WO2007139497A1 - Dérivés levoglucosenone pour le traitement de troubles tels que cancer, maladies auto-immunes et maladies du cœur. - Google Patents

Dérivés levoglucosenone pour le traitement de troubles tels que cancer, maladies auto-immunes et maladies du cœur. Download PDF

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Publication number
WO2007139497A1
WO2007139497A1 PCT/SE2007/050363 SE2007050363W WO2007139497A1 WO 2007139497 A1 WO2007139497 A1 WO 2007139497A1 SE 2007050363 W SE2007050363 W SE 2007050363W WO 2007139497 A1 WO2007139497 A1 WO 2007139497A1
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substituted
alkyl
unsubstituted
aryl
compound according
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PCT/SE2007/050363
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English (en)
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Jacob Westman
Klas Wiman
Nina Mohell
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Aprea Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Definitions

  • the present invention relates to levoglucosenone derivatives for use in therapy. More particularly, the present invention relates to levoglucosenone derivatives for the treatment and prevention of disorders and diseases such as, for example cancer, autoimmune diseases and heart diseases.
  • p53 The most common target for mutations in tumors is the p53 gene.
  • p53 halts the cell cycle and/or triggers apoptosis in response to various stress stimuli, including DNA damage, hypoxia, and oncogene activation (Ko and Prives, 1996; Sherr, 1998).
  • p53 Upon activation, p53 initiates the p53-dependent biological responses through transcriptional transactivation of specific target genes carrying p53 DNA binding motifs.
  • the multifaceted p53 protein may promote apoptosis through repression of certain genes lacking p53 binding sites and transcription-independent mechanisms as well (Bennett et al., 1998; Gottling and Oren, 1998; Ko and Prives, 1996). Analyses of a large number of mutant p53 genes in human tumors have revealed a strong selection for mutations that inactivate the specific DNA binding function of p53; most mutations in tumors are point mutations clustered in the core domain of p53 (residues 94-292) that harbours the specific DNA binding activity (Beroud and Soussi, 1998).
  • p53-induced cell cycle arrest and apoptosis could be involved in p53-mediated tumor suppression. While p53-induced cell cycle arrest could conceivably be reversed in different ways, p53-induced cell death would have the advantage of being irreversible. There is indeed evidence from animal in vivo models (Symonds et al., 1994) and human tumors (Bardeesy et al., 1995) indicating that p53-dependent apoptosis plays a major role in the elimination of emerging tumors, particularly in response to oncogenic signaling. Moreover, the ability of p53 to induce apoptosis often determines the efficacy of cancer therapy (Lowe et al., 1994).
  • Tumor cells are particularly sensitive to p53 reactivation, suppos- edly for two main reasons. First, tumor cells are sensitized to apoptosis due to oncogene activation (reviewed in (Evan and Littlewood, 1998)). Second, mutant p53 proteins tend to accumulate at high levels in tumor cells.
