KR20100037545A - N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine napsylate - Google Patents
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine napsylate Download PDFInfo
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Abstract
Description
본 발명은 포유류에게서 암과 같은 과증식성 질환을 치료하는 데 유용한 하기 화학식 1로 표현되는 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민의 납실레이트 염에 관한 기술이다.The present invention provides N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazoline represented by the following formula (1) which is useful for treating hyperproliferative diseases such as cancer in mammals. A technique relating to the lead silate salts of amines.
기존에 표피 성장 인자 수용체 (EGFR) 와 같은 종양원성 및 원종양원성 단백질 티로신 키나제의 ErbB족 저해제로 사람에게 있어 암과 같은 증식성 질환 치료에 유용한 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 히드로클로라이드 물질이 US 5,747,498 호에 공지되었다. 시판 중인 N-(3-에티닐페닐)-6,7-비 스(2-메톡시에톡시)-4-퀴나졸린아민 히드로클로라이드 염은 최대 용해도 (0.4 mg/ml)를 보이는 pH 2 에서조차 난용성 이며, 이보다 높은 pH 에서 용해도는 더욱 감소하여 위장의 pH 에 장기간 영향을 주는 오메프라졸과 같은 PPI (proton pump inhibitor) 약물과 함께 복용시에는 용해도가 더욱 떨어져 흡수율이 46% 감소하는 등의 단점을 가지고 있다(Full Prescribing Information of Tarceva: Erlotinib Tablets, Oral, FDA). N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 히드로클로라이드 염의 주요 부작용이 위천공이고 위천공을 일으키는 주요 원인 중 하나가 위궤양임을 감안하면 위궤양 치료제인 PPI 약물 및 기타 위의 pH 에 영향을 줄 수 있는 기타 다른 약들과 동시 복용할 수 없는 것은 큰 단점이다.N- (3-ethynylphenyl) -6,7, a conventional ErbB inhibitor of oncogenic and protoplasmic protein tyrosine kinases, such as epidermal growth factor receptor (EGFR), is useful for treating proliferative diseases such as cancer in humans. -Bis (2-methoxyethoxy) -4-quinazolinamine hydrochloride material is known from US Pat. No. 5,747,498. Commercially available N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine hydrochloride salts are not even at pH 2 with maximum solubility (0.4 mg / ml). Soluble, solubility at higher pH is further reduced and when taken with proton pump inhibitor (PPI) drugs such as omeprazole, which have a long-term effect on gastrointestinal pH. Full Prescribing Information of Tarceva: Erlotinib Tablets, Oral, FDA. Considering that the major side effect of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine hydrochloride salt is gastric perforation and one of the major causes of gastric perforation is gastric ulcer It is a major disadvantage that it cannot be co-administered with PPI drug, which is a treatment for gastric ulcer, and other medicines that may affect the pH of the stomach.
WO 99/55683 호에는 앞서 상술한 히드로클로라이드 염과 동일한 항암 유용성을 갖는 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 메실레이트 무수물 및 수화물 형태의 염을 기술하고 있다. 이 메실레이트 염들은 수용성 조성에서 상기의 히드로클로라이드 염에 비해 보다 용해되기 쉬워 비경구적인 (Parenteral) 방법에 따라서 보다 쉽게 전달될 수 있다고 기재되어있다. 그러나, 메실레이트 염은 알콜용매 하에서 제조시 인체에 치명적인 독성을 가진 메실레이트 에스터 화합물을 형성 할 수 있다(Handbook of Pharmaceutical Salts: Properties, Selection, and Use; P. Heinrich Stahl, Camille G. Wermuth.,Ed.; International Union of Pure and Applied Chemistry; p 295). 상기 WO 99/55683 호에서 메실레이트 염들을 제조하는 방법이 대부분 이소프로필 알콜을 사용하여 제조하는 것인 만큼 메실레이트 에스터 화합물이 형성되는지 모니터링을 철저히 하여야 하는 등의 어려움을 가지고 있다. 더욱이, 상기의 메실레이트 염들은 정제 및 캅셀제로 개발하기 위하여 확보되어야 하는 고체의 열에 대한 안정성이 떨어져 그 개발이 용이하지 않은 것으로 본 발명자들의 실험에 의해 밝혀졌다(본원의 시험예 1). 