EP0258264A1

EP0258264A1 - N,n'-(bisfurfuryl)-2-furylmethanediamine, its production and use

Info

Publication number: EP0258264A1
Application number: EP19870900067
Authority: EP
Inventors: Gustav Sotek
Original assignee: Individual
Current assignee: Individual
Priority date: 1985-12-30
Filing date: 1986-12-30
Publication date: 1988-03-09
Also published as: DE3546319A1; WO1987004160A1; JPS63502504A; DE3546319C2

Abstract

Des N,N'(bisfurfuryle)-2-furfurylméthanediamines novatrices ont la formule générale (I), dans laquelle le(s) résidu(s) de furfural peuvent le cas échéant être substitués une ou plusieurs fois. L'invention concerne également leurs sels, leur production par la conversion d'un hydrofuramide avec un hydrure de bore et l'isolation du produit de la réduction et l'utilisation de ces composés comme médicaments.Novel N, N '(bisfurfuryle) -2-furfurylmethanediamines have the general formula (I), in which the furfural residue (s) can optionally be substituted one or more times. The invention also relates to their salts, their production by the conversion of a hydrofuramide with a boron hydride and the isolation of the reduction product and the use of these compounds as medicaments.

Description

N, N '- (bisfurfuryl) -2-furylmethane diamine, its preparation and its use.

description

Technical field

The invention relates to N, N '- (bisfurfuryl) -2-furfurylmethane diamines and processes for their preparation and their use.

State of the art

It is known, for example from German patent application P 19 35 259, that N, N'-di-2-furfuryl-2-furfurylindendiaine (hereinafter referred to as hydrofuramide) increases the cholesterol esterase values and also has beneficial effects which has blood viscosity. However, this known compound is not suitable for pharmaceutical use in that it easily disintegrates and is not stable under normal storage conditions.

Presentation of the invention

It is therefore an object of the invention to provide a connection with similarly favorable properties which is stable.

The task is accomplished by N, N '(bisfurfuryl) -2-furfuryl) -2- furfurylmetttandiamine of the general formula:

solved, wherein the (the) furfural residue (s) may or may be substituted one or more times, and their salts.

N, N '- (bisfurfuryl) -2-furfurylmethanediamine has a melting point of 107 to 109 ° C, a molecular weight of 272 and an elemental analysis of 54.2% C, 5.26% H, 6.03% N and 34.45% 0.

The process according to the invention for the preparation of the new compounds is characterized by the following steps: reacting a hydrofuramide optionally substituted on the furfuran ring (s) with a borohydride and isolating the reduction product:

A hydrofuramide is preferably reacted in the liquid phase, optionally in a polar, hydrophilic solvent, with an alkali metal or alkaline earth metal hydride salt and the hydrogenated reaction product is obtained by methods known per se, such as extraction, fractional distillation, chromatography or. similar, separated. The hydrogenated reaction product can particularly preferably be separated off by separating the liquid obtained by reacting the hydrofuramide with a borohydride in a liquid phase into an organic and an inorganic phase, and then fractionally distilling the organic phase.

It is also advantageous that hydrofuramide is dissolved in tetrahydrofuran and the solution is slowly added to the solution with cooling and stirring with an alkali metal borohydride solution; After the reaction has ended, the reaction mixture is neutralized with acid, preferably an aqueous solution of an acid, and the organic phase which forms is separated off and distilled.

The hydrofuramide can be obtained by reacting ammonia with furfural. The conversion of ammonia and furfural preferably takes place in the liquid phase.

Furfural can be introduced into an ethanolic ammonia solution while cooling and the separating solid, the hydrofuramide, can be obtained by methods known per se, such as filtration, centrifugation, decanting or the like.

Salts of N, N '(bisfurfuryl) -2-furfurylmethanediamine can be obtained by: reacting the N, N' (bisfurfuryl) -2-furfurylmethanediamine with stoichiometric amount of acid.

Thus, in a preferred process variant, N, N'- (bisfurfuryl) -2-furfurylmethanediamine can be dissolved in an organic solvent, reacted with a stoichiometric amount of acid solution, and the salt which separates out can be separated off. A preferred use of the compounds according to the invention is as a medicament.

