WO2024055932A1 - 氮杂环化合物、其药物组合物和用于预防和/或治疗疾病的用途 - Google Patents

氮杂环化合物、其药物组合物和用于预防和/或治疗疾病的用途 Download PDF

Info

Publication number
WO2024055932A1
WO2024055932A1 PCT/CN2023/118022 CN2023118022W WO2024055932A1 WO 2024055932 A1 WO2024055932 A1 WO 2024055932A1 CN 2023118022 W CN2023118022 W CN 2023118022W WO 2024055932 A1 WO2024055932 A1 WO 2024055932A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
acceptable salt
hydrate
Prior art date
Application number
PCT/CN2023/118022
Other languages
English (en)
French (fr)
Inventor
沈小昆
黄志江
卓朗
Original Assignee
亚宝药业集团股份有限公司
苏州亚宝药物研发有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 亚宝药业集团股份有限公司, 苏州亚宝药物研发有限公司 filed Critical 亚宝药业集团股份有限公司
Publication of WO2024055932A1 publication Critical patent/WO2024055932A1/zh

Links

Classifications

    • 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
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the nitrogen heterocyclic compound, its pharmaceutical composition and uses for preventing and/or treating diseases of the present invention belong to the field of medicine.
  • Type 2 diabetes mellitus is an endocrine disease characterized by relative insulin deficiency due to pancreatic beta cell dysfunction and target organ insulin resistance.
  • Data from the International Diabetes Federation (IDF) show that the incidence of diabetes continues to increase globally, indicating that diabetes is a major global challenge to the health and well-being of individuals, families and society.
  • IDF International Diabetes Federation
  • targets for drugs for the treatment of T2DM have been discovered, the main types being insulin secretion promoters, insulin mimetics and sensitizers, and starch blockers.
  • SGLT1 Sodium/glucose cotransporter 1 (SGLT1) inhibitors are a type of starch blocker. SGLT1 is mainly distributed in the small intestine, with the highest expression in the duodenum and the lowest expression in the ileum. It transports glucose and galactose across the apical membrane, driven by the sodium gradient formed by Na + /K + -ATPase. Compared with healthy controls, patients with type 2 diabetes have higher levels of SGLT1 in duodenal brush border membrane vesicles, which increases glucose uptake. Previous clinical trials have shown that inhibiting SGLT1 in the intestine reduces glucose uptake in the small intestine.
  • SGLT1 inhibitors have shown promising therapeutic effects in diabetes in some preclinical and clinical studies, to date, SGLT1 inhibitors have not been approved by the U.S. Food and Drug Administration (FDA) for the treatment of T2DM. Therefore, more exploration is needed in the application of SGLT1 inhibitors to treat T2DM, especially the dosage, efficacy, safety and/or tolerability need to be taken into consideration at the same time.
  • FDA U.S. Food and Drug Administration
  • the present invention provides a compound selected from the following formula (I), a pharmaceutically acceptable salt of a compound of formula (I), a hydrate of a compound of formula (I) and a pharmaceutically acceptable salt of a compound of formula (I).
  • a compound selected from the following formula (I) a pharmaceutically acceptable salt of a compound of formula (I), a hydrate of a compound of formula (I) and a pharmaceutically acceptable salt of a compound of formula (I).
  • the medicine is used to prevent and/or treat diabetes, postprandial hyperglycemia, postprandial hyperglycemia in people with impaired glucose tolerance, or to control postprandial blood sugar in those in need, or to control postprandial blood sugar in those with impaired glucose tolerance.
  • Diseases or symptoms related to elevated blood sugar levels are used to prevent and/or treat diabetes, postprandial hyperglycemia, postprandial hyperglycemia in people with impaired glucose tolerance, or to control postprandial blood sugar in those in need, or to control postprandial blood sugar in those with impaired glucose tolerance.
  • the "diabetes" is type I or type II diabetes, preferably type II diabetes.
  • diseases or symptoms associated with postprandial blood glucose elevation include, but are not limited to, at least one of cardiovascular diseases such as microvascular complications, atherosclerotic vasculopathy (ASVD), thrombosis, and the like.
  • cardiovascular diseases such as microvascular complications, atherosclerotic vasculopathy (ASVD), thrombosis, and the like.
  • the compound of formula (I), a pharmaceutically acceptable salt of the compound of formula (I), a hydrate of the compound of formula (I) and/or a pharmaceutically acceptable salt of the compound of formula (I) Hydrates of salts may be in their amorphous or polymorphic form.
  • the present invention also provides the above-mentioned compounds of formula (I), pharmaceutically acceptable salts of compounds of formula (I), hydrates of compounds of formula (I) and pharmaceutically acceptable salts of compounds of formula (I). At least one of the hydrates, wherein the compound of formula (I), a pharmaceutically acceptable salt of the compound of formula (I), a hydrate of the compound of formula (I) and a pharmaceutically acceptable salt of the compound of formula (I) At least one of the salt hydrates is used to prevent and/or treat diabetes, postprandial hyperglycemia, postprandial hyperglycemia in patients with impaired glucose tolerance, or to control postprandial blood sugar in those in need, or with For the control of diseases or symptoms associated with postprandial increases in blood sugar.
  • the present invention also provides a composition
  • a composition comprising the above-mentioned compound of formula (I), a pharmaceutically acceptable salt of the compound of formula (I), a hydrate of the compound of formula (I) and a pharmaceutically acceptable salt of the compound of formula (I).
  • acceptable At least one of the salt hydrates, and food (such as low-sugar food); wherein the composition is used to prevent and/or treat diabetes, postprandial hyperglycemia, and postprandial hyperglycemia in patients with impaired glucose tolerance. , or for controlling postprandial blood sugar in those in need, or for controlling diseases or symptoms associated with elevated postprandial blood sugar.
  • the present invention also provides a metabolic composition, comprising the above-mentioned compound of formula (I), a pharmaceutically acceptable salt of the compound of formula (I), a hydrate of the compound of formula (I) and a hydrate of the compound of formula (I).
  • Metabolites of at least one of the hydrates of pharmaceutically acceptable salts wherein the metabolites are metabolites produced by the aforementioned compounds for preventing and/or treating diabetes, especially for preventing and/or treating patients with diabetes. Metabolites produced by diabetic patients with postprandial hyperglycemia.
  • the food refers to a substance that can meet the body's normal physiological and biochemical energy needs and extend normal life span.
  • the food usually contains carbohydrates, fat, protein and/or water.
  • the low-sugar food is selected from foods with low carbohydrate content and/or foods that can lower blood sugar.
  • the foods include but are not limited to cereals, vegetables, fruits, meat, milk, eggs, and foods made from Food and beverages processed from these substances.
  • the metabolite is a postprandial metabolite, such as a postprandial metabolite 0.5-12h, such as 1-6h, exemplarily 2h, 3h, 4h, 5h, 6h.
  • the present invention also provides the compound of formula (I), the pharmaceutically acceptable salt of the compound of formula (I), the hydrate of the compound of formula (I), the hydrate of the pharmaceutically acceptable salt of the compound of formula (I),
  • the present invention also provides a method for preventing and/or treating postprandial hyperglycemia in patients with diabetes, postprandial hyperglycemia, and impaired glucose tolerance, or for controlling postprandial blood sugar of those in need, or for controlling postprandial blood sugar.
  • Methods for diseases or symptoms related to elevated blood sugar including administering to the patient an effective amount or a therapeutically effective amount of the compound of formula (I), a pharmaceutically acceptable salt of the compound of formula (I), or the compound of formula (I).
  • At least one of a hydrate of a compound, a hydrate of a pharmaceutically acceptable salt of a compound of formula (I), or an effective or therapeutically effective amount of a composition as described above is administered to the patient.
  • the present invention also provides a method for preventing and/or treating postprandial hyperglycemia in patients with diabetes, postprandial hyperglycemia, and impaired glucose tolerance, or for controlling postprandial blood sugar of those in need, or for controlling postprandial blood sugar.
  • Methods for diseases or symptoms related to elevated blood sugar including administering an effective amount or a therapeutically effective amount of the drug or the composition.
  • the drug or composition does not cause hypoglycemia when lowering postprandial blood sugar.
  • the daily dosage of the drug or composition is a therapeutically effective amount, such as 0.5-10 mg, such as 0.5-8 mg, preferably 1-4 mg, based on the compound of formula (I).
  • a therapeutically effective amount such as 0.5-10 mg, such as 0.5-8 mg, preferably 1-4 mg, based on the compound of formula (I).
  • Examples thereof can be 0.5mg, 1mg, 1.5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 7mg, 8mg, 9mg, 10mg.
  • the medicament or composition is preferably a pharmaceutical preparation.