따라서 고체 열안정성 및 용해도 등의 물리화학적 성질이 개선된 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민의 신규한 염의 개발은 여전히 필요한 실정이다.WO 99/55683 discloses N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine mesylate anhydride having the same anticancer utility as the hydrochloride salts described above. And salts in hydrate form. These mesylate salts are described as being more soluble in water-soluble compositions than those of the hydrochloride salts above and can be more readily delivered by parenteral methods. However, mesylate salts can form mesylate ester compounds that are lethal to the human body when prepared under alcoholic solvents (Handbook of Pharmaceutical Salts: Properties, Selection, and Use; P. Heinrich Stahl, Camille G. Wermuth., Ed .; International Union of Pure and Applied Chemistry; p 295). Since the method for preparing mesylate salts in WO 99/55683 is mostly prepared using isopropyl alcohol, it is difficult to closely monitor whether a mesylate ester compound is formed. Moreover, the above mesylate salts were found to be difficult to develop due to the poor heat stability of the solids to be secured for the development of tablets and capsules (Test Example 1 herein). Therefore, the development of new salts of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine with improved physicochemical properties such as solid thermal stability and solubility is still It is necessary.
이에, 본 발명자들은 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민의 신규 염에 대해 연구한 결과, 본 발명의 납실레이트 염이 공지의 메실레이트 염 (결정형무수물 및 수화물) 및 히드로클로라이드 염 (공지 결정형)들과 비교하여 열에 대해 안정하고, 특히 오메프라졸과 같이 위액의 산도에 영향을 주어 함께 복용 시 흡수율에 지대한 영향을 줄 수 있는 PPI (proton pump inhibitor) 약물과 병용하는 경우 상승하는 pH 4.6 에서도 용해도가 우수한 것을 발견하고 본 발명을 완성하게 되었다.Therefore, the present inventors have studied the novel salt of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine, and as a result, the lead silate salt of the present invention Compared to known mesylate salts (crystalline anhydrides and hydrates) and hydrochloride salts (known crystalline forms), they are stable to heat and can affect the acidity of gastric juices, especially omeprazole, which can have a significant effect on absorption when taken together When combined with a proton pump inhibitor (PPI) drug, it was found that the solubility is excellent even at an elevated pH of 4.6, thus completing the present invention.
본 발명은 정제 및 캅셀제로 제형화하기 위하여 확보되어야 하는 고체 열안정성 및 약효 유발에 중요한 성질인 용해도 등의 물리화학적 성질이 개선된 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민의 납실레이트 염을 제공하는 것을 목적으로 한다.The present invention relates to N- (3-ethynylphenyl) -6,7-bis (2) having improved physicochemical properties such as solubility, which is an important property for solid thermal stability and drug efficacy, which should be secured for formulation into tablets and capsules. It is an object to provide a lead silate salt of -methoxyethoxy) -4-quinazolinamine.
본 발명은,The present invention,
(1) 하기 화학식 1로 표현되는 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 납실레이트 염;(1) N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine leadylate salt represented by the following formula (1);
화학식 1Formula 1
(2) 상기 (1)에 있어서, 결정형인 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 납실레이트 염;(2) The N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine leadylate salt according to (1) above;
(3) 상기 (2)에 있어서, 하기 표 1에 나타난 바와 같은 2-세타(O)에서 나타 나는 특징적 피크를 갖는 X-선 분말 회절 패턴에 의해 특징지어지는 결정형 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 납실레이트 염; 및(3) The crystalline N- (3-ethynylphenyl described above in (2), characterized by an X-ray powder diffraction pattern having a characteristic peak represented by 2-theta ( O ) as shown in Table 1 below. ) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine leadylate salt; And
(4) 상기 (2)에 있어서, 하기 도 1에 나타난 바와 같은 X-선 분말 회절 패턴에 의해 특징지어지는 결정형 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 납실레이트 염의 4가지 양태를 특징으로 한다.(4) In the above (2), the crystalline N- (3-ethynylphenyl) -6,7-bis (2-methoxy) characterized by the X-ray powder diffraction pattern as shown in Fig. 1 below. Four embodiments of a methoxy) -4-quinazolinamine leadylate salt are featured.
