SK6492002A3 - Oncolytic combinations for the treatment of cancer - Google Patents

Abstract

Leukotriene (LTB4) antagonists enhance the effectiveness of 2',2'-difluoronucleoside anti-cancer agents.

Description

Technical field

The invention relates to a method of treating cancer with anti-cancer agents. In particular, the invention relates to the use of 2 ', 2'-difluoro-nucleoside anticancer agents in conjunction with a leukotriene antagonist (LTB ₄ ), which results in an increase in the efficacy of the anticancer agent.

BACKGROUND OF THE INVENTION

This application is related to US Provisional Application No. 60 / 164,786 filed November 11, 1999, which is hereby incorporated by reference in its entirety.

Leukotriene B ₄ (LTB ₄ ) is an inflammatory-inducing lipid that is used against the pathogenesis of psoriasis, arthritis, chronic lung disease, acute respiratory distress syndrome, shock, asthma, bone inflammation and other inflammatory conditions characterized by infiltration and activation of polymorphic leukocytes and cells associated with an inflammatory response. Therefore, activated polymorphic leukocytes release enzymes, tissue degrading and reactive chemicals cause inflammation. U.S. Pat. No. 5,462,954 discloses phenylphenolleukotriene antagonists which can be used in the treatment of psoriasis, arthritis, chronic lung diseases, acute respiratory distress syndrome, shock, asthma, bone inflammation and other inflammatory conditions characterized by infiltration and activation of leukocytes with polymorphal nuclei. U.S. Patent 5,910,505 discloses that some phenylphenolleukotriene B ₄ (LTB ₄ ) antagonists can be used to treat squamous cell carcinoma of the oral cavity. U.S. Patent 5,543,428 discloses a group of phenylphenolleukotriene antagonists that have the ability to reverse multi-drug resistance in tumor cells, hereinafter referred to as "multidrug resistance". The use of this leukotriene antagonist abolishes resistance to the drug vinblasine, vincristine, vindesine,

911 / B navelbine, daunorubicin, doxorubicin, mitoxantrone, etoposide, teniposide, mitomycin C, actinomycin, taxol, topotecan, mitramycin, colchicine, puromycin, podophyllotoxin, emetine, gramicidin and valinomycin.

SUMMARY OF THE INVENTION

The invention provides compositions and methods that can be used to treat cancers, especially cancers that are not multidrug resistant. These methods of the invention include the 2 ', 2'-difluorucleoside anticancer agents described in US Patent 5,464,826 in combination with the leukotriene antagonists (LTB ₄ ) of Formula A, Formula I and Formula II, described below.

We have surprisingly found that the combination of a 2 ', 2'-difluorucleoside anticancer drug with a leukotriene antagonist (LTB ₄ ) acts synergistically against cancers that are not multidrug resistant.

Types of cancers that can be treated with the compositions of the invention include: breast cancer, bladder cancer, colon cancer, esophageal cancer, stomach cancer, germ cell cancer, e.g. testicular cancer, gynecological carcinoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, malignant melanoma, multiple myeloma, neurological carcinoma, brain cancer, pancreatic cancer, prostate cancer, Ewing's sarcoma, osteosarcoma, soft tissue sarcoma, non-small cell lung, and small cell lung cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1 to 6 are horizontal bar graphs showing data from Tables 1 to 6 obtained in the experiment described herein as "Test Example 1". The vertical axis of the graph in each figure shows its origin for each column. The columns are numbered. Each column was obtained separately as shown in the tables. On the horizontal axis, the tumor growth delay ("TGD") is plotted in days.

911 / B

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions of important terms

The term "acidic group" means an organic group which, when attached as a "Z" substituent of formula (I) or a "Z2" substituent of formula (II), acts as a hydrogen-capable proton donor. An illustrative acidic group is carboxyl.

The term " active ingredient " means certain 2 ', 2'-difluoronucleoside compounds as well as leukotriene B ₄ antagonist compounds, generically described by Formula A as diphenylleukotriene B ₄ antagonist compounds, generically described by Formula I and Formula II, or calculating specific diphenyl compounds below and further a combination of the 2 ', 2'-difluoronucleoside leukotriene B ₄ antagonists described by formula A or formulas I and / or

II, with salts, solvates and / or prodrugs of these compounds.

The term "alkenyl" means a monovalent radical of the generic formula C _n Hn 2 _n such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, 2-butenyl and

3-butenyl.

The term "alkyl" as such or as part of another substituent means, unless otherwise defined, a linear or branched 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 with an alkyl or substituted aryl group, for example: in the term "C 6 -C 20 alkaryl", the numerical subscripts denote the total number of carbon atoms in the radical.

The term "-0 0 _{6 2} ο ,, aralkyl means an alkyl radical substituted with an aryl or substituted aryl group, for example:

911 / B

In the term "C ₆ -C 20 aralkyl", the numerical subscripts denote the total number of carbon atoms in the radical.

The term "carbocyclic group" means a five-, six- 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, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "heterocyclic radical" means a radical having a saturated, unsaturated or aromatic five-membered substituted or unsubstituted ring containing from 1 to 4 heteroatoms.

The terms "mammal" and "mammal" include humans.

The term "N-sulfonamidyl" means a radical:

Oo II ^H II wherein R 12 is C 1 -C 10 alkyl, aryl, C 1 -C 6 alkyl substituted aryl, C ₆ -C ₂ o alkaryl, or C 6 -C 20 aralkyl.

The term "substituted alkyl" means an alkyl group further substituted with one or more radicals selected from the group consisting of halogen, C 1 -C 6 alkyl, aryl, benzyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C ₃ - C ₈ cycloalkyl, C 1 -C 3 alkoxy, C 1 -C ₆ haloalkyl (e.g. -CF ₃ ).

The term "substituted aryl" means an aryl group further substituted by one or more radicals selected from the group consisting of halogen, C 1 -C 6 alkyl, aryl, benzyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C ₃ -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C ₆ haloalkyl (e.g. -CF ₃ ).

The term "tetrazolyl" means an acidic group represented by any of the formulas:

The term "therapeutically effective interval" means the period of time that begins when a mammal is administered the first of the active ingredients, including:

(a) a 2 ', 2'-difluoro nucleoside anticancer drug or (b) an LTB ₄ antagonist, and ends with an anticancer benefit limit for the treatment of cancer of either (a) or (b). Typically, the leukotriene antagonist (LTB ₄ ) anticancer drug is administered within 24 hours of each other, preferably within 4 hours, and most preferably within 1 hour.

The term " therapeutically effective combination "

(a) a 2 ', 2'-difluorucleoside anticancer drug and (b) an LTB ₄ antagonist, either simultaneously or separately, in any order.

911 / B

The anti-cancer active agents which may be used in this sense are, for example, 2 ', 2'-difluoronucleoside compounds of the formula:

R ²

OH + -F F in which:

R ₂ is hydrogen or o

II 5 —C-R where:

Rs is a base, defined by one of the formulas:

911 / B

where:

X is N or C-R4,

R ₃ is hydrogen, C 1 -C 4 alkyl or a substituent of the formula:

o —D — R ⁵

R ₄ is hydrogen, C 1 -C 4 alkyl, amino, bromo, fluoro, chloro or iodo,

Each R ₅ independently is hydrogen or C 1 -C 4 alkyl; and pharmaceutically acceptable salts of the defined compounds.

Compounds defined by the following general formula may also be used:

911 / B in which:

R 6 is hydrogen, C 1 -C 4 alkyl,

R ₇ is a base, which is defined by one of the formulas:

Λ

HN X

In which:

X is N or CR ₄ ,

R 5 is hydrogen or C 1 -C 4 alkyl,

R ₄ is hydrogen, C 1 -C 4 alkyl, amino, bromo, fluoro, chloro, and iodo, and pharmaceutically acceptable salts of the defined compounds, with the proviso that R 5 and R 5 can both be hydrogen only when X is

N, and furthermore the compounds defined by the general formula:

911 / B

------ H F

OH F in which:

R ₆ is hydrogen or C 1 -C 4 alkyl, and

R 8 is a substituent of the formula:

These compounds are described in U.S. Pat. No. 5,464,826, which is incorporated by reference herein in order to clarify methods for preparing these compounds, to make compositions based on them, and to treat cancer with these compounds.

Alternatively, preferred 2 ', 2'-difluoronucleoside compounds are those represented by the general formula:

where:

R 1 is hydrogen,

R2 is a base defined by one of the formulas:

911 / B

where:

X is CR ₄ ,

R ₃ is hydrogen,

R ₄ is hydrogen, C 1 -C 4 alkyl, bromo, fluoro, chloro or iodo, and pharmaceutically acceptable salts of the defined compounds.

More preferred are those compounds in which:

R2 is a base defined by the formula:

91 l / B

Even more preferred are anticancer agents which are selected from the following compounds or pharmaceutically acceptable salts thereof:

(i) 1- (4-amino-2-oxo-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluoribibose; (ii) 1- (4-amino-2-oxo) 1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluoroxylose, (iii) 1- (2,4-dioxo-1H, 3H-pyrimidin-1-yl) -2-desoxy-2' And (iv) 1- (4-amino-5-methyl-2-oxo-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluoribibose.

The most preferred compound is gemcitabine HCl, which is a nucleoside analogue that exhibits antitumor activity. Gemcitabine HCl is the chemical name of 2'-deoxy-2 ', 2'-difluorocytidine monohydrochloride (beta-isomer) and also known as 2', 2'-difluoro-2'-deoxycytidine monohydrochloride or also as 1- (4 amino-2) oxo-1H-pyrimidin-1-yl) -2-deoxy-2 ', 2'-difluororibose.

The structural formula is as follows:

Anti-cancer drugs are usually mixed with a vehicle, which may act as diluents (diluents, diluents) or excipients (excipients, vehicles). The anti-cancer agents may be administered in the form of

911 / B in the form of tablets, pills, powders, such as lozenges, sachets, capsules, baths, suspensions, emulsions, solutions, syrups or aerosols. Sterile injectable solutions may also be used.

Leukotriene (LTB ₄ ) antagonists useful in the present invention include compounds of Formula A:

or a pharmaceutically acceptable base addition salt thereof, wherein in formula A the general symbols have the following meanings:

R f is a C 1 -C 5 alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, C _r C ₄ alkoxy, (C1C ₄ alkyl) thio, halo, or R ₂ 'substituted phenyl, each R _2', and R ₃ 'is independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C 1 -C 4 alkoxy, (C 1 -C 4 alkyl) - (O) _q S-, trifluoromethyl or di- (C 1 -C ₃ alkyl) amino,

X 'is -O-, -S-, -C (= O) or -CH ₂ -; Y 'is -O- or -CH ₂ -, or when linked together, then -X'-Y'- represents -CH = CH- or -C = C-,

Z 'is a linear or branched C 1 -C ₁₀ alkylidenyl,

A is a bond, -0-, -S-, -CH = CH-, or -CR _a R _b - wherein R _a and R _b are each independently hydrogen, C _r C ₅ alkyl, or R _{I ''} substituted phenyl, or when combined with the carbon atom to which they are attached, they together form a C ₄ -C 6 cycloalkyl ring,

15 / LABC, 2ab

R;

where:

each F-6 is independently -COOH, 5-tetrazolyl, CON (Rg) 2 or -CONHSO ₂ R ₁₀ , each R ₇ is hydrogen, C 1 -C 4 alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, benzyl, methoxy, -WR ₆ , -TGR ₆ , (C 1 -C 4 alkyl) -T- (C 1 -C 4 alkylidenyl) -O- or hydroxy,

R ₈ is hydrogen or halogen, each R 8 is independently hydrogen, phenyl or C 1 -C 4 alkyl, or when taken together with the nitrogen atom to which they are attached to form a morpholine, piperidine, piperazine or pyrrolidine group,

R 10 is C 1 -C 4 alkyl or phenyl,

R 11 is R ₂ , -WR _6, or -TGR ₆ , each W is a bond or a branched or linear or divalent branched chain hydrocarbon radical having one to eight carbon atoms, each G is a linear or divalent branched chain hydrocarbon radical having one up to eight carbon atoms, each T is a bond, -CH ₂ -, -Ο-, -NH-, -NHCO-, -C (= O) - or (O) _q S-,

K is -C (= O) - or -CH (OH) -, each q is independently 0, 1 or 2, p is 0 or 1, and is 0 or 1, with the proviso that when X is -O- or -S-, Y is not -O-, with the proviso that when A is -O- or -S-, R 4 'is not R ₆ , and with the proviso that W is not a bond when p is 0.

Preferred compounds having activity as LTB ₄ antagonists of formula A are those wherein R ₄ 'is selected from the groups of the following formulas:

or

And even more preferably, LTB ₄ antagonists of formula A are those in which

R ₄ 'is:

Some of these preferred _LTB4 antagonist compounds or pharmaceutically acceptable derivatives of compounds defined by the derivative, in particular ester, shown below, selected from (A) to (KKKK) consisting of:

A) 2-methyl-2- (1H-tetrazol-5-yl) -7- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) heptane,

B) 2-methyl-2- (1H-tetrazol-5-yl) -7- (2-ethyl-4- (3-fluorophenyl) -5-hydroxyphenoxy) heptane,

C) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-dimethylaminocarbonylbutyloxy) phenyl) propionic acid,

D) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionic acid,

P11 / R

E) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-carboxybutyloxy) phenyl) propionic acid,

F) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6-methoxyphenyl) propionic acid,

G) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4- (1H-tetrazol-5-yl) butyloxy) phenyl) propionic acid,

H) methyl 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) - (1-butenyl)) phenyl) propionate,

(I) 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) - (1-butenyl)) phenyl) propionic acid,

J) 3- (2- (9- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) butyl) phenyl) propionic acid,

K) 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) butyl) -6-methoxyphenyl) propionic acid,

L) Methyl 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6-hydroxyphenyl) propionate,

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-hydroxyphenoxy) propoxy) -6- (4-butyloxy) phenyl) propionic acid,

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-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,

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-hydroxyphenoxy) propoxy) phenyl) propionamide,

T) N-phenylsulfonyl-3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionamide,

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,

W) 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) butyloxy) phenyl) propionic acid,

X) methyl 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4 (methoxycarbonyl) phenoxy) phenyl) propionate,

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-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,

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- (1H-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-hydroxyphenoxy) propoxy) phenyl) propionic acid,

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-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionate,

GG) 5- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -8- (4-carboxybutyl) 18 dihydrocoumarin,

HH) sodium 2-phenyl-4-ethyl-5- [6- (2H-tetrazol-5-yl) -6-methylheptyloxy) phenol,

II) 2- (4-methylphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol disodium,

JJ) sodium 2- (3-methylphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol,

KK) 2- (2-methylphenyl) -4-ethyl-5- (6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol, disodium salt,

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- (2H-tetrazol-5-yl) heptyloxy] phenol, sodium salt,

NN) 2- (4-trifluoromethylphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol, disodium salt,

00) 2- (3-dimethylaminophenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol, disodium salt,

PP) 3- (5- (6- (4-phenyl-5-hydroxy-2-ethylphenoxy) propoxy) -2-carboxymethyl-1,2,3,4-tetrahydronaphthalen-1 (2H) -one) propanoic acid,

QQ) 3- (5- (6- (4- (4-fluorophenyl) -5-hydroxy-2-ethylphenoxy) propoxy) -2-carboxymethyl-

1,2,3,4-tetrahydronaphthalen-1 (2H) -one) propanoic acid,

RR) 3- (4- (5- (4- (4-fluorophenyl) -5-hydroxy-2-ethylphenoxy) propoxy) -2-carboxymethyl-

2,3-dihydroinden-1 (2H) -one) propanoic acid,

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-yl) oxy] propoxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid acid,

UU) 8-propyl-7- [3- [4- (4-fluorophenyl) -2-ethyl-5-hydroxyphenoxy] propoxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid,

W) 2- [3- [3 - [(5-ethyl-2-hydroxy [1,1'-biphenyl] -4-yl) oxy] propoxy] -2-propylphenoxy] propanoic acid,

WW) 2- (4-chlorophenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol, sodium salt,

XX) 2- (3,5-dichlorophenyl) -4-ethyl-5- [6-methyl-5- (2H-tetrazol-5-yl) heptyloxy] phenol, sodium salt,

YY) 3- [2- [3 - [(5-ethyl-2-hydroxy [1,1'-biphenyl] -4-yl) oxy] propoxy] -1-dibenzofuran] propanoic acid, disodium salt,

ZZ) 7-Carboxy-9-oxo-3- [3- (2-ethyl-5-hydroxy-4-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, sodium hemihydrate

BBB) 3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] - [1,1'-biphenyl] -4-propanoic acid, disodium monohydrate,

CCC) 5-Ethyl-4- [3- [2-propyl-3- [2- (2H-tetrazol-5-yl) phenoxy] phenoxy] propoxy] [1,1'-biphenyl] -2-ol disodium salt, trihydrate .

DDD) 3- (4- [3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] -9-oxo-9Hxanthene]) propanoic acid, sodium hemihydrate,

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-hydroxyphenoxy] propoxy) phenoxy] benzoic acid, sodium salt,

GGG) 3- [4- [7-carboxy-9-oxo-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] -31,911 (B propoxy) -9H-xanthene]] propanoic acid, disodium salt trihydrate,

HHH) 3- [4- [9-oxo-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] -9Hxanthene]] propanoic acid,

III) 3- [2- [1- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] -4- (5-oxo-5-morpholinopentanamido) phenyl] propanoic acid,

2-Fluoro-6- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid, disodium salt monohydrate,

KKK) 4-fluoro-2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid,

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-fluorophenyl) phenoxy] butoxy] phenoxy] benzoic acid, trihydrate,

NNN) 2- [2- (2-methylpropyl) -3- [3- [2-ethyl-5-hydroxy-4- (9-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid,

OOO) 2- [2-butyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid, monohydrate,

PPP) 2- [2- (phenylmethyl) -3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid,

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,

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-hydroxyphenoxy] propoxy] thiophenoxy] benzoic acid,

911 / B

UUU) 2- (2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenylsulfinyl] benzoic acid,

VW) 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenylsulfonyl] benzoic acid, monohydrate,

WWW) 5- [3- [2- (1-Carboxy) ethyl] -4- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenyl] -4-pentanoic acid, disodium salt 0.4 hydrate,

XXX) 1-phenyl-1- (1H-tetrazol-5-yl) -6- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] hexane,

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-tetrazol-5-yl) -6- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) hexane,

AAAA) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) -Epropenoic acid,

BBBB) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) -2-methylE-propenoic acid,

CCCC) 5- (2- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) ethyl) 1H-tetrazole,

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-hydroxyphenoxy] propoxy] -3,4-dihydro-2H-1-benzopyran-2-one,

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-hydroxyphenyloxy] propoxy} -4-propylphenyl) propanoic acid, sodium salt,

HHHH) 3- (4- {3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenyloxy] propoxy} -3Q / 11-propyl phenyl) propanoic acid, III) 3- (3- {3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenyloxy] propoxy} -2-propylphenyl) propanoic acid,

3- {3- [3- (2-ethyl-5-hydroxy-phenyloxy) -propoxy] -2-propyl-phenyl} -propanoic acid, disodium salt, and

KKKK) 2- [3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] benzoyl] benzoic acid, disodium salt, hemihydrate.

These leukotriene antagonist (LTB ₄ ) compounds are known in the art and are fully described in US 5,462,954, which is specifically incorporated herein by reference for the purpose of explaining methods for preparing specific leukotriene B ₄ antagonists and compounds or formulations thereof. leukotriene antagonists which can be administered to patients. A preferred compound is 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxybenzoic acid, which may also be called 2- [3- [3- ( 5-ethyl-4'-fluoro-2-hydroxybiphen-4yloxy) propoxy-2-propylphenoxy] benzoic acid and which is described in US 5,462,954 as example no. 66 and is also shown below as Compound A (Formula B):

Compound A (Formula B)

The second class of LTB ₄ antagonists, which is used as a substantial synergistic agent in particular compositions in the practice of the method of the invention, includes the substances disclosed in related provisional patent application entitled "Heterocyclically-substituted diphenylleukotriene antagonists" (inventor: Jason Scott Sawyer; It contains 97 pages and can also be identified in the Eli Lilly Company Documentation under the reference B-13240), filed Nov. 11, 1999, and now in Provisional Patent Application no. 60 / 164,786. This second class of heterocyclic substituted diphenyl leukotriene antagonists is described in detail below.

II. Other LTB ₄ antagonists:

Other LTB ₄ antagonists are described below. These are the new heterocyclic substituted diphenyl compounds of formula (I):

(D in which:

X is selected from a file that includes:

(i) a five membered substituted or unsubstituted heterocyclic radical containing 1 to 9 heteroatoms independently selected from sulfur, nitrogen and oxygen; or (ii) a fused bicyclic radical in which the carbocyclic group is fused to two adjacent carbon atoms atoms of a five membered heterocyclic radical (i),

Y 1 is a bond or a divalent linking group containing 1 to 9 atoms,

Y ₂ and Υ 3 are bivalent linking groups which are independently selected from the group consisting of the formulas -CH 2 -, -O- and -S-,

Z is an acid group,

R 1 is C 1 -C 10 alkyl, aryl, C3-CW cycloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C ₆ -C ₂ o aralkyl, C 6 -C 20 aryl, CPCI haloalkyl, C 6 -C ₂ o CRCI aryloxy or alkoxy,

R ₂ is hydrogen, halogen, C 1 -C 10 haloalkyl, C 1 -C 10 alkoxy, C 1 -C 10 alkyl, C3C ₈ cycloalkyl, an acid group or a - _(CH2) i-7 (acid group),

R ₃ is hydrogen, halogen, C 1 -C 10 alkyl, aryl, C _r Cio haloalkyl, C 1 -C 10 alkoxy, C ₁₀ aryloxy, C ₃ -C ₈ cycloalkyl,

R ₄ is C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, - (CH ₂ ) 1-7 (cycloalkyl), C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, benzyl or aryl, and n is 0, 1, 2, 3 , 4, 5 or 6, or a pharmaceutically acceptable salt, solvate or prodrug of any of the defined compounds.

III. Preferred LTB ₄ antagonist compounds are as follows:

III A. Preferred substituents X:

The "substituted heterocyclic radical" is preferably substituted with 1 to 3 groups independently selected from hydrogen, halogen, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 1 -C ₁₀ alkoxy, aryl or C ₆ -C ₂ is aryloxy.

Preferred group 1 of substituent X (symbol "PG 1 -X").

Preferred LTB ₄ antagonist compounds used in the compositions of the invention are those in which X is a heterocyclic radical selected from the group consisting of substituents characterized by the following structural formula:

R10 \

wherein R ₁₀ is a radical selected from the group consisting of hydrogen or C 1 -C 4 alkyl, and

R is a radical selected from the group consisting of hydrogen, halogen, C _r Cio alkyl, C _r Cio haloalkyl, -C ™ alkoxy, aryl, or C ₆ -C ₂ o aryloxy. Preferred R ₁₀ radicals are hydrogen, methyl or phenyl.

In addition, any of the above heterocyclic radicals represented by the structural formulas may be attached to the diphenyl compound of formula (I), which is a leukotriene antagonist, by any single bond starting from a suitable carbon or nitrogen atom in its cyclic structure.

For example, a pyrrole radical may be attached to a diphenyl molecule by a single bond that starts from any carbon or nitrogen atom having less than three bonds in the heterocyclic ring occupied.

A preferred form of substituent X is a fused bicyclic radical in which the carbocyclic group is fused to two adjacent carbon atoms of a five membered heterocyclic radical, for example:

III B. Preferred group of 2 possible meanings of the substituent X (symbol "PG 2 -X"):

The most preferred substituents X are heterocyclic radicals:

or

911 / B

C. The following X substituents are selected:

The heterocyclic radical X of formula (I) does not include 3-bromo-1,2,4-thiadiazole since the LTB ₄ antagonist activity of a compound containing this radical is considered too low to be an aspect of the invention.

