WO2005063785A2 - Composes aromatiques a substitution glucopyranosyloxy, medicaments contenant ces composes, leur utilisation et procede pour leur production - Google Patents

Composes aromatiques a substitution glucopyranosyloxy, medicaments contenant ces composes, leur utilisation et procede pour leur production Download PDF

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WO2005063785A2
WO2005063785A2 PCT/EP2004/014319 EP2004014319W WO2005063785A2 WO 2005063785 A2 WO2005063785 A2 WO 2005063785A2 EP 2004014319 W EP2004014319 W EP 2004014319W WO 2005063785 A2 WO2005063785 A2 WO 2005063785A2
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alkyl
yloxy
hydrogen
group
general formula
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PCT/EP2004/014319
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WO2005063785A3 (fr
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Frank Himmelsbach
Peter Eickelmann
Edward Leon Barsoumian
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Boehringer Ingelheim International Gmbh
Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Priority to EP04803932A priority Critical patent/EP1699807A2/fr
Priority to JP2006546000A priority patent/JP2007515441A/ja
Priority to CA002548353A priority patent/CA2548353A1/fr
Publication of WO2005063785A2 publication Critical patent/WO2005063785A2/fr
Publication of WO2005063785A3 publication Critical patent/WO2005063785A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to aromatics of the general formula I substituted with glucopyranosyloxy
  • radicals R 1 to R 6 and R 7a , R 7b and R 7c are defined below, including their tautomers, their stereoisomers, their mixtures and their salts.
  • Another object of this invention relates to medicaments containing a compound of formula I according to the invention and the use of a compound according to the invention for the manufacture of a medicament for the treatment of metabolic diseases.
  • methods for producing a medicament and a compound according to the invention are the subject of this invention.
  • the present invention is based on the object of demonstrating new glucopyranosyloxy-substituted aromatics, in particular those which have an activity with respect to the sodium-dependent glucose cotransporter SGLT, in particular SGLT2.
  • a further object of the present invention is to demonstrate glucopyranosyloxy-substituted aromatics which have an increased inhibitory effect on sodium-dependent glucose cotransporters SGLT2 in vitro and / or in vivo compared to known, structurally similar compounds and / or have improved pharmacological or pharmacokinetic properties.
  • Another object of this invention is to provide a process for the preparation of the compounds according to the invention.
  • a first object of the present invention are glucopyranosyloxy-substituted aromatics of the general formula I.
  • R 1 is C 2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C ⁇ - 3 -alkyloxy or tetrahydropyranyl-C ⁇ - 3 -alkyloxy, or if R 3 is selected is from the group consisting of C 2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl -CC.
  • R 1 can also hydrogen, fluorine, chlorine, bromine, iodine, C- ⁇ - 4 alkyl, a methyl group substituted by 1 to 3 fluorine atoms, one by 1 to 5 Fluorine atoms substituted ethyl group, C ⁇ - alkoxy, a methoxy group substituted by 1 to 3 fluorine atoms, an ethoxy group substituted by 1 to 5 fluorine atoms, a C ⁇ -4 alkyl group substituted by a hydroxy or C ⁇ - 3 alkoxy group, one by one hydroxy or C 1 -3 alkoxy substituted C 2 alkoxy, C 2 - 6 alkenyl, C.
  • R 2 is hydrogen, fluorine, chlorine, methyl, methyl or methoxy substituted by 1 to 3 fluorine atoms
  • R 3 C 2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C ⁇ - 3 -alkyloxy or tetrahydropyranyl-C ⁇ _ 3 -alkyloxy, or if R 1 is selected from the group consisting of C 2 .
  • R 3 may additionally be hydrogen, fluorine, chlorine, bromine, iodine, C ⁇ -6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C. 3 6- Cycloalkylidenmethyl, C ⁇ .
