FI92188B - Process for the preparation of therapeutically useful phenoxyalkylpyrocatechol derivatives - Google Patents

Description

92188

Process for the preparation of therapeutically useful phenoxyalkyl pyrocatechol derivatives

The invention relates to a process for the preparation of phenoxyalkylpyrocate-5 coli derivatives of formula I

r3 '^^ y'R1

~ Y

wherein R 2 is -C (O) O R, hydrogen, acetyl or hydroxy, R 2 is -C (O) O R, hydroxy, hydrogen or alkanoyloxy, wherein R is hydrogen, lower alkyl or - (CH 2) n N- (lower alkyl) 2 , R 15 is hydrogen, lower alkyl or amino, R 4 is hydrogen, lower alkyl, halogen or amino and A is ° R 5 20 JL xJl (A,) Κ7Τ ^ (εΗ2) η-R8 or or5. R 5 is a hydrogen, lower alkanoyl or benzoyl optionally substituted with lower alkyl, R 6 is hydrogen, halogen, lower alkyl or phenyl, and R 7 and R 6 are independently hydrogen, lower alkyl or halogen, R 1 is hydrogen or lower alkyl, R 10 is lower alkyl, hydrogen or halogen, Ru is hydrogen, lower alkyl or halo 2 92188 gene, m is 0 or 1, n is one of the integers 2-10, provided that only one of R 2 and R 2 may be hydroxy, alkanoyloxy, or -C (O) O R, and when R is hydrogen, to prepare a salt of such a compound with a pharmaceutically acceptable base, and when R is - (CH 2) n N - (lower alkyl) 2, for the preparation of an addition salt of such a compound with a pharmaceutically acceptable acid.

The compounds of formula I are useful as active ingredients for the topical application of inflammatory diseases such as arthritis, inflammatory bowel diseases such as colitis, cardiovascular diseases such as myocardial chemistry, skin diseases such as pso-15 in the treatment of lung tissue-related diseases such as asthma.

As used herein, the term "lower alkyl" means a straight-chain or branched saturated carbon-20 containing 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, heptyl, and the like. . Branched saturated hydrocarbons are preferred for R6, R, and Rn. The term "halogen" refers to all halogens, i.e. bromine, chlorine, fluorine and iodine. The term "acyl" means an "alkanoyl" group derived from an aliphatic carboxylic acid having 1 to 7 carbon atoms, for example, formyl, acetyl, propionyl and the like; and an "aroyl" group derived from an aromatic carboxylic acid, for example, benzoyl and the like. The term "alkanoyloco-

• I

si "means a group derived from an aliphatic carboxylic acid having 1 to 7 carbon atoms, for example, formyloxy, acetoxy, propionyloxy and the like.

3 92188

The compounds of the formula I can also be described by the formulas Ia and Ib, according to which part A is in each case a piece A 'or A ", as follows:

Ro 1 10 ° K4 or OR5 R2 »R1vy- Ib

R9 T

R10 0 k4 wherein Rj, Rj, R3, R4, R5, Rj (R7, Rj, Rg, R10 »Rn, ® and 20 are as described herein.

Particularly good compounds of formula Ia of the invention are those in which R3 is carboxy or acetyl, R2 is hydroxy, R3 is hydrogen or propyl, R4 is hydrogen or chlorine, n is one of the integers 2-10, R5 is hydrogen or acetyl, R6 is hydrogen, lower alkyl or phenyl, R 7 and R 6 are hydrogen.

Particularly good compounds of formula Ib of the invention are those in which R 1 is carboxy or acetyl, R 2 is hydroxy, R 3 is hydrogen or propyl, R 4 is hydrogen or chlorine, m is 0 or 1, n is one of the integers 2-10, R 1 is hydrogen C 1-6 acetyl, R 1 and R 10 are hydrogen and Ru is hydrogen or chlorine.

Even more preferred compounds of formula Ia are those wherein R 3 is carboxy or acetyl, R 2 is hydroxy, R 3 is hydrogen or propyl, R 4 is hydrogen or chlorine, n is any of the integers 4-8, R 5 is hydrogen or acetyl, R 6 is hydrogen or lower alkyl and R 7 and R a are hydrogen.

Even more preferred compounds of formula Ib are those in which Rx is carboxy or acetyl, R2 is hydroxy, R3 is n-propyl, R4 is hydrogen, m is 0, n is one of the integers 4-6, R5 is hydrogen or acetyl , R 1 and R 10 are hydrogen, R 11 is hydrogen or chlorine.

The most preferred compounds of formula Ia are those wherein Rx is carboxy or acetyl, R2 is hydroxy, R3 is n-propyl, R4 is hydrogen, n is any of the integers 4-8, R5 is hydrogen, R6 is hydrogen or a -branched lower alkyl and R7 and R8 are hydrogen.

The most preferred compounds of formula Ib are those wherein Rx is carboxy or acetyl, R2 is carboxy or acetyl, R2 is hydroxy, R3 is n-propyl, R4 is hydrogen, m is 0, n is any of the integers 4-6 , R 5, R 9, R 10 and Ru are hydrogen.

Preferred compounds of the invention are: 4- [6- (2,3-dihydroxyphenyl) hexyloxy] -2-hydroxybenzoic acid; 4- [6- (2,3-dihydroxyphenyl) hexyloxy] benzoic acid; 4- [6- (3,4-dihydroxy-2,5-dimethylphenyl) hexyloxy] -2-25 hydroxy-3-propylbenzoic acid; * 4- [5- (2,3,4-trichloro-5,6-dihydroxyphenyl) pentyloxy] -2-hydroxy-3-propylbenzoic acid; 4- [4- (2,3-dihydroxyphenyl) butoxy] -2-hydroxy-3-propyl-1ibentsoehappo; 4- [6- (2,3-dihydroxyphenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid, 4- [8- (2,3-dihydroxyphenyl) octyloxy] -2-hydroxy-3-propylbenzoic acid , 4- [6- [2,3-bis (acetyloxy) phenyl] hexyloxy] -2-hydroxy-35-propylbenzoic acid; 15 92188 4- [6- [2,3-dihydroxy-4- (1-methylethyl) phenyl] hexyloxy] -2-hydroxy-3-propylbenzoic acid, 4- [3- (3,4-dihydroxyphenyl) propoxy ] -2-hydroxy-3-propylbenzoic acid, 5 4- [6- (3,4-dihydroxyphenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid, 4 - [[6- (3-4-dihydroxyphenyl) ) -6-oxohexyl] oxy] -2-hydroxy-3-propylbenzoic acid, and 1- [2-hydroxy-4- [4- (2,3-dihydroxyphenyl) butoxy] -3-prop-10-phenylphenyl] ethanone .

The process according to the invention is characterized in that the formula och3 och3 is given by r6 ^ | V'OCH3 ch3 ° —— · Rn R7J ^ T '(CH2) nBr R9T' <S> n-, CH2> nx

Re Rio o

II1 XXXVI

20 to react with the formula R2 '* 3 rY * 1'

XXXIII

HO-Y ^

:: 25 X

with a compound of formula, R 2 OCH 2 * 2 8 R * R 10 o r 4

XXXIV

XXXVII

35, or is given the formula 6 92188 0Ri2 R6 ^ YORi2

JL li XXXIX

React a compound of formula (CH2) nBr5R8 with a compound of formula to prepare a compound of the following formula y2-R6vf ^ ^ 0R12 r ^> ^ v> _cogh2 — v y

r8 R4 XXXXI

when

R 1 'is hydrogen, lower alkoxycarbonyl or acetyl; R 2 'is hydrogen or lower alkoxycarbonyl; • 1 R 12 is benzyl or acyl, R 13 is benzyl; X is bromine or methanesulfonyloxy; and other symbols are as defined above; provided that only one of R2 'and R2' may be hydroxy or lower alkoxycarbonyl, or that a1. · Only one of the symbols Rx "and R2H may be carboxy * or hydroxy; cleavage of methoxy groups in a compound of formula XXXIV or XXXVII; cleavage of a benzyl ester and any benzyl ester groups R12 in a compound of formula XXXXI; in a compound of formula XXXX, optionally esterifying a hydroxy group R 2 is hydroxy and R 12 is benzyl, and the benzyl groups are cleaved, and, if desired, the carboxy group represented by R 2 or R 2 is esterified, converted to a salt with a pharmaceutically acceptable base, or converted to a salt with a pharmaceutically acceptable acid by a di-lower alkyl substituted amino group.

The preparation of compounds of formula I and intermediates therefor is described in more detail in connection with reaction formulas I-XII.

• ^ «· 1 8 92188

Reaction Scheme I

OCH3 OCH3 5 Re ^^ YCCU3 1) C4H9Li κ6 ^^ \ ^ 0 <: Η3 2) Er (CH2) R7 ^ Jl (CH2, nBr

Rg o

III

II

10 BBr3 y

(/ y-CH 2 OH)

_R6J ^ och2- ^ Q> R / * y ^ <CH2> n R8

° IV

20 V

Ac2O

cH3- ^ y-coci 25 * m t OAc Η6 \ ^ \ ρΟΑσ 30 CEgrfi ~ ^ S — C — O 0 / = \ R7 ^ SY ^ (CH2) nBr; ^ = SA- «0“ · R / l ^ y ^ (CH2) nBr 35

II

VII

9,921,88 wherein R 9, R 7, R 8 and n are as previously described and Ac is acetyl.

In Reaction Formula I, a compound of formula II, such as known compounds, or can be prepared according to known methods, can be converted to the corresponding known compounds of formula III as described in H. Halim, H.D. Locksley and J.J. Memon, J.Chem.Soc. Perkin I, 2331 (1980). More specifically, the compound of formula II is reacted with an alkyllithium reagent, preferably butyllithium, in the presence of a solvent such as diethyl ether, tetrahydrofuran or the like at a temperature between about -75 ° -0 ° to give the corresponding lithium salt, followed directly by lithium salt. react in situ with an excess of dibromoalkane at a temperature in the range of about 0-50 °.

The compound of formula III may be converted to the corresponding compound of formula IV, for example, using boron tribromide in a halogenated hydrocarbon solvent, for example chloroform or 1,2-dichloroethane, or preferably methylene chloride, at a temperature between about -75 ° and about 25 ° C. °.

The resulting compound of formula IV can be converted to the corresponding compound of formula V *. In the presence of benzyl chloride, benzyl bromide or the like, potassium iodide or sodium iodide and an alkali metal carbonate, for example sodium or potassium carbonate, in a solvent such as acetone, methyl ethyl ketone or the like, under reflux at reflux, at room temperature, or using dimethyl about 50 ° to about 100 °.

The compound of formula IV can be converted to the corresponding compound of formula VI in the presence of an acetic anhydride and an acid catalyst, for example perchloric acid, in a solvent such as ethyl acetate and the like, at a temperature between 0 ° C and about 25 ° C.

Alternatively, the resulting compound of formula IV can be converted to the corresponding compound of formula VII using 4-methylbenzoyl chloride and an organic tertiary amine base such as triethylamine in a solvent such as tetrahydrofuran, dioxane or ethyl ether at a temperature between 0 ° - about 25 °.

10 Reaction Scheme II

och3 ch3 9 ° η3 Κργ ^^ θαί3 1) Li (CH2) nOCHOCH2CH3 ^ R6 \ p ^ v ^> CH3

R7 "(CH2) nOH

Rg r8 OH

Vili IX

H2 20

Pd

Y

och3 och3 25 c CH, SO, Cl Κ6γ ^ ΟΟΗ3

R7 (CH2) nCH2SO2CH3 R7 (CH2) nCH2OH

R8 R8 xi x 30 wherein Rg, and Rg and n are as previously described. In Reaction Formula II, an alde-35 hydride of formula VIII, such as known compounds or can be prepared according to known methods, can be <. · 11 92188 is converted to the corresponding compound of formula IX as described in J.H.P. Tyman and C.H. Khor, Chem. Ind., 526 (1974). More specifically, the aldehyde of formula VIII is reacted with a lithium-5 reagent prepared by general methods in a solvent such as ethyl ether, tetrahydrofuran or the like at a temperature between about -20 ° and about 35 °. The alcohol protecting group can be removed from the product by treatment with dilute chloro-10 hydrochloric acid at 25 ° to give the diol of formula IX.

The corresponding compound of formula X is then obtained by hydrogenolysis of a compound of formula IX by shaking in a Parr apparatus under a hydrogen pressure of about 40-60 psi, using a palladium catalyst, at a temperature between about 25 ° C and about 50 °, in a solvent such as ethyl acetate, ethanol, tetrahydrofuran and the like.

The conversion of a compound of formula X to the corresponding mesylate XI can be carried out under normal conditions, for example using methanesulphonyl chloride and triethylamine in a solvent such as methylene chloride, at a temperature between about -20 ° -. „_ O about 25.

• ·

Reaction Scheme III

12 921 88 5 OCH3 CH3 0ch3 0Η30γ ^ γΛ11 1) Li (CH2) nOCHOCH2CH3 ^ CH3 ° Np: ^ pR11

R9 ^ f ^ CHO 2) H + R9 ^ NftjH (CH2) nOH

Rio R10OH

10 XIII

h2

Pd

V

15 och3 och3 CH3 ° Vj ^ W'R11 ^ CH ^ SO2Cl CH3 ° V / * ^ v ^ 'r11

R9 (CH2) nCH2SO2CH3 R8 (CH2) nCH2OH

R10 Rio

XV XIV

25 wherein R 9, R 10 # R 2 and n are as previously described. In Reaction Formula III, a compound of Formula XII can be converted to the corresponding compound of Formula XIII and in turn can be converted to the corresponding compounds of Formulas XIV and XV using the reaction conditions set forth in Reaction Formula II.

Reaction Scheme IV

13 92188 OCH3 ° CIJ3 5 fj ^ Wp-OCH3 ci2 \ ^ (CH,) nBr γ ^ «: Η2> ηΒΓ

Cl

111 XVI

10 \ N. 2 Cl, 3 ci2 15 * N \ och3 och3 civY / t ^ -ocH3 OCHCH

ClT'S ^ ICH ^ Br ΟΙ ^^? ^ (ΟΗ2) ηΒΓ C1 Cl XVIII XVI1 OCH ·,

OCH-i I J

(CH 2) n OH

N (CH2) nOH I 2 n

Cl

30 XIX XX

35 wherein n is as previously described.

«· * * 14 92188

In Reaction Formula IV, a compound of formula III, which are known compounds or can be prepared according to known methods, can be converted to the corresponding monochloro compounds of formula XVI, dichloro compounds of formula XVII and trichloro compounds of formula XVIII by treatment with a suitable amount of chlorine in an inert solvent. methylene chloride, chloroform, 1,2-dichloroethane and the like, at a temperature between about -20 ° and about 25 °.

Conversion of a compound of formula XIX to the corresponding compound of formula XX can be performed using the reaction conditions first described above.

Reaction Scheme V

15 OCH3 9 ° H3 αΗ3θγ4γ ^ 11 HCsC (CH2) nOH_> CH3 ° v | p ^ R11

20 r (C6H5) 3P72pdCl2 R9 '^' S, ^ C ^ (CH2) nOH

XXI XXII

25 H2

Pd

Y

30? CH3? Ch3

CH3 (V'WR11 ^ CH ^ SO2? C1 CH30V ^ N-rU

CH2CE2 (CH2) nSOSO2CH3 (CH2) nOH

XXIV XXIII

35 15 921 88 wherein Rg, and and n are as previously described.

In Reaction Scheme V, a compound of formula XXI is converted to an acetylene alcohol of formula XXII by reaction with acetylene alcohol in the presence of bis-5 (triphenylphosphine) palladium dichloride, copper (1) iodide and an organic amine (triethylamine) as described in K. Sohogashira, Y. Tohda Hagihara, Tet. Letters 4467 (1975).

The reaction is carried out in a solvent, for example a halogenated hydrocarbon, for example methylene chloride, chloroform, 1,2-dichloroethane or the like, at a temperature between about 25 ° and about 50 °.

The resulting compound of formula XXII is converted to the compound of formula XXIII using normal conditions, for example catalytic hydrogenation at atmospheric pressure and room temperature.

The resulting compound of formula XXIII can be converted to a compound of formula XXIV using normal conditions, for example, methanesulfonyl chloride in the presence of triethylamine in methylene chloride as a solvent at a temperature between about -20 ° and about 25 °. 1 · k · · 16 92188

Reaction Scheme VI 5 cch3 o cch3 CHjO 1 Ru li CH3O I Rn 3 yy Monaco yy ju CF3COCCF3 yy 10 0 II fV C- (CH2) p.5r 00 0

xxv XXVI

H2

Pd 15 cch3 ch3 ° \ A / r "20 μl | CH2- (CH2Jt.Bf XXV13 wherein R8, R2 and n are as previously described.

In Reaction Scheme VI, a compound of formula XXV, such as known compounds or can be prepared according to known methods, can be converted to a compound of formula XXVI using normal acylation conditions, for example treatment with a bromo acid and trifluoroacetic anhydride at a temperature between about 25 ° to about 25 ° C. 40 °, without solvent or using a solvent such as methylene chloride, 1,2-dichloroethane or the like. Alternatively, a bromo acid chloride and aluminum chloride can also be used in a solvent such as m ·. 19 17 92188 methylene chloride or 1,2-dichloroethane, at a temperature between 0 ° and about 40 °.

Reduction of a compound of formula XXVI to the corresponding compound of formula XXVII can be accomplished by hydrogenation in a Parr apparatus under hydrogen pressures of about 50 to about 60 psi, using a palladium catalyst in a solvent such as ethanol, ethyl acetate, tetrahydrofuran or the like at a temperature between about 25 ° - about 70 °. In addition to the palladium catalyst 10, a mineral acid catalyst can be used.

«V’ »Y, · b ·

Reaction Scheme VII

18 92188 0H Η Jk 5 pk ^ COR 'BrCH2CH = CH2 ^ fj ^ pCOR' k2co3 ch2 = chch2o ^ \ ^

XXVIII XXIX

10 west 15 OH o OH 0 CH3CH2CH2Y ^ y COR '^ h9 CH2 = CHCH2vyvv ^: OR, 20 JL # J m JLj HO' HO ^

XXXI XXX

25 N-chlorosuccinimide

V

° H 0 CH3CH2CH2sA ^ COR 'jy

Cl

35 XXXII

J · J · 19 92188 wherein R 'is lower alkyl.

In Reaction Scheme VII, a compound of formula XXVIII, such as known compounds, or may be prepared according to known methods, may be converted to the corresponding compound of formula XXIX using normal alkylation conditions, for example using allyl bromide or chloride, alkali metal carbonate such as sodium carbonate or preferably potassium carbonate in a solvent such as methyl ethyl ketone, dimethylformamide, preferably acetone, at a temperature between about 40 ° and about 60 °.

The conversion of a compound of formula XXIX to a compound of formula XXX is accomplished by heating in an inert atmosphere at a temperature between about 175 ° and about 200 °.

The hydrogenation of a compound of formula XXX to the corresponding compound of formula XXXI can be performed using a normal catalytic hydrogenation reaction, for example at atmospheric pressure or hydrogen pressure such as 50 psi, in a solvent such as ethyl acetate, tetrahydrofuran, ethanol or the like at a temperature between about 25 ° C. ° to about 50 °.

Chlorination of a compound of formula XXXI to the corresponding compound of formula XXXII can be performed using a normal chlorination reaction, for example, using N-chlorosuccinimide in a solvent such as carbon tetrachloride, chloroform or the like at reflux temperature.

30 • *

Reaction Scheme VIII

20 92188 ocn3 r2 · 0CH3 K2CO3.

5 R7 ^ ^ MCH2) nX * »8 R4

III XXXIII

0CH3 R 1 Η6ν ^ γθΟΗ3 * 3JLSi.

R7'T ^ '(CH2> n °' 'V ^ R8 * 4

XXXIV

15 n2oh

V

OCH3 r2- 20 R6> ^ ^ 0CH3 Κ3γ ^ γΚΐ "R7 ^^ (CH2) n-O ^ Sj ^ R8 * 4

XXXV

25 I "*» fH * 2- 30 »8 r4 wherein R1 'is -C00R', acetyl, hydrogen or hydroxy, R1 'is -COOR', hydrogen or hydroxy, R 'is lower alkyl, R1' is carboxy , acetyl, hydrogen or hydroxy, R 2 "is carboxy, hydrogen or hydroxy, X is bromine or methane-sulphonyloxy, provided that only one of the symbols R 1 'and R 1' can be -COOR 'or that only one of the symbols R 1 "and R 2" may be carboxy, R 1, R 2, R 9, R 7 and R 8 and n are as previously described.

In Reaction Scheme VIII, a compound of formula III is reacted with a compound of formula XXXIII to give the corresponding compound of formula XXXIV. The reaction is carried out using an alkali metal carbonate as a base, for example sodium carbonate, preferably potassium carbonate for 10 minutes, with added sodium iodide or potassium iodide, in a solvent such as acetone, methyl ethyl ketone, dimethylformamide, toluene or the like, at a temperature between about 40 ° . The solid to liquid phase transition catalyst tris- [2- (2-methoxyethoxy) ethylamine can be used to facilitate the reaction when the solvent is toluene.

Hydrolysis of a compound of formula XXXIV to the corresponding compound of formula XXXV can be performed using standard conditions, for example using an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in a solvent such as methanol, ethanol or the like, sometimes with the addition of dioxane, sometimes between about 25 ° and about 65 °.

Conversion of a compound of formula XXXV to the corresponding compound of formula Ia 'can be performed using, for example, boron tribromide in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane or the like at a temperature between -70 ° and 25 °. The resulting compound of formula Ia 'is recovered and purified using known and conventional methods, for example, precipitation, crystallization, chromatography or the like.

