TW200804411A - Certain lithocholic acid analogues that inhibit sialyltransferase - Google Patents

Abstract

Certain chemical entities chosen from compounds of Formula I: and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof are described. Pharmaceutical compositions comprising at least one chemical entity chosen from compounds of Formula I and a pharmaceutically acceptable vehicle are described. Also described are methods for inhibiting α-2,3-sialyltransferase activity in cells, and methods for treating a patient having a disease responsive to inhibition of α-2,3-sialyltransferase activity.

Description

200804411 IX. OBJECTS OF THE INVENTION · Technical Fields Provided by the Invention There is provided a lithocholic acid analog and a pharmaceutical composition having membrane permeability and inhibiting α-2,3 sialyltransferase activity, which comprise at least one Membrane penetrability, inhibition of α-2,3 sialic acid transfer pottery: active choline acid analog; also provides a method for inhibiting intracellular α 2,3 sialyltransferase activity and a treatment for α-2,3 saliva A method in which an acid transferase activity is overactivated. [Prior Art] The saccharification of cellular proteins and lipids is an integral part of many normal cellular functions. In addition to saccharification, including sialylation, it may also be involved in the formation, metastasis and invasion of cancer cells. The process of sialylation is achieved by a sialyltransferase that transfers sialic acid, a negatively charged ninth carbonamine sugar under normal physiological conditions, to the sugar chain end of the sugar conjugate. High sialylation plays an important role in cell attachment, immune defense, and inflammation, and in many tumor models, altered sialyltransferase activity is also involved in tumor formation and invasion (Harvey et al., 1992; Majuri et al). 1995, DallOlio and Chiricolo, 2001; Wang et al. 9 2002). Specifically, a subtype of transferase-a-2,3 sialyltransferase (a-2,3ST) is up-regulated by overexpression of ras-oncogene (Easton et al., 1991). . Confirmation of potent sialyltransferase inhibitors represents an emerging approach to the development of cancer treatment, including therapies for the prevention of tumor metastasis. Many sialyltransferase inhibitors have been developed, including structurally transient transition state anal〇gues, double 200804411 bisubstrate analogues, donor analogues, cytosine-based Cyclic monophosphate N-acetylneuraminic acid (CMP-Neu5Ac) or acceptor analogues formed by disaccharide ( Skropeta et al., Glycoconjugate J., 2004, 21:205; Chang, Tao and W.-S. Li, Synlett, 2004, 37; Whalen, McEvoy and Halcomb, Bioorg. Med. Chem. Lett., 2003, 13:301; Schwoerer and Schmidt, J. Am. Chem. Soc., 2002, 124:1632; Muller, Schaub and Schmidt, Anyw·C/zem” /ηί· 1998, 37:2893). Although these compounds are effective in inhibiting sialyltransferase, they are mediated by cell membranes. Poor permeability, so its clinical application is limited. Similarly, since sialic acid is purified from natural products, it can only be obtained in small quantities, which limits its availability in clinical use (Hsu et al ·, 2005). In view of An object of the present invention is to provide a novel choline acid analog and a medicinal composition comprising choline acid which is effective for inhibiting α-2,3 sialyltransferase and improving cell permeability. Further, the present invention The object of the invention is to provide a method for the treatment of a disease caused by excessive activation of α-2,3 sialyltransferase activity. SUMMARY OF THE INVENTION At least one chemical selected from the compounds of formula I is provided: 7 200804411