  • R 4 and R 5 which may be the same or different, are hydrogen, fluorine, chlorine, bromine, C 3 to 3 alkyl, C 3 to 3 alkoxy, methyl or methoxy substituted by 1 to 3 fluorine atoms, and
  • R 7b , R 7 ° independently of one another have a meaning selected from the group consisting of hydrogen, (-CC 8 -alkyl) carbonyl, (-CC 8 -alkyl) oxycarbonyl, arylcarbonyl and aryl- (C ⁇ . 3 -alkyl) -carbonyl,
  • aryl groups mentioned in the definition of the abovementioned radicals are to be understood as meaning phenyl or naphthyl groups which can be mono- or disubstituted independently of one another by R h , where the substituents can be identical or different and R h is a fluorine or chlorine , Bromine, iodine, C 1 -C 3 -alkyl, difluoromethyl, trifluoromethyl, C 1 -C 3 alkoxy, difluoromethoxy, trifluoromethoxy or cyan, among the heteroaryl groups mentioned in the definition of the abovementioned radicals is a pyrrolyl, furanyl, thienyl, imidazolyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group, or a pyrrolyl, Furanyl, thienyl, imidazolyl or pyr
  • alkyl groups mentioned above can be straight-chain or branched
  • the compounds of general formula I according to the invention and their physiologically tolerable salts have valuable pharmacological properties, in particular an inhibitory action on the sodium-dependent glucose cotransporter SGLT, in particular SGLT2. Furthermore, compounds according to the invention can have an inhibitory effect on the sodium-dependent glucose cotransporter SGLT1. Compared to a possible inhibitory effect on SGLT1, the compounds according to the invention preferably selectively inhibit SGLT2.
  • the present invention also relates to the physiologically tolerable salts of the compounds according to the invention with inorganic or organic acids. Therefore, the use of the compounds according to the invention, including the physiologically tolerable salts as medicaments, is also an object of this invention.
  • Another object of this invention are medicaments containing at least one compound according to the invention or a physiologically compatible salt according to the invention in addition to optionally one or more inert carriers and / or diluents.
  • the present invention also relates to the use of at least one compound according to the invention or a physiologically tolerable salt of such a compound for the production of a medicament which is suitable for the treatment or prophylaxis of diseases or conditions which can be influenced by inhibition of the sodium-dependent glucose cotransporter SGLT, in particular SGLT2 are.
  • Another object of this invention is the use of at least one compound according to the invention or one of its physiologically tolerable salts for the production of a medicament which is suitable for the treatment of metabolic diseases.
  • Another object of this invention is the use of at least one compound according to the invention or one of its physiologically tolerable salts for the production of a medicament for inhibiting the sodium-dependent glucose cotransporter SGLT, in particular SGLT2.
  • a method for producing a medicament according to the invention is the subject of this invention, characterized in that a compound according to the invention is incorporated into one or more inert carriers and / or diluents in a non-chemical way.
  • the present invention also relates to a process for the preparation of the compounds of the general formula I according to the invention, characterized in that a) for the preparation of compounds of the general formula I in which R 6 , R 7a , R 7b and R 7c are as previously defined , but not hydrogen, a compound of the general formula
  • R 6 and R 7a , R 7b , R 7c are as previously defined, but do not mean hydrogen, and Z 1 represents a leaving group, with a compound of the general formula
  • R 1 to R 5 have the meanings mentioned above, is implemented or
  • R 1 to R 6 and R 7a , R 7b , R 7c have the meanings given above and below.
  • aryl used above and below for example in the groups R 3 , R 6 , R 7a , R 7b , R 7c and R 7d , preferably denotes phenyl.
  • the aryl group in particular the phenyl group, can be substituted once or twice with identical or different R radicals.
  • heteroaryl used above and below, for example in the group R 3 preferably denotes pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, Oxadiazolyl, thiazolyl or thiadiazolyl.
  • the heteroaryl group can be substituted once or twice with identical or different radicals Rh.
  • radical R 1 preferred meanings of the radical R 1 are ethynyl, 2-propin-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy and
  • Tetrahydropyranylmethyloxy very particularly preferred meanings here are ethynyl, tetrahydrofuran-3-yloxy and tetrahydropyran-4-yloxy, in particular ethynyl.
  • radical R 3 preferred meanings of the radical R 3 are hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, 2-cyano-2-propyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy , Difluoromethoxy, trifluoromethoxy, 1, 1,2,2-tetrafluoroethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, methylsulfanyl, 2-methyl-1-propen-1-yl, cyclopropylidenemethyl, ethynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3 yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy, tetrahydropyranylmethyl
  • R 1 is hydrogen, fluorine, chlorine, bromine, iodine, C ⁇ . 4- alkyl, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, CM alkoxy, methoxy substituted by 1 to 3 fluorine atoms, ethoxy substituted by 1 to 5 fluorine atoms, by a hydroxy or C 1 - 3 - Alkoxy group substituted -CC 4 alkyl, by a hydroxy or C 1 .
  • 3 -alkyloxy or tetrahydropyranyl-C ⁇ - 3 -Alkyloxy can mean, and
  • R 3 is selected from a group consisting of C 2 -6-alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C ⁇ -3-alkyloxy and tetrahydropyranyl-C ⁇ -3 -alkyloxy, and
  • R 2 and R 4 to R 6 and R 7a , R 7b , R 7c have the meanings given above,
  • radical R 1 are hydrogen, fluorine, chlorine, methyl, difluoromethyl, trifluoromethyl, methoxy, Difluoromethoxy, trifluoromethoxy or cyano, particularly preferably hydrogen, fluorine, methyl or cyano, very particularly preferably hydrogen.
