TW457246B - Dimeric small molecule selectin inhibitors comprising of (mannopyranosyloxy)biphenyl-substituted carboxylic acid - Google Patents

Abstract

The present invention provides compounds having the structure below: wherein X is selected from the group consisting of -CH, -(CH2)nCO2H, -(CH2)nCONHOH, -O(CH2)mCO2H, -O(CH2)mCONHOH, -(CH2)nCONHNH2, -(CH2)nCOZ, -(CH2)nZ, -CH(CO2H)(CH2)mCO2H, -(CH2)nO(CH2)mCO2H, -CONH(CH2)mCO2H, -CH(OZ)(CO2H), -CH(Z)(CO2H), -(CH2)nSO3H, -(CH2)nPO3D1D2, -NH(CH2)mCO2H, -CONH(CHR3)CO2H, (1-H-tetrazoly1-5-alkyl-), and -OH; for divalent structures, Y is -(CH2)f-, -CO(CH2)fCO-, -(CH2)fO(CH2)f-, -CO(CH2)fO(CH2)fCO-, -(CH2)gS(O)b(CH2)fS(O)b(CH2)g-, -CO(CH2)gS(O)b(CH2)fS(O)b(CH2)gCO-, -(CH2)fV(CH2)f-, -(CH2)fCOVCO(CH2)f-, -CO(CH2)COVCO(CH2)fCO-, -CO(CH2)fV(CH2)fCO-, -CONH(CH2)fNHCO-, -CO(CH2)fW(CH2)fCO-, -(CH2)fWSW(CH2)f-, -(CH2)fCONH(CH2)fNHCO(CH2)f-, -(CH2)fCOW(CH2)fWCO(CH2)f-, or -CH2(CH2)fW(CH2)fCH2- where V is -N[(CH2)q]2N- and q is independently 2 to 4, and W is aryl or heteroaryl; for trivalent structures, Y is: and T is selected from the group consisting of -(CH2)f-, -CO(CH2)f-, -(CH2)gS(O)b(CH2)f-, and -CO(CH2)gS(O)b(CH2)f-, where the carbonyl group is positioned contiguous to the biphenyl unit; R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, halogen, -OZ, -NO2, -(CH2)nCO2H, -NH2 and -NHZ; R3 is selected from the group consisting of hydrogen, alkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkyl carboxylic acid and alkyl carboxamide; f is 1 to 16, g is 0 to 6, n is 0 to 6, m is 1 to 6, p is 0 to 6, b is 0 to 2, Z is alkyl, aryl or aralkyl, and D1 and D2 are independently hydrogen or alkyl, and the pharmaceutically acceptable salts, esters, amides and prodrugs thereof. The present invention further provides a method of inhibiting the binding of E-selectin, P-selectin, or L-selectin to sLex or sLea comprising administering to a patient an effective amount of a compound of the present invention and to pharmaceutical compositions containing a compound of the present invention.

Description

457246 Printed by A7 B7, Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs 5. Description of the Invention (1) Technical Field The present invention relates to inhibiting the binding of E-selectin, P-selectin or L-selectin to salivary-Louis x (sialyl-Lewisx) or sialyl-Lewisa compounds and use of these compounds to inhibit d-selectin, P-selectin or L-selectin from binding to sialyl-Lewis X or sialyl-Lewis Method of taxi 3. The present invention also relates to a pharmaceutical composition containing a compound that inhibits the binding of E, p or l-selectin to sialic acid-Lewis x or sialyl-Lewis a. Background of the invention E-selectin (also known as ELAM-1, which is an endothelial lymphocyte-adsorbing molecule_1, and also known as LECAM-2, which is a glycoprotein-adsorbing molecule) is a cool protein molecule that was discovered It is present on endothelial cells arranged on the inner wall of microvessels. E-selectin recognizes and binds the sialoyl-Lewis X (sLex) carbohydrate located on specific white blood cells. E-selectin can help white blood cells recognize and attach to the wall of the microvascular tube when the tissue surrounding the microvessel is infected or injured. E · selectin is one of the three currently known selectins. The other two are L-selectin and ρ_selectin. ρ_selectin is expressed on endothelial tissues and platelets. It is very similar in structure to E_selectin and can also recognize salivary-Lewis X. L_selectin is expressed on the lymphosphere, and is structurally similar to selectin? _Selectin is very similar. Saliva-Lewis X and saliva-based, the structure of Louis a (sLea) is expressed by the following formula and Ib: This paper is from the Standard for Financial Professionals (CNS) A4 ((Please read the precautions on the back before filling This page}-Order 457246 A7 B7 V. Description of the invention (sLex

Neu5Ac α2-3 Gal β1-4 GIcNac- I Fuca1-3 la sLea

HO HO HO

HO AcHN (Please read the notes on the back before filling out this page)

NeuSAc a2-3 Gal β1-3 GIcNac- Fuca1-4 lb -5- The size of this paper is Chinese National Standard (CMS) A4 (210 X 297 mm) A7 B7

Revised Page of Chinese Specification for Patent Application No. J (September 1987) V. Description of Invention (3) (Read the precautions on the back of the first cabinet and then fill out this page) When a tissue is invaded or injured by microorganisms, white blood cells ( (Also known as Limba Ball) plays a very important role in the inflammatory response. One of the most important reactions in the inflammatory response involves the event of cell attachment. White blood cells generally appear in the circulating blood stream. However, when a tissue is infected or injured, white blood cells must be able to identify the affected or injured tissue, and be able to combine with the inner walls of microvessels adjacent to the affected tissue, and then penetrate through the microvessel to enter the affected tissue. Inside. P-selectin helps two specific white blood cells to identify the affected part and binds to the inner wall of microvessels, so that these white blood cells can penetrate into the affected composition. -White blood cells are mainly divided into three types: granules, monocytes and lymphocytes. In the above classification, E-selectin recognizes sLex present as glycoproteins or glycolipids on neutrophils and monocytes. Neutrophils are a subtype of granules that can engulf and destroy small microorganisms, especially bacteria. After passing through the wall of the microvessel and leaving the blood stream, the single plant bulb will mature into giant cells and decompose and break down the invading microorganisms, foreign objects and aging cells. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. When tissues surrounding good microvessels are infected or injured, E-selectin will be produced on the surface of endothelial cells on the inner wall of microvessels. Mononuclear spheres and neutrophil particles can pass through E-selectin binds to identify injured tissue. Basically, when tissues adjacent to the microvessels are affected, the production of E-selectin and P-selectin increases. P-selectin is continuously present in storage granules and can be quickly transferred to the cell surface when the endothelial layer is activated. In contrast, E-selectin requires the synthesis of its own RNA and protein, and it peaks in about 4-6 hours after activation, and gradually decreases to -6 after about 24-48 hours-this paper size is applicable to China Standard (CMS) A4 specification (210X 297 mm) 丨 revised supplement 4 5_ £ i4s Yang patent application Chinese manual amendment page (S7 September) 5. Description of the invention (basic level. White blood cells can identify the affected The region is because the sLex part on the surface of white blood cells will bind to E-selectin and p-selectin. This form of binding will make the speed of white blood cells in the blood flow slower, because this binding occurs during integration Prior to the contact and migration of the integrin medium, the sacral ball was rolled along the activated endothelial layer, thereby helping the white blood cells to be confined to the injured or infected area. When the white blood cells migrated to the injured site, they assisted against When infecting and destroying foreign substances, the accumulation of excessive white blood cells can cause damage to the tissues of the vast majority of the gardens. Therefore, compounds that can block this process may act as It is a therapeutic substance. It may be useful to develop inhibitors that prevent the binding of leukocytes to E-selectin or p-selectin. For example, some diseases that can be treated by inhibiting the combination of selectin and sLex include (But not limited to), Crohn's disease, septic shock, invasive shock, multiple organ failure ', autoimmune disease' asthma, inflammatory bowel disease, dry addiction, rheumatoid arthritis and its occurrence In heart disease, stroke, and reperfusion injury after organ transplantation. SLea—a regiochemical isomer that is not related to SLex, except that it is found on some white blood cells In addition, sLea has also been found on many cancer cells, including lung and rectal cancer cells. It has been thought that the cell adsorption effect of 31 # may also be involved in the metastasis of specific cancer cells. US Patent 5,44 VII. 50. Described is a mannanosylbiphenyl substituted derivative which can be used as a selectin inhibitor and a method for preparing the same. However, it does not disclose the divalent or trivalent The formulations of the invention, the present invention has fully made on the compound of formula 11 and the structure of the pharmaceutically acceptable salts, esters, Amides and prodrugs thereof: (Read precautions and then fill the back side of this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs · Printed by the company 457246 A7 B7 Five 'Invention (5)

(Please read the notes on the back before filling out this page) The consumer cooperation agreement of the Central Standards Bureau of the Ministry of Economic Affairs is printed in which the X group is selected from the group consisting of -CN,-(CH2) nC02H,-(CH2) nCONHOH, -0 (CH2) mC02H, -0 (CH2) mCONHOH,-(CH2) nCONHNH2,-(CH2) nCOZ,-(CH2) nZ, -CH (C02H) (CH2) mC02H,-(CH2) nO (CH2) mC02H5- C0NH (CH2) mC02H, -CH (0Z) (C02H), -CH (Z) (C02H), < CH2) nS03H, -CXCHAPOgDiE ^, -NH (CH2) mCO2H, -C0NH (CHR3) CO2H, (lH -Tetrazolyl-5-alkyl-), and -OH; when it is a divalent structure, Y is-(ch2) ", -CO (CH2) fCO-,-(CH2) {0 (CH2) r, -COfCH ^ gSCO ^ CH ^ fSCO ^ CH ^ gCO-,-(CH2) fV (CH2) r,-(0Η2) ^ 〇ν0Ο (ΟΗ2) Γ, -COCC ^^ OVCOCC ^ fCO-, -CO (CH2) fV (CH2) fCO-s -C0NH (CH2) ^ HC0-,-(CH2) fWSW (CH2) r,-(CHyfCONHCCi ^ piHCCKCHyf,-(ayfCOMCHdfWCCKCKyr, or -8-) This paper size applies to Chinese National Standard (CNS) A4 specifications (210 X297 mm) 4 57 246 'A7 B7 Printed by the Shell German Consumer Cooperative of the Central German Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (6) -CH / CHjfWCCHjfCiV where V is -N [(CH2) q] 2N- And q is 2 to 4 respectively, and W is aryl or heteroaryl; when it is a trivalent structure Y is:

And the T group is selected from the group consisting of-(CH2) f-, -CO (CH2) fs-(CH2) gS (0) b (CH2) f-, and -C0 (CH2) gS (0) b (CH2) f-, wherein the carbonyl position is adjacent to the biphenyl unit;

Rj and R_2 are each selected from :: nitrogen 'group' dentin '. -0Z, -NO2, (CH2) nC02H, -NH2 &-NHZ; R3 is selected from: hydrogen, alkyl, aralkyl, Hydroxyalkyl, aminoalkyl, alkylcarboxylic acid, and alkylcarboxamide; f is 1 to 16, g is 0 to 6, η is 0 to 6, m is 1 to 6, and p is 0 to 6, b is 0 to 2, Z is an alkyl group, an aryl group or an aralkyl group, and D2 is a hydrogen group or a hydrogen atom. More specifically, the present invention proposes a compound of formula III: -9 ™ This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

457246 A7 B7 V. Description of the invention (

m where X is -COOH,-(CH2) nCOOH or -0 (CH2) nC00H and Y is-(CH2) n-,-(CH2) nW (CH2) n-,-(CH2) nWOW (CH2) n- ,-(CH2) nS (CH2) nS (CH2) n-, -CO (CH2) nCO-, or-(CH2) nCOW (CH2) nWCO (CH2) n-, and W and n are defined as above. (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs -10- This paper size is in accordance with China National Standards (CNS) A4 (210X297 mm) Central Bureau of Standards, Ministry of Economic Affairs Printed by Employee Consumer Cooperative 457246 a? ______B7 V. Description of Invention (8) Particularly good compounds include:

Β

Η (Please read the notes on the back before filling in this page)

、 1T This paper uses China National Standards (CNS) standard M (210 × 297 mm) 457246-V. Description of the invention (9)

Ministry of Economic Affairs Central Marking Bureau M0: Printed by Industrial and Consumer Cooperatives

-12- (Please read the precautions on the back before filling in this page) Λ 'Order 0 This paper size applies to Chinese National Standard (CNS) A4 specification (2IOX297 mm)' 4 5 7 2 4 Α7 Β7 V. Description of the invention (10) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs The present invention also proposes a pharmaceutical composition comprising a compound of formula II or formula III and a pharmaceutically acceptable carrier. The invention further proposes a method for inhibiting the combination of E-selectin, P-selectin or L-selectin with sLex or sLea. The method is to administer an effective amount of a compound having the structure of formula II or formula III to a patient to inhibit E-, A combination of P- or L-selectin and sLex or a combination of P-selectin and sLea, and a pharmaceutically active composition comprising a compound of formula II or formula III and a pharmaceutically acceptable carrier. The compounds of the present invention are useful for applications such as ARDS, local ileitis, septic shock, invasive shock, multiple organ failure, autoimmune diseases' asthma, inflammatory bowel disease, psoriasis, rheumatoid arthritis and Heart Disease, Stroke, Organ Transplantation and Reperfusion Injury Disease after Cancer 'The therapy is to give the animal treated with an effective therapeutic amount of a compound of formula II or formula III to alleviate the symptoms of the disease. Detailed description of preferred embodiments We have found that compounds having the structure of formula (II) above can inhibit the binding of E_, p- or selectin to sLex or sLea. As used herein, the term "alkyl" refers to a monovalent linear or branched group having 1 to 2 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, isopropyl Propyl, n-butyl, secondary butyl, isobutyl, tertiary butyl and the like. The term "lower alkyl" means any alkyl group having one to six carbon atoms. &Amp; The term "dentin" means any element selected from the group consisting of chlorine, fluorine, bromine and iodine. -13 -This paper size applies to China National Standard (CNS) mm (please read the precautions on the back before filling this page): "

• Printed by 1T U- Printed by the Central Bureau of Standards, Ministry of Economic Affairs and Consumer Cooperatives 457246 A7 B7 V. Description of the Invention (^) The term " burnt oxygen " Basic circles, including (but not limited to) methoxy, ethoxy, isopropoxy, n-butoxy, secondary butoxy, isobutoxy, tertiary butoxy and the like. The term "alkylamino" refers to a group having the structure of _NH_ (alkyl), or _N (alkyl) 2. Examples include methylamino, ethylamino, 4propylamino, and the like. Term & quot Aromatic group, | means an aromatic group of a carbocyclic ring, which includes (but is not limited to) phenyl, 1 or 2-naphthyl, fluorenyl, (1,2) -dihydrosulfanyl, indenyl, hydrogen Pingyl, p-secenyl, phenyl-p-phenenyl, etc. The term "aralkyl" (also known as aromatic alkyl) refers to an aromatic group attached to an alkyl group, including (but not limited to) benzyl Methyl, methyl, halomethyl ', alkoxybenzyl, hydroxybenzyl, aminobenzyl, nitromethyl, guanidino, methyl, methylphenyl, phenylmethyl (benzyl), Phenylethyl, 2-phenylethyl, 1-triethyl and so on. The term "hydroxyalkyl" refers to a hydroxyl group attached to an alkyl group. Aminoalkylalkyl "refers to a group attached to an alkyl group with a _NRxRy structure. Groups 1 and Ry is selected from the group consisting of, for example, hydrogen, base, and aromatic. The term "alkylcarboxylic acid" refers to a carboxyl group (_CO2H) attached to an alkyl group. The term "aminomethylamine" refers to a group having a _CONRXRy structure attached to an alkyl group, and 1 and Ry are as defined in the aforementioned aminoalkyl group. The term used herein "medically "Acceptable salts, esters, amines and prodrugs" means the carboxylates, amino acid addition salts, esters, enzyme amines and prodrugs of the compounds of the present invention (if possible, including Compound 14 of the present invention The paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page)

