WO2023106616A1 - Novel compound, preparation method therefor, and pharmaceutical composition for treating or preventing neural damage, neural disease, or developmental disorder through proliferation promotion, differentiation, and/or regeneration of neural cells, containing same - Google Patents

Novel compound, preparation method therefor, and pharmaceutical composition for treating or preventing neural damage, neural disease, or developmental disorder through proliferation promotion, differentiation, and/or regeneration of neural cells, containing same Download PDF

Info

Publication number
WO2023106616A1
WO2023106616A1 PCT/KR2022/016040 KR2022016040W WO2023106616A1 WO 2023106616 A1 WO2023106616 A1 WO 2023106616A1 KR 2022016040 W KR2022016040 W KR 2022016040W WO 2023106616 A1 WO2023106616 A1 WO 2023106616A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
disease
present
neural
Prior art date
Application number
PCT/KR2022/016040
Other languages
French (fr)
Korean (ko)
Inventor
장사정
김연희
최가람
박현진
김예슬
Original Assignee
(주)에트노바테라퓨틱스
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by (주)에트노바테라퓨틱스 filed Critical (주)에트노바테라퓨틱스
Publication of WO2023106616A1 publication Critical patent/WO2023106616A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic System without C-Metal linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
    • C07F3/02—Magnesium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
    • C07F3/04—Calcium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System

Definitions

  • the present invention relates to a novel compound, a method for preparing the same, and a pharmaceutical composition for treating or preventing nerve damage, neurological disease, or developmental disorder by promoting proliferation, differentiation, and/or regeneration of nerve cells containing the same.
  • Nerve cells are distributed in many parts of the body, including the brain, and the body can feel, think, respond to, and exercise external situations by transmitting signals between nerve cells. Therefore, when nerve cells die due to certain factors, various symptoms such as cognitive impairment symptoms, paralysis symptoms, sensory disorder symptoms, and motor abnormalities symptoms may appear.
  • Alzheimer's disease is caused by the death of nerve cells that exist in areas responsible for memory in the brain
  • Parkinson's disease is caused by the death of nerve cells that exist in areas that control movement of the body.
  • nerve cells When nerve cells die, they are very difficult to regenerate. In the case of other cells such as the skin, even if a cell is destroyed by damage, other cells around it divide and create new cells to replace the cell, but unlike other cells, nerve cells do not undergo cell division. It is very difficult to treat diseases associated with the death of Accordingly, the treatment of many diseases caused by the death of nerve cells has been limited to relieving symptoms. There is still a need for the development of materials that can effectively treat or prevent nerve damage, neurological diseases, and developmental disorders through regeneration of nerve cells.
  • One object of the present invention is to provide a novel compound that can effectively treat or prevent nerve damage, neurological disease, or developmental disorder, a method for preparing the same, and a pharmaceutical composition containing the same.
  • a compound for one purpose of the present invention is represented by Formula 1 below.
  • M is any one selected from Gd 3+ , Mg 2+ and Ca 2+
  • A represents *-(CH 2 ) n -NH-* (where n is an integer from 0 to 5).
  • B represents a part derived from retinoic acid.
  • a in Chemical Formula 1 may be *-(CH 2 )-NH-* ethylamine.
  • the B in Formula 1 may represent the following Formula 2a, 2b, or 2c.
  • the compound may be represented by Formula 3 below.
  • M is any one selected from Gd 3+ , Mg 2+ and Ca 2+ .
  • a pharmaceutical composition for another purpose of the present invention comprises the compound or a pharmaceutically acceptable salt thereof, characterized in that it contains cranial nerve damage, degenerative brain disease, ischemic brain disease, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, Epilepsy, memory loss, or ischemic stroke, peripheral nerve injury, spinal cord injury, optic nerve injury, amyotrophic axonal sclerosis, ataxia, or peripheral nerve disease or cranial nerve development disorder.
  • a method for preparing a compound for another object of the present invention is to combine a compound represented by Chemical Formula 4-1 with a compound represented by Chemical Formula 4-2 to obtain a compound represented by Chemical Formula 4-3 It is characterized in that it comprises a first step of manufacturing.
  • the present invention is characterized by using a compound represented by Formula 4-1 using ethylamine (*-(CH 2 ) n -NH) as a linker.
  • the present invention is characterized by providing a manufacturing method suitable for mass production by providing a higher yield by using -(CH 2 ) n -NH- as a linker.
  • A represents *-(CH 2 ) n -NH (where n is an integer from 0 to 5).
  • B represents a moiety derived from retinoic acid.
  • A represents *-(CH 2 ) n -NH-* (where n is an integer from 0 to 5), and B represents a moiety derived from retinoic acid.
  • a second step of preparing a compound represented by the following Chemical Formula 1 by coordinating a metal element with the compound represented by Chemical Formula 4-3 may be further included.
  • M is any one selected from Gd 3+ , Mg 2+ and Ca 2+
  • A represents *-(CH 2 ) n -NH-* (where n is an integer from 0 to 5).
  • B represents a part derived from retinoic acid.
  • B may represent Chemical Formulas 2a, 2b, or 2c below.
  • the compound according to the present invention can directly induce or promote the generation of neurites, the growth of neurites, the differentiation of nerve cells, the regeneration of nerve cells, and/or the proliferation of nerve cells, which is fundamental for various nervous system diseases. treatment can be provided.
  • the cytotoxicity is low, there are few side effects due to drug toxicity.
  • the solubility and dissolution stability in water are high, the formulation flexibility of the formulation is high and the absorption rate in the body is increased, the nerve regeneration, differentiation, and protective effects can be further increased.
  • the production rate of by-products in the manufacturing process is very low, and a high compound synthesis yield can be provided, and mass production is easy, so there is an advantage that it can be applied to various fields.
  • a metal atom there is an effect of providing low toxicity and high stability.
  • FIG. 1 is a view showing the novel compound of the present invention and its preparation method.
  • a pharmaceutical composition containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof is provided.
  • the compound of Formula 1 according to the present invention induces generation of neurite, growth of neurite, differentiation of nerve cell, regeneration of nerve cell, and/or proliferation of nerve cell for nerve damage, neurological disease, or developmental disorder. useful to promote
  • nerve refers to projections from the cell body of a nerve cell and includes, for example, axons and dendrites.
  • the production of neurites, the growth of neurites, the differentiation of nerve cells, the regeneration of nerve cells, and/or the nerve cells containing the compound of the present invention or a pharmaceutically acceptable salt thereof A pharmaceutical composition for inducing or promoting the proliferation of is provided.
  • the compound of the present invention or a pharmaceutical thereof is administered to a subject or nerve cell in need of generation of neurite, growth of neurite, differentiation of nerve cell, regeneration of nerve cell, or proliferation of nerve cell.
  • a method of inducing or promoting neurite production, neurite growth, neuronal differentiation, neuronal regeneration, or neuronal proliferation, comprising administering an acceptable salt thereto, is provided.
  • a pharmaceutical composition for treating or preventing nerve damage, neurological disease, or developmental disorder characterized by containing the compound of the present invention or a pharmaceutically acceptable salt thereof is provided. .
  • the term “treatment” is one in which a desired therapeutic effect is achieved in a subject, and includes reduction of the rate of progression, cessation of the rate of progression, alleviation of symptoms, improvement of the condition, and cure of the condition.
  • the compounds according to the present invention can provide fundamental healing of diseases through morphological and functional recovery of damaged cells, and thus, the treatment specifically refers to the treatment of diseases by morphological and functional recovery of nerve cells.
  • prevention may refer to use for a subject who has not yet developed a disease but is at risk of developing the disease.
  • nerve injury refers to any damage to the nervous system, such as spinal cord injury or optic nerve injury, which is eg trauma-induced, chemically induced (eg by neurotoxins or having an immunosuppressive effect). therapy), or damage to the nervous system caused by a disease or disorder.
  • nerve damage includes damage to the central nervous system (CNS) and damage to the peripheral nervous system (PNS), more specifically cranial nerve damage, spinal cord damage, optic nerve damage, peripheral nerve damage, and the like.
  • neurodegenerative diseases includes neurodegenerative diseases, ischemic neurological diseases, and peripheral nerve diseases.
  • the "degenerative neurological disease” specifically includes degenerative brain diseases (eg, memory loss, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.), amyotrophic axonal sclerosis, ataxia, epilepsy, and the like.
  • the "ischemic neurological disease” specifically includes ischemic brain disease (eg, ischemic stroke).
  • peripheral nerve disease specifically includes polyneuropathy, mononeuropathy, mononeuritis multiplex, and autonomic neuropathy.
  • developmental disorder includes cranial neurodevelopmental disorders.
  • the compounds of the present invention can generate and grow neurites of nerve cells and differentiate, regenerate, and proliferate nerve cells. Accordingly, the compounds of the present invention or their A pharmaceutical composition containing a pharmaceutically acceptable salt may be used for treating or preventing nerve damage, neurological disease, or developmental disorder. In addition, the compound of the present invention can be very usefully used as an agent for improving learning ability or cognitive function.
  • nerve damage including the step of administering the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need of treatment or prevention of nerve damage, neurological disease, or developmental disorder , a neurological disease, or a method for treating or preventing a developmental disorder is provided.
  • a pharmaceutical composition for treating or preventing cranial nerve damage, degenerative brain disease, or ischemic brain disease comprising the compound of the present invention or a pharmaceutically acceptable salt thereof Provided.
  • treatment or treatment of dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, memory loss, or ischemic stroke characterized by containing the compound of the present invention or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for preventing is provided.
  • peripheral nerve damage spinal cord injury, optic nerve damage, amyotrophic axonal sclerosis, ataxia, or peripheral nerve damage characterized by containing the compound of the present invention or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for treating or preventing a neurological disorder is provided.
  • a pharmaceutical composition for treating or preventing brain neurodevelopmental disorders comprising the compound of the present invention or a pharmaceutically acceptable salt thereof.
  • the compound of Formula 1 according to the present invention may be used in the form of a pharmaceutically acceptable salt.
  • the "pharmaceutically acceptable salt” refers to a compound salt that retains the pharmacological activity of the parent compound, and includes, for example, (i) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; (ii) acetic acid, propionic acid, isobutyric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid , salts formed with organic acids such as hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid
  • the pharmaceutical composition of the present invention may contain an isomer, solvate, or prodrug of the compound represented by Formula 1 of the present invention.
  • “Isomer” herein includes all possible stereochemical isomers, including diastereomers and enantiomers. It is to be understood that the compounds of the present invention refer to mixtures of all possible stereochemically isomeric forms.
  • solvate refers to a complex of a solute (eg, a compound of Formula 1) and a solvent, and when the solvent is water, the solvate may be referred to as a hydrate.
  • prodrug refers to a compound that is converted into an active compound having a medicinal effect by absorption and metabolism after being administered in vivo.
  • the prodrug is a compound that is itself inactive or less active than the active compound, but may provide properties that are advantageous for handling, administration, or metabolism.
  • the prodrug may be in the form of an ester of the active compound (eg, a physiologically acceptable metabolically labile ester) or a form of a sugar derivative or an amino acid ester derivative.
  • the pharmaceutical composition of the present invention may include the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof alone, but may further include a pharmaceutically acceptable carrier in addition thereto.
  • the pharmaceutically acceptable carrier may be one commonly used in the pharmaceutical field, and may include an excipient (eg, starch, calcium carbonate, sucrose, lactose, sorbitol, mannitol, cellulose, etc.) or a diluent (eg, physiological saline, purified water, etc.).
  • the pharmaceutical composition of the present invention pharmaceutically acceptable additives other than the above pharmaceutically acceptable carrier, for example, binders, disintegrants, lubricants, peeling agents, film coating bases, enteric films It may further contain a coating agent, a soft capsule agent, a dissolution aid, an emulsifier, a suspending agent, a stabilizer, a buffer, an antioxidant, a surfactant, a sweetening agent, a flavoring agent, a preservative, a thickening agent, a flavoring agent, or a coloring agent.
  • binders for example, binders, disintegrants, lubricants, peeling agents, film coating bases, enteric films It may further contain a coating agent, a soft capsule agent, a dissolution aid, an emulsifier, a suspending agent, a stabilizer, a buffer, an antioxidant, a surfactant, a sweetening agent, a flavoring agent, a preservative, a thickening agent, a flavoring agent,
  • the pharmaceutical composition of the present invention may be administered orally or parenterally.
  • parenteral administration intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intradermal administration, topical administration, intranasal administration, intrapulmonary administration, and intrarectal administration may be used.
  • the pharmaceutical composition of the present invention may be formulated in the form of a solid or liquid dosage form.
  • Solid formulations may be, for example, tablets, capsules (soft & hard capsules), powders, granules, pills, troches, etc.
  • liquid formulations may be, for example, elixirs, suspensions, emulsions, solutions, syrups , rimona dese, etc. may be in the form.
  • the active ingredient in addition to the active ingredient, carriers such as lactose and corn starch, lubricants such as magnesium stearate, binders such as methylcellulose, microcrystalline cellulose, and polyvinyl alcohol, and disintegrants such as bentonite and sodium alginate are usually added. It can be.
  • the active ingredient may be formulated with a carrier such as purified water, physiological saline, and the like, and, if necessary, a solubilizing agent such as sucrose monostearate, a stabilizer such as polyvinylpyrrolidone, and the like.
  • the active ingredient may be formulated with a suspending agent and, if necessary, a surfactant, a preservative, a stabilizer, and the like.
  • the dosage of the pharmaceutical composition of the present invention can be determined in consideration of the administration method, the age and sex of the user, the severity of the patient, the condition, inactivity rate, and concomitant drugs, and can be administered once or divided into several times.