  • radical R 3 are ethynyl and tetrahydrofuran-3-yloxy.
  • radical R 4 are hydrogen and fluorine, in particular hydrogen.
  • Preferred compounds according to the present invention in particular according to the first and second embodiment, can be described by the following formulas (la), (Ib), (Ic) and (Id), in particular (la), (Ib) and (Ic) :
  • those compounds are also preferred in which the phenyl group which carries the substituent R 3 has at least one further substituent R 4 and / or R 5 which is different from hydrogen. According to these variants, those compounds are particularly preferred which have a substituent R 4 meaning fluorine.
  • the phenyl radical which carries the substituent R 3 is preferably fluorinated at most once.
  • radical R 5 are hydrogen and fluorine, in particular hydrogen.
  • radical R 2 are hydrogen, fluorine and methyl, in particular hydrogen and methyl.
  • the radical R 6 according to the invention is preferably hydrogen, (C 1-8 -alkyl) oxycarbonyl- or -C -8- alkylcarbonyl-, in particular hydrogen or (d. 6 -alkyl) oxycarbonyl, particularly preferably hydrogen, methoxycarbonyl or ethoxycarbonyl, very particularly preferably Hydrogen or methoxycarbonyl.
  • R 7a , R 7b , R 7c independently of one another are preferably hydrogen, (C 1-8 -alkyl) oxycarbonyl-, (C 1-18 -alkyl) carbonyl, benzoyl, in particular hydrogen or (C 1-6 -alkyl) oxycarbonyl-, (-C -8- alkyl) carbonyl, particularly preferably hydrogen, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl or ethylcarbonyl.
  • R 7a , R 7b and R 7c are very particularly preferably hydrogen.
  • R 6 , R 7a , R 7 and R 7c have a meaning according to the invention other than hydrogen, for example C 8 alkylcarbonyl, are preferably suitable as intermediates in the synthesis of compounds of formula I in which R 7a , R 7b and R 7c are hydrogen.
  • Particularly preferred compounds of the general formula I are selected from the group:
  • R 6 has a meaning other than hydrogen, in particular R 6 is ethoxycarbonyl or methoxycarbonyl,
  • halogen denotes an atom selected from the group consisting of F, Cl, Br and I, in particular F, Cl and Br.
  • C ⁇ . n -Alkyl where n can have a value from 1 to 18, means a saturated, branched or unbranched hydrocarbon group with 1 to n carbon atoms.
  • examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.
  • C 2 - n -alkynyl where n has a value from 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C ⁇ C double bond.
  • groups include ethynyl, 1-propynyl, 2-propynyl, iso-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5 hexynyl etc.!
  • C ⁇ . n -AIkoxy denotes a C ⁇ . n -Alkyl-O group, wherein -CC n -alkyl is as defined above.
  • groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n- Hexoxy, iso-hexoxy etc.
  • groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl, n- Hexylcarbonyl, iso- hexylcarbonyl, etc.
  • C 3 -n-cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic group with 3 to n carbon atoms.
  • groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo [3.2.1.] Octyl, spiro [4.5] decyl, norpinyl, norbonyl, Norcaryl, Adamantyl, etc.
  • the term includes C 3 . 7- Cycloalkyl saturated monocyclic groups.
  • C 3 -n-cycloalkylcarbonyl denotes a C 3 .
  • the compounds according to the invention can be obtained using synthesis processes which are known in principle.
  • the compounds are preferably obtained by the production processes according to the invention which are explained in more detail below.
  • R 6 and R 7a , R 7b , R 7c are defined as mentioned at the outset, but do not mean hydrogen
  • Z 1 is a leaving group such as a halogen atom, for example a fluorine, chlorine or bromine atom, or an acyloxy group, for example an acetyloxy group or trichloroacetimidoyloxy group, with a compound of the general formula
  • R 1 to R 5 have the meanings mentioned.
  • the reaction is advantageously carried out in a solvent such as, for example, methylene chloride, chloroform, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone, if appropriate in the presence of a base, such as, for example, potassium carbonate, cesium carbonate, sodium hydride or potassium tert-butoxide , or a silver compound such as silver (l) oxide, silver (l) carbonate or silver (l) trifluoroacetate or a catalyst such as boron trifluoride etherate at temperatures between -60 ° C and 120 ° C.
