WO2022160530A1 - 一种茴香霉素衍生物以及茴香霉素和其衍生物作为glp-1r激动剂的用途 - Google Patents
一种茴香霉素衍生物以及茴香霉素和其衍生物作为glp-1r激动剂的用途 Download PDFInfo
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- WO2022160530A1 WO2022160530A1 PCT/CN2021/096473 CN2021096473W WO2022160530A1 WO 2022160530 A1 WO2022160530 A1 WO 2022160530A1 CN 2021096473 W CN2021096473 W CN 2021096473W WO 2022160530 A1 WO2022160530 A1 WO 2022160530A1
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- Prior art keywords
- anisomycin
- glp
- optionally substituted
- pharmaceutically acceptable
- alkyl
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- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
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- DZNKOAWEHDKBEP-UHFFFAOYSA-N methyl 2-[6-[bis(2-methoxy-2-oxoethyl)amino]-5-[2-[2-[bis(2-methoxy-2-oxoethyl)amino]-5-methylphenoxy]ethoxy]-1-benzofuran-2-yl]-1,3-oxazole-5-carboxylate Chemical compound COC(=O)CN(CC(=O)OC)C1=CC=C(C)C=C1OCCOC(C(=C1)N(CC(=O)OC)CC(=O)OC)=CC2=C1OC(C=1OC(=CN=1)C(=O)OC)=C2 DZNKOAWEHDKBEP-UHFFFAOYSA-N 0.000 description 1
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- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- -1 sulfonylureas Chemical compound 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- R 1 is selected from hydrogen, optionally substituted C1-6 alkyl, -C(O)R 4 ;
- R 2 is selected from hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy , -NH-R 4 ;
- R3 is selected from hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkyl, optionally substituted C6-12 aryl, optionally substituted heteroaryl, -C(O)R 4 ;
- R 4 is selected from H, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy;
- R 5 , R 6 , R 7 , R 8 are independently selected from halogen Atom, nitro, -COOR 9 , CONHR 9 , optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy;
- R 9 is selected from H, optionally substituted C1-6 alkyl; conditions The compound of general formula (I) is not anisomycin.
- anisomycin derivatives provided by the present invention are the following compounds 1 and 2:
- a GLP-1R agonist characterized in that it contains at least one of anisomycin, anisomycin derivative shown in formula (I) or pharmaceutically acceptable salts, solvates and stereoisomers thereof as an active ingredient.
- the diabetes is selected from type 2 diabetes.
- Exendin(9-39) blocked the insulin secretion-stimulating effect of anisomycin, which indicated that the insulin-stimulating effect of anisomycin was related to the activation of GLP-1R.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
化合物1 | Ra |
1-1 | -Ph |
1-2 | -C 2H 5 |
1-3 | -4-Cl-Ph |
化合物2 | Rb |
2-1 | -Ph |
2-2 | -C 2H 5 |
2-3 | -C 3H 7 |
茴香霉素 | 美国MCE公司 |
葡萄糖 | 北京索莱宝科技有限公司 |
DispaseII | 美国Amresco公司 |
