WO2014011814A1 - Forme à trois sels de metformine - Google Patents

Forme à trois sels de metformine Download PDF

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Publication number
WO2014011814A1
WO2014011814A1 PCT/US2013/049984 US2013049984W WO2014011814A1 WO 2014011814 A1 WO2014011814 A1 WO 2014011814A1 US 2013049984 W US2013049984 W US 2013049984W WO 2014011814 A1 WO2014011814 A1 WO 2014011814A1
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Prior art keywords
compound
metformin
subject
formula
diabetes
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PCT/US2013/049984
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English (en)
Inventor
Banavara L. Mylari
Frank C. SCIAVOLINO
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Thetis Pharmaceuticals Llc
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Priority claimed from US13/841,970 external-priority patent/US8765811B2/en
Priority to AU2013290168A priority Critical patent/AU2013290168A1/en
Priority to IN76KON2015 priority patent/IN2015KN00076A/en
Priority to JP2015521784A priority patent/JP2015523382A/ja
Priority to MX2015000408A priority patent/MX2015000408A/es
Priority to EP13817534.4A priority patent/EP2872483A4/fr
Application filed by Thetis Pharmaceuticals Llc filed Critical Thetis Pharmaceuticals Llc
Priority to CA2878819A priority patent/CA2878819A1/fr
Priority to CN201380046842.4A priority patent/CN104684889A/zh
Priority to BR112015000368A priority patent/BR112015000368A2/pt
Priority to US14/413,996 priority patent/US9382187B2/en
Priority to KR20157002264A priority patent/KR20150036235A/ko
Publication of WO2014011814A1 publication Critical patent/WO2014011814A1/fr
Priority to IL236613A priority patent/IL236613A0/en
Priority to ZA2015/00274A priority patent/ZA201500274B/en

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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
    • C07C279/20—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
    • 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
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines

Definitions

  • 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.
  • thiazolidenediones such as troglitazone, rosiglitazone or pioglitazone, and DPPIV inhibitors such as sitagliptin as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory.
  • Non-insulin dependent diabetes mellitus Type II 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.
  • T2D type 2 diabetes
  • pre-diabetes as well as related conditions, such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy in diabetic patients.
  • tri-salt compounds comprising aspartate, glutamate, or homologues thereof, metformin, and polyunsaturated fatty acids, such as eicosapentaenoate or docosahexaenoate.
  • the tri-salt compounds can be used in the treatment of diabetes, diabetes with concomitant dyslipidemia (e.g. , high triglycerides) and diabetes exacerbated cardiovascular complications, such as cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy, and stroke.
  • the tri-salt compounds are also useful in treating obesity.
  • tri-salts of a compound with two acidic functional groups and one basic functional group, metformin, and a polyunsaturated fatty acid which are represented by the following Formula I:
  • G is an alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, or heteroaryl group; and R " is a polyunsaturated fatty acid.
  • G is alkyl.
  • compounds of Formula I are of the Formula II:
  • R " is a polyunsaturated fatty acid, and n is 1-10, or a pharmaceutically acceptable solvate or hydrate thereof.
  • n is 1 or 2.
  • n is 3 , 4, or 5.
  • R " is eicosapentaenoate or docosahexaenoate. In an embodiment of Formula II, R " is eicosapentaenoate or docosahexaenoate, and n is 1. In still another embodiment of Formula II, R " is eicosapentaenoate or docosahexaenoate, and n is 2.
  • composition comprising a compound of Formula I, and a pharmaceutically acceptable carrier, vehicle or diluent.
  • kits comprising a unit dosage comprising a compound of the invention with instructions on how to use the kit and at least one container for holding the unit dosage form.
  • the compounds of Formula I can be used in the treatment of a number of diseases and indications. Accordingly, in one aspect, provided herein is a method for treating diabetes in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I. In another aspect, provided herein is a method of lowering triglycerides in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I. In still another aspect, provided herein is a method for treating cardiovascular diseases in a subject in need thereof, comprising administering to the subject a therapeutically effective amount a compound of Formula I. Examples of cardiovascular diseases to be treated are cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy, or stroke.
  • provided herein is a method for treating obesity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I.
  • provided herein is a method of treating hyperlipidemia, comprising administering to a subject in need thereof an effective amount of a compound of Formula I.
  • a method of treating hypertriglyceridemia comprising administering to a subject in need thereof an effective amount of a compound of Formula I.
  • a method of treating dyslipidemia comprising administering to a subject in need thereof an effective amount of a compound of Formula I.
  • provided herein is a method of treating prediabetes, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • a method of treating atherosclerosis comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • a combination therapy comprising a compound of the structural Formula I or II above, and an antihyperlipidemic agent, to treat a metabolic disorder selected from the group consisting of T2D, pre-diabetes, obesity, metabolic syndrome, hypertriglyceridemia and T2D complications such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including atrial fibrillation, cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy in mammals, e.g. , diabetic patients.
  • T2D a metabolic disorder selected from the group consisting of T2D, pre-diabetes, obesity, metabolic syndrome, hypertriglyceridemia and T2D complications such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including atrial fibrillation, cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy in mammals, e.g. , diabetic patients.
  • An additional aspect provided herein is combination therapy comprising
  • a combination therapy comprising a compound of the structural Formula I or II above, and an antihyperglycemic agent, to treat a metabolic disorder selected from the group consisting of type 2 diabetes (T2D), pre-diabetes, obesity, metabolic syndrome, hypertriglyceridemia and T2D complications such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy in mammals, e.g., diabetic patients.
  • T2D type 2 diabetes
  • pre-diabetes e.g., obesity, metabolic syndrome, hypertriglyceridemia
  • T2D complications such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy in mammals, e.g., diabetic patients.
  • provided herein is a method for treating diabetes in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the combination therapy described above.
  • a method of lowering triglycerides in a subject in need thereof comprising administering to a subject in need thereof an effective amount of the combination therapy of the invention.
  • a method for treating cardiovascular diseases in a subject in need thereof administering to a subject in need thereof an effective amount of the combination therapy of the invention.
  • cardiovascular diseases to be treated are cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy, or stroke.
  • provided herein is a method for treating obesity in a subject in need thereof, administering to a subject in need thereof an effective amount of the combination therapy of the invention.
  • provided herein is a method of treating hyperlipidemia, administering to a subject in need thereof an effective amount of the antihyperlipidemic combination therapy of the invention.
  • a method of treating hypertriglyceridemia administering to a subject in need thereof an effective amount of the antihyperlipidemic combination therapy of the invention.
  • a method of treating dyslipidemia administering to a subject in need thereof an effective amount of the antihyperlipidemic combination therapy of the invention.
  • provided herein is a method of treating prediabetes, administering to a subject in need thereof an effective amount of the combination therapy of the invention.
  • a method of treating atherosclerosis administering to a subject in need thereof an effective amount of the combination therapy of the invention.
  • the subject is human.
  • a method for the manufacture of a compound of Formula II, wherein R is eicosapentaenoate and n is 1 comprising: a) preparing the free base of metformin from a metformin salt; and b) reacting two equivalents of the free base of metformin with one equivalent of aspartic acid one equivalent of eicosapentaenoic acid at a temperature between about 1 °C and about 60 °C.
  • Formula II wherein R " is eicosapentaenoate and n is 2, comprising: a) preparing the free base of metformin from a metformin salt; and b) reacting two equivalents of free base of metformin with one equivalent of glutamic acid one equivalent of eicosapentaenoic acid at a temperature between about 1 °C and about 60 °C.
  • Formula II wherein R " is docosahexaenoate and n is 1, comprising: a) preparing the free base of metformin from a metformin salt; and b) reacting two equivalents of the free base of metformin with one equivalent of aspartic acid one equivalent of eicosapentaenoic acid at a temperature between about 1 °C and about 60 °C.
  • a method for the manufacture of a compound of Formula II, wherein R is docosahexaenoate and n is 2, comprising: a) preparing the free base of metformin from a metformin salt; and b) reacting two equivalents of free base of metformin with one equivalent of glutamic acid one equivalent of eicosapentaenoic acid at a temperature between about 1 °C and about 60 °C.
  • Metabolic syndrome is intricately intertwined with T2D, which has become pandemic. Clinical presentation of this syndrome is patient-dependent and the co-morbidities in patients with diabetes (chronic hyperglycemia) include high blood pressure,
  • hyperlipidemia and cardiovascular complications including stroke, myocardial ischemia and cardiomyopathy.
  • cardiovascular complications including stroke, myocardial ischemia and cardiomyopathy.
  • the long-term consequences of these co-morbidities also include diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and diabetic cataracts.
