KR20100085986A - 결정질 화학요법제 - Google Patents
결정질 화학요법제 Download PDFInfo
- Publication number
- KR20100085986A KR20100085986A KR1020107010989A KR20107010989A KR20100085986A KR 20100085986 A KR20100085986 A KR 20100085986A KR 1020107010989 A KR1020107010989 A KR 1020107010989A KR 20107010989 A KR20107010989 A KR 20107010989A KR 20100085986 A KR20100085986 A KR 20100085986A
- Authority
- KR
- South Korea
- Prior art keywords
- fluoro
- amino
- methylphenyl
- phenyl
- crystalline form
- Prior art date
Links
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Abstract
N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1, 이의 제조방법, 이를 포함하는 제형 및 이것으로 제조된 제형, 그리고 이것을 사용하여 질환을 가진 환자들을 치료하는 방법이 개시된다.
Description
본 발명은 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1, 이의 제조방법, 이를 포함하는 제형 및 이것으로 제조된 제형, 및 이를 사용하여 질환을 가진 환자들을 치료하는 방법에 관한 것이다.
N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아 (ABT-869)는 세포 단백질 내의 특정 티로신 잔기의 인산화를 촉매하는 단백질 티로신 키나아제 (PTK)의 패밀리에 속한다. 면역 시스템의 부적절한 활성화에 기인하는 양성 및 악성 증식성 장애 및 질환을 포함한 많은 질환 상태에서 이상 또는 과도한 PTK 활성이 관찰되어 왔다.
ABT-869의 용매화물의 결정성(crystallinity)은, 다른 물리적 및 기계적 특성들 중에서도, 이의 안정성, 용해성, 용출 속도(dissolution rate), 경도, 압축성 및 융점에 영향을 줄 수 있다. ABT-869의 제조 및 제형의 용이성이 이들 특성의 전부는 아니지만 일부에 좌우되기 때문에, ABT-869의 결정질 형태의 확인 및 이러한 형태를 재현가능하게 제조하는 방법에 대한 필요성이 화학적 및 치료학적 기술 분야에 존재하고 있다.
발명의 요지
따라서, 본 발명의 한 양태는 0.7107Å의 방사선을 사용하여 삼사정계 결정계 및 P1 공간군에서 약 -100℃에서 측정될 때, 각각의 격자 파라미터 값 a, b 및 c가 8.971Å ± 0.006Å, 11.646Å ± 0.008Å 및 19.26Å ± 0.01Å이고, 각각의 α, β 및 γ 값이 약 87.67°± 0.1°, 90.21°± 0.1° 및 76.82°± 0.1°임을 특징으로 하는, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1에 관한 것이다.
또 다른 양태는 1.54178Å의 방사선을 사용하여 약 25℃에서 측정될 때, 분말 회절 패턴의 각각의 2θ 값이 약 4.5°, 7.7°, 11.7°, 12.2°, 14.6°, 16.9°, 17.7° 및 18.4°임을 특징으로 하는, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1에 관한 것이다.
또 다른 양태는 부형제 및, 0.7107Å의 방사선을 사용하여 삼사정계 결정계 및 P1 공간군에서 약 -100℃에서 측정될 때, 각각의 격자 파라미터 값 a, b 및 c가 8.971Å ± 0.006Å, 11.646Å ± 0.008Å 및 19.26Å ± 0.01Å이고, 각각의 α, β 및 γ 값이 약 87.67°± 0.1°, 90.21°± 0.1° 및 76.82°± 0.1°이거나, 1.54178Å의 방사선을 사용하여 약 25℃에서 측정될 때, 분말 회절 패턴의 각각의 2θ 값이 약 4.5°, 7.7°, 11.7°, 12.2°, 14.6°, 16.9°, 17.7° 및 18.4°임을 특징으로 하는, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1을 포함하는 제형에 관한 것이다.
또 다른 양태는 0.7107Å의 방사선을 사용하여 삼사정계 결정계 및 P1 공간군에서 약 -100℃에서 측정될 때, 각각의 격자 파라미터 값 a, b 및 c가 8.971Å ± 0.006Å, 11.646Å ± 0.008Å 및 19.26Å ± 0.01Å이고, 각각의 α, β 및 γ 값이 약 87.67°± 0.1°, 90.21°± 0.1° 및 76.82°± 0.1°이거나, 1.54178Å의 방사선을 사용하여 약 25℃에서 측정될 때, 분말 회절 패턴의 각각의 2θ 값이 약 4.5°, 7.7°, 11.7°, 12.2°, 14.6°, 16.9°, 17.7° 및 18.4°임을 특징으로 하는, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1의 치료학적 유효량을, 하나 이상의 추가의 항암 약물을 사용하거나 사용하지 않고, 포유류에 투여하는 것을 포함하는, 포유류에서의 암 치료 방법에 관한 것이다.
또 다른 양태는
N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아를 제조하는 단계;
N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아 및 에탄올을 포함한 용매를 포함하는 혼합물(여기서, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아는 상기 용매에 완전히 용해된다)을 제공하는 단계;
N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1이 상기 혼합물에 존재(상기 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1은, 분리되어 0.7107Å의 방사선을 사용하여 삼사정계 결정계 및 P1 공간군에서 약 -100℃에서 측정될 때, 각각의 격자 파라미터 값 a, b 및 c는 8.971Å ± 0.006Å, 11.646Å ± 0.008Å 및 19.26Å ± 0.01Å이고, 각각의 α, β 및 γ 값은 약 87.67°± 0.1°, 90.21°± 0.1° 및 76.82°± 0.1°임을 특징으로 한다)하게 하는 단계; 및
N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1을 분리하는 단계를 포함하는, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1의 제조방법에 관한 것이다.
또 다른 양태는 전술된 양태의 방법에 의해 제조되는 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1을 포함한다.
또 다른 양태는
N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아를 제조하는 단계;
N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아 및 에틸 아세테이트와 에탄올을 포함한 용매를 포함하는 혼합물(여기서, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아는 상기 용매에 완전히 용해된다)을 제공하는 단계;
N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1이 에탄올의 존재 또는 부재하에 상기 혼합물을 농축시킴으로써 상기 혼합물에 존재(상기 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1은, 분리되어 0.7107Å의 방사선을 사용하여 삼사정계 결정계 및 P1 공간군에서 약 -100℃에서 측정될 때, 각각의 격자 파라미터 값 a, b 및 c는 8.971Å ± 0.006Å, 11.646Å ± 0.008Å 및 19.26Å ± 0.01Å이고, 각각의 α, β 및 γ 값은 약 87.67°± 0.1°, 90.21°± 0.1° 및 76.82°± 0.1°임을 특징으로 한다)하게 하는 단계; 및
N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1을 분리하는 단계를 포함하는, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1의 제조방법에 관한 것이다.