A7 B7

4 5 7 Revised page of the Chinese manual for the patent application No. 5 (September 87) V. Description of the invention (12 Zwitterionic salt printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs) applies to Contact with tissues without undue toxicity, irritating, overly constrictive responses, and have a reasonably reasonable benefit / risk ratio of 4 and its use for its intended application. The term " "Salts" refers to the inorganic and organic acid addition salts of the compounds of the present invention which are relatively non-toxic. These salts can be prepared at the same time as the final isolation and purification of the compound, or the purified compound can be freed separately. The form is reacted with an appropriate organic or inorganic acid or base, and then the salts formed thereby are isolated. Representative salts include bromate, hydrochloride, sulfate, bisulfate, nitrate, acetate, Oxalate, valerate, oleate, standard palmitate, stearate, cinnamate, rotten salt, benzoate, lactate, phosphonate, methylbenzoate, Citrate, maleate, fumarate , Succinate, tartrate, gallate, formate, glucoheptonate, lactiobionate, cinnamon sulfonate, etc. ^ It can also contain metal or Earth metal cations, such as sodium, Syria, but, mai, hafnium, etc., and typical toxic ammonium, quaternary ammonium and amine cations including (but not limited to) ammonium, tetramethylammonium, tetraethylammonium, methylamine Amines, ethylamines, difluorenylamines, difluorenylamines, diethylamines, ethylamines, etc. (See, for example, SM Berge et al., "Medical salts_'j. Pharm ~ 66;! _ I? (I977), which is listed here as a reference material) Pharmaceutically acceptable, examples of non-toxic esters of the compounds of the present invention include Ci's pentyl group, which is a straight chain Or with a bell. Acceptable vinegars also include C5 to (: 7 cycloalkyl esters) and aromatic groups such as (but not limited to) hexyl. The more preferred are (^ to ^ alkyl esters α -15- The compound of the present invention is applicable to the paper size _ Jiaxian (CNS) A4 specification (21QX2_ Chu) 457246 Member of the Central Standards Bureau of the Ministry of Economic Affairs Consumption cooperative seal A7 ---_! Z___ V. Description of the invention (13) Vinegars can be prepared according to conventional methods. Pharmaceutically acceptable, examples of non-toxic amidines of the compounds of the present invention include derivatives derived from ammonia, First-order 〇 to <: 5 alkylamine 'and second-order (^ to £: 6-alkyl amine amine' in which the alkyl group is linear or branched. In the example of the secondary amine, the The amine may be a 5- or 6-membered heterocyclic ring containing one nitrogen atom. Preferred are ammonium amines derived from ammonia, (^ to (: 3 alkyl primary amidines and (^ to (: 2 dialkyl amidines). The amidines of the compounds of the present invention can be prepared according to conventional methods. The term " prodrug " refers to a compound that can be transformed in the body immediately (for example, by permanent dissolution in blood) into the parent compound of the above formula β τ Xiqi (T. HigucM) & V. Stella in "Previous Drugs as Novel Drug Delivery Systems" Volume 14 of the "A. cs Seminar Series" and at Edward B. Roche (Edward B. Roche) Edited 'American Pharmaceutical Association and Pergamon Press (American Pharmaceutical Association and Pergamon Press) published in 1987 "in drug design Convertible vehicle body "is discussed in whole redundant, both of the above are hereby incorporated by reference materials. The invention also proposes a medicinal composition containing a compound of the invention. The present invention also intends to propose that the medicinal composition contains a compound of the present invention and other compounds, and the composition can inhibit the combination of selectin or p-selectin with sLex or sLea, or compete with sLex or sLea. In combination, the composition may also contain sLex or sLea itself. The medicinal composition of the present invention comprises a physiological carrier and a compound of formula π or in. The medicinal composition of the present invention may include one or more compounds having the above-mentioned structure of formula π or III and one or more non-toxic, physiologically acceptable -16- North Korea countries; quasi (CNS) A4 specification (210X297 mm) ---------- (Please read the notes on the back before filling in this education)

-V

'IT r 457246 V. Description of the invention (ι4) A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, a planting agent, adjuvant' or a medium (collectively referred to herein as a carrier)-prepared for use = injection 'Made in solid or liquid form for oral administration, topical administration, etc. The composition can be taken orally, rectally, by injection (intravenously, intramuscularly, or inferiorly), intracranially, intravaginally, intraperitoneally, topically (powder, ointment, or drops), or intraorally or via inhalation ( Nebulized, or formulated as an intranasal spray for administration to humans or animals. Compositions suitable as injections may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders. Formulated into a solution or dispersant. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), and suitable mixtures thereof Vegetable oils (such as olive oil and cannola oil) and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained by the use of coating agents such as ovum fat, or in dispersants The required particle size is maintained using surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Various antibacterial agents and Mold agents such as paraben, chlorobutanol, phenol, sorbic acid, etc. can effectively prevent bacteria. It can also contain isotonic agents, such as sugar, sodium carbonate, etc. Injectable pharmaceutical forms that can prolong absorption can be achieved by using agents that delay absorption (such as aluminum monostearate and gelatin). If necessary, and for more effective delivery, these compounds can be incorporated into a sustained release or Timed release or specific target drug delivery systems, such as polymer media 'microlipids, and microspheres. This type of composition can be adapted to the Chinese National Standard (CNS) M specifications (210X29? Gongchu;〉 (Please read the notes on the back before filling in this page)

457246 A7 B7 V. Description of the invention (15) Sterilized by, for example, filtering a layer of bacteria-retaining filter membrane, or sterilizing with sterile water or other sterile injectable medium immediately before use . Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the effective compound is either a prodrug ester and at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate, or (a) a filler Or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, saccharose, and gum arabic , (C) humectants, such as glycerin, (d) disintegrating agents, such as agar's calcium breaking acid, potato or tapioca starch, alginic acid, specific silicate complexes, and sodium carbonate, (e ) Dissolution delaying agents, such as paraffin, (f) Accelerators, such as quaternary ammonium compounds, (g) Wetting agents, such as cetyl alcohol and glyceryl monostearate, (h) Adsorbents, such as kaolin and Silica, (丨) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium cinnamyl sulfate or mixtures thereof. In the case of capsules, tablets and pills, these dosage forms may also contain buffering agents. The solid type composition printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives can also be filled into soft or hard gelatin capsules. The excipients used can be lactose or milk sugar and high molecular weight polyethylene glycols. Wait. Solid dosage forms such as lozenges, dragees, capsules, pills, and granules can be made with film coatings and shells, such as enteric coatings and others known in the art. These coatings may contain opacifying agents, and may also be a composition that controls the delayed release of the main component compound in specific parts of the intestinal tract. Can be used -18- This paper standard is in accordance with the Chinese National Standard (CNS > A4 size (210X297)) Employees ’Central Standards Bureau, Ministry of Economic Affairs, Consumer Consumption f ± 中 紧 # 57246 at B7 V. Description of Invention (16) Package Examples of coating compositions are polymeric substances and waxes. If appropriate, the effective compounds can also be microencapsulated with one or more of the aforementioned formulations. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions , Suspension, syrup and elixir. In addition to the effective compound, the liquid dosage form may contain inert diluents commonly used in this technology, water or other solvents, co-solvents and emulsifiers, such as ethanol, isopropanol , Ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn germ Oil, olive oil, cannola oil, ramie oil and sesame oil, glycerin, tetrafuryl alcohol, polyethylene glycols and fatty acid esters of sorbose or mixtures of these compounds, etc. ^ Except Inert In addition to diluents, adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances may be included in these compositions. In addition to effective compounds, suspending agents may also contain Suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, silica-coated earth, agar and tragacanth or their Mixtures of substances, etc .. Preferred compositions for rectal administration are suppositories. Suppositories may be obtained by combining the compound of the present invention with a suitable non-irritating excipient or vehicle such as cocoa butter, polyethylene glycol or A suppository is made by mixing wax. The suppository is solid at normal temperature but liquid at body temperature, so it will be melted in the rectum or cavity to release active ingredients. This paper rule New Zealand® I National Standard隼 (_CNS) A4 specifications ((Please read the note on the back before filling this page)

Rev. -19-157246 A7 ___ B7 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (17) Dosage forms for topical administration of the compounds of this invention include ointments, powders, sprays and inhalants. The active ingredient can be exchanged with a physiologically acceptable carrier and any needed preservatives, buffers or propellants under sterile conditions as needed. Ophthalmic formulations, eye ointments, suspensions, powders, and solutions are all incorporated into the scope of the present invention. The compounds of the present invention may also be administered in the form of microfat granules. It is known to those skilled in the art that microlipids are derived from phospholipids or other fatty substances. Microlipids are formed by dispersing single or multiple hydrated liquid crystals in a water-soluble medium. Any liposome that can form microlipids and is non-toxic, physiologically acceptable and metabolizable can be used. In addition to the selectin binding inhibitor of the present invention, the present composition in the form of microlipids may further include a stabilizer, a preservative, an excipient, and the like. Preferred fats are natural or synthetic lipids or phosphocholin (lecithin). The method for forming the liposomes is well known to those skilled in the art. The actual dosage of the main ingredients of the composition of the present invention may vary depending on the particular composition used and the method of administration thereof, and the amount of the main ingredients required to achieve a therapeutic effect. Therefore, the dosage chosen will depend on the desired effect, the route of administration, the period of treatment required, and other factors. The compounds of the present invention are administered in one or several divided doses-the total daily dosage of each host ranges from about 0.3 mg to 50 mg per kg of body weight. Unit-dose composition divided into several doses per day is then distributed according to this daily dose range to achieve the daily dose Φ. However, I understand that the specific dose given to any particular patient (whether human or animal) depends on many factors, including weight, health status, gender, diet, time and route of administration, smoking ___ -20- This paper applies the China National Standard (CNS) A4 specification (21 () > < 297 Gong ^ --- ~ (Please read the precautions on the back before filling this page) IV. Order _ -or.! 457246 Α7 Β7 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (18) The rate of collection and excretion, combined with other drugs and the severity of specific diseases. In particular, the compounds of the present invention can be used to treat many and inflammation Diseases related to cell and cell recognition and contact. For example, the compounds of the present invention can be administered to patients for the treatment of septic shock, chronic inflammatory diseases such as psoriasis, rheumatoid arthritis and heart disease, stroke And reperfusion injury after organ transplantation, invasive shock, multiple organ failure, autoimmune disease, asthma, inflammatory bowel disease. In each case it will be an effective amount The compound of the invention is used alone or as part of a pharmacologically effective composition for administration to a patient in need of the treatment. I also understand that a combination of these compounds can also be administered to a patient in need of the treatment. The present invention The compounds can be used for the treatment of diseases that are in contact with cells. Since the compounds of the present invention inhibit the binding of E-selectin or p-selectin to SLex, anything related to such interactions Diseases may be treated by inhibiting this binding interaction. In addition to being found in some white blood cells, sLea is also found in many cancer cells, including lung and rectal cancer cells. I hypothesize that it is related to SLea Cell contact may be related to the migration of cancer cells, so sLea binding inhibitors may be used to treat certain forms of cancer. Many of the compounds of the present invention can be synthesized according to the following synthetic schemes. ____ -21-(CNS) (210 × 297 ^ ίΤ (Please read the precautions on the back before filling in this page) -'IT 'η £ r 4 S 7 2 Λ 6 Α7 _ Β7 Economic + Economic. -5) 1 Shiyang sample rate for monthly labor consumption Co., Ltd. as the five homes, description of the invention (19) Scheme 1

In this solution, a substituted dibenzyl (US Patent No. 5,444,050) is reacted with a diacid halide to obtain a diaryl dione. The preferred examples include a straight chain with 5 to 16 broken atoms and Branched diacid gaseous compounds. These compounds can be transported by one of several methods known to those skilled in the art, such as catalytic argonization, Wolff-Kishncr reduction, metal halide Such as triethylsilane, or the compounds produced by the reduction of Clemensen (1) -22-This paper size is applicable to Zhong Zhou's family sample China {CNS) A4 size (210X21) 7 moments) ( Please read the soap on the back of the-^ before copying the tile.] Order 457246 A7 B7 V. Description of the invention (20) lies at 0. (: At room temperature, the halogenated solvent is affected by the action of boron Conversion to phenols 1. A protected mannose unit is used to carry out sugar taste in the presence of trifluoride shed ether compounds, and then the desired compound 1 can be obtained by experimental hydrolysis. Scheme 2

reduction

MeO

8 OMe

1. BuU. Z Pd (0) X S (0Me) 3

iX (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 1. BBr3

2. {R〇) sMan, BF3 * OEU or (RO ^ Man-F, BF3 * 0Et) 3. Jiang Bao 1 Jin 23- The standard of this paper is applicable to China National Standard (CNS) A4 (210X 297 mm), ， 4572 4 0 A7 -----____ B7 V. Description of the invention (21) In certain cases, we can also construct a linker between the two soils (before the ring is connected with a carboxylic acid ring). It is then replaced with a mannose unit on the ring. For example, in this scheme, a 4- (4-methoxyphenyl) butanoic acid is first converted to acid chloride using thionyl chloride, and then Fry The Friedel-Craft reaction is reacted with methoxybenzene to obtain ketone 1. Compound i can be obtained by reducing the ketone using any of many different methods known to those skilled in the art. The methoxy group After ortho-lithiation, it can be converted to boronic acid and then obtained by palladium-diaryl coupling. After demethylating the ethers, it is glycosylated and deprotected. The target compound is 10. & (Please read the notes on the back before filling this page) r Central Bureau of Standards, Ministry of Economic Affairs Cooperatives fee scale printing equipment -24- This paper applies t National Standards (CNS) A4 size (2 〖0X297 mm) 457246 A7 B7 V. invention is described in (22) Option 3 Ministry of Economic Affairs Bureau of the Central Falcon ladder employees consumer cooperatives printed

In other cases, it is best to use a compound such as ϋ (U.S. patent (please read the precautions on the back before filling this page) Λ '* βτ. -25- This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) A7 B7 457246 V. Description of the Invention (23) Case No. 5,444,050, in which a glycosyl moiety is already attached thereto) The Dao-Fried Kraft reaction is exemplified, for example, tritium can be No 'H + island-shi- 醍 孖 彺 τ can be treated with succinic acid to obtain keto acid U ° The keto group is reduced by one of many methods known to those skilled in the art to obtain the acid, which is then gasified Thiosulfur is converted into acid fluoride 11 at low temperature (or other methods) in a production solvent. The acid chloride is then reacted with various primary or secondary amines (especially such as ethylene diamine, hexapyrine, homopiperazine, 4,4 · -trimethylene dihexahydro, or The reaction of one of the amines of other-diaminodiamine) can give a polyvalent compound such as jj_. Reduction of amidine in an oxidizing solvent at low temperature with stilbene or other appropriate reagents, followed by hydrolysis of the protecting group to obtain the desired compound, or amidine may be directly hydrolyzed to obtain amidine 12 υ square 窠 4 ( Please read the back note first and then fill in the Hongdong tile) k --- by Huang Langzhong Chuan ^ κ Industry and Consumer Cooperatives India

23 -26-The paper is full of paper. General Chinese girl's lapel (f: M;) 8 4 size (21ϋχ m 公 + 楚) 457246 B7 Central Ministry of Economic Affairs-# quasi? Printed by Employee Consumer Cooperatives 5. Description of the Invention (24) Compounds containing ether linkages can be made according to Scheme 4. The ether esters (18) are oxidized into ethers and then self-condensed to obtain ethers (12_), which are then converted into acid chlorides (@. In sequence via Fryd-Kraft coupling and reduction , Demethylation, sugar stationation and deprotection to obtain ethers (H). Scheme 5

-27- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (谙 Please read the notes on the back before filling this page) 457246 A7 B7 V. Description of invention (25) In some cases, It is possible to prepare other compounds according to a series of reactions shown in Scheme 5. Therefore, '1_ can be obtained by carrying out the Fletcher-Kraft reaction of other halogenated acid chlorides, such as 3-bromopropionic acid fluoride. The benzyl ketone can be reduced by one of the methods well known to those skilled in the art to obtain the gaseous compound ϋ. Compound g can be obtained by reacting g with 1,3-propane dithiol, or other appropriate disulfide in the presence of a suitable base. Dehydration can be achieved by one of a number of methods, in particular by boron tribromide in a halogenated solvent at a low temperature to obtain phenol red. The phenols are re-used with boron trifluoride etherate in a halogenated solvent and reacted with a protected mannose bowl. The compound can be obtained by removing the protecting group with an alkaline aqueous solution. An oxidizing agent such as m-peroxybenzoic acid is obtained in a suitable solvent. Treatment with an alkaline aqueous solution gives the final compound pull. Option 6 ‘(Please read the notes on the back before filling this page) Order Printed by the Consumers’ Cooperative of the Standards Bureau, Ministry of Economic Affairs

CCH2) f -28- This paper is in accordance with applicable standards (CNS) from the specifications (2 Huan 297 public magic -ml i-I — I — I —, " 45724 〇 A7 B7

Me. - 1

. * Β8Γ3 V. Description of the invention (26) In other cases, the intermediate] ^ with a diacid chloride in the presence of gasification of aluminum or other appropriate Lewis acid in Fide 'Kraft The reaction yields U. The final compound can be obtained by deprotecting the mannose moiety with an aqueous solution of hydrogenide or an aqueous solution of methoxide followed by an aqueous solution of hydroxide. Option 7 (CH2) £ · -Ph (Please read the notes on the back before filling this page) k'_

AlClj

L, 3r5-Ph

Jo 0H l # 3, S-Ph 2, (RO) sMan, BF3 * Et2〇or (RO) 4Man-F, BF3 * Et2〇 to protect and subscribe to the Ministry of Economic Affairs Central Standards Bureau Off-line Consumer Cooperatives Print 35 in this plan Among them, a substituted biphenyl (J_, US Patent No. 5,444,050) is reacted with a triacid chloride to obtain benzyl ketone 21. These ketones can be reduced by one of many methods well-known to those skilled in the art (listed in Scheme 1). The resulting compound is deglycosylated, glycosylated and then deprotected to obtain the desired compound g. -29- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 4 · 5 7 2 15686 Patent Application 4 5 7 2 4 ^ Revision Sheet (September 1987) V. Description of the invention (Option 8 27

