DESC:
FIELD OF THE INVENTION:
The present invention relates to novel selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) compounds of a Formula I and simple commercially viable process for preparation thereof.

Formula I
The selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) of a Formula I include optically active isomers or mixtures thereof, wherein the dissociation constant Kd of Formula I compound having binding affinity for GABA-B receptor is in the range of 0.1-5 µM.

The present selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) of a Formula I is useful in the treatment of neurodevelopmental delay associated with preterm hypoxic-ischemic encephalopathy, sluggish cognitive tempo, inattentive attention deficit hyperactivity disorder, tourette syndrome, autism spectrum disorder, epilepsy, dyslexia, cerebral palsy and developmental language disorder.

BACKGROUND OF THE INVENTION:
Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the mammalian central nervous system (CNS), playing a critical role in maintaining the balance between neuronal excitation and inhibition. Dysregulation of GABAergic signaling is implicated in a wide range of neurological and psychiatric disorders, including anxiety, epilepsy, attention-deficit disorders, autism spectrum disorders, depression, and neurodegenerative diseases.

Long-term potentiation (LTP) has become an established biomarker and mechanistic tool for understanding neurodevelopmental disorders (NDDs) such as autism spectrum disorder, intellectual disability, and ADHD. Since these disorders are marked by disruptions in excitatory–inhibitory balance, LTP assessments provide insight into how impaired GABAergic regulation alters circuit development and cognitive outcomes (e.g., language, memory, social learning). Evaluating LTP dynamics in both preclinical and clinical models allow researchers to track developmental trajectories, measure therapeutic responses, and connect synaptic changes to behavioral manifestations.

Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the central nervous system, acting through two distinct receptor types: GABA-A and GABA-B receptors. GABA-A receptors are ionotropic, ligand-gated chloride channels that mediate fast synaptic inhibition by promoting chloride influx, leading to neuronal hyperpolarization. They play a critical role in regulating anxiety, sleep, seizure control, and motor coordination and serve as pharmacological targets for benzodiazepines, barbiturates, and anesthetics.

GABA-A receptor agonists have therapeutic uses, particularly as sedatives, anxiolytics, and anticonvulsants, their clinical utility is often limited by significant side effects. Because GABA-A receptors are ion channels that directly modulate chloride ion flux, excessive activation results in profound neuronal inhibition. This can cause excessive sedation, motor incoordination, cognitive impairment, memory loss, and in severe cases, respiratory depression. Long-term use of GABA-A modulators, such as benzodiazepines or barbiturates, is also associated with tolerance, dependence, and withdrawal syndromes. Furthermore, non-selective activation of GABA-A receptors can impair normal synaptic plasticity and learning processes. G. Biggio et al., European Neuropsychopharmacology 13 (2003) 411–423.

In contrast, GABA-B receptors are metabotropic, G-protein-coupled receptors (GPCRs) responsible for slow and prolonged inhibitory signaling. Activation of GABA-B receptors modulates neuronal excitability by inhibiting calcium channels, activating inwardly rectifying potassium channels (GIRK), and reducing cyclic AMP production. These receptors are essential for controlling, memory, cognitive functions, muscle tone and pain perception. Particularly, GABA-B receptors are G protein-coupled receptors (GPCRs) that inhibit neuronal excitability by activating potassium channels, inhibiting calcium channels, and suppressing adenylate cyclase. They function as heterodimers of R1 and R2 subunits, which interact with various proteins to diversify signaling. Proc Jpn Acad Ser B Phys Biol Sci. 2018 Dec 11;94(10):390–411. doi: 10.2183/pjab.94.026.

US8344028B2 discloses Gamma-amino-butyric acid derivatives that are GABAB receptor ligands, and pharmaceutical compositions comprising such derivatives.

US7812026 B2 relates to novel imidazole derivatives having a positive allosteric GABAB receptor (GBR) modulator effect, methods for the preparation of said compounds and to their use in the treatment of gastroesophageal reflux disease, as well as for the treatment of functional gastrointestinal disorders.

The conventional GABA-B receptor agonists like baclofen induces a strong conformational shift in R2 subunit, leading to robust G-protein activation and reduction of cAMP lead to robust physiological effects, including sedation, muscle relaxation, and significant suppression of neuronal activity. However, such full activation often results in undesirable side effects, including excessive sedation, motor impairment, and tolerance development. Romito JW, Turner ER, Rosener JA, et al. Baclofen therapeutics, toxicity, and withdrawal: A narrative review. SAGE Open Medicine. 2021;9.

US6689585B1 covers polynucleotide molecules encoding a novel GABA-B receptor, enabling receptor expression in cells for screening agonists and antagonists.

