(2S)-2-aminopentanethioic s-acid for use in the therapy of diabetes mellitus or complications thereof

Abstract

The present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of diabetes mellitus and / or one or more complications thereof. Further, the invention relates to a method of treating or preventing diabetes mellitus and / or one or more complications thereof comprising administering to a subject in need thereof an effective amount of a compound of formula (I).

Description

(2S)-2-Aminopentanethioic S-acid for use in the therapy of diabetes mellitus or complications thereofField of the Invention

[0001] The present disclosure relates to (2S)-2-aminopentanethioic S-acid and compositions and methods for the treatment or prevention of diabetes mellitus and / or one or more complications thereof.Background of the invention

[0002] 2-Aminopentanethioic S-acid, having a chemical formula CH3CH2CH2CH(NH2)C(O)SH, is a chemical reagent that has been used in the synthesis of organic antibiotics. Crcchio R et al., Eur. J. Med. Chem. - Chimica Therapeutica, 1981, 16(4):301-306. PCT / RU2020 / 000661 discloses the use of (2S)-2-Aminopentanethioic S- acid for use in the therapy of amyotrophic lateral sclerosis.

[0003] Diabetes mellitus, also known as diabetes, is a group of common endocrine diseases characterized by pathologically elevated blood glucose levels. As of 2019, an estimated 463 million people had diabetes worldwide accounting for 8.8% of the adult population.

[0004] All forms of diabetes provide the high risk of long-term complications related to a damage of blood vessels, including nonexclusively diabetic retinopathy, diabetic nephropathy, diabetic skin ulceration, diabetic neuropathy. Diabetic retinopathy is caused by damage to the blood vessels in the retina of the eye and can result in loss of visual acuity and eventual blindness. 2079 Guide to Medications for the Treatment of Diabetes Mellitus 1st Edition by John R. White PA-C PharmD (Editor).

[0005] It is an object of the present invention to provide (2S)-2-aminopentanethioic S-acid, compositions comprising (2S)-2-aminopentanethioic S-acid, and methods of using (2S)-2- aminopentanethioic S-acid for the treatment of diabetes mellitus and / or compositions thereof.Summary of the invention

[0006] In one example there is provided a compound of formula (I):or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of diabetes mellitus and / or one or more complications thereof.

[0007] In another example, there is provided a method of treating or preventing diabetes mellitus and / or one or more complications thereof comprising administering to a subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof.

[0008] In another example, there is provided a composition comprising formula (I):or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of diabetes mellitus and / or one or more complications thereof.

[0009] In another example, there is provided a composition for use in treating or preventing diabetes mellitus and / or one or more complications thereof comprising a composition of formula (I):or a pharmaceutically acceptable salt thereof.

[0010] In another example, there is provided a compound of formula (I):or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment or prevention or of diabetes mellitus and / or one or more complications thereof.Brief description of the figures

[0011] Figure 1: shows blood glucose levels (mmol / L) of non-diabetic and diabetic (STZ- induced) mice when treated with vehicle, the compound of Formula (I) (25 mg / kg / day), and metformin (25 mg / kg / day).

[0012] Figure 2: shows blood glucose levels (mmol / L) (A) and behavioural mobility (B) of non-diabetic mice, diabetic (high fat, high sugar diet-fed) mice, and diabetic mice when treated the compound of Formula (I) (25 mg / kg / day).Detailed Description of the Invention

[0013] All terms and definitions explained throughout the text of the specification relate to all aspects and embodiments disclosed herein, unless otherwise specified.

[0014] In one aspect, there is provided a compound of formula (I):or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of diabetes mellitus and / or one or more complications thereof.

[0015] According to another aspect, there is provided a method of treating or preventing diabetes mellitus and / or one or more complications thereof comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0016] In another aspect, there is provided a composition of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of diabetes mellitus and / or one or more complications thereof.

[0017] In another aspect, there is provided a composition for use in treating or preventing diabetes mellitus and / or one or more complications thereof comprising a composition of formula (I) or a pharmaceutically acceptable salt.

[0018] In another aspect, there is provided a compound of formula (I) ora pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment or prevention of diabetes mellitus and / or one or more complications thereof.

[0019] The compound of formula (I) has a chemical name (2S)-2-aminopentanethioic S- acid and a chemical formula C5HnNOS.

[0020] The present disclosure relates to all tautomeric forms of the compound of formula (I), including S-acid form (I), O-acid form (II), inner salt form (III), and pharmaceutically acceptable salts thereof prepared by reaction with an appropriate acid, where X is an anion (IV), or by reaction with an appropriate base, where Y is a cation (V):

[0021] wherein non-exclusive examples of X include chloride, bromide, sulfate, phosphate, mesylate, acetate, pyruvate, lactate, citrate, succinate, fumarate, malate, and ketoglutarate; and wherein non-exclusive examples of Y include lithium, sodium, potassium, magnesium, calcium, ammonium, and an alkylammonium.

[0022] The present disclosure relates to all hydrates, solvates, and isotopologues of the compound of formula (I).

