CN101343296A - Inhibitors of sodium glucose co-transporter 2 and methods of their use - Google Patents

Inhibitors of sodium glucose co-transporter 2 and methods of their use Download PDF

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Publication number
CN101343296A
CN101343296A CNA2008100900739A CN200810090073A CN101343296A CN 101343296 A CN101343296 A CN 101343296A CN A2008100900739 A CNA2008100900739 A CN A2008100900739A CN 200810090073 A CN200810090073 A CN 200810090073A CN 101343296 A CN101343296 A CN 101343296A
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compound
optional substituted
hydrogen
benzyl
phenyl
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CN101343296B (en
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尼克勒·C·古德温
布赖斯·A·哈里森
斯彭尼尔·D·金博尔
罗斯·玛博恩
大卫·B·拉瓦琳斯
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Lexicon Pharmaceuticals Inc
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Lexicon Genetics Inc
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Abstract

Compounds and pharmaceutical compositions comprising them are disclosed that may be useful for the treatment of diseases and disorders such as diabetes and obesity.

Description

Inhibitor of sodium glucose co-transporter 2 white 2 and using method thereof
The application requires the right of priority of the U.S. Provisional Application 60/948,780 of submission on July 10th, 2007, and its full content is merged in this paper as a reference.
Technical field
The present invention relates to treat for example method of diabetes of metabolic disease and illness, and relate to compound and the pharmaceutical composition that is used for described method.
Background technology
White 2 (SGLT2) of sodium glucose co-transporter 2 absorb glucose again and prevent the translocator that glucose loses urine from kidney filtrate.Because the competitive inhibitor of SGLT2 causes the renal excretion of glucose, they can make the horizontal normalizing of hyperglycemia that for example diabetes are relevant with disease.Handlon，A.L.， Expert Opin.Ther.Patents15(11)：1531-1540(2005)。
Many SGLT2 inhibitor are disclosed.Referring to for example, Handlon, ibid; United States Patent (USP) 6,515,117; U.S. Patent application US 2006/0035841, US 2004/0138439.At least a inhibitor is in the clinical development stage, is used for the treatment of diabetes B.Referring to for example, Komoroski, B. wait the people, " Dapagliflozin (BMS-512148); a Selective Inhibitor ofthe Sodium-Glucose Uptake Transporter 2 (SGLT2), Reduces FastingSerum Glucose and Glucose Excursion in Type 2 Diabetes MellitusPatients Over 14 Days " American Diabetes Assn.67 Th Scientific Sessions, Abstract 0188-OR (2007).
First known SGLT2 inhibitor is a natural product phlorizin (glucose, 1-[2-(β-D-Glucopyranose oxygen base)-4, the 6-dihydroxy phenyl]-3-(4-hydroxy phenyl)-1-acetone), and " all SGLT2 inhibitor subsequently all are the glucosides classes derived from its structure ".Handlon, ibid, at the 1533rd page.Phlorizin comprises glucose moiety and two hydroxylated aromatic rings that are connected by the acetone compartment.Ehrenkranz, people such as J.R.L., Diabetes Metab.Res.Rev.21:31-38 (2005).Do not show any synthetic SGLT2 inhibitor about the summary of patent documentation and do not contain glucosides part or derivatives thereof.Handlon, ibid.In fact, ", find that for possible drug invention people the chemical space that is not studied becomes difficult further " owing to the relative uniformity of glucosides in the SGLT2 patent documentation.Ibid, at the 1537th page.But, still carrying out various trials.Referring to for example, people's such as Eckhardt title is " D-Xylopyranosyl-Substituted phenyl Derivatives; MedicamentsContaining Such Compounds; Their Use and Process for TheirManufacture " U.S. Patent application 11/168,905; People's titles such as Eckhardt are " methylidene-D-Xylopyranosyl-and Oxo-D-Xylopyranosyl-Substitutedphenyl Derivatives; Medicaments Containing Such Compounds; Their Useand Process for Their Manufacture " U.S. Patent application 11/182,986; With people's such as Eckhardt title be " D-Xylopyranosyl-phenyl-Substituted Cycles; Medicaments Containing Such Compounds; Their Use and Process forTheir Manufacture " U.S. Patent application 11/199,962.
Summary of the invention
The present invention relates to novel SGLT2 inhibitor.One embodiment of the invention comprise the compound of following formula:
Figure A20081009007300121
And pharmaceutically useful salt and solvate, wherein: A is optional substituted aryl, cycloalkyl or heterocycle; X is O, S or NR 3When X is O, R 1Be OR 1A, SR 1A, SOR 1A, SO 2R 1AOr N (R 1A) 2When X is S, R 1Be hydrogen, OR 1A, SR 1A, SOR 1A, or SO 2R 1AWhen X is NR 3The time, R 1Be OR 1A, SR 1A, SOR 1A, SO 2R 1A, or R 1AEach R 1ABe hydrogen or optional substituted alkyl, aryl or heterocycle independently; R 2Be fluorine or OR 2AR 2A, R 2B, and R 2CIn each is hydrogen, optional substituted alkyl, C (O) alkyl, C (O) aryl or aryl independently; R 3Be hydrogen, C (O) R 3A, CO 2R 3A, CON (R 3B) 2, or optional substituted alkyl, aryl or heterocycle; Each R 3ABe optional substituted alkyl or aryl independently; With each R 3BBe hydrogen or optional substituted alkyl or aryl independently.
Another embodiment comprises the compound of following formula:
Figure A20081009007300131
And pharmaceutically useful salt and solvate, wherein: A is optional substituted aryl, cycloalkyl or heterocycle; X is O or NR 3R 2Be fluorine or OR 2AR 2A, R 2B, and R 2CIn each is hydrogen, optional substituted alkyl, C (O) alkyl, C (O) aryl or aryl independently; R 3Be hydrogen or optional substituted alkyl, aryl or heterocycle; R 8Be hydrogen or C (O) R 8AR 8ABe hydrogen or optional substituted alkyl, alkoxyl group or aryl; R 9AAnd R 9BBe OR independently of one another 9COr SR 9C, or lump together and form O, S or NR 9CWith each R 9CBe optional substituted alkyl, aryl or heterocycle independently.
The present invention includes pharmaceutical composition, this pharmaceutical composition comprises compound disclosed herein.The present invention also comprises the active method of inhibition SGLT2, and the method for treatment, prevention and reply various diseases and illness.
Description of drawings
Can understand some aspect of the present invention with reference to figure 1, Fig. 1 represents the urine glucose excretory influence of all cpds of the present invention to mouse.Compound is used with oral the giving of 30mg/kg.
Detailed Description Of The Invention
The present invention is based in part on the discovery that following formula: compound can suppress sodium glucose co-transporter 2 white 2 (SGLT2):
Figure A20081009007300141
Substituting group wherein is as giving a definition.
Definition
Except as otherwise noted, term " thiazolinyl " refers to the hydrocarbon of straight chain, side chain and/or ring-type, has the individual carbon atom of 2 to 20 (for example, 2 to 10 or 2 to 6), and comprises at least one carbon-carbon double bond. Representational thiazolinyl comprises vinyl, pi-allyl, 1-cyclobutenyl, 2-cyclobutenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butene base, 2-methyl-2-butene base, 2,3-dimethyl-2-cyclobutenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonene base, 2-nonene base, 3-nonene base, 1-decene base, 2-decene base and 3-decene base.
Except as otherwise noted, term " alkoxyl " refers to-the O-alkyl group. The example of alkoxyl includes but not limited to-OCH3、-OCH 2CH 3、-O(CH 2) 2CH 3、-O(CH 2) 3CH 3、 -O(CH 2) 4CH 3, and-O (CH2) 5CH 3。
Except as otherwise noted, term " alkyl " refers to (" cycloalkyl ") hydrocarbon of straight chain, side chain and/or ring-type, has the individual carbon atom in 1 to 20 (for example, 1 to 10 or 1 to 4). Alkyl with 1 to 4 carbon is called " low alkyl group ". The example of alkyl includes but not limited to methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, amyl group, hexyl, isohesyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl and dodecyl. Cycloalkyl moiety can be monocycle or many rings, and the example comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and adamantyl. The other example of alkyl has straight chain, side chain and/or annulus (for example, 1-ethyl-4-methyl-cyclohexyl base). Term " alkyl " comprises saturated hydrocarbons and thiazolinyl and alkynyl.
Except as otherwise noted, term " alkylaryl " or " alkyl-aryl " are meant the moieties that is incorporated into aryl moiety.
Except as otherwise noted, term " miscellaneous alkyl aryl " or " alkyl-heteroaryl " are meant the moieties that is incorporated into heteroaryl moieties.
Except as otherwise noted, term " alkyl heterocycle " or " alkyl-heterocycle " are meant the moieties that is incorporated into heterocyclic moiety.
Except as otherwise noted, term " alkynyl " is meant straight chain, side chain and/or cyclic hydrocarbon, has the individual carbon atom of 2 to 20 (for example, 2 to 20 or 2 to 6), and comprises at least one carbon carbon triple bond.Representational alkynyl partly comprises ethynyl, proyl, ethyl acetylene base, 2-butyne base, 1-pentynyl, valerylene base, 3-methyl isophthalic acid-butynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 5-hexin base, 1-heptyne base, 2-heptyne base, 6-heptyne base, 1-octyne base, 2-octyne base, 7-octyne base, 1-n-heptylacetylene base, 2-n-heptylacetylene base, 8-n-heptylacetylene base, 1-decynyl, 2-decynyl and 9-decynyl.
Except as otherwise noted, term " aryl " is meant aromatic nucleus or aromaticity or the part aromaticity ring system of being made up of carbon and hydrogen atom.Aryl moiety can comprise in conjunction with or condense together a plurality of rings.The example of aryl includes but not limited to anthryl, Azulene base, xenyl, fluorenyl, indane, indenyl, naphthyl, phenanthryl, phenyl, 1,2,3,4-tetralin and tolyl.
Except as otherwise noted, term " arylalkyl " or " aryl-alkyl " are meant the aryl moiety that is incorporated into moieties.
Except as otherwise noted, term " halogen " and " halo " comprise fluorine, chlorine, bromine and iodine.
Except as otherwise noted, term " assorted alkyl " is meant that at least one carbon atom is by the displaced moieties of heteroatoms (for example, N, O or S) (for example, straight chain, side chain or cyclic).
Except as otherwise noted, term " heteroaryl " is meant that wherein at least one carbon atom is by the displaced aryl moiety of heteroatoms (for example, N, O or S).Example includes but not limited to acridyl, benzimidazolyl-, benzofuryl, benzisothiazole base, benzoisoxazole base, Benzoquinazole base, benzothiazolyl, benzoxazolyl, furyl, imidazolyl, indyl, isothiazolyl, isoxazolyl, oxadiazole Ji, oxazolyl, 2 base, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl (pyrimidinyl), pyrimidyl (pyrimidyl), pyrryl, quinazolyl, quinolyl, tetrazyl, thiazolyl and triazinyl.
Except as otherwise noted, term " heteroarylalkyl " or " heteroaryl-alkyl " are meant the heteroaryl moieties that is incorporated into moieties.
Except as otherwise noted, term " heterocycle " is meant aromaticity, part aromaticity or nonaromatic monocycle or polycyclic ring or the ring system of being made up of carbon, hydrogen and at least one heteroatoms (for example, N, O or S).Heterocycle can comprise a plurality of (that is, the two or more) ring that condenses or combine.Heterocycle comprises heteroaryl.Example includes but not limited to benzo [1,3] dioxa cyclopentenyl, 2,3-dihydro-benzo [1,4] two pyranyls, cinnoline base, furyl, glycolylurea base (hydantoinyl), morpholinyl, oxa-cyclobutyl, Oxyranyle, piperazinyl, piperidyl, pyrrolidone-base, pyrrolidyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydro-thienyl, tetrahydro thiapyran base and Valerolactim base (valerolactamyl).
Except as otherwise noted, term " heterocyclic radical alkyl " or " heterocycle-alkyl " are meant the heterocyclic moiety that is incorporated into moieties.
Except as otherwise noted, term " Heterocyclylalkyl " is meant non-aromaticity heterocycle.
Except as otherwise noted, term " Heterocyclylalkyl alkyl " or " Heterocyclylalkyl-alkyl " are meant the Heterocyclylalkyl part that is incorporated into moieties.
Except as otherwise noted, term " inhibition SGLT2 in the body " is meant that the SGLT2 that uses the in vivo test described in following examples to measure suppresses.
Except as otherwise noted, term " reply " and " processing " comprise that described disease of prevention or illness recur and/or prolong the time of the patient's who has suffered from this disease or illness remission in the patient who suffers from this disease or illness.This term comprises threshold value, development and/or the time length of regulating disease or illness, or changes the response mode of patient to this disease or illness.
Except as otherwise noted, term " pharmaceutically useful salt " is meant from the pharmaceutically useful nontoxic acid or the salt of alkali (comprising inorganic bronsted lowry acids and bases bronsted lowry and organic bronsted lowry acids and bases bronsted lowry) preparation.The pharmaceutically useful base addition salt that is fit to includes but not limited to the metal-salt that formed by aluminium, calcium, lithium, magnesium, potassium, sodium and zinc, or by Methionin, N, the organic salt that N '-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, quadrol, meglumine (N-methylglucosamine) and PROCAINE HCL, PHARMA GRADE form.Suitable non-toxic acid includes but not limited to mineral acid and organic acid, for example acetate, alginic acid, benzaminic acid, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, formic acid, fumaric acid, furancarboxylic acid, galacturonic acid, glyconic acid, glucuronic acid, L-glutamic acid, oxyacetic acid, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, Whitfield's ointment, stearic acid, succsinic acid, Sulphanilic Acid, sulfuric acid, tartrate, and tosic acid.Concrete non-toxic acid comprises hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid and methylsulfonic acid.Therefore, the example of specific salt comprises hydrochloride and mesylate.Other salt is as known in the art.Referring to for example, Remington ' s Pharmaceutical Sciences, 18 ThEd. (Mack Publishing, EastonPA:1990) with Remington:The Science and Practice of Pharmacy, 19thed. (Mack Publishing, Easton PA:1995).
Except as otherwise noted, " powerful SGLT2 inhibitor " is meant SGLT2 IC 50Be lower than the compound of about 500nM.
Except as otherwise noted, term " prevention " and " preventing " have considered to suffer from the behavior that takes place before described disease or the illness the patient, its inhibition or reduce the severity of this disease or illness.In other word, this term comprises diseases prevention.
Except as otherwise noted, " the prevention significant quantity " of compound is the amount that is enough to preventing disease or situation or one or more symptoms relevant with this disease or situation or prevents its recurrence." the prevention significant quantity " of compound is meant that therapeutical agent makes up separately or with other medicines, provides the amount of prophylactic preventative benefit.Term " prevention significant quantity " can comprise the amount of improving comprehensive diseases prevention or improving the preventative effectiveness of another kind of preventive medicine.
Except as otherwise noted, " selectivity SGLT2 inhibitor " is SGLT1 IC 50Than its SGLT2 IC 50Big at least 10 times compound.
Except as otherwise noted, term " SGLT1 IC 50" for using the Compound I C of the vitro human SGLT1 inhibition test mensuration described in following examples 50
Except as otherwise noted, term " SGLT2 IC 50" for using the Compound I C of the vitro human SGLT2 inhibition test mensuration described in following examples 50
Except as otherwise noted, term " three-dimensional heterogeneous mixture " comprises the mixture (for example, R/S=30/70,35/65,40/60,45/55,55/45,60/40,65/35 and 70/30) of racemic mixture and stereoisomerism enrichment.
Except as otherwise noted, term " stereoisomerism is pure " is meant that composition comprises a kind of steric isomer of compound and is substantially free of other steric isomer of this compound.For example, the pure composition of stereoisomerism with compound of a stereocenter is substantially free of the opposite steric isomer of this compound.For example, the pure composition of stereoisomerism with compound of two stereocenters is substantially free of other diastereomer of this compound.Typical stereoisomerism pure compound comprises a kind of steric isomer of this compound that surpasses about 80 weight % and is less than other steric isomer of this compound of about 20 weight %, a kind of steric isomer and other steric isomer that is less than this compound of about 10 weight % that surpass this compound of about 90 weight %, a kind of steric isomer and other steric isomer that is less than this compound of about 5 weight % that surpass this compound of about 95 weight %, surpass a kind of steric isomer and other steric isomer that is less than this compound of about 3 weight % of this compound of about 97 weight %, or surpass a kind of steric isomer and other steric isomer that is less than this compound of about 1 weight % of this compound of about 99 weight %.
Except as otherwise noted, term " replacement ", when represent chemical structure or part, be meant the deriveding group of this structure or part, one or more its hydrogen atoms in wherein said structure or the part are replaced by chemical part or functional group, described chemical part or functional group are such as but not limited to alcohol, aldehyde, alkoxyl group, alkanoyloxy, alkoxy carbonyl, thiazolinyl, alkyl (for example, methyl, ethyl, propyl group, the tertiary butyl), alkynyl, alkyl-carbonyl oxygen base (OC (O) alkyl), acid amides (C (O) NH-alkyl-or-alkyl NHC (O) alkyl), amidino groups (amidinyl) (C (NH) NH-alkyl-or-C (NR) NH 2), amine (primary amine, secondary amine and tertiary amine; for example alkylamino, arylamino, aryl-alkyl amino), aroyl, aryl, aryloxy, azo, formamyl (carbamoyl) (NHC (O) O-alkyl-or-OC (O) NH-alkyl), formamyl (carbamyl) (for example, CONH 2, and CONH-alkyl, CONH-aryl and CONH-arylalkyl), carbonyl, carboxyl, carboxylic acid, carboxylic acid anhydride, carboxyl acyl chloride, cyano group, ester, epoxide, ether (for example, methoxyl group, oxyethyl group), guanidine radicals, halo, haloalkyl (for example ,-CCl 3,-CF 3,-C (CF 3) 3), assorted alkyl, hemiacetal, imines (uncle's imines and secondary imines), isocyanic ester, lsothiocyanates, ketone, nitrile, nitro, oxo, phosphodiester, sulfide, sulfamic (for example, SO 2NH 2), sulfone, alkylsulfonyl (comprising alkyl sulphonyl, aryl sulfonyl and aryl alkylsulfonyl), sulfoxide, mercaptan (for example, sulfydryl, thioether) and urea (NHCONH-alkyl).
Except as otherwise noted, " the treatment significant quantity " of compound be compound be enough to the treatment benefit is provided in the treatment of disease or situation or reply or postpones one or more symptoms relevant or make its minimized amount with this disease or situation." the treatment significant quantity " of compound be meant therapeutical agent separately or with other therapeutic combination, the amount of therapeutic benefit is provided in the treatment of disease or situation or reply.Term " treatment significant quantity " can comprise that improvement treats comprehensively, reduces or avoid the symptom or the cause of disease of disease or situation or improve the amount that the treatment of another kind of therapeutical agent is renderd a service.
Except as otherwise noted, the behavior that takes place considered in term " treatment " when the patient suffers from described disease or illness, the progress that it reduces the severity of this disease or illness or postpones or slow down this disease or illness.
Except as otherwise noted, term " comprises " with " including but not limited to " having identical implication.Similarly, term " for example " and term " such as but not limited to " have an identical implication.
Except as otherwise noted, the tight one or more adjectives that link to each other are considered to modify each noun in a series of nouns front.For example, phrase " optional substituted alkyl, aryl or heteroaryl " has identical implication with " optional substituted alkyl, optional substituted aryl or optional substituted heteroaryl ".
It is pointed out that formation than the chemical part of the part of large compound can use in this article the title that when it exists as individual molecule, adopts usually or when its during as substituting group usually the title of employing be described.For example, term " pyridine " and " pyridyl " have identical meanings when being used for describing with other chemical part bonded part.Therefore, two words " XOH, wherein X is a pyridyl " and " XOH, wherein X is a pyridine " have identical meanings, and comprise pyridine-2-alcohol, the pure and mild pyridine of pyridine-3--4-alcohol.
It is pointed out that also if the stereochemistry of the part of a certain structure or a certain structure for example bold line of no use or dotted line when representing, then the part of this structure or this structure can be interpreted as comprising all steric isomers of this structure.In addition, thus any atom with unsaturated valence that shows among the figure is assumed to be to combine with enough hydrogen atoms and satisfies valence.In addition, the chemical bond of using a solid line parallel with dotted line to describe if valence allows, comprises singly-bound and two keys (for example aromatics).