  • a base such as, for example, potassium carbonate, cesium carbonate, sodium hydride or potassium tert-butoxide
  • a silver compound such as silver (l) oxide, silver (l) carbonate or silver (l) trifluoroacetate or a catalyst such as boron trifluor
  • the reaction can also be carried out, for example, in a phase transfer system such as sodium hydroxide solution / methylene chloride / benzyl-triethylammonium bromide, it being possible for other protective groups, such as the trimethylsilyl group on an ethynyl group, to be eliminated.
  • a phase transfer system such as sodium hydroxide solution / methylene chloride / benzyl-triethylammonium bromide
  • R 6 , R 7a , R 7b and R 7c are defined as mentioned at the outset, but do not mean hydrogen, with water or a lower alcohol such as methanol or ethanol.
  • the reaction is advantageously carried out in water, a lower alcohol such as methanol or ethanol or an aqueous solvent mixture such as methanol / tetrahydrofuran in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methylate Temperatures between -20 ° C and 60 ° C.
  • a base such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methylate
  • a compound of the general formula I in which R 6 represents a hydrogen atom is obtained according to the invention, it can be converted into a compound by means of acylation, for example by means of acylation in the presence of a base such as pyridine, collidine, triethylamine or N-ethyldiisopropylamine, in which R 6 represents a (-C 18 alkyl) carbonyl group, a (C 8 alkyl) oxycarbonyl group, an aryl carbonyl group or an aryl (C 3 alkyl) carbonyl group.
  • Suitable acylating agents are in particular the corresponding activated acyl derivatives such as acid chlorides or anhydrides.
  • any reactive groups present such as ethynyl, hydroxyl, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.
  • the trimethylsilyl group can be used as a protective radical for an ethynyl group.
  • the trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group can be used as a protective radical for a hydroxyl group.
  • Protective residues for an amino, alkylamino or imino group are, for example, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.
  • the subsequent subsequent splitting off of a protective radical used takes place, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or Sulfuric acid or in the presence of an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or aprotic, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
  • an aqueous solvent for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or Sulfuric acid or in the presence
  • a trimethylsilyl radical is split off, for example, in water, an aqueous solvent mixture or a lower alcohol such as methanol or ethanol in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methylate.
  • a benzyl, methoxybenzyl or benzyloxycarbonyl radical is advantageously split off hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • a trifluoroacetyl radical is preferably split off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C. or by treatment with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C.
  • an acid such as hydrochloric acid
  • a solvent such as acetic acid at temperatures between 50 and 120 ° C.
  • sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C.
  • the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
  • cis / trans mixtures can be separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.
  • the cis / trans mixtures obtained can be chromatographed into their cis and trans isomers, the compounds of general formula I obtained which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in " Topics in Stereochemistry ", Vol. 6, Wiley Interscience, 1971)) in their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms due to their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.
  • the separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative obtained in this way, e.g. due to different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols
  • the D and L forms of tartaric acid or dibenzoyl tartaric acid, di-O-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.
  • suitable optically active alcohol are (+) - or (-) - menthol
  • optically active acyl radicals in amides are, for example, (+) - or (-) - menthyloxycarbonyl.
  • the compounds of formula I obtained in their salts, in particular for pharmaceutical use in their physiologically compatible Salts with inorganic or organic acids.
  • suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the compounds obtained can be converted into mixtures, for example in 1: 1 or 1: 2 mixtures with amino acids, in particular with alpha-amino acids such as proline or phenylalanine, which can have particularly favorable properties such as high crystallinity.
  • the compounds according to the invention can also advantageously be obtained by the processes described in the examples below, these also using the processes known to the person skilled in the art, for example from the literature, in particular those described in WO 01/68660, WO 01/74834, WO 02/28872, WO 02/44192, WO 02/64606, WO 03/11880 and WO 03/80635 can be combined.
  • the compounds of the general formula I according to the invention and their physiologically tolerable salts have valuable pharmacological properties, in particular an inhibitory action on the sodium-dependent glucose cotransporter SGLT, preferably SGLT2.
  • the biological properties of the new compounds can be checked as follows:
  • a CHO-K1 cell line ATCC No. CCL 61
  • a HEK293 cell line ATCC No. CRL-1573
  • Expression vector pZeoSV Invitrogen, EMBL accession number L36849
  • pZeoSV Invitrogen, EMBL accession number L36849
  • CHO-hSGLT2 or HEK-hSGLT2 transport sodium-dependent 14 C-labeled alpha-methyl-glucopyranoside ( 14 C-AMG, Amersham) into the cell interior.
