MXPA03009902A - Compounds for reducing hyperammonemia in patients having cirrhosis or any inability for eliminating ammonium. - Google Patents

Abstract

Amines and salts were developed from benzoic, phenylacetic and phenylbutyric acids using arginine and ornithine amino acids. The advantage of said novel compounds is that the use of sodium salts, which are usually prescribed for hepatorenal disorders is avoided. Moreover, amino acids by themselves present a substantial hypoammonemic activity, which added to that of the aforementioned acids, results in a useful medicine for controlling urea in congenital disorders of the urea cycle metabolism or cirrhosis.

Description

COMPOUNDS TO REDUCE HYPERAMONEMIA IN PATIENTS WITH CIRRHOSIS OR OTHER DISABILITIES FOR THE ELIMINATION OF AMMONIUM FIELD OF THE INVENTION A group of compounds derived from benzoic acid, phenylacetic acid and phenylbutyric acid have been synthesized, with hypoamonemic activity in diseases of the urea cycle, or cirrhosis, favoring their excretion through alternate pathways existing in the same cycle.

BACKGROUND Conventional therapy for portal systemic encephalopathy is aimed at avoiding high levels of ammonium in the blood by inhibiting high concentrations of bacteria in the colon, supplying antibiotics such as Neomycin, or decreasing the pH of the colon with products such as lactulose or lactitol, which convert ammonia into ammonia for its excretion, thus preventing its absorption. However, these treatments produce undesirable side effects such as azotemia, diarrhea, etc. (C. L. Mendenhall et al., The Amer. J. Gastr 81, 540-543 (1986)). In addition, the high toxicity of Neomycin can lead to ototoxicity and nephrotoxicity and even strains of Klebsiella or Proteus resistant to Neomycin have been found (CL Fraser and AI Arieff, The New Eng. J. Med., 313, 865-873 ( 1985)), inconveniences that have led to the disuse of this antibiotic replaced by others with low intestinal absorption, to avoid kidney complications, such as Rifaximin. In addition to the drawbacks described, the treatments can not be applied parenterally in cirrhotic or non-cooperative patients. In these cases nasogastric or colonic intubation has been used, which are undesirable or annoying routes to administer. An alternative treatment for hyperammonaemia, although not widely used in cirrhotic patients, is the use of sodium benzoate, sodium phenylacetate (US Pat. No. 4,284,647) or sodium phenylbutyrate (US Patent No. 457,942). These compounds act by converting the waste nitrogen from the metabolism into amino acid acylation products, which can excrete the body as urinary nitrogen (US Patent 4,457,942). Specifically, the benzoate reacts with glycine to give hippurate, the phenylacetate reacts with glutamine to give phenylacetylglutamine and the phenylbutyrate is metabolized to phenylacetate, for subsequent acylation. In general it has been reported that the activation of alternative pathways of ammonium excretion can prolong Ta survival and improve the clinical status of patients with hyperammonemia (ML Batshaw et al., The New England J. Med., 306, 1387-1392 (1982)). Despite the excellent results achieved with the treatment described, its low toxicity and its low cost, its use has been restricted to patients with congenital errors in the urea synthesis cycle, with little use in cirrhotic patients with chronic severe encephalopathies ( see for example S. Sushma et al., Hepatology, 16, 138-144 (1992), CL Mendenhall et al., The Amer. J. Gastr. 81, 540-543 (1986), Ferenci, P. et al., Semin. Liver, Dis. 16, 329-338 (1996)). The greatest restriction to more widespread use is that hepatic encephalopathies resulting from cirrhotic complications are generally concomitant with poor renal function, with hyperdynamic circulation, with raised kidneys and with sodium retention. It has been reported that the development of portal hypertension is a possible initiator of increased renal vascular resistance, while deterioration in liver function may be related to poor tubular sodium manipulation (EH Forrest et al., Aliment. Ther., 10, 219-231 (1996)). Complications of the previous pathology culminate in hepatorenal syndrome characterized by uremia, oliguria and low urinary sodium. Renal retention of sodium and water contributes to the generation of ascites, which can be complicated by electrolyte abnormalities and encephalopathy. In order to prevent the ingestion of sodium benzoate saltsSodium phenylacetate or sodium phenylbutyrate involves raising sodium levels in the body of cirrhotic patients with hyperammonemia. New derivatives of these compounds have been proposed that do not contain sodium. Thus, US Pat. No. 6,060,510 proposes the use of glycerol esters and ethyl esters of phenylalkanoic or phenylalkenoic acids. On the other hand it has been reported that the compound L-ornithine-L-aspartate (OA) reduces the levels of ammonium in blood and improves the symptoms in hepatic encephalopathy (Staedt U. Y col .. J. Hepatology 19, 424-430 (1993)). It is proposed that the form of action of this compound is through its metabolic cleavage in aspartate and ornithine, with aspartate acting as a carbon source for the deficient flow of glutamine synthetase in the perivenous scavenger hepatocytes, while ornithine improves the flow through the enzymatic system of the urea cycle, especially through the enzyme carbamylphosphate synthetase located in periportal hepatocytes (Kircheis, G. et al., Hepatology, 25, 1351-1360 (1997)). However, it has been reported that among amino acids that are elevated in plasma, in patients with hyperamone encephalopathy, is aspartate (GT Berry and RD Steiner, J. Pediatrics, 138. s56-s61 (2001)), which suggests that it is not necessary to supply this amino acid in the body, under this state. Other compounds, besides aspartate, proposed to act as a carbon source to stimulate the deficient flow of glutamine synthesis are: malate, benzoate and alpha oxoglutarate (Kircheis, G. et al., Hepatology, 25, 1351-1360 (1997), Kircheis et al in Hepatic Encephalopaty: Syndromes and Therapist, Conn, HO and Bircher, J. Edwards Bloomington, III, Medi-Press, 1994: 373-383). In the present invention, benzoic, phenylacetic and phenylbutyric acid derivatives, amides and salts were synthesized, which act by decreasing overt hyperammonemia in cirrhotic patients and in other patients with inability to eliminate waste ammonium from the organism. The advantages of the compounds synthesized here compared with those commercially available, such as sodium benzoate, sodium phenylacetate and sodium phenylbutyrate, are that sodium ingestion is first avoided, which should be limited in patients with kidney damage, which is a common complication in cirrhotic patients who manifest hepatic encephalopathy and secondly it has that the compounds obtained in this invention, amides and salts of ornithine and arginine are amino acids that act by themselves decreasing the excess of ammonium and they produce appreciable improvements in patients with systemic portal encephalopathy and in those with problems in the urea cycle. These advantages make these compounds relevant for the therapeutic management of this type of ailments.

