WO2024071594A1 - Composition comprising quinazoline salt compound for treatment of arthritis and preparation method therefor - Google Patents

Composition comprising quinazoline salt compound for treatment of arthritis and preparation method therefor Download PDF

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WO2024071594A1
WO2024071594A1 PCT/KR2023/009149 KR2023009149W WO2024071594A1 WO 2024071594 A1 WO2024071594 A1 WO 2024071594A1 KR 2023009149 W KR2023009149 W KR 2023009149W WO 2024071594 A1 WO2024071594 A1 WO 2024071594A1
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composition
treating arthritis
optionally substituted
arthritis
present application
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PCT/KR2023/009149
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French (fr)
Korean (ko)
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이인현
손민희
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주식회사 베노바이오
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present application relates to a composition for treating arthritis containing a quinazoline salt compound and a method for producing the same.
  • Arthritis is an inflammatory disease of the joints, and the diseases with the largest number of cases are chronic rheumatoid arthritis and deforming arthrosis (osteoarthrosis).
  • Chronic joint rheumatism is thought to be an autoimmune disease, and is accompanied by symptoms of joint pain, stiffness, and swelling. However, as the condition progresses, it often leads to degeneration of the articular cartilage surface, such as deforming arthrosis, and eventually severe destruction of the joint bone and cartilage. happens.
  • Arthropathy deformity is a degenerative disease of the articular cartilage that frequently occurs in elderly people.
  • Osteoarthritis is a disease that causes destruction of cartilage and proliferative changes in bone or cartilage due to degenerative degeneration of joint components, and these changes can also cause secondary arthritis (e.g. , synovitis).
  • Degenerative arthrosis occurs frequently in load joints such as the knee joint, elbow joint, and hip joint, and is also confirmed to occur in non-load joints such as the shoulder joint, elbow joint, and hand joint.
  • temporomandibular arthropathy which presents the same condition in the temporomandibular joint, is known.
  • Republic of Korea Patent No. 10-1207155 relates to a treatment or prevention agent for arthritis.
  • the patent discloses a treatment for arthritis containing C-type natriuretic peptide (CNP) or a derivative thereof as an active ingredient, but does not mention a composition for the treatment of arthritis containing a quinazoline salt compound.
  • CNP C-type natriuretic peptide
  • the present application aims to solve the problems of the prior art described above and to provide a composition for treating arthritis containing a quinazoline salt compound.
  • the object is to provide a method for producing the composition for treating arthritis.
  • Another object is to provide an intra-articular injection containing the composition for treating arthritis.
  • the first aspect of the present application provides a composition for treating arthritis, comprising a quinazoline salt compound represented by the following formula (1):
  • A is HCl, HClO 3 , H 2 SO 4 , HNO 3 , HI or HBr,
  • R 1 , R 2 , and R 3 are each independently optionally substituted linear or branched C 1 -C 12 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 Aryl, or alkoxy,
  • substitution is by oxygen, nitrogen, sulfur, linear or branched C 1 -C 6 alkyl, C 6 -C 20 aryl, halogen, alkoxy, trimethylsilyl, ether, or a combination thereof) .
  • the quinazoline salt may include the following compounds, but is not limited thereto:
  • the arthritis may include, but is not limited to, degenerative arthritis.
  • the second aspect of the present application includes preparing a quinazoline derivative by reacting an aromatic aldehyde and a carbamate; and reacting the quinazoline derivative with an acid to produce a quinazoline salt.
  • the aromatic aldehyde may include, but is not limited to, 4-hydroxy-3,5-dimethyl benzaldehyde.
  • the carbamate may include Tert-Butyl N-(2-bromoethyl)carbamate, but is limited thereto. That is not the case.
  • the quinazoline derivative may include a compound represented by the following formula (2), but is not limited thereto:
  • R 1 , R 2 , and R 3 are each independently optionally substituted linear or branched C 1 -C 12 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 Aryl, or alkoxy,
  • substitution is by oxygen, nitrogen, sulfur, linear or branched C 1 -C 6 alkyl, C 6 -C 20 aryl, halogen, alkoxy, trimethylsilyl, ether, or a combination thereof) .
  • the acid may include, but is not limited to, one selected from the group consisting of HCl, HClO 3 , H 2 SO 4 , HNO 3 , HI, HBr, and combinations thereof.
  • the quinazoline salt may include a compound represented by the following formula (3), but is not limited thereto:
  • A is HCl, HClO 3 , H 2 SO 4 , HNO 3 , HI or HBr,
  • R 1 , R 2 , and R 3 are each independently optionally substituted linear or branched C 1 -C 12 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 Aryl, or alkoxy,
  • substitution is by oxygen, nitrogen, sulfur, linear or branched C 1 -C 6 alkyl, C 6 -C 20 aryl, halogen, alkoxy, trimethylsilyl, ether, or a combination thereof) .
  • the quinazoline salt may include the following compounds, but is not limited thereto:
  • a third aspect of the present application provides an intra-articular injection comprising the composition for treating arthritis according to the first aspect of the present application.
  • the composition for treating arthritis includes a quinazoline salt compound, a substance that has not previously been reported for use in treating inflammation.
  • the composition for treating arthritis may have an effect of suppressing osteoarthritis by reducing the expression of genes that cause osteoarthritis, and may be particularly effective in treating degenerative arthritis.
  • FIG. 1 is a flowchart of a method for producing a composition for treating arthritis according to an embodiment of the present application.
  • Figure 2 shows NMR results of a quinazoline salt compound prepared according to an example of the present application.
  • Figure 3 shows LC-MS results of a quinazoline salt compound prepared according to an example of the present application.
  • Figure 4 shows the results of PCR performed to confirm the anti-inflammatory effect of a composition for treating arthritis according to an experimental example herein.
  • Figure 5 shows the results of qRT-PCR performed to confirm the anti-inflammatory effect of a composition for treating arthritis according to an experimental example herein.
  • Figure 6 shows the results of a Western blot performed to confirm the anti-inflammatory effect of a composition for treating arthritis according to an experimental example herein.
  • Figure 7 shows the results of Safranin-O staining according to an experimental example herein.
  • FIG 8 shows the results of the histopathological evaluation method proposed by OARSI (Osteoarthritis Research Society International) according to an experimental example of the present institute.
  • Figure 9 shows the results of confirming the change in SBP thickness according to an experimental example herein.
  • the term "combination thereof" included in the Markushi format expression means a mixture or combination of one or more components selected from the group consisting of the components described in the Markushi format expression, It means including one or more selected from the group consisting of.
  • the first aspect of the present application provides a composition for treating arthritis, comprising a quinazoline salt compound represented by the following formula (1):
  • A is HCl, HClO 3 , H 2 SO 4 , HNO 3 , HI or HBr,
  • R 1 , R 2 , and R 3 are each independently optionally substituted linear or branched C 1 -C 12 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 Aryl, or alkoxy,
  • substitution is by oxygen, nitrogen, sulfur, linear or branched C 1 -C 6 alkyl, C 6 -C 20 aryl, halogen, alkoxy, trimethylsilyl, ether, or a combination thereof) .
  • the composition for treating arthritis includes a quinazoline salt compound, a substance that has not previously been reported for use in treating inflammation.
  • the composition for treating arthritis may have an effect of suppressing osteoarthritis by reducing the expression of genes that cause osteoarthritis, and may be particularly effective in treating degenerative arthritis.
  • the quinazoline salt may include the following compounds, but is not limited thereto:
  • the compound is 2-[4-[2-(dimethylamino)ethoxy]-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one, dihydrochloride [2- [4-[2-(dimethylamino)ethoxy]-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one, dihydrochloride], which has not been previously used as a composition for treating arthritis. material, and the inventors of the present application discovered a novel use of the quinazoline salt compound as a composition for treating arthritis.
  • the arthritis may include, but is not limited to, degenerative arthritis.
  • the second aspect of the present application includes preparing a quinazoline derivative by reacting an aromatic aldehyde and a carbamate; and reacting the quinazoline derivative with an acid to produce a quinazoline salt.
  • FIG. 1 is a flowchart of a method for producing a composition for treating arthritis according to an embodiment of the present application.
  • a quinazoline derivative is prepared by reacting aromatic aldehyde and carbamate (S100).
  • the aromatic aldehyde may include, but is not limited to, 4-hydroxy-3,5-dimethyl benzaldehyde.
  • the carbamate may include Tert-Butyl N-(2-bromoethyl)carbamate, but is limited thereto. That is not the case.