US7576217B1 discloses quinoline compounds as allosteric enhancers of the GABA-B receptors. This compound compounds are active at the GABA-B receptor and can be used for the preparation of medicaments useful in the treatment of CNS disorders comprising anxiety and depression.

WO2007073299 describes imidazoles as GABA-B receptor modulators having a positive allosteric GABAB receptor (GBR) modulator effect. It uses for the inhibition of transient lower esophageal sphincter relaxations, for the treatment of gastroesophageal reflux disease, as well as for the treatment of functional gastrointestinal disorders and irritable bowel syndrome (IBS).

US5929236B1 discloses morpholine and thiomorpholine derivatives for treatment of r treating respiratory depression associated with GABAB receptor stimulation. They also used in the treatment of petit mal seizures.

However, the recombinant production and development of GABA-B receptors and small molecule GABA agonists such as quinolines, imidazoles, and morpholine derivatives face several challenges and drawbacks. Recombinant GABA-B receptor production often encounters technical limitations, such as difficulties in achieving proper folding, membrane insertion, and post-translational modifications necessary for functional receptor expression. These issues can lead to misfolded or non-functional proteins, reducing yield and increasing production costs. Moreover, overexpression systems may trigger cellular stress responses or toxicity in host cells, further complicating large-scale production.

For quinolines, imidazoles, and morpholine-based GABA agonists, chemical synthesis and recombinant bioproduction face risks of toxic byproducts, low selectivity, and off-target activity, especially given their interaction with various receptors and enzymes in the central nervous system (CNS). These compounds can cross the blood-brain barrier but may also accumulate in the CNS, leading to side effects such as sedation, dizziness, cognitive impairment, hypotension, muscle weakness, or gastrointestinal disturbances. Some imidazole derivatives may also impact liver enzymes (e.g., CYP450), causing drug-drug interactions and hepatotoxicity. Quinolines, known for their aromatic structure, may carry genotoxic or mutagenic potential with prolonged exposure or improper formulation.

Further, morpholine derivatives can exhibit low metabolic stability and potential nephrotoxicity or cardiotoxicity depending on structural modifications. Overall, the manufacturing complexity, potential systemic side effects, long-term toxicity concerns, and regulatory hurdles limit the safe therapeutic use and large-scale production of recombinant GABA-B receptor systems and these chemical classes of GABA agonists.

Therefore, the development of GABA-B receptor agonists for therapeutic purposes has also faced several challenges and achieved limited success. Issues such as off-target effects and central nervous system (CNS) depression [GABA-B receptor agonists can cause excessive inhibition of neuronal activity, leading to side effects like sedation, dizziness, cognitive impairment, and muscle relaxation, which limit their clinical utility], tolerance and dependence [long-term administration of GABA-B agonists may lead to reduced therapeutic efficacy due to tolerance development, and abrupt discontinuation can cause withdrawal symptoms or rebound effects], and technical and formulation challenges [many GABA-B agonists have poor bioavailability, short half-life, or limited ability to cross the blood-brain barrier, complicating their formulation and consistent delivery]. Additionally, high production costs and strict regulatory requirements for CNS-active compounds further increase the expense and complexity of developing these therapies, limiting their accessibility and widespread use.

The need for selective pre-synaptic partial GABA-B-R1 agonists arises from the significant side effects, safety concerns, and lack of selectivity associated with existing non-selective GABA-B receptor agonists such as quinolines, imidazoles, and morpholine derivatives. Traditional GABA-B receptor agonists activate both pre-synaptic and post-synaptic GABA-B receptors indiscriminately, leading to excessive CNS inhibition. Hence, selective pre-synaptic partial GABA-B-R1 agonists are needed to provide safer, more targeted therapies that retain efficacy while minimizing adverse effects, toxicity, and technical production challenges associated with current therapies.

The present invention addresses this unmet need by disclosing a novel class of compounds exhibiting selective pre-synaptic GABA-B-R1 partial agonist activity.

OBJECTIVE OF THE INVENTION:
The primary objective of the invention is to provide a novel therapeutically active Selective Pre-Synaptic Partial GABA-B-R1 Agonists (SPPGA).

Another objective of the invention is to provide a simple and commercially viable process for preparation of novel Selective Pre-Synaptic Partial GABA-B-R1 Agonist (SPPGA).

Yet another objective of the invention is to provide therapeutically active compounds which ensures targeted action and improve bioavailability.

Yet another objective of the invention is to provide compounds which minimizes systemic side effects, and provides prolonged effect.

Yet another objective of the invention is to provide compounds which enhance long-term potentiation (LTP), thereby improving synaptic plasticity and supporting cognitive development in neurodevelopmental disorders.

Another objective of the invention is to provide present compounds based medicinal composition for the treatment of neurodevelopmental delay.

