MXPA97002734A - Benzopiran and benzochondensite compounds, its preparation and its use as antagonists of leukotrienob4 (lt - Google Patents

Abstract

This invention relates to a novel benzopyran and to other B4 antagonists of benzocondensated leukotrienes (LTB4) and to pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing said compounds, and to a method of using said compounds as LBT4 antagonists. The compounds of this invention inhibit the action of LTB4 and, therefore, are useful in the treatment of diseases induced by LBT4, such as inflammatory disorders, including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis and other skin disorders such as eczema, erythema, pruritus and acne, apoplexy and other forms of reperfusion ailments, graft rejection, autoimmune diseases, asthma and other conditions in which a significant neutrophil infiltration occurs

Description

BENZQPIRNNQ AND COMPOUNDS BENZQCQNPENSRPQS, ITS PREPNANCY AND ITS USE CQGIQ ANTAGONISTS PE LEUCQTRIENQ B (LTB? ANTECEPENTES PE LÂ INVENTION This invention relates to a novel ben opium and other benzyl, benzene, 7-condensed (LTFU) antagonists, to pharmaceutically acceptable salts of said compounds, to pharmaceutical compositions containing said compounds and to a method of using them. said compounds as LTtU antagonists. The compounds of this invention inhibit the action of LÍB *. and, therefore, are useful in the treatment of LTB4-induced diseases such as disorders, including rhematoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis and other skin disorders, cone, eczema, erythema, pruritus, cne, apoplexy, and odor forms of roper fusion, rejection of grafts, diseases Asina and other conditions in which there is a significant infl ull ration of neutrophils In the publications of European Patents 27f) 064 and 292977 BA antagonists of le cotppenos are described which refer to ad phenyl ethers, benrophenones and other compounds containing two phenyl groups, and derivatives thereof 7- (3-a Lcox? -4 -a canoil pheno i) alkoxyben opium, respectively.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to a new benzopyran and to other benzocondensated leucotropic antagonist compounds (LTB), of formula position 1 position 2 and pharmaceutically acceptable salts thereof, wherein ñ is 0, CHa, c- > , NH O IMyalkyl CfO *); 0 = is Rs is selected from the group consisting of - (CHs ») r? CHXc * X s, - (CH2) nX: O, and -0 (CH2) qX o; where n is ü, 1, 2 or 3; q is f], 1, or 2; X "is hydrogen, C *-Cß 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 fluorine, chlorine, C -C alkyl, C 1 -C 4 alkoxy, C 1 -C 6 perfluoroacyl, C 1 -C 6 perfluorocalkoxy, C 1 -C 6 alkyl, C 1 alkyl 0"¿) sul f'inyl, fen lsul fyl, (Ct-C6 alkyl) sulphonyl, and p-sulfonyl; X D is hydrogen, C -C alquilo alkyl, C-C ciclo cycloalkyl or one of the following optionally substituted rings: phenol, thienyl, pindyl, funyl, naphthyl, quinolyl, isocmolyl, pyrirnidyl 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 -C alkyl? C 1 -C 6 alkoxy, C 1 -C 6 perfluoroalkyl, C 1 -C 6 perfluoroalkoxy, C 1 -C 6 alkyl, C 1 alkyl C 2 sulfuyl, phenylsulfonyl, C 1 -C 5 alkyl sulfone 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, C -C alkyl, Cx-Cei alkoxy, perfluoroalkyl Cx-C and perfluoroalkoxy Cx-C_., ( alkyl Ox-C 's) t.o, (alkyl C -C «i) e? lfíni lo, feni lsu fm lo, (alkyl C -Ctó) sulfon? Lo and fem 1 cul fomlo. Rß and R? are, each independently, hydrogen or C 1 -C 4 alkyl or R 2 and R 7 are taken together with the carbon atom to which they are attached and form cycloalkyl C 2 -C 4 R is selected from the group consisting of in tetrazolyl, carboxy, cis or trans - (CHa) m -CX = CX2-C02H, - (CHO) mCX3X * Xí3, - CO ~ NG G: - and a five or six membered substituted aromatic ring optionally having one or two heteroatoms in which the heteroatoms are independently selected from the group consisting of 0, S and N; in the u3 m is 0, 1 or 2, - Y is 0, C \ - \. , S, NH or N (CX-C alkyl?); X1 and Xa are each independently hydrogen or C -C alkyl; X3 and X? are, each independently, hydrogen or C -C? alkyl, or X3 and X * become together with the carbon atom to which they are attached and form C3-C? cycloalkyl?; Xa is hydroxy, carboxy, tetrazolyl or -C0-NG G *; X * is car: > ox ?, tetrazolyl, CHa0H or -C0 ~ NGaG ?; G, G2, G3, G *, Gs and G *, each independently, are selected from the group consisting of hydrogen, CX-C alkyl, perfluoroa Cx-C * alkyl, (CX-C?) Alkyl sulfinyl, femlsul fmyl, (C -Cs alkyl) -sulfoyl, femlsulfonyl, hydroxy, phenyl and femlo substituted with (0a-) »; where a is 1 or 2; Q, in each case, is independently selected from the group consisting of fluorine, chlorine, C 1 -C 6 alkyl, C 1 -C 6 alkoxy perfluoroalkyl C v, perfluoroalkoxy C x -Cv, (C 1 -C 6 alkyl) -thio, (alkyl) C - s) sulium, pheni sulfimyl, (C x Ct alkyl) sulphonyl and phenylsulfonyl; the five or six membered substituted aromatic ring is substituted by a substituent selected from the group consisting of carboxy, tetrazolyl, -CO-N (H) (SO ^ -X7 '), -N (H) (S02-X ^), -N (H) (CO-X? And N (H) (CO-OX7) and by one or two substituents selected, each independently, from the group consisting of fluorine, chlorine, C -C? Alkyl, alkoxy, CiC * , C 1 -C perfluoroalkyl, CX-C perfluoroalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkyl, sulfinyl, isulfimyl, C 1 -C 4 alkylsulfonyl and femlsul fomyl; X "" is hydrogen, -CH3F, ~ CHF3, -CF3, C -C6 alkyl, 6, C3-C3 cycloalkyl or one of the following optionally substituted rings: phenyl, thienyl, pindyl, fuplo, naphthyl, quinolyl, isoquinolyl, pyridine idinyl or pyrazinyl, 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, Cs alkoxy, C 1 -C 4 perfluoroalkyl, fluoroalkoxy Cx-C-v, (Cx-C?) t? o alkyl, (C-C) alkyl sulphloyl, femlsulfinyl, (C? -s.) alkyl sulfonyl, phenylsulfonyl and optionally substituted phenyl; wherein the optional substituted phenyl is optionally substituted with one or two substituents independently selected from the group consisting of fluorine, chlorine, Cx-Cs alkyl, Cx-alkoxy, perflucoalkyl CX-CU, perfluoroalkoxy Cx-C, C, s) t? O, (aLquilo Cx-Cs) sulf? N? What is it? C? - s) sulfonyl and phenylisulfoyl; R = is hydrogen, fluorine, chlorine, C 1 -C 4 alkyl, C 6 -C 6 alkoxy, C 1 -C 4 -fluoroalkyl, C 1 -C 4 perfluoroalcoxy (C 1 -C 4 alkyl,) t, o (C 1 -C 6 alkyl? ) sulfinyl, phenylsulphyl, (C 1 -C 5 alkyl) sulfonyl or phenylsulfoyl; with the conditions that: Gx and G58 are hydroxy at the time; G3 and G * ro are hydroxyl at the same ti mpo; Ga and G * are not hydroxy at the same time; Rx is not phenyl substituted by carboxy, tetrazole or 1 CO-NH-Oz-X "7 when Rx is in position 1 or position 2, and Rx is not carboxy, cis or trans - (CH2) m-CX = CX: z-C02H, - (CH2) mCX3X Xs or wherein X * is carboxy, tetrazolyl or CHaOH, when R is at position 1 or position 2. A preferred group of compounds are those compounds of formula I or a pharmaceutically acceptable salt thereof, wherein Oz is / 'D where R * and R? they are, each, hydrogen; and R, R2, ft and Rs are as defined above for the formula T. A more preferred group of compounds are those compounds of formula I or a pharmaceutically acceptable salt thereof, wherein fl is 0 or CH2; flz is wherein R * and R7 are, each, hydrogen; and R, Rz and Rs are as defined above for formula T. Also another more preferred group of compounds are those compounds of formula I or a pharmaceutically acceptable salt thereof, wherein ñx is 0 or CHa; A2 is wherein RA and Rt are, each, hydrogen; Rx is (CH2) mCX3X * Xs or a five or six membered aromatic ring substituted with a substituent selected from the group consisting of carboxy, tetrazolyl, -CO-N (H) (S02-X7 '), -N (H) (S02- X ^), -N (H) (CO-X "7) and ~ N (H) (CO-OX7 ') and with one or two substituents selected, each independently, from the group consisting of fluorine, chlorine, alkyl C ? -s, alkoxy d.-Cß; perfluoroalkyl Cx-C_v, per-L-CX_C_alkyl, (Cx-Cs) alkyl, C (-C_s) alkyl, sulfinyl, femlsulfinyl, (CX-C_ alkyl) sulphonyl and femlsul fonyl; and, Xa, X *, Xa, X "7, R52 and Rs are as defined above for formula R. A still more preferred group of compounds are those compounds of formula I or a pharmaceutically acceptable salt thereof, in those that fix is 0 or CHZ; O52 is wherein R * and R are, each, hydrogen; Rx is a femlo substituted with a substituent selected from the group consisting of carboxy, -N (H) (O ^ -X "7), -N (H) (CO-X" 7) and -N (HMCO-OX7-) and with one or two substituents selected, each independently, from the group consisting of fluorine, chlorine, Cx-Cs alkyl, CX-CA alkoxy, C -C ^ perfluoroalkyl, perfluoroalkoxy C -C ", (C -C alkyl), s) t? o, (alkyl Cx-C?) sulfinyl, femlsulfini lo, (alkyl Cx-C «s) sulfonyl and phenylsulfonyl; and X'7, Ra and Rs are co or have been previously defined for the formula T. An < : most preferred group of compounds are those compounds of formula I or a pharmaceutically acceptable salt thereof, wherein fl is O or CHa, - A3 is where R * and R? they are, each, hydrogen; R is a phenyl substituted with a substituent selected from the group consisting of carboxy, and -N (H) (SOa-X7") and with one or two substituents selected, each independently, from the group consisting of fluorine, chlorine, Cx- alkyl C ?, Alkoxy Cx-C 's, l' * perfluoroalkyl, Cx-C_v, perfluoroalcoxy and Cx-Cv, (Cx-C?) Alkyl, (CX-C?) Alkyl sulfinyl, femlsul f? N? it, (C 1 -C 2) alkylsulfonyl and phenylsulfonyl, and X "7, R 52 and Ra are as defined above for the formula r. Another more preferred group of compounds are those compounds of formula I or a pharmaceutically acceptable salt thereof, wherein ñx is 0 or CHa; fla is wherein Rβ and R7 are, each, hydrogen; Rx is a phenyl substituted with a substituent selected from the group consisting of carboxy and -N (H) (SOs.-X'7) and with one or two selected ingredients, each independently, from the group consisting of fluorine, chlorine, Cx-Cs alkyl, C?-C alco alkoxy, perfluoroalkyl.Lo C x -Cv, perfluoroalkoxy C -C *, (Cx-C «-alkyl) t ?o, (C?-C &&) alkyl sulfinyl, phenylsul finyl, ( Cx- alkyl C-sulfonyl and phenylsul onyl; Rs is - (CHS) r ^ HX ^ X110, wherein X ^ is hydrogen and Xxs is one of the optionally substituted rings defined above for formula T; and X7, and R2 are as defined above for formula T. A preferred group of compounds within the group of compounds mentioned above are those compounds in which n is 1 and? or is er? 0 0 feared substituted with fem or in the position for. And the most preferred group of compounds is the following group of compounds, wherein Rx is a phenyl substituted with a substituent selected from the group consisting of carboxy and -N (H) (S02-X'7) with one or two selected substituents , each independently, from the group consisting of fluorine, chlorine and perfluoroalkyl C -C. The present invention also relates to pharmaceutical compositions for the treatment of diseases induced by LTB ^, which comprise an effective amount of a compound of formula I, as defined above, or of a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof. pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for the treatment of anti-flushing disorders, eczema, erythema, pruritus, acne, stroke, graft rejection, autoimmune diseases and asthma, which comprise an effective amount of a compound of Formula I, as defined above, or of a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

