CN101437807A - Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture - Google Patents

Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture Download PDF

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CN101437807A
CN101437807A CNA2007800159285A CN200780015928A CN101437807A CN 101437807 A CN101437807 A CN 101437807A CN A2007800159285 A CNA2007800159285 A CN A2007800159285A CN 200780015928 A CN200780015928 A CN 200780015928A CN 101437807 A CN101437807 A CN 101437807A
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alkyl
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compound
methyl
hydroxyl
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马赛厄斯·埃克哈特
弗兰克·希梅尔斯巴赫
彼得·艾克尔曼
阿基姆·索尔
利奥·托马斯
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Boehringer Ingelheim International GmbH
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Abstract

Glucopyranosyl-substituted benzonitrile derivative of formula (I) are disclosed, wherein R<3> denotes hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1 -yl, 3- hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1 -trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, methyloxy, ethyloxy, isopropyloxy, difluoromethyloxy, trifluoromethyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, (S)-tetrahydrofuran-3-yloxy, (R)-tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, 1-acetyl-piperidin-4-yloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl and cyano, or a derivative thereof wherein one or more hydroxyl groups of the ss-D-glucopyranosyl group are acylated with groups selected from (C1-18-alkyl)carbonyl, (C1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C1-3-alkyl)-carbonyl; including tautomers, stereoisomers thereof or mixtures thereof; and physiologically acceptable salts thereof. The compounds according to the invention are suitable for the treatment of metabolic disorders.

Description

The cyanobenzene derivative that is replaced by the glucopyranose base, the pharmaceutical composition that contains described compound, its purposes and preparation method thereof
The present invention relates to the cyanobenzene derivative that is replaced by the glucopyranose base of general formula I:
Figure A200780015928D00061
Radicals R wherein 3Definition sees below, and comprises its tautomer, steric isomer, mixture and salt thereof.The invention still further relates to the pharmaceutical composition that contains formula I compound of the present invention and compound of the present invention and be used for the treatment of purposes in the pharmaceutical composition of metabolic disturbance in preparation.In addition, the present invention relates to be used to prepare the method for pharmaceutical composition of the present invention and compound.
In the literature, propose the inhibiting compound of sodium dependent glucose cotransporter SGLT2 tool is used for the treatment of disease, especially diabetes.
Reach known aromatic group and the preparation and active thereof that is replaced by the glucopyranose base of the open case of wherein being quoted from international application case WO 2005/092877 as the possibility of SGLT2 inhibitor.
Goal of the invention
Target of the present invention is for finding the novel cyanobenzene derivative that is replaced by the glucopyranose base, and especially those are for the activated derivative of sodium dependent glucose cotransporter SGLT (especially SGLT2).Another target of the present invention is compared with the known structure similar compounds for finding, in vitro and/or in vivo sodium dependent glucose cotransporter SGLT2 tool is strengthened restraining effect and/or has the benzene derivative that is replaced by the glucopyranose base of better pharmacology or pharmacokinetic properties.
Another target of the present invention is for providing the novel medicament compositions that is suitable for preventing and/or treating metabolic disturbance, especially diabetes.
Directly from addressing following explanation, other targets of the present invention will become apparent to those skilled in the art.
Goal of the invention
In first aspect, the present invention relates to the cyanobenzene derivative that is replaced by the glucopyranose base of formula I, comprise its tautomer, steric isomer or its mixture; And physiologically acceptable salt
Figure A200780015928D00071
Wherein
R 3Expression hydrogen; fluorine; chlorine; bromine; iodine; methyl; ethyl; propyl group; sec.-propyl; butyl; sec-butyl; isobutyl-; the tertiary butyl; 3-methyl-Ding-1-base; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; 1-hydroxyl-cyclopropyl; 1-hydroxyl-cyclobutyl; 1-hydroxyl-cyclopentyl; 1-hydroxyl-cyclohexyl; difluoromethyl; trifluoromethyl; pentafluoroethyl group; 2-hydroxyl-ethyl; hydroxymethyl; 3-hydroxyl-propyl group; 2-hydroxy-2-methyl-third-1-base; 3-hydroxy-3-methyl-Ding-1-base; 1-hydroxyl-1-methyl-ethyl; 2; 2; 2-three fluoro-1-hydroxyl-1-methyl-ethyls; 2; 2; 2-three fluoro-1-hydroxyl-1-trifluoromethyl-ethyls; 2-methoxyl group-ethyl; 2-oxyethyl group-ethyl; hydroxyl; difluoro-methoxy; trifluoromethoxy; 2-methoxyl group-oxyethyl group; methylthio group; methylsulfinyl; methyl sulphonyl; the ethyl sulfinyl; ethylsulfonyl; trimethyl silyl and cyano group
Or derivatives thereof: wherein one or more hydroxyl of β-D-glucopyranose base is selected from (C 1-18Alkyl) carbonyl, (C 1-18Alkyl) oxygen base carbonyl, phenylcarbonyl group and phenyl-(C 1-3Alkyl)-the group acidylate of carbonyl.
Acceptable salt has the valuable pharmacological characteristic on compound of the present invention and the physiology thereof, especially to the restraining effect of sodium dependent glucose cotransporter SGLT (especially SGLT2).Compound of the present invention in addition can have the restraining effect to sodium dependent glucose cotransporter SGLT1.Compare with the possible restraining effect to SGLT1, compound of the present invention preferably selectivity suppresses SGLT2.
The present invention also relates to acceptable salt on the physiology that compound of the present invention and mineral acid or organic acid form.
The present invention also relates to pharmaceutical composition, it contains acceptable salt at least a compound of the present invention or the physiology of the present invention, randomly together with one or more inert support and/or thinner.
The present invention also relates to acceptable salt at least a compound of the present invention or its physiology and be suitable for treatment or prevention can be by the purposes in the pharmaceutical composition of disease that suppresses sodium dependent glucose cotransporter SGLT (especially SGLT2) influence or illness in preparation.
The present invention also relates to acceptable salt at least a compound of the present invention or its physiology and be suitable for treating purposes in the pharmaceutical composition of one or more metabolic disturbance in preparation.
In another aspect, the present invention relates to the purposes that acceptable salt is used for preventing the pancreatic beta cell degeneration and/or is used to improve and/or recover the pharmaceutical composition of pancreatic beta cell function in preparation at least a compound of the present invention or a kind of its physiology.
In another aspect, the present invention relates to the purposes of the pharmaceutical composition of disease that the liver fat abnormal accumulation causes in preparation is used for preventing, slow down, postpone or treats owing to patient's body that these needs are arranged of acceptable salt at least a compound of the present invention or a kind of its physiology or illness.
The present invention also relates to acceptable salt at least a compound of the present invention or its physiology is used for suppressing the pharmaceutical composition of sodium dependent glucose cotransporter SGLT (especially SGLT2) in preparation purposes.
The invention still further relates to the method that is used to prepare pharmaceutical composition of the present invention, it is characterized in that by method non-chemically acceptable salt on compound of the present invention or a kind of its physiology together with in one or more inert support and/or the thinner.
The present invention also relates to be used to prepare the method for the compound of general formula I of the present invention, it is characterized in that
A) for preparation reaches the hereinafter compound of defined general formula I as mentioned,
At Lewis acid (Lewis) or bronsted acid (Br
Figure A200780015928D0008105940QIETU
Nsted acid) there be compound and the reductive agent reaction that makes general formula I I down, can make the protecting group while or the cracking in succession of any existence simultaneously;
Figure A200780015928D00081
Wherein
R ' represents H, C 1-4Alkyl, (C 1-18Alkyl) carbonyl, (C 1-18Alkyl) oxygen base carbonyl, aryl carbonyl and aryl-(C 1-3Alkyl)-and carbonyl, wherein alkyl or aryl can be by halogen list or polysubstituted;
R 8a, R 8b, R 8c, R 8dRepresent hydrogen or allyl group, benzyl, (C independently of one another 1-4Alkyl) carbonyl, (C 1-4Alkyl) oxygen base carbonyl, aryl carbonyl, aryl-(C 1-3Alkyl)-carbonyl and aryl-(C 1-3Alkyl)-oxygen base carbonyl or R aR bR cSi base or ketal or acetal radical, especially alkylidene group or aryl alkylene ketal or acetal radical, two adjacent group R under each situation simultaneously 8a, R 8b, R 8c, R 8dCan form cyclic ketal or acetal radical or 1,2-two (C 1-3Alkoxyl group)-1,2-two (C 1-3Alkyl)-and ethylene bridge, simultaneously above-mentioned ethylene bridge forms together with two Sauerstoffatoms of pyranose ring and two relevant carbon atoms and is substituted the diox ring, and especially 2,3-dimethyl-2,3-two (C 1-3Alkoxyl group)-1,4-diox ring, and alkyl, allyl group, aryl and/or benzyl can be by halogen or C simultaneously 1-3Alkoxyl group list or polysubstituted, and benzyl also can be through two-(C simultaneously 1-3Alkyl) the amino replacement; And
R a, R b, R cRepresent C independently of one another 1-4Alkyl, aryl or aryl-C 1-3Alkyl, wherein aryl or alkyl can be by halogen lists or polysubstituted;
Aryl described in the definition of above-mentioned group refers to phenyl or naphthyl simultaneously, is preferably phenyl;
And R wherein 3Base reaches hereinafter as mentioned and defines; Or
B) be the compound of preparation general formula I,
The compound of general formula III
Figure A200780015928D00091
R wherein 8a, R 8b, R 8c, R 8dAnd R 3Reach hereinafter as mentioned and define, its restricted condition is selected from R at least one 8a, R 8b, R 8c, R 8dSubstituting group be not hydrogen;
To not be the protecting group R of hydrogen 8a, R 8b, R 8c, R 8dCracking; And
If need, then make thus obtained compound of Formula I be converted into the acyl compounds of corresponding general formula I by acidylate, and/or
If essential, then with any protecting group cracking used in the above-mentioned reaction, and/or
If need, then thus obtained compound of Formula I is split as its steric isomer, and/or
If need, then thus obtained compound of Formula I is converted into its salt, especially be converted into acceptable salt on its physiology for medicinal use.
Other aspects of the present invention relate to as reaching the novel intermediates described in the experimental section in the reaction process hereinafter.
Detailed Description Of The Invention
Aspect of the present invention, be in particular compound, medical composition and its use, relate to and reach the hereinafter cyanobenzene derivative or derivatives thereof that is replaced by the glucopyranose base of defined general formula I as mentioned, comprise acceptable salt on its tautomer, steric isomer or its mixture and the physiology thereof.
In following substituting embodiment preferred of the present invention, describe:
According to first embodiment of the present invention, R 3Expression hydrogen; fluorine; chlorine; bromine; iodine; methyl; ethyl; propyl group; sec.-propyl; butyl; sec-butyl; isobutyl-; the tertiary butyl; 3-methyl-Ding-1-base; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; difluoromethyl; trifluoromethyl; pentafluoroethyl group; 2-hydroxyl-ethyl; methylol; 3-hydroxyl-propyl group; 2-hydroxy-2-methyl-third-1-base; 3-hydroxy-3-methyl-Ding-1-base; 1-hydroxyl-1-methyl-ethyl; 2; 2; 2-three fluoro-1-hydroxyl-1-methyl-ethyls; 2; 2,2-three fluoro-1-hydroxyl-1-trifluoromethyl-ethyls; 2-methoxyl group-ethyl; 2-oxyethyl group-ethyl; hydroxyl; difluoro-methoxy; trifluoromethoxy; 2-methoxyl group-oxyethyl group; methylthio group; methylsulfinyl; methyl sulphonyl; the ethyl sulfinyl; ethylsulfonyl; TMS or cyano group.
According to second embodiment of the present invention, R 3Expression hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, difluoro-methoxy, trifluoromethoxy, 2-methoxyl group-oxyethyl group, methylthio group, methylsulfinyl, methyl sulphonyl, ethyl sulfinyl, ethylsulfonyl, TMS or cyano group.
According to the 3rd embodiment of the present invention, R 3Expression methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, 3-methyl-Ding-1-base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, pentafluoroethyl group, 2-hydroxyl-ethyl, methylol, 3-hydroxyl-propyl group, 2-hydroxy-2-methyl-third-1-base, 3-hydroxy-3-methyl-Ding-1-base, 1-hydroxyl-1-methyl-ethyl, 2,2,2-three fluoro-1-hydroxyl-1-methyl-ethyls, 2,2,2-three fluoro-1-hydroxyl-1-trifluoromethyl-ethyls, 2-methoxyl group-ethyl or 2-oxyethyl group-ethyl.
According to the 4th embodiment of the present invention, R 3Expression methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, 3-methyl-Ding-1-base, difluoromethyl, trifluoromethyl or pentafluoroethyl group.
According to the 5th embodiment of the present invention, R 3Representative ring propyl group, cyclobutyl, cyclopentyl or cyclohexyl.
According to the 6th embodiment of the present invention, R 3Expression 1-hydroxyl-cyclopropyl, 1-hydroxyl-cyclobutyl, 1-hydroxyl-cyclopentyl or 1-hydroxyl-cyclohexyl.
According to the 7th embodiment of the present invention, R 3Expression 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxyl-propyl group, 2-hydroxy-2-methyl-third-1-base, 3-hydroxy-3-methyl-Ding-1-base, 1-hydroxyl-1-methyl-ethyl, 2,2,2-three fluoro-1-hydroxyl-1-methyl-ethyls, 2,2,2-three fluoro-1-hydroxyl-1-trifluoromethyl-ethyls, 2-methoxyl group-ethyl or 2-oxyethyl group-ethyl.
According to the 8th embodiment of the present invention, R 3Expression 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxyl-propyl group or 1-hydroxyl-1-methyl-ethyl.
According to the 9th embodiment of the present invention, R 3Expression hydroxyl, difluoro-methoxy, trifluoromethoxy or cyano group.
According to the tenth embodiment of the present invention, R 3Expression methyl, ethyl, propyl group, sec.-propyl, difluoromethyl, trifluoromethyl or pentafluoroethyl group.
Preferably, as defined all hydroxyls of β-D-glucopyranose base be not substituted or only the hydroxyl O-6 of β-D-glucopyranose base be substituted.Preferred substituted is selected from (C 1-8Alkyl) carbonyl, (C 1-8Alkyl) oxygen base carbonyl and phenylcarbonyl group.More preferably substituting group is selected from ethanoyl, methoxycarbonyl and ethoxy carbonyl, especially ethanoyl and ethoxy carbonyl.
