KR100237527B1 - Benzopyran And Benzo-fuzed Compounds As Leukotriene B4 Antagonists - Google Patents

Abstract

The present invention relates to novel benzopyrans and other benzo-condensed leukotriene B ₄ (LTB ₄ ) antagonists of formula (I) or a pharmaceutically acceptable salt thereof:

Wherein A ¹ , A ² , R ¹ , R ² and R ³ are as defined in claim 1.

The compounds of the present invention inhibit the activity of LTB ₄ to inhibit inflammatory diseases such as rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis and other skin diseases such as eczema, erythema, pruritus and acne, seizures and other forms of reperfusion injury. It is useful for the treatment of LTB ₄ induced diseases such as transplant rejection, autoimmune diseases, asthma and other diseases with prominent neutrophil infiltration.

Description

Benzopyran And Benzo-fuzed Compounds As Leukotriene B4 Antagonists}

The present invention provides novel benzopyrans and other benzo-condensed leukotriene B ₄ (LTB ₄ ) antagonists and pharmaceutically acceptable salts of these compounds, pharmaceutical compositions containing these compounds and the use of such compounds as LTB ₄ antagonists It is about a method.

The compounds of the present invention inhibit the activity of LTB ₄ to inhibit inflammatory diseases such as rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis and other skin diseases such as eczema, erythema, pruritus and acne, seizures and other forms of reperfusion injury. It is useful for the treatment of LTB ₄ induced diseases, such as transplant rejection, autoimmune diseases, asthma and other diseases with prominent neutrophil infiltration.

Leukotriene B ₄ antagonists are disclosed in European Patent Publication Nos. 276064 and 292977, which diphenylether, benzophenone and other compounds containing two phenyl groups, respectively, and 7- (3-alkoxy-4-alkae) Mention is made of noyl-phenoxy) alkoxy benzopyran derivatives.

The present invention seeks to provide novel benzopyrans and other benzo-condensed leukotriene B ₄ (LTB ₄ ) antagonist compounds of formula ( ₁ ) or pharmaceutically acceptable salts thereof.

Formula 1

Where

A ¹ is O, CH ₂ , S, NH or N (C ₁ -C ₆ ) alkyl;

R ³ is hydrogen or hydroxy;

A ² is ego;

R ⁴ is hydrogen or hydroxy;

R ⁵ is selected from the group consisting of-(CH ₂ ) _n -CHX ⁹ X ¹⁰ ,-(CH ₂ ) _n X ¹⁰ and CH (OH) X ¹⁰ ;

n is 0, 1, 2 or 3;

X ⁹ is hydrogen, (C ₁ -C ₆ ) alkyl or optionally substituted phenyl, wherein the optionally substituted phenyl is fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy , (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, Optionally substituted with one or two substituents independently selected from the group consisting of (C ₁ -C ₆ ) alkylsulfonyl and phenyl sulfonyl);

X ¹⁰ is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, or phenyl, thienyl, pyridyl, furyl, naphthyl, quinolyl, isoquinolyl, pyrimidinyl and pyra An optionally substituted ring of one of the genyls, wherein the optionally substituted ring is fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoro Roalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl Is optionally substituted with one or two substituents independently selected from the group consisting of phenyl sulfonyl and optionally substituted phenyl; optionally substituted phenyl is fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulphi carbonyl, phenyl-sulfinyl, (C ₁ -C ₆₎ independently from the group consisting of alkyl sulfonyl and phenylsulfonyl Optionally substituted with one or two substituents selected);

R ⁶ and R ⁷ are each independently hydrogen or (C ₁ -C ₄ ) alkyl, or R ⁶ and R ⁷ together with the carbon atoms bonded to them form a (C ₄ -C ₇ ) cycloalkyl;

R ¹ is tetrazolyl, carboxy, cis or trans-(CH ₂ ) _m -CX ¹ = CX ² -CO ₂ H,-(CH ₂ ) _m -CX ³ X ⁴ X ⁵ , -CO-NG ¹ G ² , And a substituted 5 or 6 membered aromatic ring optionally having one or two heteroatoms independently selected from the group consisting of O, S and N:

m is 0, 1 or 2;

Y is O, CH ₂ , S, NH or N (C ₁ -C ₆ ) alkyl;

X ¹ and X ² are each independently hydrogen or (C ₁ -C ₆ ) alkyl;

X ³ and X ⁴ are each independently hydrogen or (C ₁ -C ₆ ) alkyl, or X ³ and X ⁴ together with the carbon atoms bonded thereto form a (C ₃ -C ₇ ) cycloalkyl;

X ⁵ is hydroxy, carboxy, tetrazolyl or -CO-NG ³ G ⁴ ;

X ⁶ is carboxy, tetrazolyl, CH ₂ OH or —CO-NG ⁵ G ⁶ ;

G ¹ , G ² , G ³ , G ⁴ , G ⁵ and G ⁶ are each independently hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₆ ) Alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl, phenylsulfonyl, hydroxy, phenyl and (Q ¹ ) _a -substituted phenyl, wherein a is 1 or 2, each When Q ¹ is fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy , (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl and phenyl sulfonyl independently); Selected;

Substituted 5- or 6-membered aromatic rings include carboxy, tetrazolyl, -CO-N (H) (SO ₂ -X ⁷ ), -N (H) (SO ₂ -X ⁷ ), -N (H) (CO -X ⁷ ) and one substituent selected from the group consisting of -N (H) (CO-OX ⁷ ), and fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, ( C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl and phenyl sulfonyl are each independently substituted with two substituents selected from the group consisting of;

X ⁷ is hydrogen, —CH ₂ F, —CHF ₂ , —CF ₃ , (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, or phenyl, thienyl, pyridyl, furyl, naphthyl , One of the optionally substituted rings of quinolyl, isoquinolyl, pyrimidinyl or pyrazinyl, wherein the optionally substituted ring is fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C _1- C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, Optionally substituted with one or two substituents independently selected from the group consisting of phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl, phenyl sulfonyl and optionally substituted phenyl; and optionally substituted phenyl is fluoro , Chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₆₎ alkylthio, (C ₁ -C ₆₎ alkylsulfinyl, phenyl-sulfinyl, (C ₁ -C ₆₎ alkylsulfonyl, and phenyl sulfonyl It is optionally substituted with one or two substituents independently selected from the group consisting of a) and;

R ² is hydrogen, fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoro Alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl or phenyl sulfonyl;

Provided that both G ¹ and G ² are not hydroxy at the same time;

G ³ and G ⁴ are not both hydroxy at the same time;

G ⁵ and G ⁶ are not both hydroxy at the same time;

If R ³ is hydroxy and R ⁴ is hydrogen, then R ⁵ is —CH (OH) X ¹⁰ .

A preferred group of compounds is that R ³ is hydroxy and A ² is And R ¹ , R ² , A ¹ , R ⁴ and R ⁵ are compounds of Formula 1 or pharmaceutically acceptable salts thereof, as defined in Formula 1 above.

A more preferred group of compounds is R³Is hydroxy; A^One2 O or CH₂ego; A²endego; R^One, R², R⁴And R⁵Is a compound of Formula 1 or a pharmaceutically acceptable salt thereof as defined in Formula 1 above.

A more preferred group of compounds is that R ³ is hydroxy; A ¹ is O or CH ₂ ; A ² ego; R ¹ is — (CH ₂ ) _m CX ³ X ⁴ X ⁵ or a substituted 5- or 6-membered aromatic ring, wherein the substituted 5- or 6-membered aromatic ring is carboxy, tetrazolyl, -CO-N (H ) (SO ₂ -X ⁷ ), -N (H) (SO ₂ -X ⁷ ), -N (H) (CO-X ⁷ ), and -N (H) (CO-OX ⁷ ) One substituent and fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy , Each independently selected from the group consisting of (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl and phenyl sulfonyl Substituted with two substituents; m, X ³ , X ⁴ , X ⁵ , X ⁷ , R ² , R ⁴ and R ⁵ are compounds of Formula 1 or pharmaceutically acceptable salts thereof, as defined in Formula 1 above.

Even more preferred group of compounds is that R ³ is hydroxy; A ¹ is O or CH ₂ ; A ² ego; R ¹ is substituted phenyl, wherein substituted phenyl is carboxy, -N (H) (SO ₂ -X ⁷ ), -N (H) (CO-X ⁷ ) and -N (H) (CO-OX ⁷ One substituent selected from the group consisting of fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C _1- C ₄ ) perfluoroalkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl and phenyl sulfonyl Are each independently substituted with one or two substituents; X ⁷ , R ² , R ⁴ and R ⁵ are compounds of formula 1 or pharmaceutically acceptable salts thereof, as defined in formula 1 above.

Most preferred group of compounds is that R ³ is hydroxy; A ¹ is O or CH ₂ ; A ² ego; R ¹ is substituted phenyl, wherein substituted phenyl is carboxy, -N (H) (SO ₂ -X ⁷ ), -N (H) (CO-X ⁷ ) and -N (H) (CO-OX ⁷ One substituent selected from the group consisting of fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C _1- C ₄ ) perfluoroalkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl and phenyl sulfonyl Are each independently substituted with one or two substituents; R ⁴ is hydroxy and R ³ hydroxy is cis or trans with R ⁴ hydroxy; X ⁷ , R ² and R ⁵ are compounds of Formula 1 or pharmaceutically acceptable salts thereof, as defined in Formula 1 above. Even more preferred are those compounds in which the hydroxyl groups of R ³ and R ⁴ are cis relative to one another in the aforementioned crowding of the most preferred compounds.