III D. Preferred Yv substituents

Y 1 is a bond or a divalent linking group containing 1 to 9 atoms independently selected from the group consisting of carbon, hydrogen, sulfur, nitrogen and oxygen.

Preferred group 1 of the possible meanings of the substituents Υ _Ί (symbol "PG1Yi"):

Preferred LTB ₄ antagonist compounds included in the compositions of the invention are those in which Υ _Ί is a divalent linker group selected from the group consisting of the following formulas:

--- O ----- C - h ₂

--- s --- about

--- N-R 13 include the substituents represented

what

911 / B

--c— h ₂ ry —G-- h ₂ n. at L · h ₂ --with- -c-- --N- h ₂ —c--

R13

Ο

C ---- C-H ₂

Wherein R 13 is hydrogen, methyl or ethyl.

The above bivalent groups can be used in positions such as drawn or inverted. For example, a group:

- C - CH ₂ II o

may have the following positions in the fragment of Formula (I) displayed:

or

911 / B

III E. Preferred group of 2 possible meanings of substituent Y 1 (symbol "PG 2 Y 1"):

The most preferred bivalent substituent Υϊ is:

- ABOUT -

Preferred group 1 of the possible meanings of the substituent Y ₂ (symbol "PGI-Y2") and preferred group 1 of the possible meanings of the substituent Y 3 (symbol "PGI-Y3")

The substituents Y ₂ and Y ₃ are preferably selected from the group consisting of -S- and -O-.

III G. Preferred group of 2 possible meanings of substituent Y ₂ (symbol "PG2Y ₂ ") and preferred group of 2 possible meanings of substituent Y ₃ (symbol "PG2Y ₃ ")

As the most preferred value for Y _2, and Y ₃ and the group it is:

- ABOUT -

III H. Preferred group 1 of the possible meanings of the substituent Z (symbol "PG1-Z"):

Z is an acidic group as defined above. Preferred are acidic groups selected from the following group:

tetrazolyl,

- SO ₃ H,

911 / B

Ο t

• P ---- OH

OH

ABOUT

C ---- OH or

wherein R 12 is C 1 -C ₁₀ alkyl, aryl, C ₆ -C 20 alkaryl or C 6 -C ₂₀ aralkyl. Preferred R 12 groups are:

III I. Preferred group of 2 possible meanings of the substituent Z (symbol "PG 2 -Z"):

Highly preferred are the acid groups -5-tetrazolyl, N-acylsulfonamide, -SO ₃ H and carboxyl.

III J. Preferred group of 3 possible meanings of the substituent Z (symbol "PG 3 -Z"):

The most preferred substituent Z is carboxyl.

III K. Preferred group 1 possible meanings of the variable subscript "n" (symbol "PG1-n")

Most preferably, integers which may be represented by the variable "n" in the bivalent linking group - (CH ₂ ) _n -, s n = 1, n = 2 and n = 3.

III L. Preferred group of 2 possible meanings of the variable subscript "n" (symbol "PG2-n")

Most preferably, an integer that can be a variable of "n" in a bivalent linker group - (CH ₂ ) _n is n = 1.

III M. Preferred group 1 of the possible meanings of the substituent R 1 (symbol "PGIRf"):

Preferred R 1 groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and 2-propenyl; wherein n-propyl is most preferred.

I

II N. A preferred group of possible R 1 of R ₂ (PG1-symbol ,, R ₂₎ and one preferred group of the possible meanings of R ₃ (symbol ,, _PG1-R3):

Preferred groups R ₂ and R ₃ are those that are independently selected from the group consisting of hydrogen and methyl, ethyl, methoxy, ethoxy, halogen or

-CF ₃ , wherein R ₂ and R ₃ is most preferably hydrogen.

911 / B

III A. A preferred group of one possible meanings of R ₄ (marked "PG1R _4>,)

Preferred R ₄ substituents are ethyl, propyl and isopropyl.

III P. Combinations of substituents in a compound of formula (I):

The substituents of formula (I) are defined as "Z ..... X,""n ..... R", "R ₂ ", "R ₃ ", "R ₄ ", "Ύι", "Υς" and "Y3". In addition, as mentioned above, within the scope of the substituents of formula (I), "preferred" and "most preferred" subgroups are defined to define a variety of substituents to be used to define LTB ₄ antagonists of the invention. These preferred sub-groups are defined by terms such as "PG 1 -R ₄ " as defined above. It is often preferred to use combinations of preferred groups or combinations of preferred groups together with the generally defined variables in Formula (I). Suitable substituent combinations are shown in the following three tables (see Table R, Table Y and Table XZn).

The following table R can be used to select combinations of general and preferred groups in the meanings of the variables R 1, R ₂ , R 3 and R ₄ in formula (I):

911 / B

Table of possible meanings of the substituent R-:

Combination code of variable "R" Selection of the R 1 group Choice of group R ₂ Choice of group R ₃ Choice of group R ₄ R01 ri R 2 r ₃ R ₄ . I R02 ri r ₂ r _{3 PG1-R4} R03 ri r _{2 PG1-R3} R4 R04 ri r _{2 PG1-R3 PG1-R4} R05 ri PGI-R2 r ₃ R4 R06 ri PGI-R2 r ₃ PG1-R4 R07 ri PGI-R2 _PG1-R3 R4 R08 ri PGI-R2 _{PG1-R3 PG1-R4} R09 PG1-R r ₂ r ₃ r ₄ R10 PGI-R1 r ₂ r _{3 PG1-R4} R11 PGI-R1 r _{2 PG1-R3} R4 R12 PGI-R1 r _{2 PG1-R3 PG1-R4} R13 PGI-R1 PGI-R2 r ₃ r ₄ R14 PG1-R; PGI-R2 r ₃ PG1-R4 R15 PGI-R1 PGI-R2 _PG1-R3 r ₄ R16 PGI-R1 PGI-R2 _{PG1-R3 PG1-R4}

The table is used as follows:

For example, the combination of substituents " R14 " denotes a combination choice substituent for formula (I) wherein R) is selected from a preferred set of possible variable meanings designated as " PG1-R1 " propyl, isopropyl, n-butyl, sec-butyl and 2-propenyl; preferred meanings of the variable R ₂ are "PG 1 -R ₂ ", i.e. hydrogen or methyl, ethyl, methoxy, ethoxy, halogen or -CF ₃ ; the variable R ₃ has the range defined by generic formula (I) and the substituents suitable as R ₄ are selected from the preferred group "PG 1 -R ₄ " which contains a number of preferred meanings of R ₄ , which are ethyl, propyl and isopropyl.

911 / B

The following table Y can be used to select a number of preferred combinations of groups that are preferred in the meanings of the general substituents Y 1, Y ₂ and Y 3 in formula (I):

Table of possible meanings of substituent Y-:

Combination code of "Y" Group selection Y1 Group selection Y2 Choice of Y group ₃ Y01 Y1 Y2 Y ₃ Y02 Y1 Y ₂ PGI-Y3 Y03 Y1 Y ₂ PG 2-Y3 Y04 Y1 PGI-Y2 Y ₃ Y05 Y1 _PG2-Y2 Y ₃ Y06 Y1 PGI-Y2 PGI-Y3 Y07 yl PGI-Y2 PG 2-Y3 Y08 yl _PG2-Y2 PGI-Y3 Y09 YJ _PG2-Y2 PG 2-Y3 Y10 PG 1-Y1 Y ₂ Y ₃ Y11 PG 1-Y1 Y ₂ PGI-Y3 Y12 PG 1-Y1 Y _{2 PG2-Y3} Y13 PGI-Y1 PGI-Y2 Y ₃ Y14 PG1-Y; PGI-Y2 PGI-Y3 Y15 PGI-Y1 PGI-Y2 _PG2-Y3 Y16 PGI-Y1 _PG2-Y2 Y ₃ Y17 PGI-yl _PG2-Y2 PG 1-Y3 Y18 PGI-Y1 _PG2-Y2 PG 2-Y3 Y19 PG2-Y; Y ₂ Y ₃ Y20 PG 2-Y1 Y ₂ PG 1-Y3 Y21 PG 2-Y1 Y ₂ PG 2-Y3 Y22 PG 2-Yi _PG1-Y2 Y ₃ Y23 PG 2-Yi PG 1-Y2 _PG1-Y3

•> 1,011 / n

Combination code of "Y" Group selection Yi Choice of Y group ₂ Group selection Y3 Y24 PG 2-Yi PGI-Y2 PG 2-Y3 Y25 PG 2-Yi _PG2-Y2 Y3 Y26 PG 2-Yi _PG2-Y2 PGI-Y3 Y27 PG 2-Yi _PG2-Y2 PG 2-Y3

The following table XZn can be used to find preferred combinations of groups that may be in place of the general substituents X, Z and n in formula (I):

Table of possible combinations of substituents X, Z and parameter n:

Combination code Group selection Group selection Integer dialing "Xzn" "X" »2» > About " XZnO1 X from n XZnO2 X from PG1-n XZnO3 x from PG2-n XZnO4 x PG1-Z n XZnO5 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 XZn 10 x PG1-Z PG2-n XZn 11 x PG2-Z PG2-n XZn 12 x PG3-Z PG2-n XZn 13 PG1-X FROM n XZn 14 PG1-X FROM PG1-n XZn 15 PG1-X from PG2-n XZn 16 PG1-X PG1-Z n

τι ai1 / y

Combination code Group selection Group selection Integer dialing ",, xzn "X" , .N " XZn 17 PG1-X PG2-Z n XZn 18 PG1-X PG3-Z n XZn19 PG 2-X PG1-Z, PG1-n XZn20 PG 2-X PG2-Z PG1-n XZn21 PG 2-X PG3-Z PG1-n XZn22 PG 2-X PG1-Z PG2-n XZn23 PG 2-X PG2-Z PG2-n XZn24 PG 2-X PG3-Z PG2-n

How to use these tables:

Any of the 16 R substituent combinations specified in Table R can be used in combination with any of the 27 Y substituent combinations specified in Table Y, and these can be used in combination with any of the 24 XZn substituent combinations defined in Table XZn. For example, the selected combinations of substituents "R07, Y21 and XZnO3" define a set of substituent selections for Formula (I), which defines a subset of compounds useful for a particular embodiment of the composition of the invention.

Other preferred compounds effective as LTB ₄ antagonists are described by Formula (II):

o i ηιι / ο in which:

X ₂ is a heterocyclic radical selected from the following substituents:

or

R 21 is ethyl, 2-propen-1-yl, 3-propen-1-yl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, and

R 22 is hydrogen, n-butyl, sec-butyl, fluoro, chloro, -CF ₃ or tert-butyl,

Z ₂ is carboxyl, tetrazolyl, N-sulfonamidyl.

Preferred compounds of the invention:

III R: Specific compounds preferred as LTB ₄ antagonist components for the compositions and methods of the invention are represented by the following structural formulas:

(C1)

(C2):

(C3):

(C4):

COOH

6)

(C7):

(C8):

COOH

(CII)

(12):

911 / B

C13)

(C14):

(C15):

(C16):

OH

COOH (C18):

(18):

(C19):

(C20):

'j' 011 (C21):

(C22):

and all acid derivatives, salts, solvates and prodrugs of the defined compounds.

Highly preferred LTB ₄ antagonist compounds are as follows:

Q1 O11 / Q

COOH and all acid derivatives, salts, solvates and prodrugs of the defined compounds.

IV. A process for the manufacture of compounds having LTB ₄ antagonist activity and which can be used in the compositions and methods of the invention.

General reaction schemes (not specific examples) are useful for the synthesis of compounds effective as LTB ₄ antagonists represented by formula (I). There are a number of references and Chemical Abstract registration numbers (e.g., RN 152609-60-4) where adjuvants for the preparation of reagents are used, which are used in the practice of these syntheses illustrated in the schemes of the invention.

General Reaction Schemes for the Production of LTB ₄ Antagonist Compounds Used in the Compositions and Methods of the Invention

The following scheme illustrates a method for producing the compound of Example 1, which is an LTB ₄ receptor antagonist, a chemically 4-substituted oxazole: Scheme 1 OH

(26) Known compound: RN # 156005-61-7

R. W. Harper et al., J. Med. Chem. 1994, 37 (15). 2411

(32)

1) T ( ₂ O, 2,6-lutidine)

2) lormamide

BF 1 Et; O. E1SH

1) NaOH

2) HCl

The known chloride (26) can be alkylated with benzyl bromide to give the chloride (28). Reaction with a known ester (30), catalyzed by a suitable base, provides acetophenone (32). Oxidation of bis (trifluoroacetoxy) iodobenzene provides α-hydroxyketone (34) which can be cyclized with trifluoromethanecarboxylic anhydride and formamide to give the 4-substituted oxazole (36). Debenzylation of boron trifluoride with etherate and ethanethiol affords oxazole (38), which is hydrolyzed and protonated to give the compound of Example (1).

Scheme 2

The following scheme illustrates a process for preparing the compound of Example (2), which is 5 (4) -substituted imidazole, effective as an LTB1 receptor antagonist.

Scheme 2

1) UHMDS, TMS. THF

2) NCS

3) TBAF

BFyEt10, EISH

1) UOH. MeOH

2) Raney Mi, E1OH, MeOH 3} HCl

911 / B

Acetophenone trimethylsilylenol ether (32) was prepared and treated with N-chlorosuccinimide followed by tetra-n-butylammonium fluoride to give the chloroketone (40). Treatment of the chloroketone (40) with 2-benzyl-2-thiopseudourea and a base gives imidazole (42) which is treated with boron trifluoride etherate and ethanethiol to give imidazole (44). Hydrolysis and protonation affords the compound exemplified herein (2) as the hydrochloride salt.

Scheme 3

The following scheme illustrates a process for producing the compound of Example (3), namely a 4-substituted thiazole having activity as an LTB ₄ receptor antagonist:

Q11 / R

Scheme 3

thioformamide, MgCO ₃ dioxane

BF ₃ Et ₂ O, EtSH

1) LiOH. MeOH

2) HCl

Q 4 m 4 / □

In this case, the chloroketone (40) is treated with thioformamide and magnesium carbonate to give the thiazole (46), which is debenzylated with boron trifluoride etherate and ethanethiol to provide the thiazole (48). Hydrolysis and protonation of the thus obtained compound then provides a compound, which is referred to as Example (3).

Scheme 4

The following scheme illustrates a method for producing the compound of Example (4), which is a 5 (3) -substituted pyrazole, which is effective as an LTB ₄ receptor antagonist:

Ή CH 1 / R

Scheme 4

1) LiOH, MeOH

2) HCl

3) NH 3 NH 3 H 3 O, MeOH

BF ₃ Et ₁₀ O, EtSH

Q11 / R

Treatment of acetophenone (32) with Ν, Ν-dimethylformamide with dimethylacetal affords the enone (50) which can be hydrolyzed, protonated and then heated with hydrazine monohydrate to give pyrazole (52). Debenzylation of the resulting pyrazole with boron trifluoride with ether and ethanethiol affords the compound of Example (4).

Scheme 5

The following scheme illustrates a method for producing the compound of Example (5), which is a selected 5-substituted isoxazole having effects as LTB ₄ receptor antagonists:

Scheme 5

NH ₂ OH, MeOH, H ₂ O

BFyEt10, EtSH

1) UOH, MeOH

(2) HCl (56)

(5)

Treatment of enone (50) with hydroxylamine affords isoxazole (54), which is debenzylated with boron trifluoride etherate and ethanethiol to give isoxazole (56). Hydrolysis and protonation provide Example (5).

Scheme 6

The following scheme illustrates a process for the preparation of the compound of Example (6) which is 5 (4) -substituted 1,2,3-triazole, exhibiting LTB ₄ receptor antagonist activity:

Scheme 6

152609-76-2

K, CO ₃ . KI, DMSO

2-Butanone known compounds rn 152609-60-4

J. S. Sawyef et al., J. Med. Chem. 1995, 3S, 4411

= -SnBUj

Pd (PPhJ ₄ , DMF)

TMSN ,. toluene

BF _3, Ι. EtSH

1) LiOH, MeOH

2) HQ

oi mi / D

The known phenol (30) is alkylated with the known chloride (58) to give the aryl bromide (60). Treatment of compound (60) with tri-n-butylethyltin and a palladium catalyst provides the alkyne (62). Heating (62) with trimethylsilylazide affords triazole (64), which is debenzylated with boron trifluoride etherate and ethanethiol to give triazole (66). Hydrolysis and protonation gave the compound of Example (6).

Scheme 7

The following scheme illustrates a method for producing the compound of Example (7) which is a 1-substituted pyrrole which is effective as an LTB ₄ receptor antagonist.

Scheme 7

OH

(68)

1) (KSOjJjNO, K ₂ PO _4, Hjo

2) 3-pyrroline. CH ₃ CN

3) BnBr. K ₂ CO ₂ , DMF

-bromo-3-chloropropane, CO 2, DMF

(72)

1) Nat, 2-bulanone

References to how to obtain 1-aryl substituted pyrroles:

M. Mure and J.P. Klinman, J. Am. Chem. Soc. 1995, 117 (34), 8898; Lee et al.,

J. Am. Chem. Soc., 1998, 118 (30), 7241.

Potassium 4-ethylbenzene-1,3-diol (68) is treated with potassium nitrosodisulfonate followed by treatment with 3-pyroline and benzyl bromide and a base to give the pyrrole (70). Alkylation with 1-bromo-3-chloropropane gives the chloride (72) which is used to alkylate the phenol (30) to give the pyrrole (74). Debenzylation of boron trifluoride with etherate and ethanethiol affords the compound of Example (7).

Scheme 8

The following scheme illustrates a method for producing the compound of Example (8), which is a 5-substituted 1,2,4-thiadiazole that is effective as an LTB ₄ receptor antagonist:

TI 01 1 / R

Scheme 8

H

I o o

PdCl _x (dppf)

br

N ^ N sA a

PdCl ₂ (dppf), Cs ₂ CO 3, toluene

1) BF 1 Et 10 O, EtSH

2) aq. NaOH

3) aq. HCl

(8)

Palladium catalyzed addition of 4,4,5,5-tetramethyl [1,3,2] dioxaborolan to the bromide (60) affords the boronic ester (76).

Palladium catalyzed addition of 3-bromo-5-chloro-1,2,4-thiadiazole to the derivative (76) affords the ester (78). Debenzylation of boron trifluoride with etherate and ethanethiol followed by hydrolysis and protonation affords the compound of Example (8).

Scheme 9

The following scheme illustrates a method for producing the compound of Example (9), which is a 2-substituted thiophene that is effective as an LTB ₄ receptor antagonist:

Scheme 9

Palladium catalyzed addition of boronic ester (76) to 2-bromothiophene followed by debenzylation of boron trifluoride with etherate and ethanethiol yields thiophene (80). Hydrolysis and salt formation gives the compound exemplified herein (9).

λ 4 «> n

Scheme 10

The following scheme illustrates a method for producing the compound of Example (10) which is a 4-substituted pyrazole that is effective as an LTB ₄ receptor antagonist.

Scheme 10

N-N \

known compound RN 39806-90-1

PdCl2 (CH2Cl2), toluene

1) BFyEt10, EtSH

2) aq. NaOH

3) aq. HCl

911 / B

Palladium catalyzed addition of boronic acid ester (76) to 1-methyl-

4-Iodopyrazole gives pyrazole (82). Debenzylation of boron trifluoride with etherate and ethanethiol followed by hydrolysis and protonation affords the compound of Example (10).

Scheme 11

The following scheme illustrates a method for producing the compound of Example (11), which is a 2-substituted thiazole that is effective as an LTB ₄ receptor antagonist.

911 / B

Scheme 11

br

PdCl ₂ (dppf), Cs 3 CO 3, toluene

BF 1 -Et 1 O, EtSH

1) aq. LiOH

2) HCl

911 / B

Palladium catalyzed addition of the boronic acid ester (76) to 2-bromothiazole affords the thiazole (84). Debenzylation of boron trifluoride with etherate and ethanethiol affords thiazole (86). Hydrolysis and protonation of this material then provides the compound of Example (11).

Scheme 12

The following scheme illustrates a method for producing the compound of Example (12), namely 4-substituted isoxazole, which is effective as an LTB ₄ receptor antagonist.

911 / B

Scheme 12

(76)

PdCl ₂ (dppf), Cs 3 CO 3, toluene

1) Me ₃ Sil

2) aq. HCl

3) NaOH

911 / B

Palladium catalyzed addition of boronic ester (76) to 3,5-dimethyl-iodoisoxazole affords oxazole (88). Debenzylation with trimethylsilyl iodide followed by hydrolysis and salt formation affords the compound exemplified herein (12).

Scheme 13

The following scheme illustrates a method of producing the compound of Example (13), which is a 2-substituted furan, which is effective as an LTB ₄ receptor antagonist.

911 / B

Scheme 13

(60)

B8r ₃ . CHjCIj

(92)

TBSO, imidazole

Pd (PPhJ ₄ , aq. Na / X). THF

(94)

1) aq. LiOH

2) HO

3) NaOH

Debenzylation of bromide (60) with boron tribromide affords phenol (90) which is treated with tert-butyldimethylsilyl chloride and imidazole to give silyl ether (92). Palladium catalyzed addition of derivative (92) to furan-2-boronic acid then affords the furan derivative (94). Hydrolysis and salt formation then provides the compound of Example (13).

Scheme 14

The following scheme illustrates a process for making Example (14), a 3-substituted furan, which is a potent antagonist l_TB ₄ receptor.

Q11 / R

Scheme 14

Pd (PPh 3) ₄ , aq. NaCO 3, THF

1) aq. LiOH

2) HCl

3) NaOH

Palladium catalyzed addition of (92) to furan-3-boronic acid affords the furan derivative (96). Hydrolysis and salt formation then provides the compound of Example (14).

Q11 / R

Scheme 15

The following scheme illustrates a method for producing the compound of Example (15), namely 3-substituted tetrahydrofuran, which is effective as an LTB ₄ receptor antagonist.

(WO)

(15)

911 / B

Treatment of enone (50) with hydroxylamine affords isoxazole (54), which is debenzylated with boron trifluoride etherate and ethanethiol to give isoxazole (56). Hydrolysis and protonation gave the compound of Example (5).

Scheme 16

The following scheme illustrates a method for producing the compound of Example (6), which is 5 (4) -substituted 1,2,3-triazole, which is effective as an LTB ₄ receptor antagonist.

911 / B

Scheme 16

(60)

PdtPPh1, aq. NajCO ,. THF

Hj. Pd (C) aq. LiOH

HO

Palladium catalyzed addition of bromide (60) to N-boc-pyrrole-2-boronic acid affords pyrrole (102). Hydrogenation on a palladium catalyst gives pyrrolidine (104). Hydrolysis and salt formation yields the pyrrolidine salt (106). Treatment with hydrochloric acid then affords the compound of Example (16) as the hydrochloride addition salt.

Scheme 17

The following scheme illustrates a method for producing the compound of Example (17), which is a 3-substituted thiophene, which is effective as an LTB ₄ receptor antagonist.

911 / B

Scheme 17

known compound rn »152609-78-4

J. S. Sawyec et al., J. Med. CBEM. 1995, 38, 4411

K.CO _y KI, DMSO. 2-butanone

(114)

(17)

Palladium catalyzed addition of bromide (58) to thiophene-3-boronic acid affords thiophene (108). Alkylation of the known phenol (110) with compound (108), catalyzed by a base, affords thiophene (112). Debenzylation with boron tribromide affords thiophene (114). Hydrolysis and protonation then affords the compound of Example (17).

Scheme 18

The following scheme illustrates a method for producing the compound of Example (18), which is a 5-substituted 1,2,3,4-thiatriazole that is effective as an LTB ₄ receptor antagonist.