또 다른 양태는 전술된 양태의 방법에 의해 제조되는 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1을 포함한다.
N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아의 산 또는 이산(diacid) 염을 염기와 반응시키는 단계 및 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1을 결정화 또는 재결정화하는 단계를 포함하는, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1의 제조방법에서, 본 발명의 또 다른 양태는 탈보호 반응으로부터의 하나 이상의 용매와 혼합된 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아의 고형, 반고형, 왁스 또는 오일 형태로부터 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1을 결정화 또는 재결정화하는 단계를 포함한다.
또 다른 양태는 전술된 양태의 방법에 의해 제조되는 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1을 포함한다.
N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아의 하이드로클로라이드 염 또는 디하이드로클로라이드 염을 이염기성 인산나트륨과 반응시키는 단계 및 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1을 결정화 또는 재결정화하는 단계를 포함하는, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1의 제조방법에서, 본 발명의 또 다른 양태는 탈보호 반응으로부터의 에틸 아세테이트와 혼합된 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아의 고형, 반고형, 왁스 또는 오일 형태로부터 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1을 결정화 또는 재결정화하는 단계를 포함한다.
또 다른 양태는 전술된 양태의 방법에 의해 제조되는 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1을 포함한다.
또 다른 양태는 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1의 제조시에 사용하기 위한 ABT-869를 포함한다.
또 다른 양태는 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1의 제조시에 사용하기 위한 ABT-869의 염을 포함한다.
또 다른 양태는 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1의 제조시에 사용하기 위한 ABT-869의 하이드로클로라이드 염을 포함한다.
또 다른 양태는 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1의 제조시에 사용하기 위한 ABT-869·H2O 결정질 형태 1을 포함한다.
도 1은 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1의 분말 x-선 회절 패턴이다.
본 발명은 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1, 이의 제조방법, 이의 특성화 방법, 이를 함유하는 제형 및 이것으로 제조된 제형, 및 이를 이용한 암 치료 방법의 발견에 관한 것이다. 용어 "N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아"와 "ABT-869"는 상호교환적으로 사용되는 것으로 의미된다.
본 명세서에 사용되는, 용어 "ABT-869" 및 관련된 결정성 또는 비-결정성에 대하여 어떠한 표시도 없는 "ABT-869"는 무정형 ABT-869, 결정질 ABT-869, 미세결정질 ABT-869, 용액 중의 ABT-869, ABT-869의 반고형, 왁스 또는 오일 형태, 이들의 혼합물 등을 의미한다.
본 명세서에 사용되는, 용어 "결정질" 및 "미세결정질"은 장범위(long range) 또는 외부 표면 평면들(external face planes)에 걸쳐 유지되는 분자들의 규칙적 반복 배열을 가짐을 의미한다.
달리 기술되지 않는 한, 본 명세서에서 백분율은 중량/중량(w/w) 백분율이다.
본 명세서에 사용되는, 용어 "하이드로클로라이드 염"은 이에 대해 하나 이상의 하이드로클로라이드 등가물이 회합되어 있음을 의미한다.
본 명세서에 사용되는, 용어 "용매"는, 화합물을 소정의 농도로 용해시키거나 부분 용해시키기에 충분하도록 당해 화합물을 용해 또는 부분 용해시키는 액체를 의미한다.
본 명세서에 사용되는, 용어 "반-용매(anti-solvent)"는, 화합물을 소정의 농도에서 용액으로부터 침전시키는데 효과적이기에 충분하도록 당해 화합물이 불용성인 액체를 의미한다.
용매 및 반-용매는 상 분리되거나 상 분리되지 않은 상태로 혼합될 수 있다.
많은 용매 및 반-용매는 불순물을 함유하기 때문에, 만약 불순물이 존재한다면, 본 발명의 실시를 위한 용매 및 반-용매 중의 불순물의 수준은, 불순물이 존재하는 용매의 의도된 사용을 방해하지 않을 정도로 충분히 낮은 농도인 것으로 이해되는 것으로 의미된다.
본 명세서에 사용되는, 용어 "산"은 하나 이상의 산성 양성자를 갖는 화합물을 의미한다. 본 발명의 실시를 위한 산의 예는 제한 없이, 염산, 브롬화수소산, 트리플루오로아세트산, 트리클로로아세트산, 황산, 인산 등을 포함한다.
본 명세서에 사용되는, 용어 "염기"는 양성자를 수용할 수 있는 화합물을 의미한다. 본 발명의 실시를 위한 염기의 예는 제한 없이, 탄산나트륨, 중탄산나트륨, 탄산칼륨, 중탄산칼륨, 이염기성 인산나트륨 (즉, Na2HPO4, K2HPO4 등), 트리에틸아민, 디이소프로필에틸아민 등을 포함한다.
ABT-869·¼ 에탄올레이트 결정질 형태 1이, ABT-869 및 용매를 포함하는 혼합물(여기에 ABT-869는 완전히 용해되어 있다)에 존재되게 하는 것은 핵형성(nucleation)으로 알려져 있다.
본 발명의 실시에 있어서, 핵형성은 용매 제거, 온도 변화, 용매-혼화성 반-용매 첨가, 용매-불혼화성 반-용매 첨가에 의해 발생하거나, 용기, 바람직하게는 유리 용기 내부의 마찰(chafing) 또는 스크래칭(scratching)과 같은 수단에 의해 일어나게 할 수 있으며, 이때의 핵형성은 유리 막대 또는 유리 비드 또는 유리 비드들, 또는 이들의 조합과 같은 기구를 사용하여 발생하는 것으로 의미된다.
본 발명의 실시에 있어서, 핵형성 후에 결정 성장이 뒤따르거나, 핵 형성시에 결정 성장이 수반되거나, 또는 핵형성 동안 결정 성장이 뒤따르거나 수반될 수 있으며, 이 결과, ABT-869·¼ 에탄올레이트 결정질 형태 1의 백분율이 증가된다.