35

Reaction Scheme IX

22 92188 OCHj Ri '5 Ο, 0γΛγ * Μ K3COj r / tNo .— <chi), x H0 / ir

Rio II * «XXXVI0 xxxm 10 OCHj?» * 1 “‘ YV ”xf '

15 * S

XXXVII

NtOH

20

OCH, * T

o, wu vy * ’

Ri / 'ir \ o «- (Gil), orj

Rio 0 ** 0

25 XXX VIII

BBr, YV- Ί ^ "'

Rio HR * 0 lb '35 23 92188 if Rj t R ^ i Rg t Rj ^ qt R ^ j, 1 ^ 2' '1> ^ 2' rn and X are as previously described, provided that only one of the symbols R R 1 'and R 2' may be hydroxy or -COOR 'or that only one of R 2 "and R 2" may be carboxy or hydroxy.

In Reaction Scheme IX, a compound of formula XXXVI is reacted with a compound of formula XXXIII to give the corresponding compound of formula XXXVII. The reaction is carried out using an alkali metal carbonate such as sodium carbonate or preferably potassium carbonate in a solvent such as acetone, methyl ethyl ketone, dimethylformamide or the like at a temperature between about 40 ° and about 70 °.

Conversion of a compound of formula XXXVII to the corresponding compound of formula XXXVIII may be performed using, for example, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or the like in a solvent such as methanol, ethanol or the like, sometimes with the addition of dioxane at a temperature of about 25 ° C. - about 65 °.

The conversion of a compound of formula XXXVIII to the corresponding compound of formula Ib * can be performed using, for example, boron tribromide, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane or the like, at a temperature between about -70 ° and about 25 °. The resulting compound of formula Ib1 is recovered and purified using known and conventional methods, for example, precipitation, crystallization, chromatography or the like.

If desired, a compound of formula XXXVII, XXXVIII or Ib 'where m = 1 can be converted to the corresponding compounds where m = 0 and the linking chain contains n + 1 methylene groups by shaking under hydrogen pressure. Other- -. · 92 92188 can be carried out using a catalyst such as palladium in a solvent such as ethanol, ethyl acetate or tetrahydrofuran, using a pressure of 40-60 psi. Small amounts of an acid such as concentrated sulfuric acid can be used to accelerate the reaction.

Reaction formula X

0r12 r2 0 10 R6rVORl2 Κ3γ ^ γ ^ ΟΜ2- ^) <CH2) nBr H ° "j ^ K2C03 χ

XXXIX XXXX

15 ORi 2 R6vV ° R12 R3 rj ^ p ^ 0CH2 ~

H7Y'CH2> n-OV

is R8 L

20 K4

XXXXI

h2

Pd

V

25? R5, R2 jf

* 6 γΪΓ ° 15 R3 V ^ r ^ 0H

R7 '/ ^ y ^ (CH2) n-O ^ sj ^ 30 r8 r4

Ia ".. * 35 25 92188 wherein R 2, R 3, R 4, R 9, R 2, R 8 and n are as previously described and R 2 is benzyl or acyl.

In Reaction Scheme X, a compound of formula XXXIX is reacted with a compound of formula XXXX to give the corresponding compound of formula XXXXI. The reaction is carried out using an alkali metal carbonate such as sodium carbonate or potassium carbonate, or sodium hydride in a solvent such as acetone, methyl ethyl ketone, dimethylformamide or the like at a temperature of about 25 ° to about 70 °. Hydrogenolysis of a compound of formula XXXXI to the corresponding compound of formula Ia "may be performed using a normal catalytic hydrogenolysis reaction, for example at atmospheric pressure or hydrogen pressure of up to 50 psi, at a temperature between about 25 ° and about 50 °, at a temperature such as in a solvent such as ethyl acetate, tetrahydrofuran or the like and in the presence of a catalyst such as palladium. The resulting compound of formula Ia is recovered and purified using known and conventional methods, for example, precipitation, crystallization, chromatography or the like. 1 · «

React 3-Scheme XI

921 88 26 ° TXrQz r8 n l r4

10 XXXXII

15 ^ ° R2 "O _

Vir rjv4Joch; -q R7V ^ (CH2) n-O | R8 R4

20 XXXXIXI

H2 # Pd Y

0H R2 "O

25 Κ6> ^> \ - ^ 0Η R3v ^ isv ^ C0H

r8 R4a "· wherein R4 / R8 / R7, R8 and n are as previously described and R2" 'is alkanoyloxy.

In Reaction Formula XI, a compound of Formula XXXXII can be converted to the corresponding alkanoyl derivative of Formula XXXXIII by treatment with a lower alkyl carboxylic acid anhydride in the presence of an organic base such as pyridine at a temperature between about 25 ° and about 70 °.

The resulting compound of formula XXXXIII can be converted to a compound of formula Ia "'by hydrogenolysis, for example by shaking in a hydrogen atmosphere under pressure or air at a temperature between about 25 ° to about 70 ° in the presence of a catalyst such as palladium in such a solvent. In a solvent other than ethyl acetate, tetrahydrofuran or the like.

Reaction Scheme XII

20 CH o

\ Γ C - OH

AL — Xr P-e and ».. Ra 25 30 CH n o

Re 1 CH g I3 n - c AJ1

Rl F * 35 Ia .....

28 92188 wherein R 2, R 3, R 4, R 8, R 7, R 8 and n are as previously described and R is lower alkyl or - (CH 2) n -N- (lower alkyl) 2, provided that R 2 is other than carboxy .

A lower alkyl ester or basic ester of formula Ia "" 'and, if desired, a corresponding compound of formula Ib wherein Rg is H can be prepared by reaction formula XII.

In more detail, to prepare a lower alkyl ester of formula Ia "" ', a compound of formula Ia wherein R 1 or R 2 is -C (O) OH, i.e. a compound of formula Ia "", is reacted with a lower alkyl iodide in a solvent such as acetone. dimethylformamide or the like in the presence of an alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate at a temperature between about 30 ° and about 70 ° to give the corresponding compound of formula Ia.

To prepare a basic ester of formula Ia "" ', a compound of formula Ia wherein R 1 or R 2 is -C (O) OH, i.e. a compound of formula Ia "", is reacted with a di-lower alkylamino lower alkyl chloride in a solvent such as dimethylformamide, tetrahydrofuran or the like in the presence of an alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate at a temperature between about 30 ° and about 70 ° to give the corresponding compound of formula Ia.

It will be appreciated that each intermediate prepared in Reaction Formulas I-XII is preferably recovered and isolated using known methods, for example, precipitation, crystallization, chromatography or the like, before use in the next reaction step. The final products of formula I are recovered by similar known methods.

29 92188

The invention also relates to salts of a compound of formula I when R is hydrogen, which salts are prepared by reacting said acids with a base whose cation is non-toxic and is pharmacologically acceptable. In general, any base which forms a salt with a carboxylic acid and whose pharmacological properties do not cause an adverse physiological effect is within the scope of this invention. Thus, suitable bases include, for example, alkali metal and alkaline earth metal hydroxides, carbonates and the like, for example, calcium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate and the like, ammonia, primary, secondary and tertiary amines, such as monoalkylamines, monoalkylamines, , trialkylamines, for example methylamine, diethylamine, triethylamine and the like, nitrogen-containing heterocyclic amines, for example piperidine and the like. The salt thus formed is a functional equivalent of the corresponding compound of formula I wherein R is hydrogen, and one skilled in the art will appreciate that the range of salts encompassed by the invention is limited only by the criterion that the base used to form the corresponding salts must be non-toxic and physiologically acceptable. .

The invention also relates to addition salts of compounds of formula I, wherein R is - (C 1-4) -N- (lower alkyl), which salts are prepared by reacting said amines with a non-toxic, pharmacologically or pharmaceutically acceptable acid. the compounds of formula I form pharmaceutically acceptable addition salts with, for example, both pharmaceutically acceptable organic and inorganic acids, such as acetic acid, succinic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid.

It is known that the oxidative metabolism of arachidonic acid along the Δ 2 -lipoxygenase (Δ 2 -LO) pathway results in 5 peptidoleukotrienes (LTC 2 and LTD 2) and leukotriene (LTB 4). LTC4 and LTD4 are potent human bronchodilators and contribute to edema in some species by increasing capillary permeability. LTB4 is a potent chemotactic agent for inflammatory cells. LTB4 has also been found in synovial fluid from patients with rheumatoid arthritis and gout and may be a mediator of inflammation and joint destruction in these diseases. Thus, Δ ^ -ΙιΟ: η inhibitors may be therapeutically valuable in the treatment of asthma and inflammatory diseases.

In addition, Δ ^ -LO pathway products (LTB4, LTC4, LTD4) are present in increased amounts in skin lesions of patients with psoriasis and atopic dermatitis, and may be mediators of these skin diseases. Intradermal administration of LTB4 results in a pimple and swelling reaction followed by infiltration of neutrophils at the site of administration. Neutrophil flow to the site is also observed during inflammatory reactions associated with psoriasis lesions. Topical administration of LTB4 to human skin causes abscesses resembling those of pustular psoriasis.

Oxygen-derived free radicals and their meta-30 bolites may be an additional cause of the irreversible damage that occurs with pre-perfusion of bloodless myocardial tissue. Treatment with the toxic effects of these free radicals with radical scavenging drugs can protect these against Vau-35 riot.

The compounds of formula I show activity as, for example, antioxidants, Δ5-lipoxygenase inhibitors and as described in more detail below. The beneficial pharmacological activities of the compound of formula I can be demonstrated by the experiments shown below.

The compounds of formula I are useful as active ingredients in inflammatory diseases such as arthritis; an inflammatory bowel disease such as colitis and as further described below; in the treatment of cardiovascular diseases such as myocardial ischemia; as anti-inflammatory agents in the topical treatment of leukotriene-mediated dermatitis, including psoriasis; and in the treatment of diseases associated with the lungs and lung tissue, such as asthma.

Inflammatory bowel disease (IBD) comprises a variety of gastrointestinal (GI) channel diseases, such as colon and ileum of Crohn's disease, ulcerative colitis and pseudo-membranous paksusuolehtulehduksen 20. Common symptoms of these diseases include inflammation of the lining of the gastrointestinal mucosa, ulceration of the mucosa, edema, infiltration of inflammatory cells into the mucosa, and severe diarrhea. Metabolites of the Δ ^ -LO pathway * 25 of arachidonic acid are believed to mediate IBD.

In vitro test for A5 lipoxygenase inhibitors

The effect of the compounds of formula I of the invention on Δ5-lipoxygenase from rat basophilic leukemia (RBL-1) -30 cells was studied. RBL-1 cells (CRL 1378) were obtained from the American Type Culture Collection, Rockville, MD. DMEM and Glu-amine were purchased from Flow Labs, McLean, VA. FBS (Gibco, Grand Island, NY) was heat inactivated at 35 ° C for 1 hour at 56 ° C. Protein assays.

For 32 92188, reagents were purchased from Biorad, Rockville Center, NY. Arachidonic acid (approximately 99%), ATP (disodium salt), BHT, dextran (clinical grade), tetrasodium EDTA, gelatin, gentamicin sulphate-5 solution, reduced glutathone, IM HEPES buffer, indomethacin, NaCl, reduced NADPH, Triz and Trizma 8.5 was purchased from Sigma Chemical, St. Louis, MO. CaCl 2 dihydrate, Norit A carbon, and citric acid monohydrate were purchased from Fisher 10 Scientific, Pittsburgh, PA. H7-5-HETE (specific activity 229.5 Ci / mmol) was purchased from New England Nuclear, Boston, MA. The synthetic 5-HETE standard was provided by Dr. M. Rosenberger, Dept., of Medicinal Chemistry, Hoffman-La Roche, Nytley, NJ; 15 (see Preparation for Corey, E.J. and

Hashimoto, S. (1981) Tet. Letters, 22, 299-302). Ecoscint liquid scintillation fluid was purchased from National Diagnostics, Sommerville, NJ.

Isolation of 5-Lipoxygenase The most stable enzyme preparations were obtained from RBL-1 cells thawed from liquefied β-storage, then kept in tissue culture flasks containing DMEM supplemented with 25 mM glucose, 12.5 mM HEPES, 40 mM glutamine. , 50 ug / ml gentamicin-25 nisulfate and 10% heat-inactivated FBS. Approximately 7-9 days after thawing, RBL-1 cells with log growth were seeded at a density of 7,500 viable cells / ml in a sealed 89 liter spinner flask. The cells were continuously agitated for 3-4 days at 37 ° C until they reached a density greater than 500,000 / ml but less than 800,000 / ml. RBL-1 cells were harvested by centrifugation at 1500 x 10 minutes at 4 ° C and washed 3 times with ice-cold 0.05 M Tris-HCl, pH 7.2, tetrasodium-35 EDTA solution (buffer 1). The cells were washed last with 0.05 M Tris-HCl containing 14 μM indomethacin, 1 mM glutathione, 1.5 mM NaCl and 1 μM tetran trium-EDTA (buffer 2). they were resuspended to a density of 5 x 108 '/ ml (approximately 10 ml) and broken manually at 4 ° C using a 40 ml

Dounce (type A cheat) homogenizer. After homogenization for 5 minutes, 95% cell lysis was prepared by phase contrast microscopy. The disrupted cells were diluted 1: 2 with buffer solution 2 and centrifuged at 12,380 x g for 10 minutes at 4 ° C to pellet cell debris and granules. The supernatant from centrifugation was 12,380 x g centrifuged at 113,000 x 60 minutes to pellet the microsomes. The supernatant obtained at high speed (5.9 + 0.48 mg / ml protein) was immediately frozen in 1 ml portions using a dry ice / acetone bath. The isolated cytosolic fraction was stored in liquefied N 2 for up to 8 weeks without loss of 5-LO enzyme activity.

2o Lipoxygenase assay

Compounds were dissolved to a concentration of 25 mM in DMSO, then diluted to final concentrations using 95% ethanol. Typical enzyme. for the assay, partially purified 5-LO preparation was preincubated with drug or vehicle for 10 minutes at 30 ° C. The tubes were then transferred to a 37 ° C water bath where arachidonic acid (final concentration 8.25 μM) was added to initiate 5-LO activity. For the enzyme and substrate, each reaction tube contained 12.5 μmol Tris-HCl (pH 7.2), 25 μmol glutathione, 1.4 μmol CaCl 2, and ATP to give a final volume of 250 μl. 3 M citric acid to a pH of 3.5. The samples were immediately cooled on ice 35 and neutralized by dilution with 0.05 M Tris-HCl, 34 92188 pH 8.5 containing 25 mg / l BHT. The boiled cytosolic control was placed at the end of each assay to measure non-enzymatic oxidation of Arakiconic acid.

The average specific activity of the 5-LO enzyme preparation was approximately 66.16 + 14.39 pmoles of 5-HETE 1 min / mg protein.

Radioimmunoassay to determine 5-HETE

Under the experimental conditions described, 5-LO catalyzed the conversion of arachidonic acid to 5-HPETE, which was reduced to 5-HETE due to peroxidase-10 activity. A specific radioimmunoassay was used to determine the amount (pmoles) of 5-HETE formed during the enzyme reaction. To prepare the immunogen, Dr. M. Rosenberger (Dept. of Medicinal Chemistry) converted racemic 5-HETE-lactin (Corey, E.J. and Hashimoto, S. (1981) Tet. Letters, 22, 299-302) to its hydrazine derivative. The hydrazide was coupled to thiolated Keyhole Limpet hemocyanin (Young, RN, Kakushima, M. and Rokach, J. (1982) Prostaglandins 23, 603-613) using N-ethylmaleimide as previously described for LTB2. for (Young, RN, Zomboni R. and Rokach, J. (1983) Prostaglandins, 26, 605-613). New Zealand white rabbits received multiple injections into the skin of the back with 100 ug of compound compound emulsified in complete Freund's adjuvant. The injection schedule described by Salmon (Salmon J.A. (1978) Prostaglandins, 15, 383-397) was followed. Monthly i.p. after the booster injections administered, blood was taken 5-7 days later from the ear margin calculator and the antibody titer was determined.

Rabbit 5-HETE antiserum was diluted 1: 3000 with RIA buffer (50 mM Tris-HCl plus 1.5 mM NaCl, pH 8.6 containing 0.1% gelatin) and aliquots were mixed with standard (0.75-25 pmoles of 5-HETE / ml) or 35 diluted assay samples and placed in a V · * · «35 92188 ice bath. E 2 H7-5-HETE (approximately 10,000 to 12,000 cpm) was added to give a total assay volume of 300. After incubation for 90 minutes at 25 ° C, 1 ml of ice - cold dextran - coated carbon was added to separate antibody - bound 5 - HETE from unbound 5 - HETE (Salmon.

AND. (1978) Prostaglandins, 15, 383-397). The carbon was lowered to the bottom at 2000 x g for 10 minutes, followed by 0.8 ml of supernatant. was added to 10 to 10 ml of Ecoscint liquid. Radioactivity (dpm) was determined by a 10 minute counting time using an LKB Model 1219 scintillation counter (40% efficiency for / ^ H /).

Analysis of measurement results:

Each inhibitor concentration was analyzed in triplicate. The inhibitor concentration at which 50% inhibition of control 5-HETE formation (IC-50) occurred was calculated for the dose by regression analysis of the response results. The results (IC-50) of the compounds of this invention in this experiment are shown in Table I.

Carrageenan pleurisy test (in vivo) The animals used in these experiments were male Lewis rats (Charles River Breeding Laboratories) weighing 230-250 g. Carcinogen (CG) -25 pleurisy was induced by injecting 0.2 ml of 1% lambda carrageenan (Sigma lot 60F-0652) dissolved in sterile pyrogen-free saline into the right pleural cavity of the rat using a size 26 (3/8 ") intradermal needle. Compounds suspended in an aqueous suspension vehicle (ASV, 0.5% carboxymethylcellulose containing 0.9% NaCl, 0.37% Tween 80 and 0.85% benzyl alcohol) were administered by intubation 1 hour before CG injection for a 5-hour treatment time and 1 hour before and 5 hours after CG injection time for a 24-hour treatment time, which were administered at doses that would significantly prevent CG development of pleurisy caused by 5 in our experimental conditions.

Five or 24 hours after CG injection, rats were sacrificed by decapitation, bled, and pleural cavity exposed by dissecting the ribs on either side of the sternum. Inflammatory fluid was removed from the lumen of the pleura 10 using disposable plastic pipettes and its volume was determined. The pleural cavity was then washed once with phosphate buffered saline containing fetal bovine serum (1: 1), and the washings were combined with inflammatory fluid. The total number of cells in the pleural cavity was determined using a Coulter counter (model ZM) adjusted to exclude all contaminated red blood cells. (Published in "Plant Flavonoids in Biology & Medicine: Bioche-20 mical, Pharmacological and Structure-Activity Relationships", pp. 231-242 (1986 (Alan R. Liss, Inc)).

The results obtained in this experiment for the compounds of this invention are shown in Table 1.

Mouse Ear Swelling Test (In Vivo) In this animal model system, the use of arachidonic acid in the ear results in the metabolites 5-hydroperoxy-6,8,11,14-eicosatetraenoic acid (5-HETE), leukotriene B ^ (LTB ^), leukotriene C ^ (LTCl 3), 12-hydroperoxy-5,8,10,14-eicosatra-acid (12-HETE) and prostaglandin E2 (PGE2) at the site of biosynthesis, followed by neutrophil flow to the site and rapid development of edema within 30 to 60 minutes ( see, e.g., Young, Wagern, & Spries, "Tachyphylaxis in 12-0-Tetradecanoylphorbol Acetate and Arachidonic Acid-35 Induced Ear Edema," J. Invest. Dermatol. 80:48 (1983), and Hames, Guide, and Bonney, "Arachidonic Acid Metabolites 37 92188 in Mouse Ear Edema “Advances in Inflammation Research, 11:57 (1986). Inhibitors of these metabolites and their metabolic pathways also prevent the formation of edema.

5 Male CD-1 mice weighing 15-25 g were used and labeled as follows: (1) a control group without arachidonic acid and no test compound, (2) an arachidonic acid-treated group without 10 test compounds, and ( 3) a treated group in which the test compound was administered first, followed by arachidonic acid.

In the case of animals in group (3), the test compound dissolved in acetone was administered to the dorsal surface of the right ear of the mouse using a 25 microliter pipettor, varying the dose of the test compound. After 0.5 h in some cases and after 4 h in others, arachidonic acid was applied externally, in the same manner as above, to the pretreated ear areas. For each administration of arachidone-20 acid, an amount of 0.5 mg dissolved in 25 microliters of acetone was used. After 1 hour, the mice were killed by inhalation of carbon dioxide. A standard 6 mm diameter punch was used to obtain a uniform tissue sample from the ear of each mouse so treated, and the tissue samples were weighed to the nearest 0.1 mg. The percentage inhibition of ear swelling was calculated as follows: 30 Weight in the arachidonic acid group - weight in the test group - x 100

Weight in the arachindonic acid group - weight in the control group 35 The results obtained in this experiment for the compounds of this invention are shown in Table I.