911 / B

Scheme 18

(30)

n

TsOH

2) NaH, DMF. HMPA

3) piperidine

2) NaN,

1) BF ₃ E ', H. CHjCt.

2) aq. NaOH

3) aq. HO

Reference to a method for obtaining dithioacids: N. C. Gonnella et al., Syn. Commun.

1879, 17, reference to a method for obtaining 5-substituted 1,2,3,4-thiatriazoles from dithioacids: S.I. Ikeda et al., Synthesis, 1990, 415.

The phenol (30) is alkylated with 1-bromo-3-chloropropane to give the chloride (116) which is converted to the aldehyde (118) in a known manner, followed by base treatment followed by benzylation with benzyl bromide and the base to give the aldehyde (120). From this aldehyde (120), thioacetal is prepared by treatment with 1,2-ethanedithiol. The resulting thioacetal is then treated with a base to give a thioacid. Piperidine treatment is then performed to prepare the piperidine salt (122). According to the data of Ikeda, see below (the contents of which are incorporated herein by reference), compound (122) reacts with 2-chloropyridinium methyl iodide, followed by treatment with an azide ion to give 1,2,3,4-thiatriazole (124). ). Debenzylation of boron trifluoride with etherate and ethanethiol followed by hydrolysis and protonation affords the product of Example (18).

Scheme 19

The following scheme illustrates a method for producing the compound of Example (19), which is a 4-substituted 1,2,3-thiadiazole, which is effective as an LTB ₄ receptor antagonist.

911 / B

Scheme 19

NHjNHCOOEt

SOClj

1) BF 1 El 10, EtSH

2) aq. NaOH

3) aq. HCl

Reference to the preparation of 1,2,3-thiadiazole: E. W. Thomas et al., J. Med. Chem. 1985

28, 442.

911 / B

Treatment of the acetophenone compound (32) with ethyl carbazate affords the hydrazone (128). Use of thionyl chloride according to the method of Thomas et al. (as set forth below, the contents of which are incorporated herein by reference) will provide an intermediate which is 1,2,3-thiadiazole (130), which is debenzylated with boron trifluoride etherate and ethanethiol and then hydrolyzable and protonated. There was thus obtained the product of Example (19).

Scheme 20

The following scheme illustrates a method for producing the compound of Example (20), a 3-substituted 1,2,5-thiadiazole that is effective as an LTB ₄ receptor antagonist.

911 / B

Scheme 20

CI ν ' ⁹ ''or ⁸ ' n '' ^s '

(trithiazyl trichloride)

1) BF 1 Et 10 O, EtSH

2) aq. NaOH

3) aq. HCl

Reference to the method of obtaining 1,2,5-thiadiazole: E. W. Thomas et al., J. Med.

Chem., 1985, 28,442.

Ή A14 / Q

Alkin (62) is treated with trithiazyl trichloride according to the method of Thomas et al. (as set forth below, the contents of which are incorporated herein by reference), to give thiadiazole (132). Debenzylation of boron trifluoride with etherate and ethanethiol followed by hydrolysis and protonation affords the product of Example (20).

Scheme 21

The following scheme illustrates a method for producing the compound of Example (21), which is a 2-substituted 1,3,4-thiadiazole which is effective as an LTB ₄ receptor antagonist.

911 / B

Scheme 21

Br known compound: RN 61929-24-6 PCT WO 9730981

PdCl ₂ (dppf), Cs 3 CO 3, toluene:

1) BFyEt10, EtSH

2) aq. NaOH

3) aq. HCl

Palladium catalyzed addition of the boronic acid ester (76) to 2-bromo-1,3,4-thiadiazole affords the ester (134). Debenzylation of boron trifluoride with etherate and ethanethiol followed by hydrolysis and protonation affords the product of Example (21).

Scheme 22

The following scheme illustrates a method of producing the compound of Example (22), which is a 5-substituted isothiazole that is effective as an LTB ₄ receptor antagonist.

Scheme 22

B (OH) ₂ known compound: rn 216971-00-5

PCT WO 9855480

PdfPPh,) ,. NaCO 3, EtOH. Κ, Ο

KjCOj. KI, DMSO,

1) 8F ₃ Et ₂ O. EtSH

2) aq. NaOH

3) aq. HCl

911 / B

Palladium catalyzed addition of bromide (58) to 3-methylisothiazole-5-boronic acid affords isothiazole (136). Alkylation of phenol (30) with base-catalyzed compound (136) affords isothiazole (138). Debenzylation of boron trifluoride with etherate and ethanethiol followed by hydrolysis and protonation affords the product of Example (22).

Scheme 23

The following scheme illustrates a method for producing the compound of Example (23), which is a 2-substituted oxazole which is effective as an LTB ₄ receptor antagonist.

'Λ! Q1 1 / R

Scheme 23

br

known compound: rn 125533--62-6

R. D. Miller et al., Chem. Mater. 1994, 6 (7). 1,023th

PdCl ₂ (dppf), CS ₃ CO ₃ , toluene-

COOMe

1) BFyEt10, EtSH

2) aq. NaOH

3) aq. HCl

Palladium catalyzed addition of boronic ester (76) to 2-bromoxazole affords oxazole (140). Debenzylation of boron trifluoride with etherate and ethanethiol followed by hydrolysis and protonation affords the product of Example (23).

Scheme 24

The following scheme illustrates a method of producing the compound of Example (24), which is a 3-substituted thiophane that is effective as an LTB ₄ receptor antagonist.

911 / B

Et ₃ SiH, TFA. benzene

Scheme 24

1) aq. NaOH

2) HCl

Reference to the method for obtaining tetrahydrothiophenes: N. N. Kursanov et al., Tetrahedron, 1975, 3t, 311.

Thiophene (114) can be reduced in the presence of triethylsilane and trifluoroacetic acid by the method of Kursanova et al. (as set forth below, the contents of which are incorporated herein by reference), providing thiophane (142). Hydrolysis and protonation of this material afforded the product of Example (24).

o i n 4 4 m

V. Preparative Examples 1 to 17

Example 1

Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-oxazol-4-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid or

Known compound: RN # 156005-61-7

R. W. Harper et al., J. Med. Chem., 1994, 37, 15, 2411-2420

A. Preparation of 1- [2-benzyloxy-4- (3-chloropropoxy) -5-ethylphenyl] ethanone

A mixture of 1- [2-hydroxy-4- (3-chloropropoxy) -5-ethylphenyl] ethanone (26.1 g, 102 mmol), cesium carbonate (33.4 g, 103 mmol) and benzyl bromide (12.2 mL, 103 mmol). in N, N-dimethylformamide (300 mL) was stirred for 5 hours at room temperature. It was then 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 hours and then cooled to 0 ° C for 3 hours. The obtained precipitate was collected via vacuum filtration to give 24.3 g (69%) of the title compound as white crystals.

Mp: 60-61 ° C.

911 / B ¹ H NMR (CDCl ₃ ) δ 7.68 (s, 1H), 7.40 (m, 5H), 6.48 (s, 1H), 5.17 (s, 2H), 4, 13 (t, J = 6Hz, 2H), 3.75 (t, J = 6Hz, 2H), 2.56 (s, 3H), 2.55 (q, J = 7Hz, 2H), 2 26 (quintet, J = 6Hz, 2H), 1.16 (t, J = 7Hz, 3H).

TOF MS ES ⁺ exact molecular weight was calculated for C 20 H 24 ClO 3 (p + 1): m / z = 347.1414.

Found: 347.1402.

IR spectral analysis (CHCl 3, cm ^-1 ) results: 1659, 1602, 1266.

Analysis for C20H23ClO3:

H, 6.68

Found: C, 69.30; H, 6.52.

known compound: RN # 152609-76-2

Sawyer et al., J. Med. Chem. 1995

38. 4411

B. Preparation of 2- {3- [3- (4-Acetyl-5-benzyloxy-2-ethyl-phenoxy) -propoxy] -2-propyl-phenoxy] -benzoic acid methyl ester

A mixture of 1- [2-benzyloxy-4- (3-chloropropoxy) -5-ethylphenyl] ethanone (7.27 g, 21.0 mmol) and sodium iodide (3.14 g, 23.1 mmol) in 2-butanone (100 mL) was added

Ft1 ft14 / Q was heated under reflux for 18 hours. The mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was dissolved in N, N-dimethylformamide (100 mL) and treated with 2- (3-hydroxy-2-propyl-phenoxy) -benzoic acid methyl ester (6.0 g, 21 mmol) and potassium carbonate (3.2 g, 23 mmol) at temperature. room for 15 hours. The mixture was diluted with ethyl acetate and washed four times with water and once with saturated sodium chloride solution. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue resulted in 9.2 g (72%) of the title compound being obtained as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 7.88 (d, J = 9Hz, 1H), 7.69 (s, 1H), 7.38 (m, 6H), 7.12 (d, J = 8Hz) 1H, 7.07 (d, J = 8Hz, 1H), 6.80 (d, J = 8Hz, 1H), 6.67 (d, J = 8Hz, 1H), 6.50 ( s, 1H), 6.44 (d, J = 9Hz, 1H), 5.14 (s, 2H), 4.20 (m, 4H), 3.83 (s, 3H), 2.65 ( t, J = 7Hz, 2H), 2.57 (q, J = 7Hz, 2H), 2.56 (s, 3H), 2.32 (quintet, J = 6Hz, 2H), 1.55 (hextet, J = 7Hz, 2H), 1.15 (t, J = 8Hz, 3H), 0.90 (t, J = 7Hz, 3H).

IR spectral analysis (CHCl ₃ , cm ^-1 ) results: 2965, 1726, 1602, 1461.

Analysis for C37H40O7:

H, 6.76

Found: C, 74.39; H, 6.77.

COOMe

C. Preparation of 2- (3- (3- [5-Benzyloxy-2-ethyl-4- (2-hydroxy-acetyl) -phenoxy] -propoxy} -2-propyl-phenoxy) -benzoic acid methyl ester

A mixture of 2- {3- [3- (4-acetyl-5-benzyloxy-2-ethyl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (5.31 g, 8.89 mmol) and water (10 mL) in acetonitrile (50 mL) was reacted with trifluoroacetic acid (1.4 mL, 18 mmol) and [bis (trifluoroacetoxy) iodo] benzene (7.65 g, 17.8 mmol). The resulting mixture was heated under reflux for 4 hours, 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 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 resulted in 11.68 g (31%) of the title compound as a brown oil.

¹ H NMR (CDCl ₃ ) δ 7.92 (s, 1H), 7.88 (d, J = 9Hz, 1H), 7.40 (m, 6H), 7.12 (d, J = 9Hz) (1H), 7.05 (d, J = 9Hz, 1H), 6.79 (d, J = 8Hz, 1H), 6.66 (d, J = 8Hz,

1H), 6.50 (s, 1H), 6.43 (d, J = 8Hz, 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, 2H), 1.55 (hextet, J = 7)

Hz, 2H), 1.17 (t, J = 8Hz, 3H), 0.89 (t, J = 8Hz, 3H).

TOS MS ES ⁺ exact molecular weight was calculated for C ₃₇ H _{8 4} as well as (p + 1): m / z = 613.2801. Found: 613.2833.

911 / B

D. Preparation of 2- {3- [3- (5-Benzyloxy-2-ethyl-4-oxazol-4-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester

To a solution of 2- (3- {3- [5-benzyloxy-2-ethyl-4- (2-hydroxy-acetyl) -phenoxy] -propoxy} -2-propyl-phenoxy} -benzoic acid methyl ester (1.39 g, 2.27 mmol) in methylene chloride ( 20 mL), which was cooled to -78 ° C, was added trifluoromethanesulfonic anhydride (0.57 mL, 3.4 mmol) and 2,6-lutidine (0.40 mL, 3.4 mmol). The organic layer was separated and washed once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was dissolved in 2: 1 formamide / N, N-dimethylformamide (9 ml) and heated to 120 ° C in a sealed tube for 4 hours, then cooled to room temperature 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 Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue resulted in 89 mg (6%) of the title product as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 7.92 (s, 1H), 7.85 (s, 1H), 7.83 (m, 2H), 7.35 (m, 6H), 7.03 (d, J = 8Hz, 1H), 7.00 (d, J = 8Hz, 1H), 6.73 (d, J = 8Hz, 1H), 6.62 (d, J = 8Hz, 1H), 6.52 (s, 1H), 6.35 (d, J = 8Hz, 1H), 5.07 (s, 2H), 4.14 (m, 4H), 3.76 (s, 3H), 2.61 (m, 4H), 2.26 (quintet, J = 6Hz, 2H), 1.48 (hextet, J = 7Hz, 2H), 1.15 (t, J = 8Hz, 3H) 0.84 (t, J = 8Hz, 3H).

COOMe

E. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-oxazol-4-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester

2- {3- [3- (5-Benzyloxy-2-ethyl-4-oxazol-4-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (89 mg, 0.14 mmol) in ethanethiol (2 mL) was reacted with boron trifluoride etherate (0.27 mL, 2.2 mmol) at room temperature for 4 hours. The resulting solution was quenched by pouring 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% hexane) of the residue resulted in 34 mg (45%) of the title product being obtained as a light brown oil.

¹ H NMR (CDCl ₃ ) δ 7.99 (d, J = 1Hz, 1H), 7.90 (d, J = 1Hz, 1H), 7.88 (dd, J =

8.2 Hz, 1H), 7.38 (t, J = 7Hz, 1H), 7.15 (s, 1H), 7.10 (d, J = 9Hz, 1H), 7.06 (d J = 9Hz, 1H), 6.81 (d, J = 9Hz, 1H), 6.70 (d, J = 9Hz, 1H), 6.52 (s, 1H), 6.44 ( d, J = 9Hz, 1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.65 (t, J = 8Hz, 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 = 8Hz, 3H).

MS ES ⁺ m / e = 532 (p + 1).

911 / B

F. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-oxazol-4-ylphenoxy) propoxy] -2-propylphenoxy} benzoic acid

To a solution of 2- {3- [3- (2-ethyl-5-hydroxy-4-oxazol-4-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (89 mg, 0.14 mmol) in methanol (2 mL) 1M lithium hydroxide solution (0.28 mL) was added and the resulting mixture was heated to 60 ° C for 3.5 hours. The mixture was cooled to room temperature and concentrated in vacuo. The aqueous residue was diluted with water and the pH was adjusted to 4.4. The mixture was extracted three times with methylene chloride. The combined organic extracts were dried (sodium sulfate) and the resulting mixture was filtered and concentrated in vacuo to afford 27 mg (92%) of the title compound as a yellow solid.

¹ H NMR (DMSO-d ₆ ) δ 12.83 (bs, 1H), 10.12 (bs, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 7.78 ( dd, J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.47 (t, J = 8 Hz, 1H), 7.16 (m, 2H), 6.80 (t, J = 8Hz, 2H), 6.56 (s, 1H), 6.35 (d, J = 8Hz, 1H), 4.20 (t, J = 6Hz, 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, 3 H), 0.80 (t, J = 8 Hz, 3 H).

TOF MS ES ⁺ exact molecular weight was calculated for C 30 H 32 NO 7 (p + 1): m / z = 518.2179. Found: 518.2206.

IR spectral analysis (KBr, cm ^-1 ): 2961, 1696, 1460, 1222.

Elemental analysis for C 30 H 31 NO 7:

H, 6.04; N, 2.71

Found: C, 68.71; H, 5.82; N, 2.65

Example 2

Preparation of 2- (3- {3- [2-ethyl-5-hydroxy-4- (3H-imidazol-4-yl) phenoxy] propoxy] -2-propylphenoxy) benzoic acid hydrochloride

Q H Π 11 / Ο

A. Preparation of 2- (3- {3- [5-benzyloxy-4- (2-chloroacetyl) -2-ethylphenoxy] propoxy} -2-propylphenoxy) benzoate

To a solution of 2- {3- [3- (4-acetyl-5-benzyloxy-2-ethyl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (3.04 g, 5.09 mmol) in tetrahydrofuran (50 mL) cooled to At -78 ° C, a 1M solution of lithium hexamethyldisilazide in tetrahydrofuran (11.2 mL, 11.2 mmol) was added in portions. After stirring for 20 minutes, trimethylsilyl chloride (2.6 mL, 20 mmol) was added, the mixture was warmed to 0 ° C and stirred for 30 minutes. Then the mixture was evaporated in vacuo and the residue was dissolved in hexane. The resulting solution was filtered and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (50 mL), cooled to 0 ° C and treated with N-chlorosuccinimide (750 mg, 5.6 mmol). The mixture was warmed to room temperature and stirred for 30 minutes and then heated at reflux for 2 hours. The mixture was cooled to room temperature and treated with water (4 mL) and a solution of 1N tetra-n-butylammonium fluoride in tetrahydrofuran (6 mL). After stirring for 15 minutes, the mixture was diluted in ether and washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue resulted in 1.94 g (60%) being obtained.

911 / B of the title compound as a white solid.

¹ H NMR (CDCl ₃ ) δ 7.89 (d, J = 8Hz, 1H), 7.77 (s, 1H), 7.40 (m, 6H), 7.12 (d, J = 9) Hz, 1H), 7.06 (d, J = 8Hz, 1H), 6.80 (d, J = 8Hz, 1H), 6.66 (d, J = 8Hz, 1H), 6.49 (s, 1H), 6.43 (d, J = 8Hz, 1H), 5.15 (s, 2H), 4.68 (s, 2H), 4.20 (q, J = 6Hz, 4H) ), 3.82 (s, 3H), 2.65 (t, J = 7Hz, 2H), 2.59 (q, J = 7Hz, 2H), 2.32 (quintet, J = 6Hz, 2H), 1.54 (hextet, J = 8Hz, 2H), 1.16 (t, J = 8Hz, 3H), 0.89 (t, J = 7Hz, 3H).

TOF MS ES ⁺ exact molecular weight was calculated for C 37 H 40 ClO 7 (p + 1): m / z = 631.2463. Found: 631.2470.

IR spectral analysis (CHCl ₃ , cm ^-1 ) results: 2964, 1720, 1603, 1461.

Analysis for C37H39ClO7

Calculated: C 70.41 H 6.23

Found: C, 70.04; H, 5.97.

B. Preparation of 2- (3- {3- [5-Benzyloxy-4- (2-benzylsulfanyl-3H-imidazol-4-yl) -2-ethyl-phenoxy] -propoxy} -2-propyl-phenoxy} -benzoic acid methyl ester

911 / B

A mixture of 2- (3- {3- [5-benzyloxy-4- (2-chloroacetyl) -2-ethyl-phenoxy] -propoxy} -2-propyl-phenoxy} -benzoic acid methyl ester (800 mg, 1.27 mmol), 2-benzyl-2 hydrochloride thiopseudoureas (313 mg, 1.52 mmol), sodium iodide (77 mg, 0.51 mmol) and potassium carbonate (700 mg, 5.06 mmol) in N, N-dimethylformamide (20 mL) were allowed to react for 6 hours The mixture was cooled, diluted with diethyl ether and washed once with water, and the organic layer was dried (sodium sulfate), filtered and concentrated in vacuo to give a residue which was chromatographed (silica gel, 30% ethyl acetate / 70% hexane). This gave 376 mg (40%) of the title compound as a yellow amorphous solid.

¹ H NMR (CDCl ₃ ) δ 7.89 (d, J = 8Hz, 1H), 7.36 (m, 9H), 7.20 (m, 5H), 7.21 (d, J = 9Hz) (1H), 7.06 (d, J = 8Hz, 1H), 6.79 (d, J = 8Hz, 1H), 6.67 (d, J = 8Hz, 1H), 6.55 ( s, 1H), 6.43 (d, J = 8Hz, 1H), 5.07 (s, 2H), 4.21 (t, J = 6Hz, 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 = 7Hz, 2H), 1.18 (t, J = 8Hz, 3H), 0.90 (t, J = 7Hz, 3H).

TOF MS ES ⁺ exact molecular mass calculated for C 45 H 47 N 2 O 6 S (p + 1): m / z = 743.3155. Found: 743.3142.

IR spectral analysis (CHCl 3, cm ^-1 ) results: 2963, 1720, 1602, 1453.

Analysis for C45H46N2O6S:

H, 6.24; N, 3.77

Found: C 72.69 H 6.17 N 3.56.

911 / B

100

C. Preparation of 2- (3- {3- [4- (2-Benzylsulfanyl-3H-imidazol-4-yl) 2-ethyl-5-hydroxyphenoxy] propoxy} -2-propylphenoxy) benzoate

2- (3- (3- [5-Benzyloxy-4- (2-benzylsulfanyl-3H-imidazol-4-yl) -2-ethyl-phenoxy] -propoxy) -2-propyl-phenoxy) -benzoic acid methyl ester solution (360 mg, 0.49 mmol) ) in ethanol (7 ml) was reacted with boron trifluoride etherate at room temperature for 3.5 hours. The mixture was diluted with diethyl ether and water. The organic layer was separated and washed with saturated sodium bicarbonate solution, dried (sodium sulfate), filtered and concentrated in vacuo. Chromatography (silica gel, 20% ethyl acetate / 80% hexane) of the residue resulted in 154 mg (48%) of the title compound as an orange oil.

¹ H NMR (CDCl ₃ ) δ 7.85 (d, J = 8Hz, 1H), 7.36 (t, J = 7Hz, 1H), 7.20 (m, 7H), 7.12 (s (1H), 7.05 (m, 3H), 6.79 (d, J = 8Hz, 1H), 6.65 (d, J = 8Hz, 1H), 6.54 (s, 1H), 6.41 (d, J = 8Hz, 1H), 4.20 (s, 2H), 4.17 (m, 4H), 3.82 (s, 3H), 2.62 (t, J = 8) Hz, 2H), 2.54 (q, J = 7Hz, 2H), 2.30 (quintet, J = 6Hz, 2H), 1.53 (hextet, J = 8Hz, 2H), 1.14 (t, J = 7Hz, 3H), 0.89 (t, J = 8Hz, 3H).

TOF MS ES ⁺ exact molecular weight was calculated for C _3-8 H ₄ IN ₂ O ₆ S (p + 1): m / z = 653.2685. Found: 653.2669.

Analysis for C3 ₈ H4 ₀ N ₂ O ₆ S:

911 / B

101

H, 6.18; C, 69.92;

N, 4.29

Found: C, 69.44; H, 6.25

N, 3.99.

D. Preparation of 2- (3- {3- [2-ethyl-5-hydroxy-4- (3-imidazol-4-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid hydrochloride

A solution of 2- (3- {3- [4- (2-benzylsulfanyl-3H-imidazol-4-yl) -2-ethyl-5-hydroxy-phenoxy] -propoxy} -2-propyl-phenoxy} -benzoic acid methyl ester (154 mg, 0.235 mmol) in methanol (3 mL) was treated with 1N lithium hydroxide solution at 60 ° C for 3.5 hours, cooled to room temperature and concentrated in vacuo, diluted with water and adjusted to pH 4. The aqueous solution was then extracted three times with methylene chloride, the combined organic layers were dried (sodium sulfate), the resulting mixture was filtered and concentrated in vacuo, the residue dissolved in ethanol (3 mL) and treated with 0.2 N sodium hydroxide solution (1 mL). ) and Raney Nickel (75 mg) at 75 ° C for 4 hours The mixture was cooled to room temperature, filtered through Celite ™, and the filtrate was concentrated in vacuo, the residue diluted with water and the pH of the solution adjusted

911 / B

102 to pH = 2 with 1N hydrochloric acid. The obtained precipitate was collected by vacuum filtration to give 27 mg (21%) of the title compound.

TOF MS ES ⁺ exact molecular weight was calculated for C 30 H 33 N 2 O 6 (p + 1): m / z = 517.2339. Found: 517.2340.

