WO2009088220A2 - Diamide nicotinate n,n-diméthyl imidodicarbonimidique, son procédé de production et composition pharmaceutique le comprenant - Google Patents

Diamide nicotinate n,n-diméthyl imidodicarbonimidique, son procédé de production et composition pharmaceutique le comprenant Download PDF

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WO2009088220A2
WO2009088220A2 PCT/KR2009/000071 KR2009000071W WO2009088220A2 WO 2009088220 A2 WO2009088220 A2 WO 2009088220A2 KR 2009000071 W KR2009000071 W KR 2009000071W WO 2009088220 A2 WO2009088220 A2 WO 2009088220A2
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metformin
formula
nicotinate
pharmaceutical composition
diabetes
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WO2009088220A3 (fr
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Sung Wuk Kim
Sung Soo Jun
Young Gwan Jo
Ja Seong Koo
Young Woong Kim
Byoung Ha Kim
Min Seok Kang
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Hanall Pharmaceutical Co Ltd
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Hanall Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/465—Nicotine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a novel salt of N, N-dimethyl imidodicarbonimidic diamide, a preparation method thereof, and a pharmaceutical composition thereof, and more particularly, to physicochemical properties such as solubility, stability, non-hygroscopicity, and processability as a tablet formulation.
  • diabetes mellitus complications of diabetic patients with diabetes, diabetes, obesity, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome N, N-dimethyl imidodicarbonimiddia, a very effective therapeutic agent for the prevention and treatment of complications due to the neutral lipid lowering effect as a causative agent, and for the prevention and treatment of cancer, myalgia, muscle cytotoxicity and rhabdomyolysis, which lack p53 gene Novel crystalline acid addition salts of meads, methods for preparing the same and pharmaceutical compositions thereof to be.
  • N, N-dimethyl imidodicarbonimidic diamide commonly known as metformin
  • metformin is an insulin-independent diabetes treatment that is the most effective hypoglycemic and complication of all oral diabetes medications when diabetic patients take this drug. It is a biguanide drug with the best prevention against occurrence and deterioration.
  • metformin is the only option that has been characterized in several papers.
  • AMPK AMP-activated protein kinase
  • metformin activates this enzyme to normalize hyperglycemia, improve lipid status, normalize menstrual irregularities, ovulation and pregnancy, treat fatty liver, and gene p53 (Tumor protein) prevention and treatment of cancers lacking p53) have been reported.
  • metformin an AMPK enzyme activator
  • metformin activates the AMPK enzyme, which develops energy metabolism that adapts to it, regulates sugar and lipids and removes cancer cells.
  • the p53 gene causes suicide of damaged or unwanted cells and senescent cells.
  • the p53 gene is missing and becomes a refractory cancer cell.
  • metformin activates the AMPK enzyme of refractory cancer cells lacking the p53 gene, altering metabolic pathways and killing cancer cells because they cannot adapt to the altered metabolic pathways.
  • AMPK energy metabolic regulator
  • Metformin is a drug that normalizes sugar and lipid metabolism by activating the AMPK enzyme, and metformin in cancers lacking the p53 gene alters the energy metabolic pathways of cancer cells and increases anticancer activity in proportion to the dose of metformin. It has been found to be effective in treating cancer at normal doses for treating diabetes.
  • Atrogin-1 gene causes myalgia, muscle cell damage and even rhabdomyolysis, but metformin inhibits the expression of the Atrogin-1 gene due to PGC-1 ⁇ transcription factor activity. Inhibits and prevents muscle damage caused by increased expression of
  • metformin is useful in the free base form, but because of the disadvantage of poor stability, it is administered in the form of a pharmaceutically acceptable acid addition salt.
  • Korean Patent Registration No. 90,479 discloses (1) excellent solubility in preparing in the form of a pharmaceutically acceptable salt; (2) good stability; (3) nonhygroscopic; (4) states that four physicochemical criteria such as processability as tablet formulations should be met.
  • a pharmaceutically acceptable acid addition salt it is very difficult to meet all four conditions.
  • a patent for metformin acetylsalicylate in US 3,957,853 is filed and a patent for a new addition salt of biguanide-based compound in US 4,028,402.
