CN104684889A - Tri-salt form of metformin - Google Patents

Tri-salt form of metformin Download PDF

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CN104684889A
CN104684889A CN201380046842.4A CN201380046842A CN104684889A CN 104684889 A CN104684889 A CN 104684889A CN 201380046842 A CN201380046842 A CN 201380046842A CN 104684889 A CN104684889 A CN 104684889A
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compound
acid
dimethylbiguanide
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salt
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B.L.米拉里
F.C.夏沃利诺
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Xi Disi Pharmaceutical Co
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    • A—HUMAN NECESSITIES
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    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
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    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
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Abstract

Provided herein are tri-salt compounds comprising a compound having two acidic functional groups and one basic functional groups (e.g., aspartate or glutamate), metformin, and polyunsaturated fatty acids, such as eicosapentaenoate or docosahexaenoate. The salts can be used in the treatment of diabetes, diabetes with concomitant dyslipidemia (e.g. , high triglycerides) and diabetes exacerbated cardiovascular complications, such as cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy, and stroke. The compounds of this invention are also useful in treating obesity.

Description

Three salt forms of N1,N1-Dimethylbiguanide
Related application
This application claims the U.S. Provisional Application numbers 61/669,763 submitted on July 10th, 2012; The U.S. Provisional Application numbers 61/670,376 submitted on July 11st, 2013; The U.S. Provisional Application numbers 61/670,368 submitted on July 11st, 2012; With the right of priority of the U. S. application numbers 13/841,970 submitted on March 15th, 2013.The content of all these applications is attached to herein in full with it by reference.
Background of invention
Diabetes have become international prevailing disease, and according to the prediction of the World Health Organization, the quantity to the year two thousand thirty diabetic subject will sharply increase.This is an ominous prediction, because the long-term complications (it comprises ephrosis, neuropathy, retinopathy and cardiovascular complication) controlling diabetes has serious impact by public health budget.The mark of diabetes is long-term glucose levels raised.The glucose level that also known exception raises has adverse influence to the glutathione level in the diabetic tissue of key.In addition, the production of the oxidative stress of increase and the reactive oxygen species of increase involves the hyperglycemia patient's condition.
Although the early discovery of Regular Insulin and widely using subsequently in treatment diabetes thereof, found afterwards and the sulfonylurea used and thiazole alkene diketone (thiazolidenediones), such as the troglitazone of oral antidiabetic drug, Rosiglitazone or U-721017E and DPPIV inhibitor such as Xi Gelieting, but the treatment of diabetes is not still gratifying.
The use of Regular Insulin needs multiple per daily dose, usually passes through self-injection.The determination of the suitable dosage of Regular Insulin needs the sugar in frequent estimation urine or blood.The treatment of non-insulin-dependent diabetes (type ii diabetes, NIDDM) is made up of the combination of food, exercise, oral antidiabetic drug such as thiazole alkene diketone and (in more serious case) Regular Insulin usually.But available antidiabetic drug may have the side effect limiting it and use clinically, or described medicine may be invalid to specific patient.In the case of insulin-dependent diabetes (I type), insulin administration forms the main course for the treatment of usually.
Therefore, still exist diabetes, diabetes B (T2D) and pre-diabetes and associated conditions in diabetic subject, such as neuropathy, ephrosis, retinopathy, cataract and cardiovascular complication comprise the demand of irregular pulse, myocardial infarction, apoplexy and myocardiac effective treatment.
Summary of the invention
Providing package such as, containing aspartate, glutamate or its homologue, N1,N1-Dimethylbiguanide and polyunsaturated fatty acid, three-salt compound of eicosa-pentaenoic acid group or docosahexenoic acid root herein.Three-salt compound can be used for the cardiovascular complication for the treatment of diabetes, increasing the weight of with diabetes and the diabetes of hyperlipemia (such as, high triglyceride), such as irregular pulse, myocardial ischemia, myocardial infarction, myocardosis and apoplexy.Three-salt compound also can be used for treatment of obesity.
There is provided three salt of the compound with two acidic functionalities and basic functionality, N1,N1-Dimethylbiguanide and a polyunsaturated fatty acid herein, it is represented by following formula I:
(I)
Wherein G is alkyl, cycloalkyl, assorted alkyl, heterocyclic radical, aryl or heteroaryl; And R -it is polyunsaturated fatty acid.In the embodiment of formula I, G is alkyl.
In certain embodiments, formula I has formula II:
(II)
Wherein R -be polyunsaturated fatty acid, and n is 1-10, or its pharmaceutically acceptable solvate or hydrate.In the particular of formula II, n is 1 or 2.In another specific embodiment, n is 3,4 or 5.
In the embodiment of formula I and II, R -eicosa-pentaenoic acid group or docosahexenoic acid root.In the embodiment of formula II, R -be eicosa-pentaenoic acid group or docosahexenoic acid root, and n is 1.In another embodiment of formula II, R -be eicosa-pentaenoic acid group or docosahexenoic acid root, and n is 2.
Also provide a kind of medicinal compositions herein, its contained I, and pharmaceutically acceptable carrier, medium or thinner.
Go back providing package herein containing the kit of unitary dose, it contains compound of the present invention with about how using the specification sheets of kit and at least one is for holding the container of unit dosage.
Formula I can be used for treatment numerous disease and indication.Therefore, in one aspect, be provided for the method for the treatment of diabetes in experimenter in need herein, it comprises the formula I giving subject's significant quantity.In yet another aspect, be provided in the method reducing triglyceride level in experimenter in need herein, it comprises the formula I giving subject's significant quantity.In yet another aspect, be provided for the method for Cardiovarscular in experimenter in need herein, it comprises the formula I giving subject's significant quantity.The example of the cardiovascular disorder for the treatment of is irregular pulse, myocardial ischemia, myocardial infarction, myocardosis or apoplexy.
In yet another aspect, be provided for the method for the treatment of of obesity in experimenter in need herein, it comprises the formula I giving subject's significant quantity.
In one aspect, provide the method for the treatment of hyperlipidaemia herein, it comprises the formula I giving experimenter's significant quantity in need.In yet another aspect, provide the method for the treatment of hypertriglyceridemia herein, it comprises the formula I giving experimenter's significant quantity in need.In yet another aspect, provide the method for the treatment of hyperlipemia herein, it comprises the formula I giving experimenter's significant quantity in need.
In yet another aspect, provide the method for the treatment of pre-diabetes herein, it comprises the compounds of this invention giving experimenter's significant quantity in need.In yet another aspect, provide treatment atherosclerotic method herein, it comprises the compounds of this invention giving experimenter's significant quantity in need.In yet another aspect, providing package is containing the above compound of structural formula I or II and the combination treatment of antihyperlipidemics herein, to treat Mammals, such as, the metabolic disturbance being selected from T2D, pre-diabetes, obesity, metabolism syndrome, hypertriglyceridemia and T2D complication of diabetic subject, T2D complication is neuropathy, ephrosis, retinopathy, cataract and cardiovascular complication such as, comprises atrial fibrillation, irregular pulse, myocardial infarction, apoplexy and myocardosis.Other aspect provided herein comprises the compound of structural formula I or II and the combination treatment of antihyperlipidemics, with treatment of obesity in experimenter in need, cardiovascular disorder and relevant indication.
Also have another in, there is provided herein and comprise the compound of above structural formula I or II and the combination treatment of reducing hyperglycaemia medicine, with Mammals, such as, in diabetic subject, treatment is selected from the metabolic disturbance of diabetes B (T2D), pre-diabetes, obesity, metabolism syndrome, hypertriglyceridemia and T2D complication, T2D complication is neuropathy, ephrosis, retinopathy, cataract and cardiovascular complication such as, comprises irregular pulse, myocardial infarction, apoplexy and myocardosis.
Therefore, in one aspect, be provided for the method for the treatment of diabetes in experimenter in need herein, it comprises the aforesaid combination therapy giving subject's significant quantity.In yet another aspect, be provided in the method reducing triglyceride level in experimenter in need herein, it comprises the combination treatment of the present invention giving experimenter's significant quantity in need.In yet another aspect, be provided for the method for Cardiovarscular in experimenter in need herein, it gives the combination treatment of the present invention of experimenter's significant quantity in need.The example of the cardiovascular disorder for the treatment of is irregular pulse, myocardial ischemia, myocardial infarction, myocardosis or apoplexy.
In yet another aspect, be provided for the method for the treatment of of obesity in experimenter in need herein, it gives the combination treatment of the present invention of experimenter's significant quantity in need.
In one aspect, provide the method for the treatment of hyperlipidaemia herein, it gives the anti-hyperlipidemia combination treatment of the present invention of experimenter's significant quantity in need.In yet another aspect, provide the method for the treatment of hypertriglyceridemia herein, it gives the anti-hyperlipidemia combination treatment of the present invention of experimenter's significant quantity in need.In yet another aspect, provide the method for the treatment of hyperlipemia herein, it gives the anti-hyperlipidemia combination treatment of the present invention of experimenter's significant quantity in need.
In yet another aspect, provide the method for the treatment of pre-diabetes herein, it gives the combination treatment of the present invention of experimenter's significant quantity in need.
In yet another aspect, provide treatment atherosclerotic method herein, it gives the combination treatment of the present invention of experimenter's significant quantity in need.In an embodiment of above method, experimenter is people.
The method of preparation formula II compound is also provided herein.In one aspect, the method for preparation formula II compound is provided for herein, wherein R -be eicosa-pentaenoic acid group and n be 1, the method comprises: free alkali a) preparing N1,N1-Dimethylbiguanide from melbine salt; And react under b) making the temperature of the timnodonic acid of an aspartic acid equivalent of the free alkali of the N1,N1-Dimethylbiguanide of two equivalents and an equivalent between about 1 DEG C and about 60 DEG C.
In yet another aspect, the method for preparation formula II compound is provided for herein, wherein R -be eicosa-pentaenoic acid group and n be 2, the method comprises: free alkali a) preparing N1,N1-Dimethylbiguanide from melbine salt; And react under b) making the temperature of the timnodonic acid of a L-glutamic acid equivalent of the free alkali of the N1,N1-Dimethylbiguanide of two equivalents and an equivalent between about 1 DEG C and about 60 DEG C.
In yet another aspect, the method for preparation formula II compound is provided for herein, wherein R -be docosahexenoic acid root and n be 1, the method comprises: free alkali a) preparing N1,N1-Dimethylbiguanide from melbine salt; And react under b) making the temperature of the timnodonic acid of an aspartic acid equivalent of the free alkali of the N1,N1-Dimethylbiguanide of two equivalents and an equivalent between about 1 DEG C and about 60 DEG C.
In yet another aspect, the method for preparation formula II compound is provided for herein, wherein R -be docosahexenoic acid root and n be 2, the method comprises: free alkali a) preparing N1,N1-Dimethylbiguanide from melbine salt; And react under b) making the temperature of the timnodonic acid of a L-glutamic acid equivalent of the free alkali of the N1,N1-Dimethylbiguanide of two equivalents and an equivalent between about 1 DEG C and about 60 DEG C.
Detailed Description Of The Invention
Metabolism syndrome and T2D intricate ground tied up in knots, T2D has become global prevalence disease.This syndromic clinical manifestation is patient-dependence, and the cohesive disease of diabetic subject's (chronic hyperglycemia) comprises hypertension, hyperlipidaemia and cardiovascular complication, comprises apoplexy, myocardial ischemia and myocardosis.The long-term consequence of these cohesive disease also comprises diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and diabetic cataract.
N1,N1-Dimethylbiguanide is the known compound for therapeutic treatment diabetes by U.S. food and drugs administration approved.Compound and preparation and purposes be disclosed in such as U.S. Patent number 3,174, in 901.N1,N1-Dimethylbiguanide is orally active in the treatment of diabetes B (T2D).N1,N1-Dimethylbiguanide (N, N-dimethylimino diformazan imido acid diamide (dicarbonimidic diamide)) is the anti-hyperglycemia medicine of biguanides, at present in U.S.'s 1,1-Dimethylbiguanide hydrochloride listing in the form of the hydrochloride salt.Metformin can be buied through business, and it also can such as at J. Chem. Soc., and 1922,121, be produced like that disclosed in 1790.
According to U.K. Diabetes perspective study (UKPDS) (Diabetologia such as Clarke, 2005,48,868-877), Metformin therapy is cost-save and improves the life-span expectation of Mass adjust-ment.In UKPDS, the myocardial infarction adopting the Overweight and obesity patient experience of N1,N1-Dimethylbiguanide initial therapy significantly to reduce at random and diabetes-associated death.N1,N1-Dimethylbiguanide does not promote that body weight increases and has wholesome effect to several cardiovascular risk factors.Therefore, N1,N1-Dimethylbiguanide is extensively considered as the selection of the medicine of most of diabetes B patient.But even diabetic subject also faces the danger of long-term cardiovascular complication such as irregular pulse, myocardial ischemia, myocardial infarction, myocardosis and apoplexy to Metformin therapy.Think that the triglyceride level (TG) raised may be bring out the important common biochemical link of of cardiovascular complication.Epidemiology and clinical evidence prompting, the picked-up increase of omega-3 polyunsaturated fatty acids (PUFA) prevents because of the death caused by coronary artery disease.PUFA comprises timnodonic acid (EPA) and docosahexenoic acid (DHA).Establish PUFA prevention widely and ischemia ventricular arrhythmia (Billman can be stopped dengcirculation. the Am. J. Clin. Nutr. 2002,71,202S-207S such as 1999,99,2452-2457 and Kang).Especially, known EPA is the very promising treatment of prevention Major Coronary event.PUFA has the multiple biological function by lipid-dependency and lipid-dependent/non-dependent mechanism.The mixture having shown EPA and EPA and DHA improves triglyceride level (TG) lipid level in the patient with high TG.Also show the secretion (Itoh that EPA increases fat connection albumen (adiponectin) in obese animal and obese people experimenter dengarteroscler. Thromb. Vasc. Biol. 2007,27,1918-1925).The fat connection protein level increased both the lipid regulated in animal and people and glucose metabolic in be useful.Also known many suffer from diabetes B and suffer from the pre-diabetes patient's condition be called metabolism syndrome, be sometimes referred to as the patient of insulin resistant, suffer from various glucose and lipid metabolism sexual dysfunction, comprise blood glucose and the triglyceride level of rising.
Therefore, formula I is provided herein, and treatment diabetes, with hyperlipemia (such as, high triglyceride) diabetes and the cardiovascular complication of diabetes worsens, the such as method of irregular pulse, myocardial ischemia, myocardial infarction, myocardosis and apoplexy, it comprises and gives experimenter's formula I in need.Formula I is also used in treatment of obesity in experimenter in need.
