CN103254119B - Inhibitor of sodium glucose co-transporter 2 white 2 and usage thereof - Google Patents

Abstract

This law relates to inhibitor of sodium glucose co-transporter 2 white 2 and usage thereof.Specifically, the invention discloses compound and include the pharmaceutical composition of described compound, it can be used for treating disease and disease such as diabetes and obesity.

Description

Inhibitor of sodium glucose co-transporter 2 white 2 and usage thereof

The application is the divisional application of the Chinese patent application 200810090073.9 that exercise question is " inhibitor of sodium glucose co-transporter 2 white 2 and usage thereof " that on April 2nd, 2008 submits to.

This application claims the priority of the U.S. Provisional Application 60/948,780 that on July 10th, 2007 submits to, its full content is incorporated by reference herein.

Technical field

The method that the present invention relates to treatment metabolic disease and disease such as diabetes, and relate to compound and the pharmaceutical composition of described method.

Background technology

White 2 (SGLT2) of sodium glucose co-transporter 2 are from kidney filtrate re-absorption glucose the transport protein that prevents glucose from losing urine.Because the competitive inhibitor of SGLT2 causes the renal excretion of glucose, they can make the elevated blood glucose levels normalization relevant to disease such as diabetes.Handlon,A.L.,ExpertOpin.Ther.Patents15(11):1531-1540(2005)。

Have been disclosed for many SGLT2 inhibitor.Referring to such as, Handlon, ibid；United States Patent (USP) 6,515,117；U.S. Patent application US2006/0035841, US2004/0138439.At least one inhibitor is in clinical development, is used for treating type 2 diabetes mellitus.Referring to such as, Komoroski, B. et al., " Dapagliflozin (BMS-512148); aSelectiveInhibitoroftheSodium-GlucoseUptakeTransporter2 (SGLT2), ReducesFastingSerumGlucoseandGlucoseExcursioninType2Diab etesMellitusPatientsOver14Days "AmericanDiabetesAssn.67 ^th ScientificSessions,Abstract0188-OR(2007)。

First known SGLT2 inhibitor is natural product phlorhizin (glucose, 1-[2-(β-D-glucopyra glycosyloxy base)-4,6-dihydroxy phenyl]-3-(4-hydroxy phenyl)-1-acetone), and the glucosides class of its structure " all SGLT2 inhibitor subsequently be all derived from ".Handlon, ibid, at the 1533rd page.Phlorhizin includes glucose moiety and two the hydroxylated aromatic rings connected by acetone compartment.Ehrenkranz, J.R.L. et al.,Diabetes Metab.Res.Rev.21:31-38(2005).Summary about patent documentation does not show the SGLT2 inhibitor of any synthesis without glycoside moiety or derivatives thereof.Handlon, ibid.It is true that " due to the relative uniformity of glucosides in SGLT2 patent documentation, find that not studied chemical space becomes difficulty further for possible drug invention people ".Ibid, at the 1537th page.But, still carrying out various trial.Referring to such as, the title of Eckhardt et al. is " D-Xylopyranosyl-SubstitutedphenylDerivatives; MedicamentsContainingSuchCompounds, TheirUseandProcessforTheirManufacture " U.S. Patent application 11/168,905；Eckhardt et al. title is " methylidene-D-Xylopyranosyl-andOxo-D-Xylopyranosyl-Subst itutedphenylDerivatives; MedicamentsContainingSuchCompounds; TheirUseandProcessforTheirManufacture " U.S. Patent application 11/182,986；With the title of Eckhardt et al. be " D-Xylopyranosyl-phenyl-SubstitutedCycles; MedicamentsContainingSuchCompounds; TheirUseandProcessforTheirManufacture " U.S. Patent application 11/199,962.

Summary of the invention

The present invention relates to novel SGLT2 inhibitor.One embodiment of the invention includes the compound of following formula:

I

And pharmaceutically useful salt and solvate, wherein: A is optionally substituted aryl, cycloalkyl or heterocycle；X is O, S or NR₃；When X is O, R₁For OR_1A、SR_1A、SOR_1A、SO₂R_1AOr N (R_1A)₂；When X is S, R₁For hydrogen, OR_1A、SR_1A、SOR_1A, or SO₂R_1A；When X is NR₃Time, R₁For OR_1A、SR_1A、SOR_1A、SO₂R_1A, or R_1A；Each R_1AIndependently be hydrogen or optionally substituted alkyl, aryl or heterocycle；R₂For fluorine or OR_2A；R_2A、R_2B, and R_2CIn each independently be hydrogen, optionally substituted alkyl, C (O) alkyl, C (O) aryl or aryl；R₃For hydrogen, C (O) R_3A、CO₂R_3A、CON(R_3B)₂, or optionally substituted alkyl, aryl or heterocycle；Each R_3AIndependently be optionally substituted alkyl or aryl；With each R_3BIndependently be hydrogen or optionally substituted alkyl or aryl.

Another embodiment includes the compound of following formula:

II

And pharmaceutically useful salt and solvate, wherein: A is optionally substituted aryl, cycloalkyl or heterocycle；X is O or NR₃；R₂For fluorine or OR_2A；R_2A、R_2B, and R_2CIn each independently be hydrogen, optionally substituted alkyl, C (O) alkyl, C (O) aryl or aryl；R₃For hydrogen or optionally substituted alkyl, aryl or heterocycle；R₈For hydrogen or C (O) R_8A；R_8AFor hydrogen or optionally substituted alkyl, alkoxyl or aryl；R_9AAnd R_9BIt is each independently OR_9COr SR_9C, or be combined formation O, S or NR_9C；With each R_9CIndependently be optionally substituted alkyl, aryl or heterocycle.

The present invention includes pharmaceutical composition, and this pharmaceutical composition includes compound disclosed herein.Present invention additionally comprises the method suppressing SGLT2 activity and the method treated, prevent and tackle various disease and disease.

Accompanying drawing explanation

Being referred to Fig. 1 and understand certain aspects of the invention, Fig. 1 represents the impact on the urine glucose excretion of mice of the various compounds of the present invention.Compound is administered orally to use with 30mg/kg.

Detailed Description Of The Invention

The present invention is based in part on following formula: compound can suppress the discovery of white 2 (SGLT2) of sodium glucose co-transporter 2:

III

Substituent group therein is defined below.

Definition

Except as otherwise noted, term " thiazolinyl " refers to the hydrocarbon of straight chain, side chain and/or ring-type, has 2 to 20 (such as, 2 to 10 or 2 to 6) individual carbon atom, and includes at least one carbon-carbon double bond.Representational thiazolinyl includes vinyl, pi-allyl, 1-butylene base, crotyl, isobutenyl, 1-pentenyl, pentenyl, 3-methyl-1-butene base, 2-methyl-2-butene base, 2,3-dimethyl-crotyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decene base, 2-decene base and 3-decene base.

Except as otherwise noted, term " alkoxyl " refers to-O-alkyl group.The example of alkoxyl includes but not limited to-OCH₃、-OCH₂CH₃、-O(CH₂)₂CH₃、-O(CH₂)₃CH₃、-O(CH₂)₄CH₃, and-O (CH₂)₅CH₃。

Except as otherwise noted, term " alkyl " refers to (" cycloalkyl ") hydrocarbon of straight chain, side chain and/or ring-type, has 1 to 20 (such as, 1 to 10 or 1 to 4) individual carbon atom.The alkyl with 1 to 4 carbon is called " low alkyl group ".The example of alkyl include 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 multi-ring, and the example includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and adamantyl.The other example of alkyl has straight chain, side chain and/or annulus (such as, 1-ethyl-4-methyl-cyclohexyl base).Term " alkyl " includes saturated hydrocarbons and thiazolinyl and alkynyl.

Except as otherwise noted, term " alkylaryl " or " alkyl-aryl-group " refer to the moieties being incorporated into aryl moiety.

Except as otherwise noted, term " miscellaneous alkyl aryl " or " alkyl-heteroaryl " refer to the moieties being incorporated into heteroaryl moieties.

Except as otherwise noted, term " alkyl heterocycle " or " alkyl-heterocycle " refer to the moieties being incorporated into heterocyclic moiety.

Except as otherwise noted, term " alkynyl " refers to the hydrocarbon of straight chain, side chain and/or ring-type, has 2 to 20 (such as, 2 to 20 or 2 to 6) individual carbon atom, and includes at least one triple carbon-carbon bonds.Representational alkynyl moiety includes acetenyl, propinyl, 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-octynyl, 2-octynyl, 7-octynyl, 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 " refers to the aromatic rings or armaticity or partial aromatic ring system that are made up of carbon and hydrogen atom.Aryl moiety can include combining or condensing multiple rings together.The example of aryl includes but not limited to anthryl, base, xenyl, fluorenyl, indane, indenyl, naphthyl, phenanthryl, phenyl, 1,2,3,4-tetralin and tolyl.

Except as otherwise noted, term " aryl alkyl " or " aryl-alkyl " refer to the aryl moiety being incorporated into moieties.

Except as otherwise noted, term " halogen " and " halo " include fluorine, chlorine, bromine and iodine.

Except as otherwise noted, term " assorted alkyl " refers to moieties that at least one carbon atom replaced by hetero atom (such as, N, O or S) (such as, straight chain, side chain or ring-type).

Except as otherwise noted, term " heteroaryl " refers to the aryl moiety that at least one of which carbon atom is replaced by hetero atom (such as, N, O or S).Example includes but not limited to acridinyl, benzimidazolyl, benzofuranyl, benzisothiazole base, benzisoxaAzoles base, Benzoquinazole base, benzothiazolyl, benzoAzoles base, furyl, imidazole radicals, indyl, isothiazolyl, differentAzoles base,Di azoly,Azoles base, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine radicals, pyrimidine radicals (pyrimidinyl), pyrimidine radicals (pyrimidyl), pyrrole radicals, quinazolyl, quinolyl, tetrazole radical, thiazolyl and triazine radical.

Except as otherwise noted, term " heteroaryl alkyl " or " heteroaryl-alkyl " refer to the heteroaryl moieties being incorporated into moieties.

Except as otherwise noted, term " heterocycle " refers to armaticity, partial aromatic or the nonaromatic monocycle or multi-ring ring or ring system that are made up of carbon, hydrogen and at least one hetero atom (such as, N, O or S).Multiple (that is, two or more) ring that heterocycle can include condensing or combine.Heterocycle includes heteroaryl.Example includes but not limited to benzo [1,3] dioxa cyclopentenyl, 2,3-dihydro-benzo [1,4] dioxa glutinous rehmannia base, 1,2-phthalazinyl, furyl, hydantoin base (hydantoinyl), morpholinyl, oxetanylmethoxy, Oxyranyle, piperazinyl, piperidyl, pyrrolidone-base, pyrrolidinyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydro-thienyl, tetrahydro thiapyran base and valerolactam base (valerolactamyl).

Except as otherwise noted, term " cycloheteroalkylalkyl " or " heterocycle-allcyl group " refer to the heterocyclic moiety being incorporated into moieties.

Except as otherwise noted, term " Heterocyclylalkyl " refers to non-aromatic heterocyclic rings.

Except as otherwise noted, term " hetercycloalkylalkyl " or " heterocycloalkyl-alkyl " refer to the heterocycloalkyl portion being incorporated into moieties.

Except as otherwise noted, term " internal suppression SGLT2 " refers to that the SGLT2 using the in vivo test described in following example to measure suppresses.

Except as otherwise noted, term " reply " and " process " include preventing described disease or disease to recur in suffering from the patient of this disease or disease and/or time of the remission that extends the patient having suffered from this disease or disease.This term includes regulating disease or the threshold value of disease, development and/or persistent period, or changes patient's response mode to this disease or disease.

Except as otherwise noted, term " pharmaceutically useful salt " refers to from salt prepared by pharmaceutically useful nontoxic acid or alkali (including inorganic bronsted lowry acids and bases bronsted lowry and organic bronsted lowry acids and bases bronsted lowry).The pharmaceutically useful base addition salts being suitable for includes but not limited to the slaine formed by aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or by lysine, N, N ' organic salt that formed of-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-METHYL-ALPHA-L-GLUCOSAMINE) and procaine.Suitable non-toxic acid includes but not limited to mineral acid and organic acid, such as acetic acid, alginic acid, amino benzoic Acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, formic acid, fumaric acid, furancarboxylic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, glactaric acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propanoic acid, salicylic acid, stearic acid, succinic acid, p-aminobenzene sulfonic acid, sulphuric acid, tartaric acid, and p-methyl benzenesulfonic acid.Concrete non-toxic acid includes hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid and methanesulfonic acid.Therefore, the example of specific salt includes hydrochlorate and mesylate.Other salt is as known in the art.Referring to such as, Remington ' sPharmaceuticalSciences, 18^thEd. (MackPublishing, EastonPA:1990) and Remington:TheScienceandPracticeofPharmacy, 19^thed.(MackPublishing,EastonPA:1995)。

Except as otherwise noted, " powerful SGLT2 inhibitor " refers to SGLT2IC₅₀Compound lower than about 500nM.

Except as otherwise noted, term " prevention " and " preventing " consider suffers from the behavior occurred before described disease or disease patient, and it suppresses or reduces the order of severity of this disease or disease.In other word, this term includes diseases prevention.

Except as otherwise noted, " the prevention effective dose " of compound is to be enough to prevent disease or situation or one or more symptoms relevant to this disease or situation or prevent the amount of its recurrence." the prevention effective dose " of compound refers to that therapeutic agent individually or combines with other medicines, it is provided that the amount of prophylactic preventative benefit.Term " prevention effective dose " can include the amount improving the preventative effect of comprehensive diseases prevention or the another kind of preventive medicine of raising.