Example 3

Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiazol-4-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid

A. Preparation of 2- {3- [3- (5-Benzyloxy-2-ethyl-4-thiazol-4-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester

A mixture of 2- (3- {3- [5-benzyloxy-4- (2-chloroacetyl) -2-ethyl-phenoxy] -propoxy} -2-propyl-phenoxy} -benzoic acid methyl ester (500 mg, 0.792 mmol), thioformamide (20 mL, 8.0) mmol) and magnesium carbonate in dioxane (10 mL) was heated at reflux for 2 hours, then cooled to room temperature and diluted with diethyl ether and shaken with 0.2 M sodium hydroxide solution. The organic layer was separated, washed with saturated brine. 4 / d

103 of sodium, dried (sodium sulfate), filtered and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue resulted in 254 mg (50%) of the title compound being obtained as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 8.91 (s, 1H), 8.11 (s, 1H), 7.87 (dd, J = 8.1 Hz, 1H), 7.84 (d, J = 1 Hz, 1H), 7.40 (m, 6H), 7.08 (m, 2H), 6.80 (d, J = 8Hz, 1H), 6.68 (d, J = 8Hz, 1H) ), 6.62 (s, 1H), 6.43 (d, J = 8Hz, 1H), 5.16 (s, 2H), 4.21 (t, J = 6Hz, 4H), 3, 83 (s, 3H), 2.68 (m, 4H), 2.32 (quintet, J = 6Hz, 2H), 1.56 (hextet, J = 8Hz, 2H), 1.21 (t, J = 7Hz, 3H), 0.90 (t, J = 7Hz, 3H).

TOF MS ES ⁺ exact molecular mass calculated for C ₃₈ H ₄₀ NO ₆ S (p + 1): m / z = 638.2576. Found: 638.2579.

IR spectral analysis (CHCl ₃ , cm ^-1 ) results: 2964, 1719, 1563, 1461.

B. Preparation of 2- {3- [3- (2-Ethyl-5-hydroxy-4-thiazol-4-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester

A solution of 2- {3- [3- (5-benzyloxy-2-ethyl-4-thiazol-4-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (243 mg, 0.366 mmol) in ethanol (7 mL) was added to reaction with boron trifluoride etherate at room temperature for 4 hours. The mixture was diluted with diethyl ether, washed once with water, once with saturated sodium bicarbonate solution, dried (sodium sulfate), filtered and concentrated in vacuo. Chromatography (silica gel, 15% ethyl acetate / 85% hexane)

911 / B

104 of the residue resulted in 131 mg (65%) of the title compound as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 8.88 (d, J = 1Hz, 1H), 7.88 (dd, J = 8.1Hz, 1H), 7.44 (d, J = 1Hz, 1H) ), 7.38 (m, 2H), 7.08 (m, 2H), 6.81 (d, J = 8Hz, 1H), 6.68 (d, J = 8Hz, 1H), 6, 55 (s, 1H), 6.43 (d, J = 8Hz, 1H), 4.21 (t, J = 6Hz, 4H), 3.83 (s, 3H), 2.63 (m, 4H), 2.33 (quintet, J = 6Hz, 2H), 1.56 (hextet, J = 8Hz, 2H), 1.19 (t, J = 8Hz, 3H), 0.91 (t , J = 7 Hz, 3H).

TOF MS ES ⁺ exact molecular mass calculated for C ₃₁ H ₃₄ NO ₆ S (p + 1): m / z = 548.2107. Found: 548.2085.

C. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiazol-4-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid

A solution of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiazol-4-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (130 mg, 0.236 mmol) in methanol (4 mL) was added to methanol. reaction with 1 M lithium hydroxide solution at 64 ° C for 3 hours. The mixture was cooled to room temperature, concentrated in vacuo and diluted with water. The resulting solution was adjusted to pH = 4 and extracted three times with methylene chloride. The combined organic layers were dried (sodium sulfate), the resulting mixture was filtered and concentrated in vacuo. The residue was dissolved in a minimum of methylene chloride and hexane was added until the solution became cloudy. mixture

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105 was concentrated slowly in vacuo to afford 96 mg (76%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 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 = 8Hz, 1H), 6.71 (d, J = 8Hz, 1H), 6.62 (d, J = 8Hz, 1H), 6.54 (s, 1H), 4.25 (t, J = 6Hz, 2H), 4.22 (t, J = 6Hz, 2H), 2.59 (m, 4H),

2.35 (quintet, J = 6Hz, 2H), 1.50 (hextet, J = 8Hz, 2H), 1.19 (t, J = 7Hz, 3H), 0.88 (t, J = 8 Hz, 3H).

TOF MS ES ⁺ exact molecular weight was calculated for C 30 H 32 NO 6 S (p + 1): m / z = 534.1950. Found: 534.1957.

IR spectral analysis (CHCl ₃ , cm ^-1 ) results: 2965, 1738, 1454.

Analysis for C30H31NO6S:

H, 5.86; N, 2.62

Found: C, 67.19; H, 5.72; N, 2.53.

Example 4

Preparation of 2- (3- {3- [2-ethyl-5-hydroxy-4- (2H-pyrazol-3-yl) phenoxy] propoxy} 2-propylphenoxy) benzoic acid

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106

A. Preparation of 2- (3- {3- [5-Benzyloxy-4- (3-dimethylamino-acryloyl) -2-ethyl-phenoxy] -propoxy} -2-propyl-phenyl} -benzoic acid methyl ester

A mixture of 2- (3- {3- [4-acetyl-5-benzyloxy-2-ethyl-phenoxy] -propoxy} -2-propyl-phenoxy} -benzoic acid methyl ester (3.07 g, 5.04 mmol) and dimethylformamide dimethyl acetal (0.9 mL, 7 mmol) in Ν, Ν-dimethylformamide (3 mL) was heated at 110-120 ° C for 35 hours The mixture was cooled to room temperature and diluted with ethyl acetate and 1N hydrochloric acid The organic layer was separated, washed twice with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo.The chromatography (silica gel, 30% ethyl acetate / 70% hexane to ethyl acetate) of the residue resulted in 2.1 g (63%) of the title compound being obtained as yellow oil.

TOF MS ES ⁺ exact molecular mass calculated for C 40 H 46 NO 7 (p + 1): m / z = 652.3274. Found: 652.3270.

IR spectral analysis (CHCl ₃ , cm ^-1 ) results: 2965, 1720, 1605.

Analysis for C40H45NO7:

H, 6.96; N, 2.15

Found: C 73.72 H 6.95 N 2.18.

107

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-dimethylamino-acryloyl) -2-ethyl-phenoxy] -propoxy) -2-propyl-phenoxy) -benzoic acid methyl ester (550 mg, 0.843 mmol) in methanol (30 mL) was added. was reacted with 1M lithium hydroxide solution at 60 ° C for 3 hours. The mixture was cooled to room temperature and diluted with ethyl acetate and 0.5 M hydrochloric acid. The organic layer was separated, washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was dissolved in methanol (15 mL) and treated with water (4 mL) and hydrazine monohydrate (0.50 mL, 7.7 mmol) under reflux for 3 hours. The mixture was diluted with ethyl acetate and 1N 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 resulted in 350 mg (65%) of the title compound being obtained as the acetate salt. A portion of this material was basified with sodium bicarbonate to give an analytical sample.

¹ H NMR (CDCl ₃ ) δ 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 = 8Hz, 1H), 6.65 (d, J = 8Hz, 1H), 6.61 (d, J = 8Hz, 1H) ), 6.58 (s, 1H), 6.55 (bs, 1H), 5.18 (s, 2H), 4.22 (t, J = 6Hz, 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 = 7Hz, 3H), 0.88 (t, J = 8Hz, 3H).

TOF MS ES ⁺ exact molecular mass calculated for C 37 H 39 N 2 O 6 (p + 1): m / z = 607.2808. Found: 607.2831.

IR spectral analysis (CHCl ₃ , cm ^-1 ) results: 2965, 1739, 1604, 1454.

Analysis for C37H38N2O6:

H, 6.31; N, 4.62

Found: C 73.31 H 6.30 N 4.62.

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108

C. Preparation of 2- (3- {3- [2-ethyl-5-hydroxy-4- (2H-pyrazol-3-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid

A solution of 2- (3- {3- [5-benzyloxy-2-ethyl-4- (2H-pyrazol-3-yl) phenoxy] propoxy} -2-propylphenoxy} benzoic acid (300 mg, 0.490 mmol) in ethanethiol ( 2.5 ml) was reacted with boron trifluoride etherate (2 ml) at room temperature for 3 hours at which time an additional portion of boron trifluoride etherate (1 ml) was added, the reaction mixture was stirred for an additional 1 hour and then diluted with diethyl ether and water. layer was separated, washed with water, dried (sodium sulfate), filtered and concentrated in vacuo Chromatography (silica gel, 15% ethyl acetate / 85% hexane to 60% ethyl acetate / 40% hexane) of the residue resulted in the title compound being obtained in amount of 60 mg (24%) as a white solid.

¹ H NMR (CDCl ₃ ) δ 8.23 (d, J = 8Hz, 1H), 7.61 (s, 1H), 7.42 (t, J = 7Hz, 1H), 7.30 ( s, 1H), 7.19 (d, J = 8Hz, 1H), 7.15 (d, J = 8Hz, 1H), 6.81 (d, J = 8Hz, 1H), 6.69 (d, J = 8Hz, 1H), 6.61 (s, 1H), 6.60 (d, J = 8Hz, 1H), 6.54 (s, 1H), 5.20 (m, 4H) ), 2.58 (m, 4H), 2.33 (quintet, J = 6 Hz, 2H), 1.48 (hextet, J = 8 Hz, 2H), 1.17 (t, J = 8 Hz, 3H), 0.86 (t, J = 7Hz, 3H).

TOF MS ES ⁺ exact molecular weight was calculated for C 30 H 33 N 2 O 6 (p + 1): m / z = 517.2339. Found: 517.2334.

^ 1 Q11 / R

109

IR spectral analysis (CHCl 3, cm ^-1 ) results: 2965, 1738, 1454.

Analysis for C ₃ 0 _{6 2} oH32N: calculated: C, 69.75 H, 6.24 N, 5.42 found: C, 69.73 H, 6.33 N, 5.25.

Example 5

Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-isoxazol-5-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid

A. Preparation of 2- {3- [3- (5-Benzyloxy-2-ethyl-4-isoxazol-5-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester

A mixture of 2- (3- {3- [5-benzyloxy-4- (3-dimethylamino-acryloyl) -2-ethyl-phenoxy] -propoxy} -2-propyl-phenoxy) -benzoic acid methyl ester (280 mg, 0.43 mmol) and hydroxylamine hydrochloride (75 mg). mg, 1.1 mmol) and water (1 mL) in methanol (4 mL) was heated under reflux for 2 hours. It was then cooled to room temperature and diluted with diethyl ether and water. The organic layer was separated, washed with saturated sodium chloride solution, dried (sodium sulfate),

911 / B

110 was filtered and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue resulted in 202 mg (76%) of the title compound being obtained as a white solid.

¹ H NMR (CDCl ₃ ) δ 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, 2H), 6.68 (d, J = 8Hz, 1H), 6.59 (s, 1H), 6.5 (s, 1H), 6.43 (d, J = 8Hz, 1H), 5.15 (s, 2H), 4.21 (t, J = 6Hz, 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 = 7Hz, 3H).

TOF MS ES ⁺ exact molecular mass calculated for C 38 H 40 NO 7 (p + 1): m / z = 622.2805. Found: 622.2817.

IR spectral analysis (CHCl 3, cm ^-1 ) results: 2964, 1720, 1461.

Analysis for C38H39NO7:

Calculated: C 73.41 H 6.32

N, 2.25

Found: C, 73.20; H, 6.34

N, 2.27.

B. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-isoxazol-5-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester

A solution of 2- {3- [3- (5-benzyloxy-2-ethyl-4-isoxazol-5-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (180 mg, 0.289 mmol) in ethanol (5 mL) was added to Reaction with boron trifluoride etherate (1.5 mL) at room temperature

Q11 / R

At room temperature for 2 hours, an additional portion of boron trifluoride etherate (0.5 mL) was added and stirring was continued for an additional hour. The mixture was then 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), filtered and concentrated in vacuo. Chromatography (silica gel, 15% ethyl acetate / 85% hexane) of the residue resulted in 94 mg (61%) of the title compound being obtained as a colorless oil.

¹ H NMR (CDCl 3) δ 8.28 (d, J = 1Hz, 1H), 7.88 (dd, J = 8.2Hz, 1H), 7.38 (t, J = 8Hz, 1H) 7.36 (s, 1H), 7.08 (t, J = 8Hz, 1H), 7.05 (d, J = 8Hz, 1H), 6.81 (d, J = 8Hz, 1H) ), 6.67 (d, J = 8Hz, 1H), 6.50 (s, 1H), 6.45 (s, 1H), 6.43 (d, J = 8Hz, 1H), 4, 20 (m, 4H), 3.83 (s, 3H), 2.62 (m, 4H), 2.34 (quintet, J = 6Hz, 2H), 1.54 (hextet, J = 8Hz, 2H), 1.18 (t, J = 8Hz, 3H), 0.90 (t, J = 7Hz, 3H).

TOF MS ES ⁺ exact molecular mass calculated for C ₃₁ H ₃₄ NO ₇ (p + 1): m / z = 532.2335. Found: 532.2335.

IR spectral analysis (CHCl ₃ , cm ^-1 ) results: 2964, 1715, 1601, 1461.

Analysis for C ₃₁ H ₃₃ NO ₇ :

Calculated: C 70.04

Found: C, 70.13

H, 6.26; N, 2.63

H, 6.35. N, 2.63.

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112

C. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-isoxazol-5-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid

To a solution of 2- {3- [3- (2-ethyl-5-hydroxy-4-isoxazol-5-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (94 mg, 0.18 mmol) in methanol (3 mL) 1M lithium hydroxide solution (1 mL) was added and the resulting mixture was heated to 60 ° C for 3 hours. The mixture was cooled to room temperature and concentrated in vacuo. The aqueous residue was diluted with water and the pH was adjusted to about 4. The mixture was extracted three times with methylene chloride. The combined organic layers were dried (sodium sulfate) and the resulting mixture was filtered and concentrated in vacuo to give 12 mg (13%) of the title compound as an off-white amorphous solid.

¹ H NMR (CDCl 3) δ 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 = 8Hz, 1H), 7.15 (d, J = 8Hz, 1H), 7.02 (bs, 1H), 6.80 (d, J = 8Hz, 1H), 6.69 (d, J = 8Hz, 1H), 6.60 (d, J = 8Hz, 1H), 6.50 (s, 1H),

6.46 (s, 1H), 4.22 (t, J = 6Hz, 2H), 4.19 (t, J = 6Hz, 2H), 2.57 (m, 4H), 2.34 ( quintet, J = 6Hz, 2H), 1.47 (hextet, J = 8Hz, 2H), 1.16 (t, J = 8Hz, 3H), 0.85 (t, J = 7Hz, 3H) ).

TOS MS ES ⁺ exact molecular weight was calculated for C ₃ oH ₃₂ N07 (p + 1): m / z = 518.2179. Found: 518.2175.

Analysis for Ο ₃₀ Η ₃ ιΝΟ ₇ :

H, 6.04; N, 2.71

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-propylphenoxy} benzoic acid

911 / B

113

A. Preparation of 2- {3- [3- (5-Benzyloxy-4-bromo-2-ethyl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester

A mixture of 5-benzyloxy-4-bromo-1- (3-chloropropoxy) -2-ethylbenzene methyl ester (1.19 g, 3.11 mmol), 2- (3-hydroxy-2-propylphenoxy) benzoic acid (0.89 g, 3.1 mmol), potassium carbonate (1.29 g, 9.34 mmol), potassium iodide (0.52 g, 3.1 mmol) and methylsulfoxide (2 mL) in 2-butanone (20 mL) were heated under reflux for 48 hours. It was then 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 the residue resulted in the title compound being obtained in an amount of 1.34 g (68%) as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 7.91 (dd, J = 8.2 Hz, 1H), 7.50 (d, J = 7 Hz, 2H), 7.38 (m, 5H), 7.15 (d, J = 8Hz, 1H), 7.10 (d, J = 8Hz, 1H), 6.83 (d, J = 8Hz, 1H), 6.71 (d, J = 8Hz, 1H), 6.55 (s, 1H), 6.48 (d, J = 8Hz, 1H), 5.16 (s, 2H), 4.21 (t, J = 6Hz, 2H), 4 15 (t, J = 6Hz, 2H), 3.83 (s, 3H), 2.68 (t, J = 8Hz, 2H), 2.58 (q, J = 7Hz, 2H), 2.31 (quintet, J = 6Hz, 2H), 1.58 (hextet, J = 6Hz, 2H), 1.17 (t, J = 7Hz, 3H), 0.93 (t, J = 7 Hz, 3H).

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114

B. Preparation of 2- {3- [3- (5-Benzyloxy-2-ethyl-4-ethynyl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester

A mixture of 2- {3- [3- (5-benzyloxy-4-bromo-2-ethyl-phenoxy) -propoxy] -2-propyl-phenoxy) -benzoic acid methyl ester (1.50 g, 2.37 mmol) in tri-n-butylethyltin ( 0.82 mL, 2.8 mmol) and tetrakis (triphenylphosphine) palladium (1.0 g, 0.95 mmol) in N, N-dimethylformamide (25 mL) were purged with argon and heated in a sealed tube at 120 ° C for 24 hours . The mixture was then cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate, shaken 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 resulted in the title compound being obtained in an amount of 532 mg (39%) as a brown oil.

¹ H NMR (CDCl ₃ ) δ 7.88 (dd, J = 8.2 Hz, 1H), 7.79 (s, 1H), 7.20-7.50 (m, 6H), 7.10 ( d, J = 8Hz, 1H), 7.05 (d, J = 8Hz, 1H), 6.80 (d, J = 8Hz, 1H), 6.66 (d, J = 8Hz, 1H), 6.43 (m, 2H), 5.16 (s, 2H), 4.17 (t, J = 6Hz, 2H), 4.11 (t, J = 6Hz, 2H), 3 .83 (s, 3H), 3.23 (s, 1H), 2.64 (t, J = 8Hz, 2H), 2.53 (q, J = 7Hz, 2H), 2.27 (quintet) J = 6 Hz, 2H), 1.53 (m, 2H), 1.13 (t, J = 7Hz, 3H), 0.89 (t, J = 7Hz, 3H).

TOF MS ES ⁺ exact molecular mass calculated for C ₃₇ H ₃ gO ₆ (p + 1): m / z = 579.2747. Found: 579.2739.

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115

C. Preparation of 2- (3- {3- [5-Benzyloxy-2-ethyl-4- (3H [1,2,3] triazol-4-yl) phenoxy] propoxy} -2-propylphenoxy) benzoate

A mixture of 2- {3- [3- (5-benzyloxy-2-ethyl-4-ethynyl-phenoxy) -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) and in a sealed tube at 130 ° C for 120 hours. Then the mixture was cooled to room temperature and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate / 90% hexane to 50% ethyl acetate / 50% hexane) of the residue resulted in 347 mg (88%) calculated as conversion of the starting compound) of the title compound as a brown solid.

¹ H NMR (CDCl 3) δ 8.10 (bs, 1H), 7.89 (dd, J = 8.2 Hz, 2H), 7.76 (s, 1H), 7.40 (m, 7H), 7.10 (d, J = 8Hz, 1H), 7.05 (d, J = 8Hz, 1H), 6.79 (d, J = 8Hz, 1H), 6.67 (d, J) = 8 Hz, 1H), 6.62 (s, 1H), 6.43 (d, J = 8Hz, 1H), 5.18 (s, 2H), 4.21 (m, 4H), 3, 82 (s, 3H), 2.65 (m, 4H), 2.32 (quintet, J = 6Hz, 2H), 1.56 (hextet, J = 8Hz, 2H), 1.21 (t, J = 8Hz, 3H), 0.90 (t, J = 7Hz, 3H).

TOF MS ES ⁺ exact molecular weight was calculated for C 37 H 40 N 3 O 6 (p + 1): m / z = 622.2917. Found: 622.2946.

IR spectral analysis (CHCl ₃ , cm ^-1 ) results: 3400, 1721, 1602, 1453.

Analysis for C3 ₇ H _{3 9} N ₃ O6:

H, 6.32; N, 6.76

Found: C 70.28 H 6.07 N 6.54.

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D. Preparation of 2- {3- {3- [2-ethyl-5-hydroxy-4- {3H [1,2,3] triazole-> methyl ester

4-yl) phenoxy] propoxy} -2-propyl-phenoxy) benzoic acid

2- (3- {3- [5-Benzyloxy-2-ethyl-4- (3H [1,2,3] triazol-4-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester solution (330 mg) , 0.531 mmol) in ethanethiol (9 mL) was reacted with boron trifluoride etherate (2.0 mL, 16 mmol) at room temperature for 1 hour and then with an additional portion of boron trifluoride etherate (1.0 mL) for 1 hour. 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 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 yielded 180 mg (63%) of the title compound as a brown solid.

¹ H NMR (CDCl ₃ ) δ 7.97 (s, 1H), 7.88 (dd, J = 8.2 Hz, 1H), 7.37 (t, J = 8 Hz, 1H), 7.31 (s, 1H), 7.10 (d, J = 8Hz, 1H), 7.05 (d, J = 8Hz, 1H), 6.81 (d, J = 8Hz, 1H), 6, 67 (d, J = 8Hz, 1H), 6.59 (s, 1H), 6.43 (d, J = 8Hz, 1H), 4.20 (m, 4H), 3.83 (s) s, 3H), 2.63 (m, 4H), 2.34 (quintet, J = 6Hz, 2H), 1.55 (hextet, J = 8Hz, 2H), 1.19 (t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H).

TOF MS ES ⁺ exact molecular weight was calculated for C 30 H 34 N 3 O 6 (p + 1): m / z = 532.2447. Found: 532.2466.

IR spectral analysis (CHCl ₃ , cm ^-1 ) results: 2964, 1718, 1453.

Elemental analysis for C 30 H 33 N 3 O 6:

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H, 6.26

N, 7.90

Found: C, 66.80; H, 6.02

N, 7.53.

E. Preparation of 2- (3- {3- [2-ethyl-5-hydroxy-4- {3H [1,2,3] triazol-4-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid

2- (3- {3- [2-Ethyl-5-hydroxy-4- (3H [1,2,3] triazole-) methyl ester solution]

4-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid (160 mg, 0.30 mmol) in methanol (5 mL) was treated with 1N lithium hydroxide solution (1 mL) at 60 ° C for 3.5 h. , 5 ml). The mixture was cooled to room temperature, diluted with water and adjusted to pH = 4. The resulting mixture was extracted three times with methylene chloride. The combined organic extracts were dried (sodium sulfate) and the mixture was filtered and concentrated in vacuo to afford 134 mg (86%) of the title compound as a tan solid.

¹ H NMR (DMSO-d 6) δ 14.98 (bs, 1H), 12.80 (bs, 1H), 10.02 (bs, 1H), 8.17 (bs,

1H), 7.77 (dd, J = 7.2Hz, 1H), 7.60 (bs, 1H), 7.47 (t, J = 8Hz, 1H), 7.18 (t, J =

Hz, 1H), 7.19 (t, J = 8Hz, 1H), 6.82 (d, J = 8Hz, 1H), 6.68 (d, J = 8Hz, 1H),

6.57 (s, 1H), 6.35 (d, J = 8Hz, 1H), 4.22 (t, J = 6Hz, 2H), 4.15 (t, J = 6Hz, 2H) .

2.54 (m, 4H), 2.25 (quintet, J = 6Hz, 2H), 1.45 (hextet, J = 8Hz, 2H), 1.11 (t, J

911 / B

118 = 7 Hz, 3H), 0.81 (t, J = 7 Hz, 3H).

TOF MS ES ⁺ exact molecular weight was calculated for C ₂₉ H ₁₂ N ₃ O 6 (p + 1): m / z = 518.2291. Found: 518.2302.

