NZ237264A - Use of leukotriene antagonists - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £37264 Priority 0s».8{9) Carole specification <^£~1 Class: *5) 237 2 6 4 FH«* ..**»« m PubHcatism Oat® P.O. v. 26.AUB.A992..

WO.- <\li 1 ''I ■% V? if* Atj kv '* Under the provisions of Regulation 23 (1) the Specification has been ante-dated to g/L Initials Patents Form No. 5 J'.Z. PATENT OFFICE 28 FEB 1991 JWC£IVZQ NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION METHODS OF TREATING ALLERGY OR INFIiAMMATORY DISEASES WITH LEUKOTRIENE LTD^ AND LTB^ ANTAGONISTS WE, G.D. SEARLE & CO., a corporation organized and existing under the laws of the State of Delaware, United States of Americ, having its place of business at 5200 Old Orchard Road, Skokie, Illinois, 60007, United States of America, hereby declare the invention, for which We pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: mt"w ~ 237264 Field of the Invention This invention relates to methods of treating allergy or inflammatory diseases with compounds and compositions that are described and claimed in New Zealand Patent Specification No. 226318, in particular, pharmaceutical agents which act as leukotriene D4 (LTD4) antagonists and as leukotriene B4 (LTB4) antagonists, respectively.

Prior Art The prior art generally describes LTD^ antagonists as anti-allergy compounds and LTB^ antagonists as anti-inflammatory agents.

Leukotriene D. and C. (LTD./LTC.) and 4 4 4 4 leukotriene (LTB^) are products of the arachidonic acid metabolic pathway. LTD^ and LTCA are associated with smooth muscle contraction and contract guinea pig ileum, human and guinea pig bronchi and human pulmonary artery and vein. LTB4 is associated with neutrophil stimulation and is characterized by chemotaxis, aggregation and degranulation. LTBA is believed to be an important mediator of inflammation. High levels of LTB4 are detected in rheumatoid arthritis, gout, psoriasis, and inflammatory bowel disease. Thus antagonists of LTB^ are useful in the therapy of such diseases. 237 2 Dioxolane-2-carboxylic acids of the formula R2 where R1 and I^.are the same or different H, halogen, alkyl, or alkoxy; R3 is H, alkyl, aryl or alkyl optionally substituted by halogen, lower alkyl, or lower alkoxy; X is -CH2~, -OCH2- where the O is joined to the phenyl; n is 0-3, are taught as sedatives or choleretic agents in French Patent 1,448,340.

New Zealand Patent Specification No. 226318, which is the parent of the present divisional application, discloses: (i) compounds of the hereinafter described Formula I, and pharmaceutical formulations containing such compounds; (ii) compounds of the hereinafter described Formula II, which are LTD4 antagonists, and pharmaceutical compositions thereof; and (iii) compounds 2372 6 4 of the hereinafter described Formula III, which are LTB^ antagonists, and pharmaceutical formulations thereof.

Thus, the invention of New Zealand Patent Specification No. 226318, hereinafter referred to as the parent invention, encompasses compounds of Formula I and the pharmaceutically acceptable salts and geometrica and optical isomers thereof wherein: X, Y, and Z are each independently O or S with S optionally oxidized to S = O; Alk is straight or branched chain alkylene or hydroxyalkylene containing 1-6 carbon atoms; is' hydrogen or lower alkyl; n is 0 to 5; R2 is hydrogen, lower alkyl, cycloalkyl, -{CH2)n~C02R1, phenyl, phenyl substituted with halo, lower alkyl or lower alkoxy; and Ar is 5,6,7,8-tetrahydro-l-naphthalenyl, phenyl, or phenyl substituted with lower alkyl, hydroxy, lower alkoxy, or lower alkanoyl.

I 237264 A preferred embodiment of the parent invention embraces compounds of the formula II II where Alk, Z, X, Y, R^, n, and R^ are as defined before. These compounds are characterized as having LTD^ antagonist activity. A most preferred embodiment is compounds of formula II wherein Ris lower alkyl and R1 is hydrogen as represented by Examples 61, 84 and 128(c). These compounds are particularly preferred because of their potency and oral availability.

A further preferred embodiment of the parent invention embraces compounds of formula III III where R^ is lower alkyl and Alk, Z, X, Y, n, R^, and R2 are as previously defined. These compounds are LTB^ antagonists and are useful as anti-inflamrnatory agents.

SUMMARY OF THE INVENTION The present invention provides a method of treating allergy comprising administering to an animal (excluding human beings) in need of such treatment,, a therapeutically effective amount of at least one compound of the formula (II) or pharmaceutically acceptable salts thereof or geometrical or optical isomers thereof, which compound or salts or isomers may be administered in admixture with a pharmaceutically acceptable carrier.

The present invention also provides a method of treating inflammatory diseases comprising administering to an animal (excluding human beings) in need of such treatment, a therapeutically effective amount of at least one compound of the formula (III) or pharmaceutically acceptable salts thereof or geometrical or optical isomers! thereof, which compound or salts or isomers may be administered in admixture with a pharmaceutically acceptable carrier.

The following descriptive portion of the present specification has been taken from the specification of the parent invention. Hence, the expression "compounds of this invention" as used hereinafter refers to compounds used in the methods of the present invention, as well as to compounds of the parent invention. / 237 2 6 4 The dioxolane compounds may be prepared as shown in Scheme A. The starting compound ,Ov /(CH2)nC02R, HO' -O R2 may be prepared using the procedure described in C. R. ACAD. SC. PARIS,, t.271 (July 20, 1970) p 218-220 or R. Bohm, PHARMAZIE, 36:329 (1981).

SCHEME A of Ex. 62 Procedure of Ex. 63 ,Ov .{CB^COjR, Procedure AcS of Ex. 64 O >(CH2)nC02Ri r2 ArO Alk Br Procedure of Ex. 65 ArO-Alk-S O. y(CHj)0CO2R, r2 ArO, Alk, R , R2 and n are defined as in Formula I. 237 2 6 iooaw The term "lower alkyl" means straight or branched chain alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl and the branched chain isomers thereof.

The term "lower alkoxy" means straight or branched chain alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxyV butoxy, pentoxy, hexoxy and the branched chain isomers thereof.

The term "lower alkanoyl" means straight or branched chain alkanoyl having 2 to 6 carbon atoms such as acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl and the branched chain isomers thereof.

The term, "halo" means fluoro, cloro, bromo, or iodo.

The term "pharmaceutically acceptable salts" means non-toxic salts of the acids of the compounds of this invention where the cation is sodium, potassium, lithium, calcium, magnesium, zinc, ferrous, aluminum, ammonium, tetraalkylammonium, and the like.

Compounds of this invention are generally prepared according to the following scheme: XH BF.

O ArO Alk Br Formul# I U6.9M 23 7 2 where Ar, X, Y, Z, n, Alk, R and R2 are as earlier defined. Optical isomers are resolved into enantiomers by conventional techniques.

The hereinafter set out examples further illustrate methods for preparing compounds of this invention.

The LTD4 antagonist utility compounds are illustrated by a'ctivity in one or more of the following tests.

LTD^ Antagonism in Guinea Pig Ileum Fresh segments of guinea pig ileum were suspended in 2ml. tissue baths containing oxygenated modified Tyrodes solution.. After an equilibration period, an agonist dose-response -curve was generated by exposing each tissue to 4 different LTD^ doses and measuring the ensuing contractile heights. The ileum segments were washed and rested between exposures to agonist. Following this, the tissues were incubated with a single concentration of test compound and the agonist dose-response procedure was repeated. The dose ratio is a measure of the antagonist's ability to shift the agonist dose-response curve to the right. It is derived as the concentration of agonist necessary to reach a given response level in the presence (A1) versus the absence (A) of antagonist. For example, if the test concentration of compound had no effect on the agonist-induced response (A'=A) the dose-ratio would approximate 1. Dose-ratios increase if the compound inhibits the agonist-induced response. One dose-ratio value is determined for each strip of ileum used to test 1669N 237 2 6 antagonist. If the dose-ratios increase as a function of increasing antagonist concentration, these data may be evaluated by Schild analysis to determine whether the inhibition is competitive and if so, what the pA2 value is for that compound. Schild analysis examines the linearity of the function described by the dose-ratios written as log ['(A'/A)-l] versus antagonist concentration. If the linearity is confined and the slope approximates 1, inhibition is considered to be competitive. The pA2 is the negative log of the antagonist concentration required to produce a dose-ratio of 2. This value is considered to be a measure of the affinity of the competitive antagonist.

In Vivo Assay The compounds are tested in vivo as follows. Adult male fasted Hartly guinea pigs weighing 300-350g are pretreated with pyrilamine and indomethacin to block the bronchoconstricture effects of endogenous histamine and the synthesis of thromboxane A2 respectively. Compounds of the invention are administered IV or IG at approximate times prior to the IV administration of 2000 units of LTD^. Intratracheal pressure is monitored prior to and subsequent to LTD^ in animals anesthetized with pentobarbital and attached to a rodent respirator. Compounds which antagonize the direct component of LTD4 action on respiratory smooth muscle inhibit intratracheal insufflation pressure increases (P< or = 0.05) caused by LTD4. FPL 55712 is used as a control. i o o y in 237264 Leukotriene Receptor Binding Assay (12c01) The in vitro LTD^ receptor binding assay is. carried out as follows: Specific binding of titrated LTD^ to a fixed number of guinea pig lung receptors, isolated from guinea pig lung membrane, is measured in the presence and absence of — 5 test compound. 'The initial screening dose (1 x 10 M is considered active if the specific binding of the LTD^ is reduced by 45% or more. Active compounds are tested in a dose-response manner to determine IC5Q values.

LTB4 activity of compounds of this invention is indicated by the following tests.

Preparation of Human Neutrophils Neutrophils were purified from venous blood of normal human donors using standard techniques of dextran sedimentation, centrifugation on Histopaque sterile solution (Sigma) and hypotonic lysis of erythrocytes (Boyum, A., Isolation of Leukocytes From Human Blood: Further Observations. Scand. J. Lab. Clin. Invest. 21 (Suppl. 97): 31, 1968). The purity of isolated neutrophils was 2 95%.

LTB^ Receptor Binding Assay Neutrophils (4 - 6xl06) in 1ml Hanks' balanced salt solution containing 10 mM HEPES buffer (HBSS), pH 7.4 and mM nordihydroguaiaretic acid were incubated with 0.6 3 nano M ( H) LTB^ in the presence or absence of test compounds. The incubation was carried out at 0"C for 45 minutes and terminated by adding 5ml of ice-cold HBSS 16 69N 237 2 followed by rapid filtration of incubation mixture under vacuum through GF/C glass fiber filters. The filters were further washed with 10ml HBSS and radioactivity was determined. Specific binding was defined as the difference between total binding and nonspecific binding which was not displaced by 10 M unlabeled LTB4. All data refer to specific binding.

Human Neutrophil Degranulation Assay Neutrophil degranulation was determined by measuring the release of myeloperoxidase activity into the incubation medium. Neutrophils (3 x 106) in 1ml HBSS solution were preincubated with cytochalasin B(5]jg) at 37°C for 5 minutes, followed by preincubation with test compounds for 7 minutes. Neutrophils were then incubated _Q for 2 to 20 minutes with either LTB4 (5 x 10 M) or the chemotactic peptide f-met-leu-phe (5 x 10 6 M) to induce degranulation. Following incubation, samples were centrifuged and myeloperoxidase was extracted from the cell pellets by sonication in phosphate buffer containing 0.4% Triton X-100. Triton X-100 was also added to the supernatants to a concentration of 0.4%. The supernatants and the pellet - extracts were then assayed spectrophotometrically for myeloperoxidase activity by determining the rate of decomposition of H202 with o-dianisidine as hydrogen donor as described by Renlund, et al. (Renlund, D.G., MacFarlane, J.L., Christensen, R.D., Lynch, R.E., and Rothstein, G., A Quantitative And Sensitive Method for Measurement of Myeloperoxidase, 2372 6 4 16 6.9N Clinical Research 28:75A, 1980). Myeloperoxidase activity released into the supernatant was expressed as the percent of the average total activity (pellet plus supernatant).

Guinea Pig LTB^-Induced Dermal Chemotaxis Test compound was administered intravenously or intragastrically at various times prior to the injection of leukotriene B". (LTB.) . LTB. was diluted in 4 4 4 phosphate buffered saline (PBS) and 35ng in 0.2ml were injected intradermally into the shaven backs of anesthetized guinea pigs. PBS was injected as control. Four hours later, animals were sacrificed, skins removed and stored frozen (-70°C). Injection sites were removed with a skin punch and mechanically homogenized (Polytron, Brinkmann Instruments). Myeloperoxidase (MPO), a marker enzyme for neutrophils, was extracted by 0.5% hexadecyltrimethylammonium bromide in 50 mM potassium phosphate buffer (pH 6.0), using sonication and freeze-thaw procedures. After centrifugation (40,000 x g, 30 minutes), enzyme activities in the supernatants were assayed spectrophotometrically (A4gQ) by measuring the decomposition of hydrogen peroxide with ortho-dianisidine after 15 minutes. MPO activity was found to be proportional to the number of neutrophils. In guinea pigs the level of MPO activity increased with the amount of LTB4 injected.

Modified Boyden Chamber Chemotaxis Human neutrophils were isolated from citrated peripheral blood sedimented in 5% dextran, followed by 1 o 6 9 N 237264 centrifugation on Histopaque sterile solution (Sigma) and hypotonic lysis of erythrocytes. A final cell suspension of 3-4 x 106 neutrophils/ml of HEPES-buffered Hanks' balanced salt solution (HBSS, pH 7.3) was added to the upper well (0.8ml) of a modified Boyden chamber (blind well). The lower well (0.2ml), separated by a polycarbonate membrane (Nuleopore Corp.), contained HBSS —8 or 3 x 10 M LTB^ in the presence or absence of test compound. Following a 90 minute incubation at 37°C in 5% C02~95% air, cells from the lower well were lysed and nuclei counted in a Model S-Plus-Iv Coulter counter. Percent inhibition was calculated from cell counts corrected for random migration by subtracting the mean of the HBSS control.

