DE2204989C3 - 2-Phenyl-3- (beta-dlmethylaminopropionyl) benzoturan and its pharmacologically acceptable acid addition salts and drugs containing these compounds - Google Patents

Description

and its phannacologically acceptable acid addition salts.

2. Medicament containing a compound according to Claim ! in addition to the usual inert pharmaceutical auxiliaries and / or carriers.

The invention relates to 2-phenyl-3 - (// - dimethylaminopropionyl-benzofuran the formula

CH ₃

CO - CH ₂ - CH ₂ - N

CH ₃ checks ußd with the well-known antidepressants imipramine (N - (/ - dimethylamine - propyl) - iminodw benzyl hydrochloride) and opipramol (4- [3- (5H-di- > benz [bj] -azepin-5-yl)) propyl] -1 -piperazine-ethanol- V

Dihydrochloride).

The problem with animal testing of antidepressants is the lack of an adequate one Animal model for the human disease of depression. Helped in pharmacology

ίο one therefore deals with the detection of specific effects, which are inherent in the preparations that are successful in therapy.

Reserpine antagonism

When examining the psychopharmacological effect, numerous authors consider the reserpine-antagonistic Effect on animals correlates with the

positive dynamic, mood-enhancing (antidepressant) effect on humans (W. P ö 1 d i η ger. Compendium of Psychopharmacotherapy, 1971; G. S t i 11 e, Drug Research, Vol. 14, p. 534 [1964]). Based on Ze tier and Moog,

Arch. Exp. Path. Pharmakol., Vol. 232, p. 442 (1958), The following method was used: After white mice had reserpine at a dose of 4.64 mg, kg i.v. p. is administered, the animals are attached to the climbing pole

- set and checked for catalepsy. Having catalepsy

one understands a muscular rigidity, which z. B. is triggered in animals by reserpine. Subsequently received the animals the test substance p. o., and there will be the abolition of catalepsy, i.e. the reserpm-antagonistic Effect, judged.

To the 2-phenyl-3 - (/ i-dimethylamino-propionyl) -benzofuran hydrochloride (hereinafter referred to as test substance) with the other substances To be able to, the relative effectiveness was determined according to the following formula:

and its pharmaceutically acceptable acid addition salts and medicaments containing these compounds.

It has been found that the substance according to the invention has valuable psychopharmacological properties owns. The animal experiments showed a spectrum of activity that is reflected in the typical test arrangements with that of the clinically used antidepressants. So far will be Benzofuran derivatives in therapy for the treatment of cardiovascular problems (see for example E. B e 1 e.g. F. W. S c h m a h 1 and H. H e η s e 1 in Arzneimittelforschung, Vol. 14, p. 1319 [1969]) or as uric acid-lowering preparations in the treatment of gout (see N. Zollner and W. G rö b η e r in Pharmaceutical Research, Vol. 21, p. 1500 [1971]) is used. Observation of an antidepressant effect with the substance according to the invention is therefore surprising, especially if one takes into account that hitherto predominantly compounds with tricyclically fused ring systems for the treatment of depressive states can be used in humans (see J. Schmutz in Pharmaceutica Acta Helvetiae, Vol. 48, p. 117 [1973]).

The 2 - phenyl - 3 - (jt - dimethylamine - propionyl) - benzofuran - hydrochloride (test substance) was pharmacologically tested in the following experiments: LD ₅₀ comparison substance ■ ED ₅₀ test substance LD ₅₀ test substance · ED ₅₀ comparison substance

where this = 1 for the test substance. If the value determined in this way for the reference substance is above I, it is more effective than the test substance, taking into account the toxicity, and is correspondingly weaker if the value is below 1. The ED ₅₀ is calculated according to Litchfie 1 d and V- 'i 1 c ο χ ο η (J. Pharmacol. Exptl. Therap., Vol. 96, p. 99 [1949]). The absolute values determined for the effective dose are given in Table 1.

Table 1

Absolute values

ED ₅₀ ,
mg / kg po

Test substance imipramine opipramol

170 165 100

Taking into account the LD ₅₀ given below, the relative effectiveness shown in Table 2 results.

Table!

Relative effectiveness

LD ₅₀ comparison substance - ED ₅₀ test substance LD ₅₀ test substance · ED ₅₀ comparison substance

Test substance?

Imipramine

Opipramol

0.6

0.6

evaluation

The values given in the tables show that, based on the values in mg / kg, the test substance is comparable to imipramine and opipramol. Taking into account the very low Toxicity leaves the test substance, as can be seen from Table 2, a more favorable therapeutic range than expect the mentioned preparations.

Tremoric antagonism

Most known antidepressants have an antichoiinergic component, but with their antidepressant effect not correlated (G. Zetler, Int. J. NeuropharmakoLBd. 7, p. 325 [1968]).

The antichoiinergic component causes a number of side effects in humans, such as: B. dry mouth, intestinal disorders, etc. In animal experiments, the antichoiinergic effect can be tested in the tremorin test. 1 hour after application of the test substance po, white mice receive 20 mg / kg 1,4-dipyrrolidino-2-butyne ip. The animals are observed for tremor (central anticholinergic) and salivation (peripheral anticholinergic). The ED ₅₀ is calculated according to Litchfield and W i 1 c ο χ ο η. The results are shown in Tables 3 and 4.

40

Table 3

tremor

Prülfubslanz imipramine

ED ₅₀ in> 215

mg / kg p. O.

Table 4
Salivation

185

Opipramol

147

Examination Subscription Imipramine

Opipramol

ED ₅₀ Jn> 215

mg / kg p. O.