(CHj) mS {CH2J / -1,3,5-Ph 33 < Please read the notes on the back before filling out this page) Order a similar method to Fryde 11 with bromoalkyl bromide- Kraft reaction is available. The bromofluorene is reacted with i, 3,5_ substituted I benzenetrithiol in the presence of a compound to obtain a compound. The desired compound (21) can be obtained after the protecting group is hydrolyzed. The present invention can be illustrated by the following representative examples: Example 1 M-bis- [3- (3-Epimethylphenyl) -4- (2 -a -D- Said mannosyloxy) phenyl] hexane Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Step 1: Adipic acid chloride (2.0 g, 10.9 mmol) was first dissolved in 丨, 2 Dichloroethane (55 ml) was cooled in an ice bath. Add gasified aluminum (58 g, 43 5 mmol) followed by methyl 3- (2-methoxyphenyl) phenylacetate (575 g, 22.4 mmol) [Τ. Ρ. 柯 甘, B. Doupier, IL Scott, K. Keller, D. Dow, and P. Baker, U.S. Patent No. 5,444,050 and T_P. Cogan 30-This paper is applicable to China Standard (CNS) Α4 Regulations (210 × 297 mm) Printed by the Central Consumer Bureau of the Ministry of Economic Affairs and Consumer Cooperatives r 45724b A7 B7 V. Description of the Invention (28), B, Du Pier, KM Xunle, I_L. Scott, H. Commoner R, V. Machit * 卩 'J. Zhenke, J, A. Voith, M. Reeve and D. Scott, [Med_ Chcm. 1995, 38 : 4976-49841 The mixture is then stirred at room temperature for 30 minutes, and then mixed with ice water (30 ml). After the organic matter was separated, the aqueous part was extracted with methane gas (3 X 5 ml. After the organic matter was combined, it was dehydrated (MgS04.) And concentrated under reduced pressure. The residue was subjected to flash chromatography (Si02, from hexane to 3: 3).丨 Hexane / ethyl acetate gradient dissociation) to obtain the product (2.23 g, 33%). Ll · INMJl (400MHz, CDCi3): 7.96 (£ l £ J, J = 6.6S 1,9 Hz, 2H) , 7,92 (d, J ~). 9 Hz: 2H), 7.42 (m, 2H) 7 7.34 (t, J-6 Hz, 2H): 7.18-7.28 (m, 4TI), 7.00 (d, J -6.3] [/, 2H), 3,87 (s, 6Π), 3.69 (s, 6H) · 3.68 (s: 4H), 3 0 丨 (m, 4TI), LS4 (m, 4H) ppm TR (MaCl): 1741, 1677 cm · 1 c Step 2: Part A: The product obtained from step 1 (2.23 g, 3,6 mmol) was dissolved in acetonitrile and then lithium hydroxide (0.8 g.丨 8 millimolar lice lithium oxide monohydrate in 8 ml of water) treatment :: Kun compound was stirred at room temperature overnight, then acidified to pH 4 τ with 2N HC1 and then extracted with ethyl acetate. Combined The extract was dehydrated (1 ^ 804) and then reduced and concentrated. Ut (NaCl): Π11, 1677 cm · 1. Part B: Keto acids (1.86 g, 3 Λmmol) ) Dissolved in di-fmidine (15 ml) and mixed with hydrazine (.0 ml, 3] millimolar) 5 The mixture was heated under nitrogen in a SOT: 2,5 hours' and then cooled. Tertiary potassium butoxide (3.5 g, 31 mmol) was added, and the mixture was heated to 80 ° C under a nitrogen atmosphere until meteoric night, then mixed with water (30 ml) and acidified with 2N HC1. Extract with ethyl acetate ^ Combine the extracts, and dehydrate (Μβ〇4) The paper is used according to the standard ®® furniture? M OJS Λ 4 gauge (2 U1 x mm (count the first cry on the back) Matters fill out this page again)

457246 Α7 Β7 V. Description of the invention (29) Subtracting I and concentrating to obtain 1 (1.6 g, 91%) D iR (NaCl): 1713 cm · 1. Step 3: Part A: The diacid (L6 g, 2.8 moles) obtained in step 2, part B is dissolved in dichloromethane (14 ml) in nitrophene, and then placed on dry ice / 2-propane Cool in the bath. Slowly add boron tribromide (1 ΛmL, 14 mmol); the mixture is stirred at room temperature for 2 hours, and then mixed with ice-water (25mL) = after the organic matter is separated, it is shaved and carbonic acid Aqueous hydrogen solution (20 ml), water (20 ml), saturated brine (20 ml), washed and dehydrated (MgS04) and concentrated under reduced pressure to 5 Γ to obtain 2.38 g of crude product = part B: from part A The obtained residue was strictly combined with methanol (50 liters), sulfuric acid (5 drops) was added to the mixture, and the mixture was heated to reflux temperature overnight, and then concentrated under reduced pressure. The residue was dissolved in methane (50 ml) and treated with sodium carbonate, and then filtered through a layer of silica gel. The filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography (Si02, from hexane to 3: 1 hexane / ethyl acetate). Ester gradient dissociation) purification of 1,6-bis- (3- (3-foxycarbonylmethylbenzylM-lightbenzyl) hexane (0.9 g, 38%). H NMR (400 MHz. , CDC13): 6.BO-7.50 (m, 14H), 3.70 (s, 6H), 3,68 (S. 4H). 2.55 (dd, J = 5, S, 5,5 Hz, 4H), 1.59 (m, 4H), 1.36 (m, 4H) ppm ^ 1R (NaCl): 3430, 1731 cm'J ^ Miscellaneous death of the Ministry of Economic Affairs and Economic Cooperation ^ Wac Industry and Consumer Cooperation Du Yingan I —l · --_ n I n I ^ ^ -I (Xu Xianyi Wen # 1 & Note '£ _item again ^ this page) Step 4: 1,6 · bis- (3- (3-methoxycarbonylmethylbenzyl) -4 -Hydroxybenzyl) hydrazone (0.9 g, 1,6 mmol) dissolved in 1,2-digas ethane (8 ml) β-Ammonium D-mannose pentaacetate (1.9 g τ 4.8 mmol) Mol) was added in one portion, then boron trifluoride etherate (2,5 ml f 19,2 mmol) was slowly added. The mixture was stirred overnight at room temperature under a nitrogen atmosphere, and then water (5 After separating organic matter in ml The extraction aqueous solution (3 x 2 ml) was made with two gas T. The apple extract was combined with the original organic part, and dehydrated after dehydration, and the pressure was reduced to 7 waves. -32- KJlii Ke in this paper {CNS ) A4 Tag (2ί〇 × 297mm) Printed by the Industrial and Commercial Bureau of the Ministry of Economic Affairs, China Industrial Cooperative Cooperative 4 5 7 2 4 6 A7 B7 V. Description of the invention (30) Shrink. The residue is subjected to flash chromatography ( s 丨 〇2 'From hexadecimal to 3: hexadecyl hexanoate hexanoate gradient dissociation) purification can be obtained 丨 = 6-bis- (3__oxanylmethylphenyl) -4 (forty-ethyl Base-finding-many mannosyl) oxy group base has been wan * (1.5 S f 77%) ^ II NMR (400 ΜΠζ, CDC13): 7.31-7.3 ^ (m, 6n) s 7.19- 7.24 (m, 4H), 7.09-7.13 (m, 4H), 5.25 (d: J-0.6 Hz, 2H), 3.57-3.66 (m, 6H), 3,3-3.50 (m; 10H), 2, 54 (m, 4H) f l.5fi (m, 4II) fl, 34 (m: 4H) jppm. TR (NaCl): 1752 cm · 1. Step 5: Saccharin (1.5 g, 1.2 mols) were dissolved in acetonitrile < 6 ml), and then treated with an aqueous solution of lithium hydroxide monohydrate (1.0 g ^ 24 mmol) in water (10 ml), and the mixture was transferred at Xuan temperature Overnight It was acidified to pH 2 u with concentrated hydrochloric acid, and the mixture was concentrated under reduced pressure, and then purified by HPLC (reverse phase, gradient dissolution with 5-50% acetonitrile in water '> 乂 254 nm monitoring) to obtain a white solid. , 6-bis- (3- (3-kismethylphenyl) -4- (2wL > pyranosyloxy.) Phenyl J hexane, hydrazone, (0'35g, 33%), m. p: 115-1 I7'C:! H NMR (400 MHz, CDCl3): 7.31-7.37 (m, 6H), 7.19-7.24 (m, 4H); 7.09-7.13 (m7 4H), 5.25 (d, J ^ 0.6 Hz, 2H)? 3,57-3.66 (m; 6Π), 3.3-3,50 (m, 10H), 2.54 (m, 4H),) .58 (m: 4H), 1-34 (m : 4ΤΪ) ppm, IR (KBr): 3420T 17) 1 cm'1 nf Example 2 Bis- [3- (3-carboxyf-based benzyl) -4- (2 ^ -D-grumannosyloxy) Benzyl] hexane, disodium sulfonium (another method) Step 1: Diethyl ether (16.8 ml, 112 mmol) and methyl 3- (2-methoxybenzyl) benzylacetate ( 60-9 grams, 225 millimoles) dissolved in methane (300 milliliters) and cooled at 0 ° C n added aluminum nitride (67,7 grams' (Yun Yun ¾ read the back of -ΐίι-Xiang Zai) (Fill in this page), y9 33 This original wave standard is applicable to China S passenger standard (CNS> Λ4 specifications (2 [〇Χ2! ^ 公 楚) 457246 A7 B7 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (31) 507 millimoles), stir at (TC for 5 minutes and then add ice to stop the reaction. The product was extracted with EtOAc (1 liter) and then washed with water (500 liters), saturated aqueous sodium bicarbonate solution (50 ml), and saturated brine (50 ml). The solution was dehydrated with Na2SO4 and filtered through a layer of sulfuric acid. After concentration, it was recrystallized from acetic acid / ethyl acetate to obtain saint, (64 · 7 g, 89%). Step 2: Dissolve bis-ketone 1 (15 g, 23.1 mmol) into hot EtoAc / EtOH (4: 1, 100 ml). As a result, the resulting solution was cooled and then added with difluoroethylene fe (1 ml) and Pearlman's catalyst (0.75 g). The mixture was shaken under a hydrogen atmosphere (50 psi) for 18 hours, and then filtered through a layer of celite. The solution was extracted and washed with a saturated aqueous solution of sodium bicarbonate and water'saturated brine, and then dehydrated with MgS04 and concentrated. Toluene was evaporated with the product to remove ethyl acetate, and then dried under high vacuum to quantitatively obtain 1,6-bis- [3- (3-ethoxycarbonylmethylphenyl) _4, methoxyphenyl ] Hexane. Step 3: Dissolve the bis-methyl ether (25-6 g, 41 mmol) in dichloromethane (165 ml) and cool to 0 ° C. Slowly add a solution of boron tribromide in dichloromethane (33 mL), remove the cooling bath and stir the mixture at room temperature for 20 minutes. The reaction mixture was cooled in an ice bath, a CaCl2 drying tube was placed at the nitrogen inlet, and ethanol (35 ml) was added dropwise. The reaction mixture was then poured onto ice and extracted with ethyl acetate. Organic matter is separated and extracted with 'water' brine, then dehydrated (MgS04) and concentrated under reduced pressure to obtain 1,6-bis- [3- (3-ethoxycarbonylmethylphenyl) -4-hydroxyl Phenyl] hexane (24.2 g, 100/0). Step 4: The bis-phenol (25.37 g, 42.7 mmol) and tetratrimethyl-34- This paper size applies the Chinese National Standard (CNS) A4 specification (210X2, 97 mm) (Please read the back Note $ item and fill out this page again) ^ 457246 at B7 Central Ministry of Economics and Economics Co., Ltd. Cooperate in Printing Co., Ltd. V. Inventory Description of the Invention (32) Acetyl, tf-L) Pyranoglycosyl fluoride ( 66.4 grams, 128 millimolar Scott and TP Cogan, US Open patent application filed in 1996, titled 11 High-yield stereospecific mannose saccharification f • Remote dripping of ice-cold methane (427 ml) Add BF0E 2 (47 3 ml, 3 84 mmol), and then stir the ice-cold solution for 彳 hours " after diluting the conjugation with ethyl dicarboxylate and then water (2 X), sodium hydroxide ( 2 M), water and saturated saline are lifted and washed, dehydrated with sulfuric acid, and concentrated under reduced pressure. Purified by chromatography (silica gel, dissolved in a gradient of hexane / FtOAt: 3ί): 1 to 6: 1 to obtain U6- Bis-13- (3-ethoxycarbonyl f-phenylphenyl) -4- (W-Qr trimethylethylfluorenyl π — 〇11 than mannan furfuryloxy) phenyl 1 hexane (59,8 g, 89%) ^ Step 5: Part A Methanol (24.4 milligrams) was added to the solution of this double sugar cane in + TTHF (24 mL), and then freshly prepared sodium formazan (from sodium, 0.5 g, 22 millimoles) was cooled in formazan The solution was added and the mixture was stirred at room temperature overnight. After the precipitate was collected by filtration, it was first washed with a small amount of T1IF / methanol (2X), and then washed with two ketones = the solid sodium alkane gas (6,3 g), and then stirred and purified by acetone. Part B: Stir the precipitate in water (27 ml) at room temperature for 30 minutes. Then adjust the pH to 4 and keep it at 4 with a small amount of sodium hydroxide (2 M) during the stirring period. After 4 hours, deprotection was completed by reverse-phase HPLC = the solution β was first neutralized with pre-washed ion exchange resin (Dowex 'gas ion type), and then filtered through a layer of tetracalcium iron aluminate (cdite). After the solution was freeze-dried, a slightly hygroscopic white powder Zhu Zhi 1,6-bis- [3- (3-carboxymethylbenzyl) -4- (2-a-D-pyranosyloxy) was obtained. Phenyl] hexane, dina. Salt (6.0 g, 90%) ^ 243-245O; Ή NMR (400 MTIz, D20): 7.64 (s? 2H), -35-(猗 先 ¾ 靖 背 1 & Note the macro items and fill in this page again.) This paper ruler and the universal mid-profile family standard-quasi (CNS) eight 4 acetylene (public absolute) 457246 ΑΊ Β7 Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. (33) 7.58 (d, J = 7.7 Hz, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.37 (d, J = 8'4 Hz, 2H), 7.19 (d, J = 7.3 Hz, 2H), 7.12 (s? 2H), 7.07 (d, J = 8.0 Hz, 2H), 5.66 (s, 2H), 4.27 (s, 2H), 4.00-4.20 (ms 4H), 4.04 (dd, J = 12, l and 3.3 Hz, 2H), 3.80-3.92 (m, 6H), 3.72 (d, J = 9'2 Hz, 2H), 2.52 (m, 4H), 1.60 (br, 4H), 1.39 (br, 4H); 13C NMR (100 MHz, D20) 180.9, 151.5, 138.4, 137.5, 137.4, 132.5, 130.9, 129.1, 129.0, 128.9, 127.3, 117.2, 100.2, 74.2, 70.9, 66.6, 60.9, 45 5, 32.3, 31.6, 29.5; Experiment 値: 57.54% C, 5.98% H, 5.12 Na: C46H52016Na2o3H20 Calculated 値: 57.50% C, 6.08% H, 4.78 Na 〇 Example 3 M-bis- [3- (3-carboxymethylphenyl) -4- (2 · π-D-pyranosyloxy) benzene Butyl] butane Step 1: 4- (4-methoxyphenyl) butanoic acid (2.0 g, 10.3 mmol) was treated with thionyl chloride (20 ml). The reaction was stirred at room temperature for 3 hours, and then heated at 65 ° C overnight, and then concentrated under reduced pressure to obtain 4- (4-methoxyphenyl) butanium vapor (2.3 g) as a yellow oil. Used without further purification. IR (NaCl): 1795, 1510, 1244 cm · 1. This crude acid gaseous product (2.07 g, 9.7 mmol) and methoxybenzene (1.26 g, 11.6 mmol) were dissolved in 1,2-dichloroethane (32 ml) and then placed in ice. Cool in the bath. The mixture was partially treated with vaporized aluminum (3,9 g, 29.1 mmol), stirred for 5 minutes, and then mixed with ice water (50 ml). The mixture was extracted with dichloromethane (3 X 10 ml), and the extracts were combined and washed with saturated sodium chloride, -36- (Please read the precautions on the back before filling this page) -Order_ Price ·: u; u_: This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) π one by one: 457246 A7 B7 V. Description of the invention (34) Dehydration (MgS04), and then concentrated under reduced pressure. The residue was quickly passed through silica gel at 10: 1 hexane / ethyl acetate and then concentrated to obtain 1,4-bis- (methoxyphenyl) buti-one (2.49 g, 82%). 4 NMR (400 MHz, CDC13): 7.90 (d, J = 8.8 Hz, 2H), 7.11 (d5 J = 8.4 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 3.86 (s, 3H), 3.78 (s, 3H), 2.90 (t, J = 7.3 Hz, 2H), 2.65 (t, J = 7.7 Hz, 2H), 2.02 (m, 2H) ppm. IR (NaCl): 1674, 1602, 1244 cm'1 ° Step 2: Dissolve the ketone (2.49 g, 8.8 mol) into dichloromethane (30 ml) and then sequentially with trifluoroacetic acid (2.7 ml , 35.2 mmol), triethylsilicon (2.8 ml, 17.6 mmol) and boron trifluoride etherate (4.4 ml, 3 5.2 mmol). The mixture was stirred at room temperature for 2 hours and then cooled in an ice bath and mixed with water (50 ml). The mixture was extracted with dichloromethane (3 x 5 ml), and the organic materials were combined, washed with saturated brine (100 ml) and dehydrated (MgSO4), and then concentrated under reduced pressure. The residue was quickly passed through silica gel with 10: 1 hexane and ethyl acetate and then concentrated to obtain a clear oily substance, 4-bis- (4-methoxyphenyl) butane (2.0 g, 85%). 4 NMR (400 MHz, CDC13): 7.07 (d, J = 8.4 Hz, 4H), 6.81 (d, J = 8.4 Hz, 4H), 3.78 (s, 6H), 2.56 (m, 4H), 1.61 (m , 4H) ppm. IR (NaCl): 1605, 1248 cm-1 0 Shellfish Consumption by Central Standards Bureau of the Ministry of Economic Affairs Hezhong Jiangliang Step 3: Put 1,4-bis- (4-methoxyphenyl) butane (1.78 g, 6.6 milligrams) Mol) and TMEDA (4'0 mL, 26.5 mmol) were mixed with anhydrous ether (30 mL) and cooled in an ice bath. After adding n-butyl bell (1,5 ml of 2.5 M solution, 26.5 mmol), the mixture was warmed to room temperature and stirred for τ hours. Then the mixture was cooled to 0 ° C, and then trimethyl borate (3.0 ml, 26.5 mmol-37- This paper size is applicable to China National Standard (CNS) A4 (210X: 297 mm) 457246 Central Ministry of Economic Affairs Tizhan Bureau shellfish consumption is right; ϋ .fai A7 B7 V. Invention description (35) Moore). The mixture was stirred at room temperature overnight, and the reaction was stopped by the addition of 2N HC1 (to pH 2), followed by stirring for 丨 hours. After the organic phase was separated, the aqueous solution was extracted with ethyl acetate (3 x 5 ml). The extract was combined with the previous organic portion and dehydrated (MgSO4), and then concentrated under reduced pressure to obtain boronic acid (3.0 g) which was used directly without purification. lR (NaC1): 16〇3, 149〇, 1416, 1328, 1234 cm'1〇 Crude boronic acid and 3-bromophenyl acetate (3,8 g, 16.8 mmol) and dimethoxy Ethane (30 ml) was mixed and the air was removed under a nitrogen atmosphere. The mixture was treated with tripotassium phosphate (10.7 g, 50.5 mmol) and bis- (triphenylphosphine) palladium (η) chloride (100¾ g'Chl7 mmol). The mixture was de-aired once more, then heated under reflux for 2 hours, then cooled to room temperature and mixed with water (100 ml). The mixture was extracted with dichloromethane (3 x 10 ml) and the extracts were combined, washed with water (50 ml), saturated sodium vaporized (50 ml), dehydrated (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 'gradient separation, 8: 1 hexane / ethyl acetate to 4: 1 hexane / ethyl acetate) to obtain 1,4-bis- [3 as a clear oil. -(3-fluorenyloxymethylphenyl) (4-methoxy) phenyl] butane (1.14 g, 24%). iHNMROOOMHz, CDC13): 7.41-7.44 (m, 4H), 7.34 (t, J = 7.7 Hz, 2H), 7.21-7.60 (m, 2H), 7.08-7.13 (m, 4H), 6.87 (d, J = 8.0 Hz, 2H), 3.77 (s, 6H), 3.68 (s, 6H), 3.66 (s, 4H), 2.61 (m »4H), 1.67 (m, 4H) ppm. IR (NaCl): 1737, 1606, 1239 cm.1. Step 4: Dissolve 1,4-bis- [3- (3-methoxycarbonylfluorenylphenyl) (4-methoxy) phenyl] butane (0.9 g, 1.6 mmol) in methane gas. (3.0 ml), cooled in a dry ice bath, and then treated with boron tribromide (1.2 ml, 12.8 mmol). -38- The A degree of this paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ---: ---; ----- VW clothing-- (Please read the precautions on the back before filling out this page) Order • H —-— ^ 1 457246 A7 B7 Employee Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs 5. The description of the invention (36) The mixture was stirred at -78 ° C for 3 hours and then placed in a -lot freezer overnight. The reaction was stopped by adding ice water (10 ml), and then extracted with methane (3 x 5 ml). After combining the organic materials, it was extracted and washed with water (25 ml), saturated sodium chloride (25 ml), dehydrated (MgS04) and concentrated under reduced pressure. The residue was purified by flash chromatography (Si02). , 5: 1 hexane / ethyl acetate) to obtain 1'bis- [3- (3-methoxycarbonylmethylbenzyl) -4-hydroxyphenyl] butane (0.4 g, 47%). IH NMR (400 MHz, CDC13): 7.42 (d, J = 7.4 Hz, 2H), 7.35-7. 38 (m, 4H), 7.27-7.32 (m, 2H)} 7.02-7.05 (m, 4H), 6.87 (d, J = 8.0 Hz, 2H), 5.12 (s5 2H), 3.70 (s5 6H), 3.68 (s, 4H), 2.59 (m, 4H), 1.65 (m, 4H) ppm ° IR (NaCl): 3439, 1732, 1606, 1263 cm'1 〇 Step 5: Put 1,4-double- [3_ ( 3-Methoxycarbonylmethylphenyl) _4-Chlorylphenyl] butane (0.4 g, 0.74 mmol) and 々D-mannose pentaacetate (0.72 g, 1.85 mmol) Dissolved in 1,2-dichloroethane (4.0 ml) and treated with boron trifluoride etherate (1.1 ml, 8.9 mmol). The mixture was stirred at room temperature overnight and then water was added. (10 ml) to stop the reaction, and then extract the aqueous solution (3 x 4 ml) with dichloromethane. Combine the organic materials, first wash with water (15 ml), saturated sodium gaseous (20 ml), and dehydrate (MgS. 4) and then concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 2: 2 hexane / ethyl acetate) to obtain M-bis- [3- (3-methoxycarbonylmethyl) in the form of a foam. Phenyl) -4- (2,3,4,6-tetra-2_-ethynylpyranosyloxy) phenyl] butane (0.88 g, 99%). ] H NMR (400 MHz, CDC13): 7.38-7.44 (m, 6H), 7.25-7.29 (m, 2H), 7.17 (br s, 2H), 7.07-7.11 ((ms 4H), 5.40 (s, 2H ), 5,20-5.30 (m, 6H), 4.15 (dd, J = 12.3, 4.8 Hz, 2H), 3.93 (dd, J = 12.4, 2.2 Hz, 2H)? 3.76-3.82 (m, 2H), 3.72 (s, 4H), 3.68 (s, -39- (Please read the precautions on the reverse side before filling out this page) -IL. 'Binding · Order_: π: .11 This paper size is subject to the Chinese standard (CNS) A4 Specification (210x297 mm) 457246 Patent Application Specification No. 85II5086 Revised Sheet (July S9) V. Description of the Invention (37! Ϊ Positive supplement m 6H), 2.63 (m, 4H), 2.13 (s, 6H), 2.01 (s, 6H), 2.00 (s, 6H), 1.97 (s, 6H), lj7 (m, 4H) ppin. iR (NaCl): 1748, 1219 cm · 1. Step 6: The 6-based ester (0.87 g, 0.73 mmol) was dissolved in acetonitrile (3 mmol) and then treated with an aqueous solution of lithium hydroxide monohydrate (0.46 g, 11 mmol in 2 ml of water). The mixture was stirred at room temperature overnight. After extinction: the solvent was removed and acidified to pH 2 with concentrated hydrochloric acid. A portion of the mixture was purified by reverse-phase HPLC (C18, 20-80% acetonitrile over 45 minutes). Gradient dissolution in water, monitored at 254 nm) M-bis- [3- (3-carboxymethylphenyl) -4- (α-D-mannanyloxy) phenyl] as a white solid] Butane (230 mg), mp: 195-197 ... lH NMR (400 MHz, DMSO-d6): 7.31-7.39 (m, 6H), 6.20-7.25 (m, 4H), 7.10-7.15 (m, 4H), 5.25 (s, 2H), 4.88 (br d, J = 4.0 Hz, 2H), 4.76 (bT ss 2H), 4.60 (br s, 2H), 4.45 (br t, J = 5.9 Hz, 2H) , 3.55-3.68 (m, 5H), 3.62 (s, 4H), 3.40-3.50 (m, 7H), 2.60 (m, 4H), 1.62 (m, 4H) ppm. IR (KBr): 3333, 3229 , 1729, 1224 cm · 1. Experimental value: 61.3% C, 6.15% H: C44H Calculated value of 0016.0.4 TFA > 61.32% C, 5.79% H. Example 4 N, N, -bis- [4- (3-carboxymethylbenzyl) -4- (α-D-pyranosyloxy) phenyl] but-1-fluorenyl] -4,4 Trimethylene hexahydroemei. ·; 2. _ · ·. · 'Step of printing by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 1 ·· Succinic anhydride (2.0 g, 19.9 mmol) and chlorinated name ( 17.7 g (132 mmol) and 1,2-digas ethane (45 ml) were mixed and cooled on an ice bath. The mixture was treated with 3- (2- (2,3,4,6-tetratrimethylethyl) -α-mannanyloxy) phenyl] phenylacetate (10.0 g, 132 mmol) Treatment of the solution in digas ethane (10 ml) 'The temperature of the water bath is slowly returned to -40-This paper size applies to Chinese National Standard (CNS) A4 gauge · (210X297 mm) Λ7 B7 457246 Article Ml 15686 竑Chinese Instructions for Patent Application I Revise King Page (July of Year) 5. Description of Invention () 38

