Improved in-SITU synthesis of amino methyl propanoic acid

Abstract

The invention disclosed herein relates to technically advanced in-situ synthesis of amino methyl propanoic acid. Particularly the invention relates to in-situ, recycled organocatalysed synthesis of amino methyl propanoic acid with high yield and purity. Further the amino methyl propanoic acid obtained from the process is useful in the treatment of metabolic health, cardiovascular health, muscle health, anti-inflammatory effects, neuroprotection and women health.

Description

[0001] 11691W0008

[0002] IMPROVED IN-SITU SYNTHESIS OF AMINO METHYL PROPANOIC ACID TECHNICAL FIELD:

[0003] The present invention relates to technically advanced in-situ synthesis of amino methyl propanoic acid. Particularly the invention relates to in-situ, recycled organocatalysed synthesis of amino methyl propanoic acid with high yield and purity. Further the amino methyl propanoic acid obtained from the process is useful in the treatment of metabolic health, cardiovascular health, muscle health, anti-inflammatory effects, neuroprotection and women health.

[0004] BACKGROUND OF THE INVENTION:

[0005] Amino methyl propanoic acid is a naturally occurring small molecule of growing interest for its potential roles in metabolic regulation, exercise physiology, and the management of metabolic disorders. It exists as two biologically relevant enantiomers formed in mammals through the catabolism of thymine and valine and functions as a signaling metabolite influencing fat oxidation, mitochondrial biogenesis, and energy metabolism.

[0006] Amino methyl propanoic acid or BAIBA has been identified as a myokine, a signaling molecule released by muscles during exercise. It has been implicated in various metabolic pathways, including the browning of white adipose tissue (WAT), which may contribute to increased energy expenditure and improved metabolic health. It has been shown to reduce body fat percentage through an increase in fatty acid oxidation and a decrease in hepatic lipogenesis in animals.

[0007] Amino methyl propanoic acid has been shown to stimulate hepatic fatty acid betaoxidation, promote the browning of white adipose tissue, and aid in exercise-induced protection against metabolic diseases. These effects are achieved by enhancing the expression of peroxisome proliferator-activated receptor-gamma co-activator-la (PGC-la) [Cell Metabol. 2014;19(l):96-108].

[0008] Additionally, Amino methyl propanoic acid helps to reduce insulin resistance (which results from incomplete fatty acid oxidation), suppresses inflammation, and enhances fatty acid oxidation in skeletal muscle tissue by activating the AMP-activated protein kinase (AMPK)-peroxisome proliferator-activated receptor (PPAR)-delta pathway. Increased fatty acid oxidation in skeletal muscle is linked to several benefits, including a lower body fat percentage, reduced body weight, and an elevated metabolic rate in skeletal muscle [International Journal of Toxicology 2022, Vol. 41(4) 329-346]. 11691W0008

[0009] The synthesis of amino methyl propanoic acid is important because it opens up opportunities for improving metabolic health, managing obesity, enhancing exercise benefits, and potentially developing new treatments for metabolic disorders. Effective and scalable synthesis methods are essential for advancing research and practical applications of amino methyl propanoic acid in medicine and nutrition.

[0010] The traditional method involves the reaction of a suitable precursor, often using amino acid derivatives or related compounds, under specific reaction conditions. This approach typically requires careful selection of reagents and catalysts to achieve high yields and purity.

[0011] Enzymes such as aminotransferases or reductases can be used to facilitate the synthesis of amino methyl propanoic acid from various precursors.

[0012] Microbial fermentation offers a promising method for producing P-aminoisobutyric acid, but it comes with limitations related to strain development, fermentation conditions, yield, cost, and regulatory compliance. Addressing these challenges requires ongoing research and optimization to enhance the efficiency and scalability of microbial fermentation processes for amino methyl propanoic acid production

[0013] CN103864633 discloses a method for producing a-aminoisobutyric acid, using acetone cyanohydrin and ammonium carbonate in water medium under pressure and heating to synthesize alpha-aminoisobutyric acid. However, acetone cyanohydrin use is accompanied by certain circumscriptions related to toxicity, environmental impact, stability, production challenges, and regulatory compliance.

[0014] CN 117069603 discloses synthesis method of 3-aminoisobutyric acid from methacrylic acid

[0015] US6372936 Bl provides the process for resolving racemic 3-amino-2-methylpropionic acid, wherein the diastereomeric salts are recrystallized from ethyl acetate to separate the salts into pure fractions; wherein chiral amine is quinidine, quinine.

[0016] (S)-P- Aminoisobutyric acid (L-BAIBA) is the L-enantiomer of P-aminoisobutyric acid, a non-proteinogenic amino acid with the chemical formula C4H9NO2. It is also known as (S)-3-amino-2-methylpropanoic acid and is produced in skeletal muscle during exercise through pyruvate metabolism. L-BAIBA acts as a signaling molecule that promotes fat oxidation, mitochondrial biogenesis, and improved metabolic regulation, thereby contributing to energy homeostasis and neuroprotection. Unlike its D-enantiomer, which originates from thymine 11691W0008

[0017] catabolism, L-BAIBA is specifically associated with muscle-derived metabolic pathways and plays a vital role in muscle-fat communication and overall metabolic health.

[0018] There are some alternative methods such as enzymatic resolution and derivatization to form diastereomers that can be separated using standard chromatographic techniques. The preparation of BAIBA is associated with various challenges, including issues related to enantiomeric purity, reagent selection, reaction conditions, purification, scalability, and environmental impact. Addressing these limitations requires optimization of the synthesis process, careful selection of reaction conditions, and the development of cost-effective and environmentally friendly production methods. Further research and innovation in these areas could improve the feasibility of producing BAIBA for broader applications.

[0019] The synthesis of amino methyl propanoic acid often involves multiple chemical reactions or enzymatic steps. Each step can require precise control of conditions (e.g., temperature, pH) and may involve intermediate purification, which adds time to the overall process; Isolating and purifying intermediates between reaction steps can be time-consuming. The need to achieve high purity can extend the duration of the synthesis.

[0020] The selective hydroamination of methacrylic acid is a promising method for synthesizing P-aminoisobutyric acid (BAIBA) wherein the catalysts used in the reactions affects the rate of reaction such as transition metal catalysts, such as those based on platinum, palladium, or other metals, enzymatic catalysts may be employed to facilitate the hydroamination reaction, use of such catalyst extend the reaction time and the cost thereof. Moreover, such catalysts are often come with concerns about cost, environmental impact, selectivity, stability, and scalability.

[0021] Addressing these limitations requires interdisciplinary efforts, including advances in synthetic chemistry, enzymology, process engineering, and regulatory compliance. It is need to develop more efficient and selective synthetic routes for amino methyl propanoic acid by exploring novel biocatalytic approaches to enhance yield and sustainability.

[0022] By overcoming these limitations, the present inventors unlock the full potential of BAIBA by introducing highly advantageous catalyst, wherein the strong basicity, non-nucleophilic nature, versatility nature of catalyst make it to operate under mild conditions. Its use can lead to more efficient, selective, and environmentally friendly reactions compared to other catalysts, making it effective choice in industrial settings. 11691W0008

[0023] OBJECTIVE OF THE INVENTION:

[0024] The objective of the present invention relates to technically advanced in-situ synthesis of amino methyl propanoic acid i.e. beta aminoisobutyric acid.