  • the present invention provides a compound of formula (I)
  • R represents a saturated or unsaturated, 5- or 6-membered nitrogen-containing heterocycle comprising 1-4 N atoms, O or 1 O atom and O or 1 S atom; wherein said heterocycle: - is linked to the dioxa bicycle
  • - optionally comprises one or several ring carbonyl and/or ring thiocarbonyl and/or ring sul- fonyl groups;
  • R optionally is substituted with one or several moities selected from branched or unbranched, unsubstituted or substituted, saturated or unsaturated C1-C6 alkyl; unsubstituted or substituted, saturated or unsaturated C3-C12 cycloalkyl; unsubstituted or substituted C6-C10 aryl; unsubstituted or substituted C6-C10 aryl-NH-; unsubstituted or substituted C6-C10 aryloxy; unsubstituted or substituted C4-C5 heteroaryl; unsubstituted or substituted benzyl; and -C(O)O-Cl-CO alkyl; or R represents
  • G is selected from N and CR 13 ;
  • R 10 , R 11 and R 12 are independently selected from H; unsubstituted or substituted, branched or unbranched C1-C6 alkyl; unsubstituted or substituted C6-C10 aryl and C4-C5 heteroaryl or any two of R 10 , R 11 and R 12 , together with the ring atoms to which they are attached, form a unsubstituted or substituted C5-C7 carbocycle;
  • R 13 is, independently for the two locations, selected from H and C1-C6 alkyl
  • n 0-3;
  • R represents a saturated or unsaturated, 5- or 6-membered nitrogen-containing heterocycle comprising 1-4 N atoms, 0 or 1 O atom and 0 or 1 S atom; wherein said heterocycle:is linked to the bicycle through one of the heterocyclic N atoms;
  • - optionally comprises one or several ring carbonyl and/or ring thiocarbonyl and/or ring sul- fonyl groups;
  • - optionally is substituted with one or several moities selected from branched or unbranched, unsubstituted or substituted, saturated or unsaturated C1-C6 alkyl; unsubstituted or substituted, saturated or unsaturated C3-C12 cycloalkyl; unsubstituted or substituted C6-C10 aryl; unsubstituted or substituted C6-C10 aryl-NH-; unsubstituted or substituted C6-C10 aryloxy; unsubstituted or substituted C4-C5 heteroaryl; unsubstituted or substituted benzyl; and -C(O)O-Cl-CO alkyl; as well as pharmaceutically acceptable salts or prodrugs thereof, for use as a medicament.
  • the present invention provides the use of the compounds of formula (I) or (II) or pharmaceutically acceptable salts or prodrugs thereof for the treatment of diseases associated with a malfunctioning p53 signalling pathway.
  • the invention provides pharmaceutical compositions comprising compounds of formula (I) or (II), or salts or prodrugs thereof.
  • the invention provides a method of medical treatment by administration of a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt or prodrug thereof to a mammal in the need of such treatment.
  • the invention provides the use of the inventive compounds, or salts or prodrugs thereof in the manufacture of a medicament for the treatment or prevention of a disorder selected from hypeproliferative diseases, autoimmune diseases and heart diseases.
  • Fig. 1 Fluorometric microculture cyo toxicity assay (FMCA): Percent fluorescence signal intensity vs. concentration of inventive compound 2-(4-methyl-3-phenyl-5-thioxo-4,5- dihydro[l,2,4]triazol-l-yl)-6,8-dioxa-bicyclo[3.2.1]octan-4-one in microtiter plates containing various human tumor cell lines.
  • FMCA Fluorometric microculture cyo toxicity assay
  • FIG. 2 Fluorometric microculture cyo toxicity assay (FMCA): Percent fluorescence signal intensity vs. concentration of inventive compound 2-[4-(4-chloro-phenyl)-6-trifluoromethyl- pyrimidin-2-ylsulfanyl]-6,8-dioxa-bicyclo[3.2.1]octan-4-one in microtiter plates containing various human tumor cell lines.
  • FMCA Fluorometric microculture cyo toxicity assay
  • the alkyl groups that are considered useful in the compounds according to the invention generally may be selected from unbranched or branched, cyclic, saturated or unsaturated (alkenyl or alkynyl) hydrocarbyl radicals.
  • the alkyl group is preferably C3 to C 12, more preferably C5 to ClO, most preferably C5-C7.
  • the alkyl group is preferably Cl to ClO, more preferably Cl to C6, more preferably methyl, ethyl, propyl (n-propyl, isopropyl), butyl (branched or unbranched) or pentyl, most preferably methyl.
  • C6-C10 aryl means phenyl and naphthyl.
  • heteroaryl means an aromatic group containing one or more heteroatom(s) preferably selected from N, O and S, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl or indazolyl.
  • heterocycle means a non-aromatic cyclic group containing one or more heteroatom(s) preferably selected from N, O and S, such as a cyclic amino group such as pyrrolidinyl, piperidyl, piperazinyl, morpholinyl or a cyclic ether such as tetrahydro furanyl, monosaccharide.
  • halogen means a fluorine, chlorine, bromine or iodine.
  • substituted means that the entity is substituted with at least one moiety, e.g. 1, 2 or 3 moieties, selected from saturated or unsaturated, branched, unbranched or cyclic alkyl, or at least one functional group such as hydroxyl, amine, sulfide, silyl, carboxylic acid, halogen, aryl, etc.