  • US 4,080,472 has filed a patent for a diabetes related disease of metformin clofibrate
  • US 6,031,004 discloses a pharmaceutical composition of fumarate, succinate and maleate of metformin and its use
  • Chloro-phenoxyacetate, US 3,903,141 discloses adamantane salts.
  • metformin has been approved only as a hydrochloride drug and is widely prescribed as a drug for treating non-insulin dependent diabetes mellitus.
  • the dosage is up to 2550 mg per day, with 500 mg, 750 mg tablets taken two to three times daily with meals.
  • metformin hydrochloride and other addition salts are required for improvement of physicochemical properties such as solubility, stability, non-hygroscopicity, anti-adhesion properties, and lowering of toxicity for pharmacological effects.
  • the object of the present invention is to have excellent physicochemical properties such as non-hygroscopicity, solubility, stability, processability as a tablet formulation, low toxicity, diabetes, obesity, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis or polycystic ovary syndrome.
  • the present invention provides a pharmaceutically acceptable metformin nicotinate effective for the prevention and treatment of diabetes mellitus of the metabolic syndrome and its complications, cancers lacking the p53 gene, myalgia, myoctotoxicity and rhabdomyolysis, and a method of preparing the same.
  • an object of the present invention includes a novel nicotinate of metformin as an active ingredient, a person with a so-called metabolic syndrome in which diabetes and diabetes, obesity, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, etc.
  • a very effective pharmaceutical composition for the prevention and treatment of diabetes mellitus and its complications cancer lacking the p53 gene, myalgia, muscle cell toxicity and rhabdomyolysis.
  • the present inventors completed the present invention by preparing a composition useful as metformin nicotinate, a method for preparing the same, and a diabetes therapeutic agent comprising the same.
  • metformin nicotinate represented by the following formula (1)
  • N is 1 or 2.
  • N is 1 or 2.
  • organic solvent is an organic solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone and acetonitrile;
  • composition according to the above (8) further comprising a pharmaceutically acceptable carrier, diluent, or excipient;
  • Josie M M Evans has shown a lower incidence of cancer in patients with type 2 diabetes than those who do not receive metformin [Josie MM, Evans et al. BMJ. 2005, 330, 1304-1305.
  • Samantha L. Bowker also reported that patients with type 2 diabetes who take metformin have lower cancer-related mortality than patients who take sulfonylureas or take insulin [Samantha L et al. Diabetes Care. 2006, 29, 254-258.
  • nicotinic acid has recently become widely recognized as a drug for increasing neutral lipids, which is particularly high in diabetics, and as a drug that increases HDL (High-density lipoprotein), a good lipid [Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J. Am. Coll. Cardiol. 8 (6): 1245-1255 (1986)], metformin's neutral lipid lowering action is an essential characteristic of metformin, which has long been widely known in the clinical field.
  • the new metformin nicotinate of the present invention made of metformin nicotinate can be a diabetic drug that greatly enhances the neutral lipid lowering action, which is a fundamental core cause of complications of diabetics.
  • Metformin nicotinate according to the present invention is superior to metformin hydrochloride, which has previously been used as a diabetic agent, and is particularly effective on fasting as well as postprandial blood sugar drop and increases insulin sensitivity.
  • the method for preparing metformin nicotinate according to the present invention has established a process so that it is simple and can proceed without special equipment.
  • Metformin nicotinate according to the present invention is a crystalline acid addition salt suitable for the preparation of pharmaceutical formulations, while using solubility, stability, non-hygroscopicity and tablet formulation, while using nicotinic acid having a relatively low toxicity compared to conventional metformin hydrochloride prepared using hydrochloric acid.
  • diabetes mellitus treatment in people with metabolic syndrome such as diabetes and diabetes, obesity, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis and polycystic ovary syndrome
  • metabolic syndrome such as diabetes and diabetes, obesity, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis and polycystic ovary syndrome
