Catechol carboxylic acids

The invention relates to catechol carboxylic acid derivatives of the formula ##STR1## wherein, R.sub.1 is ##STR2## acetyl, hydrogen, hydroxy or alkanoyloxy, R.sub.2 is ##STR3## hydroxy, hydrogen or alkanoyloxy, wherein R is hydrogen, lower alkyl or --(CH.sub.2).sub.n --N--(lower alkyl).sub.2, PA0 R.sub.3 is hydrogen, lower alkyl or amino, PA0 R.sub.4 is hydrogen, lower alkyl, halogen or amino PA0 A is ##STR4## wherein, R.sub.5 is hydrogen or acyl, R.sub.6 is hydrogen, halogen, lower alkyl, aryl or cycloalkyl, and R.sub.7 and R.sub.8, independently, are hydrogen, lower alkyl or halogen, or PA0 A is ##STR5## wherein, R.sub.5 is hydrogen or acyl, R.sub.9 is hydrogen, lower alkyl, R.sub.10 is hydrogen, lower alkyl or halogen, R.sub.11 is hydrogen, lower alkyl, cycloalkyl or halogen, m is 0 or 1, n is an integer of 2-10, provided, that no more than one of R.sub.1 or R.sub.2 can be hydroxy, alkanoyloxy or ##STR6## and when R is hydrogen, salts thereof with pharmaceutically acceptable bases or when R is --(CH.sub.2).sub.n --N--(lower alkyl).sub.2, salts thereof with pharmaceutically acceptable acids. The compounds of formula I are useful as agents for the treatment of inflammatory diseases such as arthritis, inflammatory bowel disease such as colitis, cardiovascular diseases such as myocardial ischemia, skin diseases such as psoriasis by topical administration, and bronchopulmonary diseases such as asthma.

BRIEF DESCRIPTION OF THE INVENTION 
The invention relates to catechol carboxylic acid derivatives of the 
formula 
##STR7## 
wherein R.sub.1 is 
##STR8## 
hydrogen, acetyl, hydroxy or alkanoyloxy, R.sub.2 is 
##STR9## 
hydroxy, hydrogen or alkanoyloxy, wherein R is hydrogen, lower alkyl or 
--(CH.sub.2).sub.n N (lower alkyl).sub.2, 
R.sub.3 is hydrogen, lower alkyl or amino, 
R.sub.4 is hydrogen, lower alkyl, halogen or amino, 
A is 
##STR10## 
wherein R.sub.5 is hydrogen or acyl, R.sub.6 is hydrogen, halogen, lower 
alkyl, aryl or cycloalkyl, and R.sub.7 and R.sub.8, independently, are 
hydrogen, lower alkyl or halogen, and n is an integer of 2-10, or 
A is 
##STR11## 
wherein R.sub.5 is hydrogen or acyl, R.sub.9 is hydrogen or lower alkyl, 
R.sub.10 is hydrogen, lower alkyl or halogen, R.sub.11 is hydrogen, lower 
alkyl, cycloalkyl or halogen, m is 0 or 1, n is an integer of 2-10, 
provided that no more than one of R.sub.1 or R.sub.2 can be hydroxy, 
alkanoyloxy or 
##STR12## 
and, when R is hydrogen, salts thereof with pharmaceutically acceptable 
bases, and, when R is (CH.sub.2).sub.n --N--(lower alkyl).sub.2, addition 
salts thereof with pharmaceutically acceptable acids. 
The compounds of formula I are useful as agents for the treatment of 
inflammatory diseases such as arthritis, inflammatory bowel diseases such 
as colitis, cardiovascular diseases such as myocardial ischemia, skin 
diseases such as psoriasis by topical administration, and bronchopulmonary 
diseases such as asthma. 
DETAILED DESCRIPTION OF THE INVENTION 
As used herein, the term "lower alkyl" denotes a straight or branched chain 
saturated hydrocarbon containing 1 to 7 carbon atoms, for example, methyl, 
ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, heptyl, and 
the like. Branched chain saturated hydrocarbons are preferred for R.sub.6, 
R.sub.9 and R.sub.11. The term "halogen" denotes all the halogens, that 
is, bromine, chlorine, fluorine, and iodine. The term "aryl" denotes 
phenyl or phenyl bearing one or two substituents independently selected 
from the group consisting of halogen, trifluoromethyl, lower alkyl, lower 
alkoxy, nitro, amino, lower alkylamino and di-lower alkylamino. The term 
"acyl" denotes an "alkanoyl" group derived from an aliphatic carboxylic 
acid of 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 "alkanoyloxy" denotes a group 
derived from an aliphatic carboxylic acid of 1 to 7 carbon atoms, for 
example, formyloxy, acetoxy, propionyloxy, and the like. The term 
"cycloalkyl" denotes preferably a cyclic hydrocarbon of 3 to 6 carbon 
atoms which may be unsubstituted or substituted by lower alkyl and most 
preferably of 5 to 6 carbon atoms, for example, cyclopropyl, cyclopentyl, 
cyclohexyl or the like. 
The invention relates to catechol carboxylic acid derivatives of the 
formula 
##STR13## 
wherein R.sup.1 is 
##STR14## 
acetyl, hydrogen, hydroxy or alkanoyloxy, R.sub.2 is 
##STR15## 
hydroxy, hydrogen or alkanoyloxy, wherein R is hydrogen, lower alkyl or 
--(CH.sub.2).sub.n N (lower alkyl).sub.2, 
R.sub.3 is hydrogen, lower alkyl or amino, 
R.sub.4 is hydrogen, lower alkyl, halogen or amino, 
A is 
##STR16## 
wherein R.sub.5 is hydrogen or acyl, R.sub.6 is hydrogen, halogen, lower 
alkyl, aryl or cycloalkyl, and R.sub.7 and R.sub.8, independently, are 
hydrogen, lower alkyl or halogen, or 
A is 
##STR17## 
wherein R.sub.5 is hydrogen or acyl, R.sub.9 is hydrogen or lower alkyl, 
R.sub.10 is hydrogen, lower alkyl or halogen, R.sub.11 is hydrogen, lower 
alkyl, cycloalkyl or halogen, m is 0 or 1, n is an integer of 2-10, 
provided, that no more than one of R.sub.1 or R.sub.2 can be hydroxy, 
alkanoyloxy or 
##STR18## 
and, when R is hydrogen, salts thereof with pharmaceutically acceptable 
bases, and, when R is --(CH.sub.2).sub.n --N--(lower alkyl).sub.2, 
addition salts thereof with pharmaceutically acceptable acids. 
The compounds of formula I can also be characterized by the formulas Ia and 
Ib, depending upon whether the moiety A is fragment A' or A", 
respectively, as follows: 
##STR19## 
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, 
R.sub.8, R.sub.9, R.sub.10, R.sub.11, m and n are as herein described. 
Preferred compounds of formula Ia of the invention are those wherein 
R.sub.1 is carboxy or acetyl, R.sub.2 is hydroxy, R.sub.3 is hydrogen or 
propyl, R.sub.4 is hydrogen or chloro, n is an integer 2-10, R.sub.5 is 
hydrogen or acetyl, R.sub.6 is hydrogen, lower alkyl or aryl, R.sub.7 and 
R.sub.8 are hydrogen. 
Preferred compounds of formula Ib of the invention are those wherein 
R.sub.1 is carboxy or acetyl, R.sub.2 is hydroxy, R.sub.3 is hydrogen or 
propyl, R.sub.4 is hydrogen or chloro, m is 0 or 1, n is an integer from 
2-10, R.sub.5 is hydrogen or acetyl, R.sub.9 and R.sub.10 are hydrogen, 
and R.sub.11 is hydrogen or chloro. 
More preferred compounds of formula Ia are those wherein R.sub.1 is carboxy 
or acetyl, R.sub.2 is hydroxy, R.sub.3 is hydrogen or propyl, R.sub.4 is 
hydrogen or chloro, n is an integer from 4 to 8, R.sub.5 is hydrogen or 
acetyl, R.sub.6 is hydrogen or lower alkyl and R.sub.7 and R.sub.8 are 
hydrogen. 
More preferred compounds of formula Ib are those wherein R.sub.1 is carboxy 
or acetyl, R.sub.2 is hydroxy, R.sub.3 is n-propyl, R.sub.4 is hydrogen, m 
is 0, n is an integer from 4-6, R.sub.5 is hydrogen or acetyl, R.sub.9 and 
R.sub.10 are hydrogen, R.sub.11 is hydrogen or chloro. 
Most preferred compounds of formula Ia are those wherein R.sub.1 is carboxy 
or acetyl, R.sub.2 is hydroxy, R.sub.3 is n-propyl or hydrogen, R.sub.4 is 
hydrogen, n is an integer from 4-8, R.sub.5 is hydrogen, R.sub.6 is 
hydrogen or .alpha.-branched lower alkyl, and R.sub.7 and R.sub.8 are 
hydrogen. 
Most preferred compounds of formula Ib are those wherein R.sub.1 is carboxy 
or acetyl, R.sub.2 is hydroxy, R.sub.3 is n-propyl, R.sub.4 is hydrogen, m 
is 0, n is an integer from 4 to 6, R.sub.5, R.sub.9, R.sub.10 and R.sub.11 
are hydrogen. 
The 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-hydroxy-3-propylbenzoic 
acid; 
4-[5-(2,3,4-trichloro-5,6-dihydroxyphenyl)pentyloxy]-2-hydroxy-3-propylbenz 
oic acid; 
4-[4-(2,3-dihydroxyphenyl)butoxy]-2-hydroxy-3-propylbenzoic acid; 
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-3-propylbenzoic acid; 
4-[6-[2,3-dihydroxy-4-(1-methylethyl)phenyl]hexyloxy]-2-hydroxy-3-propylben 
zoic acid; 
4-[3-(3,4-dihydroxyphenyl)propoxy]-2-hydroxy-3-propylbenzoic acid; 
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-propylphenyl]ethanone 
Exemplary of other compounds of the invention are: 
4-[6-[2,3-dihydroxy-4-(1,1-dimethylethyl)phenyl]hexyloxy]2-hydroxy-3-propyl 
benzoic acid; 
4-[6-[2,3-dihydroxy-4-methylphenyl]hexyloxy]2-hydroxy-3-propylbenzoic acid; 
4-[4-[2,3-dihydroxy-4-(2-methylpropyl)phenyl]butoxy]2-hydroxy-3-propylbenzo 
ic acid; 
4-[6-[2,3-dihydroxy-5,6-dimethylphenyl]hexyloxy]2-hydroxy-3-propylbenzoic 
acid; 
4-[5-[5-chloro-2,3-dihydroxyphenyl]pentyloxy]-2-hydroxy-3-propylbenzoic 
acid; 
4-[6-[2,3-dihydroxy-6-fluorophenyl]hexyloxy]2-hydroxy-3-propylbenzoic acid; 
4-[4-[2,3-dihydroxy-4-cyclohexylphenyl]butoxy]2-hydroxy-3-propylbenzoic 
acid; 
4-[4-[2,3-dihydroxy-4-(1,1-dimethylethyl)phenyl]butoxy]2-hydroxy-3-propylbe 
nzoic acid; 
4-[8-[2,3-dihydroxy-4-(1,1-dimethylethyl)phenyl]octyloxy]2-hydroxy-3-propyl 
benzoic acid; 
4-[4-[2,3-dihydroxy-4-(1,1-dimethylethyl)phenyl]butoxy]2-hydroxybenzoic 
acid; 
4-[8-[2,3-dihydroxy-4-(1-methylethyl)phenyl]octyloxy]2-hydroxybenzoic acid; 
4-[8-[2,3-dihydroxyphenyl]butoxy]-3,5-dipropyl-2-hydroxybenzoic acid; 
4-[4-[2,3-dihydroxy-4-(1-methylethyl)phenyl]butoxy]-3,5-dipropylbenzoic 
acid; 
4-[6-[2,3-dihydroxy-4-(1-methylethyl)phenyl]hexyloxy]3-propylbenzoic acid; 
4-[6-[2,3-bis(acetyloxy)-4-(1-methylethyl)phenyl]hexyloxy]2-hydroxy-3-propy 
lbenzoic acid; 
2-acetyloxy-4-[6-(2,3-dihydroxy-4-(1-methylethyl)phenyl]hexyloxy]-3-propylb 
enzoic acid; 
4-[6-[2,3-bis[4-methylbenzoyl)oxy]-4-(1-methylethyl)phenyl]-hexyloxy]-2-hyd 
roxy-3-propylbenzoic acid; 
1-[2-hydroxy-4-[6-[2,3-dihydroxy-4-(1,1-dimethylethyl)phenyl]-hexyloxy]-3-p 
ropylphenyl]ethanone; 
1-[2-hydroxy-4-[8-[2,3-dihydroxy-6-fluorophenyl]octyloxy]-3-propylphenyl]et 
hanone; 
1-[2-hydroxy-4-[6-[6-chloro-2,3-dihydroxyphenyl]hexyloxy]-3-propylphenyl]et 
hanone; 
1-[2-hydroxy-4-[6-[5,6-dichloro-2,3-dihydroxyphenyl]hexyloxy]-3-propylpheny 
l]ethanone; 
1-[2-hydroxy-4-[6-[2,3-dihydroxy-4,5,6-trichlorophenyl]hexyloxy]-3-propylph 
enyl]ethanone; 
5-[6-(2,3-dihydroxy-4-(1-methylethyl)phenyl]hexyloxy]-2-hydroxybenzoic 
acid; 
4-[6-[2,3-dihydroxy-4-(1-methylethyl)phenyl]hexyloxy]benzoic acid; 
4-[6-[2,3-dihydroxy-4-(1-methylethyl)phenyl]hexyloxy]2-hydroxy-3-propylbenz 
oic acid ethyl ester; 
4-[6-[2,3-dihydroxy-4-(1-methylethyl)phenyl]hexyloxy]-2-hydroxy-3-propylben 
zoic acid ethyl ester; 
4-[8-(3,4-dihydroxyphenyl)octyloxy]-2-hydroxy-3-propyl benzoic acid; 
4-[3-(3,4-dihydroxyphenyl)propoxy]-2-hydroxy-3-propyl benzoic acid ethyl 
ester; 
4-[6-(3,4-dihydroxyphenyl)hexyloxy]-2-hydroxy benzoic acid; 
4-[6-(3,4-dihydroxyphenyl)hexyloxy]-3-propylbenzoic acid; 
4-[8-(3,4-dihydroxyphenyl)octyloxy]benzoic acid; 
3-[8-(3,4-dihydroxyphenyl)octyloxy]benzoic acid; 
5-[8-(3,4-dihydroxyphenyl)octyloxy]-2-hydroxybenzoic acid; 
4-[[8-(3,4-dihydroxyphenyl)-8-oxooctyl]oxy]-2-hydroxy-3-propylbenzoic acid; 
4-[[4-(3,4-dihydroxyphenyl)-4-oxobutyl]oxy]-2-hydroxy-3-propylbenzoic acid; 
4-[6-(3,4-dihydroxy-5-fluorophenyl)hexyloxy]-2-hydroxy-3-propylbenzoic 
acid; 
4-[6-(3,4-dihydroxy-6-fluorophenyl)hexyloxy]-2-hydroxy-3-propylbenzoic 
acid; 
4-[6-(3,4-dihydroxy-6-chlorophenyl)hexyloxy]-2-hydroxy-3-propylbenzoic 
acid; 
4-[4-(3,4-dihydroxy-5(1-methylethyl)phenyl]butoxy]-2-hydroxy-3-propylbenzoi 
c acid; 
4-[4-[3,4-dihydroxy-5(1,1-dimethylethyl)phenyl]butoxy]-2-hydroxybenzoic 
acid; 
4-[6-[3,4-bis(acetyloxy)phenyl]hexyloxy]-2-hydroxy-3-propylbenzoic acid; 
2-acetyloxy-4-[6-(3,4-dihydroxyphenyl)hexyloxy[-3-propylbenzoic acid; 
4-[[4-[3,4-dihydroxy-5-(1-methylethyl)phenyl]-4-oxobutyl]oxy]-2hydroxybenzo 
ic acid; 
4-[6-[3,4-dihydroxy-2-(1-methylethyl)phenyl]hexyloxy]-2-hydroxy-3-propylben 
zoic acid; 
4-[[4-(3,4-dihydroxy-2,5-dimethylphenyl)-4-oxobutyl]oxy]-2-hydroxy-3-propyl 
benzoic acid; 
4-[4-(3,4-dihydroxy-2,5-dimethylphenyl)butoxy]-2-hydroxy-3-propylbenzoic 
acid; 
4-[[6-(3,4-dihydroxy-2,5-6-trimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-pro 
pylbenzoic acid; 
4-[6-(3,4-dihydroxy-,5,6-trimethylphenyl)hexyloxy]-2-hydroxy-3-propylbenzoi 
c acid; 
1-[2-hydroxy-4-[6-(3,4-dihydroxyphenyl)hexyloxy]-3-propylphenyl-1-ethanone; 
1-[2-hydroxy-4-[8-(3,4-dihydroxyphenyl)octyloxy]-3-propylphenyl-1-ethanone; 
1-[2-hydroxy-4-[6-(3,4-dihydroxy-2,5-dimethylphenyl)hexyloxy]-3-propylpheny 
l-1-ethanone; 
1-[2-hydroxy-4-[6-(3,4-dihydroxy-6-chlorophenyl)hexyloxy]-3-propylphenyl-1- 
ethanone; 
1-[2-hydroxy-4-[6-(3,4-dihydroxy-2-chlorophenyl)hexyloxy]-3-propylphenyl-1- 
ethanone; 
1-[2-hydroxy-4-[6-(3,4-dihydroxy-6-fluorophenyl)hexyloxy]-3-propylphenyl-1- 
ethanone; 
The compounds of Formula I, and intermediates therefor, can be prepared as 
described in Reaction Schemes I to XII. 
##STR20## 
wherein R.sub.6, R.sub.7, R.sub.8 and n are as previously described, and Ac 
is acetyl. 
In Reaction Scheme I, a compound of formula II, which are known compounds 
or can be prepared according to known procedures, 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 
particularly, a compound of formula II is reacted with an alkyl lithium 
reagent, preferably butyl lithium, in the presence of a solvent such as 
diethylether, tetrahydrofuran or the like at a temperature in the range of 
from about -75.degree. to 0.degree., to yield the corresponding lithium 
salt followed by reaction in situ with an excess of a dibromo alkane at a 
temperature in the range of from about 0.degree. to 50.degree.. 
A compound of formula III can be converted to the corresponding compound of 
formula IV, for example, with boron tribromide in a halogenated 
hydrocarbon solvent, for example, chloroform or 1,2-dichloroethane or 
preferably methylene chloride at a temperature in the range of from about 
-75.degree. to about 25.degree.. 
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, at reflux or with dimethyl 
formamide at a temperature in the range of from about 50.degree. to about 
100.degree.. 
The compound of formula IV can be converted to a corresponding compound of 
formula VI in the presence of acetic anhydride and acid catalyst, for 
example, perchloric acid, in a solvent such as ethyl acetate and the like, 
at a temperature in the range of from 0.degree. to about 25.degree.. 
Alternatively, the resulting compound of formula IV can be converted to a 
corresponding compound of formula VII with 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 in the range of 
from 0.degree. to about 25.degree.. 
##STR21## 
wherein R.sub.6, R.sub.7 and R.sub.8 and n are as previously described. 
In Reaction Scheme II, an aldehyde of formula VIII, which are known 
compounds or can be prepared according to known procedures, can be 
converted to the corresponding compound of formula IX as described in J. 
H. P. Tyman and C. H. Khor, Chem. Ind., 526 (1974). More particularly, the 
aldehyde of formula VIII is allowed to react with a lithium reagent, 
prepared by standard procedures, in a solvent such as ethyl ether, 
tetrahydrofuran or the like, at a temperature in the range of from about 
-20.degree. to about 35.degree.. The alcohol protecting group can be 
removed from the product by treatment with dilute hydrochloric acid at 
25.degree. to give a diol of formula IX. 
Thereafter, hydrogenolysis of a compound of formula IX gives the 
corresponding compound of formula X by shaking on a Parr apparatus under 
hydrogen pressure of from about 40-60 psi, using a palladium catalyst, at 
a temperature in the range of from about 25.degree. to about 50.degree., 
in a solvent, such as, ethyl acetate, ethanol, tetrahydrofuran and the 
like. 
Conversion of a compound of formula X to the corresponding mesylate XI can 
be carried out under standard conditions, for example, with 
methanesulfonyl chloride and triethylamine in a solvent such as methylene 
chloride at a temperature in the range of from about -20.degree. to about 
25.degree.. 
##STR22## 
wherein R.sub.9, R.sub.10, R.sub.11 and n are as previously described. 
In Reaction Scheme III, a compound of formula XII can be converted to a 
corresponding compound of formula XIII and which in turn can be converted 
to corresponding compounds of formulas XIV and XV, utilizing the reaction 
conditions set forth in Reaction Scheme II. 
##STR23## 
wherein n is as previously described. 
In Reaction Scheme IV, a compound of formula III, which are known compounds 
or can be prepared according to known procedures, can be converted to the 
corresponding monochloro compounds of formula XVI, the dichloro compounds 
of formula XVII and the trichloro compounds of formula XVIII by treatment 
with the appropriate quantity of chlorine, in an inert solvent such as a 
chlorinated hydrocarbon, for example, methylene chloride, chloroform, 
1,2-dichloromethane and the like, at a temperature in the range of from 
about -20.degree. to about 25.degree.. 
The conversion of a compound of formula XIX to the corresponding compound 
of formula XX can be carried out utilizing the reaction condition first 
described above. 
##STR24## 
wherein R.sub.9, R.sub.11 and n are as previously described. 
In Reaction Scheme V, a compound of formula XXI is converted to an 
acetylenic alcohol of formula XXII by reaction with an acetylenic alcohol 
in the presence of bis(triphenylphosphine) palladium dichloride, cuprous 
iodide and an organic amine (triethylamine) as described in K. 
Sonogashira, Y. Tohda and N. 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 and the like, at a temperature in the range of from 
about 25.degree. to about 50.degree.. 