And pharmaceutically acceptable salts, solvates, chelating agents, non-covalent complexes, prodrugs, and mixtures thereof. Wherein Ri is an optionally substituted alkyl group; R2 is selected from a hydroxyl group and a decyloxy group; R3 is hydrogen, or R2 and R3 together with the oxime to which they are attached form an oxy group (0X0 group); when Ri is ( /?)-4-carboxybutan-2-yl, shell 1J R2 is not a meridian. Further provided is a pharmaceutical composition comprising at least one therapeutically effective amount of a chemical selected from the compounds of Formula I and a pharmaceutically acceptable carrier therefor. Provided is a method for inhibiting the activity of α-2,3 sialyltransferase, comprising an amount and a performance of α-2, wherein at least one chemical selected from the compound of Formula I is sufficient to detect a decrease in sialylation of a sugar conjugate. 3 The cells of the sialyltransferase are in contact. Further provided is a method for treating a patient responsive to a decrease in α-2,3 sialyltransferase overactivation activity. The method comprises administering to the patient at least one chemical selected from the group consisting of a chemical compound of formula I. the amount. Other objects and advantages of the present invention will be set forth in the description which follows. 200804411 is limited to the embodiments of the embodiments set forth in the specification. All of the features disclosed may be combined with other methods, and all of the features may be replaced by other ones that have the same and equal disclosure. The features of the specification and the scope of the appended claims are v,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The chemical substance includes, but is not limited to, a person of the formula j, such as shown in Table 1, and all pharmaceutically acceptable forms thereof: a compound referred to herein as "a pharmaceutically acceptable form of a compound" includes medical Acceptable salts, solvates, crystals (including polymorphs and clathrates), chelates, non-covalent compound precursor drug mixtures. The compounds described in certain embodiments are pharmaceutically acceptable salts. Therefore, the terms "chemical entity" and "chemicalentities" also include pharmaceutically acceptable salts. Solvents, crystals (including polymorphs and cage compounds), chelate compounds, non-covalent compound precursor drugs, and mixtures thereof. The fluorenyl group refers to the chemical group -C(〇)R, and R as used herein refers to an alkyl group, a substituted alkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group or a substituted heteroaryl group. Representative examples include, but are not limited to, ethyl ketone, cylcohexylcarbonyl, cyclohexylmethylcarbonyl, benzamidine, benzylcarbonyl, and the like. 200804411 Alkanyl refers to a saturated chain, a straight chain or a cycloalkyl group derived by the removal of a hydrogen atom from a single carbon atom on a parent Hyun hydrocarbon. Typical paraffinic group functional groups include, but are not limited to, methanyl, ethanyl, pr〇panyis (eg, propyl ketone + propyl, propyl-2-yl (ie, Isopropyl), cyclopropane small group; butanyls such as: butyl-1-yl, butan-1-yl (this c-butyl), 2-mercapto-propanyl group (ie different) Butyl), 2-mercapto-propan-2-ylindolebutyl), cyclobutane-1-yl and the like. Alkenyl refers to an unsaturated group, a straight chain or a cycloalkyl group having at least one carbon atom removed by a single carbon atom on a parent olefin to have a carbon-carbon double bond. The double bonds of these functional groups may be in cis or trans configuration. Typical olefin-based functional groups include, but are not limited to, ethenyl, propenyl, for example: prop-1-en-1-yl, propyl-2-enyl, prop-2-enyl (4) lyl), c-_2 Alken-2-yl, cycloprop-1-enyl-yl, cyclopropanyl-- yl-yl; butenyl group, for example: butyl succinyl-1-yl, butyl hydrazino-2-yl, 2-methyl- Propylene small group, butane-2·en-1-yl, but-2-en-2-yl, butyl-i,3-diene small group, butyl 4,3-dien-2-yl, ring But-1-en-1-yl, cyclobut-1-ene-3-yl, cyclobutadiene-b-yl, and the like. In certain embodiments, the monoolefin functional group has from 2 to 20 carbon atoms; in other embodiments, it has from 2 to 6 carbon atoms. Alkoxy refers to a chemical group - 〇R, and r as used herein refers to an alkyl group, a substituted alkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group or a heteroaryl group. Representative examples include, but are not limited to, methoxy, ethoxy, propyl, butoxy, cyclohexyloxy, and the like. AlkoxyCarb〇nyl refers to a chemical group of _c(0)~alkane, wherein the alkoxy group is the alkoxy group referred to above. 200804411 Alkyl refers to a saturated monovalent hydrocarbon group derived from a saturated or unsaturated branched chain, a straight chain or a single hydrogen atom removed from a parent hydrocarbon, a hydrocarbon or an alkyne. . Typical alkyl groups include, but are not limited to, methyl, ethane (eg, hypoethyl, vinyl, ethynyl), propane (eg, propan-1-yl, propan-2-yl, cyclopropane-1) —yl, prop-1-en-1-yl, propan-1-isoenyl, allyl, propylene small dilute, cyclopropen-1-yl, propyl-hydrazine-alkyne— :^, propynyl, propyl-- alkyne "-yl, butane alkyl (eg butane-1-yl, butan-2-yl), 2-methyl-propanyl, fluorenylmethyl-propan -2-yl, cyclobutyl small group, butadiene + group, butyl + dilute base, 2: base-prop-1-en-1yl, but-2-en-1-yl, butyl 2-en-2-yl, butyl-U bis=b, butyl-1,3-diene 1-yl, cyclobutane-1, cyclobut-1·ene-3-indolyl-1 3-dien-1-yl, butynyl, butynyl, butyl-3-alkyn-1-yl, and the like. The term "alkyl" particularly refers to any degree of saturation of a functional group, such as a functional group of a carbon-carbon single bond, a fluorene having one or more carbon-carbon double bonds having one or more carbon-carbon triple bonds and having a mixed carbon _: early bond, double bond, and triple bond Functional group. It is a hydrocarbon group, an alkene group, and a fast hydrocarbon group according to a certain degree of saturation. In some embodiments, a soil has 1-20 stone anti-atoms; in other embodiments, the alkyl group contains - carbon atoms and is referred to as a lower alkyl group. Alkynyl refers to an unsaturated branch, a straight chain or a parent alkyne bond: an anti-atomic removal of a hydrogen atom derived from at least one carbon-carbon: = honesty. (d) (4) Hydrocarbyl groups include, but are not limited to, Ethyl wire, = ^-exemplified as a small small group of propyl groups, such as: butyl small base, butyl, -3-yl, butynyl and the like. In certain embodiments, 11 200804411 alkynyl has 2 to 2 carbon atoms; other carbon atoms are depleted. Also, in the sample, the 3_6 amino group means a chemical group -NH2. Aminocarbonyl refers to R and R, which are each selected from hydrogen, 埝(O)NRR functional groups, in cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted The alkyl group is substituted with a nitrogen atom attached to R and R, a heteroaryl group, or an arbitrary hetero ring. One or more heterocyclic or aromatic groups (Aryl) comprising: a five- and six-membered fluorene bicyclic system wherein at least one ring is a carbocyclic ring and a non-fragrance ring, for example: benzene; tetralin; and tricyclic; A system, at least, for example, naphthalene, anthracene, for example: hydrazine. For example, the aromatic ring includes a five-membered and six-membered aromatic ring-breaking ring that is attached to the carbocyclic ring and the aromatic ring, and the one to more than one or more selected from the group consisting of nitrogen and oxygen. Sulfur heterogene: where the cycloalkyl ring system contains a bond, in the double ring system, only one carbocyclic ring I is attached to the carbocyclic aromatic ring or heterocycloalkyl ring. Bivalent beauty, the junction may form and the ring atom has a free valence, which is called; the derivative is derived from a monovalent polycyclic hydrocarbon, which is named after the living base. Divalent group: A hydrogen atom is removed from a subatomic atom; the added word has a value from j to a unit price. For example, the extraction |en:" with two junctions is, however, the aromatic group does not contain or is a naphthylene group. Cover, therefore, if one or more of the ... ^ & 2 jin 疋 疋 疋 杂 杂 芳 在 μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ 芳The cyclo-ring cyclist is substituted by a aryl group to a hydrogen atom on the lanyard to a typical terminal carbonogen 12 200804411 or w3 carbon atom. Typical aralkyl groups include, but are not limited to, benzyl, 2 # alkanedi-, Styrene + yl, naphthyl fluorenyl, 2 - naphthylethyl bromide = ethyl 2-naphthylethylene m, benzylidene, 2 (10) phenyl quinone, an analog thereof, wherein the specific (four) group It is named after an aromatic hydrocarbon group t and a s- or an aryl-alkyne group. In certain embodiments, an alkane: an aralkyl group of a hydrocarbon of thirty carbons, for example, an alkane of an aralkyl group Two: The alkyne group y is - to ten carbons, and the aromatic group of the aryl group can be = or twenty carbons. 疋 /, yl 、,,,,,,,,,,,,,,,,,,,,,, 〇-R, wherein R is selected from the group consisting of aryl groups. 曰 (三) or substituted carbonyl means a chemical group - c (〇). The term "cancer" as used herein refers to Or physiological state, its cells A cancer with compound treatment disclosed in an abnormally finely planted animal, including it sputum. Current tumor, Indian cancer, breast cancer, endometrial cancer, cell colorectal cancer, colon cancer, digestive tract, lung cancer, Renal kidney, sputum tumor, lymph, prostate cancer, pancreatic cancer, terminal cancer, hairy sputum, chronic myelygenous leukemia, terminal-g mega-cell leukemia, renal cell carcinoma, non-ho Jigkin's lymphoma: two = cell metastasis, terminal melanoma, gastric cancer, non-small cell lung cancer, adenocarcinoma, renal cell carcinoma, multiple solid tumors, multiple m:,,, cytoplasmic lung prostate cancer , malignant glioma, multiple renal sputum θ (7) tumors, metastatic refractory metastatic disease, refractory multiple secondary = medullary tumor, lymphoma, Kaposi's sarcoma, recurrent degenerative nerve glue, 13 200804411 More specifically, cancers currently treated with compounds are disclosed, including but not limited to the heart: sarcoma (vascular aneurysm, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fiber , lipoma, malformation; lung: bronchial lung cancer (squamous cells, undifferentiated small cells, undifferentiated large cells, adenocarcinoma), alveolar (bronchiolar) cancer, bronchial adenoma, sarcoma, lymphoma, cartilage hamartoma , mesothelioma; gastrointestinal tract: esophagus (squamous cell tumor, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (pancreatic ductal adenocarcinoma, insulinoma, pancreatic Glycanoma, gastrinoma, carcinoid, Kaposi's sarcoma, uterine fibroids, hemangioma, lipoma, neurofibromatosis, fibroids, large intestine (adenocarcinoma, tubular adenoma, villous adenoma, Hamartoma, uterine fibroids, genitourinary tract: kidney (Adenoma, Wilms' tumor (renal blastoma), lymphoma, blood cancer), bladder and urethra (squamous cell tumor, transitional epithelial cell carcinoma, gland Cancer), prostate (adenocarcinoma, sarcoma), testis (sperm cell carcinoma, teratoma, embryonic cell carcinoma, teratoma, villus, sarcoma, stromal cell tumor, fibroid, fibroadenomas, adenocarcinoma Tumor, lipoma), liver: Cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Juventus Sarcoma, malignant lymphoma (reticulocyte sarcoma), multiple bone tumor, malignant notochord giant cell tumor, osteochronfroma (chondral exogenous bone fatigue), benign chrodroma, chondroblastoma, chondromyxoid fibroid, bone Osteomas and giant cell tumors; nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, deformity osteitis); meninges · (meningioma, meningioma, glioma), brain (stellate cells) Tumor, neuroblastoma, glioma, ependymoma, germ cell tumor (pine pine adenoma), glioblastoma multiforme, oligodendroglioma, schwannomas, retinoblastoma, Hereditary tumor), spinal cord tumor, neurofibromatosis, 14 200804411 meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer), cervix (cervical cancer, pre-neoplastic Cervical cytopathic (Pre-tumor cervical dsplasia), ovary (ovarian tumor (serous cystic adenocarcinoma, drilling fluid cystic adenocarcinoma, granulose-thecal cell tumors), supporting cell Leydig cells Tumor, embryonal tumor, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial neoplasia, adenocarcinoma, firosarcoma, melanoma), vaginal (leukocytic carcinoma, squamous cell carcinoma, sarcoma of squamous cell (embryonic rhabdomyosarcoma) , fallopian tube tumors; blood: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hawking's disease, Non-Hodgkin's disease (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, hyperplasia, lipoma, hemangioma, cutaneous fibroids, neoplasms, psoriasis; Adrenal gland: neuroblastoma. Carboxy refers to a chemical group -C(0)0H. "Cleavage" refers to the destruction of a chemical bond and is not limited to chemical or enzymatic reactions or mechanisms unless explicitly indicated in the context. The term "chelating" refers to a chemical group formed by the coordination of one or more points of a compound with a metal. ^ Cycloalkyl refers to a non-aromatic carbocyclic ring, usually having from 3 to 7 ring carbon atoms. The aforementioned ring carbon may be saturated or have one or more 'carbon-stone reverse double bonds. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentamethylene group, a cyclopentenyl group, a cyclohexyl group, a cyclohexenyl group, and a bridged and caged saturated ring groups, such as: A seedling (n〇rb〇r leg e). 15 200804411 Dialkylphosphonate refers to a free radical -P〇(〇Ra)(〇Rb)' where Ra and Rb are the same or different. "Disease" means any disease, abnormality, symptom, sign and sign. "Halogen" or "halogen" means a fluorine, gas, bromine or iodine functional group. "Heteroaryl" includes: a five- to seven-membered aromatic, monocyclic ring containing one or more (eg, four, or in some embodiments, one to three) selected from the group consisting of nitrogen, oxygen, and sulfur. a hetero atom, the remaining ring atoms are carbon; and the double miscellaneous ring contains one or more (eg, one to four, or in some embodiments, the core is one to two) selected from nitrogen, oxygen, sulfur The atom, i is in the form of a carbon, wherein at least one hetero atom is present in the aromatic group. For example, the aryl group includes a five- to seven-membered heteroalkyl aromatic ring bonded to a five- to seven-membered alkane ring. . To achieve such a bond, only one ring in the double heteroaromatic ring system contains one or more heteroatoms and the junction can be on the heteroaryl ring or the burn ring. When the total number of sulfur and oxygen atoms on the aryl group exceeds one, these heteroatoms are not bonded to other heteroatoms. In certain embodiments, the total number of sulfur, & atoms on the filament is no more than two; in certain embodiments, the total number of sulfur and oxygen atoms on the aromatic heterocycle is no more than one. For example, a heteroaryl group includes a five to seven member miscellaneous aromatic ring bonded to: to a ring. In order to achieve such a ring system, only one ring contains one or more heteroatoms, and ^ can be located on the heteroaryl ring. When the sulfur and oxygen atom j on the heteroaryl group exceeds -, the secret atom does not meet other heteroatoms. Second, the total number of sulfur and oxygen atoms in the medium heteroaryl group is not more than two; the total number of sulfur and oxygen atoms in the medium aromatic heterocycle is not more than one. Examples of square radicals include, but are not limited to, (from a bonding group, a 3 (tetra) group, a ke group, a group, 3 = 2 16 200804411 2, 4-pyrimidinyl, 3,5-pyrimidinyl, 2,3-pyrazole Ortholinyl, 2,4-imidazolinyl, isoindole, sigma, sigma, sigma, thiadiazolinyl, tetrazolium, sigma, Substituting benzothiophenyl, fluorenyl, benzoxanthyl, benzoimidazolinyl, dihydro-bromo, pyridiziny, triazolyl, quinolyl, pyrazolyl and 5 , 6,7,8-tetrahydroisoquinoline. The divalent group is derived from a monovalent heteroaryl group whose suffix "yl" refers to the removal of a deuterium atom from an atom having free mussels; The tail r idene 疋 is in accordance with the monovalent group. For example, a π ratio η having two joints is called a pyridylidene. However, the aromatic group does not contain or overlap with the above-mentioned aromatic group. In some embodiments, the heteroaryl group can be derived from thiophene, a ratio of 17 to each, a benzophenanthrene, a benzopyrene, a bud, a bismuth, a quinone, a miso, a carbazole, a pyridyl Bismuth, benzoxazole, isoxazole And σ- oxazole. "Hybrid aryl" and "heteroalkyl" refer to a cyclic alkyl group substituted by a heteroaryl group, the hydrogen atom of which is bonded to a typical terminal carbon atom or pregnant. 3 carbon atoms. In certain embodiments, the heteroarylalkyl group may be a six to thirty membered heteroarylalkyl group, for example, a heteroarylalkyl group and an aralkyl group refer to a ring substituted with a heteroaryl group. a hydrogen group on the cycloalkyl group bonded to a typical terminal carbon atom or a W3 carbon atom. In some embodiments, the 7 heteroaryl group may be a six to twenty membered heteroaryl group, for example The heteroaryl, alkenyl or alkynyl group of the heteroarylalkyl group may be a one to ten membered heteroaryl group and the heteroalkyl group may be a five to twenty membered heteroaryl group. """ refers to a fatty monocyclic ring, usually having three to seven ring atoms, the ring atom comprising at least two carbon atoms, one to three heteroatoms individually selected from oxygen, sulfur, nitrogen, and combinations of at least one of the foregoing heteroatoms Suitable heterocycloalkyl groups include, for example, (the number from the junction as 1}: 1 pyrrolyl, 2,4-imidaZ〇lidiny, 2,3" ratio Azolidinyl, 2·acridinyl, 3_ 17 200804411 呱 base, 4-bite base and 2,5_piperzinyl. 淋 基 也是 is also included in the consideration of choice, including 2-lineline and 3_linen (The number from the junction is taken as 1.) The substituted heterocyclic thiol also includes a ring system formed by one or more substitutions such as (=〇) or oxide (-0), for example: & Oxidation 疋 疋 、, N-oxidized morpholino, ^ oxy + thiomorpholinyl (l-〇x〇-l-thi〇morph〇linyl) & U_dioxosylthiopyrine . The term "metastasis" and grammatically identical means the process by which cancer spreads or metastasizes from the primary site to other sites, and the development of cancerous lesions also occurs in new sites. The term "non-covalent compound" refers to a chemical group formed by the interaction of a compound with other molecules, and does not form a covalent bond between the compound and the molecule. For example, mismatch reactions can result from VanDer Waals interactions, hydrogen bonding, and electrostatic forces (also known as ionic bonds). "Optional" or "optionally" means that the event or circumstance described later may, but does not necessarily occur, such that the narration includes instances in which an event or circumstance may or may not occur. For example, "selectively substituted alkyl" as used hereinafter includes "alkyl" and "substituted alkyl". In the same field of the invention, 'a person familiar with the art knows that any functional group containing one or more substituents is sterically hindered, synthetically unfeasible, and inherently unstable, and it is impossible to produce any substitution reaction or The alternative means "patient" or "individual" means an animal, such as a mammal, that has received or will be treated, observed or tested. The method of the invention is effective for both human and veterinary applications. In some embodiments, the "patient" is a mammal, and in other embodiments, the "patient" is a human.

1R 200804411 “Pharmaceutically acceptable” means a Pharmacopoeia that has been or is approved by the federal regulatory agency, the state government, or listed in the US Pharmacopoeia or other generally recognized animal (including human). "Pharmaceutically acceptable salt" means a pharmaceutically acceptable salt compound which has specific pharmaceutical activity. Such salts include: (1) from inorganic acids (such as: hydrochloric acid, hydrobromic acid, sulfuric acid, tribasic acid, phosphoric acid and the like) or organic acids (such as: acetic acid, propionic acid, caproic acid, cyclopentyl Acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, catalyzed acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid , cinnamic acid, mandelic acid, mercapto sulfonic acid, ethyl tarnishic acid, 1,2-ethane-di-dilybetic acid, 2-ethyl-ethyl-retinic acid, benzoic acid, 4-rhamninoic acid, 2-naphthalenesulfonic acid, 4-methylsulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid Acid addition of trimethyl hydroxyacetate, tertiary butyl acetate, lauryl ether sulphuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, hexadienedioic acid and the like a salt; or (2) due to the presence of a compound or an acidic proton that is replaced by a metal ion (eg, a metal ion, a soil metal ion, or a sulphur ion) or with an organic base (eg, ethanolamine, diethanolamine, triethanolamine, a salt formed by the action of N-glucamine, dicyclohexylamine, and the like. "Pharmaceutically acceptable excipient, carrier or adjuvant" means an excipient, carrier or adjuvant that can be administered to a body with at least one of the currently disclosed chemical substances without destroying its pharmaceutically active activity. It does not cause toxicity to the individual when a sufficient amount of the compound has been administered. "Pharmaceutically acceptable carrier" means a diluent, adjuvant, excipient or carrier with which at least one of the currently disclosed chemical substances is applied. 19 200804411 "Precursor drug" means a derivative of a therapeutic compound which must be transformed in vivo to produce a therapeutic compound. The prodrug may be pharmaceutically inactive prior to conversion to the parent compound. "Protecting group" means that when a group of atoms are attached to a molecule of a reactive group, the reaction force is blocked, reduced or suppressed. Examples of protecting groups can be found in "Protective Groups in Organic Chemistry," by Wiley, 2, ed. i991, and Harrison et al., "Compendium of Synthetic Organic Methods," Vols 1-8 (John Wiley). And Sons, 1971-1996) found. Representative amino protecting groups include, but are not limited to, indolyl, ethyl fluorenyl, trifluoroacetamidine, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS,,), 2-trimethylsilyl-ethanesulfonyl ("SES,,), trityl and substituted triphenyl fluorenyl, allyloxycarbonyl, 9-anthoxycarbonyl ("FMOC") ), nitro-veratryloxycarbonyl ("NVOC") and its analogs. Representative hydroxyl groups include, but are not limited to, (these hydroxyl groups have been deuterated or denatured), for example: T-based, triphenyl decyl ether, alkyl ether, tetrapyridyl pyridyl ether, three burnt stone eve Trialkylsilylethers and olefins. The "therapeutically effective amount" of the chemical substance of the present invention means that when an effective amount is administered to a human or non-human patient, the therapeutic effect can be provided, for example, improving symptoms, slowing the course of the disease, and preventing the disease. A "therapeutically effective amount" may be sufficient to reduce the symptoms of the disease caused by excessive activation of alpha-2,3 sialyltransferase. In some embodiments, a therapeutically effective amount, which is sufficient to reduce the symptoms of cancer, is 'a therapeutically effective amount' in some embodiments, which is sufficient to reduce the number of measurable cancer cells in an organism. In the implementation of the sadness in this practice, the 'effectiveness in treatment' is sufficient to detect the spread of tumors. 20200804411 or stop growing; in some embodiments, the "therapeutically effective amount" is sufficient to shrink the tumor. In some cases, patients with cancer may not have symptoms of the disease; in some embodiments, an effective amount of a chemical is sufficient to prevent tumors from significantly increasing or decreasing measurable cancer cells. The number or tumor marker appears in the blood, serum or tissue of the patient. /"Treatment" or "Treating" means any treatment of a patient with a disease, including disease prevention, that is, the clinical symptoms of at least one disease will not continue to develop; inhibit the disease; slow or hinder to y The development of the disease symptoms of the disease; and the relief of the disease, that is, the clinical symptoms of at least one disease. "Treating" or "Treatment" also means inhibiting a physical (eg, stable and identifiable symptom) or physiological (stable physiological indicator) or both, or inhibiting at least one individual. Identifyed physiological indicators. Further, "treating" or "treating" refers to delaying the progression of a disease or an individual who is likely to be exposed to or susceptible to disease, at least one clinical symptom, even if the individual has not experienced or revealed symptoms of the disease. "Substitution" means that in a monofunctional group, one or more hydrogen atoms are each replaced by the same or a different substituent. Typical substituents include, but are not limited to, -X, -R33, -0., = 0, -OR33, -SR33, -S, =S, -NR33R34, =NR33, -CX3, -CF3, - CN, - 0CN,- SCN,-NO,-N02, =N29 -N35 -S(0)20\ -S(0)20H, -S(0)2R33? ~0S(02)0\ -0S(0)2R33? A P(〇X〇-)2, -p(o)(or33)(o), -op(o)(or33)(or34), -c(o)r33, -c(s)