  • hypolipidemic action which is the core cause of complications of diabetes mellitus
  • cancers lacking p53 gene and myalgia, muscle cell toxicity and rhabdomyolysis As a composition Pharmacologically excellent effect can be expected.
  • Table 1 compares the oral toxicity of hydrochloric acid forming crystalline acid addition salt of metformin hydrochloride and nicotinic acid forming crystalline acid addition salt of metformin nicotinate. Toxicity data for two acids were extracted from Registry of Toxic Effects of Chemical Substances (RTECS) Data.
  • the hydrochloric acid used to prepare the crystalline acid addition salt of metformin is toxic as the compound itself, but the nicotinic acid used in the present invention is safe enough to be 1/5 or less than hydrochloric acid.
  • the pharmacological effects of metformin nicotinate in various ways in vivo and in vitro have shown that metformin nicotinate has a hypoglycemic effect, lipid lowering effect and metabolic syndrome compared to metformin hydrochloride. In addition to improving metabolic syndrome, it can be expected that a lower dose than metformin hydrochloride can be used to achieve the therapeutic purpose.
  • the present invention not only has better physicochemical properties such as solubility, stability, non-hygroscopicity and processability as tablet formulations, but also has low toxicity, the therapeutic effect of diabetes and its complications, cancers lacking the p53 gene and myalgia, muscle cell toxicity and Novel metformin nicotinate of formula (1) is more effective for the prevention or treatment of rhabdomyolysis.
  • N is 1 or 2.
  • the present invention includes a method for preparing metformin nicotinate of formula (1), the preparation method is prepared by adding a base to the metformin hydrochloride of formula (2) in water or an organic solvent, as shown in Scheme 1 below It consists of preparing by reacting the metformin free base represented by the nicotinic acid represented by the following formula (4).
  • N is 1 or 2.
  • Metformin crystalline acid addition salt according to the present invention is prepared by adding nicotinic acid in a solution containing metformin free base represented by the formula (3), and will be described in detail for each preparation step as follows.
  • water or an organic solvent may be used to obtain metformin free base, and it is preferable to use only an organic solvent.
  • nicotinic acid is used in an amount of 1 to 4 molar equivalents to 1 molar equivalent of metformin hydrochloride.
  • a conventional organic solvent is used as the organic solvent, and particularly preferably, an organic solvent selected from methanol, ethanol, isopropanol, acetone and acetonitrile is used.
  • the third step is the step of forming the crystalline acid addition salt, and the reaction is carried out at a temperature range of -10 to 80 ° C.
  • metformin nicotinate means metformin (1: 1) nicotinate or metformin (1: 2) nicotinate, unless otherwise indicated, metformin (1: 1) or (1: 2) Nicotinate is meant to contain unreacted metformin free base and nicotinic acid in small amounts, preferably up to 5% by weight.
  • Metformin nicotinate of the present invention includes both anhydrides and hydrates, but is preferably hemihydrates and monohydrates.
  • the process for preparing the metformin base is simple and can be carried out without special equipment.
  • US Pat. No. 4,080,472 discloses a method for synthesizing harsh production conditions using an ion exchange resin column or heating a reflux of a solvent and filtering a hot solution, as in US Pat. No. 4,028,402.
  • This free base synthesis method can be used for reaction with various acids used to prepare pharmaceutically acceptable salts.
  • the types of pharmaceutically acceptable salts to which the free base synthesis method of this patent can be applied are: hydrochloride, sulfate, nitrate, phosphate, sulfite, dithionate, acetate, benzoate, citrate, glycorate Salt, glyoxylate, mercaptoacetate, gammahydroxybutyrate, pamoate, aspartate, glutamate, pyrrolidone carboxylate, methanesulfonate, naphthalene sulfonate, glucose-1-phosphate, chlorophenoxy acetate, embossing Nate, Chlorophenoxy Acetate, Maleate, Parachlorophenoxy Isobutyrate, Formate, Lactate, Succinate, Tartrate, Cyclohexane Carboxoxylate, Hexanoate, Octanoate, Decanoate, Hexadecanoate , Octodecanoate, benzenesulfonate, trimethoxy
  • the present invention also relates to a pharmaceutical composition for treating and preventing diabetes having metformin nicotinate or metformin inicotinate of Formula 1 and Formula 2 as an active ingredient and having various formulations.