Another group of the most preferred compounds is that R ³ is hydroxy; R ⁴ is hydroxy; A ¹ is O or CH ₂ ; A ² ego; R ¹ is substituted phenyl, wherein substituted phenyl is one substituent selected from the group consisting of carboxy and -N (H) (SO ₂ -X ⁷ ), and fluoro, chloro, (C ₁ -C ₆ ) alkyl , (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) Is substituted with one or two substituents each independently selected from the group consisting of: alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl and phenyl sulfonyl; R ³ hydroxy and R ⁴ hydroxy are cis relative to each other; R ⁵ is — (CH ₂ ) _n CHX ⁹ X ^10, wherein X ⁹ is hydrogen and X ¹⁰ is one of the optionally substituted rings defined in Formula 1 above; n, X ⁷ and R ² are compounds of formula 1 or pharmaceutically acceptable salts thereof, as defined in formula 1 above. More preferred groups within the foregoing group of compounds are those wherein n is 1 and X ¹⁰ is phenyl substituted with phenyl at the para position. And R ¹ is substituted phenyl, which substituted phenyl is one substituent selected from the group consisting of carboxy and -N (H) (SO ₂ -X ⁷ ), and fluoro, chloro and (C ₁ -C ₄ ) Among the most preferred are the compounds substituted with one or two substituents each independently selected from the group consisting of perfluoroalkyl.

The invention also relates to a pharmaceutical composition for the treatment of LTB ₄ induced disease, comprising an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof as defined above and a pharmaceutically acceptable carrier or diluent . The present invention also provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable amount thereof, in an amount sufficient to treat eczema, erythema, pruritus, acne, seizures, transplant rejection, autoimmune diseases and asthma. A pharmaceutical composition for the treatment of these diseases comprising a carrier and a diluent. Preferred compositions are where the compound of formula 1 is a preferred compound.

The invention also includes a method for inhibiting receptor binding, inhibiting functional activity and inhibiting in vivo of LTB ₄ by administering to a subject in need thereof an effective amount of a compound of formula 1 and a pharmaceutically acceptable salt thereof as defined above. . The present invention provides inflammatory diseases, eczema, erythema, pruritus, acne, seizures, transplant rejection, autoimmune diseases and asthma by administering to a subject in need thereof a compound of formula 1 and a pharmaceutically acceptable salt thereof as defined above. It includes a method of treatment. Preferred methods according to the invention are those wherein the compound of formula 1 is a preferred compound or a pharmaceutically acceptable salt thereof.

The present invention also relates to intermediate compounds of the formula

Where

A ¹ is O, CH ₂ , S, NH or N (C ₁ -C ₆ ) alkyl;

A ² is ego;

R ⁴ is hydrogen or hydroxy;

R ⁵ is selected from the group consisting of-(CH ₂ ) _n CHX ⁹ X ¹⁰ ,-(CH ₂ ) _n X ¹⁰ and -CH (OH) X ¹⁰ ;

n is 0, 1, 2 or 3;

X ⁹ is hydrogen, (C ₁ -C ₆ ) alkyl or optionally substituted phenyl, wherein the optionally substituted phenyl is fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy , (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, Optionally substituted with one or two substituents independently selected from the group consisting of (C ₁ -C ₆ ) alkylsulfonyl and phenyl sulfonyl);

X ¹⁰ is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, or phenyl, thienyl, pyridyl, furyl, naphthyl, quinolyl, isoquinolyl, pyrimidinyl and pyra An optionally substituted ring of one of the genyls, wherein the optionally substituted ring is fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoro Roalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl Is optionally substituted with one or two substituents independently selected from the group consisting of phenyl sulfonyl and optionally substituted phenyl; optionally substituted phenyl is fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulphi carbonyl, phenyl-sulfinyl, (C ₁ -C ₆₎ independently from the group consisting of alkyl sulfonyl and phenylsulfonyl Optionally substituted with one or two substituents selected);

R ⁶ and R ⁷ are each independently hydrogen or (C ₁ -C ₄ ) alkyl, or R ⁶ and R ⁷ together with the carbon atoms bonded to them form a (C ₄ -C ₇ ) cycloalkyl;

R ¹ is tetrazolyl, carboxy, cis or trans-(CH ₂ ) _m -CX ¹ = CX ² -CO ₂ H,-(CH ₂ ) _m -CX ³ X ⁴ X ⁵ , -CO-NG ¹ G ² , And substituted 5 or 6 membered aromatic rings optionally having one or two heteroatoms independently selected from the group consisting of O, S and N;

m is 0, 1 or 2;

Y is O, CH ₂ , S, NH or N (C ₁ -C ₆ ) alkyl;

X ¹ and X ² are each independently hydrogen or (C ₁ -C ₆ ) alkyl;

X ³ and X ⁴ are each independently hydrogen or (C ₁ -C ₆ ) alkyl or X ³ and X ⁴ together with the carbon atom bonded thereto form a (C ₃ -C ₇ ) cycloalkyl;

X ⁵ is hydroxy, carboxy, tetrazolyl or -CO-NG ³ G ⁴ ;

X ⁶ is carboxy, tetrazolyl, CH ₂ OH or —CO-NG ⁵ G ⁶ ;

G ¹ , G ² , G ³ , G ⁴ , G ⁵ and G ⁶ are each independently hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₆ ) Alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl, phenylsulfonyl, hydroxy, phenyl and (Q ¹ ) _a -substituted phenyl, wherein a is 1 or 2, each When Q ¹ is fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy , (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl and phenyl sulfonyl independently); Selected;

Substituted 5- or 6-membered aromatic rings include carboxy, tetrazolyl, -CO-N (H) (SO ₂ -X ⁷ ), -N (H) (SO ₂ -X ⁷ ), -N (H) (CO -X ⁷ ) and one substituent selected from the group consisting of -N (H) (CO-OX ⁷ ), and fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, ( C ₁ -C ₆ ) substituted with one or two substituents each independently selected from the group consisting of alkylsulfonyl and phenyl sulfonyl;

X ⁷ is hydrogen, —CH ₂ F, —CHF ₂ , —CF ₃ , (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, or phenyl, thienyl, pyridyl, furyl, naphthyl , One of the optionally substituted rings of quinolyl, isoquinolyl, pyrimidinyl and pyrazinyl, wherein the optionally substituted ring is fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C _1- C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, Optionally substituted with one or two substituents independently selected from the group consisting of phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl, phenyl sulfonyl and optionally substituted phenyl; and optionally substituted phenyl is fluoro , Chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₆₎ alkylthio, (C ₁ -C ₆₎ alkylsulfinyl, phenyl-sulfinyl, (C ₁ -C ₆₎ alkylsulfonyl, and phenylsulfonyl It is optionally substituted with one or two substituents independently selected from the group consisting shown below);

R ² is hydrogen, fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoro Alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl or phenyl sulfonyl;

Provided that both G ¹ and G ² are not hydroxy at the same time;

G ³ and G ⁴ are not both hydroxy at the same time;

G ⁵ and G ⁶ are not both hydroxy at the same time.

'C ₁ -C ₆ alkyl' as used herein means a saturated monovalent straight or branched aliphatic hydrocarbon radical having 1 to 6 carbon atoms, for example methyl, ethyl, propyl, t-butyl, hexyl and the like. to be. Similarly, C ₃ -C ₇ cycloalkyl and C ₃ -C ₈ cycloalkyl refer to cycloalkyl groups having 3 to 7 or 3 to 8 carbon atoms, respectively, for example cyclopropyl, cyclohexyl, cyclooctyl And so on.

In the compound of Formula 1, A ¹ is oxygen and A ² is If so, the compound may be initiated with 3,4-dihydrobenzopyran or chromman.

Compounds of the invention wherein R ³ is OH have two asymmetric carbons represented by * in the formula:

Stereoisomers may be named with reference to R and S rotations according to standard nomenclature. When referred to as S, R or R, S means a single enantiomeric pure compound, while S ^* , R ^* and R ^* , S ^* mean racemic mixtures. The present invention includes racemic mixtures and optical isomers of formula (I).

According to a specific method of the present invention, the above formula is an intermediate compound of Formula 1, wherein R ¹ is-(CH ₂ ) _m X ³ X ⁴ X ⁵ , wherein m is 0 and X ⁵ is carboxy or an ester thereof. Compound 2 is prepared by reacting the compounds of Formula 3 and Formula 4 to form Compound (V) (not shown) and then reducing to form Compound 1.

The reactions of formulas (3) and (4) are generally carried out in a solvent. Suitable solvents include ether solvents such as tetrahydrofuran, diethyl ether, ethylene glycol, dimethyl ether and 1,4-dioxane; Bipolar aprotic solvents such as dimethylformamide, N, N-dimethylacetamide, acetonitrile, dimethyl sulfoxide, hexamethylphosphoramide, N, N-dimethylpropylene urea; Nonpolar aromatic solvents such as xylene, benzene, chlorobenzene and toluene; And halogenated solvents such as methylene chloride, chloroform and dichloroethane. Particularly suitable solvents are xylene or mixtures of equal volumes of ethylene glycol, dimethylether and dimethyl formamide. The reaction temperature is from -78 ° C to 200 ° C and generally in the range of about 80 ° C to about 150 ° C depending on the boiling point of the solvent used.

The reaction can be carried out in the presence of Lewis acids such as zinc chloride, aluminum chloride, magnesium bromide, tin chloride and titanium chloride. If present, the amount of Lewis acid is from about 0.05 to about 2 equivalents per mole of compound of Formula 3.

The reaction is generally carried out with a palladium catalyst. Suitable palladium catalysts are tetrakistriphenylphosphine palladium, bis-benzonitrile palladium chloride, allyl palladium chloride dimer, palladium chloride, palladium acetate, palladium on carbon and bisacetonitrile palladium chloride. In particular the catalyst comprises 5% by weight of allyl palladium chloride dimer or 5% by weight of bisbenzonitrile palladium chloride. Generally about 0.001 equivalents to 1 equivalent of catalyst per mole of substrate is used.

The reaction is generally phosphine, such as triphenylphosphine, tri-o-tolylphosphine or tri-2-furylphosphine, in an amount of about 0.1 to about 5, preferably 1 to 2 molar equivalents, per mole of substrate used. It is carried out in the presence of a ligand.

