NZ236534A - Method of treating inflammatory diseases - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £36534 Priority 7, JI CorrHta*" of ~ . ^V".. • CUw.

Publication Date gyO. Journal, No: r 2 5J.UH1932 .jSs.X., £00 33 C DRAWINGS Unoer xtvj ...... .i..., laticn 23 (1) the Specification huo boon anlc-dsted to 19 Patents Form No; 5 BEING A DIVISIONAL OUT OF NZ PATENT APPLICATION 224807 Initials NEW ZEALAND N.Z. PATENT OFFICE 19 DEC 1990 ~ i \ ~ r\ PATENTS ACT 1953 COMPLETE SPECIFICATION "METHODS OF TREATING INFLAMMATORY DISEASES WITH ALKOXY-SUBSTITUTED DIHYDROBENZOPYRAN-2-CARBOXYLATE DERIVATIVES" We, G.D. SEARLE & CO., a Corporation organized and existing under the laws of the State of Delaware, United States of America, of 5200 Old Orchard Road, Skokie, Illinois 60077, United States of America, and receiving its mail at P.O. Box 5110, Chicago, Illinois 60680, 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. * 236 5 Field of the Invention This invention relates to methods of treating inflammatory diseases characterized by the production of leukotriene with compounds and compositions that are 5 described and claimed in New Zealand Patent Specification No. 224807, in particular, pharmaceutical agents that selectively act as leukotriene B4 (LTB)^ antagonists.

Prior Art The prior art discloses compounds having structures similar to Formula I except in the prior art compounds 2 R of Formula I is replaced with hydrogen. For example: EPA 0 79,637 EPA 100,466.6.(U.S.4,665,203) U. S. Patent 4,595,882 ' u. S. Patent 4,546,194 EPA (U.S.S.N) 507383 129,906 CA 103 (19) 160 389 G Japan > 60/42378 EPA 150447 Journal of Medicinal Chemistry, 1977, 2_0 (3) 376 t 9 broadly discloses compounds where R of Formula I is hydrogen.

EPA 79,637 generically discloses a formula which encompasses compounds of Formula I wherein -OR2 is 25 -O-alkyl and B is C=0, but does not exemplify or otherwise enable the preparation and use of such compounds. EPA 79,637 extensively discloses intermediates to making compounds of this invention, that is, where -OR in formula I is -OH. EPA 79,637 does not teach the selective LTB4 antagonist activity of compounds of this invention.

U.S. 4,281,008, U.S. 3,822,148, and U.S. 4,006,245 generically disclose formulae which encompass compounds of 2 Formula I wherein -OR is -O-alkyl or O-Me and B is C=0 but do not exemplify or otherwise enable the preparation and use of such compounds, nor do they teach the selective LTB^ antagonist activity of compounds of the present invention.

The Journal of Medicinal Chemistry, 1977, Vol. 20 (3): 376 discloses a compound similar to the compounds of Formula I except the acyl ana alkvl substituents adjacent the -OR2 in Formula I are absent. The Journal of Medicinal Chemistry article also discloses a compound similar to compounds of Formula I except for a hydroxy substituent on the -0-(CH_)„-0- connecting group. ib A The prior art generally describes the above compounds as LTD4 antagonists for use as anti-allergv compounds or as antagonists of SRS-A, the slow reacting substance of anaphylaxis. In sharp contrast compounds of Formula I are selective LTB^ antagonists useful in treating inflammatory diseases. 23 6 5 Leukotriene D. and C, (LTD,/LTC,) and 4 . 4 4 4 leukotriene B^ (LTB^) are products of the arachidonic acid metabolic pathway. -TD4 and LTC^ are associated with smooth muscle contraction and contract guinea pig 5 ileum, human and guinea pig bronchi and human pulmonary- artery and vein. LTB^ is associated with neutrophil stimulation and is characterized by chemotaxis, aggregation and degranulation. LTB^ is believed to be an important mediator of inflammation. High levels of 10 LTB4 are detected in rheumatoid arthritis, gout, psoriasis, and inflammatory bowel disease. Thus antagonists of LTB^ are useful in the therapy of such diseases.

Gastroenterology, 1985: 8_8 : 580-7 discusses the role 15 of arachidonic acid metabolites in inflammatory bowel disease.

British Medical Bulletin, (1983), vol. 39, No. 3, pp. 249-254, generally discusses the pharmacology and pathophysiology of leukotriene B^. ">o Biochemical ctnd Biophysical Research Communications , Vol. 138, No. 2 (1986), pp. 540-546 discusses the pharmacology of a specific LTB^ antagonist which has a different structure than compounds of this invention.

New Zealand Patent Specification No. 224807, which is the parent of the present divisional application, discloses compounds of the hereinafter described Formula I, and pharmaceutical formulations containing such compounds. Thus, the invention of New Zealand Patent Specification No. 236534 224807, hereinafter referred to as the parent invention, encompasses compounds of Formula I and the stereoisomers, and pharraaceutically acceptable salts thereof; wherein R1 represents alkyl having 2-6 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, or -(CH0) -R wherein R 2 n represents cvcloalkvl of 3 to 5 carbons atoms and n is 1 or 2; 2 R represents methyl or ethyl; 3 R represents alkyl having 1 to 5 carbon atoms; W represents (CH2)v where x is 2 to 7, alkenylene having 3 to 7 carbon atoms, alkvnylene having 3 to 7 carbon atoms, or cyclopentyl; 4 R represents hydrogen, alkyl having 2 to 5 carbon atoms, alkenyl having 2 to 5 carbon atoms, or alkynyl having 2 to 5 carbon atoms; Q represents oxygen or CH2; B represents CH^ C=0, or CH-OH; 23 6 5 3 6 R and R independently represents hydrogen, alkyl having 1 to 6 carbon 5 6 atoms, or R and R together optionally represent a carbon to carbon bond; or R represents alkanoyl having 2 to 4 carbon atoms, o carboxy, alkoxycarbonvl, or (CH2)y-C02R Q wherein y is 0 to 4 and R is hydrogen or alkyl having 1 to 6 carbon atoms; and A represents -Z-C02R7 or -Z-CONR9R10 7 wherein R represents hydrogen or alkyl having 1 9 10 to 6 carbon atoms, R and R represent hydrogen, alkyl having 1 to 6 carbon atoms, or cvcloalkyl having 3 to 6 carbon atoms, or 9 10 NR R form a heterocyclic ring, and wherein Z is 'absent or represents straight or branched chain alkylene or alkenylene having up to 6 carbon atoms. These compounds are selective antagonists of leukotriene B4 (LTB^) with little or no antagonism of leukotriene D4 (LTD4) and are useful anti-inflammatory agents for treating inflammatory bowel disease, rheumatoid arthritis, gout', and psoriasis. 236 5 34 Preferred embodiments of the parent invention are compounds of the formula la, the stereoisomers and pharmaceutically acceptable salts thereof. 0-(CHz)x_0 la wherein R1 represents alkyl having 2-4 carbon atoms; 2 R represents methyl or ethyl; 3 R represents alkyl having 1 to 3 carbon atoms; x represents 3 to 5; 4 R represents alkyl having 2 to 4 carbon atoms; B represents CH2 or C=0; R^ and R^ independently represents hydrogen, alkyl 6 having 1 to 4 carbon atcms, or R and R together optionally represent a carbon to carbon bond; 7 • 7 A represents -Z-CC^R , wherein R represents hydrogen or alkyl having 1 to 4 carbon atoms and wherein Z is absent or represents alkylene having up to 2 carbon atoms. 236 ). \ v These compounds are selective antagonists of leukotriene (LTB^) with little or no antagonism of leukotriene (LTD^) and are useful anti-inflammatory agents for treating inflammatory bowel disease, rheumato arthritis, gout, and psoriasis.

More preferred embodiments of the parent invention are compounds of the formula II ^CH3 O O \ II I > c X T g where R5, A, 3, R are as previously defined in formula la.

Most preferred embodiments of the parent invention are compounds of the formula Ha, the stereoisomers and pharmaceutcally acceptable salts thereof CH3 h3C (CH2)pCOOH CJ03 J wherein p is 0 to 2.

A particularly preferred embodiment of the parent invention is the compound of the formula III: III 7—[ 3—(4 —acetyl-3-methoxy-2—pr opy 1 phencxv) pr opoxv ] -3 , 4-dihydro-8-propvl-2H-l-benzopyran-2-carboxyl ic acid and the pharmaceuticallv active salts thereof. This compound and its pharmaceutical lv acceptable salts are particularly preferred because of the specificity of the LTB4 antagonist activity and its oral bioavailability.

