MXPA97002731A - Benzopiran and benzo compounds fused, compositions that contain them and use of mis - Google Patents

Abstract

This invention relates to novel benzopyrans and other B4 (LBT4) leukotriene antagonists fused to benzo, to pharmaceutically acceptable salts of such compounds, to pharmaceutical compositions containing such compounds, and to the process for using such compounds as LTB4 antagonists. The compounds and pharmaceutically acceptable salts of this invention inhibit the action of LTB4 and therefore are useful in the treatment of LTB4-induced diseases such as inflammatory disorders including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis, and other disorders of skin such as eczema, erythema, purito, and acne, blow and other forms of perfusion damage, graft rejection, autoimmune diseases, asthma and other states where neutrophilic infiltration occurs accentuates

Description

COMPOUNDS PE, BENZQPIRñNQ AND BENZQ FUSED. CCflPQSITIONS THAT CONTAIN THEM AND USE THEMSELVES.

BACKGROUND OF THE INVENTION The invention relates to novel benzopi and other antagonists of the leucotrope fused to benzo, to the fataceutically acceptable salts of compounds, to the acceptable pharmaceutical compositions of such compounds, to pharmaceutical compositions containing such compounds, and by proceeding to use such compounds as antagonists of 1. IU. The compounds of this invention inhibit the action of kidney and sorbitol both useful in the treatment of liver disease induced by LGB as well as inflammatory disorders including arthritis reuriiAtoi.de, osteoarthritis, inflammatory bowel disease, psoriasis and other skin disorders, co or eczema, eri -orna, puri + oy acne, blow and other forms of reperfusion injury, graft rejection, diseases ,) aut omrnunes, asthma and other states where the infiltration neut ro r 1 ca accuse occurs. The antikoni of IU leuco + pena were reviewed in the Publication c European Patent 276 Üb4 and in the 292 977 that refer to di phenterists, benzophenones and other compounds that > !, contain phenyl groups, and derivatives of 7- (3-al cox i -4-alkanoi 1 -phen <x i)? ICOXL benzopyran, respectively.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to new benzopyrans and other leukotrope antagonist compounds r? JJ_v (LTB ^) fused with henzo, of the formula D and pharmaceutically acceptable salts of the number wherein 1 is 0, CH ^, S, NH or N (Cj-Cto) alk; R3 is hydrogen or hydroxy; fla e 13 R * is hydrogen or hydroxy, - Rs is selected from the group consisting of - (CH52) r, CHX, * X ::, -? :: > , - (CHs n * 0 and -CHÍOHJX "where n is 0, 1, 2, or 3;: ítt: > X" is hydrogen, (Ci-C6) alkyl or optionally substituted phenyl; wherein the substituted phenyl is optionally substituted by one or two substituents independently selected from the group consisting of fluorine, chlorine, (CLC ^) alkyl, (Ca.-C6) alkoxy, (Oa.- f? C_ p €? rfluoroalkyl, (C -C_v) perfluoroalkoxy, (Cx-C *,) alkylthio, (Ca.-C &) alkylsphlyl, phenyl Isui phynyl, (Ca .-- C <!,) alkylsulfonyl and phenylsul fonyl; Xaa is hydrogen, (C -C?) Alkyl, (C3-Ca) cycloalkyl or one of the following rings optionally subsumed: ip femlo, thienyl, pipdyl, fuplo, naphthyl, quinolyl, isoquinol L, pipmidinyl or pyrazyl, wherein the optionally substituted rings are optionally substituted by one or two substituents independently selected from the group consisting of fluorine, chlorine, (C -CA) alkyl, (C ~ CA) alkoxy, (C-C_perfluoroalkyl) , (d.-C ".) perfluoroalkoxy, (C? -Cto) alkyl, (Cx-C 's,) alkylsulfi or lo, femlsul fmilo, (C-C) alkylsulfonyl, phenylsulfonyl and phenyl optionally and replaced; Wherein the optionally substituted phenyl is optionally substituted by one or two sutures independently selected from the group consisting of fluorine, chlorine, (Cx-C < s) alkyl, (C3.-C?) Alkoxy, (C_. -C_ ".) Perfluoroalkyl, (C -C_v) 2E perfluoroalkoxy, (C -C_.) Alkylthio, (C -C 's) alcylsulphyl, phenylsulphim, (C -CA) alkylsulfonyl and ferul sulfonyl; R * and R "7 are each independently hydrogen or (CX-C_ alkyl or R * and R? Are bonded together with the carbon atom to which they are attached and form a (C4-C,) cycloalkyl; selected from the group consisting of tetrazolyl, carboxy, cis or trans - (SHa) m-CX3 = CXa-COaH, - (CH2) mCX3X * Xs, -CO-NG'-G *, and an optionally substituted five- or six-membered aromatic ring having one or two heteroatoms from the group consisting of 0, CJ and N; where rn is 0.1, or 2; Y is 0, CHa, S, NH or N (C -Cto) alkyl; Xa- and 2 are each independently hydrogen or (Ci- C?) Alkyl; Xa and X * are each independently hydrogen or (CX-CA) to uyl or Ka and X * are joined together with the carbon atom to which they are attached and form a (Ca-C7) cycloalkyl; Xs is hydroxy, carboxy, tetrazolyl or -C0-NG3G *; X * is carboxy, tetrazolyl, CH20H or -C0-NGaG *; G3-, Ga, G3, G, Gs and G * are each independently selected from the group consisting of hydrogen, (C-Cß) alkyl, (Cx-C ^) perfluoroalkyl, (Cx-Cß) alkylsulfite, femlsul phylo lo, (Cx-C ^) alkylsulfonyl, phenylsulfonyl, hydroxy, phenyl and phenyl substituted with (Q) a; where a is L or 2; 0'L for each case is independently selected from fluorine, chlorine, (CX-C?) Alkyl, (C? -C?) Alkoxy, (C? -C) perfluoroalkyl, (Ox-C_ perf1 uoralkoxy, (Cx-C) ^) alkyl or, (C? -C ") to quilsulf i or lo, femlsul fmi lo, (Cj.-C?) to J? ils? lfonilo and fenilsufoniio, the substituted five or six-membered aromatic ring is substituted by A substitute is selected from the group consisting of carboxy, tetrazolyl, -CO-N (H) (S02 ~ X7), -N (H) (SO ^ -X ""), -N (H) (CO-X7) and -N (H) (CO-OX ^) and by one or two substituents each independently selected from the group consisting of fluorine, chlorine, (Cx-C?) alkyl, (Cx-C?) alkoxy, (C3-) C.sub.J perluoroalkyl, (Ox-C, *) perfluoroalkoxy, (Cx-C6) alkylthio, (C? -Crt) alkylsul tinyl, fe ilsul fiml or, alkylsulfonyl and femylphonyl, where Y7 is hydrogen, -CH2F, - CHF2, -CFa, (Cx-C alkyl, C-, C) cycloalkyl or one of the following optionally substituted rings: femlo, thienyl, pi idyl, furiio, nafti or, quinolyl, isoquinol i lo, pyrimidmyl or pyrazimide; wherein the optionally substituted rings are optionally substituted with one or two subsfuents independently selected from the group consisting of fluorine, chlorine, (C? -Crt) alkyl, (C -..- CeS) alkoxy, (CX-C_J perfl uoralqui lo , C 1 -C.) Perfluoroalkoxy, (Ca-Cte) alkylthio, (Cx-C, *) alkylsulfyl, phenyl Isulfin, alkylsul fonyl, femlsul fonyl and optionally substi ted femlo; wherein the optionally substituted phenyl is optionally substituted by one or two substituents independently selected from the group consisting of fluorine, chlorine, (Cx-C ^) alkyl, (C -C?) alkoxy, (CX-C_ perfluoroalkyl, (Cx-C) «.) Perfluoroalkoxy, (Cj_- C-alkylthio, (Cx-C-alkylsulfin 1, phenylsulphine, (C? -C?) To the cellulose and amino acid, Ra is hydrogen, fluorine, chlorine, (C? -Ce) alkyl, (Cx-C ".) aleoxi, (0-C) perfl uoralkyl, (Ca.-C_J perfluoroalkoxy, (Cx-Ct) alkylthio, (Ca-C alkylsulfimyl, phenyl sulfimyl, (C -CA) alkylsulfonyl and femlsulfoni lo, with the proviso that: G3- and G21 are not both hydroxy at the same time, G3 and G * are not both hydroxy at the same time, G3 and G? they are not both hydroxy at the same time, and when R3 is hydroxy and R is hydrogen then R is - CH (OH) X't-a A preferred group of compounds are those compounds of the formula Pharmaceutically acceptable * ', of the same where R3 is hydro xi; R2 is fe5 H and R3-, Rs, R3-, R * and Ra are as defined above for formula 1. A more preferred group of compounds are that1. compounds of formula I or pharmaceutically acceptable salts thereof wherein R3 is hydroxy; fl3- is 0 or CH2; fl2 is and R3-, Ra, R and Rs are as previously defined for formul 1. A still more preferred group of compounds are those compounds of formula I or pharmaceutically acceptable salts thereof where Ra is hydroxy; R3- is O or CH. "; R2 and Rx is - (CHK or a five or six membered aromatic ring substituted by a substituent selected from the group consisting of carboxy, tatrazolyl, -CO-M (H) (Oa-X7), -N (H) (SO ^ -X7 !, -N (H) (CO-X7) and -N (H) (CO-OX "7) and by one or two f &substituents each independently selected from the group consisting of fluorine, chlorine, (C) ? -C6) alkyl, (Cx-C "_) alkoxy, (Cx-C-perfluoroalkyl, (C? -C_J perfluoroalkoxy, (Cx-C?) Alkylthio, (C? -C?) Alkylsul finyl, phenylsul finyl, ( Cx-CsJ alkylsulfonyl and phenylsulfonyl, and rn, X3, X *, Xs, Y, R2, R and L1iRs are as defined above for formula I. An even more preferred group of compounds are those compounds of the formula I or pharmaceutically acceptable salts thereof where Ra is hydroxy, R3- is 0 or CH2; R2 is & H R3- is a phenyl substituted with a substituent selected from the group consisting of carboxy, ~ N (H) (02-X ^), -N (H) (CO-X7) and -N (H) (CO-OX7") and by one or two synthetics each independently selected from the group consisting of fluorine, chlorine, (C? -C, s,) alkyl, (Cx-C ^) ) alkoxy, (C? -C, perfluoroalkyl, (CX-C_J perfluoroalkoxy, (Cx-C *) alkylthio, (Cx-C "sJ alkylsulfinyl, femlsul fmilo, (C? -C_ &) 2'? alkylsulfonyl and phenyl sulphonyl; and X, R2, * and Rs are as previously defined for formula T.

A more preferred group of participants are those that are pharmacologically compatible with the cells where R3 is hydroxyl; R3- is 0 or CNs »; fl2 is R3- is a phenyl substituted with a substituent selected from the group consisting of carboxy, -N (H) (SO -..- X "7), -NIH) OOO-X" 7 ') l [j and -N ( H) (CO-OX7 ') and by one or two substituents each independently selected from the group consisting of fluorine, chlorine, (Cx-C?) Alkyl, (Cx-C ^) alkoxy, (C? -C_ perfluoroalkyl, (C -C, J per luoralkoxy, (C? -C, _J alkylthio, (C? -C, £,) aLskylsulfinyl, femlsulfinyl, (C? -C «J Alkylsulfomyl and phenylsulphonyl; R is hydroxy and the hydroxy R3 is either cis or trans with hydroxy *; and Y, R52 and Rs are co or defined above for the formula I. In the immediately preceding group of the most preferred compounds is a still more preferred group of compounds where the groups Hydroxy R3 and R "are cis to each other.A still more preferred group of compounds are those compounds of formula I or pharmaceutically acceptable salts thereof wherein R3 is hydroxy; R? Is hydroxy; R3- is 0 or CHa; fl2 is R3- is a fem substituted with a subst? uder selected from the group consisting of carboxy and -N (H) (Oy-X-7) and by one or two substituents each independently selected from the group consisting of fluorine , chloro, (C? -C < s) alkyl, (C ^ -C ^) alkoxy, (C? -CJ perfluoroalkyl, (CX-C_J per luocoalkoxy, (Cx? Cea) alkylthio, (Cx-C *) alkylsul finyl, femlsul fyl, (Cx-C, *,) alkylsulfomyl and fe ilsul fonyl, hydroxy R3 and hydroxy R are cis to each other, Rs is - (CH! ^) rnCHX, »X:, - 0 where X "is hydrogen and Xa-0 is one of the optionally substituted rings as defined above for formula T. A group of compounds within the immediately preceding group of compounds are those compounds where n is 1; and X or is F enyl substituted in position to the phenyl. And the next group of compounds are the most preferred group of compounds thereof where R3- is phenyl substituted with a substituent selected from the group consisting of fluorine, chlorine and (d.-C +? perfiuoralkyl.) The present invention also relates to pharmaceutical compositions for the treatment of LTIU-induced disease comprising an effective amount of a compound of the formula T or a pharmaceutically acceptable salt of the same as defined above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent The invention additionally relates a pharmaceutical composition for the treatment of eczema, erythema, spot, acne, bump, graft rejection, autoimmune diseases. unes, and asthma comprising an amount of a compound of the formula T as defined above or a pharmaceutically acceptable salt thereof which is sufficient for the treatment of such diseases, and a pharmaceutically acceptable carrier or diluent. The compound of formula I is a preferred compound This invention comprises additionally a method for the inhibition of binding to the receptor, inhibition of functional activity and live inhibition of the TB '. by administration to a subject in need of such inhibition, a compound of formula I as defined above or a pharmaceutically acceptable salt thereof. This invention includes a method for the treatment of inflammatory disorders, eczema, erythema, spot, acne, bump, graft rejection, autoimmune diseases, and asthma, by administration to a subject in need of such treatment, a compound of formula I it was defined above or a pharmaceutically acceptable salt thereof The preferred methods according to this invention are those wherein the compound of formula I is a preferred compound or a pharmaceutically acceptable salt thereof.

