5-aminolevulinic acid derivative and pharmaceutical composition containing same

Abstract

The present invention relates to a 5-aminolevulinic acid derivative having improved storage stability and bioavailability, and a pharmaceutical composition comprising the same, the present invention exhibits a pharmacokinetic profile in which 5-aminolevulinic acid is more effectively exposed to blood in vivo, and reduces side effects after treatment, such as pain, erythema, swelling, edema, burning sensation, pruritus, spalling, hyperpigmentation and long-term stimulation and hypersensitivity. Further, the present invention relates to a 5-aminolevulinic acid derivative and a composition comprising the same, in which 5-aminolevulinic acid exhibits high efficiency while reducing the severity of side effects, and the 5-aminolevulinic acid derivative and the composition comprising the same are useful for photodynamic diagnosis and therapy.

Description

Technical Field

[0001] This invention relates to 5-aminolevulinic acid derivatives with improved storage stability and bioavailability, and pharmaceutical compositions comprising the derivatives. Background Technology

[0002] Photodynamic therapy or photochemotherapy, first proposed by Thomas JD et al., is a technique used to treat various abnormalities or diseases occurring on the skin or other epithelial organs or mucous membranes (especially non-malignant lesions such as psoriasis, actinic keratosis and acne, as well as tumors such as cancer) (Thomas JD et al., J. Natl. Cancer Inst. 1998; 90(12): 889-905).

[0003] Photodynamic therapy involves applying a chemical called a photosensitizer to an affected area of ​​the body, followed by exposure to photoactivated rays to activate the chemical. The resulting cytotoxic activity kills cells in the affected area or reduces the likelihood of cell proliferation. Well-known photosensitizers include psoralen, porphyrin, chlorocyanine, and phthalocyanine. Among these, the most well-known and clinically effective sensitizers are 5-aminolevulinic acid (5-ALA), represented by chemical formula A, and methyl 5-aminolevulinic acid, represented by chemical formula B, which are commercially available under the names Levulan and Metvix, respectively.

[0004] [Chemical Formula A] [Chemical Formula B] 5-Aminolevulinic acid (5-ALA) is converted into the photosensitizer protoporphyrin IX (PpIX) via the porphyrin cycle in the biosynthetic pathway of heme (which constitutes hemoglobin and acts as a transporter of oxygen in the body). In cases of external application of large amounts of 5-ALA, an excess of heme is produced in the body, which reduces the activity of the enzyme that converts PpIX to heme (i.e., ferrochelase). As a result, large amounts of PpIX accumulate in cells. PpIX is a potent photosensitizer, a substance that exhibits fluorescence when activated, and can oxidize and kill cancer cells by converting nearby oxygen into oxygen free radicals.

[0005] According to Ji Sun Kim et al., 5-ALA is not only used for photodynamic diagnosis, but also for the treatment of cancerous lesions of the skin, gastrointestinal tract, lungs, bladder, and oral cavity, because 5-ALA is selective for tumors and the 5-ALA bound to the tumor is subsequently converted into an active type of substance that exhibits cytotoxicity (Ji Sun Kim et al., Korean J Otolaryngol 2005; 48(2): 234-40).

[0006] Masanori H. et al. described the efficacy of 5-ALA in the treatment and prevention of cerebrovascular Parkinson's disease or cerebral infarction (Masanori H. et al., J. Pharmacol. Sci. 2020 Nov; 144(3): 183-187). Furthermore, Vipul Y. et al. reported significant effects of 5-ALA on various inflammatory diseases, including inflammatory bowel disease (Vipul Y. et al., Biomedicines. 2021 May 20; 9(5): 578).

[0007] It is known that photodynamic therapy using 5-ALA causes less damage to adjacent normal tissue because 5-ALA is absorbed relatively selectively under the aforementioned pathological conditions. However, because 5-ALA is hydrophilic, its absorption and penetration into the skin are less efficient when applied directly, and 5-ALA is not effective for all lesions, as it cannot be effectively used without PpIX accumulation. During photodynamic therapy using 5-ALA and its derivatives for various diseases, pain, erythema, swelling, edema, burning sensation, itching, peeling, hyperpigmentation, and long-term irritation and hypersensitivity reactions are frequently reported post-treatment, particularly in the treated area. These side effects are known to be especially severe when the treated area is the face, scalp, or neck.

[0008] Regarding the occurrence of these side effects, international patent WO2006 / 051269 reports that erythema, hyperpigmentation and peeling often occur after photodynamic therapy. It discloses the use of 5-ALA ester in photodynamic therapy for the treatment of acne, and also discloses pain, burning and itching during and after treatment.

[0009] Furthermore, in the case of products that use liquid formulations of 5-ALA, it is well known that developing substances suitable for ointments or injectable formulations is quite difficult because 5-ALA degrades during distribution and storage, resulting in a reduction in the inherent functional effects of 5-ALA.

