AU1599001A

AU1599001A - Oncolytic combinations for the treatment of cancer

Info

Publication number: AU1599001A
Application number: AU15990/01A
Authority: AU
Inventors: Douglas Wade Beight; Roger Stuart Benjamin; Jerome Herbert Fleisch; William Thomas Mcmillen; Jason Scott Sawyer; Edward C. R. Smith; Beverly Ann Teicher
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1999-11-11
Filing date: 2000-11-09
Publication date: 2001-06-06
Anticipated expiration: 2020-11-09
Also published as: PE20010701A1; NO20022245L; NO20022245D0; TR200201245T2; WO2001034137A2; NZ517667A; ZA200202822B; EA200200545A1; MXPA02004733A; AR032432A1; KR20020069512A; EP1231938A2; WO2001034137A3; HUP0204449A3; HUP0204449A2; JP2003513916A; CA2391416A1; CN1390139A; HK1050132A1; SK6492002A3

Description

WO 01/34137 PCT/USOO/31039 -l ONCOLYTIC COMBINATIONS FOR THE TREATMENT OF CANCER 5 CROSS REFERENCE TO RELATED APPLICATION This application claims priority from United States Provisional Patent Application No. 60/164,786 filed 11 November 1999; the entire disclosure of which is 10 incorporated herein by reference. FIELD OF THE INVENTION This invention relates to a method of treating cancer 15 with anti-cancer agents. More specifically, it relates to the use of 2',2'-difluoronucleoside anti-cancer agents, in conjunction with leukotriene (LTB 4 ) antagonists which enhance the effectiveness of the anti-cancer agent. 20 BACKGROUND OF THE INVENTION Leukotriene B 4

(LTB

4 ) is a proinflammatory lipid which has been implicated in the pathogenesis of psoriasis, arthritis, chronic lung diseases, acute 25 respiratory distress syndrome, shock, asthma, inflammatory bone diseases and other inflammatory states characterized by the infiltration and activation of polymorphonuclear leukocytes and other proinflammatory cells. Thus activated, the polymorphonuclear leukocytes liberate 30 tissue-degrading enzymes and reactive chemicals causing the inflammation. US Patent 5,462,954 discloses phenylphenol leukotriene antagonists that are useful in WO 01/34137 PCT/USOO/31039 -2 the treatment of psoriasis, arthritis, chronic lung diseases, acute respiratory distress syndrome, shock, asthma, inflammatory bone diseases and other inflammatory states characterized by the infiltration and activation of 5 polymorphonuclear leukocytes and other proinflammatory cells. US Patent 5,910,505 discloses that certain 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 10 phenylphenol leukotriene antagonists which have the property of reversing multi drug resistance in tumor cells. The use of the leukotriene antagonist will reverse the drug resistance of resistant tumor cells to vinblasine, vincristine, vindesine, navelbine, 15 daunorubicin, doxorubicin, mitoxantrone, etoposide, teniposide, mitomycin C, actinomycin, taxol, topotecan, mithramycin, colchicine, puromycin, podophylotoxin, emetine, gramicidin, and valinomycin. 20 BRIEF SUMMARY OF THE INVENTION This invention provides compositions and methods useful for treating cancers, in particular, cancers that are not multi drug resistant. The methods of the present invention 25 include the 2',2'-difluoronucleoside anti-cancer agents described in US Patent 5,464,826 in combination with leukotriene (LTB 4 ) antagonists of formula A, formula I and formula II, described below. 30 Surprisingly, we have found that the combination of 2',2'-difluoro nucleoside anti-cancer agents with WO 01/34137 PCT/USOO/31039 -3 leukotriene (LTB 4 ) antagonists act synergistically against cancers which are not multi-drug resistant. The types of cancers that may be treated with the 5 compositions of the present invention include: Breast Carcinoma, Bladder Carcinoma, Colorectal Carcinoma, Esophageal Carcinoma, Gastric Carcinoma, Germ Cell Carcinoma e.g. Testicular Cancer, Gynecologic Carcinoma, Lymphoma Hodgkin's, Lymphoma - Non-Hodgkin's, Malignant Melanoma, 10 Multiple Myeloma, Neurologic Carcinoma, Brain Cancer, Pancreatic Carcinoma, Prostate Carcinoma, Ewings Sarcoma, Osteosarcoma, Soft Tissue Sarcoma, Non-Small Cell Lung Cancer, Pediatric Malignancies and the like. 15 BRIEF DESCRIPTION OF THE DRAWINGS Figures 1 through 6 are horizontal bar graphs displaying the data of Tables 1 through 6 provided in the "ASSAY EXAMPLE 1", infra. The vertical axis of the graph in 20 each Figure forms the origin of the numbered horizontal bars, wherein each bar is a separate Treatment as set out in the Tables. The horizontal axis is tumor growth delay (TGD) in days. 25 DETAILED DESCRIPTION OF THE INVENTION I. Definitions: The term, "Acidic Group" means an organic group which when attached as the "Z" substituent of formula (I) or the 30 "Z2" substituent of formula (II) acts as a proton donor capable of hydrogen bonding. An illustrative acidic group is carboxyl.

WO 01/34137 PCT/USOO/31039 -4 The term, "Active Ingredient" refers both to certain 2', 2'-difluoronucleoside compounds and also leukotriene B4 antagonist compounds generically described by formula A as 5 well as diphenyl leukotriene B 4 antagonist compounds generically described by formula I and formula II or the list of specific diphenyl compounds disclosed, infra., as well as a combination of a 2', 2'-difluoronucleoside and a leukotriene B4 antagonist described by formula A or formulas 10 I and/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, 15 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 20 branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, sec-butyl, n-pentyl, and n-hexyl. The term, "alkaryl" means an aryl radical substituted 25 with an alkyl or substituted aryl group, for example:

C

3

H

8 In the term, "C 6

-C

2 0 alkaryl" the numerical subscripts refer to the total number of carbon atoms in the radical. 30 WO 01/34137 PCT/USOO/31039 -5 The term, "C 6

-C

2 0 aralkyl" means an alkyl radical substituted with an aryl or substituted aryl group, for example: 5

H

3 C In the term, "C 6

-C

2 0 aralkyl" the numerical subscripts refer to the total number of carbon atoms in the radical. The term, "carbocyclic group" refers to a five, six, 10 seven, or eight membered saturated, unsaturated or aromatic ring containing only carbon and hydrogen (e.g., benzene, cyclohexene, cyclohexane, cyclopentane). The term, "cycloalkyl" means a carbocyclic non aromatic monovalent radical such as cyclopropyl, 15 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term, "halo" means fluoro, chloro, bromo, or iodo. 20 The term, "heterocyclic radical(s)" refers to a radical having a saturated, unsaturated or aromatic five membered substituted or unsubstituted ring containing from 1 to 4 hetero atoms. 25 The terms, "mammal" and "mammalian" include human. The term, "N-sulfonamidyl" means the radical: WO 01/34137 PCT/USOO/31039 -6 C N S R12 H 0 O where R12 is C 1

-C

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

-C

2 0 alkaryl, or C6-C 2 0 aralkyl. 5 The term, "substituted alkyl" means an alkyl 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, Ci-C 8 alkoxy, Cl-C 6 haloalkyl (e.g.,

-CF

3

)

10 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, Ci-C 8 alkoxy, Ci-C 6 haloalkyl 15 (e.g.,

-CF

3

)

The term, "tetrazolyl" refers to an acidic group represented by either of the formulae: N N HN N I I or | 1| 20 N NH N N The term "therapeutically effective interval" is a period of time beginning when one of either (a) the 2', 2' difluoronuceoside anti-cancer agent or (b) the LTB 4 25 antagonist is administered to a mammal and ending at the WO 01/34137 PCT/USOO/31039 -7 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 5 preferably within 1 hour. The phrase "therapeutically effective combination", used in the practice of this invention, means administration of both (a) the 2', 2'-difluoronuceoside anti-cancer agent 10 and (b) the LTB 4 antagonist, either simultaneously or separately, in any order. The anti cancer agents which may be used are 2',2' difluoronucleoside compounds of the formula: 15 R 1 0- H 2 C O R2 F OH F wherein:

R

2 is hydrogen or 20 0 -- C-R R2 is a base defined by one of the formulae WO 01/34137 PCT/USOO/31039 -8

NHR

8 0 N N X HN 0 N R HN N N O O H 0 0 HN N HN X 0 N N 0 N H 5 NHR N N N N X is N or C-R 4

R

3 is hydrogen, C 1

-C

4 alkyl or 10 0

-C-R

WO 01/34137 PCT/USOO/31039 -9

R

4 is hydrogen, Ci-C 4 alkyl, amino, bromo, fluoro, chloro or iodo; 5 Each R 5 independently is hydrogen or Ci-C 4 alkyl; and the pharmaceutically-acceptable salts thereof. The following compounds may also be used 10

R

6

OH

2 C 0 -R7 F OH F wherein:

R

6 is hydrogen, CI-C 4 alkyl; 15 R 7 is a base of one of the formulae NHR8 O N X H N N N RHN N N WO 01/34137 PCT/USOO/31039 -10 0

NHR

8 HN X N N R-> N N N X is N or C-R 4 ;

R

8 is hydrogen or C 1

-C

4 alkyl; 5 R 4 is hydrogen, C 1

-C

4 alkyl; amino, bromo, fluoro, chloro and iodo; and the pharmaceutically-acceptable salts thereof; with the proviso that R 6 and R 8 may both be hydrogen only when X is N and R O-H 2 C 0 \\-R9 F 10 OH F wherein:

R

6 is hydrogen or Cl-C 4 alkyl; 0 HNN R is O N N HI 15 WO 01/34137 PCT/USOO/31039 -11 These compounds are disclosed in US Patent 5,464,826 which is incorporated by reference herein for its disclosure of the methods of preparing these compounds, formulating these compounds, and the treatment of cancer using these 5 compounds. Alternatively, preferred 2'2'-difluoronucleoside compounds are compounds represented by the formula:

R

1 0H 2 C R2 F HO 10 F where: R' is hydrogen; R2 is a base defined by one of the formulae:

NHR

3 N X HN N O N

R

3 HN 15 WO 01/34137 PCT/USOO/31039 -12 O NHR 3 HN N N N N N O; ,N R4 ) X is C-R 4 R 3 is hydrogen; 5 R 4 is hydrogen, Ci-C 4 alkyl, bromo, fluoro, chloro or iodo; and pharmaceutically acceptable salts thereof. 10 More preferably the compounds are whereR 2 is the base defined by the formula:

NHR

3 NX oN Even more preferred are anti-cancer agents are selected from 15 the group consisting of the following compounds or a pharmaceutically acceptable salt thereof: (i) 1-(4-amino-2-oxo-lH-pyrimidin-1-yl)-2-desoxy-2' ,2' difluororibose, (ii) 1- (4-amino-2-oxo-lH-pyrimidin-1-yl) -2-desoxy 20 2',2'-difluoroxylose, WO 01/34137 PCT/USOO/31039 -13 (iii) 1-(2,4-dioxo-1H,3H-pyrimidin-1-yl)-2-desoxy 2',2'-difluororibose, and (iv) 1-(4-amino-5-methyl-2-oxo-lH-pyrimidin-1-yl)-2 desoxy-2' , 2' -difluororibose. 5 The most preferred compound is gemcitabine HCl which is a nucleoside analogue that exhibits antitumor activity. Gemcitabine HCl is 2'-deoxy-2',2'-difluorocytidine monohydrochloride ($-isomer), also known as 2',2'-difluoro 10 2'-deoxycytidine monohydrochloride, or also as 1-(4-amino-2 oxo-lH-pyrimidin-1-yl)-2-desoxy-2',2'-difluororibose. The structural formula is as follows:

NH

2 HCI HO 0 0 H F 15 OH F The anti-cancer agents are generally mixed with a carrier which may act as a diluent, or excipient the anti cancer agents may be administered in the form of tablets, 20 pills, powders lozenges, sachets, cachets, elixirs, suspensions, emulsion, solution, syrups or aerosols. Sterile injectable solutions may also be used.

WO 01/34137 PCT/USOO/31039 -14 The leukotriene (LTB 4 ) antagonists useful in the present invention include those given in formula A. R 1 HO X'-Y'- Z'- A'- R '1 R3' 5 R Formula A or a pharmaceutically acceptable base addition salt thereof, wherein: 10 Rl' is Cl-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, Cl-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-, trifluoromethyl, or di-(Cl-C3 alkyl)amino; 15 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 Cl-C10 alkylidenyl; A' is a bond, -0-, -S-, -CH=CH-, or -CRaRb-, where Ra 20 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;

R

4 ' is

R

6 25 WO 01/34137 PCT/USOO/31039 -15 \ /O-G-R 6

R

7 R 7 0 (K)p-W-R 6

(CH

2 )t 0 70

WR

6 R7

W-R

6 T

W-R

6 7 5 where WO 01/34137 PCT/USOO/31039 -16 each R6 is independently -COOH, 5-tetrazolyl, CON(R 9

)

2 , or -CONHSO 2

R

10 ; each R7 is hydrogen, CI-C4 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, benzyl, methoxy, -W-R6, -T-G-R6, (Cl-C4 alkyl)-T 5 (Ci-C4 alkylidenyl)-O-, or hydroxy; R8 is hydrogen or halo; each R 9 is independently hydrogen, phenyl, or Cl-C4 alkyl, or when taken together with the nitrogen atom form a morpholino, piperidino, piperazino, or pyrrolidino group; 10 Ri 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; each G is a straight or branched chain divalent 15 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)-; each q is independently 0, 1, or 2; 20 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. 25 Preferred LTB 4 antagonists of Formula A are those compounds wherein R 4 ' is selected from the following formulae: WO 01/34137 PCT/USOO/31039 -17 0 R7 ,or R8 W--R6 70 An even more preferred LTB 4 antagonist of Formula A are 5 those compounds wherein R 4 ' is:

R

8

W-R

6 T 7 Some of these preferred LTB 4 antagonist compounds or pharmaceutically acceptable acid or salt derivatives thereof 10 are listed herein 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; 15 B) 2-Methyl-2-(lH-tetrazol-5-yl)-7-(2-ethyl-4 (3-fluorophenyl)-5-hydroxyphenoxy)heptane; WO 01/34137 PCT/USOO/31039 -18 C) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 dimethylaminocarbonylbutyloxy)phenyl)propion 5 ic acid; D) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; 10 E) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 carboxybutyloxy)phenyl)propionic acid; 15 F) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6 methoxyphenyl)propionic acid; G) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 20 hydroxyphenoxy)propoxy)-6-(4-(lH-tetrazol-5 yl)butyloxy)phenyl)propionic acid; H) Methyl 3-(2-(4-(2-ethyl-4-(4-fluorophenyl) 5-hydroxyphenoxy) -(1 25 butenyl))phenyl)propionate; I) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)-(1-butenyl))phenyl)propionic acid; 30 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 35 hydroxyphenoxy)butyl)-6 methoxyphenyl)propionic acid; L) Methyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl) 5-hydroxyphenoxy)propoxy)-6 40 hydroxyphenyl)propionate; M) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6 hydroxyphenyl)propionic acid; 45 N) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 butyloxy)phenyl)propionic acid; WO 01/34137 PCT/USOO/31039 -19 0) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 methylthiobutyloxy)phenyl)propionic acid; 5 P) 3-(2-(3-(2,4-Di(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 carboxybutoxy)phenyl)propionic acid; 10 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 15 hydroxyphenoxy)propoxy)phenyl)propionamide; S) N-Methanesulfonyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionamide; 20 T) N-Phenylsulfonyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionamide; 25 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 30 hydroxyphenoxy)butyloxy)phenyl)propionate; W) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyloxy)phenyl)propionic acid; 35 X) Methyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl) 5-hydroxyphenoxy)propoxy)-6-(4 (methoxycarbonyl)phenoxy)phenyl)propionate; 40 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 45 hydroxyphenoxy)propoxy)-4-(4 carboxyphenoxy)phenyl)propionic acid; WO 01/34137 PCT/USOO/31039 -20 AA) 3,3-Dimethyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; 5 BB) 2-Methyl-2-(lH-tetrazol-5-yl)-3-(2-(3-(2 ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propane; 10 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 15 hydroxyphenoxy)propoxy)phenyl)propionic acid; EE) 3-(2-(3-(2-Ethylthio-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic 20 acid; FF) Methyl 3-(2-hydroxy-3-(4 methoxycarbonylbutyl)-6-(3-(2-ethyl-4-(4 fluorophenyl)-5 25 hydroxyphenoxy)propoxy)phenyl)propionate; GG) 5-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-8-(4-carboxybuty 1)dihydrocoumarin; 30 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 35 (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 40 salt; KK) 2-(2-Methylphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol disodium salt; 45 LL) 2-(4-Methoxyphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxyiphenol sodium salt; WO 01/34137 PCT/USOO/31039 -21 MM) 2-(3-Methoxyphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxylphenol sodium salt; 5 NN) 2-(4-Trifluoromethylphenyl)-4-ethyl-5-[6 methyl-6-(2H-tetrazol-5-yl)heptyloxy]phenol disodium salt; 10 00) 2-(3-Dimethylaminophenyl)-4-ethyl-5-[6 methyl-6-(2H-tetrazol-5-yl)heptyloxylphenol disodium salt; PP) 3-(5-(6-(4-Phenyl-5-hydroxy-2 15 ethylphenoxy)propoxy)-2-carboxymethyl 1,2,3,4 -tetrahydronaphthalen-1(2H) one)propanoic acid; QQ) 3-(5-(6-(4-(4-Fluorophenyl)-5-hydroxy-2 20 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 25 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 30 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 35 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; 40 VV) 2-[3-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyll 4-yl)oxylpropoxy]-2-propylphenoxy]propanoic acid; 45 WW) 2-(4-Chlorophenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol monosodium salt; WO 01/34137 PCT/USOO/31039 -22 XX) 2-(3,5-Dichlorophenyl)-4-ethyl-5-[6-methyl 6-(2H-tetrazol-5-yl)heptyloxy]phenol monosodium salt; 5 YY) 3-[2-[3-[(5-Ethyl-2-hydroxy[1,l'-biphenyl] 4-yl)oxy]propoxy]-l-dibenzofuran]propanoic acid disodium salt; ZZ) 7-Carboxy-9-oxo-3-[3-(2-ethyl-5-hydroxy-4 10 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 15 sodium salt hemihydrate; BBB) 3-[3-(2-Ethyl-5-hydroxy-4 phenylphenoxy)propoxy][1,1'-biphenyl]-4 propanoic acid disodium salt monohydrate; 20 CCC) 5-Ethyl-4-[3-[2-propyl-3-[2-(2H-tetrazol-5 yl)phenoxy]phenoxy]propoxy][1,1'-biphenyll 2-ol disodium salt sesquihydrate; 25 DDD) 3-[4-[3-[ 3-(2-Ethyl-5-hydroxy-4 phenylphenoxy)propoxy]-9-oxo-9H xanthene]]propanoic acid sodium salt hemihydrate; 30 EEE) 2-Fluoro-6-[2-propyl-3-[3-(2-ethyl-5 hydroxy-4 phenylphenoxy)propoxy]phenoxy]benzoic acid disodium salt; 35 FFF) 2-[2-Propyl-3-(3-[2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy]propoxy]phenoxy]benzoic acid sodium salt; 40 GGG) 3-[4-[7-Carboxy-9-oxo-3-[3-[2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy]propoxy]-9H xanthene]] propanoic acid disodium salt trihydrate; 45 HHH) 3-[4-[9-Oxo-3-[3-[2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy]propoxy]-9H xanthene]]propanoic acid; WO 01/34137 PCT/USOO/31039 -23 III) 3-[2-[1-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy]propoxy]-4-(5-oxo-5 morpholinopentanamido)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-[2-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]pentoxy]phenoxy]benzoic acid; MMM) 2-[2-Propyl-3-[4-[2-ethyl-5-hydroxy-4-(4 20 fluorophenyl)phenoxy]butoxy]phenoxy]benzoic acid sesquihydrate; NNN) 2-[2-(2-Methylpropyl)-3-[3-[2-ethyl-5 hydroxy-4-(4 25 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid; 000) 2-[2-Butyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic 30 acid hydrate; PPP) 2-[2-(Phenylmethyl)-3-[3-[2-ethyl-5-hydroxy 4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic 35 acid; QQQ) 2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]phenyla cetic acid; 40 RRR) 2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]benzoylIbenzoic acid; 45 SSS) 2-[[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenyl]methyl]b enzoic acid; WO 01/34137 PCT/USOO/31039 -24 TTT) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl) -5 hydroxyphenoxy] propoxy] thiophenoxy] benzoic acid; 5 UUU) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl) -5 hydroxyphenoxy] propoxyl phenylsulfinyl] benzoi c acid; 10 VVV) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy]propoxy]phenylsulfonyl]benzoi c acid hydrate; 15 WWW) 5-[3-[2-(l-Carboxy)ethyl-4-[3-[2-ethyl-4 (4-fluorophenyl)-5 hydroxyphenoxy]propoxy]phenyl]l-4-pentynoic acid disodium salt 0.4 hydrate; 20 XXX) 2-Phenyl-l-(lH-tetrazol-5-yl)-6-(2-ethyl-4 (4-fluorophenyl)-5-hydroxyphenoxy)hexane; YYY) 1-(4-(Carboxymethoxy)phenyl)-1-(lH-tetrazol 25 5-yl)-6-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)hexane; ZZZ) 1- (4- (Dimethylaminocarbonylmethoxy)phenyl) 1-(lH-tetrazol-5-yl)-6-(2-ethyl-4-(4 30 fluorophenyl)-5-hydroxyphenoxy)hexane; AAAA) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)-E-propenoic acid; 35 BBBB) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)-2-methyl-E propenoic acid; 40 CCCC) 5-(2-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)ethyl) -iH tetrazole; DDDD) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 45 hydroxyphenoxy)propoxy)-4-(4 carboxybutyloxy)phenyl)propionic acid; WO 01/34137 PCT/USOO/31039 -25 EEEE) 5-[3-[4-(4-Fluorophenyl)-2-ethyl-5 hydroxyphenoxypropoxy]-3,4-dihydro-2H-1 benzopyran-2-one; 5 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 10 hydroxyphenyloxy]propoxy}-4 propylphenyl)propanoic acid sodium salt; HHHH) 3-(4-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy] propoxy} -3 15 propylphenyl)propanoic acid; IIII) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy]propoxy}-2 propylphenyl)propanoic acid; 20 JJJJ) 3-{3-[3-(2-Ethyl-5 hydroxyphenyloxy)propoxy] -2 propylphenyl}propanoic acid disodium salt; and 25 KKKK) 2-[3-[3-[2-Ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxylpropoxy]benzoyl]benzoic acid disodium salt hemihydrate. 30 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 leukotriene B 4 antagonists and compounds or formulations of 35 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' flouro-2-hydroxybiphen-4-yloxy)propoxy-2 40 propylphenoxy]benzoic acid, described in U.S. Patent 5,462,954 as example 66 and also shown below as Compound A (Formula B): WO 01/34137 PCT/USOO/31039 -26 F H HO O Compound A (Formula B) 5 A second class of LTB 4 antagonists to use as the essential co-agent in the compositions and practice of the 10 method of this invention are those disclosed in copending provisional patent application, titled, "Heterocycle Substituted Diphenyl Leukotriene Antagonists" (inventor, Jason Scott Sawyer) containing 97 pages and identified as Eli Lilly and Company Docket No. B-13240), filed on November 15 11, 1999, and now Provisional patent Application Serial Number 60/164,786. This second class of heterocycle substituted diphenyl leukotriene antagonists are 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 formula (I) 25 WO 01/34137 PCT/USOO/31039 -27 OH X R3 R2 y, H 2 Y 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

