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Patent 1328279 Summary

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(12) Patent: (11) CA 1328279
(21) Application Number: 1328279
(54) English Title: CATECHOL CARBOXYLIC ACID DERIVATIVES
(54) French Title: DERIVES DE L'ACIDE CATECHOLCARBOXYLIQUE
Status: Expired and beyond the Period of Reversal
Bibliographic Data
(51) International Patent Classification (IPC):
  • C07C 49/84 (2006.01)
  • A61K 31/19 (2006.01)
  • C07C 45/46 (2006.01)
  • C07C 45/67 (2006.01)
  • C07C 45/71 (2006.01)
  • C07C 65/24 (2006.01)
  • C07C 65/40 (2006.01)
  • C07C 229/64 (2006.01)
(72) Inventors :
  • CARSON, MATTHEW (United States of America)
  • HAN, RU-JEN LEE (United States of America)
  • LEMAHIEU, RONALD ANDREW (United States of America)
(73) Owners :
  • F. HOFFMANN-LA ROCHE AG
(71) Applicants :
  • F. HOFFMANN-LA ROCHE AG (Switzerland)
(74) Agent: GOWLING WLG (CANADA) LLP
(74) Associate agent:
(45) Issued: 1994-04-05
(22) Filed Date: 1988-09-28
Availability of licence: N/A
Dedicated to the Public: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): No

(30) Application Priority Data:
Application No. Country/Territory Date
103,789 (United States of America) 1987-10-01
223,470 (United States of America) 1988-07-22

Abstracts

English Abstract


Abstract
The invention relates to catechol carboxylic acid
derivatives of the formula
<IMG> I
wherein,
R1 is -C(O)OR, acetyl, hydrogen, hydroxy or alkanoyloxy,
R2 is -C(O)OR, hydroxy, hydrogen or alkanoyloxy,
wherein R is hydrogen, lower alkyl or
-(CH2)n-N-(lower alkyl)2,
R3 is hydrogen, lower alkyl or amino,
R4 is hydrogen, lower alkyl, halogen or amino
A is
<IMG> A'
wherein, R5 is hydrogen or acyl, R6 is hydrogen,
halogen, lower alkyl, aryl or cycloalkyl, and R7 and
R8, independently, are hydrogen, lower alkyl or
halogen, or
A is

<IMG> A"
wherein, R5 is hydrogen or acyl, R9 is hydrogen,
lower alkyl, R10 is hydrogen, lower alkyl or halogen,
R11 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 R1 or R2 can be -C(O)OR,
and when R is hydrogen, salts thereof with pharmaceutically
acceptable bases or when R is -(CH2)n-N-(lower alkyl)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 bronchpulmonary
diseases such as asthma.


Claims

Note: Claims are shown in the official language in which they were submitted.


- 114 -
Claims:
1. Compounds of the formula
<IMG> I
wherein,
R is -C(O)OR, hydrogen, acetyl, hydroxy or alkanoyloxy,
R2 is -C(O)OR, hydroxy, hydrogen or alkanoyloxy,
wherein R is hydrogen, lower alkyl or
-(CH2)n-N-(lower alkyl)2,
R3 is hydrogen, lower alkyl or amino,
R4 is hydrogen, lower alkyl, halogen or amino, and
A is
<IMG> (A')
or
<IMG> (A")
wherein, R5 is hydrogen or acyl, R6 is hydrogen,
halogen, lower alkyl, phenyl or (C3-C6), cyc1oalkyl, and R7 and

- 115 -
R8, independently, are hydrogen, lower alkyl or
halogen, R9 is hydrogen or lower alkyl, R10 is lower
alkyl, hydrogen or halogen, R11 is hydrogen, lower
alkyl, (C3-C6) cycloalkyl or halogen, m is 0 or 1, n is an
integer of 2 to 10, provided, that only one of R1 or
R2 can be hydroxy, alkanoyloxy or -C(O)OR ,
and, when R is hydrogen, a salt thereof with a phacmaceuti-
cally acceptable base, and, when R is -(CH2)n-N-(lower
alkyl)2, an addition salt thereof with a pharmaceutically
acceptable acid.
2. Compounds in accordance with Claim 1, of the formula
<IMG> Ia
wherein R1 is carboxy or acetyl, R2 is hydroxy, R3
is hydrogen, propyl or amino, R4 is hydrogen, chloro or
amino, n is an integer from 2 to 10, R5 is hydrogen or
acetyl, R6 is hydrogen, lower alkyl or phenyl, and R7
and R8 are hydrogen.
3. A compound in accordance with claim 1, of the formula
<IMG> Ib

- 116 -
wherein R1 is carboxy or acetyl, R2 is hydroxy, R3
is hydrogen, propyl or amino, R4 is hydrogen, chloro or
amino, m is 0 or 1, n is an integer from 2 to 10, R5 is
hydrogen or acetyl, R9 and R10 are hydrogen, and
R11 is hydrogen or chloro.
4. The compounds of formula I given in claim 1, wherein R6
is hydrogen, lower alkyl, phenyl or (C3-C6) cycloalkyl and the
remaining symbols have the significance given in claim 1:
and, when R is hydrogen, a salt thereof with a pharmaceuti-
cally acceptable base, and, when R is -(CH2)n-N-(lower
alkyl)2, an addition salt thereof with a pharmaceutically
acceptable acid.
5. 4-[6-(2,3-Dihydroxyphenyl)hexyloxy]-2-hydroxybenzoic acid.
6. 4-[4-(2,3-Dihydroxyphenyl)butoxy]-2-hydroxy-3-propylbenzoic
acid:
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propyl-
benzoic acid;
4-[8-(2,3-dihydroxyphenyl)octyloxy]-2-hydroxy-3-propyl-
benzoic acid:
4-[6-[2,3-bis(acetyloxy)phenyl]hexyloxy]2-hydroxy-3-propyl-
benzoic acid; and
4-[6-[2,3-dihydroxy-4-(1-methylethyl)phenyl]hexyloxy]-2-
hydroxy-3-propylbenzoic acid.
7. 4-[3-(3,4-Dihydroxyphenyl)propoxy]-2-hydroxy-3-propyl-
benzoic acid;
4-[6-(3,4-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propyl-
benzoic acid;
4-[[6-(3,4-dihydcoxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-
propylbenzoic acid; and
1-[2-hydroxy-4-[4-(2,3-dihydroxyphenyl)butoxy]-3-propyl-
phenyl]ethanone.

- 117 -
8. 4-[6-[2,3-Dihydroxy-4-(1.1-dimethylethyl)phenyl]hexyloxy]-
2-hydroxy-3-propylbenzoic 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-propylbenzoic 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-propylbenzoic acid:
4-[8-[2,3-dihydroxy-4-(1,1-dimethylethyl)phenyl]octyloxy]-
2-hydroxy-3-propylbenzoic 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-[4-[2,3-dihydroxyphenyl]butoxy]-3,5-dipropyl-2-hydroxy-
benzoic 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-propylbenzoic acid:
2-acetyloxy-4-[6-(2,3-dihydroxy-4-(1-methylethyl)phenyl]-
hexyloxy]-3-propylbenzoic acid:
4-[6-[2,3-bis[4-methylbenzoyl)oxy]-4-(1-methylethyl)-
phenyl]hexyloxy]-2-hydroxy-3-propylbenzoic acid:
1-[2-hydroxy-4-[6-(2,3-dihydroxy-4-(1,1-dimethylethyl)-
phenyl]hexyloxy]-3-propylphenyl]ethanone;

- 118 -
1-[2-hydroxy-4-[8-[2,3-dihydroxy-6-fluorophenyl]octyloxy]-
3-propylphenyl]ethanone;
1-[2-hydroxy-4-[6-[6-chloco-2,3-dihydroxyphenyl]hexyloxy]
3-propylphenyl]ethanone;
1-[2-hydroxy-4-[6-[5,6-dichloro-2,3-dihydroxyphenyl]hexyl-
oxy]-3-propylphenyl]ethanone;
1-[2-hydroxy-4-[6-[2,3-dihydroxy-4,5,6-trichlorophenyl]-
hexyloxy]-3-propylphenyl]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-[5-[2,3-dihydroxy-4-(1-methylethyl)phenyl]hexyloxy]-2-
hydroxy-3-propylbenzoic acid ethyl ester;
4-[6-[2,3-dihydroxy-4-(1-methylethyl)phenyl]hexyloxy]-2-
hydroxy-3-propylbenzoic 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-[6-(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-
pcopylbenzoic 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;

- 119 -
4-[4-[3,4-dihydroxy-5-(1-methylethyl)phenyl]butoxy]-2-
hydroxy-3-propylbenzoic 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-propyl-
benzoic acid;
4-[4-[3,4-dihydroxy-5-(1-methylethyl)phenyl]-4-oxobutyl]-
oxy]-2-hydroxybenzoic acid;
4-[6-[3,4-dihydroxy-2-(1-methylethyl)phenyl]hexyloxy]-2-
hydroxy-3-propylbenzoic acid;
4-[4-(3,4-dihydroxy-2,5-dimethylphenyl)-4-oxobutyl]oxy]-2-
hydroxy-3-propylbenzoic 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-propylbenzoic acid;
4-[6-(3,4-dihydroxy-5,6-trimethylphenyl)hexyloxy]-2-
hydroxy-3-propylbenzoic acid:
1-[2-hydroxy-4-[6-(3,4-dihydroxyphenyl)hexyloxy]-3-propyl-
phenyl-1-ethanone;
l-[2-hydroxy-4-[8-(3,4-dihydroxyphenyl)octyloxy]-3-propyl-
phenyl-1-ethanone;
1-[2-hydroxy-4-[6-(3,4-dihydroxy-2,5-dimethylphenyl)hexyl-
oxy]-3-propylphenyl-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.
9. The compounds of any one of claims 1-8 for use as
medicament.

- 120 -
10. A process for the preparation of the compounds according
to claim 1 which comprises reacting a compound of the formula
<IMG> or <IMG>
III XXXVI
with a compound of the formula
<IMG>
XXXIII
to produce a compound of the formula
<IMG> or <IMG>
XXXIV XXXVII
or reacting a compound of the formula
<IMG>
XXXIX
with a compound of the formula

- 121 -
<IMG>
XXXX
to produce a compound of the formula
<IMG>
XXXXI
wherein
R1' is hydrogen, lower alkoxy carbonyl or acetyl;
R2' is hydrogen, or lower alkoxy carbonyl:
R12 is benzyl or acyl,
R13 is benzyl; X is bromo or methanesulfonyloxy;
and the remaining symbols are as in claim 1;
provided that no more than one of R1' or R2' can be
hydroxy or lower alkoxy carbonyl, or that no more than
one of R1" or R2" can be carboxy or hydroxy;
cleaving the methoxy groups in a compound of formula XXXIV or
XXXVII;
cleaving the benzyl ester and any benzyl ester groups R12
in a compound of the formula XXXXI; is desired, esterifying
the hydroxy group in a compound of formula XXXXI wherein R2
is hydroxy and R112 is benzyl and cleaving the benzyl
groups,
and, if further desired, esterifying a carboxy group
represented by R1 or R2 a converting it into a salt with
a pharmaceutically acceptable base or converting a di-lower
alkyl substituted amino group into a salt with a pharma-
ceutically acceptable acid.

- 122 -
11. Pharmaceutical compositions containing a compound
according to claim 1 with a pharmaceutically acceptable acid
or base.
12. The compounds according to claim 1 for use in the manu-
facture of pharmaceutical preparations for the treatment of
inflammatory, cardiovascular or bronchopulmonary diseases.

13. A compound of the formula
<IMG>
XXXIV
wheein R1' is - C(O)OR', acetyl, hydrogen or hydroxy,
R2' is -C(O)OR', hydrogen or hydroxy, R' is hydrogen or
lower alkyl, R3 is hydrogen or lower alkyl, R4 is
hydrogen, lower alkyl or halogen, R6 is hydrogen, lower
alkyl, phenyl or (C1-C6) cycloalkyl, R7 and R8 are hydrogen,
lower alkyl or halogen, and n is an integer from 2 to 10,
provided that no more than one of R1' or R2' is
-C(O)OR', or hydroxy.
14. 4-[6-(2,3-Dimethoxyphenyl)hexyloxy]-2-hydroxy-3-propyl-
benzoic acid and the methyl ester thereof.
15. A compound of the formula
<IMG>
XXXVII
wheein R1' is -C(O)OR', acetyl, hydrogen or hydroxy,
R2' is -C(O)OR', hydrogen or hydroxy, R' is hydrogen or
loweralkyl, R3 is hydrogen or lower alkyl, R4 is
hydrogen, lower alkyl or halogen, R9 is hydrogen or
lower alkyl, R10 is hydrogen, lower alkyl or halogen,
R11 is hydrogen, loweralkyl (C3-C6) cycloalkyl or halogen,
is 0 or 1, and n is an integer from 2 to 10, provided
that no more than one of R1' or R2' is -C(O)OR' or
hydroxy.

Description

Note: Descriptions are shown in the official language in which they were submitted.


1 328279
RAN 4070/72
The invention relates to catechol carboxylic acid
derivatives of the formula
A-O
wherein
Rl is -C(O)OR, hydrogen, acetyl, hydroxy or
alkanoyloxy,
R2 is -C~O)OR, hydroxy, hydrogen or alkanoyloxy,
wherein R is hydrogen, lower alkyl or -(CH2)nN
(lower alkyl)2,
R3 is hydrogen, lower alkyl or amino,
R4 is hydrogen, lower alkyl, halogen or amino,
A is
CR~
25 ~ A'
R ~ ~(C~'2)n
~a
,wherein R5 is hydrogen or acyl~ R6 is hydrogen,
halogen, lower alkyl, aryl or cycloalkyl, and R7 and
R8, independently, are hydrogen, lower alkyl or
halogen, and n is an in~eger of 2-lO, oc
A is
Grn/5.9.88
. .
.

1 3~279
-- 2
C!f:l
RsO~R
Il I ~"
Rg/~\ (C~m--(C~ 2)n
Fl1o 11
,wherein R5 is hydrogen or acyl, Rg is hydrogen or
lower alkyl, Rlo is hydrogen, lower alkyl or.halogen,
Rll is hydrogen, lower alkyl, cycloalkyl or halogen, m
is 0 or l, n is an integer of 2-lO, provided that no
more than one of Rl or R2 can be hydroxy,
alkanDyloxy or -C(O)OR,
and, when R is hydrogen, salts theeeof with ~harmaceutically
acceptable bases, and, when R is (CH2)n-N--(lower
alkyl)2, ~ddition salts the~eof with pharmaceutically
acceptable aclds.
: ~ The comeounds of formula I aLe 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.
~:~ : 25
;: ~s u ed herein, the term "lower alkyl" denotes a
straight or branched chain saturated hydrocarbon containing
l to 7 carbon atoms, for example, me~hyl, ethyl, eropyl,
isoproeyl, butyl, t-butyl, neopentyl, eentyl, heptyl, and
. 30 the like. Branched chain saturated hydrocarbons are
pre~erred for R6, Rg and Rll. The term "halogen"
~ denotes all the halogens, that is, bromine, chlorine,
::: fluorine, and iodine. The ~erm "aryl" denotes phenyl or
~: phenyl bearing one or two substituents independently
selected from the group consisting of halogen, trifluoro-
:~ methyl, lower alkyl, lower alkoxy, nitro, amino, lower
.
~ ~ alkylamino and di-lower alkylamino. The term "acyl'l denotes

1 32827q
an "al~anoyl" group derived from an aliphatie carboxylic
acid of l to 7 carbon atoms, for axample, focmyl, aeetyl,
~ropionyl, 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 de~ived feom
an aliehatic carboxylic acid of l to 7 carbon atoms, for
example, formyloxy, acetoxy, propionyloxy, and the like.
The term ~cycloalkyl~' d~notes ~referably a cyclic hydro-
carbon of 3 to 6 carbon atoms which may be unsubstituted or
substituted by lower alkyl and most ~referably of 5 to 6
caebon atoms, for example, cyclopropyl, cyelopentyl,
cyclohexyl or the like.
The compounds of ~ormula I can also be characterized by
the formulas Ia and Ib, de~ending u~on whether the moiety A
is fragment A' or A", respectively, as follows:
~(~CI~ )n 0)~/
R~
or
~ Clm ~C~ C$/ Ib
wherein Rl. R2 ~ R3 R4 ~ Rs, 6 7 8
Rg, RLo~ Rll, m and n are as herein described.
Preferred compounds of formula Ia of ~he invention are
those wherein Rl is carboxy o~ acetyl, R2 is hydroxy,
R3 is hydcogen or propyl, R~ is hydrogen or chloro, n is

1 328279
-- 4 --
an integer 2-lO, R5 is hydrogen or acetyl, R6 is
hydrogen, lower alkyl or acyi, R7 and R8 are hydrogen.
Prefecred compounds of formula Ib of the invention are
those wherein Rl is carboxy or acetyl, R2 is hydroxy,
R3 is hyd~ogen or eropyl, ~4 is hydeogen or chloeo, m is
0 or l, n is an integer from 2-lO, R5 is hydrogen OL
acetyl, Rg and Rlo are hyd~gen, and Rll is hyd~ogen
or chloro.
More preferred compounds of formula Ia are those wherein
Rl is carboxy or acetyl, R2 ls hydcoxy, R3 is hydrogen
or propyl, R4 is hyd~ogen or chloro, n is an integer from
4 to 8, R5 is hydrogen or acetyl, R6 is hydrogen or
lower alkyl and R7 and R8 are hydrogen.
More prefer~ed compounds of formula Ib are tnose
wherein Rl is carboxy or acetyl, R2 is hydroxy, R3 is
n-propyl, R4 is hydrogen, m is O, n is an integer from
4-6, R5 is hydrogen or acetyl, ~9 and Rlo are
hydrogen, Rll is hydrogen or chlo~o.
Most preferred compounds of foLmula Ia are those wherein
Rl is carboxy or acetyl, R2 is hydroxy, R3 is
n-pro~yl, R4 is hydrogen, n is an integer from 4-8, R5
is hydrogen , R6 is hydrogen or ~-branched lower alkyl,
~nd R7 and R8 are hydrogen.
Most ~referred com~ounds of formula Ib are those wherein
30 Rl i6 carboxy or acetyl, Rz is hydroxy, R3 is
n-~ropyl, R4 is hydrogen, m is 0, n is an integer from 4
, 5, Rg, Rlo and Rll are hydrogen.
The ~referred compounds of the invention are:
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxybenzoic
acid;
- . -
.
.. , , ~ . ::, , -

1 ~28279
-- 5
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]-
Z-hydroxy-3-proeylbenzoic acid;
4-~4-(2,3-dihydroxyphenyl)butoxy]-2-hydroxy-3-propyl--
benzoic acid;
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-pLopyl-
benzoic acid:
4-~8-(2,3-dihydroxyehenyl)octyloxy]-2-hydroxy-3-propyl-
benzoic acid:
4-[6-~2,3-bis(acetyloxy)phenyl]hexyloxy]-2-hydroxy-3-
propylbenzoic acid:
4-[6-[2,3-dihydroxy-4-(l-methylethyl)phenyl]hexyloxy]-2-
hydroxy-3-propylbenzoic acid;
4-[3-(3,4-dihydcoxyphenyl)p~opoxy]-2-hydroxy-3-propyl--
benzoic acid;
4-[6-(3,4-dihydroxyphenyl)hexyloxy]-Z-hydroxy-3-propyl-
benzoic acid;
4-~6-(3,4-dihydroxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-
propylbenzoic acid; and
l-~2-hydroxy-4-~4-(2,3-dihydroxyphenyl)butoxy]-3-eropyl-
phenyl]ethanone.
In accordance with this invention, the compounds of
Formula I, and intermediates therefor, can be prepared by
reacting a compound of the formula
.
oc:-, . cc~;
;c~ 6r or ~9~(Qn - ~CI~ .Y
?.~ R lo
nI ,'{Xx~ I
3~i
with a compound of the formula
" '
~ ' ~
- . ~ ,

1 32~279
to ~roduce a compound of the formula
0 IC ~ ~ ~d~O~R,, ~i~-'`~
~;c-,n - C I ~ or ~ ~ (C,-(C-:~o
'3 - ~ lo 1I R~,
.YIV
Y'~YII
: 15
or reacting a compound of the formula
OR 12
R~ C~)n
R4
with a compound of the formula
. , .
R3J~coc;~2~ '
J~
HO
R~
XX~:Y
~ to produce a compound of ~he formula
:

1 ~2827q
- 5b -
C R . - C '` C: ' 2--'~
~; R4
wherein
Rl' is hydrogen~ lower alkoxy carbonyl or acetyl:
R~' is hydrogen, or lower alkoxy carbonyl;
Rl2 is benzyl or acyl,
Rl3 is benzyl: X is bromo or methanesulfonyloxy;
a~d the remaining symbols are as in claim l;
provided that no more than one of Rl' or R2' can be
hydroxy or lower alkoxy carbonyl, or that no more than
one of Rl" or R2" can be carboxy or hydroxy:
cleaving the methoxy groues in a compound of formula XXXIV
or XXXVII:
cleaving the benzyl ester and any benzyl ester groups Rl2
in a compound of the formula XXXXI: if desired~ esterifying
the hydroxy group in a compound of formula XXXXI wherein
R2 is hydroxy and RLl2 is benzyl and cleaving ~he benzyl
groups,
and, if further desired, esteri~ying a carboxy ~roup
represented by Rl or R2: a converting it into a salt
with a pharmaceutically acceptable base or converting a
di-lower alkyl substituted amino group into a salt wi~h a
: pharmaceutlcally acceptable acid.
The pre~aration of the compounds of formula I and inter-
media~es therefor is described in more detail in Reaction
Schemes I to XII.
:
- , ~: . . ..
, ~.: :.
-, : . : : :
: , . .. .. ~ . ~ - . .

