FI68628B - FOERFARANDE FOER FRAMSTAELLNING AV NYA TERAPEUTISKT VERKSAMMA SOCKERDERIVAT - Google Patents

Description

1 68628

A process for the preparation of new therapeutically effective sugar derivatives

Divided by application 801 472 5

The invention relates to a process for the preparation of therapeutically effective compounds of formula I R 1 Λ, HO - /

? H

1 7 2 wherein R is -C 1 OH or -COR; R is a group of the following formula I 0-CH 2 ~ 20 7 R is hydroxy, lower alkoxy or OM, and M is cationic The phrase "lower" essentially prevents groups having up to 7 C atoms. Examples of lower alkoxy groups are methoxy, ethoxy, propoxy and butoxy. The cation at residue 7 R is mainly an alkali metal cation, especially Na +.

Compounds of formula I can be obtained according to the invention by reacting a compound of formula III f

/ OAc Vv / OR2 III

AcO j OAc 2 68628 1 2 wherein Ac is acetyl and R and R are as defined above are deacetylated, and the compound of formula I thus obtained, in which Rx is lower alkoxycarbonyl, is converted, if desired, into a compound in which R1 is carboxyl, or to a salt of the compound.

Deacetylation can be accomplished by treatment with bases such as alkali metal alcoholates, e.g., sodium methylate in methanol. This reaction can be performed at room temperature.

Modification of the alkoxycarbonyl group R 1 in formula I

The carboxyl group or carboxylate group in the compound according to the invention can be realized by saponification, e.g. with an alkali such as an alcoholic solution of alkali hydroxides. The salts thus obtained can be converted into the free acids by neutralization, e.g. with cation exchangers in H + -me-15.

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 for topical application. They can also be used to treat pimples and dandruff and to treat inflammatory and allergic skin diseases. In particular, the compounds are particularly well tolerated, e.g., when applied topically, they do not irritate the skin.

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

table 1

Compound Dose Reduction of wart diameter (%) A 0.1 -22 C 1.5 -38 35 3 68628 A: p- / ~ (E) -2- (5,6,7,8-tetrahydro-5.5, 8,8-Tetramethyl-2-naphthylhpropenyl-7-benzyl- [9-D-glucopyranoside C: Sodium pZ- (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetrame -ethyl 2-naphthyl) -propenyl-7-benzyl-β-D-gluco-5-pyranosideuronate

The compounds of formula I may have use 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. Suitable for internal application are, for example, substances in the form of tablets, capsules, granules, syrups, suspensions, solutions and suppositories. Substances for injection 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 route of administration as well as the needs of the patients.

The products of the method may be administered in about 0.01 to about 5 mg daily in one or more dosages. 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. For example, tablets or granules may contain a variety of binders, excipients, carriers, or diluents. Liquid preparations may be in the form of, for example, a sterile, water-miscible solution. 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 to change 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 application, the products of the method are suitably used as ointments, tinctures, creams, solutions, washing liquids, sprays, suspensions and the like. Ointments and creams as well as solutions are preferred. These preparations for topical use can be prepared by mixing the products of the process as active ingredients with non-toxic, neutral, solid or liquid carriers suitable for topical treatment and commonly used in such preparations.

Suitable solutions for topical use are from about 0.01 to about 0.3%, mainly from 0.02 to 0.1%, and from about 0.05 to about 5%, mainly from about 0.05 to about 1% ointments or creams.

It may be possible to add an antioxidant, e.g. tocopherol, N-methyl-1-tocopheramine as well as butylated hydroxyanisole or butylated hydroxytoluene.

The following examples are intended to further illustrate the invention.

30 Example 1

A solution of 3.9 g of p-7 (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl-7-benzyl -2,3,4,6-tetra-O-acetyl- [3-D-glucopyranoside in 150 ml of 0.1-norm. methanol solution of sodium methylate, 35 was kept for 30 minutes at room temperature, neutralized with an Amberlite IR-120 cation exchanger (Form H) and 5,68628 was evaporated to dryness. Recrystallization of the 2-propano-list gave p-Z1 (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl-7-benzyl- ( <3-D-glucopyranoside, melting point 156-157 °, = "23.8 ° (c = 1 in pyridine).

