JP2015523382A - The trisalt form of metformin - Google Patents

Abstract

A trisalt containing a compound containing two acidic functional groups and one basic functional group (eg aspartate or glutamate), metformin and a polyunsaturated fatty acid such as eicosapentaenoate or docosahexaenoate Compounds are provided herein. This salt is used to treat diabetes, diabetes with associated dyslipidemia (eg hypertriglyceridemia), and cardiovascular complications that exacerbate diabetes such as cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy, and stroke be able to. The compounds of the present invention are also useful for the treatment of obesity.

Description

Related applications

  This application is based on US Provisional Patent Application No. 61 / 669,763, filed July 10, 2012, US Provisional Patent Application No. 61 / 670,376, filed July 11, 2013, July 11, 2012. Priority is claimed based on US Provisional Patent Application No. 61 / 670,368 of the application and US Patent Application No. 13 / 841,970 filed March 15, 2013. The entire contents of these applications are incorporated herein in their entirety.

  Diabetes mellitus is a global epidemic, and according to the World Health Organization, the number of diabetic patients will increase rapidly by 2030. This is a horrible expectation. The reason is that managing long-term complications of diabetes, including nephropathy, neuropathy, retinopathy, and cardiovascular complications has a significant impact on public health budgets. A prominent feature of diabetes is chronically high blood glucose levels. Abnormally high glucose concentrations adversely affect glutathione concentrations in characteristic diabetic tissues. Furthermore, increased oxidative stress and increased production of reactive oxygen species are brought about under hyperglycemic conditions.

  Early detection of insulin and its subsequent use in a wide range of diabetes treatments, and subsequent as a hypoglycemic agent of DPPIV inhibitors such as sulfonylureas and thiazolidenediones such as troglitazone, rosiglitazone, or pioglitazone, and sitagliptin Despite the discovery and use of diabetes, the treatment of diabetes is not yet satisfactory.

  Insulin use usually requires administration by self-injection multiple times per day. Determining the appropriate dose of insulin requires frequent assessment of urine or blood sugar. Treatment of non-insulin dependent diabetes mellitus (type 2 diabetes, NIDDM) usually consists of a combination of diet, exercise, oral hypoglycemic drugs such as thiazolidenedione, and, in more severe cases, insulin. However, clinically available hypoglycemic drugs may have side effects that result in limited use, or the drug may be ineffective for certain patients. In the case of insulin-dependent diabetes mellitus (type 1), administration of insulin is usually the main course of therapy.

  Thus, diabetic patients such as diabetes, type 2 diabetes (T2D), and pre-diabetes, and cardiovascular complications including neuropathy, nephropathy, retinopathy, cataracts, and cardiac arrhythmias, myocardial infarction, stroke, and cardiomyopathy There remains a need for effective treatment of related pathologies in Japan.

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  Provided herein is a tri-salt compound comprising aspartate, glutamate, or a homologue thereof, metformin, and a polyunsaturated fatty acid such as eicosapentaenoate or docosahexaenoate. Trisalt compounds are useful for diabetes, diabetes associated with dyslipidemia (eg hypertriglyceridemia), and cardiovascular complications that exacerbate diabetes such as cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy, and stroke. Can be used in therapy. Trisalt compounds are also useful in the treatment of obesity.

  Provided herein is a tri-salt compound of a compound containing two acidic functional groups and one basic functional group, metformin and a polyunsaturated fatty acid, which has the following formula I:

Wherein, G is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl group,, R ^- is the polyunsaturated fatty acids] is represented by. In one embodiment of formula I, G is alkyl.

  In a particular embodiment, the compound of formula I has formula II:

[Wherein R ⁻ is a polyunsaturated fatty acid and n is 1 to 10], or a pharmaceutically acceptable solvate or hydrate thereof. In certain embodiments of formula II, n is 1 or 2. In another specific aspect, n is 3, 4, or 5.

In one embodiment of Formulas I and II, R ^- is eicosapentaenoate or docosahexaenoate. In one embodiment of Formula II, R ^- is eicosapentaenoate or docosahexaenoate and n is 1. In yet another embodiment of Formula II, R ^- is eicosapentaenoate or docosahexaenoate and n is 2.

  Also provided herein are pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier, vehicle, or diluent.

  Also provided herein is a kit comprising a unit dose comprising a compound of the invention with instructions for using 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 symptoms. 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 reducing triglycerides in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I. In yet another aspect, there is also provided herein a method for treating a cardiovascular disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I. Examples of cardiovascular diseases to be treated are cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy, or stroke.

  In another aspect, 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.

  In one aspect, provided herein is a method of treating hyperlipidemia comprising administering an effective amount of a compound of formula I to a subject in need thereof. In another aspect, provided herein is a method of treating hypertriglyceridemia, comprising administering an effective amount of a compound of formula I to a subject in need thereof. In another aspect, provided herein is a method for treating dyslipidemia comprising administering an effective amount of a compound of formula I to a subject in need thereof.

  In another aspect, provided herein is a method of treating pre-diabetes comprising administering an effective amount of a compound of the invention to a subject in need thereof. In yet another aspect, provided herein is a method of treating atherosclerosis comprising administering an effective amount of a compound of the invention to a subject in need thereof. In another aspect, T2D, pre-diabetes, obesity, metabolic syndrome, hypertriglyceridemia, and neuropathy, nephropathy, retinopathy, cataract, and atrial fibrillation, cardiac arrhythmia, myocardial infarction in mammals such as diabetics, A combination comprising a compound of the above structural formula I or II and an antilipidemic drug for treating a metabolic disorder selected from the group consisting of stroke and T2D complications such as cardiovascular complications including cardiomyopathy A therapy is provided herein. Further aspects provided herein include a compound of structural formula I or II and a dyslipidemic agent for treating obesity, cardiovascular disease, and related symptoms in a subject in need thereof. Combination therapy.

  In yet another aspect, type 2 diabetes (T2D), pre-diabetes, obesity, metabolic syndrome, hypertriglyceridemia, and mammals such as diabetics, neuropathy, nephropathy, retinopathy, cataracts, and cardiac arrhythmias, myocardium A combination comprising a compound of structural formula I or II above and a hypoglycemic agent for treating a metabolic disorder selected from the group consisting of T2D complications such as cardiovascular complications including infarction, stroke and cardiomyopathy A therapy is provided herein.

  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 the combination therapy. In another aspect, provided herein is a method of reducing triglycerides in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a combination therapy of the invention. The In yet another aspect, a method for treating cardiovascular disease in a subject in need thereof, comprising administering an effective amount of a combination therapy of the invention to the subject in need thereof. Provided in writing. Examples of cardiovascular diseases to be treated are cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy, or stroke.

  In another aspect, provided herein is a method for treating obesity in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a combination therapy of the invention. Provided.

  In one aspect, provided herein is a method of treating hyperlipidemia comprising administering an effective amount of a hyperlipidemia combination therapy of the present invention to a subject in need thereof. In another aspect, provided herein is a method of treating hypertriglyceridemia comprising administering to a subject in need thereof an effective amount of a hyperlipidemia combination therapy of the present invention. In another aspect, provided herein is a method of treating dyslipidemia comprising administering an effective amount of a hyperlipidemia combination therapy of the present invention to a subject in need thereof.

  In another aspect, provided herein is a method of treating pre-diabetes comprising administering an effective amount of a combination therapy of the invention to a subject in need thereof.

In yet another aspect, provided herein is a method of treating atherosclerosis comprising administering an effective amount of a combination therapy of the invention to a subject in need thereof. In one aspect of the above method, a method for making a compound of formula II wherein the subject is human is also provided herein. In one embodiment, R ^- is eicosapentaenoic acid salt, n is a process for preparing a compound of formula II is 1, a) metformin free base was prepared from the metformin salt and b) from about Provided herein is a process comprising reacting 2 equivalents of metformin free base with 1 equivalent of aspartic acid and 1 equivalent of eicosapentaenoic acid at a temperature of 1 ° C to about 60 ° C.

In another embodiment, R ^- is eicosapentaenoic acid salts, a process for the preparation of compounds of formula II n is 2, a) metformin free base was prepared from the metformin salt and b) from about Provided herein is a process comprising reacting 2 equivalents of metformin free base with 1 equivalent of glutamic acid and 1 equivalent of eicosapentaenoic acid at a temperature of 1 ° C. to about 60 ° C.

In another embodiment, R ^- is docosahexaenoic acid salt, n is a process for preparing a compound of formula II is 1, a) metformin free base was prepared from the metformin salt and b) from about 1 Provided herein is a process comprising reacting 2 equivalents of metformin free base with 1 equivalent of aspartic acid and 1 equivalent of eicosapentaenoic acid at a temperature of from about 0C to about 60C.

In yet another aspect, R ^- is docosahexaenoic acid salt, a process for the preparation of compounds of formula II n is 2, a) metformin free base was prepared from the metformin salt and b) from about Provided herein is a process comprising reacting 2 equivalents of metformin free base with 1 equivalent of glutamic acid and 1 equivalent of eicosapentaenoic acid at a temperature of 1 ° C. to about 60 ° C.

Detailed Description of the Invention

  The metabolic syndrome is intricately intertwined with T2D, which has become a global epidemic. The clinical findings of this syndrome are patient-dependent, and comorbidities in patients with diabetes (chronic hyperglycemia) include hypertension, dyslipidemia, and cardiovascular complications including stroke, myocardial ischemia, and cardiomyopathy. included. The long-term consequences of these comorbidities also include diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, and diabetic cataract.

  Metformin is a known compound approved by the US Food and Drug Administration for the treatment of diabetes. The compounds and their preparation and use are disclosed, for example, in US Pat. Metformin is orally effective in the treatment of type 2 diabetes (T2D). Metformin (N, N-dimethylimidodicarbonimidic acid diamide) is a biguanide hypoglycemic drug currently marketed in the United States in the form of its hydrochloride salt, 1,1-dimethylbiguanide hydrochloride. Metformin hydrochloride can be purchased commercially, and can also be prepared as disclosed in Non-Patent Document 1, for example.

  According to the UK Prospective Diabetes Study (UKPDS), metformin therapy has reduced costs and improved life expectancy adjusted for quality of life. UKPDS significantly reduced myocardial infarction and diabetes-related mortality in overweight obese patients randomized to initial therapy with metformin. Metformin does not promote weight gain and has a beneficial effect on several cardiovascular risk factors. Therefore, metformin is widely accepted as a preferred drug for most patients with type 2 diabetes. However, even diabetic patients on metformin therapy face the risk of long-term cardiovascular complications such as cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy, and stroke. It is believed that high triglycerides (TG) can be an important common biochemical link that causes cardiovascular complications. Epidemiological and clinical evidence suggests that increasing omega-3 polyunsaturated fatty acid (PUFA) intake prevents death from coronary artery disease. PUFAs include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). It has been widely established that PUFA can prevent and terminate ischemic ventricular arrhythmias (Non-patent Documents 3 and 4). In particular, it is known that EPA is a promising treatment for the 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 improve TG lipid levels in patients with very high triglycerides (TG). EPA has also been shown to increase adiponectin secretion in obese animals and obese human subjects (Non-Patent Document 5). Increased adiponectin concentrations are advantageous in regulating lipid and glucose metabolism in animals and humans. It is also known that many patients with type 2 diabetes and those with a pre-diabetic condition known as metabolic syndrome, sometimes referred to as insulin resistance, suffer from a variety of glucose and lipid metabolism disorders, including hyperglycemia and high triglycerides It is.

  Accordingly, diabetes, diabetes associated with dyslipidemia (eg, hypertriglyceridemia), and cardiac arrhythmia comprising administering a compound of formula I or a compound of formula I to a subject in need thereof, Provided herein are methods for treating cardiovascular complications that exacerbate diabetes, such as cardiac ischemia, myocardial infarction, cardiomyopathy, and stroke. The compounds of formula I are also useful for the treatment of obesity in subjects in need thereof.

  The compound of formula I is a tri-salt of a compound containing two acidic functional groups and one basic functional group, metformin and a polyunsaturated fatty acid, having the following formula:

Wherein, G is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl group,, R ^- is the polyunsaturated fatty acids] is represented by. In one embodiment of formula I, G is alkyl. When G is alkyl, G is an alkylene, for _example, in such _{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 CH 2 One of the hydrogens may be replaced with NH ₃ ⁺ as shown in Formula I.