[0010] Therefore, there is still a need for a new 5-ALA derivative that has fewer side effects, provides a suitable balance between hydrophilicity and hydrophobicity to be applicable to all lesions, and provides stability that does not degrade during distribution and storage.

[0011] Therefore, as a result of efforts to solve the above-mentioned problems, the inventors of the present invention have demonstrated that it is possible to synthesize a new 5-ALA derivative with reduced side effects, providing a suitable balance between hydrophilicity and hydrophobicity for applicability to all lesions, and providing stability that does not degrade during distribution and storage, thereby solving the existing problems of 5-ALA, and the inventors of the present invention have completed the present invention.

[0012] Related technical documents Patent documents (Patent Document 1) International Patent Publication WO2006 / 051269 Non-patent literature (Non-patent literature 1) Thomas JD et al., J. Natl. Cancer Inst. 1998;90(12):889-905.

[0013] (Non-patent literature 2) Ji Sun Kim et al., Korean J Otolaryngol 2005;48(2):234-40.

[0014] (Non-patent literature 3) Masanori H. et al., J. Pharmacol. Sci. 2020 Nov; 144(3): 183-187.

[0015] (Non-patent literature 4) Vipul Y. et al., Biomedicines. 2021 May 20; 9(5): 578. Summary of the Invention

[0016] Technical issues The object of this invention is to provide a 5-ALA derivative compound having 5-aminolevulinic acid (5-ALA) bonded to both sides of the linker.

[0017] The 5-ALA derivative compounds according to the invention exhibit pharmacokinetic characteristics that enable more effective exposure of 5-ALA to the bloodstream when administered orally, and when provided in a transdermal form, they can reduce post-treatment side effects such as pain, erythema, swelling, edema, burning sensation, itching, peeling, hyperpigmentation, and long-term irritation and hypersensitivity reactions.

[0018] Furthermore, the 5-ALA derivative compounds according to the present invention can be degraded in vivo to 5-ALA and a linker, thus exhibiting excellent pharmaceutical activity not only in 5-ALA but also in the linker.

[0019] Solution to the problem To achieve the above objectives, the present invention provides 5-aminolevulinic acid (5-ALA) derivatives or pharmaceutically acceptable salts thereof represented by the following chemical formula 1.

[0020] [Chemical Formula 1] In chemical formula 1, R 1 R 2 R 3 and R 4 Each of the following is independently a hydrogen atom, halogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or C6-C 20 Aryl, n is an integer between 0 and 3, and m is an integer from 0 to 3.

[0021] The present invention also provides a composition for photodynamic diagnosis and photodynamic therapy comprising a 5-ALA derivative compound or a pharmaceutically acceptable salt thereof.

[0022] The present invention also provides a pharmaceutical composition for treating or preventing inflammatory diseases, cancer, metabolic diseases, insomnia, skin aging or hair loss, comprising a 5-ALA derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0023] The present invention also provides a health functional food for preventing or improving inflammatory diseases, cancer, metabolic diseases, insomnia, skin aging or hair loss, comprising a 5-ALA derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0024] The present invention also provides a pharmaceutical preparation comprising the pharmaceutical composition for the treatment or prevention of inflammatory diseases, cancer, metabolic diseases, insomnia, skin aging, or hair loss.

[0025] The present invention also provides a method for preparing a 5-ALA derivative compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof, wherein the preparation method comprises: (a) The step of reacting a solution of N-Boc-5-aminolevulinic acid with dimethylformamide and oxaloyl chloride to give the compound represented by chemical formula 2; (b) The step of reacting a suspension of the compound represented by formula 3 with a solution obtained by dissolving the compound represented by formula 2 in a solvent to obtain the compound represented by formula 4; and (c) The step of reacting a suspension of the compound represented by chemical formula 4 with an acidic solution to obtain the 5-ALA derivative compound represented by chemical formula 1.

[0026] [Chemical Formula 1] [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] In chemical formulas 1, 3, and 4 R 1 R 2 R 3 and R 4 Each of the following is independently a hydrogen atom, halogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or C6-C 20 Aryl, n is an integer between 0 and 3, and m is an integer from 0 to 3.

[0027] Advantages of the invention The 5-aminolevulinic acid (5-ALA) derivatives of the present invention are not only effective in photodynamic diagnosis, photodynamic therapy, or photochemotherapy of tumors, but also exhibit therapeutic effects on various abnormalities or diseases of the skin or other epithelial organs or mucous membranes, non-malignant lesions such as psoriasis, actinic keratosis, and acne, as well as tumors such as cancer; prevention and treatment of cholesterol reduction and xerostomia; prevention and treatment of heart disease; treatment of fatty liver or steatohepatitis; relief of insomnia and improvement of sleep quality; prevention and treatment of various inflammatory diseases such as inflammatory colitis and Crohn's disease; prevention and treatment of metabolic diseases such as diabetes, obesity, and hypertension; prevention of cell aging and cell regeneration; and prevention and treatment of hair loss. Attached Figure Description

[0028] Figure 1 The graph is obtained by tracking and analyzing the hourly concentration of the 5-ALA drug released into the bloodstream when the compound of Example 1 of the invention according to this application is administered intravenously or orally.