DESCRIPTION OF THE INVENTION Based on the results of the clinical studies described in the previous section, compounds were designed in the present invention that, first of all, had therapeutic efficacy to reduce hyperammonemia in patients with systemic portal encephalopathy, as do the described sodium salts of benzoate. , phenylacetate and phenylbutyrate and, second, did not have the inconvenience of generating elevations in the concentration of sodium ion in the body, which must be limited by the inconveniences described above. With this base we proceeded to the synthesis of the amides L - (+) - dibenzylornitine, L - (+) - diphenylcetylornithine, L- * (+) diphenylbutyrylornithine, 'L (+) - dibenzylarginine,' L (+) - diphenylacetylarginine and L (+) diphenylbutyrylaryngine and the salts of ornithine benzoate, ornithine phenylacetate, ornithine phenylbutyrate, arginine benzoate, arginine phenylacetate and arginine phenylbutyrate. In addition, the compounds synthesized here offer the additional convenience of coupling with the amino acids ornithine or arginine by unfolding in the organism, these amino acids act by themselves stimulating the elimination of ammonium through increasing the synthesis of urea (U. Staedt and col., J. Hepatology, 19, 424-430 (1993)). For the synthesis process of the compounds, object of the present invention, the corresponding acids were first reacted with thionyl chloride. At the end of the reaction and once the excess of thionyl chloride is removed, an organic solvent, such as tetrahydrofuran, is added and the L - (+) - ornithine or L (+) - arginine is added. The solution is homogenized and triethylamine is slowly added. At the end of the reaction, water is added to induce precipitation of the final product. The precipitate is filtered and washed with water and then with acetone. This procedure was used in general for the synthesis of the compounds L - (+) - dibenzylornithine, L - (+) - diphenylacetylornithine, L - (+) - diphenylbutyrylornithine, L (+) - dibenzylarginine, L - (+) - diphenylacetylarginine and L - (+) - diphenylbutyrylaryngine. The specific details of each synthesis process will be described later by an example. For the synthesis of the salts, ornithine or arginine was dissolved in ethanol and the corresponding carboxylic acids were added with vigorous stirring and gentle heating until the total dissolution of any solid remaining in the suspension. The compounds were recovered by evaporation of the ethanol. In the case of the arginine salts, it is brought to dryness and a foam is recovered, as it is not possible to crystallize, but in the case of the ornithine salts, the ethanol evaporates only until an oversaturated solution is reached, which is cooled and awaited the crystallization. The mentioned methods are illustrated with the following examples.