  • the substitution also may be by a moiety forming, together with the substituted entity, a ring system, e.g.
  • R is a nitrogen-containing heterocycle as defined herein above.
  • the nitrogen-containing heterocycle comprises 1 or 2 double bonds in the heterocycle ring.
  • the nitrogen-containing heterocycle is a 5-membered heterocycle.
  • the nitrogen-containing heterocycle is a 6- membered heterocycle.
  • the nitrogen-containing heterocycle comprises 4 heterocyclic ring N atoms.
  • the nitrogen-containing heterocycle comprises 3 heterocyclic ring N atoms.
  • the nitrogen-containing heterocycle comprises 2 heterocyclic ring N atoms.
  • the nitrogen-containing heterocycle comprises 1 double-bond in the heterocycle ring.
  • the 5-membered nitrogen-containing heterocycle is condensed with a benzene or naphthalene ring.
  • the nitrogen-containing heterocycle comprises at least one ring carbonyl, thiocarbonyl or sulfonyl group.
  • ring carbonyl or thiocar- bonyl group is meant a C atom of the nitrogen-containing heterocycle double-bonded to an O or S atom, respectively.
  • ring sulfonyl group is meant an S atom of the nitrogen- containing heterocycle double-bonded to two O atoms.
  • the nitrogen-containing heterocycle comprises one ring thiocarbonyl group.
  • the nitrogen-containing heterocycle comprises one ring thiocarbonyl and one ring carbonyl group.
  • the nitrogen-containing heterocycle comprises one ring sulfonyl group.
  • the nitrogen-containing heterocycle comprises one ring sulfonyl and one ring carbonyl group.
  • the nitrogen-containing heterocycle is a 5-membered heterocycle having one ring double bond and comprising 3 or 4 heterocyclic N atoms and a ring carbonyl or thiocarbonyl group.
  • the nitrogen-containing heterocycle is a 5-membered heterocycle comprising 2 heterocyclic N atoms or 1 heterocyclic N atom and 1 heterocyclic O atom, and a ring carbonyl or thiocarbonyl group, and being condensed to a substituted or unsubstituted benzene ring.
  • the nitrogen-containing heterocycle is a 5-membered saturated heterocycle comprising 2 heterocyclic N atoms, a ring carbonyl group and a ring thiocarbonyl group.
  • the nitrogen-containing heterocycle is a 5-membered heterocycle comprising 2 ring double bonds and 3 or 4 heterocyclic N atoms.
  • the nitrogen-containing heterocycle is a 5-membered heterocycle comprising one heterocyclic N atom and one ring sulfonyl group, said heterocycle being condensed to a substituted or unsubstituted naphthalene ring.
  • the nitrogen-containing heterocycle is a 5-membered heterocycle comprising one heterocyclic N atom, one ring sulfonyl group and one ring carbonyl group, said heterocycle being condensed to a substituted or unsubstituted benzene or naphthalene ring.
  • the nitrogen-containing heterocycle is a 5-membered heterocycle comprising 3 or 4 heterocyclic N atoms and being condensed to a substituted or unsubstituted benzene ring.
  • the nitrogen-containing heterocycle linked to the bicycle through one of the heterocyclic N atoms is selected from
  • Y is selected from S and O;
  • X is selected from N and C-R ;
  • T is selected from S and O;
  • Z is selected from O and N-R 3 ;
  • E is selected from C-R 7 and C attached to D;
  • W is selected from N and C-R 8 ;
  • Q is selected from N and C-R 9 ;
  • M is selected from N and C attached to D;
  • R is selected from H; (iii) unsubstituted or substituted C1-C6 alkyl; and (iv) unsubstituted or substituted C6-C10 aryl, C6-C10 aryl-NH-, C6-C10 aryloxy or C4-C5 heteroaryl; R 3 is selected from (v) unsubstituted or substituted benzyl;
  • R 4 and R 5 are independently selected from H and C1-C6 alkyl
  • R 6 is selected from C6-C10 aiyl
  • R 7 is selected from H; C1-C6 alkyl; and (vi) unsubstituted or substituted C6-C10 aryl;
  • R 8 and R 9 are independently selected from H and -C(O)O-Cl-Co alkyl.
