 5-HETE and 5,12-diHETE catalyzed by the 10,000 x g supernatant fraction from rat PMN leukocytes, using the procedure of Riendeau and Leblanc (Biochem . Biophys. Res. Commun., 141, 534-540 (1986)) with minor modifications. The incubation mixture contained 25 mM Na<+>/K<+->phosphate buffer, pH 7.3, 1 mM, ATP, 0.5 mM CaCl 2 , 0.5 mM. mercaptoethanol and an aliquot of the enzyme preparation in a final volume of 0.2 ml. The enzyme was pre-incubated with the inhibitor for 2 minutes at 37° C before starting the reaction with the addition of

2 ml of [14C]-arachidonic acid (25,000 DPM) in .ethanol during formation

> of a final concentration of 10 mM. Inhibitors were added as 500-fold concentrated solutions in DMSO. After incubation for 10 minutes at 37° C, the reaction was stopped by the addition of 0.8 ml of diethyl ether/methanol/1M citric acid (30:4:1).

The samples were centrifuged at 100 0 x g for 5 minutes, and they

> organic phases were analyzed by TLC on Baker Si250F-PA or Whatman silica gel 60A LKGF plates using diethyl ether/petroleum ether/acetic acid (50:50:1) as solvent. The amount of radioactivity that migrated to the positions of

Arachidonic acid, 5-HETE and 5,12-diHETE were determined using a Berthold TLC analyzer LB 2842. The activity of 5-lipoxygenase was calculated from the percentage of conversion of arachidonic acid to 5-HETE and 5,12-diHETE after 10 minutes of incubation .

Human polymorphonuclear (PMN). leukocyte LTB^ test

A. Preparation of human PMN

Human blood was obtained by antecubital venipuncture from consenting volunteers who had not taken drugs in the previous 7 days. The blood was immediately added to 10% (v/v) trisodium citrate (0.13 M) or 5% (v/v) sodium heparin (1000 IU/ml). PMN were isolated from anticoagulated blood

by dextran sedimentation of erythrocytes, followed by centrifugation through Ficoll-Hypaque (specific gravity 1.077),

as described by Boyum. Contaminating erythrocytes. were removed by lysis followed by exposure to ammonium chloride (0.16 M) in Tris buffer (pH 7.65), and PMN were resuspended to 5 x 10<5> cells/ml in the HEPES (15 mM) buffer Hanks balanced 2+ 2+

j salt solution containing Ca (1.4 mM) and Mg (0.7 mM), pH 7.4. . Viability was determined by trypan blue exclusion and was typically greater than 98%.

B. Generation and radioimmunoassay of LTB4.

5 PMN (0.5 ml; 2.5 x 10 cells) were placed in plastic tubes and incubated (37°C, 2 minutes) with the test compounds at the desired concentration or vehicle (DMSO, final concentration 0.2%) as a control. The synthesis of LTB^ was initiated by the addition of calcium ionophore A23187 (final concentration 10 mM) or o carrier in control samples, and was allowed to proceed for 5 minutes at 37° C.

The reactions were then terminated by the addition of cold methanol (0.25 mL) and samples of the complete PMN reaction mixture were removed for radioimmunodetermination of LTB^.

Samples (50 ml) of authentic LTB^ of known concentration in radioimmunoassay (RIA) buffer (potassium phosphate 1 mM; disodium EDTA 0.1 mM; Thimerosal 0.025 mM; gelatin 0.1%, pH 7.3) or PMN -reaction mixture diluted 1:1 with RIA buffer was added to the reaction tubes. Then [ H]-LTB^ became

(10 nCi in 100 ml RIA buffer) and LTB4 antiserum (100 ml of a 1:3000 dilution in RIA buffer) were added and the tubes were shaken. The reactants were allowed to equilibrate by overnight incubation at

4° C. To separate antibody-bound from free LTB^, 5 aliquots (50 ml) of activated carbon (3% activated carbon in RIA buffer containing 0.25% Dextran T-70) were added, the tubes were shaken and allowed to stand at room temperature for 10 minutes before centrifugation (1500 x g; 10 min; 4°C). The supernatants containing

antibody-bound LTB^ was decanted into vials, and Aquasol 2

10 (4 ml) was added. The radioactivity was quantified by liquid scintillation spectrometry. Preliminary studies determined that the amount of methanol in the radioimmunoassay did not influence the results. The specificity of antiserum and the sensitivity of 15pprroodsuedsyerret n i is tebst litot g bkeonsktrreovlel- t (acv a. Ro2k0 anch g/e1t 0 g acle. l2leMre) npgdrøevn is of bLlTeB^.

calculated. Inhibitory dose-response curves were constructed using a four-parameter algorithm, and from these the IC^Q values were determined.

The compounds of formula I were tested in the following assays to determine their in vivo activity as both

leukotriene antagonists and leukotriene biosynthesis inhibitors.

25

30(1) Boyum, A. Scand. J. Clin. Lab. Invest.,

(21 (Supp. 97), 77 (1968).

(2) Rokach, J.; Hayes, E. C.; Girard, Y.; Lombardo,

D. L.; Maycock, A. L.; Rosenthal, A. S.; Young,

R.N.; Zamboni, R.; Zweerink, H.J. Prostaglandins

35 Leukotrienes and Medicine, 13, 21 (1984).

Asthmatic rat test

Rats were obtained from an inbred line of asthmatic rats. Both female rats (190 - 250 g) and male rats (260 - 400 g) were used.

Egg albumin (EA), grade V, crystallized and lyophilized, was obtained from Sigma Chemical Co., St. Louis. Aluminum hydroxide was obtained from Regis Chemical Company, Chicago. Methysergide bimaleate was supplied from Sandoz Ltd., Basel.

The challenge and subsequent respiration recordings were performed in a clear plastic box with internal dimensions of 25.4 x 15.24 x 10.16 cm. The top of the box was removable; in use it was held tightly in place by four clamps, and an airtight seal was maintained by a soft rubber gasket. Through the center of each end of the chamber a Devilbiss atomizer (No. 40) was inserted via an airtight seal, and each end of the box also had an outlet. A Fleisch No. 0000 pneumotachograph was inserted into one end of the box and connected to a Grass volumetric pressure transducer (PT5-A) which was then connected to a Beckman Type R dynograph via suitable connectors. While the antigen was nebulized, the outlets were open, and the pneumotachograph was isolated from the chamber. The outlets were closed,

and the pneumotachograph and chamber were connected while recording the breathing patterns. For challenge, 2 mL of a 3% solution of antigen in saline was placed in each nebulizer, and the aerosol was generated with air from a small Potter diaphragm pump operated at 0.7 kg/cm 2 and a flow of 8 liters/ minute.

The rats were sensitized by injection (subcutaneous) of 1 ml of a suspension containing 1 mg of EA and 200 mg of aluminum hydroxide in saline. They were used between days 12 and 24 after sensitization. To eliminate the serotonin component of the response, the rats were pretreated intravenously 5 minutes before the aerosol challenge with 3.0 mg/kg methysergide. The rats were then exposed to an aerosol of 3% EA in saline for exactly 1 minute, and their respiratory profiles were recorded for an additional 30 minutes. The duration of continuous dyspnea was measured from the respiratory records.

The compounds are generally administered either orally 1-4 hours before challenge, or intravenously 2 minutes before challenge. They were either dissolved in saline or 1% methocel or suspended in 1% methocel. The injected volume was 1 ml/kg (intravenous) or 10 ml/kg (oral). Before oral treatment, the rats were fasted overnight. Their activity was measured in terms of their ability to reduce the duration of symptoms of dyspnea in comparison to a group of vehicle-treated controls. Typically, a compound was evaluated with a series of doses, and

an ED^q was determined. This is defined as the dose (mg/kg)

which will inhibit the duration of symptoms by 50%.

Pulmonary. mechanisms in trained, conscious squirrel monkeys

The test procedure involves placing trained squirrel monkeys in chairs in aerosol-exposed chambers. For control purposes, pulmonary mechanism measurements of respiratory parameters are recorded for a period of approx. 30 minutes to determine each monkey's normal control value for that day. For oral administration, the compounds were dissolved or suspended in a 1% methocel solution (methylcellulose, 65HG, 400 eps) and were given in a volume of 1 ml/kg body weight. For aerosol administration of compounds, a DeVilbiss ultrasonic nebulizer was used. Pretreatment periods varied from 5 minutes to 4 hours before the monkeys were challenged with aerosol doses of either leukotriene D4 (LTD^) or Ascaris antigen.

After challenge, every minute of data was calculated

by a computer as a percentage change from control values for each respiratory parameter, including airway resistance (RL) and dynamic compliance (cavn)• The results for each test compound were then obtained for a minimum period of 60 minutes post-challenge, which were then compared with previously obtained historical baseline control values for this monkey. in addition, the total values for 60 minutes post-treatment for each monkey (historical baseline values and test values) were separately averaged and used to calculate the total percentage inhibition of LTD4 or Ascaris antigen response by the test compound.

For statistical analysis, the paired t-test was used.

(Reference: McFarlane, C.S. et al., Prostaglandins,

28, 173-182 (1984) and McFarlane, C.S. et al., Agents Actions 22, 63-68 (1987)).

Prevention of induced bronchoconstriction in allergic sheep A. Rationale: Certain allergic sheep with known sensitivity to a specific antigen (Ascaris suum) respond to inhalation challenge with acute and delayed bronchial responses. The time course of both the acute and the late bronchial response approximates the time course observed in asthmatic subjects, and the pharmacological modification of both responses is similar to that found in humans. The effects of the antigen in these sheep are predominantly observed in the large airways and are appropriately monitored as changes in lung resistance or specific lung resistance.

B. Methods:

Animal preparation: Adult sheep with an average weight of

in 35 kg (range 18 to 50 kg) was used. All animals had to meet two criteria: a) they have a natural cutaneous reaction to 1:1000 or 1:10,000 dilutions of Ascaris suum extract (Greer Diagnostics, Lenois, NC), and b) they have previously reacted to inhalation challenge with Ascaris suum with both an acute bronchoconstriction and a late bronchial obstruction (Abraham, W.M., Delehunt, J.C., Yerger, L. and Marchette, B., Am. Rev. Resp. Dis., 128, 839-44 (1983)).

Measurement of respiratory mechanisms: The non-sedated ) sheep were held down in a cart in a supine position with their heads immobilized. After topical anesthesia of the nasal passages with 2% lidocaine solution, a balloon catheter was passed through a

nostrils down into the lower esophagus. The animals were then incubated with a cuffed endotracheal tube through the other nostril using a flexible fiberoptic bronchoscope as a guide. Pleural pressure was determined with the oesophageal balloon catheter (filled with 1 ml of air) which was positioned so that inspiration elicited a negative pressure deflection with clear

noticeable cardiogenic oscillations. Lateral pressure in the trachea is measured with a side hole catheter (internal dimensions, 2.5 mm) passed through and placed distal to the top of the nasotracheal tube. Transpulmonary pressure, the difference between tracheal pressure and pleural pressure, is measured with a differential pressure transducer (DP45; Validyne Corp., Northridge, CA). Testing of the pressure transducer catheter system shows no phase shift between pressure and flow at a frequency of 9 Hz. For measurement of pulmonary resistance (RT), the maximal end of the nasotracheal tube is connected to a pneumotachograph (Fleisch, Dyna Sciences, Blue Bell, PA). The flow and transpulmonary pressure signals are recorded on an oscilloscope (model DR-12;

Electronics for Medicine, White Plains, NY) which is referred to

a PDP-11 digital computer (Digital Equipment Corp., Maynard, MA) for on-line calculation of R^ from transpulmonary pressure, and respiratory volume obtained by integration and flow. Analyzes of 10-15 breaths are used to determine RLT. Thoracic gas volume (V ) is measured in a body plethysmograph to obtain specific pulmonary resistance (SRL = VVt<?'