Table I

38 92188

Name Δ ^ -lipoxy- Rat carcinoma- Mouse ear genease in- Gene-pulmonary edema% - hibitio IC5Q lung inhibition 1 mg pa- (5 μM) inflammation. Inexpensive% volume inhibition of inflammatory fluid at 100 mg / kg po 4- [4- (2,3-dihydroxy-0,09,7,6-phenyl) butoxy] -2-hydroxy-3-propyl-benzoic acid 4- / 5 - (2,3-Dihydroxy-0,006,630 phenyl) pentyloxy] -2-hydroxy-3-propyl-15-benzoic acid 4- [6- (2,3-dihydroxy-0,02,668 phenyl) hexyloxy] -2-hydroxy- 3-propylbenzoic acid 2Q 4- [7, (2,3-dihydroxy-0.005 57 57 phenyl) heptyloxy] -2-hydroxy-3-propylbenzoic acid 4- [3 '(2/3-dihydroxy-62% 66 78 phenyl) octyloxy-47'-hydroxy-3-propyl-

25 benzoic acid in an amount of 0.1 μM

4- [10- (2,3-Dihydroxy-0,02 61 49 phenyl) desyloxy] -2-hydroxy-3-propylbenzoic acid 30 4- [3- (2,3-dihydroxy-100% 44 64 phenyl) hexyloxy] - in the amount of 2-hydroxy-3-propyl-1,1'-benzoic acid ethyl ester 4- (6- (2,3-dihydroxy-0.67 42 48 phenyl) hexyloxy) 7,35 2-hydroxy-3-propylbenzoic acid / 2- (di-: ethylamino) ethyl ester

Table I - continued 39 92188 2- (acetyloxy-4- / 6- (2,3-0,19 42 non-tested dihydroxy-phenyl) hexyloxy] -3-propylbenzoic acid 5 4- / 6- / 2, 3-bis (acetyl-0.15 43 (75 mg / kg) non-test.

oxy) phenyl7hexyloxy-2-hydroxy-3-propylbenzoic acid 4- [6- [2,3-dihydroxy-0.147 (75 mg / kg) 45 in 4- (1-methylethyl) phenyl] hexyloxy] -2-hydroxy -3-Propylbenzoic acid 4- [6- (2,3-dihydroxy-0.17 46 48 phenyl) hexyloxy] benzoic acid 15 4- [6- (2,3-dihydroxy-0.32 0 50 phenyl) hexyloxy] 2-Hydroxybenzoic acid 4- [6- (2,3-dihydroxy-0,02,0 52 2Q phenyl) hexyloxy] -3-propylbenzoic acid 4- [6- (2,3-dihydroxy-0.46 not tested 59 phenyl) hexyloxy-3,5-dipropylbenzoic acid 25 as 4- [3- (3,4-dihydroxy-97% 55 32 phenyl) propoxy]

2-hydroxy-3-propyl-1 μM

libenzoic acid 4- [6- (3,4-dihydroxy-0,005 0 21 phenyl) hexyloxy] -2H 2-hydroxy-3-propylbenzoic acid 4- [6- (3,4-dihydroxy- 51% non-test) -phenyl) -6-oxohexyl in the amount of oxy-2-hydroxy-3-1M propylbenzoic acid / 35

Table I - continued 40 92188 1- [T2-hydroxy-4- [6- (2,3-0,03,511 dihydroxyphenyl) hexyloxy] -3-propylphenyl] ethanol 5-1- [2-hydroxy-4- Z_4- (2.3-48% 53 as untested dihydroxyphenyl) butoxy

si7-3-propylphenyl7-0.01 μM

Ethanone 1- [2-hydroxy-4-ip8- (2,3-95% O 0 dihydroxyphenyl) octyl

10 oxy-1,3-propylphenyl-0.1.1 μM

Ethanone 1 - ε-2-hydroxy-4- ε-ε 2,3-35% dihydroxy-4- (1-methyl)

ethyl) phenyl-hexyl-0.1 μM

oxy-3-propylphenyl-15-ethanone in the amount of 5-chloro-4- [6- (2,3-48% 45,5 dihydroxyphenyl) (50 mg / kg)

hexyloxy-2-hydroxy-0.1 μM

3-propylbenzoic acid '

Acetic acid-induced colitis in rats, in vivo

An animal experiment on colonic acetic acid-induced colitis has been described by J. E. Krawisz et al. in Amer. J. Proc. Gastro. Col. Rec. Surg. 31: • 25 11-18 (1980) and P. Sharon and W.F. In Stenson publications

Gastroenterology 88: 55-63 (1985) and 86: 435-460 (1984). Acetic acid-induced colitis is characterized by the movement of inflammatory cells into the colon, and the number of such cells in the mucosa is measured by myeloperoxidase activity, which is the marker enzyme of these cells. Positive desirable activity is indicated by the reduction in high myeloperoxidase levels caused by acetic acid. Male rats (Sprague-Dawley) weighing 150-300 g were pretreated twice daily for the day with either 41 92188 vehicle (water or dimethyl sulfoxide) or a test inhibitor compound suspended in water or dissolved in dimethyl sulfoxide for oral administration. On the third day, the animals received 5 doses, as defined in the previous two days, anesthetized with metofane, and 2 ml of 2.5% acetic acid was injected into the lumen of the colon via a syringe followed immediately by 3 ml of air and rinsing with a 3 ml of phosphate-buffered saline solution (acetic acid is present in 10 in the cavity long enough to cause inflammation without causing severe death or irreversible damage). The animals were given a second dose of the test compound in the same amount approximately 16 hours later.

24 hours after the acetic acid treatment the animals were TAPET-15, colonic mucosa was surgically removed and homogenized in an aqueous buffer solution at a pH of 6 using a Tissumizer or similar device and myeloperoxidase was measured in the homogenate using o-phenylenediamine as chromogen as described in 20 A. Voller, D.E. Bidwell and A. Bartlett in The Enzyme Linked Immunosorbent Assay (ELISA), Zoological Soc., London, 1979, pages 29-30. Control animals were pretreated with vehicle and saline instead of acetic acid.

25. The results obtained for representative compounds of this invention are shown in Table II.

Antibiotic-induced colitis in hamsters, in vivo

Male Syrian hamsters (LUG) weighing 80-120 g were each given a single dose of 175 mg / kg clindamycin phosphate or clindamycin hydrochloride intraperitoneally to induce colitis. Approximately seven hours after injection, the animals were administered the test compound orally or intraperitoneally and the treatment was continued twice a day for another four days. For oral administration, the antibiotic was suspended in water or dissolved in dimethyl sulfoxide and administered to the animals by gavage using an oral incubation needle. The effect of treatment was measured using a risk ratio of the mortality of animals treated with the test inhibitor compound in the vehicle to the mortality of animals treated with the test inhibitor compound-free vehicle. Mortality was determined from the test inhibitor-treated groups and the vehicle-treated groups, respectively, twice daily and estimated by comparing the survival curves of each group. The Kaplan-Meier estimate of the survival curve was calculated for each group and the Mantel-Cox (logrank) test was used to compare the survival curve of each (treatment) group treated with the 15 inhibitor compounds to the survival curve of the corresponding vehicle control group. A risk ratio of 1.0 indicates that treatment has no better effect than vehicle alone, while a risk ratio greater than 1.0 indicates that treatment prolongs survival compared to vehicle-treated group.

(See J. G. Bartlett et al. Amer. J. Vet. Res. 39: 1525-1530 (1978)).

The results obtained for representative compounds of this invention are shown in Table II.

Table II

Name Rat acetic acid Hamster colon colitis model model 30 Dose Myeloperoxy- Dose Risk (mg / kg dase accumulation (mg / kg ratio po)% inhibition po) 4- ^ 4- (2,3-dihydroxy- 10 73 + 10 10 1,35 phenyl) butoxy7-71 71 + 11 100 0,1 2-hydroxy-3-propyl-35-benzoic acid

Table II - continued 43 92188 4- / 6- (2,3-dihydroxy-10 42 + 2 10 2.26 ** phenyl) hexyloxy7-2-3067 + 15 100 4.22 ** hydroxy-3-propyl- Benzoic acid 4- [8- (2,3-dihydroxy-10 35 + 7 phenyl) octyloxy] -2-10027 + 3 hydroxy-3-propyl-benzoic acid 4- [6- / 5,3-dihydroxy-533 +12 4 - ((1-methylethyl)) - 100 86 + 9 10 phenyl7hexyloxy-2-hydroxy-3-propyl-benzoic acid 1- [2-hydroxy-4- / 4- [10,4 + 7 (2,3-dihydroxy-30 89 +11 phenyl) butoxy7-3-propylphenyl / ethanone 4- [6- (2,3-dihydroxy-1882 + 9 phenyl) hexyloxy] -2,381 + 15 hydroxybenzoic acid 4 - [] 6- (2,3- dihydroxy-3 79 + 8 20 phenyl) hexyloxy7 ~ 10 89 + 28 benzoic acid 4- [6- (2,3-dihydroxy-1 40 + 9 phenyl) hexyloxy] -367 + 11 2-hydroxy-3-propylbenzoic acid Ethyl ester 4- [6- (3,4-dihydroxy-377 + 6 2,5-dimethylphenyl) -10 85 + 13 hexyloxy] -2-hydroxy-3-propylbenzoic acid 4- [3- (2,3- dihydroxy-10 54 + 5 (phenyl) propoxy] -2-hydroxy-3-propylbenzoic acid 4- [5- (2,3-dihydroxy-96 + 13 phenyl) pentyloxy] -2-hydroxy-3-pro phenyl-2-benzoic acid

Table II - continued 44 92188 5-Chloro-4- [5- (2,3-30,4 + 6 dihydroxyphenyl) -hexyloxy] -2-hydroxy-3-propyl-4-benzoic acid 4- [3- (3,4 -dihydroxy-30,3 + 5-phenyl) -propoxy] -2-hydroxy-3-propyl-benzoic acid 4- [2- (3,4-dihydroxy-10,56-6-phenyl) -ethoxy] -2-hydroxy-3-propyl- Benzoic acid 4- [6- (2-fluoro-4,5-10-40 + 5 dihydroxyphenyl) -6-oxohexyl] oxy-2-hydroxy-3-propyl-benzoic acid 1- [4- [6- (2,3 -dihydro-10 65 + 10 oxy-4- (1-methylethyl) phenyl] hexyloxy-2-hydroxy-3-propylphenyl] ethanone 1- [4- (5- (3,4-dihydro) 6-oxyphenyl) pentyloxy-2-hydroxy-3-propyl-ethanone. (E 4- [5- (2-chloro-5,6-3,5 + 9 dihydroxyphenyl) -pentyloxy] -2-hydroxy-3-propyl Benzoic acid 4- [5- (2,3-dichloro-173 + 5,5,6-dihydroxyphenyl) -3-pentyloxy] -2-hydroxy-3-propylbenzoic acid 4- [5- (2,3,4-trichloro-1115 + 21 5,6-Dihydroxyphenyl) -pentyloxy-2-hydroxy-3-propylbenzoic acid 35 3-Amino-4- [6- (2,3-di-1,5 + 7 hydroxyphenyl) hexyl] oxybenzoic acid appo ** = p <0.01 45 92188

In vitro testing of antioxidants

The experimental system uses hypoxanthine-xanthine oxidase (XO) -Fe 2+ ADP as a free radical generator and purified original rat heart membrane phosphoglyceride in Hepes-KCl buffer, pH 7.4, as a substrate. Inhibition of superoxide-dependent iron-promoted lipid peroxidation in a linear reaction step (after 1 hour of reaction) is measured as the net formation of reactive material with thiobarbituric acid (TBA). In this system, the material reactive with TBA isolated by HPLC is exclusively (> 95%) malonide dialdehyde (MDA), a fragmentation end product of fatty acid hydroperoxides and cyclic endoperoxides.

(a) Isolation and purification of rat cardiac lipids

Conscious male Sprague-Dawley-20 rats (275 g) maintained on a normal rodent diet were decapitated. The hearts were rapidly removed and ice-cold 10 mM Hepes buffer, pH 7.4, was drained through the aorta. The aorta and atria were removed and the ventricular tissue was dried with paper 25 and weighed (wet weight). The hearts were minced on ice with scissors and finally homogenized (100 mg tissue / ml ice-cold buffer) for 15 seconds (3x5 seconds) using a Tekmar Tissumizer set to "maximum". The homogenate was filtered through 30 quadruple cheesecloths and the lipids in the homogenate were extracted and purified using a modified Bligh-Dyer method (MD Marshall and M '. Kates, Biochem. Biophys, Acta 260, 558 (1972)). C.

35 ·. . · 46 92188 b) Preparation of cardiac liposomes

Liposomes were prepared from the extracted and purified original rat heart cardiac fat and used as a substrate for free radical attack. The core fat (in CHCl 3) was placed in a glass flask and evaporated to dryness under nitrogen gas at room temperature; the flask was gently swirled during evaporation to give a thin, dry lipid film. The fat was taken up in a solution of 10 mM 10 Hepes - 0.145 M KCl, pH 7.4, and resuspended by indirect anaerobic sonication for 15 minutes at room temperature. The liposome suspension was used immediately.

c) Preparation of Fe 2+ -ADP chelate 3+ Chelate of Fe (1.0 mM FeCl 3, final concentration) and ADP (10 mM, final concentration) at pH 7.4 was formed in Hepes-KCl buffer solution. stirring at room temperature. Chelation was allowed to continue for 90 minutes before use. The chelate was reconstituted for each day's experiments to ensure iron solubility, efficient chelation, and valence state.

d) Thiobarbituric Acid Reaction for Determination of Malonidialdehyde Equivalents Malonidialdehyde (MDA) equivalents were measured as a material capable of reacting with thiobutyric acid (TBA) using the following variation of published methods. The reaction mixture, reconstituted daily, contained water: BHT (7.1 M BHT in absolute ethanol-30): TBA (1.5% TBA in 0.2 M Tris buffer, pH 7.0) in a volume ratio of 1: 1: 5. . To each 1.0 ml of the peroxidation reaction to be tested (see below) was added 0.35 ml of the reaction mixture. After thorough mixing, the tubes were incubated in an 80 ° vibrating water bath for 30 to 35 minutes. After this time, the tubes were immersed in 47,921,88 ice water baths and the reaction was immediately stopped with 0.5 mL of ice-cold 91% TCA followed by 2.0 mL of CHCl 3 · After centrifugation at 2000 rpm for 30 minutes Sorval HL-8-5 in a rotor (4 ° C), the absorbance of the washed, pink upper phase at 532 nm was read. A standard curve (0.8-40.0 nmoles of MDA) was prepared with each experiment. For each curve, fresh MDA was prepared by acidifying 1,1,3,3-tetraethoxypropane with 75% TCA - 2.3 N HCl (0.15 mL of the acid mixture to 1.0 mL of appropriately diluted tetraethoxypropane). ). Computer-aided regression analysis of the standard curve was used to determine the molar amounts of MDA equivalents in the test samples.

15 e) Lipid peroxidation reaction

Cardiac liposomes were allowed to undergo super-oxide-dependent, iron-promoted peroxidation in glass containers to avoid the known antioxidant effects of many common polymerizers used in the manufacture of plastic laboratory articles. Screening was performed using three replicates in 12 x 75 mm glass tubes, with a final reaction volume of 1.0 ml and a reaction time of 60 minutes. Per milliliter of peroxidation-25 reaction mixture were the following ingredients: Tris-KCl buffer solution (0.1 ml), cardiac liposomes (0.5 ml, corresponding to 125 μg phospholipid), 1 mM HX (0.1 ml), 01 mM Fe 2 O 3. + -1.0 mM ADP-chelate (0.1 mL), test substance (0.1 mL dissolved in Tris-KCl, ethanol or DMSO) and 10 mU XOD (0.1 mL). All α1-30 neos are listed as final concentrations and were prepared at the time of analysis. The peroxidation reaction was started by adding XOD and was performed at 37 ° C in a vibrating water bath. The peroxidation was stopped by adding 0.15 ml of an ice-cold mixture of 76% TCA - 2.3 N HCl for each 1.0 ml of peroxidation reaction mixture, which was required to examine MDA equivalents (above). To investigate the possible interfering effect of the test substance, an experiment was performed on a second set of samples, but in these the peroxidation reaction was immediately stopped with TCA-HCl. The test substances were screened at a final concentration of 1 μM.

If peroxidation was inhibited by 5050%, the IC 50 value was determined.

For kinetic studies, peroxidation was performed in glass conical flasks. At each desired time, 1.0 mL samples were taken, in three rin-10 adhesions, on ice-loaded tubes containing 0.15 mL of 76% TCA - 2.3 N HCl and then reacted with TBA (supra). ).

f) Calculation of the effect of the test substance on lipid peroxidation The effect of the test substance on cardiac lipid peroxidation during the 60-minute screening test was considered to be the ratio between the final MDA equivalents formed in the presence of the drug and the net MDA equivalents formed in its absence. The percentage inhibition of lipid per-20 oxidation was calculated as follows: drug ^ Q, - drug ^,

Peroxidation = 1 - x 100 S inhibition T60, - T0, 25 Drug ^ g, = MDA equivalents formed after 60 minutes in the presence of free radical scavenger + test substance; Drugep, = MDA equivalents formed after 0 minutes in the presence of a free radical scavenger + 30 test substances; T60 '= muo <* total number of MDA equivalents purchased in the absence of test substance at 60 minutes;

Tq, = endogenous reactivity of the reaction mixture with TBA at time 0 minutes.

The results obtained in this experiment for the compounds of this invention are shown in Table III.

k t. I · 49 92188

In vivo testing of antioxidants In this treatment, a free radical generating (FRG) system comprising a complex of purine (2.3 mM), xanthine oxidase (0.02 U / ml) and iron-loaded transferrin (Ο, β ^ νιΜ) is infused. in rats with spontaneous hypertension in the common head-state near the coronary opening. Blood is drawn before and 24 hours after administration of the FRG stimulus to determine lactic acid dehydrogenase isoenzymes (LDH 2). An increase in the LDH ^ iLDI ^ ratio indicates damage to myocardial cells. An electrocardiogram is also taken before the FRG infusion and 24 hours after the infusion. At the end of the experiment, the heart is removed, sliced like bread and stained with triphenyltetrazolium chloride to determine infarct size. The drug or vehicle is administered intravenously 10 to 30 minutes before the FRG stimulus is administered. A drug is considered active if there is an increase in the LDH ^ sLDI ^ ratio, no ECG abnormalities, and no histological evidence of blockade.

In vivo model of myocardial ischemia in rats Male spontaneously hypertensive rats (280-320 g) obtained from Taconic Farms were lightly anesthetized with sodium pentobarbital (30-50 mg / kg i.p.). Rats with pre-surgical abnormality were excluded from the study. A catheter in the PE 50 tube was placed at the right common head-state site near the coronary artery orifices, 30 and used for blood sampling and infusion of the free radical generating (FRG) system. A second catheter in a PE 10 tube was placed in the left jugular vein for drug administration. The infusion system for FRG comprised a dual syringe infusion-35 pump, Sage Model 351, with one syringe containing xanthine oxidase (0.01 units / ml) in HEPES (0.05 M) - 50 92188 buffer and the other syringe containing purine 3+ ( 2.3 mM) plus Fe-loaded transferrim (0.06 μM) in HEPES (0.05 M) buffer. Separately, the infused FRG mixes simultaneously near the openings in the coronary arteries. This infusion was performed at a rate of 0.03 ml / minute for a total infusion time of 10 minutes. The drugs were infused over one minute in 0.9% saline vehicle.

Normal coupling II-ECG was monitored continuously using a Hewlett-Packard 7758A recorder before treatment, during the FRG infusion, and 10 minutes after the infusion. The catheters were removed and the animals were allowed to recover and fed normal rat food and water allibitum. Twenty-four hours after FRG infusion, animals were re-anesthetized with sodium pentobarbital (30-50 mg / kg, ip) and an ECG was taken. Blood samples were taken before and after the FRG infusion and at the end of the experiment.

These samples were centrifuged and examined for total lactate dehydrogenase (LDH) and lactate-20 dehydrogenase isoenzymes (LDH ^ LD ^) using electrophoresis.

The animals were sacrificed, the hearts were quickly removed, and the blood was washed away and cut into sections. Left

D

the chamber was weighed and stored in a Revco freezer at -70 ° C. The left chamber was sliced into 2 mm thick rings, incubated in 1% triphenyltetrazolium chloride solution for 20 minutes, and then stored in 10% formalin solution. Areas under infarction were measured and sized as a percentage of 30 to 30 of the total volume of the left ventricle.

The results obtained in this experiment for the compounds of this invention are shown in Table III.

