Novel phosphate ester compound and preparation method thereof

Abstract

The present invention relates to novel phosphate ester compounds of formula I for use in the treatment of central nervous system (CNS) diseases. Furthermore, the present invention provides an improved process for obtaining the compound of formula (I) in high yield and high purity. The novel phosphate ester compounds of formula-I are useful in the treatment of neurological, neuropsychiatric, metabolic and neurodevelopmental disorders.

Description

Technical Field

[0001] This invention relates to a novel phosphate ester compound of formula I for the treatment of diseases of the central nervous system (CNS).

[0002]

[0003] Formula-I In particular, the present invention relates to an improved process for obtaining phosphate ester compounds of formula -I in high yield and high purity. Furthermore, the novel phosphate ester compounds of formula -I can be used to treat nervous system disorders, neuropsychiatric disorders, metabolic disorders, and neurodevelopmental disorders. Background Technology

[0004] Phosphorus is one of the most fundamental elements for life and is widely distributed in nature. It is an essential mineral found in every cell of the human body. Like calcium, sodium, magnesium, potassium, chloride, and sulfur, it is a macromineral.

[0005] Phosphorus is a mineral naturally found in many foods. It is a key element in the formation of bones, teeth, and cell membranes. It helps activate enzymes and maintain blood pH within a normal range. Phosphorus regulates the normal function of nerves and muscles (including the heart) and is also a component of human genes, as it constitutes DNA, RNA, and ATP (the body's primary energy source). Phosphorus-containing compounds participate in many important processes and functions ranging from biochemistry, biogeochemistry, ecology, agriculture, to industry.

[0006] Phosphate is the pharmaceutical salt of phosphorus. It is used as a dietary supplement for patients who typically cannot obtain enough phosphorus from their daily diet due to certain medical conditions. Phosphate is the pharmaceutical form (salt) of phosphorus, also known as phosphate ions or orthophosphates. It is a trivalent inorganic anion and the conjugate base of hydrogen phosphate. Some phosphates are used in the manufacture of medications that help treat certain urinary tract infections.

[0007] Phosphorus's primary function is to build and maintain bones and teeth. It also plays a crucial role in the formation of DNA and RNA (the building blocks of the human genome). Furthermore, phosphorus is essential in metabolism (the conversion of calories and oxygen into energy), muscle contraction, heart rhythm, and the transmission of nerve signals.

[0008] US10610469B2 relates to therapeutic calcium phosphate granules for cosmetic or plastic surgery purposes, and methods of manufacturing and using them.

[0009] WO2007047378 relates to a dihydrogen phosphate of a pharmacologically active prostaglandin D2 receptor antagonist for the treatment of allergic diseases, systemic mastocytosis, diseases with systemic mast cell activation, anaphylactic shock, bronchial stenosis, bronchitis, urticaria, eczema, and diseases with pruritus.

[0010] US9938270 B2 relates to the crystalline and amorphous forms of 6-fluoro-2-[4-(pyridin-2-yl)but-3-yn-1-yl]imidazo[1,2-a]pyridine monophosphate and methods thereof for their preparation. The compounds of this invention are modulators of the mGlu5 receptor and can be used to treat or prevent central nervous system diseases and other diseases regulated by the mGlu5 receptor.

[0011] US10137061 B2 provides dental filling materials and / or compositions containing phosphates.

[0012] WO2020255978 relates to a novel phosphate ester with a pyrrolopyrimidine backbone, which has antitumor effects.

[0013] US20070042999A discloses phosphatidyl derivatives of opioids, steroid hormones, thyroid hormones, anesthetics, or chemotherapeutic agents having a phenolic, primary, secondary, or tertiary hydroxyl group.

[0014] Inorganic phosphate (Pi) plays a crucial role in bone development, mineral metabolism, and various cellular functions involving intermediate metabolism and energy transfer mechanisms. The phosphate-calcium combination contributes to the development and normal function of organisms. [Metabolites 2023, 13(7), 860] Phosphorus is involved in almost all physiological and chemical reactions. It is essential for normal kidney function, smooth heart function, and the transmission of nerve impulses. Phosphorus is particularly important for the development of the nervous system and intellectual function in children, as well as for the normal functioning of the nervous system. Phospholipids (i.e., phosphorus compounds) are necessary for the formation of myelin sheaths that protect nerve fibers.

[0015] Phosphorus is essential for the growth, maintenance, and repair of all tissues and cells. It also helps balance and utilize other vitamins and minerals, including vitamin D, iodine, magnesium, and zinc. Phosphate-containing units are important components of nucleotides, which are the basic structural units of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).

[0016] Phosphorus-containing drugs are an important class of therapeutic agents widely used in routine clinical practice. Structurally, phosphorus-containing drugs can be classified into triphosphates, phosphonates, phosphonites, phosphorus oxides, phosphoramides, bisphosphonates, phosphoric anhydrides, and others. Functionally, phosphorus-containing drugs are often designed as prodrugs with higher selectivity and bioavailability, fewer side effects and toxicity, or as biomolecular analogs containing endogenous substances and antagonistic endonuclease supplements.