본 발명에 따른 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 납실레이트 염은 시판되고 있는 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민의 히드로클로라이드 염을 비롯한 공지의 염 및 그 결정형 화합물들에 비하여 열에 대한 안정성이 우수하여 정제 및 캅셀제로 개발하기 용이하다. 특히 공지의 염들에 비해 용해도가 매우 우수하고 산도의 변화에 따른 용해도 측정에서 0.56 mg/ml의 용해도를 나타내어 오메프라졸과 같이 위액의 산도에 변화를 주는 약물과도 함께 복용이 가능하다. 따라서 본 발명은 암과 같은 과증식성 질환을 치료하는 데 유용한 경구용 API (active pharmaceutical ingredient) 로서 유용하게 사용될 수 있다.N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine leadylate salt according to the present invention is commercially available N- (3-ethynylphenyl)- Compared with known salts and their crystalline compounds, including hydrochloride salts of 6,7-bis (2-methoxyethoxy) -4-quinazolinamine, they have excellent heat stability and are easy to develop into tablets and capsules. In particular, the solubility is very excellent compared to known salts, and the solubility of 0.56 mg / ml is measured in the solubility measurement according to the change in acidity, so that it can be taken with drugs that change the acidity of gastric juice such as omeprazole. Therefore, the present invention can be usefully used as an oral active pharmaceutical ingredient (API) useful for treating hyperproliferative diseases such as cancer.
본 발명은 하기 화학식 1로 표현되는 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 납실레이트 염에 관한 것이다.The present invention relates to an N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine leadylate salt represented by the following formula (1).
화학식 1Formula 1
상기 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 납실레이트 염의 제조방법은 다음 단계를 포함한다.The method for preparing the N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine leadsilate salt includes the following steps.
1) N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민을 비극성 혹은 극성용매에 용해시키는 단계;1) dissolving N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine in a nonpolar or polar solvent;
2) 나프탈렌-2-설폰산을 유기용매에 용해시킨 후 상기 단계 1)에서 제조한 반응액에 첨가하여 혼합물을 제조하는 단계; 및 2) dissolving naphthalene-2-sulfonic acid in an organic solvent and then adding to the reaction solution prepared in step 1) to prepare a mixture; And
3) 상기 단계 2)에서 제조한 혼합물을 교반하여 얻은 고체를 여과, 세척 및 건조시켜 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 납실레이트를 형성하는 단계.3) The solid obtained by stirring the mixture prepared in step 2) was filtered, washed and dried to obtain N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazoline Forming an amine leadsilate.
상기 방법 중 단계 2)에 있어서, 나프탈렌-2-설폰산을 유기용매에 용해시킨 용액에 단계 1)에서 제조한 반응액을 첨가하여 혼합물을 제조할 수 있다.In step 2) of the above method, a mixture may be prepared by adding the reaction solution prepared in step 1) to a solution in which naphthalene-2-sulfonic acid is dissolved in an organic solvent.
상기 방법 중 단계 1)에서 사용 가능한 비극성 또는 극성 용매는 톨루엔, 디클로로메탄, 헵탄, 에틸 아세테이트, 이소프로필 아세테이트, 테트라히드로퓨란, 메탄올, 에탄올, 이소프로판올, N-메틸피롤리딘, 디메틸포름아미드, 디메틸아세트아미드, 디메틸술폭사이드 등이고, 단계 2)에서 사용 가능한 유기용매는 메탄올, 에탄올, 이소프로판올, N-메틸피롤리딘, 디메틸포름아미드, 디메틸아세트아미드, 디메틸술폭사이드 등이다.Non-polar or polar solvents usable in step 1) of the method are toluene, dichloromethane, heptane, ethyl acetate, isopropyl acetate, tetrahydrofuran, methanol, ethanol, isopropanol, N-methylpyrrolidine, dimethylformamide, dimethyl Acetamide, dimethyl sulfoxide and the like, and the organic solvents usable in step 2) are methanol, ethanol, isopropanol, N-methylpyrrolidine, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like.