Aerosol— Delivery Systems: Aerosols of Ascaris suum extract (1:20) are generated using a disposable drug nebulizer (Raindrop<®>, Puritan Bennett) which produces an aerosol with a mass-median aerodynamic diameter of 6.2 u:M ( geometric standard deviation, 2.1) as determined by an electrical size analyzer (Model 3030; Thermal Systems, St. Paul, MN). The output from the atomizer is directed into a plastic t-tube where one end is connected to the nasotracheal tube, and the other ) end is connected to the inspiratory part of a Harvard respirator. The aerosol is delivered to a respiratory volume of 500 ml at a rate of 20 per minute. minute. Thus, each sheep receives an equivalent dose of antigen in both the placebo and drug trials.

Experimental protocol: Before antigen challenge, baseline measurements of SRLT are obtained, infusion of the test compound is started 1 hour before challenge, the measurement of SR^ is repeated, and the sheep are then challenged by inhalation with Ascaris suum antigen. Measurements of SRT Li are obtained immediately after antigen challenge

and at 1,..2, 3,. 4, 5, 6, 6.5, 7, 7.5, and 8 hours after antigen challenge. Placebo and drug tests are separated by at least 14 days. In a further study, the sheep were given a bolus dose of the test compound, followed by an infusion of the test compound for 0.5-1 hour before ascaris challenge and 8 hours after ascaris as described above.

A very important compound according to the invention is the compound according to example 32 of the structure:

With regard to EP 318 093, the attached therapeutic data shows receptor binding data for the compound according to example 1 in the counterpart and for several representative compounds according to the invention. The data clearly show that the compounds according to the invention have much better "shift" values than the reference compound. "The shift 11 value is the ratio of binding affinities of a test compound for the leukotriene D4 receptor in the presence or absence of human serum albumin.

[<3>H]leukotriene (LTD4) binding assays were performed

in vitro to determine the equilibrium inhibition constants (Ki) of LTD4 antagonists at LTD4 receptor a. K± values are a measure of affinity, which in turn is an index of the intrinsic activity of an antagonist at a given receptor. The [<3>H]LTD4 binding assay was also performed in the presence of human serum albumin (HSA) to evaluate the degree to which the β values of individual antagonists could be modulated by binding to circulating blood proteins. Compounds that have β values that increase in the presence of human serum albumin have been shown to have reduced in vivo activity in animal models, e.g. by antagonizing LTD-induced and antigen-induced bronchoconstriction in

conscious squirrel monkeys. It was therefore concluded that maximum in vivo potency should be reached using LTD4 receptor antagonist whose I^ value was not increased in the presence of human serum albumin. The ratio of K± in the presence of HSA to K± without HSA is indicated as the "shift" value.

Most of the compounds according to the invention have "shift" values of less than 5. In the presence of human serum albumin, these are thus not prevented by HSA from binding to the leukotriene receptor to a marked degree. In contrast, the closely related compound of the counterpart, the diacid of Example 1, exhibits an approximately 15-fold reduction in potency in the presence of

HSA.

Therapeutic data

Statistical analysis: A Kruskal-Wallis "one way" ANOVA test was used to compare the acute, immediate responses to antigen and the late peak response in the controls and the drug-treated animals.

The invention is further illustrated in the following examples. All temperatures are in degrees Celsius.

Example %

Sodium 3-((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-1-(3-( 2- hydroxy- 2- propyl) phenyl) methyl) thio)- 2- methylpropanoate Step 1: 3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-hydroxymethyl)benzoic acid

To the dilithium salt (5.92 mmol) obtained from 3-bromo-benzoic acid (W.E. Parham and. Y.A. Sayed, J. Org. Chem., 39, 2051

(1974)) a solution of 1.503 g (5.12 mmol) of 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde (US Patent 4,851,409, July 25, 1989, Example 24) was added , step 1) in 25 mL THF dropwise at -78° C. The mixture was stirred for 2 hours at -78° C and 25% aqueous NH 4 OAc was added. The mixture was acidified to pH 5 with AcOH and was extracted with EtOAc. The organic fractions were dried over Na 2 SO 4 and evaporated. Flash chromatography of the residue on silica using EtOAc:toluene:AcOH 30:70:1 gave the title compound.

<1>H NMR (CD3COCD3/CD3SOCD3): δ 5.90 (1H, s), 6.00 (1H,

s, OH), 7.36 - 7.58 (5H, m), 7.62 (1H, d), 7.73 (1H, d), 7.82 - 8.02 (6H, m), 8.13 (1H, s), 8.37 (1E, d) .

Step 2: Methyl 3-((3-(2-(7-chloro-2-quinolinyl)-ethenyl) phenyl) hydroxymethyl) benzoate

To a solution of HCl in MeOH, prepared from 10.0 mL (141 mmol) of acetyl chloride in 80 mL of MeOH at 0°C, 1.960 g (4.171 mmol) of the hydroxy acid from step 1 was added, and the mixture was stirred at room temperature for 4 days. It was then poured into 400 mL of cold 25% aqueous NH 4 OAc and 100 mL of THF. The ester was extracted with EtOAc:THF 1:1, dried over Na 2 SO 4 and purified by flash chromatography on silica with EtOAc:toluene 10:90 and 20:80. Yield: 1.653 g, 82%.

1 H NMR (CD3COCD3/CD3SOCD3): δ 3.85 (3H, s), 5.92 (1H,

d), 6.09 (1H, d, OH), 7.36 - 7.53 (4H, m), 7.56 (1H, d), 7.62 (1H, d), 7.75 (1H, d), 7.82 - 8.03 (6H, m) ,

8.13 (1H, br s), 8.37 (1H, d).

Step 3: 3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phen hydroxymethyl)-α,α-dimethylbenzenemethanol

To a solution of the ester from step 2 in toluene at 0° C, 3 equivalents of MeMgCl were added dropwise. The reaction mixture was stirred for an additional 1 hour at room temperature and 25% NH 4 OAc was added. Extraction with EtOAc and flash chromatography of the residue gave the title tertiary alcohol in 86% yield.

<L>H NMR (CDCl3/CD3SOCD3): δ 1.50 (6H, s), 4.70 (1H, s,

OH), 5.72 (1H, d, OH), 5.80 (1H, d), 7.27 (1H, d),

7.32 - 7.56 (6H, m), 7.64 (1E, s), 7.71 - 7.87 (5H,

m), 8.02 (1H, s), 8.22 (1E, d).

Step 4: 3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-chloromethyl)- a,g- dimethylbenzenemethanol

To a solution of 5081.rag (1.182.mmol) of the diol from step 3 in 16 ml CH 2 Cl 2 :THF 1:1 at -40° C. was added 250 µl (1.80 mmol) Et^N and 110 µl (1 .42 ymol) methanesulfonyl chloride,

and the mixture was stirred at -40°C for 30 minutes, then at 0°C for 2 hours and at room temperature for 3 hours. Aqueous 5% NaHCO 3 was added and the product was extracted with CH 2 Cl 2 , dried over Na 2 SO 4 and evaporated to dryness to give the title compound.

<X>H NMR (CDCl3): δ 1.57 (6E, s), 6.20 (1H, s), 7.25 -

7.52 (7H, m), 7.52 - 7.78 (6H, m), 8.10 (1E, s), 8.14

(1H, d).

Step 5: Ethyl-3-(acetylthio)-2-methylpropanoate

39 mmol of ethyl-2-methylpropenate was diluted with

5.6 ml (78 mmol) of thiolacetic acid and was stirred at 65° C. for 36 hours. The mixture was then diluted with ether, washed with water and the organic phase was dried with Na 2 SO 4 . Evaporation to dryness gave the title material as an orange oil which was used as such in the next step.

Step 6: Ethyl-3-mercapto-2-methylpropanoate

At -20°C, 150 mL (450 mmol) of 3N NaOH was added dropwise to a solution of 66.47 g (349 mmol, step 5) of ethyl 3-(acetylthio)-2-methylpropanate in 700 mL of MeOH, and the mixture was stirred at this temperature for 30 minutes. 25% aqueous NH 3 OAc was then added and the title thiol was extracted with EtOAc, dried over MgSO 4 , concentrated and distilled to give 42.52 g (82%) of the title compound as an oil; b.p.: 96 - 98° C/15 mmHg.

1H NMR (CDCl 3 ): δ 1-21 - 1.36 (6H, m), 1.50 (1H, t,

SH), 2.66 (2H, m), 2.81 (1H, m), 4.19 (2H, q).

Step 7: Ethyl-3-((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-1-(3-(2-hydroxy-2-propyl)phenyl)methyl) -thio)-2-methylpropane. oat

To the impure chloride from step 4 dissolved in 10 ml DMF was added 350 µl (approx. 2.4 mmol, step 6) ethyl 3-mercapto-2-methylpropanate and 1.61 g (4.9 mmol) Cs2CO2, and the mixture was stirred at room temperature for 3.5 hours. 25% aqueous NH 4 OAc was then added and the reaction mixture was extracted with EtOAc, dried over Na 2 SO 4 and purified by flash chromatography on silica using EtOAc:toluene 7.5:92.5 and 10:90 to give 347 mg of the title compound as an oil (52% yield for steps 6 and 7).

<1>H NMR (CDCl3): δ 1.20 (3H, d), 1.25 (3H, t), 1.58

(6H, s), 1.96 (1H, s, OH), 2.47 (1H, m), 2.62 (1H,

td), 2.74 (1H, m), 4.15 (2H, q), 5.23 (1H, s), 7.27 -

7.57 (8H, m), 7.57 - 7.79 (5H, m), 8.09 (1H, s), 8.12

(1H, d).

Step 8

A mixture of 6.67 mmol of the ester from Step 7 and 1.0N NaOH (13 mL) in 55 mL of MeOH:THF 3:2 was stirred at room temperature for 24 h. 25% aqueous NH 4 OAc was then added and the mixture was acidified with HOAc. The title acid was extracted with EtOAc, dried over Na 2 SO 4 and purified by flash chromatography on silica with acetone:toluene:HOAc. Yield: 74%.

To this acid in 10 ml of EtOH was added 1.0N

NaOH (1.0 equiv)..- The solvents were evaporated and the product was freeze-dried to give the title compound as a yellowish solid.

Analysis: Calculated for C31H29ClN03SNa«H20:

C 65.08 H 5.46 N 2.45

Found: C 64.85 H 5.09 N 2.38

Example 2

2(S)-(((1(S)-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-4-(2-(2-hydroxy-2-propyl)phenyl)butyl) )thio)methyl)butanoic acid Step 1: 1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-buten-1-ol Using allylmagnesium bromide, the title alcohol was obtained.

<1>H NMR (CD3COCD3): δ 2.52 (2H, t), 4.36 (1H, d), 4.78

(1H, m) 4.95-5.15 (2H, m) , 5.75-6.00 (1H, m),

7.30-7.65 (5H, m) 7.70-8.10 (5H, m), 8.32 (1H, d).

Step 2: 2-( 2-( 2- iodophenyl)- 2- propoxy) tetrahydropyran

To a solution of 7.33 g (28 mmol) of methyl-2-iodo-benzoate in 70 ml of toluene at -20° C. was added dropwise 56 ml (3 equivalents) of 1.5 M MeMgBr. When the addition was complete, the ice bath was removed and the mixture was stirred for an additional 1 hour. To the mixture was added aqueous NH 4 Cl at 0° C. Extraction with EtOAc and evaporation of the solvent gave an oil which was purified by flash chromatography using EtOAc/hexane (1:20 and 1:15) to give 2-iodo-a, α-dimethylbenzenemethanol (2.40 g) which was used as such ► To a solution of 2.40 g (9.16 mmol) of this tertiary alcohol in 20 mL of CH2Cl2 containing 4.17 mL (5 equivalents) of 3,4- dihydro-2H-pyran at 0° C., 313 mg (0.1 equivalent) of triphenylphosphine hydrobromide was added, and the mixture was stirred at room temperature for 1/2 hour. Aqueous 25% NH 4 OAc was then added and the title product was extracted with CH 2 Cl 2 , dried over Na 2 SO 4 and purified by flash chromatography on silica using EtOAc:hexane 1:20 to give 2.69 g of an oil.