• 51 92188

Table III

Name Lipid Rat ischemia model 10 mg / kg peroxy- ivation Infarction /% blockade1 inhibition total IC50 q (qu) amount 4- / 4- (2,3-dihydroxy-0.5 2/5 8 phenyl) butoxy7 ~ 2-hydroxy-3-propylbenzoic acid 4- [5- (2,3-dihydroxy-0.4 4/5 phenyl) pentyloxy] -2-hydroxy-3-propylbenzoic acid 4- [6- ( 2,3-Dihydroxy-0.3 4/5 8 phenyl) hexyloxy-2-hydroxy-3-propylbenzoic acid 4- [7- (2,3-dihydroxy-0.5 3/5 18 phenyl) heptyloxy] - 2-Hydroxy-3-propyl-benzoic acid 20 4- [8- (2,3-dihydroxy-0.3 1/58 phenyl) octyloxy] -2-hydroxy-3-propyl-benzoic acid 4- [10- (2, 3-Dihydroxy-0,4 3/3 13 phenyl) desyloxy-2-hydroxy-3-propylbenzoic acid 4- [6- [2,3-dihydroxy-0.7 1/5 5 4- (1-methylethyl ) -phenyl (hexyloxy) -2-hydroxy-3-propylbenzoic acid 30 4- [6- (2,3-dihydroxy-> 1 2/5 19 phenyl) hexyloxy] benzoic acid 4 - [(3- -dihydroxy-> 1 3/5 10 phenyl) hexyloxy / -35 2 -hydroxybenzoic acid 52 9 2 1 88

Table III - continued A-Qo- (3,4-dihydroxy-0.6 1/5 11 phenyl) hexyloxy7 '(5 mg / kg) iv) 2-Hydroxy-3-propyl-benzoic acid 5'-2-hydroxy -4- [3 '0,7 4/4 24 (2,3-dihydroxyphenyl) hexyloxy] -3-propylphenyl / ethanone 1- [2-hydroxy-4- £ 4-> 1 1/5 12 ( 2,3-Dihydroxyphenyl-10 (1-butoxy) -3-propyl-phenyl-177-ethanone 1- (2-hydroxy-4- (6-6) -2,3,113,3-dihydroxy-4- (1-methylethyl) ) phenyl-7-hexyloxyT7-3-, 5-propylphenyl-4-ethanone * = Percentage of the left ventricle of animals with a myocardial infarction

A compound of formula I, or a salt or preparation thereof, comprising a therapeutically effective amount of a compound of formula 20 I, or a salt thereof, may be administered using methods known in the art. The compound of formula I or a salt thereof may thus be administered either alone or with other pharmaceutical agents, orally,; parenterally, rectally or internally! 25 inhaled, for example in the form of an aerosol, a very finely divided powder or a melt solution. When administered orally, the described compound may be administered in the form of tablets, capsules, for example mixed with talc, starch, milk sugar or other inert ingredients, i.e. pharmaceutically acceptable carriers, in the form of aqueous solutions, suspensions, elixirs or aqueous alcoholic solutions, for example mixed with sugar or other sweetening, flavoring, coloring, thickening and other conventional pharmaceutical excipients, or in the form of beads for oral administration. For parenteral administration, the desired compound may be administered in solutions or suspensions, for example, as an aqueous or peanut oil solution or suspension, using excipients and carriers conventional for this mode of administration. For aerosol administration, they may be dissolved in a suitable pharmaceutically acceptable solvent, for example ethyl alcohol or combinations of miscible solvents, and mixed with a pharmaceutically acceptable propellant. Such aerosol preparations are packaged for use in a pressure vessel equipped with an aerosol valve suitable for releasing the pressure preparation.

Preferably, the aerosol valve is a metering valve, i.e., one that, upon activation, releases a predetermined lubricating dose of the aerosol formulation. In the case of rectal administration, the desired compound may be administered in the form of suppositories using 20 inert carriers such as cocoa butter and the like.

For topical administration, the compounds of formula I may be incorporated into ointments, creams, lotions, gels and the like. In general, the solutions, ointments and creams useful in the present invention. . For use in accordance with the invention, comprise mixtures of absorbable, water-soluble or emulsion-type bases such as petrolatum, lanolin, polyethylene glycols or the like.

Suitable solutions include compounds of formula I dissolved in a pharmaceutically acceptable solvent such as polyethylene glycol or the like.

Suitable rinsing liquids include from proper solutions to aqueous or aqueous alcohol preparations containing finely divided particles. Rinsing liquids 54 92188 may contain suspending or dispersing agents, such as cellulose derivatives, for example, methylcellulose, ethylcellulose or the like. Gels are typically semi-solid preparations prepared by coagulating a solution or suspension of a compound of formula I in a suitable aqueous or non-aqueous vehicle using a gelling agent such as carboxypolymethylene or the like and then neutralizing it with a suitable alkali. for example sodium hydroxide, and an amine, for example polyethylene cocosamine. Topical pharmaceutical preparations containing a compound of formula I may also contain conventional ingredients such as, for example, preservatives, stabilizers, wetting agents, emulsifiers, buffers and the like, in conventional amounts which are adjusted according to specific requirements and which can be adjusted by those skilled in the art. easily determined.

The dose and frequency of administration of a compound of formula I or a salt thereof to be administered in the practice of the invention will depend on the efficacy of the particular compound or salt of formula I administered and the duration and route of administration, the severity of the condition, the age of the mammal to be treated and the like. Oral doses of a compound of formula I or a salt thereof for use in the practice of the invention will range from about 25 to about 1000 mg per day, preferably from about 25 to about 250 mg, either as a single dose or in divided doses.

The following examples further illustrate the invention. All temperatures reported in the patent publication and examples are in degrees Celsius. The extracts were dried over anhydrous magnesium sulfate unless otherwise noted.

55 92188

Example 1

A solution of 1.55 M butyllithium in hexane (195 mL, 0.3 mol) was added dropwise over 30 minutes to a stirred solution of 1,2-di-5-methoxybenzene (41.4 g, 0.3 mol). ) In 700 ml of anhydrous tetrahydrofuran at room temperature under argon. The reaction mixture was stirred and warmed to 40 ° for 4 hours and then cooled to -70 °. A solution of 46 ml (0.3 mol) of 1,6-dibromohexane in 250 ml of anhydrous tetrahydrofuran was added dropwise over 30 minutes. The cooling bath was removed and the reaction mixture was stirred for 1 hour and then heated at 40 ° for 4 hours. Most of the solvent was removed, 90 mL of 3N HCl was added and the product was extracted with hexane. The extract was washed with sodium bicarbonate solution, dried and concentrated under reduced pressure to give an oil. Distillation gave 1- (6-bromohexyl) -2,3-dimethoxybenzene as a yellow oil (29 g, 32% yield, b.p. 125-140 ° / 0.15 mm).

This method is known and is described for 1- (7-bromoheptyl) -2,3-dimethoxybenzene in the following literature reference: H. Halim, H.D. Locksley and J.J. Memon, J. Chem. Soc. Perkin I, 2331 (1980). It was used to prepare all bromine intermediates where n = 3-10.

Example 2

Boron tribromide (266 mL, 1M in methylene chloride) was added dropwise over 1 hour to a cooled (-65 °) solution of 40.0 g (0.133 mol) of 1- (6-bromohexyl) -2,3-dimethoxybenzene 800 in anhydrous methylene chloride and stirred under argon. The cooling bath was then removed and the reaction mixture was stirred for 1.5 hours. After cooling in an ice bath, 100 ml of water and 50 ml of 35NN HCl were added and the mixture was stirred for 2 hours. Organic. *. The layer was separated, dried and concentrated under reduced pressure to an oil which was purified by HPLC using 5% methanol-chloroform to give 34.7 g of 1- (6-bromohexyl) -2,3-dihydroxybenzene as an oil. To this were added 32 ml (0.28 mol) of benzyl chloride, 46 g (0.28 mol) of potassium iodide, 122 g (0.88 mol) of potassium carbonate and 700 ml of anhydrous acetone, and the reaction mixture was stirred under reflux for 72 hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to an oil which was purified by HPLC using 1% ethyl acetate-hexane to give 47 g (74% yield) of 1- (6-iodohexyl) -2,3- bis- (phenylmethoxy) benzene as an oil.

Example 3 To 20 g (0.145 mol) of 1,2-dimethoxybenzene in 300 ml of anhydrous tetrahydrofuran and stirred at room temperature under argon was added 90 ml (0.145 mol) of 1.6 M butyl-20 lithium in hexane over 30 minutes. The reaction mixture was stirred and heated at 40 ° for 4 hours and then cooled in an ice bath. Ethylene oxide (14 mL, 0.29 mol) was allowed to distill into the ice-cooled reaction mixture over 45 minutes. The reaction mixture t '25 was stirred under cooling in an ice bath for 1.5 hours and then at room temperature for 17 hours. Most of the solvent was removed under reduced pressure, and water was added to the residue. The product was extracted with ether and the dried extract was concentrated under reduced pressure to an oil.

The remaining 1,2-dimethoxybenzene was removed by distillation, and the residue was purified by HPLC using 20% ethyl acetate-toluene to give 5 g of 1- (2-hydroxyethyl) -2,3-dimethoxybenzene. This intermediate was dissolved in 100% anhydrous methylene chloride and the solution was cooled in an ice bath. Triethylamine 57.918188 (7.7 mL, 0.056 mol) was added followed by 2.6 mL (0.033 mol) of methanesulfonyl chloride dropwise. The reaction mixture was stirred under ice-cooling for 2 hours and then washed with water, sodium bicarbonate solution, dried and concentrated under reduced pressure to give (7.2 g) of 1 - [(2-methanesulfonyloxy) ethyl] -2,3-dimethoxy -benzene as an oil which was used without purification.

Example 4 9.0 g (0.033 mol) of 1- (6-bromohexyl) -2,3-dihydroxybenzene in 200 ml of anhydrous tetrahydrofuran and 13.7 ml (0.099 mol) of triethylamine and stirred in an ice bath, 10.9 ml (0.082 mol) of 4-methylbenzoyl chloride was added dropwise over 30 minutes. After 30 minutes, the bath was removed and stirring was continued at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was treated with sodium bicarbonate and the product was extracted with ether.

The dried extract was concentrated to an oil which was purified by HPLC using 10% ethyl acetate-hexane to give 15.2 g (90% yield) of 1- (6-bromohexyl) -2,3-bis / (4-methylbenzoyl). ) oxy / benzene as an oil.

Example 5 To a mixture of 1.0 (3.8 mmol) of 1- (6-bromohexyl) -2,3-dihydroxybenzene in 150 mL of ethyl acetate and 15 mL of acetic anhydride was added 0.03 mL of 70% perchloric acid. . The solution was left at room temperature for 1.5 hours and then washed with sodium bicarbonate solution. After drying, the organic layer was concentrated to give 1.3 g of 1- (6-bromohexyl) -2,3-bis (acetyloxy) benzene as an oil.

Example 6 To a mixture of 3.3 g (0.018 mol) of 3,4-dimethoxyphenethyl alcohol in 50 ml of methylene chloride • · 58 92188 and 4.2 ml (0.03 mol) of triethylamine, which was cooled in an ice bath, was added 1 .6 ml (0.02 mol) of methanesulfonyl chloride with stirring. The reaction mixture was stirred for 75 minutes and then washed successively with water, 1N hydrochloric acid and sodium bicarbonate solution. After drying, the extract was concentrated under reduced pressure to give 1- [f (2-methanesulfonyloxy) ethyl] -2,3-dimethoxybenzene as an oil.

10 Example 7

A mixture of 1.0 mL (7.8 mmol) of 1,2-dimethoxybenzene and 2.0 g (10 mmol) of 6-bromohexanoic acid was briefly heated until homogeneous and stirred while adding as 1.7 ml (11.7 mmol) of trifluoroacetic anhydride were added. The reaction mixture was stirred at room temperature for 17 hours and then poured into sodium bicarbonate solution. The product was extracted with ethyl acetate and the dried extract was concentrated to an oil which was purified by chromatography using 150 g of silica gel. Elution with 25% ethyl acetate-hexane gave 1.6 g (65% yield) of 1- (6-bromo-1-oxohexyl) -3,4-dimethoxybenzene.

Example 8

A mixture of 10 g (46 mmol) of 1-bromo-3,4-, * 25 dimethoxybenzene, 3.4 g (48 mmol) of 3-butyn-1-ol and 8 ml (58 mmol) of triethylamine in 20 ml methylene chloride, stirred and purged with argon. To the mixture were added 0.12 g (0.06 mmol) of copper (1) iodide and 0.30 g (0.43 mmol) of bis (triphenylphosphine) palladium-dichloride. The reaction mixture was stirred at room temperature for 4 hours and under reflux for 16 hours. After filtration, the filtrate was washed with water, dried and concentrated. The crude product was purified by HPLC using 30% ethyl acetate-35 toluene to give 3.0 g (32% yield) of 4- (3,4-dimethoxyphenyl) -3-butyn-1-ol.

59 92188

Example 9

A mixture of 2.0 g of 4- (3,4-dimethoxyphenyl) -3-butyn-1-ol and 0.2 g of 10% palladium on carbon in 40 ml of ethanol was stirred under a hydrogen atmosphere for 4 hours.

After filtration, the filtrate was concentrated under reduced pressure to give 1.9 g of 4- (3,4-dimethoxyphenyl) -butan-1-ol as an oil.

Example 10 To 0.8 g (0.12 g atoms) of 12 g (0.06 moles) of lithium strip cut into small pieces in 50 ml of anhydrous ether, which was stirred at room temperature under an argon atmosphere, was added. 3-Bromo-propan-1-ol 1-ethoxyethyl ether / PE Eaton, G.F. Cooper, R.C. Johnston and R.H. Mueller, J. Org. Chem. 37, 15 1947 (1972) J. After about 1 ml was added, the reaction mixture was cooled in an ice-salt bath, and the rest of the bromine compound was added dropwise over 35 minutes. Stirring was continued with cooling for 1.5 hours and then 7.5 g (0.045 mol) of 2,3-dimethoxybenzaldehyde in 45 ml of anhydrous ether were added dropwise over 30 minutes. After 1 hour, the cooling bath was removed and stirring was continued at room temperature for 1 hour. The reaction mixture was poured into half-saturated ammonium sulfate solution. The ether layer was separated, dried (Na 2 SO 4) and concentrated to an oil (13.9 g). Ethanol (25 ml), water (25 ml) and 2 ml of concentrated hydrochloric acid were added and the solution was left at room temperature for 35 minutes. Potassium carbonate was added with stirring until the mixture was basic.

The ethanol was removed under reduced pressure and the product was extracted with ethyl acetate. The dried extract was concentrated to an oil (12.0 g). This was dissolved in 150 ml of ethanol, 1 g of 10% palladium on carbon was added and the mixture was shaken on a Parr hydrogenator using an initial hydrogen pressure of 55 psi for 5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to an oil. Purification by HPLC using 30% ethyl acetate-hexane gave 7.45 g (79% yield) of 4- (2,3-dimethoxy-phenyl) butan-1-ol.

5 Example 11

A mixture of 102 g (0.607 mol) of methyl 2,4-dihydroxybenzoate, 54 ml (0.619 mol) of allyl bromide and 126 g (0.91 mol) of anhydrous potassium carbonate in 300 ml of anhydrous acetone was stirred at reflux for 3 hours. for an hour. The reaction mixture was filtered and the solid was washed with acetone. After the acetone was removed from the filtrate under reduced pressure, the residue was distilled to give 85 g (67% yield) of 2-hydroxy-4- (2-propenyl-15-bp) having a bp of 106-108 ° / 0.3 mm. oxy) benzoic acid methyl ester.

Example 12 81 g of 2-hydroxy-4- (2-propenyloxy) benzoic acid methyl ester was heated in an O1 bath under argon until the internal temperature was 180-185 °. The temperature was maintained in this range for 1.5 hours and then raised to 210 ° for 1.5 hours. After cooling, the oil crystallized and recrystallized from ether-petroleum ether to give 37 g (46% yield), m.p. 65-66 ° of 2,4-dihydroxy-3- (2-propenyl) benzoic acid methyl ester. .

Example 13

A solution of 54 g of 2,4-dihydroxy-3- (2-propenyl) benzoic acid methyl ester in 900 ml of ethanol and 3 g of 10% palladium on carbon was shaken under an atmosphere of hydrogen until the uptake ceased (45 minutes). The catalyst was removed by filtration through celite and the filtrate was concentrated under reduced pressure to an oil which solidified. After mixing with hexane, the product was filtered to give 51 g of m.p. 66-68 ° 2,4-dihydroxy-35 3-propylbenzoic acid methyl ester.

•. »9218 8 61

Example 14

A solution of 37 g (0.18 moles) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester in 750 ml of methanol and 415 ml of 3N sodium hydroxide was stirred under reflux for 3 hours. The methanol was removed under reduced pressure and the residue was treated with water and 6N hydrochloric acid to acidify. The solid product was extracted with ethyl acetate and the extract was dried and concentrated under reduced pressure to give a tan solid which was used without purification. A mixture of this crude acid (35 g, 0.18 mol), 23 ml (0.2 mol) of benzyl chloride and 17 g (0.2 mol) of sodium bicarbonate in 250 ml of anhydrous dimethylformamide was stirred and heated to 60 ° C. ° for 23 hours. The solvent was removed under reduced pressure and the residue was treated with saturated sodium bicarbonate solution, and the product was extracted with ethyl acetate. The dried extract was concentrated under reduced pressure, and the residual oil was purified by HPLC using 15% ethyl acetate-hexane to give 36 g (70% yield) of m.p. 86-88 ° of 2,4-dihydroxy-3-propylbenzoic acid. phenylmethyl.

Example 15

A solution of 2.1 g (0.01 mol) of 2,4-di-hydroxy-3-propylbenzoic acid methyl ester and 1.6 g (0.012 mol) of N-chlorosuccinimide in 50 ml of carbon tetrachloride was stirred. under reflux for 9.5 hours. Additional N-chlorosuccinimide (1.6 g) was added and refluxing was continued for 30 hours. 0.8 g of N-chlorosuccinimide was added and refluxing was continued for 8 hours. Water was added. The organic layer was separated and washed with sodium thiosulfate solution, sodium bicarbonate solution, dried and concentrated under reduced pressure to give 5-chloro-2,4-dihydroxy-V · 62 92188 3-propylbenzoic acid methyl ester. Recrystallization from hexane gave an analytically pure material, mp 75-76 ° C.

Example 16 A mixture of 29.2 g (0.097 moles) of 1- (6-bromohexyl) -2,3-dimethoxybenzene, 18.5 g (0.088 moles) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester, 18.2 g (0.13 moles) of anhydrous potassium carbonate and 21.9 g (0.13 moles) of potassium iodide in 550 ml of anhydrous acetone were stirred under reflux for 22 hours.

The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to an oil which was purified by HPLC using 8% ethyl acetate-hexane to give 31.4 g (83% yield) of 4- [6- (2,3-dimethoxyphenyl) hexyl]. oxy-2-hydroxy-3-propylbenzoic acid methyl ester as an oil.

The compounds of the following Examples 17-23 were prepared following the procedure of Example 16.

Example 17 Methyl ester of 4- [2- (2,8-dimethoxyphenyl) ethoxy] -2-hydroxy-3-propylbenzoic acid, mp 77-80 ° C.

Example 18 4- [3- (2,3-Dimethoxy-phenyl) -propoxy] -2-hydroxy-3-propyl-benzoic acid methyl ester, mp 51-53 ° C.

Example 19 4-Qk- (2,3-Dimethoxy-phenyl) -butoxy] -2-hydroxy-3-propyl-benzoic acid methyl ester, oil.

Example 20 4- [3- (2,3-Dimethoxy-phenyl) -heptyloxy] -2-hydroxy-3-benzyl ester of 3-propyl-benzoic acid, oil.

Example 21 4- [8- (2,3-Dimethoxy-phenyl) -octyloxy] -2-hydroxy-3-propyl-benzoic acid methyl ester, oil.

Example 22 35 4- [10- (2,3-Dimethoxy-phenyl) -decyloxy] -2-hydroxy-3-propyl-benzoic acid benzyl ester, oil.

63 92188

Example 23 4- [6- (2,3-Dimethoxy-4-isopropyl-phenyl) -hexyloxy] -2-hydroxy-3-propyl-benzoic acid benzyl ester, oil.

5 Example 24

A solution of 31.4 g (0.073 mol) of 4- [6- (2,3-dimethoxyphenyl) hexyloxy] -2-hydroxy-3-propyl-benzoic acid methyl ester in 800 ml of methanol and 365 ml (0.0365 moles) of 1N sodium hydroxide, was stirred under reflux for 1.5 hours. The methanol was removed under reduced pressure, the residue was acidified and the product was extracted with methylene chloride. The dried extract was concentrated under reduced pressure to a solid which was recrystallized from ether-15-hexane to give 24.8 g (82% yield) of mp 115-118 °, mp 115-118 °, 4- (2,3-dimethoxyphenyl) hexyloxy]. 2-hydroxy-3-propylbenzoic acid.

The compounds of Examples 25-30 were prepared following the procedure of Example 24.

Example 25 4- [2- (2,3-Dimethoxyphenyl) ethoxy] -2-hydroxy-3-propylbenzoic acid, mp 154-156 ° C.

Example 26 4- [3- (2,3-Dimethoxyphenyl) propoxy] -2-hydroxy-3-25 propylbenzoic acid, mp 133-134 ° C.

Example 27 4- [4- (2,3-Dimethoxyphenyl) butoxy] -2-hydroxy-3-propylbenzoic acid, mp 111-113 ° C.

Example 28 4 - [[7- (2,3-Dimethoxyphenyl) heptyloxy] -2-hydroxy-3-propylbenzoic acid, mp 98-100 ° C.

Example 29 4- [8- (2,3-Dimethoxyphenyl) octyloxy] -2-hydroxy-3-propylbenzoic acid, mp 90-92 ° C.

Example 30 4- [10- (2,3-Dimethoxyphenyl) decyloxy] -2-hydroxy-3-propylbenzoic acid, mp 77-78 ° C.

64 92188

Example 31

A solution of 6.96 g of 2-hydroxy-4- [6-, 2,3-dimethoxy-4- (1-methylethyl) phenyl] hexyloxy] -3-propylbenzoic acid phenylmethyl ester in 150 ml of ethyl 5 acetate and 1.4 g of 10% palladium on carbon was stirred under an atmosphere of hydrogen for 3 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give 5.45 g of 2-hydroxy-4- [η 5 -2,3-dimethoxy-4- (1-methylethyl) -10-phenyl] hexyloxy] at 106-108 ° m. 3-propyl.

Example 32 To 5.0 g (0.012 mol) of 4- [6- (2,3-dimethoxyphenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid suspended in 250 ml of anhydrous methylene chloride was added. nichloride and cooled to -70 °, 36 mL (0.036 moles) of 1M boron tribromide in methylene chloride was added dropwise over 30 minutes. The reaction mixture was stirred at -70 ° for 30 minutes and then kept at -18 ° for 17 hours. Water (150 ml) was added dropwise with stirring and the product was extracted with ether. The extract was concentrated under reduced pressure. The residue was taken up in 500 mL of ether and shaken vigorously with 125 mL of 1N HCl. The extract was dried and concentrated under reduced pressure to a solid. Recrystallization from ether-hexane gave 3.7 g (80% yield) of 4- [6- (2,3-dihydroxyphenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid, mp 147-150 °.