This invention is also directed to an intermediate compound of IR formula (lfl) where fl3- is 0, CH2, S, NH or N (C? ~ C, s) alkyl; fl2 is R * is hydrogen or hydroxy; Rs is selected from the group consisting of - (CH_>)? NCHX, * X3-s - (CH2) 2X3-D and -CHÍOHlX3-0; where n is 0, 1, 2, or 3; X "* is hydrogen, (C? -Cβ) alkyl or optionally substituted femlo, wherein the optionally substituted phenyl is optionally substituted by one or two substituents independently selected from the group consisting of fluorine, chlorine, (d-Cs) alkyl, (Ca.-C?) Alkoxy, (0? -25 CJ-perfluoroalkyl, (CX-C_J perfluoroalkoxy, (Cx-C?) Alkylthio, (C? -C?) Alkylsulfmyl, phenylsulphrone, (C? -C < s) alkylsulfomyl and phenylsul fonyl; X3-0 is hydrogen, (C? -C 's) alkyl, (C3-Ca) cycloalkyl or one of the following optionally substituted rings: phenyl, thienyl, pipodyl, fuplo, naphthyl , quinoxy, fc isoquinolyl, piprnidinyl or pyrazymyl, wherein the optionally substituted rings are optionally substituted by one or two substituents independently selected from the group consisting of fluorine, chlorine, (C? -C, alkyl, (C? -C?) alkoxy, (Cx-U C_J perfluoroalkyl, (CL-C4) perf1oralkoxy, (C? -C?) Alkylthio, (d-C) alkylsulphyl, phenyl-1-phynyl, (CX-CIS) alkylsulfonyl, phenylsul fonyl and optionally substituted phenyl; wherein the optionally substituted femyl is optionally substituted by one or two substituents independently selected from the group consisting of fluorine, chlorine, (C -CJ alkyl, (Cx-C alkoxy, (C? -C_J perfluoroalkyl, (CX- C_J perfluoroalkoxy, (C ~ CeJ alkylthio, (C-C) 0 alkylsulfinyl, phenylsulphyl, (C -C "J alkylsulfonyl and phenylenesulfonyl; R * and R? Are each independently hydrogen or (CX-C_J alkyl or R * and R "7 are joined together with the carbon atom to which they are attached and form an I C + -C-7) cycloalkyl; R3- is selected from the group consisting of tetrazolyl, carboxy, cis or trans - (CHs,) m ~ CX3 - =: CX2-CO: 2H, - (CH3.) mCX3X * X "\ -C0-NG G2, and an optionally substituted five- or six-membered aromatic ring having one or two heteroatoms from the group consisting of 0, and N; where m is 0, 1, or 2; Y is 0, CH: 2, S, NH or CX-C ^) alkyl; X3- and X2 are each independently hydrogen or (d-C) to uyl; X3 and X * are each independently hydrogen or (C? -C?) Alkyl or X3 and X are joined together with the carbon atom to which they are attached and form a (Ca-C?) Cycloalkyl; Xs is hydroxy, carboxy, tetrazolyl or -C0-NG3G *; X * is carboxy, tetrazolyl, CH20H or -C0-NGsG < s; G3-, G2 G3, G *, 6S and 6 * are each independently selected from the group consisting of hydrogen, (C-C 'sJ alkyl, (C? -C_J perfluoroalkyl, (C? -C < s,) alkylsulfinyl , phenylsulfimyl, (C? -C?) alkylsulfonyl, phenyl, fonyl, hydroxy, phenyl and phenyl substituted by (Q3 -) », where a is 1 or 2; 0 for each case is independently selected from fluorine, chlorine, (Ca.-C6) alkyl, (Cx-C?) Alkoxy, (CX-C) perfluoroalkyl, (C ..-C-4) perfluoroalkoxy, (C? -Cto) alkylthio, (Cj.-C6) alkylsulfinyl, femlsulfinyl, (d.-C6) alkylsul fonyl and femlsul foni lo; the substituted five- or six-membered aromatic ring is substituted by a substituent selected from the group consisting of carboxy, tetrazolyl, -CO-N (H) (Oa- X7 ), -N (Hi (SO-X?), -N (H) (CO-X7) and -N (H) (CO-OX7) and by l? One or two substituents each independently selected from the group consisting of fluorine, chlorine, (Cx-CeJ aLalyl, (C? -C6) alkoxy, (C ^ -C-perfluoroalkyl, (C? ~ C_J perfluoralc oxy, (Cx-C < £,) alkylthio, (CX-CA) alkylsulfonyl, phenylsulfimyl, (Cx-C "&) alkylsulfonyl, and femlsulfonyl; where) C is hydrogen, -CH2F, -CHFa, ~ CF3, (C -C, _J alkyl, (Ca-C?) cycloalkyl or one of the following optionally substituted rings: phenyl, time, pyridi or, fuplo, naphthyl , qumolyl, isoquinol lyo, 20 pin idinyl or pyrazyl, where the optionally substituted rings are optionally substituted with one or two substituents independently selected from the group consisting of fluorine, chlorine, (Cx-C?) alkyl, (C_L-C_J alkoxy) , (C-perfluoroalkyl C, (Cx-a_J perfluoroalkoxy, (C -C <; s) alkylthio, (C -C < s.) to the quilsulfinyl, phenylsulfinyl, (Cx-C *) to the alkylsulfonyl, phenylsul fonyl and optionally substituted ferule; wherein the optionally substituted phenyl is optionally substituted by one or two substituents independently selected from the group consisting of fluorine, chlorine, (C? -C < -J alkyl, (C? -C?) alkoxy, (C? -C < J perfluoroalkyl, (Cx-C_v) perfluoroalkoxy, (Cx-C?) alkylthio (Ci-C, *) alkylsulfinyl, phenylsulfimyl, (C -C (5) alkylsulfonyl and phenyl-hydroxyl; R 2 is hydrogen, fluorine, chlorine, (C -Ce,) alkyl, (Ci-Ce.) Alkoxy, (CX-C_J perfluoroalkyl, (CX-C_J perfluoroalkoxy, (Cx-C ^) alkylthio, (Cx-Cs.) Alkylsulfinyl, phenylsulfinyl, (Cx-C «s ,) alkylsulfonyl and phenylsulfonyl, with the proviso that: G3- and G2 are not both hydroxy at the same time, G3 and G * are not both hydroxy at the same time, Gs and G * are not both hydroxy at the same time; BESCRIBE PETRLLñDfi PE Lfl INVENTION The term "Cx-C" alkyl "when used in the description herein means straight or branched monovalent aliphatic hydrocarbon radicals having from one to six carbon atoms, such as methyl, ethyl, propyl, t-butyl, Hexyl, etc. Similarly, the terms C3-Ct cycloalkyl and C3-C-, meaning cycloalkyl groups having from three to seven or eight carbon atoms, respectively, such as cyclopropyl, cyclohexyl, cyclooctyl, etc. When fl3- is oxygen and a2 is in a compound of formula I, the compound can be described as a 3, 4-d? h? drobenzop? rano or a cro anus. The compounds of the invention when R3 is OH have two asymmetric carbon atoms indicated by asterisks in the following formula The steroids can be designated with reference to the rotation of R and S according to the normal nomenclature.

When reference is made to, R or R, S means a simple pure antimer, considering that S ~, R * means a racenic mixture. The invention includes racemic mixtures and optical isomers of formula 1.

According to a specific process of the invention, compounds of the above formula II, which are intermediate compounds of formula I, wherein R3- is - (CHs) ", X3X4Xa, where rn is 0 and Xs is carboxy or the esters of the they were prepared by reacting compounds of the above formulas III and IV to form a compound of the formula V (not shown) followed by reduction to form the compound of the formula I. The reaction of compounds II and IV was generally carried out in a suitable solvent. Suitable solvents are ether solvents such as tetrahydrofuran, diethyl ether, ethylene glycol, dimethyl ether and 1,4-dioxane, aprotic dipolar solvents such as dimethylformamide, N, N-dirnethylacetamide, acetonitrile, dirnethylsulxide, hexarnet 1 phosphoramide, N, N, -dirnetylpropylene urea, non-polar aromatic solvents such as xylene, benzene, chlorobenzene and toluene, and halogenated solvents such as rnetienene chloride, chloroform and dichloroethane. Suitable specific solvents are xylene, or a mixture of equal volumes of ethylene glycol di ethyl ether and dimethyl amide. The reaction temperature ranges from -78 ° 0 to 200 ° C depending on the boiling point of the solvent used and the normal ranges of around 80 ° C to around 150 ° C. The reaction can be carried out in the presence of a Lewis acid such as zinc chloride, aluminum chloride, magnesium bromide, tin chloride and titanium chloride. When present, the amount of the Lewis acid range of about 0.05 to about 2 equivalents per mole of compound III. The reaction was generally carried out with palladium catalyst. Suitable palladium catalysts are palladium tetrakisphenyl phosphide, bis-benzonityl palladium chloride, allyl palladium chloride dimer, palladium chloride, palladium acetate, palladium on carbon, and palladium bisacetomtrilium chloride. A specific catalyst comprises 5% by weight of allyl palladium chloride dimer or 5% by weight of bisbenzonityl rile palladium chloride. Generally, about 0.001 equivalents to 1 equivalent of catalyst per mole of substrate is used. The reaction was generally carried out in the presence of a phosphine ligand such as tri-fem-phosphine, tp-o-tolylphosphine or tr? -2-fur? Lphosphine in an amount of from about 0.1 to about 5, preferably 1 or 2 molar equivalents of substrate used.

The reduction of the compound of formula V was carried out in a conventional manner with sodium borohydride in an alcoholic solvent at room temperature to form the compound of formula T after saponification. The compounds of the formula III, wherein Rs is - (CH ») r? CHX'3, X3-0 or (CHainX3-0 can be prepared as follows below.) The compound of formula VI sulfuric anhydride is reacted with trifluoromethane (also called triflic anhydride) in a suitable solvent such as rnetylene chloride in the presence of triethylamine to form the corresponding tri-lato analogue. The group Rs when it was defined as - (CHss) nCHX ^ X3-0 or - (CH2) or X3-0, where n, "* and X3-0 are as defined above for formula I, they can be introduced into the analogue t ri lato by a two step process comprising reaction with an aldehyde of formula X9X3- CH (CH) 2) «, _ xCH0 or X3-o (CH: 2) ca-CH0 to form the corresponding alkene analogue where R3 is -xX3-0, where q is 1, 2, 3 or 4, respectively, and subsequent hydrogenation.

