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KR101541791B1 - 다형태 - Google Patents

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KR101541791B1
KR101541791B1 KR1020147010530A KR20147010530A KR101541791B1 KR 101541791 B1 KR101541791 B1 KR 101541791B1 KR 1020147010530 A KR1020147010530 A KR 1020147010530A KR 20147010530 A KR20147010530 A KR 20147010530A KR 101541791 B1 KR101541791 B1 KR 101541791B1
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페터 지거
디르크 켐머
페터 콜바우어
토마스 니콜라
마르틴 렌츠
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Abstract

본 발명은 1-((4-메틸-퀴나졸린-2-일)메틸)-3,7-(2-부틴-1-일)-8-(3-(R)-아미노피페리딘-1-일)크산틴의 다형태 결정성 변형물, 이의 제조방법 및 약물을 제조하기 위한 이의 용도에 관한 것이다.

Description

다형태{Polymorphs}
본 발명은 DPP-IV 억제제의 다형태 결정성 변형물, 이의 제조방법 및 약물을 제조하기 위한 이의 용도에 관한 것이다.
명칭 CD26으로도 공지된 효소 DPP-IV는 N-말단 단부에 프롤린 또는 알라닌 그룹을 갖는 단백질에서 디펩티드의 분열을 촉진시키는 세린 프로테아제이다. 이에 따라 DPP-IV 억제제는 펩티드 GLP-1을 포함하는 생체 활성 펩티드의 플라즈마 레벨에 영향을 미친다. 이러한 유형의 화합물들은 증가된 DPP-IV 활성과 연관되거나 DPP-IV 활성을 감소시킴으로써 예방되거나 경감될 수 있는 질병 또는 상태, 특히 I형 또는 II형 당뇨병, 당뇨병 전기 또는 감소된 글루코스 내성의 예방 또는 치료에 유용하다.
국제 공개공보 제WO 2004/018468호는 우수한 약리학적 특성들을 갖는 DPP-IV 억제제를 기재하고 있다. 이 문헌에 기재된 억제제의 한 예는 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴이다.
본 발명의 범위내에서 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴은 여러가지 다형태 결정성 변형물로 존재할 수 있고, 국제 공개공보 제WO 2004/018468호에서 제조된 화합물은 주위 온도에서 2가지 에난티오트로픽(enantiotropic) 다형태의 혼합물로서 존재함이 밝혀졌다. 상기 2가지 다형태가 상호 변환되는 온도는 25 ±15℃이다(도 1 및 2 참조).
다형태 혼합물을 40℃ 초과의 온도로 가열함으로써 수득될 수 있는 순수한 고온 형태(다형태 A)는 206 ±3℃에서 용융된다. X-선 분말 다이어그램(도 3 참조)에서, 이러한 형태는 다음 d 값에서 특징적인 반사를 보여준다: 11.49Å, 7.60Å, 7.15Å, 3.86Å, 3.54Å 및 3.47Å(또한, 표 1 및 2 참조).
무수 다형태 A는
(a) 순수 에탄올 중에 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴을 환류시키고, 임의로 이들의 혼합물을 여과하고,
(b) 결정화될 때까지 고온 용액 또는 고온 여액을 냉각시키고,
(c) 3급-부틸메틸에테르와 같은 용매로 희석시키고,
(d) 용매 혼합물을 흡입 여과하고,
(e) 다형태 A를 45℃에서 진공건조시켜 제조될 수 있다.
저온 형태(다형태 B)는 10℃ 미만의 온도로 냉각시킴으로써 수득된다. X-선 분말 다이어그램(도 4 참조)에서, 이러한 형태는 다음 d 값에서 특징적인 반사를 보여준다: 11.25Å, 9.32Å, 7.46Å, 6.98Å, 및 3.77Å(또한, 표 3 및 4 참조).
무수 다형태 B는
(a) 순수 에탄올 중에 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴을 용해시키고, 이들의 혼합물을 환류시키고, 임의로 여과하고,
(b) 고온 용액 또는 고온 여액을 결정화되도록 10℃ 미만의 온도로 냉각시키고,
(c) 3급-부틸메틸에테르와 같은 용매로 희석시키고,
(d) 용매 혼합물을 흡입 여과하고,
(e) 다형태를 10℃ 미만의 온도에서 진공건조시켜 제조될 수 있다.