[0017] Most common applications are continuously being developed due to their potential advantages in medicine or pharmaceuticals. It is certain that phosphorus-containing drugs will continue to be an important and valuable class of therapeutic agents in clinical applications. Given the known applications and limitations of phosphate salts, there is currently a need for stable phosphate compounds with good bioavailability and therapeutic efficacy.

[0018] By understanding the current demand for phosphorus-containing compounds, the inventors of this invention have developed a novel biochemical entity of a stable form of formula-I phosphate with therapeutic significance.

[0019] Purpose of the invention The primary objective of this invention is to provide novel therapeutic effects of phosphate compounds of formula -I.

[0020] Another object of the present invention is to provide novel phosphate ester compounds with different functional groups.

[0021] Another object of the present invention is to provide novel phosphate compounds that are therapeutically effective.

[0022] Another object of the present invention is to provide novel phosphorus-containing entities that can be used in clinical applications.

[0023] Another object of the present invention is to provide phosphate compounds with better selectivity and bioavailability, and reduced side effects and toxicity. Summary of the Invention

[0024] To achieve the above objectives, the inventors of this invention conducted in-depth experiments to demonstrate the significant efficacy of active ingredients, minerals, inorganic acids, esters, nutrients, metabolites, drugs, precursors, or oxides in improving the treatment of diseases related to the central nervous system.

[0025] In one particular aspect, the present invention provides novel phosphorus-containing biochemical entities.

[0026] In another aspect, the present invention relates to novel therapeutically active phosphate compounds, wherein a PO anion is linked to an active cation.

[0027] In another aspect, the present invention provides a novel phosphate ester compound of formula I for the treatment of diseases of the central nervous system (CNS).

[0028]

[0029] Formula-I In a further aspect, the present invention provides a pharmaceutical composition comprising a novel phosphate ester compound for treating CNS diseases and a pharmaceutically acceptable excipient / carrier, wherein the composition contains 0.1-2000 mg of an active phosphate ester moiety. Attached Figure Description

[0030] Figure 1 It shows Figure 1 (a), 1(b) and 1(c) show the H1 NMR DMSO spectra (400 MHz, CD3OD) of 1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2H-10,4α-iminoethanesulfanthroline 2-(trimethylammonium)ethyl hydrogen phosphate.

[0031] Figure 2 It shows Figure 2 (a) and 2(b) show the H1 NMR DMSO spectra (400 MHz, CD3OD) of 4-guanidinobutane-1-ammonium-2-(trimethylammonium)ethyl hydrogen phosphate.

[0032] Figure 3 The high-performance liquid chromatography (HPLC) chromatogram for the detection of (4-aminobutyl)guanidine in 4-guanidinobutane-1-ammonium-2-(trimethylammonium)ethyl hydrogen phosphate is shown.

[0033] Figure 4 The HPLC chromatogram for the detection of 1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2H-10,4α-iminoethanephenanthrene in 2-(trimethylammonium)ethyl hydrogen phosphate is shown. Detailed Implementation

[0034] The invention will now be described in detail with reference to certain preferred and optional embodiments in order to more fully illustrate and understand its various aspects. However, any person skilled in the art or craftsman should understand the extent to which these embodiments are generalizable in practical applications.

[0035] It should also be understood that all terms used herein are for describing particular implementations only and are not intended to be limiting in any way or scope. Unless otherwise defined, all technical and scientific expressions used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the embodiments of the invention pertain.

[0036] In describing and claiming embodiments of the present invention, the following terms will be used in accordance with the definitions known in the prior art.

[0037] Unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” include the plural meaning. Furthermore, the term “composition” does not limit the scope of the invention, as the best embodiments of the invention can be embodied in a variety of compositions.

[0038] The term “pharmaceutically / nutritionalally acceptable salt” as used in this article refers to salts that, within reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, etc., and have a reasonable benefit / risk ratio.

[0039] Specifically, "pharmaceutically acceptable salts" refer to relatively non-toxic inorganic and organic acid addition salts, amino acid salts, glycosyl salts, alkali metal or alkaline earth metal salts, as well as solvates, eutectics, polymorphs, etc. of these salts.

[0040] All modifications and substitutions that conform to the meaning of this specification and their legal equivalents shall be included within its scope. The use of the word "comprising" as a transitional term allows for the inclusion of other elements within the scope of protection of this invention.

[0041] In another preferred embodiment, the present invention provides a novel phosphate ester compound of Formula I for treating diseases of the central nervous system.

[0042]

[0043] Formula-I R1, R2, and R3 are selected, either identically or independently, from hydrogen, hydroxyl, halogen, (C1-C6)alkyl, (C2-C8)alkylene, (C2-C8)alkyne, trifluoroalkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C6-C6)alkyl, trifluoroalkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C6-C6)alkyl, alkylene ... 10 ) aryl; the group consisting of heterocyclic groups, such as substituted or unsubstituted pyrrole, pyridine, indole, quinoline; or Polyamines, such as guanidine; or quaternary ammonium compounds; or polycyclic aromatic hydrocarbons, such as phenanthrene and anthracene; or nucleosides, such as adenosine, guanosine, and inosine; or Selected from Li + Na + K + Monovalent metal ions in the group; selected from Ca 2+ Mg 2+ Zn 2+ Divalent metal ions in the group, or combinations thereof.