Unless otherwise indicated, otherwise above reach in the nomenclature of hereinafter used structural formula, represent that towards the center of cyclic group this substituting group can be bonded to any free position of the cyclic group with H atom as the substituent key demonstration of cyclic group (base is benzyl ring for example).
But the known synthetic method of use principle obtains compound of the present invention.Preferably obtain these compounds by the method following of the present invention that hereinafter more describes in detail.
The glucose-derivative (flow process 1) that can synthesize formula II of the present invention from maltonic acid lactone or derivatives thereof by the benzyl benzene compound that adds the organometallic compound form of wanting.
Flow process 1: organometallic compound is added to Gluconolactone
Figure A200780015928D00121
Preferably begin to carry out the reaction of flow process 1 from the benzyl halide benzene compound of general formula I V, wherein Hal represents chlorine, bromine or iodine.R in the flow process 1 1Expression cyano group or can be converted into the group of cyano group subsequently; for example for example acetal or thiazole of the aldehyde functional group of chlorine, bromine, carboxyl, carboxylicesters, carboxylic acid amides or derivatives thereof, boron or silyl, protected or crested, or the amido functional group of protected or crested be nitro for example.Can be by so-called halogen-metal exchange reaction or by metal being inserted Grignard reagent (Grignard) or the lithium reagent (V) for preparing benzyl benzene in carbon-halogen bond from corresponding chlorination, bromination or iodate benzyl benzene IV.Can (for example) with for example just, the organolithium compound of the second month in a season or tert-butyl lithium carries out halogen-metal exchange with synthetic corresponding lithium compound V.Yet can not have or have in the presence of other salt of for example lithium chloride that can quicken metallization processes, producing similar magnesium compound by halogen-metal exchange with the suitable Grignard reagent of for example bromination isopropyl-magnesium or bromination sec-butyl magnesium or isopropyl-magnesium chloride or chlorination sec-butyl magnesium or di-isopropyl magnesium or di-secondary dibutyl magnesium; Also can produce specific commentaries on classics metallization organo-magnesium compound (for example referring to Angew.Chem.2004,116,3396-3399 and Angew.Chem.2006,118,165-169 and the document of wherein being quoted) from the appropriate precursors original position.In addition, also can adopt since will be for example butyl magnesium chloride or butyl magnesium bromide or isopropyl-magnesium chloride or the bromination isopropyl-magnesium salt complex that mixes the organo-magnesium compound that is produced with butyllithium (for example see Angew.Chem.2000,112,2594-2596 and Tetrahedron Lett.2001,42,4841-4844 and the document of wherein being quoted).Halogen-metal exchange reaction is preferably under 40 ℃ to-100 ℃, especially preferably between carrying out in inert solvent or its mixture (for example ether, diox, tetrahydrofuran (THF), toluene, hexane, methyl-sulphoxide, methylene dichloride or its mixture) under 10 ℃ to-80 ℃.Can randomly make thus obtained magnesium or lithium derived compounds change metallization is suitable for addition with formation other organometallic compound (V) with for example metal-salt of cerous compounds, zinc chloride or zinc bromide, indium chloride or indium bromide.Perhaps also can be by preparing organometallic compound V in the carbon-halogen bond that metal is inserted halogenated aromatic compound IV.Lithium or magnesium are the metal element that is suitable for this conversion.Insertion can preferably realize in the solvent of for example ether, diox, tetrahydrofuran (THF), toluene, hexane, methyl-sulphoxide and composition thereof under the temperature in-70 to 40 ℃ of scopes at-80 to 100 ℃.Do not taking place under the situation of spontaneous reaction, may need metal to activate for example with glycol dibromide, iodine, trimethylsilyl chloride, acetate, hydrochloric acid and/or supersound process in advance.Make reaction that organometallic compound V is added to Gluconolactone or derivatives thereof (VI) preferably between 40 ℃ to-100 ℃, especially preferably in inert solvent or its mixture, carrying out under 0 to-80 ℃ the temperature, to obtain formula II compound.Although all above-mentioned reactions are preferably finished in the inert atmosphere of for example argon gas and nitrogen, it also can carry out in air.Metallization and/or linked reaction also can be carried out in microreactor that can carry out with high rate of exchange and/or micro-mixer; For example similar with the method described in the WO 2004/076470.Being used for being added to metallized phenyl V by the appropriate solvent of the Gluconolactone VI of due care is (for example) ether, glycol dimethyl ether, benzene, toluene, methylene dichloride, hexane, tetrahydrofuran (THF), diox, N-Methyl pyrrolidone and composition thereof.Addition reaction can not have under any other adjuvant or at for example BF 3* OEt 2Or Me 3Under existing, the promotor of SiCl carries out (seeing M.Schlosser, Organometallics in Synthesis, John Wiley ﹠amp under the situation of the coupling of deferred reaction collocation thing; Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1994).Substituent R in the flow process 1 8Preferably be defined as benzyl, substituted benzyl, allyl group, trialkylsilkl, especially be preferably trimethyl silyl, triisopropyl silyl, allyl group, 4-methoxy-benzyl and benzyl.If two adjacent substituent R 8Link together, then these two substituting groups be preferably benzylidene acetal, 4-methoxyl group benzylidene acetal, sec.-propyl ketal part or with by butane 2 with 3 be connected with the adjacent oxygen atom of pyranose 2,3-dimethoxy-butylidene constitutes diox.R ' base is preferably represented hydrogen, C 1-4Alkyl, C 1-4Alkyl-carbonyl or C 1-4The alkyl oxy carbonyl especially is preferably hydrogen, methyl or ethyl.After being added to Gluconolactone VI, organometallic compound V or derivatives thereof introduces R ' base.If R ' equals hydrogen or C 1-4Alkyl, then in the presence of the acid of for example acetate, methylsulfonic acid, toluenesulphonic acids, sulfuric acid, trifluoroacetic acid or hydrochloric acid with for example methyl alcohol or alcoholic acid alcohols or treatment reaction solution.Also can after by the suitable electrophilic reagent prepared in reaction hydrogen compound II that in the presence of the alkali of for example triethylamine, ethyl diisopropyl amine, yellow soda ash or salt of wormwood or cesium carbonate, sodium hydroxide or potassium hydroxide or cesium hydroxide, makes different head (anomeric) hydroxyl and for example methyl-iodide, methyl-sulfate, iodoethane, ethyl sulfate, Acetyl Chloride 98Min. or diacetyl oxide, be connected R '.Also can before adding electrophilic reagent, make the hydroxyl deprotonation with (for example) sodium hydride.During connecting R ', if protecting group R 8At the corresponding protonated compound of adopt generation (is R 8Equal the Compound I I of H) the following instability of reaction conditions, then R 8Cleavable.
Can use in the organic chemistry standard conversion or at least the known method of the technical literature from organic synthesis the synthetic of halogenated aromatic compound that carry out formula IV (see J.March, Advanced OrganicReactions, Reactions, Mechanisms, and Structure, the 4th edition, John Wiley ﹠amp; Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1992 and the document wherein quoted etc.).More particularly, in different monographs, describe in detail and transition metal and organometallic compound are used for the synthesis of aromatic compound (for example see L.Brandsma, S.F.Vasilevsky, H.D.Verkruijsse, Applicationof Transition MetalCatalysts in Organic Synthesis, Springer-Verlag, Berlin/Heidelberg, 1998; M.Schlosser, Organometallics in Synthesis, JohnWiley ﹠amp; Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1994, P.J.Stang, F.Diederich, Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim, 1997 reach the document of wherein being quoted).Hereinafter described synthetic schemes is witnessed by example.In addition, also can use identical synthetic method that the aglycon part is combined with there being the pyranose part.
Flow process 2: diaryl ketone is segmental synthetic
Figure A200780015928D00141
Flow process 2 has shown that application friedel-crafts (Friedel-Crafts) acylation condition or its variant begin to prepare the precursor compound of the halogenated aromatic compound that can be used for synthesis type IV from Benzoyl chloride and second aromatic group.R in the flow process 2 1Expression cyano group or can be converted into the group of cyano group subsequently, for example for example thioacetal or thiazole of the aldehyde functional group of chlorine, bromine, carboxyl, carboxylicesters, carboxylic acid amides or derivatives thereof, protected or crested, or the amido functional group of protected or crested be nitro for example.This classical reaction has wide substrate scope, and usually at for example AlCl that uses with catalysis or stoichiometric amount 3, FeCl 3, iodine, iron, ZnCl 2, sulfuric acid or trifluoromethanesulfonic acid catalyzer carry out under existing.Also can use corresponding carboxylic acid, acid anhydrides, ester or cyanobenzene to replace Benzoyl chloride.The reaction preferably at-30 to 120 ℃, preferably under 30 to 100 ℃ temperature in for example methylene dichloride and 1, carry out in the chlorinated hydrocarbon of 2-ethylene dichloride.Yet, also can solvent-free reaction or the reaction in microwave oven.
Flow process 3: diaryl ketone and diarylcarbinols are reduced to diarylmethanes
Figure A200780015928D00151
Substituent R is represented C in flow process 3 1-3Alkyl or aryl, and R 1Expression cyano group or can be converted into the group of cyano group subsequently; for example for example acetal or thiazole of the aldehyde functional group of chlorine, bromine, carboxyl, carboxylicesters, carboxylic acid amides or derivatives thereof, boron or silyl, protected or crested, or the amido functional group of protected or crested be nitro for example.Can begin to obtain diarylmethanes from diaryl ketone or diarylcarbinols with one or two reactions steps.Diaryl ketone can two steps be reduced to diarylmethanes by corresponding diphenyl-carbinol or with a step.In two step variants, with for example metal hydride (NaBH for example 4, LiAlH 4Or iBu 2AlH) reductive agent reductone is to form alcohol.At for example BF 3* OEt 2, InCl 3Or AlCl 3Lewis acid or for example the bronsted acid of hydrochloric acid, sulfuric acid, trifluoroacetic acid or acetate exist down with for example Et 3SiH, NaBH 4Or Ph 2The reductive agent of SiClH makes gained alcohol be converted into the ditan of wanting.Can (for example) with for example Et 3The silicomethane of SiH, for example NaBH 4Hydroborate or LiAlH for example 4Aluminum hydride at for example BF 3* OEt 2, three (pentafluorophenyl group) borine, trifluoroacetic acid, hydrochloric acid, aluminum chloride or InCl 3Lewis acid or bronsted acid have the one step process that carries out beginning to obtain ditan down from ketone.Reaction is preferably being carried out in the solvent of for example halon (for example methylene dichloride, toluene, acetonitrile or its mixture) under 20 to 100 ℃ the temperature preferably at-30 to 150 ℃.Hydrogen reducing in the presence of the transition-metal catalyst of for example Pd/C may synthetic method for another.Also can be reduction reaction according to Wo Fu-Qi Xinuo (Wolff-Kishner) or its variant.At first with hydrazine or derivatives thereof for example 1, two (t-butyldimethylsilyl) hydrazines of 2-make ketone be converted into hydrazone, and hydrazone decomposes to form ditan and nitrogen under highly basic reaction conditions and heating.Reaction can a reactions steps be carried out or carry out afterwards with two independent reactions steps separation hydrazone or derivatives thereofs.Appropriate base comprises (for example) KOH, NaOH or KOtBu in the solvent of for example ethylene glycol, toluene, DMSO, 2-(2-butoxy oxyethyl group) ethanol or the trimethyl carbinol; Also can be solvent-free reaction.Reaction can preferably be carried out under the temperature between 80 to 200 ℃ between 20 to 250 ℃.The alternative condition of Wo Fu-Qi Xinuo reductive alkaline condition is Clemmensen (Clemmensen) reduction, and it takes place under acidic conditions, and this paper also can use.Alcohol functional group also can at first make the transition and be better leaving group, for example chlorine, bromine, iodine, acetoxyl, carbonyldioxy, phosphate or sulfate in the diarylcarbinols; The reduction step subsequently that forms diarylmethanes extensively is described in the organic chemistry document.
Flow process 4: the diarylmethanes unit and may precursor compound synthetic
Figure A200780015928D00161
R in the flow process 4 1Expression cyano group or can be converted into the group of cyano group subsequently; for example for example acetal or thiazole of the aldehyde functional group of chlorine, bromine, carboxyl, carboxylicesters, carboxylic acid amides or derivatives thereof, boron or silyl, protected or crested, or the amido functional group of protected or crested be nitro for example.Term " Alk " expression C 1-4Alkyl and each substituent R are independently from each other H, C 1-3Alkyl and C 1-3Alkoxyl group.Flow process 4 is described the self-metallization phenyl and is begun synthesis of diaryl methane and possibility precursor compound thereof.Can be by with the halogen-metal exchange reaction of (for example) butyllithium, isopropyl-magnesium halogenide or di-isopropyl magnesium or by metal element being inserted in halogen-carbon bond the aromatic substance that replaces from the synthetic lithium of chlorination, bromination or iodinated aromatic compounds or magnesium.Can obtain for example corresponding compound that replaces through boron of boric acid, boric acid ester or di alkylaryl borine from these metallization phenyl by boron electrophilic reagent reaction with for example boric acid ester or derivatives thereof.In addition, also can or intend halogenation precursor and two boron or borane compound and prepare borylization (borylated) aromatic substance (for example seeing Tetrahedron Lett.2003,4895-4898 page or leaf and the document of wherein being quoted) through the transition metal-catalyzed reaction of for example palladium from corresponding halogenation.The phenyl compound that lithium or magnesium are replaced adds to phenyl aldehyde, and (step 3) and phenylformic acid or derivatives thereof are (in the step 4) (for example benzamide, cyanobenzene or the Benzoyl chloride of benzoic ether, for example Wen Ruibai (Weinreb) type).These reactions can turn under another metal situation of for example cerium, indium or zinc and carry out not having under other transition-metal catalysts or do not change metal in principle; Sometimes it is favourable using one of aftermentioned alternative method.Can aryl boric acid be added in the phenyl aldehyde so that each diarylcarbinols (for example seeing Adv.Synth.Catal.2001,343-350 page or leaf and the document of wherein being quoted) to be provided by rhodium catalyst.In addition, can make aryl boric acid, its ester, di alkylaryl borine or aryl trifluoro boric acid ester and Benzoyl chloride coupling by transition metal, its complex compound or the salt adjusting of for example palladium to produce diaryl ketone.The metallization phenyl and the benzyl electrophilic reagent of for example benzyl chloride, bromotoluene or benzyl iodide are reacted to obtain diarylmethanes.The phenyl compound of lithium or magnesium derivative advantageously but be not total necessarily reaction in the presence of the transition metal of for example copper, iron or palladium (for example see Org.Lett.2001,3,2871-2874 reaches the document of wherein being quoted).Change metal from lithium or magnesium and turn to (for example) boron, tin, silicon or zinc (for example) corresponding aromatics boric acid, stannane, silicomethane or zn cpds are provided respectively, it can carry out the linked reaction with the benzyl electrophilic reagent of (for example) benzyl halogenide, benzyl carbonic ether, benzyl phosphoric acid ester, benzyl sulphonate or benzyl carboxylate.For example being reflected at, the transition metal of palladium, nickel, rhodium, copper or iron carries out under existing (for example seeing Tetrahedron Lett.2004,8225-8228 page or leaf and Org.Lett.2005,4875-4878 page or leaf and the document of wherein being quoted).
