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Publication numberCN103288715 A
Publication typeApplication
Application numberCN 201310098602
Publication date11 Sep 2013
Filing date27 Jun 2003
Priority date27 Jun 2002
Also published asCA2492060A1, CA2492060C, CN1678305A, CN101898995A, CN101898995B, CN103254114A, CN103288714A, CN103333099A, EP1534270A2, EP1534270A4, US7268156, US7626041, US7759384, US7893100, US7902378, US20050240027, US20070238774, US20070244181, US20070244182, US20070259940, US20080262069, WO2004002419A2, WO2004002419A3
Publication number201310098602.0, CN 103288715 A, CN 103288715A, CN 201310098602, CN-A-103288715, CN103288715 A, CN103288715A, CN201310098602, CN201310098602.0
Inventors克里斯托弗.S.布鲁克, 陈伟, 菲利普.C.德尔奥科, 李.M.卡特林西克, 安.M.洛维特, 乔恩.K.奥, 保罗.G.斯波尔斯, 克里斯托弗.沃纳
Applicant史密斯克莱.比奇曼(科克)有限公司
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
Carvedilol phosphate salts and/or solvates thereof, correspondinq compositions, and/or methods of treatment
CN 103288715 A
Abstract
The present invention relates to carvedilol phosphate salts, which include novel crystalline forms of carvedilol dihydrogen phosphate (i.e., dihydrogen phosphate salt of 1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy) ethyl]amino]-2-propanol) and/or carvedilol hydrogen phosphate, etc.), and/or solvates thereof, compositions containing the aforementioned salts and/or solvates, and methods of using the aforementioned salts and/or solvates to treat hypertension, congestive heart failure and angina, etc.
Claims(19)  translated from Chinese
1.化合物,其为卡维地洛磷酸二氢盐二水合物,其具有如图9所示的在2 Θ度处有特征峰的X射线衍射图。 1. The compound as carvedilol dihydrogen phosphate dihydrate, which has shown in FIG. 9 at 2 Θ degrees characteristic peaks of X-ray diffraction pattern.
2.化合物,其为卡维地洛磷酸二氢盐二水合物,其从0 (2Θ)到35 (2Θ)在约6.50.2(2 Θ ),7.10.2(2 Θ ),13.50.2(2 Θ ),14.00.2(2 Θ ),17.80.2(2 Θ ), 18.9 0.2(2 Θ )和21.00.2(2 Θ )处有特征峰。 2. The compound as carvedilol dihydrogen phosphate dihydrate, which from 0 (2Θ) to 35 (2Θ) at about 6.5 0.2 (2 Θ), 7.1 0.2 (2 Θ), 13.5 0.2 (2 Θ), 14.0 0.2 (2 Θ), 17.8 0.2 (2 Θ), 18.9 0.2 (2 Θ) and 21.0 0.2 (2 Θ) of the characteristic peaks.
3.化合物,其为卡维地洛磷酸二氢盐二水合物,其具有如图25所示的在2 Θ度处有特征峰的X射线衍射图。 3. The compound as carvedilol dihydrogen phosphate dihydrate, which has shown in Figure 25 degrees at 2 Θ characteristic peaks of X-ray diffraction pattern.
4.化合物,其为卡维地洛磷酸二氢盐二水合物,其从0 (2Θ)到35 (2Θ)在约6.40.2(2 Θ ),9.60.2(2 Θ ),16.00.2(2 Θ ),18.40.2(2 Θ ),20.70.2(2 Θ )和24.50.2(2 Θ )处有特征峰。 4. A compound as carvedilol dihydrogen phosphate dihydrate, which from 0 (2Θ) to 35 (2Θ) at about 6.4 0.2 (2 Θ), 9.6 0.2 (2 Θ), 16.0 0.2 (2 Θ), 18.4 0.2 (2 Θ), 20.7 0.2 (2 Θ) and 24.5 0.2 (2 Θ) of the characteristic peaks.
5.化合物,其为卡维地洛磷酸二氢盐的甲醇合物,其具有如图24所示的在2 Θ度处有特征峰的X射线衍射图。 5. The compound as methanolate carvedilol dihydrogen phosphate, which has shown in Figure 24 degrees at 2 Θ characteristic peaks of X-ray diffraction pattern.
6.化合物,其为卡维地洛磷酸二氢盐的甲醇合物,其从0 (2Θ)到35 (2Θ)在约6.90.2(2 Θ ), 7.20.2(2 Θ ), 13.50.2(2 Θ ), 14.10.2(2 Θ ), 17.80.2(2 Θ )和34.00.2(2 Θ )处有特征峰。 6. The compound as methanolate carvedilol dihydrogen phosphate, which is from 0 (2Θ) to 35 (2Θ) at about 6.9 0.2 (2 Θ), 7.2 0.2 (2 Θ), 13.5 0.2 (2 Θ), 14.1 0.2 (2 Θ), 17.8 0.2 (2 Θ) and 34.0 0.2 (2 Θ) of the characteristic peaks.
7.化合物,其为卡维地洛磷酸二氢盐,其具有如图28所示的在2 Θ度处有特征峰的X 射线衍射图。 7. A compound as carvedilol dihydrogen phosphate, which has shown in Figure 28 degrees at 2 Θ characteristic peaks of X-ray diffraction pattern.
8.化合物,其为卡维地洛磷酸二氢盐,其从O (2 Θ )到35 (2 Θ )在约13.20.2(2 Θ ),15.80.2(2 Θ ),16.30.2(2 Θ ),21.20.2 (2 Θ ),23.70.2 (2 Θ )和26.00.2(2 Θ )处有特征峰。 8. A compound as carvedilol dihydrogen phosphate, which from O (2 Θ) to 35 (2 Θ) at about 13.2 0.2 (2 Θ), 15.8 0.2 (2 Θ), 16.3 0.2 (2 Θ), 21.2 0.2 (2 Θ), 23.7 0.2 (2 Θ) and 26.0 0.2 (2 Θ) of the characteristic peaks.
9.化合物,其为卡维地洛磷酸氢盐,其具有如图29所示的在2 Θ度处有特征峰的X射线衍射图。 9. A compound as carvedilol hydrogen phosphate, which has shown in Figure 29 degrees in 2 Θ characteristic peaks of X-ray diffraction pattern.
10.化合物,其为卡维地洛磷酸氢盐,其从0 (2 Θ )到35 (2 Θ )在约5.50.2 (2 Θ ),I 2.30.2(2 Θ ), 15.30.2(2 Θ ), 19.50.2(2 Θ ), 21.60.2(2 Θ )和24.90.2(2 Θ )处有特征峰。 10. A compound as carvedilol hydrogen phosphate, which from 0 (2 Θ) to 35 (2 Θ) at about 5.5 0.2 (2 Θ), I 2.3 0.2 (2 Θ), 15.3 0.2 (2 Θ), 19.5 0.2 (2 Θ), 21.6 0.2 (2 Θ) and 24.9 0.2 (2 Θ) of the characteristic peaks.
11.用于治疗高血压、充血性心力衰竭或心绞痛的权利要求1的化合物。 11. A compound of claim 1 for the treatment of hypertension, congestive heart failure or angina requirements.
12.用于治疗高血压、充血性心力衰竭或心绞痛的权利要求2-10的化合物。 12. A compound of claim 2-10 for the treatment of hypertension, congestive heart failure or angina requirements.
13.权利要求1的化合物在制备用于治疗高血压、充血性心力衰竭或心绞痛的药物中的用途。 13. A compound of claim 1 for the preparation for the treatment of hypertension, congestive heart failure or angina medicament.
14.权利要求2-10 的化合物在制备用于治疗高血压、充血性心力衰竭或心绞痛的药物中的用途。 14. The compound of claim 2-10 in the manufacture for the treatment of hypertension, congestive heart failure or angina medicament.
15.权利要求1-10中任一项的化合物,其用作药物。 A compound according to any one of claim 1-10, as a medicament.
16.药物组合物,其包含根据权利要求1-4中任一项的化合物以及药学上可接受的载 16. A pharmaceutical composition according to claim comprising a compound acceptable as well as to any pharmaceutical carrier 1-4
17.药物组合物,其包含根据权利要求5-6中任一项的化合物以及药学上可接受的载 17. A pharmaceutical composition according to claim comprising a compound acceptable as well as to any pharmaceutical carrier 5-6
18.药物组合物,其包含根据权利要求7-8中任一项的化合物以及药学上可接受的载 18. A pharmaceutical composition according to claim comprising a compound acceptable as well as to any pharmaceutical carrier 7-8
19.药物组合物,其包含根据权利要求9-10中任一项的化合物以及药学上可接受的载体。 19. A pharmaceutical composition comprising a compound according to claim and a pharmaceutically acceptable carrier according to any one of 9-10.
Description  translated from Chinese

