S- and / or n-acylated glutathione derivatives

Abstract

Compounds of formula (I) (I) are described where the R-groups represent hydrogen, phenylbutyroyl, isovaleroyl or isobutyroyl, with the condition that at least one of the R-groups is different from hydrogen.

Description

[0001] S- AND / OR N-ACYLATED GLUTATHIONE DERIVATIVES

[0002] The present invention relates to new S and / or N-acylated glutathione derivatives.

[0003] STATE OF THE ART

[0004] Glutathione, a tripeptide consisting of the three amino acids cysteine, glycine and glutamine, plays a vital role in numerous physiological processes. Reduced glutathione (GSH), the major non-protein thiol compound found in animal cells, is a potent endogenous antioxidant that protects cells from damage caused by free radicals and other reactive oxygen species, helping to maintain cellular health and reduce inflammation. Glutathione also plays a crucial role in detoxification processes, participating in the neutralization and elimination of toxins, drugs, heavy metals and other toxic compounds.

[0005] Glutathione also supports the immune system by contributing to the production and activation of T lymphocytes, which are important for the defence against infection, and acts to protect DNA from oxidative damage.

[0006] Given the role of glutathione in numerous metabolic processes, a glutathione deficiency is associated with the onset and progression of several diseases.

[0007] For example, subjects with glutathione deficiency exhibit haemolytic anaemia, metabolic acidosis, bacterial infections, and progressive central nervous system dysfunction. Furthermore, hereditary deficiency of y-glutamyl cycle enzymes in humans leads to reduced glutathione production, making cells particularly vulnerable to oxidative stress and favouring apoptotic and necrotic processes. The resulting damage is the critical step for the onset and progression of many disease states, as low levels of GSH are present in a wide range of diseases, including neurodegenerative diseases, cystic fibrosis and several viral infections.

[0008] Glutathione or its precursors are therefore used as active ingredients of pharmaceutical and nutraceutical formulations. The pharmaceutical compositions are administrable intravenously or orally.

[0009] Intravenous administration is usually used at the hospital level to reduce the effects of chemotherapy treatments against cancer, Parkinson's disease, diabetes, anaemia associated with dialysis, atherosclerosis and male fertility problems.

[0010] In order to increase the bioavailability of GSH, numerous sulphur and / or nitrogen derivatives have been studied.

[0011] US 5,382,679 reports the preparation of S-acyl derivatives of glutathione, in particular acetic acid (SAG) derivatives, with pivalic acid, benzoic acid, phenylacetic acid and thienyl carboxylic acid. WO2011081715 and WO2011081716 disclose sulphur-acylated derivatives of GSH with long-chain fatty acids, both saturated and polyunsaturated, intended for mainly dermatological use.

[0012] Other syntheses of S-acyl-glutathione are described by Francesca Bartoccini, et al., in Org. Process Res. Dev. 2019, 23, 9, 2069-2073 and in DE 100 18 098.

[0013] Acyl derivatives of glutathione are often included in supplements to improve overall health, boost energy levels, improve immune function, and support detoxification.

[0014] In summary, acyl derivatives of glutathione are used to improve the overall health, beauty of the skin and to support various physiological processes thanks to their powerful antioxidant and detoxifying properties.

[0015] SUMMARY OF THE INVENTION

[0016] It has now been found that S- and / or N-acylated glutathione derivatives with short chain fatty acids and with phenylbutyric acid are useful as agents with beneficial effects on lipid metabolism in general, in particular exhibiting anti-lipogenic effects (improvement of the endoplasmic reticulum), stress from damage to Beta (insulin-producing) cells, decrease in inflammatory cytokines, improvement of atherosclerotic plaque, improvement of apolipoprotein regulation, neuronal protection.

[0017] The derivatives of the invention release in vivo glutathione and phenylbutyric acid or short chain branched fatty acids which exert synergistic effects. In fact, the compounds of the invention increase the bioavailability of glutathione, also generating beneficial compounds for the body, such as the aforesaid phenylbutyric acid and short chain branched fatty acids, whose favourable pharmacological profile is known (Pharmacological Research 144 (2019) 116-131).