  • 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. Patent No. 3,174,901. Metformin is orally effective in the treatment of type 2 diabetes (T2D). Metformin ( ⁇ , ⁇ -dimethylimidodicarbonimidic diamide) is a biguanide, anti-hyperglycemic agent currently marketed in the United States in the form of its hydrochloride salt 1,1-dimethylbiguanide hydrochloride. Metformin hydrochloride can be purchased commercially and it can also be prepared, for example, as disclosed in J. Chem. Soc, 1922, 121, 1790.
  • UPDS United Kingdom Prospective 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.
  • diabetic patients on metformin therapy face the risk of long-term cardiovascular complications such as cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy and stroke.
  • PUFAs polyunsaturated fatty acids
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • EPA is a promising treatment for prevention of major coronary events.
  • PUFAs have multiple biological functions through lipid-dependent and lipid-independent mechanisms.
  • EPA and mixtures of EPA and DHA have been shown to ameliorate triglycerides (TGs) lipid levels in patients with very high TGs.
  • EPA is shown to increase adiponectin secretion both in obese animals and obese human subjects (Itoh et al. Arteroscler. Thromb. Vase. Biol. 2007, 27, 1918-1925). Increased adiponectin levels are beneficial in regulating both lipid and glucose metabolism in animals as well as in humans.
  • metabolic syndrome sometimes referred to as insulin resistance, suffer from a variety of glucose and lipid metabolism disorders including elevated blood glucose and triglycerides.
  • compounds of Formula I as well as methods for treating diabetes, diabetes with concomitant dyslipidemia (e.g. , high triglycerides) and diabetes exacerbated cardiovascular complications, such as cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy, and stroke, comprising administering to a subject in need thereof a compound of Formula I.
  • concomitant dyslipidemia e.g. , high triglycerides
  • cardiovascular complications such as cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy, and stroke
  • Compounds of Formula I are also useful in treating obesity in a subject in need thereof.
  • Compounds of Formula I are tri-salts of a compound having two acidic and one basic functional groups, metformin, and a polyunsaturated fatty acid, and are represented by the following formula:
  • G is an alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, or heteroaryl group; and R " is a polyunsaturated fatty acid.
  • G is alkyl.
  • G can be alkylene, e.g. , CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 ,
  • n 1-10, and R " is a polyunsaturated fatty acid.
  • n 1-2.
  • n is 3-5.
  • R " is eicosapentaenoate:
  • R " is eicosapentaenoate, and n is 1. In another embodiment of Formula II, R " is eicosapentaenoate and n is 2.
  • R " is docosahexaenoate and n is 1. In another embodiment of Formula II, R " is docosahexaenoate and n is 2.
  • the compound of Formula II is selected from the group consisting of Compounds A, B, C, D, E, F, G, H, I, and J:
  • the compounds of Formula I also include isomers and enantiomers wherever it is applicable.
  • PUFAs and esters of PUFAs are practically insoluble in water. In fact, they form soap-like emulsions when mixed with water. Therefore, the potential to achieve optimum therapeutic benefits of PUFAs should be markedly facilitated by delivery of water soluble PUFAs.
  • the compounds of the present invention are markedly more water soluble than PUFAs and esters of PUFAs to achieve high oral absorption and to provide concomitant delivery of both metformin and PUFAS, thus providing a dual action in targeting both elevated blood glucose levels and TGs prevalent in type 2 diabetes in patients.
  • the new salts would offer a patient friendly dosage form of two active therapies in a fixed dosage combination with increased reliability for daily patient compliance.
  • Juvisync recently approved by the United States Food and Drug Administration, is a contemporary example of a fixed combination of two widely used drugs for reliability of usage and patient convenience (FDA News Release. October 7, 2011).
  • the compounds of the present invention enable the preparation of intravenous dosage forms.
  • alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety.
  • the alkyl comprises 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbons, 1 to 4 carbons, or 1 to 3 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, ieri-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n- heptyl, n-octyl, n-nonyl, n-decyl and the like.
  • alkyl also includes "alkenyl” and "alkynyl” groups.
  • alkenyl alone or in combination refers to a straight-chain, cyclic or branched hydrocarbon residue comprising at least one olefinic bond and the indicated number of carbon atoms.
  • Preferred alkenyl groups have up to 8, preferably up to 6, particularly preferred up to 4 carbon atoms.
  • Examples of alkenyl groups are ethenyl, 1-propenyl, 2- propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1 -cyclohexenyl, 1- cyclopentenyl.
  • alkynyl includes unsaturated aliphatic groups analogous in length to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight-chain alkynyl groups ⁇ e.g. , ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
  • alkynyl further includes alkynyl groups that include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone ⁇ e.g. , i- for straight chain, C3-C6 for branched chain).
  • C2-C6 includes alkynyl groups containing 2 to 6 carbon atoms.
  • cycloalkyl refers to saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3 to 12 carbon atoms, preferably 3 to 9, or 3 to 7 carbon atoms.
  • exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like.
  • Exemplary bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6- trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the like.
  • Exemplary tricyclic hydrocarbon groups include adamantyl and the like.
  • cycloalkyl includes “cycloalkenyl” groups.
  • cycloalkenyl refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 3 rings and 4 to 8 carbons per ring. Exemplary groups include cyclobutenyl, cyclopentenyl, and cyclohexenyl.
  • cycloalkenyl also includes bicyclic and tricyclic groups in which at least one of the rings is a partially unsaturated, carbon-containing ring and the second or third ring may be carbocyclic or heterocyclic, provided that the point of attachment is to the cycloalkenyl group.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, consisting of the stated number of carbon atoms and from 1 to 5 heteroatoms, more preferably from 1 to 3 heteroatoms, selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroalkyl group is attached to the remainder of the molecule through a carbon atom or a heteroatom.
  • aryl includes aromatic monocyclic or multicyclic e.g. , tricyclic, bicyclic, hydrocarbon ring systems consisting only of hydrogen and carbon and containing from 6 to 19 carbon atoms, or 6 to 10 carbon atoms, where the ring systems may be partially saturated.
  • Aryl groups include, but are not limited to, groups such as phenyl, tolyl, xylyl, anthryl, naphthyl and phenanthryl.
  • Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g. , tetralin).
  • heteroaryl represents a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline.
  • heteroaryl is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.
  • heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively.
  • heterocycle refers to a five-member to ten-member, fully saturated or partially unsaturated nonaromatic heterocylic groups containing at least one heteroatom such as O, S or N.
  • heteroatom such as O, S or N.
  • the most frequent examples are piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl or pyrazinyl. Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom.
  • alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, and heterocycle groups described above can be "unsubstituted” or “substituted.”
  • substituted is intended to describe moieties having substituents replacing a hydrogen on one or more atoms, e.g. C, O or N, of a molecule.
  • substituents can independently include, for example, one or more of the following: straight or branched alkyl (preferably C1-C5), cycloalkyl (preferably C3-C8), alkoxy (preferably Ci-C 6 ), thioalkyl (preferably Ci-C 6 ), alkenyl (preferably C2-C 6 ), alkynyl (preferably C2-C 6 ), heterocyclic, carbocyclic, aryl (e.g. , phenyl), aryloxy
  • aryloxyalkyl e.g. , phenyloxyalkyl
  • arylacetamidoyl alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl or other such acyl group, heteroarylcarbonyl, or heteroaryl group, (CR'R") 0 - 3 NR'R" (e.g. , -NH 2 ), (CR'R") 0 - 3 CN (e.g. , -CN), -NO2, halogen (e.g. ,
  • R' and R" are each independently hydrogen, a C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or aryl group.
  • a tri-salt having the Formula I In other embodiments provided herein is a tri-salt having the Formula II.
  • the compound of Formula II is selected from the group consisting of Compounds A, B, C, D, E, F, G, H, I, and J.
  • T2D pre-diabetes
  • obesity metabolic syndrome
  • hypertriglyceridemia T2D complications
  • neuropathy nephropathy, retinopathy, cataracts and cardiovascular complications, including cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy in diabetic patients.
  • Diabetes mellitus commonly called diabetes, refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose, referred to as hyperglycemia. See, e.g., LeRoith, D. et al. , (eds.), Diabetes Mellitus (Lippincott-Raven Publishers, Philadelphia, Pa. U.S.A. 1996). Uncontrolled hyperglycemia is associated with increased and premature mortality due to an increased risk for macrovascular and macrovascular diseases, including nephropathy, neuropathy, retinopathy, hypertension, cerebrovascular disease and coronary heart disease.
  • macrovascular and macrovascular diseases including nephropathy, neuropathy, retinopathy, hypertension, cerebrovascular disease and coronary heart disease.
  • type 1 diabetes (formerly referred to as insulin-dependent diabetes or IDEM); and type 2 diabetes (formerly referred to as noninsulin dependent diabetes or NIDDM).
