US20120178813A1 - Lipid-lowering antidiabetic agent - Google Patents

Lipid-lowering antidiabetic agent Download PDF

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Publication number
US20120178813A1
US20120178813A1 US13/348,265 US201213348265A US2012178813A1 US 20120178813 A1 US20120178813 A1 US 20120178813A1 US 201213348265 A US201213348265 A US 201213348265A US 2012178813 A1 US2012178813 A1 US 2012178813A1
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mammal
administering
effective amount
therapeutically effective
composition according
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Banavara L. Mylari
Frank C. Sciavolino
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Thetis Pharmaceuticals LLC
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Thetis Pharmaceuticals LLC
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Priority to US13/348,265 priority Critical patent/US20120178813A1/en
Priority to CA2824192A priority patent/CA2824192A1/en
Priority to PCT/US2012/021070 priority patent/WO2012097144A1/en
Priority to AU2012205547A priority patent/AU2012205547B2/en
Priority to KR20137018679A priority patent/KR20140092228A/ko
Priority to MX2013008131A priority patent/MX2013008131A/es
Priority to BR112013017845A priority patent/BR112013017845A2/pt
Priority to EA201391028A priority patent/EA201391028A1/ru
Priority to JP2013549539A priority patent/JP5911514B2/ja
Priority to CN201280005222.1A priority patent/CN103533833B/zh
Priority to EP12734013.1A priority patent/EP2663186A4/en
Assigned to THETIS PHARMACEUTICALS LLC reassignment THETIS PHARMACEUTICALS LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SCIAVOLINO, FRANK C., MYLARI, BANAVARA L.
Publication of US20120178813A1 publication Critical patent/US20120178813A1/en
Priority to US13/923,829 priority patent/US8901107B2/en
Priority to IL227346A priority patent/IL227346A0/en
Assigned to THETIS PHARMACEUTICALS LLC reassignment THETIS PHARMACEUTICALS LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MYLARI, BANAVARA L., SCIAVOLINO, FRANK C.
Priority to US14/136,843 priority patent/US9012507B2/en
Priority to US14/524,721 priority patent/US9216951B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/52—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing groups, e.g. carboxylic acid amidines
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/04—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/06—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
    • C07C251/08—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton being acyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/03—Monocarboxylic acids

Definitions

  • the present invention relates to salts of poly unsaturated fatty acids with biguanides.
  • Diabetes mellitus has become pandemic and according to a forecast by the World Health Organization, there will be a sharp increase in the number of diabetic patients by the year 2030. This is an ominous forecast, because managing the long-term complications of diabetes, which include nephropathy, neuropathy, retinopathy, and cardiovascular complications, will have a serious impact on public health budgets.
  • the hallmark of diabetes is chronically elevated blood glucose levels. It is also known that abnormally elevated glucose levels have an adverse impact on glutathione levels in key diabetic tissues. Furthermore, increased oxidative stress and increased production of reactive oxygen species are implicated under hyperglycemic conditions.
  • non-insulin dependent diabetes mellitus type 2 diabetes, NIDDM
  • NIDDM non-insulin dependent diabetes mellitus
  • the clinically available hypoglycemic agents can either have side effects limiting their use, or an agent may not be effective with a particular patient.
  • insulin dependent diabetes mellitus Type I
  • insulin administration usually constitutes the primary course of therapy.
  • the biguanide metformin is a known compound approved by the U.S. Food & Drug Administration for the therapeutic treatment of diabetes.
  • the compound and its preparation and use are disclosed, for example, in U.S. Pat. No. 3,174,901.
  • Metformin is orally effective in the treatment of type 2 diabetes.
  • Metformin N,N-dimethylimidodicarbonimidic diamide
  • Metformin is a biguanide, anti-hyperglycemic agent currently marketed in the United States in the form of its hydrochloride salt 1,1-dimethylbiguanide hydrochloride (Formula 1a).
  • Metformin hydrochloride can be purchased commercially and can also be prepared, for example, as disclosed in J. Chem. Soc., 1922, 121, 1790.
  • U.S. Pat. No. 7,973,073 B2 (Mylari) describes use of metformin R-(+) lipoate as being useful for treating diabetes or diabetic complications.
  • U.S. Patent Publication 2005/0165102 describes complexes of drugs (metformin being mentioned) with transport moieties (fatty acids being mentioned) to enhance absorption and control delivery of the drugs being used.