1 32827q
-- 6
REACTION SCHEM~
CCH3
OC!-13 . CC.
1) C4~ r~OCr.3
~) 3r(C~ 3r R~ ~ (C:'2;n-r
II nI
¦~Er;
r :
~C;~2
:~ 15 )~OC~a~ ~C.'-'2C! F.,~
r,~ L
Pa (C~ '2)n~ 3C~ ~~ F ~ (C ~2)n^'r
'3~ C~
~: 25
,~ O , ~_.;c
C;' ~ O .^_~ O C~
~-3~C-C~ 3 _~ (C~
r., ~ (C:~~ r
T
~II
~ ~ .
wherein R6, R7, R~ and n aee as ereviously
desccibed, and ~c is acetyl.
:~:
:. : :,. : . :: . ~ : ~ - :

1 3~8~9
In Reaction Scheme I, a compound of formula II, which
are known compounds or can be prepared according to known
~rocedures, 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. Peckin I, 2331
(1980). More particularly, a com~ound of formula II is
reacted with an alkyl lithium reagent, preferably butyl
lithium, in the ~resence of a solvent such as diethylethec,
tetrahydrofuran or the like at a temperature in the range of
from about -75 to ~, 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 to 500.
A compound of formula III can be converted to the
corresponding comeound of form~lla IV, for example, with
boron tribeomide in a halogenated hydrocarbon solvent, for
example, chloroform or l,Z-dichloroethane or preferably
methylene chloeide at a temperature in the range of from
about -75 to about 25.
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 to about 100.
The compound of formula IV can be conve~ted to a
corres~onding comeound of formula VI in the ~cesence of
acetic anhydride and acid catalyst, for example, perchlocic
acid, in a sclvent such as ethyl acetate and the like, at a
tem~ecature in the range of from 0 to about 25.
i,~

1 32~27q
-- 8
Alternatively, the resulting compound of formula IV can
be converted to a corresponding compound of ~ormula 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 temeerature in the range of
from 0 to about 25.

1 328~79
g
REACTION SCHEME I I
5 CC~13 C~3 CC:'3 .
~ccH3 ",~c~ c~oC~,O~
F~7 C~10 2) Ht R7~ CH(C~31n~H
R3 . . 1~8 1
CH
10 Vtll
. .
I r2
¦ Pd
T
CC:'3 CCr:3
r I CC:' CH,5O2rl ~CC~
,-7 1 (C-2~nCn2C~; 2C~a ~/ (C '~
r~ ~ ?
: X l ~
~ .
whe~ein R6, R7 and R8 and n are as previously
described.
~ ~ ,
,
~: 35~
.

1 328279
-- 10 --
In Reaction Scheme II, an aldehyde of formula VIII,
which are known compounds or can be erepared according to
known proceduces, 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, tetrahydcofuran or the like, at a
temperatuce in the range of from about -20 to about 35.
The alcohol protecting group can be removed from the product
by treatment with dilute hydrochloric acid at 25 to give a
diol of formula IX.
Thereafter, hydrogenolysis of a com~ound of formula IX
gives the corresponding compound of formula X by shaking on
a Parr apparatus under hydrogen pressure of from about
40-60psi, using a palladium catalyst, at a temperature in
the range of from about 25 to about 50, in a solvent, such
as, ethyl acetate, ethanol, tetrahydrofuran and the like.
Conversion of a com2ound of formula X to the
corresponding mesylate XI can be carried out under standard
conditions, for example, with methaneulfonyl chloride and
triethylamine in a solvent such as methylene chloride aS a
temeerature in the range of from about -20 to about 25O.
.
, ~ .
.
".
: . .

1 32827~
11
REACTION SCHE~ME III
CC~3 C'3 CC~3
C'13O ~ Rll 1) Li(Ch,),jjOCHOC~.CH; ~ R
l ~ I
/ ~ CHO ~) H~ ~9 ~ C:-,(CH23nCH
Rlo R10 C;~
.~II X3
. :
~ .
.
: GC~i3 CC~3
20~ Rl1 CE~SO~CI CHlO ~ nj,
~9 ~ (C~2)nC'~~i2~S~2C~~3 r- I !C 2`n~'C'
Fijo
Y
:
:
SO wherein Rg. Rlo, Rll and n are as previously
: described.
~: :
~ .
::

113~8279
In Reaction Scheme III, a com~ound of formula XII can be
converted to a corresponding comeound of formula XIIl and
which in turn can be convected to corLesponding compounds of
foemulas XIV and XV, utiliæing the reaction conditions set
~ forth in Reaction Scheme II.
: ~'
~'
'
", , . , -

f~,
1 32~27q
-- 13 --
REP~CT I ON SCHEME IV
oc~3 CCn3
(C~2~n8r ~ CC:~
m c~
101 . XYI
3C7 \a2
. ~ \ .
CC'.-13 ~ \ CC."3
C'~¢~ C~`n \ C J¢~ cc _
Cl C;
xYm . ~YII
~ r ~ ~
Cl~ C:'.^
W~ r'~
~Cl2!n~H C~
YIX
~: : wherein n is as ~reviously described.
. .

1 32~279
- 14 -
In Reaction Scheme IV, a compound of formula III, which
are known compounds or can be pre~ared according to known
procedures, can be converted to the corceseonding monochloro
compounds of formula XVI, the dichloro compounds of formula
XVII and the trichloro compounds of formula XVIII by
treatment with the appropriate qua~ltity of chlorine, in an
inert solvent such as a chlorinated hydrocarbon, foe
example, methylene chloride, chlorofoem, L,2-dichloromethane
and the like, at a temperature in the range of from about
-20 to about 25.
The conversion of a com~ound of formula XIX to the
corresponding comeound of foemula XX can be carried out
utilizing the reaction condition first described abo~e.
:: . ~ ; . . . .

1 3~8279
-- 15 --
REACT I ON S CH~3ME V
QC:'3 CC:'3
CH30 J~ ~11 c~,oJ~"~R;
'11 `t' _-c~- Ll 1~
Rg Er [(C~5)3P],PdC~ /~'' C.~ ~;C: '2~n'`~;
(C~5)3~ ~'
~XI
~~
1 5
CC:-!3 rr - 3
.~ 20C:J30~ C~ SO^
/~''J\ C'. '2C'. '^~C.i^!n~,7C:-3 r,. C:
'~,IV
,
wherein Rg, Rll and n are as previously described.
~:

1 328279
- 16 -
In Reac~ion 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) a~ described in K.
Sonogashira, Y. Tohda and N. Hagihara, Tet. Letters, 4467
(1975).
The reaction is carried out in a solvent, for example, a
1~ halogenated hydrocarbon, for example, methylene chloride,
chloroform, L,2-dichloroethane and the like, at a
temperature in the range of from about 25 to about 50.
A resulting compound of formula XXII i5 converted to a
compound of formula XXIII utilizing standard conditions, for
example, catalytic hydrogenation at atmospheric eressure 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 methylane chloride, as the solvent at a
temperature in the range of from about -20 to about 25.
3S
:
.

- l7 -
REACTION SCHEME VI
CC'-i3 0 CC. ?3
: CiR30 ~ R11 Br(~rl,)~COH CR30
L O ICI--(C~z)n_~
X~Y X~VI
- . P~i
,
CC'-?3
- C:-?3
~: 20 i
R_/~ C. ?2--;C.-?^!.,-
:: , .
1~ ~XYII
;~ 25
wherein Rg, Rll and n are as previously~described.
;

1 328279
- 18 -
In Reaction Scheme VI, a compound of fo~mula xXv~ which
ace known compounds or can be prepaeed according to known
procedures, can be converted to a compound o~ ~ormula XXVI
utili2ing standard acylation conditions, for example,
treatment wlth a bromo acid and trlfluoroacetic anhydride at
a temperature in the eange of from 250 to about 40 wlthout
&olve~t or with a ~olvent such as methylene chloride,
1,2-dichloroethane o~ the like. Alternatively, a bromoacid
chloride and aluminum chloride in a solvent such a~
methylene chloride or 1,2-dichloroethane at a temperature in
the range of from 0 to about 40 can be also be utilized.
The reduction of a com~ound of foemula XXVI to the
correspondin~ compound of formula XXVII can be accomplished
by hydrogenation in a Pa~r apparatus at hydroge~ pcessures
of about 50 to about 60 p8i, using a palladium cataly6t in a
solvent such as ethanol, ethyl acetate, tetrahydrofuran or
~he like, at a temperatuEe in the range of from 250 to about
70. A mineral acid catalyst can be used in addition to
palladium catalyst.
: -
* Tr~demark
~ .
d
~ ' . ~, ' :...... . ~`
,; ~

~ `
~ ~28279
~9
REACTION SCH~ME VI I
OH o CH o
E.C;~.,CH--c! 12 __ ~3,
HO/~ CH2~ CHCH20
X ~'III X~
r
'17C'~ C;l l ll H~ Crt o
r ~X~ COR ~d
::: ZO.';~:YJ X~ :~
~-C.~i5~5~ in ~
:~ 25
'~' . ,
C''. o
' C:~,C~,C~J^ I
30HG
C.
:; ~
wherein P~' is lowee alkyl.

1 328279
- 20 -
In Reactlon Scheme VII, a compound of formula XXVIII,
which are known com~ounds or can be prepared according to
known procedures, can be converted to the coeresponding
compound of formula XXIX utilizing standard alkylation
conditions, for example, utilizing allyl bromide or
chloride, an alkali metal carbonate such a~ sodium
carbonate, or ~referably pota6sium carbonate in a solvent
such as methyl ethyl ketone, dimethyl- formamide,
p~eferably, acetone at a temperature in the range of from
about 400 to about 60.
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 to about 200.
The hydrogenation of a com~ound of formula XXX to the
corres~onding compound of formula XXXI can be cacried out
utilizing a standard catalytic hydrogenation reaction, for
example, at atmospheric pressure or under hydrogen eressure
such as 50 p~i, in a solvent such as e~hyl acetate,
tetrahydrofuran, ethanol or the like, at a temperature in
the range of from about 250 to about 50.
:
The chlorination of a`comeound of formula XXXI to ~he
corresponding compound of formula XXXII can be carried out
utili2ing a standard chlorination reaction, for example,
with N-chlorosuccinimide in a solvent such a~ carbon
tetrachloride, chloroform or the li~e, at the re1ux
temperature.
.
. ~ ' : ' :" " ' ' '
.
- ~ . i: .. .. . -

~ 328279
- 21 -
REACTION SCHEME VIII
0~ Rl'
~ ' R~
~x HC ~
XXXII5
~ R2'
R7 ~ ~ Ot~
XXX~
~3~H
. '.
~7~e~ o~r
xx~
: B3~
OH F~-
~OH R~
a)ll ~ ~ :
wherein Rl', is -COOR', acetyl, hydrogen or hydroxy,
R2' is -COOR', hydrogen or hydroxy, R~ i6 lower alkyl,
Rl", is carboxy, acetyl, hydrogen or hydroxy, R2" is
carboxy, hydrogen or hydroxyt X i5 bromo or
methanesul~onyloxy, pcovided that only one of Rl' and
R2' can be -COOR', or that only one of Rl" and R2"
can:be carboxy. R3, R4, R6, R7 and R8 and n are
as ereviously described.

1 328279
- Z2 -
In Reaction Scheme VIII, a compound of formula III is
reacted with a com~ound of formula ~XXIII 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 to
about 70. The solid-liquid phase-tcansfer catalyst
tris[2-t2-methoxyethoxy)ethyl~amine can be used to facilitate
the reaction when toluene is the solvent.
The hydrolysis of a compound of formula XX~IV to the
corcesponding compound of formula XXXV can be carried out
utilizing standard conditions, fo~ exam21e, utilizing an alkali
metal hydroxide sl~ch 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 to about 65.
The conversion of a comeound 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~ to 2S. The
resulting comeound of formula Ia' is recovered and purified
utilizing known and conventional procedures, for example,
precipitation, crystallization, chroma~ography or the like.

- ; `
1 32827~
- 23 -
REACTION SCHEME I~
0~1~ Rl'
0~ RI~ ~13
R~ XHO
R~
XXX~I XXXIII
R2'
C~O ~ ~ R~
Y 1o
X,XXY~
M~O~
..
0~RI~ RI`
~9~ , O
P~o 1I h
XXXYIII
.
; 25 9~-l
O~ 23-
%~ ~2~ ~
Rlo ll R~
o
Ib'
wherein R3- R4~ Rg~ Rlo~ Rll' 2
X2", Rl", m, n and X are as previously described,
3S provided that only of of Rl' and R2' can be hydroxy or
-COOR', o~ that no more than one of Rl" and R2" can be
carboxy or hydroxy.

1 328279
- 24 -
In Reaction Scheme IX, a compound of fo~mula XXXVI is
reacted with a compound of formula XXXIII to yield the
corres~onding compound of fo~mula~XXXVII. The reaction is
carried out utilizing an alkali metal carbonate such as
sodium ca~bonate or preferably potassium carbonate in a
solvent such as acetone, methyl ethyl ketone,
dimethylformamide or the like, at a tem~erature in the range
of from about 40 to about 70.
The conversion of a compound of formula XXXVII to the
corresponding compound of formula XXXVIII can be carried out
u~ilizing, for examele, 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 to about 65 .
The conversion of a compound of formula XX~VIII to the
corresponding compound of formula Ib' can be carried out
utilizing, for example, boron tribromide, in a solvent such
as methylene chloride, chloroform; l,Z-dichloroethane or the
like at a temperature in the r~nge of from about -70 to
about 25. The resulting compound of formula Ib' is
recovered and purified utilizing known and conventional
erocedures, for example, precipitation, crystallization,
chromatography or the like.
If desired, a compound of formula XXXVII, XXXVIII or Ib'
wherein m=l can be converted to the corresponding compounds
where m=0 and the linking chain contains n+l methylene
groups by shaking under hydrogen ~ressure. The conversion
can be carried out using a catalyst such as ealladîum in a
solvent such as ethanol, ethyl acetate or tetrahydrofuran
using 2ressure of 40-60 esi. Small amounts of an acid such
as concentra~ed sulfuric acid can be used to accelerate the
reaction.
.. . . .......................................... .
~ .
.,

1 32~7~
-- 25 --
REACTION SCHE~qE X
F;~O~,2 I~C
R7 (CH2jn~r HO
P~ R~
XXXX
C;~2 F3~CCCHZ--
R~(C'~2~n--G
P- R.
: ~ :
F
;~ 20 ,
Pd
; 25 ~ ~C9z ~CS.H
I.a"
wherein R2 ~ R3 ~ R4 ~ R6 ~ R7 ~ R8
~: 35 ~reviously descr ibed and R12 is benzyl or acyl .
~: :
::

1 32827~
- 2~ -
In Reaction Scheme X, a compound o 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 ~rom about 25 to about 70. The hydrogenolysis of a
com~ound o~ formula XXXXI to the corresponding compound of
formula Ia" can be carrie~ out utilizing a standard
catalytic hydrogenolysis reaction, for exam~le, at
atmospheric pressuLe or hydrogen ~ressure up to 50 psi at a
temperature in the range of from about 25 to about 50, in
a solvent such as ethyl acetate, tetrahydeoêuran 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 pLocedures, for
exam~le, precipitation, crystallization, chromatography or
the like.
.
,

1 328279
-- z7 _
R'~ACTION SCHEME XI
h2~ 0 CH -~J=\
R3~CCCH
F~ R4
XX~
\~o R3~COC~12 ~,~\
P.7 ~t~z)n /~
~ct ~ Ftc
.
:: 20
~, '
r
: Ch _ .~ o
: 30 F~t
I~
,
: :
wherein R3, R4, R6, R7. R8 and n are pre~riou51y
described and R2" ~ is alkanoylo~
:

`'~` 1 32827q
- Z8 -
In Reaction Scheme XI, a compound o~ formula XXXXII can
be converted to the corresponding alkanoyl derivative of
formula XXXXI~I b~ treatment wi~h 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 to
about 70.
A resulting compound of formula XXXXIII can be converted
to a compound of formula Ia"' by hydrogenolysis, ~or
example, by shaking in a hyd~ogen atmosphere under pressure
or at atmospheric pressure at a temeerature in the range of
from about 25 to about 70~ in the presence of a catalyst
such as palladium in a solvent such as ethyl acetate,
tetrahydrofuran or the like.
.
:, , . ' '
::
.

1 328~79
-- 29 --
REACTION SCE~EME XI I
F7~ 9 )n ~
~3 ~" " RJ,
.
~ .
~\(C) z)n 0
R3 ~4
: .
wherein Rz, R3 . R4, R6 ~ R7 : R8
: ~ 35 previously described, and R" is lower alkyl or
-(CH2)n-~-(low~r alkyl) ~, provided that R2 is other
: ~ thall carboxy.

1 328279
- 30 -
A lower alkyl ester or basic es~er of formula Ia""', and
if desired the corre6ponding compound of formula Ib, where
-R5 is H can be pcepared by Scheme XII.
More particularly, to prepace a lower alkyl ester of
formula Ia""' a compound of formula Ia, wherein Rl or R2
is -C~O)OH, that i5, a compound of formula Ia"", i5 reacted
with a lower alkyl iodide in a solvent such as acetone,
dimethylfoLmamide oc ~he like in the presence of an alkali
metal bicarbonate, such as sodium bicarbonate or ~otassium
bicarbonate at a temperature in the range of ~rom about 30
to about 70 to yield the corres2onding compound of focmula
I a l~
To prepare a basic ester of formula Ia""', a compound of
formula Ia wherein Rl or R2 is -C(O)OH, that is, a
compound of formula Ia"", is reacted with di-lower-alkyl-
amino-lower-alkyl çhloride in a solvent such as dimethyl-
formamide, tetcahydrofuran or the like in the presence of an
~: 20 alkali metal bicarbonate, such as sodium bicarbonate or
potassium bicarbonate at a temperature in the range of from
about 30 to about 70 to yield the corresponding compound
of formula Ia""'.
It is understood tha~ preferably any intermediate
prepared in Reaction Schemes I-XII is recovered and isolated
utilizing ~nown erocedures, for example, ~recipita~ion,
crystallization, chromatography or the like, prior to use in
the next reaction ste~. The end-products of rormula I are
recovered by similar known procedures.
The invention also relates to salts of the compound of
formula I, when ~ is hydLogan, which salts are prepared by
the reaction o~ the said acids with a base having a
non-toxic, pha~macologically acceptable cation. In general,
any base which will form a salt with a carboxylic acid and
whose phacmacological proeecties will not cause an adverse
. ~ ~ , , .
~. , , ! . ~ : - :

" ~ ` 1 32~3279
- 31 -
physiological effect is within the scope of this invention.
Suitable bases thus include, for example, the alkali metal
and alkaline earth metal hydcoxides, carbonates, and the
like, for example, calcium hydroxide, sodium hydroxide,
sodium carbonate, potassium carbonate and the like, ammonia,
erimary, secondary and tertiary amines, such as
monoalkylamines, dialkylamines, trialkylamines, for example,
methylamine, diethylamine, triethylamine and the like,
nitrogen containing heterocyclic amines, for exam~les,
pi~eridine and the like. A sal~ thus produced i8 the
functional equivalent of the corresponding compound of
formula I wherein R is hydrogen and one skilled in the art
will ap~reciate that the variety o~ salts embraced by the
invention is limited only by the criterion that a base
1~ em~loyed 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 -(CH2)n-N-tlower
alkyl)2, which salts are pre~ared by the reaction of said
amines with a non-toxic pharmacologically or
phaemaceutically acceptable acid. In general, the referred
to compounds of formula I form pharmaceutically acceptable
addition salts with, ~or example, both ~harmaceutically
acceptable organic and inorganic acids, such as, acetic
acid, succinic acid, formic acid, methanesulfonic acid,
e-toluene5ulfonic acid, hydrochloric acid, nitric acid,
phosphoric acid, sulfuric acid and the like.
It i8 known that oxidative metabolism of arachidonic
acid by the ~5-lieoxygenase (~5-Lo) pathway leads to
the pe~tidoleukotrienes (LTC4 and LTD4) and leukotriene
B4 ~LTB4). LTC~ and LTD4 are ~otent broncho-
constrictors of human bronchi and contcibute to edema in
some species by increasing caeillary psrmeability. LTB4
is a po~ent chemotactic facto for inflamma~ory cells.
LTB4 has also been found in synovial fluid from ~atients

1 328279
- 32 -
with rheumatoid arthritis and gout and may be a mediator of
inflammation and joint destruction in these diseases.
Consequently, inhibitors of a -LO may be of ~herapeutic
value in the treatment of asthma and inflammatory diseases.
Furthermore, eroducts of the Q -LO pathway (LTB4,
LTC4, LTD4) are present in elevated levels in skin
lesions of patients with p60riasis and atopic dermatitiE and
may be mediators of these skin diseases. The intracutaneous
application of LTB4 to human skin gives a wheal and flare
react;on followed by infiltration of neutroehils into the
site of application. The influx of neutro~hils is also
observed during the inflammatory reactions associated with
~soriatic lesions. Topical application of LTB4 to human
skin causes abscesses similar to those of pu~tular ~soriasis.
Oxygen - derived free radicals and their metabolites may
contribute to the irrevarsible injury which occurs on
reperfusion of previously ischemic myocardial tissue.
Theraey directed toward the toxic e~fects of these free
radicals by radical scavenging drugs may provide ~rotection
against this injury.
The compound6 of formula I exhibit activity, for
exam~le, as antioxidants, as ~ -lipoxygenase inhibitors,
and as hereinafter further described. The useful
pharmacological activities of the compound of formula I can
be demonstrated by the tests hereinafter se~ forth.
The compounds of formula I are useul as agents for ~he
treatment of inflammatory diseases such as arthritis:
in~lammatory bowel disase such as colitis and as hereinafter
further described: cardiovascuLac diseases such as
myocardial ischemia: as an~i-inflammatory agents in the
to~ical therapeutic treatment of leukotriene-mediated desmal
in~lamations including esoriasis: and bronchopulmonary
diseases such as asthma.
: . .
: - ~
~ - .