Formula I is three salt of the compound with two acidity and basic functionality, N1,N1-Dimethylbiguanide and a polyunsaturated fatty acid, and is expressed from the next:
(I)
Wherein G is alkyl, cycloalkyl, assorted alkyl, heterocyclic radical, aryl or heteroaryl; And R -it is polyunsaturated fatty acid.In the embodiment of formula I, G is alkyl.When G is alkyl, G can be alkylidene group, such as, and CH 2, CH 2cH 2, CH 2cH 2cH 2, CH 2cH 2cH 2cH 2, CH 2cH 2cH 2cH 2cH 2deng, one of them hydrogen is by the NH described in formula I 3+ substitute.
In one embodiment, formula I is represented by formula II:
(II)
Wherein n is 1-10, and R is polyunsaturated fatty acid.In the specific embodiment of formula II, n is 1-2.In another specific embodiment of formula II, n is 3-5.
In an embodiment of formula II, R -eicosa-pentaenoic acid group:
or
Docosahexenoic acid root:
。
In an embodiment of formula II, R -be eicosa-pentaenoic acid group, and n is 1.In another embodiment of formula II, R -be eicosa-pentaenoic acid group and n be 2.
In another embodiment of formula II, R -be docosahexenoic acid root and n be 1.In another embodiment of formula II, R -be docosahexenoic acid root and n be 2.
In certain embodiments, formula II compound is selected from compound a, b, c, d, e, f, g, h, iwith j:
。
Formula I also comprises isomer and enantiomorph, no matter when is all applicatory.
Well known, highly water soluble drugs preparation, when administered orally, causes the effective absorption entering this type of preparation of systemic circulation from gi tract.Another mark of such preparation is that they are rapidly absorbed into the speed of systemic circulation, causes one or more promoting agents of the high density in blood.In addition, for transmitting xenobiotic via intravenous route, they must exist as clear soln.The ester of PUFA and PUFA is water-soluble hardly.In fact, they form soap sample emulsion when mixing with water.Therefore, PUFA reach the potentiality of optimal treatment benefit should by transmitting the remarkable promotion of water-soluble PUFA.The compounds of this invention water-soluble significantly higher than the ester of PUFA and PUFA, to obtain high oral absorption rate and to transmit while providing both N1,N1-Dimethylbiguanide and PUFA, therefore provide for the blood glucose levels raised in diabetes B patient and TG the two dual function popular.In addition, new salt, by being supplied to patient with the formulation of the close friend of two kinds of active therapy of fixing dosage combination, which increases the reliability that patient complys with every day.Recently by the modern example (news of FDA issue that the Juvisync of U.S. food and drugs administration approved is to use the reliable and convenience of patient and the fixed Combination of widely used two kinds of medicines.October 7,2011).In addition, compound of the present invention can prepare intravenous dosage form.
As used herein, term " alkyl " refers to the hydrocarbon part of completely saturated branch or non-branch.Preferably alkyl comprises 1 to 20 carbon atom, more preferably 1 to 16 carbon atom, 1 to 10 carbon atom, 1 to 7 carbon atom, 1 to 6 carbon, 1 to 4 carbon, or 1 to 3 carbon atom.The representative example of alkyl comprises, but be not limited to, methyl, ethyl, n-propyl group, iso-propyl group, n-butyl, the second month in a season-butyl, iso-butyl, tert-butyl, n-amyl group, isopentyl, neo-pentyl, n-hexyl, 3-methylhexyl, 2,2-dimethyl amyl group, 2,3-dimethyl amyl groups, n-heptyl, n-octyl group, n-nonyl, n-decyl etc.As used herein, term " alkyl " also comprises " thiazolinyl " and " alkynyl " group.
Term " thiazolinyl ", refers to comprise the straight chain of at least one ethylene linkage and the carbon atom that specifies number, ring-type or branch's hydrocarbon residue alone or in combination.Preferred thiazolinyl has at the most 8, and preferably at the most 6, preferred 4 carbon atoms at the most especially.The example of thiazolinyl is vinyl, 1-propenyl, 2-propenyl, pseudoallyl, 1-butylene base, crotyl, 3-butenyl, isobutenyl, 1-cyclohexenyl, 1-cyclopentenyl.
Term " alkynyl " comprises the unsaturated aliphatic group that length is similar to abovementioned alkyl, but it contains at least one triple bond.Such as, term " alkynyl " comprises the alkynyl of straight-chain alkynyl (such as, ethynyl, proyl, butynyl, pentynyl, hexin base, heptyne base, octyne base, n-heptylacetylene base, decynyl etc.), branch alkynyl and cycloalkyl or cycloalkenyl group replacement.Term alkynyl also comprises the alkynyl of the oxygen of the one or more carbon comprising alternative hydrocarbon skeleton, nitrogen, sulphur or phosphorus atom.In certain embodiments, straight or branched alkynyl has 6 or less carbon atom (such as, C in its skeleton 2-C 6for straight chain, C 3-C 6for side chain).Term C 2-C 6comprise the alkynyl containing 2-6 carbon atom.
As used herein, term " cycloalkyl " refers to 3 to 12 carbon atoms, the saturated or unsaturated monocycle of preferably 3 to 9, or 3 to 7 carbon atoms, dicyclo or tricyclic hydrocarbon base.Exemplary monocyclic alkyl includes, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl etc.Exemplary bicyclic alkyl comprises bornyl (bornyl), indyl (indyl), six hydrogen indyls, tetralyl, decahydro naphthyl, dicyclo [2.1.1] hexyl, dicyclo [2.2.1] heptyl, dicyclo [2.2.1] heptenyl, 6,6-dimethyl dicyclo [3.1.1] heptyl, 2,6,6-trimethylammonium dicyclo [3.1.1] heptyl, dicyclo [2.2.2l octyl group etc.Exemplary tricyclic hydrocarbon base comprises adamantyl etc.As used herein, " cycloalkyl " comprises " cycloalkenyl group " group.
Term " cycloalkenyl group " refers to the part unsaturated cyclic alkyl containing 1-3 ring and each ring 4-8 carbon.Exemplary groups comprises cyclobutene base, cyclopentenyl and cyclohexenyl.Term " cycloalkenyl group " also comprises dicyclo and three cyclic groups, wherein at least one ring be part undersaturated can be carbocyclic ring or heterocycle containing carbocyclic ring and second or the 3rd ring, as long as tie point is on cycloalkenyl group.
Term " assorted alkyl ", itself or combine with another term, mean the straight or branched that (unless otherwise indicated) is stable, or its combination, by defined amount carbon atom and be selected from O, N, Si and S from 1 to 5 heteroatoms, more preferably from 1 to 3 heteroatoms composition, and wherein nitrogen and sulphur atom can be optionally oxidized optionally quaternary ammoniated with nitrogen heteroatom.Assorted alkyl is connected to the rest part of molecule by carbon atom or heteroatoms.
Term " aryl " comprises and to be only made up of hydrogen and carbon and containing from 6-19 carbon atom, or the aromatic monocyclic of 6-10 carbon atom or many rings are such as, and three rings, two rings, hydrocarbon loop systems, wherein loop systems can be fractional saturation.Aryl includes, but not limited to group such as phenyl, tolyl, xylyl, anthryl (anthryl), naphthyl and phenanthryl.Aryl also can condense or bridge joint with for non-aromatic aliphatic ring or assorted cyclic rings, to form many rings (such as, naphthane).
Term " heteroaryl ", as used herein, represents stable monocycle or on each ring, has the dicyclo of 7 atoms at the most, and wherein at least one ring is aromatics and containing the heteroatoms being selected from O, N and S from 1 to 4.Heteroaryl in this range of definition includes but not limited to: acridyl, carbazyl, cinnolines base, quinoxalinyl, pyrazolyl, indyl, benzotriazole base, furyl, thienyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrazolyl, tetrahydroquinoline.As the definition of following heterocycle, will also be understood that " heteroaryl " comprises the N-oxide derivative of any nitrogen-containing hetero aryl.Heteroaryl substituent to be dicyclo and ring be non-aromatic or not containing in heteroatomic situation wherein, should understand connection is respectively via aromatic ring or via containing heteroatomic ring.
Term " heterocycle " or " heterocyclic radical " refer to 5 yuan-10 yuan, containing the completely saturated of at least one heteroatoms such as O, S or N or the undersaturated non-aromatic heterocycle of part.Modal example is piperidyl, morpholinyl, piperazinyl, pyrrolidyl or pyrazinyl.The connection of heterocyclyl substituent can occur via carbon atom or via heteroatoms.
In addition, abovementioned alkyl, assorted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic group can be " unsubstituted " or " replacement ".Term " replacement " is intended to be described in one or more atom on molecule, as C, O or N having the substituent part of alternative hydrogen.Such substituting group can comprise independently, such as following one or more: straight or branched alkyl (preferably C 1-C 5), cycloalkyl (preferably C 3-C 8), alkoxyl group (preferably C 1-C 6), alkylthio (preferably C 1-C 6), thiazolinyl (preferably C 2-C 6), alkynyl (preferably C 2-C 6), heterocyclic radical, carbocylic radical, aryl (such as; phenyl), aryloxy (such as; phenoxy group), aralkyl (such as; benzyl), aromatic yloxy yl alkyl (such as, phenyl oxygen base alkyl), arylaceto amido (acetamidoyl), alkylaryl, heteroaralkyl, alkyl-carbonyl and aryl carbonyl or other this type of acyl group, Heteroarylcarbonyl or heteroaryl, (CR ' R ") 0-3nR ' R " (such as ,-NH2), (CR ' R ") 0-3cN (such as ,-CN) ,-NO 2, halogen (such as ,-F ,-Cl ,-Br or-I), (CR ' R ") 0-3c (halogen) 3(such as ,-CF 3), (CR ' R ") 0-3cH (halogen) 2, (CR ' R ") 0-3cH 2(halogen), and (CR ' R ") 0-3cONR ' R ", (CR ' R ") 0-3(CNH) NR ' R ", (CR ' R ") 0-3s (0) 1-2nR ' R ", (CR ' R ") 0-3cHO, (CR ' R ") 0-3o (CR ' R ") 0-3h, (CR ' R ") 0-3s (O) 0-3r ' (such as ,-SO 3h ,-OSO 3h), (CR ' R ") 0-3o (CR ' R ") 0-3h (such as ,-CH 2oCH 3with-OCH 3), (CR ' R ") 0-3s (CR ' R ") 0-3h (such as ,-SH and-SCH 3), (CR ' R ") 0-3oH (such as ,-OH), (CR ' R ") 0-3cOR ', (CR ' R ") 0-3(replacement or unsubstituted phenyl), and (CR ' R ") 0-3(C 3-C 8cycloalkyl), (CR ' R ") 0-3cO 2r ' (such as ,-CO 2or (CR ' R ") H) 0-3oR ' group, or any naturally occurring amino acid whose side chain; Wherein R ' and R " be hydrogen, C independently of one another 1-C 5alkyl, C 2-C 5thiazolinyl, C 2-C 5alkynyl or aryl.
Methods for the treatment of
Three-the salt with formula I is provided herein.In other embodiment, provide the three-salt with formula II herein.In certain embodiments, formula II compound is selected from compound a, b, c, d, e, f, g, h, iwith j.
These compounds are for the treatment T2D of diabetic subject, pre-diabetes, obesity, metabolism syndrome, hypertriglyceridemia and T2D complication such as neuropathy, ephrosis, retinopathy, cataract and cardiovascular complication, and it is effective for comprising irregular pulse, myocardial infarction, apoplexy and myocardosis.
Diabetes (Diabetes mellitus), are commonly referred to diabetes (diabetes), refer to be caused by multiple paathogenic factor and be characterised in that plasma glucose levels raises, be called the lysis of hyperglycemia.See, such as, LeRoith, D. deng, (editor), Diabetes Mellitus (Lippincott-Raven Publishers, Philadelphia, Pa. U.S.A. 1996).Uncontrolled hyperglycemia, due to great vessels and macrovascular diseases, comprise ephrosis, neuropathy, retinopathy, hypertension, cerebrovascular disease and coronary heart disease risk to increase and relevant to that increase and too early death.
There are the diabetes of two kinds of principal modes: type 1 diabetes (being called insulin-dependent diabetes or IDEM in the past); With diabetes B (being called non-insulin-dependent diabetes mellitus (NIDDM) or NIDDM in the past).
Diabetes B (T2D) is characterized as the disease with relative and nisi insulinopenic insulin resistant.Diabetes B can from main insulin resistant with relative insulin deficit to main insulin deficit with in the scope of some insulin resistant.Insulin resistant reduces the ability that Regular Insulin plays its biological action in concentration range widely.In insulin resistant individuality, the pancreas islet of the abnormal a large amount of body secretes usually makes up this defect.When the pancreas islet of Shortcomings amount usually compensates insulin resistant and suitably controls glucose, impaired glucose tolerance state development.In a large amount of individualities, insulin secretion reduces and plasma glucose levels rising further, leads diabetogenic clinical state.Diabetes B may be the tissue to main insulin-sensitive owing to resisting insulin stimulating: the deep opposing of the glucose in muscle, liver and fatty tissue and the regulating effect of lipid metabolism.When this opposing to insulin response causes glucose uptake, oxidation and stores in muscle, the insufficient Regular Insulin of insufficient cells activated by insulin and the steatolysis in fatty tissue and the glucose production in liver and secretion suppresses.In diabetes B, free fatty acid levels is usually raise and lipid oxidation increase in obese person and some non-obese patient.
Term " obesity " is defined as wherein individual BMI and is equal to or greater than 30 kg/m 2state.According to WHO definition, term obesity can be classified as follows: term " I class obesity " is that wherein BMI is equal to or greater than 30 kg/m 2but lower than 35 kg/m 2state; Term " II class obesity " is that wherein BMI is equal to or greater than 35 kg/m 2but lower than 40 kg/m 2state; Term " III class obesity " is that wherein BMI is equal to or greater than 40 kg/m 2state.
Term " blood sugar is normal " is defined as wherein experimenter and has fasting blood glucose concentration in normal range, is greater than 70 mg/dL (3.89 mmol/L) and is less than the state of 100 mg/dL (5.6 mmol/L).Word " on an empty stomach " has the ordinary meaning as medical terminology.
Term " hyperglycemia " is defined as the fasting blood glucose concentration of wherein experimenter more than normal range, is greater than the patient's condition of 100 mg/dL (5.6 mmol/L).Word " on an empty stomach " has the ordinary meaning as medical terminology.
