CZ20021551A3 - Oncolytic combinations for treating cancer - Google Patents

Abstract

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

Description

The invention relates to a method of treating cancer with anti-cancer drugs. 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 of other inflammatory conditions, and activation of inflammatory-related leukocytes characterized by infiltration with polymorphic nucleus and cell reactions. Therefore, activated polymorphic leukocytes release enzymes, degrading tissue and reactive chemicals causing inflammation. US Patent 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 a polymorphic nucleus of pro-inflammatory cells. US

Patent 5,910,505 discloses leukotriene B ₄ (LTB ₄ ) that some phenylphenol antagonists can be used to treat cancer

• ·

Squamous cells of the oral cavity. U.S. Patent 5,543,428 discloses a class 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 drug resistance in resistant tumor cells by vinblasin, vincristine, vindesine, navelbine, daunorubicin, doxorubicin, mitoxantrone, etoposide, teniposide, mitomycin C, actinomycin, taxol, topotecan, eminycin, eminycin, emramycin, emramycin, emramycin and valinomycin.

SUMMARY OF THE INVENTION

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

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

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

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 Z ₂ substituent of formula (II), acts as a hydrogen bonding proton donor. Illustrative acidic carboxyl group.

The term active ingredient means both certain 2 ', 2'-difluoro nucleoside 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 enumerating the specific biphenyl compounds below, and further a combination of the 2 ', 2'-difluoro nucleoside leukotriene B ₄ antagonists described by the modified side of Formula A or Formula I and / or prodrugs thereof.

II, with salts, solvates and / or

The term "alkenyl" means a monovalent radical of the generic formula C _n H _{n 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 C6-C20 alkaryl, numeric subscripts denote the total number of carbon atoms in the radical.

The term, C ₆ -C ₂₀ aralkyl means an alkyl radical substituted with an aryl or substituted aryl group, for example:

In the term C 8 -C 50 aralkyl, numeric 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 (eg, benzene, cyclohexene, cyclohexane, cyclopentane).

The term, monovalent cyclopentyl, cycloalkyl means a carbocyclic non-aromatic radical such as cyclopropyl, cyclobutyl, 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 mammalian include human.

The term N-sulfonamidyl means a radical:

- C-N-S-R12

I ^H I

Wherein R 12 is C 1 -C 10 alkyl, aryl, C 1 -C 8 alkyl substituted with aryl, C ₆ -C ₂₀ alkaryl, or C ₆ -C ₂₀ aralkyl.

The term "substituted alkyl" means an alkyl 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 8 haloalkyl (eg, -CF 3).

The term "substituted aryl" means an aryl 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 ₈ alkoxy, C 1 -C 6 haloalkyl (eg, -CF 3).

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

N ~

N

AND

NH

HN

AND

N or

N

II

N

The term "therapeutically effective interval" refers to a period of time that begins when a first of the active ingredients is administered to a mammal, including (a) a 2 ', 2'-difluoroukeoside anti-cancer drug or (b) an LTB4 antagonist and ending with an anti-cancer limit. a beneficial effect for the treatment of cancer of any of (a) or (b). Usually, the anti-cancer leukotriene antagonist (LTB ₄ ) is administered within 24 hours of each other, preferably within 4 hours, and most preferably within 1 hour.

The term "therapeutically effective combination ⁰ " used in the practice of the invention means the administration of (a) a 2 ', 2'-difluoroukeoside anticancer drug and (b) an LTB ₄ antagonist, either simultaneously or separately, in any order.

The anticancer active compounds which can be used in this sense, for example, are the 2 ', 2'-difluoro nucleoside compounds of the formula:

R ¹ OH, C °

V, 2

OH in which:

R ₂ is hydrogen or

II

-CR ⁵

R ₅ is a base as defined by one of the formulas

where

X is N or C-R 4

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

O

II 5 —C-R • 1 • 1 <

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 can also be used

R ⁶ OH ₂ c _x c>

OH in which:

R ₆ is hydrogen, C 1 -C 4 alkyl;

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

NHR ⁸

HN

O

N r ⁸ hn ^> _n A

HN X

N ·· ·· • «• · ·· in which:

X is N or CR ₄ ;

R 8 is hydrogen or C 1 -C ₄ alkyl;

R ₄ is hydrogen, C 1 -C 4 alkyl; amino, bromine, fluorine, chlorine and iodine;

and pharmaceutically acceptable salts of the defined compounds;

with the proviso that R 6 and R 8 can both be hydrogen only when X is N, and furthermore the compounds defined by the general formula r ⁶ oh may be used

OH in which:

R ₆ is hydrogen or C 1 -C ₄ alkyl;

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 provide clear methods for preparing these compounds, formulating compositions based thereon, and treating cancer with these compounds.

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

where:

R 1 is hydrogen;

R ₂ is a base defined by one of the formulas:

About:

where:

X is CR ₄ ;

Ra 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

R ₂ is a base defined by the formula:

Even more preferred are anticancer active compounds selected from the group consisting of 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, · * * *,,,,,,,,,,, pyr (Iii) 1- (2,4-dioxo-1H, 3H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluorribose, 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 2'-deoxy-2 ', 2'-difluorocytidine monohydrochloride (β-isomer) and is also known as 2', 2'-difluoro-2'-deoxycytidine monohydrochloride, or also as 1- (4- amino-2-oxo-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluoribibose

The structural formula is as follows:

The anticancer drug is 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 tablets, pills, 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.

• · · · ·

HIM

R

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

R 1 'is C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, C 1 -C 4 alkoxy, (C 1 -C 4 alkyl) thio, halogen, or R ₂ ' -substituted phenyl;

each of R ₂ 'and R ₃ ' is independently hydrogen, halogen, hydroxy, C 3 -C 4 alkyl, C 1 -C 4 alkoxy, (C 1 -C 4 alkyl) - (O) _q S-, trifluoromethyl, or di- (C 1 -C 4 alkyl); -C3 alkyl) amino;

X 'is -O-, -S-, -C (= O), or -CH ₂ -; Y 'is -O- or -CH ₂ -;

or when connected together, then -X'-Y'- represents -CH = CH or -C = C-;

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

9 9 9

99 «999 999 999 999 999 999 999 999 999 999 999 999 999 999 999 999 999 999 999 999 999 999 999 9999

A 'is a bond, -0-, -S-, -CH = CH-R b or -CR _a, wherein R _a and R _b are each independently hydrogen, C1-C5 alkyl, or R 7 -substituted phenyl or ¹ when associated together with the carbon atom to which they are attached together form a C 1 -C 8 cycloalkyl ring;

R ₄ 'is R ₆ ,

15 / labc, 2ab

R

wherein each R ₆ is independently -COOH, 5-tetrazolyl, CON (R ₉ ) 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 , -TR ₆ , (C 1 -C 4 alkyl) -T (C 1 -C 4 alkylidenyl) -O-, or hydroxy;

R 5 is hydrogen or halogen;

each R ₉ is independently hydrogen, phenyl, or C 1 -C 4 alkyl, or when taken together with the nitrogen atom to which they are attached form a morpholine, piperidine, piperazine, or pyrrolidine group;

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

R 11 is R 2 or _{R 6} -WR -TG-Rg;

each W is a bond or a linear or bivalent branched chain hydrocarbon radical having one to eight carbon atoms;

· ♦ / / / / / / / / / / / / / / / / / / / / / / Each G is a linear or divalent branched-chain hydrocarbon radical having one to eight carbon atoms;

each T is a bond, -CH 2 -, -O-, -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 t is 0 or 1;

with the proviso that when X is -O- or -S-, then Y is not -O-;

with the proviso that when A is -O- or -S-, then 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

4 »

18:

• 4 • 4

4 · »• 4 4 • 4 * 44

4 4 4

4 4 t 4

4 * 44

4 4

4 4

4444

Even more preferred antagonists are those wherein R ₄ 'is:

The LTB _{4 of} Formula A are

Some of these preferred _LTB4 antagonist compounds or pharmaceutically acceptable derivatives of compounds defined as derivatives, especially ester, shown below, selected from the group (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;

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;

· <· · · # # # # # # # # 9 9 9 9 e e e

> · · 9 · * ··

I * * »A * 999

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) -1- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) undecane;

20 ·.

·· ·· ·· · · I · * · · · · ·

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) dihydrocoumarin;

HH) Sodium 2-phenyl-4-ethyl-5- [6- (2H-tetrazol-5-yl) -6-methylheptyloxy] phenol;

II) Disodium 2- (4-Methylphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol;

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) hepyloxy] phenol, sodium salt;

·· ·· »· ·

MM) 2- (3-Methoxyphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) hepyloxy] 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-ethyl-phenoxy) 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 :

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

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

• · · ·· :::

• 4 · 4 · 4 ·· ···

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, sodium 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-9H-xanthene]) propanoic acid, sodium hemihydrate;

EEE) 2-Fluoro-6- [2-propyl-3- [3- (2-ethyl-5-hydroxy-4-phenyl-phenoxy) -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;

k ·· • · · · · ·

GGG) 3- [4- [7-Carboxy-9-oxo-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy] -9H-xanthene] propanoic acid, biphenyl sodium trihydrate;

HHH) 3- [4- [9-Oxo-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] -9H-xanthene] propanoic acid;

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

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

000) 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;

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;

«« · Ti ·

ΑΑΑΑ) 3- (2- (3- (2-Ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) -E-propenoic acid;

BBBB) 3- (2- (3- (2-Ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) -2-methyl-E-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} -3-propylphenyl) propanoic acid;

IIII) 3- (3- (3- [2-Ethyl-4- (4-fluorophenyl) -5-hydroxyphenyloxy] propoxy} -2-propylphenyl) propanoic acid;

JJJJ) 3- {3- [3- (2-Ethyl-5-hydroxyphenyloxy} propoxy] -2-propylphenyl} propanoic acid, disodium salt;

and

27 «» · 4

«· · ·

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-4-yloxy) 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 listed in the related provisional patent application entitled

28:

• · · «

Heterocyclic-substituted diphenylleukotriene antagonists (inventor: Jason Scott Sawyer; this application contains 97 pages and can also be identified in Eli Lilly's business file B-13240) filed November 11, 1999, and now in provisional patent application No. 60 / 164,786. This second class of heterocyclically substituted diphenyl leukotriene antagonists is described in further detail below:

II. Other LTB4 antagonists:

Other LTB4 antagonists are described below. They are novel heterocyclically substituted diphenyl compounds of formula (I)

in which:

X is selected from the group consisting of: (i) a five-membered substituted or unsubstituted heterocyclic radical containing from 1 to 9 heteroatoms independently selected from the group consisting of sulfur, nitrogen and oxygen;

or (ii) a fused bicyclic radical in which the carbocyclic group is fused to two adjacent carbon atoms of a five membered heterocyclic radical (i);

Y 1 is a bond or a bivalent linking group containing 1 to 9 atoms;

Y ₂ and Y ₃ are divalent linking groups that are independently selected from the group consisting of the formulas

-CH ₂ -, -O- and -S-;

Z is an acidic group;

Ri is Ci-Cio alkyl, aryl, C ₃ -Cio cycloalkyl, C ₂ -C ₀ alkenyl, C2 -C10 alkynyl, Cg-C ₂ o aralkyl, Ce-C ₂ o alkylaryl, C 1 -C 10 -haloalkyl, C ₆ -C _two of aryloxy, or C1-C10 alkoxy;

R ₂ is hydrogen, halo, C1-C10 haloalkyl, C1-C10 alkoxy, C Οχο alkyl, C3-C8 cycloalkyl, an acidic group, or - _{(CH2) 1} _ ₇ (acidic 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 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 of any of the defined compounds.

III. Preferred LTB4 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 the group consisting of hydrogen, halogen, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 1 -C 10 alkoxy, aryl, or C 8 -C 20 aryloxy.

Preferred group 1 of substituent X (symbol PG1-X).

Preferred LTB4 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:

or prodroga

R10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10

R11

• · · · ·

• · · «··

Wherein R 10 is a radical selected from the group consisting of hydrogen or hydrogen

C 1 -C 4 alkyl; and

R 11 is a radical selected from the group consisting of hydrogen, halogen, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 1 -C ₁₀ alkoxy, aryl, or C 6 -C 20 aryloxy. Preferred radicals R _I0 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 starting from any carbon or any nitrogen atom having less than three bonds in the heterocyclic ring occupied;

Binding Location for Pyrrole:

·· 4 «• ·

33 :: :: :: ::

· «·· · ♦ ·»

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, PG2-X):

The most preferred substituents X are heterocyclic radicals:

or

C. The following X substituents are excluded:

· · E e e e e e e e e e e e e e e e e e

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 has been found to be too low to be an aspect of the invention.

III D. Preferred Y 1 substituents:

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

Preferred group 1 of the possible meanings of the substituents Y 1 (symbol, PG 1 -Y 1)

Preferred LTB ₄ antagonist compounds included in the compositions of the invention are those wherein Y 1 is a divalent linker group selected from the group consisting of substituents represented by the following formulas:

-CH,

SO;

S-NR13

-NR13

35 ·· · • · · · · • · · · · · • · · · · · · · «« ·· ·· • · · * • ♦ · • · ♦ * · · ···· -C- -C- h ₂ h ₂ -O- -C- h ₂ -with- -C- h ₂ -N—- -C-

R13

Q

O ^θ

-C-cH ₂ O

Wherein R 13 is hydrogen, methyl or ethyl;

The aforementioned divalent groups can be used in positions as drawn or in inverted positions. For example, a group;

- C - CH ₂ '

II o

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

• · ··

3β ·.

· «• • • • * * * * * * * * * *

4 ·

III Ε. Preferred group of 2 possible meanings of substituent Υχ (symbol, PG2-Yx)

The most preferred divalent substituent Υχ is a group;

Preferred group 1 of the possible meanings of the substituent Y2 (symbol PGI-Y2) and preferred group 1 of the possible meanings of the substituent Y3 (symbol PGI-Y3 ”)

The substituents Y ₂ and which include -S- and -ΟΥ 3 are preferably selected from;

III G. Preferred Group 2 possible meanings of Y2 substituent (symbol, _'PG2-Y2) and a preferred group of two possible meanings of Y ₃ substituent (symbol,' _PG2-Y3 ')

Most preferably, both Y ₂ and Y ₃ is

- 0 -.

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:

• 4 • 4

4 • 4 ·

4 • 4 «4 4 4 4 4 4

4 4

4 4

4444 n

C-N-S-R12

II H II tetrazolyl,

-SO ₃ H, f

P-OH

OH t

O-ΡΟΗ

OH

C-OH or

-OH · · · · · · · · · ·

39. 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 represented by the formulas:

III I. Preferred group of 2 possible meanings of the substituent Z (symbol, PG2-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 of 1 possible meanings of variable subscript n (symbol PG1-n)

The most preferred integers that can be represented by the variable n 'in the divalent linking group - (CH ₂ ) n - are n = 1, n = 2 and n = 3.

III L. Advantageous group of 2 possible meanings of variable subscript n '(symbol' PG2-n ')

Most preferably, an integer which may represent the value of the variable n in a divalent linking group - _(CH2) n-, n is the first

··

33 ..

• A • · ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft 9 9 9 9 9 9 9 9 9 9 9

III M. Preferred group (symbol PG1Ri):

possible meanings of R 1

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

III N. Preferred Group 1 of possible meanings of the substituent R ₂ (symbol _PG1-R2) and one preferred group of possible meanings of R3 (PGI symbol R3):

Preferred groups R ₂ and R 3 are those that are independently selected from the group consisting of hydrogen or methyl, ethyl, methoxy, ethoxy, halo or -CF3; wherein R ₂ and R 3 are most preferably hydrogen.

III 1 0. A preferred group of possible meanings of the substituent R ₄ (symbol PGI-4 :)

Preferred R 4 substituents are ethyl, propyl and isopropyl.

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

The substituents of formula (I) are defined as Z, X, n, R 1, R ₂ , R ₃ , R ₄ , Y ₁ , Y ₂ and Y ₃ . In addition, as mentioned above, within the scope of substituents of formula (I), preferred and most preferred subgroups are defined, thereby defining a number of different substituents to be used to define LTB ₄ antagonists of the invention. These preferred subgroups are defined by terms such as PGI-R4 as defined above. It is often preferred to use combinations of preferred groups or combinations of preferred groups

The groups of formula I together with the generally defined variables in formula (I). Suitable combinations of substituents 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 variables _from the symbols R 2, R 3 and R ₄ in formula (I):

Table of possible meanings of the substituent R-:

Combinatorial choice Choice choice choice code groups groups groups groups Variables R Ri r ₂ r ₃ r ₄ R01. ' Ri r ₂ r ₃ r ₄ R02 · Ri r ₂ r ₃ PGI-R4 R03 Ri r ₂ PGI-R3 R ₄ . R04 Ri r ₂ PGI-R3 PGI-R4 R05 Ri PGI-R2 r ₃ R ₄ RQ6 Ri PGI-R2 R ₃ PGI-R4 R07 Ri PGI-R2 PGI-R3 r ₄ ROS Ri PGI-R2 _PG1-R3 PG1-R4 R09 PG1-Ri r ₂ r ₃ r ₄ R10 PG1-Oi r ₂ r ₃ PGI-R4 Rll PG1-Ri r ₂ PGI-R3 r ₄ R12 PG1-Ri r ₂ PGI-R3 PGI-R4 R13 PG1-Ri PGI-R2 r ₃ r ₄ R14 PG1-Ri PGI-R2 r ₃ PGI-R4 R15 PG1-Ri PGI-R2 PG1-R3 r ₄ R16 PG1-Ri PGI-R2 ' PG1-R3 PG1-R4.

