DE2450353A1 - OLEANCARBONIC ACID DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND PHARMACEUTICAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

Patent attorneys Dipl.-Ing. F. \ 7ι · tckmann,

Dipl.-Ing. Η.Ψειοκμανν, Dipl.-Phys. Dr. K. Fincke Dipl.-Ing. F. A. Weickmann, Dipl.-Chem. B. Huber

8 MUNICH 86, DEN

PO Box 860 820

MÖHLSTRASSE 22, CALL NUMBER 98 39 21/22

F.3067 / p / H / KR

BIOREX Laboratories Ltd., Biorex House, Canonbury Villas,

London, N1 2HB / England

Oleancarboxylic acid derivatives, processes for their preparation and pharmaceutical compositions containing these compounds

The invention relates to new and pharmaceutically usable derivatives of oleancarboxylic acid (caryophylline) and the
Making these connections.

In GB-PS 1 060 3 ^ 4, inter alia, connections the general formula:

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R "

where R and R "together with the nitrogen atom to which they are attached form a heterocyclic Form a radical which can contain further heteroatoms, and where X is an acyl radical of the oleancarboxylic acid (Caryophyllin), the hydroxyl group acylating with a monocarboxylic acid or a polycarboxylic acid can be and furthermore carboxylic acid groups contained therein either in the free form or in May be in salt form. The only derivatives of oleancarboxylic acid that are specifically mentioned in this publication are mentioned are 3-0-acetyl-oleancarboxylic acid-o-carbomethoxy-anilide and oleancarboxylic acid o-carboxyanilide.

It has now been found that the N-methylpiperazinamides the oleancarboxylic acid (caryophyllin) and the 3-O-acylcaryophylline derivatives have a better anti-inflammatory effectiveness than the oleancarboxylic acid derivatives, which are specifically mentioned in the aforementioned patent.

The invention therefore relates to oleancarboxylic acid derivatives (Caryophy11in derivatives) of the general formula:

CO-N N-CH

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wherein R is a hydrogen atom or one of a mono- or polycarboxylic acid-derived acyl radical and where carboxylic acid groups are present in free form or in the form of a salt or an ester.

Examples of acids with which the 3-hydroxyl group can be esterified, are preferably aliphatic mono- and polycarboxylic acids with up to 20 carbon atoms, preferably up to 10 carbon atoms, such as acetic acid, propionic acid, butyric acid, malonic acid, maleic acid, Lauric acid, stearic acid, succinic acid and glutaric acid.

To prepare the new compounds according to the invention, the 3-hydroxyl group of the oleancarboxylic acid is first used (Caryophyllin) acylated with a monocarboxylic acid, for example by using a suitable acid halide or acid anhydride converts. The carboxylic acid group in the acyl compound thus obtained is thereupon in an acid halide group, preferably an acid chloride group, e.g., by reaction with thionyl chloride. The acid halide thus obtained is then reacted with N-methylpiperazine, whereupon if desired the acyloxy group is hydrolyzed to give the hydroxyl group to release, which, if desired, can be acylated again with a mono- or polycarboxylic acid can, then any free carboxylic acid groups esterified or with a non-toxic inorganic or organic base can be converted to a salt.

The invention is illustrated in the examples.

509819/1 149

example 1

23 g of 3-O-acetyloleancarboxylic acid chloride in 200 ml of dry benzene were mixed with 12 g of N-methylpiperazine and the mixture was stirred for 3 hours at ambient temperature and then left to stand overnight and filtered off. The precipitate was washed with benzene and the combined washings and the filtrate were concentrated. Petroleum ether was then added and crystallization occurred. The obtained crystals were recrystallized twice from ethyl acetate, whereby 14.1 g of pure 3β-acetoxy-18β-olean-28-carboxylic acid N-methylpiperazinamide were obtained. The product was determined by thin layer chromatography as a pure, had a melting point of 214-216 ⁰ C, £ öO_7ß ² "+ 44 ° (c. = V / o in chloroform).

Example 2

20 g of 3ß-acetoxy-18ß-olean-12-en-28-carboxylic acid-N-methyl piperazinamide (see. Example 1), 400 ml of ethanol and 100 ml of 20% aqueous potassium hydroxide solution were heated for 15 min on a steam bath, followed by a Thin-layer chromatogram indicated that the reaction was complete. The reaction mixture was diluted with water and extracted with dichloromethane. The extract was washed with water until the washing waters became neutral, and then washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed and the resulting yellow oil was crystallized from ethyl acetate / petroleum ether (bp. 60 to 80 ⁰ C). The product was filtered off, washed with petroleum ether and

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dried, whereby 17.8 g of 3ß-hydroxy-18ß-olean-12-en-28-carboxylic acid N-methylpiperazinamide were obtained. After recrystallization from ethyl acetate / petroleum ether (bp. 60 to 80 ⁰ C) the product has a melting point of 250-251 ⁰ C, l'COJ ^ = + 48 ° (c. = 1% in chloroform) had.