또한, 상기 방법 중 단계 2)에서, 나프탈렌-2-설폰산은 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 화합물 1몰당량에 대하여 0.1 내지 5.0몰당량으로 반응시키는 것이 바람직하고, 반응 온도는 10 내지 100℃가 바람직하며, 단계 3)에서, 최종 생성물인 염 석출 온도는 -10 내지 50 ℃가 바람직하다.In addition, in step 2) of the method, naphthalene-2-sulfonic acid is added to 1 molar equivalent of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine compound. The reaction temperature is preferably 0.1 to 5.0 molar equivalents, the reaction temperature is preferably 10 to 100 ° C, and in step 3), the salt precipitation temperature as the final product is preferably -10 to 50 ° C.
이하, 본 발명을 실시예에서 보다 상세히 설명한다. 그러나, 본 발명의 범위가 하기 실시예에 의하여 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail in the Examples. However, the scope of the present invention is not limited by the following examples.
실시예 1. N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 납실레이트 염의 제조Example 1 Preparation of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine leadylate salt
N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 8 g (20 mmol)을 메탄올 160 mL에 용해하고 반응액을 55~65℃로 가열했다. 나프탈렌-2-설폰산 4.23 g(20 mmol)을 메탄올 80 mL에 용해시킨 후 상기 반응액에 서서히 첨가 하였다. 이 혼합물을 2시간 동안 환류한 후 실온에서 2시간 동안 교반하였다. 생성된 고체를 여과하고 메탄올 16 mL로 세척한 후 건조시켜 흰색 또는 옅은 노란색 결정의 표제 화합물 7.9 g을 얻었다. 상기 결정은 약 169℃에서 용융되었다 (시차주사 열량계로 측정).8 g (20 mmol) of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine was dissolved in 160 mL of methanol and the reaction solution was heated to 55-65 ° C. Heated. 4.23 g (20 mmol) of naphthalene-2-sulfonic acid was dissolved in 80 mL of methanol and slowly added to the reaction solution. The mixture was refluxed for 2 hours and then stirred at room temperature for 2 hours. The resulting solid was filtered, washed with 16 mL of methanol and dried to give 7.9 g of the title compound as white or pale yellow crystals. The crystals melted at about 169 ° C. (measured with a differential scanning calorimeter).
1H-NMR (400MHz, DMSO-d6)δ(ppm) : 10.9(br, 1H), 8.12(s, 1H), 8.03(s, 1H), 7.86-7.94(m, 2H), 7.80-7.84(m, 2H), 7.67-7.70(m, 2H), 7.47-7.51(m, 3H), 7.40(d, 1H), 7.25(s, 1H), 4.28-4.32(m, 4H), 4.26(s, 1H), 3.73-3.77(m, 4H), 3.32(s, 6H) 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 10.9 (br, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.86-7.94 (m, 2H), 7.80-7.84 (m, 2H), 7.67-7.70 (m, 2H), 7.47-7.51 (m, 3H), 7.40 (d, 1H), 7.25 (s, 1H), 4.28-4.32 (m, 4H), 4.26 (s , 1H), 3.73-3.77 (m, 4H), 3.32 (s, 6H)
실시예 2. N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 납실레이트염의 필름 코팅정의 제조Example 2 Preparation of Film-Coated Tablets of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine leadsilate salt
하기 성분을 함유한 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 납실레이트염의 필름 코팅정을 WO 04/072049 에 개시된 종래의 방법으로 제조할 수 있다:Film-coated tablets of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine leadylate salt containing the following components have been described in the prior art disclosed in WO 04/072049 Can be manufactured with:
활성 성분을 체로 거르고 미세결정질 셀룰로오스와 혼합한 다음, 혼합물을 폴리비닐피롤리돈 수용액과 함께 과립화하였다. 상기 과립을 소듐 전분 글리콜레이트 및 마그네슘 스테아레이트과 혼합 및 압축하여 각각 120 또는 350 mg 의 핵을 수득하였다. 상기 핵에 상기 필름 코팅용 수용액/현탁액을 입혔다. The active ingredient was sieved and mixed with microcrystalline cellulose, and then the mixture was granulated with an aqueous polyvinylpyrrolidone solution. The granules were mixed and compressed with sodium starch glycolate and magnesium stearate to yield nuclei of 120 or 350 mg, respectively. The nucleus was coated with the aqueous solution / suspension for film coating.