Flow process 5: the introducing of cyano group part
Figure A200780015928D00181
Flow process 5 has shown that the different steps at synthetic target molecule makes the cyano group residue be connected in the possible path of center phenyl.Cyano group is introduced with the linked reaction of halogenation or plan halogenation phenyl in the suitable cyano group source of for example sodium cyanide, Repone K, zinc cyanide or cupric cyanide that can be by transition metal mediation.Suitable catalyst can be derived from for example transition metal of palladium, rhodium, nickel, iron or copper, these transition metal for example palladium/carbon basic form, with the salt of for example Palladous chloride, palladium bromide or acid chloride or with for example triphenylphosphine, tri-butyl phosphine or 1, the complex compound of the phosphine of 1 '-two (diphenylphosphino) ferrocene (dpPf) or for example the alkene of dibenzalacetone use.But the active catalyst original position produces or produced before being added into reaction mixture.For example can be favourable (see Tetrahedron Lett.2005,46,1849-1853 and Tetrahedron Lett.2005,46,1815-1818 and the document of wherein being quoted) for the additive of the zinc of element or salt.Make to be another feasible method (for example see Synth.Commun.1996,3709-3714 reaches the document of wherein being quoted) that adds cyano functional group by halogen metal permutoid reaction or the cyano group electrophilic reagent reaction by each metal being inserted in halogen bond the corresponding zinc, magnesium or the lithium compound that obtain from chlorination, bromination or iodinated compounds and for example p-methylphenyl alkylsulfonyl prussiate, cyanogen bromide or cyanic acid 2-pyridine.
Flow process 6: introduce the cyano group residue from aldehyde or carboxylic acid derivative
Figure A200780015928D00191
Another kind of cyano group be introduced as synthetic (flow process 6) that begins from aldehyde or carboxylic acid amides.Aldehyde functional group self can itself, protected or crested introduces.The general protecting group of aldehyde functional group is an acetals, but also can use other protecting groups (to see T.W.Greene, P.G.M.Wuts, Protective Groups inOrganic Synthesis, John Wiley ﹠amp; Sons, Inc., New York, 1999).The suitable screening agent of aldehyde functional group is (for example) alkene and thiazole.Can use with (for example) formic acid, concentrated hydrochloric acid, Tripyrophosphoric acid or pyridine-toluene blended (for example) azanol makes aldehyde be converted into cyano functional group.Formed intermediate oxime under these reaction conditionss can be separated, dewater afterwards to produce final product.Also can use for example two trifluoroacetyl group azanols and NH 2OSO 3Other azanol reagent and obtain nitrile not having under other reagent situations.Other available reagents are (for example) NH in acetate 4PO 4H 2And nitropropane, trimethyl silyl triazo-compound or S, S-dimethyl sulphide imide.
Carboxylic acid amides also can be suitable nitrile precursor.For example trifluoroacetic anhydride, Vanadium Pentoxide in FLAKES, POCl 3, CCl 4The combination of-phosphine, Cl 3The combination of COCl-amine, burgess (Burgess) reagent, Wei Simeier (Vilsmeyer) reagent, SOCl 2Or the dewatering agent of cyanuryl chloride transforms.Can not separate any next pot of intermediate situation formation nitrile from corresponding monoalkylation carboxylic acid amides, carboxylic acid, ester or carboxyl acyl chloride thing yet.
Flow process 7: introduce the cyano group residue from the aniline precursor
Figure A200780015928D00201
The method of the introducing nitrile functionality of having set up for so-called mountain De Maier (Sandmeyer) reaction of cupric cyanide and the corresponding diazonium compound that can the diazotization by each anils obtains.Diazonium compound synthetic and subsequently cyano group go diazotization to prove widely in the organic chemistry document.
Flow process 8: the unitary another kind of diarylmethanes is synthetic
Figure A200780015928D00202
Shown in the flow process 8 and be used to make up the unitary another kind of method of diarylmethanes.
Use the commercially available cyanobenzene that maybe can replace by the adjacent fluorine that aforesaid method obtains.Under alkaline condition, make cyanobenzene that adjacent fluorine replaces with by R 3The phenylacetic acid alkyl esters reaction that replaces (for example see J.Org.Chem.55,1990,4817-4821; J.Heterocycl.Chem, 32,1995,1461-1466) ester cracking subsequently and decarboxylation (for example see J.Heterocycl.Chem, 32,1995,1461-1466; Org.Prep.Proced.Int.37,2005,550-555) or directly take off alkoxy carbonyl (for example see J.Med.Chem.46,2003,5249-5257; Angew.Chem.Int.Ed.47,2004,6493-6496).
Be the compound of preparation general formula I, method of the present invention a) in, in the presence of Lewis acid or bronsted acid, the compound of general formula I I and reductive agent are reacted,
Wherein R ' and R 3As hereinbefore defined and
R 8a, R 8b, R 8c, R 8dRepresent (for example) ethanoyl, valeryl, benzoyl, tert-butoxycarbonyl, benzyl oxygen base carbonyl, allyl group, trialkylsilkl, benzyl or substituted benzyl or two adjacent group R under each situation as hereinbefore defined and independently of one another 8a, R 8b, R 8c, R 8dForm benzylidene acetal or isopropylidene ketal or by butylidene 2 and 3 be connected to pyranose ring Sauerstoffatom 2,3-dimethoxy-butylidene and form substituted diox with above-mentioned group,
It can as indicated abovely obtain.
The suitable reductive agent of reaction comprises (for example) for example silicomethane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borine, lithium aluminum hydride, diisobutylaluminium hydride or means of samarium iodide of triethyl-silicane, tripropyl silicomethane, triisopropyl silicomethane or diphenylmethyl silane.Reduction is not having or is having the suitable bronsted acid of for example hydrochloric acid, toluenesulphonic acids, trifluoroacetic acid or acetate or for example carrying out in the presence of the Lewis acid of boron-trifluoride etherate, trifluoromethanesulfonic acid trimethyl silyl ester, titanium tetrachloride, tin tetrachloride, trifluoromethanesulfonic acid scandium or zinc iodide.Decide on reductive agent and acid, reaction can be between carrying out in the solvent of for example methylene dichloride, chloroform, acetonitrile, toluene, hexane, ether, tetrahydrofuran (THF), diox, ethanol, water or its mixture under-60 ℃ to 120 ℃ the temperature.Especially a suitable mixing of reagent is made up of (for example) triethyl-silicane and boron-trifluoride etherate, these two kinds of compounds easily-60 ℃ with 60 ℃ of temperature under in acetonitrile or methylene dichloride, use.In addition can be in for example Pd/C or Ruan in the solvent of for example tetrahydrofuran (THF), ethyl acetate, methyl alcohol, ethanol, water or acetate, use hydrogen to be used for transforming in the presence of the transition-metal catalyst of (Raney) nickel.
Perhaps, for preparation method b of the present invention) the compound of general formula I, in the compound of general formula III, the protecting group cracking,
Figure A200780015928D00221
R wherein 3As hereinbefore defined and
R 8aTo R 8dExpression one of defined protecting group above, for example acyl group, arylmethyl, allyl group, acetal, ketal or silyl, and it can (for example) also obtain by the compound from formula II as indicated above originally.
Should be appreciated that in above-mentioned synthetic method and can change radicals R 8aTo R 8dOne or some groups.
Used any acyl group protecting group (for example) in aqueous solvent (for example in water, isopropanol, acetic acid/water, tetrahydrofuran (THF)/water Huo diox/water) in the presence of trifluoroacetic acid for example, hydrochloric acid or vitriolic acid or hydrolytic rupture or (for example) in the presence of the alkali metal base of for example lithium hydroxide, sodium hydroxide or potassium hydroxide in the presence of the iodate trimethyl silyl under the temperature between 0 to 120 ℃, preferably in non-proton property cracking under the temperature between 10 to 100 ℃.Preferably by randomly in the presence of the solvent of for example acetate under the temperature between 50 to 120 ℃ with the acid treatment of for example hydrochloric acid, or by randomly under the temperature between 0 to 50 ℃, making the trifluoroacetyl group cracking in the presence of for example tetrahydrofuran (THF) or the methanol solvent with the sodium hydroxide solution processing.
Used any acetal or ketal protected (for example) in aqueous solvent (for example in water, isopropanol, acetic acid/water, tetrahydrofuran (THF)/water Huo diox/water) in the presence of trifluoroacetic acid for example, hydrochloric acid or vitriolic acid hydrolytic rupture or (for example) in the presence of the iodate trimethyl silyl under the temperature between 0 to 120 ℃, preferably in non-proton property cracking under the temperature between 10 to 100 ℃.
Trimethyl silyl (for example) is in water, aequeous solvent mixture or for example cracking in the presence of the alkali of for example lithium hydroxide, sodium hydroxide, salt of wormwood or sodium methylate in methyl alcohol or the alcoholic acid lower alcohol.
In water-based or alcoholic solvent, for example the acid of hydrochloric acid, trifluoroacetic acid or acetate also is fit to.Be cracking in the organic solvent of for example ether, tetrahydrofuran (THF) or methylene dichloride, for example using, the fluoride reagents of tetrabutylammonium also is fit to.
(for example) in the presence of the catalyzer of for example palladium/charcoal in the suitable solvent of for example methyl alcohol, ethanol, ethyl acetate or Glacial acetic acid, randomly under the acid of adding hydrochloric acid for example under the temperature between 0 to 100 ℃, but, but preferably under the hydrogen pressure of 3 to 5 crust, make advantageously hydrocracking of benzyl, methoxy-benzyl or benzyloxycarbonyl with hydrogen preferably under the surrounding temperature between 20 to 60 ℃ and at 1 to 7 crust.Yet, 2, the preferably cracking in trifluoroacetic acid in the presence of methyl-phenoxide of 4-dimethoxy-benzyl.
Preferably by the solvent of methylene dichloride, diox, methyl alcohol or ether makes the tertiary butyl or tert-butoxycarbonyl cracking with the Iodotrimethylsilane processing with the acid treatment of for example trifluoroacetic acid or hydrochloric acid or by for example randomly using.
In above-mentioned reaction, any reactive group of during reaction existing for example ethynyl, hydroxyl, amino, alkylamino or imino-can be by cracked GPF (General Protection False base protection once more after reaction.
For example, the protecting group of ethynyl can be trimethyl silyl or triisopropyl.Different third-2-the base of 2-hydroxyl also can be used as protecting group.
For example, the protecting group of hydroxyl can be trimethyl silyl, ethanoyl, trityl, benzyl or THP trtrahydropyranyl.
The protecting group of amino, alkylamino or imino-can be (for example) formyl radical, ethanoyl, trifluoroacetyl group, ethoxy carbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxy-benzyl or 2,4-dimethoxy-benzyl.
In addition, as indicated above, removable its enantiomer and/or the diastereomer of being divided into of the compound of the general formula I that is obtained.Therefore, for example, suitable/back mixing compound is removable to be divided into its genial trans isomer, and has that the compound of at least one optical activity carbon atom is separable to be its enantiomer.
Therefore, for example, can make suitable/back mixing compound be split as its genial trans isomer by chromatography, can (compare Allinger N.L. and Eliel E.L. " Topics inStereochemistry " by known method itself, the 6th volume, Wiley Interscience, in 1971) compound separation that makes the general formula I that exists with racemoid that is obtained can be split as its diastereomer by chromatogram and/or fractional crystallization based on its known method of physical-chemical difference use (for example) itself for its optical antipode and compound with general formula I of at least 2 unsymmetrical carbons, and be then it to be resolved to aforesaid enantiomer subsequently by these compounds of racemic form if obtain.
Preferably by separate at chirality phase upper prop enantiomer or by recrystallization from the optical activity solvent or by with can form salt or for example optically active substance (especially its acid and reactive derivative or the alcohols) reaction of the derivative of ester or acid amides with racemic compound, and (for example) non-enantiomer mixture of thus obtained salt or derivative is separated and make stage enantiomer separation, free enantiomorph is discharged from pure diastereo-isomerism salt or derivative based on its dissolubility difference.Optical activity acid commonly used is (for example) D-type and L-type tartrate or dibenzoyl tartaric acid, di-o-tolyl tartrate, oxysuccinic acid, amygdalic acid, camphorsulfonic acid, L-glutamic acid, aspartic acid or quinic acid.Optical activity alcohol can be (for example) (+) or (-)-menthol and for example, and the optical activity acyl group can be (+)-or (-)-menthyl oxygen base carbonyl in the acid amides.
In addition, the compound of formula I can be converted into its salt, especially is converted into acceptable salt on the physiology of the medicinal use that forms with mineral acid or organic acid.The acid that can be used for this purpose comprises (for example) hydrochloric acid, Hydrogen bromide, sulfuric acid, methylsulfonic acid, phosphoric acid, fumaric acid, succsinic acid, lactic acid, citric acid, tartrate or toxilic acid.
In addition, the compound that is obtained can be converted into mixture, for example with amino acid, and 1:1 or the 1:2 mixture that forms with the a-amino acid of for example proline(Pro) or phenylalanine especially, these amino acid can have especially favourable characteristic, for example high-crystallinity.
Also can use the method described in the following example advantageously to obtain compound of the present invention, these methods also can make up with those skilled in the art's known method (for example method described in WO98/31697, WO 01/27128, WO 02/083066, WO 03/099836, WO 2004/063209, WO 2005/092877 and the WO 2006/120208) from document for this purpose.
The present invention also relates to described in the reaction process as mentioned and the novel intermediate compound described in experimental section hereinafter.