Table 1 illustrates the LTD. and LTB. activity of 4 4 representative compounds of this invention. 166 9N 237264 A TABLE I LTD„ ANTAGONISM 4 Example Receptor Binding Assay (ICc;o) Guinea Pig Ileum Assay (pA?) In Vivo Broncho-constriction Assay Inhibition at 5mpk 0, rH cn in |iM 8. 05 93 38 9 , ,37, i vlM 7. 84 87.2 61 , . 02 |iM 8. 02 95.6 50 9 , .47 liM 7 . 84 91.2 84 7, , 10 jiM 7 . 77 CO M 3 3, . 56 jiM 7 . 67 96.9 70 6, .24 pM 7 . 57 59 .2 LTB. ANTAGONISM 4 Receptor Binding Example Assay (IC^n) 81 0.06 jiM The compounds can be administered in such oral dosage forms as tablets, capsules, softgels, pills, powders, granules, elixirs, or syrups. The compounds may also be administered intravascularly, intraperitoneally, subcutaneously, or intramuscularly, using forms known to the pharmaceutical art. In general, the preferred form of administration is oral. For the orally administered pharmaceutical compositions and methods of the present invention the foregoing active ingredients will typically be administered in admixture with suitable pharmaceutical 16 6,9 M 237 2 6 diluents, excipients, or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, softgels, elixirs, syrups, drops, and the like, and consistent with conventional pharmaceutical practices.

For example', for oral administration in the form of tablets or capsules, the active drug components may be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate mannitol, and the like, or various combinations thereof. For oral administration in liquid forms, such as in softgels, elixirs, syrups, drops and the like, the active drug components may be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as water, saline, ethanol, polyethylene glycol, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, various buffers, and the like, or various combinations thereof. Moreover, when desired or necessary suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated in the mixture. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethyl-cellulose^, polyethylene glycol, and waxes, or combinations thereof. Lubricants for use in these dosage forms include boric acid, sodium benzoate, sodium acetate, sodium 1 b o>N 237 2 6 chloride, and the like, or combinations thereof. Disintegrators include, without limitation, starch, methyl-cellulose, agar, bentonite, guar gum, and the like, or combinations thereof. Sweetening and flavoring agents and preservatives can also be included where appropriate.

For intravascular, intraperitoneal, subcutaneous, or intramuscular administration, active drug components may be combined with a suitable carrier such as water, saline, aqueous dextrose, and the like. Regardless of the route of administration selected, the compounds of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art. The compounds may also be formulated using pharmacologically acceptable base addition salts. Moreover, the compounds or their salts may be used in a suitable hydrated form.

Topical formulations of salves and ointments are useful in treating conditions such as psoriasis.

Regardless of the route of administration selected, a non-toxic but therapeutically effective quantity of one or more compounds of this invention is employed in any treatment. The dosage regimen for preventing or treating inflammatory conditions with the compounds of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, and medical condition of the patient, the severity of the inflammatory condition, the route of administration, and the particular compound employed in the treatment. A physician or 16 6 9N 237 2 6 veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent or arrest the progress of the condition. In so proceeding, the physician or veterinarian could employ relatively low doses at first and subsequently increase the dose until a maximum response is obtained. Daily dosages of the compounds of the invention are ordinarily in the range of about 1 to 50 mg/kg are generally suitable.

The accompanying examples illustrate the methods used to prepare the compounds of this invention. These examples are given by way of illustration only and in no way should be construed as limiting the invention in spirit or in scope, as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. 2 3 7 2 6 1 o o 9N DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1 Diethyl 4-(mercaptomethyl)-1,3-oxathiolane-2,2-dipropanoate Diethyl 4-oxo pimelate (37g, 0.16 mol) and 2,3-dimercapto-l-propanol (20g, 0.16 mol) were dissolved in methylene chloride (600ml). Distilled boron trifluoride etherate (5ml) was added and the reaction was stirred for three days at room temperature under a nitrogen atmosphere.

The reaction was quenched by adding 5% aqueous potassium bicarbonate solution (200ml). The layers were separated and the organic phase was washed with water and dried over magnesium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator. The residual oil was chromatographed on silica gel using 3% ethyl acetate/toluene as eluent to give 27.5g (51%) of the above titled compound as an oil.

Analysis calculated for ci4H24°5S2: Calc.: C, 49.99; H, 7.19; S, 19.03.

Found: C, 49.92; H, 7.23; S, 19.11. 16 6 9 N 237 2 EXAMPLE 2 Diethyl 4-[[[3-(4-acetyl~3-hydroxy-2~• propylphenoxy)propyl]thio]methyl]-1,3-oxathiolane-2,2-dipropanoate C 0 2 C 2 H j CO2 Cg Hj 0 3-(2-n-Propyl-3-hydroxy-4-acetylphenoxy)-l-bromopropane (2.0g, 0.006 mol), prepared by the method described in U.S. Patent 4,565,882, Example 14, incorporated herein by reference, was dissolved in methyl ethyl ketone (20ml). To this solution was added the thiol of Example 1 (2.0g, 0.006 mol) and anhydrous potassium carbonate (2.5g) and the reaction mixture was refluxed with stirring under a nitrogen atmosphere for 24 hrs. The reaction was cooled to room temperature, filtered and the filtrate concentrated on the rotary evaporator. The residue was chromatographed on silica gel using 25% ethyl acetate/ hexane as eluent to give 3.3g (95%) of the title compound as an oil.

Analysis calculated for C„oH,o0oS^: 28 42 8 2 Calc.: C, 58,73; H, 7.41; S, 11.21.

Found: C, 58.55; H, 7.40; S, 11.51. 16 6SN 237 2 EXAMPLE 3 4—[[[3—(4-Acety1-3—hydroxy-2-propylphenoxy)propyl]thio] methyl]-l,3-oxathiolane-2,2-dipropanoic acid The product of Example 2 (3g, 0.0052 moi) was dissolved in ethanol (50ml). Aqueous lithium hydroxide solution (2 M, 9.2ml) as added and the reaction solution was stirred at room temperature for 3 hrs. Ethanol was removed using the rotary evaporator and the aqueous residue was acidified to pH2 using aqueous 0.5 N sodium bisulfate solution. The oil which separated was extracted with ethyl acetate and the organic layer dried over anhydrous magnesium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator to give 2.53g of a colorless oil which was dried at 70° (0.1 mm Hg) for 5 hrs. to give the title compound.

Analysis calculated for C24H34°8S2: Calc.: C, 56.02; H, 6.67; S, 12.43.

Found: C, 56.07; H, 6.85; S, 12.79.

C02H COzH 137 2 6 4 166 9N EXAMPLE 4 Diethyl 4-[[[5-(4-acetyl-3-hydroxy-2-propylphenoxy) pentyl]thio]methyl]-l,3-oxathiolane-2,2-dipropanoate The reaction of the mercaptan from Example 1 (2.0g, 0.006 mol) and 5-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-l-bromopentane (described in U.S. Patent 4,565,882, Example 1) (2.1g, 0.06 mol) in methyl ethyl ketone (20ml) was carried out and worked up in the same manner as described in Example 2. After chromatography on silica gel using 25% ethyl acetate/hexane as eluent, 3.3g (93%) of the title compound was obtained as an oil.

Analysis calculated for C3oH46°8S2' Calc.: C, 60.18; H, 7,75; S, 10.69.

Found: C, 60.01; H, 7.80; S, 10.79. 1669N 237 2 6 4 EXAMPLE 5 4—[ [ 15-(4-Acetyl-3-hydroxy-2-propylphenoJcy) osntyl]thiolmethyl 1-1.3-oxathiolane-2,2-dipropanoic acid The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 4 (l.Og, 0.0016 mol) and aqueous lithium hydroxide solution (2 M, 3.0ml). Following the workup procedure of Example 3, 0.99g (96%) of the product was obtained as a colorless oil.

Analysis calculated for CorH.o0oS„: /. b Jo o Z Calc.: C, 57.55; H, 7.09; S, 11.79.

Found: C, 57.33; H, 7.35; S, 11.68. co2h co2h ho 237 2 6 4 EXAMPLE 6 Diethyl 4-[[(3-phenoxypropyl)thio]methyli 1,3-oxathiolane-2,2- dipropanoate ;>c COjCj Hj co2c2h5 The product of Example 1 (2.0g, 0.006 mol) and 3-phenoxy-l-bromopropane (1.3g, 0.006 mol) were dissolved in methyl ethyl ketone (20ml). Anhydrous potassium carbonate (2.5g) was added and the reaction was run and worked up as described in the procedure of Example 2. Chromotography of the resulting oil on silica gel using 15% ethyl acetate/hexane as eluent gave 2.70g (96%) of the title compound as an oil.

Analysis calculated for C23H34OgS2: Calc.: C, 58.70; H, 7.28; S, 13.60. Found: C, 58.20; H, 7.33; S, 13.24. 1669N 237 2 EXAMPLE 7 -(4-Bromobutoxy)-l,2,3,4-tetrahydronaphthalene A solution of 5,6,7,8-tetrahydronaphthalene-l-ol (4.2g, 0.028 mol) in methylene chloride (50ml) was mixed with a solution of sodium hydroxide (2.3g, 0.0575 mol) in water (50ml). ■■••After adding tetra-n-butylammonium bisulfate (9.6g, 0.028 mol) and 1,4-dibromobutane (31g, 0.14 mol), the reaction mixture was refluxed with vigorous stirring for 2 hrs. The reaction was cooled to room temperature, the layers separated and the organic phase washed with saturated sodium chloride solution. After drying over sodium sulfate, the organic phase was concentrated on the rotary evaporator and the residual oil heated under vacuum (0.1 mm Hg) to remove remaining 1,4-dibromobutane. The residue was chromatographed on silica gel using 100% hexane as eluent to give 8.lg (71%) of the title compound as an oil.

Analysis calculated for C14HigOBr: Calc.: C, 59.35; H, 6.70; Br, 28.23.

Found; C, 59.11; H, 6.60; Br, 28.71. 1669N 237 2 EXAMPLE 8 Diethyl 4—[[[5-(2-propylphenoxy)pentyl]thio]methyl]-1,3-oxathiolane-2,2-dipropanoate Potassium carbonate (2.5g) was mixed with a solution of 5-(2-n-propylphenoxy)-l-bromopentane (1.7g, 0.006 mol) and the product of Example 1 (2.0g, 0.006 mol) in methyl ethyl ketone (20ml). The reaction mixture was stirred and refluxed under a nitrogen atmosphere for 4 hrs. and then worked up according to the procedure described in Example 2. The residue was chromatographed on silica gel using 4% acetone/benzene as eluent to give 1.8g (80%) of the title compound as an oil.

Analysis calculated for C„oH..0cS • Zo 4 4 o Z Calc. : C, '62.20; H, 8.20; S, 11,84.

Found: C, 62.10; H, 8.35; S, 11.56.

COj C2 He C02C2 H5 2372 6 4 16 69N EXAMPLE 9 4-[[[5-(2-Propylphenoxy)pentyl]thio]methyl]-1,3-oxathiolane-2,2-dipropanoic acid The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 8 (0.80g, 0.0015 mol) and aqueous lithium hydroxide solution (2 M, 3.0ml). The product, 0.78g A* (89%), tyas obtained as an oil.

Analysis calculated for C24H36°5S2: Calc.: C, 59.28; H, 7.48; S, 13.20. Found: C, 59.00; H, 7.60; S, 12.90. lb69N 2372 EXAMPLE 10 Diethyl 4-[[[4-[(5,6,7,8-tetrahydro-l-naphthalenyl)oxy] butyl]thio]methyl]-1,3-oxathiolane-2,2-dipropanoate procedure of Example 2 using the mercaptan produced in Example 1 (2.0g, 0.006 mol) and the bromide produced in Examples (1.7g, 0.006 mol). The crude product was chromatqgraphed on silica gel using 20% ethyl acetate/hexane as eluent to give 2.5g (77%) of the product as an oil.

Analysis calculated for C28H42°6S2' Calc.: C, 61.43; H, 7.86; S, 11.88.

Found: C, 61.31; H, 7.81; S, 11.73.

CO2C2H5 CO2C2 Hg The title compound was prepared according to the 1 b 6 9 N 237 2 EXAMPLE 11 4—[[[[4—(5,6,7,8-Tetrahydro-l-naphthalenyl)oxy]butyl]thio] methyl1-1,3-oxathiolane-2,2-dipropanoic acid The title compound was prepared using the procedure of Example 3 using the ester produced in Example 10 (2.0g, 0.0037 mol) and aqueous lithium hydroxide solution (2 M, 6.5ml). 'The product, 1.78g (91%) was obtained as an oil. i Analysis calculated for C24H34°6S2: Cale.: C, 59.73; H, 7.10; S, 13.26.

Found: C, 59.89; H, 7.35; S, 13.49. 1669N 237 2 6 4 EXAMPLE 12 l-(3-Bromopropoxy)-2-propylbenzene Br The, title compound was prepared according to the procedure of Example 7 using 2-n-propylphenol (30g, 0.22 mol) in methylene chloride (400ml), sodium hydroxide (18.8g, 0.44 mol) in water (400ml), 1,3-dibromopropane (lOOg, I mol) and tetra-n-butylammonium bisulfate (80g, 0.22 mol). Distillation of the crude product yielded 55g (751) of pure material, b.p. 85-87° (0.1 mm Hg).

Analysis calculated for C12H17BrO: Calc.: C, 56.02; H, 6.66; Br, 31.10.