1 328279
- 33 -
Inflammatory bowel disease (IBD) include~ a variety o~
disea~e~ of the gastrointestinal t~I ) tract ~uch as C~ohn ' 5
disease of the colon and ileum, ulcerative coliti~ and
pseudomembraneous colitis. Common GymptOmS of these diseases
include inflammation of the affected area of the GI mucosa,
mucosa ulce~ation, edema, infiltration of the mucosa with
in~lammatory cells and severe diarrhea. ~rachidonic acid
metabolites from the a -LO pathway are believed to
madiate IBD.
IN VITRQ TEST_FOR ~ -LIPOXYGENASE INHIBITORS
Compounds of ~ormula I of the invention weEe tested for
their effect on ~5~ oxygena~e from rat basophilic
leukema (RBL-l) cells. Materials. RBL-l cells (CRL 1378)
were obtained from the ~me~ican Type Culture Collection,
Rockville, MD. DMEM ~nd glu~amine were purcha~ed from Flow
Labs, McLean, VA. FBS (Gibco, Grand Island, NY~ wa~ heat-
-inactivated ~or 1 hour at 56~C. Reagent6 for protein
2~ determination~ were obtained from ~iorad, Rockville Center,
NY. Arachidonic acid (approx. 9~%). ATP (disodium salt),
BHT, dextran (clinical grade), tetra~odium EDTA, gelatin,
gentamycin ~ulate solution, reduced glutathione, 1 M HEPES
buf~e~, indomethacin, NAC1, reduced NADPH, Trizma 7.2, and
T~izma*8.5 were purcha~ed from Sigma Chemical, St. Loui6,
MO, CaC12 dihydrate, Norit A charcoal~ and citric acid
monohydrate we~e obtained rom Fisher Scientific,
Pittsburgh, PA. [3H]-5-HETE (specific activity 229.5
Ci/mmol) was purchased ~rom New England Nuclear, Bos~on, MA.
A synthetia 5-HETE standard wa~ supelied by
Dr,M.Rosenberger, Deet. of Medicinal Chem~stry, Hoffmann-La
Roche, Nutley, NJ; ~see Corey, E.J., and Hashimoto, S.
(1981) Tet. Letters, 22, 299-302 for method of preparation~.
Ecoscint liquid scintillation ~luid wa6 purchased form
National Diagnostics, Sommerville, NJ.
* Trademark
~,~ ....
: , : ,: . ~ .-

'I 32827q -J
_ 34 -
Isolation of 5-liPoxYaenase. The most stable enzyme
preparations were ob~ained from RBL-l cells thawed from
liquid N2 storage, then maintained in tissue culture
flasks containing DME~ supplemented with 25 mM glucose,
12.5 mM HEPES, 40 mM glutamine, 50 ug/ml gentamycin sulfate.
and 10% heat-inactivated FBS. ~pproximately 7-9 days after
thawing, RBL-l cells growing in log phase were seeded at a
density of 7500 viable cells/ml ;n a closed 89-liter spinner
flask. The cells were stirred constantly for 3-4 days at
37C until they reached a density greater than 500,000/ml
but less than 800,000/ml. RBL-l cells were harvested by
centrifugation at 4C at lS00 x g for 10 minutes and were
washed 3 times with ice cold 0.05 M ~ris-HCl, pH 7.2,
tetrasodium EDTA (buffer 1). The cells we~e washed last in
05 ~ Tris-HC1 containing 14 ~M indomethacin, 1 m~ gluta-
thione, l.S mM NaCl, and 1 mM tetrasodium EDTA (bu~fer 2),
resuspended at a density of 5 x 108'/ml (approximately
10 ml) and disrupted manually at 4C using a 40 ml Dounce
~type A pestle) homogenizer. After 5 minutes of homogeni-
zation, 95% cell lysis was confirmed by phase contrastmicroscopy. ~he broken cells were diluted 1:2 with buffer 2
and centrifuged at 12,380 x g ~or 10 minutes at 4C to
eellet cellular debris and granules. The 12,380 x g super-
natant was centrifuged at 113,000 x g for 60 minutes to
pelle~ microsomes. The high-speed sueernatant (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 N2 for up to 8 wee~s without loss of 5-L0
enzyme activity.
LipoxYqenase ~ssaY Compounds were dissol~ed at Z5 mM
concentration in DMS0, then diluted to final concentrations
using 95% ethanol. For a typical enzyme assay, the partially
purified 5-L0 peeparation was preincubated with drug or
vehicle for 10 minutes at 30OC. The assay tubes were then
transfe~red at a 37C water bath where they received
arachidonic acid (8.25 ~M final concentration) to initiate
, . ,
:'.
,

1 3~827r~
- 35 -
s-Lo activity. In additicn to enzyme and ~ubstrate, each
reaction tube contained: 12.5 ~moles of T~ls-HCl (pH 7.2),
25 ~moles glutathione, L.4 ~moles indomethacin, and 1.25
~moles of CaC12 and ATP to yield a to~al voluma o~
250 ~1 0.3 M ~tric acid to yield pH 3.5. The samples were
immediately cooled on ice and neutralized by dilution with
O.OS M Tris-HCl, pH 8.5, which contained 25 mg/l BHT. ~
boiled cytosol control was placed at the end o~ each assay
to emasure non-enzymatic oxidation of arachidonlc acid. The
mean specific activity of the 5-LO enzyme preparation was
approximately 66.16 ~ 14.39 pmol 5-HETE 1 min/mg erotein.
_adioimmunoassay for 5-HETE Under the assay conditions
describ~d, the 5-L0 ca~alyzed the conver~ion o~ arachidonic
acid to 5-HPETE which, as a consequence of ~eroxidase acti-
vi~y, was reduced to 5-HE~E. A ~pecific radioimmunoas6ay was
employed to quantitate the amount tpmoles) o~ 5-HETE formed
during the enzyme reaction. To prepare the immunogen, Dr. M.
Rosenberger (Dept. of Medicinal Chemi~ry) converted the
racemic 5-HETE lactone (Corey, E.J., and Hashimoto, S.
(1981) Tet. Letters, 22, 299-302) to its hydrazine
I derivative. The hydrazide was conjuga~ed to thiolated
Keyhole Limpet ~emocyanin (Young, R.N., Kakushima, ~., and
Rokach, J. (1982) Prostaglandlns 23, 603-613) using
N-ethyl-maleimide as p~eviously described ~or LTB4 by
(Young, R.N., Zomboni, R. and ~okach, J. 9L983) Prosta~
glandins, 26, 605-613). New Zealand ~hite Eabbits received
multiple intradermal in3ections on ~heir back~ with 100 og
con~ugate emulsified in complete Freund's ad~uvant. A
schedule o~ in~ections reported by Salmon tSalmon, J.~.
(1978) P~ostaglandins, 15, 383-397) wa~ followed. After the
mon~hly i.p. booscec injections, blood was obtained from the
marginal ear vein 5-7 days later and assessed for antibody
titer.
Rabbit 5-HETE anti-sea was diluted L:300 in RIA~buffer
(50 mM Trl6-~lCl plu8 1. 5 mM NaCl, pH 8.6, containing 0.1%
* Trademark
..~ ~
., I'.\
,i~
l.
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1 32827~
- 36 -
gelatin) and aliquots were mixed with standard (0.75-25
pmole 5-HETE/ml) or dilute assay samples and placed in an
ice bath. ~3~l]-5-HETE (approximately 10,000-12,000 cpm)
was added ~o yield a to~al as6ay volume of 300 l. After a
90 minute incubation at 25C, 1 ml ice-bold dextran-coated
charcoal was added ~o ~eparate an~ibody-bound ~rom unbound
5-HETE (Salmon, J.A. (1978) Prostaglandins, 15, 383-397).
The charcoal was sed~mented at 2000 x g f or 10 minutes.
a~ter which Q.8 ml of supernatant was added to lo mls
Ecoscint ~luid. Radioactivity (dpm) was determined after
10 minute count6 using a LKB model 1219 scintillation
counter (40S eficiency foc ~3N].
Data ~nalysis - Each inhibitor concentcation was tested
in quadruplicate. The inhibito~y concentration that yielded
a 50% inhibition (IC-50) of control 5-HETE formation was
calculated by cegression analysi~ of the dose-cesponse data.
Data (IC-50) for the compounds of ~his invention in this
test is reported in Table I.
Carraqeenan Pleurisy Test ~In Vivo~
The animals utilized in these ~udies were male Lewi6
rats (Charles ~ivec Bceeding Labocatories) weighing between
230-250 g. Carrageenan tCG) pleurisy wa~ induced by
iniecting 0.2 ml of 1% lambda cacrageenan ~Sigma Lot
~60F-Q652) dlssolved in sterile, pyrogen f~ee, 6aline into
the ri~ht pleural cavity of the rat u6ing a 26 gauge (3/8~l)
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 beore CG
injection for the 5 hour tceatment period and l hour before
and 5 hour after CB injection ~or the 24 hour treatment
period. Drugs were administeced at doses which, on the
basis of prel~minary expeciments, would sLgaificantly
suppress the d~velopment of CG-induced pleurisy under ouc
* Trademark
,
:

1 328279
~ 37 -
experimental conditions.
At 5 or 24 hours after CG injection, the rats were
killed by decapitation. exsanguinated, and the pleural
5 cavity exposed by cutting the ribs on both sides of the
sternum. The exudate fluid was removed from the pleural
cavity with disposable ~lastic pipettes and its volume
quantitated. The pleural cavity was then washed once with
phosphate buffe~ed saline containing fetal bovine serum
10 (1:1) and the washings combined with ~he exudate. The total
number of cells in the pleural cavity was quantitated using
a Coulter Counter ~odel ZM) adjusted to exclude any v
contaminating RBC. (Published in "Plant Flavonoids in
Biology ~ Medicine: Biochemical, Pharmacological and
Structure~~ctivity Relationships" p. 231-242 (1986) Alan R.
Liss, Inc.)
Data foL the comeounds of this invention in this test is
reeorted in Table I.
Mouse Ear Edema Test (In Vivo~
In this animal model system, the application of
arachidonic acid to the ear resul~s in the biosynthesis of
the metabolic products 5-hydroperoxy-6,8,11,14-eicosa-
tetraenoic acid (5-HETE), leukotriene B4 (LTB4),
leukotriene C4(LTC4), lZ-hydroperoxy-5,8,10,14-eicosa-
tetraenoic acid (12-HETE), and pros~aglandin ~2 (PGE2)
at the site of apelication, followed by the in~lux ~f
neutrophils into the site and the rapid development of edema
within ~0 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, O~as and Bonney,
"Arachidonic Acid Metabolites in Mouse Ear Edema" Advances
in Inflamma~ion Research, 11:57 (19~6). Inhibitors of these
metabolites and o~ their metabolic pathways also inhibit
.
~'`'' . : ' :. ' :~. '
. .

l 3~827q
edema formation.
CD-l male mice weighing L5 to 25 g were employed, and
they were designated as follows: (1) Control Grou~, in which
no arachidonic acid or test compound was to be a~plied, (2)
Arachidonic Acid-Treated Groue, in which no test compound
was to be apelied, and (3~ Treated Group, in which the test
compound was to be applied first, followed by the appli-
cation of acachidonic acid.
In the case of the Group t3) 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 arachidionic 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 6mm-diameter standard
biopsy punch was used to obtain a uniform tissue samele from
the ear of each mouse so treated, and the tissue ~am~les
were weighed to the neares~ 0.1 mg. The percent inhibition
of ear edema formation was calculated as follows:
Wt. of ~rachidonic Acid GrouP - Wt. of Testin~ GrouP
Wt. of Arachidonic Acid Group - Wt. of Control group
Data for compounds of this invention in this test is
reported in Table I.

1 3~79
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1 32827q
- 41 -
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1 32827q
- 42 -
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 ~lg80), and by P. Sharon and W. F.
Stenson in Gastroenterolgy 88: 55-63 (1985)and 86:453-460
(1984). ~cetic acid-i~duced coli~is 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 o~ myeloperoxidase caused by
acetic acid. Male rat~ ~S~rague-Dawley), weighing 150 to
300g, were pretreated twice daily foc two days with ei~her
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 ~he previous two
days, anesthetized with meto~ane, and 2 ml of 2.5% acetic
acid was injected by syringe into the colonic lumen,
~ollowed im~ediately by 3 ml of air and a ~inse consisting
of 3 ml of phosphate-buffered saline (the acetic acid is
present in the lumen ~or a sufficient period to cause
inflammatio~ without producing severe necro~is or
irreversible damage). The animals were administered a
second do6e 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
Tis~umizer or similar device and myeloperoxidase was
measured in the homogena~e u6ing o-phenylenediamine as a
chromagen, as described by A. Voller, D. E. Bidwell and A.
Bartlett in The Enzyme Linked Immunosorbent ~ssay ~ELISA),
Zoological Soc., London, 1979, pages 29-30. Control animals
were pretreated with the vehicle and saline in place o~
acetic acid.
,, I . ~ -
.
.
.. ..
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1 3~279
- ~3 -
Data for rep~esen~ative compounds of this invention is
reported in Table II.
Antibiotic-Induced Colitis in Hamsters, In Vivo
Male Syrian hamsters (LUG), weighing ao to 120 g were
each given a single dose of 175 mg/kg of
clindamycin-phospha~e or of clindamycin-hydrochlo~ide
intraperito~eally, to induce colitis. Ap~roximately seven
hours after injection, the animals were given the test
comeound orally or intraperitoneally and the therapy was
continued twice a day for a period of four more days. For
oral admini~tration, the antibiotic was suspended in water
or dissolved in dimethylsulfoxide and delivered to the
1~ animals by gavage using an oral intubating needle. The
effect of the theraey 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 foe the test inhibitor
compound-treated groues 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 comeare the
'1 survival curve o~ each test inhibitor compound-treated
(therapy) group to that o~ the corresæonding vehicle control
group. ~ Haæard ~atio o~ 1.0 indicate6 that the thera~y has
no better e~fect compared with the vehicle alone, while a
Hazard Ratio greater than 1.0 (>1.0) indicates that ~he
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)).
:~S
I Da~a foe representative compounds of this invention are
re~orted in Table II.

1 32~27q
-- 44 --
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1 328279
- 45 -
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1 328279
- 47 -
In Vi~ro Testinq of AntiPeroxidative ~qents
The test system employ6 hypoxanthine-xanthine oxidase
tX0)-Fe ADP as the free ~adical genera~or and
purified, native rat-heart membrane phosphoglyceride in
He~es-KCl buffe~, pH 7.4, as the substrate. Inhibition of
superoxide-dependent, iron-promoted lipid peroxidation in
the linear reaction phase (after L hour of reaction) is
measured as the net formation of thiobarbituric acid
~TBA)-reactive material. In this sys~em, the TB~-reactive
material, isolated by HPLC, is exclusively (>95%)
malondialdehyde (MDA), a fragmentation end-product arising
from fatty acyl hydroperoxides and cyclic endoperoxideG.
a) Isolation and Purification of Rat Cardiac Lipid
Conscious male Sprague-Dawley rats (~ 275g)maintained
on a normal rodent diet were decapita~ed. The hearts were
rapidly removed and perfused via the aorta with ice-cold lO
mM Hepes buffer, pH 7.4. The aorta and atria were removed,
and the ven~ricula~ tissue was blotted and weighed (wet
weight)., The hearts were minced on ice with scissors and
finally homogenized (lO0 mg tissue/ml ice-cold buffer) for
15 seconds (3 x 5 seconds) with a Tekmar Tissumizer at
"maximal" setting. The homogenate was filtered through
4-ply chee6ecloth, and homogena~e lipids were extracted and
purified by a modified Bligh-Dyer procedure (M.D. Marshall
and M. Kates, Biochem. Biophys. ~cta 260, 558 (1972). The
cardiac lipids were s~ored in CHC13 under nitrogen at
-20C.
b) PreParation of Cardiac LiPosomes
Liposomes were prepared from extracted and purified,
native rat heart cardiac lipid and were used as substra~e
~or free-radical attack. Cardiac lipid (in CHCl3) was
placed in a glass flask and evaporated to dryness under
:.
. , ~ ~ . :.

1 32827~
- 48 -
nitrogen at room temperature; the flask was gently rotated
during evaporation to yield~a thin, dry lipid film. The
lipid was taken ue in 10 mM ~epes-0.145M CKl, pH 7.4, and
was resuspended by indirect anaerobic sonication for L5
minutes at room temperature. The lieosome suspension was
used immediately.
c) Pre~aration of Fe3+-~DP chelate
A chelate was formed in Hepes-KCl buffer between Fe
(l.OmM FeC13, final concentration) and ADP (10 m~, final
concentration) at eH 7.4 with stirring at room temeerature.
Chelation was allowed to proceed for 90 minutes ~rior to
use. The chelate wa~ prepared fresh for each days
experiments to ensuLe iron solubility, effective chelation,
and valence state~ -
d) Thiobarbituric Acid Reaction for Determinationo~ Malondialdehvde 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 (~.5% TB~ in 0.2M Tris, pH 7.0) in the
volume ratio l:L:5. To each 1.0 ml o~ peroxidation reaction
assayed (see below), 0.35 ml reaction mixture was added.
A~ter thorough mixing, ~he tubes were incubated in an 80C
shaking water bath for 30 minutes. After this time, the
tubes were plunged into an ice water bath, and the reaction
was immediately stop~ed with 0.5 ml ice-cold ~1% TCA
followed by 2.0 ml CHC13. Aftee centrifugation for 30
minutes at 2000 rem in a "So~al'~ ~IL-8 rotor (4C), 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, MD~ was freshly preeared by
acidification of 1,1,3,3-te~raethoxy~ro~ane with 75%
* Trademark
~''S
. ~ `
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,. - ,~ . ... . . ~ .

1 328279
TCA-2.3N HCl (0.15 ml acid mixture with 1.0 ml suitably
diluted tetraethoxy~ropane). 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-
-de~endent, iLon-promoted peroxidation in glass vessels to
avoid the well-known antioxidant e~fec~s of many common
polymerizing agents used to fabricate plastic labware.
Screening was performed in tri~licate in glass 12 x 75 mm
tubes at a final reaction volume of 1.0 ml and a reaction
time of 60 minutes. Per m;lliliter of eeroxidation
reaction, the component6 were: Tris-KCl bufer (0.1 ml),
cardiac liposome~ t0.5 ml, equivalent to 125 ~g
phospholipid), 1 mM H~ t0.1 ml~, 0.1 mM Fe -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
componen~s aee listed at their final concentrations and were
erepared at the time of assay~ The peroxidation reaction
was started with the addition of XOD and was carried out at
37C in a shaking ~ater bath. Paroxidation was terminated
by adding 0.15 ml ice-cold 76% TCA-2.3N HCl for each 1.0 ml
Of ~eroxidation reaction to be as~ayed for MDA equivalents
(above). To check for possible interference by test
sub~tance, a second set of samples was run, but in these the
peroxidation reaction was stopped immediately with the
TCA-~Cl mixture. Test substances were scLeened at 1.0 ~M
final concentration. If peroxidation were inhibited by
> 50~, an IC50 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.L5 ml 76% TCA-2.3N HCl and were then reacted
with TBA tabove).
. ~ .
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1 32827q
- 50 -
f~ Calculation of the Effect o~ a Test Substance
on LiPid Peroxidatio~
The effect of a test sub~tance on cardiac lipid
peroxidation during the 60 minute screening assay was taken
as the ratio between the end MDA equivalents ~roduced in the
presence of the drug and the net MDA equivale~ts produced in
its absence. The percent inhibition of li~id peroxidation
was calculated by:
Drug60, - VrUgO ~
% Inhibition , l~ -------- x lO0
of peroxidation T60 - Tol
5 Drug ~0, = MDA equivalents pcoduced after 60 minutes with
the free radical generator + ~est substance.
Drug 0, _ MDA equivalents ~roduced after 0 minutes with
the free radical generator ~ test substance
T 60' = Total MDA equivalents produced without test
substance at 60 minutes.
T 0, = Endogenous TBA reactivity of ceaction mixeure
at 0 minutes.
Data for the compounds of this invention in this test is
reported in Table III.
In Vivo Te6tinq of Anti~eroxidative A ~nts
In this p~eparation a free eadical generating (F~G)
system consisting of purine (2.3 mM), xanthine oxidase (0.02
U/ml) and i~on loaded transferrin (0.6 ~M) com~lex is
infused into the caro~id artery near the ostium of the
coronary artery in spontaneously hypertensive rats. Blood
is withdLawn before and 24 hours after the FRG challenge for
measuring the i~oenzymes of lactic acid dehydrogenase
(LDH~:LDH2). ~n increase in LDHl:LDH2 ratio reflects
cell damage to the myocardium. The electrocardiogram is

1 ~8279
also taken before and 24 hours a~ter the FRG infusion. ~t
the end of the experiment ~he heart i8 ~emoved, sliced in a
breadloa~ fashion, and ~tained with triphenyltetrazolium
chloride to determinQ infa~ct size. ~ d~ug or vehicle is
admini3tered intravenously 10-30 minutes befo~e ~he FRG
challeng~. A dcug i~ congidered active i~ thece is no
elevation o~ the LDHl:LDH2 catio, no EC~ abnormalities
and no hi~tologic evidence of an infarction.
Rat,In ~ivo Model_o~ MYocardial Ischemia
Male spontaneously hyperte~sive ~ats ~280-320g) from
Taconic Farms, were lightly anesthetized with sodium
~entobarbital (30-50 mg/kg, i.p), Ra~s exhibiting abnormal
patterns prio~ to su~gery we~e eliminated from the study. A
catheter of PE 50 tubing wa~ lnserted int~ the right common
carotid artery to a ~osition proximal to tlle 06tia of the
coconary acteriQs and used to sam~le blood and in~use the
free eadical generator (FRG~ ~y~tem, ~ second catheter o~
P~ 10 tubing was inse~ted into the left 3ugula~ vein to
administec deu~s. The infusion sy6tem for the FRG consisted
o~ a double syringe infusion pum~, Sage ~odel 351, with one
syringe containing xanthine oxidase (0.01 units/ml) in a
HEPES (0.05 M) bu~fer and the other yringe containing
purine (2.3 mM) plus Fe ~ loaded tran6ferring S0.06 ~M)
in a HEPES (0.05 M) bu~fer. The FRG in~used sepaeately
mlxes ~imultaneously near the ostia of the coronary
arte~les. This infusion was delivered at a rate of 0.03
ml~minute for a total infusion time of 10 minute6. The
dcug6 we~e infused over a one minute ~eriod in a 0.9~ saline
vehicle.
Standacd Lead II ~CG was monitored continuously on a
Hewlett-Packa~d 7758A recocdeE prior to treatment,
thcoughout the FRG infusion and 10 minutes po~t in~usion.
Cathete~s we~e removed and animals were allowed to recover
and fed standacd cat chow and watec ad libitum. 24 hours
* Trademark
.
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1 32827q
- 52 -
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
(LDHl:LDH2), using electrophoresis.
The animals were sacrificed, the hearts rapidly excised,
and washed free of blood and sectioned. The left ventricle
was weighed and stoeed in a Revco freezer at -70C.
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 measuEed and quan~itated as a
percentage of the total left vent~icular volume.
Data ~or the compounds of this invention in this test is
Leported in Table III.
. . .. . . .. .
, ~ , .. . .

