TW202328132A - HEMI-FUMARATE CRYSTALS OF PI3Kδ/γ DUAL INHIBITOR COMPOUND AND PREPARATION METHOD THEREOF - Google Patents
HEMI-FUMARATE CRYSTALS OF PI3Kδ/γ DUAL INHIBITOR COMPOUND AND PREPARATION METHOD THEREOF Download PDFInfo
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Abstract
Description
本發明涉及藥物領域,具體的涉及一種PI3Kδ/γ雙重抑制劑化合物(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮化合物的富馬酸鹽結晶及其製備方法。 The present invention relates to the field of medicine, in particular to a PI3Kδ/γ dual inhibitor compound (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)- Fumarate crystals of 4H-chromen-4-one compounds and methods for their preparation.
本發明要求於2021年12月31日提交到中國國家智慧財產權局的發明名稱為“PI3Kδ/γ雙重抑制劑化合物的半富馬酸鹽結晶及其製備方法”的中國專利申請202111679233.5,以及於2022年3月11日提交到中國國家智慧財產權局的發明名稱為“PI3Kδ/γ雙重抑制劑化合物的半富馬酸鹽結晶及其製備方法”的中國專利申請202210245006.X的優先權,上述發明內容均通過引用以整體併入本文。 The present invention requires the Chinese patent application 202111679233.5 submitted to the China National Intellectual Property Office on December 31, 2021, with the title of "PI3Kδ/γ dual inhibitor compound hemifumarate crystallization and its preparation method", and in 2022 The priority of the Chinese patent application 202210245006.X with the title of "PI3Kδ/γ dual inhibitor compound hemifumarate crystallization and its preparation method" submitted to the China National Intellectual Property Office on March 11, 202210245006.X, the content of the above invention Both are incorporated herein by reference in their entirety.
磷酸肌醇-3激酶(PI3K)屬於一類細胞內脂質激酶,所述激酶磷酸化磷酸肌醇脂質(PI)的肌醇環的3位羥基,從而產生脂質第二信使。已有技術報導,磷酸肌醇-3-激酶(PI3K)途徑的靶向抑制劑可以作為免疫調節劑。 Phosphoinositide-3 kinases (PI3Ks) belong to a class of intracellular lipid kinases that phosphorylate the 3-hydroxyl of the inositol ring of phosphoinositide lipids (PI), thereby generating lipid second messengers. It has been reported in the art that targeted inhibitors of the phosphoinositide-3-kinase (PI3K) pathway can be used as immunomodulators.
大規模生產藥物化合物的一個主要問題是活性物質應具有穩定的結晶多晶型物以確保一致的加工參數和藥物品質。如果使用不穩定的結晶形式,則在製造和/或儲存期間晶體多晶型物可能 會改變,導致品質控制問題和製劑不規則性。這種變化可能會影響製造方法的可重複性,導致最終製劑不符合施加在藥物組合物配製上的高品質和嚴格要求。就這一點而言,應該大體注意到,可以改善其物理和化學穩定性的藥物組合物的固態的任何改變賦予相對於相同藥物的不太穩定形式的顯著優點。此外,開發始終生產活性物質的穩定生產方法至關重要。存在具有相近溶解度的多種結晶形式,在大規模製造藥物化合物方面造成了艱難挑戰。 A major issue in the large-scale production of pharmaceutical compounds is that the active substance should have stable crystalline polymorphs to ensure consistent processing parameters and drug quality. If an unstable crystalline form is used, the crystalline polymorph may can change, leading to quality control issues and formulation irregularities. Such variations may affect the reproducibility of the manufacturing process, resulting in a final formulation that does not meet the high quality and stringent requirements imposed on the formulation of pharmaceutical compositions. In this regard, it should generally be noted that any modification of the solid state of a pharmaceutical composition that improves its physical and chemical stability confers significant advantages over less stable forms of the same drug. Furthermore, it is crucial to develop stable production methods that consistently produce active substances. The existence of multiple crystalline forms with similar solubility poses a difficult challenge in the large-scale manufacture of pharmaceutical compounds.
