公开(公告)号：US09416098B2

公开(公告)日：2016-08-16

申请号：US13520902

申请日：2011-01-06

申请人： Sung Wuk Kim ,  Sung Soo Jun ,  Chang Hee Min ,  Young Woong Kim ,  Min Seok Kang ,  Byung Kyu Oh ,  Se Hwan Park ,  Yong Eun Kim ,  Duck Kim ,  Ji Sun Lee ,  Ju Hoon Oh

发明人： Sung Wuk Kim ,  Sung Soo Jun ,  Chang Hee Min ,  Young Woong Kim ,  Min Seok Kang ,  Byung Kyu Oh ,  Se Hwan Park ,  Yong Eun Kim ,  Duck Kim ,  Ji Sun Lee ,  Ju Hoon Oh

IPC分类号： C07C277/02 ,  C07C279/02 ,  A61K31/155 ,  C07C279/26 ,  C07C277/04 ,  C07C279/04 ,  C07C279/06 ,  C07C279/08 ,  C07C279/18 ,  C07D213/38 ,  C07D307/52 ,  C07D317/58 ,  C07D333/20

CPC分类号： A61K31/155 ,  A61K31/341 ,  A61K31/4406 ,  A61K31/472 ,  C07C277/04 ,  C07C279/04 ,  C07C279/06 ,  C07C279/08 ,  C07C279/16 ,  C07C279/18 ,  C07C279/26 ,  C07C2601/08 ,  C07C2601/14 ,  C07C2601/18 ,  C07C2603/74 ,  C07D213/38 ,  C07D307/52 ,  C07D317/58 ,  C07D333/20

摘要： A biguanide derivative compound with N1-N5 substitution, which is represented by Formula 1, or a pharmaceutically acceptable salt thereof, a method of preparing the same, and a pharmaceutical composition containing the same as an active ingredient are provided. The biguanide derivative may exhibit excellent effect on activation of AMPKα and inhibition of cancer cell proliferation in a low dose, compared to conventional drugs, and thus, may be useful to treat diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovarian syndrome, metabolic syndrome, cancer, etc.

摘要翻译： 提供了由式1表示的具有N1-N5取代基的双胍衍生化合物或其药学上可接受的盐，其制备方法和含有它们作为活性成分的药物组合物。 与常规药物相比，双胍衍生物可能对AMPKα的活化和低剂量的癌细胞增殖具有优异的作用，因此可用于治疗糖尿病，肥胖症，高脂血症，高胆固醇血症，脂肪肝，冠状动脉疾病 ，骨质疏松症，多囊卵巢综合征，代谢综合征，癌症等

公开(公告)号：US20120283299A1

公开(公告)日：2012-11-08

申请号：US13520902

申请日：2011-01-06

申请人： Sung Wuk Kim ,  Sung Soo Jun ,  Chang Hee Min ,  Young Woong Kim ,  Min Seok Kang ,  Byung Kyu Oh ,  Se Hwan Park ,  Yong Eun Kim ,  Duck Kim ,  Ji Sun Lee ,  Ju Hoon Oh

发明人： Sung Wuk Kim ,  Sung Soo Jun ,  Chang Hee Min ,  Young Woong Kim ,  Min Seok Kang ,  Byung Kyu Oh ,  Se Hwan Park ,  Yong Eun Kim ,  Duck Kim ,  Ji Sun Lee ,  Ju Hoon Oh

IPC分类号： A61K31/155 ,  C07C277/08 ,  A61P3/10 ,  A61P3/04 ,  A61P3/06 ,  A61P1/16 ,  A61P19/10 ,  A61P35/00 ,  A61P29/00 ,  C07C279/18 ,  C07D213/58 ,  A61K31/4406 ,  C07C279/16 ,  C07C279/14 ,  A61K31/22 ,  C07D307/54 ,  A61K31/341 ,  C07C279/04

CPC分类号： A61K31/155 ,  A61K31/341 ,  A61K31/4406 ,  A61K31/472 ,  C07C277/04 ,  C07C279/04 ,  C07C279/06 ,  C07C279/08 ,  C07C279/16 ,  C07C279/18 ,  C07C279/26 ,  C07C2601/08 ,  C07C2601/14 ,  C07C2601/18 ,  C07C2603/74 ,  C07D213/38 ,  C07D307/52 ,  C07D317/58 ,  C07D333/20