\ I —--.. · _ · J Let the mixture stir overnight at room temperature. The reaction was mixed with ice water (100 ml) for 1 minute and stirred for 15 minutes. The organic matter was separated, and the aqueous layer was extracted with dichloromethane (3 x 5 ml). The organic matter was combined and dehydrated (MgS. 4) Post-decompression: Liaoning's Deco can be used directly without purification (13.5 g) 3 IK (NaCl): 1738, 1685, 1228 cm'1-Step 2: Acid (ϋ_) ( 13_5 g, 19.7 mmoles) were dissolved in methane (65 ml) and treated with boron trifluoride etherate (15.3 ml, 122 mmoles). It was then treated with trifluoroacetic acid (9.4 ml, 122 mmol). : Compound was treated with triethylsilane (9.4 ml, 59.1 mmol) and stirred overnight at room temperature. The reaction was mixed with water (200 mmol) and then organic matter was separated. Dichloromethane (3 X 10 ml) was used to extract the aqueous layer portion, the extract was combined with the original organic portion, dehydrated (MgS04), and then concentrated under reduced pressure to obtain 4- (3- ( 3-ethoxycarbonylmethylbenzyl) -4- (273,4,6-tetra · α · trifylethylfluorenyl-α-D-pyranosyl) phenyl] butyl ) (1_49 g, 97%) »IR (NaCl): 1737, 1 132 cm * 1-Step 3: Acid UJ (16.0 g, Ϊ: 3.8 mmol) to vaporize thionine (50 ml) Treatment • The mixture was stirred at room temperature for 3 6 hours, and then concentrated under reduced pressure to obtain an acid gas which can be used directly without purification 1 £ (16.3 g, 99%). IR (NaCl): 2974, 1797, 1740, Π35 cm-1 ° Step 4: A solution of 474__trimethylene dihexapyridine (0.4 g, 1.9 mmol) in methane (5 ml), At 0 ° C, add the acid gaseous K2.S (g 3.26 mmol) to a solution in dichloromethane (5 ml). 3 Add triethylamine (0.61 ml, 4.4 mmol) 4-di T Aminopyridine (35 mg 1 L0 mol%), and then the mixture was stirred at room temperature for 丨 hours, and then with water (2 041-this paper's universal medium ® ® household tenon ratio (CNS) A4 specifications ί 210x29? Public 韪) ^^ 1 In J-----^ A " ^. ^ 11----ί--^^^ 1; ^ (汴 Please refer to the notice on the back before filling this page) In the Ministry of Health and Welfare, the employees of the Ministry of Health and Wealth Poverty Alleviation and Sealing of Hewei News Agency 1S- A 7 B7 457246 Patent Application Sling Order No. SSI 15 Post No. 6 Description of repairing earthen tiles (July of the year) Five Description of inventions () 丨丨 Repair ml) mix. The organic material was extracted and washed with saturated potassium gas (20 ml), dehydrated (MgS04), and then concentrated by tanzine. The residue was purified by flash chromatography (Si02, 2: 1 ethyl hexanoate / hexane) to obtain bisphosphonium g * IS%) ^ NMR (400 CDClj): 7,40-7.45 (m, 4HJ, 6.98-7,30 (m, 10H) (5.25-5.42 (m. 6H), 4.09-4 19 (m, 4H), 3.50-3.96 (m, 8H), 2.62-2,69 (m, 4H ), 2.28-2,36 (m, 4H), 1.90-2.02 (m, 4H) f 1.60-1.74 (m, 6H), 1.35-1.50 (m, 2H), 1,24 (ϋ, 18H), t .ij (s, 18H), 1.11 (s, 36H), 1.08-1.28 (m, 26H)-IR (NaCl): 1739 cm'1 ^ Step 5: Dissolve diamidine g i 0.54 mmol) THF (3 ml) t, and then treated with an aqueous solution of sodium hydroxide (0.40 g, 10 mmol, in 3 ml of water). The mixture was stirred at room temperature overnight, the THF was removed under reduced pressure, and the residue was acidified with concentrated acid. It was purified to pH 2 by reverse phase HPLC to obtain N, N1 · bis_ [4- (3- (3 + carboxymethylphenyl) -4- (a, D · mannosyloxy) benzene as a white solid. Butyl) -I-hexyl] 4,4 · -trimethylene hexagas p specific bite (17, (30 mg, 5%), mp: 119-mgC-1HNMR (400 MHz, DMSO- < i6): 7.32_ 7.40 (m7 6H), 7.20-7.27 (m. 4H), 7.10-7.14 (m, 4H), 5,26 (br s (2H) f 4.36 (br d, J = U Hz, 2H ) S 4.05 (br s, 8H), 3.77 (br d, J = U Hz, 2H), 3.50-3.70 (mf 8H), 3.40-3,52 (m7 5H), 3.31-3.40 (m, 2H), 2.92 (br t, J = l4 Hi, 2H), 2.55- 2.62 (m, 4H); 2 42-2.53 (m, 3H), 2.27 ^ 2.34 (m, 4H), 1.73-1.82 (mt 4H), 1.57-1,67 (m, 4H), 1.36-Γ47 (m , 2H) T 1.22- 1,33 (m, 2H), 1.11-L20 (m, 4H) f 0.80-1.02 (m, 4H) a IR (KBr): 3415, IM3, 1609 cm]. iViS (FAB): 1150 (M + + Na) Analysis: C61H78N2Oia ".4 TFA: 59.54% C, 6 22% H, 2.18¼ N ° Experimental plant: -42- General standard tSSI home standard (CMS) A4 Guiluo (. 公 麾) — 11 -----.― F ί I ^ Outfit ------------- (Poems First, "Please on the back;: I intend matters and then Qi Xiao (Benedict)