Compound
One embodiment of the invention comprise the compound of following formula:
Figure A20081009007300211
And pharmaceutically useful salt and solvate, wherein: A is optional substituted aryl, cycloalkyl or heterocycle; X is O, S or NR 3When X is O, R 1Be OR 1A, SR 1A, SOR 1A, SO 2R 1AOr N (R 1A) 2When X is S, R 1Be hydrogen, OR 1A, SR 1A, SOR 1A, or SO 2R 1AWhen X is NH 3The time, R 1Be OR 1A, SR 1A, SOR 1A, SO 2R 1A, or R 1AEach R 1ABe hydrogen or optional substituted alkyl, aryl or heterocycle independently; R 2Be fluorine or OR 2AR 2A, R 2B, and R 2CIn each is hydrogen, optional substituted alkyl, C (O) alkyl, C (O) aryl or aryl independently; R 3Be hydrogen, C (O) R 3A, CO 2R 3A, CON (R 3B) 2, or optional substituted alkyl, aryl or heterocycle; Each R 3ABe optional substituted alkyl or aryl independently; With each R 3BBe hydrogen or optional substituted alkyl or aryl independently.
Specific compound is expressed from the next:
Figure A20081009007300212
Some compounds are expressed from the next:
Figure A20081009007300213
Some compounds are expressed from the next:
Figure A20081009007300221
One embodiment of the invention comprise the compound of following formula:
Figure A20081009007300222
And pharmaceutically useful salt and solvate, wherein: A is optional substituted aryl, cycloalkyl or heterocycle; B is optional substituted aryl, cycloalkyl or heterocycle; X is O, S or NR 3Y is O, S, SO, SO 2, NR 4, (C (R 5) 2) p), (C (R 5) 2) q-C (O)-(C (R 5) 2) q, (C (R 5) 2) q-C (O) O-(C (R 5) 2) q, (C (R 5) 2) q-OC (O)-(C (R 5) 2) q, (C (R 5) 2) q-C (O) NR 4-(C (R 5) 2) q, (C (R 5) 2) q-NR 4C (O)-(C (R 5) 2) q, or (C (R 5) 2) q-NR 4C (O) NR 4-(C (R 5) 2) qWhen X is O, R 1Be OR 1A, SR 1A, SOR 1A, SO 2R 1AOr N (R 1A) 2When X is S, R 1Be hydrogen, OR 1A, SR 1A, SOR 1A, or SO 2R 1AWhen X is NH 3The time, R 1Be OR 1A, SR 1A, SOR 1A, SO 2R 1A, or R 1AEach R 1ABe hydrogen or optional substituted alkyl, aryl or heterocycle independently; R 2Be fluorine or OR 2AR 2A, R 2B, and R 2CIn each is hydrogen, optional substituted alkyl, C (O) alkyl, C (O) aryl or aryl independently; R 3Be hydrogen, C (O) R 3A, CO 2R 3A, CON (R 3B) 2, or optional substituted alkyl, aryl or heterocycle; Each R 3ABe optional substituted alkyl or aryl independently; Each R 3BBe hydrogen or optional substituted alkyl or aryl independently; Each R 4Be hydrogen or optional substituted alkyl independently; Each R 5Be hydrogen, hydroxyl, halogen, amino independently, cyano group, OR 5A, SR 5A, or optional substituted alkyl; Each R 5ABe optional substituted alkyl independently; P is 0-3; With each q be 0-2 independently.
Specific compound is expressed from the next:
Figure A20081009007300231
Some compounds are expressed from the next:
Figure A20081009007300232
Some compounds are expressed from the next:
Figure A20081009007300233
Some compounds are expressed from the next:
Figure A20081009007300234
Wherein: each R 6Be hydrogen, hydroxyl, halogen, amino, cyano group, nitro, C ≡ CR independently 6A, OR 6A, SR 6A, SOR 6A, SO 2R 6A, C (O) R 6A, CO 2R 6A, CO 2H, CON (R 6A) (R 6A), CONH (R 6A), CONH 2, NHC (O) R 6A, NHSO 2R 6A, or optional substituted alkyl, aryl or heterocycle; Each R 6ABe optional substituted alkyl, aryl or heterocycle independently; Each R 7Be hydrogen, hydroxyl, halogen, amino, cyano group, nitro, C ≡ CR independently 7A, OR 7A, SR 7A, SOR 7A, SO 2R 7A, C (O) R 7A, CO 2R 7A, CO 2H, CON (R 7A) (R 7A), CONH (R 7A), CONH 2, NHC (O) R 7A, NHSO 2R 7A, or optional substituted alkyl, aryl or heterocycle; Each R 7ABe optional substituted alkyl, aryl or heterocycle independently; M is 1-3; With n be 1-3.
Some compounds are expressed from the next:
Figure A20081009007300241
Some compounds are expressed from the next:
Some compounds are expressed from the next:
Figure A20081009007300243
One embodiment of the invention comprise the compound of following formula:
Figure A20081009007300244
And pharmaceutically useful salt and solvate, wherein: A is optional substituted aryl, cycloalkyl or heterocycle; X is O or NR 3R 2Be fluorine or OR 2AR 2A, R 2B, and R 2CIn each is hydrogen, optional substituted alkyl, C (O) alkyl, C (O) aryl or aryl independently; R 3Be hydrogen or optional substituted alkyl, aryl or heterocycle; R 8Be hydrogen or C (O) R 8AR 8ABe hydrogen or optional substituted alkyl, alkoxyl group or aryl; R 9AAnd R 9BBe OR independently of one another 9COr SR 9C, or lump together formation O, S or NR 9CWith each R 9CBe optional substituted alkyl, aryl or heterocycle independently.
For disclosed herein various, in due course, specific compound of the present invention is to make that A is the aryl or the heterocycle of optional substituted 6-unit.In other situation, A is the first heterocycle of optional substituted 5-.In some cases, A is optional substituted condensed-bicyclic heterocycle.
In some cases, B is optional substituted 6-unit's aryl or heterocycle.In other situation, B is the first heterocycle of optional substituted 5-.In other situation, B is optional substituted condensed-bicyclic heterocycle.
In some cases, X is O.In other situation, X is S.In other situation, X is NR 3
In some cases, Y is (C (R 4) 2) pAnd for example, p is 1.In some cases, Y is (C (R 5) 2) q-C (O)-(C (R 5) 2) qWith, for example, each q is 0 or 1 independently.
In some cases, R 1Be OR 1AIn other situation, R 1Be SR 1AIn other situation, R 1Be SOR 1AIn other situation, R 1Be SO 2R 1AIn other situation, R 1Be N (R 1A) 2In other situation, R 1Be hydrogen.In other situation, R 1Be R 1A
In some cases, R 1ABe hydrogen.In other situation, R 1ABe optional substituted alkyl (for example, optional substituted low alkyl group).
In some cases, R 2Be fluorine.In other situation, R 2Be OR 2A
In some cases, R 2ABe hydrogen.
In some cases, R 2BBe hydrogen.
In some cases, R 2CBe hydrogen.
In some cases, R 3Be hydrogen.In other situation, R 3Be optional substituted low alkyl group (for example, optional substituted methyl).
In some cases, R 4Be hydrogen or optional substituted low alkyl group.
In some cases, each R 5Be hydrogen or optional substituted low alkyl group (for example, methyl, ethyl, CF 3).
In some cases, R 6Be hydrogen, hydroxyl, halogen, OR 6AOr optional substituted low alkyl group (for example, optional methyl, ethyl or the sec.-propyl that is replaced by halogen).In some cases, R 6Be hydrogen.In some cases, R 6Be halogen (for example, chlorine).In some cases, R 6Be hydroxyl.In some cases, R 6Be OR 6A(for example, methoxyl group, oxyethyl group).In some cases, R 6Be optional substituted methyl (for example, CF 3).
In some cases, R 7Be hydrogen, C ≡ CR 7A, OR 7AOr optional substituted low alkyl group (for example, optional methyl, ethyl or the sec.-propyl that is replaced by halogen).In some cases, R 7Be hydrogen.In some cases, R 7Be C ≡ CR 7AAnd R 7AFor, for example, optional substituted (for example, being replaced) monocyclic aryl or heterocycle by low alkyl group or halogen.In some cases, R 7Be OR 7A(for example, methoxyl group, oxyethyl group).In some cases, R 7Be ethynyl or optional substituted methyl or ethyl.
Specific compound of the present invention is expressed from the next:
Figure A20081009007300271
Other compound is expressed from the next:
Figure A20081009007300272
Other compound is expressed from the next:
Figure A20081009007300273
Other compound is expressed from the next:
Figure A20081009007300274
Other compound is expressed from the next:
Figure A20081009007300281
Other compound is expressed from the next:
Figure A20081009007300282
In the specific compound of formula I (a)-(d), X is O.In other situation, X is S.In other situation, X is NR 3And R 3Be for example hydrogen.In the specific compound of formula I (a)-(f), R 1ABe hydrogen.In other situation, R 1ABe optional substituted methyl or ethyl.
Preferred compound is powerful SGLT2 inhibitor.Specific compound has and is lower than about 500,400,300,250,200,150,100,75,50 or the SGLT2 IC of 25nM 50
Specific compound is a SGLT2 inhibitor optionally.For example, the SGLT1 IC that has of some compound 50Than their SGLT2 IC 50At least 10,15,20,25,50,75 or 100 times greatly.
Synthetic method
Compound of the present invention can be by methods known in the art or the method preparation by describing herein.For example, compound can prepare by the method shown in the following reaction scheme 1:
Figure A20081009007300291
Reaction scheme 1
In this method, under the condition that is fit to (for example) with the oxygenant oxalyl chloride in DMSO for example with known pure 1 (a) (referring to for example, Nucleosides Nucleotides, 20:649-652 (2001)) and oxidation formation aldehyde 1 (b).With reagent for example butyllithium or butyl magnesium bromide handle the bromide of formula 1 (c), add aldehyde 1 (b) subsequently, obtain alcohol 1 (d).Under acidic conditions,, obtain compound 1 (e) with alcohol or this compound of water treatment.If expectation can use method well known in the art compound 1 (e) to be converted into various other compounds (for example, wherein one or more R that the present invention includes 2A, R 2BAnd R 2CNot hydrogen, and/or R 1Be SR 1AOr NHR 1AThe compound of formula I).
For reaction scheme 1 and described herein other synthetic method, the method for preparing A and A-Y-B part is known, and the method that is used to prepare the SGLT2 inhibitor with them is the same.For example, in prepared product SGLT2 inhibitor the process of the synthetic diaryl derivatives that connects at United States Patent (USP) 7,045,665 and 7,053,060; U.S. Patent application 10/735,179,10/745,075,11/080,150 and 11/182,986; With describe among International Patent Application WO 2006/006496 and the WO2006/089872.
The synthesizing of SGLT2 inhibitor that comprises the phenyl-isocyclic part of connection for example describing in the U.S. Patent application 11/190,315 and 11/199,962.
The connection heterocyclic is synthetic to be used to obtain the purposes of SGLT2 inhibitor at for example U.S. Patent application 10/540 with them, 519,10/734,573,11/247,216,11/247,356 and International Patent Application WO 03/020737, WO2004/058790, WO2004/080990, WO2004/089967, WO2005/011592, WO2005/012242, WO2005/012243, WO2005/012318, WO2005/021566 and WO2005/085265 in describe.
The piperidin-1-yl compound can prepare by the method shown in the following reaction scheme 2:
Figure A20081009007300301
Reaction scheme 2
In this method, the compound 2 (a) of preparation shown in reaction scheme 1 and trinitride (for example, azide diphenyl phosphate) are contacted under the condition that fully obtains trinitride 2 (b).Under acidic conditions, handle trinitride then, obtain the furans 2 (c) of deprotection, under acidic conditions, it is handled with reductive agent (for example, the hydrogen in the presence of platinum oxide) subsequently, obtain compound 2 (d).If expectation can use method as known in the art that compound 2 (d) is converted into various other compounds that the present invention includes (for example, R wherein 2A, R 2BAnd R 2CIn one or more be not hydrogen and/or R 1Be SR 1AOr NHR 1AThe compound of formula I).
Tetrahydric thiapyran-based compound can prepare shown in following reaction scheme 3:
Figure A20081009007300311
Reaction scheme 3
In this method, make the compound 3 (a) of preparation shown in reaction scheme 1 and suitable sulfocompound (for example, thioacetate) (for example, in the presence of the diethylazodicarboxylate) contact under the condition that is fit to, obtain thioacetate 3 (b).Handle thioacetate with the alkali (for example, cesium hydroxide) that is fit to then, obtain the mercaptan of formula 3 (c), under acidic conditions, it is used alcohol or water treatment subsequently, obtain compound 3 (d).If expectation can use method as known in the art that compound 3 (d) is converted into various other compounds that the present invention includes (for example, R wherein 2A, R 2BAnd R 2CIn one or more be not hydrogen and/or R 1Be SR 1AOr NHR 1AThe compound of formula I).
Compound (the R wherein that comprises fluorizated sugar or sugar analogue 2Compound for the formula I of F) can use the starting raw material preparation of methods known in the art from corresponding replacement.Referring to for example, U.S. Patent application 10/735,179.
The compound of open loop form (for example, the compound of formula II) easily prepares by methods known in the art.For example, they can use those method preparations as shown in following reaction scheme 4:
Figure A20081009007300321
Reaction scheme 4
In this method, the compound 4 (a) of preparation shown in reaction scheme 1 and reactive compounds (for example, methyl-chloroformate) are contacted under the condition that is fit to, obtain methyl carbonate 4 (b).Under acidic conditions, methyl carbonate is handled with alcohol then, obtained compound 4 (c).If expectation can use method as known in the art that compound 4 (c) is converted into various other compounds that the present invention includes (for example, R wherein 2A, R 2BAnd R 2CIn one or more be not the compound of the formula II of hydrogen).
Use methods known in the art, easily change above-mentioned synthetic method, to obtain various compounds.And can use chiral chromatography and other technique known to obtain the stereoisomerism pure compound.Referring to for example, Jacques, people such as J., Enantiomers, Racemates and Resolutions(Wiley Interscience, New York, 1981); Wilen, people such as S.H., Tetrahedron33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds(McGraw Hill, NY, 1962); And Wilen, S.H., Tables of Resolving Agents and Optical Resolutions, p.268 (E.L.Eliel, Ed., Univ.ofNotre Dame Press, Notre Dame, IN, 1972).In addition, the synthetic starting raw material that can utilize chirality is to obtain the pure product of stereoisomerism enrichment or stereoisomerism.
Usage
The present invention includes and suppress the active method of SGLT2, this method comprises the The compounds of this invention (that is novel compound disclosed herein) that makes SGLT2 contact significant quantity.In one embodiment, protein in vivo.In another embodiment, it is ex vivo (ex vivo).
The present invention also comprises the method that reduces patient's (for example, Mammals such as people, dog or cat) blood sugar, and this method comprises gives the compound of the present invention of using significant quantity to the patient.
The present invention also comprises increases glucose excretory method in patient's urine, and this method comprises gives the compound of the present invention of using significant quantity to the patient.
The present invention also comprises the method for recovering or increasing patient's insulin sensitivity, and this method comprises gives the compound of the present invention of using significant quantity to the patient.
The present invention also comprises the method for treatment, reply or prevention disease of patient or illness, and this method comprises gives the compound of the present invention of using treatment or prevention significant quantity to the patient.The example of disease and illness comprises atherosclerosis, cardiovascular disorder, diabetes (1 and 2 type), hyperglycemia, hypertension, dyslipidemias (lipid disorder), obesity and X syndromes.Specific disease is a diabetes B.
The dosage of compound, route of administration and according to dosage the administration time table can decide the specific indication of for example to be treated, prevention or reply, patient's age, sex and situation according to multiple factor.The effect of these factors is as known in the art, and can adjust by the experiment of routine.
Pharmaceutical preparation
The present invention includes the pharmaceutical composition that contains one or more compounds of the present invention.The some drugs composition is the single unit dosage that is suitable for patient's per os, mucous membrane (for example nose, hypogloeeis, vagina, cheek or rectum), non-enteron aisle (for example subcutaneous, intravenously, bolus injection, intramuscular or intra-arterial) or transdermal administration.The example of formulation includes, but are not limited to: tablet; Lozenge (caplets); Capsule is as soft elastic gelatin capsule; Cachet; Lozenge (troches); The rhombus agent; Dispersion agent; Suppository; Paste; Poultice (mud agent); Paste; Pulvis; Dressing; Creme; Plaster; Solution; Paster; Aerosol (for example nose sprays into agent or inhalation); Gelifying agent; Be suitable for liquid dosage form, comprise suspension agent (for example water-based or non-aqueous liquid suspension agent, oil-in-water emulsion, or water-in-oil liquid emulsion), solution, and elixir patient's per os or mucosa delivery; Be suitable for liquid dosage form to patient's parenterai administration; With can rebuild so that the sterile solid that is suitable for the liquid dosage form of patient's parenterai administration (for example crystallization or amorphous solid) to be provided.
Preparation should be suitable for the mode of administration.For example, oral administration needs enteric coating to be degraded in gi tract to avoid compound of the present invention.Similarly, preparation can comprise the composition of being convenient to activeconstituents is delivered to site of action.For example, compound can be given usefulness in liposome, is degraded to avoid their enzymes that is degraded, and promotes the transhipment in the recycle system and realizes that cross-cell membrane arrives sending of position in the born of the same parents.
The composition of formulation, shape and type change according to the different of its purposes.For example, the formulation of using in the emergency treatment disease is compared with the formulation of using in this disease long-term treatment, can contain more substantial one or more activeconstituentss.Similarly, non-parenteral dosage forms is compared with the employed oral dosage form of treatment same disease, can comprise one or more activeconstituentss of less amount.Included discrepant each other these modes of particular dosage form and the alternate manner of the present invention is conspicuous for those skilled in the art.Referring to for example, Remington ' s PharmaceuticalSciences, 18 ThEd. (Mack Publishing, Easton PA:1990).
Pharmaceutical composition preferred oral of the present invention is given and is used.The discrete formulation that is suitable for oral administration comprises tablet (for example, chewable tablet), lozenge, capsule and liquid agent (for example, seasoning syrup agent).This formulation comprises the activeconstituents of predetermined amount, and can be by well known to a person skilled in the art the practice of pharmacy preparation.Referring to for example, Remington ' s Pharmaceutical Sciences, 18 ThEd. (Mack Publishing, Easton PA:1990).
Typical oral dosage form is by being mixed with activeconstituents and at least a vehicle pharmaceutical technology according to routine closely.Vehicle can take various forms according to the difference that is used for the required dosage form of administration.
Owing to be convenient to administration, tablet and capsule have been represented best oral dosage unit form.If expectation, water-based that can be by standard or non-aqueous technology are with tablet coating.This formulation can be by conventional practice of pharmacy preparation.Usually, the two mixes, makes if necessary then product to be configured as the outward appearance of expectation and pharmaceutical compositions and formulation equably and closely by making activeconstituents and liquid vehicle, finely divided solid carrier or its.Can in solid dosage, incorporate disintegrating agent into, to promote stripping rapidly.Can also incorporate lubricant into, so that the production of formulation (for example, tablet).
Embodiment
Understand all respects of the present invention by following examples, but these embodiment are not used in restriction protection scope of the present invention.
Embodiment 1:(2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-methoxyl group-tetrahydrochysene-pyrans-3,4,5-triol synthetic
Figure A20081009007300351
Prepare title compound by following step.
A. [(3aS, 5S, 6R, 6aS)-and 6-(tertiary butyl-dimethyl-silyl oxygen base)-2, the 2-dimethyl- Tetrahydrochysene-furo [2,3-d] [1,3] dioxole-5-yl]-methyl alcoholPreparation: this compound uses methods known in the art synthetic.Referring to for example, Nucleosides Nucleotides, 20:649-652 (2001) and reference wherein.
