WO2021218638A1 - 用于糖尿病及其并发症治疗的联合用药及其药物组合物 - Google Patents

用于糖尿病及其并发症治疗的联合用药及其药物组合物 Download PDF

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WO2021218638A1
WO2021218638A1 PCT/CN2021/087266 CN2021087266W WO2021218638A1 WO 2021218638 A1 WO2021218638 A1 WO 2021218638A1 CN 2021087266 W CN2021087266 W CN 2021087266W WO 2021218638 A1 WO2021218638 A1 WO 2021218638A1
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substituents
alkyl
component
ring
salt
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French (fr)
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黄圣健
鲁先平
潘德思
廖国强
赵一如
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Shenzhen Chipscreen Biosciences Co Ltd
Chengdu Chipscreen Pharmaceutical Ltd
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Shenzhen Chipscreen Biosciences Co Ltd
Chengdu Chipscreen Pharmaceutical Ltd
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Priority to BR112022022024A priority Critical patent/BR112022022024A2/pt
Priority to CA3181558A priority patent/CA3181558A1/en
Priority to AU2021264698A priority patent/AU2021264698A1/en
Priority to US17/922,133 priority patent/US20230190705A1/en
Priority to MX2022013588A priority patent/MX2022013588A/es
Priority to EP21795269.6A priority patent/EP4144373A4/en
Priority to JP2022566471A priority patent/JP2023525687A/ja
Priority to KR1020227040340A priority patent/KR20230005237A/ko
Publication of WO2021218638A1 publication Critical patent/WO2021218638A1/zh
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the invention relates to the field of biotechnology, in particular to a combination medicine and a pharmaceutical composition for the treatment of diabetes and its complications.
  • Diabetes is a disease caused by a variety of genetic disorders, and it currently plagues a considerable number of people in the world. It is mainly divided into two types: (1) Type I diabetes or insulin-dependent diabetes (IDDM), in which patients secrete little or no insulin; (2) Type II diabetes or non-insulin-dependent diabetes (NIDDM).
  • IDDM insulin-dependent diabetes
  • NIDDM non-insulin-dependent diabetes
  • the core problem of patients with type II diabetes is insulin resistance, that is, peripheral tissues such as muscle, liver, and adipose tissue have obstacles to the absorption and metabolism of insulin stimulated by insulin, which in turn increases the burden of insulin secretion by the pancreatic islets, and ultimately leads to a progressive decline or loss of pancreatic islet function. . 90% of diabetic patients have type II diabetes.
  • This metabolic disorder is characterized by high blood sugar and can cause various complications such as cardiovascular and cerebrovascular diseases, nephropathy, retinopathy, liver disease, and nervous system disease.
  • the treatment of type II diabetes usually includes lifestyle management and medication.
  • oral or injectable therapeutic drugs have at least 8 categories according to the treatment mechanism, but the effective population and long-term efficacy of the existing single-drug therapy have limitations.
  • the purpose of the present invention is to provide a combination medicine and its pharmaceutical composition with excellent effects in preventing and/or treating diabetes and its complications.
  • the present invention provides component (i): a compound represented by general formula (I) and its pharmaceutically acceptable salts, and their isomers, and component (ii): Use of a combination of sodium-glucose transporter-2 (SGLT2) inhibitors in the preparation of a medicament for the prevention and/or treatment of diabetes and/or diabetic complications, the diabetes is preferably type II diabetes, and the diabetic complications Including cardiovascular and cerebrovascular diseases, kidney diseases and liver diseases:
  • SGLT2 sodium-glucose transporter-2
  • ring A and ring B are respectively a benzene ring, there is no substituent or one or more substituents on the ring, and the substituents are fluorine, alkyl or alkoxy;
  • X is a covalent bond, O or S;
  • R1 is H or alkyl
  • R2 is H or alkyl
  • R3 is H or alkyl
  • R4 and R5 are respectively H or alkyl, or R4 and R5 together form a benzene ring, which has no substituents or one or more substituents, and the substituents are fluorine, alkyl or alkoxy;
  • Alk1 is C1-6 alkylene
  • Alk2 is C1-2 alkylene
  • Ar1 is a benzene ring with no substituents or one or more substituents on the ring, and the substituents are fluorine, alkyl or alkoxy;
  • Ar2 is a benzene ring or a pyridine ring, which has no substituents or one or more substituents on the ring, and the substituents are fluorine, alkyl or alkoxy.
  • the component (i) is a compound having the structure represented by formula (II) and its pharmaceutically acceptable salts, and their isomers:
  • the pharmaceutically acceptable salt includes alkali metal salt, alkaline earth metal salt, ammonium salt and N+(C1-4 alkyl)4 salt
  • the alkali metal salt includes potassium salt and sodium salt, the sodium salt of which is Siegler Other sodium
  • the alkaline earth metal salt includes calcium salt and magnesium salt
  • the isomer includes S configuration and R configuration.
  • Component (i) is a small molecule compound independently developed by Shenzhen Microchip Biotechnology Co., Ltd. with completely independent intellectual property rights. It has excellent hypoglycemic and lipid-lowering activities. Component (i) is disclosed in Chinese patent CN1257893C and is combined Obtained protection, the full text of the patent is incorporated into the present invention.