The compounds of Examples 33-39 were prepared following the procedure of Example 32.

Example 33 4- [4- (2,3-Dihydroxyphenyl) ethoxy] -2-hydroxy-3-propylbenzoic acid, mp 184-189 °.

Example 34 4- [3- (2,3-Dihydroxyphenyl) propoxy] -2-hydroxy-35 3-propylbenzoic acid, mp 189-191 ° C.

, <· 65 92188

Example 35 4- [4- (2,3-Dihydroxyphenyl) butoxy] -2-hydroxy-3-propylbenzoic acid, mp 160-162 ° C.

Example 36 4- [7- (2,3-Dihydroxyphenyl) heptyloxy] -2-hydroxy-3-propylbenzoic acid, mp 144-146 ° C.

Example 37 4- [8- (2,3-Dihydroxyphenyl) octyloxy] -2-hydroxy-3-propylbenzoic acid, mp 136-139 ° C.

Example 38 4- [10- (2,3-Dihydroxyphenyl) decyloxy] -2-hydroxy-3-propylbenzoic acid, mp 126-128 ° C.

Example 39 4- [6- (2,3-Dihydroxy-4-isopropylphenyl) hexyl] oxy] -2-hydroxy-3-propylbenzoic acid, mp 104-105 ° C.

Example 40

A mixture of 6.88 g (0.0138 mol) of 1- (5-iodopentyl) -2,3-diphenylmethoxybenzene, 3.60 g (0.0125 mol) of 2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester, 2.60 g (0.0188 moles) of anhydrous potassium carbonate and 3.10 g (0.0188 moles) of potassium iodide in 150 ml of anhydrous acetone were stirred under reflux for 42 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC using 10% ethyl acetate-hexane to give 7.37 g (91% yield) of 2-hydroxy-4- [5- [2,3-bis (phenylmethoxy) phenyl] pentyloxy] -3- propylbenzoic acid phenylmethyl ester as an oil which solidified, mp 65-69 ° C.

A solution of 7.2 g of the above ester in 500 ml of tetrahydrofuran and 1.4 g of 10% palladium on carbon was stirred under a hydrogen atmosphere for 25 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. . · 66 92188 to a solid which was recrystallized from ether-hexane to give 3.8 g (90% yield) of 4- [5- (2,3-dihydroxyphenyl) mp 155-157 °). pentyloksi7 ~ 2-hydroxy-3-propylbenzoic acid.

5 Example 41

A mixture of 1.40 g (4.8 mmol) of 1- (6-bromohexyl) -2,3-dimethoxybenzene, 1.00 g (4.8 mmol) of 4-hydroxy-3-propylbenzoic acid ethyl ester, 1 , 30 g (9.6 mmol) of potassium carbonate and 0.72 g (4.8 mmol) of sodium iodide in 35 ml of acetone were stirred under reflux for 47 hours. Further work-up and purification as described in Example 16 gave 2.0 g of 4- [6- (2,3-dimethoxyphenyl) hexyloxy] -3-propylbenzoic acid ethyl ester as an oil.

15 Example 42

A solution of 2.0 g of 4-β- (2,3-dimethoxy-phenyl) -hexyloxy-3-propyl-benzoic acid ethyl ester in 70 ml of methanol and 24 ml of 1N sodium hydroxide was stirred under reflux for 3 hours. Further work-up as in Example 24 gave 1.87 g of 4- [6- (2,3-dimethoxy-phenyl) -hexyloxy] -3-propyl-benzoic acid having a mp of 107-108 °.

Example 43 To 1.80 g of 4- [6- (2,3-dimethoxyphenyl) -25 hexyloxy] -3-propylbenzoic acid in 125 ml of methylene chloride cooled to -70 ° was added 14 ml of 1M boron tribromide in methylene chloride. After 30 minutes at -70 ° and 5 hours at -20 °, the reaction mixture was further treated as in Example 32 and the product was recrystallized from ether-hexane to give 1.12 g of mp 123-124 °. 4- [6- (2,3-dihydroxyphenyl) hexyloxy] -3-propylbenzoic acid.

Example 44

A mixture of 1.20 g (4.0 mmol) of 1- (6-bromo-35-hexyl) -2,3-dimethoxybenzene, 1.00 g (4.0 mmol) of «67 92188 3,5-dipropyl 4-Hydroxy-benzoic acid ethyl ester, 1.10 g (8 mmol) of potassium carbonate and 0.6 g (4 mmol) of sodium iodide in 35 ml of acetone were stirred under reflux for 47 hours. Treatment and purification as in Example 16 gave 4- [6- (2,3-dimethoxy-phenyl) -hexyloxy] -3,5-dipropyl-benzoic acid ethyl ester as an oil.

Example 45

A solution of 1.8 g of 4- [6- (2,3-dimethoxyphenyl-1010) hexyloxy] -3,5-dipropylbenzoic acid ethyl ester in 100 ml of methanol and 20 ml of 1N sodium hydroxide was stirred under reflux for 3 hours. Further work-up as in Example 24 gave 4- [6- (2,3-dimethoxyphenyl) hexyloxy] -3,5-dipropyl-15-benzoic acid, mp 61-65 ° C.

Example 46 To 1.7 g of 4- [6- (2,3-dimethoxyphenyl) hexyloxy] -3,5-dipropylbenzoic acid in 125 ml of methylene chloride cooled to -70 ° was added 14 ml of 20 M boron tribromide in methylene chloride. After 30 minutes at -70 ° and 5 hours at -20 °, the reaction mixture was further treated as in Example 32 and the product was recrystallized from ether-hexane to give 0.27 g of m.p. 96 ° 4- [6- (2,3-dihydroxyphenyl-25H) hexyloxy] -3,5-dipropylbenzoic acid.

Example 47

A mixture of 0.90 g (0.0023 mol) of 4- [6- (2,3-dihydroxyphenyl) ethyl iodide and 0.21 g of sodium bicarbonate in 10 ml of anhydrous dimethylformamide was stirred and heated at 50 °. For 6 hours. The solvent was removed using an oil pump, the residue was treated with sodium bicarbonate solution and the product was extracted with ethyl acetate. The dried extract was concentrated and the residue was chromatographed on 35 g of silica gel. Elution with 35% ethyl acetate-toluene gave 0.89 g of an oil, 68 92188 which was mixed with hexane and filtered, _% to give 0.71 g (70% yield) of mp 54-57 °, mp 54-57 °. - (2,3-dihydroxyphenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid ethyl ester.

5 Example 48

A mixture of 1.0 g (2.57 iranol) of 4- [6- (2,3-dihydroxyphenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid, 3.5 g (25.7 mmol) 2 diethylaminoethyl chloride and 0.24 g (2.83 mmol) of sodium bicarbonate in 20 ml of anhydrous dimethylformamide were stirred and heated at 50 ° C for 1.5 hours. The solvent was removed using an oil pump. The residue was treated with sodium bicarbonate solution and the product was extracted with ethyl acetate. The dried extract was concentrated and the residue was chromatographed on 50 g of silica gel. Eluting with CH 2 Cl 2. 95% MeOH: NH 4 OH (95: 5: 0.05) gave 1.0 g of 4- [6- (2,3-dihydroxyphenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid ε-2- (diethylamino) ethyl x7 ester free base. This was dissolved in methylene chloride, treated with 3.2 mL of 2M HCl in ethanol. After concentration and addition of hexane, 0.91 g (68% yield) of 4- [6- (2,3-dihydroxyphenyl) hexyloxy] -2-hydroxy-3- propylbenzoic acid [2- (diethylamino) ethyl / ester hydrochloride.

25 Example 49

A mixture of 1.91 g (3.75 mmol) of 1- (6-bromohexyl) -2,3-bis (4-methylbenzoyl) oxy] benzene, 1.07 g (3.75 mmol) 2 , 4-dihydroxy-3-propyl-benzoic acid phenylmethyl ester, 0.94 g (5.63 mmol) of potassium 30-iodide and 0.75 g (5.63 mol) of potassium carbonate in 40 ml of acetone, were stirred under reflux for 26 hours. . The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC using 5% ethyl acetate-hexane to give 0.85 g (32% yield) of 2-hydroxy-4- [6- [2,3-bis (4-methylbenzoyl) oxy] phenyl7hexyloxy7-69 92188 Phenylmethylbenzoate of 3-propylbenzoic acid.

Example 50

A solution of 0.78 g of 2-hydroxy-4- [6- [2,3-bis] - (4-methylbenzoyl) oxy] phenyl] hexyloxy] -3-prop-5-ylbenzoic acid phenylmethyl ester in 65 ml of tetrahydrofuran and 0, 16 g of 10% palladium on carbon, was shaken under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to a solid which was recrystallized from methylene chloride-hexane to give 0.57 g of 2-hydroxy-4- [6- [2,3-bis] having a mp of 141-143 °. - £ 4-metyylibentsoyl) oksi7fenyyli7heksyloksi7-3-propyl-benzoic acid.

Example 51 To a suspension of 0.14 g (3.5 mmol, 60% in oil) of sodium hydride in 10 mL of anhydrous dimethylformamide and stirred at room temperature was added 0.88 g (3.1 mmol) of 2 , 4-dihydroxy-3-propyl-benzoic acid phenylmethyl ester. The reaction mixture was stirred for 2 hours and then 1.09 g (3.1 mmol) of 1- (6-bromohexyl) -2,3-bis (acetyloxy) benzene in 10 ml of dimethylformamide were added dropwise. Stirring at 50 ° was continued for 16 hours and then the solvent was removed using an oil pump. The crude product was purified by 25. HPLC using 25% ethyl acetate-hexane to give 0.55 g (28% yield). 4- [6- [2,3-Bis (acetyloxy) phenyl] hexyloxy] -2-hydroxy-3-propylbenzoic acid phenyl methyl ester as an oil.

Example 52 A solution of 0.53 g of phenylmethyl ester of 4- [6- [2,3-bis (acetyloxy) phenyl] hexyloxy] -2-hydroxy-3-propylbenzoic acid in 50 ml of tetrahydrofuran and 0.10 g of 10% palladium on carbon , was shaken under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through celite 35 and the filtrate was concentrated to a solid which was recrystallized from ether-hexane to give>% · 70 92188 0.35 g of a spin of 120-122 ° 4-4-6,3-bis (acetyloxy). -fenyyli7heksyloksi7-2-hydroxy-3-propylbenzoic acid.

Example 53

A mixture of 1.31 g (2.6 mmol) of 1- (6-iodo-5-hexyl) -2,3-bis (phenylmethoxy) benzene, 0.74 g (2.6 mmol) of 2,4-dihydroxy 3-Propyl-benzoic acid phenylmethyl ester and 0.54 g (3.9 mmol) of potassium carbonate in 35 ml of acetone were stirred under reflux for 39 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to an oil which was purified by HPLC using 8% ethyl acetate-hexane to give 1.03 g (60% yield) of 2-hydroxy-4- {6- [2,3- bis (phenylmethoxy) phenyl] hexyloxy] -3-propylbenzoic acid phenyl methyl ester 15 as an oil.

Example 54

A solution of 1.15 g of 2-hydroxy-4- [6- [2,3-bis (phenylmethoxy) phenyl] hexyloxy] -3-propylbenzoic acid phenylmethyl ester in 15 ml of pyridine and 15 ml of acetic anhydride was stirred and heated. At 50 ° for 15 hours. The reaction mixture was concentrated using an oil pump. The residue was dissolved in ethyl acetate, and the solution was washed with sodium bicarbonate solution, dried and concentrated under reduced pressure to give 1.03 g of 2-acetyloxy-4- [6- [2,3-bis (phenylmethoxy) phenyl] hexyloxy] -3-propylbenzoic acid phenyl methyl ester as an oil.

Example 55

A solution of 1.02 g of phenylmethyl 2-acetyloxy-4- [6- (2,3-30-30) bis (phenylmethoxy) phenyl] hexyloxy] -3-propylbenzoic acid in 65 ml of tetrahydrofuran and 0.02 g of 10% palladium on carbon, stirred under an atmosphere of hydrogen for 24 hours. The reaction mixture was filtered through celite and the filtrate was concentrated, and the residue was crystallized from ether-hexane to give 0.51 g. · 71 92188 (82% yield) m.p. 130-132 ° C 2-acetyloxy-4- [6- (2,3-dihydroxyphenyl) hexyloxy] -3-propylbenzoic acid.

Example 56 A mixture of 0.41 g (0.8 mmol) of 1- (6-iodohexyl) -2,3-bis (phenylmethoxy) benzene. 0.18 σ (0.74 mmol) of 5-chloro-2,4-dihydroxy-3-methylbenzoic acid methyl ester and 0.22 g (1.6 mmol) of potassium carbonate in 15 ml of acetone were stirred under reflux for 16 hours. I drive. The reaction mixture was filtered and the filtrate was concentrated to an oil. Chromatography on 30 g of silica gel eluting with 10% ethyl acetate-hexane gave 0.31 g (68% yield) of 5-chloro-2-hydroxy-4- / 6- / 2,3-bis (phenylmethyloxy) phenyl7-hexyloxy-3-propyl-benzoic acid methyl ester as an oil.

Example 57

A solution of 0.30 g of 5-chloro-2-hydroxy-4- [6- (2,3-bis (phenylmethoxy) phenyl] hexyloxy] -3-propyl-20-benzoic acid methyl ester in 10 ml of methanol, 5 ml of dioxane and 2 In 5 ml of 1N sodium hydroxide was left at room temperature for 3 days, the solvent was removed under reduced pressure and the residue was acidified and extracted with ethyl acetate, and the dried extract was concentrated and chromatographed using 30 g of silica gel and acetic acid: ethyl acetate: toluene (1: 2). 75) to give 0.21 g of 5-chloro-2-hydroxy-4- [6- [2,3-bis (phenylmethoxy) phenyl] hexyloxy] -3-propylbenzoic acid as an oil.

30 Example 58

A solution of 0.21 g of 5-chloro-2-hydroxy-4- [6- [2,3-bis (phenylmethoxy) phenyl] hexyloxy] -3-propylbenzoic acid in 30 ml of ethyl acetate and 0.073 g of 10% palladium on carbon, was shaken under hydrogen pressure (2-2.7 35 bar) for 21 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to an oil. Chromatography on 20 g of silica gel eluting with acetic acid: ethyl acetate / toluene (5:20:75) gave 82 mg of 5-chloro-2-hydroxy-4- [6- (2) at 110-113 °. (3-dihydroxyphenyl) hexyloxy-3-propylbenzoic acid.

Example 59

A mixture of 1.0 g (3.3 mmol) of 1- (6-bromohexyl) -2,3-dimethoxybenzene, 0.55 g (3.3 mmol) of 2,4-dihydroxybenzoic acid methyl ester, 1.2 g (9 mmol-10 l) of potassium carbonate and 0.75 g (4.5 mmol) of potassium iodide in 25 ml of acetone were stirred under reflux for 20 hours. Further work-up as in Example 16 gave 1.2 g of 4- [6- (2,3-dimethoxy-phenyl) -hexyloxy] -2-hydroxy-benzoic acid methyl ester 15 as an oil.

Example 60

A solution of 0.45 g (1.2 mmol) of 4- [6- (2,3-dimethoxyphenyl) hexyloxy] -2-hydroxybenzoic acid methyl ester in 25 ml of methanol and 8 ml of 1N sodium hydroxide was heated to reflux. For 7 hours. Further work-up as in Example 24 and recrystallization from methanol gave 0.36 g (82% yield) of 4- [6- (2,3-dimethoxyphenyl) hexyloxy] -2-hydroxybenzoic acid, m.p. 115-116 °.

25 Example 61

To a stirred mixture of 0.35 g of 4- [6- (2,3-dimethoxyphenyl) hexyloxy] -2-hydroxybenzoic acid in 10 ml of methylene chloride, cooled to -70 ° C, was added 3.5 ml of 1M boron tribromo-30 dia in methylene chloride. The reaction mixture was stirred at -70 ° for 20 minutes and at -20 ° for 6.5 hours. Further work-up as in Example 32 and crystallization from methanol gave 0.20 g (60% yield) of 4- [6- (2,3-dihydroxyphenyl) hexyl] oxy] -2-hydroxybenzoic acid, m.p. 179-180 ° C.

73 92188

Example 62

A mixture of 1.00 g of 1- (6-iodohexyl) -2,3-bis (phenylmethoxy) benzene, 0.34 g of 2,5-dihydroxybenzoic acid methyl ester and 1.0 g of potassium carbonate-5 in 30 ml: in acetone, stirred under reflux for 17 hours. Further work-up as in Example 16 and chromatography using 60 g of silica gel and 1% ethyl acetate in toluene gave 0.42 g (39% yield) of 2-hydroxy-5- [6- [2,3-bis (phenyl-10-ylmethoxy)]. phenyl7hexyloxy7benzoic acid methyl ester as an oil.

Example 63

A solution of 0.42 g of 2-hydroxy-5- [6- [2,3-bis (phenylmethoxy) phenyl / hexyloxy] benzoic acid methyl ester in 12 ml of ethanol and 4 ml of 1N sodium hydroxide was stirred under reflux for 1 hour. , For 5 hours. Further work-up as in Example 24 and recrystallization from ether-hexane gave 0.25 g of 2-hydroxy-5- [6- [2,3-bis (phenyl-20-ylmethoxy) phenyl] hexyloxy / benzoic acid having a mp of 97-10 °.

Example 64

A mixture of 0.22 g of 2-hydroxy-5- [6- [2,3-bis (phenylmethoxy) phenyl] hexyloxy] benzoic acid and 30 mg of 10% palladium on carbon in 10 ml of methanol was stirred under a hydrogen atmosphere for 5 hours. Further work-up as in Example 36 and recrystallization from acetone-hexane gave 0.10 g of 2-hydroxy-5- [6- (2,3-dihydroxyphenyl) hexyloxy] benzoic acid, m.p. 159-161 ° C.

30 Example 65

A mixture of 1.00 g (3.3 mmol) of 1- (6-bromohexyl) -2,3-dimethoxybenzene, 0.45 g (3.0 mmol) of 4-hydroxybenzoic acid methyl ester, 0.62 g (4, 5 mmol) of potassium carbonate and 0.75 g (4.5 mmol) of potassium iodide in 25 ml of acetone were stirred under reflux for 23 hours. Further work-up as in 74 92188 in Example 16 and purification by HPLC using 15% ethyl acetate-hexane gave 1.10 g (89% yield) of 4- / 6- (2,3-dimethoxyphenyl) hexyloxy / benzoic acid methyl ester as an oil. .

5 Example 66

To a stirred mixture of 0.80 g (2.2 mmol) of 4- [6- (2,3-dimethoxyphenyl) hexyloxy] benzoic acid methyl ester in 25 ml of methylene chloride, cooled to -70 °, was added 8. 0 ml of 10 M boron tribromide in methylene chloride. The reaction mixture was stirred at -70 ° C for 30 minutes and at -20 ° C for 7 hours. Further work-up as in Example 32 and recrystallization from ethyl acetate-hexane gave 0.30 g (42% yield) of 4- [6- (2,3-dihydroxyphenyl) hexyloxy] benzoic acid, m.p. 170-172 ° C.

Example 67

A mixture of 0.58 g of 1- (6-iodohexyl) -2,3-bis- (phenylmethoxy) benzene, 0.18 g of 3-hydroxybenzoic acid methyl ester and 0.25 g of potassium carbonate in 15 ml of acetone, stirred under reflux for 18 hours. Further work-up as in Example 16 and purification by HPLC using toluene gave 0.40 g (66% yield) of 3- [6- [2,3-bis (phenylmethoxy) -phenyl] -hexyloxy] -benzoic acid methyl ester as an oil.

25 Example 68

A solution of 0.5 g of 3- [2,3-bis (phenylmethoxy) phenyl] hexyloxy / benzoic acid methyl ester in 15 ml of methanol and 5 ml of 1N sodium hydroxide was stirred under reflux for 2 hours. Further work-up as in Example 24 and crystallization from methanol gave 0.34 g (70% yield) of 3- / 6- / 2,3-bis (phenylmethoxy) phenyl / hexyloxy / benzoic acid having a mp of 72-74 ° C. .

Example 69 A mixture of 0.33 g of 3- [6-Z2,3-bis (phenylmethoxy) phenyl] hexyloxy] benzoic acid and 95 mg of 10% 92188 75 palladium on carbon in 20 [mu] l of ethyl acetate and 5 ml of ethanol was stirred under a hydrogen atmosphere for 11 hours. . The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to an oil. Chromatograph on 5 g of silica gel eluting with 10% methanol-chloroform to give a solid which was recrystallized from ether-hexane to give 0.14 g (63% yield) of mp 123-125 °. - / 6- (2,3-dihydroxyphenyl) heksyloksi7bentsoehappoa.

10 Example 70

A mixture of 5.6 g of 1- (6-iodohexyl) -2,3-bis (phenylmethoxy) benzene, 2.1 g of 3-chloro-4-hydroxy-benzoic acid methyl ester and 5.0 g of potassium carbonate in 50 ml of acetone, stirred under reflux for 20 hours. Further work-up as in Example 16, chromatography on 100 g of silica gel and 15% ethyl acetate-hexane and crystallization from ethyl acetate-hexane gave 3.7 g (59% yield) of 3-chloro-4- m.p. 68-69 ° C. E 6- [2,3-bis (phenyl-20-methoxy) -phenyl] -hexyloxy] -benzoic acid methyl ester.

