KR20240002206A - Novel immunomodulatory amide derivatives, manufacturing method thereof and use thereof - Google Patents
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- 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
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- A—HUMAN NECESSITIES
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Abstract
본 발명은 신규한 면역조절아마이드 유도체와 이의 제조방법 및 용도에 관한 것이다. 본 발명에서 개발한 신규한 면역조절아마이드 유도체는 세레블론에 결합력이 매우 우수하고, 세포 독성이 거의 없으며, 최기형성 부작용 가능성이 낮고, TNF-α 및 전염증 사이토카인 발현을 조절할 수 있을 뿐만 아니라, 신경 보호 및 신경 염증 억제 효과를 가지고 파킨슨 병과 같은 퇴행성 뇌질환에 우수한 효과를 발휘하는 바, 기존의 탈리도마이도 유도체들을 대체할 수 있는 치료제로 개발이 가능한 장점이 있다. The present invention relates to novel immunomodulatory amide derivatives and their preparation methods and uses. The novel immunomodulatory amide derivative developed in the present invention has excellent binding ability to Cereblon, has almost no cytotoxicity, has a low possibility of teratogenic side effects, and is capable of controlling the expression of TNF-α and pro-inflammatory cytokines, as well as neurotoxicity. It has protective and neuroinflammation inhibitory effects and is excellent for degenerative brain diseases such as Parkinson's disease, so it has the advantage of being developed as a treatment that can replace existing thalidomide derivatives.
Description
본 발명은 신규한 면역조절아마이드 유도체와 이의 제조방법 및 용도에 관한 것이다.The present invention relates to novel immunomodulatory amide derivatives and their preparation methods and uses.
탈리도마이드(Thalidomide)는 1950년대 후반부터 1960년대까지 임산부들의 입덧 방지용으로 판매된 약물이었으나, 최기형성의 부작용이 보고되면서 임산부는 물론 가임기에 있는 사람이나 임신 가능성이 있는 사람의 복용 및 취급이 금지되었다. 그러나, 탈리도마이드가 결절성 홍반(ENL) 치료와 HIV 소모성 증후군 및 다양한 암 치료에 임상적으로 효과적인 것으로 밝혀진 후 약제에 대한 관심이 다시 높아졌다. Thalidomide was a drug sold from the late 1950s to the 1960s to prevent morning sickness in pregnant women, but as teratogenic side effects were reported, its use and handling was prohibited for pregnant women, as well as people of childbearing age or those with the potential to become pregnant. However, interest in the drug increased again after thalidomide was found to be clinically effective in the treatment of erythema nodosum (ENL), HIV wasting syndrome, and various cancers.
ENL 활성에 대한 기전 연구로부터 항종양 괴사 인자 알파(항TNF-α) 작용을 확인하였는데, 구체적으로, 탈리도마이드(thalidomide)는 TNF-α RNA의 분해를 증가시켜 합성 및 분비를 저하시킨다. 추가 연구에서는 CD8+ 및 CD4+ T 세포 모두의 공동 자극제로 알려졌으며, 기본 섬유아세포 성장 인자(bFGF), 혈관 내피 성장 인자(VEGF) 및 전사 인자인 NF-κB에 대한 억제제로써 혈관 신생 억제제로도 작용할 수 있음이 밝혀졌다. Anti-tumor necrosis factor alpha (anti-TNF-α) activity was confirmed from mechanistic studies on ENL activity. Specifically, thalidomide increases the degradation of TNF-α RNA, thereby reducing its synthesis and secretion. Further studies have shown that it is a known co-stimulator of both CD8+ and CD4+ T cells and may also act as an angiogenesis inhibitor as an inhibitor of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and the transcription factor NF-κB. It turned out that there was.
TNF-α 및 그 패밀리 멤버들은 세포 증식 및 분화, 세포사멸, 면역 반응의 조절 및 염증 유도를 포함하는 다양한 생리학적 및 병리학적 과정에서 중추적인 역할을 한다. TNF-α는 두 개의 수용체인 TNFR1과 TNFR2를 통해 작용하는데, 전자는 모든 조직에서 발현되며 TNF-α에 대한 주된 신호 수용체이다. 후자는 주로 면역 세포에서 발현되며 보다 제한된 생물학적 반응을 매개한다. 세포가 TNF-α에 노출되면 카스파제 캐스케이드(caspase cascade)가 활성화되어 세포사멸을 통해 세포가 죽을 수 있다. 실제로, 세포사멸을 개시할 수 있는 주요 세포 표면 분자는 TNF 패밀리 멤버의 리간드 및 수용체이다. 예를 들어, TNF 수용체 패밀리의 죽음을 유도하는 멤버 각각은 세포질 'death domain'(DD)을 포함하며, 이는 신호 전달 기전의 다운스트림 구성 요소에 결합하는 데 중요한 단백질-단백질 상호 작용 모티프이다. TNF-α and its family members play a pivotal role in various physiological and pathological processes, including cell proliferation and differentiation, apoptosis, regulation of immune responses, and induction of inflammation. TNF-α acts through two receptors, TNFR1 and TNFR2, the former of which is expressed in all tissues and is the main signaling receptor for TNF-α. The latter is mainly expressed in immune cells and mediates more limited biological responses. When cells are exposed to TNF-α, the caspase cascade is activated, causing cells to die through apoptosis. In fact, the main cell surface molecules that can initiate apoptosis are the ligands and receptors of TNF family members. For example, each death-inducing member of the TNF receptor family contains a cytoplasmic 'death domain' (DD), a protein-protein interaction motif that is important for binding to downstream components of the signaling machinery.
최근 종양 괴사 인자와 관련된 세포 사멸 유도 리간드인 TRAIL은 대부분의 정상 세포가 아닌 종양 세포의 세포 사멸을 선택적으로 유도하는 것으로 나타났다. TRAIL은 흉선세포의 세포 사멸을 매개하고 자가면역질환의 유도에 중요한 역할을 하는 것으로 알려져 있다. 그러나 더 자주, TNF-α 수용체 결합은 전사 인자, AP-1 및 NFκB의 활성화를 유도하고, 그 후 급성 및 만성 염증 반응에 관여하는 유전자를 유도한다. 따라서 TNF-α의 과잉 생산은 류마티스 관절염, 이식편대숙주병 및 크론병과 같은 많은 염증성 질환에 연루되어 있으며 ENL, 패혈성 쇼크, AIDS 및 알츠하이머병(AD)과 관련된 치매를 추가로 악화시키는 것으로 알려져 있다. Recently, TRAIL, a tumor necrosis factor-related apoptosis-inducing ligand, was shown to selectively induce apoptosis of tumor cells but not most normal cells. TRAIL is known to mediate apoptosis of thymocytes and plays an important role in the induction of autoimmune diseases. More often, however, TNF-α receptor binding leads to activation of the transcription factors, AP-1 and NFκB, and subsequently genes involved in acute and chronic inflammatory responses. Therefore, overproduction of TNF-α has been implicated in many inflammatory diseases, such as rheumatoid arthritis, graft-versus-host disease, and Crohn's disease, and is known to further exacerbate dementias associated with ENL, septic shock, AIDS, and Alzheimer's disease (AD). .
상용화된 탈리도마이드계 치료제로는 탈리도마이드, 보르테조밉, 레날리도마이드, 포말리도마이드가 있으며, 주사제인 보르테조밉은 꾸준히 시장을 유지하며 성장 추세이고, 경구제는 기존 탈리도마이드의 지위(position)를 레날리도마이드가 대체하며 시장에서 높은 성장세를 기록하고 있다. 레날리도마이드는 탈리도마이드의 차세대 약물로서 더 강력한 암세포 사멸과 면역 조절로 탈리도마이드보다 더 우수한 치료 효과를 보인다. 기존 치료에 재발하거나 치료 불응인 경우에 레날리도마이드와 덱사메타손을 병용하여 치료했을 때 무병생존기간이 13.4개월, 전체생존기간이 38개월로 상당히 효과적인 것으로 알려져 있다. 부작용은 기존의 탈리도마이드에서 나타났던 말초신경병증 등의 문제는 거의 없어졌으며, 단지 골수억제 부작용이 조금 더 심해졌지만, 백혈구 촉진인자 등을 투여하면 큰 문제가 없는 것으로 알려져 있다. 포말리도마이드는 2013년 미국 FDA에 의해 재발 및 내화 다발성 골수종 치료제로 승인되면서, 레날리도마이드와 보르테조밉을 포함한 적어도 2개의 종전 치료를 받은 사람들에게 마지막 치료가 완료된 후 60일 이내에도 질병이 진행되는 경우 사용된다. 포말리도마이드는 혈관 신생 및 골수종 세포 성장을 직접적으로 억제하는데, 이러한 이중 효과는 TNF-α 억제와 같은 다른 경로보다는 골수종에서의 활성이 중심이 된다. IFN-γ, IL-2 및 IL-10의 발현 강화뿐만 아니라 IL-6의 발현 억제를 통해 포말리도마이드는 항 혈관신생 및 항 골수종 활성을 나타낸다. Commercialized thalidomide-based treatments include thalidomide, bortezomib, lenalidomide, and pomalidomide. The injectable drug bortezomib is steadily maintaining its market and growing, and the oral drug is taking over the existing thalidomide position. Domide has replaced it and is recording high growth in the market. Lenalidomide is the next-generation drug of thalidomide and shows better therapeutic effects than thalidomide through more powerful cancer cell killing and immune regulation. In cases of recurrence or refractoriness to existing treatment, the combined treatment of lenalidomide and dexamethasone is known to be quite effective, with a disease-free survival of 13.4 months and an overall survival of 38 months. As for side effects, problems such as peripheral neuropathy that occurred with existing thalidomide have almost disappeared, and the side effects of bone marrow suppression have become slightly more severe, but it is known that there is no major problem if leukocyte stimulating factors are administered. Pomalidomide was approved by the U.S. Food and Drug Administration in 2013 for the treatment of relapsed and refractory multiple myeloma, making it possible for people who have received at least two prior treatments, including lenalidomide and bortezomib, to experience disease progression within 60 days of completing the last treatment. It is used if applicable. Pomalidomide directly inhibits angiogenesis and myeloma cell growth, and this dual effect is centered on its activity in myeloma rather than on other pathways such as TNF-α inhibition. Through enhancing the expression of IFN-γ, IL-2 and IL-10 as well as inhibiting the expression of IL-6, pomalidomide exhibits anti-angiogenic and anti-myeloma activities.
미국 등록특허 9,623,020에서는 탈리도마이드 유도체로 티오 화합물을 새로이 합성하였고, 이들 티오 화합물이 TNF-α 활성을 조절하고, TCR-자극 T 세포에 의한 면역 사이토카인의 발현을 변화시킬 수 있음을 확인한 바 있다. In US Patent 9,623,020, thio compounds were newly synthesized using thalidomide derivatives, and it was confirmed that these thio compounds can regulate TNF-α activity and change the expression of immune cytokines by TCR-stimulated T cells.
본 발명자들은 상기 탈리도마이드의 약학적 효과를 개선하기 위한 추가적인 유도체를 개발하기 위하여 예의 노력한 결과, [화학식 1], [화학식 2], [화학식 3] 의 화합물이 세레블론 결합력을 가지고, 골수세포 억압이나 생식 독성과 같은 부작용 없이 면역 조절 및 항산화 효과가 강화되고, 혈장 내 안정성이 개선되어, 다양한 치료제로서의 개발이 가능함을 확인함으로써 본 발명을 완성하였다. The present inventors have made diligent efforts to develop additional derivatives to improve the pharmaceutical effect of thalidomide, and as a result, compounds of [Formula 1], [Formula 2], and [Formula 3] have cereblon binding ability and suppress bone marrow cells. The present invention was completed by confirming that the immunomodulatory and antioxidant effects were strengthened without side effects such as reproductive toxicity, and the stability in plasma was improved, enabling development as a variety of therapeutic agents.
본 발명의 목적은 신규한 탈리도마이드 유도체, 이의 제조방법 및 이의 용도를 제공하는 것이다. The object of the present invention is to provide novel thalidomide derivatives, methods for their preparation and uses thereof.
상기 목적을 달성하기 위하여, 본 발명은 [화학식 1] 내지 [화학식 3]으로 구성된 군에서 선택되는 어느 하나의 화합물을 제공한다:In order to achieve the above object, the present invention provides any one compound selected from the group consisting of [Formula 1] to [Formula 3]:
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
. .
본 발명은 또한, 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 염증 질환 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating inflammatory diseases containing the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에 있어서, 상기 염증 질환은 건선, 류마티스 관절염 및 크론병으로 구성된 군에서 선택되는 것을 특징으로 할 수 있다. In the present invention, the inflammatory disease may be selected from the group consisting of psoriasis, rheumatoid arthritis, and Crohn's disease.
본 발명에 있어서, 상기 [화학식 1] 내지 [화학식 3]으로 구성된 군에서 선택되는 어느 하나의 화합물은 비-기형유발성인 것을 특징으로 할 수 있다. In the present invention, any one compound selected from the group consisting of [Formula 1] to [Formula 3] may be characterized as being non-teratogenic.
본 발명은 또한, 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 뇌질환 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating brain diseases containing the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에 있어서, 상기 뇌질환은 외상성 뇌손상, 알츠하이머병, 파킨슨병, 헌팅턴병, 루게릭병, 다계통위축증, 알츠하이머성 치매, 혈관성 치매, 전두측두 치매, 루이 치매, 허혈성 뇌졸중, 출혈성 뇌졸중 및 다발성 경화증으로 구성된 군에서 선택되는 것을 특징으로 할 수 있다. In the present invention, the brain disease includes traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, multiple system atrophy, Alzheimer's dementia, vascular dementia, frontotemporal dementia, Lewy dementia, ischemic stroke, hemorrhagic stroke and multiple sclerosis. It may be characterized as being selected from the group consisting of.
본 발명에 있어서, 상기 [화학식 1] 내지 [화학식 3]으로 구성된 군에서 선택되는 어느 하나의 화합물은 비-기형유발성인 것을 특징으로 할 수 있다. In the present invention, any one compound selected from the group consisting of [Formula 1] to [Formula 3] may be characterized as being non-teratogenic.
본 발명은 또한, 다음 단계를 포함하는 하기 화학식 1 화합물의 제조방법을 제공한다:The present invention also provides a method for preparing a compound of formula 1 comprising the following steps:
[화학식 1][Formula 1]
(a) 포말리도마이드를 다이옥세인에 용해시키는 단계; 및(a) dissolving pomalidomide in dioxane; and
(b) 오황화인을 첨가하고 60 내지 100℃에서 반응시키는 단계.(b) Adding phosphorus pentasulfide and reacting at 60 to 100°C.
본 발명에 있어서, 상기 제조방법은 (b) 단계 이후,In the present invention, the manufacturing method includes, after step (b),
(c) 여과 및/또는 크로마토그래피로 정제하는 단계;를 추가로 포함하는 것을 특징으로 할 수 있다. (c) purifying by filtration and/or chromatography.
본 발명은 또한, 다음 단계를 포함하는 화학식 2 화합물의 제조방법을 제공한다:The present invention also provides a method for preparing a compound of formula 2 comprising the following steps:
[화학식 2][Formula 2]
(a) 레날리도마이드를 다이옥세인에 용해시키는 단계; 및(a) dissolving lenalidomide in dioxane; and
(b) 질소 분위기 하에서 Lawesson 시약을 첨가하고 80 내지 120℃에서 반응시키는 단계.(b) Adding Lawesson reagent under a nitrogen atmosphere and reacting at 80 to 120°C.
본 발명에 있어서, 상기 제조방법은 (b) 단계 이후,In the present invention, the manufacturing method includes, after step (b),
(c) 크로마토그래피로 정제하는 단계;를 추가로 포함하는 것을 특징으로 할 수 있다. (c) purifying by chromatography.
본 발명은 또한, 다음 단계를 포함하는 화학식 3 화합물의 제조방법을 제공한다:The present invention also provides a method for preparing a compound of formula 3 comprising the following steps:
[화학식 3][Formula 3]
(a) 1,6'-디티오포말리도마이드를 DMSO 및 물에 용해시키는 단계;(a) dissolving 1,6'-dithiopomalidomide in DMSO and water;
(b) 상기 용액을 40-80℃에서 교반시킨 후 용매를 제거하는 단계; 및(b) stirring the solution at 40-80°C and then removing the solvent; and
(c) 상기 용매가 제거된 조생성물을 MeOH:THF(50%)로 용출하는 단계.(c) Eluting the crude product from which the solvent has been removed with MeOH:THF (50%).
본 발명에 있어서, 상기 제조방법은 (c) 단계 이후,In the present invention, the production method is after step (c),
(d) 크로마토그래피로 정제하는 단계;를 추가로 포함하는 것을 특징으로 할 수 있다. (d) purifying by chromatography.
본 발명에서 개발한 신규한 면역조절아마이드 유도체는 세레블론에 결합력이 매우 우수하고, 세포 독성이 거의 없으며, 최기형성 부작용 가능성이 낮고, TNF-α 및 전염증 사이토카인 발현을 조절할 수 있을 뿐만 아니라, 신경 보호 및 신경 염증 억제 효과를 가지고 파킨슨 병과 같은 퇴행성 뇌질환에 우수한 효과를 발휘하는 바, 기존의 탈리도마이도 유도체들을 대체할 수 있는 치료제로 개발이 가능한 장점이 있다. The novel immunomodulatory amide derivative developed in the present invention has excellent binding ability to Cereblon, has almost no cytotoxicity, has a low possibility of teratogenic side effects, and is capable of controlling the expression of TNF-α and pro-inflammatory cytokines, as well as neurotoxicity. It has protective and neuroinflammation inhibitory effects and is excellent for degenerative brain diseases such as Parkinson's disease, so it has the advantage of being developed as a treatment that can replace existing thalidomide derivatives.
도 1a는 화학식 1 화합물의 세레블론 결합 활성을 in vitro에서 경쟁적 저해 반응을 통해 포말리도마이드와 비교한 결과이다.
도 1b는 화학식 2 화합물의 세레블론 결합 활성을 in vitro에서 경쟁적 저해 반응을 통해 레날리도마이드와 비교한 결과이다.
도 1c는 화학식 3 화합물의 세레블론 결합 활성을 in vitro에서 경쟁적 저해 반응을 통해 포말리도마이드와 비교한 결과이다.
도 2a는 화학식 1 화합물의 MM.1R 세포주에 대한 세포 독성을 평가한 결과이다.
도 2b는 화학식 2 화합물의 MM.1S 세포주에 대한 세포 독성을 평가한 결과이다.
도 3a는 화학식 1 화합물을 MM.1S 세포에 처리하고, 세포 내 Ikaros, Aiolos 분해 효과를 포말리도마이드와 면역 블라팅으로 비교한 결과이다.
도 3b는 화학식 2 화합물을 MM.1S 세포에 처리하고, 세포 내 Ikaros, Aiolos 분해 효과를 레날리도마이드와 면역 블라팅으로 비교한 결과이다.
도 3c는 화학식 3 화합물을 MM.1S 세포에 처리하고, 세포 내 Ikaros, Aiolos 분해 효과를 포말리도마이드와 면역 블라팅으로 비교한 결과이다.
도 4a는 화학식 1 화합물을 Tera-1 세포에 처리하고, 세포 내 SALL4 분해 정도를 포말리도마이드와 면역 블라팅으로 비교한 결과이다.
도 4b는 화학식 2 화합물을 Tera-1 세포에 처리하고, 세포 내 SALL4 분해 정도를 레날리도마이드와 면역 블라팅으로 비교한 결과이다.
도 4c는 화학식 3 화합물을 Tera-1 세포에 처리하고, 세포 내 SALL4 분해 정도를 포말리도마이드와 면역 블라팅으로 비교한 결과이다.
도 5a는 화학식 1 화합물을 PBMC 세포에 처리하고, 전-염증 사이토카인인 TNF-α, IL-1β, IL-6, IL-8의 생산 억제 효과를 mRNA 레벨에서 포말리도마이드와 RT-PCR로 비교한 결과이다.
도 5b는 화학식 2 화합물을 PBMC 세포에 처리하고, 전-염증 사이토카인인 TNF-α, IL-1β, IL-6, IL-8의 생산 억제 효과를 mRNA 레벨에서 레날리도마이드와 RT-PCR로 비교한 결과이다.
도 5c는 화학식 2 화합물을 PBMC 세포에 처리하고, 전-염증 사이토카인인 TNF-α 억제 효과를 단백질 레벨에서 레날리도마이드와 비교한 결과이다.