<1>H NMR (CD3COCD3) : 6 1.4-2.0 (6H, m) , 1.72 (3H, s) ,

1.79 (3H, s), 3.38 (1H, m), 3.90 (1H, m), 4.58 (1H,

m), 6.98 (1H, dt), 7.38 (1H, dt), 7.58 (1H, dd), 8.03

(1H, dd).

Step 3: 1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-4-(2-(2-( 2- tetrahydropyranyloxy)- 2- propyl) phenyl)- 1- butanone 2 .69 g (7.78 mmol) of the iodide from Step 2 was coupled with 2.11 g (7.0 mmol) of the homoallylic alcohol from Step 1 at 100° C. for 4 h to give 1.50 g of the title compound and 1.04 g of 2-(2-(4-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-4-oxobutyl)phenyl)-2-propanol, which can be converted to the title product using the procedure of step 2. 1 H NMR (CD 3 COCD 3 ): δ 1.35-1.85 (6H, m), 1.53 (3H, s),

1.72 (3H, s) 2.12 (2H, m), 2.99 (1H, m), 3.19-3.40

(4H, m), 3.88 (1H, s) 4.50 (1H, m), 7.05-8.40 (15H,

m).

Step 4: 1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-4-(2-( 2-( 2- tetrahydropyranyloxy)- 2- propyl) phenyl)- 1 - butanol Using the procedure of Example 4, Step 4, the ketone from Step 3 was reduced to the title (R)-alcohol.

1E NMR (CD3COCD3): δ 1.35-2.00 (10H, m), 1.55 (3H,

s), 1.68 C3H, s), 2.80-3.40 (3H, m), 3.85 <1H, m),

4.44 (1H, m), 4.80 (1H, m), 7.00-8.05 (14H, m), 8.34

(1H, d).

Step 5:

Using the procedures of Example 15, Step 7, the mesylate of the alcohol from Step 4 was prepared.

To a solution of 144 mg (1.1 mmol) of the thiol from Example 32, step 10 in .1 mL of DMSO in a water bath was added 56 mg (2.26 mmol) of 97% NaH. After 15 minutes, a solution of 523 mg (0.82 mmol) of the above mesylate in 2 ml of DMSO was added dropwise. After stirring for 1 hour, the reaction mixture was added with 25% aqueous NH4OAc at 0° C. Acidification with HOAc, extraction with EtOAc, drying over Na2SO4 and flash chromatography of the residue on silica using EtOAc: hexane:HOAc 20:80:1. gave the impure thioether.

Finally, the tetrahydropyranyl ether was hydrolyzed as indicated in Example 15, step 10, to form the title acid.

<1>H NMR (CD3COCD3): δ 0.82 (3H, t), 1.40-1.85 (4H, ra),

1.55 (6H, s), 2.00 (2H, m), 2.38-2.65 (3H, m), 3.00

(2H, t), 4.06 (1H, t), 7.08 (3H, m), 7.35-7.69 (6H,

m), 7.70-8.05 (5H, m) 8.35 (1H, d).

Example 3

Sodium-3- ( (1- (3- (2- (7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2-( 2- hydroxy- 2- propyl) phenyl) propyl) thio)- 2 - methylpropanoate Step 1: 3-bromobenzenemethanol

157 mmol of 3-bromobenzaldehyde was dissolved in 300 ml of THF. At 0°C, 800 mL of EtOH was added, followed by 5.93 g (157 mmol) of NaBH 2 . The mixture was then stirred at room temperature for 1 hour and poured into cold 25% aqueous NH 4 OAc. The organic solvents were evaporated and the residue was extracted with toluene:THF 1:1, dried over Na 2 SO 4 and filtered through silica to give the title compound.

Step 2: 2-((3-bromophenyl)methoxy)tetrahydropyran

41.23 mmol of the alcohol from step 1, 12.5 mL (137 mmol) of dihydropyran and 725 mg (2.11 mmol) of triphenylphosphine hydrobromide were mixed together in 200 mL of CH 2 Cl 2 and stirred for 2 days. The solvent was then evaporated and the title product was purified by flash chromatography on silica using EtOAc:toluene.

Step 3: 3,4-dihydro-l-naphthalenyl acetate

A mixture of 200 mL (1.5 mol) α-tetralone and 4 mL concentrated H 2 SO 4 in 1.0 L (9.08 mol) isopropenyl acetate was heated to reflux overnight. The solution was cooled to room temperature and was filtered through a mixture of celite, NaHCO 3 and silica (ca. 1:1:0.2) with EtOAc and was concentrated to give 317.1 g of crude title product; k.p. : 90°C/0.5 mitiHg.

<1>H NMR (CDCl3) : δ 2.30 (3H, s), 2.44 (2H, td), 2.87

(2H, t), 5.70 (1H, t), 7.10 (1H, m), 7.13 - 7.20 (3H,

raw).

Step 4: 2-(3-oxopropyl)benzoic acid

At -50° C., 200 ml of MeOH was added to a solution of 214 g (about 1.04 mol) of the enol acetate from step 3 in 800 ml of acetone. At -78° C, ozone was bubbled through this solution for 7 hours (or until the excess of 0 2 produced a green color). The excess 0^ was blown away with a stream of N 2 , and a solution of 327 g (1.25 mol) of triphenylphosphine in 1 liter of acetone was then added slowly at -7 8° C. The temperature was slowly raised to -10° C over 30 minutes, 700 mL of 1N HCl was added slowly, and the mixture was stirred at 3°C

for 16 hours. The organic solvent was evaporated, 500 mL of EtOAc was added, and the mixture was made alkaline with an excess of NaHCO 3 (ca. 270 g). The aqueous phase was washed with 2 x 1 L of EtOAc, and the organic layers were re-extracted with 1 L of saturated NaHCO 3 under stirring for 2 hours. The combined aqueous extracts were then acidified with concentrated HCl and extracted with EtOAc. The extract was dried over Na 2 SO 4 , the solvent was evaporated and the acetic acid was co-evaporated with toluene to give 13 9.6 g of the title compound

(75% for steps 3 and 4) as a white solid.

<1>H NMR (CDCl 3 ): δ 2.88 (2H, t), 3.36 (2H, t), 7.35

(2H, dd), 7.53 (1H, dd), 8.11 (1H, d), 9.86 (1H, s).

Step 5: 2-(3-hydroxy-3-(3-((2-tetrahydropyranyloxy)-methyl) phenyl) propyl) benzoic acid

At -10°C, a solution of 5.045 g (28.3 mmol)

of the aldehyde from Step 4 in 50 mL THF added dropwise to 0.57 M 3-((2-tetrahydropyranyloxy).methyl)phenylmagnesium bromide in THF (12 0 mL, 68.4 mmol, prepared from the bromide from Step 2 and Mg in THF , and filtered to remove excess Mg), and the mixture was stirred at room temperature for 30 minutes. At 0° C, 25% aqueous NH4OAc was added. The title product was extracted with EtOAc, dried over Na 2 SO 4 and purified by flash chromatography on silica using acetone:toluene:HOAc 5:95:1 and 15:85:1.

LK NMR (CD3COCD3): δ 1.41 - 1.86 (8H, in), 1.93 - 2.08

(2H, m), 3.11 (2H, m), 3.45 (1H, m), 3.83 (1H, m),

4.45 (1H, d), 4.66 (2H, m), 7.10 - 7.53 (7H, m), 7.91

(1H, d)..

Step 6: 3-(2-acetylphenyl)-1-(3-((2-tetrahydropyranyloxy)-methyl) phenyl) propanol

At 0 °C, 7.5 mL (11.25 mmol) of 1.5 M MeLi was added dropwise to a solution of 2.65 mmol of the hydroxy acid from step 5 in 30 mL of THF, and the mixture was stirred at 0 °C for 1 h .

At 0°C, 2.8 mL (22.1 mmol) of distilled TMSC1 (chlorotrimethylsilane) was added, and the mixture was stirred at room temperature for 1 hour. At 0°C, 25% aqueous NH4OAc was then added,

and the solution was stirred at room temperature for 1.5 hours. The title product was extracted with EtOAc, dried over Na 2 SO 4 and purified by flash chromatography on silica.

Step 7: Ethyl 3-((3-(2-acetylphenyl)-1-(3-((2-tetrahydro-pyranyloxy )methyl)phenyl)propyl)thio)-2-methylpropanoate

At -40° C., 1.60 ml (11.5 mmol) of Et^N (triethylamine) and 750 µl (9.69 mmol) of methanesulfonyl chloride were added to a solution of 7.39 mmol of the alcohol from step 6 in 74 ml CH 2 Cl 2 , and the mixture was stirred at -40° C. for 1 hour and at -10° C. for 45 minutes. Saturated aqueous NaHCO 3 was then added, and the mesylate was extracted with CH 2 Cl 2 , dried over Na 2 SO 4 , and concentrated. To this mesylate in 150 ml of anhydrous CH^CN,

2.20 ml (approx. 15 mmol) of ethyl 3-mercapto-2-methylpropanoate (Example 4, step 6) and 7.57 g (23.2 mmol) of Cs 2 CO 3 were added, and the mixture was stirred under a stream of N-2 for 2 hours. 25% aqueous NH 4 OAc was then added, and the title product was extracted with EtOAc, dried over Na 2 SO 4

and purified by flash chromatography on silica with EtOAc:toluene.

Step 8: 3-((3-(2-acetylphenyl)-1-(3-((2-tetrahydropyranyloxy)-methyl) phenyl) propyl) thio)- 2- methylpropanoic acid

A mixture of 6.67 mmol of the ester from step 7 and

13 ml of 1.0N NaOH in 55 ml of MeOH:THF 3:2 was stirred at room temperature for 24 hours. 25% aqueous NH 4 OAc was then added and the blading was acidified with HOAc. The title acid was extracted with EtOAc, dried over Na 2 SO 4 and purified by flash chromatography on silica with acetone:toluene:HOAc.

Step 9: Methyl 3-((3-(2-(2-hydroxy-2-propyl)-phenyl-1- (3-( (2-tetrahydropyranyloxy)methyl) phenyl) propyl) thio)- 2- methylpropanoate

To a well-stirred solution of 5.39 mmol of the methyl ketone from step 8 in 100 ml of anhydrous toluene, 9.0 ml (13.5 mmol) of 1.5 M MeMgBr was added dropwise at -10° C, and the suspension was stirred at 0° C. for 30 minutes. Saturated aqueous NH 4 Cl was then added and the product was extracted with EtOAc, dried over Na 2 SO 4 and purified by flash chromatography on silica using acetone:toluene:HOAc 4:96:1.

The crude acid was dissolved in Et 2 O, and diazomethane was added at 0° C. When the reaction was complete, HOAc was added, followed by 25% aqueous NH 4 OAc. The title ester was extracted with EtOAc, washed with 5% aqueous NaHCO 3 , dried over Na 2 SO 4 and purified by flash chromatography on silica.