  • Component (ii) Sodium-glucose transporter-2 (SGLT2) is a new type of anti-diabetic drug, which can inhibit the reabsorption of glucose by the kidney, excrete excess glucose from the urine, and lower blood sugar.
  • SGLT2 Sodium-glucose transporter-2
  • the component (ii) sodium-glucose transporter-2 (SGLT2) inhibitor includes Canagliflozin, Dapagliflozin, Empagliflozin, Ipragliflozin or Ipragliflozin L-Proline (Iggliflozin or its complex with L-proline), Luseogliflozin, Tofogliflozin and Ertuglifolzin.
  • the amount of component (i) and component (ii) is a therapeutically effective amount, the amount of component (i) is 1-100 mg, preferably 12-48 mg; the amount of component (ii) is 1-500 mg,
  • the corresponding therapeutically effective dose is selected according to the type of the specific sodium-glucose transporter-2 (SGLT2) inhibitor.
  • the therapeutically effective dose of canagliflozin is 50-300mg, and the therapeutically effective dose of dapagliflozin is 2.5 -10mg, the therapeutically effective dose of empagliflozin is 5-25mg, the therapeutically effective dose of empagliflozin L-proline is 12.5-50mg, the therapeutically effective dose of ruggliflozin is 1.25-5mg, The therapeutically effective amount of net is 5-20 mg, and the therapeutically effective amount of Ertuglifolzin is 2.5-15 mg.
  • the present invention also provides a pharmaceutical composition, which comprises component (i): a compound represented by the general formula (I) and pharmaceutically acceptable salts thereof, and their isomers, and component ( ii): Sodium-glucose transporter-2 (SGLT2) inhibitor:
  • ring A and ring B are respectively a benzene ring, there is no substituent or one or more substituents on the ring, and the substituents are fluorine, alkyl or alkoxy;
  • X is a covalent bond, O or S;
  • R1 is H or alkyl
  • R2 is H or alkyl
  • R3 is H or alkyl
  • R4 and R5 are respectively H or alkyl, or R4 and R5 together form a benzene ring, which has no substituents or one or more substituents, and the substituents are fluorine, alkyl or alkoxy;
  • Alk1 is C1-6 alkylene
  • Alk2 is C1-2 alkylene
  • Ar1 is a benzene ring with no substituents or one or more substituents on the ring, and the substituents are fluorine, alkyl or alkoxy;
  • Ar2 is a benzene ring or a pyridine ring, which has no substituents or one or more substituents on the ring, and the substituents are fluorine, alkyl or alkoxy.
  • the component (i) is a compound having the structure represented by formula (II) and its pharmaceutically acceptable salts, and their isomers:
  • the pharmaceutically acceptable salt includes alkali metal salt, alkaline earth metal salt, ammonium salt and N+(C1-4 alkyl)4 salt
  • the alkali metal salt includes potassium salt and sodium salt
  • the alkaline earth metal salt includes calcium.
  • the isomers include S configuration and R configuration.
  • the component (ii) sodium-glucose transporter-2 (SGLT2) inhibitor includes Canagliflozin, Dapagliflozin, Empagliflozin, Ipragliflozin or Ipragliflozin L-Proline (Iggliflozin or its complex with L-proline), Luseogliflozin, Tofogliflozin and Ertuglifolzin.
  • the amount of component (i) and component (ii) is a therapeutically effective amount, the amount of component (i) is 1-100 mg, preferably 12-48 mg; the amount of component (ii) is 1-500 mg,
  • the corresponding therapeutically effective dose is selected according to the type of the specific sodium-glucose transporter-2 (SGLT2) inhibitor.
  • the therapeutically effective dose of canagliflozin is 50-300mg, and the therapeutically effective dose of dapagliflozin is 2.5 -10mg, the therapeutically effective dose of empagliflozin is 5-25mg, the therapeutically effective dose of empagliflozin L-proline is 12.5-50mg, the therapeutically effective dose of ruggliflozin is 1.25-5mg, The therapeutically effective amount of net is 5-20 mg, and the therapeutically effective amount of Ertuglifolzin is 2.5-15 mg.
  • the present invention provides a compound medicine, which comprises the aforementioned pharmaceutical composition, and one or more pharmaceutically acceptable excipients or carriers.
  • the compound medicine of the present invention can be prepared into solid preparations or liquid preparations by common methods in the art.
  • the solid preparations include tablets, capsules, granules, pills, powders, suppositories, and the like.
  • suitable pharmaceutically acceptable excipients or carriers include, but are not limited to: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , Solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, Preservatives, stabilizers, surfactants and buffers, etc.
  • Suitable pharmaceutically acceptable excipients or carriers include, but are not limited to: lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin , Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methylcellulose, water, syrup, talc, magnesium stearate, mineral oil, methyl hydroxybenzoate and propyl hydroxybenzoate, etc. .
  • the present invention provides a kit comprising the aforementioned pharmaceutical composition.
  • the component (i) and component (ii) are unit preparations with the same or different specifications, which can be placed in separate units. Provided in the container.
  • the present invention also provides a method for preventing and/or treating diabetes and/or diabetic complications including cardiovascular and cerebrovascular diseases, kidney diseases, and liver diseases, which includes administering a therapeutically effective amount of the aforementioned pharmaceutical composition or compound Steps of medicine or pill box.
