WO2010012153A1

WO2010012153A1 - Phlorizin derivatives and their preparation and application

Info

Publication number: WO2010012153A1
Application number: PCT/CN2009/000705
Authority: WO
Inventors: 孙伟新; 赵维民; 顾书华
Original assignee: 常州高新技术产业开发区三维工业技术研究所有限公司
Priority date: 2008-07-29
Filing date: 2009-06-24
Publication date: 2010-02-04
Also published as: CN101638423B; CN101638423A

Abstract

Phlorizin derivatives of formula (I), their preparation and their use for manufacture of pharmaceutical compositions. The said compounds exhibit SGLT2 inhibitory activity and can be used to treat metabolic diseases such as diabetes and its complication.

Description

根皮苷衍生物及其制备方法和应用技术领域 Phlorizin derivative and preparation method and application thereof

本发明主要涉及根皮苷衍生物和合成方法、药物组合物及其应用。背景技术 The present invention generally relates to phlorizin derivatives and methods of synthesis, pharmaceutical compositions and uses thereof. Background technique

根皮苷 (phlorizin)属于二氢査耳酮类化合物，于 19世纪被发现存在于蔷薇科的根茎中（如苹果、梨）。 1987年报道根皮苷的衍生物具有治疗镰刀细胞贫血的功效（美国专利 US4665058 ), 同年又有研究发现根皮苷及其衍生物对于癌症的治疗也有疗效（美国专利 US4684627)。根皮苷还具有降压降脂作用，根皮苷能阻止糖类成分进入表皮细胞，抑制皮腺的过度分泌，治疗分泌旺盛型粉剌；根皮苷能治疗银屑病（美国专利 US4853388); 根皮苷能抑制黑色素细胞活性，对各种皮肤色斑有淡化作用等（美国专利 US6093408 );根皮苷对疟疾的治疗有一定功效（欧洲专利 EP0046270 ); 根皮苷对基质金属蛋白酶具有抑制活性（US2004209952); 此外根皮苷提取物还能治疗病理老化的糖基化最终产物，具有增强记忆力、改善学习能力、预防或治疗骨质疏松、降低血糖、老年痴呆和延缓衰老等独特的生理活性和保健功效（美国公开专利 US2006189512)。 Phlorizin belongs to the dihydrochalcone compound and was found in the rhizome of Rosaceae (such as apples and pears) in the 19th century. In 1987, a derivative of phlorizin was reported to have an effect on the treatment of sickle cell anemia (US Patent US 4,465,058). In the same year, it was found that phlorizin and its derivatives are also effective for the treatment of cancer (US Patent US 4,684,627). Phloridin also has antihypertensive and lipid-lowering effects. Phlorizin can prevent carbohydrates from entering epidermal cells, inhibit excessive secretion of dermis, and treat secreted whitefly; phlorizin can treat psoriasis (US Pat. No. 4,853,388) Phloridin can inhibit melanocyte activity and have a dilute effect on various skin spots (US Pat. No. 6,093,408); phlorizin has certain effects on the treatment of malaria (European Patent EP0046270); phlorizin has a matrix metalloproteinase Inhibitory activity (US2004209952); In addition, phlorizin extract can also treat glycosylation end products of pathological aging, with unique functions such as enhancing memory, improving learning ability, preventing or treating osteoporosis, lowering blood sugar, dementia and delaying aging. Physiological activity and health care efficacy (U.S. Patent No. US2006189512).

但是根皮苷不能通过肠道吸收，口服利用率低，限制了其在临床上的应用。为此需要对根皮苷迸行进一步研究。发明内容 However, phlorizin cannot be absorbed through the intestine, and its oral utilization rate is low, which limits its clinical application. Further research is needed on phlorizin. Summary of the invention

本发明对根皮苷进行结构改造，提高了根皮苷的生物利用度。 The invention structurally reforms phloridzin and improves the bioavailability of phlorizin.

本发明提供了一类含有氮原子的根皮苷衍生物，是一类结构新颖的 SGLT2抑制剂；本发明提供了一类根皮苷衍生物的制备方法； The invention provides a kind of phlorizin derivative containing nitrogen atom, which is a novel structure of SGLT2 inhibitor; the invention provides a method for preparing a phlorizin derivative;

本发明提供了一类活性根皮苷衍生物，可使尿葡萄糖增加，抑制肾小管葡萄糖再吸收，并且有优异的降低血糖的活性； The present invention provides a class of active phlorizin derivatives which can increase urinary glucose, inhibit renal tubular glucose reabsorption, and have an excellent blood sugar lowering activity;

本发明提供了一类含有根皮苷衍生物的药物组合物，其为含有有效治疗量的根皮苷提取物或根皮苷衍生物和可药用载体； The present invention provides a pharmaceutical composition comprising a phlorizin derivative which comprises a therapeutically effective amount of a phlorizin extract or a phlorizin derivative and a pharmaceutically acceptable carrier;

本发明提供了一类根皮苷衍生物或其药学上可接受的盐用来制备治疗糖尿病、糖尿病肾病、糖尿病视网膜病、糖尿病性神经病、延迟伤口愈合、胰岛素抗性、髙血糖、高胰岛素血症、脂肪酸或甘油的水平升高、高脂血症、肥胖症、高甘油三酯血症、动脉粥 The present invention provides a phlorizin derivative or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, delayed wound healing, insulin resistance, blood stasis, high insulin blood Symptoms, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, arteritis

1 1

替换页（细则第 26条) 样硬化、高血压、代谢综合症（X综合症）、糖尿病并发症和肿瘤、骨质疏松、镰刀细胞贫血等多种疾病的药物。 Replacement page (Article 26) Drugs such as sclerosis, hypertension, metabolic syndrome (X syndrome), diabetic complications and tumors, osteoporosis, sickle cell anemia, etc.

本发明提供了一种药物组合物，其含有 SGLT2抑制剂 3' -胺亚甲基根皮苷衍生物和一种或多种下列药物：抗糖尿病药物、治疗糖尿病并发症的药物、抗肥胖症药物、抗高血压药物、抗血小板药物、抗动脉粥样硬化药物 /或降血脂药物、抗氧化剂、肉碱（尤其是左旋肉碱)、肉碱（尤其是左旋肉碱）衍生物、肉碱棕榈酰转移酶抑制剂、乙酰肉碱***、抗肿瘤药物、抗抑郁症药物、抗老年痴呆药物、抗痛风药物、抗骨质疏松药物。发明描述 The present invention provides a pharmaceutical composition comprising a SGLT2 inhibitor 3'-amine methylene phlorizin derivative and one or more of the following drugs: antidiabetic drugs, drugs for treating diabetic complications, and anti-obesity Drugs, antihypertensive drugs, antiplatelet drugs, anti-atherosclerotic drugs/or hypolipidemic drugs, antioxidants, carnitine (especially L-carnitine), carnitine (especially L-carnitine) derivatives, carnitine Palmitoyltransferase inhibitors, acetylcarnitine stimulants, antitumor drugs, antidepressants, anti-senile dementia drugs, anti-gout drugs, anti-osteoporosis drugs. Description of the invention

本发明涉及式（ I ) 根皮苷衍生物及其药学上可接受的盐: The present invention relates to a formula (I) phlorizin derivative and a pharmaceutically acceptable salt thereof:

R为开链或环状的仲胺基或叔胺基结构其中 R is an open-chain or cyclic secondary or tertiary amino group structure

和独立为氢、任意取代的 C₈的烷基，其选自 C¾、 CH(C CH₃) ₂、 C (C )_nCH₃、 d- C₄烷氧基 CH₂0(C 〉_mCH₃、 C「C₄垸巯基 CH₂S (CH₂〉„CH₃、（C¾)„CX₃、（C¾)_BCN、（C )„C00H、 d-C₄烷酰基 (Cft COOR^ (CH₂)_m0H、（CH X、 S0₂(C¾)_mCH₃、 (CH2) _BS0₂R\ C₂-C₄烯基、 C₂- C₄ 炔基、 d - C₄烷基氨基，其中 X为卤素， R¹为 d- C₄烷基、 d- C₄烯基、 d-C₄炔基， m为 0-10 的整数， n为 2-6的整数， a为 0-4的整数；或者 And an independently substituted C ₈ alkyl group selected from the group consisting of C 3⁄4, CH(C CH ₃ ) ₂ , C (C ) _n CH ₃ , d-C ₄ alkoxy CH ₂ 0 (C > _m CH ₃ , C "C ₄ fluorenyl CH ₂ S (CH ₂ 〉 „CH ₃ , (C3⁄4) „CX ₃ , (C3⁄4) _B CN, (C ) „C00H, dC ₄ alkanoyl (Cft COOR^ (CH ₂ ) _m 0H, (CH X, S0 ₂ (C3⁄4) _m CH ₃ , (CH2) _B S0 ₂ R\ C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, d - C ₄ alkylamino, wherein X Is halogen, R ¹ is d-C ₄ alkyl, d-C ₄ alkenyl, dC ₄ alkynyl, m is an integer from 0 to 10, n is an integer from 2 to 6, and a is an integer from 0 to 4;

！^及^和它们相连的氮原子与氧、硫或氮原子环合成可任选被取代的 3- 7元的杂环，该类杂环取代基选自：羟基、羧基、氨基、磺酰基、 d- C₄烧基、羟基 d-C₄焼基、羧基 C!- 烷基、氮基 d- C₄烷基、 C₂- C₄炼基、 C厂 C₄炔基、苯基、 Cr~C₄烷氧苯基、羟基 C_rC₄ 烷基苯基、羧基 d- C₄烷基苯基、卤代 Cr C₄垸基苯基、苯基 - C₄垸基、苯基 C₂- C₄烯基、含氧或含氮的 C₅- ( ^杂环基、含氧或含氮的 C₅- C₆杂环羰基、含氧或含氮的 C₅- C₆杂环院基。 ! ^ and ^ and their attached nitrogen atom are cyclized with an oxygen, sulfur or nitrogen atom to form an optionally substituted 3- 7 membered heterocyclic ring selected from the group consisting of: hydroxy, carboxy, amino, sulfonyl, D-C ₄ alkyl, hydroxy dC ₄ fluorenyl, carboxy C!-alkyl, nitrogen d-C ₄ alkyl, C ₂ - C ₄ refinery, C plant C ₄ alkynyl, phenyl, Cr~C ₄ -alkoxyphenyl, hydroxy C _r C ₄ alkylphenyl, carboxy d-C ₄ alkylphenyl, halogenated Cr C ₄ nonylphenyl, phenyl-C ₄ fluorenyl, phenyl C ₂ - C ₄ -alkenyl, oxygen- or nitrogen-containing C ₅ - (^heterocyclyl, oxygen- or nitrogen-containing C ₅ -C ₆ heterocyclocarbonyl, oxygen- or nitrogen-containing C ₅ -C ₆ heterocyclic compound.

本发明中所述的 3-7元的杂环选自哌啶、吗啉、哌嗪、噻唑、咪唑、吡啶、吡咯、四氢吡咯、吡嗪。 The 3-7 membered heterocyclic ring described in the present invention is selected from the group consisting of piperidine, morpholine, piperazine, thiazole, imidazole, pyridine, pyrrole, Tetrahydropyrrole, pyrazine.

式（I )化合物具有抑制哺乳动物的肠道和肾中的钠依赖性葡萄糖转运蛋白的活性，因而用于治疗糖尿病和糖尿病的微血管和大血管并发症，如视网膜病、神经病、肾病和伤口愈合。 The compound of formula (I) has an activity of inhibiting sodium-dependent glucose transporter in the gut and kidney of mammals, and thus is useful for treating microvascular and macrovascular complications such as retinopathy, neuropathy, nephropathy and wound healing of diabetes and diabetes. .

本发明提供式（I ) 的化合物、使用式（I ) 化合物的药用组合物和使用式（I )化合物的方法。 The present invention provides a compound of the formula (I), a pharmaceutical composition using the compound of the formula (I) and a method of using the compound of the formula (I).

本发明提供一种治疗或延缓下列疾病的发展或发作的药物，该药物包括对哺乳动物一种或多种疾病或身心状态有效量的式（I )所述的化合物或其光学异构体、对映异构体、非对映异构体、外消旋体或外消旋混合物、酯、前药、或其药学上可接受的盐及药学上可接受的载体。该一种或多种疾病或身心状态为：增加高密度脂蛋白的水平、增强记忆力、改善学***升高、高脂血症、肥胖症、高甘油三酯血症、动脉粥样硬化、高血压、代谢综合症 (X综合症)、贫血（如镰刀细胞贫血)、粉刺、肿瘤、风湿性关节炎、关节炎、肠炎、银屑病、多发性硬化症、神经变性紊乱、充血性心力衰竭、中风、主动脉瓣狭窄、肾炎、肾衰竭、痛风、红斑狼疮、 IgA肾病、阑尾炎、胰腺炎、 ***反应（如鼻炎、鼻窦炎）、纤维症、骨病、骨质疏松、心血管疾病（如心律失常、心血管休克、心绞痛）、放疗及化疗并发症、肝病（如肝炎）、胃肠道病症（如胃炎和胃肠炎）、结膜炎、斯耶格伦 (Sjogren' s ) 综合症、肺病、肾病（如多囊肾病）、皮炎、 HIV相关病症、疟疾（如脑疟）、强直性脊椎炎、麻风病、免疫性疾病、抑郁症、老年痴呆症、水肿、溃疡、精神***症、精神障碍性疾病、过敏性休克、尿崩症、哮喘、青光眼、线粒体疾病、帕金森、病理老化的糖基化终端产物、能量代谢异常疾病、基质金属蛋白酶病理性疾病等相关疾病。 The present invention provides a medicament for treating or delaying the development or onset of a disease comprising an effective amount of a compound of the formula (I) or an optical isomer thereof, for one or more diseases or a state of mind and body of a mammal, Enantiomers, diastereomers, racemates or racemic mixtures, esters, prodrugs, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers. The one or more diseases or physical and mental states are: increasing high-density lipoprotein levels, enhancing memory, improving learning ability, aging, diabetes (types I and II), diabetic nephropathy, diabetic foot disease, diabetic retinopathy, diabetes Sexual neuropathy, diabetic complications, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis , hypertension, metabolic syndrome (X syndrome), anemia (such as sickle cell anemia), acne, tumor, rheumatoid arthritis, arthritis, enteritis, psoriasis, multiple sclerosis, neurodegenerative disorders, congestive Heart failure, stroke, aortic stenosis, nephritis, renal failure, gout, lupus erythematosus, IgA nephropathy, appendicitis, pancreatitis, allergies (eg rhinitis, sinusitis), fibrosis, bone disease, osteoporosis, cardiovascular Diseases (such as arrhythmia, cardiovascular shock, angina pectoris), radiotherapy and chemotherapy complications, liver Diseases (such as hepatitis), gastrointestinal disorders (such as gastritis and gastroenteritis), conjunctivitis, Sjogren's syndrome, lung disease, kidney disease (such as polycystic kidney disease), dermatitis, HIV-related disorders, Malaria (eg cerebral malaria), ankylosing spondylitis, leprosy, immune diseases, depression, Alzheimer's disease, edema, ulcers, schizophrenia, mental disorders, anaphylactic shock, diabetes insipidus, asthma, glaucoma , mitochondrial diseases, Parkinson's disease, glycosylation end products of pathological aging, abnormal energy metabolism diseases, pathological diseases of matrix metalloproteinases and other related diseases.

此外，根据本发明，提供一种治疗如在此前和此后定义的糖尿病和相关疾病的药物组合物，其中含有有效治疗量的结构式（I )的化合物与抗糖尿病药物和 /或其它类型的治疗药物，可用于治疗哺乳动物一种或多种疾病或身心状态：增加高密度脂蛋白的水平、增强记忆力、改善学***升高、高脂血症、 BE胖症、高甘油三酯血症、动脉粥样硬化、高血压、代谢综合症（X综合症）、贫血（如镰刀细胞贫血）、粉刺、肿瘤、风湿性关节炎、关节炎、肠炎、银屑病、多发性硬化症、神经变性紊乱、充血性心力衰竭、中风、主动脉瓣狭窄、肾炎、肾衰竭、痛风、红斑狼疮、 IgA肾病、阑尾炎、胰腺炎、 ***反应（如鼻炎、鼻窦炎）、纤维症、骨病、骨质疏松、心血管疾病（如心律失常、心血管休克、心绞痛)、放疗及化疗并发症、肝病（如肝炎）、胃肠道病症（如胃炎和胃肠炎)、结膜炎、斯耶格伦（Sjogren' s)综合症、肺病、肾病（如多囊肾病)、皮炎、 HIV相关病症、疟疾（如脑疟）、强直性脊椎炎、麻风病、免疫性疾病、抑郁症、老年痴呆症、 7j肿、溃疡、精神***症、精神障碍性疾病、过敏性休克、尿崩症、哮喘、青光眼、线粒体疾病、帕金森、病理老化的糖基化终端产物、能量代谢异常、基质金属蛋白酶病理性疾病等相关疾病。 Further, according to the present invention, there is provided a pharmaceutical composition for treating diabetes and related diseases as defined hereinbefore and hereinafter, which comprises a therapeutically effective amount of a compound of formula (I) and an antidiabetic agent and/or other type of therapeutic agent It can be used to treat one or more diseases or physical and mental states in mammals: increase high-density lipoprotein levels, enhance memory, improve learning ability, aging, diabetes (types I and II), diabetic nephropathy, diabetic foot disease, diabetes Retinopathy, diabetic neuropathy, diabetic complications, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, BE fatness, hypertriglyceridemia , atherosclerosis, hypertension, metabolic syndrome (X syndrome), anemia (such as sickle cell anemia), acne, swelling Tumor, rheumatoid arthritis, arthritis, enteritis, psoriasis, multiple sclerosis, neurodegenerative disorders, congestive heart failure, stroke, aortic stenosis, nephritis, renal failure, gout, lupus erythematosus, IgA nephropathy, Appendicitis, pancreatitis, allergies (such as rhinitis, sinusitis), fibrosis, bone disease, osteoporosis, cardiovascular disease (such as arrhythmia, cardiovascular shock, angina pectoris), radiotherapy and chemotherapy complications, liver disease (such as hepatitis) ), gastrointestinal disorders (such as gastritis and gastroenteritis), conjunctivitis, Sjogren's syndrome, lung disease, kidney disease (such as polycystic kidney disease), dermatitis, HIV-related disorders, malaria (such as the brain) Malaria, ankylosing spondylitis, leprosy, immune disease, depression, Alzheimer's disease, 7j swollen, ulcer, schizophrenia, mental disorder, anaphylactic shock, diabetes insipidus, asthma, glaucoma, mitochondrial disease , Parkinson's disease, glycosylation end products of pathological aging, abnormal energy metabolism, pathological diseases of matrix metalloproteinases and other related diseases.

本发明所说的哺乳动物包括人、马、猴、猪、鼠、狗、兔等。 The mammals referred to in the present invention include humans, horses, monkeys, pigs, rats, dogs, rabbits and the like.

本发明所说的化合物 ( I)的前药包括但不限于化合物（I)的一种或多种 ΐί羟基和 /或酚羟基酰化物如乙酰、丙酰、丁酰产物及一种或多种醇羟基和 /或酚羟基苄基、甲基、乙基产物等。 The prodrug of the compound (I) according to the present invention includes, but is not limited to, one or more of the compounds (I), and/or a phenolic hydroxy acylate such as an acetyl, propionyl, butyryl product and one or more Alcoholic hydroxyl and/or phenolic hydroxybenzyl, methyl, ethyl, and the like.

本发明所说的病理老化的糖基化终端产物相关疾病包括但不限于糖尿病、老年痴呆症、动脉粥样硬化、肾病、骨关节炎、骨质疏松、衰老等疾病中的一种或多种。 The pathologically aged glycosylation end product related diseases of the present invention include, but are not limited to, one or more of diabetes, Alzheimer's disease, atherosclerosis, kidney disease, osteoarthritis, osteoporosis, aging and the like. .

本发明所说的基质金属蛋白酶病理性疾病包括但不限于动脉粥样硬化、中枢神经系统炎症、阿耳茨海默（氏)病、哮喘、皮肤老化、类风湿性关节炎、骨关节炎、骨质疏松、脓毒性关节炎、子宫内膜异位症、角膜溃疡粘连、骨病、蛋白尿、腹主动脉瘤、退化性软骨损耗、多动性硬化症、髓鞘神经耗损、肝纤维化、 nephroglomerular病、胚膜破裂、肠炎、牙周病、老年黄斑变性、糖尿病视网膜疾病、视网膜玻璃体增生、视网膜发育不良、眼炎、角膜溃疡、 Sjogren' s并发症、眼近视瘤、肿瘤转移中的一种或多种。 The matrix metalloproteinase pathological diseases of the present invention include, but are not limited to, atherosclerosis, central nervous system inflammation, Alzheimer's disease, asthma, skin aging, rheumatoid arthritis, osteoarthritis, Osteoporosis, septic arthritis, endometriosis, corneal ulcer adhesion, bone disease, proteinuria, abdominal aortic aneurysm, degenerative cartilage loss, hyperactivity sclerosis, myelin nerve loss, liver fibrosis , nephroglomerular disease, rupture of the blastum, enteritis, periodontal disease, age-related macular degeneration, diabetic retinal disease, vitreoretinal retina, retinal dysplasia, ophthalmia, corneal ulcer, Sjogren's complications, ocular myopia, tumor metastasis One or more.

本发明所说的线粒体疾病包括但不限于眼肌麻痹、肌肉病变、运动失调、癲痫发作、肌阵挛、中风、视神经病变、感音神经性聋、痴呆、周围神经病、肌张力障碍、脊髓病变、心肌病、白内障、色素性视网膜病变、代谢性酸中毒、恶心、呕吐、肝病、肾病、假性肠梗阻、铁粒幼细胞贫血、糖尿病、胰腺外分泌功能障碍和甲状旁腺功能低下症中的一种或多种。 The mitochondrial diseases of the present invention include, but are not limited to, ophthalmoplegia, muscle lesions, movement disorders, seizures, myoclonus, stroke, optic neuropathy, sensorineural hearing loss, dementia, peripheral neuropathy, dystonia, spinal cord Lesions, cardiomyopathy, cataracts, pigmented retinopathy, metabolic acidosis, nausea, vomiting, liver disease, kidney disease, pseudo-intestinal obstruction, iron granulocyte anemia, diabetes, pancreatic exocrine dysfunction, and hypoparathyroidism One or more.

本发明所说的能量代谢异常疾病包括但不限于创伤、缺血及再灌注损伤导致的疾病，如各种急性化学物理因素所致的创伤、中毒、休克、高原病、放射病、尘肺、电击伤、暈动病、急慢性心功能不全，心律失常、心脏传导异常、人工心脏起搏、心血管介入疗法、瓣膜病、动脉粥样硬化、冠心病、（包括猝死)、先天性心脏病、高血压、感染性心内膜炎、肺源性心脏病、心包炎、心肌病、周围血管疾病（包括多发性大动脉炎、雷诺综合症、血栓闭塞性脉管炎、闭塞性动脉硬化等)、心脏移植手术、神经痛、神经炎、各种周围神经病、各种脊髓疾病、急性脑血管疾病（包括脑梗死、脑栓塞、脑出血、蛛网膜下腔出血等）、颅内肿瘤、中枢神经***感染（包括病毒和细菌性脑炎、脑膜炎等)、运动障碍性疾病（帕金森病、舞蹈病、肝豆状核变性、肌张力障碍、抽搐与振颤）发作性疾病（包括癫痫、偏头痛、发作性睡病与猝倒症等）、脱髓鞘性疾病（包括多发性硬化症、视神经脊髓炎、脑白质营养不良)、骨骼肌肉病（包括肌营养不良症、强直性肌病、重症肌无力、炎症性肌病、代谢性肌病、周期性瘫痪)、自主神经疾病（包括雷诺病、红斑性肢痛、间脑综合症）、弥散性血管内凝血等；胰岛素抵抗及内分泌等因素引起的疾病，如肥胖症、各种原因所致低血糖、胰岛素抵抗综合症、代谢综合症、营养不良（营养不良性干瘦、恶性营养不良、继发性蛋白质能量营养不良)、肠内营养、肠外营养、水电解质代谢紊乱、酸碱平衡紊乱、糖尿病、糖尿病心血管疾病、糖尿病周围神经病变、糖尿病视网膜病变、糖尿病肾病、糖尿病足、妊娠与糖尿病、糖尿病并发感染、糖尿病急性代谢并发症、乳酸性酸中毒、各型糖原累积病、血脂蛋白紊乱、高氨基酸尿症、黄瘤、粘多糖病、果糖不耐受症、半乳糖血症、其他嘌吟和嘧啶代谢疾病、营养与代谢障碍性皮肤病（维生素缺乏、肠病性肢端皮炎、原发性皮肤淀粉样变、皮肤卟啉病、黄瘤病）、糖尿病视网膜并发症、生长激素缺乏性侏儒症、成年人腺垂体功能减退症、肾上腺病、甲状腺病、甲状旁腺病、卵巢病、性早熟、胰岛内分泌肿瘤、多发性内分泌腺病等疾病；肿瘤等疾病，如各种肿瘤、癌症、肉瘤、血癌、急慢性白细胞及粒细胞性白血病、各种原因所致的贫血（包括骨髓性贫血、再生障碍性贫血、镰状红细胞性贫血）、淋巴组织细胞病、自身免疫性疾病、原发性和继发性免疫缺陷病、肺部肿瘤、肺肉瘤、消化性溃疡、食道癌、胃癌、胃肿瘤、大肠癌、肾脏肿瘤、口腔肿瘤、原发性和继发性肝癌、胆管肿瘤、艾滋病、各种皮肤癌、骨髓肿瘤等疾病；炎症、严重感染和免疫反应导致的疾病，如感染性休克、多脏器功能衰竭、高温、低温综合症、感染性疾病（.呼吸道感染、哮喘、严重急性呼吸综合症、病毒性肝炎、流行性腮腺炎、流行性乙型脑炎、狂犬病、脊髓灰质炎、麻疹、风疹、天花、水痘、单纯疱疹、带状疱疹、流行性出血热、黄热病、肠道病毒所致的各***感染、传染性单核细胞增多症、巨细胞病毒感染、艾滋病、立克次体病、衣原体感染、支原体感染、细菌性疾病（包括结核性疾病厌氧菌感染、败血症、破伤风等）、真菌性疾病、螺旋体病、寄生虫病、各种原因引起的感染性腹泻、急性出血坏死性小肠炎、溃疡性结肠炎、肠梗阻、胃动力性和功能性疾病、急性腹膜炎、急性胰腺炎、各种原因引起肝硬化、脂肪肝、黄疸、腹泻、消化道出血、反流性食管炎、爆发性肝功能衰竭、肝性脑病、胆石病、胆囊炎、急慢性肾功能衰竭、血液净化疗法、急慢性呼吸功能不全、慢性阻塞性肺疾病、支气管哮喘、支气管扩张、各种原因引起的肺炎、肺脓肿、肺水肿、肺栓塞、肺静脉瘘、肺结核、先天性肺发育不全、阻塞性睡眠呼吸暂停综合症、呼吸衰竭、急性呼吸窘迫综合征、急慢性肾炎、肾病综合症、微小病变性肾病、膜性肾病、局灶性肾小球硬化症、系膜增殖性肾小球肾炎、系膜毛细血管增生性肾炎、继发性肾小球疾病、遗传性肾炎、泌尿道感染、间质性肾炎、肾小管疾病、肾石病、牙周脓肿、病毒性皮肤疾病、细菌性皮肤疾病、真菌性皮肤病、荨麻疹类皮肤病、失聪、美尼尔氏综合症、急慢性中耳炎、结膜病、角膜病、白内障、青光眼、葡萄膜病、视网膜病、视神经病、急慢性扁桃体炎、扁桃体脓肿、骨关节炎、代谢性骨病、骨质疏松症、痛风和高尿酸血症、结节病、淀粉样变性、大骨节病、色素性皮肤病（白癜风、黄褐斑、雀斑、黑变病、遗传性大疱性表皮松解症、鱼鳞病、毛周角化病、家族性良性天疱疮、日光性皮肤病、冻疮、放射性皮肤病、痤疮、脂溢性皮炎、斑秃、雄激素源性脱发、风湿热、 ***性红斑囊疮、类风湿性关节炎、脊柱关节病、多发性肌炎和皮肌炎、硬皮病和***性硬化症、过敏性疾病等；各种原因所致线粒体功能障碍导致的退行性病变以及神经精神性疾病，如衰老、阿尔兹海默病、各种原因导致的线粒体疾病，如亨廷顿氏疾病、帕金森病 (PD)、肌萎缩性侧索硬化、线粒体脑肌病伴乳酸中毒及中风样发作综合征 (MELAS)、肌阵挛性癫痫伴破碎红纤维病 (MERRF)、 Leber遗传性视神经病 (LH0N)、线粒体心肌病、肌病、痴呆、突发的不能控制的肌肉收缩 (肌阵挛性的癫痫）、精神疾病包括器质性精神障碍（痴呆综合症、谵妄综合症、遗忘综合症、艾滋病所致精神障碍）、精神活性物质所致精神障碍（酒精中毒和酒精依赖、药物依赖）、精神***症、情感障碍、神经症性障碍（恐怖症、焦虑症、强迫症、神经衰弱、瘛症、疑病症）、进食障碍、睡眠障碍、广泛性发育障碍、精神发育迟滞、多动障碍、抽动障碍、男性性功能障碍等疾病急慢性缺血、创伤、严重感染、糖尿病和肿瘤等。 The abnormal energy metabolism diseases according to the present invention include, but are not limited to, diseases caused by trauma, ischemia and reperfusion injury, such as trauma, poisoning, shock, altitude sickness, radiation sickness, pneumoconiosis, electric shock caused by various acute chemical and physical factors. , motion sickness, acute and chronic heart failure, arrhythmia, cardiac conduction abnormalities, artificial cardiac pacing, cardiovascular interventional therapy, valvular disease, atherosclerosis, coronary heart disease, (including sudden death), congenital heart disease, high Blood pressure, infection Endocarditis, pulmonary heart disease, pericarditis, cardiomyopathy, peripheral vascular disease (including multiple arteritis, Raynaud's syndrome, thromboangiitis obliterans, occlusive arteriosclerosis, etc.), heart transplant surgery, Neuralgia, neuritis, various peripheral neuropathy, various spinal diseases, acute cerebrovascular diseases (including cerebral infarction, cerebral embolism, cerebral hemorrhage, subarachnoid hemorrhage, etc.), intracranial tumors, central nervous system infections (including viruses) And bacterial encephalitis, meningitis, etc.), dyskinesia (Parkinson's disease, chorea, hepatolenticular degeneration, dystonia, convulsions and chattering). Episodes (including epilepsy, migraine, seizures) Sleep sickness and cataplexy, etc., demyelinating diseases (including multiple sclerosis, optic neuromyelitis, leukodystrophy), musculoskeletal diseases (including muscular dystrophy, myotonic myopathy, myasthenia gravis, Inflammatory myopathy, metabolic myopathy, periodic paralysis, autonomic diseases (including Raynaud's disease, erythema limb pain, diencephalon syndrome), Mi Disseminated intravascular coagulation; diseases caused by factors such as insulin resistance and endocrine, such as obesity, hypoglycemia caused by various causes, insulin resistance syndrome, metabolic syndrome, malnutrition (nutrition, thinness, malignant malnutrition, Secondary protein energy malnutrition), enteral nutrition, parenteral nutrition, water and electrolyte metabolism disorders, acid-base balance disorders, diabetes, diabetes cardiovascular disease, diabetic peripheral neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic foot, pregnancy And diabetes, diabetes complicated by infection, acute metabolic complications of diabetes, lactic acidosis, various types of glycogen accumulation disease, dyslipoprotein disorders, high amino aciduria, xanthomas, mucopolysaccharidosis, fructose intolerance, galactose blood Disease, other sputum and pyrimidine metabolic diseases, nutritional and metabolic disorders (vitamin deficiency, enteric acral dermatitis, primary skin amyloidosis, porphyria, xanthomatosis), diabetic retinal complications Growth hormone deficiency dwarfism, adult glandularity Dysfunction, adrenal gland disease, thyroid disease, parathyroid disease, ovarian disease, precocious puberty, islet endocrine tumor, multiple endocrine adenosis, etc.; diseases such as tumors, such as various tumors, cancer, sarcoma, blood cancer, acute and chronic diseases Leukocyte and granulocyte leukemia, anemia caused by various causes (including myeloid anemia, aplastic anemia, sickle cell anemia), lymphoid histiocytosis, autoimmune diseases, primary and secondary immunity Defective diseases, lung tumors, pulmonary sarcoma, peptic ulcer, esophageal cancer, gastric cancer, stomach cancer, colorectal cancer, kidney tumor, oral tumor, primary and secondary liver cancer, biliary tract cancer, AIDS, various skin cancer, Diseases such as bone marrow tumors; diseases caused by inflammation, severe infections and immune reactions, such as septic shock, multiple organ failure, high temperature, hypothermia syndrome, infectious diseases (respiratory tract infections, asthma, severe acute respiratory syndrome, viruses) Hepatitis, mumps, Japanese encephalitis, rabies, Polio, measles, rubella, smallpox, chickenpox, herpes simplex, herpes zoster, epidemic hemorrhagic fever, yellow fever, various systemic infections caused by enterovirus, infectious mononucleosis, cytomegalovirus infection , AIDS, rickettsial disease, chlamydial infection, mycoplasma infection, bacterial diseases (including tuberculosis anaerobic infections, sepsis, tetanus, etc.), fungal diseases, spirochetes, parasitic diseases, various causes Infectious diarrhea, acute hemorrhagic necrotic enteritis, ulcerative colitis, intestinal obstruction, gastric motility and function Sexual diseases, acute peritonitis, acute pancreatitis, cirrhosis caused by various causes, fatty liver, jaundice, diarrhea, gastrointestinal bleeding, reflux esophagitis, fulminant hepatic failure, hepatic encephalopathy, cholelithiasis, cholecystitis, Acute and chronic renal failure, blood purification therapy, acute and chronic respiratory insufficiency, chronic obstructive pulmonary disease, bronchial asthma, bronchiectasis, pneumonia caused by various causes, lung abscess, pulmonary edema, pulmonary embolism, pulmonary venous fistula, tuberculosis, congenital Spontaneous pulmonary hypoplasia, obstructive sleep apnea syndrome, respiratory failure, acute respiratory distress syndrome, acute and chronic nephritis, nephrotic syndrome, minimally pathological nephropathy, membranous nephropathy, focal glomerulosclerosis, mesangium Proliferative glomerulonephritis, mesangial capillary proliferative nephritis, secondary glomerular disease, hereditary nephritis, urinary tract infection, interstitial nephritis, renal tubular disease, nephrolithiasis, periodontal abscess, viral Skin diseases, bacterial skin diseases, fungal skin diseases, urticaria skin diseases, loss Cong, Ménière's syndrome, acute and chronic otitis media, conjunctival disease, corneal disease, cataract, glaucoma, uveopathy, retinopathy, optic neuropathy, acute and chronic tonsillitis, tonsil abscess, osteoarthritis, metabolic bone disease, Osteoporosis, gout and hyperuricemia, sarcoidosis, amyloidosis, Kashin-Beck disease, pigmented skin disease (vitiligo, chloasma, freckles, melanosis, hereditary bullous epidermolysis) , ichthyosis, keratosis, familial benign pemphigus, solar dermatosis, frostbite, radiation skin disease, acne, seborrheic dermatitis, alopecia areata, androgenetic alopecia, rheumatic fever, systemic erythema Sores, rheumatoid arthritis, spondyloarthropathy, polymyositis and dermatomyositis, scleroderma and systemic sclerosis, allergic diseases, etc.; degenerative diseases and nerves caused by mitochondrial dysfunction Mental illness, such as aging, Alzheimer's disease, mitochondrial diseases caused by various causes, such as Huntington's disease, Parkinson's disease (PD), muscle weakness Lateral lateral sclerosis, mitochondrial myopathy with lactic acidosis and stroke-like seizure syndrome (MELAS), myoclonic epilepsy with broken red fiber disease (MERRF), Leber hereditary optic neuropathy (LH0N), mitochondrial cardiomyopathy, muscle Disease, dementia, sudden uncontrollable muscle contraction (myoclonic epilepsy), mental illness including organic mental disorder (dementia syndrome, delirium syndrome, amnesia syndrome, mental disorder caused by AIDS), spirit Mental disorders caused by active substances (alcoholism and alcohol dependence, drug dependence), schizophrenia, affective disorder, neurosis (phobia, anxiety, obsessive-compulsive disorder, neurasthenia, snoring, suspected illness), eating disorders , sleep disorders, generalized developmental disorders, mental retardation, hyperactivity disorder, tic disorder, male sexual dysfunction and other diseases such as acute and chronic ischemia, trauma, serious infections, diabetes and tumors.