The invention further comprises a method for the inhibition of receptor binding, functional inhibition and live inhibition of LTIU, which comprises administering to a patient in need of such inhibition an effective amount of a compound of formula I, as defined above, or of a pharmaceutically acceptable salt thereof. The invention includes methods for the treatment of inflammatory disorders, eczema, erythema, pruritus, acne, stroke, rejection of grafts, autoimmune diseases and asthma, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula T, as defined above, or a pharmaceutically acceptable salt thereof. The invention is also directed to intermediate compounds of formula 1A wherein fl is 0, CH ", 5, NH or N (alkyl C? -Cto); Ra is selected from the group consisting of - (CHs » - (CH2) nXxo, -0 (CHS!) C, CHX "X oy -0 (CH2) t, X s, where n is 0, 1, 2 or 3, q is 3, 1 or 2; X "is hydrogen, C -Cs alkyl or optionally substituted phenyl; wherein the optionally substituted femyl is optionally substituted with one or two substituents independently selected from the group consisting of fluorine, chlorine, Cx-Cs alkyl, Cx-C &alkoxy, perfluoroalkyl C -CU, perfluoroalkoxy C -C ^, ( alkyl C-C «s) t? o, (alkyl C? -C 's) sulf? n? lo, phenylsulfonyl, (Cx -i, Cslsulfonyl, femlsulfonyl, Xxo is hydrogen, Cx-Cs alkyl, Ca-Cβ cycloalkyl or one of the following optionally substituted rings: phenyl thienyl, pipdyl, fuplo, naphthyl, qumolyl, ioquinolyl, pipmidinyl or pyrazinyl, in which the optionally substituted rings are substituted Optionally with fluorine, chlorine, C -Cs alkyl, C-O alkoxy, perfluoroalkyl C -C_v, CX-C ^ perfluoroalkoxy, C -Cs) alkyl, C -C6 alkyl, sulfinyl, femlsul finyl, (C-C?) alkyl sulphonyl, phenylsulfonyl and optionally substituted phenyl; wherein the optional substituted phenyl is substituted Optionally with one or two substituents independently selected from the group consisting of fluorine, chlorine, CX-C alkyl, C 1 -C 6 alkoxy, C 1 perfluoroalkyl, C 1 -C 6 perfluoroalkoxy, C 1 -C 6 alkyl, s) t? o, (Cx-C alkyl) sulfinyl, ilsulfinyl, (Cx-C &) sulfonyl, and Phenylsulfonyl; R * and R7"are, each independently, hydrogen or Cx-C * alkyl, or ß and R "7 are taken together with the carbon atom to which they are attached and form cycloalkyl C4-C7; Rx is selected from the group consisting of tetrazole lo, carboxy, cis c trane - ( CHa ^ -CX ^ CX ^ -CO ^ H, - (CH2) mCX3X * Xa, -00-5 NGXG2, 1, and a 5 or 6 membered substituted aromatic ring optionally having one or two heteroatoms, wherein the heteroatoms are independently selected from the group consisting of 0, S or N; 15 in which rn is 0, 1 or 2; Y is 0, CHs ,, S NH or Nalkyl Cx-Cβ); Xx and X3 are each independently hydrogen or C -C alkyl; X3 and X * are each independently hydrogen or 2D Cx-C alkyl; or X3 and X * are taken together with the carbon atom to which they are added and form C3-C cycloalkyl; Xa is h? D "ox ?, carboxy, tetrazolyl or -C0-NG G *; X * is carboxy, tetrazolllo, CHa0H or -C0-NGaG *; G, G2, G3, G *, Ga and Grt are selected, each independently, from the group consisting of hydrogen, C-C, s, perfluoroalkyl CX-C, (Cx-Cs alkyl) sulfonyl, phenylsul or lo, (C- alkyl- C) sulfonyl, fonmyl, hydroxyl, femyl and phenyl substituted with (O1) »wherein a is 1 or 2, - Qx in each case is selected from fluorine, chlorine, alkyl Cx-Cs, alkoxy C -C, perfluoroalkyl C -C_, perfluoroalkoxy C -C < v, (C-Cs alkyl) t, or (C x -Cß alkyl) sulfimyl, phenylsulfinyl, (C 1 -C 4 alkyl sulphonyl and phenylsulphyl, the five or six membered substituted aromatic ring is substituted with a substituent selected from the group consisting in carboxy, tetrazolyl, -CO-N (H) - (SOa-X "7), -N (H) - (Oz-X7 !, -M (H) - (CO-X7) and -N (H) - (CO-Xr) with one or two substituents, each independently selected from the group consisting of fluorine, chlorine, C 1 -C 4 alkyl, C 1 -C 6 alkoxy, perfluoroalkyl C 1 -Ct, perfluoroalkoxy C 3 -C 6 ., (alkyl 0X-Cs) t? o, (Cx-Cs alkyl) sul finyl, phenylsulfinyl, (Cs-Cs-sulphonyl and phenylsulfonyl), wherein X7- is hydrogen, -CH-zF, CHF2, -CF, alkyl C -C, s, C3-C? Cycloalkyl, or one of the following optionally substituted rings: phenylthio, thienyl, pipdoyl, furyl, naphthyl, quinolyl, 1-soquinolyl, pyrirnidinyl or pyrazinyl, wherein the optionally substituted rings are substituted optionally with one or two substituyent.es seleccio independently of fluorine, chlorine, C 1 -C 4 alkyl, C 1 -C 6 alkoxy, C 1 -C perfluoroalkyl, perfluoroalkoxy, C 1 -C 4 alkyl, C 1 -Ct & Cs) sulfinyl, phenylsufinyl, (C? -C alkyl) sulfonyl, phenylsul onyl and phenyl optionally substituted; wherein the optionally substituted phenyl is optionally substituted with one or two substituents independently selected from the group consisting of fluorine, chlorine, C 1 -C 3 alkyl, C 1 -C 6 alkoxy, < s, perfluoroalkyl CX-CA, perfluoroalkoxy C -C *. (C alquilo-C)) alkyl, (CL-C 3 alkyl) sulfinyl, fem lsulfinyl, (C 5-Cs alkyl) sulfonyl, and phenyl sulforyl; R2 is pheogen, fluorine, chlorine, Cx-Cs alkyl, Cs-alkoxy, CX-C ^ perfluoroalkyl, C-C * perfluoroalkoxy, Cs-Cs alkyl) t, or (Cx- =) alkyl sulfinyl, phenylsul end it, (C-Ce alkyl) sulfonyl or femlsul fomlo; with the conditions that: x, - Gx and G2 are not hydroxy at the same time; G3 and G * are not hydroxy at the same time; Ga and 66 are not hydroxy at the same time; R is not phenyl substituted with carboxy, tetrazole or o-CO-NH-SOz-X7"when R is in position 1 or in position Rx is not carboxy, cis or trans - (CH2) m-CX = CX2-C02H, (CH2) mCX3X * Xa or wherein X * 5 is carboxy, tetrazolyl or CH2OH, when R is at position 1 or at position 2.

DESCRIPTION DETftl_ LflD DE Lfl INVENTION The term "C C-Cs alkyl", whenever used in the description and in the appended claims, denotes monovalent radicals of saturated, linear or branched aliphatic hydrocarbons, having one to six carbon atoms, such as methyl, ethyl , propyl, -butyl, hexyl, etc. Similarly, the terms cycloalkyl C.a-07 and cycloalkyl Ca-CB denote a cycloalkyl group having three to seven or eight carbon atoms, respectively, such as cyclopropyl, cycloalkyl, etc. When, in a compound of formula I, Ax is oxygen and A2 is a substituted methylene, the compound can be described as 3, 4-d? H? Drobenzop? Rano or chroman. The compounds of the invention have two asymmetric carbon atoms, indicated by asterisks in the following formula: The "stereos" can be designated with reference to the rotation R and > Yes, according to the conventional nomenclature. When reference is made here to S, R or R, S, means an enantiomerically pure compound, while S *, R * and R ~, * denote a "racemic nezcla." The invention also includes mixtures and optical isomers of formula T.

