ARYLALKYL ESTERS OF 4 ,5-DIHYDROXY-9,10-DIHYDRO-9,10-DIOXO-2-ANTHRACENE CARBOXYLIC ACID HAVING THERAPEUTICAL ACTIVITY

ESTERS ARYLALKYLIQUES DE L'ACIDE 4,5-DIHYDROXY-9,10-DIHYDRO-9,10-DIOXO-2-ANTHRACENECARBOXYLIQUE A ACTIVITE THERAPEUTIQUE

English Abstract

2086521 9219584 PCTABS00017
Arylalkyle esters of
4,5-dihydro-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid, a process
for the preparation thereof and the use thereof as therapeutical agents.

Claims

WO 92/19584 PCT/EP92/00881
CLAIMS
1. Compounds of general formula (I)
<IMG> (I)
where n R-CH2-O- is the residue of an R-CH2OH alcohol
deriving from the reduction of an R-COOR carboxylic
acid having antiinflammatory action, which belongs in
the class of salicylic, arylacetic, arylpropionic,
anthranylic acids; the enantiomers, diastereoisomers
and mixtures thereof and the pharmaceutically
acceptable salts thereof.
2. Compounds according to claim 1 wherein the
R-CH2-O- residue derives from the following compounds:
salicyclic acids: calicylic acid, acetylsalicylic acid,
5-aminosalicylic acid, diflunisal, fendosal;
arylacetic acids: acemetacin, alclofenac, amfenac, ben-
zadac, bufexamac, bumadizone, cinmetacin, clidanac,
clometacin, clopirac, diclofenac, etodolac, fenclofe-
nac, indobufen, indometacin, methiazinic acid, sulin-
dac, tolmetin, zomepirac;
propionic acids: alminoprofen, benoxaprofen, bucloxic
acid, carprofen, flurbiprofen, ibuprofen, ketoprofen,
loxoprofen, naproxen, oxaprozin, protizinic acid, pi-
neprofen, pirprofen, pranoprofen, suprofen, thiaprofe-
nic acid;
anthranylic acids: flufenamic acid, meclofenamic acid,

WO 92/19584 PCT/EP92/00881
mefenamic acid, niflumic acid, lobenzarit, tolfenamic
acid.
3. Compounds according to claims 1-2, wherein the
R-CH2-O- residue derives from the compounds: salicylic
acid, diflunisal, ibufenac, ibuprofen, naproxen,
indometacin.
4. A process for the preparation of the compounds of
formula (I), characterized in that a 4,5-diacetoxy-
9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid
reactive derivative is reacted with an alcohol of
formula R-CH2-OH, wherein R is as defined above, and
the hydroxy groups at the 4- and 5-positions of the
anthracene ring are subsequently restored.
5. A process according to claim 4, characterized in
that the acid chloride is used as the 4,5-diacetoxy-
9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid
reactive derivative.
6. A process according to claim 4 o 5 characterized
in that 10% aqueous NH3 is used to restore the hydroxy
groups.
7. Pharmaceutical compositions containing the
compounds of claims 1-3 as the active ingredients in
admixture with pharmaceutically acceptable carriers and
excipients.
8. The use of the compounds of claims 1-3 for the
preparation of a medicament for the treatment of
arthritis.

Description

W092/1gs~ PCT/EP92/00881
2 ~ 8 6 ~ 2 1
ARYLALRYL ~STERS OF 4,5-DI~YDROXY-9,10-DIBYDRO-9tl0-
DIOXO-2-ANT~RACENECARBOXYLIC ACID EAVlNG T~ERAP~TICAL
ACTIVITY
The present _nvent-on relates to arylalkyl esters
of 4,5-dihydroxy-9,10-dihydro-9,10-dioxo-2-anthracene-
carboxylic ac_d of general formula:
.
O o~
C-O~ R (I)
O O
wherein R-C;12-O- is the residue of an R-CH2O~ alcohol
deriving from the reduction of an R-COOH carboxylic
acid having antiin'lammatory action, which belongs in
the class o' sal cylic, arylacet_c, arylprop_onic,
ar.thranylic aci~s.
1~ Examples of ar.ti-r.'lammatcry a_ _s are reported
here nbelow:
salic~lic acids: sal-cyl c zcid, acetylsalicyl c acid,
5-aminosalicylic acid, diflunisal, fendosal;
arvlacetic acids: acemetacin, zlclofenac, amfenac, ben-
zadac, bufexamac, bumadizone, cinmetacin, clidanac,
clometacin, clopirac, diclofenac, etodolac, fenclofe-
nac, indobufen, indometacin, methiazinic acid, sulin-
dac, tolmetin, zomepirac;
pro~ionic ac ds: alminoprofen, benoxaprofen, bucloxic
acid, carprofen, flurbiprofen, ibuprofen, ketoprofen,
loxoprofen, naproxen, oxaprozin, protizinic acid, pi-
neprofen, p rprofen, pranoprofen, suprofen, thia?rofe-
,
~ ,
;" ,; -, : . :. .

