DE2238054B2 - 0-Dimethyla minoäthyl-acyloxy- (or -alkoxycarbonyloxy-) thymoles and process for their preparation - Google Patents

Description

(ID

O- (CH ₂ ) ₂ -N (CH ₃ ) ₂

35

40

CH,

with the anhydride of the corresponding alkanecarboxylic acid in pyridine or quinoline for one to several hours at 100 to 17O ⁰ C, or by heating the compound II in tetrahydrofuran, optionally in the presence of dimethylformamide or dimethyl sulfoxide, with sodium hydride or alkali metal alcoholate in it alkali metal salt and stirred over this heating in suspension with the appropriate alkanoic acid chloride or alkoxycarbonyl chloride to 2 hours and at 40 to 80 C ^r.

From the group of the basic substituted thymol ethers Until now only one product could be found, the [/ M4-acetoxythymoxy) -ethyl] -dimethylamine (WHO non-proprietary name »Moxisylyt«) important as a therapeutic agent to a limited extent in peripheral circulatory disorders to win. There has been no lack of attempts to investigate the pharmaceutical disadvantages of this substance, such as low resorbability, short duration of action, rela

65 tive toxicity and instability (see Vol. Diel Pharmaceutical Research 17,305 to 309 [1967]), but the only effective derivatives obtained through molecular manipulation could not be included due to their haloalkylamine (nitrogen mustard) function find the therapy.

In an effort to dilate new peripherally Moxisylyte derivatives with improved properties to develop, it was surprisingly found that compounds of general formula I

15th

in which R is an alkyl group with 4 to 11 carbon atoms or an alkoxy group R 'O having 3 to 10 carbon atoms and their pharmaceutically acceptable salts.

2. [/ H4-isovaleryloxythymoxy) ethyl] dimethylamine.

3. [fH4-Ca; pronyloxythymoxy) ethyl] dimethylamine.

4. [/ i- (4-Capryloxythymoxy) ethyl] dimethylamine.

5. [^^ - Caprinyloxythymoxyi-ethylj-dimethylamine.

6. [/ i- (4-Isopropoxycarbonyloxythymoxy) ethyl] dimethylamine.

7. Process for the preparation of compounds of the general formula I in which R is the above Has meaning, characterized in that the compound II is known per se

O- (CH ₂ J ₂ -N (CH ₃ ) J

in which R is an alkyl group with 4 to 11 carbon atoms or an alkoxy group R '- O with 3 to IOC atoms is, and their pharmaceutically acceptable salts have these properties.

Examples of typical compounds of formula 1 include:

[/ M4-isopropoxycarboxythymoxy) ethyl] -

dimethylamine,
[/ M4-capronyloxythymoxy) ethyl] -

dimethylamine,
[, Ή 4-isovaleryloxythymoxyJ-ethyl] -

dimethylamine,
[itf- (4-CapryIoxythymoxy) ethyl] -

dimethylamine,
[iM4-Capiinyloxythymoxy) ethyl] -

dimethylamine,
[/ H4-Laurinyloxythymoxy) ethyl] -

dimethylamine,
[/ H4-isocaprinyloxythymoxy) ethyl] -

dimeihylamine
and the salts of these compounds.

The compounds of the formula I can be prepared according to a.i. processes which are known - where however, because of the great steric hindrance, special techniques must be used - for example, by connecting the connection II

CH,

HO

(H)

0- (CH ₂ J ₂ -N (CH ₃ J ₂

CH

CH,

CH ₃

with the anhydride of the corresponding alkanecarboxylic acid in pyridine or quinoline for one to several hours at 100 to 170 ° C, preferably 130 to 150 ° C, heated or by the compound II in tetrahydrofuran, optionally in the presence of dimethylformamide or dimethyl sulfoxide, with sodium hydride or alkali metal alcoholate in its alkali metal salt transferred and this in suspension with the corresponding alkanecarboxylic acid chloride or alkoxy

carbonyl chloride at 40 to SO C for 2 to 6 hours warmed up.