비교예 1. N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 말레이트 염의 제조Comparative Example 1. Preparation of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine maleate salt
N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 10 g (25 mmol) 을 메탄올 150 mL에 용해하고 반응액을 55~65℃로 가열했다. 말산 3.41 g(25 mmol)을 메탄올 100 mL에 용해시킨 후 상기 반응액에 서서히 첨가 하였다. 이 혼합물을 2시간 동안 환류한 후 실온에서 2시간 동안 교반하였다. 생성된 고체를 여과하고 메탄올 20 mL로 세척한 후 건조시켜 흰색 또는 옅은 노란색 결정의 표제 화합물 9.1 g을 얻었다. 상기 결정은 약 141℃에서 용융되었다 (시차주사 열량계로 측정). 10 g (25 mmol) of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine was dissolved in 150 mL of methanol and the reaction solution was heated to 55-65 ° C. Heated. 3.41 g (25 mmol) of malic acid was dissolved in 100 mL of methanol and slowly added to the reaction solution. The mixture was refluxed for 2 hours and then stirred at room temperature for 2 hours. The resulting solid was filtered, washed with 20 mL of methanol and dried to give 9.1 g of the title compound as white or pale yellow crystals. The crystals melted at about 141 ° C. (measured with a differential scanning calorimeter).
1H-NMR (400MHz, DMSO-d6)δ(ppm) : 9.45(s, 1H), 8.48(s, 1H), 7.96(s, 1H), 7.84-7.88(m ,2H), 7.38(t, 1H), 7.18-7.21(m, 2H), 4.28-4.32(m, 4H), 4.22-4.25(t, 0.5H), 4.26(s, 1H), 3.73-3.77(m, 4H), 3.32(s, 6H), 2.30-2.61(m, 1H) 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 9.45 (s, 1H), 8.48 (s, 1H), 7.96 (s, 1H), 7.84-7.88 (m, 2H), 7.38 (t , 1H), 7.18-7.21 (m, 2H), 4.28-4.32 (m, 4H), 4.22-4.25 (t, 0.5H), 4.26 (s, 1H), 3.73-3.77 (m, 4H), 3.32 ( s, 6H), 2.30-2.61 (m, 1H)
비교예 2. N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 히퓨레이트 염의 제조Comparative Example 2. Preparation of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine hyperate salt
N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 10 g (25 mmol)을 메탄올 150 mL에 용해하고 반응액을 55~65℃로 가열했다. 히퓨릭산 4.55 g(25 mmol)을 메탄올 100 mL에 용해시킨 후 상기 반응액에 서서히 첨가 하였다. 이 혼합물을 2시간 동안 환류한 후 실온에서 2시간 동안 교반하였다. 생성된 고체를 여과하고 메탄올 20 mL로 세척한 후 건조시켜 흰색 또는 옅은 노란색 결정의 표제 화합물 11 g을 얻었다. 상기 결정은 약 168℃에서 용융되었다 (시차주사 열량계로 측정). 10 g (25 mmol) of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine was dissolved in 150 mL of methanol, and the reaction solution was heated to 55-65 ° C. Heated. 4.55 g (25 mmol) of hyplic acid was dissolved in 100 mL of methanol and slowly added to the reaction solution. The mixture was refluxed for 2 hours and then stirred at room temperature for 2 hours. The resulting solid was filtered, washed with 20 mL of methanol and dried to give 11 g of the title compound as white or pale yellow crystals. The crystals melted at about 168 ° C. (measured with a differential scanning calorimeter).