  • the metformin nicotinate of the present invention prepared by the above method includes a pharmaceutically acceptable carrier, and in the form of sustained-release and immediate-release tablets, soft capsules, hard capsules, pills, granules or powders, injections, solutions, etc.
  • Pharmaceutical formulations can be prepared for the treatment and prevention of comorbidities pathological conditions associated with the disease.
  • a component selected from an enteric polymer, a hydrophobic substance, a hydrophilic polymer, and the like is used as the matrix base used for the purpose of sustained release.
  • the enteric polymer may be a mixture of one or more selected from polyvinylacetate phthalate, methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, shellac, cellulose acetate phthalate, cellulose propionate phthalate, Eudragit L, Eudragit S, and the like. May be used, and preferably hydroxypropylmethylcellulose phthalate is used.
  • the hydrophobic materials are pharmaceutically acceptable polyvinyl acetate, poly (methacrylate, methyl methacrylate) copolymer, poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate as polymethacrylate copolymers).
  • Acrylate copolymers ethyl cellulose and cellulose acetate, fatty acids and fatty acid esters, fatty alcohols, waxes and inorganic substances, and the like, specifically, glyceryl palmitostearate, Fatty acid alcohols such as glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and stearic acid; waxes such as cetostearyl alcohol, cetyl alcohol and stearyl alcohol; carnauba wax, beeswax and microcrystalline wax Talc, precipitated coal as inorganic materials Can be used to select one or more selected from calcium, calcium hydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and bigeom.
  • the hydrophilic polymer may be selected from sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers, polyethylene derivatives and carboxyvinyl polymers, and specifically, as the sugars, dextrin, polydextrin, dextran, Pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose, amylopectin and the like can be used selectively, and hydroxypropylmethylcellulose , Hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose can be selected and used as a gum , By Custard bean gum, tragacanta, carrageenan, acacia gum, gum arab
  • Gelatin, casein, zein, etc. can be selected and used as proteins.
  • Alcohol, polyvinyl pyrrolidone, polyvinyl acetal diethylamino acetate, and the like can be selected and used as the polymethacrylate copolymer, and poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate Rate) copolymer, poly (methacrylic acid, methyl methacrylate) copolymer, poly (methacrylic acid, ethyl acrylate) copolymer, etc. can be selected and used, and polyethylene glycol, polyethylene oxide, etc. are selected as a polyethylene derivative.
  • Carbomer may be used as the carboxyvinyl polymer.
  • Starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol and dicalcium phosphate may be used as a pharmaceutically acceptable diluent within the scope of not impairing the effects of the present invention.
  • binders starch, microcrystalline cellulose, highly dispersible silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, natural gums, synthetic gums, copovidone and gelatin can be used. Can be.
  • Starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch as a disintegrating agent, clays such as bentonite, montmorillonite, veegum, microcrystalline cellulose, hydroxypropyl cellulose or carboxy Celluloses such as methyl cellulose, algins such as sodium alginate or alginic acid, cross-linked celluloses such as croscarmellose sodium, gums such as guar gum and xanthan gum, and crosslinks such as crospovidone A polymer and boiling agents, such as sodium bicarbonate and a citric acid, can be mixed and used.
  • clays such as bentonite, montmorillonite, veegum, microcrystalline cellulose, hydroxypropyl cellulose or carboxy Celluloses such as methyl cellulose, algins such as sodium alginate or alginic acid, cross-linked celluloses such as croscarmellose sodium, gums such as guar gum and
  • talc magnesium stearate and alkaline earth metal stearate-type calcium, zinc and the like
  • lauryl sulfate hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, polyethylene glycol 4000, and the like can be used.
  • metformin nicotinate can be used as a preparation for oral administration in various forms, and the dosage of the pharmaceutical composition according to the present invention to the human body depends on the patient's age, sex, weight, nationality, health condition and degree of disease. Depending on the prescriber's judgment, divided doses are also available.