29

Acute oral toxicity

The test substance, imipramine and opipramol were tested on 1Q mice per dose. The LD ₅₀ was calculated 7 days after the application according to I.'teilfield and Wilcoxon. The results are shown in Table 5.

55

6c

evaluation

In contrast to imipramine and opipramol, the test substance does not show any anticholinergic properties and can therefore be expected to have fewer side effects than the preparations mentioned.

Table 5

LD ₅₀ in
mg / kg po

Imipramine test substance

1470

840

Opipramol

565

Of the substances tested, the test substance thus has the lowest toxicity.

For the treatment of depression in human medicine, preparations are used that both z> Mtral-stimulating as well as sedating properties own. The substances according to the invention show these properties.

Particularly noteworthy is the very low toxicity. This allows a great therapeutic breadth expect. In an experiment on patients with predominantly endogenous depression it was shown that 2-phenyl-3 - (/ * - dimethylatnino-propiony l) -benzofuran hydrochloride has a pronounced effect on agitated feelings of guilt. The effect picture can be subdivided:

1. Strong agitation damping parallel to drive normalization.

2. Mild sedation.

3. Significant brightening of mood.

No serious side effects were observed. The dosages were depending on the severity of depression between 25 and 200 mg per day p. O.

The compound according to the invention and its pharmaceutically applicable salts can be used as medicinal agents Find use, for example in the form of pharmaceutical preparations, which these compounds in a mixture with an inorganic compound customary for peroral or parenteral administration or organic inert pharmaceutical carrier material, such as water, gelatin, lactose, starch, Magnesium stearate, talc, vegetable oils, gum, polyalkylene glycol, petroleum jelly and the like. the pharmaceutical preparations can be in solid form (e.g. as tablets, coated tablets, suppositories, capsules) or in liquid form (e.g. as solutions, suspensions or emulsions). If applicable, are they are sterilized and / or contain additives such as preservatives, stabilizers, wetting or emulsifying agents

lubricants, salts to change osmotic pressure or buffers.

The new compound according to the invention is prepared by adding the 2-phenyl-3-acetylbenzofuran of the formula _r

CO - CH ₃

in the usual Wsise with formaldehyde and dimethylamine in a suitable solvent ¹ , reacted at elevated temperature . Suitable solvents are, for example, aliphatic alcohols with 1 to 5 carbon atoms, preferably ethyl or isopropyl alcohol. The amine component is expediently added in the form of a salt, for example the hydrochloride. You can also add additional acid, such as hydrogen chloride, which can be dissolved in the aliphatic alcohol used. The formaldehyde can take effect in the form of a concentrated aqueous solution, as paraformaldehyde or trioxane.

To purify the process product, the acid addition salts can be in a solvent such as lower alcohols, dissolve and precipitate again with ether. It is also possible to use the acid addition salt to convert into the free base, this with a suitable solvent, for. B. extract ether, and stir it back into the desired salt.

The 2-phenyl-3-acetylbenzofuran to be used as the starting material is described in the literature. The same production is by JN Chatterjep in the Journal of the Indian Chemical Society, Vol.? ' (1957), pp. 347 to 356, described and takes place dun ... Reaction of 2-phenylbenzcfuran with acetyl chloride in the presence of tin tetrachloride. You can also get to 2-phenyl-3-acetylbenzofuran if you 2-phenylbenzofuran with acetic anhydride or an acetyl halide, especially acetyl chloride.

in a suitable solvent such as ethyl acetate reacts in the presence of catalytic amounts of percloic acid.

The production of the acid addition salts concerned happens in the usual way. One can, for example, the ethereal solution of the base with the alcoholic Add a solution of an appropriate acid, such as hydrochloric acid, whereby the acid addition salt, in this case the hydrochloride separates out in crystalline form. For the production of non-toxic acid addition salts, for example also acetic acid, propionic acid, diethyl acetic acid. Malonic acid, succinic acid, fumaric acid, maleic acid, Lactic acid, tartaric acid, malic acid, lemon seeds, Sulfuric acid, hydrobromic acid or orthophosphoric acid.

example

2-phenyl-3 - (// - dimethylamino-propionyl) -benzofuran

20 g of 2-phenyl-3-acetylbenzofuran were dissolved in 60 ml of isopropanol, and 3.6 g of paraformaldehyde and 9.7 g of dimethylamine hydrochloride were added to this solution. It was refluxed for 12 hours. then the isopropanol is distilled off in vacuo and 100 ml of water and 20 ml of 10% hydrochloric acid are added to the residue. To remove undissolved parts, extraction was carried out with ether and the ether extract was separated off. The aqueous acidic solution of the hydrochloride was made alkaline with 5% sodium hydroxide solution and the deposited oily base was taken up in ether. After drying the ethereal solution over sodium sulphate, a solution of hydrogen chloride in ethanol was added in excess, whereupon the hydrochloride of 2-phenyl-3- (β- dimethylamino-propionyl) -benzofuran separated out in crystalline form. F. = 148 to 150 C. The yield was 14.5 g. Any necessary cleaning of the salt can be done by dissolving it in ethanol, adding 3 times the volume of dry ether and, after good cooling, suctioning off.

To prepare the maleic acid salt, equimolar amounts of the base and maleic acid were dissolved separately in ether and the solutions were combined. The maleic acid salt separated out in white crystals. F. = 127 to 128 ⁰ C (from ethanol).

Claims (1)

Patent claims: J. 2 - Phenyl - 3 - (f> - dimethylaminopropionyl) - benzofuran of the formula CH ₃ CO - CH ₂ - CH ₂ - N CH ₃