IR spectral analysis (CHCl ₃ , cm ^-1 ) results: 2965, 1738, 1454.

Analysis for Ο ₂₉ Η ₃ ιΝ ₃ Ο ₆ : Calculated: C 67.30 H, 6.04 N, 8.12 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-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester

A. Preparation of 5-benzyloxy-2-ethyl-4-pyrrol-1-yl-phenol

At room temperature, a solution of 4-ethylbenzene-1,3-diol (10.0 g, 2 g) was added to a mixture of potassium nitrosodisulfonate (40.0 g, 149 mmol) and potassium hydrogen phosphate (10 g) in water (1.2 L). , 37 mmol) and potassium hydrogen phosphate (10.5 g) in water (150 mL). The mixture was stirred for 15 minutes and the pH was adjusted to pH = 3. The resulting solution was extracted three times with diethyl ether. The organic 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-pyroline (12 mL). The resulting mixture was stirred for 1 hour and concentrated in vacuo,

Q11 / R

119 was dissolved in ethyl acetate and hexane and filtered through 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 hours. The resulting 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 resulted in the title compound 316 mg (2%).

TOF MS ES ⁺ exact molecular weight was calculated for C 19 H 20 NO 2 (p + 1): m / z = 294.1494. Found: 294.1471.

B. Preparation of 1- [2-benzyloxy-4- (3-chloropropoxy) -5-ethylphenyl] -1H-pyrrole ci

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-dimethylformamide (5 mL) was stirred at room temperature for 18 hours. It was then diluted with ethyl acetate and water, washed four times with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. Chromatography (silica gel, 5% ethyl acetate / 95% hexane) of the residue resulted in the title compound 314 mg (79%) as a colorless oil.

TOF MS ES ⁺ exact molecular mass calculated for C22H25NCIO2 (p + 1):

m / z = 370.1574. Found: 370.1548.

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120

C. Preparation of 2- {3- [3- (5-Benzyloxy-2-ethyl-4-pyrrol-1-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl 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 mmol) in 2-butanone ( 5 ml) was heated under reflux for 6 hours. Then the mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was dissolved in N, N-dimethylformamide (7 mL) and treated with 2- (3-hydroxy-2-propyl-phenoxy) -benzoic acid methyl ester (242 mg, 0.85 mmol) and potassium carbonate (129 mL) at room temperature for 15 h. g, 93 mmol). The mixture was diluted with ethyl acetate and water, washed four times with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. Chromatography (silica gel, 5% ethyl acetate / 95% hexane) of the residue resulted in 196 mg (37%) of the title compound as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 7.86 (dd, J = 8.2 Hz, 1H), 7.37 (dt, J = 8.2 Hz, 1H), 7.30 (m, 5H), 7 07 (m, 3H), 6.84 (m, 2H), 6.79 (d, J = 8Hz, 1H), 6.65 (d, J = 8Hz, 1H), 6.58 (s 1 H, 6.42 (d, J = 8 Hz, 1 H), 6.29 (m, 2H), 4.92 (s, 2 H), 4.17 (t, J = 6 Hz, 2 H), 4.15 (t, J = 6Hz, 2H), 3.83 (s, 3H), 2.65 (t, J = 8Hz, 2H), 2.58 (q, J = 7Hz, 2H) 2.30 (quintet, J = 6Hz, 2H), 1.55 (hextet, J = 8Hz, 2H), 1.16 (t, J = 7Hz, 3H), 0.80 (t, J = 7 Hz, 3H).

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121

TOF MS ES ⁺ exact molecular weight was calculated for C 39 H 42 NO 6 (p + 1): m / z = 620.3012. Found: 620.3021.

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-propyl-phenoxy} -benzoic acid methyl ester (195 mg, 0.315 mmol) in ethanol (15 mL) was added to Reaction with boron trifluoride etherate (1.3 mL, 9.5 mmol) at room temperature for 2.5 hours. The mixture was diluted with diethyl ether and water. The organic layer was washed with saturated sodium bicarbonate solution, dried (sodium sulfate), filtered and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue resulted in 39 mg (23%) of the title compound being obtained as a colorless oil.

¹ H NMR (CDCl 3) δ 7.89 (d, J = 8Hz, 1H), 7.37 (t, J = 8Hz, 1H), 7.07 (m, 2H), 6.98 (s, 1H), 6.68 (m, 3H), 6.65 (d, J = 8Hz, 1H), 6.57 (s, 1H), 6.42 (d, J = 8Hz, 1H), 6 35 (m, 2H), 5.04 (bs, 1H), 4.19 (m, 2H), 3.83 (s, 3H), 2.64 (t, J = 8Hz, 2H), 2 58 (q, J = 7Hz, 2H), 2.32 (quintet, J = 6Hz, 2H), 1.55 (m, 2H), 1.14 (t, J = 7Hz, 3H), 0.90 (t, J = 7Hz, 3H).

TOF MS ES ⁺ exact molecular mass calculated for C ₃ 2H ₃ 6NO ₆ (p + 1):

m / z = 530.2543. Found: 530.2516.

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122

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

A. Preparation of 2- (3- {3- [5-benzyloxy-2-ethyl-4- (4,4,5,5 tetramethyl [1,3,2] dioxaborolan-2-yl) phenoxy] propoxy} methyl ester -2-propyl-phenoxy) benzoic acid

A mixture of 2- {3- [3- (5-benzyloxy-4-bromo-2-ethyl-phenoxy) -propoxy] -2-propyl-phenoxy) -benzoic acid methyl ester (8.30 g, 13.1 mmol) in triethylamine (5.2 mL) , 39 mmol) and PdCl ₂ (dppf) (320 mg, 0.39 mmol) in deoxygenated toluene (80 mL) was reacted in tetrahydrofuran with a 1M solution of 4,4,5,5-tetramethyl [1,3,2 Dioxaborolane (20 mL, 20 mmol) and heated at reflux for 6 hours. The mixture was filtered through a short column of silica gel and the filtrate was concentrated in vacuo. Chromatography (silica gel, 35% ethyl acetate / 65% hexane) of the residue resulted in a dark oil which was subjected to further chromatography (silica gel, hexane to 30% ethyl acetate / 70% hexane) to give 7.70 g (84%). %) of the title compound.

¹ H NMR (CDCl 3) δ 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 = 8Hz, 1H), 7.09 (d, J = 9Hz, 1H), 7.04 (d, J = 9)

Hz, 1H), 6.79 (d, J = 9Hz, 1H), 6.66 (d, J = 9Hz, 1H), 6.47 (s, 1H), 6.43 (d, J =

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123

Hz, 1H), 5.07 (s, 2H), 4.18 (m, 4H), 3.81 (s, 3H), 2.64 (t, J = 8 Hz, 2H), 2.56 (s) q, J = 7Hz, 2H), 2.30 (quintet, J = 6Hz, 2H), 1.53 (hextet, J = 8Hz, 2H), 1.34 (s, 12H), 1.14 (t, J = 7Hz, 3H), 0.89 (t, J = 7Hz, 3H).

TOF MS ES ⁺ exact molecular weight was calculated for C ₄₁ H ₅₃ NBO ₈ (p + NH ₄ ): m / z = 698.3864. Found: 698.3889.

IR spectral analysis (CHCl 3, cm ^-1 ) results: 2964, 1720, 1604, 1453.

Analysis for C41H49BO8:

H, 7.26

Found: C, 72.30; H, 7.12.

B. Preparation of 2- (3- {3- [5-Benzyloxy-4- (3-bromo [1,2,4] thiadiazol-5-yl) -2-ethyl-phenoxy] -propoxy} -2-propyl-phenoxy) -benzoic acid methyl ester

2- (3- (3- [5-Benzyloxy-2-ethyl-4- {4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenoxy] propoxy} -2- methyl ester mixture propylphenoxy) benzoic acid (310 mg, 0.46 mmol), 3-bromo-5-chloro-1,2,4-thiadiazole (120 mg, 0.60 mmol), cesium carbonate (300 mg, 0.92 mmol) and PdCl ₂ (dppf) (20 mg, 0.024 mmol) in deoxygenated toluene (10 mL) was heated at 100 ° C for 15 hours. The mixture was diluted with a solution of 35% ethyl acetate / 65% hexane and filtered on a short silica gel column. The filtrate was concentrated in vacuo.

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124

Chromatography of the residue (silica gel, gradient elution from hexane to 30% ethyl acetate / 70% hexane) resulted in 232 mg (70%) of the title compound.

¹ H NMR (CDCl 3) δ 8.13 (s, 1H), 7.87 (dd, J = 8.2 Hz, 1H), 7.44 (m, 2H), 7.37 (m, 4H), 7.08 (t, J = 8.1Hz, 1H), 7.04 (d, J = 9Hz, 1H), 6.78 (d, J = 9Hz, 1H), 6.66 (d, J = 9Hz, 1H), 6.55 (s, 1H), 6.43 (d, J = 8Hz, 1H), 5.28 (s, 2H), 4.21 (t, J = 6Hz) 2H, 4.19 (t, J = 6Hz, 2H), 3.81 (s, 3H), 2.62 (m, 4H), 2.34 (quintet, J = 6Hz, 2H), 1.55 (hextet, J = 8Hz, 2H), 1.17 (t, J = 7Hz, 3H), 0.88 (t, J = 7Hz, 3H).

MS ES ⁺ : m / e = 717.719.

C. Preparation of 2- (3- {3- [4- (3-bromo [1,2,4] thiadiazol-5-yl) -2-ethyl-5-hydroxy-phenoxy] -propoxy} -2-propyl-phenoxy) -benzoic acid

2- (3- {3- [5-Benzyloxy-4- (3-bromo [1,2,4] thiadiazol-5-yl) -2-ethyl-phenoxy] -propoxy} -2-propyl-phenoxy} -benzoic acid methyl ester solution (230 mg, 0.31 mmol) in ethanethiol (4 mL) was reacted with boron trifluoride etherate (0.32 mL,

2.5 mmol) at room temperature for 6 hours after which time an additional portion of boron trifluoride etherate was added and stirring was continued for 7 hours. The reaction mixture was diluted with water, concentrated in vacuo and extracted with diethyl ether. The residue was dissolved in methanol (5 mL) and treated with 1N hydroxide solution

911 / B

125 L (2 mL) at 65 ° C for 1 hour. The mixture was concentrated in vacuo and the residue was diluted with water and adjusted to pH ~ 3 with 1N hydrochloric acid. The resulting precipitate was collected by vacuum filtration and dissolved in dilute aqueous base. Reverse phase chromatography (1: 1 acetonitrile / water) gave 43 mg (23%) of the title compound as a yellow solid.

¹ H NMR (DMSO-d ₆ ) δ 7.85 (s, 1H), 7.80 (dd, J = 8.2 Hz, 1H), 7.45 (m, 2H), 7.15 (m, 3H), 6.83 (d, J = 9Hz, 1H), 6.80 (d, J = 9Hz, 1H), 6.62 (s, 1H), 6.35 (d, J = 9) Hz, 1H), 4.20 (m, 4H), 2.55 (m, 4H), 2.27 (quintet, J = 5 Hz, 2H), 1.44 (hextet, J = 8 Hz, 2H) 1.13 (t, J = 7Hz, 3H), 0.81 (t, J = 7Hz, 3H).

MS ES ⁺ (p + 1): m / e = 551 (p + NH ₄ -Br).

IR spectral analysis (KBr, cm ^-1 ) results: 2900, 1696, 1603, 1461.

Analysis for C 9 H _{2 2} 9BrN2O6S:

H, 4.76; N, 4.56

Found: C 56.63 H 4.72 N 3.98.

Example 9

Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiophen-2-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid sodium salt

A. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiophen-2-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester

2- (3- {3- [5-Benzyloxy-2-ethyl-4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenoxy] propoxy} -2-methyl ester mixture propylphenoxy) benzoic acid (300 mg, 0.44 mmol), 2-bromothiophene (110 mg, 0.66 mmol), cesium carbonate (300 mg, 2.17 mmol) and PdCl ₂ (dppf) (20 mg, 0.024 mmol) in degassed toluene (10 mL) was heated at 105 ° C for 66 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in methylene chloride and filtered through a short column of silica gel. The filtrate was concentrated in vacuo.

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126

Chromatography (silica gel, 30% ethyl acetate / 70% hexane) of the residue resulted in an oil which was dissolved in ethanol (4 mL) and treated with boron trifluoride etherate (0.44 mL, 3.4 mmol) at temperature room for 3 hours. The mixture was diluted with water and extracted with diethyl ether. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, gradient elution hexane to 30% ethyl acetate / 70% hexane) of the residue resulted in 120 mg (50%) of the title compound as a yellow film.

¹ H NMR (CDCl ₃ ) δ 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 = 9Hz, 1H), 6.66 (d, J = 9Hz, 1H), 6.51 (s, 1H) ), 6.42 (d, J = 8Hz, 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 = 7Hz, 3H), 0.90 (t, J = 7Hz, 3H).

MS ES ⁺ m / e: 545 (p < -1 >).

B. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiophen-2-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid sodium salt

A solution of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiophen-2-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (120 mg, 0.22 mmol) in methanol (3 mL) was added. at room temperature for 1 hour was reacted with 1N lithium hydroxide solution (0.5 mL) followed by an additional 1N solution

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127 Lithium hydroxide (0.75 mL) for 18 hours. The mixture was heated to 50 ° C and then concentrated in vacuo. The residue was acidified with dilute hydrochloric acid and extracted with diethyl ether. The organic layer was washed once with water and concentrated in vacuo. The residue was diluted with 1N sodium hydroxide solution (0.22 mL), diethyl ether and toluene. The mixture was concentrated in vacuo, dissolved in methylene chloride and concentrated in vacuo to give 120 mg (98%) of the title compound as a green film.

¹ H NMR (DMSO-d ₆ ) δ 7.71 (d, J = 8Hz, 1H), 7.42 (m, 2H), 7.31 (m, 2H), 7.10 (m, 2H) 6.99 (m, 1H); 6.76 (t, J = 7Hz, 2H); 6.52 (s, 1H); 6.30 (d, J = 8Hz, 1H); 16 (t, J = 7Hz, 2H), 4.07 (t, J = 7Hz, 2H), 2.50 (m, 4H), 2.20 (m, 2H), 1.40 (m, 2H), 1.06 (t, J = 8Hz, 3H), 0.77 (t, J = 7Hz, 3H).

MS ES ⁺ : m / e = 533 (p + 1 - Na ^< ^{+ >} ).

IR spectral analysis (CHCl ₃ , cm ^-1 ) results: 2900, 1738, 1604, 1454.

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

A. Preparation of 4-iodo-1-methylpyrazole (known compound, RN: 39806-90-1)

To a solution of 4-iodopyrazole (1.3 g, 6.8 mmol) in dioxane (10 mL) was added iodomethane (0.42 mL, 6.8 mmol) and the resulting mixture was stirred at room temperature.

911 / B

128 for 96 hours. It was then concentrated in vacuo and the residue was mixed with methylene chloride and filtered. The filtrate was concentrated in vacuo to afford 1.35 g (95%) of the title compound as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 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-propyl-phenoxy) -benzoic acid methyl ester

2- (3- {3- [5-Benzyloxy-2-ethyl-4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenoxy] propoxy} -2-methyl ester mixture propylphenoxy) benzoic acid (100 g, 1.47 mmol), 4-iodo-1-methylpyrazole (450 mg, 2.16 mmol), cesium carbonate (1.20 g, 3.62 mmol) and PdCl ₂ (dppf) ( 72 mg, 0.088 mmol) in deoxygenated toluene (35 mL) was heated at 100 ° C for 24 hours. Additional portions of 4-iodo-1-methylpyrazole (~ 30 mg) and PdCl 3 (dppf) (~ 30 mg) were then added and heating at 100 ° C was continued for 40 hours. The mixture was cooled to room temperature, concentrated in vacuo, diluted with methylene chloride and filtered through a short pad of silica gel. The filtrate was concentrated in vacuo. Chromatography (silica gel, gradient elution from 35% ethyl acetate / 65% hexane to 65% ethyl acetate / 35% hexane) of the residue gave the title compound 710 mg (76%).

¹ H NMR (CDCl 3) δ 7.86 (d, J = 8.2 Hz, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.37 (m, 6H), 7.28 (s, 1H), 7.09 (d, J = 9Hz, 1H), 7.04 (d, J = 9Hz, 1H), 6.78 (d, J = 9Hz, 1H) 6.67 (J = 9Hz, 1H), 6.56 (s, 1H), 6.42 (d, J = 8Hz, 1H), 5.08 (s, 2H), 4.18 (t J = 6Hz, 2H), 4.15 (t, J = 6Hz, 2H), 3.85 (s, 3H), 3.81 (s, 3H), 2.63 (t, J = 8) Hz, 2H), 2.59 (q, J = 7Hz, 2H), 2.30 (quintet, J = 6Hz, 2H), 1.55 (hextet, J = 8Hz, 2H), 1.23 (t, J = 7Hz, 3H), 0.89 (t, J = 7Hz, 3H).

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129

C. Preparation of 2- (3- {3- [2-ethyl-5-hydroxy-4- (1-methyl-1H-pyrazol-4-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid

2- (3- {3- [5-Benzyloxy-2-ethyl-4- (1-methyl-1H-pyrazol-4-yl) -phenoxy] -propoxy} -2-propyl-phenoxy) -benzoic acid methyl ester solution (710 mg, 1.12 mmol) in ethanol (5 mL) was reacted with boron trifluoride etherate (1.42 mL, 11.2 mmol) at room temperature for 20 h. The reaction mixture was diluted with water, concentrated in vacuo and extracted 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 was dissolved in methanol (5 mL). This solution was treated with 1N lithium hydroxide solution (5 mL) at -95 ° C for 2 hours. The mixture was concentrated in vacuo and the residue was diluted with water, washed twice with diethyl ether, and the aqueous layer was acidified with 1N 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% methanol / 90% methylene chloride) resulted in 338 mg (57%) of the title compound as a brownish foam.

¹ H NMR _(DMSO-ds) δ 12.85 (bs, 1H), 9.50 (bs, 1H), 7.98 (s, 1H), 7.78 (m, 2H), 7.48 ( dt, J = 8.2Hz, 1H), 7.44 (s, 1H), 7.18 (t, J = 8Hz, 1H), 7.13 (t, J = 9Hz, 1H), 6 79 (d, J = 9Hz, 1H), 6.77 (d, J = 9Hz, 1H), 6.53 (s, 1H), 6.35 (d, J = 9Hz, 1H), 4.20 (t, J = 6Hz, 2H), 4.08 (t, J = 6Hz, 2H), 3.85 (s, 3H), 2.50 (m, 4H), 2.24 ( quintet, J = 5Hz, 2H), 1.45 (hextet, J = 8Hz, 2H), 1.09 (t, J = 7Hz, 3H),

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130

0.82 (t, J = 7Hz, 3H).

MS ES ⁺ : m / e = 531 (p + 1).

IR spectral analysis (KBr, cm ^-1 ) results: 2961, 1697, 1602, 1460, 1222.

Analysis for C31H34N2O6:

H, 6.46; N, 5.28

Found: C, 69.27; H, 6.08; N, 4.63.

Example 11

Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiazol-2-ylphenoxy) propoxy] -2-propylphenoxy} benzoic acid

A. Preparation of 2- {3- [3- (5-Benzyloxy-2-ethyl-4-thiazol-2-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester

2- (3- {3- [5-Benzyloxy-2-ethyl-4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenoxy] propoxy} -2-methyl ester mixture propylphenoxy) benzoic acid (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 deoxygenated

911 / B

131 toluene (35 mL) was heated at 60 ° C for 16 hours, then at 100 ° C for 7 hours. Additional portions of 2-bromothiazole (0.13 mL) and PdCl ₂ (dppf) (~ 30 mg) were then added and heating was continued at 100 ° C for 72 hours. The mixture was cooled to room temperature, concentrated in vacuo, diluted with methylene chloride and filtered through a short pad of silica gel. The filtrate was concentrated in vacuo. Chromatography (silica gel, hexane to 35% ethyl acetate / 65% hexane) of the residue resulted in 282 mg (31%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.20 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 3Hz, 1H), 7.49 ( d, J = 7Hz, 2H), 7.35 (m, 4H), 7.23 (d, J = 3Hz, 1H), 7.09 (d, J = 9Hz, 1H), 7.04 (d, J = 9Hz, 1H), 6.78 (d, J = 9Hz, 1H), 6.65 (d, J = 9Hz, 1H), 6.57 (s, 1H), 42 (d, J = 8Hz, 1H), 5.24 (s, 2H), 4.17 (m, 4H), 3.81 (s, 3H), 2.63 (m, 4H), 2, 33 (quintet, J = 6Hz, 2H), 1.55 (hextet, J = 8Hz, 2H), 1.19 (t, J = 7Hz, 3H), 0.88 (t, J = 7Hz) , 3H).

B. Preparation of 2- {3- [3- (2-ethyl-5-benzyloxy-4-thiazol-2-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester

A solution of 2- {3- [3- (5-benzyloxy-2-ethyl-4-thiazol-2-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (282 mg, 0.442 mmol) of vetanethiol (3 mL) was reacted with boron trifluoride etherate (0.56 mL, 4.9 mmol) at room temperature for 3 hours. The reaction mixture was diluted with water, concentrated in vacuo

911 / B

132 vacuum and extracted with diethyl ether. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, ethyl acetate / hexane) afforded 107 mg (44%) of the title compound with the following properties.

¹ H NMR (CDCl ₃ ) δ 7.88 (d, J = 8.2Hz, 1H), 7.80 (d, J = 4Hz, 1H), 7.35 (t, J =

8.2 Hz, 1H), 7.28 (d, J = 4 Hz, 1H), 7.24 (s, 1H), 7.09 (t, J = 9.2 Hz, 1H), 7.05 (t, J = 9Hz, 1H), 6.79 (d, J = 9Hz, 1H), 6.66 (d, J = 9Hz, 1H), 6.61 (s, 1H), 42 (d, J = 9Hz, 1H), 4.24 (t, J = 6Hz, 2H), 4.18 (t, J = 6Hz, 2H), 3.81 (s, 3H), 2 63 (t, J = 7Hz, 2H), 2.58 (q, J = 7Hz, 2H), 2.34 (quintet, J = 6Hz, 2H), 1.52 (hextet, J = 8) Hz, 2H), 1.17 (t, J = 7Hz, 3H), 0.88 (t, J = 7Hz, 3H).

MS ES ⁺ : m / e = 548 (p + 1).

C. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiazol-2-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid

2- {3- [3- (2-Ethyl-5-hydroxy-4-thiazol-2-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (107 mg, 0.196 mmol) was dissolved in methanol / dioxane 1 solution 1: 3 (3 ml) and treated at 60 ° C for 2 hours with 1N lithium hydroxide solution (1 ml). The mixture was concentrated in vacuo and the residue was diluted with water, washed twice with diethyl ether, and the aqueous layer was acidified with 1N hydrochloric acid. The resulting solution was extracted twice with methylene chloride and the combined organic layers were dried (magnesium sulfate),

911 / B

The filtrate was concentrated in vacuo. Trituration (hexane) of the residue yielded the title compound 72 mg (69%) as a brownish powder.

¹ H NMR (CDCl ₃ ) δ 8.22 (dd, J = 8.2 Hz, 1 H), 7.70 (d, J = 4 Hz, 1H), 7.41 (t, J =

8.2 Hz, 1H), 7.35 (s, 1H), 7.18 (m, 3H), 6.82 (d, J = 9Hz, 1H), 6.69 (d, J = 9Hz) 1H, 6.62 (d, J = 9Hz, 1H), 6.55 (s, 1H), 4.22 (t, J = 6Hz, 2H), 4.21 (t, J = 6) Hz, 2H), 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).

MS ES ⁺ : m / e = 534 (p + 1).