Abstract

Disclosed in the present invention are a novel compound, a preparation method therefor, and a pharmaceutical composition comprising same. The compound of the present invention is represented by the following chemical formula 1. [Chemical formula 1] In chemical formula 1, M represents any one selected from Gd3+, Mg2+ and Ca2+, A represents *-(CH2)n-NH-* (wherein, n is an integer of 0 to 5) and B represents a moiety derived from retinoic acid.

Description

신규한 화합물, 이의 제조방법 및 이를 함유하는 신경 손상, 신경 질환, 또는 발달 장애에 대한 신경세포의 증식 촉진, 분화, 및/또는 재생을 통한 치료 또는 예방용 약제학적 조성물A novel compound, a method for preparing the same, and a pharmaceutical composition for treating or preventing nerve damage, neurological disease, or developmental disorder containing the same by promoting proliferation, differentiation, and/or regeneration of nerve cells.
본 발명은 신규한 화합물, 이의 제조방법 및 이를 함유하는 신경 손상, 신경 질환, 또는 발달 장애에 대한 신경세포의 증식 촉진, 분화, 및/또는 재생을 통한 치료 또는 예방용 약제학적 조성물에 관한 것이다.The present invention relates to a novel compound, a method for preparing the same, and a pharmaceutical composition for treating or preventing nerve damage, neurological disease, or developmental disorder by promoting proliferation, differentiation, and/or regeneration of nerve cells containing the same.
신경 세포는 뇌를 비롯하여 몸의 수많은 곳에 분포되어 있으며, 신체는 신경 세포들 간의 신호 전달에 의해 외부 상황을 느끼고, 생각하고, 반응하고, 운동할 수 있다. 따라서, 어떠한 요인으로 인해 신경 세포가 사멸하게 되면 인지 장애 증상, 마비 증상, 감각 장애 증상, 운동 이상 증상 등과 같은 다양한 증상이 나타날 수 있다. 알츠하이머병은 뇌 안의 기억을 담당하는 곳에 존재하는 신경 세포의 사멸로 인해 발생하며, 파킨슨병은 신체의 운동을 조절하는 곳에 존재하는 신경 세포가 사멸되어 증상이 나타나는 것이다. Nerve cells are distributed in many parts of the body, including the brain, and the body can feel, think, respond to, and exercise external situations by transmitting signals between nerve cells. Therefore, when nerve cells die due to certain factors, various symptoms such as cognitive impairment symptoms, paralysis symptoms, sensory disorder symptoms, and motor abnormalities symptoms may appear. Alzheimer's disease is caused by the death of nerve cells that exist in areas responsible for memory in the brain, and Parkinson's disease is caused by the death of nerve cells that exist in areas that control movement of the body.
신경 세포는 사멸되면 다시 재생하기가 매우 어렵다. 피부와 같은 다른 세포의 경우 손상에 의해 세포가 파괴되어도 주위의 다른 세포들이 세포 분열을 하여 그 세포를 대체할 새로운 세포를 만들지만, 신경 세포는 다른 세포와는 달리 세포분열이 일어나지 않기 때문에 신경 세포의 사멸과 관련된 질환을 치료하는 것은 매우 어렵다. 이에 따라, 현재까지 신경 세포의 사멸로 인한 많은 병의 치료는 증상을 완화시키는 방법에 그치고 있는 수준이다. 신경 세포의 재생을 통해 신경 손상이나 신경 질환, 발달 장애를 효과적으로 치료 또는 예방할 수 있는 물질의 개발이 여전히 요구되고 있다.When nerve cells die, they are very difficult to regenerate. In the case of other cells such as the skin, even if a cell is destroyed by damage, other cells around it divide and create new cells to replace the cell, but unlike other cells, nerve cells do not undergo cell division. It is very difficult to treat diseases associated with the death of Accordingly, the treatment of many diseases caused by the death of nerve cells has been limited to relieving symptoms. There is still a need for the development of materials that can effectively treat or prevent nerve damage, neurological diseases, and developmental disorders through regeneration of nerve cells.
본 발명의 일 목적은 신경 손상, 신경 질환, 또는 발달 장애를 효과적으로 치료 또는 예방할 수 있는 신규한 화합물, 이의 제조방법 및 이를 함유하는 약제학적 조성물을 제공하는 것이다.One object of the present invention is to provide a novel compound that can effectively treat or prevent nerve damage, neurological disease, or developmental disorder, a method for preparing the same, and a pharmaceutical composition containing the same.
본 발명의 일 목적을 위한 화합물은 하기 화학식 1으로 표시된다.A compound for one purpose of the present invention is represented by Formula 1 below.
[화학식 1][Formula 1]
Figure PCTKR2022016040-appb-img-000001
Figure PCTKR2022016040-appb-img-000001
상기 화학식 1에서, M은 Gd3+, Mg2+ 및 Ca2+ 중에서 선택된 어느 하나이며, A는 *-(CH2)n-NH-*(여기서, n은 0 내지 5인 정수)를 나타내고, B는 레티노산(retinoic acid)에서 유래된 부분을 나타낸다.In Formula 1, M is any one selected from Gd 3+ , Mg 2+ and Ca 2+ , and A represents *-(CH 2 ) n -NH-* (where n is an integer from 0 to 5). , B represents a part derived from retinoic acid.
일 실시에에서, 상기 화학식 1에서 A는 *-(CH2)-NH-* 에틸아민일 수 있다.In one embodiment, A in Chemical Formula 1 may be *-(CH 2 )-NH-* ethylamine.
일 실시예에서, 상기 화학식 1에서 상기 B는 하기 화학식 2a, 2b, 또는 2c를 나타낼 수 있다.In one embodiment, the B in Formula 1 may represent the following Formula 2a, 2b, or 2c.
[화학식 2a][Formula 2a]
Figure PCTKR2022016040-appb-img-000002
Figure PCTKR2022016040-appb-img-000002
[화학식 2b][Formula 2b]
Figure PCTKR2022016040-appb-img-000003
Figure PCTKR2022016040-appb-img-000003
[화학식 2c][Formula 2c]
Figure PCTKR2022016040-appb-img-000004
Figure PCTKR2022016040-appb-img-000004
일 실시예에서, 상기 화합물은 하기 화학식 3으로 표시될 수 있다.In one embodiment, the compound may be represented by Formula 3 below.
[화학식 3][Formula 3]
Figure PCTKR2022016040-appb-img-000005
Figure PCTKR2022016040-appb-img-000005
상기 화학식 3에서, M은 Gd3+, Mg2+ 및 Ca2+ 중에서 선택된 어느 하나이다.In Formula 3, M is any one selected from Gd 3+ , Mg 2+ and Ca 2+ .
본 발명의 다른 목적을 위한 약제학적 조성물은 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 함유하는 것을 특징으로 하는 뇌 신경 손상, 퇴행성 뇌질환, 허혈성 뇌질환, 치매, 알츠하이머병, 파킨슨병, 헌팅턴병, 간질, 기억력 감퇴, 또는 허혈성 뇌졸중, 말초 신경 손상, 척 수 손상, 시신경 손상, 근위축성 축색 경화증, 운동 실조, 또는 말초 신경 질환 또 는, 뇌 신경 발달 장애를 치료 또는 예방하기 위한 것이다.A pharmaceutical composition for another purpose of the present invention comprises the compound or a pharmaceutically acceptable salt thereof, characterized in that it contains cranial nerve damage, degenerative brain disease, ischemic brain disease, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, Epilepsy, memory loss, or ischemic stroke, peripheral nerve injury, spinal cord injury, optic nerve injury, amyotrophic axonal sclerosis, ataxia, or peripheral nerve disease or cranial nerve development disorder.