Preparation of starting material 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-naphthalene is reacted with acetyl chloride and AlCl 3 in nitrobenzene (5,6,7,8-tetrahydro-5,5,8 , 8-tetramethyl-10-naphthyl) methyl ketone. Reduction of the ketone with lithium aluminum hydride in ether gives 5,6,7,8-tetrahydro-o-5,5,8,8-pentamethyl-2-naphthalenemethanol, which is converted with phosphorus tribromide in ether-hexane in the presence of a small amount of pyridine in 2-bromoethyl. 5,6,7,8-15 to tetrahydro-5,5,8,8-tetramethyl-naphthalene. The bromoethyl compound is obtained with triphenylphosphine in xylene under heating for 12 hours with 1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -ethyl] -1-triphenylphosphonium bromide, of which Wittig reaction with 4-ethoxycarbonyl-benzaldehyde gives p- [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetraraethyl-2-naphthyl) -propenyl] -benzoic acid ethyl ester, melting point 90-91 °. The ester is reduced with LiAlH 2 in ether / tetrahydrofuran p - / (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-25 tetramethyl-2-naphthyl) -propenyl] -benzyl alcohol. -, melting point 123-124 ° (from methanol).

A mixture of 5 g of this alcohol, 6.3 g of 2,3,4,6-tetra-O-acetyl-cis-D-glucopyranosyl bromide and 1.5 g of mercury-II-cyanide is heated to reflux in 250 ml. toluene for 5 hours. The salts are filtered off and the solution is washed with water, dried and evaporated to dryness. Recrystallization from methanol gives p- (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl-7-benzyl-2,3,4,6- tetra-O-acetyl-β-D-glucopyranoside, 35 mp 134-135 ° (from methanol).

6,68628

Example 2

Methyl-p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] -benzyl-2,3, From 4-tri-O-acetyl-β-D-glucopyranoside 7-uronate according to Example 1, methyl (p- / TE) -2- (5,6,7,8-tetrahydro-5,5,8, 8-Tetramethyl-2-naphthyl) -propenyl] -benzyl-γ- '-D-glucopyranoside-7-uronate, m.p. 103-104 ° (iso-25 ° from propyl ether, dec.), Δ </ = -65.6 (c = 1 in chloroform) - Example 3 1.9 g of methyl (p- (1E)) - 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ) -propenyl-7-benzyl- (b-D-glucopyranoside-7-uronate) is heated for one hour by boiling in 190 ml of methanol with 10.8 ml of a 1N solution of 1N NaOH in methanol. propanol until cloudy and cooled, sodium p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] -benzyl li-PD-glucopyranoside uronate crystallized apart, melting point 240-242 ° (decomposed), // 77-4-44.1 ° (c = 1 in H2O).

A solution of 4.3 g of methyl (β-TE) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl benzyl p-D-glucopyranoside 7-uronate in 430 ml of methanol was heated at reflux for 24 h with 24.5 ml of 25 L-norm. A methanol solution of NaOH and then evaporated to dryness. The residue was dissolved in 100 ml of water, the solution was neutralized with Amberlite IR-120 (H +) resin and lyophilized. There was obtained p- [I (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] -7'-benzyl- [N-D-glucopyranoside- 30 uronic acids, melting point 174-175 ° (from methanol-benzene-2 5 decomposition), [.alpha.] D @ 20 = -28 DEG (c = 1 in pyridine).

Claims (2)

7 68628 A process for the preparation of therapeutically active compounds of the formula I R 1 O '' 'HO j OH 1 7 2 wherein R is -C 1 OH or -COR; R is a group of the following formula I - · - CH2 ~ 20. is hydroxy, lower alkoxy or OM, and M is a cation, characterized in that the compound of formula III I1 AcO \ OAc 1 '2 in which Ac represents acetyl and R and R are as defined above, deacetylated, and the compound of formula I thus obtained, in which R 1 is lower alkoxycarbonyl, is, if desired, converted into a compound in which R 1 is carboxyl, or a salt of such a compound.