[0044] In another embodiment, the present invention relates to a novel phosphate ester compound of formula I for treating diseases of the central nervous system.

[0045]

[0046] Formula-I R1, R2, and R3 are selected, either identically or independently, from the group consisting of hydrogen, hydroxyl, halogen, (C1-C6) alkyl groups; or similar groups.

[0047]

[0048]

[0049] R4, R5, R6, R7, and R8 are selected, either identically or independently, from hydrogen, hydroxyl, halogen, (C1-C6)alkyl, (C2-C8)alkylene, (C2-C8)alkyne, (C1-C6)alkoxy, (C1-C6)trifluoroalkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, -C=O, and -(CH2). n A group consisting of -OH, -NH2, and NO2, where n is an integer from 1 to 10.

[0050] In a preferred embodiment, the present invention relates to an improved process for preparing a phosphate ester compound of formula (I) and its pharmaceutically acceptable salt.

[0051] In another embodiment, the present invention provides a cost-effective and feasible process for preparing phosphate ester compounds of formula (I) with high purity and high yield.

[0052] In another embodiment, the present invention provides an improved process for preparing a novel phosphate ester compound of formula (I).

[0053]

[0054] Formula (I) Includes the following steps: i. Preparation of the free base of R1 salt; ii. Preparation of a free base for 2-(trimethylammonium)ethyl phosphate; iii. The free base entity of step i) and the free base 2-(trimethylammonium)ethyl phosphate are added to a suitable solvent at ambient temperature to obtain the compound of formula -I in high yield and high purity.

[0055] In another preferred embodiment, the present invention provides a compound of formula I, wherein R1 is selected from the group consisting of:

[0056]

[0057] Where R2 is hydrogen, and R3 is selected from...

[0058] R4, R5, R6, R7 and R8 are selected, either identically or independently, from the group consisting of hydrogen, hydroxyl, halogen, (C1-C6)alkyl, (C2-C8)alkylene, (C2-C8)alkyne, (C1-C6)alkoxy, (C1-C6)trifluoroalkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, -C=O, -(CH2)-OH, -NH2 and NO2.

[0059] In another preferred embodiment, the present invention provides a compound of formula I, wherein the R1 salt is selected from the group consisting of amino acid salts, chlorides, sulfates, phosphates, diphosphates, bromides, nitrates, hydrochlorides, hydrobromic acid salts, malates, maleates, fumarate hydrochloride, tartrates, succinates, citrates, taurines, threonates, acetates, lactates, methanesulfonates, benzoates, ascorbic acid salts, sulfonates, salicylates, and sodium, potassium, calcium, lithium, magnesium, and ammonium (including substituted ammonium).

[0060] As used in this article, "solvent" refers to a compound, mixture, or substance, usually a liquid in which other materials can dissolve to form a solution. The role of a solvent in a chemical reaction can be non-participating or participating, depending on the type and strength of the solvent. Some solvents do not participate in the chemical reaction. They merely act as a reaction medium, enabling the chemical reaction to proceed more rapidly.

[0061] In a further embodiment, the solvent used in the reaction is a polar or nonpolar solvent, or a mixture thereof, wherein the solvent includes water, acetone, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), isopropanol, propanol, butanol, ethanol, and methanol; pentane, hexane, toluene, diethyl ether, benzene, tetrahydrofuran (THF), ethyl acetate, 1,4-dioxane, chloroform, carbon tetrachloride, acetic acid, used alone or in mixtures thereof.

[0062] In some embodiments, the green solvent used is a lower alcohol, such as ethanol or methanol, which can be easily recovered by distillation after the reaction is complete.

[0063] In a further embodiment, the ambient temperature is maintained in the range of 20°C to 45°C when the free alkali is added.

[0064] In another preferred embodiment, the phosphate compound of Formula I is selected from 1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2H-10,4α-iminoethanophenanthren 2-(trimethylammonio)ethyl hydrogen phosphate; 4-guanidinobutan-1-aminium 2-(trimethylammonio)ethyl hydrogen phosphate; 1H-pyrrole 2-(trimethylammonio)ethyl hydrogen phosphate. phosphate); 3-hydroxymethylpyridine 2-(trimethylammonio)ethyl hydrogen phosphate; (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol 2-(trimethylammonio)ethy1 hydrogen The group consists of phosphates, 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6,9-dihydro-3H-purin-6-one 2-(trimethylammonio)ethyl hydrogen phosphate, etc.

[0065] In another embodiment, the free base of the compound of formula I may optionally be stabilized by a pharmaceutically acceptable salt, such as chloride, bromide, hydrochloride, hydrobromide, hydrate, sodium, magnesium, carbonate, calcium, etc.

[0066] In another embodiment, the currently improved in-situ process provides compounds of formula I with high purity and high yield, wherein the purity of the dried HPLC is not less than 90%.

[0067] In another embodiment, the currently improved in-situ process provides compounds of formula -I with high purity and high yield, wherein both the yield and purity are not less than 70%. Preferably, the actual yield is in the range of 75% to 100%.

[0068] In another embodiment, the present invention provides novel phosphate ester compounds for treating central nervous system diseases or other metabolic diseases, the novel phosphate ester compounds comprising biochemical entities.