일 실시예에서, 본 발명의 또 다른 목적을 위한 화합물의 제조방법은 하기 화학식 4-1으로 표시되는 화합물과 하기 화학식 4-2로 표시되는 화합물을 결합시켜 하기 화학식 4-3으로 표시되는 화합물을 제조하는 제1 단계를 포함하는 것을 특징으로 한다. 본 발명은 에틸아민(*-(CH2)n-NH)을 링커로 하는 하기 화학식 4-1으로 표시되는 화합물을 이용하는 것을 특징으로 한다. DO3A 화합물에 RA(Retinoic acid, 레티노산)을 결합하는 종래 기술에서는 DO3A에 aminde bond(CONH)-(CH2)n-NH-를 링커로 붙인 후 RA를 결합하는 방법을 사용하고 있으나, 이는 제조과정에서 많은 양의 부산물이 생성되어 수율이 낮은 문제점이 있었다. 본 발명에서는 링커로 -(CH2)n-NH-를 사용함으로써 보다 높은 수율을 제공하여 대량생산에 적합한 제조 방법을 제공하는 것을 특징으로 한다.In one embodiment, a method for preparing a compound for another object of the present invention is to combine a compound represented by Chemical Formula 4-1 with a compound represented by Chemical Formula 4-2 to obtain a compound represented by Chemical Formula 4-3 It is characterized in that it comprises a first step of manufacturing. The present invention is characterized by using a compound represented by Formula 4-1 using ethylamine (*-(CH 2 ) n -NH) as a linker. In the prior art for binding RA (retinoic acid) to a DO3A compound, a method of attaching an aminde bond (CONH)-(CH 2 ) n -NH- to DO3A as a linker and then binding RA is used, but this is In the process, a large amount of by-products were generated, resulting in a low yield. The present invention is characterized by providing a manufacturing method suitable for mass production by providing a higher yield by using -(CH 2 ) n -NH- as a linker.
[화학식 4-1][Formula 4-1]
Figure PCTKR2022016040-appb-img-000006
Figure PCTKR2022016040-appb-img-000006
화학식 4-1에서,In Formula 4-1,
A는 *-(CH2)n-NH (여기서, n은 0 내지 5인 정수)를 나타낸다.A represents *-(CH 2 ) n -NH (where n is an integer from 0 to 5).
[화학식 4-2][Formula 4-2]
Figure PCTKR2022016040-appb-img-000007
Figure PCTKR2022016040-appb-img-000007
화학식 4-2에서, B는 레티노산(retinoic acid)에서 유래된 부분을 나타낸다.In Formula 4-2, B represents a moiety derived from retinoic acid.
[화학식 4-3][Formula 4-3]
Figure PCTKR2022016040-appb-img-000008
Figure PCTKR2022016040-appb-img-000008
화학식 4-3에서, A는 *-(CH2)n-NH-*(여기서, n은 0 내지 5인 정수)를 나타내고, B는 레티노산(retinoic acid)에서 유래된 부분을 나타낸다.In Formula 4-3, A represents *-(CH 2 ) n -NH-* (where n is an integer from 0 to 5), and B represents a moiety derived from retinoic acid.
일 실시예에서, 상기 제1 단계 이후, 화학식 4-3으로 표시되는 화합물에 금속원소를 배위결합시켜 하기 화학식 1으로 표시되는 화합물을 제조하는 제2 단계를 추가로 더 포함할 수 있다.In one embodiment, after the first step, a second step of preparing a compound represented by the following Chemical Formula 1 by coordinating a metal element with the compound represented by Chemical Formula 4-3 may be further included.
[화학식 1][Formula 1]
Figure PCTKR2022016040-appb-img-000009
Figure PCTKR2022016040-appb-img-000009
상기 화학식 1에서, M은 Gd3+, Mg2+ 및 Ca2+ 중에서 선택된 어느 하나이며, A는 *-(CH2)n-NH-*(여기서, n은 0 내지 5인 정수)를 나타내고, B는 레티노산(retinoic acid)에서 유래된 부분을 나타낸다.In Formula 1, M is any one selected from Gd 3+ , Mg 2+ and Ca 2+ , and A represents *-(CH 2 ) n -NH-* (where n is an integer from 0 to 5). , B represents a part derived from retinoic acid.
일 실시예에서, 상기 화학식 4-2에서, 상기 B는 하기 화학식 2a, 2b, 또는 2c를 나타낼 수 있다.In one embodiment, in Chemical Formula 4-2, B may represent Chemical Formulas 2a, 2b, or 2c below.
[화학식 2a][Formula 2a]
Figure PCTKR2022016040-appb-img-000010
Figure PCTKR2022016040-appb-img-000010
[화학식 2b][Formula 2b]
Figure PCTKR2022016040-appb-img-000011
Figure PCTKR2022016040-appb-img-000011
[화학식 2c][Formula 2c]
Figure PCTKR2022016040-appb-img-000012
Figure PCTKR2022016040-appb-img-000012
현재까지 신경 손상 또는 신경 퇴화 및 이와 관련된 각종 질병의 치료는 질병의 진행을 완화하는 수준이었으며, 이들의 완전한 치료제는 전무한 상황이었다. 본 발명에 따른 화합물은 직접적으로 신경 돌기의 생성, 신경 돌기의 성장, 신경 세포의 분화, 신경 세포의 재생, 및/또는 신경 세포의 증식을 유발 또는 촉진시킬 수 있는 바, 각종 신경계 질환에 대한 근본적인 치료를 제공할 수 있다. 아울러, 세포 독성이 낮아서 약물 독성에 따른 부작용이 적다. 또한, 물에 대한 용해도 및 용해 안정성이 높아서 제제의 제형 유연성이 높고 체내 흡수율이 증가하게 되므로 신경 재생, 분화, 보호 효과가 더욱 증대될 수 있다.Until now, treatment of nerve damage or neurodegeneration and various diseases related thereto has been at a level of mitigating the progression of the disease, and there is no complete cure for these diseases. The compound according to the present invention can directly induce or promote the generation of neurites, the growth of neurites, the differentiation of nerve cells, the regeneration of nerve cells, and/or the proliferation of nerve cells, which is fundamental for various nervous system diseases. treatment can be provided. In addition, since the cytotoxicity is low, there are few side effects due to drug toxicity. In addition, since the solubility and dissolution stability in water are high, the formulation flexibility of the formulation is high and the absorption rate in the body is increased, the nerve regeneration, differentiation, and protective effects can be further increased.
또한 본 발명에 따르면, 제조 공정에서 부산물의 생성율이 매우 낮아 높은 화합물 합성 수율을 제공할 수 있고, 대량생산이 용이하여 다양한 분야에 응용할 수 있는 장점이 있다. 또한, 금속원자를 포함함으로써 독성이 낮고 높은 안정성을 제공할 수 있는 효과가 있다.In addition, according to the present invention, the production rate of by-products in the manufacturing process is very low, and a high compound synthesis yield can be provided, and mass production is easy, so there is an advantage that it can be applied to various fields. In addition, by including a metal atom, there is an effect of providing low toxicity and high stability.
도 1는 본 발명의 신규한 화합물 및 이의 제조방법을 나타내는 도면이다.1 is a view showing the novel compound of the present invention and its preparation method.
이하, 본 출원에서 사용한 용어는 단지 특정한 실시 예를 설명하기 위해 사용된 것으로서 본 발명을 한정하려는 의도가 아니다. 다르게 정의되지 않는 한, 기술적이거나 과학적인 용어를 포함해서 여기서 사용되는 모든 용어들은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 가지고 있다. 일반적으로 사용되는 사전에 정의되어 있는 것과 같은 용어들은 관련 기술의 문맥 상 가지는 의미와 일치하는 의미를 가지는 것으로 해석되어야 하며, 본 출원에서 명백하게 정의하지 않는 한, 이상적이거나 과도하게 형식적인 의미로 해석되지 않는다.Hereinafter, terms used in this application are only used to describe specific embodiments and are not intended to limit the present invention. Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related art, and unless explicitly defined in the present application, they should not be interpreted in an ideal or excessively formal meaning. don't
본 발명의 일 양태에 따르면, 전술한 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 함유하는 약제학적 조성물이 제공된다.According to one aspect of the present invention, a pharmaceutical composition containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof is provided.
본 발명에 따른 화학식 1의 화합물은 신경 손상, 신경 질환, 또는 발달 장애에 대해 신경 돌기의 생성, 신경 돌기의 성장, 신경 세포의 분화, 신경 세포의 재생, 및/또는 신경 세포의 증식을 유발 또는 촉진하는데 유용하다.The compound of Formula 1 according to the present invention induces generation of neurite, growth of neurite, differentiation of nerve cell, regeneration of nerve cell, and/or proliferation of nerve cell for nerve damage, neurological disease, or developmental disorder. useful to promote