다른 다형태(다형태 C)는 X-선 분말 다이어그램(도 5 참조)에서 다음 d 값에서 특징적인 반사를 보여준다: 12.90Å, 11.10Å, 6.44Å, 3.93Å, 및 3.74Å(또한 표 5 참조).
다형태 C는
(a) 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴을 메탄올에 용해시키고, 환류시키고, 임의로 활성탄의 존재하에 여과하고,
(b) 상기 메탄올성 용액을 40 내지 60℃의 온도로 냉각시키고,
(c) 3급-부틸메틸에테르 또는 디이소프로필에테르와 같은 용매를 부가하고,
(d) 수득된 현탁액을 먼저 15 내지 25℃로 냉각시키고, 이어서 0 내지 5℃로 냉각시키고,
(e) 형성된 결정을 흡입 여과하고, 3급-부틸메틸에테르 또는 디이소프로필에테르로 다시 세척하고,
(f) 수득된 결정을 70℃의 온도에서 진공 건조기에서 건조시켜 제조될 수 있다.
다른 다형태(다형태 D)는 150 ±3℃에서 용융된다. 이러한 다형태는 다형태 C가 30 내지 100℃의 온도로 가열되고, 이 온도에서 건조되는 경우에 수득된다.
마지막으로, 다형태 E가 또한 존재하고, 이는 175 ±3℃의 온도에서 용융된다. 무수 다형태 E는 다형태 D가 용융된 경우에 형성된다. 다형태 D를 추가로 가열하면, 다형태 E가 용융물로부터 결정화된다.
이로서 수득된 다형태는 동종 이식(allograft)이 수행된 환자 뿐만 아니라 I형 및 II형 당뇨병, 당뇨병 전기 또는 감소된 글루코스 내성을 갖는 환자, 및 류머티스성 관절염, 비만, 또는 칼시토닌-유도된 골다공증 환자를 치료하는데 적합한 약제학적 조성물을 제조하기 위해 WO 2004/018468호에 기재된 2가지 다형태 A 및 B의 혼합물과 동일한 방법으로 사용될 수 있다. 이들 약물은 1개 이상의 불활성 담체 이외에 적어도 0.1% 내지 0.5%, 바람직하게는 적어도 0.5% 내지 1.5%, 특히 바람직하게는 적어도 1% 내지 3%의 다형태 A, B 및 C 중의 하나를 함유한다.
본 발명의 일 구체예로, 206±3℃에서 용융되는, 화합물 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴의 무수 다형태(polymorph) A가 사용되는 것을 특징으로 하는 약제의 제조 방법으로서,
상기 약제는 0.1% 내지 0.5%, 또는 0.5% 내지 1.5%, 또는 1% 내지 3%의 상기 무수 다형태 A를 하나 이상의 불활성 담체와 함께 포함하고,
상기 무수 다형태 A는
(a) 순수 에탄올 중에 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴을 환류시키고, 임의로 이들의 혼합물을 여과하고,
(b) 결정화될 때까지 고온 용액 또는 고온 여액을 냉각시키고,
(c) 3급-부틸메틸에테르와 같은 용매로 희석시키고,
(d) 용매 혼합물을 흡입 여과하고,
(e) 다형태 A를 45℃에서 진공건조시켜 제조되거나,
다형태 B 또는 다형태 A와 B의 혼합물을 40℃ 초과의 온도로 가열함으로써 제조되는, 약제의 제조 방법을 들 수 있다.
