TW201908320A - Crystalline form of btk kinase inhibitor and a preparation method thereof - Google Patents
Crystalline form of btk kinase inhibitor and a preparation method thereofInfo
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Abstract
Description
本發明涉及一種BTK激酶抑制劑的結晶形式及製備方法，具體地涉及(R)-1-(1-丙烯醯哌啶-3-基)-4-胺基-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氫-7H-吡咯并[2,3-d]噠嗪-7-酮的II型結晶及製備方法。根據本發明的方法製備獲得的式(I)化合物可用於B細胞惡性腫瘤和自身免疫疾病的治療。 The present invention relates to a crystalline form of BTK kinase inhibitor and a preparation method thereof, in particular, to (R)-1-(1-propenylpiperidin-3-yl)-4-amino-3-(4-(2, Form II crystal of 6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one and preparation method thereof. The compounds of formula (I) prepared according to the methods of the invention are useful in the treatment of B cell malignancies and autoimmune diseases.
Bruton酪胺酸蛋白激酶(BTK)是一個非受體胞質酪胺酸激酶，屬於Tec家族激酶，其中Tec家族激酶成員還包括Tec、Itk、Txk和Bmx，這些激酶大多數都主要表達於造血細胞。BTK對於B細胞發育，分化，成熟和信號是至關重要的。BTK的功能喪失性突變在人體中引起X連鎖丙球蛋白缺乏血症(XLA)，在小鼠中引起與X相關的免疫缺陷。XLA患者在他們的骨髓中具有正常的前B細胞群，但這些細胞無法成熟並進入循環。因此，這些患者基本上也沒有循環的B細胞，並且不能產生抗體。BTK在由B細胞受體(BCR)介導的B細胞增殖和活化中起著關鍵性的作 用。對於BCR活化，BTK易位到質膜，質膜被磷酸化，隨後啟動信號事件包括啟動磷脂酶Cγ2(PLCγ2)，最終導致鈣動員和涉及核因子κB的轉錄調控。因為在BCR信號通路中不可缺少的作用，BTK的激酶活性對於各種B細胞惡性腫瘤的發育和修護是關鍵性的，包括慢性淋巴細胞白血病(CLL)和一些非霍奇金淋巴瘤的(關鍵非霍奇金淋巴瘤)的亞型，套細胞淋巴瘤(MCL)，和彌漫性大B細胞淋巴瘤(DLBCL)。此外，B細胞在類風濕關節炎，系統性紅斑狼瘡，多發性硬化症，以及其他免疫疾病的發病機理中的作用已被臨床證實。因此，靶向小分子抑制劑BTK在B細胞惡性腫瘤和自身免疫疾病的治療過程中有好處。 Bruton tyrosine protein kinase (BTK) is a non-receptor cytoplasmic tyrosine kinase belonging to the Tec family of kinases. Tec family kinase members also include Tec, Itk, Txk and Bmx. Most of these kinases are mainly expressed in hematopoiesis. cell. BTK is critical for B cell development, differentiation, maturation and signaling. The loss-of-function mutation of BTK causes X-linked agammaglobulin deficiency (XLA) in humans, causing X-related immunodeficiency in mice. XLA patients have a normal pre-B cell population in their bone marrow, but these cells are unable to mature and enter the circulation. Therefore, these patients have essentially no circulating B cells and are unable to produce antibodies. BTK plays a key role in B cell proliferation and activation mediated by B cell receptors (BCR). For BCR activation, BTK translocates to the plasma membrane, and the plasma membrane is phosphorylated. Subsequent initiation of signaling events involves the initiation of phospholipase Cγ2 (PLCγ2), which ultimately leads to calcium mobilization and transcriptional regulation involving nuclear factor kappa B. Because of its indispensable role in the BCR signaling pathway, BTK kinase activity is critical for the development and repair of various B-cell malignancies, including chronic lymphocytic leukemia (CLL) and some non-Hodgkin's lymphomas. Subtypes of non-Hodgkin's lymphoma, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). In addition, the role of B cells in the pathogenesis of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and other immune diseases has been clinically confirmed. Therefore, targeting the small molecule inhibitor BTK is beneficial in the treatment of B cell malignancies and autoimmune diseases.