SUMMARY OF THE INVENTION:
To meet the above objectives, the inventors of the instant invention carried out thorough experiments to establish significant effects of the selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) that ameliorate therapeutic efficacy in the treatment of neurodevelopmental delay and disabilities by selective partial agonism of GABA-B receptor.

In an aspect, the present invention provides a selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) which is prepared by commercially viable and non-hazardous process.

In another aspect, the present invention provides a selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) of Formula I with potent and targeted approach.

In yet another aspect, the invention provides a conjugate compound which easily penetrates the blood-brain barrier and effectively influence GABA-B-R1 receptor and ensures targeted action with prolonged effect.

In another aspect, the invention provides therapeutically effective, non-toxic and safe conjugate compound with no major side effects.

In another aspect, the present invention provides compounds that enhance long-term potentiation (LTP), thereby promoting synaptic plasticity, cognitive function, and recovery of impaired learning and memory in neurodevelopmental disorders.

In a further aspect, the present invention provides pharmaceutical composition comprising selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) along with pharmaceutically acceptable excipients/carriers useful in the treatment of neurodevelopmental delay associated with preterm hypoxic-ischemic encephalopathy, sluggish cognitive tempo, inattentive attention deficit hyperactivity disorder, tourette syndrome, autism spectrum disorder, epilepsy, dyslexia, cerebral palsy and developmental language disorder.

BRIEF DESCRIPTION OF FIGURES:
Figure 1 illustrates 1H NMR spectrum of compound 1a i.e. magnesium (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido) butanoate.

Figure 2 illustrates 1H NMR spectrum of compound 1b i.e. iron(II) (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoate.

Figure 3 illustrates 1H NMR spectrum of compound 1c i.e. zinc (II) (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido) butanoate.
Figure 4 illustrates Latency time (sec) arm for Group 1 to Group 6.
Figure 5 illustrates Ambulation score [number of squares crossed] for Group 1 to Group 6.
Figure 6 illustrates Rearing Responses [the number of times the animal raised both forefeet off the floor and extended its body] for Group 1 to Group 6.
Figure 7 illustrates BDNF values for Group 1 to Group 6.

DESCRIPTION OF THE INVENTION:
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.

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.

The singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Also, the term ‘composition’ does not limit the scope of the invention for multiple compositions that can be illustrated for best mode of the invention.

The term “pharmaceutically/nutraceutically acceptable salt,” as used herein, represents those salts which are within the scope of sound medical judgment, 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, amino acid salt, sugar-based salt, alkali or alkaline earth metal salts, as well as solvates, co-crystals, polymorphs and the like of the salts.

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 transition “comprising” allows the inclusion of other elements to be within the scope of the invention.

The inventors of the present invention have developed therapeutically significant novel selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) in stable form.

In a preferred embodiment, the present invention provides the invention relates to novel therapeutically active selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) represented by Formula-I,

Formula I
wherein R1 and R2 are similar or independently selected from the group consisting of H, (C1-C9) alkyl, aryl, aralkyl, (C1-C9)-O-, heterocyclic group, halide. X is divalent metal selected from Mg, Fe and Zn.

In another embodiment, the present invention provides cost-effective, industrially viable process for the preparation of a selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) of Formula I.

In another preferred embodiment the invention provides feasible process for the preparation of selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) of Formula I, the process comprising steps of:

Step I

Formula-IV Formula-III Formula-II

A compound of Formula (IV) is reacted with an amino acid derivative of Formula (III) in the presence of an esterification catalyst and a suitable solvent. The reaction may be conducted under reflux conditions or at an elevated temperature, preferably in the range of 50°C to 100°C. Optionally, a dehydrating agent may be employed to enhance ester bond formation, where Formula (IV) represents an ester or cyclic carbonate of a substituted pantolactone, and Formula (III) represents an amino acid with a terminal carboxyl functional group. The reaction is performed in the presence of a catalyst, which may include acid catalysts such as p-toluenesulfonic acid, sulfuric acid, or Lewis’s acids like zinc chloride. Solvents such as methanol, ethanol, tetrahydrofuran (THF), or dichloromethane may be employed. The resulting product of Formula (II) consists of an amide or esterified pantothenate derivative with a free carboxyl functional group suitable for metal ion complexation.

Step II

Formula-II Formula- I

In the second step, the compound of Formula (II) is reacted with a divalent metal salt in an appropriate solvent to yield a metal complex of Formula (I), wherein X is a divalent metal cation, such as Mg²?, Zn²? and ?Fe²?. The reaction is preferably conducted in an aqueous or alcoholic medium at ambient or slightly elevated temperatures, typically 25°C to 80°C. The resulting metal complex (Formula I) exhibits enhanced bioavailability and stability, making it particularly suitable for pharmaceutical applications. The final product may be isolated via filtration, crystallization, or lyophilization to obtain a highly pure and stable compound(s) of Formula I.