  In one embodiment, the compound of formula I has formula II:

[Wherein n is 1 to 10 and R ⁻ is a polyunsaturated fatty acid]. In certain embodiments of formula II, n is 1-2. In another specific embodiment of formula II, n is 3-5.

In one embodiment of formula II, R ^- is eicosapentaenoate:

Or docosahexaenoate:

It is.

In one embodiment of Formula II, R ^- is eicosapentaenoate and n is 1. In another embodiment of formula II, R ^- is eicosapentaenoate and n is 2.

In another embodiment of formula II, R ^- is docosahexaenoate and n is 1. In another embodiment of formula II, R ^- is docosahexaenoate and n is 2.

  In certain embodiments, the compound of formula II is a compound A, B, C, D, E, F, G, H, I, and J:

Selected from the group consisting of

  Compounds of formula I also include isotopes and enantiomers where applicable.

  It is well known that pharmaceutical preparations with high water solubility are efficiently absorbed from the digestive tract into the systemic circulation when administered orally. Another characteristic of such a formulation is the rate at which it is absorbed into the systemic circulation, which increases the concentration of the active ingredient in the blood. Furthermore, for the delivery of xenobiotics via the venous route, the active ingredient must be provided as a clear solution. PUFAs and PUFA esters are practically insoluble in water. In fact, they form soapy emulsions when mixed with water. Therefore, the possibility of achieving the optimal therapeutic effect of PUFA should be significantly facilitated by the delivery of water soluble PUFA. The compounds of the present invention have much greater water solubility than PUFA and PUFA esters, resulting in greater oral absorption and simultaneous delivery of metformin and PUFA, resulting in hyperglycemia that is widespread in patients with type 2 diabetes Dual effects are obtained when targeting concentrations and high TGs. In addition, these novel salts provide patients with easy-to-use dosage forms of two active therapies in multidrug combinations, increasing their confidence in daily patient compliance. Juvissync recently approved by the US Food and Drug Administration is the latest example of a multi-drug mixture of two drugs widely used in terms of reliability of use and patient convenience (Non-Patent Document 6). In addition, the compounds of the invention allow the preparation of intravenous dosage forms.

  As used herein, the term “alkyl” refers to a fully saturated branched or unbranched hydrocarbon moiety. Alkyl is preferably 1-20 carbon atoms, more preferably 1-16 carbon atoms, 1-10 carbon atoms, 1-7 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms. Or containing 1 to 3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-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. As used herein, the term “alkyl” also includes “alkenyl” and “alkynyl” groups.

  The term “alkenyl”, alone or in combination, represents a straight, cyclic, or branched hydrocarbon residue containing at least one olefinic bond and the indicated number of carbon atoms. Preferred alkenyl groups have a maximum of 8, preferably a maximum of 6 carbon atoms, with a maximum of 4 carbon atoms being particularly preferred. Examples of alkenyl groups are ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-cyclohexenyl, 1-cyclopentenyl.

The term “alkynyl” includes unsaturated aliphatic groups that are similar in length to the alkyl but contain at least one triple bond. For example, the term “alkynyl” includes straight chain alkynyl groups (eg, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched alkynyl groups, and cycloalkyl or cycloalkenyl substituents Alkynyl groups are included. The term “alkynyl” further includes alkynyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (eg, C ₂ -C ₆ for straight chain, C ₃ -C _{6 for} branched chain). . The term C ₂ -C _6, includes alkynyl groups containing 2 to 6 carbon atoms.

  As used herein, the term “cycloalkyl” refers to a saturated or unsaturated monocyclic, bicyclic, or tricyclic of 3 to 12 carbon atoms, preferably 3 to 9 or 3 to 7 carbon atoms. Represents a cyclic hydrocarbon group. Examples of monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like. Examples of 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. Can be mentioned. Examples of the tricyclic hydrocarbon group include adamantyl and the like. As used herein, “cycloalkyl” includes “cycloalkenyl” groups.

  The term “cycloalkenyl” refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 3 rings and 4 to 8 carbons per ring. Examples of groups include cyclobutenyl, cyclopentenyl, and cyclohexenyl. The term “cycloalkenyl” includes that the second or third ring is carbon, provided that at least one ring is a partially unsaturated carbon-containing ring and the point of attachment is to the cycloalkenyl group. Bicyclic and tricyclic groups that may be cyclic or heterocyclic are also included.

  The term “heteroalkyl” by itself or in combination with another terminology is selected from the group consisting of the indicated number of carbon atoms and O, N, Si, and S, unless otherwise indicated. Means a stable straight chain or branched chain consisting of ˜5 heteroatoms, more preferably 1-3 heteroatoms, or a combination thereof, the nitrogen and sulfur atoms may be optionally oxidized, Nitrogen heteroatoms may optionally be quaternized. A heteroalkyl group is attached to the remainder of the molecule through a carbon or heteroatom.

  The term “aryl” includes aromatic monocyclic or polycyclic, eg, tricyclic, consisting solely of hydrogen and carbon and containing 6-19 carbon atoms or 6-10 carbon atoms. Bicyclic hydrocarbon ring systems are included and 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 (eg, tetralin).

  As used herein, the term “heteroaryl” refers to a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and is O, N, And 1-4 heteroatoms selected from the group consisting of and S. Heteroaryl groups within 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 are included. It is also understood that “heteroaryl” includes N-oxide derivatives of nitrogen-containing heteroaryl, as in the definition of heterocycle below. When a heteroaryl substituent is bicyclic and one ring is non-aromatic or does not contain a heteroatom, the linkage is understood to be through an aromatic ring or through a heteroatom-containing ring, respectively. .

  The term “heterocycle” or “heterocyclyl” is a 5-10 membered fully saturated or partially unsaturated non-aromatic heterocyclic containing at least one heteroatom such as O, S, or N. Represents a group. The most frequent examples are piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, or pyrazinyl. The bond of the heterocyclyl substituent may be via a carbon atom or a heteroatom.

Furthermore, the alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups described above may be “unsubstituted” or “substituted”. The term “substituted” is intended to describe a moiety having a substituent that replaces one or more atoms of the molecule, eg, hydrogen on C, O, or N. Such substituents independently include, for example, one or more of the following: linear or branched alkyl (preferably C ₁ -O ₅ ), cycloalkyl (preferably C ₃ -C ₈ ), alkoxy (preferably Is C ₁ -C ₆ ), thioalkyl (preferably C ₁ -C ₆ ), alkenyl (preferably C ₂ -C ₆ ), alkynyl (preferably C ₂ -C ₆ ), heterocyclic, carbocyclic, aryl (Eg phenyl), aryloxy (eg phenoxy), aralkyl (eg benzyl), aryloxyalkyl (eg phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl or other such acyl Group, heteroarylcarbonyl, or heteroaryl group, ( R'R _") 0~3 _NR'R" (e.g. _{-NH 2), (CR'R ")} 0~3 CN ( e.g. -CN), - NO _2, halogen (e.g., -F, -Cl, - Br or _{-I), (CR'R ") 0~3} C ( _{halogen) 3} (e.g., _{-CF 3), (CR'R")} 0~3 CH ( _{halogen) 2, (CR'R ") 0} , _{to 3} CH _{2 (halogen), (CR'R ") 0~3 CONR'R} ", (CR'R ") 0~3 (CNH) NR'R", (CR'R ") 0~3 S ( O) _1-2 NR′R ″, (CR′R ″) _0-3 CHO, (CR′R ″) _0-3 O (CR′R ″) _0-3 H, (CR′R ″) _{0 3} S (O) _0-3 R ′ (eg, —SO ₃ H, —OSO ₃ H), (CR′R ″) _0-3 O (CR′R ″) _0-3 H (eg, —CH ₂ OCH ₃ and -OCH _3), (C _{'R ") 0~3 S (CR'R} ") 0~3 H ( e.g. -SH and _{-SCH 3), (CR'R ")} 0~3 OH ( e.g. -OH), (CR'R") _{0~3 COR ', (CR'R ")} 0~3 ( substituted or unsubstituted _{phenyl), (CR'R") 0~3 (} C 3 ~C 8 _cycloalkyl), (CR'R _") 0~ ₃ CO ₂ R ′ (eg —CO ₂ H), or (CR′R ″) _0-3 OR ′ groups, or side chains of natural amino acids; where R ′ and R ″ are each independently Hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or an aryl group.

Provided herein are tri-salts having the therapeutic method Formula I. In other aspects, provided herein are tri-salts having Formula II. In certain embodiments, the compound of formula II is selected from the group consisting of compounds A, B, C, D, E, F, G, H, I, and J.

  Such compounds include T2D, pre-diabetes, obesity, metabolic syndrome, hypertriglyceridemia, and neuropathy, nephropathy, retinopathy, cataract, and heart including diabetic heart arrhythmia, myocardial infarction, stroke, and cardiomyopathy It is effective for the treatment of T2D complications such as vascular complications.

  Diabetes mellitus, commonly referred to as diabetes, represents a disease process derived from multiple causative factors and is characterized by a high concentration of plasma glucose called hyperglycemia. For example, see Non-Patent Document 7. Uncontrolled hyperglycemia increases mortality and premature death due to increased risk for macrovascular and macrovascular disease, including nephropathy, neuropathy, retinopathy, hypertension, cerebrovascular disease, and coronary heart disease Accompanied by.

  There are two main forms of diabetes: type 1 diabetes (previously called insulin-dependent diabetes or IDDM) and type 2 diabetes (formerly called non-insulin-dependent diabetes or NIDDM).

  Type 2 diabetes (T2D) is a disease characterized by insulin resistance associated with a relative deficiency rather than absolute insulin. Type 2 diabetes ranges from significant insulin resistance with relative insulin deficiency to significant insulin deficiency with some insulin resistance. Insulin resistance is a diminished ability of insulin to exert its biological action over a wide range of concentrations. In individuals who are insulin resistant, the body secretes abnormally high amounts of insulin to compensate for this defect. If there is an inappropriate amount of insulin to compensate for insulin resistance and proper control of glucose, an impaired glucose tolerance condition develops. In a significant number of individuals, insulin secretion is further reduced, plasma glucose levels are increased, resulting in a clinical state of diabetes. Type 2 diabetes can be attributed to severe resistance to insulin, which stimulates regulatory effects on glucose and lipid metabolism in insulin-sensitive main tissues: muscle, liver, and adipose tissue. This resistance to the insulin response prevents activation by insulin with poor glucose uptake, oxidation and storage in the muscle, as well as lipolysis in adipose tissue, and inappropriate insulin suppression of glucose production and secretion in the liver. Bring. In type 2 diabetes, free fatty acid levels are often high in obese and some non-obese patients, increasing lipid oxidation.

The term “obesity” is defined as a condition in which an individual has a BMI of 30 kg / m ² or more. According to the definition of WHO, the term obesity can be classified as follows: The term “class I obesity” is a condition where the BMI is greater than or equal to 30 kg / m ² but less than 35 kg / m ^2. The term “class II obesity” is a condition with a BMI of 35 kg / m ² or more but less than 40 kg / m ² ; the term “class III obesity” is a BMI of 40 kg / m 2. It is a state of ² or more.

  The term “normal blood glucose level” means that the subject's fasting blood glucose level is within the normal range, ie higher than 70 mg / dL (3.89 mmol / L) and lower than 100 mg / dL (5.6 mmol / L). Defined as state. The term “fasting” has its usual meaning as a medical term.

  The term “hyperglycemia” is defined as a condition in which a subject's fasting blood glucose level is above the normal range, ie, greater than 100 mg / dL (5.6 mmol / L). The term “fasting” has its usual meaning as a medical term.

  The term “abnormal glucose tolerance” or “IGT” means that a subject's blood glucose or serum glucose concentration at 2 hours after meal is higher than 140 mg / dL (7.78 mmol / L) and 200 mg / dL (11.11 mmol). / L) is defined as a lower state. Abnormal glucose tolerance, ie blood glucose or serum glucose concentration 2 hours after meal, can be measured as a blood glucose level in mg glucose per dL of plasma 2 hours after ingesting 75 g glucose after fasting. Subjects with “normal glucose tolerance” have a blood glucose or serum glucose concentration of less than 140 mg / dL (7.78 mmol / L) at 2 hours postprandial.