荦 中 局 中 中 棣 失 棣 局 局 工 工 消 t cooperation Du Yin A 457246 A " V. Description of the invention (40) 59.65% C, 6.56% H, 2.23% N-f Example 5 2-6- 丨 3-(3 -Lean methylphenyl) -4- (2-4 -D- ^ t-mannanyloxy_) benzyl | hexyl ether Step 1: The tritium gasification (〗 _65 milliwells, 2 Μ in two gases f-alkane, 3_3ϋ millipods) was added to -78 " C in anhydrous two gas form (1ϋml). Dimethyl ethyl sulfone (0.5 (5 ml, 7-26 millimoles)) was added dropwise over a period of several minutes, and the resulting solution was stirred for 10 minutes, and ethyl 6-hydroxyhexanoate was added dropwise ( 0.50 ml, 3.07 mmol, after 30 minutes # Triethylamine (2.10 ml, 15.1 mmol) was added dropwise and the mixture was stirred for 10 minutes. The liquid phases were separated and extracted with methane. Aqueous solution layer. The organic materials were combined, dehydrated (MgS () 4), and then evacuated to remove the solvent = silica chromatography (2: 1 hexane: ethyl acetate) to obtain the pure product (0.44 g, 91%) = Α1.Ι NMR (400 MHz, CDC13): 9J5 (1 ΪΤ) (4,10 (2Η), 2.45 (211), 2.30 (211), j .ή5 (4Π), 1.24 (3Η) =橾 窣 工 消 Φ: Cooperative Pregnancy Indications (Dian first read the back note and then write the book I) Step 2: Yu (TC will be triethylsilane (0.89¾ liter, 5,57 millimoles) And trimethylsilyl trifluoromethanesulfonate (63 ml, 0.28 mmol) were dissolved in anhydrous diflatoxane (6 ml), and then 5-pentyloxycarbonylvaleraldehyde (0.44 g, 2.78 mmol) was added. Ear) in methylene chloride (3 ml) Solution. Remove the cooling bath and allow the reaction to proceed at room temperature for 80 minutes. After removing the solvent with air, the product is purified by silica gel chromatography (6: 1 hexane: ethyl acetate) to obtain the product (0.31 g, 74%). ).] 11 NMR (400 MHz, CDC1.): 4.10 (4H) f 3.37 (4H), 2.28 (4Π), 1.60 (RU); i J6 (4Π), 1.24 (fill) = Step 3: 5-Ethoxycarbonylpentyl ether (0.16 ml, 0.53 mmol) This paper is available in standard paper (CXS > Λ4 gauge 210 × 297) 457246 A7 B7 V. Description of the invention ( 41) Dissolve in methyl cyanide (1 ml) and deduct 1 N sodium hydride (1,05 ml, 1,05 mmol). The resulting solution was stirred at room temperature for 3 hours. The methanol was removed under reduced pressure. After that, the residual liquid was acidified (concentrated hydrochloric acid) and then extracted with diethyl ether. The extracts were combined, dehydrated (MgS04.) # Min., And concentrated. The residue was concentrated twice more with acetonitrile to obtain a white solid. The product (0 "6 g, generated in equal amounts). LH NMR (400 MHz, CDC1-;): 3.40 (4H)? 2.36 (4H), L60 (8H), 1.42 (4H) ^ Step 4: -5-Carboxypentyl ether (0.15 ml, (J3 mmol) and DMF (1 ) Was dissolved in anhydrous methane gas (2.5 mL) and cooled to 〇fC u slowly added oxalyl stuffed vaporized solution (0.5 to 9 ml of the second gas 2 [mu] A pregnant solution of 1 - S Shu mmol). After the reaction was stirred at TC for 20 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 20 minutes. After the solution was cooled to 0 ° C, 3- (2-methoxyphenyl) benzyl acetate (0.29 g) was added. , 1,07 millimoles) in methane gas (1 ml) = aluminum chloride is divided into three parts (0, 17 grams, 0_17 grams, 0_08 grams, a total of 3.15 millimoles in 1 minute) ) Add. Stir the solution for 5 minutes, then pour it into ice and extract with two portions of ethyl acetate. The organic layers are combined and extracted with water, saturated sodium bicarbonate aqueous solution, and saturated sodium gas solution in order. .Results The solution was dehydrated (MgS04) and concentrated under reduced pressure. It was printed by the Ministry of Economic Affairs of the Ministry of Economics and Technology in China. (诮 Please read the back first and pay attention to the item before filling the lettuce vx). Gel chromatography Purification by a method (gradient from 4: 丨 to 1: 1) gave the product as a yellow oil (0.34 g, 85%). IHNMRGOOMHz, CDC13): 7_91 (4H), 7.41 (6H), 7.28 (2ΤΪ), 6.99 (2H): 4.14 (4H) f 3.86 (6H), 3,66 (4Π), 3.40 (4H), 2.94 (4H), 2.16 (4H), L75 (4H); 1.59 (4H), J-43 ( 4H), 1,26 (6Π). Step 5: Di-6-L3- (3-ethoxycarbonylmethylphenyl) -4-methylfluorenylbenzyl 丨 6-6-44- This paper size is applicable to the standard of ten charters (CN_S) 8-4格 {2Η) Χ2ί7 male t 457246 Λ7 B7 V. Description of the invention (桠) The hexadecyl ether (0.34 g, 0.45 mmol) is first dissolved in an anhydrous digas pit {2.5 mmol) and the result is produced. The solution was cooled (TC. Trifluoroacetic acid (0.23 ml, 3.0 mmole) was added, followed by triethylsilane (0_29 ml, 1,8 mmoles) and osmium trifluoride etherate (0_33 ml, 2_7) Millimoles). After removing the cooling bath, the reaction was stirred at room temperature for 2 h. After adding digas formamidine, it was extracted with saturated sodium bicarbonate solution and water. The organic layer was dehydrated (MgS04) and then reduced. Concentrated under pressure. The product was obtained as a clear oil ((K23 g, 71%) after purification by silica gel string method (6: 1 hexane: ethyl acetate). 4 NMR (4 () () MHz, CDC13) : 7_42 (4H), 7J5 (2H), 7,25 (2Π), 7-09 (4H), 6,87 (2H), 4.16 (4TI), 3.77 (6H), 3.65 (4Η), 3.37 (4Η ); 2.57 (4Π), 1.57 (10Η)? 1.35 (ΚΗ); 1.25 (fill) ^ Step 6: Di-6 · [3- (3-ethoxycarbonyl Methylphenyl) -4-methoxyphenyl 1-hexyl ether (0.23 g, 0.32 mmol) was first dissolved in anhydrous dioxane (1,6 mmol) #The resulting solution was cooled to tTC s Add the bromide solution (1VI in digas, 1.40 milliwells, 1.40 millimoles) dropwise and remove the cooling bath. Twenty minutes later, the solution is cooled to 0t and dripped into anhydrous water. Ethanol (1 ml, then the reaction mixture was poured into ice and then extracted with ethyl acetate. The organic layer was dehydrated (MgS () 4) after being washed with a planer, sodium gaseous extract and water, and then minified by the Central Ministry of Economic Affairs Printed by the consumer cooperative FIJI ^^^^ 1 ^^^^ 1 ^^^^ 1 ^^^^ 1 ^^^^ 1 ^^^^ 1 ^ ^^^^ 1 ^^^^ 1 ^^^^ 1 ^^^^ 1 ^^^^ 1 ^^^^ 1 V " (is on the back of the reading; iJ · Hongshiqiaohui fills in this page) Pressure concentration. Purified by silica gel chromatography (2: 1 to The product was obtained after 1: 1 hexane: ethyl acetate (0.2 g, 50%).] II NMR (400 MIIz, CDCI3): 7.42 (8H), 7.04 (4FT), 6.RR (2H )? 5.J4 (2H), 4.16 (4H), 3.67 (4H), 3,38 (4H), 2.57 (4H); 1.85 (4H)? 1.62 (6H), 1.40 (6H), 1.27 (6H) . Step 7: Put 2,3,4,6-tetratrimethylethylsulfonium, cr -D-pyranomannose-4S- This paper size applies to the countries of China 囷 (OS) Λ4 ^ grid (210X297 male S } d57246 A7 B7 V. Description of the invention (43) -fluoride (0.52 g, 1.00 mmol) and di-6_ [3- (3-ethoxycarbylmethylbenzyl) -4-hydroxyphenyl] Hexafluorene (0'23 g, 0-33 millimoles) was dissolved in anhydrous digas methane (2 milliwells) and the resulting solution was cooled to 0ta. Boron trifluoride etherate (0.3 S ml, 3,0 mmol), and the reaction was stirred for 90 minutes. The reaction mixture was diluted with ethyl acetate, first washed with two portions of water, and then continued with 1 N NaOH 'water' and saturated gasification. The solution was extracted and washed. The resulting solution was dehydrated (M @ 〇4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (15: 1 hexane: ethyl acetate) to obtain the product (0'45 Grams, 82%). 4 delete only (400 delete 7; [〇 (:! 3): 7.45 (7 (7.15 (7 (), 5.32 (8Η), 4.14 (4Η), 3.86 (4Η); 3.72 (4ΤΤ ), 3-54 (2Π); 3.40 (4Η), 2,59 (4Η), 1.85 (4Η), 1.62 (4Η), 1.46 (4Η), 1.36 (4Η), 1-26 (24Π), 1.15 (1ΗΗ): Κΐϋ (36Η) =

Step S Printed by the Consumers Cooperative of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the People's Republic of China. f-Acetoethyl-cD-pyranosyloxy) phenyl] hexyl ether (0,45 g, 0,27 mmol) was dissolved in anhydrous tetrahydrofuran (0.9 ml) and methanol (1,8 ml) a Add sodium methoxide (49 mg, 0,84 millimoles), and stir the reaction crystals at Xuan temperature overnight. 3 Add another portion of sodium trioxide (50 mg, t). 93 millimoles) Add, after 4 hours, add a third portion () 丨 2 mg, 21 (7 7 mol) 4 The reaction is continued to stir for another 4 hours, then filtered and washed with a 2: 1 mixture of tetrahydrofuran and methanol = collected solid = then Dissolve the solid in water (〗 ml), add hydrogenated sodium water tooth solution (1 M) until p] 丨 reaches 14. The solution is searched and stirred for 4 hours, and then Dowcx 50 ion exchange resin (H1.® !) Neutralization. After the resin is removed by filtration, the filtrate is freeze-dried. Then the product is dried at -46-

In the 57 2 step t§5U5658 Bailey's application for the amendment to the Chinese manual (June 90) V. In the description of the invention (44) P ;: Vacuum drying in 05 can get 2 · 6_ [3_ (3_carboxyl Alkylbenzyl) -4, (2H said mannoseoxy) phenyl 1hexyl ether (0 21 g, 7S%). (Η NMR (400 MHz, CD3CN / D20): 7.46 (2H), 7.34 (2H), 7.16 (10H), 5.31 (2H) 7 3.79 (2H) S 3.66 (2H), 3,51 (4H), 3.42 (5H) S 28 (2H), 2.56 (4H), 1.80 (4HX 1.60 (4H), 1.36 (6H). Real fd bis- [3_ (3 · | methylphenyl) _4- 〇-〇_7 ratio Mannosyloxy) _3_benzenebis-1 -yl] -1,3-dithiopropionate Step 1: _ Part eight: Put 3- (2-methoxyoxyphenyl) phenylacetate ethyl ester ( 5.04 g * 18.66 millimoles) and 3-bromobenzene gaseous (1.88 mL, 18.66 millimoles) were mixed with methane (30 mL). The mixture was cooled in an ice-water bath and treated with vaporized aluminum (7.6 g, 57 mmol). After 15 minutes, it was mixed with ice water (100 mg), and the organic matter was separated. The solution phase was extracted with a two-gauge radon gauge (3 x 5 ml). After combining the organic matter, the solution was saturated with a saturated aqueous sodium hydroxide solution (50 Milliliter) extraction, dehydration (MgS04), and then concentrated under reduced pressure a residue can be used directly in the next step without purification, part B: the product of part A (8.5 g, 1-9 millimoles) dissolved in methane (40 ml) and then cooled in an ice-water bath. Then add trifluoroacetic acid (5.9 ml, 76 millimoles), triethylsilane (6, 丨 ml> 38 millimoles), and tri-gas boron etherate. (9.4 ml ^ 76 millimoles) and remove the ice water bath = stir the mixture overnight at room temperature and then put it back in the ice water bath to cool and add ice water (100 ml) to stop the reaction. After the separation of the organic substance M, the aqueous phase was extracted with methane (3 X 5 ml), the organic substances were combined, extracted and washed with a saturated sodium gas solution (50 ml), dehydrated (M g S Ο 4), and then decompressed. Concentration can be obtained: J-(2-甲 -47- id (please read the weeping of the back * to save the original tile)-= 5% training Passed the standard of Danzhongpu Family Home (CNS} A4 specification Ø ZIUX mm) 457246 Economy Zou Tyang Jun Jun Feng Fenggong Consumer Cooperation Du printed A7 B7 V. Description of the invention (45) Oxybenzyl-5 · (3 -Ethyl bromopropyl) benzyl acetate (0.53 g 1 90%). 4 NMR (400 MHz, CDC1 ;,): 7.4J-7.45 (m, 2H), 7,36 (t, J = 8 Hz: ill), 7.25-7.28 (m, 1H). 7,12-7, 16 (m, 2H), 6.90 (d, J-8.6 TIz, 1H), 4.15 (q, J =? 〇2H): 3,78 (s, 3H), 3.67 (s, 2H)? 3.41 (t, J = 6, 6 Hz, 2H), 2.75 (t, J = 7.〇Hz, 2H), 2,15 (m, 2H), 1.26 (t, J = 7.3 I) to 3U), IR (Nadi) : 1736 cm1. Step 2: A solution of M-propane dithiol (0.09 g, 0.94 mmol) in tritium (4-5 ml) was used to remove air under a nitrogen atmosphere, and then cooled in an ice-water bath. After adding sodium argon (K6.5 mg, 2.1 mmol), the mixture was stirred at room temperature for 2 hours. A solution of the bromide (0.83 g, 2.12 mmol) in THF (10 mmol) was added, and the mixture was stirred overnight at reflux temperature. The reaction was partitioned between water and ethyl acetate. (20 milliwells: 1 mixture), the organic substance 1 was separated and extracted with saturated sodium gaseous (20 ml), dehydrated (MgS04) and then decompressed under reduced pressure. The residue was subjected to flash chromatography (Si02, hexane to 3: 1 hexane / ethyl acetate gradient gradient separation) S, S-bis [3- (3-ethoxycarbonylmethylbenzyl) -4- ( (Methoxy) -3-phenylpropan-I-yl] -1,3-dithiopropane (166.2 mg, 24%). MT NMR (400 MHz; CDC13): 7.39-7.45 (m, AU), 7.32-7.38 (m, 2H); 7.21-7.28 (m, 211), 7.08-7. [5 (m, 4TI) 5 6.85- 6.92 (m, 2H), 4.14 (q, J = 7.0 TT /, 4IT), 3.77 (s, price), 3.65 (s, 4ΪΤ), 2.80-2.95 (m; 2H); 2.77 (tf J = 7, 3 Hz, 2H), 2.68 (t, J = 8,0 Hz; 4H) 3 2.60 (t;) = Ί, ΰ Hz, 2H), 2.52 (t, J = 7.0 Hz? 2H), 2.04-2.16 { m, 2H), 1.81-1.93 (m, 4H), 1-25 (UJ = 7-0 Τϊζ5 6H). TR (NaCI): 173 1 cm'1 -steps 3: -48- ^ Paper Wave Scales in use ® Sleepy Elephant List (CNS) M Specification (uouy moment) ϋ nn _ _ ____ ^ _____,.: J—.: [_ T} ^ I ^ rt n [— .¾ (tabularly read the "&"; "items on the back and fill in this tile) 457246 A7 ______B? V. Description of the invention (46) Step 2 Solution of bis-sulfide (+70,7 mg, 0.1 mmol) in digas methane (2 ml) in a dry ice / acetone bath + cooling and boron tribromide (0.8 ml '1 M in digas In a solution of methane, 0.8 millimolar) was treated with Mixture 1 at -1 05C overnight. The reaction was mixed with water (10 mL) and extracted with digas formamidine (3.2 mL). Organic substances are combined, dehydrated (MgS04) and then reduced | concentrated to obtain S, S-bis · 13 · (3 · ethoxycarboxymethylphenylphenyl 4- (hydroxy) -3-phenylpropyl-butyl) -1 : 3-dithiopropane (68 mg, 100%) 〇lIT NMR (400 MTT7, CDC13): 7,43 (ί, J-7.7 Hz, 2Η), 7.34.7, 39 (m, 4Π), 7 -30 (br d, J = 7.3 Nzf 2H), 7.03-7.08 (m, 4II); 6.87 (brά, J-8.8 Hz, 2H), 4.96-^. 30 (br s, 2H): 4.15 (q , J = 7.0 IT /, 4M): 3.6 (s, 4H) f 2.66 (L, J-7.3 Hz, 4H), 2,60 (t, .1 = 7.0 Πζ: 2H), 2.52 (l: J -7.0 H7, 4II) f 1.80-1,92 (m; 6ΤΓ), 1.26 (l, J-7.3 Hz, 6H), 1,21-1.27 (m, 2H) ^ 1R (NaCl): 3420, 1726 cm1 ^