2 0 aralkyl, C 6

-C

2 0 25 alkaryl, CI-C 1 0 haloalkyl, C 6

-C

2 0 aryloxy, or CI-C 10 alkoxy; WO 01/34137 PCT/USOO/31039 -28 R2 is hydrogen, halogen, Cj-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, Ci-CiO alkoxy, C 1

-C

10 aryloxy, C 3

-C

8 cycloalkyl; R4 is Cl-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, C 1

-C

10 alkoxy, aryl, or C 6

-C

2 0 aryloxy. 25 Preferred Group 1 of X substituent (symbol, "PG1-X") Preferred LTB 4 antagonist compounds used in the composition of the invention are those wherein X is a heterocyclic radical selected from the group consisting of substituents represented by the following structural 30 formulae: WO 01/34137 PCT/USOO/31039 -29 R1 / R11 / R1 0 s N R10 N CR1 R,1111 0 , S0 NR11 R11N - R11 S , N 0 R10 N-N R11 N R11 N-N S N N N N N I I R50 RiR N--N Nl1 N--Rl /--N l / \\ R11 N ~N N 1 5 RiO RIO N-N Rll N-N S N N N N R1 R 1 7jR11 7 7 N S 0 WO 01/34137 PCT/USOO/31039 -30 R10 N N N N N N N N S 0 N R11, 0 S N H R10 N R11 / and R 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, C 1

-C

10 haloalkyl, C 1

-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 WO 01/34137 PCT/USOO/31039 -31 atom or any nitrogen atom which has less than three bonds in the heterocyclic ring; Location of attachment bond for pyrrole, N N N H H 5 A preferred form of the substituent X is a fused bicyclic radical wherein a carbocyclic group is fused to two adjacent carbon atoms of the five membered heterocyclic radical, for example: 10 H N N and H 15 III B. Preferred Group 2 of X substituent (symbol, "PG2 X") : Most preferred as the X substituents are the heterocyclic radicals; WO 01/34137 PCT/USOO/31039 -32 N S

CH

3 N \ or S 5 1II 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. 10 III D. Preferred Yi substituents: Yi is a bond or divalent linking group containing 1 to 9 atoms independently selected from carbon, hydrogen, sulfur, nitrogen, and oxygen; 15 Preferred Group 1 of Yi substituent (symbol, "PGl-Yi") Preferred LTB 4 compounds included in the composition of the invention are those wherein Yi is a divalent linking group selected from the group consisting of substituents 20 represented by the following formulae: WO 01/34137 PCT/USOO/31039 -33

H

2 0 -- S S-----N 0 0 -N C R13 0 -C C

H

2

H

2 -- C

H

2 --- 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 01/34137 PCT/USOO/31039 -34 The above divalent groups may be used in their forward or reversed positions. For example, the group; 5 o C

H

2 0 may be positioned as either, R2 R2 R3 R3 10 R1 0 Z or R1 0 Z 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 III F. Preferred Group 1 of Y 2 substituent (symbol, "PG1

Y

2 ") and Preferred Group 1 of Y 3 substituent (symbol, "PG1 Y3"): The Y 2 and Y 3 substituents are preferably selected from 25 -S- and -0-.

WO 01/34137 PCT/USOO/31039 -35 III G. Preferred Group 2 of Y 2 substituent (symbol, "PG2

Y

2 ") and Preferred Group 2 of Y 3 substituent (symbol, "PG2 Y3") : Most preferably both Y 2 and Y 3 are the group; 5 0 III H. Preferred Group 1 of Z substituent (symbol, "PGl-Z"): 10 Z is the Acidic Group as previously defined. Preferred is an acidic group selected from the following: -C-N-S-R12 H O 0 tetrazolyl, 15 -SO3H, 0 P OH OH 0-P OH

OH

WO 01/34137 PCT/USOO/31039 -36 0 C OH or -. N HO N

--

S where R12 is Ci-C 10 alkyl, aryl, C 6

-C

2 0 alkaryl, or C6-C20 aralkyl. Preferred R12 groups are represented by the 5 formulae:

CH

3 and 10 III I. Preferred Group 2 of Z substituent (symbol, "PG2-Z"): Highly preferred are the acidic groups; -5 tetrazolyl, N-acyl sulfonamide, -SO3H, and carboxyl. 15 III J. Preferred Group 3 of Z substituent (symbol, "PG3-Z"): Carboxyl is the most preferred Z substituent. 20 III K. Preferred Group 1 of n subscript variable (symbol, "PG1-n") WO 01/34137 PCT/USOO/31039 -37 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 5 (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 10 R1"): A preferred Rl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and 2-propenyl; with n propyl being most preferred. 15 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, 20 ethyl, methoxy, ethoxy, halo, or -CF 3 ; with R2 and R3 both being hydrogen as most preferred. III 0. Preferred Group 1 of R4 substituent (symbol, "PGl-R4":) 25 Preferred R4 substituents are ethyl, propyl, and isopropyl. III P. Combinations of substituents of the compound of Formula (I): 30 The substituents of formula (I) are defined as "Z", "n", "R ", "R2", "R3", "R4"', "Yl", "Y2", and "Y3". Moreover, as described in the preceding section, within WO 01/34137 PCT/USOO/31039 -38 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 5 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 10 substituents are shown in the following three Tables (viz., R-Table, Y-Table & XZn-Table).

WO 01/34137 PCT/USOO/31039 -39 The following R-Table is used to select combinations of general and preferred groupings of the variables Rl, 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 PG1-R3 R4 R04 R1 R2 PG1-R3 PG1-R4 R05 R1 PG1-R2 R3 R4 R06 R1 PGl-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 PG1-01 R2 R3 PG1-R4 R11 PG1-Rl R2 PG1-R3 R4 R12 PG1-R1 R2 PG1-R3 PG1-R4 R13 PG1-R1 PG1-R2 R3 R4 R14 PG1-R1 PG1-R2 R3 PGl-R4 R15 PG1-R1 PG1-R2 PG1-R3 R4 R16 PG1-R1 PGl-R2 PG1-R3 PG1-R4 Thus, for example, the substituent combination, "R14" describes a substituent combinatorial choice for Formula 10 (I) wherein Rb 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 01/34137 PCT/USOO/31039 -40 variables, "PGl-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 Y1, Y2, and Y3 for 10 substitution in formula (I) , as follows: WO 01/34137 PCT/USOO/31039 -41 Y-Table Y variables Yl group Y2 group Y3 group combination choice choice choice code Y0l Yl Y2 Y3 Y02 Y1 Y2 PGl-Y3 Y03 Y1 Y2 PG2-Y3 Y04 Yl PGl-Y2 Y3 Y05 Yl PG2-Y2 Y3 Y06 Yl PGI-Y2 PG1-Y3 Y07 Yl PGI-Y2 PG2-Y3 Y08 Y1 PG2-Y2 PGI-Y3 Y09 Yl PG2-Y2 PG2-Y3 Y10 PG1-Y1 Y2 Y3 Y11 PGl-Y1 Y2 PG1-Y3 Y12 PG1-Y1 Y2 PG2-Y3 Y13 PG1-YI PG1-Y2 Y3 Y14 PG1-Yl PG1-Y2 PGl-Y3 Y15 PG1-Y1 PG1-Y2 PG2-Y3 Y16 PG1-Yl PG2-Y2 Y3 Y17 PG1-Y1 PG2-Y2 PG1-Y3 Y18 PGI-Yl PG2-Y2 PG2-Y3 Y19 PG2-Yl Y2 Y3 Y20 PG2-Yl Y2 PGI-Y3 Y21 PG2-YI Y2 PG2-Y3 Y22 PG2-Yl PGl-Y2 Y3 Y23 PG2-Y1 PG1-Y2 PGl-Y3 Y24 PG2-Y1 PG1-Y2 PG2-Y3 Y25 PG2-Yl PG2-Y2 Y3 Y26 PG2-Yl PG2-Y2 PGl-Y3 Y27 PG2-Y1 PG2-Y2 PG2-Y3 WO 01/34137 PCT/USOO/31039 -42 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 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 PG1-Z PG1-n XZnO8 X PG2-Z PG1-n XZnO9 X PG3-Z PG1-n XZnlO X PG1-Z PG2-n XZn11 X PG2-Z PG2-n XZnl2 X PG3-Z PG2-n XZn13 PG1-X Z n XZnl4 PG1-X Z PG1-n XZnl5 PG1-X Z PG2-n XZn16 PG1-X PG1-Z n XZn17 PG1-X PG2-Z n XZnl8 PG1-X PG3-Z n XZnl9 PG2-X PGl-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 01/34137 PCT/USOO/31039 -43 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 composition and method of invention. III Q. Additional preferred LTB 4 antagonists are described by formula (II): H X2 R22 S O ->G H 2 O 0 R21 Z2 15 wherein; 20 25 WO 01/34137 PCT/USOO/31039 -44 X2 is a heterocyclic radical selected from, N S

CH

3 N 0 or S 5 R21 is ethyl, 2-propen-l-yl, 3-propen-l-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 antagonist component of the composition and method of the invention 15 are represented by the following structural formulae: (Cl): / N OH O -'- O O COOH 20 (C2): WO 01/34137 PCT/USOO/31039 -45 H -HCI N OH N. 0 COOH (C3): / N OH S O O OP COOH 5 (C4): N'NH OH O- "-O OP COOH 10 (C5):

N-

0 OH O0 , O O COOH (C6): WO 01/34137 PCT/USOO/31039 -46 /N-N* OH N. COOH (C7): 5 COOMe 10 (C8): SI OH COOH (c9): 15 WO 01/34137 PCT/USOO/31039 -47 N- OH COOH (ClO) 5 ~NOH C I COOH (Cll) O OH COONa 10 (C12): /I OH 0 0N COOH 15 (C13): WO 01/34137 PCT/USOO/31039 -48 OH 0N

O

I | COOH 5 (C14): O OH 0 0 H COONa (C15): 10 OH HOI 00 COOH (C16): s 0 0 S"-' OHP COOH 15 WO 01/34137 PCT/USOO/31039 -49 (C17) .N-N OH N,S I COOH 5 (C18) NzN OH COOH (C19): S'N OH N I NN COOH 10 15 (C20): WO 01/34137 PCT/USOO/31039 -50 N-N OH K'I S 0 0.

COOH (C21) OH S N O O O - o -COOH (C22) //N OH 0 ), 'NI O O OP COOH 5 (C23) OH S SO 0 O OP COOH 10 and all acid, salt, solvate and prodrug derivatives thereof. III S. Highly Preferred LTB 4 Antagonists are as follows: WO 01/34137 PCT/USOO/31039 -51 S OH COOH O OH COONa 5 OH s OO Oj COOH 10 N_ OH -NI I O O O OH

COOH

WO 01/34137 PCT/USOO/31039 -52 OH COOH OH 0 COOH 5 and all acid, salt, solvate and prodrug derivatives thereof. IV. Method of Making the LTB 4 Antagonist Compounds of the Composition and Method of the Invention 10 General reaction schemes (not represented to be specific Examples) applicable for synthesis of the LTB 4 antagonist compounds represented by formula (I) are set out below. Numerous literature references and Chemical Abstract registry numbers (e.g., RN 152609-60-4) are 15 supplied as additional aids for preparing reagents used in practicing the synthesis schemes of the invention. REACTION SCHEMES FOR MAKING LTB 4 ANTAGONIST COMPOUNDS USED IN THE COMPOSITIONS AND METHOD 20 OF THE INVENTION The following scheme illustrates a process for making Example (1), a 4-substituted oxazole LTB 4 receptor antagonist: WO 01/34137 PCT/USOO/31039 -53 Scheme 1 O OH benzyl bromide, CS 2 C0 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 O ' 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 O 0 N0 CF 3 N O O 'lii O CF 3 COOMe TFA, H20, CH 3 CN (32) 0 0 N HO O 1) Tf 2 O, 2,6-lutidine 0 0 2) formamide COOMe (34) / N O 0 I o

BF

3 Et 2 O, EtSH COOMe (36) WO 01/34137 PCT/USOO/31039 -54 N H 0 I 1) NaOH O 2) HCI COOMe (38) /--N H 00 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 01/34137 PCT/USOO/31039 -55 Scheme 2 0 1) LiHMDS, TMSCI, THF O O Op 2) NCS COOMe 3) TBAF (32) 0 0 N NH C 2 H 2 N SBn N 0 K 2

CO

3 , Nal, DMF COOMe (40) NHO -N N0 BF3-Et20, EtSH COOMe (42) N.H OH SOp1) LiOH, MeOH O 0 0 CO2) Raney Ni, EtOH, NaOH COOMe 3) HOI (44) .H /N OH HCI O 0 COOH (2) WO 01/34137 PCT/USOO/31039 -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: 15 WO 01/34137 PCT/USOO/31039 -57 Scheme 3 CI thioformamide,MgCO 3 0 dioxane COOMe (40) / N 0 S

BF

3 -Et 2 O, EtSH O o-- o 0 COOMe (46) / N OH S A 1) LiOH, MeOH A O O 2) HCI COOMe (48) /--N OH S COOH (3) WO 01/34137 PCT/USOO/31039 -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 01/34137 PCT/USOO/31039 -59 Scheme 4 OMe o O Me 2 N-( OMe OI DMF COOMe (32) 0 Me 2 N 1) LiOH, MeOH 0 P 2) HCI COOMe 3) NH 2

NH,.H

2 0, MeOH (50) N-N.H 0

BF

3 Et 2 0, EtSH O O O COOH (52) N'NH OH COOH 0 (4) WO 01/34137 PCT/USOO/31039 -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 01/34137 PCT/USOO/31039 -61 Scheme 5 Me2N O O NH2OH, MeOH, H20 0 0 0 COOMe (50)

N-

0 0 N

BF

3 -Et 2 o, EtSH COOMe (54)

N-

0 OH 1) LiOH, MeOH O O ON 2) HCI COOMe (56)

N-

0 OH COOH (5) WO 01/34137 PCT/USOO/31039 -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 01/34137 PCT/USOO/31039 -63 Scheme 6 Br O HO O K 2

CO

3 , KI, DMSO O CC OOMe 2-butanone (58) (30) known compounds: RN 152609-60-4 152609-76-2 J. S. Sawyer et al. J. Med. Chem. 1995, 38, 4411 BrO Br, - SnBu 3 O -'-o O Pd(PPha) 4 , DMF COOMe (60) O 00 O O-' O | TMSNs, toluene COOMe (62) ,N-N 0 N

BF

3 -Et 2 O, EtSH - O O 0-9 COOMe (64) ,,-N' OH 1) LiOH, MeOH O, o,-_O O 2) HCI COOMe (66) ,N-' OH N O O--- OP COOH (6) WO 01/34137 PCT/USOO/31039 -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 01/34137 PCT/USOO/31039 -65 Scheme 7 OH O 1) (KSO 3

)

2 NO, K 2

PO

4 , H20 N OH 2) 3-pyrroline, CH 3 CN OH 3) BnBr, K 2

CO

3 , DMF (68) (70) 0 1 -bromo-3-chloropropane N O1) Nal, 2-butanone

K

2

CO

3 , DMF O " 'Ci 2) K 2

CO

3 , DMF (72) HO O COOMe (30) N BF 3 Et 2 0, EtSH O0__ _O Op COOMe (74) OO OOO 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 01/34137 PCT/USOO/31039 -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 01/34137 PCT/USOO/31039 -67 Scheme 8 H Br O B O O O- PdCl 2 (dppf) COOMe (60) Br OCO O OMe PdCl 2 (dppf), Cs 2

CO

3 , toluene (76) Br N N 1) BF3-Et20, EtSH O O~h O2) aq. NaOH COOMe 3) aq. HCI (78) Br N OH N, COOH (8) WO 01/34137 PCT/USOO/31039 -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 01/34137 PCT/USOO/31039 -69 Scheme 9 O Br B I PdCl 2 (dppf), Cs 2

CO

3 , toluene O -_ -'_ O O , PIN COOMe 2) BF 3 -Et 2 O, EtSH (76) OH S N ' O O O 1) aq. LiOH COOMe 2) NaOH (80) OH S NN COONa (9) The palladium-catalyzed addition of boronic ester (76) to 2 5 bromothiophene, followed by debenzylation with boron trifluoride etherate and ethanethiol, provides thiophene (80) . Hydrolysis and salt formation provides Example (9).

