Erythritol ester of phenylbutyric acid

Abstract

The present application discloses erythritol analogs of phenylbutyrate and compositions containing same. Methods of using the erythritol analogs of phenylbutyrate are also disclosed.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to the field of pharmaceutical sciences. In particular, the present invention relates to erythritol esters of phenylbutyric acid, methods for preparing the compounds, compositions containing the compounds, and uses thereof for treating disorders associated with mutations in the SLC6A1, STXBP1, SYNGAP, and FOXG1 genes and other disorders or conditions associated with endoplasmic reticulum stress.

[0002] Background of the Invention Phenylebutyrate esters of alcohols are known in the art. For example, EP 2607367 discloses monophenylbutyrate, diphenylbutyrate, or triphenylbutyrate of glycerol for the treatment of cancer. US 5945407 discloses the tetrabutylate ester of threitol, particularly a pharmaceutical composition containing the tetrabutylate ester of threitol, for the treatment of cancer selected from the group consisting of carcinoma, myeloma, melanoma, lymphoma, and leukemia. EP 0858441 discloses monophenylbutyrate, diphenylbutyrate, or triphenylbutyrate of glycerol for the treatment of patients with nitrogen retention disorders, certain β-hemoglobinopathies, anemia, and cancer. US6060510 discloses monophenylbutyrate, diphenylbutyrate, or triphenylbutyrate of glycerol for the treatment of patients with nitrogen retention diseases, certain beta-hemoglobinopathies, anemia, and cancer. US20140206763 discloses phenylbutyrate esters of glycerol for the treatment of sporadic inclusion body myositis and disorders related to impaired autophagy or accumulation of amyloid beta 42. US20140155358 discloses only glyceryl tributyrate for boosting innate antibacterial activity in the lungs, trachea, urinary tract, kidney, jejunum, and ileum. WO2013079205 discloses pharmaceutical compositions containing glyceryl 4-phenylbutyrate (phenylbutyrate esters of glycerol) as an active ingredient for treating various diseases and disorders, including neurodegenerative disorders. It does not disclose or suggest any other alternatives to glyceryl 4-phenylbutyrate. WO 2010025303 discloses phenylbutyrate esters of glycerol for the treatment of patients with nitrogen-retaining conditions, including urea cycle disorders (UCDs), cirrhosis complicated by hepatic encephalopathy (HE), and chronic renal failure.

[0003] However, none of the prior art compounds disclose phenylbutyrate esters of erythritol. The present invention is the first to disclose phenylbutyrate esters of erythritol and demonstrates that these compounds have enhanced therapeutic efficacy over other compounds in the art.

[0004] Summary of the Invention The present invention relates to phenylbutyrate esters of erythritol, methods for preparing same, compositions containing same and uses thereof.

[0005] Description of the Invention The present invention relates to erythritol analogs of phenylbutyrate esters, which are used to treat SLC6A1 and related disorders, including neurodevelopmental disorders, including epilepsy and intellectual disability.

[0006] Since its first description in 2015 (Carvill et al., 2015), solute carrier family 6 member 1 (SLC6A1)-related disorders have emerged as a common cause of developmental and epileptic encephalopathies. SLC6A1 encodes the GABA transporter protein type 1 (GAT1), which is responsible for the reuptake of GABA into presynaptic neurons and glia (Broeer and Gether, 2012). Disruption of SLC6A1 is a prominent cause of neurodevelopmental disorders, including autism spectrum disorder, intellectual disability, and seizures of various types and severities. The three largest genome screens to date of individuals with epilepsy (8,565, 9,170, and 9,769 patients, respectively) listed SLC6A1 among the top 10–20 genes with the highest number of pathogenic variants (Lindy et al., 2018; Epi25 Collaborative, 2019, p. 25; Truty et al., 2019). In the largest autism sequencing study to date (N=11,986), SLC6A1 was among the top 10 genes with the most significant variant enrichment in autism patients compared with 23,598 controls (Satterstrom et al., 2019). Recently, exome sequencing of individuals with schizophrenia found that rare de novo missense variants in SLC6A1 were associated with schizophrenia in three patients, extending the phenotype beyond epilepsy (Rees et al., 2020). Overall, the incidence of SLC6A1-related disorders is estimated to be 2.65 cases per 100,000 live births (90% CI: 2.38–2.86) ( Lopez-Rivera et al., 2020 ).