[0023] The term “isotopologue”, as used herein, refers to molecules that differ only in their isotopic composition. Non-exclusive examples of isotopes are1H and2H isotopes ofhydrogen,11C,12C,13C, and14C isotopes of carbon,150,160,17O, and18O isotopes of oxygen,13N,14N, and15N isotopes of nitrogen, and32S,33S,34S, and36S isotopes of sulphur.

[0024] The present disclosure relates to all prodrugs of the compound of formula (I). The term “prodrug”, as used herein, refers to a compound that being administered to a subject in need thereof, will result in a therapeutic effect through the intermediate formation of the compound of formula (I).

[0025] The term “diabetes mellitus”, as used herein, refers to the metabolic disease classified in the International Classification of Diseases, Tenth Revision (ICD-10-CM), under the code E10-E14, and includes type 1 , type 2, maturity-onset diabetes of the young (MODY), gestational diabetes, neonatal diabetes, steroid-induced diabetes, and prediabetes.

[0026] The term “therapy”, as used herein, refers to any treatment which is designed to cure, alleviate, remove or lessen the symptoms of, or prevent or reduce the possibility of malfunction of the subject body.

[0027] The term “treating” or “treatment” refers to the administration of a medicament, composition or compound to a patient to cure, alleviate, remove or lessen the symptoms of, or prevent or reduce the possibility of malfunction of the subject body.

[0028] The term “preventing” refers to preventing or reducing the possibility of developing diabetes mellitus and / or a complication thereof as herein defined.

[0029] The term “complication thereof” as used herein includes, but is not limited to diabetic retinopathy, diabetic nephropathy, diabetic skin ulceration, and diabetic neuropathy. Diabetic retinopathy is caused by damage to the blood vessels in the retina of the eye and can result in loss of visual acuity and eventual blindness.

[0030] The compound of formula (I) can be administered by different routes, e.g. orally, parenterally, by inhalation spray, buccally, sublingually, nasally, rectally, or parenterally, with oral route being preferred. The term “parenteral”, as used herein, includes subcutaneous, intracutaneous, intravenous, intramuscular, intrathecal, intralesional and intracranial injection or infusion techniques.

[0031] The term “an effective amount”, as used herein, refers to the amount of the active agent that is required to confer the intended therapeutic effect in the subject. Effective amounts may vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, medical conditions, and the possibility of co-usage with other agents.

[0032] The effective amounts of the compound of formula (I) or a pharmaceutically acceptable salt thereof may vary from 0.1 to 100 mg per kg body weight of the subject.

[0033] The term “subject”, as used herein, refers to human and non-human mammals.

[0034] Effective amounts of the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered to the same subject one time or multiple times.

[0035] Effective amounts of the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered to the same subject for one day or longer.

[0036] The compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered as an active pharmaceutical ingredient of a pharmaceutical composition. In some embodiments, the composition can contain from 0.01 to 99.99 per cent of the compound of formula (I). These compositions can contain some optional ingredients. Such optional ingredients generally are used individually at levels from about 0.01 to about 99.99 per cent by weight of the composition. Examples of suitable optional ingredients include, but are not limited to, excipients, carriers, minerals, carbohydrates, lipids, vitamins, cofactors, buffers, flavors and sweeteners, inorganic salts, cations and anions, taste modifying and / or masking agents, amino acids, organic acids, antioxidants, preservatives, colorants, and other suitable ingredients.

[0037] In some embodiments, the compositions can be formulated in different dosage forms. Nonexclusive examples of such forms include an orally acceptable dosage form, an injectable dosage form, an inhalation and an intranasal dosage form, and a rectal dosage form.

[0038] The oral composition can be any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, aqueous solutions, suspensions, emulsions, and dispersions. Non-exclusive examples of carriers fortablets include lactose and corn starch. Non-exclusive examples of lubricating agents include magnesium stearate. Non-exclusive examples of diluents for oral administration in a capsule form include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with suspending or emulsifying agents.

[0039] The sterile injectable composition can be any acceptable dosage form including, but not limited to, a sterile injectable solution or suspension in a parenterally acceptable diluent or solvent, for example, as a solution in pharmaceutical water, propylene glycol, mannitol, Ringer's solution, isotonic sodium chloride solution. In addition, sterile oils such as synthetic mono- or diglycerides, fatty acids, such as oleic acid and its glyceride derivatives, can be conventionally used as a solvent or suspending medium. Such oil solutions or suspensions can also contain a long-chain alcohol or carboxymethyl cellulose as a diluent or dispersant.

[0040] The inhalation and intranasal composition can be any acceptable dosage form including, but not limited to, solutions and dispersions in water or saline that may contain suitable preservatives, absorption promoters to enhance bioavailability, and / or other solubilizing agents known in the art.

[0041] The rectal composition can be prepared according to procedures well known in the art in form of suppositories comprising the active ingredient and base capable to be melted or dissolved at a human body temperature to release the active ingredient. Non-exclusive examples of such bases include cacao butter, polyethylene glycol, and synthetic esters of glycerol like Witepsol bases.