본 명세서에 사용되는, 용어 "분리하는"은 용매, 반-용매 또는 용매, 반-용매의 혼합물로부터 ABT-869·¼ 에탄올레이트 결정질 형태 1을 분리하는 것을 의미한다. 이는 통상적으로 원심분리, 진공을 사용하거나 사용하지 않은 여과, 양압을 사용한 여과, 증류, 증발 또는 이들의 조합과 같은 수단에 의해 수행된다.
ABT-869·¼ 에탄올레이트 결정질 형태 1의 치료학적 허용량은 치료 대상, 치료될 장애 및 이의 중증도, 이를 함유하는 조성물, 투여 시간, 투여 경로, 치료 지속시간, 이의 효능, 이의 청소율(rate of clearance) 및 또 다른 약물이 동시-투여되지는 지의 여부에 좌우된다. 단회 용량 또는 분할 용량으로 환자에게 매일 투여될 제형을 제조하는 데 사용되는 ABT-869·¼ 에탄올레이트 결정질 형태 1의 양은 약 0.03 내지 약 200mg/kg 체중이다. 단회 용량 제형은 상기 양 또는 상기 양의 서브멀티플들(submultiples)의 조합을 포함한다.
ABT-869·¼ 에탄올레이트 결정질 형태 1은 부형제와 함께 또는 부형제 없이 투여될 수 있으며, 통상적으로는 부형제와 함께 투여된다. 부형제는 제한 없이, 예를 들어 캡슐화 재료 및 첨가제, 예를 들면 흡수 촉진제, 산화방지제, 결합제, 완충제, 캐리어, 코팅제, 착색제, 희석제, 붕해제, 유화제, 증량제, 충전제, 착향제, 활택제, 보습제, 윤활제, 방향제, 방부제, 추진제, 이형제, 안정제, 감미제, 가용화제, 습윤제, 이들의 혼합물 등이다.
고체 투여형으로 경구 투여될 ABT-869·¼ 에탄올레이트 결정질 형태 1을 포함하거나 이로 제조된 제형의 제조를 위한 부형제는, 예를 들어 한천, 알긴산, 수산화알루미늄, 벤질 알코올, 벤질 벤조에이트, 1,3-부틸렌 글리콜, 카보머(carbomer), 피마자유, 셀룰로스, 셀룰로스 아세테이트, 코코아 버터, 옥수수 전분, 옥수수 오일, 면실유, 크로스-포비돈, 디글리세라이드, 에탄올, 에틸 셀룰로스, 에틸 라우레이트, 에틸 올레에이트, 지방산 에스테르, 젤라틴, 배아유, 글루코스, 글리세롤, 땅콩유, 하이드록시프로필메틸 셀룰로스, 이소프로판올, 등장 식염수, 락토스, 수산화마그네슘, 스테아르산마그네슘, 맥아, 만니톨, 모노글리세라이드, 올리브유, 피넛유, 인산칼륨염, 감자 전분, 포비돈, 프로필렌 글리콜, 링거액, 홍화유, 호마유, 나트륨 카복시메틸 셀룰로스, 인산나트륨염, 나트륨 라우릴 설페이트, 나트륨 소르비톨, 대두유, 스테아르산, 스테아릴 푸마레이트, 수크로스, 계면활성제, 활석, 트래거캔스, 테트라하이드로푸르푸릴 알코올, 트리글리세라이드, 물, 이들의 혼합물 등을 포함한다.
액체 투여형으로 안내(ophthalmically) 또는 경구 투여될 ABT-869·¼ 에탄올레이트 결정질 형태 1을 포함하거나 이로 제조된 제형의 제조를 위한 부형제는, 예를 들어 1,3-부틸렌 글리콜, 피마자유, 옥수수유, 면실유, 에탄올, 소르비탄의 지방산 에스테르, 배아유, 땅콩유, 글리세롤, 이소프로판올, 올리브유, 폴리에틸렌 글리콜, 프로필렌 글리콜, 호마유, 물, 이들의 혼합물 등을 포함한다.
삼투압적으로 투여될 ABT-869·¼ 에탄올레이트 결정질 형태 1을 포함하거나 이로 제조된 제형의 제조를 위한 부형제는, 예를 들어 클로로플루오로하이드로카본, 에탄올, 물, 이들의 혼합물 등을 포함한다.
비경구 투여될 ABT-869·¼ 에탄올레이트 결정질 형태 1을 포함하거나 이로 제조된 제형의 제조를 위한 부형제는, 예를 들어 1,3-부탄디올, 피마자유, 옥수수유, 면실유, 덱스트로스, 배아유, 땅콩유, 리포솜, 올레산, 올리브유, 피넛유, 링거액, 홍화유, 호마유, 대두유, U.S.P. 또는 등장성 염화나트륨 용액, 물, 이들의 혼합물 등을 포함한다.
직장내 또는 질내 투여될 ABT-869·¼ 에탄올레이트 결정질 형태 1을 포함하거나 이로 제조된 제형의 제조를 위한 부형제는 제한 없이, 코코아 버터, 폴리에틸렌 글리콜, 왁스, 이들의 혼합물 등을 포함한다.
ABT-869·¼ 에탄올레이트 결정질 형태 1로 제조된 제형의 구체적인 실시예에서는, 캐리어 중합체 (코포비돈 타입 K 28), 활택제 (콜로이드성 이산화규소) 및 ABT-869·¼ 에탄올레이트 결정질 형태 1을 텀블 블렌더에서 사전-블렌딩하였다. 수득한 사전-블렌드를 체질하여 응괴를 부수었다. 체질한 사전-블렌드를 (프로필렌 글리콜 타입 1 및 비타민 E TPGS와) 최종 블렌딩 단계로 블렌딩하고, 압출기에 공급하였다. 압출 동안, 분말 블렌드를 용융하였으며, 계면활성제(만니톨, 나트륨 스테아릴 푸마레이트 및 콜로이드성 이산화규소)를 액체 주입 시스템에 의해 압출기 내로 펌핑하였다. 혼합물을 이축 압출기를 따라 추가로 운반하여 ABT-869를 중합체 계면활성제 매트릭스에 균일하게 분산시켰다. 압출기 배럴(barrel) 및 압출기 속력을 제어하였다. 압출기의 단부 부근에는 용융물의 탈기를 위하여 진공을 인가하였다. 캘린더링에 의해 냉각 및 고화시킨 후, 압출물 과립을 수득하였다.