  • IDEM insulin-dependent diabetes
  • NIDDM noninsulin dependent diabetes
  • Type 2 diabetes is a disease characterized by insulin resistance accompanied by relative, rather than absolute, insulin deficiency. Type 2 diabetes can range from
  • Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations.
  • the body secretes abnormally high amounts of insulin to compensate for this defect.
  • inadequate amounts of insulin are present to compensate for insulin resistance and adequate control of glucose, a state of impaired glucose tolerance develops.
  • insulin secretion declines further and the plasma glucose level rises, resulting in the clinical state of diabetes.
  • Type 2 diabetes can be due to a profound resistance to insulin stimulating regulatory effects on glucose and lipid metabolism in the main insulin-sensitive tissues: muscle, liver and adipose tissue.
  • This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in liver.
  • free fatty acid levels are often elevated in obese and some non-obese patients and lipid oxidation is increased.
  • the term "obesity" is defined as the condition wherein the individual has a BMI equal to or greater than 30 kg/m 2 .
  • the term obesity may be categorized as follows: the term “class I obesity” is the condition wherein the BMI is equal to or greater than 30 kg/m 2 but lower than 35 kg/m 2 ; the term “class II obesity” is the condition wherein the BMI is equal to or greater than 35 kg/m 2 but lower than 40 kg/m 2 ; the term “class III obesity” is the condition wherein the BMI is equal to or greater than 40 kg/m 2 .
  • euglycemia is defined as the condition in which a subject has a fasting blood glucose concentration within the normal range, greater than 70 mg/dL (3.89 mmol/ L) and less than 100 mg/dL (5.6 mmol L).
  • fasting has the usual meaning as a medical term.
  • hypoglycemia is defined as the condition in which a subject has a fasting blood glucose concentration above the normal range, greater than 100 mg/dL (5.6 mmol L).
  • fasting has the usual meaning as a medical term.
  • ITT paired glucose tolerance
  • the abnormal glucose tolerance i. e. the 2 hour postprandial blood glucose or serum glucose concentration can be measured as the blood sugar level in mg of glucose per dL of plasma 2 hours after taking 75 g of glucose after a fast.
  • a subject with "normal glucose tolerance” has a 2 hour postprandial blood glucose or serum glucose concentration smaller than 140 mg/dL (7.78 mmol/L).
  • hyperinsulinemia is defined as the condition in which a subject with insulin resistance, with or without euglycemia, has fasting or postprandial serum or plasma insulin concentration elevated above that of normal, lean individuals without insulin resistance, having a waist-tohip ratio ⁇ 1.0 (for men) or ⁇ 0.8 (for women).
  • Insulin-sensitizing Asperger's trademark for a wide range of materials, including but not limited to a wide range of materials, including but not limited to a wide range of materials, including but not limited to a wide range of materials, including but not limited to a wide range of materials, including but not limited to a wide range of materials, including but not limited to a wide range of materials, including but not limited to a wide range of materials, including but not limited to insulin resistance-improving” or “insulin resistance- lowering” are synonymous and used interchangeably.
  • insulin resistance is defined as a state in which circulating insulin levels in excess of the normal response to a glucose load are required to maintain the euglycemic state (Ford ES, et al. JAMA. (2002) 287:356-9).
  • a method of determining insulin resistance is the euglycaemichyperinsulinaemic clamp test. The ratio of insulin to glucose is determined within the scope of a combined insulin-glucose infusion technique. There is found to be insulin resistance if the glucose absorption is below the 25th percentile of the background population investigated (WHO definition).
  • insulin resistance the response of a patient with insulin resistance to therapy, insulin sensitivity and hyperinsulinemia may be quantified by assessing the "homeostasis model assessment to insulin resistance (HOMA- IR)" score, a reliable indicator of insulin resistance (Katsuki A, et al. Diabetes Care 2001 ; 24: 362-5).
  • HOMA-IR homeostasis assessment model
  • the patient's triglyceride concentration is used, for example, as increased triglyceride levels correlate significantly with the presence of insulin resistance.
  • the "metabolic syndrome”, also called “syndrome X” (when used in the context of a metabolic disorder), also called the “dysmetabolic syndrome” is a syndrome complex with the cardinal feature being insulin resistance (Laaksonen D E, et al. Am. J. Epidemiol. 2002; 156: 1070-7).
  • diagnosis of the metabolic syndrome is made when three or more of the following risk factors are present:
  • Abdominal obesity defined as waist circumference>40 inches or 102 cm in men, and >35 inches or 94 cm in women; or with regard to a Japanese ethnicity or Japanese patients defined as waist circumference of 85 cm in men and 90 cm in women;
  • Patients with a predisposition for the development of IGT or IFG or T2D are those having euglycemia with hyperinsulinemia and are by definition, insulin resistant.
  • a typical patient with insulin resistance is usually overweight or obese. If insulin resistance can be detected, this is a particularly strong indication of the presence of pre-diabetes.
  • pancreatic beta-cells The methods to investigate the function of pancreatic beta-cells are similar to the above methods with regard to insulin sensitivity, hyperinsulinemia or insulin resistance:
  • An improvement of beta-cell function can be measured for example by determining a HOMA- index for beta-cell function (Matthews et ah , Diabetologia 1985, 28:412-19), the ratio of intact proinsulin to insulin (Forst et al.
  • Pre-diabetes is the condition wherein an individual is pre-disposed to the development of type 2 diabetes. Pre-diabetes extends the definition of impaired glucose tolerance to include individuals with a fasting blood glucose within the high normal range 100 mg/dL (J. B. Meigs, et al. Diabetes 2003; 52:1475-1484) and fasting hyperinsulinemia (elevated plasma insulin concentration).
  • the scientific and medical basis for identifying prediabetes as a serious health threat is laid out in a Position Statement entitled "The Prevention or Delay of Type 2 Diabetes” issued jointly by the American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Diseases (Diabetes Care 2002; 25:742-749).
  • insulin resistance is defined as the clinical condition in which an individual has a HOMA-IR score>4.0 or a HOMA-IR score above the upper limit of normal as defined for the laboratory performing the glucose and insulin assays.
  • type 2 diabetes is defined as the condition in which a subject has a fasting blood glucose or serum glucose concentration greater than 125 mg/dL (6.94 mmol L).
  • the measurement of blood glucose values is a standard procedure in routine medical analysis. If a glucose tolerance test is carried out, the blood sugar level of a diabetic will be in excess of 200 mg of glucose per dL (11.1 mmol/1) of plasma 2 hours after 75 g of glucose have been taken on an empty stomach. In a glucose tolerance test 75 g of glucose are administered orally to the patient being tested after 10-12 hours of fasting and the blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after taking it.
  • the blood sugar level before taking the glucose will be between 60 and 110 mg per dL of plasma, less than 200 mg per dL 1 hour after taking the glucose and less than 140 mg per dL after 2 hours. If after 2 hours the value is between 140 and 200 mg, this is regarded as abnormal glucose tolerance.
  • late stage T2D mellitus includes patients with a secondary drug failure, indication for insulin therapy and progression to micro- and macrovascular complications e.g. diabetic nephropathy, or coronary heart disease (CHD)
  • the methods, compositions, and kits of the invention are useful in treating diabetic complications, including, but not limited to, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataracts and diabetic retinopathy.
  • treating refers to retarding, arresting, or reversing the progress of, or alleviating or preventing either the disorder or condition to which the term “treating”, applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating a disorder, symptom, or condition, as the term “treating,” is defined above.
  • 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.
  • Atherosclerosis refers to the buildup of fats and cholesterol in and on artery walls (plaques), which can restrict blood flow. These plaques can also burst, triggering a blood clot.
  • plaques can also burst, triggering a blood clot.
  • atherosclerosis is often considered a heart problem, it can affect arteries anywhere in the body. An animal model of atherosclerosis research is described in
  • compounds of Formula I can be administered in combination with additional forms of metformin.
  • compounds of Formula I can be administered to a subject in combination with metformin docosahexaenoate, metformin eicosapentaenoate, or a mixture thereof.
  • compounds of Formula I can be administred in combination with a non- fatty acid salt form of metformin, e.g. , metformin hydrochloride, succinate, or fumarate, or in combination with the free base of metformin.
  • Metformin hydrochloride can be purchased commercially and can also be prepared, for example, as disclosed in J. Chem. Soc, 1922, 121 , 1790.
  • compounds of Formula I can be administered in combination with eicosapentanoic acid, and/or docosahexaenoic acid.
  • the tri-salts of the present invention are well-suited to use in combination therapy.
  • combination therapy refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate containers (e.g., capsules) for each active ingredient.
  • administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • single formulation refers to a single carrier or vehicle formulated to deliver effective amounts of both therapeutic agents to a patient.