용어 "신경 돌기"는 신경 세포의 세포체로부터의 돌출부를 의미하며, 예를 들어 축삭 및 수상돌기를 포함한다. The term “neurite” refers to projections from the cell body of a nerve cell and includes, for example, axons and dendrites.
이에, 본 발명의 일 양태에 따르면, 본 발명의 화합물 또는 이의 약학적으로 허용 가능한 염을 함유하는 신경 돌기의 생성, 신경 돌기의 성장, 신경 세포의 분화, 신경 세포의 재생, 및/또는 신경 세포의 증식을 유발 또는 촉진하기 위한 약제학적 조성물이 제공된다. Accordingly, according to one aspect of the present invention, the production of neurites, the growth of neurites, the differentiation of nerve cells, the regeneration of nerve cells, and/or the nerve cells containing the compound of the present invention or a pharmaceutically acceptable salt thereof A pharmaceutical composition for inducing or promoting the proliferation of is provided.
또한, 본 발명의 다른 일 양태에 따르면, 신경 돌기의 생성, 신경 돌기의 성장, 신경 세포의 분화, 신경 세포의 재생, 또는 신경 세포의 증식이 필요한 대상체 또는 신경 세포에 본 발명의 화합물 또는 이의 약학적으로 허용 가능한 염을 투여하는 단계를 포함하는, 신경 돌기의 생성, 신경 돌기의 성장, 신경 세포의 분화, 신경 세포의 재생, 또는 신경 세포의 증식을 유발 또는 촉진하는 방법이 제공된다. In addition, according to another aspect of the present invention, the compound of the present invention or a pharmaceutical thereof is administered to a subject or nerve cell in need of generation of neurite, growth of neurite, differentiation of nerve cell, regeneration of nerve cell, or proliferation of nerve cell. A method of inducing or promoting neurite production, neurite growth, neuronal differentiation, neuronal regeneration, or neuronal proliferation, comprising administering an acceptable salt thereto, is provided.
또한, 본 발명의 일 양태에 따르면, 본 발명의 화합물 또는 이의 약학적으로 허용 가능한 염을 함유하는 것을 특징으로 하는 신경 손상, 신경 질환, 또는 발달 장애를 치료 또는 예방하기 위한 약제학적 조성물이 제공된다.In addition, according to one aspect of the present invention, a pharmaceutical composition for treating or preventing nerve damage, neurological disease, or developmental disorder characterized by containing the compound of the present invention or a pharmaceutically acceptable salt thereof is provided. .
본 명세서에서 사용되는 용어 "치료"는 대상체에게 바람직한 치료 효과가 구현되는 것이며, 진행 속도의 감소, 진행 속도의 중단, 증상의 경감, 병태의 개선, 및 병태의 치유를 포함한다. 본 발명에 따른 화합물은 손상된 세포의 형태적 및 기능적 회복을 통해 질환의 근본적인 치유를 제공할 수 있으며, 이에, 상기 치료는 구체적으로는 신경 세포의 형태적 및 기능적 회복에 의한 질환의 치료를 의미한다. 또한, 용어 "예방"은 아직 병이 발병되지 않았으나 발병 위험이 있는 대상체에 대한 사용을 의미할 수 있다.As used herein, the term “treatment” is one in which a desired therapeutic effect is achieved in a subject, and includes reduction of the rate of progression, cessation of the rate of progression, alleviation of symptoms, improvement of the condition, and cure of the condition. The compounds according to the present invention can provide fundamental healing of diseases through morphological and functional recovery of damaged cells, and thus, the treatment specifically refers to the treatment of diseases by morphological and functional recovery of nerve cells. . Also, the term “prevention” may refer to use for a subject who has not yet developed a disease but is at risk of developing the disease.
용어 "신경 손상"은 척수 손상이나 시신경 손상과 같은 신경계의 임의 손상을 지칭하는 것으로서, 이는 예를 들어 외상에 의해 유발되거나, 화학적으로 유발되거나 (예를 들어, 신경독에 의해 또는 면역억제 효과를 가지는 치료 요법에 의해 유발), 또는 질환이나 장애에 의해 유발된 신경계의 손상을 포함한다. 또한, 상기 신경 손상은 중추 신경계(CNS)의 손상 및 말초 신경계(PNS)의 손상, 더 구체적으로는 뇌 신경 손상, 척수 손상, 시신경 손상, 말초 신경 손상 등을 포함한다.The term “nerve injury” refers to any damage to the nervous system, such as spinal cord injury or optic nerve injury, which is eg trauma-induced, chemically induced (eg by neurotoxins or having an immunosuppressive effect). therapy), or damage to the nervous system caused by a disease or disorder. In addition, the nerve damage includes damage to the central nervous system (CNS) and damage to the peripheral nervous system (PNS), more specifically cranial nerve damage, spinal cord damage, optic nerve damage, peripheral nerve damage, and the like.
용어 "신경 질환"은 퇴행성 신경 질환, 허혈성 신경 질환, 및 말초 신경 질환을 포함한다. 상기 "퇴행성 신경 질환"은 구체적으로는 퇴행성 뇌질환 (예를 들어, 기억력 감퇴, 치매, 알츠하이머병, 파킨슨병, 헌팅턴병 등), 근위축성 축색 경화증, 운동 실조, 간질 등을 포함한다. 상기 "허혈성 신경 질환"은 구체적으로 허혈성 뇌질환 (예를 들어, 허혈성 뇌졸중)을 포함한다. 상기 "말초 신경 질환"은 구체적으로는 다발신경병증, 단일신경병증, 다발성 단일신경염, 및 자율 신경병증을 포함한다.The term “neurological disease” includes neurodegenerative diseases, ischemic neurological diseases, and peripheral nerve diseases. The "degenerative neurological disease" specifically includes degenerative brain diseases (eg, memory loss, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.), amyotrophic axonal sclerosis, ataxia, epilepsy, and the like. The "ischemic neurological disease" specifically includes ischemic brain disease (eg, ischemic stroke). The "peripheral nerve disease" specifically includes polyneuropathy, mononeuropathy, mononeuritis multiplex, and autonomic neuropathy.
용어 "발달 장애"는 뇌 신경 발달 장애를 포함한다.The term "developmental disorder" includes cranial neurodevelopmental disorders.
본 발명의 화합물은, 후술하는 실시예에서도 알 수 있듯이 본 발명의 화합물은 신경 세포의 신경 돌기를 생성, 성장시키고 신경 세포를 분화, 재생, 증식시킬 수 있으므로, 이에 따라 본 발명의 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 함유하는 약제학적 조성물은 신경 손상, 신경 질환, 또는 발달 장애를 치료 또는 예방하는 용도로 사용될 수 있다. 아울러, 본 발명의 화합물은 학습능력 향상제 또는 인지기능 개선제로서도 매우 유용하게 사용될 수 있다.As can be seen from the examples described later, the compounds of the present invention can generate and grow neurites of nerve cells and differentiate, regenerate, and proliferate nerve cells. Accordingly, the compounds of the present invention or their A pharmaceutical composition containing a pharmaceutically acceptable salt may be used for treating or preventing nerve damage, neurological disease, or developmental disorder. In addition, the compound of the present invention can be very usefully used as an agent for improving learning ability or cognitive function.
또한, 본 발명의 다른 일 양태에 따르면, 신경 손상, 신경 질환, 또는 발달 장애의 치료 또는 예방이 필요한 대상체에 본 발명의 화합물 또는 이의 약학적으로 허용 가능한 염을 투여하는 단계를 포함하는, 신경 손상, 신경 질환, 또는 발달 장애의 치료 또는 예방 방법이 제공된다. In addition, according to another aspect of the present invention, nerve damage, including the step of administering the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need of treatment or prevention of nerve damage, neurological disease, or developmental disorder , a neurological disease, or a method for treating or preventing a developmental disorder is provided.