Example 71

A solution of 3.6 g of 3-chloro-4- [6- [2,3-bis- (phenylmethoxy) phenyl] hexyloxy] benzoic acid methyl ester in 90 ml of methanol and 30 ml of 1N sodium hydroxide was heated under reflux for 2 hours.

Further work-up as in Example 24, chromatography on 70 g of silica gel and 50% ethyl acetate-hexane and recrystallization from ether-hexane gave 1.3 g of m.p. 87-89 ° C, 3-chloro-4-76- / 5,3-bis. (phenylmethoxy) phenyl / hexyloxy] benzoic acid.

Example 72

A mixture of 0.6 g of 3-chloro-4- [6- / 2,3-bis- (phenylmethoxy) phenyl] hexyloxy / benzoic acid and 60 mg of 10% palladium on carbon in 20 ml of tetrahydrofuran was stirred under a hydrogen atmosphere for 6 hours.

Further work-up as in Example 40 and recrystallization from ethyl acetate-hexane gave 0.24 g of 3-chloro-4- [6- (2,3-dihydroxyphenyl) hexyloxy] benzoic acid, m.p. 157-160 ° C.

5 Example 73

A mixture of 3.4 g (0.016 moles) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester, 4.7 g (0.018 moles) of 1 - [(2-methanesulfonyloxy) ethyl] -2,3-dimethoxybenzene, 4.4 g (0.032 mol) of potassium carbonate and 2.7 g (0.018 mol) of sodium iodide in 90 ml of acetone were stirred under reflux for 18 hours, and 4.7 g of 1- (E-2-methanesulfonyloxy) ethyl) was added. “2,3-Dimethoxybenzene and 4.4 g of potassium carbonate and refluxing were continued for 41 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to an oil which was purified by high pressure liquid chromatography using 10% ethyl acetate-hexane to remove impurities and then ethyl acetate. 5 g of oil.

This was mixed with hexane and filtered to give 1.65 g (28% yield) of 4- [2- (3,4-dimethoxyphenyl) ethoxy] -2-hydroxy-3-propyl having a mp of 56-58 °. -benzoic acid methyl ester.

Example 74 25. A mixture of 9.5 g (0.037 moles) of 1- (3-bromopropyl) -3,4-dimethoxybenzene. Douglas, C.R.

Walk and H. Smith, J. Med. Chem. 9.27 (1966Γ / # 7.0 g (0.033 moles) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester, 6.9 g (0.05 moles) of potassium carbonate 30 and 8.3 g (0.05 moles) of potassium iodide) In 250 ml of acetone, stirred under reflux for 24 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to an oil which was purified by high pressure liquid chromatography using 15% ethyl acetate-hexane-hexane to give 7.2 g (56% yield) of 4 N- (3- (3,4-dimethoxyphenyl) propoxy] -2-hydroxy-3-propyl-92,9188 benzoic acid methyl ester as an oil.

The compounds of Examples 75-77 were prepared using the method of Example 74.

Example 75 4- [4- (3,4-Dimethoxy-phenyl) -butoxy] -2-hydroxy-3-propyl-benzoic acid methyl ester, yield 49%.

Example 76 4- [5- (3,4-Dimethoxyphenyl) pentyloxy] -2-hydroxy-3-propylbenzoic acid methyl ester, yield 80% Example 77 4- [6- (3,4-Dimethoxyphenyl) hexyloxy] -2-hydroxy-3 -propylbenzoic acid methyl ester, yield 77%

Example 78

A solution of 7.1 g of methyl 4- [3- (3,4-dimethoxyphenyl) -15-propoxy] -2-hydroxy-3-propylbenzoic acid in 180 ml of methanol and 90 ml of 1N sodium hydroxide was stirred. under reflux for 1 hour. The solvent was removed under reduced pressure, the residue was acidified and the product was extracted with methylene chloride. The dried (MgSO 4) extract was concentrated to 6.5 g of 4- [3- (3,4-dimethoxyphenyl) propoxy] -2-hydroxy-3-propylbenzoic acid, mp 104-110 °.

The compounds of Examples 79, 80 and 82 were prepared using the method of Example 78. The compound of Example 84 · - * 25 was prepared using the method of Example 40, hydrogenolysis in tetrahydrofuran.

Example 79 4- [2- (3,4-Dimethoxyphenyl) ethoxy] -2-hydroxy-3-propylbenzoic acid, mp 156-157 °.

Example 80 4- [N- (3,4-dimethoxyphenyl) butoxy] -2-hydroxy-3-propylbenzoic acid, mp 125-127 °.

Example 81 4- [5- (3,4-Dimethoxyphenyl) pentyloxy] -2-hydroxy-35-3-propylbenzoic acid, mp 133-136 °.

. ·· • 1 78 92188

Example 82 4- [6- (3,4-Dimethoxyphenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid, mp 99-101 °.

Example 83 3.0 g (0.008 mol) of 4- [3- (3,4-dimethoxyphenyl) propoxy] -2-hydroxy-3-propylbenzoic acid suspended in 250 ml of methylene chloride and cooled to -70 ° to, was added 24 mL (0.024 moles) of 1M boron tribromide in methylene chloride dropwise over 30 minutes. The reaction mixture was stirred at -70 ° C for 1 hour and then in an ice bath for 1.5 hours. water (100 ml) was added dropwise with stirring and the product was extracted with ether. The extract was concentrated under reduced pressure and the residue was taken up in ether (500 ml) and vigorously spent with 100 ml of 1N hydrochloric acid. The dried extract was concentrated and the residue was recrystallized from ether-hexane to give 2.2 g (79%; yield) of 4- [3- (3,4-dihydroxyphenyl) propoxy] -2-hydroxy, mp 194-195 °. -3-propyl.

The compounds of Examples 84-87 were prepared using the method of Example 83.

Example 84 4- [2- (3,4-Dihydroxyphenyl) ethoxy] -2-hydroxy-3-propylbenzoic acid, mp 164-165 °.

• 25 Example 85 4- [4- (3,4-dihydroxyphenyl) butoxy] -2-hydroxy-3-propylbenzoic acid, mp 190-193 °.

Example 86 4- [5- (3,4-Dihydroxyphenyl) pentyloxy] -2-hydroxy-3-propylbenzoic acid, mp 159-162 °.

Example 87 4- [5- (3,4-Dihydroxyphenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid, mp 113-114 °.

Example 88 35 A mixture of 2.56 g (9.9 mmol) of 1- (3-bromopropyl) -3,4-dimethoxybenzene 1.50 g (9 mmol) of 79 9 2 1 88 4-hydroxybenzoic acid ethyl ester, 1.38 g (10 mmol) of potassium carbonate and 1.66 g (10 mmol) of potassium iodide in 50 ml of acetone were stirred under reflux for 22 hours. Further work-up as in Example 16, purification by HPLC using methylene chloride and recrystallization from 2-propanol gave 1.23 g (40% yield) of mp 70-71 °, mp 70-71 ° (3.4 -dimethoxyphenyl) -propoxy] -benzoic acid ethyl ester.

10 Example 89

A solution of 1.2 g of 4- [3- (3,4-dimethoxyphenyl) propoxy] benzoic acid ethyl ester in 40 ml of methanol and 18 ml of 1N sodium hydroxide was stirred under reflux for 1 hour. Further work-up as in Example 24 gave 1.1 g of 4- [3- (3,4-dimethoxyphenyl) propoxy] benzoic acid having a mp of 150-154 °.

Example 90 To 1.08 g (3.4 mmol) of 4- [3- (3,4-dimethoxy-20-phenyl) propoxy] benzoic acid suspended in 60 ml of methylene chloride and cooled to -70 ° was added 10 ml (10 mmol) of 1M boron tribromide in methylene chloride. The reaction mixture was stirred at -70 ° for 2.5 hours and then further worked up as in Example 32. Recrystallization from ether-hexane gave 0.40 g (41% yield) of a mp of 180-185 °, m.p. ^ 3- (3,4-dihydroxyphenyl) propoksijbentsoe acid.

Example 91 A mixture of 1.60 g (5 mmol) of 6-bromo-1- (3,4-dimethoxyphenyl) -1-hexanone, 0.95 g (4.5 mmol) of 2,4-dihydroxy-3 -propylbenzoic acid methyl ester, 1.38 g (10 mmol) of potassium carbonate and 0.75 g (5 mmol) of sodium iodide in 40 ml of acetone were stirred under reflux for 45 hours.

The reaction mixture was filtered and the filtrate was concentrated and treated with water. The product was filtered and recrystallized from methylene chloride-methanol to give 1.40 g (70% yield) of 4- [6- (3,4-dimethoxyphenyl) -6-oxohexyloxy] -2-2. -hydroxy-3-5 propylbenzoic acid methyl ester.

Example 92

A solution of 1.36 g of (3,4-dimethoxy-phenyl) -6-oxo-hexyl-7-oxy-2-hydroxy-3-propyl-benzoic acid methyl ester in 35 ml of methanol and 13 ml of 1N sodium hydroxide was stirred under reflux. , For 5 hours. The solvent was removed under reduced pressure, the residue was acidified and the product was filtered. Recrystallization from ethyl acetate-hexane gave 0.94 g (71% yield) of 4- (N- (3,4-dimethoxyphenyl) -6-oxohexyl) oxy-2-hydroxy- 3-propyl.

Example 93 To 0.93 g of 4 - [/ 6- (3,4-dimethoxyphenyl) -6-oxohexyl] oxy] -2-hydroxy-3-propylbenzoic acid suspended in 60 ml of methylene chloride and cooled to -70 °: 7 ml of boron tribromide in methylene chloride was added. The reaction mixture was stirred at -70 ° for 1 hour and then at -18 ° for 20 hours. Further work-up as in Example 32 and chromatography on the crude product using 100 g of silica gel and a mixture of acetic acid: ethyl acetate / beer (5:25:70) followed by recrystallization from ethyl acetate-hexane gave 0.42 g of m.p. 191 ° 4- [X6- (3,4-dihydroxyphenyl) -6-oxohexyl] -30-oxy] -2-hydroxy-3-propylbenzoic acid.

Example 94

A mixture of 4.36 g (15.9 mmol) of 1- (4-bromobutyl) -2,3-dimethoxybenzene, 3.10 g (15.9 mmol) of 1- (2,4-dihydroxy-3- propylphenyl) ethanone, 4.4 g (32 to 35 mmol) of potassium carbonate and 2.4 g (16 mmol) of sodium 81 92188 in iodide in 100 ml of acetone were stirred under reflux for 30 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by high pressure liquid chromatography using 20% ethyl acetate-hexane gave 5.07. g (88% yield) of 1-Z2-hydroxy-4- [4- (2,3-dimethoxyphenyl) -butoxy] -3-propylphenyl] ethanone as an oil.

The compounds of Examples 95-97 were prepared using the method of Example 94.

Example 95 1-Z2-Hydroxy-4-[[5- (2,3-dimethoxyphenyl) hexyloxy] -3-propylphenyl] ethanone.

Example 96 1 H-2-Hydroxy-4- [8- (2,3-dimethoxyphenyl) octyloxy] -3-propylphenyl] ethanone, oil.

Example 97 1- [2-Hydroxy-4- [6- (2,3-dimethoxy-4-isopropyl-phenyl) -hexyloxy] -3-propyl-phenyl] -ethanone, oil.

Example 98 To a mixture of 5.02 g of 1- [2-hydroxy-4- [4- (2,3-dimethoxyphenyl) butoxy] -3-propylphenyl] ethanone in 300 ml of methylene chloride and stirred and cooled to -70 ° , 39 ml of 1M boron tribromide in methylene chloride was added. The reaction mixture was stirred at -70 ° for 30 minutes and kept at -20 ° for 5.5 hours. Further work-up as in Example 32 and recrystallization from acetone-hexane gave 3.81 g (82% yield) of 1-10-hydroxy-4- [4- (2,3-dihydroxyphenyl) butoxy] having a mp of 103-105 °. -3-30 propylphenyl7ethanone.

The compounds of Examples 99-101 were prepared by the method of Example 98.

Example 99 1- [2-Hydroxy-4- [N- (2,3-dihydroxyphenyl) hexyl] oxy] -3-propylphenyl] ethanone, mp 106-108 °.

82 92188

Example 100 1- [2-Hydroxy-4- [g- (2,3-dihydroxyphenyl) octyloxy] -3-propylphenyl] ethanone, mp 116-118 °.

Example 101 1- [2-Hydroxy-4- [6- (2,3-dihydroxy-4-isopropyl-phenyl) -hexyloxy] -3-propyl-phenyl] -ethanone, oil.

Example 102 3.0 g (0.013 mol) of 5- (3,4-dimethoxyphenyl) pentan-1-ol was converted to the mesylate as described in Example 10. A mixture of this mesylate was converted to 2.6 g (0.013 mol). 1- (2,4-dihydroxy-3-propylphenyl) ethanone, 2.8 g (0.02 mol) of potassium carbonate and 0.28 ml (0.9 mmol) of tris- [2- (2-methoxyethoxy) ethyl] amine (TDA-1) in 75 mL of toluene, stirred under reflux for 6.5 hours. The reaction mixture was washed with half-saturated brine, then 1N sodium hydroxide, dried and concentrated under reduced pressure to an oil. Purification by HPLC using 25% ethyl acetate-hexane gave 4.05 g (75% yield) of 1- [2-hydroxy-4- [5- (3, 4-dimethoxyphenyl) pentyloxy-3-propylphenyl-7-ethanone.

Example 103 To 3.95 g (0.01 mole) of 1- [2-hydroxy-4- [5, (3,4-dimethoxyphenyl) pentyloxy] -3-propylphenyl] -25-1-ethanone was 80 ml: methylene chloride cooled to -70 °, 30 ml (0.03 mol) of 1M boron tribromide in methylene chloride was added. After 30 minutes at -70 ° and 6 hours at -20 °, the reaction mixture was further treated as in Example 32 and the product was recrystallized from ether-hexane to give 3.24 g (88% yield) of m.p. n-4- [4- [3- (3,4-dihydroxyphenyl) pentyloxy] -2-hydroxy-3-propylphenyl] -1-ethanone having 126-127 °.

Example 104 A solution of 2.5 M butyllithium in hexane: (16 mL, 0.04 mol) was added dropwise over 15 minutes to a stirred solution of 8.3 g (0.039 mol) of 2,3-dimethoxybiphenyl. Bruce and F.K. Sugcliffe, J. Chem. Soc. 4435 (1955) in 7,160 ml of anhydrous tetrahydrofuran cooled to 0 ° under argon-5 gas. The reaction mixture was stirred at 0 ° for 2.5 hours and then heated to reflux for 30 minutes. After cooling to 5 °, 6.3 ml (0.039 mol) of 1,6-dibromohexane were added. Stirring was continued at 5 ° for 30 minutes, at 25 ° C for 30 minutes and under reflux for 20 hours. Further work-up as in Example 1 gave an oil. Purification by HPLC using 3% ethyl acetate-hexane gave 5.7 g of unreacted 2,3-dimethoxybiphenyl and 3.3 g of 4- (6-bromohexyl) -15,3,3-dimethoxy-1,1'-biphenyl as an oil.

Example 105

A mixture of 3.3 g (8.75 mmol) of 4- (6-bromohexyl) -2,3-dimethoxy-1,1'-biphenyl, 2.5 g (8.75 mmol) 2.4 -dihydroxy-3-propyl-benzoic acid phenyl-20-methyl ester, 1.8 g (13.1 mmol) of potassium carbonate and 0.2 ml (0.63 mmol) of tris- [2- (2-methoxyethoxy) ethyl] -amine (TDA-1 ) In 65 ml of anhydrous toluene, was stirred under reflux for 30 hours. The reaction mixture was washed with half-saturated filtrate and then 1N sodium hydroxide. After the organic layer was dried, the solvent was removed under reduced pressure to give an oil which was purified by chromatography using 100 g of silica gel. Elution with 10% ethyl acetate-hexane gave 3.7 g (73% yield) of 2-hydroxy-4 - [[N- (2,3-dimethoxy-1,1'-biphenyl) -4-yl] hexyloxy] Phenylmethyl ester of 3-propylbenzoic acid.

Example 106

A mixture of 3.76 g of 2-hydroxy-4 - [[6- (2,3-35 dimethoxy-1,1'-biphenyl) -4-yl] hexyloxy] ** 3-propyl-84 92188 phenylmethyl benzoic acid and 0 .30 g of 10% palladium on carbon in 80 ml of tetrahydrofuran were stirred under a hydrogen atmosphere for 17 hours. Further work-up as in Example 40 and recrystallization from hexane gave 2.4 g of 2-hydroxy-4- [6 '(2,3-dimethoxy-1,1'-biphenyl) -4-yl] hexyloxy] having a mp of 78-80 °. ~ 3-propylbenzoic acid.

Example 107 To 1.72 g (3.5 mmol) of 2-hydroxy-10 4-Z.Z6- (2,3-dimethoxy-1,1'-biphenyl) 4-yl-4-hexyloxy] propylbenzoic acid, suspended in 150 ml of methylene chloride and cooled to -70 °, 10.5 ml (10.5 mmol) of 1M boron tribromide in methylene chloride was added. The reaction mixture was stirred at -70 ° for 20 ml-15 minutes and then kept at -18 ° for 17 hours.

Further work-up as in Example 32 and recrystallization twice from methylene chloride gave 1.03 g (63% yield) of m.p. 151-155 ° of 2-hydroxy-4- [η 6 - (2,3-dihydroxy-1 , (1'-Biphenyl) -4-yl-hexyl-20-oxy-3-propyl-benzoic acid.

Example 108 To 0.6 g (0.08 g atoms) of lithium strip cut into small pieces in 40 ml of anhydrous ether stirred at room temperature under an argon atmosphere was added 9.5 g ( 0.04 moles) of 2-bromopentanol 2-ethoxyethyl ether. After about 1 ml was added, the reaction mixture was cooled to -5 ° and the rest of the bromine compound was added dropwise. Stirring at -5 ° was continued for 1 hour and thus 6.0 g (0.03 mol) of 2-chloro-3,4-dimethoxybenzaldehyde (J. Weinstock et al., J. Med. Chem. ., 29, 2315 (1986) in a mixture of 50 ml of ether and 20 ml of tetrahydrofuran dropwise over 1 hour, the cooling bath was removed and stirring was continued for 1 hour.

The reaction mixture was further treated as in Example 10, Λ · 85 92188 to give an oil which was dissolved in a mixture of 25 ml of ethanol, 20 ml of water and 2 ml of concentrated hydrochloric acid was added. The solution was left at 25 ° for 45 minutes. Potassium carbonate was added with stirring until the mixture was basic. The ethanol was removed under reduced pressure and the product was extracted with ethyl acetate. The dried extract was concentrated to an oil (10 g). This was purified by HPLC using 60% ethyl acetate-hexane to give 2.9 g (34% yield) of 6- (2-chloro-3,4-dimethoxybenzene) - mp 65-70 °. 6-hydroksiheksanolia.

This was dissolved in 50 mL of ethanol, 0.3 g of 10% palladium on carbon was added, and the mixture was shaken using an initial hydrogen pressure of 54 psi for 21 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to an oil. Purification by HPLC using 15% ethyl acetate-toluene gave 1.74 g (64% yield) of 2-chloro-3,4-dimethoxybenzene-hexanol as an oil.

Example 109 To 1.74 g (6.4 mmol) of 2-chloro-3,4-dimethoxybenzenehexanol in 25 mL of methylene chloride cooled in an ice bath was added 1.8 mL (12.8 mmol) of ) triethylamine followed by 0.65 ml (8.3 mmol) of methanesulfonyl chloride. The reaction mixture was stirred under cooling in an ice bath for 80 minutes and then further treated as in Example 3. A mixture of the mesylate obtained gave 1.24 g (5.9 mmol) of 2,4-dihydroxy-3-propylbenzoic acid. methyl ester 1.8 g (13 mmol) of potassium carbonate and 0.2 m 1 (0.7 mmol) of tris- [2- (2-methoxyethoxy) ethyl] amine (TDA-1) in 40 ml of toluene were stirred under reflux for 39 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC using 35% ethyl acetate-hexane to give 2.11 gc · · • 1 86 92188 (77% yield) 4- [6- (2-chloro-3,4-dimethoxyphenyl) -hexyloxy-2-hydroxy-3-propylbenzoic acid methyl ester as an oil.

Example 110 A solution of 2.1 g (4.5 mmol) of 4- [6- (2-chloro-3,4-dimethoxyphenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid methyl ester in 50 ml of methanol and In a mixture of 15 ml of dioxane and 18 ml of 1N sodium hydroxide, it was heated under reflux for 8 hours. The solvents were removed under reduced pressure, the residue was acidified and the product was extracted with ethyl acetate. The dried extract was concentrated and the residue was recrystallized from ethyl acetate-hexane to give 1.86 g (92% yield) of 4- [6- (2-chloro-3,4-dimethoxyphenyl) hexyloxy] having a mp of 107-108 ° C. 2-2-hydroxy-3-propylbenzoic acid.

Example 111 1.80 g (4 mmol) of 4- [6- (2-chloro-3,4-dimethoxyphenyl) hexyloxy] -2-hydroxy-3-propyl-20-benzoic acid suspended in 120 ml of methylene chloride - nichloride and cooled to -70 ° C, 14 ml (14 mmol) of 1M boron tribromide in methylene chloride were added. The reaction mixture was stirred at -70 ° for 15 minutes and kept at -18 ° for 6 hours. Further work-up as in Example 32 and recrystallization twice from ethyl acetate-hexane gave 1.03 g (61% yield) of m.p. 145-146 ° 4- [6- (2-chloro-3,4-dihydroxyphenyl) heksyloksi7-2-hydroxy-3-propyl-benzoic acid.