  • the SGLT-2 assay is performed as follows:
  • CHO-hSGLT2 cells are cultivated in Ham's F12 medium (BioWhittaker) with 10% fetal calf serum and 250 ⁇ g / ml Zeocin (Invitrogen), HEK293-hSGLT2 cells in DMEM medium with 10% fetal calf serum and 250 ⁇ g / ml Zeocin (Invitrogen).
  • the cells are detached from the culture bottles by washing twice with PBS and then treating them with trypsin / EDTA. After adding cell culture medium, the cells are centrifuged off, resuspended in culture medium and counted in a casy-cell counter.
  • the reaction is started by adding 5 ⁇ l of 4 C-AMG (0.05 ⁇ Ci) to each hole. After a 2-hour incubation at 37 ° C., 5% CO 2 , the cells are washed again with 250 ⁇ l PBS (20 ° C.) and then lysed by adding 25 ⁇ l 0.1 N NaOH (5 minutes at 37 ° C.). 200 ⁇ l of MicroScint20 (Packard) are added to each hole and incubated at 37 C for a further 20 min. After this incubation, the radioactivity of the recorded 4 C-AMG is measured in a top count (Packard) using a 14 C scintillation program.
  • 4 C-AMG 0.05 ⁇ Ci
  • an analog test is set up in which the cDNA for hSGLTI (Genbank Acc. No. NM000343) is expressed in CHO-K1 or HEK293 cells instead of the hSGLT2 cDNA.
  • the compounds of general formula I according to the invention can have, for example, EC50 values below 1000 nM, in particular also below 50 nM.
  • the compounds of general formula I according to the invention and their corresponding pharmaceutically acceptable salts are in principle suitable for treating and / or preventing all those conditions or diseases which are caused by inhibiting SGLT activity , especially the SGLT-2 activity.
  • Compounds according to the invention are therefore, in particular for the prophylaxis or treatment of diseases, in particular metabolic diseases, or conditions such as type 1 and type 2 diabetes mellitus, diabetic complications (such as, for example, retinopathy, nephropathy or neuropathies, diabetic foot, ulcer, macroangiopathies), metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolism disorder, insulin resistance, metabolic syndrome, dyslipidemia of various origins, atherosclerosis and related diseases, obesity, hypertension, chronic heart failure, edema, hyperuricaemia are suitable.
  • these substances are suitable for beta-cell degeneration such as To prevent apoptosis or necrosis of pancreatic beta cells.
  • the substances are also suitable for improving or restoring the functionality of pancreatic cells, and also increasing the number and size of pancreatic beta cells.
  • the compounds according to the invention can also be used as diuretics or antihypertensives and are suitable for the prophylaxis and treatment of acute kidney failure.
  • the compounds according to the invention are very particularly suitable for the prophylaxis or treatment of diabetes, in particular type 1 and type 2 diabetes mellitus, and / or diabetic complications.
  • the dosage required to achieve a corresponding effect in treatment or prophylaxis usually depends on the compound to be administered, on the patient, on the type and severity of the disease or the condition and the The type and frequency of administration depends on the doctor to be treated.
  • the dosage for intravenous administration can range from 1 to 100 mg, preferably 1 to 30 mg, and for oral administration can range from 1 to 1000 mg, preferably 1 to 100 mg, 1 to 4 times a day.
  • the compounds of the formula I prepared according to the invention optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, Water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures, in conventional pharmaceutical preparations such as tablets, dragées, capsules, powders, solutions, suspensions or Work in suppositories.
  • inert customary carriers and / or diluents for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, Water, water
  • the compounds according to the invention can also be used in combination with other active substances, in particular for the treatment and / or prophylaxis of the diseases and conditions mentioned above.
  • further active substances are in particular those which, for example, increase the therapeutic effectiveness of an SGLT antagonist according to the invention with regard to one of the indications mentioned and / or allow a reduction in the dosage of an SGLT antagonist according to the invention.
  • Therapeutics suitable for such a combination include, for example, anti-diabetic agents such as metformin, sulfonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g.
  • PPAR-gamma agonists e.g. Gl 262570
  • - Antagonists PPAR-gamma / alpha modulators
  • alpha-glucose inhibitors eg acarbose, Voglibose
  • DPPIV inhibitors eg LAF237, MK-431
  • alpha2-antagonists insulin and insulin analogues
  • GLP-1 and GLP -1 analogues e.g. exendin-4 or amylin.