WO2016/007185涉及一種式(I)化合物，即(R)-1-(1-丙烯醯哌啶-3-基)-4-胺基-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氫-7H-吡咯并[2,3-d]噠嗪-7-酮，該化合物為新型BTK激酶抑制劑，在激酶選擇性，臨床療效或適應症及安全性等方面均有所改善。但該專利中未對該化合物的結晶形式進行任何研究。 WO2016/007185 relates to a compound of formula (I), ie (R)-1-(1-propenylpiperidin-3-yl)-4-amino-3-(4-(2,6-difluorophenoxy) Phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one, a novel BTK kinase inhibitor in kinase selectivity, clinical efficacy or indication And safety and other aspects have been improved. However, no studies have been conducted on the crystalline form of the compound in this patent.
CN106939002A公开了一種式(I)化合物的無定形物和I晶型，但上述無定形物和I晶型均存在穩定性不佳的問題，因此，改善上述產物的各方面性質是很有必要的，需要找到其更好的晶型。 CN106939002A discloses an amorphous form and a crystalline form I of the compound of the formula (I), but both the above amorphous form and the crystalline form I have problems of poor stability, and therefore, it is necessary to improve various aspects of the above products. Need to find a better crystal form.
本發明提供了(R)-1-(1-丙烯醯哌啶-3-基)-4-胺基-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氫-7H-吡咯并[2,3-d]噠嗪-7-酮(如式(I)所示)的II型結晶及製備方法，
式(I)所示化合物在不同結晶條件下得到的一系列結晶產物，對所得結晶產物進行了X-衍射及DSC檢測，發現式(I)所示化合物在常規的結晶條件下，可以得到一種穩定性良好的晶型，我們稱其為II型結晶。本申請中的II型結晶的DSC圖譜顯示在165℃附近有熔融吸熱峰，使用Cu-Ka輻射，得到以2θ角度和晶面間距(d值)表示的X-射線粉末衍射圖譜，其衍射角2θ角在4.64、5.18、5.62、11.43、12.21和20.47處有特徵峰，其中，每個特徵峰2θ角的誤差範圍為±0.2。 A series of crystalline products obtained by the compound of the formula (I) under different crystallization conditions, the obtained crystalline product was subjected to X-ray diffraction and DSC detection, and it was found that the compound of the formula (I) can be obtained under the conventional crystallization conditions. A crystal form with good stability, we call it type II crystal. The DSC pattern of the type II crystal in the present application shows a melting endothermic peak near 165 ° C, and an X-ray powder diffraction pattern expressed by a 2θ angle and a crystal plane spacing (d value) is obtained using Cu-Ka radiation, and the diffraction angle thereof is obtained. The 2θ angle has characteristic peaks at 4.64, 5.18, 5.62, 11.43, 12.21, and 20.47, wherein the error range of the 2θ angle of each characteristic peak is ±0.2.
進一步地，該結晶使用Cu-Ka輻射，得到以衍射角2θ角度表示的X-射線粉末衍射圖譜，其衍射角2θ角在4.64、5.18、5.62、11.13、11.43、12.21、12.87、14.03、19.60、20.47和24.16處有特徵峰，其中，每個特徵峰2θ角的誤差範圍為±0.2。 Further, the crystallization uses Cu-Ka radiation to obtain an X-ray powder diffraction pattern expressed by a diffraction angle 2θ angle, and the diffraction angle 2θ angles are 4.64, 5.18, 5.62, 11.13, 11.43, 12.21, 12.87, 14.03, 19.60, There are characteristic peaks at 20.47 and 24.16, where the error angle of the 2θ angle of each characteristic peak is ±0.2.
進一步地，該結晶的X-射線粉末衍射圖譜如第3圖所示，其衍射角2θ角在4.64(19.04)、5.18(17.05)、5.62(15.71)、8.11(10.89)、8.99(9.83)、10.34(8.55)、11.13(7.94)、11.43(7.74)、12.21(7.24)、12.87(6.87)、14.03(6.31)、14.47(6.12)、14.86(5.96)、15.63(5.66)、16.07(5.51)、16.49(5.37)、17.78(4.98)、18.40(4.82)、19.60(4.53)、20.47(4.34)、21.31(4.17)、24.16(3.68)、25.13(3.54)、26.87(3.32)和28.50(3.13)處有特徵峰，其中，每個特徵峰2θ角的誤差範圍為±0.2。 Further, the X-ray powder diffraction pattern of the crystal is as shown in Fig. 3, and the diffraction angle 2θ angles are 4.64 (19.04), 5.18 (17.05), 5.62 (15.71), 8.11 (10.89), 8.99 (9.83), 10.34 (8.55), 11.13 (7.94), 11.43 (7.74), 12.21 (7.24), 12.87 (6.87), 14.03 (6.31), 14.47 (6.12), 14.86 (5.96), 15.63 (5.66), 16.07 (5.51), 16.49 (5.37), 17.78 (4.98), 18.40 (4.82), 19.60 (4.53), 20.47 (4.34), 21.31 (4.17), 24.16 (3.68), 25.13 (3.54), 26.87 (3.32) and 28.50 (3.13) There are characteristic peaks in which the error range of the 2θ angle of each characteristic peak is ±0.2.