  • the quinazoline derivative may include a compound represented by the following formula (2), but is not limited thereto:
  • R 1 , R 2 , and R 3 are each independently optionally substituted linear or branched C 1 -C 12 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 Aryl, or alkoxy,
  • substitution is by oxygen, nitrogen, sulfur, linear or branched C 1 -C 6 alkyl, C 6 -C 20 aryl, halogen, alkoxy, trimethylsilyl, ether, or a combination thereof) .
  • the quinazoline derivative may include, but is not limited to, the one represented by Compound 1 below:
  • the protecting group Boc group (tert-butylcarbonyl group) is a material selected from the group consisting of trifluoroacetic acid (TFA), hydrochloric acid, hydrogen chloride, trimethylsilyl iodide, aluminum chloride, and combinations thereof. It may be deprotected and substituted with hydrogen and have an amine group at the end, but is not limited thereto.
  • Compound 1 whose terminal is substituted with an amine group may include, but is not limited to, Compound 2 below.
  • the hydrogen of the amine group may be replaced with an alkyl group by a substance that acts as a strong reducing agent such as formaldehyde, sodium borohydride, etc., but is not limited thereto.
  • a substance that acts as a strong reducing agent such as formaldehyde, sodium borohydride, etc.
  • the compound in which the hydrogen of the amine group of Compound 2 is replaced with an alkyl group may include, but is not limited to, Compound 3 below.
  • the acid may include, but is not limited to, one selected from the group consisting of HCl, HClO 3 , H 2 SO 4 , HNO 3 , HI, HBr, and combinations thereof.
  • the quinazoline salt may include a compound represented by the following formula (3), but is not limited thereto:
  • A is HCl, HClO 3 , H 2 SO 4 , HNO 3 , HI or HBr,
  • R 1 , R 2 , and R 3 are each independently optionally substituted linear or branched C 1 -C 12 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 Aryl, or alkoxy,
  • substitution is by oxygen, nitrogen, sulfur, linear or branched C 1 -C 6 alkyl, C 6 -C 20 aryl, halogen, alkoxy, trimethylsilyl, ether, or a combination thereof) .
  • the quinazoline salt may include the following compounds, but is not limited thereto:
  • a third aspect of the present application provides an intra-articular injection comprising the composition for treating arthritis according to the first aspect of the present application.
  • An intra-articular injection containing the composition for treating arthritis according to the present application may be administered into the joint space to reduce the expression of genes that cause osteoarthritis and thereby have an effect of suppressing osteoarthritis.
  • the prepared quinazoline salt compound was confirmed by NMR, and its purity was confirmed by LC-MS.
  • Figure 2 shows NMR results of a quinazoline salt compound prepared according to an example of the present application.
  • Figure 3 shows LC-MS results of a quinazoline salt compound prepared according to an example of the present application.
  • the quinazoline salt compound according to an example of the present application was actually produced.
  • the prepared quinazoline salt compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a composition for treating arthritis. Manufactured.
  • DMSO dimethyl sulfoxide
  • JQ-1 which is used as a BET (Bromodomain and extra terminal containing protein) inhibitor, was used.
  • cartilage cells were isolated from mouse joints using collagenase.
  • the separated chondrocytes were cultured in FBS/DMEM medium for 3 days and treated with interleukin 1-beta (IL-1 ⁇ ) to induce inflammation, and then the composition for treating arthritis of the examples was added at different concentrations (0 ⁇ M to 20 ⁇ M). ) was treated for 24 hours.
  • IL-1 ⁇ interleukin 1-beta
  • Figure 4 shows the results of PCR performed to confirm the anti-inflammatory effect of a composition for treating arthritis according to an experimental example herein.
  • Figure 5 shows the results of qRT-PCR performed to confirm the anti-inflammatory effect of a composition for treating arthritis according to an experimental example herein.
  • Figure 6 shows the results of a Western blot performed to confirm the anti-inflammatory effect of a composition for treating arthritis according to an experimental example herein.
  • a 12-week-old B6 mouse was anesthetized, the knee was cut in a straight line using a No. 11 blade, the knee ligament was pushed to the side, and the meniscus was identified, excised, and sutured. On the other leg, a portion of the knee skin was excised in a straight line, and the knee ligament was pushed to the side and restored to its original state.
  • Degenerative arthritis was induced, and after 4 weeks, the test substance (Example 1) was injected intraarticularly into the mouse knee joint at different doses (25, 50, and 100 mg/kg).
  • mice knees were fixed with 4% PFA and decalcification was performed for 2 weeks using EDTA (ethylene-diamine-tetraacetic acid) solution. Paraffin was absorbed into knee cartilage that had undergone a paraffinization process, and then Safranin-O staining was performed to confirm bone tissue.
  • EDTA ethylene-diamine-tetraacetic acid
  • Figure 7 shows the results of Safranin-O staining according to an experimental example herein.
  • test substances (Example 1) were administered at different doses, and bone tissue was confirmed through Safranin O-staining at 6 weeks. As a result, it was confirmed that the effect of inhibiting cartilage destruction was shown in a dose-dependent manner.
  • OARSI Ostoarthritis Research Society International
  • SBP subchondral bone plate
  • Figure 8 shows the results of performing the histopathological evaluation method proposed by OARSI according to an experimental example of the present institution.
  • Figure 9 shows the results of confirming the change in SBP thickness according to an experimental example herein.

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Abstract

The present invention relates to a composition comprising a quinazoline salt compound represented by the following chemical formula 1 for treatment of arthritis: [Chemical formula 1] (in chemical formula 1, A is HCl, HClO3, H2SO4, HNO3, HI, or HBr, and R1, R2, and R3 are each independently a substitutable linear or branched C1-C12 alkyl, a substitutable C3-C12 cycloalkyl, a substitutable C6-C18 aryl, or an alkoxy, wherein the substitution may be achieved with oxygen, nitrogen, sulfur, linear or branched alkyl of C1-C6 , an aryl of C6-C20 , halogen, alkoxy, trimethylsilyl, ether, or a combination thereof).

Description

퀴나졸린염 화합물을 포함하는 관절염 치료용 조성물 및 이의 제조 방법Composition for treating arthritis comprising a quinazoline salt compound and method for producing the same
본원은 퀴나졸린염 화합물을 포함하는 관절염 치료용 조성물 및 이의 제조 방법에 관한 것이다.The present application relates to a composition for treating arthritis containing a quinazoline salt compound and a method for producing the same.
관절염증은 관절의 염증성 질환으로서, 증례의 수가 가장 많은 질환이 만성관절 류머티즘 (rheumatoid arthritis) 및 변형성 관절증(골관절증)이다. Arthritis is an inflammatory disease of the joints, and the diseases with the largest number of cases are chronic rheumatoid arthritis and deforming arthrosis (osteoarthrosis).
만성관절 류머티즘은 자기면역질환이라고 생각되는 것으로, 관절의 동통, 경직, 종창의 증상을 수반하지만, 병상이 진행하면 자주 변형성 관절증과 같은 관절연골 표면의 변성으로 이어져, 마침내 관절의 뼈나 연골의 중증 파괴가 일어난다. Chronic joint rheumatism is thought to be an autoimmune disease, and is accompanied by symptoms of joint pain, stiffness, and swelling. However, as the condition progresses, it often leads to degeneration of the articular cartilage surface, such as deforming arthrosis, and eventually severe destruction of the joint bone and cartilage. happens.
변형성 관절증은 고령자에게 다발하는 관절연골의 변성질환이다. 변형성 관절증(OA)이라 함은 관절의 구성요소 의 퇴행변성에 따라, 연골의 파괴와 골이나 연골의 증식성 변화를 초래하는 질환으로서, 또한 상기 변화에 의해 2차적(속발성) 관절염(예를들어, 활막염; synovitis)을 초래하는 것이다. 변형성 관절증은 하중관절인 슬관절, 팔꿈치 관절 및 고관절에서 많이 발생하고 있는바, 어깨 관절, 팔꿈치 관절, 수관절과 같은 비하중 관절에서도 발생이 확인된다. 그리고 악관절에 있어서도 마찬가지 병태를 나타낸 악관절증이 알려져 있다. Arthropathy deformity is a degenerative disease of the articular cartilage that frequently occurs in elderly people. Osteoarthritis (OA) is a disease that causes destruction of cartilage and proliferative changes in bone or cartilage due to degenerative degeneration of joint components, and these changes can also cause secondary arthritis (e.g. , synovitis). Degenerative arthrosis occurs frequently in load joints such as the knee joint, elbow joint, and hip joint, and is also confirmed to occur in non-load joints such as the shoulder joint, elbow joint, and hand joint. Also, temporomandibular arthropathy, which presents the same condition in the temporomandibular joint, is known.