卡维地洛磷酸盐和/或其溶剂合物相应的组合物和/或治疗方法[0001] 本申请是申请日为2003年6月27日、申请号为201010152481.X、发明名称为“卡维地洛磷酸盐和/或其溶剂合物和/或相应组合物和/或治疗方法”的发明专利申请的分案申请。 Carvedilol phosphate and / or a solvate corresponding compositions and / or treatment [0001] The present application is filed on June 27, 2003, Application No. 201010152481.X, titled "Card The divisional application carvedilol phosphate and / or a solvate and / or the corresponding compositions and / or treatment, "the patent application. [0002] 本发明涉及卡维地洛的盐和/或其相应溶剂合物,含有该盐和/或其相应溶剂合物的组合物,和/或使用上述化合物治疗在哺乳动物,尤其是人的一些疾病的方法。 [0002] The present invention relates to carvedilol salts and / or corresponding solvates, containing the salts and / or compositions corresponding solvate, and / or use of such compounds for the treatment in mammals, especially humans Some of illness. [0003] 本发明还涉及到卡维地洛磷酸盐,其中包括卡维地洛磷酸二氢盐(即例如1_(咔唑-4-基氧基-3-[[2-(邻-甲氧苯氧基)乙基]氨基]-2-丙醇)的磷酸二氢盐)、卡维地洛磷酸氢盐等的新晶形,和/或其别的相应的溶剂合物,含有该盐和/或溶剂合物的组合物,使用上述化合物治疗高血压、充血性心力衰竭和心绞痛等的方法。 [0003] The present invention also relates to carvedilol phosphate, including carvedilol dihydrogen phosphate (ie such as 1_ (carbazol-4-yl-3 - [[2- (o - methoxy phenoxy) ethyl] amino] -2-propanol) dihydrogen phosphate), carvedilol hydrogen phosphate and other new crystalline form, and / or other appropriate solvates, containing the salt and / solvate or composition, the use of the above compound of hypertension, congestive heart failure, angina and treatment methods. 背景技术[0004] 化合物,1_(咔唑-4-基氧基-3-[[2_(邻-甲氧苯氧基)乙基]氨基]-2-丙醇被称为卡维地洛(Carvedilol)。卡维地洛的化学结构式如下:[0005][0006] 卡维地洛在Wiedemann等的美国专利N0.4, 503, 067 (已转让给Boehringer Mannheim, GmbH, Mannheim-ffaldhof, Fed.Rep.0f Germany)中被公开,公开日1985 年3 月5曰。[0007] 现在,卡维地洛已有市售,并以药物中的游离碱形式合成。上述卡维地洛的游离碱形式是R(+)和S(-)对映体的外消旋混合物,其中S(-)对映体表现出非选择性β_肾上腺素受体阻滞活性,而R(+)和S(_)对映体都表现出α-肾上腺素能的阻滞活性。这些与外消旋卡维地洛混合物有关的异常的特征或特性是因为两种互补的药理作用:即混合静脉和动脉血管扩张和非心选择性β肾上腺素能阻滞。[0008] 卡维地洛用于治疗高血压、充血性心力衰竭和心绞痛。在美国现在市售的卡维地洛产品是一种常规的片剂,药物治疗的规定用量为2次/天(BID)。[0009] 卡维地洛含有α -轻基仲胺官能团,pKa值为7.8。卡维地洛于中性或碱性介质中,即PH值大于9.0时具有可预测的溶解度性质,卡维地洛的溶解度相对较低(〈I μ g/ml)。 pH值降低时,卡维地洛溶解度提高,在pH = 5附近时达到平稳值,即室温下饱和溶解度在发明领域pH = 7时约23 μ g/ml,在pH = 5时约100 μ g/ml。在pH值较低时(即不同的缓冲体系中PH值I到4),卡维地洛的溶解度受到其质子化形式和在原位形成的相应的盐的溶解度的限制。在模拟胃液的酸性介质中,在原位生成卡维地洛盐酸盐,更不溶于该介质中。[0010] 根据上述内容,具有更大的水溶性、化学稳定性等的卡维地洛的盐和/或新晶形将能发挥潜在的优势以提供含有药物卡维地洛的医药产品。这些优势包括产品通过维持沿哺乳动物(即比如人类)胃肠道的吸收,特别是维持在药物如卡维地洛溶解度最小的中性PH值区域的吸收,以获得预期或延长的全身系统药物水平。[0011] 令人吃惊的是,已有显示卡维地洛磷酸盐(即如卡维地洛磷酸二氢盐和/或卡维地洛磷酸氢盐等)的新晶形可以分离得到纯的结晶固体,较之相应的卡维地洛游离碱或其他卡维地洛制成的结晶盐,如盐酸盐,它们具有更高的水溶性。 BACKGROUND OF THE INVENTION [0004] The compound 1_ (carbazol-4-yl-3 - [[2_ (o - methoxyphenoxy) ethyl] amino] -2-propanol is known as carvedilol ( . Carvedilol) chemical structure of carvedilol as follows: [0005] [0006] Carvedilol in Wiedemann et al U.S. Patent N0.4, 503, 067 (assigned to Boehringer Mannheim, GmbH, Mannheim-ffaldhof, Fed. Rep.0f Germany) is open, public, 1985 March 5 said. [0007] Now, carvedilol are commercially available, and synthetic drugs in order to free base form above carvedilol free base in the form of R (+) and S (-) enantiomer of the racemic mixture outside, where S (-) enantiomer β_ exhibit non-selective adrenergic receptor blocking activity, and R (+) and S (_) enantiomer showed α- adrenergic blocking activity of these racemic mixture of carvedilol for exceptions related features or characteristics are due to the pharmacological effects of two complementary: namely mixed venous and arterial vasodilation and non-cardiac-selective β-adrenergic blocking. [0008] carvedilol for the treatment of hypertension, congestive heart failure and angina in the United States is now commercially available carvedilol product is a conventional tablets, prescribed amount of medication 2 times / day (BID) [0009] Carvedilol contain α -. Light based secondary amine functional group, pKa value of 7.8 carvedilol in neutral or alkaline medium. that the PH value greater than 9.0 with predictable solubility properties, carvedilol relatively low solubility (<I μ g / ml). When the pH was lowered to improve the solubility of carvedilol in the vicinity when the pH = 5 reaches a plateau value, that the saturation solubility at room temperature in the area of invention pH = 7 at about 23 μ g / ml,. PH at pH = 5 at about 100 μ g / ml at low pH values (that is, different buffer system the value of I to 4), the solubility of carvedilol by its protonated form and in situ formation of the corresponding salt of the solubility limit in simulated gastric acidic medium, generate carvedilol hydrochloride in situ more insoluble in the medium. [0010] According to the above, have greater solubility in water, chemical stability, etc. carvedilol salts and / or new crystalline form will be able to play to the potential advantages to provide medicines containing carvedilol carvedilol in pharmaceutical products. These advantages include product along by maintaining a mammal (ie, such as humans) Gastrointestinal absorption, especially in drug absorption as maintain carvedilol minimum solubility of neutral PH value of an area, to obtain the desired or prolonged systemic drug levels. [0011] Surprisingly, there are displays of carvedilol phosphate (ie, such as carvedilol dihydrogen phosphate salts and / or carvedilol hydrogen phosphate, etc.) The new crystalline form can be isolated pure crystalline solid, compared to the corresponding free base or carvedilol carvedilol other crystalline salt made, such as hydrochloride, they have higher water solubility. 该新晶形也具有提高制剂中卡维地洛稳定性的潜力,这是因为连接至卡维地洛母核结构上的仲胺官能团(对降解起关键作用的部分)经过质子化形成了盐。 The new crystalline form also has to improve the stability of the formulation of carvedilol potential, this is because the connection to the secondary amine functional group of carvedilol on the nucleus structure (degradation plays a key role in part) after protonated form a salt. [0012] 如上所述需要分别开发不同形式的卡维地洛和/或不同的组合物,其应具有更高的水溶性、化学稳定性、维持或延长的药物水平或吸收水平(即如在中性的胃肠道pH值区域中等)。 [0012] As described above were required to develop different forms of carvedilol and / or various combinations thereof, should have a higher water-solubility, chemical stability, maintain or prolong drug levels or absorption levels (ie as in neutral pH value region gastrointestinal medium). [0013] 同样也需要开发治疗高血压、充血性心力衰竭或心绞痛等的方法,包括给药上述卡维地洛磷酸盐和/或其溶剂合物或相应的含有该盐和/或溶剂合物的药物组合物。 [0013] also need to develop high blood pressure, congestive heart failure or angina treatment method comprising administering said carvedilol phosphate and / or a solvate or the corresponding salts and / or solvates containing pharmaceutical compositions. [0014] 本发明用于克服本领域中遇到的此类或其它问题。 [0014] The present invention is to overcome these and other problems encountered in this field. [0015] 发明概述[0016] 本发明涉及卡维地洛的盐和/或其相应的溶剂合物、含有该卡维地洛和/或其相应溶剂合物的组合物、和/或使用上述化合物治疗某种在哺乳动物,尤其是人中的疾病的方法。 [0015] SUMMARY [0016] The present invention relates to carvedilol salts and / or corresponding solvates, containing the carvedilol and / or compositions corresponding solvate, and / or use of such compounds in the treatment of certain mammals, particularly humans disease method. [0017] 本发明还涉及卡维地洛磷酸盐,其中包括卡维地洛磷酸盐(即如1-(咔唑-4-基氧基_3-[[2-(邻-甲氧苯氧基)乙基]氨基]-2-丙醇)的磷酸二氢盐,卡维地洛磷酸氢盐等)的新晶形,和/或其别的相应的溶剂合物。 [0017] The present invention also relates to carvedilol phosphate, including carvedilol phosphate (ie, such as 1- (carbazol-4-yloxy _3 - [[2- (o - Methoxyphenoxy The new crystalline-yl) ethyl] amino] -2-propanol) dihydrogen phosphate, carvedilol hydrogen phosphate, etc.), and / or other corresponding solvates. [0018] 本发明涉及一种药物组合物,含有卡维地洛磷酸盐和/或其溶剂合物。 [0018] The present invention relates to a pharmaceutical composition containing carvedilol phosphate and / or a solvate. [0019] 本发明还涉及一种治疗高血压、充血性心力衰竭和心绞痛的方法,包括向需要的受治者给药有效量的卡维地洛磷酸盐(其中包括新的晶形)和/或其溶剂合物或药物组合物(即其中含有卡维地洛磷酸盐和/或其溶剂合物)等。 [0019] The present invention also relates to a method of treating hypertension, congestive heart failure and angina, comprising administering to a subject in need of treatment by administering an effective amount of carvedilol phosphate (including new crystalline form) and / or solvates or pharmaceutical compositions (ie, containing carvedilol phosphate and / or a solvate) and the like. [0020] 附图简单说明[0021] 图1是卡维地洛磷酸二氢盐半水合物(I型)的X射线粉末衍射图。 [0020] BRIEF DESCRIPTION [0021] FIG. 1 is carvedilol dihydrogen phosphate hemihydrate (I type) X-ray powder diffraction pattern. [0022] 图2显示卡维地洛磷酸二氢盐半水合物(I型)的热分析结果。 [0022] Figure 2 shows carvedilol dihydrogen phosphate hemihydrate (I type) thermal analysis results. [0023] 图3是卡维地洛磷酸二氢盐半水合物(I型)的FT-拉曼光谱。 [0023] FIG. 3 is carvedilol dihydrogen phosphate hemihydrate (I type) FT- Raman spectroscopy. [0024] 图4是卡维地洛磷酸二氢盐半水合物(I型)在谱图4000-2000CHT1区域的FT-拉曼光谱。 [0024] FIG. 4 is carvedilol dihydrogen phosphate hemihydrate (I type) in the spectrum 4000-2000CHT1 area FT- Raman spectroscopy. [0025] 图5是卡维地洛磷酸二氢盐半水合物(I型)在谱图2000-400CHT1区域的FT-拉曼光谱。 [0025] FIG. 5 is carvedilol dihydrogen phosphate hemihydrate (I type) in the spectrum 2000-400CHT1 area FT- Raman spectroscopy. [0026] 图6是卡维地洛磷酸二氢盐半水合物(I型)的FT-1R光谱。 [0026] FIG. 6 is carvedilol dihydrogen phosphate hemihydrate (I type) FT-1R spectrum. [0027] 图7是卡维地洛磷酸二氢盐半水合物(I型)在谱图4000-2000CHT1区域的FT-1R光谱。 [0027] FIG. 7 is carvedilol dihydrogen phosphate hemihydrate (I type) FT-1R spectrum in the spectrum 4000-2000CHT1 region.