  • fatty acid complexing agents mentioned are caprate, laurate, palmitate and oleate.
  • U.S. Patent Publication 2005/0182029 describes metformin salts of lipophilic acid salts (fatty acids being mentioned), their pharmaceutical formulations, and methods of administering the metformin salts for the treatment of hyperglycemia.
  • UPDS United Kingdom Perspective Diabetes Study
  • metformin therapy was cost-saving and increased quality-adjusted life expectancy.
  • overweight and obese patients randomized to initial therapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths.
  • Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors. Accordingly, metformin is widely regarded as the drug of choice for most patients with Type 2 diabetes.
  • Prediabetes is a syndrome. Many patients with type 2 diabetes and with a prediabetic condition known as metabolic syndrome suffer from a variety of lipid disorders including elevated triglycerides.
  • the body uses triglycerides to store fat but high (>200 mg/dl) and very high (>500 mg/dl) triglycerides are associated with atherosclerosis which increases the patients risk of heart attack and stroke.
  • Incipient diabetes with impaired glucose tolerance is another prediabetic condition.
  • type 2 diabetes and incipient diabetes with impaired glucose tolerance are intimately intertwined with obesity, hyperlipidemia, including hypertriglyceridemia, and cardiovascular complications including arrhythmia, cardiomyopathy, myocardial infarction, stroke and heart failure.
  • pre-diabetes means that blood sugar level is higher than normal, but it's not yet increased enough to be classified as type 2 diabetes.
  • prediabetes is likely to become type 2 diabetes over time
  • diabetic patients have impaired circulation which manifests itself in the slow healing of wounds in the foot and lower leg and puts the patient at risk for amputation.
  • Elevated triglycerides may be lowered by diet and exercise.
  • Niacin and omega-3 fatty acids commonly known as fish oil, are frequently used in the management of hypertriglyceridemia.
  • Omega-3 fatty acids are unsaturated carboxylic acids which have a terminal double bond three carbons from the methyl terminus, the 3 position.
  • Omega-3 fatty acids are commonly extracted from oily fish like salmon, mackerel and menhaden. They are also extracted from other marine sources like squid and krill. Omega-3 fatty acids are commercially available.
  • the omega-3 fatty acids most commonly extracted from fish are eicosapentaenoic acid and docosahexaenoic acid. These compounds have been shown to have beneficial effects in treating obesity, arrhythmia, and myocardial infarction and have the structures:
  • Resolvins are a special class of polyhydroxylated omega-3 fatty acids which possess potent antinflammatory and immunoregulatory actions. These biological actions of resolvins are thought to play a significant role in cardiovascular and diabetic conditions.
  • HR is an omega-3 polyunsaturated C 16-24 fatty acid optionally substituted with from 1-3 hydroxy groups.
  • compositions are typically compounds in the form of salts of metformin and an omega-3 polyunsaturated fatty acid (RH) in which the biguanide moiety is protonated and the acid moiety is at least partially in ionic form. In some instances, however, for example depending on the pH of the environment, the composition may be in the form of a mixture of the biguanide and acid components.
  • the invention also provides pharmaceutical compositions comprising compositions of formula I and pharmaceutically acceptable excipients.
  • the invention further provides methods for treating diabetes (especially type 2 diabetes), obesity, cardiac arrhythmia, myocardial infarction and elevated triglycerides.
  • the compounds and compositions of this invention may provide high blood levels of the compositions of structure 1, when administered to patients, preferably by oral administration.
  • Particularly useful compounds are those wherein HR is a fatty acid of 20 or 22 carbon atoms with four or five unsaturated bonds in addition to the required omega-3 unsaturated bond such as 4,7,10,13,16,19 docoshexaenoic acid, 5,8,11,14 eicosopentanoic acid and resolvins derived from these acids such as the 5,12,18 trihydroxy eicosopentanoic acid known as resolvin E1, the 15,18 dihydroxy eicosopentanoic acid, known as resolvin E2, the 7,8,17 trihydroxy docosahexaenoic acid known as resolvin DE and its 7,16,17 trihydroxy eipmer known as resolvin D2, the 4,11,17 trihydroxy docosahexaenoic acid known as resolvin D3 and the 4,5,17 trihydroxy docosahexaenoic acid known as resolvin D4.