R33, -C(0)0R33, -C(0)NR33R34, -C(0)0\ -C(S)OR33, -NR35C(0)NR 33r34, one nr35c(s)nr33r34, one nr35c(nr33) Nr33r34, —c(nr33)nr33r34, -s(o)2nr33r34, -nr35s(o)2r33, —nr35c(o)r33 and —s(o)r33, each of which is a halogen; each R33, R34 Are argon, alkyl, 21 200804411 A, ruthenium diaryl, substituted aryl, aryl, substituted aryl, cyclopentadienyl (tetra), heterocyclic, substituted heterocyclic, heteroaryl, desorbed , 35 heteroaralkyl, substituted heteroaralkyl, nr35r36, -C(〇)R35 or -S(〇)2r or r33 and r34 are selectively attached to the atomic ring, straightening, alkane, Heteroaromatic ring, substituted (tetra) ring 1 ^A - 舁R, respectively, hydrogen, alkyl, substituted alkyl, aryl, substituted = 2 alkyl, arylalkyl, cycloalkyl, substituted ring & a hetero Wei group, a substituted heterofilament, a heteroaryl or a aryl group; or R and R36 are optionally substituted with a nitrogen atom attached thereto or a plurality of heterocyclic rings Heterocyclic ring, heteroaryl ring, and = heteroaryl ring. In certain embodiments, the tertiary amine or nitrogen-containing aromatic compound can be substituted with one or more oxygen atoms to form the corresponding nitrogen oxide. , -s(o)2nr33r34, -nr35s(o)2r33, -nr35c(o)r, cyclyl, c5_1()heteroaryl, 33-nr33r34 35~a, d33 In certain embodiments, substituted aryl Substituted heteroaryl groups include one or more of the following substituents: fluoro, chloro, dimethyl, C13 alkyl, substituted leuco, Ci3 oxy-CF3, =0CF3, -CN, C5-H) alkyl, C5_1G substituted Base, c5_1()heteroaryl, c5, substituted heteroaryl-C(0)0R, -N〇2, -C(0)R, -C(〇)nr33r34, -〇cHF2, Cu group, -SR33 ,, -S(0)20H, -S(〇)2R33, _s(〇)r33, _c(S) R33, -c(0)0-, -c(s)〇R33, -NR35C(〇)NR33R34 _nr3 = (s) nr33r34 and _c(nr35)nr33r34, c3 8 cycloalkyl and C3 8 substituted % alkyl, Cs-8 heterocycloalkyl and C3. 8 substituted heterocycloalkyl. In certain embodiments, the substituted aryl and substituted heteroaryl groups include one or more of the following substituents: fluorine, gas, bromine, Cl_3 alkyl, substituted alkyl, 22 200804411

Ci.3 alkoxy, -S(0)2NR33R34, -nr33r34, -CF3, -OCF3, -CN,-nr35s(0)2R33,-NR35C(O)R33,C5-10 aryl, substituted alkyl, C5_10 substituted aryl, C5-H)heteroaryl, C5-10 substituted heteroaryl, -C(0)0R33, -N〇2, -C(0)R33, -C(0)NR33R34, mono-CHF2 ,

Cl-3, a group of SR33, -S(0)2〇H,-S(0)2R33, -S(0)R33, —C(S)R33, —C(0 )0\ -C(S OR33, an nr35c(o)nr33r34, -nr35c(s)nr33r34 and -c(nr35)nr33r34, a C3_8 cycloalkyl group and a C3-8 substituted cycloalkyl group. In certain embodiments, substituted aralkyl and substituted heteroarylalkyl include one or more of the following substituents: Cm alkoxy, -NR33R34, c5_1() substituted heteroaryl, -SR33, Cm alkoxy, -S(0)2NR33R34, cyano, fluoro, chloro, -CF3, -OCF3, -NR35S(0)2R33, —nr35c(o)r33, c5-10 aryl, c5_10 substituted aryl, c5_1() heteroaryl Substituent, c5_1() substituted heteroaryl, C(0)0R33, -N02, -C(0)R33, -C(0)NR33R34, -0CHF2, Cm acyl, one S(0)20H, one S(0 ) 2R33, a S(0)R33, —C(S)R, -C(0)0, a C(S)OR33, an NR35C(0)NR33R34, —NR35C(S)NR33R34, and —C(NR35 NR33R34, C3-8 cycloalkyl and C3-8 substituted cycloalkyl. In certain embodiments, a substituted alkenyl group includes one or more of the following substituents: C1-8 alkyl, substituted institutional, C5-10 aryl, C5-10 substituted aryl, C5-H) heteroaryl, C5_1() substituted heteroaryl, c3-8 cycloalkyl, c3-8 substituted cycloalkyl, cycloheteroalkylalkyl and substituted cycloheteroalkylalkyl. The term "substituted amino" refers to a functional group -NHRd or an NRdRd wherein each R is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, fluorenyl, substituted oxime 23 200804411 aryl, substituted Aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocycloalkyl, alkoxycarbonyl and thio. Representative examples include, but are not limited to, dimethylamino, methylethylamino, bis-(1-methylethynyl)amino, (cyclohexyl)(methyl)amine, (cyclohexyl) (ethyl) Amino, (cyclohexyl) (propyl) amine groups and analogs thereof. Providing at least one chemical selected from the group consisting of the compounds of Formula I:

