WO2004082601A2 - Methode de traitement du diabete et maladies liees au diabete - Google Patents

Methode de traitement du diabete et maladies liees au diabete Download PDF

Info

Publication number
WO2004082601A2
WO2004082601A2 PCT/US2004/006906 US2004006906W WO2004082601A2 WO 2004082601 A2 WO2004082601 A2 WO 2004082601A2 US 2004006906 W US2004006906 W US 2004006906W WO 2004082601 A2 WO2004082601 A2 WO 2004082601A2
Authority
WO
WIPO (PCT)
Prior art keywords
glucose
compound
diabetes
lowering activity
agents
Prior art date
Application number
PCT/US2004/006906
Other languages
English (en)
Other versions
WO2004082601A3 (fr
Inventor
James N. Livingston
Manami Tsutsumi
Original Assignee
Bayer Pharmaceuticals Corporation
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 Bayer Pharmaceuticals Corporation filed Critical Bayer Pharmaceuticals Corporation
Publication of WO2004082601A2 publication Critical patent/WO2004082601A2/fr
Publication of WO2004082601A3 publication Critical patent/WO2004082601A3/fr

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 

Definitions

  • This invention relates to a method of treating diabetes and diabetes-related disorders. Specifically, the method of the present invention relates to administering a single compound that lowers blood glucose levels, lowers serum triglyceride levels, and increases serum high density lipoproteins (HDL) levels thereby providing a treatment option for individuals afflicted with a metabolic disorder such as diabetes mellitus, insulin resistance, impaired glucose tolerance, and dyslipidemia.
  • a metabolic disorder such as diabetes mellitus, insulin resistance, impaired glucose tolerance, and dyslipidemia.
  • Diabetes is characterized by impaired glucose metabolism manifesting itself among other symptoms by an elevated blood glucose level in the diabetic patient. Underlying defects lead to the classification of diabetes into two major groups: type 1 diabetes, or insulin dependent diabetes mellitus (IDDM), which arises when patients lack ⁇ -cells ( ⁇ -cells produce insulin in the pancreatic gland), and type 2 diabetes, or non- insulin dependent diabetes mellitus (NIDDM), which occurs in patients with an impaired ⁇ - cell function and alterations in insulin action.
  • IDDM insulin dependent diabetes mellitus
  • NIDDM non- insulin dependent diabetes mellitus
  • Type 2 diabetes is the more common form of diabetes, with 90-95% of hyperglycemic patients experiencing this form of the disease.
  • type 2 diabetes there appears to be a reduction in the pancreatic ⁇ -cell mass, several distinct defects in insulin secretion, or a decrease in tissue sensitivity to insulin.
  • the symptoms of this form of diabetes include fatigue, frequent urination, thirst, blurred vision, frequent infections and slow healing of sores, diabetic nerve damage, retinopathy, and renal disease.
  • Insulin resistance is characterized by impaired uptake and utilization of glucose in insulin-sensitive target organs, for example, adipocytes and skeletal muscle, and by impaired inhibition of hepatic glucose output.
  • the functional insulin deficiency and the failure of insulin to suppress hepatic glucose output results in fasting hyperglycemia.
  • Pancreatic ⁇ -cells compensate for insulin resistance by secreting increased levels of insulin. However, the ⁇ -cells are unable to maintain this high output of insulin, and eventually, the glucose-induced insulin secretion falls, leading to the deterioration of glucose homeostasis and to the subsequent development of overt diabetes.
  • Improving diabetic dyslipidemia that is, lowering triglycerides and/or LDL, and raising HDL levels, significantly reduces the progression of macrovascular complications in patients with type 2 diabetes (Diabetes Atherosclerosis Intervention Study (DAIS) Investigators, Lancet 357:905-910, 2001; Tan, et al., Atherosclerosis 154:469-474, 2001 ; Frost, et al., Amer. J. Cardiol. 87:44-48, 2001).
  • DAIS Diabetes Atherosclerosis Intervention Study
  • Hyperinsulinemia is also linked to insulin resistance, hypertriglyceridemia, and increased plasma concentration of low-density lipoproteins.
  • Syndrome X The association of insulin resistance and hyperinsulinemia with these metabolic disorders has been termed "Syndrome X,” and has been strongly linked to an increased risk of hypertension and coronary artery disease.
  • Type 1 diabetic patients are currently treated wi tlh insulin, while the majority of type 2 diabetic patients are treated with agents that sti mi ulate ⁇ -cell function or with agents that enhance the tissue sensitivity of these pati ei nts towards insulin. Over time, almost one-half of type 2 diabetic subjects lose their response to these agents and then, must be placed on insulin therapy.
  • the drugs presently used to treat type 2 diabetes include, for example, alpha- glucosidase inhibitors which reduce the excursion of postprandial glucose by delaying the absorption of glucose from the gut. These drugs are safe and provide treatment for mild to moderately affected diabetic subjects. However, gastrointestinal side effects have been reported.
  • Insulin sensitizers such as rosiglitazone and pioglitazone activate the peroxisome proliferator activated receptor (PPAR) gamma receptor and modulate the activity of a set of genes that have not been well characterized. Although effective, these drugs are associated with edema and do not specifically address macrovascular component of diabetic complications.
  • PPAR peroxisome proliferator activated receptor
  • Insulin secretagogues such as sulfonylureas (SFUs), and other agents that act by the ATP-dependent K+ channel, are standard therapy for type 2 diabetics that have mild to moderate fasting glycemia.
  • SFUs have limitations that include a potential for inducing hypoglycemia, weight gain, and high primary and secondary failure rates. Ten to 20% of initially treated patients fail to show a significant treatment effect (primary failure). Secondary failure is demonstrated by an additional 20-30% loss of treatment effect after six months on SFU treatment. Insulin treatment is required in 50% of the SFU responders after 5-7 years of therapy (Scheen et al., Diabetes Res. Clin. Pract. 6:533- 543, 1989).
  • Metformin is a biguanide that lowers blood glucose by decreasing hepatic glucose output and increasing peripheral glucose uptake and utilization.
  • the drug is effective at lowering blood glucose in mildly and moderately affected subjects and does not have the side effects of weight gain or the potential to induce hypoglycemia.
  • metformin has a number of side effects including gastrointestinal disturbances and lactic acidosis.
  • Metformin is contraindicated in diabetics over the age of 70 and in subjects with impairment in renal or liver function.
  • metformin has the same primary and secondary failure rates as the SFUs.
  • Insulin treatment is generally instituted after diet, exercise, and oral medications have failed to adequately control blood glucose. This treatment is by an injectable and it can produce hypoglycemia as well as weight gain.
  • new therapies to treat type 2 diabetes are needed.
  • new treatments to address both hyperglycemia and dyslipidemia are needed.
  • Such new drugs should have the following characteristics: dependence on glucose for promoting insulin secretion, that is, produce insulin secretion only in the presence of elevated blood glucose; correct diabetic dyslipidemia, for example, increase HDL levels and lower triglyceride and LDL levels; and minimal primary and secondary failure rates.
  • Insulin sensitizers improve glucose regulation in human type 2 diabetic patients and alleviate microvascular complications of type 2 diabetes, however, these medications have little to no effect on macrovascular complications.
  • Fibrates such as fenofibrate, and statins are another type of medication used to treat patients with type 2 diabetes to control macrovascular complications of diabetes. Fibrates are used to lower serum triglycerides, while statins are used to lower LDL levels in patients with diabetic dyslipidemia.
  • Such a compound would be more beneficial to a patient with type 2 diabetes or Syndrome X with dyslipidemia because it would possess triple activity (i.e., lower glucose and serum triglyceride levels, and increase HDL levels) while minimizing potential side effects that could come from administration of multiple compounds to treat these conditions.
  • the present invention relates to a method of treating diabetes and diabetes-related disorders by administering to a subject in need a single compound with triple activity, that is, a compound which lowers blood glucose, increases serum HDL levels, and decreases serum triglyceride levels.
  • Diabetes-related disorders include hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, Syndrome X, insulin resistance, obesity, atherosclerotic disease, hyperlipidemia, hypercholesteremia, low HDL levels, hypertension, cardiovascular disease, cerebrovascular disease, peripheral vessel disease, lupus, polycystic ovary syndrome, carcinogenesis, and hyperplasia.
  • the method of the present invention may be used to treat mammals such as rodents, primates including humans, sheep, canines, felines, bovines, and swine.
  • the method of the present invention comprises administering to a subject in need a compound which has glucose-lowering activity, triglyceride-lowering activity, and increases HDL levels in combination with one or more hypoglycemic agents.
  • the method of the present invention comprises administering to a subject in need a compound which has glucose-lowering activity, triglyceride-lowering activity, and increases HDL levels in combination with one or more agents including HMG CoA reductase inhibitors, bile acid binding agents, fibric acid derivatives, agents that regulates hypertension, or agents that regulates body weight.
  • a compound which has glucose-lowering activity, triglyceride-lowering activity, and increases HDL levels in combination with one or more agents including HMG CoA reductase inhibitors, bile acid binding agents, fibric acid derivatives, agents that regulates hypertension, or agents that regulates body weight.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound which has glucose-lowering activity, triglyceride-lowering activity, and increases HDL levels with a pharmaceutically acceptable carrier.
  • This pharmaceutical composition may also include one or more hypoglycemic agents, HMG CoA reductase inhibitors, bile acid binding agents, fibric acid derivatives, agents that regulates hypertension, or agents that regulates body weight.
  • the method of the present invention may be effective in the treatment of type 2 diabetes, as well as for a number of diabetes-related disorders, such as hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, Syndrome X, insulin resistance, obesity, and in the treatment of atherosclerotic disease, hyperlipidemia, hypercholesteremia, low HDL levels, hypertension, cardiovascular disease (including atherosclerosis, coronary heart disease, coronary artery disease, and hypertension), cerebrovascular disease and peripheral vessel disease; and for the treatment of lupus, polycystic ovary syndrome, carcinogenesis, and hyperplasia.
  • Obesity is an excessive accumulation of adipose tissue.
  • adipose tissue is associated with the development of serious medical conditions, for example, type 2 diabetes, hypertension, coronary artery disease, hyperlipidemia, obesity, and certain malignancies.
  • the adipocyte may also influence glucose homeostasis through the production of tumor necrosis factor ⁇ (TNF ⁇ ) and other molecules.
  • TNF ⁇ tumor necrosis factor ⁇
  • Atherosclerotic disease is a major cause of death in type 2 diabetes and is known to be caused by a number of factors, for example, hypertension, diabetes, low levels of HDL, and high levels of LDL.
  • Atherosclerotic disease includes cardiovascular disease, coronary heart disease (CHD), cerebrovascular disease, and peripheral vessel disease.
  • Coronary heart disease includes CHD death, myocardial infarction, and coronary revascularization.
  • Cerebrovascular disease includes ischemic or hemorrhagic stroke, and transient ischemic attacks.
  • Particularly useful compounds are those with efficacy in lowering blood glucose levels and serum triglyceride levels, and raising serum HDL cholesterol levels, that is, a compound which possesses triple activity.
  • this compound with triple activity may be administered alone or in combination with one or more additional hypoglycemic agents.
  • Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound with triple activity and one or more additional hypoglycemic agent, as well as administration of a compound with triple activity and each additional hypoglycemic agents in its own separate pharmaceutical dosage formulation.
  • a compound with triple activity and hypoglycemic agent may be administered to a subject together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.
  • a compound with triple activity and one or more additional hypoglycemic agents may be administered at essentially the same time (e.g., concurrently) or at separately staggered times (e.g., sequentially).
  • a compound with triple activity may be administered in combination with one or more of the following additional hypoglycemic agents: insulin; biguanidines such as metformin or buformin; sulfonylureas such as acetohexamide, chloropropamide, tolazamide, tolbutamide, glyburide, glipizide, glyclazide; or any other insulin secretagogue such as, for example, repaglinide and nateglinide; ⁇ -glycosidase inhibitors such as acarbose, voglibose, or miglitol; or ⁇ 3 -adrenoreceptor agonists such as CL-316,243.
  • additional hypoglycemic agents such as metformin or buformin
  • sulfonylureas such as acetohexamide, chloropropamide, tolazamide, tolbutamide, glyburide, glipizide, glyclazi
  • a compound with triple activity may be used in combination with HMG Co-A reductase inhibitors (statins), bile acid binding resin, or fibric acid derivatives to improve the lipid profile of subjects with dyslipidemia and insulin resistance.
  • a compound with triple activity may also be used in combination with agents that regulate hypertension (e.g., inhibitors of angiotension converting enzyme (ACE), ⁇ -blockers, calcium channel blockers) and body weight of subjects with insulin resistance or type 2 diabetes.
  • agents that regulate hypertension e.g., inhibitors of angiotension converting enzyme (ACE), ⁇ -blockers, calcium channel blockers
  • Celite ® diatomaceous earth filter agent ® Celite Corp.
  • the reaction mixture was then diluted with CH 2 CI 2 (500 mL) and washed with N HCI (500 mL), brine (500 mL), and dried over Na 2 SO .
  • the resultant amide product (310 g, 91%), a white solid, was obtained after solvent removal and drying under vacuum. It was then dissolved in pyridine (1.25 L) and DMAP (5 g) was added. Acetic anhydride (840 mL) was added slowly and then the reaction was heated at 90°C for 2 hours. The cooled solution was poured into 7 L ice water and extracted with 6 liters of EtOAc. The organic layer was washed with 2N HCI (3 x 1 L) and 1N NaOH (1 L), dried over MgSO 4 and concentrated to afford the title compound as a white solid (301 g, 93%).
  • the suspension was cooled to 0°C, then filtered, and the solids were washed with 500 mL acetone. After drying under suction, a sample analyzed by HPLC showed 95% ee. The recrystallization process was repeated as above using 6.7 L acetone. HPLC analysis showed 99% ee. After drying under suction, 192 g salt were obtained. The salt was suspended in 2 L EtOAc and 1 L of 1 N HCI solution, and shaken in a separatory funnel, whereupon the salt dissolved. The organic layer was separated, washed with 1 N HCI (500 mL), water (2 x 300 mL), and brine, then dried over Na 2 SO 4 .
  • the title compound may also be prepared via an enzymatic process.
  • a cloudy mixture of the crude ester (500.0 g, 2.13 mol; 87% pure as determined by HPLC) prepared in Example 5, in 1 L reagent grade acetone, 2.5 L phosphate Buffer (pH 7.0, 0.05 M) and 2.5 L deionized water was treated in one portion with Amano Lipase PS (150 g), and the mixture stirred efficiently at rt overnight.
  • HPLC analysis of an aliquot homoogeneous aliquot prepared by dissolving aliquot in IPA followed by filtration) showed one peak corresponding to unreacted R-ester and another peak corresponding to desired S-acid.
  • the effective dosage of a compound of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the subject treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered may generally range from about 0.001 mg/kg to about 200 mg/kg, and preferably from about 0.01 mg/kg to about 200 mg/kg body weight per day.
  • a unit dosage may contain from about 0.05 mg to about 1500 mg of active ingredient, and may be administered one or more times per day.
  • the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous, and parenteral injections, and use of infusion techniques may be from about 0.01 to about 200 mg/kg.
  • the daily rectal dosage regimen may be from 0.01 to 200 mg/kg of total body weight.
  • the transdermal concentration may be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the specific initial and continuing dosage regimen for each subject will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age of the subject, the diet of the subject, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention may be ascertained by those skilled in the art using conventional treatment tests.
  • a compound of this invention may be utilized to achieve the desired pharmacological effect by administration to a subject in need thereof in an appropriately formulated pharmaceutical composition.
  • a subject for the purpose of this invention, is a mammal such as rodents, primates including humans, sheep, canines, felines, bovines, and swine, in need of treatment for a particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound as described herein.
  • a pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a subject at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • a pharmaceutically effective amount of a compound is that amount which produces a result or exerts an influence on the particular condition being treated.
  • a compound as described herein may be administered with a pharmaceutically-acceptable carrier using any effective conventional dosage unit forms, including, for example, immediate and timed release preparations, orally, parenterally, topically, or the like.
  • the compound may be formulated into solid or liquid preparations such as, for example, capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • the solid unit dosage forms may be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
  • the compound of this invention may be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin; disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum; lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example, talc, stearic acid, or magnesium, calcium or zinc stearate; dyes; coloring agents; and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the subject.
  • conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin
  • disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and
  • Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, those sweetening, flavoring and coloring agents described above, may also be present.
  • the pharmaceutical compositions of this invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifying agents may be (1 ) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil, or coconut oil; or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
  • the suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p- hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents.
  • sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose.
  • Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents.
  • the compound of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions; an alcohol such as ethanol, isopropanol, or hexadecyl alcohol; glycols such as propylene glycol or polyethylene glycol; glycerol ketals such as 2,2-dimethyl-1 ,1-dioxolane-4-methanol, ethers such as poly(ethyleneglycol) 400; an oil; a fatty acid; a fatty acid ester or glyceride; or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pec
  • oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum, and mineral oil.
  • Suitable fatty acids include oleic acid, stearic acid, and isostearic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • Suitable soaps include fatty alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepoiypropylene copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
  • suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides
  • compositions of this invention may typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulation ranges from about 5% to about 15% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • the pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions.
  • Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono or diglycerides.
  • fatty acids such as oleic acid may be used in the preparation of injectables.
  • a composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions may be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such material are, for example, cocoa butter and polyethylene glycol.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., U.S. Patent No. 5,023,252, incorporated herein by reference).
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • compositions of the invention may also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Any of the compositions of this invention may be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.
  • compositions for its intended route of administration include: acidifying agents, for example, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid; and alkalinizing agents such as, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine.
  • acidifying agents for example, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid
  • alkalinizing agents such as, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine.
  • adsorbents e.g., powdered cellulose and activated charcoal
  • aerosol propellants e.g., carbon dioxide, CCI 2 F 2 , F 2 CIC-CCIF 2 and CCIF 3
  • air displacement agents e.g., nitrogen and argon
  • antifungal preservatives e.g., benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate
  • antimicrobial preservatives e.g., benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal
  • antioxidants e.g., ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole,
  • clarifying agents e.g., bentonite
  • emulsifying agents but are not limited to, acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyethylene 50 stearate
  • encapsulating agents e.g., gelatin and cellulose acetate phthalate
  • flavorants e.g., anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
  • humectants e.g., glycerin, propylene glycol and sorbitol
  • levigating agents e.g., mineral oil and glycerin
  • oils e.g., arachis oil, mineral oil, olive oil, peanut
  • the compound as described herein may be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the compound of this invention can be combined with known anti-obesity, or with known antidiabetic or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • compositions which are comprised of an inert carrier and an effective amount of a compound identified by the methods described herein, or a salt or ester thereof.
  • An inert carrier is any material which does not interact with the compound to be carried and which lends support, means of conveyance, bulk, traceable material, and the like to the compound to be carried.
  • An effective amount of compound is that amount which produces a result or exerts an influence on the particular procedure being performed.
  • Formulations suitable for subcutaneous, intravenous, intramuscular, and the like; suitable pharmaceutical carriers; and techniques for formulation and administration may be prepared by any of the methods well known in the art (see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20 th edition, 2000).
  • a capsule formula is prepared from: Compound of this invention 40 mg
  • the components are blended, passed through an appropriate mesh sieve, and filled into hard gelatin capsules.
  • Tablet Formulation A tablet is prepared from:
  • a 5 mg/ml solution of the desired compound of this invention is made using sterile, injectable water, and the pH is adjusted if necessary.
  • the solution is diluted for administration to 1-2 mg/ml with sterile 5% dextrose and is administered as an IV infusion over 60 minutes.
  • the following intramuscular suspension is prepared:
  • the suspension is administered intramuscularly.
  • a large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
  • a mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient.
  • the capsules are washed and dried.
  • the active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
  • the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
  • the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
  • Demonstration of the activity of a compound may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art.
  • in vitro, ex vivo, and in vivo assays that are well known in the art.
  • the following assays may be used.
  • Example 1 Insulin Receptor Binding in 3T3-L1 Cells Treated with Compounds [095] 3T3-L1 cells were seeded at 9300 cells per well in Costar flat bottom TC and incubated for 1 week until they were 2 days post-confluent. The cells were then treated for 2 days with differentiation media (Dulbecco's Modified Eagle Medium (DMEM),100 ⁇ g/ml Penicillin/Streptomycin, 2 mM L-Glutamine, 10% Fetal Bovine Serum) containing 0.5 ⁇ M human Insulin-like Growth Factor (IGF-1) and test compounds. After treatment, the media was replaced with differentiation media, and the cells were incubated for 4 days. The cells were then assayed for insulin receptor activity.
  • differentiation media Dulbecco's Modified Eagle Medium (DMEM),100 ⁇ g/ml Penicillin/Streptomycin, 2 mM L-Glutamine, 10% Fetal Bovine Serum
  • IGF-1 Insulin-like Growth Factor
  • Example 2 Method for Measuring Blood Glucose Levels
  • the following method may be used to identify a compound that has glucose lowering activity
  • db/db mice were bled (by either eye or tail vein) and grouped according to equivalent mean blood glucose levels. They were dosed orally (by gavage in a pharmaceutically acceptable vehicle) with the test compound or control (e.g., vehicle only) once daily for 7 days. On day 8, the animals were bled again by eye or tail vein and blood glucose levels were determined. In each case, glucose levels were measured with a Glucometer Elite XL (Bayer Corporation, Elkhart, IN), and the glucose levels of control vs. treated animals were compared.
  • Glucometer Elite XL Bayer Corporation, Elkhart, IN
  • hApoAI mice were bled (by either eye or tail vein) and grouped according to equivalent mean serum triglyceride levels. They were dosed orally (by gavage in a pharmaceutically acceptable vehicle) with the test compound or control (e.g., vehicle only) once daily for 7 days. The animals were then bled by eye or tail vein on day 8, and serum triglyceride levels were determined. In each case, triglyceride levels were measured using a Technicon Axon Autoanalyzer (Bayer Corporation, Tarrytown, NY), and the triglyceride levels of control vs. treated animals were compared.
  • Example 4 Method for Measuring HDL-Cholesterol Levels [098] To identify a compound that increased plasma HDL-cholesterol levels, hApoAI mice are bled and grouped with equivalent mean plasma HDL-cholesterol levels. The mice are orally dosed once daily with vehicle or test compound or control (e.g., vehicle) for 7 days, and then bled again on day 8. Plasma is analyzed for HDL-cholesterol using the Synchron Clinical System (CX4) (Beckman Coulter), and plasma HDL-cholesterol levels of control vs. treated animals were compared.
  • CX4 Synchron Clinical System
  • Example 5 Method for Measuring Total Cholesterol, HDL-Cholesterol,
  • Triglycerides, and Glucose Levels [099] In another in vivo assays, obese monkeys are bled, then orally dosed once daily with vehicle or test compound for 4 weeks, and then bled again. Serum is analyzed for total cholesterol, HDL-cholesterol, triglycerides, and glucose using the Synchron Clinical System (CX4) from Beckman Coulter. Lipoprotein subclass analysis is performed by NMR spectroscopy as described by Oliver et al., (PNAS 98(9):5306-5311 , 2001 ).
  • Cardiovascular parameters e.g., heart rate and blood pressure
  • SHR rats are orally dosed once daily with vehicle or test compound for 2 weeks.
  • Blood pressure and heart rate are determined using a tail-cuff method as described by Grinsell et al., (Am. J. Hypertens. 13(4):370-375, 2000).
  • blood pressure and heart rate are monitored as described by Shen et al., (J. Pharmacol. Exp. Therap. 278(3):1435-1443, 1996).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention porte sur une méthode de traitement du diabète et des maladies liées au diabète. La méthode de cette invention consiste notamment à administrer un composé unique qui réduit les taux de glucose dans le sang, ainsi que les taux de triglycéride sérique et augmente les taux de lipoprotéines sériques de haute densité (HDL), ce qui entraîne éventuellement le traitement d'individus soufrant d'un trouble métabolique tel que le diabète sucré, la résistance à l'insuline, la diminution de tolérance au glucose et la dyslipidémie.
PCT/US2004/006906 2003-03-13 2004-03-05 Methode de traitement du diabete et maladies liees au diabete WO2004082601A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US45428103P 2003-03-13 2003-03-13
US60/454,281 2003-03-13

Publications (2)

Publication Number Publication Date
WO2004082601A2 true WO2004082601A2 (fr) 2004-09-30
WO2004082601A3 WO2004082601A3 (fr) 2005-03-10

Family

ID=33029869

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/006906 WO2004082601A2 (fr) 2003-03-13 2004-03-05 Methode de traitement du diabete et maladies liees au diabete

Country Status (1)

Country Link
WO (1) WO2004082601A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1630152A1 (fr) * 2003-05-30 2006-03-01 Takeda Pharmaceutical Company Limited Compose cyclique condense
WO2014165816A1 (fr) * 2013-04-05 2014-10-09 North Carolina Central University Composés utiles dans le traitement de troubles métaboliques et leur synthèse

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6028052A (en) * 1995-09-18 2000-02-22 Ligand Pharmaceuticals Incorporated Treating NIDDM with RXR agonists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6028052A (en) * 1995-09-18 2000-02-22 Ligand Pharmaceuticals Incorporated Treating NIDDM with RXR agonists

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1630152A1 (fr) * 2003-05-30 2006-03-01 Takeda Pharmaceutical Company Limited Compose cyclique condense
EP1630152A4 (fr) * 2003-05-30 2009-09-23 Takeda Pharmaceutical Compose cyclique condense
US7820837B2 (en) 2003-05-30 2010-10-26 Takeda Pharmaceutical Company Limited Condensed ring compound
WO2014165816A1 (fr) * 2013-04-05 2014-10-09 North Carolina Central University Composés utiles dans le traitement de troubles métaboliques et leur synthèse
US10005720B2 (en) 2013-04-05 2018-06-26 North Carolina Central University Compounds useful for the treatment of metabolic disorders and synthesis of the same

Also Published As

Publication number Publication date
WO2004082601A3 (fr) 2005-03-10

Similar Documents

Publication Publication Date Title
US7112597B2 (en) Indane acetic acid derivatives and their use as pharmaceutical agents, intermediates, and method of preparation
JP5420400B2 (ja) Ｇタンパク質共役型レセプター作動剤
CN110105200B (zh) 用于治疗纤维化的经取代的芳族化合物及相关方法
JP2005507932A (ja) 肥満の処置のためのフェニル置換５−員窒素含有複素環
Porcelli et al. Synthesis, characterization and biological evaluation of ureidofibrate-like derivatives endowed with peroxisome proliferator-activated receptor activity
AU2016235263A1 (en) Methods of treating liver disease using indane acetic acid derivatives
CN1348436A (zh) 新颖的核受体ppar配体
KR101662592B1 (ko) 퍼옥시좀 증식체-활성화 수용체 하위유형 델타에 대한 흥분 효과를 가진 화합물, 이의 제조방법 및 이의 용도
WO2004011446A1 (fr) Derives d'acide carboxylique d'indane, de dihydrobenzofurane et de tetrahydronaphthalene et leurs utilisations comme antidiabetiques
EP1572180B1 (fr) Utilisation d'acides alpha-phenylthiocarboxyliques ayant une activite de reduction du taux du glucose serique et du taux des lipides seriques
CN105683152A (zh) 用于治疗高血压和/或纤维化的组合物
JP4530668B2 (ja) インダン酢酸誘導体および薬剤としてのそれらの使用
US7268157B2 (en) Substituted arylalcanoic acid derivatives as PPAR pan agonists with potent antihyperglycemic and antihyperlipidemic activity
JP5252585B2 (ja) 代謝障害の治療のための化合物
WO2004082601A2 (fr) Methode de traitement du diabete et maladies liees au diabete
EP0518769B1 (fr) Nouveaux dérivés de benzoate d'éthanolamine, leur procédé de préparation et les compositions pharmaceutiques les renfermant
RU2342362C2 (ru) Замещенные производные арилалкановой кислоты как пан агонисты рапп с высокой антигипергликемической и антигиперлипидемической активностью
WO2010141690A2 (fr) Analogues d'indane, leur utilisation comme agents pharmaceutiques et leur procédé de préparation
JP2002097139A (ja) オキシイミノアルカン酸誘導体の結晶を含有する医薬

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
122 Ep: pct application non-entry in european phase