[0029] Figure 2The graph is obtained by measuring the change in brain permeability over time of the orally administered compound according to Example 1 of the invention of this application. Detailed Implementation

[0030] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Generally, the nomenclature used in this specification is well-known and commonly used in this field.

[0031] The novel derivatives of 5-aminolevulinic acid (5-ALA) according to the present invention have been shown to have reduced side effects, a suitable balance between hydrophilicity and hydrophobicity for applicability to all lesions, and stability that does not degrade during distribution and storage.

[0032] Therefore, embodiments of the present invention relate to 5-ALA derivative compounds represented by chemical formula 1 or pharmaceutically acceptable salts thereof.

[0033] [Chemical Formula 1] In chemical formula 1, R 1 R 2 R 3 and R 4 Each of the following is independently a hydrogen atom, halogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or C6-C 20 Aryl, n is an integer between 0 and 3, and m is an integer from 0 to 3.

[0034] Preferably, n is 1, m is 0, and R 1 R 2 R 3 and R 4 Each of them can be hydrogen; however, the invention is not limited thereto.

[0035] The 5-ALA derivative compound according to the invention has a form in which two 5-ALA molecules are linked by a central linker. When the 5-ALA derivative compound is metabolized in vivo via esterification, the central linker is converted into a derivative of 4-hydroxybenzyl alcohol (4-HBA), which is a compound with antioxidant, anti-anxiety, soothing, anti-apoptotic and anti-inflammatory effects, for example, a compound having a structure represented by the following chemical formula 5.

[0036] [Chemical Formula 5] Another embodiment of the invention relates to a method for preparing a 5-ALA derivative compound or a pharmaceutically acceptable salt thereof, wherein the method comprises (a) reacting an N-Boc-5-aminolevulinic acid solution with dimethylformamide and oxalyl chloride to obtain a compound represented by formula 2; (b) reacting a suspension of a compound represented by formula 3 with a solution obtained by dissolving the compound represented by formula 2 in a solvent to obtain a compound represented by formula 4; and (c) reacting a suspension of a compound represented by formula 4 with an acidic solution to obtain a 5-ALA derivative compound represented by formula 1.

[0037] [Chemical Formula 1] [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] In chemical formulas 1, 3, and 4 R 1 R 2 R 3 and R 4 Each of the following is independently a hydrogen atom, halogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or C6-C 20 Aryl, n is an integer between 0 and 3, and m is an integer from 0 to 3.

[0038] The invention will be described in more detail below.

[0039] In another embodiment of the invention, n is 1, m is 0, and R 1 R 2 R 3 and R 4 Each can be hydrogen; however, the invention is not limited thereto. In this case, the compound represented by chemical formula 1 has a structure represented by the following chemical formula 1-1.

[0040] [Chemical Formula 1-1] In this invention, after being absorbed, the compound represented by chemical formula 1-1 is converted into 5-ALA as an active substance and the compound represented by chemical formula 5 by an esterase (a physiological enzyme distributed in all tissues of the body) through the following reaction formula 1.

[0041] The compound represented by the following chemical formula 5 is a derivative of 4-hydroxybenzyl alcohol (4-HBA). The compound represented by chemical formula 5 not only functions as a connector linking two 5-ALA molecules to both sides in the 5-ALA derivative compound represented by chemical formula 1 according to the invention of this application, but also has antioxidant, anti-anxiety, soothing, anti-apoptotic and anti-inflammatory effects when esterified in vivo.

[0042] Therefore, the compound represented by chemical formula 1 according to the present invention can be esterified in vivo to exhibit the efficacy of 5-ALA and the efficacy of the compound represented by chemical formula 5.

[0043] [Reaction Formula 1] In this invention, the substance represented by Formula 1 exhibits reduced hydrophilicity because the carboxyl group of 5-ALA is converted to a form in which a lipid-soluble benzyl group is introduced. Therefore, when applied as an ointment or cream or transdermally, this substance is absorbed very rapidly by the skin, and when administered orally, the substance represented by Formula 1 is rapidly degraded to 5-ALA by esterases after absorption from the gastrointestinal wall or small intestine, resulting in a high concentration of 5-ALA in the body. Furthermore, the substance represented by Formula 1 is hydrophobic and has significantly lower hygroscopicity than 5-ALA; therefore, under normal storage conditions or in solution, the substance represented by Formula 1 exhibits significantly superior storage stability compared to the parent drug 5-ALA.

[0044] In this invention, the pharmaceutically acceptable salt may be one or more selected from hydrochloride, p-toluenesulfonate, fumarate, citrate, succinate, salicylate, oxalate, bromate, phosphate, methanesulfonate, tartrate, sulfate and mandelate, preferably hydrochloride; however, the pharmaceutically acceptable salt is not limited thereto.