IR spectral analysis (KBr, cm ^-1 ) results: 2957, 1695, 1599, 1457.

Analysis for C ₃ oH ₃₁ N06S:

H, 5.86; N, 2.62

Found: C, 67.44; H, 5.95; N, 2.55.

Example 12

Preparation of 2- {3- {3- [4- (3,5-dimethyl-isoxazol-4-yl) -2-ethyl-5-hydroxy-phenoxy] -propoxy} -2-propyl-phenoxy) -benzoic acid sodium salt

911 / TJ

134

2- (3- {3- [5-Benzyloxy-2-ethyl-4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenoxy] propoxy} -2-methyl ester mixture propylphenoxy) benzoic acid (305 mg, 0.448 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 degassed toluene (10 mL) was heated at 95 ° C for 10 hours. Additional portions of 3,5-dimethyl-4-iodoisoxazole (110 mg), cesium carbonate (260 mg) and PdCl ₂ (dppf) (1515 mg) were then added and heating was continued at 110 ° C for 20 hours. The mixture was cooled to room temperature, concentrated in vacuo, diluted with methylene chloride and filtered through a short pad of silica gel eluting with 20% ethyl acetate / 80% hexane. The filtrate was concentrated in vacuo. The obtained colorless oil was dissolved in methylene chloride (4 mL), cooled to 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 hours. An additional portion of iodotrimethylsilane (0.70 mL) was added and stirring was continued for 72 hours. The mixture was then quenched by pouring into a 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 tetrahydrofuran / 1N hydrochloric acid 1: 1 (5 mL) and stirred at room temperature for 18 hours. The mixture was concentrated in vacuo and treated with 1 equivalent of 1N sodium hydroxide in ether. The resulting mixture was concentrated in vacuo to afford 59 mg (23%) of the title compound as an off-white solid.

¹ H NMR (DMSO-d 6) δ 7.40 (dd, J = 9.2 Hz, 1H), 7.13 (t, J = 8.2 Hz, 1H), 6.97 (m, 2H), 6.79 (s, 1H), 6.68 (d, J = 9Hz, 1H), 6.65 (d, J = 9Hz, 1H), 6.60 (s, 1H), 6.21 ( d, J = 8Hz, 1H), 4.19 (t, J = 6Hz, 2H), 4.01 (t, J = 6Hz, 2H), 2.66 (t, J = 8Hz, 2H) ), 2.48 (q, J = 8Hz, 2H), 2.24 (s, 3H), 2.17 (quintet, J = 6Hz, 2H), 2.07 (s, 3H), 1, 49 (hextet, J = 8Hz, 2H), 1.07 (t, J = 7Hz, 3H), 0.85 (t, J = 7Hz, 3H). TOF MS ES ⁺ exact molecular mass calculated for C ₃ H _{3 6} NO ₇ (p + 1): m / z = 546.2492. Found: 546.2514.

Q11 / R

135

IR spectral analysis results (KBr, cm ^-1 ): 3400, 1605, 1460.

Example 13

Preparation of 2- {3- [3- (2-ethyl-4-furan-2-yl-5-hydroxyphenoxy) propoxy] -2-propylphenoxy} benzoic acid sodium salt

A. Preparation of 2- {3- [3- (4-Bromo-2-ethyl-5-hydroxy-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester

A solution of 2- {3- [3- (5-benzyloxy-4-bromo-2-ethyl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (2.50 g, 3.95 mmol) in methylene chloride (40 mL) was added. cooled to -70 ° C and treated with boron tribromide (0.25 mL, 2.6 mmol). After 25 minutes, the mixture was cooled by pouring into cold water and the resulting mixture was extracted with methylene chloride. The combined organic extracts were washed once with water, once with brine, dried (sodium sulfate), filtered and concentrated in vacuo to afford 1.1 g (52%) of the title compound as a yellow oil.

¹ H NMR (CDCl 3) δ 7.89 (d, J = 9Hz, 1H), 7.38 (t, J = 8Hz, 1H), 7.18 (s, 1H),

7.12 (d, J = 9Hz, 1H), 7.08 (d, J = 2Hz, 1H), 6.81 (d, J = 9Hz, 1H), 6.68 (d, J =

Hz, 1H), 6.56 (s, 1H), 6.46 (d, J = 9Hz, 1H), 5.40 (s, 1H), 4.18 (t, J = 6Hz, J 1) Q1 1 / R

136

2Η), 4.11 (t, J = 6Hz, 2H), 3.84 (s, 3H), 2.65 (t, J = 8Hz, 2H), 2.54 (q, J = 7Hz) .

2H), 2.32 (quintet, J = 6Hz, 2H), 1.54 (hextet, J = 8Hz, 2H), 1.13 (t, J = 7Hz, 3H), 0.89 (t , J = 7 Hz, 3H).

MS ES ⁺ : m / z = 541 (M-H), 543 (M-H + 2).

B. Preparation of 2- (3- {3- [4-Bromo-5- (tert-butyldimethylsilanylalkyl) -2-ethyl-phenoxy] -propoxy} -2-propyl-phenoxy) -benzoic acid methyl ester

A solution of 2- {3- [3- (4-bromo-2-ethyl-5-hydroxy-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (1.00 g, 1.84 mmol) in methylene chloride (20 mL) was added. was reacted with imidazole (0.19 g, 2.8 mmol) and tert-butyldimethylsilyl chloride (0.388 g, 2.57 mmol) at room temperature for 2 hours. The mixture was poured into water and the organic layer was separated, washed once with water, once with saturated sodium chloride solution, filtered through a short pad of silica gel and concentrated in vacuo to give 1.1 g (91%) of the title compound as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 7.88 (d, J = 9Hz, 1H), 7.38 (t, J = 8Hz, 1H), 7.22 (s, 1H), 7.2 (d) J = 9 Hz, 1H), 7.08 (d, J = 2 Hz, 1 H), 6.80 (d, J = 9 Hz, 1 H), 6.69 (d, J = 9 Hz, 1 H) H), 6.45 (d, J = 9Hz, 1H), 6.40 (s, 1H), 4.20 (t, J = 6Hz, 2H), 4.11 (t, J = 6Hz) (2H), 3 _: 83 (s, 3H), 2.64 (t, J = 8Hz, 2H), 2.54 (q, J = 7Hz, 2H), 2.32 (quintet, J = 6Hz) (2H), 1.54 (hextet, J = 8Hz, 2H), 1.13 (t, J = 7Hz, 3H), 1.03 (s, 9H), 0.89 (t, J = 7) Hz, 3H), 0.23 (s, 6H).

911 / B

137

C. Preparation of 2- {3- [3- (2-Ethyl-4-furan-2-yl-5-hydroxy-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester

A mixture of 2- (3- {3- [4-bromo-5- (tert-butyldimethylsilanyloxy) -2-ethyl-phenoxy] -propoxy} -2-propyl-phenoxy) -benzoic acid methyl ester (1.05 g, 1.60 mmol), furan- 2-boronic acid (0.358 g, 3.20 mmol), tetrakis (triphenylphosphine) palladium (0.185 g, 0.160 mmol) and a 2M aqueous solution of sodium carbonate (8 mL) in tetrahydrofuran (20 mL) were heated under reflux for 18 hours. 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 brine, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue resulted in 0.8 g (94%) of the title compound being obtained as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 7.90 (d, J = 9Hz, 1H), 7.48 (s, 1H), 7.38 (t, J = 8Hz, 1H), 7.21 (s 1H, 7.13 (s, 1H), 7.10 (d, J = 9Hz, 1H), 7.07 (d, J = 2Hz, 1H), 6.81 (d, J = 9 Hz, 1H), 6.69 (d, J = 9Hz, 1H), 6.52 (m, 3H), 6.44 (d, J = 9Hz, 1H), 4.20 (m, 4H) ), 3.83 (s, 3H), 2.67 (t, J = 8Hz, 2H), 2.59 (q, J = 7Hz, 2H), 2.32 (quintet, J = 6Hz, 2H), 1.55 (hextet, J = 8Hz, 2H), 1.18 (t, J = 7Hz, 3H), 0.91 (t, J = 7Hz, 3H).

MS ES ⁺ : m / z = 589 (p + AcO < + >).

«3 4 zr»

138

Analysis for C32H34O7:

H, 6.46

Found: C, 72.21; H, 6.15.

D. Preparation of sodium 2- {3- [3- (2-ethyl-4-furan-2-yl-5-hydroxyphenoxy) propoxy] -2-propylphenoxy} benzoic acid

2- {3- [3- (2-Ethyl-4-furan-2-yl-5-hydroxy-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (250 mg, 0.47 mmol) was dissolved in tetrahydrofuran (4 mL) and treated with 1N lithium hydroxide solution (2 mL) at 50 ° C for 16 h. The mixture was concentrated in vacuo, the residue diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed once with water, once with brine, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate and shaken with 1N hydrochloric acid. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in diethyl ether and treated with 1N aqueous sodium hydroxide solution (0.32 mL). The mixture was concentrated in vacuo and then azeotroped with diethyl ether, chloroform and diethyl ether and dried to give 168 mg (66%) of the title product as a cream solid.

911 / B

139 ¹ H NMR (DMSO-d 6) δ 7.56 (s, 1H), 7.44 (d, J = 8Hz, 1H), 7.35 (s, 1H), 7.13 (m,

H), 6.97 (m, 2H), 6.77 (d, J = 2Hz, 1H), 6.65 (m, 4H), 6.48 (d, J = 2Hz, 1H),

6.24 (d, J = 9Hz, 1H), 4.15 (t, J = 6Hz, 2H), 3.96 (t, J = 6Hz, 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 = 7Hz, 3H), 0.84 (t, J = 7Hz, 3H).

TOF MS ES ⁺ exact molecular weight was calculated for C ₃₁ H ₃ O ₇ (p + 1): m / z = 517.2226. Found: 517.2230.

IR spectral analysis (KBr, cm ^-1 ): 3400, 2961, 1599, 1460.

Example 14

Preparation of 2- {3- {3- [2-ethyl-5-hydroxy-4-furan-3-yl] phenoxy] propoxy} -2-propylphenoxy) benzoic acid

A. Preparation of 2- {3- [3- (2-Ethyl-4-furan-3-yl-5-hydroxy-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester

911 / B

140

A mixture of 2- (3- {3- [4-bromo-5- (tert-butyldimethylsilanyloxy) -2-ethyl-phenoxy] -propoxy} -2-propyl-phenoxy) -benzoic acid methyl ester (2.10 g, 3.19 mmol), furan acid -3-boronic acid (0.722 g, 6.45 mmol), tetrakis (triphenylphosphine) palladium (0.37 g, 0.32 mmol) and a 2M aqueous solution of sodium carbonate (16 mL) in tetrahydrofuran (30 mL) were heated under reflux. for 48 hours. It was then cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was separated, washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated under vacuum. Chromatography (silica gel, 15% ethyl acetate / 85% hexane) of the residue resulted in the title compound 0.29 g (17%) as a yellow oil.

TOF MS ES ⁺ exact molecular weight was calculated for C 32 H 35 O 7 (p + 1): m / z = 531.2383. Found: 531.2396.

B. Preparation of 2- {3- [3- (2-ethyl-4-furan-3-yl-5-hydroxy-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid sodium salt

2- {3- [3- (2-Ethyl-4-furan-3-yl-5-hydroxy-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (170 mg, 0.32 mmol) was dissolved in tetrahydrofuran (4 ml) and methanol (1 ml) and treated with 1N lithium hydroxide solution (4 ml) at 50 ° C for 2 hours. The mixture was concentrated under vacuum and the residue acidified with hydrochloric acid and the resulting mixture

911 / B

141 was extracted twice with ethyl acetate. The combined organic extracts were washed once with water, once with brine, dried (sodium sulfate), filtered, and concentrated under vacuum. Chromatography (silica gel, 2% methanol / 9% chloroform) of the residue gave 45 mg of material that was again chromatographed (silica gel, 1% methanol / 99% chloroform) to afford 25 mg (15%) of the title compound as an oil.

TOF MS ES ⁺ exact molecular weight was calculated for C 31 H 33 O 7 (p + 1); m / z = 517.226. Found: 517.2230.

Example 15

Preparation of 2- (3- {3- [2-ethyl-5-hydroxy-4- (tetrahydrofuran-3-yl) phenoxy] propoxy} -2-propylphenoxy} benzoic acid hemihydrate

A. Preparation of 2- {3- [3- (5-Benzyloxy-2-ethyl-4-furan-3-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester

A mixture of 2- {3- [3- (5-benzyloxy-4-bromo-2-ethyl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (3.00 g, 4.73 mmol) in furan-3-boronic acid (1.06 g, 9.47 mmol), tetrakis (triphenylphosphine) palladium (0.54 g, 0.47 mmol) and a 2M aqueous solution of sodium carbonate (20 mL) in tetrahydrofuran (40 mL) were added.

911 / R

142 was heated at 100 ° C for 48 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was separated, washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated under vacuum. Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue resulted in 1.9 g (65%) of the title compound as a yellow oil.

¹ H NMR (CDCl ₃ ) δ 7.88 (d, 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 = 9Hz, 1H), 6.76 (d, J = 2Hz, 1H), 6.67 (d, J = 9Hz, 1H) ), 6.60 (s, 1H), 6.43 (d, J = 9Hz, 1H), 5.11 (s, 2H), 4.18 (m, 4H), 3.83 (s, 3H) ), 2.66 (t, J = 8Hz, 2H), 2.62 (q, J = 7Hz, 2H), 2.30 (quintet, J = 6Hz, 2H), 1.57 (hextet, J = 8Hz, 2H), 1.20 (t, J = 7Hz, 3H), 0.92 (t, J = 7Hz, 3H).

MS ES ⁺ : m / z = 621 (p + 1).

IR spectral analysis (CHCl 3, cm ^-1 ) results: 3000, 1727, 1603, 1461.

B. Preparation of 2- (3- {3- [2-ethyl-5-hydroxy-4- (tetrahydrofuran-3-yl) phenoxy] propoxy} -2-propylphenoxy) benzoate

A solution of 2- {3- [3- (5-benzyloxy-2-ethyl-4-furan-3-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (1.8 g, 2.9 mmol) in ethyl acetate (40 mL) ) was reacted with 10% palladium on carbon (0.39 g) and hydrogenated at 331 kPa and 45 ° C for 72 hours. The mixture was cooled to room temperature,

143 was filtered through Celite ™ and the filtrate was concentrated under vacuum to afford 1.2 g (77%) of the title compound as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 7.88 (d, J = 8.2 Hz, 1H), 7.57 (t, J = 8.2 Hz, 1H), 7.09 (d, J = 9 Hz) 1H, 7.04 (d, J = 9Hz, 1H), 6.81 (d, J = 9Hz, 1H), 6.80 (s, 1H), 6.67 (d, J = 9) Hz, 1H), 6.44 (d, J = 9Hz, 1H), 6.43 (s, 1H), 4.19 (m, 3H), 4.10 (m, 2H), 4.02 ( dd, J = 12.3Hz, 1H), 3.88 (d, J = 12.8Hz, 1H), 3.84 (s, 3H), 3.73 (q, J = 9Hz, 1H) 3.45 (m, 1H), 2.64 (t, J = 8Hz, 2H), 2.53 (q, J = 7Hz, 2H), 2.38 (m, 1H), 2.28 (quintet, J = 6Hz, 2H), 1.99 (m, 1H), 1.55 (hextet, J = 8Hz, 2H), 1.15 (t, J = 7Hz, 3H), 0, 90 (t, J = 7Hz, 3H).

MS ES ⁺ : m / z = 593 (p + CH ₃ COO +).

IR spectral analysis (CHCl 3, cm ^-1 ) results: 2963, 1719, 1589, 1461.

Analysis for C32H38O7:

calculated:

H, 7.16

found:

71.41

H, 7.06.

C. Preparation of 2- (3- {3- [2-ethyl-5-hydroxy-4- (tetrahydrofuran-3-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid hemihydrate

4 Λ 4 4 m

144

2- (3- (3- [2-ethyl-5-hydroxy-4- (tetrahydrofuran-

3-yl) phenoxy] propoxy} -2-propylphenoxy) benzoate (0.92 g, 1.7 mmol) in tetrahydrofuran (10 mL) and methanol (5 mL) were reacted with 1M at 55 ° C for 2 h. aqueous lithium hydroxide solution (10 mL). The mixture was allowed to cool to room temperature and stirred for an additional 18 hours. The mixture was concentrated under vacuum and the remaining aqueous mixture was washed once with diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated under vacuum. The colorless oil obtained was dissolved in diethyl ether and treated with 1N aqueous sodium hydroxide solution (1.72 mL). The resulting biphasic mixture was diluted with chloroform and concentrated under vacuum. Diethyl ether was added and the mixture was concentrated under vacuum. The obtained white foam was dried under vacuum at room temperature for 60 hours to give 0.78 g (84%) of the title compound having the following properties:

Mp: 67-71 ° C.

¹ H NMR (DMSO-d 6) δ 7.62 (d, J = 8.2 Hz, 1H), 7.30 (t, J = 8.2 Hz, 1H), 7.05 (m, 2H), 6.85 (s, 1H), 6.73 (d, J = 9Hz, 1H), 6.70 (d, J = 9Hz, 1H), 6.53 (s, 1H), 6.34 (s) d, J = 9Hz, 1H), 4.15 (t, J = 6Hz, 2H), 4.04 (t, J = 6Hz, 2H), 3.95 (m, 1H), 3.88 (m, 1H), 3.75 (q, J = 9Hz, 1H), 3.49 (m, 2H), 2.60 (t, J = 8Hz, 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, J = 7 Hz, 3H), 0.83 (t, J = 7Hz, 3H).

MS ES ⁺ : m / z = 519 (p-Na ^< ^{+ >} ).

IR spectral analysis (CHCl 3, cm ^-1 ) results: 2964, 1783, 1604, 1461.

Analysis for C3iH ₃₅ NaO7.0,5 H2O:

H, 6.58

Found: C, 67.76; H, 6.68.

145

Example 16

Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-pyrrolidin-2-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid hydrochloride hydrate

A. Preparation of 2- (2-Benzyloxy-5-ethyl-4- {3- [3- (2-methoxycarbonylphenoxy) -2-propylphenoxy] propoxy) phenyl) pyrrole-1-carboxylic acid tert-butyl ester

A mixture of 2- {3- [3- (5-benzyloxy-4-bromo-2-ethyl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (3.00 g, 4.73 mmol), N-boc-pyrrole- 2-boronic acid (1.99 g, 9.43 mmol), tetrakis (triphenylphosphine) palladium (0.54 g, 0.47 mmol) and a 2M aqueous solution of sodium carbonate (25 mL) in tetrahydrofuran (60 mL) were heated to reflux. for 40 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was separated, washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated under vacuum. Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue resulted in 2.6 g (76%) of the title compound being obtained as a solid.

¹ H NMR (CDCl ₃ ) δ 7.88 (dd, J = 8.2 Hz, 1H), 7.15-7.40 (m, 7H), 7.08 (m, 3H), 6.82 ( d, J = 9Hz, 1H), 6.68 (d, J = 9Hz, 1H), 6.52 (s, 1H), 6.44 (d, J = 9Hz,

911 / B

146

Δ), 6.23 (t, J = 4Hz, 1H), 6.12 (m, 1H), 4.95 (s, 2H), 4.20 (t, J = 6Hz, 2H), 4 15 (t, J = 6Hz, 2H), 3.84 (s, 3H), 2.66 (t, J = 8Hz, 2H), 2.60 (q, J = 7Hz, 2H), 2.30 (quintet, J = 6Hz, 2H), 1.57 (hextet, J = 8Hz, 2H), 1.28 (s, 9H), 1.18 (t, J = 7Hz, 3H) 0.93 (t, J = 7Hz, 3H).

TOS MS ES ⁺ exact molecular weight was calculated for C 44 H 53 NO 8 (p + NH ₄ ): m / z = 737.3802. Found: 737.3804.

IR spectral analysis (CHCl 3, cm ^-1 ) results: 2964, 1730, 1461.

Analysis for C44H49NO8:

calculated: C, 73.41 H, 6.86 N, 1.94 found: C, 73.76 H, 6.76 N, 2.04.

B. Preparation of 2- (5-ethyl-2-hydroxy-4- {3- [3- (2-methoxycarbonylphenoxy) -2-propylphenoxy] propoxy} phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester

2- (2-Benzyloxy-5-ethyl-4- {3- [3- (2-methoxycarbonylphenoxy) -2-propylphenoxy] propoxy} phenyl) pyrrole-1-carboxylic acid tert-butyl ester (0.98 g, 1) , 4 mmol) in ethyl acetate (40 mL) was reacted with 10% palladium on carbon (0.98 g) and hydrogenated at 310 kPa and 45 ° C for 25 hours, at room temperature for 20 hours, then at 45 ° C. ° C for 19 hours. The mixture was cooled to room temperature, filtered through Celite ™ and the filtrate was concentrated below

911 / B

147 under vacuum to afford 0.76 g (88%) of the title compound as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 7.87 (d, J = 8.2 Hz, 1H), 7.37 (dt, J = 8.2 Hz, 1H), 7.10 (d, J = 9 Hz) (1H), 7.04 (d, J = 9Hz, 1H), 6.91 (s, 1H), 6.81 (d, J = 9Hz, 1H), 6.67 (d, J = 9 Hz, 1H), 6.47 (s, 1H), 6.44 (d, J = 9Hz, 1H), 5.09 (m, 1H), 4.18 (d, J = 6Hz, 2H) 4.14 (t, J = 6Hz, 2H), 3.84 (s, 3H), 3.45 (m, 2H), 2.64 (t, J = 8Hz, 2H), 2, 54 (m, 3H), 2.25 (m, 5H), 2.06 (m, 1H), 1.54 (hextet, J = 8Hz, 2H), 1.43 (s, 9H), 1, 15 (t, J = 7Hz, 3H), 0.90 (t, J = 7Hz, 3H).

C. Preparation of 2- (4- {3- [3- (2-Carboxyphenoxy) -2-propylphenoxy] propoxy} -5-ethyl-2-hydroxyphenyl) pyrrolidine-1-carboxylic acid tert-butyl ester hydrate

2- (5-Ethyl-2-hydroxy-4- {3- [3- (2-methoxycarbonylphenoxy) -2-propylphenoxy] propoxy} phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (0.114 g, 0.18) mmol) in methanol / tetrahydrofuran 1: 1 (4 mL) was treated with 1M lithium hydroxide solution (4 mL) at room temperature for 18 h. The resulting mixture was concentrated under vacuum and the residue dissolved in water. The mixture was further extracted with ethyl acetate. The organic extract was dried (sodium sulfate), filtered, and concentrated under vacuum. The residue was diluted with diethyl ether, concentrated under vacuum and dried to afford 90 mg (78%) of the title compound. MS ES ⁺ : m / z = 620 (p + 1-Li ⁺ ).

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IR spectral analysis (KBr, cm ^-1 ) results: 2964, 1672, 1603, 1416.

Analysis for C36H44NO8Li. H ₂ O:

calculated:

C, 67.17

H, 7.20

N, 2.18

found:

H, 6.99

N, 2.27.

J

D. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-pyrrolidin-2-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid hydrochloride hydrate

2- (4- {3- [3- (2-Carboxyphenoxy) -2-propylphenoxy] propoxy} -5-ethyl-2-hydroxyphenyl) pyrrolidine-1-carboxylic acid tert-butyl ester hydrate solution (0.100 g, 0 HCl (16 mL) in anhydrous diethyl ether (5 mL) was bubbled with HCl gas. The resulting mixture was allowed to stir for 1 hour. The mixture was concentrated under vacuum. Chromatography (SCX cation exchange resin, 1: 1 tetrahydrofuran / methanol to dilute ammonia / methanol solution) of the residue resulted in a brownish solid. This material was dissolved in ether and treated with HCl gas. This mixture was concentrated under vacuum to give 48 mg (52%) of the title compound.