본 발명의 일 구현예에 따르면, 본 발명의 화합물 또는 이의 약학적으로 허용가능한 염을 함유하는 것을 특징으로 하는 뇌 신경 손상, 퇴행성 뇌질환, 또는 허혈성 뇌질환을 치료 또는 예방하기 위한 약제학적 조성물이 제공된다.According to one embodiment of the present invention, a pharmaceutical composition for treating or preventing cranial nerve damage, degenerative brain disease, or ischemic brain disease, comprising the compound of the present invention or a pharmaceutically acceptable salt thereof Provided.
본 발명의 다른 일 구현예에 따르면, 본 발명의 화합물 또는 이의 약학적으로 허용가능한 염을 함유하는 것을 특징으로 하는 치매, 알츠하이머병, 파킨슨병, 헌팅턴병, 간질, 기억력 감퇴, 또는 허혈성 뇌졸중을 치료 또는 예방하기 위한 약제학적 조성물이 제공된다.According to another embodiment of the present invention, treatment or treatment of dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, memory loss, or ischemic stroke characterized by containing the compound of the present invention or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for preventing is provided.
본 발명의 또 다른 일 구현예에 따르면, 본 발명의 화합물 또는 이의 약학적으로 허용가능한 염을 함유하는 것을 특징으로 하는 말초 신경 손상, 척수 손상, 시신경 손상, 근위축성 축색 경화증, 운동 실조, 또는 말초 신경 질환을 치료 또는 예방하기 위한 약제학적 조성물이 제공된다.According to another embodiment of the present invention, peripheral nerve damage, spinal cord injury, optic nerve damage, amyotrophic axonal sclerosis, ataxia, or peripheral nerve damage characterized by containing the compound of the present invention or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for treating or preventing a neurological disorder is provided.
본 발명의 또 다른 일 구현예에 따르면, 본 발명의 화합물 또는 이의 약학적으로 허용가능한 염을 함유하는 것을 특징으로 하는 뇌 신경 발달 장애를 치료 또는 예방하기 위한 약제학적 조성물이 제공된다.According to another embodiment of the present invention, there is provided a pharmaceutical composition for treating or preventing brain neurodevelopmental disorders comprising the compound of the present invention or a pharmaceutically acceptable salt thereof.
본 발명의 약제학적 조성물에서, 본 발명에 따른 화학식 1의 화합물은 약학적으로 허용 가능한 염의 형태로 사용될 수 있다. 상기 "약학적으로 허용 가능한 염"은 모 화합물의 약물학적 활성을 유지하는 화합물 염을 의미하는 것으로서, 예를 들어 (i) 염산, 브롬화수소산, 황산, 질산, 및 인산과 같은 무기산과 형성된 염; (ii) 아세트산, 프로피온산, 이소부티르산, 글리콜산, 락트산, 피루브산, 말론산, 석신산, 글루타르산, 푸마르산, 말산, 타르타르산, 시트르산, 아스코르빈산, 팔미트산, 말레인산, 하이드록시말레인산, 벤조산, 하이드록시벤조산, 페닐아세트산, 신남산, 살리실산, 메탄설폰산, 벤젠설폰산 및 톨루엔설폰산과 같은 유기산과 형성되는 염; (iii) 모 화합물에 존재하는 산성 프로톤이 금속 이온, 예를 들어 알칼리 금속 이온, 알칼리 토금속 이온, 또는 알루미늄 이온에 의해 교체될 때 형성되는 염; (iv) 에탄올아민, 디에탄올아민, 트리에탄올아민, N-메틸글루카민과 같은 유기 염기와의 배위체; 또는 (v) 알기네이트와 같은 아미노산의 염일 수 있다.In the pharmaceutical composition of the present invention, the compound of Formula 1 according to the present invention may be used in the form of a pharmaceutically acceptable salt. The "pharmaceutically acceptable salt" refers to a compound salt that retains the pharmacological activity of the parent compound, and includes, for example, (i) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; (ii) acetic acid, propionic acid, isobutyric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid , salts formed with organic acids such as hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid; (iii) salts formed when acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth metal ions, or aluminum ions; (iv) coordination with organic bases such as ethanolamine, diethanolamine, triethanolamine and N-methylglucamine; or (v) a salt of an amino acid such as an alginate.
또한, 본 발명의 약제학적 조성물은 본 발명의 상기 화학식 1의 화합물의 이성질체, 용매화물, 또는 프로드러그(prodrug)을 함유할 수 있다. 여기서 "이성질체"는 디아스테레오머 및 에난티오머를 비롯한 모든 가능한 입체화학적 이성질체를 포함한다. 본 발명의 화합물은 모든 가능한 입체화학적 이성질체 형태의 혼합물을 지칭하는 것으로 이해하여야 한다. 또한, 용어 "용매화물"은 용질 (예를 들어 화학식 1의 화합물)과 용매의 복합체를 가리키는 것으로서, 용매가 물인 경우 상기 용매화물은 수화물로 지칭될 수 있다. 용어 "프로드러그"는 생체내에 투여된 후에 생체 흡수 및 대사에 의하여 약효를 갖는 활성 화합물로 변환되는 화합물을 가리킨다. 상기 프로드러그는 그 자체로 비활성이거나 활성 화합물보다 활성이 덜한 화합물이며, 다만, 취급, 투여, 또는 대사에 유리한 특성을 제공할 수 있다. 상기 프로드러그는 활성 화합물의 에스테르 형태 (예를 들어, 생리학적으로 허용 가능한 대사적으로 불안정한 에스테르)이거나 당 유도체의 형태, 또는 아미노산 에스테르 유도체의 형태일 수 있다.In addition, the pharmaceutical composition of the present invention may contain an isomer, solvate, or prodrug of the compound represented by Formula 1 of the present invention. "Isomer" herein includes all possible stereochemical isomers, including diastereomers and enantiomers. It is to be understood that the compounds of the present invention refer to mixtures of all possible stereochemically isomeric forms. Also, the term “solvate” refers to a complex of a solute (eg, a compound of Formula 1) and a solvent, and when the solvent is water, the solvate may be referred to as a hydrate. The term "prodrug" refers to a compound that is converted into an active compound having a medicinal effect by absorption and metabolism after being administered in vivo. The prodrug is a compound that is itself inactive or less active than the active compound, but may provide properties that are advantageous for handling, administration, or metabolism. The prodrug may be in the form of an ester of the active compound (eg, a physiologically acceptable metabolically labile ester) or a form of a sugar derivative or an amino acid ester derivative.
본 발명의 약제학적 조성물은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 단독으로 포함할 수 있으나, 그에 추가하여 약학적으로 허용 가능한 담체를 추가로 더 포함할 수도 있다. 상기 약학적으로 허용 가능한 담체는 약제학 분야에서 통상적으로 사용되는 것일 수 있으며, 부형제 (예를 들어, 전분, 칼슘 카보네이트, 수크로스, 락토스, 소르비톨, 만니톨, 셀룰로오스 등) 또는 희석제 (예를 들어, 생리식염수, 정제수 등)일 수 있다. The pharmaceutical composition of the present invention may include the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof alone, but may further include a pharmaceutically acceptable carrier in addition thereto. The pharmaceutically acceptable carrier may be one commonly used in the pharmaceutical field, and may include an excipient (eg, starch, calcium carbonate, sucrose, lactose, sorbitol, mannitol, cellulose, etc.) or a diluent (eg, physiological saline, purified water, etc.).