WO 01/34137 PCT/USOO/31039 -70 Scheme 10 The following scheme illustrates a process for making Example (10), a 4-substituted pyrazole LTB 4 receptor antagonist: 5 10 WO 01/34137 PCT/USOO/31039 -71 Scheme 10 00 IOB N-N O 0 Known compound: RN 39806-90-1 COOMe PdCl 2 (dppf), Cs 2

CO

3 , toluene (76) N--0 -ND. 1) BF 3 -Et 2 O, EtSH S0 O 2) aq. NaOH COOMe 3) aq. HCI (82) N_ OH -N. O , O OP COOH (10) 5 WO 01/34137 PCT/USOO/31039 -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 01/34137 PCT/USOO/31039 -73 Scheme 11 B'0 N -1 0- Br COOMe PdCI 2 (dppf), 0S2003, toluene (76) S I ': BF 3 -Et 2 O, EtSH COOMe (84) S N 1) aq.LiOH 0- O - 2) HCI COOMe (86) S N N OH -o'-, 0N 0OO WO 01/34137 PCT/USOO/31039 -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 01/34137 PCT/USOO/31039 -75 Scheme 12 O ~1) N 1 0 0 0 OO O I PdCl 2 (dppf), Cs 2 CO, toluene COOMe (76) N 0 0 1) MeSil

S

0 -- N.O OXP 2) aq. HC COOMe 3) NaOH (88) ,N OH O 1 O O COONa (12) 5 WO 01/34137 PCT/USOO/31039 -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 01/34137 PCT/USOO/31039 -77 Scheme 13 Br O O I BBr 3 , CH 2 Cl 2 COOMe (60) OH Br TBSCI, imidazole O O O COOMe (90) OTBS Br

B(OH)

2 O O O Pd(PPh,) 4 , aq. Na2CO3, THF COOMe (92) OH O 1) aq. LiOH O O O-P 2) HCI COOMe 3) NaOH (94) OH 0 O O OP COONa (13) WO 01/34137 PCT/USOO/31039 -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 01/34137 PCT/USOO/31039 -79 Scheme 14 TBSO Br I

B(OH)

2 O O OPd(PPh 3

)

4 , aq. Na 2

CO

3 , THF COOMe (92) OH 1) aq. LiOH COOMe 2) HCI 3) NaOH (96) OH II | 4 0O 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 01/34137 PCT/USOO/31039 -80 Scheme 15 The following scheme illustrates a process for making Example (15), a 3-substituted tetrahydrofuran LTB 4 receptor antagonist: WO 01/34137 PCT/USOO/31039 -81 Scheme 15 OBr B(OH) 2 Br 0'j O -, o 0 Pd(PPh 3

)

4 , aq. Na 2

CO

3 , THF COOMe (60) O O O

H

2 , Pd(C) COOMe (98) OH 0 1) aq. LiOH 'o -O OP 2) HCI COOMe 3) NaOH (100) OH 0 0O--,O- OP COONa (15) WO 01/34137 PCT/USOO/31039 -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 01/34137 PCT/USOO/31039 -83 Scheme 16 O O B(OH) 2 O O Pd(PPh 3

)

4 , aq. Na 2

CO

3 , THF COOMe (60) 0 O

H

2 , Pd(C) COOMe (102) OH 0N O O O O~e aq. LiOH (104) OH N O M LHCI 04 0

.

O O COOLi (106) OH N N . I I ' . HCI COOH (16) WO 01/34137 PCT/USOO/31039 -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 01/34137 PCT/USOO/31039 -85 Scheme 17 0 N S 0 Br O

B(OH)

2 O O O-OC1 Pd(PPha) 4 , aq. Na 2

CO

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

K

2

CO

3 , KI, DMSO, 2-butanone O o- O N ON CN (112) OH BBr 3 , CH 2 C1 2 1) NaOH 0 0O O 2) HCI CN (114) S OH O -'O OP COOH (17) WO 01/34137 PCT/USOO/31039 -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 01/34137 PCT/USOO/31039 -87 Scheme 18 1-bromo-3-chloropropane 1) K 2 C03, Nal, 2-butanone HO O - C1 O OP COOMe K 2 CO, DMF COOMe 0 OH H N (30) (116) / known compound: OH RN 37470-83-0 (118) 2) Cs 2

CO

3 , BnBr, DMF 0 O 1) HS'SH H TsOH O O O ) 2) NaH, DMF, HMPA COOMe 3) piperidine (120) SO ) C +N I Me QNH2 O O COOMe 2) NaN, (122) ,N-N 0 N N O S 1) BF 3 -Et 2 O, CH2C12 O O 2) aq. NaOH COOMe 3) aq. HCI (124) ,N'-N OH N. I S

S

0

-'O'

0 OCI 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 01/34137 PCT/USOO/31039 -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 01/34137 PCT/USOO/31039 -89 Scheme 19 0 0

NH

2 NHCOOEt COOMe (32) EtO 'N 0 0 SOC1 2 O O OP COOMe (128) , O 1) BFEt 2 0, EtSH S O 2) aq.NaOH COOP 3) aq. HOI COOMe (130) N=zN OH C0OH COOH (19) Reference for 1,2,3-thiadiazole formation: E. W. Thomas et al., J. Med. Chem. 1985, 28, 442.

WO 01/34137 PCT/USOO/31039 -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 01/34137 PCT/USOO/31039 -91 Scheme 20 C II CI' 'N CI | | j O0 9 (trithiazyl trichloride) COOMe (62) S'N 0 N C'\1) BFEt 2 0, EtSH 0 P 2) aq. NaOH COOMe 3) aq. HCI (132) ,S'N OH N X I 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 01/34137 PCT/USOO/31039 -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, I N SS O O Br B known compound: RN 61929-24-6 O 0,9PCT WO 9730981 O O O PdCl 2 (dppf), Cs 2

CO

3 , toluene COOMe (76) N-N 0 N S ""1) BF 3 -Et 2 O, EtSH O- O O 2) aq. NaOH COOMe 3) aq. HCI (134) N-N OH S NN 0 I. COOH (21) WO 01/34137 PCT/USOO/31039 -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 01/34137 PCT/USOO/31039 -94 Scheme 22 The following scheme illustrates a process for making Example (22), a 5-substituted isothiazole LTB 4 receptor antagonist: Scheme 22 S O

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 0 N O COOMe (30)

K

2

CO

3 , KI, DMSO, (136) N O S 1) BF3-Et 2 O, EtSH O -O O 2) aq. NaOH COOMe 3) aq. HCI (138) N OH S COOH (22) 5 WO 01/34137 PCT/USOO/31039 -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). Scheme 23 10 The following scheme illustrates a process for making Example (23), a 2-substituted oxazole LTB 4 receptor antagonist: WO 01/34137 PCT/USOO/31039 -96 Scheme 23 Br 0 Nknown compound: RN 125533-82-6 R. D. Miller et al., Chem. Mater. 1994, B' 6(7), 1023. PdCl 2 (dppf), Cs 2 C0 3 , toluene COOMe (76) j N 0 1 N _; o 1) BF 3 Et 2 O, EtSH 0 P 2) aq. NaOH COOMe 3) aq. HCI (140) SN OH I| O '_ O OP COOH (23) The palladium-catalyzed addition of boronic ester (76) to 2 bromooxazole will provide oxazole (140). Debenzylation with 5 boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation, will provide the product of Example (23).

WO 01/34137 PCT/USOO/31039 -97 Scheme 24 The following scheme illustrates a process for making Example (24), a 3-substituted thiophane LTB 4 receptor antagonist: 5 10 WO 01/34137 PCT/USOO/31039 -98 Scheme 24 OH Et 3 SiH, TFA, benzene CN (114) OH S 1) aq. NaOH O O~ O 2) HCI CN (142) OH S S0-'-'"0 0 0N 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 01/34137 PCT/USOO/31039 -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 H O 14 10 known compound: RN# 156005-61-7 R. W. Harper et al., J. Med. Chem. 1994, 37(15), 2411-20 A. Preparation of 1- [2-benzyloxy-4- (3-chloropropoxy) -5 15 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), in N,N-dimethylformamide (300 mL) was stirred for 5 h at 20 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 and hexane, allowed to stand for 18 h, then cooled at 0 OC 25 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, 1H), 7.40 (m, 5H), 6.48 (s, 1H), 5.17 (s, 2H), 4.13 (t, J = WO 01/34137 PCT/USOO/31039 -100 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

C

20

H

24 C10 3 (p+1): m/z = 347.1414. Found: 347.1402; IR 5 (CHCl 3 ' -1 cm ) 1659, 1602, 1266. Anal. Calcd for C 20

H

2 3 C10 3 : C, 69.26; H, 6.68. Found: C, 69.30; H, 6.52. 0 0 O O + HO 0 0* CI COOMe known compound: RN# 152609-76-2 J. S. Sawyer et al., J. Med. Chem. 1995, 38,4411 O O O -O OP COOMe 10 B. Preparation of 2-(3-[3-(4-acetyl-5-benzyloxy-2 ethylphenoxy)propoxy] -2-propyl-phenoxy}benzoic acid methyl ester. 15 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 temperature, filtered, and concentrated in vacuo. The WO 01/34137 PCT/USOO/31039 -101 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 g, 23 mmol) at room temperature for 15 h. The mixture was 5 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% ethyl acetate/90% hexane) of the residue provided 9.2 g 1 10 (72%) of the title compound as a colorless oil. H NMR (CDCl 3 ) 6 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), 6.44 (d, J = 9 Hz, 1H), 5.14 (s, 2H), 4.20 (m, 4H), 3.83 (s, 15 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. Anal. Calcd for C 37

H

4 0 0 7 : C, 74.48; H, 6.76. Found: C, 20 74.39; H, 6.77.

WO 01/34137 PCT/USOO/31039 -102 0 0 0 0 COOMe HO . I | O- O"' OP 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 01/34137 PCT/USOO/31039 -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. HO COOMe N 0 0 0 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 OC 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 01/34137 PCT/USOO/31039 -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-- O OP COOMe / N OH OO | | COOMe 20 E. Preparation of 2-(3-[3-(2-ethyl-5-hydroxy-4-oxazol-4-yl phenoxy)propoxy]-2-propylphenoxy)benzoic acid methyl ester.

WO 01/34137 PCT/USOO/31039 -105 To a solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-oxazol-4-yl phenoxy)propoxy)-2-propylphenoxy}benzoic acid methyl ester (89 mg, 0.14 mmol) in ethanethiol (2 mL) was treated with boron trifluoride etherate (0.27 mL, 2.2 mmol) at room 5 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 solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 15% ethyl acetate/85% 10 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, 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), 15 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 (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). 20 / N OH 0 O - O O- --- 0 COOMe N H O -- O O

COOH

WO 01/34137 PCT/USOO/31039 -106 F. Preparation of 2-{3-[3-(2-ethyl-5-hydroxy-4-oxazol-4-yl phenoxy)propoxy]-2-propylphenoxy}benzoic acid. To a solution of 2-{3-[3-(2-ethyl-5-hydroxy-4-oxazol-4-yl phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester 5 (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 temperature and concentrated in vacuo. The aqueous residue was diluted with water and the pH adjusted to -4. The 10 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 of the title compound as a yellow solid. H NMR (DMSO-d 6 ) 8 12.83 (bs, 1H), 10.12 (bs, 1H), 8.39 (s, 1H), 8.25 (s, 15 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 (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), 20 0.80 (t, J = 8 Hz, 3H); TOF MS ES exact mass calculated for C 3 0

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

31

NO

7 : C, 69.62; H, 6.04; N, 2.71. Found: C, 68.71; H, 5.82; N, 2.65. 25 30 WO 01/34137 PCT/USOO/31039 -107 Example 2 Preparation of 2- (3-{3- [2-Ethyl-5-hydroxy-4- (3H-imidazol-4 yl) phenoxy] propoxy) -2-propyl-phenoxy) benzoic acid 5 hydrochloride. 0 I I O O- O--- . COOMe O

CI

0 1 1 0 0 COOMe A. Preparation of 2- (3-{3- [5-benzyloxy-4- (2-chloroacetyl) 10 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 ester (3.04 g, 5.09 mmol) in tetrahydrofuran (50 mL) cooled 15 to -78 OC 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 to 0 OC and stirred for 30 min. The mixture was evaporated 20 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 WO 01/34137 PCT/USOO/31039 -108 0 oC, and treated with N-chlorosuccinimide (750 mg, 5.6 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 5 water (4 mL) and a solution of 1 N tetra-n-butylammonium fluoride in tetrahydrofuran (6 mL). After stirring for 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. 10 Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 1.94 g (60%) of the title compound as a white solid. H NMR (CDCl 3 ) 8 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), 15 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 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 20 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. Anal. Calcd for C 37

H

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

WO 01/34137 PCT/USOO/31039 -109 O CI1 COOMe S N . NN | N| COOMe B. Preparation of 2- (3-{3- [5-benzyloxy-4- (2-benzylsulfanyl 3H-imidazol-4-yl) -2-ethyl-phenoxy] propoxy} -2 5 propylphenoxy)benzoic acid methyl ester. A mixture of 2-(3-{3-[5-benzyloxy-4-(2-chloroacetyl)-2 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, 10 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. 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. 15 Chromatography (silica gel, 30% ethyl acetate/70% hexane) of the residue provided 376 mg (40%) of the title compound as a 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 = WO 01/34137 PCT/USOO/31039 -110 8 Hz, 1H), 6.55 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 5.07 (s, 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, 5 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: -1 743.3142; IR (CHC1 3 , cm ) 2963, 1720, 1602, 1453. Anal. Calcd for C 45

H

4 6

N

2 0 6 S: C, 72.75; H, 6.24; N, 3.77. Found: C, 72.69; H, 6.17; N, 3.56. 10 S N | | O 1 O OP COOMe S NH H N O ^ O

O

COOMe WO 01/34137 PCT/USOO/31039 -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. A solution of 2-(3-{3-[5-benzyloxy-4-(2-benzylsulfanyl-3H 5 imidazol-4-yl)-2-ethyl-phenoxy]propoxy}-2 propylphenoxy)benzoic acid methyl ester (360 mg, 0.49 mmol) in ethanethiol (7 mL) was treateu'with boron trifluoride etherate at room temperature for 3.5 h. The mixture was diluted with diethyl ether and water. The organic layer was 10 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 compound as an orange oil. H NMR (CDCl 3 ) 8 7.85 (d, J = 8 15 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, J = 7 Hz, 2H), 2.30 (quintet, J = 6 Hz, 2H), 1.53 (hextet, J 20 = 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

4 1

N

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

H

40

N

2 06S: C, 69.92; H, 6.18; N, 4.29. Found: C, 69.44; H, 6.25; N, 3.99. 25 WO 01/34137 PCT/USOO/31039 -112 S / N.H N H N 0-0 0 COOMe -HCI / N H N 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 0 C for 4 h. The mixture was cooled to room temperature, WO 01/34137 PCT/USOO/31039 -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 10 Preparation of 2-{3-[3-(2-Ethyl-5-hydroxy-4-thiazol-4-yl phenoxy)propoxy] -2-propyl-phenoxy}benzoic acid. 0 0 0- ----- __ _ __ COOMe /N S: | | 0 O 0 COOMe A. Preparation of 2-{3-[3-(5-benzyloxy-2-ethyl-4-thiazol-4 15 yl-phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl 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), 20 and magnesium carbonate in dioxane (10 mL) was heated at WO 01/34137 PCT/USOO/31039 -114 reflux for 2 h. The mixture was cooled to room temperature 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), 5 filtered, and concentrated in vacuo. Chromatography (silica 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 ) 6 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), 10 6.80 (d, J = 8 Hz, 1H), 6.68 (d, J = 8 Hz, 1H), 6.62 (s, 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 15 calculated for C 38

H

40

NO

6 S (p+l): m/z = 638.2576. Found: -1 638.2579. IR (CHCl 3 , cm ) 2964, 1719, 1563, 1461. S: COOMe N H S | | COOMe WO 01/34137 PCT/USOO/31039 -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-propy1-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 1 colorless oil. H NMR (CDCl 3 ) 6 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 31

H

34 N0 6 S (p+1): m/z = 548.2107. Found: 548.2085.

WO 01/34137 PCT/USOO/31039 -116 H O4 0- O O COOMe / N H O O O 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 ) 8 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 01/34137 PCT/USOO/31039 -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 (CHCl 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. O O 0 O' COOMe 0 OO N 0I 1 0 0 COOMe 15 A. Preparation of 2-(3-{3-E5-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 ethylphenoxypropoxy}-2-propylphenoxy)benzoic acid methyl 20 ester (3.07 g, 5.04 mmol) and dimethylformamide WO 01/34137 PCT/USOO/31039 -118 dimethylacetal (0.9 mL, 7 mmol) in N,N-dimethylformamide (3 mL) was heated at 110-120 OC 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 4 0

H

4 6

NO

7 (p+1): m/z -1 - 652.3274. Found: 652.3270. IR (CHCl 3 , cm ) 2965, 1720, 1605. Anal. Calcd for C 40

H

45

NO

7 : C, 73.71; H, 6.96; N, 2.15. Found: C, 73.72; H, 6.95; N, 2.18. N O 1 O O COOMe N-N' O'1^/~O O COOH 15 B. Preparation of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(2H pyrazol-3-yl) phenoxy] propoxy) -2-propylphenoxy) benzoic acid. A solution of 2-(3-{3-[5-benzyloxy-4-(3 20 dimethylaminoacryloyl) -2-ethyl-phenoxy]propoxy} -2 propylphenoxy)benzoic acid methyl ester (550 mg, 0.843 mmol WO 01/34137 PCT/USOO/31039 -119 in methanol (30 mL) was treated with 1 M lithium hydroxide solution at 60 0 C for 3 h. The mixture was cooled to room temperature and diluted with ethyl acetate and 0.5 M hydrochloric acid. The organic layer was separated, washed 5 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 for 3 h. The mixture was diluted with ethyl acetate and 1 N 10 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/1% acetic acid) of the residue provided 350 mg (65%) of the title compound 15 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, J = 8 Hz, 1H), 6.65 (d, J = 8 Hz, 1H), 6.61 (d, J. = 8 Hz, 20 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 mass calculated for C 37

H

39

N

2 0 6 (p+1): m/z = 607.2808. -l1 25 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 01/34137 PCT/USOO/31039 -120 HN N-N /0 COOH H N-N' H O0 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)phenoxyIpropoxy}-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. 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 01/34137 PCT/USOO/31039 -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. 0 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-propylphenoxy)benzoic 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 01/34137 PCT/USOO/31039 -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 (CDCl 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+l): m/z = 622.2805. Found: 622.2817. IR -1 (CHCl 3 , cm ) 2964, 1720, 1461. Anal. Calcd for C 38

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 COOMe

N-

0 OH 0 0 COOMe 20 WO 01/34137 PCT/USOO/31039 -123 B. Preparation of 2-(3-[3-(2-ethyl-5-hydroxy-4-isoxazol-5 yl-phenoxy)propoxy] -2-propylphenoxy)benzoic 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,lH), 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 01/34137 PCT/USOO/31039 -124

N-

0 H O _ O O-P0 COOMe N'O H I I 00 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 (CDCl3) 8 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 01/34137 PCT/USOO/31039 -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 [1,2,3] triazol-4-yl)phenoxy]propoxy)- 2 -propyl 10 phenoxy)benzoic acid. Br .I + HO 0 O CI COOMe Br OIO 0 COOMe A. Preparation of 2-(3- [3- (5-benzyloxy-4-bromo-2 ethylphenoxy) propoxy] -2-propylphenoxy} -benzoic acid methyl 15 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), potassium carbonate (1.29 g, 9.34 mmol), potassium iodide 20 (0.52 g, 3.1 mmol), and methyl sulfoxide (2 mL) in 2 butanone (20 mL) was heated at reflux for 48 h. The mixture WO 01/34137 PCT/USOO/31039 -126 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. Chromatography (silica gel, 6% ethyl acetate/94% hexane) of 5 the residue provided 1.34 g (68%) of the title compound as a 1 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 (d, J = 8 Hz, 1H), 6.55 (s, 1H), 6.48 (, J = 8 Hz, 1H), 5.16 10 (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). 0 Br COOMe OJ o | COOMe 15 B. Preparation of 2-{3-[3-(5-benzyloxy-2-ethyl-4 ethynylphenoxy) propoxy] -2-propyl-phenoxylbenzoic acid methyl ester. 20 A mixture of 2-{3-[3-(5-benzyloxy-4-bromo-2 ethylphenoxy)propoxy]-2-propylphenoxy}-benzoic acid methyl ester (1.50 g, 2.37 mmol), tri-n-butylethynyltin (0.82 mL, WO 01/34137 PCT/USOO/31039 -127 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 24 h. The mixture was cooled to room temperature and 5 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% ethyl acetate/90% hexane) of the residue provided 532 mg 1 10 (39%) of the title compound as a brown oil. H NMR (CDCl 3 ) S 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), 5.16 (s, 2H), 4.17 (t, J = 6 Hz, 2H), 4.11 (t, J = 6 Hz, 15 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 37

H

39 0 6 (p+1) : m/z = 579.2747. Found: 579.2739. 20 IN 0 0 0 COOMe HN O -- O O COOMe WO 01/34137 PCT/USOO/31039 -128 C. Preparation of 2-(3-(3-[5-benzyloxy-2-ethyl-4-(3H [1,2,3]triazol-4-y)phenoxy]-propoxy)-2 propylphenoxy)benzoic acid methyl ester. 5 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 130 OC for 120 h. The mixture was cooled to room 10 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 compound as a brown solid. H NMR (CDC1 3 ) 8 8.10 (bs, 1H), 15 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 (m, 4H), 2.32 (quintet, J = 6 Hz, 2H), 1.56 (hextet, J = 8 20 Hz, 2H), 1.21 (t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated for C 37

H

40

N

3 0 6 (p+1): m/z = -1 622.2917. Found: 622.2946. IR (CHC1 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. 25 Found: C, 70.28; H, 6.07; N, 6.54.