도 6은 화학식 3 화합물을 랫트 중뇌 유래 일차 배양 세포에 처리하고, 알파 시누클레인에 의해 유도된 신경 독소로부터의 보호 효과 및 항-신경염증 효과를 확인한 결과이다.
도 7은 지브라피쉬 동물 모델을 이용하여 화학식 2 화합물의 파킨슨 병 치료 효과를 확인한 결과이다.Figure 1a shows the results of comparing the cereblon binding activity of the compound of Formula 1 with pomalidomide through a competitive inhibition reaction in vitro .
Figure 1b shows the results of comparing the cereblon binding activity of the compound of Formula 2 with lenalidomide through a competitive inhibition reaction in vitro .
Figure 1c shows the results of comparing the cereblon binding activity of the compound of Formula 3 with pomalidomide through a competitive inhibition reaction in vitro .
Figure 2a shows the results of evaluating the cytotoxicity of the compound of Formula 1 on the MM.1R cell line.
Figure 2b shows the results of evaluating the cytotoxicity of the compound of Formula 2 to the MM.1S cell line.
Figure 3a shows the results of treating MM.1S cells with the compound of Formula 1 and comparing the intracellular decomposition effects of Ikaros and Aiolos with those of pomalidomide by immunoblotting.
Figure 3b shows the results of treating MM.1S cells with the compound of Formula 2 and comparing the intracellular decomposition effects of Ikaros and Aiolos with those of lenalidomide by immunoblotting.
Figure 3c shows the results of treating MM.1S cells with the compound of Formula 3 and comparing the intracellular decomposition effects of Ikaros and Aiolos with those of pomalidomide by immunoblotting.
Figure 4a shows the results of treating Tera-1 cells with the compound of Formula 1 and comparing the degree of intracellular SALL4 degradation with pomalidomide by immunoblotting.
Figure 4b shows the results of treating Tera-1 cells with the compound of Formula 2 and comparing the degree of intracellular SALL4 degradation with that of lenalidomide by immunoblotting.
Figure 4c shows the results of treating Tera-1 cells with the compound of Formula 3 and comparing the degree of intracellular SALL4 degradation with pomalidomide by immunoblotting.
Figure 5a shows the inhibitory effect on the production of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8 by treating PBMC cells with the compound of Formula 1 at the mRNA level using pomalidomide and RT-PCR. This is the result of comparison.
Figure 5b shows the inhibitory effect on the production of pro-inflammatory cytokines, TNF-α, IL-1β, IL-6, and IL-8, by treating PBMC cells with the compound of Formula 2 and lenalidomide and RT-PCR at the mRNA level. This is the result of comparison.
Figure 5c shows the results of treating PBMC cells with the compound of Formula 2 and comparing the inhibitory effect of TNF-α, a pro-inflammatory cytokine, with lenalidomide at the protein level.
Figure 6 shows the results of treating rat midbrain-derived primary culture cells with the compound of Formula 3 and confirming the protective effect from neurotoxin induced by alpha-synuclein and the anti-neuroinflammatory effect.
Figure 7 shows the results of confirming the Parkinson's disease treatment effect of the compound of Formula 2 using a zebrafish animal model.
다른 식으로 정의되지 않는 한, 본 명세서에서 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술분야에서 숙련된 전문가에 의해서 통상적으로 이해되는 것과 동일한 의미를 갖는다. 일반적으로, 본 명세서에서 사용된 명명법 및 이하에 기술하는 실험 방법은 본 기술분야에서 잘 알려져 있고 통상적으로 사용되는 것이다.Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by a person skilled in the art to which the present invention pertains. In general, the nomenclature used herein and the experimental methods described below are well known and commonly used in the art.
본 발명에서는 포말리도마이드 또는 레날리도마이드를 개량하여 여러 종류의 티오 화합물를 제조하고, 상기 신규 화합물의 약학적 효능을 확인하였다.In the present invention, various types of thio compounds were prepared by improving pomalidomide or lenalidomide, and the pharmaceutical efficacy of the new compounds was confirmed.
구체적으로, 본 발명에 따른 신규 화합물들은 세레블론 결합 활성이 우수하고, 세포 독성도 적어 생체 내 안전성이 우수한 것으로 확인되었다. 또한, 본 발명에 따른 신규 화합물들은 세레블론의 기질인 Aiolos 및 Ikaros의 발현을 감소시키고, 최기형성 부작용을 야기하는 SALL4의 분해를 억제하여 탈리도마이드계 화합물에 의해 야기되는 주요 부작용이 감소할 수 있음을 알 수 있었다. Specifically, the new compounds according to the present invention were confirmed to have excellent cereblon binding activity and low cytotoxicity, thereby demonstrating excellent in vivo safety. In addition, the new compounds according to the present invention reduce the expression of Aiolos and Ikaros, which are substrates of cereblon, and inhibit the degradation of SALL4, which causes teratogenic side effects, thereby reducing major side effects caused by thalidomide compounds. I was able to.
따라서, 본 발명은 일 관점에서 [화학식 1] 내지 [화학식 3]으로 구성된 군에서 선택되는 어느 하나의 화합물에 관한 것이다:Accordingly, in one aspect, the present invention relates to any one compound selected from the group consisting of [Formula 1] to [Formula 3]:
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
. .
본 발명에 있어서, [화학식 1]의 화합물은 6'-모노티오포말리도마이드(6'-Monothio pomalidomide)로 명명될 수 있고, C13H11N3O3S의 화학식으로 표시될 수 있으며, 분자량 289.31을 가지는 것을 특징으로 할 수 있다. 본 발명에서, [화학식 1]의 화합물은 6-MP로 약칭될 수 있다.In the present invention, the compound of [Formula 1] may be named 6'-Monothio pomalidomide and may be represented by the chemical formula C 13 H 11 N 3 O 3 S, It can be characterized as having a molecular weight of 289.31. In the present invention, the compound of [Formula 1] can be abbreviated as 6-MP.
본 발명에 있어서, [화학식 2]의 화합물은 1-모노티오레날리도마이드(1-Monothio lenalidomide)로 명명될 수 있고, C13H13N3O2S의 화학식으로 표시될 수 있으며, 분자량 275.33을 가지는 것을 특징으로 할 수 있다. 본 발명에서, [화학식 2]의 화합물은 1-ML로 약칭될 수 있다.In the present invention, the compound of [Formula 2] may be named 1-Monothio lenalidomide and may be represented by the chemical formula C 13 H 13 N 3 O 2 S, and has a molecular weight of It can be characterized as having 275.33. In the present invention, the compound of [Formula 2] can be abbreviated as 1-ML.
본 발명에 있어서, [화학식 3]의 화합물은 1-모노티오포말리도마이드(1-Monothio pomalidomide)로 명명될 수 있고, C13H11N3O3S의 화학식으로 표시될 수 있으며, 분자량 289.31을 가지는 것을 특징으로 할 수 있다. 본 발명에서, [화학식 3]의 화합물은 1-MP로 약칭될 수 있다.In the present invention, the compound of [Formula 3] may be named 1-Monothio pomalidomide and may be represented by the chemical formula C 13 H 11 N 3 O 3 S, and has a molecular weight of 289.31. It can be characterized as having. In the present invention, the compound of [Formula 3] can be abbreviated as 1-MP.
본 발명에 있어서, 상기 [화학식 1] 내지 [화학식 3]으로 구성된 군에서 선택되는 어느 하나의 화합물은 비-기형유발성일 수 있다. In the present invention, any one compound selected from the group consisting of [Formula 1] to [Formula 3] may be non-teratogenic.
한편, 본 발명에 따른 신규화합물들은 다양한 전 염증 사이토카인 발현을 억제할 수 있었고, 신경 독소에 대한 신경 보호 효과를 발휘하였으며, 파킨슨 병 치료 효과도 발휘할 수 있음을 확인하였다.Meanwhile, it was confirmed that the new compounds according to the present invention were able to suppress the expression of various pro-inflammatory cytokines, exerted a neuroprotective effect against neurotoxins, and could also exert a therapeutic effect for Parkinson's disease.
다른 관점에서, 본 발명은 [화학식 1] 내지 [화학식 3]으로 구성된 군에서 선택되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 뇌질환 예방 또는 치료용 약학적 조성물에 관한 것이다:From another perspective, the present invention relates to a pharmaceutical composition for preventing or treating brain diseases containing a compound selected from the group consisting of [Formula 1] to [Formula 3] or a pharmaceutically acceptable salt thereof as an active ingredient:
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
. .
본 발명에 있어서, 상기 염증 질환은 건선, 류마티스 관절염 및 크론병으로 구성된 군에서 선택되는 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다.In the present invention, the inflammatory disease may be selected from the group consisting of psoriasis, rheumatoid arthritis, and Crohn's disease, but is not limited thereto.
다른 양태로서, 본 발명은 상기 [화학식 1] 내지 [화학식 3]으로 구성된 군에서 선택되는 화합물 또는 이의 약학적으로 허용 가능한 염 또는 이를 유효성분으로 함유하는 조성물을 이를 필요로 하는 대상체에 투여하는 단계를 포함하는, 염증 질환 예방 또는 치료 방법에 관한 것이다.In another aspect, the present invention includes the step of administering a compound selected from the group consisting of [Formula 1] to [Formula 3], or a pharmaceutically acceptable salt thereof, or a composition containing the same as an active ingredient, to a subject in need thereof. It relates to a method of preventing or treating inflammatory diseases, including.
또 다른 양태로서, 본 발명은 상기 [화학식 1] 내지 [화학식 3]으로 구성된 군에서 선택되는 화합물 또는 이의 약학적으로 허용 가능한 염의 염증 질환 예방 또는 치료 용도에 관한 것이다.In another aspect, the present invention relates to the use of a compound selected from the group consisting of [Formula 1] to [Formula 3] or a pharmaceutically acceptable salt thereof for preventing or treating inflammatory diseases.
또 다른 양태로서, 본 발명은 염증 질환 예방 또는 치료를 위한 약물의 제조를 위한 상기 [화학식 1] 내지 [화학식 3]으로 구성된 군에서 선택되는 화합물 또는 이의 약학적으로 허용 가능한 염의 용도에 관한 것이다.In another aspect, the present invention relates to the use of a compound selected from the group consisting of [Formula 1] to [Formula 3] or a pharmaceutically acceptable salt thereof for the production of a drug for preventing or treating inflammatory diseases.
또 다른 관점에서, 본 발명은 [화학식 1] 내지 [화학식 3]으로 구성된 군에서 선택되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 염증 질환 예방 또는 치료용 약학적 조성물에 관한 것이다:From another perspective, the present invention relates to a pharmaceutical composition for preventing or treating inflammatory diseases containing a compound selected from the group consisting of [Formula 1] to [Formula 3] or a pharmaceutically acceptable salt thereof as an active ingredient. :
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
. .
본 발명에 있어서, 상기 뇌질환은 외상성 뇌손상, 알츠하이머병, 파킨슨병, 헌팅턴병, 루게릭병, 다계통위축증, 알츠하이머성 치매, 혈관성 치매, 전두측두 치매, 루이 치매, 허혈성 뇌졸중, 출혈성 뇌졸중 및 다발성 경화증으로 구성된 군에서 선택되는 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다. In the present invention, the brain disease includes traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, multiple system atrophy, Alzheimer's dementia, vascular dementia, frontotemporal dementia, Lewy dementia, ischemic stroke, hemorrhagic stroke and multiple sclerosis. It may be characterized as being selected from the group consisting of, but is not limited to this.
다른 양태로서, 본 발명은 상기 [화학식 1] 내지 [화학식 3]으로 구성된 군에서 선택되는 화합물 또는 이의 약학적으로 허용 가능한 염 또는 이를 유효성분으로 함유하는 조성물을 이를 필요로 하는 대상체에 투여하는 단계를 포함하는, 뇌질환 예방 또는 치료 방법에 관한 것이다.In another aspect, the present invention includes the step of administering a compound selected from the group consisting of [Formula 1] to [Formula 3], or a pharmaceutically acceptable salt thereof, or a composition containing the same as an active ingredient, to a subject in need thereof. It relates to a method of preventing or treating brain disease, including.
또 다른 양태로서, 본 발명은 상기 [화학식 1] 내지 [화학식 3]으로 구성된 군에서 선택되는 화합물 또는 이의 약학적으로 허용 가능한 염의 뇌질환 예방 또는 치료 용도에 관한 것이다.In another aspect, the present invention relates to the use of a compound selected from the group consisting of [Formula 1] to [Formula 3] or a pharmaceutically acceptable salt thereof for the prevention or treatment of brain disease.
또 다른 양태로서, 본 발명은 뇌질환 예방 또는 치료를 위한 약물의 제조를 위한 상기 [화학식 1] 내지 [화학식 3]으로 구성된 군에서 선택되는 화합물 또는 이의 약학적으로 허용 가능한 염의 용도에 관한 것이다.In another aspect, the present invention relates to the use of a compound selected from the group consisting of [Formula 1] to [Formula 3] or a pharmaceutically acceptable salt thereof for the production of a drug for preventing or treating brain diseases.
본 발명에서, 용어 “약학적 조성물(pharmaceutical composition)”또는 약학적 제형(pharmaceutical formulation)”은 본 발명의 신규 화합물에 생체 내 또는 생체 외 진단 또는 치료 용도에 특히 적합하게 만드는 희석제 또는 담체와 같은 제약상 허용되는 부형제를 포함하는 혼합물을 의미한다. 일부 실시예에 따르면, 본 발명의 조성물을 포함하는 약학적 조성물은 그 필요에 따라 대상체에게 치료적 유효량으로 투여하는 방법으로 제공될 수 있다. 일부 실시예에서, 본 발명의 조성물은 인간에게 투여할 수 있다.As used herein, the term “pharmaceutical composition” or “pharmaceutical formulation” refers to a pharmaceutical agent, such as a diluent or carrier, that makes the novel compound of the present invention particularly suitable for in vivo or in vitro diagnostic or therapeutic use. It refers to a mixture containing acceptable excipients. According to some embodiments, a pharmaceutical composition containing the composition of the present invention may be provided by administering a therapeutically effective amount to a subject according to need. In some embodiments, compositions of the present invention can be administered to humans.
본 발명에서 사용되는 "유효량(effective amount)”또는 "치료적 유효량 (therapeutically-effective amount)"은 유익하거나 원하는 결과를 달성하기에 충분한 화합물 또는 조성물 (예를 들어, 본 발명의 화합물 또는 조성물)의 양을 지칭한다. 유효량은 하나 이상의 투여, 적용 또는 투여량으로 투여될 수 있으며 특정 제제 또는 투여 경로로 제한되는 것으로 의도되지 않는다.As used herein, “effective amount” or “therapeutically-effective amount” refers to the amount of a compound or composition (e.g., a compound or composition of the invention) sufficient to achieve a beneficial or desired result. Refers to an amount. An effective amount may be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular agent or route of administration.
본 발명에서 상기 화합물은 약학적 조성물 총 중량 대비 0.01 내지 99.9%(w/w) 중량으로 함유될 수 있다. In the present invention, the compound may be contained in an amount of 0.01 to 99.9% (w/w) based on the total weight of the pharmaceutical composition.
본 발명에서 “약학적으로 허용가능한 염”은 약학적으로 허용되는 음이온을 함유하는 무독성 산 부가염을 형성하는 산, 예를 들어,황산, 염산, 질산, 인산, 브롬화수소산, 요오드화수소산 등과 같은 무기산과, 타르타르산, 포름산, 시트르산, 아세트산, 트리플루오로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 젖산, 말론산, 말산, 살리실산, 숙신산, 옥살산, 프로피온산, 아스파르탄산, 글루탐산, 구연산 등과 같은 유기산과, 메탄설폰산, 에탄설폰산, 벤젠설폰산, p-톨루엔설폰산, 나프탈렌설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염일 수 있고, 유리 카르복시 치환체를 포함하는 본 발명에 따르는 화학식으로 표시되는 화합물은 상기의 산 부가염 및 나트륨, 칼슘 및 암모늄의 염일 수 있으며, 약학적으로 허용가능한 염이기 부가염, 예를 들어, 리튬, 나트륨, 칼륨, 칼슘, 마그네슘 등에 의해 형성된 알칼리 금속 또는 알칼리 토금속 염과, 라이신, 아르기닌, 구아니딘 등의 아미노산 염과, 디사이클로헥실아민, N-메틸-D-글루카민, 트리스 (하이드록시메틸)메틸아민, 디에탄올아민, 콜린, 트리에틸 아민 등과 같은 유기염일 수 있다.In the present invention, “pharmaceutically acceptable salt” refers to an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, an inorganic acid such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc. Organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, lactic acid, malonic acid, malic acid, salicylic acid, succinic acid, oxalic acid, propionic acid, aspartic acid, glutamic acid, citric acid, etc. , may be an acid addition salt formed by sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc., and may be a compound represented by the chemical formula according to the present invention containing a free carboxy substituent. may be the above acid addition salts and salts of sodium, calcium and ammonium, and may be pharmaceutically acceptable salts, such as alkali metal or alkaline earth metal salts formed by addition salts such as lithium, sodium, potassium, calcium, magnesium, etc. , amino acid salts such as lysine, arginine, and guanidine, and organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine. .
본 발명에 따른 화합물은 통상적인 방법에 의해 그의 염으로 전환될 수 있으며, 염의 제조는 별도의 설명이 없이도 화학식 구조를 바탕으로 당업자에 의해 용이하게 수행될 수 있을 것이다.The compound according to the present invention can be converted into its salt by a conventional method, and the preparation of the salt can be easily performed by a person skilled in the art based on the chemical structure without separate explanation.
본 발명에서 제공되는 약학적 조성물은 원칙적으로 인간에게 투여하기 위한 약학적 조성물에 관한 것이지만, 통상의 기술자는 이러한 조성물이 일반적으로 모든 종류의 동물에게 투여하기 적합함을 이해할 것이다. 즉, 본 발명에 따른 약학적 조성물은 수의학적 치료를 필요로 하는 동물, 예를 들어, 가축 (예: 개, 고양이 등), 농장 동물 (예 : 소, 양, 돼지, 말 등) 및 실험실 동물 (예 : 쥐, 생쥐, 기니피그 등)과 같은 다른 포유 동물에게도 투여될 수 있다. 다양한 동물에게 투여하기 위한 약학적 조성물의 변형을 잘 이해하고, 숙련된 수의학 약리학자는 필요하다면 단순히 통상적인 실험으로 이러한 변형을 설계 및/또는 수행할 수 있다.Although the pharmaceutical compositions provided by the present invention relate in principle to pharmaceutical compositions for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to all types of animals. That is, the pharmaceutical composition according to the present invention is suitable for use in animals requiring veterinary treatment, such as livestock (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.) and laboratory animals. It can also be administered to other mammals such as rats, mice, guinea pigs, etc. A skilled veterinary pharmacologist with a good understanding of the modifications of pharmaceutical compositions for administration to various animals can design and/or perform such modifications, if necessary, simply by routine experimentation.
본 발명에서 기술한 약학적 조성물은 약리학 분야에 알려져 있거나 이후 내용에서 전개되는 임의의 방법에 의해 제조될 수도 있다. 일반적으로, 이러한 정제용 방법은 활성 성분을 부형제 및/또는 하나 이상의 다른 보조 성분과 연관시키는 단계를 포함하고, 이어서 필요하거나 원하는 경우 생성물을 원하는 단일- 또는 다중-용량 단위로 성형 및/또는 포장하는 단계를 포함한다.The pharmaceutical compositions described in the present invention may be prepared by any method known in the field of pharmacology or as discussed later in the text. Generally, these methods for tableting involve the steps of associating the active ingredient with excipients and/or one or more other auxiliary ingredients, followed by shaping and/or packaging the product into the desired single- or multi-dose units, if necessary or desired. Includes steps.
본 발명의 약학적 조성물은 단일 단위 용량 및/또는 복수의 단일 단위 용량으로서 제조, 포장, 및/또는 포장하지 않은 채로 판매될 수도 있다. 본원에서 사용하는 바와 같이, "단위 용량"은 사전 설정된 양의 활성 성분을 포함하는 약학적 조성물의 개별적인 양이다. 활성 성분의 양은 대상체에게 투여되는 활성 성분의 투여량 및/또는 그러한 투여량의 편리한 분획 예컨대 예를 들어 투여량의 1/2 또는 1/3과 일반적으로 동일하다.The pharmaceutical compositions of the present invention may be manufactured, packaged, and/or sold unpackaged as a single unit dose and/or multiple single unit doses. As used herein, a “unit dose” is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of active ingredient is generally equal to the dosage of active ingredient administered to the subject and/or a convenient fraction of such dosage such as, for example, one-half or one-third of the dosage.