Reduction of compound (V) is carried out in a conventional manner with sodium borohydride in alcoholic solvent at ambient temperature to form the compound of formula 1 after saponification.

The compound of formula 3, _wherein R ⁵ is-(CH ₂ ) _n CHX ⁹ X ¹⁰ or-(CH ₂ ) _n X ¹⁰ , may be prepared as follows.

The compound of formula 6 is reacted with trifluoromethane sulfonic anhydride (or triacid anhydride) in a suitable solvent such as methylene chloride in the presence of triethylamine to form the corresponding triflate analog:

The group R ⁵ defined by — (CH ₂ ) _n CHX ⁹ X ¹⁰ or — (CH ₂ ) _n X ¹⁰ , _wherein n, X ⁹ and X ¹⁰ are as defined above for Formula 1, is represented by Formula X ⁹ X Reacted with an aldehyde of ¹⁰ CH (CH ₂ ) _q-1 CHO or X ¹⁰ (CH ₂ ) _q-1 CHO and R ⁵ is CH (CH ₂ ) _q-1 CHX ⁹ X ¹⁰ or = CH (CH ₂ ) _{q The} corresponding alkene analogues, wherein- ₁ X ¹⁰ , wherein q is 1, 2, 3 or 4, respectively, can be formed and then introduced into the triflate analogue by a two-step method comprising hydrogenation. The reaction with the aldehyde is carried out in the presence of a pyrrolidine catalyst or with a hydrochloric acid catalyst in acetic acid. Hydrogenation is carried out by conventional methods using hydrogen and palladium catalysts.

Compounds of formula (6) are generally commercially available. If not, they can be obtained by methods known in the art. For example, A ¹ is oxygen and A ² is The compound of formula 6 may be obtained from R ² -substituted 2 ', 4'-dihydroxy-3-chloropropiophenone (hereafter formula 1) by cyclization with sodium hydroxide. The compound of formula 1 can be prepared from R ² -substituted resorcinol and 3-chloropropionic acid in the presence of an acid, preferably trifluoromethanesulfonic acid. A ¹ is sulfur and A ² is The compound of formula 6 can be similarly obtained from R ² -substituted 4 'or 5'-hydroxy-2'-sulfhydryl-3-chloro-propiophenone, which is R ² -substituted 3- It can be obtained from hydroxythiophenol.

A ² And compounds of formula 6 wherein A ¹ is O or S are similarly reacted with R ² -substituted resorcinol or 3-hydroxythiophenol and 4-chlorobutyric acid (and derivatives thereof) and cyclized with sodium hydroxide, respectively. Can be obtained.

Compounds of formula (1) wherein R ¹ is-(CH ₂ ) _m -CX ¹ = CX ² -CO ₂ H are substituted (CH ₃ ) _{3 in} the presence of a phosphine ligand as described above for the reaction of compounds of formulas 3 and 4. Palladium catalysts such as SnSn (CH ₃ ) ₃ and tetrakistriphenylphosphine palladium (Pd (PPh ₃ ) ₄ ) can be reacted with compounds of formula 3 to obtain the corresponding trimethyltin analogues. Trimethyltin analogs are ester protected compounds of the formula Z ¹ O ₂ CX ² C = CX ^1- (CH ₂ ) _m Z ² wherein Z ¹ is alkyl or cycloalkyl and Z ² is urethral, bromo or CF ₃ SO ₃ Switch. The coupling reaction proceeds in the presence of a palladium catalyst such as bistriphenyl phosphine palladium chloride, as disclosed above. Ketone esters are first reduced to the corresponding hydroxyl compound and then hydrolyzed to the corresponding acid of formula (1). Reduction proceeds using sodium borohydride. In general, the reduction proceeds in a solvent. Suitable solvents are mixtures of lower alcohols with organic solvents such as lower alcohols having 1 to 6 carbon atoms, tetrahydrofuran or dioxane, and mixtures of water-hybrid lower alcohols or other water hybrid organic solvents with water. The solvent is preferably a lower alcohol such as methanol or ethanol. The reaction temperature is generally about -78 ° C to about 100 ° C, generally about 0 ° C to about 25 ° C.

The reducing step yields a stereoisomeric mixture of ester compounds of formula 1 having the structure:

These cis and trans isomers can be separated by conventional column chromatography.

Separation of the cis and trans isomers followed by separation of the enantiomer mixture can be carried out by methods known in the art. In one method, a compound of Formula 1 wherein R ¹ contains a carboxyl group (COOH) is reacted with a chiral base such as d-ephedrine in a polar solvent such as ether to form a diastereomeric salt, which is separated and then aqueous Or by treating with an acid such as methanolic hydrogen chloride to convert to an optically pure acid. In another method, a compound of Formula 1 wherein R ¹ is a carboxylic acid ester is reacted with an optically active acid such as R-mandelic acid or Nt-butoxycarbonyl-D-tryptophan to form a diastereomeric ester with hydroxyl groups After separation it is converted to an optically pure acid by treatment with a base such as sodium hydroxide in methanol or ethanol. Removal of the separated ester groups and hydrolysis of the carboxylic ester groups of R ¹ are carried out at room temperature to the reflux or boiling temperature of the solvent or mixture of solvents used, using an aqueous base such as an alkali metal hydroxide such as sodium hydroxide. . The reaction can be carried out in the presence of a cosolvent such as methanol, ethanol or tetrahydrofuran.

Compounds of formula (1) wherein R ¹ is carboxy and R ² is hydrogen can be prepared from intermediate compounds of formula (3) by first substituting CF ₃ SO ₃ groups with methoxycarbonyl and then hydrolysis. The substitution reaction proceeds using carbon monoxide in the presence of palladium acetate, 1,1'-bis (diphenylphosphine) ferrocene (DPPF), methanol and triethylamine. Hydrolysis is as previously disclosed.

Compounds of Formula 1 wherein R ¹ is-(CH ₂ ) _m CX ³ X ⁴ X ⁵ , wherein m, X ³ , X ⁴ and X ⁵ are as defined above for Formula 1, are hereinafter referred to as Compound (XXI (Not shown). Although the following chemistry discloses the preparation of compounds of Formula 16 wherein R ¹ is — (CH ₂ ) _m CX ³ X ⁴ XCO ₂ C ₂ H ₅ , the same chemistry is described with reference to Formula 1, which is inert under the reaction conditions specified below. It is understood that it is applicable to compounds of formula 16 having different R ¹ as defined.

Compounds (XXI) wherein X ⁵ is tetrazolyl may be prepared from compounds of Formula 16:

According to this method, the compound of formula 16 is first reacted with t-butyldimethylsilylchloride in the presence of imidazole and dimethylformamide to protect the hydroxyl groups as is known in the art. The protected compound is reacted with ammonia and triethylaluminum in xylene to replace the —CO ₂ C ₂ H ₅ group with cyano. The cyano group is replaced with trimethylstannyl-tetrazolyl by reacting with trimethylstannyl azide in toluene. React with tetrabutylammonium fluoride in tetrahydrofuran to convert to tetrazolyl and remove the silyl protecting group.

The starting material of formula 16 is identical to the compound of formula 2 wherein R ¹ is-(CH ₂ ) _m CX ³ X ⁴ X ⁵ (X ⁵ is carboxy ethyl ester and m is 0). The method for preparing this starting material is as described above.

Compounds of formula (XVII) are reacted with (1) acrylonitrile, (2) hydrolyzed with concentrated hydrochloric acid and (3) cyclized to polyphosphoric acid to form compounds of formula (XVIII) Is switched. Introduction of the group R ⁵ to form a compound of formula (XIX) is as described for the compound of formula (6). Hydrogenation and hydrolysis of compounds of general formula (XIX) are as disclosed herein above.

Compounds of formula (XVII) can be prepared from 3-hydroxyphenyl acetic acid by introducing groups X ³ and X ⁴ by known methods.

m is 0, 1 or 2, and A ² is And a starting material of Formula 16 wherein A ¹ is O, S, NH or N (C ₁ -C ₆ ) alkyl, the compound of formula XVII in step (1) of Scheme 1 is obtained by BrCH ₂ CN or BrCH ₂ CH ₂ CH It can be prepared by reacting with ₂ CN and further conversion as disclosed with reference to Scheme 1.

A ¹ is CH ₂ , m is 0, 1 or 2 and A ² is

And starting materials of Formula 16, wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are defined in Formula 1, can be prepared as disclosed below.

Benzene substituted with-(CH ₂ ) _m CX ³ X ⁴ CO ₂ C ₂ H ₅ is reacted with a monovalent acid chloride monoester of malonic acid, succinic acid or glutaric acid in the presence of a Friedel Crafts catalyst such as aluminum chloride. . The resulting ketone is converted to the corresponding propylene dithiol using a propylene dithiol and boron trifluoride catalyst. The formed compound is again reduced to Raney nickel and then saponified. A ring is formed to produce bicyclic cyclic compound 19 using polyphosphoric acid. Introduction of the group R ⁵ is as described above.

Compound (XXI) wherein X ⁵ is CO ₂ H is prepared by saponification of a compound of formula 1 wherein R ¹ as disclosed above is — (CH ₂ ) _m CX ³ X ⁴ CO ₂ CH ₃ .

Compounds (XXI) in which X ⁵ is OH, m is 0, 1 or 2, and X ³ and X ⁴ are each hydrogen are such that R ¹ is — (CH ₂ ) _m CO ₂ CH ₃ (m is 0, 1 or 2) Compound of Formula 1 can be prepared by the conventional lithium aluminum hydride hydrogenation.

Compounds of formula (21) wherein X ⁵ is OH, m is 0, 1 or 2 and X ³ and X ⁴ are alkyl each comprise 1 equivalent of the corresponding compound containing groups X ³ in which X ³ and X ⁴ are each hydrogen. It can be prepared by reacting with a Grignard reagent (e.g., X ³ MgCl), followed by one equivalent of Grignard reagent (e.g., X ⁴ MgCl) containing the group X ⁴ .