• · · · · · ·

The table is used as follows:

For example, the combination of substituents &quot; R14 &quot; expresses a combination choice substituent for formula (I) wherein R 1 is selected from a preferred set of possible variable meanings, designated PG 1 -R 1, that is, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and 2-propenyl; preferred values of the variable R ₂ are PG 1 -R ₂ thus hydrogen or methyl, ethyl, methoxy, ethoxy, halogen or -CF _3; the variable R ₂ has the range defined by generic formula (I), and the substituents suitable as R ₄ are selected from the preferred set of PGI-R 4 'which contains a number of preferred meanings of R ₄ , which are ethyl, propyl and isopropyl.

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

• ·

42 * • · · ^w

I · · · · · · · ·

Table of possible meanings of substituent Y-:

the combination code of the variable y group selection Yl Y group selection ₂ Y group selection ₃ Y01 Yl Y ₂ Y ₃ Y02 Yl Y ₂ PGI-Y3 Y03 Yi Y ₂ PG2-Y ₃ Y04 Yi PGI-Y1 Y ₃ Y05 Yi _PG2-Y2 Y ₃ Y06 Yl _{PG1-Y2 PG1-Y3} Y07 Yl pgi-y ₂ PG2-Y ₃ Y08 Yi PG2-Y2 PGI-Y3 Y09 Yl _PG2-Y2 PG2-Y ₃ Y10 PG1-Yi Y ₂ Y ₃ Yll PG1-Υχ Y ₂ PGI-Y3 Y12 PG1-Yi Y ₂ PG2-Y ₃ Y13 PG1-Yi _PG1-Y2 Y ₃ Y14 PG1-Yi pgi-y ₂ PGI-Y3 Y15 PG1-Y1 pgi-y ₂ PG2-Y ₃ Y16 PG1-Yi _PG2-Y2 Y ₃ Y17 PG1-Υχ _PG2-Y2 PG1-Y3 Y18 PG1-Yi _PG2-Y2 PG2-Y3 Y19 PG2-Yx Y ₂ Y ₃ Y20 PG2-Y1 Y _{2 PG1-Y3} Y21 PG2-Yx Y ₂ PG2-Y3 Y22 PG2-Yx _PG1-Y2 Y ₃ Y23 PG2-Y1 pgi-y _{2 PG1-Y3} Y24 PG2-Y _X pgi-y ₂ PG2-Y3 Y25 PG2 = Y1 PG2-Y2 Y ₃ Y2 6 PG2-Y _X PG2-Y, _PG1-Y3 Y27 PG2-Y1 _PG2-Y2 p & L · b

• · · · · · · ·

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):

· 43

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

Combination Code 'XZn Selecting the “X Selecting the “Z Dialing an integer "n XZnOl X OF n XZnO2 X OF PG1-n XZnO3 X OF 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 XZnlO X PG1-Z PG2-n XZnll X PG2-Z PG2-n XZnl2 X PG3-Z PG2-n XZnl3 PG1-X OF n XZnl4 PG1-X OF PG1-n XZnl5 PG1-X OF PG2-n XZnl6 PG1-X PG1-Z n XZnl7 PG1-X PG2-Z n XZnl8 PG1-X PG3-Z n XZnl9 PG2-X PG1-Z PG1-n XZn20 PG2-X PG2-Z PG1-n XZn21 PG2-X PG3-Z PG1-n XZn22 PG2-X PG1-Z PG2-n XZn23 PG2-X PG2-Z PG2-n Zn24 PG2-X PG3-Z PG2-n

• · ··· · · · · · · ·

I · «· · * * *..

·· ··

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) that defines a subset of compounds useful for a particular embodiment of the composition of the invention.

III Q. Other preferred LTB ₄ antagonist compounds are described by Formula (II):

(II) wherein;

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, iso-propyl, n-butyl, sec-butyl or tert-butyl; and

R 22 is hydrogen, n-butyl, sec-butyl, flour, chlorine,

-CF ₃ or tert-butyl.

Z ₂ is carboxyl, tetrazolyl, N-sulfonamidyl.

Preferred compounds of the invention:

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

(Cl):

/ = N

OH

Sř,

<5s.

COOH (C2):

(C3):

• ·

COOH • (C6)

•. <R

COOH • (C9)

(CIO):

(C12):

COOH · «OO OO OO OO OO OO OO

· C (C14):

OH

COON (C15):

COOH> OO · OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO 30

··

(C17) .n-n

N. JI S · ^

OH

COOH (C17):

(C20):

· · · · · · · · · · · · · · · · · · ·

* C21 (C21):

(C22):

and all acid derivatives, salts, defined compounds.

solvates and prodrugs

III S. Highly preferred LTB ₄ antagonist compounds, as follows:

j are • 52

COOH

· * * * * * * *

C

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

IV. 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 LTB ₄ antagonist compounds represented by formula (I). There are a number of references and Chemical Abstract registration numbers (eg, RN 152609-60-4), which disclose adjuvants for the preparation of reagents that are used in the practice of these syntheses illustrated in the schemes of the invention.

GENERAL REACTION SCHEMES FOR THE PRODUCTION OF COMPOUNDS THAT ARE

LTB ₄ ANTAGONISTS USED IN PREPARATIONS 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:

• · • ·

·· · · · · ·

<«·· *

J 4 4 4 4 4 4 ** 4

Scheme 1

benzyl bromide., CS 2 CO 3, DMF (26) Known compound: RN # 156005-61-7 R. W. Harper et al., J. Med. Chem. 1994, 37 (15), 2411

HIM

(30)

COOMe known compound: RN 152609-76-2 J.S. Sawyer et al., J. Med. Chem. 1995, 38, 4111

K 3 CO 3, NaI, 2-butanone

(36)

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 affords 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 method for producing the compound of Example (2), which is 5 (4) -substituted imidazole, effective as an LTB ₄ receptor antagonist:

• 9

Scheme 2

Cl

NH

AT

H.N SBn

KjCO ₃ . NaI, DMF

(2) ·· ·· · · · · · ·

Acetophenone trimethylsilylenol ether (32) was prepared and treated with N-chlorosuccinimide followed by tetra-n-butylammonium fluoride to give chloroketone (40). Treatment of 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 preparing the compound of Example (3), namely a 4-substituted thiazole having LTB ₄ receptor antagonist activity:

• • • •

Scheme 3

O) · · · · · · · · · · · · · · · · · · · · · · · · · ·

In this case, the chloroketone (40) is treated with thioformamide and magnesium carbonate to give thiazole (46), which is debenzylated with boron trifluoride etherate and ethanethiol to give 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 5 (3) -substituted pyrazole, which is effective as an LTB4 receptor antagonist:

• · ·· • ·

Scheme 4

(52)

(4)

COOH • · ·

9 · 9 9

Reaction of acetophenone (32) with Ν, Ν-dimethylformamide with dimethylacetal affords 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 etherate 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 ΜβΟΗ, K ₂ 0

BF ₃ EL, O, EtSH 1) UOH, MeOH

2) HCl

(5)

Reaction 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:

(58) * 9 9 ··· · · · ···

Scheme 6 of the known compound: RN152609-60-4

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

Cl

(60)

• · • ··

K, CO ₃ , K ₁ , DMSO

2-butanone = —SnBu,

PdfPPhJ ,, DMF

TMSNj, toluene

BF 1 Et 3 O, EtSH

1) LiOH, MeOH

2) HO

• • • • 4 • 4 • 4 • 4

The known phenol (30) is alkylated with the known chloride (58) to give the aryl bromide (60). Reaction of compound (60) with tri-n-butylethynyltin and a palladium catalyst gives 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 1-substituted pyrrole, which is effective as an LTB4 receptor antagonist:

··· ♦ · · · · · · · · ·

Scheme 7

References on how to obtain 1-aryl substituted pyrroles:

M. Wall and J. P. Klinman, J. Am. Chem. Soc. 1995, 117 (34).

8898; Lee et al. J. Am. Chem. Soc. 1998, 118 (30): 7241

• · ·· ··

4-Ethylbenzene-1,3-diol (68) is treated with potassium nitrosodisulfonate followed by treatment with 3-pyrroline and benzyl bromide and a base to give 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 ether 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:

· * ♦ • • • •

9 9

9 9

9999

Scheme 8

EL .EL

Ο Ο \ ζ

PdCl ₂ (dppf)

Br

PdCl ₂ (dppf), Cs ₂ CO 3, toluene

1) BF ₃ Et ₂ O, EtSH

2) aq. NaOH

3) aq. HCl

(8)

• · · · ·

Palladium catalyzed addition

4,4,5,5-tetra methyl [1,3,2] dioxaborolan on bromide (60) affords the boronic acid 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, gives 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, which is effective as an LTB ₄ receptor antagonist:

** 9 9 9 9 99 99

A 2 t “9 · * 9> * 9 * · it ·> 9 • 9 9 9 99

9 9 • 9 9f 9

Scheme 9

Br

PdCl ₂ (dppf), CS ₃ CO ₃ , toluene

2) BFa E2O, EtSH

1) aq. LiOH

2) NaOH

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

• · .71 *

Scheme 10

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

N-N \

known compound: RN 39806-90-1

(PdCydppf), Cs2CO3, toluene

(10)

Palladium catalyzed addition of boronic acid ester (76) to 1-methyl-4-iodopyrazole affords pyrazole (82). Debenzylation of boron trifluoride with etherate and ethanethiol, followed by hydrolysis and protonation, provides 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:

(10) • · ··

Palladium catalyzed addition of boronic acid ester (76) to 2-bromothizaole affords thiazole (84). Debenzylation of boron trifluoride with ether and ethanethiol gives 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), and a 4-substituted isoxazole that is effective as an LTB ₄ receptor antagonist:

cd-Ó

• • • * · • · ·· • • ♦ · · • ·· • • «· • • 0 •

6 "

Palladium catalyzed addition of the acid ester to 3,5-dimethyl-4-iodoisoxazole affords Debenzylation with trimethylsilyl iodide, followed by salt formation to give the compound exemplified herein (12).

boronic (76) oxazole (88). hydrolysis and referred to as

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:

9 9 9 9 9 9 9 9 9 9 9

99,999 99,999 9 · «7 * 7 **** * ·· * * ·· *’ · ’* ·· ♦ ·

(60)

TBSC1, imldazole

COOMe

(13) e e e e e e e 13 13 13 13 13 13 13 «

Debenzylation of bromide (60) with boron tribromide affords phenol (90) which is treated with tert-butyldimethylsilyl chloride and imidazole to provide 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 method for producing the compound of Example (14), which is a 3-substituted furan, which is effective as an LTB ₄ receptor antagonist:

· ’

Diagram 14 • · »··

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).

• · δ * * * * * * * δ δ

Scheme 15

The following scheme illustrates compounds that represent 3-substituted tetrahydrofuran, an LTB ₄ receptor antagonist:

a method for making example (15), which is effective as

B (OH) ₂

PdfPPh ^, aq. NaCO ₃ , THF

H ₂ , Pd

1) aq. LiOH

2) HCl

3) NaOH

(15) · «♦ 15 15 * * * * * 15 15 15 15 15 15 15 15 15 15 15 15 * si * · ·· ** ·· · ♦ ··

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 diagram illustrates the method of Example (6) which is 1,2,3-triazole which is effective as a receptor:

production of the compound

5 (4) -substituted LTB ₄ antagonist

8δ

Scheme 16 ρ ~ ^ Β (ΟΗ) ₂

Pd (PPhj) ₄ , aq. NajCO3, THF (60)

Hj, Pd (C) aq. LiOH

HCl

· & 3 • ··· • ··

Palladium catalyzed addition of bromide (60) to N-boc-byrrole-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 that is effective as an LTB ₄ receptor antagonist:

• 9 9 §4 ......

Scheme 17

(17) ^{S S S S S S S. S S S... S} .... »» »» »» ·>

Palladium catalyzed addition of bromide (58) to thiophene-3-boronic acid affords thiophene (108). Alkylation of the known phenol (110) with base-catalyzed compound (108) affords thiophene (112). Debenzylation with boron tribromide gives 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 5-substituted

1,2,3,4-thiatriazole, which is effective as an LTB ₄ receptor antagonist:

F · 4

«2 · · ···

4 «fr · • · r

4 • f • 4

4 • · 4 · · ·

• 4 •

<

• 44 *

Scheme 18

hs ~ ^sh TsOH

2) NaH. DMF, HMPA 3} piperidirr

1) ΒΡ, ΕΙ, Ο, ΟΗ, α,

2) aq. NaOH 3} aq. HCl

Reference for a method for obtaining dithioacids: NC (Gonnella et al. Syn. Commun. 1879, 17 Reference for a method for obtaining 5-substituted 1,2,3,4-thiatriazoles from dithioacids: SI Ikeda et al., Synthesis 1990, 415 ·· -37 Aldehyde benzyl bromide (120)

The phenol (30) is alkylated with 1-bromo-3-chloropropane to give the chloride (116), which is converted in a known manner to the aldehyde (118) and treatment with a base followed by benzylation of the base affords the aldehyde (120). Thioacetal is produced from this by treatment

1,2-ethanedithiol. The afternoon thioacetal is then treated with a base to give the thioacid. Piperidine salt is then treated with piperidine (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 azide ion gave 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 process 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:

····························· · · · 88 88 ...........

Scheme 19

N, NHCOOEt

1) BF ₃ Et ₂ O, EtSH

2) aq. NaOH

3) aq. HQ

Reference for the preparation of 1,2,3-thiadiazole: E. W. Thomas et al

J. Med Chem. 1985, 28,442 89

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 hydrolyzed and protonated. This gave the product of Example (19).

Scheme 20

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

90

Scheme 20

(62)

Cl

N '%

CI ^S 'N'' ^S ' CI (triethiazyl trichloride)

1) BF 1 Et 10 O, EtSH

2) aq. NaOH

3) aq. HCl

Reference for a method of obtaining 1,2,5-thiadiazole: E.W., Thomas et al., Chem. 1985, 28, 442.

J, Med

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), provide 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 that is effective as an LTB ₄ receptor antagonist:

* · * * A a ► ► ► ► ► ► ► 92 92 92 92 92 92 92 92 92 92 92 92

Scheme 21

1) BF ₃ -Et ₂ O, EtSH

2) aq. NaOH

3) aq. HCl

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

·

4 44

44

Diagram 22 • 4,444 ·

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

Scheme 22

B (OH) ₂

Known compound: RN 216971-00-5 PCT WO 9855480

PdfPPh 3 H, NajCO 3, EtOH. H ₂ O

K ₂ CO ₃ , KI, DMSO,

1) BF ₃ Et ₂ O, EtSH

2) aq. NaOH

3) aq. HCl

(22) 94 94 94 94

Palladium catalyzed addition of bromide (58) to 3-methylisothiazole-5-boronic acid affords isothiazole (136). Base catalyzed alkylation of phenol (30) with compound (136) affords isothiazole (138). Debenzylation with boron trifluoride 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 that is effective as an LTB ₄ receptor antagonist:

· 95 · 95 95 95 95 95 95 95 95 101 · · · · · · · · · · · ·

Scheme 23

Br

Known compound: RN 125533-82-6 • R. D. Miller et al., Chem. Mater. 1994, 6 (7), 1023.