  The term “hyperinsulinemia” refers to a waist-to-hip ratio that is less than or equal to whether the subject's fasting or postprandial serum or plasma insulin levels are normoglycemic. It is defined as a state higher than normal, lean individuals who are not insulin resistant being 1.0 (for men) or <0.8 (for women).

  The terms “insulin sensitization”, “insulin resistance improvement” or “insulin resistance reduction” are synonymous and are used interchangeably.

  The term “insulin resistance” is defined as a condition that requires circulating insulin concentrations that exceed the normal response to glucose load to maintain a normoglycemic state (8). The method for measuring insulin resistance is the normoglycemic high insulin clamp test. The ratio of insulin to glucose is measured within the insulin-glucose simultaneous infusion technique. If glucose absorption is lower than the 25th percentile of the background population studied, it is determined to be insulin resistant (WHO definition). It is the so-called minimal model that is less laborious than the clamp test, during which the insulin and glucose concentrations in the blood are measured at regular time intervals and the insulin resistance is calculated therefrom during the intravenous glucose tolerance test. With this method, it is not possible to distinguish between liver and peripheral insulin resistance. In addition, insulin resistance, response to therapy for patients with insulin resistance, insulin sensitivity, and hyperinsulinemia are the “insulin resistance index (HOMA-IR)” score, ie, the reliability of insulin resistance. It can be quantified by evaluating a certain index (Non-patent Document 9). Further reference is made to the method for determining the HOMA index for insulin sensitivity (Non-Patent Document 10), the method for determining the ratio of complete proinsulin to insulin (Non-Patent Document 11), and the normoglycemic clamp test. In addition, plasma adiponectin concentration can be monitored as a potential alternative value for insulin sensitivity. Insulin resistance index by the insulin resistance index (HOMA-IR) score is calculated using the formula (Non-patent Document 12): HOMA-IR = [fasting serum insulin (μU / mL)] × [fasting plasma glucose (mmol / L) /22.5].

  In principle, daily clinical practice uses other parameters to assess insulin resistance. Since increasing triglyceride levels correlate significantly with the presence of insulin resistance, it is preferable to use, for example, patient triglyceride levels.

“Metabolic syndrome”, also called “syndrome X” (when used in the context of metabolic disorders) and also called “metabolic syndrome” is a complex syndrome whose basic characteristic is insulin resistance (Non-patent Document 13). . ATP III / NCEP Guidelines (Abstract of Third Report on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults by the National Cholesterol Education Program (NCEP) Expert Panel (Adult Treatment Panel III)) ), Metabolic syndrome is diagnosed when three or more of the following risk factors are present:
1. Abdominal obesity: defined as> 40 inches or 102 cm for men and> 35 inches or 94 cm for women; or for Japanese or Japanese patients, defined as 85 cm for men and 90 cm for women;
2. Triglyceride:> 150 mg / dL
3. HDL cholesterol: <40 mg / dL for men
4). Blood pressure: 130 / 85mmHg (SBP130 or DBP85)
5. Fasting blood glucose level:> 100 mg / dL
Patients with an onset of IGT or IFG or T2D are those with normoglycemia with hyperinsulinemia and, by definition, insulin resistant. A typical patient who is insulin resistant is usually overweight or obese. If insulin resistance can be detected, it is a particularly strong sign of the presence of pre-diabetes.

  Thus, maintaining glucose homeostasis may require 2-3 times as much insulin as healthy individuals, otherwise it produces some clinical symptoms.

  Methods for investigating pancreatic β-cell function are similar to those described above for insulin sensitivity, hyperinsulinemia, or insulin resistance: Improvement of β-cell function is, for example, the HOMA-index of β-cell function Determination (Non-Patent Document 10), determination of the ratio of complete proinsulin to insulin (Non-Patent Document 11), determination of insulin / C-peptide secretion after oral glucose tolerance test or dietary load test, or frequently sampled It can be measured by using a hyperglycemic clamp test and / or minimal modeling after a intravenous glucose tolerance test (15).

  “Pre-diabetes” is a condition in which an individual is more likely to develop type 2 diabetes. Prediabetes includes the definition of abnormal glucose tolerance, including individuals with a fasting blood glucose level within the normal range of 100 mg / dL (Non-patent Document 16) and fasting hyperinsulinemia (increased plasma insulin concentration). Has been expanded. Scientific and medical criteria for identifying pre-diabetes as a major health threat are the “Prevention or Delay of Type 2 Diabetes” published jointly by the American Diabetes Association and the National Institute of Diabetes, Gastroenterology and Kidney Disease. (Non-patent document 17).

  An individual suspected of having insulin resistance is one who has two or more of the following characteristics: 1) overweight or obese, 2) hypertension, 3) hyperlipidemia, 4) IGT or IFG or type 2 diabetes One or more first-degree relatives diagnosed with The insulin resistance of these individuals can be confirmed by calculating a HOMA-IR score. For the purposes of the present invention, insulin resistance is measured in clinical pathology where the individual's HOMA-IR score is> 4.0 or above the upper normal limit defined for laboratories performing glucose and insulin assays. Define as

  The term “type 2 diabetes” is defined as a condition in which a subject's fasting blood glucose level or serum glucose concentration exceeds 125 mg / dL (6.94 mmol / L). Blood glucose measurement is a standard procedure for routine pharmaceutical analysis. When the glucose tolerance test is performed, the blood glucose level in diabetes is over 2 hours after ingesting 75 g of glucose on an empty stomach, and the glucose per plasma dL exceeds 200 mg (11.1 mmol / l). In the glucose tolerance test, 75 g of glucose is orally administered to patients to be tested after 10-12 hours of fasting, and blood glucose levels are recorded immediately before and 1 and 2 hours after ingestion of glucose. In healthy subjects, the blood glucose concentration before glucose intake is 60-110 mg per dL of plasma, less than 200 mg per dL 1 hour after glucose intake, and less than 140 mg per dL after 2 hours. When the value after 2 hours is 140 to 200 mg, it is regarded as abnormal glucose tolerance.

  The term “late true T2D” has secondary ineffectiveness of drugs, indication of insulin therapy, and progression to microvascular and macrovascular complications such as diabetic nephropathy or coronary heart disease (CHD) Patient included.

  The methods, compositions, and kits of the invention include, but are not limited to, diabetic complications including diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataract, and diabetic retinopathy. It is useful in treating the disease.

  As used herein, the term “treat” refers to any disorder or condition to which the term “treat” applies, or to delay, prevent, or reverse the progression of one or more symptoms of such disorder or condition. Or mitigating or preventing them.

  As used herein, the term “treatment” refers to the act of treating a disorder, symptom, or condition, as the term “treating” is defined above.

  The effectiveness of the compounds of the present invention in reducing triglycerides can be determined in animal models according to the procedure described in Non-Patent Document 18.

  In yet another aspect, provided herein is a method of treating atherosclerosis comprising administering an effective amount of a compound of the invention to a subject in need thereof. Atherosclerosis refers to the deposition (plaque) of fat and cholesterol in and on the arterial wall, which can restrict blood flow. These plaques can also rupture and trigger blood clots. Atherosclerosis is often thought of as a heart problem, but it can affect any artery in the body. An animal model for the study of atherosclerosis is described in Non-Patent Document 19.

  In another aspect, a compound of formula I (eg, a compound of formula II and compounds A, B, C, D, E, F, G, H, I, and J) is administered in combination with additional forms of metformin. can do. For example, the compound of Formula I can be administered to a subject in combination with metformin docosahexaenoate, metformin eicosapentaenoate, or a mixture thereof. In another aspect, the compound of formula I can be administered in the form of a non-fatty acid salt of metformin, for example, in combination with 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 as disclosed in Non-Patent Document 1, for example.

  In addition, the compounds of formula I can be administered in combination with eicosapentaenoic acid and / or docosahexaenoic acid.

Combination Therapy The trisalt of the present invention is well suited for use in combination therapy.

  The term “combination therapy” refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes co-administering such therapeutic agents in a substantially simultaneous manner, eg, in a single capsule having a proportion of the active ingredients, or in a plurality of separate containers (eg, capsules) for each active ingredient. Is included. In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner at approximately the same time or at different times. In any case, the treatment regimen provides the beneficial effects of the drug combination in treating the conditions or disorders described herein.

  As used herein, the term “single formulation” refers to a single carrier or vehicle that is formulated to deliver an effective amount of a therapeutic agent to a patient. A single vehicle is designed to deliver an effective amount of each drug together with a pharmaceutically acceptable carrier or excipient. In some aspects, the vehicle is a tablet, capsule, pill, or patch. In other embodiments, the vehicle is a solution or suspension.

  As used herein, the term “unit dose” is used to mean co-administering the agents together in one dosage form to the patient to be treated. In some embodiments, the unit dose is a single formulation. In certain embodiments, a unit dose includes one or more vehicles such that each vehicle comprises an effective amount of at least one drug together with pharmaceutically acceptable carriers and excipients. In some aspects, the unit dose is one or more tablets, capsules, pills, or patches that are administered simultaneously to the patient.

  “Oral dosage forms” include unit dosage forms formulated or intended for oral administration.

  “A mixture of compounds of formula I or formula II” refers to a mixture of two or more such compounds present in a% and b%, where a and b are not zero and the sum of a and b is 100%. For example, if one compound is made from a mixture of a compound of formula I and a compound of formula II, the compound of formula I is present at 50% and the compound of formula II is present at 50%.

  In one aspect, provided herein is a combination therapy comprising an effective amount of a compound of Formula I or Formula II or a combination thereof and a dyslipidemic or hypoglycemic agent. An “effective amount” of a combination of drugs is an amount sufficient to provide an observable improvement to the clinically observable indicia and symptoms that are the basis for the disorder being treated by the combination.

  In one aspect, the combination of a compound of Formula I or Formula II or a combination thereof and a dyslipidemic or hypoglycemic agent described herein exhibits a synergistic effect. As used herein, the term “synergistic effect” refers to the effects of two drugs that produce an effect that is greater than the simple sum of the effects of each drug administered alone, eg, slowing the progression of the symptoms of diabetes or its symptoms. Represents the action. Synergistic effects include, for example, the sigmoid Emax formula (Non-Patent Document 20, incorporated herein by reference in its entirety), the Loewe additive formula (Non-patent document 21, incorporated by reference in its entirety), and half It can be calculated using any suitable method, such as a valid formula (Non-Patent Document 22, incorporated herein in its entirety). Each equation mentioned above can be applied to experimental data to create a corresponding graph to help evaluate the effects of drug combinations. The corresponding graphs associated with the above mentioned formulas are the concentration effect curve, isobologram curve, and combination index curve, respectively.

  The expression “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts, as appropriate. The expression “pharmaceutically acceptable cation salt” includes, but is not limited to, alkali metal salts (eg, sodium and potassium), alkaline earth metal salts (eg, calcium and magnesium), aluminum salts, ammonium salts, etc. Salts, as well as benzathine (N, N′-dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benetamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2- Hydroxymethyl-1,3-propanediol), and salts with organic amines such as procaine are intended to be defined.

  The expression “pharmaceutically acceptable acid addition salts” is not intended to be limiting, but is intended to define salts such as salts with pharmaceutically acceptable minerals or organic acids traditionally used in pharmaceutical preparations. Is done. Suitable acids are, for example, hydrohalic acids such as hydrochloric acid or hydrobromic acid, or inorganic acids such as sulfuric acid, nitric acid or phosphoric acid; or suitable organic acids such as aliphatic mono- or dicarboxylic acids, hydroxy Alkanoic acid or hydroxyalkanedioic acid, for example, acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanedioic acid, propanedioic acid, butanedioic acid, (Z) -2-butene diacid Suitable aliphatic acids such as acids, (E) -2-butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, or 2-hydroxy-1,2,3-propanetricarboxylic acid A phenyl-substituted alkanoic acid; or a suitable aromatic acid such as 2-hydroxybenzoic acid or 4-amino-2-hydroxybenzoic acid; or Rukansuruhon acids, such as methanesulfonic acid or ethanesulfonic acid, or aromatic sulfonic acids, for example a suitable acid, such as benzenesulfonic acid or 4-methylbenzenesulfonic acid,; or cyclohexanesulfamate. In certain embodiments disclosed herein, the acid is, for example, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, fumaric acid, maleic acid, citric acid, tartaric acid, gentisic acid, dobesylic acid, methane Sulfonic acid, ethanesulfonic acid, laurylsulfonic acid, benzenesulfonic acid, and para-toluenesulfonic acid. In certain embodiments, the pharmaceutically acceptable salt is L-arginine, benentamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino) ethanol, ethanolamine, ethylenediamine, N- Methylglucamine, hydrabamine, 1H-imidazole, lithium hydroxide, L-lysine, magnesium hydroxide, 4- (2-hydroxyethyl) morpholine, piperazine, potassium hydroxide, 1- (2-hydroxyethyl) pyrrolidine, hydroxylated Selected from the group consisting of sodium, triethanolamine, tromethamine, zinc hydroxide, sodium, calcium, potassium, magnesium, and zinc.