Except as otherwise noted, " selectivity SGLT2 inhibitor " is SGLT1IC₅₀Than its SGLT2IC₅₀The compound of big at least 10 times.

Except as otherwise noted, term " SGLT1IC₅₀" for using the compound IC of the vitro human SGLT1 inhibition test mensuration described in following example₅₀。

Except as otherwise noted, term " SGLT2IC₅₀" for using the compound IC of the vitro human SGLT2 inhibition test mensuration described in following example₅₀。

Except as otherwise noted, term " three-dimensional heterogeneous mixture " includes racemic mixture and the mixture (such as, R/S=30/70,35/65,40/60,45/55,55/45,60/40,65/35 and 70/30) of stereoisomerism enrichment.

Except as otherwise noted, term " stereoisomerism is pure " refers to that compositions includes a kind of stereoisomer of compound and is substantially free of other stereoisomer of this compound.Such as, the pure compositions of stereoisomerism with the compound of a stereocenter is substantially free of the counter stereoisomer of this compound.Such as, the pure compositions of stereoisomerism with the compound of two stereocenters is substantially free of other diastereomer of this compound.Other stereoisomer of a kind of stereoisomer that typical stereoisomerism pure compound includes exceeding this compound of about 80 weight % and this compound less than about 20 weight %, exceed a kind of stereoisomer of this compound of about 90 weight % and other stereoisomer of this compound less than about 10 weight %, exceed a kind of stereoisomer of this compound of about 95 weight % and other stereoisomer of this compound less than about 5 weight %, exceed a kind of stereoisomer of this compound of about 97 weight % and other stereoisomer of this compound less than about 3 weight %, or exceed a kind of stereoisomer of this compound of about 99 weight % and other stereoisomer of this compound less than about 1 weight %.

Except as otherwise noted, term " replacement ", when describing chemical constitution or part, refer to this structure or the deriveding group of part, its hydrogen atoms one or more in wherein said structure or 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, alkanoyloxy, alkoxy carbonyl, thiazolinyl, alkyl is (such as, methyl, ethyl, propyl group, the tert-butyl group), alkynyl, alkyl-carbonyl oxygen base (-OC (O) alkyl), amide (-C (O) NH-alkyl-or-alkyl NHC (O) alkyl), amidino groups (amidinyl) (-C (NH) NH-alkyl-or-C (NR) NH₂), amine (primary amine, secondary amine and tertiary amine; such as alkyl amino, arylamino, aryl-alkyl amino), aroyl, aryl, aryloxy, azo, carbamoyl (carbamoyl) (-NHC (O) O-alkyl-or OC (O) NH-alkyl), carbamoyl (carbamyl) (such as, CONH₂, and CONH-alkyl, CONH-aryl and CONH-aryl alkyl), carbonyl, carboxyl, carboxylic acid, carboxylic acid anhydrides, carboxyl acyl chloride, cyano group, ester, epoxide, ether (such as, methoxyl group, ethyoxyl), guanidine radicals, halo, haloalkyl (such as ,-CCl₃、-CF₃、-C(CF₃)₃), assorted alkyl, hemiacetal, imines (uncle imines and second imines), isocyanates, isothiocyanate, ketone, nitrile, nitro, oxo, di-phosphate ester, sulfide, sulfamic (such as, SO₂NH₂), sulfone, sulfonyl (including alkyl sulphonyl, aryl sulfonyl and aryl alkylsulfonyl), sulfoxide, mercaptan (such as, sulfydryl, thioether) and urea (NHCONH-alkyl).

Except as otherwise noted, " therapeutically effective amount " of compound be compound be enough to treatment benefit is provided in the treatment or reply of disease or situation or postpones one or more symptoms relevant to this disease or situation or the amount minimized it." therapeutically effective amount " of compound refer to therapeutic agent individually or with other therapeutic combination, the treatment or reply of disease or situation provide the amount of therapeutic benefit.Term " therapeutically effective amount " can include improving complete treatment, reduce or avoid the symptom of disease or situation or the amount of the treatment effect of the cause of disease or the another kind of therapeutic agent of raising.

Except as otherwise noted, term " treatment " considers the behavior occurred when suffering from described disease or disease patient, and it reduces the order of severity of this disease or disease or postpones or slow down the progress of this disease or disease.

Except as otherwise noted, term " including " and " including but not limited to " have identical implication.Similarly, term " such as " and term " such as but not limited to " there is identical implication.

Except as otherwise noted, before a series of nouns, the tight one or more adjectives being connected are considered as modify each noun.Such as, phrase " optionally substituted alkyl, aryl or heteroaryl " and " optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl " have identical implication.

It is pointed out that the chemical part constituting a relatively part for large compound can use the title generally adopted when it exists as individual molecule or the title that generally adopts when its alternatively base to be described in this article.Such as, term " pyridine " and " pyridine radicals " have identical meanings when being used for and describing the part being combined with other chemical part.Therefore, two words " XOH, wherein X is pyridine radicals " and " XOH, wherein X is pyridine " have identical meanings, and include pyridine-2-alcohol, pyridine-3-alcohol and pyridine-4-alcohol.

If it may also be noted that when the spatial chemistry of a part for a certain structure or a certain structure does not represent by such as bold line or dotted line, then a part for this structure or this structure can be interpreted as including all stereoisomers of this structure.It addition, any atom with unsaturated atomicity shown in structure is assumed to be and is combined thus meeting atomicity with enough hydrogen atoms.It addition, the chemical bond described with a solid line parallel with dotted line, if atomicity allows, including singly-bound and double bond (such as aromatics).

Compound

One embodiment of the invention includes the compound of following formula:

I

And pharmaceutically useful salt and solvate, wherein: A is optionally substituted aryl, cycloalkyl or heterocycle；X is O, S or NR₃；When X is O, R₁For OR_1A、SR_1A、SOR_1A、SO₂R_1AOr N (R_1A)₂；When X is S, R₁For hydrogen, OR_1A、SR_1A、SOR_1A, or SO₂R_1A；When X is NH₃Time, R₁For OR_1A、SR_1A、SOR_1A、SO₂R_1A, or R_1A；Each R_1AIndependently be hydrogen or optionally substituted alkyl, aryl or heterocycle；R₂For fluorine or OR_2A；R_2A、R_2B, and R_2CIn each independently be hydrogen, optionally substituted alkyl, C (O) alkyl, C (O) aryl or aryl；R₃For hydrogen, C (O) R_3A、CO₂R_3A、CON(R_3B)₂, or optionally substituted alkyl, aryl or heterocycle；Each R_3AIndependently be optionally substituted alkyl or aryl；With each R_3BIndependently be hydrogen or optionally substituted alkyl or aryl.

Specific compound is expressed from the next:

Some compounds are expressed from the next:

Some compounds are expressed from the next:

One embodiment of the invention includes the compound of following formula:

And pharmaceutically useful salt and solvate, wherein: A is optionally substituted aryl, cycloalkyl or heterocycle；B is optionally substituted aryl, cycloalkyl or heterocycle；X is O, S or NR₃；Y is O, S, SO, SO₂、NR₄、(C(R₅)₂)_p、(C(R₅)₂)_q-C(O)-(C(R₅)₂)_q、(C(R₅)₂)_q-C(O)O-(C(R₅)₂)_q、(C(R₅)₂)_q-OC(O)-(C(R₅)₂)_q、(C(R₅)₂)_q-C(O)NR₄-(C(R₅)₂)_q、(C(R₅)₂)_q-NR₄C(O)-(C(R₅)₂)_q, or (C (R₅)₂)_q-NR₄C(O)NR₄-(C(R₅)₂)_q；When X is O, R₁For OR_1A、SR_1A、SOR_1A、SO₂R_1AOr N (R_1A)₂；When X is S, R₁For hydrogen, OR_1A、SR_1A、SOR_1A, or SO₂R_1A；When X is NH₃Time, R₁For OR_1A、SR_1A、SOR_1A、SO₂R_1A, or R_1A；Each R_1AIndependently be hydrogen or optionally substituted alkyl, aryl or heterocycle；R₂For fluorine or OR_2A；R_2A、R_2B, and R_2CIn each independently be hydrogen, optionally substituted alkyl, C (O) alkyl, C (O) aryl or aryl；R₃For hydrogen, C (O) R_3A、CO₂R_3A、CON(R_3B)₂, or optionally substituted alkyl, aryl or heterocycle；Each R_3AIndependently be optionally substituted alkyl or aryl；Each R_3BIndependently be hydrogen or optionally substituted alkyl or aryl；Each R₄Independently be hydrogen or optionally substituted alkyl；Each R₅Independently be hydrogen, hydroxyl, halogen, amino, cyano group, OR_5A、SR_5A, or optionally substituted alkyl；Each R_5AIndependently be optionally substituted alkyl；P is 0-3；0-2 is independently be with each q.

Specific compound is expressed from the next:

Some compounds are expressed from the next:

Some compounds are expressed from the next:

Some compounds are expressed from the next:

Wherein: each R₆Independently be hydrogen, hydroxyl, halogen, amino, cyano group, nitro, C ≡ CR_6A、OR_6A、SR_6A、SOR_6A、SO₂R_6A、C(O)R_6A、CO₂R_6A、CO₂H、CON(R_6A)(R_6A)、CONH(R_6A)、CONH₂、NHC(O)R_6A、NHSO₂R_6A, or optionally substituted alkyl, aryl or heterocycle；Each R_6AIndependently be optionally substituted alkyl, aryl or heterocycle；Each R₇Independently be hydrogen, hydroxyl, halogen, amino, cyano group, nitro, C ≡ CR_7A、OR_7A、SR_7A、SOR_7A、SO₂R_7A、C(O)R_7A、CO₂R_7A、CO₂H、CON(R_7A)(R_7A)、CONH(R_7A)、CONH₂、NHC(O)R_7A、NHSO₂R_7A, or optionally substituted alkyl, aryl or heterocycle；Each R_7AIndependently be optionally substituted alkyl, aryl or heterocycle；M is 1-3；It is 1-3 with n.

Some compounds are expressed from the next:

Some compounds are expressed from the next:

Some compounds are expressed from the next:

One embodiment of the invention includes the compound of following formula:

II

And pharmaceutically useful salt and solvate, wherein: A is optionally substituted aryl, cycloalkyl or heterocycle；X is O or NR₃；R₂For fluorine or OR_2A；R_2A、R_2B, and R_2CIn each independently be hydrogen, optionally substituted alkyl, C (O) alkyl, C (O) aryl or aryl；R₃For hydrogen or optionally substituted alkyl, aryl or heterocycle；R₈For hydrogen or C (O) R_8A；R_8AFor hydrogen or optionally substituted alkyl, alkoxyl or aryl；R_9AAnd R_9BIt is each independently OR_9COr SR_9C, or it is combined formation O, S or NR_9C；With each R_9CIndependently be optionally substituted alkyl, aryl or heterocycle.

For disclosed herein various, in due course, the specific compound of the present invention is the aryl so that A is optionally substituted 6-unit or heterocycle.In other situation, A is optionally substituted 5-unit heterocycle.In some cases, A is optionally substituted fused bicyclic heterocycle.

In some cases, B is optionally substituted 6-unit aryl or heterocycle.In other situation, B is optionally substituted 5-unit heterocycle.When other, B is optionally substituted fused bicyclic heterocycle.

In some cases, X is O.When other, X is S.When other, X is NR₃。

In some cases, Y is (C (R₄)₂)_pAnd, for instance, p is 1.In some cases, Y is (C (R₅)₂)_q-C(O)-(C(R₅)₂)_qWith, for instance, each q independently be 0 or 1.

In some cases, R₁For OR_1A.When other, R₁For SR_1A.When other, R₁For SOR_1A.When other, R₁For SO₂R_1A.When other, R₁For N (R_1A)₂.When other, R₁For hydrogen.When other, R₁For R_1A。

In some cases, R_1AFor hydrogen.When other, R_1AFor optionally substituted alkyl (such as, optionally substituted low alkyl group).

In some cases, R₂For fluorine.When other, R₂For OR_2A。

In some cases, R_2AFor hydrogen.

In some cases, R_2BFor hydrogen.

In some cases, R_2CFor hydrogen.

In some cases, R₃For hydrogen.When other, R₃For optionally substituted low alkyl group (such as, optionally substituted methyl).

In some cases, R₄For hydrogen or optionally substituted low alkyl group.

In some cases, each R₅For hydrogen or optionally substituted low alkyl group (such as, methyl, ethyl, CF₃)。

In some cases, R₆For hydrogen, hydroxyl, halogen, OR_6AOr optionally substituted low alkyl group (methyl, ethyl or the isopropyl that such as, are optionally optionally substituted by halogen).In some cases, R₆For hydrogen.In some cases, R₆For halogen (such as, chlorine).In some cases, R₆For hydroxyl.In some cases, R₆For OR_6A(such as, methoxyl group, ethyoxyl).In some cases, R₆For optionally substituted methyl (such as, CF₃)。

In some cases, R₇For hydrogen, C ≡ CR_7A、OR_7AOr optionally substituted low alkyl group (methyl, ethyl or the isopropyl that such as, are optionally optionally substituted by halogen).In some cases, R₇For hydrogen.In some cases, R₇For C ≡ CR_7AAnd R_7AFor, for instance, optionally substituted (such as, being replaced by low alkyl group or halogen substiuted) monocyclic aryl or heterocycle.In some cases, R₇For OR_7A(such as, methoxyl group, ethyoxyl).In some cases, R₇For acetenyl or optionally substituted methyl or ethyl.

The specific compound of the present invention is expressed from the next:

I(a)

Other compound is expressed from the next:

I(b)

Other compound is expressed from the next:

I(c)

Other compound is expressed from the next:

I(d)

Other compound is expressed from the next:

I(e)

Other compound is expressed from the next:

I(f)

In the specific compound of Formulas I (a)-(d), X is O.When other, X is S.When other, X is NR₃And R₃For such as hydrogen.In the specific compound of Formulas I (a)-(f), R_1AFor hydrogen.When other, R_1AFor optionally substituted methyl or ethyl.

