AU2041801A - Oncolytic combinations for the treatment of cancer - Google Patents

Description

WO 01/34135 PCT/USOO/30944 -1 ONCOLYTIC COMBINATIONS FOR THE TREATMENT OF CANCER CROSS REFERENCE 5 This application claims priority from United States Provisional Patent Application No. 60/164,713 filed 11 November 1999; the entire disclosure of which is incorporated herein by reference. 10 FIELD OF THE INVENTION This invention relates to a method of treating cancer with anti-cancer agents. More specifically, it relates to the use of anti-cancer agents, in conjunction with 15 leukotriene (LTB 4 ) antagonists which enhance the effectiveness of the anti-cancer agents. BACKGROUND OF THE INVENTION 20 Leukotriene B 4

(LTB

4 ) is a proinflammatory lipid which has been implicated in the pathogenesis of psoriasis, arthritis, chronic lung diseases, acute respiratory distress syndrome, shock, asthma, inflammatory bone diseases and other inflammatory states characterized by 25 the infiltration and activation of polymorphonuclear leukocytes and other proinflammatory cells. Thus activated, the polymorphonuclear leukocytes liberate tissue-degrading enzymes and reactive chemicals causing the inflammation. US Patent 5,462,954 discloses 30 phenylphenol leukotriene antagonists which are useful in the treatment of psoriasis, arthritis, chronic lung diseases, acute respiratory distress syndrome, shock, WO 01/34135 PCT/USOO/30944 -2 asthma, inflammatory bone diseases and other inflammatory states characterized by the infiltration and activation of polymorphonuclear leukocytes and other proinflammatory cells. US Patent 5,910,505 discloses that certain 5 phenylphenol leukotriene B 4

(LTB

4 ) antagonists are useful as agents for the treatment of oral squamous cell carcinoma. US Patent 5,543,428 discloses a group of phenylphenol leukotriene antagonists that have the property of reversing multi-drug resistance in tumor 10 cells. The use of the leukotriene antagonist will reverse the drug resistance of resistant tumor cells to vinblastine, vincristine, vindesine, navelbine, daunorubicin, doxorubicin, mitroxantrone, etoposide, teniposide, mitomycin-C, actinomycin-D, taxol, topotecan, 15 mithramycin, colchicine, puromycin, podophylotoxin, emetine, gramicidin-D, and valinomycin. BRIEF SUMMARY OF THE INVENTION 20 This invention provides compositions and methods useful for treating cancers, which are not multi-drug resistant. The compositions of the present invention include anti cancer agents in combination with leukotriene (LTB 4 ) antagonists of formula A, formula I and formula II. 25 Surprisingly, we have found that the combination of certain anti-cancer agents with leukotriene (LTB 4 ) antagonists is highly effective in treating cancers which are not multi drug resistant.

WO 01/34135 PCT/USOO/30944 -3 DETAILED DESCRIPTION OF THE INVENTION 5 I. Definitions: The term, "Acidic Group" means an organic group which when attached as the "Z" substituent of formula (I) or the "Z2" substituent of formula (II) acts as a proton donor capable of hydrogen bonding. An illustrative acidic group 10 is carboxyl. The term, "Active Ingredient" refers both to certain anti-cancer agents defined below and also leukotriene B4 antagonist compounds generically described by formula A as 15 well as diphenyl leukotriene B 4 antagonist compounds generically described by formula A, formula I and formula II or the list of specific diphenyl compounds disclosed, infra., as well as a combination of a anti-cancer agent and a leukotriene B4 antagonist described by formula A or 20 formula I or II, and the salts, solvates, and prodrugs of such compounds. The term, "alkenyl" means a monovalent radical of the generic formula CnH2n such as ethenyl, n-propenyl, 25 isopropeneyl, n-butenyl, isobutenyl, 2-butenyl, and 3-butenyl. The term, "alkyl" by itself or as part of another substituent means, unless otherwise defined, a straight or 30 branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, sec-butyl, n-pentyl, and n-hexyl.

WO 01/34135 PCT/USOO/30944 -4 The term, "alkaryl" means an aryl radical substituted with an alkyl or substituted aryl group, for example: CH 5 In the term, "C 6

-C

20 alkaryl" the numerical subscripts refer to the total number of carbon atoms in the radical. The term, "C 6

-C

20 aralkyl" means an alkyl radical substituted with an aryl or substituted aryl group, for 10 example:

H

3 C In the term, "C 6

-C

20 aralkyl" the numerical subscripts refer to the total number of carbon atoms in the radical. 15 The term, "carbocyclic group" refers to a five, six, seven, or eight membered saturated, unsaturated or aromatic ring containing only carbon and hydrogen (e.g., benzene, cyclohexene, cyclohexane, cyclopentane). 20 The term, "cycloalkyl" means a carbocyclic non aromatic monovalent radical such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 25 WO 01/34135 PCT/USOO/30944 -5 The term, "halo" means fluoro, chloro, bromo, or iodo. The term, "heterocyclic radical(s)" refers to a radical having a saturated, unsaturated or aromatic five membered 5 substituted or unsubstituted ring containing from 1 to 4 hetero atoms. The terms, "mammal" and "mammalian" include human. 10 The term, "N-sulfonamidyl" means the radical: C N S R12 H o O where R12 is C 1

-C

10 alkyl, aryl, Cl-C6 alkyl substituted aryl, C 6

-C

20 alkaryl, or C 6

-C

20 aralkyl. 15 The term, "substituted alkyl" means an alkyl group further substituted with one or more radical(s) selected from halo, C 1

-C

6 alkyl, aryl, benzyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, C 3

-C

8 cycloalkyl, Ci-C 8 alkoxy, Ci-C 6 haloalkyl 20 (e.g.,

-CF

3

)-

WO 01/34135 PCT/USOO/30944 -6 The term, "substituted aryl" means an aryl group further substituted with one or more radical(s) selected from halo, Ci-C 6 alkyl, aryl, benzyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, C 3

-C

8 cycloalkyl, C 1

-C

8 alkoxy, Cl-C 6 haloalkyl 5 (e.g.,

-CF

3

)

The term, "tetrazolyl" refers to an acidic group represented by either of the formulae: N N HN N I or | II 10 N NH N N The term "therapeutically effective interval" is a period of time beginning when one of either (a) the anti cancer agent or (b) the LTB 4 antagonist is administered to a 15 mammal and ending at the limit of the anti-cancer beneficial effect in treating cancer of (a) or (b). Typically, the anti-cancer agents and the leukotriene (LTB 4 ) antagonist- are administered within 24 hours of each other, more preferably within 4 hours and most preferably within 1 hour. 20 The phrase "therapeutically effective combination", used in the practice of this invention, means administration of both (a) the anti-cancer agent and (b) the LTB 4 antagonist, either simultaneously or separately. 25 The types of cancers which may be treated with the compositions of the present invention include: Breast Carcinoma, Bladder Carcinoma, Colorectal Carcinoma, Esophageal Carcinoma, Gastric Carcinoma, Germ Cell Carcinoma WO 01/34135 PCT/USOO/30944 -7 e.g. Testicular Cancer, Gynecologic Carcinoma, Lymphoma Hodgkin's, Lymphoma - Non-Hodgkin's, Malignant Melanoma, Multiple Myeoma, Neurologic Carcinoma, Brain Cancer, Non-Small Cell Lung Cancer, Pancreatic Carcinoma, Prostate 5 Carcinoma, Ewings Sarcoma, Osteosarcoma, Soft Tissue Sarcoma, Pediatric Malignancies and the like. The anti cancer agents which may be used include: 10 ALKYLATING AGENTS: Busulfan, Carboplatin, Carmustine, Cisplatin, Cyclophosphamide, Dacarbazine, Ifosfamide, Lomustine, Streptozocin, Oxaliplatin, Temozolomide; ANTIBIOTICS: Bleomycin, Dactinomycin, Daunorubicin, 15 Doxorubicin, Idarubicin, Mitomycin-C, Plicamycin, Cryptophycin; ANTIMETABOLITES: Cytarabine, Floxuridine, Fludarabine, 5 Fluorouracil, Hydroxyurea, 6-Mercaptopurine, Methotrexate, 20 Thioguanine; Capecitabine; BIOLOGICALS: Aldesleukin, Interferon Alfa-2A, Interleukin 2, Interleukin-12 (recombinant), Interferon Alfa-2B (recombinant), Interferon Alfa-n3, Interferon Gamma-1B, 25 Herceptin interleukin-2, interleukin-12; HORMONAL AGENTS: Aminoglutethimide, Anastrozole, Flutamide, Goserelin, Leuprolide, Megestrol, Mitotane, Tamoxifen; 30 NITROGEN MUSTARD DERIVATIVES: Chlorambucil, Estramustine, Mechlorethamine, Melphalan, Thiotepa; WO 01/34135 PCT/USOO/30944 -8 PLANT ALKALOIDS: Docetaxel, Etoposide, Irinotecan HCl, Paclitaxel, Teniposide, Topotecan, Vinblastine, Vincristine, Vinorelbine; 5 OTHERS: Altretamine, Amifostine Asparaginase-Escherichia coli strain, BCG Live (Intravesical), Cladribine, Leucovorin, Levamisole, Mitoxantrone, Pegaspargase, Pentostatin, Procarbazine, and the like. 10 The anti-cancer agents may be used alone or in combinations of one or more anti-cancer agents. When used in combination, the anti-cancer agents may be administered at the same time, sequentially or in more complicated regimens where the agents may be administered alternately. 15 Such combinations and dosing regimens are well known to those skilled in the art. The anti-cancer agents may be formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated elixirs or solutions for convenient oral administration or administered by 20 intramuscular intravenous routes. The compounds can be administered transdermally and may be formulated as sustained relief dosage forms and the like. The compositions of the present invention are a 25 combination of therapeutically effective amounts of the leukotriene (LTB 4 ) antagonists, noted above, and a therapeutically effective amount of an anti-cancer agent. The composition may be formulated with common excipients, diluents or carriers, and compressed into tablets, or 30 formulated elixirs or solutions for convenient oral administration or administered by intramuscular intravenous routes. The compounds can be administered transdermally and WO 01/34135 PCT/USOO/30944 -9 may be formulated as sustained relief dosage forms and the like. In another embodiment, the invention relates to a 5 method of treating a patient suffering from a non-multi-drug resistant cancerous condition which comprises the separate administration of a therapeutically effective amount of the leukotriene (LTB 4 ) antagonists, and the anti-cancer agent. When administered separately, the leukotriene (LTB 4 ) 10 antagonists, and the anti-cancer agent may be administered on a different schedule. One may be administered before the other as long as the time between the two administrations falls within a therapeutically effective interval. Therapeutically effective interval is a period of time 15 beginning when one of either (a) the leukotriene (LTB 4 ) antagonists or (b) the anti-cancer agent is administered to a human and ending at the limit of the beneficial effect in the treatment of cancer of the combination of (a) and (b). 20 The methods of administration of the leukotriene LTB 4 antagonist and the anti-cancer agent may vary. Thus, one agent may be administered orally, while the other is administered intravenously. It is possible that one of the products may be administered as a continuous infusion while 25 the other is provided in discreet dosage forms. It is particularly important that the anti-cancer drug be given in the manner known to optimize its performance. The leukotriene (LTB 4 ) antagonists useful in the 30 present invention include those given in formula A.

WO 01/34135 PCT/USOO/30944 -10 - X'-Y'-Z'-A'-R 4' R, Formula A or a pharmaceutically acceptable base addition salt 5 thereof, wherein:

R

1 , is Cl-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, Ci-C4 alkoxy, (Cl-C4 alkyl)thio, halo, or R2'-substituted phenyl; each R2' and R3' are each independently hydrogen, halo, hydroxy, Cl-C4 alkyl, Cl-C4 alkoxy, (Cl-C4 alkyl)-(O)q S-, 10 trifluoromethyl, or di-(Cl-C3 alkyl)amino; X' is -0-, -S-, -C(=0), or -CH2-; Y' is -0- or -CH2-; or when taken together, -X'-Y'- is -CH=CH- or -C=C-; Z' is a straight or branched chain Cl-C1o alkylidenyl; 15 A' is a bond, -0-, -S-, -CH=CH-, or -CRaRb-, where Ra and Rb are each independently hydrogen, CI-C5 alkyl, or R7' substituted phenyl, or when taken together with the carbon atom to which they are attached form a C4-C8 cycloalkyl ring; 20 WO 01/34135 PCT/USOO/30944 -11

R

4 ' is R 6 or taken from one of the following formulae:

R

7 O-G-R 6 0 (K)p-W-R 6 R7 (CHO 0 WR1 T R7

W-R

6 R 7 R W-R6 W-R6 Ry7 5 wherein: each R6 is independently -COOH, 5-tetrazolyl, CON(R 9

)

2 , or -CONHSO 2

R

1 0

;

WO 01/34135 PCT/USOO/30944 -12 each R7 is hydrogen, C1-C4 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, benzyl, methoxy, -W-R6, -T-G-R6, (Cl-C4 alkyl)-T (Cl-C4 alkylidenyl)-O-, or hydroxy; R8 is hydrogen or halo; 5 each R 9 is independently hydrogen, phenyl, or C1-C4 alkyl, or when taken together with the nitrogen atom form a morpholino, piperidino, piperazino, or pyrrolidino group; R10 is Cl-C4 alkyl or phenyl; Rii is R2, -W-R6, or -T-G-R6; 10 each W is a bond or a straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms; each G is a straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms; each T is a bond, -CH2-, -0-, -NH-, -NHCO-, -C(=0)-, or 15 (O)q S-; K is -C(=0)- or -CH(OH)-; each q is independently 0, 1, or 2; p is 0 or 1; and t is 0 or 1; 20 provided when X is -0- or -S-, Y is not -0-; provided when A is -0- or -S-, R4 is not R6; and provided W is not a bond when p is 0. More preferred compounds of Formula A are those wherein 25 R4' is selected from the following formulae: 0 T R7 ,or WO 01/34135 PCT/USOO/30944 -13

R

8

W-R

6 T 7 An even more preferred compound is that wherein R4'is:

R

8

W-R

6 T 7 5 Preferred compounds or pharmaceutically acceptable acid or salt derivatives thereof are those wherein said compound is selected from the group (A) to (KKKK) consisting of: A) 2-Methyl-2- (lH-tetrazol-5-yl) -7- (2-ethyl-4 10 (4-fluorophenyl)-5-hydroxyphenoxy)heptane; B) 2-Methyl-2-(lH-tetrazol-5-yl)-7-(2-ethyl-4 (3-fluorophenyl) -5-hydroxyphenoxy) heptane; 15 C) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy) -6- (4 dimethylaminocarbonylbutyloxy)phenyl)propion ic acid; 20 D) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) propoxy) phenyl) propionic acid; E) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 25 hydroxyphenoxy)propoxy) -6- (4 carboxybutyloxy) phenyl) propionic acid; WO 01/34135 PCT/USOO/30944 -14 F) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) propoxy) -6 methoxyphenyl)propionic acid; 5 G) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4-(1H-tetrazol-5 yl)butyloxy)phenyl)propionic acid; H) Methyl 3-(2-(4-(2-ethyl-4-(4-fluorophenyl) 10 5-hydroxyphenoxy)-(1 butenyl))phenyl)propionate; I) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)-(1-butenyl))phenyl)propionic 15 acid; J) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyl)phenyl)propionic acid; 20 K) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyl)-6 methoxyphenyl)propionic acid; L) Methyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl) 25 5-hydroxyphenoxy)propoxy)-6 hydroxyphenyl)propionate; M) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) propoxy) -6 30 hydroxyphenyl)propionic acid; N) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 butyloxy)phenyl)propionic acid; 35 0) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 methylthiobutyloxy)phenyl)propionic acid; 40 P) 3-(2-(3-(2,4-Di-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 carboxybutoxy)phenyl)propionic acid; Q) 6-Methyl-6-(lH-tetrazol-5-yl)-11-(2-ethyl-4 45 (4-fluorophenyl)-5-hydroxyphenoxy)undecane; WO 01/34135 PCT/USOO/30944 -15 R) N,N-Dimethyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionamide; 5 S) N-Methanesulfonyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionamide; T) N-Phenylsulfonyl-3-(2-(3-(2-ethyl-4-(4 10 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionamide; U) 3-(2-(3-(2-Butyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic 15 acid; V) Ethyl 3-(2-(4-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyloxy)phenyl)propionate; 20 W) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyloxy)phenyl)propionic acid; X) Methyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl) 25 5-hydroxyphenoxy)propoxy)-6-(4 (methoxycarbonyl)phenoxy)phenyl)propionate; Y) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 30 carboxyphenoxy)phenyl)propionic acid; Z) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-4-(4 carboxyphenoxy)phenyl)propionic acid; 35 AA) 3,3-Dimethyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; WO 01/34135 PCT/USOO/30944 -16 BB) 2-Methyl-2-(lH-tetrazol-5-yl)-3-(2-(3-(2 ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propane; 5 CC) 2-Methyl-2-(lH-tetrazol-5-yl)-3-hydroxy-3 (2-(3-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propane; 10 DD) 3-(2-(3-(2-Bromo-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; EE) 3-(2-(3-(2-Ethylthio-4-(4-fluorophenyl)-5 15 hydroxyphenoxy)propoxy)phenyl)propionic acid; FF) Methyl 3-(2-hydroxy-3-(4 methoxycarbonylbutyl)-6-(3-(2-ethyl-4-(4 20 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionate; GG) 5-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-8-(4-carboxybuty 25 1)dihydrocoumarin; HH) 2-Phenyl-4-ethyl-5-[6-(2H-tetrazol-5-yl)-6 methylheptyloxy]phenol sodium salt; 30 II) 2-(4-Methylphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol disodium salt; JJ) 2-(3-Methylphenyl)-4-ethyl-5-[6-methyl-6 35 (2H-tetrazol-5-yl)heptyloxy]phenol sodium salt; KK) 2-(2-Methylphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol disodium 40 salt; LL) 2-(4-Methoxyphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol sodium salt; 45 MM) 2-(3-Methoxyphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol sodium salt; WO 01/34135 PCT/USOO/30944 -17 NN) 2-(4-Trifluoromethylphenyl)-4-ethyl-5-[6 methyl-6-(2H-tetrazol-5-yl)heptyloxy]phenol disodium salt; 5 00) 2-(3-Dimethylaminophenyl)-4-ethyl-5-[6 methyl-6-(2H-tetrazol-5-yl)heptyloxy]phenol disodium salt; 10 PP) 3-(5-(6-(4-Phenyl-5-hydroxy-2 ethylphenoxy)propoxy)-2-carboxymethyl 1,2,3,4 -tetrahydronaphthalen-1(2H) one)propanoic acid; 15 QQ) 3-(5-(6-(4-(4-Fluorophenyl)-5-hydroxy-2 ethylphenoxy)propoxy)-2-carboxymeth yl 1,2,3,4-tetrahydronaphthalen-1(2H) one)propanoic acid; 20 RR) 3-(4-(5-(4-(4-Fluorophenyl)-5-hydroxy-2 ethylphenoxy)propoxy)-2-carboxymeth yl-2,3 dihydroinden-1(2H)-one)propanoic acid; SS) 3,3-Dimethyl-5-(3-(2-carboxyethyl)-4-(3-(4 25 fluorophenyl)-5-hydroxy-2 ethylphenoxy)propoxy)phenyl)-5-oxopentanoic acid; TT) 7-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyl]-4 30 yl)oxy]propoxy]-3,4-dihydro-8-propyl-2H-1 benzopyran-2-carboxylic acid; UU) 8-Propyl-7-[3-[4-(4-fluorophenyl)-2-ethyl-5 hydroxyphenoxy]propoxy]-3,4-dihydro-2H-1 35 benzopyran-2-carboxylic acid; VV) 2-[3-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyl] 4-yl)oxy]propoxy]-2-propylphenoxy]propanoic acid; 40 WW) 2-(4-Chlorophenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol monosodium salt; 45 XX) 2-(3,5-Dichlorophenyl)-4-ethyl-5-[6-methyl 6-(2H-tetrazol-5-yl)heptyloxy]phenol monosodium salt; WO 01/34135 PCT/USOO/30944 -18 YY) 3-[2-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyl] 4-yl)oxy]propoxy]-1-dibenzofuran]propanoic acid disodium salt; 5 ZZ) 7-Carboxy-9-oxo-3-[3-(2-ethyl-5-hydroxy-4 phenylphenoxy)propoxy]-9H-xanthene-4 propanoic acid disodium salt monohydrate; AAA) 2-[2-Propyl-3-[3-(2-ethyl-5-hydroxy-4 10 phenylphenoxy)propoxy]phenoxy]benzoic acid sodium salt hemihydrate; BBB) 3-[3-(2-Ethyl-5-hydroxy-4 phenylphenoxy)propoxy][1,1'-biphenyl]-4 15 propanoic acid disodium salt monohydrate; CCC) 5-Ethyl-4-[3-[2-propyl-3-(2-(2H-tetrazol-5 yl) phenoxy] phenoxy] propoxy] [1,1' -biphenyl] 2-ol disodium salt sesquihydrate; 20 DDD) 3-[4-[3-[ 3-(2-Ethyl-5-hydroxy-4 phenyiphenoxy) propoxy] -9-oxo-9H xanthene]]propanoic acid sodium salt hemihydrate; 25 EEE) 2-Fluoro-6-[2-propyl-3-[3-(2-ethyl-5 hydroxy- 4 phenylphenoxy) propoxy] phenoxy] benzoic acid disodiinn salt; 30 FFF) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl) -5 hydroxyphenoxy] propoxy] phenoxy] benzoic acid sodium salt; 35 GGG) 3-[4-[7-Carboxy-9-oxo-3-[3-[2-ethyl-4-(4 fluorophenyl) -5 -hydroxyphenoxy] propoxy] -9H xanthene]] propanoic acid disodiun salt trihydrate; 40 HHH) 3-[4-[9-Oxo-3-[3-[2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy]propoxy]-9H xanthene] ]propanoic acid; 45 111) 3-[2-[l-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy]propoxy]-4-(5-oxo-5 morpholinopentanamido)phenylbpropanoic acid; WO 01/34135 PCT/USOO/30944 -19 JJJ) 2-Fluoro-6-[2-propyl-3-[3-[2-ethyl-5 hydroxy-4- (4 fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid disodium salt hydrate; 5 KKK) 4-Fluoro-2-[2-propyl-3-[3-[2-ethyl-5 hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid; 10 LLL) 2-[2-Propyl-3-[-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]pentoxy]phenoxy]benzoic acid; 15 MM) 2-[2-Propyl-3-[4-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]butoxy]phenoxy]benzoic acid sesquihydrate; NNN) 2-[2-(2-Methylpropyl)-3-[3-[2-ethyl-5 20 hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid; 000) 2-[2-Butyl-3-[3-[2-ethyl-5-hydroxy-4-(4 25 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid hydrate; PPP) 2-[2-(Phenylmethyl)-3-[3-[2-ethyl-5-hydroxy 4-(4 30 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid; QQQ) 2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]phenyla 35 cetic acid; RRR) 2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]benzoyl]benzoic acid; 40 SSS) 2-[[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenyl]methyl]b enzoic acid; 45 TTT) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy]propoxy]thiophenoxy]benzoic acid; WO 01/34135 PCT/USOO/30944 -20 UUU) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy]propoxy]phenylsulfinyl]benzoi 5 c acid; VVV) 2-[2-Propyl-3-[3-(2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy]propoxy]phenylsulfonyl]benzoi 10 c acid hydrate; WWW) 5-[3-[2-(1-Carboxy)ethyl]-4-[3-[2-ethyl-4 (4-fluorophenyl)-5 hydroxyphenoxy]propoxy]phenyl]-4-pentynoic 15 acid disodium salt 0.4 hydrate; XXX) 1-Phenyl-l-(lH-tetrazol-5-yl)-6-(2-ethyl-4 (4-fluorophenyl)-5-hydroxyphenoxy)hexane; 20 YYY) 1-(4-(Carboxymethoxy)phenyl)-1-(1H-tetrazol 5-yl)-6-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)hexane; ZZZ) 1-(4-(Dimethylaminocarbonylmethoxy)phenyl) 25 1-(1H-tetrazol-5-yl)-6-(2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy)hexane; AAAA) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)-E-propenoic 30 acid; BBBB) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)-2-methyl-E propenoic acid; 35 CCCC) 5-(2-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) propoxy) phenyl) ethyl) -lH tetrazole; WO 01/34135 PCT/USOO/30944 -21 DDDD) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-4-(4 carboxybutyloxy)phenyl)propionic acid; 5 EEEE) 5-[3-[4-(4-Fluorophenyl)-2-ethyl-5 hydroxyphenoxy] propoxy] -3, 4-dihydro-2H-1 benzopyran-2-one; 10 FFFF) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy]propoxy}phenyl)propanoic acid; GGGG) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5 15 hydroxyphenyloxy]propoxy}-4-propylph enyl)propanoic acid sodium salt; HHHH) 3-(4-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy]propoxy}-3 20 propylphenyl)propanoic acid; IIII) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy] propoxy} -2 propylphenyl)propanoic acid; 25 JJJJ) 3-{3-[3-(2-Ethyl-5 hydroxyphenyloxy) propoxy] -2 propylphenyl}propanoic acid disodium salt; and 30 KKKK) 2-[3-[3-[2-Ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]benzoyl]benzoic acid disodium salt hemihydrate. 35 These leukotriene (LTB 4 ) antagonists are well known in the art, and are fully described in U.S. Patent 5,462,954, which is hereby specifically incorporated by reference for its disclosure of the methods of preparation of specific 40 leukotriene B 4 antagonists and compounds or formulations of the leukotriene antagonists which may be administered to patients. A preferred compound is 2-[2-propyl-3-[3-[2 ethyl-5-hydroxy-4-(4-flourophenyl)phenoxy]propoxy]phenoxy benzoic acid which can also be named-2-[3-[3-(5-ethyl-4'- WO 01/34135 PCT/USOO/30944 -22 flouro-2-hydroxybiphen-4-yloxy) propoxy] -2 propylphhenoxy]benzoic acid, described in U.S. Patent 5,462,954 as example 66 and also shown below as Compound A (Formula B): 5 F H oo o HO 0 Compound A (Formula B) 10 A second class of LTB 4 antagonists to use as the essential co-agent in the compositions and practice of the method of this invention are those disclosed in copending provisional patent application, titled, "Heterocycle Substituted Diphenyl Leukotriene Antagonists" (inventor, Jason Scott 15 Sawyer) containing 97 pages and identified as Eli Lilly and Company Docket No. B-13240), filed on November 11, 1999, and now Provisional patent Application Serial Number 60/164,786. The subject Heterocycle substituted diphenyl leukotriene antagonists are also described in more detail below: 20 II. Additional LTB 4 Antagonists: Additional LTB 4 antagonists are described below which are novel heterocyclic substituted diphenyl compounds of 25 formula (I) WO 01/34135 PCT/USOO/30944 -23 H X R3 R2

Y

3 a.H 2 ) Y2 1 R4 R1 Z (I) wherein: X is selected from the group consisting of, 5 (i) a five membered substituted or unsubstituted heterocyclic radical containing from 1 to 4 hetero atoms independently selected from sulfur, nitrogen or oxygen; or 10 (ii) a fused bicyclic radical wherein a carbocyclic group is fused to two adjacent carbon atoms of the five membered heterocyclic radical, (i); 15 Y 1 is a bond or divalent linking group containing 1 to 9 atoms; Y2 and Y 3 are divalent linking groups independently selected from -CH 2 -, -0-, and -S-; 20 Z is an Acidic Group; Rl is Ci-C 10 alkyl, aryl, C 3

-C

10 cycloalkyl,

C

2

-C

10 alkenyl, C 2

-C

10 alkynyl, C 6

-C

20 aralkyl, C 6

-C

20 25 alkaryl, Ci-C 10 haloalkyl, C 6

-C

20 aryloxy, or Ci-Ci 0 alkoxy; WO 01/34135 PCT/USOO/30944 -24 R2 is hydrogen, halogen, C 1

-C

10 haloalkyl, Ci-C 1 0 alkoxy, Ci-C 10 alkyl, C 3

-C

8 cycloalkyl, Acidic Group, or -(CH2)1-7(Acidic Group); 5 R3 is hydrogen, halogen, Cl-C 10 alkyl, aryl, Ci-C 1 0 haloalkyl, Ci-C 10 alkoxy, Ci-C 10 aryloxy, C 3

-C

8 cycloalkyl; R4 is C 1

-C

4 alkyl, C 3

-C

4 cycloalkyl,

-(CH

2 )1- 7 (cycloalkyl), C 2

-C

4 alkenyl, C 2

-C

4 alkynyl, benzyl, 10 or aryl; and n is 0, 1, 2, 3, 4, 5, or 6; or a pharmaceutically acceptable salt, solvate, or prodrug 15 derivative thereof. III. Preferred LTB 4 Antagonists include the following: III A. Preferred X substituents: 20 A "substituted heterocyclic radical" is preferably Substituted with from 1 to 3 groups independently selected from hydrogen, halo, Ci-C 10 alkyl, Ci-C 10 haloalkyl, Ci-C 10 alkoxy, aryl, or C 6

-C

2 0 aryloxy. 25 Preferred Group 1 of X substituent (symbol, "PG1-X") Preferred LTB 4 compounds of the invention include those wherein X is a heterocyclic radical selected from the group consisting of substituents represented by the following structural formulae: 30 WO 01/34135 PCT/USOO/30944 -25 R11 R1 / R1 0 S N R10 N R11 / R11 R11 0 S 0 S , N , R10 N RR11 NR11 NN SN N RIO R10 R10 N NR1 1 N R N NR N S 5 R10 R10 R11 R1 R11 S 7 lO NN S 00 WO 01/34135 PCT/USOO/30944 -26 R10 N N N N N N N N C S , O , NR11 , 0O S , N , N R11 0/ N ,and N 5 R11 R10 where R10 is a radical selected from hydrogen or Ci-C 4 alkyl; and R11 is a radical selected from hydrogen, halo, Ci-C 10 alkyl, Ci-C 10 haloalkyl, Ci-C 10 alkoxy, aryl, 10 or C 6

-C

20 aryloxy. Preferred R10 groups are hydrogen, methyl, or phenyl. Moreover, any of the above heterocyclic radicals illustrated by structural formulae may attach to the diphenyl leukotriene antagonist of formulae (I) by any monovalent bond originating on a suitable carbon or nitrogen 15 atom in its ring structure. For example, the pyrrole radical may attach to the diphenyl molecule by a single bond originating at any carbon atom or any nitrogen atom which has less than three bonds in the heterocyclic ring; WO 01/34135 PCT/USOO/30944 -27 Location of attachment bond for pyrrole, N N N H H , A preferred form of the substituent X is a fused 5 bicyclic radical wherein a carbocyclic group is fused to two adjacent carbon atoms of the five membered heterocyclic radical, for example: H N /N and H 10 WO 01/34135 PCT/USOO/30944 -28 III B. Preferred Group 2 of X substituent (symbol, "PG2 X"): Most preferred as the X substituents are the heterocyclic 5 radicals; N S

CH

3 N 0 or S 10 III C. Excluded X substituents: The heterocyclic radical X of Formula (I) does not include 3-bromo-1,2,4 thiadiazole since the LTB 4 antagonist activity of compounds containing this radical is considered too low to be an aspect of this invention. 15 III D. Preferred Yi substituents:

Y

1 is a bond or divalent linking group containing 1 to 9 atoms independently selected from carbon, hydrogen, sulfur, nitrogen, and oxygen; 20 Preferred Group 1 of Yi substituent (symbol, "PG1-Yi"f) Preferred LTB 4 compounds of the invention include those wherein Yj is a divalent linking group selected from the group consisting of substituents represented by the 25 following formulae: WO 01/34135 PCT/USOO/30944 -29 - 0 - S - C- - SO2 ,

H

2 o 0 - N - C R13 0 -C C

H

2

H

2 ---- C

H

2 S C

H

2 -- N-C I H2 R13 0

H

2 0 and C C

H

2 0 5 where R13 is hydrogen, methyl, or ethyl; WO 01/34135 PCT/USOO/30944 -30 The above divalent groups may be used in their forward or reversed positions. For example, the group; 5 -H2 0 may be positioned as either, R2 R2 R3 R3 0R1 O Z or R1 O 10 in the displayed fragment of formula (I). III E. Preferred Group 2 of Yi substituent (symbol, "PG2 15 Yi"): The most preferred divalent Yi substituent is the group; 0 20 WO 01/34135 PCT/USOO/30944 -31 III F. Preferred Group 1 of Y 2 substituent (symbol, "PG1

Y

2 ") and Preferred Group 1 of Y 3 substituent (symbol, "PGl Y3") : The Y 2 and Y 3 substituents are preferably selected from 5 -S- and -0-. III G. Preferred Group 2 of Y 2 substituent (symbol, "PG2

Y

2 ") and Preferred Group 2 of Y 3 substituent (symbol, "PG2

Y

3 "): 10 Most preferably both Y 2 and Y 3 are the group; 0 III H. Preferred Group 1 of Z substituent 15 (symbol, "PG1-Z"): Z is the Acidic Group as previously defined. Preferred is an acidic group selected from the following: -C-N-S-R12 H 0 o tetrazolyl, 20 -SO3H, WO 01/34135 PCT/USOO/30944 -32 OH P OH OH 0 H ---- P- OH OH 100 -- -C OH or N

HO

N 5 where R12 is C1-C10 alkyl, aryl, C6-C20 alkaryl, or C6-C20 aralkyl. Preferred R12 groups are represented by -the formulae: Y1CH3 1 and 10 III I. Preferred Group 2 of Z substituent (symbol, "PG2-Z"): WO 01/34135 PCT/USOO/30944 -33 Highly preferred are the acidic groups; -5 tetrazolyl, N-acyl sulfonamide, -SO3H, and carboxyl. 5 1II J. Preferred Group 3 of Z substituent (symbol, "PG3-Z"): Carboxyl is the most preferred Z substituent. III K. Preferred Group 1 of n subscript variable 10 (symbol, "PG1-n") The most preferred integer values for the divalent linking group, -(CH2)n- , are n=1, n=2, and n=3. III L. Preferred Group 2 of n subscript variable 15 (symbol, "PG2-n") The most preferred integer value of n for the divalent linking group, -(CH2)n- is n = 1. III M. Preferred Group 1 of R1 substituent (symbol, "PG1 20 Rl"): A preferred R1 group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and 2-propenyl; with n propyl being most preferred. 25 III N. Preferred Group 1 of R2 substituent (symbol, "PG1-R2")and Preferred Group 1 of R3 substituent (symbol, "PG1-R3"): Preferred R2 and R3 groups are those wherein R2 and R3 are independently selected from hydrogen or methyl, 30 ethyl, methoxy, ethoxy, halo, or -CF 3 ; with R2 and R3 both being hydrogen as most preferred.

WO 01/34135 PCT/USOO/30944 -34 III 0. Preferred Group 1 of R4 substituent (symbol, "PGl-R4":) Preferred R4 substituents are ethyl, propyl, and isopropyl. 5 III P. Combinations of substituents of the compound of Formula (I): The substituents of formula (I) are defined as "Z", "X,"n", "R1", "R2", "R3"1, "R4"1, "%Yl", "Y2", and "Y3"'. 10 Moreover, as described in the preceding section, within each of the defined substituents of Formula (I) are "preferred" and "most preferred" subgroups which define the variety of substituents to be used in the definition of LTB 4 antagonists of the invention. These preferred 15 subgroups are defined by designations such as "PGl-R4" as recited above. It is often advantageous to use combinations of preferred groups or combinations of preferred groups together with the general definition of variables given in Formula (I). Suitable combinations of 20 substituents are shown in the following three Tables (viz., R-Table, Y-Table & XZn-Table).