Other compounds encompassed by the parent invention are as follows: 7-[ 3-( 4-acetyl-3-methoxy-2—propylphenoxy )propoMV]-3 , 4-dihydro-4-oxo-8-propyl-2H-l-benzopyran-2-propanoic acid 7-[ [ 5-( 4-acetyl-3-methoxy-2-prcpy lpheno:-:y) pentvl ]oxy] 3,4-dihydro-8-propyl-2H-l-benzopyran-2-carboxy1ic acid, ethyl ester 7—C 3 — (4-acetyl-3-methoxy-2-propy Iphenoxy)propoxy]-3,4 dihydro-2-methyl-4-oxo-8-propvl-2H-1-benzopvran-2-propanoic acid 7—[3—(4-acety1-3-inethoxy-2-pr opy 1 phenoxy)pr opoxv]-3,4 dihydro-8-propy1-2H-1-benzopyran-2-propanoic acid 7-[3-(4-acetyl-3-methoxv-2-propyIphenoxy)propoxy]-2-carboxy-3,4-dihydro-4-oxo-8-propvl-2H-l-benzcpyran-2-propanoic acid 7-[ 3-( 4-acety 1—3-methoxv-2-propylp'nenoxy)propoxy ]-3 , 4 dihydro-2-(methoxycarbonyl)-4-oxo-8-propy1-2H-1-benzopyran-2-propanoic acid, methyl ester 7—[3—(4-acetyl~3-methoxy-2-prcpyl phenoxy)propoxy]-3,4 dihydro-2-methyl-8-prcpyl-2H-l-be.nzopyr an-2-propanoic acid 7-13-(4-acetyl-3-methoxy-2-propy Iphenoxy)propoxy]-3,4 dihydro-2-methy1-8-propyl-2H-l-benzopyran-2-propanoic acid, methyl ester 7-[3-( 4-ace tyl-3-metho:-:y-2-pr opy Iphenoxy) propoxyJ-3 , 4-dihydro-2-methvl-4-oxo-8-propyl-2H-l-benzopyr an-2-propanoic acid 7 — 13 — <4-acetyl-3-methoxy-2-propylphenoxv)propoxyj-3,4-dihydro-2-methyl-4-cxo-8-propvl-2H-l-benzopyran-2-propanoic acid, methyl ester 7-[3-[4-acetyl-2-(cvclopropy1methy1)-3-methoxvphenoxyJ propoxv]-3,4-aihvdrc-8-propyl-2-H-l-benzcpvran-2-carboxylic acid 7— [ [ 5— (4-acety 1-3-methoxy-2-propy 1 phenoxy) pent vl ] o:-:y ] - 3 , 4-dihydro-8-propyl-2H-l-benzopyran-2-carboxvlic acid The present invention provides a method of treating inflammatory diseases characterized by the production of leukotriene B^, comprising administering to a mammal (excluding humans) in need of ant-i-infairanatory treatment a therapeutically effective amount of at least one compound of the formula (I): SUMMARY OF THE INVENTION 2 4 R 1 R A R 6 (I) R R O—W 0 H or the pharmaceutically acceptable salts thereof, wherein R1 represents alkyl having 2-6 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, or (CH2)nR wherein R represents cycloalkyl of 3 to 5 carbon atoms; R represents methyl or ethyl; *2 RJ represents alkyl having 1 to 5 carbon atoms; W represents (CH2)X where x is 2 to 7, alkenylene having 3 to 7 carbon atoms, alkynylene having 3 to 7 carbon atoms, or cyclopentyl; R4 represents hydrogen, alkyl having 2 to 5 carbon atoms, alkenyl having 2 to 5 carbon atoms, or alkynyl having 2 to 5 carbon atoms; Q represents oxygen or CH2; B represents CH2, C=0 or CH-OH; R5 and R6 independently represents hydrogen, alkyl having 1 to 6 carbon atoms, or and R6 together optionally represent a carbon to carbon bond; or R represents alkanoyl having 2 to 4 carbon atoms, carboxy, alkoxycarbonyl, or (CH2)y-C02R® wherein y is 0 to 4 and R® is hydrogen or alkyl having 1 to 6 carbon atoms; and A represents -Z-C02-R7 or -z-CONR9R10 wherein R7 represents hydrogen or alkyl having -11A- v J o q 1 to 6 carbon atoms, and R^® represent hydrogen, alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, or NR^R-^ form a heterocyclic ring, and wherein 5 Z is absent or represents straight or branched chain alkylene or alkenylene having up to 6 carbon atoms, which compounds or salts may be administered in admixture with a pharmaceutically acceptable carrier or adjuvant. i.O In preferred embodiments of the method of the present invention, the active compound is: (i) of the formula (IA): R (IA) o—w— o wherein R1 represents alkyl having 2-4 carbon atoms; n R represents methyl or ethyl; *3 R represents alkyl having 1 to 3 carbon atoms; W represents (CH2)X where x is 3 to 5, alkenylene having 3 to 5 carbon atoms, alkynylene having 3 to 5 carbon atoms, or cyclopentyl; -11B- R4 represents alkyl having 2 to 4 carbon atoms; R^ and R^ independently represents hydrogen, alkyl having 1 to 4 carbon atoms, or R5 and R6 together optionally represent a carbon to carbon bond; A represents -Z-CC^R7 or -Z-CONR^R^®, 7 wherein R represents hydrogen or alkyl having 1 to 4 carbon atoms, R9 and R10 represent hydrogen or alkyl having 1 to 4 carbon atoms, and wherein Z is absent or represents alkylene having up to 2 carbon atoms; and the stereoisomers and pharmaceutically acceptable salts thereof; or (ii) of the formula (IB): .0 R" O—w O (ib) wherein R1 represents alkyl having 2-4 carbon atoms; R represents methyl or ethyl; ■5 R represents alkyl having 1 to 3 carbon atoms; W represents (CH2)X where x is 3 to 5, alkenylene having 3 to 5 carbon atoms, alkynylene having 3 to 5 carbon atoms, or cyclopentyl; R4 represents alkyl having 2 to 4 carbon atoms; R^ and R® independently represents hydrogen, alkyl having 1 to 4 carbon atoms, or R^ and R^ together optionally represent a carbon to carbon bond; A represents -Z-C02R7 or -Z-CONR9R10, wherein R represents hydrogen or alkyl having 1 to 4 carbon atoms, R9 and R10 represent hydrogen or alkyl having 1 to 4 carbon atoms, and wherein Z is absent or represents alkylene having up to 2 carbon atoms; and the stereoisomers and pharmaceutically acceptable salts thereof; or (iii) of the formula (IC): wherein x is 3 to 5, R5 represents hydrogen or alkyl of 1 to 4 carbon atoms and A represents -Z-C02R wherein R7 represents hydrogen or alkyl having 1 to 4 carbon atoms and Z is absent or represents alkylene having up to 2 carbon atoms; and the stereoisomers and pharmaceutically acceptable salts thereof; or (iv) of the formula (IIA): wherein p is 0 to 2; and the pharmaceutically acceptable salts thereof; or (v) of the formula (ID): (ID) o wherein x is 3 to 5, R5 and R^ independently represents hydrogen or alkyl of 1 to 4 carbon atoms or R and R° together optionally represent a carbon to carbon bond; and A represents -Z-C02R7 wherein R7 represents hydrogen or alkyl having 1 to 4 carbon atoms and Z is absent or represents alkylene having up to 2 carbon atoms; and the stereoisomers and pharmaceutically acceptable salts thereof; or (vi) of the formula (IE): 0 II H3C (CHJ COOH 2 p R6 (IE) II o wherein R^ and R^ independently represents hydrogen or methyl or R^ and R^ together optionally represent a carbon to carbon bond; and wherein p is 0 to 2; and the pharmaceutically acceptable salts thereof; or -11F- (vii) of the formula (IF) o(ch2)3o- (IF) and the pharmaceutically acceptable salts thereof.

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.

Alkyl defined for R1, R2, R3, R4, R5, R6, 7 O Q i n R , R , R and Rx is straight or branched chain alkyl having the indicated number of carbon atoms.

Pharmaceutically acceptable salts such as ammonium, sodium, potassium, alkaline earth, tetraalkylammonium and the like are encompassed by the invention.

Compounds of this invention are generally prepared by alkylating the prior art phenol hydroxy (R2=H) compounds to form compounds of formula I by conventional techniques. Thus, the reaction of the phenol hydroxy (R =H) with methyl iodide in potassium carbonate provides the ether. Dimethyl sulfate in acetone and base is also useful in preparing ethers. Alternatively intermediates can be alkylated prior to forming the -0—bridge. Hydrolysis of the ester compounds in the presence cf lithium hydroxide and methanol gives the acid compounds.

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

Preparation of Human Neutrophils Neutrophils were purified from venous blood cf normal human donors using standard techniques of aextran sedimentation, centrifugation on Ficol1-paqueo (Pharmacia) or Histopaque© sterile solution (Sigma) and hypotonic lysis of erythrocytes (Boyum, Isolation of Leukocytes From Human Blood: Further Observations. Scand. J. Lab.

Clin. Invest., 21 (Suppl. 97): 31, 19 68). The purity of isolated neutrophils was >95%.

LTB^ Receptor Binding Assay Neutrophils (4 - 6xl06) in 1ml Hanks' balanced salt solution containing 10 mIA HEPES buffer (h'BSS), p.H 7.4 and yM nordihydroguaiaretic acid were incubated with —9 3 0.6x10 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 f 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 — 7 which was not displaced by 10 M unlabeled LT3,. All data refer to specific binding. &. \J \J sj Human .Neutrophil Degranulation Assay Neutrophil degranulation was determined by measuring the release of myeloperoxidase activity into the incubation medium. Neutrophils (3 x 106) in 1 ml HBSS solution were preincubated with cytocnalasin 3(5 ug) at 37°C for 5 minutes, followed by preincubation with test compounds for 7 minutes. Neutrophils were then incubated for 2 to 20 minutes with either LTB,(5 x 10-8M) or the chemotactic peptide f-met-1eu-phe (5 x 10~6M) 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 supernatarits 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 Reniuna, 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, 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 B4 (LTB4). -TBj was diluted in ' £. v* \J sJ 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 with 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 ^y measuring the decomposition of hydrogen peroxide with o-dianisidine after 15 minutes. MPO activity was found to be proportional to the number of neutrophils. In guinea pig the level of MPO activity increased with the amount of LTBd injected.

Modified Boyden Chamber Chemotaxis Human neutrophils were isolated from citratea peripheral blood using standard techniques of dextran sedimentation, followed by centrifugation on Histopaque® sterile solution (Sigma) or Ficol1-paque© (Pharmacia) 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 g or 3 x 10 M LTB^ in the presence of absence of test compound. Following a 90 minute incubation at 37°C in 5s CO^-95% air, cells from the lower well were lysec 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 or the HBSS control.

The compounds of this invention can be administered in a number of dosage forms. A preferred method of delivery would be oral or in such a manner so as to localize the action of the inhibitor. In an inflammatory condition such as rheumatoid arthritis the compounds coulc be injected directly into the affected joint. The compounds could also be administered in oral unit dosage forms such as tablets, capsules, pills, powders or granules. They may be introduced intraperitcneallv, subcutaneously, or intramuscularly using forms known to the pharmaceutical art. Topical application in the form of salves ana ointments are useful for treating psoriasis. Regardless of the route of administration selected, the compounds are formulated into pharmaceutically acceptable dosage forms by conventional methods known to the pharmaceutical art.

LTD ^ Antaconism 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 anc 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 ration is a measure of the antagonist's ability to shift the agonist dose-response curve to the right. It is derived as the concentration cf agonist necessary to reach a given response level in the present (A') 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 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 the compound. Schild analysis examines the linearity of the function described by the dose-ratios written as log (A"/A) versus antagonist concentration. If linearity is confirmed and the slope approximates -1, inhibition is considered to be competitive. The pA^ 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.

Leukotriene D, Receptor Assay Usir.a 4 Guinea ?ia Luna Preparations The following description discloses an LTD4 radioreceptor assay used to identify compounds which inhibit LTD4 binding to lung membrane preparations. MEMBRANE PREPARATIONS: For each membrane preparation, 10-11 male Hartley guinea pigs, weighing less than 350 cm, were sacrificed by guillotine. The lungs were rapidly removed and placed in ice-cold 50 .tjM Trisma 7.0 buffer. After all the.lungs were collected, each was probec free of bronchial tissue to at least the level of tertiary-branching as observed through a dissecting lamp. The tissue was minced with a razor blade on a damp paper towel and placed into fresh ice-cold Trisma 7.0 buffer. '.-."hen all the tissues had been processed, they were pooled, drained and weighed. Nine volumes of cold buffer were added and the tissue was polytroned for 6-10 second bursts with a 1 minute cool down period in an ice bath between each burst. The homogenate was filtered through a gauze pad and centrifuged at 1085 x g for 15 minutes at 4°C. Supernatants were saved and centrifuged at 40,000 x g for 20 minutes at 4°C. This time, supernatants were discarded and the pellets were resuspended in 30-35 ml fresh Trisma 7.0 buffer by 1-10 second bursts with the polvtron. The materials were centrifuged again at 40,000 x g. Supernatants were again discarded. Each pellet was resuspended again with approximately 7 ml buffer. All this material was pooled into a 100 ml polypropylene container and stirred with a magnetic stirring bar. The tubes were "rinsed with small amounts of buffer and the rinse was added to the membrane preparation. The homogenized membranes were aliquoted into 1.5 ml microfuge tubes ana frozen at -70°c. Three aiiquots were submitted for protein determinations by FPB (fluorescamine protein binding) assay. This procedure usually resulted in protein concentrations ranging from 1-5 mg/ml. RADIORECEPTOR ASSAY METHODS: Each guinea pig lung preparation yielded enough protein to last through several months of assaying. Because cf this, each preparation was tested for its 3H-LTD4 dissociation constant, number cf receptor populations, number of binding sites per unit protein, and the dose-response displacnent characteristics by LTD4 and the receptor antagonist FPL 55712.

Unless otherwise indicated, all binding experiments were performed in a final incubation volume of 250 pi.

Tritiated LTD. was obtained from Mew Enqlana Nuclear and 4 nonradioactive LTD. was purchased from Biomol Research 4 Laboratories, Inc. (Philadelphia, PA). Both materials were received in solutions. 3H-LTDj was solubilized in 50% EtOH with 0.01M pH 6.8 phosphate buffer while Biomol LTD^ was prepared in 65% MeOH with 35% water and small amounts of AcOH and NH^OH. 3oth solutions were brought to appropriate assay concentrations by dilution in assay buffer consisting of 50 mM Trisma 7.4 with 5 mM L-cvsteine and 20 mM CaC^- Membranes were also diluted with this assay buffer. Compounds ether than i-TD^ were solub.ilized in DMSO and added to each tube in 5 pi aliquots. Diluent was added to all other appropriate control tubes. Incubations were conducted for 30 minutes at 25°C in a shaking water bath. Termination of the reaction was achieved by pouring the incubate over 2.5 cm Whatman GF/C filters soaked in assay buffer and set ever the ports of Millipore filter vacuum manifolds. Filters were rinsed with 4 ml ice cold assay buffer 3 times. The filters were removed, placed in 10 ml Aquasol scintillation cocktail ana allowed to cool in the dark for 2 hours prior to counting. All samples were corrected for background and isotope decay before converting DPM determination to mass.