摘要： A biguanide derivative compound with N1-N5 substitution, which is represented by Formula 1, or a pharmaceutically acceptable salt thereof, a method of preparing the same, and a pharmaceutical composition containing the same as an active ingredient are provided. The biguanide derivative may exhibit excellent effect on activation of AMPKα and inhibition of cancer cell proliferation in a low dose, compared to conventional drugs, and thus, may be useful to treat diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovarian syndrome, metabolic syndrome, cancer, etc.

摘要翻译： 提供了由式1表示的具有N1-N5取代基的双胍衍生化合物或其药学上可接受的盐，其制备方法和含有它们作为活性成分的药物组合物。 与常规药物相比，双胍衍生物可能对AMPKα的活化和低剂量的癌细胞增殖具有优异的作用，因此可用于治疗糖尿病，肥胖症，高脂血症，高胆固醇血症，脂肪肝，冠状动脉疾病 ，骨质疏松症，多囊卵巢综合征，代谢综合征，癌症等

公开(公告)号：US20120309799A1

公开(公告)日：2012-12-06

申请号：US13520905

申请日：2011-01-06

申请人： Sung Wuk Kim ,  Sung Soo Jun ,  Chang Hee Min ,  Se Hwan Park ,  Yong Eun Kim ,  Duck Kim ,  Ji Sun Lee ,  Ju Hoon Oh

发明人： Sung Wuk Kim ,  Sung Soo Jun ,  Chang Hee Min ,  Se Hwan Park ,  Yong Eun Kim ,  Duck Kim ,  Ji Sun Lee ,  Ju Hoon Oh

IPC分类号： A61K31/155 ,  C07C277/08 ,  C07C279/04 ,  C07D307/52 ,  A61K31/34 ,  C07D333/20 ,  A61K31/381 ,  C07D213/36 ,  A61K31/44 ,  A61P3/10 ,  A61P3/04 ,  A61P9/10 ,  A61P19/10 ,  A61P35/00 ,  A61P21/00 ,  A61P15/00 ,  C07C279/16

CPC分类号： A61K31/155 ,  A61K31/341 ,  A61K31/4406 ,  A61K31/472 ,  C07C277/04 ,  C07C279/04 ,  C07C279/06 ,  C07C279/08 ,  C07C279/16 ,  C07C279/18 ,  C07C279/26 ,  C07C2601/08 ,  C07C2601/14 ,  C07C2601/18 ,  C07C2603/74 ,  C07D213/38 ,  C07D307/52 ,  C07D317/58 ,  C07D333/20

摘要： A biguanide derivative compound with N4-N5 substitution, which is represented by Formula 1, or a pharmaceutically acceptable salt thereof, a method of preparing the same, and a pharmaceutical composition containing the same as an active ingredient are provided. The biguanide derivative may exhibit excellent effect on activation of AMPK and inhibition of cancer cell proliferation in a low dose, compared with conventional drugs, and thus, may be useful to treat diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovarian syndrome, metabolic syndrome, cancer, etc.

摘要翻译： 提供了由式1表示的具有N4-N5取代的双胍衍生物化合物或其药学上可接受的盐，其制备方法和含有其的药物组合物作为活性成分。 与常规药物相比，双胍衍生物可能对AMPK的活化和低剂量的癌细胞增殖具有优异的效果，因此可用于治疗糖尿病，肥胖症，高脂血症，高胆固醇血症，脂肪肝，冠状动脉疾病 ，骨质疏松症，多囊卵巢综合征，代谢综合征，癌症等

公开(公告)号：US09133110B2

公开(公告)日：2015-09-15

申请号：US13520905

申请日：2011-01-06

申请人： Sung Wuk Kim ,  Sung Soo Jun ,  Chang Hee Min ,  Se Hwan Park ,  Yong Eun Kim ,  Duck Kim ,  Ji Sun Lee ,  Ju Hoon Oh

发明人： Sung Wuk Kim ,  Sung Soo Jun ,  Chang Hee Min ,  Se Hwan Park ,  Yong Eun Kim ,  Duck Kim ,  Ji Sun Lee ,  Ju Hoon Oh