  • metformin (1: 1) nicotinate and 44.2 g of microcrystalline cellulose were sieved through a No. 20 sieve, and then mixed in a V-type mixer for 60 minutes.
  • 20 g of crospovidone (collidone VA64, BASF, Germany) and 10 g of hard silicic anhydride were sieved through a No. 35 sieve, added to the mixture, and mixed for 60 minutes.
  • 5 g of stearic acid was sieved through a No. 35 sieve, added to the mixture, and mixed for 3 minutes.
  • the final mixture was compressed into tablets containing 380.8 mg of metformin (1: 1) nicotinate in one tablet, and Opadry OY-C-7000A was used as a high coater (SFC-30N, Sejong Machinery, Korea).
  • a film coating layer was formed as a coating base to prepare a tablet containing metformin (1: 1) nicotinic acid.
  • the final mixture was compressed into tablets containing 380.8 mg of metformin (1: 1) nicotinate in one tablet, and Opadry OY-C-7000A was used as a high coater (SFC-30N, Sejong Machinery, Korea).
  • a film coating layer was formed on the basis of the coating to prepare metformin sustained-release tablets containing metformin (1: 1) nicotinate.
  • the final mixture was compressed to prepare a sustained-release tablet containing 380.8 mg of metformin (1: 1) nicotinate in one tablet, and Opadry OY-C-7000A as a high coater (SFC-30N, Sejong Machinery, Korea). To form a film coating layer to produce a metformin sustained-release tablet containing metformin (1: 1) nicotinate.
  • the final mixture was compressed to prepare a sustained-release tablet containing 380.8 mg of metformin (1: 1) nicotinate in one tablet, and Opadry OY-C-7000A as a high coater (SFC-30N, Sejong Machinery, Korea). To form a film coating layer to produce a metformin sustained-release tablet containing metformin (1: 1) nicotinate.
  • metformin (1: 1) nicotinate and 99.6 g of microcrystalline cellulose were sieved through a No. 20 sieve, and then mixed in a V-type mixer for 60 minutes.
  • 5 g of hard silicic anhydride was sieved through a No. 35 sieve, added to the mixture, and mixed for 60 minutes.
  • 5 g of stearic acid was sieved through a No. 35 sieve, added to the mixture, and mixed for 3 minutes.
  • Powder X-ray diffraction was performed to confirm the diffraction pattern of the crystal structure, the plane spacing of the crystal, and the intensity of the diffraction line.
  • Metformin (1: 1) nicotinate of Formula 1 prepared by Example 2 was measured at a melting point meter (Electrothermal No.9201) of 164.7-166.0 ° C. different from the melting point of 222.8 to 224.0 ° C. The melting point was confirmed.
  • Nuclear magnetic resonance (Varian-Inova600) data are as follows. 1 H-NMR (600 MHz, D 2 O) ⁇ (ppm) 2.84 (s, 6H, N- (CH 3 ) 2 ), 7.34 (t, 1H, aromatic), 8.07 (d, 1H, aromatic), 8.42 ( d, 1H, aromatic), 8.78 (s, 1H, aromatic).
  • Metformin nicotinate in the present invention was analyzed by comparison with the free base of metformin hydrochloride of (1: 1) composition in order to confirm that the structural ratio is (1: 1) or (1: 2) composition.
  • Table 6 compares the metformin (1: 1) nicotinate and metformin (1: 2) nicotinate and metformin free bases of the same molarity with the area values of HPLC.
  • the metformin nicotinate ionized acts as an acid, base, or amphoteric compound depending on pH, a change in pH occurs at each titration point.
  • the pKa value obtained from the difference between the calculated pH value and the actually measured pH value is as follows.
  • the saturated solubility of the metformin nicotinate and the pH at saturation were measured and compared with the conventional metformin hydrochloride.
  • metformin (1: 1) nicotinate has a solubility about 9 times greater than that of metformin hydrochloride and metformin (1: 2) nicotinate is about twice as large as metformin hydrochloride. .
  • the blood LDL level was significantly lower in the metformin nicotinate group. This is 42.72% lower than untreated group and 20.77% lower than metformin hydrochloride.
  • AI In the Atherosclerotic Index, a statistically significant decrease was observed in the metformin nicotinate and metformin hydrochloride treated groups compared to the untreated group.
  • metformin nicotinate is a safe substance that does not change liver or urine levels, and it is a better compound that lowers blood Cholesterol and LDL levels compared to conventional metformin hydrochloride, so diabetes, diabetes, obesity, hyperlipidemia, fatty liver, and coronary It is a useful compound for treating arterial disease, metabolic syndrome, diabetes and preventing complications.