A resulting compound of formula XXII is converted to a compound of formula 
XXIII utilizing standard conditions, for example, catalytic hydrogenation 
at atmospheric pressure and room temperature. 
A resulting compound of formula XXIII can be converted to a compound of 
formula XXIV utilizing standard conditions, for example, in the presence 
of methanesulfonyl chloride, triethylamine in methylene chloride, as the 
solvent at a temperature in the range of from about -20.degree. to about 
25.degree.. 
##STR25## 
wherein R.sub.9, R.sub.11 and n are as previously described. 
In Reaction Scheme VI, a compound of formula XXV, which are known compounds 
or can be prepared according to known procedures, can be converted to a 
compound of formula XXVI utilizing standard acylation conditions, for 
example, treatment with a bromo acid and trifluoroacetic anhydride at a 
temperature in the range of from 25.degree. to about 40.degree. without 
solvent or with a solvent such as methylene chloride, 1,2-dichloroethane 
or the like. Alternatively, a bromoacid chloride and aluminum chloride in 
a solvent such as methylene chloride or 1,2-dichloroethane at a 
temperature in the range of from 0.degree. to about 40.degree. can be also 
be utilized. 
The reduction of a compound of formula XXVI to the corresponding compound 
of formula XXVII can be accomplished by hydrogenation in a Parr apparatus 
at 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 in the range of from 25.degree. to about 
70.degree.. A mineral acid catalyst can be used in addition to palladium 
catalyst. 
##STR26## 
wherein R' is lower alkyl. 
In Reaction Scheme VII, a compound of formula XXVIII, which are known 
compounds or can be prepared according to known procedures, can be 
converted to the corresponding compound of formula XXIX utilizing standard 
alkylation conditions, for example, utilizing allyl bromide or chloride, 
an 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 in the range of 
from about 40.degree. to about 60.degree.. 
The rearrangement of a compound of formula XXIX to a compound of formula 
XXX is carried out by heating in an inert atmosphere, at a temperature in 
the range of from about 175.degree. to about 200.degree.. 
The hydrogenation of a compound of formula XXX to the corresponding 
compound of formula XXXI can be carried out utilizing a standard catalytic 
hydrogenation reaction, for example, at atmospheric pressure or under 
hydrogen pressure such as 50 psi, in a solvent such as ethyl acetate, 
tetrahydrofuran, ethanol or the like, at a temperature in the range of 
from about 25.degree. to about 50.degree.. 
The chlorination of a compound of formula XXXI to the corresponding 
compound of formula XXXII can be carried out utilizing a standard 
chlorination reaction, for example, with N-chlorosuccinimide in a solvent 
such as carbon tetrachloride, chloroform or the like, at the reflux 
temperature. 
##STR27## 
wherein R.sub.1 ', is --COOR', acetyl, hydrogen or hydroxy, R.sub.2 ' is 
--COOR', hydrogen or hydroxy, R' is lower alkyl, R.sub.1 ", is carboxy, 
acetyl, hydrogen or hydroxy, R.sub.2 " is carboxy, hydrogen or hydroxy, X 
is bromo or methanesulfonyloxy, provided that no more than one of R.sub.1 
' or R.sub.2 ' can be hydroxy or --COOR', or that no more than one of 
R.sub.1 " or R.sub.2 " can be carboxy or hydroxy, R.sub.3, R.sub.4, 
R.sub.6 R.sub.7 and R.sub.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 yield the corresponding compound of formula 
XXXIV. The reaction is carried out utilizing an alkali metal carbonate as 
the base, for example, sodium carbonate, preferably potassium carbonate, 
with added sodium iodide or potassium iodide, in a solvent such as 
acetone, methyl ethyl ketone, dimethylformamide, toluene or the like, at a 
temperature in the range of from about 40.degree. C. to about 70.degree. 
C. The solid-liquid phase-transfer catalyst 
tris[2-(2-methoxyethoxy)ethyl]amine can be used to facilitate the reaction 
when toluene is the solvent. 
The hydrolysis of a compound of formula XXXIV to the corresponding compound 
of formula XXXV can be carried out utilizing standard conditions, for 
example, utilizing an alkali metal hydroxide such as sodium hydroxide or 
potassium hydroxide, in a solvent such as methanol, ethanol or the like, 
sometimes with added dioxane to aid solubility, at a temperature in the 
range of from about 25.degree. to about 65.degree.. 
The conversion of a compound of formula XXXV to the corresponding compound 
of formula Ia' can be carried out utilizing, for example, boron tribromide 
in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane or 
the like at a temperature in the range of from -70.degree. to 25.degree.. 
The resulting compound of formula Ia' is recovered and purified utilizing 
known and conventional procedures, for example, precipitation, 
crystallization, chromatography or the like. 
##STR28## 
wherein R.sub.3, R.sub.4, R.sub.9, R.sub.10, R.sub.11, R.sub.2 ', R.sub.1 
', R.sub.2 ", R.sub.1 ", m, n and X are as previously described, provided 
that no more than one of R.sub.1 ' and R.sub.2 ' can be hydroxy or 
--COOR', or that no more than one of R.sub.1 " and R.sub.2 " can be 
carboxy or hydroxy. 
In Reaction Scheme IX, a compound of formula XXXVI is reacted with a 
compound of formula XXXIII to yield the corresponding compound of formula 
XXXVII. The reaction is carried out utilizing 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 in the range of from about 40.degree. to about 70.degree.. 
The conversion of a compound of formula XXXVII to the corresponding 
compound of formula XXXVIII can be carried out utilizing, 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 added dioxane to aid solubility, at a temperature in the range of 
from about 25.degree. to about 65.degree.. 
The conversion of a compound of formula XXXVIII to the corresponding 
compound of formula Ib' can be carried out utilizing, for example, boron 
tribromide, in a solvent such as methylene chloride, chloroform, 
1,2-dichloroethane or the like at a temperature in the range of from about 
-70.degree. to about 25.degree.. The resulting compound of formula Ib' is 
recovered and purified utilizing known and conventional procedures, for 
example, precipitation, crystallization, chromatography or the like. 
If desired, a compound of formula XXXVII, XXXVIII or Ib' wherein 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. The 
conversion can be carried out using a catalyst such as palladium in a 
solvent such as ethanol, ethyl acetate or tetrahydrofuran using pressure 
of 40-60 psi. Small amounts of an acid such as concentrated sulfuric acid 
can be used to accelerate the reaction. 
##STR29## 
wherein R.sub.2, R.sub.3, R.sub.4, R.sub.6, R.sub.7, R.sub.8 and n are as 
previously described and R.sub.12 is benzyl or acyl. 
In Reaction Scheme X, a compound of formula XXXIX is reacted with a 
compound of formula XXXX to yield the corresponding compound of formula 
XXXXI. The reaction is carried out utilizing 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 in the range of from about 25.degree. to about 
70.degree.. The hydrogenolysis of a compound of formula XXXXI to the 
corresponding compound of formula Ia" can be carried out utilizing a 
standard catalytic hydrogenolysis reaction, for example, at atmospheric 
pressure or hydrogen pressure up to 50 psi at a temperature in the range 
of from about 25.degree. to about 50.degree., 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 utilizing known and conventional procedures, for example, 
precipitation, crystallization, chromatography or the like. 
##STR30## 
wherein R.sub.3, R.sub.4, R.sub.6, R.sub.7, R.sub.8 and n are previously 
described and R.sub.2 '" is alkanoyloxy. 
In Reaction Scheme 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 in the range of from about 25.degree. to 
about 70.degree.. 
A 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 at atmospheric pressure at a temperature in 
the range of from about 25.degree. to about 70.degree. in the presence of 
a catalyst such as palladium in a solvent such as ethyl acetate, 
tetrahydrofuran or the like. 
##STR31## 
wherein R.sub.2, R.sub.3, R.sub.4, R.sub.6, R.sub.7, R.sub.8 and n are as 
previously described, and R" is lower alkyl or --(CH.sub.2).sub.n 
--N--(lower alkyl).sub.2, provided that R.sub.2 is other than carboxy. 
A lower alkyl ester or basic ester of formula Ia""', and if desired the 
corresponding compound of formula Ib, where R.sub.5 is H can be prepared 
by Scheme XII. 
More particularly, to prepare a lower alkyl ester of formula Ia""' a 
compound of formula Ia, wherein R.sub.1 or R.sub.2 is 
##STR32## 
that is, 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 in the range of from about 
30.degree. to about 70.degree. to yield the corresponding compound of 
formula Ia""'. 
To prepare a basic ester of formula Ia""', a compound of formula Ia wherein 
R.sub.1 or R.sub.2 is 
##STR33## 
that is, a compound of formula Ia"", is reacted with 
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 in the range of from about 30.degree. to 
about 70.degree. to yield the corresponding compound of formula Ia""'. 
It is understood that preferably any intermediate prepared in Reaction 
Schemes I-XII is recovered and isolated utilizing known procedures, for 
example, precipitation, crystallization, chromatography or the like, prior 
to use in the next reaction step. The end-products of formula I are 
recovered by similar known procedures. 
The invention also relates to salts of the compound of formula I, when R is 
hydrogen, which salts are prepared by the reaction of the said acids with 
a base having a non-toxic, pharmacologically acceptable cation. In 
general, any base which will form a salt with a carboxylic acid and whose 
pharmacological properties will not cause an adverse physiological effect 
is within the scope of this invention. Suitable bases thus include, for 
example, the 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, dialkylamines, 
trialkylamines, for example, methylamine, diethylamine, triethylamine and 
the like, nitrogen containing heterocyclic amines, for examples, 
piperidine and the like. A salt thus produced is the functional equivalent 
of the corresponding compound of formula I wherein R is hydrogen and one 
skilled in the art will appreciate that the variety of salts embraced by 
the invention is limited only by the criterion that a base employed in 
forming the corresponding salts be both non-toxic and physiologically 
acceptable. 
The invention also relates to addition salts of the compounds of formula I, 
when R is --(CH.sub.2).sub.n --N--(lower alkyl).sub.2, which salts are 
prepared by the reaction of said amines with a non-toxic pharmacologically 
or pharmaceutically acceptable acid. In general, the referred to 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, nitric acid, phosphoric acid, 
sulfuric acid and the like. 
It is known that oxidative metabolism of arachidonic acid by the 
.DELTA..sup.5 -lipoxygenase (.DELTA..sup.5 --LO) pathway leads to the 
peptidoleukotrienes (LTC.sub.4 and LTD.sub.4) and leukotriene B.sub.4 
(LTB.sub.4). LTC.sub.4 and LTD.sub.4 are potent bronchoconstrictors of 
human bronchi and contribute to edema in some species by increasing 
capillary permeability. LTB.sub.4 is a potent chemotactic factor for 
inflammatory cells. LTB.sub.4 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. Consequently, 
inhibitors of .DELTA..sup.5 --LO may be of therapeutic value in the 
treatment of asthma and inflammatory diseases. 
Furthermore, products of the .DELTA..sup.5 --LO pathway (LTB.sub.4, 
LTC.sub.4, LTD.sub.4) are present in elevated levels in skin lesions of 
patients with psoriasis and atopic dermatitis and may be mediators of 
these skin diseases. The intracutaneous application of LTB.sub.4 to human 
skin gives a wheal and flare reaction followed by infiltration of 
neutrophils into the site of application. The influx of neutrophils is 
also observed during the inflammatory reactions associated with psoriatic 
lesions. Topical application of LTB.sub.4 to human skin causes abscesses 
similar to those of pustular psoriasis. 
Oxygen - derived free radicals and their metabolites may contribute to the 
irreversible injury which occurs on reperfusion of previously ischemic 
myocardial tissue. Therapy directed toward the toxic effects of these free 
radicals by radical scavenging drugs may provide protection against this 
injury. 
The compounds of formula I exhibit activity, for example, as antioxidants, 
as .DELTA..sup.5 -lipoxygenase inhibitors, and as hereinafter further 
described. The useful pharmacological activities of the compound of 
formula I can be demonstrated by the tests hereinafter set forth. 
The compounds of formula I are useful as agents for the treatment of 
inflammatory diseases such as arthritis; inflammatory bowel disease such 
as colitis and as hereinafter further described; cardiovascular diseases 
such as myocardial ischemia; as anti-inflammatory agents in the topical 
therapeutic treatment of leukotriene-mediated dermal inflammations 
including psoriasis; and bronchopulmonary diseases such as asthma. 
Inflammatory bowel disease (IBD) includes a variety of diseases of the 
gastrointestinal (GI) tract such as Crohn's disease of the colon and 
ileum, ulcerative colitis and pseudomembraneous colitis. Common symptoms 
of these diseases include inflammation of the affected area of the GI 
mucosa, mucosa ulceration, edema, infiltration of the mucosa with 
inflammatory cells and severe diarrhea. Arachidonic acid metabolites from 
the .DELTA..sup.5 --LO pathway are believed to mediate IBD. 
IN VITRO TEST FOR .DELTA..sup.5 -LIPOXYGENASE INHIBITORS 
Compounds of formula I of the invention were tested for their effect on 
.DELTA..sup.5 -lipoxygenase from rat basophilic leukemia (RBL-1) cells. 
Materials 
RBL-1 cells (CRL 1378) were obtained from the American Type Culture 
Collection, Rockville, MD. DMEM and glutamine were purchased from Flow 
Labs, McLean, Va. FBS (Gibco, Grand Island, N.Y.) was heat-inactivated for 
1 hour at 56.degree. C. Reagents for protein determinations were obtained 
from Biorad, Rockville Center, N.Y. Arachidonic acid (approx. 99%), ATP 
(disodium salt), BHT, dextran (clinical grade), tetrasodium EDTA, gelatin, 
gentamycin sulfate solution, reduced glutathione, 1 M HEPES buffer, 
indomethacin, NaCl, reduced NADPH, Trizma 7.2, and Trizma 8.5 were 
purchased from Sigma Chemical, St. Louis, Mo. CaCL.sub.2 dihydrate, Norit 
A charcoal, and citric acid monohydrate were obtained from Fisher 
Scientific, Pittsburgh, Pa. [.sup.3 H]-5-HETE (specific activity 229.5 
Ci/mmol) was purchased from New England Nuclear, Boston, Mass. A synthetic 
5-HETE standard was supplied by Dr. M. Rosenberger, Dept. of Medicinal 
Chemistry, Hoffmann La-Roche, Nutley, N.J.; [see Corey, E. J., and 
Hashimoto, S. (1981) Tet. Letters, 22, 299-302 for method of preparation]. 
Ecoscint liquid scintillation fluid was purchased form National 
Diagnostics, Sommerville, N.J. 
Isolation of 5-lipoxygenase 
The most stable enzyme preparations were obtained from RBL-1 cells thawed 
from liquid N.sub.2 storage, then maintained in tissue culture flasks 
containing DMEM supplemented with 25 mM glucose, 12.5 mM HEPES, 40 mM 
glutamine, 50 ug/ml gentamycin sulfate, and 10% heat-inactivated FBS. 
Approximately 7-9 days after thawing, RBL-1 cells growing in log phase 
were seeded at a density of 7500 viable cells/ml in a closed 89-liter 
spinner flask. The cells were stirred constantly for 3-4 days at 
37.degree. 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 
4.degree. C. at 1500.times.g for 10 minutes and were washed 3 times with 
ice cold 0.05M tris-hCl, pH 7.2, tetrasodium EDTA (buffer 1). The cells 
were washed last in 0.05M Tris-HCl containing 14 .mu.M indomethacin, 1 mM 
glutathione, 1.5 mM NaCl, and 1 mM tetrasodium EDTA (buffer 2), 
resuspended at a density of 5.times.108'/ml approximately 10 ml) and 
disrupted manually at 4.degree. C. using a 40 ml Dounce (type A pestle) 
homogenizer. After 5 minutes of homogenization, 95% cell lysis was 
confirmed by phase contrast microscopy. The broken cells were diluted 1:2 
with buffer 2 and centrifuged at 12,380.times.g for 10 minutes at 
4.degree. C. to pellet cellular debris and granules. The 12,380.times.g 
supernatant was centrifuged at 113,000.times.g for 60 minutes to pellet 
microsomes. The high-speed supernatant (5.9.+-.0.48 mg/ml protein) was 
frozen immediately in 1 ml aliquots using a dry ice/acetone bath. The 
isolated cytosolic fraction was stored in liquid N.sub.2 for up to 8 weeks 
without loss of 5-LO enzyme activity. 
Lipoxygenase Assay 
Compounds were dissolved at 25 mM concentration in DMSO, then diluted to 
final concentrations using 95% ethanol. For a typical enzyme assay, the 
partially purified 5-LO preparation was preincubated with drug or vehicle 
for 10 minutes at 30.degree. C. The assay tubes were then transferred at a 
37.degree. C. water bath where they received arachidonic acid (8.25 .mu.M 
final concentration) to initiate 5-LO activity. In addition to enzyme and 
substrate, each reaction tube contained: 12.5 .mu.moles of Tris-HCl (pH 
7.2), 25 .mu.moles glutathione, 1.4 .mu.moles indomethacin, and 1.25 
.mu.moles of CaCl.sub.2 and ATP to yield a total volume of 250 .mu.l 0.3M 
citric acid to yield pH 3.5. The samples were immediately cooled on ice 
and neutralized by dilution with 0.05M Tris-HCl, pH 8.5, which contained 
25 mg/1 BHT. A boiled cytosol control was placed at the end of each assay 
to emasure non-enzymatic oxidation of arachidonic acid. The mean specific 
activity of the 5-LO enzyme preparation was approximately 66.16.+-.14.39 
pmol 5-HETE 1 min/mg protein. 
Radioimmunoassay for 5-HETE 
Under the assay conditions described, the 5-LO catalyzed the conversion of 
arachidonic acid to 5-HPETE which, as a consequence of peroxidase 
activity, was reduced to 5-HETE. A specific radioimmunoassay was employed 
to quantitate the amount (pmoles) of 5-HETE formed during the enzyme 
reaction. To prepare the immunogen, Dr. M. Rosenberger (Dept. of Medicinal 
Chemistry) converted the racemic 5-HETE lactone (Corey, E. J., and 
Hashimoto, S. (1981) Tet. Letters, 22, 299-302) to its hydrazine 
derivative. The hydrazide was conjugated to thiolated Keyhole Limpet 
Hemocyanin (Young, R. N., Kakushima, M., and Rokach, J. (1982) 
Prostaglandins 23, 603-613) using N-ethyl-maleimide as previously 
described for LTB.sub.4 by (Young, R., N, Zomboni, R. and Rokach, J. 
91983) Prostaglandins, 26, 605-613). New Zealand White rabbits received 
multiple intradermal injections on their backs with 100 .degree.g 
conjugate emulsified in complete Freund's adjuvant. A schedule of 
injections reported by Salmon (Salmon, J. A. (1978) Prostaglandins, 15, 
383-397) was followed. After the monthly i.p. booster injections, blood 
was obtained from the marginal ear vein 5-7 days later and assessed for 
antibody titer. 
Rabbit 5-HETE anti-sera was diluted 1:300 in 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 pmole 5-HETE/ml) or dilute assay samples and placed 
in an ice bath. [.sup.3 H]-5-HETE (approximately 10,000-12,000 cpm) was 
added to yield a total assay volume of 300 .degree.l. After a 90 minute 
incubation at 25.degree. C., 1 ml ice-cold dextran-coated charcoal was 
added to separate antibody-bound from unbound 5-HETE (Salmon, J. A. (1978) 
Prostaglandins, 15, 383-397). The charcoal was sedimented at 2000.times.g 
for 10 minutes, after which 0.8 ml of supernatant was added to 10 mls 
Ecoscint fluid. Radioactivity (dpm) was determined after 10 minute counts 
using a LKB model 1219 scintillation counter (40% efficiency for [.sup.3 
H]. 
Data Analysis 
Each inhibitor concentration was tested in quadruplicate. The inhibitory 
concentration that yielded a 50% inhibition (IC-50) of control 5-HETE 
formation was calculated by regression analysis of the dose-response data. 
Data (IC-50) for the compounds of this invention in this test is reported 
in Table I. 
Carrageenan Pleurisy Test (In Vivo) 
The animals utilized in these studies were male Lewis rats (Charles River 
Breeding Laboratories) weighing between 230-250 g. Carrageenan (CG) 
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 26 gauge (3/8") intradermal needle. 
Compounds suspended in aqueous suspending 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 the 5 hour treatment period and 1 hour before and 5 hour after CG 
injection for the 24 hour treatment period. Drugs were administered at 
doses which, on the basis of preliminary experiments, would significantly 
suppress the development of CG-induced pleurisy under our experimental 
conditions. 
At 5 or 24 hours after CG injection, the rats were killed by decapitation, 
exsanguinated, and the pleural cavity exposed by cutting the ribs on both 
sides of the sternum. The exudate fluid was removed from the pleural 
cavity with disposable plastic pipettes and its volume quantitated. The 
pleural cavity was then washed once with phosphate buffered saline 
containing fetal bovine serum (1:1) and the washings combined with the 
exudate. The total number of cells in the pleural cavity was quantitated 
using a Coulter Counter (Model ZM) adjusted to exclude any contaminating 
RBC. (Published in "Plant Flavonoids in Biology & Medicine: Biochemical, 
Pharmacological and Structure-Activity Relationships" p. 231-242 (1986) 
Alan R. Liss, Inc.) 
Data for the compounds of this invention in this test is reported in Table 
I. 
Mouse Ear Edema Test (In Vivo) 
In this animal model system, the application of arachidonic acid to the ear 
results in the biosynthesis of the metabolic products 
5-hydroperoxy-6,8,11,14-eicosatetraenoic acid (5-HETE), leukotriene 
B.sub.4 (LTB.sub.4), leukotriene C.sub.4 (LTC.sub.4), 
12-hydroperoxy-5,8,10,14-eicosatetraenoic acid (12-HETE), and 
prostaglandin E.sub.2 (PGE.sub.2) at the site of application, followed by 
the influx of neutrophils into the site and the rapid development of edema 
within 30 to 60 minutes (See, for instance, Young, Wagern and Spries, 
"Tachyphylaxis in 12-0-Tetradecanoylphorbol Acetate And Arachidonic 
Acid-Induced Ear Edema", J. Invest. Dermatol. 80:48 (1983) and Hames, Opas 
and Bonney, "Arachidonic Acid Metabolites in Mouse Ear Edema" Advances in 
Inflammation Research, 11:57 (1986). Inhibitors of these metabolites and 
of their metabolic pathways also inhibit edema formation. 