본 발명의 또 다른 구체예로, 10 내지 40℃의 온도에서 제1항의 다형태 A로 가역적으로 변형되는, 화합물 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴의 무수 다형태 B가 사용되는 것을 특징으로 하는 약제의 제조 방법으로서,
상기 약제는 0.1% 내지 0.5%, 또는 0.5% 내지 1.5%, 또는 1% 내지 3%의 상기 무수 다형태 B를 하나 이상의 불활성 담체와 함께 포함하고,
상기 무수 다형태 B는
(a) 순수 에탄올 중에 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴을 용해시키고, 이들의 혼합물을 환류시키고, 임의로 여과하고,
(b) 고온 용액 또는 고온 여액을 결정화되도록 10℃ 미만의 온도로 냉각시키고,
(c) 3급-부틸메틸에테르와 같은 용매로 희석시키고,
(d) 용매 혼합물을 흡입 여과하고,
(e) 다형태를 10℃ 미만의 온도에서 진공건조시켜 제조되거나,
다형태 A 또는 다형태 A와 B의 혼합물을 10℃ 미만의 온도로 냉각함으로써 제조되는, 약제의 제조 방법을 들 수 있다.
도 1은 무수 다형태 A/B의 열분석 데이터이다.
도 2는 에난티오트로픽 상 전이의 사이클릭 DSC 다이어그램이다.
도 3은 무수 다형태 A의 X-선 분말 다이어그램이다.
도 4는 무수 다형태 B의 X-선 분말 다이어그램이다.
도 5는 다형태 C의 X-선 분말 다이어그램이다.
도 6은 다형태 C의 열분석 데이터이다.
다음 실시예들은 본 발명을 더욱 상세히 설명하고자 의도된다.
실시예 1 다형태 A의 결정화
조악한 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴을 5배의 순수 에탄올로 환류시키고, 고온 용액을 활성탄을 통해 순수하게 여과된다. 여액을 20℃로 냉각시키고, 결정화한 후, 용액을 3급-부틸메틸에테르를 사용하여 2배 용적으로 희석한다. 이어서, 이 현탁액을 2℃로 냉각시키고, 2시간 동안 교반하고, 흡입 여과하고, 진공 건조기에서 45℃에서 건조시킨다.
다형태 A는 206 ±3℃에서 용융된다. DSC 다이어그램에서 다른 약간의 흡열 신호는 약 25℃에서 나타날 수 있다. 이는 2개의 에난티오트로픽 결정성 변형물 A와 B 사이의 완전히 가역적인 고체-고체 상 전이이다. 다형태 A는 이러한 변환 온도를 초과하는 온도에서 열역학적으로 안정한 변형물인 한편, 다형태 B는 이러한 변환 온도 미만에서 열역학적으로 안정한 변형물이다.
도 2는 사이클릭 DSC 다이어그램을 나타내고, 여기서 -40℃ 내지 120℃의 상 전이 및 그 역은 총 3번에 걸쳐 수행되었다. 가열하는 동안, 상 전이는 흡열 신호로서 관찰되고, 상응하게는, 냉각시키는 동안 상 전이는 발열 신호로서 관찰된다. 제1 가열 주기 동안, 상 전이는 또한 이중 발열 신호로서 또는 매우 넓은 신호로서 관찰될 수도 있고, 반면, 그외의 다른 주기 모두에서, 신호는 가열 또는 냉각이 발생하는지 여부에 따라 매우 날카로운 흡열 또는 발열 신호로서 발생한다.
Figure 112014037516113-pat00001
Figure 112014037516113-pat00002
Figure 112014037516113-pat00003
실시예 2 다형태 B의 결정화
다형태 B는 실시예 1로부터 10℃ 미만의 온도로 다형태 A를 냉각시킴으로써 수득된다.
Figure 112014037516113-pat00004
Figure 112014037516113-pat00005
Figure 112014037516113-pat00006
Figure 112014037516113-pat00007
실시예 3 다형태 C의 결정화
조악한 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴(26kg)을 157L의 메탄올로 환류시키고, 1.3kg의 활성탄과 합하고, 30분간 교반시킨 후, 이 혼합물을 여과하고, 26L의 메탄올로 세정하였다. 122L의 메탄올을 여액으로부터 증발제거하고, 잔류물을 45 내지 55℃로 냉각시켰다. 52L의 3급-부틸메틸에테르를 30분에 걸쳐 잔류물에 부가하였다. 이어서, 상기 혼합물을 45 내지 55℃에서 또다른 60분 동안 교반시켰다. 결정화가 이 시간 내에 발생한다. 추가의 78L의 3급-부틸메틸에테르를 30분에 걸쳐 상기 현탁액에 부가하였고, 이후 45 내지 55℃에서 추가로 60분 동안 다시 교반하였다. 이를 4배 용적으로 희석하였다. 상기 현탁액을 서서히 15 내지 25℃로 냉각시키고, 이 온도에서 밤새 교반하였다. 상기 현탁액을 0 내지 5℃로 냉각시킨 후, 결정을 흡입 여과하고, 2개 배치의 3급-부틸메틸에테르로 세척하고, 진공 건조기에서 70℃에서 건조시켰다.
