KR100712573B1 - 염증성 사이토카인 억제제용 2-(2,6-디옥소피페리딘-3-일)이소인돌린 유도체, 그 제조방법 및 그 용도 - Google Patents
염증성 사이토카인 억제제용 2-(2,6-디옥소피페리딘-3-일)이소인돌린 유도체, 그 제조방법 및 그 용도 Download PDFInfo
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- KR100712573B1 KR100712573B1 KR1020007010218A KR20007010218A KR100712573B1 KR 100712573 B1 KR100712573 B1 KR 100712573B1 KR 1020007010218 A KR1020007010218 A KR 1020007010218A KR 20007010218 A KR20007010218 A KR 20007010218A KR 100712573 B1 KR100712573 B1 KR 100712573B1
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- tnfα
- dioxopiperidin
- dioxo
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Abstract
하기 일반식 I로 표시되는 1-옥소- 및 1,3-디옥소-2-(2,6-디옥소피페리딘-3-일)이소인돌린 유도체가 개시되어 있다. 하기 식에서, Y는 산소 또는 H2이고 R1 및 R2 중 하나는 각각 할로겐기(halo), 알킬기(alkyl), 알콕시기(alkoxy), 알킬아미노기(alkylamino), 디알킬아미노기 (dialkylamino), 시아노기(cyano) 또는 카르바모일기(carbamoyl)이고, R1 및 R2 중 다른 하나는, 독립적으로 수소, 할로겐기, 알킬기, 알콕시기, 알킬아미노기, 디알킬아미노기, 시아노기 또는 카르바모일기이며, R3은 수소, 알킬기 또는 벤질이다. 또한, 상기 유도체를 포유동물 체내에 투여함으로써 TNFα 및 다른 염증성 사이토카인의 레벨을 감소시키는 방법과 상기 유도체를 포함하는 약학적 조성물이 개시되어 있다.
Description
본 출원은 1998년 3월 16일자에 출원된 명칭이 "1-옥소 및 1,3-디옥소이소인돌린 및 염증성 사이토카인 양의 감소 방법"인 미합중국 가출원 제 60/078,180호의 우선권주장 출원이다.
종양괴사인자인 TNF α(tumor necrosis factor α)는 여러 가지 면역촉진제에 반응하여 단핵식세포에 의해 주로 방출되는 사이토카인이다. 이것은 다른 사이토카인 및 작용물(agent)의 생성 및/또는 방출을 야기하는 염증 캐스케이드(inflammation cascade)에서 주요 전염증성(proinflammatory) 사이토카인이다. 동물이나 인체에 투여했을 때, 염증, 발열, 심장혈관계 효과, 출혈, 혈액응고 및 급성 감염이나 쇼크 상태에서 나타나는 반응과 유사한 급성 단계 반응(acute phase response)을 유발한다. 과도하거나 조절되지 않은 TNFα생성은 다수의 질병 상태와 관련되어 있다. 이들은 내독소혈증(endotoxemia) 및/또는 약물 쇼크 증후군(toxic shock syndrome){Tracey et al., Nature
330, 662-664(1987) and Hinshaw et al., Circ Shock
30, 279-292(1990)}; 악액질(cachexia){Dezube et al., Lancet, 335(8690), 662(1990)} 및 성인 호흡 장애 증후군 (Adult Respiratory Distress Syndrome; ARDS)을 포함하며 성인 호흡 장애 증후군에 있어서, ARDS 환자의 폐 흡출시에 1,2000 pg/mL를 초과하는 TNFα 레벨이 검출되었다{Millar et al., Lancet
2(8665), 712-714(1989)}. 또한 재조합 TNFα의 전신 주입(systemic infusion)은 ARDS에서 일반적으로 보여지는 변화를 가져온다{Ferrai-Baliviera et al., Arch. Surg.
124(12), 1400-1405(1989)}.
TNFα는 관절염을 포함한 골질 재흡수 질병과 관련된 것으로 보인다. 백혈구가 활성화될 때, 골질 재흡수를 생성하며, 이 활성에 TNFα가 기여한다는 자료가 제시되고 있다{Bertolini et al., Nature
319, 516-518(1986) and Johnson et al., Endocrinology
124(3), 1424-1427(1989)}. 또한 TNFα는 조골세포의 기능 억제와 함께 파골세포 형성 및 활성을 자극함으로써 시험관내 및 생체내에서 골질 형성을 저해하고 골질 재흡수를 촉진하는 것으로 알려져 왔다. 비록 TNFα가 관절염을 포함한 많은 골질 재흡수 질병과 관련이 있을지라도, 질병과의 가장 필연적인 연계는 바로 과칼슘혈증(hypercalcemia)과 관련된 악성 종양 및 종양이나 숙주 조직에 의한 TNFα생성 사이의 연관성이다{Calci. Tissue Int. (US) 46(Suppl.), S3-10(1990)}. 이식조직편 대 숙주 반응에 있어서, 혈청 TNFα 레벨의 증가는 급성 동종 골수 이식(acute allogenic bone marrow transplants) 다음에 수반되는 주요 합병증과 관련이 있다{Holler et al., Blood,
75(4), 1011-1016(1990)}.
뇌 말라리아(cerebral malaria)는 TNFα의 혈중 고농도와 연관된 치명적인 과급성 신경성 중후군(hyperacute neurological syndrome)이며 말라리아 환자에서 발생하는 가장 심각한 합병증이다. 혈청 TNFα의 레벨은 질병의 중증도와 급성 말 라리아 감염 환자의 예후(prognosis)와 직접적인 상호 관련이 있다{Grau et al., N. Engl. J. Med.
320(24), 1586-1591 (1989)}.
TNFα가 대식세포-유도성 신생혈관형성(macrophage-induced angiogenesis)을 매개하는 것으로 알려져 있다. 레이보비치 등{Leibovich et al. Nature, 329, 630-632(1987)}은 TNFα가 생체 내에서 매우 낮은 복용량으로 쥐 각막에서의 모세 혈관 형성과 병아리의 융모요막 (chorioallantoic membranes) 발달을 유도하며, TNFα가 염증, 상처 회복 및 종양 성장에서 신생혈관형성을 유도하는 후보물질임을 제시하고 있다. 또한 TNFα생성은 불치병, 특히, 유도된 종양과 관련이 있다{Ching et al., Brit. J. Cancer, (1955) 72, 339-343, and Koch, Progress in Medical Chemistry, 22, 166-242(1985)}.
TNFα는 또한 만성적 폐염증 질병 분야와 관련이 있다. 실리카 입자가 침적되면 규폐증에 이르게 되는데, 섬유 반응에 의해 진행성 호흡기 부전질환을 일으킨다. TNFα에 대한 항체는 쥐의 폐 섬유증을 완벽하게 차단한다{Pignet et al., Nature,
344:245-247(1990)}. 혈청 및 단리된 대식세포에서 높은 레벨의 TNFα생성은 실리카와 석면 유발 섬유증의 동물 모델에서 증명되었다{Bissonnette et al., Inflammation
13(3), 329-339(1989)}. 폐 유육종증(pulmonary sarcoidosis) 환자의 폐포 대식포는 정상적인 기증자의 대식세포와 비교할 때 거대한 양의 TNFα를 자발적으로 방출한다는 것으로 알려져 있다{Baughman et al., J. Lab. clin. Med.