Combination therapy with dyslipidemic agents In another aspect, T2D, pre-diabetes, obesity, metabolic syndrome, hypertriglyceridemia, and neuropathy, nephropathy, retinopathy, cataract, and mammals such as the atria of diabetic patients A compound of the above structural formula I or II for treating a metabolic disorder selected from the group consisting of T2D complications such as fibrillation, cardiac arrhythmia, myocardial infarction, stroke, and cardiovascular complications including cardiomyopathy Combination therapies comprising dyslipidemic agents are provided herein. A further aspect provided herein is a combination comprising a compound of structural formula I or II and a dyslipidemic agent for treating obesity, cardiovascular disease, and related symptoms in a patient in need thereof It is a therapy.

  In another aspect, provided herein is a method of reducing mammalian cholesterol and / or triglyceride levels comprising administering to a mammal an effective amount of a combination therapy of the invention.

  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 the above combination therapy. In another aspect, provided herein is a method of reducing triglycerides in a subject in need thereof, comprising administering an effective amount of a combination therapy of the invention to the subject in need thereof. The In yet another aspect, a method for treating cardiovascular disease in a subject in need thereof comprising administering an effective amount of a combination therapy of the invention to the subject in need thereof. Provided in the specification. Examples of cardiovascular diseases to be treated are cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy, or stroke.

  In another aspect, a method for treating obesity in a subject in need thereof, comprising administering an effective amount of a combination therapy of the invention to the subject in need thereof. Provided.

  In one aspect, provided herein is a method of treating hyperlipidemia comprising administering an effective amount of a combination therapy of the invention to a subject in need thereof. In another aspect, provided herein is a method of treating hypertriglyceridemia comprising administering an effective amount of a combination therapy of the invention to a subject in need thereof. In another aspect, provided herein is a method of treating dyslipidemia comprising administering an effective amount of a combination therapy of the invention to a subject in need thereof.

  In another aspect, provided herein is a method of treating pre-diabetes comprising administering an effective amount of a combination therapy of the invention to a subject in need thereof.

  In yet another aspect, provided herein is a method of treating atherosclerosis comprising administering an effective amount of a combination therapy of the invention to a subject in need thereof.

  In one aspect of the above method, the subject is a human.

  In one aspect, the invention provides a compound of structural formula I or II, or a compound of structural formula I or II and a dyslipidemic agent, or two or more compounds of structural formula I or II or structural formula I or II. The present invention relates to a combination therapy comprising a combination of the above compound, a dyslipidemic agent, and a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutically acceptable salt of the prodrug. In another aspect, provided herein is a pharmaceutical composition comprising a compound of structural formula I or II or a mixture thereof, a dyslipidemic agent, and a pharmaceutically acceptable carrier. In one aspect, when the pharmaceutical composition comprises two or more compounds of structural formula I or II, or mixtures thereof, the two or more compounds are x, y, z,. . . % Is not zero and x, y, z,. . . %, X, y, z,. . . It exists in%.

  In one embodiment of the pharmaceutical composition, the dyslipidemic agent is about 0.1-1% by weight of the pharmaceutical composition. In another aspect of the pharmaceutical composition, the compound of structural formula I or II or a mixture thereof is present in a unit active ingredient content of 250, 500, 750, 1000, or 1250 mg, and said dyslipidemic agent is Present in unit active ingredient content of 1, 2.5, 5, 10, 20, 30, 40, or 50 mg. In another embodiment, the dyslipidemic agent is present in a unit active ingredient content of 5-100 mg.

  Components of combination therapy (compounds of structural formula I or II and dyslipidemia or combinations of two or more compounds of structural formula I or II and dyslipidemia) are administered in a variety of ways be able to. In one aspect, the components are in a separate formulation or unit dosage form. In another aspect, the component is administered with a pharmaceutically acceptable carrier. The components can be administered separately, substantially simultaneously, or at different times. When administered separately, they can be administered in any order.

  In one aspect, the invention provides a compound of structural formula I or II or a mixture thereof and a dyslipidemic agent, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable agent of said prodrug. It is intended for pharmaceutical compositions comprising a salt and a pharmaceutically acceptable carrier, vehicle, or diluent.

  The dyslipidemic agents that can be used in accordance with the present invention include, for example, statins that are HMG CoA enzyme inhibitors, cholesterol absorption inhibitors, and cholesterol esterase transport protein (CETP) inhibitors, and pharmaceutically acceptable salts thereof and Prodrugs, and pharmaceutically acceptable salts of the prodrugs, and others can be included.

  In one aspect of the invention, the dyslipidemic agent is a statin, cholesterol absorption inhibitor, and CETP inhibitor, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable prodrug of said prodrug It is salt. In certain embodiments, the pharmaceutically acceptable salt is propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, sulphate Acid salt, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-niate, hexyne-1,6-nitrate, benzoate , Chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionic acid Salt, phenylbutyrate, citrate, lactate, p-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfo Salt, naphthalene-2-sulfonate, mandelate, hippurate, is selected from the group consisting of gluconate or lactobionic acid salt.

  Preferred drugs among statin are atorvastatin, risvostatin, simvastatin, or pravastatin, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs. A preferred drug among cholesterol absorption inhibitors is ezetimibe, also called zetia. A preferred drug among CETP inhibitors is anacetrapib. In certain embodiments, CETP inhibitors include, but are not limited to, anacetrapib, or hydrates and solvates thereof.

  In certain embodiments, pravastatin is present in an amount ranging from 5 mg to 100 mg.

  In certain embodiments, ezetimibe is present at 5 mg to 50 mg.

  In another aspect, the disclosure herein provides a first unit dosage form comprising a compound of structural formula I or II or a mixture thereof and a dyslipidemic agent or hydrate and solvate thereof. A kit comprising two unit dosage forms and a container is provided.

In one aspect of dyslipidemia therapy described herein, G is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl group,, R ^- is the polyunsaturated fatty acids . In one embodiment of formula I, G is alkyl. When G is alkyl, G is an alkylene, for _example, in such _{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 CH 2 One of the hydrogens may be replaced with NH ₃ ⁺ as shown in Formula I.

In certain embodiments, the compounds of formula I are, R ^- is polyunsaturated fatty acids, n is a solvate or hydrate acceptable compound of Formula II, or a pharmaceutically 1 to 10 . In certain embodiments of the compound of formula II, n is 1 or 2. In one embodiment of the compounds of formulas I and II, R ⁻ is eicosapentaenoate or docosahexaenoate. In one embodiment of formula II, R ⁻ is eicosapentaenoate or docosahexaenoate and n is 1. In yet another embodiment of Formula II, R ⁻ is eicosapentaenoate or docosahexaenoate and n is 2. In a still further aspect, 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 dyslipidemic agents that can be used in accordance with the present invention include various classes of dyslipidemic agents (eg, HMG-CoA reductase inhibitors (statins), CETP inhibitors, and cholesterol absorption inhibitors, and others), pharmaceuticals And their pharmaceutically acceptable salts and prodrugs, and members of the pharmaceutically acceptable salts of the prodrugs.

  As used herein, the term “HMG-CoA reductase inhibitor” refers to a compound that competitively blocks the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. By competitively blocking this enzyme, HMG-CoA reductase inhibitors prevent cholesterol formation (the enzyme catalyzes the conversion of HMG-CoA to mevalonate). As a result, total cholesterol, low density lipoprotein cholesterol (LDL-C), apolipoprotein B (membrane transport complex of LDL-C), very low density lipoprotein (VLDL), and plasma triglycerides are reduced. For a review on HMG-CoA inhibitors, see, for example, Non-Patent Document 23 and references cited therein.

  Specific HMG-CoA reductase inhibitors that can be used in accordance with the disclosure herein include, but are not limited to, atorvastatin, which can be prepared as disclosed in US Pat. Pravastatin and related compounds which can be prepared as described above, rosuvastatin which can be prepared as disclosed in Patent Document 5, and simvastatin and related compounds which can be prepared as disclosed in Patent Document 6 and Patent Document 7. HMG-CoA reductase inhibitors also include atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, rosuvastatin, cerivastatin, mevastatin, rivastatin, pitavastatin, nisvastatin, itavastatin, verostatin, and fluindostatin.

  As used herein, the term “CETP inhibitor” refers to compounds that catalyze the transfer of cholesteryl esters from HDL to lipoprotein-containing apolipoproteins instead of triglycerides, thereby playing a major role in lipoprotein metabolism. Represent. For a review on CETP inhibitors, see, for example, Non-Patent Document 24 and references cited therein.

  CETP inhibitors that can be used in accordance with the disclosure herein are not limited by the structure or group of CETP inhibitors. CETP inhibitors that can be used in accordance with the disclosure herein include, but are not limited to, anacetrapib, which can be prepared as disclosed in US Pat.

  As used herein, the term “cholesterol absorption inhibitor” refers to a compound that inhibits absorption of bile and dietary cholesterol from the small intestine without affecting absorption of fat-soluble vitamins, triglycerides, or bile acids. For a review on cholesterol absorption inhibitors, see, for example, Non-Patent Document 25 and references cited therein.

  Cholesterol absorption inhibitors that can be used in accordance with the disclosure herein include, but are not limited to, ezetimibe (which can be prepared as disclosed in US Pat. Zetia).

  In the practice of the compositions and methods disclosed herein, any HMG Co-A reductase inhibitor in combination with any HMG Co-A reductase inhibitor, or pharmaceutically acceptable combination with any flash inhibitor. A drug can be used.

  In one aspect, the disclosure herein provides a pharmaceutical composition comprising a compound of formula I or II or a mixture thereof and a dyslipidemic agent or a pharmaceutically acceptable salt, hydrate, and solvate thereof. Offer things.

  In one aspect, the disclosure herein provides a unit dose formulation comprising a compound of formula I or II or a mixture thereof and a dyslipidemic agent or a pharmaceutically acceptable salt, hydrate, and solvate. I will provide a.

  In one aspect, the disclosure herein provides a method of treating a diabetic cardiovascular complication in a mammal comprising administering to the mammal a pharmaceutical composition as described herein below. In certain embodiments, such diabetic complications are, for example, atrial fibrillation, arrhythmia, myocardial infarction, stroke, and cardiomyopathy.

  In one aspect, the disclosure herein includes administering to a mammal a compound of formula I or II or a mixture thereof and a dyslipidemic agent or hydrate and solvate thereof. A method of treating type 2 diabetes is provided.

Accordingly, in one aspect, provided herein is a combination therapy comprising at least the following combinations of agents:
1) a compound of formula I and atorvastatin; a compound of formula I and simvastatin; a compound of formula I and pravastatin; a compound of formula I and rosuvastatin; and a compound of formula I and edimitimib; a compound of formula I and anacetrapib; Atorvastatin calcium;
2) a compound of formula II and atorvastatin; a compound of formula II and simvastatin; a compound of formula II and pravastatin; a compound of formula II and rosuvastatin; and a compound of formula II and edimitimib; a compound of formula II and an anacetrapib; Atorvastatin calcium.

  In additional embodiments, the combination therapy of paragraphs 1 and 2 above can be further combined with a compound of formula I and / or II.

Combination therapy with hypoglycemic drugs The present invention relates to type 2 diabetes (T2D), pre-diabetes, obesity, metabolic syndrome, hypertriglyceridemia, and neuropathy, nephropathy, retinopathy, cataract, and mammals such as diabetic patients A compound of formula I or II and a hypoglycemic agent for the treatment of metabolic disorders selected from the group consisting of T2D complications such as cardiac arrhythmias, myocardial infarction, stroke, and cardiovascular complications including cardiomyopathy Concomitant therapy including

  In one aspect, the invention provides for administering T2D, prediabetes, obesity, metabolic syndrome, hypertriglyceridemia, and neurology comprising administering a combination therapy described herein to a subject in need thereof. Treat metabolic disorders selected from the group consisting of disorders, nephropathy, retinopathy, cataracts, and diabetic complications such as cardiovascular complications including mammals such as cardiac arrhythmia, myocardial infarction, and cardiomyopathy Provide a way to do it.