[0025] Another objective of the present invention is to provide green synthesis of beta aminoisobutyric acid by employing recyclable organ catalyst.

[0026] Further objective of the present invention is to provide time saving, cost-effective and environmentally friendly synthesis of beta aminoisobutyric acid.

[0027] Yet another objective of present invention is to provide industrially viable in situ process for the preparation of optically active beta aminoisobutyric acid with higher purity and yield.

[0028] Another objective of the invention is to provide effective composition of beta aminoisobutyric acid in the treatment of metabolic health, cardiovascular health, muscle health, anti-inflammatory effects, neuroprotection, women health.

[0029] SUMMARY OF THE INVENTION:

[0030] To meet the above objectives, the inventors of the present invention carried out thorough experiments to establish effective, industrially viable, green, in-situ process for preparation of beta aminoisobutyric acid for treatment of treatment of metabolic health, cardiovascular health, muscle health, anti-inflammatory effects, neuroprotection, women health.

[0031] In a particular aspect, the present invention relates to organocatalyst mediated, green synthesis of beta aminoisobutyric acid.

[0032] In another aspect, the invention relates to in situ process for synthesis of beta aminoisobutyric acid comprising steps of organocatalyzed conjugate addition; hydrolysis followed by catalytic hydrogenation to obtain racemic P-aminoisobutyric acid with high yield and purity.

[0033] In another aspect, the present invention relates to cost effective, green enantioselective synthesis of optically active P-aminoisobutyric acid with enantiomeric excess of L isomer.

[0034] Further the enantioselective P-aminoisobutyric acid is useful in the treatment of metabolic health, cardiovascular health, muscle health, anti-inflammatory effects, neuroprotection, women health.

[0035] BRIEF DESCRIPTION OF THE FIGURES:

[0036] Figure. 1 illustrates the ’H NMR-400 MHz D2O data of the test sample L-3-amino-2-methylpropanoic acid. 11691W0008

[0037] Figure. 2 illustrates the HPLC chromatogram of the (a) standard and (b) test sample of L-3-amino-2-methylpropanoic acid.

[0038] Figure. 3 illustrates UCP1 protein expression in folds for G1 (Saline- Control), G2 (L-3-amino-2-methylpropanoic acid- 100 mg / kg), and G3 (L-3-amino-2-methylpropanoic acid-500 mg / kg).

[0039] DETAILED DESCRIPTION OF THE INVENTION:

[0040] The invention will now be described in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully interpreted and comprehended. However, any skilled person or artisan will appreciate the extent to which such embodiments could be generalized in practice.

[0041] It is further to be understood that all terminology used herein is for the purpose of describing particular embodiment only and is not intended to be limiting in any manner or scope. Unless defined otherwise, all technical and scientific expressions used herein have the same meaning as commonly understood by one of ordinary skill in the art to which embodiments of the invention pertain.

[0042] In describing and claiming the embodiments of the present invention, the following terminology will be used in accordance with the definitions set out below which are known in the state of art.

[0043] As used in the specification the singular forms "a" "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a solvent" includes mixtures of solvents, reference to "an agent" includes mixtures of two or more such agents, and the like.

[0044] The term “pharmaceutically / nutraceutically acceptable salt,” as use herein, represents those salts which are within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio. Particularly, the term “pharmaceutically-acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds, alkali or alkaline earth metal salts, as well as solvates, co-crystals, polymorphs and the like of the salts.

[0045] All modifications and substitutions that come within the meaning of the description and the range of their legal equivalents are to be embraced within their scope. A description using the 11691W0008

[0046] transitional phrase “comprising” allows the inclusion of other elements to be within the scope of the invention.

[0047] The end product “amino methyl propanoic acid” also referred as “3-amino 2-methylpropanoic acid” OR “3-aminoisobutyric acid” OR “beta-aminoisobutyric acid” OR “dl-3-aminoisobutyric acid” OR “BAIBA”.

[0048] In preferred embodiment, the present invention relates to technically advanced in-situ synthesis of amino methyl propanoic acid.

[0049] In another embodiment, the present invention provides cost-effective, industrially viable process for the preparation of bioactive amino methyl propanoic acid with high purity and high yield.

[0050] In another embodiment, the present invention provides a recyclable catalyst-mediated in situ process for the synthesis of amino methyl propanoic acid with improved yield and purity, comprising the steps of performing a conjugate addition reaction in the presence of a recyclable organocatalyst, followed by acid-base hydrolysis of the resulting intermediate and subsequent catalytic hydrogenation to afford 3-amino-2-methylpropanoic acid, wherein the obtained product is subjected to isolation and / or optical resolution using suitable resolving agents to yield the optically active form.

[0051] The process involved in the present invention comprising green solvents, wherein the intermediates have acceptable and appropriate toxicity and ecotoxicity.

[0052] In another embodiment, the invention provides simple, in-situ process for synthesis of beta aminoisobutyric acid comprising the steps of;

[0053] a) conjugate addition of phenylmethanamine with methyl methacrylate (MMA) in presence of recyclable organocatalyst;

[0054] b) hydrolysis of methyl 3-(benzylamino)-2-methylpropanoate to 3-(benzylamino)-2- methylpropanoic acid in presence of acid-base;

[0055] c) catalytic hydrogenation of 3-(benzylamino)-2-methylpropanoic acid to 3-amino 2- methylpropanoic acid in presence of metal catalyst.

[0056] d) isolation / resolution of optically active isomer of 3-amino 2-methylpropanoic acid by using resolving agents.

[0057] In one of the inventive features of the present invention, the recyclable organocatalyst employed in step (a) is l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU). DBU facilitates the 11691W0008

[0058] conjugate addition between benzylamine, acting as a nucleophile, and the 0-carbon of methyl acrylate, an a,P-unsaturated ester, to form the corresponding P-amino ester intermediate. The inventive use of DBU as a recyclable organocatalyst provides several advantages, including its strong basicity, non-nucleophilic nature, high catalytic efficiency, thermal stability, and excellent solubility. Moreover, DBU can be easily recovered and reused across multiple reaction cycles without significant loss of activity, thus enhancing process sustainability. These unique characteristics collectively contribute to improved yield, operational simplicity, and environmental compatibility, distinguishing the present invention as a green and efficient synthetic approach for producing 3-amino-2-methylpropanoic acid.

[0059]

[0060] In another embodiment, the present invention involves the use of DBU in the first step. Due to the use of DBU, the conjugation reaction is completed in few hours with more than 98% conversion. Moreover, DBU increases the rate of reaction which also avoids the formation of impurities (which are formed due to reaction in longer period of time).

[0061] The first step of the present invention carried out in absence of expensive solvent which increases overall cost of the reaction.

[0062] In yet another embodiment the invention provides in-situ process for synthesis of beta aminoisobutyric acid, wherein the hydrolysis of methyl 3-(benzylamino)-2-methylpropanoate to 3-(benzylamino)-2-methylpropanoic acid is carried out with saponification of base followed by neutralization or acidification with acid under suitable condition.