DETERMINATION OF IC„n VALUES: LTD. specific bincina -—■— oO 4 - was determined as the difference between 3H-LTD, binding alone and in the presence of 1 mM unlabeled LTD^. Nonspecific LTD4 binding was also removed from tubes containing compound as well. The percent inhibition of binding for each dose of compound was calculated by subtracting specific binding in the presence of compound from LTD4 specific binding in the absence of compound.

This result was then divided by the specific binding without compound and multiplied by 100. These values were logit-transformed and linear regression was performed on the .dose-response data. All dose-response sets used to calculate values contained data from 3-6 compound concentrations. Correlation coefficients for the straight *0 b i) 34 line model almost always exceeded 0.98. IC5q values were calculated from the regression equation for the line.

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 be administered in a number of dosage forms, for example, such oral dosage forms as tablets, capsules, pills, powders, or granules. They may also be administered intravascularly, intraperitoneallv, subcutaneously, or intramuscularly using forms known to the pharmaceutical art.

Ail effective but non-toxic quantity of the compound is employed in treatment. The dosage regimen for inhibition of LTB4 by*the compounds of this invention is selected in accordance with a variety of factors including the type, age, weight, sex, and medical condition cf the mamrr.al, the particular disease and its severity, the route of administration and the particular compound employed. An ordinarily skilled physician or veterinarian will readily determine and prescribe the effective amount of the compound to prevent or arrest the progress of the condition. In so proceeding, the physician or veterinarian could employ or use relatively low dosages at first, subsequently increasing the dose until a maximum response is obtained. A dosage range of 1 to 25 mg/kg generally provides a therapeutically effective anti-inflammatory response. c o u The following examples illustrate the preparation oi compounds of this invention from known starting materials. The invention, which is set forth in the foregoing disclosure, is not to be construed or limited f either in spirit or in scope by these exair.ples. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.

U.S. 4,665,203 issued May 12, 1987 discloses methods for making some cf the intermediates used in making compounds of the present invention.

Example 1 7—[3—(4-acetyl-3-methoxy-2-propylpnenoxy)propoxyj-3,4-dihydro-8-propyl-2H-l-benzcpyran-2-carboxylic acid.

Ill (a) 493mg of methyl 7-[3-(4-acetyl-3-hydroxy-2-propyi-phenoxy)propoxy]-3,4-dihvdro-8-propyl-2H-l-benzopyran-2r-carboxylate was added to 25ml of acetone containing 276 mg of anhydrous potassium carbonate and 282ma of methyl 23 6 5 iodide.. The mixture was refluxed for about 2 4 hours ana water was added and the mixture was then extracted with ethyl acetate. The extract was dried, the solvent remove under vacuum, and the residual oil was chromatograpned over silica gel vitih a 40/60 mixture of ethyl acetate/hexane to provide pure methyl ether, methyl 7- [3 - (4-acetyl-3-methoxy-2-propy iphenoxy) propoxy ] -3,4-aihydro-8-propyi-2H-l-benzcpyran-2-carboxylate havin:: the formula H3C o co2ch3 1 a (b) The methyl ether (la) (340 mg) was dissolved in methanol (5ml) containing lithium hydroxide (0.7ml of a 2N LiOH solution in water). The mixture was stirred at room temperature overnight and the solvent removed in vacuo. The residue was partitioned between ethyl acetate and 2N HC1 and the organic layer separated and washed wit brine. Evaporation of the volatiles in vacuo afforded crude acid of Formula III. This material was purified by silica gel chromatography using ethyl acetate/hexane/acetic acid (40:60:0.5) as eluant. The pure product was recrystallized from ethyl acetate/hexane to afford 200 mg of product, 7-(3-(4-acety1-3-methoxy- 2-propyIphenoxy)propoxy]-3,4-dihydro-8-propy1-benzopyran-2-carboxylic acid, m.p. 65-68°C. Microanalysis: Found C 69.22, H 7.53 Theory C 69.40, H 7.49 The NMR (CDC13) shows a -OCH3 at 63.75. \ 236534 Examole 2 Comparative Test Data For ComDound III LTBa Receotor Guinea Pic Ileum 3indina Contraction p.-.? Compound III 0% at 0.3 uH 6.5 or less Compound III where -OCH3 is replaced with -OH 3 0% at 1 pM 7 . 6 Compound Compound "ill where -OCH3 is replaced with -OH Guinea ?ia Ileum Results Test Concentration (M) lxlO-6 3x10-7 1 x 10 ~ 7 3x10~8 Dose Ratio 100 13 .24 9.97 17 .04 10.59 3.48 7 .33 1.71 1.97 3.10 1 . 89 Compound III 3xl0"6 1x10-6 3x10 -7 8. 65 11 . 16 2 . 54 1 . 95 2 . 28 1 . 67 2355 Thus, the ~OCH^ compound (III) is about 5x more potent than the -OH compound in LTB^ receptor binding and at least lOx less active as an LTDd antagonist in the guinea pig ileum smooth muscle contraction test. Compounds of this invention are selective LTBa antagonists useful in treating inflammatory disease.

Example 3 7-[3-[4-acety1-2-(cyclopropylmethyl)-3-methoxyphenoxy]-propoxy]-3 , 4-dihydro-8-propyl-2H-l-be.nzopyre.n-2-carboxylic acid. h3c: COOH (a) A mixture of Zinc/copper couple (509 mg, 7.8mMol), iodine (2 mg), and methylene iodide (2.09g, 7.8rwMol) was suspended in ether (5ml) and the mixture heated to reflux for 30 minutes. The heat was removed and 2,4-dihyaroxv-3-allylacetophenone (500 mg, 2.6mMol) was added as a solution in ether. The mixture was heated at reflux for 2 hours and a further 2g of methylene iodide was added during this time. The mixture was cooled and stirred at room temperature for 10 hours. The mixture was filtered and the ether solution washed sequentially with aqueous tm, \J \J %J \J ^ ammonium chloride,, sodium bicarbonate ana brine. The organic layer was dried over sodium sulfate and evaporated in vacuo to afford a crude residue which was purified by column chromotography on silica gel (eluting with 2:8 ethyl acetate/hexane to give 220 mg of 2,4-dihvdroxy-3-cyclopropylmethy1acetophenone NMR (S^CDCl^) 0.25-0.5 (4H, m, cvclopropyl H's), 1.0 (1H, m, cyclopropvl H), 2.5 (3H, s, acetyl CH^, 2.65(2H,d,CH?~i) 6.4(1H,d,ArH), 7.5;1H,d,ArH) O 3a (b) 1,3 chlorobromopropane (1.9g), methyl 7-hvdroxy-8-propylchroman-2-carboxylate (2.5g) and potassium carbonate (2.1g) were stirred at RT in dry aimethvIformamide under argon for 24 hours. The mixture was poured into water and thoroughly extracted with ethyl acetate. The combined organic extracts were washed sequentially with water and brine and then dried over magnesium sulfate. Filtration and evaporation of the volatiles in vacuo afforded 4.3g of crude product which was chromotographed on silica gel .<10:90 ethyl acetate/hexane) to provide 3. Og of methyl 23 55 3 7-(3-chloroprcpoxy)-8-propylcnrcman-2-carboxylate. NMR1H (6, CDC13). 0.8(3H,t. propyl CH3) 1.5-2.6 (8H,m propyl CH2' s and ring CH2's), 3.7 (3H,s,C02CH3), 3.75 <2H.t,CH2C1), 4.2 (2H,t, CH2OAc), 4.7 5(1H,d,CH-OAr) 6.4 (lH,d, ArH), 6.8 (lH,d,ArH) 3b (c) 2,4-dihvdroxy-3-cyclopropylmethylacetophenone (0.2g), methyl 7-( 3-chlor opr opoxv)-8-pr opy lchroman-2-carboxy 1 ate 0 (327mgs), sodium iodide (0.15a) and potassium carbonate (0.14g) were stirred in 3ml dry dimethylformamide (DMF) overnight at 45° under argon. The mixture was poured into water and thoroughly extracted with ethyl acetate. The combined organic extracts were washed with water and dried 3 over magnesium sulfate. Evaporation of the volatiles in vacuo afforded a crude oil which was purified by chromatography on silca gel to give 98 mgs of methyl 7-[3 — [4-acetyl-2~(cyclopropylmethyl)-3-hydroxvphenoxy] propoxy]-3,4-dihydro-8-propyl-2H-l-benzopyran-2-) carboxylate.

NMR: H(S,CDC13) 0.2-0.45 (4H, m, cyclopropyl H's), 0.9 ('3H, t, propyl CH^) , 1.0(1H, m. cyclopropyl H), 1.4—2.8(12H, m, aliphatic and cyclic CH2's), 2.55 (3H, S, CH3CO), 3.75 (3H, s, C02CH3), 4.25 (2H, t, CH2OAr), 4.35(2H.t,CH2OAr), 4.75(lH,m, CH-OAr), 6.4-7.6(4Hrm,ArH's) O CO2CH3 3c (d) Compound 3c (95 mg) was dissolved in acetone (5ml) containing dimethyl sulfate (38 mg) and potassium hydroxide (12.4 mg) and the mixture was heated at 56°C under argon for 10 hours. The solvent v;as removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was separated, washed with potassium carbonate solution and dried over magnesium sulfate. Evaporation of the volatiles in vacuo afforded crude oil which was purified by chromatography on silica gel (1:9 ethyl acetate/hexane) to give 40 mg of pure methyl 7-[3-[4-acetyl-2-(cyclopropyImethyl)-3-methoxy- £00 phencxv 3 propoxyJ-3,4-dihydro-8-propy1-2H-l-benzopyran-2-carboxvlate.

NMR 1H(6,CDC13) 3.5(3H,s,OCH3). 3d (e) Compound 3d (38 rag), was dissolved in 0.3ml of methanol containing 74pl of a 1M lithium hydroxide solution, and the solution was stirred overnight ai room temperature. The solvent was removed ana the residue partitioned between ethyl acetate and 10% hydrochloric acid solution. The organic layer was removed and dried over magnesium sulfate. Evaporation of the volatiles in vacuo afforded 35 mg of the title compound, s 7— [ 3- [ 4-acetyl-2- (eye 1 opr opy Imethyl) -3-methoxv phenoxy ] -propoxy] -3,4-dihydro-8-propyl-2H-l-benzopyr an-2-carboxylic acid.

Microanalysis: Found C 69.51, H 7.34.

Calculated for C2gH3g07.1/4H20: C 69.30, H 7.49. 7~C[3-(4-acetyl-3-methoxv-2-propylphencxy)cyclopentyl] 3 , 4-dihvdro-8-propyl-2H-I-benzopyr?.n-2-carbo:-:y 1 ic j i J (a) 2 , 4—dihydroxy-3-propyl acetopher.one (1.94g), 1,3-dihydroxycvclopentane (1.02a), cr i pnenylphospn: :-.e (2.62g), and diethyl azodicarboxy1 ate (1.7g) were dissolved in dry tetrahydrofuran (THF) (200 ml) and stirred under argon at room temperature overnight. Th solvent was evaporated and the crude residue purified silica gel chromatography (Merck 60, 4:6 ethyl acetate/hexane) to afford 1.5g of l-( 2-pr opy 1-3-hycro: acetyIphenoxy)-3-hydroxycyc1 opent ane .

NMR 1H (o, CDC13) 0.9 (3H,t,propyl CH3), 1.3-2.6(1 OH, aliphatic and cyclic CH 's), 2.55 (3H,s, CH3CO), 4.4 (1H, m, CH-OH), 4.9 (1H, m, CH-OAr), 6.4 (1H, d, ArH), 7.6 (1H, d, ArH) o oh \ (b) Compound 4a (1.4. mg, 5.0 nuMol), methyl 7-hydrc:-:y-8-propylchroman-2-carboxy1 ate (1.33 mg, 5.0lmMol), triphenylphosphine (1.32 mg, 5.0 mMol) and diethyl azodicarboxvlate (875 mg) were dissolved in dry tetrahydrofuran (120 ml) and stirred under argon at room temperature for 10 hours. The solvent was evaporated and the solid residue dissolved in dry ether and filtered through sintered glass. The filtr.ate was evaporated and the residue purified by chromatography on silica gel using 2:8 ethyl acetate/hexane as eluant. 0.7 g of methyl 7-[[3 — (4-acetv 1-3-hydroxy-2-pr opy lpneno>:v) cyclopentyl]c::y] ■ 3 , 4-dihydro-8-propyl-2H-i-benzopvran-2-carbo:-:vlate were obtained.