본 발명의 약학적 조성물 내 활성 성분, 제약상 허용되는 부형제, 및/또는 임의의 추가 성분의 상대량은 치료 대상체의 동일성, 크기, 및/또는 장애에 따라 그리고 조성물이 투여되는 경로에 따라 변할 것이다. 예로서, 조성물은 0.001% 내지 100% (w/w) 활성 성분을 포함할 수도 있다.The relative amounts of the active ingredient, pharmaceutically acceptable excipients, and/or any additional ingredients in the pharmaceutical compositions of the invention will vary depending on the identity, size, and/or disorder of the subject being treated and the route by which the composition is administered. . By way of example, the composition may include 0.001% to 100% (w/w) active ingredient.
본 발명에서 사용하는 바와 같이, 제약상 허용되는 부형제는 특정한 투여 형태 목적에 적합한 임의의 모든 용매, 분산 매질, 희석제, 또는 다른 액체 비히클, 분산액 또는 현탁 보조제, 표면 활성제, 등장화제, 증점제 또는 유화제, 보존제, 고체 결합제, 윤활제 등을 포함한다. 레밍턴(Remington)의 문헌[The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro, (Lippincott, Williams & Wilkins, Baltimore, MD, 2006]은 약학적 조성물 조제에 사용된 다양한 부형제 및 이의 제조를 위한 공지된 기술을 개시한다. 임의의 통상적인 담체 배지가 예컨대 임의의 원하지 않는 생물학적 효과를 제공하거나 다르게는 약학적 조성물의 임의의 다른 성분과 유해한 방식으로 상호작용함으로써 물질 또는 그 유도체와 공존할 수 없는 것을 제외하고, 그 용도는 본 발명의 범위 내에 있는 것으로 고려한다. 제약상 허용되는 부형제는 적어도 95%, 96%, 97%, 98%, 99%, 또는 100% 순수하다.As used herein, a pharmaceutically acceptable excipient is any solvent, dispersion medium, diluent, or other liquid vehicle, dispersion or suspension aid, surface active agent, isotonic agent, thickener or emulsifier suitable for the purpose of the particular dosage form; Contains preservatives, solid binders, lubricants, etc. Remington's (The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro, (Lippincott, Williams & Wilkins, Baltimore, MD, 2006) describes various excipients used in the preparation of pharmaceutical compositions and known methods for their preparation. The technology is disclosed, except that any conventional carrier medium is incompatible with the substance or derivative thereof, for example by providing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutical composition. and their uses are considered to be within the scope of the present invention. Pharmaceutically acceptable excipients are at least 95%, 96%, 97%, 98%, 99%, or 100% pure.
상기 부형제는 인간 및 수의학적 용도에서 승인되어 있다. 일부 실시예에서, 부형제는 미국식품의 약품국에 의해 승인되어 있다. 일부 실시예에서, 부형제는 제약 등급이다. 일부 실시예에서, 부형제는 미국 약전(USP), 유럽 약전(EP), 영국 약전, 및/또는 국제 약전(EP)의 표준을 충족한다.The excipients are approved for human and veterinary use. In some embodiments, the excipient is approved by the Food and Drug Administration. In some embodiments, the excipient is pharmaceutical grade. In some embodiments, the excipient meets the standards of the United States Pharmacopeia (USP), European Pharmacopoeia (EP), British Pharmacopoeia, and/or International Pharmacopoeia (EP).
약학적 조성물의 제조에 사용된 제약상 허용되는 부형제는 불활성 희석제, 분산제 및/또는 과립화제, 표면 활성제 및/또는 유화제, 붕해제, 결합제, 보존제, 완충제, 윤활제, 및/또는 오일을 포함하지만 이에 제한되지 않는다.Pharmaceutically acceptable excipients used in the preparation of pharmaceutical compositions include, but are not limited to, inert diluents, dispersants and/or granulating agents, surface active agents and/or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and/or oils. Not limited.
이러한 부형제는 임의로 본 발명의 제제에 포함될 수도 있다. 부형제 예컨대 코코아 버터 및 좌제 왁스, 착색제, 코팅제, 감미제, 향미제, 및 퍼퓸제는 조제사의 판단에 따라 조성물에 존재할 수 있다.Such excipients may optionally be included in the formulations of the present invention. Excipients such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, flavors, and perfumers may be present in the composition at the discretion of the formulator.
예시적인 희석제는 탄산칼슘, 탄산나트륨, 인산칼슘, 인산이칼슘, 황산칼슘, 칼슘 히드로겐 포스페이트, 인산나트륨 락토스, 수크로스, 셀룰로스, 미세결정질 셀룰로스, 카올린, 만니톨, 소르비톨, 이노시톨, 염화나트륨, 건조 전분, 옥수수 전분, 분말형 당, 및 이들의 조합을 포함하지만 이에 제한되지 않는다.Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dried starch, Including, but not limited to, corn starch, powdered sugar, and combinations thereof.
예시적인 과립화제 및/또는 분산제는 감자 전분, 옥수수 전분, 타피오카 전분, 소듐 스타치 글리콜레이트, 점토, 알긴산, 구아 검, 시트러스 펄프, 한천, 벤토나이트, 셀룰로스 및 목재 생성물, 천연 스폰지, 양이온-교환 수지, 탄산칼슘, 규산염, 탄산나트륨, 가교-결합형 폴리(비닐-피롤리돈) (크로스포비돈), 소듐 카르복시메틸전분 (소듐 스타치 글리콜레이트), 카르복시메틸 셀룰로스, 가교-결합형 소듐 카르복시메틸 셀룰로스 (크로스카르멜로스), 메틸셀룰로스, 예비젤라틴화 전분 (전분 1500), 미세결정질 전분, 수불용성 전분, 칼슘 카르복시메틸 셀룰로스, 규산알루미늄마그네슘 (비검), 소듐 라우릴 술페이트, 4급 암모늄 화합물, 및 이들의 조합을 포함하지만 이에 제한되지 않는다.Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponges, cation-exchange resins. , Calcium Carbonate, Silicate, Sodium Carbonate, Cross-Linked Poly(vinyl-pyrrolidone) (Crospovidone), Sodium Carboxymethyl Starch (Sodium Starch Glycolate), Carboxymethyl Cellulose, Cross-Linked Sodium Carboxymethyl Cellulose ( croscarmellose), methylcellulose, pregelatinized starch (Starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (vegeum), sodium lauryl sulfate, quaternary ammonium compounds, and these. Including, but not limited to, combinations of.
예시적인 표면 활성제 및/또는 유화제는 천연 유화제 (예를 들어 아카시아, 한천, 알긴산, 알긴산나트륨, 트라가칸트, 촌드럭스(chondrux), 콜레스테롤, 크산탄, 펙틴, 젤라틴, 난황, 카세인, 양모 지방, 콜레스테롤, 왁스, 및 레시틴), 콜로이드성 점토 (예를 들어 벤토나이트 [규산알루미늄] 및 비검 [규산알루미늄마그네슘]), 장쇄 아미노산 유도체, 고분자량 알콜 (예를 들어 스테아릴 알콜, 세틸 알콜, 올레일 알콜, 트리아세틴 모노스테아레이트, 에틸렌 글리콜 디스테아레이트, 글리세릴 모노스테아레이트, 및 프로필렌 글리콜 모노스테아레이트, 폴리비닐 알콜), 카르보머 (예를 들어 카르복시 폴리메틸렌, 폴리아크릴산, 아크릴산 중합체, 및 카르복시비닐 중합체), 카라기난, 셀룰로스 유도체 (예를 들어 카르복시메틸셀룰로스 소듐, 분말화 셀룰로스, 히드록시메틸 셀룰로스, 히드록시프로필 셀룰로스, 히드록시프로필 메틸셀룰로스, 메틸셀룰로스), 소르비탄 지방산 에스테르 (예를 들어 폴리옥시에틸렌 소르비탄 모노라우레이트 [트윈 20], 폴리옥시에틸렌 소르비탄 [트윈 60], 폴리옥시에틸렌 소르비탄 모노올레에이트 [트윈 80], 소르비탄 모노팔미테이트 [스팬 40], 소르비탄 모노스테아레이트 [스팬 60], 소르비탄 트리스테아레이트 [스팬 65], 글리세릴 모노올레에이트, 소르비탄 모노올레에이트 [스팬80]), 폴리옥시에틸렌 에스테르 (예를 들어 폴리옥시에틸렌 모노스테아레이트 [미르즈 45], 폴리옥시에틸렌 수소화 피마자 오일, 폴리에톡실화 피마자 오일, 폴리옥시메틸렌 스테아레이트, 및 솔루톨), 수크로스 지방산 에스테르, 폴리에틸렌 글리콜 지방산 에스테르 (예를 들어 크레모포르), 폴리옥시에틸렌 에테르, (예를 들어 폴리옥시에틸렌 라우릴 에테르 [브리즈 30]), 폴리(비닐-피롤리돈), 디에틸렌 글리콜 모노라우레이트, 트리에탄올아민 올레에이트, 올레산나트륨, 칼륨 올레에이트, 에틸 올레에이트, 올레산, 에틸 라우레이, 소듐 라우릴 술페이트, 플루로닉 F 68, 폴록사머 188, 세트리모늄 브로마이드, 세틸피리디늄 클로라이드, 벤즈알코늄클로라이드, 도큐세이트 소듐, 및/또는 이들의 조합을 포함하지만 이에 제한되지 않는다.Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and veegum [magnesium aluminum silicate]), long-chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol) , triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymers), carrageenans, cellulose derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxymethylcellulose) Ethylene Sorbitan Monolaurate [Tween 20], Polyoxyethylene Sorbitan [Tween 60], Polyoxyethylene Sorbitan Monooleate [Tween 80], Sorbitan Monopalmitate [Span 40], Sorbitan Monostearate [ span 60], sorbitan tristearate [span 65], glyceryl monooleate, sorbitan monooleate [span 80]), polyoxyethylene ester (e.g. polyoxyethylene monostearate [mirz 45]) , polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. cremophor), polyoxyethylene ethers, ( For example, polyoxyethylene lauryl ether [Brise 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl. Including, but not limited to, lauray, sodium lauryl sulfate, pluronic F 68, poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or combinations thereof. No.
예시적인 결합제는 전분 (예를 들어 옥수수 전분 및 전분 페이스트); 젤라틴; 당 (예를 들어 수크로스, 글루코스, 덱스트로스, 덱스트린, 당밀, 락토스, 락티톨, 만니톨); 천연 및 합성 검 (예를 들어 아카시아, 알긴산나트륨, 아이리쉬 모스의 추출물, 판워 검, 섀티 검, 이사폴 후스크스의 점액, 카르복시메틸셀룰로스, 메틸셀룰로스, 에틸셀룰로스, 히드록시에틸셀룰로스, 히드록시프로필 셀룰로스, 히드록시프로필 메틸셀룰로스, 미세결정질 셀룰로스, 셀룰로스 아세테이트, 폴리(비닐-피롤리돈), 규산알루미늄마그네슘 (비검), 및 라치 아라보갈락탄); 알기네이트; 폴리에틸렌 옥시드; 폴리에틸렌 글리콜; 무기 칼슘 염; 규산; 폴리메타크릴레이트; 왁스; 물; 알콜; 및 이들의 조합을 포함하지만 이에 제한되지 않는다.Exemplary binders include starches (e.g. corn starch and starch paste); gelatin; sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol); Natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, Farnwer gum, Shatty gum, Isapol Husk's slime, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl) cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (bigum), and lachi arabogalactan); alginate; polyethylene oxide; polyethylene glycol; inorganic calcium salt; silicic acid; polymethacrylate; wax; water; Alcohol; and combinations thereof.
예시적인 보존제는 항산화제, 킬레이트화제, 항미생물 보존제, 항진균 보존제, 알콜 보존제, 산성 보존제, 및 다른 보존제를 포함할 수도 있다. 예시적인 항산화제는 알파 토코페롤, 아스코르브산, 아스코르빌 팔미테이트, 부틸화 히드록시아니솔, 부틸화 히드록시톨루엔, 모노티오글리세롤, 메타중아황산칼륨, 프로피온산, 프로필 갈레이트, 아스코르브산나트륨, 중아황산나트륨, 메타중아황산나트륨, 및 아황산나트륨을 포함하지만 이에 제한되지 않는다. 예시적인 킬레이트화제는 에틸렌디아민테트라아세트산 (EDTA), 시트르산 1수화물, 이나트륨 에데테이트, 이칼륨 에데테이트, 에데트산, 푸마르산, 말산, 인산, 소듐 에데테이트, 타르타르산, 및 트리소듐 에데테이트를 포함한다. 예시적인 항미생물 보존제는 벤즈알코늄 클로라이드, 벤제토늄 클로라이드, 벤질 알콜, 브로노폴, 세트리미드, 세틸피리디늄 클로라이드, 클로르헥시딘, 클로로부탄올, 클로로크레졸, 클로로크실레놀, 크레졸, 에틸 알콜, 글리세린, 헥세티딘, 이미드우레아, 페놀, 페녹시에탄올, 페닐에틸 알콜, 페닐질산수은 (phenylmercuric nitrate), 프로필렌 글리콜, 및 티메로살을 포함하지만 이에 제한되지 않는다. 예시적인 항진균 보존제는 부틸 파라벤, 메틸 파라벤, 에틸 파라벤, 프로필 파라벤, 벤조산, 히드록시벤조산, 칼륨 벤조에이트, 소르브산칼륨, 벤조산나트륨, 프로피온산나트륨, 및 소르브산을 포함하지만 이에 제한되지 않는다. 예시적인 알콜 보존제는 에탄올, 폴리에틸렌 글리콜, 페놀, 페놀계 화합물, 비스페놀, 클로로부탄올, 히드록시벤조에이트, 및 페닐에틸 알콜을 포함하지만 이에 제한되지 않는다. 예시적인 산성 보존제는 비타민 A, 비타민 C, 비타민 E, 베타-카로틴, 시트르산, 아세트산, 데히드로아세트산, 아스코르브산, 소르브산, 및 피트산을 포함하지만 이에 제한되지 않는다. 다른 보존제는 토코페롤, 토코페롤 아세테이트, 데테록시메 메실레이트, 세트리미드, 부틸화 히드록시아니솔 (BHA), 부틸화 히드록시톨루엔드 (BHT), 에틸렌디아민, 소듐 라우릴 술페이트 (SLS), 소듐 라우릴 에테르 술페이트 (SLES), 중아황산나트륨, 메타중아황산나트륨, 칼륨 술파이트, 메타중아황산칼륨, 글리단트 플러스, 페노닙, 메틸파라벤, 저몰 115, 게르마벤 II, 네올론, 카톤, 및 에욱실을 포함하지만 이에 제한되지 않는다. 특정 실시예에서, 보존제는 항-산화제이다. 다른 실시예에서, 보존제는 킬레이트화제이다.Exemplary preservatives may include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, bisulfite. Including, but not limited to, sodium sulfate, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, disodium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and trisodium edetate. . Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, Includes, but is not limited to, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include tocopherol, tocopherol acetate, deteroxyme mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluende (BHT), ethylenediamine, sodium lauryl sulfate (SLS), Sodium Lauryl Ether Sulfate (SLES), Sodium Bisulfite, Sodium Metabisulfite, Potassium Sulfite, Potassium Metabisulfite, Glydant Plus, Fenonib, Methylparaben, Low Mol 115, Germaben II, Neolon, Katon, and E Including, but not limited to, Uxil. In certain embodiments, the preservative is an antioxidant. In another embodiment, the preservative is a chelating agent.
예시적인 완충제는 시트레이트 완충 용액, 아세테이트 완충 용액, 포스페이트 완충제 용액, 염화암모늄, 탄산칼슘, 염화칼슘, 칼슘 시트레이트, 칼슘 글루비오네이트, 칼슘 글루셉테이트, 칼슘 글루코네이트, D-글루콘산, 글리세로인산칼슘, 락트산칼슘, 프로판산, 칼슘 레불리네이트, 펜탄산, 이염기성 인산칼슘, 인산, 삼염기성 인산칼슘, 수산화칼슘 포스페이트, 아세트산칼륨, 염화칼륨, 글루콘산칼륨, 칼륨 혼합물, 이염기성 인산칼륨, 일염기성 인산칼륨, 인산칼륨 혼합물, 아세트산나트륨, 중탄산나트륨, 염화나트륨, 시트르산나트륨, 락트산나트륨, 이염기성 인산나트륨, 일염기성 인산나트륨, 인산나트륨 혼합물, 트로메타민, 수산화마그네슘, 수산화알루미늄, 알긴산, 피로겐-자유수, 등장성 염수, 링거(Ringer's) 용액, 에틸 알콜, 및 이들의 조합을 포함하지만 이에 제한되지 않는다.Exemplary buffering agents include citrate buffer solution, acetate buffer solution, phosphate buffer solution, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluvionate, calcium gluceptate, calcium gluconate, D-gluconic acid, glyceroside. Calcium phosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dibasic potassium phosphate, monobasic Basic potassium phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixture, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen -Includes, but is not limited to, free water, isotonic saline, Ringer's solution, ethyl alcohol, and combinations thereof.
예시적인 윤활제는 스테아르산마그네슘, 스테아르산칼슘, 스테아르산, 실리카, 활석, 맥아, 글리세릴 베하네이트, 수소화 식물성 오일, 폴리에틸렌 글리콜, 벤조산나트륨, 아세트산나트륨, 염화나트륨, 류신, 마그네슘 라우릴 술페이트, 소듐 라우릴 술페이트, 및 이들의 조합을 포함하지만 이에 제한되지 않는다.Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium. Including, but not limited to, lauryl sulfate, and combinations thereof.
예시적인 오일은 아몬드, 살구 커넬, 아보카도, 바바수야자, 베르가모트, 흑색 커런트 종자, 보리지, 케이드, 카모마일, 카놀라, 카라웨이, 카르나우바, 카스토르, 시나몬, 코코아 버터, 코코넛, 대구 간, 커피, 옥수수, 목화 종자, 에뮤, 유칼립투스, 달맞이꽃, 생선, 아마 씨, 게라니올, 호박, 포도 종자, 개암, 히솝, 이소프로필 미리스테이트, 호호바, 쿠쿠이 넛, 라반딘, 라벤더, 레몬, 리트세아 쿠베바, 마카데미아 넛, 아욱, 망고 종자, 메도우폼 종자, 밍크, 넛멕, 올리브, 오렌지색의 오렌지색 라피, 팜, 팜핵, 복숭아 커넬, 땅콩, 양귀비 종자, 호박 종자, 평지씨, 쌀겨, 로즈마리, 홍화, 샌달우드, 동백나무, 세이보리, 산자나무, 참깨, 시어 버터, 실리콘, 대두, 해바라기, 티트리, 엉겅퀴, 애기동백, 베티버, 호두, 및 밀 배아 오일을 포함하지만 이에 제한되지 않는다. 예시적인 오일은 부틸 스테아레이트, 카프릴산 트리글리세리드, 카프르산 트리글리세리드, 시클로메티콘, 디에틸 세바케이트, 디메티콘 360, 이소프로필 미리스테이트, 미네랄 오일, 옥틸도데칸올, 올레일 알콜, 실리콘 오일, 및 이들의 조합을 포함하지만 이에 제한되지 않는다.Exemplary oils include almond, apricot kernel, avocado, babassu palm, bergamot, black currant seed, borage, cayenne, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee. , corn, cotton seed, emu, eucalyptus, evening primrose, fish, flax seed, geraniol, pumpkin, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litthea cucumber. beba, macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange-orange rappi, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower. , sandalwood, camellia, savory, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, camellia, vetiver, walnut, and wheat germ oil. Exemplary oils include butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil. , and combinations thereof.
경구 및 비경구 투여를 위한 액체 투여 형태는 제약상 허용되는 에멀젼, 마이크로에멀젼, 용액, 현탁액, 시럽 및 엘릭시르를 포함하지만 이에 제한되지 않는다. 활성 성분 외에, 액체 투여 형태는 본 기술분야에 공동으로 사용된 불활성 희석제 예컨대, 예를 들어, 물 또는 다른 용매, 가용화제 및 유화제 예컨대 에틸 알콜, 이소프로필 알콜, 에틸 카르보네이트, 에틸 아세테이트, 벤질 알콜, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸렌 글리콜, 디메틸포름아미드, 오일 (특히, 목화씨, 땅콩, 옥수수, 싹, 올리브, 아주까리, 및 참깨 오일), 글리세롤, 테트라히드로푸르푸릴 알콜, 소르비탄의 폴리에틸렌 글리콜 및 지방산 에스테르, 및 이들의 혼합물을 포함할 수도 있다. 불활성 희석제 외에, 경구 조성물은 아주반트 예컨대 습윤제, 유화제 및 현탁화제, 감미제, 향미제, 및 퍼퓸제를 포함할 수 있다. 비경구 투여를 위한 특정 실시예에서, 본 발명의 신규 화합물는 가용화제 예컨대 크레모포르, 알콜, 오일, 변성 오일, 글리콜, 폴리소르베이트, 시클로덱스트린, 중합체, 및 이들의 조합과 혼합된다.Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents such as, for example, water or other solvents, solubilizers and emulsifiers commonly used in the art such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl. Alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, sprout, olive, castor, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, It may also include polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the novel compounds of the invention are mixed with solubilizing agents such as cremophor, alcohols, oils, denatured oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.