[0063] In some embodiment, the acidic medium used in the process is selected from dilute or concentrate organic acid or inorganic acid but not limiting to acetic acid, tartaric acid, hydrochloric acid, formic acid, phosphoric acid, benzoic acid, sulfuric acid, boric acid, malic acid, triethylammonium acetate buffer, dichloroacetic acid, trifluoroacetic acid and like thereof.

[0064] In another embodiment, the base used in the process is selected from sodium hydroxide, potassium hydroxide, ammonia hydroxide, sodium bicarbonate, sodium carbonate, lithium hydroxide, magnesium hydroxide, methylamine, ethylamine, aniline, dimethylamine, pyridine 11691W0008

[0065] ammonia, triethylamine, dimethylformamide, pyrrolidine, N-N-dimethylacetamide and like thereof.

[0066]

[0067] In yet another embodiment, the present invention provides an in-situ process for the synthesis of P-aminoisobutyric acid (BAIBA), wherein the catalytic hydrogenation of 3-(benzylamino)-2-methylpropanoic acid is carried out in the presence of a metal catalyst such as palladium on carbon (Pd / C), platinum on carbon (Pt / C), Raney nickel, ruthenium on carbon (Ru / C), or rhodium on alumina (Rh / ALOa). The catalytic hydrogenation facilitates the selective removal of the benzyl protecting group to yield the desired 3-amino-2-methylpropanoic acid. The metal catalyst, preferably Pd / C, can be conveniently recovered after the completion of the reaction by simple filtration, washed to remove impurities, and reactivated for subsequent reuse without significant loss in activity, thereby providing a sustainable and efficient hydrogenation process suitable for large-scale synthesis. After the reaction, Pd / C can be recovered and reused. The catalyst is generally filtered off after the reaction, washed, and then reactivated for further use.

[0068] Further the catalytic hydrogenation carried out in presence of green solvent systems enhances the overall environmental compatibility of the process, reduces hazardous waste generation, and contributes to the development of a sustainable and eco-friendly synthesis of P-aminoisobutyric acid (BAIBA).

[0069]

[0070] 11691W0008

[0071] In additional embodiment the racemic mixture of 3-amino-2-methylpropanoic acid is further resolved to obtain enantiomeric excess of therapeutically active L isomer of 3-amino-2-methylpropanoic acid; L-3-Aminoisobutyric acid; (L-BAIBA).

[0072]

[0073] In another embodiment the present invention provides to in-situ conversion of intermediates in order to obtain 3-amino-2-methylpropanoic acid (BAIBA) which decreases overall operation cost in plant scale resulting process industrially viable.

[0074] The green solvents used in overall synthesis are selected from water, methanol, ethanol, ethyl acetate, propanol, isopropanol, butanol, glycerol, propylene carbonate, 2-methyltetrahydrofuran (2-MeTHF), dimethyl carbonate (DMC) or mixtures thereof.

[0075] In some embodiment, the polar aprotic solvent used in the process is selected acetone, dimethyl sulfoxide, acetonitrile, dimethylformamide, tetrahydrofuran, (diethyl ether), chloroform, ether, dichloromethane, hexamethylphosphoramide, methyl ethyl ketone and like thereof.

[0076] In another embodiment, the L-isomer of P-aminoisobutyric acid (L-BAIBA), can then be separated based on its solubilities with resolving agents. The commonly used resolving agents are tartaric acid, camphorsulfonic acid, mandelic acid, mosher’s acid, chiral diphosphine, chiral crown ethers: 1,2-diaminocyclohexane, menthol, 1 -phenylethanol, cinchonidine, cinchonine, quinidine, quinine, phthalic acid, (S)-l -Phenylethylamine and like thereof.

[0077] In some embodiment, the temperature maintained in the process is ranged from 0-40°C, preferably ambient temperature.

[0078] In some embodiments, the in-situ process produces the final product amino methyl propanoic acid with a yield of 80-90% (w / w) and enantiomeric purity 95-99%.

[0079] In another embodiment, the end product attains a purity level exceeding 95%, which is confirmed through comprehensive analytical characterization employing various categories of instrumental techniques. Moreover, the structural elucidation is performed using spectroscopic instruments such as Nuclear Magnetic Resonance (NMR), Ultraviolet- Visible (UV) spectroscopy, 11691W0008

[0080] Infrared (IR) and Fourier Transform Infrared (FTIR) spectroscopy; chromatographic purity and composition are assessed using High-Performance Liquid Chromatography (HPLC), Thin Layer Chromatography (TLC), and Gas Chromatography (GC); while crystalline nature and phase identification are determined by X-Ray Diffraction (XRD) analysis.

[0081] The optical purity is equal to the percentage excess of the major enantiomer over the minor enantiomer. This term, the “enantiomeric excess”, or “e.e.” is equivalent to the optical purity or expressing the enantiomeric purity of a mixture.

[0082] Further the amino methyl propanoic acid obtained from the process is useful in the treatment of metabolic health, cardiovascular health, muscle health, anti-inflammatory effects, neuroprotection, women health.

[0083] Particularly, the therapeutically active BAIBA compound prepared from the present in-situ process is useful in the treatment and management of a wide range of metabolic and lifestyle-related disorders. These include metabolic diseases such as obesity, insulin resistance, type 2 diabetes, dyslipidemia, and metabolic syndrome; enhancement of muscle function and growth, prevention of muscle atrophy and sarcopenia; improvement of lipid profiles and reduction of systemic inflammation. Additionally, BAIBA exhibits potential in managing chronic inflammatory and oxidative stress-related conditions such as cardiovascular diseases, nonalcoholic fatty liver disease (NAFLD), atherosclerosis, and neuroinflammatory disorders including Alzheimer’s disease. It further contributes to bone health by preventing osteoporosis and promoting bone regeneration. In women’s health, the compound is beneficial in conditions such as menstrual irregularities, endometriosis, pelvic inflammatory disease, polycystic ovarian syndrome (PCOS), and Premenstrual Syndrome (PMS). Emerging studies also indicate its potential utility in promoting mitochondrial biogenesis, enhancing energy metabolism, supporting cognitive function, regulating thermogenesis, and contributing to overall metabolic homeostasis.

[0084] In another embodiment, the present invention provides a method for treating metabolic or chronic disorders in a subject in need thereof. The method comprises administering of a therapeutically effective amount of a medicinal composition comprising enantiomeric 0-aminoisobutyric acid compounds of along with pharmaceutically acceptable excipients. 11691W0008

[0085] In certain embodiments, the invention provides the potent medicinal composition comprising P-aminoisobutyric acid, wherein the effective unit dose for an oral administration is formulated in a range of 1 to 1000 mg.

[0086] In some embodiment, the daily dose of a pharmaceutical or nutritional composition comprising present amino methyl propanoic acid disclosed herein varies over a wide range from about 0.1 mg to about 5000 mg; preferably, the dose is in the range of about 1 mg to about 1000 mg per day for an average human.

[0087] In general, the total daily dose (in single or divided doses) ranges from about 0.1 mg per day to about 5000 mg per day, preferably about Img per day to about 1000 mg per day.

[0088] In some embodiment, the total daily dose can be administered in the range of about 1 mg to about 3000 mg per day, and preferably about 1 mg to about 1000 mg per day.

