4,5-dihydroxy- and 4,5,8-trihydroxy- 9,10-dihydro-9,10-dioxo-2-a

Details 4,5-dihydroxy- and 4,5,8-trihydroxy- 9,10-dihydro-9,10-dioxo-2-a 4,5-dihydroxy- and 4,5,8-trihydroxy- 9,10-dihydro-9,10-dioxo-2-a

1993-06-07

1994-11-08

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

552262, A01N 3700, A61K 3121, C07C27144, C07C32312

Patent

active

053627504

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to 2-anthracenecarboxylic derivatives of general formula (I) ##STR1## wherein: X is hydrogen or a OCOR group, in which R is as defined below; C.sub.1 -C.sub.16 alkylthioethyl; benzyloxy, 2-phenylethoxy group; R.sup.1 R.sup.2 N, wherein R.sup.1 and R.sup.2 which can be the same or different, are selected from hydrogen; straight, branched or alicyclic C.sub.1 -C.sub.10 alkyl, phenyl, benzyl, 2-phenylethyl; and to the pharmaceutically acceptable salts thereof.
Preferred compounds of the invention are those in which R is selected from: methoxy, ethoxy, propoxy, butoxy, benzyloxy, methylamino, ethylamino, propylamino, benzylamino; Y is hydrogen or C.sub.1 -C.sub.4 alkyl, ethoxyethyl or ethylthioethyl.
Exemplifications of pharmaceutically acceptable salts are the salts with alkali or alkaline-earth metals, such as sodium, potassium, calcium or magnesium salts; and the salts with organic bases, such as ethanolamine, diethanolamine, N,N-dialkylethanolamine, phenylethylamine, piperazine, morpholine, lysine and the like.
Compounds having a 9,10-anthraquinone structure, such as diacetylrhein, are known to have antiarthritic activity (DE 2711493).
Italian Patent application n. 21456 A/87 discloses rhein derivatives wherein the hydroxy groups are replaced by thio groups.
Now it has been found that rhein and 8-hydroxyrhein carbonic esters and urethans, of formula (I) , have a marked inhibitory activity against the enzymes involved in articular pathology. Particularly, the compounds of the invention proved to have a surprising effect on mammal collagenase and elastase activities, thus being advantageous in the therapeutical treatment of arthritic conditions.
Said activities are particularly important in the treatment of cartilage pathology as well as in that of collagenous tissues.
Among the observed activities, particularly important are the inhibition of free radical formation and the inhibition of spontaneous auto-lysis of cartilages.
The compounds of the invention in which R is different from NR.sup.1 R.sup.2 are prepared by reacting one compound of formula (II) ##STR2## wherein X' is hydrogen or OH and Y is as defined above, with a chlorocarbonate of formula (III)
Compounds (II) wherein Y is an alkyl, alkoxyethyl or alkylthioethyl group can be prepared by means of conventional esterification methods of compounds (II) in which Y is hydrogen.
Compounds (I) in which R is a NR.sup.1 R.sup.2 group are prepared by reacting a compound of formula (II) above with phosgene and subsequently with a compound of formula ##STR3## wherein R.sup.1 and R.sup.2 are as defined above.
Alternatively, compounds (I) wherein R is NR.sup.1 R.sup.2 are prepared by reacting a compound of formula (II) with a compound of formula R.sup.1 R.sup.2 NOCl, wherein R.sup.1 and R.sup.2 are as defined above.
The compounds of the invention can be used as such or in form of pharmaceutically acceptable salts thereof, in the preparation of medicaments, together with suitable conventional carriers.
Examples of solid formulations are tablets, capsules, pills, or other forms of suitable bio-availability. Dosages can range from 5 to 500 mg per unit dose, the daily dose depending on the severity of the arthritic pathology and the patient's conditions, according to the physician judgement.
The following Examples further illustrate the invention.


EXAMPLE 1



Preparation of
4,5-bis(methoxycarbonyloxy)-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic
2.84 g (0.01 mole) of acid (I) in 50 ml of anhydrous tetrahydrofuran are placed into a two-necked flask fitted with a thermometer and a dropper with CaCl.sub.2 valve, then 3.03 g (0.03 mole) of anhydrous triethylamine are added. 2.08 g (0. 022 mole) of methyl chloroformate dissolved in 5-10 ml of anhydrous tetrahydrofuran are dropped into the stirred mixture, at 5.degree. C. The reaction temperature must be kept below 30.degree. C. When dropping is over (after about 4 hours) the precipitate is filtered, the solvent is evaporated off under vacuum from the filtrate and the fluid residue is t

REFERENCES:
patent: 5030387 (1991-07-01), Matsuoka et al.
March Advanced Organic Chemistry, Wiley & Sons, N.Y., 1985, p. 347.

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