The reaction with the aldehyde was carried out in the presence of a pyrrolidine catalyst or with a hydrochloric acid catalyst in acetic acid. The hydrogenation was carried out with hydrogen and palladium catalyst in a conventional manner. The compounds of formula VI are generally available commercially, if not, they can be obtained by methods well known to those skilled in the art. For example, the compounds of formula VI, where flx is oxygen and is li 2 ', 4' -dih? droxi-3-15 chloropropiophenone (hereinafter compound 1) can be obtained from R2 substituted by cyclization with sodium hydroxide. Compound 1 can be prepared from R2-substituted substituent resorcionol and 3-chloroproponic acid in the presence of an acid, preferably trifluoric acid ethane sulphonic acid. The compounds of formula VI where fl is sulfur and fl2 is In a very similar manner, R2 is substituted by 4'- or 5'-25-hydroxy-2'-sulphon-3-chloro-β-piopiophenone, which, however, can be obtained from substituted R-3-hydroxythiophenol. 00 The compounds of formula VI where fl2 is and flx is 0 or 5 can similarly be obtained by reaction of substituted R 2 resorcinol or 3-hydroxethenol, respectively; and 4-chlorobutyl acid (and its derivatives), and cyclization with sodium hydroxide. Compounds of formula I where Rx is (CH52) rnCXx = CX2-C02H can be synthesized by the reaction of the compound of formula Til (CH3) aSn n (CH3) a and a palladium catalyst such as tetrakisphenylphosphma palladium (Pd (PPh3), J in the presence of foefin ligand, as described above for compounds of formulas II and IV to give the tpmethyl-tin analog The tpmethyl tin analog is converted to a protected ester compound of the formula Z 02CX 2C = CXx- (CH2) mZ2 where Z is alkyl or cycloalkyl and z2 is iodine, bromine or CF3SOa The process of the coupling reaction in the presence of palladium catalyst, such as bistriphenyl phosphide palladium chloride, is described above. corresponding hydroxyl compounds and then hydrolyzed to the corresponding acid of formula I. The reaction was carried out with sodium borohydride, generally, the reduction is carried out in a solvent. s are lower alcohols having from one to six carbon atoms, mixtures of lower alcohols with organic solvents such as rahydrofuran or dioxane, and mixtures of alcohols detectable with water or with organic solvents miscible with water. The solvent is preferably a lower alcohol such as methanol or ethanol. The reaction temperature is generally in the range of about -78 ° C to about 100 ° C, and usually around 0 ° C to about ± 5 ° C. The reduction step gives a stereoisomeric mixture of ester compounds of formula I having the following structures: trans C 1 S These cis and trans isomers can be separated * by conventional column chromatography. The resolution of the conventional enantiomeric mixture after separation of the cis and trans isomers can be achieved by methods known in the art. In a process, a compound of the formula I wherein R contains a carboxyl group (COOH) reacts with a chiral base co or d-efidrin in a polar solvent such as ether to give diastereoisomer salts that were separated and then converted to an acidic purely by treatment with an acid such as aqueous hydrogen chloride or ethanol. In another process a compound of the formula I wherein R contains an ester group of a carboxylic acid reacts with an optically active acid such as R-mandelic acid or Nt-bu + oxycarbonyl-D-tryptophan to form diasteroiso esters with the hydroxyl group which after separation are converted to optically pure acids by treatment with a base such as sodium hydroxide in methanol or ethanol. The removal of the resolving ester groups and the hydrolysis of the carboxylic acid ester group in R was conveniently carried out with aqueous base as alkali metal hydroxide, for example, sodium hydroxide at temperatures in the range of about the ambient temperature to the reflux or boiling temperature of the solvent or mixture of solvents used. The reaction can be carried out in the presence of a solvent such as methanol, ethanol or tetrahydrofuran. The compound of the formula I wherein R is carboxy and R 2 is hydrogen can be prepared from the intermediate compound of the formula III by a first substitution of the group CFaS0 with rnetoxycarbonyl, and then hydrolyzing. The procedure of the substitution reaction with carbon monoxide in the presence of palladium acetate, 1, 1 '-b? S (diffemlfosphine) ferrocene (DPPF), methanol or tri-ethylamino.

The hydrolysis is as previously described. The compounds of the formula I wherein Rx is (CH2) mCX3X * X =, where, X3, X * and Xs are as defined above for the formula I, will be referred to hereinafter as compounds of the formula XXI (not shown ). Although the following chemistry describes the preparation of compounds of formula XVI, where R is - (CH2) mCX XAC02C2Ha it is understood that the same chemistry is applied to compounds of formula XVI which have a different R, co or defined with reference to formula 1, which is inert under the reaction conditions specified below. The compounds of the formula XXI wherein X 3 is tetrazolyl can be prepared from compounds of the formula XVI According to this procedure, a compound XVI reacts first with t-but? Id? Rnet? L-s? 1 1 chloride in the presence of irnidazole and dimethyl forrnarnide to protect the hydroxyl group as is known in the art. The protected group reacted with ammonia and maximal rimet in xylene to replace the group COaCsíHs by cyano. The cyano group was replaced by tyrrene Lestanml-tetrazol lyo by reaction with tnrnenylstanrylazide in toluene. The conversion to tetrazolyl and removal of the silyl protecting group was achieved by reaction with tetrabutylammonium fluoride in tetrahydrofuran. The starting material of formula XVI is identical to the above compound of formula II where R is - (CH: a) mCX3X ', - Xs where X = is an ethyl carboxy ester, and rn is 0. t repair of this starting material described above. 2 ? ESQUE? R I (1) (2) < 3 > XV I I I XIX The compound of formula XVII was converted by subsequent reactions with (1) acrylonitrile, (2) hydrolysis with concentrated hydrochloric acid, and (3) cyclization with polyfoephoric acid to form the compound of formula XVIII. The introduction of the group Ra to form the compound of formula XIX is as described for the compounds of formula VI. The hydrogenation and hydrolysis of the compound of formula XIX is as described hereinabove. The compound of formula XVII can be prepared from 3-hydroxyphenyl acetic acid by introduction of groups X3 and X by known methods. The starting material XVI when m is 0, 1 or 2, R2 is and flx is O, S. NH, or NICx-Ca alkyl can be prepared by reaction of the compound of formula XVII with BrCH-zCH or BrCHa.CH2CN in step (1) of scheme I and additional conversion as described with reference to Scheme I. The starting material XVI when flx is CHZ, rn is 0, 1, or 2 and R2 is where R *, Rs, R * and R are as defined above for the formula I ss can be prepared as described below. A substituted benzene reacted with mono-hydrochloric acid of the rhenal, succinic or gluthac acid ester mono in the presence of a Friedel Cr fts co-catalyst or aluminum chloride. The resulting ketone was converted to the corresponding propylene dithiol with propylene diethyl L and p-fluorine boron catalyst. The formed compound was redissolved with Raney Nickel, and then saponified. The ring was formed with pol i phospho pol acid to produce the bicyclic compound XIX. The introduction of the group Ra is as described in this document above. The compounds of the formula XXI wherein Xa is CO ^ H can be prepared by saponification of a compound of the formula I wherein R is - (CH2) mCX3X * C0OCH-? the preparation of which was described above. The compounds of formula XXI wherein Xs is OH, rn is 0, 1, or 2 and Xa and X * are each hydrogen can be prepared by conventional hydrogenation with lithium aluminum hydride of a compound of formula T where R is - ( CH2) (nC02CH3, where rn is 0, 1 or 2. The compounds of formula XXI where Xa is OH, n, is 1 or 2, and X3 and < are each alkyl can be prepared by reaction of the corresponding compounds where Xa and X "* are hydrogen with one equivalent of Grignard reagent containing the group X3, for example X3f1gCl, followed by one equivalent of Gpngnard reagent containing the group X *, for example, X ^ MgCl. formula XXI where Xa is OH,, is 0, 1, or 2 and X: i and XA are joined to form a C3-C-7 cycloaluyl are prepared similarly by reaction of the corresponding compound where X3 and X * are hydrogen with Grignard reagent derivative of a C- C7 dihalo alkane, for example, ClMgíCa-C ^, (a..can? L) MgCl. The compounds of formula I where R is where X * is carboxy, tetrazolyl, -C0NGaG < s or CH2OH; Y is 0,, NH or NH (C? -C6 alkyl); and m is 0, 1, or 2, can be prepared by reaction of a compound of the formula with a tri-fluoro compound of the formula I wherein Rx is CF3 03CHsi (CH2) ", - in the presence of a base such as priethiamine or sodium hydride in an inert solvent. The tp flatos can be prepared by reaction of triflic anhydride with the compound of formula XXI where rn, is 0, 1 or 2, X3 and X * are hydrogen, and Xa is hydroxyl, the synthesis of which is described above. The compounds of the formula I wherein R is -C0NG G2 can be prepared from the corresponding compound wherein R is carboxy by reaction with an amine of the formula NH6 G2. According to a specific method of the invention, the intermediates of the above formula II wherein R is CF3-S02-0-, were prepared by reacting a compound of the formula III as defined above with a compound of the formula (IB) where R2 is as defined for formula I. This reaction is generally carried out in a solvent as solvent Lu ether, for example, tetrahydrofuran, diethyl ether, ethyl LCO! dirnetii ether,., 4-d? oxane, and preferably, tetrahydrofuran. The reaction is in the presence of a catalytic amount of a catalyst, in particular a palladium catalyst (Pd °) under reaction reactions, for example tetrakisphenyl phosphide palladium. The reaction is generally carried out at a temperature around the reflux temperature of the solvent used, preferably at about 78 ° C. The reaction time is generally around 1 to 24 hours, for example about 3 hours. The compounds of formula 1 E were prepared in situ from a compound of formula (1C) 1: - > where R2 is as defined above for formula I, by reaction of the ism with n-butyl-lith or sec-butyl-lithium in hexanes at a low temperature of about -78 ° C, and then with Z Cla or ZnBra, generally at a temperature of about 0 ° C to about 70 ° C for about one to two hours. The ketones of formula II where flx, R2, R and R2 are as defined above with reference to formula I can be reduced to the corresponding hydroxyl compounds of formula I by reaction with sodium borohydride. Generally, the reduction is carried out in a solvent. Suitable solvents are lower alcohols having from one to six carbon atoms, mixtures of lower alcohols with organic solvents such as tetrahydrofuran or dioxane, and mixtures of lower alcohols which can be diluted in water or other organic solvents which are soluble in water with water. The solvent is preferably a lower alcohol such as methanol or ethanol. The reaction temperature is in the range of about -78 ° C to about 100 ° C, and usually from 0 ° C to about 25 ° C.

ESQUE? R II The compound of the formula XVT is formed by reaction of the compound of the formula III with (CHa) 3SnSn (CH3) to V a palladium catalyst such as tetrakisphenyl phosphide to palio (Pd (PPh3) _, or bis-benzonityl palladium chloride, in the presence of a phosphine ligand, such as triphenyl phosphine, in an amount of from about 0.1 to about 5 nore equivalents per mole of substrate used The compound of formula XIV was converted to a compound of formula XV by reaction with a protected ester compound of the formula where X is C, Ch, N, or S; K is carboxy protected co or ester, tetrazolyl, - CO-N (H) (O ^ X7), -N (H) (SO ^ -X ^), -N (H) (CO ~ X ^) or -N (H) (CO-OX *) (this group was prepared as the acid before being converted to the ester), K2 is independently F, Cl, (C ^ -C ^) alkyl, (C? -C'to) alkoxy, (C ^ -C ^.) Perf 1 -oralkyl, (Ca.-C ^) perfluoroalkoxy, (Cx) -C ^) alkylthio, (Cx-O, *) alkylsul phynyl, phenyl sulfimlOj (C -CA) alkylsulphyl or fem 1 sul fom 1 o, T is 2 and Z is iodine, bromine or CFa O :, . The coupling reaction is carried out in the presence of a palladium catalyst such as tet rachistemlfosphine palladium or bis-phenylazine phosphine chloride. The ketone esters of formula XV were first reduced to the corresponding hydroxyl and then hydrolyzed <The corresponding acid of the formula T. The reduction was carried out with sodium borshydride, as described above with reference to the reduction of the ketones of formula II. The hydrolysis of the acid can be carried out with aqueous base (or alkali metal hydroxide, for example, sodium hydroxide, in the optional presence of a cosolvent such as methanol or ethanol at temperatures in the range of about room temperature to room temperature. reflux or boiling of the solvent used Compounds of formula I wherein R3 and R * are hydroxy can be prepared from esters of formula 1 by elimination of the hydroxyl group to form an olefin.This is accomplished by well-known procedures in the technique by treatment with an acid such as hydrochloric, sulfuric or triflic or preferably toluene sulfonic acid in a solvent such as benzene, acetic acid, dioxane or preferably toluene at about 25 ° C under reflux for about 0.5 to 5 hours. The produced alkene can be hydroxylated using osmium tetraoxide catalyst and an oxidant such as morfolin-N-oxide or the like in a solvent as ether, THF, or preferably acetone mixed with water. The mixture was stirred at room temperature until all the starting material was consumed, which in any case takes from 1 to 5 hours?. This provides the cis-dihi droxi compounds exclusively. The trans-dihydroxy analogues can be prepared by prolonged oxidation, about 10 to 24 hours, under the same reaction conditions followed by reduction of the 3-h product. Jrox? - 4-keto with a hydride reducing agent such as LifllH or LiOBH preferably NaBH ^. in a solvent such as THF but preferably MeOH. The hydroxy esters were saponified using an alkali metal base with a co-solvent such as low boiling alcohols, preferably ethanol, to give the acidic products. The alkene can also be treated with a peroxyacid, preferably chloroperbenzoic acid in a solvent such as THF or, preferably, dichloroethane at about 0 ° C at room temperature, preferably at 0 ° C for 1 to 5 hours to give the epoxide. The epoxide was hydrolyzed with H3 and 10% Pd / C in an inert solvent or ethyl acetate to give the 3-hydroxy ester (R3 = H, R * = OH). The compounds of formula I where R is where Rxa is independently fluorine, chloro, (C? -Ct?) alkyl, (CX-C?) alkoxy, (CX-C_ perf.oralkyl, (Cj.-CA) perfluoroalkoxy, (Cx-C ^,) alkylthio, (C ? -C &) alkylsulfinyl, femlsulfinyl, (C -C?) Alkyl sufoni lo, or femlsul fomlo and r is 1 or 2, can be obtained by reaction of compounds of formula I where R is where R a and r are as defined above, with a sulfonamide of the formula X 02NH in the presence of a coupling agent such as 1,3-d? c-clohexylcarbodrinoid or 1-C3- (d? rnet lamino) prop? p-3-et? i carbodumide and in the presence of an organic base such as pin dina, dirnetiiarninopí pdi na, trieti lamí na, diisopropilamino od? azabic? cloC5.4.0] undec-7-ene. The reaction was carried out in a solvent such as tetrahydrofuran, diethyl ether, toluene, and chlorobenzene, at a temperature range from about room temperature to about the boiling point of the reaction solvent used. The compounds of formula I wherein Xβ or R or aromatic substitution is equal to NHCO-X7, NHSO-X7 or NHCO-OX7 can be obtained by reaction of compounds of formula I wherein Xa or X * 5 on R is carboxy or substituted acid aromatic or heteroaromatic with diphenylphosphonyl azide in the presence of benzyl alcohol and an amine base such as pi idine, dneopropylether, pyrrolidine or, preferably, tpetii amide at the boiling point of the solvent used for a time of 5-4T hours , preferably, 16 hours. The product of this reaction was hydrogenated in a lower alcohol solvent in the presence of a palladium catalyst, preferably Pd (OH) a / C, followed by acylification with the appropriate carbamoyl chloride acid chloride or sulfoyl chloride. The synthetic procedures explained above together with the following examples describe procedures that were or may be employed to prepare the compounds of this invention. If possible, as can be determined by one skilled in the art capable by this disclosure, it includes pharmaceutically acceptable Leas cation salts of certain compounds of this invention, but not limited to those of sodium, potassium, calcium, magnesium, ammonium, N, N'-dibencilethiiendi amine, N-methygiucarnine, ethanolamine and diethanolamine. The pharmaceutically acceptable cationic salts of the compounds of formula I can be prepared by mixing a compound of formula T with an equivalent of an amine base or alkali metal base. The compounds of the invention can be administered to mammals, including humans, for the treatment of LTB * induced disease. by vains including oral, parenteral and topical, including the use of suppositories and enemas. In oral administration, dosage levels of about 0.5 to 1000 g per day, more preferably around 5 to 500 rng per day can be given in a single dose or even divided into three doses. For intravenous administration, the dosage levels are about 0.1 haeta 500 mg per day, more preferably about 1 from 1.0 to 100 mg per day. Intravenous administration may include a continuous drip. Variations will necessarily occur dep € > No matter the age, weight and condition of the subject to be treated and the particular route of administration chosen as it will be well known to those experienced in the field trained by this disclosure. The compounds of the invention can be administered alone, but will generally be administered together with a selected pharmaceutical excipient or diluent with a view to the desired route of administration and the normal pharmaceutical pnactics well known to those experienced in the art. matter. For example, they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or alone or mixed with excipients, or in the form of elixirs or suspensions containing sabotagers and dyes. They can be injected parenterally, for example, int amuscularly, intravenously or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain solutes, for example, salt or glucose.