1H-NMR (400MHz, DMSO-d6)δ(ppm) : 9.45(s, 1H), 8.80(m, 1H), 8.48(s, 1H), 7.97(s, 1H), 7.83-7.88(m ,4H), 7.36-7.54(m, 4H), 7.20(t, 2H), 4.28-4.32(m, 4H), 4.26(s, 1H), 3.89(d, 2H), 3.73-3.77(m, 4H), 3.32(s, 6H) 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 9.45 (s, 1H), 8.80 (m, 1H), 8.48 (s, 1H), 7.97 (s, 1H), 7.83-7.88 (m , 4H), 7.36-7.54 (m, 4H), 7.20 (t, 2H), 4.28-4.32 (m, 4H), 4.26 (s, 1H), 3.89 (d, 2H), 3.73-3.77 (m, 4H ), 3.32 (s, 6H)
비교예 3. N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 캠실레이트 염의 제조Comparative Example 3. Preparation of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine camsylate salt
N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 10 g (25 mmol)을 메탄올 150 mL에 용해하고 반응액을 55~65℃로 가열했다. (1S)-(+)-10-캠포술폰산 5.90 g(25 mmol)을 메탄올 100 mL에 용해시킨 후 상기 반응액에 서서히 첨가 하였다. 이 혼합물을 2시간 동안 환류교반한 후 실온에서 2시간 동안 교반하였다. 생성된 고체를 여과하고 메탄올 20 mL로 세척한 후 건조시켜 흰색 또는 옅은 노란색 결정의 표제 화합물 9.8 g을 얻었다. 상기 결정은 약 183℃에서 용융되었다(시차주사 열량계로 측정). 10 g (25 mmol) of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine was dissolved in 150 mL of methanol, and the reaction solution was heated to 55-65 ° C. Heated. 5.90 g (25 mmol) of (1S)-(+)-10-camphorsulfonic acid was dissolved in 100 mL of methanol and slowly added to the reaction solution. The mixture was stirred at reflux for 2 hours and then stirred at room temperature for 2 hours. The resulting solid was filtered, washed with 20 mL of methanol and dried to give 9.8 g of the title compound as white or pale yellow crystals. The crystals melted at about 183 ° C. (measured with a differential scanning calorimeter).
1H-NMR (400MHz, DMSO-d6)δ(ppm) : 9.45(s, 1H), 8.48(s, 1H), 7.96(s, 1H), 7.84-7.88(m ,2H), 7.38(t, 1H), 7.18-7.21(m, 2H), 4.25-4.28(m, 4H), 4.16(s, 1H), 3.71-3.77(m, 4H), 3.48-3.70(m, 2H), 3.33(s, 6H), 1.99(m, 1H), 1.89-2.14 (m, 2H), 1.35-1.60(m, 4H), 1.11(s, 6H) 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 9.45 (s, 1H), 8.48 (s, 1H), 7.96 (s, 1H), 7.84-7.88 (m, 2H), 7.38 (t , 1H), 7.18-7.21 (m, 2H), 4.25-4.28 (m, 4H), 4.16 (s, 1H), 3.71-3.77 (m, 4H), 3.48-3.70 (m, 2H), 3.33 (s , 6H), 1.99 (m, 1H), 1.89-2.14 (m, 2H), 1.35-1.60 (m, 4H), 1.11 (s, 6H)
상기 실시예 1 및 비교예 1 내지 3에서 제조된 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민의 염의 X-선 분말 회절 패턴은 하기 표 1 내지 4에 나타난 바와 같다.X-ray powder diffraction pattern of salts of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine prepared in Example 1 and Comparative Examples 1 to 3 above Is as shown in Tables 1 to 4 below.