  • the composition is a single-dose preparation, wherein the content of the compound of formula (I) in the single-dose preparation is a therapeutically effective amount, such as 0.5-10 mg, such as 0.5-8 mg, such as 1-5 mg, Examples thereof may be 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg.
  • the single dose preparation refers to a unit dose preparation, wherein the compound of formula (I), a pharmaceutically acceptable salt of the compound of formula (I), a hydrate of the compound of formula (I), the compound of formula (I), (I) The hydrate of the pharmaceutically acceptable salt of the compound is loaded in 1 unit package.
  • the composition is a multi-dose preparation, and the multi-dose preparation contains more than 1 unit package, for example, consists of 2 to 10 unit packages, such as 2, 3, 4, 5, 6, 7, 8, Available in packages of 9 or 10 units.
  • the compound of formula (I), the pharmaceutically acceptable salt of the compound of formula (I), the hydrate of the compound of formula (I), and the pharmaceutically acceptable salt of the compound of formula (I) contained in each unit package The content of the hydrates is the same, or the compound of formula (I), the pharmaceutically acceptable salt of the compound of formula (I), the hydrate of the compound of formula (I), the compound of formula (I) contained in at least 2 unit packages
  • the pharmaceutically acceptable salts of the compounds vary in their hydrate content.
  • the medicament or composition may also include pharmaceutically acceptable auxiliary materials, such as carriers or excipients.
  • pharmaceutically acceptable excipients are preferably chemically non-reactive or inert to the active ingredient.
  • the pharmaceutically acceptable excipients are selected from at least one of the following excipients, including but not limited to: fillers, disintegrants, binders, lubricants, surfactants, flavoring agents, wetting agents, etc. Agent, pH regulator, solubilizer or co-solvent, osmotic pressure regulator, etc.
  • the administration route of the drug or composition includes but is not limited to gastrointestinal administration or parenteral administration; wherein the gastrointestinal administration can be oral administration. ;
  • the parenteral administration can be injection administration (such as intravenous injection administration, arterial injection administration, intramuscular injection administration, transdermal administration); injection administration, intradermal injection administration, etc.), vaginal administration or mucosal administration, etc.
  • the route of administration is oral administration.
  • the administration is before a meal.
  • the number of administrations may be once a day, twice a day, three times a day or more to meet the needs of the daily dose.
  • the administration may be a single dose or multiple doses.
  • the administration is twice daily, in the morning and evening.
  • the medicament or composition is a capsule.
  • the contents of the capsule include: a compound of formula (I), a pharmaceutically acceptable salt of a compound of formula (I), a hydrate of a compound of formula (I), and a hydrate of a compound of formula (I). At least one of a pharmaceutically acceptable salt hydrate, a filler, a disintegrant and a lubricant.
  • the filler may be selected from at least one of microcrystalline cellulose, dextrin, lactose, etc.; preferably, it is microcrystalline cellulose.
  • the filler may be a mixture of two or more microcrystalline celluloses.
  • the disintegrant may be selected from at least one of croscarmellose sodium, carboxymethyl starch sodium, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, etc., Preferred is croscarmellose sodium.
  • the lubricant may be selected from at least one of magnesium stearate, micronized silica gel, talc, etc., preferably magnesium stearate.
  • the compound of formula (I), the pharmaceutically acceptable salt of the compound of formula (I), the hydrate of the compound of formula (I) and the pharmaceutically acceptable salt of the compound of formula (I) are The percentage of at least one hydrate in the mass of the content is 0.2-10%, such as 0.4-6%, as examples 0.42%, 0.5%, 1%, 2%, 3%, 4%, 4.17%, 5 %.
  • the filler accounts for 85-98% of the mass of the content, such as 90-97%, as examples, 91%, 92%, 92.5%, 93%, 94%, 95%, 96%, 96.25%, 96.5%.
  • the percentage of the disintegrant in the mass of the content is 1-4%, such as 2-3%, and examples are 1.5%, 2.5%, and 3.5%.
  • the lubricant accounts for 0.3-1.5% of the mass of the content, such as 0.5-1.2%, as examples, 0.6%, 0.7%, 0.8%, 0.83%, 0.9%, 1.0%.
  • the contents of the capsule include: 0.42% of the compound of formula (I), 96.25% of microcrystalline cellulose, 2.5% of croscarmellose sodium, hard Magnesium fatty acid 0.83%;
  • the microcrystalline cellulose consists of two different types of microcrystalline cellulose.
  • the contents of the capsule include: 4.17% of the compound of formula (I), 92.5% of microcrystalline cellulose, 2.5% of croscarmellose sodium, Magnesium stearate 0.83%;
  • the microcrystalline cellulose consists of two different types of microcrystalline cellulose.
  • the capsule further includes a capsule shell.
  • At least one other anti-diabetic compound may also be included in the medicament or composition.
  • the anti-diabetic compound may be selected from at least one of an insulin signaling pathway modulator, a compound affecting dysregulation of hepatic glucose production, an insulin sensitivity enhancer, and an insulin secretion promoter.
  • the anti-diabetic compound can be selected from the group consisting of protein tyrosine phosphatase inhibitors, glutamine-fructose-6-phosphate transamidase inhibitors, glucose-6-phosphatase inhibitors, fructose-1 , 6-bisphosphatase inhibitor, glycogen phosphorylase inhibitor, glucagon receptor antagonist, enolpyruvate phosphate carboxykinase inhibitor, pyruvate dehydrogenase kinase inhibitor, alpha-glucosidase Inhibitors, gastric emptying inhibitors, glucokinase activators, GLP-1 receptor agonists, GLP-2 receptor agonists, UCP modulators, RXR modulators, GSK-3 inhibitors, PPAR modulators, metformin, or At least one of its salts, insulin and ⁇ 2 -adrenergic antagonist.
  • protein tyrosine phosphatase inhibitors glutamine-fructose-6-phosphate transamidas
  • the anti-diabetic compound may be selected from the group consisting of G-retinoid X receptor agonists, ⁇ -3AR agonists, UCP modulators, anti-diabetic thiazolidinediones, and nonglitazone-type PPAR ⁇ agonists at least one of an agent, a PPAR ⁇ /PPAR ⁇ dual agonist, and a vanadium-containing antidiabetic compound.
  • the anti-diabetic compound can be selected from thiazolidinediones or pharmaceutically acceptable salts thereof, such as (S)-((3,4-dihydro-2-(phenyl-methane) base)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione, 5- ⁇ [4-(3-(5-methyl-2-phenyl-4 -azolyl)-1-oxo-propyl)-phenyl]-methyl ⁇ -thiazolidine-2,4-dione, 5- ⁇ [4-(1-methyl-cyclohexyl)methoxy )-phenyl]methyl]-thiazolidine-2,4-dione, 5- ⁇ [4-(2-(1-indolyl)ethoxy)phenyl]methyl ⁇ -thiazolidine-2 ,4-dione, 5- ⁇ 4-[2-(5-methyl-2-phenyl-4-azolyl)-ethoxy)]benzyl, 5-
  • the anti-diabetic compound is selected from one or more sulfonylurea derivatives.
  • the anti-diabetic compound is selected from the group consisting of glyburide, glyburide, glyburide, acetate, chlorpropamide, glyburide, tolbutamide, Tolazamide, glipizide, ambutamide, glazidione, rosiglitazone, glyburide, belbutamide, tolbutamide, glimepiride, gliclazide , ticglitza, moglitza, naglitza, acarbose, voglibose and miglitol, or at least one of the pharmaceutically acceptable salts of the above compounds.
  • the anti-diabetic compound is selected from the group consisting of incretin hormones or mimetics thereof, beta cell imidazoline receptor antagonists, and short-acting insulin secretagogues.
  • the anti-diabetic compound is selected from insulin.
  • the present invention also provides a medicament, preferably a capsule, having a composition as shown above.
  • the medicament (preferably capsule) is used to prevent and/or treat diabetes, postprandial hyperglycemia, postprandial hyperglycemia in patients with impaired glucose tolerance, or to control postprandial hyperglycemia in those in need.
  • Postprandial blood sugar or used to control diseases or symptoms associated with elevated postprandial blood sugar.
  • postprandial hyperglycemia refers to symptoms that occur in people with type 2 diabetes or non-diabetics after a meal, on an empty stomach Blood sugar is normal but elevated after meals.
  • the patient's blood sugar (PG) 1 to 2 hours after eating is >7.8mmol/L.
  • abnormal glucose tolerance refers to patients in the early stage of type 2 diabetes whose 2-hour blood glucose level in the oral 75g glucose tolerance test is 7.8 to 11.0mmol/L.
  • postprandial hyperglycemia in individuals with impaired glucose tolerance refers to symptoms that occur after meals in individuals with impaired glucose tolerance.
  • subject in need refers to a mammal in need of postprandial blood glucose control, such as a pre-diabetic human.
  • the term "effective amount” or “therapeutically effective amount” refers to an amount of a compound of the present invention sufficient to achieve the intended use, including but not limited to the treatment of disease as defined below.
  • the therapeutically effective amount may vary depending on factors such as the intended use (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition and the mode of administration, etc. It can be easily determined by those of ordinary skill in the art.
  • the specific dosage will vary depending on the particular compound selected, the dosing regimen followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system upon which it is administered.
  • patient refers to a patient in need of prevention or treatment of a disease associated with type 2 diabetes, wherein the patient is a mammal, for example selected from the group consisting of rodents, cattle, pigs, dogs, cats and primates, especially humans.
  • the present invention unexpectedly found that the compound of formula (I) and its pharmaceutically acceptable salts, hydrates, or compositions and preparations containing the above compounds can effectively prevent and/or treat diabetes (preferably type 2 diabetes), Postprandial hyperglycemia, or used to control postprandial blood sugar in those in need, or used to control diseases or symptoms related to postprandial blood sugar elevation, especially mild treatment of postprandial hyperglycemia, while lowering blood sugar without Hypoglycemia can occur.
  • diabetes preferably type 2 diabetes
  • Postprandial hyperglycemia or used to control postprandial blood sugar in those in need, or used to control diseases or symptoms related to postprandial blood sugar elevation, especially mild treatment of postprandial hyperglycemia, while lowering blood sugar without Hypoglycemia can occur.
  • the dosage of the present invention is small, and it has achieved significant advantages in terms of medication effectiveness, safety and tolerance for patients.
  • Figure 1 shows the grouping of clinical trials for the treatment of patients with type 2 diabetes
  • Figure 2 shows the trial design of clinical efficacy in treating patients with type 2 diabetes
  • Figure 3 shows the average fasting blood glucose of the experimental group and the placebo group
  • Figure 4 shows the postprandial blood glucose of the experimental group and the placebo group
  • FIG. 5 A is the C-peptide level of the experimental group and the placebo group, B is the insulin level change of the experimental group and the placebo group, C is the GLP-1 level of the experimental group and the placebo group, D is the experimental group and the placebo Group changes in GIP levels.
  • Capsule shell gelatin hollow capsule shell.
  • Capsule shell gelatin hollow capsule shell.
  • the qualifying criteria for screening are: male weight ⁇ 50 kg, and female weight ⁇ 45 kg, body mass index (BMI) 18.0-35.0 kg/m2, glycated hemoglobin (HbA1c) 7.0-9.5%, fasting blood glucose (FBG) 7-13.3 mmol/L (126-239.4 mg/dL).
  • BMI body mass index
  • HbA1c glycated hemoglobin
  • FBG fasting blood glucose
  • test group Example 1 capsules, 1 mg, 2 mg and 4 mg
  • placebo group Figure 1
  • the 1.0 mg test group is divided into two groups: 0.5 mg BID (twice a day) and 1.0 mg QD (once a day); the 2.0 mg test group is divided into two groups: 1.0 mg BID and 2.0 mg QD; the 4.0 mg test group is given 2.0mg BID.
  • the QD group took the experimental drug or placebo before breakfast every day.
  • the BID group was administered immediately before breakfast and dinner.
  • Test drug and placebo were administered orally for 7 consecutive days (from day 1 to day 7). Subjects stayed overnight in the hospital from day 0 to day 8. From day 0 to day 8, monitor the patient's pharmacokinetics and pharmacodynamics (fasting blood glucose, postprandial blood glucose, MMTT test (multi-maneuvering target tracking), C-peptide, insulin, GLP-1 and GIP) and safety indicators. In addition, all subjects were hospitalized from days 0 to 8 and provided with the same T2DM dietary and environmental conditions.
  • plasma samples were collected 10 minutes before dosing to detect FBG ( Figure 2).
  • blood samples were collected on days 0, 1, and 7. After days 0 and 7, at 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 11 hours, 12 hours, 13 hours, 14 hours after the first dose and plasma samples were collected at 21 hours. On day 1, plasma samples were collected at 2, 4, 6, 12 and 14 hours after the first dose.
  • serum samples were collected within 10 minutes before dosing and 2 hours after dosing (days 0, 1, and 7).
  • PD parameters 2-hour postprandial blood glucose elevation, mean blood glucose, and islet function index based on the homeostasis assessment model of islet ⁇ -cell function (HOMA- ⁇ ), homeostasis assessment model of insulin resistance (HOMA-IR), and modified Beta cell function index (MBCI).
  • HOMA- ⁇ homeostasis assessment model of islet ⁇ -cell function
  • HOMA-IR homeostasis assessment model of insulin resistance
  • MBCI modified Beta cell function index
  • Safety assessment includes vital signs, physical examination, 12-lead electrocardiogram, blood routine, urine routine, stool routine, blood biochemistry and coagulation function. All adverse events were recorded from signing of the informed consent form to the end of follow-up.
  • PK parameters were calculated by Phoenix WinNonlin version 8.1 (Certara LP software). Via SAS (9.4 version) to analyze PD parameters and demographics. Continuous variables were described as mean ⁇ standard deviation, and count and categorical variables were described as frequencies and percentages. For PK parameters, the geometric mean, logarithmic standard deviation, and geometric coefficient of variation need to be calculated. Adverse events were coded according to the ICH Medical Dictionary for Regulatory Activities (MEDRA 23.0 or later). A treatment-emergent adverse event (TEAE) was defined as an adverse event that occurred or worsened after receiving the first dose of study drug. The statistics include adverse events that are "definitely related, probably related, and probably not related" to the study drug.
  • TEAE treatment-emergent adverse event
  • Demographic and baseline characteristics are shown in Table 1. All subjects were Han nationality, and the duration of T2DM was ⁇ 3 months.
  • the experimental group (N 40) included 24 males (60.0%) and 16 females (40.0%), with an average age of 52.5 ⁇ 6.16 years, a height of 162.45 ⁇ 7.33 cm, a weight of 66.53 ⁇ 9.780 kg, and a body mass index of 25.11 ⁇ 2.91kg/m2.
  • There were 8 males (80.0%) and 2 females (20.0%) in the placebo group (N 10).
  • the average age was 48.7 ⁇ 9.30 years old, the height was 167.40 ⁇ 8.48 cm, and the weight was 76.89 ⁇ 10.28 kg.
  • the experimental group and the placebo group The average disease durations were 45.80 ⁇ 39.093 and 51.45 ⁇ 72.08 months respectively.
  • FBG Fasting blood glucose
  • the increase in GLP-1 in the test group was significantly higher than that in the placebo group.
  • the increase in GLP-1 after meals was greatest in the group taking 1 mg once a day (D1: 4.43 times; D7: 4.12 times), followed by the group taking 1 mg once a day (D1: 3.26 times; D8: 2.15 times). ).
  • the experimental drug has no effect on FBG, but significantly reduces postprandial blood sugar.
  • QD administration reduced blood glucose after breakfast but had no effect on blood glucose after lunch and dinner.
  • blood glucose was affected after breakfast and dinner, while there was no change in blood glucose after lunch.
  • postprandial blood sugar drops on day 1 and day 7,
  • the daily dose of 2 mg may be the maximum effective dose for clinical administration.
  • the test drug significantly reduced postprandial C-peptide and insulin secretion, stimulated GLP-1 secretion, and simultaneously inhibited GIP secretion.
  • Gastrointestinal disorders are the most common TEAEs in T2DM, including diarrhea, abdominal pain, and bloating.
  • the incidence rate was 92.5% in the test group and 80% in the placebo group. Thirty-five out of 40 subjects (87.5%) in the test group had 68 episodes of diarrhea, and 7 out of 10 subjects (70%) in the placebo group had 12 episodes of diarrhea.
  • the incidence rates of diarrhea for 0.5mg BID, 1.0mg QD, 1.0mg BID, 2.0mg QD and 2.0mg BID were 50.0% (4/8), 87.5% (7/8), 100% (8/8), 100 % (8/8) and 100% (8/8).
  • Two subjects in the 1.0 mg BID group and one subject in the 2.0 mg BID group experienced grade 2 diarrhea, and the remaining patients experienced grade 1 diarrhea. No intervention was performed on diarrheal events during the trial, and all diarrhea resolved spontaneously. In addition, the frequency of diarrhea gradually decreased over time, suggesting that subjects may develop a tolerance to diarrhea while taking the study drug daily.
  • the diagnosis of diarrhea is based on increased frequency of bowel movements or changes in stool consistency.
  • Test drug-induced diarrhea is attributed to changes in intestinal homeostasis caused by accumulation of glucose and Na + in the intestine when SGLT-1 is inhibited.
  • patients had mild diarrhea without obvious symptoms such as dehydration caused by diarrhea. All patients recovered from diarrhea without treatment.
  • test drug was 1.0-4.0 Mild diarrhea was induced across the mg dose range, which is consistent with Shin Fukudo's study that SGLT1 inhibitors caused diarrhea in the first week after dosing.
  • SGLT1 inhibition leads to a significant increase in fluid entry into the colon
  • SGLT2 inhibition leads to glucose malabsorption in the ascending colon, thereby altering the microenvironment, thereby distending the colon and inducing a propulsive colonic motility pattern
  • Glucose in the colon can also activate enterochromaffin cells to release 5-hydroxytryptamine, which will intensify colon motility and lead to relaxation. Therefore, the experimental drug may help improve chronic constipation symptoms in people with diabetes.
  • the experimental drug acts locally on the intestine, inhibits intestinal SGLT1 activity in the dose range of 1.0-4.0 mg, and significantly reduces postprandial blood sugar, C-peptide and insulin levels. It has been shown to be relatively safe and tolerable in Chinese T2DM patients.

Abstract

一种氮杂环化合物、其组合物和用于预防和/或治疗疾病的用途。式（I）化合物、式（I）化合物的药学上可接受的盐、式（I）化合物的水合物和式（I）化合物的药学上可接受的盐的水合物中的至少一种用于制备药物的用途：其中，所述药物用于预防和/或治疗糖尿病、餐后高血糖症、糖耐量低减者的餐后高血糖症，糖耐量低减者的餐后高血糖、或用于控制有需要者的餐后血糖，或用于控制与餐后血糖升高相关的疾病或症状。尤其是温和治疗餐后高血糖症，在降低血糖的同时不会出现低血糖。给药剂量小，在患者的用药有效性、安全性和耐受性方面取得了显著的优势。

Description

氮杂环化合物、其药物组合物和用于预防和/或治疗疾病的用途
本申请要求申请人于2022年9月13日向中国国家知识产权局提交的专利申请号为202211112296.7，发明名称为“氮杂环化合物、其药物组合物和用于预防和/或治疗疾病的用途”的在先申请的优先权。所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明氮杂环化合物、其药物组合物和用于预防和/或治疗疾病的用途，属于医药领域。
背景技术
2型糖尿病(T2DM)是一种内分泌疾病，其特征是由于胰岛β细胞功能障碍和靶器官胰岛素抵抗而导致相对胰岛素缺乏。来自国际糖尿病联合会(IDF)的数据显示，糖尿病的发病率在全球范围内持续上升，表明糖尿病是对个人、家庭和社会健康和福祉的重大全球性挑战。在过去的几十年中，已经发现了用于治疗T2DM的药物的几个靶点，主要类型是胰岛素分泌促进剂、胰岛素模拟物和敏化剂以及淀粉阻滞剂。
钠/葡萄糖共转运蛋白1(SGLT1)抑制剂是淀粉阻滞剂的一种。SGLT1主要分布于小肠，在十二指肠表达最高，回肠表达最低。它在Na+/K+-ATP酶形成的钠梯度的驱动下，通过顶膜运输葡萄糖和半乳糖。与健康对照组相比，2型糖尿病患者十二指肠刷状缘膜囊泡中SGLT1含量更高，这增加了葡萄糖摄取。先前的临床试验表明，抑制肠道中的SGLT1可减少小肠的葡萄糖摄取。索他格列嗪(Zynquista)是第一种SGLT1/2双抑制剂，已于2019年4月被欧洲药物管理局(EMA)批准作为T1DM患者胰岛素的辅助药物，然而其临床试验中显示在降低血糖的同时会发生严重低血糖事件。尽管SGLT1抑制剂在一些临床前和临床研究中显示出对糖尿病的良好治疗效果，但迄今为止，美国食品和药物管理局(FDA)尚未批准SGLT1抑制剂用于治疗T2DM。因此，在应用SGLT1抑制剂治疗T2DM方面需要更多的探索，尤其是需要同时兼顾给药量、有效性、安全性和/或耐受性。
发明内容
为了改善上述技术问题，本发明提供选自如下式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物和式(I)化合物的药学上可接受的盐的水合物中的至少一种用于制备药物的用途：
其中，所述药物用于预防和/或治疗糖尿病、餐后高血糖症，糖耐量低减者的餐后高血糖症，或用于控制有需要者的餐后血糖，或用于控制与餐后血糖升高相关的疾病或症状。
根据本发明的实施方案，所述“糖尿病”为I型或II型糖尿病，优选II型糖尿病。
根据本发明的实施方案，与餐后血糖升高相关的疾病或症状包括但不限于心血管疾病如微血管并发症、动脉粥样硬化性血管病(ASVD)、血栓等中的至少一种。
根据本发明的实施方案，所述式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物和/或式(I)化合物的药学上可接受的盐的水合物可以为其无定型物或多晶型物。
本发明还提供上文所述的式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物和式(I)化合物的药学上可接受的盐的水合物中的至少一种，其中所述式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物和式(I)化合物的药学上可接受的盐的水合物中的至少一种用于预防和/或治疗糖尿病、餐后高血糖症、糖耐量低减者的餐后高血糖症，或用于控制有需要者的餐后血糖，或用于控制与餐后血糖升高相关的疾病或症状。
本发明还提供一种组合物，包含上文所述的式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物和式(I)化合物的药学上可接受 的盐的水合物中的至少一种，以及食物(如低糖食物)；其中所述组合物用于预防和/或治疗糖尿病、餐后高血糖症、糖耐量低减者的餐后高血糖症，或用于控制有需要者的餐后血糖，或用于控制与餐后血糖升高相关的疾病或症状。
本发明还提供一种代谢组合物，包含上文所述的式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物和式(I)化合物的药学上可接受的盐的水合物中的至少一种的代谢物；其中所述代谢物为前述化合物用于预防和/或治疗糖尿病产生的代谢物，特别是用于预防和/或治疗患有餐后高血糖症的糖尿病患者产生的代谢物。
根据本发明的实施方案，所述食物是指是指能够满足机体正常生理和生化能量需求，并能延续正常寿命的物质。所述食物通常包含碳水化合物、脂肪、蛋白质和/或水。
根据本发明的实施方案，所述低糖食物选自糖类物质含量低的食物和/或能够降低血糖的食物，所述食物包括但不限于谷物、蔬菜、水果、肉、奶、蛋、以及由这些物质加工形成的餐饮。
根据本发明的实施方案，所述代谢物为餐后代谢物，例如餐后0.5-12h，比如1-6h，示例性2h、3h、4h、5h、6h的代谢物。
本发明还提供所述式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物、式(I)化合物的药学上可接受的盐的水合物、所述药物或所述组合物的用途，其用于预防和/或治疗糖尿病、餐后高血糖症、糖耐量低减者的餐后高血糖症，或用于控制有需要者的餐后血糖，或用于控制与餐后血糖升高相关的疾病或症状。
本发明还提供一种预防和/或治疗糖尿病、餐后高血糖症、糖耐量低减者的餐后高血糖症，或用于控制有需要者的餐后血糖，或用于控制与餐后血糖升高相关的疾病或症状的方法，包括向患者给予有效量或治疗有效量的上文所述的式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物、式(I)化合物的药学上可接受的盐的水合物中的至少一种，或者向患者给予有效量或治疗有效量的上文所述的组合物。
本发明还提供一种预防和/或治疗糖尿病、餐后高血糖症、糖耐量低减者的餐后高血糖症，或用于控制有需要者的餐后血糖，或用于控制与餐后血糖升高相关的疾病或症状的方法，包括向患者给予有效量或治疗有效量的所述药物或所 述组合物。
根据本发明的实施方案，所述药物或组合物在降低餐后血糖时，不会造成低血糖。
根据本发明的实施方案，以式(I)化合物计，所述药物或组合物的给药日剂量为治疗有效量的，例如0.5-10mg，又如0.5-8mg，优选1-4mg，其实例可以为0.5mg、1mg、1.5mg、2mg、2.5mg、3mg、3.5mg、4mg、4.5mg、5mg、5.5mg、6mg、7mg、8mg、9mg、10mg。
根据本发明的实施方案，所述药物或组合物优选为药物制剂。
例如，所述组合物为单剂量制剂，其中所述单剂量制剂中，以式(I)化合物计的含量为治疗有效量的，例如0.5-10mg，又如0.5-8mg，例如1-5mg，其实例可以为0.5mg、1mg、1.5mg、2mg、2.5mg、3mg、3.5mg、4mg、4.5mg、5mg、5.5mg、6mg、7mg、8mg、9mg、10mg。
根据本发明的实施方案，所述单剂量制剂是指单位剂量制剂，其中所述式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物、式(I)化合物的药学上可接受的盐的水合物装载于1个单元包装之内。
例如，所述组合物为多剂量制剂，所述多剂量制剂包含多于1个单元包装，例如由2至10个单元包装组成，如由2、3、4、5、6、7、8、9或10个单元包装组成。其中，各单元包装中包含的所述式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物、式(I)化合物的药学上可接受的盐的水合物的含量相同，或者至少2个单元包装中包含的所述式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物、式(I)化合物的药学上可接受的盐的水合物的含量不相同。
根据本发明的实施方案，所述药物或组合物还可以包含药学上可接受的辅料，如载体或赋形剂。所述药学上可接受的辅料优选为对活性成分无化学反应性或呈惰性的。例如，所述药用辅料药学上可接受的辅料选自包括但不限于下列辅料中的至少一种：填充剂、崩解剂、粘合剂、润滑剂、表面活性剂、矫味剂、湿润剂、pH调节剂、增溶剂或助溶剂、渗透压调节剂等。
根据本发明的一种实施方案，所述药物或组合物的给药途径包括但不限于胃肠道给药或非胃肠道给药；其中，所述胃肠道给药可以为口服给药；所述非胃肠道给药可以为注射给药(如静脉注射给药、动脉注射给药、肌内注射给药、皮 下注射给药、皮内注射给药等)、阴道给药或粘膜给药等。
在一种实施方案中，所述给药途径为口服给药。
根据本发明的实施方案，所述给药为餐前给药。
根据本发明的实施方案，给药次数可以为一日一次、一日两次、一日三次或更多次，以符合所述日剂量的需要。
根据本发明的实施方案，所述给药可以为单次剂量给药或多次剂量给药。
在一种实施方案中，给药次数一日两次，即早晚给药。
根据本发明的实施方案，所述药物或组合物为胶囊剂。
根据本发明的实施方案，所述胶囊剂的内容物包含：式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物和式(I)化合物的药学上可接受的盐的水合物中的至少一种，填充剂、崩解剂和润滑剂。
根据本发明的实施方案，所述填充剂可以选自微晶纤维素、糊精和乳糖等中的至少一种；优选为微晶纤维素。作为示例，所述填充剂可以为两种或两种以上微晶纤维素的混合物。
根据本发明的实施方案，所述崩解剂可以选自交联羧甲基纤维素钠、羧甲基淀粉钠、交联聚乙烯吡咯烷酮和低取代羟丙基纤维素等中的至少一种，优选为交联羧甲基纤维素钠。
根据本发明的实施方案，所述润滑剂可以选自硬脂酸镁、微粉硅胶和滑石粉等中的至少一种，优选为硬脂酸镁。
根据本发明的实施方案，所述式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物和式(I)化合物的药学上可接受的盐的水合物中的至少一种占内容物质量的百分比为0.2-10％，例如0.4-6％，作为示例为0.42％、0.5％、1％、2％、3％、4％、4.17％、5％。
根据本发明的实施方案，所述填充剂占内容物质量的百分比为85-98％，例如90-97％，作为示例为91％、92％、92.5％、93％、94％、95％、96％、96.25％、96.5％。
根据本发明的实施方案，所述崩解剂占内容物质量的百分比为1-4％，例如2-3％，作为示例为1.5％、2.5％、3.5％。
根据本发明的实施方案，所述润滑剂占内容物质量的百分比为0.3-1.5％，例如0.5-1.2％，作为示例为0.6％、0.7％、0.8％、0.83％、0.9％、1.0％。
根据本发明的一种实施方案，以质量百分比计，所述胶囊剂的内容物包含：式(I)化合物0.42％、微晶纤维素96.25％、交联羧甲基纤维素钠2.5％、硬脂酸镁0.83％；
优选地，所述微晶纤维素由两种不同型号的微晶纤维素组成。
根据本发明的另一种实施方案，以质量百分比计，所述胶囊剂的内容物包含：式(I)化合物4.17％、微晶纤维素92.5％、交联羧甲基纤维素钠2.5％、硬脂酸镁0.83％；
优选地，所述微晶纤维素由两种不同型号的微晶纤维素组成。
根据本发明的实施方案，所述胶囊剂还包括胶囊壳。
根据本发明的实施方案，所述药物或组合物中还可以包含至少另一种抗糖尿病化合物。
根据本发明的实施方案，所述抗糖尿病化合物可以选自胰岛素信号传导途径调节剂、影响肝葡萄糖产生调节异常的化合物、胰岛素敏感性增强剂和胰岛素分泌促进剂中的至少一种。
一种实施方式中，所述抗糖尿病化合物可以选自蛋白质酪氨酸磷酸酶抑制剂、谷氨酰胺-果糖-6-磷酸转酰胺酶抑制剂、葡萄糖-6-磷酸酶抑制剂、果糖-1,6-二磷酸酶抑制剂、糖原磷酸化酶抑制剂、胰高血糖素受体拮抗剂、烯醇丙酮酸磷酸羧激酶抑制剂、丙酮酸脱氢酶激酶抑制剂、α-葡萄糖苷酶抑制剂、胃排空抑制剂、葡萄糖激酶活化剂、GLP-1受体激动剂、GLP-2受体激动剂、UCP调节剂、RXR调节剂、GSK-3抑制剂、PPAR调节剂、二甲双胍或其盐、胰岛素和α2-肾上腺素能拮抗剂中的至少一种。
一种实施方式中，所述抗糖尿病化合物可以选自G类视黄醇X受体激动剂、β-3AR激动剂、UCP调节剂、抗糖尿病噻唑烷二酮类、非格列酮型PPARγ激动剂、PPARγ/PPARα双重激动剂和含钒的抗糖尿病化合物中的至少一种。
一种实施方式中，所述抗糖尿病化合物可以选自噻唑烷二酮类化合物或其药学上可接受的盐，例如(S)-((3,4-二氢-2-(苯基-甲基)-2H-1-苯并吡喃-6-基)甲基-噻唑烷-2,4-二酮、5-{[4-(3-(5-甲基-2-苯基-4-唑基)-1-氧代-丙基)-苯基]-甲基}-噻唑烷-2,4-二酮、5-{[4-(1-甲基-环己基)甲氧基)-苯基]甲基]-噻唑烷-2,4-二酮、5-{[4-(2-(1-吲哚基)乙氧基)苯基]甲基}-噻唑烷-2,4-二酮、5-{4-[2-(5-甲基-2-苯基-4-唑基)-乙氧基)]苄基}-噻唑烷-2,4-二酮、5-(2-萘磺酰基)-噻唑烷-2,4-二酮、双 {4-[(2,4-二氧代-5-噻唑烷基)-甲基]苯基}甲烷、5-{4-[2-(5-甲基-2-苯基-4-唑基)-2-羟基乙氧基]-苄基}-噻唑烷-2,4-二酮、5-[4-(1-苯基-1-环丙烷羰基氨基)-苄基]-噻唑烷-2,4-二酮、5-{[4-(2-(2,3-二氢吲哚-1-基)乙氧基)苯基甲基)-噻唑烷-2,4-二酮、5-[3-(4-氯-苯基])-2-丙炔基]-5-苯磺酰基)噻唑烷-2,4-二酮、5-[3-(4-氯苯基])-2-丙炔基]-5-(4-氟苯基-磺酰基)噻唑烷-2,4-二酮、5-{[4-(2-(甲基-2-吡啶基-氨基)-乙氧基)苯基]甲基}-噻唑烷-2,4-二酮、5-{[4-(2-(5-乙基-2-吡啶基)乙氧基)苯基]-甲基}-噻唑烷-2,4-二酮、5-{[4-((3,4-二氢-6-羟基-2,5,7,8-四甲基-2H-1-苯并吡喃-2-基)甲氧基)-苯基]-甲基)-噻唑烷-2,4-二酮、5-[6-(2-氟-苄氧基)-萘-2-基甲基]-噻唑烷-2,4-二酮、5-([2-(2-萘基)-苯并唑-5-基]-甲基}噻唑烷-2,4-二酮和5-(2,4-二氧代噻唑烷-5-基甲基)-2-甲氧基-N-(4-三氟甲基-苄基)苯甲酰胺中的至少一种。
一种实施方式中，所述抗糖尿病化合物选自一种或多种磺酰脲衍生物。
一种实施方式中，所述抗糖尿病化合物选自选自格列派特、格列本脲、格列本脲、醋磺己脲、氯磺丙脲、格列波脲、甲苯磺丁脲、妥拉磺脲、格列吡嗪、氨磺丁脲、格列喹酮、罗格列酮、格列己脲、苯磺丁脲、甲磺环己脲、格列美脲、格列齐特、替格列扎、莫格列扎、那格列扎、阿卡波糖、伏格列波糖和米格列醇，或以上化合物的药学上可接受的盐中的至少一种。
一种实施方式中，所述抗糖尿病化合物选自肠降血糖素激素或其模拟物、β细胞咪唑啉受体拮抗剂和短效胰岛素促泌素。
一种实施方式中，所述抗糖尿病化合物选自胰岛素。
本发明还提供一种药物，优选为胶囊剂，其具有如上文所示的组成。
根据本发明的实施方案，所述药物(优选胶囊剂)用于预防和/或治疗糖尿病、餐后高血糖症、糖耐量低减者的餐后高血糖症，或用于控制有需要者的餐后血糖，或用于控制与餐后血糖升高相关的疾病或症状。
术语定义和说明
除非另有说明，本申请说明书和权利要求书中记载的术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合应当属于本申请说明书记载的范围内。
术语“餐后高血糖症”为2型糖尿病患者或非糖尿病人餐后出现的症状，空腹 血糖正常但餐后血糖升高，患者摄食后1～2h的血糖(PG)>7.8mmol/L。
术语“糖耐量低减者”为2型糖尿病早期的患者，口服75g葡萄糖耐受量测试中2小时血糖水平为7.8～11.0mmol/L。
术语“糖耐量低减者的餐后高血糖症”为糖耐量低减者餐后出现的症状。
术语所述“有需要者”是指需要控制餐后血糖的哺乳动物，例如处于糖尿病前期的人。
术语“有效量”或者“治疗有效量”是指足以实现预期应用(包括但不限于如下定义的疾病治疗)的本发明所述化合物的量。治疗有效量可以取决于以下因素而改变：预期应用(体外或者体内)，或者所治疗的受试者和疾病病症如受试者的重量和年龄、疾病病症的严重性和给药方式等，其可以由本领域普通技术人员容易地确定。具体剂量将取决于以下因素而改变：所选择的特定化合物、所依据的给药方案、是否与其它化合物组合给药、给药的时间安排、所给药的组织和所承载的物理递送系统。
术语“患者”是指需要定预防或治疗与2型糖尿病相关的疾病的患者，其中患者为哺乳动物，例如选自啮齿类、牛、猪、狗、猫和灵长类动物，特别是人。
有益效果
本发明出人预料地发现，式(I)化合物及其药学上可接受的盐、水合物、或含有以上化合物的组合物、制剂，能够有效预防和/或治疗糖尿病(优选2型糖尿病)、餐后高血糖症，或用于控制有需要者的餐后血糖，或用于控制与餐后血糖升高相关的疾病或症状，尤其是温和治疗餐后高血糖症，在降低血糖的同时不会出现低血糖。本发明的给药剂量小，在患者的用药有效性、安全性和耐受性方面取得了显著的优势。
附图说明
图1为治疗2型糖尿病患者临床试验的分组情况；
图2为治疗2型糖尿病患者临床疗效的试验设计；
图3为试验组和安慰剂组的平均空腹血糖；
图4为试验组和安慰剂组的餐后血糖；
图5：A为试验组和安慰剂组的C肽水平，B为试验组和安慰剂组的胰岛素水平变化，C为试验组和安慰剂组的GLP-1水平，D为试验组和安慰剂组的GIP水平变化。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实施例1
胶囊剂：
内容物：式(I)化合物0.50mg，微晶纤维素PH302 86.62mg，微晶纤维素28.88mg，交联羧甲基纤维素钠3.00mg，硬脂酸镁1.00mg；
胶囊壳：明胶空心胶囊壳。
实施例2
胶囊剂：
内容物：式(I)化合物5.00mg，微晶纤维素PH302 83.25mg，微晶纤维素27.75mg，交联羧甲基纤维素钠3.00mg，硬脂酸镁1.00mg；
胶囊壳：明胶空心胶囊壳。
临床试验
一、研究方法
受试者包括50名18至65岁的患者。患者被诊断为2型糖尿病超过3个月，且未接受系统治疗。筛选的合格标准为：男性体重≥50公斤，和女性体重≥45千克，体重指数(BMI)为18.0-35.0千克/平方米，糖化血红蛋白(HbA1c)为7.0-9.5％，空腹血糖(FBG)为7-13.3毫摩尔/升(126-239.4毫克/分升)。如果受试者在1年内使用过SGLT1或SGLT2抑制剂，或有任何并发症，包括明显的血液学疾病、自主神经病变、严重的慢性胃肠道疾病、不稳定的甲状腺功能障碍、心脏病、传染病和糖尿病的急性代谢并发症，则被排除在外。
筛选出的受试者被随机分为试验组(实施例1胶囊剂，1mg、2mg和4mg)和安慰剂组(图1)。1.0mg试验组分为两组：0.5mg BID(每日两次)和1.0mg QD(每日一次)；2.0mg试验组分为两组：1.0mg BID和2.0mg QD；4.0mg试验组给予2.0mg BID。每个给药组由10名患者组成，随机分配接受试验药物(N＝8)或 安慰剂(即Placebo)(N＝2)。
QD组每天早餐前服用试验药物或安慰剂。BID组是在早餐和晚餐前立即进行的。
试验药物和安慰剂连续7天口服给药(从第1天到第7天)。受试者从第0天到第8天在医院过夜。从第0天至第8天，监测患者的药代动力学、药效学(空腹血糖、、餐后血糖、MMTT试验(multi-maneuvering target tracking)、C肽、胰岛素、GLP-1和GIP)以及安全性指标。此外，所有受试者在第0天至第8日住院，提供相同的T2DM饮食和环境条件。
药代动力学(PK)评估
对于PK评估，在第0天和第7天给药前10分钟、给药后10分钟、0.5小时、1小时、2小时和4小时采集血液。计算了以下参数：稳态峰值浓度(Cmax，ss)、稳态峰值时间(Tmax，ss)，稳态终端消除半衰期(T1/2，ss)，药时曲线下面积(AUC0- t，ss)，药时曲线下总面积(AUC0-∞,ss)，AUC0-∞的外推百分比(％AUCex)、累积比(RAUC、RCmax)和稳定谷浓度(Ctrough、ss)。
药效学(PD)评估
从第0天到第8天，在给药前10分钟采集血浆样本以检测FBG(图2)。对于MMTT，在第0天、第1天和第7天采集血样。在第0和第7天后，在第一次给药后0.5小时、1小时、2小时、3小时、4小时、5小时、6小时、7小时、11小时、12小时、13小时、14小时和21小时采集血浆样本。第1天，在第一次给药后2小时、4小时、6小时、12小时和14小时采集血浆样本。为了测定C肽、胰岛素、GLP-1和GIP，在给药前10分钟内和给药后2小时(第0天、第1天和第7天)采集血清样本。评估以下PD参数：餐后2小时血糖升高、平均血糖和基于胰岛β细胞功能(HOMA-β)稳态评估模型的胰岛功能指数，胰岛素抵抗的稳态评估模型(HOMA-IR)和改良的β细胞功能指数(MBCI)。
安全检查
安全性评估包括生命体征、体检、12导联心电图、血常规、尿常规、大便常规、血液生化和凝血功能。记录了从签署知情同意书到随访结束的所有不良事件。
统计分析
PK参数由Phoenix WinNonlin 8.1版(Certara LP软件)计算。通过SAS(9.4 版)分析PD参数和人口统计学。连续变量用平均值±标准差描述，计数变量和分类变量用频率和百分比描述。对于PK参数，需要计算几何平均值、对数标准差和几何变异系数。不良事件根据ICH监管活动医学词典(MEDRA 23.0或更高版本)进行编码。治疗期间不良事件(TEAE)定义为在接受第一剂研究药物后发生或恶化的不良事件。统计数据中包括与研究药物“肯定相关、可能相关和可能不相关”的不良事件。
二、结果
1.选定受试者的人口学特征
在本研究中，共有40名受试者接受了试验药物，包括0.5mg BID(N＝8)、1.0mg QD(N＝8)、1.0mg BID(N＝8)、2.0mg QD(N＝8)和2.0mg BID。10名受试者接受安慰剂治疗。
人口统计学和基线特征如表1所示。所有受试者均为汉族，T2DM的持续时间为≥3个月。试验组(N＝40)包括24名男性(60.0％)和16名女性(40.0％)，平均年龄为52.5±6.16岁，身高为162.45±7.33厘米，体重为66.53±9.780千克，体重指数为25.11±2.91千克/平方米。安慰剂组(N＝10)有8名男性(80.0％)，2名女性(20.0％)平均年龄为48.7±9.30岁，身高167.40±8.48厘米，体重76.89±10.28千克，试验组和安慰剂组的平均病程分别为45.80±39.093和51.45±72.08个月。
表1

2.药代动力学评价
试验组(N＝40)中的所有受试者均按计划给药。受试者口服试验药物(1.0-4.0mg)后，血浆中的药物浓度低于定量限值(BLQ)，无法获得PK参数。PK结果表明试验药物分子和代谢物很少进入血液，不会在体内累积，这与临床前结果一致(试验药物在T2DM小鼠中的先前PK-PD研究结果表明，给药后2h，试验药物在空肠和回肠中的浓度相似高，其次是十二指肠，但在血浆中的浓度最低)。PK结果与试验药物主要通过抑制肠道SGLT1活性从而抑制葡萄糖吸收而不是全身暴露而发挥降糖作用的机制一致。
3.药效学评价
空腹血糖(FBG)
给药前，六个组的空腹血糖在基线时均衡可比。安慰剂组、0.5mg BID、1mg QD、1mg BID、2mg QD和2mg BID组第8天的平均FBG较基线变化值分别为-0.47、0.19、0.15、-0.20、0.25和-0.14mmol/L。试验组和安慰剂组之间的最小均数和95％置信区间分别为0.66(-0.16，1.47)、0.62(-0.20，1.44)、0.27(-0.56，1.09)、0.22(-0.60，1.04)和0.33(-0.49，1.14)mmol/L。安慰剂组和试验组给药后第2天至第8天的平均FBG较基线(第0天)变化无剂量相关性，表明试验药物对受试者的FBG没有显著影响(图3)。
MMTT血糖
经证明，第7天早餐后，0.5mg BID、1mg QD、1g BID、2mg QD和2mg BID以及安慰剂的最大餐后葡萄糖分别增加了-0.02±2.11、-1.73±2.74、-4.65±1.79、-5.60±1.83、-6.31±1.82和-5.35±2.11mmol/L(图4)。除安慰剂组外，试验组的血糖在第7天早餐后以剂量依赖性方式显著低于基线。最大餐后血糖(午餐后)增加了-1.05±1.74(0.5mg BID)，-0.12±2.36(1mg QD)，0.50±4.46(1mg BID)，-0.23±1.97(2mg QD)，-1.47±1.36(2mg BID)和-0.27±1.80(安慰剂)mmol/L，表明午餐后血糖与基线相比没有显著变化。晚餐后，最大餐后血糖分别增加了0.12±1.15(0.5mg BID)，-1.35±3.41(1mg QD)、1.63± 3.50(1mg BID)、-2.44±1.80(2mg QD)、-0.63±2.30(2mg BID)和-3.35±1.63(安慰剂)mmol/L。在BID组中观察到餐后血糖下降的剂量依赖性趋势，而在安慰剂组和QD组中没有观察到。一般而言，0.5mg BID、1mg QD、1g BID、2mg QD和2mg BID组的患者在连续7天给药后第一餐后血糖下降，但第二餐后血糖没有下降(图4)，表明在服用药物后4小时内血糖得到控制。餐后血糖下降与剂量呈正相关(D1:R2＝0.8856，D7:R2＝0.8283)。
C肽和胰岛素
早餐后2小时，试验组和安慰剂组的C肽和胰岛素显著增加。在第1天和第7天，试验组的C肽和胰岛素的增加低于安慰剂组。此外，试验组中C肽和胰岛素的增加与药物剂量呈负相关(C肽：D1:R2＝0.8676，D7:R2＝1.8998。胰岛素：D1:R2＝0.9123，D7:R2＝0.6567)。这些结果表明，试验药物以剂量依赖性方式降低T2DM患者餐后C肽和胰岛素浓度(图5中A-B)。
GLP-1和GIP
II型糖尿病患者早餐后2h GLP-1浓度升高。在第1天和第7天，餐后2h，试验组的GLP-1升高明显高于安慰剂组。餐后GLP-1的升高在每日一次服用1mg的组中最大(D1:4.43倍；D7:4.12倍)，其次是每日一次每次服用1mg组(D1:3.26倍；D8:2.15倍)。这些结果表明，试验药物可以促进餐后GLP-1的增加。然而，GLP-1的增加与剂量之间没有显著相关性(图5中C)。在II型糖尿病患者早餐后2小时观察到GIP显著增加。在第1天和第7天，试验组的GIP增加明显小于安慰剂组。试验组GIP的增加与药物剂量呈负相关(D1:R2＝0.9973，D7:R2＝0.9722)，表明试验药物可以剂量依赖性方式降低餐后GIP浓度(图5中D)。试验组和安慰剂组之间的HOMA-β、HOMA-IR和MBCI与基线相比无显著差异(P>0.05)(表2)。
表2


HOMA-β:P＝0.516>0.05,HOMA-IR:P＝0.253>0.05；MBCI:P＝0.255>0.05.
综上，试验药物对FBG无影响，但显著降低餐后血糖。QD给药可降低早餐后的血糖，但对午餐和晚餐后的血糖无影响。对于BID给药，早餐和晚餐后血糖受到影响，而午餐后血糖没有变化。当比较餐后血糖下降时，在第1天和第7天， 2mg(1mg BID和2mg QD)和4mg(2mg BID)组之间没有显著差异(D1:P＝0.417；D7:P＝1.637)，这表明2mg的日剂量可能是临床给药的最大有效剂量。特别是，试验药物显著减少餐后C肽和胰岛素分泌，刺激GLP-1分泌，同时抑制GIP分泌。
安全评估
试验在1-4mg剂量范围内探索了试验药物对T2DM患者的安全性。0.5mg BID产生的TEAE最少，而2mg BID引起的TEAE最多。共有36名受试者出现不良反应，包括腹痛、腹泻、腹胀、丙氨酸转氨酶(ALT)升高、血胆红素升高和窦性心动过缓。三名受试者各出现一次2级腹泻，一名受试者出现ALT升高，严重程度为3级。一名受试者血液甘油三酯升高，其他患者无药物不良反应。在所有试验药物组中，整个过程中没有发生低血糖，表明试验药物以温和的方式降低餐后血糖。所有受试者均未出现导致退出试验的AE。
胃肠道疾病是T2DM最常见的TEAE，包括腹泻、腹痛和腹胀。试验组发生率为92.5％，安慰剂组为80％。试验组40名受试者中有35名(87.5％)有68次腹泻，安慰剂组10名受试人中有7名(70％)有12次腹泻。0.5mg BID、1.0mg QD、1.0mg BID、2.0mg QD和2.0mg BID的腹泻发生率分别为50.0％(4/8)、87.5％(7/8)、100％(8/8)、100％(8/8)和100％(8/8)。1.0mg BID组的两名受试者和2.0mg BID组的一名受试人出现2级腹泻，其余患者出现1级腹泻。试验期间未对腹泻事件进行干预，所有腹泻均自发缓解。此外，腹泻的频率随着用药时间的延长而逐渐降低，表明受试者在每日服用试验药物期间可能对腹泻产生耐受性。
腹泻的诊断基于排便频率的增加或大便性状的改变。基线排便频率是用药前一周的平均排便次数。例如，如果基线为0.8次，当口服给药后排便频率仅为1次时，腹泻被记录为不良事件，这导致所有组的腹泻发生率都很高。尽管腹泻中TEAE的发生与试验药物的剂量呈正相关(R2＝0.624)，但安慰剂组受试者在7例中也造成了12次腹泻，这表明试验组的部分腹泻事件实际上与饮食有关。
试验药物诱导的腹泻归因于当SGLT-1被抑制时，由肠道中累积的葡萄糖和Na+引起的肠道内稳态改变。在本研究中，患者有轻度腹泻，没有腹泻引起的脱水等明显症状。未经治疗，所有患者均从腹泻中恢复。
由于高血糖和神经病变，2型糖尿病患者胃肠运动异常，导致多种胃肠道症状。便秘在糖尿病患者中很常见，可能由结肠对喂养的肌电和运动反应异常引起，导致血糖控制不良和肾衰竭的高风险。在上述的研究中，试验药物在1.0-4.0 mg的剂量范围内引起轻度腹泻，这与Shin Fukudo的研究结论一致，即SGLT1抑制剂在给药后第一周引起腹泻。这种效应可以解释如下：(1)SGLT1抑制可导致进入结肠的液体显著增加，(2)SGLT2抑制可导致升结肠中葡萄糖吸收不良，从而改变微环境，从而扩张结肠并诱导推进结肠运动模式，(3)结肠中的葡萄糖也可激活肠嗜铬细胞释放5-羟色胺，这将加剧结肠运动，导致松弛。因此，试验药物可能有助于改善糖尿病患者的慢性便秘症状。
综上，试验药物作用于肠道局部，在1.0-4.0mg剂量范围内抑制肠道SGLT1活性，显著降低餐后血糖、C肽和胰岛素水平。在中国T2DM患者中显示出相对安全性和耐受性。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物和式(I)化合物的药学上可接受的盐的水合物中的至少一种用于制备药物的用途：
    其中，所述药物用于预防和/或治疗糖尿病、餐后高血糖症、糖耐量低减者的餐后高血糖症，或用于控制有需要者的餐后血糖，或用于控制与餐后血糖升高相关的疾病或症状。
  2. 根据权利要求1所述的用途，其中，所述“糖尿病”为1型或2型糖尿病，优选2型糖尿病；
    优选地，与餐后血糖升高相关的疾病或症状包括但不限于心血管疾病如微血管并发症、动脉粥样硬化性血管病(ASVD)、血栓中的至少一种；
    优选地，所述式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物和/或式(I)化合物的药学上可接受的盐的水合物为其无定型物或多晶型物。
  3. 式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物和式(I)化合物的药学上可接受的盐的水合物中的至少一种，其中，所述式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物和式(I)化合物的药学上可接受的盐的水合物中的至少一种用于预防和/或治疗糖尿病、餐后高血糖症、糖耐量低减者的餐后高血糖症，或用于控制有需要者的餐后血糖，或用于控制与餐后血糖升高相关的疾病或症状；
    所述式(I)化合物为权利要求1所述用途中的式(I)化合物。
  4. 一种组合物，其中，所述组合物包含式(I)化合物、式(I)化合物的药 学上可接受的盐、式(I)化合物的水合物和式(I)化合物的药学上可接受的盐的水合物中的至少一种，以及食物(如低糖食物)；其中所述组合物用于预防和/或治疗糖尿病、餐后高血糖症、糖耐量低减者的餐后高血糖症，或用于控制有需要者的餐后血糖，或用于控制与餐后血糖升高相关的疾病或症状；
    所述式(I)化合物为权利要求1所述用途中的式(I)化合物。
  5. 一种代谢组合物，其中，所述代谢组合物包含式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物和式(I)化合物的药学上可接受的盐的水合物中的至少一种的代谢物；其中所述代谢物为前述化合物用于预防和/或治疗糖尿病产生的代谢物，特别是用于预防和/或治疗患有餐后高血糖症的糖尿病患者产生的代谢物；
    所述式(I)化合物为权利要求1所述用途中的式(I)化合物。
  6. 式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物、式(I)化合物的药学上可接受的盐的水合物、药物或权利要求4所述组合物的用途，其用于预防和/或治疗糖尿病、餐后高血糖症、糖耐量低减者的餐后高血糖症，或用于控制有需要者的餐后血糖，或用于控制与餐后血糖升高相关的疾病或症状；
    所述式(I)化合物为权利要求1所述用途中的式(I)化合物；
    所述药物为权利要求1所述用途中的药物。
  7. 根据权利要求6所述的用途，其中，所述药物或组合物在降低餐后血糖时，不会造成低血糖；
    优选地，以式(I)化合物计，所述药物或组合物的给药日剂量为治疗有效量的，如0.5-10mg，又如0.5-8mg；
    优选地，所述药物或组合物为药物制剂；
    优选地，所述组合物为单剂量制剂，其中所述单剂量制剂中，以式(I)化合物计的含量为治疗有效量的，如0.5-10mg，又如0.5-8mg；
    优选地，所述药物或组合物还包含药学上可接受的辅料，如载体或赋形剂；
    优选地，所述药物或组合物为胶囊剂；
    优选地，所述胶囊剂的内容物包含：式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物和式(I)化合物的药学上可接受的盐的水合物中的至少一种，填充剂、崩解剂和润滑剂。
  8. 根据权利要求6-7任一项所述的用途，其中，所述药物或组合物中还包含至少另一种抗糖尿病化合物；
    优选地，所述抗糖尿病化合物选自胰岛素信号传导途径调节剂、影响肝葡萄糖产生调节异常的化合物、胰岛素敏感性增强剂和胰岛素分泌促进剂中的至少一种。
  9. 一种预防和/或治疗糖尿病、餐后高血糖症、糖耐量低减者的餐后高血糖症，或用于控制有需要者的餐后血糖，或用于控制与餐后血糖升高相关的疾病或症状的方法，包括向患者给予有效量或治疗有效量的权利要求1中的式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物、式(I)化合物的药学上可接受的盐的水合物中的至少一种，或者向患者给予有效量或治疗有效量的权利要求4所述的组合物；
    优选地，以式(I)化合物计，所述式(I)化合物、式(I)化合物的药学上可接受的盐、式(I)化合物的水合物、式(I)化合物的药学上可接受的盐的水合物或组合物的给药日剂量为治疗有效量的，如0.5-10mg，又如0.5-8mg；
    优选地，所述组合物为单剂量制剂，其中所述单剂量制剂中，以式(I)化合物计的含量为治疗有效量的，如0.5-10mg，又如0.5-8mg。
  10. 一种预防和/或治疗糖尿病、餐后高血糖症、糖耐量低减者的餐后高血糖症，或用于控制有需要者的餐后血糖，或用于控制与餐后血糖升高相关的疾病或症状的方法，包括向患者给予有效量或治疗有效量的权利要求1中的药物；
    优选地，以式(I)化合物计，所述药物的给药日剂量为治疗有效量的，如0.5-10mg，又如0.5-8mg；
    优选地，所述药物为单剂量制剂，其中所述单剂量制剂中，以式(I)化合物计的含量为治疗有效量的，如0.5-10mg，又如0.5-8mg。
PCT/CN2023/118022 2022-09-13 2023-09-11 氮杂环化合物、其药物组合物和用于预防和/或治疗疾病的用途 WO2024055932A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211112296 2022-09-13
CN202211112296.7 2022-09-13