B. (3aS, 5R, 6R, 6aS)-and 6-(tertiary butyl-dimethyl-silyl oxygen base)-2, the 2-dimethyl- Tetrahydrochysene-furo [2,3-d] [1,3] dioxole-5-formaldehydePreparation: at N 2Descend at-78 ℃ to oxalyl chloride (0.76ml, CH 8.7mmol) 2Cl 2(55ml) drip DMSO (0.84ml, CH 11.8mmol) in the solution 2Cl 2(5ml) solution.After 15 minutes, dropping comprises alcohol (2.40g, CH 7.9mmol) that derives from steps A 2Cl 2(20ml).After 15 minutes, slowly add NEt 3Make to be reflected at the room temperature of slowly rising again in 105 minutes, use H then 2Et is used in the O quencher 2O dilution and use H 2O, saturated NaHCO 3The aqueous solution and salt water washing.The organic phase Et that merges 2O strips, and it is washed according to identical order.With the organic phase MgSO that merges 4Drying is filtered and vacuum concentration, obtain (3aS, 5R, 6R, 6aS)-6-(tertiary butyl-dimethyl-silyl oxygen base)-2,2-dimethyl-tetrahydrochysene-furo [2,3-d] [1,3] dioxole-5-formaldehyde (2.4g, about 64% purity, NMR).The not purified use of product.
C. 4-bromo-1-chloro-2-(4-oxyethyl group-benzyl)-benzenePreparation: preparation described in the U.S. Patent application 10/745,075 that people such as this compound such as Deshpande submitted on December 23rd, 2003.
D. ( S)-[(3aS, 5S, 6R, 6aS)-and 6-(tertiary butyl-dimethyl-silyl oxygen base)-2, the 2-diformazan Base-tetrahydrochysene-furo [2,3-d] [1,3] dioxole-5-yl]-[4-chloro-3-(4-oxyethyl group-benzyl Base)-phenyl]-methyl alcoholPreparation: at N 2Down-78 ℃ to 4-bromo-1-chloro-2-(4-oxyethyl group-benzyl)-benzene that derives from step C (3.6g, drip in THF 11.1mmol) (60ml) solution BuLi (2.5M, in hexane, 4.4ml, 11.1mmol).After 30 minutes, drip and to comprise the aldehyde that derives from step B (THF 5.1mmol) (20ml), and will be reflected at-78 ℃ and stir 30 minutes makes its room temperature and stirring 60 minutes of rising again, and uses saturated NH for 2.4g, 64% purity 4Et is used in the quencher of the Cl aqueous solution 2O dilution and use H 2O and salt water washing.The aqueous cleaning solution Et that merges 2O strips, and it is washed by identical order.The organic extract MgSO that merges 4Drying is filtered and vacuum concentration.Resistates is by purified by flash chromatography (120g SiO 2, 0-20%EtOAc: hexane, 75 minutes, 85ml/min), obtain clean (S)-[(3aS, 5S, 6R, 6aS)-and 6-(tertiary butyl-dimethyl-silyl oxygen base)-2,2-dimethyl-tetrahydrochysene-furo [2,3-d] [1,3] dioxole-5-yl]-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-methyl alcohol (0.84g, 1.5mmol, 30%), and C5 epimer (0.83g) and some mixing fractions (0.51g).
1H NMR (400MHz, and the δ ppm:7.37 of chloroform-d) (d, J=8.34Hz, 1H), 7.18-7.23 (m, 1H), 7.15 (d, J=2.02Hz, 1H), and 7.06-7.11 (m, 2H), 6.80-6.84 (m, 2H), 5.99 (d, J=3.79Hz, 1H), 5.21 (d, J=2.78Hz, 1H), 5.11 (d, J=2.53Hz, 1H), 4.46 (d, J=3.54Hz, 1H), and 3.97-4.10 (m, 5H), 3.95 (t, J=2.65Hz, 1H), 1.38-1.44 (m, 6H), 1.30 (s, 3H), 0.84 (s, 9H), 0.10 (s, 3H) ,-0.08 (s, 3H).
E. ( 2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-methoxyl group-tetrahydrochysene- Pyrans-3,4, the 5-triolPreparation: by with AcCl (0.25ml, 3.5mmol) join MeOH (10ml) and stir 15 minutes the preparation 0.35 M HCl MeOH solution.(0.84g 1.5mmol), carried out 16 hours and carried out 2 hours at 80 ℃ in room temperature to derive from the alcohol of step D with this solution-treated in the bottle of sealing.To react cool to room temperature, use K 2CO 3Quencher is used CH up to being alkalescence 2Cl 2Dilution is filtered and vacuum concentration.Product is by purified by flash chromatography (40g SiO 2, 0-10%MeOH:CH 2Cl 2, 60 minutes, 35ml/min), be suspended in H 2Among the O, and freeze-drying, obtain (2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-methoxyl group-tetrahydrochysene-pyrans-3,4,5-triol (0.46g, 1.1mmol, 75%) is white solid.NMR is shown as the α and the β anomer of 1.2: 1 ratios.
1H NMR (400MHz, and the δ ppm:7.38-7.42 of chloroform-d) (m, 1H), 7.22-7.26 (m, 2H), 7.11 (d, J=8.34Hz, 2H), 6.81-6.85 (m, 2H), (4.86 d, J=3.79Hz, 1H α), 4.43 (d, J=9.85Hz, 1H α), 4.34 (d, J=7.58Hz, 1H β), 4.16 (d, J=9.35Hz, 1H β), 3.99-4.12 (m, 4H), 3.80-3.86 (m, 1H α), and 3.64-3.72 (m, 1H), 3.54 (s, 3H β), 3.46-3.54 (m, 1.5H), 3.45 (s, 3H α), 2.69 (d, J=2.53Hz, 1H β), 2.62 (d, J=2.27Hz, 1H α), 2.50 (d, J=2.27Hz, 1H β), (2.12 d, J=9.85Hz, 1H α), 2.00 (d, J=3.03Hz, 1H β), 1.98 (d, J=2.78Hz, 1H α), 1.41 (t, J=6.95Hz, 3H).MS(ES+)[M+NH 4] +＝426。
Embodiment 2:(3S, 4R, 5R, 6S)-6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-tetrahydrochysene-pyrans-2,3,4,5-tetrol synthetic
Figure A20081009007300371
With derive from embodiment 1 step D alcohol (51mg, 0.093mmol) in sealed vial at 80 ℃ with 1: 1 AcOH:H 2O (1ml) handled 18 hours.To react cool to room temperature, with EtOAc dilution transferring in the flask, and vacuum concentration.Resistates is dissolved in CH 2Cl 2, use NaHCO 3And MgSO 4Handled 30 minutes, and filtered and vacuum concentration.Product is by purified by flash chromatography (4g SiO 2, 0-12%MeOH:CH 2Cl 2, 30 minutes, 10ml/min), be suspended in H 2Among the O, and freeze-drying, obtain (3S, 4R, 5R, 6S)-6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-tetrahydrochysene-pyrans-2,3,4,5-tetrol (31mg, 0.079mmol, 85%) is white solid.NMR is shown as the α and the β anomer of 1: 1 ratio.
1H NMR (400MHz, methyl alcohol-d 4) δ ppm 7.34 (dd, J=8.08,4.04Hz, 1H), 7.22-7.30 (m, 2H), 7.09 (d, J=8.34Hz, 2H), 6.80 (d, J=8.08Hz, 2H), 5.16 (d, J=3.79Hz, 1H α), 4.65 (d, J=9.60Hz, 1H α or β), 4.59 (d, J=7.58Hz, 1H α or β), (4.14 d, J=9.60Hz, 1H α or β), 3.96-4.07 (m, 4H), 3.76 (t, J=9.35Hz, 1H α or β), (3.50 dd, J=9.60,3.79Hz, 1H α or β), (3.43 t, J=9.09Hz, 1H α or β), 3.23-3.29 (m, 1.5H), 1.36 (t, J=7.07Hz, 3H).MS(ES+)[M+NH 4] +＝412。
Embodiment 3:(2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-oxyethyl group-tetrahydrochysene-pyrans-3,4,5-triol synthetic
Figure A20081009007300381
By with AcCl (0.025ml, 0.35mmol) join among the EtOH (1ml) and stir 15 minutes the preparation 0.35 M HCl EtOH solution.The sealing bottle in 80 ℃ of alcohol (61mg, 0.11mmol) 2 hours that derive from embodiment 1 step D with this solution-treated.To react cool to room temperature, use dense NH 4The OH quencher is used NaHCO up to being alkalescence 3Handled 30 minutes, and used CH 2Cl 2Dilution is filtered and vacuum concentration.Product is by purified by flash chromatography (4g SiO 2, 0-10%MeOH:CH 2Cl 2, 40 minutes, 10ml/min), be suspended in H 2Among the O, and freeze-drying, obtain (2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-oxyethyl group-tetrahydrochysene-pyrans-3,4,5-triol (40mg, 0.095mmol, 85%) is white solid.NMR is shown as the α and the β anomer of 1.75: 1 ratios.
1H NMR (400MHz, the δ ppm:7.28-7.32 of chloroform-d) (m, 1H), 7.14 (m, 2H), 7.02 (d, J=8.84Hz, 2H), 6.72-6.76 (m, 2H), (4.88 d, J=4.04Hz, 1H α), 4.37 (d, J=9.60Hz, 1H α), 4.33 (d, J=7.83Hz, 1H β), 4.06 (d, J=9.35Hz, 1H β), 3.89-4.02 (m, 4H), 3.36-3.87 (m, 5H), 2.62 (s, 1H β), (2.54 s, 1H α), 2.41 (d, J=1.52Hz, 1H β), 2.02 (d, J=10.36Hz, 1H α), 1.92 (d, J=2.53Hz, 1H), 1.32 (t, J=6.95Hz, 3H), 1.13-1.19 (m, 3H).MS(ES+)[M+NH 4] +＝440。
Embodiment 4:(2S, 3R, 4R, 5S, 6S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-isopropoxy-tetrahydrochysene-pyrans-3,4,5-three pure and mild (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-isopropoxy-tetrahydrochysene-pyrans-3,4,5-triol synthetic
Figure A20081009007300391
By with AcCl (0.025ml, 0.35mmol) join among the i-PrOH (1ml) and stir 15 minutes the preparation 0.35 M HCl i-PrOH solution.The sealing bottle in 80 ℃ of alcohol (68mg, 0.12mmol2 hours that derive from embodiment 1 step D with this solution-treated.To react cool to room temperature, use dense NH 4The OH quencher is used NaHCO up to being alkalescence 3Handled 30 minutes, and used CH 2Cl 2Dilution is filtered and vacuum concentration.Resistates is by purified by flash chromatography (4g SiO 2, 0-10%MeOH:CH 2Cl 2, 40 minutes, 10ml/min), obtain the 50mg material, it is further passed through preparation property HPLC (19 * 50mm C18 post, 20-70%MeCN:H 2O (10mM NH 4OAc), 14 minutes, 30ml/min) purifying obtained (2S, 3R, 4R, 5S, 6S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-isopropoxy-tetrahydrochysene-pyrans-3,4,5-triol (β anomer, 7mg, 0.016mmol) and (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-isopropoxy-tetrahydrochysene-pyrans-3,4, the 5-triol (the α anomer, 25mg, 0.057mmol).
(2S, 3R, 4R, 5S, 6S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-isopropoxy-tetrahydrochysene-pyrans-3,4, the 5-triol: 1H NMR (400MHz, the δ ppm:7.37-7.40 of chloroform-d) (m, 1H), 7.26 (m, 2H), 7.12 (d, J=8.59Hz, 2H), 6.80-6.84 (m, 2H), 4.48 (d, J=7.83Hz, 1H), 4.15 (d, J=9.35Hz, 1H), 3.95-4.10 (m, 5H), 3.69 (t, J=9.09Hz, 1H), 3.46-3.52 (m, 2H), 2.69 (br.s., 1H), 2.43 (br.s., 1H), 2.05 (br.s., 1H), 1.41 (t, J=7.07Hz, 3H), 1.22 (t, J=6.57Hz, 6H).MS(ES+)[M+NH 4] +＝454。
(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-isopropoxy-tetrahydrochysene-pyrans-3,4, the 5-triol: 1H NMR (400MHz, and the δ ppm 7.39 of chloroform-d) (d, J=8.84Hz, 1H), 7.22 (m, 2H), 7.11 (d, J=8.59Hz, 2H), 6.80-6.85 (m, 2H), 5.04 (d, J=4.04Hz, 1H), 4.51 (d, J=9.60Hz, 1H), 3.98-4.10 (m, 4H), 3.93 (ddd, J=12.25,6.32,6.19Hz, 1H), 3.82 (t, J=9.22Hz, 1H), 3.62 (dd, J=9.47,3.66Hz, 1H), 3.49 (t, J=9.22Hz, 1H), 2.03 (br s, 3H), 1.41 (t, J=6.95Hz, 3H), 1.23 (d, J=6.32Hz, 3H), 1.19 (d, J=6.06Hz, 3H).MS(ES+)[M+NH 4] +＝454。
Embodiment 5:(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-methoxyl group-tetrahydrochysene-pyrans-3,4,5-three pure and mild (2S, 3R, 4R, 5S, 6S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-methoxyl group-tetrahydrochysene-pyrans-3,4,5-triol synthetic
The sample (80mg) that derives from the compound of embodiment 1 step e is dissolved in 30% ethanol/hexane of 4ml and and partly is expelled to ChiralPak AD-H post (20 * 250mm 400 μ l, 5.5ml/min, 31.55% ethanol/hexane is as the isoconcentration elutriant, envrionment temperature, operation 30min), so that two kinds of isomer are separated from one another.First isomer (retention time 23min) be defined as αYi Gouti (6R, 20mg) and second (retention time 26 minutes 21mg) is defined as beta isomer (6S).
(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol: 1H NMR (400MHz, and the δ ppm 7.39 of chloroform-d) (d, J=8.84Hz, 1H), 7.22-7.25 (m, 2H), 7.11 (d, J=8.59Hz, 2H), 6.83 (d, J=8.59Hz, 2H), 4.85 (d, J=4.04Hz, 1H), 4.42 (d, J=9.60Hz, 1H), 3.99-4.11 (m, 4H), 3.82 (t, J=9.22Hz, 1H), 3.66 (br.s., 1H), and 3.42-3.48 (m, 4H), 2.79 (br.s., 1H), 2.23 (d, J=1.26Hz, 1H), 2.12 (br.s., 1H), 1.40 (t, J=6.95Hz, 3H).MS(ES+)[M+NH 4] +＝426。
(2S, 3R, 4R, 5S, 6S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol: 1H NMR (400MHz, and the δ ppm 7.39 of chloroform-d) (d, J=8.59Hz, 1H), 7.23-7.26 (m, 2H), 7.11 (d, J=8.84Hz, 2H), 6.80-6.84 (m, 2H), 4.33 (d, J=7.58Hz, 1H), 4.07-4.17 (m, 2H), 3.98-4.04 (m, 3H), 3.68 (t, J=9.09Hz, 1H), 3.46-3.55 (m, 5H), 2.89 (br.s., 1H), 2.64 (br.s., 1H), 2.16 (br.s., 1H), 1.40 (t, J=7.07Hz, 3H).MS(ES+)[M+NH 4] +＝426。
Also use following method optionally synthetic (2S, 3R, 4R, 5S, 6S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol:
A. acetate (3S, 4R, 5S, 6S)-2,4,5-triacetyl oxygen base-6-[4-chloro-3-(4-oxyethyl group-benzyl Base)-phenyl]-preparation of tetrahydrochysene-pyrans-3-base ester:(6.80g is 12.4mmol) with 3: 2 AcOH/H at 100 ℃ of alcohol that will derive from embodiment 1 step D 2O (62ml) handled 22 hours.To react vacuum concentration,, and place under the high vacuum with toluene rotary evaporation 3 times.(9.4ml, handled 16 hours by pyridine 99.2mmol) (25ml) with containing diacetyl oxide for resistates.Reaction H 2The O quencher was stirred 1 hour, used Et 2The O dilution is with 1 M NaHSO 4The aqueous solution, H 2O, saturated NaHCO 3MgSO is used in the aqueous solution and salt water washing (reextraction) 4Drying is filtered and vacuum concentration.Resistates is by purified by flash chromatography (120g SiO 2, 0-50%EtOAc/Hex), obtain acetate (3S, 4R, 5S, 6S)-2,4,5-triacetyl oxygen base-6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-tetrahydrochysene-pyrans-3-base ester (6.10g, 10.9mmol, 87%).
1H NMR (400MHz, and the δ ppm 7.36 of chloroform-d) (dd, J=8.08,2.02Hz, 1H), 7.19 (dt, J=8.34,2.02Hz, 1H), 7.07-7.09 (m, 1H), 7.06 (dd, J=8.72,1.64Hz, 2H), 6.83 (d, J=8.59Hz, 2H), 6.44 (d, J=3.54Hz, 0.5H α), 5.84 (d, J=8.08Hz, 0.5H β), 5.55 (t, J=9.98Hz, 0.5H α), 5.33 (t, J=9.71Hz, 0.5H β), 5.20-5.27 (m, 1H), 5.09 (t, J=9.60Hz, 0.5H β), (5.03 t, J=9.73Hz, 0.5H α), 4.78 (d, J=10.11Hz, 0.5H α), 4.47 (d, J=9.85Hz, 0.5H β), 3.94-4.09 (m, 4H), 2.20 (s, 1.5H α), 2.11 (s, 1.5H β), 2.06 (s, 1.5H β), 2.05 (s, 1.5H α), 2.02 (s, 1.5H α), 2.01 (s, 1.5H β), 1.74 (s, 1.5H α), 1.72 (s, 1.5H β), 1.41 (t, J=6.95Hz, 3H).MS(ES+)[M+NH 4] +＝580。
B. acetate (2S, 3S, 4R, 5S, 6S)-4,5-diacetoxy-2-bromo-6-[4-chloro-3-(4-ethoxy Base-benzyl)-phenyl]-preparation of tetrahydrochysene-pyrans-3-base ester:(8.08g 14.4mmol) handled 1 hour with the AcOH (30ml) that contains 33%HBr with the tetraacetate that derives from steps A.Reaction CH 2Cl 2(60ml) dilution was stirred 30 minutes, with more DCM dilution, with ice-cold H 2O washs 3 times and uses saturated NaHCO 3Solution washing (reextraction) is used MgSO 4Drying is filtered and vacuum concentration, obtain acetate (2S, 3S, 4R, 5S, 6S)-4,5-diacetoxy-2-bromo-6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-tetrahydrochysene-pyrans-3-base ester.
1H NMR (400MHz, and the δ ppm 7.37 of chloroform-d) (d, J=8.34Hz, 1H), 7.17 (dd, J=8.21,2.15Hz, 1H), 7.12 (d, J=2.27Hz, 1H), 7.06 (d, J=8.59Hz, 2H), 6.83 (d, J=8.59Hz, 2H), 6.71 (d, J=4.04Hz, 1H), 5.64 (t, J=9.73Hz, 1H), 5.10 (t, J=9.73Hz, 1H), 4.92-4.98 (m, 2H), 3.94-4.11 (m, 4H), 2.13 (s, 3H), 2.03 (s, 3H), 1.74 (s, 3H), 1.41 (t, J=7.07Hz, 3H).MS(ES+)[M+NH 4] +＝602。
C. acetate (2S, 3S, 4R, 5S, 6S)-4 5-diacetoxy-6-[4-chloro-3-(4-oxyethyl group-benzyl Base)-phenyl]-preparation of 2-methoxyl group-tetrahydrochysene-pyrans-3-base ester:With derive from step B thick bromide (8.4g, 14.4mmol) and ZnO (1.2g, 14.4mmol) be dissolved in MeOH (144ml) and 70 ℃ the heating 1 hour.To react cool to room temperature, filter by diatomite and vacuum concentration with EtOAc.Resistates obtains acetate (2S, 3S in two batches from the MeOH recrystallization, 4R, 5S, 6S)-4,5-diacetoxy-6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-2-methoxyl group-tetrahydrochysene-pyrans-3-base ester (5.98g, 11.2mmol, 78%) is pure beta-anomer-.