NMR AH(6, CDC13) 0.9(6H,t, propyl CH ' s) . 1.5-2.7 (18H, aliphatic and cyclic CH2's), 2.55(3H,s,CH3CO), 3.75 (3H,s, OCH_), 4.75(1H,m,CH-CO~CH_), O J 4.9(lH,m,CH-OAr), 5.0(1H, m,CH-OAr), 6.4 (2H,2ds, ArH's) 6.8(1H,d,ArH), 7.55(1H,d.ArH) C02CH3 4b (c) Compound 4b (419 mg, 0.8 mMol) was dissolved in acetone (10ml) containing potassium hydroxide (55.3 mg, Z 0 0 D ,3 0.98mMol), and dimethyl sulfate (134.5 mg). The mixture was heated at 45°C for 10 hours and then cooled and the volatiles removed in vacuo. The residue was partitioned between ethyl acetate ana water and the organic layer-separated and dried over magnesium sulfate. Removal of solvent afforded a crude oil which was purified using radial band chromatography (Harrison chromatotron, 2:8 ethyl acetate/hexane as eluant). Hethvl 7-[[3-(4-acetyl-3-methoxy-2-propylphenoxy)cyclopentyl]oxyJ-3,4-cihydro-8-propyl-2H-l-benzopyran-2-carboxvlate was obtained pure as a colorless oil (270 mg).

NMR *H(6,CDC1-,) 0.9(6H, 2t's, crocvl CH_'s), o 3 1.5-2.8 (18H, aliphatic and cyclic CH?'s), 2.6 (3H, s, CH»CO), 3.75 (3H, s, OCH„ ether), 3.7 7 (3H,s,OCH^ JO J ester), 4.75 (lH,m, CHCO-CH.J , 4.9 (lH.m, CH-OAr), 5.0 l o (lH.m CH-OAr), 6.4(lH,d, ArH), 6.65 (lH,d, ArH), 6.8(1H,d,ArH), 7.55 (1H,c,ArH) (d) Compound 4c (150 mg) was dissolved in methanol (2ml) containing 1M lithium hydroxide (450 pL) and the mixture was stirred at room temperature overnight. The volatiles / n c02ch3 V 6 JO J 01 were removed in vacuo and the residue partitioned between ethyl acetare and dilute hydrochloric acid. The organic layer was separated and dried over magnesium sulfate. Removal of solvent afforded the title compound, 7-1 [ 3- (4-acety l-3-methoxv-2-pr opy Iphenoxy) eye lepenty1J oxy 3,4-dihydro-3-propyl-2H-l-benzopvran-2-carboxvlic acid. NMR 1H(5, CDC13) no OCH3 ester at 3.77.

ExamDle 5 7—[3—[4-acetyl-3-methoxy-2-{ 2-propenyl)phenoxy]propoxy]-3 ' dihydro-8-propyl-2H-l-benzopvran-2-carboxv1ic acid.

H3CO conh (a) 2,4-Dihydrbxy-3-(2-propenyl) acetophenone (Alcrich, 12.5g, 65mMol) and methyl 7-(3-iodoprcpoxy)-8-propvI-chroman-2-carboxylate (29.9g, 71.5inMol) were dissolved in DMF (300ml) containing powdered potassium carbonate (26.91g, 195mMol). The mixture was allowed to stir at room temperature under nitrogen for 8 hours and then partitioned between water and toluene. The organic layer was separated and washed with water and brine and then dried over sodium sulfate. Evaporation of the voiatiies in vacuo afforded 36g of crude product which was chromatographed on Merck 60 silica gel using 5:95 ethyl acetate/toluene as eluant. 25g of pure methyl 7—[3 — [4-acetyl-3-hydroxv-2-( 2-propenyl)phenoxy]propoxy]-3,4-dihydro-8-propyl-2H- 1-benzopvran-2-carboxylate were obtained in this manner.

NMR 1H (6, CDC13) 0.9(3H,t,propyl CH3 ) , 1.4-2.8(OH, aliphatic and cyclic CH *s), 2.55 (3H.d. CH^CO), 3.45(2H,d,ArCH2CH=CH2) , 3.75 (3H,s.C02CH ). 4.09(2H,t, CH20Ar), 4.22 ( 2H,t,C»2OAr) 4 . 7 5 ( 1H , t,CHOAr), 4.S5-5.00(2H,m,a 1 ly 1 H's). 5.75-6.1(lH.m.allyl CH) 6 . 4-7.12(4H,ArH's) c02ch3 oa (b) Compound 5a (20.6g, 42.7mMol) was dissolved in dry DMF (105ml) containing methyl iodide (18.4g, 128 . 5rri>loi ) and powdered potassium carbonate (17.69g, ^Smflol). The mixture was stirred under nitrogen at room temperature fc 22 hours and then partitioned between water and toluene. The organic layer was separated, washed with water and brine and dried over sodium sulfate. Removal of the volatiles in vacuo afforded 21g of product which was Z3 0 methyl 7— [ 3- [ 4—acety 1—3-methoxy-2- ( 2-propeny 1) phenoxy J propoxy]-3,4-dihydro-8-propyl-2H-l-benzopvran-2-carboxylate.

NMR 1H(6,CDC13) 3.77 (3H, s, OCH3 ether) H3CO o. c02ch3 (c) Compound 5b (16.96g, 34.l5rr.Mol) was dissolved in methanol and a solution of lithium hydroxide in water (4.3g in 43ml 102.5mMol) was added. The mixture was stirred at room temperature for 3 hours and the solvent removed in vacuo. The mixture was partitioned between toluene and dilute hydrochloric acid ana the organic lay removed. The organic extract was washed sequentially vi water, brine and then dried over sodium sulfate. Evaporation of the volatiles in vacuo afforded a yellow oil which was purified by silica gel chromatography on Biosil A using 20% ethyl acetate in toluene as eluant. The product, 7-[3-[4-acetyl-3-methoxy-2-( 2-propenyl)-phenoxy]propoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxy1i acid was isolated as a light yellow oil, 15g, which was recrystallized from ethyl acetate/hexane, mp 85.5°C. Microanalysis: Found, C 69.69, H 7.10.

Calculated for C„oHnc.0n, C 69.6, H 6.98.

Z O J D I \ £003 Example 6 7-[3—(4-acetyl-3-methoxv-2-propylphenoxy)propoxy]-3,4 • dihydro-2H-l-benzopyran-2-carboxy 1ic acid O CO^H (a) 2,4-dihyaroxyacetophenone (7.lg, 0.05 .\nd dimethyl oxylate (7.2g) were dissolved in D.'IF containing a solution of sodium methoxiae in methanol (4.Og Ma, 100ml MeOH) and the mixture was stirred at room temperature ior 48 hours. At .this point, acetic acid (180ml) was added and the mixture was heated to 100"C for 5 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was V separated, the aqueous layer was thoroughly extracted with more ethyl acetate, and the combined organic extracts were washed-with brine. Evaporation of the dried (Na_S0.) » 2 4 solvent in vacuo afforded methyl 7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate (6a) as a crude yellow solid which was crystallized from from ethyl acetate/hexane to afford 3.5g of pure product.

C O U J o H NMR 1H(6, CDC13) 4.0 (3H, s, CC>2CH3), 6.85 (1H, s, chromenone H) 6.9 - 8.0 (3H, Ar H's) O 6a (b) Compound 6a (3.57g, lemi-lol) was dissolved in ethyl acetate containing phosphoric acid and 5% palladium on carbon. The mixture was shaken- in a Parr apparatus at room temperature under an atmosphere of hydrogen for 22 hours. The solution was filtered and washed with water and the organic layer was dried over magnesium sulfate. Evaporation of the volatiles in vacuo afforded a crude oil which was purified by silica gel chromatography using ethyl acetate/hexane 6:4 as eluant. 3.3g of product, methyl 7-hydroxy-chroman-2-carbo:-:yl ate, (6b) was obtained as a clear oil.

NMR: <6, CDCl^) 2.1-2.8 (4H, m, cyclic 092*3 3.8(3H,s, C02CH3), 4.7 (1H, dd, CHOAr), <S.35-6.9(3H, Ar H's) 6b (c) Compound 6b (416 mg, 2mMol) and 3-(2-propvl-3-hydroxy-4-acetyIphenoxy)-l-iodopropane ( 720mg, 2rri>lol) vers dissolved in dry DMF (3ml) containing powdered anhydrous potassium carbonate ( 552 mg, 4rrJ-lol ) ana the mixture was stirred at 60°C for 10 hours. The mixture was ccoled ana partitioned between ethyl acetate ana water. The organic layer was separated, washed with water and dried over magnesium sulfate. Evaporation of the voiatiles in vacuo afforded a crude oil which was purified by flash chromatography on Merck 60 silica gel using ethyl acetate and hexane (2.5:7.5) as eluant. 540 mg of product, rnethvl r 7— C 3— C4-acety1-3-hydroxy-2-propyIphenoxy)propoxyJ 3,4-dihyaro-8-propyl-2H-l-benzopvran-2- carboxvlate, (6c) were obtained.

NMR:1H(6, CDC13) 0.9 (3H, t. propyl H's), 1.4-2.8 (10H, cyclic CH2's and alphatic CH2's), C 0 0 0 J 2.55(3H,s,CH3CO) 3,79 (3H,s,OCH3), 4.2 (2H,t.OAr). 4.2 (2H,t,OAr), 4.7 (lH.m.CH-OAr), 6.4-7.6(5H.ArH'2) 6C (d) Compound 6c (250mg) was dissolved in distilled acetone (5ml) containing potassium hydroxide (41.8 ~g) sr.c dimethyl sulfate (117.6 nc). The mixture was hea-ec witr. stirring under argon at 40°C for 10 hours. The mixture was cooled", the solvent removed and the residue partitioned between ethyl acetate and water. The organic layer was separated and dried over magnesium sulfate. Evaporation of the volatiles in vacuo afforded 240 rr.g of product, methyl 7-[3-(4-acetyl-3-methoxy-2-propylphencxy)-propoxy]-3,4-dihydro-8-propyl-2! I-l-benzopyran-2-carboxylate, (6d^) which was homogeneous by thin layer chromotography.

NMR 1H(6, CDCl ~) 3.65 (3H, s, OCH ) C U U J o (e) Compound 6d (200 mg) was dissolved in methanol (3ml) containing lithium hydroxide (1.0ml of a 1M solution) ana the mixture was stirred at room temperature for 10 hours. The solvent was removed and the residue partitioned between ethyl acetate and dilute hvdrocnlcric acid. The organic layer was separated, washed with brine ar.c cried over sodium sulfate. Evaporation of the volatiles in vacuo afforded 40 mg of product, 7-[3-(4-scetyi-3-methoxy-2-propyiphenoxy)propoxy-3,4-dihyaro-2H-1-benzopyran-2-carboxy1ic acid, as a gum.

Microanalysis: Found C 67.59, H 6.93.

Calculated for C25H30O7, C 67.86, H 6.83. 7-[3-(4-acetyl-3-methoxy-2-propyIphenoxy)propoxyj-4-cxo-8-propyl-4H-l-benzo?yran-2-carboxy1ic acid . (a) Methyl 7-[3-(4-acety1-3-hyaroxy-2-pr opy1rhencxv)-propoxy]-4-oxo-8-propyl-4H-l-benzopyran-2-carboxyiate (250mg, 0.48mMol) was dissolved in acetone (10ml) containing potassium hydroxide (35 mg, 0.53mMol), and dimethyl sulfate (78.3 mg 0.62mMol). The mixture was ExamDle 7 O o heated- at reflux temperature for 10 hours and then cooled. The residue was partitioned between ethyl acetate and water and the organic layer separated and ariec ever sodium sulfate. The solvent was removed in vacuo to afford 260 mg of product, methyl 7-[3-(4-acetyl-3-methoxy-2-propyIphenoxy)propoxy]-4-oxo-8-propvl-4H-1-benzopyran-2-carboxylate.