Figure 112014037516113-pat00008
실시예 4 다형태 D의 결정화
다형태 C는 실시예 3으로부터의 다형태 C가 30 내지 100℃의 온도로 가열되거나, 또는 이 온도로 건조되는 경우 수득된다.
실시예 5 다형태 E의 결정화
무수 다형태 E는 다형태 D가 용융된 경우에 수득된다. 추가로 가열하면, 다형태 E가 용융물로부터 결정화된다.
다형태 C의 DSC 다이어그램에서 전범위의 신호가 관찰될 수 있다. 가장 강한 신호는 약 206℃에서 무수 다형태 A의 융점이고, 이는 DSC 실험에서 생성된다. 융점 이전에 많은 다른 흡열 및 발열 신호가 관찰될 수 있다. 따라서, 예를 들면, 매우 넓고 약한 발열 신호는 30 내지 100℃에서 나타날 수 있고, 이는 열중량분석(TR)에서 주요 중량 손실과 상호 연관된다. TG/IR 동시 실험은 물만이 이 온도 범위에서 시료로부터 방출되는 정보를 제공한다.
100℃의 온도에서 유지된 시료로부터 측정된 X-선 분말 다이어그램은 출발 물질과 상이한 X-선 반사를 나타내고, 이로써 다형태 C가 반수화물 또는 일수화물 영역에서 화학량론비를 갖는 수화물 상인 것을 시사한다. 온도-조절된 시료는 또다른 무수 변형물 D이고, 이는 무수 상태만 안정하다. 상기 D 다형태는 약 150℃에서 용융된다. 다른 무수 결정성 변형물 E는 용융물로부터 결정화되고, 가열시 추가로 약 175℃에서 용융된다. 마지막으로, 다형태 A는 다형태 E의 용융물로부터 결정화된다. 다형태 E는 고온에서만 존재하는 준안정성 상태의 결정성 변형물이기도 하다.

Claims (12)

  1. 206±3℃에서 용융되고, X-선 분말 다이어그램에서 d 값 11.59Å, 7.60Å, 7.15Å, 3.86Å, 3.54Å 및 3.47Å에서 특징적인 반사를 나타내는, 화합물 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴의 무수 다형태(polymorph) A가 사용되는 것을 특징으로 하는 약제의 제조 방법으로서,
    상기 약제는 0.1% 내지 0.5%, 또는 0.5% 내지 1.5%, 또는 1% 내지 3%의 무수 다형태 A를 하나 이상의 불활성 담체와 함께 포함하는, 약제의 제조 방법.
  2. 10 내지 40℃의 온도에서 제1항의 다형태 A로 가역적으로 변형되고, X-선 분말 다이어그램에서 d 값 11.3Å, 9.36Å, 7.48Å, 7Å 및 3.77Å에서 특징적인 반사를 나타내는, 화합물 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴의 무수 다형태 B가 사용되는 것을 특징으로 하는 약제의 제조 방법으로서,
    상기 약제는 0.1% 내지 0.5%, 또는 0.5% 내지 1.5%, 또는 1% 내지 3%의 무수 다형태 B를 하나 이상의 불활성 담체와 함께 포함하는, 약제의 제조 방법.