[0069] Furthermore, the novel compounds of this invention can be used to treat central nervous system diseases such as trauma, infection, nerve degeneration, stroke, tumors, cancer, autoimmune diseases, attention deficit hyperactivity disorder, epilepsy / seizures, autism, multiple sclerosis, neuropathic pain, Alzheimer's disease, Huntington's disease, Parkinson's disease, cancer, leukemia, bacterial skin infections, non-alcoholic steatohepatitis (NASH), fatty liver disease (FLD), alcoholic steatohepatitis, chronic glaucoma, etc.

[0070] In addition, compounds of Formula I can be used in pharmaceuticals to visualize skeletal and cardiovascular abnormalities, and can also be used as ingredients in certain products to prevent iron deficiency anemia.

[0071] The term “therapeutic effective amount” means an amount that reduces the risk, potential, likelihood, or occurrence of a disease or disorder; or an amount that provides significant relief, alleviates, and / or reduces, restores, or modulates at least one indicator / biomarker (e.g., CRP levels in blood or serum); and / or minimizes at least one clinical symptom associated with a metabolic or neurological disorder.

[0072] The term "subjects in need" refers to subjects who are preferably mammals, and more preferably humans who have or are suspected of having metabolic or neurological disorders.

[0073] In this invention, the term "treatment" refers to alleviating, mitigating, preventing, attenuating, managing, regulating, modulating, controlling, minimizing, lessening, decreasing, downregulating, upregulating, easing, inhibiting, restoring, suppressing, limiting, blocking, reducing, preventing, inhibiting, stabilizing, improving, curing, or curing metabolic or neurological disorders observed in patients.

[0074] It is worth noting that the novel phosphate ester compounds of the present invention are harmless and non-toxic, safe for human consumption, and have no serious adverse side effects. Therefore, the pharmaceutical compositions of the present invention can also be used as preventive treatment / adjunctive treatment / additional treatment / combination treatment / adjunctive treatment for subjects in need.

[0075] Some compounds of the present invention exist in both solvated and hydrated forms, including hydrated forms. Furthermore, some compounds of the present invention exist in multiple crystalline or amorphous forms (“polymorphs”). The compounds of the present invention can be formulated into geometric isomers, enantiomers, or stereoisomers.

[0076] Generally, all physical forms are applicable to the methods contemplated in this invention and are intended to be included within the scope of this invention.

[0077] The compounds, or pharmaceutically acceptable salts thereof, include hydrates, polymorphs, solvates, enantiomers, or racemates. Some crystalline forms of the compounds exist in polymorphs and are therefore intended to be covered in this disclosure. Furthermore, some compounds can form solvates with water (i.e., hydrates) or common organic solvents, and these solvates are intended to be covered in certain embodiments.

[0078] In one embodiment, the present invention provides a pharmaceutical composition comprising an effective amount of a novel phosphate ester compound of formula I and pharmaceutically acceptable excipients.

[0079] As used herein, the term "pharmaceutically acceptable carrier, diluent, or excipient" is intended to refer to (but is not limited to) any adjuvant, carrier, excipient, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or encapsulating agent, encapsulating polymer delivery system, or polyethylene glycol matrix that may be used in subjects (preferably humans). Excipients also include, for example: anti-adhesives, antioxidants, binders, coatings, tableting aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film-forming agents or coating agents, flavorings, flow enhancers (flowability enhancers), lubricants, preservatives, adsorbents, suspending or dispersing agents, sweeteners, surfactants, anti-caking agents, food additives, or hydrated water, salts.

[0080] In another embodiment, the present invention relates to a pharmaceutical composition comprising a phosphate ester compound of formula I prepared by methods known in the pharmaceutical industry, and administered via a variety of routes, depending on whether local or systemic treatment is required and the site of treatment.

[0081] Preferred routes of administration include, but are not limited to, sublingual administration, rectal administration, local administration, parenteral administration, nasal administration, or oral administration.

[0082] In another embodiment, the compounds of formula -I of the present invention are non-toxic, cost-effective, rich in nutrients or biomolecules, and provide protection against neurotransmission-related problems without any side effects.

[0083] In some embodiments, compounds of formula -I can be formulated into pharmaceuticals using pharmaceutically acceptable excipients, such as diluents, binders, lubricants, solubilizers, surfactants, stabilizers, colorants, flavorings, sweeteners, flow aids, plasticizers, and other additives.

[0084] In another embodiment of the invention, the diluent is selected from starch, hydrolyzed starch, partially pregelatinized starch, anhydrous lactose, cellulose powder, lactose monohydrate, sugar alcohols (such as sorbitol, xylitol, and mannitol), silicified microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium lactate, calcium hydrogen phosphate (anhydrous / dihydrate / trihydrate), calcium silicate, calcium sulfate, cellulose acetate, corn starch, pregelatinized starch, dextrin, β-cyclodextrin, dextrates, dextrose, erythritol, ethyl cellulose, fructose, fumaric acid, palmitic acid glyceryl, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain triglycerides, polydextrose, polymethyl methacrylate, sodium alginate, sodium chloride, sterilizable maize, sucrose, sugar spheres, talc, trehalose, xylitol, and carriers such as vehicle-like substances. Petrolatum, dimethyl sulfoxide, and mineral oil, etc.