Term " impaired glucose tolerance " or " IGT " are defined as wherein experimenter to be had 2 hours blood glucose or serum glucose concentration is greater than 140 mg/di (7.78 mmol/L) and is less than the state of 200 mg/dL (11.11 mmol/L) after the meal.Abnormal glucose tolerance, namely 2 hours after the meal blood glucoses or serum glucose concentration can be determined as after on an empty stomach after picked-up 75 g glucose 2 hours with the glucose level of every dL blood plasma mg glucose meter.2 hours after the meal blood glucoses or the serum glucose concentration with the experimenter of " normal glucose-tolerant " are less than 140 mg/dL (7.78 mmol/L).
Term " hyperinsulinemia " be defined as wherein having insulin resistant, with or without the empty stomach of orthoglycemic experimenter or post-prandial serum or plasma insulin concentrations higher than normal, without insulin resistant, there is the patient's condition of waist-stern than the concentration of lean person's individuality of <1.0 (for the male sex) or <0.8 (for women).
Term " Regular Insulin-enhanced sensitivity ", " insulin resistant-improvement " or " insulin resistant-reduction " are synonym and can exchange use.
Term " insulin resistant " be defined as wherein needing exceeding to the circulation insulin level of the normal reaction of glucose load to maintain standard state state (Ford ES, deng JAMA. (2002) 287:356-9).Determine that the method for insulin resistant is positive sugared hyperinsulinism clamp procedure (euglycaemichyperinsulinaemic clamp test).Regular Insulin is determined in the scope of the Regular Insulin of combining-glucose infusion technology with the ratio of glucose.If glucose absorption is the 25th percentile (WHO definition) of the background population lower than investigation, then there is the basis of insulin resistant.Be so-called minimal model (minimal model) than the more effortless test of clamp procedure, wherein intravenous glucose tolerance test in, the Regular Insulin in blood and glucose concn at a fixed time interval measurement and from these calculate insulin resistants calculate.Adopt in this way, can not distinguish between liver and peripheral insulin resistance.In addition, insulin resistant, the reaction of patient to therapy with insulin resistant, insulin sensitivity and hyperinsulinemia carry out quantitatively (Katsuki A by the scoring (a kind of index of reliable insulin resistant) evaluating " Homeostasis model assessment (HOMA-IR) to insulin resistant " dengdiabetes Care 2001; 24:362-5).Mention further have HOMA-index for measuring insulin sensitivity (Matthews etc., diabetologia1985,28:412-19), the ratio of complete proinsulin and Regular Insulin (Forst etc., diabetes2003,52 (Supp1.1): A459) method and euglycemia clamp procedure research.In addition, the potential replacement that plasma adiponectin protein level can be used as insulin sensitivity is monitored.Following formula is adopted to calculate (the Diabet. Med. 1992 such as Galvin P. by stable state evaluation model (HOMA)-IR estimation insulin resistant of marking; 9:921-8): HOMA-IR=[Diagnostic Value of Fasting Serum Regular Insulin (uU/mUx [fasting plasma glucose (nunol/L)/22.5].
Usually, other parameter is used to routine clinical practice to evaluate insulin resistant.Preferably, such as, use the triglyceride concentration of patient because increase triglyceride levels and insulin resistant there is significant correlation.
" metabolism syndrome ", also referred to as " X syndrome " (time in for the background of metabolic disorder), also referred to as " metabolism disorder syndrome ", is syndrome (the Laaksonen D E etc. of the most important characteristics of the promising insulin resistant of compound am. J. Epidemiol. 2002; 156:1070-7).According to ATP III/NCEP guide, (u.s. national cholesterol education program (NCEP) panel of experts is about the 3rd report executing summary (adult treatment group III) of adult's detection of high blood cholesterol, assessment and treatment jAMA:Journal of the American Medical Association(2001) 285:2486-2497), the diagnosis of metabolism syndrome is made when 3 or more following Hazard Factor exist:
1. abdominal obesity, is defined as male sex's waistline >40 inch or 102 cm, and women's waistline >35 inch or 94 cm; Or male sex's waistline 85 cm and women's waistline 90 cm is defined as Yamato and Japanese patients;
2. triglyceride level: -150 mg/dL
3. male sex HDL-cholesterol <40 mg/dL
4. blood pressure: 130/85 mm Hg (SBP130 or DBP85)
5. fasting blood glucose: -100 mg/dL
The patient with development IGT or IFG or T2D tendency be have blood sugar normal but with hyperinsulinemia those and be defined as insulin resistant.The typical patient with insulin resistant is generally overweight or fat.If can detect insulin resistant, then this is strong especially the accusing of that pre-diabetes exists.
Therefore, this may be to maintain glucose homeostasis, and an individual need is the doubly so much Regular Insulin of Healthy People 2-3, and does not cause any clinical symptom.
The method of research Pancreatic beta cells function is similar to the above method about insulin sensitivity, hyperinsulinemia or insulin resistant: the improvement of β cell function can such as by measure be used for β cell function HOMA-index (Matthews etc., diabetologia1985,28:412-19), the former ratio with Regular Insulin of Intact Islets element (Forst etc., diabetes2003,52 (Supp1.1): A459), Regular Insulin/C-peptide secretion after Oral glucose tolerance test or feed tolerance test, or by using the minimum modeling (Stumvoll etc. after the research of hyperglycemia clamp procedure and/or the frequent intravenous glucose tolerance test sampled eur. J. Clin. Invest. 2001,31:38081) measure.
" pre-diabetes " is that wherein individuality has the tendentious in advance state of development diabetes B.Pre-diabetes expands the definition of impaired glucose tolerance to comprising the fasting blood glucose (Diabetes 2003 such as J. B. Meigs with high normal range 100 mg/dL; 52:1475-1484) and the on an empty stomach individuality of hyperinsulinemia (plasma insulin concentrations of rising).Identify that as the science of the pre-diabetes of a serious health threat and basic medical are being combined issue exercise question by ADA and state-run diabetes and digestive tube and ephrosis institute be the prevention of the diabetes B " or delay (The Prevention or Delay of Type 2 Diabetes) " (Diabetes Care 2002; Propose in situation statement 25:742-749).
The individuality of insulin resistant may be had for there are two or more with properties those: 1) overweight or fat, 2) hypertension, 3) hyperlipidaemia, 4) relevant with the diagnosis of IGT or IFG or diabetes B one or more 1 degree.Insulin resistant can be confirmed in these individualities by calculating HOMA-IR scoring.For the purposes of the present invention, insulin resistant is defined as the clinical patient's condition, wherein individual HOMA-IR mark >4.0 or HOMA-IR scoring as laboratory is carried out glucose and insulin assay more than the upper limits of normal that defines.
Term " diabetes B " is defined as such patient's condition, and wherein the fasting blood glucose of experimenter or serum glucose concentration are greater than 125 mg/dL (6.94 mmol/L).The measurement of blood glucose value is the standard program during general medical is analyzed.If carry out Glucose tolerance tests, the glucose level of diabetes will be 2 little constantly more than the every dL of 200 mg glucose (11.1 mmol/1) blood plasma after picked-up 75 g glucose on an empty stomach.In Glucose tolerance tests, 75 g glucose oral administration give the patient after empty stomach 10-12 to be tested hour and before ingestion of glucose and picked-up after 1 and 2 hour immediate record glucose level.In health volunteer, the glucose level before ingestion of glucose between the every dL blood plasma of 60 and 110 mg, will be less than the every dL of 200 mg for 1 hour after ingestion of glucose and is less than the every dL of 140 mg after 2 hours.If after 2 hours, described value is between 140 and 200 mg, and this is regarded as abnormal glucose tolerance.
Term " T2D diabetes in late period " comprises and has secondary drug failure, to the patient that insulin treatment adapts to and is in progress as diabetic nephropathy or coronary heart disease (CHD) to capillary blood vessel and macrovascular complications.
Method of the present invention, composition and kit can be used for treating diabetic complication, include, but not limited to diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataract and diabetic retinopathy.
As the term is employed herein " treatment ", refer to delay, stop or reverse illness or the patient's condition that term " treatment " uses, or the development of one or more symptoms of such illness or the patient's condition, or alleviate or prevent described illness or the patient's condition, or one or more symptoms of such illness or the patient's condition.
As the term is employed herein " treatment ", refer to treat the effect of illness, symptom or the patient's condition, as above term " treatment " define.
Triglyceride reducing effect of the compounds of this invention can according to by Sidika dengat Journal of Lipid Research, the program described in 1992,33,1-7, determines in animal model.
In yet another aspect, provide treatment atherosclerotic method herein, it comprises the compound of the present invention giving experimenter's significant quantity in need.Atherosclerosis refers to that metabolism of lipid and cholesterol is deposited in arterial wall and neutralizes (patch) on it, the flowing of its meeting limit blood.These patches also can burst, and trigger blood clotting.Although atherosclerosis is usually considered to a kind of cardiac problems, it can to affect in body artery anywhere.The animal model of atherosclerosis study is described in laboratory Animalsin (2004) 38,246-256.
In another embodiment, formula I (such as, formula II compound and compound a, b, c, d, e, f, G, H, Iwith j) can combine with the N1,N1-Dimethylbiguanide of other form and give.Such as, formula I can be combined with N1,N1-Dimethylbiguanide docosahexenoic acid salt, N1,N1-Dimethylbiguanide eicosa-pentaenoic hydrochlorate or its mixture and given experimenter.In another embodiment, formula I can with the non-fatty acid salt of N1,N1-Dimethylbiguanide, such as, Metformin, succinate or fumarate are combined, or combine with the free alkali of N1,N1-Dimethylbiguanide and give.Metformin can be buied through business and also can such as, as at J. Chem. Soc., and 1922,121, prepare disclosed in 1790.
In addition, formula I can be combined with timnodonic acid and/or docosahexenoic acid and given.
Combination treatment
Three-salt of the present invention is applicable to combination treatment completely.
Term " combination treatment " is showed and is given two or more therapeutical agents to treat the therapeutic patient's condition or the illness of disclosure description.Such administration comprises in a substantially simultaneous manner, such as, to have the single capsule of the activeconstituents of fixed proportion or jointly to give these therapeutical agents for multiple containers (such as, capsule) separated of often kind of activeconstituents.In addition, such administration also comprises in a sequential manner, or with the while of roughly or with the different time, uses the therapeutical agent of every type.In any one situation, the beneficial effect that treatment plan will provide drug regimen in the treatment patient's condition as herein described or illness.
" unitary agent " refers to two of significant quantity kinds of therapeutical agents to pass to the single carrier or medium that patient prepares as the term is employed herein.Single medium is designed to transmit each medicine of significant quantity, and any pharmaceutically acceptable carrier or vehicle.In certain embodiments, medium is tablet, capsule, pill or patch.In other embodiments, medium is solution or suspension.
Use term " unitary dose " to mean two kinds of medicines herein and give patient to be treated with a kind of formulation together simultaneously.In certain embodiments, unitary dose is unitary agent.In certain embodiments, unitary dose comprises one or more media, so that often kind of medium includes at least one medicine of effective amount and pharmaceutically acceptable carrier and vehicle.In certain embodiments, simultaneously unitary dose gives one or more tablets of patient, capsule, pill or patch.
" oral dosage form " comprise output prescription or be intended to for the oral unit dosage given.
" mixture of formula I or II compound " refers to the mixture that two or more these compounds exist with a and b %, and wherein a and b is not all 0, but the summation of a and b is 100 %.Such as, when the mixture composition of formula I and formula II compound, formula I exist with 50% and formula II compound with 50% existence.
In one embodiment, providing package contains formula I or the II compound of significant quantity herein, or its combination, and the combination treatment of antihyperlipidemics or reducing hyperglycaemia medicine." significant quantity " of drug regimen is compared with the S&S of the illness with described combined therapy observable on baseline clinical, is enough to the amount providing observable improvement.
In one embodiment, formula I or II compound or its combination, and the combination of antihyperlipidemics described herein or reducing hyperglycaemia medicine demonstrates a kind of synergy.As the term is employed herein " synergy ", refer to the effect that two kinds of medicaments tell on, such as, delay the symptom development of diabetes or its symptom, it is greater than the simple addition of the effect that often kind of medicine gives itself.Synergy can be such as, use suitable method such as Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6:429-453 (1981)) (incorporated herein by reference in full with it), additivity equation (the Loewe of Loewe, and Muischnek S., H., Arch. Exp. Pathol Pharmacol. 114:313-326 (1926)) (incorporated herein by reference in full with it) and middle efficacious prescriptions journey (median-effect equation) (Chou, T. C. and Talalay, P., Adv. Enzyme Regul. 22:27-55 (1984)) (incorporated herein by reference in full with it) calculating.Each equation above-mentioned can be applied to experimental data, to generate the effect that corresponding graphic representation helps assess drug regimen.The response curve figure relevant with equation above-mentioned is concentration-effect curve, equivalent line chart (isobologram) curve and combinatorial index curve respectively.
Express " pharmacy acceptable salt " and comprise pharmaceutically acceptable acid salt and pharmaceutically acceptable both cationic salts in due course.Express " pharmaceutically acceptable cationic salts " be intended to limit but be not limited to such salt as an alkali metal salt (such as, sodium and potassium), alkaline earth salt (such as, calcium and magnesium), aluminium salt, ammonium salt and with organic amine such as benzyl star (N, N '-dibenzyl-ethylenediamin), salt formed by choline, diethanolamine, quadrol, meglumine (N-meglumine), Benethamine diacetale (N-benzyl-1-phenylethylamine), diethylamine, piperazine, Trometamol (TRIS) and PROCAINE HCL, PHARMA GRADE.
Express " pharmaceutically acceptable acid salt " to be intended to limit but be not limited to such salt, as with formed by pharmaceutically acceptable inorganic or organic acid typically for those salt in pharmaceutics.Suitable acid is, such as, and mineral acid, such as haloid acid example hydrochloric acid, Hydrogen bromide etc., or sulfuric acid, nitric acid or phosphoric acid; Or suitable organic acid, such as suitable aliphatic acid, as aliphatic series list or dicarboxylic acid, hydroxyl alkane acid or hydroxyalkanoate diacid, as acetic acid, propionic acid, oxyacetic acid, 2 hydroxy propanoic acid, Acetylformic acid, oxalic acid, propanedioic acid, succinic acid, (Z)-(E)-butenedioic acid, (E)-(E)-butenedioic acid, 2-hydroxy-butanedioic acid, 2,3-dyhydrobutanedioic acid or 2-hydroxyl-1,2,3-tricarballylic acid; The paraffinic acid that phenyl replaces; Or suitable aromatic acid, as 2 hydroxybenzoic acid, or 4-amino-2-hydroxybenzoic acid; Or suitable sulfonic acid, as alkyl sulfonic acid, as methylsulfonic acid or ethyl sulfonic acid, or aromatic sulfonic acid, as Phenylsulfonic acid or 4-toluene sulfonic acide; Or cyclohexane sulfamic acid.In some embodiment of the present disclosure, acid is such as Hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, phenylformic acid, fumaric acid, toxilic acid, citric acid, tartrate, gentisinic acid, dobesilic, methylsulfonic acid, ethyl sulfonic acid, dodecyl sodium sulfonate, Phenylsulfonic acid and tosic acid.In certain embodiments, pharmacy acceptable salt is selected from L-arginine, benenthamine, benzyl star, trimethyl-glycine, calcium hydroxide, choline, dimethylethanolamine, diethanolamine, diethylamine, 2-(diethylin) ethanol, thanomin, quadrol, n-meglumine, Hai Baming, 1H-imidazoles, lithium hydroxide, 1B, magnesium hydroxide, 4-(2-hydroxyethyl) morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl) tetramethyleneimine, sodium hydroxide, trolamine, Trometamol, zinc hydroxide, sodium, calcium, potassium, magnesium and zinc.