I-, According to a specific method of the invention, compounds of formula I are prepared, wherein Rx is - (CHa) mCX3X'iXa, wherein X3 and X * are as defined above for formula I , is 0 and Xa is carboxy, or esters thereof, by reacting compounds of the above formulas III and IV to form a compound of formula V, which is a compound of formula III in which the residue CF3S03 * > has been replaced by (CHO) mCX3X * C0: 2X7 ', wherein rn, X3, X * and X "7 are as defined above for formula I, followed by reduction and saponification to form certain compounds of formula I. The reaction of compounds III and IV is generally carried out in a solvent. Suitable solvents are ether-type solvents, such as tetrahydrofuran, diethyl ether, ethylene glycol, dimethyl ether and 1,4-d-oxane; apolar apolar solvents, such as dimethylformarnide, N, N-dirnetylaceta ida, acetonitop, dimethyl sulfoxide, hexarnetyl osphoramide and N, N-dimethylpropyl-urea; non-polar aromatic solvents, such as xylene, benzene, chlorobenzene and toluene; and halogenated solvents, such as rnetylene chloride, chloroform and dichloroethane. Suitable specific solvents are full x or a mixture of equal volumes of ethylene glycol, dimethyl ether and di-etho-amide. The temperature of the reaction varies from -78 ° C to 200 ° C depending on the boiling point of the solvent used and usually varies from about B0 ° C to about 150 ° C. L) The reaction can be carried out in the presence of a Le is acid, such as zinc chloride, aluminum chloride, magnesium bromide, tin chloride or titanium chloride. When present, the amount of Lewis acid ranges from about 0.05 to about 2 equivalents per mole 5 of compound III. The reaction is generally carried out with a palladium catalyst. Suitable palladium catalysts are tetrakietrifemlfosphine palladium, bis (benzonitide) -palladium chloride, allyl palladium chloride dimer, palladium chloride, or palladium acetate, palladium-on-carbon, and chloride-beta (acetonitrile). ) -palad? o. A specific catalyst comprises 5% by weight of allyl palladium chloride dimer or 5% by weight of b? S (benzon? Tlo) -palladium chloride. Generally, about 0.001 equivalent to one equivalent of 5 catalyst per mole of substrate is used. The reaction is generally carried out in the presence of a ligand foe, such as triphenyl os ma, tp-o_-tolylphosphine or tp-2-fur? lfosf ina in an amount of about 0, 1 to about 5, preferably 1 to 2 molar equivalents per mole of substrate used. The reduction of the compound of formula V is carried out in a conventional manner with sodium borohydride in an alcohol as solvent, at room temperature, to form certain compounds of formula I. The compounds of formula III, wherein Ra is - (CHa) nCHX "Xxs or - (CH2) r-X10, wherein n, X9 and Xxo are as defined above for formula I, can be prepared as described below from compounds of formula VI A compound of formula VI is reacted, in which Ax, A2 and 2 are as defined above for formula I, tumloromethane sulphonic anhydride (also referred to as triflic anhydride) in a suitable solvent such as ethylene chloride, presence of triethylamine, to form the corresponding tp-flato compound. The group Ra, when defined as - (CHs,) r, CHX9X or o - (CHa ») r, Xxa, can be introduced into the triflate compound by a two-step process, which comprises reacting it with an aldehyde of formula X ^ X aCH (CH2) r, _xCH0 or Xxo (CH2) n_xCH0 to form the corresponding alkene compound and then hydrogenate it. The reaction with the aldehyde is carried out in the presence of a pyrrolidine catalyst or with a hydrochloric acid catalyst in acetic acid. The hydrogenation is carried out with hydrogen and a palladium catalyst in a conventional manner. Generally, the compounds of formula VI can be obtained cocurrently. If not, they can be obtained by methods known to those skilled in the art. For example, the compounds of formula VI wherein A is oxygen and A2 is where Ra, R * and R? are as defined above for formula I, they can be obtained from 2 ', 4'-d? h? -drox? -3-chloroprop? ofenone substituted with R2 (hereinafter referred to as compound 1), that R2 is as defined above for formula I, by cyclization with sodium hydroxide. Compound 1 can be prepared from resorcinol substituted with R 2, wherein R 2 is as defined above for formula I, and 3-chloropropic acid, in Presence of an acid, preferably phthalic trifluororne-tabasic acid. The compounds of formula VI in which A is sulfur and A2 is i .. 'in which Ra, Rβ and R "7 are as defined above for formula I, can be obtained in a similar manner from' or 5 '-h? drox? -2' -sulfhídpl-3 -chloropro of nona substituted with R2, wherein R2 is as defined above for formula I, which, in turn, can be obtained from 3-hydroxyl substituted with R2 The compounds of formula VI in which A2 is wherein Ra, R * and R "7 are as defined above for formula I, and Ax is 0 or S can be obtained similarly by reaction of resorcinol or substituted 3-h? drox? t? ofenol 25 with R2, respectively, wherein R2 is as defined above for formula I, and 4-chloro- 77 butyric, and cyclization with sodium hydroxide. Compounds of formula III in which ß or R7"are not H are prepared from generally known or available compounds of formula V which are protected as the benzylic ethers under conventional conditions and reacted with aldehyde Je formula CHO (CH3) ) lJ - xCHX,!, X or CHO (CH3) u- X a, where X * 9 and X a are as defined above for formula I and u is 1, 2, 3 or 4, in the presence of Si (OCH3) ^ and Cs2C03 in DNF, as described in the bibliography, to form the corresponding alkene compounds The group Rs, when defined as -0 (CH2) <, CHX ** X au - 0 (CHa) "X a, in which q, X" and X s are co or have been previously defined for formula I, can be introduced into a compound of formula II, wherein R, R2 and Ax are as defined above for formula I and A2 by the procedure outlined below. The compounds of formula X ? (X) in which Rx, R2 and Ax are as previously defined for formula I and X is a covalent bond, they can be prepared from the compounds of formula IX by mixing said compounds with 20% potassium hydroxide and adding phenyl diacetoxyiodide. The compounds of formula X when combined with Br (CH2) clCHX, * Xxtl or Br (CHa) "X or in which q, X" and X? O are as defined above for formula I, form the corresponding ether compounds which are then deprotected by hydrolysis with an acid such as hydrochloric acid to give the corresponding ketone compounds. By reducing the ketone compounds, as described above for the reduction of the compound of formula V, compounds of formula I are formed. Compounds of formula III in which Ra is as defined above for formula I can be converted into compounds of formula I wherein R is (CH =) mCX = CX2-CO = H, wherein rn, Xx, and X2 are co or have been previously defined for formula I, according to the following sequence of reactions. A compound of formula III is reacted with (CH3) 3SnSn (CH3 i a and a palladium catalyst such as tet rkistriphenylphosphine-palladium CPd (PPh3)] in the presence of a phosphine ligand, as described above for the reaction of compounds of formulas III and IV, to form the corresponding tpmethyltin compound. The rimethyltin compound is reacted with a compound, protected by an ester, of formula X ^ Os-CX ^ -CX3-- (CH2) mZ, wherein X "1, X2, X" 7 and rn are as have previously defined for formula I and Z is iodine, bromine or CF3S03, to form the corresponding ketone ester compound in which X "7Oi2CX2C-CX (CH:?)", - has displaced the remainder of p-methylmethane The coupling reaction is carried out in the presence of a p-ation catalyst, such as bis (tnphenylphosphine) -palladium chloride, as described above.Ketone ester compounds are reduced to the corresponding hydroxyl compounds and then the corresponding acid of formula I is hydrogenated, the reaction is carried out with sodium borohydride, generally the reduction is carried out in a solvent, suitable solvents are lower alcohols having one to six carbon atoms, lower alcohols organic solvents such as tetrahydrofuran or dioxane, and mixtures of lower alcohols compatible with water or other organic solvents niscibles with water and water. The solvent is preferably a lower alcohol such as methanol or ethanol. The temperature of the reaction generally ranges from about -78 ° C to about 100 ° C, and usually from about 0 ° C to 7 Approximately 25 ° C. The reduction step originates a stereoisomeric mixture of the ester compounds of formula T, which have the following structures: trans c These cis or trans isomers can be separated by conventional column chromatography. Compounds of formula I, wherein Rx is carboxy L and R2 are hydrogen, can be prepared from intermediate compounds of formula III, by first replacing the group CF3-S03- with rnetox Lcarbonyl and then hydrolyzing. The substitution reaction is carried out with carbon monoxide in the presence of pa.adio acetate, 1,1'-b? S (diffe ilphosfma) ferrocene (DPPF), methanol and triethyl sheet. The hydrolysis is as described above. The compounds of formula I in which R is - (CHs) mCX3X * Xa, wherein n, X3, X * and Xa are as defined above, will be referred to hereinafter as compounds of formula XXI (not shown) . Although the following chemistry describes the preparation of compounds in which Rx is - (CH =.) RnCX3X '* CO?, CaH-1, one skilled in the art should readily understand that the same chemistry is applied to compounds that have an R other than - (CH3) mCX3X * COa.C2.H., b, defined by the formula I, which are inert under the reaction conditions specified below. The starting material of formula XVI is a compound of formula II above, in which Rx is - (CH?) RnCX X'iXa in which Xa is a carboxyethyl ester and rn is 0. The preparation of this material game has been described above.

ESQUE? R I lu The compounds of formula XVII are converted by successive reactions with (1) acrylonitrile, (2) hydrolysis with concentrated hydrochloric acid, and (3) cyclization with polyphosphoric acid to form the compound of formula XVIII. The introduction of the group Ra to form compounds of formula XIX as described above. Hydrogenation e Hydrolysis of the compound of formula XIX are as described above. Can compounds of formula XVII be prepared from acido 3-hydrox? fen? lacet? co by introducing groups X3 and X by known methods. The part material of XVI, where m is 0, 1 or 2, A2 is and Aa is 0, S, MH or N-C-alkyl, s), can be prepared by reacting the compound of formula XVII with BrCH2CN or BrCHaCHsjC in step (1) of Scheme I and then reacting as described above with reference to Scheme I. Fl starting material XVI in which A is CH2, m is 0, 1 or 2 and A2 _? s It can be prepared as described below. A substituted benzene is reacted with - (CH2) m- CX3X ** C02CaHa, wherein m, X3 and X are as defined above for the formula I, with a rhonoester of acid monochloride of rnalonic acid, succinic acid or glutapco in the presence of a Friedel Crafts catalyst, such as aluminum chloride. The resulting ketone is converted into the corresponding propylendithiol with propylendithiol and tp boron fluoride as a catalyst. The formed compound is reduced with Raney nickel and then saponified. The ring is formed with polyphosphoric acid to produce the bicyclic compound XTX. The introduction of the Ra group is as described above. It is possible to prepare compounds of formula XXT, wherein Xa is C02h, by saponification of a compound of formula I in which R is - (CH =,) mCX: 3X * COs.CH:? ,, in which rn, Xa and XA are as defined above for formula I, the preparation of which has been described above. Compounds of formula XXI can be prepared, wherein Xa is OH, rn is 0, 1 or 2, and Xa and X * are each hydrogen, by conventional hydrogenation with lithium aluminum hydride of a compound of formula I in the that R is - (CH2) mC02CH3, wherein n is 0, 1 or 2. Compounds of formula XXI can be prepared, wherein Xa is OH, m is 0, 1 or 2, and X3 and X * are each alkyl, by reacting the corresponding compound in which X3 and X are hydrologized with an equivalent of a Grignard reagent containing a group X3, for example, X MgCl, followed by an equivalent of a Gpgnard reagent containing a group XA, for example, X * MgCl. Compounds of formula XX E, in which Xa is OH, is 0, which is 2, and X3 and X * are taken together to form cycloalkyl Ca-C ^, by reacting the corresponding compounds in which R and Ra are hydrogen with a Gpgnard reagent derived from a dihaloalkane Ca-C-7, eg, ClMalkylcan Ca-C7) r1gCl. Compounds of formula I, in which Rx is wherein X * is carboxy, tetrazolyl, -CONGaGβ, in which Ga and G * are as defined above for the formula r, or CH = 0H; is O, S, NH or NHÍalkyl ^ -C?); and rn is 0, 1 or 2, by reacting a compound of formula with a tp flato compound of formula I in R is CF3S03CH2 (CH2) r? -, in the presence of a base such as triethylamine or sodium hydride, in an inert solvent of the reaction. Tri-flats can be prepared by reacting triflic anhydride with the compound of formula XXI at 0, 1 or 2; X3 and X are hydrogen; and Xa is idroxyl, the synthesis of which has been described above. The compounds of formula I wherein R is -C0NGxG2, wherein Gx and G2 are co or as defined above for formula I, can be prepared by taking the corresponding compound wherein R is carboxy, and reacting it with a amine of formula NHGXG2.

SCHEME. II The compounds of formula XIV, wherein A, A2 and R2 are as defined above for formula I, are formed by reaction of compounds of formula III with (CHa) SnSn (CH3) a and a palladium catalyst, such as tetra istpfeml phosph-palladium ÜPd (PPh _,) ^] or bs (benzonitoplo) -padium chloride, in the presence of a phosphine ligand, such as triphenylphosphine, in a amount of about 0.1 to about 5 molar equivalents per mole of substrate used. The compounds of formula XIV are converted to a compound of formula XV by reaction with a compound, protected by an ester, of formula wherein X is C, CH, N, 0 or S; Kx is carboxy, tetrazolyl, -CO-N (H) (SOz-X "7), -N (H) (S02 ~ X ^), -N (H) ICO-X ^) or N (H) (CO -OX7); K2 is F, Cl, C -C alkyl, C-CA alkoxy, perfluoroalkyl, Cx-C .. ,, perfluoroalkoxy C-L-C, *, (Cx-C?) Alkyl, (C -C alkyl) sulfinyl, phenylsulfim, (alkyl) sulfonyl or phenylsulfonyl; 1 is 1 or 2; and Z is iodine, bromine or CF3S03. The coupling reaction is carried out in the presence of a palladium catalyst, such as tetrakistri phenylphosphine palladium or b? S chloride (t rifemlfosphine) -palladium. The hydroxyesters of formula XVI are also prepared by the method described in Scheme III (indicated below), wherein the oxazolm containing compound XXII or its heteroaromatic analogs defined above are treated with an alkyl-1 t 10 reagent, preferably n-BuL, at a temperature of -20 ° C to -78 ° C, preferably -78 ° C, in an inert solvent, such as toluene, ether, tet rahírofuran Or netylene chloride, preferably toluene, to provide an intermediate reactive reagent (not shown). Then, the intermediate reagent is treated with ZnCl ^ (pure or in an ether solution) to give the XXIII aluminum reagent. The reagent of aplzmc is reacted, without isolation, with compounds of formula III in the presence of a catalytic amount of a catalyst, particularly a palladium catalyst which is any palladium source that provides palladium (Pd °) under the conditions of the reaction , such as tetrakistriphenylphosphine palladium. The reaction is usually carried out at, or approximately, the reflux temperature of the solvent used, preferably as appropriate. 75 ° C. Generally, the reaction time is approximately 1 to 24 hours, preferably about 3 hours, to form the oxazole n-ketone XXIV. The oxazoline containing ketone XXIV is reduced with NaBH under conventional conditions. The cis and trans isomers are separated and the mixture of the forers is resolved as described above for the hydroxyesters. The dissociation of the oxazoline moiety can be carried out by treating the hydroxyanaloge XXV with an excess of methyl iodide at 23 ° C, at the reflux temperature, for 1 to 3 days, preferably 2 days. The solid salt of irinium is isolated by evaporation of the 3 ) excess of methyl iodide and buffer? The base is an alkali metal base in water or a mixture of water and a co-solvent such as a lower alcohol or 1HF, preferably methanol. Acid XXVI, wherein R2, A and A2 are as defined above for formula T, is used directly as an intermediate or is phylic with ethyl or neyl iodide in the presence of an inorganic base, preferably KOC0a , in a solvent such as acetone, acetonitrile or DflF, preferably acetone, to give the corresponding esters XVI.