Particularly, following intermediate compound is other aspects of the present invention:
Figure A200780015928D00241
Figure A200780015928D00251
Figure A200780015928D00261
Wherein
R 8aTo R 8dRepresent H or ethanoyl as hereinbefore defined and preferably;
R ' represents H, methyl or ethyl as hereinbefore defined and preferably;
Alk represents C 1-4Alkyl is preferably represented methyl or ethyl;
R 1Represent Br or CN as hereinbefore defined and preferably, most preferably represent CN;
R 3As hereinbefore defined, for example cyclopropyl or cyclobutyl, and preferably be selected from by following each group: chlorine, bromine, methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxyl, cyano group;
LG represents leaving group, for example Br, I ,-O-(SO 2)-CF 3, be preferably-O-(SO 2)-CF 3
U represent Cl, Br, I ,-O-CO-C 1-4Alkyl ,-O-C (=O)-O-C 1-4Alkyl or-OPO (O-C 1-4Alkyl) 2Be preferably Br.
As already mentioned, acceptable salt has the valuable pharmacological characteristic on the compound of general formula I of the present invention and the physiology thereof, especially to the restraining effect of sodium dependent glucose cotransporter SGLT (being preferably SGLT2).
The biological characteristics of compounds can followingly be studied:
Can prove in test set that these materials suppress the active ability of SGLT-2, have CHO-K1 cell strain (ATCC CCL-61) or HEK293 cell strain (ATCC CRL-1573) in this test set, described cell strain is stabilized transfection expression carrier pZeoSV (Invitrogen, EMBL deposits numbering L36849), described cell strain contains the cDNA of the sequence of the human sodium glucose cotransporter 2 of coding (the Genbank number of asking for NM_003041) (CHO-hSGLT2 or HEK-hSGLT2).These cell strains will in sodium dependence mode 14Alpha-Methyl-the glucopyranoside of C-mark ( 14C-AMG Amersham) is transported to cell interior.
SGLT-2 tests following carrying out:
The CHO-hSGLT2 cell is cultivated in Ham ' the s F12 substratum (BioWhittaker) that contains 10% foetal calf serum and 250 μ g/mL Zeocin (Invitrogen), and with the HEK293-hSGLT2 cell cultures in the DMEM substratum that contains 10% foetal calf serum and 250 μ g/mL Zeocin (Invitrogen).By washing 2 times with PBS and handling with trypsinase/EDTA subsequently cell is separated from culture flask.After adding cell culture medium, with cell centrifugation, be suspended from the substratum and in the Casy cell counter and count again.With 40,000 cell inoculations in every hole in white 96 orifice plates of poly--D-Methionin coating and at 37 ℃, 5%CO 2Following overnight incubation.Cell is tested damping fluid (Hanks balanced salt solution (Hanks Balanced Salt Solution), the CaCl of the NaCl of 137mM, the KCl of 5.4mM, 2.8mM with 250 μ l 2, 1.2mM MgSO 4And the HEPES (pH7.4) of 10mM, 50 μ g/mL gentamicins (Gentamycin)) wash 2 times.Then 250 μ l experiment damping fluid and 5 μ l test compounds are added into each hole and culture plate was hatched in incubator 15 minutes again.With 5 μ l, 10% DMSO as negative control.By with 5 μ l 14C-AMG (0.05 μ Ci) is added into each hole and makes the reaction beginning.At 37 ℃, 5%CO 2Under cultivate 2 hours after, cell washed once more with 250 μ l PBS (20 ℃) and then the NaOH (following 5 minutes) of the 0.1N by interpolation 25 μ l at 37 ℃ make cytolysis.The MicroScint20 (Packard) of 200 μ l is added into each hole and hatched again 20 minutes 37 ℃ of continuation.After this cultivates, in Topcount (Packard), use 14The measurement of C flicker formula is absorbed 14The intensity of radioactivity of C-AMG.
For measuring selectivity for human SGLT1, set up similar test, the cDNA of hSGLT1 in this test (Genbank Acc. NM_000343) replaces hSGLT2 cDNA to express in CHO-K1 or HEK293 cell.
The EC of compound of the present invention 50Value is lower than 1000nM, especially is lower than 200nM, most preferably is lower than 50nM.
Consider that it suppresses the active ability of SGLT, compound of the present invention and corresponding pharmacologically acceptable salt thereof are suitable for treatment and/or prophylactic treatment all can be by suppressing the illness or the disease of SGLT activity (especially being the SGLT-2 activity) influence.Therefore, compound of the present invention is particularly suited for prevention or treatment disease, especially be metabolic disturbance or illness, for example 1 type and diabetes B, diabetic complication (retinopathy for example, ephrosis or neuropathy, diabetic foot, ulcer, macroangiopathy), metabolic acidosis or ketoacidosis, reactive hypoglycemia disease, hyperinsulinemia (hyperinsulinaemia), the glucose metabolism obstacle, insulin resistant, metabolism syndrome, the hyperlipemia of different causes, atherosclerosis and relative disease, fat, hypertension, chronic heart failure, oedema and hyperuricemia.These materials also are suitable for preventing beta cell to degenerate for example apoptosis of pancreatic beta cell or necrosis.These materials also are suitable for improving or recovering the functional of pancreatic cell, and also increase the quantity and the size of pancreatic beta cell.Compound of the present invention also can be used as diuretic(s) or hypotensive agent, and is suitable for prevention and treatment acute renal failure.
By administration compound of the present invention, can reduce or suppress fat abnormal accumulation in liver.Therefore; according to a further aspect in the invention; provide a kind of and be used to prevent, slow down, postpone or treat the disease that causes owing to liver fat abnormal accumulation in patient's body that these needs are arranged or the method for illness, the method is characterized in that administration compound of the present invention or pharmaceutical composition.Disease or illness owing to the abnormal accumulation of liver fat especially are selected from common fats liver, non-alcoholic fatty liver disease (NAFL), non-alcoholic fatty liver disease inflammation (NASH), supernutrition inductive fatty liver, diabetes fatty liver, alcohol inductive fatty liver or poisoning fatty liver.
Particularly, compound of the present invention comprises acceptable salt on its physiology, is suitable for prevention or treatment diabetes, especially is 1 type and diabetes B and/or diabetic complication.
In addition, compound of the present invention is particularly suited for prevention or treats overweight, fat (comprising I level, II level and/or III level obesity), internal organ obesity and/or abdominal obesity.
Realize treatment or prevent the required dosage of corresponding activity to depend on character and severity and the medication and the frequency of compound, patient, disease or the illness of administration usually, and by doctor's decision of patient.Advantageously, can be 1 to 100mg, be preferably 1, and by oral route is 1 to 1000mg that be preferably 1 to 100mg, administration every day is 1 to 4 time in each situation to 30mg by intravenous route dosage.For this purpose, can be randomly and other active substances, with conventional carrier of one or more inertia and/or thinner, for example with W-Gum, lactose, glucose, Microcrystalline Cellulose, Magnesium Stearate, polyvinylpyrrolidone, citric acid, tartrate, water, water/ethanol, water/glycerine, water/Sorbitol Powder, water/polyoxyethylene glycol, propylene glycol, cetostearyl alcohol, carboxymethyl cellulose or for example stearic fatty substance or its suitable mixture come together to prepare compound of the present invention, to produce conventional Gai Lun (galenic) preparation, for example common or coated tablet, capsule, powder agent, suspensoid or suppository.
Compound of the present invention also can be used in combination with other active substances, is particularly useful for treatment and/or prevents above-mentioned disease or illness.Other active substances that are suitable for these combinations comprise (for example), and those strengthen SGLT antagonist of the present invention for the therapeutic action of mentioning one of indication and/or active substance that the dosage of SGLT antagonist of the present invention is minimized.The therapeutical agent that is suitable for this combination comprises (for example) antidiabetic, for example N1,N1-Dimethylbiguanide, sulfourea (Glyburide for example, tolbutamide (tolbutamide), glimepiride (glimepiride)), nateglinide (nateglinide), repaglinide (repaglinide), thiazolidinedione (rosiglitazone (rosiglitazone) for example, pioglitazone (pioglitazone)), PPAR-γ-agonist (for example GI 262570) and antagonist, PPAR-γ/alpha modulators (for example KRP 297), alpha-glucosidase inhibitor (acarbose (acarbose) for example, voglibose (voglibose)), DPPIV inhibitor (LAF237 for example, MK-431), α 2-antagonist, Regular Insulin and insulin analog, GLP-1 and GLP-1 analogue (for example Ai Shengding-4 (exendin-4)) or dextrin (amylin).Catalogue also comprises Protein-tyrosine-phosphatase 1 inhibitor, and it goes to regulate the material that (deregulated) glucose produces in liver for influence, and for example G-6-Pase or fructose-1,6-bisphosphatase, phosphoric acid ester Transglucosylase inhibitor; Hyperglycemic-glycogenolytic factor (glucagon) receptor antagonist and phosphoenolpyruvate carboxykinase inhibitor, glycogen synthase kinase inhibitor or pyruvic acid dehydrogenation kinase inhibitor; Lipid lowering agent, for example HMG-CoA reductase inhibitor (for example Simvastatin (simvastatin), atorvastatin (atorvastatin)); The special class (fibrates) (for example bezafibrate (bezafibrate), fenofibrate (fenofibrate)) of shellfish; Nicotinic acid and derivative thereof; The PPAR-alfa agonists; The PPAR-delta agonists; The ACAT inhibitor (for example avasimibe (avasimibe)) or the cholesterol absorption inhibitor of ezetimibe (ezetimibe) for example; The bile acide binding substance of QUESTRAN (cholestyramine) for example; The ileal bile acid transfer inhibitor; HDL rising compound, for example CETP inhibitor or ABC1 conditioning agent; Or the fat active substance of treatment, for example his spit of fland (tetrahydrolipostatin), dexfenfluramine (dexfenfluramine), Dapiclermin (axokine) are pounced in sibutramine (sibutramine) or tetrahydrochysene Lip river; Cannabin(e) 1 receptor antagonist; The MCH-1 receptor antagonist; The MC4 receptor stimulant; NPY5 or NPY2 antagonist; Or β 3-agonist, for example SB-418790 or AD-9677 and 5HT2c receptor stimulant.
In addition, also be suitable with being used to influence hypertension, chronic heart failure or atherosclerotic medicine (for example A-II antagonist or ACE inhibitor, ECE inhibitor, diuretic(s), beta blocker, Ca-antagonist, central action hypotensive agent, α-2-adrenoceptor antagonists, neutral endopeptidase inhibitor, anticoagulant and other medicines or its combination) combination.The example of angiotonin II receptor antagonist is a candesartan Cilexetil, Losartan Potassium (potassium losartan), methylsulfonic acid Eprosartan (eprosartan mesylate), valsartan (valsartan), telmisartan (telmisartan), Irb (irbesartan), EXP-3174, L-158809, EXP-3312, olmesartan medoxomill (olmesartan), medoxomil, Tasosartan (tasosartan), KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701 etc.Angiotonin II receptor antagonist is preferably used for treatment or preventing hypertension and diabetic complication, and the diuretic(s) with for example hydrochlorothiazide (hydrochlorothiazide) makes up usually.
Be suitable for treatment or prevention gout with the combination of uric acid synthetic inhibitor or uricosuric agent (uricosuric).
Can be used for treatment or prevent diabetes complication with the combination of GABA-receptor antagonist, Na-channel blocker, topiramate (topiramat), inhibitors of protein kinase C, advanced glycation endoproducts inhibitor or aldose reductase inhibitor.
The dosage of useful aforesaid combination collocation thing be the common lowest dose level of recommending 1/5 until 1/1 of common institute recommended dose.
Therefore, in another aspect, the present invention relates to acceptable salt on the physiology with the compound of the present invention of at least a above-mentioned active substance combination as the combination collocation thing or this compound preparation be suitable for treating or prevent can be by suppressing sodium dependent glucose cotransporter SGLT influence disease or the purposes in the pharmaceutical composition of illness.These diseases are preferably metabolic trouble, one of especially above listed disease or illness, more particularly diabetes or diabetic complication.
Use on compound of the present invention or its physiology acceptable salt to take place simultaneously or at staggered time with another active substance combination, but especially in the short timed interval, take place.If administration simultaneously then gives the patient together with two kinds of active substances; And, then be less than or equal to 12 hours, but especially give the patient with two kinds of active substances being less than or equal in time of 6 hours if use at staggered time.
Therefore, in another aspect, the present invention relates to pharmaceutical composition, it comprises acceptable salt and at least a above-mentioned active substance as the mix and match thing on the physiology of compound of the present invention or this compound, randomly together with one or more inert support and/or thinner.
Therefore, for example, pharmaceutical composition of the present invention comprise acceptable salt and at least a angiotonin II receptor antagonist on the physiology of compound of the present invention or this compound randomly with the mixing of one or more inert support and/or thinner.
Acceptable salt and treat to be present in a kind of preparation on compound of the present invention or its physiology with other active substances of its combination, for example tablet or capsule, or be present in dividually in two kinds of identical or different preparations, for example as so-called parts test kit (kit-of-parts).
Above reaching hereinafter, clearly do not representing the H atom of hydroxyl under each situation in the structural formula.Following embodiment is intended to the present invention is described and does not limit the present invention.Term " room temperature " reaches " surrounding temperature " replaceable use and represents about 20 ℃ temperature.
Use following abbreviation:
The DMF dimethyl formamide
NMP N-N-methyl-2-2-pyrrolidone N-
The THF tetrahydrofuran (THF)
The preparation of initial compounds:
Example I
Figure A200780015928D00311
4-bromo-3-hydroxymethyl-1-iodo-benzene
Oxalyl chloride (13.0mL) is added into 2-bromo-5-iodo-phenylformic acid in CH 2Cl 2In the ice-cold solution (200mL).Add DMF (0.2mL), and solution was at room temperature stirred 6 hours.Then under reduced pressure concentrate and resistates is dissolved among the THF (100mL).In ice bath, cool off gained solution and add a LiBH by part 4(3.4g).Remove cooling bath and mixture was stirred under room temperature 1 hour.With the THF diluted reaction mixture and with the acid treatment of 0.1M salt.Then separate organic layer and with the ethyl acetate extraction water layer.Dry (Na 2SO 4) descend evaporating solvent to generate crude product through the organic layer of merging and in decompression.
Productive rate: 47.0g (theoretical value 99%)
Example II
4-bromo-3-chloromethyl-1-iodo-benzene
Thionyl chloride (13mL) is added in the 4-bromo-3-hydroxymethyl-suspension of 1-iodo-benzene (47.0g) in the methylene dichloride that contains DMF (0.1mL) (100mL).Mixture was stirred 3 hours at ambient temperature.Then under reduced pressure remove solvent and excess reagent.With methyl alcohol wet-milling resistates and drying.