1H NMR (400MHz, and the δ ppm 7.37 of chloroform-d) (d, J=8.08Hz, 1H), 7.22 (dd, J=8.21,2.15Hz, 1H), 7.05-7.10 (m, 3H), and 6.80-6.85 (m, 2H), 5.29 (t, J=9.47Hz, 1H), 5.11 (dd, J=9.73,7.96Hz, 1H), 5.02 (t, J=9.73Hz, 1H), 4.54 (d, J=8.08Hz, 1H), 4.33 (d, J=9.85Hz, 1H), 3.96-4.09 (m, 4H), 3.49 (s, 3H), 2.08 (s, 3H), 1.99 (s, 3H), 1.71 (s, 3H), 1.41 (t, J=6.95Hz, 3H).MS(ES+)[M+NH 4] +＝552。
D. (2S, 3R, 4R, 5S, 6S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-methoxyl group-four Hydrogen-pyrans-3,4, the preparation of 5-triol:(5.98g is 11.2mmol) with containing K will to derive from the triacetate of the recrystallization of step C under vigorous stirring 2CO 3(7.7g, MeOH 56mmol) (112ml) handled 1 hour.To react and filter by diatomite and vacuum concentration.Resistates is dissolved in DCM, uses H 2MgSO is used in O and salt water washing 4Drying is filtered and vacuum concentration.Resistates uses 5%MeOH:CH by the silica gel short column 2Cl 2, vacuum concentration is suspended in H 2Among the O, and freeze-drying, obtain (2S, 3R, 4R, 5S, 6S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-methoxyl group-tetrahydrochysene-pyrans-3,4,5-triol (4.37g, 10.7mmol, 96%) is white solid.
1H NMR (400MHz, and the δ ppm 7.39 of chloroform-d) (d, J=8.59Hz, 1H), 7.23-7.27 (m, 2H), 7.11 (d, J=8.59Hz, 2H), 6.82 (d, J=8.59Hz, 2H), 4.33 (d, J=7.83Hz, 1H), 4.15 (d, J=9.35Hz, 1H), 3.98-4.12 (m, 4H), 3.68 (t, J=9.09Hz, 1H), 3.53 (s, 3H), 3.46-3.53 (m, 2H), 2.80 (br.s., 1H), 2.58 (br.s., 1H), 2.09 (br.s., 1H), 1.40 (t, J=7.07Hz, 3H).MS(ES+)[M+NH 4] +＝426。
Embodiment 6:N-{ (2S, 3S, 4R, 5R, 6S)-and 6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--tetrahydrochysene-pyrans-2-yl }-N-propyl group-ethanamide synthetic
Figure A20081009007300431
With derive from embodiment 5 step B bromide (58mg, 0.1mmol) at 40 ℃ with the CH that contains propylamine (0.1ml) 2Cl 2(0.5ml) solution-treated is 1.5 hours.Reaction blasts N 2, blast CH then 2Cl 2Twice.(78 μ l, pyridine 0.82mmol) (1ml) handle and spend the night resistates with containing diacetyl oxide.The MeOH quencher is used in reaction, stirs 30 minutes, uses Et 2The O dilution is with 1 M NaHSO 4The aqueous solution, H 2O, saturated NaHCO 3MgSO is used in the aqueous solution and salt water washing (reextraction) 4Drying is filtered and vacuum concentration.Intermediate is with containing K 2CO 3(14mg, MeOH 0.10mmol) (1ml) handled 1.5 hours.Reaction is filtered and vacuum concentration, and resistates is by purified by flash chromatography (12g SiO 2, 0-10%MeOH:CH 2Cl 2), obtain 90% pure material.Product is by HPLC (19 * 50mm C18 post, 20-70%MeCN:H 2O (10mMNH 4OAc), 14 minutes, 30ml/min) be further purified, be suspended in H 2Among the O, and freeze-drying, obtain N-{ (2S, 3S, 4R, 5R, 6S)-6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--tetrahydrochysene-pyrans-2-yl }-N-propyl group-ethanamide (3mg, 0.0063mmol, 15%), be the rotational isomer of 2: 1 ratios.
1H NMR(400MHz，MeOD)δppm 7.29-7.40(m，1H)，7.16-7.26(m，2H)，7.08(d，J＝8.6Hz，2H)，6.81(d，J＝8.6Hz，2H)，5.59(d，J＝8.6Hz，0.33H)，4.98(d，J＝11.9Hz，0.67H)，4.25(d，J＝9.3Hz，0.67H)，4.17(d，J＝9.9Hz，0.33H)，3.92-4.06(m，4H)，3.46-3.64(m，3H)，3.06-3.28(m，2H)，2.16(s，3H)，1.49-1.68(m，2H)，1.36(t，J＝6.9Hz，3H)，0.93(t，J＝7.5Hz，1H)，0.87(t，J＝7.5Hz，2H)。MS(ES+)[M+H]+＝478。
Embodiment 7:(2R, 3S, 4S, 5S)-and 5-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-2,3,4,5-tetrahydroxy-valeraldehyde oxime synthetic
With derive from embodiment 2 compound (50mg, 0.13mmol) and hydroxylamine hydrochloride (26mg 0.38mmol) is dissolved in pyridine (0.65ml) and stirring 3 hours.Reaction is diluted with EtOAc, with 1 M NaHSO 4The aqueous solution, H 2O, saturated NaHCO 3Na is used in the aqueous solution and salt water washing (reextraction) 2SO 4Drying is filtered and vacuum concentration.Resistates is suspended in H 2Among the O and freeze-drying, obtain (2R, 3S, 4S, 5S)-and 5-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-2,3,4,5-tetrahydroxy-valeraldehyde oxime (46mg, 0.11mmol, 88%) is 5: 1 mixtures of oxime isomers.
Main isomer 1H NMR (400MHz, MeOD) δ ppm 7.31-7.36 (m, 2H), 7.23-7.30 (m, 2H), 7.10 (d, J=8.8Hz, 2H), 6.80 (d, J=8.6Hz, 2H), 4.63 (d, J=8.1Hz, 1H), 4.28 (t, J=6.8Hz, 1H), 3.96-4.03 (m, 4H), 3.90-3.94 (m, 1H), 3.59 (dd, J=8.0,1.6Hz, 1H), 1.36 (t, J=6.9Hz, 3H); MS (ES+) [M+H] +=410.
Embodiment 8:(3S, 4R, 5R, 6S)-and 6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--tetrahydrochysene-pyran-2-one oxime synthetic
Figure A20081009007300451
A. acetate (3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[4-chloro-3-(4-oxyethyl group-benzyl)- Phenyl]-preparation of 2-hydroxyl-tetrahydrochysene-pyrans-3-base ester:(200mg, 0.36mmol) (39 μ l, DMF 0.36mmol) (1.8ml) handled 2 hours with containing benzyl amine to derive from the tetraacetate of embodiment 5 steps A.Reaction Et 2The O dilution is with 1 M NaHSO 4The aqueous solution, H 2O, saturated aqueous solution NaHCO 3, and salt water washing, use MgSO 4Drying is filtered and vacuum concentration.Resistates is by purified by flash chromatography (12g SiO 2, 0-50%EtOAc:Hex.), obtain acetate (3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-2-hydroxyl-tetrahydrochysene-pyrans-3-base ester (142mg, 0.27mmol, 77%), be the anomer of 3: 1 ratios.
1H NMR (400MHz, and the δ ppm 7.33-7.40 of chloroform-d) (m, 1H), 7.18-7.23 (m, 1H), 7.09-7.14 (m, 1H), 7.06 (d, J=8.6Hz, 2H), 6.82 (d, J=8.6Hz, 2H), 5.59-5.66 (m, 0.75H), 5.56 (t, J=3.7Hz, 0.75H), 5.34 (t, J=9.6Hz, 0.25H), 4.90-5.11 (m, 2.75H), 4.86 (t, J=8.2Hz, 0.25H), 4.39 (d, J=9.9Hz, 0.25H), 3.93-4.10 (m, 4H), 3.36 (d, J=8.6Hz, 0.25H), 2.81 (dd, J=3.8,1.3Hz, 0.75H), 2.12 (s, 0.75H), 2.12 (s, 2.25H), 2.02 (s, 0.75H), 2.01 (s, 2.25H), 1.73 (s, 2.25H), 1.72 (s, 0.75H), 1.41 (t, J=7.1Hz, 3H); MS (ES+) [M+NH 4] +=538.
B. acetate (3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[4-ammonia-3-(4-oxyethyl group-benzyl)- Phenyl]-2-[(Z)-oxyimino]-preparation of tetrahydrochysene-pyrans-3-base ester:With derive from steps A compound (142mg, 0.27mmol) and hydroxylamine hydrochloride (57mg 0.82mmol) is dissolved in pyridine (1.4ml).To react and stir 6 hours, with the EtOAc dilution, with 1 M NaHSO 4The aqueous solution, H 2O, saturated aqueous solution NaHCO 3, and salt water washing (reextraction), use Na 2SO 4Drying is filtered and vacuum concentration.Resistates is dissolved in CH 2Cl 2, be cooled to-78 ℃, and (49 μ L handle 0.33mmol), and (44mg 0.33mmol) handles to use N-chlorosuccinimide subsequently with DBU.To be reflected at-78 ℃ and stir 20 minutes, in 15 minutes, make its room temperature of rising again then.Reaction is diluted with EtOAc, uses H 2MgSO is used in O and salt water washing (reextraction) 4Drying is filtered and vacuum concentration.Resistates is by purified by flash chromatography (12g SiO 2, 0-50%EtOAc:Hex.), obtain acetate (3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-2-[(Z)-oxyimino]-tetrahydrochysene-pyrans-3-base ester (97mg, 0.18mmol, 67%).
1H NMR (400MHz, and the δ ppm 7.42 of chloroform-d) (d, J=8.1Hz, 1H), 7.30 (dd, J=8.2,2.1Hz, 1H), 7.18 (d, J=2.3Hz, 1H), 7.07 (d, J=8.6Hz, 2H), 6.83 (d, J=8.6Hz, 2H), 6.64 (s, 1H), 5.53 (d, J=4.5Hz, 1H), 5.28 (dd, J=5.8,4.5Hz, 1H), and 5.16-5.22 (m, 1H), 5.10-5.15 (m, 1H), and 3.98-4.10 (m, 4H), 2.19 (s, 3H), 2.07 (s, 3H), 1.78 (s, 3H), 1.41 (t, J=7.1Hz, 3H); MS (ES+) [M+H] +=534.
C. (3S, 4R, 5R, 6S)-and 6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--four The preparation of hydrogen-pyran-2-one oxime:(97mg is 0.18mmol) with containing 7.0 M NH with the compound that derives from step B 3MeOH (1.8ml) handled 1 hour.To react vacuum concentration, and resistates will be passed through purified by flash chromatography (12g SiO 2, 0-12%MeOH:CH 2Cl 2), be suspended in H 2Among the O, and freeze-drying, obtain (3S, 4R, 5R, 6S)-and 6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--tetrahydrochysene-pyran-2-one oxime (57mg, 0.14mmol, 77%) is white solid.
1H NMR(400MHz，MeOD)δppm 7.36-7.44(m，2H)，7.31-7.35(m，1H)，7.12(d，J＝8.8Hz，2H)，6.80(d，J＝8.8Hz，2H)，4.91-4.95(m，1H)，4.14(d，J＝5.6Hz，1H)，4.03-4.10(m，2H)，3.99(q，J＝7.1Hz，2H)，3.73-3.78(m，1H)，3.55(dd，J＝9.9，6.6Hz，1H)，1.36(t，J＝7.1Hz，3H)；MS(ES+)[M+H] +＝408。
Embodiment 9:(2S, 3R, 4R, 5R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-5-fluoro-6-methoxyl group-tetrahydrochysene-pyrans-3,4-glycol synthetic
Figure A20081009007300471
A. (2S, 3R, 4S)-and 2-(4-chloro-3-(4-ethoxy benzyl) phenyl)-3,4-dihydro-2H-pyrans -3, the preparation of 4-two basic diacetate esters:The HBr (33%, in HOAc) that adds 1.25ml to the flask of the tetraacetate that derives from embodiment 5 steps A (0.5mmol) that 282mg is housed.To react and stir one hour, with the dilution of 50ml methylene dichloride and by being poured over quencher in the frozen water.Organic layer separated and use saturated NaHCO 3The aqueous solution and salt water washing.After with dried over mgso, with the solvent vacuum concentration.Thick resistates accumulate in the 0.5ml methylene dichloride and join copper sulfate (II) (20mg, 0.125mmol), the Zn powder (82mg, 1.25mmol) and sodium acetate (984mg is 12mmol) in 2.5ml acetic acid/water (3: 2v: the suspension v).Mixture stirring at room 4 hours, is added the copper sulfate (II) of 20mg and 82mg Zn powder again and stirs other 18h to reaction thereafter.With the quencher of mixture water, use ethyl acetate extraction.Organic layer is removed with dried over mgso and vacuum.Through flash chromatography, obtain (2S, 3R, 4S)-and 2-(4-chloro-3-(4-ethoxy benzyl) phenyl)-3,4-dihydro-2H-pyrans-3,4-two basic diacetate esters (32mg, 16% yield).
1H NMR (400MHz, and the δ ppm 7.36 of chloroform-d) (d, J=8.08Hz, 1H), 7.20 (dd, J=8.08,2.27Hz, 1H), 7.16 (d, J=2.27Hz, 1H), 7.08 (d, J=8.59Hz, 2H), 6.82 (d, J=8.59Hz, 2H), 6.57 (dd, J=6.06,1.52Hz, 1H), 5.54 (ddd, J=7.07,2.53,1.52Hz, 1H), 5.32 (dd, J=9.60,7.07Hz, 1H), and 4.83-4.88 (m, 1H), 4.01 (q, J=6.82Hz, 2H), 3.96-4.10 (m, 2H), 1.96 (s, 3H), 1.77 (s, 3H), 1.40 (t, J=6.82Hz, 3H).MS(ES+)[M+NH4]+＝462。
B. (2S, 3R, 4R, 5R, 6R)-2-(4-chloro-3-(4-oxyethyl group-benzyl)-phenyl)-5-fluoro-6-methoxy Base-tetrahydrochysene-2H-pyrans-3, the preparation of 4-glycol:With Selectfluor TM(45mg, (38mg is 0.0853mmol) at the 0.4mL acetonitrile: methyl alcohol (1: 1v: the solution v) 0.128mmol) to join the compound that derives from steps A.Reaction is stirred at ambient temperature and is finished by the LCMS monitoring.To react saturated NH with 2mL 4Cl aqueous solution quencher and with extracted with diethyl ether (2 * 5mL).Organism dried over sodium sulfate and vacuum concentration with extraction.Obtain the fluorizated product through flash chromatography (5 to 10% ethyl acetate/hexane).Then salt of wormwood (5mg) is joined the solution of this isolating product in 0.5mL methyl alcohol.To be reflected at envrionment temperature and stir 2 hours, thereafter with it with 2mL water quencher and with ethyl acetate extraction (2 * 4mL).Organic layer filters by the silicon-dioxide pad and concentrates, obtain 6.3mg (2S, 3R, 4R, 5R, 6R)-2-(4-chloro-3-(4-oxyethyl group-benzyl)-phenyl)-5-fluoro-6-methoxyl group-tetrahydrochysene-2H-pyrans-3, the 4-glycol is clarifying oily matter.
1H NMR (400MHz, chloroform-d, 3: 2 α: β anomer ratio, 2: 1 upright: calm fluorine structure ratio, represent with italic by the isomer that a small amount of calm fluorine structure produces) and δ ppm7.41 (dd, J=8.34,2.78Hz, 1H), 7.20-7.33 (m, 2H), 7.11 (d, J=8.59Hz, 2H), 6.83 (d, J=8.59Hz, 2H), 4.92-5.02 (m, 1H), and 4.30-4.52 (m, 1H), 3.96-4.27 (m, 6H), 3.74 (t, J=9.09Hz, 0.66H α), 3.57/3.56 (s, 3H), 3.49 (t, J=9.09Hz, 0.33H β), and 3.42/3.41 (s, 3H).MS(ES+)[M+NH 4] +＝428。
Embodiment 10:(2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-hydroxyl-benzyl)-phenyl]-6-methoxyl group-tetrahydrochysene-pyrans-3,4,5-triol synthetic
Figure A20081009007300481
A.[4-(5-bromo-2-chloro-benzyl)-phenoxy group]-preparation of the tertiary butyl-dimethyl-silane:The preparation described in the people's such as Himmelsbach of announcement on November 9th, 2006 U.S. Patent Application Publication 2006/0251728 of this compound.
B. (S)-3-[4-(tertiary butyl-dimethyl-silyl oxygen base)-benzyl]-4-chloro-benzene Base }-[(3aS, 5S, 6R, 6aS)-and 6-(tertiary butyl-dimethyl-silyl oxygen base)-2,2-dimethyl-four Hydrogen-furo [2,3-d] [1,3] dioxole-5-yl]-methyl alcohol:The solution of compound in the 4.14ml ether that 0.85g (2.07mmol) is derived from steps A under inert environments is cooled to--and 78 ℃.(1.55 M are in hexane, 4.14mmol) to the tert-butyl lithium that wherein adds 2.66ml in 5 minutes by syringe.To be reflected at-78 ℃ stirred 30 minutes.Adding 0.5g (1.65mmol) derives from the solution of compound in the 1.65ml ether of embodiment 1 step B.This reaction mixture was stirred 30 minutes at-78 ℃, stirred 1.5 hours at 0 ℃ subsequently.Thick reaction is filtered by silicagel pad, uses excessive ether, subsequently its vacuum is removed.The product that obtains is the diastereomer of about 1.2: 1 ratios for the secondary alcohol place in new formation.Diastereomer easily separates (4 to 8% ethyl acetate/hexane gradient) by silica gel chromatography.Yield: 40% (diastereomer of expectation), 58% (diastereomer of not expecting).
1H NMR (400MHz, and the δ ppm 7.17 of chloroform-d) (d, J=8.34Hz, 1H), 7.07-7.11 (m, 1H), 7.03 (d, J=1.77Hz, 1H), 6.85 (d, J=8.59Hz, 2H), 6.56 (d, J=8.34Hz, 2H), 5.80 (d, J=3.79Hz, 1H), 4.70 (d, J=4.80Hz, 1H), 4.20 (d, J=3.79Hz, 1H), 4.07 (dd, J=4.80,3.03Hz, 1H), 3.97 (d, J=3.03Hz, 1H), 3.85 (d, J=3.03Hz, 2H), 3.16 (br.s., 1H), 1.27 (s, 3H), 1.13 (s, 3H), 0.80 (s, 9H), 0.73 (s, 9H), 0.00 (s, 6H) ,-0.06 (s, 3H) ,-0.18 (s, 3H).
C. (2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-hydroxyl-benzyl)-phenyl]-6-methoxyl group-tetrahydrochysene-pyrrole Mutter-3,4, the preparation of 5-triol:Acetyl Chloride 98Min. (0.17ml) is joined in the methyl alcohol of 7ml and stirring at room 15 minutes.This solution transferred to the bottle that 0.446g derives from the compound of step B is housed, seal and be heated to 80 ℃ then, 1 hour.Reaction is cooled to envrionment temperature and with the quencher of 50ml saturated sodium bicarbonate aqueous solution.Water layer ethyl acetate extraction (3 * 50ml).Dried over mgso is used in the organic layer salt water washing that merges, and solvent removed in vacuo.Resistates obtains about 1: 1 α: the mixture of β anomer by silica gel chromatography purifying (0 to 20% ethanol/methylene gradient).Yield: 65%.
1H NMR (400MHz, acetone) δ ppm 8.12 (br.s., 1H), 7.33-7.40 (m, 2H), 7.29 (dd, J=8.08,1.77Hz, 1H), 7.06 (d, J=8.34Hz, 3H), 6.75 (d, J=8.34Hz, 2H), 4.73 (d, J=3.54Hz, 0.5H α), 4.41 (d, J=9.60Hz, 0.5H α), (4.33 d, J=7.58Hz, 0.5H β), 4.19 (d, J=9.35Hz, 0.5H β), 4.01 (t, J=3.28Hz, 2H), 3.72 (t, J=9.09Hz, 0.5H), 3.44-3.55 (m, 1H), 3.41 (s, 1.5H β), (3.35 s, 1.5H α), and 3.27-3.37 (m, 1.5H).MS(ES+)[M+NH 4] +＝398。
Embodiment 11:(2S, 3R, 4S, 5R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-tetrahydrochysene-pyrans-3,4,5-triol synthetic
Figure A20081009007300501
With toluene-4-sulfonic acid (S)-(tetrahydrochysene-furans-3-yl) ester (31mg, 0.126mmol) join the compound (16mg that derives from embodiment 10 step C, 0.042mmol) and cesium carbonate (46mg, 0.126mmol) at 0.22ml N, the suspension in the dinethylformamide.With reaction vessel sealing and be heated to 80 ℃, 15 hours.After cool to room temperature, thick reaction mixture is with 2ml salt solution quencher and with ethyl acetate extraction (3 * 2ml).The organic extract that merges dried over sodium sulfate and vacuum concentration.Silica gel chromatography (0 to 10% ethanol/methylene gradient) obtains (2S, 3R, 4S, 5R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-tetrahydrochysene-pyrans-3,4, the 5-triol, be viscosity oily matter, it concentrated in methylene dichloride obtain (10mg, 55% yield) as white solid.