當化合物從溶液或漿液中結晶時,它可以以不同的空間晶格排列結晶,這種性質被稱為“多晶型”。每種晶體形式稱為“多晶型物”。雖然給定物質的多晶型物具有相同的化學組成,但它們可以在一種或多種物理性質如溶解度、解離度、真密度、溶出、熔點、晶體形狀、壓實行為、流動性質和/或固態穩定性方面彼此不同。 When a compound crystallizes from a solution or slurry, it can crystallize in different spatial lattice arrangements, a property known as "polymorphism." Each crystal form is called a "polymorph". Although polymorphs of a given substance have the same chemical composition, they can vary in one or more physical properties such as solubility, dissociation, true density, dissolution, melting point, crystal shape, compaction behavior, flow properties, and/or solid state. Stability aspects differ from each other.
一般如上所述,藥物的多晶型行為在藥理學中可能是非常重要的。多晶型物所顯示的物理性質的差異影響實際參數,如儲存穩定性、可壓縮性和密度(在配製和產品製造中很重要)以及溶出速率(決定生物利用度的重要因素)。化學反應性的變化(例如,差異氧化,使得當劑型是一種多晶型物時比劑型是另一種多晶型物時更快地變色)、機械變化(例如,片劑在儲存後隨著動力學有利的多晶型物轉化成熱力學更穩定的多晶型物而粉碎)或兩者(例如,一種多晶型物的片劑在高濕度下更容易分解)可能導致穩定性的差異。另外,晶體的物理性質在加工中可能是重要的。例如,一種多晶型物可能更可能形成溶劑合物,導致固體形式聚集並增加固體處理的難度。或者,一種多晶型物相對於另一種多晶型物的顆粒形狀和尺寸分佈可能不同,導致在過濾藥物活性物質以除去雜質時增加的挑戰。 As generally stated above, polymorphic behavior of drugs can be of great importance in pharmacology. Differences in physical properties exhibited by polymorphs affect practical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing) and dissolution rate (an important factor in determining bioavailability). Changes in chemical reactivity (e.g., differential oxidation such that discoloration occurs more rapidly when the dosage form is one polymorph than when the dosage form is another polymorph), mechanical changes (e.g., tablet changes with kinetic energy after storage) Differences in stability may result from the conversion of the chemically favorable polymorph to the thermodynamically more stable polymorph) or both (e.g., a tablet of one polymorph disintegrates more readily at high humidity). Additionally, the physical properties of the crystals may be important in processing. For example, one polymorph may be more likely to form solvates, causing aggregation of the solid form and making solid handling more difficult. Alternatively, the particle shape and size distribution of one polymorph relative to another may differ, leading to increased challenges in filtering pharmaceutical actives to remove impurities.
儘管期望具有改善的化學和物理性質的藥物製劑,但是沒有可預測的手段來製備用於此類製劑的現有分子的新藥物形式 (例如,多晶型物和其它新的結晶形式)。這些新形式將在製造和組成使用中常見的一系列環境中提供物理性質的一致性。 Although pharmaceutical formulations with improved chemical and physical properties are desired, there is no predictable means to prepare new drug forms of existing molecules for such formulations (eg, polymorphs and other novel crystalline forms). These new forms will provide consistency in physical properties across a range of environments common in fabrication and compositional use.
WO2014195888A1專利文獻公開了(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮化合物,其結構式為式I,作為遊離鹼顯示出具有PI3Kδ/γ雙重抑制功能。 WO2014195888A1 patent document discloses (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one compound, its structure The formula is formula I, and as a free base, it shows dual inhibitory functions of PI3Kδ/γ.
但是,仍迫切地希望研發出與(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮相比,在物理性質和/或藥效/藥代動力學發麵具有更優異性質、作為醫藥品的適用性高的PI3Kδ/γ雙重抑制劑。 However, it is still urgently desired to develop a combination with (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one Compared with PI3Kδ/γ dual inhibitors that have superior properties in terms of physical properties and/or pharmacodynamics/pharmacokinetics, and have high applicability as pharmaceuticals.