Found: C, 56.00; H, 6.79; Br, 31.42. 1669N 237 2 EXAMPLE 13 Diethyl 4-[[[3-(2-propylphenoxy)propyl]thio]methyl] 1,3-oxathiolane-2,2-dipropanoate The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 1 (2.0g, 0.006 mol), the bromide produced in Example 12 (1.54g, 0.006 mol) and anhydrous potassium carbonate (2.5g). The crude product was chromatographed on silica gel using 15% ethyl acetate/hexane as eluent to give 2.96g (96%) of the product as an oil.

Analysis calculated for C2gH40O6S2: Calc.: C, 60.91; H, 7.86; S, 12.48.

Found: C, 60.88; H, 7.86; S, 12.86.

C02 Cj Hg COjCJ H5 1669N 2372 6 4 EXAMPLE 14 4—[[[3—(2-Propylphenoxy)propyl]thio]methyl]-1,3-oxathiolane-2,2-dipropanoic acid The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 13 (2.58g, 0.005 mol) and aqueous lithium hydroxide solution (2 M, 10ml). The product, 2.3g (92%), was obtained as an oil.

Analysis calculated for C22H32°6S2: Calc.: C, 57.88; H, 7.07; S, 14.02. Found: C, 57.47; H, 7.20; S, 13.91. 1669N 2372 6 4 EXAMPLE 15 4-[[(3-Phenoxypropyl)thio Jmethyl]-1,3-oxathiolane-2,2-dipropanoic acid The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 6 (2.44g, 0.0052 mol) and aqueous lithium hydroxide solution (2 M, 9ml). The product, 1.86g (82%), was obtained as an oil.

Analysis calculated for C19H2606S2: Calc.: C, 55.06; H, 6.32; S, 15.44. Found: C, 54.78; H, 6.43; S, 15.30 1669N 237 2 6 EXAMPLE 16 l-[4-(4-Bromobutoxy)-2-hydroxy-3-propylphenylJethanone The title compound was prepared according to the procedure of Example 7 using 2,4-dihydroxy-3-n-propylacetophenone (lOg, 0.051 mol) in methylene chloride (100ml), sodium hydroxide (4.1g, 0.102 mol) in water (100ml), 1.4-dibromobutane (38g, 0.18 mol) and tetra-n-butylammonium bisulfate (17.6g, 0.051 mol). Chromatography of the crude product on silica gel using 15% ethyl acetate/hexane as eluent gave 13.5g (79%) of the title compound as an oil.

Analysis calculated for C15H21Br03: Calc.: C, 54.70; H, 6.43; Br, 24.29.

Found: C, 54.50; H, 6.29; Br, 24.60.

Sr lbb9N 237 2 6 4 EXAMPLE 17 Diethyl 4-[[[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyl] thiojmethyl]-l,3-oxathiolane-2,2-dipropanoate The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 1 (2.0g, 0.006 mol), the bromide produced in Example 16 (2.35g, 0.006 mol) and anhydrous potassium carbonate (2.5g). The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 3.51g (98%) of the product as an oil.

Analysis calculated for C„oH..0„S„: J 29 44 8 2 Calc.: C, 59.57; H, 7.58; S, 10.94.

Found: C, 59.37; H, 7.56; S, 10.57.

I 1669N 2372 6 4 EXAMPLE 18 4-[[[4-(4-Acetyl-3-hydroxy-2-propylphenoxy)butyl]thio] methyl]-l,3-oxathiolane-2,2-dipropanoic acid The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 17 (3.23 g, 0.0055 mol) and aqueous lithium hydroxide solution (2 M, 10ml). The crude product was recrystallized from cyclohexane to give 2.5g (91%) of the title compound, m.p. 108-109°C.

Analysis calculated for CocH_^0oS„: OD O Z Calc.: C, 56.80; H, 6.87; S, 12.10. Found: C, 56.78; H, 7.09; S, 11.80. b o 9 N 23 7 2 EXAMPLE 19 -[(5-Bromopentyl)oxy]-l,2,3,4-tetrahydronaphthalene The, title compound was prepared according to the procedure of Example 7 using 5,6,7,8-tetrahydronaphthalene- l-ol (8g, 0.0 54 mol) in methylene chloride (100ml), sodium hydroxide (4.32g, 0.108 mol) in water (100ml), 1,5-dibromopentane (37g, 0.19 mol) and tetra-n-]3utylammonium bisulfate (18.3g, 0.054 mol). Chromatography of the crude product on silica gel using 20% ethyl acetate/hexane as eluent gave I2g (69%) of the title compound as an oil.

Analysis calculated for C15H21BrO: Calc.: C, 60.59; H, 7.12; Br, 26.90.

Found: C, 60.12; H, 7.06; Br, 26.42.

I ib69N 237 2 EXAMPLE 20 Diethyl 4-[[[5—[(5,6,7,8-tetrahydro-l-naphthalenyl)oxy] pentyl]thio]methyl]-l,3-oxathiolane-2,2-dipropanoate c02c2h5 co2c2h5 The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 1 (2.0g, 0.006 mol), the bromide produced in Example 19 (1.78g, 0.006 mol) and anhydrous potassium carbonate (2.5g). The crude product was chromatographed on silica gel using 15% ethyl acetate/hexane as eluent to give 3.lg (88%) of the product as an oil.

Analysis calculated for C29H44°6°2: Calc.: C, 63.02; H, 8.02; S, 11.58.

Found: C, 62.80; H, 8.08; S, 11.61. f 237 2 1.66 9.N EXAMPLE 21 4—[[[5—[(5,6,7,8-Tetrahydro-l-naphthalenyl)oxy]pentyl]thio] methyl]-l,3-oxathiolane-2,2-dipropanoic acid The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 20 (2.8g, 0.005 mol) and aqueous lithium hydroxide solution1 (2 M, 9ml). The crude product slowly crystallized and was recrystallized from ethyl acetate/ hexane to give 2.01g (92%) of the title compound, m.p. 87-89°.

Analysis calculated for C25H36°6S2: Calc.: C, 60.46; H, 7.30; S, 12.89.

Found; C, 60.08; H, 7.21; S, 12.70. t f 1669N 237 2 6 4 EXAMPLE 22 1-(4-Bromobutoxy)-2-propylbenzene The! title compound was prepared according to the procedure of Example 7 using 2-n-propylphenol (lOg, 0.073 mol) in methylene chloride (100ml), sodium hydroxide (6.0g, 0.146 mol) in water (100ml), 1,4-dibromobutane (55g, 0.255 mol) and tetra-n-butylammonium bisulfate <26g, 0.073 mol). The crude product was distilled (b.p. 110-112°/0.25 mm hg) to give 20g (80%) of the title compound.

Analysis calculated for C13HigBrO: Calc.: C, 57.55; H, 7.06; Br, 29.49.

Found: C, 57.58; H, 7.06; Br, 29.47.

I t 23; 1669N EXAMPLE 23 Diethyl 4-[[[4-(2-propylphenoxy)butyl]thio]methyl]~ 1,3-oxathiolane-2,2-dipropanoate The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 1 (2.0g, 0.006 mol), the bromide produced in Example 22 (1.63g, 0.006 mol) and anhydrous potassium carbonate (2.5g). The crude product was chromatographed on silica gel using 15% ethyl acetate/hexane as eluent to give 2.78g (87%) of the product as an oil.

Analysis calculated for C„_H.»0,S_: 27 42 6 2 Calc.: C, 61.57; H, 8.03; S, 12.15.

Found: C, 61.39; H, 8.00; S, 11.93.

C02C2'rl5 C02CoH5 1669N 23 7*64 EXAMPLE 24 4-[[[4-(2-Propylphenoxy)butyl]thio]methyl]-1,3-oxathiolane-2,2-dipropanoic acid co2h co2h The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 23 (2.0g, 0.0038 mol) and aqueous lithium hydroxide solution (2 M, 6.7ml). The product, 1.8g (90%), was obtained as an oil.

Analysis calculated for C23H34°6S2: Calc.: C, 58.70; H, 7.28; S, 13.60.

Found: C, 58.43; H, 7.36; S, 13.58. 16 6 yw 2372 6 4 EXAMPLE 25 l-[4-(2-Bromoethoxy)-2-hydroxy-3-propylphenyllethanone CCx° The title compound was prepared according to the procedure of Example 7 using 2,4-dihydroxy-3-n-propyl-acetophenone (5g, 0.025 mol) in methylene chloride (50ml), sodium hydroxide (2g, 0.05 mol) in water (50ml), 1,2-dibromoethane (17g, 0.088 mol) and tetra-n-butylammonium bisulfate (8.7g, 0.025 mol). Chromatography of the crude product on silica gel using 15% ethyl acetate/hexane as eluent gave 13.5g (79%) of the title compound as an oil.

Analysis calculated for C13H17BrC>3 : Calc.: C, 51.82; H, 5.69; Br, 26.55. i Found: C, 51.86; H, 5.81; Br, 26.44. 237 2 6 i t> EXAMPLE 26 Diethyl 4[[[2-(4-acetyl-3-hydroxy-2-propylphenoxy) ethyl]thio Jmethyl]-l,3-oxathiolane-2,2-dipropanoate The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 1 (2.0g, 0.006 mol), the bromide produced in Example 25 (1.80g, 0.006 mol) and anhydrous potassium carbonate (2.5g). The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 3.25g (91%) of the product as an oil.

Analysis calculated for c27H4o°8S2: Calc.: C, 58.26; H, 7.24; S, 11.49.

Found: C, 57.91; H, 7.28; S, 11.49. 0 1669N 2 3/264 EXAMPLE 27 4-[ [[2-(4-Acetyl-3-hydroxy-2-propylphenoxy)ethyl]thio] methyl]-1,3-oxathiolane-2,2-dipropanoic acid The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 26 (2.75g, 0.005 mol) and aqueous lithium hydroxide solution (2 M, 8.5ml). The crude product was recrystallized from ethyl acetate/hexane to give 2.3g (92%) of the title compound, m.p. 109-111°C.

Analysis calculated for C23H32°8S2: Calc.: C, 55.13; H, 6.44; S, 12.77. Found: C, 54.99; H, 6.73; S, 12.31. 1669N 2372 6 4 EXAMPLE 28 -(3-Bromopropoxy)-l,2,3,4-tetrahydronaphthalene 0 Br The title compound was prepared according to the procedure of Example 7 using 5,6,7,8-tetrahydro-naphthalene-l-ol (lOg, 0.067 mol) in methylene chloride (100ml), sodium hydroxide (5.5g, 0.134 mol) in water (100ml), 1,3-dibromopropane (47g, 0.23 mol) and tetra-n-butylammonium bisulfate (23g, 0.067 mol). Chromatography of the crude product on silica gel using 1% ethyl acetate/hexane as eluent gave I2g (60%) of the title compound as an oil.

Analysis calculated for C13H17BrO: Calc.: C, 57.98; H, 6.36; Br, 29.70.

Found: C, 58.22; H, 6.47; Br, 29.83. 237 2 1669N EXAMPLE 29 Diethyl 4—[[[3—[(5,6,7,8-tetrahydro-l-naphthal6nyl)oxy] propyl]thio]methyl]-l,3-oxathiolane-2,2-dipropanoate The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 1 (2.1g, 0.006 mol), the bromide produced in Example 28 (1.89g, 0.0065 mol) and anhydrous potassium carbonate (2.5g). The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 3. lg (91%) of the product as an oil.

Analysis calculated for c27h40°6s2: Calc.: C, 61.81; H, 7.69; S, 12.20.

Found: C, 61.52; H, 7.77; S, 11.88.

C02Et C02Et 1669N 237 2 EXAMPLE 30 4-[[[3-[(5,6,7,8-Tetrahydro-l-naphthalenyl)oxy]propyl] thiojmethyl3-1,3-oxathiolane-2.2-dipropanoic acid The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 29 (2.6g, 0.005 mol) and aqueous lithium hydroxide solution (2 M, 8.5ml). The product, 2.45g (94%), was obtained as an oil.

Analysis calculated for : 23 32 6 2 Calc.: C, 57.96; H, 6.88; S, 13.62. Found: C, 57.99; H, 7.15; S, 13.62. 1669N 237 2 EXAMPLE 31 Diethyl-4-(mercaptomethyl)-l,3-dithiolane-2,2-dipropanoate A stirred solution of 1,2,3-trimercaptopropane (10.Og, 0.071 mol) and diethyl 4-oxopimelate (16.43g, 0.071 mol) in methylene chloride (300ml) under nitrogen atmosphere was treated with boron trifluoride etherate (2ml). After stirring for 3 days at room temperature, the reaction was quenched by addition of 200ml of 5% sodium bicarbonate solution. The organic phase was separated and dried over anhydrous sodium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator. The residue was chromatographed on silica gel using 5% ethyl acetate/hexane as eluent to give lQg (40%) of the title compound as an oil.

Analysis calculated for C, .H„ .O.S.,: -1 14 24 4 3 Calc.: C, 47.72; H, 6.87; S, 27.25.

Found: C, 47.89; H, 6.92; S, 27.69. 49 1669N 23726 EXAMPLE 32 Diethyl 4-[[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl! thioJmethy1]-l,3-dithiolane-2,2-dipropanoate C02Et The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 31 (0.5g, 0.0014 mol), 5-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-l-bromopentane (described in U.S. Patent 4,565,882, Example 1) (0.484g, 0.0014 mol) and anhydrous potassium carbonate (0.70g) in methyl ethyl ketone (5ml). The crude product was chromatographed on silica gel using 30% ethyl acetate/hexane as eluent to give 0.52g (75%) of the product as an oil.