[0045] The 5-ALA derivative compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof according to the present invention can be prepared by the following method.

[0046] (a) The step of reacting a solution of N-Boc-5-aminolevulinic acid with dimethylformamide and oxaloyl chloride to give the compound represented by chemical formula 2; (b) The step of reacting a suspension of the compound represented by formula 3 with a solution obtained by dissolving the compound represented by formula 2 in a solvent to obtain the compound represented by formula 4; and (c) The step of reacting a suspension of the compound represented by chemical formula 4 with an acidic solution to obtain the 5-ALA derivative compound represented by chemical formula 1.

[0047] [Chemical Formula 1] [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] In chemical formulas 1, 3, and 4 R 1 R 2 R 3 and R 4 Each of the following is independently a hydrogen atom, halogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or C6-C 20 Aryl, n is an integer between 0 and 3, and m is an integer from 0 to 3.

[0048] According to another embodiment of the present invention, a 5-aminolevulinic acid derivative compound of formula 1-1 or a pharmaceutically acceptable salt thereof can be prepared by the following method.

[0049] (a) The step of reacting a solution of N-Boc-5-aminolevulinic acid with dimethylformamide and oxaloyl chloride to give the compound represented by formula 2; and (b) The step of reacting a solution obtained by dissolving the compound represented by Formula 2 in a solvent with a suspension of 4-hydroxybenzyl alcohol represented by Formula 3-1 to finally obtain the 5-ALA derivative compound represented by Formula 1-1.

[0050] [Chemical Formula 1-1] [Chemical Formula 2] [Chemical Formula 3-1] The method for preparing the 5-ALA derivative compound or its pharmaceutically acceptable salt according to the present invention may further include the following steps.

[0051] (d) Filter the 5-ALA derivative compound prepared in step (c) and add a solvent such as ethyl acetate to the recovered filtrate to concentrate, elute and purify the recovered filtrate.

[0052] In this invention, for the N-Boc-5-aminolevulinic acid solution in step (a), a solvent selected from dichloromethane, acetonitrile, 1,4-dioxane, ethyl acetate and acetone can be used, and dichloromethane is preferred; however, embodiments of the invention are not limited thereto.

[0053] In this invention, for the suspension of the compound represented by chemical formula 3 in step (b), a solvent selected from acetonitrile, 1,4-dioxane, ethyl acetate and acetone can be used, and acetonitrile is preferred; however, embodiments of the invention are not limited thereto.

[0054] In this invention, for the acidic solution in step (c), one or more selected from hydrochloric acid, 1,4-dioxane and ethyl acetate can be used, and hydrochloric acid and 1,4-dioxane or ethyl acetate are preferred; however, embodiments of the invention are not limited thereto.

[0055] The 5-ALA derivative compounds according to the present invention have been proven effective for photodynamic diagnosis or photodynamic therapy of tumors, treatment of various abnormalities or diseases of the skin or other epithelial organs or mucous membranes, treatment of non-malignant lesions such as psoriasis, actinic keratosis and acne, treatment of tumors such as cancer, prevention and treatment of cholesterol reduction and xerostomia, prevention and treatment of heart disease, treatment of fatty liver or steatohepatitis, relief of insomnia and improvement of sleep quality, prevention and treatment of various inflammatory diseases such as inflammatory colitis and Crohn's disease, prevention and treatment of metabolic diseases such as diabetes, obesity and hypertension, prevention of cellular senescence and cell regeneration, and prevention and treatment of hair loss.

[0056] Therefore, another embodiment of the present invention relates to compositions for photodynamic diagnosis and for photodynamic therapy, comprising a 5-ALA derivative compound or a pharmaceutically acceptable salt thereof.

[0057] Furthermore, another embodiment of the present invention relates to a pharmaceutical composition for treating or preventing inflammatory diseases, cancer, metabolic diseases, insomnia, skin aging, or hair loss, comprising a 5-ALA derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0058] Furthermore, another embodiment of the present invention relates to a health functional food for the prevention or improvement of inflammatory diseases, cancer, metabolic diseases, insomnia, skin aging, or hair loss, comprising a 5-ALA derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0059] In this invention, the inflammatory disease can be one or more diseases selected from alopecia areata, dermatitis, allergy, atopic, asthma, conjunctivitis, periodontitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, ankylosing spondylitis, rheumatic fever, lupus, fibromyalgia, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, frozen shoulder, tendinitis, tenosynovitis, peritendinitis, myositis, hepatitis, cystitis, nephritis, Sjögren's syndrome, and multiple sclerosis.

[0060] In this invention, cancer can be selected from one or more diseases selected from brain tumors, benign astrocytomas, malignant astrocytomas, pituitary adenomas, meningiomas, brain lymphomas, oligodendrogliomas, intracranial tumors, ependymomas, brainstem tumors, head and neck tumors, laryngeal cancer, oropharyngeal cancer, nasal / paranasal sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, thoracic tumors, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumors, esophageal cancer, breast cancer, male breast cancer, abdominal tumors, gastric cancer, liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumors, penile cancer, prostate cancer, female genital tumors, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female external genital cancer, female urethral cancer, and skin cancer.