1 328279
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1 328279
- 55 -
A compound of ~o~mula I or a salt theceo~ or a
composition containing a the~apeutically e~fective amount of
a compound of formula I 01 a salt thereof can be
administered by methods well known in the art. Thus, a
compound of fo~mula I OL a sa~t thereof can be administe~ed
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
~an be administered in the focm of tablets, capsules, for
example, in admixture with talc, starch, milk sugar or other
inert ingredients, that i6, pharmaceutically acceptable
carriers, in the form o~ aqueous solutions, suspension6,
elixirs or aqueous alcoholic solutions, for e$amele, in
admixture with sugar or other sweeteninq agents, flavoring
agents, colorants, thickeners and other conventional
pharmaceutical excipients, or headlets fo~ oral
administration. Foc parenteral administration, the desired
compound can be administered in solutions or suspension, fo
example, as an aqueous or peanut oil solution or suspension
using excipients and carriers conventional for this mode of
administration. For administration as aecosols, they can be
dissolved in a ~uitable pharmaceu~ically 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 pre~surized com~osition.
Preferably, the aerosol valve i6 a metered valve, that is
one which on activation releases a predeteremined effective
dose of the areosol com~osition. For rectal administration,
the desired com~ound 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 in~o ointments,
creams, lotions, gels, and the like. In general, the
solutions, ointments and creams which are use~ul in
.. .
..:

1 32827~
- 56 -
accordance with this invention include focmulation~ having
absorbable, water soluble or emul~ion-type bases, sUch as
petrolatum, lanolin, polyethylene glycols, or the like.
Suitable solutions will contain ~he compounds of ~ormula
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
particle~. Lotions can contain suspending or di~persing
agents such as cellulose derivative~, for example, methyl
cellulose, ethyl cellulose, or the like. Gels will typically
be ~emi-~olid preparations made by gelling a ~olution or
sUspen6ion o~ a compound of formula I in a sui~able hyd~ous
or anhydrous ~ehicle, using a gelling agent such as a.
carboxy polymethylene, or the likei and thereafter
neutralizing it to proper consistency with an alkali metal
hydroxide, for example, sodium hydroxide, and an amine, for
exam~le, polyethylene- cocoamine. Topical pharmaceutical
com~ositions containing a compound of formula I can also be
formulated to include conventional ingredients such as
~reservatives, stabilizers, wetting agents, emulsiying
agent6, buffers, and the like, in conventional amounts
adjusted for particular requi~ements and which ~e readily
; determinable by those skilled in the art.
In the ~ractice of the invention, the dose of a compound
of formula I or a sal~ ~heceof ~o be administer~d and the
frequency of administration will be dependent on the potency
and duration of activity of the ~articular comeound of
formula I or salt to be administered and on the route of
adminis~ration, 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 p~acticing the invention are in the ~ange of from
about 25 to about L000 mg per day, preferably about 25 to
- :
.. . ~ , . .
:;
: :: -

t 32~27q
- 57 -
about 250 mg either as a 6in~1e dose or in divided doses.
The Examples which follow further illusteate the
invention. ~11 temperatures set forth in the specification
and the Exam~les are in degrees Centigrade. Extracts were
dried over anhydrous magnesium sulfate unless otherwise
noted.
Example 1
A solution of 1.~5M butyl lithium in hexane ~195ml, 0.3
mol) was added droewise over 30 minutes to a stirred
solution of 1,2-dimethoxybenzene (41.4g, 0.3 mol) in 700 ml
of anhydcous tetrahydrofuran at room temperature under
argon. The reaction mixture was stirred and heated at 40
or 4 hours and then cooled to -70. A solution of 46 ml
(0.3 mol) of 1,6-dibromohexane in 250 ml of anhydrous
tetrahydLofuran was added dropwise over 30 minu~es. The
cooling bath was removed and the reaction mixture was
stirred for 1 hour and then heated at 40 for 4 hours. Most
o~ the solvent was removed, 90ml of 3NHCl was added and the
product was extracted with hexane. The extract was washed
with sodium bicarbonate solution, dried and concenteated
under reduced ~ressure to yield an oil. Distillatio~ ga~e
1-(6-bromohexyl)-2,3-dimethoxybenzene as a yellow oil (29g,
32% yield, b.p. 125-140/0.15mm).
This procedure is known and described ~or 1-(7-bromo-
heptyl)-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 o
all of the bromo intermediates wherein n = 3 - 10.
Example 2
36
Boron tribromide (266 ml, lM in methylene chloride) was
added dropwise over 1 hour to a cooled (-65O) solution of

~ ~\
" 1 ~2827~
40.0g (0.133 mol) of 1-(6-bromohexyl)--2,3-dimethoxybenzene
in 800 ml of anhydLous methylene chloride which was stirred
in an argon atmosphere. The cooling bath was then removed
and the reaction mix~ure was stirred foc 1.5 hours. A~ter
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 concentra~ed under
reduced eres6ure to an oil which was purified by HPLC using
5~ m~thanol-chloroform to yield 34.7g of 1-(6-bromohexyl)-
2,3-dihydroxybenzene as an oil. To this was added 3Z ml
(0.28 mol) of benzyl chloride, 46 g (0.28 mol) of potassium
iodide, 122g (0.88 mol) of ~otassium carbonate and 700 ml o~
anhydrous acetone and the reaction mixture was stirred at
reflux for 72 hours. The solid was removed by filtration
and the filtrate was concentrated unde~ reduced pressure to
an oil which was purified by HPLC using 1% ethyl acetate-
-hexane to give 47 g (74% yield) of 1-(6-iodohexyl)-2,3-
-bis-(phenylmethoxy) benzene as an oil.
Example 3
To 20 g (0.145 mol) of 1,2-dimethoxybenzene in 300 ml of
anhydrous tetrahydrofuran stirred at room temperature under
argon was added 90 ml (0.145 mol) of 1.6 M butyl lithium i~
hexane over 30 minutes. The reaction mixture was stirred
and heated at 40 for 4 hours and ~hen 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 Loom temperature ~or 17
hours. Most o~ the solvent was removed under reduced
pressure and water was added to the residue. The product
was extracted with ether and the dried extract was
concentrated under reduced pressure to an oil. The
remaining 1,2-dimethoxybenzene was removed by distillation
and the residue was puri~ied by ~IPLC using 20% ethylace~ate-
-toluene to give 5 g of 1-(2-hydroxyethyl)-2,3-dimethoxy-
,
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: , ~ . ~ :, . :

1 32827~
- 59 -
benzene. This intecmediate was dissolved in 100 ml of
anhydrous methylene chlocide and the solution was cooled in
an ice bath. Trie~hylamine (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 s~irred
with ice bath cooling for two hours and ~hen was washed with
water, with sodium bicarbonate ~olution, dried and
concentLated under reduced pressure to give (7.Z g) of
1-~(2-methanesulfonyloxy)ethyl]-2~3-dimethoxybenzene as an
oil which was used without purification.
ExampLe 4
To 9.0 g (0.033 mol) of 1-(6-bromohexyl)-2,3-dihydroxy-
benzene in 200ml 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 unde
reduced pcessure, the residue was treated with sodium
bicarbonate and the ~roduct was extracted with ether. The
dried extract was concentrated to an oil which was purified
by HPLC using 10% ethyl acetate- hexane to give 15.2g (90%
yield) of 1-(6-bromohexyl)-2,3-bis~(4-methylbenzoyl)oxy]-
benzene as an oil.
Example 5
To l.Og (3.8 mmol) of 1-(6-bromohexyl)-2,3-dihydroxy-
benzene in lS0 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 L.5 hours and then
was washed with sodium bica~bonate solution. Aftec drying,
the organic layer was concentca~ed to give 1.3 q of
L-~6~bromohexyl)-Z,3-bis(acetyloxy)benzene as an oil.
- '
.
,
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1 328279
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Example 6
To 3.3g (0.018 mol) of 3,4-dimethoxy~henethyl alcohol in
50 ml of methylene chloride and 4.2 ml (0.03 mol) of
trie~hylamine cooled in an ice bath was added 1.6 ml (0.02
mol) of methanesulfonyl chloride with stiering. The
reaction mixture was stirred for 75 minutes and then washed
successively with water, lN hydrochloric acid and sodium
bicarbonate solution. ~fter dcying, the extract was
concentrated under reduced pressure to give 1-~(2-methane-
sulfonyloxy)ethyl]-Z,3-dimethoxybenzene as an ail.
ExamPle 7
~ mixtuee of 1.0 ml (7.8 mmol) of 1,2-dimethoxybenzene
and 2.0g (L0 mmol) of 6-bromshexanoic acid was warmed
briefly until homogeneous and stirred while 1.7 ml (11.7
mmol) of trifluoro- acetic anhydride was added. The
reac~ion mixture was stirred at room temperatuee for 17
hours and then was poured into sodium bicarbonate solution.
The product was extracted with ethyl acetate and the dried
extract wa~ concentrate.d ~o an oil which was eurified 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.
.
E~3~ple 8
A mixtuLe of lOg ~46 mmol) o~ 1-bromo-3,4-dime~hoxy-
ben2ene, 3.4g (48 mmol) of 3-butyn-1-ol and 8 ml (58 mmol)
o~ triethyl- amine in 20 ml of methylene chloride was
stirred and flu6hed with argon. To the mix~ure there was
added 0.12 g (0.06 mmol) of cupeous iodide and 0.30g (0,43
mmol) of bi6(triphenylpho6ehine)ealladium dichloride~ The
- 35 reaction mixture was sticred at room tem~erature for 4 houcs
and at reflux for 16 houes. After filtration, the filtrate
was washed wi~h water, dried and concentrated. The crllde
.
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1 32827q
- 61 -
product was eurified by HPLC using 30% ethyl acetate-toluene
to give 3.0g (32% yield) of 4-(3,4-dimethoxyphenyl)-3-butyn-
-l-ol.
ExamPle_9
A mixture of 2.0g of 4-(3,4-dimethoxyphenyl~-3-butyn-
-l-ol and 0.2 g of 10% palladium on carbon in ~0 ml of
ethanol was stirred in a hyd~ogen atmosehere foc 4 houLs.
10 ~fter filtration, the filtrate was concentrated unde~
reduced pressure to give 1.9 g of 4-(3,4-dimethoxyphenyl)-
butan-l-ol as an oil.
Example 10
To 0.8g (0.12g-atoms) of lithium ribbon cut in small
~ieces in 50 ml of anhydcou~ ether s~irred at ~oom
temperature under an argon atmosphere was added l2g (0.06
mol) of 3-bromo-pro~an-1-ol l-ethoxy ethyl ether [P.E.
Eaton, G.F. Coo~er , 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-~alt bath and ~he
rest o~ the bromo compound was added dro~wi~e over 35
minutes. Stirring was con~inued with cooling for 1.5 hours
and then 7.5g (0.045 mol) o~ 2,3-dimethoxybenzaldehyde in 45
ml of anhydrous ethec was added dro~wise over 30 minutes.
A~ter 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 sul~at0
solution. The ether layer was separated, dricd (Na2SO4)
and concentrated to an oil (13.9g). Ethanol (25 ml), water
(25 ml) and 2 ml of concentrated hydrochlo~ic acid were
added and ~he solution was left at ~oom tempeLatU~e for 35
minutes. Potassium carbonate was added with sti~ring until
the mixture was basic. ~he ethanol was removed under
reduced eresSure and the product was extracted with ethyl
acetate. The dried extract was concentrated to an oil

~ 328279
- 62 -
(12.0g). This was dls~olved in lSO ml o~ ethanol, lg of 10%
palladium on carbon was added and the mixture was shaken on
a Parr hydrogenator under an initial hydcogen pre~suee of 55
p6i ~or 5 hour~. The reaction mixture wa~ filtered through
Celite*and the filt~ate was concentrated to an oil.
Purification by HPLC using 30~ ethylacetate-hexane gave 7.45
g t79% yield) o 4-~2,3-dimethoxy~henyl)butan-1-ol.
Example LL
A mixture of 102g (0.607 mol) of methyl 2,4-dihydroxy-
benzoat~, 54 ml (0.619 mol) of allyl bromide and 126g (0.91
mol) of anhydrou6 potas6ium carbonate in 300 ml of anhydrous
acetone was stlr~ed at ~e~lux ~or 3 hou~s. The reaction
mixture was filtered and the ~olid was wa~hed with acetone.
After removal of the acetone ~om the filt~ate under reduced
pressu~e, the residue was distilled to give 85g (67~ yield),
bp 106-iO8 /0.3mm of 2-hydLoxy-4-[2-pro~enyloxy)benzoic
acid methyl es~er.
Example 12
81g of 2-hydroxy-4-(2-~copenyloxy)benzoic acid methyl
ester was heated in an oil bath under argon until the
internal te~perature reached 1~0-185. The tem~eratuee was
maintained in this range for l.S hou~s and then raised to
210 fo~ 1.5 hours. After cooling, the oil cry6tallized and
was rec~ystallized from ether-petroleum ether to give 37g
(46% yield~, mp 65-66 of 2,4-dihydroxy-3-(2-proeenyl)-
benzoic acid methyl ester,
Example 13
A solution of 54g of 2,4-dihydcoxy-3-(2-propenyl)benzoic
3S acid methyl ester in 900 ml of ethanol and 3g of 10%
palladium on carbon was ~haken in a hydrogen atmosphere
until the uptake ceased (45 minutes). The catalyst was
Trademark
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~ 32827~
- 63 -
removed by filtration through Celite and the filtra~e was
concentrated under reduced pressure to an oil which
solidified. ~fter stir~ing with hexane, the product was
filtered to give 51g, mp 66-68, of 2,4-dihydroxy-3-propyl-
benzoic acid methyl ester.
Example 14
~ solution of 37g (0.18 mol) of 2,4-dihydroxy-3- propyl-
10 benzoic 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 ~roduct was extracted with ethyl acetate
and the extract was dried and concentLated under reduced
pressure to a tan solid which was used wi~hout eu~if ication.
Thi6 crude acid ~35 g, 0.18 mol), 23 ml (0.2 mol3 of benzyl
chloride and 17g (0.2 mol) o~ sodium bicarbonate in 250 ml
of anhydrous dimethylformamide was s~irced and heated at 6Q
for 23 hours. The solvent was removed unde~ reduced
~ressure 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 ~urified by HPLC
using 15% ethyl acetate hexane to give 36g (70~ yield), mp
86-88 of 2,4-dihydroxy-3-~ropylbenzoic acid ~henylmethyl
ester.
Example 15
A solution of 2.1g (0.31 mol) of 2,4-dihydroxy-3-
~ro~ylbenzoic acid methyl ester and 1.6g (0.012 mol) of
N-chlorosuccinimide in 50 ml of carbon tetrachloride was
stirred at ceflux foL 9.5 hours. Additional N-chloro-
3S succinimide (1.6g) was added and reflux was continued for 17hours. 0.8g of N-chlorosuccinimide was added and reflux was
continued for 8 hours. Water was added. The organic layer
. ~
.

1 32827~
- 64 -
was separated and washed with sodium thiosulfate solution,
sodium bicarbonate solution, dried and concentrated under
reduced pressure ~o give 5-chloro-2,4-dihydroxy-3-propyl-
benzoic acid methyl esteL. Recrystallization from hexane
gave analytically pure material, mp 75-76O.
ExamPle 16
A mixture of 29.2 g (0.097 mol) o~ 1-(6-beomohexyl)-~,3-
dimethoxybenzene, 18.5g (0.088 mol) of 2,4-dihydeoxy-3-
-propylbenzoic acid methyl ester, L8.2 g (0.13 mol) of
anhydrous po~assium carbonate and 2L.9g ~0.13 mol) of
potassium iodide in 550 ml of anhydrous acetone was stirred
at re~lux for 22 hou~s. The reaction mixture was filtered
and the filtrate was conc~ntrated undee reduced pressure to
an oil which was purified by HPLC using 8% ethyl acetate-
-hexane to gi~e 31.4g (83% yield) of 4-[6-(2,3-dimethoxy-
phenyl)hexyloxy~-2-hydroxy-3-propylbenzoic acid methyl ester
as an oil.
Compounds of Examples 17-23 which follow were prepared
in accordance with the procedure of Example 16.
ExamPle 17
4-~6-(2,3-Dimethoxyphenyl)ethoxy]-2-hydroxy-3-p~opyl-
benzoic acid methyl ester, m.p. 77-80.
Example 18
4-~6-(2,3-Dimethoxyphenyl)propoxy]-2-hydeoxy-3-propyl-
benzoic acid methyl ester, m.p. 51-53.
Example 19
4-~6-(Z,3-Dimethoxyphenyl)butoxy]-Z-hydroxy-3-~roeyl-
benzoic acid methyl ester, oil.
. .
,, ~, : ' :

~ 328279
- 65 -
Example 20
4-[6-(2,3-Dimethoxyphenyl)heptyloxy]-2-hydroxy-3-pcopyl-
benzoic acid benzyl es~er, oil.
ExamPle 21
4-~6-(2,3-Dimethoxy~henyl)octyloxy]-2-hydroxy-8-proeyl-
benzoic acid me~hyl ester, oil.
Example 22
4-[6-(2,3-Dimethoxyphenyl)decyloxy]-2-hydroxy-3-pro~yl-
benzoic acid benzyl ester, oil.
4-~6-(2,3-Dimethoxy-4-isopropylphenyl)hexyloxy]-2-hydroxy-
3-propylbenzoic acid benzyl e~ter, oil.
Exam~le 24
A solution of 31.4g (0.073 mol) o~ 4-~6-~2,3- dimethoxy-
phenyl~hexyloxy]-2-hydroxy-3-propylbenzoic acid methyl es~er
in 800 ml o~ methanol and 365 ml (0.0365 mol~ of lN sodium
hydroxide was ~tirred at reflux for 1.5 hours. The methanol
was removed under reduced eressure, the residue was
acidified and the product was extracted with methylene
chloride. The dried extract was concentrated under reduced
eres6ure to a solid which was recrystallized from
ether-hexane to give ~.8g (82% yield), mp 115-118, of
4-~6~(2,3-dime'choxyphenyl)hexyloxy]-2-hydroxy-3-proeylbenzoic
acid.
Comeounds of Examples 25-30 were ere~ared by the
procedure of Examele 24.
, . ,

1 32~27q
- ~6 -
ExamDle 25
~ 4-~6-(2,3-Dimethoxyphenyl)ethoxy]-2-hydroxy-3-propyl~
ben20ic acid, m.p. 154-156.
Example 26
4-t6-(2.3-DimethoxYphenyl)propoxy]-2-hydroxy-3-pr
benzoic acid~ m.p. 133-134.