Analysis calculated for C3(JH4607S3: Calc.: C, 58.61; H, 7.54; S, 15.62. Found: C, 58.22; H, 7.66; S, 15.90. i to o 9.N 23 7 2 EXAMPLE 33 4-[[[5-(4-Acetyl-3-hydroxy-2-propylphenoxy)pentyl]thio] methyl]-l,3-dithiolane-2,2-dipropanoic acid sv^co^ co2h The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 32 (0.48g, 0.00078 mol) and aqueous lithium hydroxide solution (2 M, 1.5ml). The crude product was chromatographed on silica gel using 3% ethyl acetate/ toluene (containing 0.5% acetic acid). The product, 0.40g, was obtained as a viscous oil containing two molar equivalents of acetic acid.

Analysis calculated for C0-H_o0_So*2H0Ac: zd oo / J Calc.: C, 53.08; H, 6.83; S, 14.14. Found; C, 52.87; H, 6.98; S, 14.33. 237 2 6 16 6 9N EXAMPLE 34 Diethyl 4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy) propyl]thio]methyl 1-1,3-dithiolane-2,2-dipropanoate S C02Et 'COjEt The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 31 (2.0g, 0.0056 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-l-bromopropane (prepared as described in U.S. Patent 4,565,882, Example 14) (2.0g, 0.006 mol) and anhydrous potassium carbonate (3.5g) in methyl ethyl ketone (25ml) at reflux overnight. The crude product was chromatographed on silica gel using 20% ethyl acetate/ hexane as eluent to give 2.1g (70%) of the product as an oil.

Analysis calculated for CooH.o0_,S_: /o 4 A / o Calc*.: C, 57.32; H, 7.21; S, 16.43. Found: C, 57.18; H, 7.30; S, 16.68. 1669N 237264 EXAMPLE 35 4—[[[3—(4-Acetyl-3-hydroxy-2-propylphenoxy)propyl]thio] methyl]-l.3-dithiolane-2,2-dipropanoic acid The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 34 (1.5g, 0.0025 mol) and aqueous lithium hydroxide solution (2 M, 5ml). The crude product was chromatographed on silica gel using 40% ethyl acetate/hexane/O.5% acetic acid as eluent to give 1.lg of product as an oil. The oily product was azeotroped twice with toluene to give the title compound containing 0.5 mol of toluene. The toluene was removed by heating at 100°C under vacuum (0.1 mm Hg) for 4 hrs.

Analysis calculated for C24H34°7S3: Calc.: C, 54.33; H, 6.46; S, 18.09.

Found: C, 54.64; H, 6.51; S, 18.01. c02h co2h ho /*Q 1669N 2372 6 4 EXAMPLE 36 Ethyl 4-(mercaptomethyl)-2-methyl-l,3-oxathiolane-2- propanoate HS A stirred solution of 2,3-dimercapto-l-propanol (20.Og, 0.161 mol) and ethyl levulinate (22g, 0.161 mol) in methylene chloride (600ml) under a nitrogen atmosphere was treated with boron trifluoride etherate (5ml). After stirring; for 3 days at room temperature, the reaction was quenched by addition of 250ml of 5% potassium bicarbonate solution. The organic phase was separated and dried over anhydrous sodium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator. The residue was chromatographed on silica gel using 6% ethyl acetate/hexane as eluent to give 17g (43%) of the l title compound as an oil.

I Analysis calculated for cxgHi8S2°3: Calc.: C, 47.99; H, 7.25; S, 25.57.

Fourth C, 48.01; H, 7.40; S, 25.89. 1669N 237 2 6 EXAMPLE 37 Ethyl 4—[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl] thio]methyl]-2-methy1-1,3-oxathiolane-2-propanoate O PH.

C02 Et The title compound was prepared- according to the procedure of Example 2 using the mercaptan produced in Example 36 (1.5g, 0.006 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-l-bromopropane (1.9g, 0.006 mol) and anhydrous potassium carbonate (2.5g). The crude product was chromatographed on silica gel using 20% ethyl acetate/ hexane as eluent to give 2.7g (93%) of the product as an oil.

Analysis calculated for C24H36°6S2: Calc.: C, 59.48; H, 7.49; S, 13.20. Found: C, 59.26; H, 7.61; S, 13.03. 1669N 23 7 2 EXAMPLE 38 4—[[[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propyl]thio] methyl]-2-methyl-l,3-oxathiolane-2-propanoic acid The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 37 (2.2g, 0.0043 mol) and aqueous lithium hydroxide solution (2 M, 6ml). The product, 2.05g (90%) was obtained as an oil.

Analysis calculated for A A J c O Z Calc.: C, 57.88; H, 7.07; S, 14.02.

Found: C, 57.62; H, 7.20; S, 13.92. s s COjH 0 ch3 1669N 2 3 7 2 6 4 EXAMPLE 39 Diethyl 4-[ [ [3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropyl1 thiolmethyl]-l,3-oxathiolane~2,2-dipropanoate The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 1 (2.0g, 0.0066 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1,2-epoxypropane (described in U.S. Patent 4,565,882) (1.5g, 0.006) and anhydrous potassium carbonate (3.0g). The crude product was chromatographed on silica gel using 40% ethyl acetate/hexane as eluent to give 3.22g (92%) of the product as an oil.

Analysis calculated for C28H42°9S2: Calc.: C, 57.32; H, 7.21; S, 10.90.

Found: C, 57.25; H, 7.28; S, 10.53. 1669N 23 7 2 EXAMPLE 40 4-[ [[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropyl] thio]methyl]-!,3-oxthiolane-2,2-dipropanoic acid The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 39 (2.67g, 0.0045 mol) and aqueous lithium hydroxide solution (2 M, 8.5ml). The product, 2.2g (91%), was obtained as an oil.

Analysis calculated for C24H340gS2: Calc.: C, 54.33; H, 6.46; S, 12.06.

Found: C, 54.61; H, 6.86; S, 11.62. 237 2 1669N EXAMPLE 41 Ethyl 4—[[[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyl] thio]methyl]-2-methyl-l,3-oxathiolane-2-propanoate COict 0 CHi The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 36 (1.5g, 0.006 mol), the bromide produced in Example 16 (2.0g, 0.006 mol) and anhydrous potassium carbonate (2.5g). The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 2.73g (91%) of the product as an oil.

Analysis calculated for C25H38°6S2: Calc.: C, 60.22; H, 7.68; S, 12.84.

Found: C, 60.19; H, 7.83; S, 13.04. 1669N 23 7 2 EXAMPLE 42 4-[ [[4-(4-Acetyl-3-hydroxy-2-propylphenoxy)butylJthio] methyl]-2-methy1-1,3-oxathiolane-2-propanoic acid C03H The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 41 (2;7g, 0.0052 mol) and aqueous lithium hydroxide solution (2 M, 8.5ml). The product, 2.23g (91%), was obtained as an oil.

Analysis calculated for C23H34°6S2: Calc.: C, 58.70; H, 7.28; S, 13.60. Found: C, 58.44; H, 7.30; S, 13.40. 1669N 23 7 2 EXAMPLE 43 Diethyl 5-(hydroxymethyl)-l,3-oxathiolane-2.2-dipropanoate The title compound was prepared according to the procedure of Example 1 using 3-mercapto-l,2-propanediol (10.8g, 0.1 mol), diethyl 4-oxopimelate (23g, 0.1 mol) and boron trifluoride etherate (2.5ml) in methylene chloride (300ml). The crude product was chromatographed on silica gel using 40% ethyl acetate/hexane as eluent to give 14.5g (45%) of product.

Analysis calculated for C^H^O^S: Calc.: C, 52.49; H, 7.55; S, 9.99.

Found: C, 52.61; H, 7.71; S, 10.10. 1669N 2372 6 4 EXAMPLE 4 4 Diethyl 4-[[[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyl] thio jmethyl3-1,3-dithiolane-2,2-dipropanoate The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 31 (2.0g, 0.0056 mol), the bromide produced in Example 16 (2.0g, 0.0065 mol) and anhydrous potassium carbonate (2.5g). The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 1.56g (60%) of the product as an oil.

Analysis calculated for C29H44°7S3: Calc.: C, 57.98; H, 7.38; S, 15.98.

Found: C, 57.95; H, 7.48; S, 15.59.

C02Et C02Et o 1669N 2372 EXAMPLE 4 5 4-[ [[4-(4-Acetyl-3-hydroxy-2-propylphenoxy)butyl]thio] methyl]-l,3-dithiolane-2,2-dipropanoic acid, ethyl acetate salt The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 44 (l.Og, 0.00167 mol) and aqueous lithium hydroxide solution (2 M, 3.5ml). The product, 0.90g (85%), was obtained as a viscous oil containing one molar equivalent of ethyl acetate.

Analysis calculated for C25H36°7S3*C4H8°2: Calc.: C, 53.53; H, 6.84; S, 16.32.

Found: C, 53.67; H, 6.72; S, 16.14. c0,h co2h O 1669N 237264 EXAMPLE 4 6 4—[ [[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propyl]sulfinyl] methyl1-1,3-dithiolane-2,2-dipropanoic acid To a cold (0°C), stirred solution of the sulfide from Example 35 (0.25g, 0.00047 mol) in methylene chloride (5ml) was added 85% m-chloroperbenzoic acid (0.081g, 0.00047 mol). After stirring 2 hrs. at 0°C, the solvent was evaporated using a nitrogen stream and the residue chromatographed on silica gel using ethyl acetate containing 0.5% acetic acid as eluent. The title compound (0.20g, 75%) was obtained as an oil.

Analysis calculated for C^H^OgS^: Calc.: C, 51.57; H, 6.27; S, 17.16.

Found: C, 51.24; H, 6.35; S, 16.83. hc c02h cc2h ^0 1669N 2372 6 EXAMPLE 4 7 Ethyl 4-(mercaptomethyl)-2-methyl-l,3-dithiolane-2- propanoate The title compound was prepared according to the procedure of Example 1 using 1,2,3-trimercaptopropane (5.6g, 0.04 mol), ethyl levulinate (5.8g, 0.04 mol) and boron trifluoride etherate (1.25ml) in methylene chloride (150ml).; The crude product was chromatographed on silica gel using 5% ethyl acetate/hexane as eluent to give 3.35g (31%) of product.

Analysis calculated for Calc.: C, 45.11; H, 6.81; S, 36.06.

Found; C, 45.56; H, 6.82; S, 36.42. s ch3 1669N 23726 4 EXAMPLE 48 Ethyl 4—[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl] thio]methyl]-2-methyl-l,3-dithiolane-2-propanoate L CO2 Et s ch3 The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 47 (1.5g, 0,0056 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-l-bromopropane (described in U.S. Patent 4,565,88?, Example 14) (1.8g, 0.006 mol) and anhydrous potassium carbonate (2.5g). The crude product was chromatographed on silica gel using 15% ethyl acetate/ hexane as eluent to give 1.85g (60%) of the product as an oil.

Analysis calculated for C_.H_^OcS_: J 1 24 36 5 3 Calc.: C, 56.54; H, 7.42; S, 19.65.

Found: C, 56.94; H, 7.41; S, 19.39. 237 2 6 4 1669N EXAMPLE 49 Ethyl 4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hyaroxypropyl]thio]methyl]-2-methy1-1,3-dithiolane-2- propanoate The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 47 (1.5g, 0.006 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-l,2-epoxypropane (described in U.S.

Patent 4,565,882) (1.4g, 0.006 mol) and anhydrous potassium carbonate (2.5g). The crude product was chromatographed on silica gel using 35% ethyl acetate/hexane as eluent to give 1.7g (65%) of the product as an oil.

Analysis calculated for C24H3g06S3: Calc.: C, 54.75; H, 7.19; S, 19.01. Found: C, 55.07; H, 7.29; S, 18.98. 23 7 2 i c o y N . .1 V EXAMPLE 5 0 4—([[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propyl] thio]methyl]-2-methy1-1,3-dithiolane-2-propanoic acid ^ coah s ch3 The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 48 (1.5g, 0.003 mol) and aqueous lithium hydroxide solution (2 M, 3.5ml). The product, 1. 4g (90%), was obtained as a viscous oil containing 0.33 molar equivalent of ethyl acetate.

Analysis calculated for C22H3205S3«0.33 C^HgC^: Calc.: C, 55.83; H, 6.96; S, 19.12.

Found: C, 55.55; H, 6.88; S, 18.99. 1669N 2372 EXAMPLE 51 4-[[[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropyl]thio]methyl]-2-methyl-l,3-dithiolane-2- propanoic acid The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 49 (1.3g, 0.0025 mol) and aqueous lithium hydroxide solution (2 M, 10ml). The product, 1.27g (97%), was obtained as a viscous oil.

Analysis calculated for C22H32°6S3: Calc.: C, 54.00; H, 6.60; S, 19.65.

Found: C, 53.68; H, 6.90; S, 19.89. -^0 co2h 237 2 6 4 i 669N EXAMPLE 52 4-[[[3—(4-Acetyl—3-hydroxy-2-propylphenoxy)propyl] sulfinyl]methyl3-2-methyl-l,3-oxathiolane-2-propanoic acid The title compound was prepared according to the procedure of Example 46 using the sulfide obtained in Example 38 (0;30g, 0.00066 mol) and m-chloroperbenzoic acid (0.113g, 0.00066 mol). The crude product was chromatographed on silica gel using ethyl acetate containing 0.5% acetic acid to give 0.157g (50%) of the desired product as an oil.

Analysis calculated for C22H32°7S2: Calc.: C, 55.88; H, 6.82; S, 13.53.

Found: C, 55.52; H, 6.87; S, 13.07. 23 7 2 1 o o ^ N EXAMPLE 53 Separation Of Racemates Of Example 37 The racemates of Example 37 were separated on HPLC using a 500 x 9 mm column of Cyclobond B and 55/45 methanol/water as eluent. Repetitive injections yielded 68mg of racemate A and 84 mg of racemate B. lb69N 237 2 EXAMPLE 54 Saponification of racemate A to racemic acid.