[0089] The term "therapeutically effective amount" denotes an amount that reduces the risk, potential, possibility or occurrence of a disease or disorder, or provides advanced alleviation, mitigation, and / or reduction or restoration or modulation, regulation of at least one indicator / biomarker (e.g., blood or serum CRP level), and / or minimize at least one clinical symptom related to metabolic disorders like obesity.

[0090] The term "subject in need thereof" refers to a subject, preferably a mammal and more specifically a human, suffering from or suspected of having overweight.

[0091] In the context of the present invention, the term “treatment” refers to alleviate, mitigate, prophylaxis, attenuate, manage, regulate, modulate, control, minimize, lessen, decrease, down regulate, up regulate, moderate, inhibit, restore, suppress, limit, block, decrease, prevent, inhibit, stabilize, ameliorate, cure, heal metabolic or nervous system related disorders observed in the patient. Notably, the present bioactive non-hazardous, non-toxic, and safe for human consumption without any severe adverse effects, therefore the present medicinal composition can also be used as preventive therapy, adjuvant therapy, add-on therapy, combination, adjunctive therapy in a subject in need thereof.

[0092] In general, all physical forms are of use in the methods contemplated by the present invention and are intended to be within the scope of the invention.

[0093] Compound(s) or pharmaceutically acceptable salts includes but not limited to, hydrates, polymorphs, solvates, enantiomers or racemates. Some of the crystalline forms of the compound(s) exist as polymorphs and as such are intended to be included in the present 11691W0008

[0094] disclosure. In addition, some of the compound(s) may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are intended to be encompassed by some embodiments.

[0095] In some of the embodiments, the present invention provides medicinal composition comprising the present amino methyl propanoic acid which is present in therapeutically effective amount along with pharmaceutically acceptable excipients.

[0096] As used herein, the term “pharmaceutically acceptable carriers, diluents or excipients” is purported to mean, without limitation, any adjuvant, carrier, excipient, sweetening agent, diluents, preservative, dye / colorant, flavour enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or encapsulating agent, encapsulating polymeric delivery systems or polyethylene glycol matrix, which is acceptable for use in the subject, preferably humans. Excipients also include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, surfactant, anticaking agent, food additives, or waters of hydration, salts.

[0097] In another embodiment, the present invention relates to medicinal composition of the amino methyl propanoic acid prepared in a manner well known in the pharmaceutical art and administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.

[0098] The preferable route of administration includes but is not limited to sublingual, rectal, topical, parenteral, nasal, or oral.

[0099] In certain embodiments, the medicinal composition comprising amino methyl propanoic acid is administered to a subject in need thereof in a form suitable for oral administration, without limitation to any specific dosage form such as a tablet, capsule (in the form of delayed release, extended release, sustained release, enteric coated release); hard gelatin capsules, soft gelatin capsules in an oily vehicle, veg capsule, hard or soft cellulose capsule, granulate for sublingual use, effervescent or carbon tablets, aqueous or oily solution, suspension or emulsion, encapsulate, matrix, coat, beadlets, nanoparticles, caplet, granule, particulate, agglomerate, spansule, chewable tablet, lozenge, troche, solution, suspension, rapidly dissolving film, elixir, gel, tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, sprays or 11691W0008

[0100] reconstituted dry powdered form with a liquid medium or syrup; for topical use including transmucosal and transdermal use, such as a cream, ointment, gel, aqueous or oil solution or suspension, salve, parch or plaster; for nasal use, such as a snuff nasal spray or nasal drops; for vaginal or rectal use, such as a suppository; for administration by inhalation, such as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, such as a tablet, capsule, film and spray.

[0101] In a further embodiment, the present composition is formulated in the form of age-appropriate pediatric oral dosage forms such as syrup, inhalation, spray minitablets, chewable formulations, orodispersible films and orodispersible tablets.

[0102] The magnitude of a prophylactic or therapeutic dose typically varies with the nature and severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient.

[0103] In some embodiment, the amino methyl propanoic acid or pharmaceutically acceptable salts thereof, are formulated for medicaments, which preferably take the form of therapeutically effective individual doses adjusted to the form of administration.

[0104] A "therapeutically effective amount" means the amount of the compound that, when administered to a subject to treat a disease or condition referred to herein, is sufficient to perform such treatment for the disease or condition.

[0105] The "therapeutically effective amount" will vary depending on the form of the compound (for example, the form of the salt), the disease or condition in question and its severity, as well as the age, weight, etc., of the subject to be treated.

[0106] The use of any and all examples, or exemplary language (e.g., such as) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.

[0107] While in the foregoing specification this invention has been described in relation to certain embodiments thereof, and many details have been put forth for the purpose of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details described herein can be varied considerably without departing from the basic principles of the invention. 11691W0008

[0108] The present invention is not limited to the specific embodiments described, which serve as illustrations of its various aspects. The following examples are provided for illustrative purposes and should not be construed as limiting the invention’s scope. The scope is defined by the appended claims, and any modifications or equivalents fall within its scope.

[0109] Having described the basic aspects of the present invention, the following non-limiting examples illustrate specific embodiments thereof. Those skilled in the art will appreciate that many modifications may be made in the invention without changing the essence of invention. In general, all physical forms are of use in the methods contemplated by the present invention and are intended to be within the scope of the invention. Compound or pharmaceutically acceptable salts, hydrates, polymorphs or solvates of a compound intends the inclusive meaning of “or”, in those materials meeting more than one of the stated criteria are included, e.g., a material that is both a salt and a solvate is encompassed. Some of the crystalline forms of the compound exist as polymorphs and as such are intended to be included in the present disclosure. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are intended to be encompassed by some embodiments.

[0110] In some embodiment, the invention provides medicinal compositions comprising optically active P-aminoisobutyric acid (BAIBA) present in effective amount along with pharmaceutically acceptable excipients.

[0111] In general, all physical forms are of use in the methods contemplated by the present invention and are intended to be within the scope of the invention.

[0112] Compound(s) or pharmaceutically acceptable salts includes, hydrates, polymorphs, solvates, enantiomers or racemates. Some of the crystalline forms of the compound(s) exist as polymorphs and as such are intended to be included in the present disclosure. In addition, some of the compound(s) may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are intended to be encompassed by some embodiments.

[0113] In some of the embodiments, the present invention provides medicinal composition comprising the present bioactive nucleotide compound(s) which is present in therapeutically effective amount along with pharmaceutically acceptable excipients.

[0114] As used herein, the term “pharmaceutically acceptable carriers, diluents or excipients” is purported to mean, without limitation, any adjuvant, carrier, excipient, sweetening agent, diluents, preservative, dye / colorant, flavour enhancer, surfactant, wetting agent, dispersing agent, 11691W0008

[0115] suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or encapsulating agent, encapsulating polymeric delivery systems or polyethylene glycol matrix, which is acceptable for use in the subject, preferably humans. Excipients also include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colours), emollients, emulsifiers, fillers (diluents), film formers or coatings, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, surfactant, anticaking agent, food additives, or waters of hydration, salts.

[0116] In some embodiments, the amino methyl propanoic acid can be formulated in medicaments by using pharmaceutically acceptable excipients, without limitation, such as diluents, binders, disintegrants, lubricants, solubilizing agents, surfactants, stabilizers, colours, flavouring agents, sweeteners, glidants, plasticizers and other additives.