WO 01/34137 PCT/USOO/31039 -129 H ,N'N' 0 I 0 COOMe ,,N'NH H N NI II COOMe D. Preparation of 2-(3-(3-[2-ethyl-5-hydroxy-4-(3H [1,2,3] triazol-4-yl)phenoxy] -propoxy)-2-propyl 5 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) was treated with boron trifluoride etherate (2.0 mL,16 mmol) 10 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 bicarbonate solution, once with saturated sodium chloride 15 solution, dried (sodium sulfate), filtered, and concentrated 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 ) 8 7.97 (s, 1H), 7.88 (dd, J = 8, 2 20 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, WO 01/34137 PCT/USOO/31039 -130 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 (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. 5 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. ,N-N' H N I N COOMe ,,' .H H IN-N' H N 0'-'-0 0 COOH 10 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 15 [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 20 was extracted three times with methylene chloride. The WO 01/34137 PCT/USOO/31039 -131 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, 5 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, 10 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 (CHC1 3 , cm ) 2965, 1738, 1454. Anal. Calcd for C 29

H

3 1

N

3 0 6 : C, 67.30; H, 6.04; N, 8.12. 15 Found: C, 67.15; H, 5.98; N, 7.93. Example 7 Preparation of 2-(3- [3- (2-Ethyl-5-hydroxy-4-pyrrol-1-yl 20 phenoxy)propoxy]-2-propyl-phenoxy}benzoic acid methyl ester. OH N.N OH OH 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 25 L) at room temperature was added a solution of 4- WO 01/34137 PCT/USOO/31039 -132 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 5 layer was dried (sodium sulfate), filtered, and concentrated 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 10 hexane, and filtered down a short column of silica gel. The 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. 15 The mixture 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, ethyl acetate/hexane gradient) of the residue provided 316 mg (2%) of the title 20 compound. TOF MS ES exact mass calculated for C 19

H

20 NO2 (p+1): m/z = 294.1494. Found: 294.1471. B. Preparation of 1- [2-benzyloxy-4- (3-chloropropoxy) -5 ethylphenyl] -1H-pyrrole. N O N O OH O ICI 25 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- WO 01/34137 PCT/USOO/31039 -133 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 5 concentrated in vacuo. Chromatography (silica gel, 5% ethyl 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 2 2

H

2 5 NC10 2 (p+1) : m/z = 370.1574. Found: 370.1548. 10 N HO 0_ __ O "-- Cl + COOMe N O - O O COOMe C. Preparation of 2-(3- [3- (5-benzyloxy-2-ethyl-4-pyrrol-l yl-phenoxy) propoxy] -2-propylphenoxy}benzoic acid methyl 15 ester. A mixture of 1- [2-benzyloxy-4- (3-chloropropoxy) -5 ethylphenyl]-1H-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, 20 filtered, and concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (7 mL) and treated with WO 01/34137 PCT/USOO/31039 -134 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 ethyl acetate and water, washed four times with water, once 5 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 colorless oil. H NMR (CDCl 3 ) 6 7.86 (dd, J = 8, 2 Hz, 1H), 10 7.37 (dt, J = 8, 2 Hz, 1H), 7.30 (m, 5H), 7.07 (m, 3H), 6.84 (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), 15 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+1): m/z = 620.3012. Found: 620.3021. N O 1- O OP COOMe ZOH OO OOO COOMe 20 WO 01/34137 PCT/USOO/31039 -135 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 phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester 5 (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 saturated sodium bicarbonate solution, dried (sodium 10 sulfate), filtered, and concentrated in vacuo. 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, 15 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 20 calculated for C 32

H

36

NO

6 (p+1): m/z = 530.2543. Found: 530.2516.

WO 01/34137 PCT/USOO/31039 -136 Example 8 Preparation of 2-(3-{3-[4-(3-Bromo-[1,2,4]thiadiazol-5-yl) 2-ethyl-5-hydroxyphenoxy] -propoxy) -2-propylphenoxy) benzoic acid. 5 Br 0 0---- O COOMe O I N COOMe 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 10 propylphenoxy)benzoic acid methyl ester. A mixture of 2-{3- [3-(5-benzyloxy-4-bromo-2 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 15 (80 mL) was treated with a 1 M solution of 4,4,5,5 tetramethyl-[1,3,2]dioxaborolane in tetrahydrofuran (20 mL, 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% 20 ethyl acetate/65% hexane) of the residue provided a dark oil that was subjected to further chromatography (silica gel, hexane to 30% ethyl acetate/70% hexane) to give 7.70 g (84%) WO 01/34137 PCT/USOO/31039 -137 of the title compound. H NMR (CDCl 3 ) 8 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), 5 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 NB0 8 10 (p + NH 4 ): m/z = 698.3864. Found: 698.3889. IR (CHCl 3 ' cm ) 2964, 1720, 1604, 1453. Anal. Calcd for C 4 1

H

4 9

BO

8 : C, 72.35; H, 7.26. Found: C, 72.30; H, 7.12. COOMe Br N N \ S O - O OP COOMe 15 B. Preparation 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.

WO 01/34137 PCT/USOO/31039 -138 A mixture of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5 tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxypropoxy}-2 propylphenoxy)benzoic acid methyl ester (310 mg, 0.46 mmol), 3-bromo-5-chloro-1,2,4-thiadiazole (120 mg, 0.60 mmol), 5 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 10 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 15 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 = 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. 20 WO 01/34137 PCT/USOO/31039 -139 Br N N I S O - O O-P3 COOMe Br N H N I S N COOH C. Preparation of 2-(3-(3-[4-(3-bromo-[1,2,4]thiadiazol-5 yl) -2-ethyl-5-hydroxyphenoxy] propoxy) -2 5 propylphenoxy)benzoic acid. 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 10 etherate (0.32 mL, 2.5 mmol) at room temperature for 6 h, at 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 15 dissolved in methanol (5 mL) and treated with 1 N lithium hydroxide solution (2 mL) at 65 OC for 1 h. The mixture was concentrated in vacuo and the residue diluted with water and adjusted to -pH 3 with 1 N hydrochloric acid. The resulting precipitate was collected via vacuum filtration and 20 dissolved in dilute aqueous base. Reverse phase chromatography (1:1 acetonitrile/water) provided 43 mg (23%) WO 01/34137 PCT/USOO/31039 -140 1 of the title compound as a yellow solid. H NMR (DMSO-d 6 ) 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, 5 4H), 2.27 (quintet, J = 5 Hz, 2H), 1.44 (hextet, J = 8 Hz, 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. 10 Example 9 Preparation of 2-(3-[3-(2-Ethyl-5-hydroxy-4-thiophen-2-yl phenoxy)propoxy]-2-propyl-phenoxy)benzoic acid sodium salt. 15 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 20 propylphenoxy)benzoic acid methyl ester (300 mg, 0.44 mmol), 2-bromothiophene (110 mg, 0.66 iol), 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 OC for 66 h. The mixture was cooled to room temperature and concentrated 25 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 an oil that was dissolved in ethanethiol (4 mL) and treated WO 01/34137 PCT/USOO/31039 -141 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. 5 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 = 10 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). 15 B. Preparation of 2-(3-[3-(2-ethyl-5-hydroxy-4-thiophen-2 yl-phenoxy) propoxy] -2-propylphenoxy}benzoic acid sodium salt. OH 0S 3 I I_ _ _ COOMe OH I I 0'--0 0 COONa 20 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 WO 01/34137 PCT/USOO/31039 -142 lithium hydroxide solution (0.5 mL) at room temperature for 1 h and then with an additional portion of 1 N lithium hydroxide solution (0.75 mL) for 18 h. The mixture was heated at 50 OC then concentrated in vacuo. The residue was 5 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 sodium hydroxide solution (0.22 mL), diethyl ether, and toluene. The mixture was concentrated in vacuo, dissolved 10 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, 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, 15 2H), 4.07 (t, J = 7 Hz, 2H), 2.50 (m, 4H), 2.20 (m, 2H), 1.40 (m, 2H), 1.06 (t, J = 8 Hz, 3H), 0.77 (t, J = 7 Hz, + + 3H) ; MS ES m/e 533 (p + 1 - Na ) . IR (CHCl 3 , cm ) 2900, 1738, 1604, 1454. 20 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 25 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 WO 01/34137 PCT/USOO/31039 -143 resulting mixture stirred at room temperature for 96 h. The 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 5 compound as a colorless oil. iH NMR (CDCl 3 ) 8 7.47 (s, 1H), 7.38 (s, 1H), 3.90 (s, 3H). B. Preparation of 2-(3-(3-[5-benzyloxy-2-ethyl-4-(1-methyl 1H-pyrazol-4-yl) phenoxy] -propoxy) -2-propylphenoxy) benzoic 10 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 (1.00 g, 1.47 rmol), 4-iodo-l-methylpyrazole (450 mg, 2.16 mmol), cesium 15 carbonate (1.20 g, 3.62 mmol), and PdCl 2 (dppf) (72 mg, 0.088 mmol) in de-oxygenated toluene (35 mL) was heated at 100 OC for 24 h. Additional portions of 4-iodo-1-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 20 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 25 (76%) of the title compound. H NMR (CDCl 3 ) 8 7.86 (dd, J = 8, 2 Hz, iH), 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 30 Hz, 2H), 4.15 (t, J = 6 Hz, 2H), 3.85 (s, 3H), 3.81 (s, 3H), WO 01/34137 PCT/USOO/31039 -144 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 -N O - O Olpa COOMe ,N H -NN COOH 5 C. Preparation of 2- (3-(3- [2-ethyl-5-hydroxy-4- (1-methyl 1H-pyrazol- 4 -yl) -phenoxy] propoxy) -2-propylphenoxy) benzoic acid. 10 A solution of 2

-(

3 -{3-[5-benzyloxy-2-ethyl-4-(1-methyl-lH 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 15 diluted with water, concentrated in vacuo, and extracted 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 20 lithium hydroxide solution (5 mL) at -95 0 C for 2 h. The mixture was concentrated in vacuo and the residue diluted with water, washed twice with diethyl ether, and the aqueous WO 01/34137 PCT/USOO/31039 -145 layer acidified with 1 N hydrochloric acid. The resulting solution was extracted with diethyl ether. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% 5 methanol/90% methylene chloride) provided 338 mg (57%) of 1 the title compound as a tan foam. H NMR (DMSO-d 6 ) 8 12.85 (bs, 1H), 9.50 (bs, 1H), 7.98 (s, 1H), 7.78 (m, 2H), 7.48 (dt, J = 8, 2 Hz, 1H), 7.44 (s, 1H), 7.18 (t, J = 8 Hz, 1H), 7.13 (t, J = 9 Hz, 1H), 6.79 (d, J = 9 Hz, 1H), 6.77 (d, J = 10 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 -1I m/e 531 (p+1); IR (KBr, cm ) 2961, 1697, 1602, 1460, 1222. 15 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.

WO 01/34137 PCT/USOO/31039 -146 Example 11 Preparation of 2-(3- [3-(2-Ethyl-5-hydroxy-4-thiazol-2-Yl phenoxy)propoxy] -2-propyl-phenoxy}benzoic acid. 0 -- O O 09 N O- OO S Br COOMe CN O S I - | O 1- O Op COOMe 5 A. Preparation of 2-{3- [3-(5-benzyloxy-2-ethyl-4-thiazol-2 yl-phenoxy) propoxy] -2-propylphenoxy)benzoic acid methyl ester. 10 A mixture of 2-(3-{3-[5-benzyloxy-2-ethyl- 4

-(

4

,

4 ,5,5 tetramethyl- [1, 3, 2]dioxaborolan-2-yl)phenoxypropoxy}- 2 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 15 oxygenated toluene (35 mL) was heated at 60 OC for 16 h then 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 20 methylene chloride, and filtered down a short plug of silica gel. The filtrate was concentrated in vacuo.

WO 01/34137 PCT/USOO/31039 -147 Chromatography (silica gel, hexane to 35% ethyl acetate/65% hexane) of the residue provided 282 mg (31%) of the title compound. H NMR (CDCl 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), 5 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 10 (t, J = 7 Hz, 3H), 0.88 (t, J = 7 Hz, 3H). S O - O OP COOMe N H S O' - O O COOMe B. Preparation of 2-(3- [3- (2-ethyl-5-hydroxy-4-thiazol-2 15 yl-phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester. A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-thiazol-2-yl phenoxy)propoxy]-2-propylphenoxylbenzoic acid methyl ester (282 mg, 0.442 mmol) in ethanethiol (3 mL) was treated with 20 boron trifluoride etherate (0.56 mL, 4.4 mmol) at room temperature for 3 h. The reaction mixture was diluted with WO 01/34137 PCT/USOO/31039 -148 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 5 title compound. H NMR (CDCl 3 ) 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), 10 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 (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+1). 15 N H S COOMe N H S 0 I 0 COOH C. Preparation of 2-(3- [3- (2-ethyl-5-hydroxy-4-thiazol-2 yl-phenoxy) propoxy] -2-propylphenoxy}benzoic acid. 20 2-{3-[3-(2-Ethyl-5-hydroxy-4-thiazol-2-yl-phenoxy)propoxy] 2-propylphenoxy}benzoic acid methyl ester (107 mg, 0.196 WO 01/34137 PCT/USOO/31039 -149 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 5 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 1 10 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 = 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), 15 2.57 (m, 4H), 2.35 (quintet, J = 6 Hz, 2H), 1.49 (hextet, J = 8 Hz, 2H), 1.18 (t, J = 7 Hz, 3H), 0.86 (t, J = 7 Hz, 3H); + -1 MS ES m/e 534 (p+l); IR (KBr, cm ) 2957, 1695, 1599, 1457. Anal. Calcd for C 30

H

31

NO

6 S: C, 67.52; H, 5.86; N, 2.62. Found: C, 67.44; H, 5.95; N, 2.55. 20 WO 01/34137 PCT/USOO/31039 -150 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 O O'P+ N COOMe 0 N 1

-

COOMe ,0 OH NN I | O O OP COONa 5 A mixture of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5 tetramethyl- [1, 3, 21 dioxaborolan-2-yl) phenoxy] propoxy} -2 propylphenoxy)benzoic acid methyl ester (305 mg, 0.448 10 mmol), 3,5-dimethyl-4-iodoisoxazole (110 mg, 0.493 mmol), 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 0 C for 10 h. Additional portions of 3,5-dimethyl-4 iodoisoxazole (110 mg), cesium carbonate (260 mg), and 15 PdCl 2 (dppf) (-15 mg) were added and heating continued at 110 OC for 20 h. The mixture was cooled to room temperature, WO 01/34137 PCT/USOO/31039 -151 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 5 chloride (4 mL), cooled to 0 0 C, 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 10 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 15 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, 20 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, 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 25 (s, 3 H), 1.49 (hextet, J = 8 Hz, 2H), 1.07 (t, J = 7 Hz, 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.

WO 01/34137 PCT/USOO/31039 -152 Example 13 Preparation of 2-{3-[3-(2-Ethyl-4-furan-2-yl-5 hydroxyphenoxy) propoxy] -2 -propylphenoxy} -benzoic acid sodium salt. Br I | | COOMe H Br COOMe 5 A. Preparation of 2-(3-[3-(4-bromo-2-ethyl-5 hydroxyphenoxy) propoxy] -2-propylphenoxy)benzoic acid methyl ester. 10 A solution of 2-{3-[3-(5-benzyloxy-4-bromo-2 ethylphenoxy)propoxy]-2-propylphenoxy}-benzoic acid methyl ester (2.50 g, 3.95 mmol) in methylene chloride (40 mL) was cooled to -70 OC and treated with boron tribromide (0.25 mL, 2.6 mmol). After 25 min the mixture was poured into cold 15 water and the resulting mixture extracted with methylene chloride. The combined organic extracts were washed once 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 20 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 WO 01/34137 PCT/USOO/31039 -153 (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 5 (quintet, J = 6 Hz, 2H), 1.54 (hextet, J = 8 Hz, 2H), 1.13 (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 COOMe TBS Br Br II O ' O O COOMe 10 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 15 hydroxyphenoxy) propoxy] -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 20 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 WO 01/34137 PCT/USOO/31039 -154 provide 1.1 g (91%) of the title compound as a colorless oil. H NMR (CDCl 3 ) 6 7.88 (d, J = 9 Hz, 1H), 7.38 (t, J = 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), 5 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, 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). 10 OTBS Br 00-_ __ _ COOMe OH 00 0 COOMe C. Preparation of 2-{3-[3-(2-ethyl-4-furan-2-yl-5 15 hydroxyphenoxy)propoxy]-2-propyl-phenoxy}benzoic acid methyl 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), 20 furan-2-boronic acid (0.358 g, 3.20 mmol), tetrakis(triphenylphosphine)palladium(0) (0.185 g, 0.160 mmol), and 2 M aqueous sodium carbonate solution (8 mL) in WO 01/34137 PCT/USOO/31039 -155 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 separated, washed once with water, once with saturated 5 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 (CDCl 3 ) 8 7.90 (d, J = 9 Hz, 1H), 7.48 (s, 1H), 7.38 (t, J = 10 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 (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 15 = 8 Hz, 2H), 1.18 (t, J = 7 Hz, 3H), 0.91 (t, J = 7 Hz, 3H); MS ES m/z = 589 (p + AcO Anal. Calcd for C 32 H 34 0 7 : C, 72.43; H, 6.46. Found: C, 72.21; H, 6.15. OH 0- '-' O O I COOMe H 0 I 0 O O COONa 20 WO 01/34137 PCT/USOO/31039 -156 D. Preparation of 2-(3-[3-(2-ethyl-4-furan-2-yl-5 hydroxyphenoxy)propoxy]-2-propylphenoxylbenzoic acid sodium salt. 5 2-{3-[3-(2-Ethyl-4-furan-2-yl-5-hydroxyphenoxy)propoxy]-2 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 10 with water and 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. The residue was dissolved in ethyl acetate and shaken with 1 N 15 hydrochloric acid. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo. The residue 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 20 diethyl ether, chloroform, and diethyl ether and dried to provide 168 mg (66%) of the title product as a cream solid. 1 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 25 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 (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 30 Found: 517.2230. IR (KBr, cm ) 3400, 2961, 1599, 1460.