ExamPIe 27
4--[6-(2,3-Dimethoxyphenyl)butoxy]-2-hydroxy-3-pro~yl-
benzoic acid, m.p. 111-113.
Exam~le 28
4-[6-(2,3-Dimethoxyphenyl)heptyloxy]-2-hydcoxy-3-eropyl-
benzoic acid. m.p. 98-100~.
~ Example_29
:~ 4-~6-~2,3-Dimethoxyphenyl)octyloxy]-~-hydLoxy-3-propyl-
benzoic acid, m. e. 90-92.
~ ~ Exam~le 30
,~ 4-~6-(2,3-Dimethoxyphenyl)decyloxy~-2-hydroxy-3-propyl-
benzoic acid, m~p. 77-78.
ExamPle 31
A solution of 6.96g of 2-hydroxy-4-~6-~2,3-dimethoxy-4-
(l-methylethyl)phenyl~hexyloxy]-3-propylbenzoic acid phenyl-
methyl ester in ~50 ml of ethyl acetate and 1.4g of 10~paIladium o~ carbon was stirced in a hydrogen atmosphere for
3 hours. The reaction mixture was filtered through a Celite

1 328279
- 67 -
pad and the filtrate was concentrated undeL reduced pre6sure
to 5.45g, mp 106-lOQ, of 2-hydroxy-4-[6-~2,3-dimethoxy-4-
(l-methylethyl)phenyl]hexyloxy]-3-~ropylbenzoic acid.
Example 32
To 5.0g (0.012 mol) of 4-~6-(2,3-dimethoxyphenyl)hexyl-
oxy]-2 hydroxy-3-propylbenzoic acid suspended in 250 ml of
anhydrou~ methylene chlo~ide and cooled at -70 wa~ added 36
ml (0.036 mol) of lM bo~on trib~omide in methylene chloride
dropwi~e over 30 minutes. The Leaction mix~ure was stirred
at -70 for 30 minutes and then keet at -18 ~or 17 hours.
Water (150 ml) was added dropwise with stirring and the
product was extracted with ether. The ext~act was
concentrated undeL reduced ~ressure. The residue wa~ taken
up in 500 ml of ether and shaken vigorously with lZ5 ml of
lN HCl. The extract was dried and concent~ated undeL
reduced p~essule to a solid. Recrystallization from
ether-hexane gave 3.7g (80~ yield), me 147-150, of
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic
acid.
The compounds of Examples 33-39 were prepared by the
pLocedure of Example 32.
Example 33
4- L 6-(2~3-Dihydroxyphenyl)ethoxy~-2-hydroxy-3-propyl_
benzoic acid, m.p. 184-189.
Example 34
4-~6-(2,3-Dihydroxyehenyl)pcoeoxy]-2-hydroxy-3-~ropyl-
benzoic acid, m.p. lR9-191 .
3~
.- :
. ~

328279`~
- 68 -
Example 3s
4-[6-(2,3-Dihydroxyphenyl)butoxy]-2-hydroxy-3-propyl-
benzoic acid, m.p. 160-162.
Example 36
4-[6-(2,3-Dihydroxyphenyl)heptyloxy]-2-hydLoxy-3-propyl-
benzoic acid, m.p. 144-146.
Example 37
4- L 6-(2,3-Dihydroxyphenyl)oct~loxy~-2-hydroxy-3_po~yl_
benzoic acid~ m.p. 136-139.
Example 38
'
4-~6-(2,~-Dihydroxyehenyl)decyloxy]-2-hydro~y-3-pro~yl-
benzoic acid, m~p. 126-128.
Example 39
4-~6-(2,3-Dihydroxy-4-isoproeylphenyl~hexyloxy]-2-
-hydroxy-3-propylbenzoic acid, m.p. 104-105.
Example 40
A mixture of 6.88g (O.OL38 msl) o~ 1-(6-iodohexyl)-2,3-
diphenylmethoxybenzene, 3.60g (0.0125 mol) o~ 2,~-dihydroxy-
3-~ropylbenzoic acid phenylmethyl ester, 2.60 g 10.0188 mol)
of anhydrous potassium carbonate and 3.10g ~0.0188 mol) of
" potassium iodide in 150ml of anhydrous acetone was stirred
at ~eflux for 42 hours. The reac~ion mixture was filtered
and the iltLate was concentrated under Leduced pressure.
I 3~ The residue was purified by HPLC using 10% ethyl
acetate-hex~ne to give 7.37g (9~% yield) o~ the phenylmethyl
ester of 2-hydroxy-~-[5-[2,3-bis(phenylmethoxy)pentyloxy]-
"~ ,,,

~ 32827~
- 69 -
-3-propylbenzoic acid as an oil which solidified, mp 65-69.
A solution of 7.2 g of 2-hydroxy-4-~5-~2,3-bis (phenyl-
methoxy)~entyloxy]-3-propylbenzoic acid phenylmethyl ester
in 500 ml of tetrahydeofuran and L.4g of 10% palladium on
ca~bon was stireed in a hydrogen atmosphere fo~ 25 hours.
The reaction mixture was fil~ered through a Celite ead and
the filtrate was concentLated under reduced pressure to a
solid which was recrystallized from ether-hexane to give
3.8g (90~ yield), mp 155-157, of 4-~5-(2,3-dihydroxy-
phenyl)pentyloxy] 2-hydroxy-3-propylbenzoic acid.
ExamDle 41
A mixture of 1.40g (4.B mmol) of 1-(6-bromohexyl)-2,3-
dimethoxybenæenev l.OOg (4.8 mmol) of 4-hydroxy-3-proeyl-
benzoic acid ethyl estsr, 1.30g (9.6 mmol) of potassium
carbonate and 0.72g (4.8 mmol) of sodium iodide in 35 ml of
acetone was 6tirred at reflux for 47 hours. Workup and
purification as desc~ibed in Example 16 gave 200 g of
4-~6-tZ,3-dimethoxyphenyl)hexyloxy]-3-propylbenzoic acid
ethyl ester as an oil.
ExamPle 42
A solution of 2.0g of 4-[6-(2,3-dimethoxyphenyl)-
hexyloxy]~3-proeylbenzoic acid ethyl ester in 70 ml of
methanol and 24 ml of lN sodium hydroxide was stirred at
re~lux ~or 3 hours. Wor~up as in Example 24 gave 1.87g, mp
107-108, of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-3-propyl-
benzoic acid.
Example ~3
3S To 1.80 g of 4-L6-(2,3-dime~hoxYphenyl)hexyloxy]-3-
-propylbenzoic acid in 125 ml of methylene chloride cooled
at -70 was added 14 ml of lM boron ~ribromide in methylene
, .

~ 32~279
- 70 -
chloride. Aftes 30 minutes at -70 and 5 hours at -20, the
reaction was worked up as in Example 3Z and the product was
recrystallized from ether-hexane to give l.L2g, mp lZ3-1~4
of 4-~6-(2,3-dihydroxyphenyl)hexyloxy]-3-propylbenzoic acid.
Example 44
A mixture of 1.20 (4.0 mmol) of L-(6-bromohexyl)-~,3-
dimethoxybenzene, 1.00 g (4.0 mmol) of 3,5-dipropyl-4-
-hydroxybenzoic acid ethyl ester, l.lOg (8 mmol) o~
potassium carbonate and 0.6g t4 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-dimethoxy-
ehenyl)hexyloxy]-3,5-dipro~ylbenzoic acid ethyl ester as an
oil.
ExamPle 45
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 Z0 ml of lN sodium hydroxide was stirred at
reflux for 3 hours. Worku~ as in Exam~le 24 gave 4-~6-(2,~-
~ dimethoxyphenyl)hexyloxy]-3,5-dieropylbenzoic acid, mp
:: 61-65.
Example 46
To 1. 7g of 4-~6-(Z,3-dimethoxyphenyl)hexyloxy]-3,5-
dipropylbenzoic acid in 125 ml of methylene chloride cooled
at -70 was added 14 ml of lM boron tribromide in methylene
chloride. After 30 minutes at -70 and 5 hours at -20, the
reaction was wocked up as in Exam~le 32 and the product was
: recrystallized ~eom ether-hexane to give 0.27g, mp g4-960;
o~ 4-[6-(2,3-dihydLoxy~henyl)hexyloxy]-3,5-dieropylbenzoic
acid.
: '
.. . . . . . . . . . . .
,. : ~ -

1 32~279
- 71 -
- ExamDle 47
A mixture of 0.90g (0.00~3 mol) of 4-[6-(2,3-dihydroxy-
phenyl)hexyloxy]-2-hydroxy-3-~rvpylbenzoic acid, 1.9 ml
(0.023 mol) of ethyl iodide and 0.2L g o sodium bicarbonate
in 10 ml of anhydrous dimethylformamide was stiLred and
heated at SO for 6 hours. ~he solvent was Lemoved on the
oil pump, the residue was treated with sodium bicarbonate
solution and the eroduct was extracted with ethyl acetate.
10 The dried extrac~ was concentrated and the re6idue was
chcomatogra~hed on 35g o~ silica gel. Elution with 10~
ethyl acetate-toluene gave 0.89g of an oil which wa~ ~tirred
with hexane and filtered to give 0.71g (70~ yield), mp
54-57; of 4-t6-(2,3-dihydroxyphenyl)hexyloxy]-2-hyd~oxy-
-3-propylbenzoic acid ethyl e~ter.
~xam~le 48
A mixture of 1.0g (2.57 mmol) of 4 [6-(2,3-dihydroxy-
phenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid, 3.5g (25.7
mmol) of 2-diethylaminoethyl chloride and 0.24 g (2~83 mmol)
of sodium bicarbonate in 20ml of anhydrous dimethylformamide
was stirred and hea~ed at 50 ~or 1.5 hours. The solvent
was removed on the oil pump. The residue wa~ treated with
sodium bicarbonate solution and the product was extracted
with ethyl acetate. The dried extract was concentrated and
the re~idue was chromatographed on 50g of silica gel.
Elutio~ with CH2C12: 95% ~eOH: NH40H (9S:5:0.05) gave
1.0 g of the free base of 4-C6-(Z,3-dihydroxyphenyl)hexyl-
oxy]-2-hyd~oxy-3-~ropylbenzoic acid [2-(diethylamino)ethyl]-
ester. This was dissolved in methylene chloride, treated
with 3.2 ml of 2M HCl in ethanol. ~fter concen~ration and
addition of hexane, 0.91g (68% yield), mp 98-100, of
4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-proeylbenzoic
acid t2-(diethylamino)ethyl]ester hydrochloride was obtained.
. .

1 32827q
- 72 -
. Exam~le 49
A mixture of L.9lg (3.75 mmol) of 1-(6-bromohexyl)-Z,3-
-bisC(4-methylbenzoyl)oxy]benzene, 1.07g (3.75 mmol)
2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester, 0.94g
(5.63 mmol) of po~assium iodide and 0.75 g (5.63 mol) of
potassium cacbonate in 40 ml of acetone was stirred at
reflux for 26 hours. The reaction mixture was filteeed and
the filtrate was concentrated under reduced pressuLe. The
crude ~roduct was purified by HPLC using 5% ethyl ace~ate-
-hexane to give 0.85g (32% yield) of 2-hydroxy-4-~6-~2,3-bis
~t4-methYlbenzoyl)oxy]phenyl]hexyloxy3-3-~ro~ylbenzoic acid
phenylmethyl ester as an oil.
Example 50
A solution of 0.78g of 2-hydroxy-4-~6-t2,3-bis-
[(4-methylbenzoyl)oxy]phenyl]hexyloxy~-3-propylbenzoic acid
phenylmethyl ester in 65 ml of tetLahydrofuran and 0.16g of
20 L0% ~alladium on carbon was shaken in a hydrogen atmosphere
~or 3 hours. The reac~ion mixture was filtered through
Celite and ~he filtrate was concentrated under ceduced
~ressure to a solid which was recrystallized from methylene
chloride-hexane to give 0.57g, m~ 141-143, of 2-hydroxy-4-
25 -~6-~2, 3-bis~4-methy1benzoyl)oxy]phenyl]hexyloxy]-3-eroeyl-
benzo ic ac id .
ExamDle 51
To a suseen~ion of 0.14g (3.5 mmol, 60% on oil) of
sodium hydride in 10 ml of anhydrous dimethylformamide
- stirred at room temperature was added 0.88g ~3.1 mmol) of
2,4-dihydroxy-3-eropylbenzoic acid ~hanylmethyl ester. The
reaction mixture was stirred for 2 hours and then 1.09 q
35 (3.1 mmol) of 1-(6-bLomohexyl)-2,3-bis (acetyloxy)benzene
in 10 ml of dimethylformamide was added dro~wise. Stir~ing
at 50 was continued for 16 hours and then the solvent was
.. . .
.

1 32~279
removed on the oil pump. The crude product was puri~ied by
HPLC using 25% ethyl acetate-hexane to gi~e 0.55 g ~28%
yield) of 4-[6-[2,3-bis(acetyloxy)phenyl]hexyloxy]-Z-
-hydroxy-3-propylbenzoic acid phenylmethyl ester as an oil.
Example 52
A solution of 0.53g of 4-[6-~2,3-bis(acetyloxy)phenyl]-
hexyloxy]-Z-hydroxy-3-proeylbenzoic acid ehenylmethyl estee
in 50ml of tetrahydrofuran and O.lOg of 10% palladium on
carbon was shaken in a hydrogen atmosphere for 3 hours. The
reac~ion mixture was filtered ~hrough Celite and the
filtrate was concentrated to a solid which was recry talli-
zed from ether-hexane to give 0.35g, mp 120-122~ of
4-t6-~2,3-bis(acetYloxy)phenyl]hexyloxy]-2-hydroxy-3-pr
benzoic acid.
Example 53
A mixture of 1.3lg (2.6 mmol) of 1-(6-iodohexyl)-2,3-
bis(phenylmethoxy)benzene, 0.74g (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 ~or 39 hours. The rea~tion mixture
was filtered and the filtrate was concentrated under reduced
~ressure ~o an oil which was purified by HPLC using 8% ethyl
acetate~hexane to give 1.03g (60% yield) of 2-hydroxy-4-~6-
~2,3-bis~phenylmethoxy)phenyl]hexyloxy]-3-eropylbenzoic acid
phenylmethyl ester as an oil.
Examvle 54
A solution of l.L5g of 2-hydroxy-4-[6-r2,3-bis tphenyl-
methoxy)phenyl]hexyloxy]-3-propylbenzoic acid phenylmethyl
ester in L5 ml of ~yridine and 15 ml of acetic anhydride was
stirred and heated at 500 for L5 hours. The reaction
mixture was concentrated on the oil pump. The residue was
.:
: ,: . . -

1 32~279
- 74 -
dissolved in ethyl acetate and the solution was washed with
sodium bicarbonate solution, dried and concentrated u~der
reduced pressure to give 1.03g of 2-acetyloxy-4-~6-[2,3-bi~
(phenylmethoxy)phenyl] hexyloxy]-3-~ropylbenzoic acid
phenylmethyl ester as an oil.
Example 55
A solution o~ 1.02g of 2-acetyloxy-4-[6- r 2,3-bis~phenyl-
methoxyphenyl]hexyloxy]-3-~ropylbenzoic acid phenylmethyl
ester in 65 ml of tetrahydrofuran and 0.20g of 10% ~alladium
on carbon was stirced in hydrogen atmosehere for 24 hours.
The reaction mixture was filtered through Celite and the
~iLtrate was concentrated and the residue was crystallized
from ether-hexane to give 0.5Lg (82~ yield), mp 130-132, of
2-acetyloxy~~-t6-(2,3-dihydroxyphenyl)hexyloxy~-3-proeyl-
benzoic acid.
Example 56
A mixture of 0.41g (0.8mmol) of 1-(6-iodohexyl)-2,3-bis
(phenylmethoxy)benzene, 0.18g (0.74 mmol) of 5-chloro-2,4-
dihydroxypropylbenzoic acid methyl ester and 0.22g (1.6
mmol) of potassium carbonate in 15 ml o~ acetone was stirred
at reflux for 16 hours. The ~eaction mixture was filtered
and the filtrate was concentrated to an oil. Chromatography
on 30g of silica gel and elution with 10% ethyl acetate-
-hexane gave 0.31g (68~ yield) of 5-chloro-2-hydroxy-4-
-[6-rZ,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylbenzoic
acid methyl ester as an oil.
Example 57
A solution of 0.30g of 5-chlo~o-2-hyd~oxy-~-t6-C2,3-bis
(phenylmethoxy)phenyl]hexyloxy]-3-propylbenzoic acid methyl
ester in 10 ml of methanol, 5ml of dioxane and 2.5 ml of lN
sodium hydroxide was left at room ~emperature ~or 3 days.

1 328279
- 75 -
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 30g of
silica gel using ace~ic acid: ethyl acetate: toluene
(1:25:75) ~o give 0.2Ig of 5-chloro-~-hydroxy-4-[6-t2,3-bis-
(phenylmethoxy)phenyl]hexyloxy]-3-propylbenzoic acid as an
Oil .
Example 58
A solution of 0.21g of 5-chloro-2-hydroxy-4-~6-[2,3-bi6
(phenylmethoxy)phenyl]hexyloxy]-3-propylbenzoic acid in 30
ml of ethyl acetate and 0.073g of 10% ~alladium on cacbon
was shaken under hydrogen pressure (2-2,7 bar) for 2~
hours. The reac~ion mixture was filtered through Celite and
the filtrate was concentrated to an oil. Chromatography on
20g o~ silica gel and elution with acetic acid:ethyl
acetate:toluene (5:20:75) gave 8Zmg, mp 110-113, of
5-chloro-2-hydroxy-4-~6-~2,3-dihydroxyphenyl]hexyloxy]-3-
-PrO~ylbenzoic acid.
Example 59
mixture of l.Og (3.3 mmol) of 1-(6-bromohexyl)-Z,3-
dimethoxybenzene, 0.55g t3.3 mmol~ of 2,4-dihydroxybenzoic
acid methyl ester, 1.2g ~9 mmol) of potassium carbonate and
0.75g (4.5 mmol) of potassium iodide in 25 ml of acetone was
stirred at reflux for Z0 hours. Workup as in Example 16
gave 1.2g of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-2-hydroxy-
benzoic acid methyl ester as an oil.
ExamPle 60
~ solution of 0.45g (1.2 mmol) of 4-[6-t2,3-dimethoxy-
phenyl)hexyloxy]--2-hydroxybenzoic acid methyl ester in 25 ml
of methanol and 8 ml of lN sodium hydroxide was refluxed for
7 hours. Workup as in Example 24 and recrystalliza~ion from
- . ~ , , .

1 32827~
- 76 -
methanol gave 0.36g (82% yield), mp 115-116 o~ 4-[6-(2,3-
dimethoxy~henyl)hexyloxy] 2-hydroxybenzoic acid.
Example 61
To 0.35 g of 4-~6-(2,3-dimethoxyphenyl)hexyloxy~-2-
hydroxybenzoic acid in 10 ml of methylene chloride sticced
and cooled at -70~ was added 3.5 ml of lM boron ~ribromide
in methylene chloride. The reaction mixture was stirced at
-70 for 20 minutes and at -20 for 6.5 hours. Workup as in
Example 32 and crystallizatioh from methanol gave 0.20g (60%
yield), mp 179-180~, of 4-r6-(2,3-dihydroxyphenyl)hexyloxy]-
2-hydroxy-benzoic acid.
Example-6?
A mixture of L.OOg of 1-(6-iodohexyl)-2,3-bis(phenyl-
methoxy)benzene, 0.34g of 2,5-dihydcoxybenzoic acid methyl
ester and L.Og of ~otassium carbonate in 30ml o~ acetone was
stirred at reflux for 17 hours. Workup as in Example '6 and
chromatograehy on ~og of silica gel using 1% ethyl acetate-
toluene gave 0.42g (39% yield) of 2-hydroxy-5-[~-[2,3-bi~
(phenylmethoxy)ehenyl] hexyloxy]benzoic acid methyl e~ter as
an oil.
Exam~le 63
~ solution of 0.42g of 2-hydroxy-5-~6-[2,3-bis ~ehenyl-
methoxy)phenyl.]hexyloxy]benzoic acid me~hyl ester in 12 ml
o~ ethanol and 4 ml of lN sodium hydroxide wa~ stirred at
reflux for 1.5 hours. Workup as in Example 24 and
~ecrystallization feom ethec-hexane gave 0.25g, mp 97-100,
of 2~hydroxy-5-~6-r2,3-bis(phenylmethoxy)~henyl]hexyloxy]-
benzoic acid.

