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    • 专利摘要:
    The present invention (S) -2- ethoxy-3- [4- (2- {4-methanesulfonyloxy-phenyl} ethoxy) phenyl] propanoic acid or 3- {4- [2- (4- tert - Butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof and any solvent compound thereof and a pharmaceutical combination comprising sulfonylurea .
    公开号:KR20040007624A
    申请号:KR10-2003-7015644
    申请日:2002-05-30
    公开日:2004-01-24
    发明作者:오만페터
    申请人:아스트라제네카 아베；
    IPC主号:
    专利说明:

    (S) -2-ethoxy-3- [4- (2- ｛4-methanesulfonyloxyphenyl｝ ethoxy) phenyl] propanoic acid or 3- ｛4- [2- (4- pent-butoxycar A PHARMACEUTICAL COMBINATION COMPRISING EITHER (S) -2-ETHOXY-3- [4- (Containing Combination Amino Acids) Ethoxy] Phenyl-Phenyl- (S) -2-ethoxy Propanoic Acid and Sulfonylurea 2- ｛4-METHANESULFONYLOXYPHENYL｝ ETHOXY) PHENYL] PROPANOIC ACID OR 3- ｛4- [2- (4-TERT-BUTOXYCARBONYLAMINOPHENYL) ETHOXY] PHENYL｝-(S) -2-ETHOXY PROPANOIC ACID AND A SULFONYLUREA}
    [2] Typically, therapeutic intervention in type 2 diabetes is 'glucocentric' predominantly with the use of secretory facilitating agents such as sulfonylureas and measurement of glycated hemoglobin (HbA1c) or fasting blood glucose levels (FPG) as an indicator of diabetes control. Brought the focus'. In the United States, patients with type 2 diabetes are usually treated with diet and with sulfonylurea compounds as needed. However, approximately 30% of patients initially treated with sulfonylureas had poor response, with the remaining 70% assessing a failure rate of approximately 4-5% annually. Failure rates are higher in other assessments, with few patients responding after 10 years of treatment. Weight gain associated with treatment is also experienced with these agents. In 1995, before the FDA approved metformin, insulin was the only treatment option for patients with type 2 diabetes who failed sulfonylurea therapy in the United States.
    [3] Despite the introduction of newer agents, the incidence and epidemic of type 2 diabetes continues to increase worldwide. Approximately 16 million people in the United States have diabetes mellitus, of which 90-95% have type 2 disease. This represents a significant health care burden, with direct and indirect health care costs estimated at around $ 98 billion annually in 1998. Recently, the ADA and WHO have revised the diagnostic guidelines for diabetes and further subdivided diabetes according to etiology. The diagnostic limit (FPG> 126 mg / dl) was lowered and the term 'type 2' is now used to mean adult onset diabetes.
    [4] Since the ADA implemented these new standards in 1997, the prevalence of type 2 disease has increased by nearly 6 million in seven major pharmaceutical markets (France, Germany, Italy, Japan, Spain, the United Kingdom and the United States).
    [5] Apart from frequent mild acute syndromes, type 2 diabetes also has a significant risk of developing the long-term complications of the disease. They are four to five times higher in risk of developing macrovascular disease, including CHD and PVD, and microvascular complications, including retinal disease, kidney disease and neuropathy (compared to non-diabetic). In many individuals, apparent type 2 diabetes is accompanied by a period of decrease in insulin sensitivity (insulin resistance), which is accompanied by a group of other cardiovascular risk factors and collectively called insulin resistance syndrome (IRS).
    [6] Approximately 80% of type 2 diabetes is estimated to be obese and have other concurrent diseases of the IRS, including dyslipidemia, hyperinsulinemia, increased arterial blood pressure, uric acidemia and decreased fibrin lysis. Due to the increasing global prevalence and onset of type 2 diabetes and the high cost of treating long-term complications of this disease, the development of agents that delay or prevent the development of type 2 diabetes and the development of cardiovascular complications associated with IRS Reducing risk is of great interest. This activity has resulted in the introduction of a thiazolidinone (TZD) class of insulin sensitizers that improves insulin sensitivity by improving dyslipidemia, thereby improving glycemic control and lowering HbA1c levels.
    [7] Although complex interactions between lipids and carbohydrates as metabolic fuels have been recognized for decades, it is only recently that researchers and clinicians have begun to focus on the importance of dyslipidemia observed in type 2 diabetes. Much has been dealt with about the relative sensitivity of insulin to muscle, liver and adipose tissue, and examples of the highest priority of insulin resistance in adipose tissue leading to IRS have been discussed. Typical dyslipidemic atherogenic lipoprotein phenotypes (referred to as type B) are often observed in IRS, including type 2 diabetes, characterized by more marked increases in moderately elevated LDL-C, VLDL-TG, and reduced HDL. It is done. Clearly, changes in the physicochemical properties of the VLDL-TG particles slow the plasma clearance rate, resulting in low density LDL particles. These LDL particles are more likely to penetrate into the vascular endothelium, have a greater tendency to oxidize and glycosylate, and are thought to play an important role in the development of atherosclerosis in large vessels. Although more difficult to measure, there is a growing belief that improving free fatty acid outflows will play an important role in IRS affecting metabolic activity in muscle, liver, adipose tissue and pancreas.
    [8] First generation TZDs such as troglitazone, pioglitazone, rosiglitazone were clinically developed before the mechanism of action was discovered and published in 1995 (PPARγ activation). It is clear from experience with these first generation agents that from animal pharmacology it is difficult to predict the safety and efficacy profile that these agents will have in the clinic. Thus, knowledge of this class of putative mechanisms of action coupled with safety concerns provides an opportunity to judge non-TZD activators of PPARs for the treatment of type 2 diabetes and is a subject of the present invention. In addition, the inventors have recognized that agents with dual action in α and γPPARs may have additional advantages in reducing diabetic co-disease, in particular the common dyslipidemia of type 2 diabetes. Such agents may be useful in the treatment of type 2 diabetes, IRS, dyslipidemia and in reducing the risk of cardiovascular disease.
    [1] The present invention relates to the use of a combination of certain propanoic acid derivatives that act as peroxysomal growth factor activating receptor (PPAR) antagonists, useful in the treatment of conditions of insulin resistance, including type 2 diabetes mellitus and related conditions. In addition, novel pharmaceutical combination compositions are also defined along with their preparation methods.
    [9] Thus, we provide (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid and 3- {4- [2- (4- tert -Butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutical combination comprising any solvate and sulfonylurea thereof It provides as a feature of the present invention.
    [10] The combinations of the invention may be used in conjunction with other current therapies for the treatment of type 2 diabetes and related complications thereof, including insulin (synthetic insulin analogs, amylin) and oral anti-hyperglycemic agents (they are biguanides) , Class 3 drugs, such as meal glucose modulators and alpha-glucosidase inhibitors. An example of biguanide is metformin. An example of an alpha-glucosidase inhibitor is acarbose. Meal glucose regulator is repaglinide. Combinations of the invention may also be used with PPAR modulators. PPAR modulators include, but are not limited to, for example, thiazolidine-2,4-dione such as troglitazone, siglitazone, rosiglitazone and pioglitazone. Accordingly, the present invention encompasses administering the present combinations in combination with two or more current treatments described in this paragraph.
    [11] Another aspect of the invention is (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid or 3- {4- [2- ( 4- tert -butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof and any solvate of one of these and one of the following: Pharmacy combinations that include:
    [12] 1) meal glucose modulators such as, for example, meglitinide (eg, repaglinide or nateglinide); or
    [13] 2) an alpha-glucosidase inhibitor such as, for example, acarbose, boglibose or myglytol, or
    [14] 3) PPAR modulators.
    [15] Formulations 1, 2 or 3 may replace sulfonylureas in any aspect of the invention described herein, such as, for example, combinations, compositions, parts kits, methods of treatment, methods of manufacture, combination products, and the like. Further, (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid or 3- {4- [2- (4- tert -part Oxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof and any combination of 1, 2 or 3 with any solvate may be selected from insulin (synthetic insulin). Analogs, amylin) and oral anti-hyperglycemic agents (these are classified into three classes of drugs, such as biguanides, dietary glucose regulators and alpha-glucosidase inhibitors), and the treatment of type 2 diabetes and related complications. It may be further combined with existing additional therapeutic agents. An example of biguanide is metformin. An example of an alpha-glucosidase inhibitor is acarbose. Meal glucose regulator is repaglinide. The combinations of the invention may also be used with thiazolidine-2,4-diones such as, for example, troglitazone, siglitazone, rosiglitazone and pioglitazone. Other current therapeutic agents and, in particular, dosages of Formulations 1, 2 or 3 for the treatment of type 2 diabetes and related complications thereof are known in the industry and approved by the FDA regulatory body, for example, in the Orange Book issued by the FDA. You will find it. Alternatively, smaller dosages may be used as a result of the benefits derived from the combination.
    [16] Any biologically active form or derivative of insulin can be used in the present invention. For example, bovine, swine or biosynthetic or semisynthetic human insulin, or human insulin with certain amino acid substitutions as taught, for example, in Bran et. Al., "Diabetes Care" 13: 923, 1990. Biologically active derivatives (“denatured insulins”) can be used. Denatured insulins have been developed to improve various properties, for example to improve stability or to provide an improved pharmacokinetic profile (ie, an improved profile of absorption through the lining). Insulin can be provided by injection or inhalation, such as by using the formulations described in WO 95/00127, WO 95/00128, WO 96/19197, WO 96/19207 and WO 96/19198, which are incorporated herein by reference.
    [17] Accordingly, other independent aspects of the present invention include the following:
    [18] (1) (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid or a pharmaceutically acceptable salt thereof or solvate thereof And pharmaceutical combinations including sulfonylureas;
    [19] (2) 3- {4- [2- (4- tert -butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof or these A pharmaceutical combination comprising a solvate and sulfonylurea of either.
    [20] A 'pharmaceutical combination' can be achieved by separately administering each component drug of the combination of separate formulations administered together or sequentially to the patient. Alternatively, the 'pharmaceutical combinations' together may be in the same unit dosage form.
    [21] Therefore, as another aspect of the present invention, we provide a pharmaceutical composition comprising a pharmaceutical combination as described above together with a pharmaceutically acceptable carrier and / or diluent.
    [22] Independent aspects of the invention include (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid and 3- {4- [2- ( 4-t-butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof or a solvate and sulfonylurea of one of them Pharmaceutical compositions comprising together with an acceptable carrier and / or diluent.
    [23] Sulfonylureas include glyburide, glymepiride, glybenclamide, glyclozide, glyphide, glyquidone, chloropropamide, tolbutamide, acetohexamide, glycofyramid, carbutamide, article It is suitable to be selected from one or more of ribonide, glyoxepide, glybutthiazole, glybuzol, glyhexamide, glymidine, glypinamide, phenbutamide, tolsylamide and tolazamide.
    [24] The compositions of the present invention may be used orally (eg, tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical (eg creams, ointments, gels or aqueous or Oily solutions or suspensions), for inhalation administration (e.g., fine powders or liquid aerosols), for inhalation administration (e.g., fine powders) or for parenteral administration (e.g., for intravenous, subcutaneous, intramuscular or intramuscular administration) Oily solutions or suppositories for enteral administration).
    [25] The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, oral compositions may contain, for example, one or more colorants, sweeteners, flavors and / or preservatives.
    [26] Examples of pharmaceutically acceptable excipients suitable for tablet formulations include inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; Granules and disintegrants such as corn starch or alginic acid; Binders such as starch; Glidants such as magnesium stearate, stearic acid or talc; Preservatives such as ethyl or propyl p-hydroxybenzoate; And antioxidants such as ascorbic acid. Tablet formulations may be coated or coated using conventional coatings and procedures well known in the art in any case to alter the disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve its stability and / or appearance. You can't.
    [27] Oral compositions may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules in which the active ingredient is mixed with oils such as water or peanut oil, liquid paraffin or olive oil. Can be.
    [28] Generally, aqueous suspensions include one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth rubber and acacia rubber; Dispersing and wetting agents, such as condensation products of lecithin or alkylene oxides with fatty acids (eg polyoxyethylene stearate) or condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol or ethylene oxide with fatty acids And fine powders with condensation products of partial esters derived from hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydride, such as polyethylene sorbitan monooleate It contains the active ingredient in the form. In addition, the aqueous suspension may contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate), antioxidants (such as ascorbic acid), colorants, flavors and / or sweetening agents (such as sucrose, saccharin or aspartame ) May be contained.
    [29] Oily suspensions may be formulated by suspending the active ingredient in vegetable oils (eg arachis oil, olive oil, sesame oil or coconut oil) or mineral oils (eg liquid paraffin). Oily suspensions may also contain thickening agents such as beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavoring agents such as those described above may be added to provide a flavored oral formulation. Such compositions can be preserved by adding antioxidants such as ascorbic acid.
    [30] In general, dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be exemplified by those already mentioned above. Additional excipients may also be present, such as sweetening, flavoring and coloring agents.
    [31] The pharmaceutical compositions of the invention may also be in the form of oil emulsions in water. The oil phase may be a vegetable oil such as olive oil or arachis oil or a mineral oil such as liquid paraffin or any mixture thereof. Suitable latex formulations are, for example, naturally-occurring rubbers such as acacia rubber or tragacanth rubber, soybeans, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate). It may be a naturally-occurring phosphatide and a condensation product of said partial ester with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening, flavoring and preservatives.
    [32] Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose and may contain emollients, preservatives, flavors and / or colorants.
    [33] In addition, the pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions and may be prepared according to known procedures using one or more suitable dispersing or wetting agents and suspending agents, described above. In addition, the sterile injectable preparation may be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.
    [34] Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature but liquid at the intestinal temperature and therefore will melt in the intestine to release the drug. Examples of suitable excipients are cocoa butter and polyethylene glycols.
    [35] Generally, topical preparations such as creams, ointments, gels and aqueous or oily solutions or suspensions can be obtained by formulating the active ingredient with conventional topically acceptable vehicles or diluents using conventional procedures well known in the art. have.
    [36] Compositions for inhalation administration may be in the form of fine powders containing particles having a particle size of up to 30 μ, the powder itself comprising the active ingredient alone or diluted in one or more physiologically acceptable carriers, such as lactose. It is then usual to hold the inhalable powder, for example in a capsule containing 1 to 50 mg of the active ingredient, for use in a turbo-inhaler device such as that used for inhalation of the known formulation sodium chromoglycate. .
    [37] The composition for inhalation administration may be in the form of a pressurized aerosol arranged to dispense the active ingredient as an aerosol containing fine solids or droplets. Conventional aerosol propellants can be used, such as volatile fluorinated hydrocarbons or hydrocarbons, and typically aerosol devices are arranged to dispense a metered amount of active ingredient.
    [38] For further information on formulations, see Comprehensive Medicinal Chemistry, Volume 5, Chapter 25.2; Corwin Hansch, Chairman of Editorial Board, Pergamon Press 1990.
    [39] The amount of active ingredient combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation for oral administration to humans may be prepared by combining, for example, 0.5 mg to 2 g of the active ingredient in a suitable and convenient amount of excipient which may range from about 5 to about 98% by weight of the total composition. It is common to contain. Generally, dosage unit dosage forms contain about 1 mg to about 500 mg of active ingredient. For further information on the route of administration and dosage regimen, see Comprehensive Medicinal Chemistry, Volume 5, Chapter 25.3; Corwin Hansch, Chairman of Editorial Board, Pergamon Press 1990.
    [40] The dosage size for therapeutic or prophylactic purposes of the pharmaceutical combination of the present invention will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient and the route of administration, based on well-known medical principles. In particular, the pharmaceutical combinations of the invention and compositions containing them will be used to treat diabetes, dyslipidemia associated with insulin resistance and IRS, and to prevent the development of type 2 diabetes.
    [41] The size of the dosage for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, based on well-known medical principles. As a guideline, (S) -2- ethoxy-3- [4- (2- {4-methanesulfonyloxy-phenyl} ethoxy) phenyl] propanoic acid or 3- {4- [2- (4- tert - 0.5 to 25 mg per day, preferably 1 per day, for butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof and any solvent compound thereof Doses of ˜10 mg, such as 1 mg, 2 mg, 3 mg, 4 mg or 5 mg are used. For example, chloropropamide is typically given in the range of several hundred mg per day, glybenclamide in the range of 1.75 to 15 mg (preferably 1.75 to 10 mg) and glymepiride in the range of 1 to 4 mg per day.
    [42] Thus, in another aspect, the present invention provides a method of treating or preventing diabetes, comprising administering to a patient in need thereof an effective amount of a pharmaceutical combination as defined above. The present invention provides a method of treating insulin resistance syndrome, comprising administering an effective amount of a pharmaceutical combination as defined above to a patient in need thereof.
    [43] Another aspect of the invention
    [44] (i) (S) -2- ethoxy-3- [4- (2- {4-methanesulfonyloxy-phenyl} ethoxy) phenyl] propanoic acid or 3- {4- [2- (4- tert - A container containing butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof; and
    [45] (ii) a container containing sulfonylurea
    [46] And a kit of instructions comprising sequential, separate or simultaneous administration of one of said propanoic acids and sulfonylureas to a patient in need or benefit of administration.
    [47] Another aspect of the invention
    [48] (i) (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier or 3- {4- [2- (4- tert -butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof; And
    [49] (ii) pharmaceutical preparations containing sulfonylureas in admixture with pharmaceutically acceptable adjuvants, diluents or carriers
    [50] And a prop kit and a sulfonyl urea each provided in a form suitable for administration with each other.
    [51] Another aspect of the invention is a method of making a kit of parts as defined above, wherein component (i) as defined above is combined with component (ii) so that the two components are suitable to be administered together with each other. It provides a method including the making.
    [52] "Administering together" includes administering each preparation simultaneously, separately or sequentially, over the course of treatment of the condition, which may be acute or chronic. In particular, the term encompasses the two formulations being administered close enough in time (optionally, repeatedly), where it is administered alone (optionally repeatedly) without any other preparation over the same treatment route. This is because the beneficial effect on the patient is greater in the treatment route of the condition. The two preparations are preferably administered simultaneously or sequentially at intervals of, for example, 15 minutes to 12 hours, preferably 1 to 8 hours.
    [53] It also provides:
    [54] (1) (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier or 3- {4- [2- (4- tert -butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof and sulfonylurea Pharmaceutical preparations (hereinafter, referred to as "combination preparations"); And
    [55] (2) (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl mixed with component (a) a pharmaceutically acceptable adjuvant, diluent or carrier ] Propanoic acid or 3- {4- [2- (4- tert -butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof Pharmaceutical preparations; And (b) a pharmaceutical preparation comprising sulfonyl urea mixed with a pharmaceutically acceptable adjuvant, diluent or carrier, wherein components (a) and (b) are each provided in a form suitable for administration with each other. Parts kit.
    [56] Another aspect of the present invention is a method of making a kit of parts as defined above, wherein the component (a) as defined above is combined with component (b) as defined above to make the two components suitable for administration with each other. To provide.
    [57] "Banding" two components together means that components (a) and (b)
    [58] (i) provided as separate (ie, independent of each other) formulations and combined for use with each other in subsequent combination therapy; or
    [59] (ii) packaged and provided in separate components of a "combination pack" that can be used with each other in a combination therapy.
    [60] Thus, a part comprising instructions for using one component of (II) with another of the two components together with (I) one of components (a) and (b) as defined herein; Kits are also provided.
    [61] The kits of parts described herein include (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid or 3- {4- [2- ( 4- tert -butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or one or more preparations comprising pharmaceutically acceptable salts thereof and / or suitable for repeated dosing It may comprise one or more preparations comprising an amount / use of sulfonylurea (1). If more than one preparation (which includes the active ingredient) is present, these preparations are (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) Phenyl] propanoic acid or 3- {4- [2- (4- tert -butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof It may be the same or different in terms of dosage of sulfonyl urea, chemical composition and / or physical form.
    [62] Particularly claimed herein are specific fixed dosages that combine any of the dosages mentioned for the test compounds with any of the dosages mentioned for sulfonylureas (including the dosages mentioned for the above range as a limit).
    [63] The present invention will now be described in detail by way of examples. The test compound used hereafter is (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid or 3- {4- [2- (4 tert -butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid.
    [64] It is an advantage of the present invention to administer a) control b) test compound c) sulfonylurea and d) test compound and sulfonylurea to genetically obese diabetic animals such as Male Wistar rats, fa / fa Zucher rats or ob / ob mice Plasma glucose or for example glycemic parameters (fasting plasma glucose (FPG), insulin, proinsulin, C-peptide; lipid parameters (triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, total / HDL-cholesterol ratio) Another physiology of insulin resistance syndrome, such as LDL / HDL-cholesterol ratio, Apo A1, Apo B, Apo B / Apo A1 ratio, free fatty acids); thrombosis / vascular markers (PAI-1, fibrinogen, albumin / creatinine ratio) This can be demonstrated by measuring the chemical indicators: A statistical analysis of the results obtained for each compound compared to the results obtained in the combination will have a synergistic effect.
    [65] In contrast, when a test compound of the present invention is added to the treatment of a patient with type 2 diabetes mellitus, which is not well controlled by sulfonylurea alone, a 26-week randomized double-blind multi-cardial placebo- A regulatory study was conducted. Three doses of test compound are compared to placebo. Improvement in glycemic control and dyslipidemia is not well controlled by sulfonylurea treatment with placebo adaptive period diet / exercise therapy (ie, fasting plasma glucose level (FPG) of 126-240 mg / DL). Evaluate in patients with diabetes mellitus. The number of patients to be treated is appropriate from 100 to 500.
    [66] Studies include screening period (2 weeks or more), glyburide measurement period (4 weeks or less), placebo plus glyburide adaptation period (4 weeks, single blind, glyburide plus plybo plus diet / exercise), treatment period ( 26 weeks, double blind) and the subsequent period (3 weeks). All oral antidiabetic drugs other than glyburide monotherapy are required to be discontinuous at the time of the first hospital visit for screening. During the glyburide measurement period, the patient will be measured with optimal effects taking into account fasting plasma glucose and safety / persistence. However, in order to be eligible to continue the study, patients must be measured to glyburides of 10 mg or more per day. The patient then enters the placebo adaptation period; Patients with FPG greater than 126 mg / dL and 240 mg / dL at the placebo adaptive visit are eligible to enter the treatment period. Patients will receive counseling on supplemented diet improvements throughout the treatment period. Patients with more than 270 mg / dL FPG at consecutive visits will be required to be excluded from the study. At the end of the treatment period, eligible patients will be able to enter long-term open-label expansion studies.
    [67] Inclusion Criteria
    [68] Patients may be included in the study if they meet the following conditions:
    [69] Have been diagnosed with type 2 diabetes mellitus (fasting plasma glucose 126 mg / dl or more).
    [70] Eligible if the patient has been treated with a single or multiple oral formulation; However, all oral antidiabetic drugs other than glyburide monotherapy are required to be discontinuous at initial screening. The patient is required to have a fasting plasma glucose level of at least 126 mg / dL and 240 mg / dL during the placebo plus glyburide adaptation period.
    [71] Men and women aged 30-80 at the screening visit.
    [72] Female patients must be postmenopausal (ie, no more than six months without the menstrual cycle), surgically sterile or using hormonal contraceptives or intrauterine devices. Female patients taking hormonal contraceptives should also use additional screening methods for birth control.
    [73] Endogenous insulin is produced at screening and placebo adaptation visits as evidenced by fasting C-peptide levels of 0.8 ng / mL or more.
    [74] Fasting triglyceride concentrations during the placebo adjustment period should be within 40% of each other using higher values as denominators in calculations (low / high> 0.6)
    [75] Exclusion terms
    [76] Patients who meet one or more of the following conditions are excluded from the study:
    [77] Diabetic patients treated with chronic insulin treatment or thiazolidinedione (TZD; Glitazone) within 6 months of screening or have no prior drug experience. Patients treated with metformin, sulfonylurea, meglitinide, or alpha glucosidase inhibitors are eligible to enroll; However, their antidiabetic drugs (except sulfonylureas) should be discontinuous at the screening visit.
    [78] Patients with fasting triglycerides> 600 mg / dL or LDL-C> 250 mg / dL at any visit during the screening and placebo adaptation period.
    [79] Patients with uncontrolled hypertension (mean peak blood pressure of at least 170 mmHg or mean minimum blood pressure of at least 100 mmHg). Patients undergoing antihypertensive therapy with thiazide diuretic, alpha-adren activity blockers or beta-adren activity blockers should be given a constant dose of these drugs for at least one month prior to study enrollment and remain constant throughout the study period unless medically directed. Dosage should be maintained.
    [80] Patients treated with fiber compounds or other lipid lowering agents within a month of the screening visit. HMG-CoA reductase inhibitors are permitted provided that treatment is initiated at least three months prior to the screening visit and the dosage remains unchanged for at least three months prior to the screening visit.
    [81] Patients with a body weight index (BMI) greater than 40 kg / m 2 at screening.
    [82] Patients with active arterial disease such as unstable angina, myocardial infarction, metastatic ischemic attack (TIA), cerebrovascular accident (CVA), coronary bypass graft (CABG) surgery, or angioplasty within three months of the screening visit.
    [83] Patients with cardiac abnormalities of the New York Heart Association Class III or IV.
    [84] Patients with active liver disease or liver failure, defined as elevated ALT or AST above 1.5 times the upper limit of normal at any time during the screening or placebo adaptation period.
    [85] Patients who have previously experienced liver enzyme elevations while taking Troglitazone, Pioglitazone or Risiglitazone.
    [86] Kidney injury patients defined as having a serum creatine concentration greater than 1.8 mg / dL at any time during the screening or placebo adaptation period.
    [87] Patients with anemia or hemoglobin abnormality, at which time Hgb is defined as less than 11 g / dL for males and less than 10 g / dL for females during the screening or placebo adaptation period.
    [88] Patients with a history of malignant tumors within the last 5 years except for successful treatment of basal cell carcinoma or squamous cell skin carcinoma.
    [89] In case of pregnancy or lactation.
    [90] Patients with a serious or unstable medical or psychological condition that, in the opinion of the investigator, are concerned about the patient's safety or successful participation in the experiment.
    [91] Patients suspected of interfering with the safe completion of the study as the investigator judges, and who have clinically significant abnormalities identified during screening of physical examinations, laboratory tests or electrocardiograms.
    [92] Patients with a history of alcohol or drug abuse within the last 5 years.
    [93] Patients whose weight is unstable, with a change of more than 3 kg over three months prior to screening.
    [94] result
    [95] The effect of the test compound in combination with sulfonylurea on glycemic regulation is determined by the average change obtained from the HbA1c baseline compared to the sulfonylurea alone.
    [96] In addition, compare the average change obtained from the baseline of the sulfonylurea + test compound group and the sulfonylurea + placebo group in the following parameters:
    [97] Glycemic parameters (fasting plasma glucose (FPG)), insulin, proinsulin, C-peptide, lipid parameters (triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, total / HDL-cholesterol ratio, LDL / HDL-cholesterol Ratio, Apo A1, Apo B, Apo B / Apo A1 ratio, free fatty acids); Thrombosis / vascular marker (PAI-1, fibrinogen, urinary albumin / creatinine ratio).
    [98] In addition, the following is evaluated:
    [99] Analysis of response to HbA1c (% of patients showing a decrease from baseline of at least 0.7% and 1%); FPG (% of patients showing a decrease from baseline of 30 mg / dL or more) and TG (% of patients showing a decrease from baseline of 20% or more and 40%);
    [100] HbA1c (up to 8% and up to 7%); FPG (up to 126 mg / dL); And the ratio of patients attaining the target purpose to TG (200 mg / dL or less and 150 mg / dL or less);
    [101] HOMA: Percent change from baseline in insulin sensitivity and β-cell action.
    [102] Clinical safety and sustainability assessed by changes in physical investigations, vital signs, body weight, clinical laboratory tests, reverse assays, and electrocardiograms.
    [103] The patient will receive sulfonylureas in background treatment in an open-label manner. For each background treatment, a test compound of three test compounds (two highest doses and one starting dose) will be used, given in single doses daily, for 26 weeks. If there is any safety concern using the highest dose during the six month trial, the second highest dose may be used to continue to develop. The placebo will also be used as a comparator.
    [104] Results analysis is expected to demonstrate one or more of the following:
    [105] Significant improvement in the Glysm control compared to baseline and placebo for the combination of test compound and sulfonylurea;
    [106] Lipid profile improvement compared to baseline and placebo for the combination of test compound and sulfonylurea;
    [107] Most patients are "responders" to glycemic and triglyceride control in combination with sulfonylureas;
    [108] Most patients will achieve target goals for glycemic and lipid regulation in combination with sulfonylureas;
    [109] For test compounds in combination with sulfonylureas, effective glycemic and lipid control is independent of baseline BMI, age, sex, race or severity of disease and does not have clinically significant weight gain.
    [110] Statistical analysis of the results is also expected to demonstrate that the test compound and sulfonylureas have a synergistic effect on one or more physiological responses measured.
    权利要求:
    Claims (13)
    [1" claim-type="Currently amended] (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid or 3- {4- [2- (4- tert -butoxycar Bonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutical combination comprising any solvate and sulfonylurea of any of these.
    [2" claim-type="Currently amended] (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid or 3- {4 together with a pharmaceutically acceptable carrier and / or diluent -[2- (4- tert -butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof or solvates and sulfonyl of one of them Pharmaceutical composition comprising urea.
    [3" claim-type="Currently amended] A method of treating or preventing diabetes, comprising administering an effective amount of the pharmaceutical combination of claim 1 to a patient in need thereof.
    [4" claim-type="Currently amended] A method of treating insulin resistance syndrome, comprising administering an effective amount of the pharmaceutical combination of claim 1 to a patient in need thereof.
    [5" claim-type="Currently amended] (i) (S) -2- ethoxy-3- [4- (2- {4-methanesulfonyloxy-phenyl} ethoxy) phenyl] propanoic acid or 3- {4- [2- (4- tert - A container containing butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof; and
    (ii) a container containing sulfonylurea
    And instructions for sequential, separate or simultaneous administration of one of said propanoic acids and sulfonylureas to a patient in need or advantage of administration.
    [6" claim-type="Currently amended] (i) (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier or Pharmaceutical preparations containing 3- {4- [2- (4- tert -butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof ; And
    (ii) pharmaceutical preparations containing sulfonylureas in admixture with pharmaceutically acceptable adjuvants, diluents or carriers
    Comprising a, wherein the propanoic acid and sulfonyl urea are each provided in a form suitable for administration with each other.
    [7" claim-type="Currently amended] (1) (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier or 3- {4- [2- (4- tert -butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof and sulfonylurea Pharmaceutical preparations;
    (2) (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl mixed with component (a) a pharmaceutically acceptable adjuvant, diluent or carrier ] Propanoic acid or 3- {4- [2- (4- tert -butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof Pharmaceutical preparations; And a pharmaceutical preparation comprising sulfonyl urea mixed with component (b) a pharmaceutically acceptable adjuvant, diluent or carrier, wherein components (a) and (b) are each in a form suitable for administration with each other. Parts Kits Provided
    Combination preparation comprising a.
    [8" claim-type="Currently amended] A method of making a kit of parts as defined above, comprising combining component (a) as defined above with component (b) as defined above to make the two components suitable for administration with each other.
    [9" claim-type="Currently amended] The method of claim 8, wherein (a) and (b) of the kit of parts
    (i) provided as separate preparations that are independent of each other and merged together in subsequent combination treatments; or
    (ii) packaged and provided together as separate components of a "combination pack" so that they can be used with each other in a combination therapy.
    [10" claim-type="Currently amended] (I) one of components (a) and (b) as defined herein;
    (II) Instructions for using one component of (I) with the other of the two components
    Parts kit comprising a.
    [11" claim-type="Currently amended] The method according to any one of claims 5, 6 or 10, wherein (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propane One comprising an acid or 3- {4- [2- (4- tert -butoxycarbonylaminophenyl) ethoxy] phenyl}-(S) -2-ethoxy propanoic acid or a pharmaceutically acceptable salt thereof A kit of parts comprising one or more formulations comprising the above formulations and / or sulfonylureas in an amount / dosage suitable for repeated administration.
    [12" claim-type="Currently amended] The sulfonylurea according to any one of claims 1 to 11, wherein the sulfonylurea is glyburide, glymepiride, glybenclamide, glyclazide, glyphide, glyquidone, chloropropamide, tolbut Amides, acetohexamides, glycopyyramides, carbutamides, glyburnurides, glysoxides, glybutthiazoles, glybuzols, glyhexamides, glymidines, glypinamides, phenbutamides, tolsylamides and tols Pharmaceutical combinations, pharmaceutical compositions, methods or parts kits or combination preparations selected from one or more of razamides.
    [13" claim-type="Currently amended] The pharmaceutical according to any one of claims 1 to 12, further comprising one or more current additional treatments for type 2 diabetes and related complications thereof. The pharmaceutical composition or the method according to any one of claims 3, 4, 7, 8, or 9, or a method according to claim 5 or 6, 10 or 10. 12. The kit of parts according to claim 11 or claim 11.
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    同族专利:
    公开号 | 公开日
    SK14722003A3|2004-08-03|
    NO20035235D0|2003-11-25|
    CA2448763A1|2002-12-19|
    ZA200309263B|2005-03-11|
    SE0101982D0|2001-06-01|
    EE200300583A|2004-02-16|
    RU2003136157A|2005-05-20|
    WO2002100413A1|2002-12-19|
    CO5540382A2|2005-07-29|
    MXPA03011010A|2004-02-27|
    PL367890A1|2005-03-07|
    EP1399166A1|2004-03-24|
    IL159035D0|2004-05-12|
    HU0401613A2|2004-11-29|
    US20040157927A1|2004-08-12|
    JP2004532891A|2004-10-28|
    HU0401613A3|2007-11-28|
    CN1537008A|2004-10-13|
    BR0210127A|2004-06-08|
    IS7057A|2003-11-28|
    CZ20033235A3|2004-12-15|
    CN1250226C|2006-04-12|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-06-01|Priority to SE0101982A
    2001-06-01|Priority to SE0101982-7
    2002-05-30|Application filed by 아스트라제네카 아베
    2002-05-30|Priority to PCT/SE2002/001036
    2004-01-24|Publication of KR20040007624A
    优先权:
    申请号 | 申请日 | 专利标题
    SE0101982A|SE0101982D0|2001-06-01|2001-06-01|Pharmaceutical combination|
    SE0101982-7|2001-06-01|
    PCT/SE2002/001036|WO2002100413A1|2001-06-01|2002-05-30|A PHARMACEUTICAL COMBINATION COMPRISING EITHER -2-ETHOXY-3- [4- PHENYL] PROPANOIC ACID OR 3-{4-[2- ETHOXY] PHENYL} --2-ETHOXY PROPANOIC ACID AND A SULONYLUREA|
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