Preferred compound is powerful SGLT2 inhibitor.Specific compound has lower than about 500,400,300,250,200,150,100,75,50 or the SGLT2IC of 25nM₅₀。

Specific compound is selective SGLT2 inhibitor.Such as, the SGLT1IC that some compound has₅₀SGLT2IC than them₅₀Big at least 10,15,20,25,50,75 or 100 times.

Synthetic method

The compound of the present invention can be prepared by methods known in the art or by method described herein.Such as, compound can be prepared by the method shown in following reaction scheme 1:

Reaction scheme 1

In this approach, under the suitable conditions (such as, the such as oxalyl chloride in DMSO with oxidant) by known alcohol 1 (a) (referring to such as,NucleosidesNucleotides, 20:649-652 (2001)) and oxidation formation aldehyde 1 (b).Process the bromide of formula 1 (c) with reagent such as butyl lithium or butyl magnesium bromide, be subsequently added aldehyde 1 (b), obtain alcohol 1 (d).Process this compound with alcohol or water in acid condition, obtain compound 1 (e).If so desired, can use method well known in the art that compound 1 (e) is converted into other compounds various (such as, wherein one or more R that the present invention includes_2A、R_2BAnd R_2CIt not hydrogen, and/or R₁For SR_1AOr NHR_1AThe compound of Formulas I).

For reaction scheme 1 and other synthetic method specifically described herein, the method preparing A and A-Y-B part is known, the same for the method preparing SGLT2 inhibitor with them.Such as, prepared product SGLT2 inhibitor synthesizes the process of diaryl derivatives of connection in 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；Described in international patent application WO2006/006496 and WO2006/089872.

Comprise the synthesis of SGLT2 inhibitor of the phenyl-carbocycle part of connection described in such as U.S. Patent application 11/190,315 and 11/199,962.

The synthesis connecting heterocycle is used for the purposes obtaining SGLT2 inhibitor in such as U.S. Patent application 10/540 with them, 519,10/734,573,11/247,216,11/247,356 and international patent application WO03/020737, WO2004/058790, WO2004/080990, WO2004/089967, WO2005/011592, WO2005/012242, WO2005/012243, WO2005/012318, WO2005/021566 and WO2005/085265 described in.

Piperidin-1-yl compound can be prepared by the method shown in following reaction scheme 2:

Reaction scheme 2

In this approach, the compound 2 (a) prepared as shown in reaction scheme 1 and azide (such as, diphenylphosphoryl azide) is made to contact when fully obtaining azide 2 (b).Then process azide in acid condition, obtain the furan 2 (c) of deprotection, used reducing agent (such as, the hydrogen under the existence of platinum oxide) to process subsequently in acid condition, obtain compound 2 (d).(such as, the wherein R if so desired, method as known in the art can be used to be converted into by compound 2 (d) other compounds various that the present invention includes_2A、R_2BAnd R_2CIn one or more be not hydrogen and/or R₁For SR_1AOr NHR_1AThe compound of Formulas I).

Tetrahydric thiapyran-based compound can be prepared as shown in following reaction scheme 3:

Reaction scheme 3

In this approach, make the compound 3 (a) prepared as shown in reaction scheme 1 with suitable sulfur-containing compound (such as, thiacetate) under the suitable conditions (such as, under the existence of diethylazodicarboxylate) contact, obtain thiacetate 3 (b).Then process thiacetate with the alkali (such as, Cesium hydrate .) being suitable for, obtain the mercaptan of formula 3 (c), in acid condition it is processed with alcohol or water subsequently, obtain compound 3 (d).(such as, the wherein R if so desired, method as known in the art can be used to be converted into by compound 3 (d) other compounds various that the present invention includes_2A、R_2BAnd R_2CIn one or more be not hydrogen and/or R₁For SR_1AOr NHR_1AThe compound of Formulas I).

Compound (wherein R including the sugar of fluoride or sugar analogue₂The compound of Formulas I for F) methods known in the art can be used to prepare from the corresponding initiation material replaced.Referring to such as, U.S. Patent application 10/735,179.

The compound (such as, the compound of Formula II) of open loop form easily passes through methods known in the art to be prepared.Such as, they can use those methods as shown in following reaction scheme 4 to prepare:

Reaction scheme 4

In this approach, make the compound 4 (a) prepared as shown in reaction scheme 1 and reactive compounds (such as, methylchloroformate) contact under the suitable conditions, obtain methyl carbonate 4 (b).Then in acid condition methyl carbonate alcohol is processed, obtain compound 4 (c).(such as, the wherein R if so desired, method as known in the art can be used to be converted into by compound 4 (c) other compounds various that the present invention includes_2A、R_2BAnd R_2CIn the compound of one or more Formula II not being hydrogen).

Use methods known in the art, it is easy to ground changes above-mentioned synthetic method, to obtain various compound.And chiral chromatography and other known technology can be used to obtain stereoisomerism pure compound.Referring to such as, Jacques, J. et al.,Enantiomers,RacematesandResolutions(WileyInterscience,NewYork,1981)；Wilen, S.H. et al.,Tetrahedron33:2725(1977)；Eliel,E.L.,StereochemistryofCarbon Compounds(McGrawHill,NY,1962)；And Wilen, S.H.,TablesofResolvingAgentsand OpticalResolutions,p.268(E.L.Eliel,Ed.,Univ.ofNotreDamePress,NotreDame,IN,1972).It addition, synthesis can utilize the initiation material of chirality, to obtain the product that stereoisomerism is enriched with or stereoisomerism is pure.

Usage

The present invention includes the method suppressing SGLT2 activity, and the method includes making the SGLT2 the compounds of this invention (that is, novel compound disclosed herein) contacting effective dose.In one embodiment, protein is in vivo.In another embodiment, it is (exvivo) of ex vivo.

Present invention additionally comprises the method reducing patient's (such as, mammal is people, Canis familiaris L. or cat such as) blood glucose, the method includes patient to the compound by the present invention of effective dose.

Present invention additionally comprises and increase the method for glucose excretion in Urinary, the method includes patient to the compound by the present invention of effective dose.

The method that present invention additionally comprises the insulin sensitivity recovering or increasing patient, the method includes patient to the compound by the present invention of effective dose.

The method that present invention additionally comprises the disease for the treatment of, reply or prevention patient or disease, the method includes patient to the compound with treatment or the present invention of prevention effective dose.The example of disease and disease includes atherosclerosis, cardiovascular disease, diabetes (1 and 2 type), hyperglycemia, hypertension, dyslipidemias (lipiddisorder), obesity and X syndrome.Specific disease is type 2 diabetes mellitus.

The dosage of compound, route of administration and according to dosage administration time table can determine according to many factors, for instance to be treated, prevention or reply specific indication, the age of patient, sex and situation.The effect of these factors is to it is well known in the art that and can be adjusted by conventional experiment.

Pharmaceutical preparation

The present invention includes the pharmaceutical composition of one or more compounds containing the present invention.Some drugs compositions is adapted for the single unit dosage forms to patient's per os, mucosa (such as nose, Sublingual, vagina, cheek or rectum), non-bowel (such as subcutaneous, intravenous, bolus injection, intramuscular or intra-arterial) or transdermal administration.The example of dosage form includes, but are not limited to: tablet；Lozenge (caplets)；Capsule, such as soft elastic gelatin capsule；Cachet；Lozenge (troches)；Rhombus agent；Dispersant；Suppository；Unguentum；Poultice (mud agent)；Paste；Powder；Dressing；Cream；Plaster；Solution；Paster；Aerosol (such as nose sprays into agent or inhalant)；Gel；Be suitable to the liquid dosage form to patient's per os or mucosa delivery, including suspending agent (such as aqueous or non-aqueous liquid suspensions, oil in water emulsion, or water-in-oil liquid Emulsion), solution, and elixir；Be suitable to the liquid dosage form to patient's parenterai administration；With can be reconstructed to provide that the sterile solid (such as crystallization or amorphous solid) being suitable to the liquid dosage form to patient's parenterai administration.

Preparation shall be appropriate for the mode of administration.Such as, oral administration needs enteric coating to avoid the compound of the present invention to be degraded in gastrointestinal tract.Similarly, preparation can comprise and is easy to the composition of active delivery to site of action.Such as, compound can give use in liposome, to avoid they enzymes that are degraded to be degraded, promotes the transhipment in blood circulation, and realize cross-cell membrane and arrive the delivery at position in born of the same parents.

The composition of dosage form, shape and type change according to the difference of its purposes.Such as, the dosage form used in emergency treatment disease, compared with the dosage form used in this disease long-term treatment, can contain one or more active component more substantial.Similarly, non-bowel dosage form, compared with the peroral dosage form that treatment same disease uses, one or more active component lesser amount of can be comprised.Particular dosage form included by the present invention these modes discrepant and alternate manner each other will be readily apparent to one having ordinary skill.Referring to such as, Remington ' sPharmaceuticalSciences, 18^thed.(MackPublishing,EastonPA:1990)。

The pharmaceutical composition preferred oral of the present invention is given and is used.The discrete dosage form being suitable for oral administration includes tablet (such as, chewable tablet), lozenge, capsule and liquid agent (such as, seasoning syrup agent).This dosage form comprises the active component of scheduled volume, and can pass through to well known to a person skilled in the art prepared by practice of pharmacy.Referring to such as, Remington ' sPharmaceuticalSciences, 18^thed.(MackPublishing,EastonPA:1990)。

Typical peroral dosage form is by being closely mixed with active component according to conventional pharmaceutical technology with at least one excipient.Excipient can take various forms according to the difference being used for being administered required dosage form.

Owing to being easy to the best oral dosage unit form of administration, tablet and Capsules representative.If it is desire to, it is possible to by the aqueous of standard or nonaqueous techniques by tablet coating.This dosage form can be prepared by conventional practice of pharmacy.Generally, by make active component and liquid-carrier, finely divided solid carrier or its both mix equably and closely, then make product be configured to desired outward appearance if necessary and prepare pharmaceutical composition and dosage form.Disintegrating agent can be incorporated to, to promote rapid dissolution in solid dosage forms.Lubricant can also be incorporated to, in order to the production of dosage form (such as, tablet).

Embodiment

Understand various aspects of the invention by following example, but these embodiments are not used in and limit the scope of the invention.

Embodiment 1:(2S, 3R, 4R, 5S) synthesis of-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-methoxy-tetrahydro-pyrans-3,4,5-triol

Title compound is prepared by following step.

A.[(3aS, 5S, 6R, 6aS)-6-(tert-butyI-dimethyl-silicyl oxygen base)-2,2-dimethyl-tetrahydro-furan Mutter also [2,3-d] [1,3] dioxole-5-base]-methanolPreparation: this compound use methods known in the art synthesis.Referring to such as,NucleosidesNucleotides, 20:649-652 (2001) and list of references therein.

B.(3aS, 5R, 6R, 6aS)-6-(tert-butyI-dimethyl-silicyl oxygen base)-2,2-dimethyl-tetrahydro-furan And [2,3-d] [1,3] dioxole-5-formaldehydePreparation: at N₂Under at-78 DEG C of CH to oxalyl chloride (0.76ml, 8.7mmol)₂Cl₂(55ml) solution drips the CH of DMSO (0.84ml, 11.8mmol)₂Cl₂(5ml) solution.After 15 min, dropping comprises the CH of the alcohol (2.40g, 7.9mmol) deriving from step A₂Cl₂(20ml).After 15 min, it is slowly added to NEt₃.Make reaction slowly rise again in 105 minutes room temperature, then use H₂O quencher, uses Et₂O dilutes and uses H₂O, saturated NaHCO₃Aqueous solution and salt water washing.The organic facies Et merged₂O back extraction, washs in that same order by it.By the organic facies MgSO of merging₄Dry, filter and vacuum concentration, obtain (3aS, 5R, 6R, 6aS)-6-(tert-butyI-dimethyl-silicyl oxygen base)-2,2-dimethyl-tetrahydro-furo [2,3-d] [1,3] dioxole-5-formaldehyde (2.4g, about 64% purity, NMR).The not purified use of product.

C.The chloro-2-of the bromo-1-of 4-(4-ethyoxyl-benzyl)-benzenePreparation: preparation described in the U.S. Patent application 10/745,075 that this compound such as Deshpande et al. submits at December in 2003 on the 23rd.

D.(S)-[(3aS, 5S, 6R, 6aS)-6-(tert-butyI-dimethyl-silicyl oxygen base)-2,2-dimethyl-four Hydrogen-furo [2,3-d] [1,3] dioxole-5-base]-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-methanolPreparation: at N₂Under at-78 DEG C to dropping BuLi in THF (60ml) solution of the 4-the deriving from step C chloro-2-of bromo-1-(4-ethyoxyl-benzyl)-benzene (3.6g, 11.1mmol) (2.5M, in hexane, 4.4ml, 11.1mmol).After 30 minutes, dropping comprises the THF (20ml) of the aldehyde (2.4g, 64% purity, 5.1mmol) deriving from step B, and reaction is stirred 30 minutes at-78 DEG C so that it is room temperature of rising again and stirring 60 minutes, uses saturated NH₄Cl aqueous solution quencher, uses Et₂O dilutes and uses H₂O and salt water washing.The aqueous cleaning solution Et merged₂O back extraction, is passed through identical sequential purge.The organic extract MgSO merged₄Dry, filter and vacuum concentration.Residue passes through purified by flash chromatography (120gSiO₂0-20%EtOAc: hexane, 75 minutes, 85ml/min), obtain clean (S)-[(3aS, 5S, 6R, 6aS)-6-(tert-butyI-dimethyl-silicyl oxygen base)-2,2-dimethyl-tetrahydro-furo [2,3-d] [1,3] dioxole-5-base]-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-methanol (0.84g,, and C5 epimer (0.83g) and some mixing fraction (0.51g) 1.5mmol, 30%).