[0117] In another embodiment of the present invention, the diluents are selected from but not limited to starches, hydrolyzed starches, partially pregelatinized starches, anhydrous lactose, cellulose powder, lactose monohydrate, sugar alcohols such as sorbitol, xylitol and mannitol, silicified microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium lactate, dibasic calcium phosphate (anhydrous / dibasic dehydrate / tribasic), calcium silicate, calcium sulphate, cellulose acetate, corn starch, pregelatinized starch, dextrin, P-cyclodextrin, dextrates, dextrose, erythritol, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sterilizable maize, sucrose, sugar spheres, talc, trehalose, xylitol, vehicles like petrolatum, dimethyl sulfoxide and mineral oil or the like.

[0118] In some embodiment of the invention, the diluent in the composition / formulation is present in a range of 1% to 30% by weight of the total composition / formulation.

[0119] In yet another embodiment of the invention, the binder is selected from but not limited to disaccharides such as sucrose, lactose, polysaccharides and their derivatives like starches, cellulose, or modified cellulose such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC); hydroxypropyl methyl cellulose (HPMC); sugar alcohols such as xylitol, sorbitol, or mannitol; protein like gelatin; synthetic polymers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), starch, acacia, agar, alginic acid, calcium carbonate, calcium lactate, carbomers, carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, chitosan, co-povidone, corn starch, pregelatinized starch, cottonseed 11691W0008

[0120] oil, dextrates, dextrin, dextrose, ethyl cellulose, guar gum, hydrogenated vegetable oil, mineral oil, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyl ethyl methyl cellulose, hydroxypropyl cellulose, inulin, cellulose, methyl cellulose, polyvinylpyrrolidone and polyethylene glycol, lactose, liquid glucose, hypromellose, magnesium aluminium silicate, maltodextrin, maltose, methyl-cellulose, microcrystalline cellulose, pectin, poloxamer, polydextrose, polymethacrylates, povidone, sodium alginate, stearic acid, sucrose, sunflower oil, various animal vegetable oils, and white soft paraffin, paraffin, flavourants, colorants and wax.

[0121] In further embodiment of the present invention, the binder in the composition / formulation is present in a range of 0.1 to 30% by weight of the composition / formulation.

[0122] In another embodiment of the present invention, the disintegrants are selected from but not limited to, Polyvinylpolypyrrolidone (polyvinyl polypyrrolidone, PVPP, crospovidone, crospolividone or E1202) is a highly cross-linked modification of polyvinylpyrrolidone (PVP), calcium carbonate, sodium starch glycolate, croscarmellose sodium, microcrystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC), mannitol, colloidal silicon dioxide, hydrated silica and / or hypromellose, maize starch, salts of carboxy methyl cellulose, alginic acid, sodium alginate, guar gum or mixtures thereof.

[0123] In further embodiment of the present invention, the disintegrants in the composition / formulation is present in a range of 0.1 to 10% by weight of the composition / formulation.

[0124] In another embodiment of the present invention, the lubricant is selected from but not limited to magnesium stearate, zinc stearate, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulphate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc, potassium, or sodium benzoate or the like. In some embodiment of the present invention, the lubricant in the composition / formulation is present in a range of 0.1% to 10.0% by weight of the total composition / formulation.

[0125] In some embodiment of the present invention, the glidant is selected from but not limited to colloidal silicon dioxide, magnesium stearate, fumed silica (colloidal silicon dioxide), starch, talc, calcium phosphate tribasic, cellulose powdered, hydrophobic colloidal silica, magnesium oxide, zinc stearate, magnesium silicate, magnesium trisilicate, silicon dioxide or the like. 11691W0008

[0126] In another embodiment of the present invention, the glidant in the composition / formulation is present in a range of 0.1% to 5.0% by weight of the total composition / formulation

[0127] In another embodiment of the present invention, the solubilizing agent or surfactant is selected from but not limited to polysorbate 80, sodium lauryl sulphate, anionic emulsifying wax, nonionic emulsifying wax, glyceryl monooleate, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sorbitan esters, triethyl citrate, vitamin E, polyethylene glycol succinate, microcrystalline cellulose, carboxymethylcellulose sodium, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, hypromellose, hypromellose, acetate succinate, lecithin, polyethylene alkyl ethers, aluminum oxide, poly(methylvinyl ether / maleic anhydride), calcium carbonate, crospovidone, cyclodextrins, fructose, hydroxpropyl betadex, oleyl alcohol, povidone, benzalkonium chloride, benzethonium chloride, benzyl alcohol, benzyl benzoate, cetylpyridinium chloride, inulin, meglumine, poloxamer, pyrrolidone, sodium bicarbonate, starch, stearic acid, sulfobutylether beta cyclodextrin, tricaprylin, triolein, docusate sodium, glycine, alcohol, self-emulsifying glyceryl monooleate, cationic benzethonium chloride, cetrimide, xanthan gum, lauric acid, myristyl alcohol, butylparaben, ethylparaben, methylparaben, propylparaben, sorbic acid or the like.

[0128] In another embodiment of the present invention, the amount of solubilizing agent or surfactant in the composition / formulation ranges from 0.1% to 10% by weight of the composition / formulation.

[0129] In a preferred embodiment of the present invention, the solubilizing agent or surfactant is present in a range of 0.1% to 5.0% by weight of the composition / formulation.

[0130] In some embodiment of the present invention, the stabilizers are selected from but not limited to the group consisting of alginate, agar, carrageen, gelatin, guar gum, gum arabic, locust bean gum, pectin, starch, xanthan gum, trehalose and likewise.

[0131] In some embodiment of the present invention, the stabilizer in the composition / formulation is present in a range of 0.1 % to 8.0% by weight of the total composition / formulation.

[0132] In some embodiment of the invention, the plasticizers are added to coating formulations selected from but not limited to the group propylene glycol, glycerol, glyceryl triacetate 11691W0008

[0133] (triacetin), triethyl citrate, acetyl triethyl citrate, diethyl phthalate, actetylated monoglycerides, castor oil, mineral oil and like thereof.

[0134] In some embodiment of the present invention, the plasticizer in the composition / formulation is present in a range of 0.1 % to 5.0% by weight of the total composition / formulation.

[0135] The additional additives include a polymer, a plasticizer, a sweetener, and a powdered flavour, a preservative, a colorant, a surfactant, and other excipients. The powdered flavour composition includes a flavourant associated with a solid carrier. Coating materials such as synthetic polymers, shellac, corn protein (zein) or other polysaccharides, gelatin, fatty acids, waxes, shellac, plastics, and plant fibers and like thereof are used.

[0136] In a preferred embodiment of the present invention, the additives are used in a range of 0.1 to 10% w / w of unit dose.

[0137] In some embodiment of the present invention, the solvent is selected from but not limited to water, alcohol, isopropyl alcohol, propylene glycol, mineral oil, benzyl alcohol, benzyl benzoate, flavored glycol, carbon dioxide, castor oil, corn oil (maize), cottonseed oil, dimethyl ether, albumin, dimethylacetamide, ethyl acetate, ethyl lactate, medium-chain triglycerides, methyl lactate, olive oil, peanut oil, polyethylene glycol, polyoxyl, castor oil, propylene carbonate, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, water-miscible solvents, organic polar or non-polar solvents or mixtures thereof.