[0085] In some embodiments of the present invention, the diluent content in the composition / formulation is in the range of 1% to 30% based on the total weight of the composition / formulation.

[0086] In another embodiment of the invention, the binder is selected from disaccharides (e.g., sucrose, lactose), polysaccharides and their derivatives (e.g., starch, cellulose, or modified cellulose such as microcrystalline cellulose, and cellulose ethers such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC)), sugar alcohols (e.g., xylitol, sorbitol, or mannitol), proteins (e.g., gelatin), synthetic polymers (e.g., polyvinylpyrrolidone (PVP), polyethylene glycol (PEG)), starch, gum arabic, agar, alginic acid, calcium carbonate, calcium lactate, carbomer, sodium carboxymethyl cellulose, carrageenan, cellulose acetate phthalate, chitosan, copovidone, corn starch, pregelatinized starch, cottonseed oil, glucose binder, dextrin, glucose, ethyl cellulose, guar gum, hydrogenated vegetable oil, mineral oil, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, inulin, cellulose, methyl cellulose, polyvinylpyrrolidone, polyethylene glycol, lactose, liquid glucose. 20 glucose), hydroxypropyl methylcellulose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, microcrystalline cellulose, pectin, poloxamer, polydextrose, polymethyl methacrylates, povidone, sodium alginate, stearic acid, sucrose, sunflower seed oil, various animal and vegetable oils, white paraffin wax, paraffin wax, edible flavorings, colorings and waxes.

[0087] In a further embodiment of the present invention, the content of the binder in the composition / formulation is in the range of 0.1% to 40% based on the weight of the composition / formulation.

[0088] In another embodiment of the present invention, the lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulfate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearoyl fumarate, stearic acid, talc, potassium, or sodium benzoate, etc.

[0089] In some embodiments of the present invention, the lubricant content in the composition / formulation is in the range of 0.1% to 10.0% based on the total weight of the composition / formulation.

[0090] In another embodiment of the present invention, the cosolvent is selected from polysorbate 80, sodium lauryl sulfate, anionic emulsifying wax, nonionic emulsifying wax, glyceryl monooleate, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene dehydrated sorbitan fatty acid esters, polyethylene glycol stearate, polyoxyglycerol esters, sorbitol esters, triethyl citrate, vitamin E, polyethylene glycol succinate, microcrystalline cellulose, sodium carboxymethyl cellulose, diethanolamine, ethylene glycol palmitostearate, glyceryl monostearate, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, lecithin, and polyethylene alkyl ethers. Ethers), alumina, poly(methyl vinyl ether / maleic anhydride), calcium carbonate, crospovidone, cyclodextrin, fructose, hydroxpropyl beta-cyclodextrin, oleyl alcohol, povidone, benzalkonium chloride, benzyl chloride, benzyl alcohol, benzyl benzoate, cetylpyridinium chloride, inulin, meglumine, poloxamer, pyrrolidone, sodium bicarbonate, starch, stearic acid, sulfobutyl ether-β-cyclodextrin, tricaprylin, trioleic acid, docusatesodium, glycine, ethanol, self-emulsifying monooleic acid, cationic benzyl chloride, cetrimide, xanthan gum, lauric acid, myristic alcohol, butylparaben, ethylparaben, methylparaben, propylparaben, sorbic acid, etc.

[0091] In another embodiment of the invention, the content of cosolvent or surfactant in the composition / formulation is in the range of 0.1% to 10% based on the weight of the composition / formulation.

[0092] In a preferred embodiment of the present invention, the content of the cosolvent or surfactant is in the range of 0.1% to 5.0% based on the weight of the composition / formulation.

[0093] In some embodiments of the present invention, the flow aid is selected from colloidal silica, magnesium stearate, fumed silica (colloidal silica), starch, talc, tricalcium phosphate, cellulose powder, hydrophobic colloidal silica, magnesium oxide, zinc stearate, magnesium silicate, magnesium trisilicate, silica, etc.

[0094] In another embodiment of the invention, the content of the glidant in the composition / formulation is in the range of 0.1% to 5.0% based on the total weight of the composition / formulation.

[0095] In some embodiments of the present invention, the stabilizer is selected from the group consisting of alginate, agar, carrageenan, gelatin, guar gum, gum arabic, locust bean gum, pectin, starch, xanthan gum, trehalose, etc.

[0096] In some embodiments of the present invention, the stabilizer content is in the range of 0.1% to 8.0% based on the total weight of the composition / formulation. In some embodiments of the present invention, a plasticizer is added to a coating formulation selected from the group consisting of propylene glycol, glycerol, triacetin, triethyl citrate, acetylated triethyl citrate, diethyl phthalate, acetylated monoglycerides, castor oil, mineral oil, etc.

[0097] In some embodiments of the present invention, the content of plasticizer in the composition / formulation is in the range of 0.1% to 5.0% based on the total weight of the composition / formulation.