本發明還提供了製備(R)-1-(1-丙烯醯哌啶-3-基)-4-胺基-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氫-7H-吡咯并[2,3-d]噠嗪-7-酮的II型結晶的方法。該方法包括如下步驟： The invention also provides the preparation of (R)-1-(1-propenylpiperidin-3-yl)-4-amino-3-(4-(2,6-difluorophenoxy)phenyl)- A method of crystallizing Form II of 1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one. The method comprises the following steps:
(1)將任意晶型或無定型的式(I)所示化合物溶解於適量的有機溶劑中，或將任意晶型或無定型的式(I)所示化合物在有機溶劑中轉晶，冷卻、析晶，該有機溶劑為乙腈。 (1) dissolving any of the crystalline or amorphous compounds of the formula (I) in an appropriate amount of an organic solvent, or crystallizing any of the crystalline or amorphous compounds of the formula (I) in an organic solvent, cooling And crystallization, the organic solvent is acetonitrile.
(2)過濾結晶並洗滌，乾燥。 (2) The crystals were filtered, washed, and dried.
再結晶的方法没有特别限定，可以用通常的再結晶操作方法進行。例如，可以用原料式(I)所示化合物在有機溶 劑加熱溶解後慢慢冷卻析晶，結晶完成後，經過濾乾燥，即可得到所需要的結晶。需特别说明的是，所濾取的結晶體通常在減壓下，在30~100℃左右，較佳在40~60℃加熱條件下進行真空乾燥，就能達到去除再結晶溶劑的效果。 The method of recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method. For example, the compound represented by the starting material (I) can be slowly cooled and crystallized by heating in an organic solvent, and after completion of crystallization, it can be dried by filtration to obtain a desired crystal. It should be particularly noted that the crystals to be filtered are usually vacuum-dried under reduced pressure at a temperature of about 30 to 100 ° C, preferably 40 to 60 ° C, to achieve the effect of removing the recrystallization solvent.
藉由差示掃描熱分析(DSC)、X-衍射圖譜测定，對得到的式(I)所示化合物結晶體進行了晶型研究，同時對所得結晶的溶劑殘留進行了檢測。 The crystal form of the obtained compound of the formula (I) was subjected to a crystal form study by differential scanning calorimetry (DSC) and X-ray diffraction pattern measurement, and the solvent residue of the obtained crystal was examined.
按照本發明的方法製備的式(I)所示化合物II型結晶不含有或僅含有較低含量的殘留溶劑，符合國家藥典規定的有關醫藥產品殘留溶劑的限量要求，因而本發明的結晶可以較好地作為醫藥活性成分使用。 The compound of the formula II type represented by the formula (I) prepared according to the method of the present invention does not contain or contains only a low content of residual solvent, and meets the requirements of the national pharmacopoeia for the residual solvent of the pharmaceutical product, so that the crystal of the present invention can be compared. It is used as a pharmaceutical active ingredient.
經研究表明，本發明製備的式(I)所示化合物的II型結晶在光照、高溫、高濕的條件下穩定性良好，且在研磨、壓力和受熱等條件下，晶型穩定性良好，能夠滿足生產運輸儲存的藥用要求，生產工藝穩定可重複可控，能夠適應於工業化生產。 Studies have shown that the type II crystal of the compound of the formula (I) prepared by the present invention has good stability under the conditions of illumination, high temperature and high humidity, and the crystal form stability is good under the conditions of grinding, pressure and heat. It can meet the medicinal requirements of production, transportation and storage. The production process is stable and repeatable and controllable, and can be adapted to industrial production.
第1圖為式(I)所示化合物無定型樣品的X-射線粉末衍射圖譜。 Figure 1 is an X-ray powder diffraction pattern of an amorphous sample of the compound of formula (I).
第2圖為式(I)所示化合物無定型樣品的DSC圖譜。 Figure 2 is a DSC chart of an amorphous sample of the compound of formula (I).
第3圖為式(I)所示化合物II型結晶的X-射線粉末衍射圖譜。 Figure 3 is an X-ray powder diffraction pattern of the compound II type crystal represented by the formula (I).
第4圖為式(I)所示化合物II型結晶的DSC圖譜。 Fig. 4 is a DSC chart of the compound II type crystal represented by the formula (I).