  • the diabetic mouse strain BKS-Leprem2Cd479/Nju (also known as db/db mice) in which the leptin receptor gene is knocked out is used in combination with sitaglipta sodium and an SGLT2 inhibitor (enpagliflozin or dapagliflozin) Net) for two weeks, test the changes in blood glucose and blood lipids of the combined drug group compared with the single drug group or the vehicle group.
  • sitaglipta sodium combined with SGLT2 inhibitors can synergistically lower blood sugar in db/db diabetic mice, and can also alleviate the weight gain caused by sitaglipta sodium, which has an unexpected synergistic effect.
  • sitaglipta sodium combined with SGLT2 inhibitor can also bring about improvement of blood lipid indexes, especially the improvement of serum triglyceride content.
  • Siglipta Sodium is a PPAR ⁇ / ⁇ / ⁇ receptor full agonist, which can sensitize insulin, lower blood sugar and partially improve blood lipids; SGLT2 inhibitors can inhibit the reabsorption of glucose by the kidneys, and make excess glucose from the urine It can reduce blood sugar and reduce weight effectively.
  • the mechanical benefits of combining sitaglipta sodium and SGLT2 inhibitors include at least the following three aspects: (1) SGLT2 inhibitors reduce the absorption of glucose in the body, and sitaglipta sodium increases insulin sensitivity and reduces blood sugar in different ways. , Achieving a synergistic effect. (2) Sieglipta sodium can improve blood lipids and has the potential to treat related metabolic diseases.
  • the weight loss effect of SGLT2 inhibitors is also beneficial to metabolism, achieving a synergistic effect in improving metabolic diseases.
  • the weight loss effect of SGLT2 inhibitors can offset some of the side effects of sitaglipta sodium, and benefit diabetic patients with obesity complications.
  • Peroxidase proliferator activated receptor (PPAR) agonists can improve insulin resistance, prevent the risk of new diabetes, and cardiovascular protection, while sodium-glucose transporter-2 (SGLT2) inhibitors have cardiovascular and renal diseases Benefit.
  • the component (i) used in the present invention is a PPAR full agonist drug. Clinical studies have shown that it has the effect of lowering blood sugar and improving blood lipids in diabetic patients. It also has the effect of reducing systemic inflammation and certain liver and kidney protection effects, but it has A certain weight gain effect; and SGLT2 inhibitors have the effect of reducing blood sugar, blood pressure and body weight in diabetic patients, thereby bringing about renal function and cardiovascular protection.
  • the combination of the two types of drugs can also produce comprehensive effects on weight control, blood lipids, blood pressure, liver and kidney protection, etc., thereby preventing diabetes and its complications including cardiovascular and cerebrovascular diseases,
  • the prevention and/or treatment of kidney disease and liver disease brings more benefits.
  • Figure 1 shows the effect of sitaglipta sodium combined with empagliflozin on body weight and blood glucose compared to treatment alone.
  • Figure 2 shows the effect of sitaglipta sodium combined with dapagliflozin on body weight and blood glucose compared to treatment alone.
  • Figure 3 shows the effect of sitaglipta sodium combined with empagliflozin on blood lipids.
  • Figure 4 shows the effect of sitaglipta sodium combined with dapagliflozin on blood lipids.
  • the present invention discloses a combination medicine and a pharmaceutical composition for the treatment of diabetes and its complications. Those skilled in the art can learn from the content of this article and appropriately replace or modify them. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention.
  • the application of the present invention has been described through preferred embodiments, and relevant persons can obviously modify or appropriately change and combine the applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.
  • mice Oral sitaglipta sodium, empagliflozin or a combination of both in diabetic mice to investigate the effects of single drug and drug combination on the weight and blood glucose of the mice.
  • Test procedure 6-week-old male db/db mice were orally orally administered 100 microliters of solvent (0.1% sodium carboxymethylcellulose), 10 mg/kg sitaglipta sodium, and 3 mg/kg Engel once a day according to their body weight. Liegliflozin or take orally the same dose of sitaglita sodium and empagliflozin at the same time. Wild-type C57BLKS/Jnju mice were used as normal control mice (vehicle given). The administration period was 14 days, and the animals were dissected on the 15th day. From the beginning of the administration, the mice were weighed every 3 days and the fasting blood glucose was measured (fasting for 4-6 hours). The test results are shown in Figure 1.
  • mice Oral sitagliptin, dapagliflozin or a combination of both in diabetic mice to investigate the effects of single drug and drug combination on the weight and blood glucose of the mice.
  • Test procedure 6-week-old db/db male mice were orally administered 100 microliters of solvent (0.1% sodium carboxymethyl cellulose), 10 mg/kg sitaglipta sodium, and 1.5 mg/kg dag once a day according to their body weight. Liegliflozin or take the same dose of sitagliptin and dapagliflozin at the same time. Wild-type C57BLKS/Jnju mice were used as normal control mice (vehicle given). The administration period was 14 days, and the animals were dissected on the 15th day. From the beginning of the administration, the mice were weighed every 3 days and the fasting blood glucose was measured (fasting for 4-6 hours). The test results are shown in Figure 2.
  • Example 3 The effect of tresslipta sodium combined with empagliflozin on blood lipids
  • mice Oral sitagliptin sodium, empagliflozin or a combination of both in diabetic mice to investigate the effects of single drug and drug combination on total cholesterol (TC) and triglycerides (TG) in serum of mice.