COOMe

PdCl ₂ (dppt), CS 3 CO 3, toluene (76)

1) 8F ₃ Et, O, EtSH

2) aq. NaOH

3) aq. HCl

(23) V V V V »V V 23

• · · ··· 9 9 36 • 9 9

99 • ·

9999

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

Scheme 24

Scheme 24

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

9 * • 9 9

9 9 · 37

9 »* 9 8

9 *. * ♦ «9 e

9 • • 99 9 9 9999

Et ₃ SiH, TFA. benzene

1) aq. NaOH

2) HCl

Reference for a process for obtaining tetrahydrothiophene: N. N. Kursanov et al. Tetrahedron 1975, 3t, 311

Thiophene (114) can be reduced in the presence of triethylsilane and the acid of Kursanova et. al. thiophane (142) is incorporated herein. Hydrolysis and product of Example (24).

trifluoroacetate according to (as shown below, the contents of which are hereby incorporated by reference), providing by protonation of the compound provides

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.

known compound: RN # 156005-61-7

R. W. Harper et al., J. Med. Chem. 1994, 37 (15): 2411-20

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

A mixture of 1- [2-hydroxy-4- (3-chloropropoxy) -5-ethylphenyl] ethanone (26.1 g, 102 mmol), cesium carbonate (33.4 g, 103 mmol) and benzyl bromide (12.2 mL, 103 mmol) in N, N-dimethylformamide (300 mL) was stirred for 5 h at 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 under vacuum. The oil obtained was triturated with ethyl acetate and hexane, allowed to stand for 18 h 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. Mp 60-61 ° C. NMR (CDCl 3) δ 7.68 (s, 1H), 7.40 (m, 5H), 6.48 (s, 1H), 5.17 (s, 2H), 4.13 (t, J = 6) Hz, 2H), 3.75 (t, J = 6Hz, 2H), 2.56 (s, 3H), 2.55 (q, J = 7Hz, 2H), 2.26 (quintet, J = 6 Hz,

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.

Anal. Calcd for C 20 H 23 N 3 O 3 103: C, 69.26; H, 6.68.

Found: C, 69.30; H, 6.52.

known compound: RN # 152609-76-2 J.S. Sawyer et al., J. Med. Chem. 1995, 38, 4411

COOMe • * * · OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM · ··

100 ALIGN!

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-ethyl-phenyl) ethanone (7.27 g, 21.0 mmol) and sodium iodide (3.14 g, 23.1 mmol) in 2 -butanone (100 mL) was heated under reflux for 18 hours. The mixture was cooled to room temperature, filtered, and concentrated under vacuum. 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 room temperature 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 under vacuum. Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue yielded 9.2 g (72%) of the title compound as a colorless oil. NMR (CDCl 3) δ 7.88 (d, J = 9 Hz, 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 = 7 Hz, 2H), 2.57 (Qz J = 7 Hz, 2H), 2.56 (S, 3H), 2.32 (quintet, J = 6 Hz, 2H), 1.55 (Hextet, J = 7 Hz, 2H) 1.15 (t, J = 8Hz, 3H) 0, 90 (t, J = 7Hz, 3H); results IR spectral analysis

(CHCl 3, cm ^-1 ) 2965, 1726, 1602, 1461.

Anal. Calcd for C 37 H 40 O 7: C, 74.48: H, 6.76.

Found: C, 74.39; H, 6.77.

·· · ♦ · · · ·

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

mmol) 17.8 mmol)

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), and [bis (trifluoroacetoxy) iodo] benzene (7.65 g, The resulting mixture was heated under reflux for h then concentrated under vacuum. The organic layer was washed three times with saturated sodium bicarbonate solution, once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated under vacuum. (silica gel, 20% ethyl acetate / 80% hexane) of the residue led to it

102 afforded 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 = 9 Hz, 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 = 8 Hz, 1 H), 6.50 (s, 1 H), 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, 5 2H), 1.55 (hextet, J = 7Hz, 2H) 1.17 (t, J = 8Hz, 3H) 0.89 (t, J = 8Hz, 3H); TOS MS ES ⁺ exact molecular weight was

calculated for ΟβγΗ ^ Οθ (p + 1): m / z = 613.2801. Found: 613.2833.

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-hydroxyacetyl) phenoxy] propoxy} -2-propylphenoxy) benzoate (1.39 g, 2.27 mmol) in methyl ester methylene chloride (20 ml), • methylene chloride (20 ml),

103, 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 resulting mixture was stirred for 1h and then cooled by pouring into ether / water. The organic layer was separated and washed once with brine, dried (sodium sulfate), filtered, and concentrated under vacuum. 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. It was 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 under vacuum. Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue yielded 89 mg (6%) of the title product as a colorless oil. NMR (CDCl 3) δ 7.92 (s, 1H), 7.85 (s, 1H), 7.83 (m, 2H), 7.35 (m, 6H), 7.03 (d, J = 8) Hz, 1H), 7.00 (d, J = 8Hz, 1H), 6.73 (d, J = 8Hz, 1H), 6.62

(d, J-8 Hz, 1H), 6.52 (s, 1H) 6.35 (d, J = 8 Hz, 1H), 5,07 (s, 2H) 4.14 (m, 4H) 3.76 (s, 3H) 2.61 (m, 4H), 2.26 (quintet, J = 6Hz, 2H) , 1.48 (Hextet, J = 7 Hz, 2H), 1.15 (t, J = 8) Hz, 3H), 0.84 (t, J = 8 Hz, 3H).

COOMe

104 • 9 99

9 9 · ·

E. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-oxazol-4-yl-enoxy) -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 h. 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 under vacuum. 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 = 8.2Hz, 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 = 8Hz, 2H), 2.33 ( quintet, J = 6Hz, 2H), 1.55 (hextet, J = 7Hz, 2H), 1.17 (t, J = 8Hz, 3H), 0.91 (t, J = 8Hz, 3H) MS ES ⁺ m / e = 532 (P + 1) &lt; + &gt;

105 • «• ··

F. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-oxazol-4-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -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, cooled to room temperature and concentrated under vacuum. The mixture was extracted three times with methylene chloride, and the combined organic extracts were dried (sodium sulfate) and the resulting mixture was filtered and concentrated under vacuum to give 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)

(WITH, 1H), 8.25 (s, 1 H) 7.78 (dd, J = 8.1) Hz, 1H), 7.64 (with, 1H), 7.47 (t, J = 8 Hz, 1H), 7.16 (m, 2H), 6.80 (t, J = 8 Hz, 2H), 6.56 (s, 1H). 6.35 (d, J) = 8 Hz, 1H 4.20

9

9 • 99

9 9

9

106

(t, J = 6) Hz, 2H), 4.12 (t, J = 6 Hz, 2H); 2.54 (m, 4H). 2.24 (quintet, J = 6 Hz, , 2H) , i, , 43 (Hextet, J = 8Hz, 2H) 1.10 (t, J = 8) Hz, 3H), 0.80 (t, J = 8 Hz, 3H);

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

(KBr, cm ^-1 ) 2961, 1696, 1460, 1222.

Elementary

Calculated: Found:

analysis: calcd for C 30 H 31 NO 7: C, 69.62; H, 6.04; N, 2.71.

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-propyl-phenoxy) -benzoic acid hydrochloride

COOMe • ·

107 · * • 107 * * * * * * * • * • *

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

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). mL) cooled to -78 ° C was added a 1M solution of lithium hexamethyldisilazide in tetrahydrofuran (11.2 mL, 11.2 mmol) portionwise. After stirring for 20 min, trimethylsilyl chloride (2.6 mL, 20 mmol) was added, the mixture was warmed to 0 ° C and stirred for 30 min. Then the mixture was evaporated under vacuum and the residue was dissolved in hexane. The resulting solution was filtered and concentrated under vacuum. 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 min, the mixture was diluted in ether and 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 yielded 1.94 g (60%) of the title compound as a white solid.

3 H NMR (CDCl ₃ ) δ 7.89 (d, J = 8 Hz, 1H 7.77 (s, 1H),

7.40 (m, 6H) 7.12 (d, J = 9Hz, 1H), 7.06 (d, J = 8Hz, 1H), 6.80 (d, J = 8 Hz, 1H), 6.66 (d, J) = 8 Hz, 1 H 6.49 (s, 1H); 6.43 (d, J = 8 Hz, 1H), 5.15 (s, 2H), 4.68 (s, 2H), 4.20

• ·

108 · q · (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 = 7 Hz, 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.

Calcd for C37H39ClO7: C, 70.41; H, 6.23. Found: C, 70.04; H, 5.97.

COOMe

COOMe ·

• 999 • 9 9 99

99,999,999,999 9 9,999,999,999

99 99 99 99 9999

109

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.

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 hydrochloride -2-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 at 80 ° C. The mixture was then cooled, diluted with diethyl ether and washed once with water. The organic layer was dried (sodium sulfate), filtered, and concentrated under vacuum. Chromatography (silica gel, 30% ethyl acetate / 70% hexane) of the residue yielded 376 mg (40%) of the title compound.

as yellow amorphous solid lath ka. @ 3 H NMR (CDCl3) .delta ₃ ) δ 7.89 (d, J = 8 Hz, 1H), 7.36 (m, 9H) 7.20 (m, 5H), 7.21 (d, J = 9 Hz, 1H, 7.06 (d, J) = 8 Hz, 1H 6.79 (d, J = 8Hz , 1H 6, 67 (d, J = 8 Hz, 1H), 6.55 (with, 1H) 6.43 (d, J = 8 Hz, 1H), 5,07 (s, 2H) 4.21 (t, J = 6) Hz, 2H) 4.18 (t, J) = 6 Hz, 2H), 4.10 (s, 2H) :), 3.83 (s, 3h; ) 2.63 (m, 4H), 2.31 (kvin ^- tet, J = 6 Hz, 2H), 1 55 (hex tet, J = 7Hz , 2H), 1.18 (t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); TOF MS ES ⁺

exact molecular weight calculated for C45H47N20gS (P + 1):

m / z = 743.3155. Found: 743.3142; IR spectral analysis (CHCl 3, cm -1) results 2963, 1720, 1602, 1453.

Analysis:

Calcd. for C 45 H 46 N 2 O 6 S: C, 72.75; H, 6.24; N, 3.77.

C, 72.69; H, 6.17; N, 3.56.

Found:

«4

44

4 4 ··

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 ethanethiol (7 ml) was reacted with boron trifluoride etherate at room temperature for 3.5 h. The mixture was diluted with diethyl ether and water. The organic layer was separated and washed with saturated sodium bicarbonate solution, dried.

111 (sodium sulfate), filtered, and concentrated under vacuum. Chromatography (silica gel, 20% ethyl acetate / 80% hexane) of the residue yielded 154 mg (48%) of the title compound as an orange oil. 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 0.05 (m, 3H), 6.79 (d, J = 8Hz, 1H 6.65 (d, J = 8Hz, 1H), 6.54 (s, 1H 6.41 (d, J = 8) Hz, 1H), 4.20 (s, 2H), 4.17 (m, 4H), 3.82 (s, 3H), 2.62 (t, J =

Hz, 2H), 1.53

2.54 (q, J = 7Hz, 2H), 2.30 (quintet, J = 6Hz, 2H), (hextet, J = 8Hz, 2H), 1.14 (t, J = 7Hz, 3H), (t, J = 8Hz, 3H);

0.89

TOF MS ES ⁺ exact molecular weight was calculated for ^c 38 ^h 41 ⁿ 2 ° 6 ^s (P + 1): m / z = 653.2685. Found: 653.2669.

Calcd for C 39 H 40 N 2 O 5 S · C, 69.92; H, 6.18; N, 4.29. Found: C, 69.44; H, 6.25; N, 3.99.

COOH 9 9 9 9

99

112 · · 99 99

9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 • · · · ····

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

2- (3- {3- [4- (2-Benzylsulfanyl-3H-imidazol-4-yl) -2-ethyl-5-hydroxyphenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester solution (154 mg, 0.235 mmol) ) in methanol (3 mL) was treated with 1N lithium hydroxide solution at 60 ° C for 3.5 hours. The mixture was cooled to room temperature and concentrated under vacuum. The resulting solution was diluted with water and adjusted to pH 4. The aqueous solution was extracted three times with methylene chloride. The combined organic layers were dried (sodium sulfate), the mixture was filtered and concentrated under vacuum. The residue was dissolved in ethanol (3 mL) and treated with 0.2 N sodium hydroxide solution (1 mL) and Raney nickel (75 mg) at 75 ° C for 4 hours. The mixture was cooled to room temperature, filtered through Celite ™ and the filtrate was concentrated under vacuum. The residue was diluted with water and the pH of the solution was adjusted to pH = 2 with 1N hydrochloric acid. The obtained precipitate was collected via vacuum filtration to give 27 mg (21%) of the title compound. TOF MS ES ⁺ exact molecular weight was calculated for 0301133 ^ 05 (p + 1): m / z - 517.2339.

Found: 517.2340.

* · 9 9 9 9 9 9 * * 9 9 9 9

99

9 9 9

9 9

9

9 9

9999

113

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) and thioformamide (20 mL, 8 mL). (0 mmol) and magnesium carbonate in dioxane (10 mL) was heated to reflux for 2 hours. It was 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, dried (sulfate)

(Sodium hydroxide), filtered and concentrated under vacuum. Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue yielded 254 mg (50%) of the title compound as colorless.

oil. 1-H NMR (CDCl3) δ 8.91 (s, 1H), 8.11 (s, 1 H), 7.87 (dd, J = 8, 1 Hz, 1H 7.84 (d, J) = 1 Hz, 1H 7.4 0 (m, 6 H), 7.08 (m, 2H) 6, 80 (d, J = 8Hz, 1 H), 6.68 (d, J = 8 Hz, 1H) 6, 62 (s, 1 H), 6.4 3 (d, J = 8Hz, 1H), 5.16 (s, 2H) 4.21 (t, J = 6) Hz, 4H), 3.83 (s, 3H), 2.68 ( m, 4H), 2.32 (quintet, J = 6 Hz, 2H), 1.56 (Hextet, J = 8 Hz, 2H) 1,21 (t, J = 7) Hz, 3H), 0.90 (t, J = 7 Hz, 3H);

TOF MS ES ⁺ exact molecular mass calculated for 38 38 ^Η 40 ^Ν θ 6 (P + 1): m / z ⁼ 638.2576. Found: 638.2579.

IR spectral analysis (CHCl 3, cm -1) results 2964, 1719,

1563, 1461.

COOMe ··· · · · ··· · ···· · ··· · · · ·

115

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 ethanethiol ( 7 ml) was reacted 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 under vacuum. Chromatography (silica gel, 15% ethyl acetate / 85% hexane) of the residue gave the title compound in an amount of 131 mg (65%) as a colorless oil.

1h nmr (CDCl3) δ 8.88 (d, J = 1Hz, 1 H), 7.88 (dd, J = 8, 1 Hz, 1H), 7.44 (d, J) ^: = 1 Hz, 1H), 7.38 ( m, 2H) , 7.08 (m, 2H), 6 81 (d, J = 8Hz) , 1H) 6.68 (d, J - 8 Hz, 1H), 6.55 (s, 1 H), 6.43 (d, J = 8H) Hz, 1H) 4.21 (t, J) = 6 Hz , 4H), 3.83 (S, 3H), 2.63 (m, 4H); 2.33 (quintet, J = = 6 Hz, 2H), 1.56 (hextet, J = 8Hz, 2H) 1.19 (t, J = 8) Hz, 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.

··· · · · ····· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

116

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 reacted with 1M lithium hydroxide solution at 64 ° C for 3 hours. The mixture was cooled to room temperature, concentrated under vacuum, 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), filtered, and concentrated under vacuum. The residue was dissolved in a minimum of methylene chloride and hexane was added until the solution became cloudy. The mixture was concentrated slowly under vacuum to give mg (76%) of the title compound. @ 1 H NMR (CDCl3) .delta

(with, 1H), 8.23 (dd, J = 8) 1 Hz, 1H) 7.41 (m, 2H). (WITH, 1H), 7.29 (m, 2H). 6, 82 (d, Δ = 8 Hz, 1H), (d, J - 8 Hz, 1H 6.62 (d, J - 8 Hz, 1H), 6.54 (s, 1H) (t, J = 6 Hz, 2H), 4.22 (t, J = 6 Hz, 2H), 2.59 (m, 4H); (kv: intet, J = 6 Hz, 2H), 1 , 50 (hexte t, J = 8Hz, 2H)

(t, J = 7Hz,

3H), (t, J = 8Hz,

3H);

0.88

8.90

7.38

6.71

4.25

2.35

1.19

TOF

117

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

IR spectral analysis results (CHCl 3, cm -1) 2965, 1738,

1454. Analysis:

Calcd. For C30H31NO5S: C, 67.52; 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-propyl-phenoxy) benzoic acid.

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 N, N-dimethylformamide (3 ml) was heated to 110-120 ° C for 4 ° C.

118 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 under vacuum. Chromatography (silica gel, 30% ethyl acetate / 70% hexane to ethyl acetate) of the residue yielded 2.1 g (63%) of the title compound as a yellow oil. TOF MS ES ⁺ exact molecular weight was calculated for C 40 H 46 NO 7 (p + 1): m / z = 652.3274. Found: 652.3270. IR spectral analysis (CHCl 3, cm -1) 2965, 1720, 1605. Analysis: Calculated for C 40 H 45 NO 7: C, 73.71; H, 6.96; N, 2.15. Found: C, 73.72; H, 6.95; N, 2.18.