Enough to make the isotonic solution. The LTB * activity of the compounds of the invention can be determined by comparing the ability of the compounds of the? Nv? Non to complete with radiolabelled LTBA for sites of the LTB-specific receptor. Baboon membranes of guinea pigs. The membranes of the guinea pig spleen were prepared as described by Cheng et al. (3, Phar acology and Experimental Therapeutics 232: 80. 1985). Fl binding assay 3H-L T? was performed in 150 ul containing Tris 50 inri pH 7.3, MgCla 10 Mrn, 9% inetanol, 0.7 nfl H-LTB.v (NEN, approximately 200 Ci / nmnol) and 0.33 ng / ml of guinea pig spleen membranes. Unlabeled LTB. * Was added at a concentration of 5 μM to determine non-specific binding. The compounds were added at various concentrations to evaluate their effects on the binding 3H-25 I TB ?. The reactions were incubated at 4 ° C for 30 minutes. The bound aH-LTB * membranes were collected by filtration through crystal filters and the bound amount was determined by scintillation. The ICsa value for a compound is the concentration i which 50% of the bound 3H-LTB «. specific is inhibited. The functional activity of the compounds of the invention can be determined in several ways using biological assays. Either high and low affinity forms of the T receptors have been described as differentially coupling chetotaxis leukocytes and regulatory molecule adhesion respectively (Sternan, 3. W., Groetzl, E. 3. et al., 3 Im a., 1988, 140, 3900-3904). Human neutrophilic chernotaxis was measured as described by Horvath, I .. et al., 3. Im unol. 1987, 139, 3055. Human neutrophil CDIIb regulation was measured as described by Marder, P. et al. Prostaglandins, Leu otriene Exxent, Fatty flcids, 191, 46, 265-278. In addition, compounds of formula I can be tested in vivo according to the procedure analogous to the procedure described by Pettipler, E. et al. Brit. 3. Pharrnacolog, 1993, 423-427, by injection of LTB into the dermis of guinea pigs and measuring the blocking of neutrophilic migration within the skin by oral dosing of compounds of formula T. The following examples illustrate the preparation of the compounds of the invention and do not attempt to limit the scope of the invention in any way.

L EXAMPLE 1 ñci o (5S *. &S *? 2- (6-benc? I-5,6-? Í?? < 3roxi-5.5.7.8- gt.ra i < lrQ- £. 2 - (4 - f 1 uo rf in 11) - 4.4 - dirnet 11 - 4.5 - di hi d ro-oxa or 1 R a stirred solution of 2-arn? Nomet ilpropanol (0.378 mol, 33.64 rng) in 300 ml of At about 0 ° C, a solution of 4-fl uorbenzoyl chloride (0.189 nol, 22.35 ml) in 100 ml of methylene chloride was added at about 0.degree. The mixture was warmed to room temperature and stirred for about 3 hours.The mixture was poured into water and the layers were separated.The organic phase was washed with two parts of 10% HC1, one part of sodium chloride solution. The solvent was removed in vacuo to give a colorless solid which was stirred while SOCla (0.567 mmol, 41 nmol) was added dropwise over about 30 minutes. of 0.5 hours, at whose end it was added diethyl ether while stirring the solution rapidly. During this procedure, a colorless precipitate was produced. The mixture was filtered and the solid was washed with three 250 ml portions of diotyl ether. The solid was then dissolved in 300 mL of 3N KOH and the resulting solution was extracted with ethyl acetate. The organic extracts were washed with saturated aqueous NaCl solution and dried over MgSQ. Removal of the solvent in vacuo gave 32 mg of the title compound of this Example IR: RhN H (250 riHz., CDC] 3) 6: 8.00-7.91 (m, 2H): 7.10-7.02 (m, 2H); 4.11 (s, 2H); 1.39 (s, 6H). B. 2- Benzyl 11 den -fi-rnetox i-3,4-dihydro-2H-na-talen-1 -ona fl ura stirred solution of 6-rnetox? -l-tetraiina (0, 227 mol, 40 g) and benzaldehyde (0.272 mol, 27.5 rnl) in 450 rnl of rnetanol was added pyrrolidine (0.272 mol, 23.6 i). The mixture was stirred at room temperature for about 4 days until it was seen by TLC that no starting tetralone remained. The mixture was concentrated in vacuo, then dissolved in ethyl acetate, washed with four parts of 10% HC1, two parts of saturated sodium bicarbonate solution and one part of saline. The solvent was removed in vacuo and the crude oil was triturated with diethyl ether to give 38 g of the title compound of this Example IB, mp. 100-102 ° C. Analysis calculated for C BHX (? 0a 264.1146. Found 264.1149. c.-Ben? L-6-me ^ Qx? -3.ld?? «3rQ-2H-naphthalene-l Se? Place a Parr (registered trade mark) hydrogenation bottle with cro enone (15 mg), ethyl acetate (150 nmol) and 1 g of 10% palladium on charcoal.The mixture is hydrogenated on a Parr shaker (registered trademark) during about 15 hours under hydrogen pressure of 1.4 tg / cm.sup.2 The resulting mixture was filtered through a plug of Celite (registered trademark) and concentrated in vacuo to give a red oil which was purified by flash chromatography ( 3: 1 hexane / diethyl ether) to give 14.1 rng of this Example 1C, mp 50-51 ° C. Analysis calculated for CaßHa.s0a: 266.302. Found: 266.308.

D. 2-Benz? LBh? Drox? -3.4-d? H? Dro-2 H -naphthalene-1 -one R a stirred solution of the compound of Example 1C (benzyl tetralone) (5 mg, 19 mmol) in methylene chloride (40 rnl) at the end of -78 ° C tri boron bromide (1.95 rnl, 21 mmol) was added. The cooling bath was removed and the reaction mixture was stirred overnight at room temperature, after which time an additional 1.5 nl of tp boron bromide was added. The stirring continued at room temperature for another 4 hours after which the mixture was poured into ice water and stirred for about 0.5 hour. The aqueous mixture was saturated with sodium chloride and extracted with portions of methylene chloride. The layers were separated and the organic phase was washed with water and dried over sodium sulfate. Filtration and removal of the solvent in vacuo gave a brown solid which was purified by flash chromatography (3: 2 hexane / ether) to give 3 mg of the compound of this Example ID, mp. 160-162 ° C. Analysis calculated for Cx-, HX? 0a: 252.1146. Econt. 252, 1144. E. Ester 6-benzl-5-oxo-R .6.7. B-tetrahydronaphthalen-2-yl < A fluorinated solution of the compound of Example ID (2.75 mg, 11 mmol), triethylamine (4.56 ml, 33 mmol) and DMAP (0.05 mg) in sodium chloride was added to the solution. Methylene (100 ml) at about -78 ° C was added tri-chloroethanolamine anhydride (2 ml, 12 mmol) The cooling bath was removed and the reaction mixture was warmed to room temperature and stirred overnight. The mixture was then poured into ice water and extracted with ethyl acetate.The resulting organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo. ? or h by flash column to give 3.9 g of the compound of this Example 1E, pf. 52-53.7 ° C. Analysis calculated for C? AH? -, 0.SFa: 384.0638. Econted 384.0602. F. 2-Benc? 1 -6-C2-. 4-d? Met? L--, 5-d? H? Dro-oxazol-2-yl) -5-fluorfen? Ll-. -d? h? dro-2H-naph talen-1-one Lü To a stirred solution of n-buty 1 -lithium (3, b mi of a 2.5 M solution in hexanes, 9 mmoles) in toluene (10 ml) ) at about -40 ° C was added a solution of aryloxazole ma (1.76 mg, 9 rimols) in toluene (5 rnl) dropwise via a cannula. The mixture was stirred at about -40 ° C during about 0 5 hours was then heated to about -25 ° C and stirred for about another hour. To this mixture was added zinc chloride (9 nl of a 1H solution in diethyl ter, 0.009 mole). The cooling bath was removed and the mixture was warmed to room temperature and stirred for about 1 hour. hours The resulting mixture was added via a cannula to a solution of tertiary tplfate (3.5 g, 9 rnmoles) and palladium tetra-phenyl-phenyl (0.5 mmoles, 0.63 ng) in tetrahydrofuran (15 ml). The reaction mixture was heated to reflux for about two hours, cooled to room temperature atmosphere and poured into saturated ammonium chloride solution. This aqueous mixture was extracted with three portions each of ethyl acetate. The organic phase was washed with three portions of 1N HC1, saturated aqueous sodium bicarbonate and saline. The organic phase was then dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The crude product was purified by flash chromatography (2: 1 diethyl ether / hexane) to give 2.07 mg of this IF compound, mp. 114-115 ° C. Analysis calculated for CaßHa-sNOaF: 427.19848. Found 427.1956. G- 2-Benzyl-6-C2- (4.4-d? Met? L-4,5-d.?h.?dro-oxazol-2-? L) -5-fluorfen? L-l .2.3. 4-tetrahydro-naphthalene-1-ol To a stirred solution of the compound of Example 1F (1.5 mg, 3.5 mmol) in methanol (35 ml) was added sodium borohydride (0.20 mg, 5.25 mmol). . The resulting brown mixture was stirred at room temperature for about 1 hour, then poured into saline and extracted with three portions of ethyl acetate. The organic phase was then dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give 1, 20 mg of a 1: 1 mixture of the cis and trans alcohols, mp-88-89. Analysis calculated for CaaHaßNOaF: 429.2087. Found 429.2067. H. R ??JQ 2- (6-benzyl-5-hydroxy-5,6,7,8-tet rahydro-naphthalen-2-yl) -4-fluorobenzene The compound of Example 1G (1.0 ng, 2.34 mmol) was dissolved in 5 ml of methyl iodide and stirred at room temperature for about 2 days, at which time the methyl iodide was removed in vacuo. The residue was taken up in sodium chloride and concentrated to remove traces of residual ruthenium iodide. The dark red residue was dissolved in ethanol (5 mL) and 2N NaOH (5 mL) was added. The resulting mixture was heated to reflux with stirring for about 5 hours. The mixture was then cooled to room temperature and acidified with 3N HC1. The resulting mixture was extracted with three portions of ethyl acetate and the combined organic phase was washed with saline. The organic phase was dried over anhydrous sodium atoate and the solvent was removed in vacuo to give 0.80 rng of the compound of this Example 1H. H-NMR (250 MHz, methanol-d *) 6: 7.83 (dd, 1H, 3 = 7.0; 7.5); 7.50 (d, 1H, 3 = 7.0); 7.30-7.00 (, 9H X2); 4.50 (d, 1H, 3 ^ 2.0); 4.41 (d, 1H, 3 = 8.0); 3.15 (dd, IH, 3 = 5.413.9); 3.00-2.57 (m, 4H); 2.42 (dd, 1H, 3 = 11.4, 13.5); 2.09-1.35 (m, 5H x 2). I. It is reactive with 2- (6-benzyl-5-hydroxy-5.6.7.9-tetrahydro-naphthalen-2-yl) -4-fl orhenzoic acid. To a stirred solution of the compound of Example 1H ( , 80 g, 2.13 mmol) and ethyl iodide (0.34 ml, 4.26 mmol) in acetonitrile (20 mmol) was added potassium carbonate (1.03 mg, 1.45 mmol). The resulting mixture was heated to about 60 ° C for about 24 hours. The mixture was cooled to room temperature, diluted with diisopropyl ether and filtered through celite. The vacuum concentrate gave 0.72 mg of the compound of this Example II as a 1: 1 cis / trans mixture. The data for the diastereomer mixture is as follows: H NMR (250 MHz, chloroform-d) d: 7.88 (dd, 1H, 3-7.0, 7.5); 7.53 (d, IH, 3-7.0); 7.39-7.70 (rn, 9H X2); 4.58-4.52 (n, 1H X 2); 2.92-2.70 (m, 2H); 2.55 (dd, 1H, 3 = 9.4, 14.2); 2.11-1.40 (rn, 5H x 2); 1.08 (t 3 H, 3 = 7.0); 1.07 (t, 3H, 3 = 7.0). 3. Ethyl ester < fel acitio Z-t-j- ncj.! -? , 9- < 3? Dr-naphthalene-2- (1) -4-fluorobenzoic acid The round bottom flask containing the compound of Example II (0.70 mg) in benzene (50 mmol =) was added with p-toluene sulphonic acid ( 0.09 mg) "The flask was connected to a Dean-Strak trap to remove water during the course of the reaction.The mixture was heated to reflux for about 16 hours, then cooled to room temperature and concentrated at low pressure The residue was taken up in chloroform and washed with saturated aqueous sodium bicarbonate The chloroform extracts were dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give a yellow oil which was purified by flash chromatography (6: 1 hexane / ethyl acetate) to give 0.56 mg of the compound of this example 13. Analysis calculated for Ca. &Haa0aF: 386.1676. Found 386.1713. K. Ethyl ester of ci a- (S * .6S ») - 2- (6-benzyl) -fi-d? H? Drox? -5.6.7 B-tetrahydro-naphthalene-2-? L) -4-f luorbenzoic To a stirred solution of the compound of Example 13 (0.50 mg, 1.3 mmol) in 3: 1 acetone / water (6 ml) was added N-rnethylmorphol-N-oxide (0.168 mg, 1.4 mmol), followed by osmium tetroxide (0.times. , 79 ml of a 4% solution in water, 0.1 mmol). The reaction mixture was stirred at room temperature and visualized by TLC for the disappearance of the starting material. The mixture was then diluted with chloroform and washed with 10% NaHS0 solution. The chloroform extracts were dried over anhydrous sodium sulfate and the solvent was removed at low pressure. The residue was purified by flash chromatography (1: 1 hexane / ethyl acetate) to give 0.34 mg of this Example 1K, mp. 59-60 ° C. Analysis calculated for Ca 'sHasO * F: 420.1736. Found: 420.1722. L. (5S ».6S *) - 2-benzyl-I6-hydroxy-5,6-d 5.B.7.B-tetrahydro-naft_alen-2-yl) -4-fluorobenzoic acid To a stirred solution of compound Example 1K (0.30 mg, 0.71 mmol) in 3: 1 methanol / water (12 mL) was added lithium hydroxide rnonohydrate (0.15 RNG, 3.6 mrnol). The resulting mixture was heated to reflux for about 4 hours.