IPC分类号： A61K31/38 ,  A61K31/36 ,  C07D307/02 ,  C07C277/00 ,  C07C279/26

CPC分类号： A61K31/155 ,  A61K31/341 ,  A61K31/4406 ,  A61K31/472 ,  C07C277/04 ,  C07C279/04 ,  C07C279/06 ,  C07C279/08 ,  C07C279/16 ,  C07C279/18 ,  C07C279/26 ,  C07C2601/08 ,  C07C2601/14 ,  C07C2601/18 ,  C07C2603/74 ,  C07D213/38 ,  C07D307/52 ,  C07D317/58 ,  C07D333/20

摘要： A biguanide derivative compound with N4-N5 substitution, which is represented by Formula 1, or a pharmaceutically acceptable salt thereof, a method of preparing the same, and a pharmaceutical composition containing the same as an active ingredient are provided. The biguanide derivative may exhibit excellent effect on activation of AMPK and inhibition of cancer cell proliferation in a low dose, compared with conventional drugs, and thus, may be useful to treat diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovarian syndrome, metabolic syndrome, cancer, etc.

摘要翻译： 提供了由式1表示的具有N4-N5取代的双胍衍生物化合物或其药学上可接受的盐，其制备方法和含有其的药物组合物作为活性成分。 与常规药物相比，双胍衍生物可能对AMPK的活化和低剂量的癌细胞增殖具有优异的效果，因此可用于治疗糖尿病，肥胖症，高脂血症，高胆固醇血症，脂肪肝，冠状动脉疾病 ，骨质疏松症，多囊卵巢综合征，代谢综合征，癌症等

公开(公告)号：US20120135952A1

公开(公告)日：2012-05-31

申请号：US13384218

申请日：2010-07-16

申请人： Sung Wuk Kim ,  Sung Soo Jun ,  Changhee Min ,  Min Seok Kang ,  Yong Eun Kim ,  Ja Seong Koo

发明人： Sung Wuk Kim ,  Sung Soo Jun ,  Changhee Min ,  Min Seok Kang ,  Yong Eun Kim ,  Ja Seong Koo

IPC分类号： A61K31/155 ,  C07C277/00 ,  A61P35/00 ,  A61K31/7068 ,  A61P3/06 ,  A61P19/08 ,  A61P9/00 ,  A61P3/10 ,  C07C279/26 ,  A61P9/12

CPC分类号： A61K31/155 ,  C07C53/124 ,  C07C279/26

摘要： The present invention provides metformin butyric acid salt, a method of preparing the same, and pharmaceutical compositions and combinations containing the same. The metformin butyric acid salt according to the present invention has an excellent pharmacological effect as compared with metformin hydrochloride and is capable of achieving a therapeutic purpose by administering an amount less than metformin hydrochloride. Furthermore, the metformin butyric acid salt has excellent physicochemical properties, such as solubility, stability, hygroscopicity and adsorption preventing property, in processibility of formulations and thereby is capable of being usefully utilized as a pharmaceutically acceptable salt of the metformin.

摘要翻译： 本发明提供了二甲双胍丁酸盐，其制备方法，药物组合物和含有它们的组合物。 与二甲双胍盐酸盐相比，本发明的二甲双胍丁酸盐具有优异的药理作用，能够通过施用少于二甲双胍盐酸盐的量来达到治疗目的。 此外，二甲双胍丁酸盐在制剂的加工性方面具有优异的物理化学性质，例如溶解性，稳定性，吸湿性和吸附防止性，因此能够有效地用作二甲双胍的药学上可接受的盐。

公开(公告)号：US08076377B2

公开(公告)日：2011-12-13

申请号：US12733711

申请日：2008-09-19

申请人： Sung Wuk Kim ,  Sung Soo Jun ,  Young Gwan Jo ,  Ja Seong Koo ,  Young Woong Kim ,  Byoung Ha Kim ,  Duck Kim

发明人： Sung Wuk Kim ,  Sung Soo Jun ,  Young Gwan Jo ,  Ja Seong Koo ,  Young Woong Kim ,  Byoung Ha Kim ,  Duck Kim