本發明提供了一種(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮化合物的富馬酸鹽的結晶形式1,其特徵在於,所述的結晶形式在X射線衍射圖上顯示3.30°,6.60°,22.70°,28.92°,12.08°,27.58°,11.70°,20.28°,19.44°,23.54°,29.454°,24.22°,16.10°(±0.2°)的衍射角2θ處的峰。
The present invention provides a fumarate of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one compound A
進一步地,所述的結晶形式1還包括在15.66°,14.54°,12.98°,24.92°,25.28°,13.32°,9.82°,18.96°,23.54°,29.45°,10.80°,17.18°,35.85°,21.43°(±0.2°)的衍射角2θ處的峰。
Further, the
進一步地,所述的結晶形式1顯示基本如圖5所示的X射線衍射圖。
Further, said
除此之外,本發明還提供了一種結晶形式1的製備方法,其特徵在於包括以下步驟:
In addition, the present invention also provides a preparation method of
步驟(1):稱取一定品質的(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮遊離鹼化合物,加入至一定體積的異丙醇溶劑中,得到混懸液1;
Step (1): Weigh a certain quality of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4- A ketone free base compound is added to a certain volume of isopropanol solvent to obtain a
步驟(2):稱取一定品質的富馬酸配體,超聲加熱溶於一定體積的異丙醇和水的混合溶液中,得到溶液1;
Step (2): Weigh a fumaric acid ligand of a certain quality, heat it ultrasonically and dissolve it in a mixed solution of a certain volume of isopropanol and water to obtain a
步驟(3):將步驟(2)所得到的溶液1滴加至由步驟(1)所得的攪拌中的混懸液1中,得到混懸液2;
Step (3): adding the
步驟(4):將步驟(3)所得到的混懸液2攪拌後立即溶清,向溶液中加入一定體積的抗溶劑,在低溫下攪拌過夜析出固體,得到混懸液3;
Step (4): Dissolve the
步驟(5):將步驟4所得到的混懸液3離心,所得固體在室溫下真空乾燥,得到所述的結晶形式1。
Step (5): The suspension 3 obtained in Step 4 was centrifuged, and the obtained solid was vacuum-dried at room temperature to obtain the
在本發明的優選技術方案中,其中,所述的步驟(1)中所述遊離鹼化合物與步驟(2)中所述的富馬酸配體的莫耳比為1:1-1.5。 In a preferred technical solution of the present invention, wherein, the molar ratio of the free base compound in the step (1) to the fumaric acid ligand in the step (2) is 1:1-1.5.
在本發明的優選技術方案中,其中,所述的步驟(1)中游離鹼化合物與異丙醇的莫耳體積比為:1mol:0.1-1L。 In the preferred technical solution of the present invention, wherein, the molar volume ratio of the free base compound to isopropanol in the step (1) is: 1mol: 0.1-1L.
在本發明的優選技術方案中,其中,所述的步驟(2)異丙醇與水的體積比為1:0.4-1。 In the preferred technical solution of the present invention, wherein the volume ratio of the step (2) isopropanol to water is 1:0.4-1.
在本發明的優選技術方案中,其中,所述的步驟(4)中的抗溶劑選自正庚烷。 In the preferred technical solution of the present invention, wherein, the anti-solvent in the step (4) is selected from n-heptane.
除此之外,本發明還提供了一種(S)-2-(1-(9H-嘌呤-6-基
氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮化合物的半富馬酸鹽的結晶形式1,其特徵在於,所述的結晶形式在X射線衍射圖上顯示3.26°,9.64°,21.67°,22.46°,26.75°,16.00°(±0.2°)的衍射角2θ處的峰。
In addition, the present invention also provides a (S)-2-(1-(9H-purin-6-yl
Amino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one compound,
進一步地,所述的半富馬酸鹽結晶形式1還包括在11.96°,27.53°,13.86°,10.10°,10.50°,14.30°,12.80°,10.98°,18.44°,17.54°,22.17°,17.86°,20.90°,14.90°,24.71°(±0.2°)的衍射角2θ處的峰。
Further, the hemifumarate salt
進一步地,所述的半富馬酸鹽結晶形式1顯示基本如圖11所示的X射線衍射圖。
Further, the
除此之外,半本發明還提供了一種(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮化合物的半富馬酸鹽的結晶形式1的製備方法,其特徵在於包括以下步驟:
In addition, the present invention also provides a kind of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene- A process for the preparation of the
步驟(1):稱取一定品質的(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮遊離鹼化合物,加入到一定體積的乙腈中攪拌,得到混懸液1;
Step (1): Weigh a certain quality of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4- The ketone free base compound is added to a certain volume of acetonitrile and stirred to obtain a
步驟(2):稱取一定品質的富馬酸配體超聲加熱溶於一定體積的乙腈和水的混合溶液中,得到溶液1;
Step (2): Weighing a certain quality of fumaric acid ligand and ultrasonically heating and dissolving it in a certain volume of acetonitrile and water mixed solution to obtain
步驟(3):將步驟(2)所得到的溶液1滴加至攪拌中的步驟(1)所得到的混懸液1中,得到混懸液2;
Step (3): adding the
步驟(4):混懸液2攪拌後先溶清,然後析出固體,室溫攪拌,得到混懸液3;
Step (4): After the
步驟(5):將混懸液3進行固液分離所得固體在室溫下真空乾燥,得到所述的半富馬酸鹽結晶形式1。
Step (5): Suspension 3 was subjected to solid-liquid separation and the resulting solid was vacuum-dried at room temperature to obtain the
在本發明的優選技術方案中,其中,步驟(1)中的遊離鹼化合物與步驟(2)中的富馬酸配體的莫耳比為1:1.5,優選為1:1.1。 In the preferred technical solution of the present invention, wherein, the molar ratio of the free base compound in step (1) to the fumaric acid ligand in step (2) is 1:1.5, preferably 1:1.1.