WO 01/34135 PCT/USOO/30944 -35 The following R-Table is used to select combinations of general and preferred groupings of the variables R1, R2, R3 and R4 for substitution in formula (I), as follows: 5 R-Table R variables R1 R2 R3 R4 Combination group group group group Code choice choice choice choice R01 R1 R2 R3 R4 R02 R1 R2 R3 PG1-R4 R03 R1 R2 PGl-R3 R4 R04 R1 R2 PG1-R3 PG1-R4 R05 R1 PG1-R2 R3 R4 R06 R1 PG1-R2 R3 PG1-R4 R07 R1 PG1-R2 PGl-R3 R4 R08 R1 PG1-R2 PG1-R3 PGl-R4 R09 PGl-R1 R2 R3 R4 R10 PG1-01 R2 R3 PGI-R4 R11 PG1-Rl R2 PG1-R3 R4 R12 PGl-Ri R2 PGl-R3 PGl-R4 R13 PG1-RI PG1-R2 R3 R4 R14 PGl-R1 PG1-R2 R3 PG1-R4 R15 PG1-Rl PGl-R2 PGl-R3 R4 R16 PG1-RI PG1-R2 PGl-R3 PG1-R4 Thus, for example, the substituent combination, "R14" describes a substituent combinatorial choice for Formula 10 (I) wherein Ri is selected from the preferred set of variables, "PG1-R1", that is, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and 2-propenyl; the R2 substituent is selected from the preferred set of WO 01/34135 PCT/USOO/30944 -36 variables, "PG1-R2", that is, hydrogen or methyl, ethyl, methoxy, ethoxy, halo, or -CF 3 ; the variable R3 has the scope defined in the generic formula (I), and the substituents suitable for R4 are selected from the 5 preferred group, "PG1-R4" having the preferred set of variables, ethyl, propyl, and isopropyl. The following Y-Table is used to select broad and preferred groupings of the variables Yl, Y2, and Y3 for substitution in formula (I), as follows: WO 01/34135 PCT/USOO/30944 -37 Y-Table Y variables Y1 group Y2 group Y3 group combination choice choice choice code YOl Yl Y2 Y3 Y02 Y1 Y2 PG1-Y3 Y03 Y1 Y2 PG2-Y3 Y04 Yl PG1-Y2 Y3 Y05 Y1 PG2-Y2 Y3 Y06 Y1 PG1-Y2 PG1-Y3 Y07 Yl PG1-Y2 PG2-Y3 Y08 Y1 PG2-Y2 PG1-Y3 Y09 Yl PG2-Y2 PG2-Y3 Y10 PGl-Y1 Y2 Y3 Yll PG1-Y1 Y2 PG1-Y3 Y12 PG1-Y1 Y2 PG2-Y3 Y13 PG1-Y1 PG1-Y2 Y3 Y14 PG1-Yl PG1-Y2 PG1-Y3 Y15 PG1-Y1 PG1-Y2 PG2-Y3 Y16 PG1-Yl PG2-Y2 Y3 Y17 PGl-Y1 PG2-Y2 PG1-Y3 Y18 PG1-Y1 PG2-Y2 PG2-Y3 Y19 PG2-Y1 Y2 Y3 Y20 PG2-Y1 Y2 PG1-Y3 Y21 PG2-Y1 Y2 PG2-Y3 Y22 PG2-Yl PG1-Y2 Y3 Y23 PG2-Y1 PG1-Y2 PG1-Y3 Y24 PG2-Y1 PG1-Y2 PG2-Y3 Y25 PG2-Y1 PG2-Y2 Y3 Y26 PG2-Y1 PG2-Y2 PG1-Y3 Y27 PG2-Y1 PG2-Y2 PG2-Y3 WO 01/34135 PCT/USOO/30944 -38 The following XZn-Table is used to select broad and preferred groupings of the variables X, Z, and n for substitution in formula (I), as follows: XZn-Table XZn variables X Z n integer combination group Group group code choice Choice choice XZnO1 X Z n XZnO2 X Z PG1-n XZnO3 X Z PG2-n XZnO4 X PG1-Z n XZn05 X PG2-Z n XZnO6 X PG3-Z n XZnO7 X PG1-Z PG1-n XZn08 X PG2-Z PGl-n XZnO9 X PG3-Z PG1-n XZnlO X PG1-Z PG2-n XZn1l X PG2-Z PG2-n XZn12 X PG3-Z PG2-n XZn13 PG1-X Z n XZn14 PG1-X Z PG1-n XZn15 PG1-X Z PG2-n XZn16 PG1-X PG1-Z n XZn17 PG1-X PG2-Z n XZn18 PG1-X PG3-Z n XZn19 PG2-X PG1-Z PG1-n XZn20 PG2-X PG2-Z PG1-n XZn21 PG2-X PG3-Z PG1-n XZn22 PG2-X PG1-Z PG2-n XZn23 PG2-X PG2-Z PG2-n XZn24 PG2-X PG3-Z PG2-n 5 WO 01/34135 PCT/USOO/30944 -39 How to Use the Tables: Any of the individual 16 combinations of the R substituents depicted in the R-Table may be used in combination with any of the 27 individual combinations of 5 Y substituents depicted in the Y-Table, which may be used with any of the 24 combinations of XZn substituents depicted in the XZn-Table. For example, the substituent combination choice "R07, Y21, XZnO3" defines substituent set selections for a subset of formula (I) useful in the 10 practice of the invention. III Q. Additional preferred LTB 4 antagonists are described by formula (II): H X2 R22 -O-'> H 2 O 0 R21 15 wherein; 20 25 WO 01/34135 PCT/USOO/30944 -40 X2 is a heterocyclic radical selected from, N S CH:5- NO or S 5 R21 is ethyl, 2-propen-1-yl, 3-propen-1-yl, n-propyl, iso-propyl, n-butyl, sec-butyl, or tert-butyl; and R22 is hydrogen, n-butyl, sec-butyl, flouro, chloro,

-CF

3 , or tert-butyl. 10 Z2 is carboxyl, tetrazolyl, N-sulfonamidyl. Preferred Compounds of the Invention: III R. Specific compounds preferred as LTB 4 antagonists are represented by the following structural formulae: 15 (Cl): / N OH O " O O

COOH

WO 01/34135 PCT/USOO/30944 -41 (C2) HOI ~N OH N' 0-- o O0 COOH (C3): 5 /--N OH 0N -,-,

O

COOH (C4): N-N' OH COOH 10 (C5):

N-~

0 OH

COOH

WO 01/34135 PCT/USOO/30944 -42 (C6) , NN OH N. COOH 5 (C7): 0*' o 0 COOMe 10 (C8): O H 01 COOH 15 WO 01/34135 PCT/USOO/30944 -43 (C9) N- OH COOH 5 (ClO): r NOH COOH 10 (Cli): 10 OH COONa WO 01/34135 PCT/USOO/30944 -44 (C12) OH O N 00N COOH (C13) 5 OH 00 O ,- O OP COOH (C14) 10 O OH COONa (C15): OH N -HCI OO O COOH 15 WO 01/34135 PCT/USOO/30944 -45 (Ci6) S OH COOH 5 (C17): -NN OH N SI COOH (C18): 10 NzN OH

COCH

WO 01/34135 PCT/USOO/30944 -46 (C19) .S-N OH Nl COOH 5 (C2 0) N-N OH COOH (C2 1) OH COOH 10 (C22): ~NOH 0 0'N- O'p

COOH

WO 01/34135 PCT/USOO/30944 -47 (C23) OH S COOH and all acid, salt, solvate and prodrug derivatives thereof. 5 III S. Highly Preferred LTB 4 Antagonists are as follows: S OH O O-1 OP COOH 0 OH O O O COONa 10 COOH 15 WO 01/34135 PCT/USOO/30944 -48 ,N- OH - - N 0 ' II I COOH / OH OH O O O1? COOH 5 OH 0 O ^O OP COOH 10 and all acid, salt, solvate and prodrug derivatives thereof. The salts of the above diphenyl LTB 4 antagonists of the invention, represented by formulae (A), (I) and (II) and the specific compounds set out by structural formulae in 15 sections IIIR and IIIS herein, are an additional aspect of the invention. The compounds of the invention possess an Acidic Group(s) and at these sites various salts may be formed which are more water soluble and/or physiologically suitable than the parent compound in its acid form.

WO 01/34135 PCT/USOO/30944 -49 Representative pharmaceutically acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Sodium salts are particularly 5 preferred. Salts are conveniently prepared from the free acid by treating the acid form in solution with a base or by exposing the acid to an ion exchange resin. For example, the (Acidic Group) of the Z of Formula (I) may be selected as -CO 2 H and salts may be formed by reaction with 10 appropriate bases (e.g., NaOH, KOH) to yield the corresponding sodium or potassium salt. Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and 15 organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the LTB 4 antagonist compounds of this invention (see, for example, S. M. Berge, et al., 20 "Pharmaceutical Salts," J. Phar. Sci., 66: 1-19 (1977)). Certain compounds of the invention may possess one or more chiral centers and may thus exist in optically active forms. All such stereoisomers as well as the mixtures thereof are intended to be included in the invention. If a particular 25 stereoisomer is desired, it can be prepared by methods well known in the art, for example, by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively, by methods which lead to mixtures of the 30 stereoisomers and subsequent resolution by known methods. For example, a racemic mixture may be reacted with a single enantiomer of some other compound. This changes the racemic WO 01/34135 PCT/USOO/30944 -50 form into a mixture of diastereomers. Then, because the diastereomers have different melting points, different boiling points, and different solubilities, they can be separated by conventional means, such as crystallization. 5 Prodrugs are derivatives of the compounds of Formulae (A), (I) and (II), supra., which have chemically or metabolically cleavable groups and become by hydrolysis or under physiological conditions the compounds of the 10 invention which are pharmaceutically active in vivo. Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian 15 organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared 20 by reaction of the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl 25 esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularly WO 01/34135 PCT/USOO/30944 -51 preferred esters as prodrugs are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl, and N,N-diethylglycolamido. Esters of carboxylic acids are preferred prodrugs of 5 the compounds of the invention (viz., the compounds of Formula A, Formula I, Formula II and the specific compounds set out in Section IIIR and IIIS, herein). Methyl ester prodrugs may be prepared by reaction of the acid form of a compound of formula (I) in a medium such 10 as methanol with an acid or base esterification catalyst (e.g., NaOH, H 2

SO

4 ). Ethyl ester prodrugs are prepared in similar fashion using ethanol in place of methanol. N,N-diethylglycolamido ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) 15 (in a medium such as dimethylformamide) with 2-chloro-N,N diethylacetamide (available from Aldrich Chemical Co., Milwaukee, Wisconsin USA; Item No. 25,099-6). Morpholinylethyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in 20 a medium such as dimethylformamide) 4-(2 chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wisconsin USA, Item No. C4,220-3). Preferred LTB 4 antagonists include compounds of Formula A, Formula (I), or Formula (II) or the specific compounds of 25 sections IIIR and IIIS shown above by structural formula; wherein the acid, salt and prodrug derivatives thereof are respectively selected from: carboxylic acid, sodium salt, and ester prodrug.

WO 01/34135 PCT/USOO/30944 -52 IV. Method of Making the Compounds of the Invention General reaction schemes (not represented to be specific Examples) applicable for synthesis of the LTB 4 antagonist compounds represented by formula (I) are set 5 out below. Numerous literature references and Chemical Abstract registry numbers (e.g., RN 152609-60-4) are supplied as additional aids for preparing reagents used in practicing the synthesis schemes of the invention. 10 REACTION SCHEMES FOR MAKING -THE COMPOUNDS OF THE INVENTION The following scheme illustrates a process for making Example 15 (1), a 4-substituted oxazole LTB 4 receptor antagonist: WO 01/34135 PCT/USOO/30944 -53 Scheme 1 O OH benzyl bromide, CS 2

CO

3 , DMF (26) known compound: RN# 156005-61-7 R. W. Harper et al., J. Med. Chem. 1994, 37(15), 2411 HO O (30) O 0 COOMe SO CI known compound: RN 152609-76-2 J. S. Sawyer et al., J. Med. Chem. 1995, 38, 4411 (28) K 2

CO

3 , Nal, 2-butanone 0 0 CF O O 3 O -- O O O' CF 3 COOMe TFA, H 2 0 CH 3 CN (32) 0 0 HO I1) Tf 2 O, 2,6-lutidine 0 O O 2) formamide COOMe (34) /N 0 0I

BF

3 Et 2 O, EtSH COOMe (36) WO 01/34135 PCT/USOO/30944 -54 N H I I 1) NaOH O O 0 2) HCI COOMe (38) / N H O ^ O OP COOH (1) Known chloride (26) may be alkylated with benzyl bromide to provide chloride (28). Reaction with known ester (30), 5 catalyzed by a suitable base, provides acetophenone (32). Oxidation with bis(trifluoroacetoxy)iodobenzene gives alpha hydroxy ketone (34), that may be cyclized with triflic anhydride and formamide to give the 4-substituted oxazole (36). Debenzylation with boron trifluoride etherate and 10 ethanethiol gives oxazole (38), that is hydrolyzed and protonated to provide Example (1). Scheme 2 The following scheme illustrates a process for making Example 15 (2), a 5(4)-substituted imidazole LTB 4 receptor antagonist: WO 01/34135 PCT/USOO/30944 -55 Scheme 2 O O 1) LiHMDS, TMSCI, THF O O 2) NCS COOMe 3) TBAF (32) o o~ NH CI: H2N SBn O O O K 2

CO

3 , Nat, DMF COOMe (40) S H 0N I - BF3-Et2O, EtSH COOMe (42) N OH 1) LiOH, MeOH O O OCOOe 2) Raney Ni, EtOH, NaOH COOMe 3) HOI (44) .H NN OH -H C I O O O COOH (2) WO 01/34135 PCT/USOO/30944 -56 The trimethylsilyl enol ether of acetophenone (32) is formed and treated with N-chlorosuccinimide followed by tetra-n butylammonium fluoride to provide the chloroketone (40). Treatment of (40) with 2-benzyl-2-thiopseudourea and base 5 provides imidazole (42), that is treated with boron trifluoride etherate and ethanethiol to give imidazole (44). Hydrolysis and protonation provide Example (2) as the hydrochloride salt. 10 Scheme 3 The following scheme illustrates a process for making Example (3), a 4-substituted thiazole LTB 4 receptor antagonist: WO 01/34135 PCT/USOO/30944 -57 Scheme 3 0 0 CI O O thioformamide, MgCO 3 O0O O dioxane COOMe (40) / N 0 S

BF

3 -Et 2 o, EtSH

-

COOMe (46) / N OH S - 1) LiOH, MeOH O O 2) HCI COOMe (48) /N OH 0 COOH (3) WO 01/34135 PCT/USOO/30944 -58 Chloroketone (40) is treated with thioformamide and magnesium carbonate to give thiazole (46), that is debenzylated with boron trifluoride etherate and ethanethiol giving thiazole (48). Hydrolysis and protonation provides 5 Example (3). Scheme 4 The following scheme illustrates a process for making Example 10 (4), a 5(3)-substituted pyrazole LTB 4 receptor antagonist: WO 01/34135 PCT/USOO/30944 -59 Scheme 4 OMe 0 0 Me 2 N-( OMe O O O DMF COOMe (32) 00 O Me 2 N 1) LiOH, MeOH 0O O 2) HCI COOMe 3) NH 2

NH

2

-H

2 0, MeOH (50) N-NH 0 I

BF

3 'Et 2 O, EtSH O O O COOH (52) N' NH OH COOH (4) WO 01/34135 PCT/USOO/30944 -60 Treatment of acetophenone (32) with N,N-dimethylformamide dimethyl acetal gives enone (50), that may be hydrolyzed, protonated, and then heated with hydrazine hydrate to provide pyrazole (52). Debenzylation of the resulting 5 pyrazole with boron trifluoride etherate and ethanethiol gives Example (4). Scheme 5 The following scheme illustrates a process for making Example (5), a 5-substituted isoxazole LTB 4 receptor antagonist: 10 WO 01/34135 PCT/USOO/30944 -61 Scheme 5 0 0 Me2N NH0HMeOHH20 0 0 O0 COOMe (50) N- N BF -Et 2 O, EtSH 302 (54)

N-

0 OH N 1)LiOH, MeOH -0 -'-> N N 2) HCI (56)

N-

0 OH CO0H (5) WO 01/34135 PCT/USOO/30944 -62 Treatment of enone (50) with hydroxylamine provides isoxazole (54), that is debenzylated with boron trifluoride etherate and ethanethiol to give isoxazole (56). Hydrolysis and protonation provides Example (5). 5 Scheme 6 The following scheme illustrates a process for making Example (6), a 5(4)-substituted 1,2,3-triazole LTB 4 receptor antagonist: 10 WO 01/34135 PCT/USOO/30944 -63 Scheme 6 Br O HO O K 2

CO

3 , KI, DMSO +CCOOMe 2-butanone (58) (30) known compounds: RN 152609-60-4 152609-76-2 J. S. Sawyer et al. J. Med. Chem. 1995, 38, 4411 Br, i1 I J04 1 - SnBu 3 O O O- Pd(PPh 3

)

4 , DMF COOMe (60) O TMSN 3 , toluene O , O OP COOMe (62) ,N-N' H O I XBF 3 Et 2 0, EtSH O -"O OP COOMe (64) ,N'N.H OH 1) LiOH, MeOH O O O 2) HCI COOMe (66) N OH COOH (6) WO 01/34135 PCT/USOO/30944 -64 Known phenol (30) is alkylated with known chloride (58) to give aryl bromide (60). Treatment of (60) with tri-n butylethynyltin and a palladium catalyst gives alkyne (62). Heating (62) with trimethylsilyl azide provides triazole 5 (64), that is debenzylated with boron trifluoride etherate and ethanethiol to give triazole (66). Hydrolysis and protonation provides Example (6). Scheme 7 10 The following scheme illustrates a process for making Example (7), a 1-substituted pyrrole LTB 4 receptor antagonist: WO 01/34135 PCT/USOO/30944 -65 Scheme 7 OH Nz 1) (KSO 3

)

2 NO, K 2

PO

4 , H2O N OH 2) 3-pyrroline, CH 3 CN OH 3) BnBr, K 2

CO

3 , DMF (68) (70) O\N 1) Nal, 2-butanone 1-bromo-3-chloropropane I O 2) Nal, un K2C03, DMF O C1 2) K2CO3, DMF (72) HO ON COOMe (30) N

BF

3 'Et 2 O, EtSH O O-- Op COOMe (74) z\O O O COOMe (7) References for formation of 1-aryl substituted pyrroles: M. Mure and J. P. Klinman, J. Am. Chem. Soc. 1995, 117(34), 8698; Y. Lee et al. J. Am. Chem. Soc. 1996, 118(30), 7241 WO 01/34135 PCT/USOO/30944 -66 4-Ethylbenzene-1,3-diol (68) is treated with potassium nitrosodisulfonate followed by 3-pyrroline and benzylbromide and a base to provide pyrrole (70). Alkylation with 1 bromo-3-chloropropane gives chloride (72), that is used to 5 alkylate phenol (30) to give pyrrole (74). Debenzylation with boron trifluoride etherate and ethanethiol provides Example (7). Scheme 8 10 The following scheme illustrates a process for making Example (8), a 5-substituted 1,2,4-thiadiazole LTB 4 receptor antagonist: 15 WO 01/34135 PCT/USOO/30944 -67 Scheme 8 H Br O B OO~ O PdCl 2 (dppf) COOMe (60) Br 0 0 N'kN OI O O C1 COOMe PdCl 2 (dppf), Cs 2

CO

3 , toluene (76) Br N O N \ 1) BF 3 ~Et 2 O, EtSH O - O 2) aq. NaOH COOMe 3) aq. HCI (78) Br N OH S ONO O COOH (8) WO 01/34135 PCT/USOO/30944 -68 The palladium-catalyzed addition of 4,4,5,5-tetramethyl [1,3,2]dioxaborolane to bromide (60) gives boronic ester (76). The palladium-catalyzed addition of 3-bromo-5-chloro 1,2,4-thiadiazole to (76) gives ester (78). Debenzylation 5 with boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation, gives Example (8). Scheme 9 The following scheme illustrates a process for making Example 10 (9), a 2-substituted thiophene LTB 4 receptor antagonist: WO 01/34135 PCT/USOO/30944 -69 Scheme 9 PdCl 2 (dppf), Cs 2 C0 3 , toluene O - O O COOMe 2) BF3-Et 2 O, EtSH (76) OH S O O O 1) aq. LiOH COOMe 2) NaOH (80) OH S NN O -,O OP COONa (9) WO 01/34135 PCT/USOO/30944 -70 The palladium-catalyzed addition of boronic ester (76) to 2 bromothiophene, followed by debenzylation with boron trifluoride etherate and ethanethiol, provides thiophene (80). Hydrolysis and salt formation provides Example (9). 5 Scheme 10 The following scheme illustrates a process for making Example (10), a 4-substituted pyrazole LTB 4 receptor antagonist: 10 15 WO 01/34135 PCT/USOO/30944 -71 Scheme 10 00 I N-N '-B -- N Known compound: RN 39806-90-1 COOMe PdCl 2 (dppf), Cs 2

CO

3 , toluene (76)

---

0 1) BF 3 -Et 2 O, EtSH O " O OP 2) aq. NaOH COOMe 3) aq. HCI (82) ,Ns OH --- NP | | COOH (10) 5 WO 01/34135 PCT/USOO/30944 -72 The palladium-catalyzed addition of boronic ester (76) to 1 methyl-4-iodopyrazole provides pyrazole (82). Debenzylation with boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation, provides Example (10). 5 Scheme 11 The following scheme illustrates a process for making Example (11), a 2-substituted thiazole LTB 4 receptor antagonist: 10 WO 01/34135 PCT/USOO/30944 -73 Scheme 11 o0c 0 N

-

4 Br COOMe PdCI 2 (dppf), CS 2

CO

3 , toluene (76) s NN BF 3 -Et 2 O, EtSH COOMe (84) s NN 1) aq.LiOH A' -" - A N 2) HCI COOMe (86) ~NOH

COOH

WO 01/34135 PCT/USOO/30944 -74 The palladium-catalyzed addition of boronic ester (76) to 2 bromothizaole provides thiazole (84). Debenzylation with boron trifluoride etherate and ethanethiol gives thiazole (86). Hydrolysis and protonation provides Example (11). 5 Scheme 12 The following scheme illustrates a process for making Example (12), a 4-substituted isoxazole LTB 4 receptor antagonist: 10 WO 01/34135 PCT/USOO/30944 -75 Scheme 12 1) N 0 0 PdCl2 (dppf), Cs 2 CO3 , toluene COOMe (76) 0 - 11) MesSil O - O OP 2) aq. HCI COOMe 3) NaOH (88) ,N OH 00 O ", O O COONa (12) 5 WO 01/34135 PCT/USOO/30944 -76 The palladium-catalyzed addition of boronic ester (76) to 3,5-dimethyl-4-iodoisoxazole provides oxazole (88). Debenzylation with trimethylsilyl iodide, followed by hydrolysis and salt formation, provides Example (12). 5 Scheme 13 The following scheme illustrates a process for making Example (13), a 2-substituted furan LTB 4 receptor antagonist: 10 WO 01/34135 PCT/USOO/30944 -77 Scheme 13 Br OBBrs, CH 2 Cl 2 COOMe (60) OH Br OO O TBSCI, imidazole COOMe (90) TBS Br

B(OH)

2 O O) OPd(PPh 3

)

4 , aq. Na 2

CO

3 , THF COOMe (92) OH 0 ~j 1) aq. LIOH

U

1 P 2) HOI COOMe 3) NaOH (94) S OH 00 COONa (13) WO 01/34135 PCT/USOO/30944 -78 Debenzylation of bromide (60) with boron tribromide provides phenol (90), that is treated with tert-butyldimethylsilyl chloride and imidazole to give silyl ether (92). The palladium-catalyzed addition of (92) to furan-2-boronic acid 5 provides furan (94). Hydrolysis and salt formation gives Example (13). Scheme 14 The following scheme illustrates a process for making Example 10 (14), a 3-substituted furan LTB 4 receptor antagonist: WO 01/34135 PCT/USOO/30944 -79- Scheme 14 TBSO Br I

B(OH)

2 0 Pd(PPh 3

)

4 , aq. Na 2

CO

3 , THF COOMe (92) OH -P N1) aq. LiOH COOMe 2) HOI 3) NaOH (96) OH O * O O COONa (14) The palladium-catalyzed addition of (92) to furan-3-boronic acid provides furan (96). Hydrolysis and salt formation gives Example (14). 5 10 WO 01/34135 PCT/USOO/30944 -80 Scheme 15 The following scheme illustrates a process for making Example (15), a 3-substituted tetrahydrofuran LTB 4 receptor antagonist: WO 01/34135 PCT/USOO/30944 -81 Scheme 15 O O

B(OH)

2 Br0 O O O Pd(PPhs) 4 , aq. Na 2

CO

3 , THF COOMe (60) 00 0 O O O> O

H

2 , Pd(C) COOMe (98) OH 0 1) aq. LiOH O 0 O 2) HCI COOMe 3) NaOH (100) OH 0 O - O OP COONa (15) WO 01/34135 PCT/USOO/30944 -82 The palladium-catalyzed addition of bromide (60) to furan-3 boronic acid provides furan (98). Hydrogenation over a palladium catalyst gives tetrahydrofuran (100). Hydrolysis and salt formation gives Example (15). 5 Scheme 16 The following scheme illustrates a process for making Example (16), a 2-substituted pyrrolidine LTB 4 receptor antagonist: 10 WO 01/34135 PCT/USOO/30944 -83 Scheme 16 O jO B(OH) 2 Br 0 o . c Pd(PPh 3

)

4 , aq. Na 2

CO

3 , THF COOMe (60) 0 NOI

H

2 , Pd(C) (102) OH O _ o D e aq. LiOH COOMe (104) OH O Neoo O HCI 40- O O O OHP COOLi (106) OH N CI Oi C HN OOOH (16) WO 01/34135 PCT/USOO/30944 -84 The palladium-catalyzed addition of bromide (60) to N-boc pyrrole-2-boronic acid provides pyrrole (102). Hydrogenation over a palladium catalyst gives pyrrolidine (104). Hydrolysis and salt formation gives pyrrolidine (106). 5 Treatment with hydrochloric acid provides Example (16) as the hydrochloride salt. Scheme 17 The following scheme illustrates a process for making Example 10 (17), a 3-substituted thiophene LTB 4 receptor antagonist: WO 01/34135 PCT/USOO/30944 -85 Scheme 17 N S Br O

B(OH)

2 O SO COI Pd(PPh 3

)

4 , aq. Na 2

CO

3 , THF O C (58) (108) HO O CN (110) known compound: RN# 152609-78-4 0 O J. S. Sawyer et al., J. Med. Chem. 1995, 38, 4411 C , -- I

K

2 CO, KI, DMSO, 2-butanone O 0 CN (112) OH BBra, CH 2 Cl 2 N 1 1) NaOH O- O'- O < 2) HCI CN (114) OH -~O N COOH (17) WO 01/34135 PCT/USOO/30944 -86 The palladium-catalyzed addition of bromide (58) to thiophene-3-boronic acid provides thiophene (108). Alkylation of known phenol (110) with (108) catalyzed by 5 base provides thiophene (112). Debenzylation with boron tribromide gives thiophene (114). Hydrolysis and protonation provide Example (17). Scheme 18 10 The following scheme illustrates a process for making Example (18), a 5-substituted 1,2,3,4-thiatriazole LTB 4 receptor antagonist: WO 01/34135 PCT/USOO/30944 -87 Scheme 18 1-bromo-3-chloropropane | 1) K 2 C0 3 , Nal, 2-butanone HO O I C1_ __O O_ _ COOMe K 2

CO

3 , DMF COOMe 0 OH H N (30) (116) /1 O known compound: OH RN 37470-83-0 (118) 2) Cs 2 CO., BnBr, DMF 0 1) HS.SH H TsOH 00 q U ) 2) NaH, DMF, HMPA COOMe 3) piperidine (120) K> CI S O -1 1) Cl COOMe 2) NaN 3 (122) N-N O S 1) BF.-Et 2 O, CH 2 Cl 2 O O O 2) aq. NaOH COOMe 3) aq. HCI (124) ,,N-N OH N. I S O - O OP COOH (18) Reference for formation of dithioacids: N. C. Gonnella et al. Syn. Commun. 1979, 17 Reference for formation of 5-substituted 1,2,3,4-thiatriazoles from dithioacids: S. 1. Ikeda et al., Synthesis 1990, 415 WO 01/34135 PCT/USOO/30944 -88 Phenol (30) is alkylated with 1-bromo-3-chloropropane to give chloride (116), that is in turn to be treated with known aldehyde (118) and a base, followed by benzylation with benzyl bromide and a base, to provide aldehyde (120). 5 From aldehyde (120) is made the thioacetal by treatment with 1,2-ethanedithiol. The resulting thioacetal is then to be treated with base to provide the thioacid. Treatment with piperidine makes piperidinium salt (122). By the teaching of Ikeda, infra, (the disclosure of which is incorporated 10 herein by reference) treatment of (122) with 2 chloropyridinium methyl iodide followed by azide ion will give the 1,2,3,4-thiatriazole (124). Debenzylation with boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation, will provide the product of 15 Example (18). Scheme 19 The following scheme illustrates a process for making Example (19), a 4-substituted 1,2,3-thiadiazole LTB 4 receptor 20 antagonist: WO 01/34135 PCT/USOO/30944 -89 Scheme 19 0 O NH2NHCOOEt O '- O OP COOMe (32) EtO N'N O 00 O SOC12 O O OP COOMe (128) NzzN 0 N N NO 1) BF 3 Et 2 0, EtSH O O N 2) aq. NaOH COOMe 3) aq. HCI (130) N:N OH COOH (19) Reference for 1,2,3-thiadiazole formation: E. W. Thomas et al., J. Med. Chem. 1985, 28, 442.

WO 01/34135 PCT/USOO/30944 -90 Treatment of acetophenone (32) with ethyl carbazate will give the hydrazone (128). Use of thionyl chloride by the method of Thomas et. al. (infra., the disclosure of which is incorporated herein by reference) will give an intermediate 5 1,2,3-thiadiazole (130), that is to be debenzylated with boron trifluoride etherate and ethanethiol, then hydrolyzed and protonated to give the product of Example (19). Scheme 20 10 The following scheme illustrates a process for making Example (20), a 3-substituted 1,2,5-thiadiazole LTB 4 receptor antagonist: 15 WO 01/34135 PCT/USOO/30944 -91 Scheme 20 CI O CI' N II I CI" SN CI OO- O- (trithiazyl trichloride) COOMe (62) ,S'N 0 N 1) BF 3 Et 2 O, EtSH O -- O O 2) aq. NaOH COOMe 3) aq. HCI (132) ,S-N OH N\ I O - O OP COOH (20) Reference for 1,2,5-thiadiazole formation: E. W. Thomas et al., J. Med. Chem. 1985, 28, 442. Alkyne (62) is to be treated with trithiazyl trichloride by the method of Thomas et. al. (infra., the disclosure of 5 which is incorporated herein by reference) to provide thiadiazole (132). Debenzylation with boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation, will provide the product of Example (20).

WO 01/34135 PCT/USOO/30944 -92 Scheme 21 The following scheme illustrates a process for making Example (21), a 2-substituted 1,3,4-thiadiazole LTB 4 receptor 5 antagonist: Scheme 21 N N 'N S41 O O z Br known compound: RN 61929-24-6 O' PCT WO 9730981 O O OPdCl 2 (dppf), Cs 2 C0 3 , toluene COOMe (76) N-N 0 S 1) BF 3 Et 2 O, EtSH o O O- 2) aq. NaOH COOMe 3) aq. HCI (134) N-N OH S 0 N I " N COOH (21) WO 01/34135 PCT/USOO/30944 -93 The palladium-catalyzed addition of boronic ester (76) to 2 bromo-1,3,4-thiadiazole will provide ester (134). Debenzylation with boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation, will 5 provide the product of Example (21).

WO 01/34135 PCT/USOO/30944 -94 Scheme 22 The following scheme illustrates a process for making Example (22), a 5-substituted isothiazole LTB 4 receptor antagonist: Scheme 22 S

B(OH)

2 Br known compound: RN 216971-00-5 PCT WO 9855480 Pd(PPh 3

)

4 , Na 2

CO

3 , EtOH, H 2 0 (58) HO O N. S OCOOMe (30) O CI

K

2

CO

3 , KI, DMSO, (136) N 0 S 1) BF 3 Et20, EtSH O O O 2) aq. NaOH COOMe 3) aq. HCI (138) N IOH S N. O 0--'o O N COOH (22) 5 WO 01/34135 PCT/USOO/30944 -95 The palladium-catalyzed addition of bromide (58) to 3 methylisothiazole-5-boronic acid will provide isothiazole (136). Alkylation of phenol (30) with (136) catalyzed by base will provide isothiazole (138). Debenzylation with 5 boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation, will provide the product of Example (22).

WO 01/34135 PCT/USOO/30944 -96 Scheme 23 The following scheme illustrates a process for making Example (23), a 2-substituted oxazole LTB 4 receptor antagonist: Scheme 23 N Br O O known compound: RN 125533-82-6 R. D. Miller et al., Chem. Mater. 1994, O' N 6(7), 1023. O O 0O PdCl 2 (dppf), Cs 2 C0 3 , toluene COOMe (76) 0 1) BF 3 -Et 2 O, EtSH S0-'-O O 2) aq. NaOH COOMe 3) aq. HCI (140) N OH 00 O0O O -- O OP COOH (23) 5 WO 01/34135 PCT/USOO/30944 -97 The palladium-catalyzed addition of boronic ester (76) to 2 bromooxazole will provide oxazole (140). Debenzylation with boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation, will provide the product of 5 Example (23). Scheme 24 The following scheme illustrates a process for making Example (24), a 3-substituted thiophane LTB 4 receptor antagonist: 10 WO 01/34135 PCT/USOO/30944 -98 Scheme 24 -- OH S 0 N Et 3 SiH, TFA, benzene CN (114) OH S N I 1) aq. NaOH O O O 2) HCI CN (142) OH S I | COOH (24) Reference for formation of tetrahydrothiophenes: D. N. Kursanov et al. Tetrahedron 1975, 31, 311 Thiophene (114) may be reduced in the presence of triethylsilane and trifluoroacetic acid by the method of 5 Kursanov et. al. (infra., the disclosure of which is incorporated herein by reference) to provide the thiophane (142). Hydrolysis and protonation will provide the product of Example (24). 10 WO 01/34135 PCT/USOO/30944 -99 V. PREPARATIVE EXAMPLES 1 TO 17: 5 Example 1 Preparation of 2-(3- [3- (2-Ethyl-5-hydroxy-4-oxazol-4-yl phenoxy)propoxy] -2-propyl-phenoxy}benzoic acid. 0 H0 0- - C 10 known compound: RN# 156005-61-7 R. W. Harper et al., J. Med. Chem. 1994, 37(15), 2411-20 15 A. Preparation of 1- [2-benzyloxy-4- (3-chloropropoxy) -5 ethylphenyl] ethanone. A mixture of 1- [2-hydroxy-4- (3-chloropropoxy) -5 ethylphenyl]ethanone (26.1 g, 102 mmol), cesium carbonate (33.4 g, 103 mmol), and benzyl bromide (12.2 ml, 103 mmol), 20 in N,N-dimethylformamide (300 mL) was stirred for 5 h at room temperature. The mixture was diluted with ethyl acetate and washed four times with water. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo. The resulting oil was triturated with ethyl acetate 25 and hexane, allowed to stand for 18 h, then cooled at 0 OC for 3 h. The resulting precipitate was collected via vacuum filtration to provide 24.3 g (69%) of the title compound as white crystals: mp 60-61 OC. H NMR (CDCl 3 ) 8 7.68 (s, WO 01/34135 PCT/USOO/30944 -100 1H), 7.40 (m, 5H), 6.48 (s, 1H), 5.17 (s, 2H), 4.13 (t, J = 6 Hz, 2H), 3.75 (t, J = 6 Hz, 2H), 2.56 (s, 3H), 2.55 (q, J = 7 Hz, 2H), 2.26 (quintet, J = 6 Hz, 2H), 1.16 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated for 5 C 20

H

24 C10 3 (p+1): m/z = 347.1414. Found: 347.1402; IR (CHCl 3 ' -1 cm ) 1659, 1602, 1266. Anal. Calcd for C 2 0

H

2 3 ClO 3 : C, 69.26; H, 6.68. Found: C, 69.30; H, 6.52. 10 0 0 + HO 0~ -CI COOMe known compound: RN# 152609-76-2 J. S. Sawyer et al., J. Med. Chem. 1995, 38,4411 O O -- O O COOMe B. Preparation of 2-(3-[3-(4-acetyl-5-benzyloxy-2 ethylphenoxy) propoxy] -2-propyl-phenoxy}benzoic acid methyl 15 ester. A mixture of 1- [2-benzyloxy-4- (3-chloropropoxy) -5 ethylphenyl]ethanone (7.27 g, 21.0 mmol) and sodium iodide (3.14 g, 23.1 mmol) in 2-butanone (100 mL) was heated at reflux for 18 h. The mixture was cooled to room WO 01/34135 PCT/USOO/30944 -101 temperature, filtered, and concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (100 mL) and treated with 2-(3-hydroxy-2-propylphenoxy)benzoic acid methyl ester (6.0 g, 21 mmol) and potassium carbonate (3.2 5 g, 23 mmol) at room temperature for 15 h. The mixture was diluted with ethyl acetate and washed four times with water and once with saturated sodium chloride solution. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% 10 ethyl acetate/90% hexane) of the residue provided 9.2 g 1 (72%) of the title compound as a colorless oil. H NMR (CDCl 3 ) 8 7.88 (d, J = 9 Hz, 1H), 7.69 (s, 1H), 7.38 (m, 6H), 7.12 (d, J = 8 Hz, 1H), 7.07 (d, J = 8 Hz, 1H), 6.80 (d, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H), 6.50 (s, 1H), 15 6.44 (d, J = 9 Hz, 1H), 5.14 (s, 2H), 4.20 (m, 4H), 3.83 (s, 3H), 2.65 (t, J = 7 Hz, 2H), 2.57 (q, J = 7 Hz, 2H), 2.56 (s, 3H), 2.32 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 7 Hz, 2H), 1.15 (t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); IR -1 (CHCl 3 , cm ) 2965, 1726, 1602, 1461. 20 Anal. Calcd for C 37

H

4 0 0 7 : C, 74.48; H, 6.76. Found: C, 74.39; H, 6.77.