Example 3

6 g of 3ß-hydroxy-18ß-olean-12-en-28-carboxylic acid-N-methylpiperazinamide (cf. Example 2), 3 g of succinic anhydride and 15 ml of anhydrous pyridine were refluxed for 8 hours. The reaction mixture was cooled, poured into ice water, filtered, and the resulting solid material was washed well with water. This material was then stirred in hot water for 1.5 hours to decompose residual succinic anhydride and then filtered, washed with water and dried. A yield of 6.3 g of the crude 3β- (β-carboxypropionyl) -18β-olean-12-en-28-carboxylic acid N-methylpiperazinamide was obtained. After two recrystallization from ethyl acetate, one recrystallization from acetone and renewed recrystallization from ethyl acetate, the pure product was in the form of colorless needles with a melting point of 231 to 232 ° C, /^.7 _D ^ ' ⁵ = + 34.8 - 1 ° (c. = V / o in chloroform).

The invention also encompasses pharmaceutical agents which at least one of the new compounds of general formula I mixed with a solid or liquid pharmaceutically acceptable carriers.

Solid preparations for oral administration are e.g. compressed tablets, pills, dispersible powder

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-fi ver and granules. In. One of the new esters of such solid preparations is mixed with at least one inert diluent, for example calcium carbonate, starch, alginic acid or lactose. The compositions may also, as is normal practice, contain substances other than the inert diluents, for example lubricants such as magnesium stearate.

Liquid preparations for oral administration are e.g. pharmaceutically acceptable emulsions, solutions, Suspensions, syrups and elixirs containing the inert diluents commonly used, such as water and liquid paraffin. In addition to the inert diluents, such agents can also contain auxiliaries, e.g. wetting and suspending agents, as well as sweetening and flavoring agents.

The compositions of the invention for oral administration also include capsules made of absorbable material, such as gelatin, one that is one of the new with or without the addition of diluents or extenders Derivatives included.

Preparations according to the invention for parenteral administration are, for example, sterile aqueous or non-aqueous Solutions, suspensions or emulsions. Examples of non-aqueous solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters, like ethyl oleate. These agents can also contain auxiliary materials, e.g. wetting, emulsifying or dispersing agents. They can be sterilized by filter them e.g. through bacteria-retaining filters

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trated by adding sterilizing agents to them, or by irradiating or heating them. They can also be delivered in the form of sterile solid assemblies * Settlements are prepared immediately before use in sterile water or another sterile one injectable medium to be dissolved.

The proportion of the active ingredient in the agents according to the invention can be varied, it being necessary that it is so large that a suitable dosage for the desired therapeutic effect is achieved. In general, the preparations according to the invention should administered orally or parenterally to humans in such a way that 10 to 1000 mg, preferably 50 to 500 mg, of active ingredient administered per day.

The following examples describe pharmaceutical compositions according to the invention.

Example 4

Tablets of 250 mg are produced, which have the following composition:

3ß-acetoxy-18ß-olean-28-carboxylic acid-N-

methylpiperazinamide 50 mg

Strength 100 mg

Lactose 95 mg

Magnesium stearate 5 mg

Example 5

Tablets of 400 mg are produced, which have the following composition:

509819/1149

3ß- (ß-carboxypropionyl) -18ß-olean-12-

en-28-carbonate-N-methylpiperazine-

amide 100 mg

Strength 130 mg

Lactose 160 mg

Magnesium stearate 10 mg

The agents of Examples 4 and 5 are for oral administration to humans for the treatment of inflammatory conditions intended.

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Claims (7)

Claims 1. Oleancarboxylic acid derivatives (caryophylin derivatives) the general formula:. GO-N N-GH
V where R is a hydrogen atom or an acyl radical derived from a mono- or polycarboxylic acid
and in which any carboxylic acid groups present therein in free form or in the form of a salt or
an ester are present. 2. 3β-Acetoxy-18β-olean-28-carboxylic acid-N-methylpiperazinamide. 3. 3β-Hydroxy-18β-olean-28-carboxylic acid N-methylpiperazinamide. 4. 3β- (β-Carboxypropionyl) -18β-olean-12-en-28-carboxylic acid N-methylpiperazinamide. 5. Process for the production of Oleancarbonsäurede.rivaten (Caryophyllin derivatives) according to claim 1, characterized in that the 28-carboxylic acid group is used the oleancarboxylic acid, whose 3-hydroxyl -10- 509819/1149 group has been acylated with a monocarboxylic acid, Reacts with a halogenating agent to the corresponding acid halide and that this is then with N-methylpiperazine to the corresponding N-methylpiperazinamide implements, which if desired with release the 3-hydroxyl group is hydrolyzed, which if desired with a mono- or polycarboxylic acid is acylated, with any free carboxylic acid groups present, if desired, esterified or with a non-toxic inorganic or organic base in the Salt to be transferred. 6. The method according to claim 5, characterized in that g.e k e η η ζ e ic h η e t that thionyl chloride is used as the halogenating agent used. 7. Pharmaceutical agent, characterized in that it is mixed with a solid or liquid pharmaceutical diluent or carrier containing at least one compound according to claim 1. 509819/1149