The term “solvents” as used herein, represents a compound or mixture or substance, ordinarily a liquid, in which other materials dissolve to form a solution. The role of a solvent in a chemical reaction can either be non-participatory or participatory which depends on the type of solvent and its strength. Some solvents do not participate in chemical reactions. They simply serve as the reaction medium to enable chemical reactions to occur more rapidly.

In further embodiment, the solvent used in the reaction is a polar or nonpolar or mixtures thereof wherein solvents are selected from but not limited to, water, acetone, acetonitrile, dichloromethane (DCM), dimethylformamide (DMF), dimelthylsulfoxide (DMSO), isopropanol, propanol, butanol, ethanol, and methanol; pentane, hexane, toluene, diethyl ether, benzene, tetrahydrofuran, ethyl acetate, 1,4-Dioxane, chloroform, carbon tetrachloride, acetic acid either alone or mixture thereof.

The term “catalyst”, as used herein, refers to a compound, substance, or mixture that alters the rate of a chemical reaction without being consumed in the process. A catalyst functions by lowering the activation energy or by providing an alternative reaction pathway, thereby enhancing the efficiency, selectivity, or yield of the desired product. Depending on the reaction type, a catalyst may act in a purely facilitative role or may directly influence the reaction mechanism through active participation.

In one embodiment, the catalyst employed in the reaction may be acidic, basic, enzymatic, or metallic in nature, and may include, but is not limited to: Lewis acids (e.g., AlCl3, BF3, TiCl4, ZnCl2), Brønsted acids (e.g., H2SO4, HCl, H3PO4, p-TsOH), bases (e.g., NaOH, KOH, triethylamine, diethylamine, dimethylamine, pyridine), transition metal catalysts (e.g., palladium, platinum, nickel, ruthenium, copper), organocatalysts, and biocatalysts (enzymes), either alone or in combination.

In another embodiment, the present invention provides novel selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) of formula I that selectively act on GABA-B receptor in the pre-synaptic region of the brain.

In another embodiment, the present invention provides novel selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) of formula I binds to GABA-B receptors but does not fully activate them, leading to partial agonism.

In yet other embodiment, the present invention provides a selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) of Formula I, including its optically active isomers or mixtures thereof, wherein the compound exhibits a dissociation constant (Kd) in the range of 0.1-5 µM for binding to the GABA-B receptor.

In another embodiment, the present invention provides selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) that easily penetrates the blood-brain barrier and effectively influence GABA-B receptor which ensures targeted action, improve bioavailability, minimizes systemic side effects, and provides prolonged effect.

In yet another preferred embodiment, the selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) compounds of Formula I is selected from the group consisting of

Compound 1a: magnesium (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoate

Compound 1b: iron(II) (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoate

Compound 1c: Zinc (II) (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoate

Further, the present novel selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) of a Formula I is useful in the treatment of neurodevelopmental delay associated with preterm hypoxic-ischemic encephalopathy, sluggish cognitive tempo, inattentive attention deficit hyperactivity disorder, tourette syndrome, autism spectrum disorder, epilepsy, dyslexia, cerebral palsy and developmental language disorder.

The term ‘subject in need thereof’ pertains to a subject preferably mammal, more preferably a human suffering or suspected with nervous system related disorder.

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 novel conjugate moieties are 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.

Certain compounds of the present invention exist in unsolvated forms as well as solvated forms, including hydrated forms. Further, some compounds of the present invention exist in multiple crystalline or amorphous forms (“polymorphs”). Compounds of the invention are formulated in geometric or, enantiomeric or stereoisomeric forms.

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 includes, hydrates, polymorphs, solvates, enantiomers or racemates. 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.

In one of the embodiments, the present invention provides medicinal composition comprising novel selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) which is present in therapeutically effective amount along with pharmaceutically acceptable excipients.

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, flavor 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, antioxidants, food additives, or waters of hydration, salts.

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 or nervous system related disorder.

In another embodiment, the present invention relates to medicinal composition of the selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) 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.

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

In another embodiment, the compounds of Formula I of the present invention are non-toxic, cost effective, enriched with nutrients or biomolecules; and provide safeguard against problems associated with neurotransmission without any adverse effect.

In some embodiments, the compounds of Formula-I can be formulated in medicaments by using pharmaceutically acceptable excipients such as diluents, binders, lubricants, solubilizing agents, surfactants, stabilizers, colors, flavoring agents, sweeteners, glidants, plasticizers, antioxidants and other additives.

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, isomalt, silicified microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium lactate, dicalcium phosphate, dibasic calcium phosphate (anhydrous/ dibasic dehydrate/ tribasic), calcium silicate, calcium sulphate, cellulose acetate, corn starch, pregelatinized starch, dextrin, ß-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, vehicles like petrolatum, dimethyl sulfoxide, mineral oil or a combinations thereof.