1H NMR (400MHz, acetone) δ ppm 7.35-7.41 (m, 2H), 7.30 (dd, J=8.34,2.02Hz, 1H), 7.16 (d, J=7.58Hz, 2H), 6.83 (d, J=8.59Hz, 2H), 4.93-5.01 (m, 1H), (4.74 d, J=3.79Hz, 0.5H α), 4.42 (d, J=9.60Hz, 0.5H α), 4.33 (d, J=7.58Hz, 0.5H β), 4.20 (d, J=9.60Hz, 0.5H β), 4.05 (t, J=2.53Hz, 2H), 4.05 (d, J=5.31Hz, 2H), 3.93 (dd, J=10.11,4.80Hz, 1H), and 3.75-3.89 (m, 2H), 3.72 (t, J=9.09Hz, 1H), 3.50 (t, J=9.09Hz, 1H), 3.41 (s, 1.5H β), (3.35 s, 1.5H α), and 3.29-3.34 (m, 3H), 2.16-2.27 (m, 1H), 1.97-2.04 (m, 1H).MS(ES+)[M+NH4]+＝468。
Embodiment 12:(2S, 3S, 4S, 5R)-2-[4-chloro-3-(4-hydroxyl-benzyl)-phenyl]-piperidines-3,4,5-triol synthetic
Figure A20081009007300502
A. ((3aS, 5S, 6R, 6aS)-the 5-{ azido--[(S)-4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]- Methyl }-2,2-dimethyl-tetrahydrochysene-furo [2,3-d] [1,3] dioxole-6-base oxygen base)-uncle The preparation of butyl-dimethyl-silicomethane:C5 epimer (682mg to the alcohol that derives from embodiment 1 step D, 1.24mmol) and PPh3 (489mg, 1.87mmol) (366 μ l 1.87mmol) add azide diphenyl phosphate (DPPA subsequently at the middle solution adding DIAD of THF (6.2ml), 323 μ l, 1.49mmol).To react and stir 1.5 hours, use saturated NH 4Et is used in the quencher of the Cl aqueous solution 2H is used in the O dilution 2MgSO is used in O and salt water washing (reextraction) 4Drying, and vacuum concentration.Resistates is by purified by flash chromatography (40g SiO 20-8%EtOAc:Hex.), obtain ((3aS, 5S, 6R, 6aS)-the 5-{ azido--[(S)-4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-methyl }-2,2-dimethyl-tetrahydrochysene-furo [2,3-d] [1,3] dioxole-6-base oxygen base)-tertiary butyl-dimethyl-silicomethane (636mg, 1.11mmol, 89%), be yellow oil.
1H NMR (400MHz, and the δ ppm 7.40 of chloroform-d) (d, J=8.08Hz, 1H), 7.16-7.20 (m, 1H), 7.15 (d, J=2.02Hz, 1H), 7.10 (d, J=8.59Hz, 2H), 6.80-6.85 (m, 2H), 5.79 (d, J=3.54Hz, 1H), 4.58 (d, J=9.85Hz, 1H), 4.36 (d, J=3.54Hz, 1H), 4.30 (d, J=2.53Hz, 1H), 4.14 (dd, J=9.98,2.65Hz, 1H), and 3.98-4.10 (m, 4H), 1.38-1.43 (m, 6H), 1.29 (s, 3H), 0.96 (s, 9H), 0.20 (s, 6H); MS (ES+) [M+NH 4] +=591.
B. (2R, 3S, 4S, 5S)-the 5-{ azido--[(S)-4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-first Base }-tetrahydrochysene-furans-2,3, the preparation of 4-triol:(0.175ml 2.45mmol) joins among the MeOH (7ml) with Acetyl Chloride 98Min..With solution stirring 15 minutes, join then the trinitride that derives from steps A (392mg, 0.68mmol) in.To react and stir 16 hours, vacuum concentration then with MeOH rotary evaporation 2 times, and places under the high vacuum, obtains white solid.100 ℃ with solid with 1: 1 AcOH:H 2O (7ml) handled 2.5 hours.To react vacuum concentration,, and place under the high vacuum with toluene rotary evaporation 2 times.Resistates is by purified by flash chromatography (40gSiO 2, 0-6%MeOH:CH 2Cl 2), obtain (2R, 3S, 4S, 5S)-the 5-{ azido--[(S)-4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-methyl }-tetrahydrochysene-furans-2,3,4-triol (223mg, 0.53mmol, 78%) is the mixture of anomer.
1H NMR(400MHz，MeOD)δppm 7.39(dd，J＝8.46，3.41Hz，1H)，7.24-7.30(m，2H)，7.09(d，J＝8.84Hz，2H)，6.81(dd，J＝8.59，1.77Hz，2H)，5.33(d，J＝3.54Hz，0.5H)，4.98(s，0.5H)，4.84(d，J＝10.17Hz，0.5H)，4.66(d，J＝9.09Hz，0.5H)，4.10-4.23(m，2H)，3.97-4.05(m，4.5H)，3.89(dd，J＝3.66，1.89Hz，0.5H)，1.36(t，J＝6.95Hz，3H)；MS(ES+)[M+NH 4] +＝437。
C. (2S, 3S, 4S, 5R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-piperidines-3,4, the 5-triol Preparation:H at environmental stress 2(216mg is 0.52mmol) at PtO will to derive from down the compound of step B in MeOH (5ml) 2(6mg 0.026mmol) goes up and AcOH (0.25ml) hydrogenation 6 hours.To react filtration, vacuum concentration with the EtOAc dilution, is used 10%K 2CO 3Na is used in the aqueous solution and salt water washing 2SO 4Drying is filtered and vacuum concentration.A part of material (about 55mg) is passed through preparation property HPLC (Sunfire C18 30 * 100mm column, 20-70%MeCN:H 2O (10mM NH 4OAc), 15 minutes, 45ml/min) purifying and freeze-drying, obtain (2S, 3S, 4S, 5R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-piperidines-3,4, (27mg 0.071mmol), is white solid to the 5-triol.
1H NMR(400MHz，MeOD)δppm 7.35(d，J＝8.08Hz，1H)，7.29(d，J＝2.02Hz，1H)，7.21-7.25(m，1H)，7.10(d，J＝8.34Hz，2H)，6.79(d，J＝8.59Hz，2H)，4.02(s，2H)，3.99(q，J＝7.07Hz，2H)，3.57(ddd，J＝10.55，8.65，5.05Hz，1H)，3.33-3.40(m，2H)，3.25-3.29(m，1H)，3.12(dd，J＝12.00，5.18Hz，1H)，2.56(dd，J＝11.87，10.86Hz，1H)，1.35(t，J＝6.95Hz，3H)；MS(ES+)[M+H] +＝378。
Embodiment 13:(2S, 3R, 4R; 5S; 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-ethane sulfinyl-tetrahydrochysene-pyrans-3,4,5-three pure and mild (2S; 3R; 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-ethane alkylsulfonyl-tetrahydrochysene-pyrans-3; 4,5-triol synthetic
Figure A20081009007300521
A. (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-ethyl sulphur-four Hydrogen-pyrans-3,4, the preparation of 5-triol:0 ℃ to the bromide that derives from embodiment 5 step B (291mg, EtOH 0.50mmol) (5ml) solution add NaSEt (84mg, 1.0mmol).To react and stir 30 minutes, with the EtOAc dilution,, use Na then with rare NaOH solution washing with salt water washing (reextraction) 2SO 4Drying is filtered and vacuum concentration.Resistates is by purified by flash chromatography (40g SiO 2, 0-7%MeOH:CH 2Cl 2), be suspended in H 2Among the O, and freeze-drying, obtain (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-ethyl sulphur-tetrahydrochysene-pyrans-3,4,5-triol (126mg, 0.29mmol, 58%) is white powder.
1H NMR (400MHz, and the δ ppm 7.39 of chloroform-d) (d, J=8.08Hz, 1H), 7.18-7.26 (m, 2H), 7.10 (d, J=8.59Hz, 2H), and 6.80-6.85 (m, 2H), 4.46 (d, J=9.60Hz, 1H), 4.17 (d, J=9.35Hz, 1H), and 3.98-4.11 (m, 4H), 3.67-3.73 (m, 1H), and 3.49-3.57 (m, 2H), 2.79 (d, J=2.27Hz, 1H), 2.67-2.77 (m, 2H), 2.53 (d, J=1.77Hz, 1H), 2.04 (d, J=2.78Hz, 1H), 1.41 (t, J=6.95Hz, 3H), 1.29 (t, J=7.45Hz, 3H); MS (ES+) [M+NH 4] +=456.
B. (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-the inferior sulphur of 6-ethane Acyl group-tetrahydrochysene-pyrans-3,4,5-three pure and mild (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl Base)-phenyl]-6-ethane alkylsulfonyl-tetrahydrochysene-pyrans-3,4, the preparation of 5-triol:(10mg adds H in AcOH 0.023mmol) (0.5ml) solution to the compound that derives from steps A 2O 2(the H of 35wt% 2The O aqueous solution, 3mg, 0.092mmol, 9 μ l).Mixture is stirred 2 hours vacuum concentration then in envrionment temperature.Mixture is by silica gel chromatography (5%MeOH/CH 2Cl 2) purifying, obtain (2S, 3R; 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-ethane sulfinyl-tetrahydrochysene-pyrans-3; 4,5-triol (being mixture) (2mg, 19%) and (2S at the diastereomer at sulphur place; 3R, 4R, 5S; 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-ethane alkylsulfonyl-tetrahydrochysene-pyrans-3,4,5-triol (5mg; 46%), the two all is a white solid.
(2S 3R 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-ethane sulfinyl Base-tetrahydrochysene-pyrans-3,4, the 5-triol: 1H NMR (400MHz, methyl alcohol) δ ppm 7.37 (m, 3H), 7.31 (m, 1H), 7.24 (m, 2H), 7.10 (m, and 4H) 6.81 (m, 4H), 4.46 (d, J=9.9Hz, 1H), 4.28 (d, J=9.6Hz, 1H), 4.25 (d, J=9.6Hz, 1H), 4.19 (d, J=9.9Hz, 1H), 4.03 (m, 4H), 4.00 (m, 4H), 3.85 (t, J=9.6Hz, 1H), 3.76 (t, J=9.6Hz, 1H), 3.57 (m, 2H), 3.37 (m, 2H), 3.09 (m, 1H), 2.99 (m, 1H), 2.91 (m, 1H), 2.80 (m, 1H), 1.31 (m, 12H); MS (ES+) [M+H] +=455.
(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-ethane alkylsulfonyl- Tetrahydrochysene-pyrans-3,4, the 5-triol: 1H NMR (400MHz, methyl alcohol) δ ppm 7.28 (m, 1H), 7.16 (m, 2H), 6.99 (d, J=8.6Hz, 2H), 6.71 (d, J=8.6Hz, 2H), 4.46 (d, J=9.6Hz, 1H), 4.19 (d, J=9.4Hz, 1H), 3.90 (m, 4H), 3.81 (t, J=9.3Hz, 1H), 3.46 (t, J=9.1Hz, 1H), 3.24 (t, J=9.1Hz, 1H), 2.98 (m, 2H), 1.26 (t, J=6.8Hz, 3H), 1.18 (t, J=7.6Hz, 3 H); MS (ES+) [M+NH 4] +=488.
Embodiment 14: acetate (2R, 3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[4-chloro-3-(4 oxyethyl groups-benzyl)-phenyl]-2-methyl sulphur-tetrahydrochysene-pyrans-3-base ester synthetic
A. (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-methyl sulphur-four Hydrogen-pyrans-3,4, the preparation of 5-triol:0 ℃ to the bromide that derives from embodiment 5 step B (347mg, add in EtOH 0.60mmol) (6ml) solution NaSMe (70mg, 0.72mmol).To react and stir 30 minutes, with the EtOAc dilution,, use Na then with rare NaOH solution washing and with salt water washing (reextraction) 2SO 4Drying is filtered and vacuum concentration.Resistates is by purified by flash chromatography (40g SiO 2, 0-7%MeOH:CH 2Cl 2), be suspended in H 2Among the O, and freeze-drying, obtain (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-methyl sulphur-tetrahydrochysene-pyrans-3,4,5-triol (212mg, 0.43mmol, 72%) is white powder.
1H NMR (400MHz, and the δ ppm 7.39 of chloroform-d) (d, J=8.34Hz, 1H), 7.22 (dd, J=8.08,2.27Hz, 1H), 7.17 (d, J=2.02Hz, 1H), 7.10 (d, J=8.59Hz, 2H), 6.83 (d, J=8.84Hz, 2H), 4.38 (d, J=9.60Hz, 1H), 4.19 (d, J=9.35Hz, 1H), 3.98-4.11 (m, 4H), 3.67-3.73 (m, 1H), 3.48-3.59 (m, 2H), 2.80 (d, J=2.27Hz, 1H), 2.53 (d, J=2.02Hz, 1H), 2.19 (s, 3H), 2.04 (d, J=2.78Hz, 1H), 1.41 (t, J=6.95Hz, 3H); MS (ES+) [M+NH 4] +=442.
B. acetate (2R, 3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[4-chloro-3-(4-oxyethyl group-benzyl Base)-phenyl]-preparation of 2-methyl sulphur-tetrahydrochysene-pyrans-3-base ester:(45mg, 0.11mmol) (60 μ l, pyridine 0.64mmol) (0.5ml) handled 16 hours with comprising diacetyl oxide to derive from the triol of steps A.Reaction Et 2The O dilution is with 1 M NaHSO 4The aqueous solution, H 2O, saturated NaHCO 3MgSO is used in the aqueous solution and salt water washing (reextraction) 4Drying is filtered and vacuum concentration.Resistates is by purified by flash chromatography (4g SiO 2, 0-25%EtOAc/Hex), be suspended in H 2Among the O, and freeze-drying, obtain acetate (2R, 3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-2-methyl sulphur-tetrahydrochysene-pyrans-3-base ester (46mg, 0.087mmol, 79%), be white solid.
1H NMR (400MHz, and the δ ppm 7.36 of chloroform-d) (d, J=8.08Hz, 1H), 7.18 (dd, J=8.21,2.15Hz, 1H), 7.02-7.10 (m, 3H), 6.83 (d, J=8.59Hz, 2H), and 5.27-5.34 (m, 1H), 5.19 (t, J=9.60Hz, 1H), 5.04 (t, J=9.60Hz, 1H), 4.50 (d, J=9.85Hz, 1H), 4.37 (d, J=9.85Hz, 1H), 3.95-4.08 (m, 4H), 2.16 (s, 3H), 2.10 (s, 3H), 2.00 (s, 3H), 1.72 (s, 3H), 1.41 (t, J=7.07Hz, 3H); MS (ES+) [M+NH 4] +=568.
Embodiment 15:(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-methane sulfonyl-tetrahydrochysene-pyrans-3,4,5-triol synthetic
Figure A20081009007300551
(41mg adds H in AcOH 0.097mmol) (0.5ml) solution to the compound that derives from embodiment 14 steps A 2O 2(the H of 35wt% 2O solution, 20mg, 0.58mmol, 57 μ l).Mixture was stirred 18 hours in envrionment temperature, then vacuum concentration.Mixture is by silica gel chromatography purifying (5%MeOH/CH 2Cl 2), obtain (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-methane sulfonyl-tetrahydrochysene-pyrans-3,4,5-triol (20mg, 45%) is white solid.
1H NMR (400MHz, methyl alcohol) δ ppm 7.28 (m, 1H), 7.27 (m, 2H), 7.10 (d, J=8.4Hz, 2H), 6.81 (d, J=8.4Hz, 2H), 4.53 (d, J=9.6Hz, 1H), 4.30 (d, J=9.6Hz, 1H), 4.00 (m, 4H), 3.88 (t, J=9.1Hz, 1H), 3.55 (t, J=9.1Hz, 1H), 3.35 (t, J=9.1Hz, 1H), 2.92 (s, 3H), 1.36 (t, J=6.8Hz, 3H); MS (ES+) [M+NH 4] +=474.
Embodiment 16:1-{ (2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-yl }-ethyl ketone synthetic
Figure A20081009007300561
1-{ (2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperazine Pyridine-1-yl }-preparation of ethyl ketone:To the thick compound that derives from embodiment 12 step C (38mg, add in MeOH 0.1mmol) (1mL) solution diacetyl oxide (19 μ L, 0.2mmol).To react and stir 4 hours, (10 μ L 0.1mmol), and continue to stir and spend the night to add more diacetyl oxide.Reaction is diluted with EtOAc, uses saturated NaHCO 3Na is used in the aqueous solution and salt water washing 2SO 4Drying is filtered and vacuum concentration.Resistates is by purified by flash chromatography (12g SiO 2, 0-8%MeOH:CH 2Cl 2), be suspended in H 2Among the O, and freeze-drying, obtain 1-{ (2S, 3S, 4S, 5R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-yl }-ethyl ketone (14mg, 0.033mmol, 2 step yields 33%), be white solid.
1H NMR(400MHz，MeOD)δppm 7.33(d，J＝8.34Hz，1H)，7.18(dd，J＝8.46，2.15Hz，1H)，7.11(d，J＝1.77Hz，1H)，7.07(d，J＝8.84Hz，2H)，6.81(d，J＝8.84Hz，2H)，3.96-4.03(m，4H)，3.83-3.89(m，1H)，3.73-3.77(m，1H)，3.55-3.59(m，1H)，2.09(br.s.，3H)，1.36(t，J＝6.95Hz，3H)；MS(ES+)[M+H] +＝420。
Embodiment 17:(2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-carboxylic acid methyl ester synthetic
Figure A20081009007300571
0 ℃ to the crude compound that derives from embodiment 12 step C (38mg, 0.1mmol) and NaHCO 3(42mg is 0.5mmol) at 1: 1: 1 EtOAc:EtOH:H 2Solution adding methyl-chloroformate among the O (1.5mL) (23 μ L, 0.3mmol).To react and stir 1 hour, with the EtOAc dilution, use H then 2Na is used in O and salt water washing (reextraction) 2SO 4Drying is filtered and vacuum concentration.Resistates is by purified by flash chromatography (4g SiO 2, 0-10%MeOH:CH 2Cl 2, be suspended in middle H 2O, and freeze-drying, obtain (2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-carboxylic acid methyl ester (12mg, 0.026mmol, 26%, two step yield) is white solid.
1H NMR(400MHz，MeOD)δppm 7.32(d，J＝8.34Hz，1H)，7.15(dd，J＝8.34，2.02Hz，1H)，7.10(d，J＝2.27Hz，1H)，7.04-7.09(m，2H)，6.81(d，J＝8.59Hz，2H)，4.80(d，J＝6.06Hz，1H)，4.00(q，J＝7.07Hz，5H)，3.81-3.86(m，1H)，3.70-3.73(m，1H)，3.60(s，3H)，3.54-3.59(m，1H)，3.46(dd，J＝14.40，3.28Hz，1H)，1.36(t，J＝6.95Hz，3H)；MS(ES+)[M+H] +＝436。
Embodiment 18:(2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-carboxylic acid allyl group acid amides synthetic
Figure A20081009007300572
To the crude compound that derives from embodiment 12 step C (38mg, 0.1mmol) solution in 1: 1 EtOH:EtOAc (1mL) add allyl isocyanate (18 μ L, 0.2mmol).To react and stir 1 hour, then vacuum concentration.Resistates is by purified by flash chromatography (4g SiO 2, 0-10%MeOH:CH 2Cl 2, be suspended in H 2Among the O, and freeze-drying, obtain (2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-carboxylic acid allyl group acid amides (14mg, 0.030mmol, 30%, two step yield) is white solid.