¹nullHNMR(400MHz,Chloroform-d) δ ppm:7.37 (d,J=8.34Hz,1H),7.18-7.23(m,1H),7.15(d,J=2.02Hz,1H),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),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-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-methoxy-tetrahydro-pyrans-3, 4,5-triolPreparation: by AcCl (0.25ml, 3.5mmol) being joined MeOH (10ml) and stirring the MeOH solution preparing 0.35MHCl for 15 minutes.The bottle sealed derives from by this solution-treated the alcohol (0.84g, 1.5mmol) of step D, carries out 16 hours in room temperature and carry out 2 hours at 80 DEG C.Reaction is cooled to room temperature, uses K₂CO₃Quencher is until in alkalescence, using CH₂Cl₂Dilution, filters and vacuum concentration.Product passes through purified by flash chromatography (40gSiO₂, 0-10%MeOH:CH₂Cl₂, 60 minutes, 35ml/min), it is suspended in H₂In O, and lyophilizing, obtaining (2S, 3R, 4R, 5S)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-methoxy-tetrahydro-pyrans-3,4,5-triols (0.46g, 1.1mmol, 75%), for white solid.NMR is shown as α and the β anomer of 1.2:1 ratio.

¹nullHNMR(400MHz,Chloroform-d) δ ppm:7.38-7.42 (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,1Hα),4.43(d,J=9.85Hz,1Hα),4.34(d,J=7.58Hz,1Hβ),4.16(d,J=9.35Hz,1Hβ),3.99-4.12(m,4H),3.80-3.86(m,1Hα),3.64-3.72(m,1H),3.54(s,3Hβ),3.46-3.54(m,1.5H),3.45(s,3Hα),2.69(d,J=2.53Hz,1Hβ),2.62(d,J=2.27Hz,1Hα),2.50(d,J=2.27Hz,1Hβ),2.12(d,J=9.85Hz,1Hα),2.00(d,J=3.03Hz,1Hβ),1.98(d,J=2.78Hz,1Hα),1.41(t,J=6.95Hz,3H).MS(ES+)[M+NH₄]⁺=426。

Embodiment 2:(3S, 4R, 5R, 6S) synthesis of-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-ttetrahydro-pyran-2,3,4,5-tetrol

By derive from the alcohol (51mg, 0.093mmol) of embodiment 1 step D in sealed vial at 80 DEG C with 1:1AcOH:H₂O (1ml) processes 18 hours.Reaction is cooled to room temperature, dilutes to transfer in flask with EtOAc, and vacuum concentration.Residue is dissolved in CH₂Cl₂, use NaHCO₃And MgSO₄Process 30 minutes, filter and vacuum concentration.Product passes through purified by flash chromatography (4gSiO₂, 0-12%MeOH:CH₂Cl₂, 30 minutes, 10ml/min), it is suspended in H₂In O, and lyophilizing, obtaining (3S, 4R, 5R, 6S)-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-ttetrahydro-pyran-2,3,4,5-tetrols (31mg, 0.079mmol, 85%), for white solid.NMR is shown as α and the β anomer of 1:1 ratio.

¹HNMR (400MHz, methanol-d₄null)δppm7.34(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,1Hα),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+NH₄]⁺=412。

Embodiment 3:(2S, 3R, 4R, 5S) synthesis of-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-ethyoxyl-ttetrahydro-pyran-3,4,5-triol

By AcCl (0.025ml, 0.35mmol) being joined in EtOH (1ml) and stirring the EtOH solution preparing 0.35MHCl for 15 minutes.The bottle sealed derives from the alcohol of embodiment 1 step D (61mg, 0.11mmol) 2 hours at 80 DEG C by this solution-treated.Reaction is cooled to room temperature, uses dense NH₄OH quencher is until in alkalescence, using NaHCO₃Process 30 minutes, use CH₂Cl₂Dilution, filters and vacuum concentration.Product passes through purified by flash chromatography (4gSiO₂, 0-10%MeOH:CH₂Cl₂, 40 minutes, 10ml/min), it is suspended in H₂In O, and lyophilizing, obtaining (2S, 3R, 4R, 5S)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-ethyoxyl-ttetrahydro-pyran-3,4,5-triols (40mg, 0.095mmol, 85%), for white solid.NMR is shown as α and the β anomer of 1.75:1 ratio.

¹nullHNMR(400MHz,Chloroform-d) δ ppm:7.28-7.32 (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,1Hα),4.37(d,J=9.60Hz,1Hα),4.33(d,J=7.83Hz,1Hβ),4.06(d,J=9.35Hz,1Hβ),3.89-4.02(m,4H),3.36-3.87(m,5H),2.62(s,1Hβ),2.54(s,1Hα),2.41(d,J=1.52Hz,1Hβ),2.02(d,J=10.36Hz,1Hα),1.92(d,J=2.53Hz,1H),1.32(t,J=6.95Hz,3H),1.13-1.19(m,3H).MS(ES+)[M+NH₄]⁺=440。

Embodiment 4:(2S, 3R, 4R, 5S, 6S)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-isopropoxy-ttetrahydro-pyran-3,4,5-triol and (2S, 3R, 4R, 5S, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-isopropoxy-ttetrahydro-pyran-3, the synthesis of 4,5-triol

By AcCl (0.025ml, 0.35mmol) being joined in i-PrOH (1ml) and stirring the i-PrOH solution preparing 0.35MHCl for 15 minutes.The bottle sealed derives from by this solution-treated alcohol (68mg, the 0.12mmol2 hour of embodiment 1 step D at 80 DEG C.Reaction is cooled to room temperature, uses dense NH₄OH quencher is until in alkalescence, using NaHCO₃Process 30 minutes, use CH₂Cl₂Dilution, filters and vacuum concentration.Residue passes through purified by flash chromatography (4gSiO₂, 0-10%MeOH:CH₂Cl₂, 40 minutes, 10ml/min), obtain 50mg material, by it further by the property prepared HPLC (19x50mmC18 post, 20-70%MeCN:H₂O(10mMNH₄OAc), 14 minutes, 30ml/min) purification, obtain (2S, 3R, 4R, 5S, 6S)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-isopropoxy-ttetrahydro-pyran-3,4,5-triol (β anomer, 7mg, 0.016mmol) and (2S, 3R, 4R, 5S, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-isopropoxy-ttetrahydro-pyran-3,4,5-triol (α anomer, 25mg, 0.057mmol).

(2S, 3R, 4R, 5S, 6S)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-isopropoxy-ttetrahydro-pyran-3,4,5-triol:¹nullHNMR(400MHz,Chloroform-d) δ ppm:7.37-7.40 (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+NH₄]⁺=454。

(2S, 3R, 4R, 5S, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-isopropoxy-ttetrahydro-pyran-3,4,5-triol:¹nullHNMR(400MHz,Chloroform-d) δ ppm7.39 (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(brs,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+NH₄]⁺=454。

Embodiment 5:(2S, 3R, 4R, 5S, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-methoxy-tetrahydro-pyrans-3,4,5-triol and (2S, 3R, 4R, 5S, 6S)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-methoxy-tetrahydro-pyrans-3, the synthesis of 4,5-triol

The sample (80mg) deriving from the compound of embodiment 1 step E is dissolved in 30% ethanol/hexane of 4ml and by 400 μ l partial syringe to ChiralPakAD-H post (20x250mm, 5.5ml/min, 31.55% ethanol/hexane is as Isocratic clution liquid, ambient temperature, run 30min) so that two kinds of isomers are separated from one another.First isomer (retention time 23min) is defined as αisomer (6R, 20mg) and second (retention time 26 minutes, 21mg) is defined as beta isomer (6S).

(2S, 3R, 4R, 5S, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-methoxy-tetrahydro-pyrans-3,4,5-triol:¹nullHNMR(400MHz,Chloroform-d) δ ppm7.39 (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),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+NH₄]⁺=426。

(2S, 3R, 4R, 5S, 6S)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-methoxy-tetrahydro-pyrans-3,4,5-triol:¹HNMR (400MHz, chloroform-d) δ ppm7.39 (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+NH₄]⁺=426。

Following methods is also used optionally to synthesize (2S, 3R, 4R, 5S, 6S)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-methoxy-tetrahydro-pyrans-3,4,5-triol:

A. acetic acid (3S, 4R, 5S, 6S)-2,4,5-triacetoxyl group-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]- The preparation of ttetrahydro-pyran-3-base ester:At 100 DEG C, the alcohol (6.80g, 12.4mmol) deriving from embodiment 1 step D is used 3:2AcOH/H₂O (62ml) processes 22 hours.Will reaction vacuum concentration, and toluene rotary evaporation 3 times, and being placed under fine vacuum.The residue pyridine (25ml) containing acetic anhydride (9.4ml, 99.2mmol) processes 16 hours.Reaction H₂O quencher, stirs 1 hour, uses Et₂O dilutes, and uses 1MNaHSO₄Aqueous solution, H₂O, saturated NaHCO₃Aqueous solution and salt water washing (carrying out back extraction), use MgSO₄Dry, filter and vacuum concentration.Residue passes through purified by flash chromatography (120gSiO₂, 0-50%EtOAc/Hex), obtain acetic acid (3S, 4R, 5S, 6S)-2,4,5-triacetoxyl group-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-ttetrahydro-pyran-3-base ester (6.10g, 10.9mmol, 87%).

¹nullHNMR(400MHz,Chloroform-d) δ ppm7.36 (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,0.5Hα),5.84(d,J=8.08Hz,0.5Hβ),5.55(t,J=9.98Hz,0.5Hα),5.33(t,J=9.71Hz,0.5Hβ),5.20-5.27(m,1H),5.09(t,J=9.60Hz,0.5Hβ),5.03(t,J=9.73Hz,0.5Hα),4.78(d,J=10.11Hz,0.5Hα),4.47(d,J=9.85Hz,0.5Hβ),3.94-4.09(m,4H),2.20(s,1.5Hα),2.11(s,1.5Hβ),2.06(s,1.5Hβ),2.05(s,1.5Hα),2.02(s,1.5Hα),2.01(s,1.5Hβ),1.74(s,1.5Hα),1.72(s,1.5Hβ),1.41(t,J=6.95Hz,3H).MS(ES+)[M+NH₄]⁺=580。

B. acetic acid (2S, 3S, 4R, 5S, the 6S)-4,5-bromo-6-of diacetoxy-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)- Phenyl] preparation of-ttetrahydro-pyran-3-base ester:The tetracetate (8.08g, 14.4mmol) deriving from step A is processed 1 hour with the AcOH (30ml) containing 33%HBr.Reaction CH₂Cl₂(60ml) dilution, stirs 30 minutes, dilutes with more DCM, with ice-cold H₂O washs 3 times and uses saturated NaHCO₃Solution washing (carries out back extraction), uses MgSO₄Dry, filter and vacuum concentration, obtain the bromo-6-of acetic acid (2S, 3S, 4R, 5S, 6S)-4,5-diacetoxy-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-ttetrahydro-pyran-3-base ester.

¹nullHNMR(400MHz,Chloroform-d) δ ppm7.37 (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+NH₄]⁺=602。

C. acetic acid (2S, 3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-benzene Base] preparation of-2-methoxy-tetrahydro-pyrans-3-base ester:The thick bromide (8.4g, 14.4mmol) and ZnO (1.2g, 14.4mmol) that derive from step B are dissolved in MeOH (144ml) and heat 1 hour at 70 DEG C.Reaction is cooled to room temperature, is filtered through kieselguhr and vacuum concentration with EtOAc.Residue is in two batches from MeOH recrystallization, obtain acetic acid (2S, 3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-2-methoxy-tetrahydro-pyrans-3-base ester (5.98g, 11.2mmol, 78%) and for pure beta-anomer.

¹nullHNMR(400MHz,Chloroform-d) δ ppm7.37 (d,J=8.08Hz,1H),7.22(dd,J=8.21,2.15Hz,1H),7.05-7.10(m,3H),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+NH₄]⁺=552。

D. (2S, 3R, 4R, 5S, 6S)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-methoxy-tetrahydro-pyrrole Mutter the preparation of-3,4,5-triol:The triacetate (5.98g, 11.2mmol) of the recrystallization of step C will be derived from containing K with vigorous stirring₂CO₃The MeOH (112ml) of (7.7g, 56mmol) processes 1 hour.Reaction is filtered through kieselguhr and vacuum concentration.Residue is dissolved in DCM, uses H₂O and salt water washing, use MgSO₄Dry, filter and vacuum concentration.Residue passes through short column of silica gel, uses 5%MeOH:CH₂Cl₂, vacuum concentrates, and is suspended in H₂In O, and lyophilizing, obtaining (2S, 3R, 4R, 5S, 6S)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-methoxy-tetrahydro-pyrans-3,4,5-triols (4.37g, 10.7mmol, 96%), for white solid.