115(1), 36-42(1990).
또한 TNFα는 재관류 손상(reperfusion injury)이라 불리는 재관류를 수반하는 염증반응과 관련이 있고, 혈류의 손실 후에 조직 손상을 일으키는 주된 원인이다{Vedder et al., PNAS
87, 2643-2646(1990)}. TNFα는 또한 내피세포의 성질을 바꾸고, 트롬보모듈린(thrombomodulin)의 발현을 억제 조절(down-regulating)할 뿐 아니라 항응고제 단백질 C 경로를 억제하고 조직인자 전응고인자활성(tissue factor pro-coagulant activities)을 생성하는 것과 같은 다양한 전응고 활성을 갖는다{Sherry et al., J. Cell Biol. 107, 1269-1277(1988)}. TNFα는 전염증(pro-inflammation)활성을 가지고 있는데, 이것은 TNFα의 초기 생성(염증초기 단계 동안)과 함께 심근경색, 발작 및 순환계 쇼크를 포함하나 이에 한정되지 않는 몇몇 심각한 질병에서 조직 손상의 중개자로 작용하는 것으로 보인다. 세포간 부착 분자(intracellular adhesion molecule; ICAM)나 내피 세포 상에 내피 백혈구 부착분자(endothelial lymphocyte adhesion molecule; ELAM)와 같은 부착분자의 TNFα-유도성 발현이 특히 중요한 것으로 보인다{Munro et al., Am. J. Path.135(1), 121-132(1989)}.
단일클론 항-TNFα항체에 의한 TNFα저해는 류마티성 관절염에서 이로운 것으로 나타났다{Elliot et al., Int. J. Pharmc. 1995 17(2), 141-145}. 높은 레벨의 TNFα는 크론병(Crohn's disease)과 관련이 있고 {von Dullermen et al., Gastroenterology, 1995 109(1), 129-135} TNFα항체 치료법을 통해 임상적 유익함이 밝혀졌다.
더구나, 현재로서는 TNFα가 HIV-1의 활성을 포함하여 레트로바이러스 복제의 유력한 활성인자로 알려져 있다. {Duh et al., Proc. Nat. Acad. Sci.
86, 5974-5978(1989); Poll et al., Proc. Nat. Acad. Sci.
87, 782-785(1990); Monto et al., Blood
79, 2670(1990); Clouse et al., J. Immunol.
142, 431-438(1989); Poll et al., AIDS Res. Hum. Retrovirus, 191-197(1992)}. AIDS는 인체 면역 결핍성 바이러스 (Human Immunodeficiency Virus; HIV)의 T 임파구 감염으로 생긴다. 적어도 3 개의 타입 또는 계통(strain)의 HIV가 동정되었는데, HIV-1, HIV-2, HIV-3가 그것이다. HIV 감염의 결과로, T-세포 매개성 면역반응이 손상되고 감염된 개체들은 심각한 기회성 감염 및/또는 보기 드문 종양을 나타낸다. HIV가 T 임파구에 들어가기 위해서는 T 임파구가 활성화 되어야 한다. HIV-1, HIV-2와 같은 다른 바이러스들은 T 세포가 활성화 된 후에 T 임파구를 감염시키고 이러한 바이러스 단백질 발현 및/또는 복제는 T 세포 활성에 의해서 매개되거나 지속된다. 일단 활성화된 T 임파구가 HIV에 감염되면, T 임파구는 HIV 유전자 발현 및/또는 HIV 복제를 가능하게 하기 위하여 활성화된 상태를 유지하여야 한다. 사이토카인, 구체적으로 TNFα는 T 임파구 활성을 유지하는 역할을 수행함으로써 활성화된 T-세포 매개 HIV 단백질 발현 및/또는 바이러스 복제에 관련되어 있다. 따라서, 사이토카인 활성 방해, 특히 TNFα와 같은 사이토카인 생성의 억제와 방해는, HIV 감염자들에 있어서, HIV 감염에 의해 발생하는 T 임파구 유지를 제한하는데 도움이 된다.
단핵세포, 대식세포 및 쿠퍼(kupffer)세포와 신경교(glial) 세포 같은 관련 세포들 역시 HIV 감염 유지와 관련되어 있다. T 세포처럼, 이들 세포는 바이러스 복제를 위한 표적세포이며, 바이러스 복제 정도는 이들 세포의 활성화 상태에 달려있다. {Rosenberg et al., The Immunopathogenesis of HIV INfection, Advances in Immunology, 57(1989)}. TNFα와 같은 사이토카인은 단핵세포 및/또는 대식세포에 서 HIV 복제를 활성화시키는 것으로 나타났다{Poli et al. Proc. Natl. Acad. Sci.
87, 782-784(1990)}. 그러므로, 사이토카인 생성이나 활성을 방해하거나 억제하면 T 세포에서와 같이 HIV 진행을 제한하는데 도움을 준다. 추가적인 연구 결과에 의하면, TNFα가 시험관내 HIV 활성화에 있어서 공통 인자임이 밝혀졌고, 세포의 세포질에서 발견되는 핵 조절 단백질을 통한 활성 기작이 명확하게 알려졌다(Osborn, et al., PNAS
86, 2336-2340). 이러한 증거는 TNFα 합성 감소가 전사감소 및 이에 따른 바이러스 생산 감소를 통하여, HIV 감염에 있어서 항바이러스 효과를 나타냄을 보여주고 있다.
T 세포와 대식세포주에서 잠복성 HIV의 AIDS 바이러스 복제는 TNFα에 의해 유도될 수 있다{Folks et al., PNAS
86, 2336-2340(1989)}. 바이러스 유도 활성의 분자 기작은 세포의 세포질에서 발견되는 유전자 조절 단백질(NFκB)를 활성화시키는 TNFα의 능력에 의한 것으로 알려져 있는데, NFκB는 바이러스 조절 유전자 서열(LTR)에 결합함으로서 HIV 복제를 촉진시킨다{Osborn et al., PNAS
86, 2365-2368(1989)}. AIDS와 악액질(cachexia)에서 관련된 TNFα는 혈청 TNFα의 상승 및 환자의 말초 혈액 단핵세포에서 높은 레벨의 TNFα를 자발적으로 생성한다는 것이 제안되어 있다{Wright et al. J. Immunol. 141(1), 99-104(1988)}. TNFα는 사이토메갈리아 바이러스(cytomegalia virus; CMV), 인플루엔자 바이러스, 아데노바이러스 및 헤르페스계(herpes family) 바이러스와 같은 기타 바이러스성 감염의 다양한 역할과 관련되어 있다.