1 ~2~d 279
- 77 -
Exampl~ G4
A mixture of 0.22g o 2-hydroxy-5-r6-~2,3-bis(phenyl-
me~hoxy)phenyl]hexyloxy]benzoic acid and 30 mg of 10%
6 palladium on ca~bon in 10 ml o~ methanol was stiered in a -
hydrogen atmosphere for 5 hours. Wockup as in example 36
and recrystallization from acetone-hexane gave O.lOg, mp
159-161 o~ 2-hydroxy-5-[6-(2,3-dihydroxyphenyl)hexyloxy]-
benzoic acid.
ExamPle 65
A mixture of L.OOg (3.3 mmol) of 1-(6-bromohexyl)-Z,3-
dime~hoxybenzene, 0.45g (3.0 mmol~ of 4-hydeoxybenzoic acid
methyl ester, 0.62~ (4.5 mmol) of potassium carbonate and
0.75g (4.5 mmol) of potassium iodide in 25 ml of acetone was
stirred a~ reflux for 23 hours. Workup as in ~xample 16 and
puri~ication by ~IPLC using 15% ethyl acetate-hexane gave
l.lOg (89% yield) of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-
benzoic acid methyl ester as an oil.
Exam~le 66
.
To O . 80g ~ 2 . 2 mmol) of 4-~6-(2,3-dimethoxyphenyl)hexyl-
oxy]benzoic acid methyl ester in Z5 ml of methylene chloride
stirred and cooled at -70 was added 8.0 ml of lM boron
tribromide in methylene chloride. The reaction mixtu~e was
stirred at -70 ~or 30 minutes and at -20 for 7 hours.
Workup as in example 32 and recrystalliza~ion from e~hyl
acetate-hexane gave 0. 30g (42~ yield), me 170-172 of
4-~6-(2,3-dihydroxyphenyl)hexyloxy~benzoic acid.
Example 67
~ mixture of o.s8g of 1-(6-iodohexyl)-2,3-bis ~ehenyl-
methoxy)benzene, 0.18g o 3-hydroxybenzoic acid methyl ester
and 0.~5g of potassium carbonate in Ls ml of acetone was
.

``` 1 328279
- 7~
stirred at reflux for 18 hours. Workue as in Example 16 and
purification by HPLC using toluene gave 0.40g (66% yield) of
3-[6-~2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid
methyl estec as an oil.
xam~le 68
A solution of 0.5g of 3-~6-[2,3-bis(phenylmethoxy)-
~henyl]hexyloxy]benzoic acid methyl ester in L5ml of
methanol and 5 ml of lN sodium hydroxide was ~tirred at
reflux ~or 2 hours. Worku~ as in Example 24 and
crystallization from methanol gave 0.34g (70% yield), m~
72-74, of 3-[6-~Z,3-bis(phenylmethoxy)phenyl]hexyloxy]-
benzoic acid.
Example 69
A mixture of 0.33g of 3-~ 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
s~irred in a hydrogen atmosphere for 11 hours. The ceaction
mixture was ~iltered through Celite and the filtrate was
concentrated under reduced pressure to an oil. Chromato-
gcaphy on ~Og of silica gel and elution with 10% methanol-
-chloro~orm gave a solid which was recrystallized from
ether-hexane to give 0.14g (63~ yield), mp 123-125, of
3-~6-(2,3-dihydroxyphenyl)hexyloxy]benzoic acid.
ExamPle 70
~ mixture of 5.6g of 1-(6-iodohexyl)-Z,3-bis(phenyl-
methoxy)benzene, 2.1g of 3-chloro-4-hydroxybenzoic acid
methyl ester and 5.0g of potassium carbonate in 50 ml of
acetone was sticced at reflux for 20 hours. WoLkup as in
Example 16, chromatography on lOOg of silica gel using 15%
ethyl acetate-hexane and crystallization fcom ethyl acetate-
-hexane gave 3.7g (59% yield), mp 68-69, 3-chloro-4-
~1,j''
. . .

1 328279
- 79 -
-~6-[2,3-bis(phenylme~hoxy) phe~yl]hexyloxyJbenzoic acid
methyl ester.
Example 7L
A solution of 3.6g of 3-chloro-4-~6-~,3-bis(phenyl-
methoxy)ehenyl]hexyloxy~benzoic acid methyl ester in 90 ml
o~ methanol and 30 ml of lN sodium hydroxide was refluxed
for 2 hours. Workup as in Example 24, chromatogeaphy on 70
f silica gel using 50% ethyl acetate-hexane and
recLystallization from ether-hexane gave 1.3g, mp 87-89, of
3-chloro-4-[-[203-bis(phenylmethoxy)~henyl]hexyloxy]benzoic
acid.
Example 72
A mixture of 0.6g of 3-chloro-4-[S-~2,3-bis(phenyl-
methoxy)~henyl]hexyloxy]benzoic acid and 60 mg of 10%
~aliadium on carbon ia 20 ml of tetrahydrofuran was stirred
in a hydeogen atmosphere for 6 hours. Worku~ as in Exampla
40 and recry6tallization from ethyl acetate-hexane gave
0.24g, mp 157-160, of 3-chloro-4-~6-t2,3-bis(phenyl-
methoxy~hexyloxy]benzoic acid.
Example 73
A mixture of 3.4g ~0.016 mol) of 2,4-dihydroxy-3-
propylbenzoic acid methyl este~, 4.7g (0.018 mol~ of
L-~(2-methanesulfonyloxy)ethyl]-2,3-dimethoxybenzene, 4.4g
(0.03Z mol) of potas6ium carbonate and 2.7g (0.018 mol) of
sodium iodide in 90 ml of acetone was stirred at reflux for
18 hours. 4.7g of 1 [(2-methanesul~onyloxy)ethyl]-2,3-
dimethoxybenzene and 4.4g of potassium carbonate were added
and reflux was continued for 41 hours. The reaction mixture
3S was filtered and the filtcate was concentrated under reduced
pressure to an oil which was puri~ied by high pressure
liquid chLomatography using 10% ethyl acetate-hexane to

1 32~279
- 80 -
~emove impurities and then ethyl acetate to obtain 4.Sg of
oil. This was stirred with hexane and filtered ~o give
1.65g (28% yield), mp 56-58O, of 4-t2-(3,4-dimethoxYphenyl)-
ethoxy]-2-hyd~oxy-3-proeylbenzoic acid methyl ester.
ExamPle 74
~ . .
A mixture of 9.5g (0.037 mol) of 1-(3-bromopeopyl)-3,4-
dimethoxybenzene [G.H. Douglas, C. R. Walk and H. Smith, J.
10 Med. Chem., 9, 27 (L966)], 7.0g (0.033 mol) of
2,4-dihydroxy-3-propylbenzoic acid methyl ester, 6.9g (0.0
mol) of ~otassium carbonate and 8.3g (0.05 mol) of potassium
iodide in 250 ml of acetone was stirred at reflux for 24
hours. The reaction mixture was ~ilteLed and the filtra~e
: 15 was concentrated under reduced ereSsure to an oil which was
: purified by high pressure liquid chromatography using 15%
: ethyl acetate-hexane to give 7.2g ~56% yield) of
4-~3-(3,4-dimethoxyphenyl)pLopoxy]-2-hydroxy-3-propylbenzoic
acid methyl ester as an oil.
Compounds of Examples 75-77 were preeared using the
procedure of Examele 74.
ExamDle 75
4-~3-(3,4-Dimethoxyphenyl)butoxy]-2-hydroxy-3-propyl-
benzoic acid methyl ester, yield 49%.
Exam~le 76
: 30
4-[3-(3,4-Vimethoxyehenyl)pentyloxy]-2-hydroxy-3-proeyl-
benzoic acid benzyl estec, yield 80%.
ExamDle 7_
4-~3-(3,4-Dimethoxyphenyl)hexyloxy]-2-hydroxy-3-ero~yl-
benzoic acid benzyl ester, yield 77%.
.

1 328279
- 81 -
Example 78
A solution of 7.1g of 4-~3-(3,4-dimethoxyehenyl)-
~roeoxy]-2-hydroxy-3-p~opylbenzoic acid methyl e6ter in 180
ml of methanol and 90 ml of lN sodium hydroxide was sti~red
at reflux for 1 hour. The solvent wa~ removed under reduced
pressure, the residue was acidified and the product was
extracted with methylene chloride. The dried (MgS04)
ext~act was concentrated to 6.5g, m~ 104-L10, of 4-[3-(3,4-
dimethoxy~henyl)propoxy]-2-hydroxy-3-propylbenzoic acid.
Compounds of Examplss 79, 80 and 82 were prepared using
the pcocedure o~ Example 78. Compound of Exam~le 84 was
prepared usi~g the procedure of Example 40, hydLogenolysis
in tetrahydrofuran.
ExamPle 79
4-~3-(3,4-Dimethoxy~henyl)ethoxy]-2-hydroxy-3-propyl-
benzoic acid. m. e. 156-157.
Example 80
g-~3-(3~4-Dimethoxyphenyl)butoxy]-2-hydroxy-3-er
benzoic acid, m.e. 125-127.
Exam~le 81
4-~3-(3,4-Dimethoxy~henyl)pentyloxy]-2-hydroxy-3-propyl-
benzoic acid, m.p. 133-136.
Example 82
4-~3-(3,4-Dimethoxypherlyl)hexyloxy]-2-hydroxy-3-proeyl-
3~ benzoic acid, m. e . 99-101-.
- ~
~ -, ., . . ~ ~ . : ;
~ : . , ~.

~ 32827~
- 82 -
Example 83
To 3.0g (0.008mol) of 4-~3-(3,4-dimethoxyphenyl)propoxy]-
Z-hydroxy-3-propylbenzoic acid 6useended in Z50 ml o~
methylene chloride and cooled at -70, was added 24 ml (0.024
mol) of lM boron tribromide in methylene chloride dropwise
over 30 minutes. The reaction mixture was stirred at -70
for 1 hour and then in an ice bath for 1.5 hours. Water (100
ml) wa6 added dropwise with stirring and the product was
extracted with ether. The extract was concentrated under
reduced presæure and the residue was taken up i~ etheL (500
ml) and shaken vigorously with 100 ml of LN hydrochloric
acid. The dried extract was concent~ated and the residue was
recrystallized from e~her-hexane to give 2.2g (79% yield), mp
194-195, of 4-~3-(3,4-dihydroxyphenyl)proeoxy]-2-hydroxy-3-
-eroPylbenzoic acid.
Compounds of examples 84-87 were prepared using the
procedure o~ Example 83.
Example 84
4-[3-(3,4-Dihydroxyphenyl)e~hoxy]-2-hydroxy-3-plopyl-
benzoic acid, m.p. 164-1~5.
Example 85
4-~3-(3,4-Dihydroxyphenyl)butoxy]-Z-hydroxy-3-proeyl-
; 30 benzoic acid, m.p. 190-193.
ExamPle 86
4-[3-(3,4-Dihydroxyphenyl)pentyloxy]-2-hydroxy-3-propyl-
benzoic acid, m.p. L59-162.
.
.. ..

- ~3
Example 87
~ -[3-(3,4-Dihydroxyphenyl)hexyloxy]-2-hydroxy-3-peopyl-
ben70ic acid, m.~. 113-114.
Example 88
A mixture of 2.56g (9.9 mmol) o~ 3-bromopropyl)-3,4-
dimethoxybenzene, l.SOg ~9 mmol) of ~-hydLoxybenzoic acid
ethyl ester, 1.38g tlO mmol) of eotassium carbonate and 1.66g
(10 mmol3 of potassium iodide in 50 ml o~ acetone was stirred
at reflux for 22 hours. WoLkup as in Exam~le 16, purifica-
tion by high pressure liquid chromatography using methylene
chloride and recrystalliza~ion from 2-propanol gave 1.23 g
(40~ yield)~ mp 70-71, of 4-~3-(3,4-dimethoxyphenyl)-
propoxy]benzoic acid ethyl e~t~r.
.
ExamPle 89
A solution of 1.2g o~ 4-[3-(3,4-dimethoxyphenyl)propoxy]
benzoic acid ethyl ester in 40 ml of methanol and 18 ml o~ lN
so,dium hydroxide was stirred at reflux for 1 hour. Workup as
in Example 24 gave l.lg, me lSO-154, o~ 4-~3-(3,4-dimethoxy-
phenyl)propoxy]benzoic acid.
Example 90
To 1.08g (3.4 mmol) of 4-~3-(3,4-dimethoxyphenyl)pro~oxy]
benzoic acid 6uspended in 60 ml of methylene chloride and
30 cooled at -70 was added 10 ml (10 mmol) of lM boron
tribromide in methylene chloride. The reaction mixture was
stirred at -70 ~or 2.5 hours and then worked up as in
Example 32. Recrystallization from ether-hexane gave 0.40g
(41% yield), mp 180-185, of 4-~3-(3,4-dihydroxyphenyl)pro-
pox~]ben20ic acid.

`
1 32827~
- 8~ -
ExamPle 91
A mixture of 1.60g (5 mmol) of 6-bromo-1-(3,4-dimethoxy-
phenyl)-l-hexanone, 0.95g (4.5 mmol) of Z,4-dihydroxy-3-
propylbenzoic acid methyl ester, 1.38g (10 mmol) of potassiumcarbonate and 0.75g (5 mmol) of sodium iodide in 40 ml of
acetone was stirred at reflux for 45 hours. The reaction
mixture was ~iltered and the filtrate was concentrated and
treated with water. The product was filtered and recrys-
tallized from methylene chloride-methanol to give 1.40g (70%
yield), mp 117-119, of 4-[[6-(3,4-dimethoxyphenyl~-6-oxo-
hexyl]oxy]-2-hydroxy-3-propylbenzoic acid methyl ester.
ExamPle 92
A solution of 1.36g of 4-[[6-(3,4-dimethoxyphenyl)-6-
oxo- hexyl30xy]-2-hydroxy-3-propylbenzoic acid methyl ester
in 35 ml of methanol and 13 ml of lN sodium hydroxide was
stirred at reflux for 8.5 hours. The solvent was removed
under reduced pressure, the ~esidue was acidified and the
product was filtered. Recrystallization from ethyl
acetate-hexane gave 0.94g (71~ yield), mp 11~-117, of
4-[[6-(3,4-dimethoxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propyl-
benzoic acid.
ExamPle 93
To 0.93 g of 4-[[6-(3,4-dimethoxyphenyl)-6-oxohexyl]oxy]-
2-hydroxy-3-p~opylbenzoic acid suspended in 60 ml of
methylene chloride and cooled at -70 was added 7 ml of lM
boron tribromide in methylene chloride. The reaction mix~ure
was stirred at -70 for 1 hour and then at -18 for 20
hours. Workue as in Example 32 and chromatography of the
crude product on lOOg of silica gel using acetic acid:ethyl
acetate-toluene (5:25:70) followed by recrystallization from
ethyl aceta~e-hexane gave 0.42g, me L88-191, of 4-C[6-(3,4-
-dihydroxyphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic
: . - .

t 328279
- 85 -
acid.
Example ~4
A mixture of 4.36g (15.9 mmol) of 1-(4-bromobutyl)-2,3-
dimethoxybenzene, 3.~0g (15.9 mmol) of 1-(2,4-dihydroxy-3-
propylphenyl)ethanone, 4.4g (3Z mmol) of potassium carbonate
and 2.4g (16 mmol) of sodium iodide in 100 ml of acetone was
stirred at reflux for 30 ~ours. The reaction mixture was
filtered and the filtrate was concentrated under reduced
pressure. Purification by high pressure liquid chromato-
graphy using 20% ethyl acetate-hexane gave 5O07g (88% yield)
of 1-~2-Hydroxy-4-~4-(2,3-dimethoxyphenyl)butoxy]-3-proeyl-
phenyl]ethanone as an oil.
Compound~ of Examples 95-97 were prepared using the
procedure of Example 94.
Example 95
1-~2-HydLoxy-4-~4-(2,3~dimethoxyphenyl)hexyloxy]-3-
-propylphenyl]ethanone, oil.
Example 96
1-[2-E~iydroxy-4-t4-(2,3-dimethoxyphenyl)octyloxy]-3-
-propylphen~l~ethanone, oil.
Example 97
1-~2-Hydroxy-4-~4-(2,3-dimethoxy-4-isopropylphenyl)-
hexyloxy]-3-propyl~henyl]ethanone, oil.
Example 98
To 5.02g of 1-~2-hydroxy-4-[4-(2,3-dimethoxyphenyl)-
bu~oxy]-3-propylphenyl]ethanone in 300 ml o~ methylene

1 328279
- 86 -
chloride stirred and cooled at -70 was added 39 ml of lM
boron tribromide in methylene chloride. The reaction mixture
was stirred at -70 for 30 minutes and kept at -Z0 for 5.5
hou~s. ~orku~ as in Example 32 and recrystallization from
acetone-hexane gave 3.81g (82% yield), me 103-105 of
l-t2-hydroxy-4-~4-t2,3-dihydroxyphenyl)butoxy]-3-~ro~ylphenyl]-
ethanone.
Compounds of Examples 99-101 were pre~ared by the
procedure o~ Exam~le ~8.
~L~
l-r2-Hydroxy-4-[4-(2,3-dihydroxyphenyl)hexyloxy]-3-
-propylphenyl]ethanone, m.p. 106-108.
Example loo
1-~2-Hydroxy-4-[4-(2,3-dihydroxyphenyl)octyloxy]-3-
-eropylphenyl]ethanone, m.p. 116-L18.
ExamPle 101
1-~2-Hydroxy-4-[4-(2,3-dihydroxy-4-isopropylphenyl)-
hexyloxy]-3-~ropylphenyl]ethanone, oil.
ExampLe 102
.
3.0g (0.013 mol) of 5-(3,4-dimethoxyehenyl)pentan-1-ol
was converted to the mesylate as described in Example 6. A
mixture of this me~ylate, 2.6g (0.013 mol) of 1-(2,4-
-dihydroxy-3-propylphenyl)ethanone, 2.8 g (0.02 mol) of
potas6ium carbonate and 0.28 ml (0.9 mmol) of tris
~2-(2-methoxyethoxy)ethyl~amine (TDA-l) in 75ml of toluene
was stirred at reflux for 6.5 hours. The reaction mix~ure
was washed with half-saturated brine, then with lN sodium
hydroxide, dried and concentrated under reduced pressure to
.
,~ . : , ::' .. :~'
, . .
.. . .
:
., , . ~ , :
.-

1 32~79
- 87 -
an oil. Purification by HPLC using 25% ethyl acetate-hexane
gave 4.05g (75% yield), mp 72-75, of 1-~2-hydroxy-4-
-[5-(3,4-dimethoxyphenyl)pentyloxy~-3-propylphenyl]-1-ethanone.
Example 103
To 3.g5g (0.01 mole) o~ 2-hydroxy-4-[5-(3,4-dimethoxy-
phenyl~pentyloxy~-3-propylphenyl]-1-ethanone in 80 ml of
methylene chloride cooled at -70 was added 30 ml (0.03 mol)
f lM boron tribromide in methylene chloride. After 30
minute~ a~ -70 and 6 hours at -20,thereactionn~xture w~ worked
up a~ in Example 32 and the prsduct was recrystallized from
ether-hexane to give 3.24g ~88~ yield), mp 126-127, of
1-[4-~5-(3,4-dihydroxyphenyl~pentyloxy~-2-hydroxy-3-pro~yl-
pheny~ -ethanone.
Exam~le 104
A solution of 2.5M butyl lithium in hexane ~1~ ml, 0.04
2~ mol) was added dro~wise over 15 min. to a s~irred solution of
8.3 g ~0.039 mol) of 2,3-dimethoxybiehenyl ~J. M. Bruce and
F. K. Sutcliffe, J. Chem. Soc. 4435 (1955)] in L60 ml of
anhydrous tetrahydrofuran cooled at 0 under argon. The
reaction mixture was stirred at 0 for 2.5 hours and then
refluxed for 30 min. After cooling to 5, 6.3 ml (0.039
mole) of 1,6-dibromohexane was added. stirring was continued
at 5 ~or 30 min., at 25 foL 30 min. and at reflux for 20
hours. Workup as in Examele 1 gave an oil. Purification by
HPLC usiny 3% ethyl acetate-hexane gave S.7g of unreacted
2,3-dimethoxybiphenyl and 3.3g of 4-(6-bromohexyl)-Z,3-
-dimethoxy-l,l'-biphenyl as an oil.
Exampie 105
~ mixture of 3.3g (8.75 mmol) of 4-(6-bromohexyl)-2,3-
dimethoxy-L,l'-biphenyl, 2.5g (8.75 mmol) of 2,4-dihydroxy-
3-propylbenzoic acid phenylmethyl ester, 1.8g (13.1 mmol) of
~1

1 32g279
-- 88 -
potassium carbonate and 0.2 ml ~0.63 mmol) of trist2-(2-
methoxyethoxy)ethyl]amine ~TDA-l) in 65 ml o~ anhydrous
toluene was s~irred at reflux for 30 hours. The reaction
mixture was washed with half-saturated brine and then with lN
sodium hydroxide. ~fter drying the organic layer, the
solvent was removed under reduced pcessure to give an oil
which was purified by chromatography on lOOg of silica gel.
Elution with 10% ethyl acetate-hexane gave 3.7g (73% yield)
of 2-hydroxy-4-[~6-(2,3-dimethoxy~ '-biehenyl)-4-yl]hexyl]-
oxy]-3-pro~ylbenzoic acid phenylmethyl estee.
Example 106
A mixture of 3.76g of 2-hydroxy-~-[r6-(2,3-dimethoxy-
-1,1'-biphenyl)-4-yl~hexyl]oxy]-3-propylbenzoic acid
2henYlmethyl ester and 0.30g of 10% palladium on carbon in 80
ml of tetrahydrofuran was stirred in a hyd~ogen atmosphere
for 17 hours. Workup as in Exam~le 40 and recrys~allization
from hexane gave 2.4g, mp 78-80, of 2-hydroxy-~-~t6-(2,3-
dimethoxy~ '-biehenyl)-4-yl]hexyl]oxy]-3-propylbenzoic acid.
ExamPle 107
To 1.72g (3.S mmol) of 2-hydroxy-4-~t6-(2,3-dimethoxy-
1,1'-biphenyl)-4-hexyl]oxy]-3-propylbenzoic acid suspended in
150 ml of methylene chloride and cooled at -70 was added
1 10.5 ml (10.5 mmol) of lM boron tribromide in methylene
! chlorida. The reaction mixture was stirred at -70 for 20
min. and then kept at -lB for 17 hours. Workup as in
, 30 Exam~le 32 and two recrystallizations o~ the product ~rom
methylene chloride gave 1.03g (63~ yield), mp 151-155, of
2-hydroxy-4-tt6-~Z,3-dihydroxy-l,l'-biehenyl~-~-yl~hexyl]oxy~~
3-propylbenzoic acid.
ExamPle 108
To 0.6g (0.08 g-atoms) of lithium ribbon cut in small
, , .
: ' '

1 32~279
- 89 -
pieces in 40 ml of anhydrous ether stirred at room
temperature under an argon atmos~here wa~ added 9.5g (0.04
mol) of 5-bromo pentanol 2-ethoxyethyl ether. After about 1
ml was added, the reaction mixture was cooled to -5 and the
res~ of the bromo compound was added dropwise. Sti~ling at
-5 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-Z0 ml of
tetrahydrofuran was added dropwise over 1 hour. The cooling