With the combination treatment of antihyperlipidemics
In yet another aspect, providing package is containing the compound of above structural formula I or II herein, with the combination treatment of antihyperlipidemics, with Mammals, such as, in diabetic subject, treatment is selected from T2D, pre-diabetes, obesity, metabolism syndrome, hypertriglyceridemia and T2D complication such as neuropathy, ephrosis, retinopathy, cataract and cardiovascular complication, comprises atrial fibrillation, irregular pulse, myocardial infarction, apoplexy and myocardiac metabolic disorder.An other aspect provided herein comprises the compound of structural formula I or II and the combination treatment of antihyperlipidemics, with treatment of obesity in experimenter in need, cardiovascular disorder and relevant indication.
In another embodiment, be provided in Mammals the method reducing cholesterol levels and/or triglyceride levels herein, it comprises the combination treatment of the present invention giving Mammals significant quantity.
Therefore, in one aspect, be provided for the method for the treatment of diabetes in experimenter in need herein, it comprises the aforesaid combination therapy giving subject's significant quantity.In yet another aspect, be provided in the method reducing triglyceride level in experimenter in need herein, it comprises the combination treatment of the present invention giving experimenter's significant quantity in need.In yet another aspect, be provided for the method for Cardiovarscular in experimenter in need herein, it gives the combination treatment of the present invention of experimenter's significant quantity in need.The example of cardiovascular disorder to be treated is irregular pulse, myocardial ischemia, myocardial infarction, myocardosis or apoplexy.
In yet another aspect, be provided for the method for the treatment of of obesity in experimenter in need herein, it gives the combination treatment of the present invention of experimenter's significant quantity in need.
In one aspect, provide the method for the treatment of hyperlipidaemia herein, it gives the combination treatment of the present invention of experimenter's significant quantity in need.In yet another aspect, provide the method for the treatment of hypertriglyceridemia herein, it gives the combination treatment of the present invention of experimenter's significant quantity in need.In yet another aspect, provide the method for the treatment of dyslipidaemia herein, it gives the combination treatment of the present invention of experimenter's significant quantity in need.
In yet another aspect, provide the method for the treatment of pre-diabetes herein, it gives the combination treatment of the present invention of experimenter's significant quantity in need.In yet another aspect, provide treatment atherosclerotic method herein, it gives the combination treatment of the present invention of experimenter's significant quantity in need.
In an embodiment of above method, experimenter is people.
In one aspect, the present invention relates to compound and the antihyperlipidemics of compound or structural formula I or II comprising structural formula I or II, or the compound of two or more structural formulas I or II or the compound of structural formula I or II and antihyperlipidemics and pharmacy acceptable salt thereof or prodrug, or the conjoint therapy of the combination of the pharmacy acceptable salt of described prodrug.In yet another aspect, provide a kind of medicinal compositions herein, it comprises the compound of structural formula I or II, or the mixture of these compounds, antihyperlipidemics and pharmaceutically acceptable carrier.In one embodiment, when medicinal compositions comprises the compound of two or more structural formulas I or II, or during the mixture of these compounds, two or more compounds are with existence such as x, y, z ... %, prerequisite is x, y, z ... % is not all 0, but the summation of x, y, z ... % is 100%.
In an embodiment of medicinal compositions, antihyperlipidemics is the about 0.1-1% weight of medicinal compositions.In another embodiment of medicinal compositions, the compound of structural formula I or II, or its mixture exists with the unitary dose intensity of 250,500,750,1000 or 1250 mg, and described antihyperlipidemics exists with the unitary dose intensity of 1,2.5,5,10,20,30,40 or 50 mg.In another embodiment, described antihyperlipidemics exists with the unitary dose intensity of 5-100 mg.
The component of combination treatment (compound of structural formula I or II and antihyperlipidemics, or the compound of two or more structural formulas I or II and the combination of antihyperlipidemics) can administration in many ways.In one embodiment, described component presents with the preparation separated or unit dosage.In another embodiment, component gives together with pharmaceutically acceptable carrier.Component separately can give in the substantially the same time, or gives in the different time.When separately giving, they can give by any order.
In one embodiment, the present invention relates to medicinal compositions, it comprises the compound of structural formula I or II, or the mixture of these compounds and antihyperlipidemics, or its pharmacy acceptable salt or prodrug, or the pharmacy acceptable salt of described prodrug; With pharmaceutically acceptable carrier, medium or thinner.
The antihyperlipidemics that can use according to the present invention can comprise, such as, statins, it is HMG CoA enzyme inhibitors, cholesterol absorption inhibitor and Sterol esterase transfer protein (CETP) inhibitor and pharmacy acceptable salt thereof or prodrug, with the pharmacy acceptable salt of described prodrug, and other.
In one embodiment of the invention, antihyperlipidemics is statins, cholesterol absorption inhibitor and CETP inhibitor or its pharmacy acceptable salt or prodrug, or the pharmacy acceptable salt of described prodrug.In certain embodiments, pharmacy acceptable salt is selected from propionic salt, caprate, octylate, acrylate, formate, isobutyrate, caprate, enanthate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butine-1, 4-diacid salt, hexin-1, 6-diacid salt, benzoate, chloro-benzoate, tolyl acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, phthalate, terephthalate, sulfonate, xylenesulfonate, phenyl acetate salt, phenylpropionic acid salt, PB, Citrate trianion, lactic acid salt, to hydroxybutyric acid salt, glycollate, tartrate, methane sulfonates, propane sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, mandelate, hippurate, gluconate or lactobionate.
Preferred medicine in statins is atorvastatin, superstatin (risuvostatin), Simvastatin or Pravastatin, its pharmacy acceptable salt or prodrug, and the pharmacy acceptable salt of described prodrug.Preferred medicine in cholesterol absorption inhibitor is ezetimibe, also referred to as Zetia.Preferred medicine in CETP inhibitor is bent of Ansai.In certain embodiments, CETP inhibitor includes, but are not limited to bent of Ansai or its hydrate and solvate.
In certain embodiments, Pravastatin exists with the amount of scope from 5 mg to 100 mg.
In certain embodiments, ezetimibe exists with 5 mg to 50 mg.
In yet another aspect, the disclosure provides kit, and it comprises the compound containing structural formula I or II, or first of the mixture of these compounds unit dosage; Comprise second unit dosage of antihyperlipidemics or its hydrate and solvate; And container.
In an embodiment of anti-hyperlipidemia therapy described herein, G is alkyl, cycloalkyl, assorted alkyl, heterocyclic radical, aryl or heteroaryl; And R -it is polyunsaturated fatty acid.In the embodiment of formula I, G is alkyl.When G is alkyl, G can be alkylidene group, such as, and CH 2, CH 2cH 2, CH 2cH 2cH 2, CH 2cH 2cH 2cH 2, CH 2cH 2cH 2cH 2cH 2deng, one of them hydrogen is by the NH described in formula I 3 +substitute.
In certain embodiments, formula I has formula II, wherein R -be polyunsaturated fatty acid, and n is 1-10, or its pharmaceutically acceptable solvate or hydrate.In the specific embodiment of formula II, n is 1 or 2.In the embodiment of formula I and II, R -eicosa-pentaenoic acid group or docosahexenoic acid root.In the embodiment of formula II, R -be eicosa-pentaenoic acid group or docosahexenoic acid root, and n is 1.In another embodiment of formula II, R -be eicosa-pentaenoic acid group or docosahexenoic acid root, and n is 2.In further embodiment, formula II compound is selected from compound a, b, c, d, e, f, g, h, iwith j.
The antihyperlipidemics that can use according to the present invention be the member of dissimilar antihyperlipidemics (such as, HMG-CoA reductase inhibitor (statins), CETP inhibitor and cholesterol absorption inhibitor and other), its pharmacy acceptable salt and prodrug, and the pharmacy acceptable salt of described prodrug.
" HMG-CoA reductase inhibitor " refers to the competitive compound blocking enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase enzyme as the term is employed herein.Block this enzyme by competitiveness, HMG-CoA reductase inhibitor interference cholesterol forms (enzyme catalysis HMG-CoA is converted into mevalonic acid).As a result, they reduce total cholesterol, low density lipoprotein cholesterol (LDL-C), apolipoprotein B (the film transhipment complex body for LDL-C), vldl (VLDL) and plasma triglyceride.For the commentary about HMG-CoA inhibitor, see such as, drug Discovery Today:Therapeutic Strategies, 1:189 (2004) and the reference wherein quoted.
The special HMG-CoA reductase inhibitor that can use according to the disclosure include, but are not limited to: atorvastatin, and it can as at U.S. Patent number 7, and 030, preparation disclosed in 151; Pravastatin and related compound, it can as at U.S. Patent number 4,346,227 and 4, and 448, preparation disclosed in 979; Superstatin, it can as at U.S. Patent number 6, and 858, preparation disclosed in 618; Simvastatin and related compound, it can as at U.S. Patent number 4,448,784 and 4, and 450, preparation disclosed in 171.HMG-CoA reductase inhibitor also comprise atorvastatin, Simvastatin, Pravastatin, lovastatin, fluvastatin, superstatin, Cerivastatin, mevastatin, vertical cut down statin (rivastatin), pitavastatin, itavastatin, according to cutting down statin (itavastatin), velostatin and fluindostatin.
" CETP inhibitor " refers to that catalysis cholesteryl ester is transferred to the apolipoprotein B containing the lipoprotein exchanging triglyceride level from HDL and thus plays the compound of Main Function at lipoprotein metabolism as the term is employed herein.For the commentary about CETP inhibitor, see, such as, curr. Opin. Pharmacal. 6:162 (2006) and the reference wherein quoted.
The CETP inhibitor that can use according to the disclosure is not by any structure of CETP inhibitor or the restriction of group.The CETP inhibitor that can use according to the disclosure is including, but not limited to bent of: Ansai, and it can as preparation disclosed in WO 2007005572.Its disclosure is incorporated herein by reference.
" cholesterol absorption inhibitor " refers to suppress intestinal absorption bile and dietary cholesterol as the term is employed herein, and does not affect the compound of the absorption of liposoluble vitamin, triglyceride level or bile acide.For the commentary about cholesterol absorption inhibitor, see, such as, nutr. Metab. Cardiovasc. Dis., 13:42 (2004) and the reference wherein quoted.
The cholesterol absorption inhibitor that can use according to the disclosure include, but are not limited to ezetimibe (Zetia), and it can as at U.S. Patent number 5,767,115 and 5, and 846, preparation disclosed in 966.Its disclosure is incorporated herein by reference.
In the enforcement of composition of the present disclosure and method, any HMG Co-A reductase inhibitor or the pharmaceutically acceptable combination with any excitement (flushing) inhibitor can be used.
In one aspect, the disclosure provides medicinal compositions, its contained I or II compound, or its mixture; With antihyperlipidemics or pharmacy acceptable salt, its hydrate and solvate.
In one aspect, the disclosure provides unit dose formulations, its contained I or II compound, or its mixture, and antihyperlipidemics or pharmacy acceptable salt, hydrate and solvate.
In one aspect, the disclosure provides the method for the treatment of mammiferous diabetic cardiovascular complication, and it comprises, and to give described Mammals a kind of as the medicinal compositions of hereafter setting forth.In certain embodiments, the complication of such diabetes is, such as, and atrial fibrillation, irregular pulse, myocardial infarction, apoplexy and myocardosis.
In one aspect, the disclosure provides the method for the treatment of mammiferous diabetes B, and it comprises and gives described mammal I or II compound, or its mixture, and antihyperlipidemics or its hydrate and solvate.
Therefore, in one embodiment, providing package contains herein, at least, and the combination treatment of following drug regimen:
1) formula I and atorvastatin; Formula I and Simvastatin; Formula I and Pravastatin; Formula I and superstatin; With formula I and ezetimibe; Formula I and bent of Ansai; Formula I and atorvastatincalcuim;
2) formula II compound and atorvastatin; Formula II compound and Simvastatin; Formula II compound and Pravastatin; Formula II compound and superstatin; With formula II compound and ezetimibe; Formula II compound and bent of Ansai; Formula II compound and atorvastatincalcuim.
In other embodiments, the combination treatment of above paragraph 1 and 2 can combine further with formula I and/or II compound.
With the combination treatment of reducing hyperglycaemia medicine
The present invention relates to the compound comprising above structural formula I or II, with the combination treatment of reducing hyperglycaemia medicine, with Mammals, such as, metabolic disorder is treated in diabetic subject, described metabolic disorder is selected from diabetes B (T2D), pre-diabetes, obesity, metabolism syndrome, hypertriglyceridemia and T2D complication such as neuropathy, ephrosis, retinopathy, cataract and cardiovascular complication, comprises irregular pulse, myocardial infarction, apoplexy and myocardosis.
In one embodiment, the invention provides Mammals, such as, the method of metabolic disorder is treated in diabetic subject, described metabolic disorder is selected from T2D, pre-diabetes, obesity, metabolism syndrome, hypertriglyceridemia and diabetic complication such as neuropathy, ephrosis, retinopathy, cataract and cardiovascular complication, comprise irregular pulse, myocardial infarction and myocardosis, the method comprises and gives experimenter in need combination treatment described herein.
The component of combination treatment (compound of structural formula I or II and reducing hyperglycaemia medicine, or the compound of two or more structural formulas I or II and the combination of reducing hyperglycaemia medicine) can administration in many ways.In one embodiment, component presents with the preparation separated or unit dosage.In another embodiment, component gives together with pharmaceutically acceptable carrier.Component separately can give in the substantially the same time, or gives with the different time.When separately giving, they can give by any order.
In one embodiment, the present invention relates to medicinal compositions, it comprises the compound of structural formula I or II, or the mixture of these compounds, and reducing hyperglycaemia medicine, or its pharmacy acceptable salt or prodrug, or the pharmacy acceptable salt of described prodrug; With pharmaceutically acceptable carrier, medium or thinner.
