TWI308875B - Pharmaceutical composition containing nateglinide for the prevention or delay of the progression to overt diabetes - Google Patents

Description

1308875 IX. Description of the Invention: [Technical Field] The present invention relates to a hypoglycemic agent or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for preventing or delaying the progression to symptomatic diabetes ( In particular, type 2), prevent or reduce microvascular complications (such as retinopathy, neuropathy, nephropathy), prevent or reduce the incidence of serious cardiovascular disease (such as myocardial infarction, arterial obstructive disease, atherosclerosis and Stroke) and cardiovascular mortality, prevent cancer and reduce cancer mortality. [Prior Art] Glucose metabolism disorder (IGM) is defined as a blood glucose concentration higher than the normal range' but has not yet reached the diagnostic criteria for type 2 diabetes. The incidence of IQM varies from country to country, but it is usually 2 to 3 times more common than symptomatic diabetes. IGM patients are considered to be pre-diabetic patients, but until recently, data from several epidemiological studies have refuted that IGM patients are not consistent with the risk of developing diabetes and the risk of cardiovascular disease and death. These data suggest that IGM patients, especially IGT patients, do not always develop diabetes, but whether they are diabetic or non-diabetic, there is a high risk of cardiovascular disease and death. About 58% of IGM patients have glucose tolerance disorder (IGT), another 29. /. Has fasting glucose disorder (IFG) and 13% has these two abnormalities (IFG/IGT). IGT is characterized by hyperprandemia after meals, and IFG is defined by the American Diabetes Association (ADA) (see table below) based on fasting blood glucose values. The classification of normal glucose tolerance (NGT), IGM and type 2 diabetes is defined by 99616-961106.doc 1308875 ADA in 1997. The classification is as follows: NGT IGM type 2 diabetes IFG --- FPG concentration <6.1 Millol/L (<110 mg/100 ml) 6.1-7 mmol/L (110-126 mg/1 ml) >7 mmol/L (> 126 mg/1 inch) ML) and/or IGT or 2 hours postprandial glucose concentration (75 g OGTT*) <7.8 mmol/L (<140 mg/100 ml) 7.8-11.1 mTorr/L (140-220 Mg/100 ml) > 11.1 millimoles/liter (> 200 mg/loo ml) *) These criteria are defined under the conditions of implementation using the WHO recommended oral glucose tolerance test (OGTT); OGTT was administered by oral administration of a glucose load containing 75 g of anhydrous glucose and dissolved in water, and blood samples were taken 2 hours later to analyze postprandial blood glucose. Other conditions that can be used to confirm the risk of IGT and IFG OGTT trials include: J) use 5 gram grams instead of 75 grams of glucose, 2) use non-fasted glucose samples as analytes' and 3 Postprandial glucose was analyzed 1 hour after the glucose load was administered instead of 2 hours. Under all of these conditions, the blood glucose categories defined above are associated with the increased risk described below, but standardized OGTT is preferred to minimize differences in test results. It is known that patients with IGM, especially those in the IFG subclass, are significantly more likely to develop diabetes than those with normal blood glucose, and their risk of cardiovascular disease is also particularly high in those with diabetes. Interesting, IGM stalkers, especially those with subtypes of IGT, have a morbidity and mortality profile for cancer and cardiovascular disease, even those who do not have diabetes. Therefore, IGM strings, 99616-961106.doc 1308875, especially in subclass IFG patients, are clearly at high risk of developing heart disease, especially after patients have symptomatic diabetes. On the other hand, IGT is associated with high risk of cancer and cardiovascular disease and mortality in non-diabetic and diabetic patients. The increased risk associated with IGT is independent of all other known cardiovascular risk factors including age, gender, high blood pressure, low HDL, and high LDL cholesterol concentrations [[Grab (10) 1999; 354: 617-621]. In the absence of abnormal FPG characteristics of diabetes, IGM (especially IGT) is associated with microvascular disease and large blood f disease complications - the mechanism is postprandial kjk sugar alone postprandial hyperglycemia, even in non-diabetic patients It has also been shown to reduce the presence of natural free radical scavengers (TRAPs) in serum. It has been demonstrated that the reduction in concentration of TRAP under experimental conditions is associated with increased free radical formation and increased oxidative dust power. These free radicals are involved in microvascular and macrovascular diseases associated with atherosclerosis, cardiovascular disease morbidity and mortality, and cancer [Ceriello, A, Diabetic Medicine 15: 188-193, 1998]. The reduction of natural antioxidants such as TRAP during postprandial hyperglycemia can explain why cardiovascular disease is associated with the presence of IGM (especially IGT) but no diabetes. The fact that IGT is an independent risk factor among non-diabetic and diabetic patients distinguishes it from diabetes and is a new target for the prevention and treatment of cardiovascular disease, death and cancer. IGM is associated with the following underlying diseases or conditions: "Deterioration into symptomatic Type 2 diabetes (Category Code 25〇.2=1匸〇_ 250.2 in the International Classification of Diseases) [Diabetes Research and Clinical Practice '40 SI S2]' 2) increased microvascular complications of diabetes, especially 99616-961106.doc 1308875

It is diabetic retinopathy and other eye complications (ICD-9 code 250.5), nephropathy (ICD-9 code 250·4), neuropathy (ICD-9 code 250 · 6) [Diabetes Care 2000 ; 23 : 111 3 -111 8] and peripheral vascular lesions and gangrene (ICD-9 code 250.7); 3) increased incidence of cardiovascular disease (ICD-9 codes 410-414), especially myocardial infarction (ICD-9 code 410), coronary Arterial heart disease or atherosclerosis (ICD-9 code 414) and other acute and subacute coronary ischemia (ICD-9 code 411); 4) Severe brain management diseases such as stroke (ICD-9 codes 430- 438) [Circulation 1998; 98:2513-2519]; 5) increased cardiovascular mortality (ICD-9 codes 390-459) [Lancet 1999; 354: 617-621] and sudden death (ICD-9 code 798.1) ; 6) the high incidence of malignant tumors and

Mortality (ICD-9 codes 140-208) [Am J Epidemiol. 1990; 131: 254-262, Diabetologia 1999; 42: 1050-1054]. Other metabolic disorders associated with IGM include dyslipidemia (ICD-9 code 272), hyperuricemia (ICD-9 code 790,6), and hypertension (ICD-9 codes 401-404) and angina pectoris (icD-9 code) 413.9) [Ann Int Med 1998; 128: 524-533]. The wide range of diseases and conditions associated with IGM (especially IGT) clearly represents a huge area of medical needs. Many of these diseases and conditions are associated with both diabetes, but it has only recently been identified that non-diabetic individuals with IGM (especially IGT) should also be targeted for prevention and treatment. Therefore, in patients with IGM (especially IGT and / or IFG), early insulin secretion recovery and / or postprandial high glucose reduction should help prevent "delayed deterioration into symptomatic diabetes, and by prevention Symptoms of Diabetes Mellitus and Prevention or 96616-961106.doc 1308875 Reduce microvascular complications associated with diabetes. In addition, in patients with igm, especially in patients with IGT and/or 11?, early recovery of insulin secretion and/or reduction in postprandial hyperglycemia should also prevent or reduce the incidence and mortality of severe cardiovascular disease. And the prevention of cancer or the reduction of cancer mortality. Therefore, during the period between normal blood sugar and type 2 diabetes, especially the high blood sugar P from the segment, it becomes a major stage of interest, and there is a strong need for a suppression or delay. It deteriorates into type 2 diabetes and various methods of cardiovascular and microvascular conditions or diseases and cancer associated with IGM (especially IFG and/or IGT). SUMMARY OF THE INVENTION It has now unexpectedly been found that hypoglycemic agents such as insulin secretion promoters can be used to prevent or delay the progression to symptomatic diabetes, reduce microvascular complications of diabetes, reduce vascular disease morbidity and mortality, In particular, cardiovascular disease morbidity and mortality, as well as cancer mortality from IGT and/or ifg patients. The hypoglycemic agent contains, for example, an insulin secretion enhancer or an insulin sensitivity enhancer (insulin resistance remover) or insulin, and if appropriate, may be a pharmaceutically acceptable salt thereof in each case. The indole secretion promoting agent is an active ingredient having a property of promoting secretion of insulin from pancreatic fistula cells. Insulin secretion promoters (also known as secretagogues and pro-insulin agents) are, for example, short-acting or long-acting hypoglycemic agents. The short-acting hypoglycemic agent is, for example, a 婪7y horse-brown acetic acid derivative, and a hypoglycemic quinone 99616-961106.doc 1308875 (gliquidone). The corresponding phenylalanine derivative is, for example, a nateglinide having the following formula: , N-(trans-4-isopropylcyclohexylcarbonyl)_1)-phenylalanine) (see EP 1962.22 and EP 526171):

And repaglinide, (S)-2-ethoxy-4-{2-[[3-methyl-hexahydropyridyl)phenyl]butyl]amino]_2-keto Ethyl acid; it is in its free form in each case, or a pharmaceutically acceptable salt if appropriate. Similarly, the term "neglinide" includes those modified by crystallization, such as those disclosed in European Patent No. 05261171 B1 or U.S. Patent No. 5,488,510, the disclosure of each of which is incorporated herein in </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; B-type crystal modification in B1, the subject of which is particularly relevant to the identification, manufacture and characterization of &amp; type crystal modifications. In the present invention, the B- or H-type is preferably used, and the η-type is more preferably used. Long-acting hypoglycemic agents are, for example, biguanide derivatives or sulfonylurea derivatives. Suitable biguanides are, for example, metf〇rmin, or a pharmaceutically acceptable salt thereof (if appropriate), especially a hydrochloride salt. 99616-961106.doc 1308875 Examples of sulfonylurea derivatives (SU) (especially those that promote insulin secretion from the pancreatic sputum-cell via a su receptor in the cell membrane) include, but are not limited to, toluene Continued tolbutamide, chlorpropamide, methicillin (1; 〇182 &amp; 11^(16), (&amp;61〇116乂&amp;111106), 4-chloro-N -[(lp piroxicam)-based group]-glycopyramide, glibenclamide, glyburide, giclazide, 1-butyl-3-isoaniline Urinary, amine-like carbamate, glibonuride, p-glipizide, gliquidone, glisoxepid, dynasty p Glybuthiazole, glibuzole, glyhexamide, glycimidine, glypinamide, phenbutamide, and toluene Tolylcyclamide, or a pharmaceutically acceptable salt if appropriate in each case. Insulin secretion promoters include new Representatives of SU are, for example, (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolecarbonyl)-calcium propionate dihydrate (KAD-1229) and Glympirid ( Glimepiride, Hoe 490), which are free or pharmaceutically acceptable salt forms. Similarly, insulin secretion promoters include DPP-IV inhibitors, GLP1 and GLP1 agonists. DPP-IV is a serine protease and will catalyze N - cleavage of the terminal Xaa-Pro or XaaAla dipeptide residues (including glucagon-like protein-1 (GLP-1)). The corresponding inhibitor of DPP-IV increases the circulating concentration of GLP-1, so it increases Tengdaosu concentration.

Representative examples of DPP-IV inhibitors are described in WO 98/19998 and WO 99616-961106.doc -12 1308875 00/34241. Preferably, it is de-corrugated, which is -(2-[(5-1-pyridyl-2-yl)amino]ethylamine}blue 2(S)-cyano group 0 π determinate dihydrochloride (reference w Example 3) of 〇98/19998 and (8) 1-[(3-diyl-small acryl)amino]-ethinyl-2-cyano-pyrrolidine (Ref. |0 0/34241 Example GLP -1 and GLP-1 agonists promote insulin secretion. The preferred exogenous hormone secretion promoter is repaginin and metformin, and Guantaigede (4) can be the best. Min recorded increased the repair of impaired pancreatic receptor function, in order to reduce the resistance of tensin, and thus improve the sensitivity of insulin. The insulin sensitivity of the field is increased, for example, the appropriate hypoglycemic oxazolidine Ketone (Glitazong, glitaz〇ne). The appropriate glitazone (glitaz〇ne) is, for example, (sh(3,4 dihydro-2(phenylmethyl)2H-1-) and P. -6-yl)methylpyrazolidine_2,4_dione (englitazone), 5-{[4-(3-(5-methyl_2_phenyl_4_carbazolyl) )-ι-ketopropyl)-phenyl]-methylthiazolidine-2,4-dione (darglitazone), 5-{[4-((1·methyl-) Hexyl)methoxy)phenyl]-methyl}-oxazolidine-2,4-dione (sigritazia, cigmaz〇ne), 5{[4_(2-(1-mercapto)) Ethoxy)phenyl]-methyl}_oxazolidine-2,4-dione (DRF21 89), 5-{4-[2-(5-methylphenyl_4_carbazolyl)· Ethoxy)]_subunit}- oxazolidine-2,4-dione (BM-13.1246), 5-(2-oxasulfonyl) pyrazolidine-2,4-dione (AY- 31637), 贰{4-[(2,4-dimercapto-5-oxazolidinyl)methyl]phenyl}methane (YM268), 5-{4-[2-(5·methyl_2_ Phenylazolyl)-2-hydroxyethoxy]benzyl}-oxazolidine-2,4-dione (ad_5〇75), 5-[4-(1-phenyl-1-cyclopropanecarbonylamine ))-benzyl]-pyrazolidine_2, 'dioxin (dn_ 99616-961106.doc •13·1308875 108), 5-{[4-(2-(2,3-dihydro 4哚-1) -yl)ethoxy)phenyl]methylpropazolidin-2,4-dione, 5-{[3-(4-chlorophenyl)]-2-propynyl]-5-benzenesulfonate Base} plug. 2,4-dione, 5-{[3-(4-phenylphenyl)]-2-propynyl]_5_(4_-phenylphenyl-sulfonyl} oxazole Pyridine-2,4-dione, 5-{[4-(2-(methyl-2-pyridyl-amino)ethoxy)phenyl]-methyl}pyrimidine-2,4-di Ketone (Rosigli Tazon, r Osiglitazone), 5-{[4-(2-(5-ethyl-2-p-indolyl)ethoxy)phenyl]-methyl} peak ° αα定 - 2,4-dione (皮皮Oglita sinensis pioglitazone), ((3,4-diaza-6-carbyl-2,5,7,8-tetradecyl-211-1-benzo 57 oxime_2_yl) oxime Phenyl]-fluorenyl} P-pyrazolidine-2,4-dione (Troglitazol, troglitazone), 5-[6-(2-fluoro-benzyloxy)indol-2-yl Methyl]^嗤嗤0定_ 2,4-dione (MCC555), 5-{[2-(2-naphthyl)-benzoxazole·5·kibmethyl} pyrazolidine-2,4- Diketone (Τ-174) and 5-(2,4-dione-pyrimidinyl-5-ylmethyl)-2-methoxy-indole-(4-trifluoromethyl-yl) Indoleamine (KRP297). Preferred are pioglitazone, rosiglitazone and troglitazone. The structure of the active agent named by the scientific name or the trade name may be taken from the current abstract of the nThe Merck Index&quot;, or the database such as the international patent (e.g., IMS World Publication), the corresponding contents of which are incorporated herein by reference. Anyone skilled in the art will be able to adequately identify the active agent based on such references. Similarly, the medical indications and properties can be tested in standard test models (in vitro and in vivo). It has been shown that blood-suppressing agents such as insulin enhancers have a beneficial effect to confirm that they can restore early on-star reduction in post-prandial glucose concentrations in patients with IGM. A randomized study of patients with multicenter, double-blind, and f-group (4) (four) 99616-961106.doc -14 - 1308875 g_P was performed to assess the placement of Natigli trials before each main meal during the 8-week treatment period ( Read glinide) 30 mg, 6 mg or i2 mg or placebo, the effect of confirmed low return and postprandial glucose concentration. Patients selected according to the blood (four) glucose value after a 75-gram oral glucose tolerance test (〇gtt) and patients who generally met the following additional criteria were included in the study: -7.8# 11.1

OGTT was performed during the year prior to participation in the study, and the second 〇gtt was performed within two weeks prior to participation in the study); -FPG&lt; 7 millimoles/liter; - Patient's body mass index (BMI) was 20-32 Kg/m2; - patients maintain their previous diet throughout the study period; - male, infertile women and fertile women using medically controlled birth control laws are included; - no other anti-diabetic agents should be used during the trial . Take a corresponding dose of nateglinide with a large glass of water. Take 2 times, 3 times or 4 times per meal. The number of meals depends on the number of main meals (breakfast, Chinese food, snacks, dinner). The first dose is given at the first main meal (standard meal, ie 55°/carbohydrate, 25% fat and 2% protein). Visited at 0' 2, 4 and 8 weeks and the patient was fasted for at least 7 hours. All blood samples for laboratory evaluation were taken between 7 am and 1 am. HbA 1 c was measured before the start of treatment (basal value) and after 8 weeks of treatment (fasting glucose and fructosamine). Blood samples were taken at 1 week, 20, 30' 60, 120 and 180 minutes after administration of the drug (time 〇) and the glucose and insulin concentrations were measured in the grapes 99616-961106.doc -15 - 1308875. At the 3rd and 8th week of the visit, the patient received a standard meal challenge of approximately 500 仟 and a measurement of insulin and glucose. From the analysis of all the data obtained from the study, it was found that the glucose concentration, HBAlc and glucosamine concentrations were significantly reduced 2 hours after the meal, early insulin secretion was restored, and nategUnide prevented or delayed deterioration. The symptomatic type 2 sugar H can prevent or reduce the symptoms and diseases associated with IGM through longer treatment and recovery.

This study in patients with IGM (especially IFG and IGT) differs from that in diabetic patients because patients have normal FpG and are non-diabetic or diabetic. Surprisingly, a combination of hypoglycemic agents and hypoglycemic agents can be used in igm patients (especially IFG and/or IGT patients) to prevent or delay exacerbation of symptomatic Type 2 diabetes; and prevent, reduce or Delay in the occurrence of a condition selected from the group consisting of increased microvascular complications, increased incidence of cardiovascular disease, severe cerebrovascular disease, increased mortality of cardiovascular disease, sudden death, and higher incidence of malignancy Rates and mortality rates and other metabolic disorders associated with IGM. Furthermore, the combination of a hypoglycemic agent and a hypoglycemic agent can prevent, reduce or delay the occurrence of a condition selected from the group consisting of, for example, IFG patients (especially IFG and/or IGT patients): Retinopathy, other eye complications of diabetes, nephropathy, neuropathy, gangrene, myocardial infarction, atherosclerosis around coronary heart disease, other acute and subacute forms of coronary ischemia, stroke, blood lipids Abnormal, hyperuricemia, hypertension, angina p. Microvessels that are amputated. 9616-961106.doc -16· 1308875 Lesions, cancer, cancer death, obesity, uric acidemia, insulin resistance, and arterial obstructive disease. In the present invention, hypoglycemic agents can be used in patients with IGM (especially in IFG and/or IGT) to prevent or delay the progression to symptomatic diabetes, reduce microvascular complications of diabetes, and reduce vascular disease. The morbidity and mortality rates are particularly morbidity and mortality from cardiovascular disease, as well as increased mortality associated with cancer in patients. The present invention relates to a method for use in an IGM patient, particularly an ifg and/or IGT patient, which is used to prevent or delay the progression to symptomatic Type 2 diabetes; and to prevent, reduce or delay selected from the following The conditions in the ethnic group are: increased microvascular complications, increased cardiovascular disease incidence, severe cerebrovascular disease, increased cardiovascular mortality and sudden death, higher incidence of malignancy and mortality, and Other metabolic disorders associated with IGM. More particularly, the present invention relates to a method for use in an IGM patient, particularly φ is a yang and/or 1 GT patient, which method is used to prevent, reduce or delay the occurrence of a condition selected from the group consisting of, for example, the following: : Retinopathy, other eye complications of diabetes, nephropathy, neuropathy, peripheral vascular disease, gangrene, myocardial infarction, coronary heart disease, atherosclerosis, other acute and subacute forms of coronary ischemia, stroke , dyslipidemia, uric acidemia, hypertension, angina pectoris, microvascular disease resulting in amputation, cancer, cancer death, obesity, uric acidemia, insulin resistance and arterial obstructive disease. Therefore, the present invention relates to a method for use in patients with IGM, particularly IFG and 96616-961106.doc -17-1308875 IGT. This method is used to prevent or delay the progression to symptomatic diabetes, especially the second Type (ICD-9 Code 250.2); and microvascular complications such as retinopathy (ICD-9 code 250.5), neuropathy (ICD-9 code 250.6), nephropathy (ICD-9 code 250.4), and peripheral vascular lesions and gangrene ( ICD-9 code 25 0_7). Further, the present invention relates to a method for use in patients with IGM, particularly IFG and IGT, which is used to prevent or reduce the condition of severe cardiovascular disease (ICD-9 codes 410- • 414), such as myocardium Infarction (ICD-9 code 410) 'and arterial obstructive disease, atherosclerosis and other acute and subacute forms of coronary ischemia (ICD-9 c〇de 411-414); prevention, reduction or delay of severe Cerebrovascular disease occurs as a stroke (ICD-9 codes 430-438), reducing elevated cardiovascular mortality (ICD_9 codes 39〇_459) and sudden death (ICD_9(3) heart 798·丨) to prevent cancer (ICD- 9 codes 140-208) and reduce cancer deaths. The method is also concerned with preventing or reducing other metabolic disorders associated with IGM in patients with IGM, especially in patients with IFG and IGT, including high blood glucose (including postprandial hyperglycemia) and dyslipidemia (ICD_9(3) heart 272 ), uric acidemia (ICD_9 c〇de 79〇6) and hypertension code 40 1-404) and angina pectoris (ICD-9 c〇de 413 9). The classification codes described above and below are incorporated herein by reference for their respective definitions of the International Classification of Diseases, and the corresponding definitions of diseases, and constitute a part of the invention. Hypoglycemic agents induce early insulin secretion, which can quickly reverse and reduce postprandial blood glucose levels, which is beneficial to the prevention or treatment of IGM. The method comprises administering an effective amount of a hypoglycemic agent, such as an allergen promoting agent 99616-961106.doc -18 - 1308875, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. Patients in need of this method are warm-blooded animals, including humans. This is also a method of applying to patients with IGM (especially IFG and/or iwt) and related diseases and conditions (such as postprandial hyperglycemia), which is used to prevent or delay the progression to symptomatic diabetes ( In particular, 2) prevent or delay the occurrence of complications of micro-management, prevent or reduce gangrene or microvascular disease of amputation, prevent or reduce serious cardiovascular disease and cardiovascular mortality, prevent cancer and Reduce cancer deaths. The present invention also relates to methods of treating conditions and diseases associated with IGM [especially (four) and/or orders (including postprandial hyperglycemia)], such conditions and diseases including obesity, increased age, diabetes during pregnancy, Dyslipidemia, interstitial blood pressure, uric acidemia, insulin resistance, arterial obstructive disease, atherosclerosis, retinopathy, nephropathy, angina pectoris, myocardial infarction, and stroke. The subject of prevention is preferably an individual whose concentration of glucose falls within the scope of an epidemiological study that also increases the risk of heart disease, microscopic disease, and cancer. These concentrations include 匍GTT or a temporary glucose test with a plasma glucose concentration of 2 7.8 mmol/L, and/or a fast plasma glucose concentration within the IFG range (ie, fasting plasma glucose concentrations between 61 and 7 mmol) / liters). The new flow morbidity data is released to reduce the blood glucose concentration that is absolutely relevant to the above risks, or when the international standards defining the IGT and IFG risk groups change. The present invention still ensures that the risk group can be treated. The invention also relates to a method for use in an IFG patient comprising administering a therapeutically effective amount of a DPP-IV inhibitor to a subject in need thereof. The invention also relates to a hypoglycemic agent or a pharmaceutically acceptable salt thereof for the manufacture of a medicament

In the above use, the agent is used to prevent or delay the progression to symptomatic type 2 diabetes in patients with IGM, especially in KG and/or IGT patients; and to prevent, reduce or delay selected from the group of τ Conditions in the resulting population: increased micro-gray tube complications, increased cardiovascular disease incidence, severe cerebrovascular disease, increased cardiovascular mortality and sudden death, higher incidence of malignancy and mortality And other job-related metabolic disorders. The invention also relates to the use of an insulin secretion promoting agent or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or delaying the progression to symptomatic diabetes, in particular type 2, preventing or reducing microvascular complications To prevent or reduce serious cardiovascular disease and cardiovascular mortality, prevent cancer and reduce cancer death. The invention also relates to the use of an insulin secretion promoter or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in a patient for IGM (especially IFG and/or IGT) and related diseases and conditions, such as postprandial hyperglycemia, This medicine is used to prevent or delay the progression to symptomatic diabetes, especially type 2, to prevent or reduce microvascular complications, to prevent or reduce the incidence of severe cardiovascular disease and mortality, prevent cancer and reduce Cancer Death 0 The present invention also relates to a pharmaceutical composition for use in patients with IGM (especially IFG and/or IGT) for preventing or delaying the progression to symptomatic Type 2 diabetes and preventing, reducing or delaying selection The situation in the group of 96616.961106.do·-20- 1308875 consists of increased microvascular complications, increased cardiovascular disease incidence, severe brain bronchial disease, increased cardiovascular mortality, and Higher incidence and mortality of dead and malignant tumors and other metabolic disorders associated with deletion; the composition comprises a hypoglycemic agent or a pharmaceutically acceptable salt thereof And pharmaceutically permitted carrier.

The present invention also relates to a disease for preventing or delaying the progression to symptomatic diabetes, especially type 2, preventing or reducing the incidence of cardiovascular diseases with less severe microvascular complications and "tube disease mortality, pre-disease and reduction. A pharmaceutical composition for cancer mortality, comprising an insulin secretion promoter or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present invention relates to an IGM (especially IFG and/or IGT) and related diseases and A pharmaceutical composition for use in a condition (such as postprandial hyperglycemia) in a patient, which is used to prevent or delay the progression to symptomatic diabetes 'especially Type 2' prevention or reduction of microvascular complications, Prevent or reduce the incidence of severe m-tube disease and mortality of heart and blood vessel diseases, prevent cancer and reduce cancer death. The corresponding active ingredient or its pharmaceutically acceptable salt may also be used in the form of a hydrate or a solvent for crystallization. Furthermore, the present invention also relates to a composition, such as a combined preparation or a combination of pharmaceutical compositions which respectively comprise at least an insulin secretion promoter And at least one insulin sensitizer; or comprising at least two insulin secretion promoters; or comprising at least two insulin sensitizers; which are used to prevent or delay deterioration in IGM patients, especially in IFG and/or IGT patients To develop symptomatic type 2 diabetes, and to prevent, reduce, or delay the occurrence of a condition selected from the group of 96616-96I106.doc -21 - 1308875: increased material ^ and 'g complication, increased heart Vascular disease disease rate, severe cerebrovascular disease, increased cardiovascular mortality, and the high incidence and rate of death, malignant swelling, and other coffee-related metabolic disorders. The other benefit of σ ' is to reduce the dose of the individual drugs to be combined, for example, not only the value of the corpse / sputum is often small and the frequency of administration is less, thus reducing the incidence of side effects and sputum effects. Use

It depends on the expectations and needs of the patient. In accordance with the compositions of the present invention, a combination therapeutically effective amount of the active agents can be administered simultaneously, sequentially (in any order) or separately, or in a fixed combination. The term "therapeutically effective amount" means that the drug or composition elicits the desired biological or pharmaceutical response to achieve the specific/inhibiting effect of the present invention in a warm-blooded animal, including a human. A "therapeutically effective amount" may be administered in the case of a fixed or free combination of a reducing sugar or a disaccharide. In the composition according to the invention, the term &quot;joint effective amount&quot; may also include at least one combined The ineffective amount of the agent can be achieved by administering the (fixed or free) composition to achieve the desired sum effect. The pharmaceutical compositions of the present invention according to the above and below may be administered simultaneously, sequentially (in any order) or separately, or in a fixed combination. Preferred components of the composition of the present invention are those which have been identified as preferred hypoglycemic agents, and are selected from the group consisting of nateglinide, repaglinide, metformin (metf〇rmin). , Pioglitazone = (pioglitazone), Rosigli Tazon (r〇sigHtaz〇ne) and Trogirita 99616-961106.doc • 22- 1308875 (troglhazone), 2-(24(5 -cyanopyridine-2-yl)amino]ethylamino}ethinyl-2(S)-cyano-4-bromopyridine and (8)4(3-transpyradinyl)amino]-ethenyl- a 2-cyano-haha bite 'in any case, if appropriate, may be a pharmaceutically acceptable salt. · The variant form of the invention is a "set", for example, in this sense, according to the invention The components that can be combined can be used independently, given, or at different times or at different times, using different fixing compositions (ie containing different amounts of components). φ Thus, the components of the kit (for example) can be simultaneously To be administered or to be administered in a timed manner, ie any component in the kit may be administered at different time points (equal intervals or not, etc.). The preferred choice between the 3 octaves enables the group to be treated when combined The effect of treating a disease or condition is greater than that obtained by using only one component. The present invention is also directed to commercial packages comprising the compositions of the present invention, as well as instructions for how to use them simultaneously, separately or sequentially. It can be a pharmaceutically acceptable salt. If these compounds do not have, for example, at least one test center, an acid addition salt can be formed. If the corresponding acid addition salt is desired, it can be formed with a test. A compound having an acid group (for example, COOH) may also form a salt with a base. For example, a pharmaceutically acceptable salt of nateglinide is, for example, a salt formed with a base. Classes, which are referred to as cationic salts, such as metal and alkaline earth metal salts and ammonium salts. The pharmaceutical compositions according to the invention may be prepared in a manner known per se and suitable for passage via the intestinal tract (for example, the mouth or the rectum) and Parenteral administration to mammals (warm-blooded animals) includes humans, which contain a therapeutically effective amount of pharmacologically activated 99616-961106.doc

The 1308875 compound is administered alone or in combination with one or more of the mediators (especially suitable for enteral or parenteral users). ', the novel pharmaceutical preparations are ancient. W 3 has, for example, about 10 〇 / 〇 to about 1 〇〇 %

80%) of the active ingredient, from the ancient W from the W V into a knife "about 2% to about 6% of the active ingredient is relatively 仏. For the intestinal or parenteral administration of the pharmaceutical preparation of the invention, such as a unit The dosage form is, for example, a sugar-coated tablet, a tablet, a capsule or a test, and an ampoule, etc., which are prepared in a manner known per se, such as a conventional mixing,

Granulation, sugaring, dissolving or cold to dry. Thus, an oral pharmaceutical preparation can be obtained by combining the active ingredient with a solid carrier, if necessary, granulating the resulting mixture, and processing the mixture or granules, if desired, after adding appropriate excipients. Made into a chain or sugar-coated core. The dose of the hypoglycemic agent used in accordance with the present invention may, for example, be a marketed drug user. For example, for Natigli's tea key, the active ingredient dose is 0.5 mg, i mg or 2 mg; for the metformin pulser, the active ingredient dose is 500 mg or 85 mg. Likewise, the doses of the agents to be combined in the compositions of the present invention may also be employed. Those skilled in the art are, based on their knowledge, sufficient to determine the particular dosage of a particular hypoglycemic agent when used alone or in combination. When the warm-blooded animal is about 70 kilograms of human body, the dose of Na I Glyde (1) to the warm-blooded animal is preferably about 5 to 12 mg/day, preferably 25 to 800 mg. /曰 is better. Preferably, the dose comprises 3 mg, (9) mg or 120 mg of Nataglinide, preferably administered prior to the main meal. The method of administration, depending on the number of main meals, may be twice a day (BID) or three times a day "ZD" or four times (QID). 99616-961106.doc • 24· 1308875 [Embodiment] The examples are illustrative of the present invention, but are not intended to limit the scope of the invention by any means. Example 1: Natagliinide (1) lozenge 216, bismuth ingots containing 12 〇Gu Gu for every suspect Micronak Grid (I), prepared according to the following method: Electricity 12.960 kg 30.564 kg 15.336 kg 2.592 kg 3.974 kg 1.382 kg 1.231 kg 1.944 kg plus enough composition: Natig lindane (j) lactose, NF microcrystalline cellulose, NF 5 ^ Ethyl P is more than sigma sigma J, usp parent stimuli methyl cellulose nano, nf colloid dioxide dioxide, nf stearic acid town, nf ingot: opaque yellow pigment pure Water, USP*: Removal of the preparation process in the process: Microcrystalline cellulose, polyvinylpyrrolidone v μ * 嗣 嗣 partial cross-linked carboxymethyl ketovitamin sodium, Natig graninide (1) and The latex fiber π ^ is mixed with the A shear mixer and then granulated with pure water. The wet granules are dried in a flowing bed. Through the sieve, the colloidal cerium oxide ', the machine is dried and combined, passed through the sieve and dried up the silicate cellulose sodium. The m granules are blended into the v-type enthalpy to pass through the screen 'with the v-type The blender obtains the two-word sputum, blends all the mixture «disinfectant 1 color ^, then suspends the vapor pigment in pure water, 99616-961106^ -25- 1308875 and packs the tablet with the suspension Example 2: Nataglid (I) pharmaceutical formula No. 1 inside:

Natal Glyd (I) Lactose monohydrate microcrystalline cellulose polyethylene P ratio slightly _ cross-linked carboxymethyl cellulose sodium particles External: stearic acid opaque yellow pigment Example 3: Natai Glinade (I) Pharmacy: granule interior: Natalglid (I) Lactose monohydrate microcrystalline cellulose polyethylene P ratio σ each bite ketone croscarmellose sodium particles external: Cross-linked carboxymethyl cellulose sodium magnesium stearate opaque yellow pigment colloidal cerium oxide Example 4: Natale granules 108,000 tablets, each containing 120 mg 120 mg 283 mg 142 mg 24 mg 24 mg ❿ 7 Mg 20 mg square 2 120 mg 283 mg 142 mg 24 mg Lu 24 mg 12.8 mg 11.4 mg 18.0 mg _ 12.8 mg Tiger's naphthalene, according to the following system 96616-961106.doc -26- 1308875 injury: 12.960 kg 30.564 kg 15.336 kg 2.592 kg 3.974 kg 1.382 kg 1.231 kg 1.944 kg plus sufficient

Composition: Natigli tea, lactose,] SiF microcrystalline cellulose, NF polyvinylpyrrolidone, Usp crosslinked thiol cellulose sodium, NF colloidal oxidized hair, NF magnesium stearate, NF coating : opaque yellow plain pure water, USP*: removal process in the process: microcrystalline cellulose, poly, 4々a 笊 vinyl pyrrolidone, a part of cellulose sodium, Natley benzoquinone and $ T &amp; Nai' and Lishui add pure water to granulate in a collette gral granulator. Dry the wet particles in the &, i + ”, ;/; 'L moving bed dryer and pass through the sieve. The colloidal dioxide will be oxidized and the remaining right will be your m*, and the remaining parent carboxy-based fiber The sodium is mixed, passed through a sieve and blended with the dried granules in a V-type a 撬 撬 协 协 。 。. The magnesium stearate is blended with the blend obtained from the V-type blender through the network. Then, all the mixture dust is made into a tablet. The opaque yellow pigment is suspended in pure water, and the tablet is coated with the spin coating suspension. The change of the method includes the colloidal gel and residual cross-linking. The carboxymethylcellulose sodium is added to the second granulator after drying, followed by sieving and merging, up to 3 granulators/dryers per batch plus example S: Natigli 荇德纳泰Glinaded's pharmaceutical composition 120 mg 96916-961106.doc

-27- 1308875 Lactose monohydrate 283 mg microcrystalline cellulose 142 mg Polyethylene P than succinone 24 mg croscarmellose sodium 36.8 mg magnesium stearate 11.4 mg opaque yellow pigment 18.0 mg colloid Ceria 12.8 mg

99616-961106.doc 28-

Claims (1)

1308875 X. Patent application scope: a DPP IV inhibitor (8) (6) - a base of a small base, an amino group] - an acid chloride 2 cyano-pyrrolidine or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament 10,000 doses for individuals with glucose metabolism disorder (IGM) prevention or L delay to become symptomatic type 2 diabetes, prevention, reduction or L delay from the following group of ethnic groups: increased microvascular complications Increased cardiovascular disease incidence, severe cerebrovascular disease, increased cardiovascular mortality and sudden death and other intestinal-related metabolic disorders. Use of the monthly requester 1 The individual having the IGM has a fasting glucose disorder (IFG) and/or a glucose tolerance disorder (igt). 3_ The use of claim 2 or 2 for the manufacture of a medicament for the prevention or delay of deterioration into symptomatic type 2 diabetes. 4. If the application is for the purpose of item 2 or 2, the condition is selected from the group consisting of: reticular lesions, other eye complications of diabetes, nephropathy, neuropathy, peripheral vascular disease or gangrene, cans Infarction, coronary heart disease, atherosclerosis, other acute and subacute forms of coronary ischemia, stroke, dyslipidemia, hyperuricemia, hypertension, angina pectoris, microvascular disease resulting in amputation, obesity, uric acid Disease, insulin resistance and arterial obstructive disease. 5, if the purpose of the request is 'in which the condition is selected from the group consisting of: increased microvascular complications, increased incidence of cardiovascular disease, severe cerebrovascular disease, increased cardiovascular mortality and sudden death. 99616-961106.doc 1308875 6. The use of claim 1 or 2, wherein the condition is selected from the group consisting of increased microvascular complications. The use of claim 4, wherein the condition is selected from the group consisting of myocardial infarction and coronary heart disease. 8. The use of claim 13 Ge 2 for the prevention of postprandial glucose 9 in an abnormal range (2 hours after GTT or temporary glucose test, plasma glucose value 7.8 to old millimoles per liter) Pharmacy. A DPP-IV inhibitor (s) l-[(3-hydroxy-j-human, anthracene; K鮏-hydroxy-alkyl)amino]-ethinyl-2-acyl-pyrrolidine or its medicinal ^ ^ 』The salt of the article is used for the manufacture of a medicament for preventing or reducing vascular complications. 99616-961106.doc