[0098] In some embodiments of the present invention, the solvent is selected from water, ethanol, isopropanol, propylene glycol, mineral oil, benzyl alcohol, benzyl benzoate, flavored glycol, carbon dioxide, castor oil, corn oil, cottonseed oil, dimethyl ether, albumin, dimethylacetamide, ethyl acetate, ethyl lactate, medium-chain triglycerides, methyl lactate, olive oil, peanut oil, polyethylene glycol, polyoxyethylene, castor oil, propylene carbonate, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, water-soluble solvents, organic polar or non-polar solvents, or mixtures thereof.

[0099] In a preferred embodiment of the invention, the amount of solvent in the composition / formulation is sufficient to make the weight of the composition / formulation reach 100% by weight.

[0100] Additional additives include polymers, plasticizers, sweeteners and flavoring powders, preservatives, colorants, surfactants, and other excipients. Flavoring powder compositions include flavorings bound to a solid carrier. Coating materials such as synthetic polymers, shellac, corn gluten (corn gliadin) or other polysaccharides, gelatin, fatty acids, waxes, plastics, and plant fibers are used.

[0101] In a preferred embodiment of the invention, the amount of additive used is in the range of 1% to 20% of the unit dose.

[0102] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutical excipient, wherein the pharmaceutical excipient is selected from diluents, binders, lubricants, flow aids, additives, surfactants, stabilizers, or mixtures thereof.

[0103] In a preferred embodiment, based on the weight of the total composition, the content of the diluent ranges from 1% to 30%; the content of the binder ranges from 0.1% to 25%; the content of the lubricant ranges from 0.1% to 10.0%; the content of the gliding agent ranges from 0.1% to 5.0%; the content of the additive ranges from 1% to 10%; the content of the surfactant ranges from 0.1% to 5.0%; the content of the stabilizer ranges from 0.1% to 5.0%; and the content of the plasticizer ranges from 0.1% to 5.0%.

[0104] In some embodiments, a pharmaceutical composition of a novel phosphate ester compound of Formula I is administered to a subject in need in a form suitable for oral administration, such as tablets, capsules (in the form of delayed release, extended release, sustained release, or enteric release); hard gelatin capsules, soft gelatin capsules in an oily carrier, vegetarian capsules, cellulose hard or soft capsules, sublingual granules, effervescent or charcoal tablets, aqueous or oily solutions, suspensions or emulsions, encapsulated, matrix, coating, beadlets, nanoparticles, capsules, granules, particles, agglomerates, spandex, chewable tablets, lozenges, tablets, tablets, trochetes, solutions, suspensions, quick-dissolving films, elixirs, gels, tablets, pills, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, sprays, or in liquid media or syrups. The pharmaceutical composition of the novel phosphate ester compound of Formula I can be administered to a subject in need in the form of a dry powder; a topical application (including transdermal and transmembrane administration) such as a cream, ointment, gel, aqueous or oil solution or suspension, salve, paste, or plaster; a nasal spray or nasal drops such as a nasal spray or nasal drops such as a vaginal or rectal suppository; an inhalation administration such as a fine powder or liquid aerosol; or a sublingual or oral administration such as a tablet, capsule, film, or spray.

[0105] In a further embodiment, the compositions of the present invention are formulated into age-appropriate pediatric oral dosage forms, such as syrups, inhalers, spray mini tablets, microtablets, chewable formulations, orally disintegrating films, or orally disintegrating tablets.

[0106] The dosage for prophylaxis or treatment typically varies depending on the nature and severity of the disease being treated and the route of administration. Dosage and frequency of administration may also vary based on the individual patient's age, weight, and response.

[0107] Typically, the total daily dose (single dose or divided dose) ranges from about 0.1 mg / day to about 5000 mg / day, preferably from about 1 mg / day to about 1000 mg / day.

[0108] In some embodiments, the total daily dose may be administered in the range of about 1 mg / day to about 3000 mg / day, preferably in the range of about 1 mg / day to about 1000 mg / day.

[0109] Any and all embodiments or exemplary language (such as "for example") provided herein are used only to better illustrate the invention and, unless otherwise stated, do not constitute a limitation on the scope of the invention.

[0110] Although the present invention has been described in conjunction with certain embodiments in the foregoing description, and many details have been provided for illustrative purposes, it will be apparent to those skilled in the art that the present invention may have other embodiments, and that some details described herein may be modified without departing from the basic principles of the invention.

[0111] The present invention can 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 any way.

[0112] Therefore, this disclosure is to be regarded as illustrative rather than restrictive in all respects, the scope of the invention is indicated by the appended claims and embodiments, and all variations or modifications within the equivalent scope are intended to be included therein.

[0113] Example Having described the basic aspects of the invention, the following non-limiting embodiments illustrate specific implementations of the invention. Those skilled in the art will understand that many modifications can be made to the invention without altering its essential nature.

[0114] Example 1: General process for preparing phosphate ester compounds of formula I Step i)

[0115] Step ii)

[0116] Step iii)

[0117] Table 1: Compounds of Formula I

[0118]

[0119] Table 2: Purity and yield of compounds of formula I

[0120] Example 1: Preparation method of 1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2H-10,4α-iminoethanesulfanthroline-2-(trimethylammonium)ethyl hydrogen phosphate.