WO 01/34137 PCT/USOO/31039 -157 Example 14 Preparation of 2- (3-(3- [2-Ethyl-5-hydroxy-4-furan-3 yl]phenoxy]propoxy)-2-propylphenoxy)benzoic acid. OTBS Br COOMe H 0 O -- '-O OP COOMe 5 A. Preparation of 2-{3-[3-(2-ethyl-4-furan-3-yl-5 hydroxyphenoxy) propoxy] -2-propyl-phenoxylbenzoic acid methyl ester. 10 A mixture of 2-(3-{3-[4-bromo-5-(tert 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 15 mmol), and 2 M aqueous sodium carbonate solution (16 mL) in 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 20 sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 15% ethyl acetate/85% hexane) of the residue provided 0.29 g WO 01/34137 PCT/USOO/31039 -158 (17%) of the title compound as a yellow oil. TOF MS ES exact mass calculated for C 32

H

35 0 7 (p+1): m/z = 531.2383. Found: 531.2396. H 0 -- "O O COOMe H 00 COOH 5 B. Preparation of 2-{3-[3-(2-ethyl-4-furan-3-yl-5 hydroxyphenoxy)propoxy] -2-propylphenoxy}benzoic acid sodium salt. 10 2-{3-[3-(2-Ethyl-4-furan-3-yl-5-hydroxyphenoxy)propoxy]-2 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 15 residue acidified with hydrochloric acid and the resulting 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 20 gel, 2% methanol/98% chloroform) of the residue gave 45 mg of material that was again submitted to chromatography WO 01/34137 PCT/USOO/31039 -159 (silica gel, 1% methanol/99% chloroform) to provide 25 mg (15%) of the title compound as an oil. 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. O Br COOMe 0 0 0 0 0-9 COOMe 10 A. Preparation of 2-{3- [3- (5-benzyloxy-2-ethyl-4-furan-3 yl-phenoxy) propoxy] -2 -propylphenoxy}benzoic acid methyl ester. 15 A mixture of 2-{3-[3-(5-benzyloxy-4-bromo-2 ethylphenoxy)propoxyl-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 20 mL) in tetrahydrofuran (40 mL) was heated at 100 OC for 48 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer WO 01/34137 PCT/USOO/31039 -160 was 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 1.9 g 1 5 (65%) of the title compound as a yellow oil. H NMR (CDC1 3 ) 6 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), 10 2.66 (t, J = 8 Hz, 2H), 2.62 (q, J = 7 Hz, 2H), 2.30 (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 O -0 o- o 0 COOMe 0 H O O O COOMe 15 B. Preparation of 2-(3-{3-[2-ethyl-5-hydroxy-4 (tetrahydrofuran-3-yl)phenoxy]-propoxy}-2 propylphenoxy)benzoic acid methyl ester. 20 A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-furan-3-yl phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester WO 01/34137 PCT/USOO/31039 -161 (1.8 g, 2.9 mmol) in ethyl acetate (40 mL) was treated with 10% palladium-on-carbon (0.39 g) and hydrogenated at 48 psi and 45 0 C for 72 h. The mixture was cooled to room TM temperature, filtered through Celite , and the filtrate 5 concentrated in vacuo to provide 1.2 g (77%) of the title 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), 10 6.43 (s, 1H), 4.19 (m, 3H), 4.10 (m, 2H), 4.02 (dd, J = 12, 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, 15 J = 7 Hz, 3H), 0.90 (t, J 7 Hz, 3H); MS ES m/z = 593 (p + - -1

CH

3 COO); IR (CHCl 3 , cm ) 2963, 1719, 1589, 1461. Anal. Calcd for C 32

H

38 0 7 : C, 71.89; H, 7.16. Found: C, 71.41; H, 7.06. O OH I I__|_ COOMe 0 H 0 COONa 20 WO 01/34137 PCT/USOO/31039 -162 C. Preparation of 2-(3-(3-[2-ethyl-5-hydroxy-4 (tetrahydrofuran-3-yl)phenoxy]-propoxy}-2 propylphenoxy)benzoic acid sodium salt hemihydrate. 5 A solution of 2-(3-{3-[2-ethyl-5-hydroxy-4-(tetrahydrofuran 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 10 was allowed to cool to room temperature and stirred for an 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 15 ethyl acetate. The ethyl acetate layer was washed once with 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 20 mL). The resulting biphasic mixture was diluted with 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 0 C. 25 H NMR (DMSO-d 6 ) 6 7.62 (dd, J = 8, 2 Hz, 1H), 7.30 (dt, J = 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 30 2H), 2.60 (t, J = 8 Hz, 2H), 2.45 (q, J = 7 Hz, 2H), 2.15 (m, 3H), 1.90 (m, 1H), 1.48 (hextet, J = 8 Hz, 2H), 1.06 (t, WO 01/34137 PCT/USOO/31039 -163 J = 7 Hz, 3H), 0.83 (t, J = 7 Hz, 3H); MS ES m/z = 519 (p + -1 Na ); IR (CHC1 3 , cm ) 2964, 1783, 1604, 1461. Anal. Calcd for C 3 1

H

3 5 NaO 7 . 0.5 H 2 0: 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 hydrate. o Br " O O_9 COOMe \ 0 N 0 i 0 0 0 l COOMe 10 A. Preparation of 2-(2-benzyloxy-5-ethyl-4-{3-[3-(2 methoxycarbonylphenoxy) -2 propylphenoxy]propoxyiphenyl)pyrrole-1-carboxylic acid tert 15 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 (1.99 g, 9.43 mmol), 20 tetrakis(triphenylphosphine)palladium(0) (0.54 g, 0.47 mmol), and 2 M aqueous sodium carbonate solution (25 mL) in WO 01/34137 PCT/USOO/31039 -164 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 separated, washed once with water, once with saturated 5 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 ) O 7.88 (dd, J = 8, 2 Hz, 1H), 7.15-7.40 (m, 7H), 7.08 (m, 3H), 10 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 = 7 Hz, 2H), 2.30 (quintet, J = 6 Hz, 2H), 1.57 (hextet, J = 15 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 (CHCl 3 , cm ) 2964, 1730, 1461. Anal. Calcd for C 44

H

4 9

NO

8 : C, 73.41; H, 6.86; N, 1.94. 20 Found: C, 73.76; H, 6.76; N, 2.04.

WO 01/34137 PCT/USOO/31039 -165 N COOMe H N 00 01 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 propylphenoxy]propoxy}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 OC 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 01/34137 PCT/USOO/31039 -166 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 0 0N 0 N ______ COOMe H N 0 0 -N--/- o o 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 01/34137 PCT/USOO/31039 -167 +-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 H O O O 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]propoxy}-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 HC1. 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 compound. H NMR (DMSO-d 6 ) 8 12.80 (bs, 1H), 10.12 (s, 1H), WO 01/34137 PCT/USOO/31039 -168 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 S 0 Br O 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(O) (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 01/34137 PCT/USOO/31039 -169 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 0 C. H NMR (CDCl 3 ) 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 (CHC1 3 , cm ) 2969, 1613, 1501, 1138. Anal. Calcd for C 2 2

H

23 0 2 ClS: C, 68.29; H, 5.99. Found: C, 68.53; H, 6.00. + HO C0 Known compound: Sawyer et al., J. Med. Chem. 1995, 38, 4411. S o 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 01/34137 PCT/USOO/31039 -170 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 (CDC1 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 (CHC1 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 01/34137 PCT/USOO/31039 -171 C. Preparation of 2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4 (thiophen-3-yl)phenoxy]propoxy]phenoxy]benzonitrile. S 0 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]propoxy]phenoxylbenzonitrile (900 mg, 1.49 mmol) in methylene chloride (25 mL) cooled to -78 0 C 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 01/34137 PCT/USOO/31039 -172 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). D. Preparation of 2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4 5 (thiophen-3-yl)phenoxy]propoxy]phenoxy]benzoic acid hydrate. S OH I I. 0 O-0 CN S OH COOH A solution of 2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4 (thiophen-3-yl)phenoxy]propoxy]phenoxy]benzonitrile (400 mg, 0.780 mmol) in 2:1 methanol/water (6 mL) was treated with 10 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 extracted twice with methylene chloride. The combined 15 methylene chloride layers were dried (magnesium sulfate), filtered, and concentrated in vacuo to provide a tan solid: mp 90-95 0 C (dec). H NMR (CDCl 3 ) 8 8.24 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 5.0 Hz, 1H), 7.44 (t, J = 8.6 Hz, 1H), 7.36 (d, J = 3 Hz, 1H), 7.24 (d, J = 4.9 Hz, 1H), 7.19 (m, 20 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 (bs, 1H, -OH), 4.26 (t, J = 6.2 Hz, 2H), 4.21 (t, J = 7.1 WO 01/34137 PCT/USOO/31039 -173 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 (br), 2961, 1697, 1457, 1110. Anal. Calcd for C 3 1

H

32 0 6 * 5 H 2 0: C, 67.62; H, 6.22. Found: C, 67.34; H, 5.87. The previously described LTB 4 antagonists and anti cangel agents used in the composition and method of the invention are often advantageously used in the form of salt 10 derivatives which are an additional aspect of the invention. When compounds of the invention possess an Acidic Group(s) or other reactive group, salts may be formed which are more water soluble and/or physiologically suitable than the parent compound in its acid form. Representative 15 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 preferred. Salts are conveniently prepared from the free acid by treating the 20 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 appropriate bases (e.g., NaOH, KOH) to yield the corresponding sodium or potassium salt. 25 Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient 30 basicity to form salts with the LTB 4 antagonist compounds of this invention (see, for example, S. M. Berge, et al., WO 01/34137 PCT/USOO/31039 -174 "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 5 intended to be included in the invention. If a particular 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, 10 alternatively, by methods which lead to mixtures of the 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 form into a mixture of diastereomers. Then, because the 15 diastereomers have different melting points, different boiling points, and different solubilities, they can be separated by conventional means, such as crystallization. Prodrugs are derivatives of the LTB 4 antogonist and anti-cancer compounds used in the invention which have 20 chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the 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 25 derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian 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, 30 for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable WO 01/34137 PCT/USOO/31039 -175 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 5 esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularly 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 10 the compounds of the composition of the invention. Methyl ester prodrugs may be prepared by reaction of the acid form of a compound of formula (I) in a medium such as methanol with an acid or base esterification catalyst (e.g., NaOH, H 2

SO

4 ). Ethyl ester prodrugs are prepared in 15 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) (in a medium such as dimethylformamide) with 2-chloro-N,N diethylacetamide (available from Aldrich Chemical Co., 20 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 a medium such as dimethylformamide) 4-(2 chloroethyl)morpholine hydrochloride (available from Aldrich 25 Chemical Co., Milwaukee, Wisconsin USA, Item No. C4,220-3). Preferred LTB 4 compounds and anti-cancer compounds of the compositions of the wherein the acid, salt and prodrug derivatives thereof are respectively selected from: carboxylic acid, sodium salt, and ester prodrug. 30 The compositions of the present invention are a combination of therapeutically effective amounts of the leukotriene (LTB 4 ) antagonists, noted above, and a WO 01/34137 PCT/USOO/31039 -176 therapeutically effective amount of the anti-cancer agents noted above. The composition may be formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated elixirs or solutions for convenient 5 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. 10 In another embodiment, the invention relates to a 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. 15 When administered separately, the leukotriene (LTB 4 ) 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. 20 Therapeutically effective interval is a period of time beginning when one of either (a) the leukotriene (LTB 4 ) antagonist 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). 25 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 30 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.

WO 01/34137 PCT/USOO/31039 -177 Pharmaceutical Compositions of the Invention 5 Preferably compounds of the invention or pharmaceutical formulations containing these compounds are in unit dosage form for administration to a mammal. The unit dosage form can be a capsule, an IV bag, a tablet, or a vial. The quantity of Active Ingredient in a unit dose of composition 10 is a therapeutically effective amount and may be varied according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of 15 administration. The compound can be administered by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. 20 Pharmaceutical formulations of the invention are prepared by combining (e.g., mixing) a therapeutically effective amount of the anti-cancer agent (e.g., a 2',2' difluoronucleoside and an LTB 4 antagonist, such as the 25 compound of Formula A, Formula I, II) together with a pharmaceutically acceptable carrier or diluent therefor. The present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients. 30 In making the compositions of the present invention, the Active Ingredient will usually be admixed with a WO 01/34137 PCT/USOO/31039 -178 carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, lyophilzed solid or paste, 5 semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, injectable liquids, aerosols (as a solid or in a liquid medium), or ointment, containing, for example, up to 10% 10 by weight of the active compound. The compounds of the present invention are preferably formulated prior to administration. For the pharmaceutical formulations any suitable 15 carrier known in the art can be used. In such a formulation, the carrier may be a solid, liquid, or mixture of a solid and a liquid. For example, for intravenous injection the compounds of the invention may be dissolved in sterile water, sterile saline, or sterile water or saline 20 containing sugars and/or buffers at a concentration of about 0.05 to about 5.0 mg/ml in a 4% dextrose/0.5% Na citrate aqueous solution. Solid form formulations include powders, tablets and 25 capsules. A solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material. 30 Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating WO 01/34137 PCT/USOO/31039 -179 agents, such as maize, starch, or alginic acid, and/or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc. 5 In powders the carrier is a finely divided solid which is in admixture with the finely divided Active Ingredient. In tablets the Active Ingredient is mixed with a carrier having the necessary binding properties in suitable 10 proportions and compacted in the shape and size desired. Advantageously, compositions containing the compound of Formula (I) may be provided in dosage unit form, preferably each dosage unit containing from about 5 to about 500 mg 15 (from about 5 to 50 mg in the case of parenteral or inhalation administration, and from about 25 to 500 mg in the case of oral or rectal administration. 0.5 to 20 mg/kg, of Active Ingredient may be administered although it will, of course, readily be understood that Dosages from about 0.5 20 to about 300 mg/kg per day, preferably 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 circumstances. 25 Powders and tablets preferably contain from about 1 to about 99 weight percent of the Active Ingredient which is the novel compound of this invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, 30 methyl cellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter.

WO 01/34137 PCT/USOO/31039 -180 Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs. The Active Ingredient can be dissolved or suspended 5 in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the 10 recipient thereof. The Active Ingredient can also be dissolved in a suitable organic solvent, for instance aqueous propylene glycol. Other compositions can be made by dispersing the 15 finely divided Active Ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil. The following pharmaceutical formulations 1 to 22 are 20 illustrative only and are not intended to limit the scope of the invention in any way. "Active Ingredient", refers to a 2',2'-difluoronucleoside or a compound according to Formula A, Formula (I) or (II) or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 25 In one embodiment the compositions of the present invention are a combination of therapeutically effective amounts of the leukotriene (LTB 4 ) antagonists, noted above, and a therapeutically effective amount of a 2',2' 30 difluoronucleoside anti-cancer agent. The composition may be formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated elixirs or WO 01/34137 PCT/USOO/31039 -181 solutions for convenient 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. 5 In another embodiment, the 2',2'-difluoronucleoside anti-cancer agents are formulated independently of the leukotrienes (LTB 4 ) antagonists and are administered separately. The anti-cancer agents may be formulated with 10 common excipients, diluents or carriers and administered by intravenous infusion. On the other hand, the anti-cancer agents may be formulated into liquids suitable for oral administration. Anti-cancer agents may also be compressed into tablets and administered orally. If the anti-cancer 15 agents and the leukotrienes (LTB 4 ) antagonists are administered separately, the anti-cancer agents may be administered before, after or during the administration of the leukotriene (LTB 4 ) antagonists. If the anti-cancer agents are administered separately from the leukotrienes 20 (LTB 4 ) antagonists, they must be administered within a therapeutically effective interval. The method of treating a human patient according to the present invention includes both the administration of the 25 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 ) antagonists are formulated into formulations which may be 30 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 WO 01/34137 PCT/USOO/31039 -182 example, tablets, lozenges, sublingual tablets, sachets, 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 5 capsules, suppositories, injectable solutions and suspensions in physiologically acceptable media, and sterile packaged powders adsorbed onto a support material for making injectable solutions. Advantageously for this purpose, compositions may be provided in dosage unit form, preferably 10 each dosage unit containing from about 5 to about 500 mg (from about 5 to 50 mg in the case of parenteral or 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 15 300 mg/kg per day, preferably 0.5 to 20 mg/kg, of active ingredient may be administered although it will, of course, 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 20 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 present invention in any way. 25 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 A and Formula I mixed with a carrier, or diluted by a 30 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 WO 01/34137 PCT/USOO/31039 -183 ampoule. A carrier or diluent may be a solid, semi-solid or 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 5 pharmaceutical compositions of the present invention are lactose, dextrose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, fumed silicon dioxide, microcrystalline cellulose, calcium silicate, silica, polyvinylpyrrolidone, cetostearyl alcohol, 10 starch, modified starches, gum acacia, calcium phosphate, cocoa butter, ethoxylated esters, oil of theobroma, arachis oil, alginates, tragacanth, gelatin, syrup, methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitan 15 trioleate, sorbitan sesquioleate and oleyl alcohol and propellants such as trichloromonofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane. In the case of tablets, a lubricant may be incorporated to prevent sticking and binding of the powdered ingredients in 20 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. Preferred pharmaceutical forms of the present invention 25 are capsules, tablets, suppositories, injectable solutions, creams and ointments. Especially preferred are formulations for inhalation application, such as an aerosol, and for oral ingestion. 30 The following formulation examples may employ as active compounds any of the leukotriene (LTB 4 ) antagonists noted WO 01/34137 PCT/USOO/31039 -184 above. The examples are illustrative only and are not intended to limit the scope of the invention in any way. FORMULATION EXAMPLE 1 5 Hard gelatin capsules are prepared using the following ingredients: Quantity (mg/capsule) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 10 hydroxyphenoxy)propoxy)-6-(4-carboxy phenoxy)phenyl)propanoic acid 250 Starch 200 15 Magnesium stearate 10 The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities. 20 FORMULATION EXAMPLE 2 A tablet is prepared using the ingredients below: Quantity (mg/capsule) 1-(4-(Carboxymethoxy)phenyl)-1-(lH 25 tetrazol-5-yl)-6-(2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy)hexane 250 Cellulose, microcrystalline 400 30 Silicon dioxide, fumed 10 Magnesium stearate 5 The components are blended and compressed to form 35 tablets each weighing 665 mg.

WO 01/34137 PCT/USOO/31039 -185 FORMULATION EXAMPLE 3 5 An aerosol solution is prepared containing the following components: Weight % 3-(4-[7-Carboxy-9-oxo-3-[3-[2-ethyl-4 10 (4-fluorophenyl)-5-hydroxyphenoxy]propoxy] 9H-xanthene]]propanoic acid 0.25 Ethanol 30.00 15 Propellant 11 10.25 (trichlorofluoromethane) Propellant 12 29.75 (Dichlorodifluoromethane) 20 Propellant 114 29.75 (Dichlorotetrafluoroethane) The active compound is dissolved in the ethanol and the 25 solution is added to the propellant 11, cooled to -30 0 C. and 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 30 the container.