The substances according to the invention are characterized - as opposed aim moxisylyte by the fact. that even in low doses they have a typical u-receptor blocking effect even when used orally, as has been demonstrated with the help of adrenaline reversal experiments. In this way, the requirements for the desired, therapeutically extremely useful peripheral dilating effect are met when administered orally.

The compound 11 can by gentle hydrolysis technical moxisylyts or by diazotization and boiling of the thymyl - ^ - dimethylaminoethyl ether easily accessible 4-amino derivatives can be produced by nitrosation and reduction.

Because of their favorable therapeutic quotient the new thymol derivatives according to the invention can be used safely as such or in the form of pharmaceutical preparations mixed with suitable and customary carriers or auxiliaries in orally, subcutaneously, intravenously and otherwise. As pharmaceutical preparations tablets, capsules, coated tablets, suspensions and suppositories are possible. The single dose of the Derivatives are in the range from 2 to 50 mg, preferably around IG mg, depending on the indication.

Yield 37 g (60% of theory) with a melting point of 177 up to 178 C (from isopropanol).

3. [, H4-capryloxylbvmoxy) ethyl] dimethylamine · HCl

Examples (all products gave correct l'.ementar analyzes);

1. [, -H4-isovaleryloxythymoxy) ethyl] dimethylamine · HCl

31 g of II are taken up in 60 ml of pyridine dried over KOH, with 54.2 g of isovaleric anhydride added and heated to 140 ° C. for 4 hours.

The excess pyridine and anhydride are then distilled off in vacuo and the The residue is dissolved in ether, filtered and HCl gas is passed in. The crude hydrochloride is made from ethyl acetate-dioxane recrystallized.

Yield 43.0 g (82.6% of theory).

M.p. 182-183 "C.

2. [p '- (4-Capronyloxylhymoxy) ethyl] -

dimethylamine · HCl

^{45 g of II are heated to 130 °} C. for 5 hours with 85.6 g of caproic anhydride and 80 g of pyridine. Proceed as described under 1.

To a suspension of 4 g of NaH, 50 ° / oig) in 90 ml of dry THF and 30 ml of DMF, a solution of 17 g of II in 90 ml of THF is added dropwise After completion of the evolution of hydrogen was adds 13.1 g Caprylsäurechlorid dissolved> n 30 ml THF, are added and heated for 3 hours at 65 ^C C. Then the solvent is abdestüliert in vacuo and the residue partitioned between water and ether distributed. The hydrochloride is precipitated from the dried ether phase with HCl gas. It is recrystallized from isopropanol.

Yield 11.7 5 (47% of theory) from melting point 163 to 164 ^c C.

4. [fH4-Capriny) oxythymoxy) ethyl] -

dimethylamine · HCl

22.5 g of II are converted into the sodium salt analogously to 3 and condensed with 18.2 g of capric acid chloride in THF DMSO (10: 1). Heating time: 1.5 hours, temperature 70 C. It is worked up as described.
Yield 27.4 g (64% of theory) with a melting point of 157

up to 158 C (from n-butanol).

5. [ ₍ - {- (4-Isopropoxycarbonyloxythymoxy) ethyl] - »° dimethylamine ■ HCl

A suspension of 6.98 g NaH (50%) in 100 ecm dry tetrahydrofuran is presented and dropwise with a solution of 34.4 g of Il in

100 ecm THF were added with cooling. It is stirred for 30 minutes at 60 to 70 ° C and the solution the sodium compound cooled. A solution of 35 g is then added dropwise at 30.degree. To 40.degree Isopropyl chloroformate in a little THF too

40 and refluxed for 2 hours. It is evaporated in vacuo and the residue in dilute Hydrochloric acid added. It is distilled to dryness in vacuo and the residue is taken with it 200 ecm boiling isopropanol, cools and 45 filtered. The filtrate is concentrated in vacuo and the oily residue with THF for crystallization

brought.
Yield 20.8 g (from toluene) with a melting point of 180 to

181 C.

Claims (1)

Patent claims: 1. O-dimethylaminoethyl-acyloxy- or -alkoxycarbonyloxythymole of the general formula I. Il R — C — O (CH ₂ J ₂ -N (CH ₃ ), (D