  The components of the combination therapy (a compound of structural formula I or II and a hypoglycemic agent, or a combination of two or more compounds of structural formula I or II and a hypoglycemic agent) can be administered in a variety of ways. In one aspect, the components are in a separate formulation or unit dosage form. In another aspect, the component is administered with a pharmaceutically acceptable carrier. The components can be administered separately, substantially simultaneously, or at different times. When administered separately, they can be administered in any order.

  In one aspect, the invention provides a compound of structural formula I or II or a mixture thereof and a hypoglycemic agent, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug, It is intended for a pharmaceutical composition comprising a pharmaceutically acceptable carrier, vehicle, or diluent.

  In one aspect of the pharmaceutical composition, the hypoglycemic agent is about 1-20% by weight of the pharmaceutical composition. In another aspect of the pharmaceutical composition, the compound of structural formula I or II or a mixture thereof is present in a unit active ingredient content of 250, 500, 750, 1000, or 1250 mg, and the hypoglycemic agent is 1, Present in a unit active ingredient content of 2.5, 5, 10, 20, 25, 50, 100, 150, or 200 mg. In another aspect, the hypoglycemic agent is present at a unit active ingredient content of 5-100 mg.

  Hypoglycemic agents that can be used in accordance with the present invention include, for example, sulfonylureas, meglitinides, thiazolidinediones, α-glucosidase inhibitors, DPPIV inhibitors, and SGLT-2 inhibitors, and pharmaceutically acceptable salts and prodrugs thereof. And pharmaceutically acceptable salts of the prodrugs, and the like.

  In one aspect of the invention, the hypoglycemic agent is a sulfonylurea, meglitinide, thiazolidinedione, α-glucosidase inhibitor, DPPIV inhibitor, and SGLT-2 inhibitor, or a pharmaceutically acceptable salt or prodrug thereof. Or a pharmaceutically acceptable salt of the prodrug. In certain embodiments, the pharmaceutically acceptable salt is propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, sulphate Acid salt, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-niate, benzoate , Chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionic acid Salt, phenylbutyrate, citrate, lactate, p-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfo Salt, naphthalene-2-sulfonate, mandelate, hippurate, is selected from the group consisting of gluconate or lactobionic acid salt.

  Preferred drugs among thiazolidinediones are pioglitazone, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.

  Preferred α-glucosidase inhibitors include, but are not limited to, acarbose, bagribose, and miglitol, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs. .

  Preferred DPP-IV inhibitors include, but are not limited to, sitagliptin, linagliptin, vildagliptin, saxagliptin, alogliptin, denagliptin, carmeliptin, melogliptin, and ztogliptin, and pharmaceutically acceptable salts and prodrugs thereof, and Included are pharmaceutically acceptable salts of the prodrugs.

  Preferred SGLT-2 inhibitors include, but are not limited to, dapagliflozin, canagliflozin, atigliflozin, remogliflozin, and sergliflozin, and pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable. A salt of said prodrug.

In one aspect of the antihyperglycemic drug combination therapies described herein, G is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl group,, R ^- are polyunsaturated fatty acids. In one embodiment of formula I, G is alkyl. When G is alkyl, G is an alkylene, for _example, in such _{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 CH 2 One of the hydrogens may be replaced with NH ₃ ⁺ as shown in Formula I. In certain embodiments, the compounds of formula I are, R ^- is polyunsaturated fatty acids, n is a solvate or hydrate acceptable compound of Formula II, or a pharmaceutically 1 to 10 . In certain embodiments of the compound of formula II, n is 1 or 2. In one embodiment of the compounds of formulas I and II, R ^- is eicosapentaenoate or docosahexaenoate. In one embodiment of Formula II, R ^- is eicosapentaenoate or docosahexaenoate and n is 1. In yet another embodiment of Formula II, R ^- is eicosapentaenoate or docosahexaenoate and n is 2. In a further aspect, 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 hypoglycemic agents that can be used in accordance with the present invention are of various classes of hypoglycemic agents (eg, sulfonylureas, meglitinides, thiazolidinediones, α-glucosidase inhibitors, DPP-IV inhibitors, SGLT-2 inhibitors, and others). Members, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.

The term “sulfonylurea” represents a class of compounds that stimulate insulin release by binding to the sulfonylurea receptor, a subunit of the ICATP channel complex. This binding results in channel closure, resulting in an influx of Ca ²⁺ ions that alters the β-cell membrane voltage and causes exocytosis of insulin granules. For discussions on sulfonylureas, see, for example, Non-Patent Document 26, which is incorporated herein in its entirety, and references cited therein, and Non-Patent Document 27, which is incorporated herein in its entirety. See the references cited in.

  The term “thiazolidinedione” represents a class of compounds that are selective agonists for peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear hormone receptor family that functions as a coordinater-activated transcription factor. . For a review on thiazolidinediones, see, for example, Non-Patent Document 28 and references cited therein.

  The term “α-glucosidase inhibitor” refers to a class of compounds that have the ability to competitively inhibit the brush border enzyme α-glucosidase in the GI tract, which has the ability to cleave carbohydrate complexes into sugars. For a review on α-glucosidase inhibitors, see, for example, Non-Patent Document 29 and references cited therein.

  The term “DPPIV inhibitor” refers to a class of compounds that have the ability to selectively inactivate the enzyme DPP-IV, and incretin hormones that are released from the intestine throughout the day and whose concentrations increase after meals (eg glucagon Represents a class of compounds with the ability to rapidly inactivate like peptide-1 (GLP-1) and insulin secreting polypeptide (GIP)). For a review on DPP-IV inhibitors, see, for example, Non-Patent Document 30 and references cited therein. Specifically, the DPP-IV inhibitor sitagliptin can be prepared according to the procedures described in Non-Patent Document 31 and Non-Patent Document 32.

  The term “SGLT-2 inhibitor” refers to a non-insulin that selectively inhibits the sodium-glucose cotransporter 2 in the kidney, prevents renal glucose reabsorption from the glomerular filtrate, and controls hyperglycemia. Represents a class of compounds that have the ability to provide dependency means. See, for example, Non-Patent Document 33 and references cited therein for an overview of SGLT-2 inhibitors.

  In the practice of the compositions and methods of the invention, any sulfonylurea, meglitinide, thiazolidinedione, α-glucosidase inhibitor, DPP-IV inhibitor, or SGLT-2 inhibitor, or a pharmaceutically acceptable salt or A prodrug, or a pharmaceutically acceptable salt of the prodrug, or any combination thereof can be used.

  The sulfonylureas that can be used in accordance with the present invention include, but are not limited to, acetohexamide that can be prepared as described in US Pat. Methanyl urea; carbbutamide prepared as described in Patent Document 13; chlorpropamide prepared as described in Patent Document 14; glibornuride prepared as described in Patent Document 15; Gliclazide, which can be prepared as described in Patent Document 17, and can be used for oral administration; Glyquidone, which can be described and used as described in Patent Document 18; Glyburide or glibenclamide, which can be prepared and used; Glybthiazole that can be prepared as described in Patent Document 21; Glybazole that can be prepared and used as described in Patent Document 21; Glyhexamide that can be prepared and used as described in Patent Document 22; Glimepiride that can be prepared and used as described above; Glymidine that can be prepared and used as described in Patent Document 24; Tolazamide that can be prepared as described in Patent Document 25; Tolubutamide that can be prepared is included. Such patents are hereby incorporated by reference.

  As used herein, the term “pioglitazone” refers to pioglitazone, including its enantiomers, mixtures thereof, and racemates thereof, or pharmaceutically acceptable salts thereof such as hydrochloride salts.

  DPP-IV inhibitors that can be used in accordance with the present invention include, but are not limited to, linagliptin, sitagliptin, vildagliptin, alogliptin, saxagliptin, denagliptin, carmeliptin, melogliptin, and zutgliptin, or one of the DPP-IV inhibitors One pharmaceutically acceptable salt, or a prodrug thereof.

  As used herein, the term “linagliptin” refers to linagliptin and pharmaceutically acceptable salts thereof, including hydrates and solvates and crystalline forms thereof. The crystal form is described in US Pat. Methods for producing linagliptin are described in, for example, Patent Document 28 and Patent Document 29. Linagliptin combines exceptional efficacy and long-lasting effects with favorable pharmacological properties, receptor selectivity, and favorable side effect profiles, or used in combination with SGLT2 inhibitors and third anti-diabetic drugs according to the present invention If so, they are distinguished from structurally similar DPPIV inhibitors because they provide unexpected therapeutic benefits or improvements.

  As used herein, the term “sitagliptin” refers to sitagliptin (or MK-0431) and pharmaceutically acceptable salts thereof, including hydrates and solvates and crystalline forms thereof. In one aspect, sitagliptin is in the form of its dihydrogen phosphate, ie, sitagliptin phosphate. In a further aspect, sitagliptin phosphate is in the form of a crystalline anhydride or monohydrate. This class of embodiments represents sitagliptin phosphate monohydrate. Sitagliptin free base and pharmaceutically acceptable salts thereof are disclosed in Patent Document 30 and Example 7 of Patent Document 31. Crystalline sitagliptin phosphate monohydrate is disclosed in US Pat. Accordingly, reference is made to such documents for details, eg, for the process of manufacturing or formulating the compound or salt thereof. Sitagliptin tablet formulations are commercially available under the trade name Januvia®.

  As used herein, the term “virdagliptin” refers to vildagliptin (or LAF-237) and pharmaceutically acceptable salts thereof, including hydrates and solvates and crystalline forms thereof. A specific salt of vildagliptin is disclosed in US Pat. The crystalline form of vildagliptin and the formulation of vildagliptin tablets are disclosed in US Pat. Vildagliptin can be formulated as described in Patent Document 36 or Patent Document 37. A vildagliptin formulation with modified release is described in US Pat. Accordingly, reference is made to such documents and US Pat. No. 6,057,028 for details, for example, for the process of manufacturing or formulating the compound or salt thereof. The formulation of vildagliptin tablets is expected to be marketed under the trade name GALVUS®.

  As used herein, the term “saxagliptin” refers to saxagliptin and pharmaceutically acceptable salts thereof, including hydrates and solvates and crystalline forms thereof. In one aspect, saxagliptin is a free base or HCl salt (eg, a monohydrochloride or dihydrochloride salt including hydrates thereof) or a monobenzoate form disclosed in US Pat. It is. In a further aspect, saxagliptin is in the free base form. In a still further aspect, saxagliptin is in the form of the free base monohydrate disclosed in US Pat. Methods for preparing saxagliptin are also disclosed in US Pat. Saxagliptin can be formulated in tablets as described in US Pat. Accordingly, reference is made to these documents and to US Pat. Nos. 5,047,086 and 4,046, for details, eg, how to make, formulate, or use the compound or salt thereof.

  As used herein, the term “denagliptin” refers to denagliptin (or GSK-823093) and pharmaceutically acceptable salts thereof, including hydrates and solvates and crystalline forms thereof. In one aspect, denagliptin is in the form of its hydrochloride salt disclosed in Example 2 of US Pat. One class of this embodiment represents denagliptintosylate. Crystalline anhydrous denagliptintosylate is disclosed in US Pat. Accordingly, reference is made to such documents and US Pat.

  As used herein, the term “alogliptin” refers to alogliptin (or SYR-322) and pharmaceutically acceptable salts thereof, including hydrates and solvates and crystalline forms thereof. In one aspect, alogliptin is in the form of its benzoate salt, its hydrochloride salt, or its tosylate salt, each disclosed in US Pat. One class of this embodiment represents alogliptin benzoate. The polymorph of alogliptin benzoate is disclosed in US Pat. A method for preparing alogliptin is disclosed in US Pat. Alogliptin (ie, its benzoate salt) can be formulated in a tablet and administered as described in US Pat. Thus, for details, see, for example, these documents, as well as US Pat.