Racemic acid was prepared according to the procedure of Example 3 using racemate A produced in Example 53 (0.068, 0.00014 mol) and aqueous lithium hydroxide solution (2 M, o'.2ml). The product (0.054g, 85%), one of the two racemates obtained in Example 38, was obtained as an oil.

Analysis calculated for AA oA o A Calc.: C, 57.88; H, 7.07; S, 14.02.

Found: C, 57.71; H, 7.05; S, 13.99. lOO'J 1M 237 2 EXAMPLE 55 Saponification of racemate B to racemic acid.

Racemic acid was prepared according to the procedure of Example 3 using racemate B produced in Example 53 (0.084, 0.0002 mol) and aqueous lithium hydroxide solution (2 M, 0.3ml). 'The product (0.072g, 90%), one of the two racemates obtained in Example 38, was obtained as an oil.

Analysis calculated for Co„H_o0,So: Calc.: C, 57.88; H, 7.07; S, 14.02. Found: C, 57.81; H, 7.03; S, 13.89. f 1669N 2372 6 EXAMPLE 56 Diethyl-4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydiroxypropyl 3thio]methyl ]-1,3-dithiolane-2, 2-dipropanoate g C02Et C02Et The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 31 (1.5g, 0.004 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphfenoxy)-l,2-epoxypropane (described in U.S. Patent 4,565,882) (l.lg, 0.004 mol) and anhydrous potassium carbonate (1.75g) in methyl ethyl ketone (15ml). The crude product was chromatographed on silica gel using 30% ethyl acetate/hexane as eluent to give 1.9g (60%) of the product as an oil.

Analysis calculated for C28H42°8S3: Calc.: C, 55.80; H, 7.02; S, 15.93. Found: C, 55.42; H, 6.87; S, 15.63, •J C J -'J 237 2 EXAMPLE 57 4—[t[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropyl]thio]methyl] -1,3-dithiolane-2,2-dipropanoic acid CO^H C02H The title compound was prepared according to the procedure of Example 3 using the ester produced in Example'56 (1.9g, 0.0031 mol) and aqueous lithium hydroxide solution (2 M, 7.8ml). The product, 1.4g (85%), was obtained as an oil containing 0.33 molar equivalent of ethyl acetate.

Analysis calculated for C24H340gS3*0.33 C^U^O^: Calc.: C, 52.74; H, 6.41; S, 16.67. Found: C, 52.53; H, 6.60; S, 16.39.

DO Vl'i 2 3 7 2 6 4 EXAMPLE 58 Methyl 4-acetyIbutyrate O O To a rapidly stirred slurry of sodium bicarbonate (25g) in a solution of 4-acetylbutyric acid (13g, 0.1 mol) in dimethylformamide (150ml) was added methyl iodide (47g). After, stirring overnight at room temperature under nitrogen, the reaction mixture was diluted with water (300ml) and extracted with ethyl ether (250ml). The organic phase was washed with water and dried over sodium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator to give 12g of the title compound as a light yellow oil. The product can be purified by distillation: b.p. 59-60° (o.l mm Hg).

EXAMPLE 59 Methyl 4-(mercaptomethyl)-2-methyl-l,3-dithiolane-2- butanoate co2ch3 The title compound was prepared according to the procedure of Example 1 using 1,2,3-trimercaptopropane (5g, 0.03 55 mol), methyl 4-acetylbutyrate (5.1g, 0.03 55 mol) and boron trifluoride etherate (1ml) in methylene chloride (125ml). The crude product was chromatographed on silica gel using 51 ethyl acetate/hexane as eluent to give 6.5g (69%) of product.

Analysis calculated for C10H18°2S3: Calc.: C, 45.11; H, 6.81; S, 36.05.

Found: C, 45.01; H, 7.03; S, 36.38. 237264 1 o o ^ iN EXAMPLE 60 Methyl 4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy) propyl]thio]methyl]-2-methy1-1,3-dithiolane-2- butanoate The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 59 (1.2g, 0.0045 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-l~bromopropane (described in U.S. Patent 4,565,882, Example 14) (1.4g, 0.006 mol) and anhydrous potassium carbonate (2.5g). The crude product was chromatographed on silica gel using 15% ethyl acetate/ hexane as eluent to give 2.15g (96%) of the product as an oil.

Analysis calculated for C24H36°5S3: Calci. : C, 57.58; H, 7.25; S, 19.18. Found: C, 57.56; H, 7.38; S, 19.54.

L Li U ~J LH 23 7 2 EXAMPLE 61 4-[[[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propyl] thiolmethyl]-2-methyl-l,3-dithiolane-2-butanoic acid The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 60 (2.0g, 0.004 mol) and aqueous lithium hydroxide solution (2 M, 5ml). The product, 1.87g (96%), was obtained as an oil containing 0.33 molar equivalent of i ethyl acetate. The ethyl acetate was removed by drying at 100°C for 4 hrs. under vacuum (0.1 mm Hg).

Analysis calculated for C23H3405S3: Calc.: C, 56.77; H, 7.04; S, 19.73.

Found: C, 56.64; H, 7.14; S, 19.88.

O CO,H 2372 EXAMPLE 62 Diethyl 5-[t(4-methylphenyl)sulfonyl]oxy]1,3-oxathiolane-2,2-dipropanoate O _ C02Et TsO' u ^ ' 2 S C02Et To a cold (0°) stirred solution of the alcohol produced in Example 43 (3.0g, 0.0093 mol) in pyridine (30ml) was added p-toluenesulfonyl chloride (2.5g) in portions' over 15 minutes. When addition was completed, the reaction was stirred at room temperature for 2 hrs. The reaction mixture was diluted with ether and washed with water, 0.5 N aqueous sodium bisulfate solution, 5% aqueous sodium bicarbonate solution and water. The organic layer was dried over sodium sulfate, filtered, and the filtrate concentrated on the rotary evaporator to give 4.4g (97%) of the title compound as a light yellow oil.

I Analysis 'calculated for C2iH3o°8S2: Calc.: C, 53.16; H, 6.37; S, 13.49. 1 Found: C, 53.41; H, 6.11; S, 13.69. 1 O D '-J i>J 2 3 7 2 EXAMPLE 63 Diethyl 5-[(acetylthio)methyl]-l,3-oxathiolane-2,2- dipropanoate CH,COS' C02Et A stirred slurry of potassium thioacetate (0.50g) in a solution of the tosylate produced in Example 62 (2.0g, 0.0042 mol) in acetone (20ml) was refluxed under nitrogen for 5 hrs. The reaction mixture was filtered and the filtrate concentrated on the rotary evaporator. The residue was dissolved in ethyl acetate, washed with water and dried over sodium sulfate. The drying agent was filtered, the solvent removed using the rotary evaporator and the residue chromatographed on silica gel using 10% ethyl acetate/hexane as eluent to give 1.lg (72%) of the title compound as a light yellow oil.

Analysis calculated for C16H2gOgS2: Calc.: C, 50.78; H, 6.92; S, 16.91-Found: C, 50.71; H, 7.05; S, 17.10, a. <j c 237264 EXAMPLE 64 Diethyl 5-(mercaptomethyl)-l,3-oxthiolane-2,2-dipropanoate A solution of sodium ethoxide in ethanol (20mls) [prepared from 0.16g (0.006g - atom) of sodium metal] and the thioacetate produced in Example 63 (2.1g, 0.0055 mol) was stirred for one hour at room temperature under nitrogen. Ethanol was removed in vacuo on the rotary evaporator and the residue dissolved in ethyl acetate.

This organic phase was washed with 0.5 N sodium bisulfate solution and dried over sodium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator to give 1.97g (95%) of the title compound as an oil.

I Analysis calculated for ci4H24°5S2: Calb.: C, 48.99; H, 7.19; S, 19.03.

Found: C, 48.99; H, 7.12; S, 19.52. 2372 EXAMPLE 65 Diethyl 5-[ [[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl] thio1methyl]-1,3-oxathiolane-2,2-dipropanoate The: title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 64 (l.Og, 0.003 mol), (3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-l-bromopropane (described in U.S. Patent 4,565,882, Example 14) (l.lg, 0.0033 mol) and anhydrous potassium carbonate (1.6g) in methyl ethyl ketone (15ml). The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give l.54g (90%) of the product as an oil.

Analysis calculated for C28H42°8S2: Calc.: C, 58.93; H, 7.42; S, 10.21. Found: C, 58.68; H, 7.49; S, 9.94. 237264 .OU A- EXAMPLE 66 -[[[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propyl]thio] methyl]-l,3-oxathiolane-2,2-dipropanoic acid cc2h co2h The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 65 <1.3g, 0.0023 mol) and aqueous lithium hydroxide solution (2 M, 4ml). The product, 0.923g (78%), was obtained as an oil containing 0.33 molar equivalent of ethyl acetate.

Analysis calculated for C24H34°8S2 " 1/'3 EtOAc: Calc.: C, 55.93; H, 6.80; S, 11.76.

Found: C, 55.59; H, 6.87; S, 11.88.

I ^ J u 2372 6 EXAMPLE 6 7 Methyl 3-Benzoyl Propanoate The title compound was prepared according to the procedure of Example 58 using 3-benzoylpropionic acid (20.Og, 0.112 mol), methyl iodide (47.Og) and sodium bicarbonate (33g) in dimethylformamide (150ml). The product, 19.6g (91%) was obtained as an oil.

Analysis calculated for C11H12°3 Calc.: C, 68.73; H, 6.30. Found: C, 68.57; H, 6.49.

O O V ^ 237264 EXAMPLE 6 8 Methyl 4-(mercaptomethyl)-2-phenyl-l,3-oxathiolane-2- propanoate The title compound was prepared according to the procedure of Example 1 using 2,3-dimercapto-l-propanol (2.3g, 0.019 mol), methyl 3-benzoylpropionate from Example 67 (3.7g, 0.019 mol) and boron trifluoride etherate (0.5ml) in methylene chloride (50ml). The crude product was chromatographed on silica gel using 1% acetone/toluene as eluent to give l.Og (31%) of product.

Analysis calculated for C..Hlo0nS„: 14 lo o Z Calc.: C, 56.37; H, 6.08; S, 21.45.

Found: C, 56.71; H, 6.21; S, 21.85.

O C8H5 uu; 23 7 2 6 EXAMPLE 6 9 Methyl-4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy) propyl 3thio]methyl]-2-phenyl-l,3-oxathiolane-2-propanoate The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 68 (0.586g, 0.002 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-l-bromopropane (described in U.S. Patent 4,565,882, Example 14) (0.70g, 0.0025 mol) and anhydrous potassium carbonate (0.95g) in methyl ethyl ketone (10ml). The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 0.896g (84%) of the product as an oil.

Analysis calculated for C28H36°6S2: Calc.: C, 63.14; H, 6.81; S, 12.01.

Found: C, 63.01; H, 6.75; S, 11.89. 237264 EXAMPLE 7 0 4-[[[3-(4-Acetyl-3-hydroxy-2-propylphenoxyl]propyl] thio]methyl]-2-phenyl-l,3-oxathiolane-2-propanoic acid CC2H The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 69 (0.75g, 0.0014 mol) and aqueous lithium hydroxide solution (2 M, 1.75ml). The product, 0.686g (90%), was obtained as an oil containing 0.5 molar equivalent of ethyl acetate.

Analysis calculated for C„_Ho.0^S_ » 0.5 EtOAc: 27 34 6 2 Calc.: C, 61.91; H, 6.80; S, 11.38.

Found: C, 61.96; H, 6.88; S, 11.18. o o .N 237 2 6 EXAMPLE 71 4 —[ [[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propyl]sulfinyl] methyl]-2-methyl-l,3-dithiolane-2-butanoic acid co2h The title compound was prepared according to the procedure of Example 48 using the sulfide obtained in Example 61 (0.15g, 0.0003 mol) and m-chloroperbenzoic acid (0.063g, 0.0003 mol) in methylene chloride (3ml). The crude product was chromatographed on silica gel using ethyl acetate containing 1% acetic acid to give 0.063g (45%) of the desired product as an oil containing one molar equivalent of acetic acid.

Analysis calculated for C„oH_,0,S^ • CHoC0oH: ZJ J4 6 3 3 2 Calc.: C, 53.37; H, 6.80; S, 16.33. Found: C, 53.31; H, 6.81; S, 16.16. 1 o o a L-4 2372 EXAMPLE 7 2 4-[ [[3-(4-acetyl-3-hydroxy-2-propylphenoxy]propyl]sulfinyl] methyl 1-1,3-oxathiolane-2,2-dipropanoic acid The title compound was prepared according to the procedure of Example 46 using the sulfide obtained in Example 3 (0.15g, 0.0003 mol) and m-chloroperbenzoic acid (0,062g, 0.0003 mol) in methylene chloride (3ml). The crude product was chromatographed on silica gel using ethyl acetate containing 0.5% acetic acid to give 0.070g (45%) of the desired product as an oil.

Analysis calculated for C_.H_,0„S„: 24 34 9 2 Calc.: C, 54.33; H, 6.46; S, 12.06. Found: C, 54.58; H, 6.41; S, 11.70. 237 2 1 U O J i'-l EXAMPLE 73 Methyl 4-oxobutanoate ohc' , co2ch3 The title compound was prepared by hydrogenation of 3-carbomethoxypropionyl chloride (25.Og, 0.166 mol) in tetrahydrofuran (250ml) containing 2,6-dimethylpyridine (1 eg) using 10% Pd/C (2.5g) as catalyst at 5 psi. The reaction mixture was filtered and the solvent removed using the rotary evaporator. The residual oil was distilled to give 14.5g (79%), b. p. 63-65° (10 mm Hg).

Analysis calculated for C5Hg03: Calc.: C, 51.72; H, 6.89.