[0138] In a preferred embodiment of the present invention, the solvent in the composition / formulation is used in a quantity sufficient to make the weight of the composition / formulation 100% by weight.

[0139] In yet another embodiment, the present invention provides a medicinal composition comprising amino methyl propanoic acid along with pharmaceutical excipients, wherein the pharmaceutical excipients are selected from a diluent, a binder, a disintegrant, a lubricant, a glidant, a solubilizing agent or surfactant an additive, a stabilizer, a plasticizer, the additives, the solvents or mixtures thereof.

[0140] In a preferred embodiment, the diluent is present in a range of 1 to 30%; the binder is present in a range of 0.1 to 30 %; the disintegrant is present in a range of 0.1 to 10%; the lubricant is present in a range of 0.1 to 10.0 %; the glidant is present in a range of 0.1 to 5.0%; the solubilizing agent or surfactant is present in a range of 0.1 to 5.0%; the stabilizer is present in a 11691W0008

[0141] range of 0.1 to 8.0%; the plasticizer is present in a range of 0.1 to 5.0%; the additive is present in a range of 0.1 to 10% by weight of total composition and solvent is present in quantity sufficient to make the composition 100% by weight.

[0142] In another embodiment, the present invention relates to medicinal composition of the bioactive nucleotide compound(s) prepared in a manner well known in the pharmaceutical art and administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.

[0143] The preferable route of administration includes but is not limited to sublingual, rectal, topical, parenteral, nasal, or oral.

[0144] In some embodiment, the medicinal compositions of the bioactive nucleotide compound(s) are administered to a subject in need thereof, without limitation, in the form which is suitable for oral use, such as a tablet, capsule (in the form of delayed release, extended release, sustained release, enteric coated release); hard gelatin capsules, soft gelatin capsules in an oily vehicle, veg capsule, hard or soft cellulose capsule, granulate for sublingual use, effervescent or carbon tablets, aqueous or oily solution, suspension or emulsion, encapsulate, matrix, coat, beadlets, nanoparticles, caplet, granule, particulate, agglomerate, spansule, chewable tablet, lozenge, troche, solution, suspension, rapidly dissolving film, elixir, gel, tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, sprays or reconstituted dry powdered form with a liquid medium or syrup; for topical use including transmucosal and transdermal use, such as a cream, ointment, gel, aqueous or oil solution or suspension, salve, parch or plaster; for nasal use, such as a snuff nasal spray or nasal drops; for vaginal or rectal use, such as a suppository; for administration by inhalation, such as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, such as a tablet, capsule, film and spray.

[0145] In a further embodiment, the present composition is formulated in the form of age-appropriate pediatric oral dosage forms such as syrup, inhalation, spray minitablets, chewable formulations, orodispersible films and orodispersible tablets.

[0146] The magnitude of a prophylactic or therapeutic dose typically varies with the nature and severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient. 11691W0008

[0147] In some embodiment, the amino methyl propanoic acid compound or pharmaceutically acceptable salts thereof, are formulated for medicaments, which preferably take the form of therapeutically effective individual doses adjusted to the form of administration.

[0148] In some embodiment, the daily dose of a pharmaceutical composition comprising present amino methyl propanoic acid compound disclosed herein varies over a wide range from about 0.1 mg to about 5000 mg; preferably, the dose is in the range of about 1 mg to about 1000 mg per day for an average human.

[0149] In general, the total daily dose (in single or divided doses) ranges from about 0.1 mg per day to about 5000 mg per day, preferably about Img per day to about 1000 mg per day.

[0150] In some embodiment, the total daily dose can be administered in the range of about 1 mg to about 3000 mg per day, and preferably about 1 mg to about 1000 mg per day.

[0151] The term "therapeutically effective amount " denotes an amount that reduces the risk, potential, possibility or occurrence of a disease or disorder, or provides advanced alleviation, mitigation, and / or reduction or restoration or modulation, regulation of at least one indicator / biomarker (e.g., blood or serum CRP level), and / or minimize at least one clinical symptom related to cardiometabolic disorder like obesity.

[0152] A "therapeutically effective amount" means the amount of the compound that, when administered to a subject to treat a disease or condition referred to herein, is sufficient to perform such treatment for the disease or condition.

[0153] The "therapeutically effective amount" will vary depending on the form of the compound (for example, the form of the salt), the disease or condition in question and its severity, as well as the age, weight, etc., of the subject to be treated.

[0154] The use of any and all examples, or exemplary language (e.g., such as) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.

[0155] While in the foregoing specification this invention has been described in relation to certain embodiments thereof, and many details have been put forth for the purpose of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details described herein can be varied considerably without departing from the basic principles of the invention. 11691W0008

[0156] The present invention is not limited to the specific embodiments described, which serve as illustrations of its various aspects. The following examples are provided for illustrative purposes and should not be construed as limiting the invention’s scope. The scope is defined by the appended claims, and any modifications or equivalents fall within its scope.

[0157] Having described the basic aspects of the present invention, the following non-limiting examples illustrate specific embodiments thereof. Those skilled in the art will appreciate that many modifications may be made in the invention without changing the essence of invention.

[0158] The invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in anyway. The present invention is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the invention.

[0159] Examples:

[0160] Example 1: Conjugate addition of phenylmethanamine with methyl methacrylate (MMA) in presence of recyclable organocatalyst;

[0161]

[0162] In a dry 500 mL round-bottom flask fitted with a nitrogen inlet and a magnetic stirrer, benzylamine (phenylmethanamine, 50.0 mmol, 5.36 g, 1.00 equiv) and methyl methacrylate (MMA, 60.0 mmol, 6.01 g, 1.20 equiv) were charged. 2-Methyltetrahydrofuran (2-MeTHF, 100 mL) was added as the solvent along with the recyclable organocatalyst DBU (2.0 mol%, 1.00 mmol, 0.152 g). The reaction mixture was purged with nitrogen and stirred at 25 °C for 3 hours. The reaction mixture was then cooled to 20 °C, and the mixture was filtered through celite / sintered glass to remove the resin. The resin was washed with 2 x 20 mL of 2-MeTHF. The combined filtrate was concentrated under reduced pressure at 38 °C to remove the solvent.

[0163] The residue was dissolved in minimal ethyl acetate (approximately 30 mL), and crystallization was induced by the slow addition of hexane until opalescence appeared. The mixture was cooled to 0-5 °C for 2 hours, and the precipitated methyl 3-(benzylamino)-2- 11691W0008

[0164] methylpropanoate was collected by cold filtration and dried under vacuum. The reaction afforded the product in 85% yield (8.81 g).

[0165] 'H NMR (400 MHz, CDCh) 8 7.35-7.20 (m, 5H), 4.45 (s, 2H), 3.68 (s, 3H), 3.40-3.10 (m, 1H), 2.90-2.60 (m, 2H), 1.25 (d, J ~ 6.8 Hz, 3H; NH broad, D2O exchangeable); purity 97%.