¹nullHNMR(400MHz,Chloroform-d) δ ppm7.39 (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+NH₄]⁺=426。

Embodiment 6:N-{ (2S, 3S, 4R, 5R, 6S)-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxy-ttetrahydro-pyran-2-base } synthesis of-N-propyl-acetamide

The bromide (58mg, 0.1mmol) of embodiment 5 step B will be derived from 40 DEG C with the CH containing propylamine (0.1ml)₂Cl₂(0.5ml) solution-treated 1.5 hours.Reaction blasts N₂, then blast CH₂Cl₂Twice.The residue pyridine (1ml) containing acetic anhydride (78 μ l, 0.82mmol) processes overnight.MeOH quencher is used in reaction, stirs 30 minutes, uses Et₂O dilutes, and uses 1MNaHSO₄Aqueous solution, H₂O, saturated NaHCO₃Aqueous solution and salt water washing (carrying out back extraction), use MgSO₄Dry, filter and vacuum concentration.Intermediate is with containing K₂CO₃The MeOH (1ml) of (14mg, 0.l0mmol) processes 1.5 hours.Reaction is filtered and vacuum concentration, and residue passes through purified by flash chromatography (12gSiO₂, 0-10%MeOH:CH₂Cl₂), obtain 90% pure material.Product passes through HPLC (19x50mmC18 post, 20-70%MeCN:H₂O(10mMNH₄OAc), 14 minutes, 30ml/min) it is further purified, it is suspended in H₂In O, and lyophilizing, obtains N-{ (2S, 3S, 4R, 5R, 6S)-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxy-ttetrahydro-pyran-2-base }-N-propyl-acetamide (3mg, 0.0063mmol, 15%), for the rotamer of 2:1 ratio.

¹HNMR(400MHz,MeOD)δppm7.29-7.40(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) synthesis of-5-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-2,3,4,5-tetrahydroxy-valeraldehyde oxime

The compound (50mg, 0.13mmol) and hydroxylamine hydrochloride (26mg, 0.38mmol) that derive from embodiment 2 are dissolved in pyridine (0.65ml) and stir 3 hours.React and dilute with EtOAc, use 1MNaHSO₄Aqueous solution, H₂O, saturated NaHCO₃Aqueous solution and salt water washing (carrying out back extraction), use Na₂SO₄Dry, filter and vacuum concentration.Residue is suspended in H₂In O and lyophilizing, obtain (2R, 3S, 4S, 5S)-5-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-2,3,4,5-tetrahydroxys-valeraldehyde oxime (46mg, 0.11mmol, 88%), for the 5:1 mixture of oxime isomers.

Main isomer¹HNMR(400MHz,MeOD)δppm7.31-7.36(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) synthesis of-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxy-ttetrahydro-pyran-2-ketoxime

A. acetic acid (3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-2- The preparation of hvdroxv-tetrahydro-pvran-3-base ester:The tetracetate (200mg, 0.36mmol) deriving from embodiment 5 step A processes 2 hours with the DMF (1.8ml) containing benzyl amine (39 μ l, 0.36mmol).Reaction Et₂O dilutes, and uses 1MNaHSO₄Aqueous solution, H₂O, saturated aqueous solution NaHCO₃, and salt water washing, use MgSO₄Dry, filter and vacuum concentration.Residue passes through purified by flash chromatography (12gSiO₂0-50%EtOAc:Hex.), obtain acetic acid (3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-2-hvdroxv-tetrahydro-pvran-3-base ester (142mg, 0.27mmol, 77%), for the anomer of 3:1 ratio.

¹nullHNMR(400MHz,Chloroform-d) δ ppm7.33-7.40 (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+NH₄]⁺=538。

B. acetic acid (3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-2- The preparation of [(Z)-oxyimino]-ttetrahydro-pyran-3-base ester:The compound (142mg, 0.27mmol) and hydroxylamine hydrochloride (57mg, 0.82mmol) that derive from step A are dissolved in pyridine (1.4ml).Reaction is stirred 6 hours, dilutes with EtOAc, use 1MNaHSO₄Aqueous solution, H₂O, saturated aqueous solution NaHCO₃, and salt water washing (carrying out back extraction), use Na₂SO₄Dry, filter and vacuum concentration.Residue is dissolved in CH₂Cl₂, it is cooled to-78 DEG C, and processes with DBU (49 μ L, 0.33mmol), process with N-chlorosuccinimide (44mg, 0.33mmol) subsequently.Reaction is stirred 20 minutes at-78 DEG C, in 15 minutes, then makes its room temperature of rising again.React and dilute with EtOAc, use H₂O and salt water washing (carrying out back extraction), use MgSO₄Dry, filter and vacuum concentration.Residue passes through purified by flash chromatography (12gSiO₂0-50%EtOAc:Hex.), obtain acetic acid (3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-2-[(Z)-oxyimino]-ttetrahydro-pyran-3-base ester (97mg, 0.18mmol, 67%).

¹nullHNMR(400MHz,Chloroform-d) δ ppm7.42 (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),5.16-5.22(m,1H),5.10-5.15(m,1H),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)-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxy-tetrahydrochysene-pyrrole Mutter the preparation of-2-ketoxime:The compound (97mg, 0.18mmol) of step B will be derived from containing 7.0MNH₃MeOH (1.8ml) process 1 hour.Reaction vacuum is concentrated, and by residue by purified by flash chromatography (12gSiO₂, 0-12%MeOH:CH₂Cl₂), it is suspended in H₂In O, and lyophilizing, obtain (3S, 4R, 5R, 6S)-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxies-ttetrahydro-pyran-2-ketoxime (57mg, 0.14mmol, 77%), for white solid.

¹HNMR(400MHz,MeOD)δppm7.36-7.44(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) synthesis of-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl] the fluoro-6-methoxy-tetrahydro of-5--pyrans-3,4-glycol

A. (2S, 3R, 4S)-2-(the chloro-3-of 4-(4-ethoxy benzyl) phenyl)-3,4-dihydro-2H-pyrans-3,4-two base The preparation of diacetate esters:The HBr (33%, in HOAc) of 1.25ml is added to the flask of the tetracetate (0.5mmol) deriving from embodiment 5 step A equipped with 282mg.Reaction is stirred one hour, with 50ml dchloromethane and by being poured in frozen water quencher.Organic layer is separated and uses saturated NaHCO₃Aqueous solution and salt water washing.After drying over magnesium sulphate, solvent in vacuo is concentrated.Thick residue accumulation is in 0.5ml dichloromethane and joins copper sulfate (II) (20mg, 0.125mmol), Zn powder (82mg, 1.25mmol) and the sodium acetate (984mg, 12mmol) suspension in 2.5ml acetic acid/water (3:2v:v).Being stirred at room temperature by mixture 4 hours, its backward reaction adds the copper sulfate (II) of 20mg and 82mgZn powder and stirs other 18h.Mixture is used water quencher, is extracted with ethyl acetate.Organic layer magnesium sulfate dries and vacuum removes.Through flash chromatography, obtain (2S, 3R, 4S)-2-(the chloro-3-of 4-(4-ethoxy benzyl) phenyl)-3,4-dihydro-2H-pyrans-3,4-bis-base diacetate esters (32mg, 16% yield).

¹nullHNMR(400MHz,Chloroform-d) δ ppm7.36 (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),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-(the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl) the fluoro-6-methoxyl group-four of-5- The preparation of hydrogen-2H-pyrans-3,4-glycol:By Selectfluor^TM(45mg, 0.128mmol) joins the compound (38mg, 0.0853mmol) deriving from step A at 0.4mL acetonitrile: the solution in methanol (1:1v:v).Reaction is stirred at ambient temperature and has been monitored by LCMS.By saturated for reaction 2mL NH₄Cl aqueous solution quencher and with ether extract (2x5mL).By the Organic substance dried over sodium sulfate extracted and vacuum concentration.The product of fluoride is obtained through flash chromatography (5 to 10% ethyl acetate/hexane).Then potassium carbonate (5mg) is joined the product of this separation solution in 0.5mL methanol.Reaction is stirred 2 hours in ambient temperature, thereafter it with 2mL water quencher and is extracted with ethyl acetate (2x4mL).Organic layer is filtered through silicon dioxide pad and concentrates, and obtains (2S, the 3R of 6.3mg, 4R, 5R, 6R)-2-(the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl)-5-fluoro-6-methoxy-tetrahydro-2H-pyrans-3,4-glycol, for the grease of clarification.

¹nullHNMR(400MHz,Chloroform-d,α: the β anomer ratio of 3:2,2:1's is upright: calm fluorine structure ratio，The isomer produced by a small amount of calm fluorine structure represents with italic) 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),4.30-4.52(m,1H),3.96-4.27(m,6H),3.74(t,J=9.09Hz,0.66Hα),3.57/3.56(s,3H),3.49(t,J=9.09Hz,0.33Hβ),3.42/3.41(s,3H).MS(ES+)[M+NH₄]⁺=428。

Embodiment 10:(2S, 3R, 4R, 5S) synthesis of-2-[the chloro-3-of 4-(4-Hydroxy-benzvl)-phenyl]-6-methoxy-tetrahydro-pyrans-3,4,5-triol

A. the preparation of [4-(the chloro-benzyl of the bromo-2-of 5-)-phenoxy group]-t-butyl-dimethyI-sila:Preparation described in the U.S. Patent Application Publication 2006/0251728 of the Himmelsbach of this compound announcement in such as on November 9th, 2006 et al..

B. (S)-{ 3-[4-(tert-butyI-dimethyl-silicyl oxygen base)-benzyl] the chloro-phenyl of-4-}-[(3aS, 5S, 6R, 6aS)-6-(tert-butyI-dimethyl-silicyl oxygen base)-2,2-dimethyl-tetrahydro-furo [2,3-d] [1,3] dioxy Heterocyclic pentene-5-base]-methanol:0.85g (2.07mmol) derives from the compound of the step A solution in 4.14ml ether in an inert atmosphere be cooled to--78 DEG C.In 5 minutes, the tert-butyl lithium (1.55M, in hexane, 4.14mmol) of 2.66ml it is added thereto to by syringe.Reaction is stirred 30 minutes at-78 DEG C.Add 0.5g (1.65mmol) and derive from the compound of embodiment 1 step B solution in 1.65ml ether.This reactant mixture is stirred 30 minutes at-78 DEG C, stirs 1.5 hours at 0 DEG C subsequently.Thick reaction is filtered through silicagel pad, uses excessive ether, its vacuum is removed subsequently.The product obtained is at the diastereomer that secondary alcohol place is about 1.2:1 ratio being newly formed.Diastereomer easily passes through silica gel chromatography and separates (4 to 8% ethyl acetate/hexane gradient).Yield: 40% (desired diastereomer), 58% (less desirable diastereomer).

¹nullHNMR(400MHz,Chloroform-d) δ ppm7.17 (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-[the chloro-3-of 4-(4-Hydroxy-benzvl)-phenyl]-6-methoxy-tetrahydro-pyrans-3,4, The preparation of 5-triol:Chloroacetic chloride (0.17ml) joined in the methanol of 7ml and be stirred at room temperature 15 minutes.This solution is transferred to the bottle of the compound deriving from step B equipped with 0.446g, then seals and be heated to 80 DEG C, 1 hour.Reaction is cooled to ambient temperature and with 50ml saturated sodium bicarbonate aqueous solution quencher.Aqueous layer with ethyl acetate extracts (3x50ml).The organic layer washed with brine merged, dries with magnesium sulfate, and solvent removed in vacuo.Residue passes through Silica gel chromatography (0 to 20% ethanol/methylene gradient), obtains the mixture of α: the β anomer of about 1:1.Yield: 65%.

¹nullHNMR(400MHz,Acetone) δ ppm8.12 (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,0.5Hα),4.41(d,J=9.60Hz,0.5Hα),4.33(d,J=7.58Hz,0.5Hβ),4.19(d,J=9.35Hz,0.5Hβ),4.01(t,J=3.28Hz,2H),3.72(t,J=9.09Hz,0.5H),3.44-3.55(m,1H),3.41(s,1.5Hβ),3.35(s,1.5Hα),3.27-3.37(m,1.5H).MS(ES+)[M+NH₄]⁺=398。

Embodiment 11:(2S, 3R, 4S, 5R) synthesis of-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-ttetrahydro-pyran-3,4,5-triol

By toluene-4-sulfonic acid (S)-(tetrahydro-furan-3-base) ester (31mg, 0.126mmol) join the compound (16mg deriving from embodiment 10 step C, 0.042mmol) with cesium carbonate (46mg, 0.126mmol) the suspension in 0.22mlN, dinethylformamide.Reaction vessel is sealed and is heated to 80 DEG C, 15 hours.After cooling to room temperature, thick reactant mixture 2ml saline quencher and be extracted with ethyl acetate (3x2ml).The organic extract dried over sodium sulfate merged and vacuum concentration.Silica gel chromatography (0 to 10% ethanol/methylene gradient) obtains (2S, 3R, 4S, 5R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-ttetrahydro-pyran-3,4,5-triols, for sticky oil thing, it is concentrated in dichloromethane and obtains (10mg, 55% yield) as white solid.

¹nullHNMR(400MHz,Acetone) δ ppm7.35-7.41 (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,0.5Hα),4.42(d,J=9.60Hz,0.5Hα),4.33(d,J=7.58Hz,0.5Hβ),4.20(d,J=9.60Hz,0.5Hβ),4.05(t,J=2.53Hz,2H),4.05(d,J=5.31Hz,2H),3.93(dd,J=10.11,4.80Hz,1H),3.75-3.89(m,2H),3.72(t,J=9.09Hz,1H),3.50(t,J=9.09Hz,1H),3.41(s,1.5Hβ),3.35(s,1.5Hα),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) synthesis of-2-[the chloro-3-of 4-(4-Hydroxy-benzvl)-phenyl]-piperidines-3,4,5-triol

A. ((3aS, 5S, 6R, 6aS)-5-{ azido-[the chloro-3-of (S)-4-(4-ethyoxyl-benzyl)-phenyl]-methyl }- 2,2-dimethyl-tetrahydro-furo [2,3-d] [1,3] dioxole-6-base oxygen base)-tert-butyI-dimethyl-monosilane Preparation:To the C5 epimer (682mg, 1.24mmol) of alcohol and the PPh that derive from embodiment 1 step D₃(489mg, 1.87mmol) is subsequently added diphenylphosphoryl azide (DPPA, 323 μ l, 1.49mmol) at middle solution addition DIAD (366 μ l, 1.87mmol) of THF (6.2ml).Reaction is stirred 1.5 hours, uses saturated NH₄Cl aqueous solution quencher, uses Et₂O dilutes, and uses H₂O and salt water washing (carrying out back extraction), use MgSO₄Dry, and vacuum concentration.Residue passes through purified by flash chromatography (40gSiO₂0-8%EtOAc:Hex.), ((3aS, 5S are obtained, 6R, 6aS)-5-{ azido-[the chloro-3-of (S)-4-(4-ethyoxyl-benzyl)-phenyl]-methyl }-2,2-dimethyl-tetrahydro-furo [2,3-d] [1,3] dioxole-6-base oxygen base)-tert-butyI-dimethyl-monosilane (636mg, 1.11mmol, 89%), for yellow oil.