本发明所说的糖尿病并发症包括但不限于糖尿病肾病、糖尿病足病、糖尿病视网膜病、糖尿病性神经病等与糖尿病相关的微血管疾病。 The diabetic complications referred to in the present invention include, but are not limited to, diabetic nephropathy, diabetic foot disease, diabetic retinopathy, diabetic neuropathy, and the like.

统称为 "X综合症"（也称做代谢综合症）的病症、疾病和疾患是以中心性肥胖为核心，合并血压、血糖、甘油三酯升高和 /或 HDL- C降低，是胰岛素抵抗所致的糖，脂代谢紊乱，以合并出现多种代谢性疾病为临床特点的一组严重影响健康的症候群。详述于 Johannsson J. Clin. Endocrinol. Metab. , 82, 727-34 ( 1997) 中。 The diseases, diseases, and diseases collectively referred to as "X Syndrome" (also known as metabolic syndrome) are centered on obesity, combined with blood pressure, blood sugar, elevated triglycerides, and/or decreased HDL-C, which is insulin resistance. The resulting sugar, lipid metabolism disorder, combined with the emergence of a variety of metabolic diseases as a clinical feature of a group of severely affected health syndrome. Detailed in Johannsson J. Clin. Endocrinol. Metab., 82, 727-34 (1997).

此处所用的术语 "其它类型的治疗药物"包括治疗糖尿病并发症的药物、抗肥胖症药物、抗高血压药物、抗血小板药物、抗动脉粥样硬化药物 /或降血脂药物、抗氧化剂、肉碱（尤其是左旋肉碱）及其相关的盐、肉碱衍生物（尤其是左旋肉碱衍生物如乙酰肉碱、丙酰肉碱)、肉碱棕榈酰转移酶抑制剂、肉碱辛酰基转移酶抑制剂、乙酰肉碱兴奋剂、抗肿瘤药物、抗痛风药物、治疗骨质疏松药物、抗抑郁症药物、治疗贫血药物、治疗老年痴呆症药物、抗炎药物、免疫性药物及根皮苷提取物中的一种或多种。 The term "other types of therapeutic agents" as used herein includes drugs for treating diabetic complications, anti-obesity drugs, antihypertensive drugs, antiplatelet drugs, antiatherogenic drugs or hypolipidemic drugs, antioxidants, meat. Alkali (especially L-carnitine) and its related salts, carnitine derivatives (especially L-carnitine derivatives such as acetylcarnitine, propionylcarnitine), carnitine palmitoyltransferase inhibitors, carnitine octanoyl Transferase inhibitors, acetylcarnitine stimulants, antitumor drugs, anti-gout drugs, osteoporosis drugs, antidepressants, anemia drugs, Alzheimer's drugs, anti-inflammatory drugs, immunological drugs and root bark One or more of the glycoside extracts.

本发明的活性成分结构式（I ) 化合物与一种或多种其它类型的治疗药物（取决于其作用模式）的重量比为 1: 0. 0001-1： 0. 1，优选的重量比为 1: 0. 0001-1： 0. 01的范围内。 The weight ratio of the active ingredient structural formula (I) of the present invention to one or more other types of therapeutic agents (depending on the mode of action thereof) is 1: 0.001-1: 0.1, the preferred weight ratio is 1. : 0. 0001-1: 0. 01 range.

优选式（I) 的化合物- Preferred compounds of formula (I) -

其中 R为开链或环状的仲胺基或叔胺基结构 NRA。 Wherein R is an open or cyclic secondary or tertiary amine structure NRA.

和独立为氢、低级垸基、取代的低级烷基、取代的低级链烯基、取代的低级链炔基、取代的 5- 6元的碳环基、取代的杂环基、取代的芳基、或及和它们相连的氮原子分别与氧、硫或氮原子环合成可任意被取代的 3-7元的杂环。 And independently hydrogen, lower fluorenyl, substituted lower alkyl, substituted lower alkenyl, substituted lower alkynyl, substituted 5- to 6-membered carbocyclic, substituted heterocyclic, substituted aryl And or a nitrogen atom to which they are attached is cyclized with an oxygen, sulfur or nitrogen atom, respectively, to form a 3-7 membered heterocyclic ring which may be optionally substituted.

最优选式（I ) 的化合物： Most preferred are compounds of formula (I):

其中 R为开链或环状的仲胺基或叔胺基结构 N I^ Wherein R is an open or cyclic secondary or tertiary amino group structure N I^

和独立为氢、任意取代的垸基，其选自 C 、 CH(C¾C¾) ₂、 C (CH₂)„C¾、 d—C₄烷氧基 CH₂0 (CH C¾、 C「C₄垸巯基 C¾S （C ) _raC 、（C )_mCN、 (0¾) 00Η>And independently a hydrogen, optionally substituted fluorenyl group selected from C, CH(C3⁄4C3⁄4) ₂ , C (CH ₂ ) „C3⁄4, d—C ₄ alkoxy CH ₂ 0 (CH C3⁄4, C “C ₄ fluorenyl” C3⁄4S (C) _ra C , (C ) _m CN, (03⁄4) 00Η>

C「C₄烷酰基 (CH mCOOR¹ (CH 0H、（CH₂)_mX、 S0₂ (C )_mCH₃、 (CH2)_BS0₂R C₂-C₄燦基、 C₂-Q 炔基、 Cr 烧基氣基，其中 X为卤素， R¹为 d- C₄烷基、 d- C₄烯基、 Cr C₄炔基，m为 0-10 的整数， n为 2- 6的整数， a为 0-4的整数；或者 C "C ₄ alkanoyl (CH mCOOR ¹ (CH 0H, (CH ₂ ) _m X, S0 ₂ (C ) _m CH ₃ , (CH2) _B S0 ₂ RC ₂ -C ₄ cantyl, C ₂ -Q alkynyl) And a Cr-based gas group, wherein X is a halogen, R ¹ is a d-C ₄ alkyl group, a d-C ₄ alkenyl group, a Cr C ₄ alkynyl group, m is an integer of 0-10, and n is an integer of 2-6 , a is an integer from 0-4; or

及和它们相连的氮原子与氧、硫或氮原子环合成可任选被取代的 3-7元的杂环，该类杂环取代基选自：羟基、羧基、氨基、磺酰基、 CrC₄垸基、羟基 d- C₄烧基、羧基 d_C₄垸基、氨基 d-C₄垸基、 C₂ - C₄烯基、 C₂-C₄炔基、苯基、 d-C₄烷氧苯基、羟基 d-C₄ 垸基苯基、羧基 d-C₄烷基苯基、卤代 d-C₄烷基苯基、苯基 d-C₄烷基、苯基 C₂-C₄烯基、含氧或含氮的 ( ₅-(：₅杂环基、含氧或含氮的 C₅-C_e杂环羰基、含氧或含氮的 C₅- C_e杂环 d- 焼基。 And the nitrogen atom to which they are attached is cyclized with an oxygen, sulfur or nitrogen atom to form an optionally substituted 3-7 membered heterocyclic ring selected from the group consisting of: hydroxy, carboxy, amino, sulfonyl, CrC ₄ Sulfhydryl, hydroxy d-C ₄ alkyl, carboxyl D_C ₄ fluorenyl, amino dC ₄ fluorenyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, phenyl, dC ₄ alkoxyphenyl, hydroxy dC ₄ nonylphenyl, carboxy dC ₄ alkyl Phenyl, halo dC ₄ alkylphenyl, phenyl dC ₄ alkyl, phenyl C ₂ -C ₄ alkenyl, oxygenated or nitrogenous ( ₅ -(: ₅ heterocyclyl, oxygenated or nitrogenous) C ₅ -C _e heterocyclic carbonyl, oxygen-containing or nitrogen-containing C ₅ - C _e heterocyclic d-fluorenyl.

发明详述： Detailed description of the invention:

本发明的式（I) 化合物可以用如下面所示的方法进行制备。 The compound of the formula (I) of the present invention can be produced by a method as shown below.

本发明化合物式（I ) 中的化合物： The compound of the formula (I) of the present invention:

可通过始化合物（I-a) 与甲醛（或低级烷基醛）及相应的伯胺或仲胺在质子性溶剂中反应进行制备： It can be prepared by reacting the starting compound (I-a) with formaldehyde (or lower alkyl aldehyde) and the corresponding primary or secondary amine in a protic solvent:

伯胺和仲胺是 CrC,。的脂肪胺、氨基酸、芳胺、不饱和脂肪胺、环烷基胺、杂环烷基胺、不饱和环烷基胺、不饱和杂环垸基胺。 The primary and secondary amines are CrC. Fatty amines, amino acids, aromatic amines, unsaturated fatty amines, cycloalkylamines, heterocycloalkylamines, unsaturated cycloalkylamines, unsaturated heterocyclic mercaptoamines.

溶剂可以是任何不干扰反应的常规溶剂，例如水；醇（例如甲醇、乙醇、丙醇）；酯（例如乙酸乙酯）；卤代烃（例如二氯甲烷）；酰胺类（例如二甲基甲酰胺）；醚类（例如四氢呋喃）；腈类（乙腈）等，或其混合物。 The solvent may be any conventional solvent which does not interfere with the reaction, such as water; alcohol (e.g., methanol, ethanol, propanol); ester (e.g., ethyl acetate); halogenated hydrocarbon (e.g., dichloromethane); amide (e.g., dimethyl) Formamide); ethers (such as tetrahydrofuran); nitriles (acetonitrile), etc., or mixtures thereof.

该反应可在低温至加热温度下进行，优选温度为 -10Ό至 100°C，特别优选 0°C至 80 The reaction can be carried out at a low temperature to a heating temperature, preferably at a temperature of from -10 Torr to 100 °C, particularly preferably from 0 °C to 80 °

°C。本发明的化合物（I-a)可通过将蔷薇科或壳斗科植物的根、茎、叶或果实提取后经过大孔树脂或聚酰胺精制而得到髙纯度的根皮苷。 °C. The compound (Ia) of the present invention can be obtained by extracting roots, stems, leaves or fruits of Rosaceae or Fagaceae, and then purifying it with macroporous resin or polyamide to obtain ruthenium purine of ruthenium purity.

本发明中质子性溶剂包括水、吡啶、甲醇、乙醇、丙醇、异丙醇、丁醇、异丁醇、叔丁醇等各种醇类。 The protic solvent in the present invention includes various alcohols such as water, pyridine, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, and t-butanol.

本发明中化合物（I- a)与甲醛（或低级垸基醛）及相应的仲胺在质子性溶剂中进行反应则按摩尔比为化合物（I-a) ：甲醛：仲胺 =1:1:1得到相关的化合物（1)。具体流程为- In the present invention, the compound (I-a) is reacted with formaldehyde (or lower mercapto aldehyde) and the corresponding secondary amine in a protic solvent, and the molar ratio is the compound (Ia): formaldehyde: secondary amine = 1:1:1 The related compound (1) is obtained. The specific process is -

本发明中化合物 Cl-a) 与甲醛（或低级烷基醛）及相应的伯胺在质子性溶剂中当按摩尔比为化合物（I- _a) ：甲醛：仲胺 =1:1:1进行反应则得到相关的化合物（1)，而当按摩尔比为化合物（I-a) ：甲醛：仲胺 =2:2:1进行反应则得到相关的化合物（1)。具体流程为： In the present invention, the compound Cl-a) and formaldehyde (or lower alkyl aldehyde) and the corresponding primary amine are in a protic solvent when the molar ratio is compound (I- _a ): formaldehyde: secondary amine = 1:1:1. The reaction gives the related compound (1), and when the molar ratio is the compound (Ia): formaldehyde: secondary amine = 2:2:1, the related compound (1) is obtained. The specific process is:

本文使用以下缩略语- c¾o = 甲醛

This article uses the following abbreviations - c3⁄4o = formaldehyde

HDL-C =高密度脂蛋白胆固醇 HDL-C = high density lipoprotein cholesterol

V =摄氏度 V = degrees Celsius

SGLT =钠依赖性糖协同转运蛋白 SGLT = sodium-dependent sugar cotransporter

PPAR =过氧化物酶体增生物激活受体 min =分钟 PPAR = peroxisome proliferator-activated receptor min = minute

h或 hr =小时 h or hr = hour

L =升 - mL =毫升 L = liter - mL = ml

μ ΐ =微升 μ ΐ = microliter

g =克 g = gram

mg =毫克 Mg = mg

mol =摩尔 Mol = mole

腿 ol =毫摩尔 Leg ol = millimolar

nm =纳米 Nm = nanometer

μ M =微米 μ M = micron

TLC =薄层分析 TLC = thin layer analysis

HPLC =高效液相色谱 ESIMS = 电喷雾电离质谱 HPLC = high performance liquid chromatography ESIMS = electrospray ionization mass spectrometry

I = 红外 I = infrared

HNMR =氢谱 HNMR = hydrogen spectrum

CNMR ：碳谱 CNMR: carbon spectrum

m. p =熔点 m. p = melting point

DMS0 =二甲亚砜 DMS0 = dimethyl sulfoxide

mRNA =信使核糖核酸 mRNA = messenger ribonucleic acid

cDNA =互补脱氧核糖核酸 cDNA = Complementary Deoxyribonucleic Acid

除非另外指明，术语"低级烷基"在此单独或作为另一个基团的一部分使用时，包括含 1-8个碳原子的直链和支链烃，术语 "烷基"和 "alk"在此单独或作为另一基团的一部分使用时，包括含 1-20个碳原子，优选 1-10个碳原子，在直链中，更优选 1 - 8 个碳原子的直链和支链烃，例如甲基、乙基、丙基、异丙基、丁基、叔丁基、异丁基、戊基、己基、异己基、庚基、 4, 4-二甲基戊基、辛基、 2, 2， 4-三甲基戊基、壬基、癸基、十一垸基，其各种支链异构体等，以及包括 1-4个以下取代基的此类基团：例如卤代基如氟、溴、氯、碘或三氟甲基、烷基、垸氧基、芳基、芳氧基、二芳基、芳烷基、芳基烷氧基、链烯基、链炔基、环垸基、环烯基、环烷基烷基、环垸基烷氧基、任选取代的氨基、羟基、轻烷基、酰基、链垸酰基、杂芳基、杂芳氧基、杂环烷基、芳基杂芳基、芳垸氧基羰基、杂芳烷基、杂芳烷氧基、芳氧基烷基、芳氧基芳基、烷基氨基、链垸酰基氨基、芳基羰基氨基、硝基、氰基、硫羟基、卤代烷基、三卤代烷基和 /或垸硫基。 Unless otherwise indicated, the term "lower alkyl", when used alone or as part of another group, includes both straight chain and branched hydrocarbons having from 1 to 8 carbon atoms, the terms "alkyl" and "alk" When used alone or as part of another group, it includes straight chain and branched hydrocarbons having from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, in a straight chain, more preferably from 1 to 8 carbon atoms. , for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2, 2, 4-trimethylpentyl, fluorenyl, fluorenyl, undecyl, various branched isomers, and the like, and such groups including from 1 to 4 substituents: for example, halogen Alkyl such as fluoro, bromo, chloro, iodo or trifluoromethyl, alkyl, decyloxy, aryl, aryloxy, diaryl, aralkyl, arylalkoxy, alkenyl, alkyne Base, cyclodecyl, cycloalkenyl, cycloalkylalkyl, cyclodecyloxy, optionally substituted amino, hydroxy, light alkyl, acyl, decanoyl, heteroaryl , heteroaryloxy, heterocycloalkyl, arylheteroaryl, aryloxycarbonyl, heteroaralkyl, heteroaralkyloxy, aryloxyalkyl, aryloxyaryl, alkylamino, Chain decanoylamino, arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and/or sulfonylthio.

除非另外说明，术语 "环基"或 "环烷基"在此单独或作为另一个基团的一部分使用时，包括含 1-3个环的饱和或部分饱和（含 1或 2个双键）的环烃基，包括单环院基、双环烷基和三环烷基，含有形成环的总共 3-20个碳原子，优选形成环的 3-10个碳原子，所述环可以稠和于 1或 2个如对芳基所述的芳环上，其包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基、环十二烷基、环己烯基、 Unless otherwise stated, the term "cyclo" or "cycloalkyl", when used alone or as part of another group, includes saturated or partially saturated (containing 1 or 2 double bonds) containing 1-3 rings. Cycloalkyl, including monocyclic, dicycloalkyl and tricycloalkyl, containing a total of from 3 to 20 carbon atoms forming a ring, preferably forming from 3 to 10 carbon atoms of the ring, said ring being fused to one Or 2 aromatic rings as described for p-aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclo Hexenyl,

以上基团中的任何一个可由以下的取代基中任选一个取代：例如卤素、烷基、烷氧基、羟基、芳基、芳氧基、芳垸基、环烷基、垸基氨基、链垸酰基氨基、氧代基、酰基、芳基羰基氨基、氨基、硝基、氰基、硫羟基和 /或烷硫基和 /或任何烷基取代基。术语 "环烯基"在此单独或作为另一个基团的一部分使用时，指含 3-12个碳原子，优选 5- 10个碳原子和 1-2个双键的环烃。环烯基包括环戊烯基、环己熾基、环辛烯基、环己二烯基、环庚二烯基，其可如同于环烷基的定义，任选被取代。 Any of the above groups may be substituted by any one of the following substituents: for example, halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, aryl fluorenyl, cycloalkyl, decylamino, chain Decanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio and/or any alkyl substituent. The term "cycloalkenyl" as used herein, alone or as part of another group, refers to a cyclic hydrocarbon containing from 3 to 12 carbon atoms, preferably from 5 to 10 carbon atoms and from 1 to 2 double bonds. The cycloalkenyl group includes a cyclopentenyl group, a cyclohexyl group, a cyclooctenyl group, a cyclohexadienyl group, a cycloheptadienyl group, which may be optionally substituted as defined in the cycloalkyl group.

术语 "链烷酰基"在此单独或作为另一个基团的一部分使用时，指与羰基链接的烷基。 The term "alkanoyl" as used herein, alone or as part of another group, refers to an alkyl group that is linked to a carbonyl group.

除非另外说明，术语 "低级链稀基" 在此单独或作为另一个基团的一部分使用时，指 2-8个碳原子的直链或支链基团，而术语 "链烯基" 在此单独或作为另一个基团的 —部分使用时，指 2-20个碳原子，优选 2- 12个碳原子，更优选在直链上有 2- 8个碳原子的直链或支链基团，其包括在直链上的 1-6个双键，如乙烯基、 2-丙烯基、 3-丁烯基、 2 -丁烯基、 4-戊烯基、 2-己烯基、 3-辛烯基、 4-癸烯基、 3-十一烯基、 4， 8， 12-十四碳三烯基，并且这些基团中的任何一个可由 1-4个以下的取代基任选取代：例如卤素、烷基、烷氧基、羟基、芳基、芳氧基、芳烷基、环烷基、垸基氨基、链浣酰基氨基、氧代基、酰基、芳基羰基氨基、氨基、硝基、氰基、硫羟基和 /或垸硫基和 /或任何垸基取代基。 Unless otherwise stated, the term "lower chain dilute", when used alone or as part of another group, refers to a straight or branched chain group of 2 to 8 carbon atoms, and the term "alkenyl" is used herein. When used alone or as another group, it means 2-20 carbon atoms, preferably 2-12 carbon atoms, more preferably a linear or branched group having 2-8 carbon atoms in a straight chain. , which includes 1-6 double bonds on a straight chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 2-hexenyl, 3- Octenyl, 4-nonenyl, 3-undecyl, 4, 8, 12-tetradecenyl, and any of these groups may be optionally substituted by from 1 to 4 substituents For example: halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, aralkyl, cycloalkyl, decylamino, decanoylamino, oxo, acyl, arylcarbonylamino, amino, Nitro, cyano, thiol and/or sulfonylthio and/or any fluorenyl substituent.

除非另外说明，术语"低级链炔基" 在此单独或作为另一个基团的一部分使用时，指 2-8个碳原子的直链或支链基团，而术语 "链炔基" 在此单独或作为另一个基团的一部分使用时，指 2- 20个碳原子，优选 2-12个碳原子，更优选在直链上有 2- 8个碳原子的直链或支链基团，其包括在直链上的 1-2个叁键，如 2-丙块基、 3-丁炔基、 2-丁炔基、 4-戊炔基、 2-己炔基、 3-辛炔基、 4 -癸炔基、 3 -十一炔基、 4, 8, 12-十四碳三炔基，并且这些基团中的任何一个可由 1-4个以下的取代基任选取代：例如卤素、烷基、綜氧基、羟基、芳基、芳氧基、芳烷基、环垸基、烷基氨基、链垸酰基氨基、氧代基、酰基、芳基羰基氨基、氨基、硝基、氰基、硫羟基和 /或烷硫基和 /或任何烷基取代基。 Unless otherwise stated, the term "lower alkynyl" as used herein alone or as part of another group refers to a straight or branched chain group of 2 to 8 carbon atoms, and the term "alkynyl" is used herein. When used alone or as part of another group, it means 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably a linear or branched group having 2 to 8 carbon atoms in the straight chain. It includes 1-2 triple bonds on a straight chain, such as 2-propyl block, 3-butynyl, 2-butynyl, 4-pentynyl, 2-hexynyl, 3-octynyl , 4-nonynyl, 3-undecynyl, 4, 8, 12-tetradecatriynyl, and any of these groups may be optionally substituted by from 1 to 4 substituents: for example halogen , alkyl, heptoxy, hydroxy, aryl, aryloxy, aralkyl, cyclodecyl, alkylamino, decanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, Cyano, thiol and/or alkylthio and/or any alkyl substituent.

术语 "芳烷基"、 "芳链稀基"和 "芳链炔基" 单独或作为另一个基团的一部分使用时，指具芳基取代基的如上所述的烷基、链烯基和链炔基。 The terms "aralkyl", "aryl chain" and "arylalkynyl", when used alone or as part of another group, refer to alkyl, alkenyl and, as defined above, having an aryl substituent. Alkenyl group.

当如上定义的烷基基团具有连接两个不同的碳原子上的其他基团的单键时，它们被称作 "亚烷基"并可如上对 "烷基"的定义被任意取代。 When an alkyl group as defined above has a single bond linking other groups on two different carbon atoms, they are referred to as "alkylene" and may be optionally substituted as defined above for "alkyl".

当如上定义的链烯基和如上定义的链炔基分别具有连接两个不同的碳原子上的单键时，它们被称作 "亚链烯基"和 "亚链炔基"，并可如上对 "链烯基"和 "链炔基" 的定义被任意取代。 When an alkenyl group as defined above and an alkynyl group as defined above have a single bond connecting two different carbon atoms, respectively, they are referred to as "alkenylene" and "subalkynylene", and may be as above The definitions of "alkenyl" and "alkynyl" are optionally substituted.

术语"卤素"或"卤代基 "在此单独或作为另一个基团的一部分使用时，指氯、溴、氟和碘。 The term "halogen" or "halo", when used alone or as part of another group, means chlorine, bromine, Fluorine and iodine.

术语 "金属离子"指碱金属离子如钠、钾、锂和碱土金属离子如镁、钙、锌和铝。除非另外说明，术语"芳基"在此单独或作为另一个基团的一部分使用时，指在环部分含 6-10个碳的单环和双环芳族基团（如苯基或萘基包括 1-萘基和 2-萘基），并可任选包括稠和于碳环和杂环的 1-3个其他的环（如芳基、环烷基、杂芳基或杂环烷基环)，例如 The term "metal ion" refers to alkali metal ions such as sodium, potassium, lithium and alkaline earth metal ions such as magnesium, calcium, zinc and aluminum. Unless otherwise stated, the term "aryl" as used herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6-10 carbons in the ring portion (eg, phenyl or naphthyl includes 1-naphthyl and 2-naphthyl), and may optionally include 1-3 other rings fused to a carbocyclic ring and a heterocyclic ring (such as an aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring) ), E.g

并且可通过可利用的碳原子由选自以下的 1、 2或 3个基团任选取代：氢、卤代基、卤代烷基、垸基、卤代焼基、烧氧基、卤代烧氧基、链烯基、三氟甲基、三氟甲氧基、链炔基、环垸基-焼基、杂环烷基、杂环烷基垸基、芳基、杂芳.基、芳焼基、芳氧基、芳氧基垸基、芳垸氧基、垸氧基羰基、芳基羰基、芳基链烯基、氨基羰基芳基、芳硫基、芳基亚硫酰基、芳基偶氮基、杂芳基烷基、杂芳基链烯基、杂芳基杂芳基、杂芳氧基、经基、硝基、氰基、氨基、取代的氨基，其中氨基包括 1或 2个取代基（其为烷基、芳基或定义中提及的任何其他芳基化合物)、硫羟基、烷硫基、芳硫基、杂芳硫基、芳硫基院基、烷氧基芳硫基、烷基羰基、芳基羰基、烷基氨基羰基、芳基氨基羰基、烷氧基羰基、氨基羰基、烷基羰基氧基、芳基羰基氧基、烷基羰基氨基、芳基羰基氨基、芳基亚硫酰基、芳基亚硫酰基氨基和芳基磺酰氨基羰基和 /或在此提出的任何垸基取代基。

And optionally substituted by 1, 2 or 3 groups selected from the group consisting of: hydrogen, halo, haloalkyl, fluorenyl, haloalkyl, alkoxy, halogenated oxygen Alkenyl, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cyclodecyl-fluorenyl, heterocycloalkyl, heterocycloalkyl fluorenyl, aryl, heteroaryl, aryl , aryloxy, aryloxyindenyl, aryloxy, decyloxycarbonyl, arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio, arylsulfinyl, aryl Nitro, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, thio, nitro, cyano, amino, substituted amino, wherein the amino group includes 1 or 2 a substituent (which is an alkyl group, an aryl group or any other aryl compound mentioned in the definition), a thiol group, an alkylthio group, an arylthio group, a heteroarylthio group, an arylthio group, an alkoxy aryl sulfide Base, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyl Alkoxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylamino and arylsulfonylaminocarbonyl and/or any sulfhydryl substituents presented herein.

除非另外说明，术语 "低级烷氧基"、 "烷氧基"、 "芳氧基"或 "芳烷氧基"在此单独或作为另一个基团的一部分使用时，包括连接于氧原子的任何上述垸基、芳烷基或芳基。 Unless otherwise stated, the terms "lower alkoxy", "alkoxy", "aryloxy" or "aralkyloxy", when used alone or as part of another group, include attached to an oxygen atom. Any of the above fluorenyl, aralkyl or aryl groups.

除非另外的说明，术语"取代的氨基"在此单独或作为另一个基团的一部分使用时，指由一个或两个取代基取代的氨基，这些取代基可以是相同或不同的，例如焼基、芳基、芳垸基、杂芳基、杂芳烷基、杂环垸基、杂环烷基烧基、环烷基、环烷基烷基、代烷基、羟烷基、烷氧基烷基、硫代烷基。这些取代基可以羧酸和 /或上面列出的任何烷基取代基进一步取代。此外，所述氨基取代基可以与它们连接的氮慮子一起形成 1-吡咯烷基、 1-哌啶基、 1-氮杂卓基、 4-吗啉基、 4_硫代吗啉基、 1-哌嗪基、 4-垸基- 1-哌嗪基、 4 -芳烷基 -1-哌嗪基、 4-二芳基垸基 1 -哌嗪基，任选由烷基、垸氧基、垸硫基、卤代基、三氟甲基或羟基取代。 Unless otherwise stated, the term "substituted amino", when used alone or as part of another group, refers to an amino group substituted with one or two substituents which may be the same or different, for example, a fluorenyl group. ,Aryl, Aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, alkyl, hydroxyalkyl, alkoxyalkyl, sulphur Alkyne. These substituents may be further substituted with a carboxylic acid and/or any of the alkyl substituents listed above. Further, the amino substituents may form a 1-pyrrolidinyl group, a 1-piperidinyl group, a 1-azetidinyl group, a 4-morpholinyl group, a 4-thiomorpholinyl group together with a nitrogen moiety to which they are attached. 1-piperazinyl, 4-indolyl-1-piperazinyl, 4-aralkyl-1-piperazinyl, 4-diarylindenyl 1-piperazinyl, optionally alkyl, oxime Substituted with thiol, halo, trifluoromethyl or hydroxy.