WO 01/34137 PCT/USOO/31039 -186 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 U.S. sieve (355 pn) and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve (1.4 mm). The granules so produced 30 are dried at 50-600 and passed through a No. 18 mesh U.S. sieve (1.00 mm) . The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve (250 pn), are then added to the granules which, after mixing, are compressed on a tablet machine to yield 35 tablets each weighing 150 mg.

WO 01/34137 PCT/USOO/31039 -187 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-hydroxyphenoxylpropoxy] 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 U.S. 20 sieve (355 pm), 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 01/34137 PCT/USOO/31039 -188 The active ingredient is passed through a No. 60 mesh U.S. sieve (250 pm) 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) 5-hydroxyphenoxy]propoxy]phenoxy]benzoic 15 acid 50 mg Sodium carboxymethyl cellulose 50 mg Sugar 1 g 20 Methyl paraben 0.05 mg Propyl paraben 0.03 mg 25 Flavor q.v. Color q.v. Purified water to 5 mL 30 The medicament is passed through a No. 45 mesh U.S. sieve (355 pm) and mixed with the sodium carboxymethylcellulose, sugar, and a portion of the water to form a suspension. The parabens, flavor and color are 35 dissolved and diluted with some of the water and added, with WO 01/34137 PCT/USOO/31039 -189 stirring. Sufficient water is then added to produce the required volume. FORMULATION EXAMPLE 8 5 Hard gelatin capsules are prepared using the following ingredients: Quantity (mg/capsule) 10 1-(4-amino-5-methyl-2-oxo-lH pyrimidin-1-yl)-2-desoxy- 250 2',2'-difluororibose Starch dried 200 15 Magnesium stearate 10 The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities. 20 WO 01/34137 PCT/USOO/31039 -190 FORMULATION EXAMPLE 9 A tablet formula is prepared using the ingredients below: 5 Quantity (mg/tablet) 1-(2-oxo-4-amino-1H-pyrimidin 1-yl)-2-desoxy-2',2'-difluoro- 250 10 ribose Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 15 Stearic acid 5 The components are blended and compressed to form tablets each weighing 665 mg. 20 FORMULATION EXAMPLE 10 An aerosol solution is prepared containing the following components: 25 Weight .% 1-(2,4-dioxo-1H,3H-pyrimidin 30 1-yl)-2-desoxy-2',2'-difluoro ribose 0.25 Ethanol 29.75 Propellant 22 70.00 (Chlorodifluoromethane) 35 The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to - WO 01/34137 PCT/USOO/31039 -191 30.degree. C. and transferred to a filling device. The required amount is then placed in a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container. 5 FORMULATION EXAMPLE 11 Tablets each containing 60 mg of active ingredient are made up as follows: 10 1-(4-amino-2-oxo-lH-pyrimidin 1-yl)-2-desoxy-2',2'-difluoro ribose 60 mg 15 Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone 4 mg (as 10% solution in water) 20 Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg 25 The difluoronucleoside starch and cellulose are passed through a No. 45 mesh 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 U.S. sieve. The granules so produced are dried at 50.degree.

30 60.degree. C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, WO 01/34137 PCT/USOO/31039 -192 are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg. 5 FORMULATION EXAMPLE 12 Capsules each containing 80 mg of medicament are made as follows: 10 1-(4-amino-2-oxo-lH-pyrimidin 1-yl) -2-desoxy-2' ,2' -difluor oxylose 80 mg Starch 59 mg Microcrystalline cellulose 15 59 mg Magnesium stearate 2 mg The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh U.S. 20 sieve, and filled into hard gelatin capsules in 200 mg quantities.

WO 01/34137 PCT/USOO/31039 -193 FORMULATION EXAMPLE 13 Suppositories each containing 225 mg of nucleoside are made as follows: 5 1-(2,4-dioxo-1H,3H-pyrimidin 1-yl)-2-desoxy-2',2'-difluoro ribose 225 mg Saturated fatty acid 2 g 10 glycerides to The nucleoside is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The 15 mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.

WO 01/34137 PCT/USOO/31039 -194 FORMULATON EXAMPLE 14 Suspensions each containing 50 mg of medicament per 5 ml 5 dose are made as follows: 1- (4-amino-5-methyl-2-oxo-lH pyrimidin-1-yl) -2-desoxy-2' ,2' difluororibose 50 mg 10 Sodium carboxymethyl Cellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v. 15 Color q.v. Purified water to 5. ml FORMULATION EXAMPLE 15 20 An intravenous formulation is prepared as follows: 1-(4-amino-2-oxo-lH-pyrimidin 1-yl)-2-desoxy-2',2'-difluoro 25 ribose 100 mg isotonic saline 1000 ml The solution of the above ingredients is administered intravenously at a rate of 1 ml/minute to a mammal in need 30 of treatment from susceptible neoplasms.

WO 01/34137 PCT/USOO/31039 -195 FORMULATION EXAMPLE 16 Hard gelatin capsules are prepared using the following ingredients: 5 Quantity (mg/capsule) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) propoxy) -6- (4-carboxy phenoxy)phenyl)propanoic acid 10 250 2',2'-Diflouro-2'-deoxycytidine monohydrochloride 250 Starch 200 15 Magnesium stearate 10 The above ingredients are mixed and filled into hard gelatin capsules in 710mg quantities. 20 WO 01/34137 PCT/USOO/31039 -196 FORMULATION EXAMPLE 17 A tablet is prepared using the ingredients below: Quantity 5 (mg/capsule) 1-(4-(Carboxymethoxy)phenyl)-1-(lH tetrazol-5-yl)-6-(2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy)hexane 250 10 2',2'-Difluoro-2'-deoxycytidine monochloride 250 Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 15 Magnesium stearate 5 The components are blended and compressed to form tablets each weighing 915 mg. 20 WO 01/34137 PCT/USOO/31039 -197 FORMULATION EXAMPLE 18 An aerosol solution is prepared containing the following components: 5 Weight % 3-[4-[7-Carboxy-9-oxo-3-[3-[2-ethyl-4 (4-fluorophenyl)-5-hydroxyphenoxy]propoxy] 9H-xanthene]]propanoic acid 0.25 10 2',2'-difluoro-2'-deoxycytidine monohydrochloride 0.25 Ethanol 30.00 15 Propellant 11 10.00 (trichlorofluoromethane) Propellant 12 29.75 20 (Dichlorodifluoromethane) Propellant 114 29.75 (Dichlorotetrafluoroethane) 25 The active compound is dissolved in the ethanol and the solution is added to the propellant 11, cooled to -30 0 C. and 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 30 pressure-filled method. The valve units are then fitted to the container.

WO 01/34137 PCT/USOO/31039 -198 FORMULATION EXAMPLE 19 Tablets each containing 60 mg of active ingredient are 5 made up as follows: 2- [2-Propyl-3- [3-[2-ethyl-5-hydroxy-4- (4 fluorophenyl ) phenoxy] propoxy] phenoxy] benzoic acid sodium salt 60 mg 10 2',2'-difluoro-2'deoxycytidine monohydrochloride 60 mg Starch 45 mg 15 Microcrystalline cellulose 35 mg Polyvinylpyrrolidone 4 mg (as 10% solution in water) 20 Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg 25 Total 210 mg The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve (355 pm) and mixed 30 thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve (1.4 mm). The granules so produced are dried at 50-600 and passed through a No. 18 mesh U.S. sieve (1.00 mm) . The sodium carboxymethyl starch, magnesium 35 stearate and talc, previously passed through a No. 60 mesh U.S. sieve (250 pm), are then added to the granules which, WO 01/34137 PCT/USOO/31039 -199 after mixing, are compressed on a tablet machine to yield tablets each weighing 210 mg. FORMULATION EXAMPLE 20 5 Capsules each containing 80 mg of medicament are made as follows: 5-[3-[2-(1-Carboxy)ethyl]-4-[3-[2-ethyl-4-(4 10 fluorophenyl)-5-hydroxyphenoxyipropoxy] phenyl]-4-pentynoic acid 80 mg 2',2'-difluoro-2'deoxycytidine monohydrochloride 80 mg 15 Starch 59 mg Microcrystalline cellulose 59 mg 20 Magnesium stearate 2 mg Total 280 mg 25 The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve (355 pm), and filled into hard gelatin capsules in 280 mg quantities.

WO 01/34137 PCT/USOO/31039 -200 FORMULATION EXAMPLE 21 Suppositories each containing 225 mg of active 5 ingredient are made as follows: 3-(5-(6-(4-(4-Fluorophenyl)-5-hydroxy-2 ethylphenoxy)propoxy)-2-carboxymethyl 1,2,3,4-tetrahydronaphthalen-1(2H) 10 one)propanoic acid 225 mg 2',2'-difluoro-2'-deoxycytidine monochloride 225 mg Unsaturated or saturated fatty 15 acid glycerides to 2,000 mg The active ingredient is passed through a No. 60 mesh U.S. sieve (250 pm) and suspended in the fatty acid glycerides previously melted using the minimum heat 20 necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.

WO 01/34137 PCT/USOO/31039 -201 FORMULATION EXAMPLE 22 Suspensions each containing 50 mg of medicament per 5 mL dose are made as follows: 5 2-[2-Propyl-3-[3-[2-ethyl-4-(4-fluorophenyl) 5-hydroxyphenoxy]propoxy]phenoxy]benzoic acid 50 mg 10 2' ,2 '-difluoro-2' -deoxycytidine monohydrochloride 50 mg Sodium carboxymethyl cellulose 50 mg 15 Sugar 1 g Methyl paraben 0.05 mg Propyl paraben 0.03 mg 20 Flavor q.v. Color q.v. 25 Purified water to 5 mL The medicament is passed through a No. 45 mesh U.S. sieve (355 pm) and mixed with the sodium carboxymethylcellulose, sugar, and a portion of the water to form a suspension. The 30 parabens, flavor and color are dissolved and diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.

WO 01/34137 PCT/USOO/31039 -202 Pharmaceutical Compositions of the Invention The pharmaceutical composition of the invention comprises as essential ingredients: (a) an LTB 4 antagonist, and 5 (b) an anti-cancer agent. When the pharmaceutical composition of the invention is prepared in injectable form it is a composition comprising as ingredients: (a) an LTB 4 antagonist, 10 (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 containing saline, and sterile water containing sugars 15 and/or saline. atio and Amount of Ingredients in the Composition of the Invention The essential ingredients (a) an LTB 4 antagonist and 20 (b) anti-cancer compound are present in the formulation in 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, 25 preferable from 10:1 to 1:10 and most preferable from 1:4 to 4:1. The leukotriene (LTB 4 ) antagonists are generally 30 administered prior, during and after the 2',2' difluoronucleoside anti-cancer agent is administered. If the leukotriene (LTB 4 ) antagonists are administered after WO 01/34137 PCT/USOO/31039 -203 the 2',2'-difluoronucleoside anti-cancer agent they should be administered within a therapeutically effective interval.

WO 01/34137 PCT/USOO/31039 -204 ASSAY EXAMPLE 1 The Nude Mouse Xenograft test used to evaluate anti 5 oncolytic agents of this invention is well known and 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. 10 The xenograft test is more particularly described as 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, 15 human LNCaP and DU-145 prostate carcinomas, Panc-l and BxPC 3 pancreatic carcinomas, and H460 and Calu-6 non-small cell lung carcinomas (all carcinomas available from American Type Culture Collection, Manassas, VA) prepared from a brie of donor tumors (5 x 106 cells) were implanted subcutaneously 20 in a hind-leg of the mice. The mice were treated with 2-[2 propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxylpropoxy]phenoxy] benzoic acid (Formula IV), at dosages of 30, 100, 200, or 300 mg per kilogram daily, administered orally, beginning 4 days after the tumor 25 cell implantation. Gemcitabine (60 mg/kg) was administered intraperitoneally. Tumor response was monitored by tumor volume measurement performed twice per week over the course of 60 30 90 days. Body weights were determined as a general measurement of toxicity. The mice were divided into an WO 01/34137 PCT/USOO/31039 -205 untreated control group and multiple treatment groups with five mice in each group. The data was analyzed by determining the mean tumor 5 volume for the control group and each treatment group over the course of the experiment and calculated the tumor growth delay as the difference in days for the treatment versus the control tumors to reach the volume of 1000 mm 3

.

WO 01/34137 PCT/USOO/31039 -206 Table 1 Mouse Xenograft Test Results Growth Delay of Prostate Tumor 1 ) Treatment dose dose TGD TGD, sem Formula IV GEM Formula IV 30 - 1.2 0.30 Formula IV 100 - 2.0 0.30 Formula IV 200 - 2.2 0.30 GEM - 60 12.2 0.50 Formula IV 30 60 43.2 3.00 + GEM Formula IV 100 60 51.2 3.50 + GEM 5 (1) = LNCaP prostate carcinoma Formula IV = the LTB 4 antagonist, 2-[2-propyl-3-[3-[2 ethyl-5-hydroxy-4- (4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid GEM = gemcitabine hydrochloride, a 2', 2' 10 difloronucleoside anti-cancer agent, product of Eli Lilly and Company LNCaP = LNCaP Prostate Carcinoma dose = milligrams per kilogram mouse body weight TGD = average tumor growth delay in days 15 sem = standard error of the mean WO 01/34137 PCT/USOO/31039 -207 Table 2 Mouse Xenograft Test Results Growth Delay of Prostate Tumor( 2 ) Treatment dose dose TGD TGD, sem Formula IV GEM Formula IV 30 - 5.8 0.50 Formula IV 100 - 7.7 0.60 Formula IV 300 - 12.7 1.00 GEM - 60 9.6 0.80 Formula IV 30 60 15.6 1.40 + GEM Formula IV 100 60 25.2 2.20 + GEM 5 (2) = DU-145 prostate carcinoma WO 01/34137 PCT/USOO/31039 -208 Table 3 Mouse Xenograft Test Results Growth Delay of Pancreatic Tumor( 3 ) 5 Treatment dose dose TGD TGD, sem Formula IV GEM Formula IV 30 - 7.4 0.50 Formula IV 100 - 21.6 2.00 Formula IV 300 - 30.2 3.20 GEM - 60 17.1 1.50 Formula IV 30 60 22.9 1.90 + GEM Formula IV 100 60 27.0 2.30 + GEM (3) = tumor is BxPC3 pancreatic cancer WO 01/34137 PCT/USOO/31039 -209 Table 4 Mouse Xenograft Test Results Growth Delay of Pancreatic Tumor( 4 ) 5 Treatment dose dose TGD TGD, sem Formula IV GEM Formula IV 30 - 10.2 1.40 Formula IV 100 - 16.7 2.00 Formula IV 200 - 19.4 2.40 GEM - 60 7.70 0.80 Formula IV 30 60 18.2 1.50 + GEM Formula IV 100 60 23.3 2.30 + GEM Formula IV 200 60 29.1 3.00 + GEM (4) = tumor is Panc-1 pancreatic cancer WO 01/34137 PCT/USOO/31039 -210 Table 5 Mouse Xenograft Test Results Growth Delay of non-Small cell Lung Tumor( 5 ) 5 Treatment dose dose TGD TGD, sem Formula IV GEM Formula IV 30 - 10.9 1.00 Formula IV 100 - 13.2 1.20 Formula IV 200 - 13.9 1.30 GEM - 60 9.3 0.90 Formula IV 30 60 20.2 2.00 + GEM Formula IV 100 60 21.3 2.20 + GEM Formula IV 200 60 32.0 3.10 + GEM (5) = non-Small cell Lung tumor is Human H460 NSCLC WO 01/34137 PCT/USOO/31039 -211 Table 6 Mouse Xenograft Test Results Growth Delay of non-Small cell Lung Tumor( 6 ) 5 Treatment dose dose TGD TGD, sem Formula IV GEM Formula IV 30 - 7.4 0.60 Formula IV 100 - 10.0 0.80 Formula IV 200 - 17.9 1.60 GEM - 60 14.0 1.20 Formula IV 30 60 17.4 1.60 + GEM Formula IV 100 60 22.5 2.00 + GEM (6) = non-Small cell Lung tumor is Calu-6 carcinoma 10 Detailed Description of the Drawings: Figures 1 thru 6 in the Drawings display the data in the Tables 1 thru 6, supra. The Figures illustrate the increased effectiveness of a combination treatment of (i) Formula IV and (ii) gemcitabine hydrochloride in delaying 15 tumor growth over use of the individual agents (i) or (ii). Fig. 1 - displays various treatments for LNCaP prostate carcinoma.

WO 01/34137 PCT/USOO/31039 -212 Bars (1), (2), and (3) display tumor growth delay resulting from use of LTB 4 inhibitor, Formula IV, alone at doses of 30, 100, and 200 mg/kg, respectively. Bar (4) displays tumor growth delay for the anti-cancer 5 agent, gemcitabine hydrochloride, alone at a dose of 60 mg/kg. Bars (5) and (6) display tumor growth delay resulting from combined use of Formula IV (at doses of 30 and 100 mg/kg) and gemcitabine hydrochloride (at a dose of 60 10 mg/kg); respectively. Fig. 2 - displays various treatments for DU-145 prostate carcinoma. Bars (1), (2), and (3) display tumor growth delay 15 resulting from use of LTB 4 inhibitor, Formula IV, alone at doses of 30, 100, and 300 mg/kg, respectively. Bar (4) display tumor growth delay for the anti-cancer agent, gemcitabine hydrochloride, alone at a dose of 60 mg/kg. 20 Bars (5) and (6) display tumor growth delay resulting from combined use of Formula IV (at doses of 30 and 100 mg/kg) and gemcitabine hydrochloride (at a dose of 60 mg/kg); respectively. 25 Fig. 3 - displays various treatments for BxPC3 pancreatic carcinoma. Bars (1), (2), and (3) display tumor growth delay resulting from use of LTB 4 inhibitor, Formula IV, alone at doses of 30, 100, and 300 mg/kg, respectively. 30 Bar (4) display tumor growth delay for the anti-cancer agent, gemcitabine hydrochloride, alone at a dose of 60 mg/kg.

WO 01/34137 PCT/USOO/31039 -213 Bars (5) and (6) display tumor growth delay resulting from combined use of Formula IV (at doses of 30 and 100 mg/kg) and gemcitabine hydrochloride (at a dose of 60 mg/kg); respectively. 5 Fig. 4 - displays various treatments for Panc-1 pancreatic carcinoma. Bars (1), (2), and (3) display tumor growth delay resulting from use of LTB 4 inhibitor, Formula IV, alone at 10 doses of 30, 100, and 200 mg/kg, respectively. Bar (4) display tumor growth delay for the anti-cancer agent, gemcitabine hydrochloride, alone at a dose of 60 mg/kg. Bars (5), (6) and (7) display tumor growth delay 15 resulting from combined use of Formula IV (at doses of 30, 100 and 200 mg/kg) and gemcitabine hydrochloride (at a dose of 60 mg/kg); respectively. Fig. 5 - displays various treatments for Human H460 non 20 Small cell Lung carcinoma. Bars (1), (2), and (3) display tumor growth delay resulting from use of LTB 4 inhibitor, Formula IV, alone at doses of 30, 100, and 200 mg/kg, respectively. Bar (4) display tumor growth delay for the anti-cancer 25 agent, gemcitabine hydrochloride, alone at a dose of 60 mg/kg. Bars (5), (6) and (7) display tumor growth delay resulting from combined use of Formula IV (at doses of 30, 100 and 200 mg/kg), and gemcitabine hydrochloride (at a dose 30 of 60 mg/kg); respectively.