IPC分类号： A01N37/52 ,  A01N37/10 ,  A61K31/155 ,  A61K31/235

CPC分类号： C07C279/26 ,  C07C55/08 ,  C07C55/12 ,  C07C55/14 ,  C07C59/245

摘要： Disclosed herein are a novel dicarboxylic acid salt of N,N-dimethylimidodicarbonimidic diamide, a preparation method thereof and a pharmaceutical composition comprising the same. More specifically, disclosed herein are a novel dicarboxylic acid salt of N,N-dimethylimidodicarbonimidic diamide, a crystalline acid addition salt prepared by allowing N,N-dimethylimidodicarbonimidic diamide to react with a specific dicarboxylic acid, which has improved physical and chemical properties including solubility, stability, non-hygroscopicity and anti-adhesive properties, and low toxicity, and thus is very effective in the prevention and treatment of not only diabetes and its complications in patients with so-called metabolic syndromes, in which diabetes, obesity, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndromes, etc. appear in combination, but also p53 gene-deficient cancers, muscular pain, muscle cytotoxicity and rhabdomyolysis, as well as a preparation method thereof and a pharmaceutical composition comprising the same.

摘要翻译： 本文公开了N，N-二甲基亚氨基二亚甲基二酰胺的新型二羧酸盐及其制备方法和包含其的药物组合物。 更具体地，本文公开了N，N-二甲基亚氨基二甲酰亚胺二酰胺的新型二羧酸盐，通过使N，N-二甲基亚氨基二碳二亚胺二酰胺与特定二羧酸反应制备的结晶酸加成盐，其具有改善的物理和化学性质，包括溶解度 稳定性，非吸湿性和抗粘连性，低毒性，因此在预防和治疗不仅糖尿病及其所谓的代谢综合征患者的并发症方面非常有效，其中糖尿病，肥胖，高脂血症， 脂肪肝，冠状动脉疾病，骨质疏松症，多囊卵巢综合征等组合，还包括p53基因缺陷型癌症，肌肉酸痛，肌肉细胞毒性和横纹肌溶解症，以及其制备方法和包含其的药物组合物。

公开(公告)号：US20100249241A1

公开(公告)日：2010-09-30

申请号：US12733711

申请日：2008-09-19

申请人： Sung Wuk KIM ,  Sung Soo Jun ,  Young Gwan Jo ,  Ja Seong Koo ,  Young Woong Kim ,  Byoung Ha Kim ,  Duck Kim

发明人： Sung Wuk KIM ,  Sung Soo Jun ,  Young Gwan Jo ,  Ja Seong Koo ,  Young Woong Kim ,  Byoung Ha Kim ,  Duck Kim

IPC分类号： A61K31/155 ,  C07C279/26 ,  C07C277/00 ,  A61P35/00 ,  A61P3/10 ,  A61P21/00 ,  A61P29/00

CPC分类号： C07C279/26 ,  C07C55/08 ,  C07C55/12 ,  C07C55/14 ,  C07C59/245

摘要： Disclosed herein are a novel dicarboxylic acid salt of N,N-dimethylimidodicarbonimidic diamide, a preparation method thereof and a pharmaceutical composition comprising the same. More specifically, disclosed herein are a novel dicarboxylic acid salt of N,N-dimethylimidodicarbonimidic diamide, a crystalline acid addition salt prepared by allowing N,N-dimethylimidodicarbonimidic diamide to react with a specific dicarboxylic acid, which has improved physical and chemical properties including solubility, stability, non-hygroscopicity and anti-adhesive properties, and low toxicity, and thus is very effective in the prevention and treatment of not only diabetes and its complications in patients with so-called metabolic syndromes, in which diabetes, obesity, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndromes, etc. appear in combination, but also p53 gene-deficient cancers, muscular pain, muscle cytotoxicity and rhabdomyolysis, as well as a preparation method thereof and a pharmaceutical composition comprising the same.