And pharmaceutically acceptable salts, solvates, chelating agents, non-covalent complexes, prodrugs, and mixtures thereof. The core is an arbitrary alkyl group; R2 may be selected from a trans group and an acidoxy group; R3 is hydrogen, or r2 and r3 together with the carbon to which it is attached form an oxy group (OXO group); when Ri is a carboxyl group-2 -Base, then R2 is not a warp group. In certain embodiments, the oxime is selected from the group consisting of -CHR4(CH2)nR5, η is 2 and 3; R4 is selected from hydrogen or an optionally substituted lower alkyl group; and R5 is selected from the group consisting of a carboxyl group, a guanamine group, and a selective substitution. Heteroaryl. In certain embodiments, n is 2; in certain embodiments, η is 3; in certain embodiments, R4 is selected from argon or a lower alkyl group; in certain embodiments, r4 is a lower alkyl group. In certain embodiments, R4 is methyl; in certain embodiments, R5 is selected from the group consisting of carboxy, -(C0)-NHR6, and an optionally substituted triazole, wherein r6 is selected from an optionally substituted lower alkyl group. . 24 200804411 In certain embodiments, R^-CHR4(CH2)nR5, wherein η is 2 and 3, & is selected from hydrogen or an optionally substituted lower carbon number; and & is selected from the group consisting of: (CO)-NHR6 and a substituted triazole wherein the triazole ring system is substituted with a monofunctional group r?, and R7 is an optionally substituted lower alkyl group. In certain embodiments, R6 is selected from the group consisting of lower alkyl groups that are optionally substituted with one or two carboxyl groups. In certain embodiments, & is a substituted triazole whose substituent is selected from the group consisting of a low carbon number alkyl group selectively substituted with one or two thiol, gas groups, and dialkylphosphonate The lower alkyl group is substituted with at least one carboxyl group. In certain embodiments, R! is selected from the group consisting of: (and)-5-hydroxypentan-2-yl; (R)-5-(demethylmethylamine)-5-oxopent-2-yl; (R)-5-((S)-l, 2c tracylethylamine)·5-oxopentanyl; (R)-5-tetra-butoxy-5-oxopentan-2-yl; (R)-4-carboxybutan-2-yl; (R)-5-(4-(2-hydroxypyrazolyl)pentan-2-yl; (R)-5-(4-( 2-amine-2-carboxyethyl bromide) cut 4,2,3-triazole small group)pentane_2-yl; (R)-5-(4-(2-weiyl-2-(diethoxy) Phosphonic acid)ethyl)triazole small)pentan-2-yl; (8)-5-(4-(2-carboxyethane)-in-1,2,3-triazole small) pentan-2-yl (R)_5K3-carboxypropyl)-- 1,2,3-triazole small group) amyl-2-yl; and (R)-5-(diphenylphosphinic acid)pentane: yl. 25 200804411 In certain embodiments, R2 is selected from the group consisting of hydroxyl, 3-carboxypropenyloxy, and (R)-2-amine-3-carboxypropenyloxy. In certain embodiments, R3 is hydrogen. In certain embodiments, R2 and R3 are attached to carbon to form an oxy group. Further provided is a pharmaceutical composition comprising at least one chemical and a pharmaceutically acceptable carrier, wherein said therapeutically effective amount of the chemical is selected from the group consisting of Formula I. Further provided is a method for inhibiting the activity of α-2,3 sialyltransferase, comprising an amount and a performance α of at least one chemical selected from the compound of formula I, which is sufficient to detect a reduction in sialylation of the sugar conjugate. The cells of the 2,3 sialyltransferase are in contact. In certain embodiments, the cell line is a cancer cell; in certain embodiments, the cell line undergoes a cell migration process; in certain embodiments, the aforementioned cell line is accompanied by cancer cell migration; in certain embodiments, the cell is present in Mammal; in certain embodiments, the mammal is a human. Further provided is a method of treating a patient suffering from a disease responsive to inhibition of alpha-2,3 sialyltransferase overactivation, comprising administering to the patient at least one therapeutically effective amount of a chemical selected from the group consisting of: I. In certain embodiments, at least one of the aforementioned chemical species selected from Formula I comprises a pharmaceutical composition. In certain embodiments, the disease responsive to inhibition of alpha-2,3 sialyltransferase activity is cancer; in certain embodiments, the cell line undergoes a cell migration process; in certain embodiments, the aforementioned cell migration system is accompanied Cancer cell migration; in certain embodiments, the cell is present in a mammal; in certain embodiments, the mammal is a human. In certain embodiments, the method of treating a patient having a response to inhibition of alpha-2,3 sialyltransferase overactivation comprises administering to the patient at least one treatment that affects the combination therapy Agent. In certain embodiments, the pharmaceutical composition can comprise at least one currently disclosed chemical and a therapeutic agent that has an effect on the combination therapy. The chemical substances disclosed in the present invention can also be used in combination with conventional therapeutic agents and anticancer drugs. Those skilled in the art are able to distinguish between the combination of drugs and the nature of the drug and the type of cancer involved. In this field, there are a variety of chemotherapy methods, including, but not limited to, estrogen receptor modulators, cytostatic/cytotoxic agents, antiproliferative agents, cell cycle checkpoint inhibitors, angiogenesis inhibitors. Monoclonal antibody targeted therapeutic agents, lunar acid kinase inhibitors, serine/sarranic acid kinase inhibitors, histone deacetylase inhibitors, heat shock protein inhibitors And farnesyl transferase inhibitor. The chemical substances disclosed in the present invention can also be used for radiation therapy. In order to confirm the effect of treatment prevention before application to humans or other mammals, the chemical substances disclosed in the present invention may be tested in vitro and in vivo first. For example, in vitro assays can be used to determine whether to administer a specific compound disclosed or to use a compound that is effective in inhibiting alpha 2,3 salivary transferase activity or at least treating a disease. In some of the examples, the percent inhibition concentration in the chemical & mass in vitro biochemical activity assay for inhibition of alpha-2,3 sialyltransferase activity is referred to herein. Less than 25 () μΜ, in some embodiments, the semi-inhibitory concentration of the inhibiting substance in the body: biochemical activity analysis is less than: ΙΟΟμΜ, in some embodiments, the α_2 is inhibited herein. 3 sialic acid. The chemical activity of the enzyme activity in vitro biochemical activity (IC5〇) is less than 25μΜ; 辰度27 200804411 The chemical substance disclosed in the present invention can also show that the animal model system is effective and safe. In certain embodiments, a therapeutically effective amount of at least one of the chemicals disclosed herein provides a therapeutic benefit without substantial toxicity. The toxicity of the currently disclosed chemical substances can be quickly confirmed by a person skilled in the art using a standard pharmaceutical procedure. The dose ratio between toxic and therapeutic is a therapeutic index, and the chemical disclosed herein may exhibit a high therapeutic index in treating a disease or abnormality. The dosage of the compounds disclosed herein may be in the range of a small or non-toxic circulating concentration. In the case of a medicament, the chemical substance disclosed in the present invention can be administered in the form of a pharmaceutical composition. Such compositions may be prepared in a manner well known in the pharmaceutical art and may comprise at least one of the chemicals disclosed herein. In the treatment of a disease, a therapeutically effective amount of the chemical disclosed in the present invention can be administered. It can be understood that the doctor can determine the amount of the compound to be administered according to the relevant conditions, including the treatment situation, the choice of the administration route, the actual compound to be administered, the age, the body weight, the reaction after the individual is beaten, and the serious symptoms of the individual. Degree and similar situations. The pharmaceutical compositions disclosed herein may comprise a therapeutically effective amount of a chemical as disclosed herein and a pharmaceutically acceptable carrier. The pharmaceutical compositions disclosed herein may additionally comprise an additional compound which enhances the efficacy of one or more of the chemicals disclosed herein. For example, but not limited to the theory, by effectively increasing the concentration of such compounds in plasma; or reducing the degradation of currently exposed chemicals prior to application, during plasma delivery, or in plasma; or By increasing the absorption of the compound by the gastrointestinal tract to increase the concentration in the plasma, the efficacy of the currently disclosed chemical substances can be improved. The pharmaceutical composition disclosed herein may additionally comprise a therapeutic agent 28 200804411 which is normally administered to treat a disease or disorder to provide a combination therapy as described above. Certain embodiments disclosed herein are directed to compositions comprising one or more chemical substances as active ingredients for use with pharmaceutically acceptable excipients. In making certain of the compounds disclosed herein, the active ingredient may be mixed with excipients, diluted with excipients, or enclosed in a capsule, sachet, paper, or other similar container. When the excipient serves as a diluent, it may be a solid, semi-solid or liquid material which is a carrier (e.g., carrier) as an active ingredient. Thus, for example, the foregoing compositions may be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, soft capsules, hard capsules, and, for example, A syrup having from about 1 to 90% by weight of at least one of the compounds disclosed herein. When preparing a compound, the active compound must be ground to an appropriate size before being combined with other ingredients. If the active compound is insoluble, the active compound can generally be ground to a particle size of less than 200 mesh; if the active compound is water soluble, the particle size can be provided by milling to provide a single form of particle size, for example: 40 Head. Examples of suitable excipients include, but are not limited to, lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, sarcophagus, micro Crystalline cellulose, polyethylene σ pyrrolidone, modified cyclodextrin, cellulose, water, syrup and methyl cellulose. Some compositions may additionally comprise: lubricants such as: talc, magnesium stearate, mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propylhydroxy-benzoates; sweeteners; Agent. It has now been disclosed that the compounds of 29 200804411 can be formulated to provide rapid, sustained or slow release of the active substance when administered to a subject using conventional procedures. (To the end of paragraph 076) 'Some of the disclosed compounds can be formulated in unit dosage form, each dose including, for example, about 0.1 mg to 2 g of active ingredient. As used herein, "unit dosage form" refers to a physically separable unit that is suitable as a single dosage of the human body and other mammals; each unit contains a predetermined amount of active substance that is predetermined to produce a predetermined effect, and A suitable pharmaceutical excipient, diluent, carrier and adjuvant are used in combination. In certain embodiments, the presently disclosed compounds can be formulated in multiple doses. The amount of chemical currently disclosed can be used in conjunction with other substances and therapeutic agents to produce a single dosage form composition that is disclosed as being variable with the disease, the individual, and the particular mode of administration. To prepare a solid composition such as a tablet, the principal active ingredient may be combined with apharmaceutically acceptable excipient to form a solid pre-formulation composition comprising a homogeneous mixture of the presently disclosed compounds. Reference to these pro-fermentation formulas' means that the active ingredients therein are evenly distributed throughout the composition so that the composition can be quickly divided into single dosage forms of the same efficacy as tablets, pills and capsules. The pre-solids formulation can be subdivided into a single dosage form that is therapeutically effective from about 0.1 mg to 2 g. Tablets and pills containing certain compositions disclosed by uranium can be coated or otherwise provided with a long-lasting dosage form. For example, a tablet or pill may contain an inner dosage component and an outer dosage component, while the latter encloses the former. ^The two components are separated by an entere layer to resist disintegration in the stomach 30 200804411 and allow the internal dose component to reach the duodenum or #, slow release of internal dose components. A variety of materials can be used as such an enteric layer or coating. Materials such as polymeric acids or polymeric acids are blended with materials such as shellac, hammer, and cellulose acetate. ^ The liquid compositions disclosed herein may be administered orally, by injection and in other similar manners, including aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and edible oils (eg, cottonseed oil, sesame oil, coconut oil, Peanut oil) formulated flavoring emulsion, panacea and similar carriers. In certain embodiments, the presently disclosed pharmaceutical compositions can be administered orally, nasally, topically, rectally, nasally, intravitally, or vaginally by a perfusion device or other suitable route. The presently disclosed pharmaceutical compositions may comprise one or more pharmaceutically acceptable carriers. In certain embodiments, the pH of the formulation may be adjusted using a pharmaceutically acceptable acid, base or buffer. Improve the stability of the compound or delivery profile after formulation. The term "non-oral" as used herein includes subcutaneous, intraocular, intradermal, intravenous, intraperitoneal, intramuscular, intraarticular, intraportal, intraarterial, intrasynovial, intrasternal, intraperorbital, lesions. Internal, intracranial (interstitial), intraventricular, intracerebral injection or perfusion techniques. In certain embodiments, the presently disclosed pharmaceutical compositions can be delivered orally; in certain embodiments, the compounds disclosed herein, whether or not comprising at least one additional therapeutic agent, can be formulated into = There are two forms of carrier or carrier; the aforementioned carriers are usually used to synthesize sputum dosage forms such as tablets and capsules. In some embodiments, the capsule may be designed to release the active ingredient in the gastrointestinal tract release formulation, maximizing the bioavailability of the drug, and minimizing the degradation of the drug before it circulates throughout the system. . In certain embodiments, at least one additional therapeutic agent can be included in the formulation to facilitate absorption of the presently disclosed compounds and additional therapeutic agents into the systemic circulation. In certain embodiments, diluents, flavoring agents, low melting point soils, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders can be utilized. The appropriate oral dosage range will depend on the potency of the compound, which is generally about 0.1 mg to 20 mg per kg of body weight. In certain embodiments, the presently disclosed pharmaceutical compositions can optionally be delivered in a non-oral manner; in certain embodiments, the therapeutic composition can be in a carrier, without pyrogens, when considering a non-oral regimen. a non-oral acceptable aqueous solution comprising at least one of the presently disclosed chemistries and whether or not it contains an additional therapeutic agent; in certain embodiments, the parenteral injectable carrier can be formulated as a sterile isotonic solution The above parenteral injection may be sterile distilled water containing at least one of the currently disclosed chemicals, whether or not containing additional therapeutic agents. In certain embodiments, the pharmaceutical composition can include at least one currently disclosed chemical comprising a pharmaceutical agent such as: injectable homogeneous microparticles, bioerodible particulates, polymers such as polyacetic acid or poly Glycolic acid, pellets or vesicles to provide controlled or sustained release of the presently disclosed compounds by a long-acting injection. In certain embodiments, an implantable drug delivery device can deliver a compound disclosed herein to a plasma of an individual's target organ and to a particular site in the body. In certain embodiments, the presently disclosed pharmaceutical compositions are adjustable to be inhaled; in certain embodiments, the presently disclosed compounds, whether or not containing additional therapeutic agents, can be formulated as inhaled dry powders; In some embodiments, at least one of the presently disclosed compounds, whether or not containing additional therapeutic agents, can be formulated as a propellant for spray delivery; in certain embodiments, 32 200804411 sprays can be aerosolized; In the embodiment, the dry film formed by the solution, powder or the currently disclosed chemical may be sprayed or vaporized for delivery to the lungs. In certain embodiments, the pharmaceutical compositions can be formulated for topical administration, and the topical compositions comprising at least one of the currently disclosed chemistries can be combined with a variety of carrier materials well known in the art. For example: water, alcohols, aloe vera, allantoin, glycerin, vitamin A, E oil, mineral oil, propylene glycol, PPG-2 fourteen propionate and the like. Other suitable carriers for topical type include, for example, emollients, solvents, humectants, thickeners, and powders. In certain embodiments, the composition can be administered topically via implantation of a film, sponge, or other suitable material that has absorbed, coated the compound disclosed herein. In certain embodiments, the implant device can be delivered to any suitable tissue or organ and the particular drug molecule delivered via a diffusing, long-acting sustained-release pill or sustained administration. The presently disclosed pharmaceutical compositions may comprise any pharmaceutically acceptable salts, esters, salts of an ester, or other derivatives and precursors of the presently disclosed compounds, once administered to a recipient, It is possible to provide the currently disclosed compound or inhibitory metabolite or residue thereof to the recipient directly or indirectly. Examples of derivatives and prodrugs include, but are not limited to, acetic acid, formic acid, benzoic acid, and similar functional derivatives (e.g., alcohol or amine functional groups) present in the presently disclosed compounds. Derivatives and prodrugs include those compounds which increase the bioavailability of the currently disclosed chemical when applied to a mammal, for example, a compound that can be administered orally relative to a parent species Faster than 200804411 Lymphatic gland, and transfer or transfer of the progeny to the biological chamber, such as: brain or ^ Jtb ^ » to modify 1, Γ yoke, the currently disclosed pharmaceutical composition can be used Formulation materials for migration, maintenance and preservation, including pH value of the composition, permeability, sound, 'contention, color, isotropic (is〇t〇nicity), odor, real ^ 2 *铋, dissolution and release rate, absorption and penetration. In some cases, suitable formulations include, but are not limited to, amino acids (eg, amino acids, face acid, aspartic acid, arginine, lysine), anti-microbial agents, antioxidants (eg: Ascorbic acid, sodium sulfite and hydrogen sulfite, buffers (eg boric acid, bicarbonate, Tris-HCl, citric acid, acid salts and other organic acids), bulking agents (eg · mannitol and glycine) Acid), mouth 刎 (such as · ethylene diamine tetraacetic acid (EDta)), a mixture of agents (such as · caffeine, polyvinyl pyrrolidone, β_cyclodextrin, hydroxypropyl | cyclodextrin And sulfobutyl ether-β-cyclodextrin), fillers, monosaccharides, disaccharides and other carbohydrates (such as · glucose, mannose and dextrin), proteins (such as: white, white, gelatin and immune Globulin, coloring agents, flavoring agents and diluents, chemical agents, hydrophobic polymers (eg polyvinylpyrrolidone), low molecular weight peptides, salt-forming counterions (eg, nano), Preservatives (eg, dimethylammonium chloride, benzoic acid, salicylic acid, thimerosal, benzene) Ethanol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, chlorhexidine, sorbic acid and hydrogen peroxide), solvents (eg, ganpo, propylene glycol and polyethylene glycol), sugar alcohols (eg ··· Mannitol and sorbitol), suspending agents, surfactants and wetting agents (eg, Pluronics, PEG, sorbitol glycolipids, polysorbates) (eg polysorbate 20, poly Sorbitol vinegar 80, triton, tromethamine, egg gambling, cholesterol, tyloxapal), stability enhancers (such as: sucrose and sorbitol), tension enhancers (such as: alkali metal halides, such as: gasification Sodium 34 200804411 and potassium carbonate, mannitol, sorbitol), delivery vehicles, diluents, excipients and pharmaceutical adjuvants (Remington's Pharmaceutical Sciences, 18th Edition, AR Gennaro, ed.? Mack Publishing Company (1990) In certain embodiments, the optimal pharmaceutical composition can be determined by a person skilled in the art in accordance with, for example, the route of administration to be administered, the type of delivery mode (for example, reference to the aforementioned Pharmaceutical Sciences of Remington). In certain embodiments, such compositions may affect physical state, stability, in vivo release rate, and clearance of the currently disclosed chemical species in the body. Suitable dosage ranges are about 25 ~500 mg / day, at the same time, the dose can be adjusted with the amount of mole in the plasma of the individual. The delivery of the dose in the composition can be sustained by a single administration, multiple administrations, sustained release, controlled Release or any drug release at appropriate intervals and rates. The dosage range and course of treatment are determined by those skilled in the art. In certain embodiments, the frequency of administration will take into account the pharmacokinetic parameters of the currently disclosed chemical materials as well as any additional therapeutic agents used in the pharmaceutical compositions. In certain embodiments, the physician can continue to administer until a predetermined therapeutic effect is achieved. The composition may be administered in a single dose, in two or more doses, and the time of administration of the therapeutically active compound may be the same or different, or the implant or catheter may be used for continuous infusion, and the technique is familiar to the technology. The person can be routinely dosed for further actuarial. For example, therapeutically effective amounts and ingestions can be determined by appropriate dose response data. When treating a particular disease, the amount of the presently disclosed composition may depend on the compound and the condition to be treated by the individual. In general, the daily dose range is from about 100 ng/kg to 100 mg/kg, for example, oral or buccal administration 35 200804411. The dose is 0.01 mg to 40 mg per kg of body weight; the non-oral dose is 0.001 mg per kg of body weight. Kg~20 mg/kg •, as well as nasal, inhaled, and ventilated doses of 0.05 mg to 1,000 mg. In certain embodiments, pharmaceutical compositions comprising the presently disclosed compounds, whether or not containing additional therapeutic agents, can be utilized in vitro. For example, a cell, tissue or organ removed from an individual is contacted with a pharmaceutical composition containing at least one of the currently disclosed chemicals, whether or not containing an additional therapeutic agent, and then the aforementioned cells, tissues or organs are returned to the individual. . If desired, the presently disclosed compositions can be packaged into a single dosage form containing the active ingredient by means of a package or dispensing device, and the aforementioned packaging or dispensing device also has instructions for administration. Such packaged formulations comprise at least one of the currently disclosed chemicals and instructions for the treatment of a mammal, especially a human; and also provide prescription information, for example, to a patient or caregiver or as a packaged medicine A label on the preparation. Prescription information includes information about pharmaceutical preparations such as effects, dosage forms, administration methods, contraindications, and adverse reactions. The specific embodiments disclosed herein will be further defined by the following examples which illustrate the process of preparing the presently disclosed chemical materials and the testing procedures utilized by the presently disclosed chemistries. Anyone familiar with the art can modify the materials and methods without departing from the current disclosure. 36 200804411 EXAMPLES Example 1: Novel Membrane Permeability Corrosion Inhibition of α-2,3 Sialyltransferases This example describes the synthesis of lithocholic acid analogs using steroid groups ( The steroidal moiety) improves the membrane permeability of lithocholic acid and shows that non-competitive α-2,3 sialyltransferase (a-2,3-ST) occurs in cytidine-phosphate-N-acetamidine In the transition state of the (TC-Neu5Ac) analog. Soybean saponin I (Compound 1) is a robust pentacyclic system with a ginseng in soy saponin, which has been identified to produce significant inhibition of sialyltransferase activity in vivo (Ki = 2.1 μΜ) (Hsu et al., Gynecol. Oncol., 2005, 96:415) 〇 In order to confirm that steroid-related compounds inhibit the activity of α-2,3 sialyltransferase, different steroid compounds will be screened. A semi-inhibitory concentration (IC50) of 21 μΜ of lithocholic acid (Compound 3) has been identified as a potent inhibitor. Reaction Scheme I shows the structure of a strong pentacyclic system, the sugar structure of soy soap ring I (compound 1) and the structure of lithocholic acid (compound 3). When the D ring is converted to a five-membered ring, the a bond and the b bond are broken, and the compound 1 is converted into the compound 3, and at the same time, the terminal alcohol is oxidized to a carboxylic acid. ΎΊ 200804411 Reaction 1