TEA | Sigma-Aldrich(上海)贸易有限公司 |
Histopaque-1077 | Sigma-Aldrich(上海)贸易有限公司 |
Albumin bovine serum(BSA) | 北京索莱宝科技有限公司 |
RPMI 1640培养基 | 美国Hyclone公司 |
Collagenase P | 瑞士Roche制药 |
Fura 2-AM | 上海东仁化学科技公司 |
胎牛血清(FBS) | 美国Theromo Fisher科技 |
Hanks缓冲液(HBSS) | 博士德生物工程有限公司 |
分析纯NaCl | BBI生命科学有限公司 |
分析纯KCl | BBI生命科学有限公司 |
NaHCO 3 | BBI生命科学有限公司 |
HEPES | 北京索莱宝科技有限公司 |
CaCl 2 | BBI生命科学有限公司 |
分析纯MgCl 2 | BBI生命科学有限公司 |
KH 2PO 4 | BBI生命科学有限公司 |
100×青链霉素混合液 | 北京索莱宝科技有限公司 |
DMS0 | 北京索莱宝科技有限公司 |
MgSO 4 | BBI生命科学有限公司 |
细胞培养箱 | 德国Eppendorf公司 |
恒温振荡器 | 常州国华电器有限公司 |
压力蒸汽灭菌锅 | 太原兴育科教仪器设备制造有限公司 |
超净工作台 | 上海智诚分析仪器制造公司 |
医用冷藏冷冻箱 | 澳柯玛股份有限公司 |
全自动雪花制冰机 | 常熟市雪科电器有限公司 |
酸度计 | 奥豪斯仪器有限公司 |
数字转速型蠕动泵 | 保定创锐泵业有限公司 |
倒置显微镜 | 日本Olympus IX51 |
VORTEX涡旋混合器 | 海门市其林贝尔仪器有限公司 |
PCR仪 | 美国Bio-rad公司 |
凝胶成像系统 | 美国Bio-rad公司 |
Western blot垂直电泳系统 | 美国Bio-rad公司 |
Western blot半干转膜系统 | 美国Bio-rad公司 |
Octet RE96E分子相互作用分析仪 | Fortebio公司 |
天平 | 上海天美科学仪器有限公司 |
移液器 | eppendorf Research plus套装 |
SSA芯片 | Fortebio公司 |
酸度计 | 奥豪斯仪器有限公司 |
数字转速型蠕动泵 | 保定创锐泵业有限公司 |
VORTEX涡旋混合器 | 海门市其林贝尔仪器有限公司 |
茴香霉素 | 美国MCE公司 |
葡萄糖 | 北京索莱宝科技有限公司 |
DMSO | 北京索莱宝科技有限公司 |
PEG-200 | 北京索莱宝科技有限公司 |
动物天平 | 上海菲克苏工具有限公司 |
FreeStyle血糖仪及血糖试纸 | 英国雅培糖尿病护理公司 |
低温超高速离心机 | 德国Eppendorf公司 |
全自动雪花制冰机 | 常熟市雪科电器有限公司 |
数字转速型蠕动泵 | 保定创锐泵业有限公司 |
微型漩涡混合仪 | 上海沪西分析仪器厂有限公司 |
磁力搅拌器 | 上海司乐仪器有限公司 |
组别 | n | 胰岛素分泌(uIU/mL) |
2.8G | 7 | 11.0±1.2 |
2.8G+化合物1-1 | 7 | 12.6±1.3 |
2.8G+化合物1-2 | 7 | 11.9±1.3 |
2.8G+化合物2-1 | 7 | 13.0±1.6 |
2.8G+化合物2-2 | 7 | 11.6±1.0 |
11.1G | 7 | 43.7±6.0 |
11.1G+化合物1-1 | 7 | 92.6±8.7** |
11.1G+化合物1-2 | 7 | 107.3±12.5** |
11.1G+化合物2-1 | 7 | 86.8±9.4* |
11.1G+化合物2-2 | 7 | 96.8±7.1** |
Claims (10)
- 一种通式(I)所示的茴香霉素衍生物或其药学上可接受的盐、溶剂合物、立体异构体,R 1选自氢、任选取代的C1-6烷基、-C(O)R 4;R 2选自氢、任选取代的C1-6烷基、任选取代的C1-6烷氧基、-NH-R 4;R3选自氢、任选取代的C1-6烷基、任选取代的C1-6烷基、任选取代的C6-12芳基、任选取代的杂芳基、-C(O)R 4;R 4选自H、任选取代的C1-6烷基、选取代的C1-6烷氧基;R 5、R 6、R 7、R 8独立地选自卤原子、硝基、-COOR 9、CONHR 9、任选取代的C1-6烷基、任选取代的C1-6烷氧基;R 9选自H,任选取代的C1-6烷基;条件是通式(I)化合物不为茴香霉素。
- 一种GLP-1R激动剂,其特征在于,含有茴香霉素、权利要求1或2所述的茴香霉素衍生物或其药学上可接受的盐、溶剂合物、立体异构体中至少一种作为有效成分。
- 茴香霉素、权利要求1或2所述的茴香霉素衍生物或其药学上可接受的盐、溶剂合物、立体异构体中至少一种在制备GLP-1R激动剂中的用途。
- 茴香霉素、权利要求1或2所述的茴香霉素衍生物或其药学上可接受的盐、溶剂合物、立体异构体中至少一种制备治疗GLP-1R所介导的疾病的药物中的用途。
- 根据权利要求5所述的用途,所述GLP-1R所介导的疾病包括但不限于肥胖、糖尿病、降低体重、降低收缩压、癫痫、脑缺血性疾病、阿尔茨海默症、脂肪肝、改善血脂紊乱、神经保护。
- 茴香霉素、权利要求1或2所述的茴香霉素衍生物或其药学上可接受的盐、溶剂合物、立体异构体中至少一种制备治疗糖尿病、血脂异常、代谢综合征、高胰岛素血症、夜间低血糖症、肥胖、降低体重、降低收缩压、改善阿尔兹海默症、脂肪肝、神经保护的药物的用途;优选地,所述糖尿病选自2型糖尿病。
- 权利要求4-7任一项所述的用途,其特征在于,茴香霉素、权利要求1或2所述的茴香霉素衍生物或其药学上可接受的盐、溶剂合物、立体异构体中至少一种作为有效成分,剂量为0.5-50mg/kg;优选地,剂量为5-30mg/kg。
- 一种具有GLP-1R激动活性的药物组合物,包括茴香霉素、权利要求1或2所述的茴香霉素衍生物或其药学上可接受的盐、溶剂合物、立体异构体中至少一种作为有效活性成分。
- 一种用于治疗或预防糖尿病的药物组合物,包括茴香霉素、权利要求1或2所述的茴香霉素衍生物或其药学上可接受的盐、溶剂合物、立体异构体中至少一种作为有效活性成分;优选地,所述药物组合物中还可以包括二甲双胍、SGLT-2抑制剂等和辅料。
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