DE2540282A1 - Salts of embelin with primary amines - used as analgesics, tranquillisers, antiinflammatories, anthelmintics, hypotensives and antipyretics - Google Patents

Abstract

Pharmaceutical prepns. contain salts of embelin with primary amines. The salts have morphine-like analgesic activity of longer duration than that of embelin. They also have tranquillising, antiinflammatory, antipyretic, hypotensive and anthelmintic activity. Embelin can be obtd. by extracting the berries of Embelia ribes with n-hexane. The amine can be MeNH2, EtNH2; n-BuNH2, t-BuNH2, n-hexylamine, allylamine or pref. n-BuNH2. The salts can be prepd. by reacting embelin with the amine in MeOH at 0-5 degrees C. In an example, the 2,5-diisobutylamine salt was prepd. by reacting embelin with isobutylamine.

Description

Condensation product of Embelin with a primary amine

and process for its preparation. The present invention relates to a condensation product of Embelin with a primary amine and method for its.

Manufacturing. Embelin is the active principle of Embelia Ribes.

The present invention is based on the object pharmaceutical create valuable active compounds derived from Embelin. These Compounds should have few side effects and be easy to produce.

Surprisingly, it has been found that Embelin as a raw material for the manufacture of analgesics can be used; as far as known to the applicant is, such a use of Embelin is not described in the literature.

It was found that (i) Embelin had an analgesic effect of short duration Shows duration and slow onset; (ii) that when Embelin is with a primary amine such as allylamine, n-hexylamine, n-butylamine, ethylamine, methylamine or similar amines is condensed, the resulting products have a noticeable analgesic activity show with longer duration and faster onset; (iii) that if Embelin treated with isobutylamine at low temperature (optimally at 0 to 5 OC) the product has very remarkable analgesic activity. Additionally shows the compound pronounced calming, anti-inflammatory, antipyretic and worming properties.

The invention accordingly relates to condensation products from Embelin with primary amines. The primary amines are preferably aliphatic amines, and particularly preferably those having 1 to 6 carbon atoms. The aliphatic parts the amines can be saturated or unsaturated, straight-chain or branched. Particularly Isobutyl amine is preferred.

The invention also relates to a method for production of a condensation product of Embelin with a primary amine that thereby is characterized in that a primary amine with Embelin at low temperature of preferably about 0 to 5 OC in a solvent. As a solvent methanol is preferred. Appropriately, one works in such a way that one has a cooled one Solution of the amine slowly poured into a cooled suspension of Embelin, whereby the condensation product separates out in the form of crystals. This can then filtered off and, if desired, from a suitable solvent, e.g.

recrystallized from an alcohol such as ethanol. In this way one obtains connections with analgesic, based, anti-inflammatory, worming and antipyretic properties. The compounds according to the invention have a long-lasting effect, and they are great even in small doses effective.

The Embelin can be made as follows, for example: The dried Embelia Hibes fruits are powdered and extracted with n-hexane. Raw Embelin separates from the extract when it is concentrated and cooled, which when crystallizing from ethanol results in glittering, orange-colored crystals, M.p. 142 to 143 ° C. For the preparation of the compounds according to the invention, it is expedient pure Embelin used.

Example 1 5.0 g of Embelin in 80 ml of methanol are cooled to 0.5 ° C.

Isobutylamine (4.5 ml, 2.5 mol) in 25 ml of methanol is also added chilled the same temperature. The amine solution is then slowly poured into the Poured Embelin suspension, keeping the temperature between 0 and 5 ° C. The precipitate formed is filtered off and the solid is washed with cold methanol washed. The product is crystallized from methanol, turning purple in color 2: 5-diisobutylamine-embeline salt (1) obtained, mp 128 to 130 oC.

Example 2 The procedure is as described in Example 1, with the exception that isobutylamine is replaced by a 33% strength nonomethylamine solution. The received Product shows less analgesic activity, but at the same time it is pronounced hypotonic activity lasting 5 to 8 hours in anesthetized dogs.

Pharmacological Activities The compounds of Example 1 show considerable analgesic activity similar to that of narcotic analgesics like morphine. The analgesic effect was determined according to different animal species Experimental procedures observed or determined. In cats and dogs, doses are used from 2.5 to 5 mg / kg i.v. or 5 to 10 mg / kg i.p. the reaction to a painful one Stimulation in 5 to 10 minutes and 10 to 15 minutes on the appropriate Routes of administration eliminated. The duration of the effect is 3 to 4 hours at Dogs and 6 to 10 hours in cats.

The analgesic effect of (1) is not antagonized by nalorphine, as determined by the hot plate method in mice. In mice and rats the threshold compared to the painful stimulation is even tenfold increases, and the effects last for 3 to 4 hours. The analgesic effect was after oral administration in mice. In rabbits a recognizable one begins analgesic effect in 5 to 7 minutes at a dose of 10 mg / kg i.p.

The aalgesic effect is accompanied by sedative effects, without that other senses like feeling, hearing or sight or general Consciousness are obviously affected. In dogs one observes after the Oral administration did not have any side effects such as nausea, vomiting or anorexia like morphine.