NFκB(핵인자 κB, Nuclear Factor κB)는 다향성 전사 활성제(pleiotropic trnascriptional activator)이다(Lenardo, et al. Cell 1989, 58, 227-29). NFκB는 다양한 질병과 염증 상태에서 전사 활성인자와 관련되어 있으며, TNFα에만 제한된 것은 아니지만, 이를 포함한 사이토카인 레벨을 조절하고 HIV 전사의 활성인자인 것으로 여겨지고 있다(Dbaibo, et al. J. Biol. Chem. 1993, 17762-66; Duh et al. Proc. Natl. Acad. Sci. 1989, 86, 5974-78; Bachelerie et al., Nature 1991, 350, 709-12; Boswas et al., J. Acquired Immune Deficiency Syndrome 1993, 6, 778-786; Suzuki et al. Biochem. And Biophys. Res. Comm. 1993, 193, 277-83; Suzuki et al. Biochem. And Biophys. Res Comm. 1992, 189, 1709-15; Suzuki et al.
Biochem. Mol. Bio. Int. 1993, 31(4), 693-700; Shakhov et al. 1990, 171. 35-47; and Staal et al. Proc. Natl. Acad. Sci. USA 1990, 87, 9943-47). 그러므로, NFκB 결합을 억제하면 사이토카인 유전자의 전사를 조절할 수 있고, 이러한 조절과 기타 기작을 통해 다수의 질병상태를 억제하는데 유용하다. 본 명세서에 개시된 화합물들은 핵에서 NFκB의 활성을 억제할 수 있으므로 류머티즘성 관절염(rheumatoid arthritis), 류머티즘성 척추염(rheumatoid spondylitis, 골관절염(osteoarthritis), 기타 관절염 증상(arthritic conditions), 부패성 쇼크(septic shock), 패혈증(sepsis), 내독성 쇼크(endotoxic shock), 이식 대 숙주 질환(graft versus host disease), 수척(wasting), 크론병(Crohn's disease), 궤양성 대장염(ulcerative colitis), 다발성 경화증(multiple sclerosis), 전신 낭창 적혈구종증(systemic lupus erythrematosis), 나병에서의 ENL(ENL in leprosy), HIV, AIDS 및 AIDS내 기회성 감염에 제한되지 않고 이를 포함한 여러 가지 질병의 치료에 유용하다. TNFα및 NFκB 레벨은 상호간의 피드백 루프(feedback loop)에 의해 영향을 받는다. 위에서 언급한 대로, 본 발명의 화합물들은 TNFα와 NFκB 레벨에 영향을 준다.
많은 세포 기능들이 아데노신 3',5'-사이클릭 모노포스페이트(cyclic monophosphate; cAMP) 레벨에 의해 매개된다. 그런 세포 기능들은 천식, 염증 및 기타 병(condition)을 포함한 염증성 질환의 원인이 될 수 있다(Lowe and Cheng. Drugs of the Future, 17(9), 799-807, 1992). 염증성 백혈구에서 cAMP가 증가시키면 이들의 활성 및 이로 인한 TNFα와 NFκB를 포함한 염증 중개물질의 방출을 억제하는 것으로 나타났다. 또한, cAMP가 증가하면 기도 평활근이 이완된다. 포스포디에스테라제가 가수분해를 통해 cAMP 레벨을 제어하고 포스포디에스테라제의 억제제가 cAMP 레벨을 증가시킨다는 것이 밝혀졌다.
그러므로 TNFα레벨의 감소 및/또는 cAMP 레벨의 증가는 많은 염증성, 감염성, 면역성 또는 악성 질환들의 치료에 대한 유용한 치료 전략이 된다. 이러한 것들은 부패성 쇼크, 패혈증, 내독성 쇼크, 혈색동태성 쇼크(hemodynamic shock) 및 패혈 증후군(sepsis syndrome), 후허혈 재관손상증(post ischemic reperfusion injury), 말라리아(malaria), 미코박테리아성 감염(mycobacterial infection), 뇌막염(meningitis), 건선(psoriasis), 출혈성 심장쇠약증(congestive heart failure), 섬유염증(fibrotic disease), 악액질(cachexia), 이식거부(graft rejection), 암(cancer), 자기면역질환(autoimmune disease), AIDS에서의 기회성 감염 (opportunistic infections in AIDS), 류머티즘성 관절염(rheumatoid arthritis), 류머티즘성 척추염(rheumatoid spondylitis), 골관절염 (osteoarthritis), 기타 관절염 증상(arthritic conditions), 크론병(Crohn's disease), 궤양성 대장염 (ulcerative colitis), 다발성 경화증(multiple sclerosis), 전신 낭창 적혈구종증(systemic lupus erythrematosis), 나병내 ENL (ENL in leprosy), 방사능 손상 (radiation damage), 그리고 과독성 폐포손상 (hyperoxic alveolar injury)를 포함하지만 이에 제한되지는 않는다. TNFα 효과를 억제하기 위한 이전의 노력은 덱사메타손(dexamethasone)과 프리드니소론 (prednisolone)과 같은 스테로이드 이용에서부터 폴리클론항체와 단일클론항체의 사용에 이르기까지 다양하였다{Beutler et al., Science
234, 470-474(1985); WO 92/11383}.
본 발명은 본 명세서에서 보다 상세하게 설명된 어떤 종류의 비-폴리펩티드 (non-polypeptide) 화합물이 TNFα의 레벨을 감소시키고, cAMP의 레벨을 증가시키며, 염증성 사이토카인을 억제한다는 발견에 기초한 것이다. 따라서 본 발명은 이소인돌린 고리의 4번 위치가 치환되고, 임의로 2-6-디옥소피페리딘 고리의 3번 위치가 더욱 치환된 1-옥소 및 1,3-디옥소-2-(2-6-디옥소피페리딘-3-일)이소인돌린, 상기 유도체를 포유동물에 투여함으로써 TNFα 및 다른 염증성 사이토카인의 레벨을 감소시키는 방법 및 상기 유도체를 포함하는 약학적 조성물에 관한 것이다.
특히, 본 발명은 (a) 하기 일반식 I의 2-(2-6-디옥소피페리딘-3-일)이소인돌 린:
여기서, Y는 산소 또는 H2, R1 및 R2 중 하나는 각각 할로겐기(halo), 알킬기(alkyl), 알콕시기(alkoxy), 알킬아미노기(alkylamino), 디알킬아미노기 (dialkylamino), 시아노기(cyano) 또는 카르바모일기(carbamoyl)이고, R1 및 R2의 다른 하나는, 독립적으로 수소, 할로겐기, 알킬기, 알콕시기, 알킬아미노기, 디알킬아미노기, 시아노기 또는 카르바모일기이며, R3은 수소, 알킬기 또는 벤질, 및
(b)양성자를 받을 수 있는 질소 원자를 포함하고 있는 상기 화합물의 산 부가염에 관한 것이다.