NMR: 1H(6, CDC13) 0.9(6H. 2t ' s, propyl CH^s), 1.4-2.8 (10H, alphatic CH^s), 3 . 7 5 < 3H , s , 0CH3 ether), 4.0(3H,s,CH„ ester), 4.25(2H,t,CH_OAr), 4.35 j 2 (2H,t,CH2OAr) 7.05(lH,s, olefinic H) 6.7, 7.05, 7.55 ana 8.05 (4H, d's, Ar H's) methanol (2ml) containing 0.48ml of a 1M lithium nvdroxice solution. The mixture was stirred at room temperature for 10 hours and the solvent removed. The residue was partitioned between ethyl acetate and dilute hydrochloric acid and the organic layer was separated, dried over magnesium sulfate, filtered and evaporated in vacuo. The product, 7 — [3 —(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-4-oxo-8-propy1-4H-l-benzopyran-2-carboxy 1ic 3cic, C02CH3 O (b) Compound la (200 mg, 0.4mMol) was dissolved in Cm Kf \J U sj was isolated as a light yellow gum (122 mg, 62% yield). Microanalysis: Found c 66.43, H 6.59. Calculated for *~28^32"^8 ' C 66.43, H 6.59 Example 3 7— [ 3- ( 4-acetyl-3-metho:-:y-2-prcpv 1 Dhenoxv) - prcpoxv ] -3 , 4-dihvdro-N-methy1-8-propyl-2H-1-ben~opyran-l-carboxamide.

The compound of Example 1 (80 mg,) was treated with a slight excess of oxalyl chloride and the mixture left to stand at room temperature for 2 hours. The mixture was stripped, dissolved in methylene chloride and methvlamine gas was bubbled into the reaction mixture. The mixture was washed with water, dried over magnesium sulfate filtered and the solvent was evaporated in vacuo. The resultant white solid was washed with ethyl acetate/hexane (2:8) and dried in vacuo. 60 mg of product was obtained. Microanalysis: Found C 69.63, H 7.96, N 2.86, Calculated for C2gH39N06, C 70.00, H 7.9, N 2.82. 236534 Example 9 Methyl 7—[[5—(4-acetyl-3-methoxy-2-propvlphenoxy)pentyl] oxy]-3 , 4-dihydro-8-propyl-2H-l-benzopyran-2-carboxyiaie .

Methyl 7-[ [ 5-( 4-acetyl-3-hycrcxy-2-prcpyiphenoxy )centyl ] oxy]—3,4-dihydro-8-prcpvl-2H-1-benzopyran-2-carboxylate (ImMol), prepared as described in U.S. 4,565,882, was dissolved in acetone containing 2.5 equivalents of potassium hydroxide and 3 equivalents of dimethyl sulfate. The mixture was heated at 40°C for 10 hours and then cooled; the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was separated and dried over magnesium sulfate. Evaporation of the volatiles in vacuo afforded the methyl ether.

NMR 1H(6,CDC13) 0.9 (6H, 2t's, propyl CH^'s), 1.4-2.8(18H, aliphatic and cyclic CH 's), 2.55 (3H,s. CH^CO), 3.75 (3H, s, / J OCH3) 3.8 5 (3H, s, OCH3), 3.9 (2H, t, CH2OAr), 4.1 (2H, t, CH2OAr), 4.7 (1H, ad CHOAr). 6.4, 6.65, 6.8, and 7.55 (4H, ArH's) Z65 D 34 The compounds of Examples 10 to 14 vere prepared according to the procedure described in Example 9 beginning with the appropriate phenol.

Exarnpl e 10 Methyl 7 — [ 3~( 4-acety l-3-methoxy-2-propyIphenoxy )propo:-:y ]-3,4-dihvdro-2-methv 1-4-oxo-8-propy1-2H-1-benzopyran-2-propanoate.

C02CH3 O The title compound was prepared according :o the method cf Example 9 from methyl 7-[3(4-acetyl-3-hydroxy-2-?ropyl-phenoxy)propoxy] - 3,4-dihycro-2-methyl-4-oxo-3-prc?y1-2H-1-benzopyran-2-propanoate, which was prepared as described in U.S. 4 ,665,203 .

NMR 1H(6,CDC13) 0.9(6H, 2ts, propyl CH^'s), 1.4-2.7 (16H, aliphatic ana cyclic CH2's), 1.35 (3H,s,CH3), 2.6(3H, s, CH3CO), 3.7(3H, s, OCH3), 3.75 (3H,s, OCH3), 4.25 (4H, CH2OAr), 6.6, 6.7, 7.6 and 7.75 (4H, d's, ArH's) £0 D D j 4 Example 11 Methyl 7—[[4-(4-acetyl-3-methoxy-2-propylphenoxy)~ 2-butynyl]oxy]-3,4-dihydro-2-methyI-4-oxo-8-propvl-2H-1-benz~r.yran-2-propanoate.

The title compound was prepared by the method of Example 9 from methyl 7-[[4-(4-acetyl-3-hydroxy-2-prcpyIphenoxy)-2-butynyl]oxy]-3,4-dihydro-2-methvI-4-oxo-8-propyl-2H-l-benzopyran-2-propanoate.

NMR 1H(6,CDC13) 0.9 (6H, 2t's, propyl 1.4-2.7 (14H, aliphatic and cyclic CH2's), 1.35 (3H, s, CH^), 2.6 (3H, s, CH3CO), 3.7 (3H, s, 0CH3), 3.75 (3H, S, OCH3), 4.8 (4H, s, CH2OAr) 6.6, 6.7, 7.65 and 7.75 (4H, d's, ArH's) 23 6 5 3 Example 12 Methyl 7—[3 — (4-acetyl-3-methoxv-2-propyIphenoxy)propoxyJ -1,2,3, 4-tetrahydro-8-propvl-2-naphthalenecarbo:-:yl ate . (a) 1.6 grams of 3-(2-n-propyl-3-hydrcxy-4-acetylDhenoxv)-1-bromopropane (.005 mole) which was prepared as described in U.S. Patent 4,565,882 (Miya.no et al . ) was dissolved in 30 ml of methyl ethyl ketone. Two grams (2.5 equivalents) of potassium carbonate was added to the reaction along with 1.25 grams (.005 mole) of rnethvl 1,2,3,4-tetrahydro-7-hvdroxy-8-propyl-2-naphthalene-carboxylate obtained in Example 28. After 100 mg of sodium iodide was added, a nitrogen blanket was placed cn the system and the contents were refluxed for forty-eight hours. The reaction was cooled to room temperature. The mixture was filtered and the filtrate evaporated. The residue was chromatographed on silica gel with elution by 3% acetone-toluene. Eluant evaporation left 1.45 grams (60%) of compound (12a), methyl 7 —[3 — (4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-1,2,3,4-tetrahydro-8-propyl-2-naphthalenecarboxviate, m.p. 34-85°C. 2 3 6 5 3 A Microanalysis: Calc: C, 72.17; H, 7.94; for C29H38°6 Found: C, 71.87; H, 7.90 . 12a (b) The title compound was prepared by the method of Example 9 from methyl 7-[3-(4-acetyl-3-hydroxv-2-propvl-phenoxy)propoxy]-1,2,3,4-tetranydro-8-propy1-2-napthalenecarboxylate.

NMR 1H(5,CDC13) 0.95(6H, 2t' s, propyl CH^'s), 1.4-3.1 (16H, aliphatic and cyclic CH2's), 2.6 (3H, s, CH3CO), 3.75 (6H, 2 overlapping singlets, OCH3's), 4.5 (2H, t, CH2OAr), 4.25 (2H, t, CH20Ar), 6.7, 6.9, 7.55 (4H, Ar H's) Exarr.oie 13 Methyl 3 , 4-dihydro-7-[ 3-[ 3-methoxy-4-( 2-methyl-l-oxopropyl)-2-propyIphenoxyj propoxy]-8-propy1-2H-1-benzopyran-2-carboxylate. 236 5 3 (a) A solution of 495 mg (1.89 mMole) of triphenyl-phosphine,"420 mg (1.89 mMole) of 2,4-dihydroxv-3-propvlisobutyropnenone, 582 mg (1.89 mMole) of methyl 7-(3-hydroxypropoxy)-8-n-propylchrornan-2-carboxylate in 5 ml of tetrahydrcfuran was prepared and cooled in an ice bath. Diethyl azocarboxylate, 350 mg (1.89 mMole) was added and the solution was allowed to warm to room temperature and stir for 18 hours.

The solvent was removed by rotary evaporation and the residue triturated with 25 ml ether, cooled and filtered. The ether filtrate was then washed with water, brine, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, the ether removed by rotary evaporation, and the residue purified by elution chromatography on silica gel with 1% acetcne-to]uene to furnish 720 mg (75%) of the desired ester, meth\ 1 3,4-dihyaro-7-[3-[3-hvaroxy-4-(2-metnyl-l-oxopropyl)-2-propyl-phenoxy]-propoxy-8-propyl-2H-l-benzopvran-2-carboxylate, as an oil.

Microanalysis: Calc: C, 70.08; H, 7.86; Found: C, 69.51; H, 7.81. 235534 (b) The title compound was prepared by the method of Example 9 from methyl 3,4-dihyaro-7-[3-[3-hydroxy-4-(2-methyl-l-oxopropvl)-2-propyIphenoxy]-propoxy]-8-prcoy 1-2H-l-benzopyran-2-carboxylate.

NMR 1H(S,CDC13) 0.9(6H, 2t's, propyl CH^'s), 1.15 (6H, d, (CH3>2CCO), 1.4-2.7 (14H, aliphatic and cyclic CH2's), 3.7 (3H,s, OCH3) 3.75 (3H. s. OCH3), 4.15, 4.2 (4H, 2t's, CH2OAr), 4.7 5 (1H. lad, CHOAr), 6.4, 6.7, 6.8 and 7.35 (4H, d's, ArH's) Example 14 Ethyl 7—[3—(4-acetyl-3-methoxv-2-propyiphenoxy)-propoxy]-3,4-dihydro-8-propy1-2H-l-benzopyran-2-propanoate.

The title compound was prepared by the method of Example 9 from ethyl 7-[3-(4-acetyl-3-hydroxy-2-propyIphenoxy)-propoxy]-3,4-dihydro-8-propyl-2H-l-benzopyran-2-propanoate which was prepared as described in U.S. 4,665,203.

NMR 1H(8,CDC13) 0..9 (6H, 2ts, propyl CH3'"s), 1.2-2.7 (20H, aliphatic cyclic and C02CH2CH3 H's), 2.6 <3H, z. CH3CO), z a o :> 3 4 3.7 5 (3H, s, OCH3), 4.0 (1H, m, CHOAr), 4.1, 4.3 <4H, 2 triplets, CH2OAr), 6.4, 6.7, 6.8, 7.55 (4H, ArH's) Example 15 7-[[5-(4-acety1-3-methoxy-2-propyIphenoxy)pentv1]cxy]-3,4-dihydro-8-propyl-2H-l-benzopyran-2-carboxvlic acic.

The compound prepared in Example 9 (ImMol) was dissolved in methanol containing two equivalents of a 1M lithium hydroxide solution in water. The mixture was stirred at room temperature for 10 hours and then solvent was removed in vacuo. The residue was partitioned between ethyl acetate and water, the organic layer was separated and dried over magnesium sulfate and the volatiles were removed in vacuo. The product carboxylic acid may be purified by column chromatography on silica gel if necessary.