除非另外说明，术语 "低级烷硫基"、 "烷硫基"、 "芳硫基"或 "芳烷硫基"在此单独或作为另一个基团的一部分使用时，包括连接于氧原子的任何上述焼基、芳焼基或芳基。 Unless otherwise stated, the terms "lower alkylthio", "alkylthio", "arylthio" or "aralkylthio", when used alone or as part of another group, include attached to an oxygen atom. Any of the above fluorenyl, arylalkyl or aryl groups.

除非另外说明，术语 "低级烷基氨基"、 "烷基氨基"、 "芳基氨基"或 "芳基氨基" 在此单独或作为另一个基团的一部分使用时，包括连接于氧原子的任何上述浣基、芳烷基或芳基。 Unless otherwise stated, the terms "lower alkylamino", "alkylamino", "arylamino" or "arylamino" are used herein alone or as part of another group, including any attached to an oxygen atom. The above fluorenyl, aralkyl or aryl group.

除非另外指明，术语 "酰基"在此以其本身或作为在此定义的另一个基团的一部分使用时，指连接于羰基的有机基团；酰基的实例包括连接于羰基的任何烷基取代基，如链烷酰基、链烯酰基、芳酰基、芳基链垸酰基、杂芳酰基、环烷酰基、杂环烷酰基。 Unless otherwise indicated, the term "acyl" as used herein, alone or as part of another group as defined herein, refers to an organic group attached to a carbonyl group; examples of acyl groups include any alkyl substituent attached to a carbonyl group. For example, an alkanoyl group, an alkenoyl group, an aroyl group, an aryl chain decanoyl group, a heteroaroyl group, a cycloalkanoyl group, a heterocycloalkanoyl group.

除非另外说明，术语 "杂环基 "在此单独或作为另一基团的一部分使用时，指包含 1 - 3个杂原子（如氮、氧和 /或硫）的 5、 6或 7元饱和或不饱和的环（包括芳环），并且这样的环可以稠和于芳基、环烷基、杂芳基或杂环垸基环上（如苯并噻吩和吲哚基)，并且可能包括 N-氧化物。所述杂芳基可任选含 1- 个取代基，如上述的任何垸基取代基。杂环基的实例包括以下的基团 - Unless otherwise stated, the term "heterocyclyl" as used herein alone or as part of another group, refers to a 5, 6 or 7 member saturation comprising from 1 to 3 heteroatoms such as nitrogen, oxygen and/or sulfur. Or an unsaturated ring (including an aromatic ring), and such a ring may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclic fluorenyl ring (such as benzothiophene and fluorenyl) and may include N-oxide. The heteroaryl group may optionally contain from 1 substituent, such as any of the above fluorenyl substituents. Examples of the heterocyclic group include the following groups -

术语 "杂环烷基"在此单独或作为另一个基团的一部分使用时，指通过碳原子或杂原子连接于 ((¾)„链上的如上定义的杂环烷基。

The term "heterocycloalkyl" as used herein, alone or as part of another group, refers to a heterocycloalkyl group as defined above attached to a ((3⁄4)" chain through a carbon atom or a hetero atom.

术语 "杂芳烷基"或 "杂芳链烯基"在此单独或作为另一个基团的一部分使用时，指通过碳原子或杂原子连接于如上定义的 (CH₂) _n链、亚烷基或亚链烯基上的如上定义的杂芳基。 The term "heteroaralkyl" or "heteroarylalkenyl" as used herein, alone or as part of another group, refers to a (CH ₂ ) _n chain, an alkylene group, as defined above, bonded through a carbon atom or a hetero atom. A heteroaryl group as defined above on the alkenyl or alkenylene group.

术语 " 5、 6、 7元碳环或杂环"在此使用时，如上定义的环嫁基、环烯基、杂芳基或杂环芳基，如噻二唑、四唑、咪唑或噁唑。 The term "5, 6, 7-membered carbocyclic or heterocyclic ring" as used herein, as defined above, is a cyclo-glycol, cycloalkenyl, heteroaryl or heterocyclic aryl group, such as thiadiazole, tetrazole, imidazole or malignant. Oxazole.

术语 "多卤代烷基"在此使用时，指包含 2-9个，优选 2- 5个卤代取代基，如氟或氯，优选氟的如上定义的 "垸基"，如 CF₃、 CF₃CH₂或 CF₃CF₂C¾。 The term "polyhaloalkyl" when used herein, refers to one containing 2-9, preferably 2-5 halo substituents, such as fluorine or chlorine, preferably fluorine defined as "embankment" group, such as CF _{_3,} CF ₃ CH ₂ or CF ₃ CF ₂ C3⁄4.

术语 "多卤代烷氧基"在此使用时，指包含 2-9个，优选 2-5个卤代取代基，如氟或氯，优选氟的如上定义的 "烷氧基"或 "垸基氧基"，如 CF₃0、 CF₃CH₂0或 CF₃CF₂C 0。 The term "polyhaloalkoxy" as used herein, refers to an "alkoxy" or "decyloxy" group as defined above, containing 2-9, preferably 2-5, halo substituents, such as fluoro or chloro, preferably fluoro. Base ", such as CF ₃ 0, CF ₃ CH ₂ 0 or CF ₃ CF ₂ C 0.

因此本发明式（I ) 中 R的杂环胺和芳香杂环胺包括但不限于含有或不含氨基取代的基团：氮杂环丁烷基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并吡唑基、苯并三唑基、苯并噻吩基、苯并噁唑基、咔唑基、噌啉基、呋喃基、咪唑基、二氢吲哚基、吲哚基、吲嗪基、吲唑基、异苯并呋喃基、异吲哚基、异喹啉基、异噻唑基、异噁唑基、萘并吡啶基、噁二唑基、噁唑啉、异噁唑啉、氧杂环丁垸基、吡喃基、吡嗪基、吡唑基、哒嗪基、吡啶并吡啶基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹喔啉基、四氫吡喃基、四氢噻喃基、四氢异喹啉基、四唑基、四唑并吡啶基、噻二唑基、噻唑基、噻吩基、 ***基、 1, 4-二氧杂环己垸基、六氢氮杂卓基、哌嗪基、哌啶基、吡啶 -2-酮基、吡咯烷基、吗啉基、硫代吗啉基、二氢苯并咪唑基、二氢苯并呋喃基、二氢苯并噻吩基、二氢苯并噁唑基、二氢呋喃基、二氢咪唑基、二氢吲哚基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢喹啉基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢***基、二氢氮杂环丁烷基、亚甲二氧基苯、四氢呋喃基和四氢噻吩基及其 N-氧化物。 Thus, the heterocyclic amines and aromatic heterocyclic amines of R in the formula (I) of the present invention include, but are not limited to, groups having or without amino substitution: azetidinyl, benzimidazolyl, benzofuranyl, benzene Thiazolyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, oxazolyl, porphyrinyl, furyl, imidazolyl, indanyl, fluorenyl , pyridazinyl, oxazolyl, isobenzofuranyl, isodecyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthopyridyl, oxadiazolyl, oxazoline, isomer Oxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl , quinoxalinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, 1, 4-dioxacyclohexyl, hexahydroazepine, piperazinyl, piperidinyl, pyridin-2-one, pyrrolidinyl, morpholinyl, sulfur Morpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, indanyl, di Hydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrole , dihydroquinolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxy Benzobenzene, tetrahydrofuranyl and tetrahydrothiophene Base and its N-oxide.

本发明式（I)中 R可以是任意取代的哌嗪包括但不限于 4-甲基哌嗪、肉桂基哌嗪、苄基哌嗪、苯基哌嗪、曲美他嗪、环丙沙星、依诺沙星、诺氟沙星、可乐定、 2-氧代哌嗪乙酸、哌啶并哌嗪、二苯甲基哌嗪、 1- (2-甲氧基苯基）哌嗪、 1- (2-氟苯基)哌嗪、 1- (2, 3-二甲基苯基)哌嘆、 1- (2， 4-二甲基苯基)哌嗪、 1- (3， 4-二甲基苯基）哌嗪、 N_羟乙基哌嗪、 1- (5-甲基- 2-吡啶基)哌嗪、 2， 5-二甲基哌嗪、 2， 6-二甲基哌嗪、 2-甲基哌嗪、 1- (2, 4-二氟苯基)哌嗪、 1- (2, 3-二氯苯基)哌嗪、乙氧羰基哌嗪、 4-叔丁氧羰基 -2 - 甲基-哌嗪、 2-甲基 -叔丁氧羰基哌嗪、 2 -羧基哌嗪、 4-N-叔丁氧羰基哌嗪 -2-羧酸、 1-(2- 氯苯基)哌嗪、 1- [2- (2-羟基乙氧基）乙基]哌嗪、 1- (2-甲氧基乙基)哌嗪、 1-异丙基哌嗪、 N-乙酰基哌嗪、 2-乙基哌嗪、 N-叔丁氧羰基哌嗪、 4- N-叔丁氧羰基- 2-甲基哌嗪、 4 -叔丁氧羰基哌嗪叔丁酰胺、 1- (2-氟- 4-硝基苯基)哌嗪、 1-(3 -三氟甲基)苯基哌嗪、 4 -叔丁氧羰基哌嗪 -2-羧酸、 1- (2-甲基苯基)哌嗪、 1- [3, 5-二 (三氟甲基)苯基]哌嗪、 N -叔丁氧羰基 -2-甲基哌嗪、 1-环己基哌嗪、 1- (噻唑 -2-基）哌嗪、 1- (2-嘧啶基)哌嗪、 1_环戊基哌嗪、 N-丙基哌嗪、 1- (4-氟苯基)哌嗪、 2-氧代- 1-哌嗪乙酸、 4-苄基 -2- (苄氧基甲基）哌嗪、 4, 4' -二氟苯甲哌嗪、甲酰高哌嗪、 1-(2-甲基)苄基哌嗪、 1- (4 -氯二苯甲基)哌嗪、苄基- 1-哌嗪碳酸酯、 1_ (3-溴苯基)哌嗪、 N- 1-苄基- 3 -乙基哌嗪、 N - 1- 苄基- 3-甲基哌嗪、哌啶并哌嗪、 N-1-苄基 -3-异丙基哌嗪、 N-叔丁氧羰基- 2 -乙基哌嗪、 1_ (吡啶 -3-基甲基)哌嗪、 1- (2-吡啶基)哌嗪、 1- (2-甲氧基苯基〉哌嗪、 1- (4-甲氧基苯基)哌嗪、 1- (4-氯苯基)哌嗪、叔丁基哌嗪、 1-叔丁氧羰基- 2-乙基哌嗪、 1- (2-氯苯基）哌嗪、 1-(2-甲基苯基)哌嗪、 1-(2-呋喃甲酰基)哌嗪、 1- (3， 4-二氯苯基)哌嗪、 1- (噻唑- 2-基)哌嗪、 1-叔丁氧羰基- 3-乙基哌嗉、 2-甲基哌嗪 -1-甲酸苄酯、 N4-苄基- 2-异丁基哌嗪、 4-苯甲基 -2-哌嗪乙醇、 N-叔丁氧羰基 -2-苄基哌嗪、 N-叔丁氧羰基- 3-苯基哌嗪、 N-叔丁氧羰基- 3-苄基哌嗪、 2 -苯基哌嗪、 1-甲基 -3-苯基哌嗪、 N- (2, 6-二甲基苯基 ) - 1_哌嗪乙酰胺、 N-乙基哌嗪、 N-异丁基哌嗪、 N-丁基哌嗪、 N-1-苄基 -3-苯基哌嗪、 N - 1-苄基- 2-苯基哌嗪、 2-哌嗪酮、 1- (6-氯哒嗪 -3-基)哌嗪、 1- (2-硝基苯基)哌嗪、 N- 乙基双氧哌嗪、间羟基苯基哌嗪、 2-哌嗪基 -4-氨基- 6, 7-二甲氧基喹唑啉、 1_ (2-呋喃甲酰基)哌嗪、 1- (4-硝基苯基)哌嗪、四氢糠酰哌嗪、 1- (4-氟苯基)哌嗪、 1- (2-氯苯基）哌嗪、 N-叔丁氧羰基- 2-异丙基哌嗪、 N-叔丁氧羰基- 2-异丁基哌嗪、 4-哌嗪- 1-基苯甲腈、 4- (1-苄基哌嗪- 4-基)哌啶、 1， 4-苯并二恶垸- 2-羰基哌嗪、 1- [2- (4-氟苯基）乙基] 哌嗪、 5-氯- 2-甲基苯基哌嗪、 N-甲酰基哌嗪、 1- (5-硝基吡啶 -2-基)哌嗪、 1-二苯甲基哌嗪、 2-苄基哌嗪、 N-1-叔丁氧羰基 -2-苯基哌嗪、 1- (3-硝基吡啶- 2-基)哌嗪、 1, 2 -苯并异噻唑- 3 哌嗪、 1- (2三氟甲基苄基)哌嗪等。 R in the formula (I) of the present invention may be an optionally substituted piperazine including, but not limited to, 4-methylpiperazine, cinnamylpiperazine, benzylpiperazine, phenylpiperazine, trimetazidine, ciprofloxacin. , enrofloxacin, norfloxacin, clonidine, 2-oxopiperazine acetate, piperidazine piperazine, diphenylmethyl piperazine, 1-(2-methoxyphenyl) piperazine, 1 - (2-fluorophenyl) piperazine, 1-(2,3-dimethylphenyl) piperazine, 1-(2,4-dimethylphenyl)piperazine, 1- (3, 4- Dimethylphenyl) piperazine, N-hydroxyethylpiperazine, 1-(5-methyl-2-pyridyl)piperazine, 2,5-dimethylpiperazine, 2,6-dimethyl Piperazine, 2-methylpiperazine, 1-(2,4-difluorophenyl)piperazine, 1-(2,3-dichlorophenyl)piperazine, ethoxycarbonylpiperazine, 4-tert-butyl Oxycarbonyl-2,methyl-piperazine, 2-methyl-tert-butoxycarbonylpiperazine, 2-carboxypiperazine, 4-N-tert-butoxycarbonylpiperazine-2-carboxylic acid, 1-(2- Chlorophenyl)piperazine, 1-[2-(2-hydroxyethoxy)ethyl]piperazine, 1-(2-methoxyethyl)piperazine, 1-isopropylpiperazine, N- Acetylpiperazine, 2-ethylpiperazine, N-tert-butoxycarbonylpiperazine, 4-N-tert-butoxy 2-methylpiperazine, 4-tert-butoxycarbonylpiperazine tert-butyramide, 1-(2-fluoro-4-nitrophenyl)piperazine, 1-(3-trifluoromethyl)phenyl Piperazine, 4-tert-butoxycarbonylpiperazine-2-carboxylic acid, 1-(2-methylphenyl)piperazine, 1-[3,5-bis(trifluoromethyl)phenyl]piperazine, N-tert-butoxycarbonyl-2-methylpiperazine, 1-cyclohexylpiperazine, 1-(thiazol-2-yl)piperazine, 1-(2-pyrimidinyl)piperazine, 1-cyclopentylperazine Pyrazine, N-propylpiperazine, 1-(4-fluorophenyl)piperazine, 2-oxo-l-piperazinic acid, 4-benzyl-2-(benzyloxymethyl)piperazine, 4 , 4'-difluorobenzoic acid piperazine, formyl homopiperazine, 1-(2-methyl)benzylpiperazine, 1-(4-chlorobenzhydryl)piperazine, benzyl-1-piperazine Pyrazine carbonate, 1-(3-bromophenyl)piperazine, N- 1-benzyl-3-ethylpiperazine, N- 1-benzyl-3-methylpiperazine, piperidazine piperazine, N 1-benzyl-3-isopropylpiperazine, N-tert-butoxycarbonyl-2-ethylpiperazine, 1-(pyridin-3-ylmethyl)piperazine, 1-(2-pyridyl)peri Pyrazine, 1-(2-methoxyphenyl)piperazine, 1-(4-methoxyphenyl)piperazine, 1-(4-chlorophenyl)piperazine, tert-butylpiperazine, 1- Tert-Butoxycarbonyl- 2- Ethylpiperazine, 1-(2-chlorophenyl)piperazine, 1-(2-methylphenyl)piperazine, 1-(2-furoyl)piperazine, 1-(3, 4-di Chlorophenyl)piperazine, 1-(thiazol-2-yl)piperazine, 1-tert-butoxycarbonyl-3-ethylpiperidin, 2-methylpiperazine-1-carboxylic acid benzyl ester, N4-benzyl 2-isobutylpiperazine, 4-benzyl-2-piperazineethanol, N-tert-butoxycarbonyl-2-benzylpiperazine, N-tert-butoxycarbonyl-3-phenylpiperazine, N -tert-Butoxycarbonyl-3-benzylpiperazine, 2-phenylpiperazine, 1-methyl-3-phenylpiperazine, N-(2,6-dimethylphenyl)-1 Piperazine Acetamide, N-ethylpiperazine, N-isobutylpiperazine, N-butylpiperazine, N-1-benzyl-3-phenylpiperazine, N-1-benzyl-2-phenyl Piperazine, 2-piperazinone, 1-(6-chloropyridazin-3-yl)piperazine, 1-(2-nitrophenyl)piperazine, N-ethyldioxypiperazine, m-hydroxybenzene Piperazine, 2-piperazinyl-4-amino-6, 7-dimethoxyquinazoline, 1-(2-furoyl)piperazine, 1-(4-nitrophenyl)piperazine, Tetrahydroindolyl piperazine, 1-(4-fluorophenyl)piperazine, 1-(2-chlorophenyl)piperazine, N-tert-butoxycarbonyl-2-isopropylpiperazine, N-tert-butyl Oxycarbonyl- 2-iso Butyl piperazine, 4-piperazine-1-phenylbenzonitrile, 4-(1-benzylpiperazine-4-yl)piperidine, 1, 4-benzodioxin-2-carbonylpiperazine, 1-[2-(4-Fluorophenyl)ethyl]piperazine, 5-chloro-2-methylphenylpiperazine, N-formylpiperazine, 1-(5-nitropyridin-2-yl Piperazine, 1-diphenylmethyl Piperazine, 2-benzylpiperazine, N-1-tert-butoxycarbonyl-2-phenylpiperazine, 1-(3-nitropyridine-2-yl)piperazine, 1,2-benzoisothiazole - 3 piperazine, 1-(2trifluoromethylbenzyl)piperazine, and the like.

本发明中除哌嗪外其它任意取代的杂环胺和芳香杂环胺可以参考如上哌嗪类取代基团进行取代。 The optionally substituted heterocyclic amine and aromatic heterocyclic amine other than piperazine in the present invention may be substituted with reference to the above piperazine-based substituent.

本发明式（I) 中 R优选的取代基团独立地选自 N-吗啉基、 N-六氢吡啶基、 N-四氢吡咯基、 N-N-甲基哌嗪基、 N-哌嗪基、 N-二甲胺基、 N-二乙胺基、 N-二正丙胺基、 N-二异丙胺基、 N-二乙醇胺基、 N -肌氨酸基、 N-肌氨酸甲酯基、 N-甲乙胺基、 N-双 2-氯乙胺基、 N- (R) -3-羟甲基哌啶基、 N- (S) -3-羟甲基哌啶基、 N-3-甲基哌啶基、 N- 3-羟基哌啶基、 N- 4-羟基哌啶基、 N-D-氨基葡萄糖基、 N-曲美他嗪基、 N-肉桂哌嗪基、 N-苯基哌嗪、 N-苄基哌嗪、 N-四氢糠酰哌嗪、 N- β -丙氨酸基、 N- L-天门冬氨酸基、 Ν-赖氨酸、 Ν -氨基己酸。 Preferred substituents for R in the formula (I) of the present invention are independently selected from N-morpholinyl, N-hexahydropyridyl, N-tetrahydropyrrolyl, NN-methylpiperazinyl, N-piperazinyl. , N-dimethylamino, N-diethylamino, N-di-n-propylamino, N-diisopropylamino, N-diethanolamine, N-sarcosyl, N-sarcosine methyl ester , N-methylethylamino, N-bis 2-chloroethylamino, N-(R)-3-hydroxymethylpiperidinyl, N-(S)-3-hydroxymethylpiperidinyl, N-3 -methylpiperidinyl, N- 3-hydroxypiperidinyl, N- 4-hydroxypiperidinyl, ND-glucosyl, N-trimetazinyl, N-cinnapanzinyl, N-phenyl Piperazine, N-benzylpiperazine, N-tetrahydrofurfuryl piperazine, N-β-alanine group, N-L-aspartate group, Ν-lysine, Ν-aminocaproic acid.

本发明式（ I )中 R特别优选的取代基团独立地选自 Ν-吗啉基、 Ν-六氢吡啶基、 Ν- 四氢吡咯基、 Ν-Ν-甲基哌嗪基、 Ν-哌嗪基、 Ν-肌氨酸基、 Ν -甲氨基乙醇基、 Ν- 3-甲基哌啶基、 Ν-3-轻甲基哌啶基、 Ν-曲美他嗪基、 Ν-肉桂哌嗪基、 Ν-苯基哌嗪、 Ν-苄基哌嗪、 Ν -四氢糠酰哌嗪、 Ν- β -丙氨酸基、 Ν- L-天门冬氨酸基、 Ν-赖氨酸、 Ν-氨基己酸。 Particularly preferred substituent groups for R in the formula (I) of the present invention are independently selected from the group consisting of ruthenium-morpholinyl, anthracene-hexahydropyridyl, anthracene-tetrahydropyrrolyl, anthracene-indole-methylpiperazinyl, anthracene- Piperazinyl, Ν-sarcosinyl, Ν-methylaminoethanol, Ν-3-methylpiperidinyl, indole-3-methylmethylpiperidinyl, hydrazine-trimetazinyl, guanidine-cinnamon Piperazinyl, hydrazine-phenylpiperazine, hydrazine-benzylpiperazine, hydrazine-tetrahydrofurfuryl piperazine, Ν-β-alanine, Ν-L-aspartate, Ν-lysine Acid, guanidine-aminocaproic acid.

本发明根皮苷衍生物（I) 或其药学上可接受的盐包括其分子内盐、其溶剂化物或水合物。 The phlorizin derivative (I) of the present invention or a pharmaceutically acceptable salt thereof includes an intramolecular salt, a solvate thereof or a hydrate thereof.

本发明化合物有可能的内盐或两性离子，因在生理条件下，化合物中的去质子化酸性部分例如羧基可以是阴离子，并且该电荷可由质子化或烷基化的碱性部分例如季氮原子的阳离子电荷在内部平衡。具有内部平衡电荷，并因此不与分子间抗衡离子締合的分离的化合物也可以视为 "游离形式"的化合物。 The compounds of the invention are possible as internal salts or zwitterions, since under degraded conditions, the deprotonated acidic moiety in the compound, such as a carboxyl group, may be an anion, and the charge may be a protonated or alkylated basic moiety such as a quaternary nitrogen atom. The cationic charge is internally balanced. An isolated compound having an internal equilibrium charge and thus not associated with an intermolecular counterion can also be considered a "free form" compound.

本发明还提供了一种含有根皮苷衍生物或其互变异构体或其药学上可接受的溶剂化物和药学上可接受的载体的药物组合物。 The present invention also provides a pharmaceutical composition comprising a phlorizin derivative or a tautomer thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

本发明还提供了含有根皮苷衍生物或其互变异构体或其药学上可接受的溶剂化物和药学上可接受的载体的药物组合物的制备方法，此方法包括将根皮苷衍生物或其互变异构体或其药学上可接受的溶剂化物与药学上可接受的载体相混合或者溶解。 The present invention also provides a process for the preparation of a pharmaceutical composition comprising a phlorizin derivative or a tautomer thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier, which comprises deriving phlorizin The substance or tautomer thereof, or a pharmaceutically acceptable solvate thereof, is mixed or dissolved with a pharmaceutically acceptable carrier.

此处术语"药学上可接受的"包括人用和兽用的化合物、组合物和组分，如果需要，组合物可以进行包装，并附有书写或者印刷的使用说明。 The term "pharmaceutically acceptable" as used herein includes both human and veterinary compounds, compositions and components, and if desired, the compositions may be packaged with written or printed instructions for use.

本发明化合物的可药用盐可以用常规化学方法由包含碱性或酸性部分的本发明的化合物来合成。一般而言，碱性化合物的盐是通过离子交换柱或通过将游离碱与化学计量的或过量的所需的成盐的无机酸或有机酸在适宜的溶剂或溶剂的各种组合中进行反应来进行制备的。类似地，酸性化合物的盐是通过与适宜的无机或有机碱进行反应来形成的。 The pharmaceutically acceptable salts of the compounds of the invention can be synthesized from the compounds of the invention which comprise a basic or acidic moiety by conventional chemical methods. In general, the salt of the basic compound is passed through an ion exchange column or by passing the free base with a chemistry meter. The amount or excess of the desired salt-forming mineral or organic acid is prepared by reaction in various combinations of suitable solvents or solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

本发明化合物的可药用盐包括通过将碱性的本发明化合物与无机或有机酸反应而形成的本发明化合物的常规无毒盐。例如，常规无毒盐包括得自无机酸和有机酸的那些，所述无机酸是例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等，所述有机酸是例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、枸櫞酸、富马酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、大黄酸、牛黄酸、齐墩果酸、熊果酸、 2-乙酰氧基-苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等。 Pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by reacting a basic compound of the invention with an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and organic acids such as acetic acid, propionic acid, and the like. , succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, chloric acid, citric acid, fumaric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, Benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, rhein, taurine, oleanolic acid, ursolic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, B Alkanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.

本发明中优选的有机酸或无机酸包括乙酸、琥珀酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、枸橡酸、马来酸、 7 杨酸、大黄酸、牛磺酸、富马酸、草酸、轻乙基磺酸、盐酸、硫酸、磷酸、硝酸。 Preferred organic or inorganic acids in the present invention include acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, citric acid, maleic acid, 7 salicylic acid, rhein, taurine, fumaric acid. , oxalic acid, light ethyl sulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid.

当本发明化合物是酸性的时，合适的 "可药用盐"是指由可药用无毒碱，包括无机碱和有机碱制得的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、三价铁盐、二价铁盐、锂盐、镁盐、锰盐、二价锰盐、钾盐、钠盐、锌盐等。铵盐、钙盐、镁盐、钾盐和钠盐是特别优选的。得自可药用无毒有机碱的盐包括下列碱的盐：伯胺、仲胺和叔胺，取代的胺，包括天然取代的胺、环胺和碱性离子交换树脂，例如精氨酸、甜菜碱、咖啡因、胆碱， Ν, Ν' -二苄基乙二胺、二乙胺、二乙醇胺、 2-二乙基氨基乙醇、 2-二甲基氨基乙醇、乙醇胺、乙二胺、 Ν-乙基吗啉、 Ν-乙基哌啶、葡糖胺、黄连素、氨基葡糖、组氨酸、哈胺（hydrabamine 异丙基胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚 '胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三- (轻甲基)氨基甲烷（TRIS)、 N-甲基葡萄糖胺（NMG)、三乙醇胺、三丙胺、氨丁三醇和二氢枞胺等。当本发明化合物是酸性的时，术语 "游离形式"是指其非盐形式的化合物，这样的酸性官能团仍然是质子化的。 When the compound of the present invention is acidic, a suitable "pharmaceutically acceptable salt" means a salt prepared from a pharmaceutically acceptable non-toxic base, including an inorganic base and an organic base. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, divalent iron salts, lithium salts, magnesium salts, manganese salts, divalent manganese salts, potassium salts, sodium salts, zinc salts. Salt and so on. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable non-toxic organic bases include the salts of the following bases: primary, secondary and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines and basic ion exchange resins such as arginine, Betaine, caffeine, choline, hydrazine, Ν'-dibenzylethylenediamine, diethylamine, diethanolamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, Ν-ethylmorpholine, Ν-ethylpiperidine, glucosamine, berberine, glucosamine, histidine, hamamine (hydrabamine isopropylamine, lysine, methyl glucosamine, morpholine) , piperazine, piperidine, poly'amine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tris-(light methyl)aminomethane (TRIS), N-methylglucamine (NMG , triethanolamine, tripropylamine, tromethamine, indanline, etc. When the compound of the invention is acidic, the term "free form" refers to a compound in its non-salt form, such an acidic functional group is still protonated .

本发明中优选的有机碱或无机碱包括氨基葡糖、甲基葡糖胺、咖啡因、三乙胺、氢氧化钾、氢氧化钠。 Preferred organic or inorganic bases in the present invention include glucosamine, methyl glucosamine, caffeine, triethylamine, potassium hydroxide, sodium hydroxide.

上述可药用盐和其它常见的可药用盐的制备由 Berg 等人，更详细描述在 "Pharmaceutical Salts, " J. Pharm. Sci. , 1977:66: 1-19中。 The preparation of the above pharmaceutically acceptable salts and other common pharmaceutically acceptable salts is described in more detail by Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977: 66: 1-19.

本发明化合物包括所有立体异构体，无论是混合物形式或是纯异构体的形式，本发明化合物可以在任何手性碳原子（包括 R取代基中的任何一个）上形成不对称中心。这样，式（I )化合物可以以对映体或非对映体形式或其混合物的形式存在。制备方法可以使用外消旋体、对映体或非对映体作为原料。当制备非对映体或对映体产物时，它们可以通过常规方法，例如层析、化学拆分或分级结晶分离。 The compounds of the present invention include all stereoisomers, either in the form of a mixture or in the form of a pure isomer. The bright compound can form an asymmetric center on any of the chiral carbon atoms, including any of the R substituents. Thus, the compounds of formula (I) may exist in enantiomeric or diastereomeric forms or as mixtures thereof. The preparation method can use a racemate, an enantiomer or a diastereomer as a raw material. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods such as chromatography, chemical resolution or fractional crystallization.

需要时，作为第一活性成分的治疗有效量的结构（I ) 的化合物可以用于与作为第二活性成分的一种或一种以上其它类型的抗糖尿病药物和 /或一种或一种以上的其它类型的治疗药物的药物组合物联合给药，它们可以以同一剂型、以分开的剂型口服给予或经注射给予。 A therapeutically effective amount of the compound of structure (I) as a first active ingredient may be used in combination with one or more other types of antidiabetic drugs and/or one or more other than the second active ingredient, as needed. The pharmaceutical compositions of other types of therapeutic agents are administered in combination, and they may be administered orally in the same dosage form, in separate dosage forms, or by injection.

本发明药物组合物中作为第一活性成分的治疗有效量的结构（I )的化合物和作为第二活性成分的一种或多种其它类型的治疗药物的比例为 1 : 0. 0001-1： 0. 01。 The ratio of the therapeutically effective amount of the compound of the structure (I) as the first active ingredient in the pharmaceutical composition of the present invention to one or more other types of therapeutic agents as the second active ingredient is 1: 0001-1: 0. 01.

本发明中的药物组合物，其中活性成分占组合物重量的 0. 1-99. 9%。 9%。 The composition of the composition of the composition 0. 1-99. 9%.

本发明中的药物组合物，最适宜的组合物是制成单位制剂的，单位制剂通常含有活性成分的剂量根据给药途径，患者年龄体重和病情，或被治疗疾病的严重程度而变化，通常对于口服给药，剂量在 0. 001-lOOOmg/kg/天，优选为 0. 01- 100mg/kg/天，更优选为 0. 05- 50mg/kg/天。对于非肠道给药，剂量在 0. 005- 100mg/kg/天，优选为 0. 0卜 100mg/kg/天，更优选为 0. 05- 5mg/kg/天。 In the pharmaceutical composition of the present invention, the most suitable composition is a unit preparation, and the dosage of the active ingredient usually varies depending on the route of administration, the age and the condition of the patient, or the severity of the disease to be treated, usually 01至100毫克/kg/day, more preferably 0. 05- 50mg/kg/day. For oral administration, the dose is from 0.001 to 1000 mg/kg/day, preferably from 0.01 to 100 mg/kg/day, more preferably from 0.05 to 50 mg/kg/day. For parenteral administration, the dose is from 0.005 to 100 mg/kg/day, preferably from 0 to 100 mg/kg/day, more preferably from 0.05 to 5 mg/kg/day.