1~ 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 e~hanol, ~0 ml of water
and 2 ml of concentrated hydrochloric acid was added. The
solution was left at 25 for 45 minutes. Potassium carbonate
was added with stirring until the mixture was basic. The
ethanol wa~ removed under reduced ~ressure 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 2.9g t34~ yield), mp
65-70O, o~ 6-~2-chloro-3,4-dimethoxybenzene)-6-hydroxy-
hexanol. This wa~ dissolved in 50 ml of ethanol, 0.3g of L0%
palladium on carbon was added and the mixture was shaken
under an initial hydrogen pressure of 54 psi for 21 hours.
The reaction mixture wa6 filtered through Celite and the
26 filtrate wa~ concentrated under reduced eressure to an oil.
Purification by HPLC using 15% ethyl acetate-toluene gave
~-74Y t64~ yield) of 2-chloro-3,4-dimethoxyben~ene hexanol as
an oil.
~x~oe~
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 teiethylamine followed by
0.65 ml tB.3 mmol) of methanesulfonyl chloride. The reaction
mixture was s~irred with ice bath cooling for 80 min. and
then worked up as in Exam~le 3. The resulting mesylate,
, . ~ . . : . . -:
.. . ~
.: . .
.
:: ~

1 32~27q
- 9o -
1.2~g ~5.9 mmol) of 2,4~dihydroxy-3-pro~ylbenzoic acid methyl
ester, 1.8g (13 mmol) of potassium carbonate and O.Z ml (0.7
mmole) of tris~2-(2-methoxyethoxy)ethyl]amine (TVA-l) in 40
ml of toluene was stirred at reflux for 39 hours. The
reaction mixture was filtered and the filt~ate was
concentrated under reduced pressure. The crude product was
purified by HPLC using 7% ethyl acetate-hexane to give 2.11 g
t77~ yield) of 4]-t6-t2-chloro-3~4-dimethoxyphenyl)hexyloxy]
-2-hydroxy-3-propylbenzoic acid methyl ester as an oil.
ExamPle 110 -.
A solution of 2.1 g (~.5 mmol) oE 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 1~ ml
of lN sodium hydroxide was refluxed for 8 hours. The
solvents were removed at reduced pressure, the residue was
acidified and the product was ex~eacted with ethyl acetate.
The dried extract was concentrated and the residue was
recrystallized from ethyl acetate-hexane to give L.86g (~2%
yield), mp 107-108, of 4-~6-(2-chloro-3,4-dimethoxyphenyl)-
hexyloxy]-2-hydroxy-3-pro~ylbenzoic acid.
Example 111
~5
To 1.80g (4 mmol) of 4-t6-(2-chloro-3,4-dimethoxyphenyl)-
hexyloxy]-2-hydroxy-3-propyl benzoic acid suspended in lZ0 ml
of methylene chloride and cooled at -70 wa6 added 14 ml (14
mmol) of lM boron tribromide in methylene chloride. The
reaction mixture was stirred at -70 for 15 min. and kept a~
-18 for 6 hours. Workup as in Example 32 and two
recrys~allizations from ethyl acetate-hexane gave 1.03 g (61%
yield), mp 145~146, of 4-~6-(2-chloro-3,4-dihydroxyphenyl)-
hexyloxy]-2-hydroxy-3-propylbenzoic acid.

1 32~27q
91 -
ExamPle L12
To 4.0g of 1-(5-bromopentyl)-2,3-dimethoxybenzene in S0
ml of methylene chloLide cooled in an ice bath was added 18
ml of 0.8M chlorine in methylene chloride. The reaction
mixture was kept at 0 for 3 hours and ~hen was concentrated
under reduced pressu~e to yield an oil. Purification by HPLC
using 30% toluene-hexane gave 2.60g (58% yield) of
1-(5-bromopentyl)-6-chloro-2,3-dimethoxybenzene.
ExamPle 113
To 4.0g of 1-(S-bromopentyl)-2,3-dimethoxy benzene in 50
ml of methylene chloride cooled in an ice bath was added 18
ml o~ 0.8M chlorine in methylene chlsride. After 15 minutes,
17 ml o~ 0.88M chlorine in methylene chloride was added. The
reaction mixture was kept at 0 for 3 hours and then was
concentrated under Leduced pressure to yield an oil.
Puri~ication by HPLC using 30% toluene-hexane gave 2.03g t41%
yield) of 1-(5-bromo~entyl)-5,6-dichloro-2,3-dime~hoxy-
benzene.
ExamPle LL4
To l.9g of 1-(5-bromopentyl)-2,3-dime~hoxy 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, 5 ml of 1.35M chlo~ine in methylene chloride was
added. The reaction mixture was ke~t at 0 for 17 hours and
then was concentra~ed under reduced pressure to yield an
oil. Purification by ~PLC using 25% toluene-hexane gave
1.48g (56% yield) of 1-(5-bromopentyl)-2,3-dimethoxy-4,5,6-
-trichlorobenzene.
Exam~le 115
To 1.40g of 6-(3,4-dime~hoxyphenyl)hexan-1-ol in 25 ml of
.

1 32~27q
- 92 -
methylene chloride cooled in a ethanol-dry ice bath was added
4.6 ml o~ 1.35M chlorine in methylene chloride. The reaction
mixture was kept at -75 for 1.5 hour~, at -18 for 16 hours
and then at 0 for 24 hours. After concentration under
reduced pressure, the crude ~eoduct was euLified by HPLC to
give 6-(6-chloro-3,4-dimethoxyphenyl)hexan-1-ol as an oil.
Example 116
A solution of 5.0g (0.028 mol) of 3-{1-methylethyl)-1,2-
dimethoxybenzene in 5 ml of methylene chloride was added to
an ice cooled mixture of 4.4g (0.033 mol) of aluminum
chloride and 7.0g (0.033 mol) of 6-bromohexanoyl chloride in
50 ml of methylene chloride. The reaction mixture was keyt
at 0 for 18 hours. Water was added and the organic layer
was se~arated and washed with sodium bicarbonate solution.
The dried extract was concentra~ed under reduced pressure to
an oil which was purified by ~PLC using 5% ethyl acetate-
-hexane to give 8.1g (82% yield) of 6-bromo-L-[3,4-dimethoxy-
-5-(1-methylethyl)phenyl]-1-hexanone as an oil.
Example 117
~ olution o 0.227g (1.5 mmol) of 3,6-dimethylveratrole
in 1 ml of methylene chloride was added to an ice cooled
mixture of 0.245g ~1.8mmsl) of aluminum chloride and 0.41~g
(1.9 mmol) of 6~bromohexanoyl chloride in 3 ml of methylene
chloride. The reaction mixture wa kept at 0 for 19 hours.
Water was added and the oLganic layer was separated and
washed with sodium bicarbonate solution. the dried extract
was concentrated to an oil which was chroma~ographed on 60g
of silica gel using 10% ethyl acetate-hexane to give O.Z35g
of 6-bromo-1-(3,4-dimethoxy-2,5-dimethylphenyl)-1-hexanone a~ -
an oil.
.:
'~ ~' : ' ' , :

- ``
~ 32827q
- 93 -
Exam~le 118
A solution of 0.~056g t0.64 mmol) of 4-fluoroveratrole in
1 ml of methylene chloride was added to a mixture of 0.2289g
(1.~ mmol) of aluminum chloride and 0.09 ml (0.8 mmol~ of
4-chlorobutycyl chloride in 2 ml of methylene chloride at
25. The reaction mixture was stirred at 25 for Z2 hours.
Water was added and the organic layer was seearated and
washed with sodium hicarbonate solution. The dried extract
was concentrated under reduced pressure to an oil which was
chromatographed on lOg of silica gel using 25% ethyl acetate-
hexane to give 0.041g, mp 81-82, of 4-chloro-~3,4-
dime'choxy-6-fluorophenyl]-L-hexanone.
Exam~le 119
A mixture of 2.60g (8.1 mmol) of 1-(5-bromopentyl)-6
chloro-2,3-dimethoxyben~ene, 1.65g (7.8 mmol) o~
2,4-dihydroxy-3-propylbenzoic acid methyl ester and 5.0g (36
mmol) of anhydrous ~otassium caLbonate in 60 ml of acetone
and 6 ml of DMF was sticred at reflux for 24 hours. The
reac~ion mixture was filtered and the filtrate was
concentrated under eeduced pressure. Crystallization from
hexane gave 2.95g (83% yield), mp 53-55, of 4-~5-~2-chloro-
-5,6-dimethoxyphenyl)pentyloxy~-2-hydroxy-3-propylbenzoic
acid methyl ester.
Example 120
A solution of Z.95g (6.7 mmol) of 4-[5-(2-chloro-5,6-
dimethoxyphenyl)eentyloxy]-2-hydroxy-3-propylbenzoic acid
methyl ester in 80 ml of methanol and 20 ml (20 mmol) of lN
sodium hydroxide was stirred at reflux for 4 hours. Workup
as in Example 24 and recry6talli2ation from ether-hexane gave
35 2.70g (96% yield) mp 140-142, of 4-~5-(2-chloro-5,6-
dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylben20ic acid.

1 328279
- 94 -
Exam~le 12L
To 2.70g (6.2 mmol) o~ 4-[5-(2-chloro-5,6-dimethoxy-
phenyl)~entyloxy]-2-hydroxy-3-propylbenzoic acid suspended in
250 ml of methylene chloride and stirred at -60 was added
18.6 ml (18.6 mmol) of lM boron tribromide in methylene
chloride. The reaction mixture was stirred at -60 for 20
minutes and was then kept at -20 for 19 hou~s. Water was
added and the product was extracted with ether. The extract
was concentrated under reduced pressure and the residus was
dissolved in 50 ml of ether and was ~haken vigorously fsr 20
minutes with 50 ml of lN hydrochloric acid. The dried
extract was concentrated under reduced pressure and the
residue wafi crystallized from ether-chloroform to give l.lOg,
m~ 178-181, of 4-[5-(2-chloro-5,6-dihydroxy-~henyl)pentyl-
oxy]-2-hydroxy-3-propylbenæoic acid.
Exam~le 12Z
A mixture of 2.03g ~5.7 ~mol) o~ 1-(5-bromopentyl)-2,3-
dichloro-5,6-dimethoxybenzene, 1.15g (5.5 mmol) of 2,4-
dihydroxy-3-pro~ylbenzoic acid methyl ester and 3.5g (22
mmol) of potas6ium carbonate in 50 ml of acetone and 5 ml of
DMY (dimethylformamide) was 6tirred at re~lux for Z4 hours.
26 The reaction mixture was filtered and the filtrate was
concentrated under reduced pressure. Crystallization from
ether-hexane gave 1.5g (56% yield), mp 113-115, of
4-~5-t2~3-dichloro-5~6-dimethoxy~henyl)pentyloxy]-2 hydroxy-
-3-propylbenzoic acid methyl ester,
ExamPle 123
A solution of 1.5g (3.~ mmol) of 4-C5-(2,3-dichloLo-5,6-
dimethoxyphenyl)pentyloxy]-2-hydroxy-3-propylbe~zoic acid
methyl ester in 40 ml of methanol and 10 ml (L0 mmol) of 1
sodium hydroxide was stirred at reflux for 5 hours. Workup
as in Exam~le 24 and recrystallization from ether-hexane gave
. .
, ~ ,
,

- `~
~ 328279
- 95 -
- 1.2g (80% yield)~ mp 152-15~, of 4-~5-(2,3-dichloeo-5,6-
di~ethoxyphenyl)~entyloxy]-2-hydro~y-3-propylbenzoiC acid.
Example 124
To 1.2g (2.5 mmol) of 4--~5-(2,3-dichloro-5,6-dimethoxy-
ehenYl)pentyloxy]-2-hydroxy 3-propylbenzoic acid suspended in
100 ml o~ methylene chloride and stirred at -60, was added
7.5 ml (7.5 mmol) of lM boron tribLomide in methylene
chloride. After stirring at -60 for 30 minutes the ~eaction
mixture was kept at -20 foL 20 hour~. Workup a~ in example
24 gave a 601id residue which was recrystalliæed from ether-
chloroform to give 0.42g, mp 159-154, o~ 4-[5-(2,3-dichloro-
5,6-dihydeoxyphenyl)~entyloxy]-2-hydroxy-3-elopylbenzoic acid.
ExamP~ e 125
A mixture of 1.48g (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-~ropylben20ic acid methyl ester and 4.6g (33
mmol) of potassium carbonate in 30 ml of acetone and 3 ml o~
DMF was ~tirred at reflux for 23 hours. The reaction mixture
was filtered and the filt~ate was concentrated under reduced
pressure. Crystalliæation from ether-hexane gave 1.5g (76%
yield), m~ 84-87, of 4-[5-~2,3,4-trichloro-5,6-dimethoxy-
phenyl)~entyloxy]-2-hydroxy-3-propylbenzoic acid methyl ester.
ExamPle 1?6
A solution o~ 1.5g (2.3 mmol) of 4-[5-(2,3,4-trichloro-
-5,6-dimethoxyphenyl)pentyloxy]-2-hydroxy-3-~ropylbenzoic
acid methyl ester in 40 ml of me~hanol and 8.7 ml (8.7 mmol)
of LN sodium hydroxide was stirred at reflux for S hours.
Workue a6 in Example 24 and eecrystallization from ethyl
acetate-hexane gave L.3g (89% yield), mp ~48-150, of
4-[5-~2,3,4-trichloro-5,6-dimethoxyphenyl)~entyloxy]-Z-hydcoxy-
3-pro~ylbenzoic acid.
.. , , . ~ :

1 3~P~279
- 96 -
Example 127
To 1.3g (2.6 mmol) o e 4-t5-(2/3,4-trichloro-5,6-
-dimethoxyphenyl)pentyloxy-2-hydroxy-3-~ropylbenzoic acid
suspended in 110 ml o~ methylene chloride and stirred at
-60, was added 8.0ml (8 mmol) of lM boron tribromide in
methylene chloride. The eeaction mixture was stirred at
-60 for 1 hour and then ~ept at -20 f O 18 hours. Workue
as in Example Z4 gave a solid which was recrystallized from
ethee-hexane to ~ive 0.9 g t73% yield), mp 193-196. of
~-~5-(2,3,4-trichloro-5,6-dihydroxyphenyl)pentyloxy]-2-hydroxy-
3 ~ro~ylbenzoic acid.
Example 128
A mixture of 2.50g (7.2g mmol) of 6-b~omo-1-(3,4-
dimethoxy-2,5-dimethylphenyl)-1-hexanone, 1.53g (7.29 mmol)
of 2,4-dihydroxy-3-propylbenzoic acid methyl es~er and 3.30g
~24 mmol) o~ potassium carbonate in 50 ml of acetone and 5 ml
f DMF was stirred and heated at reflux for 26 hours. ~fter
workue as in Example 16 the crude product was purified by
HPLC using 10% ethyl ace~ate-hexane to give 3.40g (98% yield)
of 4-~6-(3,4-dimethoxy-2,5-dimethylphenyl)-6-oxohexyl]oxy]-
-2-hydroxy-3-~co~yl benzoic acid methyl ester as an oil.
Example 129
~ solution of 3.40g (7.2mmol) of 4-[~6-(3,4-dimethoxy-
2,5-dimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-eropylbenzoic
acid methyl ester in 90 ml of methanol and 30 ml (30mmol) of
1.0 N sodium hydroxide was stirred at reflux for 5 hours.
Worku~ as in example 24 and recrystallization of the crude
product from ether-hexane gave 3.00g (~1~ yield), mp 92-94,
of 4- r ~ 6- ( 3~4-dimethoxy-z~5-dimethylphenyl)-6-oxohexyl]oxy]
2-hydroxy-3-proeylbenzoic acid.
,. ~ ~ ,................ : : :
,
.
: ~, ~ . . . , , ~ ,

r ~ ~
1 32827q
_ 97 -
~xample 130
To l.OOg (2.2mmol) of 4-[[6-~3,4-dimethoxy-2,5-dimethyl-
phenyl)-6-oxohexyl]oxy~-2-hydroxy-3-propylbenzoic acid in 100
ml of meth~lene chlocide was added 6.6ml ~6.6 mmol) o~ 1~
boron tribromide in methylene chloride with cooling at -70.
The mixture was stirLed at -70 for 1 hour and then kept a~
-20 for 16 hours. Workup as in Example 32 and recrystal-
lization of the crude product from ether-hexane gave 0.60g
(63% yield), mp 1~1-125, of 4-~6-~3,4-dihydroxy-2,5-
-dimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-~ropylbenzoic
acid,
Exam~le 131
A mixture of 6.0g (0.017 mol) o~ 6-bromo-1-~3,4-
dimethoxy-5-tL-methylethyl)phenyl]-l-hexanone, 3.39g (0.016
mol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester and
7.0g (0.051 mol) of pota~sium cacbonate in ~20 ml of acetone
and 12 ml of DMF was stirred at reflux for lg hours. After
workue as in Example 16, the crude product was ~urified by.
HPLC usins 16% ethyl acetate-hexane to give 7.7g (98% yield)
of 4-[~6-~3,4-dimethoxy-S-(l-methylethyl)phenyl)-6-oxohexyl]-
oxy3-2-hydroxy-3-pro~ylbenzoic acid methyl ester as an oil.
ExamPle 13?
A ~olution of 7.7g (0.016 mol) o~ 4-[[6-[3,4-dimethoxy-
5-(1-methylethyl-phenyl~-6-oxohexyl~oxy]-2-hydroxy-3-eropylben-
zoic ~cid methyl ester in 80 ml o~ methanol and 60 ml (0.06
mol) of l.ON sodium hydroxide was stirred at re~lux for 5
hours. Workup as in ~xample 2~ and recrystallization of the
crude eroduct from ethyl acetate-hexane gave 6.6g (89~
yield), mp 113-115, of 4-[[6-[3,4-dimethoxy-5-(1-methyl-
ethyl)~henyl]-6-oxohexyl]oxy]-2-hydroxy-3-~ro~ylbenzoic acid.
,: . .. ~ . , .

1 32827q
- 98 -
Example 133
To 2.0g t4.2 mmol) of ~-t~6-~3,4-dimethoxy-5-(1-methyl-
ethyl)~henyl]-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid
in 200 ml of methylene chloride cooled at -65 was added 13
ml (13 mmol) of l.OM boron tribromide in methylene chloride.
The suspensio~ was stirred at -50 for 2 hours and then kept
at -20 for 16 hours. Workup as in Example 32 and recrystal-
lization o~ the crude produc~ from e~her-hexane gave 1.5g
(81~ yield), mp 169-171, of 4-~6-~3,4-dihydroxy-5-
-(L-methylethyl)phenyl]-6-oxohexyl]oxyJ-2-hydroxy-3-propyl-
benzoic acid.
Example 13
A mixtu~e o~ 2.5g of 4-[[6-[3,4-dimethoxy-5-(1-methyl-
ethyl)phenyl]-6-oxohexyl]oxy~-2-hydroxy-3-pro~ylbenzoic acid
in 50 ml of tetrahydrofuran containing Z drops of
concentrated sulfuric acid and 0.5g of 10~ palladium on
carbon was shaken on a Parr hydrogenator under an initial
hydeogen ~ressure of 3,5 bar for 20 hours. The reaction
mixture was filtered through a Celite ead and the filtrate
was concentrated under reduced pressure. The ~esidue was
dissolved in ether and washed with water. The extract was
dried and concentcated to a solid which was rec~ystallized
from hexane to give 2.4g, mp 106-108, of 4-~6-[3.4-
-dimethoxy-S-(l-methyle~hyl)~henyl]hexyloxy]-2-hydroxy-3-
-eroPylbenzoic acid.
Example 135
To 2.43g t5.3mmol) of 4-~6-(3,~-dimethoxy~ 1-methyl-
ethyl)phenyl]hexyloxy]-~-hydroxy-3-propylbenzoic acid in 250
ml of methylene chloride cooled at -75O was added L6 ml (L6
mmol) of lM boron tribromide in methylene chloride. The
reaction mixture was stirred at -75 for 1 hour and then was
kept at -Z0 or 17 hours. Workup as in Example 32 and

1 328279
99
recrystallization f~om ether-hexane gave 1.20g, mp L3a
of 4-[[6-[3,4-dihyd~oxy-5-(1-methylethyl)~henyl~hexyloxy]-
~-hydroxy-3-proeylbenzoic acid.
Example 136
4~rr6-~3,4 Dimethoxy-Z,5-dimethYlphenyl~_exyloxYl-2-hvdroxy-3-
pcopylbenzoic acid.
A mixtuce o 1.45g of 4-~6-(3,4-dimethoxy-2,5-dimethyl-
phenyl)-6-ox~hexyl]oxy]-2-hydroxy-3-propylbenzoic acid in 40
ml of te~rahydrofuran containing 2 dEops of concentrated
sulfuric acid and 0.4g of L0% palladium on carbon was shaken
on a ParL hydrogenator under an inltial hydrogen pres~ure of
3~5 bar for 20 hou~s. The reaction mixture was worked up as
in Example L34 and the product was cecrystallized from
ether-hexane to give L.20g, mp 109-llZ, of 4-~[6-(3,4-
-dimethoxy-2,5-dimethylphenyl)hexyloxy]-2-hydroxy-3-propyl-
benzoic acid.
Example 137
To L.2g (Z.7 mmol) of 4- r [ 6-(3,4-dimethoxy-2,5-dimethyl-
phenyl)hexyloxy]-~-hydroxy-3-propylbenzoic acid in ~20 ml of
methylene chloride cooled at -75 was added 8 ml (8 mmol) of
LM boron tribromide in methylene chloride. The reaction
mixture was stirred at -75 for 1 hour and kept at -20 for
17 hours. Workup as in Example 32 and recrystallization of
the crude product from ether-hexane gave 0.60g, mp 170-171,
of 4-[[6-(3,4-dihydroxy-2,5-dimethylehenyl)hexyloxy]-2-
-hydroxy-3-propylbenzoic acid.
:
xamPle 138
~ solution of 5.3g (0.034 mol) of L,2-dimethoxy-4-
fluorobenzene in 25 ml of methylene chloride was added to a
solution of 5.4g (o.0~1 mol) of aluminum chloride and 8.7g

'-``. 1 32~27q
- 100 -
(0.041 mol) of 6-bromohexanoyl chloride in 60 ml of methylene
chloride cooled in an ice ba~h. The resulting solution was
kept at 0 for 5 hours and then worked up as in Example 117.