[0121]

[0122] Step i) Water (22.6 ml) was added to 1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2H-10,4α-iminoethanealkylphenanthrene hydrobromide (10.0 g m) and toluene. The mixture was stirred and the pH was adjusted to 11-13 using a sodium hydroxide (4.0 g) and water (16.0 ml) solution. The reaction mixture was stirred for 60-70 minutes. The layers were separated, and the aqueous layer was back-extracted with toluene (10 ml). The toluene layers were combined and washed with water (20 ml). The separated toluene layer was subjected to solvent distillation under reduced pressure, and the residue was 1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2H-10,4α-iminoethanealkylphenanthrene free base (7.20 g m).

[0123] Step ii) Add water (30.0 ml) and calcium chloride 2-(trimethylammonium)ethyl phosphate (1:1:1) (6.9 gm), stir, and add calcium hydroxide (1.98 gm). Stir the reaction mixture for 60 to 70 minutes. Filter the reaction mixture and collect the filtrate as a solution of 2-(trimethylammonium)ethyl phosphate (free base).

[0124] Step iii) A solution of 1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2H-10,4α-iminoethanealkylphenanthrene as a free base was added to a solution of 2-(trimethylammonium)ethyl phosphate, and the reaction mixture was stirred for 500 to 550 minutes. The reaction mixture was filtered, washed with water, and thoroughly dried under vacuum. The wet product was dried under reduced pressure at 35°C to 40°C for 840 minutes to give 1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2H-10,4α-iminoethanealkylphenanthrene-2-(trimethylammonium)ethyl hydrogen phosphate in 90% yield and 96% purity.

[0125] The content of 1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2H-10,4α-iminoethanephenanthrene in 2-(trimethylammonium)ethyl hydrogen phosphate was determined by HPLC to be 57.47% (w / w) on a dry basis.

[0126] Moisture content (LOD) -8.28% (by weight) H1 NMR (400 MHz, DMSO) δ ppm 7.11 (1H, d), 6.81(1H, d), 6.78 (1H,d),4.1 (2H, t), 3.83 (3H, S), 3.71 (1H, m),3.61 (2H t), 3.55 (1H, m), 3.30 (9H, S), 2.8 (3H S), 2.70~2.0 (8H, m), 1.63 (1H, d), 1.60~1.35 (5H, m), 1.30~1.15 (1H, m).

[0127] Example 2: Preparation process of 4-guanidinobutane-1-ammonium-2-(trimethylammonium)ethyl hydrogen phosphate

[0128] Step i) Add water (30.0 ml) to 1-(4-aminobutyl)guanidine sulfate (10.0 gm) and stir. Add calcium hydroxide (3.25 gm) and stir the reaction mixture for 60 to 70 minutes. Filter the reaction mixture and collect the filtrate as a free alkaline solution of 1-(4-aminobutyl)guanidine.

[0129] Step ii) Add water (30.0 ml) and calcium chloride 2-(trimethylammonium)ethyl phosphate (1:1:1) (11.29 gm) and stir. Add calcium hydroxide (3.08 gm) and stir the reaction mixture for 60 to 70 minutes. Filter the reaction mixture and collect the filtrate as a solution of 2-(trimethylammonium)ethyl phosphate (free base).

[0130] Step iii) A solution of 1-(4-aminobutyl)guanidine free base was added to a solution of 2-(trimethylammonium)ethyl phosphate, and the reaction mixture was stirred for 600 to 720 minutes. The reaction mixture was filtered, washed with water, and thoroughly dried under vacuum. The wet product was dried under reduced pressure at 25°C to 30°C for 1440 minutes to give 4-guanidinobutane-1-ammonium-2-(trimethylammonium)ethyl hydrogen phosphate in 85% yield and 90% purity.

[0131] The content of (4-aminobutyl)guanidine in 4-guanidinobutane-1-ammonium-2-(trimethylammonium)ethyl hydrogen phosphate by HPLC was determined to be 37.28% (w / w) on a dry basis.

[0132] LOD is 8.42% (by weight). H1 NMR (400 MHz, D2O) δ ppm: 1.65–1.70 (m, 4 H, 2 x 1-(4-aminobutyl)guanidine methylene), 3.02 (t, 2 H, methylene), 3.19–3.22 (S, 9 H, 3 x N-methyl, 1-(4-aminobutyl)guanidine 2H-methylene), 3.55 (t, 2 H, 2-hydroxy-N,N,N-trimethylethylammonium methylene), 4.13 (t, 2 H, 2-hydroxy-N,N,N-trimethylethylammonium methylene).

[0133] Example 3: Pharmaceutical composition of a compound of formula I

Claims

1. Novel phosphate ester compounds of formula I for the treatment of central nervous system (CNS) diseases: Formula-I in, R1, R2, and R3 are selected, either identically or independently, from hydrogen, hydroxyl, halogen, (C1-C6)alkyl, (C2-C8)alkylene, (C2-C8)alkyne, trifluoroalkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C6-C6)alkyl, trifluoroalkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C6-C6)alkyl, alkylene, alkylene, trifluoroalkyl ... 10 )aryl; the group consisting of heterocyclic groups; wherein the heterocyclic groups are selected from the group consisting of substituted or unsubstituted pyrrole, pyridine, indole and quinoline; or Polyamine, wherein the polyamine is guanidine; or quaternary ammonium; or polycyclic aromatic hydrocarbon, wherein the polycyclic aromatic hydrocarbon is selected from the group consisting of phenanthrene and anthracene; or nucleoside, wherein the nucleoside is selected from the group consisting of adenosine, guanosine and inosine; or Monovalent metal ions, wherein the monovalent metal ions are selected from Li + Na + and K + The group consisting of divalent metal ions, wherein the divalent metal ions are selected from Ca 2+ Mg 2+ Zn 2+ A group consisting of or a combination thereof.