  • the single vehicle is designed to deliver an effective amount of each of the agents, along with any pharmaceutically acceptable carriers or excipients.
  • the vehicle is a tablet, capsule, pill, or a patch. In other embodiments, the vehicle is a solution or a suspension.
  • unit dose is used herein to mean simultaneous administration of both agents together, in one dosage form, to the patient being treated.
  • the unit dose is a single formulation.
  • the unit dose includes one or more vehicles such that each vehicle includes an effective amount of at least one of the agents along with pharmaceutically acceptable carriers and excipients.
  • the unit dose is one or more tablets, capsules, pills, or patches administered to the patient at the same time.
  • oral dosage form includes a unit dosage form prescribed or intended for oral administration.
  • a “mixture of compounds of Formula I or II” refers to a mixture of two or more of these compounds present in a and b %, wherein a and b are not zero, but the sum of a and b is 100 %.
  • a compound of Formula I is present at 50% and a compound of Formula II is present at 50%.
  • a combination therapy comprising an effective amount of a compound of Formula I or II, or a combination thereof, and an
  • an "effective amount" of a combination of agents is an amount sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the disorders treated with the combination.
  • the combination of a compound of Formula I or II, or a combination thereof, and an antihyperlipidemic agent or an antihyperglycemic agent described herein displays a synergistic effect.
  • the term "synergistic effect" as used herein refers to action of two agents producing an effect, for example, slowing the symptomatic progression of diabetes or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves.
  • a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet.
  • pharmaceutically acceptable salts includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts, where appropriate.
  • pharmaceutically-acceptable cationic salts is intended to define but is not limited to such salts as the alkali metal salts, (e.g.
  • alkaline earth metal salts e.g., calcium and magnesium
  • aluminum salts e.g., ammonium salts, and salts with organic amines such as benzathine ( ⁇ , ⁇ '-dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzyl phenethylamine) , diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl- l ,3- propanediol) and procaine.
  • benzathine ⁇ , ⁇ '-dibenzylethylenediamine
  • choline diethanolamine
  • ethylenediamine meglumine (N-methylglucamine)
  • benethamine N-benzyl phenethylamine
  • diethylamine diethylamine
  • piperazine tromethamine (2-amino-2-hydroxymethyl- l ,3
  • salts are, for example, inorganic acids, such as hydrohalic acid, e. g. hydrochloric, hydrobromic or the like, or sulfuric acid, nitric acid, or phosphoric acid; or suitable organic acids, for example suitable aliphatic acids, like aliphatic mono or dicarboxylic acids, hydroxyalkanoic or hydroxyalkanedioic acids, e.g.
  • acids are e.g. hydrobromic acid, sulphuric acid, phosphoric acid, acetic, benzoic, fumaric, maleic, citric, tartaric, gentisic, dobesilic, methanesulfonic,
  • the pharmaceutically acceptable salt is selected from the group consisting of an L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine,
  • a combination therapy comprising a compound of the structural Formula I or II above, and an antihyperlipidemic agent, to treat a metabolic disorder selected from the group consisting of T2D, pre-diabetes, obesity, metabolic syndrome, hypertriglyceridemia and T2D complications such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including atrial fibrillation, cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy in mammals, e.g. , diabetic patients.
  • An additional aspect provided herein is combination therapy comprising a compound of the structural Formula I or II and an antihyperlipidemic agent, to treat obesity, cardiovascular disease, and related indications in a subject in need thereof.
  • a method of lowering the cholesterol level and/or the triglyceride level in a mammal comprising administering to the mammal an effective amount of the combination therapy of the invention.
  • provided herein is a method for treating diabetes in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the combination therapy described above.
  • a method of lowering triglycerides in a subject in need thereof comprising administering to a subject in need thereof an effective amount of the combination therapy of the invention.
  • a method for treating cardiovascular diseases in a subject in need thereof administering to a subject in need thereof an effective amount of the combination therapy of the invention.
  • cardiovascular diseases to be treated are cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy, or stroke.
  • provided herein is a method for treating obesity in a subject in need thereof, administering to a subject in need thereof an effective amount of the combination therapy of the invention.
  • provided herein is a method of treating hyperlipidemia, administering to a subject in need thereof an effective amount of the combination therapy of the invention.
  • a method of treating hypertriglyceridemia administering to a subject in need thereof an effective amount of the combination therapy of the invention.
  • a method of treating dyslipidemia administering to a subject in need thereof an effective amount of the combination therapy of the invention.
  • provided herein is a method of treating prediabetes, administering to a subject in need thereof an effective amount of the combination therapy of the invention.
  • provided herein is a method of treating atherosclerosis, administering to a subject in need thereof an effective amount of the combination therapy of the invention.
  • the subject is human.
  • the invention relates to a combination therapy comprising a compound of the structural Formula I or II or a compound of the structural Formula I or II and an antihyperlipidemic agent, or a combination of two or more compounds of the structural Formulas I or II or a compound of the structural Formula I or II and an antihyperlipidemic agent and a pharmaceutically- acceptable salt or prodrug thereof, or a pharmaceutically- acceptable salt of said prodrug.
  • a pharmaceutical composition comprising a compound of the structural Formula I or II, or a mixture of these, an antihyperlipidemic agent and a pharmaceutically- acceptable carrier.
  • the pharmaceutical composition comprises two or more compounds of the structural Formula I or II, or a mixture of these
  • the two or more compounds are present in x, y, z, ... % etc. with the proviso that x, y, z, ...% are not zero, but the sum x, y, z, ...% is 100%.
  • the antihyperlipidemic agent is about 0.1-1 % by weight of the pharmaceutical composition.
  • the compound of the structural Formula I or II, or a mixture thereof is present in unit dosage strength of 250, 500, 750, 1000 or 1250 mg, and the said antihyperlipidemic agent is present in a unit dosage strength of 1, 2.5, 5, 10, 20, 30, 40, or 50 mg.
  • the said antihyperlipidemic agent is present in a unit dosage strength of 5-100 mg.
  • the components of the combination therapy can be administered in a variety of ways.
  • the components are in separate formulations or unit dosage forms.
  • the components are administered with a pharmaceutically acceptable carrier.
  • the components can be administered separately, at substantially the same time, or administered at different times. When administered separately, they can be administered in any order.
  • the present invention is directed to pharmaceutical compositions comprising compound of the structural Formula I or II, or a mixture of these and an antihyperlipidemic agent, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug; and a pharmaceutically-acceptable carrier, vehicle or diluent.
  • Antihyperlipidemic agents that may be used in accordance with the invention may include, for example, statins, which are HMG CoA enzyme inhibitors, cholesterol absorption inhibitors, and cholesterol esterase transfer protein (CETP) inhibitors and pharmaceutically- acceptable salts and prodrug thereof, and pharmaceutically-acceptable salts of said prodrug, and others.
  • statins which are HMG CoA enzyme inhibitors, cholesterol absorption inhibitors, and cholesterol esterase transfer protein (CETP) inhibitors and pharmaceutically- acceptable salts and prodrug thereof, and pharmaceutically-acceptable salts of said prodrug, and others.
  • the antihyperlipidemic agent is a statin, cholesterol absorption inhibitor, and CETP inhibitor or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug.
  • the pharmaceutically acceptable salt is selected from the group consisting of a propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4- dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathal ate, sulfonate, xylenesulfonate, phenyl acetate, phenylpropionat
  • statins are atorvastatin, risuvostatin, simvastatin, or pravastatin, pharmaceutically-acceptable salts or a prodrugs thereof, and pharmaceutically- acceptable salts of said prodrugs.
  • Preferred agents among cholesterol absorption inhibitors is ezetimibe also known as Zetia.
  • Preferred agents among CETP inhibitors is anacetrapib.
  • CETP inhibitors include, but are not limited to anacetrapib or a hydrate, and solvate thereof.
  • the pravastatin is present in the amount ranging from 5 mg to 100 mg.
  • the ezetimibe is present 5 mg to 50 mg.
  • kits comprising a first unit dosage form comprising compound of the structural Formula I or II, or a mixture of these; a second unit dosage form comprising an antihyperlipidemic agent or a hydrate, and solvate thereof; and a container.
  • G is an alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, or heteroaryl group; and R " is a polyunsaturated fatty acid.
  • G is alkyl.
  • G can be alkylene, e.g. , CH 2 , CH 2 CH 2 , CH2CH2CH2, CH2CH2CH2CH2, CH2CH2CH2CH2, etc., wherein one of the hydrogens is replaced with the NH 3 " depicted in Formula I.