可以任选式（D化合物的 SGLT2抑制剂联合其它类型的抗糖尿病药物，成为药物组合物，其它类型药物可以是一种或更多种抗糖尿病药物或抗高血糖药物，包括胰岛素、胰岛素衍生物、类胰岛素作用剂、胰岛素抵抗改善剂、糖异生抑制剂、糖吸收抑制剂、肾糖再吸收抑制剂、 β 3肾上腺素受体激动剂、胰岛素促分泌素或胰岛素增敏剂及其它抗糖尿病药物。优选具有与 SGLT2抑制剂不同作用机理的抗糖尿病药物，包括双缩胍类、磺酰脲类、葡糖苷酶抑制剂、过氧化物酶体增殖物激活受体 Y (PPAR Y )激动剂如噻唑烷二酮、 aP2抑制剂、 PPAR a / _Y双重激动剂、二肽基肽酶 IV (DP4)抑制剂和 /或氯茴苯酸，以及胰岛素、胰高血糖素-样肽 -1 (GLP- 1 )、蛋白质酪氨酸磷酸酶 IB (PTPIB )抑制剂、糖原磷酸化酶抑制剂和 /或葡糖 -6-磷酸酶抑制剂。 The SGLT2 inhibitor of the compound D may be optionally combined with other types of anti-diabetic drugs to form a pharmaceutical composition, and other types of drugs may be one or more anti-diabetic drugs or anti-hyperglycemic drugs, including insulin, insulin derivatives. , insulin-like agents, insulin resistance improvers, gluconeogenesis inhibitors, glucose absorption inhibitors, renal glucose reuptake inhibitors, beta 3 adrenergic receptor agonists, insulin secretagogues or insulin sensitizers and other antibiotics Diabetic drugs. Antidiabetic drugs with different mechanisms of action from SGLT2 inhibitors, including bifidos, sulfonylureas, glucosidase inhibitors, peroxisome proliferator-activated receptor Y (PPAR Y) Such as thiazolidinedione, aP2 inhibitor, PPAR a / _Y dual agonist, dipeptidyl peptidase IV (DP4) inhibitor and / or meglitinide, and insulin, glucagon-like peptide-1 (GLP-1), a protein tyrosine phosphatase IB (PTPIB) inhibitor, a glycogen phosphorylase inhibitor, and/or a glucose-6-phosphatase inhibitor.

可以任选用于与式（I ) 的 SGLT2抑制剂联合给予的其它类型的治疗药物包括抗肥胖药物、抗髙血压药物、抗血小板药物、抗动脉粥样硬化药物和 /或降血酯药物。 Other types of therapeutic agents that may optionally be administered in combination with the SGLT2 inhibitor of formula (I) include anti-fatty drugs, anti-spasmodic drugs, anti-platelet drugs, anti-atherosclerotic drugs, and/or hypocholesterolemic drugs.

结构（I ) 的 SGLT2抑制剂也可以任选用于与治疗糖尿病并发症的药物联合给予。这些药物包括 PKC抑制剂和 /或 AGE抑制剂。 The SGLT2 inhibitor of structure (I) may also optionally be administered in combination with a drug for the treatment of diabetic complications. These drugs include PKC inhibitors and / or AGE inhibitors.

结构（I) 的化合物与一种或多种其它抗糖尿病药物联合使用产生的抗高血糖效果大于单独使用这些药物的效果，也大于与这些药物产生的联合使用后的抗髙血糖效果。其它的抗糖尿病药物可以是口服降血糖药物，优选双胍类如二甲双胍或苯乙双胍及其盐，最优选二甲双胍盐酸盐。 Antihyperglycemic effect of a compound of structure (I) in combination with one or more other antidiabetic agents The effect greater than the use of these drugs alone is also greater than the anti-glucose effect after the combination with these drugs. Other antidiabetic agents may be oral hypoglycemic agents, preferably biguanides such as metformin or phenformin and its salts, most preferably metformin hydrochloride.

其它口服的抗糖尿病药物也可优选磺酰脲如格列本脲、格列吡嗪、格列美脲、格列齐特、格列喹酮、氯磺丙脲等，最优选格列本脲和格列美脲。 Other oral antidiabetic agents may also be preferably sulfonylureas such as glibenclamide, glipizide, glimepiride, gliclazide, gliclazone, chlorpropamide, etc., most preferably glibenclamide And glimepiride.

其它口服的抗糖尿病药物还可优选葡糖苷酶抑制剂如阿卡波糖、伏格列波糖、米格列醇。 Other oral anti-diabetic agents may also preferably be glucosidase inhibitors such as acarbose, voglibose, miglitol.

其它口服的抗糖尿病药物还可优选噻唑烷二酮如罗格列酮、吡格列酮、恩格列酮、环格列酮、伊格列酮、曲格列酮、法格列酮、 Rivoglitazone、 Risarestat. 达格列酮、 NSC363916、 BRN3621848. BRN 5769524、 BRN 5549627、 BRN 5595208、 BRN 5600016、 AIDS012476、 DRF- 2189、 5-Nmebontd^ Add 4743 > AD5075, ZINC01166114、 ZINC01154723, BAS00285492. BAS 00072174、 ZINC05003429, ZINC04645840、 DRF 2519、 AIDS209583 BRN 6543939、 AIDS352729、 AIDS352702, AIDS334931等，最优选罗格列酮、吡格列酮、伊格列酮、达格列酮、 Rivoglitazone。 Other oral antidiabetic agents may also preferably be thiazolidinediones such as rosiglitazone, pioglitazone, englitazone, ciglitazone, iglitazone, troglitazone, faglitazone, Rivoglitazone, Risarestat. Daglitazone, NSC363916, BRN3621848. BRN 5769524, BRN 5549627, BRN 5595208, BRN 5600016, AIDS012476, DRF-2189, 5-Nmebontd^ Add 4743 > AD5075, ZINC01166114, ZINC01154723, BAS00285492. BAS 00072174, ZINC05003429, ZINC04645840, DRF 2519, AIDS209583 BRN 6543939, AIDS352729, AIDS352702, AIDS 334931, etc., most preferred are rosiglitazone, pioglitazone, iglitazone, daglitazone, Rivoglitazone.

磺酰脲和噻唑綜二酮可以以低于约 150mg 口服抗糖尿病药物的量与结构 (I)的化合物一起混合在一个片剂中。 The sulfonylurea and thiazole homodione can be combined in a tablet with the compound of structure (I) in an amount of less than about 150 mg of the oral antidiabetic agent.

其它口服的抗糖尿病药物还可选自高血糖素-样肽- 1 (GLP-1 ) 如 GLP- 1 ( 1-36) 酰胺、 GLP- 1 (7-36)酰胺、 GLP- 1 ( 1-36)酰胺、 GLP- 1 (7-37 )酰胺、 GLP- 1 (S3- 20- 32)、 GLP-1 (S3- 11- 14)、 GLP-l (S6-14)、 GLP- 1 (S8 ) (如在 Habener的美国专利 5614492，中国科学院上海药物研究所的中国公开专利 1884278 )，以及 AC2993 ( Amylen ) 和 LY-315902 (Lilly), 其可通过注射、鼻内、经皮或口腔装置等给予用药。 Other oral antidiabetic agents may also be selected from the group consisting of glucagon-like peptide-1 (GLP-1) such as GLP-1 (1-36) amide, GLP-1 (7-36) amide, GLP-1 (1- 36) amide, GLP-1 (7-37) amide, GLP-1 (S3- 20- 32), GLP-1 (S3- 11-14), GLP-1 (S6-14), GLP-1 (S8 (e.g., U.S. Patent 5,714,492 to Habener, Chinese Patent No. 1884278, Shanghai Institute of Materia Medica, Chinese Academy of Sciences), and AC2993 (Amylen) and LY-315902 (Lilly), which can be administered by injection, intranasal, transdermal or oral devices. Give medication.

可任选的本发明式（I ) 的化合物联合使用的氯茴苯酸优选瑞格列奈、那格列奈、 KAD1229 (PF/Kissei ) , 最优选瑞格列奈。 Optionally, the meglitinide used in combination with the compound of formula (I) of the invention is preferably repaglinide, nateglinide, KAD1229 (PF/Kissei), most preferably repaglinide.

其它口服的抗糖尿病药物也可以是 PPAR a / Y 双重激动剂如 AR-H039242 (Astra/Zeneca) ^ GW- 409544 (Glaxo- Wellcome)、 KRP297 (Kyorin Merck)以及由 Murakami等在"充当过氧化物酶体增殖-激活的 a受体 (PPRA a )和 PPRA y的共配体 ( coligand) 的新的胰岛素增敏剂。对 PPRA a在 Zucker肥胖大鼠的肝中激活异常脂质代谢的作用 "， Diabetes, 47, 1841-1847 (1998)。 Other oral antidiabetic agents may also be PPAR a / Y dual agonists such as AR-H039242 (Astra/Zeneca) ^ GW- 409544 (Glaxo- Wellcome), KRP297 (Kyorin Merck) and by Murakami et al. A novel insulin sensitizer for the proliferator-activated a receptor (PPRA a ) and PPRA y coligand. Effect of PPRA a on aberrant lipid metabolism in the liver of Zucker obese rats" , Diabetes, 47, 1841-1847 (1998).

其它的抗糖尿病药物可以是，例如公开于美国申请序列号 09/391053 ( 1999年 9月 7日递交）和美国临时申请号 60/127745 ( 1999年 4月 5日递交）中的 aP2抑制剂，采用以上申请中提出的剂型。优选在以上申请中指定为优选的化合物。 Other anti-diabetic agents may be, for example, aP2 inhibitors disclosed in U.S. Application Serial No. 09/391,053, filed on Sep. 7, 1999, and U.S. Provisional Application No. 60/127,745, filed on Apr. 5, 1999. Pick Use the dosage form set forth in the above application. Preferred compounds are preferably designated in the above application.

其它口服的抗糖尿病药物还可以是 DP4抑制剂，如专利 W099/38501、 099/46272, W099/67279、由 Hughes 等， Biochemistry, 38 (36) , 11597- 11603, 1999 年公开的 NVP- DPP728A(Novartis)等、由 Yamada等， Bioorg. &Med. Chem. Lett. 8 (1998) 1537-1540 公开的 TSL-225, 采用以上参考文献中叙述的剂型。 Other oral anti-diabetic agents may also be DP4 inhibitors, such as the patents W099/38501, 099/46272, W099/67279, Nugh-DPP728A, published by Hughes et al, Biochemistry, 38 (36), 11597-11603, 1999 ( TSL-225, published by Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540, uses the dosage forms described in the above references.

可任选与本发明的式（I)化合物联合使用的降血脂药或降脂剂包括一种或更多 MTP 抑制剂、贝丁酸类、 HMG-CoA还原酶抑制剂、角鲨烯合成酶抑制剂、烟酸衍生物、 LDL 受体活性的上调物、脂氧化酶抑制剂、 ACAT抑制剂、胆固醇吸收抑制剂、回肠钠 7胆酸协同转运蛋白抑制剂、胆酸螯合剂。 A hypolipidemic or lipid lowering agent which may optionally be used in combination with a compound of formula (I) of the invention includes one or more MTP inhibitors, beryllonic acid, HMG-CoA reductase inhibitor, squalene synthetase Inhibitors, niacin derivatives, up-regulation of LDL receptor activity, lipoxygenase inhibitors, ACAT inhibitors, cholesterol absorption inhibitors, ileal sodium 7-cholesterine cotransporter inhibitors, bile acid sequestrants.

降血脂药物可以是 MTP抑制剂，包括但不限于 US5595872、 US5739135、 US5712279, US5760246, US5827875、 US5885983、 US5962440o 公开于以上专利的每一个优选的 MTP 抑制剂均是优选的。以上所有的美国专利结合到本文中。 The hypolipidemic agent can be an MTP inhibitor, including but not limited to US 5,958,872, US 5,739, 135, US 5,712, 279, US 5, 760, 246, US 5, 827, 875, US 5, 588, 983, US 5,962, 440, each of the preferred MTP inhibitors disclosed in the above patents are preferred. All of the above U.S. patents are incorporated herein by reference.

降血脂药物可以是贝丁酸类，包括但不限于氯贝丁酯、苯扎贝特、非诺贝特、吉非贝齐、环丙贝特、克利贝特、普罗布考。 The hypolipidemic drug may be benbutin, including but not limited to, clofibrate, bezafibrate, fenofibrate, gemfibrozil, ciprofibrate, cribbet, probucol.

降血脂药物可以是 HMG- CoA还原酶抑制剂，包括但不限于普伐他汀、美伐他汀、洛伐他汀、辛伐他汀、氟伐他汀、阿托伐他汀、 cerivastatin、伊伐他汀、尼伐他汀、 visastatin, 罗苏伐他汀、帕伐他汀等。具体如公开的 US3983140中的美伐他汀及相关化合物、公开的 US4231938 中的洛伐他汀（mevinolin) 及相关的化合物、公开的 US4346227中的普伐他汀及其相关化合物、公开的 US4448784和 US4450171中的辛伐他汀及相关化合物、公开的 US5354772中的氟伐他汀及相关化合物、公开的 US5006530和 US5177080中的 cerivastatin、公开的 US4681893、 US5011930、 US5273995, US5385929 和 US5686104 中的阿托伐他汀、公开的 US5260440 中的 Shionogi- Astra/Zeneca visastatin(ZD-4522) , 公开的 US5753675中的相关他汀类化合物、公开的 US4613610 中的甲羟戊酸内酯（mevalonolactone ) 衍生物的吡唑类似物、公开的 PCT 申请 W086/03488中的甲羟戊酸内酯的咪唑类似物、公开的法国专利 2596393中的 3 -羧基 - 2- 轻基-丙烷-膦酸衍生物、公开于欧洲专利申请号 0221025中的 2， 3-二取代的吡咯、呋喃和噻吩衍生物、公开的 US4686237中的甲羟戊酸内酯的萘基衍生物、公开的 US4499289 中的八氢萘、公开的欧洲专利申请号 0 2146A2中的 mevinolin (洛伐他汀）的酮基类似物和 US5506219及 US5691322中的喹啉和吡啶衍生物。 The hypolipidemic drug may be an HMG-CoA reductase inhibitor including, but not limited to, pravastatin, mevastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, ivavastatin, nigra Statins, visastatin, rosuvastatin, pravastatin, etc. Specifically, as disclosed in U.S. Patent No. 3,983,140, the disclosure of U.S. Patent No. 4, 398, 784 and U.S. Patent No. 4, 148, 784, the disclosure of U.S. Pat. Simvastatin and related compounds, fluvastatin and related compounds in the published US Pat. No. 5,535,772, cerivastatin in US Pat. No. 5,005, 530, and US Pat. No. 5, 177, 080, US Pat. No. 4,681,893, US Pat. No. 5, 119, 930, US Pat. Shionogi-Astra/Zeneca visastatin (ZD-4522), the related statin disclosed in US Pat. No. 5,753,675, the pyrazole analog of the mevalonolactone derivative disclosed in US Pat. No. 4,613,610, published PCT application WO86 An imidazole analog of mevalonol lactone in /03488, a 3-carboxy-2-pyranyl-propane-phosphonic acid derivative of the published French patent 2,596,393, 2, 3, which is disclosed in European Patent Application No. 0221025 - Disubstituted pyrrole, furan and thiophene derivatives, published in US 4,686,237 a naphthyl derivative of mevalonate, a ketone analog of the disclosed U.S. Patent No. 4,499,289, a ketone analog of mevinolin (lovastatin) in the published European Patent Application No. 0 2146 A2, and a quinoline of US 5,502,219 and US 5,691,322 And pyridine derivatives.

降血脂药物可以是角鲨條合成酶抑制剂，包括但不限于美国专利 5712396中的 α _ 膦酰基-磺酸酯、由 Biller等， J. Med. Chem.， 1988，第 31卷， 10期， 1869-1871公开的化合物。 The hypolipidemic drug may be a squalane synthase inhibitor, including but not limited to alpha _ in US Patent 5,712,396. Phosphono-sulfonate, a compound disclosed by Biller et al, J. Med. Chem., 1988, Vol. 31, No. 10, 1869-1871.

其它降血酯药物包括但不限于胆酸鏊合剂如考来熾胺、考来替泊，胆固醇吸收抑制剂如依替米贝，烟酸类如烟酸、阿昔莫司及其它药物如普罗布考、泛硫乙胺等。 Other hypocholesterolemic drugs include, but are not limited to, cholic acid chelating agents such as cholera, colestipol, cholesterol absorption inhibitors such as ezetimibe, niacin such as niacin, acipimox, and other drugs such as pro Clocoan, pantethine, etc.

其它的降血脂药也可以是脂氧化酶抑制剂，包括 15-脂氧化酶（15- L0)抑制剂如公开于 W097/12615中的苯并咪唑衍生物、公开于 W097/12613中的 15- L0抑制剂、公开于 96/38144中的异噻唑酮以及如由 Sendobry等 "用缺乏显著抗氧化剂特性的高度选择性的 15-脂氧化酶抑制剂在兔中减弱食物诱导的动脉粥样硬化 "， Brit. J. Pharmacology (1997) 120， 1199-1206,和 Cornicelli等, " 15-脂氧化酶及其抑制作用：一种新的血管疾病的治疗剂"， Current Pharmceutical Design, 1999, 5, 11-20 中公开的 L0-15抑制剂。 Other hypolipidemic agents may also be lipoxygenase inhibitors, including 15-lipoxygenase (15-L0) inhibitors such as the benzimidazole derivatives disclosed in W097/12615, 15-15 disclosed in W097/12613. L0 inhibitors, isothiazolone disclosed in 96/38144, and "weak food-induced atherosclerosis in rabbits by a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties," by Sendobry et al. , Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al., " 15-lipoxygenase and its inhibition: a novel therapeutic agent for vascular disease", Current Pharmceutical Design, 1999, 5, 11 The L0-15 inhibitor disclosed in -20.

式（I)化合物和降血脂药可以以同一口服剂型一起使用或在相同的时间以分开的口服剂型服用。 The compound of formula (I) and the hypolipidemic agent can be administered together in the same oral dosage form or in separate oral dosage forms at the same time.

优选的降血脂药物为普伐他汀、辛伐他汀、洛伐他汀、阿托伐他汀、氟伐他汀、 cerivastatin、伊伐他汀、尼伐他汀、 visastatin、罗苏伐他汀、帕伐他汀。 Preferred hypolipidemic drugs are pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, ivavastatin, nevastatin, visastatin, rosuvastatin, and pravastatin.

可任选与本发明的式（I)化合物联合使用的抗肥胖药物包括一种或更多 3肾上腺素能激动剂、脂酶抑制剂、血清素（和多巴胺）重摄取抑制剂、甲状腺 β受体药物、减食欲剂、 ΝΡΥ拮抗剂、 MC4激动剂。 Anti-obesity agents which may optionally be used in combination with a compound of formula (I) of the invention include one or more 3 adrenergic agonists, lipase inhibitors, serotonin (and dopamine) reuptake inhibitors, thyroid beta receptors Drugs, anorectic agents, sputum antagonists, MC4 agonists.

抗肥胖药物可以是 β 3 肾上腺素能激动剂，包括但不限于 AJ9677 (Takeda/Dainippon)、 L750355 (Merck)、以及 US5541204、 US5770615、 US5491134, US5776983和 US5488064中的 β 3肾上腺素能激动剂。 The anti-obesity agent may be a beta 3 adrenergic agonist, including, but not limited to, a β 3 adrenergic agonist in AJ9677 (Takeda/Dainippon), L750355 (Merck), and US5541204, US5770615, US5491134, US5776983, and US5488064.

抗肥胖药物可以是脂酶抑制剂，包括但不限于奥利司他、 ATL-962 (Alizyme) o 抗肥胖药物可以是血清素（和多巴胺）重摄取抑制剂包括但不限于***、托吡酉旨、 axokine₀ The anti-obesity agent may be a lipase inhibitor, including but not limited to orlistat, ATL-962 (Alizyme) o anti-obesity drugs may be serotonin (and dopamine) reuptake inhibitors including, but not limited to, sibutramine, Topira, axokine ₀

其它抗肥胖药包括伹不限于减食欲剂如右***、芬特明、苯丙醇胺、马吲哚。可任选与本发明的式（I)化合物联合使用的抗血小板药物包括阿昔单抗、噻氯匹定、双密达莫、阿司匹林、阿那格雷、 tirofiban、 eptifibatide, 氯吡格雷。 Other anti-obesity agents include, but are not limited to, anorectic agents such as dextroamphetamine, phentermine, phenylpropanolamine, and horseshoe. Antiplatelet agents which may optionally be used in combination with a compound of formula (I) of the present invention include abciximab, ticlopidine, dimiadam, aspirin, anagrelide, tirofiban, eptifibatide, clopidogrel.

可任选与本发明的式（I)化合物联合使用的抗髙血压药物包括 ACE抑制剂如依那普利、卡托普利、喹那普利、贝那普利、培哚普利，钙拮抗剂如氨氯地平、硝苯地平、尼群地平、尼莫地平、尼卡地平、地尔硫卓、维拉帕米， α -阻断剂包括特拉唑嗪、多沙唑嗪、哌唑嗪，利尿剂包括氣***、呋塞咪、螺内酯、吲达帕胺、阿米洛利，中枢 ***作用剂包括利血平、可乐定、胍法辛，血管紧张素 II拮抗剂包括氯沙坦、缬沙坦、替米沙坦，阻断剂包括米托洛尔、 ***、阿替洛尔、卡维地洛、索他洛尔，血管肽酶抑制剂包括 omapatrilat、 gemopai;:rilat。 Anti-spasmodic drugs which may optionally be used in combination with a compound of formula (I) of the invention include ACE inhibitors such as enalapril, captopril, quinapril, benazepril, perindopril, calcium Antagonists such as amlodipine, nifedipine, nitrendipine, nimodipine, nicardipine, diltiazem, verapamil, alpha-blockers including terazosin, more Salazosin, prazosin, diuretics including gas chlorothiazide, furosemide, spironolactone, indapamide, amiloride, central systemic agents including reserpine, clonidine, guanfacine, angiotensin II II antagonists include losartan, valsartan, telmisartan, blockers including mitoxolol, propranolol, atenolol, carvedilol, sotalol, vasopeptidase Inhibitors include omapatrilat, gemopai;: rilat.

肉碱衍生物包括但不限于肉碱、左卡尼汀、盐酸左卡尼汀、氯化左卡尼汀、乙酰左卡尼汀、丙酰左卡尼汀、丁酰左卡尼汀等，优选左卡尼汀。 Carnitine derivatives include, but are not limited to, carnitine, L-carnitine, L-carnitine hydrochloride, L-carnitine chloride, Acetyl L-carnitine, Propionyl L-carnitine, Butyryl L-Carnitine, and the like. L-carnitine is preferred.

肉碱棕榈酰转移酶抑制剂包括但不限于丙二酰辅酶 A、琥珀酰辅酶 A、甲基丙二酰辅酶 A、 2-溴棕榈酸、益托某西尔、缩水甘油（如 clomoxir, etomoxir)等（张芳林等，国外医学内分泌手册， 2005, 22 (3)： 166-169)。 Carnitine palmitoyltransferase inhibitors include, but are not limited to, malonyl-CoA, succinyl-CoA, methylmalonyl-CoA, 2-bromopalmitic acid, Yitoo-Sil, glycidol (eg clomoxir, etomoxir) ) et al. (Zhang Fanglin et al., Foreign Medical Endocrinology Manual, 2005, 22 (3): 166-169).

本发明的式（I )化合物联合使用的治疗贪血药物包括但不限于硫酸亚铁、富马酸亚铁、右旋糖酐铁、山梨醇枸橼酸铁、维生素、糖皮质激素、雄激素、***、叶酸、维生素 B12。 The therapeutic blood-suppressing drugs used in combination with the compound of the formula (I) of the present invention include, but are not limited to, ferrous sulfate, ferrous fumarate, iron dextran, sorbitan iron citrate, vitamins, glucocorticoids, androgens, and erythrocytes. Producer, folic acid, vitamin B12.

本发明的式（I )化合物联合使用的治疗痛风药物包括但不限于秋水仙碱、消炎痛、布洛芬、萘普生、保泰松、扶他林、炎痛喜康、西乐花、美络昔康、别嘌昤醇、枸橡酸钾、碳酸氢钠、丙磺舒、苯溴马隆、硫氧唑酮、磺酰吡唑、痛风利仙等。 The therapeutic gout drugs used in combination with the compound of formula (I) of the present invention include, but are not limited to, colchicine, indomethacin, ibuprofen, naproxen, phenylbutazone, fustatin, inflammatory pain, xixihua, meiluoxi Kang, allopurinol, potassium citrate, sodium bicarbonate, probenecid, benzbromarone, thiazolone, sulfonylpyrazole, gout, etc.

本发明的式（I )化合物联合使用的抗抑郁症药物为三环类、单胺氧化酶抑制剂、 5-羟色胺再摄取抑制剂、乙酰胆碱再摄取抑制剂等。 The antidepressant drugs used in combination with the compound of the formula (I) of the present invention are tricyclics, monoamine oxidase inhibitors, serotonin reuptake inhibitors, acetylcholine reuptake inhibitors and the like.

抗抑郁症药物可以是三环类药物，包括但不限于丙咪嗪、氯丙咪嗪、阿米替林、多虑平、去甲丙咪嗪、去甲替林。 The antidepressant may be a tricyclic drug including, but not limited to, imipramine, clomipramine, amitriptyline, doxepin, normimethamine, nortriptyline.

抗抑郁症药物可以是四环类药物，包括但不限于米安色林、马普替林。 Antidepressant drugs can be tetracyclic drugs including, but not limited to, mianserin, maprotiline.

抗抑郁症药物可以是单胺氧化酶抑制剂，包括但不限于苯乙肼、超苯环丙胺、吗氯贝胺。 The antidepressant drug may be a monoamine oxidase inhibitor including, but not limited to, phenethyl hydrazine, phenylpropanolamine, morphine.

抗抑郁症药物可以是选择性 5-HT再摄取抑制剂，包括但不限于氟西汀、帕罗西定、舍曲林、西酞普兰、伏氟沙明。 . The antidepressant agent can be a selective 5-HT reuptake inhibitor including, but not limited to, fluoxetine, paroxetine, sertraline, citalopram, and flufen samine. .

抗抑郁症药物可以是 5-HT和 NE再摄取抑制剂，包括伹不限于文拉法辛、万拉法新。抗抑郁症药物还可以是其它药物，包括但不限于瑞波西汀、布普品、曲唑酮、奈法唑酮、米它扎平、路优泰、安非拉酮。 Antidepressant drugs may be 5-HT and NE reuptake inhibitors, including 伹 not limited to venlafaxine, venlafaxine. The antidepressant may also be other drugs including, but not limited to, reboxetine, buppe, trazodone, nefazodone, dextrozapine, luteapine, amfepramone.

本发明的式（I)化合物联合使用的治疗痴呆症药物包括但不限于四氢氨基吖啶（他克林)、四羟氨基吖啶、毒扁豆碱、庚烯毒扁豆碱、加兰他敏、美曲磷脂（敌百虫)、盐酸多奈哌齐、石杉碱甲、重酒石酸卡拉巴汀、占诺美林、利培酮、吗氯贝胺、拉扎贝胺、沙贝鲁唑、依斯的明、司来吉兰、丙戊茶碱、新曲非思、安帕来斯、奈非西坦、利诺吡啶、孟替瑞林、氮替瑞林、奥氮平、 ZT- 1、普拉西坦、二苯美仑、依昔苯酮、茚洛嗪、甲氯芬酯、吡拉西坦、吡硫醇、乙酰谷酰胺、克脑迷、胞磷胆碱、茴拉西坦、尼莫地平、乙酰 -L-肉毒碱、 L-肉毒碱、尼麦角林、利伐司替明、 Sabcomedine hydrochloricde, SR-46659A, SB202026、 ENS163、 LY246078, Dup996、 RU35906. Milameline、 Talsaclidine。 The medicament for treating dementia used in combination with the compound of the formula (I) of the present invention includes, but is not limited to, tetrahydroaminoacridine (tacrine), tetrahydroxyaminoacridine, physostigmine, heptene lenola, galantamine , koji lecithin (trichlorfon), donepezil hydrochloride, huperzine A, carraga tartaric acid, nominin, risperidone, moclobemide, lazabe, Saberuzole, Istemide, Selegiline, Propofolline, New Qufusi, Apelis, Nefiracetam, Linoleide, Montesalin, Nitrorelin, Azo Ping, ZT-1, prasalam, diphenylmex, epoxone, oxazolidine, meclofenoxate, piracetam, pyrithione, acetyl glutamine, gram brain, phosphatidylcholine Alkali, aniracetam, nimodipine, acetyl-L-carnitine, L-carnitine, nigralin, rivastigmine, Sabcomedine hydrochloricde, SR-46659A, SB202026, ENS163, LY246078, Dup996, RU35906. Milameline, Talsaclidine.

本发明的式（I ) 化合物联合使用的治疗骨质疏松药物为骨吸收抑制剂、骨形成促进剂、骨矿化物质及其它治疗骨质疏松药物。 The osteoporosis drugs used in combination with the compound of the formula (I) of the present invention are bone resorption inhibitors, bone formation promoting agents, bone mineralizing substances and other osteoporosis drugs.

骨吸收抑制剂包括但不限于双膦酸盐、 ***、降钙素、孕激素、异黄酮、锶盐。双膦酸盐包括但不限于依替膦酸盐、氯膦酸盐、替鲁膦酸盐、帕米膦酸盐、阿仑膦酸盐、利塞膦酸盐、 incadronate, 唑来膦酸盐、 dtidronate、伊班膦酸盐。 Bone resorption inhibitors include, but are not limited to, bisphosphonates, estrogens, calcitonin, progestins, isoflavones, guanidinium salts. Bisphosphonates include, but are not limited to, etidronate, clodronate, tiludronate, pamidronate, alendronate, risedronate, incadronate, zoledronate , dtidronate, ibandronate.

***包括但不限于雷洛昔芬、克洛米芬（舒筋芬）、他莫昔芬、 dr₀l_0Xif_ene、 noforxidine, 艾多昔芬、巴多昔芬、拉索昔芬、替勃龙、尼尔雌醇。 Estrogens include, but are not limited to, raloxifene, clomiphene citrate, tamoxifen, dr ₀ l _0X if _ene , noforxidine, idoxifene, bazedoxifene, lasofoxifene, Tibolone, Nilestriol.

降鈣素包括但不限于密钙息、益钙宁、 salcat₀nin。 Calcitonin includes, but is not limited to, dense calcium, procalcin, salcat ₀ nin.

骨形成促进剂包括但不限于氟化物（特乐定)、甲状旁腺激素（PTH)、同化类固醇药物、人免疫球蛋白（IGF)„ Bone formation promoters include, but are not limited to, fluoride (telidine), parathyroid hormone (PTH), anabolic steroids, human immunoglobulin (IGF)

其它治疗骨质疏松的药物还可以是他汀类，丙氨酰组氨酸锌（AHZ)、组织蛋白酶 K 抑制剂、内皮整合素受体阻断剂、神经肽、生长因子（***、转化生长因子、骨形态发生蛋白）、骨保护素（osteoprotegerin 0PG)。 Other drugs for the treatment of osteoporosis may also be statins, zinc alaninate (AHZ), cathepsin K inhibitors, endostein receptor blockers, neuropeptides, growth factors (insulin-like growth factors, Transforming growth factor, bone morphogenetic protein), osteoprotegerin (osteoprotegerin 0PG).

本发明的式（I ) 化合物联合使用的抗炎药物包括但不限于阿司匹林、保泰松、萘普生、芬布芬、布洛芬、吲哚美辛、萘丁酮、二氟尼柳、对乙酰氨基酚、贝诺酯、水杨酸、依托芬那酯、依托度酸、酮洛芬、双氯芬酸、青霉胺、塞来昔布、尼美舒利、美洛昔康、洛索洛芬、来氟米特、非普拉宗、苯并氧酰胺、奥沙普嗪、舒林酸、安替比林、金诺芬、吡罗昔康、咪唑酯、托美汀、甲氯芬那酸、阿西美辛。 Anti-inflammatory drugs for use in combination with a compound of formula (I) of the present invention include, but are not limited to, aspirin, phenylbutazone, naproxen, fenbufen, ibuprofen, indomethacin, nabumetone, diflunisal, Acetaminophen, benolyl ester, salicylic acid, etofenamate, etodolac, ketoprofen, diclofenac, penicillamine, celecoxib, nimesulide, meloxicam, losolo Fen, leflunomide, non-Prazin, benzoxamide, oxaprozin, sulindac, antipyrine, auranofin, piroxicam, imidazoxil, tommettine, meclofenamic acid Assimin.

本发明的式（I )化合物联合使用的抗肿瘤药物可以为烷化剂、抗肿瘤抗生素、二氢叶酸还原酶抑制剂、嘌呤类、嘧啶类、拓扑异构酶抑制剂、肿瘤新生血管生成抑制剂、天然药物等。 The antitumor drug used in combination with the compound of the formula (I) of the present invention may be an alkylating agent, an antitumor antibiotic, a dihydrofolate reductase inhibitor, an anthraquinone, a pyrimidine, a topoisomerase inhibitor, or a tumor angiogenesis inhibitor. Agents, natural medicines, etc.