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Abstract

L'invention concerne un nouveau sel d'acide nicotinique de diamide N,N -diméthyl imidodicarbonimidique, son procédé de préparation et une composition pharmaceutique le contenant. Elle concerne, plus particulièrement, un sel d'acide nicotinique de diamide N,N- diméthyl imidodicarbonimidique, qui présente des propriétés chimiques et physiques améliorées, notamment des propriétés de solubilité, de stabilité, de non-hygroscopicité et anti-adhésives, ainsi qu'une faible toxicité, et qui se révèle donc très efficace dans la prévention et le traitement non seulement du diabète et de ses complications chez des patients souffrant de ce que l'on appelle communément syndromes métaboliques, chez qui le diabète, l'obésité, l'hyperlipidémie, la stéatose hépatique, des maladies coronariennes, l'ostéoporose, des syndromes des ovaires polykystiques, etc. apparaissent en combinaison, mais aussi des cancers à déficit de gène p53, des douleurs musculaires, la cytotoxicité musculaire et la rhabdomyolyse. L'invention concerne également un procédé de préparation de ce composé et une composition pharmaceutique le contenant.
PCT/KR2009/000071 2008-01-08 2009-01-07 Diamide nicotinate n,n-diméthyl imidodicarbonimidique, son procédé de production et composition pharmaceutique le comprenant Ceased WO2009088220A2 (fr)

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KR20080002118 2008-01-08
KR10-2008-0002118 2008-01-08

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WO2009088220A2 true WO2009088220A2 (fr) 2009-07-16
WO2009088220A3 WO2009088220A3 (fr) 2009-09-03

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Cited By (4)

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US12031128B2 (en) 2021-04-07 2024-07-09 Battelle Memorial Institute Rapid design, build, test, and learn technologies for identifying and using non-viral carriers
US12109223B2 (en) 2020-12-03 2024-10-08 Battelle Memorial Institute Polymer nanoparticle and DNA nanostructure compositions and methods for non-viral delivery
US12441996B2 (en) 2023-12-08 2025-10-14 Battelle Memorial Institute Use of DNA origami nanostructures for molecular information based data storage systems
US12458606B2 (en) 2023-09-29 2025-11-04 Battelle Memorial Institute Polymer nanoparticle compositions for in vivo expression of polypeptides

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AT325632B (de) * 1973-06-01 1975-10-27 Hurka Wilhelm Verfahren zur herstellung von nicotinsauren salzen von derivaten des biguanids
CH602612A5 (fr) * 1974-10-11 1978-07-31 Hoffmann La Roche
FR2585572B3 (fr) * 1985-07-31 1987-12-31 Hugelin Andre Nouvelles compositions pharmaceutiques a base d'un sel de l'acide p. chlorophenoxyacetique destinees au traitement des neuropathies et assurant la regeneration nerveuse
AU738804B2 (en) 1997-12-08 2001-09-27 Bristol-Myers Squibb Company Novel salts of metformin and method

Cited By (5)

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Publication number Priority date Publication date Assignee Title
US12109223B2 (en) 2020-12-03 2024-10-08 Battelle Memorial Institute Polymer nanoparticle and DNA nanostructure compositions and methods for non-viral delivery
US12433910B2 (en) 2020-12-03 2025-10-07 Battelle Memorial Institute Polymer nanoparticle and DNA nanostructure compositions and methods for non-viral delivery
US12031128B2 (en) 2021-04-07 2024-07-09 Battelle Memorial Institute Rapid design, build, test, and learn technologies for identifying and using non-viral carriers
US12458606B2 (en) 2023-09-29 2025-11-04 Battelle Memorial Institute Polymer nanoparticle compositions for in vivo expression of polypeptides
US12441996B2 (en) 2023-12-08 2025-10-14 Battelle Memorial Institute Use of DNA origami nanostructures for molecular information based data storage systems

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WO2009088220A3 (fr) 2009-09-03
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