  • TC total cholesterol
  • TG triglycerides
  • Test procedure 6-week-old male db/db mice were orally orally administered 100 microliters of solvent (0.1% sodium carboxymethylcellulose), 10 mg/kg sitaglipta sodium, and 3 mg/kg Engel once a day according to their body weight. Liegliflozin or take orally the same dose of sitaglita sodium and empagliflozin at the same time. Wild-type C57BLKS/Jnju mice were used as normal control mice (vehicle given). The administration period was 14 days, and the animals were dissected on the 15th day. Collect whole blood, collect serum by centrifugation, and measure TC and TG of serum by biochemical analyzer. The test results are shown in Figure 3.
  • Example 4 The effect of siglita sodium combined with dapagliflozin on blood lipids
  • mice Oral sitagliptin sodium, dapagliflozin or a combination of both in diabetic mice to investigate the effects of single drug and drug combination on total cholesterol (TC) and triglycerides (TG) in serum of mice.
  • TC total cholesterol
  • TG triglycerides
  • Test procedure 6-week-old db/db male mice were orally administered 100 microliters of solvent (0.1% sodium carboxymethyl cellulose), 10 mg/kg sitaglipta sodium, and 1.5 mg/kg dag once a day according to their body weight. Liegliflozin or take the same dose of sitagliptin and dapagliflozin at the same time. Wild-type C57BLKS/Jnju mice were used as normal control mice (vehicle given). The administration period was 14 days, and the animals were dissected on the 15th day. Collect whole blood, collect serum by centrifugation, and measure serum TC and TG by biochemical analyzer. The test results are shown in Figure 4.
  • sitagliptin sodium combined with SGLT2 inhibitor enpagliflozin or dapagliflozin can synergistically lower blood sugar in db/db diabetic mice, and can also alleviate sitagliptin sodium.
  • the weight gain has produced unexpected synergies.
  • sitaglipta sodium combined with SGLT2 inhibitor can also bring about improvement of blood lipid indexes, especially the improvement of serum triglyceride content.
  • Siglipta sodium is a peroxidase proliferator activated receptor (PPAR) agonist.
  • PPAR peroxidase proliferator activated receptor
  • Vascular protection, and sodium-glucose transporter-2 (SGLT2) inhibitors have benefits for cardiovascular disease and kidney disease.