NMR 1H(5, CDC13) 0.9(6H, 2ts, propyl CH3's), 1.4-2.8 (18H, aliphatic and cyclic CH^'s), 2.55 (3H, s, CH3C0), 3.7 5(3H, s, OCH3), 3.9(2H, t, CH-OAr), 4.1 (2H, t, CH2OAr) 4.75(1H, m, CHOAr), 6.4, 6.65, 6.8, and 7.55 < 4H,. ArH ' s ) C02H 23o5 34 Example 16 7—[3—<4-acetyl-3-methoxy-2-propvIphenoxy)propoxy]-3,4-dihydro-2-methyl-4-oxo-8-propy1-2H-l-benzopyran-2-propanoi c acid.

The title compound was prepared from the compound of Example 10 using the method cf Example 15.

Microanalysis: Found: C 68.55. II 7.60.

Calculated for C_, H„n 0o : C 68.87, H 7.46. 31 4 0 8 Example 17 7-[[4-(4-acetyl-3-methoxy-2-propy!phenoxy) 2-butynyl]oxy]-3,4-dihvdro-2-methy1-4-oxo-8-propvl-2H-l-benzopyran-2-propanoic acid.

The title compound was prepared from the compound of Example 11 using the method of Example 15. 2365 34 NMR *H-(6, CDC13) 0.9 (6H, 2t's, propyl CH^'s), 1.4-2.7 (14H, aliphatic and cyclic CH "s), 1.35 (3H, s CH3), 2.6 (3H, s, CH3CO) , 3.75 (3H, s, OCH^, 4.85 (4H, brs, CH2OAr), 6.6, 6.7, 7.6 ana 7.75 (4H, d's, 5 ArH's) Example 18 7—[3 — (4-acety1-3-methoxv-2-propyIphenoxy)propoxy]-1,2,3, 4-tetrahvdro-8-pr opy 1-2-naphthalenecarboxy 1 ic acid .

The title compound was prepared from the compound of Example 12 using the method of Example 15. Microanalysis: Found: C 71.85, H 7.94.

Calculated for ^24H38^6: C 72,17' H 7.94. £0030 Example 19 3,4-dihydro-7-[3-[3-methoxy-4-(2-methyl-1-oxoprcpy1)-2-pr opy Iphenoxy ] propoxy ]-8-pr opy 1-2H-1 -be.nzopy ran-2-carboxylic acid.

The title compound was prepared from the compound of Example 13 using the method of Example 15.

NMR 1H(o. CDC13) 0.9 (6H , 2t's , propyl CH3 ' s). 1.15 (6H, d, (CH3>2CCO), 1.4-2.7 (14H, aliphatic ana cyclic CH2's), 3.7 (3H, s, 0CH3), 4.15, 4.2 (4H, 2t's, CH20Ar) 4.75 (1H, dd, CHOAr), 6.4, 6.7, 6.82 ana 7,35 (4H, d's, ArH's) Example 20 7-[3-(4-acety1-3-methoxy-2-propyIphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-l-benzopvran-2-propanoic acid. £0 v) 3 J The title compound was prepared from the compound of Example 14 "using the method of Example 15. 1.2-2.7 (18H, aliphatic and cyclic CH2's), 2.6 (3H, s, CH3CO) 3.75 (3H, s, OCH3), 4.0 (1H, m, CHOAr), 4.1, 4.3 (4H, 2t's, CH2OAr), 6.4, 6.7, 6.8, 7.55 (4H, ArH's) Example 21 7—[3—(4-acetyl-3-ethoxy-2-propylphenoxy)-propoxv]-3,4-'dihydro-8-propyl-2H-l-benzopyran-2-carboxvlic acid. (a) 4-(3-chloropropoxv)-2-hydroxy-3-propylacetopnenone (5.0g, 18.47mMol), potassium carbonate (7.3g), and iodoethane (3.0ml) were dissolved in dry DMF (50ml) and the mixture stirred overnight at room temperature. The reaction mixture was then partitioned between ether and water and the organic layer separated. The ether extracts were washed with water and brine and then dried over sodium sulfate. Evaporation of the volatiles in vacuo NMR LH (6, CDC13) 0.9 (6H, 2ts, propyl CH *s).

O OCH2CH3 COOH t V U J 0 t| afforded 5.36g of crude 4-(3-chloroprcpoxv)-2-ethoxy- 3-propylacetophenone. (b) 4-(3-chloropropoxv)-2-ethoxy-3-propyl acetopnenone (5.36g) was dissolved in acetone containing 10 equivalents of sodium iodide, ana the mixture was refluxea under nitrogen for 10 hours. Solvent was removed in vacuo ana the residue partitioned between ether and water. The organic extracts were washed with water and brine, dried over sodium sulfate and evaporated in vacuo to afford 7.0g of a yellow oil, 4-(3-ioaopropoxy)-2-ethoxy-3-cropy1-acetophenone.

O OCH2CH3 2la NMR 1H (6, CDC13) 300 MHz 3.4 (2H, t, CH2I) O OCH2CH3 21b (•c) Compound 21b (2.34g, 6mMol), methyl 7-hvdroxy-8-propylchroman-2-carboxvlate (1.25g, 5m.Mol) ana potassium carbonate (2.07g, l5mMol) were suspended in dry DMF (12.5ml) and the mixture stirred at room temperature for 48 hours. The mixture was then partitioned between ether and water and the ether layer separated, washed with vate and brine and then dried over sodium sulfate. Evapora-ic of the volatiles in vacuo afforded 2.9g of crude product which was purified by chromatography on silica gel to afford 1.34g of pure methyl 7-[3-( 4-acetyl-3-ethoxy-2-propyIphenoxy)propoxyJ-3,4-dihydro-8-propy1-2H-1-benzopyran-2-carboxvlate. (d) Compound 21c (0.8g, l.56mMoles) was dissolved in methanol/water (7:3, 25ml) containing lithium hydroxide (0.13g, 3.12mMol). The mixture was stirred at room temperature for 2 hours and then partitioned between dilute hydrochloric acid and ether. The organic layer wa separated, washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 1.lg of crude product. This material was purified by chromatography on silica gel using ethyl acetate/hexane/acetic acid (50:50:1) as eluant. 7-[3-(4-acetyl-3-ethoxv-2-propy1-phenoxy)-propoxy]-3,4-dihydro-8-propy1-2H-l-benzopyran-2- 21c carboxylic acid was obtained as 0.71g of white crysta m. p. 81-84 °C.

Microanalysis: Found C 69.68, H 7.85.

Calculated for C3QH Q07, C 69.85, H.7.68.

Example 22 7— [3—( 4-acetyl-3-methoxy-2-propy lp'nenoxy) propoxy ] - 4-o 8-propy1-4H-1-benzopvran-2-propanoic acid Starring with methyl 7-[3-(4-acetyl-3-hycroxv-2-propyIphenoxy)propoxy]-4-oxo-8-propyi-4H-l-benzcpyran 2-propanoate and following the procedure cf Example 9 methyl 7—[3—(4-acetyl-3-methoxy-2-propvlphenoxy)prcpo 4-oxo-8-propy l-4"H-l-benzopyran-2-propanoate which was hydrolyzed using the procedure of Example 15 to give title compound.

Microanalysis: Calculated: C, 68.62; H, 6.92.

Found: C, 68.24; H, 6.92. 236534 Example 23 Methyl 7-[ [ 4-( 4-acetyl-3-hydroxy-2-pr opylpner.oxy )-2-butynyl ]oxy]-3 , 4-dihvdro-2-methyl-4-oxo-8-propyl-2H-l' benzopyran-2-propanoate c02ch3 A solution of 2.04 g (7.8 mMole) of 4-(4-hydroxy-2-butynyloxy)-2-hvdroxy-3-propylacetophenone, 2.49 g (7.8 mMole) of methyl -(3,4-dihydro-7-hydroxy-2-rnethyl-4-oxo-8-propyl-i2H-l-benzopyr an-2-y 1) propanoate , and 2.04 g (7.8 mMole) of triphenvlphosphine was prepared in 50 mi of dry tetrahydrofuran. After addition of 1.22 ml (7.8 mMole) of diethyl diazoaicarboxylate the solution was stirred for 18 hours.

The tetrahydrofuran was removed by rotary evaporation and the residue stirred in 50 ml of ether. Insoluble solids were removed by filtration and the ether filtrate was concentrated by rotary evaporation to give 5.94 g of a crude oil. The oil was purified by elution chromatography to furnish 3.2 g (73%) of the methyl ester product. Microanalysis: Calculated: C, 70.19; H, 7.14.

Found: C, 70.33; H, 7.18 COD30H Example 2 4 Trans-raethyl 7-[ C4 — ( 4-acetyl-3-hvdroxy-2-propylpheno>:y)--2-butenyl]oxy]-3,4-dihydro-2-mechyl-4-oxo-8-propyl-2H-1-benzopyran-2-propanoate A solution of 3.05 g (11.5 rri-'ole) trans-4-(4-hvdro:-:y-2-butenyloxy)-2-hydro:-:y-3-propyi£cetophenone, 3.70 g (11.5 mMole) of methyl 3-( 3 , 4-cihydro-7-hydro;-:v-2-methyl-4-oxo-8-propyl-2H-l-benzopvran-2-yl)propanoate, ana 3.03 g (11.5 mMole) of tripnenyipnosphine in 75 ml of dry tetrahydrofuran was prepared. Diethyl aiazodicarboxylate, 1.80 ml (11.5 mMole), was added and the solution was stirred for 18 hours at room temperature.

Solvent was removed from the reaction mixture by rotary evaporation and 75 mJ of ether was added to the residue and stirred. After removal of insoluble solids by filtration, the- ether filtrate was removed by rotary evaporation. The resulting crude material was purified by silica gel elution chromatography with 7% ethyl acetate-toluene to furnish 4.73 g (73%) of the methyl ester as an oil.

O OH H 0 V 23b t> Microanalysis: Calculated: C, 69.94; H, 7.47.

Found: C, 70.02; H, 7.45.

Example 25 Trans-7-[[4-(4-acetyl-3-methoxy-2-propylphenoxy)-2~ 5 butenyl]oxy]-3,4-dihydro-2-methyl-4-oxo-8-propv1-2K-1- benzopvran-2-propanoic acid O OCH3 0 The compound of Example 24 is methylated using the method of Example 9 to give 7-[[4-(4-acetvl-3-methoxy-2-10 propyIphenoxy)-2-butenyl]oxyJ-3,4-aihydro-2-methy1-4-oxo- 8-propyl-2H-l-benzopyran-2-propanoate which is then hydrolyzed using the method of Example 15 to give the title compound.

Example 26 Cis-methyl 7-[ 1 4-( 4-acetyl-3-hydroxv-2-propylpheno;-:y) -2-butenyl ]oxyJ-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H-l-benzopyran-2-propanoate A solution of 5.82 a (22 .Tdiole) of cis-4-( 4-hvdr o:-:v-2-butenvloxy)-2-hydroxy-3-prcpy 1 acetcpner.one, 7.05 g (22 mMole) of methyl-( 3 , 4-dihycro-7-hydrcxv-2-methyi-4-oxo-8-propyl-2H-l-benzopyr ar.-2-yl )propanoate, and 5.77 g (22 mMole) of triphenylphosphine was prepared in 150 ml of dry tetrahydrofuran. After addition of 3.5 ml (22 ntfloie) of diethyl diazodicarboxyiste, the mixture was stirred for 18 hours.

The tetrahydrofuran vas removed by rotary evaporation and the residue stirred with 100 ml of ether. Insoluble solids were removed by filtration and the ether filtrate r was concentrated by rotary evaporation to give 16.6 g of yellow oil. The oil was purified by silica gel chromatography using 10% ethyl acetate-toluene to furnish 6.28 g (50%) of pure methyl ester product.

O Microanalysis: Calculated: C, 69.94; H, 7.47 Found: C, 69.52; H, 7.36.