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.

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, lactitol, maltitol, isomalt; 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, sodium starch glycolate, cottonseed 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 aluminum 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, flavorants, colorants, wax or a combinations thereof.

In further embodiment of the present invention, the binder in the composition/formulation is present in a range of 0.1 to 40% by weight of the composition/formulation.

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 a combinations thereof.

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.

In another embodiment of the present invention, the solubilizing agent is selected from but not limited to, polysorbates such as polysorbate 80, polysorbate 60, polysorbate 20; 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, 15 methylparaben, propylparaben, sorbic acid or a combinations thereof.

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.

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.

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 a combination thereof.

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.

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.
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.

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 or a combination thereof.

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. In some embodiment of the invention, the plasticizers are added to coating formulations selected from the group propylene glycol, glycerol, glyceryl triacetate (triacetin), triethyl citrate, acetyl triethyl citrate, diethyl phthalate, actetylated monoglycerides, castor oil, mineral oil and like thereof.

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.

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.

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.
In some embodiment of the present invention, the antioxidants are selected from but not limited to, ascorbic acid, citric acid, sodium ascorbate, ascorbyl palmitate, sodium bisulfite, sodium sulfite, sodium thiosulfate, sodium metabisulfite, sodium citrate, butyl hydroxyanisole (BHA), butylated hydroxytoluene (BHT) or mixtures thereof.
In an embodiment the antioxidants are present in the range of 0.1% to 10% by the weight of the total composition.

The additional additives include a polymer, a plasticizer, a sweetener, and a powdered flavor, a preservative, a colorant, a surfactant, and other excipients. The powdered flavor 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.

In a preferred embodiment of the present invention, the additives are used in a range of 1 to 20% w/w of unit dose.

In yet another embodiment, the present invention provides a medicinal composition comprising compounds of Formula I along with pharmaceutical excipients, wherein the pharmaceutical excipients are selected from a diluent, a binder, a lubricant, a glidant, an additive, a surfactant, a stabilizer or mixtures thereof.

In a preferred embodiment, the diluent is present in a range of 1 to 30%; the binder present is present in a range of 0.1 to 25%; 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 additive is present in a range of 1 to 10%; the surfactant is present in a range of 0.1 to 5.0%; the stabilizer is present in a range of 0.1 to 5.0%; and the plasticizer is present in a range of 0.1 to 5.0%; the antioxidant is present in a range of 0.1 to 10% by weight of total composition.

In some embodiment, the medicinal compositions of the selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) are administered to a subject in need thereof, 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, spray.

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.

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.

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 1mg per day to about 1000 mg per day.

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.

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.

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.

The invention may be further be 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 disclosure is therefore to be considered as in all respects illustrative and not restrictive, the scope of the invention being indicated by the appended claims and examples, and all changes or alterations which come within the ambit of equivalency are intended to be encompassed therein.

EXAMPLES:

Example 1:
Composition 1
Each tablet/capsule contains
Selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) compound 300 mg
Excipients ----

Example 2: Composition 2
Ingredient mg unit dose
Compound 1a - Magnesium (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoate 300 mg
Stearic Acid 0.5–2
Sodium Ascorbate 0.1–2
Dicalcium Phosphate 1–5
Crospovidone 0.5–3
Hydroxypropyl Cellulose 0.5–2
Sucrose 1–5
Talc 0.1–1
Poloxamer 0.1–2
Xylitol 0.5–3
Water QS
Average weight 500–1000 mg

Example 3: Composition 3
Ingredient mg unit dose
Compound 1b - iron(II) (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoate 300 mg
Magnesium Stearate 1-5
Ascorbic acid 0.1-2
Microcrystalline Cellulose 0.1-2
Colloidal Silicon dioxide 0.1-2
Hydroxypropyl Methylcellulose 0.1-2
Sucrose 0.1-5
Polyvinylpolypyrrolidone 0.1-2
Talc 0.1-1
Polysorbate 80 0.1-2
Mannitol 0.1-2
Water QS
Average weight 500-1000 mg

Example 4: Composition 4
Ingredient mg unit dose
Compound 1c - Zinc (II) (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoate 300 mg
Calcium Stearate 0.5–2
Sodium Citrate 0.1–2
Microcrystalline Cellulose 1–5
Croscarmellose Sodium 0.5–3
Polyethylene Glycol 4000 0.5–2
Isomalt 1–5
Talc 0.1–1
Polysorbate 60 0.1–2
Mannitol 0.5–3
Water QS
Average weight 500–1000 mg

Example 5: Process for preparation of (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoic acid.