달리 정의되지 않으면, 알킬기이라는 용어는 1가의 포화된 분지형(univalent saturated branched) 또는 1 ∼ 4개의 탄소원자를 갖고 있는 직쇄형의 탄화수소사슬(straight hydrocarbon chain)를 나타낸다. 상기 알킬 그룹을 대표하는 것들은 메틸기, 에틸기, 프로필기, 이소프로필기, 부틸기, 이소부틸기, 2차부틸기(sec-butyl), 3차부틸기(tert-butyl)이다. 알콕시기는 에테르의 산소원자를 통해 분자의 잔여기에 결합하고 있는 알킬 그룹을 말한다. 상기 알콕시 그룹을 대표하는 것들은 메톡시기, 에톡시기, 프로폭시기, 이소프로폭시기, 부톡시기, 이소부톡시기, 2차부톡시기(sec-butoxy), 3차부톡시기(tert-butoxy)이다.
할로겐기는 브로모(bromo), 클로로(chloro), 플루오로(fluoro)를 포함한다.
일반식 I의 화합물은 TNFα의 바람직하지 않은 효과와 인터루킨 IL-1, IL-6, IL-12를 포함하는 다른 염증성 사이토카인을 억제하기 위해 자격있는 전문가의 감독하에 사용된다. 이 화합물들은 경구적으로, 직장으로 또는 비경구적으로(parenterally), 단독 또는 항생제, 스테로이드, 화학요법 치료제 등을 포함하는 다른 치료제와 함께, 치료가 필요한 즉, 암치료, 류머티즘성 관절염, 염증성 장 질병, 근위축증, 크론병 등의 치료가 필요한 포유동물에 투여될 수 있다.
본 발명의 화합물은 또한 과다한 TNFα생성에 의해 매개되거나 악화된 질병 상태의 치료나 예방에 국부적으로 사용될 수 있는데, 각각 바이러스 감염, 그리고 헤르페스 바이러스 또는 바이러스성 결막염, 건선, 아토피성 피부염 등에 의해 일어나는 감염과 같은 것이 있다.
본 발명 화합물은 또한 인간뿐만 아니라 TNFα생성의 저해나 예방을 필요로 하는 다른 여러 포유동물의 수의(veterinary)치료에 사용될 수 있다. 동물에 있어서, 치료상 또는 예방상 치료를 필요로 하는 TNFα 매개성 질병들은 상기에 언급한 바와 같은 질병상태, 특히 바이러스 감염을 포함한다. 예를 들면, 다른 렌티바이러스(lentivirus) 뿐만 아니라, 고양이과 면역결핍 바이러스(feline immunodeficiency virus), 말 감염성 빈혈 바이러스(equine infectious anaemia virus), 염소의 관절염 바이러스 (caprine arthritis virus), 비스나 바이러스(visna virus), 그리고 매디 바이러스(maedi virus)이다.
일반식 I의 화합물은 여러 가지 경로를 통해 준비된다. 첫 번째 태양에서, 무수물 또는 락톤을 3-아미노-2,6-디옥소-피페리딘과 반응시킨다:
상기 반응에서, R1, R2, R3 및 Y 각각은 위에 정의한 바와 같다.
3-아미노-2,6-디옥소피페리딘은 종래의 아미드화(amidation)를 통한 유사한 글루탐산 무수물로부터 또는 적합한 글루타민 유도체의 사이클라이제이션 (cyclization)으로부터 얻을 수 있다.
Y가 H2인 화합물은 택일적으로, 하기 반응에 따라 디메틸아미노피리딘 또는 트리에틸아민과 같은 산 수용기(acid acceptor)의 존재하에서 이중치환된 벤조산염 중간 생성물(disubstituted benzoate intermediate)로부터 얻을 수 있다:
여기서, R3은 CHO 또는 CH2Br이다.
이중치환된 벤조산염 중간 생성물은 알려져 있는 또는 종래의 공정을 통해 얻을 수 있다. 예를 들어, 3,6-이중치환된 오르소-톨루산 (3,6-disustituted ortho-toluic acid)의 저급 알킬(lower alkyl) 에스테르는 광의 영향 하에서 N-브로모숙시네이트(N-bromosuccinate)로 브롬화(brominate)시켜 저급 알킬 2-(브로모에틸)-3,6-이중치환벤조산염을 생성한다.
택일적으로, 디알데하이드를 2,6-디옥소피페리딘-3-암모늄과 반응시켜 Y가 H2인 일반식 I의 화합물을 얻는다:
마지막 방법으로, 디알데히드를 글루타민과 반응시킨 다음, 그 결과로서 생기는 2-(1-옥소-이소인돌린-2-일)글루타르산에 고리를 형성시켜 일반식 I의 4,7-이치환된 1-옥소-2-(2,6-디옥소피페리딘-3-일)-이소인돌린을 얻는다. 여기서 Y는 H2이다:
일반식 I의 화합물에서 R3가 결합되어 있는 탄소원자는 키랄중심(chiral center)를 이루고 있어, 광학적 이성질체를 야기한다:
두 번째 키랄중심이 존재할 때, 디아스테레오머 (diastereomers)뿐 아니라, 이들 이성질체의 두 라세메이트(racemate) 및 각각의 이성질체 자체는 본 발명의 범위 내에 있다. 라세메이트들은 상기와 같이 사용될 수 있고 또는 키랄 흡착제를 이용한 크로마토그래피에 의해 각각의 이성질체로 기계적으로 분리될 수 있다. 별법으로, 각각의 이성질체들은 키랄 형태로 제조하거나, 10-캠퍼술폰산(10-camphosulfonic acid), 캠퍼산(camphoric acid), α-브로모캠퍼산(α-bromocamphoric acid), 메톡시아세트산(methoxyacetic aicd), 주석산 (tartaric acid), 디아세틸주석산(diacetyltartaric acid), 말산(malic acid), 피롤리돈-5-카르복실산(pyrrolidone-5-carboxylic acid) 등의 각각의 에난티오머 (enantiomers)들과 같은 키랄 산 또는 염기로 염을 형성함으로써 혼합물로부터 화학적으로 분리할 수 있다. 그리고 나서, 분할된(resolved) 염기의 하나 또는 양쪽 모두를 유리시키고(free) 임의로 그 과정을 반복하여 실질적으로 다른 염들이 존재하지 않는 95% 초과의 광학적 순도를 지닌 광학 이성체 하나 또는 둘을 얻는다.
또한 본 발명은 양성자를 받을 수 있는 그룹, 예를 들어, 아미노기를 가지고 있는 일반식 I의 화합물의 생리학적으로 허용되는 비독소 산 부가염(non-toxic acid addition salts)에 관한 것이다. 이러한 염은, 제한 없이, 염산, 브롬화수소산, 인산, 술폰산, 메탄술폰산, 아세트산, 주석산, 젖산, 숙신산, 구연산, 말산(malic acid), 말레산(maleic acid), 소르브산, 아코니트산, 살리실산, 프탈산(phthalic acid), 엠본산(embonic acid), 에난트산(enanthic acid) 등과 같은 유기산 및 무기산으로부터 유도된 것들을 포함한다.