[표 1]TABLE 1
N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 납실레이트N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine leadylate
음극: 구리-파장 = 1.54059Å (Cu/K-alpha1)Cathode: Copper-Wave = 1.54059Å (Cu / K-alpha1)
범위# 1-Coupled: 3.0 to 40 StepSize : 0.02 Steptime : 0.6Range # 1-Coupled: 3.0 to 40 StepSize: 0.02 Steptime: 0.6
Threshold: 3.0, Cutoff = 5.0%Threshold: 3.0, Cutoff = 5.0%
[표 2]TABLE 2
N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 말레이트N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine maleate
음극: 구리-파장 = 1.54059Å (Cu/K-alpha1)Cathode: Copper-Wave = 1.54059Å (Cu / K-alpha1)
범위# 1-Coupled: 3.0 to 40 StepSize : 0.02 Steptime : 0.6Range # 1-Coupled: 3.0 to 40 StepSize: 0.02 Steptime: 0.6
Threshold: 3.0, Cutoff = 5.0%Threshold: 3.0, Cutoff = 5.0%
[표 3][Table 3]
N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 히퓨레이트N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine hypurate
음극: 구리-파장 = 1.54059Å (Cu/K-alpha1)Cathode: Copper-Wave = 1.54059Å (Cu / K-alpha1)
범위# 1-Coupled: 3.0 to 40 StepSize : 0.02 Steptime : 0.6Range # 1-Coupled: 3.0 to 40 StepSize: 0.02 Steptime: 0.6
Threshold: 3.0, Cutoff = 5.0%Threshold: 3.0, Cutoff = 5.0%
[표 4][Table 4]
N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 켐실레이트N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine chemlate
음극: 구리-파장 = 1.54059Å (Cu/K-alpha1)Cathode: Copper-Wave = 1.54059Å (Cu / K-alpha1)
범위# 1-Coupled: 3.0 to 40 StepSize : 0.02 Steptime : 0.6Range # 1-Coupled: 3.0 to 40 StepSize: 0.02 Steptime: 0.6
Threshold: 3.0, Cutoff = 5.0%Threshold: 3.0, Cutoff = 5.0%
하기 시험예에 있어서, N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 히드로클로라이드의 결정질 동질다상체 A와 B는 WO 01/34574에 개시된 방법에 따라 수득하였고, 동질다상체 E는 WO 04/072049에 개시된 방법에 따라 수득하였으며, 메실레이트 무수물 및 수화물 형태는 WO 99/55683에 기술된 방법에 따라 수득하여 X-선 분말회절 패턴 및 융점이 알려진 것과 같음을 확인하고 사용하였다.In the following test examples, crystalline polymorphs A and B of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine hydrochloride were prepared according to WO 01/34574. Obtained according to the method disclosed in, polymorph E was obtained according to the method disclosed in WO 04/072049, and mesylate anhydride and hydrate forms were obtained according to the method described in WO 99/55683 to obtain an X-ray powder diffraction pattern. And the melting point was found to be known and used.
시험예 1. 고체 열안정성 시험Test Example 1 Solid Thermal Stability Test
고체의 우수한 열안정성은 정제 및 캅셀제에 매우 중요하다. 열안정성을 평 가하기 위해 실시예 및 비교예에서 수득한 염들을 60℃에서 밀폐상태로 보관하여 방치한 후 시간별로 순도를 측정하여 변화를 비교하였으며 그 결과를 표 5에 나타내었다. Good thermal stability of solids is very important for tablets and capsules. In order to evaluate the thermal stability, the salts obtained in Examples and Comparative Examples were stored in a sealed state at 60 ° C. and left to stand, and the change was measured by time to compare the changes. The results are shown in Table 5 below.
<분석조건><Analysis Condition>
검출기: 자외부흡광광도계 (230 nm)Detector: ultraviolet absorbance photometer (230 nm)
컬럼: ODS (5 μm, 4.6×150 mm, C18)Column: ODS (5 μm, 4.6 × 150 mm, C18)
이동상: 물 1000 ml 에 2 ml Et3N을 첨가하고 이용액의 pH를 인산을 천천히 첨가하며 9로 조정하였다. 이 용액을 아세토나이트릴과 6:4 (v/v) 비율로 혼합하여 사용하였다.Mobile phase: 2 ml Et 3 N was added to 1000 ml of water and the pH of the solution was adjusted to 9 with slowly adding phosphoric acid. This solution was used after mixing with acetonitrile in a 6: 4 (v / v) ratio.
유속: 1.0 ml/minFlow rate: 1.0 ml / min
[표 5]TABLE 5
그 결과 실시예 1의 납실레이트 염은 열에 대한 가장 우수한 안정성을 나타내었다. 메실레이트 염의 경우 열에 대한 안정성이 특히 좋지 않은 것으로 확인되 었다. As a result, the lead silate salt of Example 1 showed the best stability against heat. The mesylate salt was found to be particularly poor in heat stability.