  • compounds of Formula I are of the Formula II, wherein
  • R " is a polyunsaturated fatty acid, and n is 1-10, or a pharmaceutically acceptable solvate or hydrate thereof. In a particular embodiment of Formula II, n is 1 or 2. In an embodiment of Formulas I and II, R " is eicosapentaenoate or docosahexaenoate. In an embodiment of Formula II, R " is eicosapentaenoate or docosahexaenoate, and n is 1. In still another embodiment of Formula II, R " is eicosapentaenoate or docosahexaenoate, and n is 2. In still further embodiments, the compounds of Formula II are selected from the group consisting of Compounds A, B, C, D, E, F, G, H, I, and J.
  • antihyperlipidemic agents that may be used in accordance with the invention are members of different classes of antihyperlipidemic agents (e.g., HMG-CoA reductase inhibitors (statins), CETP inhibitors, and cholesterol absorption inhibitors and others), pharmaceutically-acceptable salts and prodrugs thereof, and pharmaceutically-acceptable salts of said prodrugs.
  • HMG-CoA reductase inhibitor refers to a compound that competitively blocks the enzyme 3-hydroxy-3-methyl-glutaryl-co-enzyme A (HMG-CoA) reductase.
  • HMG-CoA reductase inhibitors interfere with cholesterol formation (enzyme catalyzes the conversion ofHMG-CoA to mevalonate). As a result, they decrease total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (a membrane transport complex for LDL-C), very low-density lipoprotein (VLDL), and plasma triglycerides.
  • LDL-C low-density lipoprotein cholesterol
  • VLDL very low-density lipoprotein
  • HMG-CoA reductase inhibitors which may be used in accordance with the disclosure include, but are not limited to: atorvastatin, which may be prepared as disclosed in U.S. Pat. No. 7,030,151 ; pravastatin and related compounds which may be prepared as disclosed in U.S. Pat. Nos.4,346,227 and 4,448,979; rosuvastatin, which may be prepared as disclosed in U.S. Pat. No.6,858,618; simvastatin and related compounds which may be prepared as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171.
  • HMG-CoA reductase inhibitors also include atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, rosuvastatin, cerivastatin, mevastatin, rivastatin, pitavastatin, nisvastatin, itavastatin, velostatin and fluindostatin.
  • CETP inhibitor refers to a compound which catalyses the transfer of cholesteryl ester from HDL to apolipoprotein B containing lipoproteins in exchange for triglyceride and thereby plays a major role in lipoprotein metabolism.
  • CETP inhibitors see, for example, Curr. Opin. Pharmacol. 6:162 (2006) and references cited therein.
  • CETP inhibitors which may be used in accordance with the disclosure are not limited by any structure or group of CETP inhibitors.
  • CETP inhibitors which may be used in accordance with the disclosure include, but are not limited to: anacetrapib, which may be prepared as disclosed in WO 2007005572. The disclosure thereof is incorporated herein by reference.
  • cholesterol absorption inhibitors refers to a compound that inhibits the absorption ofbiliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides, or bile acids.
  • cholesterol absorption inhibitors see, for example, Nutr. Metab. Cardiovasc. Dis., 13:42 (2004) and references cited therein.
  • Cholesterol absorption inhibitors which may be used in accordance with the disclosure include, but are not limited to ezetimibe (Zetia), which may be prepared as disclosed in U.S. Pat. Nos. 5,767,115 and 5, 846,966. The disclosures thereof are incorporated herein by reference.
  • any HMG Co-A reductase inhibitors (or) or in a pharmaceutically acceptable combination with any flushing inhibiting agent may be employed.
  • the disclosure provides for pharmaceutical compositions comprising a compound of Formula I or II, or a mixture thereof; and an antihyperlipidemic agent or a pharmaceutically acceptable salt, hydrate, and solvate thereof.
  • the disclosure provides for unit dose formulations comprising a compound of Formula I or II, or a mixture thereof, and an antihyperlipidemic agent or a pharmaceutically acceptable salt, hydrate, and solvate.
  • the disclosure provides for methods of treating a diabetic
  • cardiovascular complication in a mammal comprising administering to said mammal a pharmaceutical composition as set forth herein below.
  • diabetic complications are, for example, atrial fibrillation, arrhythmia, myocardial infarction, stroke and cardiomyopathy.
  • the disclosure provides for methods of treating type 2 diabetes in a mammal comprising administering to said mammal a compound of Formula I or II, or a mixture thereof, and an antihyperlipidemic agent or a hydrate, and solvate hereof.
  • combination therapies comprising, at least, the following combination of agents:
  • the present invention relates to a combination therapy comprising a compound of the structural Formula I or II above, and an antihyperglycemic agent, to treat a metabolic disorder selected from the group consisting of type 2 diabetes (T2D), pre-diabetes, obesity, metabolic syndrome, hypertriglyceridemia and T2D complications such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy in mammals, e.g. , diabetic patients.
  • T2D type 2 diabetes
  • pre-diabetes e.g., obesity
  • metabolic syndrome e.g., pre-diabetes
  • hypertriglyceridemia e.g., pre-diabetes
  • T2D complications such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy in mammals,
  • the present invention provides a method of treating a metabolic disorder selected from the group consisting of T2D, pre-diabetes, obesity, metabolic syndrome, hypertriglyceridemia and diabetes complications such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including cardiac arrhythmia, myocardial infarction, and cardiomyopathy in mammals, e.g. , diabetic patients, comprising administering to a subject in need thereof the combination therapy described herein
  • the components of the combination therapy can be administered in a variety of ways.
  • the components are in separate formulations or unit dosage forms.
  • the components are administered with a pharmaceutically acceptable carrier.
  • the components can be administered separately, at substantially the same time, or administered at different times. When administered separately, they can be administered in any order.
  • the present invention is directed to pharmaceutical compositions comprising a compound of the structural Formula I or II, or a mixture of these, and an antihyperglycemic agent, or a pharmaceutically- acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug; and a pharmaceutically-acceptable carrier, vehicle or diluent.
  • the antihyperglycemic agent is about 1-20% by weight of the pharmaceutical composition.
  • said compound of the structural Formula I or II, or a mixture thereof is present in unit dosage strength of 250, 500, 750, 1000 or 1250 mg, and the said antihyperglycemic agent is present in a unit dosage strength of 1 , 2.5, 5, 10, 20, 25, 50, 100, 150, or 200 mg.
  • the antihyperglycemic agent is present in a unit dosage strength of 5-100 mg.
  • Antihyperglycemic agents that may be used in accordance with the invention may include, for example, sulfonylureas, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, DPP IV inhibitors, and SGLT-2 inhibitors and pharmaceutically-acceptable salts and prodrug thereof, and pharmaceutically-acceptable salts of said prodrug, and others.
  • the antihyperglycemic agent is a sulfonylurea, meglitinide, thiazolidinedione, alpha-glucosidase inhibitor, DPP IV inhibitor, and SGLT-2 inhibitors or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug.
  • the antihyperglycemic agent is a sulfonylurea, meglitinide, thiazolidinedione, alpha-glucosidase inhibitor, DPP IV inhibitor, and SGLT-2 inhibitors or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug.
  • pharmaceutically acceptable salt is selected from the group consisting of a propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- 1 ,4-dioate, hexyne-1 ,6- dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathal ate, sulfonate, xylenesulfonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, p- hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonates, naphthalene- 1-sulfonate, n
  • Preferred agents among thiazolidinediones are pioglitazone, pharmaceutically- acceptable salts or a prodrugs thereof, and pharmaceutically-acceptable salts of said prodrugs.
  • Preferred alpha-glucosidase inhibitors include, but are not limited to, acarbose, vaglibose, and miglitol, pharmaceutically-acceptable salts and prodrugs thereof, and pharmaceutically-acceptable salts of said prodrugs.
  • Preferred DPP-IV inhibitors include, but are not limited to, sitagliptin, linagliptin, vildagliptin, saxagliptin, alogliptin, denagliptin, carmegliptin, melogliptin and dutogliptin. and pharmaceutically-acceptable salts and prodrugs thereof, and pharmaceutically-acceptable salts of said prodrugs.
  • Preferred SGLT-2 inhibitors include, but are not limited to, dapagliflozin
  • G is an alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, or heteroaryl group; and R " is a polyunsaturated fatty acid.
  • G is alkyl.
  • G can be alkylene, e.g. , CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , etc., wherein one of the hydrogens is replaced with the NH 3 " depicted in Formula I.
  • compounds of Formula I are of the Formula II wherein R " is a polyunsaturated fatty acid, and n is 1-10, or a pharmaceutically acceptable solvate or hydrate thereof. In a particular embodiment of Formula II, n is 1 or 2. In an embodiment of Formulas I and II, R " is eicosapentaenoate or docosahexaenoate. In an embodiment of Formula II, R " is eicosapentaenoate or docosahexaenoate, and n is 1. In still another embodiment of Formula II, R " is eicosapentaenoate or docosahexaenoate, and n is 2. In still further embodiments, the compounds of Formula II are selected from the group consisting of Compounds A, B, C, D, E, F, G, H, I, and J.