Publications (1)

Publication Number Publication Date
WO2024055932A1 true WO2024055932A1 (zh) 2024-03-21

Family

ID=90274258

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/118022 WO2024055932A1 (zh) 2022-09-13 2023-09-11 氮杂环化合物、其药物组合物和用于预防和/或治疗疾病的用途

Country Status (1)

Country Link
WO (1) WO2024055932A1 (zh)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006035796A1 (ja) * 2004-09-29 2006-04-06 Kissei Pharmaceutical Co., Ltd. １－（β－Ｄ－グリコピラノシル）－３－置換含窒素ヘテロ環化合物、それを含有する医薬組成物及びその医薬用途
CN102307577A (zh) * 2009-02-13 2012-01-04 贝林格尔.英格海姆国际有限公司 包含sglt2抑制剂、dpp-iv抑制剂和任选的另一种抗糖尿病药的药物组合物及其用途
CN103179960A (zh) * 2010-11-02 2013-06-26 贝林格尔.英格海姆国际有限公司 治疗代谢疾病的药物组合
CN104427985A (zh) * 2012-05-09 2015-03-18 勃林格殷格翰国际有限公司 用于治疗代谢性疾病的药物组合
CN105636972A (zh) * 2013-11-01 2016-06-01 伊莱利利公司 吡喃葡萄糖基取代的吲哚脲衍生物及其作为sglt抑制剂的用途
CN110128493A (zh) * 2018-02-08 2019-08-16 亚宝药业集团股份有限公司 吡喃糖取代杂环化合物的盐及其制备方法和用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006035796A1 (ja) * 2004-09-29 2006-04-06 Kissei Pharmaceutical Co., Ltd. １－（β－Ｄ－グリコピラノシル）－３－置換含窒素ヘテロ環化合物、それを含有する医薬組成物及びその医薬用途
CN102307577A (zh) * 2009-02-13 2012-01-04 贝林格尔.英格海姆国际有限公司 包含sglt2抑制剂、dpp-iv抑制剂和任选的另一种抗糖尿病药的药物组合物及其用途
CN103179960A (zh) * 2010-11-02 2013-06-26 贝林格尔.英格海姆国际有限公司 治疗代谢疾病的药物组合
CN104427985A (zh) * 2012-05-09 2015-03-18 勃林格殷格翰国际有限公司 用于治疗代谢性疾病的药物组合
CN105636972A (zh) * 2013-11-01 2016-06-01 伊莱利利公司 吡喃葡萄糖基取代的吲哚脲衍生物及其作为sglt抑制剂的用途
CN110128493A (zh) * 2018-02-08 2019-08-16 亚宝药业集团股份有限公司 吡喃糖取代杂环化合物的盐及其制备方法和用途

Similar Documents

Publication Publication Date Title
JP6995822B2 (ja) Ｄｐｐ ｉｖインヒビターの使用
RU2261096C2 (ru) Способ улучшения передачи сигнала в островках лангерганса при сахарном диабете и его профилактике
RU2264811C2 (ru) Применение гипогликемического агента для лечения нарушенного метаболизма глюкозы
TWI278312B (en) Pharmaceutical composition for treating diabetes or a disease or condition associated with diabetes
TWI241185B (en) Antidiabetic formulation
JP4845740B2 (ja) 糖尿病を治療するための組成物および方法
Culy et al. Repaglinide: a review of its therapeutic use in type 2 diabetes mellitus
US6559188B1 (en) Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes
JP4976281B2 (ja) 代謝を調節するための材料および方法
Rendell et al. Targeting postprandial hyperglycemia
JP2002529417A (ja) スルホニル尿素、グリタゾンおよびビグアニドを含有する糖尿病用組み合わせ薬剤
TW200911275A (en) Pharmaceutical composition comprising a pyrazole-O-glucoside derivative
JP2013540801A (ja) 代謝異常の治療のための組合せ医薬
BRPI0609371A2 (pt) usos de roflumilast na produção de composições farmacêuticas para o tratamento de diabetes mellitus
CN106109469A (zh) 保护血管及保护心脏的抗糖尿病性治疗
TW201202238A (en) 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine for the treatment of a metabolic disorder of a predominantly carnivorous non-human animal
WO2002004024A1 (en) Composition for the treatment of diabetes
Gökçay Canpolat et al. Glucose lowering treatment modalities of type 2 diabetes mellitus
US20050124663A1 (en) Method of treating metabolic disorders, especially diabetes, or a disease or condition associated with diabetes
Provilus et al. Weight gain associated with antidiabetic medications
Eldor et al. Oral insulin (ORMD‐0801) in type 2 diabetes mellitus: A dose‐finding 12‐week randomized placebo‐controlled study
Karl et al. Pramlintide as an adjunct to insulin in patients with type 2 diabetes in a clinical practice setting reduced A1C, postprandial glucose excursions, and weight
McFarlane Antidiabetic medications and weight gain: implications for the practicing physician
WO2024055932A1 (zh) 氮杂环化合物、其药物组合物和用于预防和/或治疗疾病的用途
KR20240037955A (ko) 혈당 조절 및 당뇨병 및 관련 질환의 치료 방법