  As used herein, the term “carmegliptin” refers to carmegliptin and pharmaceutically acceptable salts thereof, including hydrates and solvates and crystalline forms thereof. Methods for preparing this compound (specifically, its dihydrochloride salt) are also disclosed in US Pat. This compound can be formulated into a pharmaceutical composition as described in US Pat. Accordingly, reference is made to such documents and US Pat. No. 6,057,028 for details, for example, how to make, formulate, or use the compound or salt thereof.

  As used herein, the term “melogliptin” refers to melogliptin and pharmaceutically acceptable salts thereof, including hydrates and solvates and crystalline forms thereof. Methods for preparing it are disclosed, inter alia, in US Pat. Specifically claimed salts include methanesulfonate and p-toluene-sulfonate. Accordingly, reference is made to such documents for details, eg, how to make, formulate, or use the compound or salt thereof.

  As used herein, the term “ztogliptin” refers to ztogliptin (or PHX-1149, PHX-1149T) and pharmaceutically acceptable salts thereof, including hydrates and solvates and crystal forms thereof. . A method for preparing it is disclosed, inter alia, in US Pat. Pharmaceutically acceptable salts include tartrate. Accordingly, reference is made to such documents for details, eg, how to make, formulate, or use the compound or salt thereof.

  The disclosure of each of the above documents cited above in connection with specific DPPIV inhibitors is hereby incorporated by reference in its entirety.

  SGLT-2 inhibitors that can be used in accordance with the present invention include, but are not limited to, dapagliflozin, canagliflozin, atigliflozin, remogliflozin, and sergliflozin.

  As used herein, the term “dapagliflozin” refers to dapagliflozin, including hydrates and solvates thereof and crystalline forms thereof. The compound and its synthesis method are described in, for example, Patent Document 65. Preferred hydrates, solvates and crystalline forms are described, for example, in US Pat.

  As used herein, the term “canagliflozin” refers to canagliflozin, including hydrates and solvates thereof, and crystal forms thereof, and has the following structure: The compounds and methods for their synthesis are described in, for example, Patent Document 68 and Patent Document 69. Preferred hydrates, solvates and crystalline forms are described, for example, in US Pat.

  As used herein, the term “atigliflozin” refers to atigliflozin, including hydrates and solvates thereof and crystalline forms thereof. A compound and a method for synthesizing the compound are described in Patent Document 71, for example.

  The term “remogliflozin” as used herein refers to prodrugs of remogliflozin and remogliflozin, including hydrates and solvates and crystalline forms thereof, in particular remogliflozin etabonate. The synthesis method is described in, for example, Patent Document 72 and Patent Document 73.

  As used herein, the term “sergliflozin” refers to sergliflozin and prodrugs of sergliflozin, including hydrates and solvates and crystalline forms thereof, in particular sergliflozin etavone. Represents the acid salt. The synthesis method is described in, for example, Patent Document 74 and Patent Document 75.

Accordingly, in one aspect, provided herein is a combination therapy comprising at least the following combinations of agents:
1) Compound of formula I and miglitol; Compound of formula I and glipizide; Compound of formula I and glyburide; Compound of formula I and saxagliptin; Compound of formula I and sitagliptin; Compound of formula I and vildagliptin; Compound of formula I and linagliptin A compound of formula I and zutgliptin; a compound of formula I and metformin; a compound of formula I, metformin, and sitagliptin;
2) Formula II compound and miglitol; Formula II compound and glipizide; Formula II compound and glyburide; Formula II compound and saxagliptin; Formula II compound and sitagliptin; Formula II compound and vildagliptin; Formula II compound and linagliptin A compound of formula II and ztogliptin; a compound of formula II and metformin; and a compound of formula II, metformin, and sitagliptin.

  In additional embodiments, the combination therapy of paragraphs 1 and 2 above can be further combined with a compound of formula I and / or II.

Pharmaceutical Compositions The trisalts of the present invention are particularly suitable as active ingredients in pharmaceutical compositions effective for the treatment of diabetes, obesity and related conditions. The pharmaceutical composition in various embodiments has a pharmaceutically effective amount of the active ingredient of the present invention together with other pharmaceutically acceptable excipients, carriers, fillers, diluents and the like. Pharmaceutical compositions suitable for delivery of the 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 can be found, for example, in Non-Patent Document 34.

  The term “pharmaceutical composition” includes preparations suitable for administration to mammals, eg, humans. When a compound of the invention is administered as a medicament to a mammal, such as a human, this may be as such or in combination with a pharmaceutically acceptable carrier, for example, 0.1-99.5% (more preferably , 0.5-90%) of the active ingredient.

  The phrase “pharmaceutically acceptable carrier” is art-recognized and includes pharmaceutically acceptable materials, compositions, or vehicles suitable for administering a compound of the present invention to a mammal. Carriers are liquid or solid fillers, diluents, excipients, solvents, or capsules necessary to carry or transport the drug of interest from one organ or body part to another organ or body part Chemicals are included. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate and the like Derivatives; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; propylene glycol, etc. Glycols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; Buffers such as arm and aluminum hydroxide; alginic acid; no pyrogens water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solution; as well as other non-toxic compatible substances used in pharmaceutical formulations.

  In addition to wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, mold release agents, coating agents, sweeteners, fragrances and flavoring agents, preservatives and antioxidants are also compositions. May be present inside.

  Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite; ascorbyl palmitate, butylated hydroxyanisole (BHA), butyl And oil-soluble antioxidants such as hydrogenated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

  Formulations of the present invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal, vaginal, and / or parenteral administration. The formulations can conveniently be presented in unit dosage form and can be prepared by any method well known in the pharmaceutical art. 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. In general, this amount ranges from about 1% to about 99% active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30% of the 100%.

  Methods for preparing such formulations or compositions comprise combining a compound of the present invention with a carrier and optionally one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compounds of the present invention with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.

  Formulations of the present invention suitable for oral administration include capsules, cachets, pills, tablets, troches (using aroma bases, usually sucrose and acacia or tragacanth), powders, granules, or solutions or aqueous or non-aqueous As a suspension in an aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a troche (using gelatin and glycerin, or inert substrates such as sucrose and acacia) And / or can be present as a mouthwash or the like, each containing a predetermined amount of a compound of the invention as an active ingredient. The compounds of the present invention can also be administered as a rapid intravenous, electuary or paste.

  In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.) the active ingredient is sodium citrate or dicalcium phosphate and / or any of the following: starch, Fillers or spreading agents such as lactose, sucrose, glucose, mannitol and / or silicic acid; binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; moisturizing such as glycerin Agents; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarders such as paraffin; absorption enhancers such as quaternary ammonium compounds; Alcohol and monostearate One or more of a wetting agent such as serol; an absorbent such as kaolin and bentonite clay; a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and a colorant Mixed with a pharmaceutically acceptable carrier. In the case of capsules, tablets and pills, the pharmaceutical composition may comprise a buffer. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using lactose or milk sugars and excipients such as high molecular weight polyethylene glycols.

  A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets contain a binder (eg, gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (eg, sodium starch glycolate or crosslinked sodium carboxymethylcellulose), a surfactant, or a dispersant. Can be prepared using. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

  Other solid dosage forms of the pharmaceutical compositions of the present invention, such as tablets and dragees, capsules, pills, and granules, optionally by coatings and shells such as enteric coatings and other coatings well known in the art of pharmaceutical formulation, Can be obtained or prepared. It is formulated to release the active ingredient slowly or controlled using various proportions, eg hydroxypropylmethylcellulose, to provide the desired release profile, other polymer matrix, liposomes and / or microspheres It can also be converted. This can be sterilized, for example, by filtration through a bacteria retaining filter, or by a sterilizing agent incorporated in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile infusion medium just prior to use. Such compositions may optionally contain opacifiers and may be compositions that release only the active ingredient, preferably in a delayed manner, in certain portions of the gastrointestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may be in microencapsulated 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. In addition to the active ingredient, liquid dosage forms may be, for example, water or other solvents, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (Specifically cottonseed, Apios, corn, germ, olive, castor, and sesame oil), solubilizers such as fatty acid esters of glycerin, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan, and mixtures thereof, and Inert diluents commonly used in the art, such as emulsifiers, can be included.

  In addition to inert diluents, oral compositions can also include adjuvants such as wetting, emulsifying, and suspending agents, sweetening, flavoring, coloring, flavoring, and preserving agents.

  The relative amounts of the active ingredient, pharmaceutically acceptable carrier, and any additional ingredients in the pharmaceutical composition of the present invention can be further determined depending on the identity, size, and condition of the subject being treated. Depending on the route taken. For example, the composition can include 0.1% to 100% (by weight) of the active ingredient.

  Methods for preparing various pharmaceutical compositions containing specific amounts of active compound are known, or will be apparent, to those skilled in the art. For example, see Non-Patent Document 35.

  The pharmaceutical compositions of the invention can be prepared, packaged, or sold in bulk as a single unit dose or as multiple single unit doses. As used herein, a “unit dose” is an individual amount of a pharmaceutical composition that includes a predetermined amount of an active ingredient. The amount of active ingredient is generally equal to the dose of active ingredient administered to the subject, or a convenient fraction of such dose, eg, one half or one third of such dose.

Dose For administration to human patients, the total daily dose of the compounds of the invention will usually be 0.25 g to 6 g, 0.25 g to 4 g, 0.25 g to 2 g, or 0, depending on the mode of administration. The range is from 25 g to 1 g. In one aspect, the total daily dose ranges from 1 g to 10 g, and in another aspect, the total daily dose ranges from 1 g to 6 g. The total daily dose can be administered in single or divided doses.

  Such doses are based on an average human subject having a weight of about 65 kg to 70 kg. The physician can readily determine the dose for subjects whose weight falls outside this range, such as infants and the elderly.

  Methods for preparing various pharmaceutical compositions containing specific amounts of active compound are known, or will be apparent, to those skilled in the art. For example, see Non-Patent Document 35.

  The pharmaceutical compositions of the invention can be prepared, packaged, or sold in bulk as a single unit dose or as multiple single unit doses. As used herein, a “unit dose” is an individual amount of a pharmaceutical composition that includes a predetermined amount of an active ingredient. The amount of active ingredient is generally equal to the dose of active ingredient administered to the subject, or a convenient fraction of such dose, eg, one half or one third of such dose.

Kits Advantageously, the present invention also provides kits for use by consumers to treat diseases. The kit comprises a) a pharmaceutical composition comprising the trisalt of the present invention and a pharmaceutically acceptable carrier, vehicle, or diluent, and optionally b) a pharmaceutical composition for treating a specific disease. Including instructions for use.

  A “kit” as used in this application comprises a container for containing individual unit dosage forms such as divided bottles or divided foil packets. The container is a pharmaceutically acceptable material, such as a paper or cardboard box, a glass or plastic bottle or jar, a resealable bag (eg to hold a “refill” of tablets for placement in a different container), or It may be any conventional shape or form known in the art made from a blister pack containing individual doses for extruding the pack according to the treatment schedule. The container used can depend on the exact dosage form required, for example, traditional cardboard boxes are generally not used to hold liquid suspensions. It is also feasible to sell a single dosage form using more than one container together in a single package. For example, a tablet is contained in a bottle that is contained in a box.

  An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively hard material, preferably covered with a foil of transparent plastic material. During the packaging process, a recess is formed in the plastic foil. The recess can have the size and shape of individual tablets or capsules to be packaged, or can have the size and shape to accommodate a plurality of tablets and / or capsules to be packaged. The tablet or capsule is then placed in the recess accordingly, and a sheet of relatively hard material is sealed against the plastic foil at the foil surface opposite to the direction in which the recess was formed. As a result, the tablets or capsules are sealed individually or collectively as desired in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that a tablet or capsule can be taken out by forming an opening of the sheet at the position of the recess by manually applying pressure from above the recess. The tablet or capsule can then be removed from the opening.

  It may be desirable to provide a memory aid document, where the memory aid document is, for example, the number adjacent to the tablet or capsule corresponding to the date of the dosing schedule on which the specified tablet or capsule should be taken, or A type that contains information and / or instructions for a doctor, pharmacist, or subject in the form of a card that contains the same type of information. Another example of such a memory aid is a calendar printed on a card, such as “first week, Monday, Tuesday”, etc., as follows: “second week, Monday, Tuesday, "... etc. Other variations of memory assistance are readily apparent. A “daily dose” may be a single tablet or capsule or several tablets or capsules taken on a given day.