The mixture was then cooled to room temperature and acidified with 1N HCl. The aqueous mixture was extracted with ethyl acetate. The organic phase was washed with saline, dried over anhydrous sodium sulfate and the solvent removed in vacuo to give 0.24 mg of the compound of this Example 1L (the title product), mp. 127-130 ° C. Analysis calculated for Ca ^ Hax F: 392.1423. Found: 392.1948.

EXAMPLE 2 7- (2-Carboxy-5-trifluoromethylphenyl) -3-phen-lmethyl-3-hydrox -3.4-m ensopiouro shot A. 2 '' -D? H? Drox? -3-chloroDroDiophenone To a stirred mixture of resorcmol (200 g, 1.82 mol) and 3-chlorohydroponic acid (200 g, 1.84 mol) was added t-pfluoromethane sulfonic acid (1 kg) in one portion. The solution was heated slowly for about 45 minutes at about 80 ° C then cooled to room temperature for about 15 minutes and poured into chloroform (4.0 1). The organic part was poured slowly over water (4.0 1) and the layers were separated. The organic phase was extracted with chloroform (2 X 2.0 1). The combined organic phases were washed with saline, dried over sodium sulfate and filtered. Concentration in vacuo gave an orange sernisolide (244.1 g) which was used without purification in the next step. RNN H (300 MHz, CDC13): 12.56 (1H, s); 7.63 (1H, d, 3 = 7.6); 6.37-6.46 (2H, m); 3.92 (2H, t, 3-6.3); 3.41 (2H, t, 3 = 6.3). R a cold solution (about 5 ° C) was 2N sodium hydroxide (10.0 1) the compound of Example 2A (244.1 g) was added from one sol to the other. The solution was heated at room temperature for about 2 hours using a hot water bath, cooled again to about 5 ° C and adjusted to pH 2 with sulfuric acid 611 (1.2 1). The mixture was extracted with 3 X 3.0 1 of ethyl acetate, washed with saline (1 X 2.0 1), dried over sodium sulfate and filtered. The concentrated vacuum gave a solid cinnamon color. Trituration with hexanes, the filtrate gave 173.7 g (58% yield) of this Example 2 B. pf. 136-137 ° C. c. iRTpfluormet? lsufon? p-benz? Diran-4-one To a stirred solution of the compound of Example 2B (173 g, 1.05 mole) in methylene chloride (3.0 1) at about -78 ° C was added to adi-tethylamine (320 g, 3.16 mole) and dimethylaminopyne pdma (2.5 g). After the total dissolution, The addition of nonsulfonic tpfluormet anhydride (327 g, 1.16 moles) was added dropwise over about 20 minutes, the material was stirred for about 30 minutes at about -78 ° C, and then heated to room temperature. for about 2 hours. The reaction mixture was poured into saturated ammonium chloride solution (2.5 1) and the layers were separated. The aqueous phase SE > extracted with 2 x 2.0 1 of methylene chloride. The combined organic fractions were washed with water (1 x 1.0 1), dried over magnesium sulfate and filtered. The concentrate in vacuo gave a red oil. Chromatography on silica gel (1 kg) eluting with (8: 1) hexane: ethyl acetate gave the solvent 211.1 g (69% yield) dpi the product of the title of this Example 2C. mp 43-44 ° C.

D. 7-r (Tp fluormet? Lsufon? L) ox? ] -3- fen? l -met? len-t > in? Qp? ran- -ona fl ura stirred solution of the compound of Example 2C (27 g, 91.2 mmol) followed by pyrrolidine (9.1 mmol, 109 mmol). The mixture was stirred at room temperature overnight, cooled to about 0 ° C and filtered. The solid was washed once with 50 ml of cold methanol on ice and dried in vacuo, 35.2 g (75% yield) of the title product of this Example 2D was recovered. Pf. L33-135 ° C. RtlN Hx (300 NHz, CDCla) 8.11 (1H, d, 3 = 8.7); 7.91 (1H, bs); 7.40-7.51 (2H, rn), 7.24-7.38 (3H, m); 6.97 (1H, dd, 3 = 8.7, 2.4); 6.91 (1H, d, 3- 2.4); 5.40 (1H, bs). E. 7-r (Tr? Fluormet? Lsufon? L) ox?] - 3-phemethyl-1-en-P.Piran- -ooa. To a solution of the compound of Example 2D (26.6 g, 69.2 mmoles) in 250 ml of ethyl acetate in a Parr shaker flask (registered trademark) of 500 rpm was added to 10% palladium on carbon catalyst (1.3 g). The mixture is hydrogenated at 2.8 kg / cm52 until the uptake of hydrogen ceases after about 3 hours. The mixture was filtered through Celite (trademark by diatomaceous eart) to remove the palladium catalyst, and was chromatographed on silica gel (hexane-ether), 25.1 g (94% yield) of the compound were obtained of this Example 2E. Mp. 56-58 ° C. H NMR (300 MHz, CDC13): or 8.01 (1H, d, 3 = 8.5); 7.20-7.35 (5H n); 6.81-6.96 (2H,); 4.42 (1H, dd, 3 = 11.6; 4.4); 4.22 (1H, dd, 3 = 11.6, 8.7); 3.26 (1H, dd, 3 = 14.0, 4.4); 2.90-3.05 (1H,); 2.70 (1H, dd, 3 = 14, 0; 8.7). F: 7- (2-CarbQetox? -5-tr? Fi ^ orp? Et? Lfn,?, -3-phen? Lrnet? L-3,4-d? H? Dro-benzoDirano Using the procedure described in Example 1F-13, but using 2- (4-tp fluormethyl phenyl) -4,4-d? Met? L-4, 5-d? H? Dro-oxazole or reagent, gave the desired product of this Example 2F. NMR Hx (300 MHz, CDCl 3) 6: 7.87 (1H, d, 3 = 8.0); 7.68-7.61 (2H, n); 7.41-7.22 (5H, rn) 6.97 (1H, d, 3 = 7.8), 6.85-6.73 (2H, rn), 6.21 (1H, s), 4.71 (2H, s), 4.20 (2H, q, 3-7.2), 3.48 (2H, s), 1.15 (4H, 3 = 7.2), G. 7- (2-Cabobotoxin? -5-tri-fluoroquinolone) fem l) -3-phenyl? -4-o-phenyl-benzopranol To a solution of the olefin of Example 2 F (230 mg, 0.53 mmolee) in methylene chloride at about 0 ° C. C m-CBPA (89 mg, 0.53 mmol) was added.After about 1 hour, the mixture was diluted with ether and washed with NaOH IN solution and saline The organic phase was dried (NgSO) ), filtered and concentrated, purification by flash chromatography (elution with 3: 1 hexane-acetate). ethyl) gave the corresponding epoxide of this Example 2G (209 mg, 87%). The product was used immediately for the next step. H. 7 - (? - Carboetox? -5-tr? Fluor et i 1 fem 1) -3-phenethrhene-3-hydrox? ) -benzooi rano To a solution of the epoxide of Example 2G (150 ng, 0.33 mmoles) in ethyl acetate was added 10% palladium on carbon (100 mg). The system was connected to a balloon containing Ha and the flask was purged several times. After stirring for about 16 hours, the solution was filtered and concentrated. Flash chromatography with elution of 5: 1 hexane-ethyl acetate gave the desired alcohol of this Example 2H (80 mg, 53%). NMR (300 MHz, CDC13) 6 7.89 (1H, d, 3 = 8.0); 7.70-7-62 (2H, m); 7.42-7.25 (5H, m); 7.07 (1H, d, 3 = 7.8); 6.90-6.80 (2H, rn); 3.95 (2H, s); 4.19 (2H, q, D- 7.1); 3.04-2.72 (4H, rn). I. 7 - (2 -Ca rbox i-5- ri fluormet11 pheny1) -3-fem 1.met11 3-hi4rQx.i- en.Qp i ra no The saponification of the compound of Example 2H analogous to the procedure described in Example 1L gave the desired product of Example 2. H-NMR (300 MHz, CDC13) d: 7.98 (1H, d, 3 = 7.8); 7.67-7.64 (2H, rn); 7.38-7.26 (5H, rn); 7.06 (IH, d, 3 = 7.8); 6.88 (2H, m); 2.99-2.72 (4H, n).

EXAMPLE 3 (3S ».4R *) - 7- (2-Carbox? -5-tr? Uoromethyl-3,4-dihydroxyphen?) -3-phenylmethyl-3,4-dihydrobenzodiran A. 7 - (Cabobotoxin -5- tn fluormet11 feni 1) -3- phen i lmet..i 1 -3-h? drox? -benzoD.? ran ~ 4-one To a solution of the olefin of Example 2F (3.7 g, 8.44 rnmoles) _ > n acetone-water (3: 1) was added N-rnet? imorfol? na-N-oxide (83.0 g, 25.3 mmol) followed by OsO. After stirring overnight, the solution was diluted with water and extracted with ethyl acetate. The combined extracts were dried and concentrated. Purification of the residue by flash chromatography the corresponding hydroxy ketone of this Example A (3.0 g, 76%). Mp. 85-87 ° C. B. (3s * .4R ») - 7- (2-Carboethoxy? -5-tr? F.luorrnet? Lfen? L) - 3 -d? H? ? p ?? - 3-phenylme? -benap? r PQ To a solution of the ketone of Example 3A (3.0 g, 6.4 rnmoles) in methanol (50 ml) at room temperature to adio NaBH (250 rng, 6.4 rnrnoies). After about 30 minutes, the reaction was stopped (solid Nl-UCl), extracted (ethyl acetate), dried (MgSO), filtered and concentrated. Flash chromatography (elution with 2: 1 hexane-ethyl acetate) gave the desired trans-diol of this example 3B (2.9 g, 97%). H NMR (300 Mhz, CDCly) fi: 7.89 (1H, d, 3 = 8.0); 7.69-7.55 (2H, rn); 7.42-7.20 (5H, m); 6.90-6.82 (2H, m); 4.43 (1H, s); 4.15 (1H, d, 3 = 12.1); 3.90 (1H, d, 3 = 12.1); 3.79 (3H, s), 3.13 (IH, d, 3 = 13.5); 2.85 (1H, d, 3 = 13.5). C (3S * .4R *) - 7- (2-Carbox? -5- trif luormet U -3.4 - 4? Hi'3ro? < ?? - 3-f «5n lmet l- in op,?, RanQ The saponification of the compound of Example 3B in a manner analogous to the procedure described in Example 1L gave the desired acid of this Example 3. Mp. 100-102 ° C.