SCHEME III XXV XXVI The ketone esters of formula XV are first reduced to the corresponding hydroxylcomposite XVI (not 1 its formula shown) and then hydrolyzed to the corresponding acid of formula I. The reduction is carried out with sodium borohydride, as has been described with reference to the reduction of the ketones of formula II. The resolution of the enan lomera mixture resulting after separation of the cis and trans isomers can be accomplished by methods known in the art. In one method, a compound of formula I, in which R contains a carboxyl group (COOH), is reacted with a chiral base such as ephedrine, in such a polar solvent or ether, to diastereomeric diastereomeric formations they are separated and converted after optically put acids or treatment with an acid such as aqueous or methanolic hydrogen chloride. In another method, a compound of formula I, wherein Rx contains an ester group of a carboxylic acid, is reacted with an optically active acid, such as R-mandelic acid or Nt-butoxycarbonyl-D-tpptophan, to form diastereomeric esters with the hydroxyl group which, after being separated, are converted into optically pure acids by treatment with a base such as sodium hydroxide in methanol or ethanol. The separation of the resolving ester group and the hydrolysis of the ester group of the carboxylic acid in R are conveniently carried out with an aqueous base such as an alkali metal hydroxide, for example, sodium hydroxide, at temperatures ranging from about room temperature to the reflux temperature of the solvent or mixture of solvents used. The reaction it can be carried out in the presence of a cosolvent such as methanol, ethanol or tetrahydrofuran. The compounds of formula I, where X * of the Rx group or of the aromatic substitution is equal to N (H) (CO-X "7), N (H) 5 (SOa-X" 7) or N (H) (CO-OX "7), can be obtained by reacting compounds of formula I in which Xa or * of the Rx group is carboxy or a substituted aromatic or heteroaromatic acid, with di phenylisophoxy azide in a solvent such as toluene, DMF, THF or dirioroethane, in the presence of benzyl alcohol and of an? '? Base amine such as pin dina, dn sopropiletiiarnin, pyrrole dao, preferably, tpetilarnin, at the boiling point temperature of the solvent used, for a time of 5-48. hours, preferably 16 hours.The product of this reaction is hydrogenated in a lower alcohol as solvent, in L5 the presence of a palladium catalyst, preferably Pd (OH) 3 / C, followed by acylation with the appropriate acid chloride, carbamoyl chloride or sulfonyl chloride. The synthesis methods outlined above, together with the following examples, describe methods that were used and can be used to prepare the compounds of this invention. Where possible, as can be ascertained by one skilled in the art skilled in the art, pharmaceutically acceptable cationic salts of certain compounds of this invention include, but are not limited to, those of sodium, potassium, calcium, magnesium, ammonium. , N, N'- dLbenciletiien liamina, N-rnef ílgl uca ma, ethanolami a and dietnolarnina. The pharmaceutically acceptable cationic salts of the compounds of formula I can be prepared by mixing a compound of formula I with an equivalent of a base amine or an alkali metal base. The compounds of the invention can be administered to mammals, including humans, for the treatment of LTB-induced diseases, by various routes, including oral, para-al and topical, including the use of suppositories and L'Ü enemas. In oral administration, dose levels of about 0.5 to 1,000 mg / day, more preferably about 5-500 mg / day, may be given in a single dose or divided up to 3 do LS. In intravenous administration, the dose levels are about 0.1-500 rng / day, more preferably about 1.0-100 mg / day. Intravenous administration may include a continuous drip. There may necessarily be variations, depending on the age, weight and condition of the patient to be treated and on the particular route of administration chosen, as it should be well known to those skilled in the art trained in this description. The compounds of the invention can be administered alone, but are generally administered in admixture with a pharmaceutical carrier or diluent, selected in relation to the intended route of administration and with conventional pharmaceutical practice well known to those skilled in the art. For example, they can be administered orally in form of tablets containing excipients such as starch or lactose, or in capsules, alone or mixed with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They can be injected parenterally, for example, intramuscularly, intravenously or subcutaneously. In parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salt or glucose to make the solution isotonic. The LTB_t activity of the compounds of the invention can be determined by comparing the ability of the compounds of the invention to compete with radiolabelled LTB at LTB receptor sites specific for guinea pig spleen membranes. The guinea pig spleen membranes are prepared as described by Cheng et al. (3. Pharmacology and Experimental Therapeut is, 222: 80, 1985). The aH-LTB4 binding assay. performed in 150 μl containing 50 nfl of Tris pH 7.3, 10 md of MgCla., 9% methanol, 0.7 nfl of H-LTB (from New England Nuclear, approximately 200 Ci / millimole) and 0.33 rng / rnl of guinea pig spleen membranes. Unlabelled LTB ^ at a concentration of 5 μM is added to determine non-specific binding. Compounds are added at varying concentrations to assess their effects on 3H-LTBA binding. The reactions are incubated at 4 C for 30 minutes. 3H-LTB4 bound to membrane is collected by filtration through glass fiber filters and the bound amount is determined by counting by scintiation, The ICsa value of a compound is the concentration at which 50% of the specific binding to 3H-LTB * is inhibited. The functional activity of the compounds of the invention can be determined in several ways using bioassays. Large and low-affinity forms of the LTB receptor have been described that bind differentially to leukocyte immunocytes and regulation of adhesion molecules., respectively. (3. U. Sterrnan, E. 3., Groetzl et al., 3. Irn a., 19T8, 140, 3.900-3.904). Chirocytoma to human neutrophils is measured as described by Horvath et al., 3. Immunol., 1987, 139, 3.055. The CD1 Ib regulation of human neutrophils is measured as described by P. Marder et al., Prostaglandins, Leukotriene Essent. Fatty Acids, 1991, 46, 265-278. In addition, compounds of formula I can be tested in vivo according to a method analogous to the method described by E. R. Pettipler et al., Bpt. 3. Pharrnacol ogy, 1993, 423-427, injecting LTB * into the dermis of guinea pigs and measuring the obstruction of neutrophil migrations in the skin by compounds of formula I administered orally. The following Examples illustrate the preparation of the compounds of the invention and should not be considered in any way as limiting the scope of this invention.

EXAMPLE 1 (3S.R) -7- (:? - TRIFLUO OMETTHNOSULFONILflHINfl-5-FLUOROFENIL) -4- HIPRQXI-3-FENILMETIL 2-H-1-BENZQPIRñNQ R. 2 ', 4'-Pih? O: roxi-3-ciorQprQPÍQfenpna To a stirred mixture of resorcmol (200 g, 1.82 mol) and 3-chloropropronic acid (200 g, 1.84 mol) tpfluoromethanesulfomco acid (1 kg) was added in one portion. The solution was heated slowly for about 45 minutes at approximately 80 ° C, and then cooled to room temperature in about 15 minutes and poured into chloroform (4.01). The p > Organic ore was slowly poured into water (4.0 1) and the layers were separated. The aqueous layer was extracted with chloroform (2x2.0 1). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo gave an orange sernisolide (244.1 g) which was used in the rough in the next step. NMR-XH (300 MHz, CDC13): 12.56 (1H, s); 7.63 (1H, d, 3 = 7.6 z): 6.37-6.46 (2H, m); 3.92 (2H, t, 3 = 6.3 Hz); 3.41 (2H, t, 3 = 6.3 H).

B. 7-HydroxylensiPiran-Qna To a cooled solution (about 5 ° C) of 2N sodium hydroxide (10.0 1) was added the compound of Example 1A (244.1 g) in one portion. The solution was heated to room temperature for approximately 2 hours using a warm water bath and then cooled again to approximately 5 ° C and the pH was adjusted to 2 with 6M sulfuric acid (1.2 i). The mixture was extracted with 3x3.0 1 ethyl acetate, washed with brine (1x2.0 1), dried over sodium sulfate and filtered. Concentration in vacuo gave a brown solid. Trituration with hexanes and filtration gave 173.7 g (58% yield) of the title compound of this Example IB. P.f. 136-137 ° C.

C. 7 - [(Tr? Fluc.roroethylsulfonyl) oxy] benzoDiran-4-one A ura stirred solution of the compound of Example IB (173.7 g, 1.05 mol) in methylene chloride (3.01) at about - 78 ° C were added tnetiiarnma (320 g, 3.16 moles) and di-ethylaminopipdine (2.5 g). After total dissolution, trifluoromethanesulphonic anhydride (327 g, 1.16 moles) was added dropwise in about 20 minutes, the material was stirred for about 30 minutes at about -78 ° C and then warmed 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 layer was extracted with 2x2.0 1 of ethylene chloride. The combined organic fractions were washed with water (1x1.0 1), dried over magnesium sulfate and filtered, the in vacuo concentration gave a red oil. Chromatography on silica gel (1 kg) eluting with hexane: ethyl acetate 8: 1 gave, after Separate the solvent, 211.1 g (69% yield) of the product of the epigraph. P.f. 43-44"C.

JL 7- [i (TriflyQrQme iIsulfQnil? Q? I] -3-phenyleneopentanPQranone To a stirred solution of the product of Example 1C (27 g; 91.2 milliliters) in 183 ml of methanol was added benzaldehyde (11.1 ml; 109 rnilinols) followed by pyrrolidine (9.1 rnl; 10 {) iliols). The mixture was stirred at room temperature overnight, cooled to about 0 ° C and filtered. The solid was washed once with 50 ml of ice-cooled methanol and then dried m vacuo; 35.2 g (yield 75Z) of the product of the epigraph of this example ID were recovered. P.f. 133-135 ° C. NMR-H (300 PHz, CDC13): 8.11 (1H, d, 3 = 8.7 Hz); 7.91 (1H, bs), 7.40-7.51 (2H, m) 7.24-7.38 (3H, in); 6.97 (1H, dd, 3 = 8.7 Hz, 2.4 Hz); 6.91 (1H, d, 3 = 2.4 Hz); 5.40 (1H, bs).

E- Z - [(5-F3.uorQ (2- (-dimethyl-2-Qxao-Iin? Lpfen? Ll-3-pheneime ilen-i-penzQpyran-l-Qna To a stirred solution of 2- (4- fluorofen?) -4,4-d? rnet? i-2-oxazole (1.0 equivalent in tetrahydrofuran; concentration 0.5M) at about -78 ° C, under Na`, was added n- butyl lithium in hexanes (1.1 equivalents, 2.5M solution) The mixture was stirred at about 78 ° C for about 1 hour and then ZnCl 2 was added. (ip solution in ether, 1.1 equivalents). The mixture was heated to approximately 10 ° C for about 1 hour to give 2- (4-fluorophen-1-2-chloroznec) -4,4-d? Et? I -oxazolma (which is not isolated) . To this solution were added 7-5 C ((t-pfluoromethyl-1-sulfonyl) -ox) -3-phenylmethyl-1-benzopran-4-one (1.0 equivalent) and Pd (PPh3) «( 0.02 equivalents). The mixture was refluxed (approximately 68 ° C) for about 3 hours, cooled to room temperature and poured into NHAC1 solution. The solution was extracted 3 times with Diethyl ether and the combined organic fraction were dried over ligSO ^. Filtration followed by removal of the solvent in vacuo and column chromatography (silica gel, hexane: ether 2: 1) gave the title compound of this Example 1F as a yellow solid. Performance 65%. P.f. 110-112 ° C. RHNH 5 (300 MHz, CDCl 3): 8.04 (1H, d); 7.91 (1H, s); 7.78 (1H, dd); 7.41-7.52 (3H, m); 7.31 (2H, d); 7.06-7.18 (3H,); 7.02 (1H, s); 5.40 (2H, =); 3.86 (2H, s); 1.31 (5H, s).