  • inhibitors of protein tyrosinephosphatase 1 substances that affect deregulated glucose production in the liver, such as inhibitors' of the glucose-6-phosphatase, or fructose-1, 6-bisphosphatase, of glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvatcarboxykinase, glycogen synthase kinase or Pyruvatdehydrokinase, lipid lowering agents such as HMG-CoA reductase inhibitors (for example, simvastatin, atorvastatin), fibrates (eg bezafibrate, fenofibrate), nicotinic acid and derivatives thereof, PPAR-alpha agonists , PPAR-delta agonists, ACAT inhibitors (eg Avasimibe) or cholesterol absorption inhibitors such as ezetimibe, bile acid-binding substances such as colestyramine,
  • a combination with drugs to influence high blood pressure, chronic heart failure or atherosclerosis such as A-Il antagonists or ACE inhibitors, ECE inhibitors, diuretics, ⁇ -blockers, Ca antagonists, centrally acting antihypertensives, antagonists of the alpha-2 adrenergic receptor, inhibitors of neutral endopeptidase, platelet aggregation inhibitors and others or combinations thereof are suitable.
  • angiotensin II receptor antagonists examples include candesartan cilexetil, potassium losartan, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113 RU-64276, EMD-90423, BR-9701, etc.
  • Angiotensin II receptor antagonists are preferably used for the treatment or prophylaxis of hypertension and diabetic complications, often in combination with a diuretic such as hydrochlorothiazide.
  • a combination with uric acid synthesis inhibitors or uricosurics is suitable for the treatment or prophylaxis of gout.
  • a combination with GABA receptor antagonists, Na channel blockers, topiramate, protein kinase C Inhibitors, advanced glycation end product inhibitors or aldose reductase inhibitors For the treatment or prophylaxis of diabetic complications, a combination with GABA receptor antagonists, Na channel blockers, topiramate, protein kinase C Inhibitors, advanced glycation end product inhibitors or aldose reductase inhibitors.
  • the dose for the combination partners mentioned above is expediently 1/5 of the usually recommended lowest dose up to 1/1 of the normally recommended dose.
  • a further subject of this invention therefore relates to the use of a compound according to the invention or a physiologically tolerable salt of such a compound in combination with at least one of the active ingredients described above as a combination partner for the production of a medicament which is suitable for the treatment or prophylaxis of diseases or conditions which are caused by Inhibition of the sodium-dependent glucose cotransporter SGLT can be influenced.
  • This is preferably a metabolic disease, in particular one of the diseases or conditions mentioned above, very particularly diabetes or diabetic complications.
  • both active ingredients are administered to the patient together; in the case of staggered use, the two active substances are administered to the patient in succession in a period of less than or equal to 12, in particular less than or equal to 6 hours.
  • a further subject of this invention relates to a medicament which has a compound according to the invention or a physiologically tolerable salt of such a compound and at least one of the active ingredients described above as a combination partner in addition to optionally one or more inert carriers and / or diluents.
  • a medicament according to the invention has a combination of a compound according to the invention of the formula I or a physiologically tolerable salt of such a compound and at least one angiotensin II receptor antagonist in addition to, if appropriate, one or more inert carriers and / or diluents.
  • the compound according to the invention, or a physiologically compatible salt, and the further active ingredient to be combined therewith can be present together in one dosage form, for example a tablet or capsule, or separately in two identical or different dosage forms, for example as a so-called kit-of-parts.
  • Composition 1 tablet contains: Active ingredient 100.0 mg milk sugar 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg
  • Active ingredient, milk sugar and starch are mixed and moistened evenly with an aqueous solution of the polyvinylpyrrolidone. After sieving the moist mass (2.0 mm mesh size) and drying in a rack drying cabinet at 50 ° C, sieving is again carried out (1.5 mm mesh size) and the lubricant is added. The ready-to-press mixture is processed into tablets.
  • Tablet weight 220 mg, diameter: 10 mm, biplane with double-sided facet and one-sided partial notch.
  • Composition 1 tablet contains: active substance 150.0 mg milk sugar powder. 89.0 mg corn starch 40.0 mg Colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg
  • the active substance mixed with milk sugar, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a sieve with a 1.5 mm mesh size.
  • the granules dried at 45 ° C are rubbed through the same sieve again and mixed with the specified amount of magnesium stearate. The mixture becomes
  • Tablet weight 300 mg stamp: 10 mm, flat
  • 1 capsule contains: Active ingredient 150.0 mg corn starch dr. approx. 180.0 mg powdered milk sugar approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg
  • the active ingredient is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously in a suitable device.
  • the final mix is filled into size 1 hard gelatin capsules.