[0166] Example 2: Hydrolysis of methyl 3-(benzylamino)-2-methylpropanoate to 3-(benzylamino)-2-methylpropanoic acid in presence of acid-base;

[0167]

[0168] Methyl 3-(benzylamino)-2-methylpropanoate (50.0 mmol, -8.81 g) was charged into a dry 500 mL round-bottom flask containing methanol (MeOH, 100 mL). The mixture was cooled to 20-25 °C under a nitrogen atmosphere. Aqueous NaOH (60.0 mmol, 2.40 g NaOH dissolved in 20 mL FLO, 1.20 equiv) was added dropwise over 5-10 minutes while maintaining the temperature at 25 °C, and the reaction mixture was stirred at 20-25 °C for 1.0- 1.5 hours. The reaction was then cooled to 5-10 °C, and the basic solution was acidified slowly with 1.0 M HC1 (~60 mL, ~60 mmol, added dropwise to reach pH ~2) over 10-20 minutes to protonate the carboxylate and precipitate 3-(benzylamino)-2-methylpropanoic acid in situ.

[0169] The resulting cold suspension was stirred for 15-30 minutes at 5-10 °C to complete crystallization. The solid product was collected by vacuum filtration, washed on the filter with cold MeOH (2 x 10 mL) and cold hexane (1 x 10 mL), and dried under reduced pressure at 35 °C to yield 3-(benzylamino)-2-methylpropanoic acid (yield 82%, -7.22 g).

[0170] 'H NMR (400 MHz, DMSO-d6) 812.0-10.5 (broad, 1H, COOH, D2O-exchangeable), 7.35-7.20 (m, 5H, Ar-H), 4.45 (s, 2H, CIL-Ph), 3.40-3.10 (m, 1H, CH adjacent to NH), 2.85-2.60 (m, 2H, CH2 backbone), 1.25 (d, J ~ 6.8 Hz, 3H, C-2 CH3); (purity 98.5% );

[0171] Example 3: Catalytic hydrogenation of 3-(benzylamino)-2-methylpropanoic acid to 3-amino 2-methylpropanoic acid (BAIBA) in presence of metal catalyst. 11691W0008

[0172]

[0173] 3-(Benzylamino)-2-methylpropanoic acid (50.0 mmol, -7.22 g) was dissolved in methanol (100 mL) in a 500 mL round-bottom flask fitted with a hydrogen inlet and magnetic stirrer. 10% Pd / C (20 wt%, 1.44 g) was added, the system was purged with hydrogen, and the reaction was stirred under 1-3 bar H2 at 25-30 °C for 4-6 hours until HPLC confirmed complete conversion of the benzyl intermediate. The mixture was then filtered through celite to remove the catalyst, and the filtrate was concentrated under reduced pressure.

[0174] The resulting residue was dissolved in ethanol (30 mL), acidified in situ with 1 M HC1 (~60 mL, pH ~ 2), and cooled to 0-5 °C for 1 hour to precipitate 3-amino-2-methylpropanoic acid (BAIBA). The precipitate was collected by filtration, washed with cold ethanol :ether (1:4), and dried under vacuum to afford BAIBA in 75-85% yield (typically 80%, 4.12 g) with a purity greater than 95%.

[0175] 'H NMR (400 MHz, D2O): 5 3.25 (dd, 1H, CH), 2.75-2.55 (m, 2H, CIL), 1.18 (d, 3H, CH3); purity >98%.

[0176] After hydrogenation, the crude racemic 3-amino-2-methylpropanoic acid (50.0 mmol, theoretical 5.16 g) was adjusted to 2-methyl tetrahydrofuran (2-MeTHF, 80 mL) in the same 500 mL flask and warmed to 35-40 °C. (S)-l -Phenylethylamine (52.5 mmol, 1.05 equiv, 6.36 g) was added portionwise, and the mixture was stirred for 15 minutes at 35-40 °C to form diastereomeric salts. The reaction mixture was then cooled slowly to 0-5 °C to selectively crystallize the less-soluble diastereomeric salt enriched in the L-enantiomer. The crystalline salt was collected by vacuum filtration and washed with cold 2-MeTHF (2 x 10 mL).

[0177] The obtained salt was suspended in water (30 mL) and basified with 1.0 M NaOH (-55 mL) to liberate the L-acid as its carboxylate. The aqueous phase was cooled to 0-5 °C and acidified with 1.0 M HC1 (~55 mL, pH ~2) to precipitate L-3-amino-2-methylpropanoic acid. The 11691W0008

[0178] precipitate was filtered, washed with cold water (2 x 10 mL), and dried under vacuum to yield L-3-amino-2-methylpropanoic acid (single-crop yield 55-68%, ee 98% by chiral HPLC).

[0179] After hydrogenation, the crude racemic 3-amino-2-methylpropanoic acid (50.0 mmol, theoretical 5.16 g) was adjusted to 2-methyl tetrahydrofuran (2-MeTHF, 80 mL) in the same 500 mL flask and warmed to 35-40 °C. (S)-l -Phenylethylamine (52.5 mmol, 1.05 equiv, 6.36 g) was added portionwise, and the mixture was stirred for 15 minutes at 35-40 °C to form diastereomeric salts. The reaction mixture was then cooled slowly to 0-5 °C to selectively crystallize the less-soluble diastereomeric salt enriched in the L-enantiomer. The crystalline salt was collected by vacuum filtration and washed with cold 2-MeTHF (2 x 10 mL).

[0180] The obtained salt was suspended in water (30 mL) and basified with 1.0 M NaOH (~55 mL) to liberate the L-acid as its carboxylate. The aqueous phase was cooled to 0-5 °C and acidified with 1.0 M HC1 (~55 mL, pH ~2) to precipitate L-3-amino-2-methylpropanoic acid. The precipitate was filtered, washed with cold water (2 x 10 mL), and dried under vacuum to yield L-3-amino-2-methylpropanoic acid (single-crop yield 55-68%, ee 98% by chiral HPLC).

[0181] 'H NMR (400 MHz, D2O) 5 3.25 (dd, 1H, CH), 2.75-2.55 (m, 2H, CIL), 1.18 (d, 3H, CH3); chemical purity 98%; The resolving amine is recovered from the aqueous basic wash and recycled to minimize waste.

[0182] Example 4: HPLC Analysis of L-P- Aminoisobutyric acid (L-BAIBA)

[0183] The High-Performance Liquid Chromatography (HPLC) method for the analysis of L-0-Aminoisobutyric acid (L-BAIBA) purity generally involved using reverse-phase HPLC with appropriate conditions for detecting end product quantifying it, and ensuring its purity.

[0184] Column Type: Daicel Crownpak CR (150 x 4.0 mm, 5 pm)

[0185] Mobile Phase: Methanol: Acetonitrile 20:80 mixture with 0.1% trifluoroacetic acid (TFA) Detection Method: UV detection 220 nm

[0186] Column Temperature: 30°C

[0187] Flow Rate: 0.8 mL / min.

[0188] Injection Volume: 10 pL

[0189] Sample Preparation:

[0190] For sample preparation, approximately 10 mg of bulk L-BAIBA was accurately weighed, dissolved, and diluted to 100 mL with mobile phase to obtain a 0.10 mg / mL test solution, which was then filtered through a 0.22 pm PVDF or PTFE membrane before injection. Under these 11691W0008

[0191] chromatographic conditions, the typical retention time (Rt) for L-BAIBA was approximately 7-7.5 minutes. Standard purity 99.8%; ( L-BAIBA) Test Sample Purity - 98.5%.