  • Clinical studies have shown that sitaglipta sodium has the effect of lowering blood sugar and improving blood lipids in diabetic patients. It also has the effect of reducing systemic inflammation and a certain liver and kidney protection effect, but has a certain weight gain effect; and SGLT2 inhibitors are effective In diabetic patients, it has the effect of lowering blood sugar, blood pressure, and weight, thereby bringing about renal function and cardiovascular protection.
  • the combination of the two types of drugs can also produce comprehensive effects on weight control, blood lipids, blood pressure, liver and kidney protection, etc., thereby preventing diabetes and its complications including cardiovascular and cerebrovascular diseases,
  • the prevention and/or treatment of kidney disease and liver disease brings more benefits.

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Abstract

组分(i)：具有通式(I)所示的化合物及其药用盐，以及它们的异构体，与组分(ii)：SGLT2抑制剂的联合在制备用于预防和/或治疗糖尿病和/或糖尿病并发症的药物中的用途，以及含有组分(i)和组分(ii)的药物组合物。

Description

用于糖尿病及其并发症治疗的联合用药及其药物组合物 技术领域
本发明涉及生物技术领域，具体涉及用于糖尿病及其并发症治疗的联合用药及其药物组合物。
背景技术
糖尿病是多种基因紊乱而导致的疾病，目前它困扰着全球相当一部分人群。它主要分为两种类型：(1)I型糖尿病或胰岛素依赖型糖尿病(IDDM)，患者分泌极少或根本不分泌胰岛素；(2)II型糖尿病或非胰岛素依赖型糖尿病(NIDDM)。II型糖尿病患者的核心问题是胰岛素抵抗，即外周组织如肌肉、肝脏和脂肪组织等对胰岛素刺激的血糖吸收和代谢出现障碍，进而加重胰岛分泌胰岛素的负担，最终导致胰岛功能进行性下降乃至丧失。糖尿病患者中90％为II型糖尿病。这种代谢异常疾病的特征是高血糖，并会引起心脑血管疾病、肾病、视网膜病、肝脏疾病、神经系统疾病等多种并发症。
II型糖尿病的治疗通常包括生活方式管理和药物治疗。除胰岛素外的口服或注射治疗药物按照治疗机制已经有至少8大类，但是现有药物的单药治疗的有效人群和长期疗效都存在局限性。
此外，糖尿病患者相比其他人群具有更高的心脑血管、肾脏和肝脏等并发症风险，而现有治疗药物除了控制血糖外对于这些并发症的预防和控制效果各有差异。
寻找能够有效预防和/或治疗糖尿病及其并发症的联合用药具有重大意义。
发明内容
本发明的目的是提供一种预防和/或治疗糖尿病及其并发症效果优异的联合 用药及其药物组合物。
为解决上述技术问题，第一方面，本发明提供了组分(i)：具有通式(I)所示的化合物及其药用盐，以及它们的异构体，与组分(ii)：钠-葡萄糖转运体-2(SGLT2)抑制剂的联合在制备用于预防和/或治疗糖尿病和/或糖尿病并发症的药物中的用途，所述糖尿病优选为II型糖尿病，所述糖尿病并发症包括心脑血管疾病、肾病和肝脏疾病：
Figure PCTCN2021087266-appb-000001
其中，环A和环B分别为苯环，环上无取代基或有一个或多个取代基，取代基为氟、烷基或烷氧基；
X为共价键、O或S；
R1为H或烷基；
R2为H或烷基；
R3为H或烷基；
R4、R5分别为H或烷基，或R4和R5一起组成苯环，环上无取代基或有一个或多个取代基，取代基为氟、烷基或烷氧基；
Alk1为C1-6烷撑；
Alk2为C1-2烷撑；
Ar1为苯环，环上无取代基或有一个或多个取代基，取代基为氟、烷基或烷 氧基；
Ar2为苯环或吡啶环，环上无取代基或有一个或多个取代基，取代基为氟、烷基或烷氧基。
优选的，所述组分(i)为具有式(II)所示结构的化合物及其药用盐，以及它们的异构体：
Figure PCTCN2021087266-appb-000002
其中，所述药用盐包括碱金属盐、碱土金属盐、铵盐和N+(C1-4烷基)4的盐，所述碱金属盐包括钾盐和钠盐，其钠盐为西格列他钠，所述碱土金属盐包括钙盐和镁盐；所述异构体包括S构型和R构型。
组分(i)是深圳微芯生物科技股份有限公司自主研发的、拥有完全自主知识产权的小分子化合物，其具有优异的降糖降脂活性，组分(i)在中国专利CN1257893C中公开并获得保护，该专利全文被引入本发明中。
组分(ii)钠-葡萄糖转运体-2(SGLT2)是一类新型抗糖尿病药物，其可以抑制肾脏对葡萄糖的重吸收，使过量的葡萄糖从尿液中排出，降低血糖。
优选的，所述组分(ii)钠-葡萄糖转运体-2(SGLT2)抑制剂包括Canagliflozin(坎格列净)、Dapagliflozin(达格列净)、Empagliflozin(恩格列净)、Ipragliflozin或Ipragliflozin L-Proline(依格列净或其与L-脯氨酸的复合物)、Luseogliflozin(鲁格列净)、Tofogliflozin(托格列净)和Ertuglifolzin。
