Arylalkyl esters of 4,5-dihydroxy-9,10-dihydro-9,10-dioxo-2-anth

Details Arylalkyl esters of 4,5-dihydroxy-9,10-dihydro-9,10-dioxo-2-anth Arylalkyl esters of 4,5-dihydroxy-9,10-dihydro-9,10-dioxo-2-anth

1992-12-30

1994-07-19

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ortho-hydroxybenzoic acid or derivative doai

5142248, 514291, 514352, 514374, 514375, 514411, 514416, 514419, 514420, 514423, 514427, 514429, 514448, 514507, 514510, 544 35, 546310, 549 70, 549 89, 548224, 548235, 548427, 548432, 548444, 548486, 548490, 548494, 548539, 548562, 548565, 552262, A61K 3160, A61K 3144, A61K 3140, A61K 31215

Patent

active

053309812

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to arylalkyl esters of 4,5-dihydroxy-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid of general formula: ##STR1## wherein R--CH.sub.2 --O-- is the residue of an R--CH.sub.2 OH alcohol deriving from the reduction of an R--COOH carboxylic acid having antiinflammatory action, which belongs in the class of salicylic, arylacetic, arylpropionic, anthranylic acids.
Examples of antiinflammatory acids are reported hereinbelow: salicylic acids: salicylic acid, acetylsalicylic acid, 5-aminosalicylic acid, diflunisal, fendosal; arylacetic acids: acemetacin, alclofenac, amfenac, benzadac, bufexamac, bumadizone, cinmetacin, clidanac, clometacin, clopirac, diclofenac, etodolac, fenclofenac, indobufen, indometacin, methiazinic acid, sulindac, tolmetin, zomepirac; propionic acids: alminoprofen, benoxaprofen, bucloxic acid, carprofen, flurbiprofen, ibuprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, protizinic acid, pineprofen, pirprofen, pranofropen, suprofen, thiaprofenic acid; anthranilic acids: flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid, lobenzarit, tolfenamic acid.
Particularly preferred are the compounds of formula (I) wherein R is, according to the above definition, a residue from the following compounds: acid salicylic, acid acetylsalicylic, diflunisal, ibufenac, ibuprofen, naproxen, indometacin.
The present invention also relates to the compounds of formula (I) wherein the hydroxy groups at the 4,5-positions of the anthracenedione ring and any hydroxy groups present on the aryl moiety of the R residue are esterified with lower aliphatic acids. The present invention further relates to the compounds of formula (I) in which any amino groups present in the R residues are acetylated or, if possible, salified.
The compounds of formula (I) are prepared by reacting 4,5-di(acetyloxy)-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid chloride of formula (II) ##STR2## with a primary alcohol R--CH.sub.2 OH 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 acid can directly be reacted with an alcohol R--CH.sub.2 OH 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-binding agent, for example triethylamine.
The resulting ester is treated with aqueous ammonia, preferably 10% ammonia, in order to deacetylate the hydroxy groups at the 4- and 5-positions of the anthracene ring, to give a compound of formula (I) wherein said hydroxy groups are free.
The compounds of the invention have interesting pharmacological properties, which are higher than those predictable by the mere addition of compounds having antiinflammatory activity with the (4,5-dihydroxy-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid) molecule, which is already used in the osteoarthritis therapy.
The advantageous pharmacological properties of the compounds of the invention make them useful as such or in form of pharmaceutically acceptable salts (or esters) thereof for the preparation of medicaments, in admixture with appropriate conventional carriers. Examples of pharmaceutical compositions are tablets, capsules, pills, injectable solutions or suspensions, ointments, creams and the like. Doses will 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 conditions of the patient.
The following examples further illustrate the invention.


EXAMPLE 1



2-Hydroxybenzyl
4,5-dihydroxy-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylate
A solution of 1.55 g (12.5 mmoles) of 2-hydroxybenzyl alcohol in 20 ml of anhydrous chloroform, cooled in ice-bath, is added with 1.66 ml (12 mmoles) of anhydrous triethylamine. A solution of 4.7 g (12 mmoles) of 4,5-acetoxy-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid chloride in 80 ml of anhydrous chloroform is added to the stirred solution, with cooling. The rea

REFERENCES:
Morrison & Boyd, Organic Chemistry, 4th Ed., (1983), pp. 827-828, 831, 820-825, 837-838.

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