현재 넓게 이용되고 있는 표준적인 변형성 관절증의 치료제는, 경구로 투약되는 소염진통제나, 관절 내에 주사되는 히알론산이나 부신피질 스테로이드 등으로 서, 모두 관절동통의 억제제인바, 골관절염을 유발하는 유전자 발현이 감소하는 약학적 조성물의 개발이 요구되는 실정이다.Currently, the standard treatments for osteoarthritis that are widely used include anti-inflammatory painkillers administered orally, hyaluronic acid or corticosteroids injected into the joint, which are all inhibitors of joint pain and reduce the expression of genes that cause osteoarthritis. There is a need for the development of pharmaceutical compositions that do this.
대한민국 등록 특허 제10-1207155호는 관절염증 치료제 또는 예방제에 관한 것이다. 상기 특허에서는 관절염증 치료제로서 C형 나트륨 이뇨 펩티드(CNP) 또는 그것의 유도체를 유효성분으로 함유하는 것을 개시하고 있으나, 퀴나졸린염 화합물을 포함하는 관절염 치료용 조성물에 관하여는 언급하고있지 않다.Republic of Korea Patent No. 10-1207155 relates to a treatment or prevention agent for arthritis. The patent discloses a treatment for arthritis containing C-type natriuretic peptide (CNP) or a derivative thereof as an active ingredient, but does not mention a composition for the treatment of arthritis containing a quinazoline salt compound.
본원은 전술한 종래 기술의 문제점을 해결하기 위한 것으로서, 퀴나졸린염 화합물을 포함하는 관절염 치료용 조성물을 제공하는 것을 목적으로 한다.The present application aims to solve the problems of the prior art described above and to provide a composition for treating arthritis containing a quinazoline salt compound.
또한, 상기 관절염 치료용 조성물의 제조 방법을 제공하는 것을 목적으로 한다.Additionally, the object is to provide a method for producing the composition for treating arthritis.
또한, 상기 관절염 치료용 조성물을 포함하는 관절강 내 주사제를 제공하는 것을 목적으로 한다.Another object is to provide an intra-articular injection containing the composition for treating arthritis.
다만, 본원의 실시예가 이루고자 하는 기술적 과제는 상기된 바와 같은 기술적 과제들로 한정되지 않으며, 또 다른 기술적 과제들이 존재할 수 있다.However, the technical challenges sought to be achieved by the embodiments of the present application are not limited to the technical challenges described above, and other technical challenges may exist.
상기한 기술적 과제를 달성하기 위한 기술적 수단으로서, 본원의 제 1 측면은 하기 화학식 1 로 표시되는 퀴나졸린염 화합물을 포함하는, 관절염 치료용 조성물을 제공한다:As a technical means for achieving the above technical problem, the first aspect of the present application provides a composition for treating arthritis, comprising a quinazoline salt compound represented by the following formula (1):
[화학식 1][Formula 1]
Figure PCTKR2023009149-appb-img-000001
Figure PCTKR2023009149-appb-img-000001
(상기 화학식 1 에서,(In Formula 1 above,
A 는 HCl, HClO3, H2SO4, HNO3, HI 또는 HBr 이고,A is HCl, HClO 3 , H 2 SO 4 , HNO 3 , HI or HBr,
R1, R2, 및 R3 은 각각 독립적으로 치환될 수 있는 선형 또는 분지형의 C1-C12 알킬, 치환될 수 있는 C3-C12 사이클로알킬, 치환될 수 있는 C6-C18 아릴, 또는 알콕시이고,R 1 , R 2 , and R 3 are each independently optionally substituted linear or branched C 1 -C 12 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 Aryl, or alkoxy,
상기 치환은, 산소, 질소, 황, 선형 또는 분지형의 C1-C6 의 알킬, C6-C20 의 아릴, 할로겐, 알콕시, 트라이메틸실릴, 에테르 또는 이들의 조합에 의해 치환되는 것임).The substitution is by oxygen, nitrogen, sulfur, linear or branched C 1 -C 6 alkyl, C 6 -C 20 aryl, halogen, alkoxy, trimethylsilyl, ether, or a combination thereof) .
본원의 일 구현예에 따르면, 상기 퀴나졸린염은 하기 화합물을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다:According to one embodiment of the present application, the quinazoline salt may include the following compounds, but is not limited thereto:
Figure PCTKR2023009149-appb-img-000002
.
Figure PCTKR2023009149-appb-img-000002
.
본원의 일 구현예에 따르면, 상기 관절염은 퇴행성 관절염을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.According to one embodiment of the present application, the arthritis may include, but is not limited to, degenerative arthritis.
또한, 본원의 제 2 측면은 방향족 알데하이드 및 카르밤산염을 반응시켜 퀴나졸린 유도체를 제조하는 단계; 및 상기 퀴나졸린 유도체를 산과 반응시켜 퀴나졸린염을 제조하는 단계를 포함하는, 관절염 치료용 조성물의 제조 방법을 제공한다.In addition, the second aspect of the present application includes preparing a quinazoline derivative by reacting an aromatic aldehyde and a carbamate; and reacting the quinazoline derivative with an acid to produce a quinazoline salt.
본원의 일 구현예에 따르면, 상기 방향족 알데하이드는 4-하이드록시-3,5-디메틸-벤즈알데하이드(4-hydroxy-3,5-dimethyl benzaldehyde)를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.According to one embodiment of the present application, the aromatic aldehyde may include, but is not limited to, 4-hydroxy-3,5-dimethyl benzaldehyde.
본원의 일 구현예에 따르면, 상기 카르밤산염은 터트-부틸 N-(2-브로모에틸)카바메이트(Tert-Butyl N-(2-bromoethyl)carbamate)를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.According to one embodiment of the present application, the carbamate may include Tert-Butyl N-(2-bromoethyl)carbamate, but is limited thereto. That is not the case.
본원의 일 구현예에 따르면, 상기 퀴나졸린 유도체는 하기 화학식 2 로 표시되는 화합물을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다:According to one embodiment of the present application, the quinazoline derivative may include a compound represented by the following formula (2), but is not limited thereto:
[화학식 2][Formula 2]
Figure PCTKR2023009149-appb-img-000003
Figure PCTKR2023009149-appb-img-000003
(상기 화학식 2 에서,(In Formula 2 above,
R1, R2, 및 R3 은 각각 독립적으로 치환될 수 있는 선형 또는 분지형의 C1-C12 알킬, 치환될 수 있는 C3-C12 사이클로알킬, 치환될 수 있는 C6-C18 아릴, 또는 알콕시이고,R 1 , R 2 , and R 3 are each independently optionally substituted linear or branched C 1 -C 12 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 Aryl, or alkoxy,
상기 치환은, 산소, 질소, 황, 선형 또는 분지형의 C1-C6 의 알킬, C6-C20 의 아릴, 할로겐, 알콕시, 트라이메틸실릴, 에테르 또는 이들의 조합에 의해 치환되는 것임).The substitution is by oxygen, nitrogen, sulfur, linear or branched C 1 -C 6 alkyl, C 6 -C 20 aryl, halogen, alkoxy, trimethylsilyl, ether, or a combination thereof) .
본원의 일 구현예에 따르면, 상기 산은 HCl, HClO3, H2SO4, HNO3, HI, HBr 및 이들의 조합들로 이루어진 군에서 선택되는 것을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.According to one embodiment of the present application, the acid may include, but is not limited to, one selected from the group consisting of HCl, HClO 3 , H 2 SO 4 , HNO 3 , HI, HBr, and combinations thereof.
본원의 일 구현예에 따르면, 상기 퀴나졸린염은 하기 화학식 3 으로 표시되는 화합물을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다:According to one embodiment of the present application, the quinazoline salt may include a compound represented by the following formula (3), but is not limited thereto:
[화학식 3][Formula 3]
Figure PCTKR2023009149-appb-img-000004
Figure PCTKR2023009149-appb-img-000004
(상기 화학식 3 에서,(In Formula 3 above,
A 는 HCl, HClO3, H2SO4, HNO3, HI 또는 HBr 이고,A is HCl, HClO 3 , H 2 SO 4 , HNO 3 , HI or HBr,
R1, R2, 및 R3 은 각각 독립적으로 치환될 수 있는 선형 또는 분지형의 C1-C12 알킬, 치환될 수 있는 C3-C12 사이클로알킬, 치환될 수 있는 C6-C18 아릴, 또는 알콕시이고,R 1 , R 2 , and R 3 are each independently optionally substituted linear or branched C 1 -C 12 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 Aryl, or alkoxy,
상기 치환은, 산소, 질소, 황, 선형 또는 분지형의 C1-C6 의 알킬, C6-C20 의 아릴, 할로겐, 알콕시, 트라이메틸실릴, 에테르 또는 이들의 조합에 의해 치환되는 것임).The substitution is by oxygen, nitrogen, sulfur, linear or branched C 1 -C 6 alkyl, C 6 -C 20 aryl, halogen, alkoxy, trimethylsilyl, ether, or a combination thereof) .