  Another specific embodiment of the kit is a retrieval container designed to retrieve one daily dose at a time. Preferably, the retrieval container comprises a memory aid to further facilitate adherence to the dosing schedule. One example of such a memory aid is a mechanical counter, which indicates the number of daily doses that have been removed. Another example of such a memory aid is a battery powered microchip memory device combined with a liquid crystal readout, or an audible reminder of the day on which the last daily dose was taken and / or the next dose should be taken Expression reminder signal.

  One aspect of the present invention relates to a kit comprising a unit dosage form comprising a compound of the present invention with at least one container for holding the kit instructions and the unit dosage form.

Methods of Making The trisalts of the present invention can be prepared using any number of synthetic techniques known to those skilled in the art.

R ^- is eicosapentaenoic acid salts, the compounds of formula II n is 1, can be prepared by reacting 1 equivalent of aspartic acid 2 equivalents of metformin free base, followed by 1 equivalent of EPA . The solvent for carrying out the reaction may be an alcoholic solvent such as ethanol, methanol, propanol, and isopropanol, a ketonic solvent such as acetone, ethyl methyl ketone, and methyl isopropyl ketone, and acetonitrile. The reaction can be carried out at a temperature between 0 ° C. and the reflux temperature of the solvent used. The reaction time is determined by completion of the reaction monitored by analytical techniques such as high pressure liquid chromatography.

R ^- is eicosapentaenoic acid salts, the compounds of formula II n is 2, it can be, except for replacing the aspartic acid and glutamic acid prepared by the above procedure.

R ^- is docosahexaenoic acid salt, a compound of formula II n is 1, can be prepared by reacting 1 equivalent of aspartic acid 2 equivalents of metformin free base, followed by 1 equivalent of DHA. The solvent for carrying out the reaction may be an alcoholic solvent such as ethanol, methanol, propanol, and isopropanol, a ketonic solvent such as acetone, ethyl methyl ketone, and methyl isopropyl ketone, and acetonitrile. The reaction can be carried out at a temperature between 0 ° C. and the reflux temperature of the solvent used. The reaction time is determined by completion of the reaction monitored by analytical techniques such as high pressure liquid chromatography.

R ^- is docosahexaenoic acid salt, a compound of formula II n is 2, can be, except for replacing the aspartic acid and glutamic acid prepared by the above procedure.

Animal Model The following example describes a diabetic rat model that can be used to determine the underlying conditions of a method for treatment and prevention after ischemic injury of the heart and heart tissue.

  Auto-onset diabetic Bio-Bred (BB / W) rats are considered a useful model of autoimmune human insulin-dependent diabetes (DM). Similar to human IDDM, self-onset diabetes appears during adolescence and is accompanied by a sudden clinical onset characterized by weight loss, hyperglycemia, hypoinsulinemia, and ketosis. As in human diabetes, lesions in the retina, heart muscle, liver, kidney, bone metabolism, and peripheral nerves are all well described in the literature for BB rats, as described in Non-Patent Document 36.

Isolated Perfused Heart Model This example describes the isolated perfused rat heart model used in the development of the present invention. The study is performed using a fixed volume of isolated rat heart samples. Acute diabetic male BB / W rats and non-diabetic age (3-4 months old) controls are pretreated with heparin (1000 u; IP) followed by sodium pentobarbital (65 mg / kg; IP). After deep anesthesia, as determined by a footclaw defect, the heart is quickly removed and placed in ice-cold saline. Heart failure is retroperfused from the aorta in a non-recirculating model within 2 minutes after resection. Left ventricular pressure (LVDP) is measured using a latex balloon in the left ventricle using a high pressure tube connected to a pressure transducer. Perfusion pressure is monitored using a high pressure tube disconnected from 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 a common temperature control allows for rapid replacement of the perfusion medium. The heart is perfused using a precision roller pump. Perfusate consists _{118mM NaCl, 47mM KCl, 12mM CaCl} 2, 12mM MgCl 2, 25mM NaHCO 3, and 11mM glucose as substrate. The perfusion device is strictly temperature controlled and a heating bath is provided for the perfusate and water jacket around the perfusion tube to maintain the heart temperature at 37 ± 0.5 ° C under all conditions. use. The oxygenated perfusate in the room temperature reservoir passes through a 7.62 m (25 ft) thin-walled silicone tube surrounded by distilled water saturated with 95% oxygen at 37 ° C.

  The perfusate then enters a water jacket (37 ° C.) tube that is directed to the heart through a bubble trap with a water jacket. This sample has an excellent oxygen supply and is stable for 3-4 hours on a daily basis.

Model for Zero Flow Ischemia This example describes the procedure used to study zero flow ischemia in diabetic control, diabetic treatment, non-diabetes, and control excised hearts. Diabetes control (DC), diabetic treatment (DZ) normal (C) control, and normal treatment (CZ) hearts have 20 minutes normoxic perfusion followed by 20 minutes when the perfusate is completely stopped. Subject to zero flow ischemia followed by 60 minutes of reperfusion. The heart is treated with 10 μM metformin eicosapentaenoate. In the diabetic group (DZ) treated with metformin eicosapentaenoate, the heart is treated with normal Krebs-Henselite buffer for 10 minutes normoxic perfusion and 10 μM metformin eicosapentaenoate containing Krebs-Henselite. A 10 minute normoxic perfusion with buffer is applied. The heart is then subjected to 20 minutes of zero flow ischemia followed by 60 minutes of reperfusion. To avoid any variation in reperfusion conditions, both DC and DZ hearts are reperfused with normal Krebs-Henseleit buffer.

Model for Low Flow Ischemia This example describes the procedure used to study low flow ischemia in diabetic control, diabetic treatment, non-diabetes, and non-diabetic control excised hearts. Diabetic control heart (DC) has a normobaric perfusion rate of 12.5 mL / min for 20 minutes, followed by a perfusion fluid flow of 1.25 mL / min, i.e. about 10% of normal perfusion. Slowed 30 minutes of low flow ischemia followed by 30 minutes of reperfusion at normal flow rate (12.5 mL / min). In the diabetic or non-diabetic group (DZ or CZ) treated with metformin eicosapentaenoate (DZ or CZ), the heart is subjected to 10 minutes normoxic perfusion (flow rate 12.5 mL / min) and 10 μM using normal Krebs-Henseleit buffer. Is subjected to normobaric perfusion (flow rate 12.5 mL / min) for 10 minutes using Krebs-Henseleit buffer containing metformin eicosapentaenoate. The heart is subjected to 30 minutes of low flow ischemia (flow rate of 1.25 mL / min) and 30 minutes of reperfusion at normal flow rate (12.5 mL / min).

An animal model for measuring the effect of the compounds of the present invention on diabetes and diabetic complications is reviewed by [37]. Antidiabetic activity can also be tested according to the protocols described in the following patents: Patent Document 76, Patent Document 77, Patent Document 78, Patent Document 79, Patent Document 80, and Patent Document 81. Additional references relating to this application include US Pat.
Example 1
Bis [{[(dimethylamino) (imino) methyl] amino} (imino) methanaminium] (2S) -2-aminium (5Z, 8Z, 11Z, 14Z, 17Z) -Eicosa-5, 8, 11, 14 Of 17-pentaenoic acid-pentanic acid salt, (Met2-Glu-EPA)

Step 1 — Preparation of bis [{[(dimethylamino) (imino) methyl] amino} (imino) methanaminium] (2S) -2-aminopentanic acid salt

N, N-dimethyl-imide dicarboxylic imide acid diamide (1.00 g, 7.74 mmol) dissolved in methanol (40 mL), _{N 2} at room temperature with L- glutamic acid (0.570 g, 3.87 mmol) Treat with a solution in methanol (40 mL). The mixture is stirred for 1/2 hour at room temperature. The methanol is evaporated and the residual oil is triturated with CH ₃ CN to give a white solid. The solid is dried under high vacuum at room temperature for 3 hours and then stirred in CH ₃ CN (50 ml) at room temperature for 2 hours. The solid was collected by filtration and dried at room temperature under high vacuum for 1 hour to yield 1.3 g (90% yield) of bis [{[(dimethylamino) (imino) methyl] amino}-(imino) methanamine as a white solid. Nium] (2S) -2-aminopentanic acid salt is obtained. ¹ H NMR (300 MHz, MeOD) δ1.88 (m, 1H) 2.06 (m, 2H) 2.30 (m, 2H) 3.05 (s, 12H) 4.91 (s, 14H); C ₅ H ₉ NO ₄ m / z 146 (MH) ^- of the _{MS (ESI-) C 4 H 11} N 5 m / z 130 (M + H) + of the MS (ESI +) elemental _{analysis:.. C 13 H 31 N} 11 O 4 + 0.75% H Calculated for ₂ O: C, 38.22; H, 7.73; N, 37.71. Found: C, 38.57; H, 7.65; N, 36.73.
Step 2- Bis [{[(dimethylamino) (imino) methyl] amino} (imino) methanaminium] (2S) -2-aminium (5Z, 8Z, 11Z, 14Z, 17Z) -icosa-5,8, Preparation of 11, 14, 17-pentaenoic acid-pentanic acid salt (Met2-Glu-EPA)

Bis [{[(dimethylamino) (imino) methyl] amino} (imino) methanaminium] (2S) -2-aminopentanic acid salt (4.28 g, 15.5 mmol) dissolved in methanol (180 mL) The resulting solution in an amber flask at room temperature under N _{2 for} 1 hour (5Z, 8Z, 11Z, 14Z, 17Z) -eicosa-5,8,11,14,17-pentaenoic acid (5.15 g, 17.0 mmol) ). The methanol is evaporated and the residual 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 room temperature in the dark under high vacuum. Yield = 10 g (91% yield) of bis [{[(dimethylamino) (imino) methyl] amino} (imino) methanaminium] (2S) -2-aminium (5Z, 8Z, 11Z, 14Z, 17Z) -Eicosa-5, 8, 11, 14, 17-pentaenoic acid-pentanic acid salt. ¹ H NMR (300 MHz, MeOD) δ0.92 (t, 3H) 1.67 (m, 2H) 2.10 (m, 8H) 2.47 (m, 2H) 2.86 (m, 8H) 3.05 (s, 12H) 3.57 (m , 1H) 4.88 (m, 15H ) 5.37 (m, 10H); C 20 H 30 O 2 m / z 301 (M -) of MS (ESI-); elemental _{analysis: C 33 H 61 N 11 O} 6 + 1.26 Calculated% H ₂ O: C, 55.28; H, 8.72; N, 21.49. Found: C, 55.24; H, 8.71; N, 20.81. MP = 127-130 ° C. (Softens @ 100 ° C).
Example 2
Bis [{[(dimethylamino) (imino) methyl] amino} (imino) methanaminium] (2S) -2-aminium (5Z, 8Z, 11Z, 14Z, 17Z) -Eicosa-5, 8, 11, 14 17-pentaenoic acid-pentanic acid salt (Met2-Glu-EPA) -stoichiometric combination method

(5Z, 8Z, 11Z, 14Z, 17Z) -eicosa-5,8,11,14,17-pentaenoic acid (6.79 g, 22.4 mmol) in 400 ml of methanol with L-glutamic acid (3.30 g, 22 .4 mmol) and N, N-dimethyl-imide dicarboxylic imide acid diamide (5.80 g, a mixture of recrystallized) from 44.9 mmol) (EtOAc, _{N 2} is added below. When the mixture is mixed for 1/2 hour at room temperature, a small amount of precipitate is formed. Methanol is evaporated and the resulting homogeneous oil is taken up in CH ₃ CN (300 ml). A solid is formed and CH ₃ CN is evaporated. The solid was dried under high vacuum at 40 ° C. overnight over P ₂ O _{5 to} yield 13.52 g (85% yield) of bis [{[(dimethylamino) (imino) methyl] amino} (imino) as a brown solid Methaneaminium] (2S) -2-aminium (5Z, 8Z, 11Z, 14Z, 17Z) -eicosa-5, 8, 11, 14, 17-pentaenoic acid-pentanic acid salt is obtained. ¹ H NMR (300 MHz, MeOD) δ0.92 (t, 3H) 1.67 (m, 2H) 2.10 (m, 8H) 2.47 (m, 2H) 2.86 (m, 8H) 3.05 (s, 12H) 3.57 (m , 1H) 4.88 (m, 15H ) 5.37 (m, 10H); C 20 H 30 O 2 m / z 301 (M -) of MS (ESI-) elemental _{analysis: C 13 H 31 N 11 O} 4 + 0.87% Calculated value for H ₂ O: C, 55.40; H, 8.69; N, 21.79. Found: C, 55.30; H, 8.50; N, 21.65.
Example 3
Bis [{[(dimethylamino) (imino) methyl] amino} (imino) methanaminium]-(5Z, 8Z, 11Z, 14Z, 17Z) -eicosa-5, 8, 11, 14, 17-pentaenoic acid (3S) -3-Ammonio-3-carboxypropionate (Met2-Asp-EPA)