주사가능한 제제, 예를 들어, 멸균 주사가능한 수성 또는 유성 현탁액은 분산제 또는 습윤제 및 현탁화제를 사용하여 공지된 기술 분야에 따라 조제될 수도 있다. 멸균 주사가능한 제제는 비독성 비경구 허용되는 희석제 또는 용매, 예를 들어, 1,3-부탄디올 내 용액에서의 멸균 주사가능한 용액, 현탁액 또는 에멀젼일 수도 있다. 허용되는 비히클 및 용매 중에서 채택될 수도 있는 것은 물, 링거(Ringer's) 용액, U.S.P. 및 등장성 염화나트륨용액이다. 또한, 멸균, 고정 오일은 통상적으로 용매 또는 현탁 매질로서 채택되고 있다. 이를 위하여 합성 모노- 또는 디글리세리드를 포함하는 임의의 무자극 고정 오일이 채택될 수 있다. 또한, 지방산 예컨대 올레산이 주사제의 제조에 사용되고 있다.Injectable preparations, for example, sterile injectable aqueous or oily suspensions, may be prepared according to the known art using dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, such as solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. Additionally, sterile, fixed oils are commonly employed as solvents or suspending media. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid have been used in the preparation of injectables.
주사가능한 제제는 예를 들어 박테리아-보유 필터를 통한 여과에 의해, 또는 사용 전에 멸균수 또는 다른 멸균 주사가능한 배지에 용해 또는 분산될 수 있는 멸균 고체 조성물의 형태인 멸균제를 포함시킴으로써 멸균될 수 있다.Injectable preparations may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. .
약물의 효과를 연장하기 위하여, 흔히 피하 또는 근육내 주사로부터 약물의 흡수를 느리게 하는 것이 바람직하다. 이는 낮은 수용해도를 갖는 결정질 또는 무정형 물질의 액체 현탁액을 사용함으로써 이루어진다. 그러면 약물의 흡수율은 결국 결정 크기 및 결정질 형태에 좌우될 수 있는 용해율에 좌우된다. 대안으로, 비경구 투여 약물의 지연된 흡수는 오일 비히클에서 약물을 용해 또는 현탁화함으로써 이루어진다.To prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This is achieved by using liquid suspensions of crystalline or amorphous substances with low water solubility. The absorption rate of the drug then depends on the dissolution rate, which may ultimately depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug is achieved by dissolving or suspending the drug in an oil vehicle.
경구 투여를 위한 고체 투여 형태는 캡슐, 정제, 환제, 분말, 및 과립을 포함한다. 이러한 고체 투여 형태에서, 활성 성분은 하나 이상의 불활성 제약상 허용되는 부형제 또는 담체 예컨대 시트르산나트륨 또는 인산이칼슘 및/또는 a) 충전제 또는 증량제 예컨대 전분, 락토스, 수크로스, 글루코스, 만니톨, 및 규산, b) 결합제 예컨대, 예를 들어, 카르복시메틸셀룰로스, 알기네이트, 젤라틴, 폴리비닐피롤리디논, 수크로스, 및 아카시아, c) 함습제 예컨대 글리세롤, d) 붕해제 예컨대 한천, 탄산칼슘, 감자 또는 타피오카 전분, 알긴산, 특정 규산염, 및 탄산나트륨, e) 용해 지연제 예컨대 파라핀, f) 흡수 촉진제 예컨대 4급 암모늄 화합물, g) 습윤제 예컨대, 예를 들어, 세틸 알콜 및 글리세롤 모노스테아레이트, h) 흡수제 예컨대 카올린 및 벤토나이트 점토, 및 i) 윤활제 예컨대 활석, 스테아르산칼슘, 스테아르산마그네슘, 고체 폴리에틸렌 글리콜, 소듐 라우릴 술페이트, 및 이들의 혼합물과 혼합되어 있다. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active ingredient may be combined with one or more inert pharmaceutically acceptable excipients or carriers such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b ) binders such as, for example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch. , alginic acid, certain silicates, and sodium carbonate, e) dissolution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) humectants such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof.
캡슐의 경우, 정제 및 환제, 투여 형태는 완충제를 포함할 수 있다. 유사한 유형의 고체 조성물은 락토스 또는 유당뿐만 아니라 고분자량 폴리에틸렌 글리콜 등을 그러한 부형제로서 사용하는 연질 및 경질-충전된 젤라틴 캡슐에서 충전제로서 채택될 수도 있다. 정제, 당의정, 캡슐, 환제, 및 과립의 고체 투여 형태는 코팅 및 쉘 예컨대 장용 코팅 및 제약 조제 분야에 잘 알려진 다른 코팅과 함께 제조될 수 있다. 이들은 임의로 불투명화제를 포함할 수도 있고, 활성 성분만을, 또는 우선적으로, 장관의 특정 부분, 임의로는 지연된 방식으로 방출하는 조성물일 수 있다. 사용될 수 있는 포매 조성물의 예는 중합체 물질 및 왁스를 포함한다. 유사한 유형의 고체 조성물은 락토스 또는 유당뿐만 아니라 고분자량 폴리에틸렌 글리콜 등을 그러한 부형제로서 사용하는 연질 및 경질-충전된 젤라틴 캡슐에서 충전제로서 채택될 수도 있다.In the case of capsules, tablets and pills, dosage forms may contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar as well as high molecular weight polyethylene glycols and the like as such excipients. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may be compositions that release the active ingredient only, or preferentially, in a specific part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar as well as high molecular weight polyethylene glycols and the like as such excipients.
활성 성분은 상술한 하나 이상의 부형제와 함께 마이크로-캡슐화된 형태일 수 있다. 정제, 당의정, 캡슐, 환제, 및 과립의 고체 투여 형태는 코팅 및 쉘 예컨대 장용 코팅, 방출 제어 코팅 및 제약 조제 분야에 잘 알려진 다른 코팅과 함께 제조될 수 있다. 이러한 고체 투여 형태에서 활성 성분은 하나 이상의 불활성 희석제 예컨대 수크로스, 락토스 또는 전분과 혼합될 수도 있다. 이러한 투여 형태는 보통 실시에서처럼 불화성 희석제가 아닌 추가 물질, 예를 들어, 정제 윤활제 및 다른 정제 보조제 예컨대 스테아르산마그네슘 및 미세결정질 셀룰로스를 포함할 수 있다. 캡슐의 경우, 정제 및 환제, 투여 형태는 완충제를 포함할 수도 있다. 이들은 임의로 불투명화제를 포함할 수도 있고, 활성 성분만을, 또는 우선적으로, 장관의 특정 부분, 임의로는 지연된 방식으로 방출하는 조성물일 수 있다. 사용될 수 있는 포매 조성물의 예는 중합체 물질 및 왁스를 포함한다.The active ingredient may be in micro-encapsulated form with one or more of the excipients described above. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings, and other coatings well known in the pharmaceutical formulation art. In these solid dosage forms the active ingredient may be mixed with one or more inert diluents such as sucrose, lactose or starch. These dosage forms may contain additional substances other than inert diluents as in common practice, such as tablet lubricants and other tablet auxiliaries such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may be compositions that release the active ingredient only, or preferentially, in a specific part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
본 발명의 신규 화합물 또는 이를 함유하는 약학적 조성물의 국소 및/또는 경피 투여를 위한 투여 형태는 연고, 페이스트, 크림, 로션, 겔, 분말, 용액, 스프레이, 흡입제 및/또는 패치를 포함할 수도 있다. 일반적으로, 활성 성분은 멸균 장애하에서 제약상 허용되는 담체 및/또는 임의의 필요한 보존제 및/또는 요구될 수도 있는 완충제와 혼합되어 있다. 추가로, 본 발명은 흔히 활성 성분의 몸체로의 제어된 전달을 제공하는 추가 장점을 갖는 경피 패치의 사용을 고려한다. 이러한 투여 형태는 예를 들어 활성 성분을 적당한 배지에 융해 및/또는 분산시킴으로써 제조될 수 있다. 대안으로 또는 추가로, 비율 제어 막을 제공하고/거나 활성 성분을 중합체 매트릭스 및/또는 겔에 분산시킴으로써 비율이 제어될 수도 있다.Dosage forms for topical and/or transdermal administration of the novel compounds of the present invention or pharmaceutical compositions containing them may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. . Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and/or any necessary preservatives and/or buffering agents that may be required. Additionally, the present invention contemplates the use of transdermal patches, which often have the additional advantage of providing controlled delivery of the active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispersing the active ingredient in a suitable medium. Alternatively or additionally, the rate may be controlled by providing a rate controlling membrane and/or dispersing the active ingredient in a polymer matrix and/or gel.
국소 투여를 위한 제제는 액체 및/또는 세미 액체 제제 예컨대 도찰제, 로션, 수중유 및/또는 유중수 에멀젼 예컨대 크림, 연고/또는 페이스트, 및/또는 용액 및/또는 현탁액을 포함하지만 이에 제한되지 않는다. 활성 성분의 농축이 용매 내 활성 성분의 용해도 한계만큼 높을 수도 있지만, 국소-투여가능한 제제는 예를 들어 약 1% 내지 약 10% (w/w) 활성 성분을 포함할 수도 있다. 국소 투여를 위한 제제는 본원에서 기술한 하나 이상의 추가 성분을 추가로 포함할 수도 있다.Formulations for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments/or pastes, and/or solutions and/or suspensions. Although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent, topically-administrable formulations may also comprise, for example, from about 1% to about 10% (w/w) of the active ingredient. Formulations for topical administration may further comprise one or more additional ingredients described herein.
본원에서 기술한 본 발명의 신규 화합물 또는 이를 함유하는 약학적 조성물은 전형적으로 쉬운 투여 및 균일한 투여를 위하여 투여 단위 형태로 제조된다. 그러나 본 발명의 조성물의 총 일일 용법은 타당한 의학적 판단의 범위 내에서 담당의에 의해 결정될 것임을 이해하게 될 것이다. 임의의 특정 대상체에 대한 특정한 치료 유효 용량 수준은 질환, 장애, 또는 치료 중인 장애 및 장애의 심각도를 포함하는 다양한 인자; 채택된 특정 활성 성분의 활성; 채택된 특정 조성물; 대상체의 나이, 체중, 전반적인 건강, 성별 및 다이어트; 채택된 특정 활성 성분의 투여 시간, 투여 경로, 및 배설율; 치료 기간; 채택된 특정 활성 성분과 조합하거나 동시에 사용한 약물; 및 의료 분야에 잘 알려진 인자 등에 좌우될 것이다.The novel compounds of the invention described herein or pharmaceutical compositions containing them are typically prepared in dosage unit form for easy administration and uniform administration. However, it will be understood that the total daily dosage of the composition of the present invention will be determined by the attending physician within the scope of sound medical judgment. The particular therapeutically effective dose level for any particular subject will depend on a variety of factors, including the disease, disorder, or disorder being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; The subject's age, weight, general health, gender, and diet; the time of administration, route of administration, and rate of excretion of the particular active ingredient employed; duration of treatment; Drugs used in combination or simultaneously with the specific active ingredients employed; and factors well known in the medical field.
본 발명의 신규 화합물, 이의 염, 또는 이의 약학적 조성물은 임의의 경로로 투여될 수도 있다. 일부 실시예에서, 신규 화합물, 이의 염, 또는 이의 약학적 조성물은 경구, 정맥내, 근육내, 동맥내, 수질내, 척수강내, 피하, 뇌실내, 경피, 피내, 직장, 질내, 복강내, 국소(분말, 연고, 크림, 및/또는 액적에 의함), 점막, 코, 입, 경장, 설하; 기관내 점적주입, 기관지 점적주입, 및/또는 흡입; 및/또는 경구 스프레이, 비강 스프레이, 및/또는 에어로졸을 포함하는 다양한 경로에 의해 투여된다. 구체적으로 고려되는 경로는 침투성 정맥내 주사, 혈액 및/또는 림프 공급을 통한 국부 투여, 및/또는 환부 부위에 대한 직접 투여이다. 일반적으로 투여의 가장 적합한 경로는 작용제의 특성(예를 들어, 위장관의 환경에서의 안정성), 및 대상체의 장애(예를 들어 대상체가 경구 투여를 참을 수 있는지 여부)를 포함하는 다양한 인자에 좌우될 것이다. The novel compound of the present invention, its salt, or pharmaceutical composition may be administered by any route. In some embodiments, the novel compound, salt thereof, or pharmaceutical composition thereof may be administered orally, intravenously, intramuscularly, intraarterially, intramedullarily, intrathecally, subcutaneously, intracerebroventricularly, transdermally, intradermally, rectally, intravaginally, intraperitoneally, Topically (by powder, ointment, cream, and/or drop), mucosal, nasal, oral, enteral, sublingual; endotracheal instillation, bronchial instillation, and/or inhalation; and/or administered by various routes, including oral spray, nasal spray, and/or aerosol. Particularly contemplated routes are permeable intravenous injection, local administration via the blood and/or lymphatic supply, and/or direct administration to the affected area. In general, the most appropriate route of administration will depend on a variety of factors, including the properties of the agent (e.g., stability in the environment of the gastrointestinal tract), and the disorder of the subject (e.g., whether the subject can tolerate oral administration). will be.
본 발명의 신규 화합물 또는 이의 염은 약학적 조성물의 총 중량 대비 0.001 내지 99.9%의 함량으로 포함될 수 있다. The novel compound of the present invention or its salt may be included in an amount of 0.001 to 99.9% of the total weight of the pharmaceutical composition.
특정 실시예에서, 본 발명의 신규 화합물, 이의 염, 또는 이의 약학적 조성물은 매일 대상체 체중의 약 0.001 mg/kg 내지 약 1000 mg/kg, 약 0.01 mg/kg 내지 약 500 mg/kg, 약 0.1 mg/kg 내지 약 400 mg/kg, 약 0.5 mg/kg 내지 약 300 mg/kg, 약 1 mg/kg 내지 약 200 mg/kg, 약 10 mg/kg 내지 약 100 mg/kg, 또는 약 3 mg/kg 내지 약 90 mg/kg을 하루에 1회 이상 전달하기 충분한 투여량 수준으로 투여하여 원하는 치료 효과를 얻을 수도 있다. 목적 투여량은 하루에 세 번, 하루에 두 번, 하루마다, 이틀마다, 삼일마다, 매주마다, 2주마다, 3주마다, 또는 4주마다 전달될 수도 있다. 특정 실시양태에서, 목적 투여량은 다중 투여(예를 들어 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 회 이상의 투여)를 통해 전달될 수도 있다. In certain embodiments, the novel compounds of the present invention, salts thereof, or pharmaceutical compositions thereof are administered at a daily dose of about 0.001 mg/kg to about 1000 mg/kg, about 0.01 mg/kg to about 500 mg/kg, or about 0.1 mg/kg of the subject's body weight. mg/kg to about 400 mg/kg, about 0.5 mg/kg to about 300 mg/kg, about 1 mg/kg to about 200 mg/kg, about 10 mg/kg to about 100 mg/kg, or about 3 mg. /kg to about 90 mg/kg may be administered at a dosage level sufficient to deliver once or more per day to achieve the desired therapeutic effect. The intended dosage may be delivered three times a day, twice a day, daily, every two days, every three days, weekly, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered via multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more administrations). .
본 발명에서 기술한 용량 범위는 성인에게 제공된 약학적 조성물의 투여에 대한 가이던스를 제공함을 이해하게 될 것이다. 예를 들어 어린이 또는 청소년에게 투여되는 양은 전문의 또는 본 기술분야의 숙련자에 의해 결정될 수 있고, 성인에게 투여되는 것보다 적거나 동일할 수 있다. 유효량을 달성하는 데 요구되는 본 발명에 따른 화합물의 정확한 양은 예를 들어 대상체의 종, 나이, 및 전반적인 장애, 부작용 또는 장애의 심각도, 특성 화합물의 동일성, 투여 방식 등에 따라 대상체마다 다를 것이다.It will be understood that the dosage ranges described herein provide guidance for administration of pharmaceutical compositions provided to adults. For example, the amount administered to a child or adolescent may be determined by a physician or person skilled in the art, and may be less or the same as that administered to an adult. The exact amount of a compound according to the invention required to achieve an effective amount will vary from subject to subject, depending, for example, on the subject's species, age, and overall disorder, severity of side effects or disorders, identity of the specific compound, mode of administration, etc.
본 발명의 신규 화합물 및 약학적 조성물은 조합 요법으로 사용될 수 있다는 것이 이해될 것이다. 조합 요법에 사용되기 위한 치료의 특정한 조합(치료제 또는 절차)은 달성될 목적 치료 효과 및 목적 치료제 및/또는 절차의 적합성을 고려할 것이다. It will be appreciated that the novel compounds and pharmaceutical compositions of the present invention can be used in combination therapy. The particular combination of treatments (treatments or procedures) for use in combination therapy will take into account the desired therapeutic effect to be achieved and the suitability of the desired treatments and/or procedures.
본 발명의 약학적 조성물은 단독으로 또는 하나 이상의 치료 활성제와 조합(combination)하여 투여될 수 있다. "조합"의 경우, 다음 전달 방법이 본 발명의 범위에 속하긴 하지만, 작용제가 꼭 동일한 시간에 투여되어야 하고/하거나 같이 전달되기 위해 제형화되어야 한다는 것을 시사하도록 의도되진 않는다. 조성물은 하나 이상의 다른 목적 치료제 또는 의료 절차와 동시에, 그보다 먼저, 또는 그 이후에 투여될 수 있다. 일반적으로, 각 작용제는 그 작용제에 대해 정해진 투여량 및/또는 시간 스케쥴로 투여될 것이다. 추가로, 본 발명은 신체 내에서 그의 생체이용률을 개선시키고, 그의 대사를 감소 및/또는 수정하고, 그의 분비를 억제하고, 및/또는 그의 분포를 수정할 수 있는 작용제와 조합하여 본 발명의 약학적 조성물을 전달하는 것을 아우른다. 이 조합에서 사용되는 본 발명의 신규 화합물 및 치료 활성제는 단일 조성물로 같이 투여되거나 상이한 조성물로 별도로 투여될 수 있다는 것이 더 이해될 것이다.The pharmaceutical composition of the present invention can be administered alone or in combination with one or more therapeutically active agents. As for "combination", it is not intended to imply that the agents must be administered at the same time and/or be formulated for delivery together, although the following delivery methods are within the scope of the present invention. The composition may be administered concurrently with, prior to, or subsequent to one or more other therapeutic agents or medical procedures. Generally, each agent will be administered at a dose and/or time schedule established for that agent. Additionally, the present invention provides a pharmaceutical form of the present invention in combination with agents capable of improving its bioavailability, reducing and/or modifying its metabolism, inhibiting its secretion, and/or modifying its distribution within the body. It encompasses delivering the composition. It will be further understood that the novel compound of the invention and the therapeutically active agent used in this combination may be administered together in a single composition or may be administered separately in different compositions.
조합 요법에 사용되는 특정한 조합은 달성될 목적 치료 효과 및/또는 본 발명의 화합물을 포함하는 절차 및/또는 치료 활성제의 적합성을 고려할 것이다. 사용되는 조합은 동일한 장애에 대해 목적 효과를 달성할 수 있고(예를 들어, 본 발명의 신규 화합물은 동일한 장애를 치료하는 데 사용되는 또 다른 치료 활성제(예컨대, 제2 치료제)와 병용하여 투여될 수 있다), 및/또는 이것들은 상이한 효과를 달성할 수 있다(예를 들어, 임의의 부작용 제어)는 것이 이해될 것이다.The particular combination used in combination therapy will take into account the desired therapeutic effect to be achieved and/or the suitability of the therapeutically active agent and/or procedure comprising the compound of the invention. The combination used may achieve the desired effect for the same disorder (e.g., a novel compound of the invention may be administered in combination with another therapeutically active agent (e.g., a second therapeutic agent) used to treat the same disorder. It will be understood that they may achieve different effects (e.g., control of any side effects), and/or they may achieve different effects (e.g., control of any side effects).