F. (3S * .4R *) - 7-C5-FlUQr0- (2- (4,4-dimethyl-2-Qxazolinyl) phen? 3-4- 0 hydroxy-3-phenylimethyl-2H-1-benzopyran To a stirred solution of the compound of Example 1E in THF (0, ip) at about 0 ° C was added dropwise, in about 10 minutes, liAlH *. (111 in ether, 2.2 equivalents) The mixture was heated to ternr > The mixture was cooled to approximately 0 ° C, cooled by immersion in Rochelle's salt. and filtered through diatomaceous earth. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO *. Filtration and separation of the solvent gave a yellow oil. Chromatography on silica gel (ethyl acetate: hexane) gave a yield of 60% of a white solid. P.f. 65-7D ° C (decomposes). Analysis calculated for Cs ^ HaJMOaF: C 75.15; H 6.07; N, 3.25. Found: C, 74.75; H b, 02; N 3.09. NMR-XH (300 MHz, CDCl 3): 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). fi * (3S * .4R "? - 7-y2-CarbQxi-5-fluorophenyl) -4-hydroxy-3-phenyl-methyl-2H-l-ben-QPiranQ The compound of step 1F is dissolved in iodide of Methyl (0.511) at room temperature and stirred for about 24 hours.Methyl iodide was separated m vacuo, the oily solid was dissolved in CH2C1S and the solvent was removed m vacuo.This operation was repeated to remove traces of iodide from The solid was dissolved in methanol (0.5M), 2N1 NaOH (0.5M) was added and the mixture was refluxed 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 brine and dried over flcono. solvent? r > vacuo, followed by chromatography (silica gel; etiienyl chloride: methanol 10: 1) gave the desired acid. Performance ^ 13%. RHN-XH (300 rlHz, CD3C0CD3): 7.80 (1H, dd); 7.48 (1H, d); 7.18 (7H, rn); 7.13 (1H, dd); 6.91 (1H, dd); ñ, T0 5 (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, rn).

Hl. (3S.4R) -7- (2-Carboxy-5-fluorophenyl) -4-hydroxy-3-phenylmethyl-2H-l-pen2QPiranQÍÍÍ The compound from step 1G is dissolved in diethyl ether (0.111) and heat to reflux. To the solution is added dropwise, in about 10 minutes, S (~) - rnethylbenzylamine (1 equivalent) in diethyl ether (Q, 1M). The mixture was cooled to room temperature and stirred for approximately 48 hours. The precipitated salt was filtered and then stirred again under reflux in diethyl ether (0.111) for about 24 hours, followed by filtration. The salt (mp 170-173 ° C) was taken up in ethylene chloride, washed 3 times with 111 HCl and then once with brine, dried over MgSO * 20 and filtered. Separation of the solvent jn vacuo and recrystallization (hexane: ether 1: 1) gave fine white crystals, plus 99.8% excess enantiomer by HPLC analysis. C «] n2a = +23.8; c = 0.6 in CHC13. P.f. 119-121 ° C. Analysis calculated for C23H 90 ^. F: C 73.01; H 5.06. Found: C 72.88; H, 4.715.

H2- (3R.451 -7- t? -Carbox? -5-? Luorophenyl) -4-hydroxy-3-phenylmethyl-2H-1-penzppiranp The filtrate from the combined salt suspensions of Example ID was washed three times with IM HCl and once with brine, and dried over MgSO. Filtration and separation of the solvent left a yellow solid. A procedure similar to that described in Example ID using R (+) rnethylbenzene gave the desired product. [a] D25 = -23.4 (c = 0.6 in CHC13). P.f.118-120 ° C. Analysis calculated for C: α3H «, 0? F: 0 73.01; H 5.06. Found C73.03; H 4.84. . (3S.4R) -7- (β-Carbobenzyloxyamino-5-fluoro-feroyl) -4-hydroxy-3-phenylmethyl-2H-1-penz, QpiranQ To a solution of the compound prepared in Example 1H1 (1 millirnol) in Example 1 nl of 1,4-dioxane were added 1.05 equivalents of diphenylphosphoyl azide, 1.1 equivalents of benzyl alcohol and 2.2 equivalents of triet ilamma. The mixture was refluxed for approximately 16 hours, the solvent was removed in vacuo and the residue was chromatographed on silica gel (hexane: Et? Ac 1: 1) to give the product N-CBZ (68% yield). RHN-XH (300 MHz, CDC1.3: 8.10 (1H, bs); 7.48-7.28 (11H, m); 7.05 (1H, dt; 3 = 7.1, 2.0 Hz), 6.97-6.83 (3H, m), 6.67 (1H, s), 5.17 (2H, s), 4.56 (1H, s), 4.27 (1H, dd) , 3 = 13.1, 1.8 Hz), 4.01 (1H, dd, 3 = 13, 2, 5, 0 Hz); 2.80 (1H, dd, 3 = .14.2, 7, 0 Hz), 2.58 (1H, dd, 3 = 14.2, 9.1 H), 2.40-2.22 (1H, m). i (3S .4R? -7- (2-Tri fluprpmetanpsulfpnilafflinp-5-f luprpfer i) -4-hydrox? -3-phenylmethyl-2H-1-benzydirane To a solution of the compound prepared in Example II in 10 ml of EtOH were added 0.05 weight equivalents of Pd (OH) s> and the suspension was hydrogen in a stirring apparatus ParrR for about 3 hours at 1 atmosphere. The mixture was filtered through Cel? TeR and the filtrate was evaporated. The yellow oil was redissolved in CHaCla (10 ml), cooled to approximately 0 ° C and added to the titepiarin (2.2 equivalents) followed by trifluorine-methanesulphonic anhydride (1.1 equivalents). After stirring for about 2 hours, 2 equivalents of solid NaOMe were added, the reaction was stirred for about 15 minutes and H20 (10 mL) was added. The pH of the mixture was adjusted to 2 with 0.111 HCl and then extracted with 3x10 rnl of EtOAc. The combined organic layers were washed with brine, dried over NgSO and filtered, and the solvent was removed in vacuo to give a yellow sernisolide. Chromatography on silica gel (EtOAc: hexane 1: 1-10: 1) gave the desired sulfonamide. P.f. 63-65 ° C.

AXIS? PLO 2 3S .4R-7 - (2-CQRBOXI-5-FLUORQFENIL) -4-HYDROXY-3- (4- PHENYLPHENYLNETHYL? -2H-I-BENZQPIRflNQ to. 7- [pnfluprpme ilsulfpnilrP * i3-3-U-phenyl phenylme il? -benzoDiran-4-pna To a solution of 7-C (tr? Fluoromet? Lsulfon? 1) ox? 1-3- (4-phenolfen? Lmet? Len) benzop? Ran-4-one, prepared analogously to the procedure described in Example ID, (30.2 g; 69.2 mmol) in 25 D ml of ethyl acetate, in a 500 ml ParrR shaker flask, 10% palladium on carbon catalyst (1.3 g) was added. The mixture was hydrogenated at 2.8 kg / cm2 until the evolution of hydrogen ceased after about 3 hours. The mixture was filtered through Cel? TeR to remove the palladium catalyst and cured on silica gel (hexanether) yielding 28.4 g (yield 94%) of the title product of this Example 2A. P.f. 110 ° C. RI1N-H (300 MH, CDC13): 8.01 (1H, d, 3 = 8.5 Hz); 7.20-7.35 (9H, m); 6.81-6.96 (2H, m); 4.42 (1H, dd, 3 = 11.6, 4.4 Hz); 4.22 (1H, dd, 3 = 11.6 Hz, 8.7 Hz); 3.26 (1H, dd, 3 = 14.0, 4.4 Hz); 2.90-3.05 (1H, m); 2.70 (1H, dd, 3 = 14.0, 8.7 Hz).

B. 7- (Trimethylstannyl) -3- (4-phenylmethylmethyl) enzoDiran-4-one To a stirred solution of the compound prepared in the Example 2A (10.95 g, 25.0 mmol) in 200 rnl of dioxane was they added lithium chloride (3.20 g, 75.0 ilirnols), Pd (PPha)., (1.15 g, 1.0 milliol), 3 crystals of butylated hydroxytoluene and hexamethyldies year (9.0 g; 27.5 millimoles). The mixture was refluxed for about 1.5 hours, cooled to room temperature and poured into 150 nl of saturated aqueous ammonium chloride solution. The mixture was extracted with 3x150 rnl diethyl ether and the combined organic fractions were washed with brine, dried over sodium sulfate and filtered. Evaporation in vacuo gave a yellow semi-solid which was chromatogenated on silica gel (hexane: ether 5: 1) to give 9.8 g (89% yield) of the product of the epigraph of this Example 2B. NMR-H (300 rHz, CDC13): 7.85 (1H, d, 3 = 8.7 H); 7.18-7.37 (9H, m); 7.14 (HI, d, 3 = 8.7 Hz); 7.11 (1H, s); 4.38 (1H, dd, 3 = 11.6, 4.5 Hz); 4.17 (1H, dd, 3 = 11.6 Hz, 8.4 Hz); 3.28 (1H, dd, 3 = 14.0, 4.4 Hz); 2.84-2.95 (1H, rn); 2.71 (1H, dd, 3 = 14 Hz, 3 = 11.0 Hz); 0.31 (9H, s).

Q 7- (2-Carboethoxy-5-fluorophenyl) -3-β4-phenylphenylmethyl) -penz.ppiran- -poa To a stirred solution of the compound of Example 2B (8.28 g, 17.5 mmol) in dimethylformamide (DMF) (35 mL) were added Pd (PPh3) 2 Cl2 (490 ng, 0.7 mmol), 3 crystals of BHT and 2-iodo-5-fluorobenzoate ethyl (5.4 g, 19.1 rmlimoles). The mixture was stirred at reflux for about 1.5 hours, cooled to room temperature and poured into 150 nill of saturated aqueous ammonium chloride solution. The mixture extracted with 3x150 rnl of diethyl ether and the combined extract was washed with 2x100 ml of water and then with brine. The solution was dried over sodium sulfate, filtered and evaporated m vacuo to give a yellow oil. Chromatography on silica gel (eluting with hexane: ether 4: 1) gave 6.51 g of the title compound of this Example 2C as a viscous oil. NMR-XH (300 MHz, CDC13): 7.95 (2H,); 7.28-7.65 (9H, rn); 6.92-7.22 (4H, m); 4.49 (1 H, dd, 3 = 11, 6, 4, 5 H); 4, 29 (1H, dd, 3 = 11.6, 8.5 Hz); 4.15 (2H, q); 3.31 (1H, dd, 3 • = 14.0, 4.4 Hz); 2.91-2.99 (1H, rn); 2.73 (1 H, dd, 3 = 14.0, 11.1 Hz); 1.20 (3H, t).

JL 7- (2-Carppe ^ p? I-5-fiuprpfer? Il) - ^ - idrp? I -3-phenyl-feniimet.ii) pengppjrno To a stirred solution of the compound described in Example 2C (6.60 g, 17.5 mmol) in 35 ml of methanol at room temperature was added sodium borohydride (940 g, 26.0 mmol) in one portion. The dark mixture was stirred at room temperature for about 2 hours, then poured into saturated aqueous ammonium chloride solution (75 ml) and extracted with 3x75 ml diethyl ether. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a yellowish oil. Chromatography on silica gel eluting with hexane: ether 4: 1 gave first 3.26 g of the cis ring isomer of L composed of the epigraph of this Example 2D, and then 1.98 g of the trans isomer of the title compound of this Example 2D, in the form of viscous oils, total yield 81%. I shallow of the cis ring: NMR-H (300 tHz, CDC1-3): 7.95 (1H, dt); 6.8-7.61 (14H, rn); 4.58 (1H, t, 3 = 7.2 H); 4.28 (1H, dd, 3-9.1, 2.5 H); 4.03 (1 H, dd, 3 = 9.1, 5.4 H); 4.15 (2H, q); 2.78 (1 H); 2.77 (1H, dd, 3 = 13.7, 6.2 Hz); 2.58 (1H, dd, 3 = 13.7, 9.1 HZ); 2.20-2.29 (1H, rn); 1.83 (1H, d, 3 = 7.2 Hz); 1.1 (3H, t). Trans-ring isomer: RHN-H (300 rlHz, CDC13): 7.95 (1H, dt); 6.8-7.60 (14H, rn); 4.56 (1H, dt, 3 = 4.7, 3.8 H); 4.12-4.19 (2H, rn); 4.10 (2H, q); 2.90 (1H, dd, 3 = 13.6, 8, i Hz); 2.70 (1H, dd, 3 = 13.6, 7.2 Hz); 2,36-2,39 (1H, rn); 1.75 (1H, d, 3 = 4.7 Hz); 1.12 (3H, i).