Step 10: Methyl 3-((3-(2-(2-hydroxy-2-propyl)phenyl)-1-(3-hydroxymethyl) phenyl) propyl) thio)- 2- methylpropanoate

A mixture of 5.019 mmol of the ester from Step 9 and 500 mg (1.99 mmol) of pyridinium p-toluenesulfonate in 30 mL of MeOH was stirred at room temperature for 16 h and then evaporated to dryness. Flash chromatography of the residue on silica gave the title compound.

Step 11: Methyl 3-((1-(3-formylphenyl)-3-(2-(2-hydroxy-2-propyl) phenyl) propyl) thio)- 2- methylpropanoate

To a solution of 6.20 mmol of the benzyl alcohol from step 10 in 120 mL of EtOAc, 10.15 g (114 mmol) of activated MnO 2 was added portionwise, and the reaction was monitored by TLC.

When the reaction was complete (about 2 hours), the mixture was filtered through silica, concentrated and the title product was purified by flash chromatography on silica.

<X>H NMR (CD3COCD3): δ 1.11 (3H, 2d), 1.58 (6H, s),

2.25 (2H, m), 2.45 (1H, m), 2.61 (2H, m), 2.90 (1H,

m), 3.16 (1H, in), 3.61 and 3.65 (3H, 2s), 4.00 (1H,

2s), 4.15 (1H., 2t), 7.13 (3H, m) , 7.41 (1H, d), 7.60

(1H, t), 7.93 (2H, m), 8.00 (1H, s), 10.10 (1H, s).

Step 12: Methyl-3-((1-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)-phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl )-thio)- 2- methylpropanoate

To 525 mg (1.01 mmol) ((7-chloro-2-quinolinyl)methyl)-<5>triphenylphosphonium bromide (US Patent 4,851,409, Example 4, Step 2) in 2 mL of THF solution at -78° C, 472 ml (0.945 mmol) of 1.6 M nBuLi were added dropwise. After a few minutes, 140 mg (0.338 mmol) of the aldehyde from step 11 was then added and the resulting mixture was stirred at -78°C for 30 minutes. 3 The reaction mixture was then allowed to warm to room temperature within 30 minutes and 25% aqueous NH40Ac was added. The title product was then extracted with EtOAc, dried over Na 2 SO 4 and evaporated under reduced pressure. After purification by flash chromatography (20% EtOAc in toluene) the title compound was obtained as an oil (170 mg, 89%).

^■H NMR (CD 3 COCD 3 ): δ 1.10 (3H, 2d), 1-53 (6H, s),

2.25 (2H, m), 2.41 (1H, m), 2.66 (2H, m), 2.90 (1H,

m), 3.16 (1H, m), 3.58 and 3.60 (3H, 2s), 4.02 (1H, 2s), 4.08 (1H, m), 7.08 (3H, m), 7.33 - 7.55 (5H, m),

'7.61 (1H, m), 7.75 - 8.00 (5H, m), 8.28 (1H, d).

Step 13

Using the procedure of Example 1, Step 8, the ester from Step 12 was hydrolyzed to the title sodium salt.

Analysis calculated for C3-H,,GlNO,SNa«2H90:

Example 4

Sodium 3-((1-(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl ) thio)- 2-( S )- methylpropanoate Step 1: 1-( 3-( 2-( 7- chloro- 2- quinolinyl) ethenyl) phenyl) ethanone

To 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde was added MeMgBr (in THF at 0°C) to form an ethanol derivative, which was oxidized to the title compound as described in Example 3, step 11.

03

<1>H NMR (CD3COCD3): δ 2.68 (3H, s), 7.55 - 7.68 (3H,

m), 7.89 - 8.05 (6H, m), 8.36 (2H, m) .

Step 2: Methyl-2-(iodomethyl)benzoate

The title compound was prepared according to Example 10, Step 1.

Step 3: Methyl 2-(3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-oxopropyl) benzoate

To a suspension of 10.0 g (32.6 mmol) of the ketone

from step 1 and 2.7 g (47.4 mmol) of the iodide from step 2 in THF was added 4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The ketone was dissolved by heating, and the resulting solution was cooled to -60° C. A solution of 89.7 mL (30.9 mmol) of 0.35 M lithium diisopropylamide was then added dropwise. After the addition was complete, the dry ice bath was removed and the reaction mixture was allowed to warm to +10° C. The reaction was stopped by the addition of 25% aqueous NH40Ac,

and the desired product was extracted with EtOAc, dried over Na 2 SO 4 and evaporated under reduced pressure. The resulting mixture was purified by flash chromatography (toluene to 5%

EtOAc in toluene), yielding 8 g (55%) of the title product. <X>H NMR (CD3COCD3): δ 3.40 (4H, m), 3.87 (3H, s), 7.35

(1H, h), 7.40 - 7.65 (5H, m), 7.80 - 8.05 (7H, m),

8.30 (1H, d), 8.39 (1H, s).

Step 4: Methyl 2-(3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)- 3( R )- 3- hydroxypropyl) benzoate

At -20° C., 3.82 g (0.014 mol) of (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo(1,2-c)(1,3,2)oxazaborole (J. Am. Chem. Soc., 104, 5551 - 5553 (1987) added to a solution of 30.0 g (66 mmol) of the ketone from step 3 in 556 ml of THF. To this mixture was slowly added 111 ml 1.0M BH^ * THF over 10 minutes. After 15 minutes, the reaction was quenched with 250 mL of 2M HCl. After extraction with EtOAc, the organic phase was washed with 25% aqueous NH^OAc, followed by saturated NaCl. The solvent was removed at reduced pressure to give an oil which was purified by flash chromatography to give the title compound.

Step 5: α,α-dimethyl-2-(3-(3-(2-(7-chloro-2-quinoliny)ethenyl)-phenyl)-3(R)-3-hydroxypropyl)-benzenemethanol

At 0°C, 90 mL (270 mmol) of 3.0MMeMgCl was added slowly to a solution of 61 mmol of the ester from Step 4 in 350 mL of toluene, and the mixture was stirred at 0°C for 30 minutes. At 0° C, 25% aqueous NH4OAc was added, and the title product

was extracted with EtOAc, dried over Na 2 SO 4 and purified by flash chromatography on silica.

Step 6: 2-(3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3(R)-3-(diphenyl(2-methyl-2-propyl)-siloxy)propyl )-g,g-dimethylbenzenemethanol

A mixture of 24.37 g (52.75 mmol) of the diol from step 5, 22.0 ml (158 mmol) Et^N, 10.96 g (89.7 mmol) 4-(dimethyl-amino)pyridine and 28.0 ml (108 mmol) of t-butylchlorodiphenylsilane in 260 ml of CH 2 Cl 2 was stirred according to the invention for 18 hours and at the reflux temperature for 4 hours. At 0°C, 25% aqueous NH 4 OAc was added and the phases were separated. The aqueous phase: was extracted with EtOAc, and the combined organic layers were dried over Na 2 SO 4 and concentrated. The residue was purified twice by flash chromatography on silica with EtOAc:toluene 2.5:97.5 and 5:95 to give 28.92 g (79%) of the title silyl ether.

Step 7: 7-chloro-2-(2-(3-(3-(2-(2-(2-tetrahydropyranyloxy)-2-propyl)phenyl)-1-(R)-diphenyl(2-methyl-2 -propyl)-siloxy)propyl)phenyl)ethenyl)-quinoline

28.88 g (41.23 mmol) of the tertiary alcohol from

step 6, 12.5 mL (137 mmol) of dihydropyran and 725 mg (2.11 mmol) of triphenylphosphine hydrobromide were mixed together in 200 mL of CH 2 Cl 2

and was stirred for 2 days. The solvent was then evaporated and the title product was purified by flash chromatography on silica to give toluene and EtOAc:toluene 1.5:98.5 and 2.5:97.5. Yield: 29.90 g, 92%.

Step 8: 1-(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-( 2-( 2- tetrahydropyranyloxy)- 2- propyl) phenyl) propanol To a solution of 29.89 g (38.11 mmol) of the silyl ether from step 7 in 130 ml of anhydrous THF was added a 1.0 M loose-65

ning of Bu^NF in 100 mL of THF, and the resulting solution was kept at 8°C for 15 hours and then stirred at room temperature for 2 hours. At 0°C, 25% aqueous NH 4 OAc was added and the title alcohol was extracted with EtOftc, dried over Na 2 SO 4 and purified by flash chromatography on silica with EtOAc:toluene 10:90, 15:85 and 20:80.

Step 9: 3-((1-(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-(2-tetrahydropyranyloxy)-2-propyl) )phenyl)-propyl)thio)-2-(S)-methylpropanoic acid

1.58 mmol of the mesylate of the alcohol from step 8 was prepared using the procedure of Example 8, step 7. To a solution of 3.35 mmol of 2(S)-3-mercapto-2-methylpropanoic acid (prepared from commercially available 3 -(acetylthio)-2-(S)-methylpropanoic acid as in Example 4, step 6) 1 15 ml of anhydrous DMF at 0° C was added 530 mg (13.3 mmol) of 60% NaH in oil, and the mixture was stirred at room temperature for 2 hours. 25% aqueous NH 4 OAc was then added and the solution was acidified with AcOH and was extracted with EtOAc:THF 1:1.

The organic layers were dried over Na 2 SO 4 and evaporated. Flash chromatography of the residue on silica gave the title compound.

Step 10:

A mixture of 3.254 g (5.019 mmol) of the acid from step 10 and 500 mg (1.99 mmol) of pyridinium p-toluenesulfonate in 30 mL of MeOH was stirred at room temperature for 16 h and then evaporated to dryness. Flash chromatography of the residue on silica with EtOAc:hexane:HOAc 25:75:1 and 30:70:1 gave 2.458 g.

(87%) of the tertiary alcohol. The title sodium salt was then formed as indicated in Example 4, Step 8.

[α]D = -86.0° (c 1.00, THF)

Analysis calculated for C-^H-^ClNOoSNa*2H-0:

bb

Example 5

Sodium 3-((1-(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl) thio)-2-(S)-methylpropanoate

Step 1: 1-(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-(2-tetrahydropyranyloxy)-2-propyl)-phenyl) propanol

At 0°C, 7.6 ml (48.3 mmol) of diethyl azodicarboxylate was added dropwise to a solution of 17.47 g (31.97 mmol) of the alcohol from Example 16, step 8, 12.60 g (48.04 mmol ) triphenylphosphine and 8.07 g (48.6 mmol) of R-(-)-ct-methoxyphenylacetic acid in 320 ml of anhydrous THF. The mixture was stirred at 0°C for 30 minutes and the solvents were evaporated. Flash chromatography of the residue on silica using EtOAc:toluene 2.5:97.5, 5:95 and 7.5:92.5 gave 21.84 g (98%) of the inverted alcohol as the almond ester. This ester was hydrolyzed to the title alcohol as indicated in Example i, Step 8.

Step 2:

Using the procedure of Example 4, steps 9-10, the benzylic alcohol from step 1 was converted to the title sodium salt.

[ot] = +116.6° (c 1.08, THF)

Analysis calculated for C33H33<C>1N03SNa«2H20:

Example 18

Sodium 3-((1(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-1-(( 3- hydroxy- 3- methylbutyl) thio) methyl) thio)- propanoate Analysis calculated for C^gH^ClNC^S^a* 1.5H20:

67

Example . 6

3-((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2- propyl) phenyl) propyl) thio)- 2- ethyl - propanoic acid Melting point: 124 - 126° C.

Analysis calculated for C34H36C1N03S:

Example 7 3-((1-(3-(2-(7-chloro-2-quinolyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)- 2 - methoxypropanoic acid <X>H NMR (CD3COCD3): δ 1.55 (6H, s), 2.15-2.35 (2H, m), 265-2.95 (3H, m), 3.10-3.25 (1H, m), 3.35 ( 3H, d), 3.80-3.95 (1H, m), 4.20 (1H, t), 7.05-7.20 (3H,

m), 7.35-7.70 (6H, m), 7.80-8.00 (5H, m), 8.30 (1H,

d).