Example 2 7 Cis-7-[[4-(4-acetyl-3-methoxy-2-propyIphenoxy)-2-cu oxy] -3,4-dinydro-2-methy1-4-oxo-8-propy1-2H-1-benic 2-propanoic acid The compound of Example 26 is methylated using method of Example 9 to give cis-methyl 7-[[4-(4-ace methoxy-2-propy1phenoxy)-2-butenyl]-oxy]-3,4-cihycr methyl-4-oxo-8-propy1-2H-1-benzopyran-2-propanoate * is then hydrolyzed using the method of Example 15 -the title compound. \ £0003 Example 28 (a) methyl 1,2,3,4-tetranydro-7-methoxy-l-oxo-2-naphthalene carboxylate 28a A 50% slurry cf NaH (30c, 0.62 moles) in hexane was filtered through a fritted glass funnel to remove the mineral oil. The NaH was then added to a 2L flask, covered with 300ml of tetrahydrofuran (THF), and placed under a N2 atmosphere. upon the addition of 0.62 moles 10 of dimethyl carbonate at one rime with stirring, the reaction mixture was heated to 40°-50°C, whereupon 50g (0.28 moles) of commercially available 7—methoxy—1-tetralone in 150ml of THF was added at a rate to minimize foaming (1 hr.). After refluxing the reaction 15 mixture for 2 hrs., the solution (red) was cooled to room r ; temperature and slowly acidified by the addition of 45ml of acetic acid. The resulting paste was dissolved upon addition of 50ml of water. Ether was added and the layers were separated. The organic phase was washed with HnO, ** £* 3% NaHCC>3 solution, and dried (Na^SO^). After filtration, the solvent was evaoorated on a rotarv evaporator. The residue was distilled at 168°-170°C at .2mm Hg. " Analysis for C13H1 o4 (MW=236.26): Calcd: C,66.66; H.6.02.

Found: C,66.87; H.6.07. (b) methyl 1,2,3,4-tetrahydro-7-methoxy-2-napnthalene-carboxylate To 58g (.248 mole) of the product from Example 28(a) dissolved in a mixture of 387ml of acetic acid and 16.6ml of perchloric acid and placed in a 1L pressure bottle was added 5.8g of 5% Pd/C. The bottle was placed in a Parr shaker and hydrogenated at R.T. at 30 p.s.i. for 2 nr. After filtration, the filtrate was diluted with l.l liter of CHCl^, washed with Huntil the pH was neutral (5x). The organic phase was dried (Ma^SO^) and the solvent evaporated to produce 49g of a crude yellow oil (,the titled product). o 28b £ %J u J 0 H Analysis for C13H 03 (MW=220.26): Calcd: C,70.88; H.7.32.

Found: C,70.62; H,7.09. < c) 1,2,3, 4-tetrahydro-7-metho:-:y-2-naphthalenecarbo>:y 1 ic acid To 49g (0.22 mole) of the product of Example 28(b) dissolved in 600ml of methanol at R.T. was added 150ml of 2M LiOH with stirring, After heating the stirred solution at 50°C for 2 hr., the methanol was removed by rotary evaporation, the aqueous residue was washed l:< with ether, and acidified to pH 2 with HC1. Upon cooling and stirring, the crude acid precipitated and was separated by filtration. The crude acid was recrystallized from ether-hexane to give 30g (67%) of the product, in.p. 119 °-122 °C. 28c Analysis for C12H1/}03 (MW=206.23 ) Calcd: C,69.89: H,6.84 . Found: C,69.70; H.6.92. 235534 (d) 1.2,3, 4-tet rahydro-7-hydroxv-2-naphthalenecar bo:-:y 1 ic acid' • 28d To a 500ml flask containing lOOg of pyridine hydrochloride was added 30g of the product of Example 28(c) and the reaction mixture was blanketed with M2. The reaction mixture was placed in an oil bath ana heated to 215°C for 2 hr. Upon cooling to R.T., 200ml of IN HC1 was added with stirring followed by 300ml of 1:1 mixture of ether/ethyl acetate. The organic phase was separated, washed 3x with H^O, dried (MgSO^), and filtered. Upon evaporation of the solvent, the residue was recrystallized from ether/hexane to produce 21.4g of the titled product, m.p. 170°-171°C.

Analysis for (MW=192.21) Calcd: C,68.73; H.6.29. Found: C,68.58; H,6.35. t V V/ ^ f (e) methyl 1,2,3,4-tetrahydro-7-hydroxy-2-naphthalene-carboxylate To 21g of the product of Example 23(d) dissolved in 250ml of methanol and placed in a 1L flask was added 30ml of trimethylorthof orniate and Sml of H2SO^ . The- flask was covered and allowed to stand at room temperature for 3 days. Upon rotary evaporation of the methanol. 500ml of ether was added and the organic phase was washed 2x with 3% NaHCO^ solution, ana 2x with water. The organic phase was dried (Na2S04), filtered, and the solvent removed by rotary evaporation. The residue was recrysta 11ized from ethyl acetate-hexane to cive 22g of the product, m.p. 83-84°C. o II 2Se Analysis for C12H14°3 ^Mw=206■24) Calcd: C,69.89; H,6.84. Found: C,69.86; H.6.82. 23 6 5 3 A (f) methyl 1,2,3,4-tetrahvdro-7-(2-propenyloxy)-2-naphthalenecarboxylate 28f To 20g (0.097 mole) of the product of Example 28(e) 5 dissolved in 300ml of dry acetone was added 35g (2.5 eq.) of K2CC>3 with vigorous stirring. An excess (20g) of allvl bromide was then added to the reaction vessel and the mixture was refluxed with a drying tube attached for 1 day. The reaction mixture was filtered and the solvent in 10 the filtrate evaporated by rotary evaporation. The residue was taken up in 50ml of toluene ana chromatographed on a 500g silica gel flash column, eluting * with toluene. The eluent was evaporated and 17.5g (78%) of the product was isolated as a clear oil.

Analysis for C15Hlg03 (MW=2 4 6.31): Calcd: C,73.15; H,7.37.

Found: C,72.84; H.7.44. (g) methyl l,2,3,4-tetrahydro-7-hydroxv-8-(2-propenyl)-2- To 20g of diet'nvlani 1 ine in a reaction vessel was added under argon 17g of the product of Example 28(f). After the reaction mixture was heated at 215°C for 6 hr. , thin-layer' chromatography (TLC) showed that two products had formed. Upon cooling, the reaction contents were poured into a 3:1 mixture of ethyl acetate/ether and the resulting solution washed with 200ml of 2N HCl and 100ml of water. The organic layer was separated, dried (Na^SO^), and filtered. Upon removal of the solvent by rotary evaporation, the crude residue (17g) was chromatographed on silica gel, eluting with 3% acetone/toluene. The most non-polar material (12.5g) was the titled product, 28g, mp. 90°-91°C. The most polar material was methyl l,2,3,4-tetranydro-7-hydroxy-6-(2-propenyl)-2-naphthalenecarboxy1 ate. naphthalenecarboxylate 28g ZO 0 t) 5 4 Analysis for C15Hlg03 (MW=246.31): Calcd: C,73.15; H,7.37.

Found: C,73.01; H,7.34. (h) methyl 1,2,3,4-tetrahydro-7-hyaroxy-8-propyl-2-naphthalenecarboxylate To 12g of the product of Example 28{g) dissolved in 125ml of methanol and placed in a pressure bottle was added 1.25g of 5% Pd/C. The bottle was placed in a Parr shaker and the mixture hydrogenated at room temperature and 2 p.s.i. for 1 hr. Upon filtration of the reaction mixture and evaporation of the solvent, 12g of the product 28h was produced as an oil.

HO OCHj 28h Analysis for C15H20°3 ^MW=2<18 • 32) Calcd: C,72.55; H.8.12. Found: C.71.83; H,8.20.

CO 0 D ^ Example 29 7—[ 3-( 4-acetyl-3-methoxy-2-propylphenoxy )propoxy J -3 . 4 — dihvdro—4—hydroxv-S-propyl-2H-l-benzopyran-2-propanoic acid Starting with methyl 7-(3-(4-acetyl-3-hyaroxy-2-pr opy Iphenoxy) propoxy ]-3 . 4-dihydro-4-hydroxv-8-pro?yl-2H-l-benzopvran~2-propanoate prepared as disclosed in U. S. 4,665,203 and methvlating the compound following the procedure of Example 9 then hydrolyzing that product according to the procedure of Example 15 gives the title compound.

COOH OH Table 1 and Table 2 show embodiments of the invention. Receptor Binding test results. test results for some Table 3 shows the LTDa ZO o 0 4 Table 1 Compound Receptor Binding LTB. ^50 LTD (1) — 50 Chemotaxis (Boyden) (2) Degranulat io LTB, IC. 0 •Example 3 1 .9x10 - IC5Q,2xl0~7M 1 .3x10 7M Example 4 5X10 6M - 62%(10~8M) 2 . 7 x 1 0 ~ 6 H Example 1X10~7M - IC5Q,0.5X10~6M 4x10 7M Example 6 2 .6xlO~6M Inactive 4 8% Cl0_6M) 8X10~6M Example 7 0 .5x10~6M Inact ive IC50,3.6X10~6M 3 .7x10 6M Example 8 1 .8x10~6M - 12%(10~6M) Example o .5xlO~6M - IC5Q,6.6X10~6M . 1 , . 5:-:10~6M Example 16 o; .25x10~6M Inact ive IC5Q.0.65X10~6M 0 . . 5 5x10 ""6: Example 17 o, ,8X10~6M - 31%(10~6M) 2 . 1X10~6M Example 18 3 , ,7X10~7M - 87% <10~5M) 2. 6X10~6M Example 19 l. 2X10~6iM - % C10_6M) 5x10 6M Example 0 . 5X10~6M Inact ive IC.n,1.7x10_6M o0 0 . 4x10 'm Example 21 1x10 6M - - - Example 1 0 . 48X10~6M Inactive IC5Q,3X10"6M 1. 5X10~6M Example 22 0 . 5X10~6M IC 0 , 1 . 2xlO*"6M 1 . 6X10~6M (1) Inactive means the compound tested was inactive at (2) — 5 ^ M. These results are from Table 3.

IC5Q.is the effective concentration needed to cause 50% inhibition.

Table 2 Compound Example 7 Example 15 Example 2 0 Guinea Pig Ileurr, Contraction oA? 6 . 74 Inactive 6 . 5 Table 3 LTD4 Receptor 5itiding (1) ltb4 Antagonist Testing Against an LTD4 Receptor Percent Inhibition Compound [10 uM] Test HI Test 42 Act: FPL 55712 54 , . 68 46 . . 96 Example 1 4 , . 07 16 , .40 T Example + 12 . . 96 23 . , 51 1 Example 16 16. , 49 24 . , 08 T J.

Example 7 28. 90 34 . 40 r Example 6 + 1. 63 . 97 T (1) This method employs LTD4 membrane receptors prepared from a male guinea pig lung homogenate which was aliquoted and stored at -70°C. The particular preparation used to test the compounds of Table 3 was GPLP 9, having a of 0.262 nM and yielding 0.447 pmol receptor/mg protein. Protein concentrations in these assays were adjusted to provide approximately 0.1 nM receptor in the presence of InM 2H-LTD4. Incubation was conducted for; 30 min. at 24°C and filtration methods were used to separate bound from £0 0 3 free ligand. Under these conditions, IC5Q values for LTD4 and FPL 55712, a known LTD4 receptor antagonist, were 1.71 x io-8M and 10.37 x 10~6m respectively. All compounds tested were intially solubilized in DMSO. Each compound was evaluated at dose of 10 pM (io~5M) in triplicate in 2 separate assays. The percent inhibition of LTD4 specific binding for each compound is shown in Table 3. By th criteria established for potential LTD4 receptor antagonists, compounds are active if the 10 pM test concentration inhibits LTD4 specific binding by 45% or more. Using this parameter, all the Table 3 compounds were considered inactive relative to FPL 55712.

Scheme A and Scheme B show two preferred synthesis routes for making the compound of Formula III.

Scheme C shows a general method for making compounds of the present invention. 2365 SCHEME A hjc BrCHjCHjCHjCI (3 ma | K,COj. MEK CHj KOfi. Acalont (C^OIjSOJ CHj (1) 1. NKJCH, DMF Oimrnyl oi&:sla 2. HO Ac, 25'C COOCHj n») CHjOH ES'C CV COOCHj %PdC ElOAc.