또한, 필요에 따라, 본 발명의 약제학적 조성물은 상기 약학적으로 허용 가능한 담체 이외의 약학적으로 허용 가능한 첨가제, 예를 들어, 결합제, 붕해제, 활택제, 제피제, 필름 코팅 기제, 장용성 필름 코팅 기제, 연질 캡슐 기제, 용해보조제, 유화제, 현탁화제, 안정화제, 완충제, 항산화제, 계면활성제, 감미제, 교미제, 보존제, 점증제, 방향제, 또는 착색제를 더 포함할 수도 있다.In addition, if necessary, the pharmaceutical composition of the present invention, pharmaceutically acceptable additives other than the above pharmaceutically acceptable carrier, for example, binders, disintegrants, lubricants, peeling agents, film coating bases, enteric films It may further contain a coating agent, a soft capsule agent, a dissolution aid, an emulsifier, a suspending agent, a stabilizer, a buffer, an antioxidant, a surfactant, a sweetening agent, a flavoring agent, a preservative, a thickening agent, a flavoring agent, or a coloring agent.
본 발명의 약제학적 조성물은 경구 또는 비경구로 투여할 수 있다. 비경구의 경우에는 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 내피 투여, 국소 투여, 비강내 투여, 폐내 투여, 및 직장내 투여 등으로 투여할 수 있다. 경구 투여시, 본 발명의 약제학적 조성물은 고체 또는 액제 제형의 형태로 제형화될 수 있다. 고체 제형은 예를 들어, 정제, 캡슐제(연질 & 경질 캡슐제), 산제, 과립제, 환제, 트로키제 등일 수 있으며, 액체 제형은 예를 들어, 엘릭서, 현탁액제, 유액제, 용액제, 시럽제, 리모나아데제 등의 형태일 수 있다. 정제의 경우, 활성 성분 이외에도, 락토스, 옥수수 전분 등과 같은 담체, 마그네슘 스테아레이트 등과 같은 활택제, 메틸셀룰로오스, 미결정 셀룰로오스, 폴리비닐알코올 등과 같은 결합제, 벤토나이트, 알긴산나트륨 등과 같은 붕해제 등이 통상적으로 추가될 수 있다. 액제의 경우, 활성 성분을 정제수, 생리식염수 등과 같은 담체, 및 필요에 따라 모노스테아린산수크로스 등과 같은 용해보조제, 폴리비닐피롤리돈 등과 같은 안정화제 등과 함께 제제화할 수 있으며, 경구용 수성 현탁액제의 경우, 활성 성분을 현탁화제, 및 필요에 따라 계면활성제, 보존제, 안정화제 등과 함께 제제화할 수 있다.The pharmaceutical composition of the present invention may be administered orally or parenterally. In the case of parenteral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intradermal administration, topical administration, intranasal administration, intrapulmonary administration, and intrarectal administration may be used. For oral administration, the pharmaceutical composition of the present invention may be formulated in the form of a solid or liquid dosage form. Solid formulations may be, for example, tablets, capsules (soft & hard capsules), powders, granules, pills, troches, etc., and liquid formulations may be, for example, elixirs, suspensions, emulsions, solutions, syrups , rimona dese, etc. may be in the form. In the case of tablets, in addition to the active ingredient, carriers such as lactose and corn starch, lubricants such as magnesium stearate, binders such as methylcellulose, microcrystalline cellulose, and polyvinyl alcohol, and disintegrants such as bentonite and sodium alginate are usually added. It can be. In the case of a liquid formulation, the active ingredient may be formulated with a carrier such as purified water, physiological saline, and the like, and, if necessary, a solubilizing agent such as sucrose monostearate, a stabilizer such as polyvinylpyrrolidone, and the like. In some cases, the active ingredient may be formulated with a suspending agent and, if necessary, a surfactant, a preservative, a stabilizer, and the like.
본 발명의 약제학적 조성물의 투여량은 투여방법, 복용자의 연령, 성별, 환자의 중증도, 상태, 불활성율, 및 병용되는 약물을 고려하여 결정할 수 있으며, 1회 또는 수회로 나누어 투여할 수 있다. The dosage of the pharmaceutical composition of the present invention can be determined in consideration of the administration method, the age and sex of the user, the severity of the patient, the condition, inactivity rate, and concomitant drugs, and can be administered once or divided into several times.
이하, 본 발명의 상세한 이해를 위하여 본 발명의 대표 화합물을 들어, 본 발명에 따른 화합물, 이의 제조 방법, 및 이를 함유하는 약제학적 조성물의 특성에 대해서 설명하기로 한다. 단, 본 발명이 다음의 실시예에 의해 한정되는 것은 아니다.Hereinafter, for a detailed understanding of the present invention, representative compounds of the present invention will be described for the properties of the compounds according to the present invention, methods for their preparation, and pharmaceutical compositions containing them. However, the present invention is not limited by the following examples.
실시예Example
도 1을 참조하여, 본 발명의 실시예를 상세하게 설명하기로 한다.Referring to Figure 1, an embodiment of the present invention will be described in detail.
1) 화합물 A의 합성1) Synthesis of Compound A
Figure PCTKR2022016040-appb-img-000013
Figure PCTKR2022016040-appb-img-000013
화합물 a 및 화합물 b, K2CO3 및 아세토니트릴(acetonitrile)을 혼합하여 교반하여 화합물 c를 수득하였다. 그런 다음, 수득된 화합물 c를 TFA(trifluoroacetic acid) 및 클로로포름(chloroform, CHCHl3)을 혼합하여 화합물 d를 수득하였다. 상기 수득된 화합물 d에 하이드라진(hydrazine)과 반응시켜, 아민기를 포함하는 화합물 A를 수득하였다.Compound a and compound b, K 2 CO 3 and acetonitrile were mixed and stirred to obtain compound c. Then, compound d was obtained by mixing the obtained compound c with trifluoroacetic acid (TFA) and chloroform (CHCHl 3 ). Compound A containing an amine group was obtained by reacting the obtained compound d with hydrazine.
2) 화합물 B의 합성2) Synthesis of Compound B
Figure PCTKR2022016040-appb-img-000014
Figure PCTKR2022016040-appb-img-000014
All trans retinoic acid (4 g, 13.31 mmol)를 90 ml의 THF에 녹인 후 DCC(4.12 g, 19.97 mmol)를 첨가하여 30분간 교반하였다. 30 ml의 THF에 녹인 N-하이 드록시숙신이미드(NHS)(2.30 g, 19.97 mmol) 용액을 4℃에서 적가한 후 상온에서 18시간 반응시켰다. 생성된 고체를 여과한 후 용매를 제거하고, 디클로로메탄(DCM)에 다시 녹여 실리카겔 칼럼에 통과시켜 화합물 B를 정제하여 얻었다. 수율은 4.6 g (87.0 %)이다.After dissolving all trans retinoic acid (4 g, 13.31 mmol) in 90 ml of THF, DCC (4.12 g, 19.97 mmol) was added and stirred for 30 minutes. A solution of N-hydroxysuccinimide (NHS) (2.30 g, 19.97 mmol) dissolved in 30 ml of THF was added dropwise at 4°C, followed by reaction at room temperature for 18 hours. After filtering the resulting solid, the solvent was removed, dissolved again in dichloromethane (DCM), and passed through a silica gel column to obtain compound B to be purified. The yield is 4.6 g (87.0%).
3) 본 발명의 화합물 MBP-11903의 합성3) Synthesis of MBP-11903, the compound of the present invention
Figure PCTKR2022016040-appb-img-000015
Figure PCTKR2022016040-appb-img-000015
상기에서 얻은 화합물 A 및 화합물 B를 반응시킨 후, 금속원자를 배위시키는 과정을 수행하여, 본 발명의 일 실시예 따라 제조된 화합물인 MBP-11903B을 얻었다.After reacting compound A and compound B obtained above, a process of coordinating metal atoms was performed to obtain MBP-11903B, a compound prepared according to an embodiment of the present invention.
상기에서는 본 발명의 바람직한 실시예를 참조하여 설명하였지만, 해당 기술 분야의 숙련된 당업자는 하기의 특허 청구 범위에 기재된 본 발명의 사상 및 영역으로부터 벗어나지 않는 범위 내에서 본 발명을 다양하게 수정 및 변경시킬 수 있음을 이해할 수 있을 것이다.Although the above has been described with reference to preferred embodiments of the present invention, those skilled in the art can variously modify and change the present invention without departing from the spirit and scope of the present invention described in the claims below. You will understand that you can.