ABT-869·¼ 에탄올레이트 결정질 형태 1은 또한 항암 약물, 예를 들면 알킬화제, 혈관신생 억제제, 항체, 항대사물질, 항유사분열제, 항증식제, 오로라(aurora) 키나제 억제제, Bcr-Abl 키나제 억제제, 생물학적 반응 조절제, 사이클린-의존성 키나제 억제제, 세포 사이클 억제제, 사이클로옥시게나제-2 억제제, 백혈병 바이러스의 발암유전자 동족체 (ErbB2) 수용체 억제제, 성장 인자 억제제, 열 충격 단백질 (HSP)-90 억제제, 히스톤 데아세틸라제 (HDAC) 억제제, 호르몬 요법제, 면역학적 약물, 삽입 항생제, 기타 키나제 억제제 - 기타 PTK, 포유류 표적 라파마이신 억제제, 미토겐-활성화된 세포외 신호-조절된 키나제 억제제, 비-스테로이드성 소염제 (NSAID), 백금 화학요법제, 폴로형(polo-like) 키나제 억제제, 프로테아솜 억제제, 푸린 유사체, 피리미딘 유사체, 수용체 티로신 키나제 억제제, 레티노이드/델토이드 식물 알칼로이드, 토포이소머라제 억제제를 포함함 - 등과 함께 투여될 때 유용하다.
알킬화제는 알트레타민, AMD-473, AP-5280, 아파지퀀, 벤다무스틴, 브로스탈리신, 부설판, 카르보퀀, 카르무스틴 (BCNU), 클로람부실, Cloretazine™ (VNP 40101M), 사이클로포스파미드, 데카르바진, 에스트라무스틴, 포테무스틴, 글루포스파미드, 이포스파미드, KW-2170, 로무스틴 (CCNU), 마포스파미드, 멜팔란, 미토브로니톨, 미토락톨, 니무스틴, 질소 머스타드 N-산화물, 라니무스틴, 테모졸로미드, 티오테파, 트레오설판, 트로포스파미드 등을 포함한다.
혈관신생 억제제는 내피-특이적 수용체 티로신 키나제 (Tie-2) 억제제, 표피 성장 인자 수용체 (EGFR) 억제제, 인슐린 성장 인자-2 수용체 (IGFR-2) 억제제, 매트릭스 메탈로프로테이나제-2 (MMP-2) 억제제, 매트릭스 메탈로프로테이나제-9 (MMP-9) 억제제, 혈소판-유래 성장 인자 수용체 (PDGFR) 억제제, 트롬보스폰딘 유사체 혈관 내피 성장 인자 수용체 티로신 키나제 (VEGFR) 억제제 등을 포함한다.
오로라 키나제 억제제는 AZD-1152, MLN-8054, VX-680 등을 포함한다.
Bcr-Abl 키나제 억제제는 DASATINIB® (BMS-354825), GLEEVEC® (이마티니브) 등을 포함한다.
CDK 억제제는 AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, 플라보피리돌, GPC-286199, MCS-5A, PD0332991, PHA-690509, 셀리시클리브 (CYC-202, R-로스코비틴), ZK-304709 등을 포함한다.
COX-2 억제제는 ABT-963, ARCOXIA® (에토리콕시브), BEXTRA® (발데콕시브), BMS347070, CELEBREX™ (셀레콕시브), COX-189 (루미라콕시브), CT-3, DERAMAXX® (데라콕시브), JTE-522, 4-메틸-2-(3,4-디메틸페닐)-1-(4-설파모일페닐-1H-피롤), MK-663 (에토리콕시브), NS-398, 파레콕시브, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXX® (로페콕시브) 등을 포함한다.
EGFR 억제제는 ABX-EGF, 안티-EGFR 면역리포솜, EGF-백신, EMD-7200, ERBITUX® (세툭시마브), HR3, IgA 항체, IRESSA® (제피티니브), TARCEVA® (에를로티니브 또는 OSI-774), TP-38, EGFR 융합 단백질, TYKERB® (라파티니브) 등을 포함한다.
ErbB2 수용체 억제제는 CP-724-714, CI-1033 (카네르티니브), HERCEPTIN® (트라스투주마브), TYKERB® (라파티니브), OMNITARG® (2C4, 페투주마브), TAK-165, GW-572016 (이오나파르니브), GW-282974, EKB-569, PI-166, dHER2 (HER2 백신), APC-8024 (HER-2 백신), 안티-HER/2neu 이중특이성 항체, B7.her2IgG3, AS HER2 3작용성 이중특이성 항체, mAB AR-209, mAB 2B-1 등을 포함한다.
히스톤 데아세틸라제 억제제는 뎁시펩티드, LAQ-824, MS-275, 트라폭신, 서베로일아닐리드 하이드록삼산 (SAHA), TSA, 발프로산 등을 포함한다.
HSP-90 억제제는 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, 겔다나마이신, IPI-504, KOS-953, MYCOGRAB®, NCS-683664, PU24FCl, PU-3, 라디시콜, SNX-2112, STA-9090 VER49009 등을 포함한다.
MEK 억제제는 ARRY-142886, ARRY-438162, PD-325901, PD-98059 등을 포함한다.
mTOR 억제제는 AP-23573, CCI-779, 에베롤리무스, RAD-OO1, 라파마이신, 템시롤리무스 등을 포함한다.
비-스테로이드성 소염제는 AMIGESIC® (살살레이트), DOLOBID® (디플루니살), MOTRIN® (이부프로펜), ORUDIS® (케토프로펜), RELAFEN® (나부메톤), FELDENE® (피록시캄) 이부프로펜 크림, ALEVE® 및 NAPROSYN® (나프록센), VOLTAREN® (디클로페낙), INDOCIN® (인도메타신), CLINORIL® (설린닥), TOLECTIN® (톨메틴), LODINE® (에토돌락), TORADOL® (케토롤락), DAYPRO® (옥사프로진) 등을 포함한다.
PDGFR 억제제는 C-451, CP-673, CP-868596 등을 포함한다.
백금 화학요법제는 시스플라틴, ELOXATIN® (옥살리플라틴) 에프타플라틴, 로바플라틴, 네다플라틴, PARAPLATIN® (카르보플라틴), 사트라플라틴 등을 포함한다.