[0061] In this invention, metabolic diseases can be one or more diseases selected from obesity, diabetes, hypertension, cardiovascular disease and hyperlipidemia.

[0062] As used in this specification, the term "treatment" refers to any action that advantageously improves or alters the symptoms of a disease by applying a composition according to the invention. The term "prevention" as used in this specification refers to any action that inhibits or delays the onset of a disease by applying a composition according to the invention. The term "improvement" as used in this specification refers to any action that improves the negative condition of a disease by administering a composition according to the invention to an individual or allowing an individual to take a composition according to the invention.

[0063] The pharmaceutical compositions according to the invention can be administered to mammals, including humans, via any route of administration, and can be for oral, transdermal, subcutaneous, or topical application. Preferably, the pharmaceutical compositions according to the invention can be administered orally or parenterally.

[0064] Examples of parenteral administration may include intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, percutaneous, subcutaneous, intraperitoneal, intranasal, intraenteral, local, sublingual, or rectal administration; but are not limited thereto.

[0065] The pharmaceutical compositions according to the invention may further comprise a pharmaceutically acceptable carrier.

[0066] As pharmaceutically acceptable carriers, for example, carriers for oral administration or parenteral administration can be used. Carriers for oral administration may contain lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Furthermore, carriers for parenteral administration may contain water, suitable oils, physiological saline, glucose solutions, ethylene glycol, etc., and may additionally contain stabilizers, preservatives, etc. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite, and ascorbic acid. Suitable preservatives include benzalkonium chloride, methylparaben or propylparaben, chlorobutanol, etc. For other pharmaceutically acceptable carriers, refer to well-known literature in the art to which this invention pertains.

[0067] Another embodiment of the invention relates to a pharmaceutical preparation containing the pharmaceutical composition for the treatment or prevention of inflammatory diseases, cancer, metabolic diseases, insomnia, skin aging, or hair loss.

[0068] In this invention, the pharmaceutical formulation can be an oral administration formulation, a transdermal administration formulation, a subcutaneous injection formulation, or a topical skin formulation. In the case of an oral administration formulation, the composition of this invention can be formulated into powders, granules, tablets, pills, sugar-coated tablets, capsules, liquids, gels, syrups, pastes, suspensions, etc., using methods known in the relevant art. For example, for oral pharmaceutical formulations, tablets can be obtained by mixing the active ingredient with a solid excipient, then pulverizing them, adding suitable additives, and then processing the resulting mixture into a granular mixture. Examples of suitable excipients may include sugars, such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, etc.; starches, such as corn starch, wheat starch, rice starch, potato starch, etc.; celluloses, such as cellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, etc.; and fillers, such as gelatin and polyvinylpyrrolidone. In addition, in some cases, croscarmellose, agar, alginate, or sodium alginate may be added as disintegrants. Furthermore, the pharmaceutical compositions according to the invention may additionally comprise anticoagulants, lubricants, wetting agents, flavoring agents, emulsifiers, and preservatives. Additionally, to reduce gastrointestinal irritation, enteric coating or microencapsulation may be performed, which aims to release the drug as it passes through the intestines without releasing it in the stomach.

[0069] Topical preparations can be formulated into forms selected from creams, lotions, ointments, oils, moisturizers, gels, aerosols, and nasal inhalers using methods known in the relevant field.

[0070] In addition to the above-mentioned components, the pharmaceutical compositions according to the present invention may also contain lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc.

[0071] The pharmaceutical compositions according to the invention can be prepared by mixing various known ingredients, which are then applied to the skin or mucous membranes after mixing. Each ingredient can be thoroughly mixed with a suitable matrix as needed, according to well-known methods for preparing topical skin preparations or cosmetic compositions. The pharmaceutical preparation prepared in this manner is then applied to the lesion site as needed.

[0072] The pharmaceutical formulation according to the invention comprises a content of 0.01% to 30% by weight, preferably 1% to 10% by weight, relative to the total weight of the quasi-pharmaceutical composition or cosmetic composition of the invention. If the content is less than 0.01% by weight, therapeutic and preventive effects cannot be achieved; if the content is greater than 30% by weight, it is difficult to formulate and its performance may be deteriorated.

[0073] The routes of administration and methods of administration of the pharmaceutical compositions according to the present invention can be independent of each other, and there are no particular limitations on the manner of administration and methods of administration. Any route of administration and method of administration can be followed, as long as the pharmaceutical composition can reach the target site.

[0074] For single or multiple administrations, the effective dosage is typically from about 0.01 to about 20 mg / body weight / day, preferably from about 0.1 to about 10 mg / body weight / day, and most preferably 1 to 5 mg / body weight / day. Dosage levels below the lower limit of the above range may be appropriate depending on age, sex, and the disease or condition being treated. In other cases, larger dosages may be used without harmful side effects. For daily administration, a larger dosage can be divided into several smaller dosages. Methods for determining the appropriate dosage are well known in the art to which this invention pertains.

