DE2238054A1 - NEW THYMOL DERIVATIVES AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

PatentanwHfe - ~ '

757 Fiirtcn-Baden-Belg
Or. W ₁ -D ₁ HUNKrL-DIpL-UIg-RM KERN.

Γ. ·. LuÜiar FEILER
8 Munich SU, Eduard-Solunid-fltr. 8th

I AUG 2. 1972

Gödecke AG 1 Berlin IO 'Salzufer 16

New thymol derivatives and processes for their preparation

The invention relates to new thymol derivatives with strong sympathicolytic Effect and low Toxizltat and a method too their manufacture.

From the group of basic substituted thymol ethers, only one product, [ß- (4-acetoxythymoxy) -ethyl] -dimethylamine (thymoxamine.), Has been able to gain importance as a therapeutic agent to a limited extent for peripheral circulatory disorders. There has been no lack of attempts, the pharmaceutical disadvantages of this substance as poorly absorbed, short duration of action, "relative toxicity and instability to resolve (see, for example Arzneiniittelforschung 17, 305 - ^ 09 (1967) _s but the only ones obtained by Molekülrnanipulationen effective derivatives could Due to their haloalkylamine (nitrogen mustard) function, they cannot be used in therapy.

409808/1162 "

BATH ORIGINAL

In an effort to find new, peripherally diatetic thymoxaii.in-abköiui.-linge Developing with improved properties was surprising found that compounds of general formula I

Il
RCO

0- (CH ₂ ) ₂ -.N (CH ₃ ) ₂

in which R is an alkyl group of at least 4 to 11 carbon atoms or is an alkoxy group R'-O of at least J5-1O C-atoms, and their pharmaceutically acceptable salts have these properties. ■

Examples of typical compounds of the formula I are: [ß- (4-Isopropoxycarboxy thymoxy) -äthyIj -dimethylamine, [ß- (4-Ca'proriyloxythyrr.oxy) -äthylj-dimethylamine, [ß- (4-Isovaleryloxythymoxy) -ethyl] -dimethylar! iin, [ß - ^ - CapryloxythymoxyJ-ethylj-dimethylamine, [ß- (4-caprinyloxythymoxy) ethyl] dimethylamine, [ß- (4-laurinyloxythymoxy ) -äthylJ-dimethylamine, [ß- (^ -Isocaprinyloxythymoxy) ethyl] dimethylamine and the salts of these compounds.

The compounds of the formula I can be prepared by processes known per se are produced - but because of the great steric hindrance special techniques must be used - for example by connecting the connection II

II

with the anhydride of the corresponding alkanecarboxylic acid in pyridine • or quinoline for one to several hours at 100 - 170 ° C, preferably

409808/1162

BATH ORIGINAL

as 130 - 150 ° C or by converting the compound II in an ether, preferably in tetrahydrofuran and in the presence of dimethylformamide or dimethyl sulfoxide using sodium hydride or alkali metal alcoholate in -is alkali metal salt and this in suspension with the chloride of the corresponding alkane or alkoxy-carboxylic acid, 2-6 hours at 4o - reacted '80 ⁰ C.

In contrast to thymoxamine, the substances according to the invention are distinguished by the fact that they are already used in low doses. tion, blocking typical ^ -receptors even with peroral use Have an effect, as could be proven with the help of adrenaline reversal experiments. With that are the prerequisites for the desired, therapeutically extremely useful peripheral dilating effect when administered orally.

The compound II can by gentle hydrolysis of the technical thymoxamine or by diazotization and boiling of the, from the Thymyl-ß-dimethylaminoethyl ether by hydrogenation and reduction easily accessible 4-amino derivatives are produced.

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 in admixture with suitable and customary carriers or excipients in oral, subcutaneous, intravenous and other ways. Tablets, capsules, coated tablets, suspensions and suppositories are suitable as pharmaceutical preparations. The single dose the derivatives - depending on the indication, are in the range of 2-50 mg, preferably around 10 mg.