第5圖為式(I)所示化合物I型結晶的X-射線粉末衍射圖譜。 Figure 5 is an X-ray powder diffraction pattern of the compound type I crystal of the formula (I).
第6圖為式(I)所示化合物I型結晶的DSC圖譜。 Figure 6 is a DSC chart of the crystalline form I of the compound of formula (I).
第7圖為式(I)所示化合物I型結晶的DVS圖。 Fig. 7 is a DVS chart of the compound I type crystal represented by the formula (I).
第8圖為式(I)所示化合物II型結晶的DVS圖。 Fig. 8 is a DVS chart of the compound II type crystal represented by the formula (I).
以下將結合實施例更詳細地解釋本發明，本發明的實施例僅用於說明本發明的技術方案，並非限定本發明的實質和範圍。 The invention is explained in more detail below with reference to the embodiments, which are intended to illustrate the technical scope of the invention and not to limit the scope and scope of the invention.
實驗所用的測試儀器 Test instrument used in the experiment
1、DSC譜 1, DSC spectrum
儀器型號：Mettler Toledo DSC 1 STARe System Instrument model: Mettler Toledo DSC 1 STAR e System
吹掃氣：氮氣 Purge gas: nitrogen
升溫速率：10.0℃/min Heating rate: 10.0 ° C / min
溫度範圍：40-250℃ Temperature range: 40-250 ° C
2、X-射線衍射譜 2. X-ray diffraction spectrum
儀器型號：Bruker D8 Focus X-射線粉末衍射儀 Instrument model: Bruker D8 Focus X-ray powder diffractometer
射線：單色Cu-Kα射線(λ=1.5406) Ray: Monochrome Cu-Kα ray (λ=1.5406)
掃描方式：θ/2θ，掃描範圍：2-40° Scanning mode: θ/2θ, scanning range: 2-40°
電壓：40kV，電流：40mA Voltage: 40kV, current: 40mA
實施例1 Example 1
取5g式(I)所示化合物(按WO2016/007185中公開的方法製備)於100ml單口瓶中，加入50ml乙腈，加熱至固體全部溶解，降溫析晶，攪拌過夜。次日，抽濾，乾燥得固 體4.03g，收率為80.6%。該結晶樣品的X-射線衍射見第3圖，其中在約4.64(19.04)、5.18(17.05)、5.62(15.71)、8.11(10.89)、8.99(9.83)、10.34(8.55)、11.13(7.94)、11.43(7.74)、12.21(7.24)、12.87(6.87)、14.03(6.31)、14.47(6.12)、14.86(5.96)、15.63(5.66)、16.07(5.51)、16.49(5.37)、17.78(4.98)、18.40(4.82)、19.60(4.53)、20.47(4.34)、21.31(4.17)、24.16(3.68)、25.13(3.54)、26.87(3.32)和28.50(3.13)處有特徵峰。DSC譜圖見第4圖，在165℃附近有熔融吸熱峰，將此晶型定義為II晶型。 5 g of the compound of the formula (I) (prepared according to the method disclosed in WO2016/007185) was placed in a 100 ml single-mouth bottle, 50 ml of acetonitrile was added, and the mixture was heated until the solid was completely dissolved, and the crystal was cooled and stirred overnight. The next day, it was suction filtered and dried to give a solid (4.03 g). The X-ray diffraction of the crystal sample is shown in Fig. 3, which is about 4.64 (19.04), 5.18 (17.05), 5.62 (15.71), 8.11 (10.89), 8.99 (9.83), 10.34 (8.55), and 11.13 (7.94). 11.43 (7.74), 12.21 (7.24), 12.87 (6.87), 14.03 (6.31), 14.47 (6.12), 14.86 (5.96), 15.63 (5.66), 16.07 (5.51), 16.49 (5.37), 17.78 (4.98) Characteristic peaks at 18.40 (4.82), 19.60 (4.53), 20.47 (4.34), 21.31 (4.17), 24.16 (3.68), 25.13 (3.54), 26.87 (3.32), and 28.50 (3.13). The DSC spectrum is shown in Fig. 4, and there is a melting endothermic peak near 165 ° C, and this crystal form is defined as the II crystal form.