  • antihyperglycemic agents that may be used in accordance with the invention are members of different classes of antihyperglycemic agents (e.g., sulfonylureas, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, DPP-IV inhibitors, SGLT-2 inhibitors and others), pharmaceutically-acceptable salts and prodrugs thereof, and pharmaceutically- acceptable salts of said prodrugs.
  • antihyperglycemic agents e.g., sulfonylureas, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, DPP-IV inhibitors, SGLT-2 inhibitors and others
  • pharmaceutically-acceptable salts and prodrugs e.g., sulfonylureas, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, DPP-IV inhibitors,
  • sulfonylureas refers to a class of compounds that stimulate insulin release by binding to the sulfonylurea receptor, a subunit of the ICATP channel complex. This binding leads to closure of the channel, resulting in voltage change in the beta-cell membrane and, in turn, influx of Ca 2+ ions causing exocytosis of insulin granules.
  • sulfonylureas see, for example, Metabolism, 55, 20 (2006) incorporated by reference, herein, in its entirety and references cited therein, and Lancet, 358, 1709 (2001) incorporated by reference, herein, in its entirety and references cited therein.
  • thiazolidinediones refers to a class of compounds that are selective agonists for the peroxisome proliferator- activated receptor gamma (PPARy), a member of family of nuclear hormone receptors that function as ligand-activated transcription factors.
  • PPARy peroxisome proliferator- activated receptor gamma
  • thiazolidinediones see, for example, Trends Endocrin. Met., 10, 9 (1999) and references cited therein.
  • alpha-glucosidase inhibitors refers to a class of compounds having the ability to competitively inhibit brush border enzyme alpha-glucosidase in the GI tract, which has the ability to cleave complex carbohydrates into sugars.
  • alpha-glucosidase inhibitors see, for example, Diabetes Res. Clin. Pr., 40, S51 (1998) and references cited therein.
  • DPP IV inhibitors refers to a class of compounds that have the ability to selectively inactivate the enzyme DPP-IV, and those which have the ability to rapidly inactivate incretin hormones (e.g., glucagon-like peptide- 1 (GLP-1) and insulinotropic polypeptide (GIP)), that are released by the intestine throughout the day, and whose levels are increased after a meal.
  • GLP-1 glucagon-like peptide- 1
  • GIP insulinotropic polypeptide
  • the DPP-IV inhibitor sitagliptin can be prepared according to procedure described by Kim et al. in Journal of Medicinal Chemistry, 48, 141-151 , (2005) and in Journal of Medicinal Chemistry, 51, 589- 602, (2008).
  • SGLT-2 inhibitors refers to a class of compounds that have the ability to selectively inhibit renal sodium-glucose co-transporter 2 and prevent renal glucose reabsorption from the glomerular filtrate and provide an insulin- independent means of controlling hyperglycemia.
  • SGLT-2 inhibitors see, for example, Journal of Medicinal Chemistry, 52, 1785 1794, (2009) and references cited therein.
  • any sulfonylurea, meglitinide, thiazolidinedione, alpha-glucosidase inhibitor, DPP-IV inhibitor, or a SGLT-2 inhibitor or a pharmaceutically- acceptable salt or a prodrug thereof, or a pharmaceutically- acceptable salt of said prodrug, or any combination thereof, may be employed.
  • Sulfonylureas that may be used in accordance with the invention include, but are not limited to, acetohexamide, which may be prepared as described in U.S. Patent No. 3,013,072; 1- Butyl-3-methanilyl urea, which may be prepared as described in U.S. Patent No.
  • carbutamide which may be prepared as described in U.S. Patent No. 4,324,796
  • chlorpropamide which may be prepared as described in U.S. Patent No. 4,381,304
  • glibornuride which may be prepared as described in U.S. Patent No. 4,153,710
  • gliclazide which may be prepared as described in U.S. Patent No. 6,733,782
  • glipizide which may be prepared and its use as oral administration as described in U.S. Patent No. 5,545,413 ;
  • glyburide or glibenclamide which may be prepared and its use as described in U.S. Patent No. 6,830,760; glybuthiazole, which may be prepared as described in U.S. Patent
  • DPP-IV inhibitors that may be used in accordance with the invention include, but are not limited to, linagliptin, sitagliptin, vildagliptin, alogliptin, saxagliptin, denagliptin, carmegliptin, melogliptin, and dutogliptin, or a pharmaceutically-acceptable salt of one of the beforementioned DPP IV inhibitors, or a prodrug thereof.
  • linagliptin refers to linagliptin and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline forms thereof. Crystalline forms are described in WO 2007/128721. Methods for the manufacture of linagliptin are described in the patent applications WO 2004/018468 and WO 2006/048427 for example. Linagliptin is distinguished from structurally comparable DPP IV inhibitors, as it combines exceptional potency and a long- lasting effect with favorable pharmacological properties, receptor selectivity and a favorable side-effect profile or bring about unexpected therapeutic advantages or improvements when used in combination with an SGLT2 inhibitor and a third antidiabetic agent according to this invention.
  • sitagliptin refers to sitagliptin (or MK-0431) and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline forms thereof. In one embodiment, sitagliptin is in the form of its
  • sitagliptin phosphate is in the form of a crystalline anhydrate or monohydrate.
  • a class of this embodiment refers to sitagliptin phosphate monohydrate.
  • Sitagliptin free base and pharmaceutically acceptable salts thereof are disclosed in U.S. Patent No. 6,699,871 and in Example 7 of WO 03/004498.
  • Crystalline sitagliptin phosphate monohydrate is disclosed in WO 2005/003135 and in WO 2007/050485. For details, e.g. on a process to manufacture or to formulate this compound or a salt thereof, reference is thus made to these documents.
  • a tablet formulation for sitagliptin is commercially available under the trade name Januvia®.
  • vildagliptin refers to vildagliptin (or LAF-237) and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline forms thereof. Specific salts of vildagliptin are disclosed in WO 2007/019255. A crystalline form of vildagliptin as well as a vildagliptin tablet formulation are disclosed in WO 2006/078593. Vildagliptin can be formulated as described in WO 00/34241 or in WO 2005/067976. A modified release vildagliptin formulation is described in WO 2006/135723. For details, e.g.
  • saxagliptin refers to saxagliptin and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline forms thereof
  • saxagliptin is in the form of the free base or a HC1 salt (for example as mono- or dihydrochloride, including hydrates thereof), or a mono-benzoate salt as disclosed in WO 2004/052850 and WO 2008/131149.
  • saxagliptin is in the form of the free base.
  • saxagliptin is in the form of the monohydrate of the free base as disclosed in WO 2004/052850.
  • a process for preparing saxagliptin is also disclosed in WO 2005/106011 and WO 2005/ 115982.
  • Saxagliptin can be formulated in a tablet as described in WO 2005/117841.
  • a process to manufacture, to formulate or to use this compound or a salt thereof reference is thus made to these documents and U.S. Patent No. 6,395,767 and WO 01/68603.
  • denagliptin refers to denagliptin (or GSK-823093) and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline forms thereof.
  • denagliptin is in the form of its hydrochloride salt as disclosed in Example 2 of WO 03/002531 or its tosylate salt as disclosed in WO 2005/009956.
  • a class of this embodiment refers to denagliptin tosylate.
  • Crystalline anhydrous denagliptin tosylate is disclosed in WO 2005/009956.
  • alogliptin refers to alogliptin (or SYR-322) and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline forms thereof
  • alogliptin is in the form of its benzoate salt, its hydrochloride salt or its tosylate salt each as disclosed in WO 2007/035629.
  • a class of this embodiment refers to alogliptin benzoate.
  • Polymorphs of alogliptin benzoate are disclosed in WO 2007/035372.
  • a process for preparing alogliptin is disclosed in WO 2007/112368 and, specifically, in WO 2007/035629.
  • Alogliptin (namely its benzoate salt) can be formulated in a tablet and administered as described in WO 2007/033266.
  • Alogliptin namely its benzoate salt
  • WO 2007/033266 For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents and to US 2005/261271, EP 1586571 and WO 2005/095381.
  • carmegliptin refers to carmegliptin
  • melogliptin refers to melogliptin
  • Specifically claimed salts include the methanesulfonate and p-toluene-sulfonate.
  • methanesulfonate and p-toluene-sulfonate are examples of compounds that are used in the production of salts.
  • p-toluene-sulfonate for details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents.
  • dutogliptin refers to dutogliptin (or PHX-1149, PHX- 1149T) and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline forms thereof. Methods for its preparation are inter alia disclosed in WO 2005/047297. Pharmaceutically acceptable salts include the tartrate. For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents.