[0028] 图8是卡维地洛磷酸二氢盐半水合物(I型)在谱图ZOOO-SOOcnT1区域的FT-IR 光谱。 [0028] FIG. 8 is carvedilol dihydrogen phosphate hemihydrate (I type) FT-IR spectrum in the spectrum ZOOO-SOOcnT1 region.

[0029] 图9是卡维地洛磷酸二氢盐二水合物(II型)的X射线粉末衍射图。 [0029] FIG. 9 is carvedilol dihydrogen phosphate dihydrate (II type) X-ray powder diffraction pattern.

[0030] 图10显示卡维地洛磷酸二氢盐二水合物(II型)的热分析结果。 [0030] Figure 10 shows carvedilol dihydrogen phosphate dihydrate (II type) thermal analysis results.

[0031] 图11是卡维地洛磷酸二氢盐二水合物(II型)的FT-拉曼光谱。 [0031] FIG. 11 is carvedilol dihydrogen phosphate dihydrate (II type) FT- Raman spectroscopy.

[0032] 图12是卡维地洛磷酸二氢盐二水合物(II型)在谱图4000-2000CHT1区域的FT-拉曼光谱。 [0032] FIG. 12 is carvedilol dihydrogen phosphate dihydrate (II type) in the spectrum 4000-2000CHT1 area FT- Raman spectrum.

[0033] 图13是卡维地洛磷酸二氢盐二水合物(II型)在谱图2000-400CHT1区域的FT-拉 [0033] FIG. 13 is carvedilol dihydrogen phosphate dihydrate (II type) in the spectrum region FT- pull 2000-400CHT1

曼光谱。 Raman spectroscopy.

[0034] 图14是卡维地洛磷酸二氢盐二水合物(II型)的FT-IR光谱。 [0034] FIG. 14 is carvedilol dihydrogen phosphate dihydrate (II type) of FT-IR spectroscopy.

[0035] 图15是卡维地洛磷酸二氢盐二水合物(II型)在谱图4000-2000CHT1区域的FT-IR 光谱。 [0035] FIG. 15 is carvedilol dihydrogen phosphate dihydrate (II type) FT-IR spectrum in the spectrum 4000-2000CHT1 region.

[0036] 图16是卡维地洛磷酸二氢盐二水合物(II型)在谱图2000-500CHT1区域的FT-IR 光谱。 [0036] FIG. 16 is carvedilol dihydrogen phosphate dihydrate (II type) FT-IR spectrum in the spectrum 2000-500CHT1 region.

[0037] 图17显示卡维地洛磷酸二氢盐甲醇合物(III型)的热分析结果。 [0037] Figure 17 shows carvedilol dihydrogen phosphate methanol compound (III type) thermal analysis results.

[0038] 图18是卡维地洛磷酸二氢盐甲醇合物(III型)的FT-拉曼光谱。 [0038] FIG. 18 is carvedilol dihydrogen phosphate methanol compound (III type) FT- Raman spectroscopy.

[0039] 图19是卡维地洛磷酸二氢盐甲醇合物(III型)在谱图4000-2000CHT1区域的FT-拉曼光谱。 [0039] FIG. 19 is carvedilol dihydrogen phosphate methanol compound (III type) in the spectrum 4000-2000CHT1 area FT- Raman spectroscopy.

[0040] 图20是卡维地洛磷酸二氢盐甲醇合物(III型)在谱图2000-400CHT1区域的 [0040] FIG. 20 is carvedilol dihydrogen phosphate methanol compound (III type) in the spectrum 2000-400CHT1 region

FT-拉曼光谱。 FT- Raman spectroscopy.

[0041] 图21是卡维地洛磷酸二氢盐甲醇合物(III型)的FT-IR光谱。 [0041] FIG. 21 is carvedilol dihydrogen phosphate methanol compound (III type) of the FT-IR spectrum.