  • HR is a fatty acid of 20 or 22 carbon
  • the invention relates to a compound of formula I which is a salt of metformin and an omega-3 polyunsaturated fatty acid and is meant to include any polymorphs, solvates, and hydrates thereof.
  • RH is a resolving. In the most preferred embodiment, RH is eicosapentaenoic acid or docosahexaenoic acid.
  • Compounds of the present invention can be considered as designer dual-acting drugs and additionally possess a means for improving the bioavailability of their component moieties as a result of their high degree of water solubility.
  • the invention relates to a mixture of metformin or a pharmaceutically acceptable salt thereof, (e.g., hydrochloride, succinate, fumarate) with an omega-3 polyunsaturated fatty acid (RH), or a pharmaceutically acceptable salt thereof.
  • RH is a resolvin.
  • RH is eicosapentaenoic acid or docosahexaenoic acid.
  • the present invention provides a pharmaceutical composition of the invention comprising compound of formula I and a pharmaceutically-acceptable carrier, vehicle or diluent.
  • the pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion.
  • Such compositions and methods for their preparation may be found, for example, in ‘Remington's Pharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995).
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and an active compound.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled lozenges), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.
  • Tablet dosage forms typically also include a disintegrant (such as sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate) a binder (such as microcrystalline cellulose, gelatin, a sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose) and a lubricant (such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate).
  • a disintegrant such as sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidone, methyl cellulose, microcrystalline
  • compositions of the invention may also be present.
  • Compositions of the invention may also be administered for example as capsules made, for example, from gelatin or hydroxypropylmethylcellulose.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compositions of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).
  • the invention further provides methods for treatment or lowering the risk of developing conditions such as diabetes, especially type 2 diabetes, prediabetes, obesity, arrhythmia, myocardial infarction and stroke by administering therapeutically effective amounts of compositions of formula I.
  • Such compositions may also be used to lower triglyceride levels in a subject and so have a role in treatment of diabetes exacerbated with high triglyceride levels.
  • Suitable dosages may be determined by conventional means.
  • the triglyceride lowering efficacy of the compounds of the present invention can be determined in animal models according to the procedure described by Sidika et al in Journal of Lipid Research, 1992, 33, 1-7.
  • the following example describes a diabetic rat model that may be used for determination of conditions leading to a method for treatment and prevention of post-ischemic damage of the heart and heart tissue.
  • BB/W rats Spontaneously diabetic Bio-Bred (BB/W) rats from the colony maintained at the University of Massachusetts Medical Center, Worcester, were used in this study.
  • BB/W rats were chosen for the current study because the BB/W rats have been considered a useful model of autoimmune human insulin-dependent diabetes DM).
  • BB/W rats have been considered a useful model of autoimmune human insulin-dependent diabetes DM.
  • DM autoimmune human insulin-dependent diabetes DM
  • Like human IDDM spontaneous diabetes appears during adolescence, with an abrupt clinical onset characterized by weight loss, hyperglycemia, hypoinsulinemia, and ketonuria.
  • pathological changes in retina, myocardium, liver, kidney, bone metabolism and peripheral nerves have all been well documented in BB rats, as described in Diab. Metab. Rev., 8:9 (1992).
  • the BB/W rats were 3 to 4 months old and weighed about 300 to 350 g.
  • the BB/W rats received daily insulin, which was discontinued 24 h prior to performing the isolated heart perfusion studies, leading to a hyperglycemic state.
  • the rats were acutely diabetic, receiving 2.02 ⁇ 0.04 units of insulin daily, and had been diabetic for at least 12 ⁇ 3 days.
  • the mean blood glucose levels in these diabetic rats were 386 ⁇ 24 mg/dL.
  • the age-matched non-diabetic controls had mean blood glucose levels of 92 ⁇ 12 mg/dL.
  • This example describes an isolated perfused rat heart model used in development of the invention. Studies are performed using an isovolumic isolated rat heart preparation. Acutely diabetic male BB/W rats and non-diabetic age-matched (3 to 4 months old) control are pretreated with heparin (1000 u; IP), followed by sodium pentobarbital (65 mg/kg; IP). After deep anaesthesia is achieved as determined by the absence of a foot reflex, the hearts are rapidly excised and placed into iced saline. The arrested hearts are retrograde perfused in a non-recirculating model through the aorta within 2 minutes following their excision.