[0075] The health-functional foods according to the present invention can be used with other foods or food additives, except for active ingredients such as 5-ALA derivatives or their pharmaceutically acceptable salts, and can be used appropriately according to conventional methods. The amount of active ingredients mixed can be appropriately determined according to the purpose of use of the active ingredients (e.g., prevention, health care, treatment).

[0076] The effective dosage of compounds contained in health supplements can be used according to the effective dosage of therapeutic agents. However, in cases of long-term intake for health and hygiene or for health control, the dosage may be lower than the above range, and it is certain that, since there are no safety concerns, an amount of active ingredient equal to or greater than the above range can be used.

[0077] There are no specific restrictions on the types of health foods, and examples of health foods include meat, sausage, bread, chocolate, candy, snacks, sweets, pizza, ramen, other noodles, chewing gum, dairy products (including ice cream), various soups, beverages, tea, drinks, alcoholic beverages, and multivitamins.

[0078] Another embodiment of the invention relates to the use of a 5-aminolevulinic acid derivative compound or a pharmaceutically acceptable salt thereof, wherein the use is for the treatment or prevention of inflammatory diseases, cancer, metabolic diseases, insomnia, skin aging, or hair loss.

[0079] Another embodiment of the invention relates to a method for treating inflammatory diseases, cancer, metabolic diseases, insomnia, skin aging, or hair loss, comprising the step of administering a 5-aminolevulinic acid derivative compound or a pharmaceutically acceptable salt thereof to a subject.

[0080] Another embodiment of the invention relates to the use of a 5-aminolevulinic acid derivative or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for the prevention or treatment of inflammatory diseases, cancer, metabolic diseases, insomnia, skin aging, or hair loss.

[0081] Preferred embodiments will be provided below to aid in understanding the invention. However, the following embodiments are intended to illustrate the invention only, and it will be apparent to those skilled in the art that various changes and modifications can be made within the scope and spirit of the invention, and such changes and modifications naturally fall within the scope of the appended claims.

[0082] Embodiments of the present invention Example 1: Preparation of 4-((5-amino-4-oxopentanoyl)oxy)benzyl 5-amino-4-oxopentanoic acid ester dihydrochloride 1.1 g of N-Boc-5-aminolevulinic acid (purchased from Fure Chem, China) was dissolved in 10 ml of dichloromethane (purchased from Sigma-Aldrich Co. LLC), and a catalytic amount of dimethylformamide (purchased from Sigma-Aldrich Co. LLC) was added. 1 ml of oxaloyl chloride (purchased from Sigma-Aldrich Co. LLC) was gradually added dropwise over 5 minutes at room temperature. The reaction was completed by stirring at room temperature for 3 hours and 30 minutes, followed by concentration under reduced pressure to give a yellow oily residue. In a separate container, 0.5 g of 4-hydroxybenzyl alcohol (purchased from Sigma-Aldrich Co. LLC) and 2.35 g of cesium carbonate (purchased from Sigma-Aldrich Co. LLC) were suspended in 10 ml of acetonitrile (purchased from Sigma-Aldrich Co. LLC), and the resulting product was dissolved in 10 ml of acetonitrile, which was then added dropwise over 10 minutes. The reaction was completed by stirring at room temperature for 2 to 3 hours, followed by filtration with diatomaceous earth to recover the filtrate. To dilute the filtrate, 30 ml of ethyl acetate (purchased from Sigma-Aldrich Co. LLC) was added again, followed by washing with 30 ml of deionized water. The filtrate was dried and filtered through anhydrous magnesium sulfate, then concentrated under reduced pressure. The organic layer from which the concentrated residue had been separated was dissolved in 10 ml of dioxane containing 4N HCl, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution under reduced pressure, the solution was eluted and purified using a silica gel-packed column. Concentration of the fraction under reduced pressure (ethyl acetate: n-hexane = 1:10) yielded 0.86 g of the title compound as a dihydrochloride salt, a white solid.

[0083] 1 H NMR (400 MHz, DMSO-d6) 8.2 (bs, 6H), 7.42 (d, 2H, J = 8.4 Hz), 7.12 (d, 2H, J = 8.4 Hz), 5.10 (s, 2H), 4.00 (s, 2H), 3.98 (s, 2H), 2.93 (d, 2H, J = 6.4 Hz), 2.82 (dd, 2H, J = 5.1, 6.4 Hz), 2.64 (d, 2H, J = 5.1 Hz) Experiment Example 1: Pharmacokinetic Evaluation of Bioavailability In order to develop the 5-ALA-derived compound of the invention according to this application into an orally administered pharmaceutical composition, an attempt was made to confirm its bioavailability under oral administration. The 5-ALA-derived compound of the invention according to this application degrades to 5-ALA under oral administration. Therefore, the concentration of 5-ALA present in the blood was measured to confirm the bioavailability of the 5-ALA-derived compound.

[0084] Specifically, Sprague-Dawley rats were administered a single oral (po) and intravenous (iv) dose of a 5-ALA-derived compound prepared according to Example 1 as the experimental material. The hourly concentrations of the 5-ALA drug released into the bloodstream via metabolic processes were then tracked and analyzed.

[0085] Each 5-ALA derivative compound was prepared using the same method and then administered to rats at a dose of 10 mg / kg. Blood was collected at fixed time points, and plasma was then separated. HPLC (Xbridge column C10) was used to analyze the plasma. 18 The drug was analyzed using Waters with a mobile phase of 0.1% formic acid:acetonitrile (30:70, % / %) and MS / MS (ESI positive ion, MRM). Rat co-plasma was mixed with each commercial standard solution at a ratio of 9:1 to prepare and calibrate mixtures with concentrations of 5, 50, 100, 500, 1,000, and 5,000 ng / ml. Additionally, to prepare QC samples, rat co-plasma was mixed with QC standard solutions at a ratio of 9:1 to prepare QC samples with concentrations of 100, 750, and 2,500 ng / ml. For pretreatment, 100 μL of plasma sample was transferred to a centrifuge tube, 10 μL of internal standard solution and 300 μL of methanol were added, and the mixture was stirred for approximately 30 seconds. The tube was centrifuged at 3,000 × g (4 °C) for approximately 5 minutes, and the supernatant was collected, transferred to an LC vial, and then injected into the apparatus. The concentrations of the active ingredient 5-ALA in rat plasma were then quantified using a pre-validated assay method. For pharmacokinetic parameters, the Win Nonlin 5.2 program (available from Pharsight, USA) was used, and the AUC was calculated based on a non-compartmental model (best fit). 0-t AUC 0-∞ C max T max and t 1 / 2 The results of the pharmacokinetic parameters are expressed as mean and standard deviation, and statistically processed using SPSS (Statistical Package for Social Sciences, 10.0 K, USA).

[0086] The blood concentrations of 5-ALA derivatives administered intravenously (iv) and orally (po) were determined using the methods described above. The measured blood 5-ALA concentrations are shown in Tables 1 and 2 below. Figure 1 ).

[0087] [Table 1] [Table 2] In order to develop a compound into an oral formulation, its bioavailability should be confirmed to be equal to or higher than that of intravenous administration at a certain level. In this case, the bioavailability of the invention according to this application is 55.8% (average concentration in oral administration / average concentration in intravenous administration), which is therefore a sufficiently good value to be developed into an oral pharmaceutical formulation.

[0088] As described above, even with small doses of the 5-ALA-derived compound according to the invention of this application, the 5-ALA-derived compound can be used as an orally administered pharmaceutical formulation because it can maintain high blood concentrations over a prolonged period and exhibits high bioavailability. Furthermore, with increasing doses of 5-ALA, clinical side effects are often associated with hypotension and may lead to more severe symptoms. However, by providing a blood concentration pattern similar to that of the compound according to the invention, a reduction in side effects can be expected because sufficient blood concentrations are provided even with small doses.

[0089] Experimental Example 2: Evaluation of Brain Permeability An attempt was made to measure the rate of delivery of orally administered 5-ALA-derived compounds to the brain. Rats were given a single oral (po) administration of the 5-ALA-derived compound according to Example 1 at a dose of 10 mg / kg. The rat brains were then extracted at fixed time points, and the concentration of 5-ALA was determined using the same method described in Experimental Example 1. The results are shown in Table 3. Figure 2 ).

[0090] [Table 3] As a result, the brain penetration rate of the orally administered compound according to the invention of this application reached 83% (average concentration in brain penetration / average concentration under oral administration conditions), confirming excellent brain penetration.

[0091] Experiment Example 3: Stability Evaluation The stability test of the compound in Example 1 was carried out as follows.

[0092] The 5-ALA derivative compound prepared in Example 1 was used as the test substance, and 5-ALA (purchased from Sigma-Aldrich Co. LLC) was used as the control substance. 1 g of the test substance and 1 g of the control substance were placed in a polyethylene plastic bag, which was then filled with a bag of silica gel. The plastic bag was then placed in an aluminum bag and sealed. The mixture was then stored in a long-term storage chamber (25°C, 75% relative humidity) and a harsh conditions chamber (45°C, 85% relative humidity). The purity of the substances was observed visually and by HPLC over two weeks, and the results are summarized in Table 4.

[0093] [Table 4] Stability comparison under long-term storage conditions and harsh conditions As shown in Table 4 above, it has been confirmed that the 5-ALA derivative compound of Example 1 maintains a color and purity equivalent to or higher than that of 5-ALA under long-term storage conditions and under harsh conditions, and therefore its quality remains unchanged.

[0094] As described above, specific aspects of the invention have been described in detail. However, it will be apparent to those skilled in the art that such a detailed description is merely a preferred embodiment and therefore does not limit the scope of the invention. Consequently, the essential scope of the invention should be defined by the claims and their equivalents.

Claims

1. A 5-aminolevulinic acid (5-ALA) derivative compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] ###0001### In Chemical Formula 1, n is an integer of 0 to 3, and m is an integer of 0 to 3.

3. The 5-aminolevulinic acid derivative compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is one or more selected from the group consisting of a hydrochloride, a p-toluenesulfonate, a fumarate, a citrate, a succinate, a salicylate, an oxalate, a bromate, a phosphate, a methanesulfonate, a tartrate, a sulfate, and a mandelate. ， wherein, 4. The 5-aminolevulinic acid derivative compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein the pharmaceutically acceptable salt is a hydrochloride. R 1 R 2 R 3 and R 4 Each of the following is independently a hydrogen atom, halogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or C6-C 20 Aryl, 5. A composition for photodynamic diagnosis or photodynamic therapy, comprising: a 5-aminolevulinic acid derivative compound or a pharmaceutically acceptable salt thereof according to claim 1.

6. A pharmaceutical composition for treating or preventing an inflammatory disease, a cancer, a metabolic disease, insomnia, skin aging, or hair loss, comprising a 5-aminolevulinic acid derivative compound or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.

2. The 5-aminolevulinic acid derivative compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein n is 1, m is 0, and R 1 , R 2 , R 3 , and R 4 are each a hydrogen atom.

7. The pharmaceutical composition according to claim 6, wherein the inflammatory disease is one or more selected from the group consisting of alopecia areata, dermatitis, allergy, atopy, asthma, conjunctivitis, periodontitis, rhinitis, otitis media, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, ankylosing spondylitis, rheumatic fever, lupus, fibromyalgia, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, frozen shoulder, tendonitis, tenosynovitis, peritendinitis, myositis, hepatitis, cystitis, nephritis, Sjogren's syndrome, and multiple sclerosis.

8. The pharmaceutical composition according to claim 6, wherein the cancer is one or more selected from the group consisting of brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioblastoma, intracranial tumor, ependymoma, brain stem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal cavity / paranasal sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cavity cancer, chest tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, gastric cancer, liver cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestinal cancer, colon cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female external genital cancer, female urethral cancer, and skin cancer.

9. The pharmaceutical composition according to claim 6, wherein the metabolic disease is one or more selected from the group consisting of obesity, diabetes, hypertension, cardiovascular disease, and hyperlipidemia.

10. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is for oral administration, transdermal administration, subcutaneous injection, or external use on the skin. ​ ​ ​ ​ ​ 11.The pharmaceutical composition of claim 10, wherein the external preparation for skin is selected from the group consisting of a cream, a lotion, an ointment, an oil agent, a moisturizer, a gel, an aerosol, and a nasal inhalant. 12.A method of preparing a 5-aminolevulinic acid derivative compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, the method comprising: (a) a step of reacting a solution of N-Boc-5-aminolevulinic acid with dimethylformamide and oxalyl chloride to obtain a compound represented by Chemical Formula 2; (b) a step of reacting a suspension of a compound represented by Chemical Formula 3 with a solution obtained by dissolving the compound represented by Chemical Formula 2 in a solvent to obtain a compound represented by Chemical Formula 4; and (c) a step of reacting a suspension of the compound represented by Chemical Formula 4 with an acidic solution to obtain the 5-ALA derivative compound represented by Chemical Formula 1, [Chemical Formula 1] ， [Chemical Formula 2] ， [Chemical Formula 3] ， [Chemical Formula 4] ， wherein, in Chemical Formula 1, Chemical Formula 3, and Chemical Formula 4, R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, halogen, Ci-C6alkyl, C2-C4alkenyl, C2-C4alkynyl, Ci-C6alkoxy, C3-C7cycloalkyl or C6-C 20 aryl, n is an integer of 0 to 3, and m is an integer of 0 to 3. 13.The method of claim 12, further comprising: (d) a step of filtering the 5-ALA derivative compound prepared in step (c) and adding a solvent to the recovered filtrate to concentrate, elute, and purify the recovered filtrate. 14.Use of the 5-aminolevulinic acid derivative compound or a pharmaceutically acceptable salt thereof according to claim 1 in the treatment or prevention of an inflammatory disease, cancer, a metabolic disease, insomnia, skin aging, or hair loss. 15.A method of treating an inflammatory disease, cancer, a metabolic disease, insomnia, skin aging, or hair loss, comprising a step of administering the 5-aminolevulinic acid derivative compound or a pharmaceutically acceptable salt thereof according to claim 1 to a subject. 16.Use of the 5-aminolevulinic acid derivative compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a pharmaceutical composition for the prevention or treatment of an inflammatory disease, cancer, a metabolic disease, insomnia, skin aging, or hair loss.

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