Example 112 To 4.0 g of 1- (5-bromopentyl) -2,3-dimethoxybenzene in 50 mL of methylene chloride cooled in an ice bath was added 18 mL of 0.8 M chlorine in methylene chloride. The reaction mixture was kept at 0 ° C for 3 hours and then concentrated under reduced pressure. · 87 92188 under pressure to oil. Purification by HPLC using 30% toluene-hexane gave 2.60 g (58% yield) of 1- (5-bromopentyl) -6-chloro-2,3-dimethoxybenzene.

Example 113 To 4.0 g of 1- (5-bromopentyl) -2,3-dimethoxybenzene in 50 ml of methylene chloride cooled in an ice bath was added 18 ml of 0.8 M chlorine in methylene chloride. After 15 minutes, 10 ml of 0.88 M chlorine in methylene chloride was added. The reaction mixture was kept at 0 ° for 3 hours and then concentrated under reduced pressure to an oil. Purification by HPLC using 30% toluene-hexane gave 2.03 g (41% yield) of 1- (5-bromopentyl) -5,6-dichloro-2,3-15 dimethoxybenzene.

Example 114 To 1.9 g of 1- (5-bromopentyl) -2,3-dimethoxybenzene in 25 ml of methylene chloride cooled in an ice bath was added 23 ml of 0.88 M chlorine in methylene chloride. After 1.5 hours at 0 °, 5 ml of 1.35 M chlorine in methylene chloride was added. The reaction mixture was kept at 0 ° for 17 hours and then concentrated under reduced pressure to an oil. Purification by HPLC using 25% toluene-hexane gave 1.48 g (56% yield) of 1- (5-bromopentyl) -2,3-dimethoxy-4,5,6-trichlorobenzene.

Example 115 To 1.40 g of 6- (3,4-dimethoxyphenyl) hexan-1-ol in 25 ml of methylene chloride cooled in an ethanol-carbonic acid ice bath was added 4.6 ml of 1.35 M chlorine in methylene chloride. . The reaction mixture was kept at -75 ° for 1.5 hours, at -18 ° for 16 hours and then at 0 ° for 24 hours. After concentration under reduced pressure, the crude product was purified by HPLC to give 6- (6-chloro-3,4-dimethoxyphenyl) hexan-1-ol as an oil.

* · 88 92188

Example 116

A solution of 5.0 g (0.028 mol) of 3- (1-methylethyl) -1,2-dimethoxybenzene in 5 ml of methylene chloride was added to an ice-cooled mixture of 4.4 g (0.033 mol) of aluminum chloride. and 7.0 g (0.033 mol) of 6-bromohexanoyl chloride in 50 ml of methylene chloride. The reaction mixture was kept at 0 ° for 18 hours. Water was added and the organic layer was separated and washed with sodium bicarbonate solution. The dried extract was concentrated under reduced pressure to an oil which was purified by HPLC using 5% ethyl acetate-hexane to give 8.1 g (82% yield) of 6-bromo-1- [3,4-dimethoxy]. -5- (1-methylethyl) phenyl] -1-hexanone as an oil.

15 Example 117

A solution of 0.227 g (1.5 mmol) of 3,6-dimethylveratrol in 1 mL of methylene chloride was added to an ice-cooled mixture of 0.245 g (1.8 mmol) of aluminum chloride and 0.416 g (1.9 mmol) of 6-bro-20 mexanoyl chloride in 3 ml of methylene chloride. The reaction mixture was kept at 0 ° for 19 hours. Water was added and the organic layer was separated and washed with sodium bicarbonate solution. The dried extract was concentrated to an oil which was chromatographed using 60 g of silica gel and 10% ethyl acetate-hexane to give 0.235 g of 6-bromo-1- (3,4-dimethoxy-2,5-dimethylphenyl) -1-hexanone as an oil.

Example 118

A solution of 0.1056 g (0.64 mmol) of 4-fluoro-30 verazole in 1 mL of methylene chloride was added to a mixture of 0.2229 g (1.7 mmol) of aluminum chloride and 0.09 mL (0, 8 mmol) of 4-chlorobutyryl chloride in 2 ml of methylene chloride at 25 °. The reaction mixture was stirred at 25 ° for 22 hours. Water was added and the organic layer was separated and washed with sodium bicarbonate solution. The dried extract was concentrated under reduced pressure to give an oil which was chromatographed on 10 g of silica gel and 25% ethyl acetate-hexane to give 0.041 g of 4-chloro-3,4-di- methoxy-6-fluorifenyyli7 ~ l-butanone.

5 Example 119

A mixture of 2.60 g (8.1 mmol) of 1- (5-bromo-pentyl) -6-chloro-2,3-dimethoxybenzene - 1.65 g (7.8 mmol) of 2,4-dihydroxy 3-Propyl-benzoic acid methyl ester and 5.0 g (36 mmol) of anhydrous potassium carbonate-10 in 60 ml of acetone and 6 ml of DMF were stirred under reflux for 24 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Crystallization from hexane gave 2.95 g (83% yield) of 4- [5- (2-15 chloro-5,6-dimethoxyphenyl) pentyloxy] -2-hydroxy-3-propylbenzoic acid methyl ester having a mp of 53-55 °.

Example 120

A solution of 2.95 g (6.7 mmol) of 4- [5- (2-chloro-5,6-dimethoxyphenyl) pentyloxy] -2-hydroxy-3-20 propylbenzoic acid methyl ester in 80 ml of methanol and 20 ml of: (20 mmol) of 1 N sodium hydroxide, was stirred under reflux for 4 hours. Further work-up as in Example 24 and recrystallization from ether-hexane gave; . 2.70 g (96% yield) of 4- [5- (2-chloro-5,6-dimethoxyphenyl) pentyloxy] -2-hydroxy-3-propylbenzoic acid having a mp of 140-142 °.

Example 121 To 2.70 g (6.2 mmol) of 4- [5- (2-chloro-5,6-dimethoxyphenyl) pentyloxy] -2-hydroxy-3-propylbenzoic acid suspended in 250 ml: To methylene chloride and stirred at -60 °, 18.6 mL (18.6 mmol) of 1M boron tribromide in methylene chloride was added. The reaction mixture was stirred at -60 ° for 20 minutes and then kept at -20 ° for 19 hours. Water was added and the product was extracted with ether. The extract was concentrated under reduced pressure, and the residue was dissolved in 50 ml of ether and shaken vigorously for 20 minutes with 50 ml of 1N hydrochloric acid.

The dried extract was concentrated under reduced pressure, and the residue was crystallized from ether-chloroform to give 1.10 g of 4- [3- (2-chloro-5,6-dihydroxyphenyl) pentyloxy] -2-hydroxy-3 having a mp of 178-181 °. propyl-benzoic acid.

10 Example 122

A mixture of 2.03 g (5.7 mmol) of 1- (5-bromopentyl) -2,3-dichloro-5,6-dimethoxybenzene, 1.15 g (5.5 mmol) of 2,4- dihydroxy-3-propyl-benzoic acid methyl ester and 3.5 g (22 mmol) of potassium carbonate-15 in 50 ml of acetone and 5 ml of DMF (dimethylformamide) were stirred under reflux for 24 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Crystallization from ether-hexane gave 1.5 g (56% yield) of 4- [5- (2,3-dichloro-5,6-dimethoxyphenyl) pentyloxy] -2-hydroxy, mp 113-115 ° 20. -3-Propyl-benzoic acid methyl ester.

Example 123

A solution of 1.5 g (3.2 mmol) of 4- [5- (2,3-dichloro-5,6-dimethoxyphenyl) pentyloxy] -2-hydroxy-3-25 propylbenzoic acid methyl ester in 40 ml of methanol and 10 ml of in 1 ml (10 mmol) of 1N sodium hydroxide, was stirred under reflux for 5 hours. Further work-up as in Example 24 and recrystallization from ether-hexane gave 1.2 g (80% yield) of 4- [5- (2,3-dimethoxyphenyl) pentyloxy] having a mp of 152-154 °. 2-hydroxy-3-propyylibentsoe acid.

Example 124 1.2 g (2.5 mmol) of 4- [5- (2,3-dichloro-3,5,6-dimethoxyphenyl) pentyloxy] -2-hydroxy-3-propylbenzoic acid suspended To 100 ml of methylene chloride and stirred at -60 ° was added 7.5 ml (7.5 mmol) of 1 M boron tribromide in methylene chloride. After stirring at -60 ° for 30 minutes, the reaction mixture was kept at -20 ° for 20 hours.

Further work-up as in Example 24 gave a solid residue which was recrystallized from ether-chloroform to give 0.42 g of 4-75- (2,3-dichloro-5,6-dihydroxyphenyl) pentyloxy] having a mp of 159-164 °. -2-hydroxy-3-propylbenzoic acid.

10 Example 125

A mixture of 1.48 g (3.8 mmol) of 1- (5-bromo-pentyl) -5,6-dimethoxy-2,3,4-trichlorobenzene, 0.76 g (3.6 mmol) 2, 4-Dihydroxy-3-propyl-benzoic acid methyl ester and 4.6 g (33 mmol) of potassium carbonate in 30 ml of acetone and 3 ml of DMF were stirred under reflux for 23 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Crystallization from ether-hexane gave 1.5 g (76% yield) of 4- [5- (2,3,4-trichloro-5,6-20 dimethoxyphenyl) pentyloxy] -2-hydroxy, mp 84-87 °. -3-propyl-benzoic acid methyl ester.

Example 126

A solution of 1.5 g (2.3 mmol) of 4- [5- (2,3,4-trichloro-5,6-dimethoxyphenyl) pentyloxy] -225-hydroxy-3-propylbenzoic acid methyl ester in 40 ml of methanol and in 8.7 ml (8.7 mmol) of 1N sodium hydroxide, stirred under reflux for 5 hours. Further work-up as in Example 24 and recrystallization from ethyl acetate-hexane gave 1.3 g (89% yield) of mp 148-150 ° of 4- [5- (2,3,4-trichloro-5,6-dimethoxyphenyl). ) pentyloksij-2-hydroxy-3-propylbenzoic acid.

Example 127 1.3 g (2.6 mmol) of 4- [5- (2,3,4-trichloro-5,6-dimethoxyphenyl) pentyloxy} -2-hydroxy-3-propylbenzoic acid was suspended in 110 ml of y2'i 88 92 methylene chloride and stirred at -60 °, 8.0 ml (8 mmol) of 1M boron tribromide in methylene chloride was added. The reaction mixture was stirred at -60 ° for 1 hour and then kept at -20 ° for 18 hours. Further work-up as in Example 24 gave a solid which was recrystallized from ether-hexane to give 0.9 g (73% yield) of 4- [3- (2,3,4-trichloro) 4-3- (2,3,4-trichloro) m.p. 5,6-dihydroxy-phenyl) pentyloxy-7-2-hydroxy-3-propylbenzoic acid.

10 Example 128

A mixture of 2.50 g (7.29 mmol) of 6-bromo-1- (3,4-dimethoxy-2,5-dimethylphenyl) -1-hexanone, 1.53 g (7.29 mmol) 2, 4-Dihydroxy-3-propyl-benzoic acid methyl ester and 3.30 g (24 mmol) of potassium carbonate in 50 ml of acetone and 5 ml of DMP were stirred and refluxed for 26 hours. After further treatment as in Example 16, the crude product was purified by HPLC using 10% ethyl acetate-hexane to give 3.40 g (98% yield) of 4- [6- (3,4-dimethoxy). Methyl ester of -2,5-dimethylphenyl) -6-oxohexyl / oxy-2-hydroxy-3-propylbenzoic acid as an oil.

Example 129

A solution of 3.40 g (7.2 mmol) of 4- [6- (3,4-25 dimethoxy-2,5-dimethylphenyl) -6-oxohexyl] oxy] -2-hydroxy-3-propylbenzoic acid methyl ester in 90 ml: in methanol and 30 ml (30 mmol) of 1.0N sodium hydroxide, was stirred under reflux for 5 hours. Further work-up as in Examples 24 and 30, recrystallization of the crude product from ether-hexane gave 3.00 g (91% yield) of m.p. 92-94 ° of 4- [6- (3,4-dimethoxy-2,5- dimethylphenyl) -6-oxohexyl-7-oxy-2-hydroxy-3-ptopylbenzoic acid.

Example 130 35 1.00 g (2.2 mmol) of 4- [6- (3,4-dimethoxy-2,5-dimethylphenyl) -6-oxohexyl] oxy] -2-hydrol 3-propylbenzoic acid in 100 ml of methyl. lene chloride, 6.6 mL (6.6 mmol) of 1M boron tribromide in methylene chloride was added with cooling to -70 °. The mixture was stirred at -70 ° for 1 hour and then kept at -20 ° for 16 hours. Further work-up as in Example 32 and recrystallization of the crude product from ether-hexane gave 0.60 g (63% yield) of 4- [6- (3,4-dihydroxy-2,5-dimethyl) mp 121-125 °. -phenyl) -6-oxohexyl-7-oxy-2-hydroxy-3-propylbenzoic acid.

Example 131

A mixture of 6.0 g (0.017 mol) of 6-bromo-1- [3,4-dimethoxy-5- (1-methylethyl) phenyl] -1-hexanone, 3.39 g (0.016 mol) of 2,4- dihydroxy-3-propylbenzoic acid methyl ester and 7.0 g (0.051 mol) of potassium carbonate in 120 ml of acetone and 12 ml of DMF were stirred under reflux for 19 hours. After further work-up as in Example 16, the crude product was purified by HPLC using 16% ethyl acetate-hexane to give 7.7 g (98% yield) of 4- [6- [3,4-dimethoxy]. -5- (1-methylethyl) phenyl] -6-oxohexyl-7-oxy-2-hydroxy-3-propylbenzoic acid methyl ester as an oil.

Example 132

A solution of 7.7 g (0.016 mol) of 4- [6- [3,4-dimethoxy-5- (1-methylethyl) phenyl) -6-oxohexyl] oxy] -2-hydroxy-3-propylbenzoic acid methyl ester 3q In 80 ml of methanol and 60 ml (0.06 mol) of 1.0 N sodium hydroxide, the mixture was stirred under reflux for 5 hours. Further work-up as in Example 24 and recrystallization of the crude product from ethyl acetate-hexane gave 6.6 g (89% yield) of 4-// 6- / 3,4-dimethoxy-5- (1 -methyl ethyl) phenyl-6-6-oxohexyl-7-oxy-2-hydroxy-3-propyl-benzoic acid.

94 92188

Example 133 2.0 g (4.2 mmol) of 4- [6-Z3,4-dimethoxy-5- (1-methylethyl) phenyl] -6-oxohexyloxy] -2-hydroxy-3- propylbenzoic acid in 200 mL of 5 methylene chloride cooled to 65 ° was added 13 mL (13 mmol) of 1.0 M boron tribromide in methylene chloride. The suspension was stirred at -50 ° for 2 hours and then kept at -20 ° for 16 hours. Further work-up as in Example 32 and recrystallization of the crude product from ether-hexane gave 1.5 g (81% yield) of 4- ^ 6- / 3,4-dihydroxy-5- (1- methylethyl) phenyl] -6-oxohexyloxy-2-hydroxy-3-propylbenzoic acid.

Example 134 A mixture of 2.5 g of 4- [N- [3,4-dimethoxy-5- (1-methylethyl) phenyl] -6-oxohexyl] oxy-2-hydroxy-3-propylbenzoic acid in 50 ml of tetrahydrofuran and which containing 2 drops of concentrated sulfuric acid and 0.5 g of 10% palladium on carbon, was shaken in a Parr hydrogenator 20 using an initial hydrogen pressure of 3.5 bar for 20 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ether and washed with water. The extract was dried and concentrated to a solid which was recrystallized from hexane to give 2.4 g of a 4-10-26 ° [3,4-dimethoxy-5- (1-methylethyl) phenyl] hexyloxy] -2-hydroxy 3-propyl-benzoic acid.

Example 135 2.43 g (5.3 mmol) of 4- [Z6 '(3,4-dimethoxy-5- (1-methylethyl) phenyl] hexyloxy] -2-hydroxy-3-propylbenzoic acid in 250 ml of methylene chloride cooled to -75 °, 16 ml (16 mmol) of 1M boron tribromide in methylene chloride were added, and the reaction mixture was stirred at -75 ° for 1 hour and then kept at -20 ° for 17 hours, working up as in Example 32 and recrystallizing 92188 95 of ether. hexane gave 1.20 g of 4-1H- [3,4-dihydroxy-5- (1-methylethyl) phenyl] hexyloxy] -2-hydroxy-3-propylbenzoic acid, m.p. 138-140 °.

Example 136 4- [6- (3,4-Dimethoxy-2,5-dimethylphenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid.

A mixture of 1.45 g of 4- [6- (3,4-dimethoxy-2,5-dimethylphenyl) -6-oxohexyl] oxy] -2-hydroxy-3-propylbenzoic acid in 40 ml of tetrahydrofuran and which si-10 contained 2 drops of concentrated sulfuric acid and 0.4 g of 10% palladium on carbon was shaken in a Parr hydrogenator using an initial hydrogen pressure of 3.5 bar for 20 hours. The reaction mixture was further treated as in Example 134 and the product was recrystallized from ether-hexane to give 1.20 g of 4- [6- (3,4-dimethoxy-2,5-dimethylphenyl) hexane having a mp of 109-112 °. oxy-2-hydroxy-3-propylbenzoic acid.

Example 137 To 1.2 g (2.7 mmol) of 4- [6- (3,4-dimethyl-2-phenyl) -hexyloxy] -2-hydroxy-3-propyl-benzoic acid in 120 ml of methylene chloride under cooling was added. °, 8 ml (8 mmol) of 1M boron tribromide in methylene chloride was added. The reaction mixture was stirred at -75 ° for 1 hour and kept at -20 ° for 17 hours. Further work-up as in Example 32 and recrystallization of the crude product from ether-hexane gave 0.60 g of 4- [6- (3,4-dihydroxy-2,5-dimethylphenyl) m.p. 170-171 °. heksy ^ oksi7-2-hydroxy-3-propyylibentsoe acid.

30 Example 138

A solution of 5.3 g (0.034 mol) of 1,2-diraethoxy-4-fluorobenzene in 25 ml of methylene chloride was added to a solution of 5.4 g (0.041 mol) of aluminum chloride and 8.7 g (0.041 mol) 6-Bromohexa-35-noyl chloride in 60 ml of methylene chloride cooled in an ice bath. The resulting solution was kept at 0 ° for 5 hours 96 92188 and then further treated as in Example 117. The crude product was recrystallized from methylene chloride-ether to give 6.98 g (62% yield) of mp 81-83 °. 6-bromo-1- (2-fluoro-4,5-dimethoxyphenyl-5H) -1-hexanone.

Example 139

A mixture of 4.0 g (12 mmol) of 6-bromo-1- (2-fluoro-4,5-dimethoxyphenyl) -1-hexanone, 2.5 g (12 mmol) of 2,4-dihydroxy-3- propylbenzoic acid methyl ester and 5.0 g (36 mmol) of potassium carbonate in 80 ml of acetone and 8 ml of DMF, were stirred under reflux for 86 hours. DMF (12 mL) and potassium carbonate (3 g) were added and refluxing was continued for 18 hours. Further work-up as in Example 16 and recrystallization of the crude product from ethyl acetate gave 4.3 g (78% yield) of a spin 127-129 ° of 4- [Y6- (2-fluoro-4,5-dimethoxyphenyl) - 6-Oxohexyl-7-oxy-2-hydroxy-3-propyl-benzoic acid methyl ester.

20 Example 140

A solution of 4.3 g (9.3 mmol) of 4- [6- (2-fluoro-4,5-dimethoxyphenyl-6-oxohexyl] oxy] -2-hydroxy-3-propylbenzoic acid methyl ester in 135 ml of methanol and 45 ml of per ml (45 mmol) of 1N sodium hydroxide, stirred at reflux for 5 hours Further work-up as in Example 24 and recrystallization of the crude product from ethyl acetate-hexane gave 3.7 g of a spin 146-147 ° Α-[β- (2 (fluoro-4,5-dimethoxyphenyl) -6-oxohexyl-7-oxy-2-30-hydroxy-3-propylbenzoic acid.

Example 141 2.0 g (4.46 mmol) of 4- [6- (2-fluoro-4,5-dimethoxyphenyl) -6-oxohexyl] oxy] -2-hydroxy-3-propylbenzoic acid in 200 ml of methylene-35 chloride cooled to -75 °, 13 mL (13 mmol) of 1M boron tribromide in methylene chloride was added. The reaction mixture was stirred at -75 ° for 1 hour and kept at -20 ° for 17 hours. Additional boron tribromide 97 92188 (7 ml) was added and the mixture was stirred at -5 ° for 5 hours. Further work-up as in Example 32 and recrystallization of the crude product from ether-hexane gave 0.84 g of 4-E2- (2-fluoro-4,5-dihydro-5-oxyphenyl) -6-oxohexyloxy] -7- 2-hydroxy-3-propylbenzoic acid.

Example 142

A mixture of 0.400 g of 4- [6- (2-fluoro-4,5-dimethoxyphenyl) -6-oxohexyloxy] -2-hydroxy-3-propyl-10-benzoic acid and 0.150 g of 10% palladium on carbon in 20 ml: in tetrahydrofuran and containing 2 drops of concentrated sulfuric acid was shaken, using an initial hydrogen pressure of 3.5 bar, in a Parr hydrogenator for 20 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to a solid.

Recrystallization from ethyl acetate-hexane gave 0.37 g of 4- [6- (2-fluoro-4,5-dimethoxyphenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid, m.p. 127-130 °.