CD-1 male mice weighing 15 to 25 g were employed, and they were designated 
as follows: (1) Control Group, in which no arachidonic acid or test 
compound was to be applied, (2) Arachidonic Acid-Treated Group, in which 
no test compound was to be applied, and (3) Treated Group, in which the 
test compound was to be applied first, followed by the application of 
arachidonic acid. 
In the case of the Group (3) animals, the test compound, dissolved in 
acetone, was applied to the dorsal surface of the right ear of the mouse 
with a 25-microliter pipettor, with the dose of the test compound being 
varied. After 0.5 hours in some cases and 4 hours in others, the 
arachidonic acid was topically applied in the same manner as above to the 
pretreated ear areas. In each case of arachidonic acid application, an 
amount of 0.5 mg dissolved in 25 microliters of acetone was used. After 1 
hour, the mice were sacrificed by carbon dioxide inhalation. A 6 
mm-diameter standard biopsy 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 percent inhibition of ear edema 
formation was calculated as follows: 
##EQU1## 
Data for compounds of this invention in this test is reported in Table I. 
TABLE I 
__________________________________________________________________________ 
Rat Carra- 
geenan Pleurisy 
Inhib. of .DELTA..sup.5 
% Inhib. of 
Mouse Ear Edema 
Lipoxygenase 
Exudate Volume 
% Inhibition at 1 mg 
Name IC.sub.50 (.mu.M) 
at 100 mg/kg p.o 
Topically 
__________________________________________________________________________ 
4-[4-(2,3-dihydroxyphenyl)butoxy]- 
0.09 76 17 
2-hydroxy-3-propylbenzoic acid 
4-[5-(2,3-dihydroxyphenyl)pentyloxy]- 
0.006 63 0 
2-hydroxy-3-propylbenzoic acid 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]- 
0.02 68 46 
2-hydroxy-3-propylbenzoic acid 
4-[7-(2,3-dihydroxyphenyl)heptyloxy]- 
0.005 57 57 
2-hydroxy-3-propylbenzoic acid 
4-[8-(2,3-dihydroxyphenyl)octyloxy]- 
62% at 66 78 
2-hydroxy-3-propylbenzoic acid 
0.1 .mu.M 
4-[10-(2,3-dihydroxyphenyl)decyloxy]- 
0.02 61 49 
2-hydroxy-3-propylbenzoic acid 
4-[6-(2,3-dihydroxyphenyl)hexyloxy] 
100% at 
44 64 
2-hydroxy-3-propylbenzoic acid 
1 .mu.M 
ethyl ester 
4 [6-(2,3-dihydroxyphenyl)hexyloxy] 
0.67 42 48 
2-hydroxy-3-propylbenzoic acid 
[2-(diethylamino)ethyl]ester 
2 (acetyloxy-4-[6-(2,3-dihydroxy- 
0.19 42 Not Tested 
phenyl)hexyloxy]-3-propylbenzoic acid 
4-[6-[2,3-bis(acetyloxy)phenyl] 
0.15 43 (75 mg/kg) 
Not Tested 
hexyloxy]2-hydroxy-3-propylbenzoic acid 
4-[6-[2,3-dihydroxy-4-(1-methylethyl) 
0.1 47 (75 mg/kg) 
45 
phenyl]hexyloxy]-2-hydroxy-3-propyl 
benzoic acid 
4-[6-(2,3-dihydroxyphenyl)hexyloxy] 
0.17 46 48 
benzoic acid 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]- 
0.32 0 50 
2-hydroxybenzoic acid 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]- 
0.02 0 52 
3-propylbenzoic acid 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]- 
0.46 Not tested 
59 
3,5-dipropylbenzoic acid 
4-[3-(3,4-dihydroxyphenyl)propoxy]- 
97 % at 
55 32 
2-hydroxy-3-propylbenzoic acid 
1 .mu.M 
4-[6-(3,4-dihydroxyphenyl)hexyloxy]- 
0.005 0 21 
2-hydroxy-3-propylbenzoic acid 
4-[[6-(3,4-dihydroxyphenyl)-6-oxohexyl] 
51% at Not Tested 
Not Tested 
oxy]-2-hydroxy-3-propylbenzoic acid 
1 .mu.M 
1-[2-hydroxy-4-[6-(2,3-dihydroxyphenyl) 
0.03 51 21 
hexyloxy]-3-propylphenyl]ethanone 
1-[2-hydroxy-4-[4-(2,3-dihydroxyphenyl) 
48% at 53 Not Tested 
butoxy]-3-propylphenyl]ethanone 
0.01 .mu.M 
1-[2-hydroxy-4-[8-(2,3-dihydroxyphenyl) 
95% at 0 0 
octyloxy]-3-propylphenyl]ethanone 
0.1 .mu.M 
1-[2-hydroxy-4 [6-[2,3 dihydroxy- 
35% at 
4-(1-methylethyl)phenyl]hexyloxy]- 
0.1 .mu.M 
3 propylphenyl]ethanone 
5-chloro-4 [6 (2,3 dihydroxyphenyl) 
48% at 45 (50 mg/kg) 
51 
hexyloxy] 2 hydroxy 3 propylbenzoic 
0.1 .mu.M 
acid 
__________________________________________________________________________ 
Acetic Acid-Induced Colitis in Rats, In Vivo 
The rat acetic acid-induced colitis bioassay has been described by J. E. 
Krawisz, et al. in Amer. J. Proc. Gastro. Col. Rec. Surg. 31: 11-18 
(1980), and by P. Sharon and W. F. Stenson in Gastroenterolgy 88: 55-63 
(1985) and 86: 453-460 (1984). Acetic acid-induced colitis is 
characterized by the movement of inflammatory cells into the colon, with 
the number of such cells in the mucosa being measured by the activity of 
myeloperoxidase, a marker enzyme for these cells. Positive desirable 
activity is indicated by a reduction in the high levels of myeloperoxidase 
caused by acetic acid. Male rats (Sprague-Dawley), weighing 150 to 300 g, 
were pretreated twice daily for two days with either the vehicle (water, 
or dimethylsulfoxide) or the test inhibitor compound suspended in water or 
dissolved in dimethylsulfoxide and orally administered. On the third day, 
the animals were dosed the same as on the previous two days, anesthetized 
with metofane, and 2 ml of 2.5% acetic acid was injected by syringe into 
the colonic lumen, followed immediately by 3 ml of air and a rinse 
consisting of 3 ml of phosphate-buffered saline (the acetic acid is 
present in the lumen for a sufficient period to cause inflammation without 
producing severe necrosis or irreversible damage). The animals were 
administered a second dose of the test compound in the same amount about 
16 hours later. 24 hours after the acetic acid treatment, the animals were 
sacrificed, the colonic mucosa was surgically removed and homogenized in 
an aqueous buffer at pH 6 with a Tissumizer or similar device and 
myeloperoxidase was measured in the homogenate using o-phenylenediamine as 
a chromagen, as described by 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 the vehicle and 
saline in place of acetic acid. 
Data for representative compounds of this invention is reported in Table 
II. 
Antibiotic-Induced Colitis in Hamsters, In Vivo 
Male Syrian hamsters (LUG), weighing 80 to 120 g were each given a single 
dose of 175 mg/kg of clindamycin-phosphate or of clindamycin-hydrochloride 
intraperitoneally, to induce colitis. Approximately seven hours after 
injection, the animals were given the test compound orally or 
intraperitoneally and the therapy was continued twice a day for a period 
of four more days. For oral administration, the antibiotic was suspended 
in water or dissolved in dimethylsulfoxide and delivered to the animals by 
gavage using an oral intubating needle. The effect of the therapy was 
measured by use of the Hazard Ratio, which is the ratio of the mortality 
of the animals treated with the test inhibitor compound contained in a 
vehicle to the mortality of the animals treated with the vehicle 
containing none of the test inhibitor compound. The mortality was 
determined for the test inhibitor compound-treated groups and for the 
vehicle-treated groups, respectively, twice daily, and was evaluated 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 test 
inhibitor compound-treated (therapy) group to that of the corresponding 
vehicle control group. A Hazard Ratio of 1.0 indicates that the therapy 
has no better effect compared with the vehicle alone, while a Hazard Ratio 
greater than 1.0 (&gt;1.0) indicates that the therapy prolongs survival in 
comparison with the group treated with the vehicle alone. (See, J. G. 
Bartlett et al. Amer. J. Vet. Res. 39: 1525-1530 (1978)). 
Data for representative compounds of this invention are reported in Table 
II. 
TABLE II 
__________________________________________________________________________ 
Rat Acetic Acid 
Colitis Model 
% Inhib. 
Hamster 
of Myelo- 
Colitis Model 
Dose peroxidase 
Dose Hazard 
Name (mg/kg p.o) 
Accumulation 
(mg/kg p.o) 
Ratio 
__________________________________________________________________________ 
4-[4-(2,3-dihydroxyphenyl)butoxy]- 
10 73 .+-. 10 
10 1.35 
2-hydroxy-3-propylbenzoic acid 
30 71 .+-. 11 
100 0.1 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]- 
10 42 .+-. 2 
10 2.26** 
2-hydroxy-3-propylbenzoic acid 
30 67 .+-. 15 
100 4.22** 
4-[8-(2,3-dihydroxyphenyl)octyloxy]- 
10 35 .+-. 7 
2-hydroxy-3-propylbenzoic acid 
100 27 .+-. 3 
4-[6-[2,3-dihydroxy-4-(1-methylethyl) 
10 53 .+-. 12 
phenyl]hexyloxy]-2-hydroxy-3-propyl 
100 86 .+-. 9 
benzoic acid 
1-[2-hydroxy-4-[4-(2,3-dihydroxyphenyl) 
10 46 .+-. 7 
butoxy]-3-propylphenyl]ethanone 
30 89 .+-. 11 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]- 
1 82 .+-. 9 
2-hydroxybenzoic acid 
3 81 .+-. 15 
4-[6 (2,3 dihydroxyphenyl)hexyloxy] 
3 79 .+-. 8 
benzoic acid 10 89 .+-. 28 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]- 
1 40 .+-. 9 
2-hydroxy-3 propylbenzoic acid 
3 67 .+-. 11 
ethyl ester 
4-[6-(3,4-dihydroxy-2,5-dimethyl- 
3 37 .+-. 6 
phenyl)hexyloxy]-2-hydroxy-3- 
10 85 .+-. 13 
propylbenzoic acid 
4-[3-(2,3-Dihydroxyphenyl)propoxy]- 
10 54 .+-. 5 
2-hydroxy-3-propylbenzoic acid 
4-[5 (2,3 Dihydroxyphenyl)pentyloxy] 
1 96 .+-. 13 
2-hydroxy 3 propylbenzoic acid 
5 Chloro 4 [6 (2,3 dihydroxyphenyl) 
30 44 .+-. 6 
hexyloxy] 2-hydroxy-3-propylbenzoic 
acid 
4 [3-(3,4 Dihydroxyphenyl)propoxy] 
30 39 .+-. 5 
2 hydroxy 3 propylbenzoic acid 
4 [2 (3,4 Dihydroxyphenyl)ethoxy]- 
10 56 .+-. 6 
2 hydroxy 3 propylbenzoic acid 
4-[[6-(2 Fluoro 4,5 dihydroxyphenyl) 
10 40 .+-. 5 
6 oxohexyl]oxy 2 hydroxy 3 propyl 
benzoic acid 
1-[4-[6-(2,3-Dihydroxyphenyl)hexyloxy] 
10 51 .+-. 5 
1-[4-[6-(2,3-Dihydroxy-4-(1-methylethyl) 
10 65 .+-. 10 
phenyl]hexyloxy-2-hydroxy-3-propylphenyl] 
ethanone 
1-[4-[5-(3,4-Dihydroxyphenyl)pentyloxy]- 
10 52 .+-. 6 
2-hydroxy-3-propyl]ethanone 
4-[5-(2-Chloro-5,6-dihydroxyphenyl)penty- 
3 54 .+-. 9 
loxy]-2-hydroxy-3-propylbenzoic acid 
4-[5-(2,3-Dichloro-5,6-dihydroxyphenyl) 
1 73 .+-. 5 
pentyloxy]-2-hydroxy-3-propylbenzoic acid 
4 [5-(2,3,4 Trichloro-5,6-dihydroxy- 
1 115 .+-. 21 
phenyl)pentyloxy] 2 hydroxy-3 propyl- 
benzoic acid 
3-Amino-4-[6-(2,3-dihydroxyphenyl) 
1 55 .+-. 7 
hexyloxy]benzoic acid 
__________________________________________________________________________ 
**p &lt; 0.01 
In Vitro, Testing of Antiperoxidative Agents 
The test system employs hypoxanthine-xanthine oxidase (XO)-Fe.sup.3+. ADP 
as the free radical generator and purified, native rat-heart membrane 
phosphoglyceride in Hepes-KCl buffer, pH 7.4, as the substrate. Inhibition 
of superoxide-dependent, iron-promoted lipid peroxidation in the linear 
reaction phase (after 1 hour of reaction) is measured as the net formation 
of thiobarbituric acid (TBA)-reactive material. In this system, the 
TBA-reactive material, isolated by HPLC, is exclusively (&gt;95%) 
malondialdehyde (MDA), a fragmentation end-product arising from fatty acyl 
hydroperoxides and cyclic endoperoxides. 
(a) Isolation and Purification of Rat Cardiac Lipid 
Conscious male Sprague-Dawley rats (.about.275 g) maintained on a normal 
rodent diet were decapitated. The hearts were rapidly removed and perfused 
via the aorta with ice-cold 10 mM Hepes buffer, pH 7.4. The aorta and 
atria were removed, and the ventricular tissue was blotted 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 (3.times.5 
seconds) with a Tekmar Tissumizer at "maximal" setting. The homogenate was 
filtered through 4-ply cheesecloth, and homogenate lipids were extracted 
and purified by a modified Bligh-Dyer procedure (M. D. Marshall and M. 
Kates, Biochem. Biophys. Acta 260, 558 (1972). The cardiac lipids were 
stored in CHCl.sub.3 under nitrogen at -20.degree. C. 
(b) Preparation of Cardiac Liposomes 
Liposomes were prepared from extracted and purified, native rat heart 
cardiac lipid and were used as substrate for free-radical attack. Cardiac 
lipid (in CHCl.sub.3) was placed in a glass flask and evaporated to 
dryness under nitrogen at room temperature; the flask was gently rotated 
during evaporation to yield a thin, dry lipid film. The lipid was taken up 
in 10 mM Hepes-0.145M CKl, pH 7.4, and was resuspended by indirect 
anaerobic sonication for 15 minutes at room temperature. The liposome 
suspension was used immediately. 
(c) Preparation of Fe.sup.3+ -ADP chelate 
A chelate was formed in Hepes-KCl buffer between Fe.sup.3+ (1.0 mM 
FeCl.sub.3, final concentration) and ADP (10 mM, final concentration) at 
pH 7.4 with stirring at room temperature. Chelation was allowed to proceed 
for 90 minutes prior to use. The chelate was prepared fresh for each days 
experiments to ensure iron solubility, effective chelation, and valence 
state. 
(d) Thiobarbituric Acid Reaction for Determination of Malondialdehyde 
Equivalents 
Malondialdehyde (MDA) equivalents were measured as thiobarbituric acid 
(TBA)-reactive material by the following modification of published 
methods. The reaction mixture, prepared fresh daily, contained water:BHT 
(7.1M BHT in absolute ethanol):TBA (1.5% TBA in 0.2M Tris, pH 7.0) in the 
volume ratio 1:1:5. To each 1.0 ml of peroxidation reaction assayed (see 
below), 0.35 ml reaction mixture was added. After thorough mixing, the 
tubes were incubated in an 80.degree. C. shaking water bath for 30 
minutes. After this time, the tubes were plunged into an ice water bath, 
and the reaction was immediately stopped with 0.5 ml ice-cold 91% TCA 
followed by 2.0 ml CHCl.sub.3. After centrifugation for 30 minutes at 2000 
rpm in a Sorval HL-8 rotor (4.degree. C.), the absorbance of the washed, 
pink upper phase was read at 532 nm. A standard curve (0.8-40.0 nmol MDA) 
was run with every assay. For each curve, MDA was freshly prepared by 
acidification of 1,1,3,3-tetraethoxypropane with 75% TCA-2.3N HCl (0.15 
ml acid mixture with 1.0 ml suitably diluted tetraethoxypropane). 
Computer-assisted regression analysis of the standard curve was used to 
quantify the molar amounts of MDA equivalents in the experimental samples. 
(e) Lipid Peroxidation Reaction 
Cardiac liposomes were subjected to superoxide-dependent, iron-promoted 
peroxidation in glass vessels to avoid the well-known antioxidant effects 
of many common polymerizing agents used to fabricate plastic labware. 
Screening was performed in triplicate in glass 12.times.75 mm tubes at a 
final reaction volume of 1.0 ml and a reaction time of 60 minutes. Per 
milliliter of peroxidation reaction, the components were: Tris-KCl buffer 
(0.1 ml), cardiac liposomes (0.5 ml, equivalent to 125 .mu.g 
phospholipid), 1 mM HX (0.1 ml), 0.1 mM Fe.sup.3+ -1.0 mM ADP chelate (0.1 
ml), test substance (0.1 ml solubilized in Tris-KCl, ethanol, or DMSO) and 
10 mU XOD (0.1 ml). All components are listed at their final 
concentrations and were prepared at the time of assay. The peroxidation 
reaction was started with the addition of XOD and was carried out at 
37.degree. C. in a shaking water bath. Peroxidation was terminated by 
adding 0.15 ml ice-cold 76% TCA-2.3N HCl for each 1.0 ml of peroxidation 
reaction to be assayed for MDA equivalents (above). To check for possible 
interference by test substance, a second set of samples was run, but in 
these the peroxidation reaction was stopped immediately with the TCA-HCl 
mixture. Test substances were screened at 1.0 .mu.M final concentration. 
If peroxidation were inhibited by .gtoreq.50%, an IC.sub.50 value was 
determined. 
For kinetic studies, peroxidation was carried out in glass Erlenmeyer 
flasks. At each desired time, 1.0 ml samples, in triplicate, were 
withdrawn into iced tubes containing 0.15 ml 76% TCA-2.3N HCl and were 
then reacted with TBA (above). 
(f) Calculation of the Effect of a Test Substance on Lipid Peroxidation 
The effect of a test substance on cardiac lipid peroxidation during the 60 
minute screening assay was taken as the ratio between the end MDA 
equivalents produced in the presence of the drug and the net MDA 
equivalents produced in its absence. The percent inhibition of lipid 
peroxidation was calculated by: 
##EQU2## 
Drug.sub.60' =MDA equivalents produced after 60 minutes with the free 
radical generator+test substance. 
Drug.sub.0' =MDA equivalents produced after 0 minutes with the free radical 
generator+test substance 
T.sub.60' =Total MDA equivalents produced without test substance at 60 
minutes. 
T.sub.0' =Endogenous TBA reactivity of reaction mixture at 0 minutes. 
Data for the compounds of this invention in this test is reported in Table 
III. 
In Vivo Testing of Antiperoxidative Agents 
In this preparation a free radical generating (FRG) system consisting of 
purine (2.3 mM), xanthine oxidase (0.02 U/ml) and iron loaded transferring 
(0.6 .mu.M) complex is infused into the carotid artery near the ostium of 
the coronary artery in spontaneously hypertensive rats. Blood is withdrawn 
before and 24 hours after the FRG challenge for measuring the isoenzymes 
of lactic acid dehydrogenase (LDH.sub.1 :LDH.sub.2). An increase in 
LDH.sub.1 :LDH.sub.2 ratio reflects cell damage to the myocardium. The 
electrocardiogram is also taken before and 24 hours after the FRG 
infusion. At the end of the experiment the heart is removed, sliced in a 
breadloaf fashion, and stained with triphenyltetrazolium chloride to 
determine infarct size. A drug or vehicle is administered intravenously 
10-30 minutes before the FRG challenge. A drug is considered active if 
there is no elevation of the LDH.sub.1 :LDH.sub.2 ratio, no ECG 
abnormalities and no histologic evidence of an infarction. 
Rat In Vivo Model of Myocardial Ischemia 
Male spontaneously hypertensive rats (280-320 g) from Taconic Farms, were 
lightly anesthetized with sodium pentobarbital (30-50 mg/kg, i.p.). Rats 
exhibiting abnormal patterns prior to surgery were eliminated from the 
study. A catheter of PE 50 tubing was inserted into the right common 
carotid artery to a position proximal to the ostia of the coronary 
arteries and used to sample blood and infuse the free radical generator 
(FRG) system. A second catheter of PE 10 tubing was inserted into the left 
jugular vein to administer drugs. The infusion system for the FRG 
consisted of a double syringe infusion pump, Sage Model 351, with one 
syringe containing xanthine oxidase (0.01 units/ml) in a HEPES (0.05M) 
buffer and the other syringe containing purine (2.3 mM) plus Fe.sup.3+ 
loaded transferring (0.06 .mu.M) in a HEPES (0.05M) buffer. The FRG 
infused separately mixes simultaneously near the ostia of the coronary 
arteries. This infusion was delivered at a rate of 0.03 ml/minute for a 
total infusion time of 10 minutes. The drugs were infused over a one 
minute period in a 0.9% saline vehicle. 
Standard Lead II ECG was monitored continuously on a Hewlett-Packard 7758A 
recorder prior to treatment, throughout the FRG infusion and 10 minutes 
post infusion. Catheters were removed and animals were allowed to recover 
and fed standard rat chow and water ad libitum. 24 hours following the FRG 
infusion, animals were reanesthetized with sodium pentobarbital (30-50 
mg/kg, i.p.) and an ECG was obtained. Blood samples were taken prior to 
and after the FRG infusion and at the conclusion of the experiment. These 
samples were centrifuged and assayed for total lactate dehydrogenase (LDH) 
and lactate dehydrogenase isoenzymes (LDH.sub.1 :LDH.sub.2), using 
electrophoresis. 