Compounds of formula 21 wherein X ⁵ is OH, m is 0, 1 or 2, and X ³ and X ⁴ together form C ₃ -C ₇ cycloalkyl represent compounds of the corresponding compounds wherein X ³ and X ⁴ are hydrogen; It can be prepared analogously by reacting with a Grignard reagent derived from ₃ -C ₇ dihalo alkanes (eg ClMg (C ₃ -C ₇ alkanyl) MgCl).

R ¹ is Wherein X ⁶ is carboxy, tetrazolyl, -CONG ⁵ G ⁶ or CH ₂ OH, Y is O, S, NH or NH (C ₁ -C ₆ alkyl) and m is 0, 1 or 2) Compound of Formula 1 is Can be prepared by reacting a compound of with a triflate of the compound of formula 1 wherein R ^{1 in} the presence of a base such as triethylamine or sodium hydroxide in a reaction inert solvent is CF ₃ SO ₃ CH ₂ (CH ₂ ) _m-. have.

Triflate can be prepared by reacting compound (XXI), in which m is 0, 1 or 2, X ³ and X ⁴ are hydrogen and X ⁵ is hydroxyl, with triflic acid anhydride, the synthesis of which is disclosed above.

Compounds of formula (1) wherein R ¹ is -CONG ¹ G ² can be prepared by reaction with an amine of formula NHG ¹ G ² from the corresponding compound where R ¹ is carboxy.

According to a specific method of the present invention, the intermediate compound of Formula 2 wherein R ¹ is CF ₃ -SO ₂ -O- may be prepared by reacting a compound of Formula 3 with a compound of Formula 1b as defined above:

Wherein R ² is as defined in formula (1). This reaction is generally carried out in ether solvents such as tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, 1,4-dioxane, preferably in tetrahydrofuran. The reaction proceeds in the presence of a catalyst, in particular in the presence of a catalytic amount of a palladium catalyst, for example tetrakistriphenylphosphine palladium, which is any palladium catalyst that provides palladium (Pd) under reaction conditions. The reaction is generally carried out near the reflux temperature of the solvent used, preferably at about 78 ° C. The reaction time is generally about 1 to 24 hours, for example about 3 hours.

The compound of formula 1b is reacted with n-butyllithium or sec-butyllithium in hexane at a low temperature of about −78 ° C., and then generally at about 0 ° C. to about 78 ° C. for 1 to 4 hours. Prepared immediately from compounds of formula 1c by reacting with ZnCl ₂ or ZnBr ₂ :

Ketones of formula ( ²⁾ , wherein A ¹ , A ² , R ¹ and R ² are mentioned in formula (1), can be reduced to the corresponding hydroxyl compounds of formula (1) by reaction with sodium borohydride. In general, the reduction is carried out in a solvent. Suitable solvents include lower alkyl having 1 to 6 carbon atoms; Mixtures of lower alcohols with organic solvents such as tetrahydrofuran or dioxane; And water-hybrid lower alcohols or other water-hybrid organic solvents and mixtures of 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, generally about 0 ° C to about 25 ° C.

The compound of formula XIV is composed of (CH ₃ ) ₃ SnSn (CH ₃ ) _{3 in} the presence of a phosphine ligand such as triphenyl phosphine in an amount of about 0.1 to about 5 molar equivalents per mole of the substrate using the compound of formula ₃ and It is formed by reacting with a palladium catalyst such as tetrakistriphenylphosphine palladium (Pd (PPh ₃ ) ₄ ) or bis-benzonitrile palladium chloride. Compounds of formula XIV are converted to compounds of formula XV by reaction with ester-protected compounds of formula

Where

X is C, CH, N, O or S,

K ¹ is ester, tetrazolyl, -CO-N (H) (SO ₂ -X ⁷ ), -N (H) (SO ₂ -X ⁷ ), -N (H) (CO-X ⁷ ) or -N Carboxy protected, such as (H) (CO-OX ⁷ ) (this group is prepared with acid before being converted to ester);

K ² is F, Cl, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, ( C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl or phenyl sulfonyl,

l is 1 or 2,

Z is iodo, bromo or CF ₃ SO ₃ .

The coupling reaction is carried out in the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium or bistriphenylphosphine palladium chloride.

Ketone esters of general formula XV are first reduced to the corresponding hydroxyl and then hydrolyzed to the corresponding acid of formula (1). The reduction proceeds to sodium borohydride as described above with reference to the reduction of the ketone of formula (2). Hydrolysis to the acid can be carried out in a co-solvent such as methanol or ethanol, optionally in the temperature range from room temperature to reflux or boiling temperature of the solvent used together with an aqueous base such as alkali metal hydroxide such as sodium hydroxide.

Compounds of formula (1) wherein R ³ and R ⁴ are hydroxy can be prepared from esters of formula (1) by removing hydroxyl groups to form olefins. It is treated at about 25 ° C. to reflux for about 0.5 to 5 hours with an acid such as hydrochloric acid, sulfuric acid, triflic acid or preferably toluene sulfonic acid in a solvent such as benzene, acetic acid, dioxane or preferably toluene. It is done in the way used.

The alkene to be prepared can be hydroxylated with an oxidizing agent such as catalytic osmium tetraoxide and morpholine-N-oxide in ether, THF or preferably acetone mixed with water. The mixture is stirred at room temperature until all starting material is consumed, which takes 1 to 5 hours.

This exclusively provides cis-dihydroxy compounds. The trans-dihydroxy analogs are prolonged oxidized for about 10 to 24 hours under the same reaction conditions, and 3-hydroxy-4-keto with a hydride reducing agent such as LiAlH ₄ or LiBH _{4 in a} solvent such as THF, preferably MeOH. It can be prepared by reducing the product.

The hydroxylated esters are saponified with alkali metal bases with co-solvents such as alcohols, preferably ethanol, with low boiling points to obtain acid products.

Alkenes can also be obtained by treatment with THF or a peroxide, preferably dichloroethane, preferably metachloroperbenzoic acid, at 0 ° C. to room temperature, preferably 0 ° C. for 1 to 5 hours. The epoxide can be hydrolyzed with H ₂ and 10% Pd / C in an inert solvent such as ethyl acetate to give 3-hydroxy ester (R ³ is H and R ⁴ is OH).

R ¹ is Wherein R ¹⁰ is independently fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) purple Uroalkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl or phenyl sulfonyl and r is 1 or 2 ) the compound of formula (1) R ¹ is Wherein R ¹⁰ and r are as defined above, the compound of formula 1 is combined with 1,3-dicyclohexylcarbodiimide or 1- [3- (dimethylamino) propyl] -3-ethyl carbodiimide presence and pyridine, dimethylaminopyridine, triethylamine, diisopropylethylamine or amino dia Jovi cycloalkyl of such coupling agents [5.4.0] formula in the presence of an organic base such as undec-7-ene X ⁷ SO ₂ NH ₂ It can be obtained by reaction with sulfonamide of. The reaction is carried out at temperatures ranging from room temperature to the boiling point of the reaction solvent used in solvents such as tetrahydrofuran, diethyl ether, toluene and chlorobenzene.

The compound of formula 1, wherein the X ⁶ or aromatic substituent of R ¹ is NHCO-X ⁷ , NHSO ₂ -X ⁷ or NHCO-OX ⁷ , is a compound of formula 1 wherein X ⁵ or X ⁶ on R ¹ is a carboxy or substituted aromatic or heteroaromatic acid; Compounds of diphenylphosphoryl azide in a solvent such as toluene, DME, THF or dichloroethane in the presence of benzyl alcohol, and pyridine, diisopropylethyl amine, pyrrolidine or preferably triethyl amide. It can be obtained by reacting the amine base with the boiling point temperature of the solvent used for 5 to 48 hours, preferably 16 hours. The product from this reaction is hydrogenated in a lower alcohol solvent in the presence of a palladium catalyst, preferably Pd (OH) ₂ / C, and then acylated with an appropriate acid chloride, carbamoyl chloride or sulfonyl chloride.

The synthetic methods disclosed above in conjunction with the following examples were used and may be used to prepare the compounds of the present invention.

Pharmaceutically acceptable cation salts of a class of compounds of the invention as will be apparent to those skilled in the art available herein are sodium, potassium, calcium, magnesium, ammonium, N, N'-dibenzylethylenediamine, N-methylglucamine, ethanolamine and diethanolamine, including but not limited to. Pharmaceutically acceptable cationic salts of compounds of formula 1 may be prepared by mixing the compound of formula 1 with 1 equivalent of an amine base or an alkali metal base.

The compounds of the present invention can be administered to mammals, including humans, for the treatment of LTB ₄ induced diseases by a variety of routes including oral, parenteral and topical, including suppositories and intestinal use. For oral administration, a dose of about 0.5 to 1000 mg / day, more preferably about 5 to 500 mg / day, may be administered in a single dose or up to three divided doses. For intravenous administration, the dosage is about 0.1 to 500 mg / day, more preferably about 1.0 to 100 mg / day. Intravenous administration can include continuous dripping. The choice of particular route of administration may be utilized herein, as it will vary essentially depending on the age, weight and disease of the patient being treated and as is known to those skilled in the art.

The compounds of the present invention may be administered alone, but may generally be administered in admixture with a pharmaceutical carrier or diluent selected for the intended route of administration and standard pharmaceutical practice known to those skilled in the art. For example, they may be administered orally in the form of excipients such as starch or lactose, or capsules alone or in admixture with excipients, or elixirs or suspensions containing flavoring or coloring agents. They can be injected parenterally, for example intramuscularly, intravenously or subcutaneously. For parenteral administration, they are optimally used in the form of sterile aqueous solutions which may contain other solutes, for example, salts or glucose sufficient for the solution to be isotonic.