Claims (7)

  1. 하기 화학식 1으로 표시되는 화합물:A compound represented by Formula 1 below:
    [화학식 1][Formula 1]
    Figure PCTKR2022016040-appb-img-000016
    Figure PCTKR2022016040-appb-img-000016
    상기 화학식 1에서,In Formula 1,
    M은 Gd3+, Mg2+ 및 Ca2+ 중에서 선택된 어느 하나이며,M is any one selected from Gd 3+ , Mg 2+ and Ca 2+ ;
    A는 *-(CH2)n-NH-*(여기서, n은 0 내지 5인 정수)를 나타내고,A represents *-(CH 2 ) n -NH-* (where n is an integer from 0 to 5);
    B는 레티노산(retinoic acid)에서 유래된 부분을 나타낸다.B represents a part derived from retinoic acid.
  2. 제1항에 있어서, According to claim 1,
    상기 화학식 1에서,In Formula 1,
    상기 B는 하기 화학식 2a, 2b, 또는 2c를 나타내는 것을 특징으로 하는 화합물:A compound characterized in that B represents Formula 2a, 2b, or 2c:
    [화학식 2a][Formula 2a]
    Figure PCTKR2022016040-appb-img-000017
    Figure PCTKR2022016040-appb-img-000017
    [화학식 2b][Formula 2b]
    Figure PCTKR2022016040-appb-img-000018
    Figure PCTKR2022016040-appb-img-000018
    [화학식 2c][Formula 2c]
    Figure PCTKR2022016040-appb-img-000019
    Figure PCTKR2022016040-appb-img-000019
  3. 제2항에 있어서, According to claim 2,
    상기 화합물은 하기 화학식 3으로 표시되는 것을 특징으로 하는 화합물:A compound characterized in that the compound is represented by the following formula (3):
    [화학식 3][Formula 3]
    Figure PCTKR2022016040-appb-img-000020
    Figure PCTKR2022016040-appb-img-000020
    상기 화학식 3에서,In Formula 3,
    M은 Gd3+, Mg2+ 및 Ca2+ 중에서 선택된 어느 하나이다.M is any one selected from Gd 3+ , Mg 2+ and Ca 2+ .
  4. 제1항에 따른 화합물 또는 이의 약학적으로 허용 가능한 염을 함유하는 것을 특징으로 하는 뇌 신경 손상, 퇴행성 뇌질환, 허혈성 뇌질환, 치매, 알츠하이머병, 파킨슨병, 헌팅턴병, 간질, 기억력 감퇴, 또는 허혈성 뇌졸중, 말초 신경 손상, 척 수 손상, 시신경 손상, 근위축성 축색 경화증, 운동 실조, 또는 말초 신경 질환 또 는, 뇌 신경 발달 장애를 치료 또는 예방하기 위한, 약제학적 조성물.Cranial nerve damage, degenerative brain disease, ischemic brain disease, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, memory loss, or ischemic disease characterized by containing the compound according to claim 1 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for treating or preventing stroke, peripheral nerve injury, spinal cord injury, optic nerve injury, amyotrophic axonal sclerosis, ataxia, or peripheral nerve disease or cranial nerve development disorder.
  5. 하기 화학식 4-1으로 표시되는 화합물과 하기 화학식 4-2로 표시되는 화합물을 결합시켜 하기 화학식 4-3으로 표시되는 화합물을 제조하는 제1 단계를 포함하는 것을 특징으로 하는, 화합물의 제조방법:A method for preparing a compound comprising a first step of preparing a compound represented by the following Chemical Formula 4-3 by combining a compound represented by the following Chemical Formula 4-1 with a compound represented by the following Chemical Formula 4-2:
    [화학식 4-1][Formula 4-1]
    Figure PCTKR2022016040-appb-img-000021
    Figure PCTKR2022016040-appb-img-000021
    화학식 4-1에서,In Formula 4-1,
    A는 *-(CH2)n-NH 를 나타낸다.A represents *-(CH 2 ) n -NH .
    [화학식 4-2][Formula 4-2]
    Figure PCTKR2022016040-appb-img-000022
    Figure PCTKR2022016040-appb-img-000022
    화학식 4-2에서, B는 레티노산(retinoic acid)에서 유래된 부분을 나타낸다.In Formula 4-2, B represents a moiety derived from retinoic acid.
    [화학식 4-3][Formula 4-3]
    Figure PCTKR2022016040-appb-img-000023
    Figure PCTKR2022016040-appb-img-000023
    화학식 4-3에서, In Formula 4-3,
    A는 *-(CH2)n-NH-*(여기서, n은 0 내지 5인 정수)를 나타내고, A represents *-(CH 2 ) n -NH-* (where n is an integer from 0 to 5);
    B는 레티노산(retinoic acid)에서 유래된 부분을 나타낸다.B represents a part derived from retinoic acid.
  6. 제5항에 있어서,According to claim 5,
    상기 제1 단계 이후, 화학식 4-3으로 표시되는 화합물에 금속원소를 배위결합시켜 하기 화학식 1으로 표시되는 화합물을 제조하는 제2 단계를 추가로 더 포함하는 것을 특징으로 하는, 화합물의 제조방법:After the first step, a method for preparing a compound further comprising a second step of preparing a compound represented by the following Chemical Formula 1 by coordinating a metal element with a compound represented by Chemical Formula 4-3:
    [화학식 1][Formula 1]
    Figure PCTKR2022016040-appb-img-000024
    Figure PCTKR2022016040-appb-img-000024
    상기 화학식 1에서,In Formula 1,
    M은 Gd3+, Mg2+ 및 Ca2+ 중에서 선택된 어느 하나이며,M is any one selected from Gd 3+ , Mg 2+ and Ca 2+ ;
    A는 *-(CH2)n-NH-*(여기서, n은 0 내지 5인 정수)를 나타내고,A represents *-(CH 2 ) n -NH-* (where n is an integer from 0 to 5);
    B는 레티노산(retinoic acid)에서 유래된 부분을 나타낸다.B represents a part derived from retinoic acid.
  7. 제5항에 있어서, According to claim 5,
    상기 화학식 4-2에서,In Formula 4-2,
    상기 B는 하기 화학식 2a, 2b, 또는 2c를 나타내는 것을 특징으로 하는,Characterized in that B represents the following formula 2a, 2b, or 2c,
    화합물의 제조방법:Method for preparing the compound:
    [화학식 2a][Formula 2a]
    Figure PCTKR2022016040-appb-img-000025
    Figure PCTKR2022016040-appb-img-000025
    [화학식 2b][Formula 2b]
    Figure PCTKR2022016040-appb-img-000026
    Figure PCTKR2022016040-appb-img-000026
    [화학식 2c][Formula 2c]
    Figure PCTKR2022016040-appb-img-000027
    Figure PCTKR2022016040-appb-img-000027
PCT/KR2022/016040 2021-12-10 2022-10-20 Novel compound, preparation method therefor, and pharmaceutical composition for treating or preventing neural damage, neural disease, or developmental disorder through proliferation promotion, differentiation, and/or regeneration of neural cells, containing same WO2023106616A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20210176264 2021-12-10
KR10-2021-0176264 2021-12-10