WO92/195~ PCT/EP92/00881
2 0 ~
.
nic acld;
anthranYlic acids: flufenamic acid, meclofenamic acid,
mefenamic acid, niflumic acid, lobenzarit, tolfenam_c
acid
Part cularly preferred are the compounds of
formula (I) wherein R is, according to the above
definition, a residue from the follow ng compounds:
acid salic.lic, acid acetylsalicylic, d-flun-sal,
ibufenac, buprofen, naproxen, indometacin.
The present invention also relates to the
compounds OL formula (I) wherein the hydroxy groups at
the 4,5-pos t ons of the anthracenedione ring ar.d any
hydroxy groups present on the aryl moiety of the R
residue are esterified with lower aliphatic ac ds. The
present invention further relates to the compounds of
formula (I) J n which any amino groups present in the R
res dues are ace~ylzted or, if poss ble, sal f ed.
The com?ounds of formula (I) are prepared by
react_ng 4,5-di(acetylc~y)-9,lO-d hydro-9,lO-d oxo-2-
anthracenec2rboY.yl-c ac-d ch7Oride of formula (II)
C3OCO 1 3
~ ~ (II)
O
with a primary alcohol R-CH2OH in which R is as defined
above.
The acid chloride (II~ can be replaced by any
reactive derivative of said acid (such as the ester,
mixed anhydride, and the like); or the ac_d can
,.:

WO92/195~ 2 ~ ~ 6 ~ 2 ~ PCT/EP92/00881
directly be reacted with an alcohol R-CH2OH in the
presence of dicyclohexylcarbodiimide and the like.
The esterification reaction is carried out in an
inert solvent, such as chloroform, in the presence of
an acid-bindlng agent, for example triethylamine.
The resulting ester is treated with aqueous
ammonia, preferably lOD~ ammonia, in order to
deacetylate the hydroxy groups at the 4- and 5-
positions of the anthracene ring, to give a com?ound of
formula (I) wherein said hydroxy groups are free.
The compounds of the invention have ,nteresting
pharmacolog cal pro?ertles, which are h sher than those
pred-ctable by the mere addition of compounds having
antilnflammatory activity with the rhein (4,5-
dihydroxy-9,lO-dihydro-9,lO-dioxo-2-anthracenecarboxy-
lic acid) molecule, which is already used in the
osteoarthrit s therapy.
~he advantageous pharmacological properties of the
com?o~nds c- the invertion make them useful 2S such or
in form cf pharmaceutically acceptable salts (or
esters) thereof for the preparation of medicaments, in
admixture with appropriate conventional carriers.
Examples of pharmaceutical compositions are tablets,
ca?sules, pllls, injectable solut-ons cr suspens ons,
- 25 o ntments, creams and the like. Doses w-ll range from 5
to 500 mg for unit dose, the daily dose depending on
the severity of the condition to treat as well as on
the general condit ons of the patient.
The follow ng examples further illustrate the
nvention.
:

WO92/195~ 2 0 ~ 6 ~ 2 ~ PCT/EP92/00881
The procedure of example 1 is repeated, but using
2.3 g (12 mmoles) of 2-(4-isobutylphenyl)-propyl
alcohol. The title product is obta_ned whlch is
purified by silica gel chromatography with a 1:9 ethyl
acetate/cyclohexane mixture. M.p. 115C.
IR and lH NMR in agreement. Elementary analysis for
C28H266
Calculated % Found %
C73.34 73.28
H5.71 5.66
o20.93 20.86
~XAMPLE S
2-(6-~ethoxv-2-na~hthyl)-propY1 4,;-dihydroxy-9,10-
d-hYdro-9,10-dioxo-2-anthracenecarboxylate
The procedure of example 1 is repeated, but using
2.6 g (12 mmoles) of 2-(6-methoxy-2-naphthyl)-propyl
alcohol. The title product is obta-ned wh.ch is
pur fied by silica gel chromatography w th a 4:6 ethyl
acetate/cyc'ohexane m-xture. M.p. 147-151C.
I~ and H ~ n agreement. Elementary analysis for
C29~227
C 21 cul ated %Found %
C 72.19 72.26
H 4.59 4.63
O 23.21 23.29
EXAMPLE 6
2-~1-(4-ChlorobenzoYl)-2-methyl-5-methoxy-lH-indol-3-
yl]-ethyl 4~5-dihydroxY-9~lo-dihydro-9~lo-dloxo-2
anthracenecarboxYlate
The procedure of example 1 is repeated, but using
3.95 g ~12 mmoles) of 2-[1-(4-chlorobenzoyl)-2-methyl-
.. .. .
~ .' .' ' . . ~ . '
;
i.
- . ~ , :' :' - ' .

W092/19~ PCT/EP92/008XI
2~8~
5-methoxy-lH-indol-3-yl]-ethyl alcohol. The tltle
product is obtained which is purified by silica gel
chromatography with a 3:7 ethyl acetate/cyclohexane
mixture. M.p. 139-146C.
S IR and H NMR in agreement. Elementary analysis for
C34H24C 8
Calculated % Found ~
C 68.50 68.41
H 4.05 4.00
O 21.47 21.42
;, .
, ~ .
.;
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