The LTB ₄ activity of the compounds of the present invention can be determined by comparing the ability of the compounds of the present invention to compete with radio-labeled LTB ₄ for specific LTB ₄ receptor sites on the guinea pig germ membrane. Guinea pig zira membranes are described in Cheng et al. Pharmacology and Experimental Therapeutics 232: 80, 1985. ³ H-LTB ₄ binding assay was performed with 50 μl Tris pH 7.3, 10 mM MgCl ₂ , 9% methanol, 150 μl and 0.33 mg / ml guinea pig zirconia containing 0.7 nM ³ H-LTB ₄ (NEN, about 200 Ci / mmole). Is performed on the membrane. Unlabeled LTB ₄ is added at a concentration of 5 μM to determine non-specific binding. ^Add compounds at varying concentrations to assess the effect on ³ H-LTB ₄ binding. The reaction was incubated at 4 ° C. for 30 minutes. ³ H-LTB ₄ bound to the membrane is collected by filtration through glass fiber filter paper and the amount of binding is determined by scintillation counting. The IC ₅₀ value for the compound is the concentration at which 50% of certain ³ H-LTB ₄ binding is inhibited.

The functional activity of the compounds of the present invention can be determined in several ways using bioassays. Both high- and low-affinity types of LTB ₄ receptors have been disclosed to couple differently upregulation of leukocyte chemotaxis and adhesion molecules (Sterman JW; Gloetzl, EJ), J. Immun., 1988, 140, 3900-3904. Human neutrophil chemotaxis is described by Hovarth, L. et al. Immunol. 1987, 139, 3055. Upregulation of human neutrophil CD11b is described by Marder, P et al., Prostaglandins, Leukotriene Essent. Fatty Acids, 1991, 46, 265-278.

Compounds of formula (1) are also described in Pettipler, ER et al. J. Pharmacology, 1993, 423-427, by injecting LTB ₄ into the dermis of guinea pigs according to a method analogous to that described, and determining that neutrophils prevent migration to the skin by oral administration of a compound of formula (1). Can be tested in vivo.

The following examples illustrate the preparation of the compounds of the invention but are not intended to limit the scope of the invention in any way.

Example 1

(5S ^* , 6S ^* ) 2- (6-benzyl-5,6-dihydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl) -4-fluorobenzoic acid

A. 2- (4-fluorophenyl) -4,4-dimethyl-4,5-dihydro-oxazole

A stirred solution of 2-amino-methylpropanol (0.378 moles, 33.64 g) in 300 ml of methylene chloride at about 0 ° C. was added to a solution of 4-fluorobenzoyl chloride in 100 ml of methylene chloride for about 0.5 hour. The mixture was allowed to warm to room temperature and stirred for about 3 hours. The mixture was then poured into water and the layers separated. The organic phase was washed with two portions of 10% HCl, one portion of saturated sodium chloride solution and dried over anhydrous MgSO ₄ . The solvent was removed in vacuo to yield a colorless solid, during which SOCl ₂ (0.567 mol, 41 mL) was added dropwise for about 30 minutes. The resulting solution was stirred for about 0.5 hours, at which time diethyl ether was added, during which the solution was stirred rapidly. During this process, a colorless precipitate formed. The slurry was filtered and the solid was washed three times with 250 ml of diethyl ether. The solid was then dissolved in 300 ml 3N KOH and the resulting solution was extracted with ethyl acetate. The organic extract was washed with saturated aqueous NaCl solution and dried over MgSO ₄ . The solvent was removed in vacuo to give 32 g of the title compound of Example 1A: ¹ HNMR (250 MHz., CDCl ₃ ) δ: 8.00-7.91 (m, 2H), 7.10-7.02 (m, 2H), 4.11 (s, 2H), 1.39 (s, 6H).

B. 2-benzylidene-6-methoxy-3,4-dihydro-2H-naphthalen-1-one

Pyrrolidine (0.272 mol, 23.6 ml) was added to a stirred solution of 6-methoxy-1-tetralone (0.227 mol, 40 g) and benzaldehyde (0.272 mol, 27.5 ml) in 450 ml methanol. . The mixture was stirred at room temperature for about 4 days until TLC indicated no further starting tetralinone was present. 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 afford 38 g of the title compound of Example 1B. Melting point: 100-102 ° C. Analytical Calcd for C ₁₈ H ₁₆ O ₂ : 264.1146. Found: 264.1149.

C. 2-benzyl-6-methoxy-3,4-dihydro-2H-naphthalen-1-one

A Parr® hydrogenation bottle was loaded with 10% palladium on chromonone (15 g), ethyl acetate (150 mL) and 1 g charcoal. The mixture was hydrogenated for about 15 hours under 20 psi of hydrogen in a wave shaker. The resulting mixture was filtered through a pad of Celite® and concentrated in vacuo to afford a red oil which was purified by flash chromatography (3: 1 hexanes / diethyl ether) to give this Example 1C 14.1. g was obtained. Melting point: 50-51 ° C. Analytical Calcd for C ₁₈ H ₁₈ O ₂ : 266.1302. Found: 266.1308.

D. 2-benzyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one

Boron tribromide (1.95 mL, 21 mmol) was added to a stirred solution of the compound of Example 1C (benzyl tetralinone) (5 g, 19 mmol) in methylene chloride (40 mL) at about -78 ° C. The cooling bath was removed and the reaction mixture was stirred overnight at room temperature before additional 1.5 ml of boron tribromide was added. Stirring continued at room temperature for 4 hours and the mixture was poured into ice water and stirred for about 0.5 hours. 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 removal of solvent in vacuo gave a brown solid which was purified by flash chromatography (3: 2 hexanes / ether) to give 3 g of compound of Example 1D. Melting point: 160-162 캜. Analytical Calcd for C ₁₇ H ₁₆ O ₂ : 252.1146. Found: 252.1144.

E. trifluoromethanesulfonic acid 6-benzyl-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl ester

Trifluoromethanesulfonic acid in a stirred solution of the compound of Example 1D (2.75 g, 11 mmol), triethylamine (4.56 mL, 33 mmol) and DMAP (0.05 g) in methylene chloride (100 mL) at about -78 ° C. Anhydride (2 mL, 12 mmole) was added. The cooling bath was removed and the reaction mixture was allowed to warm 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 removed in vacuo. The crude product was purified by flash chromatography to yield 3.9 g of compound of Example 1E. Melting point: 52-53.7 ° C. Analytical Calcd for C ₁₈ H ₁₅ O ₄ SF ₃ : 384.0638. Found: 384.0602.

F. 2-benzyl-6- [2- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl) -5-fluorophenyl] -3,4-dihydro-2H-naphthalene -1-on

A solution of aryl oxazoline (1.76 g, 9 mmol) in toluene (5 mL) was added to a stirred solution of n-butyllithium (3.6 mL of 2.5 M solution in hexane, 9 mmol) in toluene (10 mL) at about -40 ° C. Dropwise via cannula. The mixture was stirred at about −40 ° C. for about 0.5 hours, then warmed to about −25 ° C. and stirred for about 1 hour. To this mixture was added zinc chloride (9 ml of a 1M solution in diethyl ether). The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for about 1 hour. The resulting mixture was added via cannula to a solution of tetraral triflate (3.5 g, 9 mmoles) and palladium tetrakistriphenylphosphine (0.5 mmoles, 0.63 g) in tetrahydrofuran (15 mL). The reaction mixture was heated to reflux for about 2 hours, cooled to room temperature and poured into saturated aqueous ammonium chloride solution. The aqueous mixture was extracted with three portions of each ethyl acetate. The organic phase was washed with 3 portions of 1M HCl, saturated aqueous sodium bicarbonate and brine. The organic layer was then dried over anhydrous sodium sulfate and the solvent removed in vacuo. The crude product was purified by flash chromatography (2: 1 diethyl ether / hexane) to afford 2.07 g of compound of Example 1F. Melting point: 114-115 ° C. Analytical Calcd for C ₂₈ H ₂₆ NO ₂ F: 427.1948. Found: 427.1956.

G. 2-benzyl-6- [2- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl) -5-fluorophenyl] -1,2,3,4-tetrahydro Naphthalene-1-ol

To a stirred solution of the compound of Example 1F (1.5 g, 3.5 mmol) in methanol (35 mL) was added sodium borohydride (0.20 g, 5.25 mmol). The resulting brown mixture was stirred at room temperature for about 1 hour, then poured into brine and extracted with three portions of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the solvent removed in vacuo to yield a 1: 1 mixture of 1.20 g cis and trans alcohol. Melting point: 88-89 ° C. Analytical Calcd for C ₂₈ H ₂₈ NO ₂ F: 429.2087. Found: 429.2067.

H. 2- (6-Benzyl-5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl) -4-fluorobenzoic acid

Compound (IG) (1.0 g, 2.34 mmol) was dissolved in 5 ml of methyl iodide and stirred at room temperature for about 2 days, at which time methyl iodide was removed in vacuo. The residue was taken up in methylene chloride and concentrated to remove traces of remaining methyl iodide. The dark red residue was dissolved in methanol (5 mL) and 2N NaOH (5 mL) was added. The resulting mixture was stirred for about 5 hours while heating to reflux. The mixture was then cooled to room temperature and acidified with 3N HCl. The resulting slurry was extracted with three portions of ethyl acetate and the combined organic phases were washed with brine. The organic phase was dried over anhydrous sodium sulfate and the solvent removed in vacuo to yield 0.80 g of the compound of this Example 1H.