N, N '(bisfurfuryl) -2-furfurylmethanediamines are also to be understood as meaning salts of this class of compounds and derivatives thereof, as can be prepared, for example, by using substituted furfurals.

The new compounds are characterized by a surprising physiological activity. In particular, the N, N '(bisfurfuryl) -2-furfurylmethanediamine reduces the viscosity of blood.

Furthermore, the new active ingredient brings about an increase in the cholesterol esterase values which, for example, decrease from 78 units to 34 to 40 units in the case of degeneration diseases. At the same time, an increase in the albumin content in the serum is found when the active ingredient according to the invention is used.

The new active ingredients are suitable for oral administration as well as for parenteral use, infusion. As an indicator. Areas of application are recommended, inter alia, for all diseases which are associated with an increase in the viscosity of the blood, such as angina pectoris, cardiac arrhythmia, circulatory disorders, Parkinsonism. They are also suitable for the treatment of all kinds of liver diseases, including the consequences of alcoholism.

The compound is also stable at room temperature so that there are no storage problems.

The production of the new active ingredients will now be described below. example 1

N, N '- (bisfurfuryl) -2-furfurylmethanediamine

67 g of hydrofuramide are dissolved in 300 ml of tetrahydrofuran at 40 ° C, 38 g of sodium borohydride are dissolved in 80 ml of water and slowly added dropwise at 40 ° C. A post-reaction of 8 hours is carried out. The pH is then adjusted to 1 using dilute hydrochloric acid (1: 1). The consumption of dilute hydrochloric acid was 270 ml.

The pH is then adjusted to 10 using 30% sodium hydroxide solution and the anoraganic salts which have precipitated are suctioned off. The reaction mixture separates into two phases. The tetrahydrofuran phase is separated off and concentrated under a water jet pump vacuum. The residue is added to ^"70 ml Diisopopylether and crystallized. The crystals dersrrt obtained are filtered off with suction. The Filter¬ cake is taken up in 150 ml of acetone and boiled for 30 minutes under reflux. The solids are filtered hot with suction and the acetone was completely evaporated. The crystalline return The stand is taken up in 80 ml of diisopropyl ether and suction filtered, and the solid is washed with diisopopyl ether and dried at 40 ° C.

Yield: 65 g melting point: 107-109 ° C molecular weight: 272

Example 2

Manufacture of hydrofuramide 300 ml of an ethanolic 65% ammonia solution were slowly mixed with 96 g of furfural while cooling with water. The temperature of the reaction mixture was kept at below 50 ° C. Yellow crystals formed, which were filtered off, washed with water and sucked dry. The crystals, which were still wet with water, were recrystallized from ethanol over activated carbon.

The hydrofuramide obtained in this way had the following properties:

Melting point: 112 ^β C molecular weight: 268.26

Example 3

Determination of the effectiveness of N, '' (bisfurfuryl) -2- furfuryl ethandia incitrate

The effectiveness of the substance is examined by a pharmacological screening program.

Antihypertensive effect:

Ten spontaneously hypertensive rats were given 6 mg / kg test substance per os. 2, 4 and 6 hours after the administration, the blood pressure was measured indirectly with a tail cuff on the anesthetized, non-tempered animal. In 7 out of 10 rats examined, a clear drop in blood pressure by 10 to 15% was found.

Antiarhythmic effect: 12 mice were anesthetized with chloroform and treated ip with 0.15 test substance. 30 minutes after administration of the test substance, the heartbeat rate of 9 mice was below 200 / min (ECG).

Inotropy:

Electrically stimulated left auricles of guinea pigs increased their contractility by 42% when using a 0.2% (2.5 mg / 5 ml) N, N '(bisfurfuryl) -2-furfural methanediamine solution. As a result, the furfuryl derivative has an inotropic effect.

Inhibition of the β, 1-andrenergic effect:

Tachycardia (ECG) was induced in 12 rats by administering 0.01 mg / kg isoproterenol (IV). 6 rats / kg of the test substance N, N '(bisfurfuryl) 2-furfurylmethanediamine were administered to 12 rats per os. An ECG was taken 30 minutes after the substance was administered and 70% of the animals showed a clear inhibition of tachycardia.