  • LVDP Left ventricular developed pressure
  • Perfusion pressure is monitored using high pressure tubing off the perfusion line. Hemodynamic measurements are recorded on a 4-channel Gould recorder.
  • the system has two parallel perfusion lines with separate oxygenators, pumps and bubble traps, but common temperature control allows rapid change perfusion media.
  • the hearts are perfused using an accurate roller pump.
  • the perfusate consists of 118 mM NaCl, 0.47 mM KCl, 12 mM CaCl 2 , 12 mM MgCl2, 25 mM NaHCO 3 , and the substrate 11 mM glucose.
  • the perfusion apparatus is tightly temperature-controlled, with heated baths being used for the perfusate and for the water jacketing around the perfusion tubing to maintain heart temperature at 37 ⁇ 0.5° C. under all conditions.
  • the oxygenated perfusate in the room temperature reservoir is passed through 25 ft. of thin-walled silicone tubing surrounded by distilled water at 37° C. saturated with 95% oxygen.
  • the perfusate then enters the water-jacketed (37° C.) tubing leading to the heart through a water jacketed bubble trap. This preparation provides excellent oxygenation that routinely has been stable for 3 to 4 hours.
  • Diabetic control (DC) diabetic treated (DZ) normal (C) control and normal treated (CZ) hearts are subjected to 20 minutes of normoxic perfusion followed by 20 minutes of zero-flow ischemia where the perfusate flow is completely shut off, followed by 60 minutes of reperfusion.
  • Hearts are treated with 10 ⁇ M metformin eicosapentaenoate.
  • metformin eicosapentaenoate treated diabetic group DZ
  • hearts are subjected to 10 minutes of normoxic perfusion with normal Krebs-Henseleit buffer and 10 minutes of normoxic perfusion with Krebs-Henseleit buffer containing 10 ⁇ M metformin eicosapentaenoate.
  • the hearts are then subjected to 20 minutes of zero-flow ischemia followed by 60 minutes of reperfusion.
  • both DC and DZ hearts are reperfused with normal Krebs-Henseleit buffer.
  • Diabetic control hearts are subjected to 20 minutes of normoxic perfusion at a flow rate of 12.5 mL/minute followed by 30 minutes of low-flow ischemia where the perfusate flow is slowed down to 1.25 mL/min, that is about 10% of normal perfusion, followed by 30 minutes of reperfusion at a normal flow rate (12.5 mL/min).
  • metformin eicosapentaenoate treated diabetic or non-diabetic groups DZ or CZ
  • hearts are subjected to 10 minutes of normoxic perfusion (flow rate 12.5 mL/min) with normal Krebs-Henseleit buffer and 10 minutes of normoxic perfusion with Krebs-Henseleit buffer containing 10 ⁇ M metformin eicosapentaenoate.
  • the hearts are subjected to 30 minutes of low-flow ischemia (flow rate 1.25 mL/min) and 30 minutes of reperfusion at normal flow rate (12.5 mL/min).
  • the present invention is exemplified by the following non-limiting examples.
  • N,N-dimethylimidodicarbonimidic diamide N,N-dimethylimidodicarbonimidic diamide hydrochloride (4.01 g, 24.3 mmol) was dissolved in 1N sodium hydroxide (24.2 mL, 24.2 mmol) and stirred at room temperature for 30 minutes. The solution was concentrated in vacuo and to the residue was added ethanol (80 mL). The mixture was carefully concentrated to azeotropically remove water. To the resulting solid was added EtOH (60 mL) and the suspension was filtered to remove precipitated NaCl. The filtrate was concentrated and the resulting solid was placed on high vacuum overnight to yield 3.18 g (102%) of metformin as a white solid.
  • Metformin free base (2.67 g, 20.7 mmol) was dissolved in acetonitrile (100 mL) and the resulting solution was filtered through a medium frit to remove a small amount of NaCl that precipitated.
  • To the filtrate was added dropwise at room temperature (over a 5 minute period) a solution of (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoic acid (5.40 g, 17.8 mmol) in acetonitrile (30 mL). A white solid precipitated immediately upon addition of the acid.
  • the reaction flask was covered in foil to protect it from light. The mixture was stirred for one hour at room temperature and was then chilled to 0° C.
  • Example 1 was a light tan solid; MP 121-124° C.