烷化剂包括但不限于环磷酰胺、氮芥、噻替派、萘达铂、奥沙利铂、美法仑、氮甲、卡莫司汀、洛莫司汀、司莫司汀、尼莫司汀、雷莫司汀、特莫唑胺、米托唑酶胺、特洛西酮、白消胺。 Alkylating agents include, but are not limited to, cyclophosphamide, nitrogen mustard, thiotepa, nadropaplatin, oxaliplatin, melphalan, nitrite, carmustine, lomustine, semustine, nis Mustine, ramustine, temozolomide, mitoxazole amine, troxidone, mesamine.

抗肿瘤抗生素包括但不限于阿霉素、丝裂霉素、争光霉素、正定霉素、表柔比星、丝裂霉素、柔红霉素、阿克拉霉素、洋红霉素、米托蒽醌、依达柔比星、吡柔比星、戊柔吡星。 Antitumor antibiotics include, but are not limited to, doxorubicin, mitomycin, bleomycin, gentamicin, epirubicin, Mitomycin, daunorubicin, aclarithromycin, erythromycin, mitoxantrone, idarubicin, pirarubicin, pentopirin.

二氢叶酸还原酶抑制剂包括但不限于甲氨碟昤、六甲蜜胺。 Dihydrofolate reductase inhibitors include, but are not limited to, methotrexate, hexamethylene melamine.

嘌吟类药物包括伹不限于巯嘌呤。 Terpenoids include 伹 not limited to 巯嘌呤.

嘧啶类药物包括但不限于氟尿嘧啶、卡莫氟。 Pyrimidine drugs include, but are not limited to, fluorouracil, carmofur.

抗肿瘤天然药物包括但不限于喜树碱、长春新碱、紫杉醇、秋水仙碱、绿舒筋、复方醋酸棉酚、康莱特 (薏苡仁提取物)、榄香烯 (莪术油提取物)、三尖杉酯碱、猪苓多糖、茯苓多糖、香菇多糖、人参多糖、银耳多糖、云芝多糖、地黄多糖、枸杞多糖、猕猴桃多糖、黄芪多糖、当归多糖、绞股蓝多糖、竹荪多糖、刺五加多糖、牛膝多糖等。 Anti-tumor natural drugs include, but are not limited to, camptothecin, vincristine, paclitaxel, colchicine, green gluten, compound acetate gossypol, Kanglaite (barley extract), elemene (artemisia oil extract), Harringtonine, Polyporus polysaccharide, Lycium barbarum polysaccharide, Lentinus edodes polysaccharide, Ginseng polysaccharide, Tremella polysaccharide, Yunzhi polysaccharide, Rehmannia polysaccharide, Lycium barbarum polysaccharide, Kiwi polysaccharide, Astragalus polysaccharide, Angelica polysaccharide, Gynostemma polysaccharide, Radix polysaccharide, Prickly ash Add polysaccharides, Achyranthes polysaccharides, etc.

拓扑异构酶抑制剂包括但不限于伊立替康、拓扑替康和芦比替坎。 Topoisomerase inhibitors include, but are not limited to, irinotecan, topotecan, and rebitantan.

肿瘤新生血管生成抑制剂包括但不限于舒拉明、沙利度胺、夫马洁林、单克隆抗体、巴马司他、马立马司他。 Tumor angiogenesis inhibitors include, but are not limited to, suramin, thalidomide, fumagillin, monoclonal antibodies, bamstat, and marimastat.

本发明化合物 ( I )用来制备***的药物，其中肿瘤包括急性粒细胞性白血病、慢性粒细胞性白血病、肾透明性癌、乳腺癌、淋巴细胞白血病、 ***癌、肝癌、淋巴瘤、肺癌、胃癌、食道癌、结肠癌等多种肿瘤。 The compound (I) of the invention is used for preparing a medicament for treating tumor, wherein the tumor comprises acute myeloid leukemia, chronic myeloid leukemia, renal transparent cancer, breast cancer, lymphocytic leukemia, prostate cancer, liver cancer, lymphoma, lung cancer , gastric cancer, esophageal cancer, colon cancer and other tumors.

本发明的式 α )化合物联合使用的免疫抑制药物包括伹不限于***、强的松龙、 ***、氢化可的松、达那唑、环磷酰胺、环孢菌素4、霉酚酸酯、来氟米特、雷公藤，硫唑嘌呤、肝素-华法林、双密达莫、他克莫司、西罗莫司、康乐霉素(、咪唑立宾、免疫球蛋白、二十碳五烯酸、二十二碳六烯酸（DHA)、益赛普、达昔单抗、利妥昔单抗、英夫利昔单抗、干扰素。 The immunosuppressive drugs used in combination with the compound of the formula α) of the present invention include guanidine, not limited to prednisone, prednisolone, dexamethasone, hydrocortisone, danazol, cyclophosphamide, cyclosporin 4, mold Phenolic acid ester, leflunomide, tripterygium wilfordii, azathioprine, heparin-warfarin, dimetamol, tacrolimus, sirolimus, kalemycin (imidazole, immunoglobulin, Eicosapentaenoic acid, docosahexaenoic acid (DHA), escital, daximab, rituximab, infliximab, interferon.

本发明的式（I )化合物联合使用的抗氧化剂包括但不限于谷胱甘肽、维生素 E、维生素 (：、维生素 A、超氧化物歧化酶 (SOD)、奥古蛋白、血球铜蛋白、茶多酚、牛磺酸、尿酸、疏基蛋白、丙丁酚、谷氨酸酯、琥珀酸酯、泛醌、叶绿醌、辅酶 Q、高半胱氨酸、甲基萘醌、 α -硫辛酸、丹曲林、多苯酚类黄酮、卵磷脂、熊去氧胆酸、辅酶 Α、亚油酸、硫酸软骨素、齐墩果酸、肌醇、水飞蓟素、联苯双酯、门冬氨酸钾镁、甘草甜素、蛋氨酸、核酸、葡萄糖醛酸内酯、维丙胺、甘草酸、免疫球蛋白等。 Antioxidants for use in combination with the compounds of formula (I) of the present invention include, but are not limited to, glutathione, vitamin E, vitamins (:, vitamin A, superoxide dismutase (SOD), archoprotein, hemagglutinin, tea Polyphenols, taurine, uric acid, thioglycoprotein, probucol, glutamate, succinate, ubiquinone, chlorophyllin, coenzyme Q, homocysteine, menaquinone, alpha-lipoic acid , dantrolene, polyphenol flavonoids, lecithin, ursodeoxycholic acid, coenzyme, linoleic acid, chondroitin sulfate, oleanolic acid, inositol, silymarin, biphenyl diester, potassium aspartate Magnesium, glycyrrhizin, methionine, nucleic acid, glucuronolactone, propylamine, glycyrrhizic acid, immunoglobulin, and the like.

本发明药物组合物制备成药物制剂，该制剂剂型包括口服给药制剂、注射给药制剂或局部给药制剂，其中： The pharmaceutical composition of the present invention is prepared into a pharmaceutical preparation comprising an orally administered preparation, an injectable preparation or a topically administered preparation, wherein:

( 1 ) 口服给药制剂包括普通片、缓释片、颗粒剂、硬或软胶囊、糖浆剂、溶液剂、乳剂；口服给药制剂的载体包括填充剂、崩解剂、粘合剂、润滑剂、着色剂、矫味剂或者其他常规添加剂，具体包括淀粉、乳糖、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯垸酮、聚乙烯吡咯烷酮、羟丙甲纤维素、硬脂酸镁、二氧化硅和聚山梨脂一 80、十二垸基硫酸钠； (1) Oral administration preparations include ordinary tablets, sustained release tablets, granules, hard or soft capsules, syrups, solutions, emulsions; carriers for oral administration include fillers, disintegrators, binders, lubricants Agent, colorant, flavoring agent or Other conventional additives, including starch, lactose, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, polyvinylpyrrolidone, hypromellose, magnesium stearate, silica and poly Yamanite 80, sodium decyl sulfate;

(2)注射给药制剂包括无菌注射的水溶液、无菌注射的水包油微乳液、注射用无菌粉末；注射给药制剂的载体包括注射用溶剂、注射用附加剂，具体注射溶剂包括注射用水、注射用油如大豆油，注射用增溶剂如乙醇、丙二醇、聚乙二醇、甘油，等渗物质如氯化钠、葡萄糖； (2) The preparation for administration by injection includes a sterile injection aqueous solution, a sterile injection oil-in-water microemulsion, a sterile powder for injection; a carrier for injecting the preparation preparation includes a solvent for injection, an additional agent for injection, and the specific injection solvent includes Water for injection, oil for injection such as soybean oil, solubilizer for injection such as ethanol, propylene glycol, polyethylene glycol, glycerin, isotonic substances such as sodium chloride, glucose;

(3 ) 局部给药制剂是贴剂、栓剂、霜剂、膏剂、凝胶剂、溶液、混悬液或靶向制剂，其中靶向制剂包括脂质体、微球剂、毫微粒、包含物、单克隆抗体耦联物；局部给药制剂的载体包括药学上用于局部给药的常规载体。 (3) The topical preparation is a patch, a suppository, a cream, a cream, a gel, a solution, a suspension or a targeted preparation, wherein the targeted preparation comprises a liposome, a microsphere, a nanoparticle, an inclusion. , monoclonal antibody conjugates; carriers for topical formulations include conventional carriers for pharmaceutically acceptable topical administration.

本发明的药物制剂给药形式包括：静脉、肌内、腹膜、皮下、口服、直肠栓剂*** 法、 ***栓剂***法、靶向给药、吸入式、灌胃式、鼻饲式、舌下给药、滴药法、微针式给药、连续给药***和局部给药，局部给药方式如贴皮制剂、或植入式连续给药释放 ***，其中贴皮制剂载体包括骨架材料如疏水的聚硅氧烷和亲水的聚乙烯醇等，控释膜材料如聚硅氧烷和乙烯-醋酸乙烯共聚物等，压敏胶如聚异丁烯、聚硅氧烷和聚丙烯酸酯，活性成分一般分散在压敏胶中；其中植入式连续给药释放***所选用的高分子材料包括聚乳酸一乙醇酸共聚物、聚乙二醇聚乳酸共聚物、聚乳酸 /聚己内酯、聚 [碳酸（亚丁酯 -co- ε -己内酯）酯]、聚丁内酯戊内酯、聚二氧环己酮 (PDS )、聚 - 3 _羟基丁酸酯 (ΡΗΒ )、聚左旋乳酸 (PLLA)、聚乙醇酸 (PGA)、聚 ε -己内酯 (PCL：)、聚己内酯 /聚乙交酯丙交酯（PCL / PLGA)、甲基丙烯酸羟乙酯 (HEMA)。 The pharmaceutical preparation forms of the present invention include: intravenous, intramuscular, peritoneal, subcutaneous, oral, rectal suppository insertion, vaginal suppository insertion, targeted administration, inhalation, gavage, nasal feeding, sublingual administration , a drip method, a micro-needle administration, a continuous administration system, and a topical administration, a topical administration method such as a skin preparation, or an implantable continuous administration release system, wherein the skin preparation carrier comprises a skeleton material such as hydrophobic Polysiloxane and hydrophilic polyvinyl alcohol, etc., controlled release film materials such as polysiloxane and ethylene-vinyl acetate copolymer, pressure sensitive adhesives such as polyisobutylene, polysiloxane and polyacrylate, the active ingredients are generally Dispersed in pressure sensitive adhesive; the polymer materials selected for the implantable continuous drug delivery system include polylactic acid-glycolic acid copolymer, polyethylene glycol polylactic acid copolymer, polylactic acid/polycaprolactone, poly[ Carbonic acid (butylene ester-co-ε-caprolactone) ester], polybutyrolactone valerolactone, polydioxanone (PDS), poly-3-hydroxybutyrate (ΡΗΒ), poly-L-lactic acid ( PLLA), polyglycolic acid (PGA), poly ε-Caprolactone (PCL:), polycaprolactone/polyglycolide lactide (PCL / PLGA), hydroxyethyl methacrylate (HEMA).

在实施本发明的方法中，将使用含与药学上可接受的载体或稀释剂结合的结构（I) 化合物的药用组合物，该组合物可含有或不含有另一种抗糖尿病药物和 /或抗高血脂药物，或其它类型的治疗药物。使用常规的固体或液体载体或稀释剂以及适合于所需给药方式的某种类型的药用添加剂，可以配置成药用组合物。该化合物可以以例如片剂、胶囊、颗粒剂或散剂的形式，通过口服途径给予哺乳动物等，包括人、猴、狗、猪、鼠等，或者它们可以以注射制剂的形式经胃肠外途径给予，或者它们可以经鼻腔或以经皮贴剂的形式给予。对于成人，剂量优选在 10-2000rag/日之间，其可以单一剂量或以分开的剂量的形式，每日 1-4次给予。 In practicing the methods of the invention, a pharmaceutical composition comprising a compound of structure (I) in association with a pharmaceutically acceptable carrier or diluent, which may or may not contain another anti-diabetic agent, and/or Or antihyperlipidemic drugs, or other types of therapeutic drugs. The pharmaceutical composition can be formulated using conventional solid or liquid carriers or diluents, as well as some type of pharmaceutical additive suitable for the desired mode of administration. The compound can be administered to a mammal or the like by a oral route, for example, in the form of a tablet, a capsule, a granule or a powder, including humans, monkeys, dogs, pigs, rats, etc., or they can be administered parenterally in the form of an injection preparation. They are administered, or they can be administered nasally or in the form of a transdermal patch. For adults, the dosage is preferably between 10 and 2000 rag/day, which may be administered in a single dose or in divided doses, one to four times daily.

本发明化合物的 SGLT2抑制剂活性可通过使用如下所述的测定***测定。 The SGLT2 inhibitor activity of the compounds of the invention can be determined by using an assay system as described below.

SGLT2活性的测定采用标准分子生物学技术，通过逆转录和扩增，从人肾 mRNA克隆人 SGLT2的 mRNA 序列（GenBank#M95549)。 cDNA序列被稳定地转染至 CH0细胞中，基本如 Ryan (1994) 所述，对克隆物进行 SGLT2活性的测定。基本如 Ryan等所述，伹作了以下修改，在克隆选择的细胞系中，进行 SGLT2活性的抑制作用的评价。在 96-孔板上，在 F-12营养混合物（Ham， s F-12), 10%胎牛血清、 300 μ _g/ml遗传霉素和青霉素-链霉素中，使细胞生长 2- 4天，以达到每孔 75000或 30000个细胞。汇合后，用 lOmM Determination of SGLT2 activity The mRNA sequence of human SGLT2 was cloned from human kidney mRNA by reverse transcription and amplification using standard molecular biology techniques (GenBank #M95549). The cDNA sequence was stably transfected into CH0 cells, and the clones were assayed for SGLT2 activity as described generally by Ryan (1994). Basically, as described by Ryan et al., the following modifications were made to evaluate the inhibition of SGLT2 activity in the cell line selected for cloning. Cell growth 2 - 4 in 96-well plates in F-12 nutrient mixture (Ham, s F-12), 10% fetal bovine serum, 300 _μg / ml geneticin and penicillin-streptomycin Days to reach 75,000 or 30,000 cells per well. After confluence, use lOmM

Hepes/Tris (pH7. 4) , 137raM N-甲基- D-葡糖胺、 5. 4mM氯化钾、 2. 8mM氯化钙、 1. 2mM硫酸镁洗涤细胞两次。然后于 37°C，使细胞与 10 μ Μ ["C]AMG和 ΙΟ μ Μ抑制剂（最终 DMS0=0. 5%)在 lOmM Hepes/Tris (pH7. 4) , 137mM氯化钠、 5· 4n 氯化钾、 2. 8mM氯化钙、 1. 2mM硫酸镁中孵育 1. 5小时。用含 0. 5mM根皮苷的冰冷的 1 XPBS猝灭摄取测定物，然后用 0. 1%氢氧化钠溶解细胞。假如 MicroScint闪烁液体后，使细胞振摇 1小时，然后在 TopCourrt闪烁计数器上对 ["C]AMG定量。对照试验可在有和无氯化钠的情况下进行。对于 EC50值的测定，在合适的响应范围内，以 21og间隔，采用 10个抑制剂浓度，在测定板上对一式三份板进行平均（Ryan MJ, Johnson G, Kirk J, Fuerstenberg SM， Zager RA和 Torok-Storb B. 1994. HK-2：一种得自正常成人肾的无限增殖化近端小管上皮细胞系。 Kidney International 45:48-57)。具体实施方式 . The cells were washed twice with Hepes/Tris (pH 7.4), 137 raM N-methyl-D-glucosamine, 5. 4 mM potassium chloride, 2. 8 mM calcium chloride, 1. 2 mM magnesium sulfate. Then, at 37 ° C, the cells were supplemented with 10 μM ["C] AMG and ΙΟ μ Μ inhibitor (final DMS0 = 0.5%) in 10 mM Hepes/Tris (pH 7.4), 137 mM sodium chloride, 5· 4%氢。 The 1N hydrogen is incubated with an ice-cold IX PBS containing 0.5 mM phlorizin. Sodium oxide lyses the cells. If the MicroScint scintillation fluid, shake the cells for 1 hour and then quantify ["C]AMG on a TopCourrt scintillation counter. Control experiments can be performed with and without sodium chloride. For the determination of EC50 values, triplicate plates were averaged on the assay plate at a 21 og interval with a concentration of 10 inhibitors (Ryan MJ, Johnson G, Kirk J, Fuerstenberg SM, Zager RA) And Torok-Storb B. 1994. HK-2: An immortalized proximal tubular epithelial cell line obtained from normal adult kidneys. Kidney International 45:48-57). detailed description .

本发明将结合实施例作进一步的说明。 The invention will be further illustrated in conjunction with the examples.

本发明的分子结构有的存在立体异构体，它们通过手性试剂定向合成、化学拆分或经手性柱制得单纯的立体异构体，这些立体异构体在本实施例中未全部说明，但不限制本发明。 The molecular structure of the present invention may exist as stereoisomers, which are prepared by chiral reagent directed synthesis, chemical resolution or chiral column to obtain simple stereoisomers. These stereoisomers are not fully described in this embodiment. However, the invention is not limited.

-（四氢吡咯- 1-基-亚甲基）根皮苷的制备 -(Tetrahydropyrrole-1-yl-methylene) phloridzin preparation

将根皮苷（0.25g， 0.58mmol)溶于 25raL无水乙醇中倒入圆底烧瓶中，置磁力搅拌器搅拌，控制温度在 3—10°C，向根皮苷乙醇溶液中缓慢滴加 37%甲醛水溶液（0.059niL， 0.87iraiol),继续搅拌 30min。再缓慢滴加吡咯烷 (0.066mL, 0.87mmol),控制温度在 0〜 70 °C, 继续搅拌反应 6(hni_n，反应结束将母液置 60Ό真空蒸干，加 10mL水溶解产物，有白色产物析出，充分振摇（搅拌） 2小时使产物完全析出，抽滤得白色固体粉末，在白色固体粉末中加入 2mL水在 60°C7j浴中搅拌并滴加甲醇使其溶解，冷却静置析出白色针状晶体，抽滤后 70°C真空干燥 4小时得白色针状晶体。称重 0.13g，得率为 52%。

The phlorizin (0.25g, 0.58mmol) was dissolved in 25raL absolute ethanol and poured into a round bottom flask. Stir it with a magnetic stirrer and control the temperature at 3-10 °C. Slowly add to the phlorizin ethanol solution. A 37% aqueous solution of formaldehyde (0.059 niL, 0.87 iraiol) was stirred for 30 min. Further, pyrrolidine (0.066 mL, 0.87 mmol) was slowly added dropwise, and the temperature was controlled at 0 to 70 ° C. Stirring reaction 6 was continued (hni _n , the mother liquor was placed in a vacuum of 60 Torr under vacuum, and 10 mL of water was added to dissolve the product, and a white product was obtained. Precipitate, shake well (stirred) for 2 hours to completely precipitate the product, and filter to obtain a white solid powder. Add 2 mL of water to a white solid powder, stir in a 60 ° C 7j bath, add methanol dropwise to dissolve, and cool to precipitate white. Needle-like crystals were vacuum-dried at 70 ° C for 4 hours to obtain white needle-like crystals. The weight was 0.13 g, and the yield was 52%.

m. p.194.5-196.5"C m. p.194.5-196.5"C

HPLC检验仪器：岛津 LC— 10A,色谱柱： C18柱（4.6*150mm, 5 μ m),流速： 1. Oml/min, 柱温： 40Ό ，检测波长： 284nm，流动相： 60%磷酸水溶液（2mmol/L) +40%甲醇，保留时间： 2.953min HPLC test instrument: Shimadzu LC-10A, column: C18 column (4.6*150mm, 5 μm), flow rate: 1. Oml/min, column temperature: 40Ό, detection wavelength: 284nm, mobile phase: 60% phosphoric acid aqueous solution (2mmol/L) +40% methanol, retention time: 2.953min

Element Analyzing: C 58.46%, H 6.55%, 032.48%, N 2.51% Element Analyzing: C 58.46%, H 6.55%, 032.48%, N 2.51%

ESI-MS(m/z) :518[(M-1)1 及 ESI_MS(m/z) :520[(M+1)⁺] 和 ESI-MS(ra/z) : 542[(M+Na)⁺] ESI-MS (m/z): 518 [(M-1)1 and ESI_MS (m/z): 520[(M+1) ⁺ ] and ESI-MS (ra/z): 542[(M+Na ) ⁺ ]

1R cm"¹: 3408, 3300, 1616， 1547, 1517, 1079， 1046, 989， 832 1R cm" ¹ : 3408, 3300, 1616, 1547, 1517, 1079, 1046, 989, 832

丽 R(DMSO- d_s) δ ： 1.83(4H, s)， 2.79 (2H， t, J=7.4Hz), 2.86 (4H, s)， 3.16-3.71 (8H, m)， 3.91 (2H, s), 4.92 (1H, d, J=7.3Hz), 5.91(1H, s), 6.64 (2H, d, 8.4Hz), 7.04(2H, d, J=8.4Hz) R (DMSO- d _s ) δ : 1.83(4H, s), 2.79 (2H, t, J=7.4Hz), 2.86 (4H, s), 3.16-3.71 (8H, m), 3.91 (2H, s ), 4.92 (1H, d, J=7.3Hz), 5.91(1H, s), 6.64 (2H, d, 8.4Hz), 7.04(2H, d, J=8.4Hz)

¹³C-NMR(DMSO-d₆) δ： 23.0(X2), 29.4, 44.3, 49.7, 52.7(X2), 60.6, 69.5, 73.2, 76.7, 77.2, 95.6, 100.4, 100.6， 102.3, 115.0(X2), 129.1(X2), 131.8, 155.3, 160. , 163.9, 170.6, 202.6 实施例 2 3' - (六氢吡啶- 1-基-亚甲基）根皮苷的制备 ¹³ C-NMR (DMSO-d ₆ ) δ: 23.0 (X2), 29.4, 44.3, 49.7, 52.7 (X2), 60.6, 69.5, 73.2, 76.7, 77.2, 95.6, 100.4, 100.6, 102.3, 115.0 (X2) , 129.1 (X2), 131.8, 155.3, 160., 163.9, 170.6, 202.6 Example 2 Preparation of 3'-(hexahydropyridine-1-yl-methylene) phloridin

对根皮苷：甲醛：六氢吡啶 =1: 1： 1 (摩尔比）按照实施例 1的操作方法进行，得到白色针状晶体，得率为 80%。 For phloridzin: formaldehyde: hexahydropyridine = 1: 1: 1 (molar ratio) according to the method of operation of Example 1, To white needle crystals, the yield is 80%.

m. p.184.2-186.0"C m. p.184.2-186.0"C

HPLC检验仪器: 岛津 LC—10A，色谱柱： C18柱（4.6*150腿, 5um)，流速： lml/min，柱温： 35°C，检测波长： 284nm，流动相： 80%水， 20%甲醇〜 40%水， 60%甲醇， 0〜 16rain，保留时间： 14.707min HPLC test instrument: Shimadzu LC-10A, column: C18 column (4.6*150 legs, 5um), flow rate: lml/min, column temperature: 35°C, detection wavelength: 284nm, mobile phase: 80% water, 20 % methanol ~ 40% water, 60% methanol, 0~ 16rain, retention time: 14.707min

Element Analyzing: C 58.83%, H 6.92%, 031.74%, N 2.51% Element Analyzing: C 58.83%, H 6.92%, 031.74%, N 2.51%

ESI-MS(m/z) :532[(M-1)⁺] 及 ESI— MS(m/z) :534[(M+1)+] 和 ESI— MS(m/z): 556[(M+Na)⁺] ESI-MS (m/z): 532 [(M-1) ⁺ ] and ESI-MS (m/z): 534[(M+1)+] and ESI-MS (m/z): 556[( M+Na) ⁺ ]

IR cm—¹: 3360, 1616, 1543, 1517, 1078, 987, 832IR cm- ¹ : 3360, 1616, 1543, 1517, 1078, 987, 832

-匪 R(DMS0-d₆) δ ： 1.45(2H, ra), 1.56(4H, m), 2.59 (4H, s), 2.79 (2H, t， J=7.4Hz)， 3.15-3.71 (8H, m)， 3.73(2H, s)， 4.95 (1H, d, J=7.3Hz), 6.00 (1H, s)， 6.65(2H， d, 8.4Hz), 7.04 (2H, d, J=8.4Hz) -匪R(DMS0-d ₆ ) δ : 1.45(2H, ra), 1.56(4H, m), 2.59 (4H, s), 2.79 (2H, t, J=7.4Hz), 3.15-3.71 (8H, m), 3.73(2H, s), 4.95 (1H, d, J=7.3Hz), 6.00 (1H, s), 6.65(2H, d, 8.4Hz), 7.04 (2H, d, J=8.4Hz)

¹³C -匪 R(DMS0-d6) δ： 23.0, 24.8(X2), 29.2, 44.7, 52.6 (X2) , 53.2, 60.6， 69.6， 73.2， 76.7, 77.2, 94.9, 100.2， 100.6， 103.5， 115.0(X2), 129.1(X2), 131.6, 155.3, 160.0， 163.3, 168.2， 203.9 ¹³ C -匪R(DMS0-d6) δ: 23.0, 24.8(X2), 29.2, 44.7, 52.6 (X2), 53.2, 60.6, 69.6, 73.2, 76.7, 77.2, 94.9, 100.2, 100.6, 103.5, 115.0 ( X2), 129.1 (X2), 131.6, 155.3, 160.0, 163.3, 168.2, 203.9

3' - (4-甲基哌嗪- 1-基-亚甲基）根皮苷的制备 Preparation of 3'-(4-methylpiperazine-1-yl-methylene) phlorizin

将根皮苷 (0.25g, 0.58ramol)溶于 25mL无水异丙醇中倒入圆底烧瓶中，置磁力搅拌器搅拌，控制温度在 3〜10°C，向根皮苷乙醇溶液中缓慢滴加 37%甲醛水溶液 (0.059mL, 0.87mmol),继续搅拌 20min。再缓慢滴加 N-甲基哌嗪（0.096mL, 0.87ramol), 控制温度在 3— 10°C，继续搅拌反应 60min, 反应结束将母液置 40°C真空蒸干，加入适量甲醇重结晶得到淡黄色簇晶。称重 0.2g，得率为 80%。 The phlorizin (0.25 g, 0.58 ramol) was dissolved in 25 mL of anhydrous isopropanol and poured into a round bottom flask. The mixture was stirred with a magnetic stirrer. The temperature was controlled at 3 to 10 ° C, and the solution was slow to the phlorizin ethanol solution. A 37% aqueous solution of formaldehyde (0.059 mL, 0.87 mmol) was added dropwise and stirring was continued for 20 min. N-methylpiperazine (0.096 mL, 0.87 ramol) was added dropwise slowly, the temperature was controlled at 3-10 ° C, and the reaction was further stirred for 60 min. At the end of the reaction, the mother liquid was evaporated to dryness at 40 ° C, and an appropriate amount of methanol was added to recrystallize. Light yellow cluster crystal. Weighing 0.2g, the yield is 80%.

m. ρ·138·0〜140.0。C m. ρ·138·0~140.0. C

HPLC检验仪器：岛津 LC— 10A，色谱柱： C18柱（4.6*150mm, 5um),流速: 0.8ml/min, 柱温： 40°C，检测波长: 284nn！，流动相： 70%磷酸水溶液（2mm₀l/L) +30%甲醇，保留时间： 3.581min HPLC test instrument: Shimadzu LC-10A, column: C18 column (4.6*150mm, 5um), flow rate: 0.8ml/min, Column temperature: 40 ° C, Detection wavelength: 284nn! , Mobile phase: 70% aqueous phosphoric acid solution (2mm ₀ l/L) +30% methanol, retention time: 3.581min

Element Analyzing: C 54.54%, H 7.02%, 033.78% N 4.66% Element Analyzing: C 54.54%, H 7.02%, 033.78% N 4.66%

ESI— MS (m/z)： 547 [ (M—l) ⁺]及 ESI— MS (m/z)： 549 [ (M+l) ⁺] ESI-MS (m/z): 547 [ (M-l) ⁺ ] and ESI-MS (m/z): 549 [ (M+l) ⁺ ]

IR cm-1: 3433, 3401, 1613, 1538, 1514, 1212, 1074 IR cm-1: 3433, 3401, 1613, 1538, 1514, 1212, 1074

¾-NMR(DMS0-d_e) δ ： 2.17 (3H, s), 2.36 (4H, s), 2.55(4H, s), 2.79 (2H, t, J=7.4Hz), 3.16-3.71 (8H, m), 3.69 (2H, s), 4.96 (1H, d, J=7.3Hz) , 6.09 (1H, s), 6.65 (2H, d， 8.4Hz) , 7.04 (2H, d， J=8.4Hz) 3⁄4-NMR(DMS0-d _e ) δ : 2.17 (3H, s), 2.36 (4H, s), 2.55(4H, s), 2.79 (2H, t, J=7.4Hz), 3.16-3.71 (8H, m), 3.69 (2H, s), 4.96 (1H, d, J=7.3Hz), 6.09 (1H, s), 6.65 (2H, d, 8.4Hz), 7.04 (2H, d, J=8.4Hz)

¹³C -醒 (丽 S0-d₆) δ： 29.1, 44.9, 45.4, 51.7(X2), 52.2, 54.3(X2), 60.7， 69.6, 73.2, 76.7, 77.3, 94.5, 100.7, 101.0, 104.3， 115.0(X2), 129.2(X2), 131.6， 155.3， 159.9， 163.1, 165.0， 204.7 实施例 4 3' - (吗啉-卜基-亚甲基）根皮苷的制备 ¹³ C - wake up (Li S0-d ₆ ) δ: 29.1, 44.9, 45.4, 51.7 (X2), 52.2, 54.3 (X2), 60.7, 69.6, 73.2, 76.7, 77.3, 94.5, 100.7, 101.0, 104.3, 115.0 (X2), 129.2 (X2), 131.6, 155.3, 159.9, 163.1, 165.0, 204.7 Example 4 Preparation of 3'-(morpholine-buyl-methylene)openoin

对根皮苷：甲醛：吗啉 =1: 1： 1 (摩尔比）按照实施例 3的操作方法进行，得到淡黄色针状晶体，得率为 80%。 For phlorizin: Formaldehyde: Morpholine = 1: 1: 1 (molar ratio) The procedure of Example 3 was carried out to obtain pale yellow needle crystals, yield 80%.

Element Analyzing: C 54.54%, H 7.02%, 033.78%, N 4.66% Element Analyzing: C 54.54%, H 7.02%, 033.78%, N 4.66%

ESI- MS (m/z)： 534 [ (M-l) +]及 ESI- MS (m/z)： 536 [ (M+l) +] ESI-MS (m/z): 534 [ (M-l) +] and ESI-MS (m/z): 536 [ (M+l) +]

¾-NMR(DMS0-d₆) δ： 2.50 (4H, s), 2.79(2H, t, J-7.4Hz), 3.16-3.71 (12H, m), 3.65 (2H, s), 4.95(1H, d, J=7.1Hz), 6.12 (1H, s)， 6.64 (2H, d, 8.2Hz)， 7.03 (2H, d, J=8.2Hz) 实施例 5 3， - (N， N-二乙胺基亚甲基）根皮苷的制备 _{¾-NMR (DMS0-d 6} ) δ: 2.50 (4H, s), 2.79 (2H, t, J-7.4Hz), 3.16-3.71 (12H, m), 3.65 (2H, s), 4.95 (1H, d, J=7.1Hz), 6.12 (1H, s), 6.64 (2H, d, 8.2Hz), 7.03 (2H, d, J=8.2Hz) Example 5 Preparation of 3, - (N, N-diethylaminomethylene) phloridin

操作过程参见实施例 1，只是用 N， N-二乙胺代替四氢吡咯。得到淡黄色结晶，得率为 58%。 For the procedure, see Example 1, except that N, N-diethylamine was used instead of tetrahydropyrrole. A pale yellow crystal was obtained with a yield of 58%.