摘要翻译： 本文公开了N，N-二甲基亚氨基二亚甲基二酰胺的新型二羧酸盐及其制备方法和包含其的药物组合物。 更具体地，本文公开了N，N-二甲基亚氨基二甲酰亚胺二酰胺的新型二羧酸盐，通过使N，N-二甲基亚氨基二碳二亚胺二酰胺与特定二羧酸反应制备的结晶酸加成盐，其具有改善的物理和化学性质，包括溶解度 稳定性，非吸湿性和抗粘连性，低毒性，因此在预防和治疗不仅糖尿病及其所谓的代谢综合征患者的并发症方面非常有效，其中糖尿病，肥胖，高脂血症， 脂肪肝，冠状动脉疾病，骨质疏松症，多囊卵巢综合征等组合，还包括p53基因缺陷型癌症，肌肉酸痛，肌肉细胞毒性和横纹肌溶解症，以及其制备方法和包含其的药物组合物。

公开(公告)号：US08058312B2

公开(公告)日：2011-11-15

申请号：US12524695

申请日：2008-01-29

申请人： Sung Wuk Kim ,  Sung Soo Jun ,  Young Gwan Jo ,  Ja Seong Koo ,  Young Woong Kim

发明人： Sung Wuk Kim ,  Sung Soo Jun ,  Young Gwan Jo ,  Ja Seong Koo ,  Young Woong Kim

IPC分类号： A01N37/52 ,  A61K31/155 ,  C07C277/00 ,  C07C279/00

CPC分类号： A61K31/155 ,  C07C279/26

摘要： The present invention relates to N,N-dimethyl imidodicarbonimidic diamide acetate, a method of preparing the same and a pharmaceutical composition comprising the same, and more particularly, to N,N-dimethyl imidodicarbonimidic diamide acetate which is a crystalline acid addition salt prepared by reacting N,N-dimethyl imidodicarbonimidic diamide with acetic acid, and which is very effective as a therapeutic agent for treating metabolic syndromes that glycosuria and diabetes mellitus, obesity, hyperlipidemia, fatty liver, coronary heart disease, osteoporosis, polycystic ovarian syndrome, a cancer depleted of gene P53, etc. are complexly occurred; treating diabetes mellitus and preventing its complication; and treating a cancer and preventing myalgia, muscle cell cytotoxicity and rhabdomyolysis, etc. since the acid addition salt is excellent in physicochemical properties such as solubility, stability, non-hygroscopicity, anti-adhering property, etc., and low toxicity, a method of preparing the same and a pharmaceutical composition comprising the same.

摘要翻译： 本发明涉及N，N-二甲基亚氨基二甲酰亚胺二酰胺乙酸盐，其制备方法和包含其的药物组合物，更具体地涉及作为结晶酸加成盐的N，N-二甲基亚氨基二甲酰亚胺二酰胺乙酸盐，其是由 使N，N-二甲基亚氨基二亚甲基二酰胺与乙酸反应，作为治疗代谢综合征的糖尿病，糖尿病，肥胖症，高脂血症，脂肪肝，冠心病，骨质疏松症，多囊卵巢综合症，癌症， 贫血基因P53等复杂发生; 治疗糖尿病并预防其并发症; 并且由于酸加成盐在溶解性，稳定性，非吸湿性，抗附着性等等的物理化学性质和低毒性方面都是优异的，因此治疗癌症并防止肌肉痛，肌肉细胞毒性和横纹肌溶解等。 的制备方法和包含其的药物组合物。

公开(公告)号：US20100087544A1

公开(公告)日：2010-04-08

申请号：US12524695

申请日：2008-01-29

申请人： Sung Wuk Kim ,  Sung Soo Jun ,  Young Gwan Jo ,  Ja Seong Koo ,  Young Woong Kim

发明人： Sung Wuk Kim ,  Sung Soo Jun ,  Young Gwan Jo ,  Ja Seong Koo ,  Young Woong Kim