본원에서 사용되는, "치료 활성제"는 장애를 치료, 예방, 지연, 환원 또는 개선시키기 위한 의약으로서 사용되는 임의의 물질을 가리키고, 예방적 및 치유적 치료를 포함하는, 치료에 사용되는 물질을 가리킨다.As used herein, “therapeutically active agent” refers to any substance used as a medicine to treat, prevent, delay, reduce or ameliorate a disorder, and refers to substances used in treatment, including prophylactic and curative treatments. .
일부 실시예에서, 본 발명의 약학적 조성물은 하나 이상의 증상 또는 특징을 치료, 경감, 개선, 완화시키고, 그 개시를 지연시키고, 그 진행을 억제시키고, 그 중증도를 감소시키고, 및/또는 그 발생률을 감소시키는 데 유용한 임의의 치료 활성제 또는 절차 (예를 들어, 수술, 방사선 요법)와 조합하여 투여될 수 있다.In some embodiments, the pharmaceutical compositions of the invention treat, alleviate, ameliorate, alleviate, delay the onset, inhibit the progression, reduce the severity, and/or the incidence of one or more symptoms or characteristics. Can be administered in combination with any therapeutically active agent or procedure (e.g., surgery, radiation therapy) useful for reducing .
일 양태로서, 본 발명은 염증 질환 또는 뇌질환으로 구성된 군에서 선택되는 어느 하나 이상의 질환을 앓고 있는 대상체에게 상기 질환을 치료하기 위한 키트로 제공될 수 있다. In one aspect, the present invention may be provided as a kit for treating any one or more diseases selected from the group consisting of inflammatory diseases and brain diseases to a subject suffering from said diseases.
일부 양태에서, 상기 키트는 i) 본 발명에 따른 신규 화합물 또는 약학적 조성물을 상기 질환을 앓고 있는 대상체에게 투여하기 위한 설명서 (instruction), 및 ii) 본 발명에 따른 신규 화합물 또는 약학적 조성물을 포함한다. 일부 양태에서, 상기 키트는 대상체에서 상기 질환을 치료하는 데 효과적인 본 발명에 기재된 바와 같은 용량의 신규 화합물 또는 약학적 조성물을 함유하는 하나 이상의 단위 투여 형태 (unit dosage form)를 포함할 수 있다. 일부 양태에서, 상기 대상체는 인간 환자이다. In some embodiments, the kit comprises i) instructions for administering the novel compound or pharmaceutical composition according to the invention to a subject suffering from the disease, and ii) the novel compound or pharmaceutical composition according to the invention. do. In some embodiments, the kit may include one or more unit dosage forms containing a dose of the novel compound or pharmaceutical composition as described herein effective for treating the disease in a subject. In some embodiments, the subject is a human patient.
일부 양태에서, 상기 키트는 멸균 주사기, 멸균 바늘, 멸균 IV 백, 주입 펌프 또는 이들의 임의의 조합을 포함하는 군으로부터 선택된 하나 이상을 추가로 포함한다.In some embodiments, the kit further includes one or more selected from the group comprising a sterile syringe, a sterile needle, a sterile IV bag, an infusion pump, or any combination thereof.
다른 관점에서, 본 발명은 또한, [화학식 1] 내지 [화학식 3]으로 구성된 군에서 선택되는 어느 하나의 화합물을 함유하는 식품 조성물을 제공한다:From another perspective, the present invention also provides a food composition containing any one compound selected from the group consisting of [Formula 1] to [Formula 3]:
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
. .
본 발명에 있어서, 상기 식품은 염증 완화 또는 염증 개선을 위한 건강기능식품일 수 있다. In the present invention, the food may be a health functional food for alleviating or improving inflammation.
본 발명에 있어서, 상기 식품은 뇌질환 치료 보조용 건강기능식품일 수 있다. In the present invention, the food may be a health functional food for assisting in the treatment of brain diseases.
본 발명의 용어, 식품 조성물은 영양성분을 함유하는 물질을 포괄하는 넓은 의미로 사용되며, 음료수, 차, 드링크제, 알코올음료, 비타민 복합제, 프리바이오틱스, 프로바이오틱스, 포스트 바이오틱스, 건강보조식품, 건강기능식품 및 건강식품 등이 있으며, 통상적인 의미에서의 식품을 모두 포함할 뿐만 아니라, 식품에 첨가되는 "식품 첨가제" 또는 "식품 첨가용 조성물"을 포함하는 의미로 사용된다.The term food composition of the present invention is used in a broad sense to encompass substances containing nutritional ingredients, such as beverages, tea, drinks, alcoholic beverages, vitamin complexes, prebiotics, probiotics, postbiotics, health supplements, health There are functional foods and health foods, and it not only includes all foods in the conventional sense, but is also used to include “food additives” or “compositions for food addition” added to foods.
본 발명에 있어서, 상기 식품 조성물은 뇌질환을 완화하거나 개선하는 기능을 갖는 건강기능(성)식품인 것을 특징으로 할 수 있다.In the present invention, the food composition may be characterized as a health functional (sexual) food that has the function of alleviating or improving brain diseases.
본 발명의 용어, 건강기능(성) 식품(functional food)이란, 특정보건용 식품(food for special health use, FoSHU)과 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미한다. 여기서 "기능(성)"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 식품은 당 업계에서 통상적으로 사용되는 방법에 의하여 제조 가능하며, 상기 제조시에는 당 업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 식품의 제형 또한 식품으로 인정되는 제형이면 제한 없이 제조될 수 있으며, 본 발명에 따른 건강기능식품은 분말, 과립, 정제, 캡슐 또는 음료의 형태일 수 있다.The term of the present invention, functional food, is the same as food for special health use (FoSHU), and is a medical product processed to efficiently exhibit bioregulatory functions in addition to nutritional supply. It refers to food with high medical effectiveness. Here, “function” means adjusting nutrients to the structure and function of the human body or obtaining useful effects for health purposes, such as physiological effects. The food of the present invention can be manufactured by methods commonly used in the industry, and can be manufactured by adding raw materials and ingredients commonly added in the industry. In addition, the formulation of the food can be manufactured without limitation as long as it is a formulation recognized as a food, and the health functional food according to the present invention may be in the form of powder, granules, tablets, capsules, or beverages.
상기 건강식품(health food)은 일반식품에 비해 적극적인 건강 유지나 증진 효과를 가지는 식품을 의미하고, 건강보조식품(health supplement food)은 건강보조 목적의 식품을 의미한다. 경우에 따라, 건강 기능 식품, 건강식품, 건강보조식품의 용어는 혼용된다.The above-mentioned health food refers to food that has a more active health maintenance or promotion effect compared to general food, and health supplement food refers to food for the purpose of health supplementation. In some cases, the terms health functional food, health food, and health supplement are used interchangeably.
상기 식품 조성물은 생리학적으로 허용 가능한 담체를 추가로 포함할 수 있는데, 담체의 종류는 특별히 제한되지 않으며 당해 기술 분야에서 통상적으로 사용되는 담체라면 어느 것이든 사용할 수 있다.The food composition may further include a physiologically acceptable carrier. The type of carrier is not particularly limited, and any carrier commonly used in the art can be used.
또한, 상기 조성물은 식품 조성물에 통상 사용되어 냄새, 맛, 시각 등을 향상시킬 수 있는 추가 성분을 포함할 수 있다. 예들 들어, 비타민 A, C, D, E, B1, B2, B6, B12, 니아신(niacin), 비오틴(biotin), 폴레이트(folate), 판토텐산(panthotenic acid) 등을 포함할 수 있다. 또한, 아연(Zn), 철(Fe), 칼슘(Ca), 크롬(Cr), 마그네슘(Mg), 망간(Mn), 구리(Cu), 크륨(Cr) 등의 미네랄을 포함할 수 있다. 또한, 라이신, 트립토판, 시스테인, 발린 등의 아미노산을 포함할 수 있다.Additionally, the composition may contain additional ingredients that are commonly used in food compositions to improve smell, taste, vision, etc. For example, it may include vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, pantothenic acid, etc. Additionally, it may contain minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), and chromium (Cr). Additionally, it may contain amino acids such as lysine, tryptophan, cysteine, and valine.
또한, 상기 조성물은 방부제(소르빈산 칼륨, 벤조산나트륨, 살리실산, 데히드로초산나트륨 등), 살균제(표백분과 고도 표백분, 차아염소산나트륨 등), 산화방지제(부틸히드록시아니졸(BHA), 부틸히드록시톨류엔(BHT) 등), 착색제(타르색소 등), 발색제(아질산 나트륨, 아초산 나트륨 등), 표백제(아황산나트륨), 조미료(MSG 등), 감미료(둘신, 사이클레메이트, 사카린, 나트륨 등), 향료(바닐린, 락톤류 등), 팽창제(명반, D-주석산수소칼륨 등), 강화제, 유화제, 증점제(호료), 피막제, 검기초제, 거품억제제, 용제, 개량제 등의 식품 첨가물(food additives)을 포함할 수 있다. 상기 첨가물은 식품의 종류에 따라 선별되고 적절한 양으로 사용될 수 있다.In addition, the composition contains preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), disinfectants (bleaching powder, high bleaching powder, sodium hypochlorite, etc.), and antioxidants (butylhydroxyanisole (BHA), butylhydroxyanisole). toluene (BHT), etc.), colorants (tar color, etc.), coloring agents (sodium nitrite, sodium nitrite, etc.), bleaching agents (sodium sulfite), seasonings (MSG, etc.), sweeteners (dulcine, cyclemate, saccharin, sodium, etc.) ), flavorings (vanillin, lactones, etc.), leavening agents (alum, D-potassium hydrogen tartrate, etc.), strengthening agents, emulsifiers, thickeners (greasings), coating agents, gum base agents, anti-foam agents, solvents, improvers, etc., food additives (food) additives) may be included. The additives can be selected depending on the type of food and used in an appropriate amount.
본 발명의 상기 다당체와 함께 식품학적으로 허용가능한 식품 보조 첨가제를 더 포함할 수 있으며, 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다.Together with the polysaccharide of the present invention, a foodologically acceptable food auxiliary additive may be further included, and may be used together with other foods or food ingredients, and may be used appropriately according to conventional methods. The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment).
본 발명에 사용된 용어 "약 (about)"은 대략, 가량, 대충, 또는 일정 정도의 의미로 해석될 수 있다. "약" 이라는 용어가 숫자 범위와 함께 사용되는 경우, 지정된 숫자 값의 위아래로 경계를 확장하여 해당 범위를 수정하여 해석한다. 일반적으로, 용어 "약"은 10%의 분산에 의해 명시된 값의 위와 아래의 수치 값을 수정하기 위해 본 발명에서 사용된다.The term “about” used in the present invention may be interpreted to mean approximately, roughly, approximately, or to a certain extent. When the term "about" is used with a numeric range, it is interpreted as modifying that range by extending the boundaries above and below the specified numeric value. Generally, the term "about" is used herein to modify a numerical value above or below a specified value by a variance of 10%.
"개체 (individual)", "환자 (patient)" 및 "대상체 (subject)"는 상호 교환 적으로 사용되며 포유류, 예를 들어 마우스, 쥐, 기타 설치류, 토끼, 개, 고양이, 돼지, 소, 양, 말, 또는 인간을 포함한 영장류를 포함하여 임의의 동물을 포함한다.“Individual,” “patient,” and “subject” are used interchangeably and refer to mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, and sheep. , horses, or any animal, including primates, including humans.
본 발명에서 "치료"란, 달리 언급되지 않는 한, 상기 용어가 적용되는 질환 또는 질병, 또는 상기 질환 또는 질병의 하나 이상의 증상을 역전시키거나, 완화시키거나, 그 진행을 억제하거나, 또는 예방하는 것을 의미하며, 본원에서 사용된 상기 치료란 용어는 "치료하는"이 상기와 같이 정의될 때 치료하는 행위를 말한다. 따라서 포유류에 있어서 질환의 "치료" 또는 "치료요법"은 하기의 하나 이상을 포함할 수 있다:In the present invention, unless otherwise stated, "treatment" means reversing, alleviating, inhibiting the progression of, or preventing the disease or disease to which the term applies, or one or more symptoms of the disease or disease. means, and the term treatment as used herein refers to the act of treating when “treating” is defined as above. Accordingly, “treatment” or “therapy” of a disease in a mammal may include one or more of the following:
(1) 질환의 발달을 저지시킴,(1) arresting the development of the disease;
(2) 질환의 확산을 예방함,(2) preventing the spread of disease;
(3) 질환을 경감시킴,(3) alleviating disease;
(4) 질환의 재발을 예방함 및(4) preventing disease recurrence and
(5) 질환의 증상을 완화함(palliating)(5) Alleviating symptoms of disease (palliating)
본 발명에서 "예방” 이란, 달리 언급되지 않는 한, 본 발명에 따른 약학적 조성물의 투여에 의해 염증 질환 또는 뇌질환을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.In the present invention, “prevention”, unless otherwise specified, means any action that suppresses or delays the onset of inflammatory disease or brain disease by administering the pharmaceutical composition according to the present invention.
본 발명은 또 다른 관점에서 다음 단계를 포함하는 하기 화학식 1 화합물의 제조방법에 관한 것이다:In another aspect, the present invention relates to a process for preparing a compound of formula 1, comprising the following steps:
[화학식 1][Formula 1]
(a) 포말리도마이드를 다이옥세인에 용해시키는 단계; 및(a) dissolving pomalidomide in dioxane; and
(b) 오황화인을 첨가하고 60 내지 100℃에서 반응시키는 단계.(b) Adding phosphorus pentasulfide and reacting at 60 to 100°C.
본 발명에 있어서, 상기 (b) 단계는 70 내지 90℃에서 반응시킬 수 있으며, 바람직하게는 약 80℃에서 반응시킬 수 있다. In the present invention, step (b) can be carried out at 70 to 90°C, and preferably at about 80°C.
본 발명에 있어서, 상기 (b) 단계는 10분 내지 6시간, 예컨대, 30분 내지 3시간, 바람직하게는 약 1시간 동안 반응시키는 것일 수 있다. In the present invention, step (b) may be performed for 10 minutes to 6 hours, for example, 30 minutes to 3 hours, preferably about 1 hour.
본 발명에 있어서, 상기 (b) 단계는 포말리도마이드를 오황화인과 약 1 : 0.5 내지 2의 몰비로 반응시키는 것을 특징으로 할 수 있으며, 바람직하게는 약 1 : 1의 몰비로 반응시키는 것을 특징으로 할 수 있다. In the present invention, step (b) may be characterized in that pomalidomide is reacted with phosphorus pentasulfide at a molar ratio of about 1:0.5 to 2, preferably at a molar ratio of about 1:1. You can do this.
본 발명에 있어서, 상기 제조방법은 (b) 단계 이후, (c) 여과 및/또는 크로마토그래피로 정제하는 단계;를 추가로 포함하는 것을 특징으로 할 수 있다. In the present invention, the production method may further include, after step (b), (c) purifying by filtration and/or chromatography.
본 발명에 있어서, 상기 (c) 단계에서, 여과는 상기 (b) 단계에서 고체를 제거하고 용매를 수득하는 것일 수 있으며, 상기 용매는 이후 농축시켜 크로마토그래피로 정제하는 것을 특징으로 할 수 있다. In the present invention, in step (c), filtration may be performed to remove the solid in step (b) and obtain a solvent, and the solvent may then be concentrated and purified by chromatography.
본 발명에 있어서, 상기 크로마토그래피는 관 크로마토그래피일 수 있고, 바람직하게는 실리카겔 (SiO2) 크로마토그래피일 수 있으며, 이동상으로 바람직하게는 클로로포름 (CHCl3) : 아세톤 (Acetone) = 80 내지 120 : 5(v/v)로 사용하는 관 크로마토그래피일 수 있다. In the present invention, the chromatography may be tube chromatography, preferably silica gel (SiO2) chromatography, and the mobile phase is preferably chloroform (CHCl 3 ): Acetone = 80 to 120: 5. It may be tube chromatography using (v/v).
본 발명에 있어서, 상기 크로마토그래피로 정제된 화합물은 디클로로메탄을 이용하여 고체화할 수 있다. In the present invention, the compound purified by chromatography can be solidified using dichloromethane.
본 발명은 또 다른 관점에서, 다음 단계를 포함하는 화학식 2 화합물의 제조방법에 관한 것이다:The present invention, in another aspect, relates to a process for preparing a compound of formula 2 comprising the following steps:
[화학식 2][Formula 2]
(a) 레날리도마이드를 다이옥세인에 용해시키는 단계; 및(a) dissolving lenalidomide in dioxane; and
(b) 질소 분위기 하에서 Lawesson 시약을 첨가하고 80 내지 120℃에서 반응시키는 단계.(b) Adding Lawesson reagent under a nitrogen atmosphere and reacting at 80 to 120°C.
본 발명에 있어서, 상기 제조방법은 (b) 단계 이후, (c) 크로마토그래피로 정제하는 단계;를 추가로 포함하는 것을 특징으로 할 수 있다. In the present invention, the production method may further include, after step (b), (c) purifying by chromatography.
본 발명에 있어서, 상기 (b) 단계는 90 내지 110℃에서 반응시킬 수 있으며, 바람직하게는 약 100℃에서 반응시킬 수 있다.In the present invention, step (b) can be carried out at 90 to 110°C, and preferably at about 100°C.
본 발명에 있어서, 상기 (b) 단계는 밤새 반응시키는 것일 수 있다. In the present invention, step (b) may be performed overnight.
본 발명에 있어서, 상기 (b) 단계는 레날리도마이드를 Lawesson 시약과 약 1 : 0.5 내지 2의 몰비로 반응시키는 것을 특징으로 할 수 있으며, 바람직하게는 약 1 : 1의 몰비로 반응시키는 것을 특징으로 할 수 있다. 이 경우, Lawesson 시약은 수 회에 나누어 첨가할 수 있다. In the present invention, step (b) may be characterized by reacting lenalidomide with Lawesson's reagent at a molar ratio of about 1:0.5 to 2, preferably at a molar ratio of about 1:1. It can be characterized. In this case, Lawesson's reagent can be added in several installments.
본 발명에 있어서, 상기 상기 크로마토그래피는 관 크로마토그래피일 수 있고, 바람직하게는 실리카겔 (SiO2) 크로마토그래피일 수 있으며, 이동상으로 디클로로메탄 : 메탄올 = 30 내지 25 : 1 (v/v)을 사용하는 관 크로마토그래피일 수 있다.In the present invention, the chromatography may be column chromatography, preferably silica gel (SiO2) chromatography, and dichloromethane: methanol = 30 to 25: 1 (v/v) as a mobile phase. It may be tube chromatography.
본 발명은 또 다른 관점에서, 다음 단계를 포함하는 화학식 3 화합물의 제조방법에 관한 것이다:The present invention, in another aspect, relates to a process for preparing a compound of formula 3 comprising the following steps:
[화학식 3][Formula 3]
(a) 1,6'-디티오포말리도마이드를 DMSO 및 물에 용해시키는 단계;(a) dissolving 1,6'-dithiopomalidomide in DMSO and water;
(b) 상기 용액을 40 내지 80℃에서 교반시킨 후 용매를 제거하는 단계; 및(b) stirring the solution at 40 to 80° C. and then removing the solvent; and
(c) 상기 용매가 제거된 조생성물을 MeOH:THF(50%)로 용출하는 단계.(c) Eluting the crude product from which the solvent has been removed with MeOH:THF (50%).
본 발명에 있어서, 상기 (b) 단계는 50 내지 70℃에서 교반시킬 수 있으며, 바람직하게는 약 60℃에서 교반시킬 수 있다. In the present invention, step (b) can be stirred at 50 to 70°C, and preferably at about 60°C.
본 발명에서, 상기 (b) 단계는 10 내지 30시간, 예컨대, 13 내지 23시간, 바람직하게는 약 18시간 교반시키는 것일 수 있다. In the present invention, step (b) may be stirred for 10 to 30 hours, for example, 13 to 23 hours, preferably about 18 hours.
본 발명에 있어서, 상기 (b) 단계는 예컨대, C18-SiO2로 채워진 컬럼을 이용하여 용매를 제거하여 조생성물을 생성하는 것일 수 있다. In the present invention, step (b) may be, for example, producing a crude product by removing the solvent using a column filled with C 18 -SiO 2 .