The synthesis of the cholic acid analog (compound 7-22) is then carried out to confirm the membrane permeability of the a-2,3-ST inhibitor. The synthesis of the compounds was carried out according to the following general procedure using the following materials, all of which were purchased from Sigma, Aldrich or Acros Organics, and all of the amino acids were purchased from Advanced Chemtech. The CMP-Neu5Ac synthesis reaction is based on sialic acid (Traving & Schauer, CW/. Mo/·1> 汾Scz··, 1998, 54:1330; Schwarzkopf et al., Proc. Natl. Acad. Sci USA, 2002, 99: 5267); The synthesis of lactose receptors is described in Harduin-Lepers et al. (Harduin-Lepers et al., β沁c/i/mie, 2001, 83:727). The 2,3-ST of the old rat liver was taken from CalBiochem at a concentration of 3.7 mU/pL and stored at -80 ° C for use within one week. The melting point was recorded with an Electrothermal MEL-TEMP; the FT-IR spectrum was recorded on a Perkin Elmer FT-IR infrared spectrometer (Paragon 1000, compressed in KBr); 1H and 13C nuclear magnetic were recorded on a Bruker AMX400 or 500 MHz instrument. Resonance spectrum; the proton chemical shift (δ) is expressed in parts per million, which is a relatively single peak signal at 7.24 ppm, or 氘 in comparison with the gas-like imitation of the sulfhydryl group. The methyl residue of 1-H-nonanol 38 200804411 (CHD2OD) in methanol (CD3OD-d4) was defined by a five-fold signal of 3.30 ppm. The description of the carbon chemical shift is based on the comparison of the 13C signal (77.0 ppm, 49.0 ppm) in CDC13 and CD3OD-d4. FAB JMS-700 dual focus mass spectrometer (JEOL, Tokyo, Japan), MALDI Voyager DE-PRO (Applied Biosystem Houston, USA) and ESI Finnigan LCQ mass spectrometer ESI (Finnigan LCQ mass spectrometer, Thermo Finnigan, San Jose, CA, United States) measured mass spectra in negative mode. The peptide compound was purified by reverse-phase high performance liquid chromatography using a Vydac 214TP510 C4 column (1 cm x 25 cm) to obtain a purity higher than 95%. The separation was carried out with 1% water, 1% trifluoroacetic acid and acetonitrile/0.05% TFA (B) as the extract. The general procedure for steroid phosphorylation is as follows: · Dissolve tris(p-nitrophenyl) stone oxalate (1.30 mmol) and steroid (1.43 mmol) in methylene chloride (2〇cm3), then add 7,1 L-diazabicyclo[5A0]undec-ll«ene (1 82 mmol), after stirring for 12 hours at room temperature, eluting several times with saturated sodium bicarbonate solution, and drying the organic extract with sodium sulfate, and After filtration, it was concentrated. The finally obtained pale yellow solid was dissolved in dioxane (1 ^ cm 3 ), and methanol (13.00 mmol, 0·54 cm 3 ) and 7, ll-diazabicyclo [5.4.0] undec-ll-ene (6) were added. · 5 mmol), after stirring for 15 hours in the chamber and the west, eluting with a saturated sodium bicarbonate solution, drying the organic extract with #& sodium sulfate, and concentrating after filtration; Ethyl acetate and hexane were used as the eluent, and the residue was purified using yttrium gel to give the final product. The deprotection process of steroid phosphate methoxy is as follows: sulphate class @ alcohol compound (0.25 mmol) is dissolved in methylene chloride (1.50 cm3), and dimethyl bromide (0.13 cm3, 1.000 mmol) is added. After stirring for 30 minutes at room temperature, the reaction was terminated by adding a saturated sodium hydrogencarbonate solution, and the solvent was removed by evaporation under reduced pressure. The mixture was again precipitated with dichloromethane and hexanes, filtered and concentrated, and dried in vacuo to give the final product. The general procedure for the coupling of succinic anhydride with steroids is as follows: steroid (〇69 mmol) > gluten in the mouth (1〇cm3)' followed by the addition of dimethylhydrazine to the mouth (〇69 mmol) and succinic anhydride After (2·〇7 mmol), reflux for 15 hours. After the pyridine was removed by vacuum pumping, the mixture was dissolved in dichloromethane and eluted with saturated sodium hydrogen carbonate and 6% EtOAc. The extract is dried and evaporated to give a crude product, e.g., heavy oil, which is obtained by column chromatography using ethyl acetate and hexane. The esterification process of 3-light-lithocholic acid with amino acids is as follows: in the protective gas-containing lithocholic acid (0.35 mmol), amino acid (〇·45 mmol) and 4-dimethylaminopyridine (0.10 mmol) In a solution of methane (8 cm3), dicyclohexyldiimide was added to dichloromethane (2 cm3), stirred at room temperature for 30 minutes, then the solvent was removed with rotary evaporation, and then ethyl acetate was used. The product was obtained by chromatography on an alkane rubber column. The formation process of lithocholic acid and amino acid peptide bonds is as follows: Add diisopropyl ester to dimercaptodecylamine (DMF) (5 cm3) containing lithocholic acid (1.3^mmol) and amino acid α·39 mmol) Ethylethylamine (3·99 mm〇l) and 2-(lfbenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (1牝mmol) After stirring at room temperature for one hour, the solvent was removed in vacuo. The mixture was dissolved in dichloromethane (50 cm3) and washed twice with water. The extract was dried and evaporated to give a crude product, e.g., heavy oil, obtained from ethyl acetate and hexanes. product. 200804411

The general process of deprotection of Fmoc group is as follows: Adding 1,ll-diazabicyclo[5.4.0]undec- in dioxane (5 cm3) containing Fmoc-protected steroidal compound (0.15 mmol) Ll-ene (0·15 mmol), stirred at room temperature for 30 minutes, concentrated under reduced pressure to remove the reaction solvent to give a crude product, such as heavy oil, followed by ethyl acetate and hexane. The product was purified by column chromatography.