Example 8-Sodium-3-((1(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl) ) propyl) thio) - 2 ( R) - ethylpropanoate-Analysis calculated for C34H35ClN03SNa*2H20:

Example 9

Sodium 3-((1(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-( 2-( 2- hydroxy- 2- propyl) phenyl) propyl) thio )- 2( R)- methylpropanoate Analysis calculated for C,,H,,ClNO.,SNa' 2Ho0:

Example 10

3-((1-(S)-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio) - 2-( S )- ethylpropanoic acid Step 1: Methyl- 2-( iodomethyl) benzoate

Following the procedure described in Tetrahedron, 22, 2107 (1966), phthalide was converted to 2-(bromomethyl)benzoic acid using HBr in HOAc. The methyl ester was prepared by treatment with oxalyl chloride and methanol.

A mixture of 180 g Nal and 82.44 g (360 mmol) methyl-2-(bromomethyl)benzoate in 500 ml acetone was stirred at

room temperature for 2 hours. The acetone was evaporated and the product redissolved in EtOAc. This was washed with 25% aqueous NH 4 OAc, followed by 10% aqueous NaHCO 3 , a sodium bisulfite solution and brine. Evaporation to dryness afforded 100 g (100% yield) of the title iodide.

<X>H NMR (CDCl 3 ): δ 3.95 (3H, s), 4.93 (2H, s), 7.32

(1H, m), 7.43 (2H, m), 7.94 (1H, d).

Step 2: 1-(3-f2-(7-chloro-2-quinolinyl)ethenyl)phenyl)ethanone

To 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde

(US Patent 4,851,409, July 25, 1989, Example 24, Step 1)

was added MeMgBr (in THF at 0°C) to form an ethanol derivative which was oxidized to the title compound as described in Example 15, step 11.

<X>H NMR (CD3COCD3): δ 2.68 (3H, s), 7.55 - 7.68 (3H,

m), 7.89 - 8.05 (6H, m), 8.36 (2H, m).

Step 3: Methyl 3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-oxopropanoate

In a 500 mL flask equipped with a condenser, 57.05 g (185 mmol) of the ketone from step 2 and 13.70 mL (2.5 equiv) of dimethyl carbonate were suspended in 230 mL of THF. 16.70 g (3 equiv.) of 80% NaH was added portionwise over a few minutes, and the reaction was started by the addition of 370 µL of MeOH. The mixture was stirred at room temperature. The solids were gradually dissolved, and when the evolution of hydrogen had ceased, the mixture was heated to 70° C. for 1 hour. After cooling to room temperature, it was poured into cold 25% aqueous NH^OAc. The solid was collected and air dried and treated in 600 mL EtOH containing 50 mL EtOAc for 18 h. The title compound was collected as a light beige solid (60.3 g, 89% yield).

<X>H NMR (CD 3 COCD 3 ): 3.70 (s, 3H); 3.73 (small peak,

OCH3 of enol form); 7.45 - 7.70 (m, 6H); 7.90 - 8.10

(m, 3H) , 8.36 (d, 2H) .

Step 4: Methyl 2-(3-(3-(2-(7-chloro-2-quinolinyl)-ethenyl) phenyl)- 3- oxopropyl) benzoate

To a solution of 50.0 g (0.136 mol) of the B-ketoester from step 3 and 41.5 g (1.1 equiv.) of the iodide from step 1 in DMF at 0° C. was added 4, 51 g (1.1 equiv.) 80% NaH. The ice bath

was removed and the mixture was stirred at room temperature. After 2 hours when no starting material remained, the reaction mixture was poured into cold 25% aqueous NH 2 OAc. The collected solid was slurried in 60 mL of EtOH overnight, yielding 60.0 g of the pure adduct (97%).

The material obtained above was suspended in HOAc/conc. HCl mixture (1.2 L/240 mL) and was heated

to 90° C for 4 hours. After this had cooled to room temperature, it was poured into cold aqueous NH^Cl. The solid material was collected and air dried.

The above mixture (containing the title ester and its acid) was suspended in 500 ml of acetone containing 4.25 ml of Mel and 18 g of powdered K 2 CO 3 . The mixture was heated to 50° C. for 3 hours until the methylation was complete. The reaction mixture was partitioned between EtOAc and H 2 O.

The aqueous phase was extracted twice with EtOAc, and the combined organic phase was washed with brine, dried and concentrated. The resulting residue was recrystallized from EtOAc:hexane 1:1 to give 37.7 g (53% yield)

of the title compound.

Step 5: 4-( S )-( 1- methylethyl )- 2- oxazolidinone

The title compound was prepared according to Evans, Mathre and Scott (J. Org. Chem., 50, 1830 (1985)) from (S)-(+)-2-amino-3-methyl-1-butanol and diethyl carbonate in the presence of K2C03.

Step 6: 3-(1-oxobutyl)-4-(S)—methylethyl)-2- oxazolidinone

A mechanically stirred, cooled (-78°C) solution of 32.3 g (250 mmol) of the oxazolidinone from Step 5 in 830 mL of anhydrous THF was metalated with 163 mL (1.6M in hexane, 261 mmol) of n-BuLi , and was treated with 28.1 mL (271 mmol) of freshly distilled butanoyl chloride. The reaction mixture was heated to 0°C

and was stirred for 1/2 hour. Excess acid chloride was hydro-

lysed by the addition of 165 mL of 1M aqueous K"2CO3, followed by stirring the resulting two-phase mixture for 1 hour at room temperature. Volatiles were removed in vacuo, and the product was extracted three times into CB^Cl^. The combined organic extracts were successively washed with H 2 O and brine, dried over MgSO 4 and concentrated to give the title compound as a pale yellow oil (52.1 g, quantitative). A portion of this crude product was purified by flash chromatography on silica with EtOAc r hexane 1:4 during the formation of a colorless liquid.

<X>H NMR (CDCl 3 ): δ 0.88 (3H, d), 0.92 (3H, d), 0.99

(3H, t), 1.70 (2H, m), 2.38 (1H, m), 2.77 - 3.04 (2H,

m), 4.18 - 4.31 (2H, m), 4.44 (1H, m).

Step 7: 3-(l-oxo-2-(S)-(((phenylmethyl)thio)methyl)-butyl)- 4-( S)-( 1- methylethyl)- 2- oxazolidinone

A solution of 36.9 g (185 mmol) of the N-acylated product from Step 6 in 70 mL of anhydrous THF was added to a magnetically stirred, cooled (-78° C.) solution of LDA (lithium diisopropylamide) (prepared from 28, 6 mL (20.6 g, 204 mmol) diisopropylamine and 127.5 mL (1.6 M in hexane, 204 mmol) n-butyllithium) in 240 mL anhydrous THF. After stirring for 1/2 at -78° C, the resulting lithium enolate was treated with 52.3 g (241 mmol) of benzyl bromomethylsulfide for 2 hours at -20° C. The reaction was quenched by the addition of 200 ml of half-saturated aqueous NH 4 Cl. Volatiles were removed in vacuo and the product was extracted three times into C 2 C 2 . The combined organic extracts were successively washed twice with 1M aqueous sodium bisulfate, twice with 1M aqueous KHCO 3 and brine, dried over MgSO 4 and concentrated in vacuo to give 76.5 g of yellow liquid. This crude material was thoroughly purified by flash chromatography on silica with EtOAc:hexane 1:99, 2:98, 5:95, 10:90 and 15:85 to give the title compound as a colorless liquid (48.9 g) which was used as such in the next step.

Step 8: Benzyl-2-(S)-(((phenylmethyl)thio)methyl)-butanoate

To a magnetically stirred, cooled (-10°C) solution of lithium benzyloxide in anhydrous THF (400 mL), prepared from 28.7 mL (30.0 g, 277 mmol) of freshly distilled benzyl alcohol and 127.5 mL (1.6M in hexane, 204 mmol) n-BuLi, a solution of 48.9 g (ca. 146 mmol) of the product" from step 7 in 170 ml anhydrous THF was added over a 1/2 hour period. After 15 minutes at -10° C., the reaction mixture was warmed to 0° C., stirred for 2 h and the reaction was then quenched by the addition of 300 mL of semi-saturated aqueous NH 4 Cl . Volatiles were removed in vacuo and the product was extracted three times into CH 2 Cl 2 . The combined organic extracts were washed successively 3 times with H 2 O and brine, dried over MgSO 4 , and concentrated in vacuo to give 74 g of a pale yellow oil.This crude material was purified in two portions by flash chromatography on silica with toluene to give of the title compound as a colorless liquid (32.8 g), containing a small amount of benzyl butanoic acid ester and an unidentified impurity. This product was used as such in the next step.

<X>H NMR (CDCl 3 ): δ 0.87 (3H, t), 1.63 (2H, m),

2.48-2.61 (2H, m), 2.64- 2.76 (1H, m), 3.68 (2H, s),

5.16 (2H, s), 7.28 (5H, br s), 7.37 (5H, br s).

Step 9: 2-( S )-((( phenylmethyl) thio) methyl) butanoic acid

120 mL of ice—HOAc was added to a suspension

of 32.4 g (ca. 103 mmol) of the product from step 8 in 210 ml of 30-32% anhydrous HBr in ice-HOAc (ca. 1.03 mol) to complete the dissolution. The resulting solution was stirred at 70°C for 6 hours and at 50°C overnight. The reaction mixture was then cooled to room temperature, was diluted with

750 mL H 2 O and was extracted seven times with CH 2 Cl 2 . The combined organic extracts were concentrated in vacuo. The residue was diluted with 500 ml of toluene and was concentrated in vacuo five times to remove HOAc. The residue was dissolved in 750 mL 1M aqueous KOH, washed four times with CH 2 Cl 2 , acidified to pH 1 with concentrated HCl and extracted six times with CH 2 Cl 2 . The combined organic extracts were dried over Na 2 SO 4 and concentrated in vacuo to give 17.6 g of the title compound as a pale yellow liquid which was used as such in the next step.

<3->H NMR (CDCl3): δ 0.91 (3H, t), 1.66 (2H, m), 2.44 -

2.56 (2H, m), 2.65 - 2.75 (1H, m), 3.73 (2H, s), 7.31

(5H, br s).

Step 10: 2-( S )-( mercaptomethyl) butanoic acid

A solution of 17.4 g (77.6 mmol) of the carboxylic acid from step 9 in 30 ml of dry THF was added to ca. 200 ml of ammonia (condensed in the flask from the cylinder) at -78° C. The solution was warmed to -50° C, and 5.2 g (226 mmol) of sodium was added in small portions over a 1/2 hour period. After the reaction mixture had turned dark blue within 1/2 hour, the reaction was stopped by the addition of 10 g of NH 2 Cl. Ammonia was evaporated under a stream of nitrogen and THF was removed in vacuo. The residue was dissolved in 400 mL 1M aqueous KOH and was washed three times with Et 2 O. The aqueous solution was cooled to 0°C and acidified to pH 1 with concentrated HCl, and the product was extracted four times into Et 2 O. The organic extracts were dried over Na 2 SO 4 and concentrated in vacuo to give 11.0 g of crude product which was distilled under reduced pressure (short Vigreux column) to give the title product as a colorless liquid which solidified on cooling (8.43 g, 81%), b.p.: 102 - 104°C/approx. 2mmHg.

[cc]D = -20.3° (c 1.96, CHCl 3 ).

<1>H NMR (CDCl3): δ 0.98 (3H, t), 1.54 (1H, t), 1.64 -

1.82 (2H, m), 2.50 - 2.87 (3H, m).