1H NMR(400MHz，MeOD)δppm 7.32(d，J＝8.1Hz，1H)，7.16-7.20(m，2H)，7.07(d，J＝8.8Hz，2H)，6.80(d，J＝8.8Hz，2H)，5.68-5.79(m，J＝17.2，10.2，5.3，5.2Hz，1H)，4.92-5.00(m，2H)，4.77(d，J＝6.3Hz，1H)，3.94-4.05(m，4H)，3.86(dd，J＝14.0，3.4Hz，1H)，3.69-3.81(m，3H)，3.59-3.68(m，1H)，3.56(dd，J＝7.3，5.1Hz，1H)，3.47(dd，J＝13.9，3.5Hz，1H)，1.36(t，J＝6.9Hz，3H)；MS(ES+)[M+H] +＝461。
Embodiment 19:(2S, 3S, 4S, 5R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-1-methyl-piperidines-3,4,5-triol synthetic
To the compound that derives from embodiment 12 step C (50mg, 0.13mmol) and K 2CO 3(55mg, 0.40mmol) solution in DMF (0.65mL) add methyl iodide (10 μ L, 0.16mmol).To react and stir 3 hours, with the EtOAc dilution, use H then 2Na is used in O and salt water washing (reextraction) 2SO 4Drying is filtered and vacuum concentration.Resistates is by purified by flash chromatography (12g SiO 2, 2-12%MeOH:CH 2Cl 2), be suspended in H 2Among the O, and freeze-drying, obtain (2S, 3S, 4S, 5R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-1-methyl-piperidines-3,4,5-triol (16mg, 0.040mmol, 31%) is white solid.
1H NMR(400MHz，MeOD)δppm 7.35(d，J＝8.1Hz，1H)，7.20-7.24(m，1H)，7.17(dd，J＝8.2，1.9Hz，1H)，7.09(d，J＝8.6Hz，2H)，6.80(d，J＝8.6Hz，2H)，4.03(s，2H)，3.99(q，J＝7.1Hz，2H)，3.64(ddd，J＝10.5，9.2，4.8Hz，1H)，3.33-3.37(m，1H)，3.21(t，J＝9.0Hz，1H)，3.03(dd，J＝11.1，4.8Hz，1H)，2.74(d，J＝9.3Hz，1H)，2.15(t，J＝10.9Hz，1H)，1.95(s，3H)，1.36(t，J＝6.9Hz，3H)；MS(ES+)[M+H] +＝392。
Embodiment 20:(2S, 3S, 4R, 5R, 6R)-2-[3-(4-oxyethyl group-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-piperidines-3,4,5-triol synthetic
Figure A20081009007300591
A. (3R, 4S, 5R, 6R)-3,4,5-three (benzyl oxygen base)-6-(benzyl oxygen ylmethyl) tetrahydrochysene-2H-pyrrole Mutter-preparation of 2-ketone:(2.07g 3.8mmol) is dissolved in DMSO (10.1mL) with four-O-benzyl-D-Glucopyranose.To this mixture adding diacetyl oxide (7.0mL) and in stirred overnight at room temperature.Add ice and stirred 1 hour to reaction mixture.With mixture extracted with diethyl ether (3 * 20mL).The extraction liquid water (2 * 10mL), sodium bicarbonate aqueous solution (2 * 10mL), the salt water washing, dry (sodium sulfate) and vacuum concentration.The fast silica gel chromatogram method is used the 0-25% ethyl acetate/hexane, obtain 1.712g (3R, 4S, 5R, 6R)-3,4,5-three (benzyl oxygen base)-6-(benzyl oxygen ylmethyl) tetrahydrochysene-2H-pyran-2-one (83%).
B. (3R, 4S, 5R, 6R)-3,4,5-three (benzyl oxygen base)-6-(benzyl oxygen ylmethyl)-2-(4-chlorine -3-(4-ethoxy benzyl) phenyl) preparation of tetrahydrochysene-2H-pyrans-2-alcohol:(1.263mL 3.16mmol) is added drop-wise to-78 ℃ the compound that derives from embodiment 1 step C (1.028g, 3.16mmol) solution in anhydrous THF (15mL) with n-Butyl Lithium (2.5N is in hexane).After-78 ℃ were stirred 30 minutes, (1.7g, anhydrous THF (10mL) solution 3.16mmol) and stirring 1 hour made its room temperature of rising again simultaneously to drip the compound that derives from steps A.(10mL) joins in the reaction mixture with aqueous ammonium chloride solution, and vacuum is removed THF, and with water layer ethyl acetate extraction (2 * 20mL).The organic phase salt water washing that merges, dry (sodium sulfate) and vacuum concentration.Thick mixture is by quick silica gel column chromatography purifying, use the 0-20% ethyl acetate/hexane, obtain (the 3R of 712mg, 4S, 5R, 6R)-3,4,5-three (benzyl oxygen base)-6-(benzyl oxygen ylmethyl)-2-(4-chloro-3-(4-ethoxy benzyl) phenyl) tetrahydrochysene-2H-pyrans-2-alcohol (29%).M+H 2O＝802.1。
C. (2R, 3R, 4S)-2,3,4,6-four (benzyl oxygen base)-1-(4-chloro-3-(4-ethoxy benzyl) phenyl) Hexane-1, the preparation of 5-diketone:CH to the Dess-Martin reagent (500mg, excessive) that stirs 2Cl 2(10mL) adding the anhydrous methylene chloride (10mL) and the stirring that contain the compound (500mg, 0.6mmol)) that derives from step B in the solution spends the night.Reaction mixture 1N sodium hydroxide (3mL) quencher, (2 * 10mL), dried over sodium sulfate is used in the salt water washing of the organic extract liquid of merging, and concentrating under reduced pressure obtains thick product 487mg with dichloromethane extraction.(M+H 2O＝800.1)。
D. (3R, 4R, 5S)-3,4,5-three (benzyl oxygen base)-2-(benzyl oxygen ylmethyl)-6-(4-chloro-3-(4- Ethoxy benzyl) preparation of piperidines phenyl):With derive from step C compound (400mg, 0.5mmol), the MeOH solution (1.0mL) of 7N ammonia and new activatory 4
Figure A20081009007300601
Methylene dichloride (20mL) solution of molecular sieve (250mg) refluxes and spends the night.With the reaction mixture cool to room temperature, add then sodium cyanoborohydride (160mg, 2.55mmol) and refluxed other 2 hours.Reaction mixture is filtered, with methylene dichloride (20mL) dilution, water, salt water washing, dry (sodium sulfate), and concentrating under reduced pressure.Chromatography on the silica gel (50 to 100% acetonitriles contain 0.1% ammonium acetate/water gradient), obtain (3R, 4R, 5S)-3,4,5-three (benzyl oxygen base)-2-(benzyl oxygen ylmethyl)-6-(4-chloro-3-(4-ethoxy benzyl) phenyl) piperidines (136mg, 34%).
1H NMR (400MHz, δ ppm 1.41 (t, J=7.07Hz, 3H) 2.98 (ddd of chloroform-d), J=9.40,8.50,2.53Hz, 1H) 3.40 (t, J=9.22Hz, 1H) 3.41 (t, J=8.59Hz, 1H) 3.43 (t, J=9.09Hz, 1H) 3.56 (d, J=9.35Hz, 1H) 3.68 (t, J=8.84Hz, 1H) 3.79 (dd, J=8.97,2.65Hz, 1H) 3.84 (d, J=10.36Hz, 1H) 3.97 (d, J=13.60Hz, 1H) 3.99 (q, J=7.07Hz, 2H) 4.10 (d, J=15.30Hz, 1H) 4.43 (d, J=10.36Hz, 1H) 4.48 (d, J=2.53Hz, 2H) 4.56 (d, J=10.86Hz, 1H) 4.88 (d, J=10.86Hz, 1H) 4.89 (d, J=11.12Hz, 1H) 4.93 (d, J=10.86Hz, 1H) 6.77 (d, J=8.59Hz, 2H) 6.88 (dd, J=7.71,1.64Hz, 2H) 7.07 (d, J=8.59Hz, 2H) 7.16-7.38 (m, 21H); MS (ES+) [M+H] +=768.2.
E. (3R, 4R, 5S)-3,4,5-three (benzyl oxygen base)-2-(benzyl oxygen ylmethyl)-6-(4-chloro-3-(4- Ethoxy benzyl) phenyl)-preparation of 1-methyl piperidine:With derive from step D compound (50mg, 0.065mmol) be dissolved in acetonitrile (1mL) and with salt of wormwood (18mg 0.13mmol) handles 30 minutes.To this mixture add methyl iodide (20 μ L, 0.32mmol) and stir and spend the night.Reaction mixture dilutes with ethyl acetate (10mL), water, salt water washing, dry (sodium sulfate), and vacuum concentration.Silica gel chromatography (50 to 100% acetonitriles contain 0.1% ammonium acetate/water gradient), obtain (3R, 4R, 5S)-3,4,5-three (benzyl oxygen base)-2-(benzyl oxygen ylmethyl)-6-(4-chloro-3-(4-ethoxy benzyl) phenyl)-1-methyl piperidine (29mg, 56%).MH+782.1。
F. (2S, 3S, 4R, 5R, 6R)-2-[3-(4-oxyethyl group-benzyl)-phenyl]-6-hydroxymethyl-1-first Base-piperidines-3,4, the preparation of 5-triol:At H 2To handle 4 hours with 5% wet Pd-C (10mg) at the compound that derives from step e (50mg) in methyl alcohol and the acetate (25 μ L) under the atmosphere.Reaction mixture filters by Celite pad and concentrates.Chromatography on the silica gel (10 to 100% acetonitriles contain 0.1% ammonium acetate/water gradient) obtain (2S, 3S, 4R, 5R, 6R)-2-[3-(4-oxyethyl group-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-piperidines-3,4,5-triol (6mg, 70%).
1H NMR (400MHz, δ ppm 1.40 (t, the J=6.95Hz of chloroform-d), 3H) 2.02 (s, 3H) 2.05 (br.s., 3H) 2.15 (d, J=8.84Hz, 1H) 3.01 (d, J=4.55Hz, 2H) 3.50 (d, J=5.05Hz, 2H) 3.77 (br.s., 2H) 3.85 (d, J=8.59Hz, 2H) 3.91 (br.s., 2H) 3.99 (q, J=7.24Hz, 2H) 6.81 (d, J=8.59Hz, 2H) 7.06 (d, J=8.59Hz, 2H) 7.09 (br.s., 1H) 7.18 (br.s., 2H) 7.24 (d, J=7.58Hz, 1H); MS (ES+) [M+H] +=387.0.
Embodiment 21:(2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxy benzyl) phenyl)-6-methoxyl group tetrahydrochysene-2H-thiapyran-3,4,5-triol synthetic
Figure A20081009007300611
A. (S-(1S)-((3aS, 6S, 6aS)-and 6-(t-butyldimethylsilyl oxygen base)-2, the 2-diformazan The base tetrahydrofuran (THF) is [2,3-d] [1,3] dioxole-5-yl also) (4-chloro-3-(4-ethoxy benzyl) benzene Base) preparation of methyl thiobenzoic acid ester:At room temperature (150 μ L 0.914mmol) join triphenyl phosphine (240mg, 0.914mmol) solution in the THF of 1.0mL with the diethylazodicarboxylate.After one hour, by syringe be added in the C5 epimer that derives from embodiment 1 step D among the 0.5mL THF (167mg, 0.305mmol), subsequently by syringe add thiobenzoic acid (110 μ L, 0.914mmol).With this orange solution stirring at room 22 hours.After solvent removed in vacuo, resistates obtains title compound by purified by flash chromatography (0 to 10% ethyl acetate/hexane gradient), is light yellow oil (104mg, 50% yield).MS(ES+)[M+NH 4] +＝566。
B. (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxy benzyl) phenyl)-6-methoxyl group tetrahydrochysene -2H-thiapyran-3,4, the preparation of 5-triol:Sodium methylate (the 4.3M methanol solution of 0.3mL) is joined compound (104mg, 0.152mmol) solution in 6mL methyl alcohol that derives from steps A.After 30 minutes, reaction 20mL ethyl acetate dilution and water and salt solution (20mL respectively) washing.The organic layer dried over mgso is filtered and solvent removed in vacuo.Resistates promptly directly uses to prevent that disulphide from forming by purified by flash chromatography (5% ethyl acetate/hexane) and product.
An Acetyl Chloride 98Min. is joined in the methyl alcohol of 1mL and stirring at room 15 minutes.This acidic solution joined in the above-mentioned free mercaptan that obtains and 80 ℃ of heating 42 hours.To react cool to room temperature and solvent removed in vacuo.(30 * 250mm C18 post, the 5-75% acetonitrile: water (10mM ammonium acetate) 15 minutes, 45mL/min), obtains title compound (α anomer, t=13.82 minute, 8.7mg, 13% yield, two step yields) to thick resistates by preparation property HPLC purifying.
1H NMR (400MHz, acetone-d 6) δ ppm 7.33 (m, 2H), 7.25 (dd, J=2.27,8.34Hz, 1H), 7.13 (d, J=8.59Hz, 2H), 6.82 (d, J=8.59Hz, 2H), 4.48 (d, J=3.03Hz, 1H), 4.02 (s, 2H), 3.99 (q, J=7.07Hz, 2H), 3.91 (d, J=10.36Hz, 1H), 3.80-3.85 (m, 2H), 3.68 (dd, J=8.37,9.35Hz, 1H), 3.42 (s, 3H), 1.33 (t, J=7.07Hz, 3H).MS(ES+)[M+NH 4] +＝424。
Embodiment 22:(2S, 3S, 4R, 5R, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-hydroxymethyl-piperidines-3,4,5-triol synthetic
Figure A20081009007300631
A. (2R, 3R, 4S, 5R, 6S)-3,4,5-three-allyl group oxygen base-2-allyl group oxygen ylmethyl-6-first The preparation of oxygen base-tetrahydrochysene-pyrans:To α-D-methyl glucoside (3g, add in DMF 15.45mmol) (50ml) solution NaH (60% mineral oil disperses thing, 3.34g, 0.14mol).In adition process, form thick suspension, the DMF (15ml) that adds additional quantity is to revert to solution.After stirring at room 30 minutes, with mixture be cooled to 0 ℃ and slowly add allyl bromide 98 (17g, 0.14mol, 12ml).Make rise again room temperature and stirring 18 hours of mixture then.Add MeOH with quencher excessive N aH to the light brown mixture carefully, then mixture is concentrated.Resistates CH 2Cl 2Dilution and use H 2The O washing, dry (MgSO 4) and concentrate, obtain yellow oil.By silica gel chromatography purifying (20%EtOAc/ hexane) obtain (2R, 3R, 4S, 5R, 6S)-3,4,5-three-allyl group oxygen base-2-allyl group oxygen ylmethyl-6-methoxyl group-tetrahydrochysene-pyrans (4.06g, 11.47mmol, 74%) is colorless oil.TLC:R f=0.20, the 20%EtOAc/ hexane.
B. (3R, 4S, 5R, 6R)-3,4,5-three-allyl group oxygen base-6-allyl group oxygen ylmethyl-tetrahydrochysene-pyrrole Mutter-preparation of 2-alcohol:(10g, AcOH 0.028mol) (400ml) solution is warmed up to 90 ℃ with the compound that derives from steps A.Add the TfOH (H of 2 N 2O solution, 16.69g, 0.112mol 56ml) and with mixture stirred 75 minutes at 90 ℃.With solution cooling and use CH 2Cl 2H is used in dilution 2O (x3), saturated NaHCO 3Solution washing, dry (MgSO 4) and concentrate, obtain yellow solid.By silica gel chromatography purifying (20%-40%EtOAc/ hexane) obtain (3R, 4S, 5R, 6R)-3,4,5-three-allyl group oxygen base-6-allyl group oxygen ylmethyl-tetrahydrochysene-pyrans-2-alcohol is the mixture (5.85g of anomer, 17.2mmol, 61%), be white solid.TLC:R f=0.40, the 40%EtOAc/ hexane.
C. (3R, 4S, 5R, 6R)-3,4,5-three-allyl group oxygen base-6-allyl group oxygen ylmethyl-tetrahydrochysene-pyrrole Mutter-preparation of 2-ketone:(2.75g, 21.7mmol 1.89ml) are dissolved in CH with oxalyl chloride 2Cl 2Be cooled to-78 ℃ (90ml) and with mixture.Be added in CH 2Cl 2DMSO (60ml) (3.39g, 43.4mmol, 3.08ml) solution.Mixture was added in CH in 15 minutes then-78 ℃ of stirrings 2Cl 2The compound that derives from step B (150ml) (6.70g, solution 19.7mmol).Reaction mixture was stirred other 15 minutes and added Et at-78 ℃ 3N (9.97g, 98.5mmol, 13.7ml).Mixture was stirred other 5 minutes at-78 ℃, make its room temperature of in 30 minutes, rising again then.To react and use H 2O quencher and separation organic layer are used H 2The O washed twice, dry and concentrated, obtain light yellow oil.By silica gel chromatography purifying (15%EtOAc/ hexane) obtain (3R, 4S, 5R, 6R)-3,4,5-three-allyl group oxygen base-6-allyl group oxygen ylmethyl-tetrahydrochysene-pyran-2-one (2.49g, 7.37mmol, 37%) is colorless oil.TLC:R f=0.40, the 20%EtOAc/ hexane.
D. (3R, 4S, 5R, 6R)-3,4,5-three-allyl group oxygen base-6-allyl group oxygen ylmethyl-2-[4-ammonia -3-(4-oxyethyl group-benzyl)-phenyl]-preparation of tetrahydrochysene-pyrans-2-alcohol:(2.37g 7.31mmol) is dissolved in THF (25ml) and be cooled to-78 ℃ with the compound that derives from embodiment 1 step C.(7.31mmol is 2.92ml) and with solution stirring 15 minutes for the hexane solution of 2.5 N, 0.47g to drip n-BuLi.(2.47g, solution 7.31mmol) also stirs reaction mixture other 15 minutes at-78 ℃, makes its room temperature of rising again in 30 minutes then to be added in the compound that derives from step C among the THF (25ml).To react and use saturated NH 4Quencher of Cl solution and separation organic layer.Water layer Et 2O strips and the organism that merges is dry and concentrated, obtain yellow oil, obtain (3R, 4S, 5R by silica gel chromatography purifying (10%-20%EtOAc/ hexane), 6R)-3,4,5-three-allyl group oxygen base-6-allyl group oxygen ylmethyl-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-tetrahydrochysene-pyrans-2-alcohol (0.95g, 1.63mmol, 22%), is colorless oil.MS(ES+)[M+NH 4] +＝602。
E. (2R, 3R, 4S)-2,3,4,6-four-allyl group Oxy-1-[4-chloro-3-(4-oxyethyl group-benzyl)-benzene Base]-hexane-1, the preparation of 5-diketone:To the compound that derives from step D (0.93g, CH 1.59mmol) 2Cl 2(25ml) add in the solution Dess-Martin periodide (0.68g, 1.59mmol).Mixture stirring at room 1 hour, is added the Dess-Martin periodide (1 equivalent) of second section then.Continue to stir other 1 hour, will react (～4ml) quencher then with 1N NaOH.Add H 2O also separates organic layer.Water layer CH 2Cl 2Strip, dry and concentrated, obtain yellow waxy solid.By silica gel chromatography purifying (15%-20%EtOAc/ hexane) obtain (2R, 3R, 4S)-2,3,4,6-four-allyl group Oxy-1-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-hexane-1,5-diketone (0.60g, 1.03mmol, 65%) is white solid.MS(ES+)[M+NH 4] +＝600。
F. (2R, 3R, 4R, 5S, 6S)-3,4,5-three-allyl group oxygen base-2-allyl group oxygen ylmethyl-6-[4- Chloro-3-(4-oxyethyl group-benzyl)-phenyl]-preparation of piperidines:(0.60g adds 4 in MeOH 1.03mmol) (12ml) solution to the compound that derives from step e
Figure A20081009007300651
MS, add subsequently ammonium formiate (0.13g, 2.06mmol).Disposable then adding NaBH 3CN (0.14g, 2.3mmol) and with mixture stirring at room 1 hour 30 minutes.Then reaction mixture is filtered and concentrates.Obtain (2R, 3R, 4R by silica gel chromatography purifying (10%-20%EtOAc/ hexane), 5S, 6S)-3,4,5-three-allyl group oxygen base-2-allyl group oxygen ylmethyl-6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-piperidines (155mg, 0.27mmol, 27%).MS(ES+)[M+H] +＝568。
G. (2S, 3S, 4R, 5R, 6R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-three -[((E)-propenyl) oxygen base]-6-[((E)-propenyl) oxygen ylmethyl]-preparation of piperidines:Will be at Ir (the COD) [PCH among the THF (0.3ml) 3Ph 2] PF 6(8mg is 30mol%) at H 2Stir under the atmosphere, become light yellow (～5 minutes) from redness up to color.(19mg stirring at room 45 minutes, concentrates then 0.033mol) and with mixture to be added in the compound that derives from step F among the THF (0.5ml) then.Obtain (2S by silica gel chromatography purifying (20%EtOAc/ hexane), 3S, 4R, 5R, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-three-[((E)-propenyl) oxygen base]-6-[((E)-propenyl) oxygen ylmethyl]-piperidines (15mg, 0.026mmol, 80%), be colorless oil.MS(ES+)[M+H] +＝568。
H. (2S, 3S, 4R, 5R, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-the 6-hydroxymethyl- Piperidines-3,4, the preparation of 5-triol:(15mg 0.026mmol) is dissolved in THF/AcOH/1N HCl solution (0.2ml: 0.3ml: 0.15ml) and be heated to 70 ℃, 30 minutes with the compound that derives from step G.Mixture is concentrated, obtain light yellow oil.By preparation property HPLC purifying (sunfire C18,30 * 100mm, 5 μ m, 10%-100%B is in 15 minutes) obtain (2S, 3S, 4R, 5R, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-hydroxymethyl-piperidines-3,4,5-triol (5mg, 0.012mmol, 46%), be white solid.MS(ES+)[M+H] +＝408。
1H NMR (400MHz, MeOD) δ ppm 7.36 (m, 2H), 7.28 (m, 1H), 7.12 (d, J=8.6Hz, 2H), 6.81 (d, J=8.6Hz, 2H), 4.05 (m, 2H), 4.00 (q, J=6.8Hz, 2H), 3.92 (dd, J=3.0Hz and 10.8Hz, 1H), 3.58 (dd, J=7.6Hz and 11.1Hz, 1H), 3.47 (m, 1H), 3.26-3.36 (m, 3H), 2.70 (m, 1H), 1.37 (t, J=7.1Hz, 3H).