Example 143 To 0.36 g of 4- [6- (2-fluoro-4,5-dimethoxy-phenyl) -hexyloxy] -2-hydroxy-3-propyl-benzoic acid in 60 ml of methylene chloride cooled to -75 °: 2.8 ml of 1M boron tribromide in methylene chloride was added. The reaction mixture was stirred at -75 ° for 30 minutes and then kept at -20 ° for 20 hours. Further work-up as in Example 32 and recrystallization of the crude product from ether-hexane gave 0.18 g of 4- [6- (2-fluoro-4,5-dihydroxy-30-phenyl) hexyloxy] -2-hydroxy-m.p. 3-propyl.

Example 144

A solution of 2.956 g (16 mmol) of 1,2-dimethoxy-3,4,6-trimethylbenzene in 10 mL of methylene chloride was added to a solution of 2.40 g (18 mmol) of 35 aluminum chloride and 3.80 g of g (18 mmol) of 6-bromohexanoyl chloride in 30 ml of methylene chloride cooled to 98,928,88 in an ice bath. The solution was kept at 3 ° for 45 minutes and then at 23 ° for 42 hours. An additional 2.0 g of aluminum chloride and 3.0 g of 6-bromohexanoyl chloride were added and the reaction mixture was stirred at reflux for 22 hours. Further work-up as in Example 117 and purification by HPLC using 4% ethyl acetate-hexane gave 0.95 g of 6-bromo-1- (3,4-dimethoxy-2,5,6-trimethylphenyl) -1- hexanone as an oil.

Example 145 10 A mixture of 0.194 g (2.6 mmol) of 6-bromo-1- (3,4-dimethoxy-2,5,6-trimethylphenyl) -1-hexanone, 0.55 g (2.6 mmol) ) Methyl ester of 2,4-dihydroxy-3-propylbenzoic acid and 1.10 g (7.8 mmol) of potassium carbonate in 20 ml of acetone and 2 ml of DMF were stirred under reflux for 17 hours. After further work-up as in Example 16, the crude product was purified by chromatography on 100 g of silica gel. Elution with 10% ethyl acetate-hexane gave 1.05 g (83% yield) of 4- [E] 6- (3,4-dimethoxy-2Si-2,5,6-trimethylphenyl) -6-oxohexyl] oxy- 2-Hydroxy-3-propyl-benzoic acid methyl ester.

Example 146

A solution of 1.05 g (2.16 mmol) of 4- [6- (3,4-dimethoxy-2,5,6-trimethylphenyl) -6-oxohexyloxy] -2-hydroxy-3-propylbenzoic acid methyl ester 30 in 1 ml of methanol and 7 ml (7 mmol) of 1N sodium hydroxide, was stirred under reflux for 7 hours. Further work-up as in Example 24 gave 0.98 g of A-CO 2 - (3,4-dimethoxy-2,5,5,6-trimethylphenyl) -6-oxohexyl-7-oxy-2-hydroxy-3- propylbenzoic acid.

Example 147 To 0.98 g (2.07 mmol) of (3,4-dimethoxy-2,5,6-trimethylphenyl) -6-oxohexyl7oxy] -2-35 hydroxy-3-propylbenzoic acid was 100 ml. in methylene chloride cooled to -75 °, 7 ml (7 mmol) of 1M boron tribromide in methylene chloride were added. The reaction mixture was stirred at -75 ° for 30 minutes and then kept at -20 ° for 18 hours. Further work-up as in Example 32 and recrystallization of the crude product from ether-hexane gave 0.51 g of 4- [6- (3,4-dihydroxy-2,5,6-trimethyl-phenyl) -. 6-oksoheksy ^ 7oksi7_2-hydroxy-3-propyylibentsoe acid.

Example 148 A mixture of 1.00 g (2.57 mmol) of 4- [6- (2,8-dihydroxyphenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid was 0.76 ml (5.15 mmol). ) n-hexyl iodide and 0.26 g (3.36 mmol) of sodium bicarbonate in 15 ml of anhydrous dimethylformamide were stirred and heated at 70 ° for 16 hours. The solvent was removed using an oil pump, water was added and the product was extracted with ethyl acetate. The dried extract was concentrated under reduced pressure to an oil which was purified by chromatography on silica gel with 5% ethyl acetate-toluene to give 1.01 g (83% yield) of 4- [6- (2,3-dihydroxyphenyl) hexyloxy] 2-Hydroxy-3-propyl-benzoic acid hexyl ester as an oil.

Example 149

A mixture of 5.8 g (0.013 mol) of 1- (6-bromo-25-mexyl) -2,3-bis (phenylmethoxy) benzene, 3.5 g (0.013 mol) of 3-hydroxy-4-nitrobenzoic acid phenyl methyl ether, 3.5 g (0.026 mol) of anhydrous potassium carbonate and 2.9 g (0.019 mol) of sodium iodide in 125 ml of acetone and 13 ml of dimethylformamide, were stirred and refluxed for 42 days. Further work-up as described in Example 16 and purification by HPLC using 10% ethyl acetate-hexane gave 5.45 g of 4-nitro-3- [6- / 2,3-bis (phenylmethoxy) phenyl] hexyloxy / benzoic acid phenyl methyl ester as an oil. .

100 92188

Example 150

A solution of 5.4 g of 4-nitro-3- [6- [2,3-bis- (phenylmethoxy) phenyl] hexyloxy] benzoic acid phenyl methyl ester in 250 ml of tetrahydrofuran and 1 g of 10% palladium on carbon was shaken under an atmosphere of hydrogen at room temperature. for an hour. The catalyst was removed by filtration through celite and the filtrate was concentrated under reduced pressure to a solid. Recrystallization from ether-methylene chloride gave 1.80 g (62% yield) of 4-amino-3- [6- (2,3-dihydroxyphenyl) hexyloxy] benzoic acid having a mp of 130-132 °.

Example 151

A mixture of 5.8 g (0.013 mol) of 1- (6-bromohexyl) -2,3-bis (phenylmethoxy) benzene, 3.5 g (0.013 mol) of 4-hydroxy-3-nitrobenzoic acid phenyl methyl ester 3.5 g (0.026 mol) of potassium carbonate and 2.9 g (0.019 mol) of sodium iodide in 125 ml of acetone and 13 ml of dimethylformamide were stirred and refluxed for 5 days. Further work-up as described in Example 16 and purification by HPLC using 50% methylene chloride-hexane gave 6.85 g (83% yield) of 3-nitro-4- [6- / 2,3- bis (phenylmethoxy) phenyl7hexyloxy7benzoic acid phenylmethyl ester as an oil.

25 Example 152

A solution of 6.8 g of 3-nitro-4- [6- [2,3-bis- (phenylmethoxy) phenyl] hexyloxy] benzoic acid phenyl methyl ester in 250 ml of tetrahydrofuran and 1.3 g of 10% palladium on carbon was shaken under a hydrogen atmosphere. at room temperature for 12 hours. The catalyst was removed by filtration through celite and the filtrate was concentrated under reduced pressure to a solid. Recrystallization from acetone-hexane gave 2.36 g (65% yield) of 3-amino-35 4- [6- (2,3-dihydroxyphenyl) hexyloxy] benzoic acid, mp 172-174 °.

. · 101 92188

Example 153 To 27.0 g (0.139 moles) of 1,2-dimethoxy-3- (1,1-dimethylethyl) benzene in 350 ml of anhydrous tetrahydrofuran cooled in an ice-salt-5 water bath at -5 ° , 87 ml (0.139 mol) of 1.6M butyllithium in hexane were added over 30 minutes. The reaction mixture was stirred at -5 ° for 3 hours and then heated to reflux for 1 hour. After cooling in an ice bath, 21.5 ml (0.139 mol) of 1,6-dibromohexane in 75 ml of tetrahydrofuran were added dropwise. The reaction mixture was then stirred at reflux for 17 hours. The solvent was removed under reduced pressure, 50 ml of 3N hydrochloric acid was added and the product was extracted with ether. The extract was washed with sodium bicarbonate solution, dried and concentrated under reduced pressure to an oil. Purification by HPLC using 20% toluene-hexane gave 7.6 g (15% yield) of 1- (6-bromohexyl) -2,3-dimethoxy-4- (1,1-dimethylethyl) benzene.

20 Example 154

A mixture of 4.0 g (11.2 mmol) of 1- (6-bromohexyl) -2,3-dimethoxy-4- (1,1-dimethylethyl) benzene, 3.2 g (11.2 mmol) ) 2,4-dihydroxy-3-propyl-benzoic acid phenylmethyl ester, 3.1 g (22.4 mmol) of potassium carbonate and 1.7 g (11.2 mmol) of sodium iodide in 70 ml of anhydrous acetone and 7 g of in ml of anhydrous dimethylformamide, was stirred under reflux for 31 hours. Further work-up as in Example 16 and purification by HPLC using 5% ethyl acetate-hexane gave 5.3 g (84% yield) of 2-hydroxy-4- / 6- / 2,3-dimethoxy-4- (1,1-Dimethylethyl) phenyl] hexyloxy-3-propylbenzoic acid phenyl methyl ester as an oil.

A solution of 5.25 g of 2-hydroxy-4- [6- [2,3-35 dimethoxy-4- (1,1-dimethylethyl) phenyl] hexyloxy] -3-propylbenzoic acid phenylmethyl ester in 200 ml of 10210292188 tetrahydrofuran and 0.5 g of 10% palladium on carbon, was shaken under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to give 4.0 g of 2-hydroxy-5 4- [6- [2,3-dimethoxy-4- (1,1-dimethylethyl) phenyl] hexyl] having a mp of 106-108 °. oksi7-3-propyl.

Example 155 To 4.0 g (8.5 mmol) of 2-hydroxy-4- [6- [2,3-dimethoxy-4- (1,1-dimethylethyl) phenyl] hexyloxy] -10-3-propylbenzoic acid suspended To 200 mL of methylene chloride and cooled to -70 °, 26 mL (26 mmol) of 1M boron tribromide in methylene chloride was added over 30 minutes. The reaction mixture was stirred at -70 ° for 30 minutes and kept at -20 ° for 41 hours.

Further work-up as in Example 32 and recrystallization of the crude product from ether-hexane gave 1.78 g (47% yield) of m.p. 85-87 ° 4- [6- / 2,3-dihydroxy-4- ( 1,1-dimethylethyl) phenyl / hexyloxy / -2-hydroxy-3-propylbenzoic acid.

20 Example 156

A mixture of 2.4 g (5.3 mmol) of 1- (6-bromohexyl) -2,3-bis (phenylmethoxy) benzene, 0.88 g (5.3 mmol) of 4-hydroxybenzoic acid ethyl ester, 2.5 g (18 mmol) of potassium carbonate and 0.8 g (5.3 mmol-25 l) of sodium iodide in 40 ml of acetone were stirred under reflux for 22 hours. Further work-up as in Example 16 and recrystallization of the crude product from ethyl acetate-hexane gave 2.3 g of m.p. 63-65 ° (81% yield) of 4- [5- / 2,3-30 bis (phenylmethoxy) phenyl] hexyloxy]. £ 7 Benzoic acid is an ethyl ester.

A solution of 2.3 g of 4- [6- [2,3-bis (phenylmethoxy) phenyl] hexyloxy] benzoic acid ethyl ester in 50 ml of ethyl acetate and 0.3 g of 10% palladium on carbon was stirred under a hydrogen atmosphere for 22 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to a solid. Recrystallization from ethyl acetate-hexane gave 1.3 g of ethyl 4- (2,3-dihydroxyphenyl) hexyloxy / benzoate having a mp of 45-47 ° (85% yield).

5 Example 157

A mixture of 1.0 g (2.9 mmol) of 4- [16- (2,3-dihydroxyphenyl) hexyloxy] -2-hydroxybenzoic acid, 0.295 g (3.5 mmol) of sodium bicarbonate and 2.4 ml (29 mmol) of ethyl iodide in 10 ml of anhydrous dimethyl-10 formamide, stirred at 50 ° for 6 hours, the solvent was removed using an oil pump and the residue was treated with sodium bicarbonate solution, extracted with ethyl acetate and the dried extract concentrated under reduced pressure to a solid. g m.p. 63-68 ° (74% yield) of ethyl 4- (2,3-dihydroxyphenyl) hexyloxy] -2-hydroxybenzoic acid ethyl ester Example 158

A mixture of 0.170 g (1.68 mmol) of 4-Z3-20 (3,4-dihydroxy-2,5-dimethylphenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid, 0.157 g (1.87 mmol) sodium bicarbonate and 1.4 ml (16.8 mmol) of ethyl iodide in 10 ml of dimethylformamide were stirred at 50 ° for 10 hours. Further work-up as in Example 16 gave an oil which was purified by chromatography on 20 g of silica gel. Elution with 25% ethyl acetate-hexane gave the product which was recrystallized from hexane to give 0.50 g of mp 61-64 ° (67% yield) of 4- [6- (3,4-dihydroxy-30 2). 5-Dimethyl-phenyl) -hexyloxy-2-hydroxy-3-propyl-benzoic acid ethyl ester.

, «104 92188

Example 159

Tablet formulation (wet granulation)

No. Ingredient mg / tablet _100 mg_500 mg_1000 mg ^ 1. 4- [6- (2,3-dihydroxyphenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid 100 500 1000 2. Lactose 132 - - 10 3. Pregelatinized starch 16 30 50 4. Modified starch 30 40 50 5. Magnesium stearate 268

Total amount 280,576,1108

Preparation method: 1. Mix numbers 1, 2, 3 and 4 and granulate with water.

2. Dry the granules at 50 ° C.

3. Pass the granules through a suitable grinder.

4. Add number 5 and stir for three minutes; compress in a suitable press.

Example 160 Capsule preparation

No. Ingredient mg / capsule - · - 25. --- 1. 4- [6- (2,3-Dihydroxy-phenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid 25 50 100 500 2. Aqueous lactose 143 168 148 30 3. Maize starch 20 20 40 70 4 Talc 10 10 10 25 5. Magnesium stearate 222 5 35 Total amount 200 250 300 600 105 92188

Preparation method: 1. Mix numbers 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add numbers 4 and 5 and mix for 3 minutes.

5 3. Place the filler in suitable capsules.

Example 161 Wet granulation preparation

No. Ingredient mg / tablet 1. 4- [δ- (2,3-dihydroxy-phenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid 25 50 2. Polyvinylpyrrolidone 5 10 3. Anhydrous lactose DTG 133 142 15 4. Fine crystalline cellulose 25 30 5. Modified starch 10 15 6. Magnesium stearate 2 3 2Q Total 200 250

Method of preparation: 1. Dissolve number 2 in water.

2. Mix the numbers lf 3, 4 and 5 in a suitable mixer and granulate with the solution from step 1.

. 25 3. Dry overnight at 45 ° C, sieve through a sieve * £ 20 mesh and add number 6 and mix. Squeeze in a suitable press.

Example 162 Ointment 5% 2Q The following is the quantitative composition of the drug:. I · 106 92188

No Ingredient g / kg Reasonable variations 1. 4- [6- (2,3-dihydroxy-phenyl) -hexyloxy] -2-hydroxy-3-propyl-benzoic acid 51.50 * 2. Glyceryl monostearate SE1 2 3 4 100, 00 80-120 3. Polysorbate 60 ^ 20.00 15-25 10 4. Cetyl alcohol 50.00 40-60 5. Vaseline 70.00 50-90 6. Methyl paraben 1.50 1.25-1.75 7. Propyl paraben 0.50 0.4-0.6 ^ 8. Propylene glycol 200.00 150-250 9. Purified water 521.70 475-575

Total 1015.20 * 3% excess 20, xArlacel 165 2

Tween 60

Example 163

Soft gelatin capsule preparation 25 No. Ingredient mg / capsule. «4- [6- (2,3-dihydroxy-phenyl) hexyloxy] -2-hydroxy-3-propyl-2-benzoic acid 50 150 30 2. Polyethylene glycol 400 325 550 3 Monoglycide suitable for the manufacture of a medicinal product

Polysorbate 80 25 50 35 Total amount 500 1000 107 92188

Preparation method: 1. Dissolve number 1 in number 2.

2. Add number 3 and mix well.

3. Add number 3 and mix well until 5 is dissolved.

4. Place the filling in soft gelatin capsules.

Example 164 Rae (Beadlet)

Preparation (for intestinal use) I 10 No. Granules mg / capsule 1. 4 - [* 6- (2,3-dihydroxy-phenyl) hexyloxy] -2-hydroxy-3-propylbenzoic acid 25 100 250 15 2. Fine crystalline cellulose 100 200 250 3. Polyvinylpyrrolidone K-90 10 20 30

Total number 135 320 530

Method: 2Q 1 · Mix with fine crystalline cellulose and granulate pVP with K-90 solution.

2. Pass the granules through an extruder and a marumarizer to obtain uniform spheres.

3. Coat the granules with an enteric polymer such as polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate or acrylic polymer.

4. Place the capsules for filling using a suitable filling weight.

3q Rae (beadlet) preparation (for intestine) II

Starting with a layer of nonpare particles, a polymer suitable for the surface of the particles, such as polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose or the like. Dry the particle 3g cartridges and add a suitable film to the intestine, such as 108 92188 polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate and / or acrylic polymer. Determine the drug concentration per gram of granule and place the filling in Kap-5 slags.

. ♦

Claims (12)

A process for the preparation of therapeutically useful phenoxyalkylpyrocatecol derivatives of the formula R 3Ar JU 10 * 4 wherein R 2 Sr is hydrogen, lower alkyl or - (CH2) nN- (lower alkyl) 2, R3 is hydrogen, lower alkyl or amino, R4 is hydrogen, lower alkyl, halogen or amino and A is or5 Ti Ji yA (A ') R7 T ^ (CH2) n-R8 or ORc 2. In 5 Jl (An) R9 ηΓ '(jf) m - (CH and R7 and R6 are independently hydrogen, lower alkyl or halogen, R, is hydrogen or lower alkyl, R10 is lower alkyl, hydrogen or halogen, R12 is hydrogen, lower alkyl or halogen, m is 0 or 1 N is a hot 2-10, provided that only one of the symbols R 3 and R 2 can be hydroxyl, alkanoyloxyl or -C (O) O R, and where R is hydrogen, to produce a site of such a compound having a pharmaceutically acceptable base, and where R is - (CH 2) n N- (lower alkyl) 2, to prepare an addition salt of such a compound with a pharmaceutically acceptable acid, characterized in that a compound of formula JP? CIJ3 R ^ Y ° ch3 CH30 ^ ik_Ru R'V ^ ', CH2> nBr or R9V ^ (5> n- <CH2 »' x8 R10 ' XIII XXXIII to prepare a compound of the formula ... AND and R3 OCH2 "CH3asA> ^ Ru r3v / Wr1 R8 r4 R10 0 R4 xxxiv XXXVII or to give a compound of formula 35. 116 92188 orR2 R6YiiT ^ ORl2 JL [I XXXIX 5 (CH2) nBr r8 to react with a compound of formula 10 Γ2 Wherein R r is hydrogen, lower alkoxycarbonyl or acetyl; R2 is hydrogen or lower alkoxycarbonyl; R 12 is benzyl or acyl; R 13 is benzyl; X is bromine or methanesulfonyloxyl; and the other symbols are as defined above; provided that only one of the symbols R2 'and R2' may be hydroxyl or lower alkoxycarbonyl, or only one of the symbols R2 'and R2' may be carboxyl or hydrogen. · · Roxl; the compound of formula XXXIV or XXXVII containing the methoxyl groups is cleaved; the benzyl ester and any benzyl ester groups R12 in the compound of formula XXXXI are cleaved; if desired, the hydroxyl group 1 is esterified. . The compound of formula XXXXI wherein R2 is hydroxy and R12 is benzyl and the benzyl ester groups are split off and, if desired, the carboxy group represented by R2 or R2 is esterified; it is converted into a salt with a pharmaceutically acceptable base or the di-lower alkyl substituted amino group is converted into a salt with a pharmaceutically acceptable acid. 2. A process according to claim 1, characterized in that 4- [6- (2,3-dihydroxyphenyl) hexyloxy] -2-hydroxybenzoic acid is prepared. 3. A process according to claim 1, characterized in that 4- [5- (2,3-dihydroxyphenyl) pentyloxy] -2-hydroxy-3-propylbenzoic acid is prepared. 4. Compound of Formulas 15 and 3 R 2 R 6 YVOC 3 3 ry ^ Vri 'A Jl J xxxiv Κ7 ^ γ ^ (ΟΗ2) η-ο Characterized in that R 1 'is -C (O) O R', acetyl, hydrogen or hydroxy, R 2 'is -C (O) O R', hydrogen or hydroxy, R 'is hydrogen or lower alkyl, R 3 is hydrogen or lower alkyl, R4 is hydrogen, lower alkyl or halogen, R6 is hydrogen, lower alkyl or phenyl, R7 and Re are hydrogen, lower <alkyl or halogen, and n is a hot 2-10, previously - provided that only one of the symbols Rx 'and R2' is -C (O) OR 'or hydroxy. 5. 4- [6- (2,3-Dimethoxyphenyl) hexoxyloxy] -2-hydroxy-3- propylbenzoic acid and its methyl ester. 6. Compound of Formula OCH3 R2 · CH3QV ^ RR1 R3Y ^ Yr1 ' Characterized in that R1 is -C (O) OR ', acetyl, hydrogen or hydroxy, R2' is -C (O) OR ', hydrogen or hydroxyl, R 'is hydrogen or lower alkyl, R3 is hydrogen or lower alkyl, R4 is hydrogen, lower alkyl or halogen, R, is hydrogen or lower alkyl, R10 is hydrogen, lower alkyl or halogen, R1X is hydrogen, lower alkyl or halogen, m is 0 or 1, and n is a hotline 2-10, provided that only one of the symbols Rx 'and R2' is -C (O) OR 'or hydroxy. $ I • • I II