The animals were sacrificed, the hearts rapidly excised, and washed free of 
blood and sectioned. The left ventricle was weighed and stored in a 
Revco.RTM. freezer at -70.degree. C. The left ventricle was sliced into 2 
mm-thick rings, incubated in a 1% triphenyltetrazolium chloride solution 
for 20 minutes, and then fixed in a 10% formalin solution. Infarcted areas 
were measured and quantitated as a percentage of the total left 
ventricular volume. 
Data for the compounds of this invention in this test is reported in Table 
III. 
TABLE III 
__________________________________________________________________________ 
Rat Ischemia Model 
Inhib. of Lipid 
10 mg/kg iv 
Peroxidation 
Infarcts/ 
Name IC.sub.50 (.mu.M) 
Total % Infarction* 
__________________________________________________________________________ 
4-[4-(2,3-dihydroxyphenyl)butoxy]- 
0.5 2/5 8 
2-hydroxy-3-propylbenzoic acid 
4-[5-(2,3-dihydroxyphenyl)pentyloxy]- 
0.4 4/5 15 
2-hydroxy-3-propylbenzoic acid 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]- 
0.3 4/5 8 
2-hydroxy-3-propylbenzoic acid 
4-[7-(2,3-dihydroxyphenyl)heptyloxy]- 
0.5 3/5 18 
2-hydroxy-3-propylbenzoic acid 
4-[8-(2,3-dihydroxyphenyl)octyloxy]- 
0.3 1/5 8 
2-hydroxy-3-propylbenzoic acid 
4-[10-(2,3-dihydroxyphenyl)decyloxy]- 
0.4 3/3 13 
2-hydroxy-3-propylbenzoic acid 
4-[6-[2,3-dihydroxy-4-(1 methylethyl) 
0.7 1/5 5 
phenyl]hexyloxy]-2-hydroxy-3-propyl 
benzoic acid 
4-[6-(2,3-dihydroxyphenyl)hexyloxy] 
&gt;1 2/5 19 
benzoic acid 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]- 
&gt;1 3/5 10 
2-hydroxy benzoic acid 
4-[6-(3,4-dihydroxyphenyl)hexyloxy] 
0.6 1/5 11 
2-hydroxy-3 propylbenzoic acid 
(5 mg/kg iv) 
1-[2-hydroxy-4-[6-(2,3-dihydroxy 
0.7 4/4 24 
phenyl)hexyloxy]-3-propylphenyl] 
ethanone 
1 [2-hydroxy-4 [4-(2,3-dihydroxy- 
&gt;1 1/5 12 
phenyl)butoxy] 3 propylphenyl] 
ethanone 
1 [2 hydroxy 4 [6 [2,3-dihydroxy 
0.7 2/5 11 
4 (1 methylethyl)phenyl]hexyloxy] 
3 propylphenyl]ethanone 
__________________________________________________________________________ 
*Percent of left ventricle infarcted of the animals with an infarct. 
A compound of formula I or a salt thereof or a composition containing a 
therapeutically effective amount of a compound of formula I or a salt 
thereof can be administered by methods well known in the art. Thus, a 
compound of formula I or a salt thereof can be administered either singly 
or with other pharmaceutical agents, orally, parenterally, rectally, or by 
inhalation, for example, in the form of an aerosol, micropulverized powder 
or nebulized solution. For oral administration the described compound can 
be administered in the form of tablets, capsules, for example, in 
admixture with talc, starch, milk sugar or other inert ingredients, that 
is, pharmaceutically acceptable carriers, in the form of aqueous 
solutions, suspensions, elixirs or aqueous alcoholic solutions, for 
example, in admixture with sugar or other sweetening agents, flavoring 
agents, colorants, thickeners and other conventional pharmaceutical 
excipients, or beadlets for oral administration. For parenteral 
administration, the desired compound can be administered in solutions or 
suspension, for example, as an aqueous or peanut oil solution or 
suspension using excipients and carriers conventional for this mode of 
administration. For administration as aerosols, they can 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 compositions are packaged for use in a 
pressurized container fitted with an aerosol valve suitable for release of 
the pressurized composition. Preferably, the aerosol valve is a metered 
valve, that is one which on activation releases a predetermined effective 
dose of the areosol composition. For rectal administration, the desired 
compound can be administered in the form of suppositories utilizing an 
inert carrier material cocoa butter and the like. For topical 
administration, the compounds of formula I can be incorporated into 
ointments, creams, lotions, gels, and the like. In general, the solutions, 
ointments and creams which are useful in accordance with this invention 
include formulations having absorbable, water soluble or emulsion-type 
bases, such as petrolatum, lanolin, polyethylene glycols, or the like. 
Suitable solutions will contain the compounds of formula I dissolved in a 
pharmaceutically acceptable solvent, such as polyethylene glycol, or the 
like. 
Suitable lotions include, true solutions to aqueous or hydroalcoholic 
formulations containing finely divided particles. Lotions can contain 
suspending or dispersing agents such as cellulose derivatives, for 
example, methyl cellulose, ethyl cellulose, or the like. Gells will 
typically be semi-solid preparations made by gelling a solution or 
suspension of a compound of formula I in a suitable hydrous or anhydrous 
vehicle, using a gelling agent such as a carboxy polymethylene, or the 
like, and thereafter neutralizing it to proper consistency with an alkali 
metal hydroxide, for example, sodium hydroxide, and an amine, for example, 
polyethylenecocoamine. Topical pharmaceutical compositions containing a 
compound of formula I can also be formulated to include conventional 
ingredients such as preservatives, stabilizers, wetting agents, 
emulsifying agents, buffers, and the like, in conventional amounts 
adjusted for particular requirements and which are readily determinable by 
those skilled in the art. 
In the practice of the invention, the dose of a compound of formula I or a 
salt thereof to be administered and the frequency of administration will 
be dependent on the potency and duration of activity of the particular 
compound of formula I or salt to be administered and on the route of 
administration, as well as the severity of the condition, age of the 
mammal to be treated and the like. Oral doses of a compound of formula I 
or a salt thereof contemplated for use in practicing the invention are in 
the range of from about 25 to about 1000 mg per day, preferably about 25 
to about 250 mg either as a single dose or in divided doses.

The Examples which follow further illustrate the invention. All 
temperatures set forth in the specification and the Examples are in 
degrees Centigrade. Melting points were taken on a Thomas Hoover capillary 
melting point apparatus and are uncorrected. All compounds were 
characterized by proton magnetic resonance spectra taken on a Varian 
XL-100 or SL-200 spectrometer and mass spectra taken on a CEC 21-110 mass 
spectrometer at 70 eV. Preparative high-pressure liquid chromatography 
(HPLC) was performed on silica gel Prep-Pak 500 cartridges using a Waters 
Associates Prep LC 500A. Extracts were dried over anhydrous magnesium 
sulfate unless otherwise noted. 
EXAMPLE 1 
1-(6-Bromohexyl)-2,3-dimethoxybenzene 
A solution of 1.55M butyl lithium in hexane (195 mL, 0.3 mol) was added 
dropwise over 30 minutes to a stirred solution of 1,2-dimethoxybenzene 
(41.4 g, 0.3 mol) in 700 mL of anhydrous tetrahydrofuran at room 
temperature under argon. The reaction mixture was stirred and heated at 
40.degree. for 4 hours and then cooled to -70.degree.. 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.degree. 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 
yield an oil. Distillation gave 1-(6-bromohexyl)-2,3-dimethoxybenzene as a 
yellow oil (29 g, 32% yield, b.p. 125.degree.-140.degree./0.15 mm). 
This procedure is known and described for 
1-(7-bromoheptyl)-2,3-dimethoxybenzene in the following reference: H. 
Halim, H. D. Locksley and J. J. Memon, J. Chem. Soc. Perkin I, 2331 
(1980). It was used for the preparation of all of the bromo intermediates 
wherein n=3-10. 
EXAMPLE 2 
1-(6-Iodohexyl)-2,3-bis-(phenylmethoxy)benzene 
Boron tribromide (266 mL, 0.266 mol, 1M in methylene chloride) was added 
dropwise over 1 hour to a cooled (-65.degree.) solution of 40.0 g (0.133 
mol) of 1-(6-bromohexyl)-2,3-dimethoxybenzene in 800 mL of anhydrous 
methylene chloride which was stirred in an argon atmosphere. 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 3N HCl were 
added and the mixture was stirred for 2 hours. The organic layer was 
separated, dried and concentrated under reduced pressure to an oil which 
was purified by HPLC using 5% methanol-chloroform to yield 34.7 g of 
1-(6-bromohexyl)-2,3-dihydroxybenzene as an oil. To this was 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 at 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. 
The nmr spectrum was consistent with the structure (CH.sub.2 I at 
.delta.3.14) and the mass spectrum showed the molecular ion at m/e 500 
(C.sub.26 H.sub.29 IO.sub.2). 
EXAMPLE 3 
1-[(2-Methanesulfonyloxy)ethyl]-2,3-dimethoxybenzene 
To 20 g (0.145 mol) of 1,2-dimethoxybenzene in 300 mL of anhydrous 
tetrahydrofuran stirred at room temperature under argon was added 90 mL 
(0.145 mol) of 1.6M butyl lithium in hexane over 30 minutes. The reaction 
mixture was stirred and heated at 40.degree. 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 
was stirred with ice bath cooling 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 (7.5 g) was removed by 
distillation (bp 45.degree.-60.degree./0.2 mm) and the residue was 
purified by HPLC using 20% ethylacetate-toluene to give 5 g (19% yield) of 
1-(2-hydroxyethyl)-2,3-dimethoxybenzene. This intermediate (5 g, 0.028 
mol) was dissolved in 100 mL of anhydrous methylene chloride and the 
solution was cooled in an ice bath. Triethylamine (7.7 mL, 0.056 mol) was 
added and followed by 2.6 mL (0.033 mol) of methane sulfonyl chloride 
added dropwise. The reaction mixture was stirred with ice bath cooling for 
two hours and then was washed with water, with sodium bicarbonate 
solution, dried and concentrated under reduced pressure to give (7.2 g) of 
1-[(2-methanesulfonyloxy)ethyl]-2,3-dimethoxybenzene as an oil which was 
used without purification. 
EXAMPLE 4 
1-(6-Bromohexyl)-2,3-bis[(4-methylbenzoyl)oxy]benzene 
To 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 stirred 
in an ice bath was added 10.9 mL (0.082 mol) of 4-methylbenzoyl chloride 
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 
1-(6-Bromohexyl)-2,3-bis(acetyloxy)benzene 
To 1.0 g (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 was 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 
1-[(2-Methanesulfonyloxy)ethyl]-2,3-dimethoxybenzene 
To 3.3 g (0.018 mol) of 3,4-dimethoxyphenethyl alcohol in 50 mL of 
methylene chloride and 4.2 mL (0.03 mol) of triethylamine 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-[(2-methanesulfonyloxy)ethyl]-2,3-dimethoxybenzene as 
an oil. 
EXAMPLE 7 
1-(6-Bromo-1-oxohexyl)-3,4-dimethoxybenzene 
A mixture of 1.0 mL (7.8 mmol) of 1,2-dimethoxybenzene and 2.0 g (10 mmol) 
of 6-bromohexanoic acid was warmed briefly until homogeneous and stirred 
while 1.7 mL (11.7 mmol) of trifluoroacetic anhydride was added. The 
reaction mixture was stirred at room temperature for 17 hours and then was 
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 on 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. The nmr spectrum was 
consistent with the structure. 
EXAMPLE 8 
4-(3,4-Dimethoxyphenyl)-3-butyn-1-ol 
A mixture of 10 g (46 mmol) of 1-bromo-3,4-dimethoxybenzene, 3.4 g (48 
mmol) of 3-butyn-1-ol and 8 mL (58 mmol) of triethylamine in 20 mL of 
methylene chloride was stirred and flushed with argon. To the mixture 
there was added 0.12 g (0.06 mmol) of cuprous 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 at 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-toluene to give 3.0 g (32% yield) of 
4-(3,4-dimethoxyphenyl)-3-butyn-1-ol. 
EXAMPLE 9 
4-(3,4-Dimethoxyphenyl)butan-1-ol 
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 in 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 
4-(2,3-Dimethoxyphenyl)butan-1-ol 
To 0.8 g (0.12 g-atoms) of lithium ribbon cut in small pieces in 50 mL of 
anhydrous ether stirred at room temperature under an argon atmosphere was 
added 12 g (0.06 mol) of 3-bromo-propan-1-ol 1-ethoxy ethyl ether [P. E. 
Eaton, G. F. Cooper, R. C. Johnston, and R. H. Mueller, J. Org. Chem. 37, 
1947 (1972)]. After about 1 mL was added, the reaction mixture was cooled 
in an ice-salt bath and the rest of the bromo 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 was 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.sub.2 SO.sub.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 under 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% ethylacetate-hexane gave 7.45 g (79% yield) of 
4-(2,3-dimethoxyphenyl)butan-1-ol. 
This procedure has been reported in the literature to prepare 
7-(2,3-dimethoxyphenyl)heptan-1-ol. J. H. P. Tyman and C. H. Khor, Chem. 
Ind. (1974), 526. 
EXAMPLE 11 
2-Hydroxy-4-(2-propenyloxy)benzoic acid methyl ester 
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. The reaction mixture was filtered and the solid was washed with 
acetone. After removal of the acetone from the filtrate under reduced 
pressure, the residue was distilled to give 85 g (67% yield), bp 
106.degree.-108.degree./0.3 mm of 2-hydroxy-4-(2-propenyloxy)benzoic acid 
methyl ester. 
EXAMPLE 12 
2,4-Dihydroxy-3-(2-propenyl)benzoic acid methyl ester 
81 g of 2-hydroxy-4-(2-propenyloxy)benzoic acid methyl ester was heated in 
an oil bath under argon until the internal temperature reached 
180.degree.-185.degree.. The temperature was maintained in this range for 
1.5 hours and then raised to 210.degree. for 1.5 hours. After cooling, the 
oil crystallized and was recrystallized from ether-petroleum ether to give 
37 g (46% yield), mp 65.degree.-66.degree. of 
2,4-dihydroxy-3-(2-propenyl)benzoic acid methyl ester. Anal. Calcd for 
C.sub.11 H.sub.12 O.sub.4 : C, 63.46; H, 5.81; C, 63.65; H, 6.09. 
EXAMPLE 13 
2,4-Dihydroxy-3-propylbenzoic acid methyl ester 
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 in a 
hydrogen atmosphere 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 stirring with 
hexane, the product was filtered to give 51 g, mp 66.degree.-68.degree., 
of 2,4-dihydroxy-3-propylbenzoic acid methyl ester. 
Anal. Calcd for C.sub.11 H.sub.14 O.sub.4 : C, 62.85; H, 6.71. Found: C, 
62.95; H, 6.74. 
EXAMPLE 14 
2,4-Dihydroxy-3-propylbenzoic acid phenylmethyl ester 
A solution of 37 g (0.18 mol) of 2,4-dihydroxy-3-propylbenzoic acid methyl 
ester in 750 mL of methanol and 415 mL of 3N sodium hydroxide was stirred 
at 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 a tan solid which was 
used without purification. 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 at 60.degree. 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), mp 86.degree.-88.degree. of 
2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester. 
EXAMPLE 15 
5-Chloro-2,4-dihydroxy-3-propylbenzoic acid methyl ester 
A solution of 2.1 g (0.01 mol) of 2,4-dihydroxy-3-propylbenzoic acid methyl 
ester and 1.6 g (0.012 mol) of N-chlorosuccinimide in 50 mL of carbon 
tetrachloride was stirred at reflux for 9.5 hours. Additional 
N-chlorosuccinimide (1.6 g) was added and reflux was continued for 17 
hours. 0.8 g of N-chlorosuccinimide was added and reflux 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-3-propylbenzoic acid methyl ester. 
Recrystallization from hexane gave analytically pure material, mp 
75.degree.-76.degree.. 
Anal. Calcd for C.sub.11 H.sub.13 ClO.sub.4 : C, 54.00; H, 5.35; Cl, 14.49. 
Found: 54.26; H, 5.32; Cl, 14.20. 
EXAMPLE 16 
4-[6-(2,3-Dimethoxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid methyl 
ester 
A mixture of 29.2 g (0.097 mol) of 1-(6-bromohexyl)-2,3-dimethoxybenzene, 
18.5 g (0.088 mol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester, 
18.2 g (0.13 mol) of anhydrous potassium carbonate and 21.9 g (0.13 mol) 
of potassium iodide in 550 mL of anhydrous acetone was stirred at 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)hexyloxy]-2-hydroxy-3-propylbenzoic acid methyl 
ester as an oil. 
Anal. Calcd for C.sub.25 H.sub.34 O.sub.6 : C, 69.74; H, 7.96, Found: C, 
69.72; H, 7.81. 
Compounds of Examples 17-23 which follow were prepared in accordance with 
the procedure of Example 16. 
__________________________________________________________________________ 
##STR34## 
% EtoAc-Hexane Microanalysis 
Ex. used in HPLC, 
Yield Calcd Found 
No. 
R.sub.6 
R n mp (.degree.C.) 
% Formula 
C H C H 
__________________________________________________________________________ 
17 H CH.sub.3 
2 5, 77-80 
19 C.sub.21 H.sub.26 O.sub.6 
67.36 
7.00 
67.24 
7.15 
18 H CH.sub.3 
3 10, 51-53 
74 C.sub.22 H.sub.28 O.sub.6 
68.02 
7.27 
68.26 
7.54 
19 H CH.sub.3 
4 10, oil 88 C.sub.23 H.sub.30 O.sub.6 
68.64 
7.51 
68.50 
7.55 
20 H Benzyl 
7 8, oil 93 C.sub.32 H.sub.40 O.sub.6 
73.82 
7.74 
74.04 
7.66 
21 H CH.sub.3 
8 10, oil 96 C.sub.27 H.sub.38 O.sub.6 
70.72 
8.35 
70.62 
8.42 
22 H Benzyl 
10 10, oil 89 C.sub.35 H.sub.46 O.sub.6 
74.70 
8.24 
74.46 
8.50 
23 CH(CH.sub.3).sub.2 
Benzyl 6 5, oil 95 C.sub.34 H.sub.44 O.sub.6 
not submitted 
__________________________________________________________________________ 
EXAMPLE 24 
4-[6-(2,3-Dimethoxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid 
A solution of 31.4 g (0.073 mol) of 
4-[6-(2,3-dimethoxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid methyl 
ester in 800 ml of methanol and 365 mL (0.0365 mol) of 1N sodium hydroxide 
was stirred at 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-hexane to give 
24.8 g (82% yield), mp 115.degree.-118.degree., of 
4-[6-(2,3-dimethoxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid. 
Anal. Calcd for C.sub.24 H.sub.32 O.sub.6 : C, 69.21; H, 7.74 Found: C, 
69.50; H, 7.69 
Compounds of Examples 25-30 were prepared by the procedure of Example 24. 
______________________________________ 
##STR35## 
Microanalysis 
Ex. Yield Calcd Found 
No. n mp (.degree.C.)* 
% Formula 
C H C H 
______________________________________ 
25 2 154-156 88 C.sub.20 H.sub.24 O.sub.6 
66.65 
6.71 66.83 
6.58 
26 3 133-134 92 C.sub.21 H.sub.26 O.sub.6 
67.36 
7.00 67.26 
6.98 
27 4 111-113 78 C.sub.22 H.sub.28 O.sub.6 
68.02 
7.27 67.87 
7.35 
28 7 98-100 91 C.sub.25 H.sub.34 O.sub.6 
69.74 
7.96 69.79 
8.05 
29 8 90-92 81 C.sub.26 H.sub.36 O.sub.6 
70.24 
8.16 70.03 
7.92 
30 10 77-78 90 C.sub.28 H.sub.40 O.sub.6 
71.16 
8.53 71.14 
8.52 
______________________________________ 
*All compounds were recrystallized from ether hexane 
EXAMPLE 31 
2-Hydroxy-4-[6-[2,3-dimethoxy-4-(1-methylethyl)phenyl]hexyloxy]-3-propylben 
zoic acid 
A solution of 6.96 g of 
2-hydroxy-4-[6-[2,3-dimethoxy-4-(1-methylethyl)phenyl]hexyloxy]-3-propylbe 
nzoic acid phenylmethyl ester in 150 mL of ethyl acetate and 1.4 g of 10% 
palladium on carbon was stirred in a hydrogen atmosphere for 3 hours. The 
reaction mixture was filtered through a Celite pad and the filtrate was 
concentrated under reduced pressure to 5.45 g, mp 106.degree.-108.degree., 
of 
2-hydroxy-4-[6-[2,3-dimethoxy-4-(1-methylethyl)phenyl]hexyloxy]-3-propylbe 
nzoic acid. 
Anal. Calcd for C.sub.27 H.sub.38 O.sub.6 ; C, 70.72; H, 8.35. Found: C, 
70.74; H, 8.27. 
EXAMPLE 32 
4-[6-(2,3-Dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid 
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 and cooled at 
-70.degree. was added 36 mL (0.036 mol) of 1M boron tribromide in 
methylene chloride dropwise over 30 minutes. The reaction mixture was 
stirred at -70.degree. for 30 minutes and then kept at -18.degree. 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), mp 147.degree.-150.degree., of 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid. 
Anal. Calcd for C.sub.22 H.sub.28 O.sub.6 : C, 68.02; H, 7.27. Found: C, 
67.82; H, 7.33. 
The compounds of Examples 33-39 were prepared by the procedure of Example 
32. 
__________________________________________________________________________ 
##STR36## 
Microanalysis 
Ex. Yield Calcd Found 
No. 