Step 11

Using the procedure described in Example 4 steps 4-10, but replacing 3-mercapto-2-(S)-methylpropanoic acid with 2-(S)-(mercaptomethyl)butanoic acid (the thiol from step 10), the title product, sm .p. 115 - 117° C, obtained from the keto ester from step 4.

[ct]D for the acid = -115° (c 2.00, CHC13)

Analysis calculated for C3 .H-gClNC^S:

Example 11

3-((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl) phenyl) propyl) thio)- 2, 2 - dimethylpropanoic acid Melting point: 123 - 126° C.

Analysis calculated for C., ..H., ,C1N0.,S:

Example 12

Sodium 3-((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3- (3-( 2- hydroxy- 2- propyl) phenyl) propyl) thio)- 2 - ethylpropanoate Analysis calculated for Co4H,,-ClN0-.SNa«H?0:

Example 13

Sodium-3-((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-{1,1,1,3,3,3-hexafluoro-2 -hydroxy-2-propy 1) phenyl) - propyl) thio)- 2- ethylpropanoate

Analysis calculated for C^H^ClNO-jSFgNa* 2H20:

Example 14

Sodium 3-((1(R)-(3-(2-(7-chloro-2-quinolinyl ethenyl)phenyl)-3-(2-( 2- hydroxy- 2- propyl) phenyl) propyl) thio) - 2- <S) - ethylpropanoate [a]D (free acid) = +85.6° (c 1.64, CHClg).

Analysis calculated for C~ .H^t-ClNCsSNa• 1, 8H_0:

Example 15

Sodium 3-((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-( 2- hydroxy- 2- methylpropyl) phenyl) propyl) thio) propanoate Assay calculated for C-.^H^ClNO-.SNa* 2H-0:

Example 16 2-(((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)methyl )-pentanoic acid Melting point: 127 - 130° C. Example 17 Sodium-2(S)-(((1(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl) -3-( 2-( 2- hydroxy- 2- methylpropyl) phenyl) propyl) thio) methyl) butanoate Step 1: 1-( 2- iodophenyl)- 2- methyl- 2- propanol A 100 ml round flask was filled with 2 .6 g (9.4 mmol) of methyl 2-iodophenyl acetate, 10 ml of THF and 30 ml of toluene, and was kept under an argon atmosphere. This solution was cooled to -10°C and a solution of methylmagnesium bromide (14.4 ml of 1.5M in THF/toluene (1:3)) was added dropwise over 15 minutes. The reaction was allowed to proceed at room temperature for 3 hours. The reaction was quenched by the addition of 100 mL of 25% aqueous NH 4 OAc, and the product was extracted with 2 x 100 mL of EtOAc. The combined organic layers were dried over MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography and was eluted with EtOAc/hexane 15% v/v,

to give 1.38 g (53%) of the title compound as a colorless oil.

!h NMR (CD3COCD3): δ 1.20 (6H, s), 2.95 (2H, s), 3.40

(1H, s, OH), 6.90 (1H, dt), 7.30 (1H, dt), 7.50 (1H,

dd), 7.80 ppm (1H, dd).

Step 2: 1-(2-(3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-oxopropyl)phenyl)- 2- methyl- 2- propanol

Using 1-(2-iodophenyl)-2-methyl-2-propanol (Step 1) the title compound was prepared.

<1>H NMR (CDCl3): δ 1.30 (6H, s), 2.90 (2H, s), 3.20

(2H, h), 3.35 (2H, h), 7.17-7.30 (4H, m), 7.38-7.55

(3H, m), 7.65 (1H, d), 7.70-7.85 (3H, m), 7.93 (1H, d), 8.08-8.18 (2H, m), 8.25 (1H, s).

Step 3: 1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-(2-tetrahydropyranyloxy)-2-methylpropyl)phenyl)-1- propanone

A solution of 390 g (8.29 mmol) of the alcohol from step 2, 7.4 ml (81 mmol) of 3,4-dihydro-2H-pyran and 684 mg (2.7 mmol) of pyridinium p-toluenesulfonate in 44 ml CH 2 Cl 2 was heated to reflux for 23 h. The reaction mixture was allowed to cool to room temperature and 10% aqueous NaHCO 3 was added. The title product was extracted with CH 2 Cl 2 , dried over Na 2 SO 4 and purified by flash chromatography on silica using EtOAc:toluene 5:95. Yield: 4.22 g, 92%.

Step 4:

Using the procedure of Example 4, Step 4, the ketone from Step 3 was reduced to the (R)-alcohol. The mesylate was then formed as described in Example 3, Step 7, and was substituted with the thiol from Example 10, Step 10, using the procedure of Example 2, Step 5. Finally, the tetrahydropyranyl ether was hydrolyzed as in Example 3, Step 10, and the sodium salt of the acid was prepared as described in example ^ step 8.

Analysis calculated for C35H37ClN03SNa-4H20:

Example <18>

4-((1(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy- 2- propyl) phenyl) propyl) thio)- butanoic acid

This compound was prepared using ethyl 4-mercaptobutanoate (Chem. Abstr. 58 P11490c).

Example 19

4-((1(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy- 2- propyl) phenyl) propyl) thio)- 2- methylbutanoic acid

This compound was prepared according to the procedure of Example 28, but using methyl 2-methyl-4-mercapto-butanoate (Heiv. Chim. Acta 1980, 63, 2508) instead of the thiol.

Example 2t)

3- ((1-(S) - (3- (2- (7-chloro-2-quinolinyl) ethenyl) phenyl) -3-(3-(2-hydroxy- 2- propyl) phenyl) propyl) thio) - 2( S )-ethylpropanoic acid From methyl-3-iodobenzoate, the alcohol and the thiol of Example 10, step, 10, this compound was prepared by Method K, using the silylation-THP-desilylation-protection sequence of Method G.

Example 21

3-((1-(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(4-(2-hydroxy-2-propyl)phenyl)propyl)thio) - 2(S)-ethylpropanoic acid

This compound was prepared from methyl-4-bromo-benzoate by first treating it with methylmagnesium bromide to form the tertiary alcohol. The alcohol was then protected as a tetrahydropyranyl ether. Metallation followed by iodine addition gave the corresponding iodide, which was converted to the title compound by Method K using the thiol of Example 10, Step 10.

Example 2 2

3- ((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2- hydroxy- 2- propyl) phenyl) propyl). thio) butanoic acid

The title compound was prepared according to Method K, using the mesylate from Example 31,

step 7. The thiol was obtained from addition of thiolacetic acid on methylcrotonate, followed by K^CO^/MeOH hydrolysis of the resulting thiol ester.

Example 2 3

3- ( (1(R) - (3-(2- (7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy- 2- propyl) phenyl) propyl) thio)- 2- methylbutanoic acid

The title compound was prepared according to Method K using the mesylate from Example 31,

step 7. The thiol was prepared by reacting tiglic acid with benzyl mercaptan and piperidine, followed by Na/NH 2 debenzylation.

Example 24 3 (S)-((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl) propyl)thio)-butanoic acid The title compound was prepared according to Method K, using the mesylate of Example 31, step 7, and methyl 3(S)-mercaptobutanoate. This thiol was obtained by hydrazine deprotection of the thiol ester described below.

Methyl-3(S)-(acetylthio)butanoate

To a -23° C. solution of 10.48 g (40 mmol) PPh3 in 100 mL THF was added 6.28 mL (40 mmol) diethyl azodicarboxylate dropwise, and the mixture was stirred at -23° C. for 16 h, during which time a white precipitate was obtained. 30 ml of a THF solution of 2.36 g (20 mm) methyl-3(R)-hydroxybutanoate and 2.85 ml (20 mmol) thiolacetic acid were slowly added, and the mixture was allowed to slowly warm to 25° C. and was stirred for 16 h at 25° C. Most of the THF was removed in vacuo and 10 mL of EtOAc and 100 mL of hexane were added. Insolubles were removed by filtration, and the residue was purified by chromatography on silica gel to give the title compound.

[α]D<25>= -21'°' (c = 3, CHCl 3 ).

1-H NMR (acetone d6) δ 1.30 (3H, d), 2.25 (3H, s),

2.45-2.80 (2H, m), 3.62 (3H, s), 3.75-3.95 (1H, m).

Example 25 3 (R) - ( (1 (R) -(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl) propyl)thio)-butanoic acid The title compound was prepared according to Method K, using the mesylate from Example 31, step 7, and methyl 3(R)-mercaptobutanoate. This thiol was obtained by hydrazine deprotection of the thiol ester described below.

Methy. 1^ 3 ( R ) - acetyl thiobutanoate

The title compound was prepared from methyl 3(S)-hydroxybutyrate in an identical manner to that described for the (S)-isomer in Example 24.

[α]D<25>= +20.7° (c 3 , CHCl 3 ).

Example 26

3-(S)-((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-( 2- hydroxy- 2- propyl) phenyl) propyl ) thio)- 2-( S )- methylbutanoic acid This compound was prepared in accordance with the procedure of Example 24, but methyl 3-(R)-hydroxybutanoate was first alkylated with methyl iodide as described by

Keck et al., (J. Org. Chem., 1985, 4317) to form methyl 3-(R)-hydroxy-2-(S)-methylbutanoate. The latter was converted to the thiol according to the procedure of Example 24.

<*>H NMR (acetone<-d6> 5 1.10 (d, 3H), 1.33 (d, 3H),

1.50 (s, 6H), 2.15-2.30 (m, 2H), 2.43 (quintet, 1H) , 2.75-2.90 (m, 2H), 3.15 (m, 1H), 4.13 (t, 1H), 7.05-

7.28 (m, 3H), 7.35-7.65 (m, 6H), 7.80-8.05 (m, 5H),

8.35 (d, 1H).

Example 27

3-(R)-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-( 2- hydroxy- 2- propyl) phenyl) propyl)thio)-2-(R)-methylbutanoic acid

The title compound was prepared according to the procedure of Example 26, but using methyl 3-(S)-hydroxy-2-(S)-methylbutanoate.

Example 28

3-((1-(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio) - pentanoic acid

The title compound was prepared according to Method K using the mesylate from Example 31, step 7. The thiol was obtained by treating 2-pentenoic acid with benzyl mercaptan and piperidine, followed by sodium in ammonia debenzylation.

Example 29

3-( (1(R)-(3-(2-/7-Chloro-2-quinolinyl)ethenyl)phenyl)-^3-( 2-(2-hydroxy-2-propyl)phenyl)propyl)thio) - 3- methylbutanoic acid Step 1: 3- benzylthio- 3- methylbutanoic acid

A solution of 7 g (70 mmol) of 3,3-dimethylacrylic acid and 8.9 ml (7.5 mmol) of benzyl mercaptan in 70 ml of piperidine was heated to reflux for 2 days. The piperidine was then evaporated and the product partitioned between EtOAc and an aqueous solution of 1N HCl. The organic phases were washed with brine and dried over MgSO 4 . After evaporation of the solvent, the product was distilled with a ball tube apparatus under high vacuum (1 mmHg) to form 15.5 g with a 99% yield.

<X>H NMR (CDCl3) δ 1.50 (6H, s), 2.67 (2H, s), 3.82

<2H, s), 7.30 (5H, m).

Step 2: 3-mercapto-3-methylbutanoic acid

About. 300 ml of ammonia was condensed in a three-necked flask maintained at -70° C. Then 8.3 g of sodium metal (0.35 mol) was added in small portions and with vigorous stirring.

15.5 g (69 mmol) of the 3-benzylthio-3-methylbutanoic acid from step 1, dissolved in 50 ml of THF, was added dropwise at -78° C. The deep blue solution was stirred for 1 hour at -78° C, and solid NH4Cl and an aqueous solution was then added until the blue

color disappeared. The solution was then warmed to room temperature and the NH 3 was evaporated with a stream of nitrogen. The reaction mixture was then acidified with HOAc, extracted with EtOAc, washed with brine and dried over MgSO 4 . The solvent was evaporated and the residual oil was used without further purification.