E. Ester N - '- t-Pu picarcarnil-l-rip pfanp-7- [2-carppe p? I-5-fluprpphenyl? -3- -phenylphenylmethylf 3crpmanp- -ilp] A urja stirred solution of the compounds of Example 2D (2.6 g; 6j 7 millirnoles) in 70 rnl of CH3Cla were added DflAP (897 mg, 7.34 mmol, 1.1 equivalents), DCC (1.51 g, 7.34 nilimoles, 1.1 equivalents) and Nt-BOC-L-tryptophan (2.4 g, 8.01 millirnole) s, 1.2 equivalents). The mixture was stirred at room temperature for approximately 12 hours, filtered and stripped with lCl HCl and brine. The organic layer was dried over HgSO, filtered and concentrated in vacuo. Chromatography (silica gel; cyclohexane: ether: ethyl acetate) gave 860 mg of the less polar diastereomer (= 0.3) and 700 rng of the ditas you more polar mobile reomer (R-r = 0.2). Product less polar (3S, 4R): NMR-XH (300 tlHz, CDCla): 8.91 (1H, s); 7.92 (1H, dt), 7.0-7.6 (15H,); 6.8-6.92 (2H,); 6.22 (1H, s); 5.65 (1H, s); 5.16 (1 H, d, 3 = 8.4 Hz); 4.68-4, 82 (1H, rn), 3.90 (2H, q); 3.82 (1H, d?, 3.51 (1H, d); 3.39 (1H, dd); 3.1 (1H, dd); 2.45-2.61 (2H, rn); , 09-2.15 (1H, broad s), 1.49 (9H, s), 1.40 (3H, t), more polar product (3R, 4S): RP1N-XH (300 MHz, CDC13): 9.16 i 1 H, s), 7.96 (1H, dt), 6.85-7.65 (16H, m); 6.62 (1H, S); 5.91 11H, s); 5.08 (1H, d, 3 = 8.2 Hz); 4.55-4.60 (1H, rn); 4.12 (2H, q); 3.75-3.86 (2H, m); 3.5 (2H, rn); 3.28-3.38 (1H, dd); 2.90 (2H, s); 2.42-2.60 (2H, m); 1.39 (9H, s); 1.30 (3H, t).

F_. 3S.4R-7- (2-Carboxy-5-fluorophenyl) -4-hydroxy-3- (4-f: enyl-phenylmethyl) -? H-1-henzooiran To a stirred solution of the 4R, 3S ester of tpptophan minus of Example 2E (840 ng, 1.08 rnil) in 10 nl of methanol were added 10 rnl of 2H NaOH solution. The mixture was refluxed for about 8 hours, cooled and acidified to a pH of 4 with 1M HCl. The cloudy emulsion was extracted with 2x20 ml of ethyl acetate and the combined organic fractions were washed with brine and dried over rigS0A. Filtration and separation of the solvent m vacuo gave a yellow foam. Chromatography (silica gel; ethyl acetate: hexane: acetic acid 35: 75: 1) gave 210 mg of product. NMR-XH (300 tlHz, CDC13): 7.97 (1H, dt, 3 = 7.8, 1.7 H); 6.85-7.09 (14H, m); 4.54 (1H, d, 3 = 4.9 Hz); 4.22 (1H, dd, 3 = 9.1, r-, 7 2.5 Hz); 3.97 (1H, dd, 3 = 9.1, 5.4 Hz); 2.72 (1H, dd, 3 = 13.7, 6.2 Hz), 2.51 (1H, dd, 3 = 13.7, 9.1 Hz); 2.04-2.20 (3H, rn). Isomer (• -). Saponification, as before, of the more polar 3R, 4S ester of 5-tptoptophane (700 mg) gave the 3R, 4S enantiomer. NMR-H (300 riHz, CDC13): same RUN spectrum as the previous one. Isomer (-).

EXAMPLE 3 i flCIPQ 3- (-FENYLPHENYLNETHYL) - ^ - HIBRQXICRQH N-7-IL? - (2- CICLQPENTENQ) -1-CflRBQXILICQ R. 3- (-phenylphenylmethyl) -crpman-7-ylr-l-acetatp From Etilp b? S (acetomtrile) -palladium-15 (II) chloride (173 mg, 0.45 mmol), tri- o-tolylphosphma (690 mg, 2.26 mmol) and the compound of Example 2A (2.1 g, 4.52 mmol) in dioxane (20 mmol) was stirred for approximately 5 minutes, then one third (1 ml) was added. , 33 g; 4.57 milliards) of the total amount of ethylenetrnnylsilylketone acetal together with ZnCl2 (2.3ml, 1.13nilirnols) and DfF (20ml). The resulting mixture was heated to reflux (bath at 130 ° C). After approximately 15 minutes, a second aliquot of silyl ketone acetal was added (L, 33 g, 4.57 ilimoles) (1/3 of the total). After approximately another 30 minutes, the final aliquot (1.33 g, 4.57 mmol) was added and the resulting mixture was stirred at reflux for about two hours. The resulting dark brown solution was cooled, cooled by immersion in saturated NH 4 Cl solution and extracted with CH 2 C 12. The combined extracts were washed with brine, dried over MgSO *, filtered and evaporated. Flash chromatography of the residue, eluting with 6: 1 hexane: ethyl acetate, gave 180 ng of the desired product as a light yellow viscous oil. RHN-H (300 MHz, CDC13): 7.91 (1H, d, 3 = 3.3 Hz), 7.63-7.20 (9H, r), 6.98 (1H, d, 3 = 8 , 3 Hz), 6.92 (1H, s), 4.42 (1H, dd, 3 - 10.1, 5.1 Hz), 4.26-4.12 (3H, m), 3.62 (2H, s), 3.32 (1H, dd, 3 = 14.1, 6.2 Hz), 3.05-2 , 88 (1H, rn), 2.76 (dd, 3 = 14.1, 10.0 Hz), 1.28 (3H, t, 3 = 7.0 Hz). £ _, 3- (4-Phenylphenylmethyl? -Ihydrpxicrpmar -yl) -1-acetatp de.

To a solution of the ketone of Example 3A (0.45 nilimoles) in MeOH-methylene chloride (15 ml approx 2: 1) at about 0 ° C was added NaBH * (17 g, 0.45 mmol). After stirring for about 1.5 hours, the reaction was cooled by immersion in NH 4 Cl solution, extracted with CH 2 Cl 2, washed with brine, dried over MgSO 4, filtered and evaporated. Flash chromatography, eluting with hexane: ethyl acetate 4: 1, yielded 160 mg of the cis alcohol followed by 90 mg of the desired trans alcohol as a yellow-white colloidal solid.H NMR (300 11Hz, CDCla) of the trans alcohol: 7.65-7.23 (11H, rn); 6.91 (1H, d, 3 = 8.0 H); 6.83 (1H, s); 4.54 (1H, s); 4.30-4.22 (3H, rn); 4.02 (12H, dd, 3.5 Hz); 3.58 (2H, s); 2.77 (1H, dd, 3 = 14.0, 6.8 Hz); 2.58 (1H, dd, 3 -14.0, 9.8 Hz), 2.33-2.21 (1H, rn); 1.28 (3H, t, 3 = • 7, 1 Hz).

Ethyl 3- (4-phenylphenylphenyl) -4-t-butyldimethylsilyloxyroman-7-yl) -1-acyl To a solution of the alcohol rans prepared in Example 3B (90 rng, 0.22 millinole) in DMF (1.0 nl) was added amidazole followed by t-butyldirneflysilyl chloride (335 μl, solution I, OM in CH ^Cls, 0.335 mmol). After stirring overnight at room temperature, the solution was diluted with water and extracted with ether. The combined extracts were dried, filtered and concentrated. Flash chromatography, eluting with hexane: ethyl acetate 6: 1, gave 80 mg of a light yellow viscous oil. RMN-XH (300 HHz, CDC13): 7.66-7.21 (9H, rn); 7.23 (d, 3 = R, 1 H); 6.87 (d, 3 = 8.2 Hz); 6.82 (1H, s); 4.45 (1H, s); 4.32 (1H, dd, 3 = 9.8, 2.1 Hz); 4.19 (2H, q, 3 = 7.1 HZ); 4.06 (1H, d, 3 = 9.8 Hz); 3.58 (2H, S); 2.57 (2H, d, 3 = 8.3 Hz); 2.15-2.05 (1H, m); 1.30 (1H, t, 3-7, D H); 0.88 (9H, s); 0.07 (6H, s).

JL 3- ethylphenylmethyl? - -t-putld? Methylsilp? Icrp an-7-yl? -2-cycloheptane) -l-carboxylic acid ethyl ester To a solution of the ester prepared in Example 3C (70 mg, 0.13 millyrol ) in THF (4 ml) at about 78 ° C was added potassium t-butoxide (150 μl, 1.0 M solution in THF, 0.149 rnil) followed by DMPU (0.8 ml). The mixture was stirred for about 15 minutes, after which cis-1,4-d-chloro-2-butene (19 mg, 0.149 mmol) was added. After about 1 hour, an additional amount of potassium t-butoxide was added and the resulting mixture was allowed to warm to room temperature and stir overnight. The reaction was cooled by immersion in saturated aqueous ammonium chloride solution and extracted with methylene chloride. The combined extracts were washed with water, dried, filtered and evaporated. Flash chromatography, eluting with hexane: ethyl acetate 8: 1, gave 14 mg of the desired product. NMR-H (300 HHz, CDC13): 7.62-7.18 (9H,); 7.11 (1 H, d, J = 8.0 Hz); 6.91-6.82 (2H, rn); 5.76 (2H, s); 4.45 (1H, s); 4.30 (1H, d, 3 = 9.7 Hz); 4.25 (2H, q, 3 = 7, .0 Hz); 4.02 (1H, d, 3 = 9.7 Hz); 3.40 (2H, d, 3 = 14.2 Hz); 2.77 (2H, d, 3 = 14.2 Hz); 2.77 (2H, d, 3 = 14.2 Hz); 2.57 (2H, d, 3 = 8.0 Hz); 1.20 (3H, t, 3 = 7.0 Hz); 0.87 (9H, s); 0.07 (3H, s); 0.04 (3H, S).

LM 3- (4-Phenylphenylmethyl) -4-hydroxy-roman-7-yl) - (2-cyclopentene? -l-carp? -licp acid To a solution of the ester prepared in Example 3D in methanol (2.0 ml) was added NaOH solution (1.0 ml) The mixture was heated to about 60 ° C for about 48 hours, after which it was cooled and acidified with 1N HCl solution. The mixture was extracted with methylene chloride and the combined extracts were dried, filtered and evaporated, and flash chromatography, eluting with 3: 1 ethyl acetate: hexane with 1% acetic acid, gave 5 mg of the desired acid H-NMR (300 MHz, CDC13). ): 7.62-7.10 (10H, r), 6.98 (1H, d, 3 = 9.0 Hz) j 6.90 (1H, s), 5.77 (2H, s); 51 (1H, s), 4.23 D (1H, dd, 3 = 12.2, 3.0 H), 4.0 (1H, dd, 3 = 12, 1, 5.0 Hz); , 40 (2H, s), 2.80-2.70 (3H, m), 2.57 (1H, dd, 3 = 14.0, 9.2 Hz), 2.32-2.17 (1H , rn).