WO 01/34135 PCT/USOO/30944 -102 00 I |P COOMe O HO COOMe C. Preparation of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(2 hydroxyacetyl) phenoxy] propoxy) -2-propylphenoxy) benzoic acid 5 methyl ester. A mixture of 2-{3-[3-(4-acetyl-5-benzyloxy-2 ethylphenoxy) propoxy] -2-propyl-phenoxy}benzoic acid methyl ester (5.31 g, 8.89 mmol) and water (10 mL) in acetonitrile (50 mL) was treated with trifluoroacetic acid (1.4 mL), 18 10 mmol) and [bis(trifluoroacetoxy)iodo]benzene (7.65 g, 17.8 mmol) . The resulting mixture was heated at reflux for 4 h then concentrated in vacuo. The residue was dissolved in methylene chloride and washed once with water. The aqueous layer was extracted twice with fresh portions of methylene 15 chloride. The combined organic layers were washed three times with saturated sodium bicarbonate solution, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 20% ethyl acetate/80% hexane) of the residue provided 1 20 1.68 g (31%) of the title compound as a brown oil. H NMR (CDCl 3 ) 6 7.92 (s, 1H), 7.88 (d, J = 9 Hz, 1H), 7.40 (m, WO 01/34135 PCT/USOO/30944 -103 6H), 7.12 (d, J = 9 Hz, 1H), 7.05 (d, J = 9 Hz, 1H), 6.79 (d, J = 8 Hz, 1H), 6.66 (d, J = 8 Hz, 1H), 6.50 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 5.15 (s, 2H), 4.65 (s, 2H), 4.22 (m, 4H), 3.83 (s, 3H), 2.65 (m, 4H), 2.34 (quintet, J = 6 Hz, 5 2H), 1.55 (hextet, J = 7 Hz, 2H), 1.17 (t, J = 8 Hz, 3H), 0.89 (t, J = 8 Hz, 3H); TOS MS ES exact mass calculated for C 37

H

41 0 8 (p+1): m/z = 613.2801. Found: 613.2833. 0 HO 0 COOMe / N 0:00 COOMe 10 D. Preparation of 2-(3- [3- (5-benzyloxy-2-ethyl-4-oxazol-4 yl-phenoxy) propoxy] -2-propylphenoxy)benzoic acid methyl ester. To a solution of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(2 15 hydroxyacetyl) phenoxy]propoxy} -2-propylphenoxy)benzoic acid methyl ester (1.39 g, 2.27 mmol) in methylene chloride (20 mL) cooled to -78 0 C was added triflic anhydride (0.57 mL, 3.4 mmol) and 2,6-lutidine (0.40 mL, 3.4 mmol). The resulting mixture was stirred for 1 h then poured into ether 20 and water. The organic layer was separated and washed once with saturated sodium chloride solution, dried (sodium WO 01/34135 PCT/USOO/30944 -104 sulfate), filtered, and concentrated in vacuo. The residue was dissolved in a 2:1 mixture of formamide/N,N dimethylformamide (9 mL) and heated at 120 oC in a sealed tube for 4 h. The mixture was cooled to room temperature 5 and diluted with ethyl acetate. The mixture was washed four times with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 89 mg (6%) of the title 10 product as a colorless oil. H NMR (CDCl 3 ) 6 7.92 (s, 1H), 7.85 (s, 1H), 7.83 (m, 2H), 7.35 (m, 6H), 7.03 (d, J = 8 Hz, 1H), 7.00 (d, J = 8 Hz, 1H), 6.73 (d, J = 8 Hz, 1H), 6.62 (d, J = 8 Hz, 1H), 6.52 (s, 1H), 6.35 (d, J = 8 Hz, 1H), 5.07 (s, 2H), 4.14 (m, 4H), 3.76 (s, 3H), 2.61 (m, 4H), 2.26 15 (quintet, J = 6 Hz, 2H), 1.48 (hextet, J = 7 Hz, 2H), 1.15 (t, J = 8 Hz, 3H), 0.84 (t, J = 8 Hz, 3H). /N 0 0 OP COOMe N H COOMe WO 01/34135 PCT/USOO/30944 -105 E. Preparation of 2-(3-[3-(2-ethyl-5-hydroxy-4-oxazol-4-yl phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester. To a solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-oxazol-4-yl phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester 5 (89 mg, 0.14 mmol) in ethanethiol (2 mL) was treated with boron trifluoride etherate (0.27 mL, 2.2 mmol) at room temperature for 4 h. The solution was poured into ether and washed once with water, once with saturated sodium bicarbonate solution, once with saturated sodium chloride 10 solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 15% ethyl acetate/85% hexane) of the residue provided 34 mg (45%) of the title product as a light brown oil. H NMR (CDCl 3 ) 6 7.99 (d, J 1 Hz, 1H), 7.90 (d, J = 1 Hz, 1H), 7.88 (dd, J = 8, 2 Hz, 15 1H), 7.38 (t, J = 7 Hz, 1H), 7.15 (s, 1H), 7.10 (d, J = 9 Hz, 1H), 7.06 (d, J = 9 Hz, 1H), 6.81 (d, J = 9 Hz, 1H), 6.70 (d, J = 9 Hz, 1H), 6.52 (s, 1H), 6.44 (d, J = 9 Hz, 1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.65 (t, J = 8 Hz, 2H), 2.58 (q, J = 8 Hz, 2H), 2.33 (quintet, J = 6 Hz, 2H), 1.55 20 (hextet, J = 7 Hz, 2H), 1.17 (t, J = 8 Hz, 3H), 0.91 (t, J = 8 Hz, 3H); MS ES+ m/e = 532 (p + 1).

WO 01/34135 PCT/USOO/30944 -106 N H 00 COOMe N H 0 0 0 COOH F. Preparation of 2-(3-[3-(2-ethyl-5-hydroxy-4-oxazol-4-yl phenoxy)propoxy]-2-propylphenoxy}benzoic acid. 5 To a solution of 2-{3-[3-(2-ethyl-5-hydroxy-4-oxazol-4-yl phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester (89 mg, 0.14 mmol) in methanol (2 mL) was added 1 M lithium hydroxide solution (0.28 mL) and the resulting mixture warmed at 60 OC for 3.5 h. The mixture was cooled to room 10 temperature and concentrated in vacuo. The aqueous residue was diluted with water and the pH adjusted to -4. The mixture was extracted three times with methylene chloride. The combined organic extracts were dried (sodium sulfate), filtered, and concentrated in vacuo to provide 27 mg (92%) 1 15 of the title compound as a yellow solid. H NMR (DMSO-d 6 ) 6 12.83 (bs, 1H), 10.12 (bs, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 7.78 (dd, J = 8, 1 Hz, 1H), 7.64 (s, 1H), 7.47 (t, J = 8 Hz, 1H), 7.16 (m, 2H), 6.80 (t, J = 8 Hz, 2H), 6.56 (s, 1H), 6.35 (d, J = 8 Hz, 1H), 4.20 (t, J = 6 Hz, 2H), 4.12 20 (t, J = 6 Hz, 2H); 2.54 (m, 4H), 2.24 (quintet, J = 6 Hz, 2H), 1.43 (hextet, J = 8 Hz, 2H), 1.10 (t, J = 8 Hz, 3H), WO 01/34135 PCT/USOO/30944 -107 0.80 (t, J = 8 Hz, 3H); TOF MS ES exact mass calculated for C 30

H

32

NO

7 (p+1): m/z = 518.2179. Found: 518.2206; IR -1 (KBr, cm ) 2961, 1696, 1460, 1222. Anal. Calcd for C 3 0

H

3 1

NO

7 : C, 69.62; H, 6.04; N, 2.71. 5 Found: C, 68.71; H, 5.82; N, 2.65. Example 2 Preparation of 2- (3-(3- [2-Ethyl-5-hydroxy-4- (3H-imidazol-4 10 yl) phenoxy] propoxy) -2-propyl-phenoxy) benzoic acid hydrochloride. 0 COOMe 00 COOMe 15 A. Preparation of 2- (3-{3- [5-benzyloxy-4- (2-chloroacetyl) 2-ethylphenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester. To a solution of 2-{3- [3- (4-acetyl-5-benzyloxy-2 ethylphenoxy) propoxy] -2-propyl-phenoxy}benzoic acid methyl 20 ester (3.04 g, 5.09 mmol) in tetrahydrofuran (50 mL) cooled WO 01/34135 PCT/USOO/30944 -108 to -78 0 C was added a solution of 1 M lithium hexamethyldisilazide in tetrahydrofuran (11.2 mL, 11.2 mmol) portion wise. After stirring for 20 min, trimethylsilyl chloride (2.6 mL, 20 mmol) was added and the mixture warmed 5 to 0 OC and stirred for 30 min. The mixture was evaporated in vacuo and the residue dissolved in hexane. The resulting solution was filtered and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (50 mL), cooled to 0 OC, and treated with N-chlorosuccinimide (750 mg, 5.6 10 mmol). The mixture was warmed to room temperature and stirred for 30 min, then heated at reflux for 2 h. The mixture was cooled to room temperature and treated with water (4 mL) and a solution of 1 N tetra-n-butylammonium fluoride in tetrahydrofuran (6 mL). After stirring for 15 15 min the mixture was diluted in ether and washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 1.94 g (60%) of the title compound as a 20 white solid. H NMR (CDCl 3 ) 6 7.89 (d, J = 8 Hz, 1H), 7.77 (s, 1H), 7.40 (m, 6H), 7.12 (d, J = 9 Hz, 1H), 7.06 (d, J = 8 Hz, 1H), 6.80 (d, J = 8 Hz, 1H), 6.66 (d, J = 8 Hz, 1H), 6.49 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 5.15 (s, 2H), 4.68 (s, 2H), 4.20 (q, J = 6 Hz, 4H), 3.82 (s, 3H), 2.65 (t, J = 7 25 Hz, 2H), 2.59 (q, J = 7 Hz, 2H), 2.32 (quintet, J = 6 Hz, 2H), 1.54 (hextet, J = 8 Hz, 2H), 1.16 (t, J = 8 Hz, 3H), 0.89 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated for C 37

H

4 0 C10 7 (p+1): m/z = 631.2463. Found: 631.2470; IR -1 (CHCl 3 , cm ) 2964, 1720, 1603, 1461.

WO 01/34135 PCT/USOO/30944 -109 Anal. Calcd for C 37

H

39 C10 7 : C, 70.41; H, 6.23. Found: C, 70.04; H, 5.97.

O

CI COOMe S N , N 0 0 0 COOMe 5 B. Preparation of 2-(3-(3-[5-benzyloxy-4-(2-benzylsulfanyl 3H-imidazol-4-yl) -2-ethyl-phenoxy] propoxy) -2 propylphenoxy)benzoic acid methyl ester. A mixture of 2-(3-{3-[5-benzyloxy-4-(2-chloroacetyl)-2 10 ethylphenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester (800 mg, 1.27 mmol), 2-benzyl-2-thiopseudourea hydrochloride (313 mg, 1.52 mmol), sodium iodide (77 mg, 0.51 mmol), and potassium carbonate (700 mg, 5.06 mmol) in N,N-dimethylformamide (20 mL) was treated at 80 OC for 6 h. 15 The mixture was cooled, diluted with diethyl ether, and washed once with water. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 30% ethyl acetate/70% hexane) of the residue provided 376 mg (40%) of the title compound as a WO 01/34135 PCT/USOO/30944 -110 yellow amorphous solid. H NMR (CDCl 3 ) 8 7.89 (d, J = 8 Hz, 1H), 7.36 (m, 9H), 7.20 (m, 5H), 7.21 (d, J = 9 Hz, 1H), 7.06 (d, J = 8 Hz, 1H), 6.79 (d, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H), 6.55 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 5.07 (s, 5 2H), 4.21 (t, J = 6 Hz, 2H), 4.18 (t, J = 6 Hz, 2H), 4.10 (s, 2H), 3.83 (s, 3H), 2.63 (m, 4H), 2.31 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 7 Hz, 2H), 1.18 (t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated for C 45

H

47

N

2 0 6 S (p+1): m/z = 743.3155. Found: -1 10 743.3142; IR (CHCl 3 , cm ) 2963, 1720, 1602, 1453. Anal. Calcd for C 45

H

46

N

2 0 6 S: C, 72.75; H, 6.24; N, 3.77. Found: C, 72.69; H, 6.17; N, 3.56. S N COOMe S N.H H N 0 CO COOMe WO 01/34135 PCT/USOO/30944 -111 C. Preparation of 2-(3-(3-[4-(2-benzylsulfanyl-3H-imidazol 4-yl) -2-ethyl-5-hydroxyphenoxy]propoxy) -2 propylphenoxy)benzoic acid methyl ester. 5 A solution of 2-(3-{3-[5-benzyloxy-4-(2-benzylsulfanyl-3H imidazol-4-yl)-2-ethyl-phenoxy]propoxy}-2 propylphenoxy)benzoic acid methyl ester (360 mg, 0.49 mmol) in ethanethiol (7 mL) was treated with boron trifluoride etherate at room temperature for 3.5 h. The mixture was 10 diluted with diethyl ether and water. The organic layer was separated and washed with saturated sodium bicarbonate solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 20% ethyl acetate/80% hexane) of the residue provided 154 mg (48%) of the title 15 compound as an orange oil. H NMR (CDC1 3 ) 8 7.85 (d, J = 8 Hz, 1H), 7.36 (t, J = 7 Hz, 1H), 7.20 (m, 7H), 7.12 (s, 1H), 7.05 (m, 3H), 6.79 (d, J = 8 Hz, 1H), 6.65 (d, J = 8 Hz, 1H), 6.54 (s, 1H), 6.41 (d, J = 8 Hz, 1H), 4.20 (s, 2H), 4.17 (m, 4H), 3.82 (s, 3H), 2.62 (t, J = 8 Hz, 2H), 2.54 (q, 20 J = 7 Hz, 2H), 2.30 (quintet, J = 6 Hz, 2H), 1.53 (hextet, J = 8 Hz, 2H), 1.14 (t, J = 7 Hz, 3H), 0.89 (t, J = 8 Hz, 3H); TOF MS ES exact mass calculated for C 38

H

41

N

2 0 6 S (p+1): m/z = 653.2685. Found: 653.2669. Anal. Calcd for C 38

H

40

N

2 0 6 S: C, 69.92; H, 6.18; N, 4.29. 25 Found: C, 69.44; H, 6.25; N, 3.99.

WO 01/34135 PCT/USOO/30944 -112 S N, NH H ~N H I~ II O " O O COOMe N H N. O O"""0 O COOH D. Preparation of 2- (3-(3- [2-ethyl-5-hydroxy-4- (3H imidazol-4-yl) phenoxy] propoxy) -2-propyl-phenoxy) benzoic acid 5 hydrochloride. A solution of 2-(3-{3-[4-(2-benzylsulfanyl-3H-imidazol-4 yl) -2-ethyl-5-hydroxyphenoxy]propoxy} -2 propylphenoxy)benzoic acid methyl ester (154 mg, 0.235 mmol) in methanol (3 mL) was treated with 1 N lithium hydroxide 10 solution at 60 OC for 3.5 h. The mixture was cooled to room temperature and concentrated in vacuo. The solution was diluted with water and adjusted to pH 4. The aqueous solution was extracted three times with methylene chloride. The combined organic layers were dried (sodium sulfate), 15 filtered, and concentrated in vacuo. The residue was dissolved in ethanol (3 mL) and treated with 0.2 N sodium hydroxide solution (1 mL) and Raney nickel (75 mg) at 75 OC for 4 h. The mixture was cooled to room temperature, WO 01/34135 PCT/USOO/30944 -113 TM filtered through Celite , and the filtrate concentrated in vacuo. The residue was diluted with water and adjusted to pH 2 with 1 N hydrochloric acid. The resulting precipitate was collected via vacuum filtration to provide 27 mg (21%) 5 of the title compound. TOF MS ES exact mass calculated for C 30

H

33

N

2 0 6 (p+1): m/z = 517.2339. Found: 517.2340. Example 3 Preparation of 2-(3- [3- (2-Ethyl-5-hydroxy-4-thiazol-4-yl 10 phenoxy)propoxy]-2-propyl-phenoxy}benzoic acid. 0

O

CI COOMe N 0 0 COOMe A. Preparation of 2-(3- [3- (5-benzyloxy-2-ethyl-4-thiazol-4 yl-phenoxy) propoxy] -2-propylphenoxy)benzoic acid methyl 15 ester. A mixture of 2-(3-{3-[5-benzyloxy-4-(2-chloroacetyl)-2 ethylphenoxy]propoxy}--2-propylphenoxy)benzoic acid methyl ester (500 mg, 0.792 mmol), thioformamide (20 mL, 8.0 mmol), and magnesium carbonate in dioxane (10 mL) was heated at 20 reflux for 2 h. The mixture was cooled to room temperature WO 01/34135 PCT/USOO/30944 -114 and diluted with diethyl ether and 0.2 M sodium hydroxide solution. The organic layer was separated, washed with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica 5 gel, 10% ethyl acetate/90% hexane) of the residue provided 1 254 mg (50%) of the title compound as a colorless oil. H NMR (CDCl 3 ) 8 8.91 (s, 1H), 8.11 (s, 1H), 7.87 (dd, J = 8, 1 Hz, 1H), 7.84 (d, J = 1 Hz, 1H), 7.40 (m, 6H), 7.08 (m, 2H), 6.80 (d, J = 8 Hz, 1H), 6.68 (d, J = 8 Hz, 1H), 6.62 (s, 10 1H), 6.43 (d, J = 8 Hz, 1H), 5.16 (s, 2H), 4.21 (t, J = 6 Hz, 4H), 3.83 (s, 3H), 2.68 (m, 4H), 2.32 (quintet, J = 6 Hz, 2H), 1.56 (hextet, J = 8 Hz, 2H), 1.21 (t, J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated for C 38

H

40

NO

6 S (p+1): m/z = 638.2576. Found: -1 15 638.2579. IR (CHCl 3 , cm ) 2964, 1719, 1563, 1461. /- N S: COOMe N H COOMe WO 01/34135 PCT/USOO/30944 -115 B. Preparation of 2-(3-[3-(2-ethyl-5-hydroxy-4-thiazol-4 yl-phenoxy) propoxy] -2-propylphenoxy}benzoic acid methyl ester. A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-thiazol-4-yl 5 phenoxy)propoxy]-2-propyl-phenoxy}benzoic acid methyl ester (243 mg, 0.366 mmol) in ethanethiol (7 mL) was treated with boron trifluoride etherate at room temperature for 4 h. The mixture was diluted with diethyl ether, washed once with water, once with saturated sodium bicarbonate solution, 10 dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 15% ethyl acetate/85% hexane) of the residue provided 131 mg (65%) of the title compound as a colorless oil. H NMR (CDC1 3 ) 8 8.88 (d, J = 1 Hz, 1H), 7.88 (dd, J = 8, 1 Hz, 1H), 7.44 (d, J = 1 Hz, 1H), 7.38 (m, 15 2H), 7.08 (m, 2H), 6.81 (d, J = 8 Hz, 1H), 6.68 (d, J = 8 Hz, 1H), 6.55 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 4.21 (t, J = 6 Hz, 4H), 3.83 (s, 3H), 2.63 (m, 4H), 2.33 (quintet, J = 6 Hz, 2H), 1.56 (hextet, J = 8 Hz, 2H), 1.19 (t, J = 8 Hz, 3H), 0.91 (t, J = 7 Hz, 3H); TOF MS ES exact mass 20 calculated for C 3 1

H

34 NO6S (p+1): m/z = 548.2107. Found: 548.2085.

WO 01/34135 PCT/USOO/30944 -116 N H S I | O -- O

O

COOMe N H S II I COOH C. Preparation of 2-{3-[3-(2-ethyl-5-hydroxy-4-thiazol-4 yl-phenoxy) propoxy] -2-propylphenoxy}benzoic acid. 5 A solution of 2-{3- [3- (2-ethyl-5-hydroxy-4-thiazol-4-yl phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester (130 mg, 0.236 mmol) in methanol (4 mL) was treated with 1 M lithium hydroxide solution at 60 OC for 3 h. The mixture was cooled to room temperature, concentrated in vacuo, and 10 diluted with water. The solution was adjusted to pH -4 and extracted three times with methylene chloride. The combined organic layers were dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in a minimum of methylene chloride and hexane was added until the 15 solution became cloudy. The mixture was concentrated slowly 1 in vacuo to give 96 mg (76%) of the title compound. H NMR (CDCl 3 ) 6 8.90 (s, 1H), 8.23 (dd, J = 8, 1 Hz, 1H), 7.41 (m, 2H), 7.38 (s, 1H), 7.29 (m, 2H), 6.82 (d, J = 8 Hz, 1H), 6.71 (d, J = 8 Hz, 1H), 6.62 (d, J = 8 Hz, 1H), 6.54 (s, 20 1H), 4.25 (t, J = 6 Hz, 2H), 4.22 (t, J = 6 Hz, 2H), 2.59 WO 01/34135 PCT/USOO/30944 -117 (m, 4H), 2.35 (quintet, J = 6 Hz, 2H), 1.50 (hextet, J = 8 Hz, 2H), 1.19 (t, J = 7 Hz, 3H), 0.88 (t, J = 8 Hz, 3H); TOF MS ES exact mass calculated for C 30

H

32 NO6S (p+1): m/z -1 = 534.1950. Found: 534.1957. IR (CHC1 3 , cm ) 2965, 1738, 5 1454. Anal. Calcd for C 30

H

31 NO6S: C, 67.52; H, 5.86; N, 2.62. Found: C, 67.19; H, 5.72; N, 2.53. 10 Example 4 Preparation of 2- (3-(3- [2-Ethyl-5-hydroxy-4- (2H-pyrazol-3 yl) phenoxy] propoxy) -2-propyl-phenoxy) benzoic acid. 0 COOMe 0 N O O O COOMe 15 A. Preparation of 2-(3-(3-[5-benzyloxy-4-(3 dimethylaminoacryloyl) -2-ethyl-phenoxy] propoxy) -2 propylphenoxy)benzoic acid methyl ester. A mixture of 2-(3-{3-[4-acetyl-5-benzyloxy-2 ethylphenoxy]propoxy} -2-propylphenoxy) benzoic acid methyl 20 ester (3.07 g, 5.04 mmol) and dimethylformamide WO 01/34135 PCT/USOO/30944 -118 dimethylacetal (0.9 mL, 7 mmol) in N,N-dimethylformamide (3 mL) was heated at 110-120 0 C for 35 h. The mixture was cooled to room temperature and diluted with a mixture of ethyl acetate and 1 N hydrochloric acid. The organic layer 5 was separated, washed twice with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 30% ethyl acetate/70% hexane to ethyl acetate) of the residue provided 2.1 g (63%) of the title compound as a yellow oil. 10 TOF MS ES exact mass calculated for C 40

H

46

NO

7 (p+l): m/z -1 = 652.3274. Found: 652.3270. IR (CHCl 3 , cm ) 2965, 1720, 1605. Anal. Calcd for C 4 0

H

45

NO

7 : C, 73.71; H, 6.96; N, 2.15. Found: C, 73.72; H, 6.95; N, 2.18. 15 0 NI _ O O O-3 COOMe N-N' |. | 0 COOH B. Preparation of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(2H pyrazol-3 -yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid. 20 A solution of 2-(3-{3-[5-benzyloxy-4-(3 dimethylaminoacryloyl) -2-ethyl-phenoxy] propoxy }-2- WO 01/34135 PCT/USOO/30944 -119 propylphenoxy)benzoic acid methyl ester (550 mg, 0.843 mmol in methanol (30 mL) was treated with 1 M lithium hydroxide solution at 60 OC for 3 h. The mixture was cooled to room temperature and diluted with ethyl acetate and 0.5 M 5 hydrochloric acid. The organic layer was separated, washed with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in methanol (15 mL) and treated with water (4 mL) and hydrazine monohydrate (0.50 mL, 7.7 mmol) at reflux 10 for 3 h. The mixture was diluted with ethyl acetate and 1 N hydrochloric acid. The organic layer was separated, washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. Chromatography (30% ethyl acetate/69% hexane/l% acetic acid) 15 of the residue provided 350 mg (65%) of the title compound as the acetate salt. A portion of this material was free based with sodium bicarbonate to provide an analytical sample. H NMR (CDCl 3 ) 8 8.20 (dd, J = 8, 2 Hz, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 7.38 (m, 5H), 7.15 (m, 2H), 6.78 (d, 20 J = 8 Hz, 1H), 6.65 (d, J = 8 Hz, 1H), 6.61 (d, J = 8 Hz, 1H), 6.58 (s, 1H), 6.55 (bs, 1H), 5.18 (s, 2H), 4.22 (t, J = 6 Hz, 2H), 4.17 (t, J = 6 Hz, 2H), 2.58 (m, 4H), 2.30 (quintet, J = 6 Hz, 2H), 1.47 (hextet, J = 8 Hz, 2H), 1.18 (t, J = 7 Hz, 3H), 0.88 (t, J = 8 Hz, 3H); TOF MS ES exact 25 mass calculated for C 37

H

39

N

2 0 6 (p+1): m/z = 607.2808. -1 Found: 607.2831. IR (CHCl 3 , cm ) 2965, 1739, 1604, 1454. Anal. Calcd for C 37

H

38

N

2 0 6 : C, 73.25; H, 6.31; N, 4.62. Found: C, 73.31; H, 6.30; N, 4.62.

WO 01/34135 PCT/USOO/30944 -120 H I/II '0 0

N-'

0 0 N__ __ COOH H N-N' H I N O -' O O COOH C. Preparation of 2-(3-{3- [2-ethyl-5-hydroxy-4- (2H-pyrazol 3-yl)phenoxy]propoxy)-2-propylphenoxy)benzoic acid. 5 A solution of 2-(3-{3-[5-benzyloxy-2-ethyl-4- (2H-pyrazol-3 yl)phenoxy]propoxy}-2-propylphenoxy)benzoic acid (300 mg, 0.490 mmol) in ethanethiol (2.5 mL) was treated with boron trifluoride etherate (2 mL) at room temperature for 3 h, at which time an additional portion of boron trifluoride 10 etherate (1 mL) was added and stirring resumed for an additional 1 h. The mixture was diluted with diethyl ether and water. The organic layer was separated, washed with water, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 15% ethyl acetate/85% 15 hexane to 60% ethyl acetate/40% hexane) of the residue provided 60 mg (24%) of the title compound as a white solid. 1 H NMR (CDCl 3 ) 8 8.23 (d, J = 8 Hz, 1H), 7.61 (s, 1H), 7.42 (t, J = 7 Hz, 1H), 7.30 (s, 1H), 7.19 (d, J = 8 Hz, 1H), 7.15 (d, J = 8 Hz, 1H), 6.81 (d, J = 8 Hz, 1H), 6.69 (d, J 20 8 Hz, 1H), 6.61 (s, 1H), 6.60 (d, J = 8 Hz, 1H), 6.54 (s, 1H), 4.20 (m, 4H), 2.58 (m, 4H), 2.33 (quintet, J = 6 Hz, WO 01/34135 PCT/USOO/30944 -121 2H), 1.48 (hextet, J = 8 Hz, 2H), 1.17 (t, J = 8 Hz, 3H), 0.86 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated for C 30

H

33

N

2 0 6 (p+1): m/z = 517.2339. Found: 517.2334. -1 IR (CHCl 3 , cm ) 2965, 1738, 1454. 5 Anal. Calcd for C 30

H

32

N

2 0 6 : C, 69.75; H, 6.24; N, 5.42. Found: C, 69.73; H, 6.33; N, 5.25. Example 5 10 Preparation of 2-(3- [3- (2-Ethyl-5-hydroxy-4-isoxazol-5-yl phenoxy) propoxy] -2-propylphenoxy}benzoic acid. O N O 1 O O COOMe N'O O - O O COOMe A. Preparation of 2-(3-[3-(5-benzyloxy-2-ethyl-4-isoxazol 15 5-yl-phenoxy) propoxy] -2-propylphenoxylbenzoic acid methyl ester. A mixture of 2-(3-{3-[5-benzyloxy-4-(3 dimethylaminoacryloyl) -2-ethylphenoxy] propoxy} -2 propylphenoxy)benzoic acid methyl ester (280 mg, 0.43 mmol), 20 hydroxylamine hydrochloride (75 mg, 1.1 mmol), and water (1 WO 01/34135 PCT/USOO/30944 -122 mL) in methanol (4 mL) was heated at reflux for 2 h. The mixture was cooled to room temperature and diluted with diethyl ether and water. The organic layer was separated, washed with saturated sodium chloride solution, dried 5 (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 202 mg (76%) of the title compound as a white solid. H NMR (CDC1 3 ) 8 8.20 (d, J = 2 Hz, 1H), 7.88 (dd, J = 9, 2 Hz, 1H), 7.79 (s, 1H), 7.40 (m, 7H), 7.08 (m, 10 2H), 6.68 (d, J = 8 Hz, 1H), 6.59 (s, 1H), 6.58 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 5.15 (s, 2H), 4.21 (t, J = 6 Hz, 4H), 3.82 (s, 3H), 2.65 (m, 4H), 2.33 (quintet, J 6 Hz, 2H), 1.56 (hextet, J = 8 Hz, 2H), 1.20 (t, J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated 15 for C 38

H

40

NO

7 (p+1): m/z = 622.2805. Found: 622.2817. IR -1 (CHCl 3 , cm ) 2964, 1720, 1461. Anal. Calcd for C 3 8

H

39

NO

7 : C, 73.41; H, 6.32; N, 2.25. Found: C, 73.20; H, 6.34; N, 2.27.

N-

0 O - O O- --- W COOMe

N-

0 H I I COOMe 20 WO 01/34135 PCT/USOO/30944 -123 B. Preparation of 2-{3-[3-(2-ethyl-5-hydroxy-4-isoxazol-5 yl-phenoxy) propoxy] -2-propylphenoxylbenzoic acid methyl ester. 5 A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-isoxazol-5-yl phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester (180 mg, 0.289 mmol) in ethanethiol (5 mL) was treated with boron trifluoride etherate (1.5 mL) at room temperature for 2 h, at which time an additional portion of boron 10 trifluoride etherate (0.5 mL) was added and stirring resumed for an additional 1 h. The mixture was diluted with diethyl ether and water. The organic layer was separated, washed once with saturated sodium bicarbonate solution, once with saturated sodium chloride solution, dried (sodium sulfate), 15 filtered, and concentrated in vacuo. Chromatography (silica gel, 15% ethyl acetate/85% hexane) of the residue provided 1 94 mg (61%) of the title compound as a colorless oil. H NMR (CDCl 3 ) 8 8.28 (d, J = 1 Hz, 1H), 7.88 (dd, J = 8, 2 Hz, 1H), 7.38 (t, J = 8 Hz,1H), 7.36 (s, 1H), 7.08 (t, J = 8 Hz, 20 1H), 7.05 (d, J = 8 Hz, 1H), 6.81 (d, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H), 6.50 (s, 1H), 6.45 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.62 (m, 4H), 2.34 (quintet, J = 6 Hz, 2H), 1.54 (hextet, J = 8 Hz, 2H), 1.18 (t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); TOF MS ES exact 25 mass calculated for C 31

H

34

NO

7 (p+1): m/z = 532.2335. -1 Found: 532.2335. IR (CHCl 3 , cm ) 2964, 1715, 1601, 1461. Anal. Calcd for C 31

H

33

NO

7 : C, 70.04; H, 6.26; N, 2.63. Found: C, 70.13; H, 6.35; N, 2.63.