Embodiment 23:(2S, 3S, 4R, 5R, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-piperidines-3,4,5-triol synthetic
Figure A20081009007300661
A. (2R, 3R, 4R, 5S, 6S)-3,4,5-three-allyl group oxygen base-2-allyl group oxygen ylmethyl-6-[4- Chloro-3-(4-oxyethyl group-benzyl)-phenyl]-preparation of 1-methyl-piperidines:(135mg adds K in MeCN solution 0.24mmol) to the compound that derives from embodiment 22 step F 2CO 3(164mg, 1.19mmol).With mixture stir added then in 30 minutes MeI (676mg, 4.76mmol).Continuation filters mixture and concentrate then stirring at room 8 hours.Obtain (2R, 3R, 4R, 5S by silica gel chromatography purifying (10%EtOAc/ hexane), 6S)-3,4,5-three-allyl group oxygen base-2-allyl group oxygen ylmethyl-6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-1-methyl-piperidines (90mg, 0.15mmol, 65%), be colorless oil.MS(ES+)[M+H] +＝582。
B. (2S, 3S, 4R, 5R, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-1-methyl-3,4,5- Three-[((E)-propenyl) oxygen base]-6-[((E)-propenyl) oxygen ylmethyl]-preparation of piperidines:Will be at Ir (the COD) [PCH among the THF (1ml) 3Ph 2] PF 6(27mg is 30mol%) at H 2Stir under the atmosphere and become light yellow (～5 minutes) from redness up to color.(62mg, (1.5ml) solution of THF 0.11mol) also concentrated mixture in 45 minutes in stirring at room then to add the compound derive from steps A then.Obtain (2S by silica gel chromatography purifying (20%EtOAc/ hexane), 3S, 4R, 5R, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-1-methyl-3,4,5-three-[((E)-propenyl) oxygen base]-6-[((E)-propenyl) oxygen ylmethyl]-piperidines (62mg, 0.11mmol, 100%), be colorless oil.MS(ES+)[M+H] +＝582。
C. (2S, 3S, 4R, 5R, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-the 6-hydroxymethyl -1-methyl-piperidines-3,4, the preparation of 5-triol:(54mg 0.093mmol) is dissolved in THF/AcOH/1N HCl solution (0.5ml: 0.6ml: 0.30ml) and be heated to 70 ℃, 30 minutes with the compound that derives from step B.Mixture is concentrated, obtain light yellow oil.By preparation property HPLC purifying (sunfire C18,30 * 100mm, 5 μ m, 10%-100%B over 15 minutes) obtains (2S, 3S, 4R, 5R, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-piperidines-3,4,5-triol (22mg, 0.052mmol, 56%), is white solid.MS(ES+)[M+H] +＝422。
1H NMR (400MHz, MeOD) δ ppm 7.31 (m, 2H), 7.22 (m, 1H), 7.07 (d, J=8.8Hz, 2H), 6.77 (d, J=8.8Hz, 2H), 4.00 (m, 2H), 3.96 (q, J=7.1Hz, 2H), 3.90 (m, 2H), 3.52 (dd, J=9.4Hz and 9.4Hz, 1H), 3.23-3.32 (m, 3H), 2.88 (d, J=8.8Hz, 1H), 2.00 (s, 3H), 1.34 (t, J=7.1Hz, 3H).
Additional compounds
Use method and the methods known in the art described herein, the additional compounds of enumerating in the preparation following table 1.Powerful SGLT2 inhibitor asterisk mark.
Table 1
Compound Molecular formula MS(M+H) +
(2S, 3R, 4R, 5S)-2-[3-(4-oxyethyl group-benzyl)-phenyl]-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 21H 26O 6 374
(2S, 3R, 4R, 5S, 6S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-(2-hydroxyl-oxyethyl group)-tetrahydrochysene-pyrans-3,4, the 5-triol * C 22H 27ClO 7 438.1
(3S, 4R, 5R, 6S)-2-benzyl oxygen base-6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-tetrahydrochysene-pyrans-3,4, the 5-triol * C 27H 29ClO 6 484.1
(2S, 3R, 4R, 5S)-2-(4 '-oxyethyl group-biphenyl-3-yl)-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 20H 24O 6 378(M+NH 3) +
(2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-(2,2,2-three fluoro-oxyethyl groups)-tetrahydrochysene-pyrans-3,4, the 5-triol * C 22H 24ClF 3O 6 476.1
(2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-(2-methoxyl group-oxyethyl group)-tetrahydrochysene-pyrans-3,4, the 5-triol * C 23H 29ClO 7 452.1
(2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-(2-dimethylamino-oxyethyl group)-tetrahydrochysene-pyrans-3,4, the 5-triol * C 24H 32ClNO 6 466.1
(2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-propylthio-tetrahydrochysene-pyrans-3,4, the 5-triol * C 23H 29ClO 5S 452
(2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-imidazoles-1-base-tetrahydrochysene-pyrans-3,4, the 5-triol C 23H 25ClN 2O 5 445.1
(3S, 4R, 5R, 6S)-and 6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--tetrahydrochysene-pyrans-2-base oxygen base }-the acetate methyl ester * C 23H 27ClO 8 466.1
(2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-(4-methyl-piperidines-1-yl)-tetrahydrochysene-pyrans-3,4, the 5-triol C 26H 34ClNO 5 475.1
(2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-(5-methyl-thiazol-2-yl amino)-tetrahydrochysene-pyrans-3,4, the 5-triol C 24H 27ClN 2O 5S 491
(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-phenoxy group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 26H 27ClO 6 470.1
N-{ (2S, 3S, 4R, 5R, 6S)-and 6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--tetrahydrochysene-pyrans-2-yl }-N-methyl-ethanamide C 23H 28ClNO 6 450
Acetate (2S, 3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-2-methoxyl group-tetrahydrochysene-pyrans-3-base ester C 27H 31ClO 9 552(M+NH 3) +
(2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-oxyethyl group-phenoxy group)-phenyl]-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol C 20H 23ClO 7 428(M+NH 3) +
(2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-methoxyl group-phenyl sulphur)-phenyl]-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 19H 21ClO 6S 430(M+NH 3) +
(2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-methoxyl group-benzenesulfinyl)-phenyl]-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol C 19H 21ClO 7S 429
(2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-(3-hydroxyl-propoxy-)-tetrahydrochysene-pyrans-3,4, the 5-triol * C 23H 29ClO 7 452.2
(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-(2-hydroxyl-ethyl sulphur)-tetrahydrochysene-pyrans-3,4, the 5-triol * C 22H 27ClO 6S 472(M+NH 3) +
(2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-(2-sulfydryl-oxyethyl group)-tetrahydrochysene-pyrans-3,4, the 5-triol * C 22H 27ClO 6S 456.3
(2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-(2,3-dihydroxyl-propoxy-)-tetrahydrochysene-pyrans-3,4, the 5-triol * C 23H 29ClO 8 468.2
(2S, 3R, 4R, 5S)-2-{4-chloro-3-[4-(2-methoxyl group-oxyethyl group)-benzyl]-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 22H 27ClO 7 456(M+NH 3) +
(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-ethyl sulphur-tetrahydrochysene-pyrans-3,4, the 5-triol * C 22H 27ClO 5S 456(M+NH 3) +
(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-methyl sulphur-tetrahydrochysene-pyrans-3,4, the 5-triol * C 21H 25ClO 5S 442(M+NH 3) +
[2-chloro-5-((2S, 3R, 4R, 5S, 6S)-3,4,5-trihydroxy--6-methoxyl group-tetrahydrochysene-pyrans-2-yl)-phenyl]-(4-oxyethyl group-phenyl)-ketone * C 21H 23ClO 7 423
(2S, 3R, 4R, 5S, 6S)-2-{4-chloro-3-[(4-oxyethyl group-phenyl)-hydroxyl-methyl]-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 21H 25ClO 7 407
(2S, 3R, 4R, 5S)-2-[3-(4-oxyethyl group-benzyl)-4-methyl-phenyl]-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 22H 28O 6 406(M+NH 3) +
(2S, 3R, 4R, 5S)-2-{4-chloro-3-[4-(2-methyl sulphur-oxyethyl group)-benzyl]-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 22H 27ClO 6S 472(M+NH 3) +
(2S, 3R, 4R, 5S)-2-{4-chloro-3-[4-(pyridin-4-yl oxygen base)-benzyl]-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 24H 24ClNO 6 458
(2S, 3R, 4R, 5S, 6S)-2-(4-chloro-3-{ (4-oxyethyl group-phenyl)-[(Z)-the propyl group imino-]-methyl }-phenyl)-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol C 24H 30ClNO 6 464
(2S, 3R, 4R, 5S)-2-{4-chloro-3-[4-(thiazol-2-yl oxygen base)-benzyl]-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 22H 22ClNO 6S 464
(2S, 3R, 4R, 5S)-2-{4-chloro-3-[4-(pyrimidine-5-base oxygen base)-benzyl]-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 23H 23ClN 2O 6 459
(2S, 3R, 4R, 5S)-2-{4-chloro-3-[4-(2,6-dimethoxy-pyrimidine-4-base oxygen base)-benzyl]-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 25H 27ClN 2O 8 519
2-{ (2R, 3S, 4R, 5R, 6S)-and 6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--tetrahydrochysene-pyrans-2-base sulphur }-ethanamide * C 22H 26ClNO 6S 468.1
(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-(furans-2-ylmethyl sulphur)-tetrahydrochysene-pyrans-3,4, the 5-triol * C 25H 27ClO 6S 490.1
(2S, 3R, 4R, 5S, 6S)-2-{4-chloro-3-[(4-oxyethyl group-phenyl)-imino--methyl]-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol C 21H 24ClNO 6 422
(2S, 3R, 4R, 5S, 6S)-2-{3-[(4-oxyethyl group-phenyl)-hydroxyl-methyl]-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol C 21H 26O 7 390
(2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-carboxylic acid benzyl ester C 28H 30ClNO 6 511
(2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-carboxylic acid allyl group acid amides * C 24H 29ClN 2O 5 461
N-(2-{ (2R, 3S, 4R, 5R, 6S)-and 6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--tetrahydrochysene-pyrans-2-base sulphur }-ethyl)-ethanamide * C 24H 30ClNO 6S 496.1
(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-(2,2,2-three fluoro-ethyl sulphur)-tetrahydrochysene-pyrans-3,4, the 5-triol * C 22H 24ClF 3O 5S 492.1
(2S, 3R, 4R, 5S, 6S)-2-{4-chloro-3-[1-(4-oxyethyl group-phenyl)-1-hydroxyl-ethyl]-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol C 22H 27ClO 7 438
Dimethyl-thiocarbamate O-{4-[2-chloro-5-((2S, 3R, 4R, 5S)-3,4,5-trihydroxy--6-methoxyl group-tetrahydrochysene-pyrans-2-yl)-benzyl]-phenyl } ester * C 22H 26ClNO 6S 468
(2S, 3R, 4R, 5S, 6S)-2-{3-[1-(4-oxyethyl group-phenyl)-ethyl]-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol C 22H 28O 6 406(M+NH 3) +
Diethyl-dithiocarbamic acid (2R, 3S, 4R, 5R, 6S)-and 6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--tetrahydrochysene-pyrans-2-base ester C 25H 32ClNO 5S 2 526.2
(2S, 3R, 4R, 5S, 6S)-2-(4-chloro-3-{4-[(R)-(tetrahydrochysene-furans-3-yl) oxygen base]-benzyl }-phenyl)-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 23H 27ClO 7 468(M+NH 3) +
(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-ethane sulfinyl-tetrahydrochysene-pyrans-3,4, the 5-triol * C 22H 27ClO 6S 455
(2S, 3R, 4R, 5S)-2-{4-chloro-3-[4-((S)-1-methyl-tetramethyleneimine-3-base oxygen base)-benzyl]-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 24H 30ClNO 6 522(M-H+Ac)
(2S, 3R, 4R, 5S)-2-{4-chloro-3-[4-(tetrahydrochysene-pyrans-4-base oxygen base)-benzyl]-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 24H 29ClO 7 523(M-H+Ac)
(2S, 3R, 4R, 5S)-2-(4-chloro-3-{4-hydroxyl-3-[1-(2-methylamino-ethyl)-allyl group]-benzyl }-phenyl)-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol C 25H 32ClNO 6 478
(2S, 3R, 4R, 5S)-2-{4-chloro-3-[4-(1-methyl-piperidin-4-yl oxygen base)-benzyl]-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 25H 32ClNO 6 478
(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-methanesulfinyl-tetrahydrochysene-pyrans-3,4, the 5-triol * C 21H 25ClO 6S 441
(2S, 3S, 4S, 5R)-1-benzyl-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-piperidines-3,4, the 5-triol * C 27H 30ClNO 4 468
(2S, 3R, 4R, 5S)-2-{3-[4-(2-benzyl oxygen base-oxyethyl group)-benzyl]-4-chloro-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 28H 31ClO 7 532(M+NH 3) +
(2S, 3R, 4R, 5S)-2-{3-[4-(2-hydroxyl-oxyethyl group)-benzyl]-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 21H 26O 7 408(M+NH 3) +
(2S, 3R, 4R, 5S)-2-{4-chloro-3-[4-(2-hydroxyl-oxyethyl group)-benzyl]-phenyl }-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 21H 25ClO 7 442(M+NH 3) +
2-{ (2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-yl }-ethanamide * C 22H 27ClN 2O 5 435
(2S, 3S, 4S, 5R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-1-isobutyl--piperidines-3,4, the 5-triol * C 24H 32ClNO 4 492(M-H+Ac)
(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-(2-methyl-tetrahydrochysene-furans-3-base sulphur)-tetrahydrochysene-pyrans-3,4, the 5-triol * C 25H 31ClO 6S 512(M+NH 3) +
(R)-2-amino-3-{ (2R, 3S, 4R, 5R, 6S)-and 6-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--tetrahydrochysene-pyrans-2-base sulphur }-propionic acid * C 23H 28ClNO 7S 498
(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-cyclopentyl sulphur-tetrahydrochysene-pyrans-3,4, the 5-triol * C 25H 31ClO 5S 496(M+NH 3) +
(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-cyclohexyl sulphur-tetrahydrochysene-pyrans-3,4, the 5-triol C 26H 33ClO 5S 510(M+NH 3) +
(2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-(3-methyl-butyl sulphur)-tetrahydrochysene-pyrans-3,4, the 5-triol * C 25H 33ClO 5S 498(M+NH 3) +
(2S, 3R, 4R, 5S)-2-[3-(4-oxyethyl group-benzyl)-phenyl]-6-methoxyl group-tetrahydrochysene-pyrans-3,4, the 5-triol * C 27H 31ClO 9 552(M+NH 3) +
1-{ (2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-yl }-ethyl ketone * C 22H 26ClNO 5 420
(2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-carboxylic acid benzyl ester C 28H 30ClNO 6 529 [M+NH 4]+
(2S, 3S, 4S, 5R)-1-benzyl-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-piperidines-3,4, the 5-triol * C 27H 30ClNO 4 468
2-{ (2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-yl }-ethanamide * C 22H 27ClN 2O 5 435
(2S, 3S, 4S, 5R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-1-isobutyl--piperidines-3,4, the 5-triol * C 24H 32ClNO 4 492[M+Ac] -
(3S, 4R, 5R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-hydroxymethyl-piperidines-3,4, the 5-triol * C 21H 26ClNO 5 408
Vitro human SGLT2 inhibition test
People's sodium/glucose cotransporter 2 types (SGLT2, registration number P31639, GI:400337) are cloned into the pIRESpuro2 carrier (structure: HA-SGLT2-pIRESpuro2) that is used for Mammals and expresses.
With HEK293 cell personnel selection HA-SGLT2-pIRESpuro2 carrier transfection and in the presence of 0.5 μ g/ml puromycin, select the clone of body stable (bulk stable).People HA-SGLT2 cell is remained in the DMEM substratum that comprises 10%FBS, 1%GPS and 0.5 μ g/ml puromycin.
In the DMEM substratum in 384 orifice plates (30,000 cells/well), the DMEM substratum comprises 10%FBS with the HEK293 cell inoculation of expressing human HA-SGLT2, and 1%GPS and 0.5 μ g/ml puromycin are then at 37 ℃, 5%CO 2Following overnight incubation.Then cell is used picked-up damping fluid (140mM NaCl, 2mM KCl, 1mM CaCl 2, 1mM MgCl 2, 10mM HEPES, 5mM Tris, 1mg/ml bovine serum albumin (BSA), pH 7.3) washing.Picked-up damping fluid with 20 microlitres under being with or without the situation of test compound joins in the cell.Then, will comprise 14The 20 microlitres picked-up damping fluid of C-AMG (100 nCi) joins in the cell.With cell plate at 37 ℃, 5%CO 2The middle cultivation 1-2 hour.After cell is washed with the picked-up damping fluid, add scintillating liquid (40 microlitres/hole) and use scintillometer (TopCoulter NXT; Packard Instruments) the counting radioactivity is measured 14The C-AMG picked-up.
Vitro human SGLT1 inhibition test
People's sodium/glucose cotransporter 1 type (SGLT1, registration number NP_000334, GI:4507031) is cloned into the pIRESpuro2 carrier (structure: HA-SGLT1-pIRESpuro2) that is used for Mammals and expresses.
With the transfection of HEK293 cell personnel selection HA-SGLT1-pIRESpuro2 carrier, and in the presence of 0.5 μ g/ml puromycin, select to pile up stable clone.People HA-SGLT1 cell is remained in the DMEM substratum that comprises 10%FBS, 1%GPS and 0.5 μ g/ml puromycin.
In the DMEM substratum in 384 orifice plates (30,000 cells/well), the DMEM substratum comprises 10%FBS, 1%GPS and 0.5 μ g/ml puromycin, then at 37 ℃, 5%CO with the HEK293 cell inoculation of expressing human HA-SGLT1 2Following overnight incubation.Then cell is used picked-up damping fluid (140mM NaCl, 2mM KCl, 1mM CaCl 2, 1mM MgCl 2, 10mM HEPES, 5mM Tris, 1mg/ml bovine serum albumin (BSA), pH 7.3) washing.Picked-up damping fluid with 20 microlitres under being with or without the situation of test compound joins in the cell.Then, also will comprise 14The 20 microlitres picked-up damping fluid of C-AMG (100nCi) joins in the cell.With cell plate at 37 ℃, 5%CO 2The middle cultivation 1-2 hour.After cell is washed with the picked-up damping fluid, add scintillating liquid (40 microlitres/hole) and use scintillometer (TopCoulter NXT; Packard Instruments) the counting radioactivity is measured 14The C-AMG picked-up.
