CA2086521A1 - Arylalkyl esters of 4 ,5-dihydroxy-9,10-dihydro-9,10-dioxo-2-anthracene carboxylic acid having therapeutical activity - Google Patents

Abstract

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.

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) ~ ~ (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 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 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 Calculated % Found ~
C 68.50 68.41 H 4.05 4.00 O 21.47 21.42 ;, .
, ~ .

.;

-: ' ~ ~ . ' '

Claims (8)

1. Compounds of general formula (I) (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, 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.