WO 01/34135 PCT/USOO/30944 -124

N-

0 H I | O O"' OP COOMe

N-

0 H O -- O O COOH C. Preparation of 2-(3-[3-(2-ethyl-5-hydroxy-4-isoxazol-5 yl-phenoxy) propoxy] -2-propylphenoxy)benzoic acid. 5 To a solution of 2-{3-[3-(2-ethyl-5-hydroxy-4-isoxazol-5-yl phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester (94 mg, 0.18 mmol) in methanol (3 mL) was added 1 M lithium hydroxide solution (1 mL) and the resulting mixture warmed at 60 OC for 3 h. The mixture was cooled to room 10 temperature and concentrated in vacuo. The aqueous residue was diluted with water and the pH adjusted to -4. The mixture was extracted three times with methylene chloride. The combined organic extracts were dried (sodium sulfate), filtered, and concentrated in vacuo to provide 12 mg (13%) 1 15 of the title compound as an off-white amorphous solid. H NMR (CDCl 3 ) 6 8.26 (s, 1H), 8.20 (dd, J = 8, 1 Hz, 1H), 7.49 (t, J = 6 Hz, 1H), 7.36 (s, 1H), 7.18 (d, J = 8 Hz, 1H), 7.15 (d, J = 8 Hz, 1H), 7.02 (bs, 1H), 6.80 (d, J = 8 Hz, 1H), 6.69 (d, J = 8 Hz, 1H), 6.60 (d, J = 8 Hz, 1H), 6.50 20 (s, 1H), 6.46 (s, 1H), 4.22 (t, J = 6 Hz, 2H), 4.19 (t, J = 6 Hz, 2H); 2.57 (m, 4H), 2.34 (quintet, J = 6 Hz, 2H), 1.47 WO 01/34135 PCT/USOO/30944 -125 (hextet, J = 8 Hz, 2H), 1.16 (t, J = 8 Hz, 3H), 0.85 (t, J = 7 Hz, 3H); TOS MS ES exact mass calculated for C 30

H

32 NO7 (p+l): m/z = 518.2179. Found: 518.2175. Anal. Calcd for C 30

H

31

NO

7 : C, 69.62; H, 6.04; N, 2.71. 5 Found: C, 69.57; H, 6.15; N, 2.74. Example 6 Preparation of 2-(3-(3-[2-Ethyl-5-hydroxy-4-(3H 10 [1,2,3]triazol-4-yl)phenoxy]propoxy)-2-propyl phenoxy)benzoic acid. + HO O O C-"cI COOMe Br I | O - O O COOMe A. Preparation of 2-(3-[3-(5-benzyloxy-4-bromo-2 15 ethylphenoxy) propoxy] -2-propylphenoxy} -benzoic acid methyl ester. A mixture of 5-benzyloxy-4-bromo-1- (3-chloropropoxy) -2 ethylbenzene (1.19 g, 3.11 mmol), 2-(3-hydroxy-2 propylphenoxy)benzoic acid methyl ester (0.89 g, 3.1 mmol), 20 potassium carbonate (1.29 g, 9.34 mmol), potassium iodide (0.52 g, 3.1 mmol), and methyl sulfoxide (2 mL) in 2- WO 01/34135 PCT/USOO/30944 -126 butanone (20 mL) was heated at reflux for 48 h. The mixture was cooled to room temperature, diluted with diethyl ether, and washed once with water. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo. 5 Chromatography (silica gel, 6% ethyl acetate/94% hexane) of the residue provided 1.34 g (68%) of the title compound as a colorless oil. H NMR (CDCl 3 ) 8 7.91 (dd, J = 8, 2 Hz, 1H), 7.50 (d, J = 7 Hz, 2H),. 7.38 (m, 5H), 7.15 (d, J = 8 Hz, 1H), 7.10 (d, J = 8 Hz, 1H), 6.83 (d, J = 8 Hz, 1H), 6.71 10 (d, J = 8 Hz, 1H), 6.55 (s, 1H), 6.48 (, J = 8 Hz, 1H), 5.16 (s, 2H), 4.21 (t, J = 6 Hz, 2H), 4.15 (t, J = 6 Hz, 2H), 3.83 (s, 3H), 2.68 (t, J = 8 Hz, 2H), 2.58 (q, J = 7 Hz, 2H), 2.31 (quintet, J = 6 Hz, 2H), 1.58 (hextet, J = 6 Hz, 2H), 1.17 (t, J = 7 Hz, 3H), 0.93 (t, J = 7 Hz, 3H). 15 Br COOMe 0 COOMe B. Preparation of 2-{3-[3-(5-benzyloxy-2-ethyl-4 ethynylphenoxy)propoxy]-2-propyl-phenoxyjbenzoic acid methyl 20 ester. A mixture of 2-{3- [3-(5-benzyloxy-4-bromo-2 ethylphenoxy) propoxy] -2-propylphenoxy} -benzoic acid methyl WO 01/34135 PCT/USOO/30944 -127 ester (1.50 g, 2.37 mmol), tri-n-butylethynyltin (0.82 mL, 2.8 mmol), and tetrakis(triphenylphosphine)palladium (0) (1.0 g, 0.95 mmol) in N,N-dimethylformamide (25 mL) was purged with argon and heated in a sealed tube at 120 OC for 5 24 h. The mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate, washed four times with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% 10 ethyl acetate/90% hexane) of the residue provided 532 mg 1 (39%) of the title compound as a brown oil. H NMR (CDCl 3 ) 8 7.88 (dd, J = 8, 2 Hz, 1H), 7.79 (s, 1H), 7.20-7.50 (m, 6H), 7.10 (d, J = 8 Hz, 1H), 7.05 (d, J = 8 Hz, 1H), 6.80 (d, J = 8 Hz, 1H), 6.66 (d, J = 8 Hz, 1H), 6.43 (m, 2H), 15 5.16 (s, 2H), 4.17 (t, J = 6 Hz, 2H), 4.11 (t, J = 6 Hz, 2H), 3.83 (s, 3H), 3.23 (s, 1H), 2.64 (t, J = 8 Hz, 2H), 2.53 (q, J = 7 Hz, 2H), 2.27 (quintet, J = 6 Hz, 2H), 1.53 (m, 2H), 1.13 (t, J = 7 Hz, 3H), 0.89 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated for C 3 7

H

3 9 0 6 (p+1): m/z = 20 579.2747. Found: 579.2739.

WO 01/34135 PCT/USOO/30944 -128 0 0 COOMe ,N- N N O -' O OP COOMe C. Preparation of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(3H [1,2,3]triazol-4-yl)phenoxy]-propoxy)-2 5 propylphenoxy)benzoic acid methyl ester. A mixture of 2-{3-[3-(5-benzyloxy-2-ethyl-4 ethynylphenoxy) propoxy] -2-propyl-phenoxy}benzoic acid methyl ester (517 mg, 0.893 mmol) and trimethylsilyl azide (3.0 mL, 18 mmol) was heated in toluene (20 mL) in a sealed tube at 10 130 OC for 120 h. The mixture was cooled to room temperature and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane to 50% ethyl acetate/50% hexane) of the residue provided 347 mg (88% based upon recovered starting material) of the title 1 15 compound as a brown solid. H NMR (CDCl 3 ) 8 8.10 (bs, 1H), 7.89 (dd, J = 8, 2 Hz, 1H), 7.76 (s, 1H), 7.40 (m, 7H), 7.10 (d, J = 8 Hz, 1H), 7.05 (d, J = 8 Hz, 1H), 6.79 (d, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H), 6.62 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 5.18 (s, 2H), 4.21 (m, 4H), 3.82 (s, 3H), 2.65 20 (m, 4H), 2.32 (quintet, J = 6 Hz, 2H), 1.56 (hextet, J = 8 Hz, 2H), 1.21 (t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); TOF WO 01/34135 PCT/USOO/30944 -129 MS ES exact mass calculated for C 3 7

H

40

N

3 0 6 (p+1): m/z = -1 622.2917. Found: 622.2946. IR (CHCl 3 , cm ) 3400, 1721, 1602, 1453. Anal. Calcd for C 37 H 39

N

3 0 6 : C, 71.48; H, 6.32; N, 6.76. 5 Found: C, 70.28; H, 6.07; N, 6.54. H ,,N'N' O N N COOMe H ,N N' H N 0 0 0 COOMe D. Preparation of 2-(3-(3-[2-ethyl-5-hydroxy-4-(3H 10 [1,2,3] triazol-4-yl)phenoxy] -propoxy)-2-propyl phenoxy)benzoic acid methyl ester. A solution of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(3H [1,2,3]triazol-4-yl)phenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl ester (330 mg, 0.531 mmol) in ethanethiol (9 mL) 15 was treated with boron trifluoride etherate (2.0 mL,16 mmol) for 1 h at room temperature and then with an additional portion of boron trifluoride etherate (1.0 mL) for 1 h. The mixture was diluted with diethyl ether and water. The organic layer was washed once with saturated sodium 20 bicarbonate solution, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated WO 01/34135 PCT/USOO/30944 -130 in vacuo. Chromatography (silica gel, 30% ethyl acetate/70% hexane to 50% ethyl acetate/50% hexane) of the residue provided 180 mg (63%) of the title compound as a brown solid. H NMR (CDCl 3 ) 6 7.97 (s, 1H), 7.88 (dd, J = 8, 2 5 Hz, 1H), 7.37 (t, J = 8 Hz, 1H), 7.31 (s, 1H), 7.10 (d, J = 8 Hz, 1H), 7.05 (d, J = 8 Hz, 1H), 6.81 (d, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H), 6.59 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.63 (m, 4H), 2.34 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H), 1.19 10 (t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated for C 30

H

34

N

3 0 6 (p+1) : m/z = 532.2447. -1 Found: 532.2466. IR (CHCl 3 , cm ) 2964, 1718, 1453. Anal. Calcd for C 30

H

33

N

3 0 6 : C, 67.78; H, 6.26; N, 7.90. Found: C, 66.80; H, 6.02; N, 7.53. 15 H ,,N'N' HH N 00 __ 0_ _ COOMe ,N N' OH N - |' T

COOH

WO 01/34135 PCT/USOO/30944 -131 E. Preparation of 2-(3-(3-[2-ethyl-5-hydroxy-4-(3H [1,2,3]triazol-4-yl)phenoxy]-propoxy}-2 propylphenoxy)benzoic acid. A solution of 2-(3-{3-[2-ethyl-5-hydroxy-4-(3H 5 [1,2,3]triazol-4-yl)phenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl ester (160 mg, 0.30 mmol) in methanol (5 mL) was treated 1 N lithium hydroxide solution (1.5 mL) at 60 OC for 3.5 h. The mixture was cooled to room temperature, diluted with water, and adjusted to -pH 4. The resulting mixture 10 was extracted three times with methylene chloride. The combined organic extracts were dried (sodium sulfate), filtered, and concentrated in vacuo to provide 134 mg (86%) 1 of the title compound as a tan solid. H NMR (DMSO-d) 8 14.98 (bs, 1H), 12.80 (bs, 1H), 10.02 (bs, 1H), 8.17 (bs, 15 1H), 7.77 (dd, J = 7, 2 Hz, 1H), 7.60 (bs, 1H), 7.47 (t, J = 8 Hz, 1H), 7.18 (t, J = 8 Hz, 1H), 7.14 (t, J = 8 Hz, 1H), 6.82 (d, J = 8 Hz, 1H), 6.68 (d, J = 8 Hz, 1H), 6.57 (s, 1H), 6.35 (d, J = 8 Hz, 1H), 4.22 (t, J = 6 Hz, 2H), 4.15 (t, J = 6 Hz, 2H), 2.54 (m, 4H), 2.25 (quintet, J = 6 Hz, 20 2H), 1.45 (hextet, J = 8 Hz, 2H), 1.11 (t, J = 7 Hz, 3H), 0.81 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated for C 29

H

32

N

3 0 6 (p+1): m/z = 518.2291. Found: 518.2302. -1 IR (CHCl 3 , cm ) 2965, 1738, 1454. Anal. Calcd for C 2 9

H

3 1

N

3 0 6 : C, 67.30; H, 6.04; N, 8.12. 25 Found: C, 67.15; H, 5.98; N, 7.93.

WO 01/34135 PCT/USOO/30944 -132 Example 7 Preparation of 2-(3- [3- (2-Ethyl-5-hydroxy-4-pyrrol-1-yl phenoxy) propoxy] -2 -propyl-phenoxy}benzoic acid methyl ester. OH XN OH I OH 5 A. Preparation of 5-benzyloxy-2-ethyl-4-pyrrol-1-yl-phenol. To a mixture of potassium nitrosodisulfonate (40.0 g, 149 mmol) and potassium hydrogen phosphate (10 g) in water (1.2 L) at room temperature was added a solution of 4 10 ethylbenzene-1,3-diol (10.0 g, 2.37 mmol) and potassium hydrogen phosphate (10.5 g) in water (150 mL). The mixture was stirred for 15 min and adjusted to pH -3. The solution was extracted three times with diethyl ether. The organic layer was dried (sodium sulfate), filtered, and concentrated 15 in vacuo. The residue was dissolved in acetonitrile (70 mL) and treated at room temperature with 65% 3-pyrroline (12 mL). The resulting mixture was stirred for 1 h and concentrated in vacuo, dissolved in ethyl acetate and hexane, and filtered down a short column of silica gel. The 20 resulting solution was concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (10 mL) and treated with benzyl bromide (0.85 mL, 7.1 mmol) and potassium carbonate (960 mg, 6.9 mmol) at room temperature for 15 h. The mixture was diluted with ethyl acetate, washed four 25 times with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, ethyl acetate/hexane gradient) of the residue provided 316 mg (2%) of the title WO 01/34135 PCT/USOO/30944 -133 compound. TOF MS ES exact mass calculated for C 19

H

20 NO2 (p+l): m/z = 294.1494. Found: 294.1471. B. Preparation of 1-[2-benzyloxy-4-(3-chloropropoxy)-5 5 ethylphenyl] -1H-pyrrole. N O NO OH O A mixture of 5-benzyloxy-2-ethyl-4-pyrrol-1-yl-phenol (316 mg, 1.08 mmol), potassium carbonate (223 mg, 1.62 mmol), and 1-bromo-3-chloropropane (0.16 mL, 1.6 mmol) in N,N 10 dimethylformamide (5 mL) was stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate and water, washed four times with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 5% ethyl 15 acetate/95% hexane) of the residue provided 314 mg (79%) of the title compound as a colorless oil. TOF MS ES exact mass calculated for C 22

H

25 NC10 2 (p+1): m/z = 370.1574. Found: 370.1548.

WO 01/34135 PCT/USOO/30944 -134 N HO O_ O o--CI + COOMe SNN O O O COOMe C. Preparation of 2-{3-[3-(5-benzyloxy-2-ethyl-4-pyrrol-1 yl-phenoxy)propoxy] -2-propylphenoxy)benzoic acid methyl 5 ester. A mixture of 1- [2-benzyloxy-4- (3-chloropropoxy) -5 ethylphenyl]-lH-pyrrole (310 mg, 0.85 mmol) and sodium iodide (140 mg, 0.94 mol) in 2-butanone (5 mL) was heated at reflux for 6 h. The mixture was cooled to room temperature, 10 filtered, and concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (7 mL) and treated with 2- (3-hydroxy-2-propylphenoxy)benzoic acid methyl ester (242 mg, 0.85 mmol) and potassium carbonate (129 g, 93 mmol) at room temperature for 15 h. The mixture was diluted with 15 ethyl acetate and water, washed four times with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 5% ethyl acetate/95% hexane) of the residue provided 196 mg (37%) of the title compound as a 20 colorless oil. H NMR (CDCl 3 ) 8 7.86 (dd, J = 8, 2 Hz, 1H), 7.37 (dt, J = 8, 2 Hz, 1H), 7.30 (m, 5H), 7.07 (m, 3H), 6.84 WO 01/34135 PCT/USOO/30944 -135 (m, 2H), 6.79 (d, J = 8 Hz, 1H), 6.65 (d, J = 8 Hz, 1H), 6.58 (s, 1H), 6.42 (d, J = 8 Hz, 1H), 6.29 (m, 2H), 4.92 (s, 2H), 4.17 (t, J = 6 Hz, 2H), 4.15 (t, J = 6 Hz, 2H), 3.83 (s, 3H), 2.65 (t, J = 8 Hz, 2H), 2.58 (q, J = 7 Hz, 2H), 5 2.30 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H), 1.16 (t, J = 7 Hz, 3H), 0.80 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated for C 39

H

42

NO

6 (p+l): m/z = 620.3012. Found: 620.3021. NK COOMe OH NN O '-O

O

COOMe 10 D. Preparation of 2-{3-[3-(2-ethyl-5-hydroxy-4-pyrrol-1-yl phenoxy)propoxy] -2-propyl-phenoxy}benzoic acid methyl ester. A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-pyrrol-1-yl 15 phenoxy) propoxy] -2-propylphenoxy}benzoic acid methyl ester (195 mg, 0.315 mmol) in ethanethiol (5 mL) was treated with boron trifluoride etherate (1.3 mL, 9.5 mmol) at room temperature for 2.5 h. The mixture was diluted with diethyl ether and water. The organic layer was washed with 20 saturated sodium bicarbonate solution, dried (sodium sulfate), filtered, and concentrated in vacuo.

WO 01/34135 PCT/USOO/30944 -136 Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 39 mg (23%) of the title compound as a colorless oil. H NMR (CDCl 3 ) 8 7.89 (d, J = 8 Hz, 1H), 7.37 (t, J = 8 Hz, 1H), 7.07 (m, 2H), 6.98 (s, 1H), 6.68 (m, 5 3H), 6.65 (d, J = 8 Hz, 1H), 6.57 (s, 1H), 6.42 (d, J = 8 Hz, 1H), 6.35 (m, 2H), 5.04 (bs, 1H), 4.19 (m, 2H), 3.83 (s, 3H), 2.64 (t, J = 8 Hz, 2H), 2.58 (q, J = 7 Hz, 2H), 2.32 (quintet, J = 6 Hz, 2H), 1.55 (m, 2H), 1.14 (t, J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); TOF MS ES exact mass 10 calculated for C 32

H

36

NO

6 (p+1): m/z = 530.2543. Found: 530.2516. Example 8 15 Preparation of 2-(3-(3-[4-(3-Bromo-[1,2,4]thiadiazol-5-yl) 2-ethyl-5-hydroxyphenoxy]-propoxy)-2-propylphenoxy)benzoic acid. Br

S

0 O1--", 0 O-9 COOMe COOMe 20 WO 01/34135 PCT/USOO/30944 -137 A. Preparation of 2-(3-(3-[5-benzyloxy-2-ethyl-4-(4,4,5,5 tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy)-2 propylphenoxy)benzoic acid methyl ester. A mixture of 2-{3-[3-(5-benzyloxy-4-bromo-2 5 ethylphenoxy)propoxy]-2-propylphenoxy}-benzoic acid methyl ester (8.30 g, 13.1 mmol), triethylamine (5.2 mL, 39 mmol), and PdCl 2 (dppf) (320 mg, 0.39 mmol) in de-oxygenated toluene (80 mL) was treated with a 1 M solution of 4,4,5,5 tetramethyl-[1,3,2]dioxaborolane in tetrahydrofuran (20 mL, 10 20 mmol) and heated at reflux for 6 h. The mixture was filtered down a short column of silica gel and the filtrate concentrated in vacuo. Chromatography (silica gel, 35% ethyl acetate/65% hexane) of the residue provided a dark oil that was subjected to further chromatography (silica gel, 15 hexane to 30% ethyl acetate/70% hexane) to give 7.70 g (84%) of the title compound. H NMR (CDCl 3 ) 6 7.86 (dd, J = 8, 2 Hz, 1H), 7.60 (d, J = 8 Hz, 2H), 7.47 (s, 1H), 7.34 (m, 3H), 7.24 (t, J = 8 Hz, 1H), 7.09 (d, J = 9 Hz, 1H), 7.04 (d, J = 9 Hz, 1H), 6.79 (d, J = 9 Hz, 1H), 6.66 (d, J = 9 Hz, 1H), 20 6.47 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 5.07 (s, 2H), 4.18 (m, 4H), 3.81 (s, 3H), 2.64 (t, J = 8 Hz, 2H), 2.56 (q, J = 7 Hz, 2H), 2.30 (quintet, J = 6 Hz, 2H), 1.53 (hextet, J = 8 Hz, 2H), 1.34 (s, 12H),1.14 (t, J = 7 Hz, 3H), 0.89 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated for C 41

H

53 NBO8 25 (p + NH 4 ): m/z = 698.3864. Found: 698.3889. IR (CHCl 3 , -1 cm ) 2964, 1720, 1604, 1453. Anal. Calcd for C 41

H

4 9

BO

8 : C, 72.35; H, 7.26. Found: C, 72.30; H, 7.12.

WO 01/34135 PCT/USOO/30944 -138 I| 00 COOMe Br N \ S O -- O O COOMe B. Preparation of 2-(3-(3-[5-benzyloxy-4-(3-bromo [1,2,4]thiadiazol-5-yl)-2-ethyl-phenoxy]propoxy)-2 5 propylphenoxy)benzoic acid methyl ester. A mixture of 2-(3-{3-(5-benzyloxy-2-ethyl-4-(4,4,5,5 tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy}-2 propylphenoxy)benzoic acid methyl ester (310 mg, 0.46 mmol), 3-bromo-5-chloro-1,2,4-thiadiazole (120 mg, 0.60 mmol), 10 cesium carbonate (300 mg, 0.92 mmol), and PdCl 2 (dppf) (20 mg, 0.024 mmol) in de-oxygenated toluene (10 mL) was heated at 100 OC for 15 h. The mixture was diluted with a solution of 35% ethyl acetate/65% hexane and filtered down a short column of silica gel. The filtrate was concentrated in 15 vacuo. Chromatography (silica gel, hexane to 30% ethyl acetate/70% hexane) of the residue provided 232 mg (70%) of the title compound. H NMR (CDCl 3 ) 8 8.13 (s, 1H), 7.87 (dd, J = 8, 2 Hz, 1H), 7.44 (m, 2H), 7.37 (m, 4H), 7.08 (t, dJ = 8, 1 Hz, 1H), 7.04 (d, J = 9 Hz, 1H), 6.78 (d, J = 9 20 Hz, 1H), 6.66 (d, J = 9 Hz, 1H), 6.55 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 5.28 (s, 2H), 4.21 (t, J = 6 Hz, 2H), 4.19 (t, J WO 01/34135 PCT/USOO/30944 -139 = 6 Hz, 2H), 3.81 (s, 3H), 2.62 (m, 4H), 2.34 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H), 1.17 (t, J = 7 Hz, 3H), 0.88 (t, J = 7 Hz, 3H); MS ES m/e 717, 719. Br N N.S I N ~ . N 0 COOMe Br N H N. I S 3 1 I |~N~N N | , O- O O COOH 5 C. Preparation of 2-(3-{3-[4-(3-bromo-[1,2,4]thiadiazol-5 yl) -2-ethyl-5-hydroxyphenoxy]propoxy) -2 propylphenoxy)benzoic acid. 10 A solution of 2-(3-{3-[5-benzyloxy-4-(3-bromo [1,2,4] thiadiazol-5-yl) -2-ethyl-phenoxy] propoxy} -2 propylphenoxy)benzoic acid methyl ester (230 mg, 0.31 mmol) in ethanethiol (4 mL) was treated with boron trifluoride etherate (0.32 mL, 2.5 mmol) at room temperature for 6 h, at 15 which time an additional portion of boron trifluoride etherate was added and stirring continued for 7 h. The reaction mixture was diluted with water, concentrated in vacuo, and extracted with diethyl ether. The residue was dissolved in methanol (5 mL) and treated with 1 N lithium 20 hydroxide solution (2 mL) at 65 0 C for 1 h. The mixture was concentrated in vacuo and the residue diluted with water and WO 01/34135 PCT/USOO/30944 -140 adjusted to -pH 3 with 1 N hydrochloric acid. The resulting precipitate was collected via vacuum filtration and dissolved in dilute aqueous base. Reverse phase chromatography (1:1 acetonitrile/water) provided 43 mg (23%) 1 5 of the title compound as a yellow solid. H NMR (DMSO-d 6 ) 7.85 (s, 1H), 7.80 (dd, J = 8, 2 Hz, 1H), 7.45 (m, 2H), 7.15 (m, 3H), 6.83 (d, J = 9 Hz, 1H), 6.80 (d, J = 9 Hz, 1H), 6.62 (s, 1H), 6.35 (d, J = 9 Hz, 1H), 4.20 (m, 4H), 2.55 (m, 4H), 2.27 (quintet, J = 5 Hz, 2H), 1.44 (hextet, J = 8 Hz, 10 2H), 1.13 (t, J = 7 Hz, 3H), 0.81 (t, J = 7 Hz, 3H); MS ES + -1 m/e 551 (p+NH 4 -Br); IR (KBr, cm ) 2900, 1696, 1603, 1461. Anal. Calcd for C 29

H

29 BrN 2 0 6 S: C, 56.77; H, 4.76; N, 4.56. Found: C, 56.63; H, 4.72; N, 3.98. 15 Example 9 Preparation of 2-{3-[3-(2-Ethyl-5-hydroxy-4-thiophen-2-yl phenoxy)propoxy]-2-propyl-phenoxy}benzoic acid sodium salt. 20 A. Preparation of 2-(3-[3-(2-ethyl-5-hydroxy-4-thiophen-2 yl-phenoxy)propoxy]-2-propylphenoxy)benzoic acid methyl ester. A mixture of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5 tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy}-2 25 propylphenoxy)benzoic acid methyl ester (300 mg, 0.44 mmol), 2-bromothiophene (110 mg, 0.66 mmol), cesium carbonate (300 mg, 2.17 mmol), and PdCl 2 (dppf) (20 mg, 0.024 mmol) in de oxygenated toluene (10 mL) was heated at 105 0 C for 66 h. The mixture was cooled to room temperature and concentrated WO 01/34135 PCT/USOO/30944 -141 in vacuo. The residue was dissolved in methylene chloride and filtered down a short column of silica gel. The filtrate was concentrated in vacuo. Chromatography (silica gel, 30% ethyl acetate/70% hexane) of the residue provided 5 an oil that was dissolved in ethanethiol (4 mL) and treated with boron trifluoride etherate (0.44 mL, 3.4 mmol) at room temperature for 3 h. The mixture was diluted with water and extracted with diethyl ether. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo. 10 Chromatography (silica gel, hexane to 30% ethyl acetate/70% hexane) of the residue provided 120 mg (50%) of the title compound as a yellow film. H NMR (CDCl 3 ) 8 7.85 (dd, J = 8, 2 Hz, 1H), 7.35 (t, J = 8 Hz, 1H), 7.15 (d, J = 7 Hz, 1H), 7.03-7.15 (m, 5H), 6.80 (d, J = 9 Hz, 1H), 6.66 (d, J = 15 9 Hz, 1H), 6.51 (s, 1H), 6.42 (d, J = 8 Hz, 1H), 5.44 (bs, 1H), 4.18 (m, 4H), 3.82 (s, 3H), 2.62 (t, J = 8 Hz, 2H), 2.58 (q, J = 7 Hz, 2H), 2.54 (quintet, J = 6 Hz, 2H), 1.52 (hextet, J = 8 Hz, 2H), 1.16 (t, J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); MS ES m/e 545 (p - 1). 20 WO 01/34135 PCT/USOO/30944 -142 B. Preparation of 2-(3-[3-(2-ethyl-5-hydroxy-4-thiophen-2 yl-phenoxy)propoxy] -2-propylphenoxy)benzoic acid sodium salt. / I OH S II I_ _ _ O O O COOMe OH S N III COONa 5 A solution of 2-{3-[3-(2-ethyl-5-hydroxy-4-thiophen-2-yl phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester (120 mg, 0.22 mmol) in methanol (3 mL) was treated with 1 N lithium hydroxide solution (0.5 mL) at room temperature for 1 h and then with an additional portion of 1 N lithium 10 hydroxide solution (0.75 mL) for 18 h. The mixture was heated at 50 OC then concentrated in vacuo. The residue was acidified with dilute hydrochloric acid and extracted with diethyl ether. The organic layer was washed once with water and concentrated in vacuo. The residue was diluted with 1 N 15 sodium hydroxide solution (0.22 mL), diethyl ether, and toluene. The mixture was concentrated in vacuo, dissolved in methylene chloride, and concentrated in vacuo to provide 1 120 mg (98%) of the title compound as a green film. H NMR (DMSO-d 6 ) 8 7.71 (d, J = 8 Hz, 1H), 7.42 (m, 2H), 7.31 (m, 20 2H), 7.10 (m, 2H), 6.99 (m, 1H), 6.76 (t, J = 7 Hz, 2H), 6.52 (s, 1H), 6.30 (d, J = 8 Hz, 1H), 4.16 (t, J = 7 Hz, 2H), 4.07 (t, J = 7 Hz, 2H), 2.50 (m, 4H), 2.20 (m, 2H), WO 01/34135 PCT/USOO/30944 -143 1.40 (m, 2H), 1.06 (t, J = 8 Hz, 3H), 0.77 (t, J = 7 Hz, + + -1 3H); MS ES m/e 533 (p + 1 - Na ). IR (CHCl 3 , cm ) 2900, 1738, 1604, 1454. 5 Example 10 Preparation of 2- (3-(3- [2-Ethyl-5-hydroxy-4- (1-methyl-1H pyrazol-4-yl) -phenoxy] propoxy) -2-propylphenoxy) benzoic acid. N-N N-N H 10 A. Preparation of 4-iodo-1-methylpyrazole (Known compound: RN 39806-90-1). To a solution of 4-iodopyrazole (1.3 g, 6.8 mmol) in dioxane (10 mL) was added iodomethane (0.42 mL, 6.8 mmol) and the resulting mixture stirred at room temperature for 96 h. The 15 mixture was concentrated in vacuo and the residue mixed with methylene chloride and filtered. The filtrate was concentrated in vacuo to provide 1.35 g (95%) of the title compound as a colorless oil. H NMR (CDCl 3 ) 6 7.47 (s, 1H), 7.38 (s, 1H), 3.90 (s, 3H). 20 B. Preparation of 2- (3-(3- [5-benzyloxy-2-ethyl-4- (1-methyl 1H-pyrazol-4-yl) phenoxy] -propoxy) -2-propylphenoxy) benzoic acid methyl ester. A mixture of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5 25 tetramethyl- [1,3,2] dioxaborolan-2-yl)phenoxy]propoxy}-2 propylphenoxy)benzoic acid methyl ester (1.00 g, 1.47 mmol), 4-iodo-l-methylpyrazole (450 mg, 2.16 mmol), cesium carbonate (1.20 g, 3.62 mmol), and PdCl 2 (dppf) (72 mg, 0.088 WO 01/34135 PCT/USOO/30944 -144 mmol) in de-oxygenated toluene (35 mL) was heated at 100 OC for 24 h. Additional portions of 4-iodo-l-methylpyrazole (-30 mg) and PdCl 2 (dppf) (-30 mg) were added and heating continued at 100 OC for 40 h. The mixture was cooled to 5 room temperature, concentrated in vacuo, diluted with methylene chloride, and filtered down a short plug of silica gel. The filtrate was concentrated in vacuo. Chromatography (silica gel, 35% ethyl acetate/65% hexane to 65% ethyl acetate/35% hexane) of the residue provided 710 mg 10 (76%) of the title compound. H NMR (CDCl 3 ) 8 7.86 (dd, J = 8, 2 Hz, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.37 (m, 6H), 7.28 (s, 1H), 7.09 (d, J = 9 Hz, 1H), 7.04 (d, J = 9 Hz, 1H), 6.78 (d, J = 9 Hz, 1H), 6.67 (d, J = 9 Hz, 1H), 6.56 (s, 1H), 6.42 (d, J = 8 Hz, 1H), 5.08 (s, 2H), 4.18 (t, J = 6 15 Hz, 2H), 4.15 (t, J.= 6 Hz, 2H), 3.85 (s, 3H),. 3.81 (s, 3H), 2.63 (t, J = 8 Hz, 2H), 2.59 (q, J = 7 Hz, 2H), 2.30 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H), 1.23 (t, J = 7 Hz, 3H), 0.89 (t, J = 7 Hz, 3H). -N I I ' COOMe IN H

S

0 "'.O O COOH 20 WO 01/34135 PCT/USOO/30944 -145 C. Preparation of 2-(3-(3-[2-ethyl-5-hydroxy-4-(1-methyl 1H-pyrazol-4-yl)-phenoxy]propoxy}-2-propylphenoxy)benzoic acid. A solution of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(l-methyl-1H 5 pyrazol-4-yl)phenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl ester (710 mg, 1.12 mmol) in ethanethiol (5 mL) was treated with boron trifluoride etherate (1.42 mL, 11.2 mmol) at room temperature for 20 h. The reaction mixture was diluted with water, concentrated in vacuo, and extracted 10 with diethyl ether. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was triturated twice with hexane and the residue dissolved in methanol (5 mL). This solution was treated with 1 N lithium hydroxide solution (5 mL) at -95 OC for 2 h. The 15 mixture was concentrated in vacuo and the residue diluted with water, washed twice with diethyl ether, and the aqueous layer acidified with 1 N hydrochloric acid. The resulting solution was extracted with diethyl ether. The organic layer was dried (magnesium sulfate), filtered, and 20 concentrated in vacuo. Chromatography (silica gel, 10% methanol/90% methylene chloride) provided 338 mg (57%) of the title compound as a tan foam. H NMR (DMSO-d 6 ) 6 12.85 (bs, 1H), 9.50 (bs, 1H), 7.98 (s, 1H), 7.78 (m, 2H), 7.48 (dt, J = 8, 2 Hz, IH), 7.44 (s, 1H), 7.18 (t, J = 8 Hz, 1H), 25 7.13 (t, J = 9 Hz, 1H), 6.79 (d, J = 9 Hz, 1H), 6.77 (d, J = WO 01/34135 PCT/USOO/30944 -146 9 Hz, 1H), 6.53 (s, 1H), 6.35 (d, J = 9 Hz, 1H), 4.20 (t, J = 6 Hz, 2H), 4.08 (t, J = 6 Hz, 2H), 3.85 (s, 3H), 2.50 (m, 4H), 2.24 (quintet, J = 5 Hz, 2H), 1.45 (hextet, J = 8 Hz, 2H), 1.09 (t, J = 7 Hz, 3H), 0.82 (t, J = 7 Hz, 3H); MS ES -1 5 m/e 531 (p+l); IR (KBr, cm ) 2961, 1697, 1602, 1460, 1222. Anal. Calcd for C 31

H

34

N

2 0 6 : C, 70.17; H, 6.46; N, 5.28. Found: C, 69.27; H, 6.08; N, 4.63. 10 Example 11 Preparation of 2-{3- [3- (2-Ethyl-5-hydroxy-4-thiazol-2-yl phenoxy) propoxy] -2 -propyl-phenoxylbenzoic acid. 0 O'B N O7O O,9 + S Br I COOMe fN 0N S 0 COOMe 15 A. Preparation of 2-(3- [3- (5-benzyloxy-2-ethyl-4-thiazol-2 yl-phenoxy) propoxy] -2-propylphenoxy}benzoic acid methyl ester. A mixture of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5 20 tetramethyl- [1,3,2] dioxaborolan-2-yl)phenoxy]propoxy}-2- WO 01/34135 PCT/USOO/30944 -147 propylphenoxy)benzoic acid methyl ester (960 mg, 1.41 mmol), 2-bromothiazole (0.25 mL, 2.8 mmol), cesium carbonate (1.15 g, 3.52 mmol), and PdCl 2 (dppf) (35 mg, 0.040 mmol) in de oxygenated toluene (35 mL) was heated at 60 OC for 16 h then 5 at 100 OC for 7 h. Additional portions of 2-bromothiazole (0.13 mL) and PdCl 2 (dppf) (-30 mg) were added and heating continued at 100 OC for 72 h. The mixture was cooled to room temperature, concentrated in vacuo, diluted with methylene chloride, and filtered down a short plug of silica 10 gel. The filtrate was concentrated in vacuo. Chromatography (silica gel, hexane to 35% ethyl acetate/65% hexane) of the residue provided 282 mg (31%) of the title compound. H NMR (CDC1 3 ) 8 8.20 (s, 1H), 7.86 (dd, J = 8, 1 Hz, 1H), 7.82 (d, J = 3 Hz, 1H), 7.49 (d, J = 7 Hz, 2H), 15 7.35 (m, 4H), 7.23 (d, J = 3 Hz, 1H), 7.09 (d, J = 9 Hz, 1H), 7.04 (d, J = 9 Hz, 1H), 6.78 (d, J = 9 Hz, 1H), 6.65 (d, J = 9 Hz, 1H), 6.57 (s, 1H), 6.42 (d, J = 8 Hz, 1H), 5.24 (s, 2H), 4.17 (m, 4H), 3.81 (s, 3H), 2.63 (m, 4H), 2.33 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H), 1.19 20 (t, J = 7 Hz, 3H), 0.88 (t, J = 7 Hz, 3H).