Productive rate: 41.0g (theoretical value 82%)
EXAMPLE III
Figure A200780015928D00321
4-bromo-1-iodo-3-phenoxymethyl-benzene
The phenol (13g) that will be dissolved in the 4M KOH solution (60mL) is added in the 4-bromo-3-chloromethyl-1-iodo-benzene (41.0g) that is dissolved in the acetone (50mL).Add NaI (0.5g) and descend stirring to spend the night in 50 ℃ in the gained mixture.Then add water and with ethyl acetate extraction gained mixture.Dry extract and vapourisation under reduced pressure solvent through merging.By silica gel chromatography purifying resistates (cyclohexane/ethyl acetate 19:1).
Productive rate: 38.0g (theoretical value 79%)
EXAMPLE IV
Figure A200780015928D00322
(5-bromo-2-chloro-phenyl)-(4-methoxyl group-phenyl)-ketone
38.3mL oxalyl chloride and 0.8mL dimethyl formamide are added in the mixture of 5-bromo-2-chloro-phenylformic acid in the 500mL methylene dichloride of 100g.Reaction mixture was stirred 14 hours, then filter and in rotary evaporator, separate from all volatile components.Resistates is dissolved in the 150mL methylene dichloride, gained solution is cooled to-5 ℃, and add the 46.5g methyl-phenoxide.Then portion-wise addition 51.5g aluminum chloride is so that temperature is no more than 5 ℃.Solution was stirred 1 hour down and then inclines to trash ice in 1 to 5 ℃.Separate organic phase, and with the dichloromethane extraction water.With 1M salt acid elution ECDC organic phase, 1M sodium hydroxide solution (2 times) and salt water washing ECDC also organic phase also.Then through the dried over sodium sulfate organic phase, remove solvent and with resistates from ethyl alcohol recrystallization.
Productive rate: 86.3g (theoretical value 64%)
Mass spectrum (ESI +): m/z=325/327/329 (Br+Cl) [M+H] +
EXAMPLE V
Figure A200780015928D00331
1-bromo-4-chloro-3-(4-methoxyl group-benzyl)-benzene
86.2g (5-bromo-2-chloro-phenyl)-(4-methoxyl group-phenyl)-ketone and the solution of 101.5mL triethyl-silicane in 75mL methylene dichloride and 150mL acetonitrile are cooled to 10 ℃.Then follow stirring, add the 50.8mL ether and close boron trifluoride so that temperature is no more than 20 ℃.Solution was stirred 14 hours at ambient temperature, add 9mL triethyl silicane and 4.4mL boron-trifluoride etherate subsequently again.With solution 3 hour period of 45-50 ℃ of following restir and then be cooled to surrounding temperature.Add 28g potassium hydroxide in 70mL water solution and the gained mixture stirred 2 hours.Separate organic phase and water is extracted 3 times again with Di Iso Propyl Ether.With the 2M potassium hydroxide solution and once, and then through dried over sodium sulfate with the salt water washing with the organic phase washed twice that merges.After evaporating solvent, with washing with alcohol resistates and dry down in 60 ℃.
Productive rate: 50.0g (theoretical value 61%)
Mass spectrum (ESI +): m/z=310/312/314 (Br+Cl) [M+H] +
Example VI
4-(5-bromo-2-chloro-benzyl)-phenol
1-bromo-4-chloro-3-(4-methoxyl group-benzyl)-solution of benzene in the 150mL methylene dichloride of cooling 14.8g in ice bath.The boron tribromide that adds 50mL in methylene dichloride 1M solution and gained solution stirred 2 hours at ambient temperature.Then cooling solution and dropwise add the unsaturated carbonate aqueous solutions of potassium in ice bath once more.With the 1M aqueous hydrochloric acid mixture being adjusted to the pH value at ambient temperature is 1, separates organic phase and with ethyl acetate extraction water 3 times.Through dried over sodium sulfate through merging organic phase and remove solvent fully.
Productive rate: 13.9g (theoretical value 98%)
Mass spectrum (ESI -): m/z=295/297/299 (Br+Cl) [M-H] -
Example VII A
Figure A200780015928D00341
[4-(5-bromo-2-chloro-benzyl)-the phenoxy group]-tertiary butyl-dimethyl-silicomethane
4-(5-bromo-2-chloro-the benzyl)-solution of phenol in the 140mL methylene dichloride of cooling 13.9g in ice bath.Then make an addition to the 7.54g tertiary butyl dimethylsilane chlorine in the 20mL methylene dichloride, add the 4-dimethylamino pyridine of 9.8mL triethylamine and 0.5g then.Gained solution is stirred 16h at ambient temperature and then dilute with the 100mL methylene dichloride.Wash organic phase 2 times with the 1M aqueous hydrochloric acid, and with sodium bicarbonate aqueous solution washing 1 time and then through dried over sodium sulfate.After removing solvent, via filtered through silica gel resistates (cyclohexane/ethyl acetate 100:1).
Productive rate: 16.8g (theoretical value 87%)
Mass spectrum (EI): m/z=410/412/414 (Br+Cl) [M] +
Example VII A I
Figure A200780015928D00342
1-bromo-4-(1-methoxyl group-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene
The 2M solution of iPrMgCl in THF (11mL) is added among the anhydrous LiCl (0.47g) that is suspended among the THF (11mL).At room temperature stir the mixture and all dissolve until all LiCl.This solution dropwise is added under argon atmospher in the solution of 4-bromo-1-iodo-3-phenoxymethyl-benzene (8.0g) in tetrahydrofuran (THF) (40mL) that is cooled to-60 ℃.With the solution temperature to-40 ℃ and then make an addition to 2,3,4 in the tetrahydrofuran (THF) (5mL), 6-four-O-(trimethyl silyl)-D-grape pyrone (10.7g, 90% is pure).With gained solution in cooling bath temperature to-5 ℃ and under this temperature restir 30 minutes.Add NH 4The Cl aqueous solution and with ethyl acetate extraction gained mixture.Go down to desolventize through the organic extract of merging and in decompression through dried over sodium sulfate.Resistates is dissolved in the methyl alcohol (80mL) and with methylsulfonic acid (0.6mL) handles.After stirring is spent the night under 35-40 ℃ with reaction soln, with solid NaHCO 3Neutralization solution, and under decompression, remove methyl alcohol.With NaHCO 3Aqueous solution dilution residue and with ethyl acetate extraction gained mixture.Through dried over sodium sulfate through merging extract and evaporating solvent to generate crude product, this crude product reduces without being further purified promptly.
Productive rate: 7.8g (theoretical value 93%)
Example I X
Figure A200780015928D00351
1-bromo-4-(2,3,4,6-four-O-ethanoyl-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene
Ether is closed boron trifluoride (4.9mL) with temperature maintenance in the speed below-10 ℃ and be added into 1-bromo-4-(1-methoxyl group-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene (8.7g) and triethyl silicane (9.1mL) being cooled in-20 ℃ the solution in methylene dichloride (35mL) and acetonitrile (50mL).Through period of 1.5h with gained solution temperature to 0 ℃, and then handle with sodium bicarbonate aqueous solution.The gained mixture was stirred 0.5 hour, remove organic solvent and with the ethyl acetate extraction resistates.Through organic layer and the removal solvent of dried over sodium sulfate through merging.Resistates is dissolved in the methylene dichloride (50mL), connects and in solution, add diacetyl oxide (9.3mL), 4-dimethylamino pyridine (0.5g) and pyridine (9.4mL).Solution was stirred 1.5 hours at ambient temperature and then dilute with methylene dichloride.With 1M hydrochloric acid with this solution washing 2 times and through dried over sodium sulfate.After removing solvent, resistates is the product of colorless solid shape with generation from ethyl alcohol recrystallization.
Productive rate: 6.78g (theoretical value 60%)
Mass spectrum (ESI +): m/z=610/612 (Br) [M+NH 4] +
Embodiment X
Figure A200780015928D00361
2-(phenoxymethyl)-4-(2,3,4,6-four-O-ethanoyl-D-glucopyranose-1-yl)-cyanobenzene
With the argon flushing zinc cyanide (1.0g), zinc (30mg), Pd are housed 2(dibenzalacetone) 3* CHCl 3(141mg) and the flask of Tetrafluoroboric acid three uncle Ding Ji Phosphonium (111mg).Then add 1-bromo-4-(2,3,4,6-four-O-ethanoyl-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene (5.4g) in degassing NMP (12mL) solution and the gained mixture stirred under room temperature 18 hours.With after the ethyl acetate dilution, filtering mixt and with the sodium bicarbonate aqueous solution wash filtrate.Dry (sodium sulfate) organic phase and removal solvent.With resistates from ethyl alcohol recrystallization.
Productive rate: 4.10g (theoretical value 84%)
Mass spectrum (ESI +): m/z=557[M+NH 4] +
According to the following step, also obtain above-claimed cpd:
The flask that stirring rod, 1-bromo-4-(2,3,4,6-four-O-ethanoyl-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene (14.7g), cupric cyanide (4.1g) and NMP (100mL) will be housed heated 8 hours down in reflux temperature.After Yi Shui (600mL) dilution, precipitation separation, with water washing for several times and be dissolved in subsequently in the ethyl acetate (200mL).Gained solution is filtered via the silica gel plug that uses ethyl acetate (300mL) as eluent.In the following concentrated filtrate and resistates being dissolved in the methylene dichloride (100mL) of decompression with the oxygen base of acetylize deprotection during cyanogenation again.Correspondingly, in turn add pyridine (4mL), 4-dimethylamino pyridine (0.3g) and diacetyl oxide (4.4mL).Gained solution was stirred under room temperature 1 hour.Then with methylene dichloride (50mL) diluted reaction mixture and with 1M aqueous hydrochloric acid washing 3 times, with sodium bicarbonate aqueous solution washing 1 time and with water washing 1 time.Dry (sodium sulfate) organic phase and removal solvent.With resistates from ethyl alcohol recrystallization.
Productive rate: 10.0g (theoretical value 75%)
Embodiment XI
Figure A200780015928D00371
2-brooethyl-4-(2,3,4,6-four-O-ethanoyl-D-glucopyranose-1-yl)-cyanobenzene
33% solution of Hydrogen bromide in acetate (15mL) is added in 2-phenoxymethyl-4-(2,3,4,6-four-O-ethanoyl-D-glucopyranose-1-yl)-cyanobenzene (0.71g) and the solution of diacetyl oxide (0.12mL) in acetate (10ml).Gained solution was stirred 6 hours down and then cools off in ice bath in 55 ℃.With cooling wet chemical neutralization reaction mixture, and with ethyl acetate extraction gained mixture.Through dried over sodium sulfate through merging organic extract and under reduced pressure removing solvent.Resistates is dissolved in ethyl acetate/hexanaphthene (1:5) and by filtering separation precipitation and dry down to generate pure products in 50 ℃.
Productive rate: 0.52g (theoretical value 75%)
Mass spectrum (ESI +): m/z=543/545 (Br) [M+NH 4] +
Embodiment XII
Figure A200780015928D00381
1-chloro-4-(β-D-glucopyranose-1-yl)-2-(4-hydroxybenzyl)-benzene
[4-(5-bromo-2-chloro-benzyl)-the phenoxy group]-solution of the tertiary butyl-dimethyl-silane in the 42mL anhydrous diethyl ether of 4.0g is cooled to-80 ℃ under argon.The 1.7M of 11.6mL tert-butyl lithium in pentane ice-cold (-50 ℃ approximately) solution slowly is added in the cooling solution and then solution was stirred 30 minutes under-80 ℃.Then this solution dropwise is added into 2,3,4 of 4.78g, in the solution of 6-four-O-(trimethyl silyl)-D-glucopyranose ketone being cooled in the 38mL ether-80 ℃ through shifting pin with the dry ice refrigerative.Gained solution was stirred 3 hours down in-78 ℃.Then add the 1.1mL methylsulfonic acid in 35mL methyl alcohol solution and with gained reaction soln restir 16 hours at ambient temperature.Then, add ethyl acetate and concentrated gained solution under decompression with the solid sodium bicarbonate neutralization solution.Sodium bicarbonate aqueous solution is added in the surplus solution with ethyl acetate extraction 4 times.Through dried over sodium sulfate through merging organic phase and evaporating solvent.Resistates is dissolved in 30mL acetonitrile and the 30mL methylene dichloride and with gained solution is cooled to-10 ℃.After adding the 4.4mL triethyl silicane, dropwise add the 2.6mL boron-trifluoride etherate so that temperature is no more than-5 ℃.After interpolation is finished,, and then end by adding sodium bicarbonate aqueous solution with in-5 to-10 ℃ of following restir of reaction soln 5 hours.Separate organic phase and with ethyl acetate extraction water 4 times.Through the organic phase of dried over sodium sulfate, remove solvent and pass through silica gel column chromatography (methylene chloride) purifying resistates through merging.Then the product that obtains is an isomer mixture, and this mixture can be by carrying out full acetylated hydroxyl with the diacetyl oxide in methylene dichloride, pyridine and 4-dimethylamino pyridine and the gained acetylate being separated from ethyl alcohol recrystallization.The pure acetylize β-product (from the precipitation of ethanolic soln) that obtains like this changes into title product by remove ethanoyl with the 4M potassium hydroxide solution in methyl alcohol.
Productive rate: 1.6g (theoretical value 46%)
Mass spectrum (ESI +): m/z=398/400 (Cl) [M+NH 4] +
Embodiment XIII
Figure A200780015928D00391
1-chloro-2-(4-cyclopentyloxy benzyl)-4-(β-D-glucopyranose-1-yl)-benzene
0.16mL iodo pentamethylene is added in 1-chloro-4-(β-D-glucopyranose-1-yl)-2-(4-the hydroxybenzyl)-benzene and the mixture of 0.4g cesium carbonate in the 2.5mL dimethyl formamide of 0.25g.Mixture was stirred 4 hours down in 45 ℃, add 0.1g cesium carbonate and 0.05ml iodo pentamethylene subsequently again.After 45 ℃ of following restir 14 hours, add sodium chloride aqueous solution and with ethyl acetate extraction gained mixture.Through the dried over sodium sulfate organic phase, and removal solvent and use silica gel (methylene chloride 1:0-〉5:1) the purifying resistates.
Productive rate: 0.23g (theoretical value 78%)
Mass spectrum (ESI +): m/z=466/468 (Cl) [M+NH 4] +
Be similar to embodiment XIII and obtain following compounds:
(1) 1-chloro-4-(β-D-glucopyranose-1-yl)-2-[4-((S)-tetrahydrofuran (THF)-3-base oxygen base)-benzyl]-benzene
React as coupling collocation thing with (S)-toluene-4-sulfonic acid tetrahydrofuran (THF)-3-base ester.