시험예 2. 용해도 시험Test Example 2 Solubility Test
시판되고 있는 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 히드로클로라이드 염은 PPI (Proton Pump Inhibitor) 약물, 즉 오메프라졸 과 같은 약물과 동시 복용시 그 용해도가 급격히 감소하여 흡수율이 약 46% 감소하므로 함께 복용할 수 없는 것으로 되어있다. 따라서, 수득한 염들을 25℃에서 문헌상에 보고 되어진 Omeprazole 복용 전 위액의 평균 pH 조건인 pH 2.0 완충용액과 Omeprazole 복용 후 위액의 평균 pH 조건인 pH 4.6 완충용액으로 40분간의 평형 후 각각 측정하여 그 결과를 표 6에 나타내었다. Commercially available N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine hydrochloride salts can be combined with PPI (Proton Pump Inhibitor) drugs, namely drugs such as omeprazole. When taken at the same time, the solubility is drastically reduced and the absorption rate is reduced by about 46%. Therefore, the obtained salts were measured after equilibration with pH 2.0 buffer, the average pH condition of gastric juice before taking Omeprazole, and pH 4.6 buffer, the average pH condition of gastric juice after taking Omeprazole. The results are shown in Table 6.
<분석조건><Analysis Condition>
각 5 ml 유리용기에 pH 2, pH 4.6 용액 3 ml를 넣고 과량 (약 100 mg)의 시료를 넣어 과포화 시켰다. 이 액을 25℃, 200 rpm 조건으로 40분 동안 인큐베이터 안에서 Shaking한 후 여과 한다. 여액을 50% 아세토니트릴로 약 20배로 희석하여 HPLC 조건으로 분석하고 peak 면적을 미리 준비된 농도에 따른 자외부 흡광도 검량곡선에 대입하여 구하였다.3 ml of pH 2, pH 4.6 solution was added to each 5 ml glass container, and an excess (about 100 mg) of sample was supersaturated. The solution is shaken in an incubator at 25 ° C. and 200 rpm for 40 minutes and then filtered. The filtrate was diluted by about 20-fold with 50% acetonitrile and analyzed under HPLC conditions, and the peak area was determined by substituting the ultraviolet absorbance calibration curve according to the prepared concentration.
[표 6]TABLE 6
그 결과, 실시예 1의 납실레이트 염의 시료는 상기의 pH 조건에서 모두 히드로클로라이트 염들의 최대 용해도 수준 이상으로 그 용해도가 나타났으며, 특히 pH 4.6 조건에서 그 용해도가 0.56 mg/ml로 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 히드로클로라이드 염의 경우 pH 2에서 그 흡수에 문제가 없었던 0.4 mg/ml 이상의 수준인 것으로 확인되었다. As a result, all samples of the lead sillate salt of Example 1 exhibited solubility above the maximum solubility level of hydrochlorite salts at all of the above pH conditions, and especially at pH 4.6, solubility was 0.56 mg / ml. It was found that the (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine hydrochloride salt was at a level of 0.4 mg / ml or higher which had no problem in its absorption at pH 2. .
도 1은 실시예 1에서 제조한 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 납실레이트 염의 X-선 분말 회절패턴을 도시하고 있다.1 shows the X-ray powder diffraction pattern of the N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine leadylate salt prepared in Example 1 have.
도 2는 비교예 1에서 제조한 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 말레이트 염의 X-선 분말 회절패턴을 도시하고 있다.FIG. 2 shows the X-ray powder diffraction pattern of the N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine maleate salt prepared in Comparative Example 1 have.
도 3은 비교예 2에서 제조한 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 히퓨레이트 염의 X-선 분말 회절패턴을 도시하고 있다.FIG. 3 shows an X-ray powder diffraction pattern of the N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine hypohydrate salt prepared in Comparative Example 2 have.
도 4는 비교예 3에서 제조한 N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민 켐실레이트염의 X-선 분말 회절패턴을 도시하고 있다.FIG. 4 shows the X-ray powder diffraction pattern of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine chemsylate salt prepared in Comparative Example 3 have.
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