WO 01/34135 PCT/USOO/30944 -148 S S : I II COOMe N OH S O O-l1 OP COOMe B. Preparation of 2-(3-[3-(2-ethyl-5-hydroxy-4-thiazol-2 yl-phenoxy)propoxy] -2-propylphenoxy}benzoic acid methyl 5 ester. A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-thiazol-2-yl phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester (282 mg, 0.442 mmol) in ethanethiol (3 mL) was treated with boron trifluoride etherate (0.56 mL, 4.4 mmol) at room 10 temperature for 3 h. The reaction mixture was diluted with water, concentrated in vacuo, and extracted with diethyl ether. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, ethyl acetate/hexane) provided 107 mg (44%) of the 15 title compound. H NMR (CDCl 3 ) 8 7.88 (dd, J = 8, 2 Hz, 1H), 7.80 (d, J = 4 Hz, 1H), 7.35 (dt, J = 8, 2 Hz, 1H), 7.28 (d, J = 4 Hz, 1H), 7.24 (s, 1H), 7.09 (dt, J = 9, 2 Hz, 1H), 7.05 (t, J = 9 Hz, 1H), 6.79 (d, J = 9 Hz, 1H), 6.66 (d, J = 9 Hz, 1H), 6.61 (s, 1H), 6.42 (d, J = 9 Hz, 1H), 20 4.24 (t, J = 6 Hz, 2H), 4.18 (t, J = 6 Hz, 2H), 3.81 (s, 3H), 2.63 (t, J = 7 Hz, 2H), 2.58 (q, J = 7 Hz, 2H), 2.34 WO 01/34135 PCT/USOO/30944 -149 (quintet, J = 6 Hz, 2H), 1.52 (hextet, J = 8 Hz, 2H), 1.17 (t, J = 7 Hz, 3H), 0.88 (t, J = 7 Hz, 3H); MS ES m/e 548 (p+l). CN OH S 0 COOMe N H S 0 0- 0 COOH 5 C. Preparation of 2-(3-[3-(2-ethyl-5-hydroxy-4-thiazol-2 yl-phenoxy) propoxy] -2-propylphenoxy)benzoic acid. 2-{3- [3- (2-Ethyl-5-hydroxy-4-thiazol-2-yl-phenoxy)propoxy) 10 2-propylphenoxy}benzoic acid methyl ester (107 mg, 0.196 mmol) was dissolved in a 1:1 solution of methanol/dioxane (3 mL) and treated with 1 N lithium hydroxide solution (1 mL) at 60 OC for 2 h. The mixture was concentrated in vacuo and the residue diluted with water, washed twice with diethyl 15 ether, and the aqueous layer acidified with 1 N hydrochloric acid. The resulting solution was extracted twice with methylene chloride and the combined organic layers dried (magnesium sulfate), filtered, and concentrated in vacuo. Trituration (hexane) of the residue provided 72 mg (69%) of 20 the title compound as a tan powder. H NMR (CDCl 3 ) 8 8.22 (dd, J = 8, 2 Hz, 1H), 7.70 (d, J = 4 Hz, 1H), 7.41 (dt, J = WO 01/34135 PCT/USOO/30944 -150 8, 2 Hz, 1H), 7.35 (S, 1H), 7.18 (m, 3H), 6.82 (d, J = 9 Hz, 1H), 6.69 (d, J = 9 Hz, 1H), 6.62 (d, J = 9 Hz, 1H), 6.55 (S, 1H), 4.22 (t, J = 6 Hz, 2H), 4.21 (t, J = 6 Hz, 2H), 2.57 (m, 4H), 2.35 (quintet, J = 6 Hz, 2H), 1.49 (hextet, J 5 = 8 Hz, 2H), 1.18 (t, J = 7 Hz, 3H), 0.86 (t, J = 7 Hz, 3H); + -1 MS ES m/e 534 (p+1); IR (KBr, cm ) 2957, 1695, 1599, 1457. Anal. Calcd for C 30

H

31 NO6S: C, 67.52; H, 5.86; N, 2.62. Found: C, 67.44; H, 5.95; N, 2.55. 10 Example 12 Preparation of 2-(3-{3-[4-(3,5-Dimethylisoxazol-4-yl)-2 ethyl-5-hydroxyphenoxy]propoxy)-2-propylphenoxy)benzoic acid sodium salt. O + N 0 0 ,00 NN 0-- O O- O COOMe 0 N \I I " , III COOMe ,0 OH NN COONa 15 WO 01/34135 PCT/USOO/30944 -151 A mixture of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5 tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy}-2 propylphenoxy)benzoic acid methyl ester (305 mg, 0.448 mmol), 3,5-dimethyl-4-iodoisoxazole (110 mg, 0.493 mmol), 5 cesium carbonate (293 mg, 0.899 mmol), and PdCl 2 (dppf) (15 mg, 0.018 mmol) in de-oxygenated toluene (10 mL) was heated at 95 OC for 10 h. Additional portions of 3,5-dimethyl-4 iodoisoxazole (110 mg), cesium carbonate (260 mg), and PdCl 2 (dppf) (-15 mg) were added and heating continued at 110 10 OC for 20 h. The mixture was cooled to room temperature, concentrated in vacuo, diluted with methylene chloride, and filtered down a short plug of silica gel with 20% ethyl acetate/80% hexane. The filtrate was concentrated in vacuo. The resulting colorless oil was dissolved in methylene 15 chloride (4 mL), cooled to 0 OC, and treated with iodotrimethylsilane (0.40 mL, 2.7 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 18 h. An additional portion of iodotrimethylsilane (0.70 mL) was added and stirring continued for 72 h. The 20 mixture was poured into dilute sodium thiosulfate solution. The organic layer was separated, washed with water, dried (sodium sulfate), filtered, and concentrated in vacuo. The resulting foam was dissolved in a 1:1 mixture of tetrahydrofuran/1 N hydrochloric acid (5 mL) and stirred at 25 room temperature for 18 h. The mixture was concentrated in vacuo and treated with 1 equivalent 1 N sodium hydroxide solution in ether. The resulting mixture was concentrated in vacuo to provide 59 mg (23%) of the title compound as an off-white solid. H NMR (DMSO-d 6 ) 8 7.40 (dd, J = 9, 2 Hz, 30 1H), 7.13 (dt, J = 8, 2 Hz, 1H), 6.97 (m, 2H), 6.79 (s, 1H), 6.68 (d, J = 9 Hz, 1H), 6.65 (d, J = 9 Hz, 1H), 6.60 (s, WO 01/34135 PCT/USOO/30944 -152 1H), 6.21 (d, J = 8 Hz, 1H), 4.19 (t, J = 6 Hz, 2H), 4.01 (t, J = 6 Hz, 2H), 2.66 (t, j = 8 Hz, 2H), 2.48 (q, J = 8 Hz, 2H), 2.24 (s, 3H), 2.17 (quintet, J = 6 Hz, 2H), 2.07 (s, 3 H), 1.49 (hextet, J = 8 Hz, 2H), 1.07 (t, J = 7 Hz, 5 3H), 0.85 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated for C 32

H

36

NO

7 (p+1): m/z = 546.2492. Found: -1 546.2514; IR (KBr, cm ) 3400, 1605, 1460. Example 13 10 Preparation of 2-(3-[3-(2-Ethyl-4-furan-2-yl-5 hydroxyphenoxy)propoxy]-2-propylphenoxy)-benzoic acid sodium salt. Br COOMe H Br O - O OP COOMe 15 A. Preparation of 2-(3-[3-(4-bromo-2-ethyl-5 hydroxyphenoxy)propoxy] -2-propylphenoxy)benzoic acid methyl ester. A solution of 2-{3-[3-(5-benzyloxy-4-bromo-2 ethylphenoxy) propoxy] -2-propylphenoxy} -benzoic acid methyl 20 ester (2.50 g, 3.95 mmol) in methylene chloride (40 mL) was WO 01/34135 PCT/USOO/30944 -153 cooled to -70 OC and treated with boron tribromide (0.25 mL, 2.6 mmol). After 25 min the mixture was poured into cold water and the resulting mixture extracted with methylene chloride. The combined organic extracts were washed once 5 with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo to provide 1.1 g (52%) of the title compound as a pale yellow oil. H NMR (CDCl 3 ) 8 7.89 (d, J = 9 Hz, 1H), 7.38 (t, J = 8 Hz, 1H), 7.18 (s 1H), 7.12 (d, J = 9 Hz, 1H), 7.08 10 (d, J = 2 Hz, 1H), 6.81 (d, J = 9 Hz, 1H), 6.68 (d, J = 9 Hz, 1H), 6.56 (s, 1H), 6.46 (d, J = 9 Hz, 1H), 5.40 (s, 1H), 4.18 (t, J = 6 Hz, 2H), 4.11 (t, J = 6 Hz, 2H), 3.84 (s, 3H), 2.65 (t, J = 8 Hz, 2H), 2.54 (q, J = 7 Hz, 2H), 2.32 (quintet, J = 6 Hz, 2H), 1.54 (hextet, J = 8 Hz, 2H), 1.13 15 (t, J = 7 Hz, 3H), 0.89 (t, J = 7 Hz, 3H); MS ES m/z = 541 (M - H), 543 (M - H + 2). H Br 0 0 0 COOMe TBS Br COOMe WO 01/34135 PCT/USOO/30944 -154 B. Preparation of 2-(3-(3-[4-bromo-5-(tert butyldimethylsilanyloxy) -2-ethylphenoxy] -propoxy) -2 propylphenoxy)benzoic acid methyl ester. A solution of 2-{3-[3-(4-bromo-2-ethyl-5 5 hydroxyphenoxy)propoxyl-2-propylphenoxy}benzoic acid methyl ester (1.00 g, 1.84 mmol) in methylene chloride (20 mL) was treated with imidazole (0.19 g, 2.8 mmol) and tert butyldimethylsilyl chloride (0.388 g, 2.57 mmol) at room temperature for 2 h. The mixture was poured into water and 10 the organic layer separated, washed once with water, once with saturated sodium chloride solution, filtered through a short pad of silica gel, and concentrated in vacuo to provide 1.1 g (91%) of the title compound as a colorless oil. H NMR (CDC1 3 ) 8 7.88 (d, J = 9 Hz, 1H), 7.38 (t, J = 15 8 Hz, 1H), 7.22 (s 1H), 7.12 (d, J = 9 Hz, 1H), 7.08 (d, J = 2 Hz, 1H), 6.80 (d, J = 9 Hz, 1H), 6.69 (d, J = 9 Hz, 1H), 6.45 (d, J = 9 Hz, 1H), 6.40 (s, 1H), 4.20 (t, J = 6 Hz, 2H), 4.11 (t, J = 6 Hz, 2H), 3.83 (s, 3H), 2.64 (t, J = 8 Hz, 2H), 2.54 (q, J = 7 Hz, 2H), 2.32 (quintet, J = 6 Hz, 20 2H), 1.54 (hextet, J = 8 Hz, 2H), 1.13 (t, J = 7 Hz, 3H), 1.03 (s, 9H), 0.89 (t, J = 7 Hz, 3H), 0.23 (s, 6H).

WO 01/34135 PCT/USOO/30944 -155 TBS Br O--. OJ O- COOMe H 0 I | ;0 0 0 COOMe C. Preparation of 2-(3-[3-(2-ethyl-4-furan-2-yl-5 hydroxyphenoxy)propoxy]-2-propyl-phenoxy)benzoic acid methyl 5 ester. A mixture of 2-(3-{3-[4-bromo-5-(tert butyldimethylsilanyloxy) -2-ethylphenoxy] propoxy} -2 propylphenoxy)benzoic acid methyl ester (1.05 g, 1.60 mmol), furan-2-boronic acid (0.358 g, 3.20 mmol), 10 tetrakis(triphenylphosphine)palladium(0) (0.185 g, 0.160 mmol), and 2 M aqueous sodium carbonate solution (8 mL) in tetrahydrofuran (20 mL) was heated at reflux for 18 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was 15 separated, washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 0.8 g 1 (94%) of the title compound as a colorless oil. H NMR 20 (CDCl 3 ) 8 7.90 (d, J = 9 Hz, 1H), 7.48 (s, 1H), 7.38 (t, J = 8 Hz, 1H), 7.21 (s 1H), 7.13 (s, 1H), 7.10 (d, J = 9 Hz, 1H), 7.07 (d, J = 2 Hz, 1H), 6.81 (d, J = 9 Hz, 1H), 6.69 WO 01/34135 PCT/USOO/30944 -156 (d, J = 9 Hz, 1H), 6.52 (m, 3H), 6.44 (d, J = 9 Hz, 1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.67 (t, J = 8 Hz, 2H), 2.59 (q, J = 7 Hz, 2H), 2.32 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H), 1.18 (t, J = 7 Hz, 3H), 0.91 (t, J = 7 Hz, 5 3H); MS ES m/z = 589 (p + AcO Anal. Calcd for C 32

H

3 4 0 7 : C, 72.43; H, 6.46. Found: C, 72.21; H, 6.15. OH 00 COOMe OH 0 -o' -o o0 COONa 10 D. Preparation of 2-{3-[3-(2-ethyl-4-furan-2-yl-5 hydroxyphenoxy) propoxy] -2-propylphenoxy}benzoic acid sodium salt. 2-{3-[3-(2-Ethyl-4-furan-2-yl-5-hydroxyphenoxy)propoxy]-2 15 propylphenoxy}benzoic acid methyl ester (250 mg, 0.47 mmol) was dissolved in tetrahydrofuran (4 mL) and treated with 1 N lithium hydroxide solution (2 mL) at 50 0 C for 16 h. The mixture was concentrated in vacuo and the residue diluted with water and extracted twice with ethyl acetate. The 20 combined organic extracts were washed once with water, once with saturated sodium chloride solution, dried (sodium WO 01/34135 PCT/USOO/30944 -157 sulfate), filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate and shaken with 1 N hydrochloric acid. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo. The residue 5 was dissolved in diethyl ether and treated with 1 N aqueous sodium hydroxide solution (0.32 mL). The mixture was concentrated in vacuo and azeotroped successively with diethyl ether, chloroform, and diethyl ether and dried to provide 168 mg (66%) of the title product as a cream solid. 10 H NMR (DMSO-d 6 ) 8 7.56 (s, 1H), 7.44 (d, J = 8 Hz, 1H), 7.35 (s, 1H), 7.13 (m, 1H), 6.97 (m, 2H), 6.77 (d, J = 2 Hz, 1H), 6.65 (m, 4H), 6.48 (d, J = 2 Hz, 1H), 6.24 (d, J = 9 Hz, 1H), 4.15 (t, J = 6 Hz, 2H), 3.96 (t, J = 6 Hz, 2H), 2.66 (t, J = 8 Hz, 2H), 2.42 (q, J = 7 Hz, 2H), 2.13 15 (quintet, J = 6 Hz, 2H), 1.48 (hextet, J = 8 Hz, 2H), 1.09 (t, J = 7 Hz, 3H), 0.84 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated for C 31

H

33 0 7 (p+1): m/z = 517.2226. -1 Found: 517.2230. IR (KBr, cm ) 3400, 2961, 1599, 1460.

WO 01/34135 PCT/USOO/30944 -158 Example 14 Preparation of 2-(3-(3- [2-Ethyl-5-hydroxy-4-furan-3 yl]phenoxy]propoxy}-2-propylphenoxy)benzoic acid. TBS BrI 0 0 ______0_0 COOMe H OD O - O

O

COOMe 5 A. Preparation of 2-(3-[3-(2-ethyl-4-furan-3-yl-5 hydroxyphenoxy) propoxy] -2-propyl-phenoxy}benzoic acid methyl ester. A mixture of 2-(3-{3-[4-bromo-5-(tert 10 butyldimethylsilanyloxy) -2-ethylphenoxy]propoxy}-2 propylphenoxy)benzoic acid methyl ester (2.10 g, 3.19 mmol), furan-3-boronic acid (0.722 g, 6.45 mmol), tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.32 mmol), and 2 M aqueous sodium carbonate solution (16 mL) in 15 tetrahydrofuran (30 mL) was heated at reflux for 48 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was separated, washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, 20 and concentrated in vacuo. Chromatography (silica gel, 15% ethyl acetate/85% hexane) of the residue provided 0.29 g (17%) of the title compound as a yellow oil. TOF MS ES WO 01/34135 PCT/USOO/30944 -159 exact mass calculated for C 32

H

35 0 7 (p+1): m/z = 531.2383. Found: 531.2396. H 0 0 0 COOMe H O ^" O

O

COOH 5 B. Preparation of 2-(3-[3-(2-ethyl-4-furan-3-yl-5 hydroxyphenoxy)propoxy]-2-propylphenoxy)benzoic acid sodium salt. 2-{3- [3- (2-Ethyl-4-furan-3-yl-5-hydroxyphenoxy)propoxy] -2 10 propylphenoxy}benzoic acid methyl ester (170 mg, 0.32 mmol) was dissolved in tetrahydrofuran (4 mL) and methanol (1 mL) and treated with 1 N lithium hydroxide solution (4 mL) at 50 OC for 2 h. The mixture was concentrated in vacuo and the residue acidified with hydrochloric acid and the resulting 15 mixture extracted twice with ethyl acetate. The combined organic extracts were washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 2% methanol/98% chloroform) of the residue gave 45 mg 20 of material that was again submitted to chromatography (silica gel, 1% methanol/99% chloroform) to provide 25 mg (15%) of the title compound as an oil.

WO 01/34135 PCT/USOO/30944 -160 TOF MS ES exact mass calculated for C 31

H

33 0 7 (p+1): m/z = 517.226. Found: 517.2230. 5 Example 15 Preparation of 2- (3-(3- [2-Ethyl-5-hydroxy-4 (tetrahydrofuran-3-yl)phenoxy]propoxy)-2 propylphenoxy)benzoic acid sodium salt hemihydrate. 0 Br O '--O O COOMe 0 COOMe 10 A. Preparation of 2-(3-[3-(5-benzyloxy-2-ethyl-4-furan-3 yl-phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester. A mixture of 2-{3-[3-(5-benzyloxy-4-bromo-2 15 ethylphenoxy) propoxy] -2-propylphenoxy} -benzoic acid methyl ester (3.00 g, 4.73 mmol), furan-3-boronic acid (1.06 g, 9.47 mmol), tetrakis(triphenylphosphine)palladium(0) (0.54 g, 0.47 mmol), and 2 M aqueous sodium carbonate solution (20 mL) in tetrahydrofuran (40 mL) was heated at 100 OC for 48 20 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was separated, washed once with water, once with saturated WO 01/34135 PCT/USOO/30944 -161 sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 1.9 g 1 (65%) of the title compound as a yellow oil. H NMR (CDCl 3 ) 5 8 7.88 (dd, J = 8, 2 Hz, 1H), 7.87 (s, 1H), 7.40 (m, 7H), 7.26 (s 1H), 7.05 (m, 2H), 6.80 (d, J = 9 Hz, 1H), 6.76 (d, J = 2 Hz, 1H), 6.67 (d, J = 9 Hz, 1H), 6.60 (s, 1H), 6.43 (d, J = 9 Hz, 1H), 5.11 (s, 2H), 4.18 (m, 4H), 3.83 (s, 3H), 2.66 (t, J = 8 Hz, 2H), 2.62 (q, J = 7 Hz, 2H), 2.30 10 (quintet, J = 6 Hz, 2H), 1.57 (hextet, J = 8 Hz, 2H), 1.20 (t, J = 7 Hz, 3H), 0.92 (t, J = 7 Hz, 3H); MS ES m/z = 621 -1 (p + 1); IR (CHCl 3 , cm ) 3000, 1727, 1603, 1461. 0 0 COOMe 0 H 0 0 0 COOMe 15 B. Preparation of 2-(3-{3-[2-ethyl-5-hydroxy-4 (tetrahydrofuran-3-yl)phenoxy] -propoxy) -2 propylphenoxy)benzoic acid methyl ester. A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-furan-3-yl 20 phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester (1.8 g, 2.9 mmol) in ethyl acetate (40 mL) was treated with WO 01/34135 PCT/USOO/30944 -162 10% palladium-on-carbon (0.39 g) and hydrogenated at 48 psi and 45 OC for 72 h. The mixture was cooled to room TM temperature, filtered through Celite , and the filtrate concentrated in vacuo to provide 1.2 g (77%) of the title 5 compound as a colorless oil. H NMR (CDCl 3 ) 8 7.88 (dd, J = 8, 2 Hz, 1H), 7.57 (dt, J = 8, 2 Hz, 1H), 7.09 (d, J = 9 Hz, 1H), 7.04 (d, J = 9 Hz, 1H), 6.81 (d, J = 9 Hz, 1H), 6.80 (s, 1H), 6.67 (d, J = 9 Hz, 1H), 6.44 (d, J = 9 Hz, 1H), 6.43 (s, 1H), 4.19 (m, 3H), 4.10 (m, 2H), 4.02 (dd, J = 12, 10 3 Hz, 1H), 3.88 (dd, J = 12, 8 Hz, 1H), 3.84 (s, 3H), 3.73 (q, J = 9 Hz, 1H), 3.45 (m, 1H), 2.64 (t, J = 8 Hz, 2H), 2.53 (q, J = 7 Hz, 2H), 2.38 (m, 1H), 2.28 (quintet, J = 6 Hz, 2H), 1.99 (m, 1H), 1.55 (hextet, J = 8 Hz, 2H), 1.15 (t, J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); MS ES m/z = 593 (p + -1 15 CH 3 COO); IR (CHCl 3 , cm ) 2963, 1719, 1589, 1461. Anal. Calcd for C 32

H

3 8 0 7 : C, 71.89; H, 7.16. Found: C, 71.41; H, 7.06. O H I | _ _ _ 0- 0 0 COOMe O H - aP COONa 20 WO 01/34135 PCT/USOO/30944 -163 C. Preparation of 2-(3-(3-[2-ethyl-5-hydroxy-4 (tetrahydrofuran-3-yl)phenoxy]-propoxy)-2 propylphenoxy)benzoic acid sodium salt hemihydrate. A solution of 2-(3-{3-[2-ethyl-5-hydroxy-4-(tetrahydrofuran 5 3-yl)phenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl ester (0.92 g, 1.7 mmol) in tetrahydrofuran (10 mL) and methanol (5 mL) was treated with 1 M aqueous lithium hydroxide solution (10 mL) at 55 0 C for 2 h. The mixture was allowed to cool to room temperature and stirred for an 10 additional 18 h. The mixture was concentrated in vacuo and the remaining aqueous mixture was washed once with diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and the resulting solution extracted with ethyl acetate. The ethyl acetate layer was washed once with 15 water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. The resulting colorless oil was dissolved in diethyl ether and treated with 1 N aqueous sodium hydroxide solution (1.72 mL). The resulting biphasic mixture was diluted with 20 chloroform and concentrated in vacuo. Diethyl ether was added and the mixture concentrated in vacuo. The resulting white foam was dried in vacuo at room temperature for 60 h to provide 0.78 g (84%) of the title compound: mp 67-71 OC. 1 H NMR (DMSO-d 6 ) 8 7.62 (dd, J = 8, 2 Hz, 1H), 7.30 (dt, J = 25 8, 2 Hz, 1H), 7.05 (m, 2H), 6.85 (s, 1H), 6.73 (d, J = 9 Hz, 1H), 6.70 (d, J = 9 Hz, 1H), 6.53 (s, 1H), 6.34 (d, J = 9 Hz, 1H), 4.15 (t, J = 6 Hz, 2H), 4.04 (t, J = 6 Hz, 2H), 3.95 (m, 1H), 3.88 (m, 1H), 3.75 (q, J = 9 Hz, 1H), 3.49 (m 2H), 2.60 (t, J = 8 Hz, 2H), 2.45 (q, J = 7 Hz, 2H), 2.15 30 (m, 3H), 1.90 (m, 1H), 1.48 (hextet, J = 8 Hz, 2H), 1.06 (t, WO 01/34135 PCT/USOO/30944 -164 J = 7 Hz, 3H), 0.83 (t, J = 7 Hz, 3H); MS ES m/z = 519 (p + -1 Na ); IR (CHCl 3 , cm ) 2964, 1783, 1604, 1461. Anal. Calcd for C 3 1

H

3 5 NaO 7 . 0.5 H20: C, 67.50; H, 6.58. Found: C, 67.76; H, 6.68. 5 Example 16 Preparation of 2- (3- [3- (2-Ethyl-5-hydroxy-4-pyrrolidin-2-yl phenoxy)propoxy]-2-propyl-phenoxy}benzoic acid hydrochloride 10 hydrate. 0 Br COOMe 0 N COOMe A. Preparation of 2- (2-benzyloxy-5-ethyl-4-(3- [3- (2 methoxycarbonylphenoxy) -2 15 propylphenoxy]propoxyiphenyl)pyrrole-1-carboxylic acid tert butyl ester. A mixture of 2-{3-[3-(5-benzyloxy-4-bromo-2 ethylphenoxy) propoxy] -2-propylphenoxy} -benzoic acid methyl ester (3.00 g, 4.73 mmol), N-boc pyrrole-2-boronic acid 20 (1.99 g, 9.43 mmol), tetrakis(triphenylphosphine)palladium(0) (0.54 g, 0.47 WO 01/34135 PCT/USOO/30944 -165 mmol), and 2 M aqueous sodium carbonate solution (25 mL) in tetrahydrofuran (60 mL) was heated at reflux for 40 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was 5 separated, washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 2.6 g 1 (76%) of the title compound as a solid. H NMR (CDCl 3 ) 6 10 7.88 (dd, J = 8, 2 Hz, 1H), 7.15-7.40 (m, 7H), 7.08 (m, 3H), 6.82 (d, J = 9 Hz, 1H), 6.68 (d, J = 9 Hz, 1H), 6.52 (s, 1H), 6.44 (d, J = 9 Hz, 1H), 6.23 (t, J = 4 Hz, 1H), 6.12 (m, 1H), 4.95 (s, 2H), 4.20 (t, J = 6 Hz, 2H); 4.15 (t, J = 6 Hz, 2H), 3.84 (s, 3H), 2.66 (t, J = 8 Hz, 2H), 2.60 (q, J 15 = 7 Hz, 2H), 2.30 (quintet, J = 6 Hz, 2H), 1.57 (hextet, J = 8 Hz, 2H), 1.28 (s, 9H), 1.18 (t, J = 7 Hz, 3H), 0.93 (t, J = 7 Hz, 3H); TOS MS ES exact mass calculated for

C

44

H

53

N

2 0 8 (p + NH 4 ): m/z = 737.3802. Found: 737.3804; -1 IR (CHC1 3 , cm ) 2964, 1730, 1461. 20 Anal. Calcd for C 44

H

49

NO

8 : C, 73.41; H, 6.86; N, 1.94. Found: C, 73.76; H, 6.76; N, 2.04.

WO 01/34135 PCT/USOO/30944 -166 N COOMe H N COOMe B. Preparation of 2-(5-ethyl-2-hydroxy-4-(3-[3-(2 methoxycarbonylphenoxy) -2-propylphenoxy] propoxy)phenyl) 5 pyrrolidine-1-carboxylic acid tert-butyl ester. A solution of 2-(2-benzyloxy-5-ethyl-4-{3-[3-(2 methoxycarbonylphenoxy) -2 propylphenoxylpropoxy}phenyl)pyrrole-l-carboxylic acid tert butyl ester (0.98 g, 1.4 mmol) in ethyl acetate (40 mL) was 10 treated with 10% palladium-on-carbon (0.98 g) and hydrogenated at 45 psi and 45 0 C for 25 h, at room temperature for 20 h, then at 45 0 C for 19 h. The mixture TM was cooled to room temperature, filtered through Celite and the filtrate concentrated in vacuo to provide 0.76 g 1 15 (88%) of the title compound as a colorless oil. H NMR (CDCl 3 ) 8 7.87 (dd, J = 8, 2 Hz, 1H), 7.37 (dt, J = 8, 2 Hz, 1H), 7.10 (d, J = 9 Hz, 1H), 7.04 (d, J = 9 Hz, 1H), 6.91 (s, 1H), 6.81 (d, J = 9 Hz, 1H), 6.67 (d, J = 9 Hz, 1H), 6.47 (s, 1H), 6.44 (d, J = 9 Hz, 1H), 5.09 (m, 1H), 4.18 (d, 20 J = 6 Hz, 2H), 4.14 (t, J = 6 Hz, 2H), 3.84 (s, 3H), 3.45 (m, 2H), 2.64 (t, J = 8 Hz, 2H), 2.54 (m, 3H), 2.25 (m, 5H), WO 01/34135 PCT/USOO/30944 -167 2.06 (m, 1H), 1.54 (hextet, J = 8 Hz, 2H), 1.43 (s, 9H), 1.15 (t, J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H). H N -_ 0 ~COOMe H N N 00 -- 0-/- o OP COOLi 5 C. Preparation of 2-(4-{3-[3-(2-carboxyphenoxy)-2 propylphenoxy] propoxy) -5-ethyl-2-hydroxyphenyl) pyrrolidine 1-carboxylic acid tert-butyl ester lithium salt hydrate. A solution of 2-(5-ethyl-2-hydroxy-4-{3-[3-(2 10 methoxycarbonylphenoxy) -2 propylphenoxy]propoxy}phenyl)pyrrolidine-l-carboxylic acid tert-butyl ester (0.114 g, 0.18 mmol) in a 1:1 mixture of methanol/tetrahydrofuran (4 mL) was treated with solution of 1 M lithium hydroxide (4 mL) at room temperature for 18 h. 15 The mixture was concentrated in vacuo and the residue dissolved in water. The resulting mixture was extracted with ethyl acetate. The organic extract was dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was diluted with diethyl ether, concentrated in vacuo, and 20 dried to provide 90 mg (78%) of the title compound. MS ES WO 01/34135 PCT/USOO/30944 -168 + -1 m/z = 620 (p + 1 - Li ); IR (KBr, cm ) 2964, 1672, 1603, 1416. Anal. Calcd for C 3 6

H

4 4

NO

8 Li . H 2 0: C, 67.17; H, 7.20; N, 2.18. Found: C, 66.72; H, 6.99; N, 2.27. 5 H N COOLi OH N I I 0 0 COOH D. Preparation of 2-(3-[3-(2-ethyl-5-hydroxy-4-pyrrolidin 2-yl-phenoxy)propoxy]-2-propylphenoxy}benzoic acid 10 hydrochloride hydrate. Into a solution of 2-(4-{3-[3-(2-carboxyphenoxy)-2 propylphenoxy] propoxyl -5-ethyl-2 -hydroxyphenyl) pyrrolidine 1-carboxylic acid tert-butyl ester lithium salt hydrate (0.100 g, 0.16 mmol) in anhydrous diethyl ether (5 mL) was 15 bubbled gaseous HCl. The resulting mixture was allowed to stir for 1 h. The mixture was concentrated in vacuo. Chromatography (SCX cation exchange resin, 1:1 tetrahydrofuran/methanol to dilute ammonia/methanol) of the residue provided a tan solid. This material was dissolved 20 in ether and treated with gaseous HCl. This mixture was concentrated in vacuo to provide 48 mg (52%) of the title 1 compound. H NMR (DMSO--d 6 ) 6 12.80 (bs, 1H), 10.12 (s, 1H), WO 01/34135 PCT/USOO/30944 -169 9.34 (bs, 1H), 8.36 (bs, 1H), 7.79 (dd, J = 9, 2 Hz, 1H), 7.47 (dt, J = 8, 2 Hz, 1H), 7.17 (t, J = 8 Hz, 1H), 7.12 (d, J = 9 Hz, 1H), 7.07 (s, 1H), 6.80 (d, J = 9 Hz, 1H), 6.78 (d, J = 9 Hz, 1H), 6.58 (s, 1H), 6.35 (d, J = 9 Hz, 1H), 5 4.56 (m, 1H), 4.20 (t, J = 6 Hz, 2H); 4.11 (t, J = 6 Hz, 2H), 3.25 (m, 2H), 2.50 (m, 5H), 1.90-2.60 (m, 5H), 1.44 (hextet, J = 8 Hz, 2H), 1.08 (t, J = 7 Hz, 3H), 0.82 (t, J = 7 Hz, 3H); TOS MS ES exact mass calculated for C 31

H

38 NO6 (p + 1): m/z = 520.2699. Found: 520.2672. 10 Example 17 Preparation of 2-(3- [3- (2-Ethyl-5-hydroxy-4-thiophen-3-yl phenoxy)propoxy]-2-propyl-phenoxy)benzoic acid hydrate. o N, I S 0oz Br O0 15 Known compound: Sawyer et al., J. Med. Chem. 1995, 38, 4411. 20 A. Preparation of 3- [2-benzyloxy-4- (3-chloropropoxy) -5 ethylphenyl] thiophene. A mixture of 4- (benzyloxy) -5-bromo 2-(3-chloropropoxy)ethylbenzene (1.90 g, 5.30 mmol), 3 thiopheneboronic acid (2.00 g, 15.9 mmol), tetrakis(triphenylphosphine)palladium(0) (312 mg, 0.270 25 mmol), 2 M aqueous sodium carbonate solution (4 mL), and n propanol (4 mL) in toluene (16 mL) was refluxed for 4 h. The mixture was cooled to room temperature, diluted with diethyl ether, washed once with water and once with WO 01/34135 PCT/USOO/30944 -170 saturated sodium chloride solution. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 5% ethyl acetate/95% hexane) of the residue provided 1.54 g (80%) of the title 1 5 product as a white solid: mp 65-67 OC. H NMR (CDC1 3 ) 6 7.58 (d, J = 2.8 Hz, 1H), 7.49 (d, J = 5.2 Hz, 1H), 7.45 7.30 (m, 7H), 6.62 (s, 1H), 5.13 (s, 2H), 4.14 (t, J = 5.8 Hz, 2H), 3.81 (t, J = 6.3 Hz, 2H), 2.66 (q, J = 7.5 Hz, 2H), 2.29 (quintet, J = 6.0 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H); MS -1 10 FD m/e 386 (p); IR (CHCl 3 , cm ) 2969, 1613, 1501, 1138. Anal. Calcd for C 22

H

23 0 2 C1S: C, 68.29; H, 5.99. Found: C, 68.53; H, 6.00. + HO 0 O' o Ci CN Known compound: Sawyer et al., J. Med. Chem. 1995, 38, 4411. S 0 I | O"' O OP CN 15 B. Preparation of 2-[2-propyl-3-[3-[5-(benzyloxy)-2-ethyl 4- (thiophen-3-yl) phenoxy] propoxy] phenoxy] benzonitrile. A mixture of 4- (benzyloxy) -2- (3-chloropropoxy) -5- (thiophen 3-yl)ethylbenzene (1.25 g, 3.23 mmol), 3-(2-cyanophenoxy)-2 20 propylphenol (0.82 g, 3.2 mmol), potassium iodide (0.21 g, WO 01/34135 PCT/USOO/30944 -171 1.3 mmol), potassium carbonate (1.12 g, 8.08 mmol), and methyl sulfoxide (2 mL) in 2-butanone (10 mL) was refluxed for 60 h. The mixture was cooled to room temperature, diluted with ether, and washed with water. The organic 5 layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 5% ethyl acetate/95% hexane) of the residue provided 1.31 g (67%) of the title product as a colorless oil. H NMR (CDCl 3 ) 6 7.66 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 2.9 Hz, 1H), 7.48 (d, J = 10 5.2 Hz, 1H), 7.45-7.25 (m, 8H), 7.20 (t, J = 8.2 Hz, 1H), 7.10 (t, J = 8.1 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 6.64 (s, 1H), 6.63 (d, J = 6.4 Hz, 1H), 5.11 (s, 2H), 4.26 (t, J = 6.0 Hz, 2H), 4.22 (t, J = 6.0 Hz, 2H), 2.65 (m, 4H), 2.36 (quintet, J = 5.9 Hz, 2H), 1.58 15 (hextet, J = 7.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H), 0.95 (t, -1 J = 7.3 Hz, 3H); MS FD m/e 603 (p); IR (CHCl 3 , cm ) 2967, 2250, 1613, 1501. Anal. Calcd for C 38