Figure A200780015928D00392
Mass spectrum (ESI +): m/z=451/453 (Cl) [M+H] +
Embodiment XIV
1-chloro-4-(β-D-glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyl oxygen base)-benzyl]-benzene
The 4-dimethylamino pyridine of 10mg is added into the N of 1-chloro-4-(β-D-glucopyranose-1-yl)-2-(4-hydroxybenzyl)-benzene, 0.21ml triethylamine and the 0.39g of 0.38g, N-is two-solution of (trifluoromethane sulfonyl group)-aniline in the 10ml anhydrous methylene chloride in.Solution was stirred 4 hours at ambient temperature, and then merge with salt solution.With ethyl acetate extraction gained mixture, through the dried over sodium sulfate organic extract, and remove solvent.By silica gel column chromatography (methylene chloride is 1:0-〉4:1) purifying resistates.
Productive rate: 0.33g (theoretical value 64%)
Mass spectrum (ESI +): m/z=530/532 (Cl) [M+NH 4] +
Be similar to embodiment XIV and obtain following compounds:
(1) 1-cyano group-4-(β-D-glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyl oxygen base)-benzyl]-benzene
Figure A200780015928D00402
Mass spectrum (ESI +): m/z=504[M+H] +
Embodiment XV
Figure A200780015928D00411
1-chloro-4-(2,3,4,6-four-O-ethanoyl-β-D-glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyl oxygen base)-benzyl]-benzene
To the 1-of 5.6g chloro-4-(β-D-glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyl oxygen base)-benzyl)-the 4-dimethylamino pyridine of 7mL pyridine, 7.8mL diacetyl oxide and 0.12g added in the solution of benzene in the 75mL methylene dichloride successively.Solution was stirred 1 hour at ambient temperature.After adding 50mL water, with gained mixture restir 5 minutes.Separate organic phase and with 1M aqueous hydrochloric acid and sodium bicarbonate aqueous solution washing.After dried over mgso and evaporation organic solvent, generate the solid product that is white in color.
Productive rate: 7.0g (theoretical value 94%)
Mass spectrum (ESI +): m/z=698/700 (Cl) [M+NH 4] +
Be similar to embodiment XV, obtain following compounds:
(1) 1-cyano group-4-(2,3,4,6-four-O-ethanoyl-β-D-glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyl oxygen base)-benzyl]-benzene
Figure A200780015928D00412
Mass spectrum (ESI +): m/z=689[M+NH 4] +
Embodiment XVI
1-chloro-2-(4-ethynyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene
With 25mg cupric iodide, 44mg two-(triphenyl phosphine)-palladium chloride, 0.30ml triethylamine and final 0.14ml trimethyl silyl acetylene is added into 1-chloro-4-(β-D-glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyl oxygen base)-benzyl of 0.32g under argon)-solution of benzene in 3ml dimethyl formyl in.Flask is closely sealed and mixture was stirred 8 hours down in 90 ℃.Then add again 25mg two-(triphenyl phosphine)-palladium chloride and 0.1ml trimethyl silyl acetylene, and with solution in 90 ℃ of following restir 10 hours.Then add sodium bicarbonate aqueous solution, with ethyl acetate extraction gained mixture 3 times, and through the organic phase of dried over sodium sulfate through merging.After evaporating solvent, resistates is dissolved in the 5ml methyl alcohol and with 0.12g salt of wormwood merges.Mixture is stirred 1h at ambient temperature and then neutralize with 1M hydrochloric acid.Then methyl alcohol is removed in evaporation, with resistates with the salt solution merging and with ethyl acetate extraction.Through dried over sodium sulfate collected organic extract and removal solvent.By silica gel column chromatography (methylene chloride 1:0-〉5:1) purifying resistates.
Productive rate: 0.095g (theoretical value 40%)
Mass spectrum (ESI +): m/z=406/408 (Cl) [M+NH 4] +
Embodiment XVII
Figure A200780015928D00422
1-chloro-2-(4-ethyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene is dissolved in 1-chloro-2-(4-ethynyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene of 2.87g in 10ml ethyl acetate and the 5ml ethanol.Add palladium-carbon of 10% of 0.3g and the gained mixture stirred down in nitrogen atmosphere (latm) and spend the night.Concentrate through the diatomite filtration reaction mixture and with filtrate.Go up the purifying resistates by silica gel column chromatography (methylene chloride is 1:0-〉5:1).
Productive rate: 1.0g (theoretical value 34%)
Mass spectrum (ESI +): m/z=410/412 (Cl) [M+NH 4] +
Embodiment XVIII
Figure A200780015928D00431
1-chloro-2-[4-((S)-tetrahydrofuran (THF)-3-base oxygen base)-benzyl]-4-(2,3,4,6-four-O-ethanoyl-β-D-glucopyranose-1-yl) benzene
To the 1-of 2.02g chloro-4-(β-D-glucopyranose-1-yl)-2-[4-((S)-tetrahydrofuran (THF)-3-base oxygen base)-benzyl]-the 4-dimethylamino pyridine of 2.5mL pyridine, 2.8mL diacetyl oxide and 50mg added in the solution of benzene in the 20mL methylene dichloride successively.Reaction soln was stirred 4 hours at ambient temperature.With 50mL methylene dichloride diluting soln, with the 1M salt acid elution 2 times of 50mL and with sodium hydrogen carbonate solution washing 1 time.After dried over sodium sulfate, evaporating solvent is to produce product.
Productive rate: 2.53g (theoretical value 91%)
Mass spectrum (ESI +): m/z=642/644 (Cl) [M +Na] +
Be similar to embodiment XVIII and obtain following compounds:
(1) 1-chloro-2-(4-ethyl-benzyl)-4-(2,3,4,6-four-O-ethanoyl-β-D-glucopyranose-1-yl)-benzene
(2) 2-(4-acetoxyl group-benzyl)-1-chloro-4-(2,3,4,6-four-O-ethanoyl-β-D-glucopyranose-1-yl)-benzene
Figure A200780015928D00442
Mass spectrum (ESI +): m/z=608/610 (Cl) [M+NH 4] +
(3) 1-cyano group-2-(4-methoxyl group-benzyl)-4-(2,3,4,6-four-O-ethanoyl-β-D-glucopyranose-1-yl)-benzene
Figure A200780015928D00443
Mass spectrum (ESI +): m/z=567[M+Na] +
Embodiment XIX
Figure A200780015928D00451
1-chloro-2-(4-methyl-benzyl)-4-(2,3,4,6-four-O-ethanoyl-β-D-glucopyranose-1-yl)-benzene
Diisobutyl aluminium hydride (54 μ L, the 1mol/l in toluene) is added into 1,1 '-two (diphenylphosphino) ferrocene-dichloro palladium (II) (22mg) in the mixture in THF (3mL) and cool off in ice bath under Ar atmosphere.Mixture stirred in ice bath 0.5 hour and then add 1-chloro-4-(2,3,4,6-four-O-ethanoyl-β-D-glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyl oxygen base)-benzyl successively]-benzene (0.60g) and Me 2Zn (0.88mL, the 1mol/L in toluene).Remove ice bath and mixture is descended heating 2.5 hours in backflow.After being cooled to room temperature, add 1M hydrochloric acid and with the gained mixture with ethyl acetate extraction gained mixture.Through dried over sodium sulfate collected extract and removal solvent.By silica gel column chromatography (methylene chloride is 1:0-〉2:1) purifying resistates.
Productive rate: 0.25g (theoretical value 52%)
Embodiment XX
Figure A200780015928D00452
1-chloro-2-(4-cyano group-benzyl)-4-(2,3,4,6-four-O-ethanoyl-β-D-glucopyranose-1-yl)-benzene
Four (triphenyl phosphine) palladium (0) (0.13g) is added under argon gas atmosphere 1-chloro-4-(2 is housed; 3; 4,6-four-O-ethanoyl-β-D-glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyl oxygen base)-benzyl]-flask of benzene (0.80g) and zinc cyanide (0.14g) in.Mixture was stirred 3 hours down in 100 ℃.After being cooled to room temperature, adding ethyl acetate and filter the gained mixture, with NaHCO 3Solution washing, dry (sodium sulfate), and remove solvent.With resistates from ethyl alcohol recrystallization.
Productive rate: 0.45g (theoretical value 69%)
Mass spectrum (ESI +): m/z=580/582 (Cl) [M+Na] +
Embodiment XXI
Figure A200780015928D00461
4-cyclopropyl-phenyl-boron dihydroxide
Dropwise be added in the hexane solution (14.5mL) with the 2.5M n-Butyl Lithium in the 1-bromo-4-cyclopropyl-benzene (5.92g) in THF (14mL) and toluene (50mL) that is cooled to-70 ℃.Gained solution was stirred 30 minutes down in-70 ℃, add triisopropyl borate ester (8.5mL) subsequently.With the solution temperature to-20 ℃ and then handle with 4M aqueous hydrochloric acid (15.5mL).With reaction mixture further temperature to room temperature and then separate organic phase.With ethyl acetate extraction and drying (sodium sulfate) through merging organic phase.Evaporating solvent and be the product of colorless solid with the mixture debris of ether and hexanaphthene with generation.
Productive rate: 2.92g (theoretical value 60%)
Mass spectrum (ESI -): m/z=207 (Cl) [M+HCOO] -
Be similar to embodiment XXI and obtain following compounds:
(1) 4-difluoro-methoxy-phenyl-boron dihydroxide
Figure A200780015928D00462
Mass spectrum (ESI -): m/z=233 (Cl) [M+HCOO] -
Be different from above-mentioned steps, use iPrMgCl to generate arylide and catch this intermediate and prepare this compound with boric acid trimethylammonium ester from 4-difluoro-methoxy-1-iodo-benzene.
(2) 4-difluoro-methoxy-phenyl-boron dihydroxide
Figure A200780015928D00471
Mass spectrum (ESI +): m/z=172 (Cl) [M+H] +
Be different from above-mentioned steps, use iPrMgCl to generate arylide and catch this intermediate and prepare this compound with trimethyl borate from 4-difluoromethyl-1-iodo-benzene (the diethyl amido sulfur trifluoride (DAST) that is used in the methylene dichloride prepares from the 4-benzaldehyde iodine).
Embodiment XXII
1-bromo-4-cyano group-3-(4-methoxyl group-benzyl)-benzene
Temperature is remained on below 10 ℃, the mixture of N-methyl-pyrrolidin-2-one of the 1-bromo-4-cyano group-3-fluoro-benzene of (4-methoxyl group-phenyl)-ethyl acetate of 25g, 27.4g and 20mL slowly is added in the 31.4g potassium tert.-butoxide in 130mL N-methyl-pyrrolidin-2-one.At room temperature stir after the 1h, add 100mL methyl alcohol and 137mL 1M aqueous sodium hydroxide solution and mixture stirred under room temperature and spend the night.Evaporation methyl alcohol part is with 1M aqueous sodium hydroxide solution alkalization resistates and with the tertiary butyl-methyl ether extraction.Come the acidifying water and with the ethyl acetate extraction several times with 4M hydrochloric acid.Evaporation is through the acetic acid ethyl ester extract of merging and with the N of resistates together with 120mL, and dinethylformamide and 24.9g salt of wormwood heated 1 hour down in 100 ℃.With the sodium bicarbonate aqueous solution diluted reaction mixture and with the ethyl acetate extraction several times.Evaporation through merging extract and with resistates from methanol crystallization.
Productive rate: 13g (theoretical value 33%)
Mass spectrum (ESI +): m/z=319/321 (Br) [M+NH 4] +
Be similar to embodiment XXII and obtain following compounds:
(1) 1-bromo-4-cyano group-3-(4-cyclopropyl-benzyl)-benzene
Figure A200780015928D00481
Mass spectrum (ESI +): m/z=329/331 (Br) [M+NH 4] +
Be used to prepare the required phenyl acetic acid derivatives of this compound according to later step embodiment XXIII is synthetic.
Embodiment XXIII
Figure A200780015928D00482
4-cyclopropyl-Phenylacetic acid ethylester
According to Tetrahedron Lett.2002,43,6987-6990, be used in Tetrafluoroboric acid San Huan Ji Ji Phosphonium in toluene and the water, acid chloride, potassiumphosphate by transition metal-catalyzed down and the cyclopropylboronic acid coupling prepare by 4-bromo-Phenylacetic acid ethylester.
Mass spectrum (ESI +): m/z=205[M+H] +
Embodiment XXIV
Figure A200780015928D00491
1-cyano group-4-(β-D-glucopyranose-1-yl)-2-(4-methoxy-benzyl)-benzene
Stirring rod will be housed and be dissolved in 1-bromo-4-cyano group-3-(4-methoxyl group-benzyl)-benzene (9.90g) among the anhydrous THF (120mL) and the flask that remains under the argon atmospher is cooled to-87 ℃.(1.7M, pre-cooled (-70 ℃ approximately) solution in 39mL) slowly add so far in the solution and with gained solution and stirred 30 minutes down in-87 ℃ in pentane with tert-butyl lithium.Then add 2,3,4,6-four-O-(trimethyl silyl)-D-glucopyranose ketone (16.5g) is dissolved in the solution among the THF (80mL) and the solution that merges was stirred 1 hour down in-75 ℃.With NH 4Cl aqueous solution stopped reaction and with ethyl acetate extraction gained mixture.At dry (Na 2SO 4) organic extract and removing after the solvent, be dissolved in resistates in the methyl alcohol (150mL) and add methylsulfonic acid (5mL).Gained solution is stirred 8 hours down to generate required end group isomery (anomeric) configuration in 55 ℃.After being cooled to the cycle temperature, with the solid sodium bicarbonate neutralization solution, and vapourisation under reduced pressure methyl alcohol.Be added into salt solution in the residue and with ethyl acetate extraction gained mixture.Dry (sodium sulfate) extract and evaporating solvent through merging.Resistates is dissolved in acetonitrile (50mL) and the methylene dichloride (50mL) with reduction end group isomery carbon center.This solution being cooled to-20 ℃ and add triethyl silicane (16mL) afterwards, dropwise add boron trifluoride diethyl etherate compound (9.2mL).Reaction soln is slowly to warm to 0 ℃ and then by adding the sodium bicarbonate aqueous solution stopped reaction in cooling bath.Separate organic phase and with the ethyl acetate extraction water.Dry (sodium sulfate) organic phase through merging is removed solvent and by silica gel column chromatography (methylene chloride is 1:0-〉9:1) purifying resistates.