본원의 일 구현예에 따르면, 상기 퀴나졸린염은 하기 화합물을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다:According to one embodiment of the present application, the quinazoline salt may include the following compounds, but is not limited thereto:
Figure PCTKR2023009149-appb-img-000005
.
Figure PCTKR2023009149-appb-img-000005
.
또한, 본원의 제 3 측면은 본원의 제 1 측면에 따른 관절염 치료용 조성물을 포함하는, 관절강 내 주사제를 제공한다.Additionally, a third aspect of the present application provides an intra-articular injection comprising the composition for treating arthritis according to the first aspect of the present application.
상술한 과제 해결 수단은 단지 예시적인 것으로서, 본원을 제한하려는 의도로 해석되지 않아야 한다. 상술한 예시적인 실시예 외에도, 도면 및 발명의 상세한 설명에 추가적인 실시예가 존재할 수 있다.The above-described means of solving the problem are merely illustrative and should not be construed as intended to limit the present application. In addition to the exemplary embodiments described above, additional embodiments may be present in the drawings and detailed description of the invention.
본원에 따른 관절염 치료용 조성물은 이전에 염증 치료 용도로서 보고된 바 없는 물질인 퀴나졸린염 화합물을 포함한다. 구체적으로, 상기 관절염 치료용 조성물은 상기 골관절염을 유발하는 유전자 발현을 감소시켜 골관절염 억제 효과를 가질 수 있으며, 특히 퇴행성 관절염의 치료에 효과를 가질 수 있다.The composition for treating arthritis according to the present application includes a quinazoline salt compound, a substance that has not previously been reported for use in treating inflammation. Specifically, the composition for treating arthritis may have an effect of suppressing osteoarthritis by reducing the expression of genes that cause osteoarthritis, and may be particularly effective in treating degenerative arthritis.
다만, 본원에서 얻을 수 있는 효과는 상기된 바와 같은 효과들로 한정되지 않으며, 또 다른 효과들이 존재할 수 있다.However, the effects that can be obtained herein are not limited to the effects described above, and other effects may exist.
도 1 은 본원의 일 구현예에 따른 관절염 치료용 조성물의 제조 방법의 순서도이다.1 is a flowchart of a method for producing a composition for treating arthritis according to an embodiment of the present application.
도 2 는 본원의 일 실시예에 따라 제조된 퀴나졸린염 화합물의 NMR 결과이다.Figure 2 shows NMR results of a quinazoline salt compound prepared according to an example of the present application.
도 3 은 본원의 일 실시예에 따라 제조된 퀴나졸린염 화합물의 LC-MS 결과이다.Figure 3 shows LC-MS results of a quinazoline salt compound prepared according to an example of the present application.
도 4 는 본원의 일 실험예에 따른 관절염 치료용 조성물의 항염증효능을 확인하기 위해 수행한 PCR 결과이다.Figure 4 shows the results of PCR performed to confirm the anti-inflammatory effect of a composition for treating arthritis according to an experimental example herein.
도 5 는 본원의 일 실험예에 따른 관절염 치료용 조성물의 항염증효능을 확인하기 위해 수행한 qRT-PCR 결과이다.Figure 5 shows the results of qRT-PCR performed to confirm the anti-inflammatory effect of a composition for treating arthritis according to an experimental example herein.
도 6 은 본원의 일 실험예에 따른 관절염 치료용 조성물의 항염증효능을 확인하기 위해 수행한 웨스턴 블랏(Western blot) 결과이다.Figure 6 shows the results of a Western blot performed to confirm the anti-inflammatory effect of a composition for treating arthritis according to an experimental example herein.
도 7 은 본원의 일 실험예에 따른 사프라닌-오 염색(Safranin-O staining) 결과이다.Figure 7 shows the results of Safranin-O staining according to an experimental example herein.
도 8 은 본원의 일 실험예에 따른 OARSI(Osteoarthritis Research Society International)에서 제시한 조직병리학적 평가법을 수행한 결과이다.Figure 8 shows the results of the histopathological evaluation method proposed by OARSI (Osteoarthritis Research Society International) according to an experimental example of the present institute.
도 9 는 본원의 일 실험예에 따른 SBP 두께의 변화를 확인한 결과이다.Figure 9 shows the results of confirming the change in SBP thickness according to an experimental example herein.
아래에서는 첨부한 도면을 참조하여 본원이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 본원의 실시예를 상세히 설명한다. 그러나 본원은 여러 가지 상이한 형태로 구현될 수 있으며 여기에서 설명하는 실시예에 한정되지 않는다. 그리고 도면에서 본원을 명확하게 설명하기 위해서 설명과 관계없는 부분은 생략하였으며, 명세서 전체를 통하여 유사한 부분에 대해서는 유사한 도면 부호를 붙였다.Below, with reference to the attached drawings, embodiments of the present application will be described in detail so that those skilled in the art can easily implement them. However, the present application may be implemented in various different forms and is not limited to the embodiments described herein. In order to clearly explain the present application in the drawings, parts that are not related to the description are omitted, and similar reference numerals are assigned to similar parts throughout the specification.
본원 명세서 전체에서, 어떤 부분이 다른 부분과 "연결"되어 있다고 할 때, 이는 "직접적으로 연결"되어 있는 경우뿐 아니라, 그 중간에 다른 소자를 사이에 두고 "전기적으로 연결"되어 있는 경우도 포함한다. Throughout this specification, when a part is said to be “connected” to another part, this includes not only the case where it is “directly connected,” but also the case where it is “electrically connected” with another element in between. do.
본원 명세서 전체에서, 어떤 부재가 다른 부재 "상에", "상부에", "상단에", "하에", "하부에", "하단에" 위치하고 있다고 할 때, 이는 어떤 부재가 다른 부재에 접해 있는 경우뿐 아니라 두 부재 사이에 또 다른 부재가 존재하는 경우도 포함한다.Throughout this specification, when a member is said to be located “on”, “above”, “at the top”, “below”, “at the bottom”, or “at the bottom” of another member, this means that a member is located on another member. This includes not only cases where they are in contact, but also cases where another member exists between two members.
본원 명세서 전체에서, 어떤 부분이 어떤 구성요소를 "포함" 한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.Throughout the specification of the present application, when a part is said to “include” a certain element, this means that it may further include other elements rather than excluding other elements, unless specifically stated to the contrary.
본 명세서에서 사용되는 정도의 용어 "약", "실질적으로" 등은 언급된 의미에 고유한 제조 및 물질 허용오차가 제시될 때 그 수치에서 또는 그 수치에 근접한 의미로 사용되고, 본원의 이해를 돕기 위해 정확하거나 절대적인 수치가 언급된 개시 내용을 비양심적인 침해자가 부당하게 이용하는 것을 방지하기 위해 사용된다. 또한, 본원 명세서 전체에서, "~ 하는 단계" 또는 "~의 단계"는 "~를 위한 단계"를 의미하지 않는다.As used herein, the terms “about,” “substantially,” and the like are used to mean at or close to a numerical value when manufacturing and material tolerances inherent in the stated meaning are presented, and to aid understanding of the present application. It is used to prevent unscrupulous infringers from unfairly exploiting disclosures in which precise or absolute figures are mentioned. Additionally, throughout the specification herein, “a step of” or “a step of” does not mean “a step for.”
본원 명세서 전체에서, 마쿠시 형식의 표현에 포함된 "이들의 조합"의 용어는 마쿠시 형식의 표현에 기재된 구성 요소들로 이루어진 군에서 선택되는 하나 이상의 혼합 또는 조합을 의미하는 것으로서, 상기 구성 요소들로 이루어진 군에서 선택되는 하나 이상을 포함하는 것을 의미한다.Throughout this specification, the term "combination thereof" included in the Markushi format expression means a mixture or combination of one or more components selected from the group consisting of the components described in the Markushi format expression, It means including one or more selected from the group consisting of.
본원 명세서 전체에서, "A 및/또는 B" 의 기재는, "A, B, 또는, A 및 B" 를 의미한다.Throughout this specification, description of “A and/or B” means “A, B, or A and B.”
이하, 본원의 퀴나졸린염 화합물을 포함하는 관절염 치료용 조성물 및 이의 제조방법에 대하여 구현예 및 실시예와 도면을 참조하여 구체적으로 설명하도록 한다. 그러나, 본원이 이러한 구현예 및 실시예와 도면에 제한되는 것은 아니다.Hereinafter, the composition for treating arthritis containing the quinazoline salt compound of the present application and the method for manufacturing the same will be described in detail with reference to embodiments, examples, and drawings. However, the present application is not limited to these embodiments, examples, and drawings.