  • N,N-dimethylimidodicarbonimidic diamide N,N-dimethylimidodicarbonimidic diamide hydrochloride (4.06 g, 24.5 mmol) was dissolved in IN sodium hydroxide (24.5 mL, 24.5 mmol) and stirred at room temperature for 30 minutes. The solution was concentrated in vacuum and to the residue was added ethanol (80 mL). The mixture was carefully concentrated to azeotropically remove water. To the resulting solid was added (60 mL) and the suspension was filtered to remove precipitated sodium chloride. The filtrate was concentrated and the resulting solid was placed on high vaccum overnight to yield 3.22 g (102%) of N,N-dimethylimidodicarbonimidic diamide as a white solid.
  • N,N-Dimethylimidodicarbonimidic diamide (968 mg, 7.61 mmol) was dissolved in acetonitrile (36 mL) and the resulting solution was filtered through a medium frit to remove a small amount of sodium chloride that precipitated.
  • To the filtrate was added dropwise at room temperature (over a 5 minute period) a solution of (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16, 19-hexaenoic acid (2.00 g, 6.09 mmol) in acetonitrile (35 mL). A white solid precipitated immediately upon addition of the acid.
  • the reaction flask was covered in foil to protect it from light.
  • Metformin hydrochloride (331.25 g, 2 moles) was weighed into a 4000 mL beaker containing a stir bar. 1N KOH (1980 mL, 1.998 moles) was added, the beaker was covered, and the mixture was stirred for 2 h. The solids were collected by vacuum filtration, and the filtrate was concentrated to a damp solid. Isopropanol (500 mL) was added and after brief swirling, the mixture was concentrated. The residual white solid was dried for 16 h in a vacuum oven (yield: 269.08 g).
  • Metformin free base 50.10 g, 0.366 mole was weighed into a 4000 mL beaker containing a stir bar. CH 3 CN (2000 mL) was added and the mixture was rapidly stirred until all metformin had dissolved. A fine white solid was removed by vacuum filtration. After ⁇ 30 min, the hazy filtrate was vacuum filtered through the same medium, and the clear filtrate was transferred to a 5000 mL 3-necked round bottom flask, which was fitted with a complete stir shaft assembly, N 2 inlet and addition funnel and bubbler.
  • the funnel was charged with a solution of eicosapentaenoic acid (100.01 g, 0.324 mole) in acetonitrile (500 mL) which was added drop-wise over 70 min. After stirring for 2 h, the flask was fitted with a N 2 balloon, sealed, and placed in the refrigerator over-night. The off-white solid was collected by vacuum filtration and washed with acetonitrile (500 mL). The damp solid was transferred to a pyrex dish, which was stored in a vacuum oven for 24 h. The oven was vented with nitrogen gas, and the beige solid was coarsely ground in a mortar with pestle then transferred to an amber jar that had been flushed with N 2 to obtain the compound of Example 3 (yield: 130.49 g).
  • Measurement of the water solubility of the test compounds is accomplished by using methods well known to those skilled in the art. Specifically, to a weighed amount of the test compound of Example 1 distilled water is added in small portions until a clear solution is obtained. The total-volume of the solution is measured. The water solubility is calculated by dividing the weight of the salt, in mg, by the volume of the solution, in mL. The water solubility of the compound of Example 1 when measured using the above technique, was determined to be 50 mg/ml. Likewise, the water solubility of EPA was found to be ⁇ 0.2 mg/mL. The compound of Example 1 is therefore, at least, 250 times more soluble in water than EPA itself.

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US13/348,265 2011-01-12 2012-01-11 Lipid-lowering antidiabetic agent Abandoned US20120178813A1 (en)

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US13/348,265 US20120178813A1 (en) 2011-01-12 2012-01-11 Lipid-lowering antidiabetic agent
CN201280005222.1A CN103533833B (zh) 2011-01-12 2012-01-12 降脂抗糖尿病剂
EP12734013.1A EP2663186A4 (en) 2011-01-12 2012-01-12 ANTIDIABETIC AGENT LOWERING THE LIPID LEVEL
AU2012205547A AU2012205547B2 (en) 2011-01-12 2012-01-12 Lipid-lowering antidiabetic agent
KR20137018679A KR20140092228A (ko) 2011-01-12 2012-01-12 지질-저하 항당뇨제
MX2013008131A MX2013008131A (es) 2011-01-12 2012-01-12 Agente antidiabetico hipolipemiante.