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 introduced) to • · • ·

119 reaction 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 under vacuum. 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 under vacuum. Chromatography (30% ethyl acetate / 69% hexane / 1% acetic acid) of the residue yielded 350 mg (65%) of the title compound as the acetate salt. A portion of this material was basified with sodium bicarbonate to give an analytical sample. NMR (CDCl 3) δ

8.20 (dd, J = 8.2 Hz (1H), 7.55 (s, 1 H), 7.44 (s, 1 H), 7.38 (m, 5H), 7.15 (m, 2H); 6.78 (d, J = = 8Hz, 1H), 6, 65 (d, J = 8 Hz, 1H), 6.61 (d, J = 8) Hz, 1H) 6.58 (s, 1 H), 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 = 8Hz, 2H) , 1.18 (t, J = 7Hz, 3H), 0.88 (t, J = 8Hz, 3H); TOF MS ES ⁺ exact molecular mass, calcd for C37H39N2O6 (p + 1 ): m / z = 607 2808. Found: 607.2831. IR results spectral analysis (CHCI3,

cm ^-1 ) 2965, 1739, 1604, 1454.

Anal Calcd for C 37 H 38 N 2 O 8: C, 73.25; H, 6.31; N, 4.62. Found: C, 73.31; H, 6.30: N, 4.62.

120

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

2- (3- {3- [5-Benzyloxy-2-ethyl-4- (2H-pyrazol-3-yl) -phenoxy] -propoxy} -2-propyl-phenoxy) -benzoic acid solution (300 mg, 0.4 90 mmol) in ethanethiol (2.5 mL) was reacted with boron trifluoride etherate (2 mL) at room temperature for 3 hours at which time another portion of boron trifluoride etherate (1 mL) was added, the reaction mixture was stirred for an additional 1 hour and then diluted diethyl ether and water. The organic layer was separated, washed with water, dried (sodium sulfate), filtered, and concentrated under vacuum. Chromatography (silica gel, 15% ethyl acetate / 85% hexane to 60% ethyl acetate / 40% hexane) of the residue yielded the title compound in an amount of 60 mg (24%) as a white solid. @ 3 H-NMR (CDCl3) .delta.8.23

(d, J = 8 Hz, 1H) , 7.61 (with, 1H), 7.42 (t, J = 7 Hz, 1H), 7.30 (with, 1H), ' /, 19 (d, J = 8 Hz, 1H), 7.15 (d, J = 8 Hz, 1H), 6, 81 (d, J = 8 Hz, 1H) , 6.69 (d, J = 8 Hz, 1H), r 6, 61 (with, 1H), 6, 60 (d, J = 8 Hz, 1H) , 6.54 (with, 1H), 9,20 (m, 4H), 2.58 (m, 4H),

2.33 (quintet, J = 6 Hz, 2H), 1.48 (hextet, J = 8 Hz, 2H),

121

1.17 (t, J = 8Hz, 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. IR spectral analysis (CHCl 3, cm -1) 2965, 1738, 1454. Analysis: Calculated for C 30 H 32 N 2 O 6: C, 6.75; 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)-122-benzoic acid methyl ester (280 mg, 0.43 mmol) and hydroxylamine hydrochloride (75 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), filtered and concentrated under vacuum. Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue yielded 202 mg (76%) of the title compound as a white solid. 1 H NMR (CDCl 3) δ 8.20 (d, J = 2Hz, 1H), 7.88 (dd, J = 9.2Hz, 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 = 6Hz, 2H), 1.56 (hextet, J = 8Hz, 2H), 1.20 (t, J = 7Hz, 3H), 0.90 (t, J = 7 Hz, 3 H); TOF MS ES + exact molecular weight was calculated for C 31 H 40 QNO7 (p + 1): m / z = 622.2805. Found: 622.2817. IR spectral analysis (CHCl 3, cm -1) results 2964, 1720, 1461.

Anal. Calcd. For C 31 H 38 NO 7: C,

Found: C, 73.20; H, 6.34; N, 2.27.

73.41; H, 6.32; N, 2.25.

COOMe

123

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

7.38 (t, J = 8 Ηζ, ΐΗ 7.36) (s,: 7.05 (d, J = 8Hz, 1 H) 6.81 (d, J = 8 Hz, 1H), 6.50 (with, (d, J = 8 Hz, 1H), 4.20 (m, 4H), 2.34 (quintet, J = 6Hz, 2H)

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 ethanethiol (5 mL) was was reacted with boron trifluoride etherate (1.5 ml) at room temperature for 2 hours, after which an additional portion of boron trifluoride etherate (0.5 ml) was added and stirring 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 under vacuum. Chromatography (silica gel, 15% ethyl acetate / 85% hexane) of the residue yielded mg (61%) of the title compound as a colorless oil. NMR (CDCl ₃ ) δ 8.28 (d, J = 1Hz, 1H), 7.88 (dd, J = 8.2Hz, 1H), 7.08 (t, J = 8Hz, 1H) .delta. (d, J = 8Hz, 1H), 6.67

H), 6.45 (s, 1H), 6.43), 83 (s, 3H), 2.62 (m, 4H), 54 (hextet, J = 8 Hz, 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.

The results of IR spectral analysis (CHCl 3, cm ^_ l) 2964, 1715,

1601, 1461.

Calcd for C34H33NO7: C, 70.04; H, 6.26: N, 2.63.

Found: C, 70.13; H, 6.35; N, 2.63.

124

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 under vacuum. 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 extracts were dried (sodium sulfate) and the resulting mixture was filtered a

thickened under vacuum, thereby acquired 12 mg (13%) title compounds like dirty white amorphous graphite substance. 1 H NMR (CDCl 3) δ 8.26 (s, 1 H), 8.20 (dd, J - 8, 1 Hz, 1H), 7.49

(t, J = 6Hz, 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);

♦ · * * * φ φ φ φ φ φ «

125

2.57 (m, 4Η), 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 30 H 32 NO 7 (p + 1): m / z = 518.2179. Found: 518.2175.

Anal Calcd for C 30 H 31 NO 7: C, 69.62; H, 6.04; N, 2.71. 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) phenoxylpropoxy} -2-propylphenoxy) benzoic acid.

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), carbonate.

126 potassium (1.29 g, 9.34 mmol), potassium iodide (0.52 g, 3.1 mmol) and methyl sulfoxide (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 under vacuum. Chromatography (silica gel, 6% ethyl acetate / 94% hexane) of the residue resulted in the title compound (1.34 g, 68%) being obtained as colorless.

oil. ^Χ Η NMR (CDCl 3) δ 7, 91 (dd, J = 8) , 2 H z: 1H) 7.50 (d, J = 7 Hz, 2H), 7.38 (m, 5H) 1 7.15 (d, J = 8 Hz, 1 H 7.10 (d, J = 8 Hz, 1H 6.83 (d, J = 8 Hz, 1H 6.71 (d, J = 8 Hz, 1H) , 55 (WITH, 1H), 6.48 (d, J = 8 Hz, 1H) 5.16 (s, 2H) 4.21 (t, J = 6 Hz, 2H), 4.15 (t, J = 6 Hz, 2H) 3.83 (s, 3H) 2.68 (t, J = 8 Hz, 2H), 2.5 8 ( q, J = 7 Hz, 2H), 2.31 (quint et, J = 6 Hz, 2H) 1, 58 (Hextet, J = 6Hz, 2H), 1.17 (t, J = 7 Hz, 3H), 0.93 (t, J = 7 Hz, 3H).

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

· * · · * * * *

127

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 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 under vacuum. Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue gave the title compound 532 mg (39%) as a brown solid.

oil. 1h NMR (CDCl 3) δ 7.88 (dd, J = 8.2 Hz, 1H), 7.79 (s, 1 H), 7.20 -7.50 (m, 6H); 10 (d, J = 8Hz, 1 H), 7, 05 (d, J = 8) Hz, 1H), 6.80 (d, J = 8 Hz, 1H), 6.66 (d, J = 8 Hz, 1H), 6.43 (m, 2H), 5.16 (s, 2H), 4.17 (t, J = 6Hz, 2H), 4,11 (t, J = 6) Hz, 2H), 3.83 (s, 3H), 3.23 (s, 1H). 2.64 (t, J = 8) Hz, 2H), 2.53 (q, J = 7Hz, 2H) 2.27 (quintet, J = 6 Hz, 2H), 1.53 (m, 2H), 1.13 (t, J = 7 Hz,

3H), 0.89 (t, J = 7Hz, 3H); TOF MS ES ⁺ exact molecular weight was calculated for C 37 H 39 O 6 (p + 1): m / z = 579.2747.

Found: 579.2739.

COOMe

99 * 9 • 9 9

99 99 9 ·

9 «9 9

9 98 9 9 9

9 99 99 ·· 99 9 999 9999

128

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

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) in trimethylsilyl azide (3.0 mL) , 18 mmol) was heated in toluene (20 mL) in a sealed tube at 130 ° C for 120 hours. The mixture was then cooled to room temperature and concentrated under vacuum. 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), 10 (d, J = 8Hz, 1H 7.05 (d, J = 8Hz, 1H), 6.79 (d, J = 8Hz,

1H), 6.67 (d, J = 8Hz, 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 = 6 Hz, 2H), 1.56 (hextet, J = 8 Hz, 2H),

1.21 (t, J = 8Hz, 3H), 0.90 (t, J = 7Hz, 3H); TOF

MS ES ⁺ exact molecular weight 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. Anal. Calcd. For C 37 H 39 N 3 O 6: C, 71.48; H, 6.32; N, 6.76. Found: C, 70.28; H, 6.07; N, 6.54.

«« * * * * *

129

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

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, 1 g mmol) at room temperature for 1 hour, followed by 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 under vacuum. 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. NMR (CDCl 3) δ 7.97

(WITH, 1H), 7.88 (dd , J = 8.2 Hz, 1H 7.37 (t, J = 8 Hz, 1H), 7.31 (with, 1H 7, 10 (d, J = 8Hz, 1H), 7.05 (d, J = 8 Hz, 1H), 6.81 (d, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H) , 6.59 (with, 1H),

* * * * * * * * * * *

130 · <

• ♦ • • • · • • • •

6.43 (d, J = 8Hz, 1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.63 (m, 4H), 2.34 (quintet, J = 6) Hz, 2H), 1.55 (hextet, J = 8Hz, 2H), 1.19 (t, J = 8Hz, 3H), 0.90 (t, J = 7Hz, 3H); TOF MS ES ⁺ exact molecular weight calculated for C 30 H 34 N 3 O 5 (p + 1): m / z = 532.2447 Found: 532.2466.It spectral analysis results (CHCl 3, cm -1) 2964, 1718, 1453. Elemental analysis:

Calcd for C 18 H 18 N 8 O 8: C, 67.78; H, 6.26; N, 7.90.

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] triazol-4-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester solution (160 mg, 0 , 30 mmol) in methanol (5 mL) was reacted at 60 ° C for 3.5 h with 1N lithium hydroxide solution 9 9 9 9

9 9 99 9 9 9 9 9 9 9 9 9 9 9 9

9999 99999 999

9 · 99 99 · 9 99 9999

131 (1.5 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 under vacuum to give 134 mg (86%) of the title compound as a brownish solid. NMR (DMSO-d) δ 14.98 (bs, 1H), 12.80 (bs, 1H 10.02 (bs, 1H), 8.17 (bs, 1H), 7.77 (dd, J = 7) 2 Hz, 1H 7.60 (bs, 1H), 7.47 (t, J = 8Hz, 1H), 7.18 (t, J = 8Hz, 1H), 7.19 (t, J = 8 Hz, 1 H, 6.82 (d, J = 8 Hz, 1 H), 6.68 (d, J = 8 Hz, 1 H), 6.57 (s, 1H 6.35 (d, J = 8) Hz, 1H) 4.22 (t, J = 6Hz, 2H), 4.15 (t, J = 6Hz, 2H), 2.54 (m, 4H), 2.25 (quintet, J = 6) Hz, 2H), 1.45 (hextet, J = 8Hz, 2H), 1.11 (t, J = 7Hz, 3H), 0.81 (t, J = 7Hz, 3H); TOF MS ES ⁺ exact molecular weight was calculated for? -29? 12? 0 (? (p + 1): m / z = 518.2291. Found: 518.2302. IR spectral analysis results (CHCl 3, cm -1) 2965, 1738 Calcd for C 29 H 31 N 3 O 6: 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.

9 · · * * 9 9 9 9 9 9 9 9 9 9 9

9 99 9

9 9 9 9 9

99 99 99 99 9999

132

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 under vacuum. The residue was dissolved in acetonitrile (70 mL) and treated at room temperature with 65% 3-pyrroline (12 mL). The resulting mixture was stirred and concentrated under vacuum for 1 hour, dissolved in ethyl acetate and hexane and filtered through a short column of silica gel. The resulting solution was concentrated under vacuum. 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 under vacuum. 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 19 19 20 20 2 2 (P + 1) m / z ⁼ 294.1494. Found:

294.1471.

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

· * 44 44 44 44 44 44 44 44 44 44 44 44 44 4 44 44

133

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 under vacuum. Chromatography (silica gel, 5% ethyl acetate / 95% hexane) of the residue gave the title compound 314 mg (79%) as a colorless oil. TOF MS ES ⁺ exact mass calculated for C 22 ^H 25 ^N C1C> 2 (p + 1): m / z = 370, 1574 Found: 370.1548.

COOMe • 4 «« 44

4 4 44 · · · 4 44 4 4 44

4 «44 44 44 44 4444

134

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 mol) in 2-butanone ( 5 ml) was heated under reflux for 6 hours. Then the mixture was cooled to room temperature, filtered and concentrated under vacuum. The residue was dissolved in N, N-dimethylformamide (7 mL) and treated with methyl acid ester at room temperature for 15 hours.

2- (3-hydroxy-2-propylphenoxy) benzoic acid (242 mg, 0.85 mmol) and potassium carbonate (129 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 under vacuum. Chromatography (silica gel, 5% ethyl acetate / 95% hexane) of the residue resulted in it being obtained

title compound in amount 196 mg (37%) as 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 = 8) Hz, 1H), 6.65 (d, J = 8) Hz, 1H) 6, 58 (with, 1H), 6.42 (d, J = 8 Hz, 1 H), 6.29 (m, 2 H), 4.92 (with, 2H), 4.17 (t, J = 6Hz, 2H) 4.15 (t, J = 6Hz, 2H); 3. $ 3 (with, 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 = 7Hz, 3H); TOF MS ES + exact molecular weight was calculated for C 39 H 42 NO 6 (p + 1): m / z = 620.3012. Found: 620.3021.

· T t t t t t t t t e e e e e e e e e e e e e e e e e e e e ·>

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 ethanethiol 15 mL) was reacted 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 under vacuum. 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 (with, 1H), 6, _r 68 (m , 3H), 6, 65 (d, J - 8 Hz, 1H) 6.57 (s, 1H), 6.42 : (d, J = 8 Hz, 1H) 6.35 (m, 2H), 5, 04 (bs, 1 H), 4.19 (m, 2H), 3, 83 (s, 3H) 2.64 (t, J = 8 Hz, 2H), 2 58 (q, J = 7 Hz, 2H), 2.32 (quintet, J = 6 Hz, 2H) 1.55 (m, 2H), 1.14 (t, J = 7 Hz, 3H) , 0.90 (t, J = 7Hz, 3H) 1;

··

9 · 5>

9 9 9 99

9 9

9 • «« 9

9 * «

99

9 9

9 ·

136

TOF MS ES + exact molecular mass calculated for C 32 H 36 NO 5 (P + 1): m / z = 530.2543. Found: 530.2516.

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-propylphenoxy) 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) and triethylamine (5.2 mL, 39 mL). mmol) and PdCl 2 (pf) (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] dioxaborolan (20 mL) , 20 mmol) and 0) ··

137 was heated under reflux for 6 hours. The mixture was filtered through a short silica gel column and the filtrate concentrated under vacuum. 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 = 9Hz,

1H), 6.79 (d, J = 9Hz, 1H), 6.66 (d, J = 9Hz, 1 H), 6.47 (3, 1H), 6.43 (d, J = 8Hz, 1H), 5.07 (s, 2H), 4.18 (m, 4H), 3.81 (s, 3H), 2.64 (t, J) = 8Hz, 2H) 2.56 (q, J = 7Hz, 2H), 2.30 (quintet, J = 6 Hz, 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.

Calcd for C41H49BO8: C, 72.35; H, 7.26.

Found: C, 72.30; H, 7.12.