[0007] The present invention relates to (2R,3S)-butane-1,2,3,4-tetrayltetrakis(4-phenylbutanoate) and (2S,3R)-4-hydroxybutane-1,2,3-triyltris(4-phenylbutanoate).

[0008] The compounds of the present invention are provided herein below in Formula (I) and Formula (II) ("Listed Compounds").

[0009] [Table 1]

[0010] Without being bound by theory, it is submitted that the structural features of the compounds of the present invention result in enhanced pharmacokinetics of other prior art compounds, as also evidenced by enhanced activity over other prior art ester derivatives as shown in the examples herein below.

[0011] In another aspect, a composition comprising (2R,3S)-butane-1,2,3,4-tetrayl-tetrakis(4-phenylbutanoate) and / or (2S,3S)-butane-1,2,3,4-tetrayl-tetrakis(4-phenylbutanoate) and a pharmaceutically acceptable salt is disclosed.

[0012] By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0013] A "pharmaceutically acceptable carrier" can include a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting the disclosed compositions or active agents from one organ or part of the body to another without affecting their biological effect.

[0014] Further embodiments provide pharmaceutical formulations comprising the compounds of the present invention described herein and formulated for a specific delivery mode. Formulations can be prepared by methods well known in the pharmaceutical arts. For example, the recited compounds are mixed with a carrier and / or diluent as a suspension or solution. Optionally, one or more accessory ingredients (e.g., buffers, flavoring agents, surfactants, etc.) are also added. The choice of carrier is well within the skill of one of ordinary skill in the art and is determined by the solubility and chemical properties of the compound, the selected route of administration, and standard pharmaceutical practice. These auxiliary ingredients and materials are well known in the art and include, for example: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, hydroxypropyl methylcellulose, sucrose, and gum arabic; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium starch glycolate, cross-linked sodium carboxymethylcellulose, and sodium carbonate; (5) solution retarders, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) humectants, such as cetyl alcohol and glycerol monostearate. (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium lauryl sulfate; (10) suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth; (11) buffering agents; (12) excipients, such as lactose, milk sugar, polyethylene glycol, animal and vegetable fats and oils, oils, waxes, paraffin, cocoa butter, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicones, bentonite, silicic acid, talc, salicylates, zinc oxide, aluminum hydroxide, calcium silicate, and polyamide powder; (13) inert diluents, such as water or other solvents;(14) preservatives; (15) surfactants; (16) dispersing agents; (17) sustained-release or absorption-retarding agents, such as hydroxypropyl methylcellulose, other polymer matrices, biodegradable polymers, liposomes, microspheres, aluminum monostearate, gelatin, and waxes; (18) opacifying agents; (19) adjuvants; (20) wetting agents; (21) emulsifying agents and suspending agents; (22) solubilizing agents and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, (23) propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane; (24) antioxidants; (25) agents that render the formulation isotonic with the blood of the intended recipient, such as sugars and sodium chloride; (26) thickening agents; (27) coating materials, such as lecithin; and (28) one or more auxiliary ingredients selected from sweeteners, flavoring agents, coloring agents, fragrances, and preservatives.