Examples

(All products gave correct elemental analyzes)

1. [β- (4-Isova.leryloxythymoxy) -r.thyl -dii.rethylamine · ■ HCl

31 S II are aufgenoirancn in 60 ml of pyridine dried over KOH, treated with 54.2 g isovaleric anhydride and heated for 4 hours at ⁰ C 1- ¹ IO ". . ■

4 0.980871 16'2

BATH ORIGINAL

The excess pyridine and anhydride are then distilled off in vacuo, the residue is taken up in ether, filtered and HCl gas is passed in. The crude hydrochloride is recrystallized from ethyl acetate-dioxane. Yield 43.0 g (82.6 # of th.)
Mp I82 -. ⁰

2. [β- (4-Capronyloxythymoxy) ethyl] dimethylamine »HCl

45 g II .werden with 85.6 g caproic anhydride and 80 g of pyridine for 5 hours at ⁰ C IJO heated. Proceed as described under 1).

Yield 37 g (6q $ d Th.). Mp. 177 - 178 ⁰ C £ ius isopropanol).

3 · [ß- (4-Capryloxythymoxy) -äthylj-d in; ethylamine · HCl

A solution of 17 g of II in 90 ml of THP is added dropwise to a suspension of 4 g of NaH (50 # ig) in 90 ml of dry THP and 30 ml of DMF ml of THF are added and the mixture is heated to 65 ^° C. for 3 hours. The solvent is then distilled off in vacuo and the residue is partitioned between water and ether. The hydrochloride is precipitated from the dried ether phase using HCl gas. It is unicrystallized from isopropanol.
Yield 11.7 g (47 $ of theory) of: mp 163-164 ° C.

4. Jβ- (4-caprinyloxythymoxy) -ethy3 j -djmethylamine · 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 (.. 6k% of theory) of melting point 157 -. 158 ⁰ C (from n-butanol).

409808/1 162

A suspension of 6.98 g of NaH (5%) in 100 ecm of dry tetrahydrofuran is placed in a vessel and a solution of 3.4 g of II in 100 ecm of THF is added dropwise with cooling. The mixture is stirred for 30 minutes at 60 ° -70 ° and the sodium solution is cooled. Is then added dropwise at 30 - 40 C, a solution of 35 g ChlOrameisensaureisopropylester in some THP and heated to reflux for 2 hours. It is evaporated in vacuo and the residue is taken up in dilute hydrochloric acid. It is distilled to dryness in vacuo and the residue is taken up with 200 ecm of boiling isopropanol, cooled and filtered. The filtrate is concentrated in vacuo and the oily residue is crystallized using THF. Yield 20.8 g (from toluene) with a melting point of 180-118 ° C.

Claims (1)

PATE N TA NS P RÜ C H E J compounds of the general formula wherein R is an alkyl group of at least 4-11 carbon atoms or is an alkoxy group R'O- of at least 3 - 10 carbon atoms, and their pharmaceutically acceptable salts. 40 9 808/1162 BATH ORIGINAL 2. ß- (4-Capronyloxythymoxy) -ethyl-dimethylamine 3. ß- (4-Isovaleryloxythymoxy) -ethyl-dimethylamine 4. ß- (4-Capryloxythymoxy) -äthyl -din; ethylarrdn 5., ß- (4-CaprinyloxythyniOxy) ethyl diiriethylamine 6. ß- (4-Isopropoxycarboxythymoxy) -ethyl-dimethylamine 7. Process for the preparation of compounds of. general formula I. characterized in that ■ that the compound II II with the anhydride of the corresponding alkanecarboxylic acid in pyridine or quinoline for one to several hours at 100-170 ° G preferably heated to 1 ^ 0 - 150 ° C or by the Compound II in an ether, preferably in tetrahydrofuran and in the presence of dimethy if ormarrdd or dirnethyl sulfoxide converted into their alkali metal salt by means of sodium hydride or Alkalirr.etallalkoholat and this in suspension with the chloride of the corresponding alkanoic or alkoxycarboxylic acid Allowed to react for 2-6 hours at 40-80 ° C. 4098 08 / 116.2 BATH ORIGINAL