在本發明的優選技術方案中,其中,步驟(2)中的乙腈與水的體積比為2:1。 In the preferred technical solution of the present invention, wherein, the volume ratio of acetonitrile and water in step (2) is 2:1.
在本發明的優選技術方案中,其中,步驟(1)中的乙腈與步驟(2)中的乙腈的體積比為5:1。 In the preferred technical solution of the present invention, wherein, the volume ratio of the acetonitrile in the step (1) to the acetonitrile in the step (2) is 5:1.
除此之外,本發明還提供了一種(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮化合物的半富馬酸鹽的結晶形式2,其特徵在於,所述的結晶形式在X射線衍射圖上顯示3.36°,6.92°,22.91°,19.65°,16.37°,18.98°,9.13°,27.52°,6.37°,26.32°,25.18°,11.64°,9.84°,10.92°,15.80°,20.26°,24.13°,20.98°,27.77°,12.12°(±0.2°)的衍射角2θ處的峰。
In addition, the present invention also provides a kind of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4 -
進一步地,所述的半富馬酸鹽的結晶形式2還包括在22.532°,12.67°,24.45°,22.03°,17.75°,17.52°,23.61°,29.08°,13.12°,13.74°,17.18°(±0.2°)的衍射角2θ處的峰。
Further, the
進一步地,所述的半富馬酸鹽的結晶形式2顯示基本如圖17所示的X射線衍射圖。
Further, the
除此之外,本發明還提供了一種(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮半富馬酸鹽的結晶形式2的製備方法,其特徵在於,包括以下步驟:
In addition, the present invention also provides a kind of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4 -The preparation method of the
步驟(1):稱取一定品質的(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮遊離鹼化合物,加入一定體積的異丙醇,得到混懸液1;
Step (1): Weigh a certain quality of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4- A ketone free base compound, adding a certain volume of isopropanol to obtain a
步驟(2):稱取一定品質的富馬酸配體超聲加熱溶於一定體積異丙醇和水的混合溶液中,得到溶液1;
Step (2): Weighing a certain quality of fumaric acid ligand and ultrasonically heating and dissolving it in a mixed solution of a certain volume of isopropanol and water to obtain
步驟(3):將步驟(2)得到的溶液1滴加至攪拌中的步驟(1)所得到的混懸液1中,得到混懸液2;
Step (3): adding the
步驟(4):將步驟(3)所得到的混懸液2攪拌後立即溶清,室溫攪拌未析出固體,經室溫小孔揮發一天后瓶壁上析出少量透明晶體,加無孔蓋,室溫攪拌析出白色固體,繼續攪拌,得到混懸液3;
Step (4): Dissolve the
步驟(5):將混懸液3減壓抽濾,用水輕輕沖洗濾餅表面,所
得固體在室溫下真空乾燥,得到所述的半富馬酸鹽結晶形式2。
Step (5): The suspension 3 is filtered under reduced pressure, and the surface of the filter cake is gently rinsed with water.
The resulting solid was dried under vacuum at room temperature to obtain the
在本發明的上述優選技術方案中,其中,步驟(1)中的遊離鹼化合物與步驟(2)中的富馬酸配體的莫耳比為1:1-1.5,優選為1:1.1。 In the above preferred technical solution of the present invention, wherein, the molar ratio of the free base compound in step (1) to the fumaric acid ligand in step (2) is 1:1-1.5, preferably 1:1.1.
在本發明的上述優選技術方案中,其中,步驟(2)中的異丙醇與水的體積比為3:2。 In the preferred technical solution of the present invention, wherein the volume ratio of isopropanol to water in step (2) is 3:2.