^ Institute of Industrial and Consumer Cooperatives, Central Bureau of Tension of the Ministry of Economic Affairs ^^^ 1 urn ^^^ 1 ^^^ 1 ^^^ 1 ^^^ 1 · * 1 J Tooth-a Acer ^ Refill-this page} Step 4: Mix phenol ((M7 g, millimolar) with a-D-mannose pentaethylacetoate (0_8g, 2_0 millimolar) and digas acetamidine ( 8 ml) mixed and then treated with boron trifluoride etherate (1.0 ml, 8,0 mmol). The reaction was stirred overnight at room temperature, then water (10 ml) was added to stop the reaction. After separation of the organic substances β Two-gas formazan extraction (3 X 2 milliliters) t combined with organic matter t, dehydration (MgS04) and reduced concentration. The residue was subjected to rapid chromatography (Si02 '3: 1 hexane / ethyl acetate to 1: 1 hexane). Gradient dissociation of alkane / ethyl acetate) to obtain bis-I 3 (3-ethoxycarbonylmethylphenyl) -4- (2,3,4,6-tetra-ethylacetinyl ^ -〇-pyran Mannyloxy) -3-phenylpropan-1-ylb, 1,3-dithiopropane pits <0.331 g f 36%) IR (NaCl): 1752 cm'1 c Step 5: The ethyl from the previous step Ethyl ester (0,64g * &lt; M7 millimolar) dissolved in -49-__ Surface paper Le scale Maibiet Zhou Gujia car iCNS) A4 this grid (2; 0 × is 7 mm) 457246 A7 B7 Economy Central ladder Ping, ^ Μ Η 消 #Printed by a cooperative V. Description of the invention (47) Acetonitrile (5 mmol) was treated with sodium trioxide solution (5.0 ml of 2 N solution, 0 mmol) and then at room temperature Stir overnight. The mixture was concentrated to pH 2 with concentrated hydrochloric acid, and the volatile materials were removed under reduced pressure. A part of the water-soluble residue was purified by reverse phase chromatography to obtain S, S-bis- [3- (3-carboxymethyl) Phenyl) -4-tv-D-pyranosylmethyl] -3-benzyl-1-ylb 1,3-dithiopropane mp, 96-1 0〇rC &quot; lH NMR ( 400 MHz, DMSO-d6): 7.3 1-7.39 (m: 6H), 7,20-7.27 4H), 7.11-7.15 (m, 4H), 5.26 (s: 2TT), 3.30-3,75 (m, 2R []); 2.64 (t? J = 7.7 Hz, 4H), 2.57 (t, J = 7 (〇Hz, 4H), 2.45-2,52 (m, 4K), 1.75-1.84 (m, 4H) , 1.66-], 74 2H) ^ TR (K.Br): 3430, 1711 cm'1 5 Example 7 1: 6-bis-3- (3_ # methylpenyl) -4-U -D- Gansu: glycosyloxy) phenyl] -1,6-bis-fluorinated hexane Step 1: 3- (2- (2,3,4,6-tetra-ethylethyl-α-D- Pyranylmannosyl) Benzoyl) Ethyl phenylacetate (0,56 g, 0A6 mol) and adipic acid chloride (0-068 g, 0.47 mmol) are first dissolved in dichloride Ethane (0¾: liter) was cooled in an ice-water bath, and then treated with vaporized aluminum (2.56 g, 19.2 mmol). After _5 hours, mix the reactants with Bingyong (25 ml) and stir for 15 minutes = separate the organic matter and extract the aqueous part with methane (3 X 2 ml). D Combine the organic matter and dehydrate it (MgS (4) It was then concentrated under reduced pressure. The residue was purified by flash chromatography (Si02,]: 1 hexane / ethyl acetate) to obtain bis- [3- (3-ethoxycarbonylfluorenylbenzyl) -4-b-D-pyranomannan. Glycosyloxy) phenyl] -1,6-bis · oxohexane (0,43 g, 35%) «NMR (40ϋ MHz, CDC13): M) 〇 (d, J-2.2 Hz, 2H), 7.93 (dd, J = 8-6; 2.2 Hz, 2H), 7.42-7.48 (m? _-50- Chinese paper stock standard scales (CNS> A4 present grid (21 OX public dream)) (Please Please read the first note, please fill in the ears and fill in the island &quot; order

45724G A7 __B7 V. Description of the invention (48) 6H), 7.31-7.35 (m, 2H), 7.25-7.29 (m. 2H) f 5.60 (d, J-0.2 Hz, 211), 5,31-5.34 (m ; 2TT), 5.28 (ά, J = 9.1 Hz, 2H), 5.23-5-2S (m, 2H); 4.21 (dd; J ^ 12.3, 5.1 Η /, 2ΪΤ), 4,15 ^ j-7.4 Hz , 4H), 3.9K (dd, J = 12,4, 2.2 IJz. 2H), 3.79-3.85 (m, 2H), 3.73 (s, 4H), 3.00-3.06 (m, 4H), 2.17 (s, 6H) t 2.03 (s. 6IT); 2.01 (s, 6H), 1.98 (s, 6ΤΪ), LiU-1.85 (m, 4H), 1.26 (t, J = 7.5 Hz. 611) -IR (NaCl): 1747, 1680 cm'1 ^ Step 2: Aluminium acetamate (0,43 g, 0_33 mmol) obtained in the previous step was mixed with 6 nitrile (4 ml) and the solution was mixed with 2 N sodium halide (8 ml , No mol)-from the locust. After being stirred at room temperature for 18 hours, the reaction was neutralized with Do we X 50W acidic ion-exchange lipids, and then the volatile substances were removed by using minus r. 3 Then a part of the residue was purified by reverse phase chromatography HPTX. 1,6-bis- [3- (3-carboxymethylbenzyl) -4- (can be found in -D-pyranomanninomethyl group (fluorenyl Jl, 6-bis-oxo虼, mp: 127-12VC. ⑴ NMR (400 MIlz, DMSO-d5): 7.98 (dt J = KK Hz, 2H), 7,90 (s, 2H), 7.35-7, 48 (mf SH); 7.27 (d, J = 8.6 Hz, 2H), 5.53 (s, 2H): 3.71 (s? 2H), 3.66 (s, 4Π), 3.ΰϋ (d? J = 11.4 H7, 2IT), 3.42-3.51 ( m7 6H), 3.2B-3.35 (m, 2ΤΪ), 3.07-3.15 (m, 4H), 1.67-K73 (m, 4Π)-IR (KBr): 3430, 1716, 1672 cm1. Sub-fold: c: 46H500ls * 〇6 Calculated value of TFA: 59.1 0% C: f 5.32% H. Experiment 値: 5K · 92ΰ / 〇Cf 5.68% H.

Example S 1,3,5-tris- [3, (3-Tanmethylphenyl) -4- (2-λ-D mannosylhydrazone) phenylmethyl J. Step 1: 3 &gt; Tricarboxyl trigas (1.0 g, 3.8 mmol) first dissolved -51-This paper ruler becomes a universal t S national standard (} Λ4 蚍 grid (2〗 0 X 297 male dragon): Shi Xianwen · ^ # Mingzhi Note Heng Xiang Fen S) Order 457241) A 7 B7 _____ V. Description of the invention (49) in 1,2-Digas (20 ml). After adding aluminum vaporization (2.6 g '18'8 mmol), 3 (2-methoxybenzyl) phenylacetic acid benzyl ester (4.8 g' 18.8 mmol- 毫) was added, and the mixture was mixed. After heating at 65,0 overnight and cooling in an ice bath, slowly add ice water (20 ml) 3 to separate the organic matter, and then extract the aqueous solution with -methane (3 X 5 mmol) to combine the organic matter. Dehydration (MgS04) and concentrated under reduced pressure, the residue was purified by flash chromatography, and the gradient was 1: 1 hexane / ethyl acetate gradient purification) to obtain the triketone lllf = 1) '(I.Od ^ CT / OJHNMRHOOMHz'CDCDUiidh-l ''

Hz. 3H), 7.93 (m: 3ti), 7.80-7.83 (m, 3H)? 7.45 (m? 6II); 7.38 (l; J-7.3 Hz, 3H), 7.21-7.29 (m, 3H), 6.95 (dd7 J = 8.76, 1.44 Hz; 3H), 3,88 (s, 9T ”, 3.67 (, 6H), 〇, 911) ppm. 1R (NaCl): 1734, 1654 cm'1-Step 2: Triketone (3 ", 3 g, 3.4 mmol) is first dissolved in methane (16 ml), cold-chilled in an ice bath, and then triethylsilicon pit (3.8 ml, 23.7 mmol) ), Ethyl trifluoroacetate (2.6 ml, 33.S mmol), boron triethyl ether dihydrate (4 J ml, 33, R mmol). The mixture was stirred at room temperature and then mixed with water (25 ml). The organic material was separated and the aqueous solution was extracted with dichloromethane (3 X 5 ml). The organic materials were combined, dehydrated (MgS04) and concentrated under reduced pressure. Take the residue as ethyl acetate: 丨 The central government of the Ministry of Economics and Economics of the People's Republic of China must print the policy for the shellfish consumer cooperative ^^ 1- ^^^ 1 ^^^ 1--ii—p L_E--1 (Please turn on the gate first Read it carefully and pay attention to the following table.) After passing through the silica gel quickly and concentrating, you can get 1,3,5-tri- "3- (3-Toxycarbonylmethylbenzyl) -4- (2-form Oxy) phenylmethyl 1benzene (0_S8 g, 28%). 4 NMR (400 MH7, CDCl3): 7.38-7,43 (m, 6H), 7.33 (i5 J-7.68 Hz, 3H): 7.23 ( s; 3H) f 7.14 (d, J = 2,2 Η /, 3ΤΪ), 7.08 (dd, J-8.08, 1.84 Hzf 3Π), 6,90 (s, 3H), 6-85 (D, J- 8.4 Hzf 3H) (3.89 (s. Paper ruler and user's home nuclear half (CNS) A4AU ^ (mm 1 457 246 economy Langzhong 楯 楯 楯 楯 楯 消费 工 合作 工 合作 工 合作 合作 社 印 印 A 7 7) A7 B7 V. Description of the invention ( 5〇) ήΤΐ), 3.76 (s, 9H), 3,68 (s, 9Η), 3.66 (s, 6Η) ppm ^ TR (NaCl): 173S cm'1 ^ Step 3: Part A: Put 1,3 , 5-tri-13- (3-methoxycarbonylmethylphenyl) -4- (2-foxy) phenylmethyl] benzyl (0, in grams of 110 mmol) is first dissolved in di Put it into a dry ice / acetone bath and cool it in 11ml (5ml). Slowly add boron tribromide (0,7ml, 7.0mmol). ), And then stirred at () _: C for 2 hours, and then mixed with ice water (10 ml) &quot; separate the organic matter and take the aqueous solution with dichloromethane (.3 X 5 ml). Combine the organic matter After that, it was dehydrated (MgS04) and concentrated under reduced pressure to obtain 0.82 g of a crude product. Part B: The residue obtained from A Lang was combined with V alcohol (20 ml) + ¾, and then sulfuric acid (1 mmol) was added. The mixture was heated overnight at reflux temperature and then concentrated under reduced pressure. The residue was mixed with dichloromethane (20 ml) and saturated sodium bicarbonate solution (10 ml). The organic phase material was separated and dehydrated (MgS04) and then reduced. .Pressure concentration. Dissolve the residue with ethyl ether: ethyl hexanoate /]: 1, dissolve it quickly, and then concentrate it through silica gel to obtain U3f5-tri- [3- (3-methyloxomethylmethylbenzyl 4- ( 2-boryl) Benzoyl Tyl] Benzoyl (0.63 g, 75%). Hi NMR (400 MHz, CDC13): 7.20-7.50 (m, 12H), 7.0 (d, J = 2.2 Ilz; 2H) 7 6.98 (s, 2H), 6,9i (dd, 1 = 8,08, 2.2 Hz, 2H), 6.83 (s, 3H) f 6.77 (d, J = 8.44, 3Π), 3.85 (s, 6H), 3 &lt; 69 (s, 9H), 3,66 (s, 61T) ppm = 1R (NaCl): 3429, 1 737 cm'1 ^ Step 4: Triphenol (0.6 2 grams, 0.7 millimoles) dissolved in 1,2-dichloroethane (4 ml), and then added mannose pentaacetic acid (1.4 grams '3.7 millimoles)' and then slowly added boron trifluoride ether The mixture (well U2, 13.3 mmol) was stirred at room temperature overnight and then mixed with water (10 ml). Separated with (please read the note on the back of the greet filial piety ## 筘 筘 太 .-1)

The scale of this paper is generally in accordance with China ’s sample rate (CNS) A4 specification (210X2W male gage) 457246 A? B7 M. Qing _ Zhongdezhenglu Bureau Shellfish Consumer Cooperative Co., Ltd. V. Description of the invention (51) The aqueous solution was extracted with two gaseous methane (3 × 2 ml) to combine the organic substances, and then dehydrated (MgS04) and concentrated under reduced pressure. The residue was purified by flash chromatography (Si02, gradient separation of hexane to 2: 1 ethyl acetate / hexane) to obtain 1,3,5-tri- [3- (3-methoxycarbonylmethylphenyl). 4- (2- (H4,6-tetra-g-ethylfluorenyl) -a-D-pyranosyloxy) fluorenylmethyl (0.9 g, 67%). NMR (400 MHl CDC13): 6-98-7.50 (m, 21 ⑴, 6.86 (Private, 3Η), 5.26 (m; 3H): 3.90-3.93 (m, 6H), 6H); 3.71 (Sf 6H); 3.66 (s. 9H), 1,94-2, Π (m. 36H) ppm ΰ IR (NaCl): 1745 cm'1 3 Step 5: Acetyl ester (¢) obtained in the previous step. 88 g, 〇_ 48 mmol) was dissolved in acetonitrile (2 ml) and treated with a solution of potassium hydroxide (0.4 g, mmol) in water (2 ml). The reaction was stirred overnight at room temperature and acidified to pH 2 with concentrated hydrochloric acid. After depressurizing the reaction, the residue was purified by HPT, C (C- 丨 8 reverse phase, gradient gradient dissociation with 20-K0% acetonitrile in water, and monitoring at 254 nm) to obtain 1,3,5-tri-1 &gt; (3 · carboxymethylphenyl) -4- (2-π-D · mannanylfluorenyl) benzylmethyl] benzene (0J5 g, 57%), tn.p .: 155-biTC. hNMRGOU MHz, DMSG-d6): 7,27-7.34 (m, 9H), 7.17-7.22 (m, 9H), 7.08 ^ 7.10 (dd, JK.44, 1,70 Hz, 3H), 7.01 (h, 3H) f 5.24 3H); 3.85 (s, 6H) f 3.33-3.64 (m, 24H) ppm ° IR (KBr): 343 1, 1710 cnr1. Separation: &lt;: 69Η72024 · 1.ϋ TFA value: 60- + 94% C, 5.26% Η. Experiment 値: 60.85% C, 5.23% Π. Example 9 1,3,5-tri- [4- [3- (3-carboxymethylbenzyl) -4- (shen-o-mannosyloxy) phenyl] -4_oxothiobutane Base] Power Step 1: 3- (2- (2,3,4,6-tetra-g-ethylamyl &amp; pyranosyloxy) -54- (^ Yunwen Please fill in the notes on the back Benwa &gt; Bindings, Paper Scales, Universal, Gugo Family, CNS) 2! 0 × 297 Gong) 457246 A7 B7 Five 'Invention Description (52) Benzy) Ethyl Phenylacetate (0.32 g, (K547 mmol) And bromoacetamidine (0.06 ml, 0.6 &amp; 9 mmol) were dissolved in digas ethane (3 ml) and then placed in a dry ice / two-bath bath to cool. The mixture was cooled with aluminum chloride (丨. 45 g, 1 0.9 mmol-year) After treatment, replace the dry ice bath with an ice-water bath = 15 minutes, add ice water (25 m 弁), mix and stir away for 15 minutes. 3 X 2 ml) to extract the aqueous solution. After combining the organic substances, dehydration (MgS04) and decompression; 0,387 g of substance A can be obtained by agricultural shrinkage, which can be used directly without further purification. "4 NMR (400 MHz, CDCl # S.〇3 (d, J = 2, 5 Il7, 1IT) 5 7.95 (dd: J-8.8, 2.5 Hz, 1H), 7.41-7.47 (m, 3H): 7.35 (m, 1H), 7.3 1 (d, J = 8,8 Hz, 1H), 5.62 (d, J = 1.8 H? .R ΠΪ), 5.21-5.34 (m , 3H), 4.42 (s, 2H), 4.10-4.25 (m, 5TT), 3.99 (dd, J = 12.1f 2.2 Hz, 1H), 3.80-3.85 (m, 1H), 3,74 (s, 2H ), 2.18 (s, 3H), 2,03 (s, 3H), 2.02 (s; 3H) f 1.98 (s7 3H) f 1.26 (t3 J = 8.0 Hz, 3IT) 〇IR (NaCl): 1746, 1220 cm.1. Step 2: 1Λ3,5-tris- (thiol-T-group) benzyl (102 mg, 0,47 mmol) in sodium THF (59.8 mg, 1_49 mmol) After the treatment, the mixture was stirred at room temperature for 30 minutes. The bromo group (1.02 g, 1.44 mmol) obtained in step 1 was added to a solution of THF (2-0 ml) and added slowly. The mixture was stirred overnight at room temperature. The reaction mixture was mixed with water and extracted with ethyl acetate (3 X 5 ml). The organic materials were combined and dehydrated (Mθ () 4) and concentrated under reduced pressure. The residue was subjected to flash chromatography. Purification by method (Sio2, 3: hexane / ethyl acetate to 1: 1 hexane / ethyl acetate gradient separation) purification can be obtained 丨, 3,5-tri- [4 '[3' (3-ethyl Oxycarbonylmethylbenzyl) -4-〇 (2,3,4,0-tetramethylamino_D_l! Phenylmethyl J-benzyl (0.59 g, 60% "NMR (4㈨ 55- this paper is a universal standard for CNS) .M specifications (2U to correct the weight) Acoustic--β r Ministry of Economy Standard string 扃 贝 工 消 f 合 # 杜 印 取 457457 A7 B7_ V. Description of the invention (53)