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149 ¹ H NMR (DMSO-d 6) δ 12.80 (bs, 1H), 10.12 (s, 1H), 9.34 (bs, 1H), 8.36 (bs, 1H), 7.79 ( d, J = 9.2 Hz, 1H), 7.47 (dt, J = 8.2 Hz, 1H), 7.17 (t, J = 8 Hz, 1H),

7.12 (d, J = 9Hz, 1H), 7.07 (s, 1H), 6.80 (d, J = 9Hz, 1H), 6.78 (d, J = 9Hz,

1H), 6.58 (s, 1H), 6.35 (d, J = 9Hz, 1H), 4.56 (m, 1H), 4.20 (t, J = 6Hz, 2H),

4.11 (t, J = 6Hz, 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 molecular weight was calculated for C3iH ₃ H 8 NO ₆ (p + 1): m / z = 520.2699. Found: 520.2672.

Example 17

Preparation. 2- {3- [3- (2-ethyl-5-hydroxy-4-thiophen-3-ylphenoxy) propoxy] -2-propylphenoxy} benzoic acid hydrate

Known compound:

(Sawyer et al., J. Med. Chem., 1995, 38, 4411)

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 (312 mg, 0.270 mmol), a 2M aqueous solution of sodium carbonate (4 mL) and n-propanol (4 mL) in toluene (16 mL) was refluxed for 4 hours. The mixture was cooled to room temperature, diluted with diethyl ether, washed once with water and once

911 / B

150 was saturated with sodium chloride solution. The organic layer was dried (magnesium sulfate), filtered and concentrated under vacuum. Chromatography (silica gel, 5% ethyl acetate / 95% hexane) of the residue resulted in 1.54 g (80%) of the title product as a white solid.

Mp: 65-67 ° C.

¹ H NMR (CDCl 3) δ 7.58 (d, J = 2.8 Hz, 1H), 7.49 (d, J = 5.2 Hz, 1H), 7.54-7.30 (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 1.66 (q, J = 7.5 Hz, 2H), 2.29 (quintet, J = 6.0 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H).

MS FD m / e 386 (p).

IR spectral analysis (CHCl 3, cm ^-1 ) results: 2969, 1613, 1501, 1138.

Analysis for C22H23O2CIS:

H, 5.99

Found: C, 68.53; H, 6.00.

Known compound: Sawyer et al., J. Med. Chem., 1995, 38, 4411.

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151

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-propylphenol (0 , 82 g, 3.2 mmol), potassium iodide (0.21 g, 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 hours. It was then cooled to room temperature, diluted with ether and washed with water. The organic layer was dried (magnesium sulfate), filtered, and concentrated under vacuum. Chromatography (silica gel, 5% ethyl acetate / 95% hexane) of the residue resulted in 1.31 g (67%) of the title product as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 7.66 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 2.9 Hz, 1H), 7.48 (d, J =

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 = 8.3Hz, 1H), 6.77 (d, J = 8.6Hz, 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 (hextet, J = 7.5 Hz, 2H), 1.24 (t, J =

7.5 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H).

MS FD m / e 603 (p).

IR spectral analysis (CHCl 3, cm ^-1 ) results: 2967, 2250, 1613, 1501.

Analysis for C38H37NO4S:

H, 6.18; N, 2.32

Found: C 74.65 H 6.21 N 2.57.

C. Preparation of 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (thiophen-3-yl) phenoxy] propoxy] phenoxy] benzonitrile

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152

To a solution of 2- [2-propyl-3- [3- [5- (benzyloxy) -2-ethyl-4- (thiophen-3-yl) phenoxy] propoxy] phenoxy] benzonitrile (900 mg, 1.49 mmol) in methylene chloride (25 mL). mL), which was cooled to -78 ° C, was added over 2 minutes a 1M solution of boron tribromide in methylene chloride (2.99 mL, 2.99 mmol). The resulting violet solution was stirred for 30 minutes and allowed to warm to room temperature. The mixture was diluted with water and shaken. The organic layer was separated, dried (magnesium sulfate), filtered, and concentrated under vacuum. Chromatography (silica gel, 25% ethyl acetate, 75% hexane) gave 400 mg (52%) of the title product as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 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 = 6.9Hz, 1H), 6.85 (s, 1H), 6.89 (d, J = 8.1Hz, 1H), 6 74 (d, J = 8.5 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 4.71 (s, 1H, -OH), 4.26 (t, J = 6.0 Hz, 4H), 2.72 (q, J = 7.4 Hz, 2H), 2.59 (t, J = 7.3 Hz, 2H), 2.39 (quintet, J = 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- (thiophen-3-yl) phenoxy] propoxy] phenoxy] benzoic acid hydrate

04 4 iO

153

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 methanol / water 2: 1 (6 mL) was reacted with 12.5 M aqueous sodium hydroxide solution (4.0 mL) under reflux for 36 hours. 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 methylene chloride layers were dried (magnesium sulfate), the resulting mixture was filtered and concentrated under vacuum to give a brownish solid having the following characteristics:

Mp: 90-95 ° C.

¹ H NMR (CDCl ₃ ) δ 8.24 (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, 2H), 09 (s, 1H), 6.84 (d, J = 8.0Hz, 1H), 6.73 (d, J = 8.3Hz, 1H), 6.64 (J = 8.0Hz, 1H), 6.55 (s, 1H), 5.38 (bs, 1H, -OH), 4.26 (t, J = 6.2Hz, 2H), 9.21 (t, J = 7, 1 Hz, 2H), 2.60 (m, 4H), 2.36 (quintet, J = 5.8 Hz, 2H), 1.51 (hextet, J = 7.1 Hz, 2H), 1.19 (t, J = 7.5Hz, 3H), 0.90 (t, J = 7.4Hz, 3H).

MS FD m / e 532 (p).

IR (KBr, cm ^-1 ): 3200 (br), 2961, 1697, 1457, 1110.

Analysis for C ₃₁ H ₃₂ O ₆ S. H ₂ O:

Calculated: C 67.62 H 6.22

154

Found: C, 67.34; H, 5.87.

The LTB ₄ antagonists which have been discussed above and the above-described anti-cancer agents and the like in the compositions and method of the invention are often preferably used in the form of salts, which are also part of the invention. When the compounds of the invention carry an acidic group or acidic groups or other reactive groups, they may form salts which are more soluble in water and / or physiologically more suitable and acceptable than the parent compound and its acid form. Representative pharmaceutically acceptable salts include, but are not limited to, alkali salts and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum, and the like. Sodium salts are particularly preferred. Salts are usually prepared from the free acids by reacting the acid form in solution with a basic compound or by treatment with an ion exchange resin. For example, the (acid group) of the compound of formula (I) may be defined as -CO ₂ H and may form salts by reaction with a suitable base (e.g. NaOH, KOH) to give the corresponding sodium or potassium salts.

Included within the definition of pharmaceutically acceptable salts are the relatively nontoxic, inorganic and organic addition salts of the compounds of the invention, such as ammonium salts, quaternary ammonium compounds, and amine cations derived from nitrogen-containing bases with sufficient basicity to form salts with 1_TB ₄ antagonists that are the subject of the present invention (see e.g.

S. M. Berge et al., "Pharmaceutical Salts", J. Phar. Sci., 66, 1-19 (1977). Certain compounds of the invention may also have one or more chiral centers and may exist in optically active forms. All such stereoisomers, as well as mixtures thereof, are part of the invention. If a particular stereoisomer is desired, it may be prepared by methods well known in the art, for example, by using stereospecific reactions with starting materials that contain asymmetric centers and already separated or alternatively, by methods that result in mixtures of stereoisomers and subsequent resolution by known methods. methods. For example, a racemic mixture may be reacted with one enantiomer of another compound. This turns the racemic form into a mixture of diastereomers. Then look

155 to different boiling points having different diastereomers and due to different solubilities, these diastereomers can be separated from one another by conventional means, for example crystallization may be used.

"Prodrugs" are derivatives of LTB ₄ antagonists and anticancer compounds used according to the invention which have chemically or metabolically cleavable groups and undergo solvolysis or compounds of the invention which, under physiological conditions, are pharmaceutically active in vivo. Derivatives of the compounds of the invention have activity both in the form of acid derivatives and in the form of basic derivatives, but acid derivatives often offer advantages in terms of solubility, tissue tolerance, or delayed release in mammalian organisms, see Bundgard, H., Design of Prodrugs, p. 7-9,2124, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives, which are well known to those skilled in the art, including, for example, esters of the starting compound prepared with a suitable alcohol, amides prepared by reaction with a suitable amine. Preferred prodrugs are simple aliphatic or aromatic esters derived from acidic groups attached to the compounds of the invention. In some cases, it is desirable to prepare double ester prodrugs such as: (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkyl esters. Particularly preferred esters which can be used as prodrugs are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl and N, N-diethylglycolamido.

Preferred prodrugs are carboxylic acid esters of the compounds of the invention.

The methyl ester prodrugs can be prepared by reacting the acid form of a compound of formula (I) in an environment such as methanol with an acidic or basic esterification catalyst (e.g. NaOH, H ₂ SO ₄ ). Ethyl ester prodrugs are prepared in a similar manner using ethanol, which in this case is preferable to methanol.

Ν, Ν-Diethylglycolamide ester prodrugs can be prepared by reacting the sodium salts of the compound of formula (I) (in an environment such as dimethylformamide) with 2-chloro, Ν-diethyl acetamide (available from Aldrich Chemical Co., Milwaukee,

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156

Wisconsin USA, Record no. 25, 099-6).

Morpholinylethyl ester prodrugs can be prepared by reacting the sodium salt of a compound of formula (I) (in an environment such as dimethylformamide) with 4- (2-chloroethyl) morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wisconsin, USA, Record No. C4, 220 -3).

Preferred LTB ₄ compounds used as active compounds of the compositions and preparations are those in the form of acids, salts and prodrug derivatives thereof, and are especially selected from the group consisting of: carboxylic acids, sodium salts, and ester prodrugs.

The compositions of the invention consist of therapeutically effective amounts of the leukotriene (LTB ₄ ) antagonists listed above and a therapeutically effective amount of the anti-cancer drugs also mentioned above. The formulation may be formulated using conventional excipients, diluents or carriers and compressed into tablets or formulated as baths or solutions for conventional oral administration or for administration by the intramuscular or intravenous route. The compounds can be administered transdermally and can be formulated for uniform release formulations, in various dosage unit forms, and the like.

In another embodiment, the invention relates to a method of treating a patient suffering from a cancer that is non-multi-drug resistant, the treatment in which case comprising separately administering a therapeutically effective amount of a leukotriene (LTB ₄ ) antagonist and an anticancer drug. If leukotriene (LTB ₄ ) antagonists and anticancer drugs are administered separately, different schedules of administration over time may also be used. It may be administered in the intermediate period of administration of the second agent, for as long as the intervals of administration of the second agent are within each other, the administration of one active agent being within the therapeutically effective administration interval of the other active agent. A therapeutically effective interval is a period of time that begins when one of the two administered agents (a) ie the leukotriene antagonist (LTB ₄ ) or (b) ie the anti-cancer active agent is administered to a human patient and ends when will cease to be effective

O 4 Λ4 4 ID

The effect of treating cancer by combining (a) and (b). The routes of administration of the leukotriene antagonist (LTB ₄ ) and the anticancer drug may vary. For example, one active agent may be administered orally while the other is administered intravenously. It is possible that one of the products is to be administered as a continuous infusion, while the other is administered in separate doses. It is particularly important that the anticancer agent is administered in a manner that optimizes its efficacy.

Pharmaceutical preparations according to the invention

Preferred compounds of the invention or pharmaceutical compositions containing them are unit dosage forms for administration to mammals. The unit dosage form may be a capsule, sachet, tablet or ampoule. The amount of active ingredient per unit dose of the composition of the invention is a therapeutically effective amount and may vary according to the particular treatment conditions. In many cases, it may be appropriate to use conventional dosage variations that are adjusted according to the age and condition of the patient. The dosage will also depend on the route of administration.

The compound can be administered by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal.

The pharmaceutical compositions of the invention are prepared by assembling (e.g., mixing) a therapeutically effective amount of an anti-cancer drug (e.g., 2 ', 2'-difluoronucleoside) and an LTB ₄ antagonist such as a compound of Formula A, Formula (I) and Formula (II). Other ingredients which are added with mixing are a pharmaceutically acceptable carrier or diluent. Current pharmaceutical preparations are made by known methods using well known and readily available ingredients.

In the manufacture of the compositions according to the invention, the active ingredient is usually admixed with the carrier or diluent by means of the carrier or incorporated into the carrier, which may be in the form of capsules, lozenges and paper, or

158 cans. Where carriers are used as diluents, the formulation may be a solid, lyophilized solid, or a paste, a semi-solid, or a liquid material, wherein the carriers serve as vehicles or may be formulated as tablets, pills, powders, lozenges, baths, suspensions, emulsions, solutions, syrups, injectable solutions and injectable liquids, aerosols (as solid or liquid media), or may be liquid creams containing, for example, up to 10 wt. of the active compound. The compounds of the invention are preferably formulated prior to administration.

For the purposes of pharmaceutical preparations, any known carrier may be used. In such a formulation, the carrier may be a solid, liquid, or a mixture of solids and liquids. For example, for intravenous injection, the compound of the invention may be dissolved in sterile water, sterile saline or sterile water or sterile saline containing sugars and / or buffers at a concentration of about 0.05 to about 5.0 mg / ml in aqueous solution containing 4% dextrose and 0.5% sodium citrate.

Solid form preparations include powders, tablets and capsules. One or more substances which may also act as flavoring agents, solubilizing agents, suspending agents, binders, tablet disintegrating agents and encapsulating and encapsulating material may be used as solid carriers.

Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, which may be added together with disintegrating agents such as starch, corn starch, alginic acid and / or binders, for example gelatin or acacia and glidants additives such as magnesium stearate, stearic acid or talc.

In powders, the carrier is a finely divided solid which is admixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and solidified in the shape and size desired.

Preferably, the compositions comprise a compound of formula (I), in suitable dosage unit forms, for example each dosage unit,

159 containing 5 to about 500 mg (about 5 to 50 mg for the parenteral or inhalation route of administration and from about 25 to 500 mg for the oral or rectal administration). 0.5 to 20 mg / kg of active ingredient can also be administered, it being understood that the daily dose is preferably between 0.5 to about 300 mg / kg, always calculated for the compound of formula (I) to be administered. , the exact dose will be determined by your doctor, based on all circumstances that may affect this dose.

The powders and tablets may preferably contain about 1 to 99 wt. % of the active ingredient represented by the novel compound of the invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, and cocoa butter.

Sterile fluid formulations include, but are not limited to, suspensions, emulsions, syrups, and baths.

The active ingredient may be dissolved or admixed in a pharmaceutically acceptable carrier, such as sterile water, a sterile organic solvent, or a mixture of both. By "pharmaceutically acceptable" is meant a carrier, diluent or excipient which is compatible with the other ingredients of the compositions of the invention and has no deleterious effect on the recipient.

The active ingredient may also be dissolved in a suitable organic solvent, for example aqueous propylene glycol. Other compositions may be prepared by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethylcellulose or in a suitable oil.

The following pharmaceutical formulations 1 to 22 are illustrative only and are not intended to limit the scope of the invention in any way. "Active ingredient" in this case means a 2 ', 2'-difluoro nucleoside or a compound of the invention of formula A, formula (I) or formula (II), or a pharmaceutically acceptable salt, solvate or prodrug thereof.

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In one embodiment of the composition of the invention, a combination of therapeutically effective amounts of the leukotriene (LTB ₄ ) antagonists mentioned above and a therapeutically effective amount of the 2 ', 2'-difluoronucleoside anticancer drug is used. The composition may be formulated with conventional excipients, additives, diluents or carriers and compressed into tablets or formulated as baths or solutions for conventional oral administration or administration by the intramuscular and / or intravenous route. The compounds may be administered transdermally and may be presented in dosage forms for uniform release of the active ingredient and the like.

In another embodiment, the 2 ', 2'-difluorucleoside anticancer drug and leukotriene antagonists (LTB ₄ ) are independently administered, each administered separately. The anti-cancer agents may be formulated into the formulations with the aid of conventional excipients, additives, diluents or carriers and administered by intravenous infusion. On the other hand, the anti-cancer drugs may be formulated as liquids suitable for oral administration. The anti-cancer agents may also be compressed into tablets and administered orally. If the anti-cancer agent and leukotriene antagonists (LTB ₄ ) are administered separately, the anti-cancer agent may be administered before, after or during the administration of the leukotriene antagonists (LTB ₄ ). If the anti-cancer agent is administered separately from leukotriene (LTB ₄ ) antagonists, it must be administered at a therapeutically effective interval.

The method of treating a human according to the invention comprises both administering a combination of leukotriene antagonists (LTB ₄ ) and administering an anti-cancer active agent in the form of separate administration of leukotriene antagonists (LTB ₄ ) and an anti-cancer active agent. When administered separately, the leukotriene antagonists (IVB ₄ ) are formulated into compositions that can be administered orally and rectally, topically, parenterally, for example by injection, and continuously or discontinuously by intraarterial infusion in the form of, for example, tablets, lozenges, tablets for administration under administration. tongue, lozenges, baths, gels, suspensions, aerosols, lotions, for example containing from 1 to 10 wt. % of active compound in a suitable base cream composition,

161 soft or hard gelatin capsules, suppositories, injectable solutions and suspensions in a physiologically acceptable environment, and sterile packaged powders adsorbed on a carrier material, for the preparation of sterile injectable solutions prior to injection. Preferred for this purpose are compositions in unit dosage form, preferably those in which each dosage unit contains from about 5 to about 500 mg (from about 5 to 50 mg in the case of parenteral or inhalational administration, and from about 25 to 500 mg in a single dose). in the case of oral or rectal administration) of a compound of formula (I) or formula (II). Doses of from about 0.5 to about 300 mg / kg per day, preferably 0.5 to 20 mg / kg per day, with the weight being calculated as the active ingredient, may be administered advantageously, and it is to be understood that the compound or the compounds of formula (I) are administered in particular in an amount determined by the physician, based on all relevant circumstances, including the disease and condition to be treated, the choice of the compound to be administered and the route of administration of the compound. The above ranges are not intended to limit the scope of the invention in any way.

Formulations suitable for separate administration of leukotriene (LTB ₄ ) antagonists normally comprise at least one compound selected from compounds of Formula A and Formula (I), admixed with or dissolved in a carrier or incorporated or encapsulated in a digestible carrier in the form of a capsule, lozenge, pill, paper or other containers or manipulable containers that can be carried, such as ampoules. The carrier or diluent may be a solid, semi-solid or liquid material that serves as a vehicle, excipient, or environment for the active therapeutic agents. Some examples of diluents or carriers that can be used in the pharmaceutical compositions of the invention are lactose, dextrose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, fumed silica, microcrystalline cellulose, silicate silicon dioxide, polyvinylpyrrolidone, ketostearyl alcohol, starch, modified starches, gum arabic, calcium phosphate, cocoa butter, ethoxylated esters, cocoa oil, peanut oil, alginates, tragacanth, gelatin, syrup, methylcellulose, polyoxyethylene sorbitan, mono-propyl, ethyl-laurate, propyl, ethyl laurate, -hydroxybenzoáty.

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162 sorbitan trioleate, sorbitan quioleate and oleyl alcohol and blowing agents (hereinafter also referred to as "propellants") such as trichlorofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane. In the case of tablets, a lubricant or lubricant may be added in advance to the molds and the compression tool of the tablet machine to prevent sticking and joining of the powder additives. For this purpose, for example, aluminum stearate, magnesium stearate or calcium stearate, talc or mineral oil may be used.

Preferred pharmaceutical forms of the invention are capsules, tablets, suppositories, injectable solutions, creams and ointments. Especially preferred are formulations for inhaled administration such as an aerosol and for oral administration.

For any of the leukotriene (LTB ₄ ) antagonists listed above, the following formulation formulations, exemplified, may be used. These examples are illustrative only and are not intended to limit the scope of the invention in any way.

Examples of particular embodiments of the compositions of the invention

Example of composition of mixture

Hard gelatin capsules are prepared using the smoke component:

Quantity (mg / capsule) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl)) -5-hydroxy-) phenoxy) propoxy) -6- (4-carboxyphenoxy) phenyl) propanoic acid 250 starch 200 Magnesium stearate 10

The above ingredients are mixed and filled into hard gelatin capsules in an amount of 460 mg per dosage unit.

163

Example of composition 2

A tablet is prepared using the ingredients listed below:

Quantity (mg / tablet) 1- (4- (carboxymethoxy) phenyl) -1- (1H-tetrazol-5-yl) -6- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) hexane 250 Cellulose, microcrystalline 400 Silica, fumed 10 Magnesium stearate 5

The ingredients are mixed and compressed into tablets, each of which has a weight

665 mg.

Example of composition 3

The aerosol solution is prepared by mixing the following smoke components:

Weight% 3- [4- [7-carboxy-9-oxo-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxy- phenoxy] propoxy] -9H-xanthene]] propanoic acid 0.25 ethanol 30.00 Propellant 11 (trichlorotrifluoromethane) 10.25 Propellant 12 (dichlorodifluoromethane) 29.75 Propellant 114 (dichlorotetrafluoroethane) 29.75

The active compound is dissolved in ethanol and the solution is added to the propellant

11, cooled to -30 ° C and transferred to a filler. The required amount is then filled into a container and further filled with a premix of propellants 12a

114, using a cold filling or pressure filling method.

Valve units are then connected to the vessels.

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Example of composition 4

Tablets, each containing 60 mg of active ingredient, are prepared as follows:

Quantity (mg / tablet) 2- [2-Propyl-3- [3- [2-ethyl-5-hydroxy-] sodium salt 4-4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid 60 starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone (as a 10% aqueous solution) 4 sodium carboxymethyl 4.5 Magnesium stearate 0.5 talc 1 Pretty 150

The active ingredient, starch and cellulose are passed through a 45 mesh U.S. sieve sieve and mixed thoroughly. The obtained powders are mixed with a solution of polyvinylpyrrolidone and then the resulting mixture is passed through a 14 mesh U.S. sieve. The granules so obtained are then dried at 50-60 ° C and passed through a 18 mesh U.S. sieve. To these granules are then added sodium carboxymethyl starch, magnesium stearate and talc, pre-screened to a mesh size of about 60 µm (60 mesh U.S. sieve), and after mixing the mixture is compressed on a tablet machine to give tablets each weighing 150 mg.

Example of composition of the mixture

Capsules are prepared, each containing 80 mg, using the following ingredients:

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Quantity (mg / capsule) 5- [3- [2- (1-Carboxy) ethyl] -4- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenyl] -4-pentanoic acid 80 starch 59 Microcrystalline cellulose 59 Magnesium stearate 2 Pretty 200

The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a 45 mesh U.S. sieve and filled into hard gelatin capsules at 200 mg per dosage unit.

Example of composition 6

Suppositories, each containing 225 mg of active ingredient, are prepared as follows:

Quantity (mg / suppository) 3- (5- (6- (4- (4-Fluorophenyl) -5-hydroxy-2-ethylphenoxy) propoxy) -2-carboxymethyl-1,2,3,4-tetrahydronaphthalen-1 (2H) -one) propanoic acid 225 Glycerides of unsaturated or saturated fatty acids up to 2 000

The active ingredient is passed through a 60 mesh U.S. sieve and mixed in molten (using minimal heat required) fatty acid glycerides. The mixture is then cooled by pouring into a suppository mold with a nominal weight of 2 g and allowed to cool.