[0015] In another embodiment, methods are provided for treating SLC6A1 and related disorders, including neurodevelopmental disorders, including epilepsy and intellectual disability, by administering a therapeutically effective amount of a compound or composition described herein to a subject in need thereof. As used herein, the terms "treat," "treating," or "treatment of" refer to providing any type of medical management to a subject. Treating includes, but is not limited to, administering a composition to a subject using any known method, with the intent of curing, reversing, alleviating, reducing the severity of, inhibiting the progression of, or reducing the likelihood of a disease, disorder, or condition, or one or more symptoms or signs of a disease, disorder, or condition. The term "therapeutically effective amount" refers to the dose of a substance that will produce a desired pharmacological and / or therapeutic effect. The desired pharmacological effect is the alleviation of a condition or disease described herein or symptoms associated therewith. A therapeutically effective amount of a substance may vary depending on factors such as the individual's medical condition, age, sex, and weight, and the ability of the substance to elicit a desired response in an individual. Dosage regimens may be adjusted to provide an optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

[0016] For administration to a suitable subject, preferably a human patient suffering from or suspected of suffering from SLC6A1 and related disorders, including epilepsy and neurodevelopmental disorders, including intellectual disability, the compounds described herein are prepared into a formulation suitable for any administration route and in a suitable dose by methods known in the art. Suitable subjects for administration and treatment can be rats, mice, dogs, cats, farm animals, such as cows, sheep, horses, etc., or any mammal.

[0017] The appropriate dose of the listed compounds depends on several factors within the knowledge of an ordinary physician, veterinarian, or researcher, such as the identity, size, and condition of the subject or sample being treated, and further depends on the route by which the composition will be administered, the frequency of administration, the severity of the disease, and the effect desired by the expert from the active agent. Furthermore, the appropriate dose of the active agent depends on its efficacy with respect to the target to be modulated. Such appropriate doses can be determined using assays described herein or assays convenient for the expert and known in the art. When one or more of these active agents are administered to an animal (e.g., a human), a relatively low dose may be prescribed initially, followed by increasing the dose until an appropriate response is obtained. In addition, the specific dose level for any particular subject depends on a variety of factors, including the activity of the particular compound used, the subject's age, weight, general health, sex, and diet, the time of administration, the route of administration, the rate of excretion, any drug combinations, and the degree of expression or activity to be modulated.

[0018] The dosage and regimen for administration can be determined by those skilled in the art, including physicians.The composition comprising the compound described herein can be administered once or at intervals, for example, by continuous infusion, or by repeated oral administration over a period of time, 4 times a day, twice a day, daily, every other day, weekly, monthly, or any interval that should be determined by those skilled in the art based on the subject concerned.Treatment can include administration for only one day, for one week, one month, several months, several years, or lifelong.The regimen and duration can vary according to any system known in the art, and are known to those skilled in the art.

[0019] Pharmaceutical compositions suitable for oral administration may be in the form of a capsule, cachet, pill, tablet, powder, granule, solution or suspension in an aqueous or non-aqueous liquid, oil-in-water or water-in-oil liquid emulsion, elixir or syrup, troche, bolus, electuary, or paste. These formulations may be prepared by methods known in the art, for example, by conventional pan-coating, mixing, granulating, or lyophilizing processes.

[0020] Solid dosage forms for oral administration (such as capsules, tablets, pills, dragees, powders, granules, etc.) can be prepared, for example, by mixing the active ingredient with one or more pharmaceutically acceptable carriers and, optionally, one or more fillers, extenders, binders, humectants, disintegrants, solution retarders, absorption accelerators, wetting agents, absorbents, lubricants, and / or coloring agents. Solid compositions of a similar type may be used as fillers in soft and hard-filled gelatin capsules using appropriate excipients. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using suitable binders, lubricants, inert diluents, preservatives, disintegrants, surface active agents, or dispersing agents. Molded tablets can be made by molding in a suitable machine. Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may also be formulated to provide sustained or controlled release of the active ingredient therein. They may be sterilized, for example, by filtration through a bacteria-retaining filter. These compositions may also optionally contain opacifying agents and may be of a composition that releases the active ingredient only or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner. The active ingredient may also be in microencapsulated form.

[0021] Oral liquid dosage forms include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.Liquid dosage forms may contain suitable inert diluents commonly used in the art.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying agents and suspending agents, sweeteners, flavoring agents, coloring agents, fragrances and preservatives.Suspensions may contain suspending agents.