상기한 기술적 과제를 달성하기 위한 기술적 수단으로서, 본원의 제 1 측면은 하기 화학식 1 로 표시되는 퀴나졸린염 화합물을 포함하는, 관절염 치료용 조성물을 제공한다:As a technical means for achieving the above technical problem, the first aspect of the present application provides a composition for treating arthritis, comprising a quinazoline salt compound represented by the following formula (1):
[화학식 1][Formula 1]
Figure PCTKR2023009149-appb-img-000006
Figure PCTKR2023009149-appb-img-000006
(상기 화학식 1 에서,(In Formula 1 above,
A 는 HCl, HClO3, H2SO4, HNO3, HI 또는 HBr 이고,A is HCl, HClO 3 , H 2 SO 4 , HNO 3 , HI or HBr,
R1, R2, 및 R3 은 각각 독립적으로 치환될 수 있는 선형 또는 분지형의 C1-C12 알킬, 치환될 수 있는 C3-C12 사이클로알킬, 치환될 수 있는 C6-C18 아릴, 또는 알콕시이고,R 1 , R 2 , and R 3 are each independently optionally substituted linear or branched C 1 -C 12 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 Aryl, or alkoxy,
상기 치환은, 산소, 질소, 황, 선형 또는 분지형의 C1-C6 의 알킬, C6-C20 의 아릴, 할로겐, 알콕시, 트라이메틸실릴, 에테르 또는 이들의 조합에 의해 치환되는 것임).The substitution is by oxygen, nitrogen, sulfur, linear or branched C 1 -C 6 alkyl, C 6 -C 20 aryl, halogen, alkoxy, trimethylsilyl, ether, or a combination thereof) .
본원에 따른 관절염 치료용 조성물은 이전에 염증 치료 용도로서 보고된 바 없는 물질인 퀴나졸린염 화합물을 포함한다. 구체적으로, 상기 관절염 치료용 조성물은 상기 골관절염을 유발하는 유전자 발현을 감소시켜 골관절염 억제 효과를 가질 수 있으며, 특히 퇴행성 관절염의 치료에 효과를 가질 수 있다.The composition for treating arthritis according to the present application includes a quinazoline salt compound, a substance that has not previously been reported for use in treating inflammation. Specifically, the composition for treating arthritis may have an effect of suppressing osteoarthritis by reducing the expression of genes that cause osteoarthritis, and may be particularly effective in treating degenerative arthritis.
본원의 일 구현예에 따르면, 상기 퀴나졸린염은 하기 화합물을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다:According to one embodiment of the present application, the quinazoline salt may include the following compounds, but is not limited thereto:
Figure PCTKR2023009149-appb-img-000007
.
Figure PCTKR2023009149-appb-img-000007
.
상기 화합물은 2-[4-[2-(디메틸아미노)에톡시]-3,5-디메틸-페닐]-5,7-디메톡시-3H-퀴나졸린-4-온, 디히드로클로라이드 [2-[4-[2-(dimethylamino)ethoxy]-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one, dihydrochloride] 로서, 이전에 관절염 치료용 조성물로 사용된 바가 없는 물질이며, 본원 발명자들은 상기 퀴나졸린염 화합물을 이용하여 관절염 치료용 조성물로서의 신규한 용도를 발견했다.The compound is 2-[4-[2-(dimethylamino)ethoxy]-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one, dihydrochloride [2- [4-[2-(dimethylamino)ethoxy]-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one, dihydrochloride], which has not been previously used as a composition for treating arthritis. material, and the inventors of the present application discovered a novel use of the quinazoline salt compound as a composition for treating arthritis.
본원의 일 구현예에 따르면, 상기 관절염은 퇴행성 관절염을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.According to one embodiment of the present application, the arthritis may include, but is not limited to, degenerative arthritis.
또한, 본원의 제 2 측면은 방향족 알데하이드 및 카르밤산염을 반응시켜 퀴나졸린 유도체를 제조하는 단계; 및 상기 퀴나졸린 유도체를 산과 반응시켜 퀴나졸린염을 제조하는 단계를 포함하는, 관절염 치료용 조성물의 제조 방법을 제공한다.In addition, the second aspect of the present application includes preparing a quinazoline derivative by reacting an aromatic aldehyde and a carbamate; and reacting the quinazoline derivative with an acid to produce a quinazoline salt.
본원의 제 2 측면에 따른 관절염 치료용 조성물의 제조 방법에 대하여, 본원의 제 1 측면과 중복되는 부분들에 대해서는 상세한 설명을 생략하였으나, 그 설명이 생략되었더라도 본원의 제 1 측면에 기재된 내용은 본원의 제 2 측면에 동일하게 적용될 수 있다.Regarding the method for producing a composition for treating arthritis according to the second aspect of the present application, detailed description of parts overlapping with the first aspect of the present application has been omitted. However, even if the description is omitted, the information described in the first aspect of the present application is the same as the present application. The same can be applied to the second aspect of .
도 1 은 본원의 일 구현예에 따른 관절염 치료용 조성물의 제조 방법의 순서도이다.1 is a flowchart of a method for producing a composition for treating arthritis according to an embodiment of the present application.
먼저, 방향족 알데하이드 및 카르밤산염을 반응시켜 퀴나졸린 유도체를 제조한다 (S100).First, a quinazoline derivative is prepared by reacting aromatic aldehyde and carbamate (S100).
본원의 일 구현예에 따르면, 상기 방향족 알데하이드는 4-하이드록시-3,5-디메틸-벤즈알데하이드(4-hydroxy-3,5-dimethyl benzaldehyde)를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.According to one embodiment of the present application, the aromatic aldehyde may include, but is not limited to, 4-hydroxy-3,5-dimethyl benzaldehyde.
본원의 일 구현예에 따르면, 상기 카르밤산염은 터트-부틸 N-(2-브로모에틸)카바메이트(Tert-Butyl N-(2-bromoethyl)carbamate)를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.According to one embodiment of the present application, the carbamate may include Tert-Butyl N-(2-bromoethyl)carbamate, but is limited thereto. That is not the case.
본원의 일 구현예에 따르면, 상기 퀴나졸린 유도체는 하기 화학식 2 로 표시되는 화합물을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다:According to one embodiment of the present application, the quinazoline derivative may include a compound represented by the following formula (2), but is not limited thereto:
[화학식 2][Formula 2]
Figure PCTKR2023009149-appb-img-000008
Figure PCTKR2023009149-appb-img-000008
(상기 화학식 2 에서,(In Formula 2 above,
R1, R2, 및 R3 은 각각 독립적으로 치환될 수 있는 선형 또는 분지형의 C1-C12 알킬, 치환될 수 있는 C3-C12 사이클로알킬, 치환될 수 있는 C6-C18 아릴, 또는 알콕시이고,R 1 , R 2 , and R 3 are each independently optionally substituted linear or branched C 1 -C 12 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 Aryl, or alkoxy,
상기 치환은, 산소, 질소, 황, 선형 또는 분지형의 C1-C6 의 알킬, C6-C20 의 아릴, 할로겐, 알콕시, 트라이메틸실릴, 에테르 또는 이들의 조합에 의해 치환되는 것임).The substitution is by oxygen, nitrogen, sulfur, linear or branched C 1 -C 6 alkyl, C 6 -C 20 aryl, halogen, alkoxy, trimethylsilyl, ether, or a combination thereof) .
예를 들어, 상기 퀴나졸린 유도체는 하기 화합물 1 로 표시되는 것을 포함할 수 있으나, 이에 제한되는 것은 아니다:For example, the quinazoline derivative may include, but is not limited to, the one represented by Compound 1 below:
[화합물 1][Compound 1]
Figure PCTKR2023009149-appb-img-000009
.
Figure PCTKR2023009149-appb-img-000009
.
상기 화합물 1 에서 보호기인 Boc 기(터트-부틸카보닐기)가 트리플루오로아세트산(TFA), 염산, 하이드로겐 클로라이드, 트리메틸실릴 요오다이드, 알루미늄 클로라이드 및 이들의 조합들로 이루어진 군에서 선택되는 물질에 의해서 탈보호하여 수소로 치환되어, 말단에 아민기를 가질 수 있으나, 이에 제한되는 것은 아니다. 예를 들어, 말단이 아민기로 치환된 상기 화합물 1 은 하기 화합물 2 로 표시되는 것을 포함할 수 있으나, 이에 제한되는 것은 아니다.In Compound 1, the protecting group Boc group (tert-butylcarbonyl group) is a material selected from the group consisting of trifluoroacetic acid (TFA), hydrochloric acid, hydrogen chloride, trimethylsilyl iodide, aluminum chloride, and combinations thereof. It may be deprotected and substituted with hydrogen and have an amine group at the end, but is not limited thereto. For example, Compound 1 whose terminal is substituted with an amine group may include, but is not limited to, Compound 2 below.