¹nullHNMR(400MHz,Chloroform-d) δ ppm7.40 (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),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+NH₄]⁺=591。

B. (2R, 3S, 4S, 5S)-5-{ azido-[the chloro-3-of (S)-4-(4-ethyoxyl-benzyl)-phenyl]-methyl }-four The preparation of hydrogen-furan-2,3,4-triol:Chloroacetic chloride (0.175ml, 2.45mmol) is joined in MeOH (7ml).By solution stirring 15 minutes, it is then added to derive from the azide (392mg, 0.68mmol) of step A.Reaction is stirred 16 hours, then vacuum concentration, and MeOH rotary evaporation 2 times, and be placed under fine vacuum, obtain white solid.At 100 DEG C by solid 1:1AcOH:H₂O (7ml) processes 2.5 hours.Will reaction vacuum concentration, and toluene rotary evaporation 2 times, and being placed under fine vacuum.Residue passes through purified by flash chromatography (40gSiO₂, 0-6%MeOH:CH₂Cl₂), obtain (2R, 3S, 4S, 5S)-5-{ azido-[the chloro-3-of (S)-4-(4-ethyoxyl-benzyl)-phenyl]-methyl }-tetrahydro-furan-2,3,4-triol (223mg, 0.53mmol, 78%), for the mixture of anomer.

¹HNMR(400MHz,MeOD)δppm7.39(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+NH₄]⁺=437。

C. the system of (2S, 3S, 4S, 5R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-piperidines-3,4,5-triol Standby:H at ambient pressure₂Under will derive from the compound (216mg, 0.52mmol) of step B at PtO in MeOH (5ml)₂(6mg, 0.026mmol) goes up and AcOH (0.25ml) hydrogenates 6 hours.Reaction being filtered, vacuum concentrates, and dilutes with EtOAc, uses 10%K₂CO₃Aqueous solution and salt water washing, use Na₂SO₄Dry, filter and vacuum concentration.By a part of material (about 55mg) by the property prepared HPLC (SunfireC1830x100mmcolumn, 20-70%MeCN:H₂O(10mMNH₄OAc), 15 minutes, 45ml/min) purification and lyophilizing, obtain (2S, 3S, 4S, 5R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-piperidines-3,4,5-triol (27mg, 0.071mmol), for white solid.

¹HNMR(400MHz,MeOD)δppm7.35(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-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-Ethanesulfinyl-ttetrahydro-pyran-3,4,5-triol and (2S; 3R; 4R, 5S, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-ethanesulfonyl-ttetrahydro-pyran-3; the synthesis of 4,5-triol

A. (2S, 3R, 4R, 5S, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-ethyl sulfur-tetrahydrochysene-pyrrole Mutter the preparation of-3,4,5-triol:NaSEt (84mg, 1.0mmol) is added at 0 DEG C of EtOH (5ml) solution to the bromide (291mg, 0.50mmol) deriving from embodiment 5 step B.Reaction is stirred 30 minutes, then dilutes with EtOAc, with rare NaOH solution washing with salt water washing (carrying out back extraction), use Na₂SO₄Dry, filter and vacuum concentration.Residue passes through purified by flash chromatography (40gSiO₂, 0-7%MeOH:CH₂Cl₂), it is suspended in H₂In O, and lyophilizing, obtaining (2S, 3R, 4R, 5S, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-ethyl sulfur-ttetrahydro-pyran-3,4,5-triols (126mg, 0.29mmol, 58%), for white powder.

¹nullHNMR(400MHz,Chloroform-d) δ ppm7.39 (d,J=8.08Hz,1H),7.18-7.26(m,2H),7.10(d,J=8.59Hz,2H),6.80-6.85(m,2H),4.46(d,J=9.60Hz,1H),4.17(d,J=9.35Hz,1H),3.98-4.11(m,4H),3.67-3.73(m,1H),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+NH₄]⁺=456。

B. (2S, 3R, 4R, 5S, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-Ethanesulfinyl-four Hydrogen-pyrans-3,4,5-triol and (2S, 3R, 4R, 5S, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-ethane sulphur The preparation of acyl group-ttetrahydro-pyran-3,4,5-triol:To derive from step A compound (10mg, 0.023mmol) AcOH (0.5ml) solution in add H₂O₂(the H of 35wt%₂O aqueous solution, 3mg, 0.092mmol, 9 μ l).Mixture is stirred then vacuum concentration in 2 hours in ambient temperature.Mixture passes through silica gel chromatography (5%MeOH/CH₂Cl₂) purification; obtain (2S; 3R; 4R; 5S, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-Ethanesulfinyl-ttetrahydro-pyran-3,4; 5-triol (being the mixture of diastereomer at sulfur place) (2mg; 19%) and (2S, 3R, 4R; 5S; 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-ethanesulfonyl-ttetrahydro-pyran-3,4,5-triol (5mg; 46%), both of which is white solid.

(2S, 3R, 4R, 5S, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-Ethanesulfinyl-tetrahydrochysene- Pyrans-3,4,5-triol: ¹nullHNMR(400MHz,Methanol) δ ppm7.37 (m,3H),7.31(m,1H),7.24(m,2H),7.10(m,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-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-ethanesulfonyl-tetrahydrochysene-pyrrole Mutter-3,4,5-triol: ¹HNMR (400MHz, methanol) δ ppm7.28 (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, 3H)；MS(ES+)[M+NH₄]⁺=488。

Embodiment 14: the synthesis of acetic acid (2R, 3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[the chloro-3-of 4-(4 ethyoxyls-benzyl)-phenyl]-2-methyl sulfur-ttetrahydro-pyran-3-base ester

A. (2S, 3R, 4R, 5S, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-methyl sulfur-tetrahydrochysene-pyrrole Mutter the preparation of-3,4,5-triol:0 DEG C to derive from embodiment 5 step B bromide (347mg, 0.60mmol) EtOH (6ml) solution in add NaSMe (70mg, 0.72mmol).Reaction is stirred 30 minutes, then dilutes with EtOAc, with rare NaOH solution washing and with salt water washing (carrying out back extraction), use Na₂SO₄Dry, filter and vacuum concentration.Residue passes through purified by flash chromatography (40gSiO₂, 0-7%MeOH:CH₂Cl₂), it is suspended in H₂In O, and lyophilizing, obtaining (2S, 3R, 4R, 5S, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-methyl sulfur-ttetrahydro-pyran-3,4,5-triols (212mg, 0.43mmol, 72%), for white powder.

¹nullHNMR(400MHz,Chloroform-d) δ ppm7.39 (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+NH₄]⁺=442。

B. acetic acid (2R, 3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-benzene Base] preparation of-2-methyl sulfur-ttetrahydro-pyran-3-base ester:The triol (45mg, 0.11mmol) deriving from step A processes 16 hours with the pyridine (0.5ml) comprising acetic anhydride (60 μ l, 0.64mmol).Reaction Et₂O dilutes, and uses 1MNaHSO₄Aqueous solution, H₂O, saturated NaHCO₃Aqueous solution and salt water washing (carrying out back extraction), use MgSO₄Dry, filter and vacuum concentration.Residue passes through purified by flash chromatography (4gSiO₂, 0-25%EtOAc/Hex), it is suspended in H₂In O, and lyophilizing, obtain acetic acid (2R, 3S, 4R, 5S, 6S)-4,5-diacetoxy-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-2-methyl sulfur-ttetrahydro-pyran-3-base ester (46mg, 0.087mmol, 79%), for white solid.

¹nullHNMR(400MHz,Chloroform-d) δ ppm7.36 (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),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+NH₄]⁺=568。

Embodiment 15:(2S, 3R, 4R, 5S, 6R) synthesis of-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-methane sulfonyl-ttetrahydro-pyran-3,4,5-triol

To derive from embodiment 14 step A compound (41mg, 0.097mmol) AcOH (0.5ml) solution in add H₂O₂(the H of 35wt%₂O solution, 20mg, 0.58mmol, 57 μ l).Mixture is stirred 18 hours in ambient temperature, then vacuum concentration.Mixture passes through Silica gel chromatography (5%MeOH/CH₂Cl₂), obtaining (2S, 3R, 4R, 5S, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-methane sulfonyl-ttetrahydro-pyran-3,4,5-triols (20mg, 45%), for white solid.

¹HNMR (400MHz, methanol) δ ppm7.28 (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+NH₄]⁺=474。

Embodiment 16:1-{ (2S, 3S, 4S, 5R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxy-piperidin-1-yl } synthesis of-ethyl ketone

1-{ (2S, 3S, 4S, 5R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxy-piperidines-1- Base } preparation of-ethyl ketone:To derive from embodiment 12 step C thick compound (38mg, 0.1mmol) MeOH (1mL) solution in add acetic anhydride (19 μ L, 0.2mmol).Reaction is stirred 4 hours, adds more acetic anhydride (10 μ L, 0.1mmol), and continue stirring overnight.React and dilute with EtOAc, use saturated NaHCO₃Aqueous solution and salt water washing, use Na₂SO₄Dry, filter and vacuum concentration.Residue passes through purified by flash chromatography (12gSiO₂, 0-8%MeOH:CH₂Cl₂), it is suspended in H₂In O, and lyophilizing, obtain 1-{ (2S, 3S, 4S, 5R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxies-piperidin-1-yl }-ethyl ketone (14mg, 0.033mmol, 2 step yields 33%), for white solid.

¹HNMR(400MHz,MeOD)δppm7.33(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) synthesis of-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxy-piperidines-1-carboxylic acid methyl ester

At 0 DEG C to the crude compound (38mg, 0.1mmol) and the NaHCO that derive from embodiment 12 step C₃(42mg, 0.5mmol) is at the EtOAc:EtOH:H of 1:1:1₂Solution in O (1.5mL) adds methylchloroformate (23 μ L, 0.3mmol).Reaction is stirred 1 hour, then dilutes with EtOAc, use H₂O and salt water washing (carrying out back extraction), use Na₂SO₄Dry, filter and vacuum concentration.Residue passes through purified by flash chromatography (4gSiO₂, 0-10%MeOH:CH₂Cl₂, it is suspended in middle H₂O, and lyophilizing, obtain (2S, 3S, 4S, 5R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxies-piperidines-1-carboxylic acid methyl ester (12mg, 0.026mmol, 26%, two step yield), for white solid.

¹HNMR(400MHz,MeOD)δppm7.32(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) synthesis of-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxy-piperidines-1-carboxylic acid allyl amide

Allyl isocyanate (18 μ L, 0.2mmol) is added to deriving from the crude compound (38mg, 0.1mmol) of the embodiment 12 step C solution in the EtOH:EtOAc (1mL) of 1:1.Reaction is stirred 1 hour, then vacuum concentration.Residue passes through purified by flash chromatography (4gSiO₂, 0-10%MeOH:CH₂Cl₂, it is suspended in H₂In O, and lyophilizing, obtain (2S, 3S, 4S, 5R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxies-piperidines-1-carboxylic acid allyl amide (14mg, 0.030mmol, 30%, two step yield), for white solid.

¹HNMR(400MHz,MeOD)δppm7.32(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) synthesis of-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-1-methyl-pi-3,4,5-triol

To the compound (50mg, 0.13mmol) and the K that derive from embodiment 12 step C₂CO₃(55mg, 0.40mmol) solution in DMF (0.65mL) adds iodomethane (10 μ L, 0.16mmol).Reaction is stirred 3 hours, then dilutes with EtOAc, use H₂O and salt water washing (carrying out back extraction), use Na₂SO₄Dry, filter and vacuum concentration.Residue passes through purified by flash chromatography (12gSiO₂, 2-12%MeOH:CH₂Cl₂), it is suspended in H₂In O, and lyophilizing, obtaining (2S, 3S, 4S, 5R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-1-methyl-pi-3,4,5-triols (16mg, 0.040mmol, 31%), for white solid.

¹HNMR(400MHz,MeOD)δppm7.35(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) synthesis of-2-[3-(4-ethyoxyl-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-pi-3,4,5-triol

A. (3R, 4S, 5R, 6R)-3,4,5-three (benzyl oxygen base)-6-(benzyloxymetliyl) tetrahydrochysene-2H-pyran-2-one Preparation:Four-O-benzyl-D-Glucopyranose. (2.07g, 3.8mmol) are dissolved in DMSO (10.1mL).Add acetic anhydride (7.0mL) to this mixture and be stirred at room temperature overnight.Add ice to reactant mixture and stir 1 hour.Mixture ether is extracted (3x20mL).Extract use water (2x10mL), sodium bicarbonate aqueous solution (2x10mL), salt water washing, dry (sodium sulfate) and vacuum concentration.Silica flash chromatography, uses 0-25% ethyl acetate/hexane, obtains (3R, 4S, 5R, 6R)-3,4,5-tri-(benzyl oxygen base)-6-(benzyloxymetliyl) tetrahydrochysene-2H-pyran-2-one (83%) of 1.712g.