AXIS? PLQS 5-9 The following compounds of formula were synthesized using methods analogous to the indicated methods.

(*) Using the compound of Preparation 1 and reacting it according to the methods described in Examples 1.3, gave this compound.

PREPRESSION 1 RCIPQ2- (6-BENCIL-5-HIDRQXI-5.6.7.9. -TETRñHIDRONRFTRLEN-2-I) - * - FmQRQBENZQICQ R. 2-Benc? Lidenp-6-metp? I-3. ^ - di idrp-2H-naphthalene-l-pna To a stirred solution of 6-rnetoxy-l-tetralone (227 millirnols, 40 g) and benzaldehyde ( 272 mmol, 27.5 ml) in 450 ml of methanol was added pyrrolidine (272 rnilirnols, 23.6 ml). The mixture was stirred at room temperature for about 4 days until TLC indicated that there was no starting tetralone. The mixture was concentrated in vacuo and then dissolved in EtOAc and washed with four portions of 10% HCl, two portions of saturated NaHCO 3 solution and one portion of brine. 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 Preparation IR. P.f. 100-102 ° C. Analysis calculated for CmHuiOa: 264.1146. Found: 264.1149.

B. 2-Benzyl-6-methoxy-3 -di idrp-2H-naphthalene-1-pna A Parr * hydrogenation bottle was charged with naphthalen-1-one (15 g), ethyl acetate (150 nl) and 1 g do not % palladium on charcoal. The mixture is hydrogenated on a ParrR stirrer for about 15 hours at a pressure of 1.4 g / cm2 of hydrogen. The resulting mixture was filtered through a Celite felt and concentrated in vacuo to give a red oil which was purified by flash chromatography (hexane: diethyl ether 3: 1) to give 14.1 g of benzyltrtralone. . P.f. 50-51 ° C. Analysis calculated for C18Hiß02: 266.1302. Found: 266.1300.

C. 2-Benzyl-6-hydroxy-3,4-dihydro-2H-naphthalene-l -one To a stirred solution of benzyltrtralone (5 g, 19 mmol) in ethylene chloride (40 ml), at about -78 ° C, boron tribromide (1.95 rnl, 21 millimoles) was ana- lyzed. The cooling bath was removed and the reaction mixture was stirred overnight at room temperature, after which an additional 1.5 ml of boron tri-romide was added. Stirring was continued at room temperature for about 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 four portions of methylene chloride. The layers were separated and the organic phase was washed with water and dried over anhydrous sodium sulfate. Filtration and separation of the solvent m vacuo gave a brown solid which was purified by flash chromatography (hexane: ether 3: 2) to give 3 g of the phenol. P.f. 160-162 ° C. Analysis calculated for C? 7H1 < s02: 252.1146. Found: 52, 1144? D. Ester of 6-benc? l-5-oxo-5.6 7.8-tetrahydronaphthalene-2-yl of the tpfluoromethanesulonic acid To a stirred solution of the phenol (2.75 g, 11 rnilirnoles), triethylamine (4.56 ml, 33 ylnol) and DNAP (0). 0.05 g) in netylene chloride (100 nl) at about -78 ° C was added p-fluoromethanesulphonic anhydride (2 ml, 12 mmol). The cooling year was removed and the reaction mixture was warmed to room temperature and stirred overnight.

Then, the mixture was poured into ice water and extracted with ethyl acetate. The resulting organic layer was washed with water, dried over anhydrous sodium sulfate and filtered, and the solvent was removed in vacuo. The crude product was purified by flash chromatography to give 3.9 g of tn flato. P.f. 52-53, 7 ° C. Analysis calculated for C aH ^ sO ^ SFa: 384.0638. Found: 384.0602. E. 2-Benzyl-6-r2-. 4-dimethyl-4,5-di nidrooxazol-2? L) -5-f luoro-phenyl] -3-dih; < Jrp-2H-naphthalene-1-pna To a stirred solution of n-butyllithium (3.6 of 2.5M solution in hexanes, 9-mmol) in toluene (10 i) at about -40 ° C was added dropwise drop, by means of a cannula, a solution of aploxazoline (1.76 g, 9 mmol) in toluene (5 ml). The mixture was stirred at about -0 ° C for about 0.5 hour and then warmed to about -25 ° C and stirred for about another hour. To this mixture was added CNT chloride (9 ml of a 1% solution of diethyl ether, 9 mmol). The cooling bath was removed and the mixture was warmed to room temperature and stirred for about 1 hour. The resulting mixture was added by means of a cannula to a tri-tetralone solution of tetralone (3.5 g, 9 mmol) and tet rakistp fem 1 phosphine-palladium (0.5 rulirnole, 0.63 g) in tetrahydrofuran. furano dro (15 rnl). The reaction mixture was refluxed for approximately 2 hours, cooled to room temperature and poured into saturated aqueous ammonium chloride solution. The aqueous mixture was extracted with three portions of ethyl acetate. The organic phase was washed with three portions of 1N HCl, saturated aqueous sodium bicarbonate and brine. Then, the organic phase was dried over anhydrous sodium sulfate and filtered, and the solvent was removed m vacuo. The crude product was purified by flash chromatography (diethyl ether: hexane 2: 1) to give 2.07 g of the coupled product. P.f. 114-115 ° C. An isis calculated for C ^ H ^^ O ^ F: 427.1948. Found: 427.1956.

F. 2-Benzyl-6-C2- (4,4-dimethyl-4,5-dihydrooxazol-2? L) -5-fluoro-phenyl] -! .2.3.t-tetrahydranaphthalene-1-Pl To a stirred solution of tetralonaoxazolma (1.5 g; 3.5 mmol) in ethanol (35 ml) was added sodium borohydride (0.20 g, 5.25 rni limoles). The resulting brown mixture was stirred at room temperature for about 1 hour and then poured into brine and extracted with three portions. of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed m vacuo to give 1.20 g of a 1: 1 mixture of cis and trans alcohols. P.f. 88-89 ° C. Analysis calculated for : 429,2087. Found: 429.2067.

S 0 £ idO Z? (6-encyl-5-hi-3rp? I-5.6.7. B-tetrahydren-phthalen-2-yl? - -fluprp en -picp Oxazolm (1.0 g, 2.34 mmol) was dissolved in 5 ml. of methyl iodide and stirred at room temperature for about 2 days, after which the methyl iodide was removed in vacuo, the residue was taken up in methylene chloride and concentrated to remove traces of residual methyl iodide. The dark red residue was dissolved in methanol (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 HCl. The resulting suspension was extracted with three portions of ethyl acetate and the combined organic phase was washed with brine, the organic phase was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give 0.80 g of the alcohol-carboxylic acid. ico NMR - ^ - H (250 nHz, methanol-d ^) or 7.83 (dd, 1H, = 7.0, 7.5), 7.50 (d, 1H, 3 - 7.0), 7.30-7.00 (in 9Hx2); 4.50 (d, 1H, 3 = 2.0); 4.41 (d, 1H, 3 = 8.0); 3.15 (dd, 1H, 3 = 5 4, 13.9); 3.00-2.57 (m, 4H); 2.42 (dd, 1H, 3 = 11.4, 13.5); 2 09-1.35 (m, 5Hx2).

Claims (15)