  • SGLT-2 inhibitors that may be used in accordance with the invention include, but are not limited to dapagliflozin, canagliflozin, atigliflozin, remogliflozin and sergliflozin.
  • dipagliflozin refers to dapagliflozin, including hydrates and solvates thereof, and crystalline forms thereof.
  • the compound and methods of its synthesis are described in WO 03/099836 for example.
  • Preferred hydrates, solvates and crystalline forms are described in the patent applications WO 2008/116179 and WO 2008/ 002824 for example.
  • canagliflozin refers to canagliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure: The compound and methods of its synthesis are described in WO 2005/012326 and WO
  • hydrates, solvates and crystalline forms are described in the patent applications WO 2008/069327 for example.
  • atigliflozin refers to atigliflozin, including hydrates and solvates thereof, and crys-talline forms thereof. The compound and methods of its synthesis are described in WO 2004/007517, for example.
  • remogliflozin refers to remogliflozin and prodrugs of remogliflozin, in particular remogliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods of its synthesis are described in the patent applications EP 1213296 and EP 1354888 for example.
  • sergliflozin refers to sergliflozin and prodrugs of sergliflozin, in particular sergliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods for its manufacture are described in the patent applications EP 1344780 and EP 1489089 for example.
  • combination therapies comprising, at least, the following combination of agents:
  • combination therapies of paragraphs 1 and 2, above can be further combined with compounds of Formula I and/or II.
  • the tri-salts of the present invention are suitable as active agents in pharmaceutical compositions that are efficacious particularly for treating diabetes, obesity, and related conditions.
  • the pharmaceutical composition in various embodiments has a pharmaceutically effective amount of the present active agent along with other pharmaceutically acceptable excipients, carriers, fillers, diluents and the like.
  • Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences' , 19th Edition (Mack Publishing Company, 1995).
  • composition includes preparations suitable for administration to mammals, e.g. , humans.
  • compounds of the present invention When the compounds of the present invention are administered as pharmaceuticals to mammals, e.g. , humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • phrases "pharmaceutically acceptable carrier” is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present invention to mammals.
  • the carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil;
  • glycols such as propylene glycol
  • polyols such as glycerin, sorbitol, mannitol and polyethylene glycol
  • esters such as ethyl oleate and ethyl laurate
  • agar buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, ⁇ -tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin
  • Formulations of the present invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and glycerol monostea
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical- formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and e
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • compositions of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • a pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses.
  • a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • the total daily dose of the compounds of the invention is typically in the range of 0.25 g - 6 g, 0.25 g - 4 g, 0.25 g - 2 g, or 0.25 g - 1 g, depending, of course, on the mode of administration.
  • the total daily dose is in the range 1 g to 10 g and in another embodiment the total daily dose is in the range 1 g to 6 g.
  • the total daily dose may be administered in single or divided doses.
  • These dosages are based on an average human subject having a weight of about 65kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • a pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses.
  • a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. Kits
  • kits for use by a consumer for treating disease comprise a) a pharmaceutical composition comprising a tri-salt of the invention and a pharmaceutically acceptable carrier, vehicle or diluent; and, optionally, b) instructions describing a method of using the pharmaceutical composition for treating the specific disease.
  • a "kit” as used in the instant application includes a container for containing the separate unit dosage forms such as a divided bottle or a divided foil packet.
  • the container can be in any conventional shape or form as known in the art which is made of a
  • a pharmaceutically acceptable material for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
  • the container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle which is in turn contained within a box.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material.
  • recesses are formed in the plastic foil.
  • the recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed.
  • the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • the written memory aid is of the type containing information and/or instructions for the physician, pharmacist or subject, e.g. , in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested or a card which contains the same type of information.
  • a calendar printed on the card e.g., as follows "First Week, Monday,
  • a “daily dose” can be a single tablet or capsule or several tablets or capsules to be taken on a given day.
  • kits are a dispenser designed to dispense the daily doses one at a time.
  • the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen.
  • a memory-aid is a mechanical counter, which indicates the number of daily doses that, has been dispensed.
  • a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
  • One embodiment of the present invention relates to a kit comprising a unit dosage comprising a compound of the invention with instructions on how to use the kit and with provision for at least one container for holding the unit dosage form.
  • the tri-salts of the invention can be prepared using any number of synthesis techniques known to the skilled artisan.
  • the compound of Formula II, wherein R " is eicosapentaenoate and n is 1, can be prepared by reacting one equivalent of aspartic acid with two equivalents of metformin free base followed by one equivalent of EPA.
  • the solvents for conducting the reaction can be alcoholic solvents, such as ethanol, methanol, propanol, and isopropanol, ketonic solvents, such as acetone, ethyl methyl ketone, and methyl isopropyl ketone, acetonitrile.
  • the reaction can be conducted at a temperature from between 0 °C to reflux temperature of the solvent used.
  • the reaction time is determined by completion of reaction as monitored by analytical techniques, such as high pressure liquid chromatography.
  • the compound of Formula II wherein R " is eicosapentaenoate and n is 2, can be prepared according to the procedure described above, except that aspartic acid is replaced by glutamic acid.
  • the compound of Formula II, wherein R " is docosahexaenoate and n is 1, can be prepared by reacting one equivalent of aspartic acid with two equivalents of metformin free base followed by one equivalent of DHA.
  • the solvents for conducting the reaction can be alcoholic solvents, such as ethanol, methanol, propanol, and isopropanol, ketonic solvents, such as acetone, ethyl methyl ketone, and methyl isopropyl ketone, acetonitrile.
  • the reaction can be conducted at a temperature from between 0 °C to reflux temperature of the solvent used.
  • the reaction time is determined by completion of reaction as monitored by analytical techniques, such as high pressure liquid chromatography.
  • the compound of Formula II wherein R " is docosahexaenoate and n is 2, can be prepared according to the procedure described above, except that aspartic acid is replaced by glutamic acid.
  • 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 Spontaneously diabetic Bio-Bred (BB/W)rats are considered a useful model of autoimmune human insulin-dependent diabetes DM).
  • vLike 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). Isolated Perfused Heart Model
  • 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, .47 mM KC1, 12 mM CaCl 2 , 12 mM MgC12, 25 mM NaHC0 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 ⁇ metformin eicosapentaenoate.
  • This example describes a procedure used for study of low-flow ischemia in diabetic controls, diabetic treated, non-diabetic treated and non-diabetic control isolated hearts .
  • Diabetic control hearts DC 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 ⁇ 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).
  • Step 2 Preparation of Bisri r(dimethylamino)(imino)methyllamino](imino)methanaminiuml (2S)-2-amininium (5Z,8Z,l lZ,14Z,17Z)-icosa-5,8,l l,14,17-pentaenoate-pentanedioate (Met2-Glu-EPA)
  • (2S)-2-aminopentanedioate (4.28 g, 15.5 mmol) in methanol (180 mL) is stirred with (5Z,8Z,l lZ,14Z,17Z)-eicosa-5,8,l l ,14,17-pentaenoic acid (5.15 g, 17.0 mmol) at RT in an amber flask under N 2 for 1 hour.
  • the methanol is evaporated and the remaining oil is triturated with ice cold CH 3 CN (50 ml) to form a solid. This solid is collected by filtration in the dark and dried at RT in the dark under hi- vac.
  • Yield lOg (91 % yield) of bis[ ⁇ [(dimethylamino)(imiTO (2S)-2-amininium (5Z,8Z,l lZ,14Z,17Z)-eicosa-5,8,l l ,14,17-pentaenoate-pentanedioate as a light tan solid.
  • eicosapentaenoate prepared by the procedure described in Example 1, were determined in Sprague-Dawley rats. Di-metformin glutamate eicosapentaenoate was administered by oral gavage as an aqueous solution in 0.5% carboxymethyl cellulose to 6 rats, 3 males and 3 females. Rats were dosed at 52 mg/kg. Blood samples were obtained from each rat by jugular vein catheter. Samples were collected at 0.25, 0.5, 1 , 2, 4, 8, 12, and 24 hours post dose. Blood samples were centrifuged to separate red blood cells and the resulting plasma samples were analyzed for eicosapentaenoic acid. Calculated pharmacokinetic parameters shown below in Table 1 are mean values from 6 rats.
  • Treating patients with type 2 diabetes with the pharmaceutical composition according to the invention in addition to producing an acute improvement in the glucose metabolic situation, prevents a deterioration in the metabolic situation in the long term. This can be observed when patients are treated for a longer period, e.g. 3 months to 1 year or even 1 to 6 years, with the pharmaceutical composition according to the invention and are compared with patients who have been treated with other antidiabetic medicaments. There is evidence of therapeutic success compared with patients treated with other antidiabetic medicaments if no or only a slight increase in the fasting glucose and/or HbAlc value is observed.