COOMe

• · · · · · · · · · · · · · · · · ·

138

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 degassed toluene (10 mL) was heated at 100 ° C for 15 hours. The mixture was diluted with 35% ethyl acetate / 65% hexane and filtered through a short silica gel column. The filtrate was concentrated under vacuum. Chromatography of the residue (silica gel, gradient elution from hexane to 30% ethyl acetate / 70% hexane) afforded the title compound 232 mg (70%). NMR

(CD Cl ₃ ) δ 8.13 (s, 1H), 7.8 7 (dd, J = = 8, 2 Hz, 1H), 7, 44 (m, 2H) , 7.37 (m, 4H) 7.08 (t, d, J = 8, 1 Hz, 1H 7.04 (d, J = 9 Hz, 1H) 6.78 (d, J = 9 Hz, 1H) , 6.66 (d, J = 9 Hz, 1H) , 6.55 (s, 1 H), 6.43 (d, J = 8 Hz, 1H) , 5.28 (with, 2H) , 4.21 (t, J = 6 Hz, 2H) 4.19 (t, J = 6 Hz, 2H) , 3.81 (with, 3H) , 2.62 (m, 4H), 2.34 (kvil ntet, i J = 6 Hz t 2H), 1.55 (he xtet, J = 8 Hz, 2H) i, 1, 17 (t, J = - Ί Hz, 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-hydroxyphenoxy] propoxy} -2-propylphenoxy) 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 h, after which an additional portion of boron trifluoride etherate was added and stirring was continued. continued for 7 hours. The reaction mixture was diluted with water, concentrated under vacuum, and extracted with diethyl ether. The residue was dissolved in methanol (5 mL) and treated with 1N lithium hydroxide solution (2 mL) at 65 ° C for 1 hour. The mixture was concentrated under vacuum and the residue diluted with water and adjusted to pH pH 3 with 1N hydrochloric acid. The resulting precipitate was collected by vacuum filtration and was dissolved in a dilute aqueous base solution. Reverse phase chromatography (1: 1 acetonitrile / water) resulted in a: 1: 1 acetonitrile / water reaction. to give 43 mg (23%) of the title compound as a yellow solid. NMR (DMSO-d6) δ 7.85 (s, 1H), 7.80 (dd, J = 8.2Hz, 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 = 9Hz, 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 + + -1 m / e 551 (P + NH 4 - Br); IR spectral analysis (KBr, cm -1) 2900, 1696, 1603, 1461. Anal. Calcd. for C 29 H 28 BrN 2 O 5 S: C,

56.77; 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-propyl-phenoxy} -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} -, methyl ester - 2-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 deoxygenated toluene (10 mL) was heated at 105 ° C for 66 h, cooled to room temperature and concentrated under vacuum The residue was dissolved in methylene chloride and filtered through a short column of silica gel.

· · ·

141

Chromatography (silica gel, 30% ethyl acetate / 70% hexane) of the residue resulted in an oil which was dissolved in ethanethiol (4 mL) and treated with boron trifluoride etherate (0.44 mL, 3.4 mmol) at room temperature. temperature for 3 hours. The mixture was diluted with water and extracted with diethyl ether. The organic layer was dried (sodium sulfate), filtered, and concentrated under vacuum. Chromatography (silica gel, gradient elution hexane to 30% ethyl acetate / 70% hexane) of the residue yielded 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 = 7Hz, 2H), 2.54 (quintet, J = 6Hz, 2H), 1.52 (hextet, J = 8Hz, 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

COONa

142

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 reacted at room temperature for 1 h with 1N lithium hydroxide solution (0.5 mL) and then with an additional portion of 1N lithium hydroxide solution (0.75 mL) for 18 hours. The mixture was heated to 50 ° C and then concentrated under vacuum. The residue was acidified with dilute hydrochloric acid and extracted with diethyl ether. The organic layer was washed once with water and concentrated under vacuum. The residue was diluted with 1N sodium hydroxide solution (0.22 mL), diethyl ether and toluene. The mixture was concentrated under vacuum, dissolved in methylene chloride and concentrated under vacuum to give 120 mg (98%) of the title compound as a green film. 1 H NMR (DMSO-d 6) δ 7.71

(d, J = 8 Hz, 1H), 7.42 (m, 2H) F 7.31 (m, 2H); 7.10 (m, 2H), 6, 99 (m, 1H) 6.76 (t, J = 7 Hz 6.52 (s, 1H). 6.30 (d, J = 8 Hz, 1H), 4.16 (t, J = 7 Hz, 2H), 4.07 (t, J = 7 Hz, 2H), 2.5C 1 (m, 4H); , 20 (m, r 2H), 1.40 (m, 2H), 1.06 (t, J = 8 Hz, 3H), 0.77 (t, J = 7 Hz, 3H); MS ES ⁺ m / e 533 (P +

- 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-propyl-phenoxy) -benzoic acid.

AND

N-N \

• · »♦ ♦» ♦ ♦ ♦ · T · t · t · · · · · · · ·

143 * · • · • · • · · · • · · · AND. Preparation of 4-iodo-1-methylpyrazole (Yippee it 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 resulting the mixture was stirred at room temperature AFTER 96 hours. Then

It was concentrated under vacuum and the residue was mixed with methylene chloride and filtered. The filtrate was concentrated under vacuum to yield

1.35 g (95%) of the title compound as a colorless oil. 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-propylphenoxy) 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} methyl ester mixture -2-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 (ppf) ( 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 ₂ (dppf) (~ 30 mg) were then added and heating at 100 ° C was continued for 40 hours. The mixture was cooled to room temperature, concentrated under vacuum, diluted with methylene chloride, and filtered through a short pad of silica gel. The filtrate was concentrated under vacuum. 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%).

«·

144 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 = 9 Hz,

1H) , 7.04 (d, J = 9Hz, i) H), 6.78 (d, J = 9 Hz, 1H), 6, 67 (J = 9 Hz, 1H), 6.56 (s, 1H 6.42 (d, J = 8 Hz, 1H), 5.08 (with, 2H), 4 18 (t, J = 6Hz) 2H), 4.15 (t , J = 6 Hz , 2H), 3.85 (with, 3H], 3.81 (s, 3H); 2.63 (t, J) = 8 Hz, 2H), 2.59 (q, J = 7 Hz, 2H), 2.30 (quintet, J = 6 Hz, 2H), 1.55 (he xtet, J = 8Hz, 2H) 1.23 (t, J) = 7 Hz, 3H), 0.89 (t, J = 7 Hz, 3H).

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

2- (3- {3- [5-Benzyloxy-2-ethyl-4- (1-methyl-1H-pyrazol-4-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester solution (710 mg, 1 , 12 mmol) in ethanethiol (5 mL) was reacted with boron trifluoride etherate (1.42 mL, 11.2 mmol) at room temperature for 20 hours. The reaction mixture was diluted with water, concentrated under vacuum, and extracted

145 • diethyl ether. The organic layer was dried (magnesium sulfate), filtered, and concentrated under vacuum. 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 under vacuum and the residue diluted with water, washed twice with diethyl ether, and the aqueous layer acidified with 1N hydrochloric acid. The resulting solution was extracted with diethyl ether. The organic layer was dried (magnesium sulfate), filtered, and concentrated under vacuum. Chromatography (silica gel, 10% methanol / 90% methylene chloride) resulted in 338 mg (57%) of the title compound as a brownish foam. NMR

(DMSO-d6) δ 12.85 (bs, 1H, 9.50 (bs, 1H), 7.98 (s, 1 H), 7.78 (m, 2H) 7.48 (dt, J = 8.2 Hz, 1H, 7.44 (s, 1 H 7.18 (t, J = 8) Hz, 1H), 7.13 (t, J = 9Hz, 1H) 6.79 (d, J = 9 Hz, 1H), 6.77 (d, J = 9 Hz, 1 H), 6.53 (s, 1 H), 6.35 (d, J = 9 Hz, 1H), 4.20 (t, J = 6Hz, 2H), 4.08 (t, J) = 6 Hz, 2H) 3.85 (s, 3H), 2.50 (m, 4H), 2.24 (quintet, J = 5 Hz, 2H) 1.45 (Hextet, J = 8 Hz, 2H), 1.09 (t, J = 7 Hz, 3H), 0, 82 (t, J = 7 Hz, 3H); MS ES + m / e 531 (p + 1); IR results spectral analysis (KBr, cm -1) 2961, 1697, 1602 1460, 1222.

Anal. Calcd for C 31 H 34 N 2 O 5: C 70.17; H, 6.46; N, 5.28. Found: C, 69.27; H, 6.08; N, 4.63.

145 • · * ·· *

Example 11

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

COOMe

Br

COOMe

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) methyl ester mixture -2-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 toluene (35 mL) was heated at 60 ° C for 16 h then at 100 ° C for 7 h. Additional portions of 2-bromothiazole (0.13 mL) and PdCl 2 (dppf) (3030 mg) were then added and heating was continued at 100 ° C for 72 hours. The mixture was cooled to room temperature, concentrated under vacuum, diluted with methylene chloride, and filtered through a short pad of silica gel. The filtrate was concentrated under vacuum.

• 9 • 9 9 9 99

9

9 9 9 99 99 147 9,999,999 9 ·· 9999 Chromatography (silica gel, hexane up to 35% ethyl acetate / 65% hexane) of the residue led to the fact that it was obtained 282 mg (30%) of the title compound. ¹ H NMR (CDCl 3) δ 8,20 (s, 1H), 7.86

(d, J = 8.1Hz, 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 = 9 Hz, 1H), 6.65 (d, J = 9Hz, 1H), 6.57 (s, 1H), 6.42 (d, J = 8Hz, 1H), 5.24 (s, 2H) 4.17 (m, 4H), 3.81 (s, 3H), 2.63 (m, 4H), 2.33 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J) = 8 Hz, 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) in ethanethiol (3 mL) ) was reacted with boron trifluoride etherate (0.56 mL, 4.9 mmol) at rt

148 • Room temperature for 3 hours. • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • The reaction mixture was diluted with water, concentrated under vacuum, and extracted with diethyl ether. The organic layer was dried (magnesium sulfate), filtered, and concentrated under vacuum. Chromatography (silica gel, ethyl acetate / hexane) resulted in 107 mg (44%) of the title compound having the following properties: 1 H NMR

(CDC1 ₃₎ δ 7.88 (d, J = 8, 2 Hz, 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 = 9 Hz, 1 H), 6.79 (d, J = 9Hz, 1H), 6.66 (d, J = 9Hz, 1H) 6.61 (s, 1H). 6.42 (d, J = 9Hz, 1H); 4.24 (t, J = 6 Hz, 2H), 4.18 (t, J = 6Hz, 2H), 3.81 (s, 3H), 2.63 (t, J = 7 Hz, 2H), 2.58

(q, J = 7Hz, 2H), 2.34 (quintet, J = 6Hz, 2H), 1.52 (hextet, J = 8Hz, 2H), 1.17 (t, J = 7Hz, 3H), 0.88 (t, J = 7Hz, 3H); MS ES + m / e 548 (p + 1).

COOH

149 · 9 · 9 ··· 99 · 9 * 9 · · ·

9 9 ·· 9 · 9 · 9 · ♦

99 9 9 9 ··. 999 · 9

9999 9 9 9 9 9 9 «9 99 99 99 9999

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: 1 (3 mL) was treated with 1N lithium hydroxide solution (1 mL) at 60 ° C for 2 h. The mixture was concentrated under vacuum and the residue 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), filtered, and the filtrate was concentrated under vacuum. Trituration (hexane) of the residue yielded the title compound 72 mg (69%) as a brownish powder. NMR (CDC1 ₃₎ δ 8.22 (dd, J = 8, 2 Hz, 1H), 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 = 9 Hz, 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 = 6Hz, 2H), 2.57 (m, 4H), 2.35 (quintet. J = 6Hz, 2H), 1.49 (hextet, J = 8Hz, 2H), 1.18 (t, J = 7Hz, 3H), 0.86 (t, J = 7Hz, 3H); MS ES + m / e 534 (p + 1); IR spectral analysis (KBr, cm -1) 2957, 1695, 1599, 1457 results.

Anal Calcd for C 30 H 31 NO 6 S: C, 67.52; H, 5.86; N, 2.62. Found: C, 67.44; H, 5.95; N, 2.55.

150 • t · «o o o o o o o o o o o o o o o o o o o o o o o 99 ····· · ·

Example 12

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

2- (3- {3- [5-Benzyloxy-2-ethyl-4- (4,4,5, stetramethyl- [1,3,2] -dioxaborolan-2-yl) phenoxy] propoxy} -, methyl ester - 2-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 (ppf) (15 mg, 0.018 mmol) ) in deoxygenated 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 under vacuum, diluted with methylene chloride, and filtered through a short pad of silica gel eluting with 20% ethyl acetate / 80% hexane. The filtrate was concentrated under vacuum. 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 under vacuum. The resulting foam was dissolved in tetrahydrofuran / ΙΝ hydrochloric acid 1: 1 (5 mL) and stirred at room temperature for 18 hours. The mixture was concentrated under vacuum and treated with 1 equivalent of 1N sodium hydroxide in ether. The resulting mixture was concentrated under vacuum to afford 59 mg (23%) of the title compound as an off-white solid. NMR (DMSO-d6) δ 7.40

(dd, J = 9 , 2 Hz, 1H), 7.13 (t, J = 8.2) Hz, 1H), 6.97 (m, 2H), 6.79 (with, 1H 6.68 (d, J = = 9Hz, 1H) 6.65 (d, J = 9Hz) 1H), 6, 60 (with, 1H 6.21 (d, J = = 8Hz, 1H), 4.19 (t, J = 6 Hz) 2H), 4, 01 (t, J = = 6Hz, 2H), 2.66 (t, J) = 8 Hz, 2H), 2.48 (q, J = 8 Hz, 2H) , 2.24 (s, 3H), 2.17 (quintet, J = 6 Hz, 2H), 2.07 (with , 3 H, 1.49 (hextet, J = = 8 Hz, 2H), 1.07 (t, J = 7 Hz, 3H), 0.85 (t, J = 7) Hz, 3H): TOF

MS ES ⁺ exact molecular mass calculated for C 32 H 36 NO 7 (p + 1): m / z = 546.2492. Found: 546.2514; IR spectral analysis results (KBr, cm -1) 3400, 1605, 1460.

152

Example 13

Preparation of 2- {3- [3- (2-ethyl-4-furan-2-yl-5-hydroxy-phenoxy) -propoxy] -2-propyl-phenoxy} -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 cooled to -70 ° C and treated with boron tribromide (0.25 mL, 2.6 mmol). After 25 min 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 saturated sodium chloride solution, dried (sodium sulfate), and concentrated. · · · · · ·

153 filtered and concentrated under vacuum to afford 1.1 g (52%) of the title compound as a pale yellow oil. 1 H NMR (CDCl 3)

δ 7 89 (d, J = 9 Hz, 1H) 7.38 (t, J = 8Hz, 1H), 7.1 8 (with 1H), , 7.12 (d, J = = 9 Hz, 1H), 7.08 (d, J = 2 H) (1H, 1H), 6, 81 (d, J = 9 Hz 1H), 6.68 (d, J = 9 Hz 1H), 6.56 (s, 1 H), 6, 46 (d, J = 9 Hz 1H), 5.40 (s, 1H), 4.18 (t, J = 6) Hz, 2H) 4, 11 (t, J = 6 Hz 2H), 3.84 (s, 3H), 2.65 (t, J = 8) Hz, 2H) 2, 54 (q, J = 7Hz, [0100] 2H ), 2.32 (quintet, J = 6 Hz 2H), 1, 54 (Hextet, J = 8 Hz, 2H), 1.13 (t, J = 7Hz, 3H), 0, 89 (t, J = 7Hz, 3H); MS ES + mi z = 541 (M @ +) 543 (Μ - H +) 2)

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

2- {3- [3- (4-Bromo-2-ethyl-5-hydroxy-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester solution (1.00 g,

1.84 mmol) in methylene chloride (20 mL) was reacted with 0 · 0 ° C. · · · · · · · · · · · · · · · · · · · · · · · · ·

154 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 under vacuum to give 1.1 g (91%) of the title compound as a colorless oil. NMR (CDCl 3) δ 7.88

(d, J = 9 Hz 1H), 7.38 (t, J = 8Hz, 1H), 7 , 22 (p 1H), 7.12 (d, J = 9 Hz 1H), 7.08 (d, J = 2Hz, 1H), 6 80 (d, J = 9 Hz 1H) , 6.69 (d, J = 9 Hz (1H), 6.45 (d, J = 9 Hz, 1H), 6.40 (with, 1H), 4.20 (t, J = 6) Hz, 2H), 4.11 (t, J = = 6 Hz, 2H), 3.83 (with, 3H), 2.64 (t, J = 8) Hz, 2H), 2.54 (q, J = = 7 Hz, 2H), 2.32 (kv intet, J = 6Hz, 2H) , 1.54 (hextet, J 8 Hz, 2H), 1.13 (t, J = 7Hz, 3H), 1.03 (s, 9H) 0.89 (t, J = = 7 Hz, 3H), 0.23

(s, 6 H).