R.sub.6 
n mp (.degree.C.)* 
% Formula 
C H C H 
__________________________________________________________________________ 
33 H 2 184-189 
67 C.sub.18 H.sub.20 O.sub.6 
65.05 
6.07 
64.70 
6.03 
34 H 3 189-191 
86 C.sub.19 H.sub.22 O.sub.6 
65.88 
6.40 
65.75 
6.46 
35 H 4 160-162 
87 C.sub.20 H.sub.24 O.sub.6 
66.65 
6.71 
66.49 
6.67 
36 H 7 144-146 
81 C.sub.23 H.sub.30 O.sub.6 
68.64 
7.51 
68.53 
7.65 
37 H 8 136-139 
81 C.sub.24 H.sub.32 O.sub.6 
69.21 
7.74 
69.11 
7.93 
38 H 10 126-128 
75 C.sub.26 H.sub.36 O.sub.6 
70.24 
8.16 
70.05 
8.17 
39 CH(CH.sub.3).sub.2 
6 104-105 
68 C.sub.25 H.sub.34 O.sub.6 
69.74 
7.96 
69.85 
8.21 
__________________________________________________________________________ 
*All compounds were recrystallized from ether hexane 
EXAMPLE 40 
4-[5-(2,3-Dihydroxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoic acid 
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 mol) 
of anhydrous potassium carbonate and 3.10 g (0.0188 mol) of potassium 
iodide in 150 mL of anhydrous acetone was stirred at 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 the phenylmethyl ester of 
2-hydroxy-4-[5-[2,3-bis(phenylmethoxy)pentyloxy]-3-propylbenzoic acid as 
an oil which solidified, mp 65.degree.-69.degree.. 
Anal. Calcd for C.sub.42 H.sub.44 O.sub.6 : C, 78.23; H, 6.88. Found: C, 
78.04; H, 6.80. 
A solution of 7.2 g of 2-hydroxy-4-[5-[2,3-bis 
(phenylmethoxy)pentyloxy]-3-propylbenzoic acid phenylmethyl ester in 500 
mL of tetrahydrofuran and 1.4 g of 10% palladium on carbon was stirred in 
a hydrogen atmosphere for 25 hours. The reaction mixture was filtered 
through a Celite pad and the filtrate was concentrated under reduced 
pressure to a solid which was recrystallized from ether-hexane to give 3.8 
g (90% yield), mp 155.degree.-157.degree., of 
4-[5-(2,3-dihydroxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoic acid. 
Anal. Calcd for C.sub.21 H.sub.26 O.sub.6 : C, 67.36; H, 7.00. Found: C, 
67.14; H, 7.16 
EXAMPLE 41 
4-[6(2,3-Dimethoxyphenyl)hexyloxy]-3-propylbenzoic acid ethyl ester 
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 was stirred at reflux for 47 hours. Workup 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. The mass spectrum showed the molecular ion at m/e 428. 
EXAMPLE 42 
4-[6-(2,3-Dimethoxyphenyl)hexyloxy]-3-propylbenzoic acid 
A solution of 2.0 g of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-3-propylbenzoic 
acid ethyl ester in 70 mL of methanol and 24 mL of 1N sodium hydroxide was 
stirred at reflux for 3 hours. Workup as in Example 24 gave 1.87 g, mp 
107.degree.-108.degree., of 
4-[6-(2,3-dimethoxyphenyl)hexyloxy]-3-propylbenzoic acid. 
Anal. Calcd for C.sub.24 H.sub.32 O.sub.5 : C, 71.97; H, 8.05. Found C, 
71.75; H, 8.05 
EXAMPLE 43 
4-[6-(2,3-Dihydroxyphenyl)hexyloxy]-3-propylbenzoic acid 
To 1.80 g of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-3-propylbenzoic acid in 
125 mL of methylene chloride cooled at -70.degree. was added 14 mL of 1M 
boron tribromide in methylene chloride. After 30 minutes at -70.degree. 
and 5 hours at -20.degree., the reaction was worked up as in Example 32 
and the product was recrystallized from ether-hexane to give 1.12 g, mp 
123.degree.-124.degree. of 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-3-propylbenzoic acid. 
Anal. Calcd for C.sub.22 H.sub.28 O.sub.5 : C, 70.94; H, 7.58. Found: C, 
70.99; H, 7.83 
EXAMPLE 44 
4-[6-(2,3-Dimethoxyphenyl)hexyloxy]-3,5-dipropylbenzoic acid ethyl ester 
A mixture of 1.20 (4.0 mmol) of 1-(6-bromohexyl)-2,3-dimethoxybenzene, 1.00 
g (4.0 mmol) of 3,5-dipropyl-4-hydroxybenzoic 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 was stirred at reflux for 47 hours. Workup and purification as 
in Example 16 gave 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-3,5-dipropylbenzoic 
acid ethyl ester as an oil. 
EXAMPLE 45 
4-[6-(2,3-Dimethoxyphenyl)hexyloxy]-3,5-dipropylbenzoic acid 
A solution of 1.8 g of 
4-[6-(2,3-dimethoxyphenyl)hexyloxy]-3,5-dipropylbenzoic acid ethyl ester 
in 100 mL of methanol and 20 mL of 1N sodium hydroxide was stirred at 
reflux for 3 hours. Workup as in Example 24 gave 
4-[6-(2,3-dimethoxyphenyl)hexyloxy]-3,5-dipropylbenzoic acid, mp 
61.degree.-65.degree.. 
Anal. Calcd for C.sub.27 H.sub.38 O.sub.5 : C, 73.27; H, 8.65. Found: C, 
73.30; H, 8.72. 
EXAMPLE 46 
4-[6-(2,3-Dihydroxyphenyl)hexyloxy]-3,5-dipropylbenzoic acid 
To 1.7 g of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-3,5-dipropylbenzoic acid in 
125 mL of methylene chloride cooled at -70.degree. was added 14 mL of 1M 
boron tribromide in methylene chloride. After 30 minutes at -70.degree. 
and 5 hours at -20.degree., the reaction was worked up as in Example 32 
and the product was recrystallized from ether-hexane to give 0.27 g, mp 
94.degree.-96.degree.; of 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-3,5-dipropylbenzoic acid. 
Anal. Calcd. for C.sub.25 H.sub.34 O.sub.5 : C, 72.44; H, 8.27. Found: C, 
72.70; H, 8.32 
EXAMPLE 47 
4-[6-(2,3-Dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid ethyl 
ester 
A mixture of 0.90 g (0.0023 mol) of 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid, 1.9 mL 
(0.023 mol) of ethyl iodide and 0.21 g of sodium bicarbonate in 10 mL of 
anhydrous dimethylformamide was stirred and heated at 50.degree. for 6 
hours. The solvent was removed on the 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 10% ethyl 
acetate-toluene gave 0.89 g of an oil which was stirred with hexane and 
filtered to give 0.71 g (70% yield), mp 54.degree.-57.degree.; of 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid ethyl 
ester. 
Anal. Calcd for C.sub.24 H.sub.32 O.sub.6 : C 69.21; H, 7.74. Found: C, 
68.85; H, 7.82. 
EXAMPLE 48 
4-[6-(2,3-Dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid 
[2-(diethylamino)ethyl]ester hydrochloride. 
A mixture of 1.0 g (2.57 mmol) of 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid, 3.5 g 
(25.7 mmol) of 2-diethylaminoethyl chloride and 0.24 g (2.83 mmol) of 
sodium bicarbonate in 20 mL of anhydrous dimethylformamide was stirred and 
heated at 50.degree. for 1.5 hours. The solvent was removed on the 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. 
Elution with CH.sub.2 Cl.sub.2 :95% MeOH:NH.sub.4 OH (95:5:0.05) gave 1.0 
g of the free base of 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid 
[2-(diethylamino)ethyl]ester. 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), mp 98.degree.-100.degree., of 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid 
[2-(diethylamino)ethyl]ester hydrochloride was obtained. 
Anal. Calcd for C.sub.28 H.sub.41 NO.sub.6 HCl: C, 64.17; H, 8.08; N, 2.67; 
Cl.sup.-, 6.76. Found: C, 64.35; H, 8.38; N, 2.51; Cl.sup.-, 6.55 
EXAMPLE 49 
2-Hydroxy-4-[6-[2,3-bis[(4-methylbenzoyl)oxy]phenyl]hexyloxy]-3-propylbenzo 
ic acid phenylmethyl ester 
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-propylbenzoic acid phenylmethyl ester, 0.94 g (5.63 mmol) 
of potassium iodide and 0.75 g (5.63 mol) of potassium carbonate in 40 mL 
of acetone was stirred at 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]phenyl]hexyloxy]-3-propylbenz 
oic acid phenylmethyl ester as an oil. 
Anal. Calcd for C.sub.45 H.sub.46 O.sub.8 : C, 75.61; H, 6.49. Found: C, 
75.63; H, 6.57 
EXAMPLE 50 
2-Hydroxy-4-[6-[2,3-bis[4-methylbenzoyl)oxy]phenyl]hexyloxy]-3-propylbenzoi 
c acid 
A solution of 0.78 g of 
2-hydroxy-4-[6-[2,3-bis[(4-methylbenzoyl)oxy]phenyl]hexyloxy]-3-propylbenz 
oic acid phenylmethyl ester in 65 mL of tetrahydrofuran and 0.16 g of 10% 
palladium on carbon was shaken in 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, mp 141.degree.-143.degree., 
of 
2-hydroxy-4-[6-[2,3-bis[4-methylbenzoyl)oxy]phenyl]hexyloxy]-3-propylbenzo 
ic acid. 
Anal. Calcd for C.sub.38 H.sub.40 O.sub.8 : C, 73.06; H, 6.45. Found: C, 
72.91, H, 6.56. 
EXAMPLE 51 
4-[6-[2,3-Bis(acetyloxy)phenyl]hexyloxy]-2-hydroxy-3-propylbenzoic acid 
phenylmethyl ester 
To a suspension of 0.14 g (3.5 mmol, 60% on oil) of sodium hydride in 10 mL 
of anhydrous dimethylformamide stirred at room temperature was added 0.88 
g (3.1 mmol) of 2,4-dihydroxy-3-propylbenzoic 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 
was added dropwise. Stirring at 50.degree. was continued for 16 hours and 
then the solvent was removed on the oil pump. The crude product was 
purified by HPLC using 25% ethyl acetate-hexane to give 0.55 g (28% yield) 
of 4-[6-[2,3-bis(acetyloxy)phenyl]hexyloxy]-2-hydroxy-3-propylbenzoic acid 
phenylmethyl ester as an oil. 
Anal. Calcd for C.sub.33 H.sub.38 O.sub.8 : C, 70.44; H, 6.81. Found: C, 
70.07; H, 6.83. 
EXAMPLE 52 
4-[6-[2,3-Bis(acetyloxy)phenyl]hexyloxy]-2-hydroxy-3-propylbenzoic acid 
A solution of 0.53 g of 
4-[6-[2,3-bis(acetyloxy)phenyl]hexyloxy]-2-hydroxy-3-propylbenzoic acid 
phenylmethyl ester in 50 mL of tetrahydrofuran and 0.10 g of 10% palladium 
on carbon was shaken in a hydrogen atmosphere for 3 hours. The reaction 
mixture was filtered through Celite and the filtrate was concentrated to a 
solid which was recrystallized from ether-hexane to give 0.35 g, mp 
120.degree.-122.degree., of 
4-[6-[2,3-bis(acetyloxy)phenyl]hexyloxy]-2-hydroxy-3-propylbenzoic acid. 
Anal. Calcd for C.sub.26 H.sub.32 O.sub.8 : C, 66.09; H, 6.83. Found: C, 
66.08; H, 6.87 
EXAMPLE 53 
2-Hydroxy-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylbenzoic acid 
phenylmethyl ester 
A mixture of 1.31 g (2.6 mmol) of 
1-(6-iodohexyl)-2,3-bis(phenylmethoxy)benzene, 0.74 g (2.6 mmol) of 
2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester and 0.54 g (3.9 
mmol) of potassium carbonate in 35 mL of acetone was stirred at 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 phenylmethyl ester as an oil. 
Anal. Calcd for C.sub.43 H.sub.46 O.sub.6 : C, 78.39; H, 7.04. Found: C, 
78.24; H, 7.06 
EXAMPLE 54 
2-Acetyloxy-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylbenzoic 
acid phenylmethyl ester 
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.degree. for 15 hours. The reaction mixture 
was concentrated on the 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 phenylmethyl ester as an oil. 
Anal. Calcd for C.sub.45 H.sub.48 O.sub.7 : C, 77.12; H, 6.90. Found: C, 
77.17; H, 7.18. 
EXAMPLE 55 
2-Acetyloxy-4-[6-(2,3-dihydroxyphenyl)hexyloxy]-3-propylbenzoic acid 
A solution of 1.02 g of 
2-acetyloxy-4-[6-[2,3-bis(phenylmethoxyphenyl]hexyloxy]-3-propylbenzoic 
acid phenylmethyl ester in 65 mL of tetrahydrofuran and 0.20 g of 10% 
palladium on carbon was stirred in hydrogen atmosphere 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 (82% yield), mp 130.degree.-132.degree., of 
2-acetyloxy-4-[6-(2,3-dihydroxyphenyl)hexyloxy]-3-propylbenzoic acid. 
Anal. Calcd for C.sub.24 H.sub.30 O.sub.7 : C, 66.96; H, 7.02. Found: C, 
67.27; H, 7.16 
EXAMPLE 56 
5-Chloro-2-hydroxy-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylben 
zoic acid methyl ester 
A mixture of 0.41 g (0.8 mmol) of 
1-(6-iodohexyl)-2,3-bis(phenylmethoxy)benzene, 0.18 g (0.74 mmol) of 
5-chloro-2,4-dihydroxypropylbenzoic acid methyl ester and 0.22 g (1.6 
mmol) of potassium carbonate in 15 mL of acetone was stirred at reflux for 
16 hours. The reaction mixture was filtered and the filtrate was 
concentrated to an oil. Chromatography on 30 g of silica gel and elution 
with 10% ethyl acetate-hexane gave 0.31 g (68% yield) of 
5-chloro-2-hydroxy-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylbe 
nzoic acid methyl ester as an oil. 
EXAMPLE 57 
5-Chloro-2-hydroxy-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylben 
zoic acid 
A solution of 0.30 g of 
5-chloro-2-hydroxy-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylbe 
nzoic acid methyl ester in 10 mL of methanol, 5 mL of dioxane and 2.5 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. The dried extract was concentrated and 
chromatographed on 30 g of silica gel using acetic acid:ethyl 
acetate:toluene (1:25:75) to give 0.21 g of 
5-chloro-2-hydroxy-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylbe 
nzoic acid as an oil. 
EXAMPLE 58 
5-Chloro-2-hydroxy-4-[6-(2,3-dihydroxyphenyl]hexyloxy]-3-propylbenzoic acid 
A solution of 0.21 g of 
5-chloro-2-hydroxy-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylbe 
nzoic acid in 30 mL of ethyl acetate and 0.073 g of 10% palladium on carbon 
was shaken under hydrogen pressure (30-40 p.s.i.) 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 and elution 
with acetic acid:ethyl acetate:toluene (5:20:75) gave 82 mg, mp 
110.degree.-113.degree., of 
5-chloro-2-hydroxy-4-[6-(2,3-dihydroxyphenyl]hexyloxy]-3-propylbenzoic 
acid. 
Anal. Calcd for C.sub.22 H.sub.27 ClO.sub.6 : C, 62.48; H, 6.44; Cl, 8.38. 
Found: C, 62.58; H, 6.75; Cl, 8.16. 
EXAMPLE 59 
4-[6-(2,3-Dimethoxyphenyl)hexyloxy]-2-hydroxybenzoic acid methyl ester 
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) of potassium carbonate and 0.75 g (4.5 mmol) of potassium iodide in 
25 mL of acetone was stirred at reflux for 20 hours. Workup as in Example 
16 gave 1.2 g of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-2-hydroxybenzoic acid 
methyl ester as an oil. 
EXAMPLE 60 
4-[6-(2,3-Dimethoxyphenyl)hexyloxy]-2-hydroxybenzoic acid 
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 refluxed for 7 
hours. Workup as in Example 24 and recrystallization from methanol gave 
0.36 g (82% yield), mp 115.degree.-116.degree. of 
4-[6-(2,3-dimethoxyphenyl)hexyloxy]-2-hydroxybenzoic acid. 
Anal. Calcd for C.sub.21 H.sub.26 O.sub.6 : C, 67.36; H, 7.00. Found: C, 
67.12; H, 7.14. 
EXAMPLE 61 
4-[6-(2,3-Dihydroxyphenyl)hexyloxy]-2-hydroxybenzoic acid 
To 0.35 g of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-2-hydroxybenzoic acid in 
10 mL of methylene chloride stirred and cooled at -70.degree. was added 
3.5 mL of 1M boron tribromide in methylene chloride. The reaction mixture 
was stirred at -70.degree. for 20 minutes and at -20.degree. for 6.5 
hours. Workup as in Example 32 and crystallization from methanol gave 0.20 
g (60% yield), mp 179.degree.-180.degree., of 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxy-benzoic acid. 
Anal. Calcd for C.sub.19 H.sub.22 O.sub.6 : C, 65.58; H, 6.40. Found: C, 
65.94; H, 6.57 
EXAMPLE 62 
2-Hydroxy-5-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid methyl 
ester 
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 in 30 mL of acetone was stirred at reflux for 17 hours. Workup 
as in Example 16 and chromatography on 60 g of silica gel using 1% ethyl 
acetate-toluene gave 0.42 g (39% yield) of 
2-hydroxy-5-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid methyl 
ester as an oil. 
EXAMPLE 63 
2-Hydroxy-5-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid 
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 at 
reflux for 1.5 hours. Workup as in Example 24 and recrystallization from 
ether-hexane gave 0.25 g, mp 97.degree.-100.degree., of 
2-hydroxy-5-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid. 
Anal. Calcd for C.sub.33 H.sub.34 O.sub.6 : C, 75.26; H, 6.51. Found: C, 
75.28; H, 6.58 
EXAMPLE 64 
2-Hydroxy-5-[6-(2,3-dihydroxyphenyl)hexyloxy]benzoic acid 
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 in a 
hydrogen atmosphere for 5 hours. Workup as in example 36 and 
recrystallization from acetone-hexane gave 0.10 g, mp 
159.degree.-161.degree. of 
2-hydroxy-5-[6-(2,3-dihydroxyphenyl)hexyloxy]benzoic acid. 
Anal. Calcd. for C.sub.19 H.sub.22 O.sub.6 : C, 65.88; H, 6.40. Found: C, 
65.91; H, 6.56 
EXAMPLE 65 
4-[6-(2,3-Dimethoxyphenyl)hexyloxy]benzoic acid methyl ester 
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 was stirred at reflux for 23 hours. Workup as 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. 
Anal. Calcd for C.sub.22 H.sub.28 O.sub.5 : C, 70.94; H, 7.58. Found: C, 
70.86; H, 7.59 
EXAMPLE 66 
4-[6-(2,3-Dihydroxyphenyl)hexyloxy]benzoic acid 
To 0.80 g (2.2 mmol) of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]benzoic acid 
methyl ester in 25 mL of methylene chloride stirred and cooled at 
-70.degree. was added 8.0 mL of 1M boron tribromide in methylene chloride. 
The reaction mixture was stirred at -70.degree. for 30 minutes and at 
-20.degree. for 7 hours. Workup as in example 32 and recrystallization 
from ethyl acetate-hexane gave 0.30 g (42% yield), mp 
170.degree.-172.degree. of 4-[6-(2,3-dihydroxyphenyl)hexyloxy]benzoic 
acid. 
Anal. Calcd for C.sub.19 H.sub.22 O.sub.5 : C, 69.07; H, 6.71 Found: C, 
68.81; H, 6.70 
EXAMPLE 67 
3-[6-[2,3-Bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid methyl ester 
A mixture of 0.58 g of 1-(6-iodohexyl)-2,3-bis(phenyl-methoxy)benzene, 0.18 
g of 3-hydroxybenzoic acid methyl ester and 0.25 g of potassium carbonate 
in 15 mL of acetone was stirred at reflux for 18 hours. Workup 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. 
Anal. Calcd for C.sub.34 H.sub.36 O.sub.5 : C, 77.85; H, 6.92. Found: C, 
77.62; H. 6.89. 
EXAMPLE 68 
3-[6-[2,3-Bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid 
A solution of 0.5 g of 3-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic 
acid methyl ester in 15 mL of methanol and 5 mL of 1N sodium hydroxide was 
stirred at reflux for 2 hours. Workup as in Example 24 and crystallization 
from methanol gave 0.34 g (70% yield), mp 72.degree.-74.degree.of 
3-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid. 
Anal. Calcd for C.sub.33 H.sub.34 O.sub.5 : C, 77.62; H, 6.71. Found: C, 
77.10; H, 6.66 
EXAMPLE 69 
3-[6-(2,3-Dihydroxyphenyl)hexyloxy]benzoic acid 
A mixture of 0.33 g of 3-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic 
acid and 95 mg of 10% palladium on carbon in 20 mL of ethyl acetate and 5 
mL of ethanol was stirred in a hydrogen atmosphere for 11 hours. The 
reaction mixture was filtered through Celite and the filtrate was 
concentrated under reduced pressure to an oil. Chromatography on 10 g of 
silica gel and elution with 10% methanol-chloroform gave a solid which was 
recrystallized from ether-hexane to give 0.14 g (63% yield), mp 
123.degree.-125.degree., of 3-[6-(2,3-dihydroxyphenyl)hexyloxy]benzoic 
acid. 
Anal. Calcd for C.sub.19 H.sub.22 O.sub.5 : C, 69.07; H, 6.71. Found: C, 
69.17; H, 6.93 
EXAMPLE 70 
3-Chloro-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid methyl 
ester 
A mixture of 5.6 g of 1-(6-iodohexyl)-2,3-bis(phenylmethoxy) benzene, 2.1 g 
of 3-chloro-4-hydroxybenzoic acid methyl ester and 5.0 g of potassium 
carbonate in 50 mL of acetone was stirred at reflux for 20 hours. Workup 
as in Example 16, chromatography on 100 g of silica gel using 15% ethyl 
acetate-hexane and crystallization from ethyl acetate-hexane gave 3.7 g 
(59% yield), mp 68.degree.-69.degree., 
3-chloro-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid methyl 
ester. 