Found: C, 51.89; H, 7.15. i 003 I'i 237 2 8 EXAMPLE 7 4 Methyl 4-(mercaptomethyl)-l,3-dithiolane-2-propanoate The title compound was prepared according to the procedure of Example 1 using 1,2,3-trimercaptopropane (4.21g, 0.03 mol), methyl 4-oxobutanoate from Example 73 (3.5g, 0.03 mol) and boron trifluoride etherate (1ml) in methylene chloride (75ml). The crude product was chromatographed on silica gel using 5% ethyl acetate/hexane as eluent to give 2.5g (35%) of product.

Analysis calculated for CgH1202S3: Calc.: C, 40.34; H, 5.92; S, 40.30.

Found: C, 40.01; H, 6.10; S, 40.61. s h EXAMPLE 7 5 Methyl 4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl] thio]methyl]-1,3-dithiolane-2-propanoate c02ch3 The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 74 (l.Og, 0.004 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-l-bromopropane (described in U.S. Patent 4,565,882, Example 14) (1.4g, 0.004 mol) and anhydrous potassium carbonate (2.0g). The crude product was chromatographed on silica gel using 15% ethyl acetate/hexane as eluent to give 1.60g (81%) of the product as an oil.

Analysis calculated for G22H32°5S3: Calc.: C, 55.92; H, 6.82; S, 20.31. Found: C, 55.87; H, 6.78; S, 20.02.

^ 'J "J J 23726 4 EXAMPLE 7 6 4—[[[3—<4-Acetyl-3-hydroxy-2-propylphenoxy)propyl]thio] methyl]-!r3-dithiolane-2-propanoic acid ^0 • The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 75 (1.30g, 0.00275 mol) and aqueous lithium hydroxide solution (2 M, 3.5ml). The product, 1.06g (85%), was obtained as an oil containing 0.33 molar equivalent of ethyl acetate.

Analysis calculated for C_-.H__0.-S- o 0.33 EtOAc: 2130 5 3 Calc.: C, 54.98; H, 6.75; S, 19.67.

Found: C, 55.30; H, 6.58; S, 19.26.

U O 23 7 2 6 4 EXAMPLE 7 7 Methyl 4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropyl]thio]methyl]-2-methyl-l,3-dithiolane-2- butanoate The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 59 (1.12g, 0.00425 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-l,2-epoxypropane (described in U.S. Patent 4,565,882, Example 18) (1.05g, 0.00425 mol) and anhydrous potassium carbonate (1.5g). The crude product was chromatographed on silica gel using 25% ethyl acetate/hexane as eluent to give 2.l0g (96%) of the product as an oil.

Analysis calculated for Co.H„c0cS_: Z4 J b b o Calc.: C, 55.80; H, 7.02; S, 18.73.

Found: C, 55.73; H, 7.15; S, 18.64. 2372 6 4 EXAMPLE 7 8 4- ([[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropyl' thiolmethyl]-2-methyl-l,3-dithiQlane-2-butanoic acid CO,H The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 77 (1.75g, 0.0034 mol) and aqueous lithium hydroxide solution (2 M, 6ml). The product, 1.55g (91%), was obtained as an oil containing 0.33 molar equivalent of ethyl ether.

Analysis calculated for C^H^OgS^oO . 33 C4H1Q0: Calc.: C, 55.43; H, 7.13; S, 18.21.

Found: C, 55.55; H, 7.05; S, 17.86. 2372 6 4 EXAMPLE 79 3-(2-n-Propyl-3-methoxy-4-acetylphenoxy)-1-bromopropane 3.15g (0.01 mole) of 3-(2-n-propyl-3-hydroxy-4-acetylpheiioxy)-l-bromopropane was dissolved in 50ml of dry acetone. To this solution was added 2.75g (0.02 mole) of anhydrous potassium carbonate and 3g (0.02 mole) of methyl iodide. After refluxing for four days under an argon atmosphere, the reaction mixture was filtered and the filtrate concentrated on the rotary evaporator. The residue was chromatographed on silica gel eluting with 2% ethyl acetate/toluene to give 3.1g (94%) of the title compound as an oil.

Analysis calculated for C,cHo10oBr: JL O Z J, o Calc.: C, 54.70; H, 6.43; Br, 24.29.

Found: C, 54.65; H, 6.57; Br, 24.03. 237264 J. o ij "J EXAMPLE 80 Methyl 4-[[[3-(4-acetyl-3-methoxy-2-propylphenoxy)propyl] thio]methyl]-2-methyl-l,3-dithiolane-2-butanoate 1.24g (0.0037 mole) of bromide described in Example 79 was dissolved in 15ml of methyl ethyl ketone containing lg (0.0037 mole) of material described in Example 59. To this solution was added lg (7.24 mmol) of anhydrous potassium carbonate and the mixture was refluxed 14 hrs. under an argon atmosphere. The reaction was cooled and filtered and the filtrate was evaporated. The residue was chromatographed on silica gel using 4% ethyl acetate/ toluene as eluent to give l.8g (95%) of product as an oil.

Analysis calculated for C~.-H,.o0,-S~: ZO Jo D 3 Calc.: C, 58.35; H, 7.44; S, 18.65. Found: C, 58.28; H, 7.56; S, 18.51.

L o-6 y N 2372 6 EXAMPLE 81 4-[[t 3-(4-Acetyl-3-methoxy-2-propylphenoxy)propyl]thio] methyl]-2-methvl-l,3-dithiolane-2-butanoic acid 1. 8g (0.035 mole) of compound described in Example 80 was dissolved in 30ml of methanol. To this mixture was added 5ml of -aqueous 2 M lithium hydroxide solution. The mixture was stirred at room temperature for 4 hrs. and warmed to 40°C for 1 hr. The reaction mixture was concentrated on the rotary evaporator and the residue dissolved in water. This was acidified to pH 3.5 using 0.5 N KHSC>4 and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator to give a viscous oil. The oil was further dried at 100°c (0.05 mm Hg) for 3 hrs. to give 1.56g (89%) of the title compound as an oil.

Analysis calculated for C„ : 24 36 5 3 Calc.: C, 57.58; H, 7.25; S, 19.17.

Found: C, 57.20; H, 7.38; S, 19.14. s ch3 co2h h3co O EXAMPLE 82 Methyl 4-(mercaptomethyl)-2-methyl-l,3-oxathiolane-2- butanoate . hs s CO^CH^ a o ch3 The title compound was prepared according to the procedure of Example 1 using 2,3-dimercaptopropanol (2.8g, 0.022 mol), methyl 4-acetylbutyrate (3.2g, 0.022 mol) and boron trifluoride etherate (0.62ml) in methylene chloride (70ml). The crude product was chromatographed on silica gel using 10% ethyl acetate/hexane as eluent to give 0.91g (16.5%) of product.

Analysis calculated for CinH1o0_S»: X U 1 o o Z Calc.: C, 47.99; H, 7.25; S, 25.57.

Found: C, 48.07; H, 7.31; S, 25.74. loo? L 4 23 7 2 EXAMPLE 83 Methyl-4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy) propyl]thio]methyl]~2-methyl-l,3-oxathiolane-2-butanoate CO2CH1 The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 82 (0.90g, 0.0036 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane (described in U.S. Patent 4,565,882, Example 14) (1.2g, 0.0036 mol) and anhydrous potassium carbonate (1.5g) in methyl ethyl ketone (15ml). The crude product was chromatographed on silica gel using 5% ethyl acetate/hexane as eluent to give 1.3g (75%) of the product as an oil.

Analysis calculated for C„ .H.^O^S,.: Z4 Jo b Z Calc.: C, 59.49; H, 7.49; S, 13.20, Found: C, 58.98; H, 7.30; S, 12.90. 237264 EXAMPLE 84 4-[[[3-(4-Acetyl-3-hydroxy-2-propylphenoxy]propyl] thiolmethyl-2-methyl-l,3-oxathiolane-2-butanoic acid The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 83 (1.05g, 0.002 mol) and aqueous lithium hydroxide solution (2 M, 2.5ml). The product, 0.90g (96%), was obtained as an oil.

Analysis calculated for C23H34°6S2: Calc.: C, 58.70; H, 7.28; S, 13.60.

Found: C, 58.38; H, 7.37; S, 13.71. 237 2 EXAMPLES 8 5 TO 94 Compounds 1 (a-d) and 2(a-d) are prepared according to the following reaction scheme.

-SH -SH -OH NJ •A (CH^COjRJ S (CH^COjRJ O R, 1 + S .(CHjInCOiRj S R, Example No. 85 86 87 88 Compound la lb lc Id n 3 3 1 2 R1 Et cyclo-hexyl Me Et *2 Me Me Et Me Example 89 IX fie) S, .%\s. X02Me Et Example 90 Is HQ Example No. Compound n 91 2A Et R2 Me 237 2 6 92 2b 3 cyclo- Me hexyl 93 2c 1 Me Et 94 2d 2 Et Me The oxa and dithiolane compounds of Examples 85 to 94 were prepared according to the following procedure.

General Procedure for the Synthesis of Oxa and Dithiolane Ring Systems 1 and 2 An equimolar ratio of the appropriate keto ester and 2,3-dimercapto-l-propanol were dissolved in benzene (0.68-1.3 mmol/ml) and a minimum amount of con. hydrochloric acid (85-300 mg) was added. The reaction was stirred at room temperature for 3-4 days. In the case of .lc, the reaction was refluxed for an additional 2 days. The reaction was poured into 5% ^CO^ solution, the layers separated and the organic layer washed once with saturated aqueous sodium chloride solution. After drying the organic layer over sodium sulfate, the drying agent was filtered and the filtrate stripped on the rotary evaporator. The residual oil was purified by chromatography on silica gel using mixtures of ethyl acetate and hexane. The oxa and dithiolanes were isolated pure. la: 37% yield 2a: 25% yield Careful chromatography of 6.4g of id on preparative HPLC using 2 columns of silica gel in series and 5% ethyl 237 2 8 4 acetate/hexane as eluent gave 1.5g of the slightly less polar racemate (le) and 3.8g of the slightly more polar racemate (If) as oils. Racemate le possesses either the structure shown for Example 89 or Example 90. Racemate If. possesses the other of these two structures. 237 2 6 EXAMPLES 9 5 TO 12 6 Compounds 3a-_f and 4_a-f are prepared according to the following reaction scheme.

Example No.

Compound n Rl *2 95 3a 3 Et Me 96 3b 3 cyclo-hexyl Me 97 3c 1 Me Et 98 M 2 Et Me 99 3e 2 Et Me 100 3f 2 Et Me 101 4a 3 Et hydroxy-2-propylphenoxy) propyl]thio]methyl]-2-ethyl-l,3-oxathiolane-2-butanoic acid 237264 102 4b cyclo-hexyl 4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy) propyl]thio]methyl]-2-cyclohexyl-1,3-oxathiolane-2-butanoic acid 103 4c Me 4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy) propyl]thio]methy1]-2-methy1-1,3-oxathiolane-2-acetic acid 104 M 105 4e 106 4f Et — 4-[[13-(4-acetyl-3- hydroxy-2-propylphenoxy) propyl]thio]methy1]-2-ethyl-l,3-oxathiolane-2-propanoic acid Et — (+)trans(or cis)-4-[[[3- (4-acetyl- 3-hydroxy-2-propylphenoxy) propyl]thio] methyl]-2-ethyl-l,3-oxathiol ane-2-propanoic acid Et — (+)cis(or trans)-4-[[[3- (4-acetyl-3- hydroxy-2-propylphenoxy) propyl]thio] methyl]-2-ethyl-l,3-oxathiol ane-2-propanoic acid 3e and 3f are stereoisomers 4e and 4f are stereoisomers Compounds 5. (a-d), 6. (a-d), 7 (a-d), 8. (a-d), and 9. (a.-d) were prepared according to the following reaction scheme. soa2 a^3. ksac '—s n. a <> xam No 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 237 2 6 Compound n R1 *2 5A 3 Et Me 5b 1 Me Et 5c 2 Et Me 5d 2 Et Me 6a 3 Et Me 6b • « 1 Me Et 6c 2 Et Me M 2 Et Me 5c. and 5d are stereoisome 6c and M are stereoisome 7a 3 Et Me 7b 1 Me Et 7c 2 Et Me 7d 2 Et Me 8a 3 Et Me 8b 1 Me Et 8c 2 Et Me M 2 Et Me 9a 3 Et — 9b 1 Me 4-[t[3-(4-acetyl-3-hydroxy-2-propylphenoxy) propyl]thio]methy1]-2-ethyl-l,3-dithiolane-2-butanoic acid 4-[[[3-(4~acetyl-3-hydroxy-2-propylphenoxy) propyl]thio]methyl]-2-methyl-1,3-dithiolane-2-acetic acid 237 2 6 125 2c 2 Et — (+)trans(or cis)-4-[[[3- (4-acetyl- 3-hydroxy-2-propylphenoxy) propyl]thio] methyl]-2- ethyl-2,3-(3ithiolane-2- propanoic acid 126 9d 2 Et — (±)cis(or trans)-4-[[[3- (4-acetyl-3- hydroxy-2-propylphenoxy) propyl]thio] methyl]-2- ethyl-1,3-dithiolane-2- propanoic acid ' % 7c and 7d are stereoisomers 8c and 8d are stereoisomers The compounds of Example 95 to 100 (3a-3f) and 119 to 122 (8a-8d) were prepared according to the following procedure.