EXAMPLE. (3S ».4S ') - 7- (2-Tr fluormetanosulfon lam non-5-fluorfen l????) D -3.4- hydroxy-3-hydroxy-3-phenylmethyl-2H-l-3.4-dihydrobenzopyran? A. - [(5-flupr- (2-.t-dimg -Z-QxaaQ inilr1 phen.? 3 - *) - fen lri) and len-, I-ben = PL'iran-- -one A solution of 2- (4-fluorfeml) -4,4-d-rnet 11 -2-oxazolm (1.0 equivalent in tetrahydrofuran, concentration 0.5 M) at about -78 ° C under Na atmosphere was added n -butyllithium in hexanes (1.1 equivalents, 2.5 M solution). The mixture was stirred at about -78 ° C for about 1 hour, then ZnCl was added (1M solution in ether 1.1 equivalents). The mixture was heated at about 10 ° C for about 1 hour to give 2- (4-fluorfen? L-2-chloro-z? Nc) -, 4-d? Et? I-2-oxazole ina (not isolated). To that solution was added 7-r ((t rifl uormetil) sulfom 1) ox] -???? 3-phen l-lan- lrnet benzop ran-4 -one (1.0 equivalents) and Pd (PPh3) ( 0.02 equivalents). The mixture was refluxed (about 68 ° C) for about 3 hours, cooled to room temperature and poured into NH C1 solution. The solution was extracted three times with diethyl ether and the combined organic fractions were dried over MgSO. Filtration was followed by the elimination n the solvent in vacuo and column chromatography (silica gel 2: 1 I < year: ether) gave the title compound of this Example 4A co or a yellow solid, 65% yield, pf. 110-112 ° C. NMR H3- (300 MHz, CDCla): 8.04 (1H, d); 7.91 (1H, s); 7.78 (1H, dd); 7.41-7.52 (3H, rn); 7.31 (2H, d); 7.06-7.18 (3H, rn); 7.02 (1H, s); 5.40 (2H, s); 3.86 (2H, s); 1.31 (6H, s). B. (3S * .4R *) 7-r5-fluor- (2- (4.4-d? Rnet? L.-2-oxazole? P? .1) phene 11-4-hydrox? -3- phen ? lrnet? l-2H- l-benzooi rano to a stirred solution of Example 5 compound 4R in THF (0.1 M) at about 0 ° C to adio LiAlH * (1M in ether, 2.2 equivalents) drop by drop for about 10 minutes.The mixture was warmed to room temperature and stirred for about 1 2 hours.The mixture was cooled to about 0 ° C, stopped with Rochelles salt, and filtered through the earth from LC) diatorneas. The aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were washed with saline and sebated over MgSO. Filtering and removing the solvent gave a yellow oil. Chromatography on silica gel (ethyl acetate, hexane) gave a yield of 60% of the title compound of this Example 4B as a white solid. Mp. 65-70 ° C (decomposed). Calculated analytical for Ca H ^ NOa: C, 75.15; H, 6.07; N, 3.25. Found C, 74.75; H, 6.02; N, 3.09. H NMR (300 MhZ, CDCla) or: 7.70 (1H, dd); 7.02-7.37 (8H, m); 6.96 (1H, dd); 7.91 (1H, d); 4.51 (1H, d); 4.23 (1H, dd); 4.39 (1H, dd); 3.87 (2H, dd); 2.74 (1H, dd); 2.55 (1H, dd); 2.18-2.28 (1H, m); 1.31 (6H, d). c. I 35 * R »r 7- (2- ar p? -5- fluprfen l? -4-h '3rp?.?, - 3-phe- tropette? L ~ 2H-] -benz, P? > ?, ranp The compound of Example 4B was dissolved in iodide of Methyl (0.5 M) at room temperature and stirred for about; 4 hours. The methyl iodide was removed in vacuo, the oily solid was dissolved in ChaCl and the solvent was removed in vacuo. This operation was repeated to eliminate methyl iodide races. The solid was dissolved in methanol (0.5M) and NaOH (0.5M) was added. The mixture was kept at reflux for about 5 hours, cooled to room temperature and acidified to pH 2 with 1M HCl. The mixture was extracted twice with ethyl acetate, washed with saline, and dried over MgSO *. Filtration and removal of the solvent in vacuo, followed by chromatography (silica gel, 10: 1 LU rnet full. methanol) gave the desired acid of this Example 4C, 93% yield. NMR H3- (300 Mhz, CD3COCD3) 6 7.80 (1H, dd); 7.48 (1H, d), 7.18 (7H, m); 7.13 (1H, dd); 6.91 (1H, dd); 6.80 (1H, d); 4.52 (1H, d); 4.23 (1H, dd), 3.96 (1H, dd); 2.89 (1H, dd); 2.54 (1H, dd); 2.19-2.30 (1H, m). l'- > D. (3S * .4S *) 7- (2-Carbox? -5-fluorfen? L) -3.4-d? .h.? Drox? ~ 3 -- . 3 - f in ime,?,, 1 - 2H - 1 - t »en¿p? JL rano Using the procedures of Examples II to 1L, the compound of this Example 4D was prepared from the compound of Example 40. 20: 3S ».4S») 7- (2-Carbobenzo? Lox? Am? No. -5-fluor) -3.4- '3 ,? h tirpx-3-f em rnet 1 - 2H- - pencp i rano To a solution of the compound prepared in Example 4D (1 mmol) in 10 mL of 1,4 dioxane was added 1.05 equivalents of diphenylphosphonlazide, 1.1 equivalents of benzyl alcohol and 2.2 equivalents of t petiimamna. The mixture was refluxed for about 16 hours, the solvent removed in vacuo and the residue chromatographed on silica gel (1: 1 hexane: ethyl acetate) to give the N-CBZ product of this Example 4E. NMR H3- (300 Mhz CDCla) 6 8.02 (1H, s); 7.39-7.22 (1H, rn); 7.03 (1H, dt, 3 = 7.2); 6.95-6.87 (2H, m); 6.83 (1H, s); 5.11 (2H, s); 4.48 (1H, s); 3.98 (1H, d, 3 = 10.1); 3.80 (1H, d, 3 = 10.1), 2.89 (2H, s). F. (3S *, 4S *) 7- (2-Tr? Fluorrhetans? Lfon? Larn? No-5-fluor) - .4-d? H? Drox? -3-h? Dro? -3-fen? METHL-2H-L-BENZOO? To a solution of the compound prepared in Example 4E in 10 rolls of EtOH, 0.05 equivalents of PdOHa was added and the mixture was hydrogenated in a Parr shaker (registered trademark) at 1 atm for 3 hours. The mixture was filtered through celite (registered trademark) and the filtrate was evaporated. The yellow oil was redissolved in rne-ileum chloride (10 rnl), cooled to about 0 ° C, and tintethylane (2.2 equivalents) was added, followed by t-fluoromethylammonium anhydride (2.2 equivalents). ), followed by anhydride tpf Luormetanosul phonic (1.1 equivalent). After stirring for about 2 hours, 2 equivalents of solid sodium ethoxide were added, the reaction was stirred for about 15 minutes, and water (10 nl) was added. The pH of the mixture was adjusted to 2 with 0.1 M HCl and then extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saline, dried over magnesium sulfate, filtered and the solvent removed in vacuo to give a yellow semi-solid. Chromatograph on silica gel (1.1-10_1 ethyl acetate-hexane) to give the desired phonarnide of this Example 4F. Pf. 55-570C.

AXIS? PLQ ssolid l- (3S.4S) - ((3- phenyl? -phenylmethyl) -3-hydroxy) -4-hydroxy) -chroman-7-yl) cyclopentane carboxylic A.- (3- (4-Fen? L-phenol? L) ~ 4-chromanone ~ 7-iD-cyclopentane ethyl carboxylate 3-4 (Fen? L-benz?) -7-t rif luorrnet? Lsufomlox? -4 ~ crornanone ( 35 g, 91.0 rnmoles) prepared from the product of the Example 2C with biphenyl aldehyde using the procedures of Example 2D and Example 2E, was dissolved in a mixture of dimethylformamide (230 ml) and dimethoxyethane (230 ml). To this solution was added in the following order, tr? s (2-rnethylphenyl) phosphma (7.48 g, 24.6 mrnol), b? s chloride (benzon? tplo) palladium (II) 82.44 g, 6.37 mmole), tprnet-isilyl ketone acetic acid cyclopentanecarboxylate (29.26 g, 136.5 mmol), and a 1.0 M etheral solution of zinc chloride (25 t? 1.25 mmol). The light yellow solution was refluxed for about 1 hour. P-phenylsilyl ketone acetal (9.75 g, 45.5 mmol) was added at this point and the raffle continued for about another hour. The cold mixture was diluted with water (1 liter) and extracted with ether. The combined ether extracts were washed with water (1 liter) and then dried over magnesium sulfate. The filtrate and concentrate of the extracts gave a yellow oil which was chromatographed on silica gel (8:92 ethyl acetate / hexane). This gave 22.13 (64%) of the title compound of this Example 5A as a white solid; mp 50-56 ° C; NMR H3- (CDC13); 1.23 (3H, t, 3 = 7.0); 1.75 (1H, dd, 3 = 4.3, 13.8); 4.08 (2H, d, 3-7.0); 4.15 (1H, dd, 3 = 8.2; 11.5); 4.35 (dd, 3-4.3, 11.5); 6.95 (1H, d, 3 = 1.7); 7.02 (1H, dd, 3 = 1.7, 8.3); 7.2-7.4 (5H, tn); 7.84 (1H, d, 3-8.3). B- 2- (4-H? Drox? -3- (4-fem-1-phenyl-1-et-1) cro-n-7-yl) -g glopentane-carpoxilap «Je eip The compound of Example 5A (111.99 g , 295.9 mmol) was dissolved in ethanol (2.5 l) and treated cautiously with sodium borohydride (12.3 g, 325.5 mmol) at room temperature. After about 3 hours the reaction mixture was concentrated to a small volume and diluted with ether. The ether was washed with saturated sodium bicarbonate solution and dried over sodium sulfate. The extract was filtered and concentrated to an oil which was chromatographed on silica gel (20:80 ethyl acetate / hexane). This gave 63.4 g (56%) of the product with higher R *, that is, 3R *, 4R ~. as an oil. NMR H3- (CDCl3: 1.15 (t, 3 = 7.1, 3H); 1.7 (rn, 4H); 1.8-1.9 (n, 2H); 2.3 (n, 1H ), 2.5-2.6 (m, 2H), 2.66 (dd, 3 = 7.2, 13.6, LH) 2.86 (dd, 3 = 8.4, L3.6, 1H ), 4.0-4.1 (m, 4H), 4.47 (br, 1H) 6.85 (d, 3 = 1.8, 1H), 6.88 (dd, 3 = 3 1.8 7.9, 1H), 7.12 (d, 3 = 7.9, 1H), 7.1-7.35 (m, 5H), and 43.3 g (38%) of the product with inenor Rr, that is to say 5 *, 4R ~ as an NMR oil H3- (CDC13) d: 1.17 (t, 3-7.0, 3H); L, 7 (m, 4H); 1.8-1 9 (rn, 2H), 2.2 (m, 1H), 2.52 (dd, 3 = 9.3, 13.7, 1H), 2.6 (rn, 2H), 2.70 (dd) , 3 = 6.3, 13.7, 1H), 3.95 (dd, 3 = 3.7, 11.2, 1H), 4.07 (q, 3 = 7.0, 2H), 4, 18 (dd, 3 = 2.6, 11.2, 1H), 4.47 (br t, 1H), 6.88 (d, 3 = 1.8, LH), 6.94 (dd, 3 = 1.8; 8.0 1H); 7.15-7.3 (, 6H). "> C. Acid l- (3S.4S) - ((3- (4-phen? L-phen? Lmet (1) -3-h? drox?) - 4-h? d -oxi) -crornan-7-? l) -cyclooentane carboxylic acid The desired product was obtained from the cis and trans mixture of the compound of Example 5B by reaction of the compound of Example 5 E1 analogously to the process described in Hl Examples L3 to 1L to give the title compound of this Example 5. p.f. 185-187 ° C.