<X>H NMR (CDCl 3 ) δ 1.50 (6H, s), 2.38 (1H, s) and 2.72

(2H, p).

Step 3: 3-((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl) thio)-3-methylbutanoic acid

A solution of 560 mg (4.1 mmol) of the thiol from step 2 in 5 mL of DMSO was degassed using a stream of argon bubbled through the solution for 10 min, then cooled to 5 °C before addition of 280 mg (11 mmol) oil-free NaH in portions. The resulting suspension was stirred for 10 minutes, and a solution of 1.7 g (2.7 mmol) of the mesylate from Example 146, step 7, in a mixture of 5 mL of DMSO:THF 1:2 was added. The solution was stirred at room temperature for 1 hour and then poured into an aqueous solution of NH 2 Cl in ice. The solution was acidified with HOAc and was extracted with EtOAc. The combined organic phases were washed twice with water and brine, dried over MgSO 4

and the solvent was evaporated. The residual oil was purified by flash chromatography using 5:1 toluene:EtOAc with 2% acetic acid to give 1.1 g (60%) of the title compound.

<X>H NMR (CDCl3) 6 1.32 and 1.38 (6H, two s), 1.47 (6H,

br s), 1.70 (6H, m), 2.15 (2H, m), 2.50 (2H, AB

system), 2.68, 2.93, 3.10 and. 3.40 (2H, four: dt),

3.33 (1H, m), 3.90 (1H, m), 4.08 (1H, br t), 4.33

(1H, m), 7.08 to 7.55 (9H, m), 7.68 (3H, m), 7.75

(1H, m), and. 8.10 (2H, m).

Step 4:

To a solution of 1.1 g (1.64 mmol) of the tetrahydropyranyl ether from step 3 in 8 ml of MeOH was added 85 mg (0.33 mmol) of pyridinium p-toluenesulfonate, and the solution was stirred for 5 days at room temperature. MeOH was evaporated, H 2 O was added and the aqueous layer was extracted twice using EtOAc with 2% HOAc. The combined organic layers were washed with brine and dried over Na 2 SO 4 . After evaporation of the solvent, the residual oil was purified by flash chromatography using 7:1 toluene:EtOAc with 2% HOAc to give the title compound.

<X>H NMR (CDCl3) δ 1.32 Pg 1.42 (6H, two s), 1.58 (6H,

two s), 2.17 (2H, m), 2.52 (2H, AB system), 2.80 (1H,

dt), 3.18 (1H, dt), 4.08 (1H, t), 4.50 (1H, m), 7.05

to 7.52 (9H, m), 7.60 (4H, m), 8.10 (2H, m).

Example 30

4-((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3- (2-(2-hydroxy- 2- propyl) phenyl) propyl) thio)- 3-methyl-butanoic acid

The title compound was prepared according to Method K using the mesylate from Example 31,

step 7. The thiol was prepared from ethyl 3-mercapto-2-methylpropanoate by first protecting the thiol with a benzyl group. The ester was then removed with LiOH in THF/H 2 O. Reaction with oxalyl chloride, followed by diazomethane gave diazo-

the ketone which was rearranged with silver benzoate in MeOH.

Saponification and Na/NH^ debenzylation gave the thiol.

[α]D = -43.6° (c = 1.29, acetone).

MS, m/e (relative intensity) 602 (M+1, 86), 468(62),

292 (100), 229 (45), 196 (54).

Example 140

2- (2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-((4-hydroxy- 4- methylpentyl)thio)propyl)- 5- chlorophenyl) butanoic acid

The title compound was prepared according to Example 138, except that the palladium-catalyzed coupling was carried out using methyl 2-(2-bromo-5-chlorophenyl)butanoate. This bromide was obtained as described in Example 138, step 1, using methyl 2-bromo-5-chlorophenylacetate in place of 2-iodo-phenylacetic acid, and a single equivalent of base.

Example 31

Sodium 4-((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio )-3,3-dimethylbutanoate

Step 1: Methyl 2-(3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)- 3-oxopropyl) benzoate

A degassed suspension of 50.30 g (156 mmol) of 1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-2-propen-l-ol (Example 80, Step 1), 41 .2 g (404 mmol) LiOAc/2H2O, 6.84 g (161 mmol) LiCl, 1.00 g (4.45 mmol) Pd(OAc)2 and 33.5 g (156 mmol) methyl 2-bromobenzoate in 300 ml DMF was stirred at 95° C. for 4 hours. The mixture was cooled to room temperature and 1.8 liters of water was added. The product was extracted with hot EtOAc, dried over Na 2 SO 4 and concentrated. It was dissolved in toluene and filtered through silica with toluene. Recrystallization in 1.2 liters of EtOAc:hexanes 1:1 gave 65.57 g of the title compound. Recrystallization of the mother liquors in 400 mL EtOAc:hexanes

1:3 gave an additional 8.30 g (86% overall yield) of the title material.

■*"H NMR identical to Example 1-0, step 4.

Step 2: Methyl 2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl) phenyl)- 3- hydroxypropyl) benzoate

To a solution of 72.2 g (0.225 mol) (-)-B-chlorodi-isopinocampheylborane in 300 ml of THF cooled to -25° C, was added. pevis added to a solution of 68.5 g (0.15 mol) of the ketone from step 1 in 350 ml of THF. The red-orange solution was stirred overnight at 15° C. and then poured into ice water with stirring. The precipitate formed was collected and washed twice with water and then with EtOAc. The solid material was partitioned between 2.5 liters of CH 2 Cl 2 and 1.2 liters of 6% diethanolamine in water. The organic phases were washed with brine and dried over Na 2 SO 4 . The solvent was evaporated and 700 mL of MeOH was added. The product was crystallized by adding 70 ml of water slowly with vigorous stirring. The solid was collected and washed with MeOH:H 2 O, 10:1 to give the title compound (44.7 g, 65%).

<1>H NMR (CDCl3) δ 2.10 (2H, m), 3.12 (3H, m), 3.90

(3H, S), 4.75 (1H, t), 7.22 to 7.55 (8H, m), 7.67

(4H, m), 7.92 (1H, d), 8.10 (2H, m).

Step..3: 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinylthenyl)-

phenyl)- 3- hydroxypropyl) phenyl)- 2- propanol

To a solution of 38.68 g (84.36 mmol) of the hydroxy ester from Step 2 in 600 mL of toluene at 0° C. was slowly added 225 mL of 1.5 M MeMgBr in toluene:THF 3:1 and the mixture was stirred at room temperature for 4 hours. It was then poured into 2 liters of cold 12% NH 4 OAc and 25 ml of AcOH was added. The products were extracted into EtOAc, washed with brine, dried over Na 2 SO 4 and concentrated. Flash chromatography of the residue with EtOAc:toluene 15:85 and 25:75 gave first the methyl ketone derivative, then the title compound.

Yield 24.06 g, 62%.

<X>H NMR (CD3COCD3) δ 1.59 (3H, s), 1.62 (3H, s), 2.11

(2H, m), 3.16 (2H, td), 4.15 (1H, s, OH), 4.52 (1H,

d, OH), 4.81 (1H, m), 7.04-7.28 (3H, m), 7.37-7.57

(5H, m), 7.60 (1H, m), 7.78 (1H, s), 7.83-8.02 (4H,

m), 8.32 (1H, d).

Step 4: 2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-(dimethyl(2-methyl-2-propyl)silyloxy) propyl) phenyl)- 2- propanol

To 36.56 g (79.8 mmol) of the diol from step 3 in 400 ml of CH2Cl2 was added 18.21 g (121 mmol) of tert-butyl-chloro-dimethylsilane, 10.97 g (161 mmol) of imidazole and 0.988 g

(8.1 mmol) of 4-(dimethylamino)pyridine, and the mixture was stirred at room temperature for 3 days. 400 mL of toluene was then added and the product was filtered through silica with EtOAc:toluene 0:100 to 5:95. The title product was concentrated and stripped with toluene to remove any remaining silyl chloride.

Step 5: 2-(2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(dimethyl(2-methyl-2-propyl) )silyloxy)-propyl)phenyl)-2-propoxy)-tetrahydropyran

To a 0.2 M solution of the tertiary alcohol from step 4 in CH 2 Cl 2 was added 5 equivalents of dihydropyran and 0.1 equivalents of triphenylphosphonium bromide, and the mixture was stirred at the reflux temperature for 1 day. Then the same amount of dihydropyran and triphenylphosphonium bromide was added and the mixture was stirred at the reflux temperature for another 1 day. Toluene was added and the resulting solution was filtered through silica with EtOAc:toluene 0:100 to 2.98 to give the title product.

Step 6: 1-(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(2-((tetrahydropyran-2-yl)oxy)-2 -propyl)phenyl)-1-propanol 85 ml of 1.0M tetrabutylammonium fluoride in THF was slowly added to a solution of 33.31 g (47 mmol) of the product from step 5 in 250 ml of anhydrous THF at 0°C, and the mixture was leave in a refrigerator overnight at room temperature for 4 hours. 25% aqueous NH 4 0 Ac was then added and the product was extracted into EtOAc, dried over Na 2 SO 4 and purified by flash chromatography on silica with EtOAc:toluene 10:90 and 15:85 to give the title product. Yield for steps 4 - 6: 81%.

<1>H NMR (CD3COCD3) δ 1.35-1.90 (12H, m), 2.10 (2H, m), 2.88-3.45 (3H, m), 3.88 (1H, m), 4.49 (2H, m, 1OH),

4.90 (1H, m), 7.05-7.55 (8H, m), 7.61 (1H, br d),

7.80-8.04 (5H, m), 8.33 (1H, d).

Step 7: 2-(2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-(methanesulfonyloxy(propyl)phenyl)- 2- propoxy) tetrahydrofuran

To a 0.1M solution of the alcohol from step 6 in CH2Cl2 at -40°C was added 1.3 equivalents of methanesulfonyl chloride and 1.5 equivalents of Et3N, and the mixture was stirred for 30 minutes at -40°C and for 1 hour at 0° C. Saturated NaHCO 3 was then added, and the title mesylate was extracted into CH 2 Cl 2 / was dried over Na 2 SO 4 , concentrated and stripped twice with toluene. The remaining title compound was used for subsequent reactions without further purification.

Step 8: Methyl-3,3-dimethyl-4-hydroxybutanoate

To a suspension of 4.9 g (0.129 mol) of LAH (lithium aluminum hydride) in 300 ml of THF maintained at -78° C., a solution of 16.5 g (0.129 mol) of 2,2-dimethylsuccinic anhydride was added over 45 minutes in 350 mL of THF. After 45 minutes of vigorous stirring, the reaction mixture was warmed to -60° C. and poured into 500 ml of IM aqueous sodium potassium tartrate and stirred for 2 hours at room temperature. The mixture was then acidified with 150 mL of acetic acid and was extracted three times with EtOAc. The combined organic phases were washed with brine and dried over Na 2 SO 4 . The residual oil was dissolved in ether, and a solution of diazomethane in ether (ca. 300 ml, 0.15 mol) was added until the yellow color persisted. An aqueous solution of NH 4 Cl was added and the ester was extracted with EtOAc and dried over MgSO 4 . The oil was purified by flash chromatography with 2:3 EtOAc:hexane to give the title compound (13.5 g, 72%).

<X>H NMR (CDCl 3 ) <5 1.00 (6H, s), 2.33 (3H, br s), 3.42

(2H, s), 3.70 (3H, s).