General Procedure for Attachment of Sidechain to 1 and 7 to Give Compounds 3a-f and 8a-d To an equimolar solution of the mercaptan (la-f and 7a-d) and the same bromide used in Example 2 in methyl ethyl ketone (0.16-0.40 mmol/ml) was added potassium carbonate (2.5 molar equivalents) and the reaction mixture was refluxed with stirring under a nitrogen atmosphere for 6-15 hrs. The reaction was filtered and the filtrate stripped on the rotary evaporator. The residual oil was purified by chromatography on silica gel using mixtures of ethyl acetate and hexane as eluents. 3a: 89% yield; Anal. Calcd. for <'25H38°6^2: H, 7.68; S, 12.83. Found: C, 59.84; H, 7.75; S, 12.39. 2372 6 4 3b: 92% yield: Anal. Calcd. for C29H44°6S2' C' 63,02' H, 8.02; S, 11.58. Found: C, 62.61; H, 8.06; S, 11.12. 3c: 92% yield 3d: 60% yield; Anal. Calcd. for C24H36^6^2' ^9.49; H, 7.48; S, 13.20.. ^ Found: C, 59.21; H, 7.63; S, 13.21, 3e: 80% yield 3f: 65% yield 8a: 95% yield; Anal. Calcd. for C-cH,,o0[-S • C, 58.35; 2 o 3 o 3 3 H, 7.44; S, 18.65. Found: C, 57.80; H, 7.64; S, 18.21. 8b: 60% yield; Anal. Calcd. for C23H34°5S3: C, 56.78; H, 7.04; S, 19.73. Found: C, 56.60; H, 7.21; S, 19.67, 8c: 92% yield 8d: 95% yield 237 2 6 The compounds of Examples 101 to 106 (4_a-4_f) and 123 to 126 (9a-9d) were prepared according to the following procedure.

General Procedure for Saponification to Target Acids 4a-f and 9a-d To a solution of pure ester 3 or 8 in the alcohol of the ester radical (ethanol or methanol) (0.07-0.19 mmol/ml) was added aqueous 2M lithium hydroxide solution (2.5 eq). After stirring at room temperature under N2 for 15-24 hrs, the reaction mixture was concentrated on the rotary evaporator, diluted with water, and acidified to pH 2.5 with 0.5N KHS04. The aqueous mixture was extracted with ethyl acetate and the organic layer dried over MgSO^. The drying agent was filtered and the filtrate concentrated on the rotary evaporator; to give an oil. The oil was dried on the oil pump at 65-75° for 4-6 hrs to give the target acid.

Compounds 4e and 4f were purified by chromatography on silica gel using 30% ethyl acetate/hexane containing 0.5% HOAc as eluent. The chromatographed material was evaporated twice with methanol and dried 4 hrs at 70° under vacuum I (0.1 mm Hg).

I 4a: 88% yield; NMR (ppm in CDC1„ solution): 1.0, multiplet, i -1 6H (2 C-CH3); 2.56, s, 3H (acetyl); 3.56-3.68, multiplet, IH (ring hydrogen); 7.60, 1H, d, J=10 Hz (aromatic H); 6.44, 1H, d,. j=lo Hz (aromatic H) . Anal. Calcd. for 237 2 6 C24H36°6S2; C' 59-50; H' 7-49; s» 13.12. Found: C, 59.28; H, 7.58; S, 12.76. 4b: 89% yield; NMR (ppra in CDC13 solution):0.94, t, J=7 Hz, 3H (CH3); 2.56, s, 3H (acetyl); 3.50-3.60, mult., 1H (ring hydrogen); 3.92-4.0, mult., 1H (ring hydrogen); 4.18-4.22, mult., IH (ring hydrogen); 6.44, 1H, d, J=10Hz (aromatic H); 7.60, IH, d, J=10Hz (aromatic H); 12.74, IH, s (phenol H).

Anal. Calcd. for C_DH.: C, 62.43; H, 7.86; S, Z a 4 Z b Z 11.88. Found: C, 62.81; H, 7.93; S, 12.06. 4c: 89% yield; NMR (ppm in CDC13 solution): 0.94, t, J=7 Hz, 3H (CH3); 1.62, 3H, s (ring methyl of one diastereomeric racemate); 1.72, 3H, s (ring methyl of other diastereomeric racemate); 2.56, 3H, s (acetyl); 3.62-3.72, IH, mult. '(H on C-2); 6.44, IH, d, J=10Hz (aromatic H); 7.60, IH, d, J=10Hz (aromatic H); 12.74, IH, s (phenol H). Anal. Calcd. for c2iH3o°6S2: C' 57-00' H' 6.83; S, 14.46.

Found: C, 56.90; H, 6.88; S, 14.76. 4d: 91% yield; NMR (ppm in CDC13 solution): 0.90-1.00, 6H, mult, (two'C-CH3's); 2.56, 3H, s (acetyl); 3.56-3.70, IH, mult, (rincj H) ; 4.03, IH, d of d, J=4 and 5 Hz (ring H) ; 4.20, 2H, d of d, J=4 and 5 Hz (ring H); 6.44, IH, d, J=10Hz (aromatic H); 7.60 (IH, d, J=10Hz (aromatic H); 12.74, IH, s (phenol H). Anal. Calcd. for C23H34°6S2: C' 58*71' H' 7.28; S, li.60. Found: C, 58.72; H, 7.40; S, 13.79. 4e: 93% yield; NMR (ppm in CDC13 solution): 0.90-1.00, 6H, mult., (overlapping signals for two C-CH^'s); 4.06-4.18, 4H, mult, (two ring H and ; remaining signals are identical to 4d. Anal. Calcd. for C_oH_.0^S_: C, A6 o A 58.71; H, 7.28; S, 13.60. Found: C, 58.46; H, 7.27; S, 13.5 4f: 94% yield; NMR (ppm in CDCl^ solution): 0.95, 3H, t, J=7Hz (C-CH3); 0.99, 3H, t, J=7Hz (C-CH3); remaining signals are identical to 4d. Anal. Calcd. for : C, 58.71; H, 7.28; S, 13.60. Found: 7.36; S, 13.71. 0CS_ 23 34 6 2 58.48; H, 9a: 97% yield; NMR (ppm in CDC13 solution): 0.94, 3H, t, J=7Hz (C-CH3); 1.04, 3H, t, J=7Hz (CH3 on ethyl group); 2.56, 3H, t, 7Hz (acetyl); 3.20-3.38, 2H, mult, (ring H); 3.82- 3.91, IH, mult, (ring H); 6.44, IH, d, J=10Hz (aromati H); 7.60, IH, d, J=10Hz (aromatic H); 12.74, IH, singlet (phenol). Anal. Calcd. for C..H_.0cSo: C, 57.58; H, A 4 JO z> J 7.25; S, 19.17. Found: C, 57.24; H, 7.25; S, 19.17. 9b: 89% yield; NMR (ppm in CDC13 solution): 0.94, 3H, t, J=7Hz (C-CHg); 1.90, 3H, s (ring CH3 from one diastereomer); 1.95, 3H, s (ring CH3 from other diastereomer); 2.56, 3H, s (acetyl); 3.88-4.20, IH, mult, (ring H); 6.44, IH, d, J=10Hz (aromatic H); 7.60, IH, d, J=10Hz (aromatic H); 12.74, IH, s (phenol H). Anal. Calcd. for C2iH3o^5S3; C' 55-01'' H' 6.60; S, 20.94. Found: C, 54.96; H.6.65; S, 20.96. / 2372 6 9c; 91% yield; NMR (ppm in CDCl^ solution): 0.94, 3H, t, J=7Hz (C-CH3);1.06, 3H, t, J=7Hz (CH3 of ethyl group); 2.54, 3H, s (acetyl); 3.84-3.92, IH, mult, (ring H); 6.44, IH, d, J=10Hz (aromatic H); 7.58, IH, d, J=10Hz (aromatic H); 12.74, IH, s (phenol H). Anal. Calcd. for C_..H_, : C, 56.77; H, 7.04; S, 19.73. Found: C, 2.6 3 6 56.58; H, 7.14; S;/< 19.48. 9d: 82% yield; NMR (ppm in CDC13 solution): 0.94, 3H, t, J=7Hz (C-CH3);1.06, 3H, t, J=7Hz (CH3 of ethyl group); 2.54, 3H, s (acetyl); 3.84-3.92, IH, mult, (ring H); 6.44, IH, d, J=10Hz (aromatic H); 7.58, IH, d, J=10Hz (aromatic H); 12.74, IH, s (phenol H). Anal. Calcd. for C^H^O^S.^: C, 56.77; H, 7.04; S, 19.73. Found: C, 56.67; H, 7.04; S, 19.85.

General Procedure For the Conversion of Alcohols 2a-d to Chlorides 5a-d To a solution of the alcohol in benzene (0.6-0.7 mmol/ml) was added one molar equivalent of thionyl chloride. The I reaction mixture was refluxed with stirring for 1 hr. The reaction wks worked up by either Workup A or Workup B.

Workup A: The reaction mixture was poured onto dilute NaHCO^, solution, and the layers separated. The organic layer was washed saturated NaCl solution and dried over Na2S04. 237 2 6 The drying agent was filtered and the filtrate concentrated on the rotary evaporator. The residual oil was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents. The pure product was obtained as an oil.

Workup B: The reaction mixture was stripped on the rotary evaporator and the residue chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents. The pure product was obtained as an oil. 5a: Workup B; 97% yield 5b: Workup A; 76% yield The product of the reaction of dithiolane 2d (8.9g, 35.5 mmol) with thionyl chloride (4.7g) obtained according to Workup A was carefully chromatographed on silica gel using 5% ethyl acetate/hexane to give 1.7g (17.9%) of a slightly less polar racemate (He) and 1.4g (14.7%) of a slightly more polar racemate (5d). There was also obtained 4.5g of an overlap fraction (total yield 80%). i 237 2 6 The compounds of Examples 111 to 114 (6a-6d) were prepared according to the following procedure.

General Procedure for the Synthesis of Thioacetates 6a-d From Chlorides 5a-d To a stirred solution of chloride 5. in dimethylformamide (0.3-0.5 mmol/ml) was added 3-3.5 molar equivalents of potassium thioacetate. The reaction mixture was stirred 2-3 days at room temperature under a nitrogen atmosphere. The reaction mixture was poured onto water and extracted with ethyl acetbte. The organic layer was washed with saturated sodium chloride solution and dried over sodium sulfate. The drying agent was filtered and the filtrate stripped on the rotary evaporator to give the oily crude product. The crude product was chromatographed on silica gel using mixtures of ethyl acet.ate and hexane as eluents to give the pure product as an oil. 6a.: 75% yield 6b: 63% yield 6c: 87% yield I 6d: 75% yield 23 7 2 6 The compounds of Examples 115 to 118 (7a-7d) were prepared according to the following procedure.

General Procedure for the Synthesis of Mercaptans 7a-d From Thioacetates 6a-d The sodium alkoxide solution was prepared from 1.2 molar equivalents of sodium metal (based on the amount of thioacetate) and :the alcohol corresponding to the ester radical of 6. (ethanol or methanol) . Thioacetate 6. was added (final concentration of £ was 0.20-0.37 mmol/ml) and the reaction was stirred at room temperature under N2 for 1-2 hrs. The reaction was poured into 0.5N KHSO^, extracted with ethyl acetate and dried over Na^SO^. The drying agent was filtered, the filtrate concentrated in vacuo and the residue chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the pure mercaptan 7 as an oil.

Za: 92% yield 7b: 63% yield 7c: 89% yield l 7d: 84% yield 237264 EXAMPLE .127 4—[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio] methyl 1-2-methyl-l, 3-dithiolane-2-butanoic acid, sodium =;al co? Na To a stirred solution of the product of Example 61 (458 mg, 0.94 mmol) in methanol (10 ml) was added 1.00 ml of 0.996N NaOH solution. After stirring the reaction at room temperature for 1 hr., solvent was removed using the rotary evaporator and the residue was evaporated three times with methanol and once with benzene. The resulting product was a glass.

Anal. Calcd. for C„_H_„0,.S_Na: C, 54.32; H 6.54; Zj JJ D j S, 18.88.

Found: C, 53.87; H, 6.46; S, 19.32.

Z O J 2372 6 4 EXAMPLE 128 (a) Methyl 4-(mercaptomethyl)-2-ethyl-l,3-oxathiolane-2-propanoate To a solution of methyl 4-oxohexanoate (10 g, 0.069 mol) and 2,3-dimercapto-l-propanol (9 g, 0.072 mol) in benzene (120 ml) was added con, hydrochloric acid (1 ml). The reaction mixture was stirred at room temperature under for 3 days. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with 5% aqueous K2CO3 (twice with 100 ml portions). After washing with saturated aqueous NaCl, the organic layer was dried over Na^SO,. 2 4 The drying agent was filtered and the filtrate l concentrated in vacuo. The residual oil was chromatographed on silica gel (Waters PrepPak-500/Silica) using 15% ethyl acetate/hexane to give 6.4 g (37%) of the * title compound and 4.0 g (23%) of methyl 4-(h^droxymethyl)-2-ethyl-l,3-dithiolane-2-propanoate. o c2h5 2372 6 4 Oxathiolane NMR S (ppm): 0.9-1.05, t, J = 6 Hz (CH2CH3); 1.60, t, J = 9.8 Hz and 1.62, t, J = 9.8 Hz, IH (SH); 1.80-1.90, 2H, mult. (CH2CH3); 3.68, 3H, s (OCH3). f 2 3 7 2 6 (b) Methyl 4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]-thio]methyl]-2-ethyl-l,3-oxathiolane-2-propanoate (compound 3d) A mixture of (10 g) and a solution of the mercaptan prepared in part (a) (6.4 g, 0.0255 mol) and the same bromide used in Example 2 (8.0 g, 0.0255 mol) in methyl ethyl ketone (100 ml) was refluxed with stirring under N2 for 12 hrs.

The reaction was cooled and filtered. The filtrate was concentrated in vacuo and the oily residue chromatographed on silica gel (Waters PrepPak 500) using % ethyl acetate/hexane to give 12 g (97% yield) of the titled compound. NMR 6 (ppm): 1.52, 2H, sextet, J = 6 Hz (CH2CH2CH3); 1.80-1.92, 2H, mult. (methylene of ethyl group); 3.68, 3H, singlet (OCH ); l J 6.46, IH, d and 7.60, IH, d (aromatic H); 12.75, IH, single^ (phenol).