폴로형 키나제 억제제는 BI-2536 등을 포함한다.
트롬보스폰딘 유사체는 ABT-510, ABT-567, ABT-898, TSP-1 등을 포함한다.
VEGFR 억제제는 AVASTIN® (베바시주마브), ABT-869, AEE-788, ANGIOZYME™, 악시티니브 (AG-13736), AZD-2171, CP-547,632, IM-862, Macugen (페가프타미브), NEXAVAR® (소라페니브, BAY43-9006), 파조파니브 (GW-786034), (PTK-787, ZK-222584), SUTENT® (서니티니브, SU-11248), VEGF 트랩, 바탈라니브, ZACTIMA™ (바데타니브, ZD-6474) 등을 포함한다.
항대사물질은 ALIMTA® (페메트렉세드 디나트륨, LY231514, MTA), 5-아자시티딘, XELODA® (카페시타빈), 카르모푸르, LEUSTAT® (클라드리빈), 클로파라빈, 시타라빈, 시타라빈 옥포스페이트, 시토신 아라비노시드, 데시타빈, 데페록사민, 독시플루리딘, 에플로르니틴, EICAR, 에노시타빈, 에트닐시티딘, 플루다라빈, 하이드록시우레아, 5-플루오로우라실 (5-FU) 단독 또는 류코보린과의 배합물, GEMZAR® (겜시타빈), 하이드록시우레아, ALKERAN® (멜팔란), 머캅토푸린, 6-머캅토푸린 리보사이드, 메토트렉세이트, 마이코페놀산, 넬라라빈, 놀라트렉세드, 옥포스페이트, 펠리트렉솔, 펜토스타틴, 랄티트렉세드, 리바비린, 트리아핀, 트리메트렉세이트, S-1, 티아조푸린, 테가푸르, TS-1, 비다라빈, UFT 등을 포함한다.
항생제는 삽입 항생제 아클라루비신, 악티노마이신 D, 암루비신, 안나마이신, 아드리아마이신, BLENOXANE® (블레오마이신), 다우노루비신, CAELYX® 또는 MYOCET® (독소루비신), 엘사미트루신, 에피르부신, 글라르부신, ZAVEDOS® (이다루비신), 미토마이신 C, 네모루비신, 네오카르지노스타틴, 페플로마이신, 피라루비신, 레벡카마이신, 스티말라메르, 스트렙토조신, VALSTAR® (발루비신), 지노스타틴 등을 포함한다.
토포이소머라제 억제제는 아클라루비신, 9-아미노캄프토테신, 아모나피드, 암사크린, 베카테카린, 벨로테칸, BN-80915, CAMPTOSAR® (이리노테칸 하이드로클로라이드), 캄프토테신, CARDIOXANE® (덱스라족신), 디플로모테칸, 에도테카린, ELLENCE® 또는 PHARMORUBICIN® (에피루비신), 에토포시드, 엑사테칸, 10-하이드로시캄토테신, 지마테칸, 루르토테칸, 미톡산트론, 오라테신, 피라루비신, 픽산트론, 루비테칸, 소부족산, SN-38, 타플루포시드, 토포테칸 등을 포함한다.
항체는 AVASTIN® (베바시주마브), CD40-특이적 항체, chTNT-1/B, 데노수마브, ERBITUX® (세툭시마브), HUMAX-CD4® (자놀리무마브), IGF1R-특이적 항체, 린투주마브, PANOREX® (에드레콜로마브), RENCAREX® (WX G250), RITUXAN® (리툭시마브), 티실리무마브, 트라스투지마브 등을 포함한다.
호르몬 요법제는 ARIMIDEX® (아나스트로졸), AROMASIN® (엑세메스탄), 아르족시펜, CASODEX® (비칼루타미드), CETROTIDE® (세트로렐릭스), 데가렐릭스, 데슬로렐린, DESOPAN® (트릴로스탄), 덱사메타손, DROGENIL® (플루타미드), EVISTA® (랄록시펜), 파드로졸, FARESTON® (토레미펜), FASLODEX® (풀베스트란트), FEMARA® (레트로졸), 포르메스탄, 글루코코르티코이드, HECTOROL® 또는 RENAGEL® (독세르칼시페롤), 라소폭시펜, 류프롤리드 아세테이트, MEGACE® (메게스테롤), MIFEPREX® (미페프리스톤), NILANDR0N™ (닐루타미드), NOLVADEX® (타목시펜 시트레이트), PLENAXIS™ (아바렐릭스), 프레드니손, PROPECIA® (피나스테리드), 릴로스탄, SUPREFACT® (부세렐린), TRELSTAR® (황체형성 호르몬 방출 호르몬(LHRH)), VANTAS (히스트렐린 이식제), VETORYL® (트릴로스탄 또는 모드라스탄), ZOLADEX® (포스렐린, 고세렐린) 등을 포함한다.
델토이드 및 레티노이드는 세오칼시톨 (EB1089, CB1093), 렉사칼시트롤 (KH1060), 펜레티니드, PANRETIN® (알리레티노인), ATRAGEN® (리포솜 트레티노인), TARGRETIN® (벡사로텐), LGD-1550 등을 포함한다.
식물 알칼로이드는 제한 없이, 빈크리스틴, 빈블라스틴, 빈데신, 비노렐빈 등을 포함한다.
프로테아솜 억제제는 VELCADE® (보르테조미브), MG132, NPI-0052, PR-171 등을 포함한다.
면역학적 물질의 예는 인터페론 및 기타 면역-증강제를 포함한다. 인터페론은 인터페론 알파, 인터페론 알파-2a, 인터페론 알파-2b, 인터페론 베타, 인터페론 감마-1a, ACTIMMUNE® (인터페론 감마-1b) 또는 인터페론 감마-n1, 이들의 배합물 등을 포함한다. 기타 약제는 ALFAFERONE®, BAM-002, BEROMUN® (타소네르민), BEXXAR® (토시투모마브), CamPath® (알렘투주마브), CTLA4 (세포독성 림프구 항원 4), 데카르바진, 데닐류킨, 에프라투주마브, GRANOCYTE® (레노그라스팀), 렌티난, 백혈구 알파 인터페론, 이미퀴모드, MDX-010, 흑색종 백신, 미투모마브, 몰그라모스팀, MYLOTARG™ (젬투주마브 오조자미신), NEUPOGEN® (필그라스팀), OncoVAC-CL, OvaRex® (오레조보마브), 펨투모마브 (Y-muHMFG1), PROVENGE®, 사르가라모스팀, 시조필란, 테셀류킨, TheraCys®, 우베니멕스, VIRULIZIN®, Z-1OO, WF-10, PROLEUKIN® (알데스류킨), ZADAXIN® (티말파신), ZENAPAX® (다클리주마브), ZEVALIN® (90Y-이브리투모마브 티욱세탄) 등을 포함한다.