Element Analyzing: C 59.87%, H 6.76%, 0 30.68%, N 2.69% Element Analyzing: C 59.87%, H 6.76%, 0 30.68%, N 2.69%

ESI— MS (m z) :520[(M— 1)⁺]及 ESI— MS (m/z) :522[(M+1)⁺]ESI-MS (mz): 520 [(M-1) ⁺ ] and ESI-MS (m/z): 522 [(M+1) ⁺ ]

— NMR(DMS0—d₆) δ： 1.08(6H, t), 2.71 (4H, q), 2.78 (2H, t, J=7.4Hz) , 3.16—3.71 (8H, m), 3.82 (2H, s), 4.93 (1H, d, J=7.2 Hz) , 5.93(1H, s)， 6.64 (2H, d, 8.4Hz) , 7.03 (2H, d, J=8.4Hz) 实施例 6 3' - (N-甲基- N-e -羟乙胺基亚甲基）根皮苷的制备 — NMR(DMS0—d ₆ ) δ: 1.08(6H, t), 2.71 (4H, q), 2.78 (2H, t, J=7.4Hz), 3.16—3.71 (8H, m), 3.82 (2H, s ), 4.93 (1H, d, J = 7.2 Hz), 5.93 (1H, s), 6.64 (2H, d, 8.4 Hz), 7.03 (2H, d, J = 8.4 Hz) Example 6 3' - (N -Methyl-Ne-hydroxyethylaminomethylene) phloridzin preparation

操作过程参见实施例 1，只是用 N-甲基- N-0-羟乙胺代替四氢吡咯。得到淡黄色结晶，得率为 62%。 For the procedure, see Example 1, except that N-methyl-N-0-hydroxyethylamine was used instead of tetrahydropyrrole. A pale yellow crystal was obtained with a yield of 62%.

Element Analyzing: C 57.35%, H 6.35%, 0 33.62%, N 2.68% Element Analyzing: C 57.35%, H 6.35%, 0 33.62%, N 2.68%

ESI— MS (m/z)： 522 [ (M_l) +]及 ESI— MS (m/z)： 524 [(M+1) +] ESI-MS (m/z): 522 [ (M_l) +] and ESI-MS (m/z): 524 [(M+1) +]

¾-NMR(DMS0-d_e) δ： 2.27 (3H, s), 2.55 (2H, t, J=6.5Hz), 2.74(2H, t, J=7.4Hz),3⁄4-NMR(DMS0-d _e ) δ: 2.27 (3H, s), 2.55 (2H, t, J=6.5Hz), 2.74(2H, t, J=7.4Hz),

3.16-3.71 (8H, m), 3.63(2H, t, J=6.5Hz) , 3.64(2H, s)， 4.94 (1H, d， J=7.4Hz), 6.08 (1H, s), 6.67 (2H, d, 8.4Hz), 7.02 (2H, d, J-8.4Hz) 实施例 7 3' - (N-甲基- N-羧甲基胺基亚甲基）根皮苷的制备 3.16-3.71 (8H, m), 3.63(2H, t, J=6.5Hz), 3.64(2H, s), 4.94 (1H, d, J=7.4Hz), 6.08 (1H, s), 6.67 (2H , d, 8.4Hz), 7.02 (2H, d, J-8.4Hz) Example 7 Preparation of 3'-(N-methyl-N-carboxymethylaminomethylene) phlorizin

操作过程参见实施例 1，只是用肌氨酸代替四氢吡咯。得到淡黄色结晶，得率为 54%。 Element Analyzing: C 55.86%, H 5.81%, 035.72%, N 2.61% For the procedure, see Example 1, except that sarcosine is substituted for tetrahydropyrrole. A pale yellow crystal was obtained with a yield of 54%. Element Analyzing: C 55.86%, H 5.81%, 035.72%, N 2.61%

ESI- MS (m/z)： 536 [ (M- 1) ⁺]及 ESI- MS (m/z)： 538 [ (M+l) ⁺] ESI-MS (m/z): 536 [ (M- 1) ⁺ ] and ESI-MS (m/z): 538 [ (M+l) ⁺ ]

¾- NMR(DMS0-d_e) δ : 2.27(3H, s), 2.74 (2H, t, J=7. Hz) , 3.16—3.71 (8H， m), 3.30 (2H, s)， 3.62 (2H, s)， 4.96 (IH, d, J-7.4Hz) , 6.12 (IH, s), 6.68 (2H, d, 8.4Hz) , 7.02 (2H, d, J=8.4Hz) 实施例 8 3' - (哌嗪 -1_基-亚甲基）根皮苷的制备 3⁄4-NMR (DMS0-d _e ) δ : 2.27(3H, s), 2.74 (2H, t, J=7. Hz) , 3.16—3.71 (8H, m), 3.30 (2H, s), 3.62 (2H , s), 4.96 (IH, d, J-7.4Hz), 6.12 (IH, s), 6.68 (2H, d, 8.4Hz), 7.02 (2H, d, J=8.4Hz) Example 8 3' - Preparation of (piperazine-1_yl-methylene) phlorizin

操作过程参见实施例 1, 只是用哌嗪代替四氢吡咯。得到淡黄色粉末，得率为 73。/。。 Element Analyzing: C 58.42%， H 6.41%, 029.93%, N 5.24% For the procedure, see Example 1, except that piperazine was used instead of tetrahydropyrrole. A pale yellow powder was obtained with a yield of 73. /. . Element Analyzing: C 58.42%, H 6.41%, 029.93%, N 5.24%

ESI- MS (m/z)： 533 [ (M-l) +]及 ESI- MS (m/z)： 535 [ (M+l) +] ESI-MS (m/z): 533 [ (M-l) +] and ESI-MS (m/z): 535 [ (M+l) +]

¾— NMR(DMSO-de) δ ： 2.41 (4H, s), 2.54 (4H, s) 2.78 (2H， t, J=7.4Hz), 3.16- 3.71 (8H, m), 3.70 (2H, s), 4.95 (IH, d, J=7.4Hz), 6.09 (IH, s), 6.64 (2H, d, 8.4Hz), 7.03 (2H, d, J=8.4Hz) 3⁄4— NMR (DMSO-de) δ : 2.41 (4H, s), 2.54 (4H, s) 2.78 (2H, t, J=7.4Hz), 3.16- 3.71 (8H, m), 3.70 (2H, s) , 4.95 (IH, d, J=7.4Hz), 6.09 (IH, s), 6.64 (2H, d, 8.4Hz), 7.03 (2H, d, J=8.4Hz)

实施例 9 3' - (N -葡萄糖氨基-亚甲基）根皮苷的制备 Example 9 Preparation of 3'-(N-glucosylamino-methylene) phlorizin

操作过程参见实施例 1，只是用哌嗪代替四氢吡咯。得到淡黄色粉末，得率为 83%。 Element Analyzing: C 53. 59%, H 5. 94% 0 38. 24%, N 2. 23% For the procedure, see Example 1, except that piperazine was used instead of tetrahydropyrrole. A pale yellow powder was obtained with a yield of 83%. Element Analyzing: C 53. 59%, H 5. 94% 0 38. 24%, N 2. 23%

ESI - MS (m/z)： 626 [ (M— 1) +]及 ESI— MS (m/z)： 628 [ (M+l) ⁺] ESI - MS (m/z): 626 [ (M-1) +] and ESI-MS (m/z): 628 [ (M+l) ⁺ ]

¾-NMR(DMS0-d₆) δ： 2. 78 (2H, t, J=7. 4Hz) , 3. 16-3. 71 (14H, m) , 3. 68 (2H, s) , 4. 95 (1H, d, J-7. Hz) , 5. 01 (1H, d， J=7. 5Hz) , 6. 02 (1H, s) , 6. 62 (2H, d, 8. 4Hz) , 7. 06 (2H, d, J=8. 4Hz) 实施例 10 3' - (N -曲美他嗪基-亚甲基）根皮苷的制备 3⁄4-NMR(DMS0-d ₆ ) δ: 2. 78 (2H, t, J=7. 4Hz), 3. 16-3. 71 (14H, m) , 3. 68 (2H, s), 4. 95 (1H, d, J-7. Hz), 5. 01 (1H, d, J=7. 5Hz), 6. 02 (1H, s), 6. 62 (2H, d, 8. 4Hz), 7. 06 (2H, d, J=8. 4Hz) Example 10 Preparation of 3'-(N-trametazinyl-methylene) phloridin

称取根皮苷 2. 5g于 250ml的圆底烧瓶中，加入 30ml乙醇溶解并常温搅拌使均匀；向乙醇溶液中滴加 1. 5ml的 37%甲醛水溶液充分搅拌 10分钟；向该圆底烧瓶中滴加溶有 2. 3g***美他嗪的 15ml水溶液，并常温搅拌 2-3小时。

The phlorizin was weighed in a 250 ml round bottom flask, dissolved in 30 ml of ethanol and stirred at room temperature to make a uniform; 1. 5 ml of 37% formaldehyde aqueous solution was added dropwise to the ethanol solution and stirred for 10 minutes; A solution of 2.3 g of trimetazidine hydrochloride in 15 ml of water was added dropwise, and stirred at room temperature for 2-3 hours.

在 35- 4CTC减压浓缩反应液至千，用乙醇溶解后滴加丙酮溶液至析出白色固体，抽滤并在 40°C真空珙箱中干燥即得白色粉末。 The reaction solution was concentrated under reduced pressure at 35 - 4 CTC to hexane, dissolved in ethanol, and then the acetone solution was added dropwise to precipitated a white solid, which was suction filtered and dried in a vacuum oven at 40 ° C to obtain a white powder.

分子量： 714，分子式为： C_3e N₂0_13; Element Analyzing: C 60.49%, H 6.49%, N 3.92%， 0 29.10%; Molecular weight: 714, molecular formula: C _3e N ₂ 0 _13; Element Analyzing: C 60.49%, H 6.49%, N 3.92%, 0 29.10%;

ESI - MS(m/s)： 713[M-1]⁺;ESI-MS (m/s): 713 [M-1] ⁺ ;

—匪 R(D₂0) δ： 7.05(1H, d, J=8.7Hz), 6.90 (2H, d， J=8.5Hz), 6.75 (IH, d， J=8.7Hz), 6.59 (2H, d, J=8.5Hz) , 6.18 (IH, s)， 5.09 (IH, d， J=7.6Hz) , 4.25 (2H, s)， 4.18 (2H, s)， 3.78 (3H, s), 3.73 (3H, s), 3.71(3H, s)， 3.21-3.84 (6H, m), 3.40- 3.46 (8H, m), 3.40-3.46 (2H, t， J=7.2Hz) , 2.65 (2H, t, J=7.2Hz)。 —匪R(D ₂ 0) δ: 7.05(1H, d, J=8.7Hz), 6.90 (2H, d, J=8.5Hz), 6.75 (IH, d, J=8.7Hz), 6.59 (2H, d, J=8.5Hz), 6.18 (IH, s), 5.09 (IH, d, J=7.6Hz), 4.25 (2H, s), 4.18 (2H, s), 3.78 (3H, s), 3.73 ( 3H, s), 3.71(3H, s), 3.21-3.84 (6H, m), 3.40- 3.46 (8H, m), 3.40-3.46 (2H, t, J=7.2Hz), 2.65 (2H, t, J = 7.2 Hz).

¹³C -匪 R(D₂0) δ : 206.7, 164.9, 163.5， 161.5, 155.5, 153.6, 152.4, 141.1, 133.1, 129.6(X2), 128.1， 115.3(X2)， 113.5, 108.4, 105.3, 99.5, 97.0， 93.8, 76.5, 76.1 72.7, 69.3， 61.6, 61.5， 61.0, 60.8, 56.1, 47.8, 45.0, 33.5， 29.3, 18.4。实施例 11 3' - (脯氨酸 -1_基-亚甲基）根皮苷的制备 ¹³ C -匪R(D ₂ 0) δ : 206.7, 164.9, 163.5, 161.5, 155.5, 153.6, 152.4, 141.1, 133.1, 129.6(X2), 128.1, 115.3(X2), 113.5, 108.4, 105.3, 99.5, 97.0, 93.8, 76.5, 76.1 72.7, 69.3, 61.6, 61.5, 61.0, 60.8, 56.1, 47.8, 45.0, 33.5, 29.3, 18.4. Example 11 Preparation of 3'-(Proline-1_yl-methylene)openoin

对根皮苦：甲醛：脯氨酸 =1: 1： 1 (摩尔比）按照实施例 10的操作方法进行，得到白色粉末，得率为 80%。 To the root bark: Formaldehyde: Proline = 1: 1: 1 (molar ratio) The procedure of Example 10 was carried out to obtain a white powder, yield 80%.

分子量 563 分子式 C₂₇H₃₃N0_l2 Molecular Weight 563 Molecular Formula C ₂₇ H ₃₃ N0 _l2

Element Analyzing: C 57.54%, H 5.90%, 0 34.07%, N 2.49% Element Analyzing: C 57.54%, H 5.90%, 0 34.07%, N 2.49%

ESI— MS (m/z)： 562 [ (M— 1) +] 及 ESI— MS (m/z)： 564 [ (M+1) +] ESI-MS (m/z): 562 [ (M-1) +] and ESI-MS (m/z): 564 [ (M+1) +]

¾一匪 R (DMSO-CIB) δ： 1.83 (4H, m), 2.2 (2H, t, J-6.5Hz)， 2.79 (2H, t， J-7.4Hz) , 3.12(1H, t, J=6.8Hz), 3.16— 3.71 (8H， m), 3.68(2H, s)， 4.92 (IH, d， J=7.3Hz), 6.06 (IH, s)， 6.64 (2H, d, J=8.4Hz), 7.04 (2H, d, J=8.4Hz) 3⁄4一匪R (DMSO-CIB) δ: 1.83 (4H, m), 2.2 (2H, t, J-6.5Hz), 2.79 (2H, t, J-7.4Hz), 3.12(1H, t, J= 6.8Hz), 3.16— 3.71 (8H, m), 3.68(2H, s), 4.92 (IH, d, J=7.3Hz), 6.06 (IH, s), 6.64 (2H, d, J=8.4Hz) , 7.04 (2H, d, J=8.4Hz)

¹³C—丽 R(DMS0-d₆) δ： 23.0, 29.4, 30.6, 44.5, 44.7, 55.0, 62.2, 66.7, 71.5, 73.4, 76.8, 77.8, 94.3, 101.0, 101.8, 102.5, 115.0(X2)， 129. l(X2), 133.9, 155.7, 158.1, 162.2， 162.3， 174.7, 205.4 实施例 12 根皮苷氨基己酸衍生物的制备 ¹³ C—丽 R(DMS0-d ₆ ) δ: 23.0, 29.4, 30.6, 44.5, 44.7, 55.0, 62.2, 66.7, 71.5, 73.4, 76.8, 77.8, 94.3, 101.0, 101.8, 102.5, 115.0 (X2), 129. l(X2), 133.9, 155.7, 158.1, 162.2, 162.3, 174.7, 205.4 Example 12 Preparation of phlorizine aminocaproic acid derivative

对根皮苷：甲醛：氨基己酸 =2: 2： 1 (摩尔比）按照实施例 10的操作方法进行，得到白色粉末，得率为 70%。 For phloridzin: formaldehyde: aminocaproic acid = 2: 2: 1 (molar ratio) The procedure of Example 10 was carried out to give a white powder, yield 70%.

分子量 1027 分子式 C₅。H_elN0₂₂ Molecular weight 1027 Formula C ₅ . H _el N0 ₂₂

Element Analyzing: C 58.42%, H 5.98%, 034.24%, N 1.36% Element Analyzing: C 58.42%, H 5.98%, 034.24%, N 1.36%

ESI- MS (ra/z)： 1026 [ (M-l) ⁺] 及 ESI-MS (m/z)： 1028 [ (M+l) +] ESI-MS (ra/z): 1026 [ (Ml) ⁺ ] and ESI-MS (m/z): 1028 [ (M+l) +]

¾-應 R(DMS0- d_e〉 δ： 1.29-1.52 (6H， m), 2.30(2H,t, J=6.5Hz), 2.46 (2H, t， J=6.8Hz) 2.79(411, t, J=7.4Hz) , 3.16— 3.71 (16H， m)， 3.68 (4H, s), 5.12 (2H, d, J=7.3Hz), 6.06 (2H, s), 6.64 (4H, d, J=8.4Hz), 7.04 (4H, d， J-8.4Hz) 3⁄4- should be R(DMS0-d _e 〉 δ: 1.29-1.52 (6H, m), 2.30 (2H, t, J=6.5Hz), 2.46 (2H, t, J=6.8Hz) 2.79(411, t, J=7.4Hz) , 3.16— 3.71 (16H, m), 3.68 (4H, s), 5.12 (2H, d, J=7.3Hz), 6.06 (2H, s), 6.64 (4H, d, J=8.4 Hz), 7.04 (4H, d, J-8.4Hz)

¹³C-NMR(DMS0-d₆) δ： 24.4, 26.7, 28.0, 30.6(X2), 34.0, 44.5(X2), 47.7(X2), 53.9， 62.2(X2)， 71.5(X2), 73.4(X2), 76.8(X2), 77.8(X2), 94.3(X2), 101.0(X2〉， 101.8(X2), 102.5(X2), 115.8(X4), 130.2(X4), 133.9(X2), 155.7 (X 2), 158.1(X2), 162.2 (X 2), 162.3(X2), 178.4, 205. (X 2) ¹³ C-NMR (DMS0-d ₆ ) δ: 24.4, 26.7, 28.0, 30.6 (X2), 34.0, 44.5 (X2), 47.7 (X2), 53.9, 62.2 (X2), 71.5 (X2), 73.4 (X2) ), 76.8(X2), 77.8(X2), 94.3(X2), 101.0(X2>, 101.8(X2), 102.5(X2), 115.8(X4), 130.2(X4), 133.9(X2), 155.7 (X 2), 158.1 (X2), 162.2 (X 2), 162.3 (X2), 178.4, 205. (X 2)

实施例 13根皮苷肉桂哌嗪衍生物的制备 Example 13 Preparation of cadaverin cinnamazine piperazine derivative

Χ ϋ皮苷：甲醛：肉桂哌嗪 =1:1:1 (摩尔比）按照实施例 10的操作方法进行，得到白色粉末，得率为 87%。

Χ quercetin: formaldehyde: cinnamazine hydrochloride = 1:1:1 (molar ratio) The procedure of Example 10 was carried out to give a white powder, yield 87%.

分子量 650 分子式 C₃₅H₄₂N₂0₁₀ Molecular Weight 650 Molecular Formula C ₃₅ H ₄₂ N ₂ 0 ₁₀

Element Analyzing: C 64.60%, H 6.51%, 024.59%, N 4.31% Element Analyzing: C 64.60%, H 6.51%, 024.59%, N 4.31%

ESI— MS (m/z)： 649 [ (M- 1) +] 及 ESI-MS (m/z) : 651 [ (M+l) ⁺] ESI-MS (m/z): 649 [ (M- 1) +] and ESI-MS (m/z) : 651 [ (M+l) ⁺ ]

'H-NMR (DMSO-de) δ： 2.35 (4H, t， J=5.6Hz) , 2.48 (4H, t， J=5.6Hz)， 2.79 (2H, t, J=7.4Hz) , 3.02 (2H, d， J=3.4Hz) , 3.16— 3.71 (8H， m), 3.68 (2H, s)， 4.98 (IH, d, J=7.3Hz) , 6.06 (IH, s), 6.19 (IH, dd, J=8.5， 3.4Hz), 6.56 (IH, d, J=8.5Hz)， 6.64 (2H, d, J=8.他）, 7.04(2H, d, J=8.4Hz)， 7.24 (2H, d， J=7.2Hz)， 7.33-7.40 (3H, m) 'H-NMR (DMSO-de) δ: 2.35 (4H, t, J=5.6Hz), 2.48 (4H, t, J=5.6Hz), 2.79 (2H, t, J=7.4Hz) , 3.02 (2H , d, J = 3.4 Hz), 3.16 - 3.71 (8H, m), 3.68 (2H, s), 4.98 (IH, d, J = 7.3 Hz), 6.06 (IH, s), 6.19 (IH, dd, J=8.5, 3.4Hz), 6.56 (IH, d, J=8.5Hz), 6.64 (2H, d, J=8. he), 7.04(2H, d, J=8.4Hz), 7.24 (2H, d , J=7.2Hz), 7.33-7.40 (3H, m)

¹³C-NMR(DMSO-d₆) δ： 30.6, 44.5， 47.5, 52.6(X2), 54.1(X2), 57.0, 62.2, 71.5, 73.4, 76.8, 77.8, 94.3, 101.0, 101.8， 102.5， 115.8(X2)， 127. , 127.9, 128.5 (X 2)， 128.6 (X 2), 130.2 (X2), 133.9, 136.2, 136.4, 155.7， 158.1, 162.2, 162,3， 205.4 ' 实施例 14根皮苷苄基哌嗪衍生物的制备 ^{13 C-NMR (DMSO-d} 6) δ: 30.6, 44.5, 47.5, 52.6 (X2), 54.1 (X2), 57.0, 62.2, 71.5, 73.4, 76.8, 77.8, 94.3, 101.0, 101.8, 102.5, 115.8 ( X2), 127., 127.9, 128.5 (X 2), 128.6 (X 2), 130.2 (X2), 133.9, 136.2, 136.4, 155.7, 158.1, 162.2, 162, 3, 205.4 'Example 14 phloridin benzyl Preparation of niperazine derivatives

对根皮苷：甲醛:苄基哌嗪 =1:1:1 (摩尔比）按照实施例 10的操作方法进行，得到白色粉末，得率为 87%。 For phloridzin: formaldehyde: benzylpiperazine = 1:1:1 (molar ratio) The procedure of Example 10 was carried out to give a white powder, yield 87%.

分子量 624 分子式 C₃₅ 。N₂0₁₍₎ Molecular weight 624 Molecular Formula C ₃₅ . N ₂ 0 ₁₍₎

Element Analyzing: C 63.45%, H 6.45%, 025.61%, N 4.48% Element Analyzing: C 63.45%, H 6.45%, 025.61%, N 4.48%

ESI— MS (m/z)： 623 [ (M-l) +] 及 ESI-MS (m/z)： 625 [ (M+l) ⁺] ESI-MS (m/z): 623 [ (Ml) +] and ESI-MS (m/z): 625 [ (M+l) ⁺ ]

¾-丽 R (DMSO-de) δ： 2.35 (4H, t, J=5.6Hz)， 2.48 (4H， t, J=5.6Hz) , 2.79 (2H, t, J=5.4Hz) , 3.16-3.71 (8H, m), 3.66(4H, s)， 4.98 (IH, d, J=7.3Hz) , 6.06 (IH, s)， 6.70 (2H, d, J-8.4Hz) , 7.12 (2H, d, J-8.4Hz), 7.23 (2H, d, J=7.2Hz), 7.26-7.33 (3 m) 3⁄4-丽R (DMSO-de) δ: 2.35 (4H, t, J=5.6Hz), 2.48 (4H, t, J=5.6Hz), 2.79 (2H, t, J=5.4Hz), 3.16-3.71 (8H, m), 3.66(4H, s), 4.98 (IH, d, J=7.3Hz), 6.06 (IH, s), 6.70 (2H, d, J-8.4Hz), 7.12 (2H, d, J-8.4Hz), 7.23 (2H, d, J=7.2Hz), 7.26-7.33 (3 m)

¹³C-NMR (DMS0-d_e) δ： 30.6, 44.5, 47.5, 52.5(X4), 61.9, 62.2, 71.5, 73.4, 76.8, 77.8, 94.3， 101.0, 101.8, 102.5, 115·8(Χ2)， 127.2， 128.4(X2), 128.8 (X 2) 130.2(X2)， 133.9， 138.6， 155.7,158.1, 162.2, 162.3, 205.4 实施例 15 根皮苷苯基哌嗪衍生物的制备 ¹³ C-NMR (DMS0-d _e ) δ: 30.6, 44.5, 47.5, 52.5 (X4), 61.9, 62.2, 71.5, 73.4, 76.8, 77.8, 94.3, 101.0, 101.8, 102.5, 115·8 (Χ2), 127.2, 128.4 (X2), 128.8 (X 2) 130.2 (X2), 133.9, 138.6, 155.7, 158.1, 162.2, 162.3, 205.4 Example 15 Preparation of phlorizin phenyl piperazine derivatives

对根皮苷：甲醛:苯基哌嗪 =1:1:1 (摩尔比）按照实施例 10的操作方法进行，得到白色粉末，得率为 92%。 For phloridzin: formaldehyde: phenylpiperazine = 1:1:1 (molar ratio) According to the procedure of Example 10, a white powder was obtained, yielding 92%.

分子量 610 分子式 C₃₂H₃₈N 。 Molecular weight 610 Molecular Formula C ₃₂ H ₃₈ N .

Element Analyzing: C 62.94%, H 6.27%, 026.20%, N 4.59% Element Analyzing: C 62.94%, H 6.27%, 026.20%, N 4.59%

ESI— MS (m/z)： 609 [ (M-l) ⁺] 及 ESI— MS (m/z) :611 [ (M+l) +] ESI-MS (m/z): 609 [ (Ml) ⁺ ] and ESI-MS (m/z) : 611 [ (M+l) +]

¾-NMR(DMS0-d_e) δ： 2.62 (4H, t, J=5.6Hz) , 2.71 (2H, t, J=3.4Hz) , 2.88 (2H, t, J=3.4Hz), 3.19(4H,t, J=5.6Hz), 3.16— 3.71 (6H， m), 3.66 (2H, s), 4.98 (IH, ά, J=7.3Hz), 6.06 (IH, s)， 6.70 (2H, d, J=8.4Hz), 7.12 (2H, d, J=8.4Hz), 6.79 (IH, d， J=7.6Hz) , 6.94 (2H, dd， J=7.6, 7.4Hz) , 7.27 (2H, d, J=7.4Hz) 3⁄4-NMR(DMS0-d _e ) δ: 2.62 (4H, t, J=5.6Hz), 2.71 (2H, t, J=3.4Hz), 2.88 (2H, t, J=3.4Hz), 3.19(4H ,t, J=5.6Hz), 3.16— 3.71 (6H, m), 3.66 (2H, s), 4.98 (IH, ά, J=7.3Hz), 6.06 (IH, s), 6.70 (2H, d, J=8.4Hz), 7.12 (2H, d, J=8.4Hz), 6.79 (IH, d, J=7.6Hz), 6.94 (2H, dd, J=7.6, 7.4Hz), 7.27 (2H, d, J=7.4Hz)

¹³C-NMR(DMS0-d₆) δ： 30.6, 44.5, 47.5, 49.8(X2), 52.1(X2), 62.2, 71.5, 73.4, 76.8, 77.8, 94.3, 101.0， 101.8, 102.5， 114.3(X2), 115.8(X2), 121.9, 129.6(X 2), 130.2(X2), 133.9, 149.6, 155.7, 158.1, 162.2, 162.3, 205.4 实施例 16 根皮苷二苯甲基哌嗪衍生物的制备 ¹³ C-NMR (DMS0-d ₆ ) δ: 30.6, 44.5, 47.5, 49.8 (X2), 52.1 (X2), 62.2, 71.5, 73.4, 76.8, 77.8, 94.3, 101.0, 101.8, 102.5, 114.3 (X2) , 115.8 (X2), 121.9, 129.6 (X 2), 130.2 (X2), 133.9, 149.6, 155.7, 158.1, 162.2, 162.3, 205.4 Example 16 Preparation of phloridin diphenylmethylpiperazine derivative

对根皮苷：甲醛:二苯甲基哌嗪 =1:1:1 (摩尔比）按照实施例 10的操作方法进行，得到白色粉末，得率为 85%。 For phloridzin: formaldehyde: diphenylmethylpiperazine = 1:1:1 (molar ratio) The procedure of Example 10 was carried out to give a white powder, yield: 85%.

分子量 700 分子式

Molecular weight 700 formula

Element Analyzing: C 66.84%, H 6.33%, 022.83%, N 4.00% Element Analyzing: C 66.84%, H 6.33%, 022.83%, N 4.00%

ESI-MS (m/z)： 699 [ (M- 1) +] 及 ESI—MS (m/z) : 701 [ (M+l) ⁺] ESI-MS (m/z): 699 [ (M- 1) +] and ESI-MS (m/z) : 701 [ (M+l) ⁺ ]

¾一匪 R (DMSO-de) δ： 2.35 (4H, t, J=5.6Hz) , 2.48 (4H， t， J-5.6Hz) , 2.71 (2H, t， J=3.4Hz)， 2.88 (2H, t, J=3.4Hz), 3.16— 3.71 (6H， ra), 3.66(2H, s)， 4.98 (IH, d， J=7.3Hz) , 5.14 (IH, s), 6.06 (IH, s)， 6.70 (2H, d, J=8.4Hz), 7.12 (2H, d， J=8.4Hz), 7.26 (2H, d， J=7.6Hz) , 7.33(4H, dd, J=7.6, 7.4Hz) , 7.37 (4H, d， J=7.4Hz) 3⁄4一匪R (DMSO-de) δ: 2.35 (4H, t, J=5.6Hz), 2.48 (4H, t, J-5.6Hz), 2.71 (2H, t, J=3.4Hz), 2.88 (2H , t, J=3.4Hz), 3.16— 3.71 (6H, ra), 3.66(2H, s), 4.98 (IH, d, J=7.3Hz) , 5.14 (IH, s), 6.06 (IH, s) , 6.70 (2H, d, J=8.4Hz), 7.12 (2H, d, J=8.4Hz), 7.26 (2H, d, J=7.6Hz), 7.33(4H, dd, J=7.6, 7.4Hz) , 7.37 (4H, d, J=7.4Hz)

¹³C-NMR(DMS0-d₆) δ： 30.6, 44.5, 47.5, 51.9(X2), 52.8(X2)， 62.2, 71.5, 73.4, 76.0, 76.8, 77.8, 94.3, 101.0, 101.8， 102.5, 115.8(X2), 126.2 (X2), 128.2 (X 4), 129.2 (X4), 130.2 (X 2), 133.9, 142.7(X2), 155.7, 158.1， 162.2, 162.3, 205.4 ¹³ C-NMR (DMS0-d ₆ ) δ: 30.6, 44.5, 47.5, 51.9 (X2), 52.8 (X2), 62.2, 71.5, 73.4, 76.0, 76.8, 77.8, 94.3, 101.0, 101.8, 102.5, 115.8 ( X2), 126.2 (X2), 128.2 (X 4), 129.2 (X4), 130.2 (X 2), 133.9, 142.7 (X2), 155.7, 158.1, 162.2, 162.3, 205.4

实施例 17 根皮苷呋喃甲酰哌嗪衍生物的制备 Example 17 Preparation of phloridin furoyl piperazine derivative

对根皮苷：甲醛:呋喃甲酰哌嗪 =1:1:1 (摩尔比）按照实施例 10的操作方法进行，得到白色粉末，得率为 87%„ For phloridzin: formaldehyde: furoylpiperazine = 1:1:1 (molar ratio) according to the procedure of Example 10, Obtained a white powder with a yield of 87%

分子量 628 分子式 C_3lH_3SN₂0₁₂ Molecular weight 628 Molecular formula C _3l H _3S N ₂ 0 ₁₂

Element Analyzing: C 59.23%, H 5.77%, 030.54%, N 4.46% Element Analyzing: C 59.23%, H 5.77%, 030.54%, N 4.46%

ESI-MS(m/z) :627[(M-1)⁺] 及 ESI - MS(m/z) :629[(M+1)⁺] ESI-MS (m/z): 627[(M-1) ⁺ ] and ESI - MS (m/z): 629[(M+1) ⁺ ]

¾-NMR (DMSO-de) δ： 2.35 (4H, t, J=5.6Hz)， 2.48 (4H, t, J=5.6Hz) , 2.71 (2H, t, J=3.4Hz) , 2.88 (2H, t, J=3.4Hz) , 3.16-3.71 (6H, m)， 3.68 (2H, s), 4.98 (IH, d, J=7.3Hz), 6.06 (IH, s)， 6.70 (2H, d， J=8.4Hz) , 6.83(1H, dd， J=7.6, 7.4Hz) , 7.12 (2H, d, J=8.4Hz), 7.27 (IH, d, 1=7. Hz),8.09 (IH, d, J=7.6Hz) 3⁄4-NMR (DMSO-de) δ: 2.35 (4H, t, J = 5.6 Hz), 2.48 (4H, t, J = 5.6 Hz), 2.71 (2H, t, J = 3.4 Hz), 2.88 (2H, t, J=3.4Hz) , 3.16-3.71 (6H, m), 3.68 (2H, s), 4.98 (IH, d, J=7.3Hz), 6.06 (IH, s), 6.70 (2H, d, J =8.4Hz), 6.83(1H, dd, J=7.6, 7.4Hz), 7.12 (2H, d, J=8.4Hz), 7.27 (IH, d, 1=7. Hz), 8.09 (IH, d, J=7.6Hz)

¹³C-NMR (DMS0-d_e) δ： 30.6, 44.5, 47.5, 47.8(X2), 52.0(X2)， 62.2, 71.5, 73.4， 76.8, 77.8, 94.3, 101.0， 101.8, 102.5, 111.7, 115.8(X2), 117.9， 130.2(X2), 133.9， 143： 8, 147.0, 155.1， 155.7, 158.1, 162.2， 162.3, 205.4 实施例 18 3' - ( , N-二甲胺基亚甲基）根皮苷的制备 ¹³ C-NMR (DMS0-d _e ) δ: 30.6, 44.5, 47.5, 47.8 (X2), 52.0 (X2), 62.2, 71.5, 73.4, 76.8, 77.8, 94.3, 101.0, 101.8, 102.5, 111.7, 115.8 ( X2), 117.9, 130.2 (X2), 133.9, 143: 8, 147.0, 155.1, 155.7, 158.1, 162.2, 162.3, 205.4 Example 18 3'-(, N-dimethylaminomethylene) phlorizin Preparation

操作过程参见实施例 1，用 N， N-二甲胺代替四氢吡咯为原料。得到淡黄色粉末，得率为 67%。 For the procedure, see Example 1, using N, N-dimethylamine instead of tetrahydropyrrole as a starting material. A pale yellow powder was obtained with a yield of 67%.