본 발명에 있어서, 상기 제조방법은 (c) 단계 이후,In the present invention, the production method is after step (c),
(d) 크로마토그래피로 정제하는 단계;를 추가로 포함하는 것을 특징으로 할 수 있다. (d) purifying by chromatography.
즉, 본 발명에서, 상기 조생성물은 이후 농축시켜 크로마토그래피로 정제하는 것을 특징으로 할 수 있다. That is, in the present invention, the crude product may be subsequently concentrated and purified by chromatography.
본 발명에 있어서, 상기 크로마토그래피는 관 크로마토그래피일 수 있고, 바람직하게는 실리카겔 (SiO2) 크로마토그래피일 수 있으며, 이동상으로 클로로포름 (CHCl3) : 아세톤 (Acetone) = 20 내지 5 : 1 (v/v)을 사용하는 관 크로마토그래피일 수 있다. In the present invention, the chromatography may be column chromatography, preferably silica gel (SiO2) chromatography, and the mobile phase is chloroform (CHCl 3 ): Acetone = 20 to 5: 1 (v/ It may be tube chromatography using v).
본 발명에서 "크로마토그래피"는 본 발명의 화합물을 위한 분리 및 정제하기 위한 방법을 의미하며, 여기서, 본 발명 화합물이 함유된 용액이 고정 상 위의 액체 스트림을 사용하여 통과되고, 혼합물의 성분은 분획화된다. 고정 상은 바람직하게는 크로마토그래피 컬럼 내의 충전 물질이다. 이후에 소위 겔 물질이라고도 부르는 충전 물질은 바람직하게는 대략 동일한 크기의 다공성 또는 비다공성 입자로 이루어진 고형 지지 물질로 이루어지며, 이 위에 분리 방식을 설정하는 관능성 그룹이 공유 결합되어 존재한다. 지지 물질은, 예를 들어, 아가로스, 셀룰로스 및 덱스트란(바람직하게는 세파로스 및 세파덱스)와 같은 생물중합체, 또는 예를 들어, 메타크릴레이트, 폴리비닐벤젠, 폴리스티렌 및 폴리아크릴아미드와 같은 합성 중합체 또는 예를 들어, 실리카 또는 다공성 유리 비이드와 같은 무기 중합체일 수 있다. In the present invention, “chromatography” means a method for separation and purification for the compounds of the invention, wherein a solution containing the compounds of the invention is passed using a liquid stream over a stationary phase, and the components of the mixture are It is fractionated. The stationary phase is preferably the packing material in the chromatography column. The filling material, hereinafter also referred to as the so-called gel material, preferably consists of a solid support material consisting of porous or non-porous particles of approximately equal size, on which the functional groups that establish the mode of separation are covalently bonded. Support materials can be biopolymers such as, for example, agarose, cellulose and dextran (preferably Sepharose and Sephadex), or polymers such as, for example, methacrylates, polyvinylbenzene, polystyrene and polyacrylamide. It may be a synthetic polymer or an inorganic polymer such as, for example, silica or porous glass beads.
본 발명에서, 상기 크로마토그래피는 소수성 상호작용 크로마토그래피 (HIC), 이온 교환 크로마토그래피 (IEC), 크기 배제 크로마토그래피 (SEC), 친화성 크로마토그래피, 및 역상 크로마토그래피로 구성된 그룹으로부터 선택된다.In the present invention, the chromatography is selected from the group consisting of hydrophobic interaction chromatography (HIC), ion exchange chromatography (IEC), size exclusion chromatography (SEC), affinity chromatography, and reversed phase chromatography.
한편, 본 발명에서는 화합물을 추가 정제 및/또는 농축하기 위하여, 선택적으로 한외여과 또는 정용여과 (UF 또는 DF) 하는 단계를 추가로 포함할 수 있다. Meanwhile, in the present invention, in order to further purify and/or concentrate the compound, the step of selectively performing ultrafiltration or diafiltration (UF or DF) may be additionally included.
본 발명에서 상기 화합물의 제조 과정 중 농축을 위하여 회전증발농축기를 사용할 수 있으나, 이에 한정되지는 않는다. In the present invention, a rotary evaporator may be used for concentration during the manufacturing process of the compound, but is not limited to this.
본 발명에서 대조군으로 사용되는 포말리도마이드는 (R,S)-4-아미노-2-(2,6-디옥소피페리딘-3-일)이소인돌-1,3-디온으로 공지되어 있으며, [화학식 I]로 표시되는 것을 특징으로 할 수 있다.Pomalidomide used as a control in the present invention is known as (R,S)-4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione, It may be characterized by being represented by [Chemical Formula I].
[화학식 I][Formula I]
본 발명에서 대조군으로 사용되는 레날리도마이드는 (R,S)-3-(4-아미노-1-옥소 1,3-디히드로-2H-이소인돌-2-일)피페리딘-2,6-디온으로 공지되어 있으며, 화학식 II]로 표시되는 것을 특징으로 할 수 있다.Lenalidomide used as a control in the present invention is (R,S)-3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl)piperidine-2, It is known as 6-dione and can be characterized as being represented by the formula (II).
[화학식 II][Formula II]
본 발명에서 합성시 재료물질로 사용되는 1,6'-디티오포말리도마이드(1,6'-Dithiothalidomide)는 [화학식 III]으로 표시될 수 있다.1,6'-Dithiothalidomide, used as a material for synthesis in the present invention, can be represented by [Chemical Formula III].
[화학식 III][Formula III]
기존 상용화된 탈리도마이드 유도체들은 다발성 골수종 치료에 특이적인 효능을 가지는 반면, 관련된 작용으로 골수세포 억압과 같은 부작용을 유발할 수 있었으나, 본 발명에 따른 유도체들은 이에 대한 작용이 최소화 되고 면역 조절 및 항산화 효능이 강화되어 보다 안전하게 면역관련 질환 치료제로서 적용할 수 있다. 또한 본 발명에서의 모노티오 화합물들은 디티오화합물에 비해 혈장내 안정성이 뛰어나 실제 생체 적용 및 약물작용 분석등에 유리한 측면을 갖고 있다.While existing commercially available thalidomide derivatives have specific efficacy in the treatment of multiple myeloma, related effects can cause side effects such as bone marrow cell suppression. However, the derivatives according to the present invention minimize this effect and enhance immune regulation and antioxidant efficacy. It can be applied more safely as a treatment for immune-related diseases. In addition, the monothio compounds in the present invention have superior stability in plasma compared to dithio compounds, which is advantageous for actual biological application and drug action analysis.
구체적으로, 화학식 1 화합물은 포말리도마이드의 다발성 골수종 사멸과 관련된 타겟 단백질에 대한 분해효능 및 세레블론에 대한 결합력이 약하여 포말리도마이드의 독성을 줄이고 염증 조절 같은 다른 효능은 유사한 치료제로 사용이 가능하다.Specifically, the compound of Formula 1 has a weak decomposition effect on the target protein related to the death of pomalidomide in multiple myeloma and a weak binding force to cereblon, so it reduces the toxicity of pomalidomide and can be used as a similar treatment for other effects such as inflammation control. .
또한, 화학식 2 화합물은 레날리도마이드 보다 우수한 세레블론 결합력을 가졌음에도 다발성골수종 사멸 및 관련 단백질 분해 효능이 매우 약하여 관련 독성을 가질 가능성이 상대적으로 낮으며, 특히 탈리도마이드 계열의 발생 독성과 관련된 유전자인 SALL4의 감소가 거의 없어 발생학적 독성의 가능성도 낮다. 그에 비해 염증조절 효능은 레날리도마이드와 유사하고, 파킨슨 동물모델에서 효능이 확인되어 파킨슨 병 치료제로서 활용할 수 있다. In addition, although the compound of formula 2 has a better binding ability to cereblon than lenalidomide, its efficacy in killing multiple myeloma and decomposing related proteins is very weak, so it is relatively unlikely to have related toxicity. In particular, it is a gene related to developmental toxicity of the thalidomide series. There is little decrease in SALL4, so the possibility of developmental toxicity is low. In contrast, its inflammation control efficacy is similar to that of lenalidomide, and its efficacy was confirmed in a Parkinson's animal model, so it can be used as a treatment for Parkinson's disease.
화학식 3 화합물은 우수한 세레블론 결합력을 가졌으나 포말리도마이드의 다발성 골수종 사멸 관련 타겟 단백질 및 발생 독성과 관련된 SALL4 유전자의 분해 효능은 덜하며, 랫드 중뇌를 이용한 도파민성 뉴런의 알파 시누클레인 독성 시험에서 신경보호 효능 및 염증 보호효능이 확인되어 파킨슨 병 치료제로서 적용 가능하다.The formula 3 compound has excellent cereblon binding ability, but is less effective in degrading pomalidomide's target protein related to multiple myeloma death and the SALL4 gene related to developmental toxicity, and has a negative effect on neurons in alpha-synuclein toxicity tests on dopaminergic neurons using rat midbrain. The protective effect and inflammation protection effect were confirmed, so it can be applied as a treatment for Parkinson's disease.
실시예Example
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as limited by these examples.
실시예 1Example 1
포말리도마이드(Combi Block, QB-4271) (2.00 g, 7.32 mmol)을 다이옥세인(dioxane) (SAMCHUN, D0654)(200 mL)에 넣어 용해시킨 후 오황화인(phosphorous pentasulfide) (Aldrich, 232106)(P2S5) (1.63 g, 7.32 mmol)를 적가하고 80℃에서 1 시간 교반하였다. 실온으로 반응온도를 낮춘 후, 필터(Advantec, F12-510-221)를 이용하여 고체를 제거하고 용매를 회전증발농축기 (EYELA, N-1300)로 농축하였다 . 잔류물을 아세톤(SAMCHUN, A0098)(10 mL) 으로 녹인 후 실리카겔(MERCK, 1.09385.2500)을 넣어 흡착시키고 관크로마토그래피(CHCl3(대정화금, 2548-4480) : Acetone (Samchun, A0098) = 100 : 5)로 정제하였다. 화합물을 디클로로메탄 (dichloromethane) (Samchun, M0822)으로 고체화하여 주황색 고체의 화학식 1의 화합물, 즉, 6'-모노티오-말리도마이드(804 mg, 38 %)를 얻었다.Pomalidomide (Combi Block, QB-4271) (2.00 g, 7.32 mmol) was dissolved in dioxane (SAMCHUN, D0654) (200 mL) and then dissolved in phosphorous pentasulfide (Aldrich, 232106). (P 2 S 5 ) (1.63 g, 7.32 mmol) was added dropwise and stirred at 80°C for 1 hour. After lowering the reaction temperature to room temperature, solids were removed using a filter (Advantec, F12-510-221), and the solvent was concentrated using a rotary evaporator (EYELA, N-1300) . The residue was dissolved in acetone (SAMCHUN, A0098) (10 mL), adsorbed with silica gel (MERCK, 1.09385.2500), and subjected to column chromatography (CHCl 3 (Daejung Chemical, 2548-4480): Acetone (Samchun, A0098). = 100 : 5). The compound was solidified with dichloromethane (Samchun, M0822) to obtain the compound of Formula 1 as an orange solid, that is, 6'-monothio-maledomide (804 mg, 38%).
실시예 2Example 2
레날리도마이드(Combi-Blocks, OR-2352)(3.30g, 12.7mmol) 에 다이옥세인(SAMCHUN, D0654)(200 mL)을 넣어 용해시킨 후 질소 분위기 하에서 Lawesson 시약(Alfa, A14530)(2.83g, 7.00mmol)을 첨가하였다. 혼합물을 100℃에서 6시간 동안 교반하고 Lawesson 시약(2.32 g, 5.73 mmol)을 반응 혼합물에 추가로 첨가하였다. 혼합물을 100℃에서 밤새 교반하였다. 반응 혼합물을 실온으로 냉각하고, 회전증발농축기 (EYELA, N-1300)로 농축하고, 잔류물을 실리카겔 (SiO2) (MERCK, 1.09385.2500) [디클로로메탄 (Samchun, M0822) : 메탄올 (대정화금, 5558-4410) = 30:1 내지 25:1) 관크로마토그래피로 정제하여 회백색 고체로서 화학식 2의 화합물, 즉, 1-티오레날리도마이드(580 mg, 17%, T0075-03)를 얻었다.Dioxane (SAMCHUN, D0654) (200 mL) was dissolved in lenalidomide (Combi-Blocks, OR-2352) (3.30 g, 12.7 mmol) and Lawesson reagent (Alfa, A14530) (2.83 g) under nitrogen atmosphere. , 7.00 mmol) was added. The mixture was stirred at 100°C for 6 hours and Lawesson's reagent (2.32 g, 5.73 mmol) was further added to the reaction mixture. The mixture was stirred at 100°C overnight. The reaction mixture was cooled to room temperature, concentrated with a rotary evaporator (EYELA, N-1300), and the residue was dissolved in silica gel (SiO2) (MERCK, 1.09385.2500) [dichloromethane (Samchun, M0822): methanol (Daejeong Chemical Gold). , 5558-4410) = 30:1 to 25:1) was purified by column chromatography to obtain the compound of Formula 2, i.e., 1-thiorenalidomide (580 mg, 17%, T0075-03) as an off-white solid. .
실시예 3Example 3
다이메틸설폭사이드 (dimethylsulfoxide) (대정화금, 3047-4400) (250mL) 및 물(Samchun, W0003)(250mL)에 용해된 1,6'-디티오포말리도마이드(에스티에이블, T0014) (1,6'-DT-POM)(500mg, 1.64mmol) 용액을 60℃에서 18시간 동안 교반하고 실온으로 냉각시켰다. 용액을 C18-SiO2로 채워진 컬럼에 통과시켜 용매를 제거하였다. 컬럼 상부에 포획된 조생성물을 MeOH:THF(50%)로 용출하고 조생성물이 포함된 용액을 회전증발농축기 (EYELA, N-1300)로 농축하였다. 잔류물을 실리카겔 (SiO2) (MERCK, 1.09385.2500) [클로로포름 (CHCl3) (대정화금, 2548-4480) : 아세톤 (acetone) (Samchun, A0098) = 10:1] 상에서 관크로마토그래피로 정제하여 적색 고체로서 화학식 3의 화합물, 즉, 1-모노티오-포말리도마이드(207 mg, 44 %, T0069-01-01)을 얻었다. Dimethylsulfoxide (Daejeong Chemical, 3047-4400) (250mL) and 1,6'-dithiopomalidomide (STAble, T0014) (1 ,6'-DT-POM) (500 mg, 1.64 mmol) solution was stirred at 60°C for 18 hours and cooled to room temperature. The solution was passed through a column filled with C 18 -SiO 2 to remove the solvent. The crude product captured at the top of the column was eluted with MeOH:THF (50%), and the solution containing the crude product was concentrated using a rotary evaporator (EYELA, N-1300). The residue was purified by column chromatography on silica gel (SiO2) (MERCK, 1.09385.2500) [chloroform (CHCl 3 ) (Daejeong Chemical, 2548-4480) : acetone (Samchun, A0098) = 10:1] Thus, the compound of Formula 3, i.e., 1-monothio-pomalidomide (207 mg, 44 %, T0069-01-01), was obtained as a red solid.
실험예 1.Experimental Example 1. In vitro In vitro CRBN binding assay CRBN binding assay
탈리도마이드계 화합물은 E3 리가아제인 세레블론 (CRBN)에 결합하여, 그 기질로서 전사인자인 Aiolos 및 Ikaros를 분해함으로써 면역세포의 기능을 조절하고 다양한 약리학적 효과를 발휘하는 것으로 알려져 있다. 이에 각각 화학식 1, 화학식 2, 화학식 3 화합물의 세레블론 결합력을 in vitro 상에서 포말리도마이드 또는 레날리도마이드와 비교하였다.Thalidomide-based compounds are known to regulate the function of immune cells and exert various pharmacological effects by binding to Cereblon (CRBN), an E3 ligase, and decomposing the transcription factors Aiolos and Ikaros as its substrates. Accordingly, the cereblon binding ability of compounds of formula 1, formula 2, and formula 3, respectively, was compared with pomalidomide or lenalidomide in vitro .
세레블론에 대한 결합력의 측정은 Fluorescence Resonance Energy Transfer (FRET) 기반의 'AlphaScreen' 방식을 이용하였으며, 해당 시험은 PROTAC Optimization kit for BET Bromodomain-Cereblon binding 키트 (#79770, BPS bioscience, CA USA)를 사용해 키트 내 매뉴얼에 표기된 'Competitive Inhibition of the PROTAC assay'에 따라 진행하였다. 후보물질, DMSO 및 Flag/Glutathione bead (#6765300, PerkinElmer, USA)를 제외한 모든 시약은 키트 내에 포함되어 있는 것을 사용하였다.The binding force to Cereblon was measured using the 'AlphaScreen' method based on Fluorescence Resonance Energy Transfer (FRET), and the test was performed using the PROTAC Optimization kit for BET Bromodomain-Cereblon binding kit (#79770, BPS bioscience, CA USA). It was carried out according to the 'Competitive Inhibition of the PROTAC assay' written in the manual in the kit. All reagents except the candidate substance, DMSO, and Flag/Glutathione beads (#6765300, PerkinElmer, USA) were used as those included in the kit.
그 결과, 도 1a 내지 도 1c에서와 같이, 화학식 1, 화학식 2, 화학식 3 화합물 모두 세레블론과 효과적으로 결합하는 것으로 확인되었으며, 특히, 화학식 2 화합물은 레날리도마이드에 비해 세레블론과 결합력이 현저히 높았으며, 화학식 3 화합물은 포말리도마이드에 비해 결합력이 현저히 높은 것으로 확인되었다. As a result, as shown in FIGS. 1A to 1C, it was confirmed that all compounds of Formula 1, Formula 2, and Formula 3 bind effectively to Cereblon. In particular, Compound of Formula 2 has a significantly stronger binding force to Cereblon than lenalidomide. It was confirmed that the compound of Formula 3 had a significantly higher binding force than pomalidomide.
실험예 2. 세포 독성 평가Experimental Example 2. Cytotoxicity evaluation
인간 다발성 골수종 세포주인 MM.1R 및 MM.1S 세포주에 각각 화학식 1, 화학식 2 화합물을 농도별로 처리하고 세포 독성을 평가하였다. MM.1R은 MM.1S에서 dexamethasone에 대한 저항성을 획득한 세포주이다. Human multiple myeloma cell lines, MM.1R and MM.1S cell lines, were treated with compounds of Formula 1 and Formula 2, respectively, at different concentrations, and cytotoxicity was evaluated. MM.1R is a cell line that acquired resistance to dexamethasone from MM.1S.
인간 다발성 골수종 세포주인 MM.1S (CRL-2974) 및 MM.1R (CRL-2975) 세포주는 American Type Culture Collection (ATCC, Manassas, VA, USA)로부터 구입하여 사용하였고, 10% 우태아 혈청 (Corning, MD, USA), 100 U/ml penicillin (Corning, MD, USA), 및 100 ㎍/ml streptomycin (Corning, MD, USA)이 보충된 RPMI1640 배지 (Corning, MD, USA)를 사용하여 37℃, 5% CO2 배양기에서 24시간 배양하였다. 세포를 1 × 104 cells/웰로 96웰 플레이트에 분주하고 24시간 배양 후, 화학식 1, 화학식 2 화합물을 농도별로 처리하고 3일 동안 추가로 배양한 후, CCK 분석 키트 (Dojindo, Japan)를 사용하여 제조사 매뉴얼에 따라 분석을 진행하였다. 대조군으로는 포말리도마이드 또는 레날리도마이드를 동일한 농도로 처리하였다. Human multiple myeloma cell lines, MM.1S (CRL-2974) and MM.1R (CRL-2975), were purchased from American Type Culture Collection (ATCC, Manassas, VA, USA) and incubated with 10% fetal calf serum (Corning , MD, USA), 100 U/ml penicillin (Corning, MD, USA), and 100 μg/ml streptomycin (Corning, MD, USA) at 37°C using RPMI1640 medium (Corning, MD, USA). Cultured for 24 hours in a 5% CO 2 incubator. Cells were distributed in a 96-well plate at 1 The analysis was conducted according to the manufacturer's manual. As a control group, pomalidomide or lenalidomide was treated at the same concentration.
그 결과, 도 2a에서와 같이 화학식 1 화합물은 포말리도마이드와 유사한 수준의 세포 독성을 나타내었으며, 도 2b에서와 같이 화학식 2 화합물은 레날리도마이드와 비교하여 세포 독성(혈액 독성)이 없다는 것을 확인할 수 있었다. As a result, as shown in Figure 2a, the compound of formula 1 showed a similar level of cytotoxicity as pomalidomide, and as shown in Figure 2b, the compound of formula 2 showed no cytotoxicity (blood toxicity) compared to lenalidomide. I was able to confirm.
