HU219346B - N-[(4,5-dihydroxi-9,10-dihydro-9,10-dioxo-2-anthracenyl)-carbonyl]-amino acids and pharmaceutical compositions containing the same - Google Patents

Abstract

In the compounds of the present invention, X is a hydrogen atom, R is a C1-7 alkyl group, optionally substituted with C1-4alkylthio. The invention encompasses the above compounds for pharmaceutical compositions. The compounds of formula (I) inhibit human leukocyte elastase activity. ŕ

Description

The present invention relates to novel anthracenylcarbonyl amino acid derivatives and pharmaceutical compositions containing them.

More particularly, the present invention relates to N - [[4,5-dihydroxy-9,10-dihydro-9,10-dioxo-2-anthracenyl] carbonyl] amino acid derivatives of the formula I, their enantiomers and racemic mixtures, and their pharmaceutically acceptable salts. , in the formula

X is hydrogen,

R is C 1 -C 7 alkyl, which may be optionally substituted with C 1 -C 4 alkylthio.

Particularly preferred are compounds of the formula

R is the above alkyl group which is a natural amino acid attached to the -NH-CH (COOH) - group.

The compounds of the invention are derived from rhein, which has the chemical name 4,5-dihydroxy-9,10-dihydro-9,10-dioxo-2anthracenecarboxylic acid and which has therapeutic properties. Diacerhein, which is a diacetyl derivative of rhein, is commonly known for its anti-arthritic activity. Diacetyl-rhein and its anti-inflammatory activity are described, for example, in FR 2 508 798.

The natural amino acid derivatives of rhein, which are within the scope of the present invention, have valuable pharmacological properties for use in the treatment of joint diseases. Preliminary pharmacological experiments have shown that the compounds exhibit significant inhibitory activity on human leukocyte elastase activity as well as free radical formation.

Human leukocyte elastase is known to be involved in the induction and development of osteoarthritis.

The compounds of the invention may be prepared in conventional manner. The rhein or derivative thereof, such as rhein chloride, diacetyl rhein or diacetyl rhein chloride, is condensed with R-CH (NH ₂ ) -COOR *

R ¹ is C 1 -C 4 alkyl.

The reaction is preferably carried out in an anhydrous solvent such as methylene chloride in the presence of an acid acceptor such as triethylamine. It is found on the aromatic ring

The 4,5-hydroxyl group and the carboxyl group of the amino acid moiety are restored by hydrolysis of the corresponding ester. In one embodiment of the invention, diacetylrheinchloride is used.

The invention is further illustrated by the following examples, which are not to be construed as limiting the scope thereof.

Example 1

2 - [[4,5-Dihydroxy-9,10-dihydro-9,10-dioxo-2-anthracenyl] carbonylamino] -4-methylpentanoic acid

4,5-Dihydroxy-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid chloride (3.1 g, 8 mmol) was added as methyl 2-amino-4- (1.8 g, 10 mmol). methyl pentanoate hydrochloride, 50 mg of pN, N-dimethylaminopyridine and 2.4 ml (16 mmol) of triethylamine in 70 ml of dichloromethane with stirring. The reaction mixture was refluxed for 5 minutes and then allowed to cool to room temperature overnight with stirring.

The reaction was monitored by silica gel thin layer chromatography (10: 1 dichloromethane / diethyl ether).

After completion of the reaction, the reaction mixture was washed with water, the organic phase separated and the solvent removed under reduced pressure. The residue is taken up in a mixture of 50 ml of methanol and 5 g of potassium hydroxide in 50 ml of water to give a deep red solution. After about 30 minutes, the solution was acidified with 8% hydrochloric acid and filtered. The precipitate was crystallized from acetone / diethyl ether to give about 1.4 g of product, m.p. 204-206 ° C.

Analysis for C ₂₁ H ₁₉ NO ₇ molecular formula: C 63.47%, H 4.81%, N 3.52%; Found: C 63.40%, H 4.77%, N 3.56%.

The IR and ^1H-NMR spectra are consistent with structure.

The following compounds can be prepared analogously.

example Number R Molecular formula melting point (° C) Second (CH ₃ ) ₂ CH- c ₂₀ h ₁₇ no ₇ > 210 Third CH ₃ S (CH ₂ ) ₂ - c ₂₀ h ₁₇ no ₇ s 175-178

Elemental analysis, IR and 1 H-NMR data are consistent with the expected structure.

The pharmacological activity of the compounds of the present invention relative to rhein is shown in the following table based on the inhibition of human leukocyte elastase (HLE) and the suppression of superoxide anion (SO).

agent Concentration (Pmol) Inhibitory effect (%) HLE SALT Rhein 10 3.2 1.2 50 10.2 12.3 100 15.5 24.5 Example 1 10 7.0 4.1 50 21.6 20.2 100 35.2 37.8 Example 2 10 6.7 4.4 50 20.9 19.6 100 32.4 35.2 Example 3 10 12.3 - 50 17.3 - 100 34.2 -

The results show that the compounds of the present invention show significantly better efficacy than rhein. This effect was not expected based on the structure of the compounds. Moreover, if the amide bond is cleaved before exerting a pharmacological action, the compounds will have the same potency as rhein. This indicates that the compounds of the present invention have different activity2

EN 219 346 Β mechanism, which is not currently known.

The compounds of the present invention are useful as active ingredients in conventional pharmaceutical compositions based on their pharmacological activity. 5

Examples of pharmaceutical compositions include tablets, capsules, powders, syrups, injectables and suppositories.

The dosage unit may vary from 5 to 500 mg of active ingredient per dose. The dosage depends on the severity of the disease being treated and the condition of the patient.

Claims (4)

PATENT CLAIMS What is claimed is: 1. N - [[4,5-Dihydroxy-9,10-dihydro-9,10-dioxo-2-anthracenyl] carbonyl] amino acid derivatives of the formula (I), their enantiomers and racemic mixtures and pharmaceutically acceptable derivatives thereof. their salts in the formula X is hydrogen, R is C 1 -C 7 alkyl optionally substituted with C 1 -C 4 alkylthio. Compounds according to claim 1, characterized in that R is the above alkyl group which is a natural amino acid attached to the -NH-CH (COOH) - group. Compounds according to claim 1, characterized in that R is an isobutyl group, an isopropyl group or a methylthioethyl group, and the absolute configuration of the carbon atoms substituted by -NH-, -COOH and -R is R. Pharmaceutical composition, characterized in that the active substances according to claims 1-3 are active ingredients. A compound according to any one of claims 1 to 6 in addition to pharmaceutical carriers and other pharmaceutical excipients.