Morphine shows an analgesic effect in test animals in 5 to 10 mg / kg i.p. or with S.C. administrations. The effect lasts for 3 hours. In dogs, no analgesic occurs at an oral dose of 10 mg / kg of itorphium Effect on, but anorexia is present.

In cats, dilatation of the pupils occurs at the onset of analgesic Effect on (as also observed with morphine). It remains for the duration the analgesic effect obtained. Si cats occurs in the agent according to the invention no horphine addiction syndrome. The sedative effects can also be used Nalorphine can be antagonized Intravenous administration of the compound to young Chick gives analgesia and a crouching position. Let these results concluded that the compound falls under the group of analgesics of the narcotic Type falls.

-In dogs and cats, the provoked anger or frenzy is eliminated, and the animals become very docile. This shows one possible use of this connection as a potential tranquilizer, similar to that of the well-known major tranquilizers like reserpine and chlorpromazine.

The compound also has considerable anti-inflammatory properties Activity comparable in level to that of dexamethasone. To some extent hypothermic and antipyretic effects are also observed in rats. (These effects are also described for morphine.) In anesthetized dogs a dose of 10 mg / kg IV gives a small drop in blood pressure and a Stimulation of respiration. (Morphine is reported to be respiratory suppressed.) The isolated bowel has a slowly developing contraction as obtained with morphine. Studies of worming activity of Embelin and its derivatives showed that the derivatives are more effective than Embelin and that they are comparable to known worming agents.

The therapeutic ratio of the compound is favorable.

The ED50 in mice is 2.5 to 5 mg / kg i.p. (determined according to different Method) and the LD50 is 50 mg / kg i.p. (24 hour mortality). It is with that It is expected that the effective dose (ED50) of this compound in humans will be low will be since it is reported that the trial pain is immensely brief and that at the same time there is a feeling of security. The pathological pain can prolonged and associated with anxiety and on analgesic drugs address. K. Beecher, J. Pharmacol.

(1950), 100, 141.) It is therefore to be expected that the therapeutic Ratio in humans will be even higher.

However, the effective dose of this compound in humans will be in view to the known fact that the human Nervous system around is many times more sensitive to drugs than that of animals, yet be lower because the doses, expressed in mg / 70 kg human, are often the doses in mg / kg animal are equivalent; (Physiological Pharmacology, edited by Water S. Root Frederick, G. Hoffman, Volume I, page 321). Morphine is tested on animals effective at doses of 5 to 10 mg / kg, whereas it is clinically effective at a dose of 0.5 mg / kg is effective.

The compounds according to the invention are thus therapeutic for humans valuable and they can because of their powerful analgesic and sedative activities and also for their anti-inflammatory, antipyretic and worming effects Properties are used. The compounds are of some of the side effects, observed with morphine, and their duration of action is longer.

It is therefore likely that they use morphine in therapeutic Use can replace. As the main tranquilizer, the compounds are used in schizophrenia and be useful in patients with psychotic illnesses. If found Being that the compounds are addictive free, they can be effective to help To rid individuals of addiction in terms of both social and psychological Aspects of the individual and society is of great importance.

In particular that obtained by reacting Embelin with isobutylamine 2,5-bis-isobutylamine derivative from Embelin shows remarkable analgesic, calming, hypotensive, anti-inflammatory, worming and antipyretic properties. The analgesic effect is similar to that of morphine with certain exceptions. the Duration of the analgesic effect is much longer compared to morphine, what is desirable in therapeutics. The calming effect is similar to those of the main tranquilizers such as reserpine and chlorpromazine with longer duration of action, and the connection may be specific in schizophrenics because of this activity and insane patients. The connection has a high therapeutic relationship with fewer side effects and they can be addictive free (this is currently being checked). It is in animals at doses of 5 to 10 mg / kg i.p. and 2.5 to 5 mg / kg intravenously effective (morphine is at equivalent amounts also effective).

The compound may also have some new pharmacological activity show in clinical use, sometimes not found in animal studies will.

Patent claims:

Claims (8)

Embelinntt a Primary Amine Condensation Product and Process for its manufacture PATENT CLAIMS: y) i½ condensation product of Embelin with a primary amine. 2. Condensation product according to claim 1, d a d u r c h g e k e n n note that the primary amine is an aliphatic amine. 3. condensation product according to any one of claims 1 to 2, characterized characterized in that the primary amine is an aliphatic amine having 1-6 carbon atoms is. - - 4. condensation product according to one of claims 1 to 3, characterized in that that the primary amine is isobutylamine. 5. Process for the preparation of a condensation product according to a of claims 1 to 4, characterized in that a primary amine with Embelin at a low temperature of preferably about 0 to 5 OC in a solvent implements. 6. The method according to claim 5, characterized in that the solvent Nethanol is used. - - 7. The method according to any one of the claims 5 or 6, characterized in that a cooled solution of the amine is slowly poured into a cooled suspension of Embelin and filtered off the precipitate formed. 8. Medicinal product consisting of one or more compounds of the Claims 1 to 7 and customary auxiliaries and / or carriers.