I. 2- (6-Benzyl-5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl) -4-fluorobenzoic acid ethyl ester

To a stirred solution of the compound of Example 1H (0.80 g, 2.13 mmol) and ethyl iodide (0.34 mL, 4.26 mmol) in acetonitrile (20 mL) was added potassium carbonate (1.03 g, 1.45 mmol). The resulting slurry was heated to about 60 ° C. for about 24 hours. The mixture was cooled to rt, diluted with diisopropyl ether and filtered through celite. Concentration in vacuo gave 0.72 g of the compound of Example 1I as a 1: 1 cis / trans mixture. Data for diastereomers are as follows:

J. 2- (6-Benzyl-7,8-dihydro-naphthalen-2-yl) -4-fluorobenzoic acid ethyl ester

To a round bottom flask containing the compound of Example 1I (0.70 g) in benzene (50 mL) was added p-toluenesulfonic acid (0.09 g). The flask was tightly closed with a Dan-Stark trap to remove water during the reaction. The mixture was heated to reflux for about 16 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in chloroform and washed with saturated aqueous sodium bicarbonate. The chloroform extract was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to yield a yellow oil which was purified by flash chromatography (6: 1 hexanes / ethyl acetate) to afford 0.56 g of compound of this Example 1J. Analytical Calcd for C ₂₆ H ₂₃ O ₂ F: 386.1676. Found: 386.1713.

K. cis- (5S ^* , 6S ^* )-2- (6-benzyl-5,6-dihydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl) -4-fluorobenzoic acid Ethyl ester

To a stirred solution of the compound of Example 1J (0.50 g, 1.3 mmol) in 3: 1 acetone / water (6 mL) was added N-methylmorpholine-N-oxide (0.168 g, 1.4 mmol) followed by osmium tetraoxide ( 0.79 mL of a 4% solution in water, 0.1 mmol) was added. The reaction mixture was stirred at room temperature and monitored by TLC to see if the starting material disappeared. The mixture was then diluted with chloroform and washed with 10% aqueous NaHSO ₃ solution. The chloroform extract was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (1: 1 hexanes / ethyl acetate) to yield 0.34 g of the compound of Example 1K. Melting point: 59-60 ° C. Analytical Calcd for C ₂₆ H ₂₅ O ₄ F: 420.1736. Found: 420.1722.

L. (5S ^* , 6S ^* ) -2- (6-benzyl-5,6-dihydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl) -4-fluorobenzoic acid

To a stirred solution of the compound of Example 1K (0.30 g, 0.71 mmol) in 3: 1 acetone / water (12 mL) was added lithium hydroxide monohydrate (0.15 g, 3.6 mmol). 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 slurry was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to afford 0.24 g of Example 1L compound (title product). Melting point: 127-130 ° C. Analytical Calcd for C ₂₄ H ₂₁ O ₄ F: 392.1423. Found: 392.1948.

Example 2

7- (2-carboxy-5-trifluoromethylphenyl) -3-phenylmethyl-3-hydroxybenzopyran

A. 2 ', 4'-dihydroxy-3-chloropropiophenone

Trifluoromethane sulfonic acid (1 kg) was added in one portion to a stirred mixture of resorcinol (200 g, 1.82 mmol) and 3-chloropropionic acid (200 g, 1.84 mol). The solution was slowly heated to about 80 ° C. for about 45 minutes, then cooled to room temperature for about 15 minutes and poured into chloroform (4.0 L). The organic portion was slowly poured into water (4.0 L) and the layers separated. The aqueous layer was extracted with chloroform (2x 2.0 L). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo afforded an orange semi solid (244.1 g) which was used as raw material for the next step. ¹ H-NMR (300 MHz, CDCl ₃ ): 12.56 (1H, s), 7.63 (1H, d, J = 7.6 Hz), 6.37-6.46 (2H, m), 3.92 (2H, t, J = 6.3 Hz) , 3.41 (2H, t, J = 6.3 Hz).

B. 7-hydroxybenzopyran-4-one

To a cooled (about 5 ° C.) solution of 2N sodium hydroxide (10.0 L) was added the compound of Example 2A (244.1 g) in one portion. The solution was warmed to room temperature using a warm water bath for about 2 hours, recooled to about 5 ° C. and titrated to pH 2 with 6M sulfuric acid (1.2 L). The mixture was extracted with 3 × 3.0 L of ethyl acetate, washed with brine (1 × 2.0 L), 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 compound of this Example 2B. Melting point 136-137 ° C.

C. 7- [trifluoromethylsulfonyloxy] -benzopyran-4-one

Triethylamine (320 g, 3.16 mmoles) and dimethylaminopyridine (2.5 g) were added to a stirred solution of the compound of Example 2B (173.7 g, 1.05 mole) in methylene chloride (3.0 L) at about -78 ° C. After all dissolution, trifluoromethane sulfonic anhydride (327 g, 1.16 mol) was added dropwise for about 20 minutes, and the material was stirred at about -78 ° C for about 30 minutes and warmed to room temperature for about 2 hours. The reaction mixture was poured into saturated ammonium chloride solution (2.5 L) and the layers separated. The aqueous layer was extracted with 2 × 2.0 L of methylene chloride. The combined organic fractions were washed with water (1 × 1.0 L), dried over magnesium sulfate and filtered. Concentration in vacuo gave a red oil. (8: 1) Elution with hexane: ethyl acetate gave chromatography on silica gel (1 kg) to remove the solvent to afford 211.1 g (69% yield) of the title product of this Example 2C. Melting point: 43-44 ° C.

D. 7-[(trifluoromethylsulfonyl) oxy] -3-phenyl-methylene-benzopyran-4-one

To a stirred solution of the product of Example 2C (27 g, 91.2 mmol) in 183 mL methanol was added benzaldehyde (11.1 mL, 109 mmol) and then pyrrolidine (9.1 mL, 109 mmol). The mixture was stirred overnight at room temperature, cooled to about 0 ° C. and filtered. The solid was washed once with 50 ml of ice-cold methanol and dried in vacuo; 35.2 g (75% yield) of the title product of Example 2D were obtained.

E. 7-[(trifluoromethylsulfonyl) oxy] -3-phenylmethyl-benzopyran-4-one

To a solution of the compound of Example 2D (26.6 g, 69.2 mmole) in 250 ml ethyl acetate in a 500 ml shake shake flask was added a 10% palladium catalyst on carbon (1.3 g). After about 3 hours the mixture was hydrogenated at 40 psi until hydrogen uptake ceased. The mixture was filtered through celite (trade name of diatomaceous earth) to remove the palladium catalyst and chromatographed on silica gel (hexane-ether); 25.1 g (94% yield) of the title product of Example 2E were obtained.

F. 7- (2-Carboethoxy-5-trifluoromethylphenyl) -3-phenylmethyl-3,4-dihydrobenzopyran

Obtaining the desired product of Example 2F using 2- (4-trifluoromethylphenyl) -4,4-dimethyl-4,5-dihydro-oxazole as reactant and using the method disclosed in Examples 1F-1J It was.

G. 7- (2-Carboethoxy-5-trifluoromethylphenyl) -3-phenylmethyl-3,4-oxyranobenzopyran

M-CPBA (89 mg, 0.53 mmol) was added to an olefin solution of Example 2F (230 mg, 0.53 mmol) in methylene chloride at about 0 ° C. After about 1 hour, the mixture was diluted with ether and washed with 1N NaOH solution and brine. The organic layer was dried (MgSO ₄ ), filtered and concentrated. Flash chromatography (eluted with 3: 1 hexanes-ethyl acetate) gave the corresponding epoxide (209 mg, 87%) of Example 2G. The product was soon used in the next step.

H. 7- (2-Carboethoxy-5-trifluoromethylphenyl) -3-phenylmethyl-3-hydroxy) -benzopyran

To a solution of epoxide (150 mg, 0.33 mmol) of Example 2G in ethyl acetate was added 10% Pd (100 mg) on carbon. The system was tightly sealed with a balloon containing H ₂ and the flask was purged several times. After stirring for about 16 hours the solution was filtered and concentrated. Flash chromatography eluted with 5: 1 hexane-ethyl acetate gave the preferred alcohol (80 mg, 53%) of this Example 2H.

I. 7- (2-carboxy-5-trifluoromethylphenyl) -3-phenylmethyl-3-hydroxybenzopyran

Saponification of the compound of Example 2H, analogous to the method described in Example 1L, afforded the desired product of Example 2.

Example 3

(3S ^* , 4R ^* )-7- (2-carboxy-5-trifluoromethyl-3,4-dihydroxy) -3-phenylmethyl-benzopyran

A. 7- (Carboethoxy-5-trifluoromethylphenyl) -3-phenylmethyl-3-hydroxybenzopyran-4-one

To a solution of olefin of Example 2F (3.7 g, 8.44 mmol) in acetone-water was added N-methylmorpholine-N-oxide (3.0 g, 25.3 mmol) followed by OsO ₄ . After stirring overnight, the solution was diluted with water and extracted with ethyl acetate. The combined extracts were dried and concentrated. The residue was purified by flash chromatography to give the corresponding hydroxy ketone (3.0 g, 76%) of Example 3A. Melting point: 85-87 ° C.

B. (3S ^* , 4R ^* )-7- (2-carboethoxy-5-trifluoromethylphenyl) -3,4-dihydroxy-3-phenylmethyl-benzopyran

NaBH ₄ (250 mg, 6.4 mmol) was added to a solution of ketone (3.0 g, 6.4 mmol) of Example 3A in methanol (50 mL) at room temperature. After about 30 minutes, the reaction was quenched (NH ₄ Cl solution), extracted (ethyl acetate), dried (MgSO ₄ ), filtered and concentrated. Flash chromatography (eluted with 2: 1 hexanes-ethyl acetate) gave the preferred trans-diol (2.9 g, 97%) of Example 3B.

C. (3S ^* , 4R ^* )-7- (2-carboxy-5-trifluoromethyl-3,4-dihydroxy) -3-phenylmethyl-benzopyran

Similar to the method described in Example 1L, the compound of Example 3B was saponified to give the preferred acid of this Example 3. Melting point: 100-102 ° C.