실험예 3. 세포 독성 감소 기전Experimental Example 3. Mechanism of reducing cytotoxicity
탈리도마이드계 화합물은 E3 리가아제인 세레블론 (CRBN)에 결합하여, 그 기질로서 전사인자인 Aiolos 및 Ikaros를 분해함으로써 면역세포의 기능을 조절하는 것으로 알려져 있는바, 화학식 1, 화학식 2, 화학식 3 화합물에 의해 Aiolos 및 Ikaros의 발현이 감소하는지 확인하고자 하였다. Thalidomide-based compounds are known to regulate the function of immune cells by binding to Cereblon (CRBN), an E3 ligase, and decomposing the transcription factors Aiolos and Ikaros as its substrates. Compounds of Formula 1, Formula 2, and Formula 3 We sought to determine whether the expression of Aiolos and Ikaros was decreased.
이를 위하여, MM.1S 세포주를 10% 우태아 혈청 (Corning, MD, USA), 100 U/ml penicillin (Corning, MD, USA), 및 100 ㎍/ml streptomycin (Corning, MD, USA)이 보충된 RPMI 배지 (Corning, MD, USA)를 사용하여 37℃, 5% CO2 배양기에서 배양하였다. 세포를 1 × 106 cells/웰로 12 웰 플레이트에 분주하고 24시간 배양 후, 화학식 1 화합물, 화학식 2 화합물, 화학식 3 화합물을 농도별로 처리하고 4시간 추가 배양한 후, 세포에 protease inhibitor cocktail (Thermo Fisher Scientific)을 포함하는 RIPA buffer를 넣어 파쇄하고, 14,000rpm에서 15분 동안 4℃에서 원심분리하여 세포추출액을 획득하였다. 세포추출액을 동일한 양 loading하여 SDS-PAGE를 이용해 분리하고, PVDF 막으로 트랜스퍼 하였다. 단백질이 트랜스퍼 된 막을 skim milk를 이용하여 블록킹하고, 1차 항체로 3시간 상온에서 인큐베이션 한 후, HRP-부착된 2차 항체로 상온에서 1시간 인큐베이션 하였다. 각 단계 사이 TBS-T로 3회 세척하였다. 검출은 chemoluminescence 시약 (Thermo Fisher Scientific)을 적용하여 수행하고 Chemidoc (iBright CL1500, Invitrogen, CA, USA)을 사용하여 확인하였다. 1차 항체로 사용된 Aiolos (#15103), Ikaros (#9034), GAPDH (#2118S) 항체와 2차 항체는 Cell signaling technology (Danvers, MA, USA)에서 구입하였다. For this purpose, the MM.1S cell line was supplemented with 10% fetal bovine serum (Corning, MD, USA), 100 U/ml penicillin (Corning, MD, USA), and 100 μg/ml streptomycin (Corning, MD, USA). RPMI medium (Corning, MD, USA) was used and cultured at 37°C in a 5% CO 2 incubator. Cells were distributed in 12-well plates at 1 Fisher Scientific), disrupted by adding RIPA buffer, and centrifuged at 4°C at 14,000 rpm for 15 minutes to obtain a cell extract. The same amount of cell extract was loaded, separated using SDS-PAGE, and transferred to a PVDF membrane. The protein-transferred membrane was blocked using skim milk, incubated with primary antibody at room temperature for 3 hours, and then incubated with HRP-attached secondary antibody at room temperature for 1 hour. Washed three times with TBS-T between each step. Detection was performed by applying a chemoluminescence reagent (Thermo Fisher Scientific) and confirmed using Chemidoc (iBright CL1500, Invitrogen, CA, USA). Aiolos (#15103), Ikaros (#9034), and GAPDH (#2118S) antibodies used as primary antibodies and secondary antibodies were purchased from Cell signaling technology (Danvers, MA, USA).
그 결과, 도 3a 내지 3c에서와 같이 각각 화학식 1, 화학식 2, 화학식 3 화합물에 의해 Aiolos 및 Ikaros의 발현이 감소되는 것을 확인하였다. As a result, it was confirmed that the expression of Aiolos and Ikaros was reduced by compounds of Formula 1, Formula 2, and Formula 3, respectively, as shown in Figures 3a to 3c.
실험예 4. 생식 독성 감소 기전Experimental Example 4. Reproductive toxicity reduction mechanism
탈리도마이드계 화합물과 같은 세레블론 (CRBN) 결합 치료제는 앞다리 단축 또는 단지증과 같은 심각한 선천성 기형을 유발할 수 있고, 이는 SALL4의 분해와 밀접한 연관이 있음이 보고되었다. 따라서, 화학식 1 화합물, 화학식 2 화합물, 화학식 3 화합물의 SALL4 분해 효과를 확인하였다. It has been reported that cereblon (CRBN)-binding treatments, such as thalidomide-based compounds, can cause serious congenital deformities such as forelimb shortening or brachydactyly, and that this is closely related to the degradation of SALL4. Therefore, the SALL4 decomposition effect of compounds of formula 1, compounds of formula 2, and compounds of formula 3 was confirmed.
이를 위하여, 인간 Embryonic carcinoma 세포주인 Tera-1 세포주 (HTB-105)를 American Type Culture Collection (ATCC, Manassas, VA, USA)로부터 구입하여 사용하였고, 10% 우태아 혈청 (Corning, MD, USA), 100 U/ml penicillin (Corning, MD, USA), 및 100 ㎍/ml streptomycin (Corning, MD, USA)가 보충된 DMEM 배지 (Corning, MD, USA)를 사용하여 37℃, 5% CO2 배양기에서 배양하였다. For this purpose, Tera-1 cell line (HTB-105), a human embryonic carcinoma cell line, was purchased from American Type Culture Collection (ATCC, Manassas, VA, USA), 10% fetal bovine serum (Corning, MD, USA), DMEM medium (Corning, MD, USA) supplemented with 100 U/ml penicillin (Corning, MD, USA) and 100 ㎍/ml streptomycin (Corning, MD, USA) was used at 37°C in a 5% CO 2 incubator. Cultured.
세포를 5 × 105 cells/웰로 12웰 플레이트에 분주하고 24시간 배양 후, 화학식 1 화합물, 화학식 2 화합물, 화학식 3 화합물을 각각 농도별로 처리하고 4시간 추가 배양하였다. 세포에 protease inhibitor cocktail (Thermo Fisher Scientific)을 포함하는 RIPA buffer를 넣어 파쇄하고, 14,000rpm에서 15분 동안 4℃에서 원심분리하여 세포추출액을 획득하였다. 세포추출액을 동일한 양 loading하여 SDS-PAGE를 이용해 분리하고, PVDF 막으로 트랜스퍼 하였다. 단백질이 트랜스퍼된 막을 skim milk를 이용하여 블록킹하고, 1차 항체로 3시간 상온에서 인큐베이션 한 후, HRP-부착된 2차 항체로 상온에서 1시간 인큐베이션 하였다. 각 단계 사이 TBS-T로 3회 세척하였다. 검출은 chemoluminescence 시약 (Thermo Fisher Scientific)을 적용하여 수행하고 Chemidoc (iBright CL1500, Invitrogen, CA, USA)을 사용하여 확인하였다. 1차 항체로 사용된 SALL4 (#5850)와 GAPDH (#2118S) 항체 및 2차 항체는 Cell signaling technology (Danvers, MA, USA)에서 구입하였다. Cells were distributed at 5 × 10 5 cells/well in a 12-well plate and cultured for 24 hours, then treated with compounds of Formula 1, compounds of Formula 2, and compounds of Formula 3, respectively, at different concentrations and cultured for an additional 4 hours. Cells were disrupted by adding RIPA buffer containing protease inhibitor cocktail (Thermo Fisher Scientific), and centrifuged at 14,000 rpm for 15 minutes at 4°C to obtain cell extract. The same amount of cell extract was loaded, separated using SDS-PAGE, and transferred to a PVDF membrane. The protein-transferred membrane was blocked using skim milk, incubated with primary antibody at room temperature for 3 hours, and then incubated with HRP-attached secondary antibody at room temperature for 1 hour. Washed three times with TBS-T between each step. Detection was performed by applying a chemoluminescence reagent (Thermo Fisher Scientific) and confirmed using Chemidoc (iBright CL1500, Invitrogen, CA, USA). SALL4 (#5850) and GAPDH (#2118S) antibodies used as primary antibodies and secondary antibodies were purchased from Cell signaling technology (Danvers, MA, USA).
그 결과, 도 4a 내지 4c에서와 같이 화학식 1 화합물, 화학식 2 화합물, 화학식 3 화합물은 포말리도마이드 또는 레날리도마이드와 비교하여 SALL4 분해가 더 적게 확인되는바, 본 발명에 따른 화합물이 최기형성 부작용을 더 잘 억제할 수 있음을 알 수 있었다. As a result, as shown in Figures 4a to 4c, the compounds of formula 1, compounds of formula 2, and compounds of formula 3 were confirmed to have less SALL4 degradation compared to pomalidomide or lenalidomide, and the compounds according to the present invention had no teratogenic side effects. It was found that it could be better suppressed.
실험예 5. 염증 억제 효과Experimental Example 5. Inflammation inhibition effect
면역 조절 제제인 포말리도마이드나 레날리도마이드는 T 세포-매개 면역과 자연살해 (NK)세포-매개 면역을 향상시키고, 단핵구에 의한 전 (pro)-염증 사이토카인 (예컨대, TNF-α, IL-1β, IL-6, IL-8)의 생산을 억제하는 것으로 알려져 있다. 따라서, 화학식 1 화합물, 화학식 2 화합물의 전-염증 사이토카인 생산 억제 효과를 mRNA 레벨에서 포말리도마이드 또는 레날리도마이드와 비교하였다. Immunomodulating agents pomalidomide or lenalidomide improve T cell-mediated immunity and natural killer (NK) cell-mediated immunity, and promote pro-inflammatory cytokines (e.g., TNF-α, It is known to inhibit the production of IL-1β, IL-6, and IL-8). Therefore, the inhibitory effect of compounds of Formula 1 and Formula 2 on pro-inflammatory cytokine production was compared with pomalidomide or lenalidomide at the mRNA level.
이를 위하여, 말초 혈액 단핵세포 (PBMC, StemExpress, CA, USA)를 96 웰 플레이트 (Corning, MD, USA)에 1 × 106 cells/웰 분주하고 10% 우태아 혈청 (Corning, MD, USA) 및 100 U/ml의 penicillin/streptomycin (Corning, MD, USA) 이 포함된 RPMI1640 (Corning, MD, USA) 배지를 이용하여, 37℃, 5% CO2 배양기에서 하루 동안 배양하여 안정화하였다. 포말리도마이도, 레날리도마이드, 화학식 1 화합물, 화학식 2 화합물의 10 mM DMSO stock (Sigma, USA)을 PBMC의 배양액과 동일한 배지를 이용해 0.1 또는 1 μM 로 희석하여 해당하는 PBMC 웰에 넣고 (Final 10, 1 μM) 37℃, 5% CO2 배양기에서 1시간 동안 반응시켰다. 염증 비유도군을 제외한 모든 PBMC 웰에 250㎍/㎕ (5% DMSO in RPMI1640)의 PHA (Sigma, USA)를 넣고 (Final 25 ㎍/㎕), 37℃, 5% CO2 배양기에서 6시간 동안 반응시켰다.For this purpose, peripheral blood mononuclear cells (PBMC, StemExpress, CA, USA) were distributed at 1 × 10 6 cells/well in a 96-well plate (Corning, MD, USA) and 10% fetal bovine serum (Corning, MD, USA) and RPMI1640 (Corning, MD, USA) medium containing 100 U/ml of penicillin/streptomycin (Corning, MD, USA) was used to stabilize the cells by culturing them in an incubator at 37°C and 5% CO 2 for one day. 10 mM DMSO stock (Sigma, USA) of pomalidomide, lenalidomide, compound of formula 1, and compound of formula 2 was diluted to 0.1 or 1 μM using the same medium as the PBMC culture medium and added to the corresponding PBMC well ( Final 10, 1 μM) and reacted for 1 hour at 37°C in a 5% CO 2 incubator. Add 250 ㎍/㎕ (5% DMSO in RPMI1640) of PHA (Sigma, USA) to all PBMC wells except the non-inflammation group (Final 25 ㎍/㎕) and react for 6 hours in a 37℃, 5% CO 2 incubator. I ordered it.
PBMC는 RNA prep kit (Monarch Total RNA Miniprep kit, NEB, UK)을 이용하여 키트 매뉴얼에 따라 RNA prep을 수행하였으며, Nanophotometer (NP80, Implen, Germany)를 이용해 농도를 측정하였다. 각 RNA 샘플의 농도에 따라 1㎍에 해당하는 양의 RNA를 넣고 cDNA 합성 키트 (LunaScript RT SuperMix kit, NEB, UK)의 매뉴얼에 따라 cDNA를 합성하였다. For PBMC, RNA prep was performed according to the kit manual using an RNA prep kit (Monarch Total RNA Miniprep kit, NEB, UK), and the concentration was measured using a Nanophotometer (NP80, Implen, Germany). Depending on the concentration of each RNA sample, an amount of RNA equivalent to 1 μg was added, and cDNA was synthesized according to the manual of the cDNA synthesis kit (LunaScript RT SuperMix kit, NEB, UK).
합성한 cDNA 내 각 사이토카인의 발현양을 Real-Time PCR (StepOne™USA) 장비를 이용해 분석 및 비교하였다. 분석을 위해 48웰 플레이트 (MicroAmp®Fast Optical 48-well plate, Applied Biosystem, USA)의 각 웰에 1 ㎕의 cDNA, 유전자별 10 pmol의 forward 와 reverse primer, 8 ㎕의 D.W. 와 10 ㎕의 SYBR green (Luna®Mix, NEB, UK)가 포함되었다. PCR 반응은 SYBR green 키트의 매뉴얼에 따라 진행되었으며, 사용된 primer의 염기서열은 표 1과 같다. Real-Time PCR을 통해 얻어진 각 샘플의 유전자별 CT 값은 각 샘플의 Internal control gene (β-actin)의 값을 통해 normalization 되었으며, 2ΔΔCT 계산에 의해 발현양을 역추산하였고, 각 군의 결과 값을 PHA 단독 처리군 대비 100분율의 값으로 상대정량하여 표기하였다.The expression level of each cytokine in the synthesized cDNA was analyzed and compared using Real-Time PCR (StepOne™USA) equipment. For analysis, 1 μl of cDNA, 10 pmol of forward and reverse primers for each gene, 8 μl of DW and 10 μl of SYBR green were added to each well of a 48-well plate (MicroAmp ® Fast Optical 48-well plate, Applied Biosystem, USA). (Luna®Mix, NEB, UK) was included. The PCR reaction was carried out according to the manual of the SYBR green kit, and the base sequences of the primers used are shown in Table 1. The C T value for each gene in each sample obtained through real-time PCR was normalized to the value of the internal control gene (β-actin) of each sample, and the expression amount was inversely estimated by calculating 2ΔΔC T , and the results for each group were The value was expressed as a relative quantification as a 100% value compared to the PHA treatment group alone.
한편, 화학식 2 화합물은 주요한 염증성 사이토카인인 TNF-α의 단백질 발현 차이를 해당 시험과정에서 함께 분석하였으며, 이를 위해 단백질은 프로테아제 저해제(Thermo)가 함유된 단백질 추출 버퍼(RIPA, 89900, Thermo)를 이용하여 준비하였고, Human TNF alpha uncoated ELISA kit (88-7346-22, Invitrogen)를 사용하여 제조사 지침에 따라 TNF-α의 단백질 양을 분석하였다.Meanwhile, the chemical formula 2 compound was analyzed for differences in protein expression of TNF-α, a major inflammatory cytokine, during the test process. For this purpose, the protein was extracted with a protein extraction buffer (RIPA, 89900, Thermo) containing a protease inhibitor (Thermo). The protein amount of TNF-α was analyzed using the Human TNF alpha uncoated ELISA kit (88-7346-22, Invitrogen) according to the manufacturer's instructions.
그 결과, 도 5a 및 도 5b에서와 같이, 화학식 1 화합물, 화학식 2 화합물 모두 포말리도마이드나 레날리도마이드와 유사한 수준으로 전 (pro)-염증 사이토카인 (예컨대, TNF-α, IL-1β, IL-6, IL-8)의 생산을 억제하는 것을 확인하였으며, 도 5c에서와 같이, 화학식 2 화합물은 TNF-α 단백질을 포말리도마이드와 유사한 수준으로 억제하는 것을 확인할 수 있었다. As a result, as shown in FIGS. 5A and 5B, both compounds of Formula 1 and Formula 2 produced pro-inflammatory cytokines (e.g., TNF-α, IL-1β) at a similar level to pomalidomide or lenalidomide. , IL-6, and IL-8), and as shown in Figure 5c, the compound of Formula 2 was confirmed to inhibit TNF-α protein to a similar level as pomalidomide.
실험예 6. 신경보호 및 항신경염증 효과Experimental Example 6. Neuroprotective and anti-neuroinflammatory effects
한편, 화학식 3 화합물의 경우 신경보호 및 항신경염증 효능을 분석하였다.Meanwhile, the neuroprotective and anti-neuroinflammatory effects of the compound of Formula 3 were analyzed.
15일 된 랫드 배아의 중뇌의 조직 배양에서 파킨슨병의 원인체로 추정되는 알파시누클레인의 독성에 대한 화학식 3 화합물의 보호 효능을 확인하였다. 해당시험은 뇌신경모델 전문 CRO인 뉴로시스에서 수행되었다. 조직 배양을 위해 임신 15일령의 Wistar rat (Janvier, France)에서 배아를 꺼내어 중뇌를 분리해 얼음에 의해 미리 차가워진 2%의 페니실린-스트렙토마이신 (PS, P06-07100, DUTSCHER) 과 1%의 소 혈청 알부민 (BSA, P06-1391100, DUTSCHER)가 포함된 Leibovitz(L15, P04-27055, DUTSCHER) 배지에 넣어 준비하였다. 중뇌 부분 중 도파민성 뉴런이 풍부한 간뇌굴곡의 배쪽 부분을 37℃에서 20분동안 트립신화(최종농도 - 트립신 0.05%, EDTA 0.02%, P10-023100, DUTSCHER)에 의해 해리시켰으며, DNase I grade II (0.5 mg/ml, P60-37780100, DUTSCHER)와 태아 송아지 혈청 (FCS) 10%를 함유한 Dulbecco's modified Eagle's medium (DMEM, P04-03600, DUSTCHER) 첨가를 통해 반응을 중단시켰다. 이후 10 ml 피펫을 통해 세포를 3개의 계대로 분리시켰으며, L15 배지의 BSA(3.5%) 층에서 4℃에서 180g로 10분 동안 원심분리시켰다. 상등액을 폐기시킨 후, 세포 펠렛을 신경세포 배양에 기본적인 B27 (2%), L-글루타민 (2mM, P04-80100, DUTSCHER) 및 PS 용액 2%와 뇌유래신경영양인자(BDNF, CB-1115002, DUTSCHER) 10ng/ml와 미세아교세포 신경성장인자 (GDNF) 1ng/ml 가 포함된 배지 (11570556, FISHER SCIENTIFIC)로 재부유시켰다. Neubauer 세포계수기를 이용한 트립판 블루 배재시험법을 통해 생존세포를 확인하였다. 세포는 24-well plate (폴리-L-리신으로 사전 코팅됨)에 225,000 세포/well의 밀도로 배양시켰으며, 5% CO2, 37℃ 가습 인큐베이터 조건에서 유지시켰다. 배지의 절반은 신선 배지로 이틀에 한 번씩 교체시켰다. The protective effect of the compound of formula 3 against the toxicity of alpha-synuclein, which is presumed to be the cause of Parkinson's disease, was confirmed in tissue culture of the midbrain of 15-day-old rat embryos. The test was conducted by Neurosys, a CRO specializing in cranial nerve models. For tissue culture, embryos were taken from Wistar rats (Janvier, France) at 15 days of gestation, the midbrain was isolated, and the cells were incubated with 2% penicillin-streptomycin (PS, P06-07100, DUTSCHER) and 1% bovine solution pre-chilled on ice. It was prepared in Leibovitz (L15, P04-27055, DUTSCHER) medium containing serum albumin (BSA, P06-1391100, DUTSCHER). Among the midbrain parts, the ventral part of the diencephalic flexure, which is rich in dopaminergic neurons, was dissociated by trypsinization (final concentration - trypsin 0.05%, EDTA 0.02%, P10-023100, DUTSCHER) at 37°C for 20 minutes, DNase I grade II. The reaction was stopped by adding Dulbecco's modified Eagle's medium (DMEM, P04-03600, DUSTCHER) containing (0.5 mg/ml, P60-37780100, DUTSCHER) and 10% fetal calf serum (FCS). Afterwards, the cells were separated into three passages using a 10 ml pipette and centrifuged at 180g at 4°C for 10 minutes in the BSA (3.5%) layer of L15 medium. After discarding the supernatant, the cell pellet was incubated with basic B27 (2%), L-glutamine (2mM, P04-80100, DUTSCHER) and 2% PS solution and brain-derived neurotrophic factor (BDNF, CB-1115002, DUTSCHER) for neuronal culture. ) and resuspended in medium (11570556, FISHER SCIENTIFIC) containing 10ng/ml and microglial nerve growth factor (GDNF) 1ng/ml. Viable cells were confirmed through trypan blue exclusion test using a Neubauer cell counter. Cells were cultured at a density of 225,000 cells/well in a 24-well plate (pre-coated with poly-L-lysine) and maintained in a humidified incubator at 5% CO 2 and 37°C. Half of the medium was replaced with fresh medium every two days.