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166

Example of composition 7

Suspensions, each containing 5 ml of 50 mg of the active substance, are prepared as follows:

The drug substance is passed through a 45 mesh U.S. sieve and mixed with sodium carboxymethylcellulose, sugar, and a sufficient amount of water to form a suspension. The parabens, flavor and coloring agents are first dissolved and diluted in a certain amount of water and added in this form with concomitant mixing. Water is then filled to the required volume.

The ingredients used are as follows:

number 2- [2-Propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-] acid hydroxy-phenoxy] propoxy] phenoxy] benzoic acid 50 mg sodium carboxymethylcellulose 50 mg sugar 1 g methylparaben 0.05 mg Propyl 0.03 mg flavor as needed coloring as needed Purified water to 5 ml

The drug is passed through a 45 mesh U.S. sieve and mixed with sodium carboxycellulose, sugar, and water to form a suspension. The parabens, flavors and colorants are dissolved and diluted in water before addition, and then added to the mixture with stirring. Sufficient water is then added to reach the desired volume.

Example of composition 8

Hard gelatin capsules are prepared using the smoke component:

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Quantity (mg / capsule) 1- (4-amino-5-methyl-2-oxo-1H-pyrimidin-1-yl) -2- deoxy-2 ', 2'-difluororibose 250 Dried starch 200 Magnesium stearate 10

The above ingredients are mixed and filled into hard gelatin capsules in an amount of 460 mg per dosage unit.

Example of composition 9

A tablet is prepared using the ingredients listed below:

Quantity (mg / tablet) 1- (2-oxo-4-amino-1H-pyrimidin-1-yl) -2-deoxy-2 ', 2'- difluororibose 250 Cellulose, microcrystalline 400 Silica, fumed 10 Stearic acid 5

The ingredients are mixed and compressed to form tablets, each weighing 665 mg.

Example of composition 10

An aerosol solution is prepared containing the following smoke components:

mass 1- (2,4-dioxo-1H, 3H-pyrimidin-1-yl) -2-deoxy-2 ', 2'-difluoro-ribose 0.25 ethanol 29.75 Propelent 22 (chlorodifluoromethane) 70.00

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The active compound is mixed with ethanol and this mixture is added to a proportion of propellant 22, cooled to 30 ° C and then transferred to a filling machine. The required amount is then filled into a stainless steel container and diluted with the remaining propellant. The valve units are then connected to the vessel.

Example composition 11

Tablets, each containing 60 mg of active ingredient, are prepared as follows:

Quantity (mg / capsule) 1- (4-amino-2-oxo-1H-pyrimidin-1-yl-2-deoxy-2 ', 2'- difluoro-ribose 60 starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone (as a 10% aqueous solution) 4 sodium carboxymethyl 4.5 Magnesium stearate 0.5 talc 1

The difluoronucleoside, starch and cellulose are passed through a 45 mesh U.S. sieve and mixed thoroughly. The polyvinylpyrrolidone solution is then mixed with the obtained powder, which is then passed through a 14 mm U.S. sieve. The granules so obtained are then dried at 50-60 ° C and passed through an 18 mesh U.S. sieve. The carboxymethyl starch, magnesium stearate and talc, pre-screened on a 60 mesh U.S. sieve, are then added to the granules, and after mixing, the mixture is compressed on a tabletting machine to a tablet size such that each tablet weighs 150 mg.

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Example of composition of the mixture 12

Capsules each containing 80 mg of the active substance are prepared as follows:

Mixture used:

Quantity (mg / capsule) 1- (4-amino-2-oxo-1H-pyrimidin-1-yl) -2-deoxy-2 ', 2'- difluórxylóza 80 starch 59 Microcrystalline cellulose 59 Magnesium stearate 2

The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a 45 mesh U.S. sieve and filled into hard gelatin capsules at 200 mg per dosage unit.

Example composition 13

Suppositories, each containing 225 mg nucleoside, are prepared as follows:

Composition of the mixture:

number 1- (2,4-dioxo-1H, 3H-pyrimidin-1-yl) -2-deoxy-2 ', 2'-difluororibose 225 mg Saturated fatty acid glycerides up to 2 g

The nucleoside is passed through a 60 mesh U.S. sieve, mixed in advance, using the minimum heat required, of molten saturated fatty acid glycerides. The mixture is then cooled by pouring into a suppository mold having a nominal weight of 2 g and then allowed to cool.

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Example of composition 14

Suspensions are prepared, each containing 50 mg of the active substance in a 5 ml dose, as follows:

number 1- (4-amino-5-methyl-2-oxo-1H-pyrimidin-1-yl) -2-deoxy-2 ', 2'- difluororibose 50 mg sodium carboxymethylcellulose 50 mg syrup 1.25 ml Benzoic acid solution 0,10 ml flavor as needed coloring as needed Purified water to 5 ml

Example of composition 15

An intravenous formulation is prepared as follows using the following ingredients:

number 1- (4-amino-2-oxo-1H-pyrimidin-1-yl) -2-deoxy-2 ', 2'-difluororibose 100 mg Isotonic brine 1000 ml

A solution of the above component is administered intravenously to the mammal at a rate of 1 ml / minute, wherein said mammal is treated with neoplasms that are susceptible to the treatment.

Example of composition of the mixture 16

Hard gelatine capsules are prepared using the following ingredients:

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Quantity (mg / capsule) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) - propoxy) -6- (4-carboxyphenoxy) phenyl) propanoic acid 250 2 ', 2'-difluoro-2'-deoxycytidine monohydrochloride 250 starch 200 Magnesium stearate 10

The above ingredients are mixed and filled into hard gelatin capsules in an amount of 710 mg per dosage unit.

Example of composition 17

Tablets are prepared using the ingredients listed below:

Quantity (mg / tablet) 1- (4- (carboxymethoxy) phenyl) -1- (1 H-tetrazol-5-yl) -6- (2- ethyl 4- (4-fluorophenyl) -5-hydroxyphenoxy) hexane 250 2 ', 2'-Difluoro-2'-deoxycytidine monochloride 250 Cellulose, microcrystalline 400 Silica, fumed 10 Magnesium stearate 5

The ingredients are mixed and compressed to form tablets each weighing 915 mg.

Example of composition 18

An aerosol solution is prepared containing the following components:

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Weight% 3- [4- [7-carboxy-9-oxo-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxy- phenoxy] propoxy] -9H-xanthene]] propanoic acid 0.25 2 ', 2'-difluoro-2'-deoxycytidine monohydrochloride 0.25 ethanol 30.00 Propellant 11 (trichlorofluoromethane) 10.00 Propellant 12 (dichlorodifluoromethane) 29.75 Propellant 114 (dichlorotetrafluoroethane) 29.75

The active compound is dissolved in ethanol and the solution thus obtained is added to propellant 11, cooled to -30 ° C and transferred to a filling apparatus. The required amount is then filled into the tank and further filled with the premixes of propellants 12 and 114, proceeding by a cold filling method or a pressure filling method. Valve units are then connected to the tank.

Example of composition 19

Tablets, each containing 60 mg of the active ingredient, are prepared from the following ingredients:

mass 2- [2-Propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid, sodium salt 60 mg 2 ', 2'-difluoro-2'-deoxycytidine monohydrochloride 60 mg starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as a 10% solution in water) 4 mg sodium carboxymethyl 4.5 mg Magnesium stearate 0.5 mg talc 1 mg Pretty 210 mg

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173

The active ingredient, starch and cellulose are passed through a 45 mesh U.S. sieve and mixed intimately. The resulting powder is then mixed with polyvinylpyrrolidone and then passed through a No. 14 mesh U.S. sieve. The granules so obtained are then dried at 50 to 60 ° C and passed through an 18 mesh U.S. sieve. Next to these granules are added other ingredients, such as sodium carboxymethyl starch, magnesium stearate and talc, which are pre-sized by passing them through a 60 mesh US sieve and after mixing the mixture is compressed into a tablet tablet machine, using a form such that each tablet weighs 210 mg.

Example of composition 20

Capsules, each containing 80 mg of the active ingredient, are prepared as follows:

Quantity (mg / capsule) 5- [3- [2- (1-carboxy) -ethyl] -4- [3- [2-ethyl-4- (4-fluorophenyl) -5- hydroxyphenoxy] propoxy] phenyl] -4-pentanoic acid 80 mg 2 ', 2'-difluoro-2'-deoxycytidine monohydrochloride 80 mg starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Pretty 280 mg

The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a 45 mesh U.S. sieve and filled into hard gelatin capsules at 280 mg per dosage unit.

Example of composition of the mixture 21

Q11 / R

174

Suppositories, each containing 225 mg of the active ingredient, are prepared as follows:

mass 3- (5- (6- (4- (4-Fluorophenyl) -5-hydroxy-2-ethylphenoxy) propoxy) -2-carboxymethyl-1,2,3,4-tetrahydronaphthalen-1 (2H) -one) propanoic acid 225 mg 2 ', 2'-Difluoro-2'-deoxycytidine monochloride 225 mg Glycerides of unsaturated or saturated fatty acids up to 2000 mg

The active ingredient is passed through a 60 mesh U.S. sieve and mixed in fatty acid glycerides previously melted using the minimum heat required. The mixture is then rapidly cooled by pouring into a suppository mold with a nominal weight of 2 g and allowed to cool.

Formulation Example 22

Suspensions, each containing 50 mg of the active substance in a 5 ml dose, are prepared as follows and using the following ingredients:

number 2- [2-Propyl-3- [3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenoxy] benzoic acid 50 mg 2 ', 2'-difluoro-2'-deoxycytidine monohydrochloride 50 mg sodium carboxymethylcellulose 50 mg sugar 1 g methylparaben 0.05 mg Propyl 0.03 mg flavor as needed coloring as needed Purified water to 5 ml

Q1 1 / R

175

The drug is passed through a 45 mesh U.S. sieve and mixed with sodium carboxymethylcellulose, sugar and water to form a suspension. The parabens, flavor and color are dissolved and diluted with an additional portion of water and added with stirring to the mixture prepared previously. Sufficient water is then added to reach the desired volume.

Pharmaceutical compositions of the invention

The following main ingredients are included in the pharmaceutical compositions of the invention:

(a) an LTB ₄ antagonist; and (b) an anticancer drug.

When the pharmaceutical compositions of the present invention are prepared in injectable form, the following ingredients are included as ingredients:

(a) an LTB ₄ antagonist, (b) an anticancer drug, and (c) an injectable liquid vehicle.

Pharmaceutically acceptable vehicles are those well known in the medical art, such as sterile water, sterile saline-containing water and sterile sugars and / or saline-containing water.

The ratios and amounts of the components in the composition of the invention

The main components (a) of the LTB ₄ antagonist and (b) the anticancer active compound are provided in the compositions, wherein their composition and the proportions in the dose of such a composition provide a pharmaceutically effective amount of each component to the patient being treated. Typically, the weight ratio of the amount of LTB ₄ antagonist to the amount of anticancer drug is 1: 100 to 100: 1, preferably 10: 1 to 1: 10, and most preferably 1: 4 to 4: 1.

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Leukotriene (LTB ₄ ) antagonists are generally administered before, during and after administration of the 2 ', 2'-difluorucleoside anticancer drug. When leukotriene (LTB ₄ ) antagonists are administered after a 2 ', 2'-difluoronucleoside anticancer drug, they should be administered at a time that falls within the therapeutically effective interval.

Experiments now confirm the effect of the invention.

Test Example 1

The nude mouse xenograft assay used to evaluate the antionolytic drugs of the invention is a well known procedure and is described in the manuals and publications: Beverly A. Teicher, Ed. Anticancer Drug Development Guide, Humana Press, Totowa, New Jersey, 1997, p. 75-124 (ISBN 0-89603-461-5). The information disclosed in this publication is hereby incorporated by reference. The xenograft test can be described in more detail as follows:

Male or female nude mice that were selected as needed for a given tumor type (Charles River) were totally irradiated (450 rad). After 24 hours, mice were implanted subcutaneously in the hind leg with human prostate cancers LNCaP and DU-145, pancreatic cancers Panc-1 and BxPC _3, and non-small cell lung cancers H460 and Calu-6 (all of these cancers are available from American Type Culture Collection, Manassas) , VA), which were prepared from donor-derived tumor tissue (5 x 10 ⁶ cells). Mice were treated with 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid (Formula IV) at 30, 100, 200, or 300 mg per kilogram daily administered orally, starting at 4 days post-implantation. Gemcitabine (60 mg / kg) was administered intraperitoneally.

Tumor response was monitored by measuring tumor volume, which was performed twice weekly for 60 to 90 days. The body weights of the test animals were determined to determine overall toxicity. The mice were divided into

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177 control and treatment groups, with five mice per group.

The results obtained were analyzed by determining the mean tumor volume in the control group and in each treatment group throughout the experiment, and the deceleration of daily tumor increments was calculated as the difference between the time until the tumors in the treated and control groups reached 1000 mm ³ .

Table 1 Results of Prostate Tumor Xenograft Growth Test ⁽¹⁾

treatment dose Formula IV dose GEM TGD TGD, sem 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 + GEM 30 60 43.2 3.00 Formula IV + GEM 100 60 51.2 3.50

Explanation:

prostate cancer LNCaP

Formula IV LTB ₄ antagonist, ie 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid GEM gemcitabine hydrochloride, i.e. 2 ', 2'-difluoronucleoside an anticancer drug, the product of Eli Lilly and Company dose milligrams per kilogram of mouse body weight LNCaP LNCaP prostate cancer TGD average tumor growth retardation in days

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TGD, here the standard deviation of the mean TGD

Table 2 Results of mouse xenograft test Deceleration of prostate tumor growth ⁽²⁾

treatment dose Formula IV dose GEM TGD TGD, sem 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 + GEM 30 60 15.6 1.40 Formula IV + GEM 100 60 25.2 2.20

Explanation:

⁽²⁾ prostate cancer DU-145

GEM gemcitabine hydrochloride, ie 2 ', 2'-difluoronucleoside anticancer drug, product of Eli Lilly and Company dose milligrams per kilogram body weight of mouse

TGD average tumor growth retardation in days

TGD, here the standard deviation of the mean TGD

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Table 3 Pancreatic tumor growth retardation xenograft test ⁽³⁾

treatment dose Formula IV dose GEM TGD TGD, sem 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 + GEM 30 60 22.9 1.90 Formula IV + GEM 100 60 27.0 2.30

Explanation:

⁽³⁾ pancreatic cancer tumor BxPC3

GEM gemcitabine hydrochloride, ie 2 ', 2'-difluoronucleoside anticancer drug, product of Eli Lilly and Company dose milligrams per kilogram body weight of mouse

TGD average tumor growth retardation in days

TGD, here the standard deviation of the mean TGD

Ή Q44 / Q

180

Table 4 Pancreatic tumor growth retardation xenograft test ⁽⁴⁾

treatment dose Formula IV dose GEM TGD TGD, sem 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 + GEM 30 60 18.2 1.50 Formula IV + GEM 100 60 23.3 2.30 Formulas EM IV + GEM 200 60 29.1 3.00

Explanation:

⁽⁴⁾ Panc-1 pancreatic cancer tumor

GEM gemcitabine hydrochloride, ie 2 ', 2'-difluoronucleoside anticancer drug, product of Eli Lilly and Company dose milligrams per kilogram body weight of mouse

TGD average tumor growth retardation in days

TGD, here the standard deviation of the mean TGD 'i 4 Λ1 4 / D

181

Table 5 Non-small cell lung cancer tumor growth xenograft test results ⁽⁵⁾

treatment dose Formula IV dose GEM TGD TGD, sem 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 + GEM 30 60 20.2 2.00 Formula IV + GEM 100 60 21.3 2.20 Formula IV + GEM 200 60 32.0 3.10

Explanation:

^{(5) a} non-small cell tumor of human lung cancer H460 NSCLC

GEM gemcitabine hydrochloride, ie 2 ', 2'-difluoronucleoside anticancer drug, product of Eli Lilly and Company dose milligrams per kilogram body weight of mouse

TGD average tumor growth retardation in days

TGD, here the standard deviation of the mean TGD

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Table 6 Non-small cell lung cancer tumor growth xenograft test results ⁽⁶⁾

treatment dose Formula IV dose GEM TGD TGD, sem 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 + GEM 30 60 17.4 1.60 Formula IV + GEM 100 60 22.5 2.00

Explanation:

^{(6) a} non-small cell tumor of human lung cancer Calu-6

GEM gemcitabine hydrochloride, ie 2 ', 2'-difluoronucleoside anticancer drug, product of Eli Lilly and Company dose milligrams per kilogram body weight of mouse

TGD average tumor growth retardation in days

TGD, here the standard deviation of the mean TGD

Detailed description of attached pictures

Figures 1 to 6 in the image section show the data in Tables 1 to 6, see above. The figures show the increasing effect of combining the administration of compound (i), which is a compound of formula IV and compound (ii), which is gemcitabine hydrochloride, which slows down the rate of tumor growth compared to the compounds (i) or (ii) alone. .

183

Fig. 1 depicts various treatments for LNCaP prostate cancer.

Columns (1), (2) and (3) show tumor growth retardation as a result of the use of the LTB ₄ inhibitor, Formula IV, alone at doses of 30, 100 and 200 mg / kg.

Column (4) shows the tumor growth retardation for the anticancer drug, gemcitabine hydrochloride alone at 60 mg / kg.

Columns (5) and (6) show tumor growth retardation as a result of the concomitant use of the compound of formula IV (at doses of 30 and 100 mg / kg) and gemcitabine hydrochloride (at dose of 60 mg / kg).

Fig. 2 shows various treatments of implanted DU-145 prostate cancer.

Columns (1), (2) and (3) show tumor growth retardation as a result of the use of an LTB ₄ inhibitor, in particular a compound of Formula IV, alone at doses of 30, 100 and 300 mg / kg.

Column (4) shows the tumor growth retardation for the anticancer drug, which in this case is gemcitabine hydrochloride alone at 60 mg / kg.

Columns (5) and (6) show tumor growth retardation as a result of the concomitant use of the compound of formula IV (at doses of 30 and 100 mg / kg) and gemcitabine hydrochloride (at dose of 60 mg / kg).

Fig. 3 shows various treatment procedures for the treatment of implanted pancreatic carcinoma BxPC3.

Columns (1), (2) and (3) show tumor growth retardation as a result of the use of the LTB ₄ inhibitor, a compound of Formula IV, alone at doses of 30, 100 and 300 mg / kg.

Column (4) shows the tumor growth retardation for the anticancer drug, gemcitabine hydrochloride alone at 60 mg / kg.

184

Columns (5) and (6) show tumor growth retardation as a result of the concomitant use of the compound of formula IV (at doses of 30 and 100 mg / kg) and gemcitabine hydrochloride (at dose of 60 mg / kg).

Fig. 4 shows various treatments of implanted pancreatic carcinoma Panc-1.

Columns (1), (2) and (3) show tumor growth retardation as a result of the use of the LTB ₄ inhibitor, a compound of Formula IV, alone at doses of 30, 100 and 200 mg / kg.

Column (4) shows the tumor growth retardation for the anticancer drug, gemcitabine hydrochloride alone at 60 mg / kg.

Columns (5), (6) and (7) show tumor growth retardation as a result of co-administration of the compound of formula IV (at doses of 30, 100 and 200 mg / kg) and gemcitabine hydrochloride (at dose of 60 mg / kg).

Fig. 5 shows various treatments of human tumor type H460 non-small cell lung cancer.

Columns (1), (2) and (3) show tumor growth retardation as a result of the use of the LTB ₄₁ inhibitor, i.e. the compound of Formula IV, alone, at doses of 30, 100 and 200 mg / kg.

Column (4) shows the tumor growth retardation when the anticancer drug, gemcitabine hydrochloride, was administered alone at a dose of 60 mg / kg.

Columns (5), (6) and (7) show tumor growth retardation as a result of co-administration of the compound of formula IV (at doses of 30, 100 and 200 mg / kg) and gemcitabine hydrochloride (at dose of 60 mg / kg).

Fig. 6 shows various treatments of implanted non-small cell

185 human lung carcinoma Calu-6.

Columns (1), (2) and (3) show tumor growth retardation as a result of the use of the LTB ₄ inhibitor, a compound of Formula IV, alone at doses of 30, 100 and 200 mg / kg.

Column (4) shows the growth retardation of the implanted tumor when administered with the anti-cancer drug, gemcitabine hydrochloride, alone at a dose of 60 mg / kg.

Columns (5) and (6) show tumor growth retardation as a result of the concomitant use of the compound of formula IV (at doses of 30 and 100 mg / kg) and gemcitabine hydrochloride (at dose of 60 mg / kg).

O 4 Λ 4 4 / n

186

Claims (7)

PATENT CLAIMS A composition comprising a therapeutically effective amount of an antagonist leukotriene (LTB ₄ ) and a therapeutically effective amount of a 2 ', 2'-difluoronucleoside anticancer agent. A composition comprising a therapeutically effective amount of an antagonist leukotriene (LTB ₄ ) and a therapeutically effective amount of a 2 ', 2'-difluoro nucleoside anti-cancer agent, wherein the anti-cancer agent is a therapeutically effective amount of a compound characterized by the formula: where: R 1 is hydrogen, R ₂ is a base defined by one of the formulas: Q11 / R 187 Ο where: X is C-R4, R ₃ is H, R ₄ is hydrogen, C ₁ -C ₄ alkyl, bromo, fluoro, chloro, or iodo, and pharmaceutically acceptable salts thereof. The composition of claim 2, wherein R ₂ is a base defined by the formula: The composition of claim 2, wherein the anticancer drug is selected from the following compounds and pharmaceutically acceptable salts thereof: (i) 1- (4-amino-2-oxo-1 H -pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluorobibose, (ii) 1- (4-amino-2-oxo-1) H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluoroxylose, 31,011 / R 188 (iii) 1- ₍₂ '4-dioxo-1H, 3H-pyrimidin-1-yl) -2-deoxy-2', 2'-difluororibose and (iv) 1- (4-amino-5-methyl- 2-oxo-1H-pyrimidin-1-yl) -2-deoxy-2 ', 2'-difluororibose. The composition of claim 2, wherein the anticancer agent is gemcitabine hydrochloride. The composition of claim 1 or 2 or 3 or 4 or 5, wherein the leukotriene antagonist (LTB ₄ ) is of formula I: in which: X is selected from a file that includes: (i) a five membered substituted or unsubstituted heterocyclic radical containing 1 to 9 heteroatoms independently selected from sulfur, nitrogen and oxygen; or (ii) a fused bicyclic radical in which the carbocyclic group is fused to two adjacent carbon atoms atoms of a five membered heterocyclic radical (i), Y 1 is a bond or a divalent linking group containing 1 to 9 atoms, 31,911 / B 189 Y ₂ and Υ 3 are bivalent linking groups which are independently selected from the group consisting of the formulas -CH 2 -, -O- and -S-, Z is an acid group, R f is CF CFO alkyl, aryl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkenyl, C ₂ -C ₀ alkynyl, C ₆ -C ₂ o aralkyl, C ₆ -C ₂ o aryl, C _w haloalkyl, C ₆ -C ₂ aryloxy or C 1 -C ₁₀ alkoxy, R ₂ is hydrogen, halogen, C 1 -C 10 haloalkyl, C 1 -C 10 alkoxy, C 1 -C 6 alkyl, C ₃ -C 8 cycloalkyl, an acid group or - (CH 2) i -7 (acid group), R ₃ is hydrogen, halogen, C 1 -C 10 alkyl, aryl, C 1 -C 10 haloalkyl, C 1 -C 10 alkoxy, C 1 -C 10 aryloxy, C ₃ -C 8 cycloalkyl, R ₄ is C _r C ₄ alkyl, C ₃ -C ₄ cycloalkyl, - _(CH2) i-7 (cycloalkyl), C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, benzyl, aryl, and n is 0, 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt, solvate or prodrug of any of the defined compounds. The composition of claim 6, wherein X is a heterocyclic radical selected from the group consisting of substituents characterized by the following structural formulas: