5-aminolevulinic acid derivative and pharmaceutical composition comprising same

Abstract

The present invention relates to a 5-aminolevulinic acid derivative having improved storage stability and bioavailability, and a pharmaceutical composition comprising same, the present invention exhibiting pharmacokinetic characteristics in which 5-aminolevulinic acid is more effectively exposed to blood in the body, and alleviating side effects such as pain, erythema, swelling, edema, burning, itching, exfoliation, hyperpigmentation, and long-term irritation and hypersensitivity following treatment. In addition, the present invention relates to a 5-aminolevulinic acid derivative and a composition comprising same in which 5-aminolevulinic acid is highly effective while reducing the severity of side effects, and which can be used for photodynamic diagnosis and treatment.

Description

5-aminolevulinic acid derivative and pharmaceutical composition containing the same

[0001] The present invention relates to a 5-aminolevulinic acid derivative with improved storage stability and bioavailability and a pharmaceutical composition containing the same.

[0002] Photodynamic therapy or photochemical therapy, first introduced by Thomas JD et al., is a technique for treating various abnormalities or diseases occurring in 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 chemicals called photosensitizing agents to the affected area of ​​the body, exposing them to photoactivating light to activate them, and then the active substances that are released in a cytotoxic form kill the cells in the affected area or reduce the possibility of proliferation of the cells. Well-known photosensitizers include psoralens, porphyrins, chlorines, and phthalocyanines, but well-known and clinically useful photosensitizers are 5-aminolevulinic acid (5-ALA) with the following chemical formula A and methyl 5-aminolevulinic acid ester (5-ALA) with the following chemical formula B, commercially available under the names Levulan and Metvix, respectively.

[0004] [Chemical Formula A]

[0005]

[0006] [Chemical Formula B]

[0007]

[0008] 5-Aminolevulinic acid (5-ALA) is converted into protoporphyrin IX (PpIX), a photosensitizer, through the porphyrin cycle, a biosynthetic pathway of heme, which is a component of hemoglobin, a substance that transports oxygen in the body. When a large amount of 5-ALA is administered externally, an excess of heme is produced in the body, which reduces the activity of ferrochelatase, an enzyme that converts PpIX to heme, and causes a large accumulation of PpIX in the cells. This PpIX is a powerful photosensitizer that exhibits fluorescence when activated and is a substance that can oxidize and kill cancer cells by converting surrounding oxygen into oxygen radicals.

[0009] According to Ji Sun Kim et al., 5-ALA can be used not only for photodynamic diagnosis, but also for treating cancer lesions of the skin, gastrointestinal tract, lung, bladder, oral cavity, etc., as 5-ALA is selective for tumors and is converted into an active substance that exhibits cytotoxicity after binding to the tumor (Ji Sun Kim et al., Korean J Otolaryngol 2005; 48(2):234-40).

[0010] Masanori H. et al. reported that 5-ALA is also effective in the treatment and prevention of cerebrovascular Parkinson's disease and stroke (Masanori H. et al. J. Pharmacol. Sci. 2020 Nov; 144(3): 183-187). In addition, Vipul Y. et al. reported that 5-ALA has significant effects on various inflammatory diseases, including inflammatory bowel disease (Vipul Y. et al., Biomedicines. 2021 May 20; 9(5): 578).

[0011] Photodynamic therapy of the skin using 5-ALA is known to be relatively selectively absorbed in the pathological conditions described above, causing little damage to surrounding normal tissues. However, because 5-ALA is hydrophilic, its absorption and penetration efficiency are low when applied to the skin. In addition, it is not effective in cases where PpIX does not accumulate, so it is not effective in all lesions. During photodynamic therapy of a wide range of diseases using 5-ALA and its derivatives, pain, erythema, swelling, edema, burning, itching, peeling, hyperpigmentation, and long-term irritation and hypersensitivity after treatment are known to occur frequently, especially at the treatment site. These side effects are known to be particularly severe when the treatment area is the face, scalp, or neck.

[0012] Regarding the occurrence of such side effects, International Patent Publication No. WO2006 / 051269, which discloses 'Use of 5-ALA ester in photodynamic therapy for treating acne', reports that erythema, hyperpigmentation and peeling often occur after photodynamic therapy, and also discloses pain, burning and itching during and after treatment.

[0013] Additionally, in the case of liquid formulations using 5-ALA, it is known that there is a problem that 5-ALA decomposes during distribution and storage, which reduces the original functional effect of 5-ALA, making it quite difficult to develop materials for ointment or injection formulations.

[0014] Therefore, there is still a need for novel derivatives of 5-ALA that have reduced side effects, an appropriate balance of hydrophilicity and hydrophobicity for use in all lesions, and stability that does not decompose during distribution and storage.

[0015] Accordingly, the inventors of the present invention have made diligent efforts to solve the above problems, and as a result, have confirmed that a novel 5-ALA derivative can be synthesized that solves the problems of the prior art of 5-ALA by reducing side effects, appropriately balancing hydrophilicity and hydrophobicity so that it can be used for all lesions, and having stability that does not decompose during distribution and storage, thereby completing the present invention.

[0016] [Prior Art Literature]

[0017] (Patent Document 1) International Patent Publication No. WO2006 / 051269

[0018] (Non-patent literature 1) Thomas JD et al., J. Natl. Cancer Inst. 1998; 90(12): 889-905

[0019] (Non-patent literature 2) Ji Sun Kim et al., Korean J Otolaryngol 2005; 48(2):234-40

[0020] (Non-patent literature 3) Masanori H. et al. J. Pharmacol. Sci. 2020 Nov; 144(3): 183-187

[0021] (Non-patent literature 4) Vipul Y. et al., Biomedicines. 2021 May 20; 9(5): 578

[0022] The purpose of the present invention is to provide a 5-ALA derivative compound having a form in which 5-aminolevulinic acid (5-ALA) is bound to both sides of a linker.

[0023] The 5-ALA derivative compound of the present invention exhibits pharmacodynamic characteristics that allow 5-ALA to be more effectively exposed to the blood when administered orally, and when provided in a transdermal absorption formulation, can alleviate side effects such as pain, erythema, swelling, edema, burns, itching, peeling, hyperpigmentation, and long-term irritation and hypersensitivity after treatment.

[0024] In addition, the 5-ALA derivative compound of the present invention can be decomposed into 5-ALA and a linker in the body, and thus not only 5-ALA but also the linker can exhibit excellent pharmacological activity in the body.

[0025] To achieve the above purpose, the present invention provides a 5-aminolevulinic acid (5-ALA) derivative compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0026] [Chemical Formula 1]

[0027]

[0028] In chemical formula 1

[0029] R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, halogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl or C6-C 20 It's Aryl,

[0030] n is an integer from 0 to 3, and m is an integer from 0 to 3.

[0031] The present invention also provides a photodynamic diagnostic and therapeutic composition comprising the 5-ALA derivative compound or a pharmaceutically acceptable salt thereof.

[0032] The present invention also provides a pharmaceutical composition for treating or preventing inflammatory diseases, cancer diseases, metabolic diseases, insomnia, skin aging, or hair loss, comprising the 5-ALA derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0033] The present invention also provides a health functional food for preventing or improving inflammatory diseases, cancer diseases, metabolic diseases, insomnia, skin aging or hair loss, comprising the 5-ALA derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0034] The present invention also provides a pharmaceutical formulation comprising a pharmaceutical composition for treating or preventing inflammatory diseases, cancer diseases, metabolic diseases, insomnia, skin aging, or hair loss.

[0035] The present invention also provides a method for preparing a 5-ALA derivative compound of formula 1 or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0036] (a) a step of reacting a solution of N-Boc-5-aminolevulinic acid with dimethylformamide and oxalyl chloride to obtain a compound of chemical formula 2; and

[0037] (b) A step of reacting a suspension of a compound of formula 3 with a solution of a compound of formula 2 dissolved in a solvent to obtain a compound of formula 4.

[0038] (c) A step of reacting a suspension of a compound of chemical formula 4 with an acidic solution to obtain a 5-ALA derivative compound of chemical formula 1.

[0039] [Chemical Formula 1]

[0040]

[0041] [Chemical Formula 2]

[0042]

[0043] [Chemical Formula 3]

[0044]

[0045] [Chemical Formula 4]

[0046]

[0047] In chemical formulas 1, 3 and 4

[0048] R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, halogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl or C6-C 20 It's Aryl,

[0049] n is an integer from 0 to 3, and m is an integer from 0 to 3.

[0050] The 5-aminolevulinic acid (5-ALA) derivative according to the present invention is not only effective in photodynamic diagnosis, photodynamic therapy or photochemical therapy of tumors, but also has an active effect in treating various abnormalities or diseases of the skin or other epithelial organs or mucous membranes, non-malignant lesions such as psoriasis, actinic keratosis and acne, tumors such as cancer, lowering cholesterol, preventing and treating dry mouth diseases, preventing and treating heart diseases, treating fatty liver or steatohepatitis, reducing insomnia and improving sleep quality, preventing and treating various inflammatory diseases such as inflammatory colitis and Crohn's disease, preventing and treating metabolic diseases such as diabetes, obesity and hypertension, and preventing and treating cell aging, regeneration and hair loss.

[0051] Figure 1 is a graph showing the time-dependent concentration of 5-ALA drug released into the blood when the compound of Example 1 of the present invention is administered intravenously or orally.

[0052] Figure 2 is a graph showing the brain penetration rate of the compound of Example 1 of the present invention administered orally measured over time.

[0053] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In general, the nomenclature used herein is well known and commonly used in the art.

[0054] It was confirmed that the novel derivative of 5-aminolevulinic acid (5-ALA) according to the present invention has reduced side effects, has an appropriate balance of hydrophilicity and hydrophobicity so that it can be used for all lesions, and has stability that does not decompose during distribution and storage.

[0055] Therefore, an embodiment of the present invention relates to a 5-ALA derivative compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0056] [Chemical Formula 1]

[0057]

[0058] In chemical formula 1

[0059] R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, halogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl or C6-C 20 It's Aryl,

[0060] n is an integer from 0 to 3, and m is an integer from 0 to 3.

[0061] Preferably, n is 1, m is 0, and R 1 , R 2 , R 3 and R 4 Each may be hydrogen, but is not limited thereto.

[0062] The 5-ALA derivative compound of the present invention has a structure in which two 5-ALA molecules are linked via a central linker. When the 5-ALA derivative compound is metabolized by esterification in the body, the central linker is converted into a compound having antioxidant, anti-anxiety, sedative, anti-apoptotic, and anti-inflammatory effects as a derivative of 4-hydroxybenzyl alcohol (4-HBA), for example, a compound having a structure represented by the following chemical formula 5.

[0063] [Chemical Formula 5]

[0064]

[0065] Another embodiment of the present invention relates to a method for preparing a 5-ALA derivative compound or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) reacting a solution of N-Boc-5-aminolevulinic acid with dimethylformamide and oxalyl chloride to obtain a compound of formula 2; (b) reacting a suspension of a compound of formula 3 with a solution of the compound of formula 2 dissolved in a solvent to obtain a compound of formula 4; and (c) reacting a suspension of the compound of formula 4 with an acidic solution to obtain a 5-ALA derivative compound of formula 1.

[0066] [Chemical Formula 1]

[0067]

[0068] [Chemical Formula 2]

[0069]

[0070] [Chemical Formula 3]

[0071]

[0072] [Chemical Formula 4]

[0073]

[0074] In chemical formulas 1, 3 and 4

[0075] R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, halogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl or C6-C 20 It's Aryl,

[0076] n is an integer from 0 to 3, and m is an integer from 0 to 3.

[0077] The present invention is described in detail below.

[0078] In another embodiment of the present invention, n is 1, m is 0, and R 1 , R 2 , R3 and R 4 Each may be hydrogen, but is not limited thereto. At this time, the compound of chemical formula 1 has the structure of chemical formula 1-1 below.

[0079] [Chemical Formula 1-1]

[0080]

[0081] In the present invention, the compound of chemical formula 1-1 is converted into the active substance 5-ALA and the compound of chemical formula 5 through the following reaction scheme 1 by esterase, a physiological enzyme distributed in all tissues in the body after absorption.

[0082] The compound of chemical formula 5 below is a derivative of 4-hydroxybenzyl alcohol (4-HBA). The compound of chemical formula 5 not only functions as a linker connecting two 5-ALA molecules on both sides in the 5-ALA derivative compound of chemical formula 1 of the present invention, but is also a compound that has antioxidant, anti-anxiety, sedative, anti-apoptotic, and anti-inflammatory effects when esterified in the body.

[0083] Therefore, the compound of chemical formula 1 of the present invention can exhibit the effects of both 5-ALA and the compound of chemical formula 5 while being esterified in the body.

[0084] [Reaction Formula 1]

[0085]

[0086] In the present invention, the substance of chemical formula 1 is converted to a form in which the carboxyl group of 5-ALA is introduced into a form in which a benzyl group having fat solubility is introduced, thereby lowering hydrophilicity, and is absorbed into the skin very quickly when administered in the form of an ointment or cream or transdermally, and when administered orally, is absorbed in the gastrointestinal wall or small intestine and then rapidly decomposed into 5-ALA by an ester hydrolase, thereby enabling a high concentration of 5-ALA in the body. In addition, the substance of chemical formula 1 has hydrophobicity with significantly lower hygroscopicity than 5-ALA, and thus exhibits significantly superior storage stability compared to the parent drug 5-ALA under general storage conditions or in solution.

[0087] In the present invention, the pharmaceutically acceptable salt may be at least one selected from the group consisting of hydrochloride, p-toluenesulfonate, fumarate, citrate, succinate, salicylate, oxalate, bromate, phosphate, methanesulfonate, tartrate, sulfate, and mandelate, and preferably, the pharmaceutically acceptable salt is hydrochloride, but is not limited thereto.

[0088] The 5-ALA derivative compound of chemical formula 1 according to the present invention or a pharmaceutically acceptable salt thereof can be prepared by the following method.

[0089] (a) A step of reacting a solution of N-Boc-5-aminolevulinic acid with dimethylformamide and oxalyl chloride to obtain a compound of chemical formula 2;

[0090] (b) a step of reacting a suspension of a compound of formula 3 with a solution of a compound of formula 2 dissolved in a solvent to obtain a compound of formula 4; and

[0091] (c) A step of reacting a suspension of a compound of chemical formula 4 with an acidic solution to obtain a 5-ALA derivative compound of chemical formula 1.

[0092] [Chemical Formula 1]

[0093]

[0094] [Chemical Formula 2]

[0095]

[0096] [Chemical Formula 3]

[0097]

[0098] [Chemical Formula 4]

[0099]

[0100] In chemical formulas 1, 3 and 4

[0101] R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, halogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl or C6-C 20 It's Aryl,

[0102] n is an integer from 0 to 3, and m is an integer from 0 to 3.

[0103] According to an additional embodiment of the present invention, a 5-aminolevulinic acid derivative compound of chemical formula 1-1 or a pharmaceutically acceptable salt thereof can be prepared by the following method.

[0104] (a) a step of reacting a solution of N-Boc-5-aminolevulinic acid with dimethylformamide and oxalyl chloride to obtain a compound of chemical formula 2; and

[0105] (b) A step of reacting a solution of the compound of Chemical Formula 2 dissolved in a solvent with a suspension of 4-hydroxybenzyl alcohol of Chemical Formula 3-1 to ultimately obtain a 5-ALA derivative compound of Chemical Formula 1-1.

[0106] [Chemical Formula 1-1]

[0107]

[0108] [Chemical Formula 2]

[0109]

[0110] [Chemical Formula 3-1]

[0111]

[0112] In the method for preparing a 5-ALA derivative compound or a pharmaceutically acceptable salt thereof according to the present invention, the following steps may be additionally included:

[0113] (d) A step of filtering the 5-ALA derivative compound produced in step (c) and concentrating, eluting and purifying the recovered filtrate by adding a solvent such as ethyl acetate.

[0114] In the present invention, the N-Boc-5-aminolevulinic acid solution of step (a) may use a solvent selected from the group consisting of dichloromethane, acetonitrile, 1,4-dioxane, ethyl acetate, and acetone, and dichloromethane may be preferably used, but is not limited thereto.

[0115] In the present invention, the suspension of the compound of chemical formula 3 in step (b) may use a solvent selected from the group consisting of acetonitrile, 1,4-dioxane, ethyl acetate, and acetone, and acetonitrile may be preferably used, but is not limited thereto.

[0116] In the present invention, the acidic solution of step (c) may be at least one solution selected from the group consisting of hydrogen chloride, 1,4-dioxane, and ethyl acetate, preferably hydrogen chloride and 1,4-dioxane or ethyl acetate, but is not limited thereto.

[0117] It was confirmed that the 5-ALA derivative compound according to the present invention is effective in photodynamic diagnosis or photodynamic therapy of tumors and the like, various abnormalities or diseases of the skin or other epithelial organs or mucous membranes, non-malignant lesions such as psoriasis, actinic keratosis and acne, treatment of tumors such as cancer, lowering cholesterol, preventing and treating dry mouth disease, preventing and treating heart disease, treating fatty liver or steatohepatitis, reducing insomnia and improving sleep quality, preventing and treating various inflammatory diseases such as inflammatory colitis and Crohn's disease, preventing and treating metabolic diseases such as diabetes, obesity, and hypertension, and preventing and treating cell aging, regeneration, and hair loss.

[0118] Accordingly, another embodiment of the present invention relates to a photodynamic diagnostic and therapeutic composition comprising the 5-ALA derivative compound or a pharmaceutically acceptable salt thereof.

[0119] In addition, another embodiment of the present invention relates to a pharmaceutical composition for treating or preventing inflammatory diseases, cancer diseases, metabolic diseases, insomnia, skin aging or hair loss, comprising the 5-ALA derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0120] In addition, another embodiment of the present invention relates to a health functional food for preventing or improving inflammatory diseases, cancer diseases, metabolic diseases, insomnia, skin aging or hair loss, comprising the 5-ALA derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0121] In the present invention, the inflammatory disease may be at least one disease selected from the group consisting of alopecia areata, dermatitis, allergy, atopy, 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, periarthritis of the shoulder joint, tendinitis, tenosynovitis, peritendinitis, myositis, hepatitis, cystitis, nephritis, Sjogren's syndrome, and multiple sclerosis.

[0122] In the present invention, the cancer disease is a group consisting of brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial tumor, ependymoma, brainstem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal cavity / paranasal sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, thoracic tumor, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, stomach cancer, liver cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine 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. There may be one or more selected diseases.

[0123] In the present invention, the metabolic disease may be one or more diseases selected from the group consisting of obesity, diabetes, hypertension, cardiovascular disease, and hyperlipidemia.

[0124] The term "treatment" as used herein refers to any action that improves or beneficially alters the symptoms of a disease by administering a composition according to the present invention. The term "prevention" as used herein refers to any action that suppresses or delays the onset of a disease by administering a composition according to the present invention. The term "improvement" as used herein refers to any action that improves the worsening condition of a disease by administering or ingesting a composition according to the present invention to a subject.

[0125] The pharmaceutical composition of the present invention can be administered to mammals, including humans, via any route of administration, and may be a pharmaceutical composition for oral administration, transdermal administration, subcutaneous injection, or external application to the skin. Preferably, the pharmaceutical composition of the present invention can be administered orally or parenterally.

[0126] Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal administration.

[0127] The pharmaceutical composition of the present invention may additionally comprise a pharmaceutically acceptable carrier.

[0128] The pharmaceutically acceptable carrier may be, for example, a carrier for oral administration or a carrier for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. In addition, carriers for parenteral administration may include water, suitable oils, saline solution, aqueous glucose, glycol, etc., and may further include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. For other pharmaceutically acceptable carriers, reference may be made to well-known literature in the field to which the present invention pertains.

[0129] Another embodiment of the present invention relates to a pharmaceutical formulation comprising a pharmaceutical composition for treating or preventing inflammatory diseases, cancer diseases, metabolic diseases, insomnia, skin aging or hair loss.

[0130] In the present invention, the pharmaceutical formulation may be an oral administration, transdermal administration, subcutaneous injection, or external skin formulation, and in the case of an oral administration formulation, the composition of the present invention may be formulated into a powder, granules, tablet, pill, sugar-coated tablet, capsule, liquid, gel, syrup, slurry, suspension, etc. using a method known in the art. For example, an oral formulation may be obtained by mixing an active ingredient with a solid excipient, grinding the mixture, adding a suitable additive, and then processing the mixture into a granule mixture to obtain a tablet. Examples of suitable excipients may include sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, and maltitol; starches including corn starch, wheat starch, rice starch, and potato starch; cellulosics including cellulose, methylcellulose, sodium carboxymethylcellulose, and hydroxypropylmethylcellulose; and fillers such as gelatin and polyvinylpyrrolidone. In addition, cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added as a disintegrant, if desired. Furthermore, the pharmaceutical composition of the present invention may further include anticoagulants, lubricants, wetting agents, flavoring agents, emulsifiers, and preservatives. In addition, the drug may be enterically coated or microencapsulated so that it is released as it passes through the intestines rather than being released in the stomach to alleviate gastrointestinal irritation.

[0131] The above external skin formulation can be formulated in a form selected from the group consisting of creams, lotions, external ointments, oils, moisturizers, gels, aerosols, and nasal inhalers by a method known in the art.

[0132] The pharmaceutical composition of the present invention may further include, in addition to the above ingredients, a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, etc.

[0133] The pharmaceutical composition of the present invention can be prepared by mixing various known ingredients that are incorporated into a composition applied to the skin or mucous membrane, and can be prepared by mixing each ingredient well with an appropriate base, if necessary, according to a method well known in the art for preparing a skin external preparation or cosmetic composition, and the preparation thus prepared is applied to a lesion, if necessary.

[0134] The formulation according to the present invention is contained in an amount of 0.01 to 30 wt%, more preferably 1 to 10 wt%, based on the total weight of the quasi-drug composition or cosmetic composition of the present invention. If the content is less than 0.01 wt%, therapeutic and preventive effects cannot be achieved, and if it exceeds 30 wt%, formulation may be difficult and the usability may be impaired.

[0135] The route and method of administration of the pharmaceutical composition of the present invention may be independent of each other, and are not particularly limited in their method, and any route and method of administration may be followed as long as the pharmaceutical composition can reach the target area.

[0136] An effective dosage is generally about 0.01 to about 20 mg / kg body weight per day, administered as a single or divided dose, preferably about 0.1 to about 10 mg / kg body weight per day, and most preferably about 1 to 5 mg / kg body weight per day. Dosage levels below the lower end of this range may be appropriate depending on age, sex, and the disease or condition being treated. In other cases, larger doses may be used without harmful side effects. Larger doses may be divided into several smaller doses for administration throughout the day. Methods for determining appropriate dosages are well known in the art.

[0137] The health functional food according to the present invention may be used in combination with other foods or food additives in addition to the active ingredient of the 5-ALA derivative compound or a pharmaceutically acceptable salt thereof, and may be used appropriately according to conventional methods. The amount of the active ingredient mixed may be appropriately determined depending on the intended use, such as preventive, health, or therapeutic treatment.

[0138] The effective dose of the compound contained in the above health food can be used in accordance with the effective dose of the above therapeutic agent, but in the case of long-term intake for the purpose of health and hygiene or health control, it may be below the above range, and it is certain that the effective ingredient can be used in an amount exceeding the above range because there is no problem in terms of safety.

[0139] There are no special restrictions on the types of the above health foods, and examples include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes.

[0140] Another embodiment of the present invention relates to the use of a 5-aminolevulinic acid derivative compound or a pharmaceutically acceptable salt thereof for the treatment or prevention of inflammatory diseases, cancer diseases, metabolic diseases, insomnia, skin aging or hair loss.

[0141] Another embodiment of the present invention relates to a method for treating an inflammatory disease, a cancer disease, a metabolic disease, insomnia, skin aging or hair loss, comprising administering to a subject a 5-aminolevulinic acid derivative compound or a pharmaceutically acceptable salt thereof.

[0142] Another embodiment of the present invention relates to the use of a 5-aminolevulinic acid derivative compound or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for preventing or treating inflammatory diseases, cancer diseases, metabolic diseases, insomnia, skin aging or hair loss.

[0143] Hereinafter, preferred examples are presented to help understand the present invention, but the following examples are only illustrative of the present invention, and it is obvious to those skilled in the art that various changes and modifications are possible within the scope and technical idea of ​​the present invention, and it is also natural that such changes and modifications fall within the scope of the appended patent claims.

[0144] [Example]

[0145] Example 1: Preparation of 4-((5-amino-4-oxopentanoyl)oxy)benzyl 5-amino-4-oxopentanoate 2HCl

[0146] 1.1 g of N-Boc-5-aminolevulinic acid (source: China Furechem) was dissolved in 10 ml of dichloromethane (source: Sigma-Aldrich), and a catalytic amount of dimethylformamide (source: Sigma-Aldrich) was added. 1 ml of oxalyl chloride (source: Sigma-Aldrich) was slowly added dropwise over 5 minutes at room temperature. The mixture was stirred at room temperature for 3 hours and 30 minutes to complete the reaction, and then concentrated under reduced pressure to obtain a yellow oily residue. In a separate container, 0.5 g of 4-hydroxybenzyl alcohol (source: Sigma-Aldrich) and 2.35 g of cesium carbonate (source: Sigma-Aldrich) were suspended in 10 ml of acetonitrile (source: Sigma-Aldrich), and the obtained result was dissolved in 10 ml of acetonitrile and added dropwise for 10 minutes. The mixture was stirred at room temperature for 2-3 hours to complete the reaction, then filtered through Celite to collect the filtrate. 30 ml of ethyl acetate (source: Sigma-Aldrich) was added again to dilute the mixture, and washed with 30 ml of deionized water. After drying over anhydrous magnesium sulfate and filtering, the filtrate was concentrated under reduced pressure. The organic layer from which the concentrated residue was separated was dissolved in 10 ml of 4 N HCl in dioxane and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by elution with a column filled with silica gel (ethyl acetate: n-hexane = 1:10). The fractions were concentrated under reduced pressure to obtain 0.86 g of the title compound as a white solid in the form of dihydrochloride. 1 H NMR (400 MHz, DMSO-d6) 8.2 (bs, 6 H), 7.42 (d, 2H, J = 8.4 Hz), 7.12 (d, 2 H, J = 8.4 Hz), 5.10 (s, 2H), 4.00 (s, 2H), 3.98 (s, 2 H), 2.93 (d, 2 H, J = 6.4 Hz), 2. 82 (dd, 2 H, J = 5.1, 6.4 Hz), 2.64 (d, 2 H, J = 5.1 Hz)

[0147] Experimental Example 1: Pharmacokinetic Evaluation of Bioavailability

[0148] In order to develop the 5-ALA derivative compound of the present invention into a pharmaceutical composition for oral administration, the bioavailability upon oral administration was examined. Since the 5-ALA derivative compound of the present invention is decomposed into 5-ALA when administered orally, the bioavailability of the 5-ALA derivative compound of the present invention was examined by measuring the concentration of 5-ALA present in the blood.

[0149] Specifically, a single oral (po) and intravenous (iv) administration of a 5-ALA derivative compound prepared according to Example 1 as a test substance was administered to Sprague-Dawley rats. Thereafter, the hourly concentration of the 5-ALA drug released into the blood through the metabolic process was tracked and analyzed.

[0150] The above 5-ALA derivative compounds were each prepared in the same manner and administered to rats at a dose of 10 mg / kg. Blood was collected at a set time and plasma was separated. The drug was analyzed by HPLC (XBridge column C 18, Waters, mobile phase 0.1% formic acid: acetonitrile (30:70, % / %)) and MS / MS (ESI positive, MRM) were used, and rat plasma and each commercial standard solution were mixed in a 9:1 ratio to prepare and calibrate at concentrations of 5, 50, 100, 500, 100, and 5,000 ng / ml. In addition, the QC samples were prepared by mixing rat plasma and QC standard solutions in a 9:1 ratio to prepare concentrations of 100, 750, and 2,500 ng / ml. The pretreatment method was to transfer 100 μl of plasma sample to a centrifuge tube, add 10 μl of internal standard solution and 300 μl of methanol, and mix for approximately 30 seconds. The tube was centrifuged at 3,000 xg (4℃) for approximately 5 minutes, the supernatant was transferred to an LC vial, and then injected into the device. The concentration of the active ingredient, 5-ALA, in rat plasma was quantified using a pre-validated analytical method. Pharmacokinetic parameters were determined using the Win Nonlin 5.2 program (source: Pharsight, USA), and AUC was calculated using noncompartment modeling (best fit). 0-t , AUC 0-∞ , C max , T max , t 1 / 2 The results of pharmacokinetic parameters were expressed as mean and standard deviation, and statistically processed using the SPSS program (Statistical Package for the Social Sciences, 10.0K, USA).

[0151] Blood drug concentrations of intravenously (iv) administered 5-ALA derivatives and orally (po) administered 5-ALA derivative compounds were measured using the methods described above, and the measured blood 5-ALA concentrations are shown in Tables 1 and 2 below (Fig. 1).

[0152] time (h) intravenous administration (iv) mean concentration (ng / ml) standard deviation (SD) ng / ml 0 0 0 0.08 3 1 7 0 4.8 5.10.25 8 9 3.12 7.50.54 7 1.85 9.51 15 5.81 14.22 11 3.05 8.64 87.36 4.06 6 2.83 7.18 34.62 1.11 0 11.5 10.4 AUC 0-10 1191.5457.9

[0153] time (h) oral administration (po) mean concentration (mean) ng / ml standard deviation (SD) ng / ml 0 0 0 0.25 2 5 2.4 1 5 6.8 0.5 3 36.12 2 0.7 1 2 4 3.3 1 5 4.12 1 1 0.39 4.9 4 4.7 3 4.86 2 1.8 1 5.8 8.86 1 0 5.15 2 AUC 0-10 665.1430.8

[0154] To develop a compound into an oral dosage form, a certain level of bioavailability must be confirmed compared to intravenous administration. The oral bioavailability of the present invention was 55.8% (average oral concentration / average intravenous concentration), demonstrating a sufficiently high value for development into an oral formulation.

[0155] In this way, even if administered in small amounts, the 5-ALA derivative compound of the present invention can maintain high blood concentrations for a long period of time and exhibit high bioavailability, allowing it to be utilized as an oral administration formulation. In addition, the clinical side effects of 5-ALA typically worsen with increasing dosage, accompanied by symptoms such as hypotension. However, if the compound of the present invention has a blood concentration pattern similar to that of the present invention, sufficient blood concentrations can be achieved even with small doses, so it is expected that side effects will be reduced.

[0156] Experimental Example 2: Brain Penetration Evaluation

[0157] The aim was to measure the rate at which orally administered 5-ALA derivative compounds were delivered to the brain. After a single oral (po) administration of 10 mg / kg of the 5-ALA derivative compound according to Example 1 to rats, the rat brains were extracted at a set time, and the 5-ALA concentration was measured using the same method as described in Experimental Example 1. The results are shown in Table 3 (Fig. 2).

[0158] time (h) brain penetration rate mean concentration (ng / g standard deviation (SD) ng / g 000 168.4 19.12 113.73 1.46 45.9 12.5 10 21.2 15.4 AUC 0-10 552.1

[0159] As a result, the brain penetration rate of the orally administered compound of the present invention reached 83% (average brain penetration concentration / average concentration upon oral administration), confirming excellent brain penetration rate.

[0160] Experimental Example 3: Stability Evaluation

[0161] A stability test for the compound of Example 1 was conducted as follows.

[0162] The test substance was the 5-ALA derivative compound manufactured in Example 1, and the control substance was 5-ALA (Source: Sigma-Aldrich). 1 g of the test substance and control substance were placed in a polyethylene plastic bag, a packaging container, and one packet of silica gel was added. The bag was then placed in an aluminum bag and sealed. After storage in a long-term storage (25°C, 75% relative humidity) and harsh condition (45°C, 85% relative humidity) chamber, the purity of the substance was observed visually and by HPLC for two weeks, and the results are summarized in Table 4.

[0163] Comparison of stability under long-term storage conditions and harsh conditions Initial 1 day 2 days 3 days 4 days 5 days 7 days 14 days Note 5-ALA Long-term Color / Purity % White / 98.3 White / 98.3 White / 98.2 White / 98.2 Light beige / 97.8 Light beige / 97.7 Light beige / 97.7 Yellow / 95 Slightly sticky 5-ALA Harsh Color / Purity % White / 98.3 White / 98.3 Light beige / 97.5 Light beige / 96.8 Light beige / 96.4 Yellow / 96.4 Yellow / 95.9 Brown / 89.6 Sticky Example 1 Long-term color / purity% White / 98.8 White / 98.8 White / 98.8 White / 98.8 White / 98.8 White / 98.8 White / 98.8 White / 98.8 White / 98.8 White / 98.8 Powder Example 1 Severe color / purity% White / 98.8 White / 98.8 White / 98.8 White / 98.8 White / 98.8 White / 98.8 White / 98.8 White / 98.8 Light gray / 98.6 Powder

[0164] As shown in Table 4 above, the 5-ALA derivative compound of Example 1 maintained its color and purity at a level higher than 5-ALA under both long-term storage conditions and harsh conditions, confirming that there was no change in quality.

[0165] While specific aspects of the present invention have been described in detail above, it will be apparent to those skilled in the art that these specific descriptions merely represent preferred embodiments and are not intended to limit the scope of the present invention. Therefore, the substantial scope of the present invention is 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] In chemical formula 1 R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, halogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl or C6-C 20 It's Aryl, n is an integer from 0 to 3, and m is an integer from 0 to 3.

2. In the first paragraph, n is 1, m is 0, and R 1 , R 2 , R 3 and R 4 A 5-aminolevulinic acid derivative compound or a pharmaceutically acceptable salt thereof, wherein each of the compounds is hydrogen.

3. A 5-aminolevulinic acid derivative compound or a pharmaceutically acceptable salt thereof, characterized in that in paragraph 1, the pharmaceutically acceptable salt is at least one selected from the group consisting of hydrochloride, p-toluenesulfonate, fumarate, citrate, succinate, salicylate, oxalate, bromate, phosphate, methanesulfonate, tartrate, sulfate, and mandelate.

4. A 5-aminolevulinic acid derivative compound or a pharmaceutically acceptable salt thereof, characterized in that the pharmaceutically acceptable salt in the third paragraph is a hydrochloride.

5. A composition for photodynamic diagnosis or treatment comprising the 5-aminolevulinic acid derivative compound of paragraph 1 or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition for the treatment or prevention of inflammatory diseases, cancer diseases, metabolic diseases, insomnia, skin aging or hair loss, comprising the 5-aminolevulinic acid derivative compound of paragraph 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

7. A pharmaceutical composition for treating or preventing inflammatory diseases, cancer, metabolic diseases, insomnia, skin aging or hair loss, characterized in that the inflammatory disease in paragraph 6 is at least one disease selected from the group consisting of alopecia areata, dermatitis, allergy, atopy, 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, periarthritis of the shoulder joint, tendinitis, tenosynovitis, peritendinitis, myositis, hepatitis, cystitis, nephritis, Sjogren's syndrome and multiple sclerosis.

8. In paragraph 6, the cancer disease is a brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial tumor, ependymoma, brainstem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal cavity / paranasal sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, thoracic tumor, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, stomach cancer, liver cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine 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 A pharmaceutical composition for the treatment or prevention of inflammatory diseases, cancers, metabolic diseases, insomnia, skin aging or hair loss, characterized in that it is one or more diseases selected from the group consisting of skin cancer.

9. A pharmaceutical composition for treating or preventing inflammatory diseases, cancer diseases, metabolic diseases, insomnia, skin aging or hair loss, characterized in that the metabolic disease in paragraph 6 is one or more diseases selected from the group consisting of obesity, diabetes, hypertension, cardiovascular disease and hyperlipidemia.

10. A pharmaceutical composition for oral administration, transdermal administration, subcutaneous injection or external application to the skin according to paragraph 6.

11. A pharmaceutical composition according to claim 10, characterized in that the external skin application is selected from the group consisting of creams, lotions, external ointments, oils, moisturizers, gels, aerosols, and nasal inhalants.

12. A method for producing a 5-aminolevulinic acid derivative compound of chemical formula 1 or a pharmaceutically acceptable salt thereof, comprising the following steps: (a) A step of reacting a solution of N-Boc-5-aminolevulinic acid with dimethylformamide and oxalyl chloride to obtain a compound of chemical formula 2; (b) a step of reacting a suspension of a compound of formula 3 with a solution of a compound of formula 2 dissolved in a solvent to obtain a compound of formula 4; and (c) A step of reacting a suspension of a compound of chemical formula 4 with an acidic solution to obtain a 5-ALA derivative compound of chemical formula 1. [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 are each independently a hydrogen atom, halogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl or C6-C 20 It's Aryl, n is an integer from 0 to 3, and m is an integer from 0 to 3.

13. A method for producing a 5-aminolevulinic acid derivative compound of formula 1 or a pharmaceutically acceptable salt thereof, in accordance with claim 12, further comprising the following steps: (d) A step of filtering the 5-ALA derivative compound produced in step (c) and adding a solvent to the recovered filtrate to concentrate, elute, and purify it.

14. Use of the 5-aminolevulinic acid derivative compound of paragraph 1 or a pharmaceutically acceptable salt thereof for the treatment or prevention of inflammatory diseases, cancer, metabolic diseases, insomnia, skin aging or hair loss.

15. A method for treating inflammatory diseases, cancer diseases, metabolic diseases, insomnia, skin aging or hair loss, comprising a step of administering to a subject a 5-aminolevulinic acid derivative compound of paragraph 1 or a pharmaceutically acceptable salt thereof.

16. Use of the 5-aminolevulinic acid derivative compound of paragraph 1 or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition for preventing or treating inflammatory diseases, cancer diseases, metabolic diseases, insomnia, skin aging or hair loss.

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