The crude product was recrystallized from methylene
chloride-ether to give 6.98g (62~ yield), mp 81-83, of
6-bromo-1-(2-fluoro-4~5-dimethoxyphenyl)-1-hexanone.
Example L39
A mixture of 4.0g (12 mmol) of 6-bromo-1-(2-fluoro-~,5-
dimethoxyphenyl)-l-hexanone, 2.5g (12 mmol) of
2,4-dihydroxy-3- propylbenzoic acid msthyl ester and 5.0g (36
mmol) of eotas~ium carbonate in 80 ml of acetons and 8 ml o~
DMF was s~iered at reflux for ~6 hours. DMF (12 ml) and
potassium carbonate (3g) were added and reflux was continued
for 18 hou~s. Workup as in Example 16 and recrystallization
of the ccude product f~om ethyl acetate gave 4O3g (78%
yield), mp 127-129, of 4-[[6-(2-fluoro-4,5-dimethoxy~henyl)-
-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid methyl ester.
Example 140
A solution of 4.3g (9.3 mmol) of 4-~6-(2-~luoro-4,5-
dimethoxy-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid
methyl ester in 135 ml of methanol and 45 ml (45 mmol) of ~N
sodium hydroxide was stirred at ~eflux fo~ 5 hours. ~orkue
as in Example 24 and recrystallization of the crude product
from ethyl acetate--hexane gave 3.7g, mp 146-147, of 4-~[6-
(2-~luoeo-4,5-dimethoxyphenyl)-6-oxohexyl] oxy]-2-hydroxy-
3-pro~ylbenzoic acid.
Example 14L
To 2.0g (4.~6 mmol) of 4-~[6-(2-fluoro-4,5-dimethoxy-
phenyl~-6-oxohexyl]oxy]-2-hyd~oxy-3-pro~ylbenzoic acid in ~00
ml of methylene chloride cooled at -75 was added 13 ml (13
mmol) of lM boeon teibromide in methylene chloride. The
;. . , ~,

1 328279
- 101 -
reaction mixture was stirred at -75O for 1 hour and kept at
-20O for 17 hours. Additional bo~on tribromide (7 ml) was
added and ~he mixture was sti~red at -5 for 5 hours. Workue
as in Example 32 and recrystallization of the crude eroduct
from ether-hexane gave 0.84g, m~ 193-195,, of 4-r~6-12-
fluoro-4,5-dihydroxyphenyl)-6-oxohexyl]oxy]-Z-hydroxy-3-
-proeylbenzoic acid.
Example 14Z
~ mixture of 0.400g of 4-[[6-(Z-fluoro-4,5-dimethoxy-
ehenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid and
O.L50g of 10% palladium on carbon in 20 ml of tetrahydrofuran
containing 2 dro~s of concentrated ~ulfuric acid was shaken
under an initial hydrogen pressure of 3,5 bar on a PaLr
hydrogenator for 20 hours. The reaction mixture was filtered
through a Celi~e pad and the filtrate was concentra~ed under
reduced pressure to a zolid. RecLystallization from ethyl
acetate-hexane gave 0.37g mp 127-130, of 4-r6-(2-fluoro-
4,5-dimethoxyphenyl)-hexyloxy]-2-hydroxy-3-propylbenzoic acid.
Example 143
To 0.36g of 4-~6-(2-fluoro-4,5-dimethoxyphenyl)hexyloxy~-
2-hydLoxy-3-propylbenzoic acid in 60 ml of methylene chloride
cooled at -75 was added 2.8 ml of 1~ boron tribromide in
methylene chloride. The reaction mixture was 6tir~ed at -75
for 30 minutes and then was kept at -20 for 20 hours.
Workup as in Exam~le 32 and recrys~allization o~ the crude
product from e~her-hexane gave 0.18g, m~ llO-lla, of 4-[6-(2-
fluoro-4,5-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-proeyl-
benzoic acid.
Example L44
~5
A solution o~ 2.956g (16 mmol) of 1,2-dimethoxy-3,4,6-
trimethylbenzene in 10 ml of methylene chloride wa~ added to

1 328279
- 102 -
2.40g (18 mmol) of aluminum chloride and 3.80g (18 mmol) o~
6-bromohexanoyl chloride in 30 ml of methylene chloride
cooled in an ice bath. The solution was kept at 3 for 45
minutes and then at 23 for 42 hours. An additional 2.0g of
aluminum chloride and 3.0g of 6-bLomohexanoyl chloride were
added and the reaction mixture was stirred at reflux for 22
hours. Workue as in Example 117 and eurification by HPLC
using 4% ethyl acetate-hexane gave 0.95g of 6-bromo-1-(3,4-
-dimethoxy-2,5,6-trimethylphenyl)-1-hexanone as an oil.
1~
Example 145
A mixture of 0.194g (2.6 mmol) of 6-bcomo-1-(3,4-
dimethoxy-2,5,6-trime~hylphenyl)-1-hexanone, 0.55g (z.6 mmol)
~ 2,4-dihydroxy-3-pro~ylbenzoic acid methyl ester and l.lOg
(7.B mmol) of potassium carbonate in 20 ml o~ acetone and 2
ml of DMF was stirred at ~eflux for 17 houLs. A~ter workup
as in Example 16, the crude ~roduct was ~urified by chromato-
graphy on lOOg of silica gel. Elution with 10% ethyl
acetate-hexane gave 1.05g (83% yield) of 4-[~6-(3,4-
-dimethoxy-2,5,6-trimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy
--3-proeylbenzoic acid methyl ester.
Example 146
Z5
A solution of 1.05g (2.16 mmol) of 4-~6-(3,4-dimethoxy-
2,5,6-trimethyl~henyl)-6-oxohexyl]oxy]-2-hydroxy-3-propyl-
ben~oic acid methyl estee in 30 ml of methanol and 7 ml (7
- mmol) of lN sodium hydroxide was stirred at reflux for 7
hours. Workup as in Examele Z4 gave 0.98g, mp 108-112, o~
4-[~6-(3,4-dimethoxy-2,5,6-trimethylphenyl)-6-oxohexyl]oxy]-
-2-hydroxy-3-propylbenzoic acid.
ExamPle 147
To 0.98g (2.07 mmol) of 4-[[6-(3,4-dimethoxy-2,5,6-
~rimethylphenyl)-6-oxohexyl]oxy~-2-hydroxy-3-p~o~ylbenzoic
: :
, . : ~

- 103 I 3 2 8 27 ~
acid in 100 ml of methylene chlocide cooled at -75 was added
7 ml t7 mmol) of lM boron trib~omide in methylene chloride.
The ~eaction mixture was stirred at -75 for 30 minutes and
then was ke~t at -20 for 18 hours. Wor~up as in Example 32
and recrystallization of the ceude product from ether-hexane
gave 0.51g, mp 169-170 of 4-~6-(3,4-dihydroxy-2,5,6-
-t~imethylphenyl)-6-oxohexyl]oxyJ-2-hydroxy-3-propylbenzoic
acid.
Example 14B
A mixture of l.OOg (2.57 mmol) of 4-~6-(2,3-dihydroxy-
phenyl)hexyloxy]-2-hydroxy-3-propylben20ic acid, 0.76 ml
(5.15 mmol) of n-hexyl iodide and 0.26g ~3.36 mmol) of sodium
bicarbonate in 15 ml o~ anhydrous dimethylformamide was
stiLred and heated at 70 for 16 hours. The solvent was
removed on the oil pump, ~ater was added and the product was
extracted with ethyl acetate. The dried extract was
concentrated under reduced pressu~e to an oil which was
20 pu~if ied by chromatography on silica gel using 5% ethyl
acetate-toluene to give l.Olg (83% yield) of
4-~6-(Z,3-dihydroxyehenyl)hexyloxy]-2-hydroxy-3-
propylben20ic acid hexyl ester as an oil.
ExamPle 149
A mixtu~e of 5.8g (0.013 mol) of 1-(6-b~omohexyl)-
-2,3-bis(phenylmethoxy)benzene, 3.5g (0.013 mol) o~
3-hydroxy-4-nitrobenzoic acid phenylmethyl ester, 3.5 g
(0.026 mol) of anhydrous potassium carbonate and 2.9g (0.019
mol) of sodium iodide in 125 ml of acetone and 13 ml of
dimethylfo~mamide was stir~ed and heated at reflux for 42
hours. ~o~kup as desc~ibed in exam~le 16 and purif ication by
~IPLC using 10% ethyl acetate-hexane gave ~.~5g of
36 4-nitro-3-~6-t2,3-bis~phenylmethoxy)phenyl]hexyloxy]benzoic
acid phenylmethyl ester as an oil.
, , .

~ `
1 3~827q
- 104 -
Exam~le 150
A solution of 5.4g of 4-nitro-3-~6-C2,3-bis(phenyl-
methoxy)phenyl~hexyloxy]benzoic acid phenylmethyl ester in
250 ml of te~rahydrofuran and lg of 10~ ealladium on carbon
was shaken in a hydrogen atmosphere at room temperature for
17 hours. The catalyst was removed by ~iltEation through
celite and he filtrate was concentrated under reduced
peessure to a solid. Recrystallization foLm ether-methylene
chloride gave ~.80g (62% yield), m~ 130-132, of
4-amino-3-~6-(2,3-dihydroxyphenyl)- hexyloxy[benzoic acid.
Exam~le 151 .
A mixture of 5.8g ~0.013 mol) of 1-(6-bromohexyl)-Z,3-
-bis(phenylmethoxy)benzene, 3.5g (0.013 mol) of 4-hydroxy-3-
nitrobenzoic acid ~henylmethyl ester, 305g (0.026 mol) of
potassium carbonate and 2.9g (0.019 mol) of sodium iodide in
125 ml of acetone and 13 ml of dimethylformamide was stirred
and heated at reflux ~or 5 days. Workup as described in
Example 16 and euri~ication by HPLC using 50% methylene
chloride-hexane gave 6.85g (83% yield) of 3-nitro-4-~6-
~2,3-bis(phenylmethoxy)ehenyl~hexyloxy]benzoic acid
phenylmethyl ester as an oil.
~5
Example 152
A solution of 6.8g of 3-nitro-4-r6-~2,3-bis(phenyl-
methoxy)phenyl]hexyloxy]benzoic acid phenylmethyl ester in
250 ml of tetrahydrofuran and 1.3g of 10% ~alladium on carbon
was shaken in a hydrogen atmosphere at room ~emperature for
L2 hours. The catalyst was removed by filtration though
Celite and the filtrate was concentrated under reduced
eressure to a solid. Recrystallization form acetone-hexane
gave 2.36g (65% yield), mp 172-174, of 3-amino-4-r6-(2,3-
-dihydroxyphenyl)hexyloxy]benzoic acid.

1 328279
- 105 -
Example 153
To 27.0g (0.139 mole) of 1,2-dimethoxy-3-(1,1-dimethyl-
ethyl)benzene in 3~0 ml of anhydrous tetrahydrofuran cooled
in an ice-brine bath at -5 was added. 87 ml (0.139 mole) of
1.6M butyl lithium in hexane over 30 minutes. The reaction
mixture was stirred at -5 for 3 hours and then at reflux for
1 hour. ~fter cooling in an ice bath, 21.5ml (O.L39 mole) of
1,6-dibromohexane in 75 ml of tetrahydrofuran was added
dropwise. The reaction mixture was then stirred at reflux
for 17 houcs. The solvent was removed undec 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. Pu~i~ication by HPLC using 20
toluene-hexane gave 7.6g ((L5% yield) of 1-~6-bromohexyl)-
2,3-dimethoxy-4-(1,1-dimethylethyl)benzene.
Example 154
A mixture of 4.0g (lL.2 mmole) of 1-(6-bromohexyl)-
2,3-dimethoxy-4-(1,1-dimethylethyl)benzene, 3.2g (11.2 mmole)
of 2,4-dihydroxy-3-ero~ylbenzoic acid phenylmethyl ester,
3.1g (22.4 mmole~ of ~otassium carbonate and 1.7g (11.2
mmole) of sodium iodide in 70 ml of anhydrous acetone and 7
ml of anhydeous dimethylformamide wa6 ~tirred at reflux for
31 hours. Workup as in Example 16and purification by ~IPLC
using 5% ethyl acetate-hexane gave 5.3g, (84% yield) of
2-hydroxy-4-~6-[2,3-dimethoxy-~-(1,1-dimethylethyl)ehenyll-
hexyloxyl-3-propylben20ic acid phenylmethyl ester as an oil.
A solution of 5.25 g of 2-hydroxy-4-~6-~2,3-dimethoxy-4-
(l,l-dimethylethyl)phenyl]hexyloxy]-3-propylbenzoic acid
phenylmethyl estec in 200 ml of tetrahydrofuran and 0.5g of
3S 10% palladium on carbon was shaken in a hydrogen atmosphere
~or 3 hour~. The reaction mixt1lre was filtered through
Celite and the filtrate was concentrated to yield 4.0g my
~': , ~.
.

1 32~27q
- 106 -
106-108, of 2-hydroxy-4-[6-C~,3-dimet~oxy-4-(L,l-dimethyl-
ethyl~phenyl]hexyloxy]-3-propylbenzoic acid.
Example 155
To 4.0g (8.5 mmole) of Z-hydroxy-4-~6-~2,3-dimethoxy-4-
(l,l-dimethylethyl)phenyl]hexyloxy]-3-propylbenzoic acid
suspended in 200 ml of methylene chloride and cooled at -70O
was added 26 ml (26 mmole) of lM boron tribromide in
methylene chloride over 30 minutes. The reaction mixture was
~tirred at -70 for 30 minutes and kept at -20 for 41
hours. Workup as in Example 32 and recrystalliza~ion of the
crude product feom ether-hexane gave 1.7~g (47% yield~, mp
85-87O, o~ 4-t6-~Z,3-dihyd~oxy-4-(~,1-dimethylethyl)phenyl]-
hexyloxy]-2-hydroxy-3-2ropylbenzoic ~cid.
2xamPle 156
A mixtuee of 2.4g (5.3 mmole~ of 1-(6-bromohexyl)-2,3-
bis-tphenylmethoxy)benzene, 0.88g (5.3 mmole) of 4-hydroxy-
benzoic acid e~hyl ester, 2.5g (18 mmole) of potassium
carbonate and 0.8g (5.3 mmole) o~ 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 ~rom
ethyl acetate-hexane gave 2.3g, m~ 63-65O (81% yield) of
4-t6-t2,3-bis(ehenYlmethoxy)~henyl]hexyloxy]benzoic acid
ethyl ester.
A solution of 2.3g of 4-t6-tZ,3-bis(phenylmethoxy)-
phenyl]hexylox~]benzoic acid ethyl ester in 50 ml of ethyl
acetate and 0.3g of 10% palladium on carbon was stirred in a
hydrogen atmos~here 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~, m~ 45-47, (85% yleld) to
4-[6-(203-dihydLoxyphenyl)hexyloxy]benzoic acid ethyl es~er.

1 32~279
- 107 -
Example 157
A mixture of l.Og 1~.9 mmole) of 4-[6-(2,3-dihydroxy-
phenyl)hexyloxy]-2-hydroxybenzoic acid, 0.295g (3.5 mmole) of
sodium bicarbonate and 2.4 ml (29 mmole) of ethyl iodide in
10 ml o~ anhydrous dimethyl~ormamide was stirred at 50 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 ~he dried
extract was concentrated at ~educed pressure to a solid~
Recrystallization from ether-hexane gave 0.8g, mp 63-68,
(74~ yield) of 4-[6-(2,3-dihyd~oxyphenyl)hexyloxy]--2-hydroxy-
benzoic acid ethyl ester.
Ex~p~e 158
A mixture of 017Gg (1.68 mmole3 of 4-~6-(3,4-dihydroxy-
2,5-dimethylphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid,
0.157g (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 for 10 hours. Workup as in Example 16 gave an
oil which was purified by chromatography on 20g of silica
gel. Elution with Z5% ethyl acetate-hexane gave the product
which was recrystallized from hexane to give 0-50g, me
61-64, (67% yield) of 4-r6-[3,4-dihydroxy-2,5-dimethyl-
phenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid ethyl ester.
:~
.

1 328279
-- lo~ --
Exam~le 159
TABLET FORMULATION (Wet Granulation)
mq/tablet
S
Item Inqcedient 100 ma 500mq lOOOmq
1. 4~[6-(2,3-dihydroxy~henyl)
hexyloxy]-2-hydroxy-3-
~ropyl-benzoic acid. 100 500 lOoo
2. Lactose 132 -- --
3. Pregelati~zed Stacch 16 30 50
4. Modified Starch 30 40 50
5. Magnesium Stearate 2 6 8
TOTAL 280 576 1108
Manufacturina Procedure:
1. Mix items 1, 2, 3 and 4 and g~anulate with water.
2. Dry the granulation a~ 50C.
3. Pass the granulation th~ough suitable milling equipment.
4. Add item 5 and mix for three minutes; com~ress on a
suitable press.
, L~ .
~.i,S.~
. ~ , . , .., ; . ~ ~

1 3~827~
- 109 -
Example 160
CAPSULE FORMULAT I ON
Inaredient mn/ca~sul Q
1. 4-[6-(2,3-dihydroxyphenyl)
hexyloxyJ-2-hydroxy-3-pro~yl-
benzoic acid. 25 50 100 500
2. Lactose Hydrous 143 168 148 --
3. Corn Starch ZO 20 40 70
4. Talc 10 19 10 25
5. Magnesium Stearate 2 ? Z 5
TOTAL 200 250 300 600
Manufacturin~ Procedure-
1. Mix items 1. 2 and 3 in a suitable mixer fo~ 30 minute~.
~; 20
2. Add items 4 and 5 and mix for 3 minutes.
3. Fill into suitable capsules.
: ~ :
:: .
: 36

1 328279
-- 110 -
Example 161
WET GRA`NULAT I ON FORMU LAT I ON
Inqredientma/tablet
1. 4-~6-(2,3-dihydroxy~henyl)
hexyloxy]-2-hyd~oxy-3-proeyl-
benzoic acid. 25 50
10 Z~ Polyvinyl Py~rolidone 5 10
~. Lactose Anhydrous DTG L33 142
4. Microcrystalline Cellulose 25 30
5. Modified Sta~ch 10 15
6. Magnesium Stearate _ 2 3
: 15 TOTAL 200 250
Manu~acturinq Procedure:
~: 1. Dissolve I~em 2 in water.
: 2. Mix Items 1, 3, 4 and 5 in a suitable mixer and granulate
with ~olution in Ste~ 1.
3. Dry vvernight at 45C, screen through #20 mesh, and add
~Item 6 and mix. Comeress on a suitable ~res6.
.~
:'
.
~ .
: 35 , ,
:
.

1 32~279
111
Exam~le 162
CRE~M 5S
5 The following i~ the guanti~ative compo6ition o~ dcug:
Rea~onable
Inqredient q/kq variations
1. 4-C6-(2,3-dihYdroxY~henYl)
hexyloxy~-2~hydroxy-3-eropyl-
benzoic acid. 51.50* --
2. Glyceryl Monostearate S.E.l100.00 8Q - 120
3. PolysoEbate 60 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. P~opylparaben 0.50 0.4-0.6
8. Propylene Glycol 200.00 150-250
9- Purified ~ate~ 521.70 475-575
Total 1015.20
~ 3~ exce~.
1 Arlacel*165
2 Tween$60
,
: 30
* Trademark
,~ ' .

1 32~279
- 112 -
Example 163
SOFT G~LATIN CAPSULE FORMULATION
Inqredient matcaPsule
l . 4- [ 6- (2, 3-d~ hydroxyphenyl )
hexyloxy]~2-hydroxy-3-p~opyl-
benzoic acid. 50 150
2. Polyethyleneglycol 400 325 550
3. Med. Change Mono~lycide 100 150
4. Poly~orbat~$80 25 _50
TOT~L5 0 0 l 0 o o
15 Manufacturinq Procedl~re:
1. Di~sol~e Item 1 in Item 2.
2. Add Item 3 and mix well.
~0
3. Add Item 4 and mix well until dissolved.
.
; 4. Fill in so~ gelatin capsule6. :.
xam~le 164
BEADLET FOR~ULATION ~ENTERIC~ I
,
Beadlets mqtcap ule_
1. 4-C6-(2,3-dihydroxy~henyl)
hexyloxyJ-2-hydroxy-3-prop~l- .
benzoic aoid. 25 100 250
2. Microcrystalli~e sellulo~2 100 200 250
35 3. Polyvinyl ~yrrolidone K-90 l0 20 30
TOTAL 135320 530
* ~rrademark

1 328279
- 113 -
Procedure:
1. Mix with microcrystalline cellulose and granulate with a
solution of ~VP K-90.
5 2. Pass the granulation through an extruder and marumaeizer
to obtain uniform beads.
3. Coat the beads with an enteric ~olymer such as Polyvinyl
~cetate Phthalate, Hydroxypropyl Methylcellulose Phthalate,
Cellulose Acetate phthalate, or an Acrylic Polymer.
4. Fill into capsules at the ap~ropriate fill weight.
Beadle~ Formulation (Enteric)~
Starting with non-pareil seeds, deposit on the 6eeds wi~h
an appropriate polymer, such as Polyvinyl Pyrrolidone,
Hydroxypropyl Cellulose, Hydroxyeropyl Methylcellulose or the
like. Dry the seeds and apply an enteric membrane such as
Polyvinyl Acetate Phthalate, Hydroxyproeyl Methylcellulose
Phthalate;Cellulose ~cetate Phthalate and/or an Acrylic
Polymer. Determine the concentration of the drug per gram of
Beadlet and fill into capsules.
, ,
- ~ -

Representative Drawing
A single figure which represents the drawing illustrating the invention.
Administrative Status

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Event History

Description Date
Inactive: IPC from MCD 2006-03-11
Inactive: IPC from MCD 2006-03-11
Inactive: IPC from MCD 2006-03-11
Inactive: IPC from MCD 2006-03-11
Inactive: IPC from MCD 2006-03-11
Time Limit for Reversal Expired 1997-04-07
Inactive: Adhoc Request Documented 1997-04-05
Letter Sent 1996-04-05
Grant by Issuance 1994-04-05

Abandonment History

There is no abandonment history.

Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
F. HOFFMANN-LA ROCHE AG
Past Owners on Record
MATTHEW CARSON
RONALD ANDREW LEMAHIEU
RU-JEN LEE HAN
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Cover Page 1994-07-22 1 29
Claims 1994-07-22 10 309
Abstract 1994-07-22 2 59
Drawings 1994-07-22 1 11
Descriptions 1994-07-22 115 4,099
Representative drawing 2001-07-25 1 2
Examiner Requisition 1992-12-16 1 72
Examiner Requisition 1991-01-30 1 50
Prosecution correspondence 1991-05-28 5 153
Prosecution correspondence 1993-04-16 3 123
PCT Correspondence 1993-12-30 1 31