  • the compound of formula (I) may be represented by formula (T)
  • R is a nitrogen-containing heterocycle and A represents C(OH)-D wherein D represents a 1-3 membered, substituted or unsubstituted chain of C, N and/or O atoms, attached to a carbon atom of the nitrogen-containing heterocycle so as to form a 6-7 membered heterocycle.
  • the compound of formula (I) may be represented by formula (I")
  • D represents a 1-3 membered, substituted or unsubstituted chain of C, N and/or O atoms, attached to E or M, respectively, so as to form a 6-7 membered heterocycle.
  • n 1 or 2.
  • R represents a saturated or unsaturated, 5-membered nitrogen-containing heterocycle comprising 1-4 N atoms, 0 or 1 O atom and 0 or 1 S atom.
  • the compound of formula (II) is according to the formula (H')
  • n is 0-3, preferably 1 or 2
  • X and Y are as defined herein above.
  • reference to a compound of formula (I) should be understood also as a reference to a compound of formula (Y) or (I"), and reference to a compound of formula (II) should be understood also as a reference to a compound of formula (IY).
  • the compounds according to formula (I) or (II) will be useful for treating or preventing various diseases such as hyperproliferative diseases, e.g. cancer, autoimmune diseases, such as rheumatoid arthritis and Sjogren's syndrome, and heart diseases such as hereditary idiopatic cardiomyopathy.
  • the treatment may be preventive, palliative or curative.
  • Examples of pharmaceutically acceptable addition salts for use in the pharmaceutical compositions of the present invention include those derived from mineral acids, such as hydrochlo- rid, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic acids.
  • the pharmaceutically acceptable excipients described herein, for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available to the public.
  • the pharmaceutically acceptable carrier may be one which is chemically inert to the active compounds and which have no detrimental side effects or toxicity under the conditions of use.
  • Pharmaceutical formulations are found e.g. in Remington: The Science and Practice of Pharmacy. A. R. Gennaro, Editor. Lippincott, Williams and Wilkins, 20th edition (2000).
  • Prodrugs of the compounds of formula (I) or (II) may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent.
  • Prodrugs include compounds of formula (I) or (II) wherein a hydroxy, amino, sulfhydryl, carboxy or carbonyl group in a compound of formula (I) or (II) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
  • prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives, N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs” pl-92, Elesevier, New York-Oxford (1985).
  • composition according to the invention may be prepared for any route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal.
  • routes of administration e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal.
  • a parenterally acceptable aqueous solution is suitably employed, which is pyrogen free and has requisite pH, isotonicity, and stability.
  • suitable solutions and numerous methods are described in the literature. A brief review of methods of drug delivery is also found in e.g. Langer (1990).
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable time frame.
  • dosage will depend upon a variety of factors including the potency of the specific compound, the age, condition and body weight of the patient, as well as the stage/severity of the disease.
  • the dose will also be determined by the route (administration form), timing and frequency of administration.
  • the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of formula (I) or (II) or the corresponding amount of a pharmaceutically acceptable salt or prodrug thereof.
  • the compounds of the present invention may be used or administered in combination with one or more additional drugs useful in the treatment of diseases mediated by mutant p53, or wherein a malfunction of the p53 signalling pathway is involved, such as cytostatic drugs.
  • the components may be in the same formulation or in separate formulations for administration simultaneously or sequentially.
  • the compounds of the present invention may also be used or administered in combination with other treatment such as irradiation for the treatment of cancer.
  • cytotstatic compounds for use as indicated herein above are DNA alkylating compounds, topoisomerase I inhibitors, topoisomerase II inhibitors, compounds interfering with RNA and DNA synthesis, compounds polymerising the cytoskeleton, and compounds depolymerising the cytoskeleton.
  • the compounds of the present invention may be formed in a one step reaction, wherein a suitable nucleophile is reacted with levoglucosenone in a Michael addition reaction under basic conditions.
  • the nucleophile may be an N-, S-, O- or C- nucleophile.
