CA1328279C - Catechol carboxylic acid derivatives - Google Patents

Abstract

Abstract The invention relates to catechol carboxylic acid derivatives of the formula 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 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 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.

Description

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 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 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 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 R~ C~)n 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 REACTION SCHEM~

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 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~

.

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~

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 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 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 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

~~

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.

~:

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.

:

.

- 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.

;

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

C.

:; ~

wherein P~' is lowee alkyl.

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 REACTION SCHEME VIII

0~ Rl' ~ ' R~
~x HC ~

~ 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.

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~

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.

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~

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.

.

, -- 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 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 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.

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 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 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.

: . .
: - ~

~ - .

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~

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.
`.,; : ' ' , ` , `': . ` . '~
.' `' . ,' , ~ : .
'~ ' ` ' , , ` : `
, 1 32827~

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 , :

~ 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 -- 39 -- .

E r~
C
O
._~
~ ~l ~
.,, ~ r~ o ~ ~ co ~ S ~ ~1 O O
;~E dP E~

.a ~ G.
I Y
, ~ O O~
0 ~ ;~ ~
4 :L, . C
4 J~ ~D
~G C~ t` ~D ~ D
U ~ a o ~1 ~ X

~ ~2E ~, X
S 5. Lr O O o O ~,-- o o C~ o O O O O ~D O O

X ~ X ~ X
--' O X ~ X O ~C
O _I O -- O
X U UV ~ ~ V X~-~
$ S O -- S
~0 ~O ~ O~0 ~0C o ~-~
C W N C NC N C N~ N C O
Cl C~ C ~LI C ~JC` C S ~-- ~` N
C ~D~Ll C C~ C ~S ~ D e" C
~ :~X ~ X :~ X ~X :~ O ~ X -~
O ~O - ~ O GO G 0 G- G C
0 4 04 0 J C~ ~ O u u G ~ G ~ G ~ ~

X r~ X ~ X ~ X ~ X ~ X ~-- ~, V
O~ O ` O~ O ~ G ~ ^ ~C 'D
~ ~~ L~ ~ ~r~ ut~ u _ u `~ o Z, ~ .e~ ~ ~ .er .~ . C . e~

1 32~7~7 ~1 C
.r1 .~ _/ ~ .
.0 .~ ~ t~
al ~ 'J ~ E~
S l L~
OO O O ~ o 0 N ~
Z Z ~r ~ ul Lll Ln C
.~ F
Ll 1 r v I C~ O O ~ ~ ~ 5 ;
N N E t~
v o ~ ~r S ~ O u~ .n C C 5:
~ç JJ Iq r~ ~ o o ~
~ ~ ~ ~ ~:r ~ ~ Z
v -C

, o ' ~ ' '- ~ C
O _ 1 0 01" ~ ~ ?` ~ ~ ~O
,~ ~ O O O O O O o O
~ U
x , ~~ ~ x x ~ex ~ ~ ~ o - o o o o --I X ~ N
'V O O
~-rl 4 N ~ X X
4 ~ C C J~
~ ~ i c s -- ) S ~ C
_I U ~ ~ ~ I X
O ~ O
i o r_~ ~ ~ 4 ~ 4 C C
O N --~~ O X ~ I ~ ~1 ~ ~ aJ~J a~
s ~ ~~ , o, ~ ~ S-rl C ~~
P- ~ SN G ~ V
~ ~ ~~ r) ~ ~ X ~ ~ X X ~X o O >. ~ ) X O i O O U O O N
O ~ U 0 4-- 4 t~ UL.l C
C~ C ~ ~ ~ 4 ~ ~ ~ 5:~ 0 rC"~
.~ ~ X ~ x ~ ~ N ~ O
s ~ e, o ~ s O ~ ~ ~ s N_--~
_i X ~ ~ N I X U I ~ ~ ~ ~ . i ~ LJ
~ X ~~ S ~ ~ ` S ~ ~ O ` ~
N O a.lv ~ N X N ~ V N U ~ U N ~ N ~r/
O i O ~ ~ 1 4 ' ~V~ ~ N ~O N D . C ~O ~ ~ Lll E_ S I`~ c~ ~ x --~ C .
2C N --N G e:l S ~ !~

;~ '' ` ' `:: , . ` : : .
, .