實施例3 Example 3
取300mg式(I)所示化合物(按WO2016/007185中公開的方法製備)於25ml單口瓶中，加入2ml乙醇，加熱溶解，降溫析晶，攪拌過夜。次日，抽濾，乾燥得固體241mg，收率為80.3%。該結晶樣品的X-射線衍射見第5圖，其中在約4.29(20.56)、6.58(13.42)、7.58(11.66)、10.07(8.78)、10.72(8.24)、11.68(7.57)、12.49(7.08)、13.74(6.44)、14.12(6.26)、15.86(5.58)和19.98(4.44)處有特徵峰。DSC譜圖見第6圖，在141℃附近有熔融吸熱峰，將此晶型定義為I晶型。 300 mg of the compound of the formula (I) (prepared according to the method disclosed in WO2016/007185) was placed in a 25 ml single-mouth bottle, 2 ml of ethanol was added, dissolved by heating, crystallized by cooling, and stirred overnight. The next day, suction filtration and drying gave a solid 241 mg in a yield of 80.3%. The X-ray diffraction of the crystal sample is shown in Fig. 5, where about 4.29 (20.56), 6.58 (13.42), 7.58 (11.66), 10.07 (8.78), 10.72 (8.24), 11.68 (7.57), 12.49 (7.08). Characteristic peaks are found at 13.74 (6.44), 14.12 (6.26), 15.86 (5.58), and 19.98 (4.44). The DSC spectrum is shown in Fig. 6. There is a melting endothermic peak near 141 ° C, and this crystal form is defined as the I crystal form.
實施例4 Example 4
取200mg式(I)所示化合物(按實施例2製備)，加入2ml乙腈，攪拌過夜。次日，抽濾，乾燥得固體172mg，收率為86.0%。該結晶樣品的X-射線衍射和DSC圖譜經研究比對，確定產物為II晶型。 200 mg of the compound of the formula (I) (prepared as in Example 2) was taken, 2 ml of acetonitrile was added and stirred overnight. The next day, suction filtration and drying gave a solid 172 mg, yield: 86.0%. The X-ray diffraction and DSC spectra of the crystalline sample were compared by study to confirm that the product was Form II.
實施例5 Example 5
將實施例1所得的II型結晶產物樣品和實施例3所得的I型結晶產物樣品敞口平攤放置，考察在光照(4500Lux)，加熱(40℃，60℃)，高濕(RH75%，RH90%)條件下樣品的穩定性。考察取樣時間為5天和10天，HPLC檢測純度見表1。 The sample of the type II crystalline product obtained in Example 1 and the sample of the type I crystalline product obtained in Example 3 were placed in an open position, and examined under illumination (4,500 Lux), heated (40 ° C, 60 ° C), and high humidity (RH 75%, Stability of the sample under RH90%) conditions. The sampling time was 5 days and 10 days, and the purity of HPLC was shown in Table 1.
穩定性考察結果表明式(I)所示化合物I型結晶和II型結晶樣品分別在敞口的條件下放置，光照、高溫條件下，II型結晶的穩定性好於I型結晶樣品，高濕條件下兩者相當。 The stability investigation results show that the compound type I crystal and type II crystal sample of formula (I) are placed under open conditions respectively. Under light and high temperature conditions, the stability of type II crystal is better than that of type I crystal sample, high humidity. The two are equivalent under the conditions.
實施例6 Example 6
將按實施例1方法制得的式(I)所示化合物II型結晶進行研磨、加熱及壓片處理，研究結果表明晶型穩定，詳細的實驗資料參見下表2。 The compound II type crystal represented by the formula (I) obtained by the method of Example 1 was subjected to grinding, heating and tableting treatment, and the results showed that the crystal form was stable. For detailed experimental data, see Table 2 below.
實施例7 Example 7
將實施例1所得的II型結晶產物樣品和實施例2所得的I型結晶產物樣品在25℃，不同濕度下進行DVS試驗，研究結果表明，I晶型引濕性較大，RH為0%~80%時，增重4.18%，在正常儲存條件下(即25℃，RH60%)下吸水約3.26%，II晶型有引濕性，RH為0%~80%時，增重1.18%，在正常儲存條件下(即25℃，RH60%)下吸水約0.93%，詳細的實驗資料參見第7圖及第8圖。 The sample of the type II crystalline product obtained in Example 1 and the sample of the type I crystalline product obtained in Example 2 were subjected to a DVS test at 25 ° C and different humidity. The results of the study showed that the wettability of the I form was large, and the RH was 0%. At ~80%, the weight gain is 4.18%. Under normal storage conditions (ie 25 °C, RH60%), the water absorption is about 3.26%. The II crystal form has the hygroscopicity. When the RH is 0%~80%, the weight gain is 1.18%. Under normal storage conditions (ie 25 ° C, RH 60%) water absorption of about 0.93%, detailed experimental data see Figure 7 and Figure 8.
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