EXAMPLE 71 
3-Chloro-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid 
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 refluxed for 2 hours. Workup as in Example 24, 
chromatography on 70 g of silica gel using 50% ethyl acetate-hexane and 
recrystallization from ether-hexane gave 1.3 g, mp 87.degree.-89.degree., 
of 3-chloro-4-[-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid. 
EXAMPLE 72 
3-Chloro-4-[6-(2,3-dihydroxyphenyl)hexyloxy]benzoic acid. 
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 in a 
hydrogen atmosphere for 6 hours. Workup as in Example 36 and 
recrystallization from ethyl acetate-hexane gave 0.24 g, mp benzoic acid. 
Anal. Calcd for C.sub.19 H.sub.21 ClO.sub.5 : C, 62.55; H, 5.80; Cl, 9.72. 
Found: C, 62.40; H, 5.95; Cl, 9.51 
EXAMPLE 73 
4-[2-(3,4-Dimethoxyphenyl)ethoxy]-2-hydroxy-3-propylbenzoic acid methyl 
ester 
A mixture of 3.4 g (0.016 mol) of 2,4-dihydroxy-3-propylbenzoic acid methyl 
ester, 4.7 g (0.018 mol) 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 was stirred at reflux for 18 hours. 4.7 g of 
1-[(2-methanesulfonyloxy)ethyl]-2,3-dimethoxybenzene and 4.4 g of 
potassium carbonate were added and reflux was continued for 41 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 10% ethyl acetate-hexane to remove impurities and 
then ethyl acetate to obtain 4.5 g of oil. This was stirred with hexane 
and filtered to give 1.65 g (28% yield), mp 56.degree.-58.degree., of 
4-[2-(3,4-dimethoxyphenyl)ethoxy]-2-hydroxy-3-propylbenzoic acid methyl 
ester. 
Anal. Calcd for C.sub.21 H.sub.26 O.sub.6 : C, 67.36; H, 7.00. Found: C, 
67.37; H, 7.06 
EXAMPLE 74 
4-[3-(3,4-Dimethoxyphenyl)propoxy]-2-hydroxy-3-propylbenzoic acid methyl 
ester 
A mixture of 9.5 g (0.037 mol) of 1-(3-bromopropyl)-3,4-dimethoxybenzene 
[G. H. Douglas, C. R. Walk and H. Smith, J. Med. Chem., 9, 27 (1966)], 7.0 
g (0.033 mol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester, 6.9 g 
(0.05 mol) of potassium carbonate and 8.3 g (0.05 mol) of potassium iodide 
in 250 mL of acetone was stirred at 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 to give 7.2 g (56% yield) of 
4-[3-(3,4-dimethoxyphenyl)propoxy]-2-hydroxy-3-propylbenzoic acid methyl 
ester as an oil. 
Anal. Calcd for C.sub.22 H.sub.28 O.sub.6 : C, 68.02; H, 7.27. Found: C, 
67.90; H, 7.37. 
Compounds of Examples 78-80 were prepared using the procedure of Example 
77. 
______________________________________ 
##STR37## 
Microanalysis 
Ex. Yield Calcd Found 
No. R n % Formula C H C H 
______________________________________ 
75 CH.sub.3 
4 49 C.sub.23 H.sub.30 O.sub.6 
68.64 
7.51 68.74 
7.96 
76 Benzyl 5 80 C.sub.30 H.sub.36 O.sub.6 
73.15 
7.37 72.99 
7.51 
77 Benzyl 6 97 C.sub.31 H.sub.38 O.sub.6 
not submitted 
______________________________________ 
EXAMPLE 78 
4-[3-(3,4-Dimethoxyphenyl)propoxy]-2-hydroxy-3-propylbenzoic acid 
A solution of 7.1 g of 
4-[3-(3,4-dimethoxyphenyl)propoxy]-2-hydroxy-3-propylbenzoic acid methyl 
ester in 180 mL of methanol and 90 mL of 1N sodium hydroxide was stirred 
at 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.sub.4) extract was concentrated to 6.5 g, mp 
104.degree.-110.degree., of 
4-[3-(3,4-dimethoxyphenyl)propoxy]-2-hydroxy-3-propylbenzoic acid. 
Anal. Calcd for C.sub.21 H.sub.26 O.sub.6 : C, 67.36; H, 7.00. Found: C, 
67.11; H, 7.00. 
Compounds of Examples 82, 83 and 85 were prepared using the procedure of 
Example 81. Compound 84 was prepared using the procedure of Example 36, 
hydrogenolysis in tetrahydrofuran. 
______________________________________ 
##STR38## 
Microanalysis 
Ex. Yield Calcd Found 
No. n mp (.degree.C.) 
% Formula 
C H C H 
______________________________________ 
79 2 156-157 40 C.sub.20 H.sub.24 O.sub.6 
66.28 
7.23 66.37 
6.82 
80 4 125-127 87 C.sub.22 H.sub.28 O.sub.6 
68.02 
7.27 67.84 
7.33 
81 5 133-136 83 C.sub.23 H.sub.30 O.sub.6 
68.64 
7.51 68.45 
7.42 
82 6 99-101 65 C.sub.24 H.sub.32 O.sub.6 
69.21 
7.74 68.96 
7.85 
______________________________________ 
EXAMPLE 83 
4-[3-(3,4-Dihydroxyphenyl)propoxy]-2-hydroxy-3-propylbenzoic acid 
To 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 at -70.degree., was 
added 24 mL (0.024 mol) of 1M boron tribromide in methylene chloride 
dropwise over 30 minutes. The reaction mixture was stirred at -70.degree. 
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 shaken vigorously 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), mp 
194.degree.-195.degree., of 
4-[3-(3,4-dihydroxyphenyl)propoxy]-2-hydroxy-3-propylbenzoic acid. 
Anal. Calcd for C.sub.19 H.sub.22 O.sub.6 : C, 65.88; H, 6.40. Found: c, 
65.51; H, 6.47 
Compounds of examples 87-90 were prepared using the procedure of Example 
86. 
______________________________________ 
##STR39## 
Microanalysis 
Ex. Yield Calcd Found 
No. n mp (.degree.C.) 
% Formula 
C H C H 
______________________________________ 
84 2 164-165 32 C.sub.18 H.sub.20 O.sub.6 
65.05 
6.07 64.66 
6.01 
85 4 190-193 95 C.sub.20 H.sub.24 O.sub.6 
66.65 
6.71 66.36 
6.87 
86 5 159-162 70 C.sub.21 H.sub.26 O.sub.6 
67.36 
7.00 66.96 
7.08 
87 6 113-114 58 C.sub.22 H.sub.28 O.sub.6 
68.02 
7.27 67.91 
7.56 
______________________________________ 
EXAMPLE 88 
4-[3-(3,4-Dimethoxyphenyl)propoxy]benzoic acid ethyl ester 
A mixture of 2.56 g (9.9 mmol) of 1-(3-bromopropyl)-3,4-dimethoxybenzene, 
1.50 g (9 mmol) of 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 was stirred at reflux for 22 hours. Workup as in Example 16, 
purification by high pressure liquid chromatography using methylene 
chloride and recrystallization from 2-propanol gave 1.23 g (40% yield), mp 
70.degree.-71.degree., of 4-[3-(3,4-dimethoxyphenyl)propoxy]benzoic acid 
ethyl ester. 
EXAMPLE 89 
4-[3-(3,4-Dimethoxyphenyl)propoxy]benzoic acid 
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 at 
reflux for 1 hour. Workup as in Example 24 gave 1.1 g, mp 
150.degree.-154.degree., of 4-[3-(3,4-dimethoxyphenyl)propoxy]benzoic 
acid. 
Anal. Calcd for C.sub.18 H.sub.20 O.sub.5 : C, 68.34; H, 6.37. Found: C, 
68.07; H, 6.16 
EXAMPLE 90 
4-[3-(3,4-Dihydroxyphenyl)propoxy]benzoic acid 
To 1.08 g (3.4 mmol) of 4-[3-(3,4-dimethoxyphenyl)propoxy]benzoic acid 
suspended in 60 mL of methylene chloride and cooled at -70.degree. was 
added 10 ml (10 mmol) of 1M boron tribromide in methylene chloride. The 
reaction mixture was stirred at -70.degree. for 2.5 hours and then worked 
up as in Example 32. Recrystallization from ether-hexane gave 0.40 g (41% 
yield), mp 180.degree.-185.degree., of 
4-[3-(3,4-dihydroxyphenyl)propoxy]benzoic acid. 
Anal. Calcd for C.sub.16 H.sub.16 O.sub.5 : C, 66.66; H, 5.59. Found: C, 
66.37; H, 5.64 
EXAMPLE 91 
4-[[6-(3,4-Dimethoxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid 
methyl ester 
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 was stirred at 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), mp 117.degree.-119.degree., of 
4-[[6-(3,4-dimethoxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid 
methyl ester. 
Anal. Calcd for C.sub.25 H.sub.32 O.sub.7 : C, 67.55; H, 7.26. Found: C, 
67.27; H, 7.29 
EXAMPLE 92 
4-[[6-(3,4-Dimethoxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid 
A solution of 1.36 g of 
4-[[6-(3,4-dimethoxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid 
methyl ester in 35 mL of methanol and 13 mL of 1N sodium hydroxide was 
stirred at reflux for 8.5 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 (71% yield), mp 
114.degree.-117.degree., of 
4-[[6-(3,4-dimethoxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic 
acid. 
Anal. Calcd for C.sub.24 H.sub.30 O.sub.7 : C, 66.96, H, 7.02; Found: C, 
66.98; H, 7.20 
EXAMPLE 93 
4-[[6-(3,4-Dihydroxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid 
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 at -70.degree. was 
added 7 mL of 1M boron tribromide in methylene chloride. The reaction 
mixture was stirred at -70.degree. for 1 hour and then at -18.degree. for 
20 hours. Workup as in Example 32 and chromatography of the crude product 
on 100 g of silica gel using acetic acid:ethyl acetate-toluene (5:25:70) 
followed by recrystallization from ethyl acetate-hexane gave 0.42 g, mp 
188.degree.-191.degree., of 
4-[[6-(3,4-dihydroxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic 
acid. 
Anal. Calcd for C.sub.22 H.sub.26 O.sub.7 : C, 65.66; H, 6.51. Found: C, 
65.29; H, 6.55 
EXAMPLE 94 
1-[2-Hydroxy-4-[4-(2,3-dimethoxyphenyl)butoxy]-3-propylphenyl]ethanone 
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 
mmol) of potassium carbonate and 2.4 g (16 mmol) of sodium iodide in 100 
mL of acetone was stirred at 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-[2-Hydroxy-4-[4-(2,3-dimethoxyphenyl)butoxy]-3-propylphenyl]-ethanone as 
an oil. 
Anal. Calcd for C.sub.23 H.sub.30 O.sub.5 : C, 71.48; H, 7.82. Found: C, 
71.58; H, 7.85. 
Compounds of Examples 98-100 were prepared using the procedure of Example 
97. 
__________________________________________________________________________ 
##STR40## 
Microanalysis 
Ex. Yield* 
% EtoAc-Hexane 
Calcd Found 
No. 
R.sub.6 
n Formula 
% used in HPLC 
C H C H 
__________________________________________________________________________ 
95 H 6 C.sub.25 H.sub.34 O.sub.5 
88 20 not submitted 
96 H 8 C.sub.27 H.sub.38 O.sub.5 
80 10 73.27 
8.65 
73.30 
8.77 
97 CH(CH.sub.3).sub.2 
6 C.sub.28 H.sub.40 O.sub.5 
57 5 73.65 
8.83 
73.75 
8.95 
__________________________________________________________________________ 
*All compounds are oils 
EXAMPLE 98 
1-[2-Hydroxy-4-[4-(2,3-dihydroxyphenyl)butoxy]-3-propylphenyl]ethanone 
To 5.02 g of 
1-[2-hydroxy-4-[4-(2,3-dimethoxyphenyl)butoxy]-3-propylphenyl]ethanone in 
300 mL of methylene chloride stirred and cooled at -70.degree. was added 
39 mL of 1M boron tribromide in methylene chloride. The reaction mixture 
was stirred at -70.degree. for 30 minutes and kept at -20.degree. for 5.5 
hours. Workup as in Example 32 and recrystallization from acetone-hexane 
gave 3.81 g (82% yield), mp 103.degree.-105.degree. of 
1-[2-hydroxy-4-[4-(2,3-dihydroxyphenyl)butoxy]-3-propylphenyl]ethanone. 
Anal. Calcd for C.sub.21 H.sub.26 O.sub.5 : C, 70.37; H, 7.31. Found: C, 
70.28; H, 7.43 
Compounds of Examples 102-104 were prepared by the procedure of Example 
101. 
__________________________________________________________________________ 
##STR41## 
Recrystn 
Microanalysis 
Ex. Yield 
Solvent Calcd Found 
No. 
R.sub.6 
n Formula 
% mp (.degree.C.) 
C H C H 
__________________________________________________________________________ 
99 
H 6 C.sub.23 H.sub.30 O.sub.5 
90 EtOAc hexane 
71.48 
7.82 
71.31 
7.84 
106-108 
100 
H 8 C.sub.25 H.sub.34 O.sub.5 
95 Acetone hexane 
72.44 
8.27 
72.32 
8.27 
116-118 
101 
CH(CH.sub.3).sub.2 
6 C.sub.26 H.sub.36 O.sub.5 
99 HPLC 72.87 
8.47 
72.63 
8.64 
25% EtOAc 
hexane, oil 
__________________________________________________________________________ 
EXAMPLE 102 
1-[2-Hydroxy-4-[5-(3,4-dimethoxyphenyl)pentyloxy]-3-propylphenyl]-1-ethanon 
3.0 g (0.013 mol) of 5-(3,4-dimethoxyphenyl)pentan-1-ol was converted to 
the mesylate as described in Example 6. A mixture of this mesylate, 2.6 g 
(0.013 mol) of 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 was stirred at 
reflux for 6.5 hours. The reaction mixture was washed with half-saturated 
brine, then with 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), mp 72.degree.-75.degree., of 
1-[2-hydroxy-4-[5-(3,4-dimethoxyphenyl)pentyloxy]-3-propylphenyl]-1-ethano 
ne. 
Anal. Calcd for C.sub.24 H.sub.32 O.sub.5 : C, 71.97; H, 8.05. Found: C, 
71.82; H, 8.05. 
EXAMPLE 103 
1-[4-[5-(3,4-Dihydroxyphenyl)pentyloxy]-2-hydroxy-3-propylphenyl]-1-ethanon 
e 
To 3.95 g (0.01 mole) of 
1-[2-hydroxy-4-[5-(3,4-dimethoxyphenyl)pentyloxy)-3-propylphenyl]-1-ethano 
ne in 80 mL of methylene chloride cooled at -70.degree. was added 30 mL 
(0.03 mol) of 1M boron tribromide in methylene chloride. After 30 minutes 
at -70.degree. and 6 hours at -20.degree., the reaction was worked up as 
in Example 32 and the product was recrystallized from etherhexane to give 
3.24 g (88% yield), mp 126.degree.-127.degree., of 
1-[4-[5-(3,4-dihydroxyphenyl)pentyloxy]-2-hydroxy-3-propylphenyl]-1-ethano 
ne. 
Anal. Calcd. for C.sub.22 H.sub.28 O.sub.5 : C, 70.94; H, 7.58. Found: C, 
70.80; H, 7.63. 
EXAMPLE 104 
4-(6-Bromohexyl)-2,3-dimethoxy-1,1'-biphenyl 
A solution of 2.5M butyl lithium in hexane (16 mL, 0.04 mol) was added 
dropwise over 15 min. to a stirred solution of 8.3 g (0.039 mol) of 
2,3-dimethoxybiphenyl [J. M. Bruce and F. K. Sutcliffe, J. Chem. Soc. 4435 
(1955)] in 160 mL of anhydrous tetrahydrofuran cooled at 0.degree. under 
argon. The reaction mixture was stirred at 0.degree. for 2.5 hours and 
then refluxed for 30 min. After cooling to 5.degree., 6.3 mL (0.039 mole) 
of 1,6-dibromohexane was added. Stirring was continued at 5.degree. for 30 
min., at 25.degree. for 30 min. and at reflux for 20 hours. Workup 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)-2,3-dimethoxy-1,1'-biphenyl as an oil. The structure was 
confirmed by the nmr and mass spectra (molecular ion at m/e 376). 
EXAMPLE 105 
2-Hydroxy-4-[[6-(2,3-dimethoxy-1,1'-biphenyl)-4-yl]hexyl]oxy]-3-propylbenzo 
ic acid phenylmethyl ester 
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) of 
2,4-dihydroxy-3-propylbenzoic acid phenylmethyl 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 at reflux for 30 hours. The reaction mixture was washed with 
half-saturated brine and then with 1N sodium hydroxide. After drying the 
organic layer, the solvent was removed under reduced pressure to give an 
oil which was purified by chromatography on 100 g of silica gel. Elution 
with 10% ethyl acetate-hexane gave 3.7 g (73% yield) of 
2-hydroxy-4-[[6-(2,3-dimethoxy-1,1'-biphenyl)-4-yl]hexyl]oxy]-3-propylbenz 
oic acid phenylmethyl ester. 
Anal. Calcd for C.sub.37 H.sub.42 O.sub.6 : C, 76.26; H, 7.26. Found: C, 
76.11; H. 7.31. 
EXAMPLE 106 
2Hydroxy-4-[[6-(2,3-dimethoxy-1,1'-biphenyl)-4-yl]hexyl]oxy]-3-propylbenzoi 
c acid 
A mixture of 3.76 g of 
2-hydroxy-4-[[6-(2,3-dimethoxy-1,1'-biphenyl)-4-yl]hexyl]oxy]-3-propylbenz 
oic acid phenylmethyl ester and 0.30 g of 10% palladium on carbon in 80 mL 
of tetrahydrofuran was stirred in a hydrogen atmosphere for 17 hours. 
Workup as in Example 36 and recrystallization from hexane gave 2.4 g, mp 
88.degree.-80.degree., of 
2-hydroxy-4-[[6-(2,3-dimethoxy-1,1'-biphenyl)-4-yl]hexyl]oxy]-3-propylbenz 
oic acid. 
EXAMPLE 107 
2-Hydroxy-4-[[6-(2,3-dihydroxy-1,1'-biphenyl)-4-yl]hexyl]oxy]-3-propylbenzo 
ic acid 
To 1.72 g (3.5 mmol) of 
2-hydroxy-4-[[6-(2,3-dimethoxy-1,1'-biphenyl)-4-hexyl]oxy]-3-propylbenzoic 
acid suspended in 150 mL of methylene chloride and cooled at -70.degree. 
was added 10.5 mL (10.5 mmol) of 1M boron tribromide in methylene 
chloride. The reaction mixture was stirred at -70.degree. for 20 min. and 
then kept at -18.degree. for 17 hours. Workup as in Example 32 and two 
recrystallizations of the product from methylene chloride gave 1.03 g (63% 
yield), mp 151.degree.-155.degree., of 
2-hydroxy-4-[[6-(2,3-dihydroxy-1,1'-biphenyl)-4-yl]hexyl]oxy]-3-propylbenz 
oic acid. 
Anal. Calcd. for C.sub.28 H.sub.32 O.sub.6 : C, 72.39; H, 6.94. Found: C, 
72.32; H, 6.93. 
EXAMPLE 108 
2-Chloro-3,4-dimethoxybenzene hexanol 
To 0.6 g (0.08 g-atoms) of lithium ribbon cut in small pieces in 40 mL of 
anhydrous ether stirred at room temperature under an argon atmosphere was 
added 9.5 g (0.04 mol) of 5-bromopentanol 2-ethoxyethyl ether. After about 
1 mL was added, the reaction mixture was cooled to -5.degree. and the rest 
of the bromo compound was added dropwise. Stirring at -5.degree. was 
continued for 1 hour and then 6.0 g (0.03 mol) of 
2-chloro-3,4-dimethoxybenzaldehyde [J. Weinstock et al., J. Med. Chem., 
29, 2315 (1986)] in 50 mL of ether-20 mL of tetrahydrofuran was added 
dropwise over 1 hour. The cooling bath was removed and stirring was 
continued for 1 hour. The reaction mixture was worked up as in Example 10 
to yield an oil which was dissolved in 25 mL of ethanol, 20 mL of water 
and 2 mL of concentrated hydrochloric acid was added. The solution was 
left at 25.degree. 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), mp 
75.degree.-70.degree., of 
6-(2-chloro-3,4-dimethoxybenzene)-6-hydroxyhexanol. This was dissolved in 
50 mL of ethanol, 0.3 g of 10% palladium on carbon was added and the 
mixture was shaken under 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. The structure was 
confirmed by nmr and mass spectra (molecular ion at m/e 272). 
EXAMPLE 109 
4-[6-(2-Chloro-3,4-dimethoxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid 
methyl ester 
To 1.74 g (6.4 mmol) of 2-chloro-3,4-dimethoxybenzene hexanol 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 with ice bath cooling for 80 min. and 
then worked up as in Example 3. The resulting mesylate, 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 mL (0.7 mmole) of 
tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) in 40 mL of toluene was 
stirred at 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 7% ethyl acetate-hexane to give 2.11 g (77% yield) 
of 4]-[6-(2-chloro-3,4-dimethoxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic 
acid methyl ester as an oil. The structure was confirmed by the nmr and 
mass spectra (molecular ion at m/e 464). 
EXAMPLE 110 
4-[6-(2-Chloro-3,4-dimethoxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid 
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 15 mL dioxane and 18 mL of 1N 
sodium hydroxide was refluxed for 8 hours. The solvents were removed at 
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), mp 
107.degree.-108.degree., of 
4-[6-(2-chloro-3,4-dimethoxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic 
acid. 
Anal. Calcd for C.sub.24 H.sub.31 ClO.sub.6 : C, 63.92; H, 6.93; Cl, 7.86. 