H, (60 t»i. 2S*C) COOCHj (*> (6) Po-IXirtXK! KjCOj a* ^C°sX°^ 0 0 v. COOCHj TXT D o (7 t «Q bOM. CHjCJH J. HjO* SCHEME B ho chj (2) KjOO, DWF.CH,! CH3 (3) Ml) Ac«lana ch3 (<) BfCH,CM?CH,CI|3.q) KjCO,. MEK 1 ' 1.NjOCH,.OMF Dimmest aJai* 2.HOAC. 100-C o cooch) (5) %P<JC ElOAe. H3P04 Hj (60 ki. 25'CJ C> COOCHj (6) V.?COj CHj 0 (7) O COOCHs 1 >a L/OM CHjOM 3 HjO* CHj CHj SCHEME C o oh OH Br-(CH2)XB r o oh R5 B' „<CH2)r-CO2R0 . R6 H r2i k,co3 DMF or Acetone or P? OR ,(CH2)y-C02R® R6 H LiOH Mc0ii-Hi0 B' ,{CH2)yC02H H v = 0 lo 6 X = 2 to 7 B = CH2, C = O, C-OH R2 = methvl or cthvl R3 = alkyl' Rs = H, alkyl or Rs and R6 form a carbon to carbon bond.

R4 = H or alkyl R! = alkyl, alkenyl, alkynyl, or (CII2)n -K where n = 1 or 2 and R = cycloalkyl of 3-5 carbon atoms.

R s = nlkvl The matter contained in each of the following claims is to be read as part of the general description n-F -t-Vio nrpRpnt- invention.

Claims (33)

WHAT WE CLAIM IS:

1. A method of treating inflammatory diseases characterized by the production of leukotriene B4, comprising administering to a mammal (excluding humans) in need of anti-inflammatory treatment a therapeutically effective anti-inflammatory amount of at least one compound of the fomula (I): or the pharmaceutically acceptable saits thereof, wherein R1 represents alkyl having 2-6 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, or (CH2)nR wherein R represents cycloalkyl of 3 to 5 carbon atoms and n is 1 or 2; R represents methyl or ethyl; R represents alkyl having 1 to 5 carbon atoms; W represents (CH2)X where x is 2 to 7; alkenylene having 3 to 7 carbon atoms, alkynylene having 3 to 7 carbon atoms, or cyclopentyl; R^ represents hydrogen, alkyl having 2 to 5 carbon atoms, alkenyl having 2 to 5 carbon atoms, or alkynyl having 2 to 5 carbon atoms; . ^ ^ . / f "V tWU J.)'!; Q represents oxygen or CH2; B represents CH2, C=0 or CH-OH; and R6 independently represents hydrogen, C 25 alkyl having 1 to 6 carbon atoms, or R and £ R together optionally represents a carbon to carbon bond; or R^ represents alkanoyl having 2 to 4 carbon atoms, carboxy, alkoxycarbonyl, or 30 (CH2)y-C02R8 wherein y is 0 to 4 and R8 is hydrogen or alkyl having 1 to 6 carbon atoms; and

A represents -Z-C02R7 or -Z-CONR^R^ n wherein R' represents hydrogen or alkyl having 35 1 to 6 carbon atoms, R9 and R"^ represent hydrogen, alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, or NR9R-*-° form a heterocyclic ring, and wherein Z is absent or represents straight or branched 4q chain alkylene or alkenylene having up to 6;carbon atoms.;2. A method according to Claim 1 wherein said compound is of the formula (IA):;3/;(IA);o—w o;c 0 D 0 J;wherein represents alkyl having 2-4 carbon atoms;;R represents methyl or ethyl;;R3 represents alkyl having 1 to 3 carbon atoms; W represents (CH2)X where x is 3 to 5;;alkenylene having 3 to 5 carbon atoms, alkynylene having 3 to 5 carbon atoms, or cyclopentyl; R^ represents alkyl having 2 to 4 carbon atoms; R^ and R^ independently represents hydrogen,;C;alkyl having 1 to 4 carbon atoms, or R and R^ together optionally represent a carbon to carbon bond;;A represents -Z-CC^R7 or -Z-CONR^R^°,;n wherein R represents hydrogen or alkyl having 1 to 4 carbon atoms, and R^® represent hydrogen or alkyl having 1 to 4 carbon atoms, and wherein Z is absent or represents alkylene having up to 2 carbon atoms; and the stereoisomers and pharmaceutically acceptable salts thereof.;

3. A method according to Claim 1 wherein said compound is of the formula (IB);o—w— o;(IB);>;23 6 5 34;«1;wherein R represents alkyl having 2-4 carbon atoms; 3 R represents methyl or ethyl;;R3 represents alkyl having 1 to 3 carbon atoms; W represents (CH2)X where x is 3 to 5,;alkenylene having 3 to 5 carbon atoms, alkynylene having 3 to 5 carbon atoms, or cyclopentyl; R4 represents alkyl having 2 to 4 carbon atoms;;tr c;R and R° independently represents hydrogen,;c alkyl having 1 to 4 carbon atoms, or R and R^ together optionally represent a carbon to carbon bond;;j A represents -Z-C02R7 or -Z-CONR9R10,;wherein R' represents hydrogen or alkyl having 1 to 4 carbon atoms, R9 and R^-0 represent hydrogen or alkyl having 1 to 4 carbon atoms, and wherein Z is absent or represents alkylene having i up to 2 carbon atoms; and the stereoisomers and pharmaceutically acceptable salts thereof.;

4. A method according to Claim 2 wherein said compound is of the formula (IC):;/;(ic);—(CV*- -o 23 5 5 3 4 wherein x is 3 to 5, represents hydrogen or alkyl of 1 7 to 4 carbon atoms and A represents -Z-CO2R wherein R represents hydrogen or alkyl having 1 to 4 carbon atoms and Z is absent or represents alkylene having up to 2 carbon atoms; and the stereoisomers and pharmaceutically acceptable salts thereof.

5. A method according to Claim 4 wherein said compound is of the formula (IIA): /CH3 H3C lid (CHj) (ch2) p-co°H (iia) wherein p is 0 to 2; and the pharmaceutically acceptable salts thereof.

6. A method according to Claim 3 wherein said compound is of the formula (ID): wherein x is 3 to 5, R^ and R® independently represents hydrogen or alkyl of 1 to 4 carbon atoms or and R^ together optionally represent a carbon to carbon bond; and A represents -Z-CC^R7 wherein R7 represents hydrogen or alkyl having 1 to 4 carbon atoms and Z is absent or represents alkylene having up to 2 carbon atoms; and the stereoisomers and pharmaceutically acceptable salts thereof.

7. A method according to Claim 6 wherein said compound is of the formula (IE): H3C (CHJ COOH £ P 6 (IE) R H 0 wherein R^ and independently represents hydrogen or methyl or R5 and R6 together optionally represent a carbon to carbon bond; and wherein p is 0 to 2; and the pharmaceutically acceptable salts thereof.

8. A method according to Claim 5 wherein said compound is of the formula (IF): o(ch2) 3o (if) c o U J and the pharmaceutically acceptable salts thereof.

9. A method according to Claim 2 wherein said compound is 7-[3-[4-acetyl-2-(cyclopropylmethyl)-3-methoxyphenoxy]-propoxy]-3,4-dihydro-8-propyl-2H-l-benzo-pyran-2-carboxylic acid.

10. A method according to Claim 2 wherein said compound is 7-[[3-(4-acetyl-3-methoxy-2-propylphenoxy)-cyclopentyl]oxy]-3,4-dihydro-8-propyl-2H-l-benzopyran-2-carboxylic acid.

11. A method according to Claim 2 wherein said compound is 7-[3-[4-acetyl-3-methoxy-2-(2-propenyl) phenoxy]propoxy-3,4-dihydro-8-propyl-2H-l-benzopyran-2-carboxylic acid.

12. A method according to Claim 2 wherein said compound is 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy-3,4-dihydro-2H-l-benzopyran-2-carboxylic acid.

13. A method according to Claim 3 wherein said compound is 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylie acid.

14. A method according to Claim 2 wherein said compound is 7-[3-(4-acetyl-3-methoxy-2-propyIphenoxy)-propoxy]-3,4-dihydro-N-methyl-8-propyl-2H-l-benzopyran-2-carboxamide. \ 2365 34

15. A method according to Claim 2 wherein said compound is methyl 7-[5-(4-acetyl-3-methoxy-2-propyl-phenoxy)pentyl]oxy]-3,4-dihydro-8-propyl-2H-l-benzopyran-2-carboxylate.

16. A method according to Claim 3 wherein said compound is methyl 7-[3-(4-acetyl-3-methoxy-2-propyl-phenoxy)propoxy]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H-l-benzopyran-2-propanoate.

17. A method according to Claim 3 wherein said compound is methyl 7-[[4-(4-acetyl-3-methoxy-2-propyl-phenoxy)-2-butynyl]oxy]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H-l-benzopyran-2-propanoate.

18. A method according to Claim 1 wherein said compound is methyl 7-[3-(4-acetyl-3-methoxy-2-propyl-phenoxy)propoxy]-1,2,3,4-tetrahydro-8-propyl-2-naphthalenecarboxylate.

19. A method according to Claim 2 wherein said compound is methyl 3,4-dihydro-7-[3-[3-methoxy-4-(2-methyl- 1-oxopropyl)-2-propyIphenoxy)-propoxy]-8-propyl-2H-1-benzopyran-2-carboxylate.

20. A method according to Claim 2 wherein said compound is ethyl 7-[3-(4-acetyl-3-methoxy-2-propyl-phenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran- 2-yl-propanoate. 23 6 5

21. A method according to Claim 2 wherein said compound is 7-[[5-(4-acetyl-3-methoxy-2-propylphenoxy)-pentyljoxy]-3,4-dihydro-8-propyl-2H-l-benzopyran-2-carboxylic acid.

22. A method according to Claim 3 wherein said compound is 7 — [3—(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H-l-benzo-pyran-2-propanoic acid.

23. A method according to Claim 3 wherein said compound is 7-[[4-(4-acetyl-3-methoxy-2-propyIphenoxy)-2-butynyl]oxy]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H-l-benzopyran-2-propanoic acid.

24. A method according to Claim 2 wherein said compound is 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-l,2,3,4-tetrahydro-8-propyl-2-naphthalenecarboxyl acid.

25. A method according to Claim 2 wherein said compound is 3,4-dihydro-7-[3-[3-methoxy-4-(2-methyl-l-oxopropyl)-2-propylphenoxy]propoxy]-8-propyl-2H-l-benzopyran-2-carboxylic acid.

26. A method according to Claim 2 wherein said compound is 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-propyl-2H-l-benzopyran-2-propanoic acid. Z6 v o

27. A method according to Claim 2 wherein said compound is 7-[3-(4-acetyl-3-ethoxy-2-propyIphenoxy)-propoxy]-3,4-dihydro-8-propyl-2H-l-benzopyran-2-carboxylie acid.

28. A method according to Claim 3 wherein said compound is 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-4-oxo-8-propyl-4H-l-benzopyran-2-propanoic acid.

29. A method according to Claim 2 wherein said compound is methyl 7-[3-(4-acetyl-3-methoxy-2-propyl-phenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate.

30. A method according to any one of Claims 1 to 29 wherein said compound or pharmaceutically acceptable salts thereof is administered in admixture with a pharmaceutically acceptable carrier or adjuvant.

31. A method according to any one of Claims 1 to 30 wherein the inflammatory disease is rheumatoid arthritis.

32. A method according to any one of Claims 1 to 30 wherein the inflammatory disease is psoriasis. 33. A method according to any one of Claims 1 to 30 wherein the inflammatory disease is inflammatory bowel disease. CO u

33. A method according to any one of Claims 1 to 30 wherein the inflammatory disease is gout. "BATED this day of 1-990 G. D. SEARLE & CO., By its Patent Attorneys, , son &~"caRey——, -88-