[화합물 2][Compound 2]
Figure PCTKR2023009149-appb-img-000010
.
Figure PCTKR2023009149-appb-img-000010
.
상기 화합물 2 는 폼알데하이드, 수소화붕소나트륨 등과 같은 강한 환원제로 작용하는 물질에 의해 상기 아민기의 수소가 알킬기로 치환될 수 있으나, 이에 제한되는 것은 아니다. 예를 들어, 상기 화합물 2 의 아민기의 수소가 알킬기로 치환된 화합물은 하기 화합물 3 으로 표시되는 것을 포함할 수 있으나, 이에 제한되는 것은 아니다.In Compound 2, the hydrogen of the amine group may be replaced with an alkyl group by a substance that acts as a strong reducing agent such as formaldehyde, sodium borohydride, etc., but is not limited thereto. For example, the compound in which the hydrogen of the amine group of Compound 2 is replaced with an alkyl group may include, but is not limited to, Compound 3 below.
[화합물 3][Compound 3]
Figure PCTKR2023009149-appb-img-000011
.
Figure PCTKR2023009149-appb-img-000011
.
이어서, 퀴나졸린 유도체를 산과 반응시켜 퀴나졸린염을 제조한다 (S200).Next, the quinazoline derivative is reacted with acid to prepare a quinazoline salt (S200).
본원의 일 구현예에 따르면, 상기 산은 HCl, HClO3, H2SO4, HNO3, HI, HBr 및 이들의 조합들로 이루어진 군에서 선택되는 것을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.According to one embodiment of the present application, the acid may include, but is not limited to, one selected from the group consisting of HCl, HClO 3 , H 2 SO 4 , HNO 3 , HI, HBr, and combinations thereof.
본원의 일 구현예에 따르면, 상기 퀴나졸린염은 하기 화학식 3 으로 표시되는 화합물을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다:According to one embodiment of the present application, the quinazoline salt may include a compound represented by the following formula (3), but is not limited thereto:
[화학식 3][Formula 3]
Figure PCTKR2023009149-appb-img-000012
Figure PCTKR2023009149-appb-img-000012
(상기 화학식 3 에서,(In Formula 3 above,
A 는 HCl, HClO3, H2SO4, HNO3, HI 또는 HBr 이고,A is HCl, HClO 3 , H 2 SO 4 , HNO 3 , HI or HBr,
R1, R2, 및 R3 은 각각 독립적으로 치환될 수 있는 선형 또는 분지형의 C1-C12 알킬, 치환될 수 있는 C3-C12 사이클로알킬, 치환될 수 있는 C6-C18 아릴, 또는 알콕시이고,R 1 , R 2 , and R 3 are each independently optionally substituted linear or branched C 1 -C 12 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 Aryl, or alkoxy,
상기 치환은, 산소, 질소, 황, 선형 또는 분지형의 C1-C6 의 알킬, C6-C20 의 아릴, 할로겐, 알콕시, 트라이메틸실릴, 에테르 또는 이들의 조합에 의해 치환되는 것임).The substitution is by oxygen, nitrogen, sulfur, linear or branched C 1 -C 6 alkyl, C 6 -C 20 aryl, halogen, alkoxy, trimethylsilyl, ether, or a combination thereof) .
본원의 일 구현예에 따르면, 상기 퀴나졸린염은 하기 화합물을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다:According to one embodiment of the present application, the quinazoline salt may include the following compounds, but is not limited thereto:
Figure PCTKR2023009149-appb-img-000013
.
Figure PCTKR2023009149-appb-img-000013
.
또한, 본원의 제 3 측면은 본원의 제 1 측면에 따른 관절염 치료용 조성물을 포함하는, 관절강 내 주사제를 제공한다.Additionally, a third aspect of the present application provides an intra-articular injection comprising the composition for treating arthritis according to the first aspect of the present application.
본원의 제 3 측면에 따른 관절강 내 주사제에 대하여, 본원의 제 1 측면과 중복되는 부분들에 대해서는 상세한 설명을 생략하였으나, 그 설명이 생략되었더라도 본원의 제 1 측면에 기재된 내용은 본원의 제 3 측면에 동일하게 적용될 수 있다.Regarding the intra-articular injection according to the third aspect of the present application, detailed description of parts overlapping with the first aspect of the present application has been omitted. However, even if the description is omitted, the contents described in the first aspect of the present application are the third aspect of the present application. The same can be applied to .
본원에 따른 관절염 치료용 조성물을 포함하는 관절강 내 주사제는 관절강 내에 투여되어 골관절염을 유발하는 유전자 발현을 감소시켜 골관절염 억제 효과를 가질 수 있다.An intra-articular injection containing the composition for treating arthritis according to the present application may be administered into the joint space to reduce the expression of genes that cause osteoarthritis and thereby have an effect of suppressing osteoarthritis.
이하 실시예를 통하여 본 발명을 더욱 상세하게 설명하고자 하나, 하기의 실시예는 단지 설명의 목적을 위한 것이며 본원의 범위를 한정하고자 하는 것은 아니다.The present invention will be described in more detail through the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present application.
[실시예 1] 관절염 치료용 조성물의 제조[Example 1] Preparation of composition for treating arthritis
먼저, 하기 반응식 1 에 따라 퀴나졸린염 화합물을 제조하였다.First, a quinazoline salt compound was prepared according to Scheme 1 below.
[반응식 1][Scheme 1]
Figure PCTKR2023009149-appb-img-000014
Figure PCTKR2023009149-appb-img-000014
제조된 퀴나졸린염 화합물은 NMR로 확인하였으며, LC-MS로 순도를 확인하였다. The prepared quinazoline salt compound was confirmed by NMR, and its purity was confirmed by LC-MS.
도 2 는 본원의 일 실시예에 따라 제조된 퀴나졸린염 화합물의 NMR 결과이다.Figure 2 shows NMR results of a quinazoline salt compound prepared according to an example of the present application.
도 3 은 본원의 일 실시예에 따라 제조된 퀴나졸린염 화합물의 LC-MS 결과이다.Figure 3 shows LC-MS results of a quinazoline salt compound prepared according to an example of the present application.
도 2 및 도 3 을 통하여 본원의 일 실시예에 따른 퀴나졸린염 화합물이 실제로 제조되었음을 확인할 수 있었다.이어서, 제조된 상기 퀴나졸린염 화합물을 디메틸설폭사이드(DMSO)에 용해하여 관절염 치료용 조성물을 제조하였다.2 and 3, it was confirmed that the quinazoline salt compound according to an example of the present application was actually produced. Next, the prepared quinazoline salt compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a composition for treating arthritis. Manufactured.
[비교예][Comparative example]
비교예로서 BET(Bromodomain and extra terminal containing protein) 억제제로서 사용되고 있는 JQ-1 을 사용하였다.As a comparative example, JQ-1, which is used as a BET (Bromodomain and extra terminal containing protein) inhibitor, was used.
[실험예 1] in vitro 항염증효능시험[Experimental Example 1] In vitro anti-inflammatory efficacy test
본원의 일 실시예에 따른 관절염 치료용 조성물의 항염증효능을 확인하기 위한 실험을 수행하였다.An experiment was performed to confirm the anti-inflammatory effect of the composition for treating arthritis according to an example herein.
먼저, 마우스의 관절에서 콜라게나아제(collagenase)를 활용하여 연골세포를 분리하였다. First, cartilage cells were isolated from mouse joints using collagenase.
이어서, 분리된 연골세포를FBS/DMEM 배지에3일 동안 배양하고 인터루킨 1-베타(IL-1β)를 처리하여 염증을 유발한 뒤, 실시예의 관절염 치료용 조성물을 농도별(0 μM 내지 20 μM)로 24 시간 동안 처리하였다. Subsequently, the separated chondrocytes were cultured in FBS/DMEM medium for 3 days and treated with interleukin 1-beta (IL-1β) to induce inflammation, and then the composition for treating arthritis of the examples was added at different concentrations (0 μM to 20 μM). ) was treated for 24 hours.
이어서, Trizol을 이용하여RNA를 추출하고 PCR, qRT-PCR 및 western blot을 통해 실시예의 관절염 치료용 조성물 처리에 의한Mmp3, Mmp13, Cox2 및 IL-6 유전자 발현의 양상을 확인하였다.Subsequently, RNA was extracted using Trizol, and the pattern of Mmp3, Mmp13, Cox2, and IL-6 gene expression by treatment with the composition for treating arthritis of the example was confirmed through PCR, qRT-PCR, and western blot.
