DE2317114C3 - Glycyrrhetinic acid derivatives and processes for their preparation - Google Patents

Description

(H)

5.3,30-dilauryl-olean-11,13 (18) -diene.
6.3,30-Di- (N, N-diethylaminoacetyI) -olean-13 (18) di

(
7.3,30-Di (trifluoroacetyl) -olean-II, 13 (18) -diene.

8. Process for the preparation of compounds of the general formula according to Claim 1, characterized characterized in that the 3,30-dihydroxy-olean-1 l, 13 (18) -diene with the corresponding carboxylic acid or the anhydride thereof is reacted in a solvent at elevated temperature and optionally then neutralized.

9. The method according to claim 8, characterized in that there is a halogen-containing product with ammonia or with a primary or secondary amine.

10. Pharmaceutical compositions containing at least one compound according to claim 1 together with a solid or liquid pharmaceutical Diluents or carriers.

The glycyrrhetinic acid derivatives according to the invention are compounds of the general formula

CH ₂ OR ₂

55

60

(D

wherein R and R ₂ , which are the same or different, are acylated by customary acylation processes or by processes which are described in the literature.

The acyl derivatives can thus be prepared by adding anhydrous carboxylic acids or their Anhydrides are preferably used in the presence of a suitable solvent at an elevated temperature. Acyl derivatives of polybasic organic acids in which at least one carboxylic acid group of the Organic acid present in the free state are preferably prepared by adding the organic acid with the compound of formula (II) heated in an organic solvent or by an acid anhydride reacts with the compound (H) in pyridine solution. Salts of these derivatives can by Neutralization can be made with non-toxic inorganic or organic bases.

If the compounds prepared contain halogen in Ri and / or R ₂ , this can be reacted with ammonia or with a primary or secondary amine as required, the halogen atom being replaced by an unsubstituted or mono- or disubstituted amine group.

The compounds according to the invention are used together with a solid or liquid pharmaceutical Diluents or carriers used as anti-inflammatory agents.

example 1

1 g of 3,30-dihydroxyolean-11,13 (18) -diene in 10 ml of pyridine is mixed with 10 ml of acetic anhydride. The reaction mixture was left overnight at room temperature

■ it

peraiur kept. Thin-layer chromatography showed after this time that the acylation was complete was. The reaction mixture was poured into water and extracted with ether. The ether extract was with an acid and then washed with water and then dried and then the ether evaporates. The residue was reduced; Methanoi recrystallized, 3,30-diacetylolean-I1.13 (18) -diene, Mp 169-170 ° C

Example 2

A solution of 10 g of 3,30-dihydroxyolean-11,13 (18) -diene in 500 ml of dry chloroform was cooled to 0 ° C. in an ice bath. 25 ml of Ν, Ν-diethylaniline were added and 15 ml of chloroacctyl chloride were then added dropwise. The reaction mixture was then stirred for 6 hours at room temperature and then washed successively with water of dilute acid and aqueous sodium bicarbonate. After drying, the solvent was evaporated and the residue was taken up in 300 ml of benzene, filtered through a thick layer of 60 g of aluminum oxide and further eluted with 31) 0 ml of benzene. After the benzene had evaporated, the residue was crystallized from a mixture of ethanol and chloroform, 12 g of 3,30-di- (chloroacetyl) -olean-ll, 13 (18) -diene, melting point 197 ° to 198 ° C. being obtained , [ä] d = - 3 Γ (c. = 1% in chloroform).

Example 3

A solution of 15 g of 3,30-dihydroxyolean-i.1,13 (18) -diene in 150 ml of pyridine was refluxed for 8 Heated for hours with 20 g of succinic anhydride. The reaction mixture was made into a mixture Poured dilute hydrochloric acid and ice and stir for 15 minutes. The get a precipitate was filtered off, washed with water, dried and dissolved in chloroform and ether (1: 2). The solution was treated with animal charcoal, filtered and concentrated. On cooling the 3,30-dihemisuccinylolean-ll, 13 (18) -diene fell out. It was recrystallized from chloroform ether and had a melting point of 203 bis 204 ° C, [ä] d = -31 ° (c = 1% in chloroform). The yield was 11.5 g.

Example 4

10.25 g of S.SO-Dihcmisuccinyl-olean-ll.niliSJ-diene (cf. Example 3) were suspended in 100 ml of methanol and mixed with a solution of 1.28 g of sodium hydroxide in 50 ml of methanol. The pH of the solution was then adjusted to 8 and the solution was diluted with 500 ml of acetone. The precipitate, which separated out on cooling, was filtered off. This gave 10 g of S ^ O-dihemisuccinyl-olean-IIIl ^ ieVdiene-diiriatrium salt, melting point above 280 ° C. (decomp.), [A] _D = -19 ° i (c. = 0.5% in methanol).

Example 5

20 ml of lauroyl chloride was -diene under cooling to a solution of 6.5 g of 3,30-Dihydroxyolean-11, l3 (18) j 50 mL of pyridine was added _n. The reaction was kept at 20 ⁼ C during 20 hours and during 30 minutes at 80 ° C. After cooling, it was poured into a mixture of ice and hydrochloric acid with vigorous stirring. The mixture was extracted with ether, the ether extract was washed with water and with an aqueous solution of sodium bicarbonate and dried and then evaporated to dryness. The remaining oil was

ίο taken up in 300 ml of petroleum ether, filtered through a column filled with 250 g of aluminum oxide in petroleum ether and then the column was eluted with a further 300 ml of petroleum ether. The eluate obtained was concentrated to a small volume and stored at -10 ° C. for crystallization. After further recrystallizations, colorless and pure 3,30-dilauryl-olean-II, 13 (18) -diene, melting point 40 to 41 were obtained ° C, [a] _D = -20 = (c = 1% in chloroform).