L-aspartic acid (2.90 g, 21.8 mmol), (5Z, 8Z, 11Z, 14Z, 17Z) -eicosa-5, 8, 11, 14, 17-pentaenoic acid (6.60 g) in methanol (300 mL) 21.8 mmol) and N, N-dimethylimidodicarbonimidic acid diamide (5.64 g, 43.7 mmol) were warmed in a 60 ° C. water bath for 30 minutes. All solids dissolved. After stirring for an additional hour at 60 ° C., the mixture was allowed to cool to room temperature, evaporated in vacuo and left to dry overnight under high vacuum to give 14.93 g (99%) of a brown solid. ¹ H NMR (300 MHz, MeOD) δppm 0.97 (t, J = 7.54 Hz, 3H) 1.53-1.78 (m, 2H) 1.96-2.28 (m, 6H) 2.57 (dd, J = 17.23, 10.15 Hz, 1H) 2.73-2.92 (m, 9H) 3.04 (s, 12H) 3.73 (dd, J = 10.15, 3.54 Hz, 1H) 4.89 (br. S., 15H) 5.18-5.51 (m, 10H). C ₄ H ₇ NO _{4 m / z 132 (MH)} -. the _{MS (ESI-) C 20 H 30} O 2 m / z 301 (MH) -. the _{MS (ESI-) C 4 H 11} N 5 m / z 130 (M + H) ⁺ MS (ESI +). Elemental Analysis: Calculated for C ₃₂ H ₅₉ N ₁₁ O ₆ : C, 55.39; H, 8.57; N, 22.20. Found: C, 55.03; H, 8.81; N, 21.76 .
Example 4
Pharmacokinetics in rats of dimethforming glutamate eicosapentaenoate The single dose oral pharmacokinetic parameters for dimethforming glutamate eicosapentaenoate prepared by the procedure described in the Examples were determined in Sprague-Dawley rats. Dimethforming glutamate eicosapentaenoate was forcibly orally administered to 6 rats, 3 males and 3 females as a 0.5% carboxymethylcellulose aqueous solution. Rats were dosed at 52 mg / kg. Blood samples were obtained from each rat with a cervical vascular catheter. Samples were collected at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after dosing. The blood sample was centrifuged to separate red blood cells and the resulting plasma sample was analyzed for eicosapentaenoic acid. The calculated pharmacokinetic parameters shown below in Table 1 are average values for 6 rats.

Combination Therapy: Pharmacology Example 2 Treatment of Type 2 Diabetes In addition to providing an acute improvement in the glucose metabolism situation, treating a type 2 diabetes patient with the pharmaceutical composition according to the present invention is a deterioration of the long-term metabolic situation. Prevent. This is when the patient has been treated with a pharmaceutical composition according to the present invention for a longer period of time, for example 3 months to 1 year or 1 to 6 years, compared to patients treated with other antidiabetic drugs. Can be observed. There is evidence of successful treatment compared to patients treated with other antidiabetic medications when there is little or no increase in fasting glucose and / or HbAlc levels. Patients treated with a pharmaceutical composition according to the invention compared to patients treated with other medicines are indicated to be treated with an additional oral anti-diabetic drug or insulin or insulin analogue, only a significantly smaller percentage. Further evidence of successful treatment is obtained if it does not result in a worsening of the glucose metabolic position (eg, an increase in the HbAlc value is> 6.5% or> 7%).

Treatment of insulin resistance In clinical studies conducted at varying lengths of time (eg, 2 weeks to 12 months), successful treatment is confirmed using a normoglycemic high insulin clamp method. A significant increase in glucose infusion rate at the end of the study compared to the initial value or compared to the placebo group or the group receiving a different therapy indicates the effectiveness of the pharmaceutical composition according to the invention in the treatment of insulin resistance. Prove that.

Treatment of Hyperglycemia In clinical studies conducted at varying lengths of time (eg, 1 day to 24 months), successful treatment in hyperglycemic patients is indicated by fasting glucose or non-fasting glucose (eg, Confirmed by measuring diet or oGTT tolerance test or regular diet). Such a marked decrease in glucose level during or at the end of the study compared to the initial value or compared to the placebo group or the group receiving different therapy is a pharmaceutical composition according to the invention in the treatment of hyperglycemia Prove the effectiveness of.

Metabolic Syndrome Treatment In clinical studies with varying durations (eg, 12 weeks to 6 years), the efficacy of the pharmaceutical composition according to the present invention can be demonstrated by fasting glucose or non-fasting glucose (eg, diet or oGTT tolerance test). Or after a regular meal), or by measuring HbAlc values. A significant decrease in these glucose or HbAlc values during or at the end of the study compared to the initial value or compared to the placebo group or the group receiving a different therapy is the active ingredient or activity in the treatment of metabolic syndrome Prove the effectiveness of the combination of ingredients. These examples include reduced systolic and / or non-systolic blood pressure, reduced plasma triglycerides, total compared to starting values at the start of the study, or compared to a group of patients treated with placebo or different therapies. Cholesterol or LDL cholesterol reduction, HDL cholesterol increase or weight loss.

Prevention of microvascular complications or macrovascular complications Treatment of type 2 diabetes or pre-diabetes with a pharmaceutical composition according to the present invention may include microvascular complications (eg diabetic neuropathy, diabetic retinopathy, diabetic kidneys). , Diabetic foot, diabetic gangrene) or macrovascular complications (eg myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial obstruction disease, cardiomyopathy, heart failure, Prevent or reduce heart rate disorders, vascular restenosis) or reduce their risk. Patients with type 2 diabetes or pre-diabetes are treated with a pharmaceutical composition according to the invention or a combination of active ingredients according to the invention for a longer period of time compared to patients treated with other antidiabetic medications or placebos, for example Treated for 1-6 years. Evidence of successful treatment compared to patients treated with other anti-diabetic medications or placebos can be seen by the smaller number of single or multiple complications. In the case of macrovascular events, diabetic foot lesions and / or diabetic ulcers, the number is counted by previous history and various test methods. In the case of diabetic retinopathy, treatment success is measured by computer-controlled illumination and background assessment of the eye, or other ophthalmic methods. In the case of diabetic neuropathy, in addition to a history and clinical examination, nerve conduction velocity can be measured using, for example, a calibrated tuning fork. For diabetic nephropathy, the following parameters: albumin secretion, creatinine clearance, serum creatinine value, time required to double serum creatinine value, time required to require dialysis is the start of the study Surveys can be conducted before, during and at the end of the survey.

Formulation Examples: Combination Therapy The following examples of formulations that can be obtained in a manner similar to methods known in the art illustrate the invention more fully without limiting the invention to the content of these examples. To help. The term “active ingredient” represents two compounds according to the invention, ie the term “active ingredient” represents two compounds according to the invention, ie a compound of formula I or II or a mixture thereof (active ingredient) And other antidiabetic agents such as statins, cholesterol absorption inhibitors, and CETP inhibitors, or pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutically acceptable salts of the prodrugs (Second component of the active ingredient). Additional suitable formulations can be prepared, for example, according to the procedures described in US Pat. Additional suitable formulations for sulfonylureas, DPPIV inhibitors are commercially available formulations, or formulations described in the paragraph “Background of the Invention” of the patent application cited above, or literature, eg “Rote Liste S "(Germany)" or "Physician's Desk Reference".
Example 1

Preparation:
(1), (2), and (3) are mixed together and granulated with the aqueous solution of (4). (5) is added to the dry granulated material. From this mixture, tablets are pressed from both sides, facets are made on both sides, and a split notch is made on one side.
Tablet diameter: 9mm
Example 2

Preparation:
(1), (2), and (3) are mixed together and granulated with the aqueous solution of (4). (5) is added to the dry granulated material. From this mixture, tablets are pressed from both sides, facets are made on both sides, and a split notch is made on one side.
Tablet diameter: 9mm
Example 3

Preparation:
(1), (2), and (3) are mixed together and granulated with the aqueous solution of (4). (5) is added to the dry granulated material. From this mixture, tablets are pressed from both sides, facets are made on both sides, and a split notch is made on one side.
Tablet diameter: 9mm
Example 4

Preparation:
Grind (1) together with (3). This ground product is added to the mixture of (2) and (4) with vigorous stirring. This powder mixture is packed into size 3 hard gelatin capsules on a capsule filling machine.
Example 5

Preparation:
Grind (1) together with (3). This ground product is added to the mixture of (2) and (4) with vigorous stirring. This powder mixture is packed into size 3 hard gelatin capsules on a capsule filling machine.

Claims (26)

Compound of formula II

Wherein, R ^- polyhydric an unsaturated fatty acid, n represents 1 to 10, or a pharmaceutically solvate or hydrate acceptable.   The compound according to claim 1, wherein n is 1 or 2.   The compound according to claim 1, wherein n is 3, 4, or 5. R ^- is eicosapentaenoic acid or docosahexaenoic acid salt A compound according to claim 1. R ^- is eicosapentaenoic acid or docosahexaenoic acid salt, n is 1 The compound of claim 1. R ^- is eicosapentaenoic acid or docosahexaenoic acid salt, n is 2, A compound according to claim 1. Compounds of formula I

Wherein, G is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl group,, R ^- are polyunsaturated fatty acids. R ^- is eicosapentaenoic acid or docosahexaenoic acid salt A compound according to claim 7.   8. A compound according to claim 7, wherein G is alkyl.   A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier, vehicle or diluent.   A kit comprising: a) a unit dosage form comprising a compound according to any one of claims 1-9, b) instructions for use of the kit, and c) at least one container for holding the unit dosage form.   10. A method for treating diabetes in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-9.   A method of reducing triglycerides in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-9.   A method for treating a cardiovascular disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-9.   15. The method of claim 14, wherein the heart disease is cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy, or stroke.   A method for treating obesity in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-9. R ^- is eicosapentaenoate and n is 1. A method for producing a compound according to any one of claims 1 to 9, comprising a) preparing a metformin free base from a metformin salt. And b) reacting 2 equivalents of metformin free base with 1 equivalent of aspartic acid and 1 equivalent of eicosapentaenoic acid at a temperature of about 1 ° C to about 60 ° C. R ^- is eicosapentaenoic acid salt, n is a method for producing a compound according to any one of claims 1-9 is 2, a) metformin free base was prepared from the metformin salt And b) reacting 2 equivalents of metformin free base with 1 equivalent of glutamic acid and 1 equivalent of eicosapentaenoic acid at a temperature of about 1 ° C. to about 60 ° C. R ^- is docosahexaenoic acid salt, n is a method for producing a compound according to any one of claims 1 to 9 is 1, a) metformin free base was prepared from the metformin salt, And b) reacting 2 equivalents of metformin free base with 1 equivalent of aspartic acid and 1 equivalent of eicosapentaenoic acid at a temperature of about 1 ° C. to about 60 ° C. R ^- is docosahexaenoic acid salt, n is a method for producing a compound according to any one of claims 1-9 is 2, a) metformin free base was prepared from the metformin salt, And b) reacting 2 equivalents of metformin free base with 1 equivalent of glutamic acid and 1 equivalent of eicosapentaenoic acid at a temperature of about 1 ° C. to about 60 ° C.   17. The method of any one of claims 12-16, further comprising administering metformin (free base) or a salt form of metformin.   24. The method of claim 21, wherein the salt form of metformin is metformin docosahexaenoate, metformin eicosapentaenoate, metformin hydrochloride, metformin succinate, or metformin fumarate.   The method according to any one of claims 12 to 16, wherein the subject is a mammal.   The method according to any one of claims 12 to 16, wherein the subject is a human.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, a therapeutic agent for dyslipidemia, and a pharmaceutically acceptable carrier.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, a hypoglycemic agent, and a pharmaceutically acceptable carrier.