[0192] Example 5: To assess the effect of L-P-Aminoisobutyric acid (L-BAIBA) on UCP1 protein expression levels in mouse adipose tissue samples using Western blot analysis.

[0193] The present study aimed to evaluate the effect of L-P-Aminoisobutyric acid (L-BAIBA) on the expression of uncoupling protein- 1 (UCP1) in mouse adipose tissue using Western blot analysis. Swiss albino mice maintained under controlled environmental conditions were divided into three groups: a saline-treated control group and two treatment groups administered with the test compound at 100 mg / kg and 500 mg / kg, respectively, for a duration of 2-4 weeks. Adipose tissues (interscapular brown and inguinal white adipose tissue) were collected and processed for total protein extraction using RIPA buffer containing protease and phosphatase inhibitors. Following quantification by the BCA assay, equal protein concentrations were subjected to SDS-PAGE and transferred onto PVDF membranes for immunodetection of UCP1. The blots were probed with anti-UCPl and P-actin antibodies, and protein bands were visualized via enhanced chemiluminescence.

[0194] Results:

[0195]

[0196] The analysis of Western blot data revealed that UCP1 protein expression increased in a dose-dependent manner in both brown and white adipose tissues of L-BAIBA-treated mice compared to the saline control. Treatment with 100 mg / kg L-BAIBA caused a moderate rise in UCP1 levels, whereas the 500 mg / kg dose resulted in a pronounced upregulation, corresponding 11691W0008

[0197] to approximately 2.7-fold increases in brown adipose tissues. Normalization to 0-actin confirmed consistent protein loading, and the reproducible results across biological replicates validated the statistical significance of UCP1 induction, indicating that L-BAIBA administration enhanced thermogenic activation in adipose tissue.

[0198] Conclusion:

[0199] The upregulation of UCP1 implies that L-BAIBA may serve as a bioactive molecule capable of enhancing energy expenditure and supporting metabolic health. L-BAIBA act as a therapeutic candidate for metabolic disorders associated with impaired adipose thermogenesis.

Claims

11691W0008We Claim:

1. A process for the in-situ synthesis of amino methyl propanoic acid comprising the steps of:(a) performing a conjugate addition reaction between phenylmethanamine and methyl methacrylate in the presence of a recyclable organocatalyst;(b) hydrolyzing the resulting methyl 3-(benzylamino)-2-methylpropanoate in an acid-base medium to obtain 3-(benzylamino)-2-methylpropanoic acid;(c) subjecting 3-(benzylamino)-2-methylpropanoic acid to catalytic hydrogenation to afford 3-amino-2-methylpropanoic acid.

2. The process as claimed in claim 1, wherein the 3-amino-2-methylpropanoic acid is resolved to obtain enantiomeric excess of therapeutically active L-isomer of 3-amino-2-methylpropanoic acid.11691W00083. The process as claimed in claim 1, wherein the recyclable organocatalyst is 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU).

4. The process as claimed in claim 1 , wherein the acid-base hydrolysis is carried in presence of dilute or concentrate organic acid or inorganic acid selected from the group consisting of acetic acid, tartaric acid, hydrochloric acid, formic acid, phosphoric acid, benzoic acid, sulfuric acid, boric acid, malic acid, triethylammonium acetate buffer, dichloroacetic acid, trifluoroacetic acid, and wherein base is selected from sodium hydroxide, potassium hydroxide, ammonia hydroxide, sodium bicarbonate, sodium carbonate, lithium hydroxide, magnesium hydroxide, methylamine, ethylamine, aniline, dimethylamine, pyridine ammonia, triethylamine, dimethylformamide, pyrrolidine, N-N-dimethylacetamide and a combination thereof.

5. The process as claimed in claim 1, wherein the catalytic hydrogenation is carried out in the presence of a metal catalyst selected from palladium on carbon (Pd / C), platinum on carbon (Pt / C), Raney nickel, ruthenium on carbon (Ru / C), or rhodium on alumina (Rh / ABOa).

6. The process as claimed in claim 1, wherein the synthesis is performed in a green solvent system, wherein the green solvent system is selected from water, methanol, ethanol, ethyl acetate, glycerol, 2-methyltetrahydrofuran, or dimethyl carbonate, alone or in combination.

7. The process as claimed in claim 2, wherein the enantioselective resolution of racemic 3-amino-2-methylpropanoic acid is completed using a resolving agent selected from the group consisting of tartaric acid, camphorsulfonic acid, mandelic acid, mosher’s acid, chiral diphosphine, chiral crown ethers, 1,2-diaminocyclohexane, menthol, 1 -phenylethanol, cinchonidine, cinchonine, quinidine, quinine, phthalic acid, (S)-l -Phenylethylamine or a combination thereof.

8. The process as claimed in claim 1, wherein the obtained L-isomer of 3-amino-2-methylpropanoic acid is formulated into a medicinal composition comprising a therapeutically11691W0008effective amount of said L-isomer in a dosage form providing from 1 mg to 1000 mg per unit dose, optionally along with pharmaceutically acceptable excipients or carriers.

9. The process as claimed in claim 1, wherein the pharmaceutical excipients, are selected from the diluent is present in a range of 1 to 30%; the binder is present in a range of 0.1 to 30 %; the disintegrant is present in a range of 0.1 to 10%; the lubricant is present in a range of 0.1 to 10.0 %; the glidant is present in a range of 0.1 to 5.0%; the solubilizing agent or surfactant is present in a range of 0.1 to 5.0%; the stabilizer is present in a range of 0.1 to 8.0%; the plasticizer is present in a range of 0.1 to 5.0% and the additive is present in a range of 0.1 to 10% by weight of total composition.

10. A medicinal composition comprising a therapeutically effective amount of amino methyl propanoic acid obtained from the process as claimed in claim 1, in combination with pharmaceutically acceptable excipients, wherein administration of said composition enhances expression of uncoupling protein-1 (UCP1) in adipose tissue by 1.5-fold to 3-fold compared to control.

11. The composition as claimed in any of the preceding claims, wherein the amino methyl propanoic acid or its pharmaceutically acceptable salt is useful in the treatment or management of metabolic and lifestyle-related disorders including, but not limited to, obesity, insulin resistance, type 2 diabetes, dyslipidemia, metabolic syndrome, muscle dysfunction, sarcopenia, cardiovascular diseases, non-alcoholic fatty liver disease, atherosclerosis, osteoporosis, and neuroinflammatory or cognitive disorders, as well as conditions related to women’s health such as menstrual irregularities, endometriosis, pelvic inflammatory disease, polycystic ovarian syndrome (PCOS), and premenstrual syndrome (PMS), and in promoting mitochondrial biogenesis, thermogenesis, energy metabolism, and overall metabolic homeostasis.

12. The medicinal composition as claimed in any of the preceding claims, comprising amino methyl propanoic acid or a pharmaceutically acceptable salt thereof, wherein the composition is formulated for oral administration as an effective unit dose ranging from 1 mg to 1000 mg.

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