  • Composition 1 suppository contains: Active ingredient 150.0 mg polyethylene glycol 1500 550.0 mg polyethylene glycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2000.0 mg
  • the active ingredient is homogeneously distributed therein and the melt is poured into pre-cooled molds.
  • composition active ingredient 10.0 mg 0.01 n hydrochloric acid s.q. Aqua bidest to 2.0 ml
  • Example F The active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules.
  • 0.01N HCl 0.01N HCl
  • composition active ingredient 50.0 mg 0.01 n hydrochloric acid s.q. Aqua bidest to 10.0 ml
  • the active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 10 ml ampoules.

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Abstract

L'invention concerne des composés aromatiques à substitution glucopyranosyloxy de formule générale (I), dont les restes R1 à R6 ainsi que R7a, R7b et R7c sont définis dans la revendication 1. L'invention concerne également les tautomères de ces composés, leurs stéréo-isomères, leurs mélanges et leurs sels, notamment leurs sels physiologiquement compatibles comprenant des acides inorganiques ou organiques et présentant des propriétés pharmacologiques intéressantes, notamment un effet inhibiteur sur le cotransporteur de glucose sodium-dépendant SGLT2. L'invention concerne en outre l'utilisation de ces composés pour traiter des maladies, notamment des maladies métaboliques comme le diabète, ainsi que la production de ces composés.
PCT/EP2004/014319 2003-12-22 2004-12-16 Composes aromatiques a substitution glucopyranosyloxy, medicaments contenant ces composes, leur utilisation et procede pour leur production WO2005063785A2 (fr)

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EP04803932A EP1699807A2 (fr) 2003-12-22 2004-12-16 Composes aromatiques a substitution glucopyranosyloxy, medicaments contenant ces composes, leur utilisation et procede pour leur production
JP2006546000A JP2007515441A (ja) 2003-12-22 2004-12-16 グルコピラノシロキシ置換芳香族化合物、前記化合物を含む医薬、それらの使用及びそれらの製造方法
CA002548353A CA2548353A1 (fr) 2003-12-22 2004-12-16 Composes aromatiques a substitution glucopyranosyloxy, medicaments contenant ces composes, leur utilisation et procede pour leur production

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WO2007128761A2 (fr) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Utilisations d'inhibiteurs de l'enzyme dpp iv
US7767651B2 (en) 2005-01-28 2010-08-03 Chugai Seiyaku Kabushiki Kaisha Spiroketal derivatives and use thereof as diabetic medicine
US7838499B2 (en) 2007-08-23 2010-11-23 Theracos, Inc. Benzylbenzene derivatives and methods of use
US8129434B2 (en) 2007-12-13 2012-03-06 Theracos, Inc. Benzylphenyl cyclohexane derivatives and methods of use
US8283454B2 (en) 2008-08-22 2012-10-09 Theracos, Inc. Processes for the preparation of SGLT2 inhibitors
US8551957B2 (en) 2007-08-16 2013-10-08 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivate
US8557782B2 (en) 2006-05-03 2013-10-15 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
US8802842B2 (en) 2009-09-30 2014-08-12 Boehringer Ingelheim International Gmbh Method for the preparation of a crystalline form
US8987323B2 (en) 2010-06-12 2015-03-24 Theracos, Inc. Crystalline form of benzylbenzene SGLT2 inhibitor
US9024010B2 (en) 2009-09-30 2015-05-05 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives
US9061060B2 (en) 2008-07-15 2015-06-23 Theracos Inc. Deuterated benzylbenzene derivatives and methods of use
US9127034B2 (en) 2005-05-10 2015-09-08 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivates and intermediates therein
US9192617B2 (en) 2012-03-20 2015-11-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9193751B2 (en) 2012-04-10 2015-11-24 Theracos, Inc. Process for the preparation of benzylbenzene SGLT2 inhibitors
US9464043B2 (en) 2013-10-12 2016-10-11 Theracos Sub, Llc Preparation of hydroxy-benzylbenzene derivatives
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US9949997B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9949998B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US20180185291A1 (en) 2011-03-07 2018-07-05 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
US10406172B2 (en) 2009-02-13 2019-09-10 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US10610489B2 (en) 2009-10-02 2020-04-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof
US11666590B2 (en) 2013-04-18 2023-06-06 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
WO2023222144A1 (fr) * 2022-05-18 2023-11-23 上海科利生物医药有限公司 Analogue de thioglycoside gliflozine, son procédé de préparation et son utilisation