EXAMPLE 1. SYNTHESIS OF ARGININE SALTS General Method: To a suspension of 0.1 moles of arginine in 100 ml of ethanol, 0.1 mol of the corresponding carboxylic acid was added and the mixture was stirred vigorously with moderate heating until total dissolution of the solid in suspension. The solution was evaporated under reduced pressure until the formation of a foam, which was pulverized and dried under high vacuum until constant weight. The obtained compounds were characterized and identified by melting point, nuclear magnetic resonance, infrared and mass spectrometry EXAMPLE 2. SYNTHESIS OF ORNITHINE SALTS General Method: 0.03 mol of ornithine was dissolved in 50 ml of distilled ethanol and to this solution 0.03 mol of the corresponding carboxylic acid was added. The mixture was stirred with gentle heating and once the solid dissolved, the solution was cooled to room temperature by precipitating the salt. This solid was vacuum filtered, washed with cold ethanol and dried under high vacuum until constant weight. The obtained compounds were characterized and identified by melting point, nuclear magnetic resonance, infrared and mass spectrometry P.F. 175-176 ° C P.F. 183-184 ° C P.F. 175-176 EXAMPLE 3. SYNTHESIS OF AMIDAS DE ARGININA General Method: A solution of 0.25 mol of arginine in 350 ml of distilled water was cooled to 10 ° C and at this temperature a solution of 30 g of NaOH in 60 ml of distilled water and 0.3 mol of the corresponding acid chloride was added slowly and simultaneously. . After the addition, the mixture was stirred at room temperature for 2 hours and then vigorous stirring of concentrated HC1 was added until pH 5.0. The precipitate formed was diluted with 100 ml of water. The solid residue was separated, which was triturated with ethyl acetate-methane 1, to obtain a fine solid, which was filtered washed with ethyl acetate and dried in vacuo to constant weight. The obtained compounds were characterized and identified by melting point, nuclear magnetic resonance, infrared and mass spectrometry P.F. 205-208 ° C P.F. 184-186 ° C P.F. 175-178 ° C For the synthesis of the ornithine amides, it was proceeded basically in the same way as for the arginine amides. 5 0 '5 0

Claims (4)

1. The amides L - (+) - dibenzylornithine, L - (+) - diphenylacetylornithine, L - (+) diphenylbutyrylomitine, L (+) - dibenzylarginine, L (+) - diphenylacetyl arginine and L (+) diphenylbutyrylaryngine and benzoate salts of ornithine , ornithine phenylacetate, ornithine phenylbutyrate, arginine benzoate, arginine phenylacetate and arginine phenylbutyrate.

2. According to clause 1, the process to obtain the salts and the amides.

3. According to clauses 1 and 2 pharmaceutical compositions in which the active principle can be any of the amides, salts or combinations thereof.

4. In accordance with clauses 1, 2 and 3 the use of pharmaceutical compositions in conditions related to the urea cycle or cirrhotic problems.