[0018] Another object of the present invention is to provide pharmaceutical compositions or supplements which can be effectively administered for therapeutic treatments.

[0019] DISCLOSURE OF THE INVENTION

[0020] The present invention relates to compounds of formula I. where the R-groups represent hydrogen, phenylbutyroyl, isovaleroyl or isobutyroyl, with the condition that at least one of the R-groups is different from hydrogen.

[0021] Preferably, the phenylbutyroyl, isovaleroyl or isobutyroyl groups are bonded to the sulphur atom. In an alternative embodiment, such groups are bonded to the nitrogen atom of the amine group. In another embodiment, the phenylbutyroyl, isovaleroyl or isobutyroyl groups are present on both the sulphur atom and the nitrogen of the amine group.

[0022] The compound S-phenyl butyroyl glutathione is particularly preferred.

[0023] The process for preparing compounds of formula I comprises the reaction of glutathione with the respective carboxylic acids under controlled acylation conditions. Preferably the process described in WO 2024 / 084406, in the name of the Applicant, is used, which comprises the activation of the carboxylic acid with carbonyl di-imidazole and subsequent reaction with glutathione in the absence of organic solvents. Diacylated products (S and N) can be obtained by acylation in aqueous environment with acyl anhydride at basic pH as described in Org. Process Res. Dev., DOI: 10.1021 / acs.oprd.9b00120: 01 Aug 2019).

[0024] The pharmaceutical compositions or supplements comprise one or more compounds of formula I, formulated in a conventional manner, for example in tablets, capsules, powders, solutions or suspensions. The dosages and methods of use are also conventional, analogous to the already known formulations based on GSH and its derivatives. Typical oral dosages will be comprised between 50 and 500 mg. The compounds of formula I were negative in the Ames test.

[0025] The invention is illustrated in more detail in the following example.

[0026] Example S- 4-phenyl butyroyl glutathione

[0027] A solution of 15.5 g of GSH in 30 mL of deionized water is prepared by adding NaOH (20%) to pH 4.5 / 5.0.

[0028] A mixture of powders of 8 g phenylbutyric acid and 8.1 g of carbonyldiimidazole (CDI) 8.1 is prepared separately. It is stirred until the end of the development of CO2. The solid 4- phenylbutyryl-imidazolide is added to the GSH solution. It dissolves in about 30 minutes with the pH rising up to 7.95. It is left stirring for another 30 minutes. The solution is clear. A 20% aqueous solution of HC1 is added. At pH 4.90, the product begins to precipitate. The pH is lowered to 3 / 3.5 and left to stir for 1 hour.

[0029] It is filtered by washing extensively with water, after drying obtaining 18 g of S-4- phenylbutyryl glutathione with a melting point of 194°C with decomposition.

[0030] Similarly, starting from isovaleric acid (15 g) and isobutyric acid (50 g) , S-isovaleryl glutathione and S-iso butyryl glutathione were synthesized with similar yields.

Claims

CLAIMS1. Compounds of formula (I)(I) wherein the R-groups represent hydrogen, phenylbutyroyl, isovaleryl or isobutyroyl, with the condition that at least one of the R-groups is different from hydrogen.

2. Compounds according to claim 1 wherein the phenylbutyroyl, isovaleroyl or isobutyroyl groups are bonded to the sulphur atom.

3. Compounds according to claim 1 wherein the phenylbutyroyl, isovaleroyl or isobutyroyl groups are bonded to the nitrogen atom of the amine group.

4. Compounds according to claim 1 wherein the phenylbutyroyl, isovaleroyl or isobutyroyl groups are present on both the sulphur atom and the nitrogen atom of the amine group.

5. Compound according to any one of the preceding claims which is S-phenyl butyroyl glutathione.

6. A process for preparing compounds of formula 1 comprising the reaction of glutathione with respective activated carboxylic acid derivatives with carbonyl imidazole in the absence of a solvent.

7. Pharmaceutical compositions or supplements comprising a compound of claims

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