H

37

NO

4 S: C, 75.59; H, 6.18; N, 2.32. Found: C, 74.65; H, 6.21; N, 2.57.

WO 01/34135 PCT/USOO/30944 -172 C. Preparation of 2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4 (thiophen-3-yl) phenoxy] propoxy] phenoxy] benzonitrile. S O O '- O OP CN S OH O O O CN To a solution of 2-[2-propyl-3-[3-[5-(benzyloxy)-2-ethyl-4 5 (thiophen-3-yl)phenoxy]propoxylphenoxy]benzonitrile (900 mg, 1.49 mmol) in methylene chloride (25 mL) cooled to -78 OC was added 1 M boron tribromide solution in methylene chloride (2.99 mL, 2.99 mmol) over 2 min. The resulting deep violet solution was stirred for 30 min and allowed to 10 warm to room temperature. The mixture was diluted with water and shaken. The organic layer was separated, dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 25% ethyl acetate, 75% hexane) provided 400 mg (52%) of the title product as a colorless 15 oil. H NMR (CDCl 3 ) 8 7.84 (d, J = 4.8 Hz, 1H), 7.71 (d, J = 4.9 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H), 7.42 (t, J = 7.1 Hz, 1H), 7.27 (t, J = 6.6 Hz, 1H), 7.20 (s, 1H), 7.08 (t, J = 6.9 Hz, 1H), 6.85 (s, 1H), 6.89 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 20 4.71 (s, 1H, -OH), 4.26 (t, J = 6.0 Hz, 4H), 2.72 (q, J = 7.4 dHz, 2H), 2.59 (t, J = 7.3 Hz, 2H), 2.39 (quintet, J = WO 01/34135 PCT/USOO/30944 -173 6.1 Hz, 2H), 1.54 (hextet, J = 7.7 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). 5 D. Preparation of 2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4 (thiophen-3-yl)phenoxy]propoxy]phenoxy]benzoic acid hydrate. S OH I _|_ _| 0 O O 3 CN S OH 0 0' 0 COOH A solution of 2- [2-propyl-3-[3-[2-ethyl-5-hydroxy-4 (thiophen-3-yl)phenoxylpropoxy]phenoxy]benzonitrile (400 mg, 10 0.780 mmol) in 2:1 methanol/water (6 mL) was treated with 12.5 M aqueous sodium hydroxide (4.0 mL) at reflux for 36 h. The mixture was cooled to room temperature, diluted with water, and extracted once with diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and 15 extracted twice with methylene chloride. The combined methylene chloride layers were dried (magnesium sulfate), filtered, and concentrated in vacuo to provide a tan solid: mp 90-95 OC (dec) . H NMR (CDCl 3 ) O 8.24 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 5.0 Hz, 1H), 7.44 (t, J = 8.6 Hz, 1H), 20 7.36 (d, J = 3 Hz, 1H), 7.24 (d, J = 4.9 Hz, 1H), 7.19 (m, 2H), 7.09 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 5.38 WO 01/34135 PCT/USOO/30944 -174 (bs, 1H, -OH), 4.26 (t, J = 6.2 Hz, 2H), 4.21 (t, J = 7.1 Hz, 2H), 2.60 (m, 4H), 2.36 (quintet, J = 5.8 Hz, 2H), 1.51 (hextet, J = 7.1 Hz, 2H), 1.19 (t, J = 7.5 Hz, 3H), 0.90 (t, -1 J = 7.4 Hz, 3H); MS FD m/e 532 (p); IR (KBr, cm ) 3200 5 (br), 2961, 1697, 1457, 1110. Anal. Calcd for C 31

H

32

O

6 S

H

2 0: C, 67.62; H, 6.22. Found: C, 67.34; H, 5.87. In one embodiment the compositions of the present invention are a combination of therapeutically effective amounts of 10 the leukotriene (LTB 4 ) antagonists, noted above, and a therapeutically effective amount of an anti-cancer agent or anti-cancer agents. The composition may be formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated elixirs or solutions for convenient 15 oral administration or administered by intramuscular intravenous routes. The compounds can be administered transdermally and maybe formulated as sustained relief dosage forms and the like. In another embodiment, the anti-cancer agents are 20 formulated independently of the leukotriene (LTB 4 ) antagonists and are administered separately. The anti cancer agents may be formulated with common excipients, diluents or carriers and administered by intravenous infusion. On the other hand, the anti-cancer agents may be 25 formulated into liquids suitable for oral administration. Anti-cancer agents may also be compressed into tablets and administered orally. If the anti-cancer agents and the leukotrienes are administered separately, the anti-cancer agents may be administered before, after or during the 30 administration of the leukotriene (LTB 4 ) antagonists. If the anti-cancer agents are administered separately from the WO 01/34135 PCT/USOO/30944 -175 leukotrienes (LTB 4 ) antagonists, they must be administered within a therapeutically effective interval. The method of treating a human patient according to the 5 present invention includes both the administration of the combination of leukotriene (LTB 4 ) antagonists and an anti cancer agent as well as the separate administration of the leukotriene (LTB 4 ) antagonists and the anti-cancer agent. When administered separately, the leukotriene (LTB 4 ) 10 antagonists are formulated into formulations which may be administered by the oral and rectal routes, topically, parenterally, e.g., by injection and by continuous or discontinuous intra-arterial infusion, in the form of, for example, tablets, lozenges, sublingual tablets, sachets, 15 cachets, elixirs, gels, suspensions, aerosols, ointments, for example, containing from 1 to 10% by weight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injectable solutions and suspensions in physiologically acceptable media, and sterile 20 packaged powders adsorbed onto a support material for making injectable solutions. Advantageously for this purpose, compositions may be provided in dosage unit form, preferably each dosage unit containing from about 5 to about 500 mg (from about 5 to 50 mg in the case of parenteral or 25 inhalation administration, and from about 25 to 500 mg in the case of oral or rectal administration) of a compound of Formula I or Formula II. Dosages from about 0.5 to about 300 mg/kg per day, preferably 0.5 to 20 mg/kg, of active ingredient may be administered although it will, of course, 30 readily be understood that the amount of the compound or compounds of Formula I actually to be administered will be determined by a physician, in the light of all the relevant WO 01/34135 PCT/USOO/30944 -176 circumstances including the condition to be treated, the choice of compound to be administered and the choice of route of administration and therefore the above preferred dosage range is not intended to limit the scope of the 5 present invention in any way. The formulations useful for separate administration of the leukotriene (LTB 4 ) antagonists will normally consist of at least one compound selected from the compounds of Formula 10 I and Formula II mixed with a carrier, or diluted by a carrier, or enclosed or encapsulated by an ingestible carrier in the form of a capsule, sachet, cachet, paper or other container or by a disposable container such as an ampoule. A carrier or diluent may be a solid, semi-solid or 15 liquid material which serves as a vehicle, excipient or medium for the active therapeutic substance. Some examples of the diluents or carrier which may be employed in the pharmaceutical compositions of the present invention are lactose, dextrose, sucrose, sorbitol, mannitol, propylene 20 glycol, liquid paraffin, white soft paraffin, kaolin, fumed silicon dioxide, microcrystalline cellulose, calcium silicate, silica, polyvinylpyrrolidone, cetostearyl alcohol, starch, modified starches, gum acacia, calcium phosphate, cocoa butter, ethoxylated esters, oil of theobroma, arachis 25 oil, alginates, tragacanth, gelatin, syrup, methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol and propellants such as trichloromonofluoromethane, 30 dichlorodifluoromethane and dichlorotetrafluoroethane. In the case of tablets, a lubricant may be incorporated to prevent sticking and binding of the powdered ingredients in WO 01/34135 PCT/USOO/30944 -177 the dies and on the punch of the tableting machine. For such purpose there may be employed for instance aluminum, magnesium or calcium stearates, talc or mineral oil. 5 Preferred pharmaceutical forms of the present invention are capsules, tablets, suppositories, injectable solutions, creams and ointments. Especially preferred are formulations for inhalation application, such as an aerosol, and for oral ingestion. 10 Pharmaceutical Compositions of the Invention The pharmaceutical composition of the invention comprises as essential ingredients: 15 (a) an LTB 4 antagonist, and (b) an anti-cancer agent. When the pharmaceutical composition of the invention is prepared in injectable form it is a composition comprising as ingredients: 20 (a) an LTB 4 antagonist, (b) an anti-cancer agent, and (c) an injectable liquid carrier. Pharmaceutically acceptable carriers are those well known in the medical arts, such as sterile water, sterile water 25 containing saline, and sterile water containing sugars and/or saline. a. Ratio and Amount of Ingredients in the Composition of the Invention 30 The essential ingredients (a) an LTB 4 antagonist and (b) anti-cancer compound are present in the formulation in WO 01/34135 PCT/USOO/30944 -178 such proportion that a dose of the formulation provides a pharmaceutically effective amount of each ingredient to the patient being treated. Typically, the weight ratio of LTB 4 antagonist to anti-cancer agent 1:100 to 100 to 1, 5 preferable from 10:1 to 1:10 and most preferable from 1:4 to 4:1. The following formulation examples may employ as active compounds any of the leukotriene (LTB 4 ) antagonists noted 10 above. The examples are illustrative only and are not intended to limit the scope of the invention in any way. FORMULATION EXAMPLE 1 15 Hard gelatin capsules are prepared using the following ingredients: Quantity (mg/capsule) 20 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) propoxy) -6- (4-carboxy phenoxy)phenyl)propanoic acid 250 Starch 200 25 Magnesium stearate 10 The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.

WO 01/34135 PCT/USOO/30944 -179 FORMULATION EXAMPLE 2 5 A tablet is prepared using the ingredients below: Quantity (mg/capsule) 1- (4- (Carboxymethoxy)phenyl) -1- (1H tetrazol-5-yl)-6-(2-ethyl-4-(4 10 fluorophenyl) -5-hydroxyphenoxy) hexane 250 Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 15 Magnesium stearate 5 The components are blended and compressed to form tablets each weighing 665 mg. 20 WO 01/34135 PCT/USOO/30944 -180 FORMULATION EXAMPLE 3 An aerosol solution is prepared containing the 5 following components: Weight % 3-[4-[7-Carboxy-9-oxo-3-[3-[2-ethyl-4 (4-fluorophenyl)-5-hydroxyphenoxy]propoxy] 10 9H-xanthene]]propanoic acid 0.25 Ethanol 30.00 Propellant 11 10.25 15 (trichlorofluoromethane) Propellant 12 29.75 (Dichlorodifluoromethane) 20 Propellant 114 29.75 (Dichlorotetrafluoroethane) The active compound is dissolved in the ethanol and the solution is added to the propellant 11, cooled to -300C. and 25 transferred to a filling device. The required amount is then fed to a container and further filled with the pre-mixed propellants 12 and 114 by means of the cold-filled method or pressure-filled method. The valve units are then fitted to the container. 30 WO 01/34135 PCT/USOO/30944 -181 FORMULATION EXAMPLE 4 Tablets each containing 60 mg of active ingredient are made up as follows: 5 2- [2-Propyl-3- [3- [2-ethyl-5-hydroxy-4- (4 fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid sodium salt 60 mg 10 Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone 4 mg 15 (as 10% solution in water) Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg 20 Talc 1 mg Total 150 mg 25 The active ingredient, starch and cellulose are passed through a No. 45 mesh (355 pm) U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh (1.4 mm)U.S. sieve. The granules so produced 30 are dried at 50-60 0 C and passed through a No. 18 mesh (1.00 pm) U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh (250 pn) U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield 35 tablets each weighing 150 mg.

WO 01/34135 PCT/USOO/30944 -182 FORMULATION EXAMPLE 5 Capsules each containing 80 mg of medicament are made as follows: 5 5-[3-[2-(1-Carboxy)ethyl]-4-[3-[2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy]propoxy] phenyl]-4-pentynoic acid 80 mg 10 Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg 15 Total 200 mg The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh 20 (355 pim) U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities. FORMULATION EXAMPLE 6 25 Suppositories each containing 225 mg of active ingredient are made as follows: 3-(5-(6-(4-(4-Fluorophenyl)-5-hydroxy-2 30 ethylphenoxy)propoxy)-2-carboxymethyl 1,2,3,4-tetrahydronaphthalen-1(2H) one)propanoic acid 225 mg Unsaturated or saturated fatty 35 acid glycerides to 2,000 mg WO 01/34135 PCT/USOO/30944 -183 The active ingredient is passed through a No. 60 mesh (250 pm) U.S. sieve and suspended in the fatty acid glycerides previously melted using the minimum heat 5 necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool. FORMULATION EXAMPLE 7 10 Suspensions each containing 50 mg of medicament per 5 mL dose are made as follows: 2-[2-Propyl-3-[3-[2-ethyl-4-(4-fluorophenyl) 15 5-hydroxyphenoxy]propoxy]phenoxy]benzoic acid 50 mg Sodium carboxymethyl cellulose 50 mg 20 Sugar 1 g Methyl paraben 0.05 mg Propyl paraben 0.03 mg 25 Flavor q.v. Color q.v. 30 Purified water to 5 mL The medicament is passed through a No. 45 mesh (355 pm) U.S. sieve and mixed with the sodium carboxymethylcellulose, sugar, and a portion of the water to 35 form a suspension. The parabens, flavor and color are dissolved and diluted with some of the water and added, with WO 01/34135 PCT/USOO/30944 -184 stirring. Sufficient water is then added to produce the required volume. The leukotriene (LTB 4 ) antagonists are generally 5 administered prior, during and after the anti-cancer agent or agents are administered. If the leukotriene (LTB 4 ) antagonists are administered before or after the anti-cancer agent or agents, they should be administered within a therapeutically effective interval. 10 ASSAY EXAMPLE 1 The Nude Mouse Xenograft test used to evaluate anti oncolytic agents of this invention is well known and 15 generally described in the textbook; Beverly A Teicher, Editor, Anticancer Drug Development Guide, Humana Press, Totowa, New Jersey, 1997, p.75-124 (ISBN 0-89603-461-5); the disclosure of which is incorporated herein by reference. The xenograft test is more particularly described as 20 follows: Male or female nude mice, selected as appropriate to the gender of the tumor (Charles River), were treated with total body gamma Radiation (450 rads). After 24 hours, 25 human DU-145 prostate carcinoma, human H460 and Calu-6 non small cell lung carcinomas, human HCT116 and HT29 colon carcinomas, and human MX-1 breast carcinoma (human DU-145 prostate carcinoma, human NCI-H460 and Calu-6 non-small cell lung carcinomas, and human HCT116 and HT29 colon carcinomas 30 available from the American Type Culture Collection, Manassas, VA; human MX-1 breast carcinoma available from the National Cancer Institute, Bethesda, MD), prepared from a WO 01/34135 PCT/USOO/30944 -185 brie of donor tumors (5 x 106 cells), were implanted subcutaneously in a hind-leg of the mice. The mice were treated with 2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxylphenoxy] benzoic acid (Formula 5 IV), at dosages of 30, 100, 200, or 300 mg per kilogram daily, administered orally, beginning 4 days after the tumor cell implantation. An anti-cancer agent (irinotecan, paclitaxel, 5-fluorouracil, carboplatin, mitoxantrone, oxaliplatin, or indomethacin) was administered 10 intraperitoneally or intravenously (paclitaxel) at dosages ranging from 30, 30, 24, 50, 1.6, 5, and 5 mg/kg, respectively. Tumor response was monitored by tumor volume 15 measurements performed twice per week over the course of 60 90 days. Body weights were determined as a general measurement of toxicity. The mice were divided into an untreated control group and multiple treatment groups with five mice in each group. 20 The data was analyzed by determining the mean tumor volume for the control group and each treatment group over the course of the experiment. The tumor growth delay was calculated as the difference in days for the treatment 25 versus the control tumors to reach the volume of 1000 mm 3

.

WO 01/34135 PCT/USOO/30944 -186 Table 1 Mouse Xenograft Test Results Growth Delay of Colon Tumor(1) With Oxaliplatin Treatment Dose Dose TGD TGD, Formula IV OXAL sem Formula IV 100 7.5 0.6 Formula IV 300 - 18.2 1.7 OXAL - 5 13.9 1.3 Formula IV 100 5 7.8 0.7 + OXAL Formula IV 300 5 17.0 1.6 + OXAL 5 (1) = Human HT29 colon carcinoma Formula IV = the LTB 4 antagonist, 2-[2-propyl-3-[3-[3 ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid OXAL = Oxaliplatin; (SP-4-2)-[(1R,2R)-1,2 10 cyclohexanediamine-KN,KN'] (ethanedioato(2-) -KO1,KO2] Platinum; C 8

H

14

N

2 0 4 Pt; Chemical Abstract Registry Number 61825-94-3 Dose = milligrams per kilogram mouse body weight TGD = average tumor growth delay in days 15 sem = standard error of the mean WO 01/34135 PCT/USOO/30944 -187 Table 2 Mouse Xenograft Test Results Growth Delay of Colon Tumor( 2 ) With Indomethacin Treatment Dose Dose TGD TGD, Formula IV INDO sem Formula IV 100 7.5 0.6 Formula IV 300 - 18.2 1.7 INDO - 5 13.9 1.3 Formula IV 100 5 16.7 1.6 + INDO Formula IV 300 5 21.5 2.2 + INDO 5 (2) = Human HT29 colon carcinoma INDO = Indomethacin; 1- (4-Chlorobenzoyl) -5-methoxy-2 methyl-lH-indole-3-acetic acid; C 1 9

H

1 6 ClNO 4 ; molecular weight 357.81; Chemical Abstract Registry Number 53-86-1 WO 01/34135 PCT/USOO/30944 -188 Table 3 Mouse Xenograft Test Results Growth Delay of Colon Tumor( 3 ) With 5-Fluorouracil 5 Treatment dose dose TGD TGD, sem Formula IV 5-FU Formula IV 100 - 9.7 1.8 5-FU - 30 14.4 2.3 Formula IV 100 30 25.4 3.8 + 5-FU (3) = Human HCT116 colon carcinoma 5-FU = 5-Fluorouracil; 5-Fluoro-2,4(lH,3H) pyrimidinedione; 2,4-dioxo-5-fluoropyrimidine;

C

4

H

3

FN

2 02; molecular weight 130.08; Chemical Abstract 10 Registry Number 51-21-8 WO 01/34135 PCT/USOO/30944 -189 Table 4 Mouse Xenograft Test Results Growth Delay of Colon Tumor(4) With Irinotecan Treatment dose Dose TGD TGD, sem Formula IV IRIN Formula IV 100 - 9.7 1.8 IRIN - 30 8.3 1.9 Formula IV 100 30 22.8 3.7 + IRIN 5 (4) = Human HCT116 colon carcinoma IRIN = Irinotecan; [1,4' -Bipiperidine] -1' -carboxylic acid; (4S)-4,11-diethyl-3,4,12,14-tetrahydro-4 hydroxy-3, 14-dioxo-lH pyrano[3',4' :6,7]indolizino[1,2-b]quinolin-9-yl 10 ester; C 33

H

38

N

4 0 6 ; Chemical Abstract Registry Number 97682-44-5 WO 01/34135 PCT/USOO/30944 -190 Table 5 Mouse Xenograft Test Results Growth Delay of Non-Small Cell Lung Tumor(s) With Paclitaxel 5 Treatment dose dose . TGD TGD, sem Formula IV PACL Formula IV 30 - 10.9 1.0 Formula IV 100 - 13.2 1.2 Formula IV 200 - 13.9 1.3 PACL - 24 7.6 0.7 Formula IV 30 24 9.7 1.0 + PACL Formula IV 100 24 12.8 1.3 + PACL Formula IV 200 24 18.6 1.9 + PACL (5) = Human H460 non-small cell lung carcinoma PACL = Paclitaxel; C 47

H

51

NO

14 ; (CCR,fOS)- $ (benzoylamino) -a-hydroxy-Benzenepropanoic acid (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b 10 bis (acetyloxy) -12- (benzoyloxy) 2a, 3,4, 4a, 5,6,9,10,11,12, 12a, 12b-dodecanhydro-4, 11 dihydroxy-4a, 8,13, 13-tetramethyl-5-oxo-7, 11-methano 1H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester; Chemical Abstract Registry Number 33069-62-4 WO 01/34135 PCT/USOO/30944 -191 Table 6 Mouse Xenograft Test Results Growth Delay of Non-Small Cell Lung Tumor( 6 ) With Carboplatin 5 Treatment dose dose TGD TGD, sem Formula IV CARB Formula IV 30 - 10.9 1.0 Formula IV 100 - 13.2 1.2 Formula IV 200 - 13.9 1.3 CARB - 50 10.7 1.1 Formula IV 30 50 17.7 1.6 + CARB Formula IV 100 50 19.1 2.0 + CARB Formula IV 200 50 33.3 3.4 + CARB (6) = Human H460 non-small cell lung carcinoma CARB = Carboplatin; (SP-4-2)-Diammine [1, 1 cyclobutanedicarboxylato (2-) -0,O' ]platinum; 1,1 cyclobutanedicarboxylic acid platinum complex; 10 C 6

H

12

N

2 0 4 Pt; molecular weight 371.25; Chemical Abstracts Registry Number 41575-94-4 WO 01/34135 PCT/USOO/30944 -192 Table 7 Mouse Xenograft Test Results Growth Delay of Non-Small Cell Lung Tumor (7) With Paclitaxel 5 Treatment dose dose TGD TGD, sem Formula IV PACL Formula IV 30 - 7.4 0.6 Formula IV 100 - 10.0 0.8 Formula IV 200 - 17.9 1.6 PACL - 24 8.2 0.7 Formula IV 30 24 10.6 0.8 + PACL Formula IV 100 24 15.0 1.3 + PACL Formula IV 200 24 16.6 1.7 + PACL (7) = Human Calu-6 non-small cell lung carcinoma PACL = Paclitaxel; C 47

H

5 1

NO

1 4 ; (cR, PS) - 0 (benzoylamino)-a-hydroxy-Benzenepropanoic acid (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b 10 bis (acetyloxy) -12- (benzoyloxy) 2a, 3,4, 4a, 5,6,9,10,11,12, 12a, 12b-dodecanhydro-4, 11 dihydroxy-4a, 8,13, 13-tetramethyl-5-oxo-7, 11-methano 1H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester; Chemical Abstract Registry Number 33069-62-4 WO 01/34135 PCT/USOO/30944 -193 Table 8 Mouse Xenograft Test Results Growth Delay of Non-Small Cell Lung Tumor(8) With Carboplatin 5 Treatment dose dose TGD TGD, sem Formula IV CARB Formula IV 30 - 7.4 0.6 Formula IV 100 - 10.0 0.8 Formula IV 200 - 17.9 1.6 CARB - 50 3.1 0.3 Formula IV 30 50 6.1 0.5 + CARB Formula IV 100 50 7.9 0.8 + CARB Formula IV 200 50 22.6 2.1 + CARB (8) = Human Calu-6 non-small cell lung carcinoma CARB = Carboplatin; (SP-4-2)-Diammine[1, 1 cyclobutanedicarboxylato(2-) -0,0' ]platinum; 1,1 cyclobutanedicarboxylic acid platinum complex; 10 C 6

H

1 2

N

2 0 4 Pt; molecular weight 371.25; Chemical Abstracts Registry Number 41575-94-4 WO 01/34135 PCT/USOO/30944 -194 Table 9 Mouse Xenograft Test Results Growth Delay of Breast Tumor With Paclitaxel 5 Treatment dose dose TGD TGD, sem Formula IV PACL Formula IV 30 - 3.8 0.3 Formula IV 100 - 6.2 0.4 PACL - 24 30.3 3.0 Formula IV 30 24 52.7 5.1 + PACL Formula IV 100 24 75.0 8.0 + PACL (9) = Human MX-1 breast carcinoma PACL = Paclitaxel; C 4 7

H

5 1

NO

1 4 ; (CR,1OS)- 0 (benzoylamino) -a-hydroxy-Benzenepropanoic acid (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b 10 bis (acetyloxy) -12- (benzoyloxy) 2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecanhydro-4,11 dihydroxy-4a, 8,13, 13-tetramethyl-5-oxo-7, 11-methano 1H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester; Chemical Abstract Registry Number 33069-62-4 WO 01/34135 PCT/USOO/30944 -195 Table 10 Mouse Xenograft Test Results Growth Delay of Breast Tumor"l 0 ) With Carboplatin 5 Treatment dose dose TGD TGD, sem Formula IV CARB Formula IV 30 - 3.8 0.3 Formula IV 100 - 6.2 0.4 CARB - 50 10.3 1.0 Formula IV 30 50 18.8 2.0 + CARB Formula IV 100 50 37.5 4.0 + CARB (10) = Human MX-1 breast carcinoma CARB = Carboplatin; (SP-4-2) -Diammine[1,1 cyclobutanedicarboxylato (2-) -0,O' ]platinum; 1,1 cyclobutanedicarboxylic acid platinum complex; 10 C 6

H

12

N

2 0 4 Pt; molecular weight 371.25; Chemical Abstracts Registry Number 41575-94-4 WO 01/34135 PCT/USOO/30944 -196 Table 11 Mouse Xenograft Test Results Growth Delay of Prostate Tumor"(11 With Mitoxantrone 5 Treatment dose dose TGD TGD, sem Formula IV MITO Formula IV 30 - 6.7 0.4 Formula IV 100 - 10.9 1.0 Formula IV 200 - 12.4 1.1 MITO - 1.6 2.8 0.3 Formula IV 30 1.6 5.0 0.4 + MITO Formula IV 100 1.6 11.2 1.0 + MITO Formula IV 200 1.6 14.2 1.3 + MITO (11) = Human DU-145 prostate carcinoma MITO = Mitoxantrone; 1,4-Dihydroxy-5,8-bis[ [2-[ (2 hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione; 1, 4-dihydroxy-5, 8-bis [[2- [(2 10 hydroxyethyl)amino]ethyl]amino]-9,10-anthraquinone;

C

22

H

28

N

4 0 6 ; molecular weight 444.09; Chemical Abstracts Registry Number 65271-80-9 WO 01/34135 PCT/USOO/30944 -197 Table 12 Mouse Xenograft Test Results Growth Delay of Prostate Tumor (12) With Oxaliplatin 5 Treatment dose dose TGD TGD, sem Formula IV OXAL Formula IV 30 - 6.7 0.4 Formula IV 100 - 10.9 1.0 Formula IV 200 - 12.4 1.1 OXAL - 5 10.3 0.9 Formula IV 30 5 12.9 1.2 + OXAL Formula IV 100 5 14.4 1.4 + OXAL Formula IV 200 5 16.2 1.5 + OXAL (12) = Human DU-145 prostate carcinoma OXAL = Oxaliplatin; (SP-4-2)-[(lR,2R)-1,2 cyclohexanediamine-KN, KN'] [ethanedioato (2-) -KO1,KO2] Platinum; C 8

H

1 4

N

2 0 4 Pt; Chemical Abstract Registry 10 Number 61825-94-3 WO 01/34135 PCT/USOO/30944 -198 Table 13 Mouse Xenograft Test Results Growth Delay of Prostate Tumor (13) With Paclitaxel 5 Treatment dose dose TGD TGD, sem Formula IV PACL Formula IV 30 - 6.7 0.4 Formula IV 100 - 10.9 1.0 Formula IV 200 - 12.4 1.1 PACL - 24 3.2 0.3 Formula IV 30 24 7.1 0.6 + PACL Formula IV 100 24 8.8 0.9 + PACL (13) Human DU-145 prostate carcinoma PACL = Paclitaxel; C 47

H

5

NO

1 4 ; (QR, PS) - $ (benzoylamino) -a-hydroxy-Benzenepropanoic acid (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b 10 bis (acetyloxy) -12- (benzoyloxy) 2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecanhydro-4,11 dihydroxy-4a, 8,13, 13-tetramethyl-5-oxo-7, 11-methano 1H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester; Chemical Abstract Registry Number 33069-62-4.

Claims (42)

1. A composition of matter comprising a 5 therapeutically effective amount of a leukotriene (LTB 4 ) antagonist and one or more anti-cancer agents.

2. The composition of claim 1 wherein the leukotriene (LTB 4 ) antagonist is represented by the formula (I) 10 H X R3 R2 Y >CH 2 Y2 R4 R1 Z (I) wherein: 15 X is selected from the group consisting of, (i) a five membered substituted or unsubstituted heterocyclic radical containing from 1 to 4 hetero atoms independently selected from sulfur, nitrogen or 20 oxygen; and (ii) a fused bicyclic radical wherein a carbocyclic group is fused to two adjacent carbon atoms of the five membered heterocyclic radical, (i); 25 WO 01/34135 PCT/USOO/30944 -200 Yi is a bond or divalent linking group containing 1 to 9 atoms; Y2 and Y 3 are divalent linking groups independently selected 5 from -CH 2 -, -0-, or -S-; Z is an Acidic Group; R1 is C 1 -C 10 alkyl, aryl, C 3 -C 8 cycloalkyl, C 2 -C 10 alkenyl, 10 C 2 -C 10 alkynyl, C 6 -C 2 0 aralkyl, C 6 -C 20 alkaryl, C 1 -C 10 haloalkyl, C 6 -C 20 aryloxy, or C 1 -Cig alkoxy; R2 is hydrogen, halogen, C 1 -C 10 haloalkyl, C 1 -C 10 alkoxy, Cl-C 10 alkyl, C 3 -C 8 cycloalkyl, Acidic Group, or -(CH 2 ) 1 - 7 -(Acidic Group); 15 R3 is hydrogen, halogen, C 1 -C 10 alkyl, aryl, C 1 -C 10 haloalkyl, Ci-C 10 alkoxy, C 6 -C 2 0 aryloxy, or C3-C8 cycloalkyl; 20 R4 is Ci-C 4 alkyl, C 3 -C 4 cycloalkyl, -(CH 2 )1-7-(C 3 -C 4 cycloalkyl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, benzyl, or aryl; and n is 0, 1, 2, 3, 4, 5, or 6; 25 or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof, in combination with a therapeutically effective amount of an anti-cancer agent or a pharmaceutically acceptable salt, solvate, or prodrug 30 derivative thereof. WO 01/34135 PCT/USOO/30944 -201

3. The composition of claim 2 wherein X is a heterocyclic radical selected from the group consisting of substituents represented by the following formulae: 5 R11 R11 R11 0 , S , N R10 R11 R11 NR11 0 S 0 / R11 R11 N-N R11 NN S , N 0 R10 N-N R1 1 NR11 N-N N N S , N N R10 R10 N NR1 1 N R11 N R11 N N S N I / 10 R10 R10 N--N R1 N-N SN N N ON WO 01/34135 PCT/USOO/30944 -202 R11 N N R11 _zN N N S 0 S /7R10 N N N' N S , 0 ' R11, 0 S ' N 5 H R10 N R11 N 'and R11 R10 where R10 is a radical selected from hydrogen or 10 Cl-C 4 alkyl; and Rl is a radical selected from hydrogen, halo, CI-C1 0 alkyl, C 1 -C 10 haloalkyl, C 1 -C 10 alkoxy, aryl, or C 6 -C 20 aryloxy.

4. The composition of claim 2 wherein the Ri, R2, R3 15 and R4 groups for substitution in formula (I) are selected from the following variables coded RO1 thru R16 WO 01/34135 PCT/USOO/30944 -203 R variables R1 R2 R3 R4 Combination group group group group Code choice choice choice choice R01 R1 R2 R3 R4 R02 R1 R2 R3 PG1-R4 R03 R1 R2 PG1-R3 R4 R04 R1 R2 PGl-R3 PG1-R4 R05 R1 PG1-R2 R3 R4 R06 R1 PG1-R2 R3 PGl-R4 R07 R1 PG1-R2 PG1-R3 R4 R08 R1 PG1-R2 PG1-R3 PG1-R4 R09 PGl-R1 R2 R3 R4 R10 PG1-01 R2 R3 PG1-R4 R11 PG1-R1 R2 PGI-R3 R4 R12 PG1-R1 R2 PG1-R3 PGl-R4 R13 PGI-R1 PG1-R2 R3 R4 R14 PGl-R1 PG1-R2 R3 PG1-R4 R15 PG1-R1 PGl-R2 PG1-R3 R4 R16 PG1-Rl PG1-R2 PGl-R3 PGl-R4 and; 5 the Y1, Y2, and Y3 groups for substitution in formula (I) are selected from the following variables coded Y01 thru Y27: Y variables Y1 group Y2 group Y3 group combination choice choice choice code Y01 Y1 Y2 Y3 Y02 Yl Y2 PG1-Y3 Y03 Y1 Y2 PG2-Y3 YO4 Y1 PG1-Y2 Y3 Y05 Yl PG2-Y2 Y3 Y06 Y1 PG1-Y2 PG1-Y3 YO7 Yl PGl-Y2 PG2-Y3 Y08 Y1 PG2-Y2 PG1-Y3 Y09 Yl PG2-Y2 PG2-Y3 Y10 PG1-Y1 Y2 Y3 Y11 PGl-Y1 Y2 PGl-Y3 Y12 PGl-Y1 Y2 PG2-Y3 Y13 PG1-Y1 PG1-Y2 Y3 WO 01/34135 PCT/USOO/30944 -204 Y14 PGl-Yl PG1-Y2 PG1-Y3 Y15 PG1-Y1 PG1-Y2 PG2-Y3 Y16 PG1-Yl PG2-Y2 Y3 Y17 PG1-Yl PG2-Y2 PG1-Y3 Y18 PG1-Yl PG2-Y2 PG2-Y3 Y19 PG2-Y1 Y2 Y3 Y20 PG2-Y1 Y2 PG1-Y3 Y21 PG2-Y1 Y2 PG2-Y3 Y22 PG2-Y1 PG1-Y2 Y3 Y23 PG2-Yl PG1-Y2 PG1-Y3 Y24 PG2-Yl PG1-Y2 PG2-Y3 Y25 PG2-Y1 PG2-Y2 Y3 Y26 PG2-Y1 PG2-Y2 PG1-Y3 Y27 PG2-Yl PG2-Y2 PG2-Y3 and; 5 the X and Z groups and the n variable for substitution in formula (I) are selected from the following variables coded XZnO1 thru XZn24: XZn variables X Z n integer combination group Group group code choice Choice choice XZnOl X Z n XZnO2 X Z PG1-n XZnO3 X Z PG2-n XZnO4 X PG1-Z n XZn05 X PG2-Z n XZnO6 X PG3-Z n XZnO7 X PGl-Z PG1-n XZn08 X PG2-Z PGl-n XZnO9 X PG3-Z PG1-n XZn1O X PGl-Z PG2-n XZnll X PG2-Z PG2-n XZn12 X PG3-Z PG2-n XZnl3 PG1-X Z n XZnl4 PG1-X Z PG1-n XZnl5 PG1-X Z PG2-n XZn16 PG1-X PGl-Z n XZnl7 PG1-X PG2-Z n WO 01/34135 PCT/USOO/30944 -205 XZn18 PG1-X PG3-Z n XZn19 PG2-X PG1-Z PG1-n XZn20 PG2-X PG2-Z PG1-n XZn2l PG2-X PG3-Z PG1-n XZn22 PG2-X PG1-Z PG2-n XZn23 PG2-X PG2-Z PG2-n XZn24 PG2-X PG3-Z PG2-n

5. The composition of claim 2 wherein the leukotriene B4 antagonist is described by formula (II): H X2 R22 0 -O " '> O H 2 0 0 R21 Z2 5 wherein; X2 is a heterocyclic radical selected from, N S 10 , or S WO 01/34135 PCT/USOO/30944 -206 R21 is ethyl, 2-propen-1-yl, 3-propen-1-yl, n-propyl, iso-propyl, n-butyl, sec-butyl, or tert-butyl; and R22 is hydrogen, n-butyl, sec-butyl, flouro, chloro, 5 -CF 3 , or tert-butyl. Z2 is the Acidic Group selected from carboxyl, tetrazolyl, or N-sulfonamidyl; 10 or a salt, solvate or prodrug thereof.

6. The composition of claim 5 wherein the leukotriene antagonist is a compound selected from the following: 15 /MN OH OC COOH .H -HCI /'N OH N COOH 20 WO 01/34135 PCT/USOO/30944 -2 07 N OH COCH N-N' OH COOH 5 N- 0 OH COOH 10 Th-N' OH N. COOH WO 01/34135 PCT/USOO/30944 -208 ONOOOO O O O OH COOMe OH COOH 5 N_ OH COOH -NOH I COOH 0 OH COONa 10 WO 01/34135 PCT/USOO/30944 -209 OH COOH OH COOH 5 O OH 0 COONa OH NN HCI 0**' "o N COOH S OH COOH 10 WO 01/34135 PCT/USOO/30944 -2 10 .N-N OH COOH NzN OH 0~ ,- o N N COOH 5 .S-N OH N . I COOH N-N OH (I I COOH 10 OH S N COOH WO 01/34135 PCT/USOO/30944 -211 N OH II 0 COOH or OH S COOH 5 or an acid, salt, solvate or prodrug derivative thereof.