생물학적 반응 조절제는 살아있는 유기체의 방어 기전 또는 생물학적 반응, 예를 들면 조직 세포의 생존, 성장 또는 분화를 조절하여 조직 세포가 항-종양 활성을 갖도록 유도하는 약제이며, 크레스틴, 렌티난, 시조피란, 피시바닐 PF-3512676 (CpG-8954), 우베니멕스 등을 포함한다.
피리미딘 유사체는 시타라빈 (ara C 또는 아라비노시드 C), 시토신 아라비노시드, 독시플루리딘, FLUDARA® (플루다라빈), 5-FU (5-플루오로우라실), 플록스우리딘, GEMZAR® (겜시타빈), TOMUDEX® (라티트렉세드), TROXATYL™ (트리아세틸우리딘 트록스아시타빈) 등을 포함한다.
푸린 유사체는 LANVIS® (티오구아닌) 및 PURI-NETHOL® (머캅토푸린)을 포함한다.
항유사분열제는 바타불린, 에포틸론 D (KOS-862), N-(2-((4-하이드록시페닐)아미노)피리딘-3-일)-4-메톡시벤젠설폰아미드, 익사베필론 (BMS 247550), 파클리탁셀, TAXOTERE® (도세탁셀), PNU100940 (109881), 파투필론, XRP-9881, 빈플루닌, ZK-EPO 등을 포함한다.
본 발명의 화합물은 또한 방사선 요법의 효능을 증강시키는 방사선감작제로서 사용되는 것으로 의도된다. 방사선 요법의 예는 제한 없이, 외부 빔 방사선 요법, 원격요법, 근접요법 및 밀봉 선원 및 비밀봉 선원 방사선 요법을 포함한다.
추가로, ABT-869·¼ 에탄올레이트 결정질 형태 1은 다른 화학요법제, 예를 들면 ABRAXANE™ (ABI-007), ABT-100 (파르네실 트랜스퍼라제 억제제), ADVEXIN®, ALTOCOR® 또는 MEVACOR® (로바스타틴), AMPLIGEN® (폴리I:폴리 C12U, 합성 RNA), APTOSYN™ (엑시설린드), AREDIA® (파미드론산), 아르글라빈, L-아스파라기나제, 아타메스탄 (1-메틸-3,17-디온-안드로스타-1,4-디엔), AVAGE® (타자로텐), AVE-8062, BEC2 (미투모마브), 카켁틴 또는 카켁신 (종양 괴사 인자), 칸박신 (백신), CeaVac™ (암 백신), CELEUK® (셀모류킨), CEPLENE® (히스타민 디하이드로클로라이드), CERVARIX™ (사람 파필로마바이러스 백신), CHOP® (C: CYTOXAN® (사이클로포스파미드); H: ADRIAMYCIN® (하이드록시독소루비신); O: 빈크리스틴 (ONCOVIN®); P: 프레드니손), CyPat™, 콤브레스타틴 A4P, DAB(389)EGF 또는 트랜스MID-107R™ (디프테리아 독소), 다카르바진, 닥티노마이신, 5,6-디메틸크산테논-4-아세트산 (DMXAA), 에닐우라실, EVIZON™ (스쿠알라민 락테이트), DIMERICINE® (T4N5 리포솜 로션), 디스코데르몰리드, DX-8951f (엑사테칸 메실레이트), 엔자스타우린, EPO906, GARDASIL® (4가 사람 파릴로마바이러스 (타입 6, 11, 16, 18) 재조합 백신), GASTRIMMUNE™ (가스트린-디프테리아 접합체), GENASENSE™ (오블리메르센 나트륨), GMK (강글리오시드 접합체 백신), GVAX® (전립선암 백신), 할로푸기논, 히스테렐린, 하이드록시카르바미드, 이반드론산, IGN-101, IL-13-PE38, IL-13-PE38QQR (신트레데킨 베수도톡스), IL-13-녹농균 외독소, 인터페론-α, 인터페론-γ, JUNOVAN™ 또는 MEPACT™ (미파무르티드), 로나파르니브, 5,10-메틸렌테트라하이드로폴레이트, 밀테포신 (헥사데실포스포콜린), NEOVASTAT®(AE-941), NEUTREXIN® (트리메트렉세이트 글루쿠로네이트), NIPENT® (펜토스타틴), ONCONASE® (리보뉴클레아제 효소), ONCOPHAGE® (흑색종 백신 치료제), OncoVAX (IL-2 백신), ORATHECIN™ (루비테칸), OSIDEM® (항체-기반 세포 약물), OvaRex® MAb (뮤린 모노클론 항체), 파클리탁셀, PANDIMEX™ (20(S)프로토파낙사디올 (aPPD) 및 20(S)프로토파낙사트리올 (aPPT)을 포함하는 인삼으로부터의 아글리콘 사포닌), 파니투무마브, PANVAC®-VF (시험용 암 백신), 페가스파가제(pegaspargase), PEG 인터페론 A, 페녹소디올, 프로카르바진, 레비마스타트, REMOVAB® (카투막소마브), REVLIMID® (레날리도미드), RSR13 (에파프록시랄), SOMATULINE® LA (란레오티드), SORIATANE® (아시트레틴), 스타우로스포린 (스트렙토마이세스 스타우로스포레스(Streptomyces staurospores)), 탈라보스타트 (PT1OO), TARGRETIN® (벡사로텐), Taxoprexin® (DHA-파클리탁셀), TELCYTA™ (TLK286), 테밀리펜, TEMODAR® (테모졸로미드), 테스밀리펜, 탈리도미드, THERATOPE® (STn-KLH), 티미탁 (2-아미노-3,4-디하이드로-6-메틸-4-옥소-5-(4-피리딜티오)퀴나졸린 디하이드로클로라이드), TNFerade™ (아데노벡터: 종양 괴사 인자-α에 대한 유전자를 함유하는 DNA 운반체), TRACLEER® 또는 ZAVESCA® (보센탄), 트레티노인 (레틴-A), 테트란드린, TRISENOX® (삼산화비소), VIRULIZIN®, 우크라인 (애기똥풀(greater celandine) 식물로부터의 알칼로이드의 유도체), 비탁신 (안티-알파v베타3 항체), XCYTRIN® (모텍사핀 가돌리늄), XINLAY™ (아트라센탄), XYOTAX™ (파클리탁셀, 폴리글루멕스), YONDELIS™ (트라벡테딘), ZD-6126, ZINECARD® (덱스라족산), 조메타 (졸렌드론산), 조루비신 등과 배합될 수 있다.