특히 바람직한 화합물은 1,3-디옥소-2-(2,6-디옥소피페리딘-3-일)-4-메틸이소인돌린, 1,3-디옥소-2-(2,6-디옥소피페리딘-3-일)-4-에틸이소인돌린, 1,3-디옥소 -2-(2,6-디옥소-3-메틸피페리딘-3-일)-4-메틸이소인돌린, 1,3-디옥소-2-(2,6-디옥소피페리딘-3-일)-4,7-디메틸이소인돌린, 1-옥소-2-(2,6-디옥소-3-메틸피페리딘-3-일)-4-에틸이소인돌린, 1-옥소-2-(2,6-디옥소-3-메틸피페리딘-3-일)-4-메틸이소인돌린, 1-옥소-2-(2,6-디옥소-3-메틸피페리딘-3-일)-7-에틸이소인돌린, 1-옥소-2-(2,6-디옥소-3-메틸피페리딘-3-일)-7-메틸이소인돌린, 1-옥소-2-(2,6-디옥소-피페리딘-3-일)-4-프로필이소인돌린, 1,3-디옥소-2-(2,6-디옥소피페리딘-3-일)-4-클로로이소인돌린, 1,3-디옥소-2-(2,6-디옥소피페리딘-3-일)-4-카르바모일이소인돌린, 1,3-디옥소-2-(2,6-디옥소피페리딘-3-일)-4-메톡시이소인돌린, 1-옥소-2-(2,6-디옥소-피페리딘-3-일)-4,7-디메틸이소인돌린, 1-옥소-2-(2,6-디옥소-피페리딘-3-일)-4-메틸-7-에틸이소인돌린 및 1-옥소-2-(2,6-디옥소-피페리딘-3-일)-4,7-디에톡시이소인돌린을 포함한다. 이들 중에서, 특히 바람직한 것은 1,3-디옥소-2-(2,6-디옥소피페리딘-3-일)-4-메틸이소인돌린, 1,3-디옥소-2-(2,6-디옥소피페리딘-3-일)-4,7-디메틸이소인돌린 및 1-옥소-2-(2,6-디옥소피페리딘-3-일)-4-메틸이소인돌린, 1-옥소-2-(2,6-디옥소피페리딘-3-일)-4,7-디메틸이소인돌린이다.
경구 투여 형태는 정제, 캡슐, 당의정 및 이와 유사한 형태로, 단위 투여량당 1 ∼ 100 mg/mL를 포함하는 압축된 제약 형태를 포함한다. 20 ∼ 100 mg/mL을 함유하는 등장 염수용액은 근육내, 경막 내(intrathecal), 정맥내, 동맥내 경로 투약을 포함한 비경구적 투여에 사용될 수 있다. 직장 투여는 코코아 버터와 같은 종래의 담체(carrier)로부터 조제된 좌약의 사용을 통하여 효능을 발휘할 수 있다.
따라서, 약학적 조성물은 적어도 한 개의 제약적 허용되는 담체, 희석제 또는 부형제와 연관된 일반식I의 화합물 한 개 또는 그 이상을 포함한다. 그러한 조성물을 제조할 때, 활성 성분들은 보통 부형제에 의해 섞이거나 또는 희석되거나, 캡슐이나 작은 향주머니(sachet)의 형태로 될 수 있는 담체(carrier)와 동봉된다. 부형제가 희석제로 작용할 때, 그것은 활성 성분의 전달수단(vehicle), 담체(carrier), 매개(medium)로 작용하는 고체, 반고체 또는 액체 물질일 수 있다. 따라서, 조성물은 정제, 알약, 분말, 엘릭서제(elixirs), 현탁액(suspensions), 유화액(emulsions), 용액(solutions), 시럽(syrups), 연하고 단단한 젤라틴 캡슐, 좌약(suppositories), 멸균된 주사 가능한(injectable) 용액과 멸균된 포장 분말(packaged powders)의 형태가 될 수 있다. 적당한 부형제의 예로는 유당(lactose), 덱스트로스, 자당(sucrose), 소르비톨, 만니톨(mannitol), 전분, 아카시아 고무(gum acacia), 칼슘 규산염(calcium silicate), 미세결정셀룰로스, 폴리비닐피롤리디논, 셀룰로스, 물, 시럽, 메틸 셀룰로스를 포함하고, 조성물은 활석, 마그네슘 스테아르산염 및 광질유(mineral oil)와 같은 윤활제, 습윤제, 유화제, 현탁제(suspension agent), 메틸기 및 프로필하이드록시 벤조산염(methyl- and propylhydroxy benzoate)과 같은 보존제, 조미료와 같은 감미제를 추가적으로 포함한다.
조성물은 바람직하게는 단위투여 형태로 조제할 수 있는데, 생리학적으로 단위 투여로 적합한 이산 단위 또는, 1회 또는 다수의 투여 섭생량으로 인체나 다른 포유 동물에게 투여되도록 예정된 단위량의 분획을 의미하는 것으로, 각 단위는 적합한 약학적 부형제와 함께 바람직한 치료 효과를 낼 수 있도록 계산된 활성물질의 양을 함유한다. 조성물은 잘 알려진 기술적 절차를 사용하여 환자에게 투여된 후 활성제의 즉각적이고, 지속적인 또는 지연된 방출을 제공하기 위해 조제될 수 있다.
TNFα에 대한 효소연결 면역흡착 검정(enzyme-linked immunosorbent assay; ELISA)은 종래의 방법으로 수행될 수 있다. PBMC는 Ficoll-Hypaque 밀도 원심 분리(Ficoll-Hypaque density centrifugation)에 의해서 정상적인 기증자로부터 단리된다. 세포들은 10%의 AB+ 혈청, 2 mM L-글루타민, 100 U/mL 페니실린 및 100 mg/mL 스트렙토마이신으로 보충된 RPMI에서 배양된다. 약은 디메틸설폭시드(Sigma Chemical)에서 용해되고 그 이상의 희석은 보충된 RPMI에서 시킨다. 약이 존재하거나 또는 존재하지 않는 PBMC 현탁액에서의 최종 디메틸설폭시드 (dimethylsulfoxide) 농도는 0.25 wt%이다. 약은 50 mg/mL에서 시작하는 반-로그(half-log) 희석에서 검정한다. 약은 LPS를 첨가하기 1 시간 전에 96개 웰 플레이트(well plate)에 있는 PBMC(106 cells/mL)에 첨가한다. 약이 존재하거나 존재하지 않는 PBMC(106 cells/mL)는 살모넬라 미네소타 R595(Salmonella minnesota R595, List Biological Labs, Campbell, CA)로부터 취한 1 mg/mL의 LSP로 치료함으로써 자극을 받는다. 그리고 나서 세포들은 18 ∼ 20 시간동안 37℃에서 배양된다. 상등액은 TNFα레벨 결과를 즉시 채취하고 검정하거나 검정될 때까지 -70℃에서(4일 이상은 넘지 않게) 동결시킨다. 상등액에서 TNFα레벨은 제조자의 지시에 따른 인간 TNFαELISA 키트 (ENDOGEN, Boston, MA)에 의해서 결정된다.