其中，组分(i)和组分(ii)的用量为治疗有效量，组分(i)的用量为1-100mg，优选为12-48mg；组分(ii)的用量为1-500mg，根据具体钠-葡萄糖转运体-2(SGLT2)抑制剂种类的不同而选择相应的治疗有效量，例如，坎格列净的治疗有效量为50-300mg，达格列净的治疗有效量为2.5-10mg，恩格列净的治疗有效量为5-25mg，依格列净L-脯氨酸的治疗有效量为12.5-50mg，鲁格列净的治疗有效量为1.25-5mg，托格列净的治疗有效量为5-20mg，Ertuglifolzin的治疗有效量为2.5-15mg。
另一方面，本发明还提供了一种药物组合物，其包含组分(i)：具有通式(I)所示的化合物及其药用盐，以及它们的异构体，与组分(ii)：钠-葡萄糖转运体-2(SGLT2)抑制剂：
Figure PCTCN2021087266-appb-000003
其中，环A和环B分别为苯环，环上无取代基或有一个或多个取代基，取代基为氟、烷基或烷氧基；
X为共价键、O或S；
R1为H或烷基；
R2为H或烷基；
R3为H或烷基；
R4、R5分别为H或烷基，或R4和R5一起组成苯环，环上无取代基或有 一个或多个取代基，取代基为氟、烷基或烷氧基；
Alk1为C1-6烷撑；
Alk2为C1-2烷撑；
Ar1为苯环，环上无取代基或有一个或多个取代基，取代基为氟、烷基或烷氧基；
Ar2为苯环或吡啶环，环上无取代基或有一个或多个取代基，取代基为氟、烷基或烷氧基。
优选的，所述组分(i)为具有式(II)所示结构的化合物及其药用盐，以及它们的异构体：
Figure PCTCN2021087266-appb-000004
其中，所述药用盐包括碱金属盐、碱土金属盐、铵盐和N+(C1-4烷基)4的盐，所述碱金属盐包括钾盐和钠盐，所述碱土金属盐包括钙盐和镁盐，所述异构体包括S构型和R构型。
优选的，所述组分(ii)钠-葡萄糖转运体-2(SGLT2)抑制剂包括Canagliflozin(坎格列净)、Dapagliflozin(达格列净)、Empagliflozin(恩格列净)、Ipragliflozin或Ipragliflozin L-Proline(依格列净或其与L-脯氨酸的复合物)、Luseogliflozin(鲁格列净)、Tofogliflozin(托格列净)和Ertuglifolzin。
其中，组分(i)和组分(ii)的用量为治疗有效量，组分(i)的用量 为1-100mg，优选为12-48mg；组分(ii)的用量为1-500mg，根据具体钠-葡萄糖转运体-2(SGLT2)抑制剂种类的不同而选择相应的治疗有效量，例如，坎格列净的治疗有效量为50-300mg，达格列净的治疗有效量为2.5-10mg，恩格列净的治疗有效量为5-25mg，依格列净L-脯氨酸的治疗有效量为12.5-50mg，鲁格列净的治疗有效量为1.25-5mg，托格列净的治疗有效量为5-20mg，Ertuglifolzin的治疗有效量为2.5-15mg。
第三方面，本发明提供了一种复方药物，其包含前述的药物组合物，以及一种或多种可药用的赋型剂或载体。
本发明的复方药物可以采用本领域一般方法制备成固体制剂或液体制剂，固体制剂包括片剂、胶囊、颗粒剂、丸剂、散剂、栓剂等。
合适的可药用的赋形剂或载体的种类包括但不限于：稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、造粒剂、包衣剂、润湿剂、溶剂、共溶剂、助悬剂、乳化剂、甜味剂、矫味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、塑化剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂等等。
合适的可药用的赋形剂或载体的实例包括但不限于：乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、西黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、甲基纤维素、水、糖浆、滑石粉、硬脂酸镁、矿物油、羟基苯甲酸甲酯和羟基苯甲酸丙酯等等。
第四方面，本发明提供了一种药盒，其包含前述的药物组合物，所述组分(i)和组分(ii)为分别具有相同或不同规格的单位制剂，可分别置于单独容器中提供。
第五方面，本发明还提供了一种预防和/或治疗糖尿病和/或糖尿病并发症包括心脑血管疾病、肾病、肝脏疾病的方法，其包括给与治疗有效量的前述药物组合物、复方药物或者药盒的步骤。
本发明的有益效果：
本发明在瘦素受体基因敲除的糖尿病小鼠品系BKS-Leprem2Cd479/Nju(也称db/db小鼠)中联合应用西格列他钠和SGLT2抑制剂(恩格列净或达格列净)两周，检测联合用药组相比单药组或溶媒组在血糖和血脂指标上的改变。结果显示，西格列他钠联合SGLT2抑制剂能够协同降低db/db糖尿病小鼠的血糖，也能缓解西格列他钠引起的体重上升，产生了预料不到的协同作用。同时，西格列他钠联合SGLT2抑制剂也能带来血脂指标的改善，特别是改善血清中甘油三脂的含量。
西格列他钠是一种PPARα/γ/δ受体全激动剂，能够增敏胰岛素，降低血糖和部分改善血脂；SGLT2抑制剂可以抑制肾脏对葡萄糖的重吸收，使过量的葡萄糖从尿液中排出，降低血糖，也能有效减轻体重。联合西格列他钠和SGLT2抑制剂机理上的受益包括至少以下三个方面：(1)SGLT2抑制剂减少体内对葡萄糖的吸收，西格列他钠增加胰岛素的敏感性，从不同途径降低血糖，达到了协同作用。(2)西格列他钠能改善血脂，有治疗相关代谢疾病的潜力，而SGLT2抑制剂的减重作用也有益于代谢，达到了改善代谢疾病的协同作用。(3)SGLT2抑制剂的减重作用可以抵消西格列他钠部分增重副作用，使有肥胖并发症的糖尿病病人受益。
过氧化物酶增殖体活化受体(PPAR)激动剂具有改善胰岛素抵抗、防止新发糖尿病风险、以及心血管保护作用，而钠-葡萄糖转运体-2(SGLT2)抑制剂 具有心血管疾病和肾病获益。本发明采用的组分(i)为PPAR全激动剂药物，临床研究显示其在糖尿病患者中具有降低血糖和改善血脂的疗效，还具有减少系统炎症的作用和一定的肝肾保护效应，但是具有一定的体重增加作用；而SGLT2抑制剂在糖尿病患者中具有降低血糖、血压、体重的疗效，从而带来肾功能及心血管保护。由此可知，两类药物的联合除了更有效地降低血糖之外，还能在体重控制、血脂、血压、肝肾保护等方面产生综合效应，从而对糖尿病及其并发症包括心脑血管疾病、肾病和肝脏疾病的预防和/或治疗带来更多获益。