实施例 19 3' - (N, N-甲乙胺基亚甲基）根皮苷的制备 Example 19 Preparation of 3'-(N, N-methylethylaminomethylene) phloridin

操作过程参见实施例 1，用 N， N-甲乙胺代替四氢吡咯为原料。得到淡黄色粉末，得率为 65%。实施例 20 3 ' - (N， N-二丙胺基亚甲基）根皮苷的制备 For the procedure, see Example 1, using N, N-methylethylamine instead of tetrahydropyrrole as a starting material. A pale yellow powder was obtained with a yield of 65%. Example 20 Preparation of 3 '-(N, N-dipropylaminomethylene) phlorizin

操作过程参见实施例 1，用 N， N-二丙胺代替四氢吡咯为原料。得到淡黄色结晶，得率为 68%。实施例 21 3 ' - (N， N-二乙醇胺基亚甲基）根皮苷的制备 For the procedure, see Example 1, using N, N-dipropylamine instead of tetrahydropyrrole as a starting material. A pale yellow crystal was obtained with a yield of 68%. Example 21 Preparation of 3 '-(N, N-diethanolaminomethylene) phloridin

操作过程参见实施例 1，用 N， N二乙醇胺代替四氢吡咯为原料。得到淡黄色结晶，得率为 64%。实施例 22 3， - (N, N-二异丙胺基亚甲基）根皮苷的制备 For the procedure, see Example 1, using N, N diethanolamine instead of tetrahydropyrrole as a starting material. A pale yellow crystal was obtained with a yield of 64%. Example 22 Preparation of 3, - (N, N-diisopropylaminomethylene) phloridin

操作过程参见实施例 1，用 N， N-二异丙胺代替四氢吡咯为原料。得到淡黄色结晶，得率为 55%。实施例 23 3' ― (N， N-二氯乙胺基亚甲基）根皮苷的制备

For the procedure, see Example 1, using N, N-diisopropylamine instead of tetrahydropyrrole as a starting material. A pale yellow crystal was obtained with a yield of 55%. Example 23 Preparation of 3'-(N,N-dichloroethylaminomethylene) phlorizin

操作过程参见实施例 1，用^ N-二氯乙胺代替四氢吡咯为原料。得到淡黄色结晶，得率为 57%。实施例 24 3' - (N-甲基- N-甲氧羰基甲基胺基亚甲基）根皮苷的制备 For the operation process, see Example 1, using n-dichloroethylamine instead of tetrahydropyrrole as a raw material. A pale yellow crystal was obtained with a yield of 57%. Example 24 Preparation of 3'-(N-methyl-N-methoxycarbonylmethylaminomethylene) phlorizin

操作过程参见实施例 1, 用肌氨酸甲酯盐酸盐代替四氢吡咯为原料。得到淡黄色结晶，得率为 57%。实施例 25 V - (( (R) -3-羟甲基哌啶- 1-基） -亚甲基）根皮苷的制备 For the procedure, see Example 1, using sarcosine methyl ester hydrochloride instead of tetrahydropyrrole as a starting material. A pale yellow crystal was obtained with a yield of 57%. Example 25 Preparation of V-(((R)-3-hydroxymethylpiperidin-1-yl)-methylene) phlorizin

操作过程参见实施例 10，用（R) -3-羟甲基哌啶代替曲美他嗪为原料。得到淡黄色结晶，得率为 47%。实施例 26 3' - (((S) -3-羟甲基哌啶- 1 -基） -亚甲基）根皮苷 For the procedure, see Example 10, using (R)-3-hydroxymethylpiperidine instead of trimetazidine as a starting material. A pale yellow crystal was obtained with a yield of 47%. Example 26 3'-(((S)-3-Hydroxymethylpiperidin-1-yl)-methylene) phloridin

操作过程参见实施例 1，用（S) -3-轻甲基哌啶代替曲美他嗪为原料。得到淡黄色结晶，得率为 53%。 For the procedure, see Example 1, using (S)-3-light methylpiperidine instead of trimetazidine as a starting material. A pale yellow crystal was obtained with a yield of 53%.

实施例 27 根皮苷乙胺衍生物的制各 Example 27 Preparation of phloridzin ethylamine derivatives

实施例 28 根皮苷哌嗪衍生物的制备

Example 28 Preparation of phlorizin piperazine derivatives

对根皮苷：甲醛:哌嗪 =2:2:1 (摩尔比）按照实施例 10的操作方法进行，得到白色粉末，得率为 82%。 For phloridzin: formaldehyde: piperazine = 2:2:1 (molar ratio), the procedure of Example 10 was carried out to give a white powder, yield: 82%.

实施例 29 根皮苷哌啶并哌嗪衍生物的制备 Example 29 Preparation of phloridizide piperidazine piperazine derivative

实施例 30 根皮苷 2-氧代哌嗪乙酸衍生物的制备 Example 30 Preparation of phloridzin 2-oxopiperazine acetic acid derivative

对根皮苷：甲醛: 2-氧代哌嗪乙酸 =1 : 1 : 1 (摩尔比）按照实施例 10的操作方法进行，得到白色粉末，得率为 85%。实施例： 31 按下列配方制得 3' - (六氢吡啶- 1-基-亚甲基）根皮苷和吡咯列酮的复方片剂：（所用含量均为重量百分含量） For phloridzin: formaldehyde: 2-oxopiperazineacetic acid = 1 : 1 : 1 (molar ratio) was carried out in the same manner as in Example 10 to give white powder. EXAMPLES: 31 A combination of 3'-(hexahydropyridine-1-yl-methylene) phlorizin and pioglitazone was prepared according to the following formula: (All contents are by weight)

3' - (六氢吡啶- 1-基-亚甲基）根皮苷 9% 3' - (hexahydropyridine-1-yl-methylene) phlorizin 9%

马来酸罗格列酮 12% Rosiglitazone maleate 12%

微晶纤维素 75% Microcrystalline cellulose 75%

PVP-k30 2% PVP-k30 2%

硬脂酸镁 2% Magnesium stearate 2%

将 3'一 (六氢吡啶- 1-基-亚甲基）根皮苷、马来酸罗格列酮、微晶纤维素、 PVP-k30 混匀，以乙醇制软材，经 12 目筛制粒， 70°C以下通风干燥后整粒，加硬脂酸镁后混匀压片，即得。其中 ₃' - (六氢吡啶- 1-基-亚甲基）根皮苷与马来酸罗格列酮的重量比为 1： 1. 33ο 实施例： 32 按下列配方制得的 3， - (哌嗪 -1-基-亚甲基）根皮苷和吉非罗齐的复方胶囊剂：（所用含量均为重量百分含量） Mix 3'-(hexahydropyridine-1-yl-methylene) phloridin, rosiglitazone maleate, microcrystalline cellulose, PVP-k30, soft material made of ethanol, sieved through 12 mesh Granulation, 70 ° C below the air drying after the whole grain, add magnesium stearate, and then mix and compress, that is. The weight ratio of ₃ ' - (hexahydropyridine-1-yl-methylene) phlorizin to rosiglitazone maleate is 1: 1. 33ο Example: 32 Compound capsules of 3,-(piperazin-1-yl-methylene) phlorizin and gemfibrozil prepared according to the following formula: (All contents are 100% by weight) Sub-content)

3， -（哌嗪 -1-基-亚甲基）根皮苷 4% 3, -(piperazin-1-yl-methylene) phlorizin 4%

吉非罗齐 6% Geffizi 6%

碳酸钙 45. 5% Calcium carbonate 45. 5%

淀粉 44. 5% Starch 44. 5%

将碳酸钙与淀粉混合、过筛，再与适量乙醇分散的 3' - (哌嗪 -1-基-亚甲基〉根皮苷、吉非罗齐粉末混合均勾，过 120目筛，于 60- 70°C下烘干 2小时，将混匀的药粉填充到空胶囊即得。其中 3' - (哌嗪 - 1_基-亚甲基）根皮苷与吉非罗齐的重量比为 1: 1. 5。实施例 33 根皮苷衍生物治疗糖尿病的药效学实验 Mixing calcium carbonate with starch, sieving, and mixing with appropriate amount of ethanol-dispersed 3'-(piperazin-1-yl-methylene) phlorizin and gemfibrozil powder, passing through a 120 mesh sieve, Drying at 60-70 °C for 2 hours, filling the mixed powder into empty capsules. The weight ratio of 3'-(piperazine-1- 1 -methylene) phlorizin to gemfibrozil 1:1. 5. Example 33 Pharmacodynamics experiment of phlorizin derivatives in the treatment of diabetes

(一）细胞模型的建立 (1) Establishment of a cell model

细胞模型：人血管内皮细胞 Cell Model: Human Vascular Endothelial Cells

观察指标：人成纤维连接蛋白（Human FN) 是细胞外基质中粘附蛋白，层连蛋白 (Larainin LN) 是一组细胞外基质糖蛋白，是基质膜非胶原性结构的主要主要成分。它们是糖尿病及其并发症的发生机制中病变的一个重要指标。 Observations: Human fibronectin (Human FN) is an adhesion protein in the extracellular matrix. Larainin LN is a group of extracellular matrix glycoproteins, which are the main components of the non-collatile structure of the matrix membrane. They are an important indicator of the pathogenesis of diabetes and its complications.

根皮苷衍生物： 3' - (六氢吡啶 -1-基-亚甲基）根皮苷， 3' - (N， N-二乙胺基亚甲基）根皮苷 Phloridin derivatives: 3'-(hexahydropyridin-1-yl-methylene) phloridzin, 3'-(N, N-diethylaminomethylene) phlorizin

抗体： FN (mouse)武汉博士德 1: 200； LN (human) 武汉博士德 1 : 100； ELISA 试剂盒 Antibody: FN (mouse) Wuhan Dr. 1:200; LN (human) Wuhan Dr. De 1 : 100; ELISA kit

(二）药效学实验及其结果 (2) Pharmacodynamic experiments and results

本实验在人的血管内皮细胞模型上，经低糖（5. 5 μ Μ) (正常对照），高糖（30 μ Μ) (糖尿病肾病模型）和高糖 +根皮苷衍生物（50 g/ml ) (给药）处理 48小时后，进行纤维连接蛋白和人层连蛋白免疫组织化学染色。 This experiment was performed on a human vascular endothelial cell model with low glucose (5.5 μM) (normal control), high glucose (30 μΜ) (diabetic nephropathy model) and high glucose + phlorizin derivative (50 g/ After 48 hours of treatment (administration), fibronectin and human laminin immunohistochemical staining were performed.

等量的细胞在 OLYMPUS CX31显微镜 400倍镜下，目测所见细胞爬片结果表明根皮苷衍生物有明显使内皮细胞外基质中的 FN、 LN的分泌量减少。 The same amount of cells were visually observed under a 400-fold microscope on an OLYMPUS CX31 microscope. The results showed that the phlorizin derivative significantly reduced the secretion of FN and LN in the endothelial extracellular matrix.

(三）药效学结果分析及初步结论 (3) Analysis of pharmacodynamic results and preliminary conclusions

药效学实验表明，根皮苷衍生物具有明显使内皮细胞外基质中的 FN、 LN的分泌量减少。实验选取的两个衍生物在该类衍生物中具有相当的代表性，因此，该类根皮苷衍生物有预防和治疗糖尿病及其并发症的作用。实施例 34根皮苷衍生物治疗糖尿病的药效学实验 Pharmacodynamic experiments showed that phlorizin derivatives have a significant amount of FN and LN secreted in the extracellular matrix of the endothelial cells. cut back. The two derivatives selected in the experiment are quite representative in such derivatives, and therefore, such phlorizin derivatives have the effects of preventing and treating diabetes and its complications. Example 34 Pharmacodynamics experiment of phlorizin derivatives in the treatment of diabetes

(一）细胞模型的建立 (1) Establishment of a cell model

细胞模型：人脐静脉内皮细胞 Cell Model: Human Umbilical Vein Endothelial Cells

药物：根皮苷， 3' - (六氢吡啶-卜基-亚甲基）根皮苷， 3' - (4-甲基哌啶-卜基- 亚甲基）根皮苷 Drugs: phloridzin, 3'-(hexahydropyridine-buki-methylene) phloridzin, 3'-(4-methylpiperidin-buyl-methylene) phloridzin

经低糖剌激组（正常对照），高糖刺激组（糖尿病模型），以及药物处理的对比来观察细胞外基质内皮素（ET 1 )，纤维连接蛋白（FN) 的表达，以观察 ¾物的抗细胞外基质分泌的活性。 The expression of extracellular matrix endothelin (ET 1 ) and fibronectin (FN) was observed by low glucose stimulation group (normal control), high glucose stimulation group (diabetes model), and drug treatment comparison to observe the content of 3⁄4 Anti-extracellular matrix secretion activity.

(二）实验方法 (2) Experimental methods

Trizol常规法抽提细胞总 RNA，去除基因组 DM; Trizol routine extraction of total cellular RNA, removal of genomic DM;

MA定量后逆转录； Reverse transcription after MA quantification;

取 cDNA 1-2 μ 1进行荧光定量 PCR实验； Take cDNA 1-2 μ 1 for fluorescence quantitative PCR experiment;

2 - Δ厶 CT方法是实时定量 PCR实验中分析基因表达相对变化的一种简便方法。 * METHODS 25， 402 - 408 (2001) doi： 10. 1006/meth. 2001. 1262, available online at http://www. idealibrary. com The 2 - Δ厶 CT method is a simple method for analyzing the relative changes in gene expression in real-time quantitative PCR experiments. * METHODS 25, 402 - 408 (2001) doi: 10. 1006/meth. 2001. 1262, available online at http://www. idealibrary.com

(三）药效学结果分析及初步结 (3) Analysis of pharmacodynamic results and preliminary conclusions

通过 GAPDH均一化处理，我们对目标基因 ET-1和 FN的表达变化进行了监测。在 8h 的时间范围内，在每一时间点都取 3个重复样本，每一样本在 cDNA合成之后都做定量 Through GAPDH homogenization, we monitored changes in the expression of target genes ET-1 and FN. In the 8h time frame, 3 replicate samples were taken at each time point, and each sample was quantified after cDNA synthesis.

- PCR ，数据分析用到了公式，即： - PCR, the data analysis uses the formula, namely:

Time x表示任意时间点， Time 0表示经 GAPDH校正后 1倍量的目标基因表达。目标序列的量通过内均一化处理之后相对于参照因子而言就是： amount of targets - ^Δ 厶结果显示根皮苷衍生物具有明显的抗分泌活性（见表 1 )，其对 ET- 1的抗分泌活性依次为： 3' - (六氢吡啶- 1-基-亚甲基）根皮苷 >3，一 (4-甲基哌啶- 1-基-亚甲基）根皮苷 >裉皮苷；其对 FN的抗分泌活性依次为 3' - (六氢吡啶- 1-基-亚甲基）根皮苷 > 根皮苷 >3' ― (4 -甲基哌啶- 1-基-亚甲基）根皮苷。 Time x represents an arbitrary time point, and Time 0 represents a target gene expression that is 1 times the amount corrected by GAPDH. The amount of the target sequence is determined by internal homogenization relative to the reference factor: amount of targets - ^Δ厶 results show that the phlorizin derivative has significant antisecretory activity (see Table 1), its resistance to ET-1 The secretory activity is: 3' - (hexahydropyridine-1-yl-methylene) phloridin >3, mono(4-methylpiperidine-1-yl-methylene) phloridin > suede Glycosides; its antisecretory activity against FN is 3'-(hexahydropyridine-1-yl-methylene) phloridin > phlorizin >3' ― (4-methylpiperidine-1-yl- Methylene) phlorizin.

表 1 根皮苷及其衍生物荧光实时定量 PCR (聚合酶链式反应）结果

实施例 35 3' - (N-曲美他嗪基-亚甲基）根皮苷抗糖尿病肾病药效学研究 Table 1 Results of real-time quantitative PCR (polymerase chain reaction) of phlorizin and its derivatives

Example 35 3'-(N-tromethetazinyl-methylene) Pharmacodynamics of phloridzin against diabetic nephropathy

(一）药效学观察方法： (1) Pharmacodynamic observation methods:

以单侧肾切除，高脂饲料喂食 2个月诱发胰岛素抵抗，再辅以小剂量链脲佐菌素 Unilateral nephrectomy, high-fat diet for 2 months induced insulin resistance, supplemented with low-dose streptozotocin

(STZ) 15mg/kg腹腔注射 1-2次的方法，制备了糖尿病肾病大鼠模型。以空腹血糖及餐后血糖、 24小时尿蛋白定量显著升髙，为成模指标。成模后给与药物干预三个月后，经血糖、血生化、 24h尿蛋白测定和病理组织形态学等观察结果，评价新药的药效。 1. 造模方法-(STZ) A rat model of diabetic nephropathy was prepared by intraperitoneal injection of 1-2 times at 15 mg/kg. With fasting blood glucose and postprandial blood glucose, 24-hour urine protein was significantly elevated, which was a model. After three months of drug intervention, the results of blood glucose, blood biochemistry, 24h urine protein determination and pathological histomorphology were used to evaluate the efficacy of the new drug. 1. Modeling method -

1 )实验动物选择：动物选用健康 Wistar 120只，雄性大鼠，体重 180- 230g，购自中科院实验动物中心 (许可证号： SCXK (沪) 2002-0002)。生长在普通级动物房，环境温度 25oC, 普通词料喂养 1周后开始造模。 1) Experimental animal selection: 120 healthy Wistar animals, male rats, weighing 180-230 g, purchased from the Experimental Animal Center of the Chinese Academy of Sciences (license number: SCXK (Shanghai) 2002-0002). It grows in the common animal room, the ambient temperature is 25oC, and the model is started after 1 week of common word feeding.

2)造模剂选择： i) 链脲佐菌素（STZ) (Sigma) ; 2) Modeling agent selection: i) Streptozotocin (STZ) (Sigma);

ϋ) 高脂饲料（基础饲料加蔗糖，炼猪油,蛋黄粉按比例 60: 22： 8： ϋ) High-fat diet (basic feed plus sucrose, refined lard, egg yolk powder in proportion 60: 22: 8:

10混合而成）（中科院动物中心） 10 mixed) (Chinese Academy of Sciences Animal Center)

3) 具体造模方法如下 3) The specific modeling method is as follows

①模型组 Wistard大鼠在安定 +*** 0. lml/100g腹腔注射麻醉下行左侧肾脏摘除术，假手术组在切开后立即缝合。术后立即注射青霉素 8万单位连续 2日。术后进食普通饲料喂养 2周使其自然恢复。 1 Model group Wistard rats were treated with diazepam 0. lml/100g intraperitoneal injection for left lateral nephrectomy, and the sham operation group was sutured immediately after incision. Immediately after the operation, penicillin was injected 80,000 units for 2 consecutive days. After eating for 2 weeks, the normal feed was naturally restored.

②投与髙脂饲料进食 8周，给予造模剂 STZ 15mg/kg, 溶于 0. lmmol/L柠檬酸 -柠檬酸钠缓冲溶液 (PH4. 5 )腹腔注射一次，（注射前给与 24小时禁食，术后立即给 50g/L 葡萄糖水饮用，以减少大鼠的死亡）一周后上代谢笼测 24h尿量，测量空腹和餐后血糖，以及血生化指标，尿量仍正常者补注射 15mg/kg 1次。 ③正常对照组给予等量 0. lmmol/L柠檬酸 -柠檬酸钠缓冲溶液（pH4. 5) 溶剂 ip。 . 实验及观察指标 2 and rouge feed for 8 weeks, give the molding agent STZ 15mg / kg, dissolved in 0. lmmol / L citric acid - sodium citrate buffer solution (PH4. 5) intraperitoneal injection, (24 hours before the injection) Food, immediately after drinking 50g / L glucose water to reduce the death of rats) one week after the metabolic cage measured 24h urine volume, measuring fasting and postprandial blood glucose, and blood biochemical indicators, urine output is still normal, 15mg injection /kg 1 time. 3 normal control group was given an equal amount of 0. lmmol / L citric acid - sodium citrate buffer solution (pH 4.6) solvent ip. . Experimental and observational indicators

①每周称体重一次，并记进食量； 1 Weigh once a week, and record the amount of food;

②主要观察指标： i ) 空腹及餐后血糖 ii ) 24h尿蛋白总量 2 main observation indicators: i) fasting and postprandial blood glucose ii) total 24h urine protein

③次要观察指标 3 times to observe indicators

i) 肝功能：谷丙转胺酶 (SGPT) i) Liver function: alanine transaminase (SGPT)

ii) 肾功能：尿素氮；肌酐 Ii) Renal function: urea nitrogen; creatinine

iii) 血脂，总胆固醇，甘油三酯， HDL-C Iii) Blood lipids, total cholesterol, triglycerides, HDL-C

iv) 病理检查禁食 12h,处死并记录肾重量,部分肾脏以 10%甲醛固定,石蜡包埋切片，行 HE染色 Iv) Pathological examination Fasted for 12h, sacrificed and recorded kidney weight, some kidneys were fixed with 10% formaldehyde, embedded in paraffin, and stained with HE

给药前测血糖耐量， 24h尿蛋白总量，肝肾功能生化指标。 Glucose tolerance before administration, total amount of 24h urine protein, biochemical indicators of liver and kidney function.

3. II型糖尿病肾病判断标准： 3. Judging criteria for type II diabetic nephropathy:

(1 ) 餐后血糖 11. 7 ramol/L (1) Postprandial blood glucose 11. 7 ramol/L

(2) 24h尿蛋白的含量显著高于对照组 (2) 24h urine protein content was significantly higher than the control group

4. 统计方法：计数资料数据以 X 士 s表示，采用方差分析 4. Statistical methods: Count data is expressed as X s s, using analysis of variance

(二）给药剂量以及给药时间 (2) Dosage and administration time

1. 药物及剂量： 1. Drugs and doses:

3' - (N-曲美他嗪基-亚甲基）根皮苷生物小剂量 20mg/kg; 大剂量组 200mg/kg 3' - (N-tromethetazinyl-methylene) phlorizin bio-dose 20mg/kg; high-dose group 200mg/kg

2. 给药时间： 3个月 2. Administration time: 3 months

(三）药效学实验结果 (3) Pharmacodynamic experiment results

1. 给药前 Before administration

( 1)体重改变：造模开始后，模型组可见体重显著超过正常对照组； STZ注射后可见体重减轻现象，给药前体重参见图 1。 (1) Weight change: After the model was started, the body weight of the model group was significantly higher than that of the normal control group; the body weight loss was observed after STZ injection, and the body weight before administration was shown in Fig. 1.

(2)进食情况 (2) Eating situation

STZ注射前进食情况（根据每周记录统计)见图 2。 The STZ injection advance food situation (based on weekly record statistics) is shown in Figure 2.

STZ注射后进食情况（根据代谢笼的记录数据) Feeding after STZ injection (according to the recorded data of the metabolic cage)

分组 n 体重 (g) 日进食量（g) 日进水量（g) 尿量（ml ) Group n Weight (g) Daily food intake (g) Daily water intake (g) Urine volume (ml)

Control 9 397. 9± 15. 7 16. 2±5. 6 15. 9±4. 7 9. 6±2. 6Control 9 397. 9± 15. 7 16. 2±5. 6 15. 9±4. 7 9. 6±2. 6

Model C 79 368. 1 ±33. 3 18. 8±5. 3 80. 6 ±46. 5*" 69士 43. 8 * Model C 79 368. 1 ±33. 3 18. 8±5. 3 80. 6 ±46. 5*" 69士 43. 8 *

48 48

替换页（细 ^ 表 2 STZ注射后正常组与模型组的血生化比较 Replacement page (fine ^ Table 2 Comparison of blood biochemistry between normal group and model group after STZ injection

CH02I CH02I

餐后血糖 24hTP UREL CRE2 TRIGL HDLC ALTL 分组 n (mmol/L Postprandial blood glucose 24hTP UREL CRE2 TRIGL HDLC ALTL group n (mmol/L

(nimol/L) (g/ (mmol/) (mol/) (mmol/L) (mmol/) (U/L) (nimol/L) (g/ (mmol/) (mol/) (mmol/L) (mmol/) (U/L)

) )

7. 16士 33. 42 + 5. 98土 36. 41 + 1. 59士 1. 13士 l. M± 53. 07土 7. 16 士 33. 42 + 5. 98 土 36. 41 + 1. 59 士 1. 13 士 l. M± 53. 07

Control 9 Control 9

1. 22 10. 76 1. 06 6. 08 0. 12 0. 34 0. 12 8. 05 1. 22 10. 76 1. 06 6. 08 0. 12 0. 34 0. 12 8. 05

15. 84+ 178. 36 + 7. 95 + 42. 46 + 1. 72士 1. 18土 1. 47土 64. 31士15. 84+ 178. 36 + 7. 95 + 42. 46 + 1. 72 士 1. 18 土 1. 47 土 64. 31 士

Model C 79 Model C 79

7 o 3 ** 104. 53*** 2. 58" 11. 57** 0. 4 0. 4 0. 38** 23. 4** 经过 3个月的左肾切除术，高糖高脂词料加小剂量的 STZ腹腔注射的造模，大鼠出现了体重下降，多饮及尿量显著增加；餐后血糖显著上升（P〈0. 001 )， 24小时尿蛋白显著升高 (P〈0. 001)的 Π型糖尿病的改变。 7 o 3 ** 104. 53*** 2. 58" 11. 57** 0. 4 0. 4 0. 38** 23. 4** After 3 months of left nephrectomy, high sugar and high fat Words and small doses of STZ intraperitoneal injection model, rats showed weight loss, polydipsia and urine output increased significantly; postprandial blood glucose increased significantly (P < 0.001), 24-hour urine protein was significantly increased (P <0. 001) Changes in type 2 diabetes.

2. 给药后 2. After administration

( 1)给药前分组情况 (1) Grouping before administration

49 49

替换页（细则第 26条) ¾ Replacement page (Article 26) 3⁄4

给药前各组动物的餐后血糖等生化指标无组间显著性差别。 The biochemical indicators such as postprandial blood glucose of the animals in each group before the administration had no significant difference between the groups.

(2)药物对模型动物体重及进食的影响 (2) Effects of drugs on body weight and feeding of model animals

3' - (N-曲美他嗉基-亚甲基）根皮苷组的动物一般状态改善的较好，尿量减少，进食量变化不大，其大剂量组体重改善更明显，伹无显著性意义，参见图 3。给药后大鼠的进食情况 The animals in the 3'-(N-trametaphthyl-methylene) phlorizin group generally improved better, the urine output decreased, and the food intake did not change much. The weight of the high-dose group improved more obviously. Significant meaning, see Figure 3. Eating condition of rats after administration

分组和剂量体重（g) 日进食量 (g) 日进水量 (g) 尿量 (ml) Grouping and dose Weight (g) Daily food intake (g) Daily water intake (g) Urine volume (ml)

Control 464.4±20.4 16.4±2.1 16.9±4.1 11.3±1.3Control 464.4±20.4 16.4±2.1 16.9±4.1 11.3±1.3

Model 422.7±53.7* 17.8±5.3 32.4±34.4 20.8±36.7Model 422.7±53.7* 17.8±5.3 32.4±34.4 20.8±36.7

Gen Deri Gen Deri

422.2 ±50.6 19.2±5.5 46.4±52.7 35.1土 53.4 20mg/kg 422.2 ±50.6 19.2±5.5 46.4±52.7 35.1 soil 53.4 20mg/kg

Gen Deri Gen Deri

432.2±64.1 16.6土 3.2 30.7±29.5 21.8±30 200mg/kg 432.2±64.1 16.6 soil 3.2 30.7±29.5 21.8±30 200mg/kg

(3)各药物对餐后血糖、尿蛋白的影响 (3) Effects of various drugs on postprandial blood glucose and urine protein

3' - (N-曲美他嗪基-亚甲基）根皮苷对餐后血糖有显著的降低效果，小剂量组的餐后血糖较模型组下降了 23.7%，大剂量组下降了 53.3%, 呈现出剂量依赖关系 (P<0.001)_: 大剂量组的 24h尿蛋白量也显著下降 (P<0.05) 各药物组对餐后血糖及 24h尿蛋白量的影响 3' - (N-tromethetazinyl-methylene) phlorizin has a significant effect on postprandial blood glucose. Postprandial blood glucose in the low-dose group decreased by 23.7% compared with the model group, and the high-dose group decreased by 53.3. %, showed a dose-dependent relationship (P<0.001) _: the amount of 24h urine protein in the high-dose group also decreased significantly (P<0.05). The effect of each drug group on postprandial blood glucose and 24h urine protein.

药物分组和剂量 n 餐后血糖 (讓 ol/L) 24hTP (g/L) Drug grouping and dose n postprandial blood glucose (let ol/L) 24hTP (g/L)

Control 5 7.76±0.7 35.79±4.03 Control 5 7.76±0.7 35.79±4.03

Model 6 16.57土 3.33* 60.08 ±9.44™ Model 6 16.57 soil 3.33* 60.08 ±9.44TM

Gen Deri 20mg/kg 6 12.65±2.1* 53.3±23.19 Gen Deri 20mg/kg 6 12.65±2.1* 53.3±23.19

Gen Deri 200mg/kg 6 7.73±1.58*** 42.92±15.68* Gen Deri 200mg/kg 6 7.73±1.58*** 42.92±15.68*

#与正常对照组比较 P<0.05; ##P<0.01； ### P<0.001 #Compared with normal control group P<0.05; ##P<0.01; ### P<0.001

*与模型对照组比较 P<0.05； **P<0.01； *** P<0.001 (4)药物对血生化指标的影响 *Compared with model control group P<0.05; **P<0.01; ***P<0.001 (4) Effect of drugs on blood biochemical parameters

替换页（细则第 26条) 与模型组比较， 3， - (N-曲美他嗪基-亚甲基）根皮苷小剂量组的血清胆固醇值降低了 13.2%, 大剂量降低了 20.5% (P<0.05);小剂量组的大鼠血清甘油三酯较模型族降低了 20.8%, 大剂量组降低了 46.5% (P<0.05)，呈剂量依赖关系。 Replacement page (Article 26) Compared with the model group, the serum cholesterol level of the 3, - (N-trimetazinyl-methylene) phloridzin group was decreased by 13.2%, and the high dose was decreased by 20.5% (P<0.05); The serum triglyceride of the rats in the group was reduced by 20.8% compared with the model family, and the high-dose group was decreased by 46.5% (P<0.05) in a dose-dependent manner.