WO 01/34137 PCT/USOO/31039 -214 Fig. 6 - displays various treatments for Calu-6 non-small cell Lung carcinoma. Bars (1), (2), and (3) display tumor growth delay resulting from use of LTB 4 inhibitor, Formula IV, alone at 5 doses of 30, 100 and 200 mg/kg, respectively. Bar (4) display tumor growth delay for the anti-cancer agent, gemcitabine hydrochloride, alone at a dose of 60 mg/kg. Bars (5) and (6) display tumor growth delay resulting 10 from combined use of Formula IV (at doses of 30 and 100 mg/kg) and gemcitabine hydrochloride (at a dose of 60 mg/kg); respectively.

Claims

3. The composition of claim 2 wherein R 2 is the base defined by the formula: NHR 3 N XX o N 15
4. The composition of claim 2 wherein the anti cancer agent is selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof: WO 01/34137 PCT/USOO/31039 -217 (i) 1-(4-amino-2-oxo-lH-pyrimidin-1-yl)-2-desoxy-2' ,2' di fluororibose, (ii) 1-(4-amino-2-oxo-1H-pyrimidin-1-yl)-2-desoxy 2',2'-difluoroxylose, 5 (iii) 1-(2,4-dioxo-lH,3H-pyrimidin-1-yl)-2-desoxy 2',2'-difluororibose, and (iv) 1-(4-amino-5-methyl-2-oxo-1H-pyrimidin-1-yl)-2 desoxy-2' , 2'-difluororibose. 10 5. The composition of claim 2 wherein the anti-cancer agent is gemcitabine hydrochloride.
6. The composition of claim 1 or 2 or 3 or 4 or 5 wherein the leukotriene (LTB4) antagonist is represented by 15 the formula (I) H x R3 R2 R 4 R 1 Z (I) wherein: 20 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 25 oxygen; and WO 01/34137 PCT/USOO/31039 -218 (ii) a fused bicyclic radical wherein a carbocyclic group is fused to two adjacent carbon atoms of the five membered heterocyclic radical, (i); 5 Y 1 is a bond or divalent linking group containing 1 to 9 atoms; Y2 and Y 3 are divalent linking groups independently selected 10 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 1 0 alkenyl, 15 C 2 -C 10 alkynyl, C 6 -C 2 0 aralkyl, C 6 -C 2 0 alkaryl, Ci-C 10 haloalkyl, C 6 -C 2 0 aryloxy, or Ci-C 10 alkoxy; R2 is hydrogen, halogen, CI-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); 20 R3 is hydrogen, halogen, C 1 -C 10 alkyl, aryl, C 1 -C 10 haloalkyl, Ci-Cio alkoxy, C6-C 2 0 aryloxy, or C3-C8 cycloalkyl; 25 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; 30 or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof. WO 01/34137 PCT/USOO/31039 -219
7. The composition of claim 6 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 R11 0 , S 0 NR11 R11 N R11 2 NS S N 0 R10 N--N R11 N R11 N-N N N S , N , N I I 10 R10 R10 R1 1 - R11 R11 1 N N N S R10 R10 WO 01/34137 PCT/USOO/31039 -220 N--N R1 N-N SN N ON ON S0 ' 0~ -NR11 NR11 N -- : R11 S N / N N S ' 0 ' 5 R10 N N N N N N O NR1 , S ' 0 ' N R R1 5 0 , S N H R10 N R11 N 'and R11 R10 where R10 is a radical selected from hydrogen or 10 CI-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 01/34137 PCT/USOO/31039 -221
8. The composition of claim 6 wherein the Rl, R2, R3 and R4 groups for substitution in formula (I) are selected from the following variables coded RO1 thru R16 R variables Rl R2 R3 R4 Combination group group group group Code choice choice choice choice R01 Rl R2 R3 R4 R02 Rl R2 R3 PG1-R4 R03 R1 R2 PGl-R3 R4 R04 R1 R2 PGl-R3 PGl-R4 R05 R1 PGl-R2 R3 R4 R06 R1 PGl-R2 R3 PGl-R4 R07 Rl PGl-R2 PG1-R3 R4 R08 Rl PG1-R2 PGl-R3 PGl-R4 R09 PGl-Rl R2 R3 R4 R10 PG1-01 R2 R3 PGl-R4 R11 PGl-Rl R2 PGl-R3 R4 R12 PGl-R1 R2 PGl-R3 PGl-R4 R13 PGl-R1 PGl-R2 R3 R4 R14 PG1-Rl PGl-R2 R3 PGl-R4 R15 PGl-R1 PG1-R2 PG1-R3 R4 R16 PG1-Rl PG1-R2 PG1-R3 PG1-R4 5 and; WO 01/34137 PCT/USOO/31039 -222 the Y1, 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 Y1 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 PG1-Yl 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 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 and; 10 WO 01/34137 PCT/USOO/31039 -223 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 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 PG1-n XZnO9 X PG3-Z PG1-n XZn1O X PGl-Z PG2-n XZnl1 X PG2-Z PG2-n XZn12 X PG3-Z PG2-n XZnl3 PG1-X Z n XZn14 PG1-X Z PG1-n XZnl5 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 PGl-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
9. The composition of claim 6 wherein the leukotriene B4 antagonist is described by formula (II): WO 01/34137 PCT/USOO/31039 -224 H X2 R22 SO >H 2 O 0 R21 Z2 (11) wherein; 5 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 R22 is hydrogen, n-butyl, sec-butyl, flouro, chloro, -CF3, or tert-butyl. 15 Z2 is the Acidic Group selected from carboxyl, tetrazolyl, or N-sulfonamidyl; or a salt, solvate or prodrug thereof. 20 WO 01/34137 PCT/USOO/31039 -225
10. The composition of claim 9 wherein the leukotriene antagonist is a compound selected from the following: / N OH O COOH 5 , HC I N//N OH O - , O OP COOH 10 / N OH S O -O OP COOH 15 N-N.H OH O0 -- O O COOH WO 01/34137 PCT/USOO/31039 -226 N- 0 OH COOH ,N'N. OH N O O COOH 5 N OO COOMe 10 OH SOO Oj COOH N_ OH COOH WO 01/34137 PCT/USOO/31039 -227 F N O COOH O0 OH COONa 5 OH 0 Oj0 COOH 10 OH COOH O OH COONa WO 01/34137 PCT/USOO/31039 -228 OH HOI O0'- O 0 COOH S OH COOH 5 OH N, 0 N I COOH Nz:N OH COOH 100 COOH WO 01/34137 PCT/USOO/31039 -229 N-N OH S N COOH OH NZI O 1 O OQ COOH 5 /N OH I I 0O O-- - - O P COOH or OH S N N COOH 10 or an acid, salt, solvate or prodrug derivative thereof.
11. The composition of claim 9 wherein the leukotriene 15 antagonist is a compound selected from the following: WO 01/34137 PCT/USOO/31039 -230 S OH - ~ 0 **' -- - N 0 COOH O OH COONa OH s I N COOH 5 N_. OH 100 OH 0 '- - ? COOH or WO 01/34137 PCT/USOO/31039 -231 OH 0 O O OP COOH or an acid, salt, solvate or prodrug derivative thereof. 5 12. The composition of claim 1 or 2 or 3 or 4 or 5 wherein the leukotriene (LTB4) antagonist is represented by a compound of the structure (Formula A): R2,I HO / / X'-Y'-Z'-A'-R4' 3 R,' 10 Formula A or a pharmaceutically acceptable base addition salt thereof, wherein: 15 Rl' 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, (Cl-C4 alkyl)-(O)q S-, trifluoromethyl, or di-(Cl-C3 alkyl)amino; 20 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 Cl-C1O alkylidenyl; A' is a bond, -0-, -S-, -CH=CH-, or -CRaRb-, where Ra 25 and Rb are each independently hydrogen, Cl-C5 alkyl, or R7- WO 01/34137 PCT/USOO/31039 -232 substituted phenyl, or when taken together with the carbon atom to which they are attached form a C4-C8 cycloalkyl ring; 5 R 4 ' is R 6 , \ /O-G-R 6 , - C0 (K)p-W-R 6 R7(CHA) WO 01/34137 PCT/USOO/31039 -233 R T R 7 W-R 6 R7 R8 W-R6 RIO T 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; R1O is Cl-C4 alkyl or phenyl; WO 01/34137 PCT/USOO/31039 -234 Rii 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
13. The composition of claim 12 wherein R 4 ' is selected from the following formulae: 0 RR1 , or R8 W-R 6 T 7 20
14. The composition of claim 13 wherein R 4 ' is: WO 01/34137 PCT/USOO/31039 -235 R8 W-R 6 T 7
15. The composition according to claim 12 wherein the 5 LTB 4 antagonist compound or pharmaceutically acceptable acid or prodrug or salt derivative thereof is selected from the group (A) to (KKKK) consisting of: A) 2-Methyl-2-(lH-tetrazol-5-yl)-7-(2-ethyl-4 10 (4-f luorophenyl) -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; F) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) propoxy) -6 30 methoxyphenyl)propionic acid; G) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy) -6- (4- (lH-tetrazol-5 yl) butyloxy) phenyl) propionic acid; 35 WO 01/34137 PCT/USOO/31039 -236 H) Methyl 3-(2-(4-(2-ethyl-4-(4-fluorophenyl) 5-hydroxyphenoxy) - (1 butenyl))phenyl)propionate; 5 I) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)-(1-butenyl))phenyl)propionic acid; J) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 10 hydroxyphenoxy)butyl)phenyl)propionic acid; K) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyl)-6 methoxyphenyl)propionic acid; 15 L) Methyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl) 5-hydroxyphenoxy) propoxy) -6 hydroxyphenyl)propionate; 20 M) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) propoxy) -6 hydroxyphenyl)propionic acid; N) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 25 hydroxyphenoxy)propoxy)-6-(4 butyloxy)phenyl)propionic acid; 0) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 30 methylthiobutyloxy)phenyl)propionic acid; P) 3-(2-(3-(2,4-Di(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 carboxybutoxy)phenyl)propionic acid; 35 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 40 fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionamide; S) N-Methanesulfonyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 45 hydroxyphenoxy)propoxy)phenyl)propionamide; WO 01/34137 PCT/USOO/31039 -237 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; V) Ethyl 3-(2-(4-(2-ethyl-4-(4-fluorophenyl)-5 10 hydroxyphenoxy)butyloxy)phenyl)propionate; W) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyloxy)phenyl)propionic acid; 15 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; Z) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 25 hydroxyphenoxy)propoxy)-4-(4 carboxyphenoxy)phenyl)propionic acid; AA) 3,3-Dimethyl-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5 30 hydroxyphenoxy)propoxy)phenyl)propionic acid; BB) 2-Methyl-2-(lH-tetrazol-5-yl)-3-(2-(3-(2 ethyl-4-(4-fluorophenyl)-5 35 hydroxyphenoxy)propoxy)phenyl)propane; CC) 2-Methyl-2-(1H-tetrazol-5-yl)-3-hydroxy-3 (2-(3-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propane; 40 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 01/34137 PCT/USOO/31039 -238 FF) Methyl 3-(2-hydroxy-3-(4 methoxycarbonylbutyl)-6-(3-(2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy) propoxy) phenyl) propionate; 5 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 (2H-tetrazol-5-yl)heptyloxy]phenol disodium 15 salt; JJ) 2-(3-Methylphenyl)-4-ethyl-5-[6-methyl-6 (2H-tetrazol-5-yl)heptyloxy]phenol sodium salt; 20 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; MM) 2- (3-Methoxyphenyl)-4-ethyl-5-[6-methyl-6 30 (2H-tetrazol-5-yl)heptyloxy]phenol sodium salt; NN) 2- (4-Trifluoromethylphenyl) -4-ethyl-5- [6 methyl-6- (2H-tetrazol-5-yl)heptyloxy]phenol 35 disodium salt; 00) 2-(3-Dimethylaminophenyl)-4-ethyl-5-[6 methyl-6- (2H-tetrazol-5-yl)heptyloxy] phenol disodium salt; 40 PP) 3- (5- (6- (4-Phenyl-5-hydroxy-2 ethylphenoxy) propoxy) -2-carboxymethyl 1,2,3,4 -tetrahydronaphthalen-1(2H) one)propanoic acid; 45 QQ) 3-(5-(6-(4-(4-Fluorophenyl)-5-hydroxy-2 ethylphenoxy)propoxy) -2-carboxymeth yl- WO 01/34137 PCT/USOO/31039 -239 1,2,3,4-tetrahydronaphthalen-1(2H) one)propanoic acid; RR) 3-(4-(5-(4-(4-Fluorophenyl)-5-hydroxy-2 5 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 10 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 15 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; 20 VV) 2-[3-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyl] 4-yl)oxy]propoxy]-2-propylphenoxy]propanoic acid; 25 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 30 6-(2H-tetrazol-5-yl)heptyloxy]phenol monosodium salt; YY) 3-[2-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyl] 4-yl)oxy]propoxy]-l-dibenzofuran]propanoic 35 acid disodium salt; ZZ) 7-Carboxy-9-oxo-3-[3-(2-ethyl-5-hydroxy-4 phenylphenoxy)propoxy]-9H-xanthene-4 propanoic acid disodium salt monohydrate; 40 AAA) 2-[2-Propyl-3-[3-(2-ethyl-5-hydroxy-4 phenylphenoxy)propoxy]phenoxy]benzoic acid sodium salt hemihydrate; 45 BBB) 3-[3-(2-Ethyl-5-hydroxy-4 phenylphenoxy)propoxy][1,1'-biphenyl]-4 propanoic acid disodium salt monohydrate; WO 01/34137 PCT/USOO/31039 -240 CCC) 5-Ethyl-4-[3-[2-propyl-3-[2-(2H-tetrazol-5 yl)phenoxy]phenoxy]propoxy][1,1'-biphenyl] 2-ol disodium salt sesquihydrate; 5 DDD) 3-[4-[3-[ 3-(2-Ethyl-5-hydroxy-4 phenylphenoxy)propoxy]-9-oxo-9H xanthene]]propanoic acid sodium salt hemihydrate; 10 EEE) 2-Fluoro-6-[2-propyl-3-[3-(2-ethyl-5 hydroxy-4 phenylphenoxy)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]-9H xanthene]]propanoic acid; III) 3-[2-[l-[2-Ethyl-4-(4-fluorophenyl)-5 30 hydroxyphenoxy]propoxy]-4-(5-oxo-5 morpholinopentanamido)phenyl]propanoic acid; JJJ) 2-Fluoro-6-[2-propyl-3-[3-[2-ethyl-5 hydroxy-4-(4 35 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid disodium salt hydrate; KKK) 4-Fluoro-2-[2-propyl-3-(3-[2-ethyl-5 hydroxy-4-(4 40 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid; LLL) 2-[2-Propyl-3-[5-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxylpentoxy]phenoxy]benzoic 45 acid; WO 01/34137 PCT/USOO/31039 -241 MMM) 2-(2-Propyl-3-[4-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]butoxy]phenoxy]benzoic acid sesquihydrate; 5 NNN) 2-[2-(2-Methylpropyl)-3-[3-[2-ethyl-5 hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid; 10 000) 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 15 4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid; QQQ) 2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 20 fluorophenyl)phenoxy]propoxy]phenoxy]phenyla cetic acid; RRR) 2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]benzoyl]benzoic 25 acid; SSS) 2-[[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenyl]methyl]b enzoic acid; 30 TTT) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy]propoxy]thiophenoxy]benzoic acid; 35 UUU) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy]propoxy]phenylsulfinyl]benzoi c acid; 40 VVV) 2-[2-Propyl-3-[3-[2-ethyl-4-(4 fluorophenyl)-5 hydroxyphenoxy]propoxy]phenylsulfonyl]benzoi c acid hydrate; 45 WWW) 5- [3-[2-(1-Carboxy) ethyl]-4-[3-[2-ethyl-4 (4-fluorophenyl)-5- WO 01/34137 PCT/USOO/31039 -242 hydroxyphenoxy]propoxy]phenyl]-4-pentynoic acid disodium salt 0.4 hydrate; XXX) 1-Phenyl-l-(lH-tetrazol-5-yl)-6-(2-ethyl-4 5 (4-fluorophenyl)-5-hydroxyphenoxy)hexane; YYY) 1-(4-(Carboxymethoxy)phenyl)-1-(lH-tetrazol 5-yl)-6-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)hexane; 10 ZZZ) 1-(4-(Dimethylaminocarbonylmethoxy)phenyl) 1-(1H-tetrazol-5-yl)-6-(2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy)hexane; 15 AAAA) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)-E-propenoic acid; BBBB) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 20 hydroxyphenoxy)propoxy)phenyl)-2-methyl-E propenoic acid; CCCC) 5-(2-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)ethyl)-1H 25 tetrazole; DDDD) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-4-(4 carboxybutyloxy)phenyl)propionic acid; 30 EEEE) 5-[3-[4-(4-Fluorophenyl)-2-ethyl-5 hydroxyphenoxy]propoxy]-3,4-dihydro-2H-1 benzopyran-2-one; 35 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 40 hydroxyphenyloxy]propoxy}-4-propylph enyl)propanoic acid sodium salt; HHHH) 3-(4-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy]propoxy}-3 45 propylphenyl)propanoic acid; WO 01/34137 PCT/USOO/31039 -243 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 16. The composition of claim 1 or 2 or 5 wherein the leukotriene (LTB4) antagonist is a compound of the structure (Formula B): F H HO 0 20 Formula B namely, 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4 25 fluorophenyl)phenoxy]propoxy] phenoxy benzoic acid, or the pharmaceutically acceptable salt thereof.
17. The composition of claim 1 wherein the anti-cancer agent is a therapeutically effective amount of a 2',2' 30 difluoronucleoside anti-cancer agent according to the formula: WO 01/34137 PCT/USOO/31039 -244 R 1 0 - H 2 C O -R2 F OH F wherein: R1 is hydrogen or 5 0 || -C-RE R 2 is a base defined by one of the formulae 10 NHR 8 0 N 0 N R 3 HN N H WO 01/34137 PCT/USOO/31039 -245 0 0 H N N H N X O N N O N H NHR 3 N NN N R4 N N 5 X is N or C-R 4 R 3 is hydrogen, CI-C 4 alkyl or 0 10 R 4 is hydrogen, C 1 -C 4 alkyl, amino, bromo, fluoro, chloro or iodo; each R 5 independently is hydrogen or Ci-C 4 alkyl; and the pharmaceutically-acceptable salts thereof. 15 WO 01/34137 PCT/USOO/31039 -246
18. The composition of claim 1 or 2 or 3 or 6 or 12 wherein the weight ratio of LTB 4 antagonist to anti-cancer agent 1:100 to 100 to 1. 5 19. The composition of claim 1 or 2 or 3 or 6 or 12 in the form of injectable solution.
20. Use of the composition of matter containing leukotriene (LTB 4 ) antagonist and anti-cancer agent of any 10 one of claims 1 or 2 or or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 12 or 13 or 14 or 15 or 16 or 17 for the manufacture of a medicament for the treatment of cancer in mammals. 15 21. A method of treating cancer in a mammalian patient by administering to said patient a therapeutically effective amount of a leukotriene (LTB 4 ) antagonist and a therapeutically effective amount of 2',2'-difluoronucleoside anti-cancer agent. 20
22. The method of claim 21 wherein the anti-cancer compound is a therapeutically effective amount of a compound represented by the formula: 25 R 1 0H 2 C O R2 F HO F where: R 1 is hydrogen; WO 01/34137 PCT/USOO/31039 -247 R 2 is a base defined by one of the formulae: NHR 3 0 N X HN N N N N N O , R3HN o NHR 3 HN N N O N N N 4R 5 X is C-R 4 R 3 is hydrogen; R 4 is hydrogen, Ci-C 4 alkyl, bromo, fluoro, chloro or 10 iodo; and pharmaceutically acceptable salts thereof.