EXEGIPLQ 6 (3S.4S) -7-Carboxy-5-trifluoromethylphenyl) -3,4-dihydroxy-3-L5-phenylmethyl-3. -dihydrobenzoDirano A- Ester 3-h? drox? -3-fen? lmet? .1. ) benzamino of 7- (2- carbometho? -5-t rt f luorrnet.il phenyl.) -4-L-t-Boc-tr.? ptofan To a solution of (35, 4S) -7- (2 ~ carbornetox? -5- t pfluormet? phenyl) -3,4-d? h? drox? l-3-phen? memethylbenzopranol (225 rng; 0.49 mmoles) in CHHC1 = (6 rnl) was added t-BOC-L-tryptophan (223 rng, 0.74 mmole) DMAP (120 g, 0.98 mmole), and EDCI (165 rng, 0.86 mmole). After stirring for about 16 hours, the solution was diluted with ethyl acetate and washed with 1N HCl and saline, dried (MgSO 4), filtered and concentrated. The purification of the residue by flash chromatography (elution with hexane-ether-ethyl chloride 3: 1: 6) gave 137 mg, 38% of the diastereoisomer that ran the most followed by 135 mg, 37% of the diastereomer that ran the least from Example 6A. NMR H3- (300 Mhz, CDC; .3) d is mero LP 8.98 (1H, s); 8.00 (1H, d, 3- = 8.0); 7.76-7.67 (2H, m); 7.68 (1H, d, 3 = 7.5); 7.40 (1H, d, 3 = 7.6); 7.37-7.09 (9H, n); 6.92-6.86 (2H, m); 6.61 (1H, s); 5.80 (IH, s); 4.93 lH, d, 3 = 6.3); 4.57 (1H, dd, 3 = 6.5, 3.0); 3.91 (2H, s); 3.82 (1H, d, 3 = 10.2); 3.72 (1H, d, 3 = 10.2); 3.50 (1H, dd, 3 = 15.7, 5.0) ,. 3.25 (1H, dd, 3 = 15.0; 6.1); 2.84 (2H, s); 1.39 (9H, s). Isomer MP 8.72 (1H, s); 8.03 (1H, d, 3-7.9); 7.78-7.71 (2H, m); 7.59 (1H, d, 3 = 8.0); 7.32-7.05 (9H, rn); 6,932-6,806 (2H,); 5.41 (1H,); 5.60 (1H, s); 5.17 (1H, d, 3 = 6.0); 4.68-4.58 (1H,); 3.95 (2H, s); 3.65 (1H, d, 3 = 10.3); 3.43 (1H, d, 3 = 10.2); 3.30 (1H, dd, 3 = 15.1, 5.3) ,. 3.13 (1H, dd, 3 = 15.0, 7.9); 2.72 (2H, s); 1.49 (9H, s). B. (3S .4S) -7- (2-Carborneto i-5-trif luormet i 1 phenyl) - 3,4-di hydro i 1 - 3-phenylmet i-henzoni a To a solution of the t-Boc tryptophan ester of greater R ^ of Example 6A (130 rng, 0.17 nnol) in ethanol-THF (7 mL, 5: 2) was added 1N NaOH (175 mL). After about one hour the solution was diluted with ethyl acetate, washed with HCl IN and with saline, dried over (MgSO *), filtered and concentrated. Purification by flash chromatography (elution with hexane-ether-methylene chloride 2: 1: 6) gave the corresponding alcohol of this example 6B (63 ng, 80%) 1 H-NMR (300 MHz, CDCL3) d 7.94 (1H, d, 3-7.8); 7.72-7.60 (2H, m); 7.46 (1H, d, 3 = 8.0); 7.40-7.22 (4H,); 6.97-6.85 (3H, rn); 4.52 (1H, s); 4.02 (1H, d, 3 = 12.1); 3.86 (1H, d, 3 = 10.1); 3, 72 (3H, s); 2.93 (2H, s); 2.48 (1H, bs) C. (3S.4S) -7- (2-Carbox? -5-tr? Fluorrnet? Lfen? L) -3.4-d? H.? Drox? -3-femlment? -Benzo-dichloride To a solution of the ether of Example 6B (60 mg, 0.13 mmol) in methanol (3 mL) was added NaOH (3 mL, 3 N). After heating to about 60 ° C for about 1 hour, the mixture was cooled and acidified with 1 N HCl. The solution was extracted with ether and the combined extracts were washed with saline, dried (MgSO 4. ), were filtered and concentrated to give the essentially pure acid of this Example 6 (46 mg, 30%), which was further purified by recrystallization in he xa non-ethyl acetate. P.f. 90-92 ° C.

E3EMPL0 7 7- < 2-carbQetp? I-5-flupr-phenyl? -4.-hydroxy-3- (-phenyl-phen lme-Hl 1 -3.4-d hydrohenzopyran A. 7- (Trirnet il staní 1) -3- (4- feml-phenylrnet, i, 1) -benzopyran-4-one To a stirred solution of the compound prepared in the Example 2E (10.95 g, 25.0 mmol) in 200 ml of dioxane was added with lithium chloride (3.20 g, 75.0 mmol), Pd (1.15 g, 1.0 mmol), three crystals of butylated hydroxytol, and hexamethyl-di (9.0 g, 27.5 mmol). The mixture was heated at reflux for about 1.5 hours, cooled to room temperature and poured into 150 ml of saturated harmonic chloride solution. The mixture was extracted with 3 X 150 ml of diethyl ether and the combined organic rations were washed with a salt solution, dried over sodium sulfate and filtered. Evaporation under vacuum gave a yellow solid cerní which was chromatographed on silica gel (5: 1 hexane: ether) to give 9.8 g (89% yield) of the title compound of this Example 7A. NMR H3- (300 MHz, CDC1: -,) d: 7.85 UH, d, 3 = 8.7); 7, 18-7, 37 (9H, rn); 7.14 (1H, d, 3 = 8.7); 7.11 (ll-l, s); 4.38 (1H, dd, 3 = 11.6, 4.5); 4.17 (1H, dd, 3 = 11.6, 8.4); 1 J LC) (LH, dd, 3 = 1¿, 0; 4.4); 2.84-2.95 (1H, rn), 2.71 (1H, dd, J-14,11); 0.31 (9H, s). B. 7- (-C-ribose 1-5-fluorine-1) -3- (4-ene-1-phenyl-phenyl, p-p-p-p-A To a stirred solution of the compound of Example 7A (8.28 g, 17.5 nm) in dirnet i] forrnamide (DMF) (35 ml) was added Pd (PPHa: -.Cl2 (490 mg, 0.7 mmol), 3 crystals of BHT and Ethyl 2-iodo-5-fluorobenzoate (5.4 g, 19.1 rnmoles). The mixture was stirred at reflux for about 1.5 hours, cooled to room temperature and poured over 150 i of solution saturated with ammonium chloride. The mixture was extracted with 3 X 150 rnl of diethyl ether, and the combined extracts were washed with water.

X 100 i of water, and then with saline. The solution was dried over sodium sulfate, filtered and evaporated in vacuo to give a yellow oil. It is cro atografio on gel of Silica (4: 1 hexane: ether) yielding 6.51 g of the title compound of this Example 7B as a viscous oil. H-NMR (300 MHz, CDC13) d: 7.95 (2H,); 7.28-7.65 (9H, rn); 6.92-7.22 (4H, rn); 4.49 (1 H, dd, 3- 11.6, 4.5); 4.29 (1H, dd, 3 = 11.6, 8.5); 4.15 (2H, q); 3.31 (1H, dd, 3 = 14.0, 4.4); 2.91-2.99 (IH, rn); 2.73 (LH, dd, 3 = 14.0, 11.1); 1.20 (3H, t). C. 7- (2-carboethoxy-5-f1oo-r-fem1) - -hydroxy-3 - (4-phenyl-enylmethyl) -benzofuran To a stirred solution of the compound of Example 7 (6.60 < j, 17.5 mmoles) in 35 ml of methanol at room temperature was added with sodium borohydride (g, 26.0 rnmoles) at one time. The dark mixture was stirred at room temperature for about 2 hours and was visualized on saturated ammonium chloride solution (75 mL) and extracted with 3 x 75 mL of diethyl ether. The combined extracts were washed with saline, dried over sodium sulfate, filtered and concentrated in vacuo to give a yellowish oil. Chromatography on silica gel eluting with 4: 1 hexane: ether gave first 3.26 g of the cis-isomer ring compound of the title of this Example 7, and then 1.98 g of the trans-isomer of the compound of this Example 7 as viscous oils, total yield 81%. Isomer of the cis ring: H-NMR (300 Mhz, CDCla) d 7.95 (1H dt); 6.8-761 (14H,); 4.58 (1H, t, 3 = 7.2); 4.28 (1H, dd, 3 = 9.1, 2.5); 4.03 (1H, dd, 3 = 9.1, 5.4); 4.15 (2H, q), 2.78 (1H); 2.77 (1H, dd, 3- 13.7, 6.2); 2.58 (1H, dd, 3 = 13.7, 9.1); 2.20-2.29 (1H, rn); 1.83 (IH, d, 3 = 7.2), 1.1 (3H, t). Trans-ring isomer: NMR H3- (300 MHz, CDC13) or: 7.95 (1H, dt); 6.8-7.60 (14H, rn); 4.56 (1H, dt, 3 = 4.7, 3.8); , 12-4.19 (2H, n); 4.10 (2H, q); 2.90 (1H, dd, 3 = 13.6, 8.4); 70 (1 H, dd, 3- 13.6, 7.2); 2.36-2.39 (1H, m); 1.75 (LH, d, 3-4.7), 1.12I3H, t).

E3EMPL0S 8 A 16 The compounds of Examples 8 to 16 were synthesized analogously to the procedure indicated, using the materials of: > corresponding article. fi9 .'OR This compound was synthesized analogously to the steps of Example 7B, then Example 7C and finally Example 1K. Bn-Benzyl

Claims (15)