도 4 는 본원의 일 실험예에 따른 관절염 치료용 조성물의 항염증효능을 확인하기 위해 수행한 PCR 결과이다.Figure 4 shows the results of PCR performed to confirm the anti-inflammatory effect of a composition for treating arthritis according to an experimental example herein.
도 5 는 본원의 일 실험예에 따른 관절염 치료용 조성물의 항염증효능을 확인하기 위해 수행한 qRT-PCR 결과이다.Figure 5 shows the results of qRT-PCR performed to confirm the anti-inflammatory effect of a composition for treating arthritis according to an experimental example herein.
도 6 은 본원의 일 실험예에 따른 관절염 치료용 조성물의 항염증효능을 확인하기 위해 수행한 웨스턴 블랏(Western blot)결과이다.Figure 6 shows the results of a Western blot performed to confirm the anti-inflammatory effect of a composition for treating arthritis according to an experimental example herein.
도 4 내지 도 6 을 참조하면, 실시예의 처리농도가 증가할수록 Mmp3, Mmp13, Cox2 및 IL-6 유전자 발현이 감소하는 경향을 나타내는 것을 확인할 수 있었다. 또한, 대조군으로 사용된 비교예(JQ-1) 대비 골관절염을 유발하는 유전자 발현이 감소하는 것을 관찰하였다. 결론적으로, 상기 시험결과로 시험물질(실시예1)의 골관절염 억제효과를 확인할 수 있었다.Referring to Figures 4 to 6, it was confirmed that as the treatment concentration of the examples increased, the expression of Mmp3, Mmp13, Cox2, and IL-6 genes tended to decrease. In addition, a decrease in the expression of genes causing osteoarthritis was observed compared to the comparative example (JQ-1) used as a control. In conclusion, the above test results confirmed the osteoarthritis inhibition effect of the test substance (Example 1).
[실험예 2] 퇴행성관절염 동물모델(DMM)을 이용한 효력시험[Experimental Example 2] Efficacy test using degenerative arthritis animal model (DMM)
12주령 B6 마우스를 마취하여 11호 블레이드를 이용하여 무릎(knee)를 일직선으로 절제하고, 무릎 인대(knee ligament)를 옆으로 밀친 후 메니스커스(meniscus)를 확인 및 절제한 후 봉합하였다. 반대쪽 다리는 무릎 피부(knee skin) 일부분을 일직선으로 절제한 후, 무릎 인대(knee ligament)를 옆으로 밀친 후 원상태로 복원시켰다. 퇴행성관절염을 유발시키고 4주 이후부터는 시험물질(실시예1)을 용량별(25, 50, 100 mg/kg)로 마우스 무릎 관절(knee joint)에 각각 관절강내 주사하였다. 시험물질 투여 시작 후 6주째 마우스 무릎(knee)를 4% PFA로 고정시키고 EDTA(ethylene-diamine-tetraacetic acid) 용액을 이용하여 2주간 탈석화작용(decalcification)을 진행하였다. 파라핀화(Paraffinization) 과정을 거친 무릎 연골(knee cartilage)에 파라핀(paraffin)을 흡수시킨 다음 사프라닌-오 염색(Safranin-O staining)을 수행하여 골조직을 확인하 였다.A 12-week-old B6 mouse was anesthetized, the knee was cut in a straight line using a No. 11 blade, the knee ligament was pushed to the side, and the meniscus was identified, excised, and sutured. On the other leg, a portion of the knee skin was excised in a straight line, and the knee ligament was pushed to the side and restored to its original state. Degenerative arthritis was induced, and after 4 weeks, the test substance (Example 1) was injected intraarticularly into the mouse knee joint at different doses (25, 50, and 100 mg/kg). Six weeks after starting test substance administration, mouse knees were fixed with 4% PFA and decalcification was performed for 2 weeks using EDTA (ethylene-diamine-tetraacetic acid) solution. Paraffin was absorbed into knee cartilage that had undergone a paraffinization process, and then Safranin-O staining was performed to confirm bone tissue.
도 7 은 본원의 일 실험예에 따른 사프라닌-오 염색(Safranin-O staining) 결과이다.Figure 7 shows the results of Safranin-O staining according to an experimental example herein.
도 7 을 참조하면, B6 마우스에 퇴행성관절염을 유도(DMM)한 후 시험물질(실시예1)을 용량별로 투여하여 6주째 사프라닌-오 염색 (Safranin O-staining) 방법을 통해 골조직을 확인한 결과, 용량의존적으로 연골파괴 억제 효과를 나타내는 것을 확인하였다.Referring to Figure 7, after inducing degenerative arthritis (DMM) in B6 mice, test substances (Example 1) were administered at different doses, and bone tissue was confirmed through Safranin O-staining at 6 weeks. As a result, it was confirmed that the effect of inhibiting cartilage destruction was shown in a dose-dependent manner.
또한, OARSI(Osteoarthritis Research Society International)에서 제시한 조직병리학적 평가법을 수행하여 본원의 일 실시예 1 에 따른 관절염 치료용 조성물의 마우스 무릎 연골의 파괴 억제능을 확인하였다. OARSI　평가법은 연골의 손상 정도에 따라 0에서 6 등급의 점수를 부여하는 평가 방법으로서, 이에 따른 채점 기준은 하기 표 1 과 같다. 추가적으로 골관절염이 발생하게 되면 SBP(subchondral bone plate) 두께가 증가하므로, 약물 투여시 SBP 두께 변화 여부도 확인하였다.In addition, the histopathological evaluation method suggested by OARSI (Osteoarthritis Research Society International) was performed to confirm the ability of the composition for treating arthritis according to Example 1 of the present invention to inhibit destruction of mouse knee cartilage. The OARSI evaluation method is an evaluation method that gives scores ranging from 0 to 6 depending on the degree of cartilage damage, and the scoring criteria are shown in Table 1 below. Additionally, since SBP (subchondral bone plate) thickness increases when osteoarthritis occurs, we also checked whether SBP thickness changed during drug administration.
[표 1] OARSI　평가법에 따른 채점 기준[Table 1] Scoring criteria according to the OARSI evaluation method
Figure PCTKR2023009149-appb-img-000015
Figure PCTKR2023009149-appb-img-000015
도 8 은 본원의 일 실험예에 따른 OARSI에서 제시한 조직병리학적 평가법을 수행한 결과이다.Figure 8 shows the results of performing the histopathological evaluation method proposed by OARSI according to an experimental example of the present institution.
도 9 는 본원의 일 실험예에 따른 SBP 두께의 변화를 확인한 결과이다.Figure 9 shows the results of confirming the change in SBP thickness according to an experimental example herein.
도 8 및 9 를 참조하면, 시험물질의 투여용량이 증가할수록 OARSI 등급이 저하되고, SBP 두께가 감소하는 것을 확인할 수 있었고, 이를 통해 시험물질의 투여용량 의존적인 골관절염 치료효과를 보임을 확인하였다. Referring to Figures 8 and 9, it was confirmed that as the administered dose of the test substance increased, the OARSI grade decreased and the SBP thickness decreased. This confirmed that the test substance had a dose-dependent osteoarthritis treatment effect.
전술한 본원의 설명은 예시를 위한 것이며, 본원이 속하는 기술분야의 통상의 지식을 가진 자는 본원의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. 예를 들어, 단일형으로 설명되어 있는 각 구성 요소는 분산되어 실시될 수도 있으며, 마찬가지로 분산된 것으로 설명되어 있는 구성 요소들도 결합된 형태로 실시될 수 있다.The description of the present application described above is for illustrative purposes, and those skilled in the art will understand that the present application can be easily modified into other specific forms without changing its technical idea or essential features. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive. For example, each component described as unitary may be implemented in a distributed manner, and similarly, components described as distributed may also be implemented in a combined form.
본원의 범위는 상기 상세한 설명보다는 후술하는 특허청구범위에 의하여 나타내어지며, 특허청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본원의 범위에 포함되는 것으로 해석되어야 한다.The scope of the present application is indicated by the claims described below rather than the detailed description above, and all changes or modified forms derived from the meaning and scope of the claims and their equivalent concepts should be construed as being included in the scope of the present application.