  3. 화합물 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴의 무수 다형태 A 또는 B가 사용되는 것을 특징으로 하는, II형 당뇨병 치료용 약제의 제조 방법으로서,
    상기 약제는 0.1% 내지 0.5%, 또는 0.5% 내지 1.5%, 또는 1% 내지 3%의 무수 다형태 A 또는 B를 하나 이상의 불활성 담체와 함께 포함하고,
    다형태 A는 206±3℃에서 용융되고, X-선 분말 다이어그램에서 d 값 11.59Å, 7.60Å, 7.15Å, 3.86Å, 3.54Å 및 3.47Å에서 특징적인 반사를 나타내며,
    다형태 B는 10 내지 40℃의 온도에서 상기 다형태 A로 가역적으로 변형되고, X-선 분말 다이어그램에서 d 값 11.3Å, 9.36Å, 7.48Å, 7Å 및 3.77Å에서 특징적인 반사를 나타내는, 약제의 제조 방법.
  4. 206±3℃에서 용융되고, X-선 분말 다이어그램에서 d 값 11.59Å, 7.60Å, 7.15Å, 3.86Å, 3.54Å 및 3.47Å에서 특징적인 반사를 나타내는, 화합물 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴의 무수 다형태 A가 사용되는 것을 특징으로 하는, II형 당뇨병 치료용 약제의 제조 방법으로서,
    상기 약제는 1% 내지 3%의 무수 다형태 A를 하나 이상의 불활성 담체와 함께 포함하는, 약제의 제조 방법.
  5. 10 내지 40℃의 온도에서 제4항의 다형태 A로 가역적으로 변형되고, X-선 분말 다이어그램에서 d 값 11.3Å, 9.36Å, 7.48Å, 7Å 및 3.77Å에서 특징적인 반사를 나타내는, 화합물 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴의 무수 다형태 B가 사용되는 것을 특징으로 하는, II형 당뇨병 치료용 약제의 제조 방법으로서,
    상기 약제는 1% 내지 3%의 무수 다형태 B를 하나 이상의 불활성 담체와 함께 포함하는, 약제의 제조 방법.
  6. 제1항, 제3항 및 제4항 중 어느 한 항에 있어서, 다형태 A가 다음의 격자 매트릭스를 갖는 것을 특징으로 하는, 방법.
    Figure 112014113950042-pat00015
  7. 제2항, 제3항 및 제5항 중 어느 한 항에 있어서, 다형태 B가 다음의 격자 매트릭스를 갖는 것을 특징으로 하는, 방법.
    Figure 112014113950042-pat00016
  8. 제1항에 있어서,
    무수 다형태 A는
    (a) 순수 에탄올 중에 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴을 환류시키고, 임의로 이들의 혼합물을 여과하고,
    (b) 결정화될 때까지 고온 용액 또는 고온 여액을 냉각시키고,
    (c) 용매로 희석시키고,
    (d) 용매 혼합물을 흡입 여과하고,
    (e) 다형태 A를 45℃에서 진공건조시켜 제조되거나,
    다형태 B 또는 다형태 A와 B의 혼합물을 40℃ 초과의 온도로 가열함으로써 제조되고,
    상기 다형태 B는 X-선 분말 다이어그램에서 d 값 11.3Å, 9.36Å, 7.48Å, 7Å 및 3.77Å에서 특징적인 반사를 나타내는 것인, 방법.
  9. 제2항에 있어서,
    무수 다형태 B는
    (a) 순수 에탄올 중에 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴을 용해시키고, 이들의 혼합물을 환류시키고, 임의로 여과하고,
    (b) 고온 용액 또는 고온 여액을 결정화되도록 10℃ 미만의 온도로 냉각시키고,
    (c) 용매로 희석시키고,
    (d) 용매 혼합물을 흡입 여과하고,
    (e) 다형태를 10℃ 미만의 온도에서 진공건조시켜 제조되거나,
    다형태 A 또는 다형태 A와 B의 혼합물을 10℃ 미만의 온도로 냉각함으로써 제조되고,
    상기 다형태 A는 X-선 분말 다이어그램에서 d 값 11.59Å, 7.60Å, 7.15Å, 3.86Å, 3.54Å 및 3.47Å에서 특징적인 반사를 나타내는 것인, 방법.
  10. 제8항 또는 제9항에 있어서, 상기 단계 (c)의 용매가 3급-부틸메틸에테르인 방법.
  11. 삭제
  12. 삭제
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