表 6 各药物对血生化指标的影响 Table 6 Effect of various drugs on blood biochemical indicators

n CH02I (mmol/L) TRIGL (腿 ol/L) HDLC (mmol/L)

n CH02I (mmol/L) TRIGL (leg ol/L) HDLC (mmol/L)

Control 5 1.83±0.44 0.90±0.15 1.0土0.35 Control 5 1.83±0.44 0.90±0.15 1.0 soil 0.35

Model 6 2.58士 0.36^s 1.44±0.52* 1.83±0.29Model 6 2.58 ± 0.36 ^s 1.44 ± 0.52 * 1.83 ± 0.29

Gen Deri 20rag/kg 6 2.24±0·27 1.14±0.24 1.73±0.22Gen Deri 20rag/kg 6 2.24±0·27 1.14±0.24 1.73±0.22

Gen Deri 200rag/kg 6 2.05±0.11* 0.77±0.21* 1.64±0.1Gen Deri 200rag/kg 6 2.05±0.11* 0.77±0.21* 1.64±0.1

#与正常对照组比较 P<O.05； m?<o. oi；画 p<o. ooi #Compared with the normal control group P<O.05; m?<o. oi; draw p<o. ooi

*与模型对照组比较 P<0.05； **P<0.01;*** P<0.001 *Compared with model control group P<0.05; **P<0.01; ***P<0.001

(5) 药物对肝肾功能指标的影响 (5) The effect of drugs on liver and kidney function indicators

3' - (N-曲美他嗪基-亚甲基）根皮苷有轻度降低尿蛋白的作用，小剂量组大鼠 24 尿蛋白总量比模型组降低了 11.3%，大剂量组降低了 28.6% (P<0.05), 可见剂量依赖关系。对肝功能无明显影响。 3'-(N-trometazinyl-methylene) phlorizin has a slight effect on reducing urinary protein. In the low-dose group, the total amount of urinary protein in the lower dose group was decreased by 11.3% compared with the model group, and the high-dose group was decreased. At 28.6% (P < 0.05), a dose-dependent relationship was observed. No significant effect on liver function.

表 7 各药物对肝肾功能指标的影响 Table 7 Effects of various drugs on liver and kidney function indicators

分组 n 24hTP (g/L) UREL (mmol/L) CRE2 (匪 ol/L) ALTL (U/L) ASTL (U/L) Group n 24hTP (g/L) UREL (mmol/L) CRE2 (匪 ol/L) ALTL (U/L) ASTL (U/L)

Control 5 35.79±4.03 5.83±0.57 39.03±1.76 72.43±11.55 137.93±42.64Control 5 35.79±4.03 5.83±0.57 39.03±1.76 72.43±11.55 137.93±42.64

Model 6 60.08 ±9.44™ 6.70±1.07 50·8±7.56^e 52.87±8.47^s 143.85±45.6Model 6 60.08 ±9.44TM 6.70±1.07 50·8±7.56 ^e 52.87±8.47 ^s 143.85±45.6

Gen Deri Gen Deri

6 53.3±23.19 5.97±0.26 47.37±2.63 58.43±13.08 109.38±18.01 20mg/kg 6 53.3±23.19 5.97±0.26 47.37±2.63 58.43±13.08 109.38±18.01 20mg/kg

Gen Deri Gen Deri

6 42.92±15.68* 6.09±0.76 46.25±4.53 53.38±13.11 139.17±51.36 200rag/kg 6 42.92±15.68* 6.09±0.76 46.25±4.53 53.38±13.11 139.17±51.36 200rag/kg

#与正常对照组比较 P<0.05； ##P<0.01；麵 P<0.001 #Compared with normal control group P<0.05; ##P<0.01; face P<0.001

*与模型对照组比较 P<0.05; **P<0.01;*** P<0.001 *Compared with model control group P<0.05; **P<0.01; ***P<0.001

(6) 药物对大鼠内脏器官 '大体病理的影响 (6) Effects of drugs on the gross pathology of rat internal organs

3' - (N-曲美他嗪基-亚甲基）根皮苷小剂量心 /体重比轻度下降（P〈0. 3' - (N-tromethetazinyl-methylene) phloridzin has a slight decrease in heart-to-weight ratio (P<0.

表 8 根皮苷衍生物对大鼠内脏器官大体病理的影响 Table 8 Effect of phlorizin derivatives on gross pathology of rat internal organs

52 52

替换页（细则备) 分组 n 心 /体重比肾 /体重比肝 /体重比Replacement page (specification) Group n heart/body weight ratio kidney/body weight ratio liver/body weight ratio

Control 5 0. 0028 ±0. 0001 0. 0026 ±0. 0002 0. 0206±0. 0009Control 5 0. 0028 ±0. 0001 0. 0026 ±0. 0002 0. 0206±0. 0009

Model 6 0. 0029±0. 0001 0. 0041 ±0. 0002™ 0. 0254±0. 0026*"Model 6 0. 0029±0. 0001 0. 0041 ±0. 0002TM 0. 0254±0. 0026*"

Gen Deri Gen Deri

6 0. 0027 ±0. 0002* 0. 0040 ± 0. 0002 0. 0229 ± 0. 0024 20mg/kg 6 0. 0027 ±0. 0002* 0. 0040 ± 0. 0002 0. 0229 ± 0. 0024 20mg/kg

Gen Deri Gen Deri

6 0. 0029±0. 0007 0. 0040 ±0. 0005 0. 0212± 0. 0029* 200mg/kg 6 0. 0029±0. 0007 0. 0040 ±0. 0005 0. 0212± 0. 0029* 200mg/kg

ft与正常对照组比较 P<O. 05； ?<o. oi；漏 p<o. ooi Ft compared with normal control group P<O. 05; ?<o. oi; leak p<o. ooi

*与模型对照组比较 P<0. 05； **P<0. 01 ; *** Ρ〈0· 001 *Compared with the model control group P<0. 05; **P<0. 01 ; *** Ρ<0· 001

(7 ) 肾脏病理改变情况：经 HE染色，在光镜 x200和 x400下，可比较肾小球的体积，肾小球固有细胞数，系膜外基质的增生，以及间质纤维化的情况。 (7) Renal pathological changes: HE staining, under light microscope x200 and x400, can compare the volume of glomeruli, the number of glomerular intrinsic cells, the proliferation of extracellular matrix, and interstitial fibrosis.

1 )从图 4- 7可以看出，低倍镜下（He染色 χ200)， 3 ' 一 (N-曲美他嗪基 -亚甲基）根皮苷对肾小球的体积的影响并不十分明显。 1) It can be seen from Fig. 4-7 that under low magnification (He stained χ200), the effect of 3'-(N-trimetazinyl-methylene) phlorizin on the volume of glomeruli is not Very obvious.

2 ) 从图 8- 11可以看出，高倍镜下（HE染色 χ400)， 3' - (N-曲美他嗪基-亚甲基）根皮苷组的大鼠肾脏的系膜外基质的分泌量有所减少，间质纤维化明显减少，尤以大剂量组为最明显。结果- 2) It can be seen from Fig. 8-11 that under high magnification (HE staining χ400), the 3'-(N-trimetazinyl-methylene) phlorizin group of the rat mesenteric matrix The amount of secretion was reduced, and interstitial fibrosis was significantly reduced, especially in the high-dose group. result-

1 ) 3' - (N-曲美他嗪基-亚甲基）根皮苷可改善糖尿病肾病模型大鼠的一般状况1) 3' - (N-tromethetazinyl-methylene) phloridzin can improve the general condition of diabetic nephropathy model rats

2) 剂量依赖性地降低 DN模型大鼠的餐后血糖 (P<0. 001) 2) Dose-dependent reduction of postprandial blood glucose in DN model rats (P<0.001)

3) 剂量依赖性地降低 DN模型大鼠的血清甘油三酯 (P<0. 05)和胆固醇值 (P〈0. 05) 3) Dose-dependently lower serum triglyceride (P<0.05) and cholesterol value in DN model rats (P<0.05)

4) 大剂量的 3' - (N-曲美他嗪基-亚甲基）根皮苷还有降低 24小时尿蛋白的作用 (P<0. 05) 4) High dose of 3'-(N-trimetazinyl-methylene) phlorizin also reduced the effect of 24-hour urine protein (P<0.05)

5 )病理检测，对 DN大鼠的肾小球体积改变不明显，对肾小球系膜基质的分泌有减少，间质纤维化程度有所减轻。附图说明 5) Pathological examination showed that the glomerular volume of DN rats did not change significantly, the secretion of mesangial matrix was reduced, and the degree of interstitial fibrosis was reduced. DRAWINGS

图 1为给药前体重曲线。 Figure 1 shows the pre-dose weight profile.

图 2为 STZ注射前每周进食量统计。 Figure 2 shows the weekly food intake statistics before STZ injection.

图 3显示了 3' - (N-曲美他嗪基-亚甲基）根皮苷对体重的影响。 Figure 3 shows the effect of 3'-(N-trimetazinyl-methylene) phlorizin on body weight.

53 53

替换页（细则第 26条) 图 4为 Contro组 He染色 x200下的照片。 Replacement page (Article 26) Figure 4 is a photograph of the Contro group under He staining x200.

图 5为 Model组 He染色 x200下的照片。 Figure 5 is a photograph of the Model Group under He staining x200.

图 6为 Gen- S组 He染色 x200下的照片。 Figure 6 is a photograph of the Gen-S group under He staining x200.

图 7为 Gen- H组 He染色 x200下的照片。 Figure 7 is a photograph of the Gen-H group under He staining x200.

图 8为 Contro组 He染色 x400下的照片。 Figure 8 is a photograph of the Hetro stained x400 in the Contro group.

图 9为 Model组 He染色 x400下的照片。 Figure 9 is a photograph of the Model group under He staining x400.

图 10为 Gen- S组 He染色 x400下的照片。 Figure 10 is a photograph of the Gen-S group under He staining x400.

图 11为 Gen- H组 He染色 x400下的照片。 Figure 11 is a photograph of the Gen-H group under He dye x400.

54 替百 (细^擎 54 百(

Claims

权利要求 Rights request

1. 下式结构的根皮苷衍生物或其药学上可接受的盐或酯，或其异构体或前药 _: A phlorizin derivative of the formula: or a pharmaceutically acceptable salt or ester thereof, or an isomer or prodrug thereof _:

其中 among them

R为通过 N原子与主结构相连的含有 N、 0或 S原子的杂环基或基团 - 其中 R is a heterocyclic group or group containing an N, 0 or S atom bonded to the main structure through a N atom - wherein

¾和 R₂独立为氢、任意取代的 C厂 ( ₈的焼基、 d-C₄烷氧基 C 0 (CH₂) _raCH₃、 d-C₄烷巯基 CH₂S (C ) _mC 、（C ) _mC 、（CH₂)„CN、（C¾) _mC00H、 C「 C₄烷酰基 (CH^COOR^ (CH₂) _m0H、 (CH X、 S0₂ (CH₂)„CH₃、 (CH2) _mS0₂R^I, C₂- C₄烯基、 C₂- C₄炔基、 C「C₄烷基氨基，其中 X为卤素， R¹为 d- C₄垸基、 C「C₄烯基、 C「C₄炔基， m为 0-10的整数， n为 2-6的整数， a为 0-4 的整数；或者 ¾ and R _{2 are} independently hydrogen, optionally substituted C plant (firing group _8, dC ₄ alkoxy _{_{C 0 (CH 2) ra CH}} 3, dC 4 alkylmercapto _{_{CH 2 S (C) m C}} , (C) _m C , (CH ₂ )„CN, (C3⁄4) _m C00H, C “C ₄ alkanoyl (CH^COOR^ (CH ₂ ) _m 0H, (CH X, S0 ₂ (CH ₂ )„CH ₃ , (CH2 _m S0 ₂ R ^I , C ₂ - C ₄ alkenyl, C ₂ - C ₄ alkynyl, C "C ₄ alkylamino, wherein X is halogen, R ¹ is d-C ₄ fluorenyl, C "C ₄ Alkenyl, C "C ₄ alkynyl, m is an integer from 0 to 10, n is an integer from 2 to 6, and a is an integer from 0 to 4;

！^及 R₂和它们相连的氮原子环合成可任选被取代的 3-7元的杂环基，该类杂环取代基选自：羟基、羧基、氨基、磺酰基、 d-C₄垸基、羟基 d- 垸基、羧基 d- C₄烷基、氨基 C厂 C₄烷基、 C₂- C₄烯基、 C₂_C₄炔基、苯基、 C厂 C₄烷氧苯基、羟基 d-C₄垸基苯基、羧基 c「 C₄垸基苯基、卤代 d- c₄烷基苯基、苯基 c「c₄垸基、苯基 c₂- c₄烯基、含氧或含氮的 c₅-c₆ 环基、含氧或含氮的 c₅-c_e杂环羰基、含氧或含氮的 c₅-c_e杂环 d-C₄烷基。 ! And R ₂ and their attached nitrogen atom are ring-cyclized to an optionally substituted 3-7 membered heterocyclic group selected from the group consisting of: hydroxy, carboxy, amino, sulfonyl, dC ₄ fluorenyl, Hydroxy d-fluorenyl, carboxy d-C ₄ alkyl, amino C plant C ₄ alkyl, C ₂ - C ₄ alkenyl, C ₂ -C ₄ alkynyl, phenyl, C plant C ₄ alkoxyphenyl, hydroxy dC ₄ nonylphenyl, carboxyl c "C ₄ nonylphenyl, halo d- c ₄ alkylphenyl, phenyl c "c ₄ fluorenyl, phenyl c ₂ - c ₄ alkenyl, oxygenated or nitrogen-containing cyclic group c ₅ -c _6, oxygen or nitrogen containing c ₅ -c _e heterocyclic carbonyl group, oxygen or nitrogen containing heterocycloalkyl c ₅ -c _e dC ₄ alkyl.

2. 权利要求 1的化合物，其中所述的杂环基选自哌啶基、吗啉基、哌嗪基、噻唑基、咪唑基、吡啶基、吡咯基、四氢吡咯基和吡嗪基。 2. A compound according to claim 1, wherein said heterocyclic group is selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, thiazolyl, imidazolyl, pyridyl, pyrrolyl, tetrahydropyrrolyl and pyrazinyl.

3. 权利要求 1的化合物，其中所述的药学上可接受的盐是：当化合物是碱性时，与有机酸或无机酸形成的盐；当化合物是酸性时，与有机碱或无机碱形成的盐。 3. The compound of claim 1, wherein the pharmaceutically acceptable salt is: a salt formed with an organic or inorganic acid when the compound is basic; and an organic or inorganic base when the compound is acidic Salt.

4.权利要求 3的化合物，其中所述的有机酸或无机酸选自乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、枸橼酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、大黄酸、牛黄酸、齐墩果酸、熊果酸、 2-乙酰氧基-苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸、盐酸、氢溴酸、硫酸、磺酸、磷酸、硝酸。 4. The compound of claim 3, wherein the organic or inorganic acid is selected from the group consisting of acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, guanidine. Tannic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, rhein, taurine, oleanolic acid, ursolic acid, 2-acetyl Oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, phosphoric acid, nitric acid .

5. 权利要求 4的化合物，其中所述的有机酸或无机酸选自乙酸、琥珀酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、枸橼酸、马来酸、水杨酸、大黃酸、牛磺酸、富马酸、草酸、羟乙基磺酸、盐酸、硫酸、磷酸、硝酸。 5. The compound of claim 4, wherein the organic or inorganic acid is selected from the group consisting of acetic acid, succinic acid, and lactic acid. Malic acid, tartaric acid, citric acid, ascorbic acid, citric acid, maleic acid, salicylic acid, rhein, taurine, fumaric acid, oxalic acid, isethionic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid.

6. 权利要求 3的化合物，其中所述的有机碱或无机碱选自甜菜碱、咖啡因、胆碱， Ν, Ν' -二苄基乙二胺、二乙胺、二乙醇胺、 2-二乙基氨基乙醇、 2-二甲基氨基乙醇、乙醇胺、乙二胺、 Ν-乙基吗啉、 Ν-乙基哌啶、葡糖胺、黄连素、氨基葡糖、组氨酸、异丙基胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三- (羟甲基)氨基甲烷（TRIS)、 N-甲基葡萄糖胺（NMG)、三乙醇胺、三丙胺、氨丁三醇和二氢枞胺、氢氧化钾、氢氧化钠。 6. The compound of claim 3, wherein the organic or inorganic base is selected from the group consisting of betaines, caffeine, choline, guanidine, Ν'-dibenzylethylenediamine, diethylamine, diethanolamine, 2-two. Ethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, hydrazine-ethylmorpholine, hydrazine-ethylpiperidine, glucosamine, berberine, glucosamine, histidine, isopropyl Base amine, lysine, methyl glucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tris-(hydroxymethyl) Aminomethane (TRIS), N-methylglucamine (NMG), triethanolamine, tripropylamine, tromethamine and indanamine, potassium hydroxide, sodium hydroxide.

7. 权利要求 6的化合物，其中所述的有机碱或无机碱选自：氨基葡糖、甲基葡糖胺、咖啡因、三乙胺、氢氧化钾、氢氧化钠。 7. The compound of claim 6 wherein said organic or inorganic base is selected from the group consisting of: glucosamine, methyl glucosamine, caffeine, triethylamine, potassium hydroxide, sodium hydroxide.

8. 权利要求 1的化合物，它是具有如下结构的化合物: 8. The compound of claim 1 which is a compound having the structure:

9. 权利要求 1的化合物，它是具有如下结构的化合物: 9. The compound of claim 1 which is a compound having the structure:

其中 i: R2: Where i: R2:

CH₃ CH₃

CH ₃ CH ₃

CH(C¾)₂ CH(C¾)₂

CH(C3⁄4) ₂ CH(C3⁄4) ₂

CH₂C¾0H CH₂CH₂0HCH ₂ C3⁄40H CH ₂ CH ₂ 0H

CH₃ CH₂CH₂0HCH ₃ CH ₂ CH ₂ 0H

CH₃ CH₂C00CH₃ CH ₃ CH ₂ C00CH ₃

CH₂CN CH₂CNCH ₂ CN CH ₂ CN

CH₃ CH₂S0₃H CH ₃ CH ₂ S0 ₃ H

CH₂0CH₃ CH₂0CH₃ CH ₂ 0CH ₃ CH ₂ 0CH ₃

H H

HH

H N-井闪霉醇胺基H N-well muscimolyl

10. 权利要求 1所述的化合物，它是具以下结构的化合物- 8S 10. The compound of claim 1 which is a compound having the structure - 8S

S0.000/600ZN3/X3d CSTZIO/OIOZ OAV 6S S0.000/600ZN3/X3d CSTZIO/OIOZ OAV 6S

S0.000/600ZN3/X3d CSTZIO/OIOZ OAV S0.000/600ZN3/X3d CSTZIO/OIOZ OAV

60

60

12. 一种制备权利要求 1所述的根皮苷衍生物的制备方法，其特征包括以下一个或几个步骤： 12. A process for the preparation of a phlorizin derivative according to claim 1, which comprises one or more of the following steps:

( 1 )将蔷薇科或壳斗科植物的根、茎、叶或果实用乙醇水溶液提取，所得提取液通过大孔吸附树脂或聚酰胺精制得到根皮苷结晶化合物； (1) extracting the root, stem, leaf or fruit of the Rosaceae or Fagaceae plant with an aqueous solution of ethanol, and extracting the obtained extract to obtain a phlorizin crystal compound by macroporous adsorption resin or polyamide;

(2) 将所得根皮苷结晶化合物在质子性溶剂中，在存在或不存在酸的条件下与甲醛和伯胺或仲胺在 0-90°C的温度下反应，得到权利要求 1的目标化合物； (2) reacting the obtained phlorizin crystal compound in a protic solvent with formaldehyde and a primary or secondary amine at a temperature of 0 to 90 ° C in the presence or absence of an acid to obtain the object of claim 1. Compound

(3)将所得的目标化合物通过重结晶或柱层析得到纯品。 (3) The obtained target compound is obtained by recrystallization or column chromatography to obtain a pure product.

13. 根据权利要求 12所述的根皮苷衍生物的制备方法，其特征是步骤（2) 中所用的质子性溶剂逸用甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇或水中任一种。 The method for preparing a phlorizin derivative according to claim 12, wherein the protic solvent used in the step (2) is occluded with methanol, ethanol, propanol, isopropanol, n-butanol, and isobutylene. Any of alcohol, tert-butanol or water.

14. 一种药物组合物，该药物组合物含有权利要求 1-11任一项所述的化合物和药用载体。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

15. 一种药物组合物，该药物组合物含有权利要求 1-11或 14任一项的化合物作为第一活性成分和一种或多种选自下列的药物作为第二活性成分：抗糖尿病药物、治疗糖尿病并发症的药物、抗肥胖症药物、抗高血压药物、抗血小板药物、抗动脉粥样硬化药物 /或降血脂药物、抗氧化剂、肉碱、肉碱衍生物、肉碱棕榈酰转移酶抑制剂、肉碱辛酰基转移酶抑制剂、乙酰肉碱***、抗肿瘤药物、抗痛风药物、治疗骨质疏松药物、抗抑郁症药物、治疗贫血药物、治疗老年痴呆症药物、抗炎药物和免疫性药物及根皮苷提取物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or 14 as a first active ingredient and one or more drugs selected from the group consisting of: an antidiabetic drug Drugs for treating diabetic complications, anti-obesity drugs, antihypertensive drugs, antiplatelet drugs, anti-atherosclerotic drugs/or hypolipidemic drugs, antioxidants, carnitine, carnitine derivatives, carnitine palmitoyl transfer Enzyme inhibitors, carnitine octanoyl transferase inhibitors, acetylcarnitine stimulants, anti-tumor drugs, anti-gout drugs, osteoporosis drugs, antidepressants, anemia drugs, Alzheimer's drugs, anti-inflammatory drugs Drugs and immunological drugs and phlorizin extracts.

16. 权利要求 15的药物组合物，其中所述的第二活性成分选自：抗糖尿病药物、治疗糖尿病并发症的药物、抗肥胖症药物、抗高血压药物、抗动脉粥样硬化药物 /或降血脂药物、左旋肉碱、左旋肉碱衍生物、抗肿瘤药物、抗炎药物和免疫性药物。 16. The pharmaceutical composition according to claim 15, wherein the second active ingredient is selected from the group consisting of: an antidiabetic drug, a drug for treating diabetic complications, an antiobesity drug, an antihypertensive drug, an antiatherogenic drug/and/or Hypolipidemic drugs, L-carnitine, L-carnitine derivatives, antitumor drugs, anti-inflammatory drugs and immunological drugs.

17. 权利要求 15的药物组合物，其特征在于含有权利要求 1-10任一项的化合物作为第一活性成分和一种或多种含有权利要求 11 的作为第二活性成分的比例为 1 : 0. 0001-1: 0. 01。 The pharmaceutical composition according to claim 15, characterized in that the compound containing any one of claims 1 to 10 as the first active ingredient and one or more of the second active ingredient having the content of claim 11 are 1: 0. 0001-1: 0. 01.

18. 权利要求 14或 15的药物组合物，其中活性成分占组合物重量的 0. 1-99. 9%。 9%。 The composition of the composition of the composition of the composition of the composition of the composition of the composition.

19. 权利要求 14或 15的药物组合物其特征在于该药物组合物的制剂剂型包括口服给药制剂、注射给药制剂或局部给药制剂，其中： 19. The pharmaceutical composition according to claim 14 or 15, characterized in that the pharmaceutical dosage form of the pharmaceutical composition comprises an orally administered preparation, an injectable preparation or a topically administered preparation, wherein:

( 1 ) 口服给药制剂包括普通片、缓释片、颗粒剂、硬或软胶囊、糖浆剂、溶液剂、乳剂；口服给药制剂的载体包括填充剂、崩解剂、粘合剂、润滑剂、着色剂、矫味剂或者其他常规添加剂，具体包括淀粉、乳糖、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯垸酮、聚乙烯吡咯烷酮、羟丙甲纤维素、硬脂酸镁、二氧化硅和聚山梨脂一 80、十二烷基硫酸钠； (1) Oral administration preparations include ordinary tablets, sustained release tablets, granules, hard or soft capsules, syrups, solutions, emulsions; carriers for oral administration include fillers, disintegrators, binders, lubricants Agent, coloring agent, flavoring agent or other conventional additives, specifically including starch, lactose, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, polyvinylpyrrolidone, hypromellose, stearic acid Magnesium, silica and polysorbate 80, sodium lauryl sulfate;

(2)注射给药制剂包括无菌注射的水溶液、无菌注射的水包油微乳液、注射用无菌粉末；注射给药制剂的载体包括注射用溶剂、注射用附加剂，具体注射溶剂包括注射用水、注射用油如大豆油，注射用增溶剂如乙醇、丙二醇、聚乙二醇、甘油，等渗物质如氯化钠、葡萄糖； (2) The preparation for administration by injection includes a sterile injection aqueous solution, a sterile injection oil-in-water microemulsion, a sterile powder for injection; a carrier for injecting the preparation preparation includes a solvent for injection, an additional agent for injection, and the specific injection solvent includes Water for injection, oil for injection such as soybean oil, solubilizer for injection such as ethanol, propylene glycol, polyethylene glycol, glycerin, isotonic materials such as sodium chloride, glucose;

(3) 局部给药制剂是贴剂、栓剂、霜剂、膏剂、凝胶剂、溶液、混悬液或靶向制剂，其中靶向制剂包括脂质体、微球剂、亳微粒、包含物、单克隆抗体耦联物；局部给药制剂的载体包括药学上用于局部给药的常规载体。 (3) The topical preparation is a patch, a suppository, a cream, a cream, a gel, a solution, a suspension or a targeted preparation, wherein the targeted preparation comprises a liposome, a microsphere, a sputum particle, an inclusion , monoclonal antibody conjugates; carriers for topical formulations include conventional carriers for pharmaceutically acceptable topical administration.

20. 权利要求 19的药物组合物，其特征在于该药物组合物的制剂给药形式包括：静脉、肌内、腹膜、皮下、口服、直肠栓剂***法、 ***栓剂***法、靶向给药、吸入式、灌胃式、鼻词式、舌下给药、滴药法、微针式给药、连续给药***和局部给药，局部给药方式如贴皮制剂、或植入式连续给药释放***，其中贴皮制剂载体包括骨架材料如疏水的聚硅氧烷和亲水的聚乙烯醇等，控释膜材料如聚硅氧烷和乙烯-醋酸乙烯共聚物等，压敏胶如聚异丁烯、聚硅氧垸和聚丙烯酸酯，活性成分一般分散在压敏胶中；其中植入式连续给药释放***所选用的高分子材料包括聚乳酸一乙醇酸共聚物、聚乙二醇聚乳酸共聚物、聚乳酸 /聚己内酯、聚 [碳酸（亚丁酯 -co- ε -己内酯）酯]、聚丁内酯戊内酯、聚二氧环己酮 (PDS )、聚 - 3 -羟基丁酸酯 (ΡΗΒ )、聚左旋乳酸 (PLLA)、聚乙醇酸 (PGA)、聚 ε -己内酯 (PCL)、聚己内酯 /聚乙交酯丙交酯（PCL / PLGA)、甲基丙烯酸羟乙酯 (HEMA)。 20. The pharmaceutical composition according to claim 19, wherein the pharmaceutical composition is administered in the form of intravenous, intramuscular, peritoneal, subcutaneous, oral, rectal suppository insertion, vaginal suppository insertion, targeted administration, Inhalation, gavage, nasal, sublingual, drip, microneedle, continuous drug delivery system and topical administration, topical administration such as skin preparation, or implantable continuous administration a drug release system, wherein the skin preparation carrier comprises a skeleton material such as a hydrophobic polysiloxane and a hydrophilic polyvinyl alcohol, a controlled release film material such as a polysiloxane and an ethylene-vinyl acetate copolymer, etc., a pressure sensitive adhesive such as Polyisobutylene, polysiloxane and polyacrylate, the active ingredient is generally dispersed in the pressure sensitive adhesive; wherein the polymer material selected for the implantable continuous drug delivery system comprises polylactic acid monoglycolic acid copolymer, polyethylene glycol Polylactic acid copolymer, polylactic acid/polycaprolactone, poly[(butylene ester-co-ε-caprolactone)], polybutyrolactone, polydioxanone (PDS), poly - 3 -hydroxybutyrate (ΡΗΒ ), poly L-lactic acid (PLLA), poly Glycolic acid (PGA), poly-ε-caprolactone (PCL), polycaprolactone/polyglycolide lactide (PCL / PLGA), hydroxyethyl methacrylate (HEMA).

21. 权利要求 1-11任一项的化合物或权利要求 14或 15的药物组合物在制备治疗下列疾病的药物中的应用： 21. Use of a compound according to any one of claims 1-11 or a pharmaceutical composition according to claim 14 or 15 for the manufacture of a medicament for the treatment of:

增加高密度脂蛋白的水平、增强记忆力、改善学***升高、高脂血症、肥胖症、高甘油三酯血症、动脉粥样硬化、高血压、代谢综合症（X综合症)、贫血（如镰刀细胞贫血)、粉剌、肿瘤、风湿性关节炎、关节炎、肠炎、银屑病、多发性硬化症、神经变性紊乱、充血性心力衰竭、中风、主动脉瓣狭窄、肾炎、肾衰竭、痛风、红斑狼疮、 IgA 肾病、阑尾炎、胰腺炎、 ***反应（如鼻炎、鼻窦炎）、纤维症、骨病、骨质疏松、心血管疾病（如心律失常、心血管休克、心绞痛）、放疗及化疗并发症、肝病（如肝炎)、胃肠道病症（如胃炎和胃肠炎）、结膜炎、斯耶格伦（Sjogren' s) 综合症、肺病、肾病 (如多囊肾病）、皮炎、 HIV相关病症、疟疾（如脑疟）、强直性脊椎炎、麻风病、免疫性疾病、抑郁症、老年痴呆症、水肿、溃疡、精神***症、精神障碍性疾病、过敏性休克、尿崩症、哮喘、青光眼、线粒体疾病、能量代谢异常疾病、帕金森、基质金属蛋白酶病理性疾病。 Increases HDL levels, enhances memory, improves learning ability, aging, diabetes, diabetic nephropathy, diabetic foot disease, diabetic retinopathy, diabetic neuropathy, diabetic complications, delayed wound healing, insulin resistance, hyperglycemia, high Insulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis, hypertension, metabolic syndrome (X syndrome), anemia (eg sickle cell anemia) ), whitefly, tumor, rheumatoid arthritis, arthritis, enteritis, psoriasis, multiple sclerosis, neurodegenerative disorder, congestive heart failure, stroke, aortic stenosis, nephritis, renal failure, gout, erythema Lupus, IgA nephropathy, appendicitis, pancreatitis, allergies (such as rhinitis, sinusitis), fibrosis, bone disease, osteoporosis, cardiovascular disease (such as arrhythmia, cardiovascular shock, angina pectoris), radiotherapy and chemotherapy complications , liver disease (such as hepatitis), gastrointestinal disorders (such as gastritis and gastroenteritis) , conjunctivitis, Sjogren's syndrome, lung disease, kidney disease (eg polycystic kidney disease), dermatitis, HIV-related illness, malaria (eg cerebral malaria), ankylosing spondylitis, leprosy, immune disease , depression, Alzheimer's disease, edema, ulcer, schizophrenia, mental disorders, anaphylactic shock, diabetes insipidus, asthma, glaucoma, mitochondrial disease, abnormal energy metabolism, Parkinson's disease, matrix metalloproteinase pathological disease .

22. 权利要求 21的应用，其中所述的疾病包括：代谢类疾病、糖尿病、糖尿病肾病、糖尿病足病、糖尿病视网膜病、糖尿病性神经病、糖尿病并发症、高脂血症、肥胖症、高血压、肿瘤。 22. The use of claim 21, wherein the disease comprises: a metabolic disease, diabetes, diabetic nephropathy, diabetic foot disease, diabetic retinopathy, diabetic neuropathy, diabetic complications, hyperlipidemia, obesity, hypertension , tumor.

23. 权利要求 21的应用，其中所述药物成人每天的用量为 0. 001-lOOOmg/kg体重。 23. The use of claim 21, wherein the dosage of the drug per day is 0.0001 - 1000 mg / kg body weight.

24. 权利要求 21的应用，其中所述药物成人每天的用量为 0. 01-100mg/kg体重。The use of the drug in an amount of 0.01 to 100 mg / kg body weight per day.

25. 权利要求 21的应用，其中所述药物成人每天的用量为 0. 05-5mg/kg体重。 The use of the drug in an amount of 0. 05-5 mg / kg body weight per day.