Claims (11)

  1. 하기 화학식 1 로 표시되는 퀴나졸린염 화합물을 포함하는, 관절염 치료용 조성물:A composition for treating arthritis, comprising a quinazoline salt compound represented by the following formula (1):
    [화학식 1][Formula 1]
    Figure PCTKR2023009149-appb-img-000016
    Figure PCTKR2023009149-appb-img-000016
    (상기 화학식 1 에서,(In Formula 1 above,
    A 는 HCl, HClO3, H2SO4, HNO3, HI 또는 HBr 이고,A is HCl, HClO 3 , H 2 SO 4 , HNO 3 , HI or HBr,
    R1, R2, 및 R3 은 각각 독립적으로 치환될 수 있는 선형 또는 분지형의 C1-C12 알킬, 치환될 수 있는 C3-C12 사이클로알킬, 치환될 수 있는 C6-C18 아릴, 또는 알콕시이고,R 1 , R 2 , and R 3 are each independently optionally substituted linear or branched C 1 -C 12 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 Aryl, or alkoxy,
    상기 치환은, 산소, 질소, 황, 선형 또는 분지형의 C1-C6 의 알킬, C6-C20 의 아릴, 할로겐, 알콕시, 트라이메틸실릴, 에테르 또는 이들의 조합에 의해 치환되는 것임).The substitution is by oxygen, nitrogen, sulfur, linear or branched C 1 -C 6 alkyl, C 6 -C 20 aryl, halogen, alkoxy, trimethylsilyl, ether, or a combination thereof) .
  2. 제 1 항에 있어서,According to claim 1,
    상기 퀴나졸린염은 하기 화합물을 포함하는 것인, 관절염 치료용 조성물:A composition for treating arthritis, wherein the quinazoline salt includes the following compounds:
    Figure PCTKR2023009149-appb-img-000017
    .
    Figure PCTKR2023009149-appb-img-000017
    .
  3. 제 1 항에 있어서,According to claim 1,
    상기 관절염은 퇴행성 관절염을 포함하는 것인,The arthritis includes degenerative arthritis,
    관절염 치료용 조성물.Composition for treating arthritis.
  4. 방향족 알데하이드 및 카르밤산염을 반응시켜 퀴나졸린 유도체를 제조하는 단계; 및Preparing a quinazoline derivative by reacting aromatic aldehyde and carbamate; and
    상기 퀴나졸린 유도체를 산과 반응시켜 퀴나졸린염을 제조하는 단계를 포함하는, 관절염 치료용 조성물의 제조 방법:Method for producing a composition for treating arthritis, comprising the step of reacting the quinazoline derivative with an acid to produce a quinazoline salt:
  5. 제 4 항에 있어서,According to claim 4,
    상기 방향족 알데하이드는 4-하이드록시-3,5-디메틸-벤즈알데하이드(4-hydroxy-3,5-dimethyl benzaldehyde)를 포함하는 것인, 관절염 치료용 조성물의 제조 방법.A method of producing a composition for treating arthritis, wherein the aromatic aldehyde includes 4-hydroxy-3,5-dimethyl benzaldehyde.
  6. 제 4 항에 있어서,According to claim 4,
    상기 카르밤산염은 터트-부틸 N-(2-브로모에틸)카바메이트(Tert-Butyl N-(2-bromoethyl)carbamate)를 포함하는 것인, 관절염 치료용 조성물의 제조 방법.A method of producing a composition for treating arthritis, wherein the carbamate includes Tert-Butyl N-(2-bromoethyl)carbamate.
  7. 제 4 항에 있어서,According to claim 4,
    상기 퀴나졸린 유도체는 하기 화학식 2 로 표시되는 화합물을 포함하는 것인, 관절염 치료용 조성물의 제조 방법:A method for producing a composition for treating arthritis, wherein the quinazoline derivative includes a compound represented by the following formula (2):
    [화학식 2][Formula 2]
    Figure PCTKR2023009149-appb-img-000018
    Figure PCTKR2023009149-appb-img-000018
    (상기 화학식 2 에서,(In Formula 2 above,
    R1, R2, 및 R3 은 각각 독립적으로 치환될 수 있는 선형 또는 분지형의 C1-C12 알킬, 치환될 수 있는 C3-C12 사이클로알킬, 치환될 수 있는 C6-C18 아릴, 또는 알콕시이고,R 1 , R 2 , and R 3 are each independently optionally substituted linear or branched C 1 -C 12 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 Aryl, or alkoxy,
    상기 치환은, 산소, 질소, 황, 선형 또는 분지형의 C1-C6 의 알킬, C6-C20 의 아릴, 할로겐, 알콕시, 트라이메틸실릴, 에테르 또는 이들의 조합에 의해 치환되는 것임).The substitution is by oxygen, nitrogen, sulfur, linear or branched C 1 -C 6 alkyl, C 6 -C 20 aryl, halogen, alkoxy, trimethylsilyl, ether, or a combination thereof) .
  8. 제 4 항에 있어서,According to claim 4,
    상기 산은 HCl, HClO3, H2SO4, HNO3, HI, HBr 및 이들의 조합들로 이루어진 군에서 선택되는 것을 포함하는 것인,The acid includes one selected from the group consisting of HCl, HClO 3 , H 2 SO 4 , HNO 3 , HI, HBr and combinations thereof,
    관절염 치료용 조성물의 제조 방법.Method for producing a composition for treating arthritis.
  9. 제 4 항에 있어서,According to claim 4,
    상기 퀴나졸린염은 하기 화학식 3 으로 표시되는 화합물을 포함하는 것인, 관절염 치료용 조성물의 제조 방법:A method for producing a composition for treating arthritis, wherein the quinazoline salt includes a compound represented by the following formula (3):
    [화학식 3][Formula 3]
    Figure PCTKR2023009149-appb-img-000019
    Figure PCTKR2023009149-appb-img-000019
    (상기 화학식 3 에서,(In Formula 3 above,
    A 는 HCl, HClO3, H2SO4, HNO3, HI 또는 HBr 이고,A is HCl, HClO 3 , H 2 SO 4 , HNO 3 , HI or HBr,
    R1, R2, 및 R3 은 각각 독립적으로 치환될 수 있는 선형 또는 분지형의 C1-C12 알킬, 치환될 수 있는 C3-C12 사이클로알킬, 치환될 수 있는 C6-C18 아릴, 또는 알콕시이고,R 1 , R 2 , and R 3 are each independently optionally substituted linear or branched C 1 -C 12 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 Aryl, or alkoxy,
    상기 치환은, 산소, 질소, 황, 선형 또는 분지형의 C1-C6 의 알킬, C6-C20 의 아릴, 할로겐, 알콕시, 트라이메틸실릴, 에테르 또는 이들의 조합에 의해 치환되는 것임).The substitution is by oxygen, nitrogen, sulfur, linear or branched C 1 -C 6 alkyl, C 6 -C 20 aryl, halogen, alkoxy, trimethylsilyl, ether, or a combination thereof) .
  10. 제 9 항에 있어서,According to clause 9,
    상기 퀴나졸린염은 하기 화합물을 포함하는 것인, 관절염 치료용 조성물의 제조 방법:A method for producing a composition for treating arthritis, wherein the quinazoline salt includes the following compounds:
    Figure PCTKR2023009149-appb-img-000020
    .
    Figure PCTKR2023009149-appb-img-000020
    .
  11. 제 1 항 내지 제 3 항 중 어느 한 항에 따른 관절염 치료용 조성물을 포함하는, 관절강 내 주사제.An intraarticular injection comprising the composition for treating arthritis according to any one of claims 1 to 3.
PCT/KR2023/009149 2022-09-30 2023-06-29 Composition comprising quinazoline salt compound for treatment of arthritis and preparation method therefor WO2024071594A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20120043168A (en) * 2009-04-22 2012-05-03 리스버로직스 코퍼레이션 Novel anti-inflammatory agents
KR101207155B1 (en) * 2004-03-31 2012-12-04 카즈와 나카오 Remedy or preventive for arthritis
KR20160033697A (en) * 2013-07-24 2016-03-28 노파르티스 아게 Substituted quinazolin-4-one derivatives
KR20160038008A (en) * 2013-07-31 2016-04-06 제니쓰 에피제네틱스 코포레이션 Novel quinazolinones as bromodomain inhibitors
KR20210065883A (en) * 2019-11-26 2021-06-04 주식회사 베노바이오 Novel quinazoline redox derivatives and their use as bet inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101207155B1 (en) * 2004-03-31 2012-12-04 카즈와 나카오 Remedy or preventive for arthritis
KR20120043168A (en) * 2009-04-22 2012-05-03 리스버로직스 코퍼레이션 Novel anti-inflammatory agents
KR20160033697A (en) * 2013-07-24 2016-03-28 노파르티스 아게 Substituted quinazolin-4-one derivatives
KR20160038008A (en) * 2013-07-31 2016-04-06 제니쓰 에피제네틱스 코포레이션 Novel quinazolinones as bromodomain inhibitors
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