또한, ABT-869·¼ 에탄올레이트 결정질 형태 1은 태아성 횡문근육종, 소아 급성 림프모구성 백혈병, 소아 급성 골수종 백혈병, 소아 폐포 횡문근육종, 소아 역형성 상의세포종, 소아 역형성 대세포 림프종, 소아 역형성 수모세포종, 중추 신경계의 소아 비정형 기형/횡문근양 종양, 소아 혼합형 급성 백혈병, 소아 버키트 림프종, 종양의 에빙 패밀리의 소아암, 예를 들면, 원시 신경외배엽 종양, 소아 미만성 역형성 윌름 종양, 소아 양호 조직형 윌름 종양, 소아 교모세포종, 소아 수모세포종, 소아 신경모세포종, 소아 신경모세포종-유래 골수구종증, 소아 pre-B-세포 암 (예를 들면, 백혈병), 소아 골육종, 소아 횡문근양 신장 종양, 소아 횡문근육종 및 소아 T-세포 암, 예를 들염, 림프종 및 피부암 등을 포함한, 소아암 또는 신생물(neoplasm)로부터 유래된 세포의 성장을 억제할 것으로 기대된다.
ABT-869의 제조 및 PTK 억제제로서의 이의 유용성은 공동-소유된 미국 특허 제7297709호에 개시되어 있다.
하기의 실시예는 본 발명의 절차 및 개념적 견지의 가장 유용하고 이해하기 쉬운 설명이라고 여겨지는 것을 제공하기 위해서 기재한다.
실시예 1
ABT-869·¼ 에탄올레이트 결정질 형태 1의 제조
에틸 아세테이트 중의 ABT-869 하이드로클로라이드와 에탄올의 혼합물[여기서, 상기 ABT-869 하이드로클로라이드는 완전히 용해되었다]을 이염기성 인산나트륨과 혼합하였다. 유기층을 분리하고, 탈색용 탄소로 처리하고, 여과하였다. 소량의 L-아스코르브산을 첨가하고, 용액을 농축시켰다. 에틸 아세테이트를 에탄올과의 공비 증류에 의해 제거하였다. 추가의 에탄올을 첨가할 수 있으며, 형성되는 임의의 고체를 용액을 가열하여 용해시킬 수 있다. 용액을 25℃로 냉각시키고, 물로 희석하여, ABT-869·¼ 에탄올레이트 결정질 형태 1이 결정화도록 하였다. 생성물을 분리하고, 물로 세척하고, 감압 하에서 건조시켰으며, 이 동안에는 잔류 에틸 아세테이트 및 에탄올(가스 크로마토그래피(GC))에 의해) 및 물(칼 피셔(KF)에 의해)을 모니터링하였다. 92%의 수율이 통상적이었다.
2 kW 정상 초점 X-선관 및 펠티어 냉각된 게르마늄 고체-상태 검출기(Peltier cooled germanium solid-state detector) (미국 캘리포니아주 서니베일 소재의 Scintag Inc.)를 구비한 XDS-2000/X-선 회절계를 사용하여 분말 X-선 회절을 수행하였다. DMSNT 소프트웨어 (버전 1.37)를 사용하여 데이터를 처리하였다. X-선원은 45kV 및 40mA에서 작동되는 구리 필라멘트 (1.54178Å의 Cu-Kα)였다. 코런덤(Corundum) 표준을 사용하여 측각계의 정렬을 매일 점검하였다. 샘플을 제로 배경판 상에 (사전 그라인딩 없이) 얇은 층으로 놓고, 2°내지 40°2θ의 범위에 걸쳐 2°2θ/분의 속도로 연속적으로 주사하였다.
도 1은 ABT-869·¼ 에탄올레이트 결정질 형태 1의 분말 X-선 회절 패턴이다.
실시예 2
ABT-869 일수화물 결정질 형태 1의 제조
실시예 1에 기재된 바와 같은 이염기성 인산나트륨에 의한 중화, 탈색용 탄소 처리 및 에틸 아세테이트의 제거 후, ABT-869의 에탄올 중 혼합물을 격렬한 교반과 함께 25℃에서 물과 점차적으로 혼합하였다. ABT-869·H2O 결정질 형태 1을 분리하고, 물로 세척하고, 감압 하에서 건조시켰으며, 이 동안에는 잔류 에틸 아세테이트 및 에탄올 (GC에 의해) 및 물 (KF에 의해)을 모니터링하였다. 76%의 수율이 통상적이었다.
2 kW 정상 초점 X-선관 및 펠티어 냉각된 게르마늄 고체-상태 검출기 (미국 캘리포니아주 서니베일 소재의 Scintag Inc.)를 구비한 XDS-2000/X-선 회절계를 사용하여 분말 X-선 회절을 수행하였다. DMSNT 소프트웨어 (버전 1.37)를 사용하여 데이터를 처리하였다. X-선원은 45kV 및 40mA에서 작동되는 구리 필라멘트 (1.54178Å의 Cu-Kα)였다. 코런덤 표준을 사용하여 측각계의 정렬을 매일 점검하였다. 샘플을 제로 배경판 상에 (사전 그라인딩 없이) 얇은 층으로 놓고, 2°내지 40°2θ의 범위에 걸쳐 2°2θ/분의 속도로 연속적으로 주사하였다.
PXRD 패턴에서 피크 높이의 상대 강도가 변화할 수 있으며, 이는 온도, 결정 크기 또는 모폴로지, 샘플 제조 또는 X-선 회절계의 분석 웰(analysis well)에서의 샘플 높이와 같은 변수들에 따라 달라질 수 있을 것임이 이해되는 것으로 의미된다.