To a stirred solution of R-(–)-dihydro-3-hydroxy-4,4-dimethyl-2(3H)-furanone (10 g, 76.8 mmol) in methanol (100 mL), ?-aminobutyric acid (4-aminobutanoic acid) (7.9 g, 76.8 mmol) was added, followed by triethylamine (8.0 mL, 57.6 mmol). The reaction mixture was stirred at room temperature for 12 hours. Completion of the reaction was monitored by thin-layer chromatography (TLC). After consumption of the starting lactone, the reaction mass was concentrated under reduced pressure to obtain the crude product, (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoic acid. Yield: 14.8 g (82%), Molecular formula: C10H19NO5 and Molecular weight: 233.26 g/mol.

Example 6: Process for preparation of Magnesium (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoate (Compound 1a)

A solution of (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoic acid (10 g, 42.9 mmol) in methanol (100 mL) was treated with magnesium carbonate (2.2 g, 21.4 mmol) at room temperature using a mechanical overhead stirrer. After 6 hours, the mass was filtered on a Büchner funnel and concentrated on a rotary evaporator (Buchi R-300).
Purification (acetone–water): The residue was dissolved in warm water (80 mL, 45–50 °C), treated with activated carbon, and hot-filtered. With stirring, acetone (4 vol relative to aqueous solution) was added as antisolvent to slight turbidity. The mixture was cooled to 0–5 °C for 2 hours, the solid was collected, washed with cold acetone (2 × 20 mL), and dried in a vacuum oven (40 °C) to give compound 1a. Yield: 11.2 g (85%), Molecular formula: C20H36MgN2O10, Molecular weight: 488.81 g mol?¹

¹H NMR (400 MHz, D2O,): d 8.62 (d, J = 8.0 Hz, 1H), 8.11 (dd, J = 8.0, 4.8 Hz, 1H), 4.65 (dd, 1H), 3.52–3.21 (m, 4H), 1.15 (s, 6H).

Example 7: Process for preparation of iron(II) (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoate (Compound 1b)

(R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoic acid (10 g, 42.9 mmol) was dissolved in methanol (120 mL) in a three-neck RBF under nitrogen with magnetic stirring. Iron(II) carbonate (3.0 g, 21.4 mmol) was added portion-wise; stirring continued 8 hours at room temperature until effervescence ceased. The mixture was filtered and concentrated by rotary evaporation.
Purification (acetone–water, deoxygenated): The residue was dissolved in deaerated water (90 mL, 40–45 °C) under nitrogen, treated with activated carbon, and hot-filtered through a nitrogen-blanketed funnel. Acetone (3–4 vol) was added slowly to induce precipitation; the slurry was cooled to 0–5 °C for 2 hours, filtered, washed with cold acetone (2 × 20 mL), and dried under high vacuum to give compound 1b. Yield: 10.8 g (80%), Molecular formula: C20H36FeN2O10 and Molecular weight: 520.35 g mol?¹.

¹H NMR (400 MHz, D2O, d 8.65 (d, J = 8.0 Hz, 1H), 8.14 (dd, J = 8.0, 4.8 Hz, 1H), 4.69 (dd, 1H), 3.50–3.25 (m, 4H), 1.18 (s, 6H).

Example 8: Process for preparation of Zinc (II) (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoate (Compound 1c)

(R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoic acid (10 g, 42.9 mmol) was suspended in methanol (100 mL) with magnetic stirring. Zinc carbonate (2.9 g, 21.4 mmol) was added slowly; the mixture was stirred 6 hours at room temperature, filtered, and concentrated by rotary evaporation.
Purification (acetone–water recrystallization): The residue was dissolved in hot water (75 mL, 50 °C), polished-filtered through 0.45 µm PTFE, and to the clear solution acetone (4 vol) was added dropwise until persistent turbidity. The mixture was cooled to 0–5 °C for 3 hours; the crystals were filtered, rinsed with cold acetone (2 × 20 mL), and dried by lyophilization (Labconco FreeZone) to give compound 1c. Yield: 11.5 g (87%), Molecular formula: C20H36N2O10Zn and Molecular weight: 529.89 g mol?¹

¹H NMR (400 MHz, D2O, d 8.61 (d, J = 8.0 Hz, 1H), 8.09 (dd, J = 8.0, 4.8 Hz, 1H), 4.63 (dd, 1H), 3.55–3.22 (m, 4H), 1.14 (s, 6H).

Example -9
Animal Study:
Evaluation of Test Substances on Scopolamine-Induced Behavioral and biochemical changes in Swiss Albino Mice Using T-Maze and Open Field Tests followed by BDNF level.