  • the efficacy of a pharmaceutical composition according to the invention can be tested in clinical studies with varying run times (e.g. 12 weeks to 6 years) by determining the fasting glucose or non- fasting glucose (e.g. after a meal or a loading test with oGTT or a defined meal) or the HbAlc value.
  • Examples of this are a reduction in systolic and/or diastolic blood pressure, a lowering of the plasma triglycerides, a reduction in total or LDL cholesterol, an increase in HDL cholesterol or a reduction in weight, either compared with the starting value at the beginning of the study or in comparison with a group of patients treated with placebo or a different therapy.
  • Type 2 diabetes or pre-diabetes patients with a pharmaceutical composition according to the invention prevents or reduces or reduces the risk of developing microvascular complications (e.g. diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic foot, diabetic ulcer) or macrovascular complications (e.g. myocardial infarct, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders, vascular restenosis).
  • microvascular complications e.g. diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic foot, diabetic ulcer
  • macrovascular complications e.g. myocardial infarct, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders, vascular restenosis.
  • Type 2 diabetes or patients with pre-diabetes are treated long-
  • the nerve conduction rate can be measured using a calibrated tuning fork, for example.
  • the following parameters may be investigated before the start, during and at the end of the study: secretion of albumin, creatinine clearance, serum creatinine values, time taken for the serum creatinine values to double, time taken until dialysis becomes necessary.
  • active ingredient denotes two compounds according to the invention, i.e., denotes
  • active ingredient denotes two compounds according to the invention, i.e., denotes a compound of Formula I or II, or a mixture thereof (first component of the active ingredient) and other antidiabetic agents such as statins, cholesterol absorption inhibitors, and CETP inhibitors or a pharmaceutically- acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug (second component of the active ingredient).
  • Additional suitable formulations may be prepared according to the procedures described in, for example in the application WO
  • sulfonylureas may be those formulations which are available on the market, or formulations described in the patent applications cited above in paragraph "background of the invention", or those described in the literature, for example as disclosed in current issues of "Rote Liste S” (Germany) or of “Physician's Desk Reference” Example 1
  • (1) , (2) and (3) are mixed together and granulated with an aqueous solution of (4).
  • (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.
  • (1) , (2) and (3) are mixed together and granulated with an aqueous solution of (4).
  • (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.
  • Diameter of the tablets 9 mm.
  • Example 5 (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing. This powder mixture is packed into size 3 hard gelatin capsules in a capsule filling machine.
  • Example 5
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing. This powder mixture is packed into size 3 hard gelatin capsules in a capsule filling machine.

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Abstract

La présente invention concerne des composés à trois sels comprenant un composé ayant deux groupes fonctionnels acides et un groupe fonctionnel basique (par exemple aspartate ou glutamate), la metformine et des acides gras polyinsaturés, tels que éicosapentaénoate ou docosahexaénoate. Les sels peuvent être utilisés dans le traitement du diabète, du diabète ayant une dyslipidémie concomitante (par exemple des triglycérides élevés) et des complications cardiovasculaires exacerbées par le diabète, telles que l'arythmie cardiaque, l'ischémie cardiaque, l'infarctus du myocarde, la myocardiopathie et l'accident vasculaire cérébral. Les composés de cette invention sont également utiles dans le traitement de l'obésité.
PCT/US2013/049984 2012-07-10 2013-07-10 Forme à trois sels de metformine WO2014011814A1 (fr)

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KR20157002264A KR20150036235A (ko) 2012-07-10 2013-07-10 트리-염 형태의 메트포민
CN201380046842.4A CN104684889A (zh) 2012-07-10 2013-07-10 二甲双胍的三盐形式
JP2015521784A JP2015523382A (ja) 2012-07-10 2013-07-10 メトホルミンの三塩形態
MX2015000408A MX2015000408A (es) 2012-07-10 2013-07-10 Forma de triple sal de metformina.
EP13817534.4A EP2872483A4 (fr) 2012-07-10 2013-07-10 Forme à trois sels de metformine
AU2013290168A AU2013290168A1 (en) 2012-07-10 2013-07-10 Tri-salt form of metformin
CA2878819A CA2878819A1 (fr) 2012-07-10 2013-07-10 Forme a trois sels de metformine
IN76KON2015 IN2015KN00076A (fr) 2012-07-10 2013-07-10
BR112015000368A BR112015000368A2 (pt) 2012-07-10 2013-07-10 forma de tri-sais de metformina
US14/413,996 US9382187B2 (en) 2012-07-10 2013-07-10 Tri-salt form of metformin
IL236613A IL236613A0 (en) 2012-07-10 2015-01-11 A tri-salt form of metformin
ZA2015/00274A ZA201500274B (en) 2012-07-10 2015-01-14 Tri-salt form of metformin

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US201261669763P 2012-07-10 2012-07-10
US61/669,763 2012-07-10
US201261670376P 2012-07-11 2012-07-11
US201261670368P 2012-07-11 2012-07-11
US61/670,368 2012-07-11
US61/670,376 2012-07-11
US13/841,970 US8765811B2 (en) 2012-07-10 2013-03-15 Tri-salt form of metformin
US13/841,970 2013-03-15

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WO2014124141A1 (fr) * 2013-02-07 2014-08-14 Mylari Banavara L Dérivés de metformine pour le traitement du diabète
WO2015195491A1 (fr) * 2014-06-18 2015-12-23 Thetis Pharmaceuticals Llc Complexes d'acides aminés minéraux d'agents actifs
US9505709B2 (en) 2014-05-05 2016-11-29 Thetis Pharmaceuticals Llc Compositions and methods relating to ionic salts of peptides
US20170119841A1 (en) * 2015-11-04 2017-05-04 Thetis Pharmaceuticals Llc Amino acid salts of unsaturated fatty acids
US10130719B2 (en) 2016-06-03 2018-11-20 Thetis Pharmaceuticals Llc Compositions and methods relating to salts of specialized pro-resolving mediators
US10471963B2 (en) 2017-04-07 2019-11-12 TuSimple System and method for transitioning between an autonomous and manual driving mode based on detection of a drivers capacity to control a vehicle
US10737695B2 (en) 2017-07-01 2020-08-11 Tusimple, Inc. System and method for adaptive cruise control for low speed following

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CN113105367B (zh) * 2021-03-30 2022-08-02 广州大学 一类二甲双胍盐及其制备方法和应用
CN114349665B (zh) * 2021-11-30 2023-06-09 潍坊博创国际生物医药研究院 二甲双胍焦谷氨酸晶体及其制备方法与应用
CN116999398A (zh) * 2022-06-30 2023-11-07 山东海赜生物科技有限公司 一种口服组合物

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WO2014124141A1 (fr) * 2013-02-07 2014-08-14 Mylari Banavara L Dérivés de metformine pour le traitement du diabète
US9505709B2 (en) 2014-05-05 2016-11-29 Thetis Pharmaceuticals Llc Compositions and methods relating to ionic salts of peptides
US9999626B2 (en) 2014-06-18 2018-06-19 Thetis Pharmaceuticals Llc Mineral amino-acid complexes of active agents
WO2015195491A1 (fr) * 2014-06-18 2015-12-23 Thetis Pharmaceuticals Llc Complexes d'acides aminés minéraux d'agents actifs
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US20170119841A1 (en) * 2015-11-04 2017-05-04 Thetis Pharmaceuticals Llc Amino acid salts of unsaturated fatty acids
US10130719B2 (en) 2016-06-03 2018-11-20 Thetis Pharmaceuticals Llc Compositions and methods relating to salts of specialized pro-resolving mediators
US11135298B2 (en) 2016-06-03 2021-10-05 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
US11925688B2 (en) 2016-06-03 2024-03-12 Thetis Pharmaceuticals Llc Compositions and methods relating to salts of specialized pro-resolving mediators
US10471963B2 (en) 2017-04-07 2019-11-12 TuSimple System and method for transitioning between an autonomous and manual driving mode based on detection of a drivers capacity to control a vehicle
US10737695B2 (en) 2017-07-01 2020-08-11 Tusimple, Inc. System and method for adaptive cruise control for low speed following

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IL236613A0 (en) 2015-02-26
BR112015000368A2 (pt) 2017-06-27
KR20150036235A (ko) 2015-04-07
EP2872483A4 (fr) 2016-03-16
ZA201500274B (en) 2017-10-25
EP2872483A1 (fr) 2015-05-20
MX2015000408A (es) 2015-07-14
CA2878819A1 (fr) 2014-01-16
CN104684889A (zh) 2015-06-03
JP2015523382A (ja) 2015-08-13
IN2015KN00076A (fr) 2015-07-31

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