[0042] 图22是卡维地洛磷酸二氢盐甲醇合物(III型)在谱图4000-2000CHT1区域的FT-IR光谱。 [0042] FIG. 22 is carvedilol dihydrogen phosphate methanol compound (III type) FT-IR spectrum in the spectrum 4000-2000CHT1 region.

[0043] 图23是卡维地洛磷酸二氢盐甲醇合物(III型)在谱图ZOOO-SOOcnT1区域的FT-IR 光谱。 [0043] FIG. 23 is carvedilol dihydrogen phosphate methanol compound (III type) FT-IR spectrum in the spectrum ZOOO-SOOcnT1 region.

[0044] 图24是卡维地洛磷酸二氢盐甲醇合物(III型)的X射线粉末衍射图。 [0044] FIG. 24 is carvedilol dihydrogen phosphate methanol compound (III type) X-ray powder diffraction pattern.

[0045] 图25是卡维地洛磷酸二氢盐二水合物(IV型)的X射线粉末衍射图。 [0045] FIG. 25 is carvedilol dihydrogen phosphate dihydrate (IV type) X-ray powder diffraction pattern.

[0046] 图26是卡维地洛磷酸二氢盐二水合物(I型)的固态13C NMR。 [0046] FIG. 26 is carvedilol dihydrogen phosphate dihydrate (I type) solid-state 13C NMR.

[0047] 图27是卡维地洛磷酸二氢盐二水合物(I型)的固态31P NMR。 [0047] FIG. 27 is carvedilol dihydrogen phosphate dihydrate (I type) solid state 31P NMR.

[0048] 图28是卡维地洛磷酸二氢盐(V型)的X射线粉末衍射图。 [0048] FIG. 28 is carvedilol dihydrogen phosphate (V-type) X-ray powder diffraction pattern.

[0049] 图29是卡维地洛磷酸氢盐(VI型)的X射线粉末衍射图。 [0049] FIG. 29 is carvedilol hydrogen phosphate (VI type) X-ray powder diffraction pattern.

[0050] 发明详述 [0050] DETAILED DESCRIPTION

[0051] 本发明涉及卡维地洛的盐和/或其相应的溶剂合物、含有该卡维地洛的盐和/或其相应溶剂合物的组合物、和/或使用上述化合物治疗在哺乳动物,尤其是人中的一些疾病的方法。 [0051] The present invention relates to carvedilol salts and / or corresponding solvates, the carvedilol salts and / or compositions corresponding solvate, and / or use of such compounds containing therapy mammals, especially humans method of some diseases.