2. The compound according to claim 1, in, R1, R2, and R3 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, and (C1-C6) alkyl groups; or selected from the group consisting of... ； R4, R5, R6, R7, and R8 are selected, either identically or independently, from hydrogen, hydroxyl, halogen, (C1-C6)alkyl, (C2-C8)alkylene, (C2-C8)alkyne, (C1-C6)alkoxy, (C1-C6)trifluoroalkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, -C=O, and -(CH2). n The group consisting of -OH, -NH2, and -NO2; and Where n is an integer in the range of 1 to 10.

3. The compound according to claim 1, wherein, The compound is selected from 1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2H-10,4α-iminoethanephenanthrene-2-(trimethylammonium)ethyl hydrogen phosphate; 4-guanidinobutane-1-ammonium-2-(trimethylammonium)ethyl hydrogen phosphate; 1H-pyrrole-2-(trimethylammonium)ethyl hydrogen phosphate; 3-hydroxymethylpyridine-2-(trimethylammonium)ethyl hydrogen phosphate; (2R The group consisting of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)oxecyclopentane-3,4-diol 2-(trimethylammonium)ethyl hydrogen phosphate; and 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxecyclopentane-2-yl]-6,9-dihydro-3H-purin-6-one 2-(trimethylammonium)ethyl hydrogen phosphate.

4. A process for preparing a novel phosphate ester compound of formula I, Formula-I Includes the following steps: i. Preparation of the free base of R1 salt; ii. Preparation of a free base for 2-(trimethylammonium)ethyl phosphate; iii. At ambient temperature, the free base from step i) and the free base of 2-(trimethylammonium)ethyl phosphate are added to a solvent to obtain a compound of formula -I with high yield and high purity; R1 is selected from the group consisting of the following groups: Where R2 is hydrogen, and R3 is selected from... ； R4, R5, R6, R7, and R8 are selected, either identically or independently, from the group consisting of hydrogen, hydroxyl, halogen, (C1-C6)alkyl, (C2-C8)alkylene, (C2-C8)alkyne, (C1-C6)alkoxy, (C1-C6)trifluoroalkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, -C=O, -(CH2)-OH, -NH2, and -NO2.

5. The process according to claim 4, wherein the R1 salt is selected from the group consisting of amino acid salts, chlorides, sulfates, phosphates, bisphosphates, bromides, nitrates, hydrochlorides, hydrobromic acid salts, malates, maleates, fumarate hydrochloride, tartrates, succinates, citrates, taurines, threonates, acetates, lactates, methanesulfonates, benzoates, ascorbic acid salts, sulfonates, salicylates, sodium, potassium, calcium, lithium, magnesium, and ammonium (including substituted ammonium).

6. The process according to claim 4, wherein the solvent is selected from water, acetone, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), isopropanol, propanol, butanol, ethanol, and methanol; pentane, hexane, toluene, diethyl ether, benzene, THF, ethyl acetate, 1,4-dioxane, chloroform, carbon tetrachloride, acetic acid, or mixtures thereof.

7. The process according to claim 4, wherein, The ambient temperature is in the range of 20°C to 45°C.

8. The process according to claim 4, wherein the compound of formula I is selected from 1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2H-10,4α-iminoethaneylphenanthrene-2-(trimethylammonium)ethyl hydrogen phosphate; 4-guanidinobutane-1-ammonium-2-(trimethylammonium)ethyl hydrogen phosphate; 1H-pyrrole-2-(trimethylammonium)ethyl hydrogen phosphate; 3-hydroxymethylpyridine-2-(trimethylammonium)ethyl The group consisting of: 2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)oxepane-3,4-diol-2-(trimethylammonium)ethyl phosphate; and 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxepane-2-yl]-6,9-dihydro-3H-purin-6-one-2-(trimethylammonium)ethyl phosphate.

9. A composition comprising a compound of formula I as described in claim 1 and at least one pharmaceutically acceptable excipient.

10. The composition according to claim 9, wherein, The pharmaceutically acceptable excipients are selected from the group consisting of diluents, binders, lubricants, flow aids, additives, surfactants, stabilizers, and plasticizers; based on the weight of the composition, the content of the diluent ranges from 1 to 30 wt%; the content of the binder ranges from 0.1 to 25 wt%; the content of the lubricant ranges from 0.1 to 10.0 wt%; the content of the flow aid ranges from 0.1 to 5.0 wt%; the content of the additive ranges from 1 to 10 wt%; the content of the surfactant ranges from 0.1 to 5.0 wt%; the content of the stabilizer ranges from 0.1 to 5.0 wt%; and the content of the plasticizer ranges from 0.1% to 5.0 wt%.

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