Mllz, CDClj): 7,98 (d, J = 2,5 Η /, 3H), 7.89 (dd, J = 8,8, 2.5 Hz, 3H). 7.40-7.46 (m, 611), 7.25-7.35 (m, 12H), 5.61 (s, 3ΪΙ), 5.22-5.33 (m, 9H), 4.10-4, 25 (m, l〇H), 3-97 (dd, J = 12.1, 2, 2 Hz, 3H). 3-78-3.R4 (m. 3ΙΓ), 3.72 (s, 6II)? 3.69 (s; 3H) f 3.64 (s, 311), 2.16 (s, 9H), 2,02 (s, 9H) f 2.01 (s; 9H); 1.97 (s, 9H); 1.25 (i, .1-8.0 Hz, 9H); IR (NaCl); 1747, 1219 cnr1 ^ Step 3: The acetylene obtained from step 2 m-ester triester (0.59 g, 0.28 mmol) in THF (3 ml) with a freshly prepared sodium methoxide solution (93 mg, 400 mmol in 3 ml methanol) and then The mixture was turbid at room temperature overnight. The resulting precipitate was collected by vacuum filtration and washed with 2: 丨 THF ..__ methanol several times, and then dried under vacuum to obtain a white solid. In water (12 ml), add 2 N sodium gasified to pH 14 and stir at room temperature for 4 hours. The reaction was acidified with acid Dowex 50W ion exchange resin, filtered, and the volatile substances were removed under reduced pressure. E A fraction of the water-soluble residue was purified by reversed-phase chromatography to obtain white 1,3,5-tri- [4- [3- (3-carboxymethylphenyl) -4- (&amp; -D-pyranosyloxy) phenyl]-'oxo- 2-thiobutyl] benzene, mp: 140-143rC = 1M NMR (400 Μ [ί / .: DMSO-d6): 7.95 (dd: J = S.8, 2.5 Hz, 3TT): 7.89 (d: J-2.2 Hz, printed out of standard in the Ministry of Tanks. Printed by Fang Cooperative ^^ 1 · ^ —Ε.---IP ^ E ^^^ 1 ^^^ 1 ^^^ 1 ^^^ 1 ^ ^^ 1 ^^^ 1 '' ffJ (Please read the 16th of Min, δ, and then Jinghong π) 3H), 7.32-7.45 (ra? 12H), 7.26 (d; J = 7.3 Hz, 3H ), 7.16-7.20 (m, 3H). 5.54 (s, 3H), 5,05 (br s, 3H), 4.85 (br s, 3Ή), 4.70 (br s, 3ΤΓ), 4.50 (br s, 3H ), 3.8K-3.92 (m, 6H), 3-58-3.73 (m. 18H) f 3.40-3,49 (m, 6H), 3-30-3.40 (m, plus H20) &lt; = IR ( KBr): 3429, Π08, 1669 cm · 1. Analysis: Calculation of C75H78027S3_1.8 TTA 値: 55.12% C, 4.79% H. Experiment 値: 55.14% C, 5 ¡20% H. The scale of the paper is in violation of Zhonggu ® Jiahuahua (CNS) Λ4 * ί (缇 公 蒂) Ministry of Economic Affairs, Ministry of Economic Affairs, cooperation, and investment Cargo 457246 A7 B7 V. Description of the invention (54) Example 1 0 Combined detection and analysis of each compound detected by detection of its inhibition Π-, &quot; P ·, and / or I, selectin combined with salivary-Louis χ Capability π E-selectin binding assay analysis includes evaluation of purified HL60 cells expressing salivary-louis ^ and salivary-louis 3 Γ, _selectin, p-selectin and L-selectin recombinant proteins Capability (Cell Protein Pickup Assay) 3 Another similar binding assay uses purified _ fat and purified L-selectin toxin (_ wax-protein) to evaluate L-selectin binding Cell-to-white matter detection and analysis Η-selectin, P-selectin, and selectin are reconstituted soluble forms of fusion proteins, nuclear proteins have a hub and constant weight region I fused to mouse IgG2A cDNA and 2 Amino ray lectin, ECiF, and similar supplements of cDNA Body regulatory repeats (CR) 丨 and 2. All selectin fusion cassettes are PCR-derived from E-selectin eDNA from the R &amp; D system (Minneapolis, MN), and from human placenta using PCR P_selectin and L-selectin cDNAs were generated from all the RNA extracted. The mouse igG2A cUNA was cloned from cU> NA amplified by PCR, and the cDN A was produced from the fusion tumor cell line. 402C 1 Ψ RN A = all fusion cassettes are expressed by the defending virus vector using SF21 cells and BakPAK purchased from Clonetech. Recombinant fusion proteins are treated with baculovirus-infected culture clear solution using Dy⑽ 丨IgG-coated magnetic particles of sheep pit mice were purified by immunoprecipitation a. Control group particles (Moc.k beads) were cultured from uninfected SF2 1 and the paper was used at a moderate rate (CNS). A4 is now UI0XM7 centimeters) (Please read the note on the back to see the item on the back, and then consume this page) Order • IC---· Λ7 _____ B7 5. Invention Description (55) ---- ^-! I Install! (Jing also read the note on the back of this page 4¾¾ page) Clear solution is produced. After immunoprecipitation, The granules cultivated in the culture clear solution could not be combined with HT, 60 cells that showed salivary-Lewis κ as a negative control group. The particles cultivated with the culture clear solution that produced Η-, L- or P-selectin were Will bind to HL60 cells. HL60 cells (10? Cells) will be fluorescently labeled with Calcein AMC-3099 (Molecular Probes) in RPMI 1640 containing 10% fetal bovine serum. Magnetic particles (7 ju 1, 4 x 1 06 particle ml), 7 1 compounds of various concentrations, and 7 μΐ calcein-labeled HL60 cells were replicated and cultivated in 96-slot micro-calibration plates widely used by the two couples. Incubate the dish at 10 ° C for 10 minutes. Then place the incubator on the magnetic separator and incubate for another 2 minutes. When the assay is still in the separator, remove the iIL6 cells from the small tank and re- Wash twice with phosphate slowly saline to remove bundle-bound HL60 cells. 3 Examine the HL60 cells still bound to the granules with a microscope, and then add 50 ml]% NP40 in PBS solution to decompose the cells. Quantitate with fluorescence The technology uses a Millipore Cytofluor 2350 fluorometer to quantify the binding amount &quot; from which a dose-response curve is determined and the concentration of the compound that inhibits 50% of cell binding is determined (C5 (}). The compounds mentioned in the table below are referred to here. The better compound c The results of these tests are shown in the following table: Zhang Jilang's central sample, half-burned, burn-in, and back-up cooperation. Du Yin «-58- The paper ruler and the side are printed with Chinese house mark '&lt; CNS) A4 specifications (in Canadian *) Λ57246 Λ7 Π7 V. Description of the invention (55) In vitro selectin detection and analysis data table Compound n = or m / p subst [selectin] c5t) (mM) or% inhib "/ (mM) i] -selectin〗 c5a (mM) or% inliib · / ( mM) L-Select # WC_S () (mM) or% inhib &quot; (mM) A-4 4 5,0 2.5 2,0 A-5 5 0.4 0.3 0.3 A-6 6 0-5 0.07 0.56 A-7 7 0.5 0.4 0.75 Λ-9 9 1.0 1,0 1.0 Bm m 0/1 0.22 3.0 Bp P 2,0 2.0 3.0 c 2.5 0.7 0/2 D 29/2 0.5 5.0 Η 6 3.27 0.54 1.4 l ·. 4 KO 1.0 3 -0 G L5 iO 0/3 H 0.7 0.2 0.5 J 4.0 0/3 2.0 凊 First, go back and forth; IJ.Ail · Item Office Guru Benbei &gt; 袈 59- Roll paper music scale 4;?] Medium Ιϋϋΐ 家 梂 莲.; CNS) Eight 4 pit piles (noxw? Public dream)

Claims (1)