在本發明的上述優選技術方案中,其中,步驟(1)中的異丙醇與步驟(2)中的異丙醇的體積比為5:3。 In the above-mentioned preferred technical solution of the present invention, wherein, the volume ratio of the isopropanol in the step (1) to the isopropanol in the step (2) is 5:3.
除此之外,本發明還提供了一種藥物組合物,其包含上述的富馬酸鹽結晶形式1、半富馬酸鹽結晶形式1或者半富馬酸鹽結晶形式2中的任意一種或其組合,以及藥學上可接受的載體。
In addition, the present invention also provides a pharmaceutical composition, which comprises any one of the above-mentioned fumarate
除此之外,本發明還提供了一種抑制磷酸肌醇-3激酶(PI3K)的方法,包括使本發明的(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮化合物的富馬酸鹽的結晶形式1、半富馬酸鹽結晶形式1或者半富馬酸鹽結晶形式2中的任意一種或其組合暴露於磷酸肌醇-3激酶,優選地,所述的PI3K選自PI3Kδ/γ。
In addition, the present invention also provides a method for inhibiting phosphoinositide-3 kinase (PI3K), comprising making (S)-2-(1-(9H-purin-6-ylamino)propyl of the present invention )-3-(3-fluorophenyl)-4H-chromen-4-one compound in
本發明的(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮化合物的富馬酸鹽的結晶具有良好的結晶度,略具有引濕性,晶型製備可控,並且表現出優異的藥代動力學,可以作為PI3K δ/γ抑制劑。 Fumarate of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one compound of the present invention The crystals have good crystallinity, slightly hygroscopicity, controllable crystal form preparation, and exhibit excellent pharmacokinetics, and can be used as PI3K δ/γ inhibitors.
圖式1 游離鹼化合物的XRPD圖譜
圖式2 游離鹼化合物的TGA圖譜
圖式3 游離鹼化合物的DSC圖譜 Scheme 3 DSC spectrum of free base compound
圖式4 游離鹼化合物的1HNMR圖譜 Scheme 4 1 HNMR spectrum of free base compound
圖式5 富馬酸鹽Form 1的XRPD圖譜
圖式6 富馬酸鹽Form 1的TGA圖譜
Scheme 6 TGA spectrum of
圖式7 富馬酸鹽Form 1的DSC圖譜
圖式8 富馬酸鹽Form 1的DVS圖譜
Scheme 8 DVS spectrum of
圖式9 富馬酸鹽Form 1的PLM圖譜
Scheme 9 PLM spectrum of
圖式10 半富馬酸鹽Form 1的1HNMR圖譜
圖式11 半富馬酸鹽Form 1的XRPD圖譜
圖式12 半富馬酸鹽Form 1的TGA圖譜
Scheme 12 TGA spectrum of
圖式13 半富馬酸鹽Form 1的DSC圖譜
Scheme 13 DSC spectrum of
圖式14 半富馬酸鹽Form 1的DVS圖譜
Scheme 14 DVS spectrum of
圖式15 半富馬酸鹽Form 1的PLM圖譜
圖式16 半富馬酸鹽Form 1的1HNMR圖譜
圖式17 半富馬酸鹽Form 2的XRPD圖譜
Scheme 17 XRPD pattern of
圖式18 半富馬酸鹽Form 2的TGA圖譜
Scheme 18 TGA spectrum of
圖式19 半富馬酸鹽Form 2的DSC圖譜
Scheme 19 DSC spectrum of
圖式20 半富馬酸鹽Form 2的DVS圖譜
圖式21 半富馬酸鹽Form 2的PLM圖譜
Scheme 21 PLM spectrum of
圖式22 半富馬酸鹽Form 2的1HNMR圖譜
Scheme 22 1 HNMR spectrum of
X射線粉末衍射儀(X-Ray Powder Diffractometer,XRPD) X-Ray Powder Diffractometer (XRPD)
利用X-粉末衍射儀對樣品進行晶型分析。樣品的2θ掃描角度為3°至40°,掃描步長為0.02°,每步的掃描時間為0.2s。光管電壓和電流分別為40kV和40mA。制樣時將適量樣品放在載樣盤上,確保樣品表面光滑平整。 The crystal form of the samples was analyzed by X-powder diffractometer. The 2θ scanning angle of the sample is from 3° to 40°, the scanning step is 0.02°, and the scanning time of each step is 0.2s. The light tube voltage and current were 40kV and 40mA, respectively. When preparing samples, place an appropriate amount of samples on the sample tray to ensure that the surface of the samples is smooth and flat.
差示掃描量熱分析(Differential scanning calorimetry,DSC) Differential scanning calorimetry (DSC)
採用TA instruments Q200 DSC對樣品進行分析。將稱量過的樣品(0.5mg-5mg)放入載樣盤中,在氮氣(50mL/min)的保護下將樣品 以10℃/min的速率升高到最終溫度。 Samples were analyzed using a TA instruments Q200 DSC. Put the weighed sample (0.5mg-5mg) into the sample tray, and put the sample under the protection of nitrogen (50mL/min). Ramp to final temperature at a rate of 10°C/min.
熱重分析(Thermogravimetric analysis,TGA) Thermogravimetric analysis (TGA)
採用TA instruments Q500對樣品進行分析。將樣品放入去掉皮重的鉑金坩堝中,系統自動稱重,然後在氮氣(40mL/min)的保護下將樣品以10℃/min的速率升高到最終溫度。 Samples were analyzed using TA instruments Q500. The sample was put into a tared platinum crucible, the system automatically weighed, and then the sample was raised to the final temperature at a rate of 10°C/min under the protection of nitrogen (40mL/min).
偏振光顯微鏡(Polarized Light Microscope,PLM) Polarized Light Microscope (PLM)
利用偏光顯微鏡對樣品進行分析,通過調節不同的放大倍數,得到晶體的形貌和微觀結構。 The samples were analyzed using a polarizing microscope, and the morphology and microstructure of the crystals were obtained by adjusting different magnifications.
動態水分吸附(Dynamic Vapour Sorption,DVS) Dynamic Vapor Sorption (DVS)
動態水分吸附採用TA Instruments Q5000 SA進行。將大約1-10mg樣品置於樣品盤中並懸掛於樣品室內。室內溫度由水浴保持在恒定的25±1℃。在step模式下,樣品在0%RH-80%RH的相對環境濕度進行迴圈測試。以10%RH/step進行分析。設置保持各濕度的時間為90min,使樣品與室內環境達到平衡。 Dynamic moisture adsorption was performed using a TA Instruments Q5000 SA. Approximately 1-10 mg of sample is placed in a sample pan and suspended from the sample chamber. The room temperature was maintained at a constant 25±1°C by a water bath. In the step mode, the sample is subjected to a cycle test at a relative humidity of 0%RH-80%RH. Analysis was performed at 10%RH/step. Set the time to maintain each humidity to 90min, so that the sample and the indoor environment can reach equilibrium.
液態核磁氫譜(1H NMR) Liquid hydrogen nuclear magnetic spectrum ( 1 H NMR)
利用Bruker Ascend 500MH對樣品進行分析,溶劑為氘代二甲基亞碸。 The samples were analyzed using Bruker Ascend 500MH, and the solvent was deuterated dimethylsulfoxide.
(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮游離鹼化合物的製備方法 Preparation method of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one free base compound
參照專利文獻CN105358560A實施例的方法製備(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮游離鹼化合物。 Prepare (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one with reference to the method of patent document CN105358560A embodiment free base compound.
(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮富馬酸鹽Form 1的製備方法
Preparation method of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one
步驟(1):稱取約200mg由實施例2.1製備得到的游離鹼化合物,加入至1mL的異丙醇中,得到混懸液1;
Step (1): Weigh about 200 mg of the free base compound prepared in Example 2.1 and add it to 1 mL of isopropanol to obtain a
步驟(2):稱取約63mg富馬酸,超聲加熱溶於0.4mL異丙醇和0.4mL水混合溶液中,得到溶液1;
Step (2): Weigh about 63 mg of fumaric acid, dissolve it in a mixed solution of 0.4 mL of isopropanol and 0.4 mL of water by ultrasonic heating, and obtain
步驟(3):將步驟(2)所得到的溶液1滴加至由步驟(1)所得的攪拌中的混懸液1中,得到混懸液2;
Step (3): adding the
步驟(4):將步驟(3)所得到的混懸液2攪拌後立即溶清,向溶液中加入16mL正庚烷,在4℃下攪拌過夜析出固體,得到混懸液3;
Step (4): Dissolve the
步驟(5):將步驟4所得到的混懸液3離心,所得固體在室溫下真空乾燥過夜,得到約198mg產物。 Step (5): The suspension 3 obtained in Step 4 was centrifuged, and the obtained solid was vacuum-dried at room temperature overnight to obtain about 198 mg of the product.
對產物進行表徵,其XRPD譜圖如圖式5所示,TGA和DSC圖譜分別如圖式6和圖式7所示,DVS如圖式8所示,PLM如圖式9所示,1HNMR如圖式10所示。
The product is characterized, its XRPD spectrum is shown in
(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮半富馬酸鹽晶型1的製備
(S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one
方法一: method one:
步驟(1):稱取約200mg由實施例2.1製備得到的游離鹼化合物加入4mL乙腈攪拌,得到混懸液1;
Step (1): Weigh about 200 mg of the free base compound prepared in Example 2.1, add 4 mL of acetonitrile and stir to obtain
步驟(2):約63mg富馬酸超聲加熱溶於0.8mL乙腈和0.4mL水的混合溶液中,得到溶液1;
Step (2): About 63 mg of fumaric acid was heated and dissolved in a mixed solution of 0.8 mL of acetonitrile and 0.4 mL of water to obtain
步驟(3):將溶液1滴加至攪拌中的混懸液1中,得到混懸液2;
Step (3): adding
步驟(4):混懸液2攪拌後先溶清,然後析出固體,室溫攪拌過夜,得到混懸液3;
Step (4): After the
步驟(5):將混懸液3離心,所得固體在室溫下真空乾燥過夜,得到約119mg半富馬酸鹽Form 1;
Step (5): The suspension 3 was centrifuged, and the obtained solid was vacuum-dried at room temperature overnight to obtain about 119 mg of
方法二: Method Two:
步驟(1):稱取約200mg由實施例2.1製備得到的游離鹼化合物,加入2mL乙腈攪拌,得到混懸液1;
Step (1): Weigh about 200 mg of the free base compound prepared in Example 2.1, add 2 mL of acetonitrile and stir to obtain
步驟(2):約64mg富馬酸超聲加熱溶於0.8mL乙腈和0.4mL
水的混合溶液中,得到溶液1;
Step (2): about 64mg of fumaric acid was dissolved in 0.8mL of acetonitrile and 0.4mL of
In the mixed solution of water,
步驟(3):將溶液1滴加至攪拌中的混懸液1中,得到混懸液2;
Step (3): adding
步驟(4):混懸液2攪拌後先溶清,然後析出固體,室溫攪拌3天,得到混懸液3;
Step (4): After the
步驟(5):將混懸液3減壓抽濾,用水沖洗濾餅表面,所得固體在室溫下真空乾燥過夜,得到約210mg半富馬酸鹽Form 1。
Step (5): The suspension 3 was suction filtered under reduced pressure, the surface of the filter cake was washed with water, and the obtained solid was vacuum-dried at room temperature overnight to obtain about 210 mg of
對產物進行表徵,XRPD譜圖如圖式11所示,TGA和DSC圖譜分別如圖式12和圖式13所示,DVS和等溫吸附曲線如圖式14所示,PLM如圖式15所示,1HNMR如圖式16所示。
To characterize the product, the XRPD spectrum is shown in Figure 11, the TGA and DSC spectra are shown in Figure 12 and Figure 13, respectively, the DVS and isotherm adsorption curves are shown in Figure 14, and the PLM is shown in Figure 15. 1 HNMR is shown in
(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮半富馬酸鹽晶型2的製備
(S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one
方法一: method one:
步驟(1):稱取約202mg由實施例2.1製備得到的游離鹼化合物,加入1mL異丙醇,得到混懸液1;
Step (1): Weigh about 202 mg of the free base compound prepared in Example 2.1, add 1 mL of isopropanol to obtain a
步驟(2):約65mg富馬酸超聲加熱溶於0.6mL異丙醇和0.4mL水混合溶液中,得到溶液1;
Step (2): About 65 mg of fumaric acid was heated and dissolved in a mixed solution of 0.6 mL of isopropanol and 0.4 mL of water to obtain
步驟(3):將溶液1滴加至攪拌中的混懸液1中,得到混懸液2;
Step (3): adding
步驟(4):混懸液2攪拌後立即溶清,室溫攪拌過夜未析出固體,經室溫小孔揮發一天后瓶壁上析出少量透明晶體,加無孔蓋,室溫攪拌3小時析出白色固體,繼續攪拌1天,得到混懸液3;
Step (4):
步驟(5):將混懸液3減壓抽濾,用水輕輕沖洗濾餅表面,所得固體在室溫下真空乾燥過夜,得到約77mg半富馬酸鹽Form 2;
Step (5): The suspension 3 was suction filtered under reduced pressure, and the surface of the filter cake was gently rinsed with water, and the obtained solid was vacuum-dried at room temperature overnight to obtain about 77 mg of
方法二: Method Two:
步驟(1):稱取約501mg由實施例2.1製備得到的游離鹼化合物,加入2.5mL異丙醇,得到混懸液1;
Step (1): Weigh about 501 mg of the free base compound prepared in Example 2.1, and add 2.5 mL of isopropanol to obtain a
步驟(2):約156mg富馬酸超聲加熱溶於1.5mL異丙醇和1mL水混合溶液中,得到溶液1;
Step (2): About 156 mg of fumaric acid was heated and dissolved in a mixed solution of 1.5 mL of isopropanol and 1 mL of water to obtain
步驟(3):將溶液1滴加至攪拌中的混懸液1中,得到混懸液2;
Step (3): adding
步驟(4):混懸液2攪拌後立即溶清,繼續攪拌10分鐘,經室溫小孔揮發約1天,瓶口析出白色固體,加無孔蓋,室溫攪拌1小時析出白色固體,繼續攪拌2天,得到混懸液3;
Step (4):
步驟(5):將混懸液3減壓抽濾,用水輕輕沖洗濾餅表面,所得固體在室溫下真空乾燥約5天,得到約240mg半富馬酸鹽Form 2。
Step (5): The suspension 3 was suction filtered under reduced pressure, and the surface of the filter cake was gently washed with water, and the obtained solid was vacuum-dried at room temperature for about 5 days to obtain about 240 mg of
對產物進行表徵,XRPD譜圖如圖式17所示,TGA和DSC圖譜分別如圖式18和圖式19示,DVS和等溫吸附曲線如圖式20所示,PLM如圖式21所示,1HNMR如圖式22所示。 To characterize the product, the XRPD spectrum is shown in Figure 17, the TGA and DSC spectra are shown in Figure 18 and Figure 19, respectively, the DVS and isotherm adsorption curves are shown in Figure 20, and the PLM is shown in Figure 21 , 1 HNMR is shown in Scheme 22.
游離鹼以及富馬酸鹽Form 1(結晶形式1)、半富馬酸鹽Form 1(結晶形式1)、半富馬酸鹽Form 2(結晶形式2)性質比較 Free base and fumarate Form 1 (crystal form 1), hemifumarate Form 1 (crystal form 1), hemifumarate form 2 (crystal form 2) property comparison
從上表中的考察方面看,相比於富馬酸鹽Form 1,半富馬酸鹽Form 1鹽型結晶度良好;相比於半富馬酸鹽Form2,半富馬酸鹽Form1具有更低的引濕性,從而更有利於藥物的開發。
From the observations in the table above, compared to
游離鹼以及富馬酸鹽結晶形式1、半富馬酸鹽結晶形式1、半富馬酸鹽結晶形式2的藥代動力學特徵比較
Comparison of pharmacokinetic characteristics of free base and fumarate
本發明還研究了(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮游離鹼以及富馬酸鹽結晶形式1、半富馬酸鹽結晶形式1、半富馬酸鹽結晶形式2口服給予Wistar大鼠的代動力學參數的比較,游離鹼的口服給藥的每組動物為4只,各個鹽型的口服給藥的每組動物為3只,6-8周齡,雄性。口服給藥10%Cremophor EL+90%(10%HP-β-CD in 1%HPMC(pH 2.2)in water,口服給藥組動物隔夜禁食,給藥4小時後恢復進食。口服給藥組動物采血點為給藥前及後0.25,0.5,1,2,4,8和24小時。頸靜脈采血,每個采血點的采血量約150μL,EDTA-K2抗凝,採樣後15分鐘內4℃ 2000g離心5min,LCMSMS-28(Triple Quad 6500+)分析。
The present invention also studies (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one free base and rich Comparison of Kinetic Parameters of Oral Administration of
結果發現,半富馬酸鹽結晶形式1的Tmax、AUC和F%明顯高於其它兩種結晶形式;與游離鹼比較,半富馬酸鹽結晶形式1的Tmax、T1/2明顯延長,F%明顯提高。詳見下表:
It was found that the Tmax, AUC and F% of the hemifumarate
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