[0042] The composition of the invention can be prepared by procedures well-known from the art. Such procedures include, but are not limited to, mixing the compound of formula (I) or a pharmaceutical salt thereof with other ingredients of the composition in conventional manner. Guidance for the preparation of compositions of the invention can be found in "Remington: The science and practice of pharmacy" 20th ed. Mack Publishing, Easton PA,2000 ISBN 0-912734-04-3 and "Encyclopaedia of Pharmaceutical Technology", edited by Swarbrick, J. & J. C. Boylan, Marcel Dekker, Inc., New York, 1988 ISBN 0-8247-2800-9 or a newer edition.

[0043] The compound of formula (I) can be prepared as described in Cricchio R etal., Eur. J. Med. Chem. - Chimica Therapeutica, 1981, 16(4):301-306, starting from (2S)-enantiomer of 2-aminopentanoic acid; or as described in PCT / RU2020 / 000661 .

[0044] The following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in anyway.ExamplesExample 1

[0045] This example illustrates a compound of formula (I) for use in the method of treating diabetes mellitus.

[0046] Diabetes mellitus was induced in C57BI / 6 male mice by a single intraperitoneal injection of streptozotocin (STZ) (100 mg / kg body weight) as described in Hayashi K, Kojima R, Ito M. Strain differences in the diabetogenic activity of streptozotocin in mice. Biol Pharm Bull. 2006 Jun;29(6):1110-9. Mice were randomized into two groups by eight mice per group and received orally the compund of formula (I) (50 mg / kg bw per day) or vehicle (control) for two weeks, via drinking water. Non-diabetic mice in a reference group (n=8) without STZ- induced diabetes received vehicle. Fasting blood glucose levels were measured at the end of the study (day 14). Results were analyzed by one-way ANOVA, Tukey’s posttest and are presented in Table 1 as mean ± SEM (n=8) of blood glucose levels.Table 1 . Blood glucose levels.*Differs significantly from STZ-induced mice, vehicle (P<0.05).

[0047] Table 1 and Figure 1 shows that there was a significant difference between groups (p<0.05, one-way ANOVA and Tukey’s test). Glucose levels were significantly increased in STZ-induced mice as compared to non-diabetic one. There were a significant reduction of the blood glucose levels in STZ-induced mice treated with the compound of formula (I) compared to vehicle-treated STZ-induced mice. Thus, the compound of formula (I) was effective in in the therapy of diabetes mellitus, and in particularType 1 diabetes mellitus.Example 2

[0048] This example further illustrates a compound of formula (I) for use in the method of treating diabetes mellitus.

[0049] Diabetes mellitus was induced in C57BI / 6 female mice as described in Comhair et al., 2011 , as referenced below. Briefly, 3-month old female C57BL6 mice are exposed for 3- weeks to a high fat, high sugar dietary regiment (Research Diets, USA). Induction of diabetes mellitus was validated by impairment of glucose tolerance on day 21 , insulin resistance, increases in leptin levels, oxidative stress and inflammation in the brain and liver, and aberrant behaviour of experimental mice (tail suspension test) (Strekalova et al., 2015, Veniaminova etal., 2017, 2020a, 2020b, Bloemendaal etal., 2023).

[0050] Mice were randomized into three groups of six mice per group and received orally the compound of formula (I) (25 mg / kg bw per day) or vehicle (control) for two weeks, via drinking water. Non-diabetic mice in a reference group (n=6) were fed a control diet (low fat, low sugar).

[0051] Fasting blood glucose levels were measured at the end of the study via glucose tolerance test conducted by female researchers. Results were analyzed by one-way ANOVA, Tukey’s posttest and are presented in Table 1 as mean ± SEM (n=6) of blood glucose levels.

[0052] Figure 2 shows that there was a significant difference between groups (p<0.05, oneway ANOVA and Tukey’s test). Glucose levels were significantly increased in diabetic high fat, high sugar diet-fed female mice as compared to non-diabetic mice fed on the control diet. There was a significant reduction of the blood glucose levels of diabetic mice fed the high fat, high sugar diet and treated with the compound of formula (I), normalising bloodglucose levels to that of control non-diabetic mice. Moreover, diabetic mice treated with the compound of formula (I) displayed normalised behaviour by the tail suspension test when compared to diabetic mice. Thus, the compound of formula (I) was effective in in the prevention and / ortreatment of diabetes mellitus, and in particularType 2 diabetes mellitus.

Claims

Claims1. A compound of formula (I):or a pharmaceutically acceptable salt thereof for use in the treatment of prevention of diabetes mellitus and / or one or more complications thereof.

2. A method of treating or preventing diabetes mellitus and / or one or more complications thereof comprising administering to a subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof.

3. A composition of formula (I):or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of diabetes mellitus and / or one or more complications thereof.

4. A composition for use in treating or preventing diabetes mellitus and / or one or more complications thereof comprising a composition of formula (I):or a pharmaceutically acceptable salt thereof.

5. A compound of formula (I):or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment or prevention of diabetes mellitus and / or one or more complications thereof.

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