Step 9: Methyl-4-(acetylthio)-3,3-diethylethylbutanoate

To a solution of 107.8 g (0.411 mol) of triphenylphosphine in 700 ml of THF maintained at 0° C., 64.7 ml (0.411 mol) of DEAD (diethyl azodicarboxylate) was added dropwise, and the mixture was stirred at 0° C. for 30 minutes until the complex was precipitated. A solution of 30 g (0.205 mol) of the alcohol from step 8 and 29.4 ml (0.411 mol) of thiolacetic acid in 300 ml of THF was then added dropwise (mechanical stirring). After 4 days at 4°C, the reaction mixture was evaporated to dryness, the white precipitate was suspended in 30:1 hexane:EtOAc and filtered. The residual oil was then purified by flash chromatography using toluene and then 100:1 toluene:EtOAc to give the title compound.

Yield: 31 g, 74%.

<1>H NMR (CDCl3) δ 1.05 (6H, s), 2.27 (2H, s) 2.37

(3H, s), 3.00 (2H, s), 3.65 (3H, s).

Step 10: Methyl-4-((1(R)-(3-(2-(7-klpr-2-quinolinyl)ethenyl)-phenyl)-3-(2-(2-(2-tetrahydropyranyloxy)-2 -propyl)-phenyl)propyl)thio)-3,3-dimethylbutanoate

7.52 g (0.037 mol) of the thiol acetate from step 9 was dissolved in 50 mL of CH-3CN and argon was bubbled through the solution for 10 minutes. At 0° C., 1.4 mL (0.044 mol) of hydrazine was then added dropwise, and the mixture was stirred for 1 hour at 0° C. This solution was then added to a suspension of 15.2 g (0.025 mol) of the mesylate from step 7 and 20 g (0.061 mol) Cs 2 CO 3 in 50 mL CH 3 CN maintained at 0° C. The reaction mixture was warmed to room temperature for 5 h and water was added. The product was extracted with EtOAc, washed with brine and dried over Na 2 SO 4 . The residual oil was purified by flash chromatography using 1:10 to 1:7 EtOAc:hexane to give 15.1 g, 89% yield, of the title compound.

3-H NMR (CDCl3) δ 1.03 (6H, s), 1.40 (6H, m), 1.60

1.70 (6H, three s), 2.20 (2H, m), 2.30 to 2.55 (4H,

m), 2.65, 2.92, 3.10 and 3.40 (2H,. f ire td), 3.33

(1H, m), 3.60 (3H, s), 3.90 (2H, t), 4.33 (1H, m),

7.08 to 7.55 (9H, m), 7.68 (3H, m), 7.75 (1H, rn),

8.10 (2H, m).■

Step 11: 4-((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl )-thio)-3,3-dimethylbutanoic acid

A solution of 10.1 g (0.015 mol) of the product from step 10 and 1.12 g (0.45 mol) of pyridinium p-toluenesulfonate in 80 mL of a mixture of MeOH:THF was heated to 60 °C overnight . Most of the MeOH was evaporated, and an aqueous solution of NH 4 Cl was added. The product was extracted with EtOAc, washed with brine and dried over Na 2 SO 4 . The residual oil was purified by flash chromatography on silica using 1:5 to 1:3 EtOAc:hexane. The product was then dissolved in 70 mL of a mixture of MeOH:THF, and the solution was cooled to 0°C before the addition of 35 mL (0.036 mol) of a 1M solution of NaOH in water. The reaction mixture was stirred for 2 days at room temperature. Most of the MeOH was evaporated and the solution was acidified with AcOH (acetic acid) to pH a 5.. An .aqueous ■. solution of NH 4 Cl was added and the acid was extracted with EtOAc. The organic phases were washed with brine and dried over Na 2 SO 4 - After evaporation of the solvent, the residual oil was purified by flash chromatography using 1:6 to 1:5 EtOAc:hexane (containing 2% AcOH) to give 7.6 g of the title product (87% yield).

<X>H NMR (CDCl 3 ) δ 1.05 (6H, two s), 1.60 (6H, two s),

2.25 (2H, m), 2.40 (2H, s), 2.58 (2H, s), 2.92 (1H,

m), 3.17 (1H, m), 3.90 (1H, t), 7.08 to 7.68 .(13H,

m), 8.10 (2H, m).

Step 12:

To a solution of the acid from step 11 in ethanol was added 1.0 equivalents of 1N NaOH. The solvent was evaporated and the remaining oil was dissolved in water and freeze-dried to give the title compound.

Analysis calculated for C^H^ClNO-jSNa' 2H20:

C 65.05 H 6.40 N 2.17 S 4.96

Found: C 65.32 H 6.23 N 2.14 S 4.63

MS, m/e (relative intensity) 632 (100, M+Na), 610

(74, M+1).

Example 32

Sodium 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)- propyl) thio) methyl) cyclopropane acetate

Step 1: 1, 1- cyclopropane dimethanol

A solution of 50 g .41.32 mol) lithium aluminum hydride

in 1.6 liters of THF was cooled to -18° C under N2» A solution of 175 g (0.94 mol) diethyl-1,1-cyclopropanedicarboxylate in 1.2 liters of THF was then added dropwise over 50 minutes with such a rate that the internal temperature of the reaction mixture remained below 10° C. The cooling bath was then removed, and after 15 minutes the temperature had reached 15° C. The reaction was then quenched by the careful addition of 50 ml of H2O, followed by 50 ml of 15% NaOH , and then 150 ml of H20. After the mixture became white, it was filtered through celite,

and the layer was washed with 4 liters of THF. Evaporation gave an oil which was distilled to give 81 g (0.79 mol, 84%) of the title compound as a colorless oil, m.p. 131 - 138°/

15mmHg.

1 H NMR (CDCl 3 ) δ 0.48 (4H, s) , 3.30 (2H, s) , 3.58 (4H, s) .

Step 2: 1-(hydroxymethyl)cyclopropanemethylbenzoate

To a solution of 81 g (0.79 mol) of the diol from step 1 and 96 ml (1.19 mol) of pyridine in 1 liter of CH2C12 cooled to 0° C, 121 ml (1.03 mol) of benzoyl- chloride. The reaction mixture was warmed to room temperature overnight and then poured over 1 aqueous solution of NH 4 Cl . The products were extracted into CH 2 Cl 2 , washed with brine and dried over Na 2 SO 4 . The residual oil was purified by flash chromatography with 2:1 hexane:EtOAc and then 1:2 hexane:EtOAc to give first 116 g (47% yield) of the diester, and then 89 g (54% yield) of the title alcohol.

<*>H NMR (CDCl 3 ) δ 0.65 (4H, m), 2.20 (1H, t), 3.53

(2H, d), 4.35 (2H, s), 7.45 <2H, m), 7.60 (1H, m),

8.07 (2H, m).

Step 3: 1-(benzoyloxymethyl)cyclopropane. cetonitrile

To a solution of 80 g (0.388 mol) of the alcohol from step 2 and 162 ml (1.16 mol) of triethylamine in 1.5 liters of CH 2 Cl 2 cooled to -40° C was added 75 ml (0.504 mol) of methanesulfonyl chloride. The reaction mixture was warmed to -10°C

for 20 minutes, then poured into an aqueous solution of NaHCO 3 and extracted with CH 2 Cl 2 . The organic phases were washed with brine and dried over Na 2 SO 4 . The residual oil was then dissolved in 1.5 liters of DMSO and 86 g (1.76 mol) of sodium cyanide was added portionwise. The reaction mixture was stirred at room temperature for 3 days and then poured into an aqueous solution of NaHCO 3 and extracted with Et 2 O. The organic phases were washed with brine and dried over Na 2 SO 4 . Evaporation of the solvent gave the title product.

<X>H NMR (CDCl 3 ) <5 0.80 (4H, m), 2.62 (2H, s), 4.27

(2H, s), 7.48 (2H, m), 7.60 (1H, m), 8.08 (2H, m).

Step 4: Methyl-1-(hydroxymethyl) cyclopropane acetate

0.388 mol of the nitrile from step 3 was dissolved in

400 ml of ethanol, 800 ml of 8N KOH were added and the reaction mixture was heated to reflux overnight. Most of the ethanol was evaporated and ice was added to the mixture.

600 ml of concentrated HCl was added dropwise at 0° C (without heating above 10° C in the solution) until a pH of 1 was obtained. The acid was then extracted twice with EtOAc and the organic phases were washed twice with brine and dried over Na 2 SO 4 . The solvent was evaporated and the solid was dissolved in 500 ml THF. A solution of diazomethane in Et 2 O (ca. 1.7 L, 0.85 mol) was added at 0 °C until the yellow color persisted and no more acid could be seen by TLC. The solvent was evaporated and the residual oil was purified by flash chromatography using 1:1 to 2:1 EtOAc:hexane to give 28.2 g (50%

dividend) of the title compound.

■"■H NMR (CDCl 3 ) 6 0.55 (4H, m) , 2.45 (2H, s) , 2.55

(1H, t), 3.5 (2H, d), 3.70 (3H, s).

Step 5: Methyl-1-(acetylthiomethyl)cyclopropane acetate

To a solution of 28.2 g (0.20 mol) of the alcohol from step 4 and 82 ml (0.59 mol) of triethylamine in 1 liter of dichloromethane cooled to -40° C was added 43.5 ml (0.3 mol ) methanesulfonyl chloride. The reaction mixture was warmed to -10°C for 20 minutes, after which an aqueous solution of NaHCO 3 was added. The product was extracted with CH 2 Cl 2 , washed with brine and dried over Na 2 SO 4 . A portion of this mesylate (0.053 mol) was then dissolved in 180 ml of DMF and was cooled to 0° C. 22 g (0.11 mol) of freshly prepared cesium thiolacetate (J. Org. Chem., 51, 3664 (1986) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into an aqueous solution of NaHCO^ and was extracted with Et 2 O. The organic phases were washed with brine and were dried over Na 2 SO 4 - . The residual oil was then purified by flash chromatography with 10:1 hexane:EtOAc to give 7.5 g, 70%, of the title compound.

<1>H NMR (CDCl3 ) δ 0.60 (4H, m), 2.30 (2H, s), 2.35

(3H, s), 3.03 (2H, s), 3.70 (3H, s).

Step 6:

Using the procedure of Example 14 6, steps 10-12, the thiol acetate from step 5 was used to prepare the title compound.

Analysis calculated for C35H3;-ClN03SNa:

MS, m/e (relative intensity) 630 (42, M+Na), 608 (21, M+1).

Claims (5)

1. Connection, characterized in that it has the formula: in which R<1> is halogen; R<2> is lower alkyl, -CF3, substituted or unsubstituted phenyl, benzyl or 2-phenethyl, or two R<2-> groups attached to the same carbon, can form a cycloalkyl ring with up to 6 members; R<3> is H or R<2>; Q<1> is -C(O)OH; m' is 2 or 3; p' is 0 or 1; m + p is 1-5; and pharmaceutically acceptable salts thereof. 2. Connection according to claim 1, characterized in that this is l-(((l(R)-(3-( 2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-( 2-hydroxy-2-propyl)phenyl) )propyl)thio)methyl)cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof. 3. Connection according to claim 1, characterized in that this is sodium-1- (((1 (R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl) phenyl )propyl)thio )methyl ) cyclopropane acetate or a pharmaceutically acceptable salt thereof. 4. Preparation, characterized in that it comprises a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 5. Pharmaceutical preparation according to claim 4, characterized in that it further comprises an effective amount of a second active ingredient selected from the group consisting of non-steroidal anti-inflammatory drugs; peripheral analgesic agents; cyclooxygenase inhibitors; leukotriene antagonists; leukotriene biosynthesis inhibitors; H2 receptor antagonists; antihistamines; prostaglandin antagonists; thromboxane antagonists; thromboxane synthetase inhibitors and ACE antagonists.