Anal. (Ealcd. for C24H3606S2: C' 59-49' H- 7-48; S, 13.20.

Found: C, 59.41; H, 7.63; S, 13.21. 2 3 7 264 (c) 4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]-thio]methyl]-2-ethyl-l,3-oxathiolane-2-propanoic acid (compound 4d) CO •? H The ester prepared in part (b) (7.0 g, 0.0144 mol) was stirred overnight at room temperature under N2 with aqueous LiOH solution (2 M, 20 ml) in methanol (100 ml). The reaction was concentrated on the rotary evaporator and the residue diluted with water. The resulting solution was washed once with ethyl ether and then acidified to pH 2.5 with 0.5N KHSO^ solution. The aqueous mixture was extracted with ethyl acetate and the organic layer dried over MgSO^.

The drying agent was filtered and the filtrate concentrated on the rotary evaporator to give an oily residue which was purified by chromatography on silica gel (Waters PrepPak 500) using 30% ethyl acetate/hexane l containing 0.5% acetic acid. The isolated product was azeotrqped three times with methanol and once with benzene to remove acetic acid. After drying under vacuum l on the foil pump at 60° for 3 hrs., there was obtained 6.27 g (92% yield) of titled product as an oil. NMR 6 2372 6 4 (ppm): 1.51, 2H, doublet, J = 7 Hz (middle methylene of propyl group); 2.58, 3H, singlet (acetyl methyl); 2.63, 2H, triplet, J = 7 Hz (ArCH2CH2~); 6.44, IH, d and 7.60, IH, d (aromatic H); 12.72, IH, singlet (phenol).

Anal. Calcd. for G23H34°6S2: c' 58-71' H- 7-28, S, 13.60., Found: C, 58.62; H, 7.40, S, 13.61.

I 237 2 6 4 EXAMPLE 12 9 Methyl 4-[t[3-(4-acety1-3-hydroxy-2-propylphenoxy)-propy11 thiol methy11-2-ethvl-l.3-oxathiolane-2-propanoate (a) Synthesis of 3e.

To a solution of the less polar racemic mercaptan compound le (0.80 g, 0.0032 M) and the same bromide used in Example 2 (1.0 g, 0.0032 M) in methyl ethyl ketone (20 ml) was added potassium carbonate (1.1 g) and the reaction mixture was refluxed with stirring overnight. The reaction mixture was filtered and the filtrate stripped on the rotary evaporator. The residual oil was purifieid by chromatography on silica gel using 20% ethyl acetate/hexane as eluents to give 1.2 g (80%) of compound 3e. 0 O 23 7 2 6 4 (b) Synthesis of 3_f To a solution of the more polar racemic mercaptan compound If. (1.0 g, 0.004 M) and the same bromide used in Example 2 (1.25 g, 0.004 M) in methyl ethyl ketone (20 ml) was added potassium carbonate (1.4 g) and the reaction mixture was refluxed with stirring overnight. i The reaction mixture was filtered and the filtrate stripped on the rotary evaporator. The residual oil was purified by chromatography on silica gel using 20% ethyl acetate/hexane as eluents to give 1.2 g (65%) of compound 3f. • I 237 2 6 EXAMPLE 13 0 (±) trans/cis-4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propvl1 thiol methyl1-2-ethvl-l.3-oxathiolane-2-propanoic acid (a) Synthesis of 4e To a solution of compound 3e (Example 129a) (0.71 g, 0.00146 M) in methanol (10 ml) was added aqueous 2M lithium hydroxide solution (2 ml). After stirring overnight at room temperature under N^, the reaction mixture was concentrated on the rotary evaporator, I diluted with water, and acidified to pH 2,5 with 0.5N KHS04. , The aqueous mixture was extracted with ethyl acetate and the organic layer dried over MgSO^. The drying 'agent was filtered and the filtrate concentrated on the rotary evaporator to give an oil. 237 2 The oil was purified by chromatography on silica gel using 30% ethyl acetate/hexane containing 0.5% HOAc as eluent to give 0.64 g (93%) of compound 4e. The acetic acid was removed by evaporating twice with methanol and drying 4 hrs. at 70° under vacuum (0.1 mm Hg).

NMR (ppm in CDC I- solution): 0.90-1.00, 6H, mult., 1 O (overlapping signals for two C-CH^s); 4.06-4.18, 4H, mult, (two ring H and -OCH2~); remaining signals are identical to 4d.

Anal. Calcd. for C__H_.0,.S • C, 58.71; H, 7.28; zj b A S, 13.60.

Found: C, 58.46; H, 7.27; S, 13.51.

Synthesis of 4_£ To a solution of compound 3f. (Example 129b) (0.68 g, 0.0014 M) in methanol (10 ml) was added aqueous 2M lithium hydroxide solution (2 ml). After stirring overnight at room temperature under N2, the reaction mixture was concentrated on the rotary evaporator, i diluted with water, and acidified to pH 2.5 with 0.5N KHS04. The aqueous mixture was extracted with ethyl acetate and the organic layer dried over MgSO^. The drying agent was filtered an the filtrate concentrated on the rotary evaporator to give an oil.

The oil was purified by chromatography on silica gel using 30% ethyl acetate/hexane containing 0.5% HOAc as eluent. Acetic acid was removed from the oily product by evaporating twice with methanol and drying 4 hrs. at 70° under vacuum (0.1 mm Hg) to give 0.62 g (93%) of compound 4_f.

NMR (ppm in CDCl^ solution): 0.95, 3H, t, J = 7 Hz (C-CH3); 0.99, 3H, t, J = 7 Hz (C-CH3; remaining signals are identical to compound 4d. i Anal. Calcd. for C23H34°6S2: C' 58-71; H' 7-28; S, 13.60.

Found: f C, 58.48; H, 7.36; S, 13.71.

EXAMPLE 131 (a) Synthesis of Sodium Salt of 4d 4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyljthio]-methvll-2-ethvl-l.3-oxathiolane-2-propanoic acid, sodium salt To a stirred solution of compound 4d (511 mg, 1.1 mmol) in methanol (10 ml) was added 1.12 ml of 0.996N NaOH solution. After stirring the reaction for 1 hr. at room temperature, the solvent was removed in vacuo and the residue evaporated with methanol (three times) and toluene (twice). The resulting glass was dried at 90° for 4 hrs. under vacuum (0.1 mm Hg).

Anal. Calcd. for Co_H__0^S„Na: C, 56.08; H, 6.75; / j j J o A S, 12.99.

Found: C, 56.00; H, 6.65; S, 12.93. 0 (b) Synthesis of the Disodium Salt of 4d 4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)- propyl]thio]methyl]-2-ethyl-l,3-oxathiolane-2-propanoic acid, disodium salt CH3 To a stirred solution of compound 4d (470 mg, 1.0 mmol) in absolute ethanol (5 ml) was added 2 ml of 0.996N NaOH solution. After stirring the reaction for 1 hr. at room temperature, the solvent was removed in vacuo and the residue dried by azeotroping three times with benzene. The residue, which solidified upon trituration with ether, was filtered and had m.p. 125-128°.

Anal. Calcd. for Co_H_„0,S_Nao: C, 53.69? A6 6 A O A A H, 6.27; Na, 8.93; S, 12.43 Found: C, 53.22; H, 6.34; Na, 8.71; S, 12.79.

EXAMPLE 13 2 (a) Methyl 4-(hydroxymethyl)-2-ethyl-l,3-dioxolane-2-propanoate Methyl 4-oxohexanoate (14.42g, 0.1 mol), glycerol (9.21g, 0.1 mol) and p-toluenesulfonic acid (100 mg) are combined in benzene (150 ml) and refluxed with stirring for 10 hrs. using a water separator to remove water formed during the ketalization. The reaction mixture is cooled, washed successively with 5% NaOH solution and water and then dried over sodium sulfate. The drying agent is filtered and the filtrate stripped on the rotary evaporator to give the crude product. The product is purified by chromatography on silica gel using mixtures of ethyl acetate and hexane as eluents. (b) Methyl 4-(chloromethyl)-2-ethyl-l,3-dioxolane-2-propanoate A solution,of the alcohol prepared in part (a) (2.18g, 10 mmol) and thionyl chloride (1.19g, 10 mmol) in benzene (17 ml) is refluxed with stirring for 1 hr. The reaction mixture is stripped on the rotary evaporator and the residue 23 7 2 6 chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the chloride product. (c) Methyl 4-[(acetylthio)methyl]-2-ethyl-l, 3-dioxolane-2-propanoate To a stirred solution of the chloride prepared in part (b) (2.37g, 10 mmol) in dimethylformamide (DMF) (20 ml) is added potassium thioacetate (3.42g, 30 mmol). The reaction mixture is stirred 2-3 days at room temperature under a nitrogen atmosphere. The reaction mixture is poured onto water and extracted'with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and dried over sodium sulfate. The drying agent is filtered and the filtrate stripped on the rotary evaporator to give the oily crude product. The crude product is chromatographed on silica gel using mixtures of ethyl_ acetate and hexane as eluents to give the thioacetate product. 237 2 6 4 (d) Methyl 4-(mercaptomethyl)-2-ethyl-l,3-dioxolane-2- propanoate o HS co2 ch3 *• « Sodium methoxide is prepared in methanol (27 ml) using sodium metal (230 mg). The thioacetate prepared in part (c) (2.52g, 10 mmol) is added and the reaction is stirred at room temperature under a nitrogen atmosphere for 2 hrs. The reaction mixture is poured into 0.5N KHSO^, extracted with ethyl acetate and dried over Na2S04. The drying agent is filtered, the filtrate concentrated in vacuo and the residue chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the mercaptan product. (e) Methyl 4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)- propyl]thio]methyl]-2-ethyl-l,3-dioxolane-2-propanoate A mixture yi. (3.45g) in a solution of the mercaptan prepared in part (d) (2.34g, 10 mmol) and bromide of Example 79 (3.15g,fl0 mmol) in methyl ethyl ketone (50 ml) is refluxed with stirring under N2 for 12 hrs.

Claims (7)

2372 6 4 The reaction is cooled and filtered. The filtrate is concentrated in vacuo and the oily residue chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the product. (f) 4-[[[3-(4-Acety1-3-hydroxy-2-propylphenoxy)propyl]thio]-methyl]-2-ethyl-l,3-dioxolane-2-propanoic acid The ester prepared in part (e) (4.69g, 10 mmol) is stirred 10 overnight at room temperature under with agueous LiOH solution (2 M, 13 ml) in methanol (60 ml). The reaction is concentrated on the rotary evaporator and the residue diluted with water. The resulting solution is washed once with ethyl ether and then acidified to pH 2.5 with 0.5N KHSO^ 15 solution. The aqueous mixture is extracted with ethyl acetate and the organic layer dried over MgSO^. The drying agent is filtered and the filtrate concentrated on the rotary, evaporator to give an oily residue which is purified by chromatography on silica gel using mixtures of 20 ethyl acetate and hexane containing 0.5% acetic acid as eluents. The purified product is evaporated with methanol and benzene to remove acetic acid. The resulting product is dried on the oil pump (0.1 mm Hg) 60° to give the acid product. 25 The matter contained in each of the following claims is to be read as .part of the general description of the present invention. -134- 2372(54 What we claim is:

1. A method of treating allergy comprising administering to an animal (excluding human beings) in need of such treatment, a therapeutically amount of a compound of the formula or pharmaceutically acceptable salts thereof, or geometrical or optical isomers thereof, wherein: X, Y, and Z are each independently 0 or S with S optionally oxidized to S = 0; 10 Alk is straight or branched chain alkylene or hydroxyalkylene containing 1-6 carbon atoms; Rj_ is hydrogen or lower alkyl; n is 0 to 5; and R2 is hydrogen, lower alkyl, cycloalkyl, 15 -(CH2)n-C02Ri, phenyl, phenyl substituted with halo, lower alkyl or lower alkoxy.

2. A method according to Claim 1 wherein said compound is 4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy) propyl]thio]methyl]-2-ethyl-l,3-oxathiolane-2-propanoic acid.

3. A method according to Claim 1 wherein said compound is 4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy) propyl]thio]methyl]-2-ethyl-l,3-oxathiolane-2-propanoic acid, sodium salt.

4. A method according to Claim 1 wherein said compound is 4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy) propyl]thio]methyl]-2-ethyl-l,3-oxathiolane-2-propanoic acid, disodium salt.

5. A method according to Claim 1 wherein said compound is(+)trans-4-[[[3-(4-acetyl-3-hydroxy-2-propylphenoxy ) propyl ]thio]methyl]-2-ethyl-l,3-oxathiolane-2-propanoic acid.

6. A method according to Claim 1 wherein said compound is (+)cis-4-[[[3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)propyl]thio]methyl]-2-ethyl-l,3-oxathiolane-2-propanoic acid.

7. A method of treating inflammatory diseases comprising administering to an animal (excluding human beings) in need of such treatment, a therapeutically effective amount of a compound of the formula ft \ -136- ^ 22 JUN/992w| 2372 8 o or pharmaceutically acceptable salts thereof, or geometrical or optical isomers thereof, wherein: X, Y, and Z are each independently 0 or S with S optionally oxidized to S - 0; Alk is straight or branched chain alkylene or hydroxyalkylene containing 1-6 carbon atoms; R-^ is hydrogen or lower alkyl; n is 0 to 5; and R2 is hydrogen, lower alkyl, -(CH2)n-COzRi, phenyl, phenyl substituted with halo, lower alkyl or lower alkoxy; and R3 is lower alkyl. G.D. SEARLE & CO. by their Attorneys BALDWIN, SON & CAREY -137- M.Z. PATENT OFFICE r 28 FEB 1991