Test System Details
Parameter Details
Species: Mouse
Strain: Swiss Albino
Sex: Male/Female
Age: 8–10 weeks
Body Weight: 25–30 g
Source: In-house bred
Number of Animals: 36 (6 groups × 6 animals per group)

Housing and Husbandry
Caging: 3 animals per autoclaved polypropylene cage with paddy husk bedding.
Lighting: 12 hours light / 12 hours dark cycle
Temperature: 22 ± 3°C
Humidity: 30–70% RH
Feed: Standard rodent chow (Purina Lab Diet 5L79 Rat and Mouse 18%)
Water: Filtered, autoclaved water provided ad libitum

Table-1 Experimental Design
Group Description Treatment equivalent Human Dose No. of Animals
G1 Normal control Vehicle only 6
G2 Disease control Scopolamine 6
G3 Standard Treatment-
4-[(2R)-2,4-Dihydroxy-3,3-dimethylbutanamido]butanoic acid 300 mg 6
G4 Compound 1a-
Magnesium (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoate 300 mg 6
G5 Compound 1b-
iron(II)(R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoate 300 mg 6
G6 Compound 1c-
Zinc(II) (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoate 300 mg 6

The vehicle used for the study was a 0.5% Carboxy Methyl Cellulose (CMC-Na) solution. All treatments were administered via oral gavage for 14 consecutive days. Scopolamine was administered as an intraperitoneal injection at a dose of 1 mg/kg, 30 minutes after the oral dosing.
Animals were acclimatized to the animal house conditions for a period of five days prior to the initiation of experimental procedures. From Day 1 to Day 14, animals received daily treatments with either the vehicle, or test compounds as per their assigned groups. On Day 14, behavioural assessments were conducted, starting with the T-Maze test followed by the Open Field test.

Behavioural Tests-T-Maze Test
The T-Maze test was performed to evaluate spatial learning and memory in mice. The apparatus consisted of a T-shaped maze with one start arm and two goal arms. Animals underwent habituation by freely exploring the maze for 10 minutes per day over two consecutive days. On the test day, each animal was placed in the start arm, and the Latency time (in seconds) to enter the correct goal arm were recorded.

Open Field Test

The Open Field test was conducted to assess locomotor activity, exploratory behaviour, and anxiety-like behaviour in mice. The apparatus comprised a square arena measuring 50 × 50 cm with walls 40 cm in height; the floor was virtually divided into squares. The central zone and peripheral zone were defined for analysis.
Each mouse was gently placed in the center of the arena and observed for a duration of five minutes. Behavioural parameters were recorded either manually or using a video tracking system. The following parameters were analyzed:
• Number of squares crossed (to assess locomotor activity).
• Frequency of rearing (indicative of exploratory behaviour).
The arena was cleaned with 70% ethanol between animals to minimize olfactory bias.
Biochemical Correlates -BDNF
Following the completion of behavioral testing, animals were sacrificed for the collection of brain tissue to perform biochemical assays. Brain-derived neurotrophic factor (BDNF) levels were measured to correlate behavioral outcomes with neurochemical changes.
The data were expressed as mean ± standard deviation (SD). Statistical analysis was performed using one-way analysis of variance (ANOVA), followed by Dunnett’s post hoc test for multiple comparisons. A p-value of less than 0.05 was considered statistically significant.

Result:
T-Maze test
Table 2: (Latency time (sec) arm)
Animals 1 2 3 4 5 6 Average
Groups
Group 1 11 12 10 12 11 12 11.33
Group 2 26 25 27 26 25 26 25.83
Group 3 20 19 21 19 20 20 19.83
Group 4 16 17 15 16 17 16 16.16
Group 5 17 16 18 16 18 17 17.00
Group 6 18 19 18 19 18 17 18.16

Open Filed Test
Table -3: Ambulation score [number of squares crossed]
Animals
1 2 3 4 5 6 Average
Groups
Group 1 123 125 124 126 123 122 123.83
Group 2 58 56 55 57 56 54 56.00
Group 3 100 103 104 100 101 103 101.83
Group 4 117 118 116 118 119 117 117.50
Group 5 109 108 105 107 106 108 107.16
Group 6 103 104 103 105 105 102 103.66

Table 4: Rearing Responses [the number of times the animal raised both forefeet off the floor and extended its body]
Animals 1 2 3 4 5 6 Average
Groups
Group 1 14 13 14 12 12 13 13.00
Group 2 5 4 4 5 3 4 4.16
Group 3 9 10 8 10 9 10 9.33
Group 4 12 11 11 12 11 12 11.50
Group 5 11 10 11 10 10 9 10.16
Group 6 9 10 10 11 9 10 9.83