Productive rate: 5.2g (theoretical value 41%)
Mass spectrum (ESI +): m/z=403[M+NH 4] +
Be similar to embodiment XXIV and obtain following compounds:
(1) 1-cyano group-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene
Figure A200780015928D00501
Mass spectrum (ESI -): m/z=413[M+H] +
Advantageously, the oxygen functional group's reduction the end group isomery carbon center that synthesizes the suitable intermediate that is obtained during this compound mutters the sugar ring with protected piperazine on.Preferably protecting group be benzyl, to methoxy-benzyl, trimethyl silyl, triethyl silyl, tertiary butyl dimethylsilyl, tri isopropyl silane base and allyl group.
Embodiment XXV
Figure A200780015928D00502
1-cyano group-2-(4-cyclopropyl-benzyl)-4-(four-O-ethanoyl-β-D-glucopyranose-1-yl)-benzene
To stirring rod, 4-(2 are housed; 3; 4,6-four-O-ethanoyl-D-glucopyranose-1-yl)-2-(4-trifluoromethyl sulfonyloxy-benzyl)-cyanobenzene (4.4g), degassed toluene (12mL) and de aerated water (8mL) and the flask that remains under the argon atmospher add cyclopropylboronic acid (0.20g), potassiumphosphate (5.0g), tricyclohexyl phosphine (0.19g) and acid chloride (II) (76mg).Mixture was stirred 6 hours down in 110 ℃, after per 1 hour, add cyclopropylboronic acid (5 x 0.20g) simultaneously.After being cooled to room temperature, with sodium bicarbonate aqueous solution diluted mixture thing and with ethyl acetate extraction.Dry (sodium sulfate) goes down to desolventize through the extract of merging and in decompression.Through silica gel (cyclohexane/ethyl acetate is 20:1-〉1:1) residue of chromatography.
Productive rate: 3.2g (theoretical value 87%)
Mass spectrum (ESI +): m/z=581[M+NH 4] +
Embodiment XXVI
4-(1-hydroxyl-cyclopropyl)-phenyl-boron dihydroxide
The 3.0M solution of ethyl-magnesium-bromide in ether (7.6mL) is added into (2.2mL) being cooled in-78 ℃ the stirred solution in ether (70mL) of titanium isopropylate (IV).Gained solution was stirred 1.5 hours down in-78 ℃, add 4-(4,4,5,5-[1,3,2] two oxa-boron heterocycles, penta-2-yl)-methyl benzoate (2.0g) subsequently.With the reaction mixture temperature to surrounding temperature and restir 12 hours.Then add the 1M aqueous hydrochloric acid and with ethyl acetate extraction gained mixture.Dry (sodium sulfate) organic extract and evaporating solvent through merging.Resistates is dissolved in the acetone (60mL), and adds the NH of 0.1M 4The OAc aqueous solution (50mL) adds NaIO then 4(2.3g).The gained reaction mixture was stirred under room temperature 18 hours.After removing acetone, with the ethyl acetate extraction resistates.Dry (sodium sulfate) extract and evaporating solvent through merging.By silica gel column chromatography (cyclohexane/ethyl acetate) purifying resistates.
Productive rate: 0.45g (theoretical value 33%)
Mass spectrum (ESI -): m/z=223[M+HCOO] -
The preparation of final compound:
Reference example 1
Figure A200780015928D00512
4-(β-D-glucopyranose-1-yl)-2-[4-((S)-tetrahydrofuran base-3-oxygen base)-benzyl]-cyanobenzene
1-chloro-2-[4-((S)-tetrahydrofuran base-3-oxygen base)-benzyl with 1.00g]-4-(2; 3; 4,6-four-O-ethanoyl-β-D-glucopyranose-1-yl)-benzene, 0.16g sodium cyanide and the microwave oven heating of the mixture of 0.35g nickelous bromide in 2.5mL N-N-methyl-2-2-pyrrolidone N-under 220 ℃ 15 minutes.After being cooled to room temperature, add water and with ethyl acetate extraction gained mixture.After dried over sodium sulfate and evaporating solvent, resistates is dissolved in the 5mL methyl alcohol.Add the 4M potassium hydroxide aqueous solution of 4mL and reaction soln was stirred 3 hours at ambient temperature.With 1M hydrochloric acid neutralization solution and evaporation methyl alcohol.With the ethyl acetate extraction resistates, through the extract of dried over sodium sulfate through merging, and in reducing pressure down to desolventize.By silica gel column chromatography (methylene chloride is 4:1) purifying resistates.
Productive rate: 0.35g (theoretical value 49%)
Mass spectrum (ESI +): m/z=442[M+H] +
Be similar to reference example 1, obtain the compound of embodiment 1,2,3 and 4:
Embodiment 1:2-(4-ethyl-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
Figure A200780015928D00521
Productive rate: 65% of theoretical value
Mass spectrum (ESI +): m/z=401[M+NH 4] +
Be similar to embodiment 6, use 4-ethylphenyl boric acid also can prepare this compound as coupling collocation thing.
Embodiment 2:4-(β-D-glucopyranose-1-yl)-2-(4-hydroxyl-benzyl)-cyanobenzene
According to above-mentioned steps, prepare this compound from 2-(4-acetoxyl group-benzyl)-1-chloro-4-(2,3,4,6-four-O-ethanoyl-β-D-glucopyranose-1-yl)-benzene.
Figure A200780015928D00531
Productive rate: 30% of theoretical value
Mass spectrum (ESI +): m/z=389[M+NH 4] +
Also by full acetylated 2-(4-methoxyl group-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene, obtain this compound with boron tribromide cracking ether and deacetylation then.
Embodiment 3:4-(β-D-glucopyranose-1-yl)-2-(4-methyl-benzyl)-cyanobenzene
Figure A200780015928D00532
Productive rate: 59% of theoretical value
Mass spectrum (ESI +): m/z=387[M+NH 4] +
Be similar to embodiment 6, use 4-aminomethyl phenyl boric acid also can prepare this compound as coupling collocation thing.
Embodiment 4:2-(4-cyano group-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
Figure A200780015928D00533
Productive rate: 58% of theoretical value
Mass spectrum (ESI +): m/z=398[M+NH 4] +
Embodiment 5
Figure A200780015928D00541
4-(β-D-glucopyranose-1-yl)-2-(4-methoxy ethoxy-benzyl)-cyanobenzene
2-bromo-ethyl-methyl ether (85 μ l) is added in 4-(β-D-glucopyranose-1-yl)-2-(4-hydroxybenzyl)-cyanobenzene (0.30g) and the mixture of cesium carbonate (0.39g) in the 3mL dimethyl formamide.Mixture was stirred 16 hours down in 80 ℃, add water and salt solution subsequently.With ethyl acetate extraction gained mixture, through the extract of dried over sodium sulfate through merging, and in reducing pressure down to desolventize.By silica gel column chromatography (methylene chloride is 1:0-〉5:1) purifying resistates.
Productive rate: 0.19g (theoretical value 49%)
Mass spectrum (ESI +): m/z=430[M+H] +
Embodiment 6
Figure A200780015928D00542
4-(β-D-glucopyranose-1-yl)-2-(4-trifluoromethoxy-benzyl)-cyanobenzene
2-brooethyl-4-(2 packs in the flask of filling through argon gas; 3; 4,6-four-O-ethanoyl-D-glucopyranose-1-yl)-the 3:1 mixture (4mL) of cyanobenzene (0.25g), 4-trifluoromethoxy-phenyl-boron dihydroxide (0.20g), salt of wormwood (0.26g) and degassing acetone and water.Mixture was stirred under room temperature 5 minutes, subsequently in ice bath with its cooling.Then add palladium chloride (5mg) and reaction mixture was stirred 16 hours at ambient temperature.Then with salt solution diluted mixture thing and with ethyl acetate extraction.Go down to desolventize through the extract of merging and in decompression through dried over sodium sulfate.Resistates is dissolved in the methyl alcohol (9mL) and with 4M potassium hydroxide aqueous solution (1mL) handles.Gained solution is stirred 1h at ambient temperature and then neutralize with 1M hydrochloric acid.Evaporation methyl alcohol, and with salt solution dilution resistates and with ethyl acetate extraction.Through dried over sodium sulfate collected organic extract and removal solvent.Through silica gel (methylene chloride 1:0-〉8:1) residue of chromatography.
Productive rate: 0.145g (theoretical value 69%)
Mass spectrum (ESI +): m/z=457[M+NH 4] +
In some cases, increase productive rate by the alkali that uses 1.5 to 2.0 normal boric acid and proportional increase.
Be similar to embodiment 6 and obtain following compounds:
Embodiment 7:4-(β-D-glucopyranose-1-yl)-2-(4-trifluoromethyl-benzyl)-cyanobenzene
Figure A200780015928D00551
Productive rate: 47% of theoretical value
Mass spectrum (ESI +): m/z=441[M+NH 4] +
Embodiment 8:4-(β-D-glucopyranose-1-yl)-2-(4-sec.-propyl-benzyl)-cyanobenzene
Figure A200780015928D00552
Productive rate: 87% of theoretical value
Mass spectrum (ESI +): m/z=415[M+NH 4] +
Embodiment 9:4-(β-D-glucopyranose-1-yl)-2-(the 4-tertiary butyl-benzyl)-cyanobenzene
Productive rate: 66% of theoretical value
Mass spectrum (ESI +): m/z=429[M+NH 4] +
Embodiment 10:4-(β-D-glucopyranose-1-yl)-2-(4-trimethyl silyl-benzyl)-cyanobenzene
Productive rate: 70% of theoretical value
Mass spectrum (ESI +): m/z=445[M+NH 4] +
Embodiment 11:4-(β-D-glucopyranose-1-yl)-2-(4-methylthio group-benzyl)-cyanobenzene
Productive rate: 47% of theoretical value
Mass spectrum (ESI +): m/z=419[M+NH 4] +
Embodiment 12:4-(β-D-glucopyranose-1-yl)-2-[4-(3-methyl-Ding-1-yl)-benzyl]-cyanobenzene
Figure A200780015928D00572
Productive rate: 69% of theoretical value
Mass spectrum (ESI +): m/z=443[M+NH 4] +
Embodiment 13:2-(4-fluoro-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
Productive rate: 34% of theoretical value
Mass spectrum (ESI +): m/z=391[M+NH 4] +
Embodiment 14:2-(4-chloro-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
Figure A200780015928D00581
Productive rate: 32% of theoretical value
Mass spectrum (ESI +): m/z=407/409 (Cl) [M+NH 4] +
Embodiment 15:2-(4-difluoro-methoxy-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
Figure A200780015928D00582
Productive rate: 32% of theoretical value
Mass spectrum (ESI +): m/z=439[M+NH 4] +
Embodiment 16:2-(4-difluoromethyl-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
Figure A200780015928D00583
Productive rate: 65% of theoretical value
Mass spectrum (ESI +): m/z=423[M+NH 4] +
Embodiment 17:2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
Figure A200780015928D00591
Mass spectrum (ESI +): m/z=413[M+NH 4] +
According to embodiment 6, use 4-cyclopropyl-phenyl-boron dihydroxide to obtain this compound as coupling collocation thing.
Productive rate: 83% of theoretical value
Perhaps, described in embodiment XXIV (1), obtain this compound.
By using the following step also to obtain the compound of embodiment 17:
(4mol/l 5mL) handles 2-(4-cyclopropyl-benzyl)-4-(2,3,4,6-four-O-ethanoyl-D-glucopyranose-1-yl)-solution of cyanobenzene (0.80g) in methyl alcohol (5mL) and THF (5mL) with potassium hydroxide aqueous solution.Reaction soln is stirred 1h at ambient temperature and then neutralize with 1M hydrochloric acid.Evaporate organic solvent and dilute resistates with salt solution, and with ethyl acetate extraction.Dry (sodium sulfate) organic extract and removal solvent.Through silica gel (methylene chloride is 1:0-〉9:1) residue of chromatography.
Productive rate: 0.54g (theoretical value 96%)
Embodiment 18:2-(4-cyclobutyl-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
According to embodiment 6, use 4-cyclobutyl boric acid (can be similar to embodiment XXI obtains) to obtain this compound as the coupling collocation.
Productive rate: 51% of theoretical value
Mass spectrum (ESI -): m/z=427[M+NH 4] +
Embodiment 19:4-(β-D-glucopyranose-1-yl)-2-(4-third-1-base-benzyl)-cyanobenzene
Figure A200780015928D00601
Productive rate: 64% of theoretical value
Mass spectrum (ESI +): m/z=415[M+NH 4] +
Embodiment 20:4-(β-D-glucopyranose-1-yl)-2-[4-(1-hydroxyl-cyclopropyl)-benzyl)-cyanobenzene
Figure A200780015928D00602
According to embodiment 6, use 4-(1-hydroxyl-cyclopropyl)-phenyl-boron dihydroxide can obtain this compound as the coupling collocation.
Embodiment 21
Figure A200780015928D00611
4-(β-D-glucopyranose-1-yl)-2-(4-iodo-benzyl)-cyanobenzene
The 1M solution of iodine monochloride in methylene dichloride (0.9mL) is added in 4-(β-D-glucopyranose-1-yl)-2-(4-trimethyl silyl-benzyl)-cyanobenzene (0.26g) that is dissolved in the methylene dichloride (5mL).Solution is at room temperature stirred 1h and then passes through to add Na 2S 2O 3The aqueous solution and NaHCO 3The aqueous solution is ended.Separate that organic phase is separated and with the ethyl acetate extraction water.Through organic phase and the removal solvent of dried over sodium sulfate through merging.Through silica gel (methylene chloride is 1:0-〉8:1) residue of chromatography.
Productive rate: 0.15g (theoretical value 88%)
Mass spectrum (ESI +): m/z=499[M+NH 4] +
Be similar to embodiment 20 and can obtain following compounds:
(22) 2-(4-bromo-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
Figure A200780015928D00612
Productive rate: 79% of theoretical value
Mass spectrum (ESI +): m/z=451/453[M+NH 4] +
According to the step of embodiment 20, use the ICl in the bromine instead of methylene chloride to obtain this compound.