[0052] 本发明还涉及卡维地洛磷酸盐,其中包括卡维地洛磷酸二氢盐(即例如1_(咔唑-4-基氧基-3-[[2-(邻-甲氧苯氧基)乙基]氨基]-2-丙醇)的磷酸二氢盐,卡维地洛磷酸氢盐等)的新晶形,和/或其它卡维地洛磷酸盐溶剂合物。 [0052] The present invention also relates to carvedilol phosphate, including carvedilol dihydrogen phosphate (ie such as 1_ (carbazol-4-yl-3 - [[2- (o - methicillin The new crystalline form) ethyl] amino] -2-propanol) dihydrogen phosphate, carvedilol hydrogen phosphate, etc.), and / or other solvates of carvedilol phosphate. [0053] 本发明涉及一种药物组合物,含有卡维地洛磷酸盐和/或其溶剂合物。 [0053] The present invention relates to a pharmaceutical composition containing carvedilol phosphate and / or a solvate. [0054] 本发明还涉及一种治疗高血压、充血性心力衰竭和心绞痛的方法,包括向需要的受治者给药有效量的卡维地洛磷酸盐(其中包括新晶形)和/或其溶剂合物或药物组合物(即其中含有卡维地洛磷酸盐和/或其溶剂合物),等等。 [0054] The present invention also relates to a method of treating hypertension, congestive heart failure and angina, comprising administering to a subject in need of treatment by administering an effective amount of carvedilol phosphate (including new crystalline form) and / or solvate or pharmaceutical compositions (ie, containing carvedilol phosphate and / or a solvate), and so on. [0055] 卡维地洛在Wiedemann等的美国专利N0.4, 503, 067中公开并被要求保护(“US' 067专利”)。 [0055] Carvedilol in Wiedemann et al U.S. Patent N0.4, 503, 067 disclosed and claimed ("US '067 patent"). 参照US' 067专利全部公开的内容,其中包括制备和/或使用卡维地洛化合物的方法等。 Referring to US '067 patent the entire disclosure, including the preparation and / or use of carvedilol compound and the like. US' 067专利所完全公开的内容在这里全文引用作为参考。 US '067 patent is full disclosure of which is hereby incorporated by reference herein. [0056] 本发明涉及一种化合物,它是卡维地洛磷酸盐和/或其新晶形(S卩,其中包括卡维地洛磷酸二氢盐、卡维地洛磷酸氢盐等的晶形)和/或卡维地洛磷酸盐的溶剂合物(即,包括卡维地洛磷酸二氢盐半水合物、卡维地洛磷酸二氢盐二水合物(即分别如II型和IV型等),和/或卡维地洛磷酸二氢盐甲醇合物等。)[0057] 根据本发明,出人意料地发现了卡维地洛磷酸二氢盐很容易以新的晶形分离,与卡维地洛的游离碱相比具有更高的溶解度。 [0056] The present invention relates to a compound which is carvedilol phosphate and / or a new crystalline form of (S Jie, including carvedilol dihydrogen phosphate, carvedilol hydrogen phosphate and other crystalline form) and / or carvedilol phosphate solvate (ie, including carvedilol dihydrogen phosphate hemihydrate, carvedilol dihydrogen phosphate dihydrate (ie, such as type II and IV, respectively, type, etc. ), and / or carvedilol dihydrogen phosphate methanol compounds and the like.) [0057] According to the present invention, it was surprisingly found that carvedilol dihydrogen phosphate easily separated with a new crystal form, and carvedilol Luo free base has higher solubility. 本发明中新卡维地洛磷酸盐的一个例子是卡维地洛憐酸二氢盐的新晶形(即,经鉴定为1_ (咔唑-4-基氧基-3_[ [2-(邻-甲氧苯氧基) 乙基]氨基]-2-丙醇)的磷酸二氢盐)。 The present invention is an example of new carvedilol phosphate is a new crystalline form of carvedilol dihydrogen pity acid (ie, identified as 1_ (carbazol-4-yloxy -3_ [[2- (o - methoxyphenoxy) ethyl] amino] -2-propanol) dihydrogen phosphate). [0058] 根据本发明,本发明其他卡维地洛磷酸盐,和/或溶剂合物可以不同的固体和/或晶形分离。 [0058] According to the present invention, the present invention other carvedilol phosphate, and / or solvates may be different solids and / or crystalline separation. 此外,具体鉴定的卡维地洛磷酸盐(或具体鉴定的相应溶剂合物)也可经分离得到不同的晶形或固体。 In addition, specific identification of carvedilol phosphate (or a corresponding solvate specific identification) can also be obtained through different crystalline or solid separation. 例如,卡维地洛磷酸二氢盐可分离为两种显著不同的晶形,II型和IV型(参见实施例2和4),分别表示并基本表示为图9至16 (对应II型)和图25 (对应IV型),具有各自光谱学和/或其它特征性数据。 For example, carvedilol dihydrogen phosphate separable into two significantly different crystal form, type II and type IV (see Example 2 and 4), respectively, and basic representation of Figure 9-16 (corresponding to type II) and Figure 25 (corresponding to the type IV), having respective spectroscopy and / or other characteristics of the data. [0059] 已经认识到本发明的化合物可以多种形式存在,例如立体异构体、区域异构体或非对映异构体等。 [0059] The compounds of this invention have recognized that can exist in many forms, e.g., stereoisomers, regioisomers or diastereoisomers and the like. 这些化合物可以包括一个或多个不对称碳原子,以外消旋或旋光形式存在。 These compounds may include one or more asymmetric carbon atoms, in racemic or optically active form. 例如,卡维地洛以R(+)和S(-)对映体的外消旋混合物形式存在,或各自单独以旋光体形式存在,即以R(+)对映体形式或以S(+)对映体形式存在。 For example, carvedilol with R (+) and S (-) enantiomer of the racemic mixture of external form, or in each individual optically active form, ie R (+) enantiomer or S ( +) enantiomer form. 所有这些单独化合物、异构体和其混合物都包括在本发明的范围内。 All of these individual compounds, isomers and mixtures thereof are included within the scope of the present invention. [0060] 本发明所说的卡维地洛磷酸盐的合适溶剂合物,包括但不限于卡维地洛磷酸二氢盐半水合物、卡维地洛磷酸二氢盐二水合物(即其中分别包括II型和IV型)、卡维地洛磷酸二氢盐甲醇合物和卡维地洛磷酸氢盐等。 [0060] The present invention said suitable solvates of carvedilol phosphate, including but not limited to carvedilol dihydrogen phosphate hemihydrate, carvedilol dihydrogen phosphate dihydrate (ie where respectively, including type II and type IV), carvedilol dihydrogen phosphate methanol compound and carvedilol hydrogen phosphate and the like. [0061] 特别地,本发明的结晶卡维地洛磷酸二氢盐半水合物可以通过从含有卡维地洛和H3PO4的丙酮-水溶剂体系中结晶制得。 [0061] In particular, the present invention crystalline carvedilol dihydrogen phosphate hemihydrate can be from acetone containing carvedilol and H3PO4 - the crystal water solvent system obtained. [0062] 根据本发明,本发明的合适溶剂合物可通过将卡维地洛磷酸盐如卡维地洛磷酸二氢盐,于溶剂如甲醇中制成浆液的方法制得。 [0062] According to the present invention, a suitable solvent compositions of the present invention can be obtained by carvedilol phosphate as carvedilol dihydrogen phosphate, in a solvent such as methanol made from a slurry methods. [0063] 根据本发明,不同形式的卡维地洛磷酸二氢盐(即其中包括其盐和/或溶剂合物) 通过不同的表征或鉴定技术很容易彼此区分开来。 [0063] According to the present invention, different forms of carvedilol dihydrogen phosphate (ie, including its salts and / or solvates) through different characterization or identification techniques can easily be distinguished from each other. 这些技术,包括固态13C核磁共振(NMR), 31P核磁共振(NMR),红外(IR),拉曼、X射线粉末衍射等,和/或其他技术,如差示扫描量热法(DSC)(即通过样品加热、冷却或恒温下保持测量吸收或释放的能量(热量))。 These techniques include solid-state 13C nuclear magnetic resonance (NMR), 31P Nuclear Magnetic Resonance (NMR), infrared (IR), Raman, X-ray powder diffraction, and / or other techniques, such as differential scanning calorimetry (DSC) ( The sample is heated through and keep measuring the absorption or release of energy (heat)) under cooling or thermostat. [0064] 通常,上述固态NMR技术是获得波谱的非破坏性技术,其中一个NMR峰表示一个固态部位的磁不等价碳。 [0064] Typically, such solid-state NMR spectroscopy technique is to obtain a non-destructive technique, in which a solid-state NMR peak represents a portion of the non-magnetic carbon equivalent. [0065] 例如,在鉴定本发明化合物时,粉末状微晶有机分子的13C NMR的波谱反映了从给定样品中观察到的峰的数目决定于每个分子中有独特化学特性的碳的数目和每个单晶胞中不等价分子的数目。 [0065] For example, in the identification of compounds of the present invention when, 13C NMR spectra of powdered microcrystalline organic molecules reflects the number of peaks from a given sample was observed to determine a unique chemical properties in the number of carbons per molecule and each unit cell is not equivalent to the number of molecules. 以与溶液态13C NMR大致相同的方式,碳原子的峰位置(化学位移) 反映了碳原子的化学环境。 In the solution state 13C NMR substantially the same manner, the peak position of carbon atom (chemical shift) reflects the chemical environment of carbon atoms. 尽管峰会重叠,但原则上每个峰对映一个单一类型的碳。 Although the summit overlap, but in principle, a single enantiomer of each peak types of carbon. 因此, 大致计算所观察到的碳位置的数目可以获得关于有机小分子晶相的有用信息。 Therefore, the number roughly calculate the observed carbon position can obtain useful information about the organic small molecule crystal phase. [0066] 基于上述内容,相同的原则也适用于磷,31P原子核还因其高灵敏度而有更多的优点。 [0066] Based on the above, the same principle applies to phosphorus, 31P nuclei but also because of its high sensitivity and has more advantages. [0067] 通过比较13C和31P光谱还可以研究多晶型现象。 [0067] By comparing the 13C and 31P spectra also can study polymorphism. 对于无定形物质,通常会观察到峰形变宽,这反映了无定形物质类型中13C或31P位点经过的环境范围。 For amorphous material, usually observed peak width deformation, which reflects the amorphous material type 13C or 31P sites through environmental range. [0068] 特别地,卡维地洛磷酸二氢盐、其水合物和/或溶剂合物,基本如图1-29中所描述的数据所示。 [0068] In particular, carvedilol dihydrogen phosphate salts, hydrates and / or solvates, substantially as described in the data shown in 1-29. [0069] 例如,结晶的卡维地洛磷酸二氢盐半水合物(参见实施例1:1型)经X射线衍射图鉴别,结果基本如图1所示,在2 Θ度:即7.00.2(2 Θ ),11.40.2(2 Θ ), 15.90.2(2 Θ ),18.80.2(2 Θ ), 20.60.2(2 Θ ), 22.80.2(2 Θ )和25.40.2(2 Θ )处有特征峰。 [0069] For example, crystalline carvedilol dihydrogen phosphate hemihydrate (see Example 1: Type 1) identification by X-ray diffraction pattern, substantially as a result, in the 2 Θ degree: namely 7.0 0.2 (2 Θ), 11.4 0.2 (2 Θ), 15.9 0.2 (2 Θ), 18.8 0.2 (2 Θ), 20.6 0.2 (2 Θ), 22.8 0.2 (2 Θ) and 25.4 0.2 ( 2 Θ) of the characteristic peaks. [0070] 结晶的卡维地洛磷酸二氢盐二水合物(参见实施例2:11型)经X射线衍射图鉴别,结果基本如图9 所示,在2 Θ 度:即6.50.2(2 Θ ),7.10.2(2 Θ ),13.50.2(2 Θ ),I4.00.2(2 Θ ), 17.80.2(2 Θ ), 18.90.2(2 Θ )和21.00.2(2 Θ )处有特征峰。 [0070] crystalline carvedilol dihydrogen phosphate dihydrate (see Example 2:11 type) by X-ray diffraction pattern identification, results are basically 9, at 2 Θ degrees: the 6.5 0.2 ( 2 Θ), 7.1 0.2 (2 Θ), 13.5 0.2 (2 Θ), I4.0 0.2 (2 Θ), 17.8 0.2 (2 Θ), 18.9 0.2 (2 Θ) and 21.0 0.2 ( 2 Θ) of the characteristic peaks. [0071 ] 结晶的卡维地洛磷酸二氢盐甲醇合物(参见实施例3:1II型)经X射线衍射图鉴别,结果基本如图24 所示,在2 Θ 度:即6.90.2(2 Θ ), 7.20.2(2 Θ ), 13.50.2(2 Θ ),14.10.2(2 Θ ),17.80.2(2 Θ )和34.00.2(2 Θ )处有特征峰。 [0071] crystalline carvedilol dihydrogen phosphate methanol compound (see Example 3: 1II type) identification by X-ray diffraction pattern, substantially as shown in the results of 24 degrees at 2 Θ: namely 6.9 0.2 ( 2 Θ), 7.2 0.2 (2 Θ), 13.5 0.2 (2 Θ), 14.1 0.2 (2 Θ), 17.8 0.2 (2 Θ) and 34.0 0.2 (2 Θ) of the characteristic peaks. [0072] 结晶的卡维地洛磷酸二氢盐二水合物(参见实施例4:1V型)经X射线衍射图鉴别,结果基本如图25 所示,在2 Θ 度:gp 6.40.2 (2 Θ ),9.60.2 (2 Θ ),16.00.2 (2 Θ ),18.40.2(2 Θ ), 20.70.2(2 Θ )和24.50.2(2 Θ )处有特征峰。 [0072] crystalline carvedilol dihydrogen phosphate dihydrate (see Example 4: 1V type) identification by X-ray diffraction pattern, substantially as shown in the results of 25, at 2 Θ degrees: gp 6.4 0.2 ( 2 Θ), 9.6 0.2 (2 Θ), 16.0 0.2 (2 Θ), 18.4 0.2 (2 Θ), 20.7 0.2 (2 Θ) and 24.5 0.2 (2 Θ) of the characteristic peaks. [0073] 结晶的卡维地洛磷酸二氢盐(参见实施例5:V型)经X射线衍射图鉴别,结果基本如图28 所示,在2 Θ 度:gp 13.20.2(2 Θ ),15.80.2(2 Θ ),16.30.2(2 Θ ),21.20• 2(2 Θ ),23.70.2(2 Θ )和26.00.2(2 Θ )处有特征峰。 [0073] crystalline carvedilol dihydrogen phosphate (see Example 5: V-type) identification by X-ray diffraction pattern, substantially as shown in the results of 28 degrees at 2 Θ: gp 13.2 0.2 (2 Θ) , 15.8 0.2 (2 Θ), 16.3 0.2 (2 Θ), 21.2 0 • 2 (2 Θ), 23.7 0.2 (2 Θ) and 26.0 0.2 (2 Θ) of the characteristic peaks. [0074] 结晶的卡维地洛磷酸氢盐(参见实施例6:VI型)经X射线衍射图鉴别,结果基本如图29 所示,在2 Θ 度:即5.50.2(2 Θ ),12.30.2(2 Θ ),15.30.2(2 Θ ),19.50.2( 2 Θ ), 21.60.2(2 Θ )和24.90.2(2 Θ )处有特征峰。 [0074] crystalline carvedilol hydrogen phosphate (see Example 6: VI type) identification by X-ray diffraction pattern, substantially as shown in the results of 29 degrees at 2 Θ: namely 5.5 0.2 (2 Θ), 12.3 0.2 (2 Θ), 15.3 0.2 (2 Θ), 19.5 0.2 (2 Θ), 21.6 0.2 (2 Θ) and 24.9 0.2 (2 Θ) of the characteristic peaks. [0075] 本发明也涉及一种药组合物,含有卡维地洛磷酸盐和/或其相应的溶剂合物。 [0075] The present invention also relates to a drug composition containing carvedilol phosphate and / or corresponding solvates. [0076] 重要的是,这里所述的各种形式的卡维地洛,包括卡维地洛磷酸二氢盐例如新的晶形和/或其溶剂合物的化学和/或物理特性,都表明了这些形式可能尤其适于包含入药物制剂、药物组合物等中。 [0076] Importantly, the various forms of carvedilol herein, including carvedilol dihydrogen phosphate salts, such as new crystalline form and / or chemical and / or physical properties of the solvent composition, show These forms may be especially suitable for inclusion into the pharmaceutical preparation, pharmaceutical compositions and the like. [0077] 例如,这里所述不同卡维地洛盐和/或溶剂合物的溶解度,有利于提供或者开发剂型,其中药物更适宜于胃肠道(即特别是较低的小肠和结肠)的生物`吸收。 [0077] For example, where the different carvedilol salt and / or solvate thereof solubility facilitates providing or develop formulations, wherein the drug is more suitable for the gastrointestinal tract (i.e., especially a lower small intestine and colon) of `biological absorption. 根据上述内容,有可能开发出含有本发明的卡维地洛磷酸盐和/或溶剂合物的稳定的控释剂型等,用作一天给药一次的剂型,延长释放或脉冲释放使药代动力学性能与药效学要求相匹配,使治疗效果最佳。 According to the above, it is possible to develop a carvedilol phosphate and / or solvates stable controlled release dosage forms comprising the present invention, etc., is used as administered once a day dosage form, extended release or pulsed release makes pharmacokinetics and pharmacodynamic properties match the requirements, so that the best treatment. [0078] 本发明范围内的化合物或组合物包括所有的化合物或组合物,其中所含的本发明的化合物有实现预期目的的有效量。 [0078] The compound or composition within the scope of the present invention include all compounds or compositions, which contain a compound of the present invention have an effective amount to achieve the desired purpose. 当个体需求变化时,各成分有效量的最佳范围是本领域普通技术人员可以决定的。 When the change to the individual requirements, the optimal range of the components of an effective amount of ordinary skill in the art can decide. [0079] 因而,本发明还涉及一种药物组合物,包括有效量的卡维地洛磷酸二氢盐和/或其溶剂合物,它们具有本文提及的任何特征,和一种或多种无毒的药学上可接受的载体和/或其稀释剂,如果需要的还可以加入其它活性成分。 [0079] Thus, the present invention also relates to a pharmaceutical composition comprising an effective amount of carvedilol dihydrogen phosphate salts and / or solvates, they have any of the features mentioned herein, and one or more non-toxic pharmaceutically acceptable carriers and / or diluents, may also be added if desired other active ingredients. [0080] 此外,本发明中化合物或组合物的给药量根据患者和给药方式而变化,可以是任意有效量。 [0080] Further, the present invention is administered in an amount of compound or a composition according to the patient and the mode of administration, can be any effective amount. [0081] 本领域普通技术人员可以很容易地确定给药本发明化合物和/或组合物的治疗方案。 [0081] Those skilled in the art can easily determine the administration of the compounds of the present invention and / or treatment compositions. 本发明中化合物或组合物的给药量在较宽范围变化,从而提供每天基于患者体重的有效量的单位剂量以获得预期疗效。 The present invention is administered in an amount of compound or composition over a wide range, thereby providing an effective amount of a unit dose based on patient body weight per day to obtain the desired effect. [0082] 特别地,本发明的组合物以单位剂量的形式给药,优选每天给药I到2次,最优选一天一次以获得预期疗效。 [0082] In particular, the compositions of the invention are administered in unit dosage form, preferably I to be administered twice a day, most preferably once a day to achieve the desired effect. [0083] 根据治疗起效情况,本发明的化合物和/或组合物可以口服、血管内给药、腹膜内给药、皮下给药、肌肉内给药或局部给药。 [0083] The therapeutic onset, the compounds of the invention and / or compositions may be administered orally administered, administration, subcutaneous administration, intramuscular administration or topical administration intravascular intraperitoneally. 优选地,组合物适合于口服给药。 Preferably, the composition is suitable for oral administration. [0084] 通常,本发明药物组合物使用常规物质和技术制备,例如混合、掺和及类似方法。 [0084] Typically, the pharmaceutical compositions of the present invention is prepared using conventional materials and techniques, such as mixing, blending and the like. [0085] 根据本发明,化合物和/或药物组合物也能包括但不限于合适的佐剂、载体、赋形剂或稳定剂等,可以是固体或液体形式例如片剂、胶囊、粉末、溶液、混悬液或乳液等。 [0085] According to the present invention, the compounds and / or pharmaceutical compositions can also include, but are not limited to suitable adjuvants, carriers, excipients or stabilizers, may be in solid or liquid form such as tablets, capsules, powders, solutions , suspension or emulsion. [0086] 典型地,组合物含有本发明的化合物,如卡维地洛的盐或活性化合物的盐,以及佐剂、载体和/或赋形剂。 [0086] Typically, compositions containing the compounds of the present invention, a salt of carvedilol salt or the active compound as well as adjuvants, carriers and / or excipients. 特别地,本发明的药物组合物包括有效量的卡维地洛的盐(即如卡维地洛磷酸二氢盐)和/或其相应的溶剂合物(即如这里所鉴定的),它们具有本文提及的任何特征,和一种或多种无毒的药学上可接受的载体和/或稀释剂,如果需要的还可以加入其它活性成分。 In particular, the pharmaceutical compositions of the present invention include an effective amount of a carvedilol salt (ie, such as carvedilol dihydrogen phosphate) and / or the corresponding solvate (ie as identified herein), they have any of the features mentioned herein, and one or more non-toxic pharmaceutically acceptable carriers and / or diluents, may also be added if desired other active ingredients. [0087] 根据本发明,固体的单位剂量形式可以是本领域已知的常规类型。 [0087] According to the present invention, the solid unit dosage form can be a conventional type known in the art. 固体形式可以是胶囊和类似物,如普通明胶型,其中含有本发明化合物和载体,例如润滑剂和惰性填料, 如乳糖、蔗糖或玉米淀粉等。 The solid form can be a capsule and the like, as the ordinary gelatin type containing the compound of the present invention and a carrier, for example, lubricants and inert fillers, such as lactose, sucrose or corn starch and the like. 在另一个实施方案中,这些化合物用常规片剂基料压片,所述基料例如乳糖、蔗糖或玉米淀粉和粘合剂如阿拉伯胶、玉米淀粉或明胶,崩解剂如玉米淀粉、土豆淀粉或褐藻酸,以及润滑剂如硬脂酸或硬脂酸镁等。 In another embodiment, the compounds using conventional tabletting tablet binder, the binder such as lactose, sucrose or corn starch and binders such as acacia, corn starch or gelatin, disintegrating agents such as corn starch, potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate. [0088] 片剂、胶囊和类似物液也可含有粘合剂,如黄芪胶、阿拉伯胶、玉米淀粉或明胶;赋形剂如磷酸二钙;崩解剂如玉米淀粉、土豆淀粉、褐藻酸;润滑剂如硬脂酸镁;和甜味剂如蔗糖、乳糖或糖精等。 [0088] Tablets, capsules and the like may also contain liquid binder, such as tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid ; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. 当剂量单位形式是胶囊时,在上述物质基础上还可含有脂肪油。 When the dosage unit form is a capsule, on the basis of the above substances may also contain fatty oil. [0089] 其它各种物质可用作包衣或改进剂量单位的物理形式。 [0089] Various other materials may be used as coatings or to improve the physical form of the dosage unit. 例如,片剂可用虫胶、糖或二者合用等包衣。 For example, tablets may be shellac, sugar or both in combination and other coatings. 糖浆在活性成分之外可含有作为甜味剂的蔗糖、作为防腐剂的对羟苯甲酸甲酯和对羟基苯甲酸丙酯,染料和调味剂如樱桃味或桔味调味剂等。 In addition to the active ingredient syrup may contain sucrose as a sweetening agent, methyl paraben and as propyl paraben, a dye and flavoring such as cherry or orange flavor flavoring agents, preservatives. [0090] 对于口服治疗给药,这些活性化合物可与赋形剂混合并以片剂、胶囊、酏剂、混悬剂、糖浆和类似的形式使用。 [0090] For oral therapeutic administration, these active compounds may be incorporated with excipients and the form of tablets, capsules, elixirs, suspensions, syrups and the like used in the form. 当然,组合物中化合物的百分比是可变的,在这些治疗用的组合物中合适剂量的活性化合物的量可以得到。 Of course, the percentage composition of the compound is variable, the amount of active compound in these compositions in a suitable therapeutic dose can be obtained. [0091] 典型地,根据本发明,口服的维持剂量在约25mg到约50mg之间,优选每天给药一次。 [0091] Typically, according to the present invention, the oral maintenance dose is between about 25mg to about 50mg, preferably administered once a day. 根据本发明,优选的单位剂量形式包括片剂或胶囊。 According to the present invention, the preferred unit dosage forms include tablets or capsules. [0092] 本发明活性化合物可口服给药,例如与惰性稀释剂,或与可同化食用的载体一起, 或者它们可封装于硬或软壳的胶囊,或压成片,或直接加入饮食的食物中,等。 [0092] The active compounds can be administered orally, for example, with an inert diluent or with an assimilable edible carrier together, or they may be enclosed in hard or soft shell capsules or compressed into tablets, or directly into the food of the diet , and so on. [0093] 适于注射使用的药物形式包括无菌水溶液或分散体以及可以即时制备的无菌注射液或分散体的无菌粉末。 [0093] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or may be dispersions. 在各种情况下,都应是无菌形式且在某种程度上可流动以方便注射。 In all cases, the form should be sterile and flowable in a way to facilitate injection. 应在制造和储存条件下应保持稳定,还应防止微生物,例如细菌和真菌的污染作用。 Should be under the conditions of manufacture and storage should remain stable, but also to prevent micro-organisms, such as bacteria and fungi contaminating action. 载体可以是溶剂或分散介质,包括如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇)、及其合适的混合物和植物油等。 The carrier can be a solvent or dispersion medium containing water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0094] 本发明的化合物或药物组合物也可通过这些物质于生理上可接受的稀释剂和药物佐剂、载体或赋形剂中的溶液或混悬液,以注射剂形式给药。 [0094] The compound or pharmaceutical composition of the present invention can also be through these materials in a physiologically acceptable pharmaceutical adjuvants and diluent, carrier or excipient solution or suspension, administered in the form of injections. 这类佐剂、载体和/或赋形齐U,包括但不限于无菌液体,例如水和油,加入或不加入表面活性剂和其他药学上和生理上可接受的载体,其中包括佐剂、赋形剂和稳定剂等。 Such adjuvants, carriers and / or excipients together U, including but not limited to, sterile liquids, such as water and oils, with or without the addition of a surfactant and other pharmaceutically and physiologically acceptable carrier, including adjuvants , excipients, and stabilizers. 示例性的油是凡士林、动物油、植物油或合成的油,例如花生油、大豆油或矿物油等。 Exemplary oils are petroleum jelly, animal, vegetable or synthetic oils, such as peanut oil, soybean oil, or mineral oil. 通常,水、盐水、葡萄糖的水溶液和相关的糖溶液,以及二醇,例如丙二醇或聚乙二醇,是优选的液体载体,特别是对于注射溶液等。 In general, water, saline, aqueous dextrose and related sugar solutions and glycols such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions and the like.