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

4 4 · · · · ····

4 4 ··· 4 ··· ·· ·

4 · 4 · 4444

155

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 under vacuum. Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue resulted in it being obtained

0.8 g (94%) title compounds as colorless oil. ^ H NMR (CDCI3) δ 7 , 90 (d J = 9 Hz 1H), 7.48 (s, 1 H), 7.38 (t, J = 8 Hz, 1H), 7.21 (s 1H), , 7.13 (s, 1 H 7.10 (d, J = 9 Hz, 1H), 7 07 (d, J = 2) Hz, 1H), 6.81 (d, J = 9) Hz, 1H), 6 69 (d, J = 9 Hz, 1H), 6.52 (m, 3H), 6.44 (d, J = 9) Hz,

1H 4.20 (m, 4H), 3.83 (s, 3H), 2.67 (t, J = 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 -). Analysis: Calcd for 03283407: 0, 72.43; H, 6.46. Found: C,

72.21; H, 6.15.

'0'

COONa · · · · · · · · · · · · · · · ·

156

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

2- {3- [3- (2-Ethyl-4-furan-2-yl-5-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 under vacuum, 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 under vacuum. The residue was dissolved in ethyl acetate and shaken with 1N hydrochloric acid. The organic layer was dried (sodium sulfate), filtered, and concentrated under vacuum. The residue was dissolved in diethyl ether and treated with 1N aqueous sodium hydroxide solution (0.32 mL). The mixture was concentrated under vacuum and then azeotroped with diethyl ether, chloroform and diethyl ether and dried to afford 168 mg (66%) of the title product as a cream solid. NMR (DMSO-d6) δ 7.56 (s, 1H), 7.44 (d, J = 8Hz, 1H 7.35 (s, 1H), 7.13 (m, 1H 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 = 8Hz, 2H), 2.42 (q, J = 7Hz, 2H), 2.13 (quintet) J = 6Hz, 2H), 1.48 (hextet, J = 8Hz, 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 33 O 7 (P + 1): m / z = 517.2226.

Found: 517.2230. IR spectral analysis results (KBr, cm ^-1 ) 3400, 2961, 1599, 1460.

• · · ·

157

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.

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 2M aqueous sodium carbonate solution (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 brine, dried (sodium sulfate), filtered, and concentrated under vacuum. Chromatography (silica gel, 15% ethyl acetate / 85% hexane) of the residue resulted in it being byla 9 · 9 9 9 9 9 9 9 9 9 9 · ·· · «·· ····

158 gave 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-hydroxyphenoxy) propoxy] -2-propylphenoxy] 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 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 / 98% chloroform) of the residue yielded 45 mg of material, and the residue yielded 45 mg of material. · * · · · · · · · · · ···

159 which 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 sodium salt 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-yl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (3.00 g, 4.73 mmol) and furan-3-boronic acid (1). (06 g, 9.47 mmol), rt

I. I

4 »·

160-4 tetrakis (triphenylphosphine) palladium (0.54 g, 0.47 mmol), and a 2M aqueous solution of sodium carbonate (20 mL) in tetrahydrofuran (40 mL) were 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 brine, dried (sodium sulfate), filtered, and concentrated under vacuum. Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue resulted in 1.9 g of 1 (65%) of the title compound as a yellow oil. @ 1 H NMR (CDCl3) .delta.8.88 (d, J = 8,

Hz, 1H), 7.87 (s, 1H), 7.40 (m, 7H), 7.26 (s 1H), 7.05 (m, 2H), 6.80 (d, J = 9 Hz) (1H), (d, J = 9Hz, 1H), 6.60 (s, 1H), (s, 2H), 4.18 (m, 4H), 3.83 (s,

2.62 (q, J = 7Hz, 2H), 2.30 ((hextet, J = 8Hz, 2H), 1.20 (t, J = 7Hz, 3H); MS ES + m / z = 621 (p + 1), IR spectral analysis (CHCl 3, cm -1) results 3000, 1727, 1603, 1461.

6.76 (d, J = 2 Hz, 1 H 6, 67 6.43 (d, J = 9Hz (1H), 5.11 3H), 2.66 (t, J = 8 Hz, 2H), quintet, J = 6 Hz, 2H), 1.57 (t, J = 7 Hz, 3H), 0.92

COOMe

161 • # · · · · · · · · · · · · · · · · · ·

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, filtered through Celite ™, and the filtrate was concentrated below

vacuum, v z v cimz í 1.2 g were obtained (77%) title compounds such as 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 = 9Hz, 1 H) 7.04 (d, J = 9 Hz, 1H), 6.81 (d, J = 9 Hz 1 H, 6.80 (s, 1 H), 6, 67 (d, J = 9 Hz, 1H), 6.44 (d, J = 9 Hz 1 H, 6.43 (s, 1 H), 4.19 (m, 3H) . 4.10 (m, 2H), 4.02 (dd, J = 12.3 Hz, 1H), 3.88 (d, J = 12, 8 Hz, 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 = 6 Hz, 2H), 1.99 (m, IH), 1.55 (hextet, J = 8 Hz, 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) 2963, 1719, 1589, 1461. Anal. Calcd. for C 32 H 38 O 7: C, 71.89; H, 7.16.

Found: C, 71.41; H, 7.06.

, 0- »OH

O

COONa

162

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

2- (3- {3- [2-Ethyl-5-hydroxy-4- (tetrahydrofuran-3-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester solution (0.92 g, 1.7 mmol) in tetrahydrofuran (10 mL) and methanol (5 mL) was treated with 1M aqueous lithium hydroxide solution (10 mL) at 55 ° C for 2 h. 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 brine, dried (sodium sulfate), filtered, and concentrated under vacuum. The obtained colorless oil 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 h to give 0.78 g (84%) of the title compound as follows:

hair of the company: t. mp 67-71 ° C. ! η NM: R (DMS 0-d ₆ ) δ 7.62 (d, J = 8, 2 Hz (1H), 7 30 (t, J = 8.2H) z, 1H ), 7, 05 (m, 2H), 6, 85 (with, 1H), 6.73 (d, J = 9Hz, 1 H), 6.70 (d, J = 9 Hz (1H), 6.53 (with, 1H), 6.34 (d, J = 9 Hz, 1 H), 4.15 (t, J - 6 Hz , 2H), 4.04 (t, J = 6 Hz 2H), 3.95 (m, 1H 3.88 (m, 1H), 3.75 (q. J = 9 Hz 1H), 3.49 (m 2H), 2, 60 (t, J = 8 Hz, - 2H), 2, 45 (q, J = 7Hz, 2H), 2.15 (m, 3H), 1, 90 (m, 1H), 1.48 (hez : tet, J = 9 Hz, 2H), 1.06 (t, J = 7Hz, 3H), 0.83

163 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 7 Hz, 3H); MS ES + m / z = 519 (p-Na &lt; + &gt;); the results of IR spectral analysis (CHCl 3, cm ^_ l) 2964, 1783, 1604, 1461. Analysis: calculated for 03 ^ 35 ^ () 7 · 0,5H2O: C, 67.50; H, 6.58. Found: C, 67.76; H, 6.68.

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.

2- {3- [3- (5-Benzyloxy-4-bromo-2-ethyl-phenoxy) -propoxy] -2-propyl-phenoxy} -benzoic acid methyl ester (3.00 g,

164

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 2M aqueous sodium carbonate solution (25 mL) in tetrahydrofuran (60 mL) was heated under 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 brine, dried (sodium sulfate), filtered, and concentrated under vacuum. Chromatography (silica gel, 10% ethyl acetate / 90% hexane) of the residue yielded 2.6 g (76%) of the title compound as a solid. 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 (with, 1H 6.44 (d, J = 9Hz, 1H), 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 = 7 Hz, 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); IT WITH 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:

calculated for C44H49NO8:

Found:

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

165 · · · · · · · · · · · ·

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 solution (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 h, at room temperature for 20 h, then at 45 ° C for 19 hours. The mixture was cooled to room temperature, filtered through Celite ™, and the filtrate was concentrated under vacuum to afford 0.76 g (88%) of the title compound as a colorless.

oil. 1 H NMR (CDC1 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 = 9 Hz, 1H), 6.67 (d, J = 9Hz, 1H), 6.47 (s, 1H), 6.44 (d, J = 9 Hz, 1H), 5.09 (m, 1H), 4.18 (d, J = 6Hz, 2H), 4.14 (t. J = 6 Hz, 2H), 3.84 (s, 3H) 3.45 (m, 2H), 2.64 (t, J = 8Hz, 2H) , 2.54 (m, 3H)

166 · · · * * * * * * * *

2.25 (m, 5H), 2.06 (m, 1H), (s, 9H), 1.15 (t, J = 7Hz,

1.54 (hextet, J 3H), 0.90 (t, J

Hz, 2H), 1.43 Hz, 3H).

C. Preparation of 2- (4- {3- [3- (2-Carboxy-phenoxy) -2-propyl-phenoxy] -propoxy} -5-ethyl-2-hydroxy-phenyl) -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 hours. The resulting mixture was concentrated under vacuum and the residue was 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 give 90 mg (78%) of the title compound. MS ES ⁺ m / z = 620 (p + 1 Li ⁺ ); the results of IR spectral analysis (KBr, cm ^_ l) 2964, 1672,

167 • · · · · · · · · · · · · · · ·

1603, 1416. Anal. Calcd. H, 7.20; N, 2.18. Found: C, for C 38 H 44 NO 8 Li 1 H 2 O: C, 67.17; 66.72; H, 6.99; N, 2.27.

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

To a solution of 2- (4- {3- [3- (2-carboxyphenoxy) -2-propylphenoxy] propoxy] -5-ethyl-2-hydroxyphenyl) pyrrolidine-1-carboxylic acid tert-butyl ester hydrate (0.100 g, 0.16 mmol) 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. The mixture was concentrated under vacuum to give 48 mg (52%) of the title compound. 1 H-NMR (DMSO-d ₆ ) δ 12.80, (bs, 1H), 10.12 (s, 1H),

168

9.34 (bs, 1H) , 8.36 (bs, 1H). 7.79 (d, J = = 9, 2 Hz, 1H) 7.47 (dt, J = 8, 2 H ₂ 1 H, 7.17 (t, J = = 8 Hz _i r 1H), 7.12 (d, J = 9 Hz 1H), 7.07 (s, 1H); 6.80 (d, J = 9 Hz, 1H) 6.78 (d, J = 9 Hz 1H), 6.58 (s, 1 H), 6.35 (d, J = 9 Hz, 1H) 4,56 (m, 1H), 4.20 (t, J = 6 Hz, 2 H); 4.11 (t, J = 6 Hz, 2H) 3.25 (m, 2H), 2.50 (m, 5H), 1.90-2.60 (m, 5H), 1.44 (hex tet, J = 8 Hz, 2H), 1.08 (t, J = 7 Hz, 3H), 0.82 (t, J = 7Hz, 3H); TOS MS ES ⁺ precision molecular mass was

calculated for Οβ ^ ΗβθΝΟβ (p + 1): m / z = 520.2699.

Found: 520.2672.

Example 17

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

known compound:

(Sawyer et al., J. Med. Chem. 1995, 38, 4111)

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,

169

9 «» · 9

9 9 4 9 9 9 9 9 99 99 9 9 9 9

15.9 mmol), tetrakis (triphenylphosphine) palladium (312 mg,

0.270 mmol), 2M aqueous sodium carbonate (4 mL), and n-propanol (4 mL) in toluene (16 mL) were refluxed for 4 hours. The mixture was cooled to room temperature, diluted with diethyl ether, washed once with water and once with saturated 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: m.p. 65-67 [deg.] C. 1 H NMR (CDCl 3) δ 7.58 (d, J = 2.8 Hz, 1H), 7.49 (d, J = 5.2 Hz, 1H 7.457.30 (m, 7H), 6.62 (s) 1H 5.13 (s, 2H), 4.14 (t, J = 5.8 Hz, 2H), 3.81 (t, J = 6.3 Hz, 2H), 2.66 (q, J) = 7.5 Hz, 2H), 2.29 (quintet, J = 6.0 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H); MS FD m / e 386 (p) IR spectral analysis results (CHCl3, cm -1)

2969, 1613, 1501, 1138. Analysis calculated for C22 ^H 23O2dS:

C, 68.29; H, 5.99. Found: C, 68.53; H, 6.00.

J. Med. Chem. 1995, 38. 4411,

• * ·

170 ·· · 9 •

9 9 9

9

9 »» · ♦ · 99

Β. 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 yielded 1.31 g (67%) of the title product as a colorless oil. NMR (CDCl 3) δ 7.66 (d, J = 7.8 Hz,

1H), 7.57 (d, J = 2.9 Hz, 1H j, 7.48 (d, J = 5.2 Hz, 1H), 7.45 -7.25 (m, 8H) 7.20 (t, J = 8.2Hz) , 1H 7.10 (t, J = 8.1 Hz, 1H 6.82 (d, J = 8.3Hz, 1H), 6, 77 (d, J = 8.6 Hz, 1H 6.64 (s, 1H 6.63 (d, J = 6.4) Hz, 1H) 5.11 (with, 2H), 4 26 (t, J = 6.0 Hz); 2H), 4.22 (t, J = = 6.0 Hz, 2H), 2, 65 (m, 4H), 2.36 (qui ntet, J = 5.9 Hz, 2H), 1.58 (hex tet, J = 7.5 Hz, 2H), 1.24 (t, J = 7.5Hz, 3H), 0.95 (t,

-1 J = 7.3 Hz. 3H); MS: FD m / e 603 (p); IR spectral analysis (CHCl 3, cm -1) results 2967, 2250, 1613, 1501. Analysis:

Calcd. for C 38 H 37 N 4 O 4 S: C, 75.59; 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.

.. X ♦ * * ♦ * * * * * * * * · * · · ·

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), which was cooled to -78 ° C, was added a 1M solution of boron tribromide in methylene chloride (2.99 mL, 2.99 mmol) over 2 minutes. The resulting violet solution was stirred for 30 min 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) resulted in 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) 1 H, 7.62 (s, 1 H), 7.42 (t, J = 7.1 Hz, 1 H), 7.27 (t, J = 6.6 Hz, 1 H), 7.20 (s) 1 H, 7.08 (d, J = 8.1 Hz, (t, J = 6.9 Hz, 1H 6.85 (s, 1H), 6.89)

1H), 6.74 (d, J = 8.5Hz, 1H), 6.60 (d, J = 7.6Hz, 1H 4.71 (s, 1H, -OH), 4.26 (t J = 6.0 Hz, 4H) 2.72 (q, J = 7.4 dHz, 2H), 2.59 (t, J = 7.3 Hz, 2H), 2.39 (quintet, J) = 6.1 Hz, 2H), 1.54 (hextet, J = 7.7 Hz,

2H), 1.25 (t, J = 7.5Hz, 3H), 0.91 (t, J = 7.4Hz, 3H).

172 · 9 9 99 4 9 4 4 »

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

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 treated with 12.5M 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 properties: mp 90-95 ° C. 1 H NMR (CDCl ₃ ) δ 8.24

(J = = 7.8 Hz, 1H), 7.47 (d, J = 5.0 Hz, 1 H) 7, 44 (t, J = 8.6 Hz, 1H) r 7.36 (d, J = 3Hz, 1 H), 7, 24 (d, J = 4.9 Hz, 1H), 7.19 ( : m, . 2H), 7.09 (s, 1H). 6, 84 (d, J = 8.0 Hz, 1H) t 6.73 (d, J = 8.3 Hz, 1 H), 6, 64 (J ' = 8.0 Hz, , 1H j, 6, 55 (s, i: H) ' 5.38 (bs, 1H, --OH), 4, 26 (t, J = 6.2 Hz, 2H), 9, 21 (t, J = 7.1 Hz, 2H), 2.60 (m, 4H )

173 ► «« »t« • · ♦

2.36 (quintet, J = 5.8 Hz, 2H) 2H), 1.19 (t, J = 7.5 Hz, 3H), FD m / e 532 (p); IR (KBr, cm -1) 1110. Analysis:

Calcd. for CggHggOgS.HgO: C, found: C, 1.51 (hextet, J = 7.1 Hz,

0.90 (t, J = 7.4Hz, 3H); MS 3200 (br), 2961, 1697, 1457,

67.62; H, 6.22.

67.34; H, 5.87.

The LTB4 antagonists referred to 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 (acidic) group of the compound of formula (I) may be defined as -COgH 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 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

9

and nitrogen-containing bases of sufficient basicity to form salts with the LTB4 antagonists of the invention (see, for example, SM Berge, et al., "Pharmaceutical Salts, J. Phar. Sci., 66: 1-19 (1977))" . Certain compounds of the invention may also carry one or more chiral centers and may thus 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, due to different boiling points having different diastereomers and due to different solubilities, the diastereomers can be separated from one another by conventional means, for example crystallization may be used.