The general procedure for deprotecting the Boc and tBu groups is as follows: a TFA solution (2 cm3) containing a protecting group compound (0.15 mmol) is treated with 2% water (0.04 cm3) at room temperature and stirred at room temperature. The reaction solvent was concentrated under reduced pressure, and the mixture was neutralized with saturated sodium hydrogen carbonate. The general procedure for the reduction of the methyl ester group is as follows: steroids (0·56 mmol) dissolved in tetrahydrofuran (1·6 cm3) are carefully added to the lithium aluminum hydride (1.13 mmol) in a drop of one drop. Tetrahydrofuran (〇·6 cm3) (more than ten minutes required). After the mixture was stirred at room temperature for ten minutes, the reaction was terminated by adding 6% HCl, and the hydrazine compound was passed; the solvent was removed by rotary evaporation, and the residue was purified by column chromatography using ethyl acetate and hexane. Solid matter to obtain the final product. The general procedure for the synthesis of diphenyl phosphate steroids is as follows: a primary steroid alcohol (2.02 mmol), dissolved in a tetrachabitane (12 cm3) containing dimercaptophosphate azide, and then added 7,1 drop by drop. l-diazabicycloDAOhndec-i Lene (5 〇5 mm〇1), after stirring at room temperature = minute, the reaction was quenched by the addition of 6% HCl. The solvent was concentrated under reduced pressure and the mixture was extracted with water and dioxane. The extract was subjected to dry refining in a reduced pressure environment 41 200804411: After the hair was taken, a crude extract was obtained, and then the ethyl acetate was burned with hexane to purify the final product by flash column chromatography. The general procedure for the synthesis of steroidal azide is as follows: Add a sodium azide (4 2 mmol) to a diphenyl phosphate steroid (0.841 mmol) dissolved in 1,4-dioxane (15 cm3). Tetrabutylammonium chloride (〇〇84 mmol) and 15-crown-5 ether (〇1 cm3) were heated under reflux under nitrogen pressure for one night. After cooling, the solvent was removed by concentration under reduced pressure. Water and two gas methane extraction residues. After the extract was dried under reduced pressure, the crude product was taken up in a powdery form, and the product was obtained by column chromatography using ethyl acetate and hexane. The general procedure for the synthesis of a double substituted 1,2,3-triazole steroid is as follows: The steroid "nitride (〇·26 mmol) and alkyne (〇·283 mmol) are dissolved in a mixed solution of tetrahydrofuran and water (4 cm3, 1:1), then add copper sulfate (catalytic amount) and sodium ascorbate (catalytic amount), stir at room temperature for three hours, then concentrate under reduced pressure to remove the solvent, and water and dichloro-alkane Extract the mixture. After the extract was dried and evaporated under reduced pressure, a crude powdery extract was obtained, which was obtained from ethyl acetate and ethyl alcohol. The conceptual method of the concept of "click chemistry" is as follows: a variety of 1,4-disubstituted U, 3, three saliva, which are formed by the use of a copper-azide azide intermediate product disc. St_ev The method described in the tracing book (Rostovtsev et al, (2〇〇2), /like" 41:2596). 42 200804411 Synthesis of compound 7: (3/?, 5 anti-105, 1311,145)-17-((/?)-5-hydroxypentan-2-yl)-10,13-dimethyl-hexadecanthazole-1//-3⁄4 pentyl[beta]non-3 - Same as

Compound 7 was synthesized from lithocholic acid (Compound 3) by two steps shown in Reaction Scheme 2. In the step (a), the compound 3 is first treated with a strong acid type ion exchange resin Amberlite IR120/nonanol at 80 ° C for 12 hours, followed by the lithium aluminum hydride (LAH) of step (b), tetrahydrofuran at 0 ° C to the chamber. The mixture was treated for 10 minutes under temperature to reduce the formate obtained therefrom. Reaction formula 2

200804411 Synthesis of compound 8: (R)-4-((3R,5R,10S,13R,14S)-3-hydroxy-10,13-dimethyl-hexadecanehydro-lH-cyclopentane [a] Phenyl-17-yl)pentyldiphenylphosphoric acid

Compound 8 was synthesized from Compound 7 according to Reaction Scheme 3. Specifically, in the step (c), the base of the compound 7 is converted into a diphenylphosphoric acid functional group in the presence of an azide-based diphenyl sulfonate at room temperature for 10 hours. Reaction formula 3

ΛΔ 200804411 Synthesis of compound 9: 2-((R)-4-((3R,5R,10S,13R,14S)-3-·* -10,13-dimethyl-hexadecane-1H-ring Pentane [a]phenanthrene-17-yl)pentanylamine)acetic acid

Compound 9 Compound 9 was synthesized from Compound 3 according to Reaction Scheme 4. The condensation of the compound 3 and the protected amino acid H-Gly-OBut is carried out in the step (4), which is based on 2-(1Η-benzotris-l-yl) in hydrazine, hydrazine-dimethyl decylamine. -1,1,3,3-tetramethyluronium hexafluorophosphate ("1!!") / diisopropylethylamine (DIPEA) as a coupling agent, reacted at room temperature for 30 minutes to be protected Conjugated intermediates. Compound 9 was obtained in the subsequent step (f) by reacting TFA and DCM at room temperature for 1 hour to remove the tBu functional group. 45 200804411 Reaction 4

Synthesis of Compound 10: (S)-2-((R)-4-((3R,5R,10S,13R,14S)-3^^yl-10,13-didecyl-hexadecanehydrol-1H -cyclopentane [a]phenanthroline-17-yl)pentaamine) bismuth succinate

46 200804411 Compound 10 was synthesized from Compound 3 according to Reaction Scheme 5. The condensation of the compound 3 and the protected amino acid LH-Asp(OBut)-OBut is carried out in step (e) using 2-(1Η-benzotriene) in N,N-dimethylformamide Zin-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (113 butyl 1;) / diisopropylethylamine (DIPEA) as a coupling agent, reacting at room temperature 30 The protected conjugated intermediate is obtained in minutes. Compound 10 was obtained in the subsequent step (1) by reacting TFA and DCM at room temperature for 1 hour to remove the tBu functional group. Reaction formula 5

Synthesis of Compound 11: (R)-4-((5R,10S,13R,14Sl·l0,13·didecyl-3-oxo-hexadecanehydro-lH-cyclopentane[a]phenanthrene-17_ Valentate 47 200804411

Compound 11 was synthesized from Compound 3 according to Reaction Scheme 6. In the oxidation reaction of the step (1), the compound 3 was reacted with acetic acid in acetic acid at 100 ° C for 30 minutes to give a compound 11. Reaction formula 6

200804411 Synthesis of compound 12: (1〇-4-((3 ft, 5艮103,13艮143)-3-(3-carboxypropenyloxy)-10,13-dimethyl-hexadecane) Hydrogen-1H-cyclopentane [a]phenanthrene-17-yl) valeric acid

Compound 12 was synthesized from Compound 3 according to Reaction Scheme 7. Specifically, in the esterification reaction of the step (1), the compound 3 was reacted with succinic anhydride, DMAP and pyridine at 60 ° C for 15 hours to obtain a compound 12. Reaction 7

200804411 Synthesis of compound 13: (R)-4-((3R,5R,10S,13R,14S)-3-((S)-21$-yl-3-carboxypropenyloxy)-10,13- Dimercapto-hexadecane-1H-cyclopentane [a]phenanthrene-17-yl)pentanoic acid

Compound 13 was synthesized from Compound 3 according to Reaction Scheme 8. For the preparation of compound 13, the hydroxy function of compound 3 in step (k) is first converted to an acetamyl group by reaction with acetic anhydride or pyridine at room temperature for 5 hours, followed by subsequent use of third butanol, DMAP, DCC, DCM, the esterification reaction step (step (I)) is carried out by reacting at room temperature for 30 minutes to obtain the first intermediate of the reaction scheme 8. The deacetylation reaction of step (m) is carried out by using sodium methoxide and methanol at room temperature for 2 hours to form a second intermediate, which is protected by a butyl hexyl carbodiimide (DCC). Coupling reaction, and deprotection of Fmoc, Boc and tBu functional groups in the next three steps: (n) Fmoc-L-ASP(OBut)-OH, DMAP, DCC, DCM reacted at room temperature for 30 minutes; (o) DBU and DCM were reacted at room temperature for 1 hour; and (h) TFA, 2% water was reacted at room temperature for 1 hour to obtain the desired product 13. 200804411 Reaction 8

ο Synthesis of compound 14: 4-((3 ft, 5 艮 103, 13 ft, 145)-17-((1〇-5-t-butoxy-5-oxopentan-2-yl)-10 ,13-dimethyl-hexadecanehydro-1Η-cyclopentane [a]non-3-yloxy)-4-oxobutanoic acid

51 200804411 Compound 14 was synthesized from Compound 3 according to Reaction Scheme 9. To prepare compound 14, the hydroxy function of compound 3 in step (k) is first converted to an oxime group by reaction with acetic anhydride or pyridine at room temperature for 5 hours, followed by subsequent use of third butanol, DMAP, DCC, DCM, reacting at room temperature for 30 minutes to carry out an esterification reaction step (step (1)) to obtain a first intermediate of the reaction scheme 8. The deacetylation reaction of the step (m) is carried out by using sodium methoxide and methanol at room temperature for 2 hours to form a second intermediate, followed by succinic anhydride, DMAP and pyridine at 60 ° C for 15 hours. The esterification reaction is carried out to obtain a compound 14. Reaction formula 9

200804411 Synthesis of compound 15: 4-((311,511,103,1311,145)-17-((1〇-5-(carboxymethylamino)-5-oxopentan-2-yl)-10 ,13-dimercapto-hexadecanehydro-1H-cyclopentane [a]phenanthr-3-yloxy)-4-oxobutanoic acid

Compound 15 was synthesized from Compound 3 according to Reaction Scheme 10. The condensation of the compound 3 and the protected amino acid LH-Gly-OBut is carried out in step (e) using 2-(1 - benzotriazole-1) in N,N-didecylguanamine. -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) / diisopropylethylamine (DIPEA) as a coupling agent, reacted at room temperature for 30 minutes to obtain a protected total扼 intermediates. The intermediate system was esterified with phenolic anhydride, DMAP, acridine at 80 ° C for 15 hours (step g), followed by reaction with TFA, 2% water at room temperature for 1 hour (step h) to obtain compound 15. 200804411 Reaction 10

Synthesis of Compound 16: (S)-2-((R)-4-((3R,5R,10S,13R,14S)-3-(3-carboxypropenyloxy: M0,13-dimethyl -hexadecanehydro-1H-cyclopentane [a]phenanthrene-17-yl)pentanylamine succinic acid

54 200804411 Compound 16 was synthesized from Compound 3 according to Reaction Scheme 11. The condensation of the compound 3 and the protected amino acid LH-AspCOButhOBut is carried out in step (e) using 2-(1Η-benzotriazol-1-yl) in N,N-dimethylformamide -l,l,3,3-tetradecylurea hexafluorophosphate (HBTU) / diisopropylethylamine (DIPEA) as a coupling agent, reacted at room temperature for 30 minutes to obtain a protected conjugate intermediate body. The interstage system was esterified with succinic anhydride, DMAP, pyridine at 80 ° C for 15 hours (step g), followed by reaction with TFA, 2% water at room temperature for 1 hour (step h) to obtain compound 16. Reaction formula 11

200804411 Synthesis of compound 17: (R)-4-((3R,5R,10S,13R,14S)-3-((R)-2j$yl-3-carboxypropenyloxy)-10,13- Dimercapto-hexadecanehydrol-1H-cyclopentane [a]phenanthrene-17-yl)pentanoic acid

Compound 17 was synthesized from Compound 3 according to Reaction Scheme 12. For the preparation of compound 17, the hydroxy function of compound 3 in step (k) is first converted to an acetamyl group by reaction with acetic anhydride or pyridine at room temperature for 5 hours, followed by subsequent use of third butanol, DMAP, DCC, DCM, reacting at room temperature for 30 minutes to carry out an esterification reaction step (step (1)) to obtain a first intermediate of the reaction scheme 8. The deacetylation reaction of the step (m) is carried out by using sodium methoxide and methanol at room temperature for 2 hours to form a second intermediate, which is then protected by dicyclohexylcarbodiimide (DCC). Coupling reaction, and deprotection of Fmoc, Boc and tBu functional groups in the next three steps: (lOFmoc-L-ASPCOButO-OH, DMAP, DCC, DCM reaction at room temperature for 30 minutes; (〇) DBU, DCM in the chamber The reaction was carried out for 1 hour at a temperature; and (h) TFA, 2% water was reacted at room temperature for 1 hour to obtain the intended product 16. 200804411

Η

.OH Ο 200804411 Synthesis of Compound 18: (3R, 5R, 10S, 13R, 14S)-17-((R)-5-(4-(2··ylethyl)-1Η-(1,2,3 -triazol-1-yl)pentan-2-yl)-10,13-dimercapto-hexadecanehydro-1H-cyclopentane [a]phenanthrene-3-one

Compound 18 was synthesized from Compound 8 according to Reaction Scheme 13. Conversion of compound 8 to the corresponding azide intermediate system can be achieved by step (d), which is carried out in excess of sodium azide, a sufficiently catalyzed dose of ferric tetraethyl sulphate, and 15-crown-5-ether at 110 The reaction was carried out at ° C for 15 hours, and the preparation of the 1,4-disubstituted-1,2,3-triazole compound 18 was carried out through the step (q), which catalyzed the coupling of the cuprous copper by the use of click chemistry. The azide intermediate is obtained by reacting with an appropriate alkyne. 200804411 Reaction formula 13

Synthesis of Compound 19: 2-Amino-3-(1-((11)-4-((3 ft, 511,103,1311,145)-3-hydroxy-10,13-didecyl-16 Alkanohydro-1H-cyclopentane [a]phenanthrene-17-yl)pentyl)-1Η-1,2,3-triazol-4-yl)propionic acid

200804411 Compound 19 was synthesized from Compound 8 according to Reaction Scheme 14. In step (d), in the presence of excess sodium azide (s〇diumazide NaN3), catalyst tetrabutylammonium iodide (TBAI), 15-crown-5 ether (15 - Crown-5), at 110 Compound 8 was converted to the corresponding azide intermediate for 15 hours at °C. In step (q), the copper (I) catalyzed azide intermediate is bonded to the appropriate alkyne to a 1,4 disubstituted 1,2,3 triazole intermediate. In step (h), the tert-butoxy carbonyl group (Boc) is deprotected in TFA 2% water at room temperature for one hour to give the racemic derivative 19. 200804411 Reaction 14