B e i s ρ i e 1 6

A mixture of 10.5 g of 3,30-di- (chloroacetyl) -olean-11,13 (18) -diene (See. Example 2), 3 g of sodium carbonate, 10 ml of diethylamine and 150 ml of benzene was under Stirring at reflux for 7 hours and then stored at room temperature overnight. to water was added to the reaction mixture. The benzene layer was separated and then with water washed, dried and evaporated to dryness.

The residue was crystallized from a mixture of benzene and petroleum ether. After recrystallization from the same solvent mixture, 10.5 g of colorless 3,30-di- (N, N-diethylaminoacetyl) -olean-II, 13 (18) -diene, melting point 127 ° to 128 ° C., were obtained >] _D = -30 °

(c. = 1% in chloroform).

Example 7

A mixture of 8 g of 3,30-dihydroxy-olean-11.13 (18) -dicn and 400 ml of dry chloroform was cooled to 0 ⁰ C. 12 ml of trifluoroacetic anhydride was added dropwise with stirring. After the addition was completed, 100 ml of cold water was added and after 10 minutes the chloroform layer was separated, washed with an aqueous solution of sodium bicarbonate and water, dried and evaporated to dryness. The residue was crystallized from methanol, giving 11 g of 3,30-di- (trifluoroacetyl) -olean-II, 13 (18) -diene, melting point 159 to 160 ° C .; [a] _D = -36 ° (c. = 1% in chloroform). In order to show the superiority of the compounds according to the invention, the compounds according to the invention were compared with known compounds, namely with the parent compound, 3,30-dihydroxyolean-li, 13 (18) -diene, and with the corresponding acetyl compound.

The LD 50 and the effectiveness in the arthritis test were determined in the usual way.

The results obtained are summarized in the table below.

connection

LD

mg / kg

R. A. Arthritis test

dose
mg / kg

Type d. effect

Administer. 14 days

Effect? 1 day

3,30-dihydroxyo! Ean-ll, 13 (18) -diene
(Root connection)

> 2400 10
100

orally
orally

0 0

continuation

connection

3,30-diacetylolean-11,13 (18) -diene (known connection for comparison)

3,30-Dihemisuccinylolean-1,13 (18) -diene disodium salt

3,30-di (trifluoroacetyl) -olean-11,13 (18) -diene 3,30-di (chloroacetyl) -olean-11,13 (18) -diene

3,30-di- (N, N-diethylaminoacetyl) -olean-II, 13 (18) -diene

3,30-Dilaurylolean-II, 13 (18) -diene

LD 50
ng / kg RA arthritis test
Dose type d.
Administering,
mg / kg orally
orally effect
14 days effect
21 days > 2Ü00 10
100 orally
orally 41 31
81 > 2000 10
100 orally
orally 0
0 25th
7th > 2000 10
100 orally
orally 10
63 11th
48 > 2Ö00 10
100 orally
orally 31
5 32
25th > 2000 10
100 orally
orally 29 15th
0 > 2000 10
100 14th
16 -

Claims (4)

Patent claims: 1. Glycyrrhetinic acid derivatives of the general form! CH ₁ OR ₁ 15th where Ri and R2, which can be the same or different, represent acyl groups which are derived from saturated aliphatic mono- or dicarboxylic acids with up to 12 carbon atoms and which can be substituted by halogen atoms or by unsubstituted or substituted amino groups, with the proviso that, if one of the two radicals Ri and R2 represents the acetyl group, the other radical denotes an acyl radical different therefrom, and salts of compounds which contain _{carboxylic acid groups in the radicals Ri and / or R 2.} 2.3,30-di- (chloroacetyl) -olean- ₁ l, 13 (18) -diene. 3,3,30-dihemisuccinyl-olean-11,13 (18) -diene. 4. Disodium salt of 3,30-dihemisuccinyl-oleandi can mean acyl groups which are derived from saturated aliphatic mono- or dicarboxylic acids with up to 2 carbon atoms and which can be substituted by halogen atoms or by unsubstituted or substituted amino groups, with the proviso that if one of the two radicals Ri and R ₂ represents the acetyl group, the other radical represents an acyl radical different therefrom, and salts of compounds which contain _{carboxylic acid groups in the radicals R 1} and / or R _2. The groups Ri and R ₂ each contain up to 12 carbon atoms. Examples of acids from which the acyl groups Ri and R ₂ can be derived are acetic acid, mono-, di- and trichloroacetic acid, mono-, di- and trifluoroacetic acid, propionic acid, butyric acid, caproic acid, acrylic acid, crotonic acid, angelic acid, tiglinic acid, geranic acid (3,7-dimethyl-2,6-octadiene-carboxylic acid), tetrolic acid, malonic acid, succinic acid, glutaric acid, sebacic acid, maleic acid, fumaric acid, tartronic acid, malic acid, oxaloacetic acid, tartaric acid and citric acid. The glycyrrhetinic acids of the invention can be prepared by adding a compound of general formula CH ₁ OH