In an embodiment of medicinal compositions, reducing hyperglycaemia medicine is the about 1-20% weight of medicinal compositions.In another embodiment of medicinal compositions, the compound of described structural formula I or II, or its mixture exists with the unitary dose intensity of 250,500,750,1000 or 1250 mg, with described reducing hyperglycaemia medicine with 1,2.5,5,10,20,25,50,100,150, or the unitary dose intensity of 200 mg exists.In another embodiment, reducing hyperglycaemia medicine exists with the unitary dose intensity of 5-100 mg.
The reducing hyperglycaemia medicine that can use according to the present invention can comprise, such as, sulfonylurea, meglitinides, thiazolidinediones, alpha-glucosidase inhibitor, DPP IV inhibitor and SGLT-2 inhibitor and pharmacy acceptable salt thereof or prodrug, with the pharmacy acceptable salt of described prodrug, and other.
In one embodiment of the invention, reducing hyperglycaemia medicine is sulfonylurea, meglitinide, thiazolidinedione, alpha-glucosidase inhibitor, DPP IV inhibitor and SGLT-2 inhibitor or its pharmacy acceptable salt or prodrug, or the pharmacy acceptable salt of described prodrug.In certain embodiments, pharmacy acceptable salt is selected from propionic salt, caprate, octylate, acrylate, formate, isobutyrate, caprate, enanthate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butine-1, 4-diacid salt, hexin-1, 6-diacid salt, benzoate, chloro-benzoate, tolyl acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, phthalate, terephthalate, sulfonate, xylenesulfonate, phenyl acetate salt, phenylpropionic acid salt, PB, Citrate trianion, lactic acid salt, p-hydroxybutyric acid salt, glycollate, tartrate, methane sulfonates, propane sulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonic acid salt, mandelate, hippurate, gluconate or lactobionate.
Preferred medicine in thiazolidinediones is U-721017E, its pharmacy acceptable salt or prodrug, and the pharmacy acceptable salt of described prodrug.
Preferred alpha-glucosidase inhibitor includes, but not limited to acarbose, voglibose (vaglibose) and miglitol, its pharmacy acceptable salt and prodrug, and the pharmacy acceptable salt of described prodrug.
Preferred DPP-IV inhibitor comprises, but be not limited to, Xi Gelieting, Li Gelieting (linagliptin), Vildagliptin, BMS-477118, Egelieting (alogliptin), Ge Lieting, carmegliptin (carmegliptin), melogliptin (melogliptin) and dutogliptin (dutogliptin), and pharmacy acceptable salt and prodrug, and the pharmacy acceptable salt of described prodrug.
Preferred SGLT-2 inhibitor comprises, but be not limited to, Da Gelie clean (dapagliflozin), Ka Gelie clean (canagliflozin), A Gelie clean (atigliflozin), Rui Gelie clean (remogliflozin) and She Gelie clean (sergliflozin), and pharmacy acceptable salt and prodrug, and the pharmacy acceptable salt of described prodrug.
In an embodiment of hyperglycemia combination treatment described herein, G is alkyl, cycloalkyl, assorted alkyl, heterocyclic radical, aryl or heteroaryl; And R -it is polyunsaturated fatty acid.In the embodiment of formula I, G is alkyl.When G is alkyl, G can be alkylidene group, such as, and CH 2, CH 2cH 2, CH 2cH 2cH 2, CH 2cH 2cH 2cH 2, CH 2cH 2cH 2cH 2cH 2deng, one of them hydrogen is by the NH described in formula I 3+ substitute.In certain embodiments, formula I has formula II, wherein R -be polyunsaturated fatty acid, and n is 1-10, or its pharmaceutically acceptable solvate or hydrate.In the specific embodiment of formula II, n is 1 or 2.In the embodiment of formula I and II, R -eicosa-pentaenoic acid group or docosahexenoic acid root.In the embodiment of formula II, R -be eicosa-pentaenoic acid group or docosahexenoic acid root, and n is 1.In another embodiment of formula II, R -be eicosa-pentaenoic acid group or docosahexenoic acid root, and n is 2.In further embodiment, formula II compound is selected from compound a, b, c, d, e, f, g, h, iwith j.
The reducing hyperglycaemia medicine that can use according to the present invention be the member of dissimilar reducing hyperglycaemia medicine (such as, sulfonylurea, meglitinides, thiazolidinediones, alpha-glucosidase inhibitor, DPP-IV inhibitor, SGLT-2 inhibitor and other), its pharmacy acceptable salt and prodrug, and the pharmacy acceptable salt of described prodrug.
Term " sulfonylurea " refers to the compounds stimulating insulin releasing by being incorporated into sulfonylurea acceptor (a kind of subunit of ICATP channel complex).This combination causes the closedown of this passage, causes the voltage change in β cytolemma also to cause the backflow of Ca2+ ion successively, causes the exocytosis of insulin granule.For the discussion about sulfonylurea, see, such as metabolism, 55, 20 (2006) (incorporated herein by reference in full with it) and the reference wherein quoted, and lancet, 358, 1709 (2001) (incorporated herein by reference in full with it) and the reference wherein quoted.
Term " thiazolidinediones " refers to the compound of a class for the selective agonist of peroxisome proliferators activated receptor γ (PPAR γ) (a kind of transcription factor as ligand activation plays the family member of the nuclear hormone receptor of function).For the commentary about thiazolidinediones, see, such as, trends Endocrin. met., 10,9 (1999) and the reference wherein quoted.
Term " alpha-glucosidase inhibitor " refers to a compounds of the ability at GI stage property competitive suppression brush border enzyme alpha-glucosidase, and it has ability mixture carbohydrate being cracked into sugar.For the commentary about alpha-glucosidase inhibitor, see, such as, Diabetes Res. Clin. Pr., 40, S51 (1998) and the reference wherein quoted.
Term " DPP IV inhibitor " refers to that a class has the compound of the ability of selective inactivation enzyme DPP-IV, with there is rapid inactivation incretin (incretin) hormone (such as, hyperglycemic-glycogenolytic factor-sample peptide-1 (GLP-1) and pancreotropic hormone polypeptide (GIP)) those of ability, it is discharged by intestines all day, and its level increases after a meal.For the commentary about DPP-IV inhibitor, see, such as, expert Opin. Inv. Drug, 12, 87 (2003) and the reference wherein quoted.Especially, DPP-IV inhibitor Xi Gelieting can according to by Kim deng? journal of Medicinal Chemistry, 48,141-151, (2005) and journal of Medicinal Chemistry, 51,589-602, the program described in (2008) preparation.
Term " SGLT-2 inhibitor " refers to that a class has Selective depression kidney sodium glucose co-transporter 2 white 2 and prevents kidney from heavily absorbing glucose from renal glomerulus filtrate and providing the compound of the ability of the Regular Insulin-dependent/non-dependent mode of control of hyperglycemia.For the prediction about SGLT-2 inhibitor, see, such as, journal of Medicinal Chemistry, 52,1,785 1794, (2009) and the reference wherein quoted.
In the enforcement of the compositions and methods of the invention, any sulfonylurea, meglitinide, thiazolidinedione, alpha-glucosidase inhibitor, DPP-1V inhibitor or SGLT-2 inhibitor or its pharmacy acceptable salt or prodrug can be adopted, or the pharmacy acceptable salt of described prodrug, or its any combination.
The sulfonylurea that can use according to the present invention include, but not limited to acetohexamide, and it can as at U.S. Patent number 3, and 013, prepare described in 072; 1-butyl-3-methanilyl urea, it can as at U.S. Patent number 3, and 183, prepare described in 260; Carbutamide, it can as at U.S. Patent number 4, and 324, prepare described in 796; P-607, it can as at U.S. Patent number 4, and 381, prepare described in 304; Glibornuride, it can as at U.S. Patent number 4, and 153, prepare described in 710; Ge Lieqi piperazine, it can as at U.S. Patent number 6, and 733, prepare described in 782; Glipizide, it can as at U.S. Patent number 5, and 545, preparation described in 413 and be used as oral administration; Gliquidone, it can as at U.S. Patent number 4, and 708, preparation described in 868 and using; Glyburide (glyburide) or Glyburide (glibenclamide), it can as at U.S. Patent number 6, and 830, preparation described in 760 and using; Glybuthiazole, it can as at U.S. Patent number 7, and 144, prepare described in 900; Glybuzole, it can as at U.S. Patent number 7, and 084, preparation described in 123 and using; Glyhexamide, it can as preparation and use thereof described in U.S. Patent number 5859037; Glimepiride, it can as at U.S. Patent number 4, and 379, preparation described in 785 and using; Glycodiazine, it can as at U.S. Patent number 4, and 007, preparation described in 201 and using; Tolazamide, it can as at U.S. Patent number 3, and 583, prepare described in 979; Tolbutamide, it can as at U.S. Patent number 4, and 639, prepare described in 436.These patents are incorporated herein by reference.
" U-721017E " refers to U-721017E as the term is employed herein, comprises its enantiomorph, its mixture and racemic modification thereof, or its pharmacy acceptable salt such as hydrochloride.
The DPP-IV inhibitor that can use according to the present invention comprises, but be not limited to, Li Gelieting, Xi Gelieting, Vildagliptin, Egelieting, BMS-477118, Ge Lieting, carmegliptin, melogliptin and dutogliptin, or the pharmacy acceptable salt of one of aforementioned DPP IV inhibitor, or its prodrug.
" Li Gelieting " refers to Li Gelieting and pharmacy acceptable salt thereof as the term is employed herein, comprises its hydrate and solvate, and crystallized form.Crystallized form is described in WO 2007/128721.Method for the preparation of Li Gelieting is described in such as patent application WO 2004/018468 and WO 2006/048427.In Li Gelieting and structure, comparable DPP IV inhibitor is distinguished, because it is when being used for combine with SGLT2 inhibitor and the third antidiabetic medicine according to the present invention, combines special effect and distribute with the long-acting of good pharmacological property, receptor-selective and favourable side effect or produce unexpected treatment advantage or improvement.
Term " Xi Gelieting " refers to Xi Gelieting (or MK-0431) and pharmacy acceptable salt thereof as used herein, comprises its hydrate and solvate, and crystallized form.In one embodiment, Xi Gelieting is with its dihydrogen phosphate, and namely the form of phosphoric acid Xi Gelieting exists.In further embodiment, phosphoric acid Xi Gelieting exists with the form of crystal anhydrous compound or monohydrate.A type in this embodiment refers to phosphoric acid Xi Gelieting monohydrate.Xi Gelieting free alkali and pharmacy acceptable salt thereof are disclosed in U.S. Patent number 6,699,871 and WO 03/004498 embodiment 7 in.Crystalline Xi Gelieting monohydrate is disclosed in WO 2005/003135 and WO 2007/050485.In order to understand in detail such as about preparation or the method preparing this compound or its salt, therefore reference can be carried out to these files.About Xi Gelieting tablet formulation can trade(brand)name Januvia through commercially available acquisition.
" Vildagliptin " refers to Vildagliptin (or LAF-237) and pharmacy acceptable salt thereof as the term is employed herein, comprises its hydrate and solvate, and crystallized form.The specific salt of Vildagliptin is disclosed in WO 2007/019255.Crystalline form and the Vildagliptin tablet formulation of Vildagliptin are disclosed in WO 2006/078593.Vildagliptin can as prepared at WO 00/34241 or described in WO 2005/067976.A kind of Vildagliptin preparation of release of improvement is described in WO 2006/135723.In order to understand such as about preparation or the method preparing this compound or its salt in detail, therefore can to these files and U.S. Patent number 6,166,063 carries out reference.Expect about Vildagliptin tablet formulation can trade(brand)name GALVUS through commercially available acquisition.
" BMS-477118 " refers to BMS-477118 and pharmacy acceptable salt thereof as the term is employed herein, comprises its hydrate and solvate, and crystallized form.In one embodiment, BMS-477118 using free alkali or HC1 salt (such as a hydrochloride or dihydrochloride, comprising its hydrate), or as disclosed in WO 2004/052850 and WO 2008/131149 form of a benzoate present.In further embodiment, BMS-477118 presents with the form of free alkali.In further embodiment, BMS-477118 with such as disclosed in WO 2004/052850 monohydrate form of free alkali present.The method preparing BMS-477118 is also disclosed in WO 2005/106011 and WO 2005/ 115982.BMS-477118 can as being formulated as tablet described in WO 2005/117841.In order to understand in detail such as about preparation, prepare or use the method for this compound or its salt, therefore can carry out reference to these files and U.S. Patent number 6,395,767 and WO 01/68603.
" Ge Lieting " refers to ground Ge Lieting (or GSK-823093) and pharmacy acceptable salt thereof as the term is employed herein, comprises its hydrate and solvate, and crystallized form.In one embodiment, ground Ge Lieting with such as disclosed in the embodiment 2 of WO 03/002531 its hydrochloride or with such as disclosed in WO 2005/009956 form of its tosylate present.A type nail Phenylsulfonic acid ground Ge Lieting in this embodiment.Anhydrous crystal toluenesulphonic acids ground Ge Lieting is disclosed in WO 2005/009956.For the details of the method about preparing this compound or its salt, thus can with reference to these files and U.S. Patent number 7,132,443.
" Egelieting " refers to Egelieting (or SYR-322) and pharmacy acceptable salt thereof as the term is employed herein, comprises its hydrate and solvate, and crystallized form.In one embodiment, Egelieting separately with such as disclosed in WO 2007/035629 form of its benzoate, its hydrochloride or its tosylate present.One type of this embodiment refers to SYR-322.The polymorphic of SYR-322 is disclosed in WO 2007/035372.The method preparing Egelieting is disclosed in WO 2007/112368 and is particularly disclosed in WO 2007/035629.Egelieting (i.e. its benzoate) can be formulated as tablet and as administration described in WO 2007/033266.In order to understand in detail such as about preparation, the method preparing or use this compound or its salt, therefore reference can be carried out to these files and US 2005/261271, EP 1586571 and WO 2005/095381.
" carmegliptin " refers to carmegliptin and pharmacy acceptable salt thereof as the term is employed herein, comprises its hydrate and solvate, and crystallized form.The method preparing this compound (particularly its dihydrochloride) is also disclosed in WO 2008/031749, WO 2008/031750 and WO 2008/055814.This compound can as being formulated in medicinal compositions described in WO 2007/017423.In order to understand in detail such as about preparation, the method preparing or use this compound or its salt, therefore reference can be carried out to these files and WO 2005/000848.