附图说明
图1显示西格列他钠联合恩格列净相比单独治疗对体重和血糖的影响。
图2显示西格列他钠联合达格列净相比单独治疗对体重和血糖的影响。
图3显示西格列他钠联合恩格列净对血脂的影响。
图4显示西格列他钠联合达格列净对血脂的影响。
具体实施方式
本发明公开了用于糖尿病及其并发症治疗的联合用药及其药物组合物，本领域技术人员可以借鉴本文内容，适当替换或改动实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说都是显而易见的，它们都被视为包括在本发明内。本发明所述应用已经通过优选实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述应用进行改动或适当变更与组合，来实现和应用本发明技术。
以下进一步通过非限制性实例来说明本发明，其不旨在限制本发明所涵盖的范围。
除非另有定义，否则本文中使用的所有技术和科学术语均具有与本领域一 般技术人员通常所理解的含义相同的含义。
实施例1 比较西格列他钠联合恩格列净相比单独治疗对体重和血糖的影响
试验设计：在糖尿病小鼠中口服西格列他钠、恩格列净或两者联合，考察单药和药物联合对小鼠体重和血糖的影响。
试验过程：6周大小的db/db雄性小鼠分别按体重每天一次口服100微升溶媒(0.1％羧甲基纤维素钠)、10毫克/千克西格列他钠、3毫克/千克恩格列净或同时口服相同剂量的西格列他钠和恩格列净。野生型C57BLKS/Jnju小鼠作为正常对照小鼠(给予溶媒)。给药周期为14天，第15天处理解剖动物。从给药开始，每3天称量一次小鼠体重和测量空腹血糖(禁食4-6小时)。试验结果如图1所示。
结果显示，西格列他钠和恩格列净单用均能在一定程度上降低血糖，两者联用产生了预料不到的协同作用，一方面能够缓解西格列他钠引起的体重上升，另一方面降低血糖效果更佳，降至接近正常对照组水平。
实施例2 比较西格列他钠联合达格列净相比单独治疗对体重和血糖的影响
试验设计：在糖尿病小鼠中口服西格列他钠、达格列净或两者联合，考察单药和药物联合对小鼠体重和血糖的影响。
试验过程：6周大小的db/db雄性小鼠分别按体重每天一次口服100微升溶媒(0.1％羧甲基纤维素钠)、10毫克/千克西格列他钠、1.5毫克/千克达格列净或同时口服相同剂量的西格列他钠和达格列净。野生型C57BLKS/Jnju小鼠作为正常对照小鼠(给予溶媒)。给药周期为14天，第15天处理解剖动物。从给药开始，每3天称量一次小鼠体重和测量空腹血糖(禁食4-6小时)。试验结果如图2所示。
结果显示，西格列他钠和达格列净单用均能在一定程度上降低血糖，两者联用产生了预料不到的协同作用，一方面能够缓解西格列他钠引起的体重上升，另一方面降低血糖效果更佳，降至正常对照组水平。
实施例3 西格列他钠联合恩格列净对血脂的影响
试验设计：在糖尿病小鼠中口服西格列他钠、恩格列净或两者联合，考察单药和药物联合对小鼠血清中总胆固醇(TC)和甘油三酯(TG)的影响。
试验过程：6周大小的db/db雄性小鼠分别按体重每天一次口服100微升溶媒(0.1％羧甲基纤维素钠)、10毫克/千克西格列他钠、3毫克/千克恩格列净或同时口服相同剂量的西格列他钠和恩格列净。野生型C57BLKS/Jnju小鼠作为正常对照小鼠(给予溶媒)。给药周期为14天，第15天处理解剖动物。采全血，离心收集血清，通过生化仪测量血清的TC和TG。试验结果如图3所示。
结果显示，西格列他钠和恩格列净单用均能在一定程度上降低血清中总胆固醇和甘油三酯的含量，其中西格列他钠效果相对较好，两者联用血清中总胆固醇和甘油三酯的含量的降低效果更佳，产生了协同作用。
实施例4 西格列他钠联合达格列净对血脂的影响
试验设计：在糖尿病小鼠中口服西格列他钠、达格列净或两者联合，考察单药和药物联合对小鼠血清中总胆固醇(TC)和甘油三酯(TG)的影响。
试验过程：6周大小的db/db雄性小鼠分别按体重每天一次口服100微升溶媒(0.1％羧甲基纤维素钠)、10毫克/千克西格列他钠、1.5毫克/千克达格列净或同时口服相同剂量的西格列他钠和达格列净。野生型C57BLKS/Jnju小鼠作为正常对照小鼠(给予溶媒)。给药周期为14天，第15天处理解剖动物。采全血， 离心收集血清，通过生化仪测量血清的TC和TG。试验结果如图4所示。
结果显示，西格列他钠和达格列净单用均能在一定程度上降低血清中总胆固醇和甘油三酯的含量，其中西格列他钠效果相对较好，而两者联用血清中总胆固醇和甘油三酯的含量的降低效果更佳，产生了协同作用。
本发明通过实施例1-4验证了西格列他钠联合SGLT2抑制剂恩格列净或达格列净能够协同降低db/db糖尿病小鼠的血糖，也能缓解西格列他钠引起的体重上升，产生了预料不到的协同作用。同时，西格列他钠联合SGLT2抑制剂也能带来血脂指标的改善，特别是改善血清中甘油三脂的含量。西格列他钠是一种过氧化物酶增殖体活化受体(PPAR)激动剂，过氧化物酶增殖体活化受体(PPAR)激动剂具有改善胰岛素抵抗、防止新发糖尿病风险、以及心血管保护作用，而钠-葡萄糖转运体-2(SGLT2)抑制剂具有心血管疾病和肾病获益。临床研究显示，西格列他钠在糖尿病患者中具有降低血糖和改善血脂的疗效，还具有减少系统炎症的作用和一定的肝肾保护效应，但是具有一定的体重增加作用；而SGLT2抑制剂在糖尿病患者中具有降低血糖、血压、体重的疗效，从而带来肾功能及心血管保护。由此可知，两类药物的联合除了更有效地降低血糖之外，还能在体重控制、血脂、血压、肝肾保护等方面产生综合效应，从而对糖尿病及其并发症包括心脑血管疾病、肾病和肝脏疾病的预防和/或治疗带来更多获益。