[0095] 这些活性化合物也可通过非胃肠道给药。 [0095] These active compounds may also be administered parenterally. 这些活性化合物的溶液或混悬液在水中制备,适当地混合以表面活性剂如羟丙基纤维素。 Solutions or suspensions of these active compounds prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. 同样可在甘油、液体聚乙二醇和其在油中的混合物内制备分散体。 Also in glycerol, liquid polyethylene glycols and mixtures thereof in oils within the dispersion. 示例性的油为凡士林,动物油,植物油,或合成源的油如花生油、大豆油、或矿物油等。 Exemplary oil as oil vaseline, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, or mineral oil. 一般而言,水、盐水、葡萄糖的水溶液和相关糖的溶液、和乙二醇类如丙二醇或聚乙二醇等为优选的液相载体,特别适用于注射溶液。 In general, water, saline, aqueous dextrose and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions. 在普通的贮藏和使用条件下,这些制剂含有防腐剂,用以防止微生物的生长。 Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0096] 根据本发明制备的化合物和/或组合物能用于治疗温血动物,例如包括人类在内的哺乳动物。 [0096] According compounds and / or compositions of this invention can be prepared for the treatment of warm-blooded animals, e.g., mammals including humans.

[0097] 常规的给药方法适用于本发明。 [0097] Conventional methods of administration suitable for the present invention.

[0098] 本发明进一步涉及一种治疗高血压、充血性心力衰竭和心绞痛的方法,包括向需要的受治疗者给药有效量的卡维地洛磷酸盐(即包括新晶形在内)和/或其溶剂合物或药物组合物(即含有该卡维地`洛磷酸盐和/或其溶剂合物)等。 [0098] The present invention further relates to a method of treating hypertension, congestive heart failure and angina pectoris comprising administering to a subject in need thereof an effective amount of carvedilol phosphate (which includes a new crystal form included) and / or a solvate thereof or a pharmaceutical composition (i.e., containing the carvedilol Rockwell 'phosphate and / or a solvate thereof) and the like.

[0099] 下面所列实施例是本发明的例证,无论如何不限制本发明的范围。 As set forth in the following [0099] Examples are illustrative of the present invention is not in any way limit the scope of the invention.

实施例 Example

[0100] 实施例1 [0100] Example 1

[0101] I型卡维地洛磷酸二氢盐半水合物的制备 [0101] Preparation of type I carvedilol dihydrogen phosphate hemihydrate

[0102] 在适当反应器内装入丙酮。 [0102] into the acetone in an appropriate reactor. 然后向丙酮溶液中依次加入卡维地洛和水。 Then successively added to the acetone solution of carvedilol and water. 加水时浆料快速溶解。 Add water slurry is rapidly dissolving. 向溶液中加入H3PO4A溶液。 H3PO4A solution was added to the solution. 室温下搅拌反应混合物,一次性加入卡维地洛磷酸二氢盐晶种。 The reaction mixture was stirred at room temperature, was added in one carvedilol dihydrogen phosphate seed. 搅拌所形成的固体沉淀,然后过滤,用丙酮水溶液洗涤收集到的滤饼。 The solid precipitate formed was stirred, then filtered, washed with aqueous acetone to collect the filter cake. 真空下将滤饼干燥至恒重。 The cake was dried to constant weight under vacuum. 称重滤饼,并贮存在聚乙烯容器中。 The filter cake weighed and stored in polyethylene containers.

[0103] 实施例2 [0103] Example 2

[0104] II型卡维地洛磷酸二氢盐二水合物的制备 [0104] Preparation of Type II carvedilol dihydrogen phosphate dihydrate

[0105] 在10〜30C下将I型在丙酮/水的混合物中制浆几天。 [0105] In 10~30 C under the Type I pulping days in a mixture of acetone / water.