NOVELTY OF Lft INVENTION CLAIMS

1. - A compound of Ja formula HJ and the pharmaceutically acceptable salts + ab.eß thereof where A1 is 0, CH2 / S, NH or) alkylene; R3 is hydrogen or hydroxy; fl52 is R is hydrogen or hydroxy; RB is selected from the group consisting of - (CH2) r? CHX * X: 1-D- (CH2) mX3-D and -CHIOHlX 0; where n is 0 / l, 2, or 3; X ^ is hydrogen, (C-CA) alkyl or optionally substituted femlo; where the substituted phenyl Optionally it is optionally substituted by one or two substitutes + is independently selected from the group consisting of fluorine, chlorine, (Ci.-C &) alkyl, (C? -Cto) alkoxy, ((-? - C) perfl ororalk , (C? -0 *) perf1 uoralkoxy, (C? -0,) alkyl + io, fC, .- C &) alkyl ui fi i, fem sul fini lo, (C? -CA) alkyl sulfoyl and feni Isulfonyl; X or is hydrogen, (Cx-C) alkyl, (C ^ -?,) Cycloalkyl or one of the following optionally substituted rings: phenyl, thienyl, μipdyl, fuplo, naphthyl, qum lyl, isoquinolyl, pyrimidimide op? ra_7in? lo; where the optionally substituted rings are optionally substituted by one or two suhst it uyentos LU independently selected from the group consisting of fluorine, chlorine, (Cx-C,.,) Alkyl, (C? -Cto) alkoxy, (C ~ 0) perfluoroalkyl; perf1 uoralkoxy, (C? -C?) alkylthio, (C? -C?) to the quilsulfimyl, phenyl sulfinyl, (C? - C?) alkylsulfoyl, phenylsulfomyl and phenyl optionally substituted S; wherein the optionally substituted phenyl is optionally substituted by one or two non-deficient substituents selected from the group consisting of fluorine, chlorine, (C -C?) alkyl, (C? -Cto) alkoxy, (C? C *) perfluoroalkyl, (C? -C perfluoroalkoxy, (Cx-C6) alkyl or, 20 (C -C?) Alkylsulfonyl, phenylsulfonyl, (C? -C 's.) Alkylsulfonyl and phenylsulfonyl; R * Y R? are each independently hydrogen or (C? -C *) alkyl or R * and R7 are joined together with the carbon atom to which they are attached and form a (C ^ - C7) loalkyl; R is selected from the group with? I ^ on p ? 5 in tetra olilo, carboxy, cis or trans - (CHa) m-CX = CXa-COaH, - (CH2) CXaX Xs, -CO-NG ^ G3, n and an optionally substituted five- or six-membered aromatic ring having one or two heteroatoms from the group consisting of 0, S and N; where? n is 0, 1, or 2; And it's 0, CH2, S, NH NH or N (C? -CA) alkyl; X and X? are each independent in hydrogen and (Cx-C ^) alkyl; Xa and X * are each independently hydrogen or (C? -C?) Alkyl or X3 and X "* are joined together with the carbon atom to which they are attached and form a (C3-C7) cycloalkyl; Xa is hydroxy, carboxy, tetrazol i lo or l -C0-NG3G; X * is carboxy, tetra olilo, CH ^ OH or -CO-NG-'G *; G, Gs, G3, G *, Gs and G * are each one independently selected from the group consisting of hydrogen, (C? -CA) alkyl, (C? -C ".) perfluoroalkyl, (Cx-C ^) alkylsulphomyl, phenylsulfyl, (C? -C?) alkylsul foml, fem lsul foni 1 o, 20 hydroxy, phenyl and femlo substituted with (O1) "; where a is 2; 0 for each case is independently selected from fluorine, chlorine, (C -Cto) alkyl, (Ca.-Cto) alkoxy, (C? ~ C.) Perfluoral which Jo, (C? ~ CA) perf1oralkoxy, (C? -C?) Alkyl * 10, (C? -0,.,) Alkylsulfinyl, fem J sul finyl, (Cl-Cß) Alkylilsul fomlo and femlsufonil; the substituted five- or six-membered aromatic ring is replaced by a substituent selected from the group consisting of carboxy, tartolyl, -CO-NíH) and by one or two substituents each selected from the group consisting of fluorine, chloro, (C? -C?) alkyl, (C? -C ".) alkoxy, (C? -C * perfluoroalkyl, (C? -C".) perfluoroalkoxy, (C ~ C6) alkylthio, ICL-G6) alkylsulfinyl, phenylsulfonyl, C -C ^) alkylsulfonyl and femlsulfonyl; wherein X "7 is hydrogen, -CH2F, -CHF2, -CHF2, -CFfJ, (C? -C" a) alkyl, (C3-C ") cycloalkyl or one of the following optionally subsituted rings: phenyl, thienyl, pipdyl, fuplo, naphthyl, quinolyl, 1 sochiol, pyrimidinyl or pyrazimide, wherein the optionally substituted rings are optionally substituted with one or two substituents independently selected from the group consisting of fl or, chloro, (C? -C, s) alkyl or , (Cx-C ^) alkoxyl, (C? -C_ perfluoroalkyl, (Cx-C ^.) Per luoralkoxy, (C ^ -C ^) alkylthio, (CL-C?) Alkylsulphyl, phenyl sulfyl , (Cx-Cß,) alkylsulfonyl, phenyl Isul fonyl and phenyl optionally substituted; Wherein the optionally substituted phenyl is optionally substiuted by one or two substituents independently selected from the group consisting of fluorine, chloro, (C? -C?) Alkyl, (C? -C &) alkoxy, (dO ^.) Perfluoroalkyl , (C? -C) perfJooralkoxy, (C -C?), Alkyl * 10, (C? -C 's) to [quilsulfiyl, phenylsulfinyl, (C? -Otho) alkylsulfonyl and phenylsulfonyl; R 2 is hydrogen, fluorine, chlorine, (C -C.) Alkyl, (C? -C?) Alkoxy, (C? -C) perfluoroalkyl, (C? -C ") perfluoroalkoxy, (C? -CA) alkylthio, (Cx-Ce.) Alkylsulfimyl, femylphosphyl, (C -C &) alkylsulfomyl, and femlsulfomyl; with the proviso that: G v Gs are not both hydroxy at the same time; G3 and G * are not both hydroxy at the same time; Gs and G * are not both hydroxy at the same time; and when R3 is hydrogen and R * is hydrogen then Ra is CH (OH) Xxo.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R3 is hydroxyl and fl2os & H

3. - A compound according to claim 2 or a pharmaceutically acceptable salt thereof where fix is 0 or CH2.

4. A compound according to claim 3 or a pharmaceutically acceptable salt thereof wherein R is (CHs) rnCX13X Xs or a five- or six-membered aromatic ring substituted by a substituent selected from the group consisting of carboxy, tetrazolyl, -CO -N (H) (SOs, -X'r), -N (H) (S02-X7), -NÍH) (CO-X7) and -N (H) (C0-OX7) and by one or two substituents each one selected from the group consisting of fluorine, chlorine, (C? -Cβ) alkyl, (C? -C 's) alkoxy, (C? -C.) perfluoroalkyl, (C? -C_ perfluoroalkoxy, (C? ~ C?) Alkylthio, (C -C.) Alkylsulfinyl, femlsulfimyl, (C? -C < s) alkylsulfonyl, and phenylsulfonyl.

5. - Jn compound according to claim 4 or a pharmaceutically acceptable salt thereof where R is a femlo substituted with a substituent selected from the group consisting of carboxy, -N (H) (SO ^ -X ^), -N (H) (CO -X "7) and -N (H) 5 (CO-OX" 7) and by one or two substituents each independently selected from the group consisting of fluorine, chlorine, (C-C?) Alkyl, (Cx-Cs) ) alkoxy, perfluoroalkyl, (C? -C_ perfluoroalkoxy, (Cx-C ^) alkylthio, (C? -CA) alkylsulfin, ferululphului, (Cx-C *) to the cholinester and femJ sulphyl. LO

6. A compound according to claim 5 or a pharmaceutically acceptable salt thereof wherein R * is hydroxy and the hydroxy R3 is either cis or trans with the hydroxy R *.

7. A compound according to claim 6 or a pharmaceutically salt acceptable from it where Rx is a fem lo l '? substituted with a substituent selected from the group consisting of carboxy and -N (H) (SO ^ -X ^), and by one or two substudents each selected independently The group consisting of fl oor, chloro, (C? -C?) alkyl, (C? -C, s) alkoxy, (C? -C, perfluoroalkyl, perfluoroalkoxy, (C-2 CA) alkylthio, (C? -C < a) alkylsul finyl, femlsulfinyl, (Ca.-C6) alkylsulfoyl ") and femlsulfomyl, and the hydroxy R3 and hydroxy R * are either cis or trans to each other

8. A compound according to claim 7 or a pharmaceutically acceptable salt thereof where Rs is 2'5 (CHa) nCHX ^ X * -0, where X "is hydrogen and X or is one of the rings optionally substituted.

9. - A compound according to claim 8 or a pharmaceutically acceptable salt thereof where n is 1; and X a is ferulo or substituted phenyl in the para position with the phenyl.

10. A compound according to claim G or a pharmaceutically acceptable salt wherein Rx is a femlo substituted with a substituent selected from the group consisting of carboxy and -N (H) (SOs.-X'7), and by one or two substituent? each independently selected from the group consisting of fluorine, chlorine and (Cx-C *.) perfluoroalkyl.

11. A pharmaceutical composition for the treatment of the disease induced by the LTBA comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or diluent. 12.- A pharmaceutical composition *. ica for the treatment of anti-inflammatory disorders, eczema, erythema, spot, acne, blow, graft rejection, autoinnunion diseases, or asthma, comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or diluent. 13. The use of an effective amount of a compound according to claim i or a pharmaceutically acceptable salt thereof, = > n the preparation of compositions for the inhibition of LTB ^ receptor binding in a mammal in need of such inhibition. 14. The use of an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, in the preparation of compositions for the treatment of inflammatory disorders, eczema, erythema, spot, acne, blow, graft rejection , autoimmune diseases, or asthma in a mammal in need of such treatment an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt of the same. 15.- A compound of the fornu where R is 0, CHa, S, NH or NICx-C, ..) alkyl; 0 = e < R * is hydrogen or hydroxy; Rs is selected from the group consisting of - (CH2) r > CHXí »X or - (CH5i) mXxo and -CH (OH) X O; where n is 0, 1, 2, or 3; 9 is hydrogen, (C? -C "s.) Alkyl or optionally substituted phenyl; wherein the optionally substituted phenyl is optionally substituted by one or two substituents independently selected from the group consisting of fluoro, chloro, (C? -C?) alkyl, (C? -Cto) alkoxy, (C? -C_,) p > erfluoroalkyl, (Cx-C *) perf1ooralkoxy, (Cx-C ^) alkylthio, (C? -CA) alkylsulfimyl, femlsulfmyl, (Cj.-Cj alkylsulfonyl and phenylsulfonyl; XD is hydrogen, (C? -C «s ) alkyl, (C3-Ca) cycloalkyl or one of the following optionally substituted rings: phenyl, thienyl, pindyl, furyl, naphthyl, quinolyl, isoquinolyl, pyrimidimyl or pyrazole, wherein the optionally substituted rings are optionally substituted by one or two substi Examples independently selected from the group consisting of fluorine, chlorine, (C? -C?) alkyl,? C? -C?) alkoxy, (C? -C?) perfluoroalkyl, perfluoroalkoxy, (Cx-C *) alkylthio, (Cx-) Cs) alkylsulfinyl, phenylsulfimyl, (C -C < s) alkylsulfomyl, phenylsulfomyl and optionally substituted phenyl; Wherein the optionally substituted phenyl is optionally substituted by one or two substituents independently selected from the group consisting of fluorine, chlorine, (Cx-C *) alkyl, (C? -C "&) alkoxy, (Cx-C *) perfluoroalkyl, (C -C_,) perfluoroalkoxy, (Cx-C ^) alkylthio, (Cx-Cβ.) alkylsulfimyl, phenylsulfimyl, (C -C ^) alkylsulfomyl and phenylsulfonyl; R * and R7 are each independently hydrogen or (C? -CA) alkyl or R * and R7, are joined together with the carbon atom to which they are attached and form a (C-v-C,.) Alkyl; R is selected from the group consisting of tetrazolyl, carboxy, cis or trans - (CHa) m-CX = CXS! -COOH, - (CHs,) mCX3X X: CO-NGxG2, and an optionally substituted five- or six-membered aromatic ring having one or two heteroatoms from the group consisting of 0, 5 and N; where? n is 0, 1 or 2; Y is 0, CHa-, S, NH or N (C -C?) Alkyl; X and X are each independently hydrogen or (C? -C?) Alkyl; X3 and XA- are each independently hydrogen or (Cx-C *) alkyl or X3 and X * are joined together with the carbon atom to which they are attached and form a (Ca-C-v) cycloalkyl; Xa is hydroxy, carboxy, tetrazolyl or ~ CO-NG3G *; X * is carboxy, tetrazolyl, CHa0H or -C0-NGrsGeS; G, G2, Ga, 6 *, Ga and G * are each independently selected from the group consisting of hydrogen, (C? -C?) Alkyl, (Cx-C) perfluoroalkyl, (C -C6) alkylsulfinyl, femlsulfyl, (C? -C?) Alkylsulfonyl, phenylene fonyl, idroxy, fen? L_ > and phenyl substituted with (Q) "; where a is 1 or 2; Q for each case is independently selected from fluorine, chlorine, (C -C?) Alkyl, (C? -C 's) alkoxy, (C? -C) perfluoroalkyl, (C? -C * l perf1 uoralkoxy, (C - C "s?) Alkylthio (C? CA) alkylsulinyl, phenylsulphimyl, (C? -C) alkylsulfonyl and phenylsulfonyl, the five or six membered aromatic ring 8J substituted is substituted by a substitute selected from the group consisting of carboxy, tetrazoyl, -CO-N (H) (03-Xt), -N (H) (Oz-X7), -N (H) (CO-X "7 ) and -N (H) (CO-CX "") and by one or two substituyent.es each independently selected from the group consisting of fluorine, chlorine, (C? -C?) alkyl, (C? -C «ü alkoxy, (C? -C.) perfluoroalkyl, (C? -Cv) perfluoroalkoxy, (C-C?) alkylthio, (C? -C?) alkylsulphmyl, phenylsulfinyl, (Cx-C *) alkylsulfonyl D and phenylsulfonyl; where X is hydrogen, -CH2F, -CHFa., -CF3, (_? - C?) alkyl, (Ca-CF3) cycloalkyl or one of the following optionally substituted rings: femlo, tieniJo, pipdilo, fuplo, naftilo, quinolilo , isoquinol lyo, piripudinyl or pyrazinyl, where the optionally substituted rings are optionally substituted with one or two substituyent.es independently selected from the group consisting of fluorine, chlorine, (C? -C?) alkyl, (C? -C < s) alkoxy, (C? -C_J perfluoroalkyl, perfluoroalkoxy, (C? - C6) alkyl io, IC-C?) alkyl sulphonyl, phenylsulfinyl, (C-CA) alkylsulfonyl, phemlsulfonyl and optionally substituted phenyl; Wherein the optionally substituted femyl is optionally substituted by one or two substituents independently selected from the group consisting of fluorine, chlorine, (C? -C?) Alkyl, (C? -C?) Alkoxy, (C? -CA) perfluoroalkyl, (C -C) perfluoroalkoxy, (C-C?) Alkylthio, (C-C?) Alkylsulfinyl, phenylsulflyl, (Cx-C ^) alkylsulfomyl and phenylsulfonyl; R 2 is hydrogen, fluorine, chlorine, (C x -Cß.) Alkyl, (C -C?) Alkoxy, (C -C ^) perfluoroalkyl, (C? -C ") perfluoroalkoxy, (C-Cι) alkylthio, (C ? -C?) To L-silylsulfinyl, phenylsulfinyl, (C-C?) Alkylsulfonyl and femls-l-phonyl; with the proviso that: G and Gz are not both hydroxy at the same time; G3 and G * are not both hydroxy at the same time; Ga and Gß are not both hydroxy at the same time.