以上对本发明进行了详细的介绍，具体应用了优选实施例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想，包括最佳方式，并且也使得本领域的任何技术人员都能够实践本发明，包括制造和使用，以及实施任何结合的方法。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行 若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。本发明专利保护的范围通过权利要求来限定，并可包括本领域技术人员能够想到的其他实施例。如果这些其他实施例具有不是不同于权利要求文字表述的结构要素，或者如果它们包括与权利要求的文字表述无实质差异的等同结构要素，那么这些其他实施例也应包含在权利要求的范围内。

Claims (15)

  1. 组分(i)：具有通式(I)所示的化合物及其药用盐，以及它们的异构体，与组分(ii)：钠-葡萄糖转运体-2(SGLT2)抑制剂的联合在制备用于预防和/或治疗糖尿病和/或糖尿病并发症的药物中的用途：
    Figure PCTCN2021087266-appb-100001
    其中，环A和环B分别为苯环，环上无取代基或有一个或多个取代基，取代基为氟、烷基或烷氧基；
    X为共价键、O或S；
    R1为H或烷基；
    R2为H或烷基；
    R3为H或烷基；
    R4、R5分别为H或烷基，或R4和R5一起组成苯环，环上无取代基或有一个或多个取代基，取代基为氟、烷基或烷氧基；
    Alk1为C1-6烷撑；
    Alk2为C1-2烷撑；
    Ar1为苯环，环上无取代基或有一个或多个取代基，取代基为氟、烷基或烷氧基；
    Ar2为苯环或吡啶环，环上无取代基或有一个或多个取代基，取代基为氟、烷基或烷氧基。
  2. 根据权利要求1所述的用途，其中所述组分(i)为具有式(II)所示结构的化合物及其药用盐，以及它们的异构体：
    Figure PCTCN2021087266-appb-100002
  3. 根据权利要求1或2所述的用途，其中所述药用盐包括碱金属盐、碱土金属盐、铵盐和N+(C1-4烷基)4的盐，所述碱金属盐包括钾盐和钠盐，所述碱土金属盐包括钙盐和镁盐；所述异构体包括S构型和R构型。
  4. 根据权利要求1-3任一项所述的用途，其中所述组分(ii)钠-葡萄糖转运体-2(SGLT2)抑制剂包括Canagliflozin(坎格列净)、Dapagliflozin(达格列净)、Empagliflozin(恩格列净)、Ipragliflozin或Ipragliflozin L-Proline(依格列净或其与L-脯氨酸的复合物)、Luseogliflozin(鲁格列净)、Tofogliflozin(托格列净)和Ertuglifolzin。
  5. 根据权利要求1-4任一项所述的用途，其中，组分(i)和组分(ii)的用量为治疗有效量，组分(i)的用量为1-100mg，组分(ii)的用量为1-500mg。
  6. 根据权利要求1-5任一项所述的用途，其中所述糖尿病为II型糖尿病，所述糖尿病并发症包括心脑血管疾病、肾病和肝脏疾病。
  7. 一种药物组合物，其特征在于，包含组分(i)：具有通式(I)所示的化合物及其药用盐，以及它们的异构体，与组分(ii)：钠-葡萄糖转运体-2(SGLT2)抑制剂：
    Figure PCTCN2021087266-appb-100003
    其中，环A和环B分别为苯环，环上无取代基或有一个或多个取代基，取代基为氟、烷基或烷氧基；
    X为共价键、O或S；
    R1为H或烷基；
    R2为H或烷基；
    R3为H或烷基；
    R4、R5分别为H或烷基，或R4和R5一起组成苯环，环上无取代基或有一个或多个取代基，取代基为氟、烷基或烷氧基；
    Alk1为C1-6烷撑；
    Alk2为C1-2烷撑；
    Ar1为苯环，环上无取代基或有一个或多个取代基，取代基为氟、烷基或烷氧基；
    Ar2为苯环或吡啶环，环上无取代基或有一个或多个取代基，取代基为氟、烷基或烷氧基。
  8. 根据权利要求7所述的药物组合物，其中所述组分(i)为具有式(II)所示结构的化合物及其药用盐，以及它们的异构体：
    Figure PCTCN2021087266-appb-100004
  9. 根据权利要求7或8所述的药物组合物，其中所述药用盐包括碱金属盐、碱土金属盐、铵盐和N+(C1-4烷基)4的盐，所述碱金属盐包括钾盐和钠盐，所述碱土金属盐包括钙盐和镁盐，所述异构体包括S构型和R构型。
  10. 根据权利要求7-9任一项所述的药物组合物，其中所述组分(ii)钠-葡萄糖转运体-2(SGLT2)抑制剂包括Canagliflozin(坎格列净)、Dapagliflozin(达格列净)、Empagliflozin(恩格列净)、Ipragliflozin或Ipragliflozin L-Proline(依格列净或其与L-脯氨酸的复合物)、Luseogliflozin(鲁格列净)、Tofogliflozin(托格列净)和Ertuglifolzin。
  11. 根据权利要求7-10任一项所述的药物组合物，其中，组分(i)和组分(ii)的用量为治疗有效量，组分(i)的用量为1-100mg；组分(ii)的用量为1-500mg。
  12. 一种复方药物，其特征在于包含权利要求7-11任一项所述的药物组合物，以及一种或多种可药用的赋型剂或载体。
  13. 根据权利要求11的复方药物，其剂型包括片剂、胶囊、颗粒剂、丸剂、散剂和栓剂。
  14. 一种药盒，其特征在于包含权利要求7-11任一项所述的药物组合物。
  15. 根据权利要求14所述的药盒，其特征在于，所述组分(i)和组分(ii) 为分别具有相同或不同规格的单位制剂，可分别置于单独容器中提供。
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