NO151283B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE NEW 5-IOD-3-NITRO-4-HYDROXYBENZONITRIL SALTS - Google Patents

Description

The present invention relates to an analogue

procedure for the preparation of new, therapeutically active, stable salts of general formula

in which R"*" denotes hydrogen, phenyl or naphthyl, substituted by C^_^q alkoxy,

R^ denotes C^-4 alkyl or hydrogen,

R 3 denotes C,_. alkyl,

4

R denotes hydrogen or

R 3 and R 4 together form a group of formula

2

and in this case R is hydrogen,

The analog method according to the invention is characterized by an amidine derivative of the general formula

12 3 4 in which R , R , R and R are as defined above, is reacted with 5-iodo-3-nitro-4-hydroxybenzonitrile of formula

If B?~ contains alkoxy, this can be straight-chain or branched, such as methoxy, isobutyloxy or n-decyloxy, preferably an alkoxy group containing 4-6 carbon atoms such as n-butyloxy or hexyloxy,

if R 2 and R 3 denote alkyl, the alkyl group may be straight-chain or branched, such as methyl, isopropyl, and preferably n-butyl.

5-iodo-3-nitro-4-hydroxybenzonitrile (nitroxynil) has been reported to exhibit activity towards the liver (Veterinary

Pesticides, page 25, London, 1969). The production of this substituted nitrophenol has been described in several patents, such as Dutch Patent No. 6,516,359, Hungarian Patent No. 167,251 and 168,748.

It is also known that the active ingredient of the preparation suitable for the treatment of liver disease - mainly in cattle - is the salt of nitroxynil, whose water solubility is very low. The sensitivity of the nitrophenol salts to polymorphism is also known. The solubility ratio for the acidic nitrophenol salts formed with bases (alkali hydroxides, amine compounds of different strength and structure) thus changes due to polymorphism, and during this change a prepared injectable solution will precipitate within a certain time and thus cannot be used for therapeutic purposes. This phenomenon is known in the case of nitroxynil (Chem. Ind. 1967, 1918).

The hepatoprotective activity of 4(5)-amino-imidazole-5(4)-carboxamide (Hungarian Patent Nos. 157,880 and 164,397) and the anthelmintic activity of certain 4-Alkoxy-N,N-dialkyl-benz-amidines have been reported (Hungarian patent document no. 157,593).

When carrying out the method according to the invention, the salt is formed by reacting the components in a mixture of water and alcohol, or in the presence of aromatic and aliphatic hydrocarbons.

The reaction is preferably carried out under heating at 40 - 100°C. The salts can generally be isolated from the reaction mixture by evaporation or crystallization by adding suitable solvents or solvent mixtures.

The salts obtained are crystalline and can be used as active ingredients of biologically active preparations without further purification.

The new salts of general formula I are less soluble in water. The salts are generally soluble in anhydrous solutions.

The compounds can be used for the cure of animals, including humans, preferably of liver diseases due to their hepatoprotective activity. Cattle suffering from natural fasciolosis were treated with a salt of 5(4)-amino-imidazole-4(5)-carboxamide with 5-iodo-3-nitro-4-hydroxybenzonitrile at a dose of 10 mg/kg i.m. in the neck muscle, after which coprological tests (enrichment by sedimentation) were carried out. The connection effected

in this form an increased effectiveness of 91.5%.

The compounds produced according to the invention can be formulated in different preparations depending on their area of application. The formulation can be made according to known methods.

The salts can be formulated into pharmaceutical preparations in human or veterinary medicine. The preparations can be administered parenterally, orally or rectally.

The preparations are made by adding carriers, fillers and further excipients to the active ingredient

according to methods known per se.

During the preparation of a parenteral preparation occurs

there are problems due to the fact that the salt produced according to the invention is generally not soluble in water. The anhydrous solvents often cause unwanted local symptoms.

It has now been found that the mixture of N-g-hydroxyethyl-lactamide, N-methylacetamide and methylcellosolv solvents with equal weight ratios exhibits an extra low toxicity in relation to the value calculated according to the addition rules. The new salts are well soluble in this solvent mixture. Thus, for example, the salt prepared according to example 3 remains in a stable solution, while the most favorable tautomeric form can also be formed.

According to a preferred embodiment

triethylamine can be added to the above solvent mixture. At the same time, biological activity can be added. Further excipients can be added to the mixture thus prepared.

In the production of orally active preparations, for example for the treatment of sheep, inorganic fillers such as calcium carbonate, bentonite and further excipients can be added, and dosage units in different forms, such as ball or disc form can be obtained.

The invention is illustrated by the following examples.

Example 1

34 g of N,N-di-n-butyl-4-n-butoxybenzamidine hydrochloride were suspended in 600 ml of a mixture of 2.8% sodium hydroxide solution and 300 ml of benzene. After thorough shaking and after separation, the aqueous layer was shaken out once more with 200 ml of benzene. The combined washed (water), dried and filtered benzene solution was added to 29 g of nitroxynil dissolved in 150 ml of benzene at 70°C, after which the orange-red solution was evaporated, and the resulting gum crystallized from 690 ml of 66% hot aq. ethanol with decolorizing carbon. The yellow crystalline product was isolated by filtration and dried at 70°C. 4-n-butoxy-N,N-di-n-butylbenzamidine nitroxynyl salt was obtained. Yield: 54 g (91.5 %), m.p. 110°C.

Example 2

A suspension of 1 g of 4-n-hexyloxy-N,N-di-n-butyl-naphthamidine hydrochloride in 50 ml of 2% potassium hydroxide was shaken out with 1 x 30 ml and 1 x 20 ml of benzene. The combined and dried benzene solution was added to 0.69 g of nitroxynil in 10 ml of benzene,

and the solution was evaporated to approx. 10.ml yellow benzene solution. To this benzene solution was added 80 ml of petroleum ether. The precipitated yellow crystals were filtered and dried at 70°C. 4-n-hex-yl-N,N-di-n-butylnaphthamidine nitroxynyl salt was obtained. Yield: 1.55 g (97%), m.p. 178°C.

Example 3

19.5 g of 5(4)-amino-imidazole-4(5)-carboxamide and 43.5 g of nitroxynil were dissolved in 1.5 liters of 80% aqueous methanol under boiling. Crystals were easily precipitated from the orange-red solution on cooling. The thick crystal paste was stirred for 2 hours in ice water at 5°C, filtered and washed with 50 ml of cold methanol. The orange crystalline product was dried at 70°C. 5(4)-amino-imidazole"4(5)-carboxamide-nitroxynyl salt was obtained. Yield: 61.2 g (97.5%), m.p. 185-186°C.

Claims (1)

Analogy method for the production of new therapeutics active, stable salts of general formula in which R<1> denotes hydrogen, phenyl or naphthyl, substituted pea with C^_^o alkoxy, R2 denotes C^_^ alkyl or hydrogen, B? denotes C,_. alkyl, 4 R denotes hydrogen or 3 4 R and R together form a group of formula and in this case R 2 is hydrogen, characterized in that an amidine derivative of general formula 12 3 4 in which R, R , R and R are as defined above, is reacted with 5-iodo-3-nitro-4-hydroxybenzonitrile of formula