1. NOVELTY OF THE INVENTION CLAIMS A compound of formula and pharmaceutically acceptable salts thereof, wherein A is 0, CHa, S, NH or N (C ^ -C * alkyl); s is RS e selects from the group consisting of - (CH2) r, CHX, 'X: 10, - (CHs pX10, -0 (0H2,) aCHX *' X: LO and -0 (CH2) c) X o; wherein n is 0, 1, 2 or 3; q is 0, 1, or 2; X "* is hydrogen, alkyl d.-Cft or optionally substituted phenyl, wherein the optionally substituted phenyl is optionally substituted with one or two substituents selected independently of the group consisting of fluorine, chlorine, alkyl Cx-C ", alkoxy C -C? , perfluoroalkyl Cx-C_, perfluoroalkoxy C-0 ^, (CX-C?) alkyl, (C-C & amp;) -sulfmyl, femlsulfinyl, (Cx-f > C?) alkyl sul foni lo and femlsulfonyl; X1D is hydrogen, alkyl , cycloalkyl Ca-Cβ, or one of the following optionally substituted rings: phenyl, thienyl, pyridyl, furyl, naphthyl, < or nolyl, iso-juyl nolyl, pyriridyl or pirazanyl, in which the optionally substituted rings are substituted ll) optionally with one or two substituents independently selected from the group consisting of fluorine, chlorine, alkyl C 1 -C, C 1 -C 6 alkoxy, C 1 -CCA perfluoroalkyl, C 1 -C 0 alkoxy, C 1 -C 4 alkyl, C 1 -C 4 alkyl sulfonated, phenylsulfiyl, (alkyl C -C?) sul fon i lo, Phenylsulfoyl and optionally substituted phemmyl; where the phenusth it t. optionally optionally substituted with one or two substituents independently selected from the group consisting of fluorine, chlorine, CX-C alkyl, C 1 alkoxy, a, perfluoroalkyl Cx-C_v, perfluoroalkoxy C_-C_, (alkyl) 21) C3.-C &) t? O (Cx-C6 alkyl) sul finyl, phenylsulimethyl, (alkyl) Cx-C?) Sulfonyl and feni Isul fonil o; R * 5 and R7 are each independently hydrogen or Cx-Crt alkyl, or R * and R "7 are taken together with the carbon atom to which they are attached and form cycloalkyl C ^ -C-R1 is selected from the group 7 consisting of tetrazolyl, carboxy, cis or trans - (CHa) m- CX ^ CX2-C0sH, - (CH2) ", CX3X * XS, -C0-NGXG2, and a substituted aromatic ring of five to six members having one or two hoteroatornos option, in which the heteroatoms are independently selected from the group consisting of 0, S and N; where it is 0, 1 or 2; Y is 0, CH2, S, NH or Ni C -C alkyl?); X and Xs are each independently hydrogen or Ci-C * alkyl; Xa and X r, each independently hydrogen or Cx-Cs alkyl, or Xa and X * are together with the carbon atom to which they are attached and form C3-C7 cycloalkyl; X * 5 is hadroxy, carbox, tet razol i lo or -C0-NG3G *; Xtí is carboxy, tetrazolyl, CH ^ OH or -CO-NG ^ G *; G "3-, 62, G3, G * G-" 9, and G *, are each independently selected from the group consisting of hydrogen, alkyl Oi-Cei, perfluoroalkyl Cx-C_, (Cx-Cft alkyl) sul fmi lo, femls? lmi lo, (alkyl CX-C?) sul fonilo, phenylsul foni lo, hydroxy, phenyl and phenyl substituted with ()., *; where a is 1 or 2; In each case it is independently selected from the group consisting of fluorine, chlorine, C -C alkyl, Cx-C ^ alkoxy, perfluoroalkyl C -C_v, perfluoroalkoxy Cx-C_v, (C_C_s-alkyl) -thio, ( alkyl C? -C6) sulfimlo, feni Isul fimlo, (Cx alkyl- C?) Sulfonyl and > phenylsulfonyl; the substituted five-to-six-membered ring is substituted with a selected substituent on the group consisting of carboxy, tetrazole l, -CO- N (H) (SO. ^ - X7), -N (H) (SO-a- X'7), -N (H) (CO-X'7) and -N (H) (00- h OX "7) and with one or two substituents each independently selected from the group consisting of fluorine, chlorine , alkyl C, _- C ?, Cx-C ^ alkoxy, perf1 uoroa C 1 -C 4 alkyl, perfluoroalcoxy C x C 4, C 1 -C 6 alkyl, C 1 -C 6 alkyl C?) Sulphi lo, feni lsuif? N? Lo, (alkyl C-? -CA) sul foni lo y L l) phenylsulfonyl; where X? is hydrogen, CH? F, -OHF?, -CFJ, C -Cto alkyl, cycloalkyl Ca-CT or one of the following optionally substituted rings: phenol, thienyl, pipdyl, furyl, naphthyl, quinolyl, isoquinol lyo, pyrimidimide 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? -C alkyl, < s, C 1 -C 4 alkoxy, C 1 -C 6 perfluoroalkyl, C 1 -C 6 perfluoroalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkyl, sulfonyl, p-sulphonyl, C 1 -C 8 alkyl ») Sul fomlo, Optionally substituted temlsulfonyl and femlo; wherein the optionally substituted phenyl is optionally substituted with one or two of its agents independently selected from the group consisting of fluorine, chlorine, alkyl CU-C ?, Ct-C6 alkoxy, perfluoroalkyl, C -C «, perfluoroalkoxy C -C , , (I rent 2!; C -C?) T? O, (a.kyl Cx-C *) sul fimlo, fem 1 sul fi my, (alkyl C? -C?) Sulfon? L (; and phen lulul fonilo; R3 is hydrogen, fluorine , hB chlorine, C? -Cto alkyl, alkoxy per luoroalk Ci-ü, perfluoroalkoxy Cx-C_v, (Cx-C?) alkyl, (alkyl 0X-C?) sulfonyl, phenylsulfinyl, (alkyl C, -C ,, -, ) sulfo 1 oo fen lsulfonilo; with the conditions that: G * and G2 are not hydroxy at the same time; G3 and G * are not hydroxy at the same time; Gs and G * are not hydroxy at the same time; R is not phenyl substituted with carboxy, tetrazolyl or -CO- N (H) (SOs.-X7 ') when R is in position l or in position 2; R1- is not carboxL, (,? S or trans - (0HS Im-OX1 -OX'-COaH, - (CH2) mCX X'X '!, o) wherein X * e carboxy, tetrazolyl or CH ^ OH, < When R is in position 1 or position 2; a compound of formula (T) can not be / a compound of formula (I) can not be 8-h? drox? - 5,6, 7, 8-etrahi dna-1-boxeric acid.
2. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein As is * \ where R * and R? they are, each one, hydrogen.
3. 3. A compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein a is 15 0 or CHa.
4. 4. A compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R'3- is - (CHs) mCX3XAXs or a five or six membered substituted aromatic ring, substituted with a selected substituent of the group 20 consisting of carboxy, tetrazolyl, -CO- N (H) (SOa-X'7), -N (H) (Os-X7), N (H) (CO-X'7) and -N (H) (CO-OX7) and with one or two substituents each independently selected from the group consisting of fluorine, chlorine, C? -C alkyl, Ca.Calkoxy, perfluoroalkyl O? -C_, perfluoroalkoxy Cx-C ^ (C 1 -C 6 alkyl) alkyl, (C 1 -C 6 alkyl) sulfinyl, phenyl alkyl, C 1 -C 6 alkyl sulfo and femlsulfonyl.
5. 5. - A compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R or a phenyl substituted with one of its constituents selected from the group consisting of carboxy, N (H) (SO - ^ - X7), N (H) (CO-X7) and -N (H) 5 (CO-OX7) and with one or two substitutes each independently of the group consisting of fluorine, chlorine, C? -C6 alkyl, alkoxy perfluoro alkoxy Cx-Ct, (CX-C?) alkyl, (C? -C3 alkyl) sulfinyl, phenylsulfyl, (Cx-C * alkyl) sulphonyl and femulphyl fonyl.
6. 6. A compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R3- is a phenyl substituted with a substituent selected from the group consisting of carboxy and -N (H) (SO-) OX7) and with one or two agents selected independently from the group consisting of fluorine, chlorine, alkylC, alkyl, C 1 -C 6 alkoxy, C 1 -Cv perfluoroalkyl, C 1 -C 6 perfluoroalkoxy, (alkyl C-C?) t? o, (alkyl 0j.-C < 5,) sulfimyl, fem Isul fi lo, (alkyl Cx-A) sulfonyl, and phenol-fonyl.
7. 7. A compound according to claim 6 or D a pharmaceutically acceptable salt of the same, wherein Rs is - (CH2) mCHX "Xxo, wherein X" is hydrogen and X or is one of the substituted rings optionalrnent o.
8. 8. A compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein n is 5 1 and X s is phen.lo or phenyl substituted with phenyl at the p ra position. °).
9. A compound according to claim 8 or an acceptable f -metabolic salt thereof, wherein R 1 is substituted phenyl with a substituent selected from the group consisting of carboxy and -N (H) (SO ^ -X " 7) and with one or two substituents each selected independently of the group consisting of fluorine, chlorine and perfluoroalkyl CX-C.
10. 10. A pharmaceutical composition for the treatment of LTI-induced diseases, comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or dimer.
11. 11. A pharmaceutical composition for the treatment of inflammatory disorders, eczema, erythema, pruritus, acne, stroke, rejection of grafts, autoimmune diseases and asthma, which corrects an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
12. 12. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, in the preparation of compositions for the inhibition of receptor binding, functional inhibition and in vivo inhibition of LTB ^., In a patient who needs such inhibition.
13. 13. The use 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, pruritus, acne, apoplexy, rejection of grafts, autoimmune diseases and asthma, in a patient in need of such treatment.
14. 14. A compound of formula (lfi) wherein A1 is 0, CHS, S, NH or Nalkyl C? -0); is Rs is selected from the group consisting of - (CH ia;) nCHXc'X or - (CHs r-X10, 0 (CH52) aCHX "Xxo and -0 (CHa i ^ 3-0, where n is 0, 1, 2 or 3, q is 0, 1 or 2, X9 is hydrogen, optionally substituted C?-C ?alkyl or fem, wherein optionally substituted phenyl is optionally substituted with one or two independently selected ituyent.es. of the group consisting of fluorine, chlorine, Cx-C ^ alkyl, C? -C? alkoxy per luoroalqu lo CX-C, perf1 uoroalcoxi? -C, +, (alkyl 0j_-Cfe) t? O, (Cx-C6 alkyl) ul fi lo, phenyl ul i nyl, (Cx-Cs alkyl) s? Lfomlo and femlsul foni lo; X1-0 is hydrogen, C ^ -C, alkyl, Cd or C-C3 alkyl or one of the following optionally substituted rings: phenyl, tjenyl, pipdyl, fuplo, naphthyl, qumolyl, isoquinolyl, pipmidinyl or piraziyl; wherein optionally substituted rings are optionally optionally substituted with fluorine, chlorine, C? -C alkyl, C ^ -C ^ alkoxy, perfluoroalkyl C -Cv, perfluoroalkoxy ^ -C *. (C 1 -C 6 alkyl), (C 1 -C 6 alkyl) sulfinyl, lysul finyl, (C 1 -C 6 alkyl) sulfonyl and optionally substituted phenyl; wherein the optionally substituted phen is optionally substituted with one or two substituents selected independently from the group consisting of fluorine, chlorine, C -Ce alkyl, CX-C alkoxy. perfluoroalkyl Cx-C_v, perfluroalkoxy (C 1 -C 6 alkyl, (C 6 alkyl) sulphonyl, phenyl sulfinyl, (C 1 -C 6 alkyl) sulfonyl and phenylsulfonyl, R 1 and R 7 are each independently hydrogen or 0X-C alkyl, or R * and R7 are taken together with the carbon atom to which they are attached and form C-chloroalkyl- Cr; Rx is selected from the group consisting of tetrazolyl, carboxy, cis or trans- (CHM) m-CX3- = CXa-C0S; H, (CHs) mCX3X * Xs, -C0-NGxG =, . and a 5 or 6 membered substituted aromatic ring having optionally one or two heteroatoms, wherein the heteroatoms are independently selected from the group consisting of 0, S and N; wherein m is 0, 1 or 2; Y is 0, CH 5, 5 NH or (C 1 -C 4 alkyl); Xx and X2 are each independently hydrogen or C? -Cto alkyl; X3 and X '* are each independently hydrogen or C ^ -C * alkyl, or X3 and X become together with the carbon atom to which they are attached and form cycloalkyl C3-C7; Xa is hydroxy, carboxy, «etrazolyl "") or -C0-NG3G *; XA is carboxy, tetrazolyl, CH-.0H or -C0-NG3G &;; G, GH, G3, G ", Gs, and G * are each independently selected from the group consisting of hydrogen, C? -C alkyl, perfluoroalkyl C -C ?, alkyl Ca-Ce sul fini lo , phenylsulfi nilc, (C? -C? alkyl) sulfonyl, phenylsul phonyl, 5-hydroxy, phenyl or femlo substituted with (G3-) », wherein a is 2; 0X in each case is selected from fluorine, chlorine , alkyl Ca-C ?, alkoxy C? -CA, [> erfluoroaiquilo C? -C, perfluoroal coxi C-C, (alkyl Cj.-C?) t? o, (alkyl C _.- CA) sulphi ni , Femlsulfi mine (Cx-C ^ alkyl) sulphonyl and femlsulfonyl, the five or six membered substituted aromatic ring is substituted with a substituent selected from the group consisting of carboxy, tetrazole, -CO-N (H) (S0a) ~ X7), N (H) (S02-X7), -N (H) (CO-X7) and -N (H) (C0-0X7) and with one or two selected substituents each independently of the 5 consistent group in fluorine, chlorine, Cx-Cs alkyl, C -C alkoxy ?, perfluoroalkyl, C? -C ?, perfluoroalkoxy Cx-C_v, (CX alkyl- C?) T? O, (Ct-C6 alkyl) sulfinyl, femls? Fyl, (Ci-C 's alkyl) sulphonyl and femlsuifonyl; wherein X "7 is hydrogen, -CHaF, -CHF2, -CFU, C? -C alkyl ?, C-cycloalkyl -CH, or one of the following optionally substituted rings: female, male, pyridyl, furyl, naphthyl, q-olyl, iso-molyl, piprnidinyl or pyrazinyl, wherein optionally substituted rings are optionally substituted with one or two substituents independently selected from fluorine, chlorine, CX-C alkyl, C alco-C alkoxy , perf1 uoroal uilo C? -CA, perfluoroalkoxy (C 1 -C 6 alkyl) t, (C-sulfinyl alkyl, phenyl sulfur, C 1 -C 4 alkyl) sulfonyl, phelsulfonyl or optionally substituted phenyl, wherein the optionally substituted phenyl is optionally substituted with one or two substituents independently selected from the group consisting of fluorine, chlorine, C ^ -O * alkyl, C? -0.3 alkoxy, C? -C? perfluoroalkyl, perfluoroalkyl, (alkyl C? -Cft) t? o, (Ct-C6 alkyl) sul fmi lo, fem 1 sul phi lo, (alkyl O? -C, s) suifon? lo and fem Isul fomlo; R3 is hydrogen, fluorine, chlorine, C? -C alkyl, Cx-C? Alkoxy, per luoroalkyl C? -C4, perfluoroalkoxy CX-C, (Cx-C? Hio alkyl, (C? -C? Alkyl) sulfonyl, femlsulfimyl, (Cx-C, *) sulfonyl or femlsulfomyl alkyl, with the provisos that: a and Gs are not hydroxy at rn? -mo time; Ga and G are not hydroxy at the same time; Gs and G * are not hydroxy at the same time, Rx is not phenyl substituted with carboxy, tetrazolyl or -CO-N (H) (SO ^ -X7") when Rx is in position 1 or position 2; R is not carboxy, cis or trans - - (CH-,) mCX3X X5 or wherein X * is carboxy, tetrazolyl or CH ^ OH, when R1 is in position l or in position 2; a compound of formula (1A) can not be a compound of formula (1A) can not be acid 8-oxo-5, 6, 7, i! -tetrah? dronaphthalen-1-carboxyl ico; a compound of formula (1A) can not be 2-hydroxyl-l -tetralone-O-carbox 111 co; a compound of formula (1A) can not be 4-oxo-2,3 ~ d? h? drobenzo ?? ran-6-carboxy acid? 11 co; and a compound of formula (Ia) can not or, er
15. 15. The acid compound 1 - (3 - (4-phene-1-phen-lrnet-ii) -4-hydroxy-1-chroman-7-l) - (2-cyclopentene) -carboxylic acid, according to claim 1 .