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TW200733966A (en) * 2005-07-27 2007-09-16 Boehringer Ingelheim Int Glucopyranosyl-substituted ((hetero)cycloalkylethynyl-benzyl)-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2009096503A1 (fr) * 2008-01-31 2009-08-06 Daiichi Sankyo Company, Limited Dérivé de benzylphényl-glucopyranoside

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WO2003011880A1 (fr) * 2001-07-31 2003-02-13 Kissei Pharmaceutical Co., Ltd. Derive de glucopyranosyloxybenzylbenzene, composition medicinale contenant ce derive, usage medicinal de cette composition et produit intermediaire pour produire cette composition

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US7767651B2 (en) 2005-01-28 2010-08-03 Chugai Seiyaku Kabushiki Kaisha Spiroketal derivatives and use thereof as diabetic medicine
US10442795B2 (en) 2005-05-10 2019-10-15 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein
US9127034B2 (en) 2005-05-10 2015-09-08 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivates and intermediates therein
US8557782B2 (en) 2006-05-03 2013-10-15 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
EP2351568A2 (fr) 2006-05-04 2011-08-03 Boehringer Ingelheim International GmbH Utilisations d'inhibiteurs de l'enzyme dpp iv
WO2007128761A2 (fr) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Utilisations d'inhibiteurs de l'enzyme dpp iv
US8551957B2 (en) 2007-08-16 2013-10-08 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivate
US8802637B2 (en) 2007-08-23 2014-08-12 Theracos, Inc. Benzylbenzene derivatives and methods of use
US8575321B2 (en) 2007-08-23 2013-11-05 Theracos, Inc. Benzylbenzene derivatives and methods of use
US7838499B2 (en) 2007-08-23 2010-11-23 Theracos, Inc. Benzylbenzene derivatives and methods of use
US8106021B2 (en) 2007-08-23 2012-01-31 Theracos, Inc. Benzylbenzene derivatives and methods of use
US8129434B2 (en) 2007-12-13 2012-03-06 Theracos, Inc. Benzylphenyl cyclohexane derivatives and methods of use
US9061060B2 (en) 2008-07-15 2015-06-23 Theracos Inc. Deuterated benzylbenzene derivatives and methods of use
US8283454B2 (en) 2008-08-22 2012-10-09 Theracos, Inc. Processes for the preparation of SGLT2 inhibitors
US9006403B2 (en) 2008-08-22 2015-04-14 Theracos, Inc. Processes for the preparation of SGLT2 inhibitors
US12115179B2 (en) 2009-02-13 2024-10-15 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US10406172B2 (en) 2009-02-13 2019-09-10 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9024010B2 (en) 2009-09-30 2015-05-05 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives
US9873714B2 (en) 2009-09-30 2018-01-23 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives
US8802842B2 (en) 2009-09-30 2014-08-12 Boehringer Ingelheim International Gmbh Method for the preparation of a crystalline form
US10610489B2 (en) 2009-10-02 2020-04-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof
US8987323B2 (en) 2010-06-12 2015-03-24 Theracos, Inc. Crystalline form of benzylbenzene SGLT2 inhibitor
US10981942B2 (en) 2010-06-12 2021-04-20 Theracos Sub, Llc Crystalline form of benzylbenzene SGLT2 inhibitor
US10533032B2 (en) 2010-06-12 2020-01-14 Theracos Sub, Llc Crystalline form of benzylbenzene SGLT2 inhibitor
US9834573B2 (en) 2010-06-12 2017-12-05 Theracos Sub, Llc Crystalline form of benzylbenzene SGLT2 inhibitor
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US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US9192617B2 (en) 2012-03-20 2015-11-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9193751B2 (en) 2012-04-10 2015-11-24 Theracos, Inc. Process for the preparation of benzylbenzene SGLT2 inhibitors
US9725478B2 (en) 2012-04-10 2017-08-08 Theracos Sub, Llc Process for the preparation of benzylbenzene SGLT2 inhibitors
US9949997B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9949998B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11090323B2 (en) 2013-04-05 2021-08-17 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US10258637B2 (en) 2013-04-05 2019-04-16 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11833166B2 (en) 2013-04-05 2023-12-05 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11918596B2 (en) 2013-04-05 2024-03-05 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11666590B2 (en) 2013-04-18 2023-06-06 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9464043B2 (en) 2013-10-12 2016-10-11 Theracos Sub, Llc Preparation of hydroxy-benzylbenzene derivatives
US10093616B2 (en) 2013-10-12 2018-10-09 Theracos Sub, Llc Preparation of hydroxy-benzylbenzene derivatives
WO2023222144A1 (fr) * 2022-05-18 2023-11-23 上海科利生物医药有限公司 Analogue de thioglycoside gliflozine, son procédé de préparation et son utilisation

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