또한, 상이한 방사선원을 사용하여 측정될 때, 피크 위치가 변화할 수 있음이 이해되는 것으로 의미된다. 예를 들어, 각각 파장이 1.54060Å, 0.7107Å, 1.7902Å 및 1.9373Å인 Cu-Kα1, Mo-Kα, Co-Kα 및 Fe-Kα 방사선은, 파장이 1.5478Å인 Cu-Kα 방사선을 사용하여 측정된 것과 상이한 피크 위치를 제공할 수 있다.
용어 "약"이 앞에 오는 일련의 피크 위치들은 "약"이 앞에 오는 그룹의 피크들 모두가 문헌[U.S. Pharmacopeia, pages 1843-1884 (1995)]에 명시된 바와 같은 ± 0.1°의 허용가능한 변동을 갖고서 각도 위치(2θ)의 관점에서 보고됨을 의미한다. ± 0.1°의 변동은 2개의 분말 X-선 회절 패턴을 비교할 때 사용되는 것으로 의도된다. 실시에 있어서는, 한 패턴으로부터의 회절 패턴 피크가, 측정된 피크 위치 ± 0.1°인 일정 범위의 각도 위치들(2θ)에 할당되고, 피크 위치들의 범위가 겹칠 경우에는, 2개의 피크가 동일한 각도 위치를 갖는 것으로 간주된다. 예를 들어, 한 패턴으로부터의 피크가 11.0°의 위치를 갖는 것으로 측정될 경우, 비교 목적을 위하여, 허용가능한 변동은 당해 피크가 10.9° 내지 11.1°의 범위의 위치에 할당되는 것을 허용한다.
따라서, 예를 들어, 본 명세서에 사용되는, 어구 "약 4.5°, 7.7°, 11.7°, 12.2°, 14.6°, 16.9°, 17.7° 및 18.4°"는 약 4.5°, 약 7.7°, 약 11.7°, 약 12.2°, 약 14.6°, 약 16.9°, 약 17.7° 및 약 18.4°임을 의미하며, 이는 또한 4.5°± 0.1°, 7.7°± 0.1°, 11.7°± 0.1°, 12.2°± 0.1°, 14.6°± 0.1°, 16.9°± 0.1°, 17.7°± 0.1° 및 18.4°± 0.1°임을 의미한다.
용어 "약"이 앞에 오는 온도는 소정의 온도 ± 2℃임을 의미한다. 예를 들어, 약 25℃는 25℃ ± 2℃ 또는 23℃ 내지 27℃임을 의미한다.
상기 내용은 본 발명의 예시로서 의미되며, 개시된 양태들로 본 발명을 제한하는 것으로 의도되지 않는다. 당업자에게 자명한 변형 및 변경은 특허청구범위에 정의된 본 발명의 범위 및 성질 내에 있는 것으로 의도된다.
Claims (6)
- 0.7107Å의 방사선을 사용하여 삼사정계 결정계 및 P1 공간군에서 약 -100℃에서 측정될 때, 각각의 격자 파라미터 값 a, b 및 c가 8.971Å ± 0.006Å, 11.646Å ± 0.008Å 및 19.26Å ± 0.01Å이고, 각각의 α, β 및 γ 값이 약 87.67°± 0.1°, 90.21°± 0.1° 및 76.82°± 0.1°임을 특징으로 하는, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1.
- 1.54178Å의 방사선을 사용하여 약 25℃에서 측정될 때, 분말 회절 패턴의 각각의 2θ 값이 약 4.5°, 7.7°, 11.7°, 12.2°, 14.6°, 16.9°, 17.7° 및 18.4°임을 특징으로 하는, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1.
- 부형제 및, 0.7107Å의 방사선을 사용하여 삼사정계 결정계 및 P1 공간군에서 약 -100℃에서 측정될 때, 각각의 격자 파라미터 값 a, b 및 c가 8.971Å ± 0.006Å, 11.646Å ± 0.008Å 및 19.26Å ± 0.01Å이고, 각각의 α, β 및 γ 값이 약 87.67°± 0.1°, 90.21°± 0.1° 및 76.82°± 0.1°이거나, 1.54178Å의 방사선을 사용하여 약 25℃에서 측정될 때, 분말 회절 패턴의 각각의 2θ 값이 약 4.5°, 7.7°, 11.7°, 12.2°, 14.6°, 16.9°, 17.7° 및 18.4°임을 특징으로 하는, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1로 제조된, 제형.
- 0.7107Å의 방사선을 사용하여 삼사정계 결정계 및 P1 공간군에서 약 -100℃에서 측정될 때, 각각의 격자 파라미터 값 a, b 및 c가 8.971Å ± 0.006Å, 11.646Å ± 0.008Å 및 19.26Å ± 0.01Å이고, 각각의 α, β 및 γ 값이 약 87.67°± 0.1°, 90.21°± 0.1° 및 76.82°± 0.1°이거나, 1.54178Å의 방사선을 사용하여 약 25℃에서 측정될 때, 분말 회절 패턴의 각각의 2θ 값이 약 4.5°, 7.7°, 11.7°, 12.2°, 14.6°, 16.9°, 17.7° 및 18.4°임을 특징으로 하는, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1의 치료학적 유효량을, 하나 이상의 추가의 항암 약물을 사용하거나 사용하지 않고, 포유류에 투여하는 것을 포함하는, 포유류에서의 암 치료 방법.
- N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아 및 에탄올을 포함한 용매를 포함하는 혼합물(여기서, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아는 상기 용매에 완전히 용해된다)을 제공하는 단계;
N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1이 상기 혼합물에 존재(상기 N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1은, 분리되어 0.7107Å의 방사선을 사용하여 삼사정계 결정계 및 P1 공간군에서 약 -100℃에서 측정될 때, 각각의 격자 파라미터 값 a, b 및 c가 8.971Å ± 0.006Å, 11.646Å ± 0.008Å 및 19.26Å ± 0.01Å이고, 각각의 α, β 및 γ 값이 약 87.67°± 0.1°, 90.21°± 0.1° 및 76.82°± 0.1°임을 특징으로 한다)하게 하는 단계를 포함하는, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1의 제조방법. - 제5항에 있어서, N-[4-(3-아미노-1H-인다졸-4-일)페닐]-N'-(2-플루오로-5-메틸페닐)우레아·¼ 에탄올레이트 결정질 형태 1을 분리하는 단계를 추가로 포함하는, 방법.
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