[0022] Pharmaceutical compositions for rectal or vaginal administration may be presented as suppositories, which can be prepared by mixing one or more active ingredients with one or more suitable non-irritating carriers that are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active compound. Pharmaceutical compositions suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing pharmaceutically acceptable carriers known in the art to be appropriate.

[0023] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, drops, and inhalants. The active agent / compound may be mixed with a suitable pharmaceutically acceptable carrier under sterile conditions. Ointments, pastes, creams, and gels may contain excipients. Powders and sprays may contain excipients and propellants.

[0024] Pharmaceutical compositions suitable for parenteral administration contain one or more drugs / compounds in combination with one or more pharmaceutically acceptable aqueous or non-aqueous sterile isotonic solutions, dispersions, suspensions, or emulsions, which may contain suitable antioxidants, buffers, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use. Proper fluidity can be maintained, for example, by the use of coating materials, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain suitable adjuvants, such as wetting agents, emulsifying agents, and dispersing agents. It may also be desirable to include an isotonic agent. In addition, prolonged absorption of injectable pharmaceutical formulations can be achieved by including an agent that delays absorption.

[0025] In some cases, in order to prolong the effect of a drug (e.g., a pharmaceutical formulation), it is desirable to slow its absorption from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility.

[0026] The rate of absorption of the active agent / drug then depends on its dissolution rate, which may further depend on crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered agents / drugs can be achieved by dissolving or suspending the active agent / drug in an oil vehicle. Injectable depot forms can be prepared by forming microencapsule matrices of the active ingredient in biodegradable polymers. The release rate of the active ingredient can be controlled depending on the ratio of the active ingredient to the polymer and the properties of the specific polymer used. Depot injectable formulations can also be prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues. Injectable materials can be sterilized, for example, by filtration through a bacteria-retaining filter.

[0027] The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials and may be stored in a freeze-dried condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0028] In another aspect, the present invention provides a method for synthesizing the compounds of formula (I) of the present invention. The compounds of the present invention are preferably prepared by (i) coupling erythritol with phenylbutyric acid in the presence of a coupling agent and a solvent, optionally in the presence of a base, to obtain a product; (ii) optionally purifying the product of step (i) to obtain a pure stereoisomer.

[0029] [ka] It can be synthesized by a method comprising the steps of:

[0030] The coupling agent in step (i) may be selected from reagents known to those skilled in the art, such as N,N-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, or any other agent capable of promoting the coupling of an acid with an alcohol to form an ester.

[0031] The base can be 4-dimethylaminopyridine or other similar bases known to those skilled in the art.

[0032] The solvent for coupling in step (i) may be selected from the group consisting of dimethylformamide, dichloromethane or any other suitable solvent known to a person skilled in the art.

[0033] The coupling reaction with phenylbutyric acid in step (i) may be carried out at ambient temperature.

[0034] The purification in step (ii) may be carried out by any suitable purification method such as column chromatography or distillation under reduced pressure.

[0035] In another aspect, the present invention provides a method for synthesizing the compounds of formula (I) of the present invention. The compounds of the present invention are preferably prepared by (i) treating a solution of erythritol with 4-phenylbutanoyl chloride in the presence of a base and a solvent to obtain a product (ii) optionally purifying the product of step (i) to obtain a pure stereoisomer.

[0036] [ka] It can be synthesized by a method comprising the steps of:

[0037] In yet another embodiment, the present invention discloses compositions / formulations containing the compounds of the present invention together with pharmaceutically acceptable excipients.

[0038] In aspects, the present invention discloses the use of compounds and compositions containing the compounds of the present invention for their use in SLC6A1 disorders, including neurodevelopmental disorders, including epilepsy and intellectual disability.

[0039] The present invention is illustrated by the examples, which are for illustrative purposes only and are not to be construed as limiting.