7. The composition of claim 5 wherein the leukotriene antagonist is a compound selected from the following: 10 S OH O O O COOH O OH OCO O O COONa WO 01/34135 PCT/USOO/30944 -212 OH S I I OO O? COOH ,N- OH 01 COOH 5 OH O OI COOH or OH O O 1 O OP COOH 10 or an acid, salt, solvate or prodrug derivative thereof. WO 01/34135 PCT/USOO/30944 -213

8. The composition of claim 1 the leukotriene (LTB 4 ) antagonist is represented by a compound of the structure (Formula A): X'-Y'-Z'-A'-R 4' 5 R, Formula A or a pharmaceutically acceptable base addition salt thereof, wherein: 10 R 1 , is Cl-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, Cl-C4 alkoxy, (Cl-C4 alkyl)thio, halo, or R2-substitutedphenyl; each R2' and R3' are each independently hydrogen, halo, hydroxy, Cl-C4 alkyl, CI-C4 alkoxy, (Ci-C4 alkyl)-(O)q S-, 15 trifluoromethyl, or di-(Cl-C3 alkyl)amino; X' is -0-, -S-, -C(=O), or -CH2-; Y' is -0- or -CH2-; or when taken together, -X'-Y'- is -CH=CH- or -C=C-; Z' is a straight or branched chain Ci-C1o alkylidenyl; 20 A' is a bond, -0-, -S-, -CH=CH-, or -CRaRb-, where Ra and Rb are each independently hydrogen, Cl-C5 alkyl, or R7 substituted phenyl, or when taken together with the carbon atom to which they are attached form a C4-C8 cycloalkyl ring; 25 WO 01/34135 PCT/USOO/30944 -214 R 4 , is R 6 , or taken from one of the following formulae: R\ ,-G-R 6 , O (K)p-W-R 6 (CHO 0 5 0 RR W-R 6 R7 W-R 6 T R 7 W-R 6 R7 WO 01/34135 PCT/USOO/30944 -215 wherein: each R6 is independently -COOH, 5-tetrazolyl, CON(R 9 ) 2 , or -CONHSO 2 R 10 ; each R7 is hydrogen, Cl-C4 alkyl, C2-C5 alkenyl, C2-C5 5 alkynyl, benzyl, methoxy, -W-R6, -T-G-R6, (Cl-C4 alkyl)-T (Cl-C4 alkylidenyl)-O-, or hydroxy; R8 is hydrogen or halo; each R 9 is independently hydrogen, phenyl, or CI-C4 alkyl, or when taken together with the nitrogen atom form a 10 morpholino, piperidino, piperazino, or pyrrolidino group; Rio is Cl-C4 alkyl or phenyl; R11 is R2, -W-R6, or -T-G-R6; each W is a bond or a straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms; 15 each G is a straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms; each T is a bond, -CH2-, -0-, -NH-, -NHCO-, -C(=0)-, or (O)q S-; K is -C(=O)- or -CH(OH)-; 20 each q is independently 0, 1, or 2; p is 0 or 1; and t is 0 or 1; provided when X is -0- or -S-, Y is not -0-; provided when A is -0- or -S-, R4 is not R6; 25 and provided W is not a bond when p is 0; and the pharmaceutically-acceptable salts thereof. WO 01/34135 PCT/USOO/30944 -216

9. The composition of claim 8 wherein R4' is selected from the following formulae: O T T 7 5

10. The composition of claim 9 wherein R4'is: R 8 W--R 6 T 7

11. The composition of claim 10 wherein said compound 10 is selected from the group (A) to (KKKK) consisting of: A) 2-Methyl-2-(lH-tetrazol-5-yl)-7-(2-ethyl-4-(4 f luorophenyl) -5-hydroxyphenoxy) heptane; B) 2-Methyl-2-(lH-tetrazol-5-yl)-7-(2-ethyl-4 15 (3-f luorophenyl) -5-hydroxyphenoxy) heptane; C) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy) -6- (4 dimethylaminocarbonylbutyloxy)phenyl)propion 20 ic acid; WO 01/34135 PCT/USOO/30944 -217 D) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; 5 E) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 carboxybutyloxy)phenyl)propionic acid; F) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 10 hydroxyphenoxy)propoxy)-6 methoxyphenyl)propionic acid; G) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4-(1H-tetrazol-5 15 yl)butyloxy)phenyl)propionic acid; H) Methyl 3-(2-(4-(2-ethyl-4-(4-fluorophenyl) 5-hydroxyphenoxy) - (1 butenyl))phenyl)propionate; 20 I) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)-(1-butenyl))phenyl)propionic acid; 25 J) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyl)phenyl)propionic acid; K) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyl)-6 30 methoxyphenyl)propionic acid; L) Methyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl) 5-hydroxyphenoxy) propoxy) -6 hydroxyphenyl)propionate; 35 M) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) propoxy) -6 hydroxyphenyl)propionic acid; 40 N) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 butyloxy)phenyl)propionic acid; 0) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 45 hydroxyphenoxy)propoxy)-6-(4 methylthiobutyloxy)phenyl)propionic acid; WO 01/34135 PCT/USOO/30944 -218 P) 3-(2-(3-(2,4-Di-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy) -6- (4 carboxybutoxy)phenyl)propionic acid; 5 Q) 6-Methyl-6-(lH-tetrazol-5-yl)-11-(2-ethyl-4 (4-fluorophenyl)-5-hydroxyphenoxy)undecane; R) N,N-Dimethyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 10 hydroxyphenoxy)propoxy)phenyl)propionamide; S) N-Methanesulfonyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionamide; 15 T) N-Phenylsulfonyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionamide; 20 U) 3-(2-(3-(2-Butyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; V) Ethyl 3-(2-(4-(2-ethyl-4-(4-fluorophenyl)-5 25 hydroxyphenoxy)butyloxy)phenyl)propionate; W) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyloxy)phenyl)propionic acid; 30 X) Methyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl) 5-hydroxyphenoxy)propoxy)-6-(4 (methoxycarbonyl)phenoxy)phenyl)propionate; 35 Y) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 carboxyphenoxy)phenyl)propionic acid; Z) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 40 hydroxyphenoxy)propoxy)-4-(4 carboxyphenoxy)phenyl)propionic acid; AA) 3,3-Dimethyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 45 hydroxyphenoxy)propoxy)phenyl)propionic acid; WO 01/34135 PCT/USOO/30944 -219 BB) 2-Methyl-2-(lH-tetrazol-5-yl)-3-(2-(3-(2 ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propane; 5 CC) 2-Methyl-2-(lH-tetrazol-5-yl)-3-hydroxy-3 (2-(3-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propane; DD) 3-(2-(3-(2-Bromo-4-(4-fluorophenyl)-5 10 hydroxyphenoxy)propoxy)phenyl)propionic acid; EE) 3-(2-(3-(2-Ethylthio-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic 15 acid; FF) Methyl 3-(2-hydroxy-3-(4 methoxycarbonylbutyl)-6-(3-(2-ethyl-4-(4 fluorophenyl)-5 20 hydroxyphenoxy)propoxy)phenyl)propionate; GG) 5-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) propoxy) -8- (4-carboxybuty 1)dihydrocoumarin; 25 HH) 2-Phenyl-4-ethyl-5-[6-(2H-tetrazol-5-yl)-6 methylheptyloxy]phenol sodium salt; II) 2-(4-Methylphenyl)-4-ethyl-5-[6-methyl-6 30 (2H-tetrazol-5-yl)heptyloxy]phenol disodium salt; JJ) 2-(3-Methylphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol sodium 35 salt; KK) 2-(2-Methylphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol disodium salt; 40 LL) 2-(4-Methoxyphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol sodium salt; 45 MM) 2-(3-Methoxyphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol sodium salt; WO 01/34135 PCT/USOO/30944 -220 NN) 2-(4-Trifluoromethylphenyl)-4-ethyl-5- [6 methyl-6-(2H-tetrazol-5-yl)heptyloxy]phenol disodium salt; 5 00) 2-(3-Dimethylaminophenyl)-4-ethyl-5-[6 methyl-6-(2H-tetrazol-5-yl)heptyloxy]phenol disodium salt; PP) 3-(5-(6-(4-Phenyl-5-hydroxy-2 10 ethylphenoxy)propoxy)-2-carboxymethyl 1,2,3,4 -tetrahydronaphthalen-1(2H) one)propanoic acid; QQ) 3-(5-(6-(4-(4-Fluorophenyl)-5-hydroxy-2 15 ethylphenoxy)propoxy)-2-carboxymeth yl 1,2,3,4-tetrahydronaphthalen-1(2H) one)propanoic acid; RR) 3-(4-(5-(4-(4-Fluorophenyl)-5-hydroxy-2 20 ethylphenoxy)propoxy)-2-carboxymeth yl-2,3 dihydroinden-1(2H)-one)propanoic acid; SS) 3,3-Dimethyl-5-(3-(2-carboxyethyl)-4-(3-(4 fluorophenyl)-5-hydroxy-2 25 ethylphenoxy)propoxy)phenyl)-5-oxopentanoic acid; TT) 7-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyl]-4 yl)oxy]propoxy]-3,4-dihydro-8-propyl-2H-1 30 benzopyran-2-carboxylic acid; UU) 8-Propyl-7-[3-[4-(4-fluorophenyl)-2-ethyl-5 hydroxyphenoxy]propoxy]-3,4-dihydro-2H-1 benzopyran-2-carboxylic acid; 35 VV) 2-[3-[3-[(5-Ethyl-2-hydroxy[1,l'-biphenyl] 4-yl)oxy]propoxy]-2-propylphenoxy]propanoic acid; 40 WW) 2-(4-Chlorophenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol monosodium salt; XX) 2-(3,5-Dichlorophenyl)-4-ethyl-5-[6-methyl 45 6-(2H-tetrazol-5-yl)heptyloxy]phenol monosodium salt; WO 01/34135 PCT/USOO/30944 -221 YY) 3-[2-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyl] 4-yl)oxy]propoxy]-1-dibenzofuran]propanoic acid disodium salt; 5 ZZ) -7-Carboxy-9-oxo-3-[3-(2-ethyl-5-hydroxy-4 phenylphenoxy)propoxy]-9H-xanthene-4 propanoic acid disodium salt monohydrate; AAA) 2-[2-Propyl-3-[3-(2-ethyl-5-hydroxy-4 10 phenylphenoxy)propoxy]phenoxy]benzoic acid sodium salt hemihydrate; BBB) 3-[3-(2-Ethyl-5-hydroxy-4 phenylphenoxy)propoxy][1,1'-biphenyl]-4 15 propanoic acid disodium salt monohydrate; CCC) 5-Ethyl-4-[3-[2-propyl-3-[2-(2H-tetrazol-5 yl) phenoxy] phenoxy] propoxy] 11,1' -biphenyl] 2-ol disodium salt sesquihydrate; 20 DDD) 3-[4-[3-[ 3-(2-Ethyl-5-hydroxy-4 phenylphenoxy) propoxy] -9-oxo-9H xanthene]]propanoic acid sodium salt hemihydrate; 25 EEE) 2-Fluoro-6-[2-propyl-3-[3-(2-ethyl-5 hydroxy- 4 phenyiphenoxy) propoxy] phenoxy] benzoic acid disodium salt; 30 FFF) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl) -5 hydroxyphenoxy] propoxy] phenoxy] benzoic acid sodium salt; 35 GGG) 3-[4-[7-Carboxy-9-oxo-3-[3-[2-ethyl-4-(4 fluorophenyl) -5-hydroxyphenoxy] propoxy] -9H xanthene]] propanoic acid disodium salt trihydrate; 40 HHH) 3-[4-[9-Oxo-3-[3-[2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy]propoxy]-9H xanthene]]propanoic acid; WO 01/34135 PCT/USOO/30944 -222 III) 3-[2-[1-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxylpropoxy] -4- (5-oxo-5 morpholinopentananido) phenyl] propanoic acid; 5 JJJ) 2-Fluoro-6-[2-propyl-3-[3-[2-ethyl-5 hydroxy-4- (4 fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid disodium salt hydrate; 10 KKK) 4-Fluoro-2-[2-propyl-3-[3-12-ethyl-5 hydroxy-4- (4 fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid; 15 LLL) 2-[2-Propyl-3-5-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]-pentoxyphenoxy]benzoic acid; 20 MMM) 2-[2-Propyl-3-[-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]butoxy]phenoxy]benzoic acid sesquihydrate; NNN) 2-[2-(2-Methylpropyl-3-[3-[2-ethyl-5 25 hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid; 000) 2-[2-Butyl-3-[3-[2-ethyl-5-hydroxy-4-(4 30 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid hydrate; PPP) 2-[2-(Phenylmethyl)-3-[3-[2-ethyl-5-hydroxy 4- (4 35 fluorophenyl)phenoxy]propoxy]phenoxylbenzoic acid; QQQ) 2-[2-Propyl-3-33--2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]phenyla 40 cetic acid; RRR) 2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]benzoyl]benzoic acid; WO 01/34135 PCT/USOO/30944 -223 SSS) 2-[12-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl) phenoxy] propoxy] phenyl Imethyl] b enzoic acid; 5 TTT) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl) -5 hydroxyphenoxy] propoxy] thiophenoxy] benzoic acid; 10 UUU) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl) -5 hydroxyphenoxy] propoxy] phenylsulfinyl] benzoi c acid; 15 VVV) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl) -5 hydroxyphenoxy] propoxy] phenylsulfonyl] benzoi c acid hydrate; 20 WWW) 5-[3-[2-(1-Carboxy)ethyl]-4-[3-[2-ethyl-4 (4-f luorophenyl) -5 hydroxyphenoxy] propoxy] phenyl] -4-pentynoic acid disodium salt 0.4 hydrate; 25 XXX) 1-Phenyl--(lH-tetrazol-5-yl)-6-(2-ethyl-4 (4-fluorophenyl)-5-hydroxyphenoxy)hexane; YYY) 1-(4-(Carboxymethoxy)phenyl)-l-(lH-tetrazol 30 5-yl)-6-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)hexane; ZZZ) 1- (4- (Dimethylaminocarbonylmethoxy) phenyl) 1-(H-tetrazol-5-yl)-6-(2-ethyl-4-(4 35 fluorophenyl)-5-hydroxyphenoxy)hexane; AAAA) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)-E-propenoic acid; 40 BBBB) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)-2-methyl-E propenoic acid; WO 01/34135 PCT/USOO/30944 -224 CCCC) 5-(2-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)ethyl)-lH tetrazole; 5 DDDD) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-4-(4 carboxybutyloxy)phenyl)propionic acid; 10 EEEE) 5-[3-[4-(4-Fluorophenyl)-2-ethyl-5 hydroxyphenoxy]propoxy]-3,4-dihydro-2H-1 benzopyran-2-one; FFFF) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5 15 hydroxyphenyloxy]propoxy}phenyl)propanoic acid; GGGG) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy]propoxy}-4-propylph 20 enyl)propanoic acid sodium salt; HHHH) 3-(4-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy]propoxy} -3 propylphenyl)propanoic acid; 25 IIII) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy] propoxy} -2 propylphenyl)propanoic acid; 30 JJJJ) 3-{3-[3-(2-Ethyl-5 hydroxyphenyloxy)propoxy] -2 propylphenyl}propanoic acid disodium salt; and 35 KKKK) 2-[3-[3-[2-Ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]benzoyl]benzoic acid disodium salt hemihydrate. WO 01/34135 PCT/USOO/30944 -225

12. The composition of claim 8 wherein the leukotriene (LTB 4 ) antagonist is a compound of the structure (Formula B): F H HO 0 5 Formula B 10 namely,2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy] phenoxy benzoic acid, and the pharmaceutically acceptable salts thereof.

13. The composition of claim 1 wherein the anti-cancer 15 agent is selected from the group consisting of Busulfan, Carboplatin, Carmustine, Cisplatin, Cyclophosphamide, Dacarbazine, Ifosfamide, Lomustine, Streptozocin, Oxaliplatin, Temozolomide, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Idarubicin, Mitomycin-C, 20 Plicamycin, Cryptophycin, Cytarabine, Floxuridine, Fludarabine, 5-Fluorouracil, Hydroxyurea, 6-Mercaptopurine, Methotrexate, Thioguanine; Capecitabine, Aldesleukin, Interferon Alfa-2A, Interleukin-2, Interleukin-12 (recombinant), Interferon Alfa-2B (recombinant), Interferon 25 Alfa-n3, Interferon Gamma-lB, Herceptin interleukin-2, interleukin-12, Aminoglutethimide, Anastrozole, Flutamide, Goserelin, Leuprolide, Megestrol, Mitotane, Tamoxifen, WO 01/34135 PCT/USOO/30944 -226 Chlorambucil, Estramustine, Mechlorethamine, Melphalan, Thiotepa, Docetaxel, Etoposide, Irinotecan HCl, Paclitaxel, Teniposide, Topotecan, Vinblastine, Vincristine, Vinorelbine, Altretamine, Amifostine Asparaginase 5 Escherichia coli strain, BCG Live (Intravesical), Cladribine, Leucovorin, Levamisole, Mitoxantrone, Pegaspargase, Pentostatin, and Procarbazine.

14. The composition of claim 13 wherein the anti 10 cancer agent is selected from the group consisting of Busulfan, Carboplatin, Carmustine, Cisplatin, Cyclophosphamide, Dacarbazine, Ifosfamide, Lomustine, Streptozocin, Oxaliplatin, Temozolomide, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Idarubicin, 15 Mitomycin-C, Plicamycin, Cryptophycin, Cytarabine, Floxuridine, Fludarabine, 5-Fluorouracil, Hydroxyurea, 6 Mercaptopurine, Methotrexate, Thioguanine; Capecitabine, Aldesleukin, Interferon Alfa-2A, Interleukin-2, Interleukin 12 (recombinant), Interferon Alfa-2B (recombinant), 20 Interferon Alfa-n3, Interferon Gamma-lB, Herceptin interleukin-2, interleukin-12, Aminoglutethimide, Anastrozole, Flutamide, Goserelin, Leuprolide, Megestrol, Mitotane, Tamoxifen, Chlorambucil, Estramustine, Mechlorethamine, Melphalan, Thiotepa, Docetaxel, Etoposide, 25 Irinotecan HCl, Paclitaxel, Teniposide, Topotecan, Vinblastine, Vincristine, Vinorelbine, Altretamine, Amifostine Asparaginase-Escherichia coli strain, BCG Live (Intravesical), Cladribine, Leucovorin, Levamisole, Mitoxantrone, Pegaspargase, Pentostatin, and Procarbazine. 30 WO 01/34135 PCT/USOO/30944 -227

15. Use in the manufacture of a medicament for the treatment of cancer in mammals comprising a therapeutically effective amount of a leukotriene (LTB 4 ) antagonist and one or more anti-cancer agents. 5

16. The use according to claim 15 wherein the leukotriene (LTB 4 ) antagonist is represented by the formula (I) 10 H X R3 R2 R4 R1 Z (I) wherein: X is selected from the group consisting of, 15 (i) a five membered substituted or unsubstituted heterocyclic radical containing from 1 to 4 hetero atoms independently selected from sulfur, nitrogen or oxygen; and 20 (ii) a fused bicyclic radical wherein a carbocyclic group is fused to two adjacent carbon atoms of the five membered heterocyclic radical, (i); WO 01/34135 PCT/USOO/30944 -228 Y 1 is a bond or divalent linking group containing 1 to 9 atoms; Y2 and Y 3 are divalent linking groups independently selected 5 from -CH 2 -, -0-, or -S-; Z is an Acidic Group; R1 is C 1 -C 10 alkyl, aryl, C 3 -C 8 cycloalkyl, C 2 -C 10 alkenyl, 10 C 2 -C 10 alkynyl, C 6 -C 2 0 aralkyl, C 6 -C 20 alkaryl, Ci-C 10 haloalkyl, C 6 -C 2 0 aryloxy, or Ci-Cig alkoxy; R2 is hydrogen, halogen, C 1 -C 10 haloalkyl, Ci-C 10 alkoxy, Ci-C 10 alkyl, C 3 -C 8 cycloalkyl, Acidic Group, or -(CH 2 )1-7-(Acidic Group); 15 R3 is hydrogen, halogen, C 1 -C 10 alkyl, aryl, C 1 -C 10 haloalkyl, Ci-C 10 alkoxy, C 6 -C 2 0 aryloxy, or C3-C8 cycloalkyl; 20 R4 is Cl-C 4 alkyl, C 3 -C 4 cycloalkyl, -(CH 2 )1- 7 -(C 3 -C 4 cycloalkyl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, benzyl, or aryl; and n is 0, 1, 2, 3, 4, 5, or 6; 25 or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof, in combination with a therapeutically effective amount of one or more anti-cancer agents. 30 WO 01/34135 PCT/USOO/30944 -229

17. The use according to claim 16 wherein X is a heterocyclic radical selected from the group consisting of substituents represented by the following formulae: 5 R11 R11 R11 0 S N R10 / R11 N R11 R11 N 0 , S , 0 R11 R11 N R11 NN S N 0 R10 N--N R1N R11 N--N ~, R11 / <R11I~ NN S N, N I I 10 R10 R10 N NR1 1 N-*R11 N R11 N N N R R1S R10 R10 WO 01/34135 PCT/USOO/30944 -230 N-N r -VR1 N-N / \\ R11 R11 R11 R11 7 N S 0 0 S R10 N N N O N , ~ 0 N 11' 5 0 S , N H R10 N R11 N 'and / R11 R10 where R10 is a radical selected from hydrogen or 10 Cl-C 4 alkyl; and Rll is a radical selected from hydrogen, halo, C 1 -C 10 alkyl, Ci-Cio haloalkyl, Ci-C 10 alkoxy, aryl, or C 6 -C 20 aryloxy. WO 01/34135 PCT/USOO/30944 -231

18. The use according to claim 16 wherein the R1, R2, R3 and R4 groups for substitution in formula (I) are selected from the following variables coded R01 thru R16 R variables RI R2 R3 R4 Combination group group group group Code choice choice choice choice R01 R1 R2 R3 R4 R02 R1 R2 R3 PG1-R4 R03 R1 R2 PG1-R3 R4 R04 R1 R2 PG1-R3 PG1-R4 R05 R1 PGI-R2 R3 R4 R06 R1 PG1-R2 R3 PG1-R4 R07 R1 PG1-R2 PG1-R3 R4 R08 R1 PG1-R2 PG1-R3 PG1-R4 R09 PG1-R1 R2 R3 R4 R10 PGi-01 R2 R3 PG1-R4 R11 PG1-R1 R2 PG1-R3 R4 R12 PGi-Rl R2 PGl-R3 PGi-R4 R13 PG1-R1 PG1-R2 R3 R4 R14 PG1-R1 PG1-R2 R3 PGI-R4 R15 PG1-Rl PGl-R2 PG1-R3 R4 R16 PG1-Rl PG1-R2 PG1-R3 PG1-R4 5 and; WO 01/34135 PCT/USOO/30944 -232 the Yl, Y2, and Y3 groups for substitution in formula (I) are selected from the following variables coded Y01 thru Y27: 5 Y variables Y1 group Y2 group Y3 group combination choice choice choice code Y01 Y1 Y2 Y3 Y02 Y1 Y2 PG1-Y3 Y03 Y1 Y2 PG2-Y3 Y04 Yl PG1-Y2 Y3 Y05 Y1 PG2-Y2 Y3 Y06 Y1 PG1-Y2 PG1-Y3 Y07 Y1 PG1-Y2 PG2-Y3 Y08 Y1 PG2-Y2 PG1-Y3 Y09 Y1 PG2-Y2 PG2-Y3 Y10 PG1-Y1 Y2 Y3 Y11 PGl-Y1 Y2 PG1-Y3 Y12 PG1-Y1 Y2 PG2-Y3 Y13 PG1-Y1 PG1-Y2 Y3 Y14 PG1-Y1 PG1-Y2 PG1-Y3 Y15 PG1-Y1 PG1-Y2 PG2-Y3 Y16 PG1-Y1 PG2-Y2 Y3 Y17 PG1-Y1 PG2-Y2 PG1-Y3 Y18 PGl-Y1 PG2-Y2 PG2-Y3 Y19 PG2-Y1 Y2 Y3 Y20 PG2-Y1 Y2 PG1-Y3 Y21 PG2-Y1 Y2 PG2-Y3 Y22 PG2-Y1 PG1-Y2 Y3 Y23 PG2-Y1 PG1-Y2 PG1-Y3 Y24 PG2-Y1 PG1-Y2 PG2-Y3 Y25 PG2-Y1 PG2-Y2 Y3 Y26 PG2-Y1 PG2-Y2 PG1-Y3 Y27 PG2-Y1 PG2-Y2 PG2-Y3 and; WO 01/34135 PCT/USOO/30944 -233 the X and Z groups and the n variable for substitution in formula (I) are selected from the following variables coded XZnOl thru XZn24: 5 XZn variables X Z n integer combination group Group group code choice Choice choice XZnO1 X Z n XZnO2 X Z PG1-n XZnO3 X Z PG2-n XZnO4 X PG1-Z n XZn05 X PG2-Z n XZn06 X PG3-Z n XZnO7 X PG1-Z PG1-n XZn08 X PG2-Z PGl-n XZnO9 X PG3-Z PG1-n XZn1O X PGl-Z PG2-n XZnl X PG2-Z PG2-n XZnl2 X PG3-Z PG2-n XZnl3 PG1-X Z n XZnl4 PG1-X Z PG1-n XZnl5 PG1-X Z PG2-n XZn16 PG1-X PG1-Z n XZnl7 PG1-X PG2-Z n XZnl8 PG1-X PG3-Z n XZnl9 PG2-X PG1-Z PG1-n XZn20 PG2-X PG2-Z PG1-n XZn2l PG2-X PG3-Z PG1-n XZn22 PG2-X PG1-Z PG2-n XZn23 PG2-X PG2-Z PG2-n XZn24 PG2-X PG3-Z PG2-n WO 01/34135 PCT/USOO/30944 -234

19. A use according to claim 16 wherein the leukotriene B4 antagonist is described by formula (II): H X2 R22 O 0~>H 2 0 0 R21 5 wherein; X2 is a heterocyclic radical selected from, N S CH 3 N 0 10 , or S R21 is ethyl, 2-propen-1-yl, 3-propen-1-yl, n-propyl, 15 iso-propyl, n-butyl, sec-butyl, or tert-butyl; and R22 is hydrogen, n-butyl, sec-butyl, flouro, chloro, -CF 3 , or tert-butyl. WO 01/34135 PCT/USOO/30944 -235 Z2 is the Acidic Group selected from carboxyl, tetrazolyl, or N-sulfonamidyl; or a salt, solvate or prodrug thereof. 5

20. The use according to claim 19, wherein the leukotriene antagonist is a compound selected from the following: 10 / N OH N O 0-- O O COOH -HCI .H / N OH N O -' O OP COOH 15 /-N OH S III 0-- O O COOH 20 WO 01/34135 PCT/USOO/30944 -236 NN'.H OH O0 -, O OP COOH N-O OH COOH 5 ,N-N. OH NN O O NN COOH 10 H N OO 0 COOMe WO 01/34135 PCT/USOO/30944 -237 OH COOH N-OH COOH C N O IN s 0 -^ o O0 COOH 5 O OH CN.~ 100 OH 0 N- -j ? COOH WO 01/34135 PCT/USOO/30944 -238 O OH COOH O OH O - O OP COONa OH NH O HCI O O O" COOH 5 S OH COOH NN OH N, s I COOH 10 WO 01/34135 PCT/USOO/30944 -239 N=N OH S COOH S'N OH COOH 5 N-N OH S COOH OH S OH 0 O-- o OO COOH 10r WO 01/34135 PCT/USOO/30944 -240 OH S S' I I O O O COOH or an acid, salt, solvate or prodrug derivative thereof. 5

21. The use according to claim 20 wherein the leukotriene antagonist is a compound selected from the following: S OH O O O COOH 10 O OH COONa OH S OOi COOH 15 WO 01/34135 PCT/USOO/30944 -241 N- OH -- N N O O Ol COOH OH O O O COOH or 5 OH 0 0 0- 0 COOH or an acid, salt, solvate or prodrug derivative thereof. 10

22. Use in the manufacture of a medicament for the treatment of cancer in mammals comprising a therapeutically effective amount of a leukotriene (LTB 4 ) antagonist represented by a compound of the structure (Formula A): R2, HO R3' ~- X'- Y'- Z'- A'- R4' 15 R, Formula A WO 01/34135 PCT/USOO/30944 -242 or a pharmaceutically acceptable base addition salt thereof, wherein: R 1 , is C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, Cl-C4 5 alkoxy, (Ci-C4 alkyl)thio, halo, or R2-substitutedphenyl; each R2' and R3' are each independently hydrogen, halo, hydroxy, Ci-C4 alkyl, Cl-C4 alkoxy, (Cl-C4 alkyl)-(O)q S-, trifluoromethyl, or di-(Cl-C3 alkyl)amino; X' is -0-, -S-, -C(=O), or -CH2-; 10 Y' is -0- or -CH2-; or when taken together, -X'-Y'- is -CH=CH- or -C=C-; Z' is a straight or branched chain Cl-C1O alkylidenyl; A' is a bond, -0-, -S-, -CH=CH-, or -CRaRb-, where Ra and Rb are each independently hydrogen, Cl-C5 alkyl, or R7 15 substituted phenyl, or when taken together with the carbon atom to which they are attached form a C4-C8 cycloalkyl ring; R 4 , is R 6 , or taken from one of the following formulae 20 \7 I "O -G -R 6 R 7 (K)p-W-R 6 (CO 2 )t 0 WO 01/34135 PCT/USOO/30944 -243 T R7 W-R 6 T R7 R 8 W-R 6 Ry 7 155W-R6 Ry wherein: each R6 is independently -COOH, 5-tetrazolyl, CON(R 9 ) 2 , or -CONHSO 2 R 10 ; 5 each R7 is hydrogen, Cl-C4 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, benzyl, methoxy, -W-R6, -T-G-R6, (Cl-C4 alkyl)-T (Cl-C4 alkylidenyl)-O-, or hydroxy; R8 is hydrogen or halo; each R 9 is independently hydrogen, phenyl, or Cl-C4 10 alkyl, or when taken together with the nitrogen atom form a morpholino, piperidino, piperazino, or pyrrolidino group; R10 is Cl-C4 alkyl or phenyl; WO 01/34135 PCT/USOO/30944 -244 Rl1 is R2, -W-R6, or -T-G-R6; each W is a bond or a straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms; each G is a straight or branched chain divalent 5 hydrocarbyl radical of one to eight carbon atoms; each T is a bond, -CH2-, -0-, -NH-, -NHCO-, -C(=O)-, or (O)q S-; K is -C(=O)- or -CH(OH)-; each q is independently 0, 1, or 2; 10 p is 0 or 1; and t is 0 or 1; provided when X is -0- or -S-, Y is not -0-; provided when A is -0- or -S-, R4 is not R6; and provided W is not a bond when p is 0; 15 in combination with a therapeutically effective amount of one or more anti-cancer agents.