  • the synthesis with N-nucleophiles has been described earlier and below is just one example based on the method described by Samet et al in 1994 and 1996:
  • the human SAOS-2 (human osteosarcoma) cell line lacking p53 expression and its trans- fected clone SAOS-2-His273 that carries tetracycline-regulated mutant p53 constructs were used for the HTS screen.
  • Cells were plated on 96-well plates at a density of 3000 cells per well per 100ml medium, cultured overnight and treated with compounds at a concentration of 1, 5, 10, 25, or 50 ⁇ M, respectively. After 96h lO ⁇ l of WST-I -cell proliferation reagent were added to each well. Samples were incubated at 37 0 C for 1-2 h and absorbance of samples was measured at 490nm. Survival of the untreated cells was taken as 100%.
  • Table 1 Some compounds of the invention showing inhibition of cell proliferation at a concenctration ranging from 1 to 50 ⁇ M
  • Stereoisomers may be obtained in pure form by standard procedures known to those skilled in the art. It also is contemplated that the invention encompasses all possible regio isomers, and mixtures thereof which possess the indicated activity. Such regio isomers may be obtained in pure form by standard separation procedures known to those skilled in the art.
  • a human cell line panel of four sensitive parental cell lines five drug resistant sublines, representing different mechanisms of resistance, and one cell line with primary resistance were used, cf. Table 3 herein below.
  • the cell lines included were the myeloma cell line RPMI 8226/S and its sublines 8226/Dox40 and 8226/LR-5, the lymphoma cell lines U-937 GTB and U-937-Vcr, the SCLC cell line NCI-H69 and its subline H69AR, the renal adenocarcinoma cell line ACHN (ATCC) and the leukaemic cell line CCRF-CEM and its subline CEM/VM-1.
  • ATCC renal adenocarcinoma cell line
  • CCRF-CEM leukaemic cell line CCRF-CEM and its subline CEM/VM-1.
  • the 8226/Dox40 was selected for doxorubicin resistance and shows the classical MDR phenotype with overexpression of P-glycoprotein 170 (Pgp-170).
  • the 8226/LR-5 was selected for melphalan resistance, proposed to be associated with increased levels of GSH.
  • the U-937-Vcr was selected for vincristine resistance, proposed to be tubulin associated.
  • the H69AR selected for doxorubicin resistance, expresses a MDR phenotype proposed to be mediated by MRP.
  • the CEM/VM-1 selected for teniposide resistance, expresses an atypical MDR, which is proposed to be topoisomerase II (topoll) associated.
  • the exact mechanism of resistance for the primary resistant ACHN cell line is not known and may be multifactorial.
  • the cell lines were grown in complete culture medium consisting of carbonate buffered culture medium RPMI- 1640 (HyClone, Cramlington, UK) supplemented with 10% inactivated FCS, 2mM glutamine, 50 ⁇ g/ml of streptomycin and 60 ⁇ g/ml of penicillin, at 37°C in humidified atmosphere containing 5% CO 2 .
  • the 8226/Dox40 cell line was treated once a month with doxorubicin at 0.24 ⁇ g/ml and the 8226/LR-5 cell line at each change of medium with melphalan at 1.53 ⁇ g/ml.
  • the U-937-Vcr cell line was continuously cultured in presence of 10 ng/ml of vincristine and the H69AR cell line was alternately fed with drug free medium and medium containing 0.46 ⁇ g/ml of doxorubicin.
  • the CEM/VM-1 cell line was cultured in drug free medium without any loss of resistance for a period of 6-8 months. The resistance patterns of the cell lines were routinely confirmed in control experiments.
  • FMCA fluorometric microculture cytotoxicity assay
  • FMCA fluorometric microculture cytotoxicity assay
  • Tumor cells were seeded in the drug prepared 384-well microtiter plates at a cell density of 5,000 cells/well. The plates were incubated at 37°C in humidified atmosphere containing 5% CO 2 for 72 hrs. At the end of the incubation period the medium was removed by aspiration. After one wash in PBS, 50 ⁇ l/well of FDA dissolved in a physiological buffer (10 ⁇ g/ml) was added. The plates were incubated for 45 minutes and the generated fluorescence from each well was measured in a 384-well scanning fluorometer. The fluorescence is proportional to the number of intact cells in the well.