Step h 50% HO,,, ' 200804411 Synthesis of compound 20: 2-(diethoxyphosphonium) each (1-(())-4-((3艮5反1(^,13艮145) )-3-hydroxy-10,13-dimercapto-hexadecane-1H-cyclopentane [a]phenanthrene-17-yl)pentyl-1H-1,2,3-triazol-4-yl Propionic acid

Compound 20 was synthesized from Compound 8 according to Reaction Scheme 15. In step (d), in the presence of excess sodium azide (NaN3), catalyst tetrabutylammonium iodide (TBAI), 15-crown-5 ether (15 - Crown-5), at 110 QC converted compound 8 to the corresponding azide intermediate for 15 hours. In step (q), the copper (I) catalyzed azide intermediate is combined with the appropriate alkyne to form a 1,4 disubstituted 1,2,3 triazole intermediate. In the step (r), saponification is carried out for 5 hours at NaOH, EtOH/H20 (1:1) and at room temperature to form a racemic derivative 20. 200804411 Reaction 15

HO,,,,

H

Step q 55%

Step r 30% HO,,, 200804411 Synthesis of compound 21: 3-(l-((R)-4-((3R,5R,10S,13R,14S)-3-)yl-10,13-dimethyl -hexadecanehydro-1H-cyclopentane [a]phenanthrene-17-yl)pentyl)-1Η-1,2,3-triazole-4-yl)propionic acid

Compound 21 was synthesized from Compound 8 according to Reaction Scheme 16. In step (d), in the presence of excess sodium azide (NaN3), tetrabutylammonium iodide (TBAI), 15 - crown-5 ether (15 - Crown-5), Compound 8 was converted to the corresponding azide intermediate for 15 hours at 110 °C. In the step (q), the copper (I)-catalyzed azide compound intermediate is bonded to a suitable alkyne to form a 1,4 disubstituted 1,2,3 triazole compound 21. 200804411 Reaction 16

Synthesis of Compound 22: 4-(l-((R)-4-((3R,5R,10S,13R,14S)-3^|;& -10,13-Dimethyl-hexadecane Hydrogen- 1H-cyclopentane [a]phenanthroline-17-yl)pentyl)_1H-1,2,3-triazol-4-yl)butyric acid HO〆

Compound 22 200804411 Compound 22 was synthesized from Compound 8 according to Reaction Scheme 17. In step (d), in the presence of excess sodium azide (NaN3), tetrabutylammonium iodide (TBAI), 15 - crown-5 ether (15 - Crown-5), Compound 8 was converted to the corresponding azide intermediate for 15 hours at 110 °C. In step (q), the copper (I) catalyzed azide intermediate is bonded to a suitable alkyne to form a 1,4 disubstituted 1,2,3 triazole compound 22. Reaction formula 17

200804411 Each compound was tested for inhibition by a-2,3-ST using CMP-Neu5Ac as a substrate and a modified disaccharide and a 4,5-dimethoxy 2-nitrobromo group as UV- Identify the receptor. In particular, the inhibition assay was performed in triplicate with a double modified with 200 mM MES buffer, 100 mM sodium chloride, 0.5 mM ethylenediamine tetraethyl disodium, 〇·〇1% Triton X-100, 20 μΜ. The sugar, 1·4 mU a-2,3-ST and an inhibitor (in DMS0 (dimethyl sulfoxide) dimercaptolithic acid) were reacted in a total volume of 55 μM. The reaction was carried out at 37 ° C for 10 minutes and then CMP-Neu5Ac (final concentration 3 μΜ) was added. The solution is then reacted at 37 ° C until a detectable amount of compound is produced. The reaction was terminated by heating the mixture at 100 ° C for a few minutes. The enzyme activity was controlled by RP-HPLC (Supelco Discovery® HS C18, 5 μιη, 4.6 mm x 25 cm)|i sialylation of the disaccharide product at 348 nm with a retention time of 20.38 minutes. 16The above 16 synthetic analogues compared to choline acid (Hth〇ch〇lic this (4) significantly reduced IQo (Table 1). Finally, ethanol 7 and its derivative 8 are lower than lithocholic acid 5.17 In addition, the fine acid group has a heavier effect on promoting affinity, and further confirms that the peptide is extended by the end of the peptide, and the inhibitory property is completely restored compared to the compound 7-8. == Raw, we found the compound with a ketone group to inhibit the activity of a-2,3-ST. The experiment has a potential of seven times. More, 隹 _ 50 is 139 μΜ, which is lower than lithocholic acid. Shows a potential of more than twice: the step stone has a affinitive affinity for the choline acid compounds 12 and 13 and the construction of the 3 _ hydroxy group which does not s acid can appear as far as the sorbent 14-16. Although the carboxylic acid at the end of compound 12 changes, it resembles a). Amazing monaural and plain phenomenon (Pla_) (the table replaces D-AsP with L-Asp compared to compound 17', 3 has a pure improvement of 2. In addition, lithocholic acid enters - 200804411 The step of replacing the carboxylic acid with a 1,4 disubstituted 1,2,3 triazole ligand. Compounds 20 and 21 have an 8-12-fold increase in effect compared to compound 19, presumably adding a positively charged amino acid can destroy The affinity of the original ethanol 18 is at least 10 times lower than that of the compound 21 and at least 20 times lower than the compound 22, which is consistent with the value of the adsorption of the terminal carboxylic acid previously observed. The analog 22 is the most active compound having an IC5 〇 of 5 μΜ. One

200804411

200804411

70 200804411

The inhibition constant (Ki) was analyzed with the most active compound 22. Inhibition The test reaction solution was prepared as described above by adding 0.3, 0.15, and 0.037 mM CMP-Neu5Ac to the existing inhibitors 5, 4·5, 3·5, 2.5, and ΟμΜ for 10 minutes. Each receptor and the inhibitor were subjected to two repetitions in the test. A rate and the concentration of each inhibitor were obtained under the IC5(R) test conditions, and the reciprocal of the rate was linearly related to the reciprocal of the substrate concentration. The Ki absolute value is derived from the horizontal intersection of the velocity as the vertical axis and the inhibitor concentration in the horizontal axis of the Lineweaver-Burk plot (first image). Compound 200804411 22 Competition inhibition of CMP-Neu5A. c has a Ki of 2.2 μΜ, showing its role as non-Ο) cytotoxicity and adhesion analysis. In the poor two, = T ', CL1-5 cells were inoculated in DMEM medium containing 10% fetal bovine serum (FBS) at a rate of 60 mm, 1χ1〇6 cells, separated by 2 to contain fetal bovine serum. Replaced with medium containing DMS0 and 5 _ 4 10 _ inhibitor. The cells in the control group were cultured in a medium containing 01% DMS0 and no inhibitor. After 48 hours, the cell number and cell survival rate were determined by trypan blue exclusion. After treatment with three inhibitors, N-Pemyonic (Compound 21), Lith_Triethyl de, (Compound 20) and Lith+Asp (Compound 13), the growth of CL1-5 cells was 10-20% compared to the control group. Suppression (as shown in Figure 2a). In addition to the effect on cell viability, treatment with a-2,3-ST inhibitor significantly increased the adhesion of CL1-5 cells to extracellular matrix protein collagen I. The 96-well microplate was first coated with collagen typel (100 pg/ml, 40 μΐ/well), and then 5% + serum protein (BSA) was added at 4C. 5χ104 cells per experiment, treated with different doses of a_2,3-ST inhibitor or DMS0, inoculated into previously coated microwells; cultured at 5% C02, 37 °C hour. Thereafter, the cells were eluted twice in serum-free DMEM medium to remove adherent cells; and solidified at 200804411 for 10 minutes at 1 °C with 1% furfural. After the fixed cells were stained with crystal violet for twenty-five minutes, the cells were lysed with a 1% SDS solution. The number of attached cells is determined by the correlation of absorbance at 59 〇 nm. After treatment with the a_2,3_ST inhibitor, the adhesion of CL1-5 cells to collagen I increased L2-15 times (as shown in the second panel). Example 3 Inhibition of migration of CL1-5 lung cancer cells To evaluate the effect of a-2, 3-ST on inhibition of cell migration, a wound healing assay was used. Highly metastatic CL1-5 lung cancer cells in a DMEM medium containing 1% fetal bovine serum (FBS) at 1 5% C〇2 with 1〇μ]ν[a-2,3-ST inhibitor -Lith-o-Asp for pre-processing. Scratch some of the cells from the plate to form a "gap". Observe the migration of the cells to the "gap" for 48 hours in the presence of a-2,3-ST inhibitor (as shown in Figure 3). Show). Example 4: a-2,3-ST minus/> Inhibition of a-2,3 sialylation antigen on the surface of fine sputum on lung pain cells In order to determine the inhibition of a-2, 3-ST, the cell surface is altered. Glycation, lung cancer cells were treated with Lith-o-Asp, and a2,3-sialylated cell surface antigen was detected by flow cytometry. After lxlO6 lung cancer cells were collected and eluted twice with Hanks Balanced Salt Solution (HBSS), the cells were treated with a-2,3-ST inhibitor for five days. The collected cells were cultured at FITC-conjugatedMAL (1:50) for 15-20 minutes at 37 °C; unbound MAL was removed by elution with HBSS' FACScalibur instrument (Becton Dickinson) 3 x 1 〇 4 binding cells. CL1-1 lung cancer cell lines with low metastatic potential and high metastatic potential were tested, and CL1-5 was derived from CL1-1 using the macro gel invasion assay (Chen et al., Cancer Res·). , 2001, 61: 5223), these cell lines all have the same genetic background. The CL1 cells treated with Utlw>Asp showed a 15% reduction in the performance of the .2,3_sialylated antigen compared to the control group treated with 5 μΜ, 20 μΜ DMSO (as shown in the fourth panel). In contrast, Lith-o-Asp inhibits the surface 2,3-sialylated cell surface antigen in high-metastatic lung cancer cells, and the dose-related association is higher than 15% (as shown in Figure 4B). . _f_Example 5: Inhibition of different cell bees and their inhibition of a_2,3_ST In order to assess the effect of a-2,3-ST inhibition on endogenous gene expression, semi-quantitative reverse transcriptase (RT)- The mRNA expression of various cell lines with different metastatic potentials was determined by PCR. Analysis of the cell lines included: normal lung epithelial BES-6 cells, low metastatic CL1-1 cells and H1299 lung cancer cells, high metastatic CL1-5, CL1-5 F4 and A549 lung cancer cells. The cells were cultured for 48 hours with a-2,3-ST inhibitor, collected and extracted by TRIzol (Invitrogen), chloroform (chloroform). After completing the reverse transcriptase (RT) reaction, use 5T3GW/-specific primers (ST3Gal /-specific primers) - Chuanbei: 5? -GGACCCTGAAAGTGCTCA-35 and reverse: 5'-TCTCCAGCATAGGGTCCA-3 for complementary DNA Amplification. The PCR conditions were as follows: · Denaturation at 95Qc, adhesion at 61 ° C, and polymerization at 72 ° C for a total of 35 cycles. The relative amount of mRNA expression is determined by comparison with the intrinsic standard (β·actin) value of the reaction. The PCR product of the SrJGW/gene was mixed with the actin sequence, and then 〇·5χ TBE was added, and electrophoresis was carried out for 3 minutes using a 1.5% ethidium bromide stained gel at 120 V. In normal cells, the expression of the 7 gene was not measured, but compared with the low metastatic potential cell, the gene showed a significant increase in the high metastatic potential cells in 74 200804411 (as shown in Figure 5A). Treatment with the a-2,3-ST inhibitor Lith-o-Asp did not significantly reduce the expression of gene mRNA in CL1-5 lung cancer cells. Example 6 · a-2,3-ST ALTERS PROTEIN inhibition in CL1-5 lung cancer cells To determine the effect of a-2,3-ST inhibition on overall protein performance in CL1-5 lung cancer cells, use A staining system specific for phosphoproteins for two-dimensional electrophoresis. In each experiment, 1 X 1〇7 CL1-5 lung cancer cells were collected and treated with 1 μμ of Lith-o-Asp or DMSO for 48 hours, followed by 8% urea (Boehringer Mannheim, Germany), 2M sulfur. A lysis buffer of urea (Aldrich, WI, USA) and 4% CHAPS (J. Baker, NJ, USA) was used to dissolve the cell pellet. After disrupting the cells by sonication, a total weight of 1 mg of protein was loaded into an immobilized pH gradient (IPG) gel strips, Amersham Pharmacia Biotech, Uppsala, pH 3 -10, 18 cm in length. Sweden); the aforementioned electrophoresis film should be placed in 7M urea, 2M thiourea, 4% CHAPS, 40 mM trishydroxymethylamino decane, 2% IPG ampholyte, 65 mM DTE and 0.0002% before use. Blue hydrated (rehydrated). When the first two-dimensional separation is performed, it is at 20. (1; at a time of 7000 V, a total of 65 kVh, using the IPGphor system (Amersham Pharmacia Biotech) for isoelectric power

swimming. After the isocratic electrophoresis is completed, the IPG film is first placed in an equilibrium solution (5 mM