BR112013017845A BR112013017845A2 (pt) 2011-01-12 2012-01-12 agente antidiabético de abaixamento de lipídio
EA201391028A EA201391028A1 (ru) 2011-01-12 2012-01-12 Гиполипидемическое противодиабетическое средство
JP2013549539A JP5911514B2 (ja) 2011-01-12 2012-01-12 脂質低下抗糖尿病薬
CA2824192A CA2824192A1 (en) 2011-01-12 2012-01-12 Lipid-lowering antidiabetic agent
PCT/US2012/021070 WO2012097144A1 (en) 2011-01-12 2012-01-12 Lipid-lowering antidiabetic agent
US13/923,829 US8901107B2 (en) 2011-01-12 2013-06-21 Lipid-lowering antidiabetic agent
IL227346A IL227346A0 (en) 2011-01-12 2013-07-04 Anti-diabetic agent to reduce fats
US14/136,843 US9012507B2 (en) 2011-01-12 2013-12-20 Lipid-lowering antidiabetic agent
US14/524,721 US9216951B2 (en) 2011-01-12 2014-10-27 Lipid-lowering antidiabetic agent

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US14/136,843 Expired - Fee Related US9012507B2 (en) 2011-01-12 2013-12-20 Lipid-lowering antidiabetic agent
US14/524,721 Expired - Fee Related US9216951B2 (en) 2011-01-12 2014-10-27 Lipid-lowering antidiabetic agent

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US14/524,721 Expired - Fee Related US9216951B2 (en) 2011-01-12 2014-10-27 Lipid-lowering antidiabetic agent

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EP (1) EP2663186A4 (enExample)
JP (1) JP5911514B2 (enExample)
KR (1) KR20140092228A (enExample)
CN (1) CN103533833B (enExample)
AU (1) AU2012205547B2 (enExample)
BR (1) BR112013017845A2 (enExample)
CA (1) CA2824192A1 (enExample)
EA (1) EA201391028A1 (enExample)
IL (1) IL227346A0 (enExample)
MX (1) MX2013008131A (enExample)
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WO2015022613A1 (en) * 2013-08-11 2015-02-19 Mahesh Kandula Compositions and methods for the treatment of diabetes and pre-diabetes
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US9382187B2 (en) 2012-07-10 2016-07-05 Thetis Pharmaceuticals Llc Tri-salt form of metformin
US20160244405A1 (en) * 2015-02-20 2016-08-25 Mohan Murali Alapati Compositions and methods for the treatment of hyperglycemia and metabolic syndrome
WO2014195810A3 (en) * 2013-06-04 2017-03-09 Cellixbio Private Limited Compositions and methods for the treatment of diabetes and pre-diabetes
US9999626B2 (en) 2014-06-18 2018-06-19 Thetis Pharmaceuticals Llc Mineral amino-acid complexes of active agents
US10130719B2 (en) 2016-06-03 2018-11-20 Thetis Pharmaceuticals Llc Compositions and methods relating to salts of specialized pro-resolving mediators
WO2019008101A1 (en) 2017-07-06 2019-01-10 Evonik Technochemie Gmbh ENTERICALLY COATED SOLID DOSAGE FORM COMPRISING AMINO ACIDS SALTS OF OMEGA-3 FATTY ACIDS
WO2019034698A1 (en) 2017-08-15 2019-02-21 Evonik Technochemie Gmbh TABLET WITH HIGH ACTIVE INGREDIENT CONTENT OF OMEGA-3 FATTY ACID AMINO ACID SALTS
WO2021023849A1 (en) 2019-08-08 2021-02-11 Evonik Operations Gmbh Down streaming process for the production of polyunsaturated fatty acid salts
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US8901107B2 (en) 2011-01-12 2014-12-02 Thetis Pharmaceuticals Llc Lipid-lowering antidiabetic agent
US9012507B2 (en) 2011-01-12 2015-04-21 Thetis Pharmaceuticals Llc Lipid-lowering antidiabetic agent
US9216951B2 (en) 2011-01-12 2015-12-22 Thetis Pharmaceuticals Llc Lipid-lowering antidiabetic agent
US9382187B2 (en) 2012-07-10 2016-07-05 Thetis Pharmaceuticals Llc Tri-salt form of metformin
US8765811B2 (en) 2012-07-10 2014-07-01 Thetis Pharmaceuticals Llc Tri-salt form of metformin