  • Quality criteria for a successful analysis included a fluorescence signal in the control wells of more than five times mean blank value, a mean coefficient of variation (CV) in the control wells of less than 30%. Experiments were performed twice (2 for ten- fold dilutions and 2 for 5 -fold), mean values are used throughout.
  • Figs.l and 2 test results are shown for two inventive compounds, viz. compound No. 21 (cf. Table 1): 2-(4-methyl-3-phenyl-5-thioxo-4,5-dihydro-[l,2,4]triazol-l-yl)-6,8-dioxa- bicyclo[3.2.1]octan-4-one (Fig. 1) and compound No. 85 (cf. Table 1): 2-[4-(4-chloro- phenyl)-6-trifluoromethyl-pyrimidin-2-ylsulfanyl]-6,8-dioxa-bicyclo[3.2.1 ]octan-4-one (Fig. 2). Results are expressed as percent fluorescence signal intensity as a function of the concentration of inventive compound in the medium of microtiter plate well and taking the blank signal as 100%. In Table 4, the corresponding EC50s calculated for the two compounds are shown.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de formule (I) ou (II) pour utilisation comme médicament, une composition pharmaceutique du composé, une utilisation du composé pour préparer un médicament pour le traitement d'un trouble parmi des maladies hyperprolifératives, auto-immunes et du cœur.
PCT/SE2007/050363 2006-05-30 2007-05-28 Dérivés levoglucosenone pour le traitement de troubles tels que cancer, maladies auto-immunes et maladies du cœur. WO2007139497A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115212212A (zh) * 2022-08-22 2022-10-21 深圳市人民医院 小分子化合物LGOd1在制备治疗癌症相关药物中的应用
WO2024172666A1 (fr) * 2023-02-13 2024-08-22 Paul Charles Dummere Newton Inhibiteur de nitrification

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JPH07188205A (ja) * 1993-12-27 1995-07-25 Ishihara Sangyo Kaisha Ltd α−グルコシダーゼ阻害剤
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JPH0859646A (ja) * 1994-08-12 1996-03-05 Ishihara Sangyo Kaisha Ltd エノピラノース誘導体又はその塩、それらを含有するα−グルコシダーゼ阻害剤
WO2004037159A2 (fr) * 2002-10-23 2004-05-06 Obetherapy Biotechnology Composes, compositions et methodes permettant de moduler le metabolisme des graisses

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US5457192A (en) * 1991-02-21 1995-10-10 Japan Tobacco Inc. Method of manufacturing D-allosan
JPH07188205A (ja) * 1993-12-27 1995-07-25 Ishihara Sangyo Kaisha Ltd α−グルコシダーゼ阻害剤
JPH0859646A (ja) * 1994-08-12 1996-03-05 Ishihara Sangyo Kaisha Ltd エノピラノース誘導体又はその塩、それらを含有するα−グルコシダーゼ阻害剤
WO2004037159A2 (fr) * 2002-10-23 2004-05-06 Obetherapy Biotechnology Composes, compositions et methodes permettant de moduler le metabolisme des graisses

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DATABASE CAPLUS [online] KATO F. ET AL.: "Preparation of 1,6-anhydro-3,4-dideoxy-beta-D-threo- and -erythro-hex-3-enopyranose and 3,4-dideoxy-beta-D-threo- and -erythro-hex-3-enopyranose derivatives as alfa-glucosidase inhibitors and cancer metastasis inhibitors", XP003016227, accession no. STN Database accession no. (1995:990641) *
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115212212A (zh) * 2022-08-22 2022-10-21 深圳市人民医院 小分子化合物LGOd1在制备治疗癌症相关药物中的应用
CN115212212B (zh) * 2022-08-22 2024-01-05 深圳市人民医院 小分子化合物LGOd1在制备治疗癌症相关药物中的应用
WO2024172666A1 (fr) * 2023-02-13 2024-08-22 Paul Charles Dummere Newton Inhibiteur de nitrification

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