1 32827q _I
e ~
C
o .,, C~
~-~ ~ U
; 3 ~ _~ SD
.~ f~
~ c.~ E~ ~
..
. o o ~i ~ o _l o $ tP E-~ ~ N Z t~ Z O u~

~a ~ c I ~ O
~--I ~ ~ ~ . _~
4 ~ ~
~a .Y
C~ o C~
O E~
~' O
Q~ X L~ ~ ~
tP ~ ~In ~ ~ Ln O ~r--.
-O

O ~ O r ~ , " ~~ S O ~ O~P o 0~ ~
i...... l ~ ~ u~ o ~ o o~ o ~,o ~ o Ul _~ ~_i _ C ~
xo ~ c~ I ~~ o OX a l:~ C ~ ~ C:~ X ~ N
O ~ r1 ~:1 0X O X ~J X O X O Cl C' 1 ~ o t:O C O C O--I ~ C~
O U X '~ 4 ~ 0 4 I o ~ s~ c ~ s ~ x ._ N ~ ~ X !~
^ V ~I C 5 (D,C ,C 5 ~U S S O "-~
O C ~~ ~ ~ 4 C N ~ (~ C
O ~ N 5~ ,C ~
I X~ ~ ~ ~ X
O ~ 0 5~ ~1 ` O
Z~Z O ~ Z O~ Z r~ ~ _Z .. .~
'I;Z LZ ~ Z 4 ~ ,, O ; ::~ , O '---Z --'C
~ LZ ~
s i ~Z x , C.. o . a~ Z~, _ .~Z lri ..Z Z~~ Z O ~ I ~ LZ~ I ~ f CZ L.~, '~ Z ;'l Z Il LZ X Z~ X Z~ X 1~ i' i ~ S ' ZN
'l Z o ~o i o ~ o s ~ e~ .
~ X ~' X ~ ~LZ r~ LZ Z 'Z ~ LZ L.) . Z , _-Z'~ ` Z(~t LZ_, > X ~ ~ X ~ Z~ J X
_ CZ _ ~ZI Z~'Z S O S ~ S O S i O O O
CZ i I --Z . X i -- . _Z ~Z _Z _Z
E ~'1 S~ ~ `--~-- N ~ ~ O N ~ t~ S ~ ~!
Z~Z ~ Z~ ~ Z.~Z ~ X ~ ~Z I ~Z I '~ I ~ rZ Z ZD '~.) ;Z ~ i ~ O ~Z ~ Z O ~Z I i Z'Z C Z~!

: . , ~ , : :: , . . . ..

1 32827q 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 . ~ -.
.
.. ..
:
. , .: . ~

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 ,~, ~ #
4 el ~I ~
~i al ~1 Ul~0 N
. . .
$ ~Is ~ ~ Q
a1 .1 Q
~ _ O ~:
tJ ~ o oo la ~ e ~ o~ o a J

r ~ ~ ~ o ~h~ ~ ~ U'l ~O
~ j~; O ~ ~ ~ ~ ~~ ~.H ~~ ~ ~ ~ ~ ~
U ~
o r~ ~
~ ~J yl _I ~ . o L O O
. ..
: ~ o o o o4 :~o o _~ ~q ~ o O E!l ~ r~l~ ~ ~ o~1 o~ r1 ~
D-- ~~
~"
" C ,~
,4u ~ ~
~ o o~o ~ o o # ~~ ~ ~ I r~
U~ IL~ Ot~ X

N C: N-- 4' ~ C C

O CL~ Q e~ bO ,~ ~u O ~ O
1~ 0 Ll O~.1 0h ~ ~ ~ .rl 4 ~3 h r~ 1 0 S . ~ ~ ~ ~ X e~

` O` O ~ O `~'~ '~ O
N 4N --I ~~ r~ ~ ~ ~ t~
Ql ~' .a ~ s w .e~o ¢ NN ca ~ ~ U~ ~
~ ~ rJ ~

N V
O
$
.
U ~ Æ
.d o ~
C~ 0 O
C~ ~

o ~J ~
I ~ ~J
' O ~O ~

Y u o r' ~ 1 o V
U 5~ , U
UJ
C~ ~ ,.
1: .
V O i:
,t~
CO ~ ~ ~ ~ ~ O ~ O
a ~1 ~

~ ~ .
--I ~ ~ W _I
o X ~
o~ ~ 0 ~ o~ x~ $ O
X ~ a, al C~
) O ;~ U
~ O I O i~ O ~ ~ ~ O ~ O ~ ~
C N41 1~1 ¢ N C M ~ 1~t: N C N '' O
al C ~ c ~ C ~ 4 O ~O i ~ O GlO Cl O~ --~ ~)~ O u O N Ll~.1 0 u O
U ~ ; ~ S ~ O
4 ~1~0 0 ~ a o . o o. c~. o ~ ~
~1~4 .C ~ U~ Ci ~ ~ .1~ N '-' ~ O N
f i~ a1 O ~ ~ 4 r-i~d C

.