Found: C, 63.73; H, 6.97; Cl, 7.98. 
EXAMPLE 111 
4-[6-(2-Chloro-3,4-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid 
To 1.80 g (4 mmol) of 
4-[6-(2-chloro-3,4-dimethoxyphenyl)hexyloxy]-2-hydroxy-3-propyl benzoic 
acid suspended in 120 mL of methylene chloride and cooled at -70.degree. 
was added 14 mL (14 mmol) of 1M boron tribromide in methylene chloride. 
The reaction mixture was stirred at -70.degree. for 15 min. and kept at 
-18.degree. for 6 hours. Workup as in Example 32 and two 
recrystallizations from ethyl acetate-hexane gave 1.03 g (61% yield), mp 
145.degree.-146.degree., of 
4-[6-(2-chloro-3,4-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic 
acid. 
Anal. Calcd for C.sub.22 H.sub.27 ClO.sub.6 : C, 62.48; H, 6.44; Cl, 8.38. 
Found: C, 62.26; H, 6.32; Cl, 8.54. 
EXAMPLE 112 
1-(5-Bromopentyl)-6-chloro-2,3-dimethoxybenzene 
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 0.8M chlorine in 
methylene chloride. The reaction mixture was kept at 0.degree. for 3 hours 
and then was concentrated under reduced pressure to yield an oil. 
Purification by HPLC using 30% toluene-hexane gave 2.60 g (58% yield) of 
1-(5-bromopentyl)-6-chloro-2,3-dimethoxybenzene. The nmr spectrum was 
consistent with the structure and the mass spectrum gave a molecular ion 
at m/z 320 (C.sub.13 H.sub.18 BrClO.sub.2). 
EXAMPLE 113 
1-(5-Bromopentyl)-5,6-dichloro-2,3-dimethoxybenzene 
To 4.0 g of 1-(5-bromopentyl)-2,3-dimethoxy benzene in 50 mL of methylene 
chloride cooled in an ice bath was added 18 mL of 0.8M chlorine in 
methylene chloride. After 15 minutes, 17 mL of 0.88M chlorine in methylene 
chloride was added. The reaction mixture was kept at 0.degree. for 3 hours 
and then was concentrated under reduced pressure to yield an oil. 
Purification by HPLC using 30% toluene-hexane gave 2.03 g (41% yield) of 
1-(5-bromopentyl)-5,6-dichloro-2,3-dimethoxybenzene. The nmr spectrum was 
consistent with the structure and the mass spectrum gave a molecular ion 
at m/z 354 (C.sub.13 H.sub.17 BrCl.sub.2 O.sub.2). 
EXAMPLE 114 
1-(5-Bromopentyl)-2,3-dimethoxy-4,5,6-trichlorobenzene 
To 1.9 g of 1-(5-bromopentyl)-2,3-dimethoxy benzene in 25 mL of methylene 
chloride cooled in an ice bath was added 23 mL of 0.88M chlorine in 
methylene chloride. After 1.5 hours at 0.degree., 5 mL of 1.35M chlorine 
in methylene chloride was added. The reaction mixture was kept at 
0.degree. for 17 hours and then was concentrated under reduced pressure to 
yield 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. The 
nmr spectrum was consistent with the structure and the mass spectrum gave 
a molecular ion at m/z 388 (C.sub.13 H.sub.16 BrCl.sub.3 O.sub.2). 
EXAMPLE 115 
6-(6-Chloro-3,4-dimethoxyphenyl)hexan-1-ol 
To 1.40 g of 6-(3,4-dimethoxyphenyl)hexan-1-ol in 25 mL of methylene 
chloride cooled in a ethanol-dry ice bath was added 4.6 mL of 1.35M 
chlorine in methylene chloride. The reaction mixture was kept at 
-75.degree. for 1.5 hours, at -18.degree. for 16 hours and then at 
0.degree. 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. The nmr spectrum was 
consistent with the structure and the mass spectrum gave a molecular ion 
at m/z 272 (C.sub.14 H.sub.21 ClO.sub.3). 
EXAMPLE 116 
6-Bromo-1-[3,4-dimethoxy-5-(1-methylethyl)phenyl]-1-hexanone 
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.degree. 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. 
The nmr spectrum was consistent with the structure and the mass spectrum 
gave the molecular ion at m/z 356 (C.sub.17 H.sub.25 BrO.sub.3). 
EXAMPLE 117 
6-Bromo-1-(3,4-dimethoxy-2,5-dimethylphenyl)-1-hexanone 
A solution of 0.227 g (1.5 mmol) of 3,6-dimethylveratrole 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-bromohexanoyl 
chloride in 3 mL of methylene chloride. The reaction mixture was kept at 
0.degree. 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 on 60 g of silica gel 
using 10% ethyl acetate-hexane to give 0.235 g of 
6-bromo-1-(3,4-dimethoxy-2,5-dimethylphenyl)-1-hexanone as an oil. The nmr 
spectrum was consistent with the structure and the mass spectrum gave the 
molecular ion at m/z 342 (C.sub.16 H.sub.23 BrO.sub.3) 
EXAMPLE 118 
4-Chloro-1-[3,4-dimethoxy-6-fluorophenyl]-1-hexanone 
A solution of 0.1056 g (0.64 mmol) of 4-fluoroveratrole in 1 mL of 
methylene chloride was added to a mixture of 0.2289 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.degree.. The reaction mixture was stirred 
at 25.degree. 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 an oil which was 
chromatographed on 10 g of silica gel using 25% ethyl acetatehexane to 
give 0.041 g, mp 81.degree.-82.degree., of 
4-chloro-[3,4-dimethoxy-6-fluorophenyl]-1-hexanone. The nmr spectrum was 
consistent with the structure and the mass spectrum gave the molecular ion 
at m/z 260 (C.sub.12 H.sub.14 ClFO.sub.3) 
EXAMPLE 119 
4-[5-(2-Chloro-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoic 
acid methyl ester 
A mixture of 2.60 g (8.1 mmol) of 
1-(5-bromopentyl)-6-chloro-2,3-dimethoxybenzene, 1.65 g (7.8 mmol) of 
2,4-dihydroxy-3-propylbenzoic acid methyl ester and 5.0 g (36 mmol) of 
anhydrous potassium carbonate in 60 mL of acetone and 6 mL of DMF was 
stirred at 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), mp 53.degree.-55.degree., of 
4-[5-(2-chloro-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoic 
acid methyl ester. 
EXAMPLE 120 
4-[5-(2-Chloro-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoic 
acid 
A solution of 2.95 g (6.7 mmol) of 
4-[5-(2-chloro-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoic 
acid methyl ester in 80 mL of methanol and 20 mL (20 mmol) of 1N sodium 
hydroxide was stirred at reflux for 4 hours. Workup as in Example 24 and 
recrystallization from ether-hexane gave 2.70 g (96% yield) mp 
140.degree.-142.degree., of 
4-[5-(2-chloro-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoic 
acid. 
Anal. Calcd for C.sub.23 H.sub.29 ClO.sub.6 : C, 63.23; H, 6.69; Cl, 8.11. 
Found: C, 63.23; H, 6.75; Cl, 8.22. 
EXAMPLE 121 
4-[5-(2-Chloro-5,6-dihydroxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoic 
acid 
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 of methylene chloride and stirred at -60.degree. 
was added 18.6 mL (18.6 mmol) of 1M boron tribromide in methylene 
chloride. The reaction mixture was stirred at -60.degree. for 20 minutes 
and was then kept at -20.degree. 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 was 
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, mp 
178.degree.-181.degree., of 
4-[5-(2-chloro-5,6-dihydroxy-phenyl)pentyloxy]-2-hydroxy-3-propylbenzoic 
acid. 
Anal. Calcd for C.sub.21 H.sub.25 ClO.sub.6 : C, 61.69; H, 6.16; Cl, 8.67. 
Found: C, 61.69; H, 6.07; Cl, 8.75 
EXAMPLE 122 
4-[5-(2,3-Dichloro-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoic 
acid methyl ester 
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-propylbenzoic acid methyl ester and 3.5 g (22 mmol) of 
potassium carbonate in 50 mL of acetone and 5 mL of DMF 
(dimethylformamide) was stirred at 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), mp 
113.degree.-115.degree., of 
4-[5-(2,3-dichloro-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoi 
c acid methyl ester. 
EXAMPLE 123 
4-[5-(2,3-Dichloro-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoic 
acid 
A solution of 1.5 g (3.2 mmol) of 
4-[5-(2,3-dichloro-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoi 
c acid methyl ester in 40 mL of methanol and 10 mL (10 mmol) of 1N sodium 
hydroxide was stirred at reflux for 5 hours. Workup as in Example 24 and 
recrystallization from ether-hexane gave 1.2 g (80% yield), mp 
152.degree.-154.degree., of 
4-[5-(2,3-dichloro-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoi 
c acid. 
Anal. Calcd. for C.sub.23 H.sub.28 Cl.sub.2 O.sub.6 : C, 58.61; H, 5.99; 
Cl, 15.04. Found: C, 58.78; H, 6.07; Cl, 15.13 
EXAMPLE 124 
4-[5-(2,3-Dichloro-5,6-dihydroxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoic 
acid 
To 1.2 g (2.5 mmol) of 
4-[5-(2,3-dichloro-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoi 
c acid suspended in 100 mL of methylene chloride and stirred at 
-60.degree., was added 7.5 mL (7.5 mmol) of 1M boron tribromide in 
methylene chloride. After stirring at -60.degree. for 30 minutes the 
reaction mixture was kept at -20.degree. for 20 hours. Workup as in 
example 124 gave a solid residue which was recrystallized from ether 
chloroform to give 0.42 g, mp 159.degree.-164.degree., of 
4-[5-(2,3-dichloro-5,6-dihydroxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoi 
c acid. 
EXAMPLE 125 
4-[5-(2,3,4-Trichloro-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylbenz 
oic acid methyl ester 
A mixture of 1.48 g (3.8 mmol) of 
1-(5-bromopentyl)-5,6-dimethoxy-2,3,4-trichlorobenzene, 0.76 g (3.6 mmol) 
of 2,4-dihydroxy-3-propylbenzoic acid methyl ester and 4.6 g (33 mmol) of 
potassium carbonate in 30 mL of acetone and 3 mL of DMF was stirred at 
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), mp 84.degree.-87.degree., of 
4-[5-(2,3,4-trichloro-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylben 
zoic acid methyl ester. 
Anal. Calcd. for C.sub.24 H.sub.29 Cl.sub.3 O.sub.6 : C, 55.45; H, 5.62; 
Cl, 20.46. Found: C, 55.53; H, 5.70; Cl, 20.20. 
EXAMPLE 126 
4-[5-(2,3,4-Trichloro-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylbenz 
oic acid 
A solution of 1.5 g (2.3 mmol) of 
4-[5-(2,3,4-trichloro-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylben 
zoic acid methyl ester in 40 mL of methanol and 8.7 mL (8.7 mmol) of 1N 
sodium hydroxide was stirred at reflux for 5 hours. Workup as in Example 
24 and recrystallization from ethyl acetate-hexane gave 1.3 g (89% yield), 
mp 148.degree.-150.degree., of 
4-[5-(2,3,4-trichloro-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylben 
zoic acid. 
Anal. Calcd for C.sub.23 H.sub.27 Cl.sub.3 O.sub.6 : C, 54.61; H, 5.38; Cl, 
21.03. Found: C, 54.60; H, 5.48; Cl, 20.88. 
EXAMPLE 127 
4-[5-(2,3,4-Trichloro-5,6-dihydroxyphenyl)pentyloxy]-2-hydroxy-3-propylbenz 
oic acid 
To 1.3 g (2.6 mmol) of 
4-[5-(2,3,4-trichloro-5,6-dimethoxyphenyl)pentyloxy-2-hydroxy-3-propylbenz 
oic acid suspended in 110 mL of methylene chloride and stirred at 
-60.degree., was added 8.0 mL (8 mmol) of 1M boron tribromide in methylene 
chloride. The reaction mixture was stirred at -60.degree. for 1 hour and 
then kept at -20.degree. for 18 hours. Workup as in Example 124 gave a 
solid which was recrystallized from ether-hexane to give 0.9 g (73% 
yield), mp 193.degree.-196.degree., of 
4-[5-(2,3,4-trichloro-5,6-dihydroxyphenyl)pentyloxy]-2-hydroxy-3-propylben 
zoic acid. 
Anal. Calcd for C.sub.21 H.sub.23 Cl.sub.3 O.sub.6 : C, 52.79; H, 4.85; Cl, 
22.26. Found: C, 52.58; H, 4.84; Cl, 22.51. 
EXAMPLE 128 
4-[[6-(3,4-Dimethoxy-2,5-dimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propyl 
benzoic acid methyl ester 
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) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester and 3.30 g (24 
mmol) of potassium carbonate in 50 mL of acetone and 5 mL of DMF was 
stirred and heated at reflux for 26 hours. After workup 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-2,5-dimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propy 
l benzoic acid methyl ester as an oil. The nmr spectrum was consistent with 
the structure. 
EXAMPLE 129 
4-[[6-(3,4-Dimethoxy-2,5-dimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propyl 
benzoic acid. 
A solution of 3.40 g (7.2 mmol) of 
4-[[6-(3,4-dimethoxy-2,5-dimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propy 
lbenzoic acid methyl ester in 90 mL of methanol and 30 mL (30 mmol) of 1.0N 
sodium hydroxide was stirred at reflux for 5 hours. Workup as in example 
24 and recrystallization of the crude product from ether-hexane gave 3.00 
g (91% yield), mp 92.degree.-94.degree., of 
4-[[6-(3,4-dimethoxy-2,5-dimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propy 
lbenzoic acid. 
Anal. Calcd. for C.sub.26 H.sub.34 O.sub.7 : C, 68.10; H, 7.47. Found: C, 
68.02; H, 7.60. 
EXAMPLE 130 
4-[[6-(3,4-Dihydroxy-2,5-dimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propyl 
benzoic acid 
To 1.00 g (2.2 mmol) of 
4-[[6-(3,4-dimethoxy-2,5-dimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propy 
lbenzoic acid in 100 mL of methylene chloride was added 6.6 mL (6.6 mmol) 
of 1M boron tribromide in methylene chloride with cooling at -70.degree.. 
The mixture was stirred at -70.degree. for 1 hour and then kept at 
-20.degree. for 16 hours. Workup as in Example 32 and recrystallization of 
the crude product from ether-hexane gave 0.60 g (63% yield), mp 
121.degree.-125.degree., of 
4-[[6-(3,4-dihydroxy-2,5-dimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propy 
lbenzoic acid. 
Anal. Calcd. for C.sub.24 H.sub.30 O.sub.7 : C, 66.96; H, 7.02. Found: C, 
66.70; H, 7.02 
EXAMPLE 131 
4-[[6-[3,4-Dimethoxy-5-(1-methylethyl)phenyl]-6-oxohexyl]oxy]-2-hydroxy-3-p 
ropylbenzoic acid methyl ester 
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 
was stirred at reflux for 19 hours. After workup 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]oxy]-2-hydroxy-3- 
propylbenzoic acid methyl ester as an oil. The nmr spectrum was consistent 
with the structure. 
EXAMPLE 132 
4-[[6-[3,4-Dimethoxy-5-(1-methylethyl)phenyl]-6-oxohexyl]oxy]-2-hydroxy-3-p 
ropylbenzoic acid 
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 in 80 mL of methanol and 60 mL (0.06 mol) 
of 1.0N sodium hydroxide was stirred at reflux for 5 hours. Workup as in 
Example 24 and recrystallization of the crude product from ethyl 
acetate-hexane gave 6.6 g (89% yield), mp 113.degree.-115.degree., of 
4-[[6-[3,4-dimethoxy-5-(1-methylethyl)phenyl]-6-oxohexyl]oxy]-2-hydroxy-3- 
propylbenzoic acid. 
Anal. Calcd for C.sub.27 H.sub.36 O.sub.7 : C, 68.62; H, 7.68. Found: C, 
68.50; H, 7.84. 
EXAMPLE 133 
4-[[6-[3,4-Dihydroxy-5-(1-methylethyl)phenyl]-6-oxohexyl]oxy]-2-hydroxy-3-p 
ropylbenzoic acid 
To 2.0 g (4.2 mmol) of 
4-[[6-[3,4-dimethoxy-5-(1-methylethyl)phenyl]-6-oxohexyl]oxy]-2-hydroxy-3- 
propylbenzoic acid in 200 mL of methylene chloride cooled at -65.degree. 
was added 13 mL (13 mmol) of 1.0M boron tribromide in methylene chloride. 
The suspension was stirred at -50.degree. for 2 hours and then kept at 
-20.degree. for 16 hours. Workup as in Example 32 and recrystallization of 
the crude product from ether-hexane gave 1.5 g (81% yield), mp 
169.degree.-171.degree., of 
4-[[6-[3,4-dihydroxy-5-(1-methylethyl)phenyl]-6-oxohexyl]oxy]-2-hydroxy-3- 
propylbenzoic acid. 
Anal. Calcd for C.sub.25 H.sub.32 O.sub.7 : C, 67.55; H, 7.26. Found: C, 
67.45; H, 7.19. 
EXAMPLE 134 
4-[[6-[3,4-Dimethoxy-5-(1-methylethyl)phenyl]hexyloxy]-2-hydroxy-3-propylbe 
nzoic acid 
A mixture of 2.5 g of 
4-[[6-[3,4-dimethoxy-5-(1-methylethyl)phenyl]-6-oxohexyl]oxy]-2-hydroxy-3- 
propylbenzoic acid in 50 mL of tetrahydrofuran containing 2 drops of 
concentrated sulfuric acid and 0.5 g of 10% palladium on carbon was shaken 
on a Parr hydrogenator under an initial hydrogen pressure of 52 psi for 20 
hours. The reaction mixture was filtered through a Celite pad 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, mp 106.degree.-108.degree., of 
4-[[6-[3,4-dimethoxy-5-(1-methylethyl)phenyl]hexyloxy]-2-hydroxy-3-propylb 
enzoic acid. 
Anal. Calcd for C.sub.27 H.sub.38 O.sub.6 : C, 70.72; H, 8.35. Found: C, 
70.71; H, 8.39 
EXAMPLE 135 
4-[[6-[3,4-Dihydroxy-5-(1-methylethyl)phenyl]hexyloxy]-2-hydroxy-3-propylbe 
nzoic acid 
To 2.43 g (5.3 mmol) of 
4-[[6-(3,4-dimethoxy-5-(1-methylethyl)phenyl]hexyloxy]-2-hydroxy-3-propylb 
enzoic acid in 250 mL of methylene chloride cooled at -75.degree. was added 
16 mL (16 mmol) of 1M boron tribromide in methylene chloride. The reaction 
mixture was stirred at -75.degree. for 1 hour and then was kept at 
-20.degree. for 17 hours. Workup as in Example 32 and recrystallization 
from ether-hexane gave 1.20 g, mp 138.degree.-140.degree., of 
4-[[6-[3,4-dihydroxy-5-(1-methylethyl)phenyl]hexyloxy]-2-hydroxy-3-propylb 
enzoic acid. 
Anal. Calcd for C.sub.25 H.sub.34 O.sub.6 : C, 69.74; H, 7.96. Found: C, 
69.81; H, 8.02 
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-propy 
lbenzoic acid in 40 mL of tetrahydrofuran containing 2 drops of 
concentrated sulfuric acid and 0.4 g of 10% palladium on carbon was shaken 
on a Parr hydrogenator under an initial hydrogen pressure of 52 psi for 20 
hours. The reaction mixture was worked up as in Example 137 and the 
product was recrystallized from ether-hexane to give 1.20 g, mp 
109.degree.-112.degree., of 
4-[[6-(3,4-dimethoxy-2,5-dimethylphenyl)hexyloxy]-2-hydroxy-3-propylbenzoi 
c acid. 
Anal. Calcd. for C.sub.26 H.sub.36 O.sub.6 : C, 70.24; H, 8.16. Found: C, 
70.11; H, 8.17. 
EXAMPLE 137 
4-[[6-(3,4-Dihydroxy-2,5-dimethylphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic 
acid 
To 1.2 g (2.7 mmol) of 
4-[[6-(3,4-dimethoxy-2,5-dimethylphenyl)hexyloxy]-2-hydroxy-3-propylbenzoi 
c acid in 120 mL of methylene chloride cooled at -75.degree. was added 8 mL 
(8 mmol) of 1M boron tribromide in methylene chloride. The reaction 
mixture was stirred at -75.degree. for 1 hour and kept at -20.degree. for 
17 hours. Workup as in Example 32 and recrystallization of the crude 
product from ether-hexane gave 0.60 g, mp 170.degree.-171.degree., of 
4-[[6-(3,4-dihydroxy-2,5-dimethylphenyl)hexyloxy]-2-hydroxy-3-propylbenzoi 
c acid. 
Anal. Calcd for C.sub.24 H.sub.32 O.sub.6 : C, 69.21; H, 7.74. Found: C, 
68.93; H, 7.80. 
EXAMPLE 138 
6-Bromo-1-(2-fluoro-4,5-dimethoxyphenyl)-1-hexanone 
A solution of 5.3 g (0.034 mol) of 1,2-dimethoxy-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) of 6-bromohexanoyl chloride in 60 
mL of methylene chloride cooled in an ice bath. The resulting solution was 
kept at 0.degree. for 5 hours and then worked up as in Example 131. The 
crude product was recrystallized from methylene chloride-ether to give 
6.98 g (62% yield), mp 81.degree.-83.degree., of 
6-bromo-1-(2-fluoro-4,5-dimethoxyphenyl)-1-hexanone. The nmr spectrum was 
consistent with the structure and the mass spectrum gave a molecular ion 
at m/z 332 (C.sub.14 H.sub.18 BrFO.sub.3). 
EXAMPLE 139 
4-[[6-(2-Fluoro-4,5-dimethoxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenz 
oic acid methyl ester 
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 was stirred at 
reflux for 86 hours. DMF (12 mL) and potassium carbonate (3 g) were added 
and reflux was continued for 18 hours. Workup as in Example 16 and 
recrystallization of the crude product from ethyl acetate gave 4.3 g (78% 
yield), mp 127.degree.-129.degree., of 
4-[[6-(2-fluoro-4,5-dimethoxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylben 
zoic acid methyl ester. 