Calculate IC 50Value
Measure the IC of compound by using Levenburg Marquardt algorithm that related data is fitted to following equation for given target 50:
y＝A+((B-A)/(1+((C/x)^D)))
Wherein A is minimum Y value; B is maximum Y value; C is IC 50With D be slope.The XLFit4 software (NJ 08807 for ID Business Solutions Inc., Bridge water) that use is used for Microsoft Excel (aforesaid equation is 205 types of this software) carries out IC 50Calculating.
Data in the body: tetrahydropyrans based compound
Use aforesaid method, measured the IC of tetrahydropyrans based compound of the present invention people SGLT1 (HSGLT1), mouse SGLT2 (M SGLT2) and people SGLT2 (H SGLT2) 50These data provide in following table 2:
Table 2:SGLT IC 50(μ M)
Figure A20081009007300741
Figure A20081009007300751
Figure A20081009007300781
Figure A20081009007300791
Figure A20081009007300801
Figure A20081009007300811
Data in the body: piperidinyl compounds
Use aforesaid method, measure the influence of piperidinyl compounds of the present invention people SGLT1 (HSGLT1), mouse SGLT2 (M SGLT2) and SGLT2 (H SGLT2).These data provide in following table 3:
Table 3:SGLT IC 50(μ M)
Compound H SGLT1 M SGLT2 H SGLT2
(2S, 3S, 4S, 5R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-piperidines-3,4, the 5-triol 13.667 0.0594 0.1462
1-{ (2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-yl }-ethyl ketone 0.2275 0.6321
(2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-carboxylic acid benzyl ester 1.4518 2.7911
(2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-carboxylic acid methyl ester 0.1111 0.2905
(2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-carboxylic acid allyl group acid amides 0.1356 0.2573
(2S, 3S, 4S, 5R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-1-methyl-piperidines-3,4, the 5-triol ＞30 0.0161 0.0731
(2S, 3S, 4S, 5R)-1-benzyl-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-piperidines-3,4, the 5-triol 15.1291 0.0553 0.0635
2-{ (2S, 3S, 4S, 5R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--piperidines-1-yl }-ethanamide 0.2551 0.9095
(2S, 3S, 4S, 5R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-1-isobutyl--piperidines-3,4, the 5-triol 13.7971 0.0267 0.076
(2S, 3S, 4R, 5R, 6R)-2-[3-(4-oxyethyl group-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-piperidines-3,4, the 5-triol 0.2008 0.8183
(3S, 4R, 5R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-hydroxymethyl-piperidines-3,4, the 5-triol 0.1361 0.4623
(2S, 3S, 4R, 5R, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-piperidines-3,4, the 5-triol 3.1151 0.0035 0.0079
(2S, 3S, 4R, 5R, 6R)-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-hydroxymethyl-piperidines-3,4, the 5-triol 3.5013 0.0075
(2S, 3S, 4R, 5R, 6R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--6-hydroxymethyl-piperidines-1-carboxylic acid methyl acid amides 0.0357 0.0633
(2S, 3S, 4R, 5R, 6R)-and 2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-3,4,5-trihydroxy--6-hydroxymethyl-piperidines-1-carboxylic acid methyl ester 0.0751 0.2056
(2S, 3S, 4R, 5R, 6R)-1-benzyl-2-[4-chloro-3-(4-oxyethyl group-benzyl)-phenyl]-6-hydroxymethyl-piperidines-3,4, the 5-triol 0.0624 0.1452
Effect in the body of compound
Use the pharmacotoxicological effect that continues 45% high fat diet and be housed in drug treating and the c57 albinism male mice mensuration The compounds of this invention vehicle processing in the Nalgene metabolic cage respectively.Mouse arbitrarily obtains the paste (2 portions of meals are to 1 part of water) of tap water and high fat diet.
Send compound in two ways.At first be to be the medicine or the vehicle of mouse tube feed 5ml/kg dose volume at first day.All the urine amount was collected in the plastics UCD of metabolic cage at subsequently 24 hours.Carry out the measurement of body weight, amount of drinking water, food consumption (moisture evaporation in having considered to stick with paste) and the urine amount of mouse every day.Collect urine every day, centrifugal, and use the Cobas automatic analyzer to estimate glucose concn.Net result from total urine amount and urine glucose concn calculating excretory glucose in milligrams number every day.
In the second approach, compound is sent in meals.This has considered baseline weight and baseline food consumption by carrying out in the paste that test compound is blended in high fat diet with suitable concentration.The paste that comprises medicine also is with excessive providing every day.Calculate the amount of the compound of sending every day by calculating the weight of animals and food consumption.
Fig. 1 be illustrated in the single oral dosage of 30mg/kg give time spent compound of the present invention to dosage give with after the influence of the amount of excretory glucose in 24 hours processes.By contrast, control animal drained about 1mg glucose in 24 hours.The compound of indication explanation in following table 4 among Fig. 1.
Table 4
Compound Chemical name
1 (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxy benzyl) phenyl-6-(methyl sulphur) tetrahydrochysene-2H-pyrans-3,4,5-triol
2 (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxy benzyl) phenyl-6-(ethyl sulphur) tetrahydrochysene-2H-pyrans-3,4,5-triol
3 (2S, 3S, 4R, 5R, 6R)-2-(4-chloro-3-(4-ethoxy benzyl) phenyl-6-(hydroxymethyl)-1-methyl piperidine-3,4,5-triol
4 (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxy benzyl) phenyl-6-(methyl sulphonyl) tetrahydrochysene-2H-pyrans-3,4,5-triol
5 (2S, 3S, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxy benzyl) phenyl-6-(methyl sulphur) tetrahydrochysene-2H-pyrans-3,4,5-three basic triacetates
6 (2S, 3R, 4R, 5S, 6R)-and 2-(4-chloro-3-(4-ethoxy benzyl) phenyl)-6-(2-hydroxyethyl sulphur) tetrahydrochysene-2H-pyrans-3,4, the 5-triol
7 (2S, 3R, 4R, 5S, 6R)-and 2-(4-chloro-3-(4-ethoxy benzyl) phenyl)-6-((S)-methylsulfinyl) tetrahydrochysene-2H-pyrans-3,4, the 5-triol
8 (2S, 3R, 4R, 5S, 6S)-and 2-(4-chloro-3-(4-ethoxy benzyl) phenyl)-6-methoxyl group tetrahydrochysene-2H-pyrans-3,4, the 5-triol
9 (2S, 3R, 4R, 5S, 6R)-and 2-(4-chloro-3-(4-ethoxy benzyl) phenyl)-6-(2,2,2-trifluoroethyl sulphur) tetrahydrochysene-2H-pyrans-3,4, the 5-triol
10 (2S, 3R, 4R, 5S, 6R)-and 2-(4-chloro-3-(4-ethoxy benzyl) phenyl)-6-(ethylsulfonyl) tetrahydrochysene-2H-pyrans-3,4, the 5-triol
11 (2S, 3S, 4S, 5R)-and 2-(4-chloro-3-(4-ethoxy benzyl) phenyl)-1-methyl piperidine-3,4, the 5-triol
12 (2R, 3S, 4R, 5R, 6S)-and 2-(1H-imidazoles-2-base sulphur)-6-(4-chloro-3-(4-ethoxy benzyl) phenyl) tetrahydrochysene-2H-pyrans-3,4, the 5-triol
13 (2S, 3R, 4R, 5S, 6R)-and 2-(4-chloro-3-(4-ethoxy benzyl) phenyl)-6-((S)-ethyl sulfinyl) tetrahydrochysene-2H-pyrans-3,4, the 5-triol
14 (2S, 3R, 4R, 5S)-and 2-(4-chloro-3-(4-ethoxy benzyl) phenyl)-6-methoxyl group tetrahydrochysene-2H-pyrans-3,4, the 5-triol
15 (2S, 3R, 4R, 5S)-and 2-(4-chloro-3-(4-hydroxybenzyl) phenyl)-6-methoxyl group tetrahydrochysene-2H-pyrans-3,4, the 5-triol
16 (2S, 3S, 4S, 5R)-and 2-(4-chloro-3-(4-ethoxy benzyl) phenyl) piperidines-3,4, the 5-triol
17 (2S, 3R, 4R, 5S, 6S)-and 2-(4-chloro-3-(4-((R)-tetrahydrofuran (THF)-3-base oxygen base) benzyl) phenyl)-6-methoxyl group tetrahydrochysene-2H-pyrans-3,4, the 5-triol
18 N-(2-((2R, 3S, 4R, 5R, 6S)-and 6-(4-chloro-3-(4-ethoxy benzyl) phenyl)-3,4,5-trihydroxy-tetrahydrochysene-2H-pyrans-2-base sulphur) ethyl) ethanamide
Above-mentioned all that quote open (for example, patent and patent application) are all incorporated into this paper as a reference in full.

Claims (67)

1. the compound of following formula:
Figure A2008100900730002C1
Its pharmaceutically useful salt, wherein:
Y is O, S, SO, SO 2, NR 4, (C (R 5) 2) p, (C (R 5) 2) q-C (O)-(C (R 5) 2) q, (C (R 5) 2) q-C (O) O-(C (R 5) 2) q, (C (R 5) 2) q-OC (O)-(C (R 5) 2) q, (C (R 5) 2) q-C (O) NR 4-(C (R 5) 2) q, (C (R 5) 2) q-NR 4C (O)-(C (R 5) 2) q, or (C (R 5) 2) q-NR 4C (O) NR 4-(C (R 5) 2) q
R 1Be OR 1A, SR 1A, SOR 1A, SO 2R 1AOr N (R 1A) 2
Each R 1ABe hydrogen or optional substituted alkyl, aryl or heterocycle independently;
R 2Be fluorine or OR 2A
R 2A, R 2B, and R 2CIn each is hydrogen, optional substituted alkyl, C (O) alkyl, C (O) aryl or aryl independently;
Each R 4Be hydrogen or optional substituted alkyl independently;
Each R 5Be hydrogen, hydroxyl, halogen, amino, cyano group, OR independently 5A, SR 5A, or optional substituted alkyl;
Each R 5ABe optional substituted alkyl independently;
Each R 6Be hydrogen, hydroxyl, halogen, amino, cyano group, nitro, C ≡ CR independently 6A, OR 6A, SR 6A, SOR 6A, SO 2R 6A, C (O) R 6A, CO 2R 6A, CO 2H, CON (R 6A) (R 6A), CONH (R 6A), CONH 2, NHC (O) R 6A, NHSO 2R 6A, or optional substituted alkyl, aryl or heterocycle;
Each R 6ABe optional substituted alkyl, aryl or heterocycle independently;
Each R 7Be hydrogen, hydroxyl, halogen, amino, cyano group, nitro, C ≡ CR independently 7A, OR 7A, SR 7A, SOR 7A, SO 2R 7A, C (O) R 7A, CO 2R 7A, CO 2H, CON (R 7A) (R 7A), CONH (R 7A), CONH 2, NHC (O) R 7A, NHSO 2R 7A, or optional substituted alkyl, aryl or heterocycle;
Each R 7ABe optional substituted alkyl, aryl or heterocycle independently;
M is 1-3;
N is 1-3;
P is 0-3; With
Each q is 0-2 independently.
2. the compound of claim 1 is expressed from the next:
Figure A2008100900730003C1
3. the compound of claim 1, wherein R 1Be OR 1A
4. the compound of claim 1, wherein R 1Be SR 1A
5. the compound of claim 1, wherein R 1Be SOR 1A
6. the compound of claim 1, wherein R 1Be SO 2R 1A
7. each compound, wherein R among the claim 3-6 1ABe hydrogen.
8. each compound, wherein R among the claim 3-6 1ABe optional substituted alkyl (for example optional substituted low alkyl group).
9. the compound of claim 1, wherein R 1Be N (R 1A) 2
10. the compound of claim 9, wherein at least one R 1ABe hydrogen.
11. the compound of claim 9, wherein at least one R 1ABe optional substituted alkyl (for example optional substituted low alkyl group).
12. the compound of claim 1, wherein R 6Be hydrogen, hydroxyl, halogen, OR 6AOr optional substituted low alkyl group (for example optional methyl, ethyl or the sec.-propyl that is replaced by halogen).
13. the compound of claim 12, wherein R 6Be hydrogen.
14. the compound of claim 12, wherein R 6Be halogen (for example chlorine).
15. the compound of claim 12, wherein R 6Be hydroxyl.
16. the compound of claim 12, wherein R 6Be OR 6A(for example methoxyl group, oxyethyl group).
17. the compound of claim 12, wherein R 6Be optional substituted methyl (CF for example 3).
18. the compound of claim 1, wherein R 7Be hydrogen, C ≡ CR 7A, OR 7AOr optional substituted low alkyl group (for example optional methyl, ethyl or the sec.-propyl that is replaced by halogen).
19. the compound of claim 18, wherein R 7Be C ≡ CR 7A
20. the compound of claim 18, wherein R 7Be OR 7A(for example methoxyl group, oxyethyl group).
21. the compound of claim 19 or 20, wherein R 7ABe optional substituted (for example being replaced) monocyclic aryl or heterocycle by low alkyl group or halogen.
22. the compound of claim 1, wherein R 7Be ethynyl or optional substituted methyl or ethyl.
23. the compound of claim 1, it is expressed from the next:
24. the compound of claim 1, it is expressed from the next:
25. the compound of claim 1, it is expressed from the next:
Figure A2008100900730005C3
26. the compound of claim 1, it is expressed from the next:
Figure A2008100900730005C4
27. each compound, wherein R among the claim 23-26 1ABe hydrogen, methyl or ethyl.
28. the compound of following formula:
Figure A2008100900730006C1
Or its pharmaceutically useful salt, wherein:
Y is O, S, SO, SO 2, NR 4, (C (R 5) 2) p, (C (R 5) 2) q-C (O)-(C (R 5) 2) q, (C (R 5) 2) q-C (O) O-(C (R 5) 2) q, (C (R 5) 2) q-OC (O)-(C (R 5) 2) q, (C (R 5) 2) q-C (O) NR 4-(C (R 5) 2) q, (C (R 5) 2) q-NR 4C (O)-(C (R 5) 2) q, or (C (R 5) 2) q-NR 4C (O) NR 4-(C (R 5) 2) q
R 1Be OR 1A, SR 1A, SOR 1A, SO 2R 1A, or R 1A
Each R 1ABe hydrogen or optional substituted alkyl, aryl or heterocycle independently;
R 2Be fluorine or OR 2A
R 3Be hydrogen or optional substituted alkyl, aryl or heterocycle;
R 2A, R 2B, and R 2CIn each is hydrogen, optional substituted alkyl, C (O) alkyl, C (O) aryl or aryl independently;
Each R 4Be hydrogen or optional substituted alkyl independently;
Each R 5Be hydrogen, hydroxyl, halogen, amino, cyano group, OR independently 5A, SR 5A, or optional substituted alkyl;
Each R 5ABe optional substituted alkyl independently;
Each R 6Be hydrogen, hydroxyl, halogen, amino, cyano group, nitro, C ≡ CR independently 6A, OR 6A, SR 6A, SOR 6A, SO 2R 6A, C (O) R 6A, CO 2R 6A, CO 2H, CON (R 6A) (R 6A), CONH (R 6A), CONH 2, NHC (O) R 6A, NHSO 2R 6A, or optional substituted alkyl, aryl or heterocycle;
Each R 6ABe optional substituted alkyl, aryl or heterocycle independently;
Each R 7Be hydrogen, hydroxyl, halogen, amino, cyano group, nitro, C ≡ CR independently 7A, OR 7A, SR 7A, SOR 7A, SO 2R 7A, C (O) R 7A, CO 2R 7A, CO 2H, CON (R 7A) (R 7A), CONH (R 7A), CONH 2, NHC (O) R 7A, NHSO 2R 7A, or optional substituted alkyl, aryl or heterocycle;
Each R 7ABe optional substituted alkyl, aryl or heterocycle independently;
M is 1-3;
N is 1-3;
P is 0-3; With
Each q is 0-2 independently.
29. the compound of claim 28, it is expressed from the next:
Figure A2008100900730007C1
30. the compound of claim 28, wherein R 1Be OR 1A
31. the compound of claim 28, wherein R 1Be SR 1A
32. the compound of claim 28, wherein R 1Be SOR 1A
33. the compound of claim 28, wherein R 1Be SO 2R 1A
34. each compound, wherein R among the claim 30-33 1ABe hydrogen.
35. each compound, wherein R among the claim 30-33 1ABe optional substituted alkyl (for example optional substituted low alkyl group).
36. the compound of claim 28, wherein R 1Be N (R 1A) 2
37. the compound of claim 28, wherein R 1Be R 1A
38. the compound of claim 36 or 37, wherein R 1ABe hydrogen.
39. the compound of claim 36 or 37, wherein R 1ABe optional substituted alkyl (for example optional substituted low alkyl group).
40. the compound of claim 28, wherein R 3Be hydrogen.
41. the compound of claim 28, wherein R 3Be optional substituted low alkyl group (for example optional substituted methyl).
42. the compound of claim 28, wherein R 4Be hydrogen or optional substituted low alkyl group.
43. the compound of claim 28, wherein each R 5Be hydrogen or optional substituted low alkyl group (for example methyl, ethyl, CF 3).
44. the compound of claim 28, wherein R 6Be hydrogen, hydroxyl, halogen, OR 6AOr optional substituted low alkyl group (for example optional methyl, ethyl or the sec.-propyl that is replaced by halogen).
45. the compound of claim 28, wherein R 6Be hydrogen.
46. the compound of claim 28, wherein R 6Be halogen (for example chlorine).
47. the compound of claim 28, wherein R 6Be hydroxyl.
48. the compound of claim 28, wherein R 6Be OR 6A(for example methoxyl group, oxyethyl group).
49. the compound of claim 28, wherein R 6Be optional substituted methyl (CF for example 3).
50. the compound of claim 28, wherein R 7Be hydrogen, C ≡ CR 7A, OR 7AOr optional substituted low alkyl group (for example optional methyl, ethyl or the sec.-propyl that is replaced by halogen).
51. the compound of claim 50, wherein R 7Be hydrogen.
52. the compound of claim 50, wherein R 7Be C ≡ CR 7A
53. the compound of claim 50, wherein R 7Be OR 7A(for example methoxyl group, oxyethyl group).
54. the compound of claim 52 or 53, wherein R 7ABe optional substituted (for example being replaced) monocyclic aryl or heterocycle by low alkyl group or halogen.
55. the compound of claim 28, wherein R 7Be ethynyl or optional substituted methyl or ethyl.
56. the compound of claim 28, it is expressed from the next:
Figure A2008100900730009C1
57. the compound of claim 28, it is expressed from the next:
Figure A2008100900730009C2
58. the compound of claim 28, it is expressed from the next:
59. the compound of claim 28, it is expressed from the next:
Figure A2008100900730010C1
60. each compound, wherein R among the claim 56-59 1ABe hydrogen, methyl or ethyl.
61. pharmaceutical preparation comprises compound and the acceptable diluents or the vehicle of claim 1 or 28.
62. suppress the active method of SGLT2, comprise the claim 1 that makes SGLT2 contact significant quantity or 28 compound.
63. reduce the method for patient's blood sugar, comprise the patient is given with the claim 1 of significant quantity or 28 compound.
64. increase glucose excretory method in patient's urine, comprise the patient is given with the claim 1 of significant quantity or 28 compound.
65. recover the method for patient's insulin sensitivity, comprise the patient that needs are arranged is given with the claim 1 of significant quantity or 28 compound.
66. the method for treatment, reply or prevention disease of patient or illness, comprise the patient that needs are arranged given with treatment or the claim 1 of prevention significant quantity or 28 compound that wherein said disease or illness are atherosclerosis, cardiovascular disorder, diabetes (1 or 2 type), hyperglycemia, hypertension, dyslipidemias, obesity or X syndromes.
67. the method for claim 66, wherein disease or illness are diabetes B.
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