이하, 본 발명의 특성을 실시예를 들어 보다 상세히 설명하고자 하지만 본 발명의 권리범위가 상기 실시예에 의해 한정되는 것은 아니다.
실시예 1: 2-(2,6-디옥소피페리드-3-일)-4-메틸이소인돌린-1,3-디온
아세트산(30 mL)내의 3-메틸프탈 무수물(2.96 g, 18.2 mmol), 3-아미노피페리딘2,6-디온 염화수소(3.0 g, 18.2 mmol) 및 아세트산나트륨(1.57 g, 19.1 mmol)을 섞은 용액을 23시간 동안 환류(reflux)에서 가열하였다. 진공상태에서 용매를 제거하여 고형체를 생성하고 고형체를 1시간동안 물(40 mL)과 함께 휘젓고 여과한 후, 물(30 mL)로 씻어내고 나서 아세톤(2 L)내의 탈색용 숯(1 g)과 함께 역류(reflux)에서 30분간 가열하였다. Celite 패드를 통해 현탁액을 여과하여 깨끗한 용액을 만들었다. 여과액의 용매를 진공상태에서 제거하여 백색 고형체(4.08 g, 수율 82%)로서의 2-(2,6-디옥소피페리드-3-일)-4-메틸이소인돌린-1,3-디온을 산출하였다- mp, 290.0-292.0℃; 1H NMR (DMSO-d6); δ2.03-2.09(m, 1H, CHH), 2.50-2.60(m, 2H, CH
2), 2.63(s, 3H, CH
3), 2.83-2.95(m, 1H, CHH), 5.13(dd, J = 5.4,12.3 ㎐, 1H, NCH), 7.65-7.79(m, 3H, Ar), 11.13(br s, 1H, NH); 13C NMR(DMSO-d6)δ17.04, 21.99, 30.93, 48.76, 121.05, 127.89, 131.63, 134.37, 136.91, 137.61, 167.04, 167.83, 167.87, 172.74. Anal. Calcd for C14H12N2O4: C, 61.76; H, 4.44; N, 10.29. Found: C, 61.68; H, 4.3 7;N, 10.17.
실시예 2
실시예 1의 과정에서 동량의 3-에틸프탈 무수물, 3-플루오로프탈 무수물, 3-클로로프탈 무수물, 3-카르바모일프탈 무수물 및 3-메톡시프탈 무수물을 치환함으로써, 각각 1,3-디옥소-2-(2,6-디옥소피페리딘-3-일)-4-에틸이소인돌린, 1,3-디옥소-2-(2,6-디옥소피페리딘-3-일)-4-플루오로이소인돌린, 1,3-디옥소-2-(2,6-디옥소피페리딘-3-일)-4-클로로이소인돌린, 1,3-디옥소-2-(2,6-디옥소피페리딘-3-일)-4-카르바모일이소인돌린, 1,3-디옥소-2-(2,6-디옥소피페리딘-3-일)-4-메톡시이소인돌린을 얻었다.
실시예 3
실시예 1의 과정에서 3-아미노피페리딘2,6-디온 염화수소를 동량의 3-아미노-3-메틸피페리딘2,6-디온 염화수소로 치환함으로써, 1,3-디옥소-2-(2,6-디옥소-3-메틸피페리딘-3-일)-4-메틸이소인돌린을 얻었다.
실시예 4
1-옥소-2-(2,6-디옥소피페리딘-3-일)-4-메틸이소인돌린
디메틸포름아미드 100 mL내의 2,6-디옥소피페리딘-3-암모늄 클로라이드 16.25 g, 메틸 2-브로모메틸-3-메틸벤조산염 30.1 g 및 트리에틸아민 12.5 g의 혼합물을 상온에서 15시간동안 휘저었다(stirred). 그리고 나서 혼합물을 진공상태에서 농축시키고 잔여물을 메틸렌 클로라이드 및 물과 함께 섞었다. 수용액층을 분리하고 메틸렌 클로라이드로 역추출하였다. 결합한 메틸렌 클로라이드 용액을 황산 마그네슘에서 건조하고 진공상태에서 농축하여 1-옥소-2-(2,6-디옥소피페리딘-3-일)-4-메틸이소인돌린을 산출하였다.
유사한 방법으로, 메틸 2-브로모메틸-3-메틸벤조에이트를 각각 동량의 메틸 2-브로모메틸-3,6-디메틸벤조에이트, 메틸 2-브로모메틸-3-에틸벤조에이트 및 메틸 2-브로모메틸-3-메톡시벤조에이트로 치환함으로써 1-옥소-2-(2,6-디옥소피페리딘 -3-일)-4,7-디메틸이소인돌린, 1-옥소-2-(2,6-디옥소피페리딘-3-일)-4-에틸이소인돌린 및 1-옥소-2-(2,6-디옥소피페리딘-3-일)-4-메톡시이소인돌린을 얻었다.
실시예 5
2-(2,6-디옥소피페리딘-3-일)-4,7-디메틸이소인돌린-1,3-디온
아세트산(10 mL)내의 2-(2,6-디옥소피페리딘-3-일)-4,7-디메틸이소인돌린은 3,6-디메틸프탈 무수물(220 mg, 1.25 mmol), 3-아미노피페리딘-2,6-디온 하이드로겐클로라이드(204 mg, 1.24 mmol) 및 아세트산 나트륨(110 mg, 1.34 mmol)으로부터 실시예 1에 의한 방법에 의해 제조하였다. 생성물은 백색 고형체(200 mg, 56% 수율)였다; mp, 263.0-265.0℃; 1H NMR(DMSO-d6)δ2.01-2.07(m, 1H, CHH), 2.50-2.89(m, 9H, CH
3, CHH, CH
2) 5.10(dd, J = 5.1, 12.4 ㎐, 1H, NCH), 7.52(s, 2H, Ar), 11.12(br s, 1H, NH); 13C NMR(DMSO-d6)δ16.82, 22.02, 30.97, 48.59, 128.01, 135.04, 136.58, 167.68, 169.98, 172.83.