Example 4

(3S ^* , 4S ^* )-7- (2-trifluoromethanesulfonylamino-5-fluoro) -3,4-dihydro-3-hydroxy-3-phenylmethyl-2H-1-benzopyran

A. 7-[(5-fluoro- (2- (4,4-dimethyl-2-oxazolinyl) phenyl] -3-phenylmethylene-1-benzopyran-4-one

N in hexane to a stirred solution of 2- (4-fluorophenyl) -4,4-dimethyl-2-oxazoline (1.0 equiv in tetrahydrofuran, 0.5 M concentration) at about -78 ° C under N ₂ -Butyllithium (1.1 equiv, 2.5 M solution) was added. The mixture was stirred at about −78 ° C. for about 1 hour before ZnCl ₂ (1.1 equiv, 1M solution in ether) was added. The mixture was warmed at about 10 ° C. for about 1 hour to afford 2- (4-fluorophenyl-2-chlorozin) -4,4-diethyl-2-oxazoline (not isolated). To this solution was added 7-[((trifluoromethyl) sulfonyl) oxy] -3-phenylmethylene-1-benzopyran-4-one (1.0 equiv) and Pd (PPh ₃ ) ₄ (0.02 equiv) . The mixture was refluxed (about 68 ° C.) for about 3 hours, cooled to room temperature and poured into NH ₄ Cl solution. The solution was extracted three times with diethyl ether and the combined organic fractions were dried over MgSO ₄ . Filtration and removal of solvent in vacuo and column chromatography (silica gel -2: 1 hexanes: ether) gave the title compound of Example 4A as a yellow solid. 65% yield.

B. (3S ^* , 4R ^* )-7- [5-fluoro- (2- (4,4-dimethyl-2-oxazolinyl) phenyl] -4-hydroxy-3-phenylmethyl-2H-1 -Benzopyran

To a stirred solution of the compound of Example 4A in THF (0.1M) at about 0 ° C. was added dropwise LiAlH ₄ (1M in ether, 2.2 equiv) for about 10 minutes. The mixture was allowed to warm to room temperature and stirred for about 12 hours. The mixture was cooled to about 0 ° C., quenched with 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 ₄ . Filtration and removal of solvent gave a yellow oil. Chromatography on silica gel (ethyl acetate: hexane) afforded the title compound of Example 4B in 60% yield as a white solid. Melting point 65-70 ° C (decomposition).

C. (3S ^* , 4R ^* )-7- (2-carboxy-5-fluorophenyl) -4-hydroxy-3-phenylmethyl-2H-1-benzopyran

The compound of Example 4B was dissolved in methyl iodide (0.5M) at room temperature and stirred for about 24 hours. Methyl iodide was removed in vacuo, the oil solid was dissolved in CH ₂ Cl ₂ and the solvent was removed in vacuo. This operation was repeated to remove traces of methyl iodide. The solid was dissolved in methanol (0.5M) and 2M NaOH (0.5M) was added. 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 MgSO ₄ . Filtration and removal of the solvent in vacuo followed by chromatography (silica gel, 10: 1 methylene chloride: methanol) afforded the acid of the desired Example 4C in 93% yield.

D. (3S ^* , 4S ^* )-7- (2-carboxy-5-fluorophenyl) -3,4-dihydroxy-3-phenylmethyl-2H-1-benzopyran

The title compound of Example 4D was prepared from the compound of Example 4C using the method of Examples 1I-1L.

E. (3S ^* , 4S ^* )-7- (2-carbenzyloxyamino-5-fluoro) -3,4-dihydroxy-3-phenylmethyl-2H-1-benzopyran

To a solution of 1 mmol prepared in Example 4D in 10 ml of 1,4-dioxane was added 1.05 equivalents of diphenylphosphoryl azide, 1.1 equivalents of benzyl alcohol and 2.2 equivalents of triethylamine. The mixture was refluxed for about 16 hours, the solvent was removed in vacuo and the residue was chromatographed on silica gel (1: 1 hexanes: EtOAc) to afford the N-CBZ product of Example 4E.

F. (3S ^* , 4S ^* )-7- (2-trifluoromethanesulfonylamino-5-fluoro) -3,4-dihydroxy-3-hydroxy-3-phenylmethyl-2H-1 -Benzopyran

To a solution of the compound prepared in Example 4E in 10 mL EtOH was added 0.05 weight equivalent of Pd (OH) ₂ and the slurry was hydrogenated in a dig shaker, 1 Atm for about 3 hours. The mixture was filtered through celite and the filtrate was evaporated. The yellow oil was redissolved in CH ₂ Cl ₂ (10 mL), cooled to about 0 ° C., triethylamine (2.2 equiv) was added followed by trifluoromethanesulfonic anhydride (1.1 equiv). After stirring for about 2 hours, 2 equivalents of solid NaOMe were added, the reaction was stirred for about 15 minutes and H ₂ O (10 mL) was added. The mixture was titrated to pH 2 with 0.1 M HCl and extracted with 3 × 10 mL EtOAc. The combined organic layers were washed with brine, dried over MgSO _4, filtered and the solvent removed in vacuo to yield a yellow semisolid. Chromatography on silica gel (1: 1 to 10: 1 EtOAc-hexane) afforded the preferred sulfonamide of Example 4F. Melting point: 55-57 ° C.

Example 5

1- (3S, 4S)-((3- (4-phenyl-phenylmethyl) -3-hydroxy) -4-hydroxy) -chroman-7-yl) cyclopentane carboxylic acid

A. Ethyl 1- (3- (4-phenyl-phenylmethyl) -4-chromanone-7-yl) cyclopentane-carboxylate

3- (4-phenyl-benzyl) -7-trifluoromethylsulfonyloxy-4-chroman prepared from the product of Example 2C using biphenyl aldehyde using the method of Example 2D and Example 2E One (35.0 g, 91.0 mmole) was dissolved in a mixture of dimethylformamide (230 mL) and dimethoxyethane (230 mL). Trimethylsilyl ketene acetal of tris (2-methylphenyl) phosphine (7.48 g, 24.6 mmol), bis (benzonitrile) palladium (II) chloride (2.44 g, 6.37 mmol) and ethyl cyclopentanecarboxylate was added to this solution in the following order. (29.26 g, 136.5 mmol) and 1.0 M ether solution of zinc chloride (25 mL, 25 mmol) were added. The resulting clear yellow solution was refluxed for about 1 hour. Additional trimethylsilyl ketene acetal (9.75 g, 45.5 mmole) was added at this point and refluxed for another hour. The cooled mixture was diluted with water (1 L) and then extracted with ether. The combined ether extracts were washed with water (1 L) and dried over magnesium sulfate. The extract was filtered and dried to give a yellow oil which was chromatographed on silica gel (8:92 ethyl acetate / hexanes). This gave 22.13 g (64%) of the title compound of Example 5A as a white solid:

B. Ethyl 2- (4-hydroxy-3- (4-phenyl-phenylmethyl) chroman-7-yl) -cyclopentane carboxylate

The compound of Example 5A (111.99 g, 295.9 mmol) was dissolved in ethanol (2.5 L) and carefully treated with sodium borohydride (12.3 g, 325.5 mmol) at room temperature. After about 3 hours, the reaction mixture was concentrated in small portions and diluted with ether. The ether was washed with saturated sodium bicarbonate solution and dried over sodium sulfate. The extract was filtered, concentrated to an oil and chromatographed on silica gel (20:80-ethyl acetate / hexanes). This gave a higher R _f product, i.e. 3R ^* , 4R ^* 63.4g (56%) as oil:

C. 1- (3S, 4S)-((3- (4-phenyl-phenylmethyl) -3-hydroxy) -4-hydroxy) -chroman-7-yl) cyclopentane carboxylic acid

Similar to the method described in Examples 1J-1L, the compound of Example 5B was reacted to obtain the title compound of Example 5, to obtain the desired product from the cis and trans mixture of the compound of Example 5B. Melting point 185-187 캜.

Example 6

(3S, 4S) -7- (carboxy-5-trifluoromethylphenyl) -3,4-dihydroxy-3-phenylmethyl-benzopyran

A. 7- (2-Carbomethoxy-5-trifluoromethylphenyl) -4-L-t-Boc-tryptophan ester-3-hydroxy-3-phenylmethyl) benzopyran

(3S, 4S) -7- (2-carbomethoxy-5-trifluoromethylphenyl) -3,4-dihydroxy-3-phenylmethylbenzopyran (225 mg, in CH ₂ Cl ₂ (6 mL), To a solution of 0.49 mmol) t-BOC-L-tryptophan (223 mg, 0.74 mmol), DMAP (120 mg, 0.98 mmol) and EDCl (165 mg, 0.86 mmol) were added. After stirring for about 16 hours, the solution was diluted with ethyl acetate and washed with 1N HCl and brine, dried (MgSO ₄ ), filtered and concentrated. Purification of the residue by flash chromatography (hexane-ether-methylene chloride, 3: 1: 6) yielded 137 mg of 38% faster diastereomer of Example 6A and then 135 mg of slower diastereomer. Obtained.

B. (3S, 4S) -7- (2-Carbomethoxy-5-trifluoromethylphenyl) -3,4-dihydroxyl-3-phenylmethyl-benzopyran

To a solution of the higher R _f t-BOC tryptophan ester (130 mg, 0.17 mmol) of Example 6A in methanol-THF (7 mL, about 5: 2) was added 1N NaOH (175 mL, 1N). After about 1 hour the solution was diluted with ethyl acetate and washed with 1N HCl and brine, dried (MgSO ₄ ), filtered and concentrated. Purification by flash chromatography (eluted with hexane-ether-methylene chloride 2: 1: 6) gave the corresponding alcohol (63 mg, 80%) of Example 6B.

C. (3S, 4S) -7- (carboxy-5-trifluoromethylphenyl) -3,4-dihydroxy-3-phenylmethyl-benzopyran

To a solution of the ester of Example 6B (60 mg, 0.13 mmol) in methanol (3 mL) was added NaOH (3 mL, 3N). After heating at about 60 ° C. for about 1 hour, the mixture was cooled and acidified with 1N HCl. The solution was extracted with ether and the combined extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated to give the essentially pure acid (46 mg, 80%) of Example 6, which was recrystallized from hexane-ethyl acetate. To further purify. Melting point: 90-92 ° C.