Embodiment 23
Figure A200780015928D00621
4-(β-D-glucopyranose-1-yl)-2-(4-pentafluoroethyl group-benzyl)-cyanobenzene
4-(2 will be housed; 3; 4,6-four-O-ethanoyl-β-D-glucopyranose-1-yl)-flask of 2-(4-iodo-benzyl)-cyanobenzene (0.16g), pentafluoroethyl group trimethyl silane (0.14g), KF (43mg), CuI (0.16g), DMF (2mL) and the charging of Ar atmosphere is in 60 ℃ of heating 24 hours down.Then add NaHCO 3The aqueous solution and with ethyl acetate extraction gained mixture.Through organic phase and the removal solvent of dried over sodium sulfate through merging.Resistates is dissolved in the methyl alcohol (8mL) and with 4M KOH solution (0.8mL) handles.Solution stirred 1h and then with NaHCO under room temperature 3Aqueous solution dilution.Under reducing pressure, remove after the methyl alcohol, with the ethyl acetate extraction resistates, dry organic extract and removal solvent through merging.Through silica gel (methylene chloride is 1:0-〉8:1) residue of chromatography.
Productive rate: 0.08g (theoretical value 69%)
Mass spectrum (ESI +): m/z=491[M+NH 4] +
Embodiment 24
Figure A200780015928D00622
4-(β-D-glucopyranose-1-yl)-2-(4-methylsulfinyl-benzyl)-cyanobenzene
The aqueous solution (48 μ L) of 35% hydrogen peroxide is added as for 1,1,1,3,3, in the 4-in the 3-hexafluoroisopropanol (2mL) (β-D-glucopyranose-1-yl)-2-(4-methylthio group-benzyl)-cyanobenzene (83mg).Gained solution is stirred 1h at ambient temperature and then passes through to add Na 2S 2O 3The aqueous solution and NaHCO 3The aqueous solution is ended.Separate organic phase and with the ethyl acetate extraction water.Through organic phase and the removal solvent of dried over sodium sulfate through merging.Through silica gel (methylene chloride is 1:0-〉5:1) residue of chromatography.
Productive rate: 24mg (theoretical value 28%)
Mass spectrum (ESI +): m/z=418[M+H] +
Embodiment 25
Figure A200780015928D00631
4-(β-D-glucopyranose-1-yl)-2-(4-methyl sulphonyl-benzyl)-cyanobenzene
With the 3-chloroperoxybenzoic acid (70%, 0.14g) be added in ice bath in 4-(β-D-glucopyranose-1-yl)-2-(4-methylthio group-benzyl)-cyanobenzene (100mg) of refrigerative in methylene dichloride (2mL).Remove cooling bath and gained solution was stirred 1 hour at ambient temperature.Add Na 2S 2O 3The aqueous solution and NaHCO 3After the aqueous solution, separate organic phase and will be with the ethyl acetate extraction water.Through organic phase and the removal solvent of dried over sodium sulfate through merging.Through silica gel (methylene chloride is 1:0-〉8:1) residue of chromatography.
Productive rate: 68mg (theoretical value 63%)
Mass spectrum (ESI +): m/z=451[M+NH 4] +
Be similar to the foregoing description or the additive method known to document also can prepare following compounds:
Figure A200780015928D00632
Figure A200780015928D00641
Figure A200780015928D00651
To describe the embodiment of some preparations now, wherein one or more compound of the present invention represented in term " active substance ", comprises its prodrug or salt.As previously mentioned with a kind of situation of other active substance combination under, term " active substance " also comprises other active substances.
Embodiment A
The tablet that contains the 100mg active substance
Form:
1 tablet contains:
Active substance 100.0mg
Lactose 80.0mg
W-Gum 34.0mg
Polyvinylpyrrolidone 4.0mg
Magnesium Stearate 2.0mg
220.0mg
The preparation method:
Active substance, lactose and starch mixed and moistening with polyvinylpyrrolidone aqueous solution homogeneous.Wet mixture is sieved (2.0mm screen size) and in frame type (rack-type) moisture eliminator after 50 ℃ of following dryings, it is sieved once more (1.5mm screen size) and adds lubricant.The final mixture compressing tablet is formed tablet.
Tablet weight: 220mg
Diameter: 10mm, two-sided, in the both sides portrayal and in a side indentation is arranged.
Embodiment B
The tablet that contains the 150mg active substance
Form:
1 tablet contains:
Active substance 150.0mg
Powdered lactose 89.0mg
W-Gum 40.0mg
Silica colloidal 10.0mg
Polyvinylpyrrolidone 10.0mg
Magnesium Stearate 1.0mg
300.0mg
Preparation:
Will and sieve by 1.5mm screen size wetting with the 20% polyvinylpyrrolidone aqueous solution with lactose, W-Gum and silicon-dioxide blended active substance.Make 45 ℃ of following dry granules and pass identical sieve once more and mix with the Magnesium Stearate of specified quantitative.Mixture is pressed into tablet.
Tablet weight: 300mg
Diameter: 10mm is flat
Embodiment C
The hard capsule that contains the 150mg active substance
Form:
1 capsule contains:
Active substance 150.0mg
W-Gum (drying) is 180.0mg approximately
Lactose (Powdered) is 87.0mg approximately
Magnesium Stearate 3.0mg
About 420.0mg
Preparation:
With active substance and mixed with excipients, by the sieve and the use suitable equipment uniform mixing of 0.75mm screen size.Final mixture is packed in the hard capsule of specification 1.
Capsule filler: about 320mg
Capsule shell: the hard capsule of specification 1.
Embodiment D
The suppository that contains the 150mg active substance
Form:
1 suppository contains:
Active substance 150.0mg
Polyethylene glycol 1500 550.0mg
Polyethylene glycol 6000 460.0mg
Polyoxyethylene sorbitan monostearate 840.0mg
2,000.0mg
Preparation:
After the fusion of suppository material, active substance is uniformly distributed in wherein, and with in the melt impouring cooling die.
Embodiment E
The ampoule that contains the 10mg active substance
Form:
Active substance 10.0mg
0.01N hydrochloric acid is an amount of
Distilled water adds to 2.0ml
Preparation:
Active substance is dissolved among the HCl of 0.01N of necessary amounts, its grade is opened, sterile filtration and being transferred in the 2ml ampoule with salt.
Embodiment F
The ampoule that contains the 50mg active substance
Form:
Active substance 50.0mg
0.01N hydrochloric acid is an amount of
Distilled water adds to 10.0ml
Preparation:
Active substance is dissolved among the HCl of 0.01N of necessary amounts, its grade is opened, sterile filtration and being transferred in the 10ml ampoule with salt.

Claims (12)

1. the cyanobenzene derivative that is replaced by the glucopyranose base of formula I; Comprise its tautomer, steric isomer or its mixture; And acceptable salt on the physiology:
Figure A200780015928C00021
Wherein
R 3Expression hydrogen; fluorine; chlorine; bromine; iodine; methyl; ethyl; propyl group; sec.-propyl; butyl; sec-butyl; isobutyl-; the tertiary butyl; 3-methyl-Ding-1-base; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; 1-hydroxyl-cyclopropyl; 1-hydroxyl-cyclobutyl; 1-hydroxyl-cyclopentyl; 1-hydroxyl-cyclohexyl; difluoromethyl; trifluoromethyl; pentafluoroethyl group; 2-hydroxyl-ethyl; hydroxymethyl; 3-hydroxyl-propyl group; 2-hydroxy-2-methyl-third-1-base; 3-hydroxy-3-methyl-Ding-1-base; 1-hydroxyl-1-methyl-ethyl; 2; 2; 2-three fluoro-1-hydroxyl-1-methyl-ethyls; 2; 2; 2-three fluoro-1-hydroxyl-1-trifluoromethyl-ethyls; 2-methoxyl group-ethyl; 2-oxyethyl group-ethyl; hydroxyl; difluoro-methoxy; trifluoromethoxy; 2-methoxyl group-oxyethyl group; methylthio group; methylsulfinyl; methyl sulphonyl; the ethyl sulfinyl; ethylsulfonyl; trimethyl silyl and cyano group
Or derivatives thereof: wherein one or more hydroxyl of β-D-glucopyranose base is selected from (C 1-18Alkyl) carbonyl, (C 1-18Alkyl) oxygen base carbonyl, phenylcarbonyl group and phenyl-(C 1-3Alkyl)-the group acidylate of carbonyl.
2. cyanobenzene derivative or its physiologically acceptable salt that is replaced by the glucopyranose base as claimed in claim 1, wherein the hydrogen atom of the hydroxyl O-6 of this β-D-glucopyranose base is through being selected from (C 1-8Alkyl) carbonyl, (C 1-8Alkyl) group displacement in oxygen base carbonyl and the phenylcarbonyl group.
3. the physiologically acceptable salt that compound as claimed in claim 1 or 2 and mineral acid or organic acid form.
4. pharmaceutical composition, it comprises acceptable salt on compound as claimed in claim 1 or 2 or the physiology as claimed in claim 3, and randomly one or more inert support and/or thinner.
5. be suitable for treating or prevent in preparation can be by the purposes in the pharmaceutical composition of disease that suppresses sodium dependent glucose cotransporter SGLT influence or illness for acceptable salt at least a compound as claimed in claim 1 or 2 or the physiology as claimed in claim 3.
6. acceptable salt is suitable for treating or prevents purposes in the pharmaceutical composition of one or more metabolic disturbance in preparation at least a compound as claimed in claim 1 or 2 or the physiology as claimed in claim 3.
7. purposes as claimed in claim 6 is characterized in that this metabolic disturbance is selected from hyperlipemia, atherosclerosis and relative disease, obesity, hypertension, chronic heart failure, oedema and the hyperuricemia of 1 type and diabetes B, diabetic complication, metabolic acidosis or ketoacidosis, reactive hypoglycemia disease, hyperinsulinemia, glucose metabolism obstacle, insulin resistant, metabolism syndrome, different causes.
8. acceptable salt is used for suppressing the purposes of the pharmaceutical composition of sodium dependent glucose cotransporter SGLT2 at least a compound as claimed in claim 1 or 2 or the physiology as claimed in claim 3 in preparation.
9. the purposes that acceptable salt is used for preventing the pancreatic beta cell degeneration and/or is used to improve and/or recover the pharmaceutical composition of pancreatic beta cell function in preparation at least a compound as claimed in claim 1 or 2 or the physiology as claimed in claim 3.
10. the purposes of the pharmaceutical composition of acceptable salt disease that the liver fat abnormal accumulation causes in preparation is used for preventing, slow down, postpone or treats owing to patient's body that these needs are arranged or illness at least a compound as claimed in claim 1 or 2 or the physiology as claimed in claim 3.
11. the purposes of acceptable salt in preparation diuretic(s) and/or hypotensive agent at least a compound as claimed in claim 1 or 2 or the physiology as claimed in claim 3.
12. formula II, formula III, formula i.1, formula i.2, formula i.3, formula i.4, formula i.5 or the formula cyanobenzene derivative that is replaced by the glucopyranose base i.6, comprise its tautomer, steric isomer or its mixture; And acceptable salt on the physiology:
Figure A200780015928C00031
Figure A200780015928C00041
Figure A200780015928C00051
Wherein
R 3As defined in claim 1, and
R ' represents H, C 1-4Alkyl, (C 1-18Alkyl) carbonyl, (C 1-18Alkyl) oxygen base carbonyl, aryl carbonyl or aryl-(C 1-3Alkyl)-and carbonyl, wherein these alkyl or aryls can be by halogen list or polysubstituted;
R 8a, R 8b, R 8c, R 8dRepresent hydrogen or allyl group, benzyl, (C independently of one another 1-4Alkyl) carbonyl, (C 1-4Alkyl) oxygen base carbonyl, aryl carbonyl, aryl-(C 1-3Alkyl)-carbonyl and aryl-(C 1-3Alkyl)-oxygen base carbonyl or R aR bR cSi base or ketal or acetal radical especially are alkylidene group or aryl alkylene ketal or acetal radical, simultaneously two adjacent group R under each situation 8a, R 8b, R 8c, R 8dCan form cyclic ketal or acetal radical or 1,2-two (C 1-3Alkoxyl group)-1,2-two (C 1-3Alkyl)-and ethylene bridge, this above-mentioned ethylene bridge forms substituted diox ring with two Sauerstoffatoms and two carbon atoms that link to each other of pyranose ring simultaneously, especially is 2,3-dimethyl-2,3-two (C 1-3Alkoxyl group)-1,4-diox ring, and alkyl, allyl group, aryl and/or benzyl can be by halogen or C 1-3Alkoxyl group list or polysubstituted, and benzyl also can be by two-(C 1-3Alkyl) the amino replacement; And
R a, R b, R cRepresent C independently of one another 1-4Alkyl, aryl or aryl-C 1-3Alkyl, wherein this aryl or alkyl can be by halogen lists or polysubstituted;
These aryl described in the definition of these above-mentioned groups refer to phenyl or naphthyl simultaneously, are preferably phenyl; And
Alk represents C 1-4Alkyl; And
R 1The aldehyde radical of expression chlorine, bromine, cyano group, carboxyl, carboxylicesters, carboxylic acid amides or derivatives thereof, boron or silyl, protected or crested, or the amino of protected or crested, R 1Preferably represent Br or CN; And
LG represents leaving group, for example Br, I or-O-(SO 2)-CF 3 -And
U represent Cl, Br, I ,-O-CO-C 1-4Alkyl ,-O-C (=O)-O-C 1-4Alkyl or-OPO (O-C 1-4Alkyl) 2
CNA2007800159285A 2006-05-03 2007-05-02 Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture Pending CN101437807A (en)

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WO2019185026A1 (en) * 2018-03-30 2019-10-03 南京明德新药研发有限公司 Glucoside derivatives acting as inhibitors of sglts, and use thereof
CN111511725A (en) * 2017-12-19 2020-08-07 勃林格殷格翰维特梅迪卡有限公司 Synthesis of 1:1:1 cocrystals of 1-cyano-2- (4-cyclopropyl-benzyl) -4- (β -D-glucopyranos-1-yl) -benzene, L-proline and water

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WO2005092877A1 (en) * 2004-03-16 2005-10-06 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
CN111511725A (en) * 2017-12-19 2020-08-07 勃林格殷格翰维特梅迪卡有限公司 Synthesis of 1:1:1 cocrystals of 1-cyano-2- (4-cyclopropyl-benzyl) -4- (β -D-glucopyranos-1-yl) -benzene, L-proline and water
CN111511725B (en) * 2017-12-19 2024-04-09 勃林格殷格翰维特梅迪卡有限公司 1-cyano-2- (4-cyclopropyl-benzyl) -4-) (beta-D-glucopyranos-1-yl) -benzene Synthesis of 1:1:1 Co-crystals of L-proline and Water
WO2019185026A1 (en) * 2018-03-30 2019-10-03 南京明德新药研发有限公司 Glucoside derivatives acting as inhibitors of sglts, and use thereof

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