US8933124B2 (en) 2012-07-10 2015-01-13 Thetis Pharmaceuticals Llc Tri-salt form of metformin
WO2014011814A1 (en) * 2012-07-10 2014-01-16 Thetis Pharmaceuticals Llc Tri-salt form of metformin
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WO2014080307A3 (en) * 2012-11-21 2014-12-24 Mahesh Kandula Compositions and methods for the treatment of diabetes and pre-diabetes
WO2014195961A1 (en) * 2013-06-04 2014-12-11 Mahesh Kandula Compositions and methods for the treatment of diabetes and pre-diabetes
WO2014195810A3 (en) * 2013-06-04 2017-03-09 Cellixbio Private Limited Compositions and methods for the treatment of diabetes and pre-diabetes
WO2015022613A1 (en) * 2013-08-11 2015-02-19 Mahesh Kandula Compositions and methods for the treatment of diabetes and pre-diabetes
US9505709B2 (en) * 2014-05-05 2016-11-29 Thetis Pharmaceuticals Llc Compositions and methods relating to ionic salts of peptides
US20160107985A1 (en) * 2014-05-05 2016-04-21 Thetis Pharmaceuticals Llc Compositions and Methods Relating to Ionic Salts of Peptides
US9242008B2 (en) 2014-06-18 2016-01-26 Thetis Pharmaceuticals Llc Mineral amino-acid complexes of fatty acids
US9999626B2 (en) 2014-06-18 2018-06-19 Thetis Pharmaceuticals Llc Mineral amino-acid complexes of active agents
US20160244405A1 (en) * 2015-02-20 2016-08-25 Mohan Murali Alapati Compositions and methods for the treatment of hyperglycemia and metabolic syndrome
US11135298B2 (en) 2016-06-03 2021-10-05 Thetis Pharmaceuticals Llc Compositions and methods relating to salts of specialized pro-resolving mediators
US10130719B2 (en) 2016-06-03 2018-11-20 Thetis Pharmaceuticals Llc Compositions and methods relating to salts of specialized pro-resolving mediators
US11925688B2 (en) 2016-06-03 2024-03-12 Thetis Pharmaceuticals Llc Compositions and methods relating to salts of specialized pro-resolving mediators
US11191840B2 (en) 2016-06-03 2021-12-07 Thetis Pharmaceuticals Llc Compositions and methods relating to salts of specialized pro-resolving mediators
WO2019008101A1 (en) 2017-07-06 2019-01-10 Evonik Technochemie Gmbh ENTERICALLY COATED SOLID DOSAGE FORM COMPRISING AMINO ACIDS SALTS OF OMEGA-3 FATTY ACIDS
WO2019034698A1 (en) 2017-08-15 2019-02-21 Evonik Technochemie Gmbh TABLET WITH HIGH ACTIVE INGREDIENT CONTENT OF OMEGA-3 FATTY ACID AMINO ACID SALTS
US11497722B2 (en) * 2017-12-18 2022-11-15 Soochow University Use of metformin salt in the treatment of cerebral infarction
WO2021023857A1 (en) 2019-08-08 2021-02-11 Evonik Operations Gmbh Solubility enhancement of poorly soluble actives
WO2021023849A1 (en) 2019-08-08 2021-02-11 Evonik Operations Gmbh Down streaming process for the production of polyunsaturated fatty acid salts

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CN103533833A (zh) 2014-01-22
EP2663186A4 (en) 2014-09-24
JP2014512333A (ja) 2014-05-22
WO2012097144A1 (en) 2012-07-19
JP5911514B2 (ja) 2016-04-27
EP2663186A1 (en) 2013-11-20
CN103533833B (zh) 2016-08-31
CA2824192A1 (en) 2012-07-19
EA201391028A1 (ru) 2013-12-30
US20140107360A1 (en) 2014-04-17
US9012507B2 (en) 2015-04-21
US20130281535A1 (en) 2013-10-24
IL227346A0 (en) 2013-09-30
BR112013017845A2 (pt) 2019-09-24
KR20140092228A (ko) 2014-07-23
MX2013008131A (es) 2014-01-08
AU2012205547B2 (en) 2015-08-27
AU2012205547A1 (en) 2013-08-01
US8901107B2 (en) 2014-12-02
US20150051284A1 (en) 2015-02-19
US9216951B2 (en) 2015-12-22

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