" melogliptin " refers to melogliptin and pharmacy acceptable salt thereof as the term is employed herein, comprises its hydrate and solvate, and crystallized form.Its preparation method is disclosed in WO 2006/040625 and WO 2008/001195 especially.Salt claimed especially comprises methane sulfonates and to toluene-sulfonate.In order to understand in detail such as about preparation, the method preparing or use this compound or its salt, therefore reference can be carried out to these files.
" dutogliptin " refers to dutogliptin (or PHX-1149, PHX-1149T) and pharmacy acceptable salt thereof as the term is employed herein, comprises its hydrate and solvate, and crystallized form.Its preparation method is disclosed in WO 2005/047297 especially.Pharmacy acceptable salt comprises tartrate.In order to understand in detail such as about preparation, the method preparing or use this compound or its salt, therefore reference can be carried out to these files.
The aforementioned document cited above disclosure separately relating to specific DPP IV inhibitor is attached to herein in full especially with it by reference.
The SGLT-2 inhibitor that can use according to the present invention include, but are not limited to that Da Gelie is clean, Ka Gelie is clean, A Gelie is clean, Rui Gelie is clean and She Gelie is clean.
" Da Gelie is clean " refers to that Da Gelie is clean as the term is employed herein, comprises its hydrate and solvate, and crystallized form.Described compound and synthetic method thereof are such as described in WO 03/099836.Preferred hydrate, solvate and crystallized form are described in such as patent application WO 2008/116179 and WO 2008/ 002824.
" Ka Gelie is clean " refers to that Ka Gelie is clean as the term is employed herein, comprises its hydrate and solvate, and crystallized form have following structure:
Described compound and synthetic method thereof are described in such as WO 2005/012326 and WO 2009/035969.Preferred hydrate, solvate and crystallized form are described in such as patent application WO 2008/069327.
" A Gelie is clean " refers to that A Gelie is clean as the term is employed herein, comprises its hydrate and solvate, and crystallized form.Described compound and synthetic method thereof are described in such as WO 2004/007517.
" Rui Gelie is clean " refers to the prodrug that Rui Gelie is clean and Rui Gelie is clean as the term is employed herein, particularly clean according to carbonic acid Rui Gelie, comprises its hydrate and solvate, and crystallized form.Its synthetic method is described in such as patent application EP 1213296 and EP 1354888.
" She Gelie is clean " refers to the prodrug that She Gelie is clean and She Gelie is clean as the term is employed herein, particularly clean according to carbonic acid She Gelie, comprises its hydrate and solvate, and crystallized form.Its preparation method is described in such as patent application EP 1344780 and EP 1489089.
Therefore, in one embodiment, providing package contains the combination treatment of at least following drug regimen herein:
1) formula I and miglitol; Formula I and Glipizide; Formula I and Glyburide; Formula I and BMS-477118; Formula I and Xi Gelieting; Formula I and Vildagliptin; Formula I and Li Gelieting; Formula I and dutogliptin; Formula I and N1,N1-Dimethylbiguanide; Formula I, N1,N1-Dimethylbiguanide and Xi Gelieting;
2) formula II compound and miglitol; Formula II compound and Glipizide; Formula II compound and Glyburide; Formula II compound and BMS-477118; Formula II compound and Xi Gelieting; Formula II compound and Vildagliptin; Formula II compound and Li Gelieting; Formula II compound and dutogliptin; Formula II compound and N1,N1-Dimethylbiguanide; With formula II compound, N1,N1-Dimethylbiguanide and Xi Gelieting.
In further embodiment, above paragraph 1 and 2 combination treatment can further with formula I and/or II compound combination.
medicinal compositions
Three-salt of the present invention is suitable as the promoting agent of especially effectively treating diabetes, obesity and associated conditions in medicinal compositions.Medicinal compositions in various embodiments has promoting agent of the present invention and other the pharmaceutically acceptable vehicle, carrier, weighting agent, thinner etc. of pharmaceutical effective amount.Being applicable to medicinal compositions transmitting compound of the present invention and preparation method thereof will be apparent to those skilled in the art.Such composition and preparation thereof such as at ' Remington ' s Pharmaceutical Sciences ', can find in the 19th edition (Mack Publishing Company, 1995).
Word " medicinal compositions " comprises and is suitable for giving Mammals, such as, and the preparation of people.When compound of the present invention gives Mammals as medicine, such as during people, they can former state to give or as containing, such as, the medicinal compositions of the activeconstituents of 0.1 to 99.5% (more preferably the 0.5-90%) mixed with pharmaceutically acceptable carrier gives.
Phrase " pharmaceutically acceptable carrier " is art-recognized and comprises the pharmaceutically acceptable raw material, composition or the medium that are suitable for giving Mammals the compounds of this invention.Carrier comprises liquid or solid weighting agent, thinner, vehicle, solvent or packaged material, participates in carrying or transport described medicine from an organ of health or part to another organ of health or part.Each carrier must be " acceptable " in the meaning that other composition with preparation is compatible and harmless to patient.Some examples that can be used as the raw material of pharmaceutically acceptable carrier comprise: sugar, such as lactose, dextrose plus saccharose; Starch, such as W-Gum and yam starch; Mierocrystalline cellulose, and derivative, such as Xylo-Mucine, ethyl cellulose and cellulose acetate; Powdered tragacanth; Fructus Hordei Germinatus; Gelatin; Talcum powder; Vehicle, such as cocoa ester and suppository wax; Oil, such as peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; Glycols, such as propylene glycol; Polyvalent alcohol, such as glycerine, sorbyl alcohol, N.F,USP MANNITOL and polyoxyethylene glycol; Ester, such as ethyl oleate and Laurate ethyl; Agar; Buffer reagent, such as magnesium hydroxide and aluminium hydroxide; Alginic acid; Without heat source water; Isotonic saline solution; Ringer's solution; Ethanol; Phosphate buffer soln; With other non-toxicity compatible substances used in pharmaceutical preparation.
Wetting agent, emulsifying agent and lubricant, such as sodium lauryl sulphate and Magnesium Stearate, and tinting material, releasing agent, Drug coating, sweeting agent, correctives and sweetener, sanitas and antioxidant also can be present in composition.
The example of pharmaceutically acceptable antioxidant comprises: water soluble antioxidant, such as xitix, cysteine hydrochloride, sodium pyrosulfate, sodium metabisulfite, S-WAT etc.; Oil-soluble inhibitor, such as Quicifal, fourth hydroxyl return ether (BHA), Butylated Hydroxytoluene (BHT), Yelkin TTS, Tenox PG, alpha-tocopherol etc.; And metal chelator, such as citric acid, ethylenediamine tetraacetic acid (EDTA) (EDTA), sorbyl alcohol, tartrate, phosphoric acid etc.
Preparation of the present invention comprise be applicable to oral, nose, locally, under cheek, sublingual, rectum, vagina and/or parenteral admin those.Described preparation can exist with unit dosage easily and prepare by any method known of pharmacy field.The amount that can be combined the activeconstituents producing single formulation with support material generally should be the amount of the compound producing curative effect.In general, according to one of percentage hundred, this weight range by the activeconstituents from about 1%-about 99%, preferably from about 5%-about 70%, most preferably from about 10%-about 30%.
The method preparing these preparations or composition comprises the step that compound of the present invention is mixed with carrier and one or more optional ancillary component.In general, preparation passes through compound of the present invention and liquid vehicle, or finely divided solid carrier, or the two mixes equably and closely, then if necessary makes product shaping to prepare.
Be applicable to the oral preparation of the present invention given and can be rendered as capsule, cachet (cachets), pill, tablet, dragee (uses flavoured base, be generally sucrose and gum arabic or tragacanth gum), powder, granule or as the solution in water-based or non-waterborne liquid or suspensoid, or as oil-in-water or water-in-oil liquid emulsion, or as elixir or syrup, or (use inert base as lozenge, such as gelatin and glycerine, or sucrose and gum arabic) and/or as forms such as collutorys, the compounds of this invention as activeconstituents of each self-contained predetermined amount.Compound of the present invention also can be used as bolus (bolus), electuary (electuary) or paste and gives.
For in the solid dosage of the present invention (capsule, tablet, pill, drageeing, powder, granule etc.) of oral administration, activeconstituents and one or more pharmaceutically acceptable carrier, such as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade, and/or any following material mixing: weighting agent or extender, such as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and/or silicic acid; Tackiness agent, such as, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; Wetting agent, such as glycerine; Disintegrating agent, such as aga agar, calcium carbonate, potato or tapioca (flour), alginic acid, some silicate and sodium carbonate; Solution retarding agents, such as paraffin; Absorption enhancer, such as quaternary ammonium compound; Wetting agent, such as, hexadecanol and monostearin; Absorption agent, such as kaolin and wilkinite; Lubricant, as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and composition thereof; And tinting material.When capsule, tablet and pill, medicinal compositions also can comprise buffer reagent.The solids composition of similar type also can use such vehicle as lactose or toffee, and high molecular weight polyethylene glycol etc., as the filler in soft hard-filled gelatin capsule.
Tablet is by compacting or molded, and optional one or more ancillary component that uses obtains.Compressed tablets can use tackiness agent (such as, gelatin or HYDROXY PROPYL METHYLCELLULOSE), lubricant, inert diluent, sanitas, disintegrating agent (such as, sodium starch glycollate or croscarmellose sodium), tensio-active agent or dispersion agent preparation.Mold pressing tablet is by by with the mold pressing and obtaining in suitable machine of the mixture of the moistening powdered compounds of inert liquid diluent.
Other solid dosage of tablet and medicinal compositions of the present invention, such as drageeing, capsule, pill and granule, optionally by indentation or with dressing and shell, other dressing material preparation that such as enteric coating and pharmaceutical-formulating art are known.They also can be formulated to provide the slow or Co ntrolled release of wherein activeconstituents, such as, use to provide the Vltra tears of the various ratios of required release characteristic, other polymeric matrix, liposome and/or microballoon.They by, such as, to be filtered by bacteria-retaining filter, or by the disinfectant at once mixing the aseptic solid composite form dissolving in sterilized water before use, or some other Sterile injectable medium.These compositions also optionally also can have only at GI certain position containing milkiness agent, or preferentially at GI certain position, optionally, with the composition of the mode release of active ingredients of time delay.The example of spendable embedding composition comprises polymkeric substance and wax.If suitable, the form that activeconstituents also can contain the micro-capsule of one or more above-mentioned vehicle presents.
The oral liquid dosage form giving the compounds of this invention comprises pharmaceutically acceptable emulsion, microemulsion, solution, suspensoid, syrup and elixir.Except activeconstituents, liquid dosage form also can contain the normally used inert diluent in this area, such as, water or other solvent, solubilizing agent and emulsifying agent, such as ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, phenylformic acid benzyl ester, propylene glycol, 1,3-butyleneglycol, oil are (especially, Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), the fatty acid ester of glycerine, tetrahydrofuran (THF) alcohol, polyoxyethylene glycol and anhydro sorbitol, and its mixture.
Except inert diluent, oral compositions also can comprise auxiliary agents as wetting agent, emulsifying agent and suspending agent, sweeting agent, correctives, tinting material, sweetener and sanitas.
The relative quantity of the activeconstituents in medicinal compositions of the present invention, pharmaceutically acceptable carrier and any other composition will depend on the feature of experimenter to be treated, body size and the patient's condition, and also depends on the approach that gives composition and change.By way of example, composition can comprise the activeconstituents between 0.1% and 100% (w/w).
The method preparing the medicinal compositions of the various active compound containing specified quantitative is known, or is apparent to those skilled in the art.Such as, see ' Remington ' s Pharmaceutical Sciences ', Mack Publishing Company, Easter, Pa., the 15th edition (1975).
Medicinal compositions of the present invention can be used as single unitary dose, or as multiple single unitary dose preparation, packaging, or with bulk outlets.As used herein, " unitary dose " is the discrete magnitude of medicinal compositions, and it comprises the activeconstituents of predetermined amount.The amount of activeconstituents is generally equal to the dosage of the activeconstituents by giving experimenter or facilitating partly such as of such dosage, the half of such dosage or 1/3rd.
Dosage
For giving people patient, every TDD of the compounds of this invention typically at 0.25 g-6 g, 0.25 g-4 g, 0.25 g-2 g, or within the scope of 0.25 g-1 g, this depends on administering mode certainly.In one embodiment, in another embodiment, every TDD is within the scope of 1 g-6 g within the scope of 1 g-10 g for every TDD.Every TDD can single dose or divided dose give.
These dosage are based on the people experimenter with average about 65kg-70kg body weight.Clinicist easily can determine that its body weight falls into the experimenter outside this scope, the dosage of such as baby and the elderly.
The method of the various medicinal compositionss of the active compound of preparation containing specified quantitative is known, or is apparent to those skilled in the art.Such as, see Remington ' s Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., the 15th edition (1975).
Medicinal compositions of the present invention can be used as single unitary dose, or as multiple single unitary dose preparation, packaging, or with bulk outlets.As used herein, " unitary dose " is the discrete magnitude of medicinal compositions, and it comprises the activeconstituents of predetermined amount.The amount of activeconstituents is generally equal to the dosage of the activeconstituents by giving experimenter or facilitating partly such as of such dosage, the half of such dosage or 1/3rd.
Kit
Advantageously, the present invention also provides and to be used for the kit of disease therapy by human consumer.Described kit comprises a) medicinal compositions, and it comprises three-salt of the present invention and pharmaceutically acceptable carrier, medium or thinner; Optionally, b) use medicinal compositions is described to treat the specification sheets of the method for specified disease.
As comprised the container of the bottle such as separated containing unit dosage separately or the Foilpac separated for " kit " of the application.Container can be used as the shape of any routine known in the art or form presents, it can according to treatment plan, by pharmaceutically acceptable material, such as Paper or cardboard box, glass or Plastic Bottle or tank, sealing bag can be repeated (such as, keep the tablet of " recharging " to be placed in different vessels), or obtain for the Blister Package containing each dosage extruding packaging.Container used can be depending on involved accurate formulation, and such as traditional carton generally will not be used for keeping liquid suspension.It is possible that more than one container one can be used from unitary package with sales slip one dosage type low temperature.Such as, tablet can be included in bottle, and bottle is included in case successively.
The example of such kit is so-called Blister Package.Blister Package is that packaging industry is known and is widely used for packaged pharmaceuticals unit dosage (tablet, capsule etc.).Blister Package is made up of the material of a slice relative rigid usually, and it covers with the paper tinsel of preferred transparent plastic material.During package processing, groove is formed in plastic foil.The size and shape that groove has single tablet to be packaged or capsule maybe can have the size and shape holding multiple tablet to be packaged and/or capsule.Secondly, tablet or capsule are correspondingly placed in groove, and plastic foil are close in the front that the sheet material of relative rigid forms the rightabout paper tinsel of groove wherein and seal.As a result, when needed, tablet or capsule are individually sealed or in the groove of integral sealing between plastic foil and sheet.Preferably, opening can be formed, tablet or capsule can be shifted out from Blister Package at the groove of sheet when the intensity of described is and makes to press on groove with hand.Then tablet or capsule can be taken out via described opening.