Hypocholesterolemia:

Fourteen mice were fed a high cholesterol-cholic acid diet for 7 days. The hypercholesterolemic animals were divided into two groups of 7 animals (control group). On the 6th and 7th day after starting the diet, 0.2 mg test substance / animal was administered orally. After fasting at night, a reduction in blood cholesterol levels of over 15% was measured compared to the mice in the control group.

λntiedema effect: 7 rats were given 5 mg / kg of N, N '(bisfurfuryl) -2-furfurylmethane diamine per os and 0.1 ml of a 1% suspension of canigeenan injected into the paws after one hour. Compared to a control group of rats, suppression of paw edema by more than 30% was observed in rats treated with the test substance.

Bronchodilatory effects in vitro:

1.5 mg of N, N'- (bisfurfuryl) -2-furfurylmethane diamine were introduced into the guinea pig lung, which was narrowed using metacholine (0.05 mg / ml) and perfused with a perfusion solution. The flow rate of Tyrod's solution through the lungs was increased by the addition of the test substance by more than 50% after the test substance was injected into the trachea concentrated proximally to the inlet of the throat.

Immunity stimulation:

10 mice were fed with 0.2 g test substance. One hour after the test substance was administered, 5 mice were treated with oxazolone on the shaved abdomen.

7 days later, the ears were irritated by applying oxazolone to one ear. The irritated ear showed a swelling of over 50% compared to the uh-treated ear of the same mouse.

Claims

1. N, N '(bisfurfuryl) -2-methanediamine of the general formula:

where the furfural residue (s) can be substituted once or more, as well as their salts.

2. N, N '- (bisfurfuryl) -2-furfurylmethanediamine, characterized by a melting point of 107 to 109 ° C, a molecular weight of 272 and an elemental analysis of 54.2% C, 5.26% H, 6.03% N and 34.45% 0.

3. A process for the preparation of N, N '(bisfurfuryl) 2-furfurylmethanediamine, characterized by: reacting a hydrofuramide which is optionally substituted on the furan ring (s) with a borohydride and isolating the reduction product.

4. The method according to claim 3, characterized in that a hydrofuramide in the liquid phase, optionally in a polar, hydrophilic solvent, is reacted with an alkali or alkaline earth metal hydride salt and the hydrogenated reaction product by methods known per se, such as extraction, fractional distillation, chromatography or the like.

5. The method according to any one of claims 3 or 4, characterized in that the separation of the hydrogenated reac liquid obtained into an organic and an inorganic phase, and subsequent fractional distillation of the organic phase.

6. The method according to any one of claims 3 to 6, characterized in that hydrofuramide is dissolved in tetrahydrofuran and aqueous alkali borohydride solution is slowly added to the solution with cooling and stirring; After the reaction has ended, the reaction mixture is neutralized with acid, preferably an aqueous solution of an acid, and the organic phase which forms is separated off and distilled.

7. The method according to any one of claims 3 to 6, characterized in that the hydrofuramide is obtained by reacting ammonia with furfural.

8. The method according to claim 7 ,, characterized in that the implementation of ammonia and furfural takes place in the liquid phase.

9. The method according to any one of claims 6 to 8, characterized in that furfural with cooling in an ethano. is introduced and the separating solid, the hydrofuramide, is obtained by methods known per se, such as filtration, centrifugation, decanting or the like.

10. A process for the preparation of salts of N, N '(bisfur¬ furyl) -2-furfurylmethanediamine according to one of claims 3 to 9, characterized by: reacting the N, N' (bisfur¬ furyl) -2-furfurylmethanediamine with stoichiometric amount of acid .

11. The method according to claim 10, characterized. that N, N * (bisfurfuryl) -2-furfurylmethanediamine is dissolved in an organic solvent, reacted with a stoichiometric amount of acid solution, and the salt which separates is separated off.

12. Use of the N, N '(bisfurfuryl) -2-furfury lmethandiamine as a medicament.