Prodrugs are derivatives of the LTB4 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 both acidic and basic derivative activity, but acidic derivatives often offer advantages in terms of solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, H., Design of

175 ·· ··· · · · · #

Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, including, for example, esters of the starting compound 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 is more preferred in this case than methanol.

N, N-diethylglycolamide ester prodrugs can be prepared by reacting the sodium salts of a compound of formula (I) (in an environment such as dimethylformamide) with 2-chloro-N, N-diethylacetamide (available from Aldrich Chemical Co., Milwaukee, Wisconsin USA; 25,099-6)

176 • 9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9

99

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 (LTB4) antagonists mentioned above and a therapeutically effective amount of the anti-cancer drugs also mentioned above. The composition may be formulated using conventional excipients, diluents or carriers and compressed into tablets or formulated as baths or solutions for routine oral administration or for intramuscular or intravenous administration. The compounds can be administered transdermally and can be formulated for uniform release formulations, into 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 antagonist (LTB4) and an anticancer drug. When leukotriene (LTB4) antagonists are administered separately

177

Various schedules of administration times over time can also be used for anticancer active agents. It is possible to administer the second agent in the meantime, as long as the intervals of administration of the second agent are between each other. The administration of one active agent falls within the therapeutically effective 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) i.e. the leukotriene antagonist (LTB4) or (b) i.e. the anti-cancer active agent is administered to a patient being human and ends in at a time when the effective effect for treating cancer of combination (a) and (b) ceases to be effective. The routes of administration of the leukotriene antagonist (LTB4) 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 depending upon the particular treatment conditions. In many cases, it may be appropriate to use conventional dosage variations that are adjusted

178 · * a a v v v v v v v v v v v na v v v v v na na v v v v v na depending on age and patient condition. The dosage will also depend on the mode 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 formulating (e.g., agitating) a therapeutically effective amount of an anticancer drug (e.g., 2 ', 2'-difluoro nucleoside) 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 the carrier or incorporated into the carrier, which may be in the form of capsules, lozenges and paper or containers. Where carriers are used as diluents, the formulation may be solid, lyophilized, or a paste, semi-solid, or liquid material, which may be a vehicle 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% by weight of the active compound. The compounds of the invention are preferably formulated prior to administration.

* 9

179 · «9 · 9 9 9 9 9 9 9 9 9

For the purposes of pharmaceutical preparations, any known carrier may be used. In such a composition, 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 can also act as flavoring agents, solubilizing agents, suspending agents, binders, tablet disintegrating agents and encapsulating and encapsulating material can 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 binder, 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 compacted in the shape and size desired.

180 • 4 • 4 • 4 • 4

Preferably, the compositions comprise a compound of formula (I), in suitable dosage unit forms, for example, each dosage unit containing 5 to about 500 mg (about 5 to 50 mg for the parenteral or inhalational route of administration) and from about 25 to 500 mg for the oral or 0.5 to 20 mg / kg of active ingredient can also be administered, and it is to be understood that the daily dose is preferably between 0.5 to about 300 mg / kg, always calculated for the compounds of formula (I) which should be administered, the exact dose will be determined by the physician, based on all circumstances that may affect this dose.

The powders and tablets may advantageously contain about 1 to 99 percent by weight 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.

Formulations in the form of sterile liquids 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.

· 9 * 99

9 9

9 9 ► · * · · · · · ► ► 9

99

181

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. The 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.

In one embodiment of the composition of the invention, a combination of therapeutically effective amounts of the leukotriene (LTB4) antagonists mentioned above and a therapeutically effective amount of the 2 ', 2'-difluoro-nucleoside anticancer agent is used. The formulation 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 formulated in a dosage form for uniform release of the active ingredient and the like.

In another embodiment, the 2 ', 2'-difluoro-nucleoside anticancer drug and leukotriene antagonists (LTB 4) are independently administered, each administered separately. The anticancer active compounds can be formulated with the aid of conventional excipients, additives, diluents or carriers and administered by intravenous infusion. On the second

182 • 3 · ···

JJ ♦ ··· · · ♦ _'t I from: · · · · · i' 4 4 4 4 · «*» ♦ ·· ».. *.» ·, Side can be adjusted anticancer active substance in forms of fluids suitable for oral administration. The anti-cancer drugs may also be compressed into tablets and administered orally. If the anti-cancer agent and leukotriene antagonists (LTB4) are administered separately, the anti-cancer agent may be administered before, after or during administration of the leukotriene antagonists (LTB4). If the anti-cancer agent is administered separately from leukotriene antagonists (LTB4), 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 (LTB4) and administering an anti-cancer drug in the form of separate administration of leukotriene antagonists (LTB4) and an anti-cancer drug. When administered separately, the leukotriene antagonists (LTB4) are formulated into compositions that can be administered orally and rectally, topically, parenterally, for example by injection and continuously or discontinuously by intraarterial infusion, such as tablets, lozenges, sublingual tablets, pastilles, baths, gels, suspensions, aerosols, lotions, for example, containing from 1 to 10 weight percent of the active compound in a suitable base composition of a cream mixture, soft or hard gelatin capsules, suppositories, injectable solutions and suspensions in a physiologically acceptable environment and sterile packaged powders adsorbed onto a carrier material, for the preparation of sterile injectable solutions before 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 &lt; 9 &gt;

183 · ♦ 9 ·· 99

9 9 9 99 99 9 9 9 9 9

Parenteral or inhalation administration, and from about 25 to 500 mg (for 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 specifically 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 antagonists (LTB4) 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 into a swallowable carrier in capsule, lozenge, pill, paper form. 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, calcium silicate, silica, polyvinylpyrrolidone, ketostearyl alcohol, starch, modified starches, acacia, phosphate

184

• *>

• · # ·· «- ·

calcium, cocoa butter, ethoxylated esters, cocoa oil, peanut oil, alginates, tragacanth, gelatin, syrup, methylcellulose, polyoxyethylenesorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoates, sorbitan trioleate, sorbitan disodium difluoride, and also trichloromethane sulphoeate, and also triethylsulfonoleate, and dichlorotetrafluoroethane. In the case of tablets, a glidant or lubricant may be added to the molds and to the compression tool of the tablet machine to prevent sticking and joining of powder additives. For example, aluminum stearate, magnesium stearate or calcium stearate, talc or mineral oil may be used for this purpose.

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

For any of the leukotriene (LTB4) antagonists mentioned 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 1 t

185 w * · 4 • ♦ • 44 • 4 • «i ·· 44 • 4 • 4 •

4 • 4

4 «

4 ·

4 · 4 · 4 4 4 4 444

Hard gelatine capsules are prepared using a fuming component:

Amount (mg / capsule) acid

3- (2- (3- (2-Ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-carboxyphenoxy) phenyl) propane 250

Starch 200

Magnesium stearate 10

The above ingredients are mixed and filled into hard gelatin capsules at 460 mg per dosage unit.

EXAMPLE OF MIXTURE COMPOSITION

A tablet is prepared using the ingredients listed below:

Amount (mg / capsule)

1- (4- (Carboxymethoxy) phenyl) -1- (1H-tetrazol-5-yl) -6- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) hexane 250

Cellulose, microcrystalline

Silica, fuming

400

Magnesium stearate

186 · ♦ 9 9 «9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 · 9 9 9999

The ingredients are blended and compressed into tablets, each weighing 665 mg.

EXAMPLE OF COMPOSITION OF MIXTURE 3

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

Mass %

3- [4- [7-Carboxy-9-oxo-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] -9H-xanthene]] propane

acid Lina 0.25 Ethanol 30,00 Propelent 11 (Trichlorofluoromethane) 10.25 Propelent 12 (Dichlordifluormetan) 29.75 Propelent 114 (Dichlortetrafluoretan) 29.75

The active compound is dissolved in ethanol and the solution is added to propellant 11, cooled to -30 ° C and transferred to a filling apparatus. The required amount is then filled into a container and further filled with the premixes of propellants 12 and 114, using a cold or pressurized filling method.

Valve units are then connected to the vessels.

187

EXAMPLE OF COMPOSITION OF MIXTURE 4

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

2- [2-Propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid, sodium salt 60 mg

Starch 45 mg

Microcrystalline cellulose 35 mg

Polyvinylpyrrolidone (as a 10% aqueous solution) 4 mg

Sodium carboxymethyl starch 4.5 mg

Magnesium stearate 0.5 mg

Talc 1 mg

Total '150 mg

The active ingredient, starch and cellulose are passed through a 45 mesh U.S. sieve sieve and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the obtained powders and then the resulting mixture is passed through a 14 mesh U.S. sieve. The granules so obtained are then dried at 50-60 ° and passed through a 18 mesh U.S. sieve. TO

188 of 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 tabletting machine to give tablets each weighing 150 mg.

EXAMPLE OF COMPOSITION OF MIXTURE 5

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

5- [3- [2- (1-Carboxy) ethyl] -4- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenyl] -4-pentanoic acid 80 mg

Starch 59 mg

Microcrystalline cellulose 59 mg

Magnesium stearate 2 mg

Total 200 mg

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

• ·

189

EXAMPLE OF COMPOSITION OF MIXTURE 6

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

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

Unsaturated or saturated fatty acid glycerides up to 2 000 mg

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.

EXAMPLE OF COMPOSITION OF MIXTURE 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 to

190

accompanying mixing. Then add water to the required volume.

The components used are as follows:

2- [2-Propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propo-

xy] phenoxy] benzoic 50 mg Sodium carboxymethylcellulose 50 mg Sugar 1 g Metylparaben 0.05 mg Propylparaben 0.03 mg Flavor according to need Dye according to need Cleaned water to 5 ml

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

·

191 • ··· • · ⁴ • 4 '

EXAMPLE OF COMPOSITION OF MIXTURE 8

Hard gelatine capsules are prepared using a fuming component:

Amount (mg / capsule) 1- (4-Amino-5-methyl-2-oxo-1H-pyrrole) midin-1-yl) -2-desoxy-2 ', 2' - difluorribosis 250 Dried starch 200 Magnesium stearate 10 The above ingredients are mixed 460 mg gelatin capsules and fills in hard per dosage unit.

• ·

9 9 9 9

192

EXAMPLE OF COMPOSITION OF MIXTURE 9

A tablet is prepared using the ingredients listed below:

Quantity (mg / tablet)

1- (2-oxo-4-amino-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluorribose 250

Cellulose, microcrystalline 400

Fumed silica 10

Stearic acid

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

EXAMPLE OF COMPOSITION OF MIXTURE 10

An aerosol solution is prepared containing the following fuming components:

Mass

1- (2,4-dioxo-1H, 3H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluorribose 0.25

Ethanol 29.75

Propellant 22 (chlorodifluoromethane) 70.00

193 ·· * .. ´i · *: ··:: ·:: ·

......

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

EXAMPLE OF COMPOSITION OF MIXTURE 11

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

1- (4-Amino-2-oxo-1H-pyrimidin-1-yl-2-desoxy-2 ', 2'-difluorribose

Starch

Microcrystalline cellulose

Polyvinylpyrrolidone (as a 10% solution in water)

Sodium carboxymethyl starch

Magnesium stearate

Talc mg mg mg

4 'mg

4.5 mg

0.5 mg mg

The difluorucleoside, starch and cellulose are passed through a 45 mesh U.S. sieve and mixed intimately. Se ··

194 · »· · ···.

> · · *. · ·· ·· ··· <

the powder obtained, which is then passed through a sieve

The 14 mesh U.S. sieve is then blended with polyvinylpyrrolidone. The granules so obtained are then dried at 50-60 ° C and passed through a 18 mesh U.S. sieve. 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.

solution

EXAMPLE OF COMPOSITION OF MIXTURE 12

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

Mixture used:

1- (4-Amino-2-oxo-1H-pyrimidin-1-yl) -2-de- soxy-2 ', 2'-difluoroxylose 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg

The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a 45 mesh U.S. sieve, and ···

195

It is filled into hard gelatin capsules in an amount of 200 mg per dosage unit.

EXAMPLE OF COMPOSITION OF MIXTURE 13

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

Mixture composition:

1- (2,4-dioxo-1H, 3H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluorribose

Saturated fatty acid glycerides

225 mg to 2 g

The nucleoside is passed through a 250 mesh U.S. sieve (250 mesh) and pre-mixed with the minimum heat required to melt 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.

· * ··

196 • ···

EXAMPLE OF COMPOSITION OF MIXTURE 14

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

1- (4-Amino-5-methyl-2-oxo-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluorribose 50 mg

Sodium carboxymethylcellulose

Syrup

Benzoic acid solution

Flavor

Dye

Purified water mg

1.25 ml

0.10 ml as needed up to 5 ml

EXAMPLE OF COMPOSITION OF MIXTURE 15

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

1- (4-Amino-2-oxo-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluorribose 100 mg

Isotonic brine 1000 ml

197

•

The 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 treatment.

EXAMPLE OF COMPOSITION OF MIXTURE 16

Hard gelatine capsules are prepared using the following ingredients:

Amount (mg / capsule)

3- (2- (3- (2-Ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-carboxyphenoxy) phenyl) propanoic acid

2 ', 2'-Difluoro-2'-deoxycytidine monohydrochloride

250

250

Starch 200

Magnesium stearate 10

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

• · «·

EXAMPLE OF COMPOSITION OF MIXTURE 17

Tablets are prepared using the ingredients listed below:

Amount (mg / capsule)

1- (4- (Carboxymethoxy) phenyl) -1- (1H-tetrazol-5-yl) -6- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) hexane 250

2 ', 2'-Difluoro-2'-deoxycytidine monochloride 250

Cellulose, microcrystalline 400

Fumed silica 10

Magnesium stearate

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

199 • · · ·

EXAMPLE OF MIXTURE 18

An aerosol solution is prepared containing the following components:

Mass %

3- [4- [7-Carboxy-9-oxo-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] -9H-xanthene]] propane

kysej Lina 0, 25 2 ', 2'-difluoro-2'-deoxycytidine monohydrochloride 0.25 Ethanol 30, 00 Propelent 11 (trichlorofluoromethane) 10, 00 Propelent 12 (Dichlorodifluoromethane) 29, 75 Propelent 114 (Dichlorotetrafluoroethane) 29.75

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

200

EXAMPLE OF COMPOSITION OF MIXTURE 19

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

Mass 2- [2-Propyl-3- [3- [2-ethyl-5-] sodium salt -hydroxy-4- (4-fluorophenyl) phenoxy] - propoxy] phenoxy-3-benzic acid 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 starch 4,5 mg Magnesium stearate 0, 5 mg Talc 1 mg Total 210 mg

The active ingredient, starch and cellulose are passed through a 45 mesh U.S. sieve and mixed intimately.

201 • · · · ···· · ···

The resulting powder is then mixed with polyvinylpyrrolidone and then passed through a 1.4 mm (No. 14 mesh U.S. sieve) screen. The granules so obtained are then dried at 50-60 ° and passed through an 18 mesh U.S. sieve. Then, other ingredients such as sodium carboxymethyl starch, magnesium stearate and talc are added to these granules and pre-screened by passing through a 60 mesh US sieve, and after mixing the mixture is compressed on a tablet machine into tablets, using a form such that each tablet weighs 210 mg.

EXAMPLE OF COMPOSITION OF MIXTURE 20

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

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

Total

280 mg

202

The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a 355 µm (No. 45 mesh U.S. sieve) sieve and filled into hard gelatin capsules at 280 mg per dosage unit.

EXAMPLE OF COMPOSITION OF MIXTURE 21

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

3- (5- (6- (4- (4-fluorophenyl) -5-hydroxy-2-ethylphenoxy) propoxy) -2-carboxymethyl-1,2,3,4-tetrahydronaphthalen-1 (2H) -one) propane 225 mg 2 ', 2'-difluoro-2'-deoxycytidine monochloride 225 mg

Unsaturated or saturated fatty acid glycerides up to 2 000 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.

203

EXAMPLE OF COMPOSITION OF THE PRODUCT 22

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

2- [2-Propyl-3- [3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenoxy] benzoic acid

2 ', 2'-difluoro-2'-deoxycytidine monohydrochloride

Sodium carboxymethylcellulose

Sugar

Metylparaben

Propylparaben

Flavor

Dye

Purified Water mg mg mg mg

0

0.05 mg

0.03 mg as needed up to 5 ml

The drug is passed through a 45 mesh U.S. sieve.

♦ · ♦ ·

204 sieve) and mixed with sodium carboxymethylcellulose, sugar and a portion of water to form a suspension. The parabens, flavor and color are dissolved and diluted with an additional portion of water and, with stirring, added to the previously prepared mixture. Sufficient water is then added to achieve the desired volume

Pharmaceutical compositions of the invention

The pharmaceutical ingredients according to the invention comprise the following main components:

(a) an LTB4 antagonist, and (b) an anticancer drug.