May need to provide a written memory prompting supplementary unit (written memory aid), wherein written memory prompting supplementary unit has and comprises for clinicist, pharmacist or the information of experimenter and/or the type fount of instructions, such as, with the digital form on tablet or capsule side, thus these numerals correspond to the number of days of dosage regimen, the tablet so indicated or capsule should be ingested or record checks card, the information containing identical typewriting on card.Another example of such memory prompting supplementary unit is the administration schedule printed on card, such as, following " first week, Monday, Tuesday, ".. etc., " second week, Monday, Tuesday.. " etc.Other change of memory prompting supplementary unit will be apparent." per daily dose " can be the single tablet or capsule or several tablet or capsule that will absorb in a given sky.
Another specific embodiments of kit designs the delivery apparatus once distributing a per daily dose.Preferably, delivery apparatus is equipped with memory prompting supplementary unit, to promote the compliance to treatment plan further.The example of such memory prompting supplementary unit is a mechanical counter, and it indicates the quantity of the per daily dose distributed.Another example of such memory prompting supplementary unit is the battery powered microchip memory storage with liquid crystal readout coupling, or voice reminder signal, such as, it reads the last per daily dose taken and/or reminds the date of when taking next dosage.
One embodiment of the invention relate to a kind of kit, and it comprises unitary dose containing compound of the present invention and about how using the specification sheets of kit and at least one is for holding the regulation of the container of unit dosage.
Preparation method
The synthetic technology preparation of any number that three-salt of the present invention can use professional and technical personnel known.
Formula II compound, wherein R -be eicosa-pentaenoic acid group and n being 1, by the N1,N1-Dimethylbiguanide free alkali of the aspartic acid and two equivalents that make an equivalent, is then prepared by the EPA reaction of an equivalent.Solvent for carrying out reacting can be alcoholic solvent, such as ethanol, methyl alcohol, propyl alcohol and Virahol; Ketone solvent, such as acetone, ethyl methyl ketone and Methyl isobutyl ketone; Acetonitrile.Reaction can carried out to the temperature between the reflux temperature of solvent for use from 0 DEG C.As passed through analytical technology, such as high pressure liquid chromatography monitoring, determine the reaction times by completing of reaction.
Formula II compound, wherein R -be eicosa-pentaenoic acid group and n be 2, can prepare according to said procedure, except aspartic acid is substituted by L-glutamic acid.
Formula II compound, wherein R -be docosahexenoic acid root and n be 1, by the N1,N1-Dimethylbiguanide free alkali of the aspartic acid and two equivalents that make an equivalent, react to prepare with the DHA of an equivalent subsequently.Solvent for carrying out reacting can be alcoholic solvent, such as ethanol, methyl alcohol, propyl alcohol and Virahol; Ketone solvent, such as acetone, ethyl methyl ketone and Methyl isobutyl ketone; Acetonitrile.Reaction can carried out to the temperature between the reflux temperature of solvent for use from 0 DEG C.As passed through analytical technology, such as high pressure liquid chromatography monitoring, determine the reaction times by completing of reaction.
Formula II compound, wherein R -be docosahexenoic acid root and n be 2, can prepare according to said procedure, except aspartic acid is substituted by L-glutamic acid.
Example
Animal model
Following examples describe diabetic rat model, and it can be used to the patient's condition determining the treatment after causing the heart and cardiac tissue ischemia damage and prevention method.
Spontaneous Diabetic Bio-Bred (BB/W) rat is considered to autoimmunity insulin human-dependent diabetes mellitus DM) the useful model of of .vLike people IDDM, Spontaneous Diabetic appears at pubescence, with the unexpected clinical onset being characterized as weight saving, hyperglycemia, hypoinsulinemia and Ketonuria.As when people's diabetes, the pathological change in retina, cardiac muscle, liver, kidney, bone metabolism and peripheral nerve all obtains sufficient proof in BioBreeding rat, as diab. Metab. Rev., described in 8:9 (1992).
The perfusion heart model be separated
This embodiment describes a kind of perfusion rat heart model for developing separation of the present invention.The rat heart prepared product of the separation that use etc. are held is studied.The male BB/W rat of acute diabetes and non-diabetic age-(3 to 4 monthly age) control group heparin (1000 u of coupling; IP) pre-treatment, then uses vetanarcol (65 mg/kg; IP) process.After reaching deep anaesthesia by foot reflection shortage is determined, cut off heart fast and be placed in icy salt solution.The heart stagnated after it cuts off in 2 minutes, one by aortal non-recirculated model in poured into by inverse.The rubber balloon be used in the left ventricle with the high pressure pipe being connected to pressure transmitter measures the pressure (LVDP) that left ventricle produces.Injection pressure uses the high pressure pipe monitoring departing from loading line.Haemodynamics is measured at the upper record of 4 passage Gu Erde registering instruments (Gould recorder).System has two parallel loading line with independent oxygenator, pump and foaming trap, but ordinary temp controls to allow fast-changing perfusion medium.A heart accurate roller pump perfusion.Perfusion liquid is by 118 mM NaC1 .47 mM KC1,12 mM CaC1 2, 12 mM MgCl 2, 25 mM NaHCO 3form with substrate 11 mM glucose.Device for casting is rigid temperature-control, has the hot water bath for perfusion liquid and the water jacket around loading line, to maintain Heart temperature in all cases in 37 ± 0.5 DEG C.Make oxygenation perfusion liquid in room temperature reservoir by 37 DEG C with 95% oxygen-saturated distilled water around 25 ft. thin-walled silicone tubes.Then make perfusion liquid enter water-chuck (37 DEG C) pipeline, described pipeline leads to heart by the foaming trap of water jacket.This preparation provides the excellent oxygenation of usually stablizing 3 to 4 hours.
For the model of zero/low ischemic
This embodiment describes and is used for diabetic controls, treating diabetes, non-diabetic treatment and the program studying zero flow ischemic in the contrast heart be separated.Diabetic controls (DC), treating diabetes (DZ), normal (C) contrast and normal therapeutic (CZ) heart stand normal oxygen perfusion in 20 minutes, then 20 minutes zero flow ischemics are stood, wherein perfusion liquid flow is fully closed, and is then the Reperfu-sion of 60 minutes.Heart 10 μMs of N1,N1-Dimethylbiguanide timnodonic acid Ficus caricaL.In the diabetic groups (DZ) of N1,N1-Dimethylbiguanide timnodonic acid salts for treating, heart stands the normal oxygen perfusion of the use normal Krebs-Henseleit damping fluid of 10 minutes and the use of 10 minutes and pours into containing the normal oxygen of the Krebs-Henseleit damping fluid of 10 μMs of N1,N1-Dimethylbiguanide eicosa-pentaenoic hydrochlorates.Then the zero flow ischemic making the heart channel of Hang-Shaoyin be subject to 20 minutes, then stands the Reperfu-sion of 60 minutes.In order to avoid any change of the Reperfu-sion patient's condition, with normal Krebs-Henseleit damping fluid to both DC and DZ hearts Reperfu-sion.
For the model of low flow ischemic
This embodiment describes treats for diabetic controls, treating diabetes, non-diabetic the program studying low flow ischemic in the contrast heart be separated with non-diabetic.The flow velocity that diabetic controls heart (DC) stands 20 minutes is the normal oxygen perfusion of 12.5 mL/ minutes, then the low flow ischemic of 30 minutes is stood, wherein perfusion liquid flow is slowed down to 1.25 mL/min, namely being the normal perfusion of about 10%, is then the Reperfu-sion of the normal flow (12.5 mL/min) of 30 minutes.N1,N1-Dimethylbiguanide timnodonic acid salts for treating diabetes or in non-diabetic group (DZ or CZ), heart stands normal oxygen perfusion (flow velocity 12.5 mL/min) of the use normal Krebs-Henseleit damping fluid of 10 minutes and the use of 10 minutes and pours into containing the normal oxygen of the Krebs-Henseleit damping fluid of 10 μMs of N1,N1-Dimethylbiguanide eicosa-pentaenoic hydrochlorates.The low flow ischemic (flow velocity 1.25 mL/min) that the heart channel of Hang-Shaoyin is subject to 30 minutes and 30 minutes normal flow (12.5 mL/min) Reperfu-sion.
Determine that the animal model of compound of the present invention to the effect of diabetes and diabetic complication is by Tirabassi deng, iLAR Journal, 2004,45,292-302 comments.Anti-diabetic activity also can be tested according to the scheme described in following patent: U.S. Patent number 4,340,605; 4,342,771; 4,367,234; 4,617,312; 4,687,777 and 4,703,052.The other reference relevant with the application comprises following: number of patent application 20030220301 disclosed in French Patent 2796551 and the U.S..
Embodiment 1
two [[R dimethylamino) (imino-) methyl] amino (imino-) methane amine (methanaminium)] (2S)-2-amine (amininium) (5Z, 8Z, 11Z, 14Z, 17Z)-two ten carbon-5,8,11, the preparation of 14,17-pentaene acid-pentane diacid salt (Met2-Glu-EPA)
Step 1- two [{ [dimethylamino) (imino-) methyl] is amino } (imino-) methane amine] preparation of (2S)-2-aminopentane diacid salt
In room temperature (RT), N 2under, by N, methyl alcohol (40 mL) solution of N-dimethylimino diformazan imido acid diamide (1.00 g, 7.74 mmol) methyl alcohol (40 mL) solution-treated of Pidolidone (0.570 g, 3.87 mmol).Mixture is stirred 1/2 hour under RT.Evaporation of methanol also uses CH 3cN grinds remaining oil, obtains white solid.Drying solid 3 hours under RT, high vacuum (hi-vac), then under RT at CH 3stir 2 hours in CN (50 ml).By solid collected by filtration and RT, high vacuum dry 1 hour, two [{ [(dimethylamino) (imino-) methyl] is amino }-(imino-) methane amine] (2S)-2-aminopentane diacid salt that to obtain 1.3g (90% yield) be white solid. 1h NMR (300 MHz, MeOD) δ 1.88 (m, 1 H) 2.06 (m, 2 H) 2.30 (m, 2 H) 3.05 (s, 12 H) 4.91 (s, 14 H); To C 5h 9nO 4 m/zmS (ESI-) be 146 (M-H) -.To C 4h 11n 5 m/zmS (ESI+) be 130 (M+H) +.To C 13h 31n 11o 4add 0.75% H 2the analytical calculation value of O: C, 38.22; H, 7.73; N, 37.71.Measured value: C, 38.57; H, 7.65; N, 36.73.
Step 2- two [{ [(dimethylamino) (imino-) methyl] is amino } (imino-) methane amine] (2S)-2-amine (5Z, 8Z, 11Z, 14Z, 17Z)-two ten carbon-5,8,11, the preparation of 14,17-pentaene acid-pentane diacid salt (Met2-Glu-EPA)
In RT, N 2under, will methyl alcohol (180 mL) solution and (5Z, the 8Z of two [{ [(dimethylamino) (imino-) methyl] amino (imino-) methane amine] (2S)-2-aminopentane diacid salt (4.28 g, 15.5 mmol), 11Z, 14Z, 17Z)-two ten carbon-5,8,11,14,17-pentaene acid (5.15 g, 17.0 mmol) is stirred 1 hour together in amber flask.Evaporation of methanol with ice-cold CH 3cN (50 ml) grinds remaining oil, forms solid.By in dark place solid collected by filtration and under RT, high vacuum, dry in dark place.=l0g (91% yield) two [{ [(dimethylamino) (imino-) methyl] is amino } (imino-) methane amine] (2S)-2-amine (5Z must be measured, 8Z, 11Z, 14Z, 17Z)-two ten carbon-5,8,11,14,17-pentaene acid-pentane diacid salt is brown solid. 1h NMR (300 MHz, Me0D) δ 0.92 (t, 3 H) 1.67 (m, 2 H) 2.10 (m, 8 H) 2.47 (m, 2 H) 2.86 (m, 8 H) 3.05 (s, 12 H) 3.57 (m, 1 H) 4.88 (m, 15 H) 5.37 (m, 10 H); For C 20h 30o 2the MS (ESI-) of m/z is 301 (M -); For C 33h 61n 110 6add 1.26% H 2the analytical calculation value of O: C, 55.28; H, 8.72; N, 21.49.Measured value: C, 55.24; H, 8.71; N, 20.81.-130 DEG C, MP=127 (softening in 100 DEG C).
Embodiment 2
two [{ [(dimethylamino) (imino-) methyl] is amino } (imino-) methane amine] (2S)-2-amine (5Z, 8Z, 11Z, 14Z, 17Z)-two ten carbon-5,8,11,14,17-pentaene acid-pentane diacid salt (Met2-Glu-EPA)-stoichiometric combination method
At N 2under, by (5Z, 8Z, 11Z, 14Z, 17Z)-two ten carbon-5,8,11,14,17-pentaene acid (6.79 g, 22.4 mmol) join Pidolidone (3.30 g, 22.4 mmol) and N, N-dimethylimino diformazan imido acid diamide (5.80 g, 44.9 mmol) (from the EtOAc recrystallize) mixture in 400 ml methyl alcohol in.Mixture is stirred 1/2 hour under RT, is formed and precipitate on a small quantity.Evaporation of methanol also makes the even oil obtained be dissolved in CH 3cN (300 ml), forms solid and evaporates CH 3cN.In 40 DEG C, under high vacuum through P 2o 5drying solid spends the night, obtain 13.52g (85% yield) two [{ [(dimethylamino) (imino-) methyl] is amino } (imino-) methane amine] (2S)-2-amine (5Z, 8Z, 11Z, 14Z, 17Z)-two ten carbon-5,8,11,14,17-pentaene acid-pentane diacid salt is brown solid. 1h NMR (300 MHz, Me0D) δ 0.92 (t, 3 H) 1.67 (m, 2 H) 2.10 (m, 8 H) 2.47 (m, 2 H) 2.86 (m, 8 H) 3.05 (s, 12 H) 3.57 (m, 1 H) 4.88 (m, 15 H) 5.37 (m, 10 H); For C 20h 30o 2 m/zmS (ESI-) be 301 (M -).For C 13h 31n 11o 4add 0.87% H 2the analytical calculation value of O: C, 55.40; H, 8.69; N, 21.79.Measured value: C, 55.30; H, 8.50; N, 21.65.