인간 알파시누클레인 펩타이드 (Watkinsville, GA)를 배지에 4μM 농도로 녹여 37℃ 암실 조건에서 3일간 천천히 흔들어주어 알파시누클레인을 형성하도록 하였다. 도파민성 뉴런 배양 일주일차에 배지에 녹인 화학식 3 화합물을 알파시누클레인 1시간 전에 미리 처치하여 안정화 시켰다. 이후 도파민성 뉴런 배양액에 알파시누클레인 용액 (250nM, ~60%의 올리고머를 포함함이 자동화 western blotting에 의해 확인됨)을 48시간 처치하였다. 이후 세포의 상등액은 분리하여 냉동하였으며 (-80℃) 세포는 PBS (L0615-1000, DUTSCHER) 로 세척하였다.Human alpha-synuclein peptide (Watkinsville, GA) was dissolved in the medium at a concentration of 4 μM and shaken slowly for 3 days at 37°C in the dark to form alpha-synuclein. In the first week of culturing dopaminergic neurons, the compound of Formula 3 dissolved in the medium was treated 1 hour before alpha-synuclein to stabilize it. Afterwards, the dopaminergic neuron culture was treated with alpha-synuclein solution (250 nM, confirmed by automated western blotting to contain ~60% of oligomers) for 48 hours. Afterwards, the supernatant of the cells was separated and frozen (-80°C), and the cells were washed with PBS (L0615-1000, DUTSCHER).
알파시누클레인 독성에 대한 화합식 3 화합물의 보호 효능을 검증하기 위해 도파민성 뉴런의 생존률, 신경돌기 네트워크 형성의 변화를 알아보았으며, 신경세포의 면역활성 억제 효능을 검증하기 위해 미세아교세포 활성지표 (Iba1) 그리고 대표적 면역 싸이토카인인 TNF-α의 발현량 변화를 확인하였다. 도파민성 뉴런의 생존 및 네트워크 형성은 타이로신 수산화효소 (TH) 면역염색을 통해, 미세아교세포 활성지표는 Iba1의 면역염색을 통해, 그리고 TNF-α의 발현량 변화는 ELISA를 통해 확인하였다. To verify the protective efficacy of Compound 3 against alpha-synuclein toxicity, we examined the survival rate of dopaminergic neurons and changes in neurite network formation, and to verify the efficacy of suppressing immune activity of neurons, microglial activity indicators were used. (Iba1) And changes in the expression level of TNF-α, a representative immune cytokine, were confirmed. Survival and network formation of dopaminergic neurons were confirmed through tyrosine hydroxylase (TH) immunostaining, microglial activity indicators were confirmed through Iba1 immunostaining, and changes in the expression level of TNF-α were confirmed through ELISA.
면역 염색을 위해 도파민성 뉴런을 실온에서 20분 동안 4% 파라포름알데히드 (in PBS, pH=7.3)에서 고정시킨 뒤 PBS로 2회 세척하였다. 비특이적 반응은 사포닌 0.1% (A4518, 0100, VWR) 와 FCS 1% 가 함유된 PBS 와의 상온에서 15분간 반응에 의해 차단되었으며, 이후 아래와 같이 반응이 이어졌다.For immunostaining, dopaminergic neurons were fixed in 4% paraformaldehyde (in PBS, pH=7.3) for 20 minutes at room temperature and then washed twice with PBS. Non-specific reactions were blocked by reaction with PBS containing 0.1% saponin (A4518, 0100, VWR) and 1% FCS at room temperature for 15 minutes, and then the reaction continued as follows.
a) 타이로신 수산화효소-도파민성 뉴런 검출: 상온에서 2시간 동안 FCS 1%, 사포닌 0.1% 를 포함하는 PBS에서 1:2000으로 희석한 토끼 유래 다클론 TH 항체(Sigma Aldrich)와 반응시켰다. 이를 통해 도파민 작용을 하는 뉴런과 특이적으로 결합하여 뉴런의 생존 및 뉴런의 신경돌기 네트워크 연구를 위해 수행하였다. a) Tyrosine hydroxylase-dopaminergic neuron detection: reaction was performed with rabbit-derived polyclonal TH antibody (Sigma Aldrich) diluted 1:2000 in PBS containing 1% FCS and 0.1% saponin for 2 hours at room temperature. Through this, it specifically binds to neurons that act on dopamine and was used to study the survival of neurons and the neurite network of neurons.
b) Iba1- 미세아교세포 검출: 상온에서 2시간 동안 FCS 1%, 사포닌 0.1%를 포함하는 PBS에서 1:500으로 희석한 마우스 유래 단클론 Iba-1 항체(Sigma Aldrich)와 반응시켰다. 이를 통해 미세아교세포의 활성화 연구를 수행하였다.b) Detection of Iba1-microglia: They were reacted with mouse-derived monoclonal Iba-1 antibody (Sigma Aldrich) diluted 1:500 in PBS containing 1% FCS and 0.1% saponin for 2 hours at room temperature. Through this, a study on the activation of microglial cells was performed.
이들은 모두 각각 상온에서 1% FCS, 0.1% 사포닌을 함유한 PBS에 의해 1:400으로 희석된 알렉사 플루오르 568 (염소-항토끼) 및 알렉사 플루오르 488 (염소 항마우스) IgG 2차 항체에 의해 1시간 동안 반응시켰다. 세포핵은 Hoehst (sigma)에 의해 대조 염색 시켰다. 10배율로 ImageXpress (Molecular Devices)에 의해 well 당 20장의 사진을 자동 촬영한 뒤, MetaXpress®(Moelcular Devices)에 의해 자동 분석이 수행되어 도파민성 뉴런 생존 (TH 양성 뉴런 수), 도파민성 뉴런의 신경돌기 네트워크 (TH 양성 신경돌기 길이) 및 총 미세아교세포 활성화 (미세아교세포 면적, Iba1 염색분 μM2)을 확인하였다.They were all incubated for 1 hour with Alexa Fluor 568 (goat-anti-rabbit) and Alexa Fluor 488 (goat anti-mouse) IgG secondary antibodies diluted 1:400 in PBS containing 1% FCS and 0.1% saponin, respectively, at room temperature. It was allowed to react for a while. Cell nuclei were counterstained by Hoehst (sigma). After automatically taking 20 pictures per well by ImageXpress (Molecular Devices) at 10x magnification, automatic analysis was performed by MetaXpress® (Moelcular Devices) to determine dopaminergic neuron survival (number of TH-positive neurons) and neurogenesis of dopaminergic neurons. Dendritic network (TH positive neurite length) and total microglial activation (microglial area, Iba1 staining μM 2 ) were determined.
TNF-α 단백질 발현의 정량을 위해 도파민성 뉴런 배양액의 상등액 (100 μl/well)을 이용하여 ELISA를 수행하였으며, 시험은 제품 (Rat TNF-alpha ELISA kit, abcam, ab46070) 매뉴얼의 지침에 따라 수행하였다.To quantify TNF-α protein expression, ELISA was performed using the supernatant (100 μl/well) of dopaminergic neuron culture, and the test was performed according to the instructions in the product (Rat TNF-alpha ELISA kit, abcam, ab46070) manual. did.
도 6에서의 모든 데이터는 ±SEM (평균의 표준오차)에 의해 표기되었다. 통계적인 분석은 Graphpad 사의 Prism을 사용하여 일원배치 분산분석 이후 Fisher's LSD에 의해 사후검정하여 진행되었다. All data in Figure 6 are expressed as ±SEM (standard error of the mean). Statistical analysis was performed using Graphpad's Prism, followed by one-way ANOVA followed by a post hoc test using Fisher's LSD.
그 결과, 도 6에서와 같이, 알파시누클레인에 의한 신경세포 독성은 화학식 3 화합물의 모든 시험 농도에서 유의하게 감소된 것으로 확인되었으며, 약물 농도 증가에 대한 효능 수치 증가의 경향성도 확인되었다. 신경돌기 네트워크 또한 30 및 60 μM에서 유의한 효능이 나타났다. 신경세포에서의 면역활성 억제능력은 미세아교활성화 지표 (Iba1) 및 TNF-α 발현 모두 모든 시험농도에서 유의한 효능이 확인되었으며, 대부분의 시험결과에서 농도와 효능의 상관관계가 확인되었다. 따라서, 화학식 3 화합물은 신경세포에서의 염증반응을 억제하여 알파시누클레인에 의한 신경세포 독성을 유의하게 감소시키는 것을 알 수 있었다. As a result, as shown in FIG. 6, it was confirmed that neuronal toxicity caused by alpha-synuclein was significantly reduced at all tested concentrations of the compound of Formula 3, and a tendency for the efficacy value to increase with increasing drug concentration was also confirmed. Neurite network also showed significant efficacy at 30 and 60 μM. Significant efficacy in suppressing immune activity in nerve cells was confirmed at all test concentrations for both microglial activation index (Iba1) and TNF-α expression, and a correlation between concentration and efficacy was confirmed in most test results. Therefore, it was found that the compound of Formula 3 significantly reduces neuronal cell toxicity caused by alpha-synuclein by suppressing the inflammatory response in nerve cells.
실험예 7. 파킨슨병 치료 효과Experimental Example 7. Parkinson’s disease treatment effect
MPTP 유발 파킨슨병 제브라피쉬 모델을 이용하여 화학식 2 화합물의 파킨슨 병 치료 효과를 확인하고자 하였다. 해당 시험은 제브라피쉬 전문 CRO 인 ㈜제핏 에서 진행되었으며, 시험에 사용된 제브라피쉬는 제핏에서 관리중인 AB strain 제브라 피쉬 치어를 선정하여 사용하였다. AB strain은 일반적으로 미국 등에서 제브라피쉬에서 연구용으로 사용되는 strain으로써, 파킨슨 모델에서 많이 사용되고 있다.We sought to confirm the effectiveness of the compound of Formula 2 in treating Parkinson's disease using the MPTP-induced Parkinson's disease zebrafish model. The test was conducted at Zefit Co., Ltd., a CRO specializing in zebrafish, and the zebrafish used in the test were AB strain zebrafish fry managed by Zefit. The AB strain is a strain commonly used in zebrafish for research in the United States and other countries, and is widely used in Parkinson's models.
Parkinson model 유발을 위해 MPTP (Sigma-Aldrich, M0896)는 dimethyl sulfoxide (DMSO)(Sigma-Aldrich, 276855)를 이용하여 100mM stock 용액을 제조하였으며, 실험에 사용 직전 최종 농도로 E3 배지에 희석하여 제브라피쉬 치어에 200μM 농도로 2dpf부터 6dpf까지 4일 동안 노출시켰으며, 24시간 간격으로 E3 배지(5mM NaCl, 0.17mM KCl, 0.33 mM CaCl2, 0.33mM MgSO4, pH 7.0-7.2)를 교체하였다. Positive control로 사용된 Rasagiline (Sigma-Aldrich, SML0124)은 제브라피쉬 치어에 1μM 농도로 2dpf부터 6dpf까지 4일 동안 200μM MPTP와 co-treatment 방식으로 노출시켰으며, 24시간 간격으로 E3 배지를 교체하였다. 시험에 사용한 포말리도마이드와 화학식 2 화합물은 dimethyl sulfoxide (DMSO)를 이용하여 10mM stock 용액을 제조하였으며, 실험에 사용 직전 최종 농도 (0.03, 0.1, 0.3, 1 μM)로 E3 배지에 희석하여 제브라피쉬 치어에 2dpf부터 6dpf까지 4일 동안 200μM MPTP와 co-treatment 방식으로 노출시켰으며, 24시간 간격으로 E3 배지를 교체하였다.To induce Parkinson model, MPTP (Sigma-Aldrich, M0896) was prepared as a 100mM stock solution using dimethyl sulfoxide (DMSO) (Sigma-Aldrich, 276855), diluted in E3 medium to the final concentration immediately before use in the experiment, and incubated in zebrafish. Fry were exposed to a concentration of 200 μM for 4 days from 2dpf to 6dpf, and E3 medium (5mM NaCl, 0.17mM KCl, 0.33mM CaCl 2 , 0.33mM MgSO 4 , pH 7.0-7.2) was replaced at 24-hour intervals. Rasagiline (Sigma-Aldrich, SML0124), used as a positive control, was exposed to zebrafish fry at a concentration of 1 μM by co-treatment with 200 μM MPTP for 4 days from 2 dpf to 6 dpf, and the E3 medium was replaced every 24 hours. Pomalidomide and the compound of Formula 2 used in the test were prepared as 10mM stock solutions using dimethyl sulfoxide (DMSO), diluted in E3 medium to the final concentration (0.03, 0.1, 0.3, 1 μM) immediately before use in the experiment, and grown in zebrafish. Fry were exposed to 200 μM MPTP and co-treatment for 4 days from 2 dpf to 6 dpf, and E3 medium was replaced at 24-hour intervals.
30마리의 제브라피쉬 치어에 약물 처리 후, 6dpf에서 20마리의 치어를 랜덤하게 선정하여 locomotor activity 측정을 위해 96well plates로 옮긴 후, 10분간 촬영하여 Total moved distance (mm)를 분석하였다. Movements는 High quality Camera(16mm Telephoto Lens for Raspberry Pi High Quality Camera)를 이용하여 30/s의 frame rate로 촬영되었으며, Dark 상태에서 Movement를 추적하기 위해 제브라피쉬가 볼 수 없는 적외선(IR)광원 (LV-BL-R 150/120 IR24)을 백라이트로 사용하여 IR filter (850nm narrow bandpass filter)로 움직임을 감지하였다. 안정적인 Movements 촬영을 위해 제브라피쉬 사육 적정 온도인 27.5±1℃의 별도의 방음 챔버에서 실험을 수행하였으며, ㈜제핏에서 자체개발한 software를 사용하여 임계값 설정 방식으로 배경과 구분되는 치어의 움직임을 추적하였다. 10분 동안의 영상 분석 중 1frame 동안 움직인 larvae의 속도가 2mm/s 이하일 경우 거리를 이동한 것이 아닌 몸을 틀거나, 떨면서 물에 떠있는 경우 등으로 판단하여 2mm/s 이상의 속도로 움직인 경우만 Total moved distance(mm)에 포함하였다.After drug treatment to 30 zebrafish fry, 20 fry were randomly selected at 6 dpf, transferred to 96 well plates to measure locomotor activity, and photographed for 10 minutes to analyze total moved distance (mm). Movements were filmed at a frame rate of 30/s using a high quality camera (16mm Telephoto Lens for Raspberry Pi High Quality Camera), and an infrared (IR) light source (LV) that zebrafish cannot see was used to track movements in the dark. -BL-R 150/120 IR24) was used as a backlight and movement was detected with an IR filter (850nm narrow bandpass filter). In order to capture stable movements, the experiment was conducted in a separate soundproof chamber at 27.5 ± 1℃, which is the appropriate temperature for zebrafish breeding. Using software developed by Zefit Co., Ltd., the movements of the fry were tracked by setting a threshold, distinguishing them from the background. did. If the speed of the larvae that moved during 1 frame during 10 minutes of video analysis is less than 2 mm/s, it is judged that the larvae is not moving a distance, but is turning its body or floating in the water while shaking, and moves at a speed of 2 mm/s or more. Only included in Total moved distance (mm).
총 이동거리를 측정한 시험결과 포말리도마이드는 0.03 및 0.3 μM 에서 MPTP 단독 처리군 대비 유의한 효능이 확인되었으나 농도 의존적인 결과는 나타나지 않았던 반면, 화학식 2 화합물의 경우 0.3 및 1 μM 에서 농도의존적으로 유의한 효능을 확인할 수 있어 물질에 의한 MPTP 독성으로 인한 파킨슨 증상 완화를 추정할 수 있었다. As a result of measuring the total distance traveled, pomalidomide was confirmed to have significant efficacy compared to the MPTP treatment group alone at 0.03 and 0.3 μM, but did not show concentration-dependent results, whereas the compound of Formula 2 showed concentration-dependent efficacy at 0.3 and 1 μM. Significant efficacy could be confirmed, making it possible to estimate relief of Parkinson's symptoms caused by MPTP toxicity by the substance.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시 양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.As the specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. something to do. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
Claims (13)
[화학식 1]
[화학식 2]
[화학식 3]
.
Any one compound selected from the group consisting of [Formula 1] to [Formula 3]:
[Formula 1]
[Formula 2]
[Formula 3]
.
A pharmaceutical composition for preventing or treating inflammatory diseases containing the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
The pharmaceutical composition for preventing or treating inflammatory diseases according to claim 2, wherein the inflammatory diseases are selected from the group consisting of psoriasis, rheumatoid arthritis, and Crohn's disease.
The pharmaceutical composition for preventing or treating inflammatory diseases according to claim 2, wherein any one compound selected from the group consisting of [Formula 1] to [Formula 3] is non-teratogenic.
A pharmaceutical composition for preventing or treating brain diseases containing the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
The method of claim 5, wherein the brain disease includes traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, multiple system atrophy, Alzheimer's dementia, vascular dementia, frontotemporal dementia, Lewy dementia, ischemic stroke, hemorrhagic stroke, and multiple A pharmaceutical composition for preventing or treating brain diseases selected from the group consisting of cirrhosis.
The pharmaceutical composition for preventing or treating brain diseases according to claim 5, wherein any one compound selected from the group consisting of [Formula 1] to [Formula 3] is non-teratogenic.
[화학식 1]
(a) 포말리도마이드를 다이옥세인에 용해시키는 단계; 및
(b) 오황화인을 첨가하고 60 내지 100℃에서 반응시키는 단계.
A method for preparing a compound of formula 1 comprising the following steps:
[Formula 1]
(a) dissolving pomalidomide in dioxane; and
(b) Adding phosphorus pentasulfide and reacting at 60 to 100°C.
(c) 여과 및/또는 크로마토그래피로 정제하는 단계;를 추가로 포함하는, 제조방법.
The method of claim 8, wherein after step (b),
(c) purifying by filtration and/or chromatography; further comprising:
[화학식 2]
(a) 레날리도마이드를 다이옥세인에 용해시키는 단계; 및
(b) 질소 분위기 하에서 Lawesson 시약을 첨가하고 80 내지 120℃에서 반응시키는 단계.
Method for preparing a compound of formula 2 comprising the following steps:
[Formula 2]
(a) dissolving lenalidomide in dioxane; and
(b) Adding Lawesson reagent under a nitrogen atmosphere and reacting at 80 to 120°C.
(c) 크로마토그래피로 정제하는 단계;를 추가로 포함하는, 제조방법.
The method of claim 10, wherein after step (b),
(c) purifying by chromatography; manufacturing method further comprising.
[화학식 3]
(a) 1,6'-디티오포말리도마이드를 DMSO 및 물에 용해시키는 단계;
(b) 상기 용액을 40-80℃에서 교반시킨 후 용매를 제거하는 단계; 및
(c) 상기 용매가 제거된 조생성물을 MeOH:THF(50%)로 용출하는 단계.
Method for preparing compounds of formula 3 comprising the following steps:
[Formula 3]
(a) dissolving 1,6'-dithiopomalidomide in DMSO and water;
(b) stirring the solution at 40-80°C and then removing the solvent; and
(c) Eluting the crude product from which the solvent has been removed with MeOH:THF (50%).
(d) 크로마토그래피로 정제하는 단계;를 추가로 포함하는, 제조방법.
The method of claim 12, wherein after step (c),
(d) purifying by chromatography; manufacturing method further comprising.
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