23. The method of claim 22 wherein R 2 is the base 15 defined by the formula: WO 01/34137 PCT/USOO/31039 -248 NHR 3 N X N
24. The method of claim 23 wherein the anti-cancer 5 agent is selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof: (i) 1-(4-amino-2-oxo-lH-pyrimidin-1-yl)-2-desoxy-2',2' difluororibose, (ii) 1-(4-amino-2-oxo-lH-pyrimidin-1-yl)-2-desoxy 10 2',2'-difluoroxylose, (iii) 1-(2,4-dioxo-lH,3H-pyrimidin-1-yl)-2-desoxy 2',2'-difluororibose, and (iv) 1-(4-amino-5-methyl-2-oxo-lH-pyrimidin-1-yl)-2 desoxy-2',2'-difluororibose. 15
25. The method of claim 22 wherein the anti-cancer agent is gemcitabine hydrochloride.
26. The method of claim 21 or 22 or 23 or 24 or 25 20 wherein the leukotriene (LTB4) antagonist is represented by the formula (I) WO 01/34137 PCT/USOO/31039 -249 H X R3 - -R2 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; 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 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-, or -S-; 20 Z is an Acidic Group; R1 is C 1 -C 10 alkyl, aryl, C 3 -C 8 cycloalkyl, C 2 -C 10 alkenyl, C 2 -C 1 0 alkynyl, C 6 -C 2 0 aralkyl, C 6 -C 2 0 alkaryl, 25 Ci-C 10 haloalkyl, C 6 -C 20 aryloxy, or Ci-C 1 0 alkoxy; WO 01/34137 PCT/USOO/31039 -250 R2 is hydrogen, halogen, C 1 -C 10 haloalkyl, Ci-C 10 alkoxy, Ci-C 1 0 alkyl, C 3 -C 8 cycloalkyl, Acidic Group, or -(CH 2 )l- 7 -(Acidic Group); 5 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; 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.
27. The method of claim 26 wherein X is a heterocyclic radical selected from the group consisting of substituents 20 represented by the following formulae: S R11 R11 R11 0 S N R10 R11 R11 R11 25 0 S 0 WO 01/34137 PCT/USOO/31039 -251 N NR1 N S N, 0 10 Rio N-N Rl1N R11 N--N R111 N N R10 R10 N$N1 N N N I R10 R10 N N N N-N N NN N s0 0 5 NR11 Rl 1 R11 S 0 R10 N NII zN N N R1 , S 0 N R i 0 S N H WO 01/34137 PCT/USOO/31039 -252 R10 N R11 N 'and R11 R10 where R10 is a radical selected from hydrogen or 5 Cl-C 4 alkyl; and R11 is a radical selected from hydrogen, halo, Ci-C 10 alkyl, Ci-Cig haloalkyl, Ci-C 10 alkoxy, aryl, or C 6 -C 2 0 aryloxy.
28. The method of claim 26 wherein the Rl, R2, R3 and 10 R4 groups for substitution in formula (I) are selected from the following variables coded R01 through R16 R variables Rl R2 R3 R4 Combination group group group group Code choice choice choice choice R01 R1 R2 R3 R4 R02 Rl R2 R3 PGl-R4 R03 Rl R2 PGl-R3 R4 R04 Rl R2 PG1-R3 PG1-R4 R05 Rl PG1-R2 R3 R4 R06 R1 PG1-R2 R3 PG1-R4 R07 Rl PG1-R2 PGl-R3 R4 R08 Rl PG1-R2 PGl-R3 PG1-R4 R09 PG1-R1 R2 R3 R4 R10 PG1-01 R2 R3 PGl-R4 R11 PG1-Rl R2 PG1-R3 R4 R12 PGl-R1 R2 PGl-R3 PGl-R4 R13 PG1-R1 PGl-R2 R3 R4 R14 PGl-Rl PGl-R2 R3 PG1-R4 R15 PG1-Rl PG1-R2 PG1-R3 R4 R16 PG1-R1 PG1-R2 PGl-R3 PG1-R4 WO 01/34137 PCT/USOO/31039 -253 and; the Y1, Y2, and Y3 groups for substitution in formula (I) 5 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 Y1 PG1-Y2 Y3 Y05 Y1 PG2-Y2 Y3 Y06 Y1 PG1-Y2 PG1-Y3 Y07 Y1 PG1-Y2 PG2-Y3 Y08 Yl PG2-Y2 PG1-Y3 Y09 Y1 PG2-Y2 PG2-Y3 Y10 PG1-Y1 Y2 Y3 Y11 PG1-Yl 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 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 10 and; WO 01/34137 PCT/USOO/31039 -254 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 XZn06 X PG3-Z n XZnO7 X PG1-Z PG1-n XZn08 X PG2-Z PG1-n XZnO9 X PG3-Z PG1-n XZnlO X PG1-Z PG2-n XZn1l X PG2-Z PG2-n XZnl2 X PG3-Z PG2-n XZn13 PG1-X Z n XZnl4 PG1-X Z PG1-n XZn15 PG1-X Z PG2-n XZnl6 PG1-X PGl-Z n XZn17 PG1-X PG2-Z n XZnl8 PG1-X PG3-Z n XZnl9 PG2-X PGl-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
29. The method of claim 26 wherein the leukotriene B4 antagonist is described by formula (II): WO 01/34137 PCT/USOO/31039 -255 H X2 R22 O H 2 O O R21 Z2 (I I) wherein; 5 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 R22 is hydrogen, n-butyl, sec-butyl, flouro, chloro, -CF 3 , or tert-butyl. 15 Z2 is the Acidic Group selected from carboxyl, tetrazolyl, or N-sulfonamidyl; or a salt, solvate or prodrug thereof. 20 WO 01/34137 PCT/USOO/31039 -256
30. The method of claim 26 wherein the leukotriene antagonist is a compound selected from the following: / N OH 00 O COOH 5 -HCI /7N OH NN 0 P COOH 10 / N OH SN S \ -- I lk: I O o O N COOH 15 N-N.H OH O0 -"--O OP COOH WO 01/34137 PCT/USOO/31039 -257 N- 0 OH O O"-- OP COOH ,,N N.H OH N. N- O O OP COOH 5 N OO COOMe 10 OH 0 J COOH N- OH COOH WO 01/34137 PCT/USOO/31039 -258 CNOH COOH O0 OH COONa 5 OH O 0 COOH 10 OH COOH O OH COONa WO 01/34137 PCT/USOO/31039 -259 OH HCI O O COOH S OH COOH 5 .N'N OH N,S I COOH NzN OH S COOH 10 SN OH N OH COOH WO 01/34137 PCT/USOO/31039 -260 N-N OH I II SO 0- O O P COOH OH N,, O *- O OP COOH 5 //N OH I II O O O COOH or OH S I , | saa O O O COOH 10 or an acid, salt, solvate or prodrug derivative thereof.
31. The method of claim 26 wherein the leukotriene 15 antagonist is a compound selected from the following: WO 01/34137 PCT/USOO/31039 -261 S OH COOH O OH COONa OH COOH 5 N_ OH COOH 10 OH 0~ ~ - C -I O C' COOH or WO 01/34137 PCT/USOO/31039 -262 OH OJ COOH or an acid, salt, solvate or prodrug derivative thereof. 5 32. The method of claim 21 or 22 or 23 or 24 or 25 wherein the leukotriene (LTB4) antagonist is represented by a compound of the structure (Formula A): R1 HO /X'-Y'-Z'-A'-R'4 R3 ~ R,' 10 Formula A or a pharmaceutically acceptable base addition salt thereof, wherein: 15 Rj' 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, Cl-C4 alkoxy, (Ci-C4 alkyl)-(O)q S-, trifluoromethyl, or di-(Cl-C3 alkyl)amino; 20 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 Cl-C1O alkylidenyl; A' is a bond, -0-, -S-, -CH=CH-, or -CRaRb-, where Ra 25 and Rb are each independently hydrogen, Cl-C5 alkyl, or R7- WO 01/34137 PCT/USOO/31039 -263 substituted phenyl, or when taken together with the carbon atom to which they are attached form a C4-C8 cycloalkyl ring; 5 R 4 ' is R 6 , R7 \ , O-G-R6 , (K)p-W-R 6 R 7 (CHO 0 WO 01/34137 PCT/USOO/31039 -264 T R1 7 W-R 6 H7 W-R 6 T W-R 6 R7 wherein: each R6 is independently -COOH, 5-tetrazolyl, CON(R 9 ) 2 , or -CONHSO 2 R 1 0 ; 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; Rio is Cl-C4 alkyl or phenyl; WO 01/34137 PCT/USOO/31039 -265 Rll 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
33. The method of claim 32 wherein R 4 ' is selected from the following formulae: O R, or 8 W-R 6 T 7 20
34. The method of claim 32 wherein R 4 ' is: WO 01/34137 PCT/USOO/31039 -266 R8 W- R 6 T 7
35. The method according to claim 32 wherein the LTB 4 5 antagonist compound or pharmaceutically acceptable acid or prodrug or salt derivative thereof is selected from the group (A) to (KKKK) consisting of: a) 2-Methyl-2-(lH-tetrazol-5-yl)-7-(2-ethyl-4-(4 10 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)propionic acid; d) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 20 hydroxyphenoxy) propoxy) phenyl) propionic 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; g) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 30 hydroxyphenoxy)propoxy)-6-(4-(1H-tetrazol-5 yl) butyloxy) phenyl) propionic acid; h) Methyl 3-(2-(4-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) - (1-butenyl) ) phenyl) propionate; 35 WO 01/34137 PCT/USOO/31039 -267 i) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)-(l butenyl))phenyl)propionic acid; j) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 5 hydroxyphenoxy)butyl)phenyl)propionic acid; k) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyl)-6-methoxyphenyl)propionic acid; 10 1) Methyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-hydroxyphenyl)propionate; m) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-hydroxyphenyl)propionic acid; 15 n) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4-butyloxy)phenyl)propionic acid; 20 o) 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 25 hydroxyphenoxy)propoxy)-6-(4 carboxybutoxy)phenyl)propionic acid; q) 6-Methyl-6-(1H-tetrazol-5-yl)-11-(2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy)undecane; 30 r) N,N-Dimethyl-3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionamide; s) N-Methanesulfonyl-3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5 35 hydroxyphenoxy)propoxy)phenyl)propionamide; t) N-Phenylsulfonyl-3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionamide; 40 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 hydroxyphenoxy)butyloxy)phenyl)propionate; 45 w) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)butyloxy)phenyl)propionic acid; WO 01/34137 PCT/USOO/31039 -268 x) Methyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)-6-(4 (methoxycarbonyl)phenoxy)phenyl)propionate; 5 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 10 hydroxyphenoxy)propoxy)-4-(4 carboxyphenoxy)phenyl)propionic acid; aa) 3,3-Dimethyl-3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; 15 bb) 2-Methyl-2-(1H-tetrazol-5-yl)-3-(2-(3-(2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy)propoxy)phenyl)propane; cc) 2-Methyl-2-(lH-tetrazol-5-yl)-3-hydroxy-3-(2-(3-(2 20 ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propane; dd) 3-(2-(3-(2-Bromo-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; 25 ee) 3-(2-(3-(2-Ethylthio-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionic acid; ff) Methyl 3-(2-hydroxy-3-(4-methoxycarbonylbutyl)-6-(3-(.2 30 ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)propionate; gg) 5-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy) propoxy) -8- (4-carboxybuty 35 1)dihydrocoumarin; hh) 2-Phenyl-4-ethyl-5-[6-(2H-tetrazol-5-yl)-6 methylheptyloxy]phenol sodium salt; 40 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-(2H-tetrazol 5-yl)heptyloxy]phenol sodium salt; 45 kk) 2-(2-Methylphenyl)-4-ethyl-5-[6-methyl-6-(2H-tetrazol 5-yl)heptyloxy]phenol disodium salt; WO 01/34137 PCT/USOO/31039 -269 11) 2-(4-Methoxyphenyl)-4-ethyl-5-[6-methyl-6-(2H-tetrazol 5-yl)heptyloxy]phenol sodium salt; mm) 2-(3-Methoxyphenyl)-4-ethyl-5-[6-methyl-6-(2H-tetrazol 5 5-yl)heptyloxy]phenol sodium salt; nn) 2-(4-Trifluoromethylphenyl)-4-ethyl-5-[6-methyl-6-(2H tetrazol-5-yl)heptyloxy]phenol disodium salt; 10 oo) 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-ethylphenoxy)propoxy)-2 carboxymethyl-1,2,3,4 -tetrahydronaphthalen-1(2H) 15 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)-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; 25 ss) 3,3-Dimethyl-5-(3-(2-carboxyethyl)-4-(3-(4 fluorophenyl)-5-hydroxy-2-ethylphenoxy)propoxy)phenyl)-5 oxopentanoic acid; tt) 7-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyl]-4 30 yl)oxylpropoxy]-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-benzopyran-2 35 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; xx) 2-(3,5-Dichlorophenyl)-4-ethyl-5-[6-methyl-6-(2H tetrazol-5-yl)heptyloxy]phenol monosodium salt; 45 yy) 3-[2-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyl]-4 yl)oxy]propoxy]-l-dibenzofuran]propanoic acid disodium salt; WO 01/34137 PCT/USOO/31039 -270 zz) 7-Carboxy-9-oxo-3- [3- (2-ethyl-5-hydroxy-4 phenylphenoxy)propoxy]-9H-xanthene-4-propanoic acid disodium salt monohydrate; 5 aaa) 2-[2-Propyl-3-[3-(2-ethyl-5-hydroxy-4 phenylphenoxy)propoxy]phenoxy]benzoic acid sodium salt hemihydrate; 10 bbb) 3-[3-(2-Ethyl-5-hydroxy-4-phenylphenoxy)propoxy][1,1' biphenyl]-4-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 15 salt sesquihydrate; ddd) 3-[4-[3-[ 3-(2-Ethyl-5-hydroxy-4 phenylphenoxy)propoxy]-9-oxo-9H-xanthene]]propanoic acid sodium salt hemihydrate; 20 eee) 2-Fluoro-6-[2-propyl-3-[3-(2-ethyl-5-hydroxy-4 phenylphenoxy)propoxy]phenoxy]benzoic acid disodium salt; fff) 2-[2-Propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5 25 hydroxyphenoxy]propoxy]phenoxy]benzoic acid sodium salt; ggg) 3-[4-[7-Carboxy-9-oxo-3-[3-[2-ethyl-4-(4-fluorophenyl) 5-hydroxyphenoxy]propoxy]-9H-xanthene]] propanoic acid disodium salt trihydrate; 30 hhh) 3-[4-[9-Oxo-3-[3-[2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy]propoxy]-9H-xanthene]]propanoic acid; iii) 3-[2-[l-[2-Ethyl-4-(4-fluorophenyl)-5 35 hydroxyphenoxy]propoxy]-4-(5-oxo-5 morpholinopentanamido)phenyl]propanoic acid; jjj) 2-Fluoro-6-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid 40 disodium salt hydrate; kkk) 4-Fluoro-2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid; 45 111) 2-[2-Propyl-3-[5-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]pentoxy]phenoxy]benzoic acid; WO 01/34137 PCT/USOO/31039 -271 mmm) 2-[2-Propyl-3-[4-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]butoxy]phenoxy]benzoic acid sesquihydrate; 5 nnn) 2-[2-(2-Methylpropyl)-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid; ooo) 2-[2-Butyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid 10 hydrate; ppp) 2-[2-(Phenylmethyl)-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid; 15 qqq) 2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenoxy]phenylacetic acid; rrr) 2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]benzoyl]benzoic acid; 20 sss) 2-[[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4 fluorophenyl)phenoxy]propoxy]phenyl]methyl]benzoic acid; ttt) 2-[2-Propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5 25 hydroxyphenoxy]propoxy]thiophenoxy]benzoic acid; uuu) 2-[2-Propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy]propoxy]phenylsulfinyl]benzoic acid; 30 vvv) 2-[2-Propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy]propoxy]phenylsulfonyl]benzoic acid hydrate; www) 5-[3-[2-(1-Carboxy)ethyl]-4-[3-[2-ethyl-4-(4 35 fluorophenyl)-5-hydroxyphenoxy]propoxylphenyl]-4 pentynoic acid disodium salt 0.4 hydrate; xxx) 1-Phenyl-1-(1H-tetrazol-5-yl)-6-(2-ethyl-4-(4 fluorophenyl)-5-hydroxyphenoxy)hexane; 40 yyy) 1-(4-(Carboxymethoxy)phenyl)-1-(1H-tetrazol-5-yl)-6-(2 ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)hexane; zzz) 1-(4-(Dimethylaminocarbonylmethoxy)phenyl)-1-(1H 45 tetrazol-5-yl)-6-(2-ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)hexane; WO 01/34137 PCT/USOO/31039 -272 aaaa) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)-E-propenoic acid; bbbb) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 5 hydroxyphenoxy)propoxy)phenyl)-2-methyl-E-propenoic acid; cccc) 5-(2-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenoxy)propoxy)phenyl)ethyl)-lH-tetrazole; 10 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 15 hydroxyphenoxylpropoxy]-3,4-dihydro-2H-1-benzopyran-2 one; ffff) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxylpropoxy}phenyl)propanoic acid; 20 gggg) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5 hydroxyphenyloxy]propoxy}-4-propylph enyl)propanoic acid sodium salt; 25 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 hydroxyphenyloxy]propoxy}-2-propylphenyl)propanoic acid; 30 jjjj) 3-{3-[3-(2-Ethyl-5-hydroxyphenyloxy)propoxy]-2 propylphenyl}propanoic acid disodium salt; and kkkk) 2-[3-[3-[2-Ethyl-5-hydroxy-4-(4 35 fluorophenyl)phenoxy]propoxy]benzoyl]benzoic acid disodium salt hemihydrate. WO 01/34137 PCT/USOO/31039 -273
36. The method of claim 21 or 22 or 25 wherein the leukotriene (LTB4) antagonist is a compound of the structure (Formula B): 5 F H 0 o 0 HO 0 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. 15 37. The method of claim 21 wherein the anti-cancer agent is a therapeutically effective amount of a 2',2' difluoronucleoside anti-cancer agent according to the formula: RO-H 2 C O -- F OH F 20 wherein: R1 is hydrogen or WO 01/34137 PCT/USOO/31039 -274 0 || -C-R3 R 2 is a base defined by one of the formulae 5 NHR 8 0 N 0 N R 3 HN N O O HN 1 NH N X N N N H 101 WO 01/34137 PCT/USOO/31039 -275 NHR 3 7, N N R4-t| \ N N X is N or C-R 4 R3 is hydrogen, Ci-C 4 alkyl or 5 0 -C-R R 4 is hydrogen, C 1 -C 4 alkyl, amino, bromo, fluoro, chloro or iodo; 10 each R 5 independently is hydrogen or Ci-C 4 alkyl; and the pharmaceutically-acceptable salts thereof.
38. A method of treating cancer in a mammalian patient by administering to said patient a therapeutically effective 15 amount of a leukotriene (LTB 4 ) antagonist and a therapeutically effective amount of 2',2'-difluoronucleoside anti-cancer agent; wherein the anti-cancer agent is gemcitabine hydrochloride and the leukotriene (LTB4) antagonist is a compound of the structure (Formula B): 20 WO 01/34137 PCT/USOO/31039 -276 F H o-" 'o 0 HO 0 or pharmaceutically acceptable salts thereof.
39. The method of claim 21 or 22 or 38 wherein the weight 5 ratio of LTB 4 antagonist to anti-cancer agent 1:100 to 100 to 1.
40. The method of claim 21 or 22 or 23 wherein the combined dose weight of LTB 4 antagonist and anti-cancer agentin from 10 0.5 to about 300 mg/kg per day.