[0040] A. Chemistry Synthesis of (2R,3S)-butane-1,2,3,4-tetrayl-tetrakis(4-phenylbutanoate) (I) Synthesis scheme:

[0041] [ka]

[0042] Procedure: A solution of N,N-dicyclohexylcarbodiimide (1.3 g, 6.30 mmol, 5.12 eq.) in dichloromethane (10 mL) was slowly added to a mixture of erythritol (150 mg, 1.23 mmol, 1 eq.), 4-phenylbutyric acid (908 mg, 5.53 mmol, 4.5 eq.), and 4-dimethylaminopyridine (75 mg, 0.61 mmol, 0.5 eq.) in dichloromethane (20 mL). The reaction mixture was stirred under argon at room temperature (25-35 °C) for 14 h and then at 0 °C for 1 h. The solid product was removed by passing the reaction mixture through Celite and rinsing with cold dichloromethane (50 mL × 2). The organic solvent was dried using sodium sulfate and evaporated under high vacuum to obtain the crude compound. The resulting product was purified by column chromatography (using 100-200 mesh and 1-2% methanol-dichloromethane) to give the desired compound (2R,3S)-butane-1,2,3,4-tetrayltetrakis(4-phenylbutanoate) (yield: 350 mg, 40%).

[0043] ESI-MS(m / z) C 44 H 50Calculated value for O8: 706.87, observed value: 724.4 [M+18] + 1 H-NMR (300MHz, DMSO-d6)δ:7.25-7.22(m,8H), 7.18-7.13(m,12H), 5.24(s,2H), 4.34-4.31 (d,J=9Hz,2H), 4.20-4.16(m,2H), 2.56-2.54(m,8H), 2.31-2.24(m,8H), 1.82-1.75(m,8H)

[0044] B. Pharmacokinetic Profiles of the Compounds of the Invention A pharmacokinetic (PK) study was conducted to evaluate the plasma exposure of two PBA analogs (ATX-2022-018 and ATX-2022-034) when orally administered (PO) at 22.5 mg / kg in 50% propylene glycol. Dosing was administered to overnight-fasted SD rats (n=6). After PO administration, blood was collected into heparinized tubes by serial blood sampling at eight different time points. Blood samples were centrifuged at 10,000 rpm at 4°C for 5 minutes to obtain plasma, which was aspirated into separate labeled tubes and stored at -80°C. Extraction solvent (150 μL of 0.1% aqueous acetic acid: 0.1% acetic acid in methanol, 20:80) was added to the plasma, vortexed, shaken on a shaker for 10 minutes, and centrifuged at 10,000 rpm at 4°C for 10 minutes. The supernatant was used for LC-MS analysis. The produced parent drug, which is PBA, was monitored by LC-MS (API3200).

[0045] Details of the LC column and mobile phase used for the analysis are provided below: Column: Gemini NX C18, 50mm*4.6mm*3.5μ Mobile phase: A: 0.1% acetic acid aqueous solution B: 0.1% acetic acid in methanol Flow rate: 0.600 mL / min, gradient program Gradient Program:

[0046] [Table 2]

[0047] Acetonitrile and plasma calibration curves were prepared to determine drug recovery from plasma. Quantitative analysis was performed using a liquid chromatography tandem mass spectrometer (API3200 LC-MS / MS). Cmax, Tmax, AUC, and t1 / 2 were calculated using GraphPad PRISM version 5.04.

[0048] [Table 3]

Claims

1. The following structure: 【Chemistry 4】 A compound comprising:

2. 10. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

3. With respect to the weight percentage of the compound of claim 1, less than 20%, 15%, 10%, 5%, 2% or 1% by weight of the following compounds: 【Chemistry 5】 The composition of claim 2 comprising:

4. A method for treating SLC6A1 and related disorders, including neurodevelopmental disorders, including epilepsy and intellectual disability, in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a composition of claim 2 or 3.

5. (i) treating a solution of erythritol with 4-phenylbutanoyl chloride in the presence of a base and a solvent to obtain a product; and (ii) optionally purifying the product of step (i) to obtain a pure stereoisomer.

10. A method for synthesizing the compound of claim 1, comprising:

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