Embodiment 3
two [{ [(dimethylamino) (imino-) methyl] is amino } (imino-) methane amine]-(5Z, 8Z, 11Z, 14Z, 17Z)-two ten carbon-5,8,11,14,17-pentaene acid-(3S)-3-ammonium-3-carboxyl propionic salt (Met2-Asp-EPA)
By L-Aspartic acid (2.90 g, 21.8 mmol), (5Z, 8Z, 11Z, 14Z, 17Z)-two ten carbon-5,8,11,14,17-pentaene acid (6.60 g, 21.8 mmol) and N, the mixture of N-dimethylimino diformazan imido acid diamide (5.64 g, 43.7 mmol) in methyl alcohol (300 mL) in 60 DEG C of oil baths warm 30 minutes.Solid is all dissolved.Stir after another hour in 60 DEG C, make mixture be cooled to RT, vacuum-evaporation dried overnight under being placed in high vacuum, obtain brown solid, 14.93g (99%). 1h NMR (300 MHz, MeOD) δ ppm 0.97 (t, J=7.54 Hz, 3 H) 1.53-1.78 (m, 2 H) 1.96-2.28 (m, 6 H) 2.57 (dd, j=17.23,10.15 Hz, 1 H) 2.73-2.92 (m, 9 H) 3.04 (s, 12 H) 3.73 (dd, j=10.15,3.54 Hz, 1 H) 4.89 (br. s., 15 H) 5.18-5.51 (m, 10 H). for C 4h 7nO 4 m/zmS (ESI-) be 132 (M-H) -.For C 20h 30o 2the MS (ESI-) of m/z is 301 (M-H) -.For C 4h 11n 5 m/zmS (ESI+) be 130 (M+H) +.C 32h 59n 11o 6analytical calculation value: C, 55.39; H, 8.57; N, 22.20.Measured value: C, 55.03; H, 8.81; N, 21.76.
Embodiment 4
the pharmacokinetics in rats of two-N1,N1-Dimethylbiguanide glutaminate eicosa-pentaenoic hydrochlorate
For the oral pharmacokinetic parameter of single dose of two-N1,N1-Dimethylbiguanide glutaminate eicosa-pentaenoic hydrochlorate (by described program preparation in embodiment 1), measure in Sprague-Dawley rat.Per os raises by force two-N1,N1-Dimethylbiguanide glutaminate eicosa-pentaenoic hydrochlorate to 6 rat given as the aqueous solution in 0.5% carboxymethyl cellulose, 3 male and 3 female.Rat is given with 52 mg/kg.Blood sample is obtained by jugular vein conduit from every rat.0.25,0.5,1,2,4,8,12 and 24 hr collections blood samples after administration.By centrifugal for blood sample with separating red blood cells and to the Plasma sample analysis timnodonic acid obtained.Pharmacokinetic parameter as calculated is in the following table 1 the average deriving from 6 rats.
table 1
For the Oral Administration in Rats pharmacokinetic parameter of two-N1,N1-Dimethylbiguanide glutaminate eicosa-pentaenoic hydrochlorate
Analyte EPA N1,N1-Dimethylbiguanide
C max (μg/mL) 14.97 2.07
T max (h) 0.5 1.0
AUC (0-24) (μg*h/mL) 228.67 8.49
Combination treatment: pharmacological examples
The treatment of diabetes B
Suffer from the patient of diabetes B with medicinal compositions treatment according to the present invention, except producing the acute improvement of glucose metabolism situation, also prevent the deterioration of long-term metabolic situation.This with in medicinal compositions long-term treatment according to the present invention (as 3 months to 1 year or even 1 to 6 year) patient, and can observe when comparing with the patient treated with other antidiabetic medicine.Evidence suggests, if do not observe the increase of fasting glucose and/or HbAlc value or only observe slight increase, then with after the patient treated with other antidiabetic medicine treat successfully.Evidence suggests, if compared with the patient treated with other antiradiation drug, the patient experience glucose metabolism site of significantly less per-cent for the treatment of with medicinal compositions according to the present invention deteriorate to certain a bit (such as HbAlc value is increased to >6.5% or >7%), wherein this site is effective with other oral antidiabetic thing or with Regular Insulin or with insulin analog treatment, then obtain and treat successfully.
The treatment of insulin resistant
In the clinical study carrying out different duration (as 2 thoughtful December), the positive sugared clamp research of successful use hyperinsulinemia for the treatment of is verified.Glucose infusion rate at the end of research, compares with initial value or compares with placebo, or compares with the group giving Different therapy and have remarkable rising, identity basis medicinal compositions of the present invention effect in treatment insulin resistant.
The treatment of hyperglycemia
In the clinical study carrying out different duration (as 1 day to 24 months), treatment suffer from hyperglycemic subject successfully pass measure fasting glucose or non-fasting glucose (as after the meal oGTT or limit meals loading test after) verify.During this research or at the end of these dextrose equivalent values, compare with initial value or compare with placebo, or comparing with the group giving Different therapy and be decreased significantly, identity basis medicinal compositions of the present invention effect in treatment hyperglycemia.
The treatment of metabolism syndrome
Can with the clinical study of different carrying out time (as 12 thoughtful 6 years) according to effect of medicinal compositions of the present invention, by measure fasting glucose or non-fasting glucose (as after the meal oGTT or limit meals loading test after) or HbAlc value test.During this research or at the end of these dextrose equivalent values or HbAlc value, compare with initial value or compare with placebo, or to compare with the group giving Different therapy and be decreased significantly, prove effect be combined in treatment metabolism syndrome of activeconstituents or activeconstituents.Such example is that initial value when starting with research compares or compares with patient's group that placebo or Different therapy treats, and systolic pressure and/or diastolic pressure reduce, and plasma triglyceride reduces, total or LDL-C reduction, HDL cholesterol increase or lose weight.
Micro--or the prevention of macrovascular complications
Prevent with medicinal compositions treatment diabetes B according to the present invention or pre-diabetic or alleviate microvascular complication (as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic pedopathy, diabetic ulcer) or macrovascular complications (as myocardial infarction, acute coronary disease syndrome, unstable stenocardia, stable stenocardia, apoplexy, Peripheral arterial occlusive disease, myocardosis, in heart failure, cardiac dysrhythmia, vascular restenosis) or reduce the above-mentioned syndromic risk of development.Diabetes B or suffer from the patient of pre-diabetes symptom with medicinal compositions according to the present invention or the combination long-term treatment such as 1-6 according to activeconstituents of the present invention, and compare with other antidiabetic medicine or with the patient of placebo treatment.Can find in the single or multiple complication of fewer number of with other antidiabetic medicine or with the successful evidence for the treatment of that the patient of placebo treatment compares.In the case of great vessels event, diabetic pedopathy and/or diabetic ulcer, by patient history and various test method counting.In the case of diabetic retinopathy, the background illumination successfully passing the eyes of computer-control for the treatment of and evaluation or other ophtamological method are determined.In the case of diabetic neuropathy, except patient history and clinical examination, nerve conduction velocity can also use such as calibrates tuning fork (tuning fork) mensuration.About diabetic nephropathy, following parameter can before the study starts, period and at the end of test: albumin secretion, CrCl, serum creatinine value, serum creatinine value double required time until dialyse necessitates the required time.
example of formulations: combination treatment
The embodiment of following preparation, it can obtain through being similar to methods known in the art, for illustrating the present invention more fully, but does not limit it in the content of these embodiments.Term " activeconstituents " represents that two kinds according to compound of the present invention, namely refer to that term " activeconstituents " represents that two kinds according to compound of the present invention, i.e. expression I or II compound, or its mixture (first component of activeconstituents) and other antidiabetic medicine such as statins, cholesterol absorption inhibitor and CETP inhibitor or its pharmacy acceptable salt or prodrug, or the pharmacy acceptable salt of described prodrug (second component of activeconstituents).Suitable preparation in addition can according to such as applying for WO 2007/128724, and the program preparation described in U.S. Patent application 2010/032011, and its disclosure is attached to herein in full with it.Other appropriate formulation for sulfonylurea, DPP IV inhibitor can be can through those preparations of commercially available acquisition, or the preparation described in patent application to quote at above paragraph " background of invention ", or at document, such as be disclosed in " Rote Liste S " (Germany) or " Physician's Desk Reference " nearest publication in describe those.
Embodiment 1
Containing 1000 mg activeconstituents tablets
Preparation:
(1), (2) and (3) are mixed and use the aqueous solution of (4) to granulate.(5) are joined in dry raw material.By this mixture compressed tablets, described tablet is biplanar, and respectively there is a facet both sides, and there is the breach of division every side.
Tablet diameters: 9 mm.
Embodiment 2
Containing the tablet of 1050 mg activeconstituentss
Composition
Preparation:
(1), (2) and (3) are mixed and use the aqueous solution of (4) to granulate.(5) are joined in dry granulation raw material.By this mixture compressed tablets, described tablet is biplanar, and respectively there is a facet both sides, and there is the breach of division every side.
Tablet diameters: 9 mm.
Embodiment 3
Containing the tablet of 1100 mg activeconstituentss
Preparation:
(1), (2) and (3) are mixed and use the aqueous solution of (4) to granulate.(5) are joined in dry granulation raw material.By this mixture compressed tablets, described tablet is biplanar, and respectively there is a facet both sides, and there is the breach of division every side.
Tablet diameters: 9 mm.
Embodiment 4
Containing the capsule of the activeconstituents of 1050 mg
Preparation:
With (3) grinding (1).With under vigorous stirring, this trituration is joined in the mixture of (2) and (4).With capsule filler, this powder mixture is loaded in the hard gelatin capsule of No. 3 sizes.
Embodiment 5
Containing the capsule of the activeconstituents of 1100 mg
Preparation:
With (3) grinding (1).With under vigorous stirring, this trituration is joined in the mixture of (2) and (4).With capsule filler, this powder mixture is loaded in the hard gelatin capsule of No. 3 sizes.

Claims (26)

1. the compound of formula II or its pharmaceutically acceptable solvate or hydrate,
(II)
Wherein R -be polyunsaturated fatty acid, and n is 1-10.
2. the compound of claim 1, wherein n is 1 or 2.
3. the compound of claim 1, wherein n is 3,4 or 5.
4. the compound of claim 1, wherein R -eicosa-pentaenoic acid group or docosahexenoic acid root.
5. the compound of claim 1, wherein R -be eicosa-pentaenoic acid group or docosahexenoic acid root, and n is 1.
6. the compound of claim 1, wherein R -be eicosa-pentaenoic acid group or docosahexenoic acid root, and n is 2.
7. the compound of formula I:
(I)
Wherein G is alkyl, cycloalkyl, assorted alkyl, heterocyclic radical, aryl or heteroaryl; And R -it is polyunsaturated fatty acid.
8. the compound of claim 7, wherein R -eicosa-pentaenoic acid group or docosahexenoic acid root.
9. the compound of claim 7, wherein G is alkyl.
10. a medicinal compositions, it comprises compound and pharmaceutically acceptable carrier, medium or the thinner of any one of foundation the claims.
11. 1 kinds of kits, it comprises the unit dosage of the compound of any one a) containing claim 1-9, b) about the specification sheets how using kit; And c) at least one for holding the container of unit dosage.
12. 1 kinds of methods for the treatment of diabetes in experimenter in need, it comprises the compound of any one of the foundation claim 1-9 giving subject's significant quantity.
13. 1 kinds of methods reducing triglyceride level in experimenter in need, it comprises the compound of any one of the foundation claim 1-9 giving subject's significant quantity.
The method of 14. 1 kinds of Cardiovarsculars in experimenter in need, it comprises the compound of any one of the claim 1-9 giving subject's significant quantity.
The method of 15. claims 14, wherein said cardiovascular disorder is irregular pulse, myocardial ischemia, myocardial infarction, myocardosis or apoplexy.
The method of 16. 1 kinds of treatments of obesity in experimenter in need, it comprises the compound of any one of the claim 1-9 giving subject's significant quantity.
17. 1 kinds of methods preparing the compound of any one of claim 1-9, wherein R -be eicosa-pentaenoic acid group and n be 1, the method comprises: free alkali a) being prepared N1,N1-Dimethylbiguanide by melbine salt; And react under b) making the temperature of the timnodonic acid of an aspartic acid equivalent of the free alkali of the N1,N1-Dimethylbiguanide of two equivalents and an equivalent between about 1 DEG C and about 60 DEG C.
18. 1 kinds of methods preparing the compound of any one of claim 1-9, wherein R -be eicosa-pentaenoic acid group and n be 2, the method comprises: free alkali a) being prepared N1,N1-Dimethylbiguanide by melbine salt; And react under b) making the temperature of the timnodonic acid of a L-glutamic acid equivalent of the free alkali of the N1,N1-Dimethylbiguanide of two equivalents and an equivalent between about 1 DEG C and about 60 DEG C.
19. 1 kinds of methods preparing the compound of any one of claim 1-9, wherein R -be docosahexenoic acid root and n be 1, the method comprises: free alkali a) being prepared N1,N1-Dimethylbiguanide by melbine salt; And react under b) making the temperature of the timnodonic acid of an aspartic acid equivalent of the free alkali of the N1,N1-Dimethylbiguanide of two equivalents and an equivalent between about 1 DEG C and about 60 DEG C.
20. 1 kinds of methods preparing the compound of any one of claim 1-9, wherein R -be docosahexenoic acid root and n be 2, the method comprises: free alkali a) being prepared N1,N1-Dimethylbiguanide by melbine salt; And react under b) making the temperature of the timnodonic acid of a L-glutamic acid equivalent of the free alkali of the N1,N1-Dimethylbiguanide of two equivalents and an equivalent between about 1 DEG C and about 60 DEG C.
The method of any one of 21. claim 12-16, it also comprises and gives N1,N1-Dimethylbiguanide (free alkali), or the salt form of N1,N1-Dimethylbiguanide.
The method of 22. claims 21, wherein the salt form of N1,N1-Dimethylbiguanide is N1,N1-Dimethylbiguanide docosahexenoic acid salt, N1,N1-Dimethylbiguanide eicosa-pentaenoic hydrochlorate, Metformin, N1,N1-Dimethylbiguanide succinate or metformin fumarate.
The method of any one of 23. claim 12-16, wherein experimenter is Mammals.
The method of any one of 24. claim 12-16, wherein experimenter is people.
25. 1 kinds of medicinal compositionss, it comprises compound and the antihyperlipidemics of any one of claim 1-9, and pharmaceutically acceptable carrier.
26. 1 kinds of medicinal compositionss, it comprises compound and the reducing hyperglycaemia medicine of any one of claim 1-9, and pharmaceutically acceptable carrier.
CN201380046842.4A 2012-07-10 2013-07-10 Tri-salt form of metformin Pending CN104684889A (en)

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US13/841,970 US8765811B2 (en) 2012-07-10 2013-03-15 Tri-salt form of metformin
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