Anal. Calcd for C.sub.25 H.sub.31 FO.sub.7 : C, 64.92; H, 6.76; F, 4.11. 
Found: C, 64.68; h, 6.81; F, 4.19 
EXAMPLE 140 
4-[[6-(2-Fluoro-4,5-dimethoxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenz 
oic acid 
A solution of 4.3 g (9.3 mmol) of 
4-[[6-(2-fluoro-4,5-dimethoxy-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic 
acid methyl ester in 135 mL of methanol and 45 mL (45 mmol) of 1N sodium 
hydroxide was stirred at reflux for 5 hours. Workup as in Example 24 and 
recrystallization of the crude product from ethyl acetate-hexane gave 3.7 
g, mp 146.degree.-147.degree., of 
4-[[6-(2-fluoro-4,5-dimethoxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylben 
zoic acid. 
Anal. Calcd. for C.sub.24 H.sub.29 FO.sub.7 : C, 64.27; H, 6.52; F, 4.24, 
Found: C, 64.14; H, 6.47; F, 4.30 
EXAMPLE 141 
4-[[6-(2-Fluoro-4,5-dihydroxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenz 
oic acid 
To 2.0 g (4.46 mmol) of 
4-[[6-(2-fluoro-4,5-dimethoxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylben 
zoic acid in 200 mL of methylene chloride cooled at -75.degree. was added 
13 mL (13 mmol) of 1M boron tribromide in methylene chloride. The reaction 
mixture was stirred at -75.degree. for 1 hour and kept at -20.degree. for 
17 hours. Additional boron tribromide (7 mL) was added and the mixture was 
stirred at -5.degree. for 5 hours. Workup as in Example 32 and 
recrystallization of the crude product from ether-hexane gave 0.84 g, mp 
193.degree.-195.degree., of 
4-[[6-(2-fluoro-4,5-dihydroxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylben 
zoic acid. 
Anal. Calcd for C.sub.22 H.sub.25 FO.sub.7 : C, 62.85; H, 5.99. Found: C, 
62.56; H, 6.01. 
EXAMPLE 142 
4-[6-(2-Fluoro-4,5-dimethoxyphenyl)-hexyloxy]-2-hydroxy-3-propylbenzoic 
acid 
A mixture of 0.400 g of 
4-[[6-(2-fluoro-4,5-dimethoxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylben 
zoic acid and 0.150 g of 10% palladium on carbon in 20 mL of 
tetrahydrofuran containing 2 drops of concentrated sulfuric acid was 
shaken under an initial hydrogen pressure of 53 psi on a Parr hydrogenator 
for 20 hours. The reaction mixture was filtered through a Celite pad and 
the filtrate was concentrated under reduced pressure to a solid. 
Recrystallization from ethyl acetate-hexane gave 0.37 g mp 
127.degree.-130.degree., of 
4-[6-(2-fluoro-4,5-dimethoxyphenyl)-hexyloxy]-2-hydroxy-3-propylbenzoic 
acid. 
Anal. Calcd. for C.sub.24 H.sub.31 FO.sub.6 : C, 66.34; H, 7.19; F, 4.37. 
Found: C, 66.33; H, 7.25; F, 4.23 
EXAMPLE 143 
4-[6-(2-Fluoro-4,5-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid 
To 0.36 g of 
4-[6-(2-fluoro-4,5-dimethoxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic 
acid in 60 mL of methylene chloride cooled at -75.degree. was added 2.8 mL 
of 1M boron tribromide in methylene chloride. The reaction mixture was 
stirred at -75.degree. for 30 minutes and then was kept at -20.degree. for 
20 hours. Workup as in Example 32 and recrystallization of the crude 
product from ether-hexane gave 0.18 g, mp 110.degree.-11.degree., of 
4-[6-(2-fluoro-4,5-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic 
acid. 
EXAMPLE 144 
6-Bromo-1-(3,4-dimethoxy-2,5,6-trimethylphenyl)-1-hexanone 
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 2.40 g (18 mmol) of aluminum 
chloride and 3.80 g (18 mmol) of 6-bromohexanoyl chloride in 30 mL of 
methylene chloride cooled in an ice bath. The solution was kept at 
3.degree. for 45 minutes and then at 23.degree. 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. Workup as in Example 131 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. The 
nmr spectrum was consistent with the structure and the mass spectrum gave 
a molecular ion at m/z 356 (C.sub.17 H.sub.25 BrO.sub.3). 
EXAMPLE 145 
4-[[6-(3,4-Dimethoxy-2,5,6-trimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-pro 
pylbenzoic acid methyl ester 
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) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester and 1.10 g (7.8 
mmol) of potassium carbonate in 20 mL of acetone and 2 mL of DMF was 
stirred at reflux for 17 hours. After workup 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-[[6-(3,4-dimethoxy-2,5,6-trimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-pr 
opylbenzoic acid methyl ester. The nmr spectrum was consistent with the 
structure and the mass spectrum gave the molecular ion at m/z 486 
(C.sub.28 H.sub.28 O.sub.7). 
EXAMPLE 146 
4-[[6-(3,4-Dimethoxy-2,5,6-trimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-pro 
pylbenzoic acid 
A solution of 1.05 g (2.16 mmol) of 
4-[[6-(3,4-dimethoxy-2,5,6-trimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-pr 
opylbenzoic acid methyl ester in 30 mL of methanol and 7 mL (7 mmol) of 1N 
sodium hydroxide was stirred at reflux for 7 hours. Workup as in Example 
24 gave 0.98 g, mp 108.degree.-112.degree., of 
4-[[6-(3,4-dimethoxy-2,5,6-trimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-pr 
opylbenzoic acid. 
EXAMPLE 147 
4-[[6-(3,4-Dihydroxy-2,5,6-trimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-pro 
pylbenzoic acid 
To 0.98 g (2.07 mmol) of 
4-[[6-(3,4-dimethoxy-2,5,6-trimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-pr 
opylbenzoic acid in 100 mL of methylene chloride cooled at -75.degree. was 
added 7 mL (7 mmol) of 1M boron tribromide in methylene chloride. The 
reaction mixture was stirred at -75.degree. for 30 minutes and then was 
kept at -20.degree. for 18 hours. Workup as in Example 32 and 
recrystallization of the crude product from ether-hexane gave 0.51 g, mp 
169.degree.-170.degree. of 
4-[[6-(3,4-dihydroxy-2,5,6-trimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-pr 
opylbenzoic acid. 
Anal. Calcd for C.sub.24 H.sub.32 O.sub.7 : C, 67.55; H, 7.26 Found: C, 
67.18; H, 7.38. 
EXAMPLE 148 
4-[6-(2,3-Dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid hexyl 
ester 
A mixture of 1.00 g (2.57 mmol) of 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid, 0.76 
mL (5.15 mmol) of n-hexyl iodide and 0.26 g (3.36 mmol) of sodium 
bicarbonate in 15 mL of anhydrous dimethylformamide was stirred and heated 
at 70.degree. for 16 hours. The solvent was removed on the 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 using 5% ethyl acetate-toluene to 
give 1.01 g (83% yield) of 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid hexyl 
ester as an oil. 
Anal. Calcd for C.sub.28 H.sub.40 O.sub.6 : C, 71.16; H, 8.53. Found: C, 
70.89; H, 8.51. 
EXAMPLE 149 
4-Nitro-3-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid 
phenylmethyl ester 
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 
3-hydroxy-4-nitrobenzoic acid phenylmethyl ester, 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 was stirred and heated at 
reflux for 42 hours. Workup 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 
phenylmethyl ester as an oil. 
Anal. Calcd for C.sub.40 H.sub.39 NO.sub.7 : C, 74.40; H, 6.09; N, 2.17. 
Found: C, 74.58; H, 6.08; N, 2.18. 
EXAMPLE 150 
4-Amino-3[6-(2,3-dihydroxyphenyl)hexyloxy]benzoic acid 
A solution of 5.4 g of 
4-nitro-3-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid 
phenylmethyl ester in 250 mL of tetrahydrofuran and 1 g of 10% palladium 
on carbon was shaken in a hydrogen atmosphere at room temperature for 17 
hours. The catalyst was removed by filtration through celite and he 
filtrate was concentrated under reduced pressure to a solid. 
Recrystallization form ether-methylene chloride gave 1.80 g (62% yield), 
mp 130.degree.-132.degree., of 
4-amino-3-[6-(2,3-dihydroxyphenyl)hexyloxy]benzoic acid. 
Anal. Calcd for C.sub.19 H.sub.23 NO.sub.5 : C, 66.07; H, 6.71; N, 4.06. 
Found: C, 66.09; H, 6.86; N, 3.85. 
EXAMPLE 151 
3-Nitro-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid 
phenylmethyl ester 
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 phenylmethyl 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 was stirred and heated at reflux 
for 5 days. Workup 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)phenyl]hexyloxy]benzoic acid 
phenylmethyl ester as an oil. 
Anal. Calcd. for C.sub.40 H.sub.39 NO.sub.7 : C, 74.40; H, 6.09; N, 2.17. 
Found: C, 74.70; H, 6.14; N, 2.12. 
EXAMPLE 152 
3-Amino-4-[6-(2,3-dihydroxyphenyl)hexyloxy]benzoic acid 
A solution of 6.8 g of 
3-nitro-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid 
phenylmethyl ester in 250 mL of tetrahydrofuran and 1.3 g of 10% palladium 
on carbon was shaken in 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 form acetone-hexane gave 2.36 g (65% yield), mp 
172.degree.-174.degree., of 
3-amino-4-[6-(2,3-dihydroxyphenyl)hexyloxy]benzoic acid. 
Anal. Calcd. for C.sub.19 H.sub.23 NO.sub.5 : C, 66.07; H, 6.71; N, 4.06. 
Found: C, 65.88; H, 6.85; N, 3.89. 
EXAMPLE 153 
1-(6-Bromohexyl)-2,3-dimethoxy-4-(1,1-dimethylethyl)benzene 
To 27.0 g (0.139 mole) of 1,2-dimethoxy-3-(1,1-dimethylethyl)benzene in 350 
mL of anhydrous tetrahydrofuran cooled in an ice-brine bath at -5.degree. 
was added. 87 mL (0.139 mole) of 1.6M butyl lithium in hexane over 30 
minutes. The reaction mixture was stirred at -5.degree. for 3 hours and 
then at reflux for 1 hour. After cooling in an ice bath, 21.5 mL (0.139 
mole) of 1,6-dibromohexane in 75 mL of tetrahydrofuran was 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 at 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. 
Anal. Calcd for C.sub.18 H.sub.29 BrO.sub.2 : C, 60.50; H, 8.18; Br, 22.36. 
Found: C, 60.35; H, 8.25; Br, 22.08. 
EXAMPLE 154 
2-Hydroxy-4[6-[2,3-dimethoxy-4-(1,1-dimethylethyl)phenyl]hexyloxy]-3-propyl 
benzoic acid 
A mixture of 4.0 g (11.2 mmole) of 
1-(6-bromohexyl)-2,3-dimethoxy-4-(1,1-dimethylethyl)benzene, 3.2 g (11.2 
mmole) of 2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester, 3.1 g 
(22.4 mmole) of potassium carbonate and 1.7 g (11.2 mmole) of sodium 
iodide in 70 mL of anhydrous acetone and 7 mL of anhydrous 
dimethylformamide was stirred at reflux for 31 hours. Workup 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-prop 
ylbenzoic acid phenylmethyl ester as an oil. 
Anal. Calcd for C.sub.35 H.sub.46 O.sub.6 : C, 74.70; H, 8.24. Found: C, 
74.96; H, 8.21. 
A solution of 5.25 g of 
2-hydroxy-4-[6-[2,3-dimethoxy-4-(1,1-dimethylethyl)phenyl]hexyloxy]-3-prop 
ylbenzoic acid phenylmethyl ester in 200 mL of tetrahydrofuran and 0.5 g of 
10% palladium on carbon was shaken in a hydrogen atmosphere for 3 hours. 
The reaction mixture was filtered through Celite and the filtrate was 
concentrated to yield 4.0 g mp 106.degree.-108.degree., of 
2-hydroxy-4-[6-[2,3-dimethoxy-4-(1,1-dimethylethyl)phenyl]hexyloxy]-3-prop 
ylbenzoic acid. 
Anal. Calcd for C.sub.28 H.sub.40 O.sub.6 : C, 71.16; H, 8.53. Found: C, 
71.08; H, 8.44. 
EXAMPLE 155 
4-[6-[2,3-Dihydroxy-4-(1,1-dimethylethyl)phenyl]hexyloxy]-2-hydroxy-3-propy 
lbenzoic acid 
To 4.0 g (8.5 mmole) of 
2-hydroxy-4-[6-[2,3-dimethoxy-4-(1,1-dimethylethyl)phenyl]hexyloxy]-3-prop 
ylbenzoic acid suspended in 200 mL of methylene chloride and cooled at 
-70.degree. was added 26 mL (26 mmole) of 1M boron tribromide in methylene 
chloride over 30 minutes. The reaction mixture was stirred at -70.degree. 
for 30 minutes and kept at -20.degree. for 41 hours. Workup as in Example 
32 and recrystallization of the crude product from ether-hexane gave 1.78 
g (47% yield), mp 85.degree.-87.degree., of 
4-[6-[2,3-dihydroxy-4-(1,1-dimethylethyl)phenyl]hexyloxy]-2-hydroxy-3-prop 
ylbenzoic acid. 
Anal. Calcd for C.sub.26 H.sub.36 O.sub.6 : C, 70.24; H, 8.16. Found: C, 
69.87; H, 8.11. 
EXAMPLE 156 
4-[6-(2,3-Dihydroxyphenyl)hexyloxy]benzoic acid ethyl ester 
A mixture of 2.4 g (5.3 mmole) of 
1-(6-bromohexyl)-2,3-bis-(phenylmethoxy)benzene, 0.88 g (5.3 mmole) of 
4-hydroxybenzoic acid ethyl ester, 2.5 g (18 mmole) of potassium carbonate 
and 0.8 g (5.3 mmole) of sodium iodide in 40 mL of acetone was stirred at 
reflux for 22 hours. Workup as in Example 16 and recrystallization of the 
crude product from ethyl acetate-hexane gave 2.3 g, mp 
63.degree.-65.degree. (81% yield) of 
4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid ethyl ester. 
Anal. Calcd for C.sub.35 H.sub.38 O.sub.5 : C, 78.04; H, 7.11. Found: C, 
77.89; H, 7.00. 
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 in 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, mp 45.degree.-47.degree., (85% yield) to 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]benzoic acid ethyl ester. 
Anal. Calcd. for C.sub.21 H.sub.26 O.sub.5 : C, 70.37; H, 7.31. Found: C, 
70.31; H, 7.50. 
EXAMPLE 157 
4-[6-(2,3-Dihydroxyphenyl)hexyloxy]-2-hydroxybenzoic acid ethyl ester 
A mixture of 1.0 g (2.9 mmole) of 
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxybenzoic acid, 0.295 g (3.5 
mmole) of sodium bicarbonate and 2.4 mL (29 mmole) of ethyl iodide in 10 
ml of anhydrous dimethylformamide was stirred at 50.degree. for 6 hours. 
The solvent was removed on the oil pump and the residue was treated with 
sodium bicarbonate solution. The product was extracted with ethyl acetate 
and the dried extract was concentrated at reduced pressure to a solid. 
Recrystallization from ether-hexane gave 0.8 g, mp 63.degree.-68.degree., 
(74% yield) of 4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxybenzoic acid 
ethyl ester. 
Anal. Calcd for C.sub.21 H.sub.26 O.sub.6 : C, 67.36; H, 7.00. Found: C, 
67.41; H, 7.13. 
EXAMPLE 158 
4-[6-(3,4-Dihydroxy-2,5-dimethylphenyl)hexyloxy]-2-hydroxy-3-propolybenzoic 
acid ethyl ester 
A mixture of 0170 g (1.68 mmole) of 
4-[6-(3,4-dihydroxy-2,5-dimethylphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic 
acid, 0.157 g (1.87 mmole) of sodium bicarbonate and 1.4 mL (16.8 mmole) 
of ethyl iodide in 10 mL of dimethylformamide was stirred at 50.degree. 
for 10 hours. Workup as in Example 160 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, mp 61.degree.-64.degree., (67% yield) of 
4-[6-(3,4-dihydroxy-2,5-dimethylphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic 
acid ethyl ester. 
Anal. Calcd for C.sub.26 H.sub.36 O.sub.6 : C, 70.24; H, 8.16. Found: C, 
70.21; H, 8.20. 
EXAMPLE 159 
TABLET FORMULATION (Wet Granulation) 
______________________________________ 
mg/tablet 
Item Ingredient 100 mg 500 mg 
1000 mg 
______________________________________ 
1. 4-[6-(2,3-dihydroxyphenyl) 
100 500 1000 
hexyloxy]-2-hydroxy-3- 
propyl-benzoic acid. 
2. Lactose 132 -- -- 
3. Pregelantinized Starch 
16 30 50 
4. Modified Starch 30 40 50 
5. Magnesium Stearate 
2 6 8 
TOTAL 280 576 1108 
______________________________________ 
Manufacturing Procedure: 
1. Mix items 1, 2, 3 and 4 and granulate with water. 
2. Dry the granulation at 50.degree. C. 
3. Pass the granulation through suitable milling equipment. 
4. Add item 5 and mix for three minutes; compress on a suitable press. 
EXAMPLE 160 
CAPSULE FORMULATION 
______________________________________ 
Ingredient mg/capsule 
______________________________________ 
1. 4-[6-(2,3-dihydroxyphenyl) 
25 50 100 500 
hexyloxy]-2-hydroxy-3-propyl- 
benzoic acid. 
2. Lactose Hydrous 143 168 148 -- 
3. Corn Starch 20 20 40 70 
4. Talc 10 10 10 25 
5. Magnesium Stearate 2 2 2 5 
TOTAL 200 250 300 600 
______________________________________ 
Manufacturing Procedure: 
1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes. 
2. Add items 4 and 5 and mix for 3 minutes. 
3. Fill into suitable capsules. 
EXAMPLE 161 
WET GRANULATION FORMULATION 
______________________________________ 
Ingredient mg/tablet 
______________________________________ 
1. 4-[6-(2,3-dihydroxyphenyl) 
25 50 
hexyloxy]-2-hydroxy-3-propyl- 
benzoic acid. 
2. Polyvinyl Pyrrolidone 
5 10 
3. Lactose Anhydrous DTG 
133 142 
4. Microcrystalline Cellulose 
25 30 
5. Modified Starch 10 15 
6. Magnesium Stearate 2 3 
TOTAL 200 250 
______________________________________ 
Manufacturing Procedure: 
1. Dissolve Item 2 in water. 
2. Mix Items 1, 3, 4 and 5 in a suitable mixer and granulate with solution 
in Step 1. 
3. Dry overnight at 45.degree. C., screen through #20 mesh, and add Item 6 
and mix. Compress on a suitable press. 
EXAMPLE 162 
CREAM 5% 
The following is the quantitative composition of drug: 
______________________________________ 
Reasonable 
Ingredient g/kg Variations 
______________________________________ 
1. 4-[6-(2,3-dihydroxyphenyl) 
51.50* -- 
hexyloxy]-2-hydroxy-3-propyl- 
benzoic acid. 
2. Glyceryl Monostearate S.E..sup.1 
100.00 80-120 
3. Polysorbate 60.sup.2 
20.00 15-25 
4. Cetyl Alcohol 50.00 40-60 
5. Petrolatum 70.00 50-90 
6. Methylparaben 1.50 1.25-1.75 
7. Propylparaben 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. 
.sup.1 Arlacel 165 
.sup.2 Tween 60 
EXAMPLE 163 
SOFT GELATIN CAPSULE FORMULATION 
______________________________________ 
Ingredient mg/capsule 
______________________________________ 
1. 4-[6-(2,3-dihydroxyphenyl) 
50 150 
hexyloxy]-2-hydroxy-3-propyl- 
benzoic acid. 
2. Polyethyleneglycol 400 
325 550 
3. Med. Change Monoglycide 
100 150 
4. Polysorbate 80 25 50 
TOTAL 500 1000 
______________________________________ 
Manufacturing Procedure: 
1. Dissolve Item 1 in Item 2. 
2. Add Item 3 and mix well. 
3. Add Item 4 and mix well until dissolved. 
4. Fill in soft gelatin capsules. 
EXAMPLE 164 
BEADLET FORMULATION (ENTERIC) I 
______________________________________ 
Beadlets mg/capsule 
______________________________________ 
1. 4-[6-(2,3-dihydroxyphenyl) 
25 100 250 
hexyloxy]-2-hydroxy-3-propyl- 
benzoic acid. 
2. Microcrystalline cellulose 
100 200 250 
3. Polyvinyl pyrrolidone K-90 
10 20 30 
TOTAL 135 320 530 
______________________________________ 
Procedure: 
1. Mix with microcrystalline cellulose and granulate with a solution of pVP 
K-90. 
2. Pass the granulation through an extruder and marumarizer to obtain 
uniform beads. 
3. Coat the beads with an enteric polymer such as Polyvinyl Acetate 
Phthlate, Hydroxypropyl Methylcellulose Phthlate, Cellulose Acetate 
phthlate, or an Acrylic Polymer. 
4. Fill into capsules at the appropriate fill weight. 
Beadlet Formulation (Enteric) II 
Starting with non-pareil seeds, deposit on the seeds with an appropriate 
polymer, such as Polyvinyl Pyrrolidone, Hydroxypropyl Cellulose, 
Hydroxypropyl Methylcellulose or the like. Dry the seeds and apply an 
enteric membrane such as Polyvinyl Acetate Phthlate, Hydroxypropyl 
Methylcellulose Phthlate, Cellulose Acetate Phthlate and/or an Acrylic 
Polymer. Determine the concentration of the drug per gram of Beadlet and 
fill into capsules.