B. (3R, 4S, 5R, 6R)-3,4,5-three (benzyl oxygen base)-6-(benzyloxymetliyl)-2-(4-chloro-3-(4-ethoxy Base benzyl) phenyl) preparation of tetrahydrochysene-2H-pyrans-2-alcohol:By n-BuLi, (2.5N, in hexane) (1.263mL, 3.16mmol) is added drop-wise to the compound (1.028g, 3.16mmol) deriving from embodiment 1 step C of-78 DEG C solution in anhydrous THF (15mL).After-78 DEG C are stirred 30 minutes, dropping derives from anhydrous THF (10mL) solution of the compound (1.7g, 3.16mmol) of step A and stirs 1 hour, makes its room temperature of rising again simultaneously.Joining in reactant mixture by aqueous ammonium chloride solution (10mL), vacuum removes THF, and aqueous layer with ethyl acetate is extracted (2x20mL).The organic phases washed with brine merged, dry (sodium sulfate) and vacuum concentration.Thick mixture passes through flash silica gel chromatography purification, use 0-20% ethyl acetate/hexane, obtain (the 3R of 712mg, 4S, 5R, 6R)-3,4,5-tri-(benzyl oxygen base)-6-(benzyloxymetliyl)-2-(the chloro-3-of 4-(4-ethoxy benzyl) phenyl) tetrahydrochysene-2H-pyrans-2-alcohol (29%).M+H₂O=802.1。

C. (2R, 3R, 4S)-2,3,4,6-four (benzyl oxygen base)-1-(the chloro-3-of 4-(4-ethoxy benzyl) phenyl) hexane- The preparation of 1,5-diketone:CH to the Dess-Martin reagent (500mg, excessive) of stirring₂Cl₂(10mL) solution adds containing the compound (500mg, 0.6mmol) deriving from step B) anhydrous methylene chloride (10mL) and stir overnight.Reactant mixture 1N sodium hydroxide (3mL) quencher, with dichloromethane extraction (2x10mL), the salt water washing of the organic extract liquid of merging, with dried over sodium sulfate, concentrating under reduced pressure, obtains thick product 487mg.(M+H₂O=800.1)。

D. (3R, 4R, 5S)-3,4,5-three (benzyl oxygen base)-2-(benzyloxymetliyl)-6-(4-chloro-3-(4-ethyoxyl Benzyl) phenyl) preparation of piperidines:The compound (400mg, 0.5mmol) of step C, the MeOH solution (1.0mL) of 7N ammonia and newly activation will be derived fromDichloromethane (20mL) solution at reflux overnight of molecular sieve (250mg).Reactant mixture is cooled to room temperature, is subsequently adding sodium cyanoborohydride (160mg, 2.55mmol) and other 2 hour of refluxing.Reactant mixture is filtered, dilutes with dichloromethane (20mL), with water, salt water washing, dry (sodium sulfate), and concentrating under reduced pressure.Chromatography (50 to 100% acetonitrile on silica gel, containing 0.1% ammonium acetate/water gradient), obtain (3R, 4R, 5S)-3,4,5-tri-(benzyl oxygen base)-2-(benzyloxymetliyl)-6-(the chloro-3-of 4-(4-ethoxy benzyl) phenyl) piperidines (136mg, 34%).

¹nullHNMR(400MHz,Chloroform-d) δ ppm1.41 (t,J=7.07Hz,3H)2.98(ddd,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-(benzyloxymetliyl)-6-(4-chloro-3-(4-ethyoxyl Benzyl) phenyl) preparation of-1-methyl piperidine:The compound (50mg, 0.065mmol) deriving from step D is dissolved in acetonitrile (1mL) and processes 30 minutes with potassium carbonate (18mg, 0.13mmol).Add iodomethane (20 μ L, 0.32mmol) to this mixture and stir overnight.Reactant mixture ethyl acetate (10mL) is diluted, with water, salt water washing, dry (sodium sulfate), and vacuum concentration.Silica gel chromatography (50 to 100% acetonitrile, containing 0.1% ammonium acetate/water gradient), obtain (3R, 4R, 5S)-3,4,5-tri-(benzyl oxygen base)-2-(benzyloxymetliyl)-6-(the chloro-3-of 4-(4-ethoxy benzyl) phenyl)-1-methyl piperidine (29mg, 56%).MH+782.1.

F. (2S, 3S, 4R, 5R, 6R)-2-[3-(4-ethyoxyl-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-pi- The preparation of 3,4,5-triol:At H₂Under atmosphere, the compound (50mg) deriving from step E in methanol and acetic acid (25 μ L) is processed 4 hours with the wet Pd-C (10mg) of 5%.Reactant mixture is filtered through Celite pad and concentrates.Chromatography (10 to 100% acetonitrile, containing 0.1% ammonium acetate/water gradient) on silica gel obtains (2S, 3S, 4R, 5R, 6R)-2-[3-(4-ethyoxyl-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-pi-3,4,5-triols (6mg, 70%).

¹nullHNMR(400MHz,Chloroform-d) δ ppm1.40 (t,J=6.95Hz,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) synthesis of-2-(the chloro-3-of 4-(4-ethoxy benzyl) phenyl)-6-methoxyl group tetrahydrochysene-2H-thiapyran-3,4,5-triol

A. (S-(1S)-((3aS, 6S, 6aS)-6-(t-butyldimethylsilyl oxygen base)-2,2-dimethyl tetrahydro furan Mutter also [2,3-d] [1,3] dioxole-5-base) (the chloro-3-of 4-(4-ethoxy benzyl) phenyl) methylthiobenzoate Preparation:At room temperature diethylazodicarboxylate (150 μ L, 0.914mmol) is joined the triphenyl phasphine (240mg, 0.914mmol) solution in the THF of 1.0mL.After one hour, it is added in the C5 epimer (167mg, 0.305mmol) deriving from embodiment 1 step D in 0.5mLTHF by syringe, adds thiobenzoate (110 μ L, 0.914mmol) by syringe subsequently.This orange solution is stirred at room temperature 22 hours.After solvent removed in vacuo, residue passes through purified by flash chromatography (0 to 10% ethyl acetate/hexane gradient), obtains title compound, for light yellow oil (104mg, 50% yield).MS(ES+)[M+NH₄]⁺=566。

B. (2S, 3R, 4R, 5S, 6R)-2-(the chloro-3-of 4-(4-ethoxy benzyl) phenyl)-6-methoxyl group tetrahydrochysene-2H-thiophene Mutter the preparation of-3,4,5-triol:Feldalat NM (the 4.3M methanol solution of 0.3mL) is joined the compound (104mg, 0.152mmol) deriving from step A solution in 6mL methanol.After 30 minutes, reaction is used 20mL diluted ethyl acetate and washs with water and saline (respectively 20mL).Organic layer magnesium sulfate dries, and filters and solvent removed in vacuo.Residue directly uses to prevent disulphide from being formed readily through purified by flash chromatography (5% ethyl acetate/hexane) and product.

A droplet chloroacetic chloride joined in the methanol of 1mL and be stirred at room temperature 15 minutes.This acid solution joined in free mercaptan obtained above and heat 42 hours at 80 DEG C.Reaction is cooled to room temperature and solvent removed in vacuo.Thick residue by prepare property HPLC purification (30x250mmC18 post, 5 75% acetonitriles: water (10mM ammonium acetate), 15 minutes, 45mL/min), obtain title compound (α anomer, t=13.82 minute, 8.7mg, 13% yield, two step yields).

¹HNMR (400MHz, acetone-d₆)δppm7.33(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+NH₄]⁺=424。

Embodiment 22:(2S, 3S, 4R, 5R, 6R) synthesis of-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-Hydroxymethyl-piperidine-3,4,5-triol

A. (2R, 3R, 4S, 5R, 6S)-3,4,5-three-pi-allyl oxygen base-2-allyloxymethyl-6-methoxyl group-four The preparation of hydrogen-pyrans:NaH (the mineral oil dispersion of 60%, 3.34g, 0.14mol) is added in DMF (50ml) solution of α-D-methyl glucoside (3g, 15.45mmol).In adition process, form dense suspension, add the DMF (15ml) of additional quantity to revert to solution.After being stirred at room temperature 30 minutes, mixture is cooled to 0 DEG C and is slowly added to allyl bromide, bromoallylene (17g, 0.14mol, 12ml).Then mixture is made to rise again room temperature and stir 18 hours.Add MeOH with the excessive NaH of quencher to light brown mixture carefully, then mixture is concentrated.Residue CH₂Cl₂Dilute and use H₂O washs, dry (MgSO₄) and concentrate, obtain yellow oil.(2R, 3R, 4S, 5R is obtained by Silica gel chromatography (20%EtOAc/ hexane), 6S)-3,4,5-tri--pi-allyl oxygen base-2-allyloxymethyl-6-methoxy-tetrahydro-pyrans (4.06g, 11.47mmol, 74%), for colorless oil.TLC:R_f=0.20,20%EtOAc/ hexane.

B. (3R, 4S, 5R, 6R)-3,4,5-three-pi-allyl oxygen base-6-allyloxymethyl-ttetrahydro-pyran-2-alcohol Preparation:AcOH (400ml) solution warms to 90 DEG C of the compound (10g, 0.028mol) of step A will be derived from.Add the TfOH (H of 2N₂O solution, 16.69g, 0.112mol, 56ml) and mixture is stirred 75 minutes at 90 DEG C.Solution is cooled down and uses CH₂Cl₂Dilution, uses H₂O (x3), saturated NaHCO₃Solution washing, dry (MgSO₄) and concentrate, obtain yellow solid.(3R is obtained by Silica gel chromatography (20%-40%EtOAc/ hexane), 4S, 5R, 6R)-3,4,5-tri--pi-allyl oxygen base-6-allyloxymethyl-ttetrahydro-pyran-2-alcohol, mixture (5.85g for anomer, 17.2mmol, 61%), for white solid.TLC:R_f=0.40,40%EtOAc/ hexane.

C. (3R, 4S, 5R, 6R)-3,4,5-three-pi-allyl oxygen base-6-allyloxymethyl-ttetrahydro-pyran-2-ketone Preparation:Oxalyl chloride (2.75g, 21.7mmol, 1.89ml) is dissolved in CH₂Cl₂(90ml)-78 ° of C it are cooled in and by mixture.It is added in CH₂Cl₂(60ml) DMSO (3.39g, 43.4mmol, the 3.08ml) solution in.Mixture is subsequently adding at CH-78 DEG C of stirrings for 15 minutes₂Cl₂(150ml) solution of the compound (6.70g, 19.7mmol) deriving from step B in.Reactant mixture is stirred other 15 minutes at-78 DEG C and adds Et₃N(9.97g,98.5mmol,13.7ml).Mixture is stirred other 5 minutes at-78 DEG C, then makes its room temperature of rising again in 30 minutes.By reaction H₂O quencher and separate organic layer, uses H₂O washes twice, and dries and concentrates, obtaining light yellow oil.(3R, 4S, 5R is obtained by Silica gel chromatography (15%EtOAc/ hexane), 6R)-3,4,5-tri--pi-allyl oxygen base-6-allyloxymethyl-ttetrahydro-pyran-2-ketone (2.49g, 7.37mmol, 37%), for colorless oil.TLC:R_f=0.40,20%EtOA_c/ hexane.

D. (3R, 4S, 5R, 6R)-3,4,5-three-pi-allyl oxygen base-6-allyloxymethyl-2-[4-chloro-3-(4-second Oxygen base-benzyl)-phenyl] preparation of-ttetrahydro-pyran-2-alcohol:The compound (2.37g, 7.31mmol) deriving from embodiment 1 step C is dissolved in THF (25ml) and is cooled to-78 DEG C.Dropping n-BuLi (hexane solution of 2.5N, 0.47g, 7.31mmol, 2.92ml) by solution stirring 15 minutes.Reactant mixture is also stirred other 15 minutes by the solution of the compound (2.47g, 7.31mmol) deriving from step C being added in THF (25ml) at-78 DEG C, then makes its room temperature of rising again in 30 minutes.Reaction is used saturated NH₄Cl solution quencher and separate organic layer.Water layer Et₂The Organic substance of merging is also dried and concentrates by O back extraction, obtain yellow oil, (3R, 4S, 5R is obtained by Silica gel chromatography (10%-20%EtOAc/ hexane), 6R)-3,4,5-tri--pi-allyl oxygen base-6-allyloxymethyl-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-ttetrahydro-pyran-2-alcohol (0.95g, 1.63mmol, 22%), for colorless oil.MS(ES+)[M+NH₄]⁺=602。

E. (2R, 3R, 4S)-2,3,4,6-four-pi-allyl Oxy-1-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-oneself The preparation of alkane-1,5-diketone:CH to the compound (0.93g, 1.59mmol) deriving from step D₂Cl₂(25ml) solution adds Dess-Martin periodide (0.68g, 1.59mmol).Mixture is stirred at room temperature 1 hour, is subsequently adding the Dess-Martin periodide (1 equivalent) of Part II.Continue other 1 hour of stirring, then by reaction 1NNaOH (～4ml) quencher.Add H₂O also separates organic layer.Water layer CH₂Cl₂Back extraction, dries and concentrates, obtaining yellow, waxy solid.(2R is obtained by Silica gel chromatography (15%-20%EtOAc/ hexane), 3R, 4S)-2,3,4,6-tetra--pi-allyl Oxy-1s-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-hexane-1,5-diketone (0.60g, 1.03mmol, 65%), for white solid.MS(ES+)[M+NH₄]⁺=600。