Example 7

7- (2-Carboethoxy-5-fluoro-phenyl) -4-hydroxy-3- (4-phenyl-phenylmethyl) -benzopyran

A. 7- (trimethylstannyl) -3- (4-phenyl-phenylmethyl) -benzopyran-4-one

To a stirred solution of the compound prepared in Example 2E (10.95 g, 25.0 mmol) in 200 mL dioxane was lithium chloride (3.20 g, 75.0 mmol), Pd (PPh ₃ ) ₄ (1.15 g, 1.0 mmol), butyl Crystal 3 of hydroxytoluene and hexamethylditin (9.0 g, 27.5 mmole) were added. The mixture was heated to reflux for about 1.5 hours, cooled to room temperature and poured into 150 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with 3 × 150 mL of 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 chromatographed on silica gel (5: 1 hexanes: ether) to give 9.8 g (89% yield) of the title product of Example 7A.

B. 7- (2-Carboethoxy-5-fluoro-phenyl) -3- (4-phenyl-phenylmethyl) -benzopyran-4-one

To a stirred solution of the compound of Example 7A (8.28 g, 17.5 mmol) in dimethylformamide (DMF) (35 mL) Pd (PPh ₃ ) ₂ Cl ₂ (490 mg, 0.7 mmol), Crystal 3 of BHT and ethyl -2-Yodo-5-fluorobenzoate (5.4 g, 19.1 mmol) was added. The mixture was stirred at reflux for about 1.5 hours, cooled to room temperature and poured into 150 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with 3 × 150 mL of diethyl ether and the combined extracts were washed with 2 × 100 mL of water and then brine. The solution was dried over sodium sulfate, filtered and evaporated in vacuo to give a yellow oil. Chromatography on silica gel (4: 1 hexanes: ether eluting) gave 6.51 g of the title compound of Example 7B as a sticky oil.

C. 7- (2-Carboethoxy-5-fluoro-phenyl) -4-hydroxy-3- (4-phenyl-phenylmethyl) -benzopyran

To a stirred solution of the compound of Example 7B (6.60 g, 17.5 mmol) in 35 mL methanol at room temperature was added sodium borohydride (940 mg, 26.0 mmol) in one portion. The dark mixture was stirred at rt for about 2 h and then poured into saturated aqueous ammonium chloride solution (75 mL) and extracted with 3 × 75 mL diethyl ether. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield a yellow oil. Chromatography on silica gel eluted with 4: 1 hexanes: ether first gave 3.26 g of the cis isomer of the title compound of Example 7, followed by 1.98 g of the trans isomer of the title compound of Example 7 as a sticky oil. It was. Total yield is 81%.

Example 8-16

The compounds of Examples 8-16 were synthesized analogously to the synthetic methods specified using the appropriate corresponding starting materials in the table below.

The present invention provides benzopyrans and benzo-condensed compounds useful as LTB ₄ antagonists.

Claims (8)

A compound of Formula 1 or a pharmaceutically acceptable salt thereof: Formula 1 Where A ¹ is NH or N (C ₁ -C ₆ ) alkyl; R ³ is hydrogen or hydroxy; A ² is ego; R ⁴ is hydrogen or hydroxy; R ⁵ is -CH (OH) X ¹⁰ ; X ¹⁰ is a (C ₃ -C ₈ ) cycloalkyl, or an optionally substituted ring of one of phenyl, thienyl, pyridyl, furyl, naphthyl, quinolyl, isoquinolyl, pyrimidinyl and pyrazinyl, wherein , Optionally substituted ring is fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) purple Optionally substituted with one or two substituents independently selected from the group consisting of fluoroalkoxy and optionally substituted phenyl; optionally substituted phenyl is fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆₎ alkoxy, (C ₁ -C ₄₎ alkyl and (C ₁ -C ₄₎ one independently from the group consisting of perfluoro-alkoxy or two substituents selected perfluoroalkyl is optionally substituted), and; R ⁶ and R ⁷ are each independently hydrogen or (C ₁ -C ₄ ) alkyl, or R ⁶ and R ⁷ together with the carbon atoms bonded to them form a (C ₄ -C ₇ ) cycloalkyl; R ¹ is substituted 5-membered optionally having one or two heteroatoms independently selected from the group consisting of tetrazolyl, carboxy,-(CH ₂ ) _m -CX ³ X ⁴ X ⁵ , and O, S and N Or a six membered aromatic ring; m is 0, 1 or 2; X ³ and X ⁴ are each independently hydrogen or (C ₁ -C ₆ ) alkyl, or X ³ and X ⁴ together with the carbon atoms bonded thereto form a (C ₃ -C ₇ ) cycloalkyl; X ⁵ is hydroxy, carboxy or tetrazolyl; Substituted 5- or 6-membered aromatic rings include -N (H) (SO ₂ -X ⁷ ), -N (H) (CO-X ⁷ ) and -N (H) (CO-O (C ₁ -C ₆₎ Substituted with one substituent selected from the group consisting of X ⁷ is —CF ₃ , (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, or phenyl, thienyl, pyridyl, furyl, naphthyl, quinolyl, isoquinolyl, pyrimidinyl And optionally substituted ring of one of pyrazinyl, wherein the optionally substituted ring is fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) Optionally substituted with one or two substituents independently selected from the group consisting of perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy and optionally substituted phenyl; optionally substituted phenyl is fluoro, chloro , Independently selected from the group consisting of (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl and (C ₁ -C ₄ ) perfluoroalkoxy Or optionally substituted with two substituents); R ² is hydrogen, fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoro Alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl or phenyl sulfonyl. The method of claim 1, Wherein R ³ is hydroxy and A ² is Phosphorus compounds or pharmaceutically acceptable salts thereof. The method of claim 2, Wherein R ¹ is-(CH ₂ ) _m CX ³ X ⁴ X ⁵ , or -N (H) (SO ₂ -X ⁷ ), -N (H) (CO-X ⁷ ) and -N (H) (CO A compound or a pharmaceutically acceptable salt thereof, which is a 5- or 6-membered aromatic ring substituted with one substituent selected from the group consisting of -O (C ₁ -C ₆ ) alkyl). The method of claim 3, wherein Wherein R ¹ is -N (H) (SO ₂ -X ⁷ ), -N (H) (CO-X ⁷ ) and -N (H) (CO-O (C ₁ -C ₆ ) alkyl) A compound or a pharmaceutically acceptable salt thereof, which is phenyl substituted with one substituent selected from. The method of claim 4, wherein Wherein R ⁴ is hydroxy; A compound wherein R ³ hydroxy is cis or trans with R ⁴ hydroxy or a pharmaceutically acceptable salt thereof. The method of claim 5, Wherein R ¹ is phenyl substituted with -N (H) (SO ₂ -X ⁷ ); A compound or a pharmaceutically acceptable salt thereof, wherein R ³ hydroxy and R ⁴ hydroxy are cis relative to one another. The method of claim 6, Wherein X ¹⁰ is phenyl or phenyl substituted with phenyl in the para position or a pharmaceutically acceptable salt thereof. A compound of formula 1a Formula 1a Where A ¹ is NH or N (C ₁ -C ₆ ) alkyl; A ² is ego; R ⁴ is hydrogen or hydroxy; R ⁵ is selected from the group consisting of — (CH ₂ ) _n X ¹⁰ and —CH (OH) X ¹⁰ ; n is 0, 1, 2 or 3; X ¹⁰ is a (C ₃ -C ₈ ) cycloalkyl, or an optionally substituted ring of one of phenyl, thienyl, pyridyl, furyl, naphthyl, quinolyl, isoquinolyl, pyrimidinyl and pyrazinyl, wherein , Optionally substituted ring is fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) purple Optionally substituted with one or two substituents independently selected from the group consisting of fluoroalkoxy and optionally substituted phenyl; optionally substituted phenyl is fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆₎ alkoxy, (C ₁ -C ₄₎ alkyl and (C ₁ -C ₄₎ one independently from the group consisting of perfluoro-alkoxy or two substituents selected perfluoroalkyl is optionally substituted), and; R ⁶ and R ⁷ are each independently hydrogen or (C ₁ -C ₄ ) alkyl, or R ⁶ and R ⁷ together with the carbon atoms bonded to them form a (C ₄ -C ₇ ) cycloalkyl; R ¹ is substituted 5-membered optionally having one or two heteroatoms independently selected from the group consisting of tetrazolyl, carboxy,-(CH ₂ ) _m -CX ³ X ⁴ X ⁵ , and O, S and N Or a six membered aromatic ring; m is 0, 1 or 2; X ³ and X ⁴ are each independently hydrogen or (C ₁ -C ₆ ) alkyl or X ³ and X ⁴ together with the carbon atom bonded thereto form a (C ₃ -C ₇ ) cycloalkyl; X ⁵ is hydroxy, carboxy or tetrazolyl; Substituted 5- or 6-membered aromatic rings include carboxy, tetrazolyl, -CO-N (H) (SO ₂ -X ⁷ ), -N (H) (SO ₂ -X ⁷ ), -N (H) (CO -X ⁷⁾ and -N (H) (CO-O (C 1 -C 6) one substituent selected from the group consisting of alkyl), and fluoro, chloro, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl and (C ₁ -C ₄ ) perfluoroalkoxy each substituted with one or two substituents independently selected from the group consisting of; X ⁷ is —CF ₃ , (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, or phenyl, thienyl, pyridyl, furyl, naphthyl, quinolyl, isoquinolyl, pyrimidinyl And optionally substituted ring of one of pyrazinyl, wherein the optionally substituted ring is fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) Optionally substituted with one or two substituents independently selected from the group consisting of perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy and optionally substituted phenyl; optionally substituted phenyl is fluoro, chloro , Independently selected from the group consisting of (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl and (C ₁ -C ₄ ) perfluoroalkoxy Or optionally substituted with two substituents); R ² is hydrogen, fluoro, chloro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoro Alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, phenylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl or phenyl sulfonyl.