Publications (1)

Publication Number Publication Date
WO2023106616A1 true WO2023106616A1 (en) 2023-06-15

Family

ID=86730637

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2022/016040 WO2023106616A1 (en) 2021-12-10 2022-10-20 Novel compound, preparation method therefor, and pharmaceutical composition for treating or preventing neural damage, neural disease, or developmental disorder through proliferation promotion, differentiation, and/or regeneration of neural cells, containing same

Country Status (2)

Country Link
KR (1) KR20230088268A (en)
WO (1) WO2023106616A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100322855A1 (en) * 2008-02-22 2010-12-23 Illinois Institute Of Technology Bimodal ligands with macrocyclic and acyclic binding moieties, complexes and compositions thereof, and methods of using
JP2012504131A (en) * 2008-09-30 2012-02-16 マリンクロッド エルエルシー Conjugates of hexoses and metal coordination bonds for imaging purposes
KR20180081558A (en) * 2015-11-06 2018-07-16 위스콘신 얼럼나이 리서어치 화운데이션 Long-term - sustained gadolinium-based tumor targeting imaging and therapeutic agents
WO2021150052A1 (en) * 2020-01-22 2021-07-29 경북대학교 산학협력단 Novel gadolinium-based compound, preparation method therefor, and mri contrast agent containing same
WO2021150049A1 (en) * 2020-01-22 2021-07-29 경북대학교 산학협력단 Novel gadolinium-based compound, method for producing same, and mri contrast agent containing same
WO2021251551A1 (en) * 2020-06-12 2021-12-16 (주)미래바이오팜 Novel compound and pharmaceutical composition containing same for treating or preventing neural damage, neural disease, or developmental disorder through promoting proliferation, differentiation, and/or regeneration of neural cells

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100322855A1 (en) * 2008-02-22 2010-12-23 Illinois Institute Of Technology Bimodal ligands with macrocyclic and acyclic binding moieties, complexes and compositions thereof, and methods of using
JP2012504131A (en) * 2008-09-30 2012-02-16 マリンクロッド エルエルシー Conjugates of hexoses and metal coordination bonds for imaging purposes
KR20180081558A (en) * 2015-11-06 2018-07-16 위스콘신 얼럼나이 리서어치 화운데이션 Long-term - sustained gadolinium-based tumor targeting imaging and therapeutic agents
WO2021150052A1 (en) * 2020-01-22 2021-07-29 경북대학교 산학협력단 Novel gadolinium-based compound, preparation method therefor, and mri contrast agent containing same
WO2021150049A1 (en) * 2020-01-22 2021-07-29 경북대학교 산학협력단 Novel gadolinium-based compound, method for producing same, and mri contrast agent containing same
WO2021251551A1 (en) * 2020-06-12 2021-12-16 (주)미래바이오팜 Novel compound and pharmaceutical composition containing same for treating or preventing neural damage, neural disease, or developmental disorder through promoting proliferation, differentiation, and/or regeneration of neural cells

Also Published As

Publication number Publication date
KR20230088268A (en) 2023-06-19

Similar Documents

Publication Publication Date Title
CN101031572B (en) (R/S) rifamycin derivatives, their preparation and pharmaceutical compositions
DE3843609A1 (en) ADENOSINE DERIVATIVES
AU703634B2 (en) Novel crystalline forms of anhydrous 7-{(1alpha,5alpha, 6alpha)-6-amino-3-azabicyclo(3.1.0)hex-3-y1}-6-fluoro-1- (2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3- carboxylic acid, methanesulfonic acid salt.
WO2011008054A2 (en) Butyric acid salt of n,n-dimethyl imidocarbon imidic diamide, method of preparing same, and pharmaceutical compositions and combinations containing same
WO2020067735A1 (en) 3-azabicyclo[3,1,1]heptane derivative and pharmaceutical composition comprising same
CH671958A5 (en)
WO2023106616A1 (en) Novel compound, preparation method therefor, and pharmaceutical composition for treating or preventing neural damage, neural disease, or developmental disorder through proliferation promotion, differentiation, and/or regeneration of neural cells, containing same
EP0413191B1 (en) 1-(Pyridinylamino)-2-pyrrolidinones, a process for their preparation and their use as medicaments
WO1999037609A1 (en) Novel naphthyl-substituted and anilide-substituted sulfonamides
CN110278711B (en) Tricyclosulfones as rory modulators
KR910009934B1 (en) Carbamoyl-2-pyrrolidinone compounds
WO2010151008A2 (en) Piperazine dithioctate and pharmaceutical composition comprising the same
WO2021251551A1 (en) Novel compound and pharmaceutical composition containing same for treating or preventing neural damage, neural disease, or developmental disorder through promoting proliferation, differentiation, and/or regeneration of neural cells
WO2022158868A1 (en) Uses of melanocortin-4 receptor agonist
WO2012008711A2 (en) Erlotinib dichloroacetate and anti-cancer agent comprising the same
WO2023106883A1 (en) Novel compound, method for producing same, and pharmaceutical composition containing same for treating or preventing nerve damage, neurological disease, or developmental disorder through proliferation promotion, differentiation, and/or regeneration of nerve cells
EP0532553B1 (en) Use of compounds for the treatment of age-related memory impairment and other cognitive disorders
WO2020171507A1 (en) Monomethyl fumarate derivatives and pharmaceutical compositions using same
WO2020159228A1 (en) Monomethyl fumarate precursor drug compounds and pharmaceutical compositions thereof
JPS63203691A (en) Pyperadine carboxylic acid, its production and pharmaceutical composition containing the same
AU704115B2 (en) Zwitterionic forms of trovafloxacin
WO2018062837A1 (en) Chalcone derivative compound, optical isomer thereof, or pharmaceutically acceptable salt thereof, and pharmaceutical composition comprising same as effective ingredient for preventing or treating disease caused by reduction in mitochondrial oxygen consumption rate
EP4004013A1 (en) Dinucleotide compounds for treating cancers and medical uses thereof
CA2379370A1 (en) Carboxylic acid derivatives of 3-hydroxy-4-oxo-1,4-dihydropyridine as iron chelators
AU755088B2 (en) Imidazo-containing heterocyclic compounds, their compositions and uses

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22904450

Country of ref document: EP

Kind code of ref document: A1