, . : ,, - :

1 32~279 -- 46 -- .
~ ol .
~U M V

3:
~ ~ O
B~
O
C~

~0 , ~ ~

q IEI :~ N
C: ~C O ::
.~ ~~ O ~ ~ ~, U~
C~ ~
U ~ '- .
.. O
C~
O
~ O
.
~a ~J fll U
CS O
3_ ~
~ ~ e ~ ~
C
o o o .e ~4 C ~ i~ c 4 O

0 Q ~ ~:1 0 ~14 F; n5 ~ r~1~
! O e~ r i~ ~ O ~ lO.
O i~ O
; G~
o o M 1.1 4; _ 1 ! ~ O U~ iO ~1U ~ ~ ~
d 4 i ~ 1 XN ~rl ~ ~ 3 ~ ~ 4 0 ~ ~
! O I I iA C ~ I~ ~1i N

X t.~ S ~; j~
v~ _ C ~ ~.1~ ~N O ~ O O ~ O
~_~ O --'~ ~ I ~ ~'~ ~
! ~ C ~ j~ o"" "~ o ~ ~ Lh e Ne ~ V
1~ I~d Cl ~ I--~ il~l;~ ~ ~i IV C ~C: Y l L~
~ , ~ ~ r~ . i V
Z ~ s . .

:: . ` ` ~ :, :

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~

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
. ~ `

:. , . , ~, : : : -,. - ,~ . ... . . ~ .

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).

. ~ .
., . . . : .

1 32827q 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 .

. ~

1 32827q 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.

. . .. . . .. .

, ~ , .. . .

_~ ta Q~
o ~ ~ _I , S: ~
.,, E

O
~5 o u~
E~ ~ ~.
N ~ ~ ~ ~ ~ _ Y ~C
_ W'~ .

~ x ol ~
.C ~ ~1 c X ~ X ~ X --~--, O X o X o v ~'!
X ~ ~ ~ ~ 1 ~
v U ~ ~X ,~ V r~
O _ '~ U ~ C
~ O ~ O ~ O ~ O ~ O C O _~ O
s~ W C N C N C N C N ~ N `-- 4 S ~ S ~D S ~D S ~ C .C ~: , X :~ X :~. X ~. X ~ X ~ oX~ ~ X N
O ' O 510 G O ^ O G Ll G O
L~ o U O~ O ~ o U 0 5: 0 ~ r--u ~ ~ ~ 4 ~ ~
(' . S, .~ ~ 5 rl X ~ Xiq X r~ X ~ X ~ X r~
N ~ t uN u N Ll N 4 _ ~ N ~ V

~ I N I NI N I t~ ; N ' N I '' Z ~ , e' I ~ i ~ I ~' I ~ , ~ G

': . ' ^
~: . :

1 3~827~

_I ~
4./
~:: C o~ O -~ ~ ~ '~
.
r~
.~ ~p ,.~ .
S ~ .
,.o E3 ~_, o ~ a ~ c ~ ~ .rl ............. .~ O .n ~ n e w E~ ~ ~ ~ ~ ~ ~ C
C N r~
_~
-C ,~ 3 -- ~ C
O
e C~ .. ~ ~L _ ~11.rl ~ O ' ' ' S
E-~ s ~ 0 ,t O
--' ~ ~1 A A A <~

X X X I ; .
O O O
I ~ X--I X X X ~
O :~- O--~O O '-X XX ~,) 4 ~ L~
r ~ ~ _ ~ x c~
--I S
cc: ~:1c ~I a. I ~I _I C L~
S J~ C ~ 40 ") ~"` C C C
r~ n ~ c~ ~ o~_ s s c~
X~ U ~ ~ I ~ . I
OO.rlO ~ ~ i ~ .
44 0Ll O
'11 N~ 4 ~ I CJ
~~ C ~ ~el' X ~--~~ S ~ --I
SC C~S I O ; ~I ~ ~
X OX--~ S O
I '`I ~ I ~ O ~C O ~O ~ ~
~ar1 X~ XLl a) ~ :J4 '' _I L.l ' O ` O~ S ~ ~
N 4rq 4::>, _ ~ ~-- C
I O i --I ^ E O U
~)~D N ~ ~ C t~ N C 1~5 N r--1 5- ( IJ
~3~_ c ~ s ~ ~ v , s ~ ,, Z~ ~ ~ ~

:

:. .
, 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~

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 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 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-, - , .
: , ~ . ~ :, . :

1 32827~

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.

- ' .
, ... ..
: . ,, : ..

,. . : ~ :

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 .
., . :~ . . .

1 32827q 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 (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 ..

; . ~ , :

~, -~ 32827~

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~

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 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.
1û
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 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`~

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~

-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 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 - 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 . 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 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.

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~

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 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'' . . .

-~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 ~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%.

.

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~

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 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 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 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 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 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 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 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 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.

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 - 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 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 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 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 (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 ;. . , ~, 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 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 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 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.

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 106-108, 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 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.

:~

.

-- 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 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~

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 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 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 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 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 * ~rrademark 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.

, , - ~ -

Claims (15)

1. Compounds of the formula 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 (A') or (A") wherein, R5 is hydrogen or acyl, R6 is hydrogen, halogen, lower alkyl, phenyl or (C3-C6), cyc1oalkyl, and R7 and 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 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 Ib 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.

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;

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;

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.

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

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 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 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.