FI69471C - FOERFARANDE FOER FRAMSTAELLNING AV NYA THERAPEUTIC EQUIPMENT - Google Patents

Description

1 69471

A process for the preparation of new therapeutically useful sugar derivatives

Divided by application 801472 5

The invention relates to a process for the preparation of novel sugar esters and glucosides having the formula:

Ci ^ OR1 «J ......... o.

| W> K1 2 «»

0 I

H 1 4

OR

15 wherein R 1 is a group of the following formula: R 1 is a lower alkoxy, and one of R 1 and R 3 is hydrogen and the other is a group R 1.

Of particular interest are the 2 2 compounds of formula I wherein R is methoxy, especially X 1 -methoxy. The phrase "lower" preferably means groups having up to 7 carbon atoms. Examples of lower alkoxy groups are methoxy, ethoxy, propoxy and butoxy.

The compounds of formula I are prepared according to the invention in such a way that a) a compound of formula: 69471

CH, OH

J \ OH '' X.-R2 II

5 hIV

OH

, 2 wherein R represents lower alkoxy, is reacted with the acid R OH or a reactive derivative thereof in the presence of a water or acid scavenger.

Suitable reactive derivatives of the acid R OH are, in particular, halides, e.g. chloride. The reaction is conveniently carried out in a neutral Liu-15 receiver. Examples of solvents are ethers, e.g.

diethyl ether, tetrahydrofuran or dioxane; or water; or mixtures thereof. Examples of bases suitable for this reaction include organic bases such as pyridine, its homologues and inorganic bases such as alkali metal 20-carbonates. The reaction is conveniently carried out at temperatures between 0 ° and room temperature.

The starting materials can be prepared as described in the examples or the like.

The compounds of the formula I are valuable as active ingredients for use in pharmaceutical preparations, e.g. for the treatment of tumors, in particular when administered topically. They can also be used to treat pimples and dandruff and to treat inflammatory and allergic skin diseases. In particular, the compounds have a particularly good tolerability, e.g. when administered topically they do not irritate the skin.

the antitumor activity of the compounds was tested in mice whose skin had been implanted with dermatitis by treatment with dimethylbenzanthracene and croton-3S oil. By administration of the compounds of formula I, atrophy of the skin warts was monitored. The test results are available in Table I.

69471

Table I

Compound Dose Decreased wart diameter (%) 5 A 0.75 -57 B 0.4 -69 A: Methyl-2,6-bis-O- [p - / "(E) -2- <5,6,7 , 8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] -benzoyl-7-D-10-glucopyranoside B: Methyl-3,6-bis-O- [p- (E) - 2- (5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl-7-benzoyl-7-β-D-glucopyranoside

The compounds of the formula I can be used as medicaments, e.g. as pharmaceutical preparations. Formulations for systemic use may be prepared, for example, by adding the compound of formula I as an active ingredient to a non-toxic, neutral solid or liquid carrier commonly used in such preparations. The agents can be administered internally or parenterally. For example, substances in the form of tablets, capsules, granules, syrups, suspensions, solutions and suppositories are suitable for internal administration. Substances suitable for infusion or injection are suitable for parenteral administration.

The dosages at which the products of the method are administered may vary depending on the mode of administration and administration as well as the needs of the patients.

The products of the method may be administered in one or more doses of from about 0.01 to about 5 mg per day.

The preferred form of administration is capsules containing from about 0.1 mg to about 1.0 mg of active ingredient.

The preparations may contain neutral or also pharmacodynamically active additives. Tablets or granules, for example, may contain a variety of binders, excipients, carriers or diluents. Liquid preparations may be in the form of a sterile water-miscible solution, for example, 4 69471. The capsules may contain, in addition to the active ingredient, an excipient or a thickener. In addition, flavoring additives may be present, as well as conventional preservatives, stabilizers, humectants and emulsifiers, further salts for varying the osmotic pressure, buffers and other additives.

The above-mentioned carriers and diluents may be organic or inorganic substances, for example, water, gelatin, milk sugar, starch, magnesium stearate, talc, acacia, polyalkylene glycols and the like. It is a prerequisite that all excipients used in the preparation of the preparations are non-toxic.

For topical administration, the products of the method are best used as ointments, tinctures, creams, solutions, lotions, sprays, suspensions and the like. Ointments and creams as well as solutions are preferred. These topical preparations can be prepared by mixing the products of the process with the active ingredient among non-toxic, neutral, topical solid or liquid carriers commonly used in such preparations.

Most suitable for topical use are solutions of about 0.01 to about 0.3%, preferably 0.02 to 0.1%, and about 0.05 to about 5%, preferably about 0.05 to about 5%. ointments or creams of about 1%.

It may be possible to add an antioxidant, e.g. tocopherol, N-methyl-γ-tocopheramine as well as butylated hydroxyanisole or butylated hydroxytoluene.

• The following examples are intended to further illustrate 35 inventions.

69471

Example 1

A solution of 100 nun of p-E- (E) - (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] -benzoyl chloride in 450 ml: ether, was added at 0 ° with stirring over 1 hour to a solution of 19.5 g of methyl, N-D-glucopyranoside in 500 ml of pyridine. The mixture was further stirred for 4 hours at 0 ° and 16 hours at room temperature and then evaporated to dryness. The residue was dissolved in ethyl acetate, and the extract was washed with 3N HCl, water, saturated aqueous sodium hydrogencarbonate solution, and water. After drying over sodium sulfate, the organic phase was evaporated to dryness and the residue was chromatographed on silica gel (hexane-ethyl acetate) to give methyl 2,6-bis-O-, p - / (E) -2- (5,6,7,8 -tet-15-dihydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl-7-benzoyl-N- [D-glucopyranoside, m.p. 203-204 ° (from ethyl acetate), = 27.4 ° (c = 1 in chloroform) and methyl 3,6-bis-O- [p- (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl-benzoyl-β-D-Glu-20 copyranoside, melting point 128-129 ° (from methanol, decomp.), = + 135 ° (c = 1 in chloroform).

The acid chloride used as a starting material can be prepared as follows: p -, '(E) -2- (5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] -benzoic acid ethyl ester The mixture is saponified with aqueous and ethanolic potassium hydroxide at 55 ° C for 18 hours to give the corresponding carboxylic acid, and the acid is converted to the acid chloride with thionyl chloride in pyridine and N, N-dimethylformamide.

Claims (5)

A process for the preparation of new therapeutically useful sugar derivatives of the formula I 5 CKLOR1 Ao / \ 9/3 N-vR τ l \? R O \ ------- 10. wherein R 1 is a group of the following formula is c 0-20 R 4 is lower alkoxy, and one of R and R is hydrogen and the other is R, characterized in that the compound of formula II 25 CH2OH! -------- O (f> 'HO | OH 2 where R represents lower alkoxy is reacted with the acid R 1 OH or a reactive derivative thereof in the presence of a water or acid scavenger.