Tris-HCl, pH 8·8, 6 尿素 urea, 2% SDS, 30% glycerol, 2% DTE) equilibrated in fifteen minutes, attaching IPG film to vertical 12·5% linear gradient polypropylene amide condensation On the gel electrophoresis film, IPG film was fixed with 〇·5% soil grease. For the second two-dimensional electrophoresis, each gel was run for five hours at 45 mA of 75 200804411 until the bromophenol blue reached the bottom of the gel. It was stained with Pro-Q Diamond PhosphoProtein Gel Stain (Molecular Probes, OR, USA) for three hours, and easily fixed for 30 minutes with a mixture of 10% sterol and 7% acetic acid. It was then immersed in deionized water for twenty minutes to remove the remaining dye. After treatment with Lith-o-Asp, CL1-5 lung cancer cells showed four points of increased intensity on the two-dimensional gel and forty-nine points with reduced intensity (as shown in Figure 6). The in-gel protein was decomposed by trypsin and its intensity was determined by tandem mass spectrometry (MSMS), and the protein identity was identified by comparison with the protein database. Among them, several proteins involved in the signal and damage response pathway have been identified, including: heat shock protein 75, glycerate kinase 1, Ran-GTP hydrolase activator protein! (Ran_GTPase activating protein 1 ) and WD-repeat c〇ntaining protein 1 ° ° Although the preferred embodiment of the invention has been disclosed above, it is not intended to limit the invention 'any of the skill Various changes and modifications can be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are also included in the scope of the following claims. 76 200804411 [Simplified Schematic] The first figure shows the Lineweaver-Burk double reciprocal relationship diagram of the inhibition analysis of the synthetic inhibitor 22 by α-2,3 sialyltransferase in mice. Figure 2 (A) shows three α-2,3 sialyltransferase inhibitors - N-Pentyonic (Compound 21), Lith-Triethyl-de (Compound 20) and Lith-o-Asp (Compound 13), respectively. Cytotoxicity in CL1-5 cells 48 hours after treatment with 5 μΜ, 10 μΜ inhibitor. Survival scores were calculated as the survival of cells in the control group treated with DMSO. The second panel (Β) shows the attachment of CL1-5 cells after treatment with α-2,3 sialyltransferase inhibitors relative to the basic level of cells attached to the control group treated with DMSO (specification 1) The case of type 1 collagen. The third panel shows the results of gap healing analysis after 48 hours of treatment of C^L1:5 cells with (A)DMS〇, (Β) 1〇 μΜ Uth 〇 Asp. The α 2,3 sialic acid transaminase inhibitor Lith-0-Asp inhibits cell migration of the injured site due to scraping of cells from cell culture orphans. The fourth panel shows the expression of α_2,3 sialylation antigen on the cell surface at low = sex: U_1 cells and (Β) highly metastatic CL1·5 cells. ^The results of the non-flow cytometry display: P1 is the background intensity of 疚^2 and p3_Λ is the percentage of cells expressing sialic acid at high intensity and calculating the various cells from Uit. The figure below shows a histogram made by the average fluorescence intensity value of the piece. The amount of expression of endogenous mRNA of a in the lung cells of different metastatic potentials. (B) shows that 200804411 did not significantly change the mRNA expression of the ST3Gal I gene in CL1-5 cells treated with DMSO or Lith-o-Asp. The sixth panel shows a two-dimensional electropherogram of (A) CL1-5 lung cells treated with DMSO control and (B) Lith-o-Asp. The IEF is pH 3-10 and the molecular weight is 21.0-97.0 kDa. Differentially expressed proteins were further identified by mass spectrometry and tandem mass spectrometry. [Main component symbol description] None 78

Claims (1)

200804411 X. Patent application scope: 1. A chemical substance selected from at least one chemical formula I: And a pharmaceutically acceptable salt, solvate, chelating agent, non-covalent complex, prodrug, and mixtures thereof, wherein R! is an optionally substituted alkyl group; R2 is selected from the group consisting of a hydroxyl group and a decyloxy group; R3 is hydrazine, or R2 and R3 together with the carbon to which they are attached form an oxy group; and when Ri is (/?)-'carboxybutan-2-yl, then R2 is not a hydroxy group. 2. The at least one chemical substance of claim 1, wherein the Ri is selected from the group consisting of -CHR4(CH2)nR5, wherein η is 2 and 3; and R4 is selected from hydrogen or an optionally substituted lower alkylene. And R5 are selected from the group consisting of a carboxyl group, a formamidine group, and an optionally substituted heteroaryl group. 3. The at least one chemical substance according to item 2 of the patent application, wherein the aforementioned η is 2. 4. At least one chemical substance as claimed in claim 2, wherein the aforementioned η is 3. 5. The at least one chemical substance of claim 2, wherein the aforementioned R4 is selected from the group consisting of hydrazine and an optionally substituted lower alkyl group. 79 200804411 6. The at least one chemical substance of claim 5, wherein the aforementioned R4 is a lower alkyl group. ' </ br /> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 8. The at least one chemical substance of claim 2, wherein the R5 is selected from the group consisting of a carboxyl group, -(CO)-NHR6, and an optionally substituted trisalin R6 is selected from the group consisting of an optionally substituted lower alkyl group. . 6. The at least one chemical substance of claim 8, wherein the R5 is selected from the group consisting of a carboxyl group, -(CO)-NHR6, and an optionally substituted trisal, wherein the triazole ring system is a monofunctional group &amp; Substituted, and &amp; is an optionally substituted lower alkyl group. 10. The at least one chemical substance of claim 8, wherein the aforementioned R6 is selected from the group consisting of a lower alkyl group substituted with one or two carboxyl groups. 11. The at least one chemical substance of claim 8, wherein the aforementioned R5 is a radical. 12. The at least one chemical according to claim 8, wherein the R5 is a monosubstituted triterpene, the substituents being selected from the group consisting of one or two rebel, amino and dialkyl phosphates Lower alkyl, and the lower carbon number is replaced by at least one rebel. 13. The at least one chemical substance of claim 1, wherein the aforementioned R3 is hydrogen. 14. The at least one chemical of claim 1, wherein the foregoing R2 and R3 together with the carbon to which they are attached form an oxy group. 15. The at least one chemical substance according to claim 1, wherein the at least one chemical substance which inhibits the activity of α-2,3 sialyltransferase has a semi-inhibitory concentration IC5 in the in vitro biochemical activity analysis. About 360 μΜ. 80 200804411 16. The at least one chemical substance according to claim 15, wherein the at least one chemical substance inhibiting α-2,3 sialyltransferase activity has a semi-inhibitory concentration in an in vitro biochemical activity assay ( IC5〇) is less than about 25 μΜ. 17. The at least one chemical substance according to claim 1, wherein the compound of the above formula I is selected from the group consisting of: (311, 511, 103, 13 ft, 145) -17-((11)-5-hydroxyl Pentane-2-yl)-10,13-dimercapto-hexadecanehydro-1Η-cyclopentane [a]phenanthrene-3-one; (R) -4-((3R,5R,10S,13R , 14S)-3-hydroxy-10,13-dimercapto-hexadecanehydrol-1H-cyclopentane [a]phenanthrene-17-yl)pentyldiphenylphosphoric acid; 2-((11)-4 -((311,511,103,1311,145)-3-hydroxy-10,13-dimethyl-hexadecanehydrol-1H-cyclopentane [a]phenanthrene-17-yl)pentanylamine)acetic acid (S) -2-((R)-4-((3R,5R, 10S,13R,14S)-3-hydroxy-10,13-didecyl-hexadecanehydrol-1H-cyclopentane [ a]phenanthroline-17-yl)pentaamine)succinic acid; (R)-4-((5R,10S,13R,14S)-10,13-dimethyl-3-oxo-hexadecanehydrol-1H -cyclopentane [a]phenanthrene-17-yl)pentanoic acid; (R)-4-((3R,5R,10S,13R,14S)-3-(3-carboxypropenyloxy)-10, 13-dimercapto-hexadecanehydro-1H-cyclopentane [a]phenanthrene-17-yl)pentanoic acid; (11)-4-((3 ft, 511, 105, 13 ft, 143)-3 -((3)-2-amino-3-carboxypropenyloxy)-10,13-dimercapto-hexadecanehydro-1H-cyclopentane [a]phenanthrene -17-yl)pentanoic acid; 4-((311,511,103,13艮143)-17-((11)-5-t-butoxy-5-oxopen-2- 81 200804411)-10, 13-dimethyl-hexadecanehydrol-1H-cyclopentane [a]phenanthr-3-yloxy)-4-oxobutanoic acid; 4-((3R,5R,10S,13R,14S)-17 -((R)-5-(carboxymethylamino)-5-oxopen-2-yl)-10,13-dimethyl-hexadecanehydro-1H-cyclopentane [a]phenanthrene-3 -yloxy)-4-oxobutyric acid; (S)-2-((R)-4-((3R,5R,10S,13R,14S)-3-(3-carboxypropenyloxy) -10,13-dimercapto-hexadecanehydro-1H-cyclopentane [a]phenanthrene-17-yl)pentanylamine succinic acid; (foot)-4-((3 ft, 5 艮 103, 13艮145)-3-((11)-2-Amino-3-carboxypropenyloxy)-10,13-dimethyl-hexadecanehydro-1H-cyclopentane [a]phenanthrene- 17-yl)pentanoic acid; (3R,5R,10S,13R,14S)-17-((R)-5-(4-(2-hydroxyethyl)-1Η-(1,2,3-triazole) -1-yl)pentan-2-yl)-10,13-dimethyl-hexadecane-1H-cyclopentane [a]phenanthrene-3-one; 2-amino group 3-3-(l- ((R)-4-((3R,5R,10S,13R,14S)-3j|*-10,13-dimercapto-hexadecanehydrol-1H-cyclopentane [a]phenanthrene-17-yl Pentyl)-1Η-1,2,3-trisyl-4-yl)propionic acid; 2-(diethoxyphosphonium) -3(l-((R)-4-((3R,5R,10S,13R,14S)-3^i*-10,13-:T-hexadecanehydrol-1H-cyclopentyl) Alkane [a]phenanthrene-17-yl)pentyl-1H-1,2,3-triazol-4-yl)propanoic acid; 82 200804411 3- (1-((4-((3), 511 ,103,13&amp;145)-3-hydroxy-1〇,13-dimethyl-hexadecane-1H-cyclopentane [a]phenanthyl-17-yl)pentyl)-iH-l,2, 3-triazol-4-yl)propionic acid; and 4-(1-(())-4-((31511,103,131^,148)-3-yl-1, 13-dimethyl -hexadecanehydrol-1H-cyclopentane [a]phenanthrene-17-yl)pentyl)·1Η-1,2,3-triazole-cardio)butyric acid. 18. A pharmaceutical composition comprising - a therapeutically effective amount of a chemical as described in claim 1 and a pharmaceutically acceptable carrier. 19. A method for inhibiting the activity of α-2,3 sialyltransferase = - sufficient to satisfactorily reduce at least one of the reduction of salivation of a sugar conjugate, such as the chemical sialyltransferase represented by the item i of claim 1 The cells are in contact. 』, /, clothing α 20 · as described in the scope of claim 19 cells. A method of sputum and sputum, wherein the aforementioned cells are cancers. 21. Cell migration is carried out as described in the second paragraph of the patent application. / /, the aforementioned cancer cell line 22. The method described in claim 21, which is accompanied by cancer cell migration. /, in the case of cell migration 23. The method of claim 19, which is a mammalian. /, in the middle of the cell line 24. As claimed in the 23rd section of the patent application for humans. It is a method of treating a mammal with a 25--type treatment of a patient suffering from a depression of α 2, 3 saliva, and a disease, and at least responsive to the activity of the patient - such as the therapeutically effective amount of the patient. As described in the scope of application for patents*25, the quality of the method is as follows. ^ The aforementioned disease which is responsive to the inhibition of 83 200804411 α-2,3 sialyltransferase activity is cancer. 27. The method of claim 26, wherein the cancer cell is subjected to cell migration. 28. The method of claim 25, wherein the aforementioned patient is a human. 29. The method of claim 25, further comprising administering at least one additional therapeutic agent that affects the combination therapy. 84