실시예 6
2-(2,6-디옥소(3-피페리딜))-4-에틸이소인돌린-1,3-디온
아세트산(10 mL)내의 2-(2,6-디옥소(3-피페리딜))-4-에틸이소인돌린-1,3-디온을 3-에틸프탈 무수물 (0.860 g, 4.89 mmol), 3-아미노피페리딘-2,6-디온 하이드로겐클로라이드(0.803 g, 4.88 mmol) 및 아세트산 나트륨(0.420 g, 5.12 mmol)으로부터 실시예 1에 의한 방법에 의해 제조하였다. 생성물은 백색 고형체(1.06 g, 76% 수율)였다; mp, 235.0-236.5℃; 1H NMR(DMSO-d6)δ1.22(t, J = 7.4 ㎐, 3H, CH
3), 2.04-2.10(m, 1H, CHH), 2.47-2.63(m, 2H, CH
2), 2.83-2.98(m, 1H, CHH), 3.07(q, J = 7.5 ㎐, 2H, CH
2), 5.13(dd, J = 5.4, 12.5 ㎐, 1H, NCH), 7.70-7.82(m, 3H, Ar), 11.13(br s, 1H, NH); 13C NMR(DMSO-d6)δ14.84, 21.95, 23.69, 30.90, 48.77, 121.09, 127.26, 131.76, 134.63, 135.39, 143.87, 166.99, 167.58, 169.85, 172.72; Anal Calcd for C15H14N2O4 : C, 62.93; H, 4.93; N, 9.79. Found: C, 62.74; H, 4.84; N, 9.54.
실시예 7
4-메톡시-2-(2,6-디옥소(3-피페리딜))이소인돌린-1,3-디온
아세트산(20 mL)내의 4-메톡시-2-(2,6-디옥소(3-피페리딜))이소인돌린-1,3-디온을 3-메톡시프탈 무수물(1.0 g, 5.6 mmol){Rao. A.V.R. et al, indianJ. Chem. 1981, 20(B), 248}, 3-아미노피페리딘-2,6-디온 하이드로겐클로라이드(0.92 g, 5.6 mmol) 및 아세트산 나트륨(0.48 g, 6.0 mmol)으로부터 실시예 1에 의한 방법에 의해 제조하였다. 생성물은 백색 고형체(0.44 g, 27% 수율)였다; mp, 281.5-282.5℃; 1H NMR(DMSO-d6)δ2.00-2.08(m, 1H, CHH), 2.56-2.62(m, 2H, CH
2), 2.82-2.91(m, 1H, CHH), 3.97(s, 3H, CH
3), 5.08(dd, J = 5.3, 12.8 ㎐, 1H, NCH), 7.46(d, J = 7.2 ㎐, 1H, Ar), 7.52(d, J = 8.5 ㎐, 1H, Ar), 7.84(dd, J = 7.8 ㎐, 1H, Ar), 11.10(br s, 1H, NH); 13C NMR(DMSO-d6)δ21.97, 30.92, 48.73, 56.33, 115.24, 116.11, 119.01, 133.19, 137.15, 156.49, 165.37, 166.84, 169.94, 172.79; Anal Calcd for C15H12N2O5 : C, 58.33; H, 4.20; N, 9.72. Found: C, 58.23; H, 3.90; N, 9.53.
실시예 8
4-디메틸아미노-2-(2,6-디옥소(3-피페리딜))이소인돌린-1,3-디온
아세트산(20 mL) 내의 4-디메틸아미노-2-(2,6-디옥소(3-피페리딜))이소인돌린-1,3-디온을 3-디메틸아미노프탈 무수물(1.34 g, 7.0 mmol), 3-아미노피페리딘-2,6-디온 하이드로겐클로라이드(1.15 g, 7.0 mmol) 및 아세트 나트륨(0.60 g, 7.3 mmol)으로부터 실시예 1에 의한 방법에 의해 제조하였다. 생성물은 황색 고형체(1.59 g, 75% 수율)였다; mp, 214.5-216.5℃; 1H NMR(DMSO-d6)δ1.98-2.09(m, 1H, CHH), 2.49-2.62(m, 2H, CH
2), 2.81-2.95(m, 1H, CHH), 3.04(s, 6H, CH
3), 5.08(dd, J = 5.5, 12.7 ㎐, 1H, NCH), 7.23(d, J = 6.6 ㎐, 1H, Ar), 7.26(d, J = 8.1 ㎐, 1H, Ar), 7.63(dd, J = 6.9, 8.6 ㎐, 1H, Ar), 11.09(br s, 1H, NH); 13C NMR(DMSO-d6)δ22.10, 30.96, 42.95, 48.77, 112.99, 113.41, 122.59, 133.90, 135.22, 149.88, 166.29, 167.13, 170.06, 172.83; Anal Calcd for C15H15N3O4 : C, 59.83; H, 5.02; N, 13.95. Found: C, 59.60; H, 4.94; N, 13.80.
실시예 9
2-(2,6-디옥소(3-피페리디릴))-4-클로로이소인돌린-1,3-디온
아세트산(10 mL)내의 2-(2,6-디옥소(3-피페리디릴))-4-클로로이소인돌린-1,3-디온을 3-클로로프탈 무수물(0.40 g, 2.2 mmol), 3-아미노피페리딘-2,6-디온 하이드로겐클로라이드(0.36 g, 2.2 mmol) 및 아세트산 나트륨(0.19 g, 2.4 mmol)으로부터 실시예 1에 의한 방법에 의해 제조하였다. 생성물은 백색 고형체(0.44 g, 69% 수율)였다; mp, 290.0-291.5℃; 1H NMR(DMSO-d6)δ2.05-2.11(m, 1H, CHH), 2.49-2.64(m, 2H, CH
2), 2.64-2.92(m, 1H, CHH), 5.17(dd, J = 5.2, 12.7 ㎐, 1H, NCH), 7.86-7.94(m, 3H, Ar), 11.17(br s, 1H, NH); 13C NMR(DMSO-d6)δ21.83, 30.91, 49.12, 122.41, 126.94, 129.84, 133.52, 136.39, 164.77, 165.76, 169.73, 172.77, 172.83; Anal Calcd for C15H9N2O4Cl: C, 53.35; H, 3.10; N, 19.57; Found: C, 53.37; H, 2.94; N, 9.30, Cl, 11.97
실시예 10
4-메틸-2-(2,6-디옥소-3-메틸-(3-피페리딜))이소인돌린-1,3-디온
아세트산(10 mL) 내의 4-메틸-2-(2,6-디옥소-3-메틸-(3-피페리딜))이소인돌린-1,3-디온을 3-메틸프탈 무수물(0.27 g, 1.7 mmol), 3-아미노-3-메틸피페리딘-2,6-디온 하이드로겐클로라이드(0.30 g, 1.7 mmol) 및 아세트 나트륨(0.15 g, 1.8 mmol)으로부터 실시예 1에 의한 방법에 의해 제조하였다. 생성물은 백색 고형체(0.13 g, 27% 수율)였다; mp, 248.0-250.0℃; 1H NMR(DMSO-d6)δ1.89(s, 3H, CH
3), 2.01-2.08(m, 1H, CHH), 2.49-2.70(m, 3H, CHH, CH
2), 2.55(s, 6H, CH
3), 7.62-7.74(m, 3H, Ar), 10.99(br s, 1H, NH); 13C NMR(DMSO-d6)δ17.0, 21.0, 28.6, 29.1, 58.6, 120.7, 127.5, 131.5, 134.2, 136.8, 137.2, 167.7, 168.6, 172.1, 172.3; Anal. Calcd. for C15H14N2O4 + 0.3 H2O : C, 61.77; H, 5.05; N, 9.60 Found: C, 62.05; H, 4.94; N, 9.20.