Table 5: BDNF-in Serum (ng/mL)
Animals 1 2 3 4 5 6 Average
Groups
Group 1 29.2 28.6 28.9 29.4 29.2 30 29.21
Group 2 13.6 13.4 14.1 13.8 13.5 13.7 13.68
Group 3 23.1 23.3 23.4 22.8 23 22.8 23.06
Group 4 26.7 26.9 27.1 26.8 26.7 27.2 26.90
Group 5 25.2 25.5 24.9 25 25.3 25.7 25.26
Group 6 24.5 24.3 24.5 23.9 24.7 24.8 24.45

Conclusion
The present study demonstrated the efficacy of a Selective Pre-Synaptic Partial GABA-B-R1 Agonist (SPPGA) compounds for managing central nervous system (CNS) excitability disorders. In vivo studies in scopolamine-induced cognitive impairment models in Swiss albino mice demonstrated significant behavioral improvements with the compounds 1a to 1c. In the T-maze test, latency times were markedly reduced to 16.16 sec (Compound 1a) and 17.00 sec (Compound 1b) and 18.16 sec (Compound 1c), respectively, versus 25.83 sec in the disease control, indicating enhanced learning and memory.
In the open field test, treated compounds 1a to 1c showed higher ambulation (103.66 to 117.50 squares) vs. 56 by diseased control, increased rearing (9.83 to 11.50) vs. 4.16 by diseased control, suggesting anxiolytic effects. BDNF levels were elevated up to 26.90 ng/mL, supporting enhanced neuroplasticity. These results confirmed the synergistic composition effectively mitigated hyperexcitability and promoted synaptic recovery.
The above and other salient features including embodiments and examples of the present invention are not to limit the scope of the subject matter and will be more clearly described in the complete specification which will be filed pursuant to the present complete specification.
,CLAIMS:
1. A selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) compound of Formula I:

wherein R1 and R2 are similar or independently selected from the group consisting of H, (C1-C9) alkyl, aryl, aralkyl, (C1-C9)-O-, heterocyclic group, halide; X is divalent metal selected from Mg, Fe and Zn, wherein the compound exhibits a dissociation constant (Kd) in the range of 0.1–5 µM for binding to the GABA-B receptor.

2. A selective pre-synaptic partial GABA-B-R1 agonist (SPPGA) compound of Formula I as claimed in claim 1, wherein the compound is selected from the group consisting of:

(Compound 1a) magnesium (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoate;

(Compound 1b) iron(II) (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido)butanoate;

(Compound 1c) zinc (II) (R)-4-(2,4-dihydroxy-3,3-dimethylbutanamido) butanoate.

3. A process for preparing a compound of Formula I as claimed in claim 1, comprising:
(a) reacting a substituted pantolactone of Formula (IV) with an amino acid derivative of Formula (III) in the presence of an esterification catalyst and solvent to form a compound of Formula (II); and

(b) reacting the compound of Formula (II) with a divalent metal salt selected from magnesium, iron or zinc salts in a solvent to obtain the compound of Formula I;

optionally followed by purification using recrystallization, filtration, lyophilization, or acetone–water precipitation.

4. The process as claimed in claim 3, wherein the solvent is selected from water, acetone, acetonitrile, dichloromethane (DCM), dimethylformamide (DMF), dimelthylsulfoxide (DMSO), isopropanol, propanol, butanol, ethanol, and methanol; pentane, hexane, toluene, diethyl ether, benzene, tetrahydrofuran, ethyl acetate, 1,4-dioxane, chloroform, carbon tetrachloride, acetic acid either alone or mixture thereof and a combination thereof.

5. A pharmaceutical composition comprising:
(a) a therapeutically effective amount of a compound of Formula I as claimed in claim 1; and
(b) one or more pharmaceutically acceptable excipients selected from diluents, binders, lubricants, glidants, solubilizers, stabilizers, sweeteners, colorants, flavors, preservatives, surfactants, or mixtures thereof.

6. The pharmaceutical composition of claim 5, wherein the excipients are selected from diluents (1–30% w/w), binders (0.1–25% w/w), disintegrants (0.1 to 10% w/w), lubricants (0.1–10% w/w), glidants (0.1–5% w/w), surfactants (0.1–5% w/w), stabilizers (0.1–5% w/w), plasticizers (0.1–5% w/w), and antioxidants (0.1 to 10% w/w) .

7. The composition of claim 5, wherein the compound of Formula I is present in an amount of 1 to 1000 mg per unit dose.

8. The composition of claim 5, wherein the dosage form is selected from a tablet, capsule, granule, syrup, suspension, solution, emulsion, lozenge, film, or injection.

9. The compound as claimed in claim 1 wherein the said compound use in the treatment of a neurological disorders such as neurodevelopmental delay, preterm hypoxic-ischemic encephalopathy, sluggish cognitive tempo, inattentive attention deficit hyperactivity disorder, tourette syndrome, autism spectrum disorder, epilepsy, dyslexia, cerebral palsy, and developmental language disorder.