[0106] 实施例3 [0106] Example 3

[0107] III型卡维地洛磷酸二氢盐甲醇合物的制备 [0107] Preparation of Type III carvedilol dihydrogen phosphate methanol compound

[0108] 在10〜30C下将I型在甲醇中制浆几天。 [0108] In 10~30 C under the Type I slurried in methanol for several days.

[0109] 实施例4[0110] IV型卡维地洛磷酸二氢盐二水合物的制备 [0110] Preparation of Form IV carvedilol dihydrogen phosphate dihydrate [0109] Example 4

[0111] 将卡维地洛磷酸二氢盐溶解在丙酮/水的混合物中。 [0111] The carvedilol dihydrogen phosphate salt is dissolved in a mixture of acetone / water. 蒸馏除去丙酮。 Acetone was distilled off. 在除去丙酮的过程中固体结晶,并被过滤出来,进行干燥。 In the process of removing acetone crystalline solid was filtered off and dried.

[0112] 实施例5 [0112] Example 5

[0113] V型卡维地洛磷酸二氢盐的制备 Preparation [0113] V-type carvedilol dihydrogen phosphate salts

[0114] 将卡维地洛磷酸二氢盐的半水合物(I型)悬浮在水中,室温下将悬浮液置于机械振荡器上。 [0114] The hemihydrate carvedilol dihydrogen phosphate salts (I type) is suspended in water at room temperature and the suspension was placed on a mechanical shaker. 震荡48小时之后,从悬浮液中过滤分离出固体,然后真空下在干燥器内干燥几天。 48 hours after the shock, the suspension is separated from the solid was filtered, then dried under vacuum in a desiccator for several days.

[0115] 实施例6 [0115] Example 6

[0116] VI型卡维地洛磷酸氢盐的制备 [0116] Preparation VI type carvedilol hydrogen phosphate salt

[0117] 在适当反应器内装入丙酮。 [0117] into the acetone in an appropriate reactor. 然后向丙酮溶液中依次加入SK&F105517和水。 Then successively added to the acetone solution and water SK & F105517. 加水时浆料快速溶解。 Add water slurry is rapidly dissolving. 向溶液中加入H3PO4水溶液(卡维地洛的1/2摩尔量)。 H3PO4 aqueous solution was added to the solution (1/2 molar amount of carvedilol). 搅拌反应混合物,使其结晶。 The reaction mixture was stirred, allowed to crystallize. 搅拌所形成的固体沉淀并冷却,然后过滤,用丙酮水溶液洗涤收集到的滤饼。 The solid precipitate formed was stirred and cooled, then filtered, washed with aqueous acetone to collect the filter cake.

[0118] 实施例7 [0118] Example 7

[0119] 卡维地洛磷酸二氢盐半水合物(I型)的13C和31P固态NMR数据分析 [0119] carvedilol dihydrogen phosphate hemihydrate (I type) solid-state 13C and 31P NMR data analysis

[0120] 用固态13C和31P NMR分析卡维地洛磷酸二氢盐半水合物(I型)的样品(即为了探测固体化合物的结构)。 [0120] Solid-state 13C and 31P NMR analysis of carvedilol dihydrogen phosphate hemihydrate (I type) sample (that is, to probe the structure of the solid compound).

[0121] 卡维地洛磷酸二氢盐(母体MW=406.5 ;盐丽=504.5)具有下述结构和编号图: [0121] Carvedilol dihydrogen phosphate (parent MW = 406.5; salt Li = 504.5) has the following structure and numbering diagram:

[0122] [0122]

Figure CN103288715AD00101

[0123] 实验细节及13C和31P的分析 [0123] The experimental details and analysis of 13C and 31P

[0124] 用于分析本发明化合物的固态13CNMR法产生了对固体材料内碳位置类型的定性图。 [0124] 13CNMR method for analysis of solid compounds of the invention to produce a solid material within the carbon position type qualitative FIG. 由于可变的极化传递速率以及边带抑制的需要,峰强度不是定量的(非常类似溶液态的13CNMR)。 Due to the variable polarization transfer rate and the need sideband suppression of peak intensity is not quantitative (very similar to the solution state 13CNMR).

[0125] 但是,31P核磁共振是固有定量的。 [0125] However, 31P NMR is inherently quantitative.

[0126] 对13C分析而言,将大约IOOmg的样品装入外径7mm的魔角自旋转子,并在5kHz下旋转。 [0126] The 13C analyzes, approximately IOOmg the sample into the outer diameter of 7mm Magic Angle Spinning son, and rotated at 5kHz. 用CP-TOSS脉冲序列(交叉极化,且伴有边带的总抑制)记录样品的13C波谱。 CP-TOSS recording pulse sequence (cross-polarization and total sideband suppression with) sample 13C spectrum. 然后,用CP-TOSS序列和NQS (非四级抑制)获得编辑波谱,该波谱仅含季和甲基的碳。 Then, edit the spectra obtained with the CP-TOSS sequence and NQS (non-IV inhibition), the spectrum contains only season and the methyl carbon. 通过固体六甲苯样品而将13C波谱外推至四甲基硅烷。 Six toluene sample through the solid and the 13C spectrum extrapolated to four methyl silane.

[0127] 对31P固态NMR分析而言,将大约40mg的样品装入外径4mm的转子,并在IOkHz下旋转。 [0127] The solid state 31P NMR analyzes, the samples were loaded into the outer diameter of 4mm about 40mg of the rotor and rotates at IOkHz. 在1H去耦合下采用CP-MAS和单脉冲的MAS31P脉冲序列。 In 1H decoupling the case of using CP-MAS and single pulse MAS31P pulse sequence. 通过第二固态基准(氧化三苯基膦),将31P的数据外推至85%的磷酸。 By the second solid-state reference (triphenylphosphine oxide), the extrapolated data 31P to 85% phosphoric acid. 用于此项工作的Bruker AMX2-360波谱仪分别在90.556、145.782和360.097MHz的13Cj1P^H频率下操作。 Bruker AMX2-360 spectrometer used in this work were operated at 13Cj1P ^ H frequency and 360.097MHz of 90.556,145.782. 所有数据均在298K下获得。 All data were obtained at 298K. [0128] 结果和讨论 [0128] Results and Discussion

[0129] 高灵敏度的13C和31P固态匪R识别法可用于分析和表征卡维地洛磷酸盐的多晶型,该多晶型证实了其固态化学结构。 [0129] the high sensitivity of the solid-state 13C and 31P R bandit identification method can be used to analyze and characterize the carvedilol phosphate polymorph, the polymorph confirmed its solid state chemical structure.

[0130] 卡维地洛磷酸二氢盐的晶形通过这些波谱确定,其中13C和31P波谱显示出清楚而明显的区别。 [0130] Carvedilol dihydrogen phosphate crystalline form determined by these spectra, 13C and 31P spectroscopy which shows a clear and significant difference.

[0131] 特别地,图26表示卡维地洛磷酸二氢盐的13C CP-TOSS波谱。 [0131] In particular, Figure 26 shows carvedilol dihydrogen phosphate salts 13C CP-TOSS spectrum. 图1中许多13C共振的归属可通过化学位移值、NQS波谱以及与溶液态13C归属的比较得到。 Figure 1. attributable to a number of 13C resonance chemical shift values can, NQS spectrum and with the solution of comparative get home state 13C. 在卡维地洛磷酸盐的这一晶形中观察到每个晶胞有至少两个不等价的分子。 We observed in carvedilol phosphate in each cell of the crystal form at least two non-equivalent molecules.

[0132] 图27表示卡维地洛磷酸二氢盐的31P MAS波谱。 [0132] FIG. 27 shows carvedilol dihydrogen phosphate 31P MAS spectrum. 在4.7ppm处观察到单个磷的信号,这是磷酸盐的特征。 At 4.7ppm observed at a single phosphorous signal which is characteristic phosphate.

[0133] 应当理解,本发明并不仅限于上面例举的实施方案,而对所说明的实施方案以及在下面权利要求书范围内的所有改进保留权利。 [0133] It should be understood that the present invention is not limited to the above exemplified embodiment, but on the illustrated embodiments, and within the scope of the following claims all modifications rights reserved.

[0134] 这里所引用的对期刊、专利和其它出版物的各种参考包括现有技术,均引入以作参考,尽管之前已有充分阐述。 [0134] various references to journals, patents and other publications cited herein include the prior art, are incorporated herein by reference, although there are fully set forth before.

Classifications
International ClassificationC07D209/82, A61K31/403, A61P9/00, A61P9/12, A61P9/10, C07D209/88, A61P9/04
Cooperative ClassificationC07D209/88
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