실시예 11
각각 50 mg의 1-옥소-2-(2,6-디옥소피페리딘-3-일)-4-메틸-이소인돌린을 함유하는 정제들은 다음의 방법으로 제조될 수 있다:
조성(1000개의 정제에 대해)
1-옥소-2-(2,6-디옥소피페리딘-3-일)-
4-메틸-이소인돌린............................ 50.0g
락토오스(lactose)............................ 50.7g
밀 전분(wheat starch).........................7.5g
폴리에틸렌 글리콜 6000........................5.0g
활석(talc)....................................5.0g
마그네슘 스테아르산염(magnesium stearate).....1.8g
탈염수(demineralized water)...................q.s.
고형체 재료들은 먼저 0.6 mm의 메쉬 폭을 갖는 체에 통과시켰다. 그 다음, 활성성분(active ingredient), 락토오스, 활석, 마그네슘 스테아르산염, 그리고 절반의 전분을 혼합하였다. 나머지 절반의 전분은 40 mL의 물에 현탁시켰다. 이 현탁액을 물 100 mL에서 끓고 있는 폴리에틸렌 글리콜 용액에 첨가하였다. 그 결과로서 만들어진 페이스트를 분말성분에 첨가하고 필요할 경우 물을 첨가하여 그 혼합물을 그래뉼 형상으로 만들었다. 이 그래뉼을 35℃에서 하룻밤 동안 건조시키고, 1.2 mm 메쉬 폭을 갖는 체에 통과시킨 다음 압축하여, 양쪽이 오목한 형상을 지닌 약 6 mm 직경의 정제를 만들었다.
실시예 12
각각 100 mg의 1,3-디옥소-2-(2,6-디옥소피페리딘-3-일)-4-메틸이소인돌린을 포함하는 젤라틴 건조-충전한(gelatin dry-filled) 정제들은 다음의 방법으로 준비할 수 있었다:
조성(1000개의 정제에 대해)
1,3-디옥소-2-(2,6-디옥소피페리딘-
3-일)-4-메틸이소인돌린.........................100.0g
미세결정셀룰로스..............................30.0g
황산 라우릴 나트륨.............................2.0g
마그네슘 스테아르산염(magnesium stearate)......8.0g
황산 라우릴 나트륨을 0.2 mm의 체눈 너비를 지닌 체를 통과시켜 1,3-디옥소-2-(2,6-디옥소피페리딘-3-일)-4-메틸이소인돌린으로 걸러낸 후, 두 구성요소를 10분간 친밀하게 혼합시켰다. 그리고 나서 미세결정 셀룰로스(microcrystalline cellulose)를 0.9 mm 체눈 너비를 지닌 체에 통과시켜 첨가한 후 그 전체를 다시 10분간 친밀하게 혼합시켰다. 마지막으로, 마그네슘 스테아르산염을 0.8 mm 체눈 너비를 지닌 체에 통과시켜 첨가하고, 3분간 더 혼합시킨 후, 혼합물을 각각 140 mg의 부분을 크기 0(연장된)의 젤라틴 건조-충전한 정제에 넣었다.
실시예 13
0.2 %의 주사액 또는 주입 용액은 예를 들면, 다음의 방법으로 준비할 수 있었다:
1,3-디옥소-2-(2,6-디옥소피페리딘-
3-일)-4,7-디메틸이소인돌린.......... 5.0g
염화나트륨(sodium chloride).........22.5g
인산염 완충제 pH 7.4................300.0g
탈염수(demineralized water).........2500.0 mL까지
1,3-디옥소-2-(2,6-디옥소피페린딘-3-일)-4,7-디메틸이소인돌린을 1000 mL의 물에 용해시키고 미세여과기(microfilter)로 여과하였다. 완충액(buffer solution)을 첨가하고 전체를 물로 2500 mL가 되게 만들었다. 투여량 단위형(dosage unit form)을 제조하기 위해, 각각 1.0 또는 2.5 mL씩 나눈 것을 유리앰플(glass ampoules)에 각각 채워 넣었다(각각 2.0 또는 5.0 mg의 이미드를 함유한다).
본 발명의 화합물인 2-(2,6-디옥소피페리딘-3-일)이소인돌린 유도체는 TNFα 및 다른 염증성 사이토카인의 레벨을 감소시키는 뛰어난 효과가 있으므로 관절염, 류머티즘성 관절염, 염증성 장 질병, 크론병, 아프토스 궤양, 악액질, 이식 대 숙주 질병, 천식, 성인 호흡 장애 증후군, 후천성 면역 결핍증, 암 등의 포유동물의 질병의 치료 및 예방에 사용될 수 있다. 따라서, 본 발명은 인간을 포함한 모든 포유동물의 질병 치료 및 예방에 매우 유용한 발명인 것이다.
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KR1020067006763A KR20060036124A (ko) | 1998-03-16 | 1999-03-16 | 염증성 사이토카인 억제제용2-(2,6-디옥소피페리딘-3-일)이소인돌린 유도체, 그제조방법 및 그 용도 |
KR1020077007093A KR20070040423A (ko) | 1998-03-16 | 1999-03-16 | 염증성 사이토카인 억제제용2-(2,6-디옥소피페리딘-3-일)이소인돌린 유도체, 그제조방법 및 그 용도 |
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US (5) | US20010006973A1 (ko) |
EP (2) | EP1064277B1 (ko) |
JP (2) | JP4695259B2 (ko) |
KR (3) | KR20060036124A (ko) |
CN (1) | CN100390163C (ko) |
AT (1) | ATE297911T1 (ko) |
AU (1) | AU745884B2 (ko) |
BR (1) | BR9908811A (ko) |
CA (1) | CA2321920C (ko) |
CZ (1) | CZ299253B6 (ko) |
DE (1) | DE69925819T2 (ko) |
DK (1) | DK1064277T3 (ko) |
ES (1) | ES2243052T3 (ko) |
FI (1) | FI121272B (ko) |
HK (1) | HK1035180A1 (ko) |
HU (1) | HUP0102113A3 (ko) |
NO (1) | NO20004175L (ko) |
NZ (1) | NZ506432A (ko) |
PT (1) | PT1064277E (ko) |
RU (1) | RU2200159C2 (ko) |
SK (1) | SK13642000A3 (ko) |
TR (7) | TR200101505T2 (ko) |
WO (1) | WO1999047512A1 (ko) |
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