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

(a) an LTB4 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 water containing brine and sterile water containing sugars and / or brine.

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

205 • · • ···

The main components (a) of the LTB 4 antagonist and (b) of the anti-cancer active compound are provided in compositions wherein their composition and the proportions in the dose of such 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 anti-cancer drug is 1: 100 to 100: 1, preferably 10: 1 to 1:10, and most preferably 1: 4 to 4: 1.

Leukotriene antagonists (LTB4) are generally administered prior to, during, and after administration of the 2 ', 2'-difluorucleoside anticancer drug. If leukotriene (LTB4) antagonists are administered after a 2 ', 2'-difluorucleoside anticancer drug, they should be administered at a time within the therapeutically effective interval.

The following experiments confirm the effect of the invention:

• 4

206 • · · ·

TEST EXAMPLE 1

The nude mouse xenograft assay, which was 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, pp.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, human LNCaP and DU-145 prostate carcinomas, Panc-1 and BXPC3 pancreatic carcinomas, and non-small cell lung carcinomas H460 and Calu-6 were implanted subcutaneously into the hind leg of the mice (all of which are available from the American Type Culture Collection, Manassas, VA) prepared from tumor tissue collected from donors (5 x 10θ cells). Mice were treated with 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid (compound of formula IV) at 30 doses. , 100, 200, or 300 mg per kilogram daily, orally administered at 4 days post-implantation. Gemcitabine (60 mg / kg) was administered intraperitoneally.

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

207 ♦ ·

9 9 ♦ · 9 9 9 9 9 9

9

99 99

9 9 99 9 9 and a series of treatment groups, with five mice in each 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 treated and control group tumors reached 1000 mm dosáh.

Table 1

Results of prostate tumor xenograft xenograft test (1)

Treatment Dose Formula IV dose GEM TGD TGD, sem Formula IV 30 - 1,2 0.30 Formula IV 100 ALIGN! - 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 ALIGN! 60 51.2 3.50

Explanatory notes:

11) ¹ = LNCaP prostate cancer

Formula IV = LTB4 antagonist, i.e. 2- [2-propyl-3208] acid 9 9

100 ·· • · ·

9 99

9 · 99

9 9 9 ·

9 9

9 9 · 999 9

GEM dose

LNCaP

TGD

TGD, sem

- [3- [2-ethyl-5-hydroxy-4-4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid = gemcitabine hydrochloride, ie 2 ', 2'-difluoro nucleoside anticancer drug, product of Eli Lilly and Company = milligrams per kilogram of mouse body weight = LNCaP prostate cancer = mean tumor growth retardation in days = standard deviation of 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 Formulas N 100 ALIGN! - 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 ALIGN! 60 25.2 2.20

Explanatory notes:

(2) = prostate cancer DU-145

GEM = gemcitabine hydrochloride, ie 2 ', 2'-difluoro-nucleoside anticancer drug, product of Eli Lilly and Company

Dose = milligrams per kilogram of mouse body weight TGD = mean tumor growth retardation in days

TGD, sem = standard deviation of the mean TGD

Table 3

Results of pancreatic tumor growth slower xenograft test (3)

Treatment Dose Formula IV Dose GEM TGD TGD, sem Formula IV 30 - 7.4 0.50 Formula IV 100 ALIGN! - 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 Formulas IV + GEM 100 ALIGN! 60 27, 0 2.30

Explanation / 3) = pancreatic cancer tumor BxPC3 GEM = gemcitabine hydrochloride, ie 2 ', 2'-difluoro-nucleoside anticancer drug, product of Eli Lilly and Company dose = milligrams per kilogram of mouse body weight TGD = average tumor growth retardation in days

TGD, sem = standard deviation of the mean TGD

210 ·· ♦♦ «· 9

9,999 9,999 9 9 9

9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

99 99 99 99 9999

Table 4

Results of xenograft test for slowing pancreatic tumor growth

Treatment Dose Formula IV Dose GEM TGD TGD, sem Formula IV 30 - 10.2 1.40 Formula IV 100 ALIGN! - 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 ALIGN! 60 23.3 2.30 Formulas EM IV + GEM 200 60 29.1 3, 00

Explanatory notes:

(4) = Panc-1 pancreatic cancer tumor GEM = gemcitabine hydrochloride, ie 2 ', 2'-difluoro-nucleoside anticancer drug, product of Eli Lilly and Company dose = milligrams per kilogram of mouse body weight TGD = average tumor growth retardation in days

TGD, sem = standard deviation of the mean TGD

211 • · «· · φ · · · · · · · · * * * * ·

Table 5

Results of Non-Small Cell Lung Cancer Tumor Xenograft Test (5)

Treatment dose Formula IV dose GEM TGD TGD, sem Formula IV 30 - 10.9 1.00 Formula IV 100 ALIGN! - 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 ALIGN! 60 21.3 2.20 Formula IV + GEM 200 60 32.0 3.10

Explanatory notes:

5) ^x '= Non-small cell tumor of human lung cancer H4 60 NSCLC

GEM = gemcitabine hydrochloride, ie 2 ´, 2´-difluoro-nucleoside anticancer drug, product of Eli Lilly and Company dose = milligrams per kilogram of mouse body weight TGD = average tumor growth retardation in TGD days, sem = standard deviation of mean TGD

212

Table 6

Results of Non-Small Cell Lung Cancer Tumor Xenograft Test (θ)

Treatment dose Formula IV dose of GEM TGD TGD, sem Formula IV 30 7.4 0, 60 Formula IV 100 ALIGN! - 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 ALIGN! 60 22.5 2.00

Explanatory notes

- Non-small cell lung cancer Calu-6 GEM = gemcitabine hydrochloride, ie 2 ', 2'-difluoro-nucleoside anticancer drug, product of Eli Lilly and Company dose = milligrams per kilogram mouse body weight TGD = average tumor growth retardation on TGD days, sem = standard deviation of TGD mean

213 • 9 • 9 • 9

99

99

9 9 9

9 99

9

9 9 9

99

99 · · · ·

Detailed description of the attached figures

Figures 1 to 6 in the pictorial 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 effect consists in retarding the rate of tumor growth compared to the compounds (i) or (ii) alone. .

Giant. 1 depicts various treatments for LNCaP prostate cancer.

Columns (1), (2) and (3) show tumor growth retardation as a result of using the LTB4 inhibitor, Formula IV, alone at doses of 30, 100 and 200 mg / kg.

Column (4) shows 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 co-administration of the compound of formula IV (at 30 and 100 mg / kg doses) and gemcitabine hydrochloride (at 60 mg / kg dose).

Giant. 2 depicts various treatments of implanted DU-145 prostate cancer.

214 · * • 4 4

4 ··· 4 · 4 ·· 4 4 * 4

4 ·· • 44 44 4 4 4 4 4 4 44 44

Columns (1), (2) and (3) show tumor growth retardation as a result of the use of an LTB4 inhibitor, in particular 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 co-administration of the compound of formula IV (at 30 and 100 mg / kg doses) and gemcitabine hydrochloride (at 60 mg / kg dose).

Giant. 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 LTB4 inhibitor, a compound of Formula IV, alone at doses of 30, 100 and 300 mg / kg.

Columns (4) show 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 co-administration of the compound of formula IV (at 30 and 100 mg / kg doses) and gemcitabine hydrochloride (at 60 mg / kg dose).

1/9 ® ® ® 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5

215

Giant. 4 shows various pancreatic carcinomas of Panc-1.

Columns (1), (2) and (3) show tumor growth retardation as a result of the use of the LTB4 inhibitor, a compound of Formula IV, alone at doses of 30, 100 and 200 mg / kg.

Columns (4) show 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 30, 100 and 200 mg / kg doses) and gemcitabine hydrochloride at 60 mg / kg doses.

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

Columns (1), (2) and (3) show tumor growth retardation as a result of the use of the LTB4 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 (in doses)

216 • · 9 4 * 9 9 4

30, 100 and 200 mg / kg) and gemcitabine hydrochloride (60 mg / kg).

Giant. 6 shows various treatments of implanted non-small cell lung carcinoma Calu-6.

Columns (1), (2) and (3) show tumor growth retardation as a result of the use of the LTB4 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 anticancer drug, gemcitabine hydrochloride alone at a dose of 60 mg / kg.

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

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217

Λ »- / # γ

PATENTOVÉ

Claims

Claims (10)

Claims A composition comprising a therapeutically effective amount of a leukotriene antagonist (LTB4) agent and a therapeutically effective amount of a 2 ', 2'-difluoro nucleoside anticancer agent. A composition comprising a therapeutically effective amount of a leukotriene antagonist (LTB4) 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: R 1 is hydrogen; R ₂ is a base defined by one of the formulas: NHR ³ N ' M 'where: · · ► · ► ► ► ► ► ► ► ► 218 • · · · ··· · 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 thereof. The composition of claim 2, wherein R ₂ is a base defined by the formula: The composition of claim 2, wherein the anti-cancer active is selected from the following and pharmaceutically acceptable salts thereof: the compound is (i) 1- (4-amino-2-oxo-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluoribibose, 4 · 4 4 · 4 4 4 4 4 44 219 (4) · 4 · 4 (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 ', 2'-difluoribose, and (iv) 1- (4-amino-5-methyl-2-oxo-) 1H-pyrimidin-1-yl) -2-deoxy-2 ', 2'-difluoribibose. The gemcitabine mixture of claim 2, the hydrochloride. in which it is anticancer in which formula I A composition according to claim 1 or 2 or a leukotriene antagonist (LTB4). 3 or 4 or 5 is imaginary (I) in which: X is selected from the file to which it belongs, 4 4 ·· · 4 · 4 · 4 · 220 (i) a five membered substituted or unsubstituted heterocyclic radical containing from 1 to 9 heteroatoms independently selected from the group consisting of sulfur, nitrogen and oxygen; or (ii) a fused bicyclic radical in which the carbocyclic group is fused to two adjacent carbon atoms of a five membered heterocyclic radical (i); Y x is a bond or a bivalent linking group containing 1 to 9 atoms; Y ₂ and Y ₃ are divalent linking groups independently selected from the group consisting of -CH ₂ -, -O-, and -S-; Z is an acidic group; R x is C 1 -C 10 alkyl, aryl, C ₃ -C 10 cycloalkyl, C ₂ -C 10 alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ -C ₂₀ aralkyl, C ₆ -C ₂₀ alkylaryl, C ₆ -C ₁₀ haloalkyl, C ₆ -C _{10 2} o aryloxy, or Οχ-Cxo alkoxy; R ₂ is hydrogen, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C ₁ -C 6 alkyl, C ₃ -C 8 cycloalkyl, an acid group, or - (CH ₂ ) x ₇ (acid group); R ₃ is hydrogen, halogen, C 1 -C ₁₀ alkyl, aryl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C ₁ -C 6 aryloxy, C ₃ -C 6 cycloalkyl; 221 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. The composition of claim 6, wherein X is a heterocyclic radical selected from the group consisting of substituents characterized by the following structural formulas: R10 R10 «· * * 10 10 4 4 · · · · · · · · · · · · · · · · · · · 9 · · 222 wherein R 10 is a radical selected from the group into which hydrogen or C 1 -C ₄ alkyl; and R 11 is a radical selected from the group consisting of hydrogen, halogen, C 1 -C ₁₀ alkyl, C 1 -C ₁₀ haloalkyl, alkoxy, aryl, or C ₆ -C ₂ aryloxy. include include C1-C10 223 8. The composition of claim 6, wherein R _lr R _2, R ₂ and R ₄ in formula (I) are selected from the following combinations of variables, denoted R01 R16 Combinatorial choice Choice choice choice code groups groups groups groups Variables R Ri r ₂ r ₃ r ₄ R01 Ri r ₂ r ₃ r ₄ R02 Ri r ₂ r ₃ pgi-r ₄ R03 Ri r ₂ PGI-R3 r ₄ R04 Ri r ₂ PGI-R3 PG1-R4 R05 Ri _PG1-R2 r ₃ R4 R06 Ri _PG1-R2 r ₃ pgi-r ₄ R07 Ri pgi-r ₂ PGI-R3 r ₄ R08 Ri pgi-r ₂ PGI-R3 pgi-r ₄ R09 PG1-Rx r ₂ r ₃ r ₄ R10 PG1-Oi r ₂ r ₃ pgi-r ₄ Rll PG1-Ri r ₂ PG1-R3 r ₄ R12 PG1-Ri r ₂ PGI-Rs pgi-r ₄ R13 PG1-Ri pgi-r ₂ r ₃ r ₄ R14 PG1-Ri PG1-R2 r ₃ pgi-r ₄ R15 PG1-Ri _PG1-R2 PG1-R3 r ₄ R16 PG1-Ri pgi-r ₂ PGI-Rs pgi-r ₄ the meanings of the general substituents Υχ, Y ₂ and Y 3 in formula (I) are selected from the variable combinations indicated in the following tables Y01 to Y27: 224 combination code of variable x \ γ // Yi group selection Y group selection ₂ Y group selection ₃ Y01 Yi Y ₂ Y3 Y02 Yi Y _{2 PG1-Y3} Y03 Yi Y ₂ PG2-Y ₃ Y04 Yi _PG1-Y2 Y ₃ Y05 Yl _PG2-Y2 Y ₃ Y06 Yi PGI-Y1 _PG1-Y3 Y07 Yi PGI-Y1 PG2-Y ₃ Y08 Yi _PG2-Y2 PGI-Y3 Y09 Yi _PG2-Y2 PG2-Y ₃ Y10 PG1-Yi Y ₂ Y ₃ Yll PG1-Yi Y _{2 PG1-Y3} Y12 PG1-Yi Y ₂ PG2-Y ₃ Y13 PG1-Yi PGI-Y1 Y ₃ Y14 PG1-Yi PGI-Y1 _PG1-Y3 Y15 PG1-Y1 _PG1-Y2 PG2-Y ₃ Y16 PG1-Υχ _PG2-Y2 Y ₃ Y17 PG1-Yi _PG2-Y2 pgi-y ₃ Y18 PG1-Yi _PG2-Y2 PG2-Y3 Y19 PG2-Yx Y ₂ Y ₃ Y20 PG2-Y1 Y _{2 PG1-Y3} Y21 PG2-Yx Y ₂ PG2-Y ₃ Y22 PG2-Y1 PGI-Y1 Y ₃ Y23 PG2-Yx PGI-Y1 _PG1-Y3 Y24 PG2-Y1 PGI-Y1 PG2-Y3 Y25 PG2-Y1 _PG2-Y2 Y ₃ Y26 PG2-Yx _PG2-Y2 PG1-Y3 Y27 PG2-Y1 PG2-Y _W. »* 9 The variables of groups X and Z and n in formula I are selected from the combinations shown in the following table, designated XZnO1 to XZn24: 225 Combination Code 'XZn Selecting the “X Selecting the “Z Dialing an integer "n XZnOl X OF n XZnO2 X OF PG1-n XZn 03 ' X OF 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 XZnlO X PG1-Z PG2-n XZnll X PG2-Z PG2-n XZnl2 X PG3-Z PG2-n XZnl3 PG1-X OF n XZnl4 PG1-X OF PG1-n XZnl5 PG1-X OF PG2-n ΧΖηΙβ PG1-X PG1-Z n XZnl7 PG1-X PG2-Z n XZnl8 PG1-X PG3-Z n XZnl9 PG2-X PG1-Z PG1-n XZn20 PG2-X PG2-Z PG1-n XZn21 PG2-X PG3-Z PG1-n XZn22 PG2-X PG1-Z PG2-n XZn23 PG2-X PG2-Z PG2-n Zn24 PG2-X PG3-Z PG2-n 9 9 ·· 99 • 9 9 9 9 9 9 * • * 9 9 • 9 9 9 9 9 9 · 226 The composition according to claim 11 of the leukotriene BA antagonist of formula II: 6, wherein which substance is characterized by (II) wherein; X ₂ is a heterocyclic radical selected from the following substituents: from file, to 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, fluorine, chlorine, 9 999 9, 9 9 9 9 9 9 · « • 9 9 9 9 9 9 9 99 9 9 9 9 9 9 9 9 9 9 9 9 99 999 227 -CF ₃ or tert-butyl. Z ₂ is carboxyl, tetrazolyl, N-sulfonamidyl; or a salt, solvate or prodrug thereof. The composition of claim 9, wherein the leukotriene antagonist compound is of the following set: is a substance selected from / = N OH COOH m ^H , NN OH COOH • 4 4 • 4,444 • 4 4 4 • 4 4 4 44 4 # 44> 1 43 4 «• 4 4 4 4 4 4 4 4 4 4 4 4 44 4444 228 COOH 9 9 9 9 9 9 9 99 99 ·· • 9 9 9 98 99 • 9 · ·