Order of the Central Committee of the Commonwealth of the Commonwealth of the People's Republic of China—Printed by the Industrial Cooperative Jf Cooperative 45724 · Dixiang 115658 Longyaoli Application AS In Chinese, the patent model IS is requested to amend this year (May) gj &quot; _________. Six ... V ... Shen Yi-Profit Scope I Notice r ^ _ = — Formula Compounds and Medically Acceptable Salts: _ Where X is -COOH,-(CH2) nCO〇H or -0 (CH2) nC00H and Y is-(CH2) n-,-(CH2) nW (CH2) ns. (CHAWOWtCHA.,-(CH2) nS (CH3) nS (CHA., -CO (CH2) nCO ^^-(CH2) nCOW (CH2) nWCO (CH2V '^^ W # phenyl or hexahydropyridyl, and n is 0 to 6 a 2. The compound in the first scope of the patent application, wherein γ is _ (CH2) r or CH2 (CH2) fW (CH2) fCiI2-, where f is 1 to 6 »3. The compound according to the first scope of the patent application * 1 where X Is 3-CH2C02H and Y is-(CHz) f- or -CH2 (CH2) fW (CH2) fCH2, f is 1 to 6. 4. The compound according to item 1 of the patent application scope is selected from: 1, 7, Bis- [3- (3-Carboxyfylbenzyl) -4- (2-a-D-pyranosyloxy) benzyl] heptyl · 14-bis- [3, (3-carboxy Fluorenylphenyl) -4 gas 2-〇: -0-pyranosyloxy) benzyl] hexane, ----- I -II ^^ 1 ^^ 1 n ^^ 1 π &quot; &quot; · --- -I— ^^ 1 ^^ 1 Ί _ ^^. ¢ ^ Read the note f on the t side and fill in the Japanese tile) The paper ruler Jt Fast-acting Middle China 1 National Union (CNS) mm} 4572Λ6 Α »58 CS D8 Economical but printed in the standard, printed by the Beibei Weiwei Cooperative Co., Ltd. 6. Patent application scope: bis- [3- (3-carboxymethylphenyl) -4, (2- a -D-pyranosyloxy) benzyl] pyrane τ 1,4 · bis- [3, (3-carboxymethylbenzyl) -4- (2-α -D-pyranosyl (Oxy) phenylphenylalkane, .. NfN_-bis, [4- (3- (3-carboxyf-ylbenzyl) -4- (a-D-pyranosyloxy) benzyl) butanyl] -4 , 4, Trimethylene dihexapyridine, SfS, bis- [3- (3-carboxymethylphenyl) -4- (2-a-D-mannosyloxy) -3. -1-yl] -13-dithiopropane, 1,?-Bis-P- (3-carboxymethylphenyl) -4- (2-a-D-this mannosyloxy) phenyl] -1,7-bis-oxoheptane, 1 &gt; bis- [3- (3-carboxymethylphenyl) -4- (2-a-D-pyranofurfuryloxy) phenyl] bis- Halohexane, U-bis- [3- (3-carboxyf-based benzyl) -4- (2- £ E -Dp than mannan fluorenyl) benzyl] -1,5-bis-oxo Pentane, 1,4 · bis- [3- (3-carboxymethylphenyl) · 4- (2 · α-D-pyranosyloxy) phenyl〗 -1,4-bis-oxo Butane, 5. — compound, 1,3., 5-1 · [3- (3-¾ fluorenylphenyl) -4- (2-a-Dp than mannosyloxy) benzene T group ] 笨 ° 6. —Compounds, 1,3,5_Tri · |; 4_1 &gt; (3 · Carboxymethylbenzyl) _4- (aD Pyran Glycosyloxy) benzyl] -4-oxo-2-thiobutyl] benzyl "7. The compound according to item 4 of the scope of application, which is 1,6-bis- [3- (3- Fluorenylbenzylmannanosyloxy) octyl hexadecyl, 8, a pharmaceutical composition for inhibiting the combination of selectin, P-selectin, or L-selectin with sLex or sLea, the grade Including the application for the report -2- The standard Jl used by Zhongxi «Furniture Car i CNS） A4 Washer (210X297 male *) -------- ^ d ------ Order ( Please read the U-Consul on the back before filling in isT Benwa) A672A6 Λβ CS DS Six patent application countries ^ &lt; Compounds and pharmaceutically acceptable carriers. According to the scope of the patent application No. 1 + 9 or 6 compounds, this compound is used to inhibit Ε_selectin 1 Ρ- 选 揣 t ^ force release element, or L-selectin combined with sLex or sLeaiL. U). According to the compound of claim 7 of the scope of the patent application, the compound is capable of inhibiting the binding of the E-selectin 'selectin group ea. --- 1 nn ^^ 1 I nn 士 ^ -Γ ----— 1 J- 1 {Please read the precautions on the back before filling in it) This paper is scaled with fa ® furniture ratio (CNS) A4, 210 X 297 mm. 丨 Notice clothing 丨 Application date 85. 12. 19. Case No. 85115658 — ~~ Category & -Η {V / af Chinese Manual Correction Page (August 88) A4 C4 457246 (The above blocks are filled by this Office) New i Patent Specification Chinese Committee Η is f Content &quot;; &quot; Ministry ^^! 1 | 4 ^: ^ Printed by Gongxiao Bone Cooperative—name one invention one, the creator includes a selectin (SELECTIN) inhibitor of a dimer small molecule of (pyranomannoxy) diphenyl substituted carboxylic acid English name Nationality residence, residence name (Name) Representative name of the country and residence (office) &quot; DIMEI ^ IC SSOT7L MOLECULE SELECTIN INHIBITORS ~ COMPRISING OF (MANNOPYRANOSYLOXY) BIPHENYL-SUBSTITUTED CARBOXYLIC ACID &quot; 1. Timothy P. Gauguin 2. Yien L. History Court 3. Jem M. Cassell 4. Brian Drew 1 and 4 to 7 are both US 5. Hong Daobao 6. Kevin M. Keller 7. Kathy L. Wheeler 2. United Kingdom 3. Lebanon 1. 3422 East Quaker Road, Sugar City, Texas, USA 2. 11030 Wakewin, Houston, Texas, USA 3. Houston, Texas, USA El Paso 1800 240〗 Apartment 4. No. 2421 Schweizer Avenue, Houston, Texas, USA 5. 2311 Changchun Road, Pearland, Texas, USA 6. Apartment 808, No. 8330, Elmond, Houston, Texas, USA 7. No. 120, Richmond Road, Nokana, Texas, USA, Texas Biotech, Inc. Richard, No. 7000, Houston, Texas, USA · A.. F. Dickson Paper Standards Applicable to Chinese National Standards (Bis) (CNS) A4 Specifications (210x297 mm binding Δ 5 7¾¾¾658658 patent application 4 text description ΐ amendment page (September 87) contractor code large category mouse PC classification ·: brother This case has been applied for: a patent (country) No. □ Yes □ No claim for priority □ No 0 No claim for priority The relevant microorganisms have been deposited in: Deposit date: Deposit number: --II --- Packing ------- Order -----. --Line (please read the precautions on the back before filling in the blocks on this page) Ji Decree Central Bureau of Standards, employees consumer cooperatives printed in this paper scale applicable Chinese National Standard (CNS) A4 size (210X297 mm) A7 B7 Revised Page of Chinese Specification for Patent Application No. J (September 1987) V. Description of Invention (3) (Read the precautions on the back of the first cabinet and then fill out this page) When a tissue is invaded or injured by microorganisms, white blood cells ( (Also known as Limba Ball) plays a very important role in the inflammatory response. One of the most important reactions in the inflammatory response involves the event of cell attachment. White blood cells generally appear in the circulating blood stream. However, when a tissue is infected or injured, white blood cells must be able to identify the affected or injured tissue, and be able to combine with the inner walls of microvessels adjacent to the affected tissue, and then penetrate through the microvessel to enter the affected tissue. Inside. P-selectin helps two specific white blood cells to identify the affected part and binds to the inner wall of microvessels, so that these white blood cells can penetrate into the affected composition. -White blood cells are mainly divided into three types: granules, monocytes and lymphocytes. In the above classification, E-selectin recognizes sLex present as glycoproteins or glycolipids on neutrophils and monocytes. Neutrophils are a subtype of granules that can engulf and destroy small microorganisms, especially bacteria. After passing through the wall of the microvessel and leaving the blood stream, the single plant bulb will mature into giant cells and decompose and break down the invading microorganisms, foreign objects and aging cells. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. When tissues surrounding good microvessels are infected or injured, E-selectin will be produced on the surface of endothelial cells on the inner wall of microvessels. Mononuclear spheres and neutrophil particles can pass E-selectin binds to identify injured tissue. Basically, when tissues adjacent to the microvessels are affected, the production of E-selectin and P-selectin increases. P-selectin is continuously present in storage granules and can be quickly transferred to the cell surface when the endothelial layer is activated. In contrast, E-selectin requires the synthesis of its own RNA and protein, and it peaks in about 4-6 hours after activation, and gradually decreases to -6 after about 24-48 hours-this paper size is applicable to China Standard (CMS) A4 specification (210X 297 mm) 丨 revised supplement 4 5_ £ i4s Yang patent application Chinese manual amendment page (S7 September) 5. Description of the invention (basic level. White blood cells can identify the affected The region is because the sLex part on the surface of white blood cells will bind to E-selectin and p-selectin. This form of binding will make the speed of white blood cells in the blood flow slower, because this binding occurs during integration Prior to the contact and migration of the integrin medium, the sacral ball was rolled along the activated endothelial layer, thereby helping the white blood cells to be confined to the injured or infected area. When the white blood cells migrated to the injured site, they assisted against When infecting and destroying foreign matter, excessive accumulation of white blood cells can cause damage to the tissues of the vast garden. Therefore, compounds that can block this process are available. It can be used as a therapeutic substance. It may be useful to develop inhibitors that prevent the binding of leukocytes to E-selectin or p-selectin. For example, some diseases can be treated by inhibiting the combination of selectin and sLex Including (but not limited to), Crohn's disease, septic shock, invasive shock, multiple organ failure ', autoimmune disease' asthma, inflammatory bowel disease, dry addiction, rheumatoid arthritis and Occurs in heart disease, stroke, and reperfusion injury after organ transplantation. SLea—a regiochemical isomer that is not related to SLex, except on some white blood cells In addition to the findings, sLea has also been found on many cancer cells, including lung and rectal cancer cells. It was thought that the cell adsorption effect of 31 # may also be involved in the metastasis of specific cancer cells. US Patent 5,44 〇〇〇 Description Selective inhibitors of mannanosyl diphenyl substituted derivatives and preparation methods thereof, however, it does not disclose two or Trivalent inhibitors. Invention, summary The present invention proposes a compound of formula 11 having the following structure and its pharmaceutically acceptable salts, esters, amines and prodrugs: (Please read the precautions on the back before (Fill in this page) Printed by the Consumers of the Central Bureau of Standards of the Ministry of Economic Affairs · Printed by the Society A7 B7 4 5 7 Revised page of the Chinese manual for the patent application No. 5 (September 87) V. Description of the invention (12 Zwitterionic salt printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs) is applicable to (in the declared physician and patient Contact with tissues without undue toxicity, irritating, overly constrictive responses, and have a reasonably reasonable benefit / risk ratio of 4 and its use for its intended application. The term &quot; "Salts" refers to inorganic and organic acid addition salts of the compounds of the present invention which are relatively non-toxic. These salts can be prepared at the same time as the final isolation and purification of the compound, or the purified compound can be free The form is reacted with an appropriate organic or inorganic acid or base, and then the salts formed thereby are isolated. Representative salts include bromate, hydrochloride, sulfate, bisulfate, nitrate, acetate, Oxalate, valerate, oleate, standard palmitate, stearate, cinnamate, rotten salt, benzoate, lactate, phosphonate, methylbenzoate, Citrate, maleate, fumarate Salt, succinate, tartrate, gallate, formate, glucoheptonate, lactiobionate, cinnamon sulfonate, etc. ^ It can also contain metal test or Soil metal cations, such as sodium, Syria, but, dance, hydrazone, etc., and typical toxic ammonium, quaternary ammonium and amine cations including (but not limited to) ammonium, tetramethylammonium, tetraethylammonium, Methylamine, ethylamine, difluorenylamine, difluorenylamine, diethylamine, ethylamine, etc. (See, for example, SM Berge et al., "Medical salts_'j Pharm ~ 66;! _ I? (I977), which is listed here as reference material) Pharmaceutically acceptable, examples of non-toxic esters of the compounds of the present invention include Ci 芏 基 g 旨 '' Chain or branched bells. Acceptable vinegars also include C5 to (: 7 cycloalkyl esters and aromatic groups such as (but not limited to) hexyl. Preferred are (^ to ^ alkyl esters). αThe compound of the present invention is -15- This paper is applicable in the standard _jiaxian (CNS) A4 specification (21QX2_Chu) Patent No. 4 · 5 7 2 15686 Request 4 5 7 2 4 ^ Revised manual (September 87) V. Description of invention (Scheme 8 27 (CHj) mS {CH2J / -1,3,5-Ph 33 &lt; Please read the notes on the back before filling out this page) Order a similar method to Fryde 11 with bromoalkyl bromide- Kraft reaction is available. The bromofluorene is reacted with i, 3,5_ substituted I benzenetrithiol in the presence of a compound to obtain a compound. The desired compound (21) can be obtained after the protecting group is hydrolyzed. The present invention can be illustrated by the following representative examples: Example 1 M-bis- [3- (3-Epimethylphenyl) -4- (2 -a -D- Said mannosyloxy) phenyl] hexane Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Step 1: Adipic acid chloride (2.0 g, 10.9 mmol) was first dissolved in 丨, 2 Dichloroethane (55 ml) was cooled in an ice bath. Add gasified aluminum (58 g, 43 5 mmol) followed by methyl 3- (2-methoxyphenyl) phenylacetate (575 g, 22.4 mmol) [Τ. Ρ. 柯 甘, B. Doupier, IL Scott, K. Keller, D. Dow, and P. Baker, U.S. Patent No. 5,444,050 and T_P. Cogan 30-This paper is applicable to China Standard (CNS) Α4 Regulations (210 × 297 mm) 457246 Patent Application No. 85II5086 t Specification Revision Sheet (July S9) V. Description of the Invention (37! Ϊ Positive m 6H), 2.63 (m, 4H) , 2.13 (s, 6H), 2.01 (s, 6H), 2.00 (s, 6H), 1.97 (s, 6H), lj7 (m, 4H) ppin. iR (NaCl): 1748, 1219 cm · 1. Step 6: The 6-based ester (0.87 g, 0.73 mmol) was dissolved in acetonitrile (3 mmol) and then treated with an aqueous solution of lithium hydroxide monohydrate (0.46 g, 11 mmol in 2 ml of water). Then, the mixture was stirred at room temperature overnight. Extinction: The solvent was removed and acidified to pH 2 with concentrated hydrochloric acid. A portion of the mixture was purified by reverse-phase HPLC (C18, gradient dissociation of 20-80% acetonitrile in water over 45 minutes, monitored at 254 nm) to obtain M-bis- [3- (3-carboxymethyl) as a white solid. Phenyl) -4- (α-D-mannanyloxy) phenyl] butane (230 mg), mp: 195-197. . . lH NMR (400 MHz, DMSO-d6): 7.31-7.39 (m, 6H), 6.20-7.25 (m, 4H), 7.10-7.15 (m, 4H), 5.25 (s, 2H), 4.88 (br d, J = 4.0 Hz, 2H), 4.76 (bT ss 2H), 4.60 (br s, 2H), 4.45 (br t, J = 5.9 Hz, 2H), 3.55-3.68 (m, 5H), 3.62 (s, 4H ), 3.40-3.50 (m, 7H), 2.60 (m, 4H), 1.62 (m, 4H) ppm. IR (KBr): 3333, 3229, 1729, 1224 cm · 1. Experimental value: 61.3% C, 6.15% H: C44H Calculated value of 0016.0.4 TFA &gt; 61.32% C, 5.79% H. Example 4 N, N, -bis- [4- (3-carboxymethylbenzyl) -4- (α-D-pyranosyloxy) phenyl] but-1-fluorenyl] -4,4 Trimethylene hexahydroemei. ·; 2. _ · ·. · 'Step of printing by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 1 ·· Succinic anhydride (2.0 g, 19.9 mmol) and chlorinated name ( 17.7 g (132 mmol) and 1,2-digas ethane (45 ml) were mixed and cooled on an ice bath. The mixture was treated with 3- (2- (2,3,4,6-tetratrimethylethyl) -α-mannanyloxy) phenyl] phenylacetate (10.0 g, 132 mmol) Treatment of the solution in digas ethane (10 ml) 'The temperature of the water bath is slowly returned to -40-This paper size applies to Chinese National Standard (CNS) A4 gauge · (210X297 mm) Λ7 B7 457246 Article Ml 15686 竑Chinese description of the patent application I Xiu Wang page (in July of July) 5. Description of the invention () 38 \ I —--.. · _ · J Under room temperature, stir the admixture overnight. The reactants Mix with ice water (100 ml), and stir for 15 minutes. Separate the organic material, and then extract the aqueous layer with dichloromethane (3 X 5 ml). Combine the organic materials and dehydrate (MgS〇4). · Re-decompression ·: Liaoning's "Liao" (13.5 g) can be used without purification 3 IK (NaCl): 1738, 1685, 1228 cm'1-Step 2: Acid (ϋ_) (13_5 g, 19.7 mmoles) in methane (65 ml) and treated with boron trifluoride etherate (15.3 ml, 122 mmoles). Then trifluoroacetic acid (9.4 ml, 122 mmoles) The compound was treated with triethylsilane (9.4 ml, 59.1 mmol) and stirred at room temperature overnight. The reaction was mixed with water (200 mmol) and then the organic matter was separated. Dichloromethane (3 X 10 ml) was used to extract the aqueous layer portion. The extract was combined with the original organic portion, dehydrated (MgS04), and then concentrated under reduced pressure to obtain 4- (3- (3 -Ethoxycarbonylmethylbenzyl) -4- (273,4,6-tetra · α · trifylethylfluorenyl-α-D-pyranosyl) phenyl] butanium (丄 2) (1_49g, 97%) »IR (NaCl): 1737, 1 132 cm * 1-Step 3: Treatment of acid UJ 16.0g, ΪΪ3.8 mmoles) with gaseous thionine (50ml) • The mixture was stirred at room temperature for 3 6 hours, and then concentrated under reduced pressure to obtain an acid gas which can be used directly without purification 1 £ _ (16.3 g, 99%). IR (NaCl): 2974, 1797, 1740 Π35 cm-1 ° Step 4: A solution of 474__trimethylene dihexapyridine (0.4 g, 1.9 mmol) in methane (5 ml), and the acid gas K2 was added at 0 ° C. S grams f 3.26 millimodou) in diqijia so (5 ml) solution to add 3 Ethylamine (0.61 ml, 4.4 mmol) 4-diTylaminopyridine (35 mg 1 L0 mole%), and the mixture was stirred at room temperature for 1 hour, then with water (2 041- This paper has a medium-to-medium ®® family tenon rate (CNS) A4 size ί 210x29? Male 韪 ^^ 1 In J-----^ A &quot; ^. ^ 11----ί--^^^ 1 ; ^ (Please note on the back of the page, please fill in this page) Samples of the Ministry of Health and Welfare, Employees' Poverty Alleviation Press, 1S- A 7 B7 457246 SSI 15 Post No. 6 Patent Application Decree Description Repairing the earthen tiles (July of the year) Five 'invention description () 丨 丨 repair ml) mixed. The organic material was extracted and washed with saturated potassium gas (20 ml), dehydrated (MgS04), and then concentrated by tanzine. The residue was purified by flash chromatography (Si02, 2: 1 ethyl hexanoate / hexane) to obtain bisphosphonium g * IS%) ^ NMR (400 CDClj): 7,40-7.45 (m, 4HJ, 6.98-7,30 (m, 10H) (5.25-5.42 (m. 6H), 4.09-4 19 (m, 4H), 3.50-3.96 (m, 8H), 2.62-2,69 (m, 4H ), 2.28-2,36 (m, 4H), 1.90-2.02 (m, 4H) f 1.60-1.74 (m, 6H), 1.35-1.50 (m, 2H), 1,24 (ϋ, 18H), t .ij (s, 18H), 1.11 (s, 36H), 1.08-1.28 (m, 26H)-IR (NaCl): 1739 cm'1 ^ Step 5: Dissolve diamidine g i 0.54 mmol) THF (3 ml) t, and then treated with an aqueous solution of sodium hydroxide (0.40 g, 10 mmol, in 3 ml of water). The mixture was stirred at room temperature overnight, the THF was removed under reduced pressure, and the residue was acidified with concentrated acid. It was purified to pH 2 by reverse phase HPLC to obtain N, N1 · bis_ [4- (3- (3 + carboxymethylphenyl) -4- (a, D · mannosyloxy) benzene as a white solid. Butyl) -I-hexyl] 4,4 · -trimethylene hexagas p specific bite (17, (30 mg, 5%), mp: 119-mgC-1HNMR (400 MHz, DMSO- &lt; i6): 7.32_ 7.40 (m7 6H), 7.20-7.27 (m. 4H), 7.10-7.14 (m, 4H), 5,26 (br s (2H) f 4.36 (br d, J = U Hz, 2H ) S 4.05 (br s, 8H), 3.77 (br d , J = U Hz, 2H), 3.50-3.70 (mf 8H), 3.40-3,52 (m7 5H), 3.31-3.40 (m, 2H), 2.92 (br t, J = l4 Hi, 2H), 2.55 -2.62 (m, 4H); 2 42-2.53 (m, 3H), 2.27 ^ 2.34 (m, 4H), 1.73-1.82 (mt 4H), 1.57-1,67 (m, 4H), 1.36-Γ47 ( m, 2H) T 1.22- 1,33 (m, 2H), 1.11-L20 (m, 4H) f 0.80-1.02 (m, 4H) a IR (KBr): 3415, IM3, 1609 cm]. iViS (FAB): 1150 (M + + Na) Analysis: C61H78N2Oia ".4 TFA: 59.54% C, 6 22% H, 2.18¼ N ° Experimental plant: -42- General standard tSSI home standard (CMS) A4 Gao Luo (. 公 麾) — 11 -----.― F ί I ^ Outfit ------------- (Poems First, "Please on the back;: I intend matters and then Qi Xiao (Beijing) Cooperating with China Zouzhong's Lost Rate Bureau, Industry Cooperation, and Du Yin A In the 57 2 step t§5U5658 Bailey's application for the amendment to the Chinese manual (June 90) V. In the description of the invention (44) P ;: Vacuum drying in 05 can get 2 · 6_ [3_ (3_carboxyl Alkylbenzyl) -4, (2H said mannoseoxy) phenyl 1hexyl ether (0 21 g, 7S%). (Η NMR (400 MHz, CD3CN / D20): 7.46 (2H), 7.34 (2H), 7.16 (10H), 5.31 (2H) 7 3.79 (2H) S 3.66 (2H), 3,51 (4H), 3.42 (5H) S 28 (2H), 2.56 (4H), 1.80 (4HX 1.60 (4H), 1.36 (6H). Real fd bis- [3_ (3 · | methylphenyl) _4- 〇-〇_7 ratio Mannosyloxy) _3_benzenebis-1 -yl] -1,3-dithiopropionate Step 1: _ Part eight: Put 3- (2-methoxyoxyphenyl) phenylacetate ethyl ester ( 5.04 g * 18.66 millimoles) and 3-bromobenzene gaseous (1.88 mL, 18.66 millimoles) were mixed with methane (30 mL). The mixture was cooled in an ice-water bath and treated with vaporized aluminum (7.6 g, 57 mmol). After 15 minutes, it was mixed with ice water (100 mg), and the organic matter was separated. The solution phase was extracted with a two-gauge radon gauge (3 x 5 ml). After combining the organic matter, the solution was saturated with a saturated aqueous sodium hydroxide solution (50 Milliliter) extraction, dehydration (MgS04), and then concentrated under reduced pressure a residue can be used directly in the next step without purification, part B: the product of part A (8.5 g, 1-9 millimolar) dissolved in digas methane (40 ml) and then cooled in an ice-water bath. Then add trifluoroacetic acid (5.9 ml, 76 millimoles), triethylsilane (6, 丨 ml> 38 millimoles), and tri-gas boron etherate. (9.4 ml ^ 76 millimoles) and remove the ice water bath = stir the mixture overnight at room temperature and then put it back in the ice water bath to cool and add ice water (100 ml) to stop the reaction. After the separation of the organic substance M, the aqueous phase was extracted with methane (3 X 5 ml), the organic substances were combined, extracted and washed with a saturated sodium gas solution (50 ml), dehydrated (M g S Ο 4), and then decompressed. Concentration can be obtained: J-(2-甲 -47- id (please read the weeping of the back * to save the original tile)-= 5% training Passed the Danzhongpu Gujia Standard f CNS} A4 Specification ί ZIUX mm) Carp and Ministry Order Central Sample Bureau—Gongshen Jf Cooperative Co., Ltd. Printing 45724 · No. 115658 Longyaoli Application AS Chinese Patent Application IS Amend this year (May) gj &quot; _________. Six ... V..Shen 锖 -Profit Range I Announcement r ^ _ = — Formula compounds and their medically acceptable salts: _ Where X is -COOH,-(CH2) nCO〇H or -0 (CH2) nC00H and Y is-(CH2) n-,-(CH2) nW (CH2) ns. (CHAWOWtCHA.,-(CH2) nS (CH3) nS (CHA., -CO (CH2) nCO ^^-(CH2) nCOW (CH2) nWCO (CH2V '^^ W # phenyl or hexahydropyridyl, and n is 0 to 6 a 2. The compound in the first scope of the patent application, wherein γ is _ (CH2) r or CH2 (CH2) fW (CH2) fCiI2-, where f is 1 to 6 »3. The compound according to the first scope of the patent application * 1 where X Is 3-CH2C02H and Y is-(CHz) f- or -CH2 (CH2) fW (CH2) fCH2, f is 1 to 6. 4. The compound according to item 1 of the patent application scope is selected from: 1, 7, Bis- [3- (3-Carboxyfylbenzyl) -4- (2-a-D-pyranosyloxy) benzyl] heptyl · 14-bis- [3, (3-carboxy Fluorenylphenyl) -4 gas 2-〇: -0-pyranosyloxy) benzyl] hexane, ----- I -II ^^ 1 ^^ 1 n ^^ 1 π &quot; &quot; · --- -I— ^^ 1 ^^ 1 Ί _ ^^. ¢ ^ Read the note f on the t side and fill in the Japanese tile) The paper ruler Jt Fast-acting Middle China 1 National Union (CNS) mm}