F. (2R, 3R, 4R, 5S, 6S)-3,4,5-three-pi-allyl oxygen base-2-allyloxymethyl-6-[chloro-3-(4-of 4- Ethyoxyl-benzyl)-phenyl] preparation of-piperidines:To derive from step E compound (0.60g, 1.03mmol) MeOH (12ml) solution in addMS, is subsequently added ammonium formate (0.13g, 2.06mmol).Then disposable addition NaBH₃Mixture is also stirred at room temperature 1 hour 30 minutes by CN (0.14g, 2.3mmol).Then reactant mixture filtered and concentrate.(2R is obtained by Silica gel chromatography (10%-20%EtOAc/ hexane), 3R, 4R, 5S, 6S)-3,4,5-three-pi-allyl oxygen base-2-allyloxymethyl-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-piperidines (155mg, 0.27mmol, 27%).MS(ES+)[M+H]⁺=568。

G. (2S, 3S, 4R, 5R, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-three-[((E)-the third Thiazolinyl) oxygen base] preparation of-6-[((E)-acrylic) oxygen ylmethyl]-piperidines:By Ir (the COD) [PCH in THF (0.3ml)₃Ph₂]PF₆(8mg, 30mol%) is at H₂Stirred under argon, until color becomes light yellow (～5 minutes) from redness.It is subsequently adding the compound (19mg, 0.033mol) deriving from step F in THF (0.5ml) and mixture is stirred at room temperature 45 minutes, then concentrating.(2S is obtained by Silica gel chromatography (20%EtOAc/ hexane), 3S, 4R, 5R, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-tri--[((E)-acrylic) oxygen base]-6-[((E)-acrylic) oxygen ylmethyl]-piperidines (15mg, 0.026mmol, 80%), for colorless oil.MS(ES+)[M+H]⁺=568。

H. (2S, 3S, 4R, 5R, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-Hydroxymethyl-piperidine-3, The preparation of 4,5-triol:The compound (15mg, 0.026mmol) deriving from step G is dissolved in THF/AcOH/1NHCl solution (0.2ml:0.3ml:0.15ml) and is heated to 70 DEG C, 30 minutes.Mixture is concentrated, obtains light yellow oil.By the property prepared HPLC purification (sunfireC18,30x100mm, 5 μm, 10%-100%B, in 15 minutes) obtain (2S, 3S, 4R, 5R, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-Hydroxymethyl-piperidine-3,4,5-triol (5mg, 0.012mmol, 46%), for white solid.MS(ES+)[M+H]⁺=408。

¹HNMR (400MHz, MeOD) δ ppm7.36 (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) synthesis of-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-pi-3,4,5-triol

A. (2R, 3R, 4R, 5S, 6S)-3,4,5-three-pi-allyl oxygen base-2-allyloxymethyl-6-[chloro-3-(4-of 4- Ethyoxyl-benzyl)-phenyl] preparation of-1-methyl-pi:To derive from embodiment 22 step F compound (135mg, 0.24mmol) MeCN solution in add K₂CO₃(164mg,1.19mmol).Stir the mixture for 30 minutes being subsequently adding MeI (676mg, 4.76mmol).Continue to be stirred at room temperature 8 hours, then mixture filtered and concentrate.(2R is obtained by Silica gel chromatography (10%EtOAc/ hexane), 3R, 4R, 5S, 6S)-3,4,5-tri--pi-allyl oxygen base-2-allyloxymethyl-6-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-1-methyl-pi (90mg, 0.15mmol, 65%), for colorless oil.MS(ES+)[M+H]⁺=582。

B. (2S, 3S, 4R, 5R, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-1-methyl-3,4,5-three- The preparation of [((E)-acrylic) oxygen base]-6-[((E)-acrylic) oxygen ylmethyl]-piperidines:By Ir (the COD) [PCH in THF (1ml)₃Ph₂]PF₆(27mg, 30mol%) is at H₂Stirred under argon is until color becomes light yellow (～5 minutes) from redness.It is subsequently adding THF (1.5ml) solution of the compound (62mg, 0.11mol) deriving from step A being stirred at room temperature by mixture 45 minutes then to concentrate.(2S is obtained by Silica gel chromatography (20%EtOAc/ hexane), 3S, 4R, 5R, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-1-methyl-3,4,5-tri--[((E)-acrylic) oxygen base]-6-[((E)-acrylic) oxygen ylmethyl]-piperidines (62mg, 0.11mmol, 100%), for colorless oil.MS(ES+)[M+H]⁺=582。

C. (2S, 3S, 4R, 5R, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-hydroxymethyl-1-methyl- The preparation of piperidines-3,4,5-triol:The compound (54mg, 0.093mmol) deriving from step B is dissolved in THF/AcOH/1NHCl solution (0.5ml:0.6ml:0.30ml) and is heated to 70 DEG C, 30 minutes.Mixture is concentrated, obtains light yellow oil.By the property prepared HPLC purification (sunfireC18,30x100mm, 5 μm, 10%-100%Bover15 minute) obtain (2S, 3S, 4R, 5R, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-pi-3,4,5-triol (22mg, 0.052mmol, 56%), for white solid.MS(ES+)[M+H]⁺=422。

¹HNMR (400MHz, MeOD) δ ppm7.31 (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).

Other compound

Use method described herein and methods known in the art, the other compound enumerated in preparation table 1 below.Powerful SGLT2 inhibitor asterisk labelling.

Table 1

Vitro human SGLT2 inhibition test

People's sodium/glucose cotransporter 2 type (SGLT2, registration number P31639, GI:400337) is cloned into (structure: HA-SGLT2-pIRESpuro2) in the pIRESpuro2 carrier for mammal expression.

By the transfection of HEK293 cell employment HA-SGLT2-pIRESpuro2 carrier the cell line selecting body stable (bulkstable) under the existence of 0.5 μ g/ml puromycin.People's HA-SGLT2 cell is maintained in the DMEM culture medium comprising 10%FBS, 1%GPS and 0.5 μ g/ml puromycin.

Being seeded in the DMEM culture medium in 384 orifice plates (30,000 cells/well) by the HEK293 cell expressing people HA-SGLT2, DMEM culture medium comprises 10%FBS, and 1%GPS and 0.5 μ g/ml puromycin, then at 37 DEG C, 5%CO₂Lower overnight incubation.Then by cell picked-up buffer (140mMNaCl, 2mMKCl, 1mMCaCl₂,1mMMgCl₂, 10mMHEPES, 5mMTris, 1mg/ml bovine serum albumin (BSA), pH7.3) washing.When being with or without test compound, the picked-up buffer of 20 microlitres is joined in cell.Then, will comprise¹⁴The 20 microlitre picked-up buffer of C-AMG (100nCi) join in cell.By cell plates at 37 DEG C, 5%CO₂Middle cultivation 1-2 hour.After by cell with picked-up buffer solution, add scintillating liquid (40 microlitres/hole) and use scintillation counter (TopCoulterNXT；PackardInstruments) Count radioactivity is measured¹⁴C-AMG absorbs.

Vitro human SGLT1 inhibition test

People's sodium/glucose cotransporter 1 type (SGLT1, registration number NP_000334, GI:4507031) is cloned into (structure: HA-SGLT1-pIRESpuro2) in the pIRESpuro2 carrier for mammal expression.

HEK293 cell employment HA-SGLT1-pIRESpuro2 carrier is transfected, and selects to pile up stable cell line under the existence of 0.5 μ g/ml puromycin.People's HA-SGLT1 cell is maintained in the DMEM culture medium comprising 10%FBS, 1%GPS and 0.5 μ g/ml puromycin.

Being seeded in the DMEM culture medium in 384 orifice plates (30,000 cells/well) by the HEK293 cell expressing people HA-SGLT1, DMEM culture medium comprises 10%FBS, 1%GPS and 0.5 μ g/ml puromycin, then at 37 DEG C, 5%CO₂Lower overnight incubation.Then by cell picked-up buffer (140mMNaCl, 2mMKCl, 1mMCaCl₂,1mMMgCl₂, 10mMHEPES, 5mMTris, 1mg/ml bovine serum albumin (BSA), pH7.3) washing.When being with or without test compound, the picked-up buffer of 20 microlitres is joined in cell.Then, also will comprise¹⁴The 20 microlitre picked-up buffer of C-AMG (100nCi) join in cell.By cell plates at 37 DEG C, 5%CO₂Middle cultivation 1-2 hour.After by cell with picked-up buffer solution, add scintillating liquid (40 microlitres/hole) and use scintillation counter (TopCoulterNXT；PackardInstruments) Count radioactivity is measured¹⁴C-AMG absorbs.

Calculate IC₅₀Value

Compound is measured for the IC of targeting by using LevenburgMarquardt algorithm that related data is fitted to below equation₅₀:

y=A+((B-A)/(1+((C/x)^D)))

Wherein A is minimum Y value；B is maximum y value；C is IC₅₀；It is slope with D.The XLFit4 software (IDBusinessSolutionsInc., Bridge water, NJ08807) for MicrosoftExcel 205 types of this software (aforesaid equation be) is used to carry out IC₅₀Calculating.

Intra-body data: Pentamethylene oxide. based compound

Make in aforementioned manners, determine the Pentamethylene oxide. based compound of the present invention IC to people SGLT1 (HSGLT1), mice SGLT2 (MSGLT2) and people SGLT2 (HSGLT2)₅₀.These data provide in table 2 below:

Table 2:SGLTIC₅₀(μM)

Intra-body data: piperidinyl compounds

Make in aforementioned manners, the impact on people SGLT1 (HSGLT1), mice SGLT2 (MSGLT2) and SGLT2 (HSGLT2) of the piperidinyl compounds of the mensuration present invention.These data provide in table 3 below:

Table 3:SGLTIC₅₀(μM)

The internal effect of compound

That continue 45% high fat diet and the drug treating that is housed in Nalgene metabolic cage respectively and that vehicle processes c57 albinism male mice is used to measure the pharmacotoxicological effect of the compounds of this invention.Mice arbitrarily obtains the paste (2 portions of meals are to 1 part of water) of drinking water and high fat diet.

Deliver compound in two ways.First, at first day it was medicine or the vehicle of mice tube feed 5ml/kg dose volume.Whole urine volume are collected in the plastics UCD of metabolic cage 24 hours subsequently.Carry out the measurement of the body weight of mice, amount of drinking water, feed intake (the moisture evaporation considering in paste) and urine volume every day.Collect urine every day, centrifugal, and use Cobas autoanalyzer to evaluate concentration of glucose.The final result of the glucose in milligrams number of excretion every day is calculated from total urine volume and urine concentration of glucose.

In the second approach, compound is delivered in meals.This is undertaken by being blended in the paste of high fat diet by test compound with suitable concentration, it is contemplated that baseline weight and baseline feed intake.The paste comprising medicine is also with excessive offer every day.The amount of the compound that every day delivers is calculated by calculating the weight of animals and feed intake.

Fig. 1 represent with the single oral dose of 30mg/kg to the compound of the used time present invention on dosage to the impact of the amount of the glucose of excretion in 24 hours period afterwards.By contrast, control animal drained about 1mg glucose in 24 hours.The compound of indication explanation in table 4 below in Fig. 1.

Table 4

Above-mentioned all open (such as, the patents and patent applicationss) quoted are incorporated in its entirety here.

Claims (10)

1. the compound of following formula:

Or its pharmaceutically useful salt, wherein:

Y is (C (R₅)₂)_p；

R₁For R_1A；

Each R_1AIndependently be hydrogen；

R₂For OR_2A；

R_2AFor hydrogen；

R₃For hydrogen or C_1-4Alkyl；

R₅For hydrogen；

R₆For hydrogen or halogen；

R₇For hydrogen or OR_7A；

R_7AFor C_1-4Alkyl；

M is 1；

N is 1；With

P is 1.

2. compound, it is selected from:

(2S, 3S, 4S, 5R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxy-piperidines-1-carboxylic acid benzyl ester；

(2S, 3S, 4S, 5R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxy-piperidines-1-carboxylic acid allyl amide；

(2S, 3S, 4S, 5R)-1-benzyl-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-piperidines-3,4,5-triol；

2-{ (2S, 3S, 4S, 5R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxy-piperidin-1-yl }-acetamide；

(2S, 3S, 4S, 5R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-1-isobutyl-piperidine-3,4,5-triol；

(3S, 4R, 5R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-6-Hydroxymethyl-piperidine-3,4,5-triol；

(2S, 3S, 4S, 5R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxy-piperidines-1-carboxylic acid methyl ester；

(2S, 3S, 4S, 5R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-1-methyl-pi-3,4,5-triol；With

(2S, 3S, 4R, 5R, 6R)-2-[the chloro-3-of 4-(4-ethyoxyl-benzyl)-phenyl]-3,4,5-trihydroxy-6-Hydroxymethyl-piperidine-1-carboxylic acid methylamide.

3. pharmaceutical preparation, including the compound of claim 1 or 2 and pharmaceutically useful diluent or excipient.

4. the compound of the claim 1 or 2 of effective dose application in the medicine that preparation is used for suppressing active for SGLT2.

5. the compound of the claim 1 or 2 of effective dose application in preparing the medicine for reducing patient blood glucose.

6. the compound of the claim 1 or 2 of effective dose is used for increasing the application in the medicine that in Urinary, glucose is drained in preparation.

7. the compound of the claim 1 or 2 of effective dose application in the medicine of the insulin sensitivity prepared for recovering patient.

8. the compound of the claim 1 or 2 for the treatment of or prevention effective dose is in preparation for treating, tackle or prevent the application in the disease of patient or the medicine of disease, and wherein said disease or disease are cardiovascular disease, 1 type or type 2 diabetes mellitus or obesity.

9. the application of claim 8, wherein disease or disease are atherosclerosis, hyperglycemia, hypertension, dyslipidemias or X syndrome.

10. the application of claim 8, wherein disease or disease are type 2 diabetes mellitus.