23. The use of claim 22 wherein R4'is selected from the following formulae: O T 20 R or R8 W-R 6 T 7

24. The use of claim 23 wherein R4'is: WO 01/34135 PCT/USOO/30944 -245 R 8 W-R 6 T 7 5

25. The use according to claim 24 wherein said compound is selected from the group (A) to (KKKK) consisting of: A) 2-Methyl-2-(lH-tetrazol-5-yl)-7-(2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy)heptane; 10 B) 2-Methyl-2-(lH-tetrazol-5-yl)-7-(2-ethyl-4 (3-fluorophenyl)-5-hydroxyphenoxy)heptane; C) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 15 dimethylaminocarbonylbutyloxy)phenyl)propion ic acid; D) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic 20 acid; E) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy) -6- (4 carboxybutyloxy)phenyl)propionic acid; 25 F) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) propoxy) -6 methoxyphenyl)propionic acid; 30 G) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4-(1H-tetrazol-5 yl)butyloxy)phenyl)propionic acid; H) Methyl 3-(2-(4-(2-ethyl-4-(4-fluorophenyl) 35 5-hydroxyphenoxy)-(1 butenyl))phenyl)propionate; WO 01/34135 PCT/USOO/30944 -246 I) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)-(1-butenyl))phenyl)propionic acid; 5 J) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyl)phenyl)propionic acid; K) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 10 hydroxyphenoxy)butyl)-6 methoxyphenyl)propionic acid; L) Methyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl) 5 -hydroxyphenoxy) propoxy) -6 15 hydroxyphenyl)propionate; M) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) propoxy) -6 hydroxyphenyl)propionic acid; 20 N) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 butyloxy)phenyl)propionic acid; 25 0) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy) -6- (4 methylthiobutyloxy)phenyl)propionic acid; P) 3-(2-(3-(2,4-Di-(4-fluorophenyl)-5 30 hydroxyphenoxy)propoxy)-6-(4 carboxybutoxy)phenyl)propionic acid; Q) 6-Methyl-6-(lH-tetrazol-5-yl)-11-(2-ethyl-4 (4-fluorophenyl)-5-hydroxyphenoxy)undecane; 35 R) N,N-Dimethyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionamide; 40 S) N-Methanesulfonyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionamide; T) N-Phenylsulfonyl-3-(2-(3-(2-ethyl-4-(4 45 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionamide; WO 01/34135 PCT/USOO/30944 -247 U) 3-(2-(3-(2-Butyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; 5 V) Ethyl 3-(2-(4-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyloxy)phenyl)propionate; W) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyloxy)phenyl)propionic 10 acid; X) Methyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl) 5-hydroxyphenoxy)propoxy)-6-(4 (methoxycarbonyl)phenoxy)phenyl)propionate; 15 Y) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 carboxyphenoxy)phenyl)propionic acid; 20 Z) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-4-(4 carboxyphenoxy)phenyl)propionic acid; AA) 3,3-Dimethyl-3-(2-(3-(2-ethyl-4-(4 25 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; BB) 2-Methyl-2-(lH-tetrazol-5-yl)-3-(2-(3-(2 30 ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) propoxy) phenyl) propane; CC) 2-Methyl-2-(1H-tetrazol-5-yl)-3-hydroxy-3 (2-(3-(2-ethyl-4-(4-fluorophenyl)-5 35 hydroxyphenoxy)propoxy)phenyl)propane; DD) 3-(2-(3-(2-Bromo-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; 40 EE) 3-(2-(3-(2-Ethylthio-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; 45 FF) Methyl 3-(2-hydroxy-3-(4 methoxycarbonylbutyl)-6-(3-(2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionate; WO 01/34135 PCT/USOO/30944 -248 GG) 5-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-8-(4-carboxybuty 1)dihydrocoumarin; 5 HH) 2-Phenyl-4-ethyl-5-[6-(2H-tetrazol-5-yl)-6 methylheptyloxylphenol sodium salt; II) 2-(4-Methylphenyl)-4-ethyl-5-[6-methyl-6 10 (2H-tetrazol-5-yl)heptyloxy]phenol disodium salt; JJ) 2-(3-Methylphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol sodium 15 salt; KK) 2-(2-Methylphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol disodium salt; 20 LL) 2-(4-Methoxyphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxylphenol sodium salt; 25 MM) 2-(3-Methoxyphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol sodium salt; NN) 2-(4-Trifluoromethylphenyl)-4-ethyl-5-[6 30 methyl-6-(2H-tetrazol-5-yl)heptyloxy]phenol disodium salt; 00) 2-(3-Dimethylaminophenyl)-4-ethyl-5-[6 methyl-6-(2H-tetrazol-5-yl)heptyloxy]phenol 35 disodium salt; PP) 3-(5-(6-(4-Phenyl-5-hydroxy-2 ethylphenoxy)propoxy)-2-carboxymethyl 1,2,3,4 -tetrahydronaphthalen-1(2H) 40 one)propanoic acid; QQ) 3-(5-(6-(4-(4-Fluorophenyl)-5-hydroxy-2 ethylphenoxy)propoxy)-2-carboxymeth yl 1,2,3,4-tetrahydronaphthalen-1(2H) 45 one)propanoic acid; WO 01/34135 PCT/USOO/30944 -249 RR) 3-(4-(5-(4-(4-Fluorophenyl)-5-hydroxy-2 ethylphenoxy)propoxy)-2-carboxymeth yl-2,3 dihydroinden-1(2H)-one)propanoic acid; 5 SS) 3,3-Dimethyl-5-(3-(2-carboxyethyl)-4-(3-(4 fluorophenyl)-5-hydroxy-2 ethylphenoxy)propoxy)phenyl)-5-oxopentanoic acid; 10 TT) 7-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyll-4 yl)oxy]propoxy]-3,4-dihydro-8-propyl-2H-1 benzopyran-2-carboxylic acid; UU) 8-Propyl-7-[3-[4-(4-fluorophenyl)-2-ethyl-5 15 hydroxyphenoxy]propoxy]-3,4-dihydro-2H-1 benzopyran-2-carboxylic acid; VV) 2-[3-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyl] 4-yl)oxy]propoxy]-2-propylphenoxy]propanoic 20 acid; WW) 2-(4-Chlorophenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxyiphenol monosodium salt; 25 XX) 2-(3,5-Dichlorophenyl)-4-ethyl-5-[6-methyl 6-(2H-tetrazol-5-yl)heptyloxy]phenol monosodium salt; 30 YY) 3-[2-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyl] 4-yl)oxy]propoxy]-1-dibenzofuran]propanoic acid disodium salt; ZZ) 7-Carboxy-9-oxo-3-[3-(2-ethyl-5-hydroxy-4 35 phenylphenoxy)propoxy]-9H-xanthene-4 propanoic acid disodium salt monohydrate; AAA) 2-[2-Propyl-3-[3-(2-ethyl-5-hydroxy-4 phenylphenoxy)propoxy]phenoxy]benzoic acid 40 sodium salt hemihydrate; BBB) 3-[3-(2-Ethyl-5-hydroxy-4 phenylphenoxy)propoxy][1,1'-biphenyl]-4 propanoic acid disodium salt monohydrate; WO 01/34135 PCT/USOO/30944 -250 CCC) 5-Ethyl-4-[3-[2-propyl-3-[2-(2H-tetrazol-5 yl) phenoxy] phenoxylpropoxy] [1,1' -biphenyl] 2-al disodium salt sesquihydrate; 5 DDD) 3-[4-[3-[ 3-(2-Ethyl-5-hydroxy-4 phenyiphenoxy) propoxy] -9-oxo-9H xanthene]lpropanoic acid sodium salt hemihydrate; 10 EEE) 2-Fluoro-6-[2-propyl-3-[3-(2-ethyl-5 hydroxy- 4 phenyiphenoxy) propoxy] phenoxy] benzoic acid disodium salt; 15 FFF) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl) -5 hydroxyphenoxy] propoxy] phenoxy] benzoic acid sodium salt; 20 GGG) 3-[4-[7-Carboxy-9-oxo-3-[3-[2-ethyl-4-(4 fluorophenyl) -5 -hydroxyphenoxy] propoxy] -9H xanthene]] propanoic acid disodium salt trihydrate; 25 HHH) 3-[4-[9-Oxo-3-[3-[2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy]propoxy]'-9-e xanthene] ]propanoic acid; 30 111) 3-[2-[l-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy]propoxy]-4-(5-oxo-5 morpholinopentanamido)phenyl]propanoic acid; JJJ) 2-Fluoro-6-[2-propyl-3-[3-[2-ethyl-5 35 hydroxy-4-(4 fluorophenyl)phenoxy]propoxyphenoxy]benzoic acid disodium salt hydrate; KKK) 4-Fluoro-2-[2-propyl-3-[3-[2-ethyl-5 40 hydroxy-4-(4 fluorophenyl)phenoxypropoxy9phenoxy-benzoic acid; WO 01/34135 PCT/USOO/30944 -251 LLL) 2-[2-Propyl-3-[5-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]pentoxy]phenoxy]benzoic acid; 5 MMM) 2-[2-Propyl-3-[4-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]butoxy]phenoxy]benzoic acid sesquihydrate; 10 NNN) 2-[2-(2-Methylpropyl)-3-[3-[2-ethyl-5 hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid; 15 000) 2-[2-Butyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid hydrate; PPP) 2-[2-(Phenylmethyl)-3-[3-[2-ethyl-5-hydroxy 20 4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid; QQQ) 2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 25 fluorophenyl)phenoxy]propoxy]phenoxy]phenyla cetic acid; RRR) 2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]benzoyl]benzoic 30 acid; SSS) 2-[[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenyl]methyl]b enzoic acid; 35 TTT) 2-(2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy]propoxy]thiophenoxy]benzoic acid; 40 UUU) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy]propoxy]phenylsulfinyl]benzoi c acid; WO 01/34135 PCT/USOO/30944 -252 VVV) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy]propoxy]phenylsulfonyl]benzoi 5 c acid hydrate; WWW) 5-[3-[2-(1-Carboxy)ethyl]-4-[3-[2-ethyl-4 (4-fluorophenyl)-5 hydroxyphenoxy]propoxy]phenyl]-4-pentynoic 10 acid disodium salt 0.4 hydrate; XXX) 1-Phenyl-l-(lH-tetrazol-5-yl)-6-(2-ethyl-4 (4-fluorophenyl)-5-hydroxyphenoxy)hexane; 15 YYY) 1-(4-(Carboxymethoxy)phenyl)-1-(lH-tetrazol 5-yl)-6-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) hexane; ZZZ) 1-(4-(Dimethylaminocarbonylmethoxy)phenyl) 20 1-(1H-tetrazol-5-yl)-6-(2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy)hexane; AAAA) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)-E-propenoic 25 acid; BBBB) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) propoxy) phenyl) -2 -methyl-E propenoic acid; 30 CCCC) 5-(2-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)ethyl)-1H tetrazole; 35 DDDD) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-4-(4 carboxybutyloxy)phenyl)propionic acid; EEEE) 5-[3-[4-(4-Fluorophenyl)-2-ethyl-5 40 hydroxyphenoxy]propoxy]-3,4-dihydro-2H-1 benzopyran-2-one; WO 01/34135 PCT/USOO/30944 -253 FFFF) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy] propoxy}phenyl) propanoic acid; 5 GGGG) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy]propoxy}-4-propylph enyl)propanoic acid sodium salt; 10 HHHH) 3-(4-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy]propoxy}-3 propylphenyl)propanoic acid; IIII) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5 15 hydroxyphenyloxy]propoxy}-2 propylphenyl)propanoic acid; JJJJ) 3-{3-[3-(2-Ethyl-5 hydroxyphenyloxy) propoxy] -2 20 propylphenyl}propanoic acid disodium salt; and KKKK) 2-[3-[3-[2-Ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]benzoyl]benzoic 25 acid disodium salt hemihydrate.

26. The use according to claim 22 wherein the leukotriene (LTB 4 ) antagonist is a compound of the structure (Formula B): 30 F OH o o o . T HO 0 Formula B WO 01/34135 PCT/USOO/30944 -254 namely,2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy] phenoxy benzoic acid, and the pharmaceutically acceptable salts thereof. 5

27. The use of claim 15 wherein the anti-cancer agent is selected from the group consisting of Busulfan, Carboplatin, Carmustine, Cisplatin, Cyclophosphamide, Dacarbazine, Ifosfamide, Lomustine, Streptozocin, Oxaliplatin, Temozolomide, Bleomycin, Dactinomycin, 10 Daunorubicin, Doxorubicin, Idarubicin, Mitomycin-C, Plicamycin, Cryptophycin, Cytarabine, Floxuridine, Fludarabine, 5-Fluorouracil, Hydroxyurea, 6-Mercaptopurine, Methotrexate, Thioguanine; Capecitabine, Aldesleukin, Interferon Alfa-2A, Interleukin-2, Interleukin-12 15 (recombinant), Interferon Alfa-2B (recombinant), Interferon Alfa-n3, Interferon Gamma-1B, Herceptin interleukin-2, interleukin-12, Aminoglutethimide, Anastrozole, Flutamide, Goserelin, Leuprolide, Megestrol, Mitotane, Tamoxifen, Chlorambucil, Estramustine, Mechlorethamine, Melphalan, 20 Thiotepa, Docetaxel, Etoposide, Irinotecan HCl, Paclitaxel, Teniposide, Topotecan, Vinblastine, Vincristine, Vinorelbine, Altretamine, Amifostine Asparaginase Escherichia coli strain, BCG Live (Intravesical), Cladribine, Leucovorin, Levamisole, Mitoxantrone, 25 Pegaspargase, Pentostatin, and Procarbazine.

28. The use of claim 26 wherein the anti-cancer agent is selected from the group consisting of Busulfan, Carboplatin, Carmustine, Cisplatin, Cyclophosphamide, 30 Dacarbazine, Ifosfamide, Lomustine, Streptozocin, Oxaliplatin, Temozolomide, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Idarubicin, Mitomycin-C, WO 01/34135 PCT/USOO/30944 -255 Plicamycin, Cryptophycin, Cytarabine, Floxuridine, Fludarabine, 5-Fluorouracil, Hydroxyurea, 6-Mercaptopurine, Methotrexate, Thioguanine; Capecitabine, Aldesleukin, Interferon Alfa-2A, Interleukin-2, Interleukin-12 5 (recombinant), Interferon Alfa-2B (recombinant), Interferon Alfa-n3, Interferon Gamma-lB, Herceptin interleukin-2, interleukin-12, Aminoglutethimide, Anastrozole, Flutamide, Goserelin, Leuprolide, Megestrol, Mitotane, Tamoxifen, Chlorambucil, Estramustine, Mechlorethamine, Melphalan, 10 Thiotepa, Docetaxel, Etoposide, Irinotecan HC1, Paclitaxel, Teniposide, Topotecan, Vinblastine, Vincristine, Vinorelbine, Altretamine, Amifostine Asparaginase Escherichia coli strain, BCG Live (Intravesical), Cladribine, Leucovorin, Levamisole, Mitoxantrone, 15 Pegaspargase, Pentostatin, and Procarbazine.

29. A method of treating cancer in a human patient by administering to said patient a composition comprising a therapeutically effective amount of a leukotriene (LTB 4 ) 20 antagonist and one or more anti-cancer agents.

30. The method according to claim 29 wherein the leukotriene (LTB 4 ) antagonist is represented by the formula (I) 25 WO 01/34135 PCT/USOO/30944 -256 H X R3 R2 ys H 2 Y R4 RI z (I) wherein: X is selected from the group consisting of, 5 (i) a five membered substituted or unsubstituted heterocyclic radical containing from 1 to 4 hetero atoms independently selected from sulfur, nitrogen or oxygen; and 10 (ii) a fused bicyclic radical wherein a carbocyclic group is fused to two adjacent carbon atoms of the five membered heterocyclic radical, (i); 15 Yi is a bond or divalent linking group containing 1 to 9 atoms; Y 2 and Y 3 are divalent linking groups independently selected from -CH 2 -, -0-, or -S-; 20 Z is an Acidic Group; Rl is Cl-C 10 alkyl, aryl, C 3 -C 8 cycloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 6 -C 20 aralkyl, C 6 -C 20 alkaryl, 25 Ci-C 10 haloalkyl, C 6 -C 20 aryloxy, or C 1 -C 10 alkoxy; WO 01/34135 PCT/USOO/30944 -257 R2 is hydrogen, halogen, C 1 -C 10 haloalkyl, Ci-C 10 alkoxy, C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl, Acidic Group, or -(CH 2 )1-7-(Acidic Group); 5 R3 is hydrogen, halogen, Ci-C 10 alkyl, aryl, Ci-C 10 haloalkyl, C 1 -C 10 alkoxy, C 6 -C 20 aryloxy, or C3-C8 cycloalkyl; R4 is Cl-C 4 alkyl, C 3 -C 4 cycloalkyl, 10 -(CH 2 )1- 7 -(C 3 -C 4 cycloalkyl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, benzyl, or aryl; and n is 0, 1, 2, 3, 4, 5, or 6; 15 or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof, in combination with a therapeutically effective amount of one or more anti-cancer agents. 20

31. The method according to claim 30 wherein X is a heterocyclic radical selected from the group consisting of substituents represented by the following formulae: 25 O R11 S R11 N R11 0 SR R1iO WO 01/34135 PCT/USOO/30944 -258 0 s0 Rll Rl - l S Ni 0. N~~RN N S N 7 N NN S RIO R10 57 0 0 N / N N s ~ 0 /R1 N' "N N N /C N KY 0 N 11 WO 01/34135 PCT/USOO/30944 -259 0 ' S N H R10 N R11 N 'and R11 R10 where R10 is a radical selected from hydrogen or 5 Cl-C 4 alkyl; and Rll is a radical selected from hydrogen, halo, CI-C 10 alkyl, Ci-C 10 haloalkyl, Ci-C 10 alkoxy, aryl, or C 6 -C 20 aryloxy. WO 01/34135 PCT/USOO/30944 -260

32. The method according to claim 31 wherein the R1, R2, R3 and R4 groups for substitution in formula (I) are selected from the following variables coded R01 thru R16 R variables R1 R2 R3 R4 Combination group group group group Code choice choice choice choice R01 R1 R2 R3 R4 R02 R1 R2 R3 PGI-R4 R03 R1 R2 PG1-R3 R4 R04 R1 R2 PGl-R3 PGI-R4 R05 R1 PGl-R2 R3 R4 R06 R1 PGl-R2 R3 PGl-R4 R07 Rl PG1-R2 PGl-R3 R4 R08 R1 PGl-R2 PGl-R3 PGl-R4 R09 PG1-R1 R2 R3 R4 R10 PGl-01 R2 R3 PG1-R4 Rll PGl-R1 R2 PG1-R3 R4 R12 PG1-R1 R2 PG1-R3 PGl-R4 R13 PG1-R1 PGl-R2 R3 R4 R14 PG1-R1 PG1-R2 R3 PGl-R4 R15 PG1-R1 PGl-R2 PGi-R3 R4 R16 PG1-R1 PGl-R2 PG1-R3 PGi-R4 5 and; WO 01/34135 PCT/USOO/30944 -261 the Y1, Y2, and Y3 groups for substitution in formula (I) are selected from the following variables coded Y01 thru Y27: Y variables Y1 group Y2 group Y3 group combination choice choice choice code Y01 Y1 Y2 Y3 Y02 Y1 Y2 PG1-Y3 Y03 Y1 Y2 PG2-Y3 Y04 Yl PG1-Y2 Y3 Y05 Y1 PG2-Y2 Y3 Y06 Y1 PG1-Y2 PG1-Y3 Y07 Y1 PG1-Y2 PG2-Y3 Y08 Y1 PG2-Y2 PG1-Y3 Y09 Y1 PG2-Y2 PG2-Y3 Y10 PGl-Y1 Y2 Y3 Y11 PG1-Y1 Y2 PG1-Y3 Y12 PG1-Y1 Y2 PG2-Y3 Y13 PG1-Y1 PG1-Y2 Y3 Y14 PGl-Yl PG1-Y2 PG1-Y3 Y15 PG1-Y1 PG1-Y2 PG2-Y3 Y16 PG1-Y1 PG2-Y2 Y3 Y17 PG1-Y1 PG2-Y2 PG1-Y3 Y18 PG1-Y1 PG2-Y2 PG2-Y3 Y19 PG2-Y1 Y2 Y3 Y20 PG2-Y1 Y2 PG1-Y3 Y21 PG2-Y1 Y2 PG2-Y3 Y22 PG2-Y1 PG1-Y2 Y3 Y23 PG2-Y1 PG1-Y2 PG1-Y3 Y24 PG2-Y1 PG1-Y2 PG2-Y3 Y25 PG2-Y1 PG2-Y2 Y3 Y26 PG2-Y1 PG2-Y2 PG1-Y3 Y27 PG2-Y1 PG2-Y2 PG2-Y3 5 and; WO 01/34135 PCT/USOO/30944 -262 the X and Z groups and the n variable for substitution in formula (I) are selected from the following variables coded XZnO1 thru XZn24: 5 XZn variables X Z n integer combination group Group group code choice Choice choice XZnOl X Z n XZnO2 X Z PG1-n XZnO3 X Z PG2-n XZnO4 X PG1-Z n XZn05 X PG2-Z n XZnO6 X PG3-Z n XZnO7 X PGl-Z PGl-n XZnO8 X PG2-Z PGl-n XZn09 X PG3-Z PGl-n XZn1O X PGl-Z PG2-n XZnll X PG2-Z PG2-n XZn12 X PG3-Z PG2-n XZnl3 PGl-X Z n XZnl4 PGl-X Z PGl-n XZn15 PGl-X Z PG2-n XZn16 PGl-X PGl-Z n XZnl7 PG1-X PG2-Z n XZn18 PGl-X PG3-Z n XZn19 PG2-X PG1-Z PGl-n XZn20 PG2-X PG2-Z PGl-n XZn21 PG2-X PG3-Z PGl-n XZn22 PG2-X PGl-Z PG2-n XZn23 PG2-X PG2-Z PG2-n XZn24 PG2-X PG3-Z PG2-n WO 01/34135 PCT/USOO/30944 -263

33. A method according to claim 30 wherein the leukotriene B4 antagonist is described by formula (II): H X2 R22 o - " H 2 O O R21 (TI) 5 wherein; X2 is a heterocyclic radical selected from, N S CH 3 N 0 or S 10 R21 is ethyl, 2-propen-1-yl, 3-propen-1-yl, n-propyl, iso-propyl, n-butyl, sec-butyl, or tert-butyl; and 15 R22 is hydrogen, n-butyl, sec-butyl, flouro, chloro, -CF 3 , or tert-butyl. Z2 is the Acidic Group selected from carboxyl, 20 tetrazolyl, or N-sulfonamidyl; WO 01/34135 PCT/USOO/30944 -264 or a salt, solvate or prodrug thereof.

34. The method according to claim 33, wherein the 5 leukotriene antagonist is a compound selected from the following: /-N OH 0 1-- N, C O ' O O COOH 10 -HCI .H N OH N COOH 15 /-N OH CO O O COOH WO 01/34135 PCT/USOO/30944 -2 65 HOO N-N OH - 0 COOH "N OH N 0 - o O0 COOH fr-N OH COOHe WO 01/34135 PCT/USOO/30944 -2 66 OH s II I 0,-, o COOH N- OH COOH NOH COOH 5 O0 OH NO~ 100 OH 0 N- o j COOH WO 01/34135 PCT/USOO/30944 -267 - OH O' COCH O OH COONa OH HCI 0 NO' 0 COOH 5 S OH COOH .N-N OH N, N I~ COOH 10 WO 01/34135 PCT/USOO/30944 -268 NN OH COOH SN OH N I COOH 5 N-N OH 0 0 0 COOH OH COOH 10 //-NOH 0 I COOH or WO 01/34135 PCT/USOO/30944 -269 OH S I N O " O 0 COOH or an acid, salt, solvate or prodrug derivative thereof. 5

35. The method according to claim 34 wherein the leukotriene antagonist is a compound selected from the following: S OH COOH 10 0 OH COONa OH S N- - 11 1 COOH 15 WO 01/34135 PCT/USOO/30944 -270 ,N - OH --- NO COOH OH O O O COOH or 5 OH 0N O 1 O O COOH or an acid, salt, solvate or prodrug derivative thereof. 10

36. The method of claim 29 wherein the leukotriene (LTB 4 ) antagonist represented by a compound of the structure (Formula A): R2, H0 X'-Y'-Z'-A'-R 4' R3 R,' 15 Formula A WO 01/34135 PCT/USOO/30944 -271 or a pharmaceutically acceptable base addition salt thereof, wherein: R 1 , is Ci-C 5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, Cl-C4 5 alkoxy, (Cl-C4 alkyl)thio, halo, or R2-substitutedphenyl; each R2' and R3' are each independently hydrogen, halo, hydroxy, Cl-C4 alkyl, Cl-C4 alkoxy, (Ci-C4 alkyl)-(O)q S-, trifluoromethyl, or di-(Ci-C3 alkyl)amino; X' is -0-, -S-, -C(=0), or -CH2-; 10 Y' is -0- or -CH2-; or when taken together, -X'-Y'- is -CH=CH- or -C=C-; Z' is a straight or branched chain Cl-C1O alkylidenyl; A' is a bond, -0-, -S-, -CH=CH-, or -CRaRb-, where Ra and Rb are each independently hydrogen, Cl-C5 alkyl, or R7 15 substituted phenyl, or when taken together with the carbon atom to which they are attached form a C4-C8 cycloalkyl ring; R 4 ' is R 6 , or taken from one of the following formulae: 20 -- R7 RR7 0-G-R 6 , (K)p-W-R 6 R 7 (CH 2 O WO 01/34135 PCT/USOO/30944 -272 70 R1 T R7 W-R 6 T R7 R8 W-R6 W-R6 R7 wherein: each R6 is independently -COOH, 5-tetrazolyl, CON(R 9 ) 2 , or -CONHSO 2 R 10 ; 5 each R7 is hydrogen, Cl-C4 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, benzyl, methoxy, -W-R6, -T-G-R6, (Cl-C4 alkyl)-T (Cl-C4 alkylidenyl)-O-, or hydroxy; R8 is hydrogen or halo; each R 9 is independently hydrogen, phenyl, or Cl-C4 10 alkyl, or when taken together with the nitrogen atom form a morpholino, piperidino, piperazino, or pyrrolidino group; R10 is Cl-C4 alkyl or phenyl; WO 01/34135 PCT/USOO/30944 -273 R11 is R2, -W-R6, or -T-G-R6; each W is a bond or a straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms; each G is a straight or branched chain divalent 5 hydrocarbyl radical of one to eight carbon atoms; each T is a bond, -CH2-, -0-, -NH-, -NHCO-, -C(=O)-, or (O)q S-; K is -C(=O)- or -CH(OH)-; each q is independently 0, 1, or 2; 10 p is 0 or 1; and t is 0 or 1; provided when X is -0- or -S-, Y is not -0-; provided when A is -0- or -S-, R4 is not R6; and provided W is not a bond when p is 0; 15 in combination with a therapeutically effective amount of one or more anti-cancer agents.

37. The method of claim 36 wherein R4'is selected from the following formulae: O 20 , or R 8 W-R 6 T 7 WO 01/34135 PCT/USOO/30944 -274

38. The composition of claim 37 wherein R4'is: Re W-R 6 T 7 5

39. The method of claim 36 wherein said compound is selected from the group (A) to (KKKK) consisting of: A) 2-Methyl-2-(lH-tetrazol-5-yl)-7-(2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy)heptane; 10 B) 2-Methyl-2-(lH-tetrazol-5-yl)-7-(2-ethyl-4 (3-fluorophenyl)-5-hydroxyphenoxy)heptane; C) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 15 dimethylaminocarbonylbutyloxy)phenyl)propion ic acid; D) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic 20 acid; E) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 carboxybutyloxy)phenyl)propionic acid; 25 F) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) propoxy) -6 methoxyphenyl)propionic acid; 30 G) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4-(lH-tetrazol-5 yl)butyloxy)phenyl)propionic acid; H) Methyl 3-(2-(4-(2-ethyl-4-(4-fluorophenyl) 35 5-hydroxyphenoxy)-(1 butenyl))phenyl)propionate; WO 01/34135 PCT/USOO/30944 -275 I) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)-(1-butenyl))phenyl)propionic acid; 5 J) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyl)phenyl)propionic acid; K) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 10 hydroxyphenoxy)butyl)-6 methoxyphenyl)propionic acid; L) Methyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl) 5-hydroxyphenoxy) propoxy) -6 15 hydroxyphenyl)propionate; M) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6 hydroxyphenyl)propionic acid; 20 N) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 butyloxy)phenyl)propionic acid; 25 0) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 methylthiobutyloxy)phenyl)propionic acid; P) 3-(2-(3-(2,4-Di-(4-fluorophenyl)-5 30 hydroxyphenoxy)propoxy)-6-(4 carboxybutoxy)phenyl)propionic acid; Q) 6-Methyl-6-(lH-tetrazol-5-yl)-11-(2-ethyl-4 (4-fluorophenyl)-5-hydroxyphenoxy)undecane; 35 R) N,N-Dimethyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionamide; 40 S) N-Methanesulfonyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionamide; WO 01/34135 PCT/USOO/30944 -276 T) N-Phenylsulfonyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionamide; 5 U) 3-(2-(3-(2-Butyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; 10 V) Ethyl 3-(2-(4-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyloxy)phenyl)propionate; W) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyloxy)phenyl)propionic 15 acid; X) Methyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl) 5-hydroxyphenoxy)propoxy)-6-(4 (methoxycarbonyl)phenoxy)phenyl)propionate; 20 Y) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 carboxyphenoxy)phenyl)propionic acid; 25 Z) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-4-(4 carboxyphenoxy)phenyl)propionic acid; AA) 3,3-Dimethyl-3-(2-(3-(2-ethyl-4-(4 30 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; BB) 2-Methyl-2-(lH-tetrazol-5-yl)-3-(2-(3-(2 35 ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propane; CC) 2-Methyl-2-(lH-tetrazol-5-yl)-3-hydroxy-3 (2-(3-(2-ethyl-4-(4-fluorophenyl)-5 40 hydroxyphenoxy)propoxy)phenyl)propane; DD) 3-(2-(3-(2-Bromo-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; 45 EE) 3-(2-(3-(2-Ethylthio-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; WO 01/34135 PCT/USOO/30944 -277 FF) Methyl 3-(2-hydroxy-3-(4 methoxycarbonylbutyl)-6-(3-(2-ethyl-4-(4 fluorophenyl)-5 5 hydroxyphenoxy)propoxy)phenyl)propionate; GG) 5-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-8-(4-carboxybuty 1)dihydrocoumarin; 10 HH) 2-Phenyl-4-ethyl-5-[6-(2H-tetrazol-5-yl)-6 methylheptyloxy]phenol sodium salt; II) 2-(4-Methylphenyl)-4-ethyl-5-[6-methyl-6 15 (2H-tetrazol-5-yl)heptyloxy]phenol disodium salt; JJ) 2-(3-Methylphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxylphenol sodium 20 salt; KK) 2-(2-Methylphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol disodium salt; 25 LL) 2-(4-Methoxyphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol sodium salt; 30 MM) 2-(3-Methoxyphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol sodium salt; NN) 2-(4-Trifluoromethylphenyl)-4-ethyl-5-[6 35 methyl-6-(2H-tetrazol-5-yl)heptyloxy]phenol disodium salt; 00) 2-(3-Dimethylaminophenyl)-4-ethyl-5-[6 methyl-6-(2H-tetrazol-5-yl)heptyloxy]phenol 40 disodium salt; PP) 3-(5-(6-(4-Phenyl-5-hydroxy-2 ethylphenoxy)propoxy)-2-carboxymethyl 1,2,3,4 -tetrahydronaphthalen-1(2H) 45 one)propanoic acid; WO 01/34135 PCT/USOO/30944 -278 QQ) 3-(5-(6-(4-(4-Fluorophenyl)-5-hydroxy-2 ethylphenoxy)propoxy)-2-carboxymeth yl 1,2,3,4-tetrahydronaphthalen-1(2H) 5 one)propanoic acid; RR) 3-(4-(5-(4-(4-Fluorophenyl)-5-hydroxy-2 ethylphenoxy)propoxy) -2-carboxymeth yl-2, 3 dihydroinden-1 (2H) -one)propanoic acid; 10 SS) 3,3-Dimethyl-5-(3-(2-carboxyethyl)-4-(3-(4 fluorophenyl)-5-hydroxy-2 ethylphenoxy)propoxy)phenyl)-5-oxopentanoic acid; 15 TT) 7-[3-[(5-Ethyl-2-hydroxy[1,l'-biphenyl]-4 yl)oxy]propoxy]-3,4-dihydro-8-propyl-2H-1 benzopyran-2-carboxylic acid; 20 UU) 8-Propyl-7-[3-[4-(4-fluorophenyl)-2-ethyl-5 hydroxyphenoxy]propoxy]-3,4-dihydro-2H-1 benzopyran-2-carboxylic acid; VV) 2-[3-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyl] 25 4-yl)oxy]propoxy]-2-propylphenoxy]propanoic acid; WW) 2-(4-Chlorophenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol 30 monosodium salt; XX) 2-(3,5-Dichlorophenyl)-4-ethyl-5-[6-methyl 6-(2H-tetrazol-5-yl)heptyloxy]phenol monosodium salt; 35 YY) 3-[2-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyll 4-yl)oxyipropoxy]-1-dibenzofuran]propanoic acid disodium salt; 40 ZZ) 7-Carboxy-9-oxo-3-[3-(2-ethyl-5-hydroxy-4 phenylphenoxy)propoxy]-9H-xanthene-4 propanoic acid disodium salt monohydrate; AAA) 2-[2-Propyl-3-[3-(2-ethyl-5-hydroxy-4 45 phenylphenoxy)propoxy]phenoxy]benzoic acid sodium salt hemihydrate; WO 01/34135 PCT/USOO/30944 -279 BBB) 3-[3-(2-Ethyl-5-hydroxy-4 phenylphenoxy)propoxy][1,1'-biphenyl]-4 propanoic acid disodium salt monohydrate; 5 CCC) 5-Ethyl-4-[3-[2-propyl-3-[2-(2H-tetrazol-5 yl)phenoxy]phenoxylpropoxy][1,1'-biphenyl] 2-ol disodium salt sesquihydrate; DDD) 3-[4-[3-[ 3-(2-Ethyl-5-hydroxy-4 10 phenylphenoxy)propoxy-9-oxo-9H xanthene]]propanoic acid sodium salt hemihydrate; EEE) 2-Fluoro-6-[2-propyl-3-[3-(2-ethyl-5 15 hydroxy-4 phenylphenoxy)propoxy]phenoxy]benzoic acid disodium salt; FFF) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 20 fluorophenyl)-5 hydroxyphenoxy]propoxy]phenoxy]benzoic acid sodium salt; GGG) 3-[4-[7-Carboxy-9-oxo-3-[3-[2-ethyl-4-(4 25 fluorophenyl)-5-hydroxyphenoxy]propoxy]-9H xanthene]] propanoic acid disodium salt trihydrate; HHH) 3-[4-[9-Oxo-3-[3-[2-ethyl-4-(4 30 fluorophenyl)-5-hydroxyphenoxy]propoxy]-9H xanthene]]propanoic acid; III) 3-[2-[l-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy]propoxy]-4-(5-oxo-5 35 morpholinopentanamido)phenyl]propanoic acid; JJJ) 2-Fluoro-6-[2-propyl-3-[3-[2-ethyl-5 hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic 40 acid disodium salt hydrate; KKK) 4-Fluoro-2-[2-propyl-3-[3-[2-ethyl-5 hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic 45 acid; WO 01/34135 PCT/USOO/30944 -280 LLL) 2-[2-Propyl-3-[5-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]pentoxy]phenoxy]benzoic acid; 5 MMM) 2-[2-Propyl-3-[4-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]butoxy]phenoxy]benzoic acid sesquihydrate; NNN) 2-[2-(2-Methylpropyl)-3-[3-[2-ethyl-5 10 hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid; 000) 2-[2-Butyl-3-[3-[2-ethyl-5-hydroxy-4-(4 15 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid hydrate; PPP) 2-[2-(Phenylmethyl)-3-[3-[2-ethyl-5-hydroxy 4-(4 20 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid; QQQ) 2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]phenyla 25 cetic acid; RRR) 2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]benzoyl]benzoic acid; 30 SSS) 2-[[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenyl]methyl]b enzoic acid; 35 TTT) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy]propoxy]thiophenoxy]benzoic acid; 40 UUU) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy]propoxy]phenylsulfinyl]benzoi c acid; 45 VVV) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy]propoxy]phenylsulfonyl]benzoi c acid hydrate; WO 01/34135 PCT/USOO/30944 -281 WWW) 5-[3-[2-(l-Carboxy)ethyl]-4-[3-[2-ethyl-4 (4-fluorophenyl)-5 hydroxyphenoxy]propoxy]phenyl]-4-pentynoic 5 acid disodium salt 0.4 hydrate; XXX) 1-Phenyl-l-(1H-tetrazol-5-yl)-6-(2-ethyl-4 (4-fluorophenyl)-5-hydroxyphenoxy)hexane; 10 YYY) 1-(4-(Carboxymethoxy)phenyl)-l-(1H-tetrazol 5-yl)-6-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)hexane; ZZZ) 1-(4-(Dimethylaminocarbonylmethoxy)phenyl) 15 1-(lH-tetrazol-5-yl)-6-(2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy)hexane; AAAA) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)-E-propenoic 20 acid; BBBB) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)-2-methyl-E propenoic acid; 25 CCCC) 5-(2-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)ethyl)-1H tetrazole; 30 DDDD) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-4-(4 carboxybutyloxy)phenyl)propionic acid; EEEE) 5-[3-[4-(4-Fluorophenyl)-2-ethyl-5 35 hydroxyphenoxy]propoxy]-3,4-dihydro-2H-1 benzopyran-2-one; FFFF) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy]propoxy}phenyl)propanoic 40 acid; GGGG) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy propoxy}-4-propylph enyl)propanoic acid sodium salt; 45 HHHH) 3-(4-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy]propoxy}-3 propylphenyl)propanoic acid; WO 01/34135 PCT/USOO/30944 -282 IIII) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy]propoxy} -2 propylphenyl)propanoic acid; 5 JJJJ) 3-{3-[3-(2-Ethyl-5 hydroxyphenyloxy) propoxy] -2 propylphenyl}propanoic acid disodium salt; and 10 KKKK) 2- [3- [3- [2-Ethyl-5-hydroxy-4- (4 fluorophenyl)phenoxy]propoxy]benzoyl]benzoic acid disodium salt hemihydrate. 15

40. The method according to claim 36 wherein the leukotriene (LTB 4 ) antagonist is a compound of the structure (Formula B): F OH o " o o HO 0 20 Formula B 25 namely,2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxylpropoxy] phenoxy benzoic acid, and the pharmaceutically acceptable salts thereof.

41. The method according to claim 36 wherein the anti 30 cancer agent is selected from the group consisting of Busulfan, Carboplatin, Carmustine, Cisplatin, WO 01/34135 PCT/USOO/30944 -283 Cyclophosphamide, Dacarbazine, Ifosfamide, Lomustine, Streptozocin, Oxaliplatin, Temozolomide, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Idarubicin, Mitomycin-C, Plicamycin, Cryptophycin, Cytarabine, 5 Floxuridine, Fludarabine, 5-Fluorouracil, Hydroxyurea, 6 Mercaptopurine, Methotrexate, Thioguanine; Capecitabine, Aldesleukin, Interferon Alfa-2A, Interleukin-2, Interleukin 12 (recombinant), Interferon Alfa-2B (recombinant), Interferon Alfa-n3, Interferon Gamma-lB, Herceptin 10 interleukin-2, interleukin-12, Aminoglutethimide, Anastrozole, Flutamide, Goserelin, Leuprolide, Megestrol, Mitotane, Tamoxifen, Chlorambucil, Estramustine, Mechlorethamine, Melphalan, Thiotepa, Docetaxel, Etoposide, Irinotecan HCl, Paclitaxel, Teniposide, Topotecan, 15 Vinblastine, Vincristine, Vinorelbine, Altretamine, Amifostine Asparaginase-Escherichia coli strain, BCG Live (Intravesical), Cladribine, Leucovorin, Levamisole, Mitoxantrone, Pegaspargase, Pentostatin, and Procarbazine. 20

42. The use of claim 40 wherein the anti-cancer agent is selected from the group consisting of Busulfan, Carboplatin, Carmustine, Cisplatin, Cyclophosphamide, Dacarbazine, Ifosfamide, Lomustine, Streptozocin, Oxaliplatin, Temozolomide, Bleomycin, Dactinomycin, 25 Daunorubicin, Doxorubicin, Idarubicin, Mitomycin-C, Plicamycin, Cryptophycin, Cytarabine, Floxuridine, Fludarabine, 5-Fluorouracil, Hydroxyurea, 6-Mercaptopurine, Methotrexate, Thioguanine; Capecitabine, Aldesleukin, Interferon Alfa-2A, Interleukin-2, Interleukin-12 30 (recombinant), Interferon Alfa-2B (recombinant), Interferon Alfa-n3, Interferon Gamma-lB, Herceptin interleukin-2, interleukin-12, Aminoglutethimide, Anastrozole, Flutamide, WO 01/34135 PCT/USOO/30944 -284 Goserelin, Leuprolide, Megestrol, Mitotane, Tamoxifen, Chlorambucil, Estramustine, Mechlorethamine, Melphalan, Thiotepa, Docetaxel, Etoposide, Irinotecan HC1, Paclitaxel, Teniposide, Topotecan, Vinblastine, Vincristine, 5 Vinorelbine, Altretamine, Amifostine Asparaginase Escherichia coli strain, BCG Live (Intravesical), Cladribine, Leucovorin, Levamisole, Mitoxantrone, Pegaspargase, Pentostatin, and Procarbazine. 10