IPC分类号： A61K31/155 ,  C07C279/00 ,  A61P3/04 ,  A61P3/10 ,  A61P9/00 ,  A61P35/00 ,  A61P19/10

CPC分类号： A61K31/155 ,  C07C279/26

摘要： The present invention relates to N,N-dimethyl imidodicarbonimidic diamide acetate, a method of preparing the same and a pharmaceutical composition comprising the same, and more particularly, to N,N-dimethyl imidodicarbonimidic diamide acetate which is a crystalline acid addition salt prepared by reacting N,N-dimethyl imidodicarbonimidic diamide with acetic acid, and which is very effective as a therapeutic agent for treating metabolic syndromes that glycosuria and diabetes mellitus, obesity, hyperlipidemia, fatty liver, coronary heart disease, osteoporosis, polycystic ovarian syndrome, a cancer depleted of gene P53, etc. are complexly occurred; treating diabetes mellitus and preventing its complication; and treating a cancer and preventing myalgia, muscle cell cytotoxicity and rhabdomyolysis, etc. since the acid addition salt is excellent in physicochemical properties such as solubility, stability, non-hygroscopicity, anti-adhering property, etc., and low toxicity, a method of preparing the same and a pharmaceutical composition comprising the same.

摘要翻译： 本发明涉及N，N-二甲基亚氨基二甲酰亚胺二酰胺乙酸盐，其制备方法和包含其的药物组合物，更具体地涉及作为结晶酸加成盐的N，N-二甲基亚氨基二甲酰亚胺二酰胺乙酸盐，其是由 使N，N-二甲基亚氨基二亚甲基二酰胺与乙酸反应，作为治疗代谢综合征的糖尿病，糖尿病，肥胖症，高脂血症，脂肪肝，冠心病，骨质疏松症，多囊卵巢综合征，癌症， 贫血基因P53等复杂发生; 治疗糖尿病并预防其并发症; 并且由于酸加成盐在溶解性，稳定性，非吸湿性，抗附着性等等的物理化学性质和低毒性方面都是优异的，因此治疗癌症并防止肌肉痛，肌肉细胞毒性和横纹肌溶解等。 的制备方法和包含其的药物组合物。

公开(公告)号：US08541474B2

公开(公告)日：2013-09-24

申请号：US13241731

申请日：2011-09-23

申请人： Sung Wuk Kim ,  Sung Soo Jun ,  Young Gwan Jo ,  Ja Seong Koo ,  Young Woong Kim

发明人： Sung Wuk Kim ,  Sung Soo Jun ,  Young Gwan Jo ,  Ja Seong Koo ,  Young Woong Kim

IPC分类号： A01N37/52 ,  A61K31/155 ,  C07C277/00 ,  C07C279/00

CPC分类号： A61K31/155 ,  C07C279/26

摘要： The present invention relates to N,N-dimethyl imidodicarbonimidic diamide acetate, a method of preparing the same and a pharmaceutical composition comprising the same, and more particularly, to N,N-dimethyl imidodicarbonimidic diamide acetate which is a crystalline acid addition salt prepared by reacting N,N-dimethyl imidodicarbonimidic diamide with acetic acid, and which is very effective as a therapeutic agent for treating metabolic syndromes that glycosuria and diabetes mellitus, obesity, hyperlipidemia, fatty liver, coronary heart disease, osteoporosis, polycystic ovarian syndrome, a cancer depleted of gene P53, etc. are complexly occurred; treating diabetes mellitus and preventing its complication; and treating a cancer and preventing myalgia, muscle cell cytotoxicity and rhabdomyolysis, etc. since the acid addition salt is excellent in physicochemical properties such as solubility, stability, non-hygroscopicity, anti-adhering property, etc., and low toxicity, a method of preparing the same and a pharmaceutical composition comprising the same.

摘要翻译： 本发明涉及N，N-二甲基亚氨基二甲酰亚胺二酰胺乙酸盐，其制备方法和包含其的药物组合物，更具体地涉及作为结晶酸加成盐的N，N-二甲基亚氨基二甲酰亚胺二酰胺乙酸盐，其是由 使N，N-二甲基亚氨基二亚甲基二酰胺与乙酸反应，作为治疗代谢综合征的糖尿病，糖尿病，肥胖症，高脂血症，脂肪肝，冠心病，骨质疏松症，多囊卵巢综合症，癌症， 贫血基因P53等复杂发生; 治疗糖尿病并预防其并发症; 并且由于酸加成盐在溶解性，稳定性，非吸湿性，抗附着性等等的物理化学性质和低毒性方